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Volume 1, 2009

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RARE TUMORS
ISSN 2036-3605 - eISSN 2036-3613
Editor-in-Chief
Robert C. Miller, Rochester, MN, USA
Editorial Staff
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Prakash Adhikari, Department of ENT and Head and Neck Surgery, GMS Memorial
Academy of ENT and Head and Neck Studies, TU Teaching Hospital, Kathmandu,
Nepal
Rafael Álvarez-González, Graduate School of Biomedical Sciences, University of
North Texas, Healt Science Center at Forth Worth, Forth Worth, Texas, USA
Armando Bartolazzi, Cellular and Molecular Tumor Pathology Laboratory, Cancer
Center Karolinska, Karolinska Hospital, Stockholm, Sweden
Archit Bhatt, Department of Neurology and Ophtalmology, Clinical Center East
Lansing, East Lansing, Michigan, USA
Kevin Camphausen, Radiation Oncology Branch, National Cancer Institute, Bethesda,
Maryland, USA
Joseph R. Carver, Abramson Cancer Center, University of Pennsylvania, Pennsylvania,
USA
William Cho, Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong
Domenico Coppola, Anatomic Pathology and Neuroendocrine Cancer Research
Divisions, Moffit Cancer Center and Research Institute, Tampa, Florida, USA
Undurti N. Fams Das, UND Life Sciences, Shaker Heights, Ohio, USA
Ozsahin E. Mahmut, Department of Radiooncology, Centre Hospitalier Universitaire
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Jimmy Thomas Efird, Centre of Health Vulnerable Populations, University of Carolina,
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Amany Elwakkad, National Research Center, Cairo, Egypt
Gulgun Engin, Department of Radiology, Faculty of Medicine, Istanbul University,
Istanbul, Turkey
Guy Eslick, Harvard School of Public Health, MA, USA
Patricia D. Evilliers, Department of Anatomic Pathology, University of Alabama at
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Luis E. Fayad, Department of Lymphoma & Myeloma, University of Texas MD
Anderson Cancer Center, Houston, Texas, USA
Faris Farassati, Department of Medicine, University of Kansas School of Medicine,
Kansas City, Kansas, USA
Ali Gholamrezanezhad, Research Institute for Nuclear Medicine, Shariati Hospital,
Tehran University of Medical Sciences, Tehran, Iran
Samy Lewiz Habib, Department of Medicine, Division of Nephrology, University of
Texas Health Science Center, San Antonio, Texas, USA
Paul H. Hartel, Broaddus Hospital of Davis Health System, Elkins, West Virginia, USA
Ghulam Sarwar Hashmi, Department of Oral and Maxillofacial Surgery, Z.A. Dental
College, Medical Colony, A.M.U. Aligarh, India
Joseph Herman, Department of Oncology, The Sol Goldman Pancreatic Cancer
Research Center, Johns Hopkins School of Medicine, Baltimore Maryland USA
Kanya Honoki, Department of Orthopedic Surgery, Nara Medical University, Nara,
Japan
Charles Hsu, Division of Plastic and Reconstructive Surgery, Stanford University
Medical Center, Palo Alto, CA, USA
Sergio Huerta, Dallas VA Medical Center Surgical Services, Dallas, Texas, USA
Abdul Hussain, Minimal Access Unit, General Surgery Department, Princess Royal
University Hospital, London, UK
Rafael Jimenez, Division of Anatomic Pathology, Department of Laboratory Medicine
and Pathology, Mayo Clinic, Rochester, Minnesota, USA
Bleddyn Jones, Gray Institute for Radiation Oncology and Biology, University of
Oxford, Oxford, UK
Honoki Kanya, Department of Orthopedic Surgery, Nara Medical University, Nara,
Japan
Babak Kateb, Intraoperative Surgical Planning Society, Los Angeles, CA, USA
Sunali Khanna, Department of Oral Medicine & Radiology, Nair Hospital Dental
College, Mumbai, India
Boris Kirshtein, Department of Surgery, Soroka University Medical Center, Beer
Sheva, Israel
Antoniades Konstantinos, School of Dentistry, Aristotle University of Thessaloniki,
Thessaloniki, Greece
Masafumi Koshiyama, Department of Ob/Gy at Otsu Red Cross Hospital, Otsu, Japan
Sunil Krishnan, Radiation Oncology, Gastrointestinal Translational Research, M.D.
Anderson Cancer Center, Houston, TX, USA
Calin Lazar, Department of Plastic and Reconstructive Surgery, Rouen University
Hospital, Rouen, France
Wei Li, Institute of Biomedical Engineering, School of Control Science and
Engineering, Shandong University, Shandong, China
Simon Lo, Department of Radiation Medicine, The Ohio State University Arthur G.
James Cancer Hospital, Columbus, OH, USA
Lorenzo Lo Muzio, Surgical Sciences Department, Faculty of Medicine, University of
Foggia, Foggia, Italy
Paulette M. Fauceglia, Roswell Park Cancer Institute, Buffalo, New York, USA
Sridhar Mani, Departments of Medicine and Molecular Genetics, Division of
Oncology, Albert Einstein School of Medicine, New York, USA
Hiroyuki Matsubayashi, Shizuoka Cancer Center, Shizuoka-ken, Japan
Toshihiro Matsuo, Department of Artificial Joints and Biomaterial, Hiroshima
University, Hiroshima, Japan
Axel Merseburger, Department of Urology, Eberhard-Karls-University, Tübingen,
Germany
Oliver Micke, Department of Radiotherapy and Radiation Oncology, Franziskus
Hospital, Bielefeld, Germany
Rene Mirimanoff, Service de Radio-Oncologie, Centre Hospitalier Universitaire
Vaudois, Lausanne, Switzerland
Luca Morelli, Operative Unit of Patological Anatomy and Cytological Diagnostics, P.O.
S. Chiara, Hospital of Trento, Trento, Italy
Charbel D. Moussallem, Orthpedic Surgery, Faculty of Medical Sciences, Lebanese
University, Beirut, Lebanon
Hidenari Nagai, Division of Gastroenterology and Hepatology, Toho University
Medical Center, Omori Hospital, Tokyo, Japan
Tan Dat Ngyuen, Department of Radiation Oncology, Institut Jean-Godinot, Reims,
France
Athanasios Papatsoris, University of Athens, Athens, Greece
Nicholas A. Pavlidis, Department of Medical Oncology, School of Medicine, University
of Ioannina, Ioannina, Greece
Yi Chu Pei, Department of Surgical Pathology, Changhua Christian Hospital,
Changhua, Taiwan
Shahid Pervez, Department of Pathology and Microbiology, Agakhan University
Hospital, Karachi, Pakistan
Camillo Porta, IRCCS San Matteo University Hospital Foundation, Pavia, Italy
Fernando Quevedo, Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
Malcolm Schinstine, Division of Pathology, Hilo Medical Center Laboratories, Hilo,
Hawaii, USA
Andrzej Semczuk, Lublin Medical University, Lublin, P oland
Khan Shah Alam, Department of Orthopaedics, All India Institute of Medical Sciences
Ansari Nagar, New Delhi, India
Mark G. Shrime, Department of Otolaryngology/Head and Neck Surgery, Boston
University Medical Center, Boston, Massachusetts, USA
Vernon Keith Sondak, Department of Cutaneous Oncology, H. Lee Moffitt Cancer
Center and Research Institute, Tampa, Florida, USA
Giuseppe Spriano, Department of Otolaryngology/Head and Neck Surgery, National
Cancer Institute Regina Elena, Rome, Italy
Keith Stubbs, University of Western Australia, Perth, Australia
Fabio Tavora, Department of Genitourinary Pathology, Armed Forces Institute of
Pathology, Washington, DC, USA
Juliette Thariat, Department of Radiation Oncology, Anti Cancer Center Antoine-
Lacassagne, University Nice Sophia-Antipolis, Nice, France
Takeshi Tomonaga, Department of Molecular Diagnosis, Graduate School of
Medicine, Chiba University, Chiba Japan
Mark Gerard Trombetta, Department of Radiation Oncology, West Penn Allegheny
Health System Allegheny General Hospital, PA, USA
Lyuba Varticovski, Laboratory of Human Carcinogenesis, Center for Cancer Research,
National Cancer Institute, Bethesda, MD, USA
Salvador Villa I Freixa, Department of Radiation Oncology, Hospital Universitari
Germans Trías, Badalona, Catalunya, Spain
Takuya Watanabe, Department of Internal Medicine and Gastroenterology, Medical
Hospital, The Nippon Dental University of Life Dentistry at Nigata, Nigata, Japan
Shigeru Yamada, Research Center for Charged Particle Therapy, National Institute of
Radiological Sciences, Chiba, Japan
Leandra Náira Zambelli Ramalho, Department of Pathology, Faculty of Medicine of
Ribeirão Preto, University of São Paulo, Ribeirdo Preto, SP, Brazil
 RARE TUMORS
2009; Volume 1

Metastatic pleomorphic sarcoma to left atrium

Ammar H. Hawasli, Rachael Cayce, Trung Luong, Evelyn Taiwo, Michael N. Feliciano, Sharon C. Reimold, John M. DiMaio,
Barbara B. Haley..........................................................................................................................................................................................................................................................1

Squamous cell carcinoma of the scrotum in a Nigerian: case report

Jerome E. Azike, N.O. Chukwujama, T.C. Oguike...................................................................................................................................................................................................4

Extraosseous osteosarcoma in Ibadan: case series over a 20-year period

Temitope O. Alonge, Henry A. Obamuyide, Gabriel Olabiyi Ogun......................................................................................................................................................................6

A multimodal approach to the treatment of bilateral choroidal metastases from thyroid carcinoma
Maria Grazia Fabrini, Federica Genovesi-Ebert, Franco Perrone, Mario De Liguoro, Clara Giovannetti, Fausto Bogazzi, Stanislao Rizzo,
Enio Martino, Luca Cionini.......................................................................................................................................................................................................................................9

Pleomorphic sarcoma metastatic to the duodenum?

Fabio R. Tavora, Allen P. Burke ...............................................................................................................................................................................................................................12

Complete small bowel obstruction caused by metastasis from primary nasopharyngeal carcinoma
Chi Pan Lau, Edwin Pun Hui, Anthony Tak-Cheung Chan .................................................................................................................................................................................16

Diagnosis of vulvar lesions by non-invasive optical analysis: a pilot study

Anne-Therese Vlastos, Igor Charvet, Ilaria Dellacasa, Federica Capanna, Marie-Françoise Pelte, Philippe Thueler,
Michel Saint-Ghislain, Christian Depeursinge, Paolo Meda.............................................................................................................................................................................18

Congenital giant melanocytic nevi

Ghulam S. Hashmi, Syed S. Ahmed, Shahla Khan ................................................................................................................................................................................................23

Intramedullary capillary hemangioma of the thoracic spine: case report and review of the literature
Rahul Kasukurthi, Wilson Z. Ray, Spiros L. Blackburn, Eriks A. Lusis, Paul Santiago..................................................................................................................................26

A case report of surgical debulking for a huge mass of elephantiasis neuromatosa

Manabu Hoshi, Makoto Ieguchi, Susumu Taguchi, Shinya Yamasaki.............................................................................................................................................................29

Value of centrifugated liquid-based cytology by Papanicolaou and May-Grünwald in oral epithelial cells
Hussain Gadelkarim Ahmed, Ali Mahmmoud Edris, Eneel Ahmed Mohmed, Mohammed Omer M. Hussein ..........................................................................................31

Retroperitoneal lipoma arising from the urinary bladder

Shingo Ukita, Masafumi Koshiyama, Megumi Ohnaka, Naoyuki Miyagawa, Yukio Yamanishi, Fumitomo Nishimura,
Michikazu Nagura, Tomoko Kim, Masaya Hirose, Tomoyuki Shirase, Hisato Kobayashi, Hiroshi Ozasa ..............................................................................................34

Primary breast lymphomas

Olivier Julen, Ilaria Dellacasa, Marie-Françoise Pelte, Bettina Borish, Christine Bouchardy, Federica Capanna, Georges Vlastos,
Jean-Bernard Dubuisson, Anne-Thérèse Vlastos..................................................................................................................................................................................................36

Neuroblastoma occurring in a 38-year old Nigerian man: a rare finding

Martin A. Nzegwu, Aloy Aghaji................................................................................................................................................................................................................................42

Primary lymphoepithelial carcinoma of the parotid gland in a North African woman

Soumaya Ben Abdelkrim, Amel Trabelsi, Faten Hammedi, Monia Omezzine, Soumaya Rammeh, Atef Ben Abdelkader,
Badreddine Sriha .......................................................................................................................................................................................................................................................44

A review of the history, epidemiology and treatment of squamous cell carcinoma of the scrotum
Jerome E. Azike ..........................................................................................................................................................................................................................................................47

Assessment of cytological atypia, AgNOR and nuclear area in epithelial cells of normal oral mucosa exposed
to toombak and smoking
Hussain Gadelkarim Ahmed, Abd-Elraheem Ali Babiker ...................................................................................................................................................................................50

Desmoplastic small round cell tumor: impact of 18F-FDG PET induced treatment strategy
in a patient with long-term outcome
Dorra Ben-Sellem, Kun-Lun Liu, Sébastien Cimarelli, André Constantinesco, Alessio Imperiale ..............................................................................................................53

[Rare Tumors 2009; volume 1]

Epithelioid hemangioendothelioma of the temporal artery presenting as temporal
arteritis: case report and literature review
Dina El Demellawy, Ahmed Nasr, Salem Alowami ..............................................................................................................................................................................................56

Retrorectal epidermoid cyst with unusually elevated serum SCC level, initially diagnosed as an ovarian tumor
Masaru Hayashi, Shigeki Tomita, Takahiro Fujimori, Hitoshi Nagata, Keiichi Kubota, Akiko Shoda, Kazumi Tada, Nobuaki Kosaka,
Ichio Fukasawa, Noriyuki Inaba ...........................................................................................................................................................................................................................59

Metastatic rectal cancer to the breast

Hsiao C. Li, Prapti Patel, Payal Kapur, Sergio Huerta .........................................................................................................................................................................................63

Plexiform neurofibroma in the hepatic hilum associated with neurofibromatosis type 1: a case report
Sojun Hoshimoto, Zenichi Morise, Chinatsu Takeura, Masahiro Ikeda, Tadashi Kagawa, Yoshinao Tanahashi, Yasuhiro Okabe,
Yoshikazu Mizoguchi, Atsushi Sugioka .................................................................................................................................................................................................................66

Cystadenofibroma of the rete ovarii: a case report with review of literature

Manisha Ram, Abdel Abdulla, Khalil Razvi, Ivilina Pandeva, Awatif Al-Nafussi..........................................................................................................................................69

Angiomyomatous hamartoma: a rare case report with review of the literature

Manisha Ram, Nazar Alsanjari, Naseem Ansari...................................................................................................................................................................................................75

Malignant neuroectodermal tumor with melanocytic and rhabdomyoblastic differentiation

Munir R. Tanas and Brian P. Rubin ........................................................................................................................................................................................................................79

Malignant Triton tumor in the retroperitoneal space associated with neurofibromatosis type 1: a case study
Sojun Hoshimoto, Zenichi Morise, Chinatsu Takeura, Masahiro Ikeda,Tadashi Kagawa, Yoshinao Tanahashi, Yasuhiro Okabe,
Yoshikazu Mizoguchi, Atsushi Sugioka ................................................................................................................................................................................................................82
A case of primary renal angiosarcoma
Kazuhiko Yoshida, Fumio Ito, Hayakazu Nakazawa, Yoshiko Maeda, Hikaru Tomoe, Motohiko Aiba..................................................................................................85

A legacy of tinnitus: multiple head and neck paragangliomas

Tricia M.M. Tan, Emma C.I. Hatfield, Rajesh V. Thakker, Eamonn R. Maher, Karim Meeran, Niamh M. Martin, Jeremy J. Turner......................................................88

Soft tissue mixed tumor of the hand

Hiroshi Shimosawa, Michiro Susa, Takayuki Honma, Eiichi Hiraishi, Hiroshi Sakihara .........................................................................................................................90

Primary sarcoma of the liver and transplantation: a case study and literature review
Benjamin Bismuth, Hélène Castel, Emmanuel Boleslawski, David Buob, Marc Lambert, Nicole Declerck,Valérie Canva,
Eli-Serge Zafrani, Philippe Mathurin, François-René Pruvot, Sébastien Dharancy ......................................................................................................................................93

Pitfalls in neuroendocrine tumor diagnosis

Emilio Bajetta, Marco Platania ..............................................................................................................................................................................................................................96

Hepatic angiosarcoma five years following spontaneous intraperitoneal bleed of a hepatic mass
Jessica L. Cioffi-Pretti, Alexandra N. Kalof, George Ebert, Laurence E. McCahill .........................................................................................................................................98

Colonic cancer in adolescents. A report of three cases

M.A.C. Odike, A.E. Dongo, E.F. Alufohai, A.I. Odike............................................................................................................................................................................................102

Tumors and tumor-like lesions of the heart valves

Shi-Min Yuan, Hua Jing, Jacob Lavee ..................................................................................................................................................................................................................105

Treatment outcome of maxillary sinus cancer

Hye Sung Won, Sang Hoon Chun, Bum-soo Kim, So Ryoung Chung, Ie Ryung Yoo, Chan-Kwon Jung, Yeon-Sil Kim,
Dong-il Sun, Min Sik Kim, Jin-Hyoung Kang ......................................................................................................................................................................................................110

Invasive neuroendocrine tumor of the kidney: a case report

Ephrem O. Olweny, Michael H. Hsieh, Jill C. Buckley, Jack W. McAninch.....................................................................................................................................................115

Bilateral angiosarcoma of the breast in a fourteen-year-old child

Albertus N. van Geel, Michael A. den Bakker......................................................................................................................................................................................................117

Primary extrauterine endometrial stromal sarcoma: response to hormone therapy

Gunjal Garg, Awoniyi O. Awonuga, Eugene P. Toy .............................................................................................................................................................................................119

[Rare Tumors 2009; volume 1]

The managament of rare nasal mass-nasal dermoid sinus cysts: open rhinoplasty
Emel Cadalli Tatar, Ömer Tarik Selçuk, Güleser Saylam, Ali Özdek, Hakan Korkmaz ..............................................................................................................................121

Lipid-rich histology in a basal-type immuno-profile breast carcinoma: a clinicopathological histochemical and

immunohistochemical analysis of a case
Serena Russo, Diana Coppola, Paola Vinaccia, Antonella Siciliano, Francesca Baldassarre, Giovanni Battista, Giuseppe Pisani.................................................124

Synchronous malignant B-cell lymphoma and gastric tubular adenocarcinoma associated with paraneoplastic cutaneous vasculitis:
hypereosinophilic syndrome with mixed cryoglobulinemia is an important sign of paraneoplastic syndrome
Kazuhisa Nozawa, Hiroshi Kaneko, Tomoyasu Itoh, Yoko Katsura, Masaaki Noguchi, Fujihiko Suzuki, Yoshinari Takasaki,
Hideoki Ogawa, Kenji Takamori, Iwao Sekigawa.............................................................................................................................................................................................128

Hemangiopericytomas of the spine: case report and review of the literature

Chad D. Cole Meic H. Schmidt...............................................................................................................................................................................................................................132

Cervical intramedullary schwannoma: a case report and review of the literature

Jardel Mendonça Nicácio, José Carlos Rodrigues Jr, Marcos Henrique Lima Galles, Igor Vilela Faquini,
Clemente Augusto de Brito Pereira, Mario Ganau.............................................................................................................................................................................................137

Primary mediastinal giant cell tumor

Judd Goldberg, Shameen Azizad, Jela Bandovic, Arfa Khan............................................................................................................................................................................141

Benign multicystic mesothelioma: a case report of three sisters

Eve M. Bernstein, Alison Tate, Dan Arin Silasi, Thomas Rutherford...............................................................................................................................................................143

Congenital infantile digital fibromatosis: a case report and review of the literature
Valérie Failla, Odile Wauters, Nazli Nikkels-Tassoudji, Alain Carlier, Josette André, Arjen F. Nikkels....................................................................................................146

Giant mesenteric cystic lymphangioma presenting with abdominal pain and masquerading as a gynecologic malignancy
John Maa, Christianne Wa, Adnan Jaigirdir, Soo-Jin Cho, Carlos U. Corvera ..............................................................................................................................................148

Malignant peritoneal mesothelioma. Is there a new treatment?

Kakil Ibrahim Rasul, David J. Kerr .......................................................................................................................................................................................................................150

Intracystic papillary carcinoma of the breast in a 21-year old premenopausal Nigerian woman: a case report
Ivy N. Umanah, Akpan S. Okpongette ..................................................................................................................................................................................................................155

Diagnostic confusion resulting from CD56 expression by cutaneous myeloid sarcoma

Thanh Ho, Franklin Sedarat, Nagesh Rao, Sheeja T. Pullarkat........................................................................................................................................................................156

The epidemiology of malignant giant cell tumors of bone: an analysis of data from the Surveillance, Epidemiology
and End Results Program (1975-2004)
Jennifer L. Beebe-Dimmer, Karynsa Cetin, Jon P. Fryzek, Scott M. Schuetze, Kendra Schwartz ...............................................................................................................159

Temsirolimus in the treatment of renal cell carcinoma associated with Xp11.2 translocation/TFE gene fusion proteins:
a case report and review of literature
Jigarkumar Parikh, Teresa Coleman....................................................................................................................................................................................................................164

Metastasizing pleomorphic adenoma presenting as an asymptomatic kidney tumor twenty-nine years after
parotidectomy – urological viewpoint and overview of the literature to date
Jan Ebbing, Carolin Blind, Harald Stein, Kurt Miller, Christoph Loddenkemper ........................................................................................................................................167

A case of primary mucosa-associated lymphoid tissue lymphoma of the prostate

Noriko Koga, Masanori Noguchi, Fukuko Moriya, Kouichi Ohshima, Nobuyuki Yoshitake, Kei Matsuoka, Jan Ebbing, Carolin Blind,
Harald Stein, Kurt Miller, Christoph Loddenkemper.........................................................................................................................................................................................169

Re: Koga et al. A case of primary mucosa-associated lymphoid tissue lymphoma of the prostate
Damien C. Weber......................................................................................................................................................................................................................................................171

A clinical and molecular project on gonadoblastoma needs international collaboration

Nicolas Kalfa, Olivier Maillet, Charles Sultan....................................................................................................................................................................................................172

Primary NK/T cell lymphoma nasal type of the stomach with skin involvement: a case report
Sebastian Kobold, Hartmut Merz, Markus Tiemann, Carolina Mahuad, Carsten Bokemeyer, Irmtraut Koop, Walter Fiedler............................................................173

[Rare Tumors 2009; volume 1]

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[Rare Tumors 2009; volume 1]


Metastatic pleomorphic
sarcoma to left atrium
Ammar H. Hawasli,1 Rachael Cayce,2
Trung Luong,2 Evelyn Taiwo,1
Michael N. Feliciano3,
Sharon C. Reimold,2,4 John M. DiMaio,5
Barbara B. Haley1,2
Departments of 1Hematology-Oncology,
2 pation of chemotherapy with adriamycin and
Internal Medicine, 3Pathology,
4
Cardiology, and 5Cardiothoracic Surgery,
University of Texas Southwestern
Medical Center, Dallas, TX, USA
Abstract
Although several thousand patients are
diagnosed with sarcoma annually in the
United States, metastases to the heart are very
uncommon. In this case report, an overall low
frequency cancer presents masquerading with
common cardiac symptomology. This case
illustrates the importance for detailed diagnos-
tic cardiac evaluations and heightened suspi-
cion by physicians to consider metastatic dis-
ease to the heart in cancer patients with car-
diovascular complications. Also discussed is a
review of surgical and chemotherapeutic
options for this problem.
Introduction
A 53-year-old Caucasian gentleman present-
ed with progressive lower back pain, urinary
and bowel incontinence, and lower extremity
swelling over a one month period. He had
been diagnosed six months prior at an outside
institution with a high-grade pleomorphic sar-
coma with focal myxoid and epithelioid ele-
ments of the duodenum. Small bowel resection
was performed because of bowel obstruction.
Perioperatively, the patient suffered a myocar-
dial infarction (MI) due to focal narrowing of
the left anterior descending artery and a drug-
eluting stent was placed during cardiac
catheterization. Post-operative transthoracic
echocardiogram (TTE) was interpreted as mild
mitral valve thickening, with flail chordae
tendineae and an estimated ejection fraction
of 35-40%. After discharge, the patient was lost
to follow-up.
Case report
On presentation to our facility, physical
examination revealed normal lower extremity
strength, focal tenderness over the sacrum,
pitting edema in the lower extremities and a
murmur of mitral regurgitation with basilar
crackles and dullness. Computed tomography
(CT) showed a wedge-shaped splenic infarct
and magnetic resonance imaging (MRI) of the
spine demonstrated osseous metastatic dis-
ease involving the vertebral bodies, with
epidural and neuroforaminal tumor extension
in the sacrum. A TTE was performed in antici-
revealed a large vegetation attached to the
anterior leaflet of the mitral valve with pro-
lapse into the left atrium and ventricle (Figure
1A, arrow) and hypoechoic regions within the
cardiac tissue (Figure 1A, arrowhead). The
patient was taken to the operating room to
remove the vegetation, biopsy the hypoechoic
mass and replace the mitral valve. A 9 cm veg-
etation was excised from the anterior mitral
valve leaflet (Figure 1B, left and middle).
Intraoperatively, the patient was noted to have
diffuse disease throughout the atrial septum
and mitral valve (Figure 1B, right) and the pro-
cedure was terminated. Post-operative cardiac
MRI showed a lobulated cardiac mass infiltrat-
ing the atrial septum, the posterior aortic wall
and the posterior aspect of the anterior mitral
valve annulus. In the axial plane, the mass
measured at least 5.3 x 2.2 cm and extended to
the superior portion of the left atrium near the
entry of the right superior pulmonary vein
Figure 1. Echocardiography (A) performed before excision of vegitation (B) and post-
operative cardiac MRI (C).
[Rare Tumors 2009; 1:e1]
Rare Tumors 2009; volume 1:e1
Correspondence: Dr. Barbara B. Haley, The
Harold C. Simmons Comprehensive Cancer
Center, University of Texas Southwestern
Medical Center at Dallas, Dallas, TX, USA
E-mail: barbara.haley@utsouthwestern.edu
Key words: sarcoma, cardiac metastases, tumor,
cancer.
Received for publication: 1 May 2009.
Accepted for publication: 5 May 2009.
Acknowledgement: we would like to thank Dr.
John Bagwell and Leah Gaither for their assis-
tance.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright A.H. Hawasli et al., 2009
Rare Tumors 2009; 1:e1
doi:10.4081/rt.2009.e1
(Figure 1C; mass indicated with arrowheads).
Histology of the atrial mass revealed a high-
grade pleomorphic sarcoma, metastatic to
heart. Low power frozen sections of the atrial
wall showed hypercellularity (Figure 2A).
Medium and high power frozen (Figure 2B and
C) and permanent (Figure 2D) sections
showed tumor giant cells (indicated with
arrowheads) among spindled and epithelioid
[page 1]
Case Report
tumor cells. The atrial mass was immunohisto-
chemically positive for vimentin, confirming
mesenchymal differentiation (Figure 2E).
Immunohistochemical stains for other mark-
ers, including CD117, AE1/AE3, desmin, myo-
genin, caldesmon, S100, HMB-34, calretinin,
CD31 and CD34 were negative (Figure 2F).
A diagnosis of metastatic cardiac sarcoma
was established and treatment with gemc-
itabine and docetaxel was initiated. Adria-
mycin-based therapy was not considered sec-
ondary to the patient’s reduced cardiac func-
tion (37% ejection fraction). Five weeks after
initiating chemotherapy, the patient was
admitted for worsening lower extremity edema
but denied shortness of breath, orthopnea,
paroxysmal nocturnal dyspnea, chest pains,
palpitations, weight gain, or symptoms of tran-
sient ischemic attacks. Electrocardiogram
revealed atrial flutter at 119 beats per minute
with 2:1 block and the old anterolateral infarct.
The patient declined cardioconversion and was
treated with amiodarone. At the time of prepa-
ration of this report, the patient was tolerating
palliative gemcitabine and docetaxel chemo-
therapy.
Discussion
Soft-tissue sarcomas are a diverse mix of
cancers with an incidence of 10,390 new cases
diagnosed annually in the United States.1
Despite aggressive treatment with surgery,
radiation and chemotherapy, outcomes remain
suboptimal as 3,680 (35%) soft-tissue sarcoma
patients die annually.1 Death secondary to
metastases is common and sites of metastases
vary depending on the type of soft-tissue sarco-
ma with most types showing a predilection for
the lungs. Metastatic involvement of the heart
by soft-tissue sarcoma has been reported in
the literature but most cases of cardiac
involvement occur in the setting of widespread
metastases.2 Our patient is among the first
reported cases of an epithelioid high-grade
pleomorphic sarcoma metastatic to the heart
in absence of known widespread metastases.
Familiarity with the unique characteristics
of the soft-tissue sarcomas will enable a physi-
cian to identify expected patterns of metastat-
ic spread. One should be suspicious of cardiac
metastases in a soft-tissue sarcoma patient
who suddenly develops unexplained congestive
heart failure, new cardiac murmurs, arrhyth-
mias or embolic phenomena. For such
patients, metastatic cardiac disease should be
included in the differential diagnosis and fur-
ther evaluation with electrocardiograms,
echocardiograms, and cardiac MRI should be
made. Accurate imaging of cardiac cancer is
very important in the multimodal medical and
surgical management of metastatic cardiac
[page 2]
Figure 2. Histology of atrial mass.
sarcoma.3 In this patient, cardiac metastasis
was only incidentally discovered during pre-
chemotherapy cardiac evaluation. However,
several aspects of this patient’s clinical course
suggested the presence of this diagnosis. The
patient’s initial myocardial infarction prompt-
ed cardiac catheterization, which showed
luminal narrowing assumed to be secondary to
atherosclerotic disease. Yet, on repeat studies,
the patient had no evidence of significant ath-
erosclerotic disease. The patient’s infarct like-
ly resulted from an embolic event originating
from the large mitral valve vegetation or from
extrinsic compression of the artery by tumor.
The splenic lesions noted on CT scans likely
represent distant emboli with infarction.
Finally, review of the outside hospital TTE
abnormalities noted after the patient’s periop-
erative MI indicated that he had cardiac metas-
tases at initial presentation. A high degree of
suspicion for cardiac involvement by sarcoma
may have hastened a correct diagnosis.
Conclusions
Management of metastatic sarcoma to the
heart remains a difficult task. Some reports
discuss surgical resection of cardiac metastat-
ic lesions with variable success,4,5 while others
report the use of cardiac transplantation.6 In
this case, surgical excision was attempted, but
the extensive infiltrating nature of the tumor
prohibited complete debridement leaving sys-
temic therapy as the only viable option. There
are several generally accepted systemic thera-
pies for metastatic sarcoma with most regi-
mens including doxorubicin as a single agent7
or in combination with other drugs. The most
widely employed combination chemotherapy
regimens are doxorubicin/dacarbazine,8,9 dox-
orubicin/ifoxfamide/mesna10,11 mesna/doxoru-
bicin/ifosfamide/dacarbazine,12 ifosfamide/epi -
[Rare Tumors 2009; 1:e1]
rubicin/mesna,13 and gemcitabine/docetaxel.14-16
However, the use of doxorubicin was felt to be
contraindicated due to the depressed cardiac
function in this patient. If a sarcoma expresses
CD117, imatinib would be a viable treatment
option due to the drug’s oral administration,
favorable toxicity profile, and anti-tumor activ-
ity on some subsets of sarcoma, particularly
gastrointestinal stromal tumors.17-19 Expression
of this marker is felt to be favorable due to this
relationship. Thus far, reports do not associate
imatinib with induction of cardiac failure.20
Unfortunately our patient’s cardiac tumor did
not express CD117 and the drug was not a
treatment option. Since metastatic sarcoma to
the heart is a rare occurrence, no prospective
or randomized trials exist to help guide treat-
ment. In fact, there are no data to show
whether systemic treatment of unresectable
cardiac sarcomas significantly improves dura-
tion or quality of life. In the setting of conges-
tive or restrictive heart failure, many of the
first-line chemotherapy options are not feasi-
ble for fear of therapy worsening cardiac func-
tion. In our case, gemcitabine/docetaxel
chemotherapy was felt to be an active regimen
with controllable toxicity and without potential
devastating cardiac side effects. Tolerance to
the treatment regimen thus far has been
acceptable and the patient is continuing this
chemotherapy.
References
1. Jemal A, Siegel R, Ward E, et al. Cancer
statistics, 2008. CA Cancer J Clin 2008;58:
71-96.
2. Catton C. The management of malignant
cardiac tumors: clinical considerations.
Semin Diagn Pathol 2008;25:69-75.
3. Yuan SM, Shinfeld A, Lavee J, et al. Imag-
ing morphology of cardiac tumours. Card-

iol J 2009;16:26-35.
4. Harting MT, Messner GN, Gregoric ID,
Frazier OH. Sarcoma metastatic to the
right ventricle: surgical intervention fol-
lowed by prolonged survival. Tex Heart Inst
J 2004;31:93-5.
5. Kono T, Amano J, Sakaguchi M, Kitahara
H. Successful resection of cardiac
metastatic liposarcoma extending into the
SVC, right atrium, and right ventricle. J
Card Surg 2005;20:364-5.
6. Goldstein DJ, Oz MC, Rose EA, et al.
Experience with heart transplantation for
cardiac tumors. J Heart Lung Transplant
1995;14:382-6.
7. Tierney J Fea. Adjuvant chemotherapy for
localised resectable soft-tissue sarcoma of
adults: meta-analysis of individual data.
Sarcoma Meta-analysis Collaboration.
Lancet 1997;350:1647-54.
8. Antman K, Crowley J, Balcerzak SP, et al.
An intergroup phase III randomized study
of doxorubicin and dacarbazine with or
without ifosfamide and mesna in
advanced soft tissue and bone sarcomas. J
Clin Oncol 1993;11:1276-85.
9. Zalupski M, Metch B, Balcerzak S, et al.
Phase III comparison of doxorubicin and
dacarbazine given by bolus versus infu-
sion in patients with soft-tissue sarcomas:
a Southwest Oncology Group study. J Natl
Cancer Inst 1991;83:926-32.
10. Edmonson JH, Ryan LM, Blum RH, et al.
Randomized comparison of doxorubicin
alone versus ifosfamide plus doxorubicin
or mitomycin, doxorubicin, and cisplatin
against advanced soft tissue sarcomas. J
Clin Oncol 1993;11:1269-75.
11. Grobmyer SR, Maki RG, Demetri GD, et al.
Neo-adjuvant chemotherapy for primary
high-grade extremity soft tissue sarcoma.
Ann Oncol 2004;15:1667-72.
12. Elias A, Ryan L, Sulkes A, et al. Response to
mesna, doxorubicin, ifosfamide, and dacar-
bazine in 108 patients with metastatic or
unresectable sarcoma and no prior
chemotherapy. J Clin Oncol 1989;7:1208-16.
13. Frustaci S, Gherlinzoni F, De Paoli A, et al.
Adjuvant chemotherapy for adult soft tis-
sue sarcomas of the extremities and gir-
dles: results of the Italian randomized
cooperative trial. J Clin Oncol 2001;19:
1238-47.
14. Hensley ML, Maki R, Venkatraman E, et al.
Gemcitabine and docetaxel in patients
with unresectable leiomyosarcoma: results
of a phase II trial. J Clin Oncol 2002;20:
2824-31.
15. Leu KM, Ostruszka LJ, Shewach D, et al.
Laboratory and clinical evidence of synergis-
[Rare Tumors 2009; 1:e1]
Case Report
tic cytotoxicity of sequential treatment with
gemcitabine followed by docetaxel in the
treatment of sarcoma. J Clin Oncol 2004;22:
1706-12.
16. Maki RG. Gemcitabine and docetaxel in
metastatic sarcoma: past, present, and
future. Oncologist 2007;12:999-1006.
17. Verweij J, Casali PG, Zalcberg J, et al.
Progression-free survival in gastrointesti-
nal stromal tumours with high-dose ima-
tinib: randomised trial. Lancet 2004;364:
1127-34.
18. Blanke CD, Demetri GD, von Mehren M, et
al. Long-term results from a randomized
phase II trial of standard- versus higher-
dose imatinib mesylate for patients with
unresectable or metastatic gastrointesti-
nal stromal tumors expressing KIT. J Clin
Oncol 2008;26:620-5.
19. Demetri GD, von Mehren M, Blanke CD, et
al. Efficacy and safety of imatinib mesylate
in advanced gastrointestinal stromal
tumors. N Engl J Med 2002;347:472-80.
20. Verweij J, Casali PG, Kotasek D, et al.
Imatinib does not induce cardiac left ven-
tricular failure in gastrointestinal stromal
tumours patients: analysis of EORTC-ISG-
AGITG study 62005. Eur J Cancer 2007;43:
974-8.
[page 3]
Rare Tumors 2009; volume 1:e2

Squamous cell carcinoma obtained. Histopathological review showed

scrotal squamous cell carcinoma with testicu- Correspondence: Jerome E. Azike, MBBS,
of the scrotum in a Nigerian: lar involvement (Figure 1). He succumbed to FWACS, Department of Surgery, College of
case report the disease after seven months. Medicine & Health Sciences, Imo State
University, Orlu, Nigeria.
Jerome E. Azike,1,2 N.O. Chukwujama,1,2 E-mail: jeazike@yahoo.com
T.C. Oguike1,2
Discussion Key words: cancer of the scrotum, occupational
1
Department of Surgery, College of cancer, automobile mechanic, used engine oil.
Medicine and Health Sciences, Imo State
The scrotum is a seven-layer pouch which Received for publication: 2 May 2009.
University, Orlu, Imo State, Nigeria;
2
invests the testes, testicular adnexae, and dis- Accepted for publication: 8 May 2009.
Imo State University Teaching Hospital,
tal spermatic cord. The scrotal lymphatics
Orlu, Imo State, Nigeria drain into the corresponding superficial This work is licensed under a Creative Commons
inguinal nodes. Anastomoses exist between Attribution 3.0 License (by-nc 3.0)
the lymphatics of the contralateral network
©Copyright J.E. Azike et al., 2009
across the median raphe. Tumors have been Rare Tumors 2009; 1:e2
Abstract reported that arise out of virtually any of the doi:10.4081/rt.2009.e2
components of the scrotal wall.1
Squamous cell carcinoma of the scrotum is Squamous cell carcinoma of the scrotum is
rare and to the best of our knowledge has now exceedingly rare. It was the first malig-
never been reported from Nigeria. We report nancy linked to occupational exposure.1-2 minimize exposure. Prognosis correlates with
on a case thought to be occupation-related in a Previously, it most commonly resulted from extent of nodal involvement with virtually no
42-year old Nigerian taxi driver who had previ- exposure to environmental carcinogens such survivors if iliac nodes are involved.3,5 Ability to
ously been an automobile mechanic and later a as chimney soot, tars, paraffin, and some achieve a negative margin at the time of initial
long-haul truck driver. He presented with a petroleum products. Currently most cases surgery is an important prognostic factor as
stage D disease and only palliation was feasi- result from poor hygiene and chronic inflam- adjunctive therapy such as radiotherapy or
ble. mation.3 chemotherapy or both has not proven useful.1
Used engine oils have elevated polycyclic In conclusion, the index patient presented very
aromatic hydrocarbons which tend to be greater late when even surgery, chemotherapy and
for petrol engines than for diesel engines. radiotherapy could not possibly offer any mean-
Case report Prolonged and repeated contact with such oils ingful improvement in terms of outcome. We
can cause skin and scrotal cancer. Car mechan- believe this case will raise the awareness in
A 42-year old taxi driver who had been a car ics are at potential risk from used engine oil.4 our environment of the existence of this dis-
mechanic for four years 25 years earlier pre- Best occupational health practices are ease and improve the index of suspicion among
sented in 2007 with a ten-year history of a invaluable at the workplace for those at risk to practicing surgeons and oncologists.
small pruritic painless nodule on his ventral
scrotal surface which had ulcerated but failed
to heal. He infrequently washed his work-out-
fit while an auto-mechanic and admitted to its
frequent soiling, sometimes up to his under-
wear, with used engine oil while at work. He
took a bath at the close of work each day; how-
ever, his personal hygiene outside the work-
place was good.
On examination he was pale, had a foul-
smelling, grotesque, fungating, ulcero-prolifer-
ative mass with rolled edges which involved
the whole scrotum and proximal third of the
penile shaft, extending 5 cm to the right thigh
antero-medially and 3 cm of the anal verge.
The scrotum was fixed to the pubis. There
were bilateral inguinal lymphadenopathy
involving both the vertical and horizontal
chains. He looked otherwise well nourished
and was ambulant. He was also rather
depressed emotionally.
Ultrasonography revealed a hepatomegaly
and para-aortic lymphadenopathy, the largest
2.8 cm in diameter. His general condition was
optimized and biopsy confirmed the diagnosis. Figure 1. a, b, c, d. Histology of the various sections of the tumor; (a) Normal skin and
He had palliative scrotectomy with bilateral contiguous areas the well differentiated squamous cell carcinoma invading the surround-
orchidectomy and subsequently cisplatinum- ing deeper tissue; (b) High magnification of the malignant squamous cells; (c) Remnants
based combination chemotherapy, after he had of the testicular tubules being invaded by the tumor; (d) The malignant squamous cells
invading the deeper testes.
been counseled and informed consent

[page 4] [Rare Tumors 2009; 1:e2]


References
1. Rowland RG, Herman JR. Tumors and
Infectious Diseases of the Testis,
Epididymis, and Scrotum. In Gillenwater
JY, Grayhack JT, Howards SS and Mitchell
ME, eds. Adult and Pediatric Urology,
Philadelphia: Lippincott, Williams and
Wilkins; 2002.
2. Waldron HA. A brief history of scrotal can-
cer. Br J Ind Med 1983;40:390-401.
3. Presti JC Jr. Genital Tumors. In Tanagho EA,
McAnich JW, editors. Smith’s General
Urology. New York: Mc Graw Hill 2008:375-87.
[Rare Tumors 2009; 1:e2]
Case Report
4. Wyre Borough Council, Lancashire U.K.,
Health and Safety Factsheet – No. 12
(internet), 2002. Available from: http://
www.wyrebc.gov.uk (Cited 5th July, 2008)
5. Ray B, Whitmore WF Jr. Experience with
Carcinoma of the Scrotum. J Urol 1977;
117:741-5.
[page 5]
Rare Tumors 2009; volume 1:e3
Extraosseous osteosarcoma
in Ibadan: case series over
a 20-year period
Temitope O. Alonge,1 Henry
A. Obamuyide,2 Gabriel Olabiyi Ogun3
1
Consultant Orthopedic Surgeon/Senior
Lecturer, Department of Orthopedics and
Trauma, University College Hospital,
and College of Medicine, University of
Ibadan, Ibadan, Nigeria;
2
Resident in Surgery, Department of
Surgery, University College Hospital,
Ibadan, Nigeria;
3
Consultant Pathologist/Lecturer,
Department of Pathology, College of
Medicine, and University College
Hospital, Ibadan, Nigeria
Abstract
Extraosseous osteosarcoma (EOO) is a rare
form of sarcoma. There have been few reports of
cases and outcome from an African population.
Out of 112 cases of sarcomas seen at the
UCH, Ibadan between 1986-2005, 5 were EOO.
All presented late on account of initial excision
without histology and outcomes were poor.
EOO occurs in the black population of Sub-
Saharan Africa. The outlook for these patients
is still bleak.
Introduction
Extraosseous osteosarcoma (EOO) is a
malignant mesenchymal neoplasm that pro-
duces osteoid, bone or chondroid material and
is located in the soft tissue without attachment
to the skeleton as determined by imaging
modalities or inspection during surgical oper-
ative procedure.1 EOO is a rare type of tumor
making up only 1% of all soft tissue sarcomas2,3
and 4% of all osteosarcomas.4
Wilson reported the first case of EOO in
19415 and since then fewer than 300 cases
have been reported in the English Language
literature.6 The tumor is most common in mid-
dle-aged and elderly patients. A previous study
showed that EOO is a doxorubicin-resistant
lesion with a poor prognosis and a form of soft
tissue sarcoma that should be viewed by clini-
cians as clinically and therapeutically distinct
from osseous osteosarcoma.6
The single most important criteria for diag-
nosis of this tumor is the presence of neoplas-
tic osteoid and bone; sometimes with neoplas-
tic cartilage.1,5 The histological variants of EOO
include osteoblastic, chondroblastic, fibroblas-
[page 6]
tic, osteoclastic or giant cell type, telangiectat-
ic, small cell or well differentiated forms. The
immunohistochemical profile includes the
expression of osteocalcin and osteonectin
which are specific for osseous osteosarcomas,
but a study by Fanburg-Smith et al.7 showed
that osteocalcin is highly sensitive for EOO
neoplastic cells.1 Closely related differentials
include calcified hematoma, myositis ossifi-
cans, synovial sarcoma, epithelial sarcoma,
liposarcoma or malignant fibrous histiocytoma.
Methods
All sarcomas recorded at our institution
between January 1986 and December 2005
were compared and extraosseous variety iden-
tified. Their charts were selected and reviewed
for relevant data. Out of 112 cases of osteosar-
coma recorded in our hospital between
January 1986 and December 2005, 5 cases
were extraosseous. This series presents the 5
cases of EOO recorded at our institution dur-
ing the 20-year period from 1986-2005 and this
includes one patient reported previously by
Ogundiran et al.8
Case Series
Case #1
A 16-year-old male student who presented
with a 4-year history of progressive left ankle
swelling and pain. He had excision of a mass
in his left ankle at a private facility without
histological evaluation a year prior to presen-
tation at the University College Hospital
(UCH), Ibadan. On presentation at the UCH,
examination revealed a 10x7 cm mass over the
left lateral malleolus that was tender, differen-
tially warm, with both cystic and solid areas.
No significant popliteal or inguinal lym-
phadenopathy was noted. Laboratory studies
were essentially normal.
He had a local excision of the mass and the
operative finding was a 10x7 cm multiloculat-
ed brownish soft tissue mass over the left lat-
eral malleolus covered with a fibrous capsule
with a pedicle arising from the ankle joint.
There was associated erosion of the adjoining
bone and the histology report revealed soft tis-
sue osteosarcoma. He was lost to follow-up but
represented two years later with recurrence.
Case #2
A 70-year-old man who presented with a
1-year history of a painful scalp swelling asso-
ciated with bleeding. A similar swelling had
recently grown on the right temporal region
prior to presentation at the UCH. Incisional
[Rare Tumors 2009; 1:e3]
Correspondence: Temitope O. Alonge,
Consultant Orthopedic Surgeon/Senior Lecturer,
Department of Orthopedics and Trauma,
University College Hospital and College of
Medicine, University of Ibadan, Ibadan, Nigeria
E-mail: alonget2003@yahoo.com
Key words: extraosseous osteogenic sarcomas,
Sub-Saharan Africa, histology.
Received for publication: 3 May 2009.
Accepted for publication: 5 May 2009.
Contributions: TOA conceived, designed, super-
vised and helped to draft the manuscript and
approved the final version; HAO participated in
the design, gathered the data, drafted the manu-
script and approved the final copy; GOO reviewed
the manuscript for critical content and approved
the final copy.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright T.O. Alonge et al., 2009
Rare Tumors 2009; 1:e3
doi:10.4081/rt.2009.e3
biopsy and histology of the initial mass at the
source of referral revealed an extraskeletal
osteosarcoma.
Examination revealed a 15x7 cm left fron-
toparietal mass with overlying scar. He also
had a smaller temporal mass. Both were tender
and hemorrhagic. Skull X-ray showed an
extensive soft tissue swelling extending from
the left frontal to the left parietal region. There
was an associated increase in the density of
the underlying subcutaneous tissue but no cal-
cifications. Routine laboratory studies were
within normal limits. He had radiotherapy but
later represented with facial recurrence after
two months.
Case #3
A 21-year-old man with a 1-year history of a
painful left upper back swelling and 4 month
history of progressive weakness of both legs
which progressed to paraplegia. He had a
biopsy of the mass at a private facility five
months before presentation at the UCH but no
histological evaluation of the mass was car-
ried out. Examination at the UCH revealed a
left periscapular fluctuant mass with overlying
hypertrophic scar which was also attached to
underlying structures. He also had a T5 para-
plegia. Chest X-ray showed a left paravertebral
soft tissue mass lesion with evidence of
destruction of the 5th rib and left sided pul-
monary effusion. Urinary Bence Jones protein
was negative, the full blood count was normal
but the ESR was elevated. Two pleural aspi-
rates were hemorrhagic and CT myelography
showed an isolated left sided isodense lesion

in the spinal cord with extensive erosion of
the ribs as well as infiltration into the left
pleural cavity.
Incisional biopsy of the left chest wall lesion
revealed osteogenic sarcoma. Chemotherapy
was to be administered but the patient could
not afford it and he was subsequently lost to
follow-up.
Case #4
A 20-year-old man who presented with an
11-month history of progressive soft tissue
swelling of the right thigh associated with
pain. The soft tissue mass was excised initial-
ly at a private facility but no histological evalu-
ation of the specimen was carried out.
Examination at the UCH revealed a massively
swollen right thigh with multiple areas of
ulceration. Biopsy and histology at the UCH
revealed extraosseous osteogenic sarcoma.
The patient was given a hemostatic dose of
radiotherapy but was subsequently lost to fol-
low-up.
Case #5
A 40-year-old housewife who presented with
a 20-month history of painful left breast lump
which had been excised previously at another
hospital without histological evaluation, but
recurred eight months before presentation at
UCH. Examination revealed a globular left
breast mass which was warm, multinodular,
fixed to the pectoralis fascia and which meas-
ured 20x18 cm. There was associated ipsilater-
al axillary lymph node enlargement. Other sys-
tems were essentially normal.
A clinical diagnosis of locally advanced can-
cer of the left breast was made. A core needle
biopsy revealed an osteogenic sarcoma which
was confirmed by the histology of the mastec-
tomy specimen. She was scheduled for post-
operative radiotherapy but defaulted and died
six months post-mastectomy.
Discussion
The exact cause of EOO is unknown and it is
presumed to be mainly an idiopathic condition.
Unlike osseous osteosarcoma (OOO), it has
not been documented in siblings or in associa-
tion with hereditary retinoblastoma but risk
factors associated with the development of this
tumor include previous exposure to radiation,
such as X-rays and radioactive thorium dioxide
(Thorothrast).9 Other associated factors sug-
gested in literature in the development of EOO
include trauma, the assessment and evalua-
tion of which is difficult and controversial.10
Some cases have been associated with intra-
muscular injection11 while some EOO have
been reported to follow myositis ossificans.12,13
A common mode of presentation is as a
swelling of insidious onset with associated
pain in one-third of patients but often the
tumor grows to a large size before the patient
seeks medical advice.14 It may ulcerate with
growth, but that usually occurs after biopsy or
attempts at excision and the tumor usually
occurs in middle-aged and elderly patients.15
The anatomic location of EOO is usually the
muscles of the thigh, which are the most com-
monly affected; the large muscles around the
pelvic and shoulder girdles and the retroperi-
toneum, though rare locations like the thyroid
gland, penis, mediastinum and the kidney are
occasionally encountered.1,12,15,17,18
At the Memorial Sloan-Kettering cancer
center, a review of 48 cases of EOO during
1950-1983 showed a median age at diagnosis
of 51 years (range, 6-80 years).14 The most
common primary sites were the thighs and
buttocks (54.2%) with preponderance in
patients aged 50 years and above and slightly
more common in males (58%) than in
females.12 In the report by Chung and Enzinger,
EOO occurs principally as a soft tissue mass
involving an extremity with a predilection for
the thighs (lower extremity 46.6%; upper
extremity 20.5%) and the retroperitoneum in
17%. In most cases, the tumor was deep seated
and firmly attached to the fascia, but occasion-
ally they are freely movable and confined to the
subcutis or dermis. The duration of symptoms
prior to presentation ranges from two weeks to
25 years (median six months). Prior trauma to
the site was observed in 12.5% and irradiation
to the affected site in 5.7% of cases.12
Although osseous osteosarcoma (OOO)
occurs predominantly in the first two decades
of life, EOO are rarely encountered under 40
years of age.15 However, in this case series, 3 of
the 5 patients were aged 21 years and under in
keeping with other cases which have been doc-
umented in the pediatric age group.16
Imaging modalities by either plain conven-
tional radiograph, CT scan or MRI of the soft tis-
sue is essential to rule out any continuity of
tumor with bone. If adjacent bone shows radio-
logical changes of involvement by the tumors, it
is most likely to be originating from the bone
rather than from the soft tissue. A soft tissue
mass with spotty to massive calcification with-
out adjacent bone involvement is one of the clas-
sic radiographic appearances of this tumor.15
EOO is a difficult disease to treat and the
optimum therapy has not been fully deter-
mined due to the relative rarity of these
tumors. Advances in the care of these patients
will require disease-specific clinical trials.6 A
wide local excision, with at least 5cm margin
of normal tissues should be the treatment of
choice.15 The local recurrence-free survival
rate observed in a recent study6 suggests that
patients with extremity EOO can be treated
with limb salvage operative procedures.
[Rare Tumors 2009; 1:e3]
Case Report
However, if these are not possible due to the
anatomic location of the tumor, amputation is
recommended.19
In a review of 48 cases of EOO and 39 trials
of chemotherapeutic agents reported by
Sordillo et al. they showed that no patient had
a major response.14 The average 5-year survival
rate in 5 previous studies ranges from 15-
25%2,9 and the response to multimodality ther-
apy is not as good as for OOO.14 Tumor size (<5
cm vs. ≥5 cm) was the major predictor of
patient survival.13
Of note, the challenges of managing malig-
nancies and other chronic illnesses in a devel-
oping economy like ours is exemplified by
these cases. The issues of late presentation,
non-submission of biopsy specimen for histo-
logical assessment, non-affordability of treat-
ment modality and default from follow-up
raise critical issues. These include late pres-
entation, lack of health or social insurance
making the patient bear the full cost of their
treatment and probably also the ignorance of
the initial managing physician regarding the
need for histological assessment of all biop-
sies or their unwillingness to insist on this
(as a measure to reduce costs and increase
their competitiveness). These factors may all
be related to cost of treatment, and patients,
therefore, have a significantly long delay
before presentation and would usually present
in a private facility with a view to reducing the
cost of treatment.
Conclusions
In conclusion, the outlook for patients with
EOO is grave and the majority of patients with
this tumor succumb to metastatic disease
within a period of three years after the initial
diagnosis.1 Extraosseous osteosarcoma occur
in the populations of Sub-Saharan Africa and
the poor prognosis for EOO in our environment
is further compounded by the factors earlier
highlighted. Since recurrence occurs mostly
within two years after surgery, adjuvant
chemotherapy and radiotherapy have been
found to be beneficial.15
References
1. Weiss SW, Goldblum J. Osseous soft tissue
tumours in Enzingers and Weiss: Soft
Tissue Tumours 4th ed. Pg 1389-1417,
Mosby St Loius, 2001.
2. Allan CJ, Soule EH. Osteogenic sarcoma of
the soft tissue: a clinicopathologic study of
26 cases and review of the literature.
Cancer 1971;27:1121-33.
3. McCarter MD, Lewis JJ, Antonescu CR, et
[page 7]
Case Report
al. Extraskeletal osteosarcoma: analysis of
outcome of a rare neoplasm. Sarcoma 2000;
4:119–23.
4. Van Rojswik CSP, Lieng TG, Kroon HM, et
al. Retroperitoneal extraosseous osteosar-
coma. J Clin Path 2002;54:77-8.
5. Wilson H. Extraskeletal ossifying tumours.
Ann Surg 1941;113:95-112.
6. Ahmad SA, Patel SR, Ballo MT, et al.
Extraosseous osteosarcoma. Response to
treatment and long term outcome. J Clin
Oncol 2002;20:521-7.
7. Fanburg-Smith JC, Bratthauer GL, Miettinen
M. Osteocalcin and osteonectin immunore-
activity in extraskeletal osteosarcoma: a
study of 28 cases. Hum Pathol 1999;30:32.
8. Ogundiran TO, Ademola SA, Oluwatosin
OM, et al. Primary osteogenic sarcoma of
the breast. World J Surg Oncol 2006;4:90.
[page 8]
9. Lee WR, Laurie J, Townsend A. Fine struc-
ture of radiation-induced osteogenic sar-
coma. Cancer 1975;76:1414-5.
10. Fine G, Stout AP. Osteogenic sarcoma of
the extraskeletal soft tissue. Cancer 1956;
9:1027-43.
11. Lee JH, Griffith WJ, Bottomley RH. Extrao-
sseous osteogenic sarcoma following an
intramuscular injection. Cancer 1977;40:
3097-101.
12. Chung EB, Enzinger F. Extraskeletal osteo-
genic sarcoma. Cancer 1987;60:1132-42.
13. Bane BL, Evans HL, Ro JY, et al. Extraskel-
etal sarcoma: a clinicopathologic review of
26 cases. Cancer 1990;65:2762-70.
14. Sordillo PP, Hadju SL, Magill GB, et al. Ext-
raosseous osteogenic sarcoma: a review of
48 patients. Cancer 1983;51:727-34.
15. Lin S-Y, Chen W-M, Wu HH, et al. Extraos-
[Rare Tumors 2009; 1:e3]
seous osteogenic sarcoma. J Chin Med
Assoc 2005;68:542-5.
16. Humphrey GM, Brown I, Squire R, et al.
Extraosseous osteogenic sarcoma-A rare
pediatric malignancy: Case report and
review of the literature. J Pediatr Surg 1999;
34:1025-8.
17. Hertel V, Basten O. Extraosseous osteosar-
coma of the thyroid gland. Laryngorhinoo-
tologie 2006;85:913-6.
18. Dudhat S, Desai S, Borges A, et al. Retro-
peritoneal extraosseous osteosarcoma. A
case report and review of literature. Indian
J Cancer 1999;36:186-9.
19. Lewis RJ, Loiz MJ, Beazley RM. Extra-
osseous osteogenic sarcoma: case report
and approach to therapy. Ann Surg 1974:40:
597-600.

A multimodal approach to the
treatment of bilateral choroidal
metastases from thyroid
carcinoma
Maria Grazia Fabrini,1
Federica Genovesi-Ebert,2
Franco Perrone,3 Mario De Liguoro,1
Clara Giovannetti,4 Fausto Bogazzi,4
Stanislao Rizzo,2 Enio Martino,4
Luca Cionini1
1
Divisions of Radiotherapy, 2Ophthalmic
Surgery, 3Health Physics and
4
Endocrinology and Metabolism of Pisa
University Hospital, Italy
Abstract
A 58-year old man, affected by metastatic
thyroid carcinoma, experienced a progressive
bilateral visual impairment. Ophthalmic exam-
ination revealed the presence of a choroidal
mass with an associated exudative retinal
detachment in both eyes. Twelve years before,
a diagnosis of metastatic thyroid carcinoma
had been established and the patient had been
subject to several therapeutic procedures.
In May 2007, he received a radiotherapy
treatment to the left eye with an episcleral
plaque and bilateral bulbar injection of beva-
cizumab. The patient had a rapid and stable
visual acuity recovery. Twenty months after
treatment, the lesion treated with radiotherapy
was still stable whereas the contra-lateral
lesion had evolved and determined a vitreal
hemorrhage.
Introduction
Choroidal metastases from thyroid cancer
are uncommon findings.1 They often occur in
advanced stages, and generally several years
after the initial diagnosis. Main related symp-
toms can include pain and impairment of visu-
al ability. Eye metastases may cause blindness
with a rapid degradation of the patient’s quali-
ty of life.2,3
This paper reports a case of bilateral
choroidal metastases in a patient in satisfacto-
ry general condition, with a long history of
metastatic thyroid carcinoma initially respond-
ing to radio-metabolic therapy.
A multimodal approach was adopted to treat
the ocular lesions, in order to restore his visu-
al acuity. After a follow-up of 18 months, the
patient’s visual ability was still good, although
multiple metastases developed in other sites. A
vitreal hemorrhage occurred 20 months after
treatment in the right eye, while the lesion
treated with brachytherapy remained unal-
tered.
Case Report
In October 1996, a 58-year old male patient
in satisfactory general condition and under
medical therapy for arterial hypertension, was
treated with total thyroidectomy, parathy-
roidectomy, bilateral cervical lymphadenecto-
my and also with resection of a single ischio-
pubic recurrence. Histo-pathological examina-
tion of the thyroid gland and of the bone
metastasis revealed a thyroid carcinoma (G3),
confirmed by positive thyroglobulin immunos-
taining, with solid and papillary areas of oxyfil
cell-type. No diffusion to neck lymph nodes
was found. Disease was scored as T3N0M1,
IVC stage following the American Joint Cancer
Committee grouping.
After surgery, the patient received a radio-
metabolic treatment with 131-I. During the fol-
low-up, the thyroglobulin hematic levels were
periodically checked.
From 1997 to 2007, a diffusion of multiple
metastases was observed; the largest recur-
rences were treated by surgical resections. In
order to limit the development of recurrences,
other systemic 131-I radio-metabolic therapies
were administered (Figure 1).
In May 2007, the patient presented a pro-
gressive visual loss in both eyes; he had a past
history of retinal venous thrombosis in his left
eye, with a residual best corrected visual acu-
ity of 20/40.
Ophthalmologic examination, performed in
May 2007, showed that ocular adnexa, extra-
ocular movements and pupillary reactions
were normal in both eyes and no exophthal-
mus was found. No pupillary defects were evi-
denced and the Best Corrected Visual Acuity
was 20/70 in the left eye (LE) and 20/25 in the
right eye (RE).
Slit lamp examination of the anterior seg-
ment revealed only a light nuclear sclerosis.
Intra-ocular pressure was 15 mm of Hg in both
eyes.
Ophthalmoscopic examination detected a
solid lesion localized in the posterior pole
closely to the macula in the RE and a similar
lesion in the posterior pole of the LE, where
hypertrophic areas of the retinal pigment
epithelium related to the previous venous
branch occlusion were also evident (Figure 2).
B-scan ultrasound examination confirmed
the presence of a slightly elevated, solid
choroidal mass in both eyes: in RE it was 1.25
mm in thickness, with an associated serous
retinal detachment, in LE it measured 3.3 mm
in height and 4.8 mm in maximum base diam-
[Rare Tumors 2009; 1:e4]
Rare Tumors 2009; volume 1:e4
Correspondence: Franco Perrone,
U.O. Fisica Sanitaria, Azienda Ospedaliero-
Universitaria Pisana, via Roma 67, 56125 Pisa, Italy
E-mail: f.perrone@ao-pisa.toscana.it
Key words: choroidal metastases, thyroid carcino-
ma, radiotherapy, anti-VEGF factors.
Acknowledgments: the authors are grateful to the
Pisa section of the “Lega Italiana per la Lotta
Contro i Tumori” for supporting the present pub-
lication.
Contributions: radiotherapy treatment and fol-
low-up: MGF, MDL; ophthalmologic follow-up:
FGE; radiotherapy treatment planning, data
analysis and dose evaluation: FP; brachytherapy:
MGF, SR, FGE; endocrinological follow-up: CG, FB,
EM; text editing: CG, MDL, MGF, FGE, FB, FP; text
reviewing: EM, LC.
Conflict of interest: the authors reported no poten-
tial conflict of interests.
Received for publication: 20 May 2009.
Revision received: 28 May 2009.
Accepted for publication: 2 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright M.G. Fabrini et al., 2009
Rare Tumors 2009; 1:e4
doi:10.4081/rt.2009.e4
eter, with an associated serous retinal detach-
ment.
Standardized A-scan echography showed in
both lesions an irregular structure with a
sharp initial spike and moderate-high internal
reflectivity.
Fundus fluorescein angiography evidenced
an area of irregular fluorescence with a mild
leakage in correspondence of the supero-tem-
poral arcade in the RE. A block of the fluores-
cence due to the retinal pigment epithelium
was noted in the posterior pole of the LE, in
correspondence of the choroidal mass. The
ischemic maculopathy, secondary to the previ-
ous venous thrombosis, appeared as an hypo-
fluorescent lesion with late staining.
Indocyanine angiography showed the hyper-
fluorescence of the lesion in the RE, especially
in the intermediate phases, with wash out of
the dye in the late phases. In the LE, indocya-
nine angiography revealed an atrophic area of
retinal pigment epithelium and of choriocapil-
laris in correspondence of the fovea, while the
mass-lesion showed an irregular staining of
the dye in the intermediate and late phases
(Figure 2).
Optical Coherence Tomography showed a
massive detachement of the neuro-epithelium
in the RE (Figure 3); a hypertrophic hyper-
reflective area of the retinal pigment epitheli-
[page 9]
Case Report

um (due to the previous macular scar) and a

Figure 1. The figure
shows hematic thi- detachment of the neuro-epithelium temporal
roglobulin concentra- to the macula were also found in the LE.
tions (in ng/mL), start- Although a biopsy was not obtained from the
ing from initial thy- choroidal masses, diagnosis of presumed bilat-
roidectomy, as a func- eral choroidal metastases from thyroid carci-
tion of the follow-up
time in months (140 noma was based on the patient’s medical his-
months from October tory and on ophthalmologic findings: the
1996 to June 2008); occurrence at the posterior pole, the solid
black dots report thy- appearance, the yellow-orange color, the pres-
roglobulin hematic lev- ence of serous detachment of the sensory reti-
els in ng/mL (left black
scale); red bars show na, the moderate echographic internal reflec-
the 131-I activities in tivity of the masses showing an irregular inter-
GBq (right red scale), nal reflectivity, the absence of demonstrable
administered during vascular pulsations and the hyperfluorescence
the follow-up.
with late staining were suggestive of a sec-
ondary lesion.
At the end of May 2007, the lesion in the LE
was treated with an episcleral 106Ru plaque
Figure 2. The figure brachytherapy.
shows, from top to bot-
tom, basal B-scan ultra- The small lesion in the RE was not irradiat-
sound, fluorescein ed because of its small volume, its localization
angiography, fundus close to the macula and the risk of macular
view, intermediate radiation damage. A week after plaque
phase indocyanine
angiography and late removal, an intra-vitreal injection of beva-
phase indocyanine cizumab (Avastin; Genentech, San Francisco,
angiography of both CA) was performed in both eyes in order to
eyes before brachythera- reduce the serous retinal detachment.
py. The images on the In October 2008 an US scan indicated that
right side refer to the
left eye. the lesion in the right eye remained
unchanged and the mass in the left eye was
reduced to 2.5 mm in height. OCT showed a
marked reduction in height of the neuro-
epithelium detachement in the right eye and a
disappearance of the temporal fluid in the left
eye (Figure 3). BCVA was still 20/20 in the
right eye and 20/40 in the left eye. The other
metastases showed a generalized progression.
At the end of 2008, the patient began a
chemotherapy treatment with anthracycline.
A vitreal hemorrhage occurred 20 months
after treatment in the right eye, while the
lesion treated with brachytherapy remained
still unaltered.

Discussion
Eye metastases are an important clinical
problem, because they represent the most
Figure 3. Optical common cancer of the eye and may occur in
Coherence Tomography
before brachytherapy 12% of patients with metastatic carcinomas.4
(top) and in October Nevertheless, ocular metastases from thyroid
2008 (bottom) of macu- carcinoma are uncommon and bilateral syn-
lar region in the right chronous metastases have a rare occurrence
eye (left side) and the and represent a clinical challenge.5-8
left eye (right side),
showing the reduction Taking into account all the currently avail-
of fluid (central black able therapeutic options, a flexible approach
area). The red region in should be planned, depending on the clinical
the left eye corresponds situation.
to the area interested by The therapeutic approach should consider
a previous thrombotic
episode. the presence of painful symptomatology,
patient’s life expectancy, clinical ophthalmo-

[page 10] [Rare Tumors 2009; 1:e4]


logic assessment and general conditions.
Enucleation should be considered in pres-
ence of painful eye with secondary neovascular
glaucoma. In all other situations, an organ
sparing approach should be considered.
Brachytherapy is particularly effective in
administering a high-dose to a single lesion of
small volume. This method involves temporary
placement of an episcleral radioactive device,
in correspondence to the tumor, until the pre-
scribed dose is administered.
Generally, the treatment can be performed
in an outpatient setting and is well tolerated,
determining mild to moderate toxicity; more-
over, the results are satisfactory in terms of
visual function and organ preservation.
Photocoagulation by means of xenon or argon
ion lasers has been used in the past as an
option in selected small choroidal melanomas.
Recently, it has been replaced by TTT that has
been proven to be effective in treating selected
small volume lesions. Currently, TTT is also
used as a supplement to plaque radiotherapy.8
Bevacizumab is a full-length recombinant
humanized monoclonal antibody directed
against VEGF, originally indicated for the treat-
ment of metastatic colorectal cancer. The
antiangiogenic properties of bevacizumab,
administered via intravenous infusion or
intravitreal injection, have been studied in
patients with age-related macular degenera-
tion, choroidal neovascularization, and other
retino-choroidal vascular diseases.9,10
Therefore, bevacizumab can reduce retinal
ischemia that could lead to radiation retinopa-
thy and exudative retinal detachment in order
to improve visual acuity and to reduce develop-
ment of neovascular glaucoma.
Macular lesions create a clinical challenge
for which treatment with intra-vitreal beva-
cizumab seemed promising. One might theo-
rize that, like laser photocoagulation, beva-
cizumab may decrease the ocular ischemia
resulting from plaque radiation or may induce
a decrease of vascular permeability in non-
vital tissue. Clearly, testing these theories is
beyond the scope of this study. However, clini-
cal series in the literature showed encourag-
ing results in treating ischemic radiation ther-
apy.
In the present case, intra-vitreal bevacizum-
ab administration probably achieved a reduc-
tion of serous detachment in the posterior
pole, thus restoring a useful visual function.
References
1. Shields CL, Shields JA, Gross NE, et al.
Survey of 520 eyes with uveal metastases.
Ophthalmology 1997;104:1265-76.
2. American Cancer Society: Cancer Facts
and Figures 2008. Atlanta, GA: American
Cancer Society, 2008.
3. Shah JP, Loree TR, Dharker D, Strong EW.
[Rare Tumors 2009; 1:e4]
Case Report
Prognostic factors in differentiated carci-
noma of the thyroid gland. Am J Surg 1992;
164:658-61.
4. Bloch RS, Gartner S. The incidence of ocu-
lar metastatic carcinoma. Arch
Ophthalmol 1971;85:673-5.
5. Gysin P, Gloor B. Cryo- and photocoagula-
tion for choroidal metastases of a thyroid
carcinoma. Klin Monatsbl Augenheilkd
1979;174:978-81.
6. Arat YO, Boniuk M. Red lesions of the iris,
choroid, and skin secondary to metastatic
carcinoma of the thyroid: a review. Surv
Ophthalmol 2007;52:523-8.
7. Bianciotto CG, Demirci HY, Shields CL,
Shields JA. Simultaneous eyelid and
choroidal metastases 36 years after diag-
nosis of medullary thyroid carcinoma.
Ophthal Plast Reconstr Surg 2008;24:62-3.
8. Shields CL, Cater J, Shields JA et al.
Combined plaque radiotheraphy and trans-
pupillary thermotherapy for choroidal
melanoma: tumor control and treatment
complications in 270 consecutive patients.
Arch Ophthalmol 2002;120: 933-40.
9. Finger PT. Radiation retinopathy is treat-
able with anti-vascular endothelial growth
factor Bevacizumab (Avastin). Int J Radiat
Oncol Biol Phys 2008;70;974-7.
10. Finger PT, Chin K. Anti-vascular endothe-
lial growth factor bevacizumab (avastin)
for radiation retinopathy. Arch Ophthalmol
2007;125:751-6.
[page 11]
Rare Tumors 2009; volume 1:e5
Pleomorphic sarcoma
metastatic to the duodenum?
Fabio R. Tavora, Allen P. Burke
Armed Forces Institute of Pathology,
Washington, DC, USA
We read with interest Hawasli et al. report of
a pleomorphic sarcoma metastatic to the left
atrium.1 However, we suspect that the true site
of origin is unknown, and may in fact be the
heart. There are several reasons for this:
- the histological appearance is similar to
left atrial tumors that have already been
reported;2
- the left atrium, is the most common site
of cardiac pleomorphic sarcoma;
- all metastatic sarcomas to the heart have
been in the right atrium or ventricle or
have involved myocardium and/or peri-
cardium; 3,4
- the tumor appears to have been present in
the heart at the time of intestinal resec-
tion, as the angiographic findings suggest,
as well as the large size of the valve tumor
(9 cm);
- tumors of such histology are very uncom-
mon in the duodenum;
- histopathological findings of the duodenal
specimen are not presented.
At the very least, we believe that it is
unknown which of the two sites is primary. For
this reason, we believe that the very rare sce-
nario of metastatic sarcoma presenting as a
left atrial mass is still not demonstrated con-
vincingly.
[page 12]
References
1. Hawasli AH, Cayce R, Luong T, et al.
Metastatic pleomorphic sarcoma to left
atrium. Rare Tumors 2009;1:e1.
2. Burke AP, Cowan D, Virmani R. Cardiac
sarcomas. Cancer 1992;9:387-95.
3. Burke AP, Virmani R. Metastatic tumors to
the heart and pericardium, in Atlas of
Tumor Pathology, Tumors of the Heart and
Great Vessels. Armed Forces Institute of
Pathology Washington DC 1996.
4. Hallahan DE, Vogelzang NJ, Borow KM, et
al. Cardiac metastases from soft-tissue
sarcomas. J Clin Oncol 1986;4:1662-9.
Correspondence: Allen P. Burke,
Armed Forces Institute of Pathology,
Washington, DC, USA
E-mail: allen.burke@gmail.com
Received for publication: 24 June 2009.
Accepted for publication: 25 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright F.R. Tavora, A.P. Burke 2009
Rare Tumors 2009; 1:e5
doi:10.4081/rt.2009.e5
[Rare Tumors 2009; 1:e5]

Multimodality treatment of
unresectable hepatic
metastases from pancreatic
glucagonoma
Guido Poggi,1 Laura Villani,2
Giovanni Bernardo1
1
Department of Oncology,
2
Pathology, IRCCS Fondazione Maugeri,
Pavia, Italy
Abstract
Glucagonomas are pancreatic islet cell
tumors arising from the alpha cells which
belong to neuroendocrine tumors. They fre-
quently metastasize to the liver. We report the
case of a 52- year old man with a pancreatic
glucagonoma with synchronous multiple liver
metastases treated by surgery, transarterial
chemoembolization, percutaneous radiofre-
quency thermal ablation and long-acting
octreotide. Our report confirms that a multi-
modal approach is very effective in patients
with unresectable liver metastases from pan-
creatic endocrine tumors providing long-last-
ing palliation and probably prolonging survival.
Case Report
A 52-year old man was referred to our hospi-
tal because of weight loss, chronic diarrhea
and an erythematous rash with bullae and ero-
sions on the feet (Figure 1), in the groin and
on the face. Blood chemical analyses showed
mild anemia (hemoglobin 10.8 g/dL), and an
impaired fasting glucose test. As a part of the
diagnostic work-up, he underwent an abdomi-
nal computed tomography which showed a
large tumor of the pancreatic tail and multiple
hepatic lesions (Figure 2). Histological exami-
nation of a specimen obtained by ultrasound-
guided percutaneous biopsy of a liver lesion
revealed a tubulo-acinar structure of moder-
ately atypical cells positive for chromogranin
(Figure 3). 111In-octreotide scan showed hepat-
ic and pancreatic uptake without evidence of
extrahepatic metastases. A high level of
glucagon in the plasma (950 pg/mL) confirmed
the diagnosis of glucagonoma. Long-acting
octreotide was started with partial improve-
ment of the symptoms. The patient was then
treated with hepatic transarterial chemoem-
bolization (TACE) combined with percuta-
neous radiofrequency thermal ablation (RFTA)
in an effort to reduce the hepatic tumor bur-
den. Two sessions of TACE, one month apart,
were performed using polyvinyl alcohol-based
microspheres (DC Bead™, Biocompatibles UK
Ltd., Farnham, UK) pre-loaded with 100 mg of
doxorubicin. One day after each TACE proce-
dure we performed ultrasound guided percuta-
neous radiofrequency. The radiofrequency sys-
tem consists of an expandable electrode with
insulated outer needle of 2.2 mm of diameter
that houses nine deployable curved tines
(Starburst XL; Rita Medical Systems).
Abdominal enhanced CT scan at one month
after the last RFTA procedure showed minimal
arterial contrast enhancement in two lesions
of the right lobe. The pancreatic tumor was
then surgically removed and the residual vital
hepatic tumors were treated with four sessions
of radiotherapy with Y-DOTATOC, a radiola-
beled somatostatin analog. Thirty-two months
after diagnosis the patient was well, he had
regained his normal body weight and the ery-
thema had completely disappeared.
Discussion
Glucagonomas are pancreatic islet cell
tumors arising from the alpha cells which
often produce elevated levels of circulating
glucagon.1 The characteristic feature of the
glucagonoma syndrome is a skin rash termed
necrolytic migratory erythema. Other findings
include a mild insulin-resistant diabetes, glos-
sitis, cheilosis, weight loss, venous thrombosis
constipation and mood changes.2 Glucagonoma
is a neuroendocrine tumor (NET) which fre-
quently metastasize to the liver.3 The particular
biological behavior of NETs, characterized by a
long natural history, even in the presence of
liver metastases, has important therapeutic
implications.4,5 Surgical resection is to be con-
sidered when the metastases are resectable
and no extrahepatic disease is present.
Unfortunately, neuroendocrine metastases are
[Rare Tumors 2009; 1:e6]
Rare Tumors 2009; volume 1:e6
Correspondence: Guido Poggi,
U.O Oncologia II, Fondazione S. Maugeri,
27100 Pavia, Italy. E-mail: guido.poggi@fsm.it
Key words: neuroendocrine tumors, liver metas-
tases, hepatic transarterial, chemoembolization.
Received for publication: 15 June 2009.
Accepted for publication: 29 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright G. Poggi et al., 2009
Rare Tumors 2009; 1:e6
doi:10.4081/rt.2009.e6
usually multiple and diffuse and therefore rad-
ical resection is feasible only in 10-20% of
patients.6 Surgical resection of liver metas-
tases with curative intent is associated with 5-
year survival rates of 73-85%7,8 but, in unre-
sectable disease, surgery is not useful as a pal-
liative tool unless more than 90% of the tumor
load can be debulked.9 In this setting, systemic
chemotherapy and octeotide have proved more
useful in controlling the endocrine syn-
drome.10,11 On the experience of the efficacy of
transarterial chemoembolization (TACE) in
hepatocellular carcinoma that shares vascular
findings with neuroendocrine hepatic metas-
tases, TACE has been effectively used in the
palliative management of these tumors.12-13
TACE has also been used in adjuvant settings
to reduce tumor load before hepatic resection,
hepatic transplantation or tumor ablation tech-
niques.4,14,15 Preliminary results show that the
new drug-eluting microspheres now available
seem to optimize TACE procedures. In fact,
these microspheres are capable of loading the
drugs and slowly delivering them directly into
the tumor, thus achieving high intratumoral
Figure 1. Necrolytic
migratory erythema on
the feet.
[page 13]
Case Report
Figure 2. Abdominal CT scan shows multi-
ple hepatic lesions.
concentrations and low plasma concentra-
tions.16,17 The results with microspheres loaded
with doxorubicin have been promising, show-
ing an advantageous pharmacokinetic profile
and good clinical response when compared
with conventional TACE both in patients with
unresectable HCC18 and in patients with liver
metastases from well differentiated NETs.19
Local therapy using RFTA provides a minimal-
ly invasive procedure that decreases tumor vol-
ume, preserves most of the normal liver and
can be repeated several times.20 Nevertheless,
histological data from liver specimens of HCC
patients who underwent RFTA showed that
tumor size has a significant impact on the
local effect of this treatment. Indeed, vessels
adjacent to the tumor cause heat loss due to
perfusion-mediated cooling.21 Balloon catheter
occlusion or TACE increase the efficacy of
RFTA by reducing tumor arterial supply.22 In
our patient we performed each RFTA exactly
one day after the TACE to obtain an increase of
the necrotic area induced by thermal ablation.
After two procedures of both TACE and RFTA,
the hepatic tumor load was considerably
reduced, so that we were then able to perform
four sessions of somatostatin receptor mediat-
ed radiotherapy using 90Y Tyr-octreotide, which
is capable of binding to the residual vital
tumor. Our report confirms that a multimodal
approach is very effective in patients with
unresectable liver metastases from pancreatic
endocrine tumors providing long-lasting palli-
ation and probably prolonging survival.
References
1. Friesen SR. Tumor of the endocrine pan-
creas. N Engl J Med 1982;306:580-90.
2. Mallinson CN, Bloom SR, Warin AP, et al. A
glucagonoma syndrome. Lancet 1974;2:1-5.
[page 14]
3. Plöckinger U, Rindi G, Arnold R, Eriksson
B, et al. Guidelines for the diagnosis and
treatment of neuroendocrine gastroin-
testinal tumours. Neuroendocrinology
2004; 80:394-24.
4. Falconi M, Bassi C, Bonora A, et al. Role of
chemoembolization in synchronous liver
metastases from pancreatic endocrine
tumours. Dig Surg 1999;16:32-8.
5. Vogl TJ, Naguib NN, Zangos S, et al. Liver
metastases of neuroendocrine carcino-
mas: interventional treatment via transar-
terial embolization, chemoembolization
and thermal ablation. Eur J Radiol 2009;
72:517-28.
6. Sarmiento JM, Que FG. Hepatic surgery
for metastases from neuroendocrine
tumors. Surg Oncol Clin N Am 2003;12:
231-42.
7. Chamberlain RS, Canes D, Brown KT, et al.
Hepatic neuroendocrine metastases: does
intervention alter outcomes? J Am Coll
Surg 2000;190:432-45.
8. Moertel CG, Johnson CM, McKusick MA, et
al. The management of patients with
advanced carcinoid tumors and islet cell
carcinomas. Ann Intern Med 1994;120:
302-9.
9. Blonski WC, Reddy KR, Shaked A, et al.
Liver transplantation for metastatic neu-
roendocrine tumor: a case report and
review of the literature. World J
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10. Öberg K. The use of chemotherapy in the
management of neuroendocrine tumors.
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11. Saltz L, Trochanowski B, Buckley M, et al.
Octreotide as an antineoplastic agent in
the treatment of functional and nonfunc-
tional neuroendocrine tumors. Cancer
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Figure 3. Liver biop-
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acinar structure of
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(x100).
ME. Hepatic arterial embolization for
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tions. Cancer 1990;65:2227-32.
13. Ruszniewski P, Rougier P, Roche A, et al.
Hepatic arterial chemoembolization in
patients with liver metastases of
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30.
14. Roche A, Girish BV, de Baère T, et al.
Trans-catheter arterial chemoemboliza-
tion as firstline treatment for hepatic
metastases from endocrine tumors. Eur
Radiol 2003;13:136-40.
15. Veenendaal LM, Borel Rinkes IH, Lips CJ,
van Hillegersberg R. Liver metastases of
neuroendocrine tumours; early reduction
of tumour load to improve life expectancy.
World J Surg Oncol 2006; 26:4-35.
16. Poggi G, Quaretti P, Minoia C, et al.
Transhepatic arterial chemoembolization
with oxaliplatin-eluting microspheres
(OEM-TACE) for unresectable hepatic
tumors. Anticancer Res 2008;28:3835-42.
17. Lewis AL, Taylor RR, Brenda H, et al.
Pharmacokinetic and safety study of dox-
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cinoma with drug eluting beads: efficacy
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Hepatol 2007;46:474-81.
19. de Baere T, Deschamps F, Teriitheau C, et
al. Transarterial chemoembolization of
liver metastases from well differentiated
gastroenteropancreatic endocrine tumors
with doxorubicin-eluting beads: prelimi-
nary results. J Vasc Interv Radiol
2008;19:855-61.
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[page 15]
Rare Tumors 2009; volume 1:e7
Complete small bowel
obstruction caused by
metastasis from primary
nasopharyngeal carcinoma
Chi Pan Lau, Edwin Pun Hui,
Anthony Tak-Cheung Chan
Department of Clinical Oncology, Prince
of Wales Hospital, The Chinese
University of Hong Kong, China
Abstract
We here report the first case in the litera-
ture on a surgical emergency of complete small
bowel obstruction caused by metastasis from
nasopharyngeal carcinoma nine months after
the primary tumor was treated with concurrent
chemoradiation. The patient achieved pro-
longed survival with prompt surgical treatment
followed by systemic chemotherapy.
Introduction
Cancers involving the bowel are usually pri-
mary large or small bowel cancers, direct inva-
sion from primary cancers arising from other
abdominal organs or peritoneal carcinomato-
sis. Metastatic cancer from malignancy out-
side the abdomen involving the intestinal
mucosa is relatively uncommon although it is
well reported in the literature, and can be asso-
ciated with multiple surgical emergencies
including intestinal bleeding, perforation, or
intussusception. Small bowel obstruction
caused by metastatic lesion from other primary
cancer is a rare event. Idelevich et al. reviewed
the literature and found that between 1988 and
2005, only 36 such cases have been reported.1
Interestingly, the most common primary can-
cer in these cases was lobular breast carcino-
ma (47%), followed by lung cancer (11%) and
malignant melanoma (8%).
These cases can occur after patients have
been in remission for many years2-4 and can be
the first site of disease presentation.5 Because
of its rarity, recurrent metastatic disease as
the cause of small bowel obstruction in
patients who have been in remission for their
primary cancer was not immediately suspected
and it was known only during pathological
assessment of the resected specimen. We here
report a case of complete small bowel obstruc-
tion caused by recurrent metastatic disease
from a patient who has been treated for pri-
mary nasopharyngeal carcinoma.
[page 16]
Case Report
A 58-year old man with good past health pre-
sented with a one year history of episodic epis-
taxis in June 2007. On examination he was
found to have bilateral cervical lymphadenopa-
thy. Endoscopic examination of the nasophar-
ynx revealed a nasopharyngeal tumor biopsy
which showed undifferentiated carcinoma.
Computer tomography (CT) of the head and
neck region showed a tumor mass extending
up to the base of skull and down to the hard
palate, with parapharyngeal extension and
involvement of the cervical lymph nodes bilat-
erally. Whole-body positron emission tomogra-
phy (PET) scan showed no metastatic disease
elsewhere. The patient was diagnosed to have
locally advanced nasopharyngeal carcinoma
(NPC) of UICC/AJCC (International Union
Against Cancer and American Joint
Committee on Cancer) stage T2bN2 and he
was treated with concurrent chemoradiation
with weekly cisplatin. He was in clinical remis-
sion for nine months after his treatment until
he developed symptoms of acute intestinal
obstruction with abdominal pain and disten-
tion. Abdominal X-ray showed dilated small
bowel loops. He underwent urgent laparotomy
and intra-operatively he was found to have a
lesion completely obstructing the distal small
bowel. The lesion was resected and resection
was followed by primary bowel anastomosis
(Figure 1). The patient recovered well one
month after his operation. Microscopic exami-
nation of the small bowel lesion showed undif-
ferentiated carcinoma and the tumor cells
were immunohistochemically positive for
cytokeratin and c-kit.
Fluorescence in situ hybridization (FISH) of
Epstein-Barr Virus (EBV) encoded RNA
(EBER) was also positive in the tumor cells
(Figure 2). The histology of the small bowel
lesion was compared to the initial nasopharyn-
geal carcinoma biopsy specimen and they were
similar. Plasma EBV-DNA was found to be ele-
vated to 150,473 copies/mL and PET scan
showed high FDG uptake (maximum SUV
17.7) at the retroperitoneal lymph nodes con-
sistent with metastatic disease at these sites.
The patient was subsequently treated with
three cycles of combination chemotherapy
with paclitaxel and carboplatin three-weekly.
Repeated whole body PET scan showed com-
plete remission with no residual disease
detectable. Plasma EBV-DNA level also
decreased to 900 copies/mL. Although the
patient had progressive disease subsequently,
his metastatic disease remained responsive to
further lines of chemotherapy with capeci-
tabine and gemcitabine and he remains well at
the present time with preserved quality of life.
[Rare Tumors 2009; 1:e7]
Correspondence: Chi Pan Lau,
Department of Clinical Oncology,
Prince of Wales Hospital, The Chinese University
of Hong Kong, Hong Kong, China
E-mail: cp_lau@clo.cuhk.edu.hk
Key words: small bowel obstruction, metastasis,
nasopharyngeal carcinoma.
Contributions: CPL and EPH contributed to
manuscript drafting. ATC contributed to critical
manuscript revision. All authors read and
approved the final manuscript.
Conflict of interest: the authors reported no poten-
tial conflicts of interests.
Consent: written informed consent was obtained
from the patient for publication of this case
report and any accompanying images.
Received for publication: 19 June 2009.
Accepted for publication: 29 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright C.P. Lau et al., 2009
Rare Tumors 2009; 1:e7
doi:10.4081/rt.2009.e7
Discussion
Small bowel metastases from primary head
and neck cancer is extremely rare. Among the
few reported cases, the majority of them were
from cancer of the larynx.6,7 Guillem et al. ana-
lyzed a 10-patient series which showed that
small bowel metastases from head and neck
cancers occurred more commonly in old male
patients (mean age 71 years).8 They were usu-
ally discovered because of occlusive, perfora-
tive or bleeding symptoms and complications.
Perforation more commonly occurred at jeju-
nal metastases while clinical bleeding and
occlusion more commonly occurred at ileal
metastases. In any case, the diagnosis of small
bowel metastases from head and neck cancer
carried poor prognosis. In these 10 patients,
deaths occurred within eight months following
diagnosis, either due to post-operative compli-
cations or cancer progression.
To our knowledge, we report the first case of
small bowel metastasis from primary nasopha-
ryngeal carcinoma. Nasopharyngeal carcinoma
(NPC) is an endemic subtype of head and neck
cancer in South East Asia especially the south-
ern part of China. In contrast to other types of
head and neck cancer, NPC has a special viral
etiology with strong association with EBV
infection.9 The other special feature of NPC is

Figure 1. Specimen resected during lapa-
rotomy. A lesion is found completely
obstructing the small bowel macroscopi-
cally.
its chemosensitivity.10 Common sites of metas-
tases from primary nasopharyngeal carcinoma
include regional lymph nodes, bone, lung, and
liver. Although poor prognosis and short sur-
vival was reported in small bowel metastases
from head and neck cancer, for our patient
prompt surgical treatment for the abdominal
emergency followed by systemic chemotherapy
for residual metastatic disease resulted in
good outcome, as illustrated by an initial radi-
ological complete remission given that NPC is
a chemosensitive type of cancer. Our patient
has survived at least 22 months till the present
time with good quality of life.
Conclusions
Although small bowel metastases from pri-
mary cancer outside the abdomen is relatively
Figure 2. Microscopic examination of the
resected specimen. Poorly differentiated
carcinoma cells stained strongly for
Epstein-Barr virus-encoded RNA (EBER).
uncommon, prompt recognition and treatment
of an abdominal emergency secondary to these
metastases can result in good outcome, espe-
cially for a cancer that shows high response
rate to systemic chemotherapy. Clinicians
need to be vigilant on unusual or unexplained
abdominal symptoms arising from patients
with malignancy outside the abdomen.
References
1. Idelevich E, Kashtan H, Mavor E, Brenner
B. Small bowel obstruction caused by sec-
ondary tumors. Surg Oncol 2006:15:29-32.
2. Bender GN, Maglinte DD, McLarney JH, et
al. Malignant melanoma: patterns of
metastasis to the small bowel, reliability of
imaging studies, and clinical relevance.
Am J Gastroenterol 2001:96:2392-400.
[Rare Tumors 2009; 1:e7]
Case Report
3. Daniels IR, Layer GT, Chisholm EM. Bowel
obstruction due to extrinsic compression
by metastatic lobular carcinoma of the
breast. J R Soc Promot Health 2002;
122:61-2.
4. Van Trappen P, Serreyn R, Elewau AE, et al.
Abdominal pain with anorexia in patients
with breast carcinoma. Ann Oncol
1998;9:1243-5.
5. Clavien PA, Laffer U, Torhos J, Harder F.
Gastrointestinal metastases as first clini-
cal manifestation of the dissemination of a
breast cancer. Eur J Surg Oncol 1990;16:
121-6.
6. Airoldi M, Gabriele P, Succo G, et al. Small
bowel metastasis from squamous cell car-
cinoma of the larynx. A case report.
Tumori 1993;79:286-7.
7. Buyukcelik A, Ensari A, Sarioglu M, et al.
Squamous cell carcinoma of the larynx
metastasized to the ampulla of Vater.
Report of a case. Tumori 2003;89:199-201.
8. Guillem P, Brygo A, Assila C, Dabrowski A.
Small bowel metastases from head and
neck cancers. Ann Chir 2004;129:422-6.
9. Zur Hausen H, Schulte-Holthausen H,
Klein G, et al. EBV DNA in biopsies of
Burkitt tumours and anaplastic carcino-
mas of the nasopharynx. Nature 1970;228:
1056-8.
10. Ma BB, Chan AT. Recent perspectives in
the role of chemotherapy in the manage-
ment of advanced nasopharyngeal carcino-
ma. Cancer 2005;103:22-31.
[page 17]
Rare Tumors 2009; volume 1:e8
Diagnosis of vulvar lesions by
non-invasive optical analysis:
a pilot study
Anne-Therese Vlastos,1 Igor Charvet,2
Ilaria Dellacasa,1 Federica Capanna,1
Marie-Françoise Pelte,3 Philippe Thueler,4
Michel Saint-Ghislain,4
Christian Depeursinge,4 Paolo Meda2
1
Department of Gynecology and
Obstetrics, 2Department of Cell
Physiology and Metabolism, 3Department
of Pathology and Immunology, Geneva
University Hospital University, Genève,
Switzerland; 4Institute of Applied Optics,
Swiss Federal Institute of Technology,
Lausanne, Switzerland
Abstract
A procedure that could allow an early in vivo
and non-invasive detection of vulvar lesions
would be extremely useful. We tested an inno-
vative optical method (Optiprobe), which uses
a harmless, visible light source for the in vivo,
on-line detection of minimal alterations in the
structure of vulvar epithelium. A group of 3
female volunteers without gynecological symp-
toms were first screened to evaluate optical
properties of normal vulvar tissue. Next, a
group of 16 patients undergoing gynecological
examination for vulvar lesions was evaluated
by the Optiprobe at suspected sites before
these sites were biopsied for histological
analysis. Adjacent, non-involved sites were
also measured to provide internal controls.
Histological analysis of the biopsies identified
one case that did not show obvious alterations,
4 cases of high-grade vulvar intraepithelial
neoplasia (VIN), 5 cases of vulvitis, and 6
cases of lichen sclerosis (LS).
The optical properties of the VIN cases were
significantly different from those of controls,
due to a decrease in the absorption spectra and
an increase in the scattering spectra. In con-
trast, a significant increase in the absorption
spectra and a decrease in the scattering spec-
tra were observed in the cases of vulvitis. In
the LS cases, the absorption spectra were as in
controls, whereas the scattering spectra were
significantly decreased. We conclude that the
Optiprobe provides a useful tool for a rapid and
non-invasive detection of vulvar alterations.
The method should contribute to reduce the
number of biopsies and to facilitate the long-
term follow-up of vulvar lesions.
[page 18]
Introduction
Vulvar squamous cell carcinoma of the
vulva (SCC) accounts for about 4% of all gyne-
cological malignancies.1 It has an incidence of
about 1.8 per 100,000, which peaks at approx-
imately 20 per 100,000 after the age of 75,
making it as common as cervical carcinoma.2,3
SCC is usually slow growing and begins as a
pre-malignant lesion, referred to as vulvar
intraepithelial neoplasia (VIN).4 This lesion
actually comprises a spectrum of epithelial
changes that range from mild to severe dyspla-
sia, which immediately precede invasive car-
cinoma. Although advanced VIN lesions may
appear as variably pigmented patches under
vulvoscopy investigation, they may be difficult
to distinguish from a variety of benign dis-
eases. This difficulty often leads to delayed
diagnosis, until the obvious stage of invading
squamous cell carcinoma.5 Presently, the stan-
dard procedure for definitive diagnosis con-
sists in performing a biopsy of all suspected
areas, even though only a fraction of these are
at risk of neoplastic transformation.6 Because
vulvar sampling is painful and bears infec-
tious risks for the patient, an alternative
method that would allow for a non-invasive
diagnosis would be of great value in the
screening programs of vulvar cancer.
Light-scattering spectroscopy is a recently
developed optical method that relies on the in
situ measurement of the light back-scattered
(reflectance) from an illuminated tissue. The
two underlying ideas are that light propaga-
tion, and thus reflectance, is modified under
conditions altering the structure and/or com-
position of a tissue,7-11 and that optical coeffi-
cients can be derived from reflectance values,
which provide information on these alter-
ations.12-14 Thus, the absorption coefficient,
which is thought to reflect the concentration of
chromophores, and the scattering coefficient,
which is thought to reflect the size and numer-
ical density of cells and organelles, significant-
ly differ in normal and pathological tissues.15-18
We have built an optical set-up, referred to
as Optiprobe, which comprises a multi-fiber
mini-probe to screen small tissue volumes of
about 1 mm3.17,19 We have found that this equip-
ment allows for an in vivo, real-time detection
of minimal tissue lesions, like those expected
at the beginning of inflammatory and cancer-
ous alterations.15,20 Here we have assessed
whether the method has a sufficient sensitivi-
ty to identify alterations of vulvar tissues in
patients undergoing vulvoscopy. We report that
the Optiprobe method discriminated normal
and pathological cases, with a sensitivity and
specificity that compared well with those of
histological analysis, while avoiding the need
of invasive biopsies.
[Rare Tumors 2009; 1:e8]
Correspondence: Ilaria Dellacasa, Department of
Gynecology and Obstetrics, Geneva University
Hospital, 1211 Geneva 4, Switzerland.
E-mail: ilydellacasa@yahoo.it
Vlastos Anne-Thérèse, Department of Gynecology
and Obstetrics, Geneva University Hospital, 1211
Geneva 4, Switzerland. E-mail: anne-therese.vlas-
tos@hcuge.ch
Key words: vulvar intraepithelial neoplasia, non
invasive diagnosis, optical analysis, absorption
spectra, scattering spectra.
Acknowledgments: the authors would like to
gratefully thank Dr. Michele Follen at The
University of Texas M.D. Anderson Cancer Center
for her helpful comments about this manuscript.
Contributions: IC and ATV contributed equally to
this research and should both be considered first
author.
Funding: the Meda team is supported by grants
from the Programme Commun de Recherche en
Génie Biomédical 1999-2002, the Swiss National
Foundation (3100-067788.02), the Juvenile
Diabetes Research Foundation International (1-
2001-622), the European Union (QLRT-2001-
01777), the Fondation Romande pour la
Recherche sur le Diabète and the National
Institute of Health (DK-63443-01), a Research
and Development grant from the Geneva
University Hospitals, le Fond National Suisse
pour la Recherche Scientifique (3100-
067788.02).
Received for publication: 29 June 2009.
Accepted for publication: 30 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright A.-T. Vlastos, et al., 2009
Rare Tumors 2009; 1:e8
doi:10.4081/rt.2009.e8
Materials and Methods
Patient selection
The study was approved by the Committee
for Ethics in Research of the University of
Geneva Hospitals, and conducted according to
the guidelines of this Committee. After
informed consent, a first group of 3 healthy
volunteers were screened with the Optiprobe
technology to determine the optical properties
of normal vulvar tissue. A second group of 16
patients, undergoing vulvoscopic examination
for suspicion of vulvar lesions, were similarly
evaluated.
The very same sites were then sampled for
standard histological analysis. Sites of non-
involved tissue from nearby regions were also
 Article

measured to provide an internal control. The
optical-biopsy combined procedure did not
imply additional discomfort for the patients,
inasmuch as the fiber-optic probe was gently
applied on vulvar surfaces for illumination
with a harmless visible light source. On aver-
age, the duration of the combined vulvoscopic-
optical-biopsy procedure was about 10 min
longer than that of the standard vulvoscopic-
biopsy examination.
Optical measurements
The optical mini-probe set-up, and the theo-
ry of the method used to collect reflectance sig-
nals and to derive optical coefficients, have
been previously described.17,19,21,22 Briefly, the tip
of the hand-held optical probe was applied on
the vulvar epithelium. Once in place, a 400
msec pulse of white-light (wavelength range
480-950 nm) provided by a halogen lamp
(Ocean Optics LS-1) was delivered through the
source fiber of the probe. Intensity of
reflectance, i.e. light backscattered from the
illuminated tissue, was simultaneously record-
ed at various distances from the source, using
the 10 collecting fibers of the probe. Collected
reflectance was brought to a spectroscope
(Jobin-Yvon CP 200), focused on a cooled CCD
camera (Hamamatsu C7041) during an expo-
sition time controlled by a mechanical shutter,
and computer digitized in 16 bits (National
Instruments PCI-MIO-16E-4). Reflectance
measurements were repeated 6-8 times per
site and averaged. In each patient, at least one
suspicious and one control site were probed
before the surgical biopsy.
Once the gynecological examination was
completed, the acquired reflectance spectra
were analyzed using a Monte Carlo simulation
and a modified form of the Henyey-Greenstein
phase function to compute an absorption and a
the number of true positive cases (i.e. cases
showing positive tests in patients with abnor-
mal histology) by the number of true plus false
negative cases (i.e. cases showing normal
tests in patients with abnormal histology).
Specificity of tests was evaluated by dividing
the number of true negative cases (i.e. cases
showing normal tests in patients with normal
histology) by the number of true negative
cases plus false positive cases (i.e. cases
showing altered tests in patients with normal
histology).
Results
The optical spectra of normal
vulvar tissue changes with
hormonal status
The optical properties of normal vulvar tis-
sue were first evaluated by recording the
absorption and scattering spectra in 3 healthy
volunteers, whose vulva was clinically normal.
In each case, maximal light absorption was
observed between 400 and 500 nm (Figure 1A),
reflecting the normal presence of chro-
mophores oxy and deoxy-hemoglobin within
surface tissues. In the same volunteers, the
scattering coefficient decreased as a function
of increasing wavelength (Figure 1B), consis-
tent with the light-scattering characteristics of
surface tissues. Comparison between the
recordings from the 3 volunteers revealed sig-
nificant (p<0.001) differences in both absorp-
tion (Figure 1A) and scattering (Figure 1B)
coefficients. These differences were repre-
sented by a variation coefficient varying from
A B
Absorption coefficient
25-140% for the absorption spectra (Figure
1C), and from 5-20% for the scattering spectra
(Figure 1D).
Histology set the standard for the
retrospective validation of the
optical findings
Immediately after the optical measure-
ments, a biopsy was taken at each of the 16
suspected sites that had been investigated.
The histopathological scoring of these samples
resulted in the identification of one site show-
ing no detectable alteration, 4 sites showing
high-grade VIN, 5 sites with vulvitis and 6 sites
with lichen sclerosis.
Optical analysis distinguished
normal and pathological vulvar
epithelium
Absorption and scattering coefficients were
determined for wavelengths between 400 and
700 nm, in 16 sites suspicious of vulvar lesion
and in nearby sites that appeared phenotypi-
cally not involved and were used as controls.
Non-parametric statistics confirmed that the
optical properties of VIN sites were signifi-
cantly (p<0.001) different from those of con-
trols, due to a decrease in the absorption coef-
ficient (Figure 2A) and an increase in the
scattering coefficient (Figure 3A). Thus, on
average, the absorption and scattering coeffi-
cients of VIN cases were 50% and 40% those of
controls (Figures 2D and 3D). Taking these
values as optical threshold for diagnosis, we
calculated that the Optiprobe would detect VIN
cases with a sensitivity of 75% (absorption) -

Scattering coefficient

scattering coefficient. These optical parame-

ters are thought to reflect the interaction of
mm–1

mm–1

light with chromophores and the changes of

light propagation in small tissue volumes,
respectively.17,19,21

Histology
Biopsies of the vulvar tissue, taken at the Wavelength (mm) Wavelength (mm)
very same sites that were probed optically, C D
were fixed in 10% formol and processed for
Absorption variation

Scattering variation

standard histological analysis by an expert

pathologist. In this study, each sample was
%

assigned to a normal, lichen sclerosis, VIN or a

vulvitis group.

Statistics
Optical measurements from altered and
control sites were compared using appropriate
non-parametric statistics, as provided by the
SPSS program (SPSS Inc., Chicago, USA).
Sensitivity of optical analysis (hereafter
referred to as tests) was estimated by dividing
Wavelength (mm) Wavelength (mm)
Figure 1. Optical spectra of normal vulvar tissue vary between healthy women. Mean
(bold line) and standard deviations (thin lines) of the absorption (A) and scattering coef-
ficients (B) measured on 3-4 adjacent sites in each healthy volunteer (a, b and c are
recordings from the 52-, 48- and 34-year old women, respectively.

[Rare Tumors 2009; 1:e8] [page 19]

Article

A B C
Absorption coefficient
mm–1

Wavelength (mm) Wavelength (mm) Wavelength (mm)

D E F
Absorption variation
%

Wavelength (mm) Wavelength (mm) Wavelength (mm)

Figure 2. (A-C) Absorption analysis discriminated VIN and inflammatory lesions, but not lichen sclerosis from normal tissue. (A) Mean
(bold line) and standard deviations (thin lines) of absorption spectra obtained at sites featuring histology characteristics of VIN (A),
inflammation (B) and lichen sclerosis (C). Absorption spectra of VIN and vulvitis (black) were significantly (p<0.001) different from
those of controls spectra (gray), for light wavelengths of 400-700 nm. In contrast, absorption spectra of lichen sclerosis (black) were
not different from those of controls (gray). (D-F) Mean (bold line) and standard deviations (thin lines) of percentage of change in
absorption spectra between pathological and control sites were calculated for the 4 VIN (D), the 5 vulvitis (E), and the 6 lichen scle-
rosis sites (F). Graphs show that VIN lesions induced a significant decrease of absorption between 400 nm and 500 nm, whereas a sig-
nificant increase was observed at inflammatory sites. No significant change was observed at lichen sclerosis sites.

A B C
Scattering coefficient
%

Wavelength (mm) Wavelength (mm) Wavelength (mm)

D E F
Scattering variation
coefficient %

Wavelength (mm) Wavelength (mm) Wavelength (mm)

Figure 3. (A-C) Scattering analysis discriminated VIN, inflammatory and lichen sclerosis lesions from normal tissue. Mean (bold line)
and standard deviations (thin lines) of scattering spectra obtained in women diagnosed with VIN (A), inflammation (B) and lichen
sclerosis (C). Scattering spectra of VIN sites, vulvitis sites and lichen sclerosis sites (black) were significantly (p<0.001) different from
controls spectra (gray) for light wavelengths of 400-700 nm, 400-500 nm, and 500-700 nm, respectively. (D-F) Mean (bold line) and
standard deviations (thin lines) of percentage change over control was calculated for the 4 VIN (D), the 5 vulvitis (E) and the 6 lichen
sclerosis sites (F). Graphs show significant scattering variation in VIN, vulvitis and lichen sclerosis cases, for light wavelengths of 400-
700 nm, 400-510 nm and 500-700, nm respectively.

[page 20] [Rare Tumors 2009; 1:e8]


50% (scattering).
Compared to controls, sites of vulvitis fea-
tured significantly (p<0.001) increased
absorption values (Figure 2B) and decreased
scattering values (Figure 3B). When expressed
as percentage of the corresponding control val-
ues, the average absorption and scattering val-
ues of vulvitis cases represented 100% and
20% of control values, respectively (Figures 2E
and 3E). Using these values, the test discrimi-
nated normal from vulvitis cases with a sensi-
tivity of 80% for both absorption and scattering
coefficients.
The absorption coefficients evaluated at
sites of lichen sclerosis were not significantly
different from controls for all investigated light
wavelengths (Figure 2 C,F). In contrast, a sig-
nificant (p<0.001) decrease in scattering spec-
tra was observed (Figure 3C), resulting, on
average, in a 20% of variation from control val-
ues (Figure 3F). Using this scattering varia-
tion as threshold optical limit, the diagnostic
test differentiated lichen sclerosis from nor-
mal cases with a sensitivity of 66%.
Discussion
We have developed a new optical procedure
and equipment for a non-invasive, in vivo
analysis of small tissue volumes. The proce-
dure is based on the spectroscopic measure-
ment of the reflectance of white light, combin-
ing wavelengths of 400-700 nm, from which
various optical parameters can be derived.28, 32,33
Among these parameters, scattering and
absorption coefficients are of particular inter-
est for medical diagnosis inasmuch as they are
thought to provide information about changes
in cell structure and organization within tis-
sues, and in content of various molecules,
respectively.35-38 We have already shown that
the determination of these optical coefficients
enable minimal alterations of skin surface to
be detected in an experimental murine
model,26 and can also correctly evaluate human
mucosa in patients undergoing gastroscopy for
suspected gastritis alterations.20 Here, we have
tested whether the procedure can also be used
to detect alterations of the vulvar epithelium,
including VIN, vulvitis and lichen sclerosis. We
have further assessed whether the method has
a sufficient sensitivity to become a useful com-
plement of standard clinical diagnosis, while
limiting the need for an invasive biopsy for
histological diagnosis.
To address these questions, we have first
studied the optical properties of normal vulvar
tissue in 3 volunteer women. The major light
absorption for 420-480 nm wavelengths fea-
tured the presence of hemoglobin, which cor-
responds to the main chromophore encoun-
tered by probing photons.23,24 Scattering spectra
revealed a slow decrease correlated to the
increase of wavelengths, as is usually observed
with surface biological tissues.23,25 Although
both absorption and scattering measurements
had a comparable shape in all volunteers, we
observed significant differences in their
absolute values. These differences could not be
attributed to variations of the optical set-up,
which probed stable standards with a variation
coefficient of less than 5% for absorption and
scattering measurement. Thus, the variation
coefficients observed for absorption (30-140%)
and scattering (5-20%) measurements of nor-
mal vulvar tissue clearly resulted from inter-
individual variation. While the reason of this
variation remains to be determined (could this
be due to hormonal status?) the data imply the
necessity of having a proper internal control
for each individual undergoing the Optiprobe
analysis. We have followed this strategy to
investigate a series of 16 patients undergoing
vulvoscopy for evaluation of benign or pre-
malignant vulvar lesions by comparing the
measurements made at suspected sites to
those of phenotypically not-involved sites that
were used as internal controls. We found sig-
nificant variations in scattering and/or absorp-
tion coefficients in all the three types of
lesions that were investigated. While the
nature of the biological parameters that affect-
ed the optical coefficients remains to be deter-
mined, this method provides a new tool for a
rapid distinction between pathological and
normal sites. The changes in absorption and
scattering appeared specific for a given type of
lesion, inasmuch as they were decreased or
increased differentially in cases of VIN, vulvi-
tis, and lichen sclerosis. The observation of
these combined variations in a clinical setting
should indicate the type of lesion. Our analysis
of spectral variations between pathological
sites and control counterparts also enabled us
to determine the wavelengths allowing for the
best detection of each type of lesion. The
absorption and scattering coefficients estimat-
ed at these wavelengths determined a sensitiv-
ity of the approach of more than 75% for the
detection of both VIN and vulvitis cases, and of
66% for the detection of lichen sclerosis. These
values show that the Optiprobe instrument can
detect a majority of vulvar lesions. Further
refinements of the set-up, based on a com-
bined analysis by spectroscopic and fluores-
cence methods or tissue imaging, should fur-
ther improve its performance. Our analysis
shows promising results for a future applica-
tion of optical methods in the diagnosis of vul-
var lesions. Improvement in the mathematical
processing of the optical coefficients from the
reflectance measurements may facilitate the
routine, clinical use of the method.
To conclude, we report here on a novel opti-
cal method that efficiently detects vulvar
lesions with a sensitivity that compares well
[Rare Tumors 2009; 1:e8]
Article
with the standard biopsy-histology approach,
while avoiding the tissue invasion required by
the latter approach. This method should prove
a useful complement to clinical diagnosis of
vulvar lesion in directing the biopsy procedure,
as well as in guiding invasive therapeutic acts
(e.g. laser irradiation, excision) to only rele-
vant areas of the vulvar surface.
References
1. Eifel P, Levenback C. Cancer of the lower
genital tract. Ed. B.D.Inc London Hamilton
2001;1-8.
2. Silverberg E. Statistical and epidemiologi-
cal information on gynecological cancer.
American Cancer Society 1986;80:9.
3. Cramer D. Epidemiology of the gynaeco-
logic cancers. Com Theor 1978;4:9-17.
4. Hart WR. Vulvar intraepithelial neoplasia:
historical aspects and current status. Int J
Gynecol Pathol 2001;20:16-30.
5. Joura EA. Epidemiology, diagnosis and
treatment of vulvar intraepithelial neopla-
sia. Curr Opin Obstet Gynecol 2002;14:39-
43
6. Girardi F, Pickel H, Joura EA, et al.
Guidelines for diagnosis and therapy of
intraepithelial neoplasia and early inva-
sive carcinoma of the female lower genital
system (cervix uteri, vagina, vulva) estab-
lished by the AGK (Colposcopy Work Group
in the OGGG) Gynakol Geburtshilfliche
Rundsch 2001;41:197-200. German
7. Rolfe P. In vivo near-infrared spectroscopy.
Annu Rev Biomed Eng 2000;2:715-54.
8. Wallace VP, Crawford DC, Mortimer PS, et
al. Spectrophotometric assessment of pig-
mented skin lesions: methods and feature
selection for evaluation of diagnostic per-
formance. Phys Med Biol 2000;45:735-51.
9. Koenig F, Larne R, Enquist H, et al.
Spectroscopic measurement of diffuse
reflectance for enhanced detection of blad-
der carcinoma. Urology 1998;51:342-5.
10. Marchesini R, Brambilla M, Clemente C, et
al. In vivo spectrophotometric evaluation
of neoplastic and non-neoplastic skin pig-
mented lesions--I. Reflectance measure-
ments. Photochem Photobiol 1991;53:77-
84.
11. Mourant JR, Bigio IJ, Boyer J, et al. Elastic
scattering spectroscopy as a diagnostic
tool for differentiating pathologies in the
gastrointestinal tract: preliminary testing.
J Biomed Optics 1996;1:192-9.
12. Kienle A, Lilge L, Patterson MS, et al.
Spatially resolved absolute diffuse
reflectance measurements for noninvasive
determination of the optical scattering and
absorption coefficients of biological tis-
sue. Appl Opt 2002;35:2304-14.
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13. Bays R, Wagnières G, Robert R, et al.
Clinical determination of tissue optical
properties by endoscopic spatially resolved
reflectometry. Appl. Opt 1996;35:1756-66.
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Determination of optical parameters of
human breast tissue from spatially
resolved fluorescence: a diffusion theory
model. Appl Opt 2002;41:4024-35.
15. Charvet I, Vermeulen B, Thueler P, et al. A
new optical method for the non invasive
detection of minimal tissue alterations.
Phys Med Biol 2002;47:2095-108.
16. Tromberg BJ, Shah N, Lanning R, et al.
Non-invasive in vivo characterization of
breast tumors using photon migration
spectroscopy. Neoplasia 2000;2:26-40.
17. Bevilacqua F, Dominique Piguet, Pierre
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4939-50.
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18. Zonios G, Perelman L, Backman, et al.
Diffuse reflectance spectroscopy of human
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19. Bevilacqua F, Depeursinge C. Monte Carlo
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transport mean free path. J Opt Soc Am A
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Diagnosis and grading of gastritis by non
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vivo endoscopic tissue diagnostics based
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Optical local and superficial probing of tis-
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dependence of the vulva. J Reprod Med
1985;30:667-74.

Congenital giant melanocytic
nevi
Ghulam S. Hashmi,1 Syed S. Ahmed,2
Shahla Khan3
1
Dept. of Oral & Maxillofacial Surgery,
Faculty of Medicine, Aligarh Muslim
University, Aligarh, India;
2
Dept. of Oral & Maxillofacial Surgery,
Faculty of Medicine, Aligarh Muslim
University, Aligarh, India;
3
Dept. of Prosthodontics, Faculty of
Medicine, Aligarh Muslim University,
Aligarh, India
Abstract
Nevi are common skin tumors caused by
abnormal overgrowth of cells from the epider-
mal and dermal layers of the skin. Most nevi
are benign, but some pre-cancerous nevi must
be monitored or removed. The giant congenital
nevus is greater than 10 cm in size, pigmented
and often hairy. Between 4% and 6% of these
lesions will develop into a malignant
melanoma. Since approximately 50% of the
melanoma develop by the age of two, and 80%
by the age of seven, early removal is recom-
mended. The objective of this paper is to pres-
ent a unique case of giant nevi and their sur-
gical management.
Introduction
The word Nevus derives from the Latin word
Knee-vus meaning birthmark or mole. The
nevus is defined as a congenital, developmen-
tal tumor-like malformation of the skin or
mucous membrane.1 Acquired nevi are
extremely common. They appear at about the
eight month of life and increase in number
with age.
Classification of nevus:
1. congenital
a. small
b. giant
2. acquired
a. intra dermal nevus (common mole)
b. junctional nevus
c. compound nevus
d. spindle cell nevus
e. epetheloid cell nevus
f. blue nevus (Jadassohn-Tieche)2
Familial tendencies exist and approximately
1 in 20,000 new born is found to have a large
congenital nevus.3 Melanocytes (pigment pro-
ducing skin cells) are found in utero at about
40 days gestation and it is thought that con-
genital nevi develop between the 2nd and 6th
month of gestation. It develops from neuro
ectodermal cell between the intra uterine life
of the 8th to 24th week of pregnancy. Body pro-
tein HGE/SF (hepatocyte growth factor/scatter
factor) seems to be responsible for encourag-
ing these neuroectodermal cells to develop,
migrate and scatter. In those of us with a
nevus, it seems that we have too much or the
wrong type of this body protein HGE/SF in
some cells, so we develop extra pigment and
abnormal skin cells called nevus cells.
Congenital nevi are generally seen in 1 in
every 20,000 children, whereas the giant vari-
ety involving much of the body surface area are
less common, possibly around one in every
200,000. While congenital nevi are typically
larger than the common acquired nevi, they
cannot always be distinguished by size alone.
They are often round or oval, clearly demarcat-
ed and some times slightly intact.
Pigmentation is usually even, although some
congenital nevi have a speckled appearance.
Coarse dark hair may be present. The conge-
nital nevi occur in 1-1.25% of neonates and
with the passage time, may change from flat,
pale, tan macules to elevated verrucous hairy
lesions. The head and neck area involve
approximately 15% of all nevus. Intraoral
occurrence is extremely rare. In cases of
acquired nevus, junctional nevus develops at
the age of two years, progressing to a com-
pound nevus through the teenage years, and
then to a dermal nevus in adulthood. Conge-
nital nevi are significant because of their
much higher incidence of melanoma transfor-
mation. A Bathing Trunk nevus is a darkly pig-
mented, disfiguring, often hairy patch of skin
present at birth, which may cover an extreme-
ly large area of the body. Some times the nevus
covers most of the trunk, the upper arm and
thigh. Bathing trunk nevi are thought to be
caused by spontaneous mutations or other
events during fetal development, but in some
families, the frequent appearance of these
lesions suggest that they may be genetically
inherited. They may be associated with other
birth defects.8 The distinction between con-
genital nevi and other forms of acquired nevi
can usually be made on clinical examination.
Any nevus larger than 1.5 cm is likely to be
congenital. The congenital nevi are rare; they
are often darkly pigmented and may be hairy
and papillary in appearance. Occasionally they
cover an extensive area of skin, up to 25% or
more of the body surface. They may undergo
malignant change even during childhood. The
life-time risk for malignant degeneration in a
large congenital nevus is approximately 6%.5,6
In these cases melanoma can arise in the first
few years of life and excision should be consid-
ered as soon as possible. No specific investiga-
tion is required for small nevi. People with
[Rare Tumors 2009; 1:e9]
Rare Tumors 2009; volume 1:e9
Correspondence: Ghulam S. Hashmi,
Dept. of Oral & Maxillofacial Surgery,
Faculty of Medicine, Aligarh Muslim University,
Aligarh-202002, India
E-mail: sarwarhashmi@rediffmail.com
Key words: nevus, melanoma, giant, congenital.
Received for publication: 23 June 2009.
Accepted for publication: 29 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright G.S. Hashmi, et al., 2009
Rare Tumors 2009; 1:e9
doi:10.4081/rt.2009.e9
nevus presenting neurological symptoms, like
worsening headache and vomiting, need to
have an MRI of the brain.4,7 Those with
seizures also need to have repeated MRI per-
formed periodically. The risk of malignant
change in giant nevi is probably the most con-
tentious issue in its management. The consen-
sus is that lesions are pre-malignant, but the
purported incidence of malignancy varies wild-
ly from 0-42%. Surgical excision remains the
mainstay of treatment for large congenital
melanocytic nevi, and most giant nevi are
managed by staged excision and resurfacing
with skin grafts or tissue expanders and flaps.
For facial nevi, laser treatment is one of the
best known options available for the removal of
giant nevi.9
Histologically, nevi are transformed
melanocytes, which are normally highly den-
dritic cells interspersed among basal ker-
atinocytes. The genetic basis of these lesions
is not known. Findings of a culture of
melanocytes from such a lesion showed chro-
mosome rearrangements involving 1p,12q, and
19p. The giant nevi might be associated to sev-
eral diseases: neurocutaneous melanosis, dif-
fuse lipomatosis, structural brain malforma-
tions, hypertrophy of skull bones, limb atrophy,
skeletal asymmetry involving both soft tissues
hyper-and hypoplasia, von Recklinghausen's
disease and vitiligo.
Case Report
A 5-year old female presented with multiple
dark black colored, wart like patches, on her
face, neck, shoulder, leg and entire back. No
other abnormality was found on physical
examination. Family history failed to show any
other individuals with a similar lesion (Figure
1). The concern of the present problem of the
patient was only esthetic. On examination
extra orally, there were 5-6 small to medium
[page 23]
Case Report
Figure 1. Pre-operative photograph of the
patient on OT table.
Figure 2. Intra-operative photograph of
the same patient.
Figure 3. Resected specimen of the same
patient.
sized black discolored patches with coarse hair
grown over it present on the right side of the
face, neck, shoulder, both the legs and the
entire back indicating Bathing Trunk nevus.
There was no history of pain, itching or dis-
comfort. The patient lives a normal life and the
only concern was the esthetic problem of the
[page 24]
Figure 4. Post-operative photograph of the
same patient on OT table.
Figure 5. Post-operative photograph of the
same patient.
Figure 6. (40x) Histopathological examina-
tion shows nevi cells are separated with
connective tissue layer.
facial nevi. Routine blood examination and X-
ray chest were in the normal range. Surgical
excision of all the facial nevi was planned and
it was excised under G.A. using Propofol.
(Figures 2-4) Primary closure was performed
using 6-0 prolene. Since all the nevi are small
in size, no reconstruction is required (Figure
[Rare Tumors 2009; 1:e9]
5). An antibiotic was advised. Cefadroxil syrup
was indicated 1tsf B. D. for 7 days.
Histopathological examination revealed large
discrete cells, each with an ovoid, vesicular
nucleus and pale cytoplasm. The nevus cells
are situated within the connective tissue and
are separated from the overlying epithelium by
a well defined band of connective tissue.
(Figures 3-6).
Discussion
Congenital nevi are generally seen in 1 in
every 20,000 children whereas giant congeni-
tal varieties involving much of the body sur-
face area are less common, possibly around 1
in 200,000. They can vary in size from being
less than 1/4 inch to covering almost the
entirebody. The cause of congenital moles
may have recently been discovered. Abnormal
HGF/SF (hepatocyte growth factor/scatter fac-
tor) seems to develop in certain body cells
accidentally, called spontaneous autosomal
dominant genetic mutations. These muta-
tions are not hereditary. Congenital moles will
hardly ever disappear on their own. However,
they are important because they can some-
times lead to a potentially deadly skin cancer
called malignant melanoma. Malignant
changes of giant nevus can occur at any age
but most often occur in infants or toddlers.
Pregnancy increases the production of
melanin in the body. Most dermatologists rec-
ommend avoiding excess sun by wearing
broad-brimmed hats, sunglasses, long-sleeved
shirts, long pants or skirts, gloves and espe-
cially avoiding sunburn by staying in the
shade, but not all are true. There are cases of
melanoma occurring in a mole locating in the
arm pit, which is a part of body that receives
virtually no sun exposure whatsoever.
Complete excision should include removal of
each and every cell of melanoma. Since it is
actually impossible to totally remove every last
single cell of the nevus, the extensive surger-
ies required to nearly totally remove a nevus
can cause other severe, sometimes nearly
fatal, complications. Literature says people
with nevus in our group die of cancer after
their giant nevus had been totally removed.
Other literature says that we have had mem-
bers who underwent numerous surgeries to
successfully remove the entire external giant
skin nevus only to die later of brain or spinal
cord melanoma. Now the cultured skin auto-
graft are sometimes used as a reconstruction
of the large excised melanoma. There are a
number of treatment options available, but
they are not ideal and also have some disad-
vantages e.g. integra, dermabrasion, laser,
chemical peels, tissue expanders and so on.

References
1. Chunj C, Forte AJ, Narayan D, et al.
A review. J Craniofac Surg 2006:1210-15.
2. Gosain AK, Santoro TD, Larson DL, et al.
Congenital Nevi: a 20 – year experience
and an algorithm for their management.
Plast Reconstr Surg 2001;108:622-36.
3. McWhorter HE, Woolner LB. Pigmented
Nevi, Juvenile Melanoma and Malignant
melanoma in children. Cancer 2006;7:564-
85.
4. Zemtsov A, Lorig R, Bergfeld W, et al.
Magnetic resonance imaging of cutaneous
melanocytic lesions. J Dermatol Surg
Oncol 1989;15:854-8.
5. Shaw M. Malignant melanoma arising
from a giant hairy naevus. Br J Plast Surg
1962;15:426-31.
6. Lorentzen M, Pers M, Brettville-Jensen G.
[Rare Tumors 2009; 1:e9]
Case Report
The incidence of malignant transforma-
tion in giant pigmented nevi. Scand J Plast
Reconstr Surg 1977;11:163-711.
7. Frieden I, Williams M, Barkovich A. Giant
congenital melanocytic nevi: Brain mag-
netic resonance findings in neurologically
asymptomatic children. J Am Acad Derma-
tol 1994;31:423-9.
8. Conway H. Bathing trunk nevus. Surgery
1939;6:585.
[page 25]
Rare Tumors 2009; volume 1:e10
Intramedullary capillary
hemangioma of the thoracic
spine: case report and review
of the literature
Rahul Kasukurthi,1 Wilson Z. Ray,2
Spiros L. Blackburn,2 Eriks A. Lusis,2
Paul Santiago2
1
Division of Plastic and Reconstructive
Surgery, Washington University School of
Medicine, Saint Louis, MO, USA;
2
Department of Neurosurgery,
Washington University School of
Medicine, Saint Louis, MO, USA
Abstract
Capillary hemangiomas are benign vascular
neoplasms. When associated with the spine,
these growths frequently involve the vertebral
body, but rarely have they been reported to
occur as intradural lesions, while even more
rarely occurring in a true intramedullary loca-
tion. We report a rare case of an intrame-
dullary capillary hemangioma of the thoracic
spinal cord and a review of the literature.
Introduction
Capillary hemangiomas are benign vascular
neoplasms typically encountered in the skin.
They occur most frequently in childhood as
cutaneous or subcutaneous lesions character-
ized histologically by nodules of capillary-sized
vessels lined by flattened endothelium.1 As the
most common primary tumor of the spine, cap-
illary hemangiomas are frequently encoun-
tered as interosseous lesions. The occurrence
of these tumors in the central nervous system,
however, is exceedingly rare and they are even
less frequently encountered as intramedullary
lesions.2 Despite the high prevalence of verte-
bral body hemangiomas, extraosseous exten-
sion causing neurological impingement
remains uncommon.
In the present case, we report an intra-
medullary capillary hemangioma of the tho-
racic spinal cord, an exceedingly rare presen-
tation with few previously reported cases exist-
ing in the literature.2-6
Case Report
The patient is a 47-year old right-handed
man with several months of non-specific mid-
back pain, lower extremity hyperesthesia, and
[page 26]
a more recent two week history of gait difficul-
ties. His past medical history is significant for
a prior left-sided intracerebral hemorrhage
with consequent hemiparesis three years ago.
The patient’s baseline deficits associated
with his prior left hemisphere stroke included
dysarthria, right facial weakness, and a dense
right hemiparesis. New deficits included 3-4/5
strength of the left lower extremity and a sen-
sory level just above the nipples consistent
with approximately a T3 spinal level. Reflexes
were 3+ in the bilateral lower extremities.
Babinski reflex was present bilaterally.
MRI of the thoracic spine both before and
after the administration of intravenous
Gadolinium demonstrated what initially
appeared to be a homogenously enhancing
intradural, extramedullary lesion displacing
the cord anteriorly with significant cord defor-
mation (Figure 1). Our differential diagnosis
included: nerve sheath tumor, meningioma,
and ependymoma.
The patient was offered an excisional biop-
sy of the lesion. T2 and T3 laminectomies were
performed, and the lesion location was con-
firmed using intra-operative ultrasound.
Intradural exploration revealed a highly vascu-
lar, partially encapsulated cherry-red lesion
that appeared to arise from the dorsal aspect of
the spinal cord. In contrast to MRI findings, the
tumor was found to be intramedullary in loca-
tion. Overlying the tumor was a region of
thickened arachnoid, but no demonstratable
dural attachment. Several involved nerve roots
were coagulated and divided. Further dissec-
tion revealed an extremely friable exophytic
tumor arising from the region of the dorsal
root entry zone of T3. Intra-operative frozen
section was consistent with a possible heman-
giopericytoma. Post-operative MRI showed no
evidence of residual tumor.
On histopathology, the tumor grossly con-
sisted of a partially circumscribed lesion with a
brownish-tan appearance. H&E staining
demonstrated a hypercellular, vascular neo-
plasm composed of cytologically bland spindled
cells with minimal cytoplasm. These cells were
arranged in vague lobules of short irregular
spindle cells and dilated vascular spaces.
Immunohistochemical findings are explained
in Figure 2. Further evaluation demonstrated
dilated, compressed vascular channels and
focal extramedullary hematopoiesis. In total,
the findings were consistent with capillary
hemangioma.
Post-operatively the patient had good func-
tional recovery. At three months follow-up the
patient had only minor residual lower extrem-
ity dysesthesia with return of baseline motor
function. The patient has remained stable 36
months post resection.
[Rare Tumors 2009; 1:e10]
Correspondence: Wilson Z. Ray,
Washington University School of Medicine,
660 S. Euclid Ave, Campus Box 8057,
St. Louis, MO 63110, USA
Key words: intramedullary capillary hemangioma,
dysembryogenesis.
Received for publication: 20 June 2009.
Accepted for publication: 29 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright R. Kasukurthi et al., 2009
Rare Tumors 2009; 1:e10
doi:10.4081/rt.2009.e10
Discussion
Capillary hemangiomas involving the spinal
cord are extremely rare, and are most fre-
quently extramedullary in location.1-3 We are
aware of only a handful of previously reported
cases of intramedullary spinal cord capillary
hemangiomas (Table 1). Notably, all but one
previously reported case involved the thoracic
spine or the conus.
MRI is the gold standard imaging modality
for intramedullary lesions.13-16 Many such
lesions can be safely removed with proper
imaging, surgical planning and technique. In
the case of intramedullary capillary heman-
giomas, however, on MRI the lesion can be
interpreted as extramedullary,5,8,10 and the orig-
inal differential diagnosis often fails to include
capillary hemangioma,2,8,11 as was the case with
our patient. As previously discussed by
Roncaroli et al. and Nowak et al., the treating
surgeon must be cognizant of intramedullary
capillary hemangiomas to avoid misdiagnosis
and potential excessive treatment.1,2 Although
extremely rare, capillary hemangiomas of the
spinal cord have a benign clinical course. Glial
based tumors, such as ependymomas and
astrocytomas, account for over 90% of
intramedullary tumors.17 The distinctive gross
appearance of capillary hemangiomas intra-
operatively often eliminates the more common
glial based lesions from the differential diag-
nosis. The remaining possibilities include
lesions ranging from: hemangiopericytoma,
hemangioblastoma, cavernous angioma, heman-
gioendothelioma, arteriovenous malforma-
tions, venous angiomas, and capillary telang-
iectasias. Fortunately, histopathological analy-
sis reliably distinguishes these lesions for
diagnosis.
Although related most closely to the catego-
ry of vascular malformations, capillary heman-
giomas that appear within the spinal cord
parenchyma may have their origins elsewhere.
 Case Report

Table 1. Cases of intramedullary capillary hemangiomas previously reported in English.2,4-12umor or/ Patient Imaging Tumor
Size/ Symptoms/ Treatment Outcome Recurrence
Author/ Patient Imaging Tumor size/ Symptoms/ Treatment Outcome Recurrence
year age/sex location deficits
Roncaroli 42 not size not reported; 1.5-year h/o abdominal surgery recovered none
2000 M reported T11 pain, leg weakness reported
50 not size not reported; 1-year h/o LBP, proximal surgery little none
M reported T11 leg weakness bilaterally, + radiotherapy improvement reported
L-1 sensory level, loss of 2 years
patellar reflex post-op
53 not size not reported; 2 year h/o UMN, LMN surgery leg weakness none
M reported conus signs bilateral lower 1.5 years post-op reported
extremities
64 not size not reported; 2 year h/o bilateral leg pain, surgery recovered none
M reported T10 leg weakness reported
Ianelli 3 months, CT: dilated size not reported; Abnormal head surgery neurologically intact none
2005 M ventricles. T 4-7 circumference; wide, full, 1 year post-op; reported
MRI: T4-7 tense anterior fontanel no focal deficits
intramedullary with diastatic sutures.
enhancing lesion Mild irritability, lethargy
apparent. No other
neurological signs
Kelleher 57 MRI: T9 & T10 2.4x1.0x0.5 cm; 7-months h/o thoracic pain; dexamethasone spastic gait none
2005 M extramedullary T9-T10 2-week h/o bilateral lower and surgery 3 months post-op reported
enhancing lesion limb weakness,
decreased lower limb DTRs
Mawk 1 month, CT: discoid mass in size not apraxia of legs, surgery rapid recovery none
1987 not stated R buttock. reported; conus hemangiomatous reported
Myelography: malformation
vascular cord lesion involving the skin and
with complete soft tissue of the buttock
myelographic block
at L1-2
Andaluz 41 MRI: intradural, 2x1 cm, 3 month h/o surgery recovered none
2002 M extramedullary conus medullaris LBP radiating to thighs. reported
enhancing mass Decreased L flexor strength
(4+/5), bilateral patellar and
Achilles areflexia
Nowak 63 MRI: intradural maximum diameter 3 year h/o intermittent surgery residual paresis none
2000 F extramedullary 1.0 cm; T12-L1 Lasègue’s sign; hypesthesia of L tibialis anterior, reported
enhancing mass and activity related 14 months post-op
lumbosciatalgia L thigh
Abe 65 not size not 2 month h/o lower limb surgery little improvement none
2004 M reported reported; T5 weakness, paraparesis 7 years post-op reported
Roncaroli 74 MRI: enhancing lower thoracic 9-month h/o bilateral surgery no changes 1 year no new
2000 M nodules on cauda cord, conus, cauda leg weakness post-op hemangiomas
equina, lower
thoracic spinal cord,
conus medullaris
Shin 66 MRI: intradural 1.3x2 cm; T8-T9 8-month h/o surgery recovered no new
2000 F mass at T8-T9; LBP, weakness of the lower hemangiomas
intramedullary and limbs, paraparesis,
extramedullary components sensory abnormality
Hida 50 MRI: Mass not reported; tetraparesis, upper surgery recovered not
1993 M from C3-T1 C3-T1 extremities hyporeflexia, to baseline reported
lower extremities flexion
spasm, decreased pain/tactile
sensation below C3, bladder/
bowel dysfunction
Although several patients had imaging studies suggesting “extramedullary” lesions, they were ultimately found to have intramedullary capillary hemangiomas.
h/o = history of; UMN = upper motor neuron; LMN = lower motor neuron; LBP = lower back pain; DTR = deep tendon reflexes; R = right; L = left.

[Rare Tumors 2009; 1:e10] [page 27]

Case Report
A
B 1993;33:1099-101.
Figure 1. (A) Sagittal T1-weighted MR
image with Gadolinium revealing a homo-
geneously hyperintense mass involving the
upper thoracic spine. (B) Axial T1-weight-
ed MR image with Gadolinium demon-
strating a centrally located lesion.
Similar to intramedullary lipomas (which
account for 1% of intramedullary lesions), cap-
illary hemangiomas of the spinal cord may rep-
resent a form of dysembryogenesis. Rather
than being a true neoplasm, these lesions
more likely arise from inclusion of mesenchy-
mal tissue into the neural tube during primary
neurulation.18-20 The available literature clearly
demonstrates the benign nature of
intramedullary capillary hemangiomas, and
gross total resection appears to be curative
with good outcomes and no reported recur-
rences (Table 1). Given the rarity of this
lesion, its benign course and straightforward
therapy, surgeon familiarity is important to
ensure patients receive appropriate diagnosis
and treatment.
[page 28]
A Trembath EJ. Metameric capillary heman-
7.
8.
B 9.
10.
11.
Figure 2. (A) Photomicrograph of H&E
stain shows a hypervascular tumor com-
posed of thin and irregular capillary ves- 12.
sels and minimal cytoplasm. Magni-
fication X 200. (B) Immunohisto-chemi-
cal staining revealed the tumor cells to be
strongly and diffusely immunoreactive for
CD31, CD34, and CD99. Scattered S-100 13.
protein and BCL-2 positive cells were
present. Epithelial membrane antigen
(EMA) and inhibin stains were negative
and MIB-1 labeling was brisk, but with
rare mitoses. Magnification X 200.
14.
References 15.
1. Nowak DA, Widenka DC. Spinal intradural
capillary haemangioma: a review. Eur
16.
Spine J 2001;10:464-72.
2. Roncaroli F, Scheithauer BW, Krauss WE.
Capillary hemangioma of the spinal cord.
Report of four cases. J Neurosurg 2000;93:
17.
148-51.
3. Holtzman RN, Brisson PM, Pearl RE,
Gruber ML. Lobular capillary hemangioma
of the cauda equina. Case report. J
18.
Neurosurg 1999;90:239-41.
4. Iannelli A, Lupi G, Castagna M, et al.
Intramedullary capillary hemangioma
19.
associated with hydrocephalus in an
infant. J Neurosurg 2005;103:272-6.
5. Kelleher T, Aquilina K, Keohane C,
O'Sullivan MG. Intramedullary capillary
20.
haemangioma. Br J Neurosurg 2005;19:
345-8.
6. Mawk JR, Leibrock LG, McComb RD,
[Rare Tumors 2009; 1:e10]
gioma producing complete myelographic
block in an infant. Case report. J Neuro-
surg 1987;67:456-9.
Abe M, Tabuchi K, Tanaka S, et al.
Capillary hemangioma of the central nerv-
ous system. J Neurosurg 2004;101:73-81.
Andaluz N, Balko MG, Stanek J, et al.
Lobular capillary hemangioma of the
spinal cord: case report and review of the
literature. J Neurooncol 2002;56:261-4.
Hida K, Tada M, Iwasaki Y, Abe H.
Intramedullary disseminated capillary
hemangioma with localized spinal cord
swelling: case report. Neurosurgery
Nowak DA, Gumprecht H, Stolzle A,
Lumenta CB. Intraneural growth of a cap-
illary haemangioma of the cauda equina.
Acta Neurochir (Wien) 2000;142:463-7;
discussion 7-8.
Roncaroli F, Scheithauer BW, Deen HG.
Multiple hemangiomas (hemangiomato-
sis) of the cauda equina and spinal cord.
Case report. J Neurosurg 2000;92:229-32.
Shin JH, Lee HK, Jeon SR, Park SH. Spinal
intradural capillary hemangioma: MR find-
ings. AJNR Am J Neuroradiol 2000;21:954-
6.
Brotchi J, Dewitte O, Levivier M, et al. A
survey of 65 tumors within the spinal cord:
surgical results and the importance of pre-
operative magnetic resonance imaging.
Neurosurgery 1991;29:651-6.
Rothwell CI, Jaspan T, Worthington BS,
Holland IM. Gadolinium-enhanced mag-
netic resonance imaging of spinal
tumours. Br J Radiol 1989;62:1067-74.
Scotti G, Scialfa G, Colombo N, Landoni L.
Magnetic resonance diagnosis of intra-
medullary tumors of the spinal cord.
Neuroradiology 1987;29:130-5.
Goy AM, Pinto RS, Raghavendra BN, et al.
Intramedullary spinal cord tumors: MR
imaging, with emphasis on associated
cysts. Radiology 1986;161:381-6.
Miller DJ, McCutcheon IE. Hemangio-
blastomas and other uncommon
intramedullary tumors. J Neurooncol 2000;
47:253-70.
Muraszko K, Youkilis A. Intramedullary
spinal tumors of disordered embryogene-
sis. J Neurooncol 2000;47:271-81.
Tihan T, Chi JH, McCormick PC, et al.
Pathologic and epidemiologic findings of
intramedullary spinal cord tumors.
Neurosurg Clin N Am 2006;17:7-11.
Warf BC, Scott RM, Barnes PD, Hendren
WH. Tethered spinal cord in patients with
anorectal and urogenital malformations.
Pediatr Neurosurg 1993;19:25-30.

A case report of surgical
debulking for a huge mass of
elephantiasis neuromatosa
Manabu Hoshi, Makoto Ieguchi, Susumu
Taguchi, Shinya Yamasaki
Department of Orthopedic Surgery,
Osaka City University Graduate School of
Medicine, Japan
Abstract
Achievement of a safe outcome for an exten-
sive mass with hypervascularity in the extrem-
ities requires a surgical team skilled in muscu-
loskeletal oncology. We report debulking sur-
gery for a huge mass of elephantiasis neuro-
matosa in the right leg of a 56-year old man
using the novel Ligasure® vessel sealing sys-
tem.
Introduction
Patients with plexiform neurofibroma rarely
suffer from hypertrophy of the skin of the leg.
Plexiform neurofibroma may become very
large and deforming, and be referred to as ele-
phantiasis neuromatosa.1,2 Owing to the cos-
metically grotesque appearance and functional
loss and pain in the affected limb, surgical
treatment is usually considered. However,
hypervascular structures are usually involved
in this disease, and these can cause sponta-
neous hemorrhage and severe bleeding, espe-
cially during surgery. Removal of such huge
masses seems impossible without massive
bleeding. As a result, conservative treatment
without surgery is usually adopted in most
cases, and, even if surgery is selected, disartic-
ulation or amputation of the affected limb is
sometimes recommended to the patients.3-5 In
the present report, we describe surgical
debulking for a huge mass of elephantiasis
neuromatosa in the right leg of a 56-year old
man using the novel Ligasure® vessel sealing
system (Valleylab, Boulder, CO, USA), and dis-
cuss how to approach an extensive mass of ele-
phantiasis neuromatosa.
Case Report
A 56-year old man with a huge mass below
both buttocks that had gradually increased in
size over 35 years was referred to our hospital.
At 20 years of age, the mass in the buttock was
the size of a baseball. The patient had under-
gone a surgical operation ten years before his
referral, and had been diagnosed with von
Recklinghausen disease. This condition had
been present for many years, and the tumor
had continued to grow gradually. Spontaneous
subcutaneous hemorrhages frequently
occurred. At four years before his referral, a
plastic surgeon had attempted debulking sur-
gery at his previous hospital, but the operation
was not completed because of massive bleed-
ing, even with a small skin incision. During
the previous year, he had only been able to
walk short distances and remained in bed in
hospital. There was no particular familial his-
tory of neurofibromatosis. On examination at
his first visit, he had an extensive mass of neu-
rofibroma over his trunk, and café-au-lait spots
were scattered around the whole body. The
right leg below the buttock was markedly
enlarged, and he required great effort to go to
the toilet and could not stand up by himself.
Dilated superficial veins and multiple skin
ulcerations were present on the huge mass. In
view of the clinical appearance, plexiform neu-
rofibroma was easily considered as a diagno-
sis. Magnetic resonance imaging (MRI)
revealed an extensive mass that infiltrated the
fat, skeletal muscle and adjacent bone in the
lower leg. A T2-weighted sequence of MRI
demonstrated dilated twisting capillaries in
the high-intensity region of a superficial sub-
cutaneous lesion, appearing as a myxomatous
lesion, compatible with the histology of neu-
rofibroma. Contrast-enhanced angiographic
computed tomography (CT) demonstrated a
rich vascular supply to the extensive mass,
arising from both sides of the major external
and internal iliac arteries. Extensive capillary
pooling was also seen. After these imaging
studies, biopsies were attempted at several
spots to exclude the possibility of sarcomatous
change. The needle biopsy specimens con-
firmed the histology of the neurofibroma. At
that time, total tumor resection was judged to
be impossible, and debulking surgery was
planned piece by piece. During surgery, reduc-
tion of the mass was carried out using a novel
bipolar vessel sealing device, Ligasure®. The
resected surgical specimen was compatible
with the histology of neurofibroma and no
malignant changes were observed. Post-opera-
tively, most parts of the operation scar gradual-
ly healed. Re-suturing was necessary at only a
small part of the skin fold. At one year after the
debulking surgery, he could move by himself
and was extremly satisfied with the outcome.
Discussion
Neurofibromatosis is estimated to occur at
rates of 1 in 2,000-3,000 births and shows an
equal sex distribution. Von Recklinghausen
[Rare Tumors 2009; 1:e11]
Rare Tumors 2009; volume 1:e11
Correspondence: Manabu Hoshi,
Department of Orthopedic Surgery, Osaka City
University Graduate School of Medicine, Japan
E-mail: hoshi@med.osaka-cu.ac.jp
Received for publication: 24 June 2009.
Accepted for publication: 1 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright M. Hoshi et al., 2009
Rare Tumors 2009; 1:e11
doi:10.4081/rt.2009.e11
disease is an autosomal dominant trait and
represents a relatively common disorder char-
acterized by neuroectodermal and mesoder-
mal tissues. The typical characteristics
include von Recklinghausen disease of the
skin, café-au-lait spots and hamartoma of the
iris. Plexiform neurofibroma characteristical-
ly shows diffuse irregular infiltration into the
adjacent muscle and fat, and occasionally
becomes huge and acquires a grotesque clini-
cal appearance, referred to as elephantiasis
neuromatosa.1,2 Radiological modalities for
elephantiasis neuromatosa play important
roles in providing anatomical data if surgery is
planned. Among the radiological assessments,
CT and MRI can provide many useful advan-
tages for surgical planning.6,7 Elephantiasis
neuromatosa may involve hypervascularity
and most reported cases have exhibited mas-
sive spontaneous bleeding.3,7 In our case, a
previous surgical attempt to debulk this lesion
had resulted in massive blood loss and was not
completed. Pre-operative assessment of the
vascular supply to such a huge mass seemed
to be inevitable, considering the importance
of controlling intra-operative bleeding. The
use of MRI enabled us to non-invasively
assess the relationships of the lesions with
the major vessels, as well as the vascular sup-
ply and angiographic features of the lesions.
The contrast-enhanced angiographic CT con-
firmed the hypertrophic nature of the abnor-
mal tissues, as well as the large drainage ves-
sels and multiple tortuous collateral branches.
These modalities may assist not only in the
correct diagnosis but also in understanding of
the anatomy of the vasculature of elephantia-
sis neuromatosa. Plexiform neurofibromato-
sis is a poorly circumscribed unencapsulated
tumor, with diffusely infiltrating cutaneous
lesions. Cosmetic and functional problems
with the affected limb are the major concerns
for the patient and doctor, regarding the indi-
cations for surgery. Plexiform neurofibroma is
often hypervascular and can lead to severe
bleeding during surgery.8 Surgeons and
patients sometimes hesitate to undertake the
challenging surgery required for huge plexi-
[page 29]
Case Report
form neurofibromas because of the high risk.
Sometimes, amputation or disarticulation,
both of which are less invasive and not as
technically demanding, may be recommended
to the patients. For any surgical procedure, the
surgeons must try to minimize the risk of
intra-operative complications and to ensure
that the surgery proceeds as smoothly and rap-
idly as possible. The Ligasure® vessel sealing
system has been used in several fields of
abdominal, urological and gynecological sur-
geries, and many clinical studies have con-
firmed its efficiency and safety.9-11 However, lit-
tle information is available concerning the
clinical applications of this technology for
musculoskeletal oncology of the extremities.
This system is a hemostatic method that
offers consistent permanent autologous seal-
ing of vessels and tissue bundles up to 7 mm
in diameter. The system is composed of an
electrosurgical generator and a hand piece
with a ratcheted scissor mechanism. When
the sacrificed tissue is grasped and com-
pressed by the instrument, sealing is automat-
ically completed. After removal of the instru-
ment, the seal is visible as a translucent
[page 30]
Figure 1. (a,b) The patient
suffers from a huge mass of
elephantiasis neuromatosa in
the right leg. (c) A T2-weight-
ed MRI sequence reveals a
high-intensity myxomatous
mass and hypervascularity.
(d) Contrast-enhanced angio-
graphic CT shows a rich vas-
cular supply arising from
both sides of the major exter-
nal and internal iliac arteries.
(e) The histopathological
findings at biopsy confirm
neurofibroma.
Figure 2. (a) The Ligasure®
vessel sealing device. (b)
Resected surgical specimens
of the elephantiasis neuro-
matosa. (c) Gross findings of
the right leg after surgery.
sealed zone, which can be safely divided.12
Sealing is accomplished with minimal char-
ring, and the delivery of thermal energy is lim-
ited to the adjacent tissues of up to 0.5-2 mm.
No foreign items are left within the body, such
as clipping wire and ligatures, which can act
as possible sources of infection and/or allergy.
The Ligasure® system seems to be safe
because control of these aspects is not
dependent on the experience of the operators.
This system is expected to reduce the risks of
intra-operative and post-operative complica-
tions compared with traditional procedures in
the musculoskeletal system.
Conclusions
The Ligasure® system is a novel device for
surgical debulking of extensive hypervascular
masses in the musculoskeletal field, such as
this case with elephantiasis neuromatosa,
because of the lack of technical demands and
the associated reductions in blood loss and
operating time.
[Rare Tumors 2009; 1:e11]
References
1 Moore BH. Some orthopedic relationships
of neurofibromatosis. J Bone Joint Surg
1941;23A:109-40.
2. Westcott RJ, Ackerman LV. Elephantiasis
neuromatosa. Arch Dermatol Syphilol
1941;55:233-41.
3. Stevens KJ, Ludman CN, Sully L, et al.
Magnetic resonance imaging of elephanti-
asis neuromatosa. Skeletal Radiol 1998;27:
696-701.
4. Martínez-García S, Vera-Casaño A, Eloy-
García Carrasco C, et al. Elephantiasis
neuromatosa in a patient with neurofibro-
matosis type 1. J Eur Acad Dermatol
Venereol 2008;22:103-5.
5. Birch PD, Davies AM. The value of comput-
ed tomography in elephantiasis neuro-
matosa. Br J Radiol 1988;61:76-8.
6. Hertzanu Y, Hirsch M, Peiser J, et al.
Computed tomography of elephantiasis
neuromatosa. J Comput Assist Tomogr
1989;13:156-8.
7. Hourani R, Rizk T, Kung S, et al. Ele-
phantiasis neuromatosa in neurofibro-
matosis type I. MRI findings with review of
the literature. J Neuroradiol 2006;33:62-6.
8. Kuo LA, Kuo RS. Plexiform neurofibro-
matosis: a difficult surgical problem. Aust
N Z J Surg 1990;60:732-5.
9. Slakey DP. Laparoscopic liver resection
using a bipolar vessel-sealing device:
LigaSure®. HPB (Oxford) 2008;10:253-5.
10. Lee WJ, Chen TC, Lai IR, et al. Randomized
clinical trial of Ligasure versus conven-
tional surgery for extended gastric cancer
resection. Br J Surg 2003;90:1493-6.
11. Jayne DG, Botterill I, Ambrose NS, et al.
Randomized clinical trial of Ligasure ver-
sus conventional diathermy for day-case
haemorrhoidectomy. Br J Surg 2002;89:
428-32.
12. Cipolla C. Ligasure in total thyroidectomy.
Surg Today 2008;38:495-8.

Value of centrifugated
liquid-based cytology
by Papanicolaou and
May-Grünwald in oral
epithelial cells
Hussain Gadelkarim Ahmed,1
Ali Mahmmoud Edris,1
Eneel Ahmed Mohmed,2
Mohammed Omer M. Hussein3
1
Department of Histopathology and
Cytology, Faculty of Medical Laboratory
Sciences, Khartoum, Sudan;
2 over conventional exfoliative cytology. Studies
Faculty of Dentistry, University of
Khartoum, Sudan;
3
Sudanese Cancer Society, Khartoum,
Sudan
Abstract
For many years, liquid-based cytology
(LBC) has been developed for cervical cancer
screening and not oral cancer, as it requires
automated devices. The aim of this study was
to compare the utility of centrifugated CLBC
preparation with that of direct preparation in
oral lesions, by Papanicolaou (Pap) and May
Grünwald-Giemsa's (MGG) methods. A total
of 100 consecutive cases of oral lesions were
investigated. We compared the results
obtained by the CLBC performed by cytocen-
trifugation with those obtained by direct
smear applying Pap and MGG methods. The
comparison between CLBC and direct smears
was based on the thickening or adequacy of
the smear, distribution of cells and staining
quality. All smears in CLBC and direct prepa-
ration were found adequate. For thickness of
the smear, 40% and 42% were excellent, 33%
and 30% were good, and 27% and 28% were
acceptable by LBC and direct preparation,
respectively. For the distribution of cells and
scantiness of background elements, 92
(92%) smears of the CLBC have revealed
clear, well distributed smears, compared to
70 (70%) of those in direct preparation. For
the staining quality with the Pap method,
39% and 69% were excellent staining quality,
25% and 20% were good, and 36% and 11%
were acceptable for CLBC and direct prepara-
tion, respectively. In MGG method, 9% and
22% were excellent staining quality, 23% and
36% were good and 68% and 43% were
acceptable for CLBC and direct preparation
respectively. CLBC performed by cytocen-
trifugation is inexpensive, and reduces inad-
equate smears and background staining.
Introduction
Oral Exfoliative Cytology (OXC) is a cost
effective and perhaps the best procedure for
the initial evaluation and diagnosis of oral
lesions.1 It is simple, safe and reliable, espe-
cially in population-based screening programs,
where repeated samples might be required.2
Early detection of a pre-malignant or cancer-
ous oral lesion can improve the survival and
the morbidity of patients suffering from these
conditions.3
Liquid-based cytology, since its inception in
the 1990s, has shown significant advantages
in cervical cytology have shown that the LBC
reduces the problems related to sampling and
preparation of better smears and reduction in
false-negative rates.4-6 Although conventional
cytology is useful when diagnosing oral PML
(better sensitivity and predictive positive value
if compared with the cervical smear test with
similar specificity), LBC gives better results,
as it is not only enhances both sensitivity and
specificity, but also provides material for fur-
ther investigation (AgNORs, DNA, immunohis-
tochemistry, etc.).7,8 LBC using a filtration
process and computer assisted thin layer depo-
sition of cells has been developed as a replace-
ment for cytocentrifugation and/or smearing,
owing to its improved cell recovery capabilities
and better cell preservation. In most published
series, LBC allows a good interobserver repro-
ducibility.9 However, LBC requires expensive
automated devices and materials, which might
not be affordable for many cytopathology labo-
ratories in countries with poor resources.
Thus, in this study we evaluated the efficiency
of the inexpensive CLBC method relying on
cytocentrifugation.
Materials and Methods
In this descriptive comparative study, a
total of 100 consecutive cases of oral lesions
were investigated. Cytological materials were
obtained by scraping the surface of the lesion.
The obtained materials were used for prepara-
tion of two direct smears and the remaining
materials were immersed in washing solution
for CLBC. One of the direct smears was imme-
diately fixed in 95% ethyl alcohol, while it was
wet (for subsequent Pap Stain), and the other
was air dried then fixed in methanol (for sub-
sequent MGG stain). The scraped materials
for CLBC were flushed out in suspending
solution (suspending medium composed of
20 mL of 95% ethanol + 6 mL of glacial acetic
acid +74 mL normal saline (Merck,
Darmstadt, Germany); for ten min, and then
spun in cytospin for 10 min at 3000 rpm. The
[Rare Tumors 2009; 1:e12]
Rare Tumors 2009; volume 1:12
Correspondence: Hussain Gadelkarim Ahmed,
University of University of Khartoum, 102,
Faculty of Medical Laboratory Sciences,
Khartoum, Sudan
E-mail: juhina2005@gmail.com
Key words: liquid-based, cytology, oral cells.
Acknowledgments: we would like to thank the
members of the Department of Oral Surgery at
the Dental Teaching Hospital for their coopera-
tion and assistance. We are very grateful to the
people at the Department of Histopathology and
Cytology, Faculty of Medical Laboratory Sciences,
University of Khartoum for their technical help
and assistance.
Contribution: HGA, assessment of the results,
statistical analysis, preparation of the manu-
script; AME, smears staining and solution prepa-
rations; EAM, specimens collection and revision
of the manuscript; MOMH, involved in manu-
script writing, references editing and data entry
for analysis.
Conflict of interest: the authors have no connec-
tion with any company and the work was support-
ed by the University of Khartoum.
Received for publication: 29 June 2009.
Accepted for publication: 30 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright H.G. Ahmed et al., 2009
Rare Tumors 2009; 1:e12
doi:10.4081/rt.2009.e12
formed supernatant was poured off and
replaced by acid alcohol for 30 min. Then the
supernatant was discarded leaving only a few
drops which were shook vigorously with acid
alcohol. Thereafter, a drop of coating medium
(glycerin/albumin) was added. Then two
smears (wet fixed and air dried) were made
from each specimen on moist, clean glass
slides. The slide was tilted and with a Pasteur
pipette, pellet was taken and replaced at the
upper end of the slides, left to drain, and then
left to dry overnight.
Direct preparation and CLBC smears were
stained using staining methods (Pap and
MGG). For the smears which were stained
using the Papanicolaou method, ethyl alcohol
fixed smears were hydrated in descending
concentrations of 95% alcohol through 70%
alcohol to distilled water for 2 min in each
stage. Then smears were treated with Harris'
Haematoxylin for 5 min, to stain the nuclei,
rinsed in distilled water and differentiated in
0.5% aqueous hydrochloric acid for a few sec-
onds to remove the excess stain. They were
then were immediately rinsed in distilled
water to stop the action of discoloration. Then
[page 31]
Article
the smears were blued in alkaline water for a
few seconds and dehydrated in ascending
alcoholic concentrations from 70% through
two changes of 95% alcohol for 2 min for each
change. The smears were next treated with
eosin Azure 50 for 4 min. For cytoplasmic
staining they were treated with Papanicolaou
Orange G6 for 2 min, rinsed in 95% alcohol
and then the smears were dehydrated in
absolute alcohol. The smears were then
cleared in Xylene and mounted in DPX
(Distrene polystyrene Xylene) mount. All
reagents used were from Thermo Electron
Corporation, UK.
For the smears which were stained using
the MGG method, the air dried methanol fixed
smears were transferred to a staining jar con-
taining May Giemsa stain freshly diluted with
an equal volume of buffered water for 15 min,
then transferred without washing to a jar con-
taining Giemsa stain freshly diluted with nine
volume of buffered water for 10 min. The
smears were then washed rapidly in three
changes of water and examined.
Assessment of cytological smears
for staining quality
The smears were assessed and evaluated by
an experienced cytotechnologist. For compara-
tive analysis of both techniques, parameters
such as thickness, cellular distribution, leuko-
cytes and red blood cells were evaluated, adopt-
ing criteria reported elsewhere.10,11 Also, given
that a good staining method must show the
shapes and sizes of the cell, provide crisp
delineation of nuclear chromatin, and demon-
strate the cytoplasm, each slide was given a
mark out of ten and graded as follows: (i) 10-8
excellent; (ii) 7-5 good; (iii) 5 acceptable. All
parameters were compared to standard param-
eters illustrated elsewhere,12 and the degrees
were given.
We compared the results obtained by the
centrifugated liquid-based cytology (CLBC)
diagnoses performed by cytocentrifugation
with those obtained by direct smear applying
Pap and MGG methods. The comparison
between CLBC and direct smear was based on
the thickening or adequacy of the smear, dis-
tribution of cells and staining quality.
Results
As the comparison between CLBC and
direct smears was based on the thickening or
adequacy of the smear, distribution of cells,
and scantiness of background elements and
staining quality, all smears in CLBC and direct
preparation were found adequate, though few
5 (5%) of direct preparation showed a reduced
amount of cells. With regard to the thickening
[page 32]
of the smear, 40% and 42% were excellent
thickness, 33% and 30 were good, and 27% and
28% were acceptable by CLBC and direct
preparation, respectively. For the distribution
of cells and scantiness of background ele-
ments, 92 (92%) smears of the CLBC have
revealed clear, well distributed smears, com-
pared to 70 (70%) of those in direct. However,
8 (8%) and 30 (30%) of the CLBC and direct
smears, respectively, have shown a disorgan-
ized pattern.
When comparing the staining quality
between the CLBC and direct smears, with the
Pap method 39% and 69% were excellent
staining quality, 25% and 20% were good, and
36% and 11% were acceptable for direct prepa-
ration and CLBC, respectively. With the MGG
method, 9% and 22% were excellent staining
quality, 23% and 36% were good, and 68% and
43% were acceptable for direct preparation
and CLBC, respectively. When comparing the
staining quality between Pap and MGG in
direct preparation, 39% and 9% were excellent
staining quality, 25% and 23% were good, and
36% and 68% were acceptable by Pap and
MGG, respectively. When comparing the stain-
ing quality between Pap and MGG in CLBC,
69% and 22% were excellent staining quality,
20% and 36% were good, and 11% and 43%
were acceptable by Pap and MGG in this order,
as shown in Table 1.
Discussion
Oral cancer (OC) mortality is very high in
the Sudan, particularly among men due to the
habit of Toombak use [Tobacco Specific
Nitrose amine (TSN) rich tobacco].13 Toombak
dippers develop a clinically and histologically
characteristic lesion at the site of dipping. The
risk for cancer of the oral cavity among
Toombak users is high (RR 7.3-73.0-fold)14
Therefore, there is an urgent need for imple-
mentation of simple and cost-effective meth-
ods to screen the population at risk.
Oral exfoliative cytology is a non-aggressive
procedure that is well accepted by the patient,
and is, therefore, a suitable choice for the
early diagnosis of oral cancer, including
epithelial atypia and squamous cell carcino-
ma.15 In recent years, LBC has acquired a wide
range of acceptance in non-cervical cytology
specimens,16 including oral cytology.17 This
method is convenient in interpreting the
results since it yields optimal cellularity for
evaluation, and studies have shown similar or
even better diagnostic accuracy as compared
to the direct smear method.10,18 In this study, 92
(92%) of the smears of the CLBC have
revealed clear, well distributed smears, com-
pared to 70 (70%) of those in direct prepara-
[Rare Tumors 2009; 1:e12]
Table 1. Showing the comparison between
direct preparation and LBC using Pap and
MGG methods.mor or/ Patient Direct
39 (39%) 9 (9%)
Direct
Excellent 39 (39%) 9 (9%)
Good 25 (25%) 23 (23%)
Fair 36 (36%) 68 (68%)
CLBC
Excellent 69 (69%) 22 (22%)
Good 20 (20%) 36 (36%)
Fair 11 (11%) 43 (43%)
tion. CLBC showed thin uniform distribution
of cells, in addition to clear background due to
reduction in both cell overlapping and the
presence of artifacts. The cells also appeared
well preserved in their morphology and this
might be due to obtaining sufficient fixation
and the release of artifacts by washing. In
regard to the thickening of the smear, both
techniques achieved similar appearance, and
we think that thickening of the smear depends
to some extent on the skilful preparation of
the smear. However, some studies reported
that the scantiness of background staining
obtained in LBC enhances sensitivity and
quality.19 Not surprisingly studies of the accu-
racy of liquid-based monolayer cytology report
sensitivity of 61% to 66% and specificity of
82-91%.20,21 Furthermore, comparable results
between LBC and direct preparation have
been reported.22
When comparing the staining quality
(using Pap and MGG stains) between the LBC
and direct smears, CLBC preparation has
shown superior staining quality compared to
that of direct preparation. Cellular details in
CLBC were more clearly seen than in direct
preparation, and such findings were previous-
ly reported applying automated LBC.23
However, some studies have found no signifi-
cant difference between LBC and convention-
al cytology.11 However, many studies have
reported the reliability of Pap stain compared
to other cytological stains by the means of dif-
ferentiating and identifying cellular details.24,25
When comparing the staining quality
between Pap and MGG in CLBC and in direct
preparation, Pap stain revealed better staining
quality. A study by James et al.26 found an
agreement between Pap and MGG stain analy-
ses with regard to specimen adequacy.
Both, the liquid-based preparation and con-
ventional smear are diagnostically reliable;
the liquid-based method showed an overall
improvement on sample preservation, speci-
men adequacy, visualization of cell morpholo-
gy and reproducibility.

References
1. Ahmed HG, Idris AM, Ibrahim SO. Study of
oral epithelial atypia among Sudanese
tobacco users by exfoliative cytology.
Anticancer Res 2003;23:1943-9.
2. Jullien JA, Downer MC, Speight PM,
Zakrzewska JM. Evaluation of health care
workers' accuracy in recognizing oral can-
cer and pre-cancer. Int Dent J 1996;46:334-
9.
3. Mehrotra R, Gupta A, Singh M, Ibrahim R.
Application of cytology and molecular biol-
ogy in diagnosing premalignant or malig-
nant oral lesions. Mol Cancer 2006;5:11.
4. Bishop JW BS, Colgan TH, Husain M, et al.
Multicenter masked evaluation of
AutoCyte Prep thin layers with matched
conventional smears-including initial
biopsy results. Acta Cytol 1998;42:189-97.
5. McGoogan E, Reith A. Would monolayers
provide more representative samples and
improved preparations for cervical screen-
ing? Overview and evaluation of systems
available. Acta Cytol 1996;40:107-19.
6. Howell LP, Davis RL, Belk TI, et al. The
AutoCyte preparation system for gyneco-
logic cytology. Acta Cytol 1998;42:171-7.
7. Navone R, Burlo P, Pich A, et al. The impact
of liquid-based oral cytology on the diagno-
sis of oral squamous dysplasia and carci-
noma. Cytopathology 2007;18:356-60.
8. Occhino JA, Smith KL, Dryfhout V, et al.
Finding of vaginitis on liquid-based papan-
icolaou test compared to wet mount and
DNA probe. Obstetrical & Gynecol Survey
2009;64:99-100.
9. Piaton E, Hutin K, Faynel J, et al. Cost effi-
ciency analysis of modern cytocentrifuga-
tion methods versus liquid based (Cytyc
Thinprep®) processing of urinary samples.
J Clin Pathol 2004;57: 1208-12.
10. Alves VA, Bibbo H, Shmitt FC, et al.
Comparison of manual and automated
methods of liquid-based cytology: morpho-
logical study. Acta Cytol 2004; 48:187-93.
11. Hayama FH, Motta AC, Silva Ade P, Migliari
DA. Liquid-based preparation versus con-
ventional cytology: specimen adequacy
and diagnostic agreement in oral lesion.
Med Oral Patol Oral Cir Bucal 2005; 10:
115-220.
12. Krishnamurthy SC. Aspiration cytology for
clinicians and pathologists. In 1st ed: Tata
memorial centre; 1991. p. 14-24.
13. Ahmed HG, Mahgoob RM. Impact of
Toombak dipping in the etiology of oral
cancer: Gender-exclusive hazard in the
Sudan. J Can Res Ther 2007;3:127-30.
14. Idris AM, Ibrahim SO, Vasstrand EN, et al.
The Swedish snus and the Sudanese
Toombak: Are they different? Oral Oncol
1998;34:558-66.
15. Mehrotra R, Gupta A, Singh M, Ibrahim R.
Application of cytology and molecular biol-
ogy in diagnosing premalignant or malig-
nant oral lesions. Mol Cancer 2006;5:11.
16. Rana DN, O'Donnell M, Malkin A, Griffin
M. A comparative study: conventional
preparation and ThinPrep 2000 in respira-
tory cytology. Cytopathology 2001;12:390-8.
17. Garbar C, Mascaux C, Fontaine V. Effic-
1iency of an inexpensive liquid-based
cytology performed by cytocentrifugations:
a comparative study using the histology as
reference standard. CytoJournal 2005;2:15.
18. Malle D, Valeri RM, Pazaitou-Panajiotou K,
et al. Use of a thin-layer technique in thy-
roid fine needle aspiration. Acta Cytol
2006;50:23-7.
19. Hayama FH, Motta AC, Silva Ade P, Migliari
DA. Liquid-based preparations versus con-
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diagnostic agreement in oral lesions. Med
Oral Patol Oral Cir Bucal 2005;10:115-22.
20. Coste J, Cochand-Priollet B, de Cremoux
P, et al. Cross sectional study of conven-
tional cervical smear, mono layer cytology,
and Human papilloma virus DNA testing
for cervical cancer screening. Br Med J
2003;326:733.
21. Kulasingan SI, Hughes JP, Kiviat NB, et al.
Evaluation of Human papilloma virus test-
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specificity, and frequency of referral. JAMA
2002;288:1749-57.
22. Kavatkar AN, Nagwanshi CA, Dabak SM.
Study of a manual method of liquid-based
cervical cytology. Indian J Pathol Microbiol
2008;51:190-4.
23. Fiel-Gan MD, Villami LCF, Mandavilli SR,
et al. Rapid Detection of HSV from cytolog-
ic specimens collected into ThinPrep fixa-
tive. Acta Cytol 1999;43:1034-8.
24. Kellogg JA, Seiple JW, Murray CL, Levisky
JS. Effects of the endocervical specimen
quality on detection of Chlamydia tra-
chomatis and on the incidence of false
positive results with the Chlamydiazyme
method. J Clin Microbiol 1990;28:1108-13.
25. Kellogg JA, Seiple JW, Klinedinst JL,
Levisky JS. Impact of endocervical speci-
men quality on apparent prevalence of
Chlamydia trachomatis infections diag-
nosed using an enzyme-linked immuno-
sorbent assay method. Arch Pathol Lab
Med 1991;115:1223-7.
26. James AK, John WS, Janet LK, Erica S. Diff-
Quick Stain as a simplified alternative to
Papanicolaou stain for determination of
quality of endocervical specimens submit-
ted for PCR detection of Chlamydia tra-
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[page 33]
Rare Tumors 2009; volume 1:e13
Retroperitoneal lipoma arising
from the urinary bladder
Shingo Ukita,1 Masafumi Koshiyama,1
Megumi Ohnaka,1 Naoyuki Miyagawa,1
Yukio Yamanishi,1 Fumitomo Nishimura,1
Michikazu Nagura,1 Tomoko Kim,1
Masaya Hirose,1 Tomoyuki Shirase,2
Hisato Kobayashi,3 Hiroshi Ozasa1
1
Department of Obstetrics and
Gynecology, Otsu Red-Cross, Otsu,
Shiga, Japan; 2Department of Pathology,
Otsu Red-Cross, Otsu, Shiga, Japan;
3
Department of Radiology, Otsu
Red-Cross, Otsu, Shiga, Japan
Abstract
Retroperitoneal benign lipomas are
extremely rare and represent about 2.9% of
all primary retroperitoneal tumors. About
80% of the tumors in the retroperitoneal cav-
ities are malignant neoplasms. We experi-
enced a case of a retroperitoneal lipoma sim-
ulating an ovarian mature cystic teratoma. A
diagnosis was correctly made by magnetic
resonance imaging (MRI) prior to surgery,
and a total tumorectomy was performed. The
retroperitoneal lipoma was recognized to
have arisen from the urinary bladder.
Histological sections revealed a tumor con-
sisting of typical adipose cells without atypia.
These types of lipomas should be carefully
followed-up because they often recur and
undergo malignant transformations.
Introduction
Primary retroperitoneal tumors represent
about 0.2% of all neoplasms. Out of these
about 80% of the tumors are malignant neo-
plasms.1 Retroperitoneal benign lipomas are
extremely rare, and represent about 2.9% of
all primary retroperitoneal tumors.2 Herein
we present a case of a large retroperitoneal
lipoma prior to resection. The tumor was
identified as having arisen from the urinary
bladder at the time of surgery.
Case Report
A 61-year old Japanese woman, gravida 3,
complained of gluteal pain. She did not have
a medical history of surgery or concomitant
[page 34]
medications. Upon a pelvic examination, an
ill-defined and soft mass was detected in the Correspondence: Masafumi Koshiyama,
right pelvic cavity. She had fullness in the Department of Obstetrics and Gynecology,
right adnexal region. Transvaginal ultra- Otsu Red-Cross Hospital, 1-1-35, Nagara, Otsu,
sound sonography showed an echogenic Shiga, 520-0046, Japan
mass without any solid portions in the right E-mail: koshiyamam@nifty.com
adnexal region. These observations suggest-
Key words: lipoma, retroperitoneum, ovarian
ed a mature cystic tumor of the ovary con-
mature cystic teratoma, urinary bladder, magnet-
taining fat. An MRI revealed a mass measur- ic resonance imaging.
ing 15 cm in the right retropelvic cavity,
which showed high intensities on T1 and T2- Contributions: SU and MK, substantial contribu-
weighted images that were the same intensi- tions to conception and design, acquisition of
ty as fatty tissues (Figure 1). Another MRI data, or analysis and interpretation of data; all
authors are responsible for drafting the article or
showed that the tumor was in the retropelvic
revising it critically for important intellectual
cavity, because the right round ligament and
broad uterine ligament were detected over content; MK, final approval of the version to be
published; all members are medical doctors of
this tumor and the right iliac artery and vein
Otsu Red-Cross Hospital.
touched the tumor. The patient underwent
surgery with a diagnosis of a retroperitoneal Conflict of interest: the authors reported no poten-
lipoma. Macroscopically, an encapsulated, tial conflict of interests.
yellowish and soft mass lay between the uri-
nary bladder and the right iliac vessels in Received for publication: 10 July 2009.
the right retropelvic space (Figure 2). The Accepted for publication: 10 July 2009.
tumor penetrated the right lateral umbilical This work is licensed under a Creative Commons
ligament, and had feeding vessels from that Attribution 3.0 License (by-nc 3.0)
ligament. The tumor showed strong adher-
ence to the urinary bladder but did not infil- ©Copyright S. Ukita et al., 2009
trate the surrounding organs. The tumor Rare Tumors 2009; 1:e13
doi:10.4081/rt.2009.e13
was thought to be a large lipoma arising
from the urinary bladder, therefore, a total
tumorectomy was performed.
Histological sections revealed a tumor
consisting of typical adipose cells without
atypia (Figure 3). Neither lipoblasts nor
malignant cells were observed in the sec-
a
tions, and the histo-pathological diagnosis
was that of a lipoma. The patient had no
post-operative complications, experienced
less gluteal pain, and was discharged on
post-operative day 8. She had an uneventful
recovery during the post-operative follow-up
period.
b
Discussion
Most lipomas are superficial, and
retroperitoneal lipomas are very rare. When
lipomas occur in retroperitoneal locations,
they are mostly renal in origin.3 A few report-
ed cases have a pancreatic origin,4 and so on.
Pelvic lipomas are exceedingly rare, but can
arise from the iliac vessels and paravaginal
tissues.5 One reported case with pelvic ori- Figure 1. Retropelvic mass showed very
gins demonstrated a urinary bladder outlet high intensities on T1-(a) and T2-(b)
obstruction secondary to a pelvic lipoma.6 To weighted images that were the same inten-
sity as fatty tissues. This mass was diag-
our knowledge, the present case arising from nosed as a retropelvic lipoma by observing
the urinary bladder is the first such report in the position of the uterine broad ligament
the world. The lipoma presented herein was (arrow), the round ligament (arrow), the
characterized by the diffuse overgrowth of uterine artery (arrow) and the lateral
umbilical ligament (arrow).
fatty tissues in the perivesical spaces, but
[Rare Tumors 2009; 1:e13]

Figure 2. Retropelvic lipoma after its
removal.
Figure 3. Histological examination reveals
an adipose tissue neoplasm without cyto-
logic atypia.
lacked any urinary obstructions. The patient
experienced only slight gluteal pain.
MRIs present greater diagnostic precision
than ultrasonographies (USGs) and computer-
ized tomographies (CTs). In the present case,
the transvaginal ultrasound sonograph showed
an echogenic mass without any solid portion
in the right adnexal region, which suggested a
mature cystic teratoma of the ovary containing
fat. On the MRIs, the lipomatous components
showed very high signal intensities on the T1-
weighted and T2-weighted images.
Furthermore, the diagnosis of retropelvic
tumors is aided by observing the position of
the uterine broad ligament, the round liga-
ment, the uterine artery and the lateral umbil-
ical ligament. Thus, we were able to diagnose
this tumor as a retropelvic lipoma prior to sur-
gery. Therefore, MRIs are effective for diagnos-
ing retroperitoneal lipomas.
Benign subcutaneous lipomas and malig-
nant liposarcomas are well-documented and
are characterized by chromosome 12 aberra-
tions. Recently, some retroperitoneal lipomas
were shown to have no detectable rearrange-
ments of chromosome 12 or its amplification.7
On the other hand, retroperitoneal lipomas
have shown rearrangements in chromosomes
1 and 8. Therefore, there are different chromo-
somal rearrangements between retroperi-
toneal lipomas and malignant liposarcomas.
However, there are no significant optical dif-
ferences in CTs or MRIs observed prior to sur-
gery between lipomas and well-differentiated
liposarcomas.8 Thus, one should consider the
possibility of a liposarcoma when trying to
resect a retroperitoneal lipoma. Furthermore,
because these types of lipomas are known to
recur and undergo malignant transformation,
subjects with resected retroperitoneal lipomas
must have careful follow-up.
[Rare Tumors 2009; 1:e13]
Case Report
References
1. Armstrong JR, Cohen I. Primary malignant
retroperitoneal tumors. Am J Surg 1965;
110:937-43.
2. Pai MR, Naik R, Raughuveer CV. Primary
retroperitoneal tumors: a 25 year study.
Indian J Med Sci 1995;49:139-41.
3. Cavazza A, Giunta A, Pedrazzoli C, et al.
Extrarenal retroperitoneal angiomyolipo-
ma: description of a case and review of the
literature. Pathologica 2001;91:44-9.
4. Moriki T, Ohtsuki Y, Takahashi T, et al.
Lipoma-like tumor mass probably arising
in the retroperitoneal heterotopic pan-
creas: A previously undescribed lesion.
Pathol Int 2004;54:527-31.
5. Hull WB, Blumenfeld ML, Jacques D. Large
paravaginal pelvic lipoma: A case report. J
Reprod Med 1999;44:636-8.
6. Berens BM, Azavan A. Bladder outlet
obstruction due to pelvic lipoma: comput-
erized tomography, magnetic resonance
imaging and radiographic evaluation. J
Urol 1991;145:138-9.
7. Foa C, Mainguene C, Dupre F, et al.
Rearrangement involving chromosomes 1
and 8 in a retroperitoneal lipoma. Cancer
Genet Cytogen 2002;133:156-9.
8. Kimura N, Morita T, Murata A. et al. A case
of giant retroperitoneal lipoma. Nihon
Rinsyo Gekagakkaishi 2002;63:2030-4.
[page 35]
Rare Tumors 2009; volume 1:e14
Primary breast lymphomas
1 1
Olivier Julen, Ilaria Dellacasa,
Marie-Françoise Pelte,2 Bettina Borish,2
Christine Bouchardy,3 Federica Capanna,1
Georges Vlastos,1 Jean-Bernard
Dubuisson,1
Anne-Thérèse Vlastos1
1
Department of Gynecology and
Obstetrics, Geneva University Hospital;
2
Department of Pathology and
Immunology, Geneva University Hospital,
Genève, Switzerland;
3 prognostic factors. The purpose of this study is
Geneva Cancer Registry, Institute for
Social and Preventive Medicine,
University of Geneva, Switzerland
Abstract
The diagnosis, prognostic factors, and opti-
mal management of primary breast lymphomas
(PBL) is difficult. Seven patients recorded at
the Geneva Cancer Registry between 1973-1998
were reviewed. Five patient had diffuse large B-
cell lymphoma, one a follicular lymphoma and
one a MALT-lymphoma. All patients had clinical
and radiological findings consistent with breast
cancer and underwent mastectomy, which is not
indicated in PBL. Diagnosis should be estab-
lished prior to operative interventions, as fine
needle aspiration missed the diagnosis for one
patient and intra-operative frozen sections for 3
patients in our study. Five-year and 10-year
overall survivals were 57% and 15%, respective-
ly. Of the 3 patients who died from PBL, 2 had
tumors that were Bcl-2 positive but Bcl-6 nega-
tive. All 3 surviving patients have positive Bcl-2
and Bcl-6 immunostaining, which could be
important prognostic factors if confirmed by a
larger study.
Introduction
The breast is one of the least common pri-
mary extranodal sites for malignant lym-
phomas. A variety of pathological subtypes
have been reported. The frequency with which
the different subtypes of primary lymphoma of
the breast occur is difficult to determine,
because both terminology and classification
vary among the relatively small case series that
have been reported. There is general agree-
ment, however, that these lymphomas are usu-
ally of Non-Hodgkin’s lymphoma (NHL) histol-
ogy.1 They account for 0.04-0.5% of all breast
neoplasms and less than 1% of all NHL.2
NHL is a potentially systemic disease; there-
fore, appropriate management must take this
[page 36]
into account.1 Clinically and pathologically, pri-
mary lymphomas of the breast must be distin-
guished from both benign lymphoid infiltrates
and non-lymphoid neoplasms of the breast.
Since the breast normally contains some lym-
phoid tissue and functions during lactation as
part of the mucosal immune system, lym-
phomas in this site may be related to lym-
phomas of mucosa-associated lymphoid tissue,
so-called MALT lymphoma. Primary breast lym-
phoma (PBL) can still be misdiagnosed as car-
cinoma, a particular point of interest for
pathologists and clinicians. In addition, there
is a lack of consensus about its treatment and
to evaluate clinical presentation and patholog-
ical features, diagnostic difficulties and poten-
tial prognostic markers of this rare tumor.
Materials and Methods
The data were derived from the Geneva
Cancer Registry, which includes information
regarding all cases of malignant neoplasms
occurring in the population of the region
(approximately 420,000 inhabitants). The reg-
istry collects information from various sources
and is considered accurate, as attested by its
very low percentage (<2%) of cases recorded
from death certificates only.3 Individual clinical
files from all university public hospitals are sys-
tematically consulted and inquiry forms are
addressed regularly to physicians for patients
treated in the private sector. Trained registrars
systematically abstract data from medical and
laboratory records. Physicians regularly receive
questionnaires to secure missing clinical and
therapeutic data. Death certificates are consult-
ed systematically. Recorded data include socio-
demographic information, method of discovery,
type of confirmation, tumor characteristics
(coded according to the International
Classification of Diseases for Oncology),4 stage
of disease at diagnosis, treatment during the
first six months after diagnosis, survival status,
and cause of death.
The registry regularly assesses survival rate
index. In brief, it refers to the date of confirma-
tion of diagnosis or the date of hospitalization if
it preceded the diagnosis and was related to the
disease. In addition to passive follow-up (routine
examination of death certificates and hospital
records), an active follow-up is performed rou-
tinely each year using the files of the Cantonal
Population Office in charge of the registration of
the resident population. Finally, cause of death is
established from clinical records and coded
according to the World Health Organization’s
classification.5
In this study we included all cases of PBL
diagnosed between January 1973 and December
1998 among the resident population. Additional
[Rare Tumors 2009; 1:e14]
Correspondence: Olivier Julen, Department of
Gynecology and Obstetrics, Geneva University
Hospital, 1211 Geneva 4, Switzerland
E-mail: olivier.julen@hcuge.ch
Anne-Thérèse Vlastos, Department of Gynecology
and Obstetrics, Geneva University Hospital, 1211
Geneva 4, Switzerland. E-mail: anne-therese.vlas-
tos@hcuge.ch
Key words: lymphoma, breast, cancer, bcl6, bcl2.
Acknowledgments: we thank the technicians of
the Department of Clinical Pathology for their
work with immunostaining. We also thank the
registrars of the Geneva Cancer Registry for col-
lecting additional data on this subset of patients.
Received for publication: 30 June 2009.
Accepted for publication: 1 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright O. Julen et al., 2009
Rare Tumors 2009; 1:e14
doi:10.4081/rt.2009.e14
clinical information was obtained from a retro-
spective review of all the patient charts.
Pathological diagnosis of primary breast
lymphoma was based on the following strict
criteria as described by Wieseman and Liao in
1972: 1) an adequate pathological specimen;
2) a close association of mammary tissue and
lymphomatous infiltrate; 3) no evidence of dis-
seminated lymphoma at the time of diagnosis;
and 4) the presence of ipsilateral axillary
nodes was acceptable if they occurred con-
comitantly with the primary lesion. Staging
was based on the WHO classification 2001.6 In
all patients, the pathological diagnosis was
established on excisional biopsy or mastecto-
my specimen. Original hematoxylin-eosin-
stained sections and formalin-fixed, paraffin-
embedded tissue were available in all cases.
Histological review of the microscopic slides
was performed by some of the authors
(MFP/ATV). Extensive immunohistochemical
studies were performed.
Histology and immunohisto-
chemistry
Conventional histology included hematox-
ilin eosin, Giemsa, and silver stain of all avail-
able tissue blocks. Immunostaining was per-
formed using the listed antibodies with a
streptavidine-biotin peroxidase system.
Antigen retrieval, if necessary, was carried out
either by microwaving or pressure cooking in
ethylenediamine tetraacetic buffer (pH 2.5).
 Article

Table 1. Clinical staging under presumption of carcinoma.

N. Age Working Clinical Side Location Size TNM Primary Secondary CR Time to D F S Cause of
yr classification presentation cm staging treatment treatment death years of death
1 86 MALT Periartritis R All breast 6.5 T4d N2 Mx Patey Rx refused Yes 5 years 5 PBL
2 78 Follicular Breast mass R UO+I NA T3 N1 Mx Patey Ch refused No 2 months progression PBL
3 74 DLBCL Breast mass L UO 5 T3 N0 Mx Mastectomy No No 15 days progression PBL
4 62 DLBCL Breast mass L UO 3 T2 N0 Mx Patey No Yes 5 years 5 Cardiac
5 71 DLBCL Breast mass R UO+I 5.4 T3 N1 Mx Patey Ch: CHOP Yes / *7,5 Alive
6 39 DLBCL Breast mass R NA 2 T2 N0 Mx LAND Rx Yes / *16,5 Alive
7 44 DLBCL Breast mass L LO 5 T3 N0 Mx Patey Ch: CHOP Yes / *4,5 Alive
UO: upper outer quadrant; UI: upper inter quadrant; LO: lower outer quadrant; R: right; L: left; TNM: classification by Tumor Node Metastasis; Age*: years; MALT: MALT lymphoma; Follicular: follicular lymphoma;
DLBCL: diffuse large B-cell lymphoma; LAND: lumpectomy and axillary dissection; Pathey: mastectomy and axillary dissection; DSF: disease free survival; CR: complete response.

Table 2. Pathological characteristics including immunochemical studies. Patient Direct

N. Age Working Keratine LCA CD3 CD20 CD79 MiB1 Bcl-2 Bcl-6 MiB1
yr classification
1 86 MALT + + - + + 60% + - 60%
2 78 Follicular - + - + + 30% - + 30%
3 74 DLBCL + + - + + 50% + - 50%
4 62 DLBCL + + - + + / - - /
5 71 DLBCL - + - + + 80% + + 80%
6 39 DLBCL - + + + + 80% + + 80%
7 44 DLBCL + + - + + 90% + - 90%
UO: upper outer quadrant; UI: upper inter quadrant; LO: lower outer quadrant; R: right; L: left; TNM: classification by Tumor Node Metastasis; Age*: years; MALT: MALT lymphoma; Follicular: follicular lymphoma;
DLBCL: diffuse large B-cell lymphoma.

The work-up included CD3, CD4, CD5, CD8,
CD20, CD21, CD23, CD30, CD45, CD68, CD79a,
MIB1, pan-cytokeratine, Bcl-2 and Bcl-6. If not
otherwise mentioned, these antibodies were
from Dako, Copenhagen. The SPSS software
(SPSS 10 version Inc., Chicago, IL.) was used
for statistical analysis. Descriptive statistics
were performed to assess the frequency distri-
bution. We calculated disease-specific and dis-
ease-free interval probabilities using the
Kaplan-Meier method.7
Results
Since its creation in 1970, the registry has
recorded over 7,800 women with breast malig-
nancies. Only 9 patients were initially diag-
nosed and recorded as primary breast lym-
phoma, representing less than 0.1% of all malig-
nant breast tumors. However, there were only 7
true PBL after histological review. In 2 women,
clinical investigations performed at diagnosis
were insufficient to definitively conclude that
the lymphoma occurred primarily in the breast.
Patients’ characteristics
Patients’ and tumor characteristics are
described in Table 1. The median age at diag-
nosis was 65 years (range 39-86); most were in
the seventh decade of life (4 patients, 57%).
Three patients (43%) had left-breast
involvement and 4 (57%) right-breast involve-
ment. None had bilateral involvement. Clinical
lesions were located predominantly in the
upper outer quadrant (UOQ) in 2 (29%)
patients, in the upper outer and inner quad-
rant in 2 (29%), in the lower outer quadrant
(LOQ) in one (14%) and involved the whole
breast in one patient (14%). Four patients
(57%) had no clinical axillary involvement. All
patients sought consultation for breast related
symptoms and presented with a palpable mass.
Only one patient reported pain, described as
located in the homolateral shoulder; however,
the whole breast was involved in this case. No
malignant lymphoma was suspected on clinical
examination, nor in complementary investiga-
tions. In particular, mammography examina-
tion before surgery was suggestive of breast
carcinoma in all cases (100%).
First diagnosis was breast carcinoma in 6
out of 7 cases (86%) and inflammatory breast
carcinoma in one case (14%). Fine needle
aspiration (FNA) was performed in 2 (29%)
cases, both suggestive of breast carcinoma.
Primary breast lymphoma was diagnosed after
surgical excision in all cases, with frozen sec-
tion diagnosis for 3 cases. Frozen section diag-
noses revealed lymphoma in 2 cases and a
malignant non-differentiated tumor.
Pathology
Table 2 summarizes pathological character-
istics among primary breast lymphoma
patients. The average tumor size at diagnosis
varied from 2 cm to 6.3 cm in the greatest
diameter (mean, 4.5 cm) (Table 1). The sec-
tion presented with homogeneous fish-flesh
surface with occasional hemorrhagic or necro-
sis foci. For small tumors, margins were regu-
lar and pushing, for larger, irregular and stel-
late. Fibrosis or sclerosis surrounding the
tumor mass may suggest a medullary carcino-
ma of the breast or a benign process. Under
light microscopy, the tumor masses were poor-
ly circumscribed, infiltrating the mammary
lobules, and surrounded mammary ducts.
Diffuse large B-cell lymphoma, or DLBCL, was
the most common entity, (5 cases; 71%). Large
blastic B cells replaced the normal architecture
of the underlying breast in a diffuse pattern
and broad or fine bands of sclerosis were
observed. The morphological variant was cen-
troblastic lymphoma for all of the masses. The
most common DLBCL were composed of medi-
um-sized to large lymphoid cells with general-
ly basophilic cytoplasm. Nuclei were character-
ized by oval to round vesicles, fine chromatin
and 2-4 membrane bound nucleoli. In some
cases, the cells were multilobated. Centro-
blastic variant of diffuse large B-cell lymphoma
was monomorphic in one case and polymor-
phic in the remaining cases. One case was
diagnosed with grade III follicular lymphoma
(Figure 1). The remaining case was an extra-
nodal marginal zone B-cell lymphoma MALT
lymphoma. The characteristic marginal zone B
cells had small to medium-sized, slightly irreg-

[Rare Tumors 2009; 1:e14] [page 37]

Article

ular nuclei with moderately dispersed chro-

matin and inconspicuous nucleoli, resembling
those of centrocytes. They had a relatively
abundant, pale cytoplasm. The glandular-
epithelium was invaded and destroyed by
aggregates of lymphoma cells resulting in so-
called lymphoepithelial lesions (Figure 2).
Four DLBCL showed additional histological
features of MALT (lymphoepithelial lesions)
(Figure 3). Our last 2 cases showed no lym-
phoepithelial lesions but clearly showed ductal
invasion by lymphoma cells (Figure 4).

Immunophenotype
Immunohistochemical studies are reported in
Table 2. As expected, DLBCL expressed the pan-
B markers CD20 and CD79. Bcl-2 was positive in
4 cases (80%) and nuclear expression of Bcl-6 in
2 cases (40%). MiB1 was highly expressed indi-
cating a high proliferative rate (up to 90%) in all
cases. The follicular lymphoma expressed the
pan-B markers CD20 and CD79 as well as Bcl-6.
Bcl-2 protein was expressed in the majority of
the reported cases, ranging from nearly 100% in
grade I to 75% in grade III however, cutaneous
follicular lymphoma is frequently Bcl-2 negative.
MiB1 was expressed in 30% of the cells. The
MALT lymphoma expressed CD20 and CD79 as
well as Bcl-2.

Treatment
Various treatment strategies were used
according to available data. Treatments are
reported in Table 1. Surgery was initially per-
formed because of the initial clinical impres-
sion of mammary carcinoma. Surgeries con-
sisted of mastectomies associated with an axil-
lary lymph node dissection for 6 patients and a
breast conserving surgery for one patient with
a small size (2 cm) lesion. The Levels I and II
axillary lymphatics were included within the
breast or chest-wall fields; 3 of the 6 performed
were positive (50%).
The treatment proposed after surgery was
chemotherapy in 3 cases (43%), of whom one
(14%) refused and radiotherapy in 2 cases
(29%), which was also refused by one patient
(14%). The last 2 cases (29%) were treated
with surgery alone. One patient had a mastec-
tomy and axillary dissection. The second
patient had a simple mastectomy and did not
receive adjuvant therapy because of her poor
condition. None of the cases received com-
bined modality approaches.
Outcome
Median follow-up was 5.8 years (range: 0.15-
16). Of the 7 patients, 5 achieved complete
response after therapy (Table 1). Two patients
never achieved complete response and died of
disease progression. In one of these patients
progression was observed to the brain and
skin. The other, because of her poor medical
Figure 1. Follicular lymphoma. (a) Follicular aspect: HE (x100); (b) large transformed
cells with one to three peripheral nucleoli: Giemsa (x200); (c) B cells with follicular
arrangement: CD79 (x50); (d) B cells with follicular arrangement: CD79 (x100); (e) reac-
tive T cells surrounding the B cells with follicular arrangement: CD3(x50); (f ) Bcl-6
staining (x200).
condition, died two weeks after surgery. One (median age: 55-60 years).1,8-10 In our series we
relapsed after five years (skin) and subse- found an older median age: 65 years (39-86
quently died of lymphoma. At time of the last years), as already described, whereas some
follow-up, 3 were alive. One died of other caus- authors find a younger median age.11 The right
es (cardiovascular disease). Five and 10-year breast was reported to be most frequently
overall survival rates were 57% and 15%, involved.1,8-11 Only a few series report the oppo-
respectively. Of the 3 patients who died from site and another had no predominant site.12 Five
their PBL, 2 had positive Bcl-2 immunostain- to 25%2,13 of reported cases were simultaneously
ing (66%) but negative Bcl-6 immunostaining bilateral at presentation,8,10,12 nevertheless no
(66%). On the other hand, of the 3 patients still such case is reported in our series. We were par-
alive, all had positive Bcl-2 immunostaining ticularly interested in the method by which
and 2 positive Bcl-6 immunostaining (66%). these tumors were detected and hypothesized
Treatment modalities and their corresponding that increased knowledge and the current wide-
effect on mortality are presented in Table 1. spread use of mammography as a screening
method for breast carcinoma may increase the
detection of breast lymphoma. Hemato-
poietic neoplasms involving the breast, although
Discussion less common than breast carcinoma, are often
In the present study we evaluated all patients clinically indistinguishable from other breast
who presented with primary lymphomatous tumors. Microscopically, these tumors can
involvement of the breast over a 26-year period mimic primary carcinoma of the breast, espe-
at our institution. Only the patients who satis- cially in limited material such as fine needle
fied the strict criteria of PLB according to aspirations (FNA). In 2 patients with FNA in our
Wiseman and Liao were analyzed for this study series, cytology was interpretated as carcinoma.
to avoid the potential inclusion of patients with In the 3 patients with frozen section diagnosis,
secondary breast involvement of NHL.2 The most only one (the follicular lymphoma case) was
frequent clinical scenario is that of a unilateral diagnosed correctly. FNA misdiagnosis has been
breast mass presenting in a middle-aged woman reported by several authors.12

[page 38] [Rare Tumors 2009; 1:e14]


Figure 2. Destruction of the glandular tis-
sue epithelium by aggregates of lym-
phoma cells. (a) Mammary gland infil-
trated by lymphoma cells: HE (x400); (b)
mammary gland infiltrated by B cells:
CD20 (x400); mammary gland: Keratin
(x400).
However, breast carcinoma is not the only
pitfall. Diabetic mastopathy (DM) may be over-
interpreted as lymphoma. DM, which has been
described in both diabetic patients and non-
diabetic patients, generally demonstrates
fibrocystic change with dense stromal fibrosis
and an extensive perivascular infiltrate of
small B-lymphocytes. However, there is no cur-
rent evidence that DM is a precursor lesion to
PBL.8,13 Traditionally a surgical approach to the
treatment of patients’ PBL has been adopted,2
even if mastectomy could be avoided in most
patients,15 and treatment confined to chemo-
therapy and radiation therapy appropriate for
the histological type. In our series, all patients
underwent a surgical treatment. It is important
to underline that all mastectomies in our
series were performed due to the initial clini-
cal and/or pathological diagnosis impression
(frozen section or FNA) of adenocarcinoma.
Similarly, although there have been reports of
radiation therapy alone for patients with PBL,16
patients with intermediate-grade and high-
grade lymphomas of the breast are best treated
with chemotherapy or with combined chemo-
therapy and radiation therapy.10
Article
Published reports on the treatment outcome
for PBL range from equivalent to worse prog-
nosis for PBL compared to other non-Hodgkin’s
lymphomas (NHL).1,2 Confounding the matter
are the different definitions of PLB used by dif-
ferent authors. Some consider the lymphoma
to be PBL if the patient presents with com-
plaints relating to the breast or if the main
tumor mass is in the breast.1,12 Others use
more strict definitions of PBL.2,16 Different
pathological types of breast lymphoma have
also been reported by different investigators at
least partially because of different histological
criteria used.9,12
Cohen et al. studied both primary and sec-
ondary breast lymphomas with a broad panel of
T- and B-cell markers using paraffin-embedded
tissue and the avidin-biotin immunoperoxi-
dase method. Cases of PBL were further tested
to determine light and heavy chain type.
Thirty-five cases were analyzed, including 16
primary lymphomas. Diffuse large cell lym-
phoma was present in 10 of 16 primary and 14
of 18 secondary cases. Lymphoepithelial
lesions in ducts and lobules and frequent vas-
cular involvement were found in both primary
and secondary cases. Immunohistochemistry
studies on 13 tumors revealed all of the pri-
mary tumors to be B-cell in origin, except for
one case of primary T-cell lymphoma; to the
authors' knowledge, this represents the first Figure 4. Primary breast lymphoma with-
description of this entity. Fifteen of 17 second- out lymphoepithelial lesion. (a)
ary tumors exhibited B-cell markers and one of Proliferation index: MiB1 (x200) (80%
17 exhibited T-cell markers; in only one case positive); (b) HE (x100); (c) mammary
could lineage not be determined.17 Among pri- gland: keratin (x200).
Figure 3. Lymphoepithelial lesions. (a) Lymphoepithelial lesion: HE (x50); (b) lym-
phoepithelial lesion: HE (x100);(c) mammary gland: keratin (x200); (d) mammary gland
infiltrated by B cells: CD20 (x200).
[Rare Tumors 2009; 1:e14] [page 39]
Article
mary B-cell cases, IgM was found to be the
most frequent heavy chain type; IgA reactivity
was found in one case only.18
In our series, the World Health Organiz-
ation Classification of Tumors was used.6
Diffuse large B-cell lymphoma (DLBCL) was
the most common diagnosis (71%) and all
cases were of B-cell phenotype. Although
there was some variation in histological
appearance from patient to patient, the char-
acteristics of large B-cell breast lymphoma
were not distinctive and resembled DLBCL
occuring at other sites. In addition, we report-
ed a follicular lymphoma and a MALT lym-
phoma. Lamovec and Jancar first reported that
some PBLs had features of MALT lymphoma.
Subsequently, several series have reported
MALT lymphoma as part of the spectrum of
PBL, comprising 0-64% of all PBL.9,10,18,19
DLBCL are a heterogeneous group of
tumors, varying in cellular content, phenotype,
cytogenetics, site of presentation and natural
history of disease. They represent the most fre-
quent type of NHL, accounting for 30-40% of
adult NHL.20 Although approximately half of the
patients with DLBCL can be cured by conven-
tional chemotherapy, the remainder will die of
their disease. Identification of patients at pres-
entation who are unlikely to be cured by stan-
dard therapy is a key step in developing new
treatment strategies. At present, the most
effective tool for the identification of prognos-
tic subgroups is the International Prognostic
Index (IPI),21 which is calculated using age,
Ann Arbor Stage, number of extranodal sites,
performance status (Eastern Cooperative
Oncology Group (ECOG) scale) and serum lac-
tate dehydrogenase (LDH), all of which are
independent risk factors. Several molecular
abnormalities, such as Bcl-222 and survivin23
expression and p53 mutations,24 were identi-
fied as prognostic indicators of DLBCL. Bcl-2
expression was reported to correlate with
reduced disease-free survival (DFS),22 but it
only predicted reduced overall survival (OS)
for patients with DLBCL in one of the reported
studies.22 The Bcl-2 protein is expressed in a
significant proportion of DLBCLs, either as a
consequence of, or independently of, the
translocation-t(14;18).21,22 This has been shown
in a number of studies to have an adverse
effect on survival21,22 and is the most widely
accepted cellular prognostic factor. In our
study, Bcl-2 was expressed in 5 cases (71.4%).
In a strange way it was expressed in 3 cases of
the surviving patients but only in 2 of the 3
(66%) cases who died from PBL.
Recently, it has been suggested that the
expression of a germinal center (GC) pheno-
type may be a favorable prognostic factor.21
Rearrangement of the Bcl-6 locus at 3q27
seems to occur more frequently in extranodal
DLBCL than in node-based disease and to be
[page 40]
an independent poor prognostic factor in nodal
diffuse large B-cell lymphoma.21
Expression of Bcl-6 protein has been report-
ed to have an antiapoptotic effect in GC
B cells21 and, by analogy with Bcl-2, it may be
expected that expression of Bcl-6 protein
would be a poor prognostic factor. However,
Bcl-6, alone and in the context of a GC pheno-
type, appeared to be associated with a favor-
able prognosis. Although not statistically sig-
nificant, it is consistent with recent observa-
tions, using gene expression and microarray
technology, that Bcl-6 expression and GC dif-
ferentiation are favorable prognostic factors.21
It is of particular interest that a significant
proportion (32%) of the cases with a Bcl-6
gene rearrangement lacked expression of Bcl-
6 protein using immunocytochemistry. This
lack of correlation has been reported previous-
ly21 and suggests that rearrangement of the
Bcl-6 gene does not directly lead to Bcl-6 pro-
tein expression in every case.
Our results are difficult to extrapolate due
to the small number of cases. In this study, we
used immunohistochemistry to define Bcl-2
and Bcl-6 expression. Bcl-6 was negative in
patients who died of PBL, but positive in 2 of 3
surviving patients. These results indicate that
Bcl-6 could serve as a surrogate predictor for
overall survival of patients with PBL. This
should be investigated in a large scale study
on PBL.
Conclusions
For patients with primary lymphomatous
involvement of the breast who will classically
present with a palpable mass, screening mam-
mography appears to contribute little to their
diagnosis, and FNA or frozen section can lead
to misdiagnosis. The results of therapy did not
appear to differ significantly from the results
seen for lymphomas occuring in other sites.
Lymphomas of the breast are uncommon,
present generally in elderly patients and have
a bad prognosis. This potentially curable neo-
plasm with a stage-for-stage clinical outcome
similar to that of patients with other lym-
phomas of similar histological type25 is, howev-
er, often misdiagnosed. Despite a number of
recent articles on lymphomas of the breast, it
appears that these tumors continue to be con-
fused with carcinomas.
As no pathognomonic clinical, pathological
or radiological findings differentiate PBL com-
pletely from adenocarcinoma, pathologists
must be attuned to the possibility of lym-
phoma, especially if the frozen section diagno-
sis of adenocarcinoma is questionable in the
operating room.10 This could save patients from
unnecessary mastectomies.
[Rare Tumors 2009; 1:e14]
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[page 41]
Rare Tumors 2009; volume 1:e15

Neuroblastoma occurring in region are reported to be the primary sites in

a 38-year old Nigerian man:
a rare finding
Martin A. Nzegwu,1 Aloy Aghaji2
1
Head Department of Morbid Anatomy,
University of Nigeria Medical School,
Enugu, Nigeria; 2Provost, College of
Medical Sciences, University of Nigeria
Medical School, Enugu, Nigeria
these individuals.3 There are no documented
reports of this lesion in adults from Nigeria or
anywhere else in Africa. It has been suggested
that the behavior of this disease may be differ-
ent in older patients than in young children
with a longer course, ultimately resulting in a
poor outcome regardless of the stage.4,5
Case Report
Correspondence: Martin Nzegwu,
Head Department of Morbid Anatomy, University
of Nigeria Medical School, Enugu, Nigeria
E-mail: martin_nze@yahoo.com
Key words: neuroblastoma, adult.
Conflict of interest: the authors reported no poten-
tial conflict of interests.
Received for publication: 11 June 2009.
Accepted for publication: 1 July 2009.

This work is licensed under a Creative Commons

Abstract
Neuroblastoma (NB) is a common malig-
nancy in children, but rarely occurs in adults.
Accepted unfavorable prognostic factors
include age over one year, low histological
grade and advanced stage, MYCN amplifica-
tion, chromosomal aberrations, elevations of
neuron specific enolase and lactate dehydro-
genase, and increased catecholamine
metabolites in urine or serum. In adults,
abdomen/retroperitoneum are the primary
sites and in children the adrenal gland. We
report a 38-year old civil servant who present-
ed at our urology clinic on the 21 st of
December 2007 with a six month history of
right flank dull pain which was worse on
walking and relieved by rest, hypertension
and a large right retroperitoneal mass. Tumor
resection revealed a grade III NB. Chemo-
therapy using a combination of vincristine,
adriamycin and cyclophosphamide was start-
ed. Follow-up showed regression of the mass
initially with a relapse after patient abscond-
ed for three months. He resurfaced with new
masses and he had a repeat chemotherapy
with disappearance of the masses and is cur-
rently undergoing further treatment. To our
knowledge this is the only report of NB in an
adult registered so far in Nigeria and perhaps
the whole of Africa. Currently, there are no
standard treatment guidelines for patients
with NB in adulthood. This study emphasizes
the need for a standard treatment regime for
adult onset neuroblastoma and its recogni-
tion as a possible differential in intra-abdom-
inal mass in adults.
Introduction
Neuroblastic tumors, of which neuroblas-
tomas are the most common, are embryonic
neoplasms of the sympathetic nervous system,
and are the most common solid neoplasms of
childhood other than central nervous system
tumors.1,2 Neuroblastoma rarely occurs in
adults, although abdomen and retroperitoneal
A 38-year old civil servant came as a referral Attribution 3.0 License (by-nc 3.0)
to our urology clinic on the 21st of December
2007 with a six month history of right flank ©Copyright M.A. Nzegwu and A. Aghaji 2009
dull non-radiating pain which was worse on Rare Tumors 2009; 1:e15
walking and relieved by rest. Three months doi:10.4081/rt.2009.e15
later, the abdominal swelling became more
generalized and tense. He had an intravenous
pyelogram which showed bilateral hydro- The diagnosis in this case report was easy;
nephrosis with a possible retroperitoneal however, no diagnosis could be made from the
malignancy. Neither family history nor social gross and clinical presentation until the histo-
history was significant. On examination, a logical tests had been performed. These
grossly distended abdomen was found tense showed sheets of small round blue proliferat-
and non-tender. Tumor resection revealed a ing cells forming circular or rosette like struc-
grade III NB. The abdominal mass measured
34x28 cm and was hard to touch. His hemoglo-
bin was 88 g/L and leukocyte count 7.3x109/L.
Chest X-ray was normal and HIV status was
negative for HIV1 and 11. Abdominal ultra-
sound showed normal liver, both kidneys were
covered by a mass 85x65 cm with little ascites.
Urinary meta-epinephrine was mildly elevated.
Figures 1, 2 and 3 show the morphological
description and appearance of the lesion, cut
surface and microscopy. A diagnosis of an
abdominal invasive neurofibroma was made
whose origin may be either from the adrenal or
from the sympathetic ganglia. In an adult, this
is a hitherto unreported lesion not only in Figure 1. Shows partly encapsulated gray-
Nigeria but perhaps in the whole of Africa. ish white lobulated seemingly encapsulat-
Hence the importance of this report is to high- ed hemorrhagic lesion altogether measur-
light the possibility that neuroblastoma, ing 34x28 cm. Firm in consistency and
though a childhood malignancy, can present as superficially resembling the brain.
an abdominal mass in an adult. The patient
was placed on combination chemotherapy
using vincristine, adriamycin and cyclophos-
phamide. He made a dramatic recovery but
later absconded only to resurface three months
later with what looked like a recurrence. He
was again counseled and a repeat course of the
same cytotoxic drugs was given with disap-
pearance of the masses. He has remained com-
pliant and relatively stable since then.
Discussion
Neuroblastoma is essentially a tumor pre-
senting in childhood, usually occurring before Figure 2. Cut surface shows a cystic and
the age of four.2 There are only a few isolated solid lesion with several areas of necrosis.
The lesion remains grayish white in color.
reports of its occurrence in adults.1,3,4

[page 42] [Rare Tumors 2009; 1:e15]


Figure 3. Shows the microscopic descrip-
tion. Sections show sheets of small round
blue cells proliferating and forming circu-
lar or rosette like structures with a central
arranged neurofibrils directed inwards
(Homer Wrights rosettes). These are dis-
posed in a background of a scanty myoxid
stroma. The lesion shows a brisk mitosis
per high-power field POINTER (magnifi-
cation x 40).
tures with central arranged neurofibrils
directed inwards (Homer Wrights rosettes).
These are disposed in a background of a
scanty myoxid stroma. The lesion also showed
a brisk mitosis per high-power field. In case of
doubt and in more experienced centers, rou-
tine immunohistochemistry tests would also
be performed for S-100, neurone specific eno-
lase, neurogranin and bombesin to further
establish the diagnosis and differentiate them
from other lesions like rhabdomyosarcoma
and lymphomas. Electron microscopy may also
be useful in centers where it is available and
will show dendritic processes, dense core
granules and desmosomes.
The successful diagnosis of NB for those in
Africa, where ancillary investigative processes
are not well established, requires awareness
and a high index of suspicion so as to see this
lesion as a possible differential of a malignant
abdominal lesion in an adult. Furthermore, a
revision of the treatment protocol of the lesion
needs to be put in place globally as in the case
of the same lesion occurring in children, as
the disease indeed appears to differ in its bio-
logical behavior. This patient is still under
observation and has just concluded another
radiological survey to ascertain the extent of
the disease.
[Rare Tumors 2009; 1:e15]
Case Report
References
1. Meltzer S. Neuroblastoma occurring in
adults. Can Med Assoc J 1926;16:647-51.
2. Ronald AD, Shamlal M. The adrenal gland
in Sternberg’s Diagnostic Surgical
Pathology, Vol 1. Fourth edition. Lippincott
Williams and Wilkins, Philadelphia, USA.
2004. p 643.
3. Maclean TW, Iskander SS, Shimada H, Hall
MC. Neuroblastoma in an adult. Urology
2004;64:1232.
4. Franks LM, Bollen A, Seeger RC, et al.
Neuroblastoma in adults and adolescents:
an indolent course with poor survival.
Cancer 1997;79:2028-35.
5. Loraine MF, Andrew B, Robert CS, et al.
Neuroblastoma in adults and adolescents,
an indolent course with poor survival.
Cancer 2000;79:2028-35.
[page 43]
Rare Tumors 2009; volume 1:e16
Primary lymphoepithelial
carcinoma of the parotid gland
in a North African woman
Soumaya Ben Abdelkrim,1Amel Trabelsi,1
Faten Hammedi,1 Monia Omezzine,2
Soumaya Rammeh,1 Atef Ben
Abdelkader,1 Badreddine Sriha1
1
Department of Pathology, Farhat Hached
Hospital, Sousse, Tunisia;
2
Department of Maxillofacial Surgery,
Sahloul Hospital, Sousse, Tunisia
Abstract
Lymphoepithelial carcinoma of the salivary
glands is a rare neoplasm that is character-
ized by a non-neoplastic lymphocytic infiltra-
tion associated with an epithelial prolifera-
tion. It involves mainly the parotid gland.
Racial and geographical factors contribute to
the pathogenesis of this tumor. We report a
case of a 70-year old woman from a non-
endemic area who presented with several
months history of swelling in the parotid
region. Magnetic resonance imaging showed
a parotid mass suggestive of a pleomorphic
adenoma. The diagnosis of lymphoepithelial
carcinoma of the parotid gland was performed
on the surgical specimen. A primitive
nasopharyngeal carcinoma was ruled out by
random biopsies of the nasopharynx mucosa.
The Epstein-Barr virus (EBV) was absent in
neoplastic cells. We insist that, even in non-
endemic areas and when clinical and radio-
logical characteristics are not suggestive of
malignancy, intra-operative frozen section
analysis should be used in order to ensure the
appropriate treatment.
Introduction
Lymphoepithelial carcinoma (LEC) is a
specific subtype of undifferentiated carcino-
ma with characteristic dense lymphoid stro-
ma. The most frequent location is the
nasopharynx. Identical tumors have been
rarely described in the major salivary glands
where they account for approximately 0.4% of
all malignant salivary gland tumors.1 A limited
number of cases were reported from non-
endemic areas. We report a new case from a
non-endemic region with an atypical clinical
presentation and an aspecific radiological
pattern and we discuss the clinical and patho-
logical pattern and management of this
uncommon tumor.
[page 44]
Case Report
A 70-year old women presented with a left
sided, slowly enlarging, painless, non-tender
mass in the parotid region of several months’
duration. Her medical and surgical history was
otherwise uneventful. On physical examina-
tion, in the left parotid gland she had a volumi-
nous mass of 7 cm with a regular border that
was mobile on the superficial and deep planes,
and did not hurt upon palpation. Her facial
nerve function was intact, and no enlarged cer-
vical lymph nodes were palpated. The remain-
ing systemic examination did not reveal any
coexistent lesions. Magnetic resonance imag-
ing detected a 7x6x6 cm mass in the superficial
lobe of the left parotid that was interpreted as
most likely representing a pleomorphic adeno-
ma (Figure 1). The patient underwent a left
parotidectomy, and the facial nerve was left
anatomically intact. Her recovery was unevent-
ful. Macroscopically, there were multiple surgi-
cal specimens that were brownish and firm in
consistency. Histological findings demonstrat-
ed a tumor located in the parotid gland that was
made of irregular sheets, islands and strands of
poorly differentiated carcinoma richly infiltrat-
ed by lymphocytes and plasma cells, accompa-
nied by large lymphoid follicles (Figure 2). The
epithelial component consisted of large cells
with indistinct cell borders resulting in synci-
tial appearance, eosinophilic cytoplasm and
oval vesicular nuclei (Figure 3). The nuclei
contained open chromatin material with promi-
nent nucleoli. Frequent mitotic figures were
also found. Areas of squamous differentiation
were noted. The surrounding parotid tissue
showed a chronic lithiasic sialadenitis.
Immunohistochemically, most of the tumor
cells were positive for cytokeratin (Figure 4).
[Rare Tumors 2009; 1:e16]
Correspondence: Soumaya Ben Abdelkrim,
Farhat Hached Hospital, Department of Pathology,
4000 Sousse, Tunisia
E-mail: benabdelkrims@voila.fr
Key words: lymphoepithelial carcinoma, parotid,
pathology.
Received for publication: 20 June 2009.
Accepted for publication: 29 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright S.B. Abdelkrim et al., 2009
Rare Tumors 2009; 1:e16
doi:10.4081/rt.2009.e16
The surrounding cellular infiltrate were a mix-
ture of CD20 and CD3 positive B and T lympho-
cytes. Immunohistochemical expression of EBV
latent membrane protein 1 (LMP1) and in situ
hybridization to EBV encoded RNA were nega-
tive. These findings were consistent with the
diagnosis of primary LEC of the left parotid
gland after excluding metastatic nasopharyn-
geal undifferentiated carcinoma to the parotid
gland by random biopsies from the nasopharyn-
geal mucosa. The patient underwent an ipsilat-
eral radical neck dissection and there were no
lymph node metastases. She remains alive and
disease free five months after treatment.
Discussion
According to the classification by Ellis and
Auclair,2 undifferentiated carcinomas of the
salivary glands can be subtyped further into
Figure 1. Magnetic
resonance imaging
showing a well cir-
cumscribed mass of
the left parotid
gland.

small cell undifferentiated carcinoma, large
cell undifferentiated carcinoma, and LEC.
LEC accounts for approximately 0.4% of
malignant salivary gland tumors and has a
characteristic extensive and dense lymphoid
stroma.1 This tumor affects the parotid gland
in approximately 80% of the cases.3 Most
cases occur in the fifth decade of life and a
predilection for female patients is reported.4
There is a racial prevalence in Inuits
(Eskimo) in the Arctic region, south-eastern
Chinese and Japanese. Most parotid LEC
cases arise de novo, but they may rarely devel-
op within lymphoepithelial sialadenitis.5 The
exact origin and pathogenesis of parotid LEC
Case Report
genetic factors, environmental factors, and
EBV infection in the oncogenic process of
LEC of the salivary glands.9 Parotid LEC usu-
ally presents as an enlarging parotid lump,
occasionally painful and with facial nerve
Figure 2. Lympho- involvement in approximately 20% of cases.4
epithelial lesion of the Clinical features suggestive of malignancy
parotid gland (hema- are rapid-growing course, pain or tenderness,
toxylin-eosin, original progressive facial nerve palsy and obvious
magnification ×40). cervical lymphadenopathy.10 Our case is par-
Islands of neoplastic
epithelial cells (arrows) ticular for the atypical presentation suggest-
associated with lym- ing a benign lesion; in fact, our patient
phoid infiltration that showed no signs suggestive of malignancy.
occasionally form lym- On presentation, up to 40% of patients have
phoid follicles.
metastases to the cervical lymph nodes, 20%
develop local recurrence or lymph node
metastases, and 20% have distant metastases
within three years following therapy. Distant
metastases usually involve the lung, liver,
bone, and brain. 1 Macroscopically, these
tumors are firm, 1-10 cm masses, multinodu-
lar, circumscribed, or clearly infiltrative into
adjacent salivary gland, fat, muscle, or skin,
with a cut surface that varies from a grey-tan
Figure 3. The epithelial
component of the to yellow-gray.11 Histologically, it is character-
lesion have a syncitial ized by a syncitial growth pattern and a dense
appearance and shows stroma made of non-neoplastic lymphoplas-
an obvious pleomor- macytic cells; the lymphoid cells include a
phism (hematoxylin- mixture of B and C cells and are sometimes
eosin, original magni-
fication ×400). associated with germinal centers. The epithe-
lial component is composed of irregular
shaped islands, cords, trabeculae of pleomor-
phic, large, malignant cells with abundant
lightly eosinophilic cytoplasm and vesicular
nuclei.3,12 Mitotic rate is variable. Histiocytes
are abundant in the tumor islands in some
cases, imparting a 'starry sky' appearance.3
Other inconsistent findings are non-caseat-
ing granulomas with or without multinucleat-
ed giant cells and amyloid deposition.13 A def-
inite squamous differentiation with intercel-
lular bridges has been identified in several
cases.3 LEC is indistinguishable from undif-
ferentiated nasopharyngeal carcinoma which
Figure 4. Immunohi- is much more common or other LECs that
stochemical expression
of cytokeratin (×400). develop in various parts of the body. 4,10
Therefore, to confirm the diagnosis of pri-
mary LEC in the major salivary glands,
metastatic nasopharyngeal carcinoma to the
remains unknown. Among the possible etiolo- salivary glands should be eliminated through
gies are a malignant transformation of the examination of the upper aerodigestive tract
glandular and ductal inclusions in the intra- with endoscopy and even random biopsy of
parotid lymph nodes6 and a malignant trans- the nasopharynx.3,4,10,13 In reality, the parotid
formation of the epi-myoepithelial island.7 In gland is the predominant site of occurrence of
1991, the presence of EBV was detected by LEC and an exceptional site of metastasis
Hamilton-Dutoit et al.8 in the malignant cells from nasopharyngeal carcinoma, which more
of salivary LECs in the Eskimo population of typically metastasizes to the cervical or sub-
Greenland. Only a few cases of EBV-negative mandibular lymph nodes.1 Histologically, the
LEC have been reported, and almost exclu- LEC must be distinguished from benign
sively in non-Inuit patients6 suggesting that lesions such as lymphoepithelial sialadenitis
the virus plays a role in the etiology of LEC. and from other epithelial malignancies, such
The association of EBV with salivary gland as primary or metastatic poorly differentiated
LEC may also exist in non-endemic areas.4 It squamous cell carcinoma, adenocarcinoma,
seems there is a complex interaction between and amelanotic melanoma; another differen-
[Rare Tumors 2009; 1:e16] [page 45]
Case Report
tial diagnosis is with large cell or anaplastic
types of lymphoma.2 The optimal management
of LEC of the major salivary glands is com-
plete excision with clear surgical margins fol-
lowed by adjuvant radiotherapy to the tumor
bed and neck.
Neck dissection is reserved for patients
who have clinically positive cervical lymph
nodes.10,14 Our patient underwent only surgical
treatment because radiotherapy was not
available at that time. Lymphoepithelial carci-
noma seems to have a better prognosis than
the other undifferentiated carcinomas of the
salivary glands, in part because of the lym-
phoid stroma that has a role in limiting the
aggressiveness of this carcinoma. Advanced
disease, the presence of metastases on diag-
nosis, and histological features such as high
mitotic rate, anaplasia, and necrosis are pre-
dictors of a worse prognosis.1,9 The 5-year sur-
vival rate has been reported to range from 50-
87%.10
In conclusion, it is worth underlining the
diagnostic difficulty in this case caused by the
absence of clinical symptoms suggestive of
malignancy and the non-specific nature of the
radiological signs. In order to ensure a correct
therapeutic approach, intra-operative frozen
section analysis of a parotid mass should be
used to exclude a malignant tumor even when
dealing with a clinical and radiological pres-
entation suggestive of pleomorphic adenoma.
[page 46]
References
1. Schneider M, Rizzardi C. Lymphoepithelial
carcinoma of the parotid glands and its
relationship with benign lymphoepi-
thelial lesions. Arch Pathol Lab Med
2008;132:278-82.
2. Ellis GL, Auclair PL. Atlas of tumor pathol-
ogy: tumors of the salivary glands.
Washington, DC: Armed Forces Institute
of Pathology, 1996.
3. Saw D, Lau WH, Ho JH, Chan JK, Ng CS.
Malignant lymphoepithelial lesion of the
salivary gland. Hum Pathol 1986;17:914-
23.
4. Manganaris A, Patakiouta F, Xirou P,
Manganaris T. Lymphoepithelial carcino-
ma of the parotid gland: is an association
with Epstein-Barr virus possible in non-
endemic areas? Int J Oral Maxillofac Surg
2007;36:556-9.
5. Gravanis MB, Giansanti JS. Malignant
histopathologic counterpart of benign
lymphoepithelial lesion. Cancer 1970;26:
1332-42.
6. Kountakis SE, SooHoo W, Maillard A.
Lymphoepithelial carcinoma of the
parotid gland. Head Neck 1995;17:445-50.
7. Batsakis JG, Bemacki EG, Rice DH,
Stebler ME. Malignancy and the benign
lymphoepithelial lesion. Laryngoscope
[Rare Tumors 2009; 1:e16]
1975;85:389-99.
8. Hamilton-Dutoit SJ, Therkildsen MH,
Nielsen NH, et al. Undifferentiated carci-
noma of the salivary gland in Greenlandic
Eskimos: demonstration of Epstein-Barr
virus DNA by in situ hybridization. Hum
Pathol 1991;22:811-5.
9. Sheen TS, Tsai CC, Ko JY, et al. Undiffer-
entiated carcinoma of the major salivary
glands. Cancer 1997;80:357-63.
10. Wang CP, Chang YL, Ko JY, et al. Lympho-
epithelial carcinoma versus large cell
undifferentiated carcinoma of the major
salivary glands. Cancer 2004;101:2020-7.
11. Jang SJ, Paik SS, Lee WM, et al. Lympho-
epithelial carcinoma of the submandibu-
lar gland – a case report. J Korean Med Sci
1997;12:252-5.
12. Cleary KR, Batsakis JG. Undifferentiated
carcinoma with lymphoid stroma of the
major salivary glands. Ann Otol Rhinol
Laryngol 1990;99:236-8.
13. Kuo T, Hsueh C. Lymphoepithelioma-like
salivary gland carcinoma in Taiwan: a
clinicopathological study of nine cases
demonstrating a strong association with
Epstein-Barr virus. Histopathology 1997;
31:75-82.
14. Hsiung CY, Huang CC, Wang CJ, et al.
Lymphoepithelioma-like carcinoma of
salivary glands: treatment results and fail-
ure patterns. Br Radiol 2006;79:52-5.

A review of the history,
epidemiology and treatment
of squamous cell carcinoma
of the scrotum
Jerome E. Azike1,2
1
Department of Surgery, College of
Medicine and Health Sciences, Imo State
Universityœ, Orlu, Campus; 2Imo State
Universitary Teaching Hospital, Orlu, Imo
State, Nigeria
Abstract
Squamous cell carcinoma of the scrotum is
a tumor that is of interest for clinical and his-
torical reasons. It was the first cancer linked to
occupational exposure when, in 1775, Perivall
Pott described it in chimney sweeps in
England. Other occupations that had a prepon-
derance of the disease included people who
worked with the distillates of coal and men
exposed to mineral oil. Currently, the disease
is very rare and most cases are thought to
result from poor hygiene and chronic irrita-
tion. Surgery with a negative resection margin
offers the best hope of cure as adjunctive ther-
apy has not proved useful. Prognosis correlates
with the extent of nodal involvement.
Introduction
The scrotum is a seven-layer pouch which
covers the testes, testicular adnexae, and dis-
tal spermatic cord. These layers are the epider-
mis, dermis, tunica dartos, the three layers of
Colles’ fascia and the parietal layer of the tuni-
ca vaginalis,1 The scrotal lymphatics drain into
the corresponding superficial inguinal lymph
nodes. Anastomoses to the lymphatics of the
contralateral network across the median raphe
occur. Testicular lymphatics drain to the para-
aortic nodes.
Tumors have been reported to arise out of
virtually any of the components of the scrotal
wall.2 Both benign and malignant tumors of the
scrotum are rare.1 Squamous cell carcinoma of
the scrotum is now very rare; the incidence
has been reported to be less than 10 cases per
year in the United States.2 Squamous cell car-
cinoma is the most common malignant tumor
of the scrotum; however, rare cases of basal
cell carcinoma, melanoma, Paget’s disease and
sarcoma have been reported.3 Secondary
tumors of the scrotum can occur; for instance,
carcinoid tumor of the small bowel can metas-
tasize to the scrotum simulating a primary
scrotal tumor.1
Squamous cell carcinoma of the scrotum is
a tumor that is of interest for clinical and his-
torical reasons. It has been identified as a sen-
tinel health event (occupational) [(SHE(0)].4
Synonyms include epidermoid carcinoma of
the scrotum, chimney sweepers cancer, mule-
spinners cancer and epithelioma of the scro-
tum. It is customary to give priority for the
description of the disease to Bassius who
described it in 1731, but it was Percivall Pott
who in 1775 described its occurrence in chim-
ney sweeps in Pott’s Chirurgical Observations,
thereby making him the first to attribute an
occupational cause to the disease. This also
established scrotal cancer as the first
described occupational cancer.1,2,5 Squamous
cell carcinoma of the scrotum has historically
been associated with exposure to occupational
(industrial) and non-occupational (environ-
mental) carcinogens. From the eighteenth
century, there have been at least three broad
occupational groups with a preponderance of
the disease: chimney sweeps, people who work
with the distillates of coal, and men exposed to
mineral oil. The common hazard in these occu-
pations arises from polycyclic aromatic hydro-
carbons in soots, tars and mineral oils.6 In
these industries, improved technology or the
decline of the industry have led to less men
being affected. Chimney sweep cancer was
commoner in England, as cases were virtually
unknown in other parts of Europe or America;
attention to personal hygiene had for long
been the practice among the continental
sweeps. The introduction of protective clothing
at work and improved personal hygiene
reduced the incidence of chimney sweep can-
cer in England.
The first public notice that the distillation of
coal might induce cancer of the scrotum was
given by Von Volkman at the Third Surgical
Congress in Berlin in 1873. Tar from gas works
blast furnaces, and coke ovens was used wide-
ly from the end of the nineteenth century, both
in the original state and for the distillation of a
series of hydrocarbons which included cre-
osote, anthracene and naphthalene. The etiol-
ogy of the disease was unclear from the time of
Pott until 1922, when Passey gave experimen-
tal evidence of the presence of weak carcino-
gens in soot, as the theory of chronic irritation
popular at the time did not fully answer all the
questions raised. Men exposed to mineral oil
included shale oil workers and engineering
workers exposed to cutting oils. Unrefined or
mildly refined mineral oils have substantial
levels of polycyclic aromatic hydrocarbons and
their use in industries such as printing and
metalworking in the past has led to skin can-
cers.5 The hazard has remained but newer cir-
cumstances may now be involved. Engine oils
have elevated polycyclic aromatic hydrocarbon
content with use; prolonged and repeated con-
[Rare Tumors 2009; 1:e17]
Rare Tumors 2009; volume 1:e17
Correspondence: Jerome E. Azike,
Department of Surgery, College of Medicine and
Health Sciences, Imo State University, Orlu, Imo
State, Nigeria.
E-mail: jeazike@yahoo.com
Key words: cancer of the scrotum, history, epi-
demiology, treatment.
Received for publication: 13 June 2009.
Accepted for publication: 12 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright J.E. Azike 2009
Rare Tumors 2009; 1:e17
doi:10.4081/rt.2009.e17
tact with used engine oil can cause skin and
scrotal cancer. Car mechanics are at potential
risk from used engine oils.7 Best occupational
health practices are invaluable to minimize
exposure at the work place. The establishment
of the concept of latent period in tumor induc-
tion in the last century helped shed light on the
observation by several writers that the scrotal
lesion appeared many years after the man had
left the job associated with squamous cell can-
cer or when he was in another trade altogeth-
er. In this respect, Henry Earle and Curling
noted the disease appearing after intervals of
15 years and 19 years, respectively.5 Other non-
occupational factors that may be associated
with the disease include prior history of can-
cer, PUVA (psoralen-ultraviolet light) treat-
ments, radiotherapy, poor personal hygiene
and treatment with arsenical compounds.3,5,8,9
Case reports exist which correlated squamous
cell carcinoma of the scrotum with human
papilloma viruses, mainly oncogenic types 16
and /or 18 or 6/118,10,11 but a direct causal rela-
tionship has not been established. Squamous
cell carcinoma of the male genitalia may be
multifocal,12 especially when oncogenic human
papillomavirus types are present.10
Patients frequently delayed seeking medical
help,5 mainly due to embarrassment, ignorance
or both; that the initial lesion is usually slowly
growing and painless may also be contributory.
In a case series of 9 patients, Mc Donald report-
ed that the interval between patient awareness
of the lesion to diagnosis averaged 3.3 years.13
In a case series of 19 patients seen between
1948 and 1971, Ray and Whitmore found the
interval before presentation was 26 months.9
However, in earlier reviews the interval
between onset of symptoms and treatment was
reported to have been about 10-12 months.9
This may suggest that as the disease became
less common, the interval between onset of
symptoms and presentation increased.
[page 47]
Review
The patients afflicted with chimney sweeps
cancer were generally young men. Writing in
1832, Henry Earle considered that the majority
of cases were in patients between the ages of
30 and 40. Green analyzed 36 cases pooled
from the eighteenth and nineteenth century
literature and found the mean age of presenta-
tion was 37.7 years.5 However in the series by
Ray and Whitmore, which involved cases seen
between 1948 and 1971, the average age was
56 years; the majority occurred in the 5th to 7th
decade of life.9
Squamous cell carcinoma of the scrotum
frequently present as a solitary wart or nodule
on the scrotum. There seems to be no
predilection for any side, if patients with occu-
pational cancer are excluded.9 Superficial
ulceration may follow increase in size or the
effect of scratching at the lesion. Ulcerated
lesions may have a sero-sanguinous discharge
that may become profuse and foul-smelling if
infected. If an ulcer is present, it is a malig-
nant squamous ulcer and would have features
expected of such. There may be ipsilateral or
bilateral inguinal lymph node enlargement
which may be inflammatory or neoplastic or
both.9 In some cases, the growth may become
large and grotesque. Pain is usually absent
until late stages of the disease. Azike,
Chukwujama and Oguike reported on a recent
case of squamous cell carcinoma of the scro-
tum with penile and testicular involvement in
a 42-year old who presented with a 10-year his-
tory.14
Spread and metastasis
The lesion tends to remain localized to the
scrotal wall, may occasionally involves the
adjacent perineal skin but rarely involve the
scrotal contents or penis; distant spread is
rare.9 The pubic bone is occasionally involved
by direct extension.14,15 In the series of 141
cases, Southan and Wilson found testicular
involvement in 6 and penile in 3 cases.16
Spread is to the inquinal which may be unilat-
eral, bilateral or crossed; iliac nodes, the para
aortic nodes, and may reach the lungs.
Metastatic involvement has been reported as
early as four months or as late as ten years.17
The iliac nodes may be involved when there is
no recognized inguinal involvement.9
Primary tumors in other sites
Dean noted the high incidence of multiple
primary tumors in patients with scrotal cancer.
In his series, 8 of 27 patients had other pri-
mary tumor.17 In the series by Ray and
Whitmore,8 9 of 19 patients had another pri-
mary tumor.9 Weinstein, Howe and Burnett
found that 8 out of the 19 cases had prior his-
tory of cancer.4 Lione and Denholm described a
patient who died of stomach cancer two years
after treatment for scrotal carcinoma.9
[page 48]
Diagnosis
The diagnosis is suggested clinically and is
confirmed by wedge biopsy of the edge of the
scrotal lesion. Refractory scrotal inflammatory
lesions should be biopsied to rule out squa-
mous cell carcinoma. General investigations
include full blood count, serum electrolytes
urea creatinine estimation, liver function
tests, urinalysis, urine culture if indicated,
wound swab culture and sensitivity if ulcera-
tion is present. There is need for extensive
evaluation with appropriate investigative
modalities to exclude associated internal
malignancy. Staging investigations include
abdomino-pelviscrotal ultrasound, MRI of the
scrotum, and chest CT.
Staging
Staging of scrotal carcinoma as proposed by
Ray and Whitmore:9
Stage A
A1 Disease localized to the scrotum
A2 Locally extensive disease involving
adjacent structures (penis, perineum,
testis and/or cord structures, pubic
bone) by continuity but without evident
metastasis.
Stage B
Regional* metastasis, resectable
Stage C
Regional metastasis, non-resectable
Stage D
Distant metastasis (beyond regional nodes)
*Inguinal or ilioinguinal
Treatment
The established treatment for squamous cell
carcinoma of the scrotum is wide excision
with a 2-3 cm margin. Surrounding subcuta-
neous tissue should be excised with the pri-
mary tumor. Resection of the scrotal contents
is rarely necessary for tumor control unless
involved by tumor.3,9 Intra-operative frozen sec-
tions may help to confirm a disease free mar-
gin. Primary scrotal closure is usually possible,
but may be a challenge after large tumor resec-
tion. Many investigators have reported various
methods to cover a healthy testis when primary
closure is not feasible. These include immedi-
ate use of local thigh flaps,18 myocutaneous
gracilis or adductor minimus myocutaneaus
flaps, and heterologous fascia grafts.19-21
Other investigators place the exposed testis in
the subcutaneous tissue of the thigh or femoral
region or do ipsilateral orchidectomy.15,22,23 Others
do contralateral testicular transposition follow-
ing a hemiscrotectomy.24 Local recurrence may
occasionally occur and may be due to insuffi-
cient tumor resection or may represent new
lesions.9,24 Adjunctive treatment like radiother-
apy or chemotherapy or both has not proved
useful, and only palliation is usually feasible
for late stage disease. A multidisciplinary
[Rare Tumors 2009; 1:e17]
approach may be necessary to fully address all
aspects of patient management.
Treatment of the regional lymph
nodes
Briefly, the optimal management of patients
with squamous cell carcinoma of the scrotum
with clinically negative inguinal node is contro-
versial and involves a decision as to whether a
prophylactic or therapeutic node dissection
should be performed. Some authors15,25 propose
bilateral radical groin dissection to remove
micrometastasis; the rationale of the contralat-
eral groin dissection being the free communi-
cation between the lymphatics of the two sides
of the scrotum. Dean emphasized that only 50%
of patients with inquinal adenopathy actually
had metastases, suggesting that routine dis-
section would be useful only in half of the
patients with inquinal adenopathy. He advocat-
ed bilateral groin dissection only for proved
metastases.17 Ray and Whitmore based on their
experience, advocated patient follow-up at 2-3
month intervals after excision of primary lesion
and to perform an ipsilateral ilioinguinal dis-
section if there is clinical evidence of metasta-
sis proved by biopsy, and to perform an ipsilat-
eral ilioinguinal dissection if there is clinical
evidence of metastasis proved by biopsy, and to
defer contralateral ilioinguinal dissection until
there is clinical evidence of metastasis. Presti
jr. advocated observation for clinically negative
lymph nodes, but patients with clinically palpa-
ble nodes to be given antibiotics first. If the
groin nodes remain clinically palpable, ilioin-
guinal lymph node dissection is performed. But
if it becomes clinically negative after broad
spectrum antibiotics, limited node sampling is
performed. If positive, ilioinguinal lymph node
dissection is performed; if negative observation
is continued.3
Prognosis
An important prognostic factor is the ability
to completely excise the tumor at the time of
initial surgery.2 Prognosis correlates with the
presence or absence of nodal involvement. If
the inguinal nodes are involved the 5-year sur-
vival rate is approximately 25%. There are vir-
tually no survivors if the iliac nodes are affect-
ed.3,9 In a review of a series of 18 patients, Ray
and Whitmore Jr found no correlation among
the patient age, duration of symptoms, size,
histological type or grade of the tumor and sur-
vival. However, they reported that patients with
high tumor burden had the worst prognosis; no
patient with non-resectable metastasis or
metastases beyond the inquinal nodes sur-
vived.9 Patient follow-up is for life.

Conclusions
Squamous cell carcinoma of the scrotum is
now a rare clinical entity and it is given only
scant attention in most urological textbooks. It
is pertinent to once again remind the medical
community of the existence of this disease and
provide a brief summary of its history, epi-
demiology and treatment from the literature to
add to the resources available to the practising
urologists and oncologists.
References
1. Rosai J. Rosai and Ackerman’s Surgical
Pathology, London. Mosby 2004:1475-8.
2. Rowland RG, Herman JR. Tumors and
Infectious Diseases of the Testis,
Epididymis, and Scrotum. In Gillenwater
JY, Grayhack JT, Howards SS and Mitchell
ME, editiors. Adult and Pediatric Urology,
Philadelphia: Lippincott, Williams and
Wilkins; 2002.
3. Presti JC Jr, Genital Tumors. In Tanagho
EA, McAnich JW, editors. Smith’s General
Urology. New York: McGraw Hill 2008:375-
87
4. Rutstein DD, Mullan RJ, Frazier TM,
Halperin WE, Melius JM, Sestito JP.
Sentinel Health Events (Occupational): A
basis for physician recognition and public
health surveillance. In Weinstein A.L,
Howe H.L, Burmett W.S. Sentinel Health
Event Surveillance: Skin Cancer of the
Scrotum in New York State. Am J public
Health 1989;79:1513-5
5. Waldron H.A. A brief history of Scrotal
Cancer. British Journal of Industrial
Medicine 1983;40:390-401.
6. Coggon D, Inskip H, Winter P, Pannett B.
Mortality from Scrotal Cancer in metal
machinists in England and Wales, 1979-80
and 1982-90. Occup Med 1996;46:69-70.
7. Wyre Borough Council, Lancashire, U.K.,
Carcinogens. In Health and Safety
Factsheet – No 12 (Internet) 2002.
Available from: htt://www.wyrebc.gov.uk
(cited 5th July, 2008).
8. Burmer GC, True LD, Krieger JN.
Squamous cell carcinoma of the scrotum
associated with human papillomaviruses.
J Urol 1993; 149:374-7.
9. Ray B, Whitmore Wf Jr, Experience with
Carcinoma of the Scrotum. J Urol 1977;
117:741-5.
10. Orihuela E, Tyring S.K, Pow-sang M, et al.
Development of Human Papillomavirus
type 16 associated squamous cell carcino-
ma of the scrotum in a patient with
Darier’s disease treated with systemic
isoretinoin. J Urol 1995; 153:1940-3.
11. Chatora GT, Rourke T, Sezhian N, Suresh
G. A case of Scrotal Cancer with Inguinal
lymph node metastasis treated by
Multidisciplinary modalities: a case report.
The Internet Journal of Urology. ISSN:
1528-8390 [internet] (cited 7th Decem-
ber, 2008).
12. Gerber WL. Scrotal malignancies: the
University of Iowa experience and a
review of the literature. In: Oribuela E,
Tyring S.K, Pow-sang M, Dozier S, Cirelli
R, Arany I, et al. Development of Human
Papillomavirus type 16 associated squa-
mous cell carcinoma of the scrotum in a
patient with Darier’s disease treated with
systemic isotretinoin. J Urol 1995;153:
1940-3.
13. Mc Donald MW. Carcinoma of the scrotum.
Urology 1982;19:269-74.
14. Azike JE, Chukwujama NO, Oguike TC.
Squamous cell carcinoma of the scrotum
in a Nigerian: case report. Rare Tumors
2009;1:e3.
15. Graves RC, Flo S. Carcinoma of the scro-
tum. In: Ray B, Whitmore WF Jr.
Experience with carcinoma of the scrotum
J Urol 1977,117:741-5
16. Southam AH, Wilson SR. Cancer of the
Scrotum; the etiology, clinical features,
and treatment of the disease. In Ray B,
Whitmore WF Jr., Experience with carcino-
ma of the scrotum, J Urol 1977;117:741-5.
17. Dean A.L. Epithelioma of Scrotum. In: Ray
B. Whitmore WF Jr,. Experience with
Carcinoma of the Scrotum J Urol 1977;117:
[Rare Tumors 2009; 1:e17]
Review
741-5.
18. Park S, Grossfeld GD, McAninch JW,
Santucci R. Extramammary Paget’s dis-
ease of the penis and scrotum: excision,
reconstruction and evaluation of occult
malignancy. In: Arango O, Bielsa O,
Lorente JA, De Leon E, Mas GA. Hemi-
scrotectomy with contralateral testicular
transposition J Urol 2002;168: 1406-7.
19. Wesfall CT, keller HB. Scrotal reconstruc-
tion utilizing bilateral gracilis myocuta-
neous flaps. In: Arango O, Bielsa O,
Lorente JA, De Leon E, Mas GA. Hemi-
scrotectomy with cantralateral testicular
transposition for scrotal cancer. J Urol
2002;168:1406-7.
20. DiGeronimo EM. Scrotal reconstruction
utilizing a unilateral adductor minimus
myocutaneous flap. In: Arango O, Bielsa O,
Lorente JA, De Leon E, Mas GA. Hemi-
scrotectomy with contralateral testicular
transposition for scrotal cancer. J Urol
2002;168: 1406-7.
21. El-Domeiri AA, Paglia MA. Carcinoma of
the scrotum, radical excision and rapair
using ox fascia: case report. In: Arango O,
Bielsa O, Lorente JA, De Leon E, Mas GA.
Hemiscrotectomy with contralateral testic-
ular transposition for scrotal cancer. J Urol
2002;167:1406-7.
22. Hoch WH. Adenocarcinoma of the scrotum
(extra Mammary Paget’s disease): case
report and review of the literature. In
Arango O., Bielsa O., lorente J.A, De Leon
E, Mas GA. Hemiscrotectomy with con-
tralaterial Testicular Transposition for
scrotal cancer. J Urol 2002;168:1406-7.
23. Lowe FC. Squamous cell carcinoma of
scrotum. In: Arango O, Bielsa O, Lorente
JA, De Leon E, Mas GA. Hemiscrotectomy
with contralateral testicular transposition
for scrotal cancer. J Urol 2003;168:1406-7.
24. Arango O, Bielsa O, Lorente JA, De Leon E,
Mas GA. Hemiscrotectomy transposition
for scrotal cancer. J Urol 2002;168:1406-7.
25. Kickham JE, dufresne M. An assessment
of carcinoma of the scrotum. In: Ray B,
Whitmore WF Jr., experience with carcino-
ma of the scrotum J Urol 1977;117:741-5.
[page 49]
Rare Tumors 2009; volume 1:e18
Assessment of cytological
atypia, AgNOR and nuclear
area in epithelial cells of
normal oral mucosa exposed
to toombak and smoking
Hussain Gadelkarim Ahmed,1
Abd-Elraheem Ali Babiker2
1
Department of Histopathology and
Cytology, Faculty of Medical Laboratory
Sciences, University of Khartoum,
Khartoum, Sudan; 2Department of
Histopathology and Cytology, Faculty of
Medical Laboratory Sciences, University
for Science and Technology, Khartoum,
Sudan
Abstract
The purpose of this study was to assess cel-
lular proliferative activity of clinically healthy
oral mucosal epithelial cells of toombak dip-
pers and smokers by means of AgNOR counts
and nuclear areas via nuclear morphometry.
Smears were collected from normal-appearing
mouth floor mucosa and tongue of 75 toombak
dippers, 75 smokers and 50 non-tobacco users
between the ages of 20 and 70 with a mean age
of 36 years. AgNORs were counted in the first
50 well-fixed, nucleated squamous cells and
nuclear areas were calculated via microscopic
stage micrometer. Cytological atypia was
ascertained in 6 tobacco users and could not be
ascertained in non-tobacco users. Statistically
mean AgNOR numbers per nucleus in the non-
tobacco users (2.45±0.30) was lower than the
toombak dippers (3.081±0.39, p<0.004), and
the smokers (2.715±0.39, p<0.02), and mean
nuclear areas of epithelial cells of toombak dip-
pers (6.081±0.39, p<0.009) and smokers
(5.68±10.08, p<0.01) was also significantly
higher than non-smokers (5.39±9.4). The
mean number of nuclei having more than 3
AgNORs was 28%, 19% and 7% in toombak dip-
pers, smokers and non-tobacco users, respec-
tively. These findings support the view that
toombak dipping and smoking are severe risk
factors for oral mucosal proliferative lesions
and exfoliative cytology is valid for screening
of oral mucosal lesions.
Introduction
The prevalence of potentially malignant oral
mucosal lesions and conditions shows wide
variations between developed and developing
countries.1 The primary risk factors for devel-
[page 50]
opment of both OSCCs or potentially malignant
lesions are considered to be similar.1,2
However, social habits of tobacco use and alco-
hol consumption have been strongly attributed
to development of these lesions1,2 In the Sudan,
the high incidence of OSCCs and an equally
high prevalence of potentially malignant oral
mucosal lesions have been strongly attributed
to the habit of snuff use, locally known as
toombak.3 Toombak has been in use in the
Sudan for centuries and its use is wide-
spread.3,4 A close relationship between use of
toombak and development of OSCCs has been
reported.3 In addition, use of toombak has been
shown to produce a variety of oral mucosal
changes such as dysplasia and hyperkerato-
sis.3,5 An unusually high level of the carcino-
genic tobacco-specific nitrosamines (TSNAs)
was found in toombak.6 In the Sudanese popu-
lation, however, and due to several reasons,
both cigarette smoking and alcohol consump-
tion are uncommon.3,5 Early diagnosis is of
great importance for oral SCC, oral exfoliative
cytology, a simple, painless and inexpensive
method has become a preferred method for
both early diagnosis of the lesion and for
establishing quantitative techniques.7,8 The
presence of two or more of the following fea-
tures were consistent with atypia: nuclear
enlargement, associated with the increased
nuclear/cytoplasmic ratio, nuclear hyperchro-
matism, chromatin clumping with prominent
nucleation, irregularity of nuclear membranes,
bi- or multinucleation, increased keratiniza-
tion.9 Nucleolar organizer regions (NORs) are
located in the cell nucleoli during interphase.
They are loops of DNA in which ribosomal RNA
is encoded.10 They are located in the acrocen-
tric chromosomes 13, 14, 15, 21 and 22.7 Their
number per nucleus has been shown to be cor-
related with the rate of ribosomal RNA tran-
scription, cell proliferation and DNA ploidy.10
Nucleolar organizer regions can be demon-
strated with the use of AgNOR technique
which is the silver staining technique for
showing NORs as black dots inside the nucle-
us when examined under a light microscope.7
Materials and Methods
A total of 200 clinically healthy volunteers
seen in our Dental Clinic, aged between 20 and
70, with a mean age of 36 years, of which 75
were toombak dippers, 75 were cigarette smok-
ers and 50 were non-tobacco users, were ini-
tially selected for this study. All toombak dip-
pers and cigarette smokers were chosen
among persons who have dipped toombak or
smoked cigaretteS at least for the last five
years and at least 5 cigarettes per day. Patients
with clinically apparent oral mucosal lesions,
and previous benign or malignant lesions were
[Rare Tumors 2009; 1:e18]
Correspondence: Hussain Gadelkarim Ahmed,
University of University of Khartoum, 102, Faculty
of Medical Laboratory Sciences, Khartoum,
Sudan: E-mail: Hussaingad1972@yahoo.com
Key words: toombak, smoking, oral mucosa,
AgNOR, nuclear area.
Acknowledgments: we would like to thank the
members of the Department of Histopathology
and Cytology, Faculty of Medical Laboratory
Sciences, Sudan University for Science and
Technology for their technical help and assis-
tance.
Financial disclosure: the authors have no connec-
tion with any company and the work was support-
ed by the authors and the Sudan University for
Science and Technology.
Received for publication: 29 June 2009.
Accepted for publication: 30 June 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright H.G. Ahmed and A.-E. A. Babiker 2009
Rare Tumors 2009; 1:e18
doi:10.4081/rt.2009.e18
excluded from this study. Also individuals who
had drunk any alcoholic beverage for the last
ten years were not included in the study.
All cytological smears were collected by the
same examiner from the mucosa of the mouth
floor and tongue (in smokers) or from the dip
site (in toombak dippers). Participants were
asked to rinse their mouth with saline solution
for a minute before collection of the samples.
The specimen collection site was dried by a
smooth wipe so as to avoid silver staining of
the mucoid material of saliva during applica-
tion of AgNOR method to the slides. The mate-
rial was collected by a smooth brush after
brushing the floor of the mouth and tongue or
dip-site two times, and rinsing and cleaning
the brush each time in a saline solution. This
was done so as to collect cells from the inner
layers of the oral mucosa. The material collect-
ed was smeared on two slides and immediate-
ly fixed in 95% ethyl alcohol for 15 minutes.
One slide was stained according to the
Papanicolaou staining method7 and the other
was stained according to AgNOR staining
method described by Ploton et al.11
Papanicolaou staining method
Ethyl alcohol fixed smears were hydrated in
descending concentrations of 95% alcohol
through 70% alcohol to distilled water, for two
minutes in each stage. Then the smears were
treated with Harris’ hematoxylin for five min-

utes to stain the nuclei, rinsed in distilled
water and differentiated in 0.5% aqueous
hydrochloric acid for a few seconds, to remove
the excess stain. They were then immediately
rinsed in distilled water, to stop the action of
discoloration. Then the smears were blued in
alkaline water for a few seconds and dehydrat-
ed in ascending alcoholic concentrations from
70%, through two changes of 95% alcohol for
two minutes for each change. The smears were
next treated with Eosin Azure 50 for four min-
utes. For cytoplasmic staining, they were treat-
ed with Papanicolaou Orange G6 for two min-
utes, rinsed in 95% alcohol and then dehydrat-
ed in absolute alcohol. The smears were then
cleared in Xylene and mounted in DPX
(Distrene Polystyrene Xylene) mount. All the
reagents used were from Thermo Electron
Corporation, UK.
Atypia was assessed cytologically by using
the criteria described elsewhere.12 The pres-
ence of two or more of the following features
were consistent with atypia: nuclear enlarge-
ment associated with increased nuclear cyto-
plasmic ratio, hyperchromatism, chromatin
clumping with moderately prominent nucleoli,
irregular nuclear membranes and bi- or multi-
nucleation, scant cytoplasm, and variation in
size and/or shape of the cells and nuclei.
AgNOR staining method
The smears were stained according to the
AgNOR staining method. Working solution was
freshly prepared by mixing one volume of 2%
gelatin in 1% formic acid solution and two vol-
umes of 50% aqueous silver nitrate solution.
All smears were incubated with this silver
solution for 30 minutes at room temperature in
a dark medium and they were protected in the
dark until each slide was analyzed.
Two investigators, blind to the study groups,
analyzed the silver-stained cells under light
microscope (Olympus BX-51, Japan) at 1000x
magnification. All smears were screened hori-
zontally from left to right and AgNORs were
counted in the nuclei of the first 50 non-over-
lapping, inner layers, nucleated epithelial
cells. Superficial cells with pyknotic nuclei
were not counted. The AgNOR count was made
adopting the method described by Crocker et
al.13
AgNORs, which were visible as black-dark
brown dots located within the nuclei of the
cells, were counted; overlapped black dots were
counted as one structure. To calibrate the
examiners, ten smears from each group
(toombak dippers, smokers and non-tobacco
users) were counted three times in a non-con-
secutive way. Mean number of AgNORs and
mean percentage of nuclei with more than
three AgNORs was also calculated.
For calculating the nuclear areas of the
epithelial cells, the smears were further
assessed. Fifty cells, having the same proper-
ties as the cells whose AgNORs were counted,
were selected and the nuclear area of each cell
was calculated via the microscopic stage
micrometer.
Statistical analysis
SPSS version 12 statistical software was
used for statistical analysis. The numeric
results (AgNOR counts and nuclear areas)
were expressed as mean±SD, and the 95%
confidence intervals (CIs) of the means were
calculated. The X2 test was used to compare the
differences in categorical variables between
the groups. Relationships between variables
were analyzed using Pearson’s correlation
analysis. A p<0.05 was considered statistically
significant.
Ethical consent
Each participant was asked to sign a written
ethical consent form during the interview,
before the specimen was taken. The informed
ethical consent form was designed and
approved by the ethical committee of the
Faculty of Medical Laboratory Research Board,
Sudan University for Science and Technology.
Results
Mean age was 36.2±10.7 in the study popu-
lation; 34.9±11.6 in non-tobacco users,
34.7±8.5 in smokers and 38.5±11.8 in toombak
dippers. All the population were males and
there were no statistically significant differ-
ences between non-smokers and toombak dip-
pers (p=0.09) or smokers (p=0.94) in age.
Cytological atypia was ascertained in 6 tobacco
users and could not be ascertained in non-
tobacco users. Among the 6 subjects with cyto-
logical atypia, there were 4 (67%) toombak dip-
pers and 2 (33%) cigarette smokers.
In toombak dippers, AgNOR numbers per
nucleus varied from 1 to 9, in smokers from 1
to 7, while the range was between 1 and 4 in
the non-tobacco users. The mean±SD of
AgNOR numbers per nucleus in the non-tobac-
co users (2.45±0.30) was lower than the toom-
bak dippers (3.081±0.39, p<0.004), and the
smokers (2.715±0.39, p<0.02), and mean±SD
nuclear areas of the oral epithelial cells of
toombak dippers (6.081±0.39, p<0.009) and
smokers (5.68±10.08, p<0.01), were also sig-
nificantly higher than non-tobacco users
(5.39±9.4). The mean number of nuclei having
more than 3 AgNORs was 28%, 19% and 7% in
toombak dippers, smokers and non-tobacco
users, respectively.
[Rare Tumors 2009; 1:e18]
Article
Discussion
In this study we have taken the smears from
the mouth floors and tongue of the study sub-
jects. It has been found that the mean AgNOR
counts in smokers are the highest in epithelial
cells of floor of the mouth when compared with
the edge of the tongue and lower lip,7 although
some studies have reported strong association
between smoking and carcinoma of the
tongue. Consequently, our cytological materi-
als were collected from the mouth floors and
tongues of the smokers. Concerning toombak
dippers we planned to take the cytological
materials from the application site (dip site).
Generally toombak is dipped and retained
between gum and lip or cheeks or floor of the
mouth, and sucked slowly for about 10±5 min-
utes.4 Toombak dippers develop a clinically and
histologically characteristic lesion at the site
of dipping.3
In the present study it can also be seen that
cytological atypia among the tobacco users is
significantly higher than the non-tobacco
users, which is a similar finding with the study
of Ahmed et al.12 Their findings suggested that
toombak dipping and cigarette smoking are
associated with a risk for occurrence of oral
epithelial atypia, which can be detected by use
of simple cytological methods. The findings
further suggested that tobacco components,
specially the TSNAs, may stimulate the epithe-
lial cells to undergo squamous differentia-
tion/or cellular morphological changes that
might lead to malignancy as suggested by oth-
ers.6,14
AgNOR counts have been of great value for
the assessment of cellular proliferative activity
that is frequently encountered in pre-malig-
nant and malignant changes.15 A number of
studies have pointed out that the AgNOR count
is a rapid and an easily reproducible method
which permits a clear distinction between
malignant and benign cells.15,16
There are many previous AgNOR studies of
oral mucosa with benign, pre-malignant and
malignant lesions, and only a few studies have
been conducted on exfoliative cells obtained
from oral mucosa exposed to cigarette smoking
or alcohol.7,17-19 It is noteworthy that to the best of
our knowledge there has been no AgNOR study
of normal oral mucosa exposed to toombak dip-
ping. Mean AgNOR counts and keratinization
are the only parameters that are sought in most
of these studies. Though some cytological stud-
ies have assessed the oral epithelial atypia of
toombak dippers,8,12 to the best of our knowl-
edge, this is the first study including cytological
atypia, mean AgNOR counts and nuclear areas
of oral mucosal cells exposed to toombak dip-
ping and cigarette smoking, and a comparison
of all these parameters.
However, there is no study from the Sudan
[page 51]
Article
measuring AgNOR or NA. Similar outcomes in
the effect of toombak in previous studies
reported that the use of toombak plays a major
role in the etiology of oral cancer in the
Sudan.3,8
Significant elevation in the mean AgNOR
number of the smoker population was previ-
ously documented by some similar studies.7,19,20
In the present study it can also be seen that
mean nuclear area of the smoker group is sig-
nificantly higher than the non-tobacco users,
which is a similar finding to another study
reported elsewhere.21
Results of both mean AgNOR counts and
mean nuclear area show that cellular prolifer-
ation is significantly higher in tobacco users
and this causes an increase in the nuclear
atypical changes of oral epithelial cells, which
can be accepted as a progression towards fea-
tures of dysplastic cellular changes. It is well
established that, changing of a normal cell to a
malignant cell requires the occurrence of a
precursor non-malignant cell, which exhibits
increased DNA changes, cell proliferation and
apoptosis.22
Another remarkable outcome of our study
was the percentage of cells with AgNOR counts
of more than three. It was greater in tobacco
users (toombak (28%) and smokers (19%)
than in non-tobacco users (7%), which is a
consistent finding with the study that com-
pared the mean AgNOR count between smok-
ers and non-smokers.17 Nevertheless, mean
AgNOR counts of both tobacco users and non-
tobacco users are relatively lower than that of
some previous studies.7,10,20 Mean nuclear areas
of both groups are also smaller than the mean
nuclear areas calculated in the previous stud-
ies.10,23 Although there might be negligible dif-
ferences in counting and calculating tech-
niques, we believe that the variation in age of
the study population may be an explanation for
the differences in our results from previous
studies. It is well-known that the risk of cyto-
logical atypia increases with increasing age.12
In conclusion, our results support the view that
tobacco use is a risk factor for the develop-
ment of oral epithelial proliferative changes,
and exfoliative cytology can be the preferred
method for screening for oral mucosal lesions.
As oral cancer is a major health problem in the
Sudan, strategy for prevention comprising
comprehensive public educational program is
highly recommended. All those involved in the
habit of toombak use should undergo a contin-
uous screening program.
[page 52]
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smoking. Acta Cytol 1999;43:117-20.
18. Sethi P, Shah PM. Oral exfoliative cytology
of smokers at discrete clinical stages using
AgNOR staining. Indian J Dent Res 2003;
14:142-5.
19. Orellana-Bustos AI, Espinoza-Santander
IL, Franco-Martínez ME, et al. Evaluation
of keratinization and AgNORs count in
exfoliative cytology of normal oral mucosa
from smokers and non-smokers. Med Oral
2004;9:197-203.
20. Cançado RP, Yurgel LS, Filho MS.
Evaluation of the nucleolar organizer
region associated proteins in exfoliative
cytology of normal buccal mucosa. Effect of
smoking. Oral Oncol 2001;37:446-54.
21. Einstein TB, Sivapathasundharam B.
Cytomorphometric analysis of the buccal
mucosa of tobacco users. Indian J Dent
Res 2005;16:42-6.
22. Schwartz JL, Muscat JE, Baker V, et al. Oral
cytology assessment by flow cytometry of
DNA adducts, aneuploidy, proliferation
and apoptosis shows differences between
smokers and non-smokers. Oral Oncol
2003;39:842-54.
23. Caruntu ID, Scutariu MM, Dobrescu G.
Computerized morphometric discrimina-
tion between normal and tumoral cells in
oral smears. J Cell Mol Med 2005;9:160-8.

Desmoplastic small round cell
tumor: impact of 18F-FDG PET
induced treatment strategy
in a patient with long-term
outcome
Dorra Ben-Sellem,1 Kun-Lun Liu,2
Sébastien Cimarelli,3
André Constantinesco,1 Alessio Imperiale1
1
Service de Biophysique et de Médecine
Nucléaire, Hôpital de Hautepierre,
Strasbourg, France; 2Service d’Onco-
hématologie, Hôpital de Hautepierre,
Strasbourg, France; 3Service de Médecine
Nucléaire, Centre Leon Berard, Lyon,
France
Abstract
The desmoplastic small round cell tumor
(DSRCT) is an uncommon and highly aggres-
sive cancer. The role of 18F-FDG PET in man-
agement of DSRCT is little reported. We report
a case of metastasized abdominal DSRCT
detected in a 43-year old patient whose diag-
nostic and therapeutic approaches were influ-
enced by 18F-FDG PET-CT. The patient is still
alive ten years after diagnosis. 18F-FDG PET-CT
seems to be a useful method for assessing
therapeutic efficiency and detecting early
recurrences even in rare malignancies such as
DSRCT.
Introduction
The desmoplastic small round cell tumor
(DSRCT) is an extremely rare and highly
aggressive neoplasm mainly affecting adoles-
cents and young male adults.1,2 DSRCT origi-
nates predominantly in the abdominal or pelvic
cavity, spreading along the peritoneum with
organ involvement and secondary phenome-
na.3 Despite multimodality aggressive therapy,
patient prognosis is unfavorable, with a medi-
an survival of less than 30 months. Only a few
long-term survivors are reported.4,5
To our knowledge, no definitive standard
recommendations exist concerning DSRCT
treatment and patient management during fol-
low-up.3 X-ray Computed Tomography (CT)
remains the first choice imaging modality
employed in patients affected by DSRCT. 18F-
fluoro-2-deoxy-D-glucose positron emission
tomography (18F-FDG PET) is a functional
imaging technique widely used in clinical
oncology because of its high diagnostic accura-
cy.6 However, the role of 18F-FDG PET in the
management of DSRCT is little described.
We report a rare case of a metastasized
abdominal DSRCT detected in a 43-year old
patient whose diagnostic and therapeutic
strategies were influenced by the 18F-FDG PET-
CT. The patient is still alive at the time of this
report, ten years after the diagnosis.
Case Report
A 43-year old man with a history of right kid-
ney cysts was referred to our Institution for
further evaluation of a preaortic intraperi-
toneal mass incidentally detected during
abdominal ultrasonography. Clinical examina-
tion and routine biological evaluation showed
no remarkable findings. Media contrast
enhancement (mce) CT of the abdomen and
pelvis showed the presence of a vascularized,
preaortic mass (7x5 cm) associated to
retroperitoneal lymphadenopathy and mesen-
teric nodules, for which the diagnosis of malig-
nancy was evoked. Chest mce-CT showed nei-
ther pathological lymphadenopathy nor lung
parenchyma abnormalities. The serum level of
common tumoral markers was normal. The
results of 24 h urine analysis showed normal
concentrations of dopamine, epinephrine and
norepinephrine. A whole body (WB) bone scan
showed no pathological foci of tracer uptake.
An ultrasound guided needle biopsy of preaor-
tic lesion was made for pathological evalua-
tion. Microscopic examination revealed neo-
plastic proliferation of small cells with abun-
dant and clear cytoplasm. The nuclei were
slightly increased in size, oval, hyperchromat-
ic, and with inconspicuous nucleoli. The tumor
cells were surrounded by fibro-sclerotic stro-
ma. The immunohistochemical studies
revealed that the tumor cells were positive for
antibodies against keratin, epithelial mem-
brane antigen, vimentin, desmin and focally
neuron specific enolase. Tumoral proliferation
index, estimated with antibodies against Ki-
67, was elevated (50%). Both the histological
aspect and immunohistochemical profile lead
to the diagnostic hypothesis of DSRCT. The
molecular analysis found no specific gene
translocation t(11;22)(p13;q12). In October
1999, the patient underwent surgery including
tumoral radical resection, partial sigmoidecto-
my, and primitive iliac and peri-aortic lym-
phadectomy. Microscopic analysis of the
excised tumor confirmed biopsy suspicion;
thus metastatic DSRCT was retained as the
final diagnosis.
Treatment was carried out according to the
99 EURO-EWING protocol.7 From December
1999 to April 2000 the patient received 6 cycles
of VIDE combining intravenous (i.v.) vin-
cristine (1.5 mg/m2 on day 1), ifosfamide (3000
mg/m2 on day 1-3), doxorubicin (20 mg/m2 on
[Rare Tumors 2009; 1:e19]
Rare Tumors 2009; volume 1:e19
Correspondence: Dorra Ben-Sellem,
Service de Biophysique et de Médecine
Nucléaire, CHU de Hautepierre, 1, Avenue de
Molière, 67098 Strasbourg, France.
E-mail: bensellem_dorra@yahoo.fr
Received for publication: 26 June 2009.
Accepted for publication: 13 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright D. Ben-Sellem et al., 2009
Rare Tumors 2009; 1:e19
doi:10.4081/rt.2009.e19
day 1-3) and etoposide (150 mg/m2 on day 1-3).
The sequence was repeated every three weeks.
No concomitant radiotherapy was performed.
Morphological imaging (CT) performed after 4
and 6 cycles of treatment demonstrated com-
plete remission. No other radiological lesion
was described.
In September 2003, retroperitoneal lym-
phadenophathy was detected on CT study and
biopsied. Microscopic examination revealed
lymphatic DSRCT relapse. Radiological partial
remission was obtained after 3 cycles of VIDE,
thus 12 cycles i.v. of irinotecan (180 mg/m2 on
day 1, every two weeks) were administered as
a second-line chemotherapy. In an attempt to
determine the response to therapy, the patient
underwent whole-body (WB) 18F-FDG PET
examination (Figure 1a). A combined PET-CT
scanner was employed (Discovery ST, GE
Medical System; Milwaukee, USA). PET-CT
acquisitions started 60 min after tracer injec-
tion (5.5 MBq/kg), including a head to thighs
CT followed by a 2D PET. CT, PET (attenuation
corrected) and fusioned PET-CT images were
displayed and visually interpreted. For quanti-
tative analysis of 18F-FDG tumoral uptake, we
use the maximum standardized uptake value
(mSUV) per focus. In all of the PET studies
performed, the mSUV was measured in the foci
of highest 18F-FDG uptake within the tumor.
Those values were then considered for tumor
residual viability assessment. 18F-FDG PET-CT
showed several retroperitoneal lymphadenopa-
thy with pathological glucidic hypermetabo-
lism, inducing modification of chemothera-
peutic strategy. Three cycles of actinomicine
(2.5 mg/m2 on day 1, every three weeks) were
performed without any considerable effect on
tumoral progression. Thereafter, the patient
was treated by VIP 500, combining i.v. etopo-
side (100 mg/m2 on day 1-5), ifosfamide (1200
mg/m2 on day 1-5) and cisplatine (20 mg/m2 on
day 1-5). The sequence was repeated every
three weeks. WB 18F-FDG PET-CT study was
performed after the completion of the first 2 of
6 cycles of VIP 500, to assess early response to
therapy. A limited area of residual abnormal
[page 53]
Case Report
glucidic hypermetabolism within the reduced
tumoral mass was recorded on PET-CT images.
No other abnormal hypermetabolic spots sug-
gestive of metastatic localizations were detect-
ed. The patient was considered to be a positive
responder to treatment; thus chemotherapy
was completed and followed by oral adminis-
tration of etoposide 50 mg daily. A follow-up 18F-
FDG PET-CT performed in September 2005
demonstrated complete regression of the trac-
er uptake abnormalities above retroperitoneal
lymphadenopathy detected on previous exami-
nation and morphologically unchanged, so the
treatment was stopped (Figure 1b). In
December, the PET-CT study showed no active
disease, and the patient was considered to be
in remission.
In June 2006, a follow-up PET-CT study
showed pathological 18F-FDG uptake within
several retroperitoneal lymphadenopathy of
one centimeter of maximal diameter, consis-
tent with second tumoral relapse (Figure 1c).
Thus, the patient was treated by oral etoposide
50 mg daily and corticoids 100 mg, day 1-5
monthly. Follow-up scintigraphic examination
was performed in July 2007, demonstrating the
persistence of hypermetabolic retroperitoneal
lymphadenopathy (Figure 1d). The same
chemotherapy was continued including oral
etoposide 50 mg daily, 3-4 days weekly accord-
ing to the hematologic results, associated to
corticoids 100 mg, day 1-5 monthly. The patient
is still alive at the time of this report, ten years
after the diagnosis.
Discussion
DSRCT is a rare and highly aggressive
malignancy of still unknown etiopathogenesis,
first described in 1989 by Gerald and Rosai.8 In
1991, it was proposed as a distinct entity with
well-recognized histological features, kary-
otype and immunochemical characteristics
with coexpression of epithelial, mesenchymal
and neural markers.1,4,9 DSRCT has a predilec-
tion for adolescent and young adult males, with
a median age of 22 years.10 The majority of
DSCRT occurs in the abdominal cavity, includ-
ing retroperitoneum, pelvis, omentum and
mesentery as primary origin site. Some cases
had presentation sites in the scrotum, pleura,
lung, mediastenum, chest wall, thigh, intracra-
nial, soft tissue, sino-nasal regions, submen-
tal, parotid gland and kidney.11-19
DSCRT are characterized by multinodular
growth on the serosal surface.11,20 These tumors
have a tendency to spread along the peri-
toneum and mesothelial-lined surfaces with
organ involvement and secondary phenome-
na.3 The most frequent sites of metastasis are
the liver, lymph nodes, lung and bone mar-
row.3,9,21 This pattern of disease spread reveals
[page 54]
Figure 1. Whole-body maximum intensity projection 18F-FDG PET-CT images in 43-year
old patient with DSRCT showing: (a) first relapse, (b) complete temporary remission
after chemotherapy, (c) second relapse, (d) with moderate response to medical treatment.
the predilection of these tumors to metastasize
through both the lymphatic and hematogenous
routes.3 In our clinical observation, metastatic
proliferation was essentially lymphatic, with-
out soft tissue or bone involvement.
DSCRT are frequently characterized by a
recurrent specific translocation t(11;22)
(p13;q12), resulting in a fusion gene between
Ewing’s sarcoma gene and Wilm’s tumor gene.5
Nevertheless, according to several reports,19,22
no specific gene translocation was found in
our patient.
Because of the rarity of this tumor, only case
reports and small series of patients are docu-
mented, thus no consensus exists concerning
standard methods for its diagnosis, treatment
and management.3
Although magnetic resonance imaging has
been reported to be more useful than other
radiological techniques in delineating the
extent of the abdominal and pelvic disease,19
CT remains the radiological investigation of
first choice. DSCRT appear as single, or multi-
ple, lobulated soft tissue masses within the
omentum, mesentery, perisplenic space, par-
avesical region, retroperitoneum and in the
scrotum.4,21
The usefulness of 18F-FDG PET-CT in the
management of patients affected by DSRCT is
scarcely reported. Dimitrakopoulou-Strauss et
al.,23 recently suggested 18F-FDG PET-CT as a
valuable diagnostic tool for monitoring thera-
peutic effect in patients with metastasized
DSRCT treated by inhibitors of mammalian
target of rapamycin (mTOR). In the report of
Rosoff et al.,24 18F-FDG PET-CT was explored
with the aim of assessing the therapeutic
effect of irinotecan in a patient with DSRCT
showing residual mass, morphologically
unchanged on CT images. PET-CT showed no
evidence of active disease, especially above
pelvic tumor, demonstrating complete treat-
[Rare Tumors 2009; 1:e19]
ment efficacy. 18F-FDG PET accuracy is higher
than that of CT in the assessment of a viable
tumor after chemoradiation treatment, in par-
ticular in lymphomas.25 Moreover, the sensitiv-
ity of a sole morphological approach may be
reduced in normal-sized metastatic lymph
node detection, considering size as the princi-
pal diagnostic criteria for tumor involvement.
Our results are in accordance with those found
by Rosoff et al.,24 showing no pathological 18F-
FDG uptake in PET images above stable lym-
phadenopathy on CT slices, after the comple-
tion of chemotherapy. The non-invasive nature
of PET and its ability to detect early responses
to therapy make it an ideal modality to evalu-
ate the effectiveness of chemotherapy.
Prognosis of patients affected by DSRCT is
extremely poor, with a median survival of less
than 30 months and a rate of 3- and 5-year sur-
vival of 29% and 15%, respectively.5,21 The long
survival observed in our patient is largely supe-
rior to the survival reported in the literature.
18
F-FDG PET-CT played an important role in
patient management, allowing detection of
early recurrence of disease and consequent
change in chemotherapeutic strategy. The rel-
atively long disease free interval of 42 months
may be due to complete tumoral resection fol-
lowed by adjuvant chemotherapy.3,5 The inva-
sive and disseminated nature of the disease
makes radical resection difficult to achieve3,9
with consequent worse patient prognosis.
Furthermore, chemotherapeutic agents are
only temporarily effective in treating DSRCT
and no consistent response to chemotherapy
has been described.9 Patients who present
extra-abdominal tumors that are amenable to
complete surgical resection appear to have a
better prognosis.19 In the series reported by
Saab et al.,19 2 patients with extra-abdominal
tumors had no evidence of disease at eight and
ten years, respectively.

Conclusions
The optimal management for DSRCT
remains to be determined. The usefulness of
non-invasive metabolic imaging modality, such
as 18F-FDG PET-CT, may improve the prognosis
of DSRCT patients by detecting tumoral
relapse earlier than conventional anatomic
imaging. Additional prospective studies are
needed to confirm these results, assessing the
validity of a morpho-functional approach in
DSRCT management.
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Cancer 2005;42:78-84.
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18. Finke NM, Lae ME, Lloyd RV, et al. Sinosal
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[page 55]
Rare Tumors 2009; volume 1:e20

Epithelioid hemangioendothe- sinus rhythm with a rate of 44 beats/min,

lioma of the temporal artery
presenting as temporal
arteritis: case report and
literature review
Dina El Demellawy,1 Ahmed Nasr,2
Salem Alowami3
1
University of Northern Ontario School of
Medicine, Thunder Bay, William Osler
Health Care-Brampton Civic Hospital,
Department of Pathology and Laboratory
Medicine, Brampton, Ontario, Canada;
2 cm. Microscopic examination showed a solid
University of Toronto, Department of
Surgery, Toronto, Ontario, Canada;
3
McMaster University, Department of
Pathology and Molecular Medicine,
Hamilton, Ontario, Canada
Introduction
In general, vascular tumors encompass a
spectrum of tumors with hemangiomas repre-
senting the benign group, angiosarcomas that
represent the opposite frankly malignant
group, and an intermediate group of heman-
gioendotheliomas. Hemangioendotheliomas
are classified as epithelioid hemangioen-
dothelioma (EHE), retiform hemangioen-
dothelioma, composite hemangioendothe-
lioma, Kaposiform hemangioendothelioma
(with or without Kasabach-Merritt syn-
drome), and spindle cell hemangioendothe-
lioma. The latter two types of hemangioen-
dotheliomas usually follow a benign course,
in contrast to the other types of hemangioen-
dotheliomas, which are considered as a low-
grade malignant sarcoma with unpredictable
prognosis. EHEs are rare tumors, mostly
described in the lungs and liver. Though
endothelial in origin, EHEs reported to origi-
nate from arteries are extremely rare. We
report a very rare case of EHE arising from
the temporal artery showing a peculiar pres-
entation.
occasional premature ventricular extrasystole
on ECG, mild mitral insufficiency, and mild
degree of mitral valve prolapse on echocardio-
gram. Her cardiac enzymes were negative and
chest X-ray was unremarkable. Ultrasound
performed on the left temporal artery showed
mild aneurysmal dilatation measuring 0.44
cm in maximum diameter. ESR was normal,
instead of being elevated as expected in cases
of temporal arteritis. Left temporal artery
excisional biopsy was performed. Gross exam-
ination showed a hemorrhagic vessel measur-
ing 1.2 cm in length and 0.15 cm in diameter
that harbored a focal aneurysm measuring 0.5
neoplasm arising from the arterial wall
(Figure 1) partially occluding and involving
the arterial wall. The tumor was formed of
sheets and anastomosing bands of plump
epithelioid cells that were embedded in a
myxoid stroma (Figure 1). The tumor cells
displayed mild pleomorphism, hyperchromat-
ic nuclei, and frequent intracytoplasmic lumi-
na (Figure 2). Mitotic figures accounting for
2/10 HPF were identified, however necrosis
was absent. Special stains using Elastic Van-
Correspondence: Dina El Demellawy,
Assistant Professor, Department of Pathology and
Laboratory Medicine, Northern Ontario School of
Medicine, Thunder Bay, William Osler Health
Care, Department of Pathology and Laboratory
Medicine, Brampton, Ontario, Canada.
E-mail: dina_eldemellawy@rogers.com
Received for publication: 7 July 2009.
Accepted for publication: 14 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright D. El Demellawy et al., 2009
Rare Tumors 2009; 1:e20
doi:10.4081/rt.2009.e20
Gieson and Trichrome confirmed that the
tumor is originating from the arterial wall
(Figures 3, 4 and 5). Immunohistochemistry
showed the tumor cells to positively react with
CD31 (Figure 6), CD34, Factor VIII and
Vimentin and negatively with Cam 5.2,
AE1/AE3, EMA, Actin (Figure 7), Desmin,
Figure 1. Epithe-
lioid hemangioen-
dothelioma show-
ing epithelioid co-
hesive cells oblit-
erating the lumen
and most of the
arterial wall. Note
residual foci of
muscularis media
(HEX100).

Case Report
A 41-year old female presented with painful
left temporal artery of one month duration of
acute onset and progressive course. The
Figure 2. Epithe-
patient’s past medical and family history was lioid hemangioen-
insignificant except for bradycardia of dothelioma show-
unknown etiology and mitral valve prolapse. ing mild pleomor-
Physical examination revealed a resting heart phism, and hyper-
rate of 40 beats/min and a thickened palpable chromatic nuclei
(HEX400).
left temporal artery. Investigations revealed a

[page 56] [Rare Tumors 2009; 1:e20]


S100, Melan A, HMB 45, and CD 68. The case
was diagnosed as EHE of the temporal artery.
The patient underwent thorough investiga-
tion by imaging which documented the
absence of any suspicious lesion or residual
tumor. The patient was followed up for three
years, during which symptoms and signs of
recurrence or/and metastasis were absent.
Case Report
largest series of 137 cases. EHE is a rare vascu-
lar tumor that is intermediate in morphological
features and biological behavior between
hemangioma and conventional angiosarcoma.
EHE has been reported in the liver, lung, gas-
trointestinal tract, head and neck, central nerv-
ous system, heart, and bone.4-11 Tumor demogra-
phy and presentation is influenced by its loca-
tion but, in general, these tumors affect middle-
aged individuals. Liver and lung lesions are
more common in females, whereas tumors of
Figure 3. Elastic the bone and soft tissues have an equal sex dis-
lamina within the tribution.12 EHEs present variably with the
arterial wall high- majority of patients’ symptoms related to the
lighted by elastic tumor mass effect. Although EHEs originate
stain (Elastic Van-
Gieson X100). from endothelial cells, those originating from
small sized peripheral arteries are rarely
described.13-16 To the best of our knowledge, 5
cases of EHEs have been reported (including the
current case) (Table 1).13-16 However, none origi-
nated from the temporal arteries and only a sin-
gle case showed symptoms mimicking dissemi-
nated vasculitis16 associated with an elevated
ESR. In the current case, several differentials
were considered including those of endothelial
cell origin such as Masson hemangioma (papil-
lary endothelial hyperplasia), epithelioid
hemangiomas, and angiosarcoma. The non-
endothelial cell origin differentials were
metastatic carcinoma, mesenchymal tumors
Figure 4. Elastic
lamina within the such as intra-vascular fasciitis, myxoid chon-
arterial wall high- drosarcoma and epithelioid sarcoma, metastatic
lighted by elastic malignant melanoma and pecomas. The pres-
stain (Elastic Van- ence of the myxoid matrix, cellular atypia, tumor
Gieson X400). infiltration into the media and adventitia, and
the absence of thrombosis excluded heman-
gioma and papillary endothelial hyperplasia. The
absence of profound atypia, brisk mitoses,
necrosis and intercommunicating channels
excluded the possibility of angiosarcomas and,
in addition, the long uncomplicated follow-up of
the patient did not suggest angiosarcoma. The
immunoprofile of the tumor with diffuse and
intense expression of CD31, CD34 and
Vimentin, and the absence of Keratin, as well as
melanoma, muscle and histiocytic markers is
classic for a vascular tumor, excluding tumors of
Figure 5. Epithe-
lioid hemangioen- non-endothelial origin. EHE is a well-differenti-
dothelioma with ated endothelial tumor with unpredictable
elastic trichome behavior. Unlike angiosarcoma, the histological
highlights stromal grading system is not useful for predicting its
reaction (Elastic prognosis. As a result, the treatment options are
Trichrome X400).
still controversial. For excised tumors, radia-
tion17 and interferon therapy may be used in an
attempt to restrain growth of incompletely
removed tumors.18 In addition, the former may
Discussion sclerose the blood vessels. In our case, the
patient received no further therapy because
thorough imaging showed no evidence of resid-
EHE is a distinct entity that was first
ual disease. In conclusion, we report a remote
described by Weiss and Enzinger in 1982,1 and case of EHE involving the temporal artery and
studied in detail by Ishak et al.2 in 1984, who presenting as temporal arteritis. To the best of
described 32 cases. However, a decade and a half our knowledge, this is the first case report of
later in 1999, Makhlouf et al.3 reported the EHE in this location and with such presentation.
[Rare Tumors 2009; 1:e20] [page 57]
Article

liver: a clinicopathologic study of 137

cases. Cancer 1999;85:562-82.
4. Dial DH, Liebow AA, Gmelich JT, et al.
Intravascular, bronchiolar, and alveolar
tumor of the lung (IVBAT): an analysis of
twenty cases of a peculiar sclerosing
endothelial tumor. Cancer 1983;51:452-4.
5. Elias KR, Ryan CK. Epithelioid hemangio-
endothelioma and the elusive vacuole.
Liver Transpl 2003;9:310-2.
6. Fryer JA, Biggs MT, Katz IA, et al.
Intracranial epithelioid hemangioen-
Figure 6. Epithe- dothelioma arising at site of previously
lioid hemangioen- atypical meningioma. Pathology 1998;30:
dothelioma dif- 95-9.
fusely expressing 7. Hamlat A, Casallo-Quilliano C, Saikali S, et
CD31 (X400).
al. Epithelioid hemangiendothelioma of
the infundibular-hypothalamic region:
case report and literature review. J
Neurooncol 2004;67:361-6.
8. Chow L, Chow W, Fong DT. Epithelioid
hemangioendothelioma of the brain. Am J
Surg Pathol 1992;16:619-25.
9. Lee JC, Lee BJ, Wang SG, Kim HW.
Epithelioid haemangioendothelioma in
the parapharyngeal space. J Laryngol Otol
2006;120:505-7.
Figure 7. Epithe- 10. Safirstein J, Aksenov S, Smith F. Cardiac
lioid hemangioen- epithelioid hemangioendothelioma with 8-
dothelioma infil- year follow-up. Cardiovasc Pathol 2007;
trating the arterial
wall with residual 16:183-6.
foci of muscularis 11. Kleer CG, Unni KK, Mcleod RA. Epithelioid
media highlight- hemangioendothelioma of bone. Am J
ened by actin. Surg Pathol 1996;20:1301-11.
(X400).
12. Weiss SW, Goldblum J, Enzinger FM.
Enzinger and Weiss' Soft Tissue Tumors
(4th ed). Philadelphia, PA: Mosby, 2001:
891-914.
Table 1. Reported cases of epithelioid hemangioendothelioma of small arteries.
13. Koh YC, Yoo H. Epithelioid haemangioen-
Case report Age in Gender Presentation and Artery Laterality Follow-up dothelioma of the sphenoid bone. J Clin
years clinical diagnosis of origin Neurosci 2001;8:63-6.
14. Tayeb T, Bouzaiene M. Epithelioid heman-
Koh et al. 26 Female Progressing Middle Left Not stated
gioendothelioma mimicking an occipital
(2001)13 exophthalmos meningeal
artery artery aneurysm. Rev Stomatol Chir
Maxillofac 2007;108:451-4.
Tayeb & 29 Female Scalp nodule, Occipital Right No recurrence 15. Akashi K, Yasuda M, Suto R, et al. A case of
Bouzaeine clinically occipital or metastasis
epithelioid hemangioendothelioma asso-
(2007)14 artery aneurysm
ciated with an artery. Tokai J Exp Clin Med
Akashi et al . 67 Female Elbow lump Branchial Left No recurrence 1997;22:65-9.
(1997)15 or metastasis
16. Castello P, Caronno R, Piffaretti G, Tozzi
Castello et al. 26 Male Forearm Radial Right Not stated M. Epithelioid hemangioendothelioma of
(2005)16 Painless mass the radial artery. J Vasc Surg 2005;41: 151-
El Demellawy et al. 41 Female Painful temple, Temporal Left No recurrence 4.
(unpublished data, clinically temporal or metastasis 17. Kubota T, Sato K, Takeuchi H, Handa Y.
2009) arteritis Successful removal after radiotheraphy
and vascular embolization in a huge tento-
rial epithelioid hemangiendothelioma: a
2. Ishak KG, Sesterhenn IA, Goodman ZD, et case report. J Neurooncol 2004;68:177-83.
References al. Epithelioid hemangioendothelioma of 18. Palmieri G, Montella L, Martignetti A,
the liver: a clinicopathologic and follow-up Bianco AR. Interferon alpha-2b at low dose
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[page 58] [Rare Tumors 2009; 1:e20]


Retrorectal epidermoid cyst
with unusually elevated serum
SCC level, initially diagnosed as
an ovarian tumor
Masaru Hayashi,1 Shigeki Tomita,2
Takahiro Fujimori,2 Hitoshi Nagata,3
Keiichi Kubota,3 Akiko Shoda,1
Kazumi Tada,1 Nobuaki Kosaka,1
Ichio Fukasawa,1 Noriyuki Inaba1
1
Department of Obstetrics and
Gynecology, Dokkyo Medical University,
Mibu, Tochigi, Japan; 2Department of
Surgical and Molecular Pathology,
Dokkyo Medical University, Mibu, Tochigi,
Japan; 3Department of Surgery 2, Dokkyo
Medical University, Mibu, Tochigi, Japan
Abstract
Retrorectal epidermoid cyst is one of the
developmental cysts which arise from rem-
nants of embryonic tissues. We report a rare
case of retrorectal epidermoid cyst, initially
diagnosed as an ovarian tumor. Serum SCC
value as tumor marker was elevated to the
high level. Laparoscopy revealed ovaries,
uterus and other pelvic organs were all normal.
This tumor existed in the retroperitoneal cavi-
ty and compressed the rectum. Later, complete
tumor resection was performed by laparotomy.
Histological study revealed the epithelium of
this tumor consisted of only squamous cells
without atypia, and the diagnosis of this tumor
was retrorectal epidermoid cyst. Retrorectal
epidermoid cyst is very rare, and difficult to
diagnose before surgery. However, if we have-
knowledge of developmental cysts, and by care-
ful digital examination and image diagnosis, a
differential diagnosis can be made.
Introduction
Retrorectal epidermoid cyst is one of the
developmental cysts which arise from remnants
of embryonic tissues. Because of the rarity of
these tumors in adults, the differential diagno-
sis is very difficult before surgery. We report a
rare case of retrorectal epidermoid cyst which
showed the elevated serum SCC level, and was
initially diagnosed as an ovarian tumor.
Case Report
A 22-year old woman, gravida 1, para 0, pre-
sented with urinary discomfort and constipa-
tion from one month. She had not been able to
urinate for a few days previously without
pressing herself. She consulted a previous hos-
pital’s department of obstetrics and gynecolo-
gy. In that hospital, the diagnosis was an ovar-
ian tumor, and she was introduced to our
department for curative surgery. In the inter-
nal and rectal examination, a hard, cystic, non-
removable, mass larger than a fist was palpat-
ed in the left side of rectum and the posterior
of the uterus. We could not insert a speculum
and a probe for transvaginal sonography into
her vagina because of the tumor’s strong com-
pression. MRI revealed a unilocular cystic
tumor measuring 11x11x12 cm in the bottom
of the pelvic cavity, compressed rectum, uter-
ine cervix, vagina and urinary bladder (Figure
1). The contents of this cyst consisted of two
different kinds of fluid, and there was a border-
line between them. The content in the back
side had T1 weighted-low intensity, T2 weight-
ed-high intensity signal. The abdominal side
showed T1 weighted-iso intensity, T2 weight-
ed-moderately high intensity signal. There
were some heterogeneous contents in both flu-
ids (Figure 1). Given the fat suppressive condi-
tion, this T1 weighted-iso intensity area slight-
ly reduced its signal. The content in the center
of the abdominal fluid had much reduced its
signal by this condition. This means the
abdominal side of this cyst contains a fat ele-
ment. The wall in this cyst was thin and
smooth. There was neither solid part in the
tumor nor signs of invasion into surrounding
tissues. White blood cell (10.5×109/L) and C-
reactive protein (2.05 mg/dL) were slightly ele-
vated. Other laboratory data were within nor-
mal limits. In these clinical findings, the diag-
nosis before the operation was an ovarian
tumor, and in particular, a mature cystic ter-
atoma of the ovary was suspected from image
diagnosis. Laparoscopy was performed for
diagnosis and treatment in the same day.
However, it revealed ovaries, uterus and other
intra-peritoneal pelvic organs were all normal.
This tumor was in the retroperitoneal cavity,
and compressed the rectum to the right and
anterior side (Figure 2). Since we could not
make a diagnosis of this retroperitoneal tumor,
we consulted the department of surgical gas-
troenterology, and we abandoned the sequen-
tial curative operation by laparoscopy. More
clinical examinations were performed after
laparoscopy including colonoscope, 3D CT.
Serum tumor markers were also proven out
after laparoscopy. SCC value was elevated to
30.4 ng/mL (cut-off value is 1.5 ng/mL). Other
tumor markers such as CA125, CA19-9, CEA,
AFP, CA72-4, CA15-3 and TPA were all within
normal limits. On the following days, laparoto-
my was performed for curative excision of this
tumor with some malignant possibilities
because of the elevated serum SCC level. This
[Rare Tumors 2009; 1:e21]
Rare Tumors 2009; volume 1:e21
Correspondence: Masaru Hayashi,
Department of Obstetrics and Gynecology,
Dokkyo Medical University, 880 Kitakobayashi,
Mibu-chou, Shimotsuga-gun, Tochigi 321-0293,
Japan. E-mail: ma-haya@dokkyomed.ac.jp
Key words: developmental cysts, retrorectal epi-
dermoid cyst, SCC-antigen, serum SCC, ovarian
tumor.
Acknowledgments: we would like to thank Ms.
Chiaki Matsuyama, Department of Surgical and
Molecular Pathology, Dokkyo Medical University
for her skillful technical assistance.
Contributions: MH, mainly took charge of this
patient as a gynecologist, and conceived,
designed and supervised this manuscript; AS, KT
and NK, also took charge of this patient; IF and
NI, reviewed this manuscript; ST and TF, diag-
nosed this tumor pathologically,and performed
immunohistochemical study; HN and KK, took
charge of this patient as a surgeon.
Conflict of interest: the authors report no con-
flicts of interest. The authors alone are responsi-
ble for the content and writing of the paper.
Received for publication: 2 July 2009.
Accepted for publication: 3 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright M. Hayashi et al., 2009
Rare Tumors 2009; 1:e21
doi:10.4081/rt.2009.e21
tumor adhered to the posterior wall of the rec-
tum, but complete resection was possible and
was performed. Both intra-operative frozen
section analysis and the cytology of the tumor’s
liquid contents did not show any malignant
finding. The resected-tumor measured 12×10
cm, and it was light gray-colored, elastic, hard
and unicystic. The cyst wall was thin and
degenerated. It weighed approximately 500
grams as a whole tumor. The content of this
cyst was filled with 300 mL of dense muddy and
fatty fluid, which partially curdled.
The cytology of this content showed abun-
dant white blood cells and squamous cells
without any atypia (Figure 3). Histological
study revealed that this tumor had a unicystic
structure, and the epithelium of this cyst wall
consisted of only keratinized, stratified squa-
mous cells (Figure 4A and B). Some portion of
squamous epithelium almost maintained a
stratified layer structure (Figure 4A), another
portion of these peeled off from their outer
surface (Figure 4B). There was no atypia of
squamous epithelium. According to these
pathological findings, this tumor was diag-
nosed as an epidermoid cyst, which was one of
[page 59]
Case Report
A B
C using anti-CEA antibody (Histofine SAB-
Figure 1. Pre-operative diagnosis of the
retrorectal epidermoid cyst by magnetic reso-
nance imaging (MRI); Open arrowhead indi-
cates uterine cervix, and closed arrowhead
indicates vaginal cavity. Open arrow indicates
rectum. Closed arrow indicates some hetero-
geneous contents in both fluids. (A) T1-
weighted transverse MRI. (B) T2-weighted
transverse MRI. (C) T2-weighted sagittal
MRI.
Figure 2. Laparoscopic finding
in the pelvic cavity; open
arrowhead indicates rectum,
which was compressed and
shifted to the right and anterior
side by the retrorectal epider-
moid cyst. Arrow indicates the
retrorectal epidermoid cyst as a
retroperitoneal tumor.
Figure 3. Cytology of the con-
tents in the presacral epider-
moid cyst; Papanicolaou stain
(x800).
the developmental cysts. Immunohisto- tive in the peeled and peeling keratinized
chemical studies using anti-CEA, CA19-9, and epithelium (Figure 5A2). SCC-antigen was
SCC-antigen antibodies were performed. strongly positive in the stratified squamous
CA19-9 was negative. On the other hand, CEA epithelium (Figure 5B1). Especially in the
was weekly positive in the stratified squamous peeled and peeling keratinized epithelium, it
epithelium (Figure 5A1) and moderately posi- was intensively positive (Figure 5B2). After
[page 60] [Rare Tumors 2009; 1:e21]
resection of this tumor, serum SCC level was
normalized. This case has been free of recur-
rence and her serum SCC level also has
remained within normal range for two years
after surgery.
Materials and Methods
Immunohistochemical study was performed
by the common avidin-biotin complex method
PO(M) Kit®; Nichirei Bio Science, Japan),
anti-CA19-9 antibody (DAKO, USA) and anti-
SCC-antigen antibody (Hepa-Ab®; XEPTAGEN,
Italy). Hepa-Ab® recently became available for
the detection of SCC-antigen in the immuno-
histochemical study.
Discussion
Retrorectal cysts are rare in adults. The inci-
dence of these tumors is estimated at 1/40,000-
63,000 admissions to large referral centers.1
The etiology of these cysts is classified into
five categories,2 which are congenital, neuro-
genic, inflammatory, osseous and miscella-
neous. Most cases of 16 retrorectal cysts are
congenital for 55-70%,1-3 and most of congeni-
tal retrorectal cysts are developmental cysts,
which are 60% of them.1,2 The term “develop-
mental cysts” was initially proposed and
defined by Hawkins in 1953.4 These are
thought to arise from caudal embryonic ves-
tiges,4 and occur mostly in middle-aged women
and in 3:1 female:male ratio.5 Originally, these
are classified into the three subtypes by histo-
logical findings, which are epidermoid cyst,
dermoid cyst, and tailgut cyst.4 Both epider-
moid cyst and dermoid cyst are lined with
stratified squamous epithelium, but dermoid
cyst also contains skin appendages, such as
hair follicle, sweat glands and tooth buds. Both
cysts result from closure defects of the ectoder-
mal tube with skin inclusion. Tailgut cyst, also
known as retrorectal cystic hamartoma or
mucus secreting cyst, is lined with various
epitheliums such as columnar cells, squamous
cells, and transitional cells, often in combina-
tions of these. This cyst arises from the rem-
nants of the embryonic postnatal gut.4-7 The
clinical presentation of retrorectal develop-
ment cysts is often non-specific, and half of
them are asymptomatic, which are incidental-
ly discovered during routine physical examina-
tion. The most common symptom is related to
tumor effect arisen by compression to the rec-
tum and lower urinary tract, such as constipa-
tion and urinary frequency.5-9 The other com-
mon symptom is pain when these cysts are
infected or generate malignant transforma-
 Case Report

A B Figure 4. Patholo-
gical features of the
retrorectal epider-
moid cyst; H.E.
stain (x200). (A)
Stratified squamous
epithelium. (B)
Peeling and peeled
squamous epitheli-
um.

A1 A2 Figure 5. Immuno-
histochemical stud-
ies of the retrorectal
epidermoid cyst.
(A) Immunostaining
for CEA (x200).
(A1) Stratified squa-
mous epithelium.
(A2) Peeling and
peeled squamous
epithelium.
(B) Immuno-stain-
ing for SCC antigen
(x200).
(B1) Stratified squa-
mous epithelium.
(B2). Peeling and
peeled squamous
B1 B2 epithelium.

tion.6,9 Chronic infection occurs in 30-50% of
developmental cysts.10 Infected cysts are source
of a perianal abscess or a draining sinus. How
infection originates is unknown, but trauma
and infection by the lymphatics or a congenital
sinus have been suggested.7 Malignant trans-
formation of developmental cysts is rare. Abel
reported an incidence of 8% in developmental
cysts.10 Hjermstad reported one case of malig-
nant transformation, which histology con-
firmed was poorly differentiated mucinous
adenocarcinoma, in 53 cases of tailgut cysts.11
Killingstone reviewed 43 cases of tailgut cyst.
The malignancy arose in 17 cases of these;
adenocarcinoma in 11 cases, carcinoid in 5
cases and neuroendocrine in one case.12 In
Japan, 58 cases of epidermoid cysts have been
reported including our case. Malignant trans-
formation occurred in 4 cases (6.9%) of these;
all were squamous cell carcinoma.13 For the
treatment of developmental cysts, complete
surgical resection is recommended so as not to
cause infection, recurrence or generate malig-
nant transformation.5,7,9 If the patients do not
have any clinical17 symptom or sufficient clini-
cal findings present any possibilities of malig-
nancy, surgical resection should be performed
because of the difficulties of operating once
infection has occurred in the developmental
cysts.7 Regarding serum tumor markers of the
developmental cysts, there were some reports
that serum CEA and/or CA19-9 level were ele-
vated in the malignant tailgut cases.14-16
However, in the retrorectal epidermoid cyst,
there is no report that the serum tumor mark-
er is positive as far as we know in the English
language literature. Nagano reported SCC,
CA19-9, CA125 and CEA levels in the aspirated
fluid of one malignant retrorectal epidermoid
cyst case (squamous cell carcinoma) were all
extensively elevated; however, all serum levels
were within the normal limit. We did not meas-
ure the tumor marker level of its contents.
From the result of immunohistochemical study
and this case’s clinical course, we supposed
elevated serum SCC level was the cause in this
case. Subacute inflammation on her epider-
moid cyst occurred due to physical stimuli or
unknown cause, and then squamous cell of
epithelium in the epidermoid cyst degenerated
and peeled off. Consequently, the SCC-antigen

[Rare Tumors 2009; 1:e21] [page 61]

Case Report
was released into the blood circulation.
Because of the rarity of developmental cysts,
they are very frequently misdiagnosed and
inappropriate surgery is performed.6 If a gyne-
cologist initially finds a retrorectal cyst, most
cases will be misdiagnosed as an ovarian
tumor. Retrorectal epidermoid cyst contains
fatty elements such as desquamated debris,
cholesterol, keratin, and water.18 A gynecologist
confuses these elements in the epidermoid
cyst with that of mature cystic teratoma, which
is a common ovarian tumor. However, if we
have knowledge of the developmental cysts, by
careful digital examination and image diagno-
sis, it is possible to make a differential diagno-
sis, since developmental cysts exist between
the presacral and retrorectal space, not in the
Douglas pouch like an ovarian tumor.18
References
1. Jao SW, Beart RW Jr, Spencer RJ, et al.
Retrorectal tumors: Mayo Clinic experi-
ence, 1960-1979. Dis Colon Rectum 1985;
28:644-52.
2. Uhlig BF, Johnson RI. Presacral tumors
and cysts in adults. Dis Colon Rectum
1975;18:581-9.
3. Stewart RJ, Humphrevs WG, Parks TG. The
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presentation and management of pre-
sacral tumors. Br J Surg 1986;73:153-5.
4. Hawkins WJ, Jackman RJ. Developmental
cysts as a source of perianal abscesses,
sinuses and fistulas. Am J Surg 1953;86:
678-83.
5. Dahan H, Arrivé L, Wendum D, et al. Retro-
rectal developmental cysts in adults: clini-
cal and radiologic histopathologic, differ-
ential diagnosis, and treatment.
Radiographics 2001;21:575-84.
6. Singer MA, Cintron JR, Martz JE, et al.
Retrorectal cyst: a rare tumor frequently
misdiagnosed. J Am Coll Surg 2003;196:
880-6.
7. Theuerkauf FJ Jr, Hill JR, ReMine WH.
Presacral developmental cysts in mother
and daughter: report of cases. Dis Colon
Rectum 1970;13:127-32.
8. Hobson KG, Ghaemmaghami V, Roe JP, et
al. Tumors of the retrorectal space. Dis
Colon Rectum 2005;48:1964-74.
9. Mentes BB, Kurukahvecioglu O, Ege B, et
al. Retrorectal tumors: a case series. Turk
J Gastroenterol 2008;19:40-4.
10. Abel ME, Nelson R, Prasad ML, et al. Para-
sacrococcygeal approach for the resection
of retrorectal developmental cysts. Dis
Colon Rectum 1985;28:855-8.
11. Hjermstad BM, Helwig EB. Tailgut cysts.
Report of 53 cases. Am J Clin Pathol 1988;
89:139-47.
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12. Killingsworth C, Gadacz TR. Tailgut cyst
(retrorectal cystic hamartoma): report of a
case and review of the literature. Am Surg
2005;71:666-73.
13. Tsukamoto Y, Samizo M, Takahashi T,
Maekawa T, Miyashita M. A case of adult
presacral epidermoid cyst. Jpn J Gastro-
enterol Surg 2008;41:705-10.
14. Maruyama A, Murabayashi K, Hayashi M,
et al. Adenocarcinoma arising in a tailgut
cyst: report of a case. Surg Today 1998;28:
1319-22.
15. Schwarz RE, Lyda M, Lew M, Paz IB. A car-
cinoembryonic antigen-secreting adeno-
carcinoma arising within a retrorectal
tailgut cyst: clinicopathological considera-
tions. Am J Gastroenterol 2000;95:1344-7.
16. Cho BC, Kim NK, Lim BJ, et al. A carci-
noembryonic antigen-secreting adenocar-
cinoma arising in tailgut cyst: clinical
implications of carcinoembryonic antigen.
Yonsei Med J 2005;46:555-61.
17. Nagano Y, Yoshimoto N, Nakajima S,
Hosoi H. Squamous cell carcinoma arising
from presacral epidermoid cyst in an adult,
report of a case. Nihon Rinsho Geka
Gakkai Zasshi 1998; 59: 2695-9.
18. Hannon J, Subramony C, Scott-Conner CE.
Benign retrorectal tumors in adults: the
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Metastatic rectal cancer
to the breast
Hsiao C. Li,1 Prapti Patel,1 Payal Kapur,2
Sergio Huerta3
University of Texas Southwestern
Medical Center/Dallas VA Medical Center
Departments of 1Medical Oncology,
2
Pathology and 3Surgery, Dallas, TX, USA
Abstract
Rectal cancer metastatic to the breast is an
exceedingly rare event with around 15 cases
reported in the literature. A metastatic breast
deposit from the rectum signifies diffuse dis-
seminated disease or a highly aggressive
tumor such that surgical intervention other
than palliation has a limited role. In the pres-
ent report, we discuss a patient who present-
ed with rectal cancer and developed a breast
metastatic deposit. She soon developed pro-
gressive metastatic involvement of the lungs
and the soft tissues and succumbed to the
malignant course of this disease 12 months
after the diagnosis of the primary rectal tumor.
Introduction
Rectal cancer is expected to affect 40,870
Americans in 2009.1 Up to 30% of patients with
attempted curative surgical intervention will
eventually develop regional recurrence.2
Further, nearly 70% of these patients have local
recurrence as well as distant metastases.3
Nineteen percent of patients newly diagnosed
with colorectal cancer present with distant
metastasis at the time of diagnosis4,5 and col-
orectal cancer patients treated for cure will
develop metastatic disease of some form in
nearly 40% of cases.6 Colorectal cancers most
typically metastasize to regional lymph nodes.
The liver is the most common site of distant
metastasis followed by the lungs and bone. Up
to one quarter of liver metastases present syn-
chronously, but most commonly liver lesions
develop metachronously following treatment of
the primary colorectal tumor. Metastases from
rectal cancer to multiple organs have been
reported either as synchronous lesions or
metachronous events.7-11 In either setting,
metastatic disease from the rectum to unusual
sites such as the spleen, skin or breast carries
a substantially poor prognosis. In the following
report, we present a patient with rectal cancer
metastatic to the breast whose aggressive
tumor led to her demise within a year follow-
ing the initial diagnosis of rectal cancer.
Case Report
A 54-year old African American female pre-
sented with nausea, vomiting, and abdominal
pain. A computed tomography scan of the
abdomen and pelvis showed diffuse wall thick-
ening of the small bowel, colon, and rectum
with ascites (Figure 1A). An exploratory
laparotomy revealed a massive amount of
purulent fluid and multiple loculated abscesses
as well as a rectal mass. A rigid proctoscopy
showed the mass to be 3-4 cm from the anal
verge with an obvious perforation. Drains were
placed and a diverting colostomy was per-
formed. Pathological evaluation of a surgical
specimen taken from the rectum showed an
invasive poorly differentiated adenocarcinoma
(Figure 2A, B, and C). A CT scan performed two
weeks after this operation showed a large het-
erogeneous soft tissue mass that distended the
rectum to 8 cm with no evidence of metas-
tases. She was clinically staged as having
cT4NxM0 adenocarcinoma of the rectum. She
remained in the hospital for two months due to
infectious complications then received pre-
operative radiation to a dose of 5040 cGy over
a period of 44 days. Concurrent chemotherapy
was recommended, but not delivered because
the patient missed multiple appointments with
medical oncology. After the completion of her
radiation therapy, however, she did receive
three cycles of capecitabine and oxaliplatin
with a partial response in the rectum. A total
mesorectal excision was planned, but the
patient then developed a firm 3 cm mass in the
upper outer quadrant of the right breast at
10:00 with a 2 cm firm mobile lymph node in
the right axilla. Mammographic examination
showed a 3.2 cm indistinctly marginated mass
(Figure 1B). An ultrasound of the right breast
showed a 3.7 cm hypoechoic, round mass with
Figure 1. Computed tomography of the abdomen and pelvis. (A) Demonstrated a thick-
ened bowel with a mass in the rectum (arrow). This study was obtained prior to treat-
ment. A mammogram of the breast (B) demonstrated a lesion shown by the arrow.
[Rare Tumors 2009; 1:e22]
Rare Tumors 2009; volume 1:e22
Correspondence: Sergio Huerta,
Assistant Professor of Surgery, Surgical Services
(112), 4500 S. Lancaster Road, Dallas, TX 75225,
USA. E-mail: sergio.huerta@utSouthwestern.edu
Key words: metastatectomy, palliative surgery,
fine needle aspiration, colonoscopy.
Received for publication: 12 July 2009.
Accepted for publication: 24 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright H.C. Li et al., 2009
Rare Tumors 2009; 1:e22
doi:10.4081/rt.2009.e22
ill-defined margins as well as an oval hypoe-
choic solid mass measuring 2.4 cm in the right
axilla. An ultrasound guided core biopsy of
both the right breast mass and the right axil-
lary lymph node showed poorly differentiated
invasive adenocarcinoma with no normal
breast parenchyma or in situ breast carcinoma.
When compared to the specimen from the pre-
vious rectal mass, the poorly differentiated
areas of the rectal biopsy showed a similar
morphology to the tumors in the breast and
right axilla. Immunostains showed the breast
and right axillary tumors to be negative for
estrogen receptor, progesterone receptor, Her-
2/neu, CK7, mammoglobin, BRST-2, and
MUC2, focally positive for monoclonal CEA and
CDX2, and positive for MUC1. Fluorescent in
situ hybridization for Her-2/neu was non-
amplified (Figure 3A, B, and C). A repeat com-
puted tomography scan showed new pul-
monary nodules. Thus, systemic chemotherapy
with capecitabine and oxaliplatin was
resumed. After one cycle, she developed a new
[page 63]
Case Report

5 cm soft tissue mass at the level of the skull

base that displaced the cervical right internal
carotid artery interiorly, encased the right ver-
tebral artery, and compressed the right inter-
nal jugular vein. She received palliative radia-
tion therapy to this area. Unfortunately, she
soon developed a new mass adjacent to the pri-
mary rectal cancer that caused right hydro-
dronephrosis for which she had a right percu-
Figure 2. Photomicrograph of rectal mass showing a poorly differentiated adenocarcino-
ma with focal better-differentiated component (right). (A) Hematoxylin and eosin stain taneous nephrostomy tube placed. Two weeks
(H&E), x200. (B) Cytokeratin 20 (CK20) immunoreactivity in more differentiated com- after this insult, she developed a small bowel
ponent only, x200; (C) CDX2 immunoreactivity in more differentiated area, x200. obstruction. Following aggressive systemic
chemotherapy, she was unable to overcome the
aggressive metastatic course of the primary
tumor and expired one year after her initial
diagnosis.

Discussion
The management of disseminated metastat-
Figure 3. Photomicrograph of breast mass showing morphology and immunoprofile sim- ic colon cancer remains a clinical challenge
ilar to the poorly differentiated adenocarcinoma in the rectum with associated dirty and surgical intervention has a limited role,
necrosis. (A) Hematoxylin and eosin stain, x200. (B) Focal CDX2 immunoreactivity,
x200. (C) Focal villin immunoreactivity, x200. typically performed exclusively for palliation.
Metastatic spread from rectal cancer occurs
both by lymphatic and hematogenous routes.
Rectal metastasis to various organs
Owing to the venous drainage into the portal
system from the superior hemorrhoidal vein,
Liver the liver is the most common site of distant
Lung metastasis from rectal cancer.12 Systemic
Bone drainage into the inferior vena cava from the
Pancreas
inferior hemorroidal plexus may lead to
metastatic involvement to the lung and bone.
Adrenal glands Unusual metastatic lesions from the rectum
Cutaneous to the pancreas (~ 7%)7,8 and adrenal glands
Breast have been reported (2-17%).9 Even more
unusual sites of metastasis originating from
the rectum have been documented to the skin
(<4%)10 and the breast (Figure 4).11
Involvement of the skin or breast from rectal
Figure 4. Frequency of rectal metastasis to various organs. The most common sites are the cancer signifies disseminated metastatic dis-
liver and lungs. ease and the prognosis for these patients is
exceedingly poor with less than a 20% 1-year
Results of 32 FNAs with metastatic deposits to the breast survival. The breast is an unusual site for
metastatic deposits. The most common
Melanoma metastatic deposit of the breast is the result of
Lung (SCC) a contralateral primary breast carcinoma.13
Lung (Adenoca.) Fine needle aspiration will identify extra-
mammary malignancy metastatic to the breast
Lung (Carcinoid)
with a range of 0.5-5%.14 The three most com-
NHL mon extra-mammary malignancies are bron-
Colon chogenic carcinoma, melanoma, and lym-
Sarcoma phoma.13-15 A wide array of rare metastatic
Gyn (endometrial, ovarian) deposits might also occur with much less fre-
Other quency and these include: papillary cancer of
the ovary, squamous carcinoma (SCC) of the
nasal cavity, SCC of the cervix, endometrial
adenocarcinoma, gastric cancer, and bladder
(Figure 5).13-15 Extra-mammary metastatic
Lung
deposits originating from the rectum is an
Figure 5. Thirty-two fine needle aspiration specimens with mestatatic deposits to the exceedingly rare event. Metastases from the
breast in 31 women and 1 man (age 61±3 years old) [range 14-91 years]. The most com- colon to the breast were first reported by
mon origin was cutaneous melanoma.14
McIntosh16 and from the rectum by Lal in

[page 64] [Rare Tumors 2009; 1:e22]


1999.17 Around 15 reports of rectal metastases
to the breast have been documented since ini-
tially described.11 As in the case in the present
report, most patients succumb to the aggres-
sive course of the disease within a year after
the diagnosis of the primary tumor. The man-
agement of disseminated metastatic rectal
cancer remains a clinical and multidisciplinary
challenge. In the past, patients would receive
systemic chemotherapy until their ultimate
demise. However, metastatectomies are
becoming increasingly common. Traditionally,
metastatectomies have been performed for col-
orectal liver and lung metastases as this has
clearly improved the survival of patients whose
primary disease has been controlled.12,18
Metastatectomies for adrenal9 and pancreatic
tumors7,8 have also been performed with suc-
cessful outcomes. However, metastasis to the
breast from rectal cancer signifies disseminat-
ed metastatic disease or a highly aggressive
tumor such that metastatectomies in this set-
ting have a limited role other than palliation.
The main form of treatment for these patients
is systemic chemotherapy.
References
1. Jemal A, Siegel R, Ward E, et al. Cancer
Statistics, 2009. CA Cancer J Clin 2009;59:
225-49.
2. Wanebo HJ, Koness RJ, Vezeridis MP, et al.
Pelvic resection of recurrent rectal cancer.
Ann Surg 1994;220:586-95.
3. Chari RS, Tyler DS, Anscher MS, et al.
Preoperative radiation and chemotherapy
in the treatment of adenocarcinoma of the
rectum. Ann Surg 1995;221:778-86.
4. Foster JH. Treatment of metastatic disease
of the liver: a skeptic's view. Semin Liver
Dis 1984;4:170-9.
5. Jemal A, Siegel R, Ward E, et al. Cancer
statistics, 2008. CA Cancer J Clin 2008;
58:71-96.
6. Wolpin BM, Meyerhardt JA, Mamon HJ, et
al. Adjuvant treatment of colorectal cancer.
CA Cancer J Clin 2007;57:168-85.
7. Bachmann J, Michalski CW, Bergmann F,
et al. Metastasis of rectal adenocarcinoma
to the pancreas. Two case reports and a
review of the literature. JOP 2007;8:214-
22.
8. Matsubara N, Baba H, Okamoto A, et al.
Rectal cancer metastasis to the head of the
pancreas treated with pancreaticoduo-
denectomy. J Hepatobiliary Pancreat Surg
2007;14:590-4.
9. Murakami S, Terakado M, Hashimoto T, et
al. Adrenal metastasis from rectal cancer:
report of a case. Surg Today 2003;33:126-
30.
10. Rendi MH, Dhar AD. Cutaneous metasta-
sis of rectal adenocarcinoma. Dermatol
Nurs 2003;15:131-2.
[Rare Tumors 2009; 1:e22]
Case Report
11. Sanchez LD, Chelliah T, Meisher I, et al.
Rare case of breast tumor secondary to
rectal adenocarcinoma. South Med J 2008;
101:1062-4.
12. Yoo PS, Lopez-Soler RI, Longo WE, et al.
Liver resection for metastatic colorectal
cancer in the age of neoadjuvant
chemotherapy and bevacizumab. Clin
Colorectal Cancer 2006;6:202-7.
13. Muttarak M, Nimmonrat A, Chaiwun B.
Metastatic carcinoma to the male and
female breast. Australas Radiol 1998;
42:16-9.
14. Wood B, Sterrett G, Frost F, et al. Diagnosis
of extramammary malignancy metastatic
to the breast by fine needle biopsy.
Pathology 2008; 40:345-51.
15. Domanski HA. Metastases to the breast
from extramammary neoplasms. A report
of six cases with diagnosis by fine needle
aspiration cytology. Acta Cytol 1996;40:
1293-300.
16. McIntosh IH, Hooper AA, Millis RR, et al.
Metastatic carcinoma within the breast.
Clin Oncol 1976;2:393-401.
17. Lal RL, Joffe JK. Rectal carcinoma metasta-
tic to the breast. Clin Oncol (R Coll Radiol)
1999;11:422-3.
18. Van CE, Nordlinger B, Adam R, et al.
Towards a pan-European consensus on the
treatment of patients with colorectal liver
metastases. Eur J Cancer 2006;42:2212-21.
[page 65]
Rare Tumors 2009; volume 1:e23

Plexiform neurofibroma in the Case Report

hepatic hilum associated with
neurofibromatosis type 1:
a case report
Sojun Hoshimoto,1 Zenichi Morise,1
Chinatsu Takeura,1 Masahiro Ikeda,1
Tadashi Kagawa,1 Yoshinao Tanahashi,1
Yasuhiro Okabe,1 Yoshikazu Mizoguchi,2
Atsushi Sugioka1
1
Department of Surgery and 2Department
of Pathology, Fujita Health University
School of Medicine, Toyoake, Aichi, Japan
Abstract
We present an extremely rare case of plexi-
form neurofibroma involving the hepatic
hilum. A 24-year old woman who had been
diagnosed with neurofibromatosis type 1 was
referred to our hospital for evaluation of an
abdominal mass found on computed tomogra-
phy and progressive aggravation of intermit-
tent abdominal pain. Abdominal computed
tomography revealed a multilobulated non-
enhancing mass involving the celiac trunk
and hepatic artery, that extended to the hepat-
ic hilum through the hepatoduodenal liga-
ment. Magnetic resonance imaging showed
the lesion extending along the intrahepatic
Glisson’s sheath. Based on the imaging find-
ings, the patient was diagnosed to have a neu-
rofibroma, although sarcomatous differentia-
tion could not be excluded. The tumor was
resected, leaving behind the intrahepatic
extension, with the aim of alleviating the
abdominal pain and preventing obstructive
jaundice. Histopathological examination
revealed the diagnosis of plexiform neurofi-
broma. At present, three years after the sur-
gery, the patient remains symptom-free, with-
out any evidence of recurrence.
A 24-year old woman who had been diag-
nosed with NF-1 during childhood was referred
to Fujita Health University Hospital in
September 2004 for evaluation of an upper
abdominal mass found on abdominal comput-
ed tomography (CT) at another hospital and
progressive aggravation of intermittent upper
abdominal pain. There was no relevant family
history. Physical examination revealed numer-
ous café-au-lait spots and cutaneous tumors.
In addition to the skin lesions, there was a his-
tory of surgical treatment for scoliosis. All lab-
oratory test results obtained at admission were
all within normal limits. Abdominal CT
revealed a multilobulated low-attenuation non-
enhancing mass involving the celiac trunk and
the common hepatic artery, extending to the
hepatic hilum through the hepatoduodenal lig-
ament (Figure 1). Hepatic angiography
showed a normal caliber of the hepatic artery
without any irregularity, and portography as
visualized through the superior mesenteric
artery revealed a patent portal vein without
encasement. On magnetic resonance imaging
(MRI), the lesion was visualized as a
hypointensity on T1-weighted images and as a
hyperintensity on T2-weighted images, and
was found to extend along the intrahepatic
Glisson’s sheath (Figure 2). On magnetic reso-
Correspondence: Sojun Hoshimoto,
Department of Surgery, Fujita Health University
School of Medicine, 1-98 Dengakugakubo,
Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
E-mail: sojunh@yahoo.co.jp
Key words: plexiform neurofibroma, neurofibro-
matosis, hepatic hilum.
Conflict of interest: the authors reported no poten-
tial conflict of interests.
Received for publication: 20 July 2009.
Accepted for publication: 23 July 2009
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright S. Hoshimoto et al., 2009
Rare Tumors 2009; 1:e23
doi:10.4081/rt.2009.e23
nance cholangiopancreatography (MRCP), the
common bile duct and the left hepatic duct
were slightly depressed, without dilatation of
the intrahepatic bile duct. Based on these
imaging findings, the patient was diagnosed to
have a neurofibroma, although sarcomatous
differentiation could not be excluded.
Although MRI findings suggested that the

Figure 1. Contrast-enhanced computed tomography showing a low-attenuation lesion

involving the celiac axis (CA), the common hepatic artery (CHA), and the portal vein
(PV), and extending into the hepatic hilum (arrows).
Introduction
Plexiform neurofibroma, which is consid-
ered pathognomonic of neurofibromatosis
type 1 (NF-1), usually occurs in the neck,
pelvis, and extremities. Plexiform neurofibro-
ma in the hepatic hilum is an unusual mani-
festation of NF-1 and is extremely rare. We
present the case of a 24-year old woman with
NF-1 diagnosed to have plexiform neurofibro-
ma involving the celiac trunk, the common
hepatic artery, the hepatoduodenal ligament Figure 2. Abdominal MRI (T2-weighted image) showing a hyperintense tumor involving
and the hepatic hilum that showed extension the hepatoduodenal ligament and the hepatic hilum (arrows), extending along the intra-
hepatic Glisson’s sheath (arrow heads).
along the intrahepatic Glisson’s sheath.

[page 66] [Rare Tumors 2009; 1:e23]


Figure 3. Laparotomy revealed a whitish
firm tumor involving the hepatoduodenal
ligament and the hepatic hilum (arrows).
tumor was unresectable owing to its intrahep-
atic extension, the tumor was removed in
February 2005, leaving behind the intrahepatic
extension, with the aim of alleviating the
abdominal pain and preventing obstructive
jaundice. Laparotomy revealed a whitish firm
tumor involving the celiac trunk, the common
hepatic artery, and the hepatoduodenal liga-
ment, extending through the hepatic hilum
(Figure 3). Since skeletonization of the hepa-
toduodenal ligament was feasible, the tumor
was resected piecemeal, without any need for
combined resection of the vessels or ducts.
On examination of the cut surface, the
tumor was whitish, firm, solid, and partially
encapsulated. Pathological examination
revealed expansion of the nerve fascicles, with
a multilobulated appearance. The tumor was
chiefly composed of elongated spindle-shaped
cells having wavy nuclei, with a myxoid matrix
(Figure 4A and B). Mucinous change in the
stroma was prominent. These findings were
consistent with the diagnosis of benign plexi-
form neurofibroma. No evidence of malignant
transformation was seen.
The post-operative course was uneventful.
At present, three years after the surgery, the
patient remains symptom-free, and shows no
evidence of recurrence.
Discussion
NF-1, also known as von Recklinghausen’s
disease, is a systemic, autosomal dominant
neurocutaneous syndrome occurring at a
prevalence of one case in 3,000 live births.1 It
is caused by mutations of the NF1 gene, which
is located on chromosome 17q11.2.2 Although
many cases are heritable, approximately 30-
50% of cases arise from spontaneous muta-
tions.1 NF-1 is characterized by café-au-lait
spots, cutaneous neurofibromas, bone malfor-
mations, Lisch nodules, and sometimes, malig-
Figure 4. (A) Multiple nerve fascicles are expanded by proliferation of tumor cells embed-
ded in a prominent myxoid matrix. (HE stain, x 40). (B) At high magnification, the
tumor was chiefly composed of elongated spindle-shaped cells having wavy nuclei, with
a myxoid matrix. (HE stain, x 400).
nant tumors.1 The average life expectancy of
patients with NF-1 is probably reduced by 10-15
years, and malignancy is the most common
cause of death.2 The most characteristic
tumors in patients with NF-1 are neurofibro-
mas which arise from cells of the nerve sheath
and consist of a mixture of Schwann cells,
fibroblasts, perineurial cells, and mast cells.3
Plexiform neurofibroma is a benign nerve
sheath tumor, which is virtually pathognomon-
ic of NF-1. It consists of the same cell types as
a cutaneous fibroma but has an expanded
extracellular matrix, and its presence is one of
the clinical criteria for the diagnosis of NF-1.3
The incidence of plexiform neurofibroma in
patients with NF-1 has been reported to be 15-
30%.4,5 It may be present superficially or be
located internally, and consists of proliferation
of cells in the nerve sheath extending across
the length of a nerve, involving multiple fasci-
cles and branches.6 Although it tends to grow
slowly, growth spurts are seen, particularly in
early childhood and during puberty or pregnan-
cy.6 Plexiform neurofibromas are at an
increased risk of developing into malignant
peripheral nerve sheath tumors (MPNSTs).
MPNSTs arise predominantly from pre-exist-
ing plexiform neurofibromas and metastasize
widely and often presage a poor outcome.3 The
lifetime risk of MPNSTs in patients with NF-1
is estimated to be about 10%.7
On CT, plexiform neurofibromas are visual-
ized as multilobulated low-attenuation masses,
usually within a major nerve distribution.8 On
MRI, the tumors are seen as conglomerate
hyperintense masses consisting of innumer-
able neurofibromas with central hypointense
regions, known as the “target sign” on T2-
weighted images.8 However, malignant trans-
formation of internal plexiform neurofibromas
into MPNSTs is difficult to assess by imaging
alone. Thus, the diagnosis of MPNSTs requires
biopsy, but there is substantial potential for
sampling error in large plexiform neurofibro-
mas.6 Although plexiform neurofibromas occur
[Rare Tumors 2009; 1:e23]
Case Report
predominantly in the head or neck in NF-1
patients,5 in approximately 40% of patients
with NF-1, lesions are detected by abdominal
or pelvic CT.9 Internal plexiform lesions in the
abdomen or pelvis are commonly located in the
paraspinal space, sciatic nerve, or perirectal
space.9 Therefore, extension of a plexiform
neurofibroma involving the retroperitoneum
and hepatoduodenal ligament into the hepatic
hilum is an unusual manifestation in cases of
NF-1. A search of PubMed using the terms
“liver”, “hilum”, “hilar”, or “porta hepatis”,
and “neurofibroma” revealed only 9 cases of
plexiform neurofibroma in the hepatic hilum
reported to date in the English language litera-
ture.10-17 All of the 10 cases, including the pres-
ent case, showed retroperitoneal involvement
or intrahepatic extension along the Glisson’s
sheath. Therefore, the imaging features of the
present case are closely similar to those of the
previously reported cases. Rodriguez et al.
reported a case with diffuse intrahepatic peri-
portal plexiform neurofibroma and described
the non-enhancing low-attenuation lesions
surrounding central and peripheral periportal
spaces as the “periportal collar sign”, which
was initially described as a finding of rejection
in liver transplantation.18
Internal plexiform neurofibromas can per-
sist for many years without causing clinical
problems and they usually remain undetected
until incidental detection by an imaging study
or following the development of clinical symp-
toms.6 When patients have substantial neuro-
logical deficits or disfigurement, removal of
plexiform neurofibromas poses challenging
problems because of infiltration by the tumors
of the surrounding tissues and nerves,19
although the current treatment of first choice
for plexiform neurofibromas remains surgery.
Therefore, there is controversy regarding the
optimal timing for surgical intervention. Some
authors advocate early surgery to prevent the
development of major cosmetic and functional
impairment, whereas there is a counter argu-
[page 67]
Case Report
ment that even small plexiform neurofibromas
can rarely be removed entirely and regrowth
after surgery may occur.6 Although in the pres-
ent case, based on the MRI findings, the tumor
was deemed as difficult to remove in its entire-
ty owing to its intrahepatic extension, removal
of the tumor was nonetheless attempted in an
attempt to alleviate the abdominal pain and
prevent obstructive jaundice. To the best of our
knowledge, this is the first reported case of
plexiform neurofibroma in the hepatic hilum
in which successful resection was carried out.
In conclusion, we have reported an unusual
case of plexiform neurofibroma, unique in
terms of its location at the hepatic hilum.
Thus, the presence of this tumor at this
uncommon location should also be borne in
mind, especially in complaints of abdominal
discomfort, and it is essential to periodically
monitor patients with NF-1 for the develop-
ment of this tumor because of the possibility of
serious clinical presentations and malignant
transformation.
References
1. Lee MJ, Stephenson DA. Recent develop-
ments in neurofibromatosis type 1. Curr
Opin Neurol 2007;20:135-41.
2. Rasmussen SA, Friedman JM. NF1 gene
and neurofibromatosis 1. Am J Epidemiol
[page 68]
2000;151:33-40.
3. Theos A, Korf BR. Pathophysiology of neu-
rofibromatosis type 1. Ann Intern Med
2006;144:842-9.
4. Huson SM. The different forms of neurofi-
bromatosis. Br Med J (Clin Res Ed) 1987;
294:1113-4.
5. McGaughran JM, Harris DI, Donnai D, et
al. A clinical study of type 1 neurofibro-
matosis in north west England. J Med
Genet 1999;36:197-203.
6. Korf BR. Plexiform neurofibromas. Am J
Med Genet 1999;89:31-7.
7. Evans DG, Baser ME, McGaughran J, et al.
Malignant peripheral nerve sheath
tumours in neurofibromatosis 1. J Med
Genet 2002;39:311-4.
8. Lin J, Martel W. Cross-sectional imaging of
peripheral nerve sheath tumors: charac-
teristic signs on CT, MR imaging, and
sonography. Am J Roentgenol 2001; 176:
75-82.
9. Tonsgard JH, Kwak SM, Short MP, et al. CT
imaging in adults with neurofibromatosis-
1: frequent asymptomatic plexiform
lesions. Neurology 1998;50:1755-60.
10. Fenton LZ, Foreman N, Wyatt-Ashmead J.
Diffuse, retroperitoneal mesenteric and
intrahepatic periportal plexiform neurofi-
broma in a 5-year-old boy. Pediatr Radiol
2001;31:637-9.
11. Gallego JC, Galindo P, Suarez I, et al. MR of
hepatic plexiform neurofibroma. Clin
[Rare Tumors 2009; 1:e23]
Radiol 1998;53:389-90.
12. Ghalib R, Howard T, Lowell J, et al. Plexi-
form neurofibromatosis of the liver: case
report and review of the literature.
Hepatology 1995;22:1154-7.
13. Gossios KJ, Guy RL. Case report: imaging
of widespread plexiform neurofibromato-
sis. Clin Radiol 1993;47:211-3.
14. Kakitsubata Y, Kakitsubata S, Sonoda T, et
al. Neurofibromatosis type 1 involving the
liver: ultrasound and CT manifestations.
Pediatr Radiol 1994;24:66-7.
15. Malagari K, Drakopoulos S, Brountzos E, et
al. Plexiform neurofibroma of the liver:
findings on mr imaging, angiography, and
CT portography. AJR Am J Roentgenol
2001;176:493-5.
16. Partin JS, Lane BP, Partin JC, et al.
Plexiform neurofibromatosis of the liver
and mesentery in a child. Hepatology 1990;
12:559-64.
17. Vilas-Ferrol I, Hernandez-Gimenez M,
Moya-Garcia MI, et al. Intrahepatic plexi-
form neurofibroma in neurofibromatosis
1. Pediatr Radiol 1998;28:733.
18. Rodriguez E, Pombo F, Rodriguez I, et al.
Diffuse intrahepatic periportal plexiform
neurofibroma. Eur J Radiol 1993;16:151-3.
19. Ferner RE. Neurofibromatosis 1 and neu-
rofibromatosis 2: a twenty first century
perspective. Lancet Neurol 2007;6:340-51.

Cystadenofibroma of the
rete ovarii: a case report
with review of literature
Manisha Ram,1 Abdel Abdulla,1
Khalil Razvi,1 Ivilina Pandeva,1
Awatif Al-Nafussi2
1
Department of Cellular Pathology,
Basildon Hospital, Basildon & Thurrock
University Hospitals NHS Foundation
Trust, Basildon, UK; 2Department of
Cellular Pathology, Royal Infirmary of
Edinburgh, Edinburgh, Scotland, UK
Introduction
The rete ovarii (RO), the homolog of the
rete testis (RT), is present in the hilus of all
ovaries.1 It is composed of irregularly anasto-
mosing tubules lined by flat, cuboidal or
columnar non-ciliated cells with scanty
eosinophilic or clear cytoplasm. Some authors
state that the RO contains ciliated cells.1 The
tubules generally lack a basement membrane,
as judged by the absence of PAS staining
beneath the epithelial lining. The histological
description of RO in humans is generally sim-
ilar to that of the mouse, including a network
of irregular tubules, sometimes communicat-
ing with mesonephric tubules in the mesovar-
ium, and lined by epithelium varying from flat-
tened to columnar and occasionally ciliated.2
However, in contrast to the apparent com-
moness of cysts and tumors of the RO in mice,
these lesions are described rarely in humans.2
Lesions of the human RO have been infre-
quently described, with the largest series to
date comprising under 20 cases.3 Similarly,
there are only a few reports of benign epithe-
lial tumors of the RT.4 We describe another
rare lesion of the RO: “cystadenofibroma” of
the RO in a 75-year old female, along with a
literature review.
Case Report
A 75-year old patient presented with sudden
onset of severe abdominal pain. Her past med-
ical and surgical history was unremarkable.
The physical examination revealed a distended
abdomen and the presence of a tender, round,
mobile right sided pelvic mass, measuring
approximately 20 cm in size. Her blood results
were within normal limits. A Computerized
Tomography (CT) scan of the abdomen and
pelvis showed a large, complex mass with solid
and cystic areas, occupying the entire pelvis.
There was a moderate amount of free fluid in
the abdomen. There was no lymphadenopathy.
The CA-125 was raised to 933 u/mL. She was
subsequently taken in for surgery. At laparoto-
my, the findings were of a large cystic mass
with smooth external surface, originating from
the right ovary and extending to the upper
abdomen. There were no adhesions to sur-
rounding organs. The rest of the pelvis and
abdominal cavity were normal. The ovarian
mass was sent for frozen section, which sug-
gested a borderline tumor. In view of this, a
staging laparotomy with total abdominal hys-
terectomy, bilateral salpingo-oophorectomy,
infracolic omentectomy and right pelvic lymph
node dissection was performed. Macrosco-
pically, a circumscribed whitish spongy mass
occupied the whole right ovary, which weighed
500 grams and measured 18x12x8 cm. The cut
surface revealed “honey-comb” like solid cystic
areas, with the cysts ranging in size from 0.2
cm to 2.5 cm and containing clear fluid (Figure
1). Microscopically, there was diffuse replace-
ment of the ovarian parenchyma, from hilus to
cortex, by a cellular proliferation of epithelial
and stromal cells (Figure 2). The epithelial
cells were arranged as tubular and slit-like
spaces (Figure 3), with numerous variably
sized cystic spaces having an irregular outline.
The tubules had an irregular branching config-
uration reminiscent of an “antler-horn” pat-
tern. The areas of prominent cystic change had
scattered tiny papillae, projecting into the cysts
(Figures 4 and 5). The cyst lumens contained
amorphous, granular, proteinaceous, eosino-
philic material along with occasional foamy
[Rare Tumors 2009; 1:e24]
Rare Tumors 2009; volume 1:e24
Correspondence: Manisha Ram,
Department of Cellular Pathology, Basildon
Hospital, Basildon & Thurrock University
Hospitals NHS Foundation Trust, Nethermayne,
Basildon, SS16 5NL, United Kingdom
E-mail: pathologist.manisha@gmail.com
Key words: ovary, rete ovarii, cystadenofibroma,
rete testis, immunohistochemistry.
Acknowledgments: we would like to thank Kerry
Hughes for her assistance in typing this manu-
script.
Contributions: MR, AAl-N, conception, design,
acquisition of data, analysis and interpretation of
data, drafting article and revising critically for
important intellectual content, final approval of ver-
sion to be published; AA, interpretation of data,
revising critically for important intellectual content,
final approval of version to be published; KR, revis-
ing critically for important intellectual content, final
approval of version to be published; IP, acquisition
of data, final approval of version to be published.
Conflict of interest: the authors reported no poten-
tial conflict of interests.
Received for publication: 22 July 2009.
Accepted for publication: 23 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright M. Ram et al., 2009
Rare Tumors 2009; 1:e24
doi:10.4081/rt.2009.e24
Figure 1. Gross photograph
showing bi-valved specimen
depicting solid- cystic appea-
rance.
Figure 2. Microphotograph
showing diffuse replacement
of ovary by epithelial and
stromal proliferation (H&E
X 40).
[page 69]
Case Report

macrophages. The lining throughout was

bland, monolayered, non-ciliated cuboidal to
columnar, with moderate amount of pale
eosinophilic cytoplasm (Figure 6). Nuclei were
basally orientated, monomorphic, round to
oval, containing dispersed chromatin and
small nucleoli. Focally, especially in areas with
marked cystic dilatation, the lining cells were
flat. The cores of the papillae and intertubular Figure 3. Microphotograph
stroma consisted of fibrovascular tissue, con- showing variably sized irreg-
taining spindle-shaped cells with monomor- ular slit-like spaces lined by
phic elongated nuclei (Figure 7). Smooth mus- monolayered bland cuboidal
epithelium and intervening
cle fibers were very occasional in the stroma mature fibrotic stroma
(Figure 8). There were no Leydig-like cells in (H&E X200).
the stroma, which was further confirmed by
negative immunostaining for Inhibin. Neither
nuclear atypia nor conspicuous mitotic figures
were seen in the epithelial or stromal cells.
Necrosis was not evident. Normal background
ovarian parenchyma was not seen (in spite of
embedding the whole specimen). The
labyrinthine channels, slit-like spaces and
mature fibrous mesenchymal type of stroma,
were all very reminiscent of RO. On immuno-
histochemistry, mesothelial markers (CK5/6,
Calretinin, WT-1, thrombomodulin) were nega-
tive. The epithelial lining cells were positive Figure 4. Microphotograph
for CK7, ER, PR, Vimentin and CD10 (Figures showing a markedly dilated
9-12). Considering the glandular and stromal cyst with papillae projecting
pattern and the immunohistochemistry into the cyst lumen (H&E
results, a diagnosis of cystadenofibroma of the X200).
RO was made. The uterus showed a benign
intramural leiomyoma along with cystic atro-
phy of the endometrium. The left ovary and
omentum were histologically unremarkable.
The right common iliac, external iliac, internal
iliac and right obturator lymph nodes showed
reactive hyperplasia only, with no evidence of
metastasis.

Discussion
Figure 5. Microphotograph
There is considerable debate regarding the showing high power view of
histogenesis of the RO. Most investigators bland cuboidal lining of
consider the RO to be of mesonephric ori- papillae (H&E X400).
gin.1,5-7 Upadhay et al.8 favor a mesonephric
origin in mice, but Nogales et al.8 state that
these results may not be transferable to
humans because of the considerable differ-
ences in gonadal development between
species. Nogales5 suggested that the RO repre-
sents a structure intermediate between the
mesonephric duct and ovarian sex cords.
Satoh9 elaborated how, during embryogenesis,
remnants of primordial sex cords in the basal
portion of the ovary give rise to the rete.
“Coelomic-epithelial” and “gonadal blaste-
mal” origins have also been advanced.1 Amidst
all this argument, Nogales et al.8 state that the Figure 6. Microphotograph
RO and RT are anatomical structures of uncer- showing bland cuboidal lin-
ing of tubules with occasion-
tain histogenesis. The position of the RO al ciliated cells (H&E X600).
varies between species. It is found most com-

[page 70] [Rare Tumors 2009; 1:e24]

 Case Report

monly in the hilus of the ovary, but may be rep-

resented by tubules or cords extending
through the medulla, or may be completely
outside the ovary, in the mesovarium, adja-
cent to the hilus.7 Age-related changes have
been described in the RO. In the human fetus,
the RO enlarges and a columnar network of
tubules extends along the length of the ovary
in the hilar regions, so that at birth, the RO is
described as strongly developed.7 The so-called
urogenital union between the rete and the
mesonephric tubules (transverse ductules in Figure 7. Microphotograph
showing cellular fibrotic
the female, homologous with the efferent duc- stroma, reminiscent of rete
tules in the male) which was lost during the ovarii (H&E X200).
morphogenesis of the gonad is regained in the
male to form the excretory pathway. Hence, in
males, the RT is fully developed and function-
al. On the other hand, the reunion in the
female may not occur or is imperfect,7 hence
the RO is said to be a vestigial structure of
unknown function.8,10 The RO seems to play an
important role in early gonadal embryogene-
sis, being related to primitive sex cord forma-
tion.10 From birth through puberty, the RO
comes to occupy less of the volume of the
ovary. The rete tubules become more separat-
ed by increasing amounts of connective tis-
Figure 8. Microphotograph
sue. In adults, the RO is described to be vari- showing focal smooth mus-
able in its appearance, from almost lacking to cle fibers (highlighted by
abundant. Though the RO is usually found SMA immunostaining) in
within the ovary, the position is variable and it the stroma (H&E X200).
may be found almost completely outside in the
mesovarium. With advancing age, it tends to
become more atrophic and may become solid,
adenomatous, cystic or polycystic.7 Tumors of
the RO proper are most unusual.1,10,11 In the lit-
erature, only one report has dealt with cysts,
adenomas and carcinomas of this structure.1
Khan et al.11 have tried to explain the reason of
the comparative rarity of benign and malig-
nant tumors arising in this structure, as com-
pared to other sites in the female genital tract
(FGT). They found lower levels of estrogen
receptor (ER) and progesterone receptor (PR)
Figure 9. Microphotograph
in the rete, suggesting a lesser degree of showing intense and diffuse
responsiveness to hormone stimulation in ER positivity in epithelial
this structure, which consequently explains cells (H & DAB X 200).
the low proliferation rate in the RO. This low
proliferation rate, detected using antibody to
Ki-67, suggests a lower growth rate in this tis-
sue than in other tissues of the FGT. They
advance the theory that this low proliferation
is responsible for the rarity of RO tumors. The
major importance to recognize the RO and its
lesions is that they can be confused with other
conditions such as endometriosis.6 A detailed
description and characterization of this
unique structure (RO) may help in difficult
differential diagnoses between benign and
malignant ovarian lesions, analogous to tes-
ticular lesions.12 Recognition of benign lesions Figure 10. Microphotograph
is important so that unnecessary and poten- showing intense and diffuse
tially morbid therapies are avoided.13 The CK7 positivity in epithelial
cells (H & DAB X200).
majority of the rete cysts are thought to repre-

[Rare Tumors 2009; 1:e24] [page 71]

Case Report

sent non-neoplastic dilatations, since they are

lined by a single layer of bland epithelium and
appear to be exaggerations of microscopic
rete dilatations.1 Rutgers and Scully1 state that
although rete cysts have been rarely described
in the literature, they are not that uncommon.
They found 16 cases of RO cysts (cystadeno-
mas), 7 of which were found in a retrospective Figure 11. Microphotograph
review of 126 ovarian cysts. Rete cyst forma- showing no staining in
tion is more common in older than younger epithelial cells for thrombo-
women.1 The age range in the 16 cases modulin (right), whereas the
described by Rutgers and Scully1 was from 23- normal ovarian surface
epithelial lining (left) is pos-
80 years, (mean age 59 years), most of whom itive for it, acting as an inter-
were post-menopausal. Similarly, our case is nal control (H & E X200).
also that of a 75-year old post-menopausal
patient. A plethora of RT lesions have been
described,4,14 including:
1. non-neoplastic and developmental abnor-
malities, which include rete hyperplasia,
nodular proliferation of calcifying connec-
tive tissue, cystic dysplasia, acquired or sec-
ondary cystic changes in the rete, rete
changes in cryptorchidism;
2. benign neoplasms, which include cystade-
noma of usual type and sertoliform cystade- Figure 12. Microphotograph
noma; showing lack of a distinct
basement membrane, high-
3. adenocarcinoma of the rete. lighted by negative staining
Strict criteria4 have been proposed in diag- for laminin (H & DAB
nosing a primary tumor of the RT, which X400).
include:
1. absence of histologically similar extra-scro-
tal tumor; Table 1. Antibodies used in the study.
2. tumor centered on the testicular hilus; Antibodies Source Dilution Type Pre-treatment Result in our case
3. morphology incompatible with any other
type of testicular or paratesticular tumour; CK5/6 Leica Pre-dilute Monoclonal ER2, 10 min - ve
4. demonstration of a transition between the ER Leica Pre-dilute Monoclonal ER2, 20 min + ve
unaffected RT and the tumor; PR Novastra 1/200 Monoclonal ER1, 20 min Patchy + ve
5. a predominantly solid appearance. SMA Leica Pre-dilute Monoclonal No pre-treatment Focal + ve
The last criterion should not be applied too Desmin Leica Pre-dilute Monoclonal ER2, 20 min Focal + ve
rigidly, since although most cystic “carcino- S100 Biogenix 1/400 Monoclonal ENZ 1, 10 min - ve
mas of the rete” are compatible with a serous CA-125 Nocacastra 1/100 Monoclonal ER2, 20 min + ve
tumor, RT carcinomas with cystic growth pat- Cam 5.2 BD Bioscience 1/20 Monoclonal ENZ 1, 10 min + ve
tern have also been encountered. Similarly, a EMA Dako 1/400 Monoclonal ER2, 20 min + ve
transition with the unaffected RT may be dif- CEA Dako 1/25 Monoclonal ENZ 1, 10 min - ve
ficult to demonstrate, but if all other criteria
CK7 Leica Pre-dilute Monoclonal ER2, 20 min + ve
are met, a diagnosis of a primary RT tumor is
CK20 Dako 1/50 Monoclonal ER1, 20 min - ve
acceptable. Although there are no such crite-
ria for diagnosing a primary tumor of the RO, E-cadherin Dako 1/50 Monoclonal ER2, 20 min + ve
certain distinguishing features of RO tumors Vimentin Dako 1/200 Monoclonal ER1, 20 min + ve
have been described.1,2 MNF-116 Dako 1/200 Monoclonal ENZ 1, 10 min + ve
They include: Ber-EP4 Dako 1/100 Monoclonal ENZ 1, 10 min + ve
1. apparent location in the hilus of the ovary; CK19 Dako 1/200 Monoclonal ER2, 20 min + ve
2. occasional ciliated cells; Ki-67 Dako 1/200 Monoclonal ER2, 20 min < 2% cells + ve
3. crevice formation of the inner surface (of PLAP Dako 1/50 Monoclonal ER2, 20 min - ve
the tubules/glands) which recapitulates the CD10 Leica Pre-dilute Monoclonal ER2, 20 min + ve
irregular outlines of the normal rete; Thrombomodulin Dako 1/10 Monoclonal No pre-treatment - ve
4. other resemblance to the normal rete;
Inhibin Dako 1/100 Monoclonal ER2, 20 min - ve
5. normal rete adjacent to some lesions;
Laminin Dako 1/40 Polyclonal ENZ1, 10 min - ve
6. a wall of fibromuscular connective tissue.
Most of the previously reported cases have WT-1 Dako 1/1000 Monoclonal ER2, 20 min - ve
involved the hilus alone or the hilus and part AFP Dako Pre-dilute Monoclonal ER1, 10 min - ve
of the medulla.1 In our case, the ovarian ER1, enzyme retrieval (low pH); ER2, enzyme retrieval (high pH); ENZ1, enzyme 1 (BondMax); ENZ2, enzyme 2 (BondMax); CK, cytokeratin;
involvement was diffuse and extensive, from WT, Wilms’ Tumour; ER, oestrogen receptor; PR, progesterone receptor; SMA, smooth muscle actin; EMA, epithelial membrane antigen;
the hilus to the cortex. Although the definite CEA, carcinoembryonic antigen; PLAP, placental alkaline phosphatise; AFP, alpha feto protein.

[page 72] [Rare Tumors 2009; 1:e24]


relation to the hilus was obscured, the cyst
walls were composed of fibrovascular tissue
with few irregularly arranged fascicles of
smooth muscle. The intervening stroma was
cellular and in places very much reminiscent
of RO. Normal ovarian tissue was not seen, in
spite of embedding and examining the whole
specimen. Similar absence of ovarian tissue
has been noted in large rete cysts of CD-1
mice.2 The possible explanations put forth by
Long2 are that ovarian tissue could have atro-
phied secondary to compression, or could have
had amyloidosis or other degenerative
changes not directly associated with the for-
mation of the cyst. Another postulated expla-
nation is that of minimal remaining ovarian
tissue, which could be missed due to limited
sectioning of the sample. But the complete
sectioning of our sample abolishes this possi-
bility. Mesonephric and rete remnants have
been described in the vicinity of the lesions in
2 cases.8 Our case also showed rete remnants
in the vicinity of the main tumor and also
admixed with it. Tumors of the RO often
exhibit stromal luteinization or Leydig-like
cells in the stroma, reproducing the normal
relations between hilar epithelial vestiges and
steroid-producing cells of the hilum.1,8,10
However, in our case, there was neither stro-
mal luteinization nor Leydig-like cells, making
the diagnosis quite difficult. Nogales et al.10
concluded that the retiform structures of
Uterine Tumor Resembling Ovarian Sex Cord
Tumor (UTROSCT) have a similar, if not iden-
tical immunophenotype to that of the RO and
the Wolffian Adnexal Tumor (WAT). They have
been regarded as different from Ovarian
Retiform Sertoli Leydig Cell Tumor (ORSLCT),
probably since these ovarian tumors seem to
recapitulate early embryogenesis reproducing
the early RO and its connection with the prim-
itive sex cords.10 Probably, they have an imma-
ture phenotype with a different antigen
expression. In our case, a number of differen-
tial diagnoses were entertained. Inclusion
cysts could not be a possibility, since firstly,
they would not be so extensive so as to replace
and involve the whole ovarian parenchyma.
Secondly, they were not stained by WT-1,
which normally stains ovarian surface epithe-
lium and ovarian inclusion cysts.15 Rete hyper-
plasia, on low power examination, reveals a
proliferation of irregularly sized anastomos-
ing channels and glands within the rete,
which do not form a circumscribed mass. The
proliferation is often vaguely lobular with
smaller glands surrounding larger cystic and
elongated forms.4 Adenomatous hyperplasia of
the rete testis (AHRT) is a benign lesion char-
acterized by solid/ glandular, papillary or crib-
riform proliferation of the epithelium with
self-limited growth. It can appear at any time
during life.14 Mesothelioma may have elongat-
ed slit-like tubules with papillary growth. But
the absence of localization within the rete, or
continuity with the RO epithelium are find-
ings that indicate a diagnosis of mesothe-
lioma, rather than RO carcinoma.4 Our case
had very bland epithelium, which was nega-
tive for mesothelial markers (calretinin,
thrombomodulin, WT-1, CK5/ 6) and positive
for epithelial markers (Cam5.2, MNF-116, Ber-
EP4). Metastatic adenocarcinoma is another
differential for RO carcinomas, though not in
our case. Bilaterality, multifocality and micro-
scopic evidence of an interstitial growth pat-
tern with lymphatic or vascular permeation
are good clues that one may be dealing with a
metastasis.4 Cystic dilatation/ transformation
of the RT has been described,4,12 but no such
entity has been described for the RO. ORSLCT
has Leydig cells (inhibin and calretinin posi-
tive) in the stroma. Positivity for inhibin and
calretinin, along with negativity for EMA and
CK7 favors the diagnosis of ORSLCT. However,
the findings in our case were the reverse: EMA
positive, inhibin and calretinin negative.
Morever, there were no Leydig cells in the
stroma. Even clinically, there were no hormon-
al manifestations in the patient. Yolk sac
tumors are known for their retiform architec-
ture.16 However, the complete absence of α
fetoprotein (AFP) in our case and the lack of
placental alkaline phosphatase (PLAP), which
occurs in about 50% of yolk sac tumors,15
makes a diagnosis of the latter most unlikely.
An ovarian adenomatoid tumor also has to be
considered in the differential diagnosis
because of some morphological features.
However, in the absence of CK5/6, calretinin
and thrombomodulin expression, such a diag-
nosis cannot be entertained. Female adnexal
tumor of probable Wolffian origin (FATWO) is
characterized by prominent tubule formation
and peritubular basement membranes.17
Laminin immunostaining accentuates a
prominent peritubular basement membrane,
and often unmasks a tubular pattern in what
may appear to be a solid proliferation.5 A reti-
form pattern may also be seen in FATWO or
WAT.9 These rare tumors are also positive for
keratins, inhibin and vimentin, with variable
ER/PR positivity. Inhibin positivity has been
reported in 68%9 and 90%9 of FATWO, but it is
patchy and weak. They are often non-reactive
for EMA.5 Although our case was positive for
vimentin, keratins and EMA, inhibin was
characteristically negative. RO has been
shown to have focal positivity for CK7, patchy
and weak staining for inhibin, 8% of cases
being positive for ER and PR.5 Our case was
diffusely positive for CK7, ER and PR, while
being negative for inhibin. EMA has been
found to be negative,5 whereas our case was
diffusely positive for EMA. Retiform uterine
tumor resembling ovarian sex cord tumor
(RUTROSCT) is another differential. But this
was not entertained in our case, since the
[Rare Tumors 2009; 1:e24]
Case Report
uterus did not show any such features.
However, RUTROSCT has been shown to have
consistent positivity for Cam5.2, CK7,
vimentin, calretinin, PR and apical CD10.
CD56 and inhibin positivity has been found in
half of the cases. EMA, desmin, SMA and
calponin have been found to be negative.10 RO
and its tumors have been found to be positive
for EMA, CA- 1256,8,10 CK7, calretinin (cytoplas-
mic), CD56 (membranous), CD10 (apical).10
They have been found to be focally positive for
vimentin and negative for CA19.9, CEA, S-100
and PR.8 However, our case was positive for
EMA, CA-125, vimentin, CK7, ER, PR, CD10,
Cam5.2, MNF-116, BerEP4, CK-19, ECadherin
and CD56. Our case was negative for WT-1,
CK5/6, calretinin, inhibin, CEA, AFP, S-100,
thrombomodulin and PLAP. Focal smooth mus-
cle in the stroma was positive for desmin and
SMA. Thus, on the basis of the histological
and immunohistochemical features of the
ovarian tumor reported here, and after exclu-
sion of other differential diagnoses, the diag-
nosis of a cystadenofibroma of the RO can be
established in this case. To summarize, to the
best of our knowledge, this is a rare case of
cystadenofibroma of the rete ovarii in a 75-
year old woman.
References
1. Rutgers JL, Scully RE. Cysts (cystadeno-
mas) and tumours of rete ovarii. Int J
Gynec Pathol 1988;7:330-42.
2. Long GG. Apparent mesonephric duct (rete
anlage) origin for cysts and proliferative
epithelial lesions in the mouse ovary.
Toxic Pathol 2002;3:592-8.
3. Heatley MK. Adenomatous hyperplasia of
the rete ovarii. Histopathol 2000;36:383-4.
4. Jones EC, Murray SK, Young RH. Cysts and
epithelial proliferations of the testicular
collecting system (including rete testis).
Semin Diagn Pathol 2000;17:270-93.
5. Devouassoux-Shisheboran M, Silver SA,
Tavassoli FA. Wolffian Adnexal Tumor, so
called female adnexal tumour of probable
Wolffian origin (FATWO): immunohisto-
chemical evidence in support of a Wolffian
origin. Hum Pathol 1999;30:856-63.
6. Woolnough E, Russol L, Khan MS, Heatley
MK. An immunohistochemical study of the
rete ovarii and epoophoron. Pathol 2000;
32:77-83.
7. Wenzel JGW, Odend’hal S. The mam-
malion rete ovarii: a literature review.
Cornell Vet 1985;75:411-25.
8. Nogales FF, Carvia RE, Donné C, et al.
Adenomas of the rete ovarii. Hum Pathol
1997;28:1428-33.
9. Mooney EE, Nogales FF, Bergeron C, et al.
Retiform Sertoli-Leydig cell tumours: clin-
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ical, morphological and immunohisto-
chemical findings. Histopath 2002;41:110-
7.
10. Nogales FF, Stolnicu S, Harilal KR, et al.
Retiform uterine tumours resembling
ovarian sex cord tumours. A comparative
immunohistochemical study with retiform
structures of the female genital tract.
Histopath 2009;54:471-7.
11. Khan MS, Dodson AR, Heatley MK. Ki-67,
oestrogen receptor and progesterone
receptor proteins in the human rete ovarii
and in endometriosis. J Clin Pathol
1999;52:517-20.
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12. Fridman E, Skarda J, Moravsky EO, et al.
Complex multilocular cystic lesion of rete
testis, accompanied by smooth muscle
hyperplasia, mimicking intratesticular
Leydig cell neoplasm. Virchows Arch
2005;447:768-71.
13. Hartwick RWJ, Ro JY, Srigley JR, et al.
Adenomatous hyperplasia of the rete
testis. A clinicopathologic study of nine
cases. Am J Surg Path 1991;15:350-7.
14. Nistal M, Castillo MC, Regadera J, et al.
Adenomatous hyperplasia of the rete
testis. A review and report of new cases.
Histol Histopathol 2003;18:741-52.
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15. O’Neil CJ, Deavers MT, Malpic A, et al. An
immunohistochemical comparison
between low grade and high grade ovarian
serous carcinomas: significantly higher
expression of p53, MIB-1, Bcl-2, Her2/nell,
and C-KIT in high grade neoplasms. Am J
Surg Pathol 2005;29:1034-41.
16. Rosai J. Rosai and Ackerman's Surgical
Pathology, 9th ed. India, Elsevier; 2004.
Chapter 19, Ovary; pp 1649-736.
17. Young RH, Scully RE. Ovarian tumours of
probable Wolffian origin. A report of 11
cases. Am J Surg Pathol 1983;7:125-35.
 open access journal

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Angiomyomatous hamartoma:
a rare case report with review
of the literature
Manisha Ram, Nazar Alsanjari,
Naseem Ansari
Department of Cellular Pathology,
Basildon Hospital, Basildon & Thurrock
University Hospitals NHS Foundation
Trust, Basildon, UK
Introduction
Angiomyomatous hamartoma (AMH) of the
lymph node (LN) is a benign vascular disorder
of unknown etiology, first described by Chan et
al. in 1991, as a distinctive lesion of LN char-
acterized by parenchymal replacement by
blood vessels, smooth muscle and fibrous tis-
sue in the absence of cellular fascicle forma-
tion.1 This rare disease particularly involves
inguinal and femoral lymph nodes,1-6 however,
one report of cervical LN involvement has been
reported.7 A single case of popliteal LN involve-
ment has also been reported.8 To the best of
our knowledge, only 17 cases of AMH of LN
have been reported in the literature.2 We pres-
ent a case of AMH of the inguinal LN in an 82-
year old male.
Case Report
An 82-year old male patient presented with a
left inguinal mass and associated ipsilateral
lower limb edema of two years duration.
Computerized tomography (CT) revealed mul-
tiple enlarged lymph nodes throughout the
abdomen. Macroscopically, the inguinal mass
measured 3x2x1 cm. On cut section, it had a
firm gray-white appearance. Microscopically, it
represented a lymph node, the parenchyma of
which was almost completely replaced from
hilum to cortex by fibrous tissue containing
numerous irregular blood vessels, interspersed
spindle cells and few lobules comprised of
benign adipocytes. These changes gradually
extended from the hilum to the convex surface
of the LN (Figure 1), leaving only a thin rim of
cortical lymphoid tissue containing a few
residual atrophic follicles (Figure 2). The cap-
sule was thickened and no subcapsular or
medullary sinuses were found. While the
hilum contained thick-walled muscular ves-
sels, the cortex was mainly rich in capillary
like vessels. Towards the cortex, the vessels
became more dispersed and associated with
smooth muscle cells, eventually splaying into
the sclerotic stroma. The fibrous tissue con-
sisted of spindle shaped cells with regular
elongated nuclei and eosinophilic cytoplasm,
dispersed haphazardly around vascular struc-
tures (Figures 3, 4 and 5). A few interspersed
islands of adipocytes were also seen (Figures 6
and 7). Cellular pleomorphism, conspicuous
mitoses and necrosis were absent. Immuno-
histochemistry (Streptavidinbiotin- complex),
showed a strong reactivity for alpha smooth
muscle actin (ASMA) and Desmin in the spin-
dle shaped cells dispersed throughout the
fibrous tissue and highlighted the muscular
nature of the blood vessels, especially present
in the LN hilum (Figure 8). The blood vessels
were decorated by CD 34 (Figure 9). The histo-
logical appearances, supported by immunohis-
tochemistry, led to the diagnosis of AMH of LN.
On account of the entirely benign nature of
this condition extensive resection was not
required and the patient is doing well six
months after the surgery, although the lym-
phedema did not regress completely.
Discussion
In a study conducted to investigate the mor-
phological and clinical findings of various pri-
mary vascular tumors of lymph nodes other
than Kaposi’s sarcoma, Chan et al. used the
term “angiomyomatous hamartoma” to
describe a distinctive clinico-pathological
lesion occurring in lymph nodes.1 AMH seems
to be a rare nodal condition as only 17 cases
have been reported in the literature so far.1,5,7
There is a tendency for AMH to occur in
inguinal lymph nodes, although a few cases
have been reported in femoral lymph nodes.1-6
Isolated cases (one each) have also been
reported in the cervical and popliteal lymph
nodes.7,8 Laeng et al. were the first to report an
angiomyomatous hamartoma with a heman-
giomatoid component and vascular transfor-
mation of sinuses in the same LN.7 Their
report of a cervical LN was also the first report
of an AMH outside of the inguinal or femoral
nodes. We report another case of AMH of the
[Rare Tumors 2009; 1:e25]
Rare
Rare
Tumors
Tumors
2009;
2009;
volume
volume
1:exxxx
1:e25
Correspondence: Manisha Ram,
Department of Cellular Pathology, Basildon
Hospital, Basildon & Thurrock University
Hospitals NHS Foundation Trust, Nethermayne
Basildon SS16 5NL, UK
E-mail: pathologist.manisha@gmail.com
Key words: angiomyomatous hamartoma, lymph
node, inguinal, popliteal, cervical, lymphedema.
Acknowledgments: we would like to thank Dr.
Adu-Poku Kwame and Toni-Ann Robinson for
their assistance.
Contributions: MR, conception, design, acquisi-
tion of data, analysis and interpretation of data,
drafting article and revising critically for impor-
tant intellectual content, final approval of version
to be published; NAl, interpretation of data, revis-
ing critically for important intellectual content,
final approval of version to be published; NAn,
acquisition of data, analysis, revising critically
for important intellectual content, final approval
of version to be published.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 21 July 2009.
Accepted for publication: 23 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright M. Ram et al., 2009
Rare Tumors 2009; 1:e25
doi:10.4081/rt.2009.e25
inguinal LN in an 82-year old male. We re-con-
firm the predilection of this lesion to occur in
inguinal lymph nodes, which may be related to
the fact that this is also the most frequent site
of other nodal mesenchymal tumors.9,10
Histologically, it was characterized by an
extensive replacement of nodal parenchyma,
from hilum to cortex, by a haphazard mixture
of smooth muscle cells, adipose tissue and
blood vessels within a fibrous stroma.
Differential diagnoses include nodal lymphan-
Figure 1. Microphotograph show-
ing low power view of angiomy-
omatous hamartoma, including
smooth muscle bundles admixed
with fibrous tissue and blood ves-
sels, extending from the lymph
node hilum (lower part) to cortical
lymphoid follicles (upper and
right side) (H&E X40).
[page 75]
Case Report

giomyomatosis, leiomyomatosis and angiomy-

olipoma of the LN.1,11 Nodal lymphangiomy-
omatosis occurs exclusively in women,
involves thoracic and abdominal lymph nodes
and is histologically characterized by the pres-
ence of smooth muscle cells forming fascicles
and sheets around anastomosing ectatic vas-
cular spaces, resulting in a pericytomatous
pattern.11 Moreover, in nodal lymphangiomy-
Figure 2. Microphotograph show-
omatosis, smooth muscle cells are plumper, ing a few residual lymphoid folli-
with lighter/clear cytoplasm and sclerosis is cles (upper part) with underlying
absent.1 Nodal leiomyomatosis, which affects smooth muscle (lower part) (H&E
intra-abdominal lymph nodes morphologically X200).
resembles extensive leiomyoma and is com-
posed of a proliferation of compact bundles of
smooth muscle cells with an insignificant vas-
cular component.11 An association with HIV/
immunodeficiency has also been reported.12
Angiomyolipoma of the LN usually affects
retroperitoneal lymph nodes and is considered
as being a manifestation of multicentricity of
angiomyolipoma of the kidney.11 The smooth
muscle cells of angiomyolipoma usually show Figure 3. Microphotograph show-
an epithelioid appearance, hypercellularity, ing all the elements of angiomyo-
pleomorphism, prominent perivascular matous hamartoma: smooth mus-
cle, fibrous tissue, adipose tissue
arrangement and positivity for melanoma and blood vessels with a disorgan-
associated antigen HMB-45.13 The histogenesis ised growth pattern (H&E X200).
of AMH of LN is still unclear.3 In the original
description, the hamartomatous nature was
postulated on the basis of a disorganized
growth pattern of smooth muscle cells and
blood vessels.1 A significant adipose tissue
component within a mixture of smooth muscle
cells and blood vessels in AMH of LN may pro-
vide morphological evidence of the hamar-
tomatous nature of the lesion. The close asso-
ciation of adipose tissue with smooth muscle Figure 4. Microphotograph show-
cells and muscular blood vessels from the hilar ing smooth muscle fibres contain-
region to the cortex indicates that adipose tis- ing benign spindle cells, together
sue may be a true component of hamartoma,5 with variably sized blood vessels in
a background of fibrous tissue
further supported by the fact that AMH is a (H&E X200).
pathological condition starting in the hilum
and extending towards the cortex.1 Adipose
cells are known to occur as a significant com-
ponent in a number of vaso-proliferative
lesions, such as nodal hemangioma, intramus-
cular hemangioma (infiltrative angiolipoma)
and angiolipomatous hamartoma associated
with Castleman’s disease.1,14,15 It has been sug-
gested that all cases of AMH of the LN with a
signficant adipose tissue component should be
termed angiomyolipomatous hamartoma.3
Figure 5. Microphotograph show-
However, the possibility that the lesion may ing high power view of benign
represent a hemangioma with a prominent spindle cells in the smooth muscle,
smooth muscle component or a reparative with a large benign adipocyte
reaction to nodal inflammation cannot be ruled (upper right) (H&E X400).
out.1 Some peculiar alterations of the lymph
node vascular supply have been described,
including increased numbers of small blood
vessels with thickened walls and formation of dered angiogenic process arising from hilar the affected lymph node, explaining the occur-
plexiform or glomeruloid structures, such as in blood vessels, presumably the hilar vein and its rence of lymphedema in some patients.1,6
primary pulmonary hypertension and glioblas- branches.6 Further, the destruction of nodal Sukarai et al. suggested that impairment of
toma multiforme.6 Such similarities suggest sinuses by all these vascular and stromal alter- lymphatic flow may be one factor related to the
that AMH of LN actually represents a disor- ations impairs the lymphatic circulation across pathogenesis of AMH.4 According to them, the

[page 76] [Rare Tumors 2009; 1:e25]


process appears to start in the hilum and
extends towards the cortex, causing normal
lymphatic tissue to become displaced and
atrophic. Recently, Piedimonte et al. described
a third case in the literature in which a patient
presented with a left sided inguinal mass, ipsi-
lateral lymphedema of the leg and AMH.2 Our
Figure 6. Microphotograph show-
ing benign adipocyte lobules
amidst smooth muscle (H&E
X200).
Figure 7. Microphotograph show-
ing high power view of benign
adipocyte lobules (H&E X400).
Figure 8. Microphotograph show-
ing positive immunostaining of
smooth muscle by desmin
(H&DAB X200).
Figure 9. Microphotograph show-
ing positive immunostaining of
blood vessels by CD34 (H&DAB
X200).
patient’s lymphedema did not regress after
excision of the AMH, similar to the case
described by Piedimonte.2 Possible explana-
tions for this discrepancy are that AMH may
represent a localized malformation in a con-
genitally damaged lymphatic system. An alter-
native possibility is that chronic impairment of
[Rare Tumors 2009; 1:e25]
Case Report
lymphatic flow results in the development of
an AMH.2 The abnormal lymphatic flow has
been revealed by examination of the radionu-
clide lymphoscintigram.6 There are specula-
tions about whether the interference of lymph
flow is the cause or the effect of AMH, which
have to be determined.4 The unique features of
our case are as follows: 1) to the best of our
knowledge, this is only the eighteenth case of
AMH reported so far in the literature;2 2) it is
the fourth case in the literature in which the
patient presented with a left inguinal mass,
ipsilateral lymphedema of the leg and AMH; 3)
all the previous 17 cases have been reported in
the age range from 10-80 years (mean age, 47
years)1,3,4,7 whereas our patient is 82-years old.
To conclude, although AMH of lymph node is
very rare, its recognition is important for dif-
ferential diagnoses from angiomatous benign
and malignant tumors of lymph nodes.
Recurrences and metastases of AMH have not
been reported,1,3,5,7 except for a single occur-
rence of a secondary lesion after tumor resec-
tion, which was presumably due to impaired
lymphatic transport.4 Hence, keeping in mind
the hamartomatous nature of AMH, in our
patient extensive resection was not needed.
Our patient is doing well, six months after the
LN excision.
References
1. Chan JKC, Frizzera G, Fletcher CDM, et al.
Primary vascular tumours of lymph nodes
other than Kaposi’s sarcoma – analysis of
39 cases and delineation of two new enti-
ties. Am J Surg Pathol 1992;16:335-50.
2. Piedimonte A, Nictolis MD, Lorenzini P, et
al. Angiomyomatous hamartoma of
inguinal lymph nodes. Plastic & Recon
Surg 2006;117:714-6.
3. Magro G, Grasso S. Angiomyomatous
hamartoma of the lymph node: Case report
with adipose tissue component. Gen &
Diagn Pathol 1997;143:247-9.
4. Sakurai Y, Shoji M, Matsubara T, et al.
Angiomyomatous hamartoma and associ-
ated stromal lesions in the right inguinal
lymph node: A case report. Pathol Int 2000;
50:655-9.
5. Allen PW, Hoffman GJ. Fat in angiomyoma-
tous hamartoma of lymph node. Am J Surg
Pathol 1993;17:748-9.
6. Dargent JL, Lespagnard L, Verdebout JM,
et al. Glomeruloid microvascular prolifera-
tion in angiomyomatous hamartoma of the
lymph node. Virchows Arch 2004;445:320-
2.
7. Laeng RH, Hotz MA, Borisch B. Angio-
myomatous hamartoma of a cervical lymph
node combined with haemangiomatoids
and vascular transformation of sinuses.
[page 77]
Case Report
Histopathol 1996;29:80-4.
8. Mauro CS, McGough RL, Rao UNM.
Angiomyomatous hamartoma of a
popliteal lymph node: an unusual cause of
posterior knee pain. Ann of Diagn Pathol
2008;12:372-4.
9. Suster S, Rosai J. Intranodal haemorrhag-
ic spindle-cell tumour with ‘amianthoid’
fibres: report of six cases of a distinctive
mesenchymal neoplasm of the inguinal
region that simulates Kaposi’s sarcoma.
Am J Surg Pathol 1989;13:347-57.
[page 78]
10. Weiss SW, Gnepp DR, Bratthauer GL.
Palisaded myofibroblastoma: a benign
mesenchymal tumour of lymph node. Am J
Surg Pathol 1989;13:341-6.
11. Warnke RA, Weiss LM, Chan JKC, et al.
Tumours of the lymph nodes and spleen,
3rd series. In: Atlas of Tumour Pathology.
1995 pp 437-42, Armed Forces Institute of
Pathology, Washington, USA.
12. Starasoler L,Vuitch F, Albores-Saavedra J.
Intranodal leiomyoma. Another distinctive
primary spindle cell neoplasm of lymph
[Rare Tumors 2009; 1:e25]
node. Am J Clin Pathol 1992;97:896-7.
13. Sullu Y, Gun S, Dabak N, et al. Angio-
myomatous hamartoma in the inguinal
lymph node: a case report. Turk J Pathol
2006;22:42-4.
14. Allen PW, Enzinger FM. Haemangioma of
skeletal muscle, an analysis of 89 cases.
Cancer 1972;29:8-22.
15. Madero S, Onate J, Garzon A. Giant lymph
node hyperplasia in an angiolipomatous
mediastinal mass. Arch Pathol Lab Med
1986;110:853-5.

Malignant neuroectodermal
tumor with melanocytic and
rhabdomyoblastic
differentiation
Munir R. Tanas and Brian P. Rubin
Department of Anatomic Pathology,
Pathology and Laboratory Medicine
Institute, The Cleveland Clinic and The
Cleveland Clinic Lerner College of
Medicine, Case Western Reserve
University, Cleveland, OH, USA
Abstract
Malignant melanoma can metastasize wide-
ly and vary significantly in its histological
appearance; it rarely presents as a deep-seated
mass without an obvious primary site else-
where. Malignant peripheral nerve sheath
tumor (MPNST) is a high-grade sarcoma char-
acterized by conventional and epithelioid sub-
types. MPNST can demonstrate heterologous
differentiation, usually in the form of osteosar-
comatous, chondrosarcomatous, or rhabdo-
myosarcomatous differentiation. MPNST does
not harbor true melanocytic differentiation,
although epithelioid MPNST typically is dif-
fusely S-100 protein positive and superficially
can resemble malignant melanoma. An unusu-
al intra-abdominal mass was recently encoun-
tered with features of both melanoma and con-
ventional or epithelioid MPNST containing a
fascicular spindle cell component, an epithe-
lioid component with melanocytic differentia-
tion, as well as a rhabdomyosarcomatous com-
ponent. The terminology “malignant neuroec-
todermal tumor with melanocytic and rhab-
domyoblastic differentiation” is proposed to
describe this neoplasm, reflecting the unusual
concomittant lines of differentiation as well as
offering a possible rationale for nosologically
challenging aspects of this neoplasm.
Introduction
The neural crest, derived from embryonic
neuroectoderm, is thought to give rise to sev-
eral cell types within the human body includ-
ing melanocytes and Schwann cells.1 The pro-
totypic malignant neoplasms arising from or
showing differentiation toward these cell types
are malignant melanoma and malignant
peripheral nerve sheath tumor (MPNST),
respectively. Malignant melanoma is a rela-
tively common neoplasm arising predominant-
ly in the skin, but also the eye, oral and
anogenital mucosal surfaces, esophagus, and
meninges. A small number of metastatic
melanomas present with no clearly identifiable
primary site. Because of its ability to metasta-
size to a wide variety of sites as well as its wide
histological spectrum, its ability to mimic
other neoplasms is well recognized. Although
spindle cell melanomas often lose immunore-
activity for melanocyte-specific markers
(HMB-45, Melan-A, tyrosinase, MiTF), they are
virtually all positive for S-100 protein.2 MPNST
comprises five to ten percent of all soft tissue
sarcomas with a peak incidence in the third to
sixth decades of life. Approximately twenty-
five to fifty percent of MPNST are associated
with neurofibromatosis-1.3,4 MPNST often aris-
es in a pre-existing neurofibroma but can
involve practically any anatomic site in the
body. In general, they are considered to be
high-grade sarcomas with a high likelihood of
local recurrence and distant metastasis.
The typical conventional MPNST is a fascic-
ular, spindle cell sarcoma with variable
immunoreactivity for S-100 protein; it is not
uncommon for conventional MPNST to be only
focally positive for S-100 or lack staining for
the antigen altogether. Of particular interest is
the tendency for MPNST to contain areas with
heterologous differentiation, most commonly
osteosarcomatous, chondrosarcomatous, or
rhabdomyosarcomatous differentiation
(malignant Triton tumor).4 Epithelioid MPNST
accounts for five percent of all MPNST. In con-
trast to the conventional subtype, these neo-
plasms have a nested growth pattern, an
epithelioid cytomorphology with prominent
nucleoli, as well as strong and diffuse positivi-
ty for S-100 protein; thus bearing a superficial
resemblance to melanoma. Many epithelioid
MPNST also have a minor spindle cell compo-
nent which resembles conventional MPNST.
Significantly, epithelioid MPNST is negative
for melanocyte-specific markers (e.g. HMB-45,
Melan-A, etc.).4
An exceptional intra-abdominal neoplasm
was recently encountered in consultation with
features of both MPNST and melanoma includ-
ing a fascicular spindle cell component consis-
tent with conventional MPNST, extensive rhab-
domyosarcomatous differentiation, as well as
an epithelioid component reminiscent of
epithelioid MPNST but showing melanocytic
differentiation. Review of the English lan-
guage literature revealed one other similar
case, a case of an MPNST with divergent
melanocytic and rhabdomyoblastic differentia-
tion.5
Materials and Methods
This case was received in consultation by
one of the authors (BPR). Immunohisto-
chemistry was performed on formalin-fixed,
[Rare Tumors 2009; 1:e26]
Rare Tumors 2009; volume 1:e26
Correspondence: Brian P. Rubin,
Departments of Anatomic Pathology and
Molecular Genetics, Taussig Cancer Center and
Lerner Research Institute, Cleveland Clinic
Foundation L25, 9500 Euclid Avenue, Cleveland,
OH 44195, USA. E-mail: rubinb2@ccf.org
Key words: malignant peripheral nerve sheath
tumor, malignant melanoma, melanocytic differ-
entiation, rhabdomyoblastic differentiation,
malignant neuroectodermal tumor.
Contributions: MRT and BPR, contributed to the
concept and design of the study, as well as the
analysis and interpretation of the data. They both
helped draft/revise the article and gave final
approval of the version to be published.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 26 July 2009.
Accepted for publication: 5 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright M.R. Tanas and B.P. Rubin, 2009
Rare Tumors 2009; 1:e26
doi:10.4081/rt.2009.e26
paraffin-embedded tissue by the avidin-biotin-
peroxidase complex technique using commer-
cially available antibodies to the following anti-
gens: S-100 (polyclonal; 1:8000; DAKO,
Carpinteria, CA, USA), HMB-45/50 (HMB 45/50
cocktail, 1:50/1:250 A. Gown), tyrosinase
(T311, 1:100, Novocastra, Norwell, MA),
Melan-A (A103, 1:200, DAKO, Carpinteria, CA,
USA), and microphthalmia transcription factor
(D5, 1:25, R. Schmidt).
Results
Clinical features
The patient was a 67-year old man who pre-
sented with a large mass in the abdomen
requiring resection of the spleen, a portion of
the pancreas, as well as a segment of colon and
small bowel. Approximately one year subse-
quent to diagnosis of the abdominal mass, the
patient presented with a brain metastasis.
Pathological features
Grossly, the intra-abdominal mass was 20
cm in greatest dimension. Histologically, it was
characterized by a proliferation of spindle cells
with enlarged hyperchromatic nuclei with
tapered ends and faintly eosinophilic cyto-
plasm arranged in intersecting fascicles. A
prominent herring-bone pattern could be
[page 79]
Case Report

observed in several fields (Figure 1A). Other

areas consisted of epithelioid cells with a mod-
erate amount of eosinophilic cytoplasm and
enlarged vesicular nuclei with prominent
nucleoli (Figure 1B). A third pattern was char-
acterized by rhabdomyoblasts containing
abundant eosinophilic cytoplasm with eccen-
trically placed, enlarged nuclei and prominent
nucleoli, representing rhabdomyosarcomatous
heterologous differentiation (Figure 1E).
Mitotic activity was brisk throughout the neo-
plasm and tumor necrosis was present.
S-100 protein was only focally positive in the
fascicles of spindle cells, but strongly and dif-
fusely positive in the epithelioid areas
(Figure1C). Melanocytic markers including
HMB-45/50 (Figure 1D), Melan-A, tyrosinase,
and MITF were strongly and diffusely positive
in the epithelioid component but were absent
from the spindle cell component. Fontana-
Masson staining did not demonstrate any
melanin pigment in either the epithelioid or
spindle cell components. Skeletal muscle dif-
ferentiation was confirmed in the rhabdomy-
oblasts by strong and diffuse immunoreactivity
for desmin (Figure 1F) and myogenin.
The brain metastasis was characterized by a
morphological appearance similar to the
epithelioid component of the abdominal mass,
including epithelioid cells with eosinophilic
cytoplasm, enlarged vesicular nuclei, and
prominent nucleoli (Figure 2A). The brain
metastasis was focally positive for S-100 pro-
tein, and variably positive for Melan-A (Figure
2B) and HMB-45.

Figure 1. Abdominal mass. (A) Fascicular spindle cell component; (B) epithelioid compo-
nent with prominent nucleoli; (C) strong and diffuse immunoreactivity for S-100 protein
Discussion in the epithelioid component; (D) uniform staining for HMB-45 in the epithelioid com-
ponent; (E) rhabdomyoblasts in areas of rhabdomyosarcomatous heterologous differenti-
ation; (F) strong and diffuse immunoreactivity for desmin in rhabdomyoblasts.
The chief differential diagnoses in this case
are malignant melanoma and MPNST. One pos-
sibility is that the neoplasm is a melanoma with
a significant spindle cell component and het-
erologous rhabdomyosarcomatous differentia-
tion. Melanocytic neoplasms displaying rhab-
domyosarcomatous differentiation have been
reported in the literature. Four case reports
have described rhabdomyosarcomas arising
within congenital melanocytic nevi, demon-
strating that cells with committed melanocytic
differentiation can undergo differentiation
toward a skeletal muscle phenotype.6-8 There is
also a report of two patients with congenital
melanocytic nevi who subsequently developed
Figure 2. Metastasis to brain. (A) Epithelioid neoplasm similar in appearance to the pri-
melanomas within their nevi showing areas of mary neoplasm shown in Figure 1B, (B) immunohistochemistry showing positivity for
rhabdomyoblastic differentiation.9 In addition, Melan-A.
the metastasis involving the brain is both clin-
ically and pathologically more suggestive of
malignant melanoma than MPNST. nent (reminiscent of epithelioid MPNST) that known primary), though possible, are rare. On
Another possibility is that this tumor repre- happens to show evidence of melanocytic dif- the other hand, MPNST commonly occurs in a
sents an MPNST with a conventional spindle ferentiation. This diagnosis is supported by deep-seated location. Furthermore, the spindle
cell component, heterologous rhabdomyoblas- the following features. First, deep-seated pri- cell component was only focally positive for S-
tic differentiation, and an epithelioid compo- mary melanomas (this patient had no other 100 protein and was negative for melanocyte-

[page 80] [Rare Tumors 2009; 1:e26]


specific markers, which is much more typical
of MPNST than spindle cell melanoma (which
is often strongly positive for S-100 protein, as
mentioned previously). In addition, the phe-
nomenon of rhabdomyoblastic differentiation
is a relatively common occurrence in MPNST,
compared to its case-reportable status in
melanoma. The feature of this case that is
most difficult to reconcile with the diagnosis of
MPNST is the epithelioid component, which
showed evidence of melanocytic differentia-
tion. Although epithelioid MPNST can be
strongly positive for S-100 protein, melano-
cyte-specific markers such as HMB-45 and
Melan-A should be negative. There are rare
cases, however, of MPNST that have been
noted to demonstrate melanocytic differentia-
tion.10-15
With the difficulties definitively classifying
the neoplasm as either a melanoma or MPNST,
we propose that an alternative term be used:
malignant neuroectodermal tumor with
melanocytic and rhabdomyoblastic differentia-
tion. As alluded to earlier, the term “neuroecto-
dermal tumor” is used to refer to the fact that
both Schwann cells and melanocytes are
derived from the neural crest, which in turn is
derived from embryonic neuroectoderm.1
Neoplasms with features of melanocytic and
schwannian differentiation are not difficult to
find. Nevi with so-called “neurotization” of
dermal nevomelanocytes are one example.
Melanotic schwannoma is a well-described
entity that occurs sporadically and in the set-
ting of Carney’s complex (cardiac and cuta-
neous myxomas, pigmented nevi, endocrine
abnormalities, and melanotic schwannomas),
and can on occasion metastasize (10-20%).
The neoplastic cells in melanotic schwannoma
can be epithelioid to spindled, and can contain
prominent nucleoli. In addition to being
strongly S-100 protein positive and HMB-45
positive, melanotic schwannomas contain true
melanin pigment, which stains positively with
Fontana-Masson stain. Ultrastructurally, they
are noted to contain premelanosomes and
melanosomes.16 Melanin-containing neurofi-
bromas have been described also. Fetsch et al.
(2000) characterized a series of 19 pigmented
“melanotic” neurofibromas including diffuse,
plexiform, diffuse/plexiform combined, and
intraneural epithelioid morphologies, which
exhibited immunopositivity for S-100 protein,
HMB-45, Melan-A, and tyrosinase, as well as
melanin pigment, confirmed with Fontana-
Masson stain.17 Furthermore, melanin-contain-
ing nerve sheath tumors have been described
in a neurofibromatosis rat model (induced by
transplacental administration of ethylnitro-
surea).18
Because both MPNST and melanoma are
thought to arise from or show differentiation
toward neural crest-derived cells, it is not sur-
prising that rare cases of melanoma might
show rhabdomyoblastic differentiation while
rare cases of MPNST might demonstrate
melanocytic differentiation. However, as dis-
cussed previously, a rigid rendering of the
diagnosis of either melanoma or MPNST to the
exclusion of the other in this case is not easily
done, nor does it capture its diagnostic
nuances. Instead of forcing this neoplasm into
the diagnostic category of melanoma or
MPNST, a more encompassing nomenclature
such as malignant neuroectodermal tumor
may be appropriate. In the end, cases such as
this help us to re-evaluate our diagnostic crite-
ria and highlight possible relationships
between different entities.
References
1. Hamilton WJ, Mossman HW. The fate of
the germ layers and the formation of the
essential (primary) tissues including
blood. In: Human Embryology, 4th ed.
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2. Ohsie SJ, Sarantopoulos GP, Cochran AJ,
et al. Immunohistochemical characteris-
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433-44.
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DG, et al. Malignant peripheral nerve
sheath tumors. A clinicopathological study
of 120 cases. Cancer 1986;57:2006-21.
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schwannoma with rhabdomyoblastic and
melanocytic differentiation. Path Res
Pract 1992;188:770-4.
6. Hoang MP, Sinkre P, Albores-Saavedra J.
Rhabdomyosarcoma arising in a congeni-
tal melanocytic nevus. Am J Dermato-
pathol 2002;24:26-9.
7. Schmidtt FC, Bittencourt A, Mendonca N,
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et al. Rhabdomyosarcoma in a congenital
pigmented nevus. Pediatric Pathol 1992;
12:93-8.
8. Zuniga S, Heras JL, Benveniste S. Rhabdo-
myosarcoma arising in a congenital giant
nevus associated with neurocutaneous
melanosis in a neonate. J Pediatr Surg
1987;22:1036-8.
9. Cohen MC, Kaschula RO, Sinclair-Smith
C, et al. Pluripotential melanoblastoma, a
unifying concept on malignancies arising
in congenital melanocytic nevi: report of
two cases. Pediatric Pathol Lab Med 1996;
16:801-12.
10. Imoto K, Yamazak Y, Kawahara E, et al.
Malignant melanocytic schwannoma of
the nasopharynx. J Otorhinolaryngol Relat
Spec 1991;53:48-51.
11. Murakami T, Kiyosawa T, Murata S, et al.
Malignant schwannoma with melanocytic
differentiation arising in a patient with
neurofibromatosis. Br J Dermatol 2000;
143:1078-82.
12. Roth MJ, Medeiros J, Kapur S, et al.
Malignant schwannoma with melanocytic
and neuroepithelial differentiation in an
infant with congenital giant melanocytic
nevus: a complex neurocristopathy. Hum
Pathol 1993;24:1371-5.
13. Schadendorf D, Haas N, Worm M, et al.
Amelanotic malignant melanoma present-
ing as malignant schwannoma. Br J
Dermatol 1993;129:609-14.
14. Shimizu S, Teraki Y, Ishiko A, et al.
Malignant epithelioid schwannoma of the
skin showing partial HMB-45 positivity.
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15. Thewes M, Jungfer-Weber B, Wiebecke B,
et al. Malignant epithelioid schwannoma
with melanocytic differentiation: a rare
tumor with an unusual feature. Acta Derm
Venereol 1997;77:493-4.
16. Weiss SW, Goldblum JR. Enzinger and
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Philadelphia: Mosby, 2008;870-2.
17. Fetsch JF, Michal M, Miettinen M. Pig-
mented (melanotic) neurofibroma: A clin-
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[page 81]
Rare Tumors 2009; volume 1:e27
Malignant Triton tumor in the
retroperitoneal space
associated with
neurofibromatosis type 1:
a case study
Sojun Hoshimoto,1 Zenichi Morise,1
Chinatsu Takeura,1 Masahiro Ikeda,1
Tadashi Kagawa,1 Yoshinao Tanahashi,1
Yasuhiro Okabe,1 Yoshikazu Mizoguchi,2
Atsushi Sugioka1
1 The left lower extremity was markedly swollen
Department of Surgery and 2Department
of Pathology, Fujita Health University
School of Medicine, Toyoake, Aichi, Japan
Abstract
We report an extremely rare case of malig-
nant Triton tumor developing in the retroperi-
toneal space in a patient with neurofibromato-
sis type 1. A 21-year old man who had been
diagnosed with neurofibromatosis type 1 was
admitted to our hospital with the chief com-
plaint of a palpable abdominal mass. Abdominal
computed tomography revealed a huge hetero-
geneous tumor measuring approximately 17
cm in diameter occupying the left retroperi-
toneal space, and numerous metastatic lesions
between the left psoas muscle and the left thigh
with dissolution of the left hip joint. After the
diagnosis of a retroperitoneal malignant neuro-
genic tumor, resection of the tumor with recon-
struction of the abdominal aorta was conduct-
ed, followed by postoperative transarterial infu-
sion chemotherapy. The histopathological diag-
nosis was malignant peripheral nerve sheath
tumor with rhabdomyosarcomatous differentia-
tion, namely malignant Triton tumor.
Postoperative chemo-therapy was in vain and
the patient died 14 months after the surgery as
a result of lung metastasis.
Introduction
Malignant Triton tumor (MTT) is a histolog-
ical variant of malignant peripheral nerve
sheath tumors (MPNSTs) with rhabdomyosar-
comatous differentiation. Although MPNSTs
have been known to develop in cases of neu-
rofibromatosis type 1 (von Recklinghausen’s
disease, NF-1) and sometimes to occur in the
retroperitoneal space, there are few reports of
MTTs developing in the retroperitoneal space.
We report an extremely rare case of MTT devel-
oping in the retroperitoneal space in a patient
with NF-1 and describe the clinicopathological
features of this tumor.
[page 82]
Case Report
A 21-year old man, who had been diagnosed
to have NF-1 by a dermatologist when he was
about a year old, was referred to Fujita Health
University Hospital in November 2004,
because of a left lower abdominal mass and
gradually increasing pain in the same region.
Physical examination revealed many café-au-
lait spots, subcutaneous masses of various
sizes, scoliosis, and a firm fixed mass in the
left lower abdomen the size of a baby’s head.
and the patient had difficulty in walking.
Laboratory examination revealed slight ane-
mia and elevated serum CRP; however, other
serum chemistry data were within normal lim-
its. Abdominal computed tomography revealed
a huge heterogeneous tumor approximately 17
cm in diameter occupying the left retroperi-
toneal space (Figure 1). Numerous other
tumors, which seemed to be metastatic
lesions, were found between the left psoas
muscle and the left thigh with dissolution of
the left hip joint (Figure 2). On magnetic reso-
nance imaging, the tumor was visualized as a
low intensity signal on T1-weighted images
and as a high intensity signal on T2-weighted
images.
After the diagnosis of retroperitoneal malig-
nant neurogenic tumor associated with NF-1, a
laparotomy was performed. A giant, firm,
whitish, well-capsulated tumor was found
occupying the left abdomen (Figure 3).
Although the main tumor appeared to be tight-
ly adherent to the psoas muscle and to involve
the abdominal aorta, there was no gross inva-
sion of other adjacent organs. Resection of the
main tumor and of the nodules in the
retroperitoneal space that were suspected to
be metastatic lesions and reconstruction of the
abdominal aorta were conducted.
Macroscopically, the extirpated main tumor
measured 19x15x13 cm in size and was encap-
sulated. The cut surface of the tumor revealed
solid and yellowish tissue in the peripheral
portion and foci of hemorrhage and necrosis in
the central portion of the tumor. Histo-
pathological examination revealed spindle-
Figure 1. Abdominal computed tomography showing a huge tumor occupying the left
retroperitoneal space and a metastatic mass in the left psoas muscle (arrows).
[Rare Tumors 2009; 1:e27]
Correspondence: Sojun Hoshimoto, Department
of Surgery, Fujita Health University School of
Medicine, 1-98 Dengakugakubo, Kutsukake-cho,
Toyoake, Aichi 470-1192, Japan.
E-mail: sojunh@yahoo.co.jp
Key words: malignant Triton tumor, malignant
peripheral nerve sheath tumor, neurofibromato-
sis, retroperitoneal tumor.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 20 July 2009.
Accepted for publication: 5 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright S. Hoshimoto et al., 2009
Rare Tumors 2009; 1:e27
doi:10.4081/rt.2009.e27
shaped cells with wavy nuclei and slightly
eosinophilic cytoplasm, showing dense prolif-
eration and forming storiform structures, with
a myxomatous stroma (Figure 4A). On
immunostaining, the spindle-shaped tumor
cells showed a positive response for S-100 pro-
tein and NSE, with sporadic distribution of
rhabdomyoblastic cells that showed positive
staining for myoglobin and desmin (Figure
4B). Immunohistochemical staining with S-
100 and desmin indicated that the tumor cells
originated from Schwann cells and showed
rhabdomyosarcomatous differentiation. Based
on these findings, a diagnosis of MTT associat-
ed with MPNST was made.
After surgical treatment, transarterial infu-
sion chemotherapy was administered via the
left common iliac artery for the remnant
tumors in the left hip joint and the left thigh,
and the patient was discharged five months
after the surgery. However, eight months after
being discharged, the patient was readmitted
for dyspnea found to be caused by lung metas-
tasis. Despite administration of transarterial
chemotherapy, the tumors increased greatly in
size, and the patient died 14 months after the
surgery. An autopsy was not performed.

Figure 2. Multiplanar reformation images
revealed lateral depression of the abdomi-
nal aorta by the main tumor (arrow
heads), and numerous metastatic lesions
between the left psoas muscle and the left
thigh, with dissolution of the left hip joint
(arrows).
Discussion
NF-1 is an autosomal dominant disorder
characterized by café-au-lait spots, cutaneous
neurofibromas, skeletal dysplasias, Lisch nod-
ules, and sometimes malignant tumors, and it
occurs with an incidence of approximately one
in 3000 live births.1 MPNSTs are well known to
arise from major and minor peripheral nerves
or within pre-existing neurofibromas, and
approximately 50 percent of patients with
MPNSTs have NF-1.2,3 The World Health
Organization coined the term MPNST in place
of the previously used, often confusing, termi-
nology such as “malignant schwannoma,”
“malignant neurilemmoma,” “neurogenic sar-
coma,” and “neurofibrosarcoma.”4 The precise
cell of origin of MPNSTs has not yet been con-
clusively identified, although the Schwann cell
is thought to be the major candidate cell for
this. The overall five-year survival rate in
patients with MPNSTs has been reported to be
34-44%, and the association of these tumors
with NF-1 is predictive of a poor prognosis.2,3
The capacity of MPNSTs to undergo focal
divergent differentiation is well known, and
tumors showing rhabdomyosarcomatous dif-
ferentiation, referred to as MTTs, are identi-
Figure 3. At laparotomy, a well-capsulated
tumor was found occupying the left
abdomen.
Figure 4. (A) Spindle-shaped cells showing
dense proliferation and forming storiform
structures (H-E stain, x200), (B) staining
for desmin was strongly positive in the
area of MTT (peroxidase-antiperoxidase
technique, x100).
fied in approximately 12 percent of patients
with MPNSTs.2
Woodruff et al. (1973) reported a series of
10 cases of malignant schwannoma with rhab-
domyoblastic differentiation, which they were
the first to refer to as MTTs.5 Immunohi-
stochemical staining for skeletal muscle mark-
ers such as myoglobin or desmin is essential
for making a correct diagnosis of MTT, because
of the histological variations of MPNSTs. The
average age of patients with MTTs is 31.7
years and these tumors occur with approxi-
mately equal frequency in males and females.6
The reported incidence of MTTs occurring in
association with NF-1 is in the range of 44-69.
Several authors have reported that MTTs are
[Rare Tumors 2009; 1:e27]
Case Report
associated with a worse prognosis than
MPNSTs, regardless of whether or not they are
associated with NF-1,7,8 with a five-year sur-
vival rate of 12-26%.6,7
The reason for the more aggressive behav-
ior of MTTs than classic MPNSTs still remains
unclear. MTTs occur predominantly in the
trunk, head and neck, and lower extremities.8
According to a review of 75 cases of MTTs by
Yakulis et al. (1996), the tumor was located in
the retroperitoneum in only one case (1.3%).6
Subsequent to the publication of this review,
we could identify only one case of retroperi-
toneal MTT by a PubMed search of the English
language literature using the terms “retroperi-
toneum” or “retroperitoneal” and “Triton.”9 All
the three cases of MTTs developing in the
retroperitoneal space reported so far, including
the present case, presented with a huge
abdominal mass,6,9 since these retroperitoneal
tumors are often asymptomatic in the earlier
stages.
Like most soft-tissue sarcomas, MTTs tradi-
tionally are insensitive to chemotherapy and
radiotherapy. However, several authors have
reported recently that repeated resection com-
bined with chemotherapy and/or radiotherapy
against recurrent MTTs might prolong the sur-
vival in patients with MTTs.10,11 Because
MPNSTs and MTTs have a high malignant
potential, patients with NF-1 should be fol-
lowed by periodic check-ups, including com-
puted tomography for early detection of such
tumors as these, and multidisciplinary treat-
ments including complete resection are
required for patients with MTTs.
References
1. Lee MJ, Stephenson DA. Recent develop-
ments in neurofibromatosis type 1. Curr
Opin Neurol 2007;20:135-41.
2. Ducatman BS, Scheithauer BW, Piepgras
DG, et al. Malignant peripheral nerve
sheath tumors. A clinicopathologic study
of 120 cases. Cancer 1986;57:2006-21.
3. Wanebo JE, Malik JM, VandenBerg SR, et
al. Malignant peripheral nerve sheath
tumors. A clinicopathologic study of 28
cases. Cancer 1993;71:1247-53.
4. Gupta G, Maniker A. Malignant peripheral
nerve sheath tumors. Neurosurg Focus
2007;22:E12.
5. Woodruff JM, Chernik NL, Smith MC, et al.
Peripheral nerve tumors with rhab-
domyosarcomatous differentiation (malig-
nant "Triton" tumors). Cancer 1973;32:
426-39.
6. Yakulis R, Manack L, Murphy AI, Jr.
Postradiation malignant triton tumor. A
case report and review of the literature.
Arch Pathol Lab Med 1996;120:541-8.
[page 83]
Case Report
7. Brooks JS, Freeman M, Enterline HT.
Malignant "Triton" tumors. Natural history
and immunohistochemistry of nine new
cases with literature review. Cancer 1985;
55:2543-9.
8. Stasik CJ, Tawfik O. Malignant peripheral
nerve sheath tumor with rhabdomyosarco-
matous differentiation (malignant triton
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tumor). Arch Pathol Lab Med 2006;130:
1878-81.
9. Murtaza B, Gondal ZI, Mehmood A, et al. A
huge malignant triton tumour. J Coll
Physicians Surg Pak 2005;15:728-30.
10. Kostler WJ, Amann G, Grunt TW, et al.
Recurrent malignant Triton tumour: first
report on a long time survivor. Oncol Rep
[Rare Tumors 2009; 1:e27]
2003;10:533-5.
11. Lang-Lazdunski L, Pons F, Jancovici R.
Malignant "Triton" tumor of the posterior
mediastinum: prolonged survival after
staged resection. Ann Thorac Surg 2003;
75:1645-8.

A case of primary renal
angiosarcoma
Kazuhiko Yoshida,1 Fumio Ito,1
Hayakazu Nakazawa,1 Yoshiko Maeda,1
Hikaru Tomoe,1 Motohiko Aiba
1
Department of Urology, 2Department of
Surgical Pathology, Tokyo Women's
Medical University Medical Center East,
Nishiogu, Arakawa-ku, Tokyo, Japan
Abstract
A 78-year old man was diagnosed with a left
bleeding renal cyst from CT scan results. Serial
CT scans revealed the left kidney mass to be
increasing in size and a new lesion in the liver.
Renal cell carcinoma with liver metastasis was
diagnosed and a radical nephrectomy per-
formed. The initial pathological diagnosis was
a benign chronic hematoma. However, the
liver mass increased in size and multiplied,
while another mass emerged in the twelfth
thoracic vertebra with spinal paralysis and was
immediately removed. Pathological findings
for that specimen showed malignancy of stro-
mal cell origin but low atypia. The renal speci-
men was re-evaluated using whole cross-sec-
tion analysis and immunohistochemistry, and
diagnosed as a primary renal angiosarcoma.
Recombinant interleukin-2 therapy was start-
ed immediately; however, the patient died of
metastatic disease 13 months after the initial
operation. Although contrast imaging depicted
the primary lesion as a non-specific hematoma
with little focal pooling, and low-grade cytolog-
ical atypia was shown pathologically, the
angiosarcoma was extremely aggressive.
Introduction
Angiosarcomas comprise only two percent of
all soft tissue sarcomas.1 The large majority
originate from the skin of the scalp and face,
while those with a visceral origin including the
kidneys are extremely rare.2 Recently we treat-
ed a case of primary renal angiosarcoma, in
which a prompt and exact diagnosis was diffi-
cult to obtain. We report here a brief review of
the literature and the clinical course of this
malignancy.
Case Report
The patient was a 78-year old Japanese man,
who was treated previously for a peptic ulcer,
an abdominal aortic aneurysm, and angina
pectoris. He had been employed until the age
of 60 years old in the production of plastic auto
parts, such as those made from polyethylene
and acrylonitrile-butadiene-styrene copo-
lymer.
In May 2006, the patient noticed a bruise on
his back after falling and become aware of per-
sistent pain in his left flank. He consulted a
family doctor, who diagnosed the condition as
a hemorrhage from a left renal cyst and pre-
scribed conservative treatment. However, the
symptoms remained and the patient was
referred to our hospital three months later.
Routine blood tests showed the presence of
anemia and an IAP value that increased to
1060, while other parameters were within the
normal range and a urine test showed no
abnormal findings including hematuria. An
abdominal CT scan demonstrated a distinctly
bordered mass located on the upper pole of the
left kidney that measured approximately 14 cm
in maximum diameter. The images also
showed that the distribution of contrast mate-
rial was limited to the margin of the mass
without focal pooling, which suggested that
the central part was hemorrhagic or necro-
tized, while the periphery had no obvious
tumor formation (Figure 1). Additionally, CT
scanning depicted a newly developed low den-
sity area with poor contrast in the sixth seg-
ment of the liver (Figure 1). Therefore, we
considered that the lesions located in the left
kidney and liver corresponded, respectively, to
primary renal and metastatic hepatic lesions of
renal cell carcinoma. We performed a radical
nephrectomy in August 2006 in order to
achieve tumor cytoreduction. The excised kid-
ney was 960 g in weight, while the tumorous
lesion was approximately 18x11x7 cm in size,
and composed of a non-specific hematoma and
surrounding fibrous capsule (Figure 2). The
Early phase
Plain
Figure 1. Abdominal CT scan findings obtained before the initial operation. An approx-
imately 14 cm-sized mass with a distinct border was found located on the upper pole of
the left kidney (A). The distribution of contrast material was limited to its margin with-
out pooling. A new lesion that later developed in the sixth segment of the liver was shown
as a low density area with poor enhancement (B).
[Rare Tumors 2009; 1:e28]
Rare Tumors 2009; volume 1:e28
Correspondence: Fumio Ito, Department of
Urology, Tokyo Women's Medical University
Medical Center East, 2-1-10, Nishiogu, Arakawa-
ku, Tokyo, Japan
E-mail: fitour@dnh.twmu.ac.jp
Received for publication: 3 August 2009.
Accepted for publication: 5 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright K. Yoshida et al., 2009
Rare Tumors 2009; 1:e28
doi:10.4081/rt.2009.e28
initial pathological diagnosis was a chronic
hematoma with no evidence of malignancy.
Two months after the operation, follow-up
CT scans showed the hepatic lesion to be
increasing in size and multiplying; however,
we were not able to perform a liver biopsy
because of the high risk of bleeding or rupture.
Four months after the operation, spinal paraly-
sis developed suddenly, and MR imaging
revealed a new tumor that had destroyed the
twelfth thoracic vertebra and compressed the
adjacent spinal cord. The tumor was removed
immediately by orthopedic surgeons.
According to the pathological report, the tumor
in the thoracic vertebra was composed of spin-
dle cells with mildly atypical nuclei and a
sheet-like appearance, and which were prolif-
erating and infiltrating the surrounding area.
Following the second surgery, cross-sections of
the total kidney specimen were prepared and
subjected to re-evaluation, which demonstrat-
ed spindle-shaped tumor cells, the same as
those seen in the thoracic vertebra (Figure 3).
Immunohistochemistry findings showed
Late phase
Enhanced
[page 85]
Case Report

that the neoplastic cells were not positive for

cytokeratin, a marker of epithelial cells, but
rather for vimentin, a marker of mesenchymal
cells. The neoplastic cells were positive also for
factor VIII-related antigen, CD31, and CD34,
which are markers of endothelial cells, and for
VEGF and its receptor, Flk-1. These immuno-
histochemical findings supported a final diag-
nosis of angiosarcoma. Immediately after the
final diagnosis, recombinant interleukin-2
monotherapy (35~70 C x 104 IU three times a
week for a total dose of 22x106 IU) was started
for the liver metastases in February 2007.
However, the patient died of metastatic dis-
ease 13 months after the initial operation.
Exterior view Cross-sectional view

Figure 2. Macroscopic appearance of affected kidney. The mass was located on the upper
Discussion pole of the left kidney. The majority of the lesion was occupied by a non-specific
hematoma and its periphery was composed of fibrous tissue. No neoplastic lesions were
Angiosarcomas comprise only two percent of observed in macroscopic observations.
all soft tissue sarcomas,1 while those deeply
located including a primary renal angiosarco-
ma are extremely rare.2 To the best of our
knowledge, 25 cases of primary renal angiosar-
coma have been reported in the English litera-
ture until the end of 2007, and the outcome for
nearly all of the affected patients has been
extremely poor.3-6 The main cause for poor prog-
nosis is the difficulty of prompt and accurate
diagnosis, especially for angiosarcomas in deep
organs such as the kidneys. In the present case,
because the actual tumor size was extremely
small, CT scanning failed to exhibit the exact
tumor shape with abnormal contrast pooling,
while a pathological examination also failed to
provide an accurate diagnosis without cross-
sections from the entire specimen. In addition,
a precise pathological diagnosis required
immunohistochemistry analysis,7 as the tumor
cells lacked some particular features, such as a
vascular architecture. In patients with an
angiosarcoma of the kidney, a prompt and exact
diagnosis is not easy to obtain in the early
stage, because clinical symptoms generally do
not develop at that point, and the disease often
shows rapid growth and metastasis. Therefore, Figure 3. Microscopic findings of the primary renal lesion. Most areas of the specimens
effective systemic treatments as standard ther- were occupied by the non-specific hematoma, whereas the tumor was located in the
apies are needed, although they have yet to be periphery of the hematoma (A). Spindle-shaped tumor cells with low-grade atypia had
established. In recent years, new treatments proliferated and invaded the adjacent parenchyma, which exhibited a sheet-like forma-
such as immunotherapy, including recombi- tion with no vascular architecture (B). The tumor cells were positive for CD31 (C), and
VEGF (D).
nant interleukin-2 (rIl-2) administration,8 and
molecular targeting therapies using beva-
cizumab9 and sorafenib10 have been utilized
increasingly. However, the long-term and large- administration.
scale effectiveness of these therapies remains In conclusion, the present case confirmed References
to be assessed. We applied rIl-2 therapy to the the aggressive biological behavior of a primary
liver metastasis in our patient via intravenous angiosarcoma of the kidney, regardless of its 1. Fata F, O’Reilly E, Ilson D, et al. Paclitaxel
administration. The patient showed good toler- relatively gentle features in imaging and patho- in the treatment of patients with angiosar-
ance for the drug; however, the metastatic logical examinations. It is important to be coma of the scalp or face. Cancer 1999;86:
lesions did not show a response, possibly aware of the possibility of angiosarcoma as well 2034-7.
because the drug was given as monotherapy as more well-known malignancies such as 2. Fletcher CDM, McKee PH. Angiosarcoma.
and in a low dose, and also because the disease renal cell carcinoma when treating a patient In: McGee JO’D, Isaacson PG, Wright NA,
was well advanced at the time of the initial with an unusual hematoma of the kidney. editors. Oxford Textbook of Pathology,

[page 86] [Rare Tumors 2009; 1:e28]


Oxford: Oxford University Press 1992,
p936.
3. Akkad T, Tsankov A, Pelzer A, et al. Early
diagnosis and straight forward surgery of
an asymptomatic primary angiosarcoma of
the kidney led to long-term survival. Int J
Urol 2006;13:1112-4.
4. Cranero LB, Fernández PI, Carrasco AJA,
et al. Renal primary angiosarcoma. Clin
Transl Oncol 2007;9:806-10.
5. Lee TY, Lawen J, Gupta R. Renal angiosar-
coma: a case report and literature review.
Can J Urol 2007;14:3471-6.
6. Souza OE, Etchebehere RM, Lima MA, et
al. Primary renal angiosarcoma. Int Braz J
Urol 2006;32:448-50.
7. Meis-Kindblom JM, Kindblom, L-G. Angio-
sarcoma of soft tissue: a study of 80 cases.
Am J Surg Pathol 1998;22:683-97.
8. Ohguri T, Imada H, Nomoto S, et al.
Angiosarcoma of the scalp treated with
curative radiotherapy plus recombinant
Case Report
interleukin-2 immunotherapy. Int J Radiat
Oncol Biol Phys 2005;61:1446-53.
9. Koontz BF, Miles EF, Rubio MA, et al. Pre-
operative radiotherapy and bevacizumab
for angiosarcoma of the head and neck:
Two case studies. Head Neck 2008;30:262-
6.
10. Wunder JS, Nielsen TO, Maki RG, et al.
Opportunities for improving the therapeu-
tic ratio for patients with sarcoma. Lancet
Oncol 2007;8:513-24.
Rare Tumors 2009; volume 1:e29
A legacy of tinnitus: multiple
head and neck paragangliomas
Tricia M.M. Tan,1 Emma C.I. Hatfield,1
Rajesh V. Thakker,2 Eamonn R. Maher,3
Karim Meeran,1 Niamh M. Martin,1
Jeremy J. Turner1
1
Department of Investigative Medicine,
Division of Investigative Science, Imperial
Healthcare NHS Trust, London, UK;
2
Nuffield Department of Clinical
Medicine, University of Oxford, Oxford,
UK; 3Department of Medical and
Molecular Genetics, Institute of
Biomedical Research, University of
Birmingham, Edgbaston, Birmingham, UK
Abstract
We describe the case of a patient who pre-
sented with a right-sided glomus jugulare
tumor and bilateral glomus vagale tumors.
These proved to be nonmalignant paragan-
gliomas on histopathological analysis. Genetic
analysis revealed a germline heterozygous
missense mutation (Pro81Leu) in the succi-
nate dehydrogenase subunit D (SDHD) gene.
We discuss the clinical presentations of the
familial paraganglioma syndrome type 1,
which is caused by mutations in SDHD, and
the implications for the clinical diagnosis and
care of such patients.
Case Report
A 35-year old lady presented with right-
sided pulsatile tinnitus, conductive deafness,
and a vascular lesion in the floor of the right
external auditory meatus. Magnetic reso-
nance imaging revealed a right-sided glomus
jugulare tumor and bilateral glomus vagale
tumors (Figure 1). Both her paternal grandfa-
ther and her father had undergone neck sur-
gery for tumors. She was an only child and had
a two-year-old son. She was normotensive,
with no clinical features of von Hippel-Lindau
(VHL) syndrome or neurofibromatosis type 1
(NF1). Serum calcium, urine catecholamine
excretion, and serum calcitonin were within
normal limits. Radiolabeled metaiodobenzyl-
guanidine scanning and MRI imaging of her
abdomen did not demonstrate any intra-
abdominal paragangliomas. She underwent
partial excision of her right glomus jugulare
tumor, with complete excision of both the glo-
mus vagale tumors. Histology showed nonma-
lignant paragangliomas. Genomic DNA analy-
[page 88]
sis revealed a germline heterozygous mis-
sense mutation (p.Pro81Leu) in exon 3 of the
succinate dehydrogenase subunit D (SDHD)
gene. Therefore she was diagnosed with
familial paraganglioma syndrome type 1
(PGL1).
Discussion
Paragangliomas are neuroendocrine
tumors of the autonomic nervous system.
Abdominal and thoracic paragangliomas are
derived from sympathetic tissue and secrete
catecholamines, like pheochromocytomas,
which are derived from the adrenal medulla.
Head and neck paragangliomas are derived
from parasympathetic tissue and usually do
not secrete catecholamines.1 Up to a third of
paragangliomas and pheochromoctyomas are
associated with hereditary causes; i.e., muta-
tions in VHL, RET (causing multiple endo-
crine neoplasia type 2A-MEN2A), NF1, and the
SDH complex genes SDHB, -C and -D.2
The SDH complex is bound to the inner
mitochondrial membrane and participates in
both the electron-transport chain and the
Krebs cycle as part of complex II. It consists of
four subunits A-D. Mutations in subunits B, C,
and D are associated with hereditary
pheochromocytomas and paragangliomas: the
PGL1 syndrome with mutations in SDHD,
PGL3 with mutations in SDHC, and PGL4 with
mutations in SDHB.
Multiple mechanisms have been implicated
in the pathogenesis of SDH subunit-related
tumors. These include abnormal activation of
[Rare Tumors 2009; 1:e29]
Correspondence: Jeremy J. Turner, Elsie Bertram
Diabetes Centre, Norfolk and Norwich University
Hospital, Norwich, NR4 7UY, UK
E-mail: Jeremy.turner@nnuh.nhs.uk
Contributions: TMMT, ECIH, KM, NMM, JJT, all
were involved in the clinical care of the patient
described; RVT, ERM, provided and interpreted
the genetic studies.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 4 July 2009.
Revision received: 9 August 2009.
Accepted for publication: 10 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright T.M.M. Tan et al., 2009
Rare Tumors 2009; 1:e29
doi:10.4081/rt.2009.e29
hypoxia-inducible pathways, producing a
pseudohypoxic state similar to that seen in
tumors from patients with VHL disease.3,4 The
HIF-1 and HIF-2 transcription factors are
major mediators of the hypoxic gene response
and the HIF-α subunits are rapidly degraded
in normoxic cells via a VHL protein (pVHL)-
dependent mechanism.5 Activation of HIF
pathways with SDH subunit inactivation has
been linked to accumulation of succinate and
resulting inhibition of the prolyl hydroxylase
enzymes that are necessary for HIF-α subunit
modification and proteosomal degradation, as
pVHL is unable to bind the unmodified sub-
Figure 1. Magnetic resonance
image scan of the neck. Fast
T2-weighted MRI scan
demonstrates the right glomus
jugulare tumor (adjacent to
right cochlea, arrow), and
bilateral glomus vagale tumors
(arrows).

units.4 In addition, animal models of SDH
inactivation suggest that reactive oxygen
species may be increased and also might pro-
voke a pseudohypoxic state.6 Therefore
SDHB/D mutations may predispose to a failure
of normal developmental apoptosis of sympa-
thetic neuronal cells leading to persistence of
“pheochromocytoma precursor cells”.5 PGL1/
SDHD disease is inherited as an autosomal
dominant trait, but demonstrates parent-of-
origin effects in that tumors only develop
when the mutation is inherited from the
father, with possible rare exceptions.6
Typically, head and neck paragangliomas are
found, but pheochromocytomas and abdomi-
nal or thoracic paragangliomas can develop
also. The tumors often are multiple, and tend
to develop early, with a median age of first
presentation of 31 years. In addition, there is
an age-dependent penetrance, with 48 per-
cent, 73 percent, and 100 percent being diag-
nosed by the ages of 30, 40, and 70 years,
respectively.7 In contrast to PGL4/SDHB dis-
ease, where metastatic disease is common,
the tumors in PGL1 tend to be benign.7
Conclusions
The clinical data accumulated regarding
familial paraganglioma syndromes raise sev-
eral important implications for their clinical
management.
• Firstly, patients with familial disease or
multiple tumors should be offered genetic
testing. In addition, individuals with
apparently sporadic pheochromocytoma or
paraganglioma disease will require genetic
screening if risk factors such as extra-
adrenal sympathetic paraganglioma,
malignant paraganglioma, or young age at
diagnosis (e.g., below 40 years) are pres-
ent.2 Depending on the clinical presenta-
tion, mutation analysis of VHL, SDHB,
SDHC, SDHD, and/or RET genes may be
indicated.
• Secondly, the relatives of patients in whom
a pathogenic mutation is detected should
be offered genetic screening, even if they
are asymptomatic, because of the age-
dependent penetrance. The inheritance
pattern of PGL1-related disease will influ-
ence the screening program (see follow-
ing) and the counseling given to patients
and their relatives. In our patient’s case,
her son is not likely to develop tumors
because of the parent-of-origin effect on
penetrance. However, he will require
genetic screening when he is older,
because if he is a carrier of the SDHD
mutation, then his children may be at risk.
• Thirdly, carriers of these mutations will
require regular, lifelong, clinical, biochem-
ical, and radiological screening. In order to
reduce the lifetime exposure to ionizing
radiation, it is necessary to use imaging
modalities such as MRI or ultrasound.
Optimum clinical management requires
the multidisciplinary expertise of sur-
geons, endocrinologists, clinical geneti-
cists, and radiologists.
[Rare Tumors 2009; 1:e29]
Case Report
References
1. Lenders JW, Eisenhofer G, Mannelli M, et
al. Phaeochromocytoma. Lancet 2005;366:
665-75.
2. Gimenez-Roqueplo AP, Lehnert H, Man-
nelli M, et al. Phaeochromocytoma, new
genes and screening strategies. Clin
Endocrinol 2006;65:699-705.
3. Pollard PJ, El-Bahrawy M, Poulsom R, et al.
Expression of HIF-1alpha, HIF-2alpha
(EPAS1), and their target genes in para-
ganglioma and pheochromocytoma with
VHL and SDH mutations. J Clin Endocrinol
Metab 2006;91:4593-8.
4. Selak MA, Armour SM, MacKenzie ED, et
al. Succinate links TCA cycle dysfunction
to oncogenesis by inhibiting HIF-alpha
prolyl hydroxylase. Cancer Cell 2005;7:77-
85.
5. Lee S, Nakamura E, Yang H, et al.
Neuronal apoptosis linked to EglN3 prolyl
hydroxylase and familial pheochromocy-
toma genes: developmental culling and
cancer. Cancer Cell 2005;8:155-67.
6. Pigny P, Vincent A, Cardot Bauters C, et al.
Paraganglioma after maternal transmis-
sion of a succinate dehydrogenase gene
mutation. J Clin Endocrinol Metab 2008;
93:1609-15.
7. Benn DE, Gimenez-Roqueplo AP, Reilly JR,
et al. Clinical presentation and penetrance
of pheochromocytoma/paraganglioma syn-
dromes. J Clin Endocrinol Metab 2006;
91:827-36.
[page 89]
Rare Tumors 2009; volume 1:e30
Soft tissue mixed tumor
of the hand
Hiroshi Shimosawa,1 Michiro Susa,1*
Takayuki Honma,1 Eiichi Hiraishi,1
Hiroshi Sakihara1
1 immunohistochemistry.
Department of Orthopaedic Surgery, Eiju
General Hospital, Tokyo, Japan
*Current address: Sarcoma Molecular
Biology Laboratory, Massachusetts
General Hospital, 70 Blossom Street,
MGR J 1115, Boston, MA 02114, USA
Abstract
Mixed tumors are relatively common in the
skin and salivary glands, but extremely rare in
soft tissues, often resulting in diagnostic prob-
lems. The occurrence of these tumors in the
hand is especially limited. In this article we
report the clinical, radiological, and histologi-
cal features of a mixed tumor of the
hypothenar region of the right hand.
Introduction
Mixed tumors of the soft tissues were recog-
nized as a separate entity only recently, and
there is a limited number of case reports to
date. Mixed tumors, along with myoepithe-
liomas, which constitute myoepithelial tumors,
are composed of myoepithelial cells predomi-
nantly and they are relatively common in major
and minor salivary glands. Because fewer than
25 soft tissue mixed tumors have been report-
ed so far, their characterization has been
scarce.1,2 To our knowledge, there has not been
a report of a mixed tumor of the soft tissue of
the hand. In this report, we present a rare case
of a soft tissue mixed tumor of the hand.
Case Report
A 79-year old woman presented with a slow-
growing mass of the hypothenar region of her
right hand with a history of several years.
There was no particular incidence of trauma or
any relevant medical history. The tumor meas-
ured 4×4 cm in size and the overlying skin was
smooth and nonadherent with slight redness.
The patient did not complain of any pain or
tenderness. Physical examination of the cervi-
cal and axillary region showed no lymph-
adenopathy.
On plain radiography, there was soft tissue
[page 90]
enlargement compatible with the physical
examination, but there was no calcification or
bone erosion. On magnetic resonance imaging
(MRI), there was a 4×4×2 cm circumscribed
mass in the subcutaneous region. T1- and T2-
weighted images depicted a heterogeneous
lesion with intermediate intensity, slightly
higher than in the muscle (Figure 1 A, B).
Incisional biopsy was performed followed by
marginal resection. The tumor was well encap-
sulated with slight adhesion to the palmar
aponeurosis (Figure 2 A, B).
On histopathology, the tumor consisted of a
circumscribed lesion with a yellowish-tan
appearance grossly. Hematoxylin and eosin
staining demonstrated a lobulated architec-
ture, composed of epithelioid cells and myoep-
ithelial elements in the chondromyxoid and
collagenous stroma. There was adipocytic dif-
ferentiation with evidence of ductal differenti-
ation (Figure 3A, B). Nuclear atypia was mild,
and although there were sporadic mitoses,
atypical mitotic figures were not identified.
Immunohistochemical examination demon-
strated positivity for cytokeratin, S-100, and
CD10. Cytokeratin and CD 10 were positive in
both spindle and epithelioid cells. S-100 pro-
tein was focally positive in the spindle cells
(Figure 3C, D, E).
The postoperative period was uneventful. By
her 18-month follow-up, no recurrence or
metastasis had developed.
Discussion
Mixed tumors and myoepitheliomas are well
characterized in salivary glands, but were rec-
ognized to occur in soft tissue only recently.2,3
Histological patterns are analogous to that of
the salivary gland counterpart. The tumors
Figure 1. (A) Axial T1-weighted magnetic resonance imaging scan revealing
a 4×4×2 cm intermediate intensity mass in the subcutaneous region of the
right hand. (B) Sagittal T2-weighted image showing a similar heterogeneous
finding. The intensity was slightly higher than in the surrounding muscle.
[Rare Tumors 2009; 1:e30]
Correspondence: Michiro Susa,
Sarcoma Molecular Biology Laboratory,
Massachusetts General Hospital, 70 Blossom
Street, MGR J 1115, Boston, MA 02114, USA.
E-mail: msusa@partners.org
Key words: mixed tumor, soft tissue, hand,
Contributions: HS, analyzed the data and wrote
the first draft of the paper; MS, TH, EH, HSa,
edited the manuscript.
Conflict of interests: the authors report no con-
flicts of interest.
Received for publication: 10 August 2009.
Accepted for publication: 13 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright H. Shimosawa et al., 2009
Rare Tumors 2009; 1:e30
doi:10.4081/rt.2009.e30
show a spectrum of cellular and architectural
morphologies. Myoepithelial cells may be spin-
dled, plasmacytoid, ovoid, or epithelioid, and
can express a wide variety of cytoplasmic fila-
ments. The growth pattern may be solid, myx-
oid, or reticular, and each individual tumor
includes areas with more than one growth pat-
tern or cell subtype.4,5
Myoepithelial tumors of soft tissue occur
equally in male and female patients. They have
been reported in a wide age range with a peak
in the third to fifth decades, most commonly
occurring in the limbs and the limb girdles.2,5
The vast majority of cases arise in the subcuta-
neous or deep subfascial soft tissue. Most
patients present with painless swelling rang-
 Case Report

ing in duration from a few weeks to several

years.5 MRI appearance of soft tissue mixed
tumors varies in accordance with the hetero-
geneity of the tumor. Depending on the
amount of hemorrhage, chondromyxoid and
fibrous stroma, it is possible for the tumor to
present various findings. Preoperative diagno-
sis based on the MRI should be performed pru-
dently, and incisional biopsy should be per-
formed at all times.
There is a debate still as to whether mixed
tumors and myoepithelioma should be distin-
guished as separate entities or considered as
the same spectrum of tumors with overlapping Figure 2. (A, B) A 4×4×2 cm soft tissue mixed tumor of the hypothenar region of the
hand.
histological appearances and similar clinical
behavior. Those tumors either lacking or with
very limited ductal differentiation generally
are classified as myoepitheliomas. Current
classification simply separates those tumors
with ductal differentiation into the mixed
tumor categories.6,7 Whereas some investiga-
tors allow up to five percent or ten percent duc-
tal differentiation in myoepitheliomas,4,8-10 oth-
ers classify tumors with any ducts as mixed
tumors. In the present case, the tumor showed
distinct duct formations; therefore we diag-
nosed it in accordance with the strict criteria.
The absence of clear-cut histopathological
clues for the diagnosis of myoepithelial tumors
is hampered further by the wide variability in
their immunohistochemical characteristics.
Immunoreactivity for the S-100 protein and
muscle actins seems to be the most constant
immunophenotype, whereas immunoexpres-
sion for epithelial markers such as cytoker-
atins and EMA, or neural markers such as
GFAP, is somewhat erratic and variable from
case to case. The same immunophenotype has
been described in salivary gland myoepithelial
tumors, which usually coexpresses immunore-
activity for S-100 protein, muscle actins, and
GFAP, with variable immunoexpression for
EMA and cytokeratins.8,11-16 Figure 3. (A, B) Photomicrograph of the soft tissue mixed tumor, showing a lobulated
Although the majority of morphologically architecture with epithelioid cells and myoepithelial elements in the chondromyxoid and
benign-looking mixed tumors of soft tissue collagenous stroma, and evidence of ductal differentiation (H&E stain). Immuno-
behave in a benign fashion, there is approxi- histochemical examination demonstrated positivity for cytokeratin (C) and CD10 (E) in
both spindle and epithelioid cells, and S-100 protein in the spindle cells (D).
mately a twenty percent risk for local recur-
rence. The malignant potency of myoepithelial
tumors varies, and it is difficult to differentiate
myoepithelial tumors into benign and malig-
nant categories on histological grounds locations, with breakpoints on 8q12, 3p21, and the tumor displays a reticular architecture
only.17,18 For the diagnosis of malignant myoep- 12q14-15 have been described in myoepithelial with chondromyxoid or hyalinized stroma,
ithelioma in salivary glands, an invasive tumors of the salivary gland.22 It is interesting extraskeletal myxoid chondrosarcoma and
growth pattern has been considered as the to note that the malignant myoepithelial tumor ossifying fibromyxoid tumor should be consid-
most important feature, because the immuno- has been reported to show different chromoso- ered as differential diagnoses. Solid spindle
histochemical features are similar for the mal abnormalities such as gains of 1p31~p34, cell myoepithelial tumors can resemble
benign and malignant forms.18 In addition, 1q21~q23, and 16q22, and loss of 15q.23 leiomyomas and schwannomas. Furthermore,
cytological atypia and mitotic rate have been Nevertheless, it is difficult to establish prog- if the tumor shows significant cytological atyp-
reported to be useful.19,20 However, in the case nostic indicators for soft tissue myoepithelial ia, metastatic carcinomas, metastatic melano-
of soft tissue myoepithelial tumors, there has tumors until further reports are available. mas, and epithelioid sarcomas should be con-
been no association between the degree of Because there is considerable morphologic sidered as well.
nuclear pleomorphism or mitotic activity and heterogeneity of soft tissue myoepithelial The mixed tumor should be considered as
clinical behavior.21 Recurrent chromosome tumors, the differential diagnosis should be one of the differential diagnoses of soft tissue
rearrangements, particularly reciprocal trans- based on the dominant histological pattern. If tumors of the hand. The rarity of this tumor

[Rare Tumors 2009; 1:e30] [page 91]

Case Report
has not enabled prediction of the possible out-
come after resection. Because there are
reports of local recurrence and malignant
transformation, complete resection with
appropriate follow-up of the patients should be
warranted.
References
1. Klijanienko J, Servois V, Jammet P, et al.
Pleomorphic adenoma. Am J Surg Pathol
1998;22:772-3.
2. Hornick JL and Fletcher CD. Myoepithelial
tumors of soft tissue: a clinicopathologic
and immunohistochemical study of 101
cases evaluation of prognostic parameters.
Am J Surg Pathol 2003;27:1183-96.
3. Go JH. A case of soft tissue myoepithelial
tumor arising in masticator space. Yonsei
Med J 2005;46:710-4.
4. Simpson RHW, Jones H, Beasley P. Benign
myoepithelioma of the salivary glands: a
true entity? Histopathology 1995;27:1-9.
5. Kilpatrick SE, Limon J. Mixed tumour/
myoepithelioma/parachordoma. In: World
Health Organization classification of
tumours: pathology and genetics of
tumours of soft tissue and bone. Lyon:
IARC Press, 2002:198-9.
6. Ellis GL, Auclair PL. Atlas of Tumor
Pathology: Tumors of the Salivary Glands,
3rd series, fascicle 17. Washington, DC:
Armed Forces Institute of Pathology, 1996.
7. Seifert G, Sobin LH. World Health
Organization International Histological
Classification of Tumours: Histological
Typing of Salivary Gland Tumours. Berlin,
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Germany: Springer-Verlag, 1991.
8. Alos L, Cardesa A, Bombi JA, et al. Myo-
epithelial tumors of salivary glands: a clin-
icopathologic, immunohistochemical,
ultrastructural, and flow-cytometric study.
Semin Diagn Pathol 1996;13:138-47.
9. Barnes L, Appel BN, Perez H, et al. Myo-
epitheliomas of the head and neck: case
report and review. J Surg Oncol 1985;
28:21-8.
10. Dardick I. Myoepithelioma: definitions
and diagnostic criteria. Ultrastruct Pathol
1995;19:335-45.
11. Anderson C, Knibbs DR, Abbott SJ, et al.
Glial fibrillary acidic protein expression in
pleomorphic adenoma of salivary gland: an
immunoelectron microscopic study. Ultra-
struct Pathol 1990;14:263-71.
12. Dardick I, Cavell S, Boivin M, et al. Salivary
gland myoepithelioma variants: histologi-
cal, ultrastructural, and immunocytologi-
cal features. Virchows Arch A Pathol Anat
Histopathol 1989;416:25-42.
13. Domagala W, Halczy-Kowalik L, Weber K,
et al. Coexpression of glial fibrillary acid
protein, keratin and vimentin: a unique
feature useful in the diagnosis of pleomor-
phic adenoma of the salivary gland in fine
needle aspiration biopsy smears. Acta
Cytol 1988;32:403-8.
14. Gupta RK, Naran S, Dowle C, et al. Co-
expression of vimentin, cytokeratin and S-
100 in monomorphic adenoma of salivary
gland: value of marker studies in the dif-
ferential diagnosis of salivary gland
tumours. Cytopathology 1992;3:303-9.
15. Nishimura T, Furukawa M, Kawahara E, et
al. Differential diagnosis of pleomorphic
adenoma by immunohistochemical
[Rare Tumors 2009; 1:e30]
means. J Laryngol Otol 1991;105:1057-60.
16. Wittchow R, Landas SK. Glial fibrillary
acidic protein expression in pleomorphic
adenoma, chordoma, and astrocytoma: A
comparison of the three antibodies. Arch
Pathol Lab Med 1991;115:1030-3.
17. Bombi JA, Alos L, Rey MJ, et al. Myo-
epithelial carcinoma arising in a benign
myoepithelioma: Immunohisto-chemical,
ultrastructural, and flow-cytometrical
study. Ultrastruct Pathol 1996;20:145-54.
18. Palma SD, Guzzo M. Malignant myoepithe-
lioma of salivary glands: clinicopathologi-
cal features of ten cases. Virchows Archiv
A Pathol Anat Histopathol 1993;423:389-
96.
19. Nagao T, Sugano I, Ishida Y, et al. Salivary
gland malignant myoepithelioma: a clini-
copathologic and immunohistochemical
study of ten cases. Cancer 1998;83:1292-9.
20. Savera AT, Sloman A, Huvos AG, et al.
Myoepithelial carcinoma of the salivary
glands: a clinicopathologic study of 25
patients. Am J Surg Pathol 2000;24:761-74.
21. Tanimoto A, Sasaguri T, Arima T, et al.
Endometrial stromal sarcoma of the uterus
with rhabdoid features. Pathol Int 1996;46:
231-7.
22. Balogh Z, Deák L, Sápi Z. Malignant myo-
epithelioma of soft tissue: a case report
with cytogenetic findings. Cancer Genet
Cytogenet 2008;183:121-4.
23. Bullerdiek J, Wobst G, Meyer-Bolte K, et al.
Cytogenetic subtyping of 220 salivary
gland pleomorphic adenomas: correlation
to occurrence, histological subtype, and in
vitro cellular behavior. Cancer Genet
Cytogenet 1993;65:27-31.
Rare Tumors 2009; volume 1:e31
Primary sarcoma of the liver
and transplantation:
a case study and literature
review
Benjamin Bismuth,1 Hélène Castel,1
Emmanuel Boleslawski,2 David Buob,3
Marc Lambert,4 Nicole Declerck,2
Valérie Canva,1 Eli-Serge Zafrani,5
Philippe Mathurin,1 François-René
Pruvot,2 Sébastien Dharancy1
1
Service des Maladies de l’Appareil
Digestif et de la Nutrition; 2Service de
Chirurgie Digestive et de Transplantation,
Hôpital Huriez; 3Anatomie et Cytologie
Pathologique, Centre de Biologie -
Pathologie; 4Service de Médecine Interne,
Hôpital Huriez, CHRU Lille, France;
5
Département d’Anatomie Pathologique,
Hôpital Henri Mondor,
AP-HP, Créteil, France
Abstract
Primary sarcomas of the liver are rare tumors
and their diagnosis is difficult to assess, particu-
larly on percutaneous liver biopsy. Epithelioid
hemangioendothelioma (EHE) is an infrequent
indication for liver transplantation, and
angiosarcoma (AS) is a widely recognized con-
traindication because of its poor prognosis. We
report the case of a young woman who under-
went liver transplantation (LT) for an infiltrative
hepatic tumor with several features suggestive
of EHE, although the analysis of the native liver
revealed AS. Everolimus was used as the main
immunosuppressive drug. More than two years
after LT, her physical condition remained stable
despite a local recurrence at 10 months. In this
setting, the ranking of new immunosuppressive
agents belonging to the family of the prolifera-
tion signal inhibitors will need to be precise, but
their intrinsic properties suggest a potential use
in treatments after LT for atypical malignancies.
Introduction
Primary sarcomas of the liver are rare tumors
(approximately 1% of liver cancers) and an
exceptional indication for liver transplantation
(LT).1 The two main histological forms are
epithelioid hemangioendothelioma (EHE) and
angiosarcoma (AS).2 Those tumors, which share
the same mesenchymal origin (endothelial cells
edging the sinusoid), have very different natural
history and prognosis, and require different
treatments (Table 1). Although LT can be indicat-
ed in some cases of EHE because of a favorable
long term outcome,1,3 it is absolutely not advised
for AS owing to a high risk of early local or gen-
eral recurrence after LT.4 We report the case of a
young woman who underwent LT for a infiltra-
tive hepatic tumor, of which some characteris-
tics and the clinical presentation were sugges-
tive of EHE. However, the histological analysis of
the explanted liver revealed AS. The preventive
use of an immunosuppressive drug with antipro-
liferative properties belonging to the mam-
malian target of rapamycine (mTOR) inhibitors
led to the usual two years’ survival after LT,
despite a local recurrence of AS.
Case Report
A 41-year-old woman was admitted in April
2002 for acute hepatitis of unknown etiology.
Previous liver function tests, performed in
March 2002, were normal. The only remarkable
medical history was obesity with a body mass
index of 31.5. There was no history of excessive
alcohol consumption (30 g/wk), medication, or
toxic exposure. Biological testing excluded viral,
bacterial, and autoimmune hepatitis. The com-
puterized tomography (CT) scan revealed a
homogeneous hepatomegaly and excluded a
thrombosis of the sus-hepatic veins. A liver biop-
sy showed a granulomatous infiltration of the
liver, with histiocytes but no centrolobular necro-
sis, as well as a steatosis (30% of the parenchy-
ma). The diagnosis of acute hepatitis related to
a vascularitis was made. Between 2002 and 2005
she was hospitalized for several episodes of
acute disease, associated fever, maculopapulous
eruption, elevation of liver enzymes (AST = 5 x
ULN, ALT = 11 x ULN), and cholestasis (alkaline
phosphatases = 20 x ULN, γGT = 10 x ULN).
Because of the lack of success of the previous
therapy, a systemic corticotherapy (dexametha-
sone = 250 mg IV) was begun in 2005, followed
by oral prednisone (1 mg/kg/day). In May 2005 a
low platelet count (99000/mm3) was observed.
[Rare Tumors 2009; 1:e31]
Rare Tumors 2009; volume 1:e31
Correspondence: Sébastien Dharancy,
Service des Maladies de l’Appareil Digestif et de
la Nutrition, Hôpital Huriez, CHU, Lille 59037,
France. E-mail: s6@chru-lille.fr
Key words: angiosarcoma, epithelioid heman-
gioendothelioma, liver transplantation
Received for publication: 23 June 2009.
Accepted for publication: 8 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright B. Bismuth et al., 2009
Rare Tumors 2009; 1:e31
doi:10.4081/rt.2009.e31
The patient underwent a second liver biopsy. A
vascular disease predominant in the pericen-
trolobular zone was observed, with congestive
sinusoids, centrolobular vein thickening, and
necrosis. The abdominal magnetic resonance
imaging (MRI) showed a diffuse nodular infiltra-
tion of the liver (Figure 1). Because of the inef-
fectiveness of corticotherapy, methotrexate (15
mg/wk) was introduced.
In October 2005 she was referred for jaundice,
ascitis, and edema. Prothrombin time was 50%,
bilirubin was 90 mg/L, and α-fetoprotein was
normal. A third liver biopsy was performed,
showing a proliferation of CD31– and CD34+
cells, compatible with the diagnosis of EHE or
AS. A second MRI (November, 2005) revealed a
hepatomegaly with diffuse, hypervascular and
nodular infiltration of the liver (Figure 2). The
measurement of the portal pressure revealed
portal hypertension with a portosystemic gradi-
ent of 16 mmHg. The upper endoscopy found a
portal hypertensive gastropathy and esophageal
varices (grade 1). Clinical presentation orients
the diagnosis toward a diffuse EHE with portal
hypertension and hepatocellular insufficiency.
Thus, LT was considered.
The patient underwent LT in December 2005.
Figure 1.
Abdominal mag-
netic resonance
imaging in June
2005 (T1 without
gadolinium injec-
tion) showing dif-
fuse nodular infil-
tration of the liver.
[page 93]
Review

Despite the preoperative suspected diagnosis,

AS was confirmed finally at the pathological Figure 2. Abdominal
magnetic resonance
analysis of the explant, consisting of a diffuse AS imaging in November
with necrosis and invasion of the centrolobular 2005 (T1 with gadolin-
veins (Figure 3). The initial immunosuppressive ium injection) showing
regimen included prednisone (20 mg/day), hepatomegaly related
to hypervascular tumo-
mycophenolate mofetyl (1 g x 2/day), and ral infiltration of the
tacrolimus (6 mg x 2/day). Tacrolimus and pred- liver.
nisone were decreased, then withdrawn in July
2006, and changed to everolimus (3 mg/day).
Residual concentrations ranged from 10-14 µg/L.
Mycophenolate mofetyl was withdrawn in
October 2006. A postoperative CT scan per-
formed at month 10 revealed a local recurrence
with a multimicronodular infiltration of the
transplant (Figure 4). Systemic chemotherapy
with paclitaxel was begun but had to be discon-
tinued in February 2007 owing to neurological Figure 3. Transversal
and mucous toxicity. Nevertheless, the CT scan section of the native
at month 16 showed a partial response, while the liver showing diffuse
patient was under everolimus and taxane thera- tumoral infiltration.
py. At month 24, the patient was under
monotherapy with everolimus (3 g/day). She had
no biological toxicity to everolimus and was
managing quite well, despite a progression of
the disease with asymptomatic vertebral metas-
tasis. At month 30 her general health status
quickly decreased with terminal liver failure
leading to death.

Figure 4. Injected com-

Discussion
We report an atypical clinical observation,
which is especially interesting in that it illus-
trates the difficulty in distinguishing the two
forms of primary sarcoma of the liver. It also
underlines the potential interest in the use of an
immunosuppressive regimen with the new
antiproliferative agents (mTOR inhibitors) in
this very particular setting. Our report is not to
promote LT for AS, based on this unusual case
study, but rather to provide some ways to opti-
mize the management of such patients. The
diagnosis of primary sarcoma of the liver is made
often at an advanced stage, because of its rarity
and the fact that it is asymptomatic for a long
time in patients with a normal nontumoral liver.2
The diagnosis is confirmed by the pathological
analysis of the tumoral tissue. Although its mes-
enchymal origin is assessed easily by panen-
dothelial markers, the distinction between EHE
and AS remains a delicate issue, particularly on
a percutaneous liver biopsy. The main histologi-
cal criteria to assess the diagnosis of EHE are
nodes formed by a hyaline stroma, and particular
epithelioid cells with intracytoplasmic red blood
cell inclusions, and sometimes calcifications
(which are not present in AS). At the edge of the
nodes, sinusoids and hepatic veins are invaded
by tumoral cells, but the architecture of the liver
is preserved.5 The histological characteristic of
AS is the presence of atypical tumoral cells at the
edge of the sinusoids, often causing vascular
dilatations (cavernous type), or more rarely
nodular solid tumors. In both histological forms,
tumoral cells are CD31– and CD34+. Hepatic AS is
a rare vascular tumor (<1/106 persons) predomi-
nant in men (sex ratio, 4:1). The mean age is
around 60 years.4 The known risk factor for AS is
exposure to a carcinogen such as arsenic and
vinyl chloride. Metastases are found frequently
at the time of the diagnosis, mainly located in
the lung, spleen, and bones. The radiological
characteristics of AS are not unequivocal. MRI or
CT scans may show a multinodular tumor, a
mass syndrome, or more rarely a diffuse infiltra-
tion of the liver.6 The outcome of AS is very poor,
regardless of the kind of therapy, with an overall
puterized tomography
scan (postoperative
month 10) showing
local recurrence of liver
sarcoma.
mortality rate of 90% in the year of the diagno-
sis.2 Some authors consider EHE as a low-grade
sarcoma, more frequent among women aged 30
to 40 years. It is a particular form of sarcoma in
that it has an intermediate malignant potential
and a slow rate of progression.7 The radiological
examinations reveal a unique tumor, sometimes
difficult to distinguish from other liver cancers.8
In AS the panendothelial markers are positive.
The gold-standard treatment is partial hepatecto-
my but, in a large number of the patients, a com-
plete resection is impossible owing to the infil-
trative pattern of the lesion.7 In this very particu-
lar situation, LT can be discussed, because post-
transplant survival is similar to that in other liver
disease.1,3 Our patient had several characteristics

[page 94] [Rare Tumors 2009; 1:e31]


Table 1. Comparison of the characteristics of HA and epithelioid hemangioendothe-
lioma.
Characteristics HA
Sex Male
Mean age 60
Risk factors Carcinogenes
Clinical presentation Aspecific
Radiological findings Unique
Multinodular
Diffuse infiltration
Anatomopathology No calcifications
Disappearance of the
architecture of the acini
Gold-standard therapy Symptomatic
Post-transplant outcome Poor (<5%)
(two-years' survival, %)
Table 2. Review of the cases of primary sarcomas of the liver reported in the literature.
Type Number of cases
Angiosarcoma 13
7 UNOS register (4)
Leiomyosarcoma 1 (18)
Epithelioid hemangioendothelioma 66
7 (7)
suggestive of EHE: gender, age, absence of toxic
exposure, and a slow progression of the tumor.
Nevertheless, the fact that the tumor presented
as a hypervascular and multinodular lesion was
less indicative of EHE, and the findings of the
liver biopsy performed before LT were compati-
ble with the diagnosis of AS. Only 16 patients
who had LT for AS and 66 for EHE were recorded
by the ELTR European Register between 1988
and 2001, representing 0.2% of the indications
for LT.1 Some isolated case reports have been
published about LT for other forms of sarcoma of
the liver (Table 2). Taking into account the high
risk of early locoregional recurrence of the dis-
ease after LT, we introduced everolimus at six
months after LT. Everolimus is an immunosup-
pressive and antiproliferative agent belonging to
the family of the mTOR inhibitors. This molecule
has a specific cytostatic effect on tumoral cell
proliferation in vivo and in vitro, and has been
evaluated as an antioncogenic therapy.9-15
Everolimus also has an antiangiogenic action,
and is able to increase the antitumoral effect of
chemotherapy.16 Moreover, the use of mTOR
inhibitors has been associated with a significant
decrease in the risk of developing de novo can-
cers after renal transplantation.17 These findings
promoted an interest in using everolimus after
LT in our patient in order to delay or decrease the
recurrence of AS. A local recurrence occurred at
month 10 but, after more than two years of fol-
low-up, the outcome for our patient is better than
that previously described in the literature. This
unusual survival after LT for AS may be
Epithelioid hemangioendothelioma
Female
40
- liver: a clinicopathologic study of 137 cases.
Aspecific
Unique
Calcifications
Preservation of the
architecture of the acini
Surgery (hepatectomy,
liver transplantation)
Good (70%)
References
ELTR register (1)
ELTR register (1)
explained, at least in part, by the antitumoral
properties of everolimus. Finally, primary sarco-
mas of the liver are very rare tumors. EHE is an
exceptional indication for LT, although AS is a
widely recognized contraindication. The belief of
mTOR inhibitors having antiproliferative and
antiangiogenic properties needs to be deter-
mined in those cases of misdiagnosed AS in
order to delay or slow down the recurrence of the
sarcoma.
References
1. Adam R, McMaster P, O'Grady JG, et al.
Evolution of liver transplantation in Europe:
report of the European Liver Transplant
Registry. Liver Transpl 2003;9: 1231-43.
2. Weitz J, Klimstra DS, Cymes K, et al.
Management of primary liver sarcomas.
Cancer 2007;109:1391-6.
3. Lerut JP, Orlando G, Sempoux C, et al.
Hepatic haemangioendothelioma in adults:
excellent outcome following liver transplan-
tation. Transpl Int 2004;17:202-7.
4. Maluf D, Cotterell A, Clark B, et al. Hepatic
angiosarcoma and liver transplantation:
case report and literature review. Transplant
Proc 2005;37:2195-9.
5. Soslow RA, Yin P, Steinberg CR, et al. Cyto-
pathologic features of hepatic epithelioid
hemangioendothelioma. Diagn Cytopathol
1997;17:50-3.
[Rare Tumors 2009; 1:e31]
Review
6. Koyama T, Fletcher JG, Johnson CD, et al.
Primary hepatic angiosarcoma: findings at
CT and MR imaging. Radiology 2002;222:
667-73.
7. Makhlouf HR, Ishak KG, Goodman ZD.
Epithelioid hemangioendothelioma of the
Cancer 1999;85:562-82.
8. Kim KA, Kim KW, Park SH, et al. Unusual
mesenchymal liver tumors in adults: radio-
logic-pathologic correlation. AJR Am J
Roentgenol 2006;187:W481-9.
9. Hidalgo M, Rowinsky EK. The rapamycin-
sensitive signal transduction pathway as a
target for cancer therapy. Oncogene
2000;19:6680-6.
10. Huang S, Shu L, Easton J, et al. Inhibition of
mammalian target of rapamycin activates
apoptosis signal-regulating kinase 1 signal-
ing by suppressing protein phosphatase 5
activity. J Biol Chem 2004;279: 36490-6.
11. Kristof AS, Pacheco-Rodriguez G, Schrem-
mer B, et al. LY303511 (2-piperazinyl-8-
phenyl-4H-1-benzopyran-4-one) acts via
phosphatidylinositol 3-kinase-independent
pathways to inhibit cell proliferation via
mammalian target of rapamycin (mTOR)-
and non-mTOR-dependent mechanisms. J
Pharmacol Exp Ther 2005;314:1134-43.
12. Panwalkar A, Verstovsek S, Giles FJ.
Mammalian target of rapamycin inhibition
as therapy for hematologic malignancies.
Cancer 2004;100:657-66.
13. Sekulic A, Hudson CC, Homme JL, et al. A
direct linkage between the phosphoinosi-
tide 3-kinase-AKT signaling pathway and
the mammalian target of rapamycin in
mitogen-stimulated and transformed cells.
Cancer Res 2000;60:3504-13.
14. Tirado OM, Mateo-Lozano S, Notario V.
Rapamycin induces apoptosis of JN-DSRCT-
1 cells by increasing the Bax: Bcl-xL ratio
through concurrent mechanisms dependent
and independent of its mTOR inhibitory
activity. Oncogene 2005;24: 3348-57.
15. Yu K, Toral-Barza L, Discafani C, et al.
mTOR, a novel target in breast cancer: the
effect of CCI-779, an mTOR inhibitor, in pre-
clinical models of breast cancer. Endocr
Relat Cancer 2001;8:249-58.
16. Seeliger H, Guba M, Kleespies A, et al. Role
of mTOR in solid tumor systems: a thera-
peutical target against primary tumor
growth, metastases, and angiogenesis.
Cancer Metastasis Rev 2007.
17. Kauffman HM, Cherikh WS, Cheng Y, et al.
Maintenance immunosuppression with tar-
get-of-rapamycin inhibitors is associated
with a reduced incidence of de novo malig-
nancies. Transplantation 2005;80: 883-9.
18. Saint-Paul MC, Gugenheim J, Hofman P, et
al. Leiomyosarcoma of the liver: a case treat-
ed by transplantation. Gastroenterol Clin
Biol 1993;17:218-22.
[page 95]
Rare Tumors 2009; volume 1:e32
Pitfalls in neuroendocrine
tumor diagnosis
Emilio Bajetta, Marco Platania
Medical Oncology Unit 2, Reference
Center for the Study and Treatment of
Carcinoids and Neuroendocrine Tumors,
Fondazione IRCCS Istituto Nazionale dei
Tumori, Milan, Italy
Carcinoids, originating from cells of the dif-
fuse endocrine system (DES), account for 0.7%
of all malignancies and are characterized by a
slow growth rate and the presence of nonspe-
cific signs and symptoms often making their
detection rather difficult. Gastroente ropancre-
atic neuroendocrine tumors (GEP-NETs) rep-
resent the majority (~70%) of DES tumors.
Historically they account for about 2% of all
gastrointestinal tumors but their incidence
and prevalence have increased recently, likely
owing to the advances accomplished with new
endoscopy procedures and diagnostic tools,
and to the achievement of long survival rates
fostered by the indolent evolution of the dis-
ease. Currently, according to the algorithm
proposed by Modlin1 for diagnosis and manage-
ment of GEP-NETs normally accepted by clini-
cians in routine clinical practice, the first
action after clinical suspicions of a NET com-
prises the measurement of circulating mark-
ers such as CgA, NSE, serotonin, gastrin, or
urinary 5-hydroxyindoleacetic acid (5-HIAA).
In the case of positive findings, the subse-
quent action lies in the octreoscan, which
allows the topographic localization of the pri-
mary lesion or of metastatic disease. Finally,
the diagnosis is completed through the surgi-
cal resection of the primary tumor or the biop-
sy of the reachable metastases. However, nei-
ther laboratory tests nor octreoscans are com-
pletely reliable diagnostic tools because other
clinical disorders or atypical radiological find-
ings may mimic a carcinoid, hence leading to
an erroneous NET diagnosis. Consequently,
the distinct possibility of false positive find-
ings exists, being the lack of experience with
the disease the major reason for an incorrect
diagnosis. Indeed, with the exception of some
sporadic case reports,2 it does not seem that
the matter of the occurrence of false positive
NETs has been taken into consideration sys-
tematically. Based on two years’ experience,
we report the occurrence of eight cases previ-
ously clinically diagnosed as NETs elsewhere,
and then referred to our specialized reference
center for pathological substantiation. After
investigation, the following diagnoses were
made: chronic atrophic gastritis (CAG) with
enterochromaffin-like cell (ECL) hyperplasia
(4 cases), estrogen-deprivation syndrome (1),
hypochondriac disorder (1), metabolic syn-
[page 96]
drome (1), and sarcoidosis (1). Relying on this
limited but significant occurrence rate, we
deem that some key points should be argued.
Primarily, a frequent mistake concerns the
interpretation of abnormal CgA plasma values:
this marker, expressed in both functioning and
non functioning NET tumors, shows a thresh-
old of sensitivity and specificity depending on
tumor histology, extension of the disease, and
biological tumor activity.3 Additionally, the
methods used to measure CgA levels are not
standardized yet, as appears from the compar-
ison of the three commercially available kits,
the outcomes of which may disagree consider-
ably.4 Other pathological conditions may hin-
der the specificity because CgA elevations can
be detected in some instances in patients with
renal and hepatic failure, untreated hyperten-
sion, inflammatory bowel disease, and even in
the presence of nonendocrine tumors.5
Lastly, the use of proton-pump inhibitors
may be responsible for the elevations of CgA
values, and long-term acid inhibition is a well
known cause of CAG with related ECL cell
hyperplasia.6 On the basis of CgA values, it
would be best for clinicians to discriminate
patients affected by carcinoids from healthy
subjects and from those whose abnormal find-
ings depend on hyperplastic lesions of
endocrine cells in the context of a CAG.
According to our experience,7 the threshold
value of CgA for identifying patients with NETs
should be 36 U/L, which gives a specificity of
83-91%. More recently, however, it has been
highlighted that there is a need to change the
current cutoff CgA values to exclude patients
in whom levels are elevated as a result of non-
neoplastic conditions.8 The authors set a 95%
specificity, corresponding to cutoff values of
84-87 U/L, arguing that this is essential to
exclude patients showing false positive CgA
increases from unnecessary examinations
specific for endocrine tumors. In our experi-
ence, when a borderline or doubtful value is
observed, before proceeding to the workup we
repeat the plasma assay with the addition of
the detection of NSE plasma dosage and of uri-
nary 5-HIAA: the latter, particularly, appears
extremely useful and crucial to this purpose.9
Another issue critical in making the NET
diagnosis easier is the correlation between
marker serum values and referred symptoms
at presentation. It should be highlighted that
at diagnosis the classical carcinoid syndrome
of flushing, sweating, diarrhea, abdominal
pain, bronchospasm, and right-sided heart
failure represents a fairly infrequent event
occurring in less than 10% of NETs,10 because
it may depend on the secretion rate of tumor
mediators, tumor size, its anatomical location
and, chiefly, the extent of liver metastases.
Additionally, octreoscan findings should be
related to the clinical setting always; conse-
quently, the need of reliable evidence is
[Rare Tumors 2009; 1:e32]
Correspondence: Emilio Bajetta, Medical Oncology
Unit 2, Fondazione IRCCS Istituto Nazionale
Tumori, Via G. Venezian 1 - 20133 Milano, Italy.
E-mail: emilio.bajetta@istitutotumori.mi.it
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 31 July 2009.
Accepted for publication: 14 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright et al., 2009
Rare Tumors 2009; 1:e32
doi:10.4081/rt.2009.e32
mandatory. Notwithstanding the fact that
octreoscan is carried out routinely in hospitals
equipped with nuclear medicine units, the
experience of the operators and the adoption
of a correct procedure for the image acquisi-
tion represent the major issues to achieve
reliable results. Based on the largest Italian
experience carried out in three hospitals and
involving 253 patients, a comparison of differ-
ent procedures of octreoscan has demonstrat-
ed that the best specificity (88%) was
obtained when a semiquantitative evaluation
was employed.11 In addition, this procedure
showed that bowel preparation is not essen-
tial; conversely, when the 24-hour image
acquisition shows accumulation in the
abdomen possibly because of the radioactive
bowel content, it is extremely important to
repeat scintigraphy after 48 hours.12 The capa-
bility of recognizing all uptake of physiological
tracers and other pathological aspects result-
ing in a false positive octreoscan response can
reduce the false positive results to 3% only.13 It
should be highlighted that the hypophysis,
thyroid, liver, spleen, kidneys, bladder, gall-
bladder, and intestinal tract represent areas of
physiological uptake of 111In-DTPA-octreo-
tide, and that somatostatin receptors are
found even in activated leukocytes in granulo-
matosis processes (sarcoidosis, tuberculo-
sis)14 and chronic inflammatory processes
(inflammatory bowel disease, ulcerative coli-
tis, rheumatoid arthritis).15
In conclusion, despite a better general
understanding of neuroendocrine disease in
terms of natural history, biology, and clinical
behavior, differential diagnosis of NETs should
be extremely extensive and accurate, needing
additional and more definite investigations.
Awaiting more specific diagnostic tests, clini-
cal data and radiological findings should be
interpreted always by taking the clinical set-
ting, particularly, into consideration. A knowl-
edge of conditions that could mimic a NET is a
key factor in the approach to the disease, and
close cooperation among dedicated physicians,

pathologists, nuclear medicine specialists, and
conventional radiologists is warranted to
define the optimal diagnostic protocol.
Therefore, to save medical resources and to
avoid the patient’s impairment, it is appropri-
ate that those patients strongly suspected of
having a NET should be referred to and man-
aged in highly experienced centers with the
support of a greatly integrated multidiscipli-
nary team.
References
1. Modlin IM, Kidd M, Latich I, et al. Current
status of gastrointestinal carcinoids.
Gastroenterology 2005;128:1717-51.
2. Fernandez A, Tabuenca O, Peteiro A. A
“False Positive“ octreoscan in ileal
Crohn’s disease. World J Gastroenterol
2008;14:5349-52.
3. Ferrari L, Seregni E, Bajetta E, et al. The
biological characteristics of chromogranin
A and its role as a circulating marker in
neuroendocrine tumours. Anticancer Res
1999;19:3415-27.
4. Ferrari L, Seregni E, Lucignani G, et al.
Accuracy and clinical correlates of two dif-
ferent methods for chromogranin A assay
in neuroendocrine tumors. Int J Biol
Markers 2004;19:295-304.
5. Nobels FR, Kwekkeboom DJ, Bouillon R, et
al. Chromogranin A: its clinical value as
marker of neuroendocrine tumours. Eur J
Clin Inv 1998;28:431-40.
6. Modlin IM, Lye KD, Kidd M. A 50-year
analysis of 562 gastric carcinoids: small
tumor or larger problem? Am J Gastro-
enterol 2004;99:23-32.
7. Bajetta E, Ferrari L, Martinetti A, et al.
Chromogranin A, neuron specific enolase,
carcinoembryonic antigen, and hydroxyin-
dole acetic acid evaluation in patients with
neuroendocrine tumors. Cancer 1999;86:
858-65.
8. Campana D, Nori F, Piscitelli L, et al.
Chromogranin A: is it a useful marker of
neuroendocrine tumors? J Clin Oncol
2007; 25:1967-73.
9. Seregni E, Ferrari L, Bajetta E, et al.
Clinical significance of blood chromo-
granin A measurement in neuroendocrine
tumours. Ann Oncol 2001;12:S69-72.
10. Soga J, Yakuwa Y, Osaka M. Carcinoid syn-
drome: a statistical evaluation of 748
[Rare Tumors 2009; 1:e32]
Letter
reported cases. J Exp Clin Cancer Res
1999;18:133-41.
11. Chiti A, Briganti V, Fanti S, et al. Results
and potential of somatostatin receptor
imaging in gastroenteropancreatic tract
tumours. Q J Nucl Med 2000;44:42-9.
12. Krenning EP, Bakker WH, Kooij PP, et al.
Somatostatin receptor scintigraphy with
indium-111-DTPA-D-Phe-1-octreotide in
man: metabolism, dosimetry and compari-
son with iodine-123-Tyr-3-octreotide. J
Nucl Med 1992;33:652-8.
13. Gibril F, Reynolds JC, Chen CC, et al.
Specificity of somatostatin receptor scinti-
graphy: a prospective study and effects of
false-positive localizations on manage-
ment in patients with gastrinomas. J Nucl
Med 1999;40:539-53.
14. Vanhagen PM, Krenning EP, Reubi JC, et
al. Somatostatin analogue scintigraphy in
granulomatous diseases. Eur J Nucl Med
1994;21:497-502.
15. Reubi JC, Laissue J, Waser B, et al.
Expression of somatostatin receptors in
normal, inflamed, and neoplastic human
gastrointestinal tissues. Ann N Y Acad Sci
1994;733:122-37.
[page 97]
Rare Tumors 2009; volume 1:e33
Hepatic angiosarcoma
five years following
spontaneous intraperitoneal
bleed of a hepatic mass
Jessica L. Cioffi-Pretti,1
Alexandra N. Kalof,2 George Ebert,3
Laurence E. McCahill4
1
Department of Surgery, University of
North Carolina at Chapel Hill, Chapel Hill;
2
Department of Pathology, Fletcher, Allen
Health Care/University of Vermont,
Burlington; 3Department of Radiology,
Fletcher Allen Health Care/University of
Vermont, Burlington; 4Lacks Cancer
Center, St. Mary’s Health Care, Grand
Rapids, Michigan, USA
Abstract
Primary hepatic angiosarcoma is a rare
and rapidly fatal disease. We present the
highly unusual identification of this lesion
five years after the initial clinical presenta-
tion.
In 2003, a 32-year-old man presented with
abdominal pain, tachycardia, and evidence of
hemorrhage. A CT scan showed a hepatic
mass with intralesional hemorrhage, intra-
peritoneal blood, and splenomegaly. The
patient was stabilized clinically. Laparoscopic
core biopsies demonstrated no malignancy,
only findings consistent with an old hemor-
rhage. Contralateral lobe biopsies revealed
normal liver tissue. A metastatic workup was
negative and the decision was made to
observe the patient clinically with radiograph-
ic follow-up, given his suspected portal hyper-
tension based on thrombocytopenia and
splenomegaly.
Sequential imaging demonstrated a
decrease in the size of the mass from 12.0 cm
in 2003 to 3.0 cm in 2007. Subsequent newly
identified esophageal varices prompted a re-
evaluation of the case. A repeat biopsy
demonstrated a neoplasm of vascular etiology
and uncertain malignant potential. By early
2008 the lesion had increased to 4.8 cm and
was resected via a left hepatic lobectomy. An
extremely vascular lesion with surrounding
dense fibrosis was identified and pathologic
examination demonstrated a high-grade
angiosarcoma.
We are unaware of any previous reports
suggesting such a prolonged natural history
of hepatic angiosarcoma. This case may rep-
resent the possibility of malignant transfor-
mation of a lower grade vascular neoplasm
such as hepatic epithelioid hemangioen-
dothelioma to an angiosarcoma.
[page 98]
Introduction
Primary hepatic angiosarcoma is a rare dis-
ease with a poor life expectancy. It is believed
to be highly lethal, with near 100% mortality by
one year. We present the highly unusual iden-
tification of a high-grade angiosarcoma in an
adult male five years following his initial pres-
entation with a spontaneously bleeding hepat-
ic mass.
Case Report
The patient is a 32-year-old man with a his-
tory of Crohn’s disease, who presented febrile
and tachycardic, with a falling hematocrit
(40.0-27.7%), and leukocytosis (23 K/cm) in
2003. An abdominal CT scan demonstrated a
12.0x11.0 cm hyperdense, highly attenuated,
heterogeneous mass in the lateral segment of
the left hepatic lobe, with a free intraperi-
toneal hemorrhage (Figure 1A). The patient
became stable hemodynamically after a trans-
fusion with two units of blood. In addition to
Crohn's disease, his past medical history was
notable for splenomegaly since the age of 18
years and persistent thrombocytopenia
(platelet count, 40,000-50,000). He denied
drinking alcohol and subsequent hepatitis
serology tests were negative.
A fine needle aspiration of the left hepatic
mass was performed and demonstrated rare
clusters of atypical cells with a background of
necrotic debris, suggestive of malignancy. The
paucity of cells present, however, precluded
immunohistochemical workup and a definitive
diagnosis. Laparoscopic needle core biopsies
were performed subsequently and revealed an
organizing hematoma without evidence of
malignancy. Biopsies of the contralateral lobe
demonstrated normal liver parenchyma with-
out cirrhosis. A full metastatic workup was
negative. Hepatic angiography was performed
and demonstrated a rounded hypovascular
lesion without a characteristic tumor blush.
Hepatic venous wedge pressures (8 torr) failed
to support a diagnosis of portal hypertension. A
bone marrow biopsy was unremarkable and
platelet function assays were normal. A deci-
sion for close observation was made secondary
to the patient’s long-standing splenomegaly
and thrombocytopenia and the concern for his
suitability for resection.
The patient was monitored closely every
four to six months with radiographic imaging,
which documented an interval decrease in the
size of the lesion (Figure 1B). He remained
asymptomatic, fully active, and otherwise
healthy. A surveillance CT scan performed four
years after the initial presentation (April 2007)
demonstrated the lesion had diminished to 3.0
[Rare Tumors 2009; 1:e33]
Correspondence: Laurence E. McCahill, Lacks
Cancer Center, 200 Jefferson SE, Grand Rapids,
MI 49503, USA. E-mail: mccahillj_l@comcast.net
Key words: hepatic angiosarcoma, hepatic mass,
spontaneous intraperitoneal bleed.
Contributions: JC-P, AK, LM, manuscript writing;
AK, GE, LM, manuscript editing/revisions.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 21 July 2009.
Accepted for publication: 27 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0)
©Copyright J.L. Cioffi-Pretti, et al., 2009
Rare Tumors 2009; 1:e33
doi:10.4081/rt.2009.e33
cm in maximum dimension, but with newly
identified asymptomatic esophageal varices
and thrombosis of the left portal vein. Over the
following eight months, the lesion increased in
size from 3.0 cm to 4.8 cm, and developed
prominent intralobular septations (Figure 1C).
A malignant process was considered and
repeat core biopsies demonstrated an atypical
vascular proliferation with features suggestive
of an epithelioid hemangioendothelioma.
Subsequently the patient underwent a left
hepatic lobectomy (Couinaud segments 2-4)
that revealed a highly vascular lesion involving
the left lateral and left medial lobes with fibro-
sis of the porta hepatis. Pathologic examina-
tion demonstrated a high-grade primary hepat-
ic angiosarcoma with negative histological
margins. The patient’s postoperative course
was complicated by the development of signif-
icant ascites. He recovered well from surgery,
and the ascites resolved. A three-month follow-
up CT scan demonstrated a single pulmonary
lesion suggestive of metastasis. The patient
underwent a video-assisted thoracoscopy pro-
cedure, with the pathologic examination
demonstrating a 1 cm focus of a high-grade
metastatic epithelioid angiosarcoma. He rapid-
ly developed a port site chest wall recurrence,
for which he has received systemic taxane-
based chemotherapy, with a durable partial
response of twelve months. Currently he
remains free of disease in the liver.
Pathologic findings
Grossly, the resected liver specimen con-
tained a tan, hemorrhagic well-demarcated
mass (6.0x5.5x5.0 cm), with a peripheral rim
of fibrous tissue and approximately 60% tumor
necrosis (Figure 2). The mass abutted on the
capsular surface with adjacent fibropurulent
 Article

serositis. Surgical resection margins were nor-
mal tissue.
Microscopically, the liver mass revealed a
high-grade malignant neoplasm composed of
epithelioid cells exhibiting marked cellular
pleomorphism, brisk mitotic activity (>50
mitotic figures/10 high power fields) and
extensive geographic tumor necrosis (Figure
3). The cells were arranged in cohesive sheets,
focally forming anastomosing vascular chan-
nels with prominent hob-nailing and scattered
intracytoplasmic lumina. The tumor infiltrated
the surrounding hepatic parenchyma with
entrapment of benign bile ducts and hepato-
cytes. Lymphovascular invasion was not identi-
fied. Positive immunohistochemical stains
included: CD31, CD34, Podoplanin (D2-40),
EMA, and Factor VIII Ag, while Keratin CAM
5.2, Keratin MAK 6, Keratin AE1-AE3, and
HepPar1 were negative. The immunohisto-
chemical findings support vascular differentia-
tion with high-grade morphology, extensive
necrosis, and epithelioid morphology charac-
teristic of an epithelioid angiosarcoma.
Acute abdominal bleeds occur spontaneously
or following percutaneous biopsy in 15-27% of
cases, and thus hepatic angiosarcoma should
be considered in the differential workup of a
patient with spontaneous hemoperitoneum.
Associated laboratory findings tend to be non-
specific, although more than half of the
patients have unexplained thrombocytopenia
and elevated alkaline phosphatase levels. The
remaining liver function tests are normal and
tumor markers are negative. To date, there has
not been any association with known viral
markers identified.3
Radiographically, hepatic angiosarcomas
have a varying appearance. There may be one
dominant focus or multiple masses that corre-
late with the gross appearance. Metastases are
A
common at the time of presentation, with the
most usual metastatic sites being the lung and
spleen. Unenhanced CT images of these mass-
es are observed to be hypodense when com-
pared to normal hepatic parenchyma, while
lesions observed with contrast-enhanced CT
may be either hypo- or hyperdense, depending
on the presence of hemorrhage within the
tumor. Optimal imaging techniques for the
diagnosis of hepatic angiosarcoma include
unenhanced, multiple-phase enhanced, and
delayed CT or MR imaging to adequately cap-
ture all phases of the tumor and eliminate
potentially benign mimickers.4
Pathologically, hepatic angiosarcomas of the
deep soft tissue and in visceral locations gen-
erally are high-grade malignant neoplasms

Discussion
Angiosarcomas are rare, malignant vascular
tumors that may occur in any area of the body,
but are most common in the region of the head
and neck. Sarcomas of the soft tissues consti-
tute less than 1% of all cancers, with angiosar-
comas compromising approximately 2% of soft
tissue sarcomas. Predisposing factors include
a prior history of radiation therapy, chronic
lymphedema, exposure to Thorotrast (thorium
dioxide, a radiologic contrast medium), use of B
anabolic steroids or synthetic estrogens, insec-
ticide exposure, and long-term exposure to
vinyl chloride. Typically angiosarcomas are
high-grade, aggressive tumors that tend to
recur and metastasize despite treatment.
Current therapies include surgical resection,
with radiation therapy and/or adjuvant
chemotherapy depending on the anatomic
location and size. Overall prognosis is poor for
soft tissue angiosarcomas, with a five-year
survival reported in the range of 10-35%.1
Hepatic angiosarcoma is very rare, consti-
tuting 2% of all primary hepatic cancers. The C
average incidence of hepatic angiosarcoma is
estimated to be 25 cases per year in the United
States. There is a male to female predomi-
nance of 3:1 with the majority of patients diag-
nosed in their sixth decade of life. Figure 1. CT images
showing regression
Approximately 60% of patients have evidence rather than progression
of metastatic disease at the time of diagnosis.2 of the liver lesion, (A)
Clinical presentation is nonspecific typical- initial presentation in
ly, with presenting symptoms including 2003, (B) diminished
abdominal pain, weakness, fatigue, and weight to 3.0 cm in 2007, and
(C) progression in
loss; while physical examination findings may 2008.
include hepatomegaly, ascites, and jaundice.

[Rare Tumors 2009; 1:e33] [page 99]

Article

that have an epithelioid to spindled appear-

ance. As in the current case, angiosarcomas of Figure 2. Gross liver
resection specimen.
the liver are characterized by nests and solid
sheets of malignant cells of high nuclear grade
that form irregular vascular channels and
exhibit invasion of the adjacent liver parenchy-
ma. Tumor necrosis is a common finding.
Grossly, the tumor may appear with one of four
different growth patterns: multiple nodules, a
single dominant mass, mixed patterns of a
dominant mass with smaller nodules, or an
infiltrating micronodular tumor.2
For the past 40 years, a link has been estab-
lished between hepatic angiosarcoma and
environmental toxins, including Thorotrast,
vinyl chloride, arsenic, radiation, and exoge-
nous estrogens or anabolic steroids. However,
in nearly 75% of cases, no causative agent is
identified. In all cases of environmental expo-
sure, a prolonged latency period has been Figure 3. Hepatic mass
established of 20-30 years on average, yet the and adjacent liver
gross and microscopic pathology of idiopathic parenchyma with asso-
angiosarcomas and those caused by environ- ciated capsular disrup-
tion and inflammatory
mental toxins remain identical.5 reaction (H&E stain,
Treatment for hepatic angiosarcoma is 40x magnification).
delayed often owing to the nonspecific symp-
toms with which the tumor typically presents.
The average time until diagnosis is six months
from the initial presentation to a health care
professional; however, many patients do not
seek medical attention for several months fol-
lowing the onset of symptoms. Thus, a large
tumor size and the presence of metastases are
common on diagnosis. Median survival time
following diagnosis is six months, with near
100% mortality by one year. Improved progno-
sis has been observed with a single tumor
mass, a smaller tumor size, lack of metastases,
a low-grade lesion, and negative surgical
resection margins; however, owing to the clinical diagnosis of portal hypertension por- to have primary hepatic angiosarcoma.8 In the
infrequent nature of the tumor, this still has to tends a worse prognosis. Pathologic examina- case of our patient, liver biopsies of the unin-
be quantified.2 Given the poor prognosis for tion results including high-grade nuclear fea- volved liver in 2003 failed to demonstrate char-
patients diagnosed with hepatic angiosarco- tures with epithelioid morphology are addi- acteristic periportal fibrosis, but this was iden-
ma, surgical resection is the only definitive tional unfavorable findings. Paradoxically, the tified on repeat liver biopsies in 2007, after the
treatment; however, this is not possible in radiographic finding of a tumor mass that had patient developed esophageal varices.
many cases either because of multifocal dis- been present for the previous five years in our We are unaware of any previous reports sug-
ease or the extent of the liver involvement.6 patient would suggest a less aggressive clinical gesting such a prolonged natural history of a
Adjuvant treatment remains undefined owing course of the disease. hepatic angiosarcoma. This case may repre-
to the rarity of the tumor. Chemotherapy has In hindsight, this patient’s splenomegaly sent the possibility of malignant transforma-
not been well studied except on a case report appears to be a result of periportal fibrosis and tion of a lower grade vascular neoplasm, such
basis, and in general angiosarcomas are the splenomegaly and thrombocytopenia were as hepatic epithelioid hemangioendothelioma,
resistant to radiation therapy. Liver transplan- long standing. These clinical findings have to a more aggressive angiosarcoma. While
tation has been attempted, but the tumor been reported previously as precursors to the angiosarcoma may present with spontaneous
recurrence rate remains high (64%) and long- development of angiosarcoma in other and often catastrophic intraperitoneal bleed-
term survival has not been observed (average patients. An analysis of patients with signifi- ing, this patient’s spontaneous intraperitoneal
survival time, 23 mth).7 If definitive resection cant polyvinyl chloride exposure by Lee et al. bleed was five years prior to eventual resection
can be achieved prior to microscopic spread of (1996)8 described a patient with a history of of the tumor. The patient had well-documented
the disease, long-term survival is possible. splenomegaly and thrombocytopenia, who later radiographic gradual reduction in size of the
This has been reported in three adult cases presented with esophageal varices and presi- lesion over four and a half years, before its
that were without evidence of recurrence at 64 nusoidal hypertension via a screening pro- rapid enlargement just prior to excision; a very
months, 38 months, and 10 years.3 gram. Ultimately a core needle biopsy lead to unusual progression in the natural history of a
Although our patient’s tumor was amenable the diagnosis of presinusoidal hepatic fibrosis. high-grade angiosarcoma, thus raising the
to resection, the associated hepatic fibrosis The patient later sustained a fatal gastroin- possibility of malignant transformation of a
documented by previous core biopsies and the testinal hemorrhage, and at autopsy was found benign precursor.

[page 100] [Rare Tumors 2009; 1:e33]


References
1. Mark RJ, Poen JC, Tran LM, et al.
Angiosarcoma. A report of 67 patients and
a review of the literature. Cancer 1996;
77:2400-6.
2. Mani H and Van Thiel DH. Mesenchymal
tumors of the liver. Clin Liver Dis 2001;5:
219-57, viii.
3. Molina E and Hernandez A. Clinical mani-
festations of primary hepatic angiosarco-
ma. Dig Dis Sci 2003;48:677-82.
4. Koyama T, Fletcher JG, Johnson CD, et al.
Primary hepatic angiosarcoma: findings at
CT and MR imaging. Radiology 2002;222:
667-73.
5. Louagie YA, Gianello P, Kestens PJ, et al.
Vinylchloride induced hepatic angiosarco-
ma. Br J Surg 1984;71:322-3.
6. Ozden I, Bilge O, Erkan M, et al. Five years
and 4 months of recurrence-free survival
[Rare Tumors 2009; 1:e33]
Article
in hepatic angiosarcoma. J Hepatobiliary
Pancreat Surg 2003;10:250-2.
7. Maluf D, Cotterell A, Clark B, et al. Hepatic
angiosarcoma and liver transplantation:
case report and literature review.
Transplant Proc 2005;37:2195-9.
8. Lee FI, Smith PM, Bennett B, et al.
Occupationally related angiosarcoma of
the liver in the United Kingdom 1972-
1994. Gut 1996;39:312-8.
[page 101]
Rare Tumors 2009; volume 1:e34
Colonic cancer in adolescents.
A report of three cases
M.A.C. Odike,1 A.E. Dongo,2 E.F. Alufohai,2
A.I. Odike3
1 2
Departments of Pathology, Surgery and
Pediatrics, Ambrose Alli University,
Ekpoma, Edo State, Nigeria
Abstract
Colorectal cancer is a common malignant
neoplasm in adults, with a peak incidence of
60-79 years. About 1 million cases of the dis-
ease and half a million deaths associated with
it are reported world-wide each year. Colorectal
cancer, however, is very uncommon in children
and adolescents. This is a presentation of 3
cases of colon cancer in Nigerians aged 17 and
19 years. Two of them were adenocarcinoma
and the other leiomyosarcoma. The pathogen-
esis and aspects of management are dis-
cussed.
Introduction
Colon cancers are the second most common
cancer in both men and women in America.1,2
World-wide they are the third major cause of
cancer for men and the fourth most common
cause of cancer for women.2,3 They are the sec-
ond most common causes of cancer-related
deaths in developed countries and the most
common gastro-intestinal carcinoma.4-6 The
incidence is highest in the westernized coun-
tries of North America, Northern Europe,
Australia, and New Zealand. Intermediate
rates are found in Southern Europe, and low
rates in Africa.2,4 Reports have shown that close
to 1 million new cases of colo-rectal cancer and
nearly half a million deaths associated with
colorectal cancer are reported world-wide each
year.4,7 About 98% of them are primary adeno-
carcinomas.4,8,9 The remaining 2% are made up
of carcinoid, mesenchymal and lymphoid
tumors. These figures have decreased in the
West due to increased rate of screening and
polyp removal.10
The peak incidence for colorectal carcinoma
is put at between ages 60 and 79 years, with
fewer than 20% occurring before the age of 50
years.8 According to another author, 90% of
patients are older than 50 years; with highest
incidence rates in individuals aged 70 to 85
years.4 Very occasionally, it may affect much
younger adults from the age of 20 years.6
The risk factors for development of colo-rec-
tal cancer include age, a diet rich in fat and
cholesterol, inflammatory bowel disease, and
[page 102]
genetic predisposition, including hereditary
polyposis and non-polyposis syndromes.4,7,11
Three cases of colonic cancer amongst
Nigerian adolescents aged 17 and 19 years are
presented. These are uncommon findings, and
hence should be of interest to clinicians to
increase their index of suspicion as early cases
are potentially curable.
Case #1
OS, a 19-year old male student presented to
the surgical out-patient (SOP) department of
the Irrua Specialist Teaching Hospital (ISTH)
with complaints of passage of bloody and
watery stools, abdominal pain, lower abdomi-
nal distension and vomiting of between one
week and three months duration. The abdomi-
nal pain was intermittent and colicky. He
reported mild weight loss. There was no family
history of similar illness. Physical examination
showed a mildly dehydrated young man with
tense and distended abdomen, visible peri-
staltic waves, and hyperactive bowel sounds.
He was admitted, and after one week the
abdominal distension worsened and he devel-
oped constipation. Digital rectal examination
and proctoscopy showed an empty rectum with
a circumferential and fungating irregular, firm
mass about 5 cm from the anal verge.
An impression of intestinal obstruction sec-
ondary to rectal tumor was made, and incision-
al biopsy taken for histology. The histopatholo-
gy diagnosis was adenocarcinoma. The patient
was offered a dysfunctioning (loop) sigmoid
colostomy after decompression of the dilated
sigmoid colon. He was commenced on 5-
flurouracil (5FU) and adriamycin following
confirmation of mesenteric lymph node
involvement in the colostomy biopsy specimen.
He received 5 courses of chemotherapy and
was referred to another center for radiothera-
py. The patients has responded well to this.
Case #2
EB was a 17-year old student. She presented
to the SOP of ISTH, six weeks after appen-
dicectomy in a private hospital, with colicky
abdominal pain, vomiting, weakness, and dis-
charge from the appendicectomy scar of about
two weeks duration. Family and social history
was not significant. Physical examination
revealed a fixed and firm, non-fluctuant mass
of about 10x11 cm in the right iliac fossa
region of the abdomen. Abdominal ultrasound
found a large intra-abdominal mass, and sug-
gested retained foreign body, to rule out infect-
ed appendix stump. At exploratory laparotomy,
an infected appendicectomy wound and a firm
to hard cecal pole mass were observed. The
mass measured about 15x12 cm and was asso-
ciated with about 20 mls of abscess. Right
hemi-colectomy was done and histopathology
examination requested. The request was never
received by the laboratory. The patient recov-
[Rare Tumors 2009; 1:e34]
Correspondence: M.A.C. Odike, Ambrose Alli
University, Ekpoma, Edo State, Nigeria.
E-mail: maxodike@yahoo.com
Key words: colon cancer, adolescents.
Received for publication: 21 June 2009.
Revision received: 17 July 2009.
Accepted for publication: 30 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright M.A.C. Odike et al., 2009
Rare Tumors 2009; 1:e34
doi:10.4081/rt.2009.e34
ered and was discharged home. Two months
post-operation, she developed a nodule on the
anterior abdominal wall over the laparotomy
scar. This was thought to be a pyogenic granu-
loma. A repeat abdominal ultrasound reported
an anterior abdominal wall mass and enlarged
inguinal lymph nodes, and made an impres-
sion of rhabdomyosarcoma. The lump was
excised and sent for histopathology examina-
tion, together with the hemi-colectomy speci-
men. Both of them showed similar histologic
features composed of malignant glands and
cells within fibro-cellular stroma. A diagnosis
of colonic adenocarcinoma with metastasis to
the anterior abdominal wall was made. The
patient was commenced on 5-FU and referred
for radiotherapy, after receiving 5 courses of
chemotherapy. She died about two and a half
years after diagnosis
Case #3
A 19-year old male, PO, presented to the
emergency room of Joe Alufohai Medical
Center, Sabongida-Ora on 26/10/07 with a two-
week history of abdominal pain and vomiting.
On examination he was found to be in painful
distress and to have moderate rebound tender-
ness and guarding. This was worse over the
right lower quadrant of the abdomen. A diagno-
sis of acute appendicitis was made and the
patient taken in for emergency appendicectomy.
Findings at surgery included a dilated,
longish and coiled appendix; dilated terminal
ileum; and an atrophic cecum with a localized
firm mass. In view of these findings, an addi-
tional intra-operative impression of congenital
hypertrophy of the ileo-cecal valve was consid-
ered and a limited right hemi-colectomy per-
formed. The specimen was sent for histology.
The patient did well and was discharged to the
out-patient clinic two weeks after surgery.
The histopathology diagnosis was leio-
myosarcoma, together with acute appendicitis.
The patient has yet to honor his out-patient
appointment, six months after discharge.

Discussion
Almost all bowel cancers arise in the colo-
rectum, since the small intestine is strikingly
free from cancer risk.6 Colon cancer is a silent
killer, often causing no recognizable symptoms
until it is too late.3 Most of them occur sporad-
ically in the absence of well-defined familial
syndromes. Regardless of the inciting event, a
well-described set of genetic alterations occurs
that ultimately leads to colorectal malignancy.8
Fitzgibbons et al. described a genetic factor
found in young patients belonging to
Scandinavian families with the Lynch syn-
drome.12
The vast majority of colorectal cancers are
adenocarcinomas, which arise from pre-exist-
ing adenomatous polyps.6 This adenoma-carci-
noma sequence is a well-characterized clinical
and histopathologic series of events with
which discrete molecular genetic alterations
have been associated.7 However, about 30% of
colorectal carcinomas arise from flat lesions
without evidence of adenomatous precursors.6
These suggest that some dysplastic lesions can
degenerate into malignancy without passing
through a polypoid stage.8 This particularly
occurs with cancers of the proximal colon and
rectum.6 Two of the cases being reported were
in the proximal colon; the third was in the rec-
tum. Sebbag et al. did not consider heredity to
be involved in the pathogenesis of colon can-
cer.13 More recently though a known genetic
link was described in first degree biological
family members of persons with colon cancer.3
They have 3 times greater risk of developing
colon cancer than the general population.
However, 80% of colon cancers strike people
without genetic connection to the disease.3 No
family history of similar illness was obtained
from any of the index patients. Vogelstein and
colleagues identified a number of very impor-
tant genetic alterations that contribute,
through their multiplicity over the years, to the
eventual development of colorectal cancer.14,15
These are grouped into two pathogenetically
distinct pathways that are believed to be
responsible for the development of colon can-
cer.16 Both pathways involve the stepwise accu-
mulation of multiple mutations. The first path-
way (APC/β-caterin pathway) is characterized
by chromosomal instability that results in
accumulation of mutations in a series of onco-
genes and tumor suppressor genes. These
include mutations of the adenomatous polypo-
sis coli (APC) gene and K-RAS gene, and loss
of SMAD4 (formerly called DPC4 – deleted in
pancreatic cancer – gene) and p53 genes.7,8
The morphologic evolution of the lesion is
through a localized colon epithelial prolifera-
tion to formation of small adenoma that pro-
gressively enlarge, become more dysplastic,
and ultimately develop into invasive cancer
(the adenoma-carcinoma sequence). The sec-
ond pathway (microsatellite instability path-
way) is characterized by inheritance of a
mutation in one of several genes involved in
DNA mismatch repair, which are MSH2, MLH1,
MSH6, PMS1 and PMS2. It is involved in 10-
15% of sporadic cases of colon cancer and in
the hereditary non-polyposis colonic cancer
(HNPCC or Lynch) syndrome.6-8 Inheritance in
this type of cancer is autosomal dominant.
Affected patients also carry an increased risk
of cancers of the stomach, ovaries, breast and
uterus. The colon cancers in this syndrome
tend to develop as flat lesions rather than as
polyps. Cancers arising through this pathway
occur at a younger age, usually before 45
years.6 Unlike in the adenoma-carcinoma
sequence, this pathway does not produce iden-
tifiable morphologic correlates.
These pathogenic pathways, which involve
stepwise accumulation of mutations, explain
why colorectal cancer is a disease of adults. It
is rare in patients under 40 years of age, and
even rarer in younger age groups.17 Of the
1,250 cases seen by Sebbag et al. over a 25-year
period, only 3 (0.24%) were under 19 years.13 It
is said that when colorectal cancer is found in
a young person, pre-existing ulcerative colitis
or one of the polyposis syndromes must be sus-
pected.8 None of our cases had any of these.
Environmental factors, especially dietary prac-
tices, have been implicated in the observed
striking geographic contrasts in incidence.
People who eat high calorie, high fat
(Western) diets are at higher risk than people
who eat balanced low fat, high fiber (Eastern)
diets.3,18 This is partly because fiber increases
the bulk and the transit time of stool. This does
not allow enough time for both bacterial break-
down of bile salts into carcinogenic lithocholic
and deoxycholic acids, and their contact with
colonic mucosa.2 It had been mentioned that
low fecal pH had a role to play in the genesis of
colon cancer. Also the role of obesity in colorec-
tal cancer has been discussed.20 There is a
well-known link between obesity and a
Western diet. Japanese and Polish families
who migrated from their low risk areas to the
US acquired, over the course of 20 years, the
rate prevailing in their new environment.6
They had adopted the dietary practices of their
hosts.8 Dietary factors account for 90% of the
risks for bowel cancer.21 A Western-type dieting
has become very common with us in Africa,
even without migrating. This may account for
why the incidence in black Africans is increas-
ing, especially in the major urban cities.2 Its
introduction to our children very early in life
may be an important influence when combined
with other environmental/racial/social factors
peculiar to us, which have not been studied.
After all, black Americans are said to be more
prone to developing colon cancer than their
white counterparts.22 Apart from this, a possi-
[Rare Tumors 2009; 1:e34]
Case Report
ble increased risk among lower socioeconomic
groups especially in the third world has been
suggested.23,24 This is related to poor nutrition
or chronic gastro-intestinal infections, such as
amoebiasis and schistosomiasis, which are
thought to be associated with an increased
incidence of malignancy. All three cases being
presented belonged to the lower socioeconom-
ic group. None of them was immunosup-
pressed. Their exposure to chronic gastro-
intestinal infestations was not determined.
Colon cancers progress slowly and may be
asymptomatic for as many as five years or until
a much later phase.9 However, patients usually
have occult blood losses from their tumor.4 It is
likely that the index tumors started while the
patients were still in the pediatric age group.
Most studies suggest a delay in diagnosis with
an associated deleterious effect on outcome.
This is because many of the clinical features
are similar to those found in common child-
hood problems such as intussusception,
appendicitis, gastro-enteritis and simple con-
stipation.23 Two of the presented cases were
initially thought to be appendicitis. This is
understandable considering the rarity of colon
cancer in children/adolescents.
Treatment must be aggressive and include a
combination of surgery and adjuvant chemo-
therapy. The surgical resection must be as rad-
ical as feasible for growth.13 Both systemic and
loco-regional chemotherapy, such as intra-
hepatic, intra-arterial for liver metastasis,
have a role.7 Where technically feasible, resec-
tion of metastatic deposits in the lungs or liver
is advisable.25,26 The chemotherapeutic agents
in use include 5-FU, irinotecan, leucovorin,
and the more recent anti-vascular endothelial
growth factor, bevacizumab.7 Radiotherapy
finds use in cases of rectal cancer to reduce
the risk of local recurrence.
When tumors are detected early, 90% of
patients survive at least five years after diag-
nosis and treatment.27 This is not the case for
adolescents where it carries an extremely poor
prognosis, owing to late diagnosis and aggres-
sive tumor biology.23
Conclusions
Colorectal cancer remains a leading cause
of death from cancer in adults, especially in
the Western world. It is a very rare disease in
children and adolescents. Even so, colon can-
cer in the young is of great concern, especially
since screening strategies are focused on older
patients.17 Progress has been made in under-
standing the molecular basis of its predisposi-
tion and progression. Efforts are being made
on to develop better treatment and preventive
approaches, and better screening strategies.
Such screening strategies must incorporate
[page 103]
Case Report
children and adolescents since they are not
immune to colorectal cancers, as demonstrat-
ed by this report. As Sebbag et al. put it, the
distribution pattern of colorectal carcinoma
appears to have changed.13 There is no point
waiting until older age to check for risks.
References
1. Mansell DE. Colon Polyps & Colon cancer.
http://www.personalweb.sunset.net.
2. Archampong EQ, Tandoh JFK, Nwako FA,
et al. Malignant tumours of the colon and
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Rocha-Afodu JT (eds). Principles and
Practice of Surgery including Pathology in
the Tropics. 3rd ed. Ghana Publishing
Corporation, Accra 2000; pp 670-82.
3. Colon cancer – A Pain in The Butt.
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4. Hassan I. Colon adenocarcinoma.
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5. Torpy JM, Lynm C,Glass RM. Colon cancer
screening. JAMA 2006;295:1208.
6. Rhodes J. Bowel cancer. http://www.net-
doctor.co.uk/cancer/index.shtml.
7. Wafik SE. Colon Cancer, Adenocarcinoma.
http://www.emedicine.com/med/topic413.h
tm.
8. Liu C, Crawford JM. Tumors of the Colon
and Rectum. In: Kumar V, Abbas AK and
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Fausto N (eds). Robbins and Cotran
Pathologic Basis of Disease. 7th ed.
Elsevier Saunders, Philadelphia 2004; 857-
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9. National Cancer Institute. http://www.can-
cer.gov.
10. Johnson RW. Colorectal cancer.
http://www.rwjuh.edu/health_information.
11. Desai PB. Carcinoma of the colon.
http://www.indiansurgeons.com.
12. Fitzgibbons R Jr, Lynch HT, Stanslav GV.
Recognition and treatment of patients
with hereditary non-polyposis colon can-
cer (Lynch syndrome I and II) Ann Surg
1987;206:289-95.
13. Sebbag G, Lantsberg L, Arish A, Levi I,
Hoda J. Colon carcinoma in the adoles-
cent. Pediatr Surg Int 1997;12:446-8.
14. Kinzler KW, Vogelstein B. Lessons from
hereditary colo-rectal cancer. Cell 1996;87:
159.
15. Glinghammar B, Rafter J. Carcinogenesis
in the colon: interaction between luminal
factors and genetic factors. Eur J Cancer
Prev 1999;8:S87-94.
16. Jass JR. Pathogenesis of colo-rectal can-
cer. Surg Clin N Am 2002;82:891.
17. Domergue J, Ismail M, Astre C, et al.
Colorectal carcinoma in patients younger
than 40 years of age: Montpellier Cancer
Institute experience with 78 patients.
Cancer 1988;61:835-40.
18. Kim Y. AGA technical review: Impact of
dietary fiber on colon cancer occurrence.
Gastroenterology 2000; 118:1235-57.
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19. Walker AR, Walker BF, Walker AJ. Fecal pH,
dietary fiber intake and proneness to colon
cancer in four South African population.
Br J Cancer 1986;53:4895-8.
20. Siegel RL, Jemal A, Ward EM. Increase in
incidence of colorectal cancer among
young men and women in the United
States. Cancer Epidemiol Biomarkers Prev
2009;18:1695.
21. Hill MJ. Mechanisms of diet and colon car-
cinogenesis. Eur J Cancer Prev 1999;8:95-
8.
22. O'Keefe SJ, Chung D, Mahmoud N, et al.
Why do African Americans get more colon
cancer than Native Africans? J Nutr
2007;137:175-82.
23. Shankar A, Whelan J, Renaut AJ, Taylor I.
Colo-rectal cancer in adolescents. Ann R
Coll Engl 1999;81:100-4.
24. Ming-Chai C. Colorectal cancer and schis-
tosomiasis. Lancet 1981;2:971-3.
25. Wilking N, Petrelli NJ, Herrera L, et al.
Surgical resection of pulmonary metasta-
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Colon Rectum 1985; 28:562-4.
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cancer.html

Tumors and tumor-like lesions
of the heart valves
Shi-Min Yuan,1,2 Hua Jing,2 Jacob Lavee1
1 ing the heart valves were reviewed. The
Department of Cardiac and Thoracic
Surgery, The Chaim Sheba Medical
Center, Tel Hashomer Israel; 2Department
of Cardiothoracic Surgery, Jinling
Hospital, School of Clinical Medicine,
Nanjing University, Nanjing, Jiangsu
Province, People’s Republic of China
Abstract
Valvular tumors and tumor-like lesions may
have similar morphological and clinical char-
acteristics, and may place the patients at a
high risk of stroke in different ways. From
January 2004 to June 2008, 11 patients under-
went surgery for a suspected valvular tumor.
Valvular tumor and tumor-like lesions
accounted for 0.32% of adult cardiac opera-
tions. Five (45.5%) valvular lesions were papil-
lary fibroelastomas, one (9.1%) was myxoma, 2
(18.2%) were organized thrombi, and 3
(27.3%) were calcification lesions. There was
a total of 5 (45.5%) atrioventricular valve
lesions, 4 arising from the atrial side of the
leaflets, and one from the ventricular side. All
5 (45.5%) semilunar valvular lesions were
from the aortic valve. One (9.1%) lesion origi-
nated from the chorda tendinea of the mitral
valve. All leaflet lesions were resected by a sim-
ple shave technique, and all the patients recov-
ered favorably. Valvular tumor and tumor-like
lesions are rare. Pre-operative differential
diagnoses among these valvular lesions pose
important clinical implications for appropriate
treatment for the underlying diseases. Prompt
therapeutic measures in view of the underly-
ing diseases of the valvular lesions are essen-
tial to prevent potential embolic events.
Introduction
Cardiac valve tumors are rare. Fibro-
elastoma is the most common valvular tumor,
followed by myxoma. Atypical valvular lesions,
such as organized thrombus,1 valvular calcifi-
cation2 and valvular abscess3 may develop
symptoms and present morphological fea-
tures similar to those of the valvular tumors.
We report on 11 patients who underwent a
valvular lesion resection in this institute, and
discuss the clinical implications.
Patients and Methods
The records from January 2004 to June
2008 for tumors and tumor-like lesions involv-
lesions mainly included valvular papillary
fibroelastoma, valvular myxoma, valvular
thrombus and valvular calcification. The diag-
noses of the tumors and tumor-like lesions
were made by echocardiography before opera-
tion and confirmed by surgery and
histopathology. Vegetations of the heart
valves subjected to infective endocarditis
were easily distinguished from the tumors
and tumor-like lesions, and were, therefore,
excluded from this study. Size of the valvular
lesions was expressed as mean ± SD.
Results
Clinical presentation
From January 2004 to June 2008, 11
patients underwent surgery in this institute
for a suspected valvular tumor, covering 32%
of 3,412 adult cardiac surgical patients in the
same period. Patients’ clinical characteristics
were listed in Table 1. There were 7 males and
[Rare Tumors 2009; 1:e35]
Rare Tumors 2009; volume 1:e35
Correspondence: Hua Jing, Department of
Cardiothoracic Surgery, Jinling Hospital, School
of Clinical Medicine, Nanjing University, Nanjing
210002, Jiangsu Province, People’s Republic of
China. E-mail: dr.jing@163.com
Jacob Lavee, Department of Cardiac and Thoracic
Surgery, The Chaim Sheba Medical Center, Tel
Hashomer 52621, Israel.
E-mail: jacob.lavee@sheba.health.gov.il
Key words: cardiac myxoma, cardiac papillary
fibroelastoma, differential diagnosis, heart valve,
intracardiac thrombus, surgical resection.
Received for publication: 20 August 2009.
Accepted for publication: 24 August 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright S-M Yuan et al., 2009
Rare Tumors 2009; 1:e35
doi:10.4081/rt.2009.e35
4 females, aged 50.91±15.21 (31-78) years. All
patients had a good left ventricular function
with an ejection fraction of 61.82±5.13 (55-
75) percent. One patient (9.1%) was asympto-
matic, 5 (45.5%) manifested shortness of
breath, fatigue and weakness, 2 (18.2%) pre-
Figure 1. Case #5. Aortic
valvular papillary fibroelas-
toma. (A) Long-axis view,
and (B) short axis view of
transesophageal echocar-
diography showed a dense,
lobulated, highly mobile
mass (arrow) extending 1.2
cm attached to the non-
coronary cusp.
[page 105]
Article

sented with vertigo or dizziness, 2 (18.2%)
had chest pain, one (9.1%) had lumbago. The
symptomatic patients had a disease course of
3.11±7.36 (0.25-24) months. The 2 patients
who had valvular thrombus were associated
with cardiac or non-cardiac diseases. One had
a history of cheek squamous cell carcinoma,
and polycythemia vera associated with severe
aortic valve stenosis and coronary artery dis-
ease, and the other had a history of peripher-
al embolic events, carotid artery stenting for
carotid artery stenosis, patent foramen ovale
and coronary artery disease.
Diagnosis
Diagnoses were made by echocardiography
pre-operatively in all cases, and none of them
were noted incidentally by surgical investiga-
tion. There was a total of 10 (90.9%) left-sided
lesions, and one (9.1%) right-sided lesion.
Echocardiographic appearances of these
lesions were round, soft, lobulated and highly
mobile in 4 papillary fibroelastomas (Figure 1)
and one myxoma, round and dense in one pap-
illary fibroelastoma, thick, dense and less
mobile in both thrombi (Figure 2), and thick,
dense and non-mobile in 3 calcification lesions
(Figure 3). All 6 tumors (54.5%), including 5
papillary fibroelastomas and one myxoma were
pedicled by a short stalk, and both patients
with a valvular thrombus (18.2%), and 3
patients with a valvular calcification (27.3%)
were sessile. Trivial mitral valve regurgitation
was noted in 2 of the 4 patients with mitral
valve lesions: one was mitral papillary fibro-
elastoma and the other was mitral thrombus.
Mild aortic regurgitation was associated with
both aortic valvular papillary fibroelastomas.
Mild tricuspid regurgitation was present in the
patient with tricuspid valve myxoma. The 3

Table 1. Patients’ clinical characteristics and valvular mass.

Case Sex Age Diagnosis Associated Presentation Location Appearance Associated
disease

1 F 34 Papillary No Weak, Atrial side of Lobulated, No

fibroelastoma fatigue 1 posterior round
month mitral
leaflet
2 F 65 Papillary No Fatigue 2 Vessel Lobulated, round No
fibroelastoma weeks side, right.
cusp of aortic
valve
3 M 33 Papillary No Vertigo, Vessel side, Dense, round No
fibroelastoma taxia non-coronary
Diplopia cusp of aortic
one week valve
5 M 31 Papillary No Chest Vessel side, Lobulated, round No
fibroelastoma pain 3 weeks non-coronary
cusp of aortic
valve
6 M 43 Myxoma No Asymptomatic Atrial side of Lobulated, round No
septal tricuspid
leaflet
7 M 78 Thrombus Coronary artery Dizziness Ventricular side Thick, dense Coronary artery
disease, aortic 10 days of posterior mitral disease, aortic
valve stenosis, leaflet valve stenosis,
polycythemia vera, polycythemia vera,
atrial fibrillation atrial fibrillation
8 M 53 Thrombus Coronary artery Lumbago Atrial side of the Thick, dense Coronary artery
disease, patent 2 weeks posterior mitral disease, paten
foramen ovale, leaflet foramen ovale,
peripheral embolic peripheral embolic
events, carotid artery events, carotid artery
stenosis stenosis
9 F 45 Calcification Aortic valve regurgitation, Shortness of Edge of the Dense, Aortic valve regurgitation,
oral and vaginal candidosis breath and left cusp of thick, oral and vaginal candidosis
weakness 1 year non-mobile
aortic valve

10 M 64 Calcification Aortic valve regurgitation, Shortness of Atrial side of Dense, Aortic valve regurgitation,
mitral valve regurgitation, breath and anterior mitral thick, mitral valve regurgitation,
hypertension, peripheral weakness 2 leaflet non-mobile hypertension, peripheral
vascular disease months vascular disease

11 M 53 Calcification Mitral valve regurgitation, Shortness of Vascular side of the Dense, Mitral valve regurgitation,
hypothyroidism breath 3 weeks right coronary cusp thick, hypothyroidism
of the aortic valve non-mobile

[page 106] [Rare Tumors 2009; 1:e35]

 Article

patients with valvular calcification presented

dominantly with severe valvular dysfunction,
with either mitral or aortic regurgitation,
which required valve replacement.
Surgery
Eight patients (80%) underwent convention-
al cardiopulmonary bypass with cardioplegic
arrest. One patient with mitral fibroelastoma
and the patient with tricuspid valve myxoma
(20%) were operated on via port access under
femoral cardiopulmonary bypass, with the for-
mer having cardioplegic arrest, and the latter, a
beating heart. All leaflet lesions were resected
by a simple shave technique as described by
Gowda et al.,4 followed by leaflet plication with
direct suture. None had impairment of the
valvular leaflet function. The patient with fibro-
elastoma of the mitral chord had trivial mitral
regurgitation after tumor resection which was
repaired successfully by implanting two artifi-
cial chordea. Simultaneous coronary artery
bypass, aortic valve replacement, and closure of
foramen ovale were carried out. The cardiopul-
monary bypass time and cross-clamp time were
68.36±29.57 (38-113) and 48.9±24.29 (21-98)
min, respectively. There was a total of 5
(45.5%) atrioventricular valve lesions, with 4
arising from the atrial side of the leaflets, and
one from the ventricular side. Five (45.5%)
semilunar valvular lesions were all from the
aortic valve. Three aortic papillary fibroelas-
tomas and one aortic valve calcification lesion
were from the vascular side of the leaflets, and
another aortic calcification lesion was from the
edge of the left cusp. Besides, one (9.1%)
lesion originated from the chorda tendinea of
the mitral valve. A solitary lesion was presented
in 10 (90.9%) patients and multiple lesions in
one (9.1%), and originated from the midportion
of the valve leaflet away from the margin or the
annulus of the leaflet in 9 (81.8%), from the
edge of the leaflet in one (9.1%), and from the
chorda tendinea in one (9.1%). Five (45.5%) of
Figure 2. Case #7. Mitral
valve thrombus. Four-
chamber view of transtho-
racic echocardiography
showed a thick, dense,
less mobile mass (arrow)
attached to the ventricu-
lar side of the anterior
mitral leaflet.
Figure 3. Case #11. Mitral
valve calcification. Long-
axis view of transthoracic
echocardiography showed
a thick, dense, non-
mobile mass (arrow)
attached to the vascular
side of the right coronary
cusp of the aortic valve.
these valvular masses were papillary fibroelas- coronary cusps in 2, 1, and 2 patients, respec-
tomas, one (9.1%) was myxoma, 2 (18.2%) tively. Three of them were papillary fibroelas-
were organized thrombi, and 3 (27.3%) were tomas, and 2 were calcification lesions. One
calcification lesions. Five (45.5%) lesions were (9.1%) originated from the atrial aspect of the
located in the mitral valve leaflets. Of them, 2 septal leaflet of the tricuspid valve, which was
were papillary fibroelastomas, 2 were thrombi, proved to be a myxoma.
and one was calcification. Three of them were Similar to pre-operative echocardiographic
on the atrial side of the posterior leaflets, one findings, gross appearances of these lesions at
was on the ventricular side of the anterior surgery were round, soft, lobulated and frond-
leaflet, and one attached to the mitral chorda like in all valvular tumors except in one aortic
tendinea. There were 5 (45.5%) aortic valvular valvular papillary fibroelastoma which were
lesions, arising from the left, right and non- round and dense. Both thrombi from the mitral

Table 2. Surgery and size of the tumor.

Case Surgery Size (cm) z-score of the size
1 Valvular tumor resection (port access) 1x0.5x0.5 0.102
2 Valvular tumor resection 0.5 -0.918
3 Valvular tumor resection, artificial chorda 0.7 -0.510
4 Valvular tumor resection 0.5 -0.918
5 Valvular tumor resection 1.2 0.510
6 Valvular tumor resection (port access) 1.5 1.327
7 Valvular tumor resection, coronary artery bypass, aortic valve replacement 1.8x0.7 1.735
8 Valvular tumor resection, coronary artery bypass, closure of foreman ovale 1.4x1.1x0.8 0.918
9 Aortic valve replacement 0.4 -1.222
10 Aortic valve replacement, resection of small mass from anterior mitral leaflet 0.4 -1.222
11 Valvular mass resection, mitral valve repair Multiple 0.3-1.0 -1.444~0.111

[Rare Tumors 2009; 1:e35] [page 107]

Article
leaflet were dense and lumpy. Three calcifica-
tion lesions were dense and thick. These
lesions measured 0.95±0.49 (0.4-1.8) cm,
while 4 papillary fibroelastomas were ≤1cm,
and one papillary fibroelastoma was larger
than 1cm. Estimation of the z-scores of the
dimensions of these lesions also showed the
papillary fibroelastoma or the calcification
lesions were smaller than the myxoma and
thrombi (Table 2). All the patients recovered
favorably. Their hospital stay was 5±1.73 (3-8)
days after surgery. All patients were doing well
without recurrence on a regular post-operative
follow-up.
Discussion
Valvular tumors are rare. Yater was the first to
describe valvular tumors in 1931.5 They area
characterized by a smaller size, greater mobility,
and more significant tendency to embolize by
way of tumor fragments or thrombus formed
around the tumor than the intramural tumors.6,7
In the past, most valvular tumors were located
incidentally by autopsy. Nowadays, the develop-
ment of non-invasive diagnostic tools, such as
echocardiography, computed tomography and
magnetic resonance imaging, has greatly con-
tributed to the prompt evaluation of valvular
tumors.7
The majority of valvular tumors are papillary
fibroelastomas, with aortic valve being the
most commonly affected valve (52%), followed
by the mitral valve (16%).7,8 Cardiac papillary
fibroelastomas although rare, constitute the
second cause of benign cardiac tumors. They
predominantly affect cardiac valves and
account for most cases of valvular tumor. Its
true incidence is unknown.9 Papillary fibroelas-
tomas are usually smaller than 1cm, attached to
the valve by a short stalk, thereby having
greater freedom and mobility, which might
explain the frequent occurrence of embolic
events.7 Papillary fibroelastomas can be reliably
diagnosed by echocardiography.10 Myxomas are
the most common primary cardiac tumors with
a growing predilection on the intraatrial sep-
tum of the left atrium.11 Valvular myxomas are
exceedingly rare accounting for 8.8% of cardiac
myxomas.12 They are gelatinous, lobulated
tumors, often solitary with a short stalk.11
Echocardiography is very helpful in the evalua-
tion of a suspected valvular myxoma in deter-
mining the location, size, attachment, and
influence on valve function.10 Myxoma differs
histologically from the cardiac papillary fibro-
elastoma by the presence of polygonal myxoma
cells and blood vessels in the papillae, while the
cardiac papillary fibroelastoma is of avascular
structure in the papillae.7 Surgical excision of
the myxoma should be performed after the
diagnosis without delay. The pedicle or broad
[page 108]
base of the tumor along with adjacent endo-
cardium should be removed. Cardiac thrombi
are more common than tumors, and timely
diagnosis and treatment are mandatory. Atrial
fibrillation,13 mitral valve dysfunction,14 patent
foramen ovale,15 carotid artery stenosis,16 poly-
cythemia vera, and a history of peripheral arte-
rial thrombosis17 have been identified as pre-
disposing risk factors for intracardiac throm-
bus formation. Valvular thrombus is also
mobile and small extending about 1 cm in size.
Most thrombi are sessile without a stalk.
However, there have been a few reported cases
in which valvular thrombi were pedicled by a
stalk1,18 and were larger than 2 cm.1 From the
present study, we observed that the dimensions
of the valvular masses formed a sequence of
thrombus > myxoma > papillary fibroelastoma
> calcification, which might be indicative of
differential diagnoses between each other.
Equivocal findings by an echocardiography
might be ascertained by magnetic resonance
imaging which demonstrates increased signal
intensity on T1-weighted, and uniform reduced
signal intensity on T2-weighted images.19
Valvular calcification or abscess is usually asso-
ciated with severe valve dysfunction and is eas-
ily distinguished from valvular tumors by
echocardiography. However, in atypical cases,
these lesions might be tumor-like and make
diagnoses difficult. One important feature of
mitral annular calcification is a heterogeneous
echo signal combining a calcified region and
soft tissue, which may extend to the anterior
mitral leaflet.20 In extreme cases of mitral valve
abscesses, definite diagnoses can only be
obtained during surgery.3 In summary, valvular
tumors and tumor-like lesions are rare. They
may have similar morphological and clinical
characteristics, such as round appearance,
small size, high mobility with movement of the
valves, predisposition for embolic events, and
amenable to surgical resection. All these small
lesions have little influence on related leaflet
function. The tumors differ from the thrombus
by a round, friable, and pedicled mass com-
pared with the thick, dense, and sessile lesion
of the latter. Degree of mobility of the valvular
masses on echocardiography might be helpful
in differentiating tumors from tumor-like
lesions. Patients with a valvular tumor are usu-
ally younger than those with a tumor-like
lesion. Valvular tumors and tumor-like lesions
place the patients at a high risk of stroke in dif-
ferent ways. Valvular tumor and tumor-like
lesions accounted for 0.34% of adult cardiac
operations. Pre-operative differential diag-
noses among these valvular lesions pose impor-
tant clinical implications for appropriate treat-
ment for the underlying diseases. Prompt sur-
gical resection is necessary to prevent potential
embolic events. Port access is a practical
approach for some valvular lesions in selected
patients.
[Rare Tumors 2009; 1:e35]
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[page 109]
Rare Tumors 2009; volume 1:e36
Treatment outcome of
maxillary sinus cancer
Hye Sung Won,1,7 Sang Hoon Chun,1,7
Bum-soo Kim,1,2 So Ryoung Chung,1,2
Ie Ryung Yoo,1,3 Chan-Kwon Jung,1,4
Yeon-Sil Kim,1,5 Dong-il Sun,1,6
Min Sik Kim,1,6 Jin-Hyoung Kang,1,7
1
Head and Neck Cancer Interdisciplinary
Team, Departments of 2Diagnostic
Radiology, 3Nuclear Medicine, 4Hospital
Pathology, 5Radiation Oncology,
6
Otorhinolaryngology, 7Medical Oncology,
The Catholic University of Korea, College
of Medicine, Seoul, Korea
Abstract
The standard treatment in the early stage of
maxillary sinus cancer is surgical resection
followed by postoperative radiation therapy.
However, for locally advanced maxillary sinus
cancer, a multimodality treatment approach is
strongly recommended to improve the survival
rate and quality of life of the patient. We deter-
mined the treatment outcomes of induction
chemotherapy, concurrent chemoradiation
therapy, and surgical resection for locally
advanced maxillary sinus cancer. Forty-four
patients with locally advanced maxillary sinus
cancer, who had been treated between January
1990 and April 2008 at Kangnam St. Mary's
Hospital, were retrospectively analyzed. The
objective response rates were 70%, 53%, and
57% in the intra-arterial induction chemother-
apy, intravenous induction chemotherapy, and
concurrent chemoradiation therapy groups,
respectively. The orbital preservation rates
were 83%, 100%, and 75% in the intra-arterial
induction chemotherapy, intravenous induc-
tion chemotherapy, and surgical resection
groups, respectively. In seven of nine patients
in whom the orbit could be preserved after
induction chemotherapy, the primary tumors
were removed completely. However, although
the orbits were preserved in three patients
who underwent surgical resection as a primary
treatment, all three cases were confirmed to be
incomplete resections. We found that active
induction chemotherapy for locally advanced
cancer of the maxillary sinus increased the
possibility of complete resection with orbital
preservation as well as tumor down-staging.
Introduction
Malignant tumors of the maxillary sinus are
rare neoplasms that account for approximately
[page 110]
3% of head and neck cancers and 0.5% of all
malignant diseases. The annual incidence of
maxillary sinus cancer is 0.5-1.0 case per
100,000 of the population.1 Squamous cell car-
cinoma is the most common histologic type,
accounting for approximately 70-80% of the
cancers. The other histologic types of maxillary
sinus cancer include adenoid cystic carcino-
mas, adenocarcinomas, mucoepidermoid car-
cinomas, sarcomas, and lymphomas. Smoking
and histories of chronic sinusitis are the most
common risk factors for maxillary sinus can-
cer. In addition, occupational exposure to
chemical substances, such as formaldehyde,
chromium, nickel, and air pollution is associat-
ed with an increased risk for malignant tumors
of the maxillary sinus.2
Most patients with maxillary sinus cancer
have no symptoms in the early stage and,
therefore, many of these patients are diag-
nosed in the advanced stage of the disease.
The complexity of the anatomy and the proxim-
ity of the eyes, brain, and cranial nerves render
complete surgical resection difficult, which
leads to local recurrence, a major cause of
treatment failure.3 The other issues pertaining
to maxillary sinus cancer include the function-
al aspects of eyesight and the cosmetic aspects
of facial contours, which make patients avoid
surgical resection.
The standard treatment for maxillary sinus
cancer has been surgical resection with or
without orbital exenteration, followed by post-
operative radiation therapy. However, in the
advanced stages, tumor control and survival
rate are still considered to be unsatisfactory,
with a local control rate of 50-60% and a five-
year disease-specific survival rate of 30-50%.3,4
Since the late 1970s, multimodality treatments
have been investigated for the treatment of
locally advanced maxillary sinus cancer, with
the purpose of improvement in tumor control
rate and reduction of functional impairment.
Notably, induction chemotherapy (ICT) and
concurrent chemoradiation therapy (CCRT)
are the most common multimodality treat-
ments for stages III and IV locally advanced
maxillary sinus cancer. We investigated the
treatment outcomes including orbital preser-
vation, complete resection, pathologic down-
staging, and relapse patterns in patients with
locally advanced maxillary sinus cancer who
underwent ICT, CCRT, and surgical resection.
Materials and Methods
Patients
Seventy-five patients who had been diag-
nosed with maxillary sinus cancer at Kangnam
St. Mary's Hospital between 1 January 1990
and 30 April 2008 were reviewed. Among these
patients, 10 received only palliative care owing
[Rare Tumors 2009; 1:e36]
Correspondence: Jin-Hyoung Kang, Division of
Oncology, Department of Internal Medicine,
Seoul St. Mary's Hospital, The Catholic
University of Korea, 505 Banpo-Dong, Seocho-Gu,
Seoul 137-701, Korea.
E-mail: jinkang@catholic.ac.kr
Key words: maxillary sinus cancer, induction
chemotherapy, intra-arterial chemotherapy,
organ preservation.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 11 August 2009
Revision received: 16 September 2009.
Accepted for publication: 17 September 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright H.S. Won et al., 2009
Rare Tumors 2009; 1:e36
doi:10.4081/rt.2009.e36
to poor performance status, and seven patients
with a history of prior surgery or chemothera-
py were excluded. In addition, fourteen
patients with malignant lymphomas or soft tis-
sue sarcomas were excluded. Finally, 44
patients were analyzed and reviewed on the
basis of their medical records, pathology slides
and interpretation reports, and imaging stud-
ies. The following data were collected: age,
gender, performance status, histopathologic
diagnosis, tumor staging, orbital invasion,
treatment modalities, recurrences, and sur-
vival rates.
A detailed assessment of the tumor extent
was performed in all patients, based on CT
scans and/or MRI including the maxillary sinus
and skull base. The orbital invasion was deter-
mined on these findings: contact of the mass
with the lamina papyracea, erosion or destruc-
tion of the medial and/or inferior orbital wall,
and invasion of the periorbital soft tissue
including the optic nerves and extraocular
muscles. Tumor staging was done using the
2006 edition of the American Joint Committee
on Cancer (AJCC) classification, and retro-
spective restaging was done in previously diag-
nosed patients. The performance status was
evaluated according to Eastern Cooperative
Oncology Group (ECOG) criteria.
Chemotherapy
One of four different treatment modalities,
including intra-arterial (IA)-ICT, intravenous
(IV)-ICT, CCRT, and surgical resection, was
selected as a primary treatment based on the
TNM stage, performance status, age, and co-
morbidity. ICT was administered through the
IA or IV route. Superselective IA infusion of
chemotherapeutic drugs was attempted via a

series of processes. The contrast-enhanced
tumor mass and tumor feeding vessels were
confirmed via diagnostic angiographic proce-
dures of the internal and external carotid
arteries by means of transfemoral access. The
internal maxillary artery was superselected
with a microcatheter, and then the chemother-
apeutic drug was administered via a micro-
catheter into the tumor-supplying artery. The
transfemoral catheter was removed on comple-
tion of the infusion. Cisplatin (100 mg/m2) was
administered via a microcatheter into the
internal maxillary artery over two hours on day
1, and then 5-FU (1000 mg/m2/day) was contin-
uously infused from day 1 to day 5 over 120
hours through the IV route. A standard hydra-
tion and mannitol diuresis regimen were
applied. The entire procedure was repeated 2-
3 times every 3-4 weeks.
The IV-ICT was performed 2-3 times every
four weeks as well. Cisplatin (100 mg/m2) was
administered intravenously over two hours on
day 1, and 5-FU (1000 mg/m2/day) was infused
continuously from day 1 to day 5 over 120
hours through the IV route. All patients who
received ICT were re-evaluated for tumor
response with CT and/or MRI at least 4-6
weeks after the completion of ICT. The deci-
sion to perform surgery after ICT was based on
the tumor response.
The chemotherapeutic agent used in the
CCRT group was cisplatin. During radiation
therapy, cisplatin (30 mg/m2) was adminis-
tered by a weekly schedule on days 1, 8, 15, 22,
29, 36, 43, and 50, or cisplatin (100 mg/m2) was
administered every 3 weeks on days 1, 22, and
43. All patients treated with CCRT were re-
evaluated for tumor response, and then the
next treatment modality, surgical resection or
salvage chemotherapy, was determined. The
periodic follow-up was done at least 6-8 weeks
after the completion of radiation therapy.
Surgical resection and radiation
therapy
In most cases, a total maxillectomy with orbital
preservation was carried out. However, if the
tumor mass extended to the lamina papyracea
and invaded the orbit and muscles, an orbital
exenteration with a total maxillectomy should be
performed. The patients with metastatic cervical
lymphadenopathy underwent a modified radical
neck dissection. Three-dimensional conformal
radiation therapy (3DCRT) was applied as an
external radiation therapy technique. The total
dose of 55-60 Gy with 1.8-2.0 Gy daily fractions
five times per week was given to the clinical tar-
get volume (CTV) in postoperative adjuvant radi-
ation therapy. In the case of CCRT, the total dose
of 70-75 Gy in 35-40 fractions was given with a
shrinking-field technique; 50 Gy was given to the
CTV with daily fractions of 1.8 Gy five times per
week, and followed by 20-25 Gy to the gross
tumor volume (GTV).
Evaluation of treatment outcomes
The primary end point of our study was the
response rate of the primary treatment modal-
ities (IA-ICT, IV-ICT, and CCRT). For the evalu-
ation of tumor response, a physical examina-
tion, nasal endoscopy, and CT or MRI were per-
formed. Tumor response was assessed accord-
ing to the RECIST criteria (version 1.0). An
objective tumor response was defined as more
than partial response (PR). When recurrence
or distant metastasis was suspected, PET-CT
and other imaging studies of suspicious
lesions were performed and, if needed, con-
firmed by biopsy.
The secondary end points were the complete
resection and orbital preservation rates in
patients who underwent surgical resection
after ICT and surgical resection as a primary
treatment. Complete resection was defined as
where there were no microscopic residual
tumor cells on the resection margin, and
incomplete resection was defined as where
there were residual tumors on the resection
margin, identified by gross and/or microscopic
examination. Orbital preservation was defined
as when a case underwent total maxillectomy
without orbital exenteration, among the
patients with the evidence of orbital invasion
on physical examinations and/or imaging stud-
ies at the time of diagnosis.
The tertiary end points were overall survival,
recurrence rate, and the toxicity profile.
Overall survival was defined as from the date
Table 1. Patient characteristics.
Patient characteristics (n=44)
Gender (male/ female)
Median age (years, range)
ECOG performance
0/1/2
Histologic type
Squamous cell carcinoma
Adenoid cystic carcinoma
Adenocarcinoma
Myoepithelial carcinoma
Undifferentiated carcinoma
TNM stage
II/III/IVa/IVb
Tstage
T2/T3/T4a/T4b
Nstage
N0/N1/N2
Orbit invasion
yes/ no
Treatment modalities
†
IA-ICT/‡IV-ICT
§
CCRT/Surgical resection
†
IA-ICT: intra-arterial induction chemotherapy, ‡IV-ICT: intravenous induction chemotherapy, §CCRT:
concurrent chemoradiation therapy.
[Rare Tumors 2009; 1:e36]
Article
of diagnosis to the date of death or date of last
follow-up. The adverse events occurring during
ICT and CCRT were graded according to the
National Cancer Institute Common Toxicity
Criteria (NCI-CTC, version 2.0).
Statistical analysis
For categorical outcomes, between-group
comparisons were done using either the
Fisher’s exact test or a Chi-square test. The
overall survival curve was estimated using the
Kaplan-Meier method, and the log-rank test
was applied to assess statistical significance.
All statistical analyses were performed using
the SPSS program (version 13.0) and a p value
of <0.05 was considered as statistically signif-
icant.
Results
Patient characteristics
The clinical characteristics of the 44
patients are summarized in Table 1. The medi-
an age was 60 years (range 33-89 years) and
93% of patients were ECOG 0-1. The most com-
mon histopathologic subtype was squamous
cell carcinoma (n=31; 70%). Of the 44
patients, 12 patients (27%) underwent surgi-
cal resection as a primary treatment, and
among these patients there were six (50%)
with stage III, five (42%) with stage IV, and one
n (%)
30(68)/14(32)
60(33-89)
17(39)/24(54)/3(7)
31(70)
6(14)
4(9)
1(2)
2(5)
1(2)/10(23)/10(23)/23(52)
1(2)/10(23)/10(23)/23(52)
36(81)/5(11)/3(8)
31(70)/13(30)
10(23)/15(34)
7(16)/12(27)
[page 111]
Article
Article

(8%) with stage II tumors. Eleven patients

with stage III-IV tumors received postoperative Table 2. Tumor response according to treatment modalities.
adjuvant radiation therapy after surgical resec-
tion. Ten (23%), 15 (34%), and 7 (16%) Treatment modalities Tumor response p
†
patients received IA-ICT, IV-ICT, and CCRT, CR(n) ‡
PR(n) §
ORR(%)
respectively. Of the 25 patients who received
Induction chemotherapy 60 0.521
ICT, there were 21 (84%) with stage IV and 3
IA-ICT 0 7 70 0.311
(16%) with stage III tumors. All patients treat- IV-ICT 2 6 53
ed with CCRT were stage IV. The median dura-
CCRT 1 3 57
tion of follow-up was 16 months.
†
CR: complete response, ‡PR: partial response, §ORR: overall response rate.

Tumor response and toxicity

The objective response rates of ICT and
CCRT were 60% and 57%, respectively
(p=0.521). The objective response rates of IA- Figure 1. Orbital preserva-
ICT and IV-ICT were 70% and 53%, respective- tion and complete resection
ly (p=0.311) (Table 2). In the 10 patients who rate according to treatment
modalities. IA-ICT: intra-
received IA-ICT, no complete response (CR) arterial induction
was achieved, seven patients (70%) had a PR, chemotherapy, IV-ICT: intra-
one patient had stable disease (SD), and one venous induction chemother-
patient had progressive disease (PD). The apy.
intended chemotherapy was interrupted in one
patient because of acute, severe toxicity. In the
15 patients treated with IV-ICT, two (13%) had
a CR, six (40%) had a PR, three (20%) had SD,
and three (20%) had PD. One patient was lost
to follow-up. The most common acute toxicity
associated with these treatment modalities
was nausea and vomiting. The frequency of
nausea and vomiting in the IA-ICT, IV-ICT, and
CCRT groups was 70%, 87%, and 86%, respec-
tively (p=0.927). The patients treated with IA- 100 Figure 2. Overall survival
ICT experienced other adverse events: three curve of 44 patients with
patients had facial swelling, three had perior- maxillary sinus malignancies
80 by the Kaplan-Meier
bital pain, one had severe mucositis, and one method.
had transient dizziness.
Survival (%)

Orbital preservation and complete
resection rate
Seven (70%) of 10 patients in the IA-ICT
group and seven (47%) of 15 patients in the IV-
ICT group underwent surgical resection with
curative intent. Of these patients, those in
whom orbital invasion had been confirmed by
imaging studies at diagnosis were six and four
patients in the IA-ICT and IV-ICT groups,
respectively. Orbital preservation was possible
in five (83%) of six patients treated with IA-
ICT and in all four (100%) patients treated
with IV-ICT. On the other hand, orbital inva-
sion was doubtful in four of 12 patients who
underwent surgical resection as a primary
treatment, and orbital preservation was possi-
ble in three (75%) of four patients. Therefore,
there were no statistically significant differ-
ences in the orbital preservation rates between
the ICT and surgical resection groups
(p=0.505). Seven (78%) of nine patients with
orbit preservation in the ICT group had com-
plete resections. However, all three patients
with orbital preservation in the primary surgi-
cal resection group had incomplete resections.
Therefore, a higher complete resection rate
60
40
20
0
0 30 60
Time (months)
was achieved in the patients who underwent
surgical resection after ICT (Figure 1).
Pathologic down-staging by ICT
Of the 14 patients who underwent ICT fol-
lowed by surgical resection, the 10 patients
with T4 tumors were available for pathologic
tumor response. Nine (90%) of 10 patients
were shown to have pathologic down-staging
of the primary tumor after ICT. Among the 10
patients with clinical T4, five had pT3, three
had pT1, and one had a pathologic CR (pT0).
All cases with remarkable down-staging to pT1
and pT0 were observed in the IA-ICT group.
90 120 150 180
Overall survival and recurrence rate
The overall survival curve of the 44 patients
is shown in Figure 2. The overall survival rate
for these 44 patients was 60% at three years
and 53% at five years.
The three-year survival rate was 57% and
50% in the IA-ICT and IV-ICT group, respective-
ly (p=0.665). The most common cause of death
was disease progression. Two of 10 patients in
the IA-ICT group died; one patient owing to
disease progression and the other patient
because of infectious disease after relapse
with lung metastasis. Five of 15 patients in the
IV-ICT group died; three as a result of disease

[page 112] [Rare Tumors 2009; 1:e36]


progression and two owing to infectious dis-
ease accompanied by disease progression. Of
the 12 patients in the surgical resection group,
eight were still alive without recurrence for
more than two years, but three of four patients
with recurrences died of disease progression
and one person was lost to follow-up.
The recurrence patterns were as follows: in
seven patients who received IA-ICT followed by
surgical resection, no local recurrences were
identified except for one pulmonary metasta-
sis. In nine patients who received IV-ICT fol-
lowed by surgical resection, three local recur-
rences and two distant metastases were
detected during the follow-up period. Hence,
the recurrence rates were 17% and 56% in the
IA-ICT and IV-ICT group, respectively. In the
surgical resection group, local recurrences
occurred in four (33%) of 12 patients.
In the ICT group, two patients with a posi-
tive resection margin died of local recurrence
within two years. In contrast, one of seven
patients with a tumor-free resection margin
died of local recurrence, and the six remaining
patients with squamous cell carcinoma had
long-term disease-free survival. In the surgical
resection group, one of three patients with a
positive resection margin died of a local recur-
rence, and the remaining two patients with
adenoid cystic carcinoma are alive still. Most
recurrences occurred within the first two years
after surgical resection or complete clinical
response to ICT, and those who had no recur-
rences within the first two years had a long-
term survival of more than five years.
Discussion
The prognosis of maxillary sinus cancer is
disappointing, despite aggressive treatments.
For successful treatment outcomes, it is neces-
sary to acquire complete surgical resection and
to secure adequate resection margins.
However, maxillary sinus cancers usually are
diagnosed at advanced stages, and the proximi-
ty of important organs such as the eyes and cra-
nial nerves makes complete surgical resection
difficult. In addition, functional impairments
after surgical resection are the major cause of a
decreased quality of life. Therefore, surgical
resection with a curative intent should be con-
sidered as a primary treatment only in the early
stages of the disease. In the advanced stages,
multimodality treatment strategies should be
arranged for prolongation of survival and
improvement in the quality of life.
CCRT is regarded as the more effective
treatment because of the radiosensitizing effi-
cacy of cisplatin compared with radiation ther-
apy alone. Several studies have demonstrated
that CCRT has a higher tumor control rate and
survival rate in head and neck cancers than
A B
C
radiation therapy alone.5 Harrison et al. report-
ed a three-year local control rate of 78% and a
three-year survival rate of 42% in 12 patients
with paranasal sinus carcinomas treated with
cisplatin-based CCRT.6 In this study, seven
patients with stage IV maxillary sinus cancer
received CCRT as a primary treatment, and the
objective response rate was 57%. However, the
assessments of recurrence and survival rate
were impossible because of small sample size
and loss to follow-up.
The most commonly used ICT in locally
advanced head and neck cancer is IV cisplatin
combined with a 5-FU continuous infusion. In
several studies, ICT produced an objective
response rate of 60-90% with a clinical CR of
20-50%.5 However, the antitumor efficacy of
ICT did not lead to a prolongation in overall
survival in every case.
To improve the antitumor efficacy, the addi-
tion of potent cytotoxic drugs such as docetax-
el to a standard chemotherapy regimen or
development of new drug delivery methods has
been investigated actively. As one of the drug
delivery methods, a superselective IA infusion
of chemotherapeutic drugs has been proposed
as an ICT in locally advanced head and neck
cancers. Direct infusion of chemotherapeutic
drugs to the feeding vessels exposed a high
concentration of drug to the tumor cells; there-
[Rare Tumors 2009; 1:e36]
Article
Figure 3. A case of a T4b maxillary sinus
cancer patient with: (A) magnetic reso-
nance imaging at diagnosis; (B) magnet-
ic resonance imaging after completion
of three cycles of intra-arterial induction
chemotherapy with cisplatin and intra-
venous 5-FU; (C) magnetic resonance
imaging six months after total maxillec-
tomy with flap reconstruction.
fore, more potent antitumor efficacy with
lower systemic toxicity was expected.7 IA
chemotherapy may be more effective when it is
administered as an initial treatment. Because
prior surgery or radiation impairs the blood
supply to the tumor bed, it makes local delivery
of chemotherapeutic drugs difficult. Although
the majority of head and neck cancers are
diagnosed at advanced stages of the disease,
distant metastases are rarely detected at the
time of presentation. Moreover, maxillary
sinus cancers are confined to the territory of
the terminal branch of the internal maxillary
artery; therefore, they are suitable for the local
infusion of chemotherapeutic drugs.8,9
Robbins et al. reported a higher objective
response rate of 92%, with a CR of 88% in 76
patients with head and neck cancers treated
with IA cisplatin and concomitant radiation
therapy.10 In another study, a five-year survival
rate of 53% was reported, with a local recur-
rence rate of 15% in 19 patients with locally
advanced paranasal sinus cancers who under-
went surgical resection after IA chemotherapy
combined with concomitant radiation therapy.
Orbital preservation was possible in three of
four patients with orbital invasion.4 Lee et al.
presented their clinical experiences with
superselective IA cisplatin combined with IV 5-
FU in advanced paranasal sinus cancers.11
[page 113]
Article
Forty-three percent of 21 evaluated patients
had a CR and 48% of the patients had a PR,
with an objective response rate of 91%. In our
study, either IA-ICT or IV-ICT was performed as
an ICT. The objective response rate in the IA-
ICT group was 70%, which was similar to pre-
vious results, and the objective response rate
in the IV-ICT group was 53%. There were no
statistically significant differences in the
response rate and toxicities between the two
groups.
The orbital preservation rates in the
patients with paranasal sinus tumors, who
received the ICT followed by surgical resection
or CCRT, have been reported to be approxi-
mately 50-70%.12,13 In this study, orbital preser-
vation was possible in five of six patients in
the IA-ICT group and all four patients in the IV-
ICT group. Although orbital preservation was
possible in three of four patients who under-
went surgical resection as a primary treat-
ment, incomplete resection with a positive
resection margin was finally ascertained in
these three patients. On the other hand, in
nine patients who underwent ICT followed by
surgical resection with orbit preservation,
incomplete resection was confirmed in only
two patients. Most of the patients with a posi-
tive resection margin experienced a local
recurrence during the follow-up, which led to a
disease progression and then death.
A case of a patient with locally advanced
maxillary sinus cancer is shown in Figure 3.
This patient was diagnosed with T4b maxillary
sinus cancer with orbital invasion in May
2007. She received three cycles of IA-ICT with
cisplatin and IV 5-FU, and then underwent
total maxillectomy with orbital preservation
and flap reconstruction. On the pathologic
reports, the tumor was removed nearly com-
pletely but close to a margin. She received
postoperative radiation therapy. She has
remained disease free to date.
Several studies have demonstrated that a
pathologic CR has a closer relationship than a
clinical CR with survival.14 In the current study,
the pathologic down-staging of the primary
tumor in the patients treated with ICT followed
by surgical resection was evaluated. In 10
cases of T4 tumors, pathologic down-staging
after the ICT was identified in nine cases with
one pathologic CR. In addition, IA-ICT was
more effective with respect to pathologic
tumor down-staging compared with IV-ICT. It is
thought that the first-passage effect and expo-
sure to higher local concentrations during IA
cisplatin have a major role in effective down-
staging.15,16 There were no statistically signifi-
cant differences in survival rate between the
[page 114]
IA-ICT and IV-ICT groups. However, the local
recurrence rate was lower in the IA-ICT group
than in the IV-ICT group.
The limitation of this study is that it is a ret-
rospective, relatively small sample size evalua-
tion. Additionally, a discrepancy in clinical
characteristics between groups existed.
Patients diagnosed with a more advanced
staged tumor or orbital invasions were more
likely to receive ICT than surgery; therefore,
comparing survival according to treatment
modalities was difficult. However, clinical
characteristics between the IA-ICT and IV-ICT
groups were comparable and the comparison
of these two groups may bear significance.
Conclusion
From our study we conclude that ICT in
locally advanced maxillary sinus cancers
increased the possibility of tumor down-stag-
ing and complete resection with orbital preser-
vation. Although there were no significant dif-
ferences in response rate and toxicity profile
between the two groups of ICT, IA-ICT was
superior to IV-ICT with respect to tumor down-
staging and local tumor control. In the future,
a large-sized, prospective randomized study to
compare ICT followed by surgical resection
with surgical resection alone is warranted clin-
ically as a primary treatment for locally
advanced maxillary sinus cancers.
References
1. Dulguerov P, Jacobsen MS, Allal AS, et al.
Nasal and paranasal sinus carcinoma: are
we making progress? A series of 220
patients and a systematic review. Cancer
2001;92:3012-29.
2. Spiro JD, Soo KC, Spiro RH. Squamous
carcinoma of the nasal cavity and
paranasal sinuses. Am J Surg 1989;158:
328-32.
3. Nishino H, Ichimura K, Tanaka H, et al.
Results of orbital preservation for
advanced malignant maxillary sinus
tumors. Laryngoscope 2003;113:1064-9.
4. Samant S, Robbins KT, Vang M, et al. Intra-
arterial cisplatin and concomitant radia-
tion therapy followed by surgery for
advanced paranasal sinus cancer. Arch
Otolaryngol Head Neck Surg 2004;130:948-
55.
5. Monnerat C, Faivre S, Temam S, et al. End
[Rare Tumors 2009; 1:e36]
points for new agents in induction
chemotherapy for locally advanced head
and neck cancers. Ann Oncol 2002;13:995-
1006.
6. Waldron JN, O'Sullivan B, Gullane P, et al.
Carcinoma of the maxillary antrum: a ret-
rospective analysis of 110 cases. Radiother
Oncol 2000;57:167-73.
7. Fujishiro Y, Nakao K, Watanabe K, et al. A
new aspect of tri-modal therapy with
superselective intra-arterial chemothera-
py in maxillary sinus carcinoma. Acta
Otolaryngol Suppl 2007;559:151-6.
8. Forastiere AA, Baker SR, Wheeler R, et al.
Intra-arterial cisplatin and FUDR in
advanced malignancies confined to the
head and neck. J Clin Oncol 1987;5:1601-6.
9. Wilson WR, Siegel RS, Harisiadis LA, et al.
High-dose intra-arterial cisplatin therapy
followed by radiation therapy for advanced
squamous cell carcinoma of the head and
neck. Arch Otolaryngol Head Neck Surg
2001;127:809-12.
10. Rabbani A, Hinerman RW, Schmalfuss IM,
et al. Radiotherapy and concomitant intra-
arterial cisplatin (RADPLAT) for advanced
squamous cell carcinomas of the head and
neck. Am J Clin Oncol 2007;30:283-6.
11. Lee YY, Dimery IW, Van Tassel P, et al.
Superselective intra-arterial chemothera-
py of advanced paranasal sinus tumors.
Arch Otolaryngol Head Neck Surg 1989;
115:503-11.
12. Kerber CW, Wong WH, Howell SB, et al. An
organ-preserving selective arterial
chemotherapy strategy for head and neck
cancer. Am J Neuroradiol 1998;19:935-41.
13. Urba SG, Forastiere AA, Wolf GT, et al.
Intensive induction chemotherapy and
radiation for organ preservation in
patients with advanced resectable head
and neck carcinoma. J Clin Oncol 1994;
12:946-53.
14. Nazar G, Rodrigo JP, Llorente JL, et al.
Prognostic factors of maxillary sinus
malignancies. Am J Rhinol 2004;18:233-8.
15. Gouyette A, Apchin A, Foka M, et al.
Pharmacokinetics of intra-arterial and
intravenous cisplatin in head and neck
cancer patients. Eur J Cancer Clin Oncol
1986;22:257-63.
16. Sileni VC, Fosser V, Maggian P, et al.
Pharmacokinetics and tumor concentra-
tion of intra-arterial and intravenous cis-
platin in patients with head and neck
squamous cancer. Cancer Chemother
Pharmacol 1992;30:221-5.

Invasive neuroendocrine tumor
of the kidney: a case report
Ephrem O. Olweny,1 Michael H. Hsieh,2
Jill C. Buckley,3 Jack W. McAninch1
Departments of Urology: 1University of
California, San Francisco, 2Stanford
University School of Medicine, 3Lahey
Clinic, Burlington, MA, USA
Abstract
Neuroendocrine tumors (NETs) involve the
genitourinary system in less than 1% of cases,
with primary renal carcinoids comprising only
19% of reported genitourinary NETs (56 cases
worldwide). We report a case of a renal NET
presenting as a large renal mass with exten-
sive local invasion, requiring definitive radical
en bloc resection via a thoracoabdominal
approach.
Introduction
The neuroendocrine cell system is divided
into gland-forming cells, such as the pituitary,
parathyroids, adrenal medulla etc., and dis-
seminated neurodendocrine cells, such as
those found in the lung, gastrointestinal tract
and genitourinary tract among other organs.
Tumors arising from the disseminated neu-
roendocrine sytem within the genitourinary
tract are referred to as carcinoids by the WHO
classification.1 In a recent comprehensive
review of the world’s literature, Romero et al.
reported on 56 cases of primary renal carci-
noids, extirpated by partial or radical nephrec-
tomy.2 To our knowledge, we report the first
case of a renal NET exhibiting wide local inva-
sion (diaphragm, pancreas, spleen and left
colon mesentery), requiring en bloc radical
resection through a thoracoabdominal
approach.
Case Report
A 61-year old woman, an immigrant from
Panama, presented in her home country with
vague abdominal pain. She was diagnosed
with diverticulitis in lieu of imaging, and was
treated conservatively. Six months subse-
quently, she had progressively worsened
abdominal pain as well as a 20lb weight loss.
An abdominal ultrasound and follow-up CT
scan revealed a large left renal mass which
was deemed unresectable. She traveled to the
Rare Tumors 2009; volume 1:e37
United States for a second opinion.
On presentation, she was an otherwise Correspondence: Ephrem O. Olweny, Department
healthy thin woman with a palpable minimally of Urology, University of California, Box 0738 400
tender mass in her left flank. A CT scan of the Parnassus Avenue, San Francisco, CA 94143, USA
abdomen and pelvis (Figure 1) showed a 16 cm E-mail: eolweny@gmail.com
necrotic renal mass invading into the tail of
the pancreas, spleen, and omentum, with Key words: neuroendocrine tumors, kidney,
surgery.
marked displacement of intraabdominal
organs. No metastatic lesions were identified. Contributions: EOO primary author and partici-
Clinical staging by chest CT and bone scan was pating surgeon; MHH and JCB co-authors and
negative for metastases. A magnetic reso- participating surgeons; JWM supervising partici-
nance imaging (MRI) of the abdomen showed pating surgeon and consultant on manuscript
no evidence of renal vein or IVC thrombus. preparation and submission; EOO primary author
She undwerwent uncomplicated en bloc and participating surgeon; MHH and JCB co-
resection, through a thoracoabdominal authors and participating surgeons; JWM super-
approach, of the left kidney, left adrenal, cuff of vising participating surgeon and consultant on
manuscript preparation and submission.
diaphragm, spleen, tail of pancreas and part of
the left colon, with a primary colocolostomy
Conflict of interest: the authors report no con-
(Figure 2). The diaphragm was closed primari-
flicts of interest.
ly and a tube thoracostomy placed. Her post-
operative recovery was unremarkable, with Received for publication: 14 September 2009.
discontinuation of the chest tube and advance- Accepted for publication: 16 September 2009.
ment to a regular diet by post-operative days 3
and 6, respectively. Pathological diagnosis was This work is licensed under a Creative Commons
a low-grade neuroendocrine tumor of Attribution 3.0 License (by-nc 3.0).
unknown primary, but with total replacement
©Copyright E.O. Olweny et al., 2009
of the left kidney and involvement of all resect- Rare Tumors 2009; 1:e37
ed organs except for the adrenal gland and the doi:10.4081/rt.2009.e37
wall of the left colon (but the colon mesentery
was involved). Resection margins were nega-
tive. There was histological variation, with a
dominant multinodular pattern composed of Previous case reports have described resec-
nests and trabeculae (Figure 3A and B) with tion of renal carcinoids up to 30 cm in size by
focal spindled morphology (Figure 3C). Tumor partial or radical nephrectomy.7-10 However,
cells were small, with small nuclei and moder-
ate cytoplasm. Immunohistochemistry was
positive for keratin, chromogranin (Figure 3D
and E), neuron-specific enolase, and synapto-
physin (consistent with neuroendocrine carci-
noma), and negative for markers of fibroblasts
and smooth muscle. An octreotide scan one
month post-operatively was limited, but was
negative for evidence of residual or recurrent
disease.
Discussion
Disseminated neuroendocrine cells are also
known as enterochromaffin cells or amine pre-
cursor uptake and decarboxylation (APUD)
cells. They are rare in the genitourinary tract,
but have been identified in the bladder trigone,
prostate, and the renal collecting system. They
are absent in the renal parenchyma.3,4 Tumors
arising from these cells are extraordinarily
rare, particularly within the kidney. Indeed, to
date, only 56 reported cases of primary renal
carcinoid tumors have been described.
Pathogenesis is controversial,5 and there is a
common association between the presence of
Figure 1. CT scan of the abdomen and
these tumors and renal anomalies, particularly pelvis.
horseshoe kidneys.6
[Rare Tumors 2009; 1:e37] [page 115]
Care Report
Figure 2. Surgical specimen.
although liver and lymph node metastases
were commonly observed with larger tumors,
extensive local invasion in the absence of
metastatic disease, as described in the above
case, has not been previously reported. Within
the gastrointestinal tract, invasive behavior of
carcinoid tumors is rare, and is associated
with poorly differentiated or sporadic tumors,
with angioinvasion and metastatic spread at
time of diagnosis commonly identified.11 As
demonstrated in the case reported, extensive
local invasion in the absence of metastatic
spread does not preclude complete surgical
resection. Evidence of complete extirpation
was negative by octreotide scintigraphy one
month post-operatively. Octreotide scintigra-
phy has been described as a useful adjunctive
diagnostic tool in detecting residual or occult
metastatic carcinoid tissue following surgical
resection.9 However, long-term follow-up is
required as metastatic disease up to seven
years following treatment has been reported.
References
1. Kloppel G. Tumour biology and histo-
pathology of neuroendocrine tumours.
Best Pract Res Clin Endocrinol Metab
2007;21:15-31.
2. Romero FR, Rais-Bahrami S, Permpong-
kosol S, et al. Primary carcinoid tumors of
the kidney. J Urol 2006;176: 2359-66.
3. Raslan WF, Ro JY, Ordonez NG, et al.
Primary carcinoid of the kidney. Immuno-
[page 116]
A B
C D
E
histochemical and ultrastructural studies
of five patients. Cancer 1993;72:2660-6.
4. di Sant'Agnese PA. Neuroendocrine cells
of the prostate and neuroendocrine differ-
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of morphologic aspects. Urology 1998;51:
121-4.
5. Murali R, Kneale K, Lalak N, Delprado W.
Carcinoid tumors of the urinary tract and
prostate. Arch Pathol Lab Med 2006;130:
1693-706.
6. Krishnan B, Truong LD, Saleh G, et al.
Horseshoe kidney is associated with an
increased relative risk of primary renal
carcinoid tumor. J Urol 1997;157:2059-66.
7. Quinchon JF, Aubert S, Biserte J, et al
Primary atypical carcinoid of the kidney: a
[Rare Tumors 2009; 1:e37]
Figure 3. (A) Trabeculated pattern in kid-
ney. (B) Representative nested pattern in
pancreas. (C) Representative spindled pat-
tern in kidney. (D) Keratin stain. E.
Chromogranin stain.
classification is needed. Pathology 2003;
35:353-5.
8. Kojiro M, Ohishi H, Isobe H. Carcinoid
tumor occurring in cystic teratoma of the
kidney: a case report. Cancer 1976;38:
1636-40.
9. McCaffrey JA, Reuter VV, Herr HW, et al.
Carcinoid tumor of the kidney. The use of
somatostatin receptor scintigraphy in
diagnosis and management. Urol Oncol
2000;5:108-11.
10. Schlussel RN, Kirschenbaum AM, Levine
A, Unger P. Primary renal carcinoid tumor.
Urology 1993;41:295-7.
11. Akerstrom G. Management of carcinoid
tumors of the stomach, duodenum, and
pancreas. World J Surg 1996;20:173-82.

Bilateral angiosarcoma of the
breast in a fourteen-year-old
child
Albertus N. van Geel,1
Michael A. den Bakker2
Departments of 1Surgical Oncology and
2 and a simple mastectomy was performed. A
Pathology, Erasmus Medical Center/
Daniel den Hoed Cancer Center,
Rotterdam, The Netherlands
Abstract
Malignant vascular tumors are rare and
angiosarcomas of the breast in patients under
21 years of age are exceedingly uncommon. In
this report an angiosarcoma in the breast of a
14-year-old girl is described. She died nine
months after mastectomy with recurrent dis-
ease in the bones and the contralateral breast.
The etiology of most primary angiosarcomas is
unknown. Secondary angiosarcomas can
develop after radiotherapy and chronic lym-
phedema. The histology of this angiosarcoma
is illustrated.
Introduction
Malignant vascular tumors are extremely
rare in patients under 21 years of age. Among
228 vascular tumors in 222 children and ado-
lescents observed in a 25-year period, only
four (2%) were malignant [three angiosarco-
mas (AS) and one Kaposi sarcoma].1 In a
series of 99 AS from all sites, only a single 3-
year-old patient is described.2 The largest
series of malignant vascular tumors in the
English literature is reported by the Italian
and German Soft Tissue Cooperative Group.3
Among 18 patients with malignant vascular
tumors, 12 patients ranging from one to 16
years of age were diagnosed with AS. The
most frequent sites of AS in childhood are the
head and neck region, liver, and skin.2-4 They
have been reported also in the brain,5 heart,6
thoracic cavity,7 and mesentery.8 Primary sar-
comas of the breast are extremely rare and
only a few patients under the age of 21 years
have been described in an overview series.9,10
The ages were 13 and 16 years, but in one
series it is clear that the 15-year-old patient
had AS.11 To our knowledge our study is of the
second youngest patient to be reported with
AS in both breasts.12
Rare
RareTumors
Tumors2009;
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Case Report Correspondence: A.N. van Geel, Department of
Surgical Oncology, Erasmus Medical Center/
A 14-year-old girl was admitted to our hospi- Daniel den Hoed Cancer Center, Groene Hilledijk
tal with a rapidly enlarging mass in the right 301 3075, EA Rotterdam, The Netherlands.
E-mail: a.n.vangeel@erasmusmc.nl
breast. Histological findings of a needle biopsy
specimen were consistent with AS. Further Keywords: angiosarcoma, infancy, breast.
investigation did not reveal distant metastases
Received for publication: 29 May 2009.
complete resection was achieved with very Revision received: 13 August 2009.
close margins (Figure 1), and for that reason Accepted for publication: 2 September 2009.
the chest wall was irradiated with a dose of 60
This work is licensed under a Creative Commons
Gy in 33 fractions. The histology of the mastec- Attribution 3.0 License (by-nc 3.0).
tomy specimen showed the typical features of
AS composed of ramifying irregular vascular ©Copyright A.N. van Geel et al., 2009
structures in the breast tissue parenchyma Rare Tumors 2009; 1:e38
(Figure 2A). Atypical endothelial cells with doi:10.4081/rt.2009.e38
hyperchromatic nuclei varying in size lined the
vascular structures. Occasional multilayering
was present, with mitoses readily identified.
Focal solid areas of tumor cells were evident.
Immunohistochemical staining confirmed the
endothelial nature of the tumor cells with
strong staining for CD31, CD34, D2-40 (Figure
2B), and FVIII (not shown). After extensive
discussion with the pediatric oncology group
she received adjuvant therapy of six courses of
paclitaxel (175 mg/m2). Five months after sur-
gery she developed several bone metastases Figure 1. Gross appearance of the complete
resection of the right breast.
and the left humerus was irradiated. One
A
B
Figure 2. (A) Histological section of the right breast illustrating typi-
cal features of AS: ramifying irregular vascular structures, focal solid
areas of tumor cells, and multilayered cells with hyperchromatic
nuclei. Note (arrows) residual normal ductal structures embedded
within angiosarcoma tissue. Hematoxylin and eosin stain; 100X mag-
nification. (B) Immunohistochemical staining of the tumor cells for
CD31 (left), CD34 (middle), and D2-40(right); 50X magnification.
[Rare Tumors 2009; 1:e38] [page 117]
Case Report
month later the left breast showed a rapidly
enlarging tumor and subsequently multiple
local recurrences appeared on the right side. A
palliative simple mastectomy of the left breast
was performed (Figure 3). Three months later
and nine months after the first diagnosis she
died with bone metastases and an extensive
local recurrence of the disease.
Discussion
AS is a rare tumor and the etiology is
unclear in most cases. Prior irradiation after
conservative therapy for breast cancer is a
well-known risk for developing mammary AS.13
AS also occurs after chronic lymphedema fol-
lowing axillary and inguinal lymph node dis-
section.14 In children AS has been described
following radiotherapy for vascular disorders
at a very young age.15 Other documented risk
factors include: xeroderma pigmentosum,16
neurofibromatosis I,7 and exposure to vinyl
chloride.17 The diagnosis of AS in the breast
may be suspected on clinical examination
when red-blue discoloration of the skin is pres-
ent; in later stages nodular tumor growth
appears. The diagnosis may be supported fur-
ther by fine needle aspiration, in particular
when combined with immunocytochemistry.18
A tissue biopsy provides confirmation of the
diagnosis of AS. The treatment of choice is
surgery whether or not in combination with
radiotherapy. In contrast to small cell sarcomas
in children (Ewing’s sarcoma or primitive neu-
roectodermal tumor, and rhabdomyosarcoma),
[page 118]
Figure 3. Extensive
local recurrence
after bilateral mas-
tectomy and radio-
therapy on the
right side.
AS, like other non-small cell soft tissue sarco-
mas, are very insensitive to chemotherapy.18,19
The prognosis is very poor, with a five-year
survival rate of 20% or less.2,20,21
References
1. Coffin CM, Dehner LP. Vascular tumors in
children and adolescents: a clinicopatho-
logic study of 228 tumors in 222 patients.
Pathol Annu 1993;28:97-120.
2. Naka N, Ohsawa M, Tomita Y, et al. Angio-
sarcoma in Japan. A review of 99 cases.
Cancer 1995;75:989-96.
3. Ferrari A, Casanova M, Bisogno G, et al.
Malignant vascular tumors in children and
adolescents: a report from the Italian and
German Soft Tissue Sarcoma Cooperative
Group. Med Pediatr Oncol 2002;39:109-14.
4. Lezama-del Valle P, Gerald WL, Tsai J, et al.
Malignant vascular tumors in young
patients. Cancer 1998;83:1634-9.
5. Lach B, Hassounah M, Khafaga Y. Primary
angiosarcoma of the brain in a child. Fetal
Pediatr Pathol 2008;27:175-83.
6. Booth AM, LeGallo RD, Stoler MH, et al.
Pediatric angiosarcoma of the heart: a
unique presentation and metastatic pat-
tern. Pediatr Dev Pathol 2001;4:490-5.
7. Elli M, Can B, Ceyhan M, et al. Intra-
thoracic malignant peripheral nerve
sheath tumor with angiosarcoma in a child
with NF1. Tumori 2007;93:641-4.
8. Costa da Cunha Castro E, Galambos C,
Shaw P, et al. Primary mesenteric angio-
sarcoma in a child with associated lym-
[Rare Tumors 2009; 1:e38]
phangectasia: a case report. Pediatr Dev
Pathol 2008;11:482-6.
9. Bousquet G, Confavreux C, Magne N, et al.
Outcome and prognostic factors in breast
sarcoma: a multicenter study from the rare
cancer network. Radiother Oncol 2007;85:
355-61.
10. Rainwater LM, Martin JK Jr, Gaffey TA, et
al. Angiosarcoma of the breast. Arch Surg
1986;121:669-72.
11. Sher T, Hennessy BT, Valero V, et al.
Primary angiosarcomas of the breast.
Cancer 2007;110:173-8.
12. Kumar A, Gupta S, Chopra P, et al. Bilateral
angiosarcoma of the breast: an overview.
Aust NZ J Surg 1990;60:341-5.
13. Kirova YM, Gambotti L, De Rycke Y, Vilcoq
et al. Risk of second malignancies after
adjuvant radiotherapy for breast cancer: a
large-scale, single-institution review. Int J
Radiat Oncol Biol Phys 2007;68:359-63.
14. Offori TW, Platt CC, Stephens M, et al.
Angiosarcoma in congenital hereditary
lymphoedema (Milroy's disease)--diag-
nostic beacons and a review of the litera-
ture. Clin Exp Dermatol 1993;18:174-7.
15. Cancellieri A, Eusebi V, Mambelli V, et al.
Well-differentiated angiosarcoma of the
skin following radiotherapy. Report of two
cases. Pathol Res Pract 1991;187:301-6.
16. Marcon I, Collini P, Casanova M, et al.
Cutaneous angiosarcoma in a patient with
xeroderma pigmentosum. Pediatr Hematol
Oncol 2004;21:23-6.
17. Kirchner SG, Heller RM, Kasselberg AG, et
al. Infantile hepatic hemangioendothe-
lioma with subsequent malignant degen-
eration. Pediatr Radiol 1981;11:42-5.
18. Boucher LD, Swanson PE, Stanley MW, et
al. Cytology of angiosarcoma. Findings in
fourteen fine-needle aspiration biopsy
specimens and one pleural fluid specimen.
Am J Clin Pathol 2000;114:210-9.
19. Chui CH. Nonrhabdomyosarcoma soft tis-
sue sarcoma (NRSTS). Surg Oncol 2007;
16:187-93.
20. Koscielniak E, Jurgens H, Winkler K, et al.
Treatment of soft tissue sarcoma in child-
hood and adolescence. A report of the
German Cooperative Soft Tissue Sarcoma
Study. Cancer 1992;70:2557-67.
21. Mark RJ, Poen JC, Tran LM, et al.
Angiosarcoma. A report of 67 patients and
a review of the literature. Cancer 1996;
77:2400-6.
 Rare
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Primary extrauterine an overgrowth of endometrial-like stromal

endometrial stromal sarcoma:
response to hormone therapy
Gunjal Garg,1 Awoniyi O. Awonuga,1
Eugene P. Toy2
1 ever, stromal overgrowth with atypia and
Department of Obstetrics and
Gynecology, Wayne State University,
Detroit, MI; 2Division of Gynecologic
Oncology, Department of Obstetrics and
Gynecology, University of Rochester,
Rochester, NY, USA
Introduction
Endometrial stromal sarcomas (ESS) of the
uterus are hormone-sensitive tumors. There
have been reports in the literature confirming
the regression of ESS with progestins,
gonadotropin analogues, and aromatase
inhibitors. We report a case of primary
extrauterine ESS of the rectovaginal septum
(RVS), which was poorly responsive and, in
fact, progressed on progestin therapy. The
question arises: is the evident lack of
response to oral progestin in our case an
exception or a trend more commonly seen in
primary extrauterine, extraovarian ESS? To
the best of our knowledge, there has been no
report in the literature to address this ques-
tion. Therefore, we conducted a review of the
literature to evaluate the response of these
tumors to hormone therapy in relation to
their estrogen and progesterone receptor sta-
tus.
Case Report
A 45-year-old G3P0030 African American
woman underwent a supracervical hysterecto-
my and bilateral salpingo-oophorectomy for
chronic pelvic pain. The pathology report of
the surgical specimen confirmed the pres-
ence of endometriosis. Subsequently, six
years later, the patient presented with vaginal
bleeding, lower abdominal pain, dyspareunia,
and difficult defecation. Vaginal examination
showed active bleeding from an exophytic
polypoid mass in the posterior vaginal fornix.
Rectovaginal examination revealed a 4x3 cm
mass in the rectovaginal septum (RVS) and a
smooth rectal mucosa. Narrowing was noted
on proctoscopy at 8 cm distance owing to
extrinsic compression from the mass. The
vaginal polyp was removed and biopsies were
obtained from the adjacent normal-appearing
vaginal mucosa at the base of the mass. On
pathological examination, the lesion showed
cells with scattered benign-appearing
endometrial-type glands. Stromal cells
showed mild to moderate cytological atypia.
The tumor was positive for both estrogen and
progesterone receptors. The differential diag-
nosis included polypoid endometriosis; how-
mitosis favored a low-grade Mullerian
adenosarcoma. Gastrointestinal stromal
tumor (GIST), though a strong possibility
when masses are encountered in this loca-
tion, was ruled out effectively by morphology.
Additionally, immunohistochemical staining
with CD117 (not performed in our case) is
considered valuable in the diagnosis of GIST.
Given that the tumor was hormone receptor
positive, megestrol acetate was prescribed
initially for the patient in an attempt to shrink
the mass in the RVS. Despite hormone thera-
py progression of the tumor with increased
vaginal bleeding was noted. Therefore, the
patient underwent a posterior exenteration
with end-sigmoid colostomy four months after
her initial presentation. Pathological exami-
nation revealed a low-grade endometrial stro-
mal sarcoma (ESS). Subsequently, the patient
also received adjuvant radiation because of
copious mucoid material being present on
debulking, and she has remained disease free
at 18 months follow-up.
Table 1. Response to hormone therapy in primary extrauterine endometrial stromal sarco-
ma.
Author Site Treatment
of tumor
*Kusaka et al. Cul-de-sac
Lacroix-Trilki et al. Sciatic nerve
Present case Rectovaginal
septum
Only case reports of patients with extrauterine extraovarian ESS with follow-up data were included in the review. ER, estrogen receptor; PR, prog-
esterone receptor; GnRH, gonadotropin releasing hormone *High-grade tumor arising from endometriosis (all other cases had low-grade tumors).
Figure 1. High power view (magnification:
400X) of endometrial stromal sarcoma
with an entrapped benign gland (indicated
by the arrow) (Stain: hematoxylin and
eosin.)
Correspondence: Gunjal Garg, 3980 John R,
Detroit, MI, 48201, USA.
E-mail: gunjalgarg@yahoo.com
Key words: extrauterine, endometrial stromal
sarcoma, rectovaginal septum, hormone therapy
Contributions: ET conception and design; GG, AA
and ET manuscript writing; ET final approval of
the manuscript.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 12 July 2009.
Revision received: 16 September 2009.
Accepted for publication: 16 September 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright G. Garg et al., 2009
Rare Tumors 2009; 1:e39
doi:10.4081/rt.2009.e39
Discussion
Endometrial stromal sarcoma is a rare mes-
enchymal neoplasm that usually occurs as a
primary tumor of the uterus. However, it rarely
Treatment ER/PR status
response
GnRH analogue, danazol Disease progression Strongly positive
GnRH analogue Disease progression Strongly positive
Megestrol acetate Disease progression Strongly positive
Figure 2. Arrow indicating the area of
extensive endometriosis. (Stain: hema-
toxylin and eosin; magnification: 200X.)

[Rare Tumors 2009; 1:e39] [page 119]

Case Report
originates in sites other than the uterus and
ovaries. The role of hormone therapy is well
documented in primary low-grade ESS of the
uterus, in patients with no evidence of resid-
ual disease after surgical treatment as well as
in patients with advanced and recurrent dis-
ease. It has been shown to be effective, partic-
ularly in tumors that express both estrogen
and progesterone receptors and which have
demonstrable evidence of concomitant
endometriosis. Our case is unique, however,
because it was a low-grade tumor positive for
both estrogen and progesterone receptors; yet
the tumor progressed on progestin therapy. In
our review of the literature, we found two
other reports (Kusaka et al.,1 Lacroix-Triki et
al.2) describing patients with primary
extrauterine, extraovarian ESS in whom hor-
mone therapy alone was administered. The
treatment used and the clinical response rela-
tive to estrogen and progesterone receptor sta-
tus is summarized in Table 1.
Interestingly, all three patients (including
our case) shown in Table 1 did not respond to
hormone therapy. All reported associated
[page 120]
endometriosis. Two other patients3,4 received
hormone therapy in conjunction with
chemotherapy; however, it is not feasible to
assess independently the role of hormone ther-
apy in these cases. One explanation for the
observed lack of response may be that, in spite
of the hormonal receptorship, not all low-grade
ESS respond to hormone therapy. Various fac-
tors have been shown to influence hormone
responsiveness: concentration of the sex
steroid receptor, and relative expression of the
progesterone receptor (PR) isoforms (PR-A
and PR-B). It is conceivable that receptor con-
centration and the predominant isoform may
vary in ESS originating in the uterus versus
extrauterine sites, such as to make the latter
less hormone responsive.
In summary, we report a trend favoring poor
responsiveness of extrauterine, extraovarian
ESS to hormone therapy. This is significant
given the predilection to extrapolate from the
treatment responses observed in uterine ESS.
Although our conclusion is based on a limited
number of cases, our report raises an important
question that needs to be investigated further.
[Rare Tumors 2009; 1:e39]
References
1. Kusaka M, Mikuni M, Nishiya M. A case of
high-grade endometrial stromal sarcoma
arising from endometriosis in the cul-de-
sac. Int J Gynecol Cancer 2006;16:895-9.
2. Lacroix-Triki M, Beyris L, Martel P, et al.
Low grade endometrial stromal sarcoma
arising from sciatic nerve endometriosis.
Obstet Gynecol 2004;104:1147-9.
3. Kaseki H, Mizuno K, Inoue T, et al. Post-
hysterectomy extra-uterine endometrial
stromal sarcoma: A case report. Jpn J Clin
Oncol 1990;20:413-9.
4. Baiocchi G, Kavanagh JJ, Wharton JT.
Endometroid stromal sarcomas arising
from ovarian and extraovarian
endometriosis: Report of two cases and
review of literature. Gynecol Oncol 1990;
36:147-51.

The managament of rare nasal
mass-nasal dermoid sinus
cysts: open rhinoplasty
Emel Cadalli Tatar, Ömer Tarik Selçuk,
Güleser Saylam, Ali Özdek,
Hakan Korkmaz
Ministry of Health, Dișkapi Research and
Educational Hospital 2.ENT Clinic,
Ankara Turkey
Abstract
The differential diagnosis of midline nasal
masses includes inflammatory lesions, post-
traumatic deformities, benign neoplasms,
malignant neoplasms, congenital and vascular
masses. Midline congenital lesions of the nose
are rare congenital anomalies. Their incidence
is estimated at 1 per 20,000 to 40,000 births
consisting of gliomas, encephaloceles, and
nasal dermoid sinus cysts. Nasal dermoid
sinus cysts account for 1-3% of dermoid cysts
overall and 11-12% of head and neck dermoids.
Most lesions are diagnosed within the first
three years of life but in some cases the diag-
nosis can be prolonged. We present an 18-year
old and a two and a half-year old male patients
who are concerned about drainage from the tip
of the nose with recurrent infection and oper-
ated with a diagnosis of nasal dermoid sinus
cyst.
Introduction
Midline congenital lesions of the nose are a
rare congenital anomaly. Their incidence is
estimated at 1 per 20,000 to 40,000 births.1-3
The differential diagnosis of midline nasal
masses includes inflammatory lesions, post-
traumatic deformities, benign neoplasms,
malignant neoplasms, and vascular masses.3,4
Gliomas, encephaloceles and nasal dermoid
sinus cysts are the main part of the congenital
midline lesions of the nose.4,5
The central nervous system's (CNS)
involvement in gliomas and encephaloceles is
well known. Nasal dermoid sinus cyst (NDSC)
has a potential for intracranial involvement.
NDSC originates from ectoderm that forms
from neuroectodermal and ectodermal insepa-
ration.1 Nasal dermoid sinus cysts account for
1-3% of dermoid cysts overall and 11-12% of
head and neck dermoids.6,7 NDSCs account for
61% of all midline nasal lesions in children.4,7
Early diagnosis is made in the first three years
after birth in most cases. But in some cases
the diagnosis may be prolonged.4,5,8 Nasal mid-
line deformities, recurrent infections, airway
obstruction and intracranial complications can
occur when the diagnosis has been prolonged.6
The oldest case in the literature was a 56-year
old patient with intracranial extension.9 We
are presenting an 18-year old adult and a two
and a half-year old child with a rare congeni-
tal nasal midline lesion and their surgical
treatment with a review of the literature.
Case Report
Case #1
An 18-year old patient with chronically
draining sinus opening after his birth and
recurrent nasal midline infection history has
been seen in our clinic. He had no other com-
plaints. He had no specific history within his
family and no maxillofacial trauma. In his
examination there was widening at nasal dor-
sum and draining sinus opening on the skin of
the nasal tip (Figure 1). In anterior rhinoscopy
nasal mucous membrane was normal. In the
cranial computed tomography (CCT) scan
there was no intracranial extension. We per-
formed an open technique rhinoplasty in local
anesthesia. During elevation of the skin of the
columella, the infratip, the tip and the supratip
[Rare Tumors 2009; 1:e40]
Rare
RareTumors
Tumors2009;
2009;volume
volume1:exxxx
1:e40
Correspondence: Ömer Tarik Selçuk, Refik
Belendir sk. 67A/3 Ayranc›, 06410, Ankara, Turkey
E-mail: omertarikselcuk@yahoo.com
Key words: congenital, dermoid cyst, adult, nasal
mass.
Received for publication: 2 July 2009.
Accepted for publication: 13 September 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright E.C. Tatar et al., 2009
Rare Tumors 2009; 1:e40
doi:10.4081/rt.2009.e40
as a flap, we entrenched a catheter to the open-
ing of the fistula which was located above the
septum and between the two alar cartilages
(Figure 1). Elevation was performed around
the catheter and tract of the fistula. The fistu-
la tract was extended to the nasion. The tract
was continuing with a cyst. The skin of the
opening of fistula, the tract of the fistula and
the cyst were excised without rupturing.
Specimen was sent for pathological examina-
tion (Figure 1). There was no problem in the
Figure 1. Draining sinus
opening on the skin of
nasal tip. The catheter
entrenched to the opening
of the fistula, which was
located above the septum
and between the two alar
cartilages. Specimen was
sent for pathological exam-
ination.
[page 121]
Case Report

post-operative period and the patient was dis-

charged after one day. The post-operative
pathology report was epidermal inclusion cyst.
The patient had no complaints in the one year
follow-up and the esthetic result was satisfy-
ing.

Case #2
A two and a half-year old child with chroni-
cally draining sinus opening after his birth and
recurrent nasal midline infection history was
seen in our clinic. He also had no specific his-
tory within the family and no maxillofacial
trauma. In his examination there was a 1x1 cm
immobile subcutaneous mass with opening of
the fistula at rhinion of the nasal dorsum. The
mass was unable to be compressed and did not Figure 2. A paranasal sinus computed tomography and magnetic resonance imagining
increase with crying. The anterior rhinoscopy showed a cyst with no intracranial extension.
was normal. A paranasal sinus computed
tomography (CT) and magnetic resonance
imaging (MRI) showed a cyst with no intracra-
nial extension (Figure 2).
We performed an open technique rhinoplas-
ty in general anesthesia (Figure 3). The tract
was continuing with a cyst, which elongated
cephalically between separated nasal bones
and eroded bony septum. The fistula tract and
the cyst were excised without rupturing. After
cyst removal, the defect was filled with surgi-
cell. Specimen was sent for pathological exam-
ination (Figure 3).
There was no problem in the post-operative
period and the patient was discharged after
three days. The post-operative pathology report
was epidermal inclusion cyst. The patient had
no complaints in the 6-month follow-up and
the esthetic result was satisfying. Figure 3. The tract that was continuing
with a cyst. The fistula tract and the cyst
were excised without rupturing.

Discussion
NDSCs are the most frequent congenital
midline lesions.6,8,10 The first report about
NDSC was published by Bramann in 1890.4,7
There are lots of theories like sequestration,
trilaminary and prenasal, about NDSCs. The
most accepted theory is Pratt’s prenasal theory.
Pratt descibed the common embriologic path-
way of gliomas, encephaloceles and naso-
frontal dermoid sinus tract.4,5 During the
extension of dura between the unconnected
bones in the skullbase to nasal region the dura
is related with dermis in the nasal tip. If the
bone tissue could not separate the dura from
dermis during the ossification, anomalies
occur.
For the congenital nasal masses, which orig-
inate from ectoderm and mesoderm, the term
NDSC was first used in 1982.1,5 The diagnosis
for most of the NDSCs is made in the first
three years of childhood. But in some cases,
like our first case, the diagnosis can be delayed
until a later age. The oldest patient in the liter-
ature is a 56-year old patient with intracranial
extension.9 There are some reports about male
predominance.10
NDSCs are typically seen as midline masses.
They usually have a sinus opening in the nasal
dorsum.1,2 Intermittent secretion of sebaceous
material and recurrent infections are seen fre-
quently. The hair outgoing from the opening is
pathognomonic for the NDSC but is found in
less than half of the patients.2,7 NDSC is seen
sporadically but familial cases have been
reported in the literature.1,6
There is no association of a syndrome with
the formation of the NDSC. There are other
congenital anomalies that have been reported.
These include craniofacial anomalies, hyper-
telorizm, cleft palate, hemifacial microsomia,
aural atresia, pinna deformities, branchial
sinus anomalies, cardiac, genital and gastroin-
testinal anomalies. These associations have
been reported with different ratios in the liter-
ature.4 There is no proved described genetic
transmission. There is some familial transmis-
sion reported in the literature. NDSCs make up
11-12% of all head and neck dermoids.5 They
can be seen between glabella and columella.
The ratio of the intracranial extension is con-
troversial. Suspicion of intracranial extension
is important for every patient with NDSC.
Cranial CT and/or MRI are essential to deter-
mine the extension.1,5,6 Cranial CT is valuable
to show the bone alterations and help diagno-
sis. Disadvantages of CCT are expectation of
ionized radiation and interpretation problems
because of the unseparated crista galli and
perpendicular plate of the ethmoid bone in
infants under one year old.4 MRI has high res-
olution in soft tissue so it clearly exhibits the
intracranial extension.1,4,5
The treatment of the NDSC is surgical exci-
sion.1,5-7 The most favorable technique is the
open rhinoplasty like in our two cases.7 The

[page 122] [Rare Tumors 2009; 1:e40]


-
reasons for choosing this technique are expo-
sure, good esthetic results and allowing the
reconstruction of the nasal dorsum. The for-
mation of the surgery depends on the lesions'
localization and extension.
With the clinical findings and imaging
modalities, we can estimate the intracranial
extension and plan appropriate surgical treat-
ment.10 In most of the cases an early diagnosis
is made in the first three years after birth. In
some cases, however, the diagnosis may be
prolonged.4,5,8 This must be kept in mind for dif-
ferential diagnosis. The treatment is surgical.
The investigation for the intracranial exten-
sion must be performed before the surgery.
With the open septorinoplasty technique we
can achieve good esthetic and functional
results.
References
1. Bilkay U, Gundogan H, Ozek C, et al. Nasal
dermoid sinus cysts and the role of open
rhinoplasty. Ann Plast Surg 2001;478-14.
2. Sreetharan V, Kangesu L, Sommerlad BC.
Atypical congenital dermoids of the face: a
25-year experience. J Plast Reconstr
Aesthet Surg 2007;60:1025-9.
3. Zapata S, Kearns DB. Nasal dermoids. Curr
Opin Otolaryngol Head Neck Surg.
2006;14:406-11.
4. Hanikeri M, Waterhouse N, Kirkpatrick N,
et al. The management of midline transcra-
nial nasal dermoid sinus cysts. Br J Plast
Surg 2005;58:1043-50.
5. Post G, McMains KC, Kountakis SE. Adult
nasal dermoid sinus cyst. Am J Otolaryngol
[Rare Tumors 2009; 1:e40]
Case Report
Article
2005;26:403-5.
6. Rahbar R, Shah P, Mulliken JB, et al. The
presentation and management of nasal der-
moid: a 30-year experience. Arch
Otolaryngol Head Neck Surg 2003;129: 464-
71.
7. Rohrich RJ, Lowe JB, Schwartz MR. The
role of open rhinoplasty in the management
of nasal dermoid cysts. Plast Reconstr Surg
1999;104:2163-70
8. Yavuzer R, Bier U, Jackson IT. Be careful: it
might be a nasal dermoid cyst. Plast
Reconstr Surg 1999;103:2082-3.
9. Hacker DC, Freeman JL. Intracranial exten-
sion of a nasal dermoid sinus cyst in a 56-
year-old man. Head Neck 1994;16:366-71.
10. Denoyelle F, Ducroz V, Roger G, Gara-bedian
EN. Nasal dermoid sinus cysts in children.
Laryngoscope 1997;107:795-800.
[page 123]
Rare Tumors 2009; volume 1:e41
Lipid-rich histology in a
basal-type immuno-profile
breast carcinoma:
a clinicopathological
histochemical and
immunohistochemical
analysis of a case
Serena Russo,1 Diana Coppola,2
Paola Vinaccia,2 Antonella Siciliano,2
Francesca Baldassarre,2
Giovanni Battista,2 Giuseppe Pisani,3
Joseph Sepe,4 Francesco M. Maiello2
1
ASL NA3 Sud, Maresca Hospital, Torre
del Greco, Naples, Italy; 2ASL NA1,
Pellegrini Hospital, Division of Pathology,
Naples, Italy; 3ASLNA1, Pellegrini
Hospital, Breast Unit, Naples, Italy.
4
University of Maryland University
College, USA
Abstract
We describe the clinicopathological and
morphological features of an unusual breast
carcinoma classifiable as a lipid-rich variant of
ductal invasive carcinoma, with a basal-type
immunohistochemical profile. Basal-type
breast cancers show no hormonal receptor
expression, rarely over-express HER-2 but
exhibit molecular high weight cytokeratins,
EGFR and c-kit positivity. Special stains and
histochemistry tests were used to elucidate the
nature of vescicles in the neoplastic cells.
Sudan IV was performed on formalin-fixed tis-
sue. Commercially available antibodies tested
were: ER, PgR, EGFR, HER2, c-kit, high molec-
ular weight cytokeratins. Cytoplasmic lipids
were highlighted as red-orange droplets on
Sudan IV staining. As for immunohistochem-
istry, the tumor showed no reactivity to ER,
PgR and HER2 (triple negative), and diffuse
and strong positivity to high weight cytoker-
atins, EGFR and c-kit, such as a basal-type
breast carcinoma. A basaloid phenotype in a
lipid-rich carcinoma has not been previously
reported.
Introduction
Breast cancer represents a heterogeneous
group of tumoral entities, associated with spe-
cific morphological changes and immunohisto-
chemical features: the clinical presentation and
molecular alterations make it a highly diverse
disease. That is why patients with the same
[page 124]
tumor types and staging respond differently to
treatment and do not share the same prognosis.
Lipid-rich invasive breast cancer is a rare enig-
matic entity among special types of infiltrating
duct carcinoma, with difficult diagnosis.1
Only a few cases are reported in the litera-
ture.2 Tumor cells contain abundant intracyto-
plasmatic lipids.3
Lipid-rich carcinoma was first described in
women by Aboumrad et al.4 These authors
thought that the lipid droplets were produced
and secreted by the tumor cells instead of
being the result of regressive degeneration
because lipid droplets existed uniformly in
metastasized lymph nodes and in tumor cells
undergoing mitosis.5
Since there was great heterogeneity in clin-
ical outcome for estrogen positive tumors com-
pared to the uniform behavior of hormone neg-
ative tumors,6 researchers have invested in
molecular aspects of breast cancer by investi-
gating biological markers.7
Recent literature8 suggests a new classifica-
tion of breast cancer, based on its biological
features and categorizes tumors according
their immunophenotype in a luminal and a
basal-type,9 corresponding to two distinct types
of epithelial cells found in the normal mamma-
ry gland.
Basal-type breast tumors show no hormonal
receptor expression, rarely over-express HER-2
(triple negative) but show high-molecular
weight cytokeratins, EGFR and c-kit positivity.
It was suggested10 that the heterogeneity of
breast cancer may be derived from the diversi-
ty of the original cells for neoplastic transfor-
mation, which is thought to exist in the termi-
nal duct lobular unit of the mammary gland.
The cells in the terminal duct lobular unit
consist of glandular, basal and myoepithelial
cells. This heterogeneous population of epithe-
lial cells arises from a common progenitor but
they each express unique markers and per-
form unique functions.
The paradigm that breast cancer is a hetero-
[Rare Tumors 2009; 1:e41]
Correspondence: Serena Russo, Via Epomeo 72,
80126 Napoli, Italy. E-mail: qubmur@tin.it
Key words: breast carcinoma, basal type, EGFR,
c-kit, lipid-rich.
Contributions: SR has contributed to data acqui-
sition and interpretation; AS and FB collected the
references and reviewed the literature; FMM,
Pathology Department Director, gave final
approval of the manuscript to be published; DC
and GB contributed to the technical histochemi-
cal studies; PV carried out the immunohisto-
chemical staining and participated in the design
of the study; GP is the surgeon who performed
the operation; JS edited the English version of
the manuscript.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 1 September 2009.
Revision received: 1 October 2009.
Accepted for publication: 5 October 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright S. Russo et al., 2009
Rare Tumors 2009; 1:e41
doi:10.4081/rt.2009.e41
geneous disease shifts to the new one that
breast cancer is at least two different diseases
with age-specific incidence. Estrogen-negative
tumors usually consist of high-grade, aggres-
sive tumors or rare histoypes (adenoid cystic,
metaplastic). The basal-like subtype has an
interval presentation and it is not usually
detected during a mammographic screening.11
We describe the clinicopathological and
morphological features of an unusual breast
carcinoma classifiable as a “lipid-rich” variant
of ductal invasive carcinoma and correlate it
with a basal immunohistochemical profile.
Figure 1. Fine nee-
dle aspiration cytol-
ogy: Large, vac-
uolized cells. 400X.
 Article

Materials and Methods Figure 2. Fine nee-

dle aspiration cytol-
ogy. E.E. 400X.
A 73-year old woman, previously in good
health, in menopause since she was 38 years
old, presented with a sudden breast mass.
Mammography performed 10 months earlier
was negative.
Imaging studies further evaluated the
extent of the disease: CT scan revealed no evi-
dence of metastatic disease.
The patient was treated at the Breast Unit of
Pellegrini Hospital (Naples, Italy). She under-
went a modified radical mastectomy with axil-
lary lymphadenectomy after a fine needle aspi-
ration cytologic diagnosis of carcinoma
(Figures 1 and 2).
All available paraffin blocks or unstained Figure 3. Sudan IV.
sections were retrieved and the original hema- 250X.
toxylin and eosin-stained sections were
reviewed. After gross examination, the speci-
men was serially sectioned into 3 mm thick
slices and formalin-fixed.
In addition, 9 invasive ductal carcinomas,
not otherwise specified were used as a control
group for histological and immunohistochemi-
cal correlations. Whole tissue sections (5 μm)
were cut and used for histochemistry and
immunohistochemistry.
The immunohistochemical stains were per-
formed using Ventana® Benchmark™
Automated Immunostainer on formalin-fixed
paraffin-embedded specimens. Commercially
available antibodies tested were: ER, PgR, Figure 4.
EGFR, HER2, c-kit (Ventana, Tucson, AZ, USA), Hematoxylin-Eosin.
high molecular weight cytokeratins (clone 250X.
34βE12-ORG-8735, Novocastra) all prediluted
according to the manufacturers’ instructions.
Peroxidase activity was visualized with
diaminobenzidine chromogen as per routine
protocol to obtain a brown-black end product.
Appropriate internal and external positive con-
trols were used. In an effort to elucidate the
nature of the vescicles, special stains and his-
tochemistry tests were performed. Sudan IV
(modified by Coppola) method for fat: after fix-
ation in 10% buffered neutral formalin, the
specimen was rinsed in water for 24 hours to
remove the excess. Then 10 micron frozen sec-
tions were cut, collected in distilled water and
stained in a Sudan IV solution (Sudan was dis-
solved in 70% alcohol). After that we mounted
slides with glycerin jelly (Figure 3). We chose measured 2.2 cm in diameter. On morphologi- (CAPSS) in uninvolved parenchima.
alcohol instead of Herxheimer solution, made cal grounds it was a high-grade invasive ductal All the axillary lymphnodes (fourteen) were
of alcohol and acetone, to avoid an excessive carcinoma with an 80% histiocyte-like neo- negative. We also observed some calcifications
extraction since we dealed with previous for- plastic component and a 15% in situ ductal car- and a mild chronic intra and peritumoral
malin that is a fat solvent. cinoma component . inflammation. No reaction with Periodic
The neoplastic cells, arranged in nests and Acid–Schiff, Alcian and PAS-D histochemical
cords were medium-sized, with a small round, technique was observed within tumor cells.
dark, nucleolatus nucleus and a large foamy Cytoplasmic lipids were highlighted as red-
Results clear cytoplasm (Figure 4). There were per- orange droplets at the Sudan IV staining. In
ineural invasion, peritumoral neoplastic agreement with the current morphological
On gross examination the tumor was firm embolization and columnar alteration with description of human and canine tumors, the
and whitish with ill defined margins and prominent apical snouts and secretion cells we examined with large vacuoles of neu-

[Rare Tumors 2009; 1:e41] [page 125]

Article

tral lipids were consistent with lipid-rich carci-

Figure 5. EGFR.
noma, a rare and distinct variant of infiltrative 250X.
ductal breast carcinoma (lipid-rich invasive
ductal carcinoma according to WHO classifica-
tion, 2003). As for immunohistochemistry, the
tumor showed no reactivity to ER, PgR and
HER2 (triple negative), and diffuse and strong
positivity to high weight cytokeratins,12 EGFR
(Figures 5 and 6) and c-kit (Figure 7), such as
a basal-type breast carcinoma.

Discussion
The foregoing data suggest that breast can-
cers show great diversity in their morpholo-
gies, clinical histories and responsiveness to Figure 6. High mole-
chemiotherapy. This wide diversity poses a cu-lar weight cytok-
eratins. 250X.
challenge to provide accurate diagnostic, prog-
nostic and predictive information and effective
treatment. Traditional therapies targeting the
estrogen-receptors or HER2 oncogene would
not be expected to be effective on basal-like
breast cancers because this subtype expresses
neither of these proteins.
“Breast cancer can no longer be viewed as
one biologic entity. If breast cancer overall con-
sists of at least two main types, we need a
stratified rather than a unified approach to
breast cancer research, prevention and treat-
ment”.13 Some investigators have previously
suggested that basal-like carcinoma may con-
sist of components of invasive ductal carcino- Figure 7. c-kit. 250X.
ma, not otherwise specified, metaplastic carci-
noma, and medullary carcinoma.14
This is the first report of a lipid-rich breast
carcinoma with a basaloid phenotype.
Even if, based on one case, definitive con-
clusions about pathogenic implications cannot
be reached, it is peculiar that we observed car-
cinoma secreting cells showing a basaloid
immunoprofile, since the secretory function
usually belongs to luminal cells.
It is reasonable to conclude that this paper
may raise new questions, but it cannot give
ultimate results.

References
1. Espinosa de los Monteros A, Hellmén E,
Ramirez GA, et al. Lipid-rich Carcinomas
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Clinicopathologic and Immunohi-
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2. Wrba F, Ellinger A, Reiner G, et al.
Ultrastructural and immunohistochemical
characteristics of lipid-rich carcinoma of
the breast. Virchows Arch A Pathol Anat
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3. Ramos CV, Taylor HB. Lipid-rich carcinoma
of the breast. A clinicopathologic analysis
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4. Aboumrad MH, Horn RC Jr, Fine G. Lipid
secreting mammary carcinoma. Report of
a case associated with Paget’s disease of
the nipple. Cancer 1963;16:521-5.
5. Reis-Filho JS, Fulford LG, Lakhani SR,
Schmitt FC. Pathologic quiz case: a 62-
year-old woman with a 4.5-cm nodule in
the right breast. Lipid-rich breast carcino-
ma. Arch Pathol Lab Med. 2003;127:396-8.
6. Paredes J, Albergaria A, Carvalho S,
Schmitt FC. “Basal-like” breast carcino-
mas: Identification by P-cadherin, P63 and
EGFR basal cytokeratins expression. Appl
Canc Res 2006;26:41-55.
7. Perou CM, Sorlie T, Eisen MB, et al.
Molecular portraits of human breast
tumours. Nature 2000;406:747-52.
8. Zhang DH, Salto-Tellez M, Chiu LL, et al.
Tissue microarray study for classification
of breast tumours. Life Sci 2003;73:3189-
99.
9. Rakha EA, El-Sayed ME, Green AR, et al.
Prognostic markers in triple negative
breast cancer. Cancer 2007;109:25-32.

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10. Anderson WF, Matsuno R. Breast cancer
heterogeneity: a mixture of at least two
main types. J Natl Cancer Inst 2006;
98:1011-4.
11. Collett K, Stefansson IM, Eide J, et al. A
basal epithelial phenotype is more fre-
quent in interval breast cancers compared
with screen detected tumors. Cancer
Epidemiol Biomark Prev 2005;14:1108-12.
12. Matos I, Dufloth R, Alvarenga M, et al. P63,
cytokeratin 5, and P-cadherin: three
molecular markers to distinguish basal
phenotype in breast carcinomas. Virchows
Arch 2005; 447:688-94.
13. Abd El-Rehim DM, Pinder SE, Paish CE, et
al. Expression of luminal and basal cytok-
[Rare Tumors 2009; 1:e41]
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eratins in human breast cancer. J Pathol
2004;203:661-71.
14. Kuroda N, Fujishima N, Inoue K, et al.
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[page 127]
Rare Tumors 2009; volume 1:e42
Synchronous malignant B-cell
lymphoma and gastric tubular
adenocarcinoma associated
with paraneoplastic cutaneous
vasculitis: hypereosinophilic
syndrome with mixed
cryoglobulinemia is an
important sign of
paraneoplastic syndrome
Kazuhisa Nozawa,1,6 Hiroshi Kaneko,1
Tomoyasu Itoh,3 Yoko Katsura,3 Masaaki
Noguchi,5 Fujihiko Suzuki,4
Yoshinari Takasaki,2 Hideoki Ogawa,6
Kenji Takamori,6 Iwao Sekigawa1,6
1
Department of Internal Medicine and
Rheumatology, Juntendo University
Urayasu Hospital, Chiba, Japan;
2
Department of Rheumatology, School of
Medicine, Juntendo University, Tokyo,
Japan; 3Department of Internal Medicine,
Juntendo University Urayasu Hospital,
Chiba, Japan; 4Department of Pathology,
Juntendo University Urayasu Hospital,
Chiba, Japan; 5Department of
Hematology, Juntendo University
Urayasu Hospital, Chiba, Japan; 6Institute
for Environment and Gender Specific
Medicine, Juntendo University Graduate
School of Medicine, Chiba, Japan
Abstract
Gastric adenocarcinoma developing con-
comitantly with a lymphoma is rare.
Furthermore, B-cell lymphoma, originating
from lymph nodes, with eosinophilia is
extremely rare. We report here a case with a
synchronous diffuse large B-cell lymphoma
(DLBCL) and an early adenocarcinoma of the
stomach. In addition, this case seemed to be
associated with paraneoplastic cutaneous vas-
culitis caused by hypereosinophilic syndrome
(HES) with mixed cryoglobulinemia (MC).
Many neoplastic diseases that affect internal
organs display cutaneous manifestations,
which may be the presenting signs and symp-
toms of the underlying malignancy. In particu-
lar, the association between cutaneous vas-
culitis and malignancy has been widely
reviewed, and recently neoplasms have been
suggested to produce antigens and the result-
ant immune complex formations, activating
the serum complement, thus cause paraneo-
plastic vasculitis. In this case, severe
eosinophilia and cryoglobulinemia with low
complements were observed in a laboratory
test. A biopsy specimen from a skin lesion
[page 128]
revealed leukocytoclastic vasculitis with severe
perivascular infiltration of eosinophils. The
cutaneous vasuculitis was considered to be a
manifestation of HES with MC, although there
were no etiological factors of HES and MC.
Therefore, the vasculitis seems to be a symp-
tom of paraneoplastic syndrome in this case.
Our finding suggests that the potential pres-
ence of malignancies should be kept in mind
as a possible underlying disorder especially in
the presence of HES with MC; this possibility
is interesting also as regards at least part of
the pathogenesis for paraneplastic syndrome.
Introduction
Hypereosinophilic syndrome (HES) is a
clinical disorder characterized by persistent
eosinophilia and systemic signs, and the cuta-
neous lesions are one of the common manifes-
tations derived from HES, including vasculitis.1
Although malignant T-cell lymphoma and other
malignant tumors associated with eosinophilia
have been reported sporadically,1-3 B-cell lym-
phoma, originating from lymph nodes, with
eosinophilia is extremely rare.4,5 On the other
hand, cryoglobulinemia is defined as the pres-
ence of circulating immunoglobulins that pre-
cipitate with cold temperature. After immuno-
chemical typing, cryoglobulinemia is classified
as type I, II, and III cryoglobulinemia.
Furthermore, type II and III are defined as
mixed cryoglobulinemia (MC), with a mono-
clonal component in type II and only polyclonal
immunoglobulins in type III. Since the discov-
ery of hepatitis-C virus (HCV) infection, it has
become clear that HCV is associated with most
cases of MC. In addition, MC is known to cause
a systemic vasculitis and, interestingly, it has
been reported that patients with non-HCV
related MC vasculitis have a four-fold
increased risk of developing B-cell lym-
phomas.6 These data suggest the presence of
MC itself is one of the risk factors for develop-
A B
Figure 1. Skin lesions. (A) The gross appearance of purpura on the lower legs; (B, C) the
histological findings of the purpura, showing massive infiltration of neutrophils and lym-
phocytes with deposits of fibrin on the vessel wall. Marked eosinophil and red blood cell
infiltration is observed in the perivascular region. The cutaneous lesion was diagnosed as
leukocytoclastic vasculitis with severe perivascular eosinophil infiltration. (Hematoxylin-
eosin stain; magnification: B, 100X and C, 400X.)
[Rare Tumors 2009; 1:e42]
Correspondence: Kazuhisa Nozawa, Department
of Rheumatology, Juntendo University Urayasu
Hospital and Institute for Environment and
Gender Specific Medicine, Juntendo University
Graduate School of Medicine, 2-1-1 Tomioka,
Urayasu, Chiba, 279-0021, Japan.
E-mail: kazunozawa@juntendo-urayasu.jp
Key words: cryoglobulinemia, malignant lym-
phoma, paraneoplastic vasculitis, tubular adeno-
carcinoma.
Contributions: KN was the main contributor for
this manuscript.
Conflict of interest: the authors report no con-
flicts of interest.
Acknowledgments: this work was supported by
the grants from The Institute for Environment
and Gender-specific Medicine, Juntendo
University Graduate School of Medicine.
Received for publication: 5 August 2009.
Revision received: 26 September 2009.
Accepted for publication: 1 October 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright K. Nozawa et al., 2009
Rare Tumors 2009; 1:e42
doi:10.4081/rt.2009.e42
ing lymphomas. Furthermore, the association
between vasculitis and malignancy has been
widely reviewed, and recently neoplasms have
been suggested to be a causative factor of the
vasculitis.7,8 Many reports regarding neoplastic
vasculitis have been published since, thus sug-
gesting that cutaneous vasculitis especially
may appear as an initiating sign of paraneo-
plastic syndrome.9-12 We report here a female
patient with cutaneous vasculitis caused by
HES and MC, subsequently diagnosed as syn-
chronous diffuse large B-cell lymphoma
C
 Case Report

(DLBCL) and early gastric cancer. Our present A B C

case is extremely rare and it suggests the
requirement of surveillance of the cutaneous
vasculitis for the underlying malignancies
especially in the presence of HES with MC.

Case Report D E

A 63-year-old female visited our outpatient

department because of continuous fever, pur-
pura with pitting edema, and dysethesia in her
lower legs (Figure 1A) for a month. She was
admitted to our hospital for further examina-
tion. A biopsy specimen from a skin lesion
Figure 2. Biopsy specimens from lymph node (A-C) and stomach (D-E), showing anti-
revealed leukocytoclastic vasculitis with severe CD20 antibody immunohistochemical staining (A) and anti-BCL2 antibody immunohis-
perivascular infiltration of eosinophils (Figure tochemical staining of the lymph node specimen (B), magnification: 40X; hematoxylin-
1B). Her laboratory findings on admission are eosin staining of the lymph node specimen (C), magnification: 12.5X; and (D) the
summarized in Table 1. These data revealed macroscopic finding of a biopsy specimen from the gastric lesion (indicated by arrow),
significant hypereosinophilia (white blood cell and (E) hematoxylin-eosin staining, magnification: 10X. The specimen from the lymph
node was strongly positive for CD20 and BCL2. Hematoxylin-eosin and BCL-2 staining
count [WBC], 7200 mm3 with 52% eosinophils; showed some follicular formations and diffuse proliferation of the cells concomitantly.
normal range: 1-5%), and elevated serum lev- The patient was diagnosed with DLBCL transformed from follicular B-cell lymphoma.
els of interleukin (IL)-4 (7.4 pg/mL; normal The gastroscopy specimen revealed irregular atypical cell proliferation in the mucosa, and
range: <6 pg/mL) and IL-5 (59.3 pg/mL; normal the patient was diagnosed with early gastric cancer (tubular adenocarcinoma).
range: <10 pg/mL), which are known to be
growth factors for eosinophils. Neither atypical
lymphocytes nor lymphoblastic cells were rec-
ognized. The C-reactive protein (CRP) level
was 0.8 mg/dL (normal range: <0.3 mg/dL),
thus indicating a weak inflammatory reaction.
Both titers of myeloperoxidase anti-neutrophil
cytoplasmic antibody (MPO-ANCA) and pro-
teinase-3 (PR3)-ANCA were negative. The
serum level of rheumatoid factor (RF) was
strongly positive (751 IU/mL; normal range:
<20 IU/mL) although no clinical symptoms of
rheumatoid arthritis (such as tenderness or
swollen joints) were observed, and antinu-
clear-antibody (ANA) titers and disease-specif-
ic antinuclear antibodies were negative (40X;
normal range: <80X). She also demonstrated
some abnormal findings such as cryoglobu-
linemia or decreased serum complement lev-
els, especially the C4 component (<3 mg/dL;
normal range: 13-35 mg/dL). Several days
before admission, she progressively developed
systemic peripheral lymphadenopathy (medi-
astinal, axillar, and inguinal), and her labora-
tory tests revealed an elevated serum level of Figure 3. A schematic figure illustrating the hypothesis for paraneoplastic vasculitis with
hypereosinophilic syndrome and mixed cryoglobulinemia. IC: immune complexes, APC:
soluble IL-2 receptor (sIL-2R). FIP1L1-PDGFRA antigen-presenting cells, T: T-lymphocytes, B: B-lymphocytes, Eo: eosinophilia, MC:
mutation was not observed. MC is known to mixed cryoglobulinemia, HES: hypereosinophilic syndrome.
cause leukocytoclastic vasculitis owing to the
deposition of immune complexes on the vessel
wall and the activation of complements result-
ing in vascular damage. Therefore, we consid- inguinal lymph node. The lymph node speci- proliferation of the cells was recognized con-
ered the cutaneous vasculitis to be a manifes- men showed an accumulation of CD20-positive comitantly. Subsequent CD10 staining was
tation of HES with MC because of the presence B-cells on immunohistochemical staining negative and genetic transformation t(14;18)
of severe eosinophila and perivascular infiltra- (Figure 2A). Initially the patient was diag- was not observed (data not shown). CD10 and
tion by eosinophils. Regarding the lym- nosed with follicular lymphoma because BCL2 t(14;18) are generally highly positive in follic-
phadenopathy and elevated serum level of sIL- staining was positive (Figure 2B); however, ular lymphoma; therefore, the patient was
2R, we suspected the presence of malignant hematoxylin and eosin (HE) staining (Figure diagnosed ultimately with DLBCL transformed
lymphoma or other hematological malignan- 2C) and BCL2 staining revealed that the follic- from follicular B-cell lymphoma. To exclude the
cies; thus, a biopsy was performed on the ular formation was not so obvious and diffuse possibility of other types of B-cell lymphomas

[Rare Tumors 2009; 1:e42] [page 129]

Case Report

such as mucosa-associated lymphoid tissue

Table 1. Laboratory findings on admission.
(MALT) lymphoma, mantle cell lymphoma,
Burkitt lymphoma, and small lymphocytic lym-
phoma, a gastroscopy was performed and it WBC 7900/mL AST 15 IU/L RF 751 IU/mL
revealed a protruding lesion with ulceration at Neutro 27.0% ALT 6 IU/L ANA 40X
the lesser curvature in the corpus ventriculi Lympho 13.0% ALP 362 IU/L αDNA Ab (-)
(Figure 2D, left). Unexpectedly, the histologi- Mono 5.0% LDH 271 IU/L αRNP Ab (-)
cal findings indicated an early stage of gastric
cancer (Figure 2D, right) and the histological Eosino 52.0% CPK 61 IU/lL αSm Ab (-)
diagnosis was a gastric cancer, IIc, tubular ade- AtyLy (-) BUN 11 mg/dL αSS-A Ab (-)
nocarcinoma (tub1), m, ly0, v0, cut margin(-), Blast (-) Crea 0.6 mg/dL αSS-B Ab (-)
although there was no evidence of lymphoma. RBC 382x104/mL UA 3.1 mg/dL αCL‚2GP1 Ab (-)
As a result, the patient was diagnosed with Hb 12.4 g/dL TP 5.9 g/dL PR3-ANCA (-)
cutaneous leukocytoclastic vasculitis with syn-
Ht 35.7% ALB 3.8 g/dL MPO-ANCA (-)
chronized occurrence consisting of DLBCL and
early gastric adenocarcinoma. An endoscopic Plt 16.1 x IgG 874 mg/dL Cryogloblin (+)
mucosal resection was performed as a treat- CRP 104/mL IgA 178 mg/dL MMP-3 41.7 ng/mL
ment for her gastric cancer, and thereafter she ESR 0.8 mg/dL IgM 170 mg/dL HCV (-)
underwent chemotherapy for the lymphoma in PT-INR 5 mm/h IgE 43.0 mg/dL HBV (-)
the hematological department of our hospital. APTT 1.18 CH50 <5 U/mL sIL-2R 2610 U/mL
The treatment for DLBCL was successfully
Ferritin 33.4 sec C3 70 U/mL IL-4 7.3 pg/mL
accomplished using chemotherapy with a THP-
COP regimen comprising cyclophosphamide, 191.4 ng/mL C4 <3 U/mL IL-5 59.3 pg/mL
pirarubicin (tetrahydropyranyl adriamycin Urinalysis CEA 0.9 U/mL ECP 2.7 μg/lL
[THP]), vincristine, and prednisolone. The Blood (-) CA19-9 1.9 U/mL
symptoms related to the cutaneous leukocyto- Protein (-) FIP1L1- mutation (-)
clastic vasculitis disappeared totally.
Glucose (-) PDGFRA

Discussion
It is extremely rare that HES occurs not in B-
cell but in T-cell lymphomas, and that lym-
phoma and gastric adenocarcinoma occur
simultaneously. In a MEDLINE literature
search (keywords: gastric cancer, B-cell lym-
phoma, and vasculitis), no item was found. We
believe that this is the first report of synchro-
nous malignant B-cell lymphoma and early
gastric cancer associated with paraneoplastic
vasculitis caused by HES with MC. In addition,
it appears clinically important for us to recog-
nize cutaneous vasculitis as paraneoplastic
syndrome. In this report, we discuss the etiolo-
gy of paraneoplastic vasculitis.
The relative risk of the occurrence of solid
tumors and hematological malignancies is
known to be higher in autoimmune patients
than in the normal population, and some
autoimmune disorders can appear to be para-
neoplastic syndrome before a malignant tumor
is identified.13 Several reports have indicated
that vasculitis can be a paraneoplastic symp-
tom in either hematological malignancies or
solid tumors.14-16 Vasculitis is an inflammatory
condition that can affect any type of blood ves-
sel owing to several immunologic mecha-
nisms. The possible mechanisms of paraneo-
plastic vasculitis include invasion of circulat-
ing tumor cells toward the vessel wall, damage
to the endothelium by cytokines released from
circulating tumor cells, the cross-reaction with
autoantibodies that can bind either tumor-spe-
cific antigens or endothelial antigens, and the
deposition of circulating immune complexes,
resulting in tissue damage because of comple-
ment-mediated cell destruction. The presence
of cryoglobulin and low plasma C4 levels in our
patient also indicate that circulating immune
complexes may play an important role in the
induction of the vasculitis. Interestingly, it has
been reported that MC itself is a risk factor for
lymphoma development.16 Although MC is
known to be observed frequently in patients
with HCV infections, our patient did not
demonstrate any antibodies or antigens for
HCVs. In a case of non-HCV related MC, we
should pay more attention to lymphocytic dis-
orders or malignant tumors, which are under-
lying MC as reported previously.6 Furthermore,
it has been reported that hypocomple-
mentemia is associated with lymphoma devel-
opment in primary Sjogren’s syndrome.17 Our
case is able to support these notions.
Regarding another etiology of paraneoplastic
vasculitis, tumor antigens may activate lym-
phocytes, thus resulting in an over-production
of T-helper (TH)-2 type cytokines, such as IL-4
or IL-5, and subsequently recruiting
eosinophils to the vessels; these phenomena
seem to have contributed to the development
of HES. In fact, higher expressions of these
cytokine proteins in certain lymphoma cells
have been reported.16 HES is defined by three
diagnostic criteria: eosinophils, >1.5x109/L,
persistent eosinophilia and/or organ damage
or dysfunction, and exclusion of secondary
causes of eosinophilia such as parasite infec-
tion or allergic reaction. HES is classified fur-
ther as myeloproliferative HES, lymphocytic
HES, familial HES, associated HES, overlap
HES, and undefined HES.18 Identification of the
lymphocytic HES rests on recognition of the
helper T-cell subset (especially TH2) and clon-
al overgrowth of specific cytokine (especially
IL-5) producing cells. Although we did not con-
firm the T-cell clonality producing IL-5, B-cell
abnormality derived from DLBCL may stimu-
late the T-cell clones resulting in HES.
Literature analyses indicate that character-
istics of representative paraneoplastic vasculi-
tis show cutaneous leukocytoclastic vasculitis
or cryoglobulinemic vasculitis. Recently,
Solans-Laque et al. reported that the most com-
mon vasculitis in solid tumors was leukocyto-
clastic vasculitis and the most common malig-
nancies were in urinary organs, gastrointesti-
nal tract, and lung.19 Furthermore, they men-
tioned that 13 of 15 patients demonstrated con-
cordance of disease activity and treatment
response for cancer and vasculitis, apart from
46.6% cases of the vasculitis that flared up,
heralding tumor recurrence or progression.
They suggested that resolution of vasculitis
following effective treatment of the putatively
linked malignancy, and recurrence of vasculi-
tis heralding tumor recurrence or progression,
provide strong evidence for vasculitis being a
true paraneoplastic syndrome, not occurring

[page 130] [Rare Tumors 2009; 1:e42]


by chance.19 Skin purpura or papules appear to
be the most common skin manifestations,
while hematological malignancies such as
lymphoma are the most common malignancies
presenting as underlying diseases.9-12 Our case
supports these notions and reminds us that we
should pay attention to the importance of per-
forming careful examinations in order to
exclude other diseases, especially malignan-
cies that may exist as underlying causes of
HES and MC, with skin involvement as an
important sign of paraneoplastic syndrome.
Finally, our hypothesis regarding the patho-
genesis of the paraneoplastic vasculitis in the
present case is shown in Figure 3. We think
two possible mechanisms for the paraneoplas-
tic vasculitis derived from gastric cancer and
lymphoma are considerable. In gastric carcino-
ma, tumor antigens of gastric cancer may be
released into the extracellular region and rec-
ognized by the immune system as autoanti-
gens in a particular individual, resulting in an
immune activation against the tumor anti-
gens. Once the immune system is activated,
anti-tumor-antigen antibodies are produced;
furthermore, aberrant cytokine production
may be induced. The antibodies possibly react
with vessel wall antigens by cross-reaction,
resulting in the formation of immune complex-
es on the vessel wall. Then, complement is
recruited to the immune complexes and acti-
vated, ultimately resulting in the vasculitis.
The aberrant cytokine production, such as IL-4
and IL-5, can promote eosinophilic prolifera-
tion and activation resulting in HES. The
eosinophilic infiltration in the perivascular
region may exacerbate the symptoms of the
vasulitis further. In lymphomas, the B-cell lym-
phomas may induce abnormal activation of the
lymphocytes resulting in autoantibody produc-
tion, such as cryoglobulin or anti-vascular cells
autoantibody. The aberrant activation of the
lymphocytes also may induce excessive IL-4
and IL-5 production. The autoantibodies may
interact with the vessel wall resulting in the
vasculitis as described previously. In the pres-
ent case, the latter appeared to be the main
factor of the vasculitis rather than the former,
because the gastric cancer is at the early stage,
and it is difficult to think that small early gas-
tric cancers cause the paraneoplastic phenom-
enon.
References
1. Gleich GJ, Leiferman KM. The hypere-
osinophilic syndromes: current concepts
and treatments. Br J Haematol 2009;145:
271-85.
2. Choi W, Park YH, Paik KH, et al. Peripheral
T-cell lymphoma-unspecified (PTCL-U)
presenting with hypereosinophilic syn-
drome and pleural effusions. Korean J
Intern Med 2006;21:57-61.
3. Gutierrez A, Solano C, Ferrandez A, et al.
Peripheral T-cell lymphoma associated
consecutively with hemophagocytic lym-
phohistiocytosis and hypereosinophilic
syndrome. Eur J Haematol 2003;71:303-6.
4. Shiraishi J, Nakagawa Y, Kurata M, et al.
Follicular lymphoma with marked infiltra-
tion of eosinophils. Pathol Int 2008;58:701-
5.
5. Krunic AL, Medenica MM, Laumann AE, et
al. Cryoglobulinaemic vasculitis, cryofib-
rinogenaemia and low-grade B-cell lym-
phoma. Br J Dermatol 2003;148:1079-81.
6. Saadoun D, Sellam J, Ghillani-Dalbin P, et
al. Increased risks of lymphoma and death
among patients with non-hepatitis C
virus-related mixed cryoglobulinemia.
Arch Intern Med 2006;166:2101-8.
7. Longley S, Caldwell JR, Panush RS.
Paraneoplastic vasculitis: Unique syn-
drome of cutaneous angitis and arthritis
associated with myeloproliferative disor-
ders. Am J Med 1986;80:1027-30.
8. McLean DI. Cutaneous paraneoplastic syn-
dromes. Arch Dermatol 1986;122:765-7.
9. Calronje JE, Greaves MW. Cutaneous
[Rare Tumors 2009; 1:e42]
Case Report
extravascular necrotizing granuloma
(Churg Strauss) as a paraneoplastic man-
ifestation of non-Hodgkin’s B-cell lym-
phoma. J R Soc Med 1993;86:549-50.
10. Sanchez NB, Canedo IF, Garcia-Patos PE,
et al. Paraneoplastic vasculitis associated
with multiple myeloma. J Eur Acad
Dermatol Venereol 2004;18:731-5.
11. Simon Z, Tarr T, Toth L, et al. Cutaneous
vasculitis as initiating paraneoplastic
symptom in Hodgkin lymphoma.
Rheumatol Int 2008;28:719-23.
12. Ydav BS, Sharma SC, Kapoor RK. Para -
neoplastic leukocytoclastic vasculitis in
chronic lymphoid leukemia. J Cancer Res
Ther 2006;2:206-8.
13. Ponyi A, Constantin T, Garami M, et al.
Cancer-associated myositis. Ann NY Acad
Sci 2005;1051:64-71.
14. Farrell AM, Stern SC, El-Ghariani K, et al.
Splenic lymphoma with villous lympho-
cytes presenting as leukocytoclastic vas-
culitis. Clin Exp Dermatol 1999;24:19-22.
15. Calvo KR, Dabir B, Kovach A, et al. IL-4
protein expression and basal activation of
Erk in vivo in follicular lymphoma. Blood
2008;112:3818-26.
16. De Re V, De Vita S, Sansonno D, et al.
Mixed cryoglobulinemia syndrome as an
additional autoimmune disorder associat-
ed with risk for lymphoma development.
Blood 2008;111:5760.
17. Ramos-Casals M, Brito-Zeron P, Yague J,
et al. Hypocomplementaemia as an immu-
nological marker of morbidity and mortali-
ty in patients with primary Sjogren’s syn-
drome. Rheumatology 2005; 44:89-94.
18. Gerald GJ, Leiferman KM. The hypere-
osinophilic syndromes: current concepts
and treatments. Br J Haematol 2009; 145:
271.
19. Solans-Laque R, Bosch-Gil JA, Perez-
Bocanegra C, et al. Paraneoplastic vasculi-
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[page 131]
Rare Tumors 2009; volume 1:e43
Hemangiopericytomas of the
spine: case report and review
of the literature
Chad D. Cole1 Meic H. Schmidt1,2
1
Department of Neurological Surgery,
University of Utah, Salt Lake City, Utah;
2
Spinal Oncology Service, Huntsman
Cancer Institute, University of Utah, Salt
Lake City, Utah
Abstract
We describe a rare case of a primary
intracranial meningeal hemangiopericytoma
(HPC) with late metastasis to the cervical
spine. A 36-year-old woman had a left occipital
lesion that was histopathologically identified
as HPC. Fourteen years after resection, the
tumor recurred and was treated with radio-
therapy. Three years later, CT imaging showed
a large mass in the liver consistent with
metastatic HPC, and MRI of the cervical spine
showed an extensive lesion of the C3 vertebral
body. The patient underwent C3 corpectomy
with en-bloc tumor removal and follow-up radi-
ation with no local recurrence or other spinal
metastasis for the following 4 years.
Regardless of the subtype of spinal HPC, com-
plete surgical removal and radiotherapy appear
to be treatment of choice.
Introduction
The term “hemangiopericytoma” (HPC) is
used to describe a wide variety of lesions shar-
ing certain morphological characteristics: a
monotonous appearance at low-power examina-
tion, moderate to high cellularity, and numer-
ous, variably thick-walled, branching ‘staghorn’
vessels.1 HPCs demonstrating obvious malig-
nant features generally behave aggressively;
however, a small proportion of benign-looking
lesions can recur and even metastasize.1
Meningeal HPCs (M-HPCs) have different
light microscopic, ultrastructural, and immuno-
histochemical features than meningiomas and
are not considered variants of meningiomas.
Their clinical behavior is more aggressive than
that of benign meningiomas, and they have a
strong tendency for local recurrence and
extracranial metastasis.2-4
Spinal HPCs are significantly less common
than intracranial M-HPCs. Despite the well-
known but rare occurrence of HPC within the
vertebral column, its natural history and man-
agement remain somewhat elusive. We
describe a patient with primary intracranial M-
[page 132]
HPC with cervical spinal metastasis that
occurred six years after the primary lesion was
detected. We also reviewed the literature to
identify HPCs affecting the spine and to identi-
fy recognized treatment options.
Case Report
A 36-year-old woman visited the emergency
room after experiencing several years of visu-
al disturbances of increasing severity and fre-
quency, nausea, dizziness, imbalance, hyper-
ventilation, and numbness and upper extremi-
ty tingling. Imaging indicated that she had a
left occipital lesion that enhanced on adminis-
tration of a contrast agent. A complete resec-
tion was performed, and her symptoms
improved. Pathological analysis of the resec-
tion was consistent with a meningioma.
The patient did well for fourteen years but
redeveloped visual and neurological symptoms
and was found to have local recurrence of the
lesion. At this time, histopathological analysis
showed the lesion to be HPC. Re-review of the
pathological analysis done of the original
lesion demonstrated that the tumor was a HPC
that had been misdiagnosed as a meningioma.
The patient underwent a course of radiothera-
py to the left tentorium cerebellar region at a
dose of 5400 cGy. Three years later, she devel-
oped right upper abdominal pain syndrome,
and a computed tomography (CT) scan showed
a large mass that filled the right lobe of the
liver. She underwent a biopsy and a right hepa-
A
B
Figure 1. A. Preoperative axial CT scan of
C3. Note the destructive process involving
the vertebral body. B. Preoperative coronal
CT scan of C3.
[Rare Tumors 2009; 1:e43]
Correspondence: Meic H. Schmidt, Department of
Neurosurgery, University of Utah, 175 N. Medical
Drive, Salt Lake City, UT 84132, USA
E-mail: meic.schmidt@hsc.utah.edu
Key words: hemangiopericytoma; neoplasm;
spinal.
Acknowledgments: we thank Kristin Kraus,
M.Sc., for editorial assistance in preparing this
paper for publication.
Contributions: Dr. Cole prepared the manuscript
under supervision of Dr. Schmidt, who also criti-
cally reviewed and contributed to the content.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 7 August 2009.
Revision received: 17 September 2009.
Accepted for publication: 17 September 2009
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright C.D. Cole and M.H. Schmidt, 2009
Rare Tumors 2009; 1:e43
doi:10.4081/rt.2009.e43
tectomy, and the tissue was found to be consis-
tent with metastatic HPC. Along with the
metastasis in the liver, a lesion at the C3 ver-
tebral body was found (Figure 1). On follow-up
clinical evaluation, the patient had mild neck
pain, with no motor deficits or sensory deficits.
Figure 2. Preoperative T2-weighted axial
MR image of C3. The hyperintense lesion
is noted anterior to the spinal canal within
the vertebral body of C3 adjacent to the
left vertebral artery.
 Case Report

Table 1. Reported cases of spinal HPC.

Study Age Level Treatment Follow-up Outcome

(yrs)/Sex period
Extradural
Schirger et al. 33/F T2 Surgery 1 yr Recurrence
195843
Kriss et al. 16/M C6-C7 Surgery, RT 9 No symptoms of
196820 months recurrence
Fathie 21/M T6 Surgery – –
197019
Pitkethly et al. 6 spinal tumors reported, no additional information
Figure 3. Postoperative sagittal CT of the
cervical spine. A corpectomy of the verte- 197036
bral body has been performed with the McMaster et al. – T1,T2 Surgery – –
placement of a titanium mesh cage, 197544 – T6,T7 Surgery – –
PMMA, and an anterior cervical plate.
– T10 Surgery – –
– T11 Surgery – –
– S1 Surgery – –
Stern et al. 31/F C6 Surgery 1 yr Tumor free
198045
Muraszko et al. 41/F L2 Surgery – –
198221 15/M T12 RT then surgery – –
11/F T11 Surgery, RT 6 yrs Recurrence at 3
yrs, surgery/RT
recurrence at 6 yrs
Bridges et al. 25/M S1 Surgery, RT 9 Tumor free
198846 months

Cappabianca et al. 52/F C6 Surgery 1 Died (unknown

198117 36/F C5 Surgery month cause)
2 yrs Died (unknown
cause)
Ciappetta et al. 48/M C4 Surgery 7 yrs Recurrence at 6 yrs
Figure 4. Postoperative T2-weighted sagit- 198518
tal MR image of the cervical spine. A cor-
pectomy of the vertebral body has been Ijiri et al. 39/F L1-L2 Surgery 2 yrs Tumor free
performed, and the C3 vertebral body is 200247
distorted by the placement of a titanium Akhaddar et al. 39/M Thoracic Surgery, RT – Tumor-free
mesh cage, PMMA, and an anterior cervi-
cal plate. 200248
Mohammadianpanah 21/M T2 Surgery, RT – –
et al. 200449
Primary osseous
Magnetic resonance imaging (MRI) of the
cervical spine showed an extensive lesion of Gerner et al. 62/M L5 Surgery, RT – –
the C3 vertebral body that occupied approxi- 197450
mately 90% of that vertebral body. It was direct- Wold et al. 47/F Sacrum Surgery, RT 1.5 yrs Died (unknown
198251 62/F Sacrum – – cause)
ly adjacent to both vertebral arteries, and there
33/F Vertebra Surgery 31 yrs Died (unknown
was no evidence of epidural extension (Figure
37/F Sacrum Surgery, RT 5 yrs cause)
2). An attempt was made to embolize the
Died (unknown
tumor, which had high vascularity, but the pro- cause)
cedure was unsuccessful because there was Died (unknown
significant arterial supply to the anterior cause)
spinal artery. None of the branches were large
Tang et al. 19/M L2 Chemotherapy, 4 yrs Local recurrence
enough to be accessed safely for embolization.
198824 RT, surgery after 3 years,
Two months later, the patient underwent a C3
treated with
corpectomy with removal of the tumor en bloc.
chemotherapy,
To reconstruct the vertebral body, a titanium persistent growth
mesh cage, polymethylmethacrylate (PMMA), 1 yr later
and an anterior cervical plate were used
(Figure 3).7 Follow-up radiation treatment of RT, radiation therapy; –, not available.

[Rare Tumors 2009; 1:e43] [page 133]

Case Report

the cervical spine was administered with a

total dose of 3750 cGy in 15 fractionated doses Table 2. Reported cases of metastatic HPC to the spine.
over 21 days. Clinical and imaging monitoring
during the past four years has demonstrated Study Age Time until Location of Location Treatment Outcome
no local recurrence or other spinal metastasis (yrs) metastasis primary of
(Figure 4). /Sex (yrs) tumor metastasis
Cranial meningeal
Discussion Kruse 22/F 8 Frontoparietal Lumbar Surgery –
196152 vertebra
HPCs are soft tissue tumors composed of Scott et al. 38/M 16 Posterior T12/L1 Surgery, RT Improvement
capillary blood vessels with one or more layers 197453 cranial fossa but death
of rounded cells showing features of pericytic after
differentiation. The thick-walled, branching complication
‘staghorn’ vessels are easily identified. Nonaka et al. 40/F 9.5 Tentorium T8 Surgery, RT Good
Pericytic differentiation, which is more diffi- 199826 recovery
cult to diagnose, has been based historically on Woitzik et al. 40/F 8 Frontal C6-T2 Surgery, RT Good
the presence of elongated cell processes, peri- 200316 recovery
cellular basal lamina, plasmalemmal pinocyto- 9 L2 RT Not stated
sis, and variable numbers of microfilaments.8 Lee et al. 48/F 6.5 Middle cranial C6-C7 Surgery, RT Improvement
Immunohistochemical analysis has shown that 200625 fossa
these tumors usually express muscle-specific Taniura et al. 30/F 4 Posterior L4-S1 Surgery, RT Improvement
actin, smooth muscle actin, and tropomyosin 200754 cranial fossa
but are mostly negative for desmin and h- Present 36/F 17 Posterior C3 Surgery, RT Good
caldesmon.9,10 case cranial fossa recovery
The clinical behavior of HPCs, especially
extrapleural HPCs, is unpredictable.
Extracranial locations
Approximately 10% to 15% of these tumors
demonstrate malignant behavior in the form of Mao and 56/M – Heart; – Surgery, RT Death due to
recurrent or metastatic disease.11,12 Systemic Angrist spine: L3 cardiac arrest
metastases from intracranial HPCs have been 196755
reported. The specific criteria that define Herrmann 68/F 2 Right arm T8 Surgery Gradual
malignancy for HPCs include large tumor size et al. (subtotal), RT improvement
(>50 mm), disseminated disease at presenta- 196856 of paraparesis
tion, infiltrative margins, high cellularity, Harris et al. 46/M 4 Groin; lung 3 C5 Surgery, RT, Neurological
nuclear pleomorphism, areas of tumor necro- 197857 years later chemotherapy deterioration
sis, and an increased mitotic index (>4 Hansen et al. 50/M 17 months Lung L3 RT ‘Relief of
mitoses per 10x high-powered field).11-14 199058 symptoms,’
Nevertheless, the correlation between mor- patient
phology and outcome is poor: some histologi- refused
cally malignant-looking lesions may behave further
benignly, and some morphologically innocuous treatment
lesions behave aggressively.1,11,13,15 Brass et al. 48/M 5 Lower T2-3 Partial 1 yr
Cases of spinal HPC are much less common 200459 cervical and resection, RT recurrence, at
than cases involving other anatomical loca- upper 2 yrs
tions. Intraspinal extradural M-HPCs and pri- thoracic complete
mary osseous HPCs are difficult to differenti- musculature sensory-motor
paralysis at
ate but are more frequent than intradural
T4 level
HPCs and secondary osseous HPCs. Thirty-one
cases of extradural and primary osseous spinal RT, radiation therapy; –, not available.
HPC have been reported within the English lit-
erature (Table 1). HPCs of intracranial or
extracranial primary sites that metastasize to the cervical spine. Often, but not always, these neck pain or pain accompanied by weakness.25
the spine (Table 2) are much rarer.5,6,16 tumors demonstrate a dural attachment.17-21 Once symptomatic spinal metastasis is diag-
Intradural spinal HPCs (Table 3) are as rare as Because of the involvement of the epidural nosed, there is no satisfactory treatment
these latter two spinal HPC subtypes. space, radiculomyelopathy is a common find- modality to stop the fast and fatal progres-
We have separated extradural (intraspinal) ing.22,23 In contrast, primary osseous HPCs of sion.25 Bone scintigraphy may be a useful
from primary osseous HPCs according to their the spine mostly affect the lumbosacral spine screening tool to detect osseous metastasis
original case reports, although delineating and have paravertebral extension 24 but do not early; however, a single negative scan may not
them is often difficult. In reviewing the litera- result in neurological deficit. The most com- be sufficient to confirm that there has been no
ture, we found that different clinical features mon complaints are pain and mass effect.24 bony metastasis.26 In addition, gadolinium-
have been observed in extradural M-HPC and Spinal metastasis should be considered a enhanced MRI provides a very sensitive
primary osseous HPC. Extradural HPCs gener- possibility when a patient who has been treat- method of detecting spinal metastasis. For
ally involve the middle and lower portions of ed previously for HPC presents with back or those patients who survive more than several

[page 134] [Rare Tumors 2009; 1:e43]


years after the diagnosis of their primary HPC,
aggressive spinal surveillance should be advo-
cated.25
Several long-term studies have documented
the propensity of M-HPCs to recur locally or
regionally within the cranial or spinal
meninges.2,27-36 Results from the literature sug-
gest that complete excision is more successful
in preventing or delaying recurrence than is
incomplete excision.2,27,31,34,37,38 Complete exci-
sion at the first operation significantly extend-
ed the average time before first recurrence
from 43 months to 111 months. The five-year
recurrence-free rate for those patients treated
with complete excision was 72.7%, whereas
that for those patients treated with incomplete
excision was just 20.8%.
The surgeon should be prepared for a sub-
stantial amount of bleeding during tumor exci-
sion because of the high vascularity of HPCs.16
This bleeding can lead to high surgery-related
morbidity and mortality and can be the great-
est hindrance to gross total resection.
Preoperative embolization can be used to
reduce blood loss. Thus, en bloc resection with
extratumoral devascularization is the option
most likely to reduce operative blood loss and
possibly decrease the risk of recurrence; how-
ever, this may not be possible for those tumors
with extensive premedullary portions.16 When
considering resection options, the surgeon
should also be mindful that a piecemeal
removal is associated with an earlier recur-
rence rate.5
Even after en bloc resection, the possibility
of recurrence necessitates close monitoring of
the patient and consideration of adjuvant ther-
apy. The length of survival for each patient also
depends on the site and size of the primary
tumor.39 Tumors larger than 6 cm are associat-
ed with much poorer prognosis than are small-
er tumors.14 Outcomes for patients with
intradural and extradural HPCs have been
found to be similar. Even with the similar
recurrence rates, however, disease-free sur-
vival was longer for those patients with an
intradural lesion (average of 6 years before
recurrence).5
Although surgery alone offers local control
of several years on average, the addition of
postoperative radiotherapy (RT) to surgical
treatment appears to be the best long-term
treatment option for HPCs.32 Using intensity-
modulated RT and fractionated stereotactic RT
with high radiation doses, the morbidity asso-
ciated with adjacent organ damage, especially
spinal cord toxicity, is minimized.40,41 Combs et
al.40 analyzed the use of high-precision RT in
patients with HPC, including 2 spine cases.
They demonstrated an overall survival rate of
100% at 5 years and 64% at 10 years for
patients treated with a combination of surgical
and RT approaches.
Radiosurgery and intensity-modulated RT
Table 3. Reported cases of spinal HPC.
Study Age Level
(yrs)/Sex
Kruse 196152 53/M C3
Pitlyk et al. 60/M C4
196560 49/F C3
39M T8
Muraszko et al. 30/M L3
198221
Betchen et al. 31/M L4
20025
RT, radiation therapy; –, not available.
can be considered in the setting of prior radia-
tion, although the role of radiosurgery for
metastatic spine disease is evolving because
new technologies that deliver higher, more
conformal doses of radiation could result in
better local control.42 The use of chemotherapy
remains controversial, as most attempts have
been disappointing.
Conclusions
Intradural, intraspinal extradural menin-
geal/primary osseous, and secondary metastat-
ic osseous HPCs in the spine are rare and have
only been infrequently reported. Regardless of
the subtype, complete surgical removal and RT
appear to be treatment of choice for HPC in the
spine. Overall and progression-free survival
times of patients with HPCs have continuously
improved; however, the treatment of HPC is
still unsatisfactory and remains a great chal-
lenge.
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Cervical intramedullary
schwannoma: a case report
and review of the literature
Jardel Mendonça Nicácio,1 José Carlos
Rodrigues Jr,2 Marcos Henrique Lima
Galles,2 Igor Vilela Faquini,1 Clemente
Augusto de Brito Pereira,3 Mario Ganau4
1
Pediatric Neurosurgery Fellow of the
Federal University of São Paulo, Brazil;
2
Neurosurgeon of the Heliopolis Hospital,
Brazil; 3Chairman of Neurosurgery of the
Heliopolis Hospital, Brazil; 4Resident in
Neurosurgery of the University of
Verona, Italy
Abstract
Intramedullary schwannomas unrelated
with neurofibromatosis are uncommon
tumors, but if correctly diagnosed and properly
treated they may have a good prognosis.
They have a wide range of clinical presenta-
tions, commonly presenting as a slowly pro-
gressive motor or sensory syndrome. We pres-
ent a case report of a patient without neurofi-
bromatosis with a surgically treated cervical
intramedullary schwannoma.
Introduction
Spinal schwannomas are tumors originating
from the Schwann cells1 and correspond to
30% of spinal tumors, most of which have an
intradural extramedullary location.2
They are generally associated with neurofi-
bromatosis types 1 and 2.3
Intraparenchimal schwannomas of the cen-
tral nervous system (CNS) are extremely rare
when no relationship with neurofibromatosis
is present and several parts of CNS can be
affected, such as the spinal cord, cerebellum
and brain stem.4-6
Intramedullary lesions represent 0.3% of all
medullary tumors and 1.1% of spinal schwan-
nomas.7 This article reports a case of
intramedullary schwannoma and presents a
review of literature.
Case Report
Our patient is a 40-year old Caucasian male.
He was admitted to the department of
Neurology and Neurosurgery of the Heliopolis
Hospital, São Paulo, Brazil, presenting spastic
tetraparesis and sphincterian disturbances.
The symptoms had developed progressively
with onset two years before admission.
Initially the patient complained of left infe-
rior limb weakness that affected the right infe-
rior limb after five months together with uri-
nary urgency , high thoracic column pain with-
out irradiation and arms and shoulders muscu-
lar fasciculations. After ten months the pares-
thesia and motor weakness achieved the supe-
rior limbs. The neurologic examination
showed an asymmetric progressive spastic
tetraparesia especially in the left side whith
impaired deambulation. Diffuse pyramidal
signs and normal deep sensitivity were also
described. The first diagnostic hypothesis was
amyotrophic lateral sclerosis and the patient
was treated with rilusole for 14 months. After
this, and given his physical weakness and
sphincterian dysfunction progression, he
sought assistance from another medical center
where a cervical spinal magnetic resonance
(MRI) was performed. This demonstrated a
C4-C6 intramedullary lesion (hypointense in
T1-weighted, hyperintense in T2-weighted,
[Rare Tumors 2009; 1:e44]
Rare Tumors 2009; volume 1:e44
Correspondence: Igor Vilela Faquini, Rua Dr
Diogo de Farias, 1201, apt. 148, Vila Clementino,
São Paulo, 04037004, Brazil.
E-mail: ifaquini@yahoo.com.br
Key words: intramedullary schwannomas, spinal
cord tumors, neurofibromatosis.
Contributions: CABP conceived and supervised
the paper, and approved the final version; JMN
and IVF wrote and translated the article; MHL and
JCJ gathered the data; MG helped in the transla-
tion and critical analysis of the paper.
Conflict of interest: the authors report no con-
flicts of interest.
Received for publication: 7 July 2009.
Accepted for publication: 14 July 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright J. M. Nicácio et al., 2009
Rare Tumors 2009; 1:e44
doi:10.4081/rt.2009.e44
Figure 1. Pre-
operative cervi-
cal spine mag-
netic resonance
(Sagittal T1- and
T2-weighted
images).
Figure 2. Post-
operative magnetic
resonance. Gross
total ressection.
[page 137]
Case Report

heterogeneous contrast impregnation and

syrin-gomyelia) (Figure 1). Intravenous Figure 3. Electronic microscopy of a
schwannoma with palisade cells and
steroids were started in the pre-operative peri- Verocay bodies.
od (30 mg/kg in bolus) followed by a mainte-
nance 5.4 mg/kg dosage over the following 23
hours. Surgical treatment was made through a
C3-C5 laminotomy with a careful duramater
microscopic opening, one centimeter mieloto-
my and tumor subtotal resection (Figure 2).
The intraoperative aspect of the lesion was
of a grayish and infiltrative mass making total
resection impossible. The nerve roots were not
involved by the tumor.
Microscopically examination demonstrated
compact palisade cells with lined nucleus
mixed with some enucleated areas called Table 1. Intramedullary schwannoma cases without Von Recklinghausen disease.
Verocay bodies (Figure 3).
During the immediate post-operative period
Author/year Sex Topography Duration of symptoms Treatment
a worsening of tetraparesis was noted with
recovery in the first 48 hours. After 24 months, Penfield, 19329 M C5 8 years Subtotal resection -
a significant regression of the motor and
Rasmussen, 194019 M C4 – C7 4 years Subtotal resection PR
sphincterian dysfunction was observed and
this allowed the patient to hold objects with his Roka, 195120 M Cervical 3 years Subtotal resection Worsening
hands and walk with help again. Riggs & Clary,195716 M C4 – C5 3 years Autopsy finding -
Ramamurthi, 1958 8
M T2 9 months Total resection PR
Lang & Bridge, 195921 M Cervical 1 year Total resection PR
Discussion M Thoracic 3 years Total resection Worsening
Scott & Bentz, 196222 F T3 – T4 12 years Subtotal resection Stable
The first surgical description of a spinal Lu, et al., 1963 23
M C4 – C5 3 months Total resection + RDT PR
tumor was made in 1888 by Sir Victor Horsley8 M C2 – C5 18 months Subtotal resection PR
who reported an extramedullary intradural McCormick, 196417 M L2 6 weeks Autopsy finding -
meningioma resection. However, it was just in
1907 that Von Eiselberg published the success- Slooff, et al., 1964 24
M C4 – C7 4 years - -
ful resection of an intramedullary neurofi- Guidetti, 196725 - Connus - Total resection TR
brosarcoma. Though Kernohan has been Mason & Keigher, 1968 26
M T8 – T10 3 months Total resection PR
recognised as the first neurosurgeon to report
Chigasaki, 196827 F T3 - Subtotal resection -
an intramedullary schwannoma case in 1952,
Penfield had already described an Van Duinen, 1971 28
M C3 - Total resection -
intramedullary lesion with schwannoma char- Cambier, et al., 197429 M C2 – C4 16 months Total resection Worsening
acteristics in 1932.9 Wood, et al., 19752 M C1 – C3 3 months RDT Death -PE
Up until today, approximately 50 cases of
intramedullary schwannomas not related to Schmitt, 197530 M Connus 6 months Autopsy finding -
neurofibromatosis have been described, some Isu, et al., 197631 F C1 6 months Subtotal resection -
of them are shown in Table 1. The melanotic Pardatscher, et al., 197932 M C4 – T9 9 months Decompressive Death
schwannomas, although not the scope of this
Vailati, et al., 197933 F T8 – T9 1 year Total resection PR
discussion, are even rare; from 39 cases
reported, just 5 were intramedullary lesions Shalit & Sandbank, 198134 F C2 – T2 6 months Total resection + RDT TR
and 10% of those malignized,10 as shown in Cantore, et al., 198235 M T12 – L1 - Total resection TR
Table 2. F C3 – C5 2 years Total resection PR
The male:female ratio for intramedullary Lesoin, et al., 198336 F C3 – C7 6 months Total resection TR
schwannomas is 3:1 with a mean age of 40- M Conus 5 years Total resection TR
years old. They are usually single lesions
affecting the cervical spinal cord (63%), the Rout, et al., 198337 F C2 – C6 5 years Total resection TR
thoracic spinal cord (26%) and the lumbar F C2 – C5 5 years Subtotal resection PR
spinal cord (11%). They have a slow growth Sharma, et al., 19843 M C2 – C6 18 months Total resection TR
pattern and because of this the average inter- Ross, et al., 1986 7
M C4 – C5 4 months Total resection TR
val between first symptoms and diagnosis is F C2 – T1 4 years Subtotal resection PR
28.2 months (from six months to 20 years).11
Gorman, et al., 198938 F C2 – C5 8 months Total resection PR
The most described clinical manifestation is
the pyramidal syndrome followed by sensitivity Herregodts, et al., 1991 1
F T3 – T4 5 years Total resection PR
complaints and sphincterian dysfunction. Nicácio, et al., 2007 M C4 – C6 2 years Subtotal resection PR
There are reports of muscular fasciculations as
the first symptom. Another complaint is the RDT, radiotherapy; PR, partial recovery; TR, total recovery; PE, pulmonary embolism.

[page 138] [Rare Tumors 2009; 1:e44]


Table 2. Intramedullary melanotic schwannoma cases in literature.
Author/year Age Signs and Duration of Location
/Sex symptoms symptoms
Solomon, et al.39 69/M Brown-Séquard
Marchese &McDonald40 72/F Tetraparesis
Sola-Perez, et al.41 63/F Radicular pain
Acciarri, et al.,42 44/F Tetraparesis
Santaguida, et al.10 35/M 39 M Hemip./Parap.
RDT, radiotherapy; CMT, chemotherapy; PR, partial recovery .
motor-sensitive alternal deficit associated with
amiotrophy in patients with predominantly
one-sized located medullary tumors.12 The X-
ray findings are correlated to tumoral growth
characteristics.
Mielography denotes precisely the tumor
location and the relationship with dura mater
and the spinal cord. However, MRI is the gold
standard to study intramedullary tumors.
In 1988, Takemoto stated that MRI allows
pre-operative diagnosis of schwannomas, neu-
rofibromas, meningiomas and hemangioblas-
tomas.13 On the other hand, according to
Nicoletti in 1994, neither the MRI nor CT scan
can differentiate the intramedullary tumor his-
tological type.14 Sagittal and axial images
demonstrate a widening of the spinal cord.
Perilesional edema and cystic cavities can
be observed. These tumors are hypointense or
isointense on T1-weighted sequences and gen-
erally hyperintense on T2-weighted sequences.
When gadolinium is injected there is a hetero-
geneous enhancement.
According to Demachi, there is no correla-
tion between the classification of Antoni and
the MRI findings.15 The Antoni A-type is char-
acterized by the presence of compact wave-
shaped cells rounded by a reticular net. The
Antoni B-type has large and loose cells sur-
rounded by a collagenous web.12
The infiltrative pattern of some intra-
medullary schwannomas make total gross
resection impossible and some authors sug-
gest in these cases the use of radiotherapy for
residual lesions.2 According to the new WHO
classification of tumors there are three types
of schwannomas: cellular, plexiform and
melanotic.
However, the controversial question about
this pathology emerges from the unknown
pathogenesis. Previous studies have claimed
that the central nervous system cells have no
Schwann cells, thus making the presence of
intramedullary schwannomas a paradox.
In the pursuit of an answer to that question,
several theories have been suggested over the
last fifty years. In 1957, Kernohan, McCarty,
Riggs and Clary proposed that the origin of
such lesions could be from Schwann cells' pro-
Treatment Results
4y C3 Total resection
20 y C4-C6 Total resection PR
C7 - T1 Partial resection PR
10 y T2 - T3 Total resection PR
10 m C4-C5/C4-C6 Total resection
+ CMT+RDT
liferation derived from nerve fibers of the
spinal arteries.16
Ramamurthi et al. suggested that a few
ectopic Schwann cells of the embrionary neu-
ral tube (during the fourth gestational week)
could be the origin of these schwannomas.8
In 1964, MacCormick and Wood stated that
intramedullary schwannomas came from some
Schwann cells found in aberrant intra -
medullary nervous fibers arising through the
posterior roots.17 But the most acceptable theo-
ry was reported by Rusell and Rubenstein in
1971. According to them, these tumors emerge
from the transformation of neuroectodermal
pial cells into Schwann cells, leading to a pos-
sible fast neoplastic growth of Schwann cells
located in a “critical area” in the dorsal roots.18
Conclusions
Although rare, the intramedullary schwan-
nomas should be considered as a possible diag-
nosis for young adults presenting with an
intramedullary lesion. Once suspected, surgi-
cal treatment is recommended. Gross total
resection is the goal but sometimes this can-
not be accomplished due to the infiltrative
characteristic of the tumor. Finally, a better
understanding of the etiology and phys-
iopathology will certainly contribute to the
treatment of these patients.
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33. Vailati G, Occhiogrosso M, Troccoli V.
Intramedullary thoracic schwannoma.
Surg Neurol 1979;11:60-2.
34. Shalit MN, Sandbank U. Cervical intra-
medullary schwannoma. Surg Neurol
1981;16:61-4.
35. Cantore G, Ciappetta P, Delfini R, et al.
Intramedullary spinal neurinomas. Report
of two cases. J Neurosurg 1982;57:143-7.
36. Lesoin F, Delandsheer E, Krivosic I, et al.
[Rare Tumors 2009; 1:e44]
Solitary intramedullary schwannomas.
Surg Neurol 1983;19:51-6.
37. Rout D, Pillai SM, Radhakrishnan VV.
Cervical intramedullary schwannoma.
Case report. J Neurosurg 1983;58:962-4.
38. Gorman PH, Rigamonti D, Joslyn JN.
Intramedullary and extramedullary
schwannoma of the cervical spinal cord-
case report. Surg Neurol 1989;32:459-62.
39. Solomon RA, Handler MS, Sedelli RV, Stein
BM. Intramedullary melanotic schwanno-
ma of the cervicomedullary junction.
Neurosurgery 1987;20:36-8.
40. Marchese MJ, McDonald JV. Intra-
medullary melanotic schwannoma of the
cervical spinal cord: report of a case. Surg
Neurol 1990;33:353-5.
41. Sola-Perez J, Perez-Guillermo M, Bas-
Bernal A, et al. Melanocytic schwannoma:
the cytologic aspect in fine-needle aspira-
tion cytology (FNAC): report of a case
located in the spinal cord. Diagn
Cytopathol 1994;11:291-6.
42. Acciarri N, Padovani R, Riccioni L.
Intramedullary melanotic schwannoma.
Report of a case and review of the litera-
ture. Br J Neurosurg 1999;13:322-5.

Primary mediastinal giant cell
tumor
Judd Goldberg, Shameen Azizad, Jela
Bandovic, Arfa Khan
Long Island Jewish Medical Center, New
Hyde Park, NY, USA
Abstract
Giant cell tumor of soft tissue is a rare
tumor first described by Salm and Sissons in
1972 as being a distinct entity.1 Histologically,
it is composed of multinucleated giant cells
dispersed among mononuclear cells, and is
indistinguishable from its bone equivalent.2
The majority of these tumors have been report-
ed to occur in the lower extremity.2,3 We
describe a case of giant cell tumor of soft tis-
sue within the posterior mediastinum. The
only other report of a primary mediastinal
giant cell tumor of soft tissue in the English lit-
erature was published by Fu et al. in 2002, in
which they described two patients with poste-
rior mediastinal masses.4
Case Report
A 53-year-old man with a history of hyper-
tension presented with increasing left anterior
chest pain. He was seen by a cardiologist and
had a treadmill stress test, which was normal.
A chest radiograph revealed a large left medi-
astinal mass (Figure 1). A follow-up non-con-
trast chest CT scan showed a large left posteri-
or mediastinal mass with compression of the
adjacent lung (Figure 2). There was pressure
erosion and sclerosis of the left posterior fifth
rib, suggestive of a slowly growing mass. The
mass contained areas of low density suggest-
ing necrosis. It was unclear on the CT scan if
the mass was arising from the rib, pleura, or
soft tissue. One week later, the patient had a
bronchoscopy, which was negative for malig-
nant cells. A PET-CT scan showed patchy
hypermetabolic uptake within the mass con-
sistent with malignancy without evidence of
metastatic disease. A CT-guided core biopsy of
the mass was performed, which revealed a
giant cell tumor.
A left lateral thoracotomy was performed
with gross resection of the tumor via a left
lower lobectomy and partial left chest wall
resection. Gross examination revealed a 13 cm
mass within the extra-pleural left chest wall
with compression of the adjacent lung and ribs
(Figure 3). Fragments of the fourth, fifth,
sixth, and eighth ribs showed no evidence of
tumor. Microscopic examination demonstrated
Rare Tumors 2009; volume 1:e45
the mass to be composed of a mixture of round
and oval mononuclear and multinucleated Correspondence: Judd Goldberg, Long Island
osteoclast-like giant cells with a background of Jewish Medical Center, 270-05 76th Ave,
rich vascular stroma (Figures 4 and 5). The New Hyde Park, NY 11040, USA.
tumor also showed areas of cystic degenera- E-mail:juddgoldberg@gmail.com
tion and hemorrhage. There was no increase
Key words: primary mediastinal giant cell tumor.
in the mitotic index. Immunohistochemically,
the mass was positive for CD68 and CD34, and Received for publication: 30 July 2009.
was diagnosed as a giant cell tumor of soft tis- Revision received: 13 October 2009.
sue. Five mediastinal lymph nodes were Accepted for publication: 16 October 2009.
resected without evidence of malignancy. The
patient had an uneventful postoperative This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
course and received postoperative radiation
treatment to the left chest wall. A follow-up ©Copyright J. Goldberg et al., 2009
non-contrast chest CT scan did not show evi- Rare Tumors 2009; 1:e45
dence of recurrent disease or metastases. doi:10.4081/rt.2009.e45
A
Discussion
Giant cell tumor of soft tissue is a rare
tumor, which demonstrates a spectrum of
benign to malignant characteristics. Microsco-
pically, these tumors are composed of multinu-
cleated giant cells evenly dispersed among
mononuclear cells, and are histologically indis-
tinguishable from their bone equivalent.2 In
1972, Salm and Sissons were the first to B
describe a series of 10 patients with giant cell
tumors of soft tissue.1 In their study, the
tumors demonstrated benign features without
metastases. However, there was local recur-
rence in two patients. In the same year,
Guccion and Enzinger reported a series of 32
patients with soft tissue tumors similar to
those studied by Salm and Sissons, but with
malignant features and widespread metas-
tases.3 These tumors were called “malignant C
giant cell tumors of soft parts.” In 2000,
O’Connell et al. described a series of 18
patients with giant cell tumors of soft tissue
that demonstrated a spectrum from benign to
malignant behavior determined by the cytolog-
D
Figure 2. Non-contrast axial computed
tomography scan showing A: soft tissue,
and B: lung windows; C: coronal, and D:
sagittal reformations. There is a large het-
erogeneous left posterior mediastinal mass
with sharp lateral margins causing com-
pressive atelectasis of the left lower lobe.
Figure 1. Frontal chest radiograph demon- There is pressure erosion of the adjacent
strating a large left mediastinal mass. posterior rib (A: arrow).
[Rare Tumors 2009; 1:e45] [page 141]
Case Report
Figure 3. Gross specimen of the giant cell
tumor of soft tissue.
Figure 4. Low-power microscopic examina-
tion demonstrating the tumor, tumor cap-
sule, and uninvolved lung.
Figure 5. Microscopic examination at 600X
magnification demonstrating the mass to
be composed of a mixture of round and
oval mononuclear and multinucleated
osteoclast-like giant cells.
[page 142]
ical appearance of the mononuclear cells and
mitotic activity.5 References
Giant cell tumors of soft tissue can be seen
at any age, but usually affect middle-aged 1. Salm R, Sissons HA. Giant-cell tumors of
adults of both sexes. These tumors can occur soft tissues. J Pathol 1972;107;27-39.
in both the superficial and deep soft tissues. 2. Oliveira AM, Dei Tos AP, Fletcher CDM, et
The majority of these tumors reported in the al. Primary giant cell tumor of soft tissues.
literature have been located in the lower Am J Surg Pathol 2000;24:248-56.
extremity, particularly in the thigh.2,3 Other 3. Guccion JG, Enzinger FM. Malignant giant
sites of involvement include the upper extrem- cell tumor of soft parts. An analysis of 32
ities, trunk, and rarely the skin.6 The most cases. Cancer 1972;29:1518-29.
common clinical presentation is a painless soft 4. Fu K, Moran CA, Suster S. Primary medi-
tissue mass.5 astinal giant cell tumors: A clinicopatho-
In a series of 22 patients with giant cell logic and immunohistochemical study of
tumor of soft tissue, Oliveira et al.2 described two cases. Ann Diagn Pathol 2002;6:100-5.
the recurrence rate to be 6.2%, which was less 5. O’Connell JX, Wehrli BM, Nielsen GP, et al.
than the 25% reported recurrence rate of giant Giant cell tumors of soft tissue: A clinico-
cell tumors of bone.1 However, the metastatic pathologic study of 18 benign and malig-
and death rates were determined to be higher nant tumors. Am J Surg Pathol 2000;
in giant cell tumors of soft tissue.1 24:386-95.
Immunohistochemically, the giant cell tumor 6. Holst VA, Elenitsas R. Primary giant cell
of soft tissue in this case report expressed tumor of soft tissue. J Cutan Pathol 2001;
CD68 and CD34. Conversely, the giant cell 28:492-5.
tumors of soft tissue reported in the literature
expressed only CD68.
This case report illustrates a primary giant
cell tumor of soft tissue located within the pos-
terior mediastinum. The only other report of a
primary mediastinal giant cell tumor of soft
tissue in the English literature was published
by Fu et al. in 2002, in which they described
two patients with posterior mediastinal mass-
es.4 Our case is very similar to those described
by Fu et al., as the cells all had low mitotic
activity and the patients had a favorable clini-
cal course without metastases or recurrence of
the tumor.
In conclusion, giant cell tumors of soft tis-
sue are rare tumors that demonstrate a spec-
trum of benign to malignant potential.
Although the majority of these tumors are
located in the lower extremity, they may occur
rarely in the posterior mediastinum and pres-
ent as a posterior mediastinal mass.
[Rare Tumors 2009; 1:e45]

Benign multicystic
mesothelioma:
a case report
of three sisters
Eve M. Bernstein,1 Alison Tate,1
Dan Arin Silasi,2 Thomas Rutherford2
1
Department of Obstetrics and
Gynecology, Yale University, New Haven,
Connecticut; 2Division of Gynecologic
Oncology, Department of Obstetrics and
Gynecology, Yale University, New Haven,
CT, USA
Introduction
Benign multicystic mesothelioma (BMCM)
is a rare tumor of the abdomen-peritoneum of
unknown etiology.1 This benign tumor was ini-
tially described by Plaut in 1928 when he
observed loose cysts in the pelvis during a sur-
gery for a uterine leiomyoma.2 The mesothelial
origin was later confirmed by electron micro-
scopy by Mennemeyer and Smith in 1979.3 To
date, there are approximately 140 cases of
BMCM reported in the literature.4 This disease
primarily occurs in pre-menopausal women
and is associated with a history of pelvic
inflammatory disease, prior abdominal sur-
gery, and endometriosis.4,5 The pathogenesis of
this disease remains controversial, with possi-
ble etiologies including a neoplastic versus a
reactive process.5
In the literature, a few case reports discuss
a possible genetic or familial association with
BMCM.6 Specifically, one report describes a
man with familial Mediterranean fever who
developed BMCM. Although familial Mediter-
ranean fever is associated with malignant
mesothelioma, he had only BMCM, and did not
suffer from malignant mesothelioma.6 A genet-
ic evaluation and chromosomal analysis were
not able to identify a specific genetic cause of
the family’s pattern of disease.
This case report describes two female sib-
lings diagnosed with BMCM. In addition, a
third sister also had findings consistent with
BMCM, however, the discrete histological diag-
nosis was never confirmed.
Case #1
K.S. is a 53-year-old G3P3003 menstruating
female who presented to her gynecologist with
a complaint of intermittent urinary urgency.
She denied symptoms of bloating, fullness, and
constipation. Her gynecological history was
significant for menarche at age 13 with regu-
lar menses, use of oral contraceptive pills for 5
years, and normal pap smears in her lifetime.
The patient had three normal spontaneous
vaginal deliveries. Her medical history was sig-
nificant for hypothyroidism, which was well
controlled on levo-thyroxine. Her past surger-
ies included a benign breast biopsy, wisdom
teeth extraction, and removal of her tonsils
and adenoids. Her family history was signifi-
cant for a maternal grandfather who died of
breast cancer in his 80’s and an aunt with
colon cancer.
On physical exam the patient was a thin,
healthy-appearing woman. She was normoten-
sive, with a blood pressure of 144/78 mmHg,
and a body mass index of 22.8 kg/m2. Her
abdomen was soft with no masses appreciated.
Her pelvic exam was notable for a 7 cm irregu-
lar mass in the cul-de-sac, which was non-ten-
der and immobile.
A transvaginal ultrasound was performed
that revealed bilateral ovarian masses. For fur-
ther evaluation, an MRI was obtained, which
revealed a multilobulated cystic structure with
septations present in the cul-de-sac. CA-125
level was normal (12 U/mL).
The patient underwent a total abdominal hys-
terectomy, bilateral salpingo-oophorectomy, and
tumor debulking to no visible residual disease.
Intra-operative findings included a 14–week
sized uterus with a globular contour and numer-
ous cystic, mucoid lesions on the uterine
serosa. The right ovary had mucinous, grape-
like cystic structures attached. The pelvic peri-
toneum had mucin-like cystic masses scattered
along the pelvic sidewalls as well as in the cul-
de-sac. Numerous similar cystic lesions were
present on the omentum at the level of the
hepatic flexure, along the right lateral margin of
the infracolic omentum and on the mesentery of
the terminal ileum. The fallopian tubes and the
left ovary appeared to be within normal limits.
Intra-operative examination revealed bilat-
eral ovaries and fallopian tubes to have multi-
ple cystic structures on their serosal surfaces.
The cysts ranged in size from 2 mm to 4.5 cm,
and were clear-walled structures containing
thin, clear fluid. The cyst walls contained no
papillary projections and were smooth. Many of
the pelvic sidewall cystic masses that were
resected were macroscopically tan-red in
appearance with irregular membranous tissue.
The largest of these cystic masses measured
9.0x5.0x0.2 cm. On microscopic evaluation,
these cysts were lined with benign appearing
mesothelial cells that were flat to cuboidal.
They stained positive for calretinin immunos-
tain further supporting the diagnosis of benign
multicystic mesothelioma.
The final diagnosis was benign multicystic
mesothelioma, endometriosis, and focal endo-
salpingiosis. The patient had an uneventful
recovery and has had no recurrences one year
after surgery.
[Rare Tumors 2009; 1:e46]
Rare Tumors 2009; volume 1:e46
Correspondence: Eve M. Bernstein, Department
of Obstetrics and Gynecology, Yale University,
New Haven, CT, USA
E-mail: eve.bernstein@yale.edu
Key words: gynecology, oncology, tumors, benign
multicystic mesothelioma, peritoneal mesothe-
lioma, genetic or familial association, peritoneal
inclusion cyst, multilocular inclusion cyst.
Received for publication: 8 July 2009.
Revision received: 1 October 2009.
Accepted for publication: 5 October 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright E.M. Bernstein et al., 2009
Rare Tumors 2009; 1:e46
doi:10.4081/rt.2009.e46
Case #2
M.S., the younger sister of K.S., was 35-
years old when a pelvic mass was discovered
on routine gynecologic exam. She is a G3P3003
with normal spontaneous vaginal deliveries
and a surgical history significant only for wis-
dom teeth removal. She is a non-smoker, takes
no medications, and is allergic to trimetho-
prim-sulfamethoxazole.
After the incidental finding of a pelvic mass,
she underwent a CT scan of the abdomen and
pelvis that confirmed a pelvic mass measuring
8.6x5.3x4.9 cm. It was located posterior to the
uterus, extending to the cul-de-sac, and
described as multicystic-appearing in nature;
no free fluid or ascites were noted. The patient
complained of occasional left lower quadrant
discomfort. Serum tumor markers were within
normal limits.
She underwent a supracervical abdominal
hysterectomy with bilateral salpingo-oophorec-
tomy and lysis of adhesions. Intraoperatively,
multiple cystic grape-like structures along the
pelvic sidewall, cul-de-sac peritoneum, and
bladder were described. Intra-operative frozen
section returned with findings of a benign
multicystic mesothelioma.
The masses were tan-pink in color, polycys-
tic, and semi-translucent on macroscopic
inspection. There were multiple varied sizes of
translucent “grape-like” cysts present along
the ovaries and fallopian tubes bilaterally.
Microscopic evaluation revealed the cystic
structures to be of varying size, and lined with
flat or low cuboidal mesothelial cells contain-
ing serous fluid. Multicystic nodules contained
marked congested fibrovascular tissue, some
with inflammatory cells with varying degrees
of severity. Several of the nodules contained
adenomatoid tumors.
[page 143]
Case Report
After her surgery, the patient was started on
continuous estrogen replacement therapy due
to her desire to prevent estrogen withdrawal
symptoms. She was then followed closely with
ultrasounds and CT scans of the abdomen and
pelvis. Two years after her surgery, the BMCM
recurred with multiple cysts throughout her
pelvis, which has been managed conservative-
ly without further surgery. The patient remains
asymptomatic, and her lesions remain stable.
Case #3
The two sisters presented above have a third
sister, who, at age 46, presented to her gyne-
cologist with a persistent left ovarian cyst. She
underwent a laparoscopic bilateral salpingec-
tomy. Intraoperatively, multiple small “blister-
like” excrescences in the cul-de-sac and on the
surface of the right ovary were noted. The peri-
toneal surfaces and omentum were found to
have multiple “blister-like” excrescences. In
addition, the distal right fallopian tube con-
tained a “simple” cystic structure and the dis-
tal left fallopian tube had a multiloculated cys-
tic structure. Intra-operative frozen section
described these specimens to be benign in
nature. The final pathology returned with
benign mesothelial and serous cysts, hydros-
alpinges, and Walthard cysts. No further stain-
ing was performed to suggest or exclude the
diagnosis of BMCM. This sister remains
asymptomatic and has had no further surger-
ies.
Discussion
Benign multicystic mesothelioma is a rare
lesion that most commonly arises from the
surfaces of the pelvic peritoneum. It has had
several different names used in the literature
due to an ongoing debate regarding its origin.
Alternate nomenclature for this disease
includes: peritoneal inclusion cyst, multilocu-
lar inclusion cyst, and multicystic mesothe-
lioma.7 It most commonly occurs in pre-
menopausal women with a mean age of onset
of 37 years.8 It has been described in post-
menopausal women, and 16-17% of cases have
been reported in men with a mean age of onset
of 47 years.7,9 There is no association with
asbestos exposure.8,10
Most patients are diagnosed incidentally
either on physical exam or as a finding on
imaging, or during laparotomy for other indi-
cations.11 A small number of patients present
with abdominal pain, distention, ascites, dys-
functional uterine bleeding, referred shoulder
pain, dysuria, or dyspareunia.9,11 Rarely, BMCM
presents as an acute abdomen.8 Diagnosis is
[page 144]
difficult as there are no reliable clinical find-
ings, features on imaging, or tumor markers
that are pathogonomic for this tumor.12
Ultrasound and CT scan reveal cystic masses
that cannot be differentiated from other pelvic
pathology.
Differential diagnosis includes both benign
and malignant abdominal lesions including
cystic lymphangioma, endosalpingiosis, ade-
nomatoid tumors, mesonephric duct remnants,
malignant mesothelioma, sarcoma, and non-
Hodgkin’s lymphoma.8,11 Clinically, the differ-
ential diagnosis of BMCM from other ovarian
tumors is important, since BMCM can be treat-
ed with ovarian preservation techniques.11
The pathogenesis of BMCM remains contro-
versial. Some believe it is a reactive process
while others believe it is a neoplastic process.
There is an association between prior surger-
ies, endometriosis, pelvic inflammatory dis-
ease, intra-peritoneal inflammation and
BMCM, which suggests a possible reactive
process. The hypothesis behind the reactive
process pathogenesis says that chronic peri-
toneal irritation may react with mesothelial
cell entrapment, and cause reactive prolifera-
tion and cyst formation.5,11 On the other hand,
others believe that a neoplastic process is the
cause, with a slow progressive nature and
marked tendency to recur after multiple surgi-
cal resections.5
The tumor is usually found on the surfaces
of the pelvic viscera, especially on the peri-
toneum of the cul-de-sac, rectum, and bladder.8
Macroscopically, BMCM appears as solitary or
multi-septated, translucent, grape-like cysts
with thin walls that are separated by fibrous
tissue.6,8 Cyst size can vary from 1-2 mm to
greater than 30 cm, and are usually multilocu-
lar.6,8 The cysts are either empty or filled with
serous, bloody or mucinous fluid. At the time of
diagnosis, the mean cyst diameter is 13 cm.7 In
women it usually arises along the peritoneal
surfaces of the uterus and rectum. In men it
arises along the peritoneal surfaces of the
bladder and rectum.7
Microscopic examination reveals cysts lined
by a single layer of flattened or cuboidal
mesothelial cells without atypia or mitosis.6,8,10
Focal reactive mesothelial changes such as
hobnail-shaped cells and foci of mesothelial
hyperplasia can be present.7 With immunohis-
tochemical analysis, these cells stain positive
for calretinin and cytokeratins, a reflection of
their mesothelial origin.7
Treatment of BMCM primarily involves sur-
gery, as complete resection has been shown to
be the only effective treatment.6 Some authors
have used more aggressive methods with some
success such as laparoscopic laser ablation
with potassium titanyl phosphate,13 sclerosing
therapy with tetracycline, hyperthermic peri-
toneal infusion with cisplatin, and peritonecto-
my with intraperitoneal chemotherapy.14,15 As
[Rare Tumors 2009; 1:e46]
recurrence is common, several investigators
have proposed alternative and more conserva-
tive treatments with hormonal therapy.
Hormonal regulation of BMCM has been
suggested by several authors who point to the
characteristically pre-menopausal state of
patients with this disease.16-18 Additionally, this
disease rarely occurs in post-menopausal
women or after bilateral salpingoophorectomy.
At present, scant literature exists regarding
estrogen receptor (ER) or progesterone recep-
tor (PR) expression in BMCM. A case series by
Sawh et al.16 found that some BMCM tumors
stain positive for either estrogen or proges-
terone receptors, or both. They identified 17
cases of BMCM at their institution spanning
over a 20 year period with sufficient clinical
and pathological tissue for evaluation.
Immunohistochemical staining for ER and PR
were performed on all samples and among
these three were identified with ER and or PR
expression. One case revealed the mesothelial
lining to be diffusely positive for ER only. A sec-
ond case was focally positive for PR and a third
case revealed the mesothelial lining to be focal-
ly positive for both ER and PR. These authors
speculate that the finding of hormone receptor
expression in only 3 of their 17 patients may be
the result of metaplastic changes in the cells
lining the cyst walls. Alternatively, immunohis-
tochemical studies may not be sensitive
enough to detect clinically relevant levels of
hormone receptor expression.
Experimental treatment with anti-estrogen
therapy (e.g., tamoxifen), GnRH agonists (e.g.,
leuprolide acetate), and intraperitoneal
chemotherapy have been attempted with vary-
ing degrees of success.11 Letterie et al.17,18
reported on two women with BMCM who
declined surgical management in favor of med-
ical management. The first case report
describes a 17-year old woman who recurred
twice after surgical intervention and was treat-
ed medically. She was started on a GnRH ago-
nist (leuprolide), which initially caused an
increase in the size of her pelvic mass as
measured on ultrasound. After one month of
treatment a decrease in the pelvic mass size
was observed. After 6 months of treatment she
began supplemental estrogen and proges-
terone to counteract the side effects of the
GnRH agonist. Within 4 weeks an increase in
mass size was appreciated and the patient
once again became symptomatic. No immuno-
histochemical staining for estrogen or proges-
terone receptors were performed on the surgi-
cal specimens from her initial surgeries.
A second case described by Letterie et al.18
describes a pre-menopausal woman who was
treated with tamoxifen. Within 4 weeks she
reported a significant reduction in pelvic pain.
Imaging with ultrasound confirmed a decrease
in pelvic mass size. However, no tissue was
obtained for histopathologic evaluation.

True prognosis of BMCM is unclear. The dis-
ease has a high recurrence rate of up to 50%.19
Time to recurrence varies from a few months
to years, with an average of 32 months.10 In
addition, size of lesions, site of disease, extent
of disease burden and previous recurrence
have not been found to be helpful in predicting
future recurrences.16 It is recommended that
patients be followed throughout their lifetime
for recurrences.
Additionally, due to high recurrence rates,
some authors regard BMCM as a borderline
tumor, possibly between the realm of an adeno-
matoid tumor and malignant mesothelioma.6
There are only two case reports to date in the
current literature that describe the malignant
transformation of BMCM to malignant meso-
thelioma.5 One of these cases presented as
both benign and malignant disease simultane-
ously, which makes it impossible to ascertain
which came first. The second case, however,
reports of a young woman who was being fol-
lowed for benign disease, and after 10 years of
conservative management with biopsy-proven
benign disease, malignant transformation
occurred.5
A familial or genetic association with BMCM
has been rarely reported in the literature.6 As
stated in the introduction, there are a few case
reports describing the already well-known
association between malignant mesothelioma
and familial Mediterranean fever. However,
there is another case report of a patient with
familial Mediterranean fever who subsequent-
ly developed BMCM.1 A different case report
discusses two sisters both with a history of
diverticulosis and cataracts who later devel-
oped BMCM. In addition to diverticulosis and
early onset cataracts with retinal detachments,
their family history was also significant for
ovarian cancer, colon cancer, and congenital
defects including renal agenesis, diaphragmat-
ic hernia, and anencephaly.
In our case report of three sisters, there are
no obvious or grossly unusual familial diseases
or anomalies in their family history.
Additionally, none of the sisters reported histo-
ries of the risk factors often associated with
BMCM such as prior surgery, pelvic inflamma-
tory disease or endometriosis.
In conclusion, BMCM is a rare disease with
an uncertain prognosis. It has a high recur-
rence rate with a high likelihood for multiple
medical and surgical treatments over a life-
time. The purported benign nature of this dis-
ease also remains in question. Therefore, a
high level of suspicion with a lifetime of close
follow-up are required for these patients. At
present, our case report is one of few illustrat-
ing a possible genetic association with BMCM.
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Case Report
9. Bansal A, Zakhour HD. Benign mesothe-
lioma of the appendix: an incidental find-
ing in a case of sigmoid diverticular dis-
ease. J Clin Pathol 2006;59:108-10.
10. Saad S, Brockmann M, Maegele M. Benign
peritoneal multicystic mesothelioma diag-
nosied and treated by laparoscopic sur-
gery. J Laparoendosc Adv Surg Tech A.
2007;17:649-52.
11. Safioleas MC, Constantinos K, Michael S,
et al. Benign multicystic peritoneal
mesothelioma: a case report and review of
the literature. World J Gastroenterol 2006;
12: 5739-42.
12. Varma R, Wallace R. Multicystic benign
mesothelioma of the peritoneum present-
ing as postmenopausal bleeding and a soli-
tary pelvic cyst – a case report. Gynecol
Oncol 2004;92:334-6.
13. Rosen DM, Sutton CJ. Use of the potassi-
um titanyl phosphate (KTP) laser in the
treatment of benign multicystic peritoneal
mesothelioma. Br J Obstet Gynaecol 1999;
106:505-6.
14. Sethna K, Mohamed F, Marchettini P, et al.
Peritoneal cystic mesothelioma: a case
series. Tumori 2003;89:31-5.
15. Cuartas JE, Maheshwari AV, Qadir R, et al.
Benign multicystic peritoneal mesothe-
lioma in a cesarean-section scar present-
ing as a fungating mass. Int J Clin Oncol
2008;13:275-8.
16. Sawh RN, Malpica A, Deavers MT, et al.
Benign cystic mesothelioma of the peri-
toneum: a clinicopathologic study of 17
cases and immunohistochemical analysis
of estrogen and progesterone receptor sta-
tus. Hum Pathol 2003;34:369-74.
17. Letterie GS, Yon JL. Use of a long-acting
GnRH agonist for benign cystic mesothe-
lioma. Obstet Gynecol 1995;85:901-3.
18. Letterie GS, Yon JL. The antiestrogen
tamoxifen in the treatment of recurrent
benign cystic mesothelioma. Gynecol
Oncol 1998;70:131-3.
19. Soreide JA, Soreide K, Korner H, et al.
Benign peritoneal cystic mesothelioma.
World J Surg 2006;30:560-6.
[page 145]
Rare Tumors 2009; volume 1:e47
Congenital infantile digital
fibromatosis: a case report
and review of the literature
Valérie Failla,1 Odile Wauters,1
Nazli Nikkels-Tassoudji,1 Alain Carlier,2
Josette André,3 Arjen F. Nikkels1
Departments of 1Dermatology and
2 on the fourth digit of the left hand, which pro-
Surgery, University Hospital of Liège,
Liège; 3Deparment of Dermatology, CHU
Brugman, Brussels, Belgium
Abstract
Infantile digital fibromatosis (IDF) is a rare
benign fibroproliferative tumor of early child-
hood. IDF preferentially affects the fingers and
the toes. Malignant transformation or metas-
tases have never been reported. Surgical treat-
ment has been advocated previously but local
recurrences were observed frequently. Recent
literature supports clinical surveillance with-
out any medical or surgical intervention as
spontaneous regression usually occurs after
two to three years. A six-month-old Caucasian
girl with IDF on the left fourth digit is present-
ed here. The tumor progressively increased in
size after birth. Topical imiquimod cream and
diflucortolone valerate cream, both displaying
antifibrotic properties, had no effect on tumor
growth. Currently the lesion size remains sta-
ble without any treatment. Early recognition of
IDF is important in order to avoid unnecessary
surgical intervention that may prove to be
potentially aggravating, unless serious func-
tional or cosmetic concerns intervene. Parents
should be reassured concerning the benign
nature of IDF and be informed that sponta-
neous involution of IDF might be expected.
Introduction
Infantile digital fibromatosis (IDF) is a rare
benign tumor of fibromatous origin. IDF pref-
erentially occurs during early childhood and is
present at birth in about 30% of the cases.1
Predilection sites include the distal phalanx of
the fingers and the toes. Initially IDF was con-
sidered as a potentially malignant tumor, lead-
ing to the amputation of the affected digits.1-3
More recently several case reports of sponta-
neous regression suggest a benign biological
behavior.3-5 Malignant transformation and
metastases have never been reported.1-6
Histopathology often reveals paranuclear
inclusion bodies within proliferating spindle-
form cells.7 Currently conservative treatment is
recommended according to the benign nature
[page 146]
of IDF, the tendency to spontaneous regression,
and the frequent recurrences after surgery.6,8 Correspondence: Arjen F. Nikkels, Department of
Dermatology, CHU of Sart Tilman, University of
Liège, B-4000 Liège, Belgium.
Case Report E-mail: af.nikkels@chu.ulg.ac.be
Key words: fibromatosis, imiquimod, surgery,
A six-month-old Caucasian girl presented
childhood.
after birth with three reddish, confluent, small,
painless, indurated, ill-circumscribed nodules Contributions: all authors provided substantial
contributions to the conception and design,
gressively increased in size (Figure 1). acquisition or analysis and interpretation of data,
Previous medical history was unremarkable drafting of the article or revising it critically for
and there was no history of trauma or inflam- intellectual content. All authors provided final
mation. No allergic history was reported. The approval of the manuscript.
other hand and both feet were unremarkable.
None of the family members had experienced Conflict of interest: the authors report no con-
similar lesions. There was no functional flicts of interest.
impairment and the size of the lesion did not
Received for publication: 21 August 2009.
appear to bother the child in daily life. No signs
Revision received: 20 October 2009.
of scratching were present. Further clinical Accepted for publication: 21 October 2009.
examination was normal and Rontgen exami-
nation revealed the cutaneous and subcuta- This work is licensed under a Creative Commons
neous location of the lesion without further Attribution 3.0 License (by-nc 3.0).
bone or joint involvement. Six months later a
©Copyright V. Failla et al., 2009
second examination showed no differences
Licensee PAGEPress, Italy
and the developmental stage of the child was Rare Tumors 2009; 1:e47
normal according to age. doi:10.4081/rt.2009.e47
A 3-mm punch biopsy was performed under
local anesthesia, and the histopathology
revealed a fibromatosis affecting the reticular
and adventitial dermis, arranged as sheets and
interlacing bundles of eosinophilic myofibrob-
lasts set in a collagenous background. Some
cells demonstrated eosinophilic cytoplasmic
inclusions (Figure 2). No mitotic figures and
no atypical cells were observed. The overlying
epidermis was unremarkable. A final diagnosis
of congenital IDF was suggested.
As the data in the current literature recom-
mend avoiding surgical intervention, non-
invasive treatments exhibiting anti-fibrotic
properties were sought. A topical treatment
with imiquimod cream (Aldara cream), applied
Figure 1. Infantile digital fibromatosis
three times a week during four weeks, failed to affecting the fourth digit.
reduce the tumor size and was associated with
significant skin irritation, forcing the inter-
ruption of the treatment. Subsequently topical
applications of diflucortolone valerate signifi-
cantly reduced the inflammation although no
effect on the lesion size was observed. Eight
months later the tumor size remained identi-
cal. As no functional concerns were revealed,
conservative management is being followed.
Discussion
IDF is a rare tumor usually affecting one or
more digits.1 Numerous synonyms describe Figure 2. High-power histological presen-
IDF, including Reye’s tumor,9 multiple hyaline tation of the characteristic perinuclear
fibromatosis, infantile dermal fibromatosis, cytoplasmic cellular inclusions found in
subdermal fibromatosis tumor of infancy, infantile digital fibromatosis.
(Hematoxylin and eosin stain).
fibroma durum multiplex, recurrent digital
[Rare Tumors 2009; 1:e47]

fibroma, and juvenile dermatofibroma. IDF typ-
ically develops during the first year of life and
the majority of cases are sporadic. Congenital
onset, although rare, is described also,7,10 as
observed in our patient. Occurrence of IDF in
adulthood has been reported only once in a 52-
year-old woman with a tumor on the dorsum of
the proximal nail fold of the right second toe.11
Clinically IDF presents as smooth, round,
indurate, confluent nodules up to 2 cm in
diameter. The lesions are single or multiple.7,8
The color is pink to reddish. Initially IDF
exhibits an indolent progression followed by a
rapid growth phase during several months.
Subsequently the tumor size remains stable
until spontaneous regression without scarring
occurs.8 IDF is painless and not pruritic. It is
localized usually on the lateral and dorsal
aspects of the fingers and/or toes sparing the
thumb and the great toe. Ulceration may occur.
Functional impairments or deformities are
rare.
Histopathology reveals a proliferation of
myofibroblasts often displaying characteristic
paranuclear eosinophilic inclusion bodies.1
They are juxtanuclear typically and sometimes
indent the nucleus.6,7 Mitotic figures are rare.
Usually the tumor cells immunohistochemical-
ly express vimentin, calponin, desmin, and α-
smooth muscle actin, whereas results for ker-
atin and muscle actin are negative.1 The posi-
tive actin staining suggests the presence of
contractile filaments. Masson trichrome histo-
chemical staining reveals a red staining and a
purple coloration with phosphotungstic acid-
hematoxylin.
The etiology of IDF remains uncertain but
the following hypothesis is proposed currently.
The differentiation from fibroblasts to myofi-
broblasts is a cornerstone process in wound
healing and tissue repair. Myofibroblasts may
create high contractile forces that are benefi-
cial for physiological tissue remodeling but
harmful for tissue function, especially when it
becomes excessive such as in hypertrophic
scars, in nearly all fibrotic diseases, and during
stroma reactions to tumors.12 The intracellular
inclusions suggest a viral origin. However, this
etiopathogenic hypothesis was invalidated as
human papillomavirus HPV DNA types 6, 11,
16, and 18, and herpes simplex virus DNA type
I and II could not be demonstrated in IDF.13 IDF
may be associated with articular alterations
and dysfunction.6,8,14 The etiopathogenesis of
IDF joint deformities is not clear. Given the
presence of contractile proteins within the
pathological cells, as suggested by histochemi-
cal, immunohistochemical, and ultrastructural
studies, they may intervene in the progressive
contracture, especially when the tumor occurs
adjacent to a joint.8
The differential diagnosis of IDF includes
keloids, hypertrophic scar tissue, terminal
osseous dysplasia and pigmentary defects, and
juvenile aponeurotic fibroma.6 The diagnosis
is clinical essentially but histological confir-
mation confirms the diagnosis and prognosis.
The current management of IDF recommends
avoiding surgical intervention, as spontaneous
involution of IDF is the rule.6 In fact, wide local
surgical excision has been associated with a
recurrence rate of up to 60%.1-3 If required by
functional impairment, Mohs micrographic
surgery is recommended.11 An patient with IDF
was treated effectively by Mohs surgery with-
out any residual functional impairment or
recurrence of the tumor.15 However even Mohs
surgery is regularly associated with recur-
rences.12 Consequently surgical treatment
should be avoided unless severe dysfunction is
observed. Several medical approaches have
been evaluated. A 7-year-old boy was treated
successfully with five monthly injections of flu-
orouracil.16 Topical imiquimod, an imidazo-
quinoline amine, acts as a toll-like receptor
(TLR) 7 and 8 agonist and stimulates the
innate and cell-mediated immune system
through induction of interferon-α (IFN-α),
IFN-γ, and interleukin-1, 6, 8, and 12 produc-
tion. Beside the antiviral and antitumor prop-
erties, imiquimod also inhibits human fibro-
blast collagen production by INF-α and INF-γ.17
Topical and intralesional corticosteroids also
display anti-fibrotic properties, and are used
for treating keloids and hypertrophic scars.17
Despite these anti-fibrotic properties, our case
failed to respond to topical imiquimod therapy
and was associated with significant adverse
events. Topical corticosteroid applications
reduced only the inflammatory aspect of IDF
without reducing the lesion size.
In conclusion, IDF is a rare benign child-
hood tumor, which is important to recognize to
avoid unnecessary surgery unless serious
functional concerns intervene. Parents should
be informed of the benign nature of IDF. This
represents a strong argument for a conserva-
tive approach until spontaneous involution
occurs.
References
1. Laskin WB, Miettinen M, Fetsch JF.
Infantile digital fibroma/ fibromatosis: a
clinicopathologic and immunohistochemi-
cal study of 69 tumors from 57 patients
with long-term follow-up. Am J Surg Pathol
2009;33:1-13.
2. Dabney KW, MacEwen GD, Davis NE.
Recurring digital fibrous tumor of child-
[Rare Tumors 2009; 1:e47]
Case Report
hood: case report with long-term follow-up
and review of the literature. J Pediatr
Orthop 1986;6:612-7.
3. Azam SH, Nicholas JL. Recurring infantile
digital fibromatosis: report of two cases. J
Pediatr Surg 1995;30:89-90.
4. Ishii N, Matsui K, Ichiyama S, et al. A case
of infantile digital fibromatosis showing
spontaneous regression. Br J Dermatol
1989;121:129-33.
5. Kawaguchi M, Mitsuhashi Y, Hozumi Y, et
al. A case of infantile digital fibromatosis
with spontaneous regression. J Dermatol
1998;25:523-6.
6. Niamba P, Léauté-Labrèze C, Boralevi F, et
al. Further documentation of spontaneous
regression of infantile digital fibromato-
sis. Pediatr Dermatol 2007;24:280-4.
7. Kanwar AJ, Kaur S, Thami GP, et al.
Congenital infantile digital fibromatosis.
Pediatr Dermatol 2002;19:370-1.
8. Heymann WR. Infantile digital fibromato-
sis. J Am Acad Dermatol 2008;59:122-3.
9. Reye RD. Recurring digital fibrous tumors
of childhood. Arch Pathol 1965;80:228-31.
10. Kang SK, Chang SE, Choi JH, et al. A case
of congenital infantile digital fibromato-
sis. Pediatr Dermatol 2002;19:462-3.
11. Plusjé LG, Bastiaens M, Chang A, et al.
Infantile-type digital fibromatosis tumour
in an adult. Br J Dermatol 2000;143:1107-
8.
12. Hinz B. Formation and function of the
myofibroblast during tissue repair. J Invest
Dermatol 2007;127:526-37.
13. Zhu WY, Xia MY, Huang YF, et al. Infantile
digital fibromatosis: ultrastructural
human papillomavirus and herpes simplex
virus DNA observation. Pediatr Dermatol
1991;8:137-9.
14. Albertini JG, Welsch MJ, Conger LA, et al.
Infantile digital fibroma treated with Mohs
micrographic surgery. Dermatol Surg
2002;28:959-61.
15. Campbell LB, Petrick MG. Mohs micro-
graphic surgery for a problematic infantile
digital fibroma. Dermatol Surg 2007;33:
385-7.
16. Oh CK, Son HS, Kwon YW, et al. Intra-
lesional fluorouracil injection in infantile
digital fibromatosis. Arch Dermatol
2005;141:549-50.
17. Berman B, Harrison-Balestra C, Perez OA,
et al. Treatment of keloid scars post-shave
excision with imiquimod 5% cream: A
prospective, double-blind, placebo-con-
trolled pilot study. J Drugs Dermatol 2009;
8:455-8.
[page 147]
Rare Tumors 2009; volume 1:e48
Giant mesenteric cystic
lymphangioma presenting
with abdominal pain and
masquerading as a
gynecologic malignancy
John Maa,1 Christianne Wa,2
Adnan Jaigirdir,1 Soo-Jin Cho,3
Carlos U. Corvera1
1
Department of Surgery, University of
California; 2University of Southern
California; 3Department of Anatomic
Pathology, University of California, San
Francisco, CA, USA
Abstract
Lymphangiomas are congenital malforma-
tions of the lymphatic system that account for
about 5% of all benign tumors in infants and
children.1 The most common sites are the neck
and axilla, which account for 95% of cases.2
Abdominal cystic lymphangiomas are quite
rare, and can arise from either the retroperi-
toneum, gastrointestinal tract, or the mesen-
tery of the abdominal viscera.3 The presenting
symptoms are painless abdominal distension,
a palpable mass, or secondary complications in
the abdomen such as intestinal obstruction,
volvulus, intestinal infarction, or bleeding.4
Typically diagnosed during childhood, these
tumors prompt surgical intervention. We
describe an atypical case of an abdominal cys-
tic lymphangioma, which did not manifest
until adulthood, with atypical symptoms of a
rapidly expanding and symptomatic mass.
Case Report
A 36-year old gravida 4 para 2 woman came
to the emergency department with vague
abdominal discomfort, abdominal distension,
and decreased energy. She had noted an
abdominal mass while on vacation approxi-
mately one month before presentation, which
had expanded rapidly over the following 10
days. She was healthy otherwise but had
undergone dilatation and curettage for a molar
pregnancy three years previously. Though she
had immigrated to the United States, she did
not report previous exposure to toxic chemical
agents. A palpable fullness in the left lower
quadrant was noted during her physical exam-
ination. A CA-125 blood test for ovarian cancer
and serum laboratory studies were normal. A
computed tomography (CT) scan revealed a
14.0x5.4x16.2 cm cystic lesion in her pelvis and
[page 148]
retroperitoneum, which was suspected to be of
ovarian origin. Magnetic resonance imaging Correspondence: John Maa, 521 Parnassus
(MRI) again demonstrated a multicystic lesion Avenue, San Francisco, CA 94131-0790, USA.
that appeared intense on a T2-weighted image E-mail: maaj@surgery.ucsf.edu
(Figure 1). The mass extended superiorly to
Key words: cystic lymphangioma, mesenteric
the base of the mesentery, abutting the superi-
or mesenteric vessels and occupying the entire lymphangioma, retroperitoneal lymphangioma.
pelvis inferiorly. Although the ovaries and
Acknowledgments: the authors thank Pamela
uterus appeared to be distinct from this mass, Derish, UCSF Department of Surgery, for editori-
a gyneocologic etiology could not be excluded. al assistance and Dr. Annemieke van Zante,
Given the concerns of either a gynecologic UCSF Department of Anatomic Pathology, for
malignancy, pseudomyxoma peritonei, or a review of the pathologic findings.
peritoneal mesothelioma, a curative resection
was planned. During the operation, a multicys- Contributions: JM, AJ, and CC were involved in the
tic mass that appeared to engulf the entire sig- design of the study, perioperative care of the patient,
moid colon was noted. It was well encapsulated and obtaining operative photographs of the tumor.
and was contained within the leaflets of the CW, JM, and CC drafted and revised the manuscript,
grossly distorted sigmoid mesentery. The tran- and approved the final version. SC was involved in
the pathologic examination of the resected speci-
sition to normal colon mesentery proximally,
men and critical revision of the manuscript.
and mesorectum distally, was clear, sharp, and
abrupt, suggesting a benign etiology. There Conflict of interest: the authors report no con-
was no evidence of either carcinomatosis or flicts of interest.
suspicious metastatic tumor deposits. The
fluctuant mass was exteriorized and resected Received for publication: 15 October 2009.
with a wide mesenteric and colon margin. A Accepted for publication: 21 October 2009.
primary hand-sewn anastomosis was utilized
This work is licensed under a Creative Commons
for bowel reconstruction. After an uneventful
Attribution 3.0 License (by-nc 3.0).
recovery, the patient was discharged on post-
operative day five. ©Copyright J. Maa et al., 2009
Gross pathologic evaluation revealed an Rare Tumors 2009; 1:e48
unremarkable segment of colon with an asso- doi:10.4081/rt.2009.e48
ciated large cystic mass (Figure 2). Permanent
sections revealed a benign cystic lymphan-
gioma, composed of innumerable thin-walled
channels, the walls of which focally contained
aggregates of bland lymphocytes. A few clus-
ters of macrophages with moderate amounts of
eosinophilic cytoplasm were present in the
lumina of the cystic spaces, as is seen com-
monly in cystic vascular spaces with sluggish
flow. Immunohistochemical staining for D2-40
(a marker of lymphatic endothelium) showed
positive staining in the attenuated cyst lining
cells, supporting the impression of lymphan-
gioma (Figure 3). In addition, immunohisto-
chemical staining for calretinin (a mesothelial
marker) was performed and the cyst lining
cells were negative, arguing against a cystic
mesothelial proliferation. The left ovary,
although cystic, was uninvolved by the lym-
phangioma.
Discussion
Cystic lymphangiomas are rare congenital
benign malformations of the lymphatic system
Figure 1. Magnetic resonance image
and account for about 5-6% of all benign demonstrating the mesenteric cystic lym-
tumors in infants and children.1 Abdominal phangioma. (A) Axial T2-weighted image.
cystic lymphangiomas are more frequent in White arrow points to the sigmoid colon
boys than girls (5:2), and approximately 80- engulfed by the tumor mass. (B) Sagittal
90% are diagnosed within the first few years of view. White arrow points to the engulfed
sigmoid colon.
life. Approximately 50% of cases involve the
[Rare Tumors 2009; 1:e48]

Figure 2. Gross specimen of resected lym-
phangioma and adjacent sigmoid colon en
bloc.
Figure 3. Immunohistochemical staining of
a representative section of the resected
specimen using the D2-40 antibody (a
marker of lymphatic endothelium).
head and neck, with only 10% occurring in
internal organs.4 These tumors result from an
abnormal embryonic development of the lym-
phatic system causing sequestration of lym-
phatic tissue and fluid, as in our patient.
Clinical manifestations are variable, with-
out characteristic signs and symptoms that can
be attributed solely to the mesenteric lymphan-
gioma. They may present as nonspecific but
painful abdominal symptoms.5 When a cystic
lymphangioma is suspected, either an abdomi-
nal ultrasound examination, CT scan, or MRI
can be used for diagnosis.6 Percutaneous biop-
sy is not recommended because the diagnostic
value is likely to be low owing to the low cellu-
larity index of these tumors. Moreover if the
tumor is demonstrated to be malignant, the
risk of needle tract metastasis or peritoneal
dissemination of the fluid is unacceptably
high. In our patient, the preoperative imaging
studies suggested the mass to be technically
resectable even if malignancy would have been
encountered, thus obviating the need for pre-
operative tissue biopsy. Although laparoscopic
approaches utilizing partial aspiration intraop-
eratively have been described,7 we selected the
open approach via laparotomy given the large
size of the lesion and the concerns of a possi-
ble malignancy.
Our patient is unusual because she was
diagnosed as an adult and experienced the
rapid onset of abdominal swelling and disten-
sion as her presenting symptoms. Given her
previous history of a molar pregnancy three
years before, a possible gynecologic origin of
trophoblastic tissue accounting for the mass
was strongly considered. No abnormalities had
been visualized on her previous abdominal
sonograms for a subsequent pregnancy. The
cause of the rapid expansion of the tumor
remains unknown. No free fluid was found at
surgery to suggest perforation.
Surgeons should be aware of this rare enti-
ty. In our case, the low Hounsfield units on CT
scan raised suspicion of lymphangioma, a
diagnosis supported by the MRI characteris-
tics, particularly on the T2-weighed images.8
However although imaging studies favored a
benign cystic condition, it was important to
consider that the patient might have a malig-
nant mucinous tumor. Accordingly she was
counseled preoperatively that if malignancy
was found, an aggressive surgical approach
would be warranted, potentially involving a
multiorgan resection to achieve gross com-
plete resection or a diverting colostomy.
In conclusion, cystic abdominal mesenteric
[Rare Tumors 2009; 1:e48]
Article
lymphangiomas are rare tumors that can pres-
ent in adult life occasionally, and masquerade
as a malignant gynecologic lesion. Continued
advances in cross-sectional imaging undoubt-
edly will help further distinguish benign cystic
lesions from malignant ones. In the meantime,
we think these cystic tumors should be man-
aged as malignant until proven otherwise.
References
1. Méndez-Gallart R, Solar-Boga A, Gómez-
Tellado M, et al. Giant mesenteric cystic
lymphangioma in an infant presenting
with acute bowel obstruction. J Can Chir
2009;5:E42-3.
2. Jang JH, Lee SL, Ku YM, et al. Small bowel
volvulus induced by mesenteric lymphan-
gioma in an adult: a case report. Korean J
Radiol 2009;10:319-22.
3. Prabhakaran K, Patankar JZ, Loh DLSK, et
al. Cystic lymphangioma of the mesentery
causing intestinal obstruction. Singapore
Med J 2007;48:E265-7.
4. Wani I. Mesenteric lymphangioma in
adult: A case series with a review of the lit-
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5. de Perrot M, Rostan O, Morel P, et al.
Abdominal lymphangioma in adults and
children. Br J Surg 1998;85:395-7.
6. Weeda VB, Booij KA, Aronson DC.
Mesenteric cystic lymphangioma: a con-
genital and an acquired anomaly? Two
cases and a review of the literature. J Ped
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7. Ryu WS, Kwak JM, Seo UH, et al. Laparo-
scopic treatment of a huge cystic lymphan-
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8. Su CM, Yu MC, Chen HY, et al. Single-cen-
tre result of treatment of retroperitoneal
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[page 149]
Rare Tumors 2009; volume 1:e49
Malignant peritoneal
mesothelioma.
Is there a new treatment?
Kakil Ibrahim Rasul,1 David J. Kerr2
1
Al-Amal Hospital, Hamad Medical
Corporation/Doha, Qatar; 2Al-Sidra
Research Center Doha, Qatar
Abstract
The authors report a novel, alternative
approach to treat malignant peritoneal mesothe-
lioma (MPeM) targeting, vascular endothelial
growth factor (VEGF) using anti-VEGF (beva-
cizumab) chemotherapy combination.
Case Report
In June 2008, a 60-year-old Jordanian man
presented with abdominal distension and para
umbilical hernia. His medical history was sig-
nificant for hypertension, diabetes mellitus and
hyperlipidemia and the patient was receiving
regular treatment. The patient underwent her-
nia repair and the hernia sac sent for histo-
pathologic examination. Histopathologic find-
ings showed atypical mesothelial cells with
prominent nucleoli and occasional mieotic fig-
ures as well as areas of focal necrosis, psammo-
matous calcification and tumor cells showed
encroachment on the adipose tissue illustrated
by microscopic appearance (resolution 200X)
of the tumor showing papillary structures on
one side and sheets of malignant tumor on the
other side, as shown in Figure 1. Immuno-
peroxidase stain for mesothelioma markers
was positive for calretinin, AE1, AE3, HBME-1,
cytokeratin 5/6 (CK 5/6), FMA, and negative for
Vimentin, CEA, CD15 and Ber-FP4 providing a
conclusive diagnosis of MPeM.
Figure 2 shows microscopic appearance
(resolution 200X) of positive immunostaining
of neoplastic cells by HRP conjugated
Cytokeratin 5/6 antibody. Cytological examina-
tion of ascitic fluid showed mesothelial cells
with features of malignancy, CEA was 2.3 IU/L,
AFP was 9.4 IU/L. Complete blood picture, renal
and liver function tests were normal. CT scan
of chest and abdomen showed gross ascites,
multiple mediastinal and abdominal lymph
nodes enlargement, diffused nodular mass in
the omentum and peritoneal lining central and
right side of the abdomen, as revealed in
Figure 3 CT scan image taken in October 2008
showing peritoneum thickening and ascites.
The patient was treated with cisplatin 75
mg/m2 + pemetrexed 500 mg/m2 i.v every three
[page 150]
weeks after draining about 10 liters of ascitic
fluid. Although repeated CT scan showed some Correspondence: Kakil Ibrahim Rasul, CABM,
resolution of the enlarged lymph nodes, omen- FRCP Edinburgh, ESMO, Senior Consultant
tal and peritoneal nodes, the patient required Physician and Haem/Oncology, Assistant
aspiration of nearly 6-8 liters of ascitic fluid Professor of Clinical Medicine, Weill Cornell
with each cycle. With other chemotherapy reg- Medical College/ Qatar, Hamad Medical
imens including gemcitabine + pemetrexed Corporation, Al-Amal Hospital, P.O. Box 3050,
Doha, Qatar. E-mail: kakil954@yahoo.com
for 2 cycles and intraperitoneal cisplatin the
patient continued to have re-accumulation of Key words: mesothelioma, oncology, rare tumors.
the ascitic fluid.
In January 2009 the patient started with Acknowledgement: Dr. Issam Bozm for preparing
combination of gemcitabine 1250 mg/m2 plus the histopathology pictures.
bevacizumab 5 mg/kg every 2 weeks. The
patient responded clinically with no require- Received for publication: 30 October 2009.
ment of aspiration from the very first cycle of Accepted for publication: 2 November 2009.
treatment and received 6 cycles of treatment
This work is licensed under a Creative Commons
providing strong evidence of clinical response Attribution 3.0 License (by-nc 3.0).
and improvement in quality of life. Side effects
like epistaxis were observed which was mild ©Copyright K.I. Rasul et al., 2009
and managed by local pressure. Licensee PAGEPress, Italy
MPeM is a cancer of extremely rare occur- Rare Tumors 2009; 1:e49
rence and arises from the mesothelial cells of doi:10.4081/rt.2009.e49
the peritoneum. It accounts for only 10% of all
mesotheliomas with majority arising from
pleura and the role of asbestos exposure in the
etiology compared to pleural mesothelioma is
not well defined.1,2 The clinical manifestations
of this disease are usually abdominal pain,
increasing abdominal girth, weight loss and
abdominal masses with or without ascites.
Though it can occur in any age group, the most
affected is the 50 to 69 year age group.2,3 The
aggressive nature of the disease is evident
with rapid spread within the confines of the
abdominal cavity involving most accessible
peritoneal and omental surfaces and requires
aggressive treatment. Mortality and morbidity Figure 1. Micro-scopic appearance of the
are associated with the spread of the disease tumor showing papillary structures on one
rather than the metastasis and without aggres- side and sheets of mali-gnant tumor on the
other side.
sive treatment the neoplasm is rapidly fatal.2,4,5
Studies that have reported patients with
peritoneal mesothelioma are few and treat-
ment of MPeM have largely extrapolated from
the treatment of pleural disease.6 Currently, no
standard treatment for this disease has been
established and management involves an
intensive loco-regional treatment strategy
including cytoreductive surgery, intraoperative
and/or perioperative intraperitoneal chemo-
therapy using doxorubicin, cisplatin, and
interferon gamma with or without abdominal
radiation and cytoreductive surgery along with
hyperthermic intraperitoneal chemotherapy
using mitomycin and cisplatin followed by
whole body irradiation.1,5 Several studies
Figure 2. Positive immunostaining of neo-
demonstrated an improved overall survival plastic cells by HRP conjugated cytoker-
with these regimes as compared to historic atin 5/6 antibody (resolution 200X).
controls, treated with systemic chemotherapy
and palliative surgery in which the median
survival was uniformly less than 1 year.4
However, extensive intraperitoneal disease morbidity.1
precludes the possibility of cytoreductive sur- A number of chemotherapeutic agents
gery always and these multimodality therapeu- either single or in combination with other
tic strategies are associated with significant drugs have shown promise in the treatment of
[Rare Tumors 2009; 1:e49]
 Case Report

MPeM. Nevertheless, the low incidence of the

disease and clinical heterogeneity precludes
Phase II efforts to define conclusively the ben-
efit of systemic chemotherapy and other treat-
ment options. The Expanded Access Program
(EAP) conducted both in the US and interna-
tionally provided access to 109 patients with
MPeM including chemo-naive or previously
treated patients with MPeM not amenable to
curative surgery. This study showed that medi-
an survival for pemetrexed (antifolates) was
10.3 months, and 1-year survival rates for
pemetrexed with cisplatin and pemetrexed
alone were 57.4% (95% CI: 10.3, 100) and
41.5% (95% CI 4.6, 78.4), respectively. The dis-
ease control rate was 71.2% in MPeM patients,
establishing the value of this treatment regime
in improving survival in patients with unre-
sectable MPeM.6-8
For patients who cannot tolerate a platinum-
based regimen a Phase II trial (20 patients)
provided an alternative regimen with gemc-
itabine and pemetrexed documenting a dis-
ease control rate (DCR) of 50%, median TTPD
(time to progressive disease) and OS of 10.4
months and 26.8 months, respectively.1
In addition, a Phase III trial where 456
patients was assigned randomly to cisplatin 75
mg/m2 alone or with pemetrexed 500 mg/m2
indicated that supplementation with folic acid
and vitamin B12 resulted in improved survival
time, TTPD, response rates and significantly Figure 3. CT scan in October 2008 showed peritoneal thickening and ascites.
reduced treatment related toxicity when com-
pared to non-supplemented patients.7
VEGF plays key role in MPeM biology and in
a Phase II trial anti VEGF antibody (beva-
cizumab 15 mg/kg) was added to gemcitabine
1250 mg/m2 plus cisplatin 75 mg/m2 regimen,
improvement in overall survival with beva-
cizumab combination was not demonstrated in
this study.9
This patient presented with abdominal dis-
tension, which is a presenting symptom in
majority of cases. CT scan findings of
mesothelioma are nonspecific but are useful
for detection, characterization and staging. It
is also useful for guiding biopsy of peritoneal
masses. Definitive diagnosis is based on histo-
logical and immunohistochemical examina-
tion.
Cytologic sampling of ascitic fluid and
Immunohistochemical expression of tumor
markers (calretinin and cytokeratin 5/6) pro-
vides a diagnosis of MPeM in approximately
80% of the cases. Since pemetrexed in combi-
nation with cisplatin showed survival improve-
ments, the patient started with this regime.
Failure to show clinical response as evidenced
by repeated aspirations of 6-8 liters, the treat-
ment was changed to gemcitabine plus peme-
trexed and cisplatin was not included in the
regime as the patient failed to respond to
intraperitoneal cisplatin. The constant non- Figure 4. CT scan in July 2009 showed resolution of the peritoneal thickening and
hydronephrosis of right kidney.
response of the patient to this regime, led to

[Rare Tumors 2009; 1:e49] [page 151]

Case Report
change in treatment and the patient was con-
tinued to be treated with bevacizumab and
gemcitabine due to a strong evidence of
improvement in clinical response and quality
of life. This was observed by no requirement of
aspiration of ascitic fluid until August 2009 (7
months post treatment) and the patient was
working and maintained his job during this
period. Figure 4 showed CT scan image taken
in July 2009 showed resolution of the peri-
toneal thickening as depicted in the anterior
and hydronephrosis of the right kidney at the
posterior. This case demonstrates that beva-
cizumab in combination chemotherapy could
be an effective alternative treatment in
patients who are non-responsive to other
proven agents and highlights the need for fur-
ther clinical studies to establish the role of
bevacizumab in the treatment of MPeM to
improve progression free survival and overall
survival.
[page 152]
References
1. Simon GR, Verschraegen CF, Janne PA, et
al. Pemetrexed plus gemcitabine as first-
line chemotherapy for patients with peri-
toneal mesothelioma: final report of a
phase II trial. J Clin Oncol 2008;26:3567-
72.
2. Brigand C, Monneuse O, Mohamed F, et al.
Peritoneal mesothelioma treated by cyto-
reductive surgery and intraperitoneal
hyperthermic chemotherapy: results of a
prospective study. Ann Surg Oncol 2006;13:
405-12.
3. Bridda A, Padoan I, Mencarelli R, et al.
Peritoneal mesothelioma: a review. Med
Gen Med 2007;9:32.
4. Yan TD, Welch L, Black D, et al. A system-
atic review on the efficacy of cytoreductive
surgery combined with perioperative
intraperitoneal chemotherapy for diffuse
malignancy peritoneal mesothelioma. Ann
Oncol 2007;18:827-34.
5. Hesdorffer ME, Chabot J, DeRosa C, et al.
Peritoneal mesothelioma. Curr Treat
[Rare Tumors 2009; 1:e49]
Options Oncol 2008;9:180-90.
6. Janne PA, Wozniak AJ, Belani CP, et al.
Open-label study of pemetrexed alone or in
combination with Cisplatin for the treat-
ment of patients with peritoneal mesothe-
lioma: outcomes of an expanded access
program. Clin Lung Cancer 2005;7:40-6.
7. Vogelzang NJ, Rusthoven JJ, Symanowski
J, et al. Phase III study of pemetrexed in
combination with cisplatin versus cis-
platin alone in patients with malignant
pleural mesothelioma. J Clin Oncol 2003;
21:2636-44.
8. Carteni G, Manegold C, Garcia GM, et al.
Malignant peritoneal mesothelioma -
Results from the International Expanded
Access Program using pemetrexed alone
or in combination with a platinum agent.
Lung Cancer 2009;64:211-8.
9. Karrison T, Kindler HL, Gandara DR, et al.
Final analysis of a multi-center, double-
blind, placebo-controlled, randomized
phase II trial of gemcitabine/cisplatin
(GC) plus bevacizumab (B) or placebo (P)
in patients (pts) with malignant mesothe-
lioma (MM). J Clin Oncol 2007;25:391.

Intracystic papillary carcinoma
of the breast in a 21-year old
premenopausal Nigerian
woman: a case report
Ivy N. Umanah, 1 Akpan S. Okpongette2
1
Departments of Pathology and 2 Surgery,
University of Uyo Teaching Hospital,
Uyo, Nigeria
Abstract
We report the case of a 21-year-old Nigerian
woman who presented to us with features of
intracystic papillary carcinoma, a rare form of
breast cancer usually seen in postmenopausal
women in their sixth to eighth decades of life.
To the best of our knowledge, there has been
only one other case report of this lesion occur-
ring in women in their second decade of life.
Physical examination showed a well-defined
mass, 54 mm in diameter, in the upper proxi-
mal quadrant of the right breast close to the
areola, histologically composed of monotypic
epithelial cells disposed in solid, cystic, and
papillary patterns. A diagnosis of intracystic
papillary carcinoma was made because of the
presence of intracystic arborization of the
fibrovascular stroma, a monotonous cell popu-
lation, the presence of mitoses, and the lack of
myoepithelial cells determined by immunohis-
tochemistry using calponin and p63 stains.
Estrogen receptor status was positive while
progesterone status and HER-2-neu receptor
status were negative.
The patient has survived for 12 months
without any sign of recurrence after the last
surgical resection of the tumor.
Introduction
Intracystic papillary carcinoma (IPC) is a
variant of intraductal papillary carcinoma, a
rare histological type of breast cancer occur-
ring only in about 1-2% of women.1-3 Papillary
carcinomas can be divided into invasive and
noninvasive forms. Intracystic (encysted) pap-
illary carcinoma is the localized, noninvasive
form, occurring as a grossly evident tumor in a
cystic and dilated duct.2-4 The patterns seen
include micropapillary, cribriform, trabecular,
and solid. Occasionally they may be mistaken-
ly diagnosed as papillomas.3,5
Because of its rarity, there is a paucity of lit-
erature on IPC in women younger than thirty
years old, as it predominantly affects elderly,
postmenopausal women.1 It has been docu-
mented in males as well.1,6 To the best of our
knowledge, there has been only one other case
report of this lesion occurring in pre-
menopausal women in their second decade of
life.4 We recently encountered a case of low
nuclear grade intracystic papillary carcinoma
of the right breast in a 21-year-old woman,
which is probably the first report in our envi-
ronment.
Case Report
Clinical history
A 21-year-old woman presented in our surgi-
cal out-patient department with a four-year
history of a right breast mass and bloody nip-
ple discharge. Her family history was negative
for breast cancer and there was no history of
exposure to anticancer drugs, radiation, or cig-
arette smoking. Clinical examination con-
firmed a well-defined 54-mm mass in the
upper proximal quadrant of the right breast
close to the areola, with an ipsilateral bloody
nipple discharge (Figure 1). There was no
associated axillary lymphadenopathy.
Mammography was not performed as facili-
ties for this are unavailable in the state. Core
needle biopsy was performed using a 23-gauge
needle and showed a papillary tumor histolog-
ically composed of monotypic epithelial cells.
The preliminary diagnosis was atypical ductal
papilloma with a differential diagnosis of
intracystic papillary carcinoma. Four weeks
after the core biopsy, excision biopsy of the
tumor was performed.
Pathological features
Grossly the excised tissue showed a mass of
fibro-fatty tissue weighing 101 g and measur-
ing 80x60x12 mm. The cut surface of the tis-
sue showed a well-defined mass approximate-
ly 17 mm in diameter, with a cystic cavity filled
with pale, friable, papillary tissue. Histologic-
ally the tumor was composed of closely packed
epithelial cells (nuclear Grade 2) with a papil-
lary architecture within a cyst (Figure 2).
Biopsy site changes were apparent in the sur-
rounding tissue.
Immunohistochemical (IHC) stains for
calponin, p63, and CK5/6 were performed on
the tumor and demonstrated the absence of a
myoepithelial cell border in the papillary cores
as well as at the periphery of the lesion. Based
on these findings, the diagnosis of intracystic
papillary carcinoma was made. Hormone
receptor analysis showed mild estrogen recep-
tor positivity (1+) while both progesterone
and HER-2-neu were negative.
The patient had another excision 15 weeks
later because of involved margins, which
revealed residual papillary lesions as well as a
few foci of mucinous carcinoma. Based on
[Rare Tumors 2009; 1:e50]
Rare Tumors 2009; volume 1:e50
Correspondence: Ivy N. Umanah, Department of
Pathology, University of Uyo Teaching Hospital,
P.M.B. 1136, Uyo, AKS, Nigeria.
E-mail: innumah@gmail.com; nnekauma19dyvi
@yahoo.com
Key words: intracystic papillary carcinoma,
breast, young women.
Acknowledgments: the authors thank Dr.
Tuyethao Vinh and Gary Braithwaithe, both of the
GYN/Breast Department, Armed Forces Institute
of Pathology, Washington DC, for assistance with
immunohistochemistry. We also thank Professors
E. Akang, E. Essien, and C. Adebamowo for their
valuable contributions in reviewing the patholog-
ical materials and the manuscript.
Contributions: INU, writing of this paper, and
reviewing and reporting all pathological materials
of this patient in conjunction with Dr. T. Vinh
(AFIP, Washington) and Prof. E. Akang (University
College Hospital, Ibadan, Nigeria); ASO, patient
biopsies and surgical resections, contributions to
the clinical history, and editing of the manuscript.
Received for publication: 18 September 2009.
Revision received: 3 November 2009.
Accepted for publication: 4 November 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright I.N. Umanah, A.S. Okpongette, 2009
Rare Tumors 2009; 1:e50
doi:10.4081/rt.2009.e50
this associated pathology and her age, we con-
sidered adjuvant radiotherapy appropriate for
her but opted for tamoxifen when her family
expressed their inability to cope with the
inconvenience and expense of radiotherapy in
another center. Although she is yet to comply
with hormonal therapy for poorly understood
reasons, she has been symptom-free for about
a year.
Discussion
Typically patients with IPC present with a
palpable mass (80% or more) and/or bloody
nipple discharge (up to 22%).6,7 Less frequent-
ly they may present as a radiographic abnor-
mality.8 Most patients are postmenopausal
women usually with median ages ranging from
63-75 years.6,7,9 Its occurrence in this 21-year-
old was a novelty. The duration of symptoms in
patients with IPC varies but prolonged periods
of one year or more is not considered unusual.1
Late presentation, as seen in our patient who
had a four-year history, is a typical feature of
most patients with breast cancer in sub-
Saharan Africa, in contrast to what occurs in
[page 153]
Case Report
Figure 1. Breast lump showing a bloody nip-
ple discharge. Skin puncture wound indi-
cates the site of the needle biopsy.
Figure 2. Intracystic papillary carcinoma
showing a monotonous population of
epithelial cells in solid, cystic, and papillary
patterns (hematoxylin and eosin stain, 10X
magnification).
the developed world where patients present
with a median duration of symptoms of six
weeks before diagnosis.7,10
Mammography, ductography, galactography,
ultrasonography, and magnetic resonance
imaging (MRI) are imaging techniques useful
in the diagnosis of breast cancer.8,11,12 On mam-
mography IPC often is seen as a round or oval
circumscribed mass, frequently in the
retroareolar region. Spiculation is rare.
Ductography and galactography may be com-
bined with mammography in patients with nip-
ple discharge to show filling defects, ductal
obstructions, and ductal wall irregularities,
while sonography usually reveals intracystic
mural nodules, papillary projections, and
septa.8,11-13 In resource-poor countries like
Nigeria, where mammographic facilities are
expensive and largely unavailable, interven-
tional procedures like core needle biopsies
often are performed blind, and surgeons have
to depend on pathological evaluation of tumor
resection margins solely, as a means to ensure
postoperative removal of all of the tumor.
Accurate diagnosis in patients with multicen-
tric tumors is limited. Universally, young
patients like ours usually are not subjected to
screening mammography because of their
[page 154]
increased breast density, except in high risk
women or those with a prior diagnosis of
breast cancer.12
Microscopically IPC is composed of an
encysted tumor within a dilated duct with
arborization of the fibrovascular stroma, and
contains nodules of papillary carcinoma sur-
rounded by a thick fibrous capsule.1-2,6-7
Excision biopsy is recommended for pathologi-
cal diagnosis because of the frequently incon-
clusive findings associated with fine needle
aspiration or core needle biopsy alone.2
Immunohistochemistry with stains such as
calponin, smooth-muscle myosin heavy chain
(SMM-HC) cytoplasmic stains, and p63
nuclear stains have been invaluable in distin-
guishing IPC, which does not appear to have a
myoepithelial cell layer around tumor nodules,
from ductal carcinoma in situ (DCIS).2,14-15
Another differential diagnosis, papilloma, can
be distinguished from IPC using the criteria
proposed by Kraus and Neubecker.5 Usually IPC
presents with low to intermediate grade, high
estrogen and progesterone receptor positivity,
and negativity for c-erb-2.3,7
There are no well-defined views on the man-
agement of IPC; however, surgical excision is
the mainstay of treatment.6-7,16 In selected stud-
ies, patients with IPC were divided into three
groups (IPC alone, IPC with associated ductal
carcinoma in situ, and IPC with associated
invasion with or without ductal carcinoma in
situ), and the prognosis did not differ among
the three groups regardless of the type of sur-
gery performed (breast-conserving surgery or
mastectomy) and whether adjuvant therapy
was administered.7,16-18 Fayanju et al.18 observed
that patients with IPC and associated DCIS or
microinvasion were treated with adjuvant radi-
ation and endocrine therapy on the basis of
this associated pathology. Therefore sentinel
lymph node biopsy has been advocated for
these patients6,7,14 owing to the low rate of axil-
lary lymph node metastases (8-11%) observed
in those evaluated for regional disease.9,19
Sentinel lymph node biopsy also seems justi-
fied in large IPC tumors owing to the occasion-
al axillary lymph node involvement observed in
a few cases of pure IPC7,20 characterized by
lesions measuring 4 cm or more. Pure IPC has
been reported to have an excellent prognosis
even when treated with local excision only, but
the current clinical management remains vari-
able with a potential for overtreatment.7,16,17
Only in a subset of younger patients (<50
years old) with pure IPC was adjuvant radio-
therapy and/or hormonal therapy administered
and this is recommended.18
The prognosis of IPC, particularly in elderly
women, is excellent with few or no cancer-
related deaths in most study series.6,7 In con-
trast to the lower relative survival rate for
patients with non-IPC cancers such as invasive
ductal carcinoma, even patients with invasive
[Rare Tumors 2009; 1:e50]
IPC had a survival rate of >90% of that of the
general population.6 Factors such as age at
presentation, tumor diameter, and nuclear
grade, necrosis, and the presence of associat-
ed lesions such as invasion and DCIS, all affect
patient survival.2,9,16-19
In summary, intracystic papillary carcinoma
is extremely rare in women in their second
decade of life but it does occur. The diagnosis
depends on finding typical clinical features,
radiologic and pathologic investigations and,
invariably, immunohistochemistry. The tumor
should be managed with or without adjuvant
therapy on the basis of any associated patholo-
gy, tumor size, and age of the patient. Although
our patient has been symptom-free for one
year now, the prognosis in this age group is yet
to be evaluated.
References
1. Rosen PP. Papillary Carcinoma. In: Rosen’s
Breast Pathology, 2nd edn. Philadelphia:
Lippincotts-Raven, 2001, pp 381-404.
2. Collins LC, Schnitt SJ. Papillary lesions of
the breast: selected diagnostic and man-
agement issues. Histopathology 2008;52:
20-9.
3. Ibarra JA. Papillary lesions of the breast.
Breast J 2006;2:237-51.
4. Jaffer S, Chen X, Lee L, et al. Pleomorphic
solid and cystic papillary carcinoma of the
breast: two cases occurring in young
women. Ann Diagn Pathol 2004;8:126-9.
5. Kraus FT, Neubecker RD. The differential
diagnosis of papillary tumors of the breast.
Cancer 1962;15:444-55.
6. Grabowski J, Salzstein LS, Sadler GB, et al.
Intracystic papillary carcinoma: a review of
917 cases. Cancer 2008;113:916-20.
7. Solorzano CC, Middleton LP, Hunt KK, et
al. Treatment and outcome of patients with
intracystic papillary carcinoma of the
breast. Am J Surg 2002;184:364-8.
8. Dogan BE, Whitman GJ, Middleton LP, et
al. Intracystic papillary carcinoma of the
breast. Am J Roentgenol 2003;181-6.
9. Lefkowitz M, Lefkowitz W, Wargotz ES.
Intraductal (intracystic) papillary carcino-
ma of the breast and its variants: a clinico-
pathological study of 77 cases. Human
Pathol 1994;25:802-9.
10. Okobia MN, Osime U. Clinicopathologic
study of carcinoma of the breast in Benin
City. Afr J Reprod Health 2001;5:56-62.
11. Liberman L, Feng TL, Susnik B. Case 35:
intracystic papillary carcinoma with inva-
sion. Radiology 2001;219:781-4.
12. Samphao S, Wheeler A.J. Rafferty E, et al.
Diagnosis of breast cancer in women aged
40 and younger: delays in diagnosis result
from underuse of genetic testing and breast

imaging. Am J Surg 2009;198:538-43.
13. Adisa Y, Easson AM. Breast cancer - A
review for African surgeons. In: Surgery in
Africa - Monthly Reviews, The Ptolemy
Project, Office of International Surgery.
Jani P, Ostrow B, editors. University of
Toronto, Toronto: 2007, pp 20.
14. Hill CB, Yeh IT. Myoepithelial cell staining
patterns of papillary breast lesions: from
intraductal papillomas to invasive papil-
lary carcinomas. Am J Clin Pathol 2005;
123:36-4.
15. Collins LC, Carlo VP, Hwang H, et al.
Intracystic papillary carcinomas of the
breast: a reevaluation using a panel of
myoepithelial cell markers. Am J Surg
Pathol 2006;30:1002-7.
16. Harris KP, Faliakou EC, Exon DJ, et al.
Treatment and outcome of intracystic pap-
illary carcinoma of the breast. Br J Surg
1999;86:1274-5.
17. Carter D, Orr SL, Merino MJ. Intracystic
papillary carcinoma of the breast. After
mastectomy, radiotherapy or excisional
biopsy alone. Cancer 1983;52:14-9.
18. Fayanju OM, Ritter J, Gillanders WE, et al.
Therapeutic management of intracystic
papillary carcinoma of the breast: the roles
[Rare Tumors 2009; 1:e50]
Case Report
of radiation and endocrine therapy. Am J
Surg 2007;194:497-500.
19. Leal C, Costa I, Fonseca D, et al. Intracystic
(encysted) papillary carcinoma of the
breast and its variants; a clinicopathologi-
cal, and immunohistochemical study. Hum
Pathol 1998;29:1097-104.
20. Mulligan AM, O'Malley FP. Metastatic
potential of encapsulated (intracystic)
papillary carcinoma of the breast: a report
of two cases with axillary lymph node
micrometastases. Int J Surg Pathol 2007;
15:143-7.
[page 155]
Rare Tumors 2009; volume 1:e51
1:exxxx
Diagnostic confusion resulting
from CD56 expression by
cutaneous myeloid sarcoma
Thanh Ho,1 Franklin Sedarat,1
Nagesh Rao,2 Sheeja T. Pullarkat,1
1
Department of Pathology and
Laboratory Medicine and 2Department of
Cytogenetics, David Geffen School of
Medicine, University of California Los
Angeles, Los Angeles, California, USA
Abstract
Myeloid sarcomas are tumor masses com-
posed of aggregates of malignant myeloid pre-
cursors in extramedullary sites including the
skin. We report a case of myeloid sarcoma in a
patient who presented with an ear lobe mass
and facial nerve paralysis. Expression of CD56
by the malignant cells led to an initial misdiag-
nosis as Merkel cell tumor. Comprehensive
pathological evaluation confirmed the diagno-
sis of myeloid sarcoma with aberrant expres-
sion of CD56 and carrying the translocation
t(8;21) (q22;q22). Aberrant antigen expression
by cutaneous myeloid sarcomas can cause
diagnostic confusion with other cutaneous
neoplasms. This is especially relevant when
myeloid sarcoma is the sole manifestation of
acute myeloid leukemia.
Introduction
Certain hematopoietic neoplasms have a
tendency to involve the skin. Of these the most
common are CD4+/CD56+ hematodermic neo-
plasms (previously termed blastic natural
killer (NK) cell lymphoma), myeloid sarcomas,
nasal-type extranodal natural killer/T-cell lym-
phoma, and cutaneous T-cell lymphomas.1 The
term myeloid sarcoma refers to tumors com-
posed of aggregates of immature leukemic
myeloid precursors in extramedullary sites.2
Myeloid sarcomas with the chromosomal
translocation t(8;21) frequently express non-
myeloid antigens including CD2, CD19, and
CD56. Myeloid sarcomas involving the skin are
a frequent cause of misdiagnosis when they
express aberrant non-myeloid antigens and
when the underlying leukemia is not overt. We
report a case of CD56-expressing myeloid sar-
coma that was misdiagnosed as Merkel cell
carcinoma, and discuss the diagnostic
approach toward CD56 expressing cutaneous
tumors.
[page 156]
Case Report
A 61-year-old woman presented to her physi-
cian with a left ear lobe skin nodule, left facial
nerve palsy, and deafness. Biopsy of the ear
lobe lesion was interpreted initially as Merkel
cell carcinoma. She was referred to our institu-
tion for further evaluation and treatment. Her
past history was relevant for acute myeloge-
nous leukemia (AML) for which she had
received chemotherapy and was in remission.
Imaging studies performed in our institution
showed a soft tissue mass involving the left
mastoid space and extending into the posteri-
or middle cranial fossa. In addition a paraver-
tebral mass extending from the third to sixth
thoracic vertebra was noted.
The biopsy specimen from the ear lobe mass
was received for consultation from the refer-
ring hospital and revealed a diffuse prolifera-
tion of atypical mononuclear cells within the
dermis with an intact epidermis (Figure 1A).
These cells were medium to large and had
moderate amounts of cytoplasm, irregular
nuclear contours, and finely dispersed chro-
matin (Figure 1B). Immunohistochemical
stains showed the tumor cells to express
myeloperoxidase (MPO) (Figure 1C). In addi-
tion they were positive for CD45 (leukocyte
common antigen), CD43, CD117, CD34
(Figure 1D), and CD56 (Figure 1E). They were
negative for CD20 and CD3. A diagnosis of
myeloid sarcoma was made. Fluorescent in situ
hybridization (FISH) studies were performed
on the skin lesion using dual-color DNA
probes: Spectrum Orange-labeled LSI
RUNX1T1 (8q22) probe and Spectrum Green-
labeled LSI RUNX1 (21q22) probe to identify
the t(8;21) fusion signals (Abbot Mol-
ecular/Vysis, Des Plaines, IL).3 The cells ana-
lyzed were positive for the reciprocal transloca-
tion t(8;21)(q22;q22) (Figure 1F).
A concurrent bone marrow biopsy showed a
hypercellular bone marrow involved by acute
myelogenous leukemia with t(8;21)(q22;q22).
She received myeloablative conditioning
chemotherapy and an allogeneic hematopoiet-
ic stem cell transplant, following which she
developed persistent pancytopenia and died
from sepsis.
Discussion
Our case highlights a pitfall in the diagnosis
of cutaneous myeloid sarcomas that express
CD56, a non-myeloid antigen. CD56 or neural
cell adhesion molecule (NCAM) is a cell mem-
brane protein involved in adhesion of neural
cells. CD56 is expressed on NK cells, on a sub-
set of peripheral CD8+ T-cells, on neural or
neuroendocrine cells, and on peripheral blood
[Rare Tumors 2009; 1:e51]
Correspondence: Sheeja Pullarkat, Department of
Pathology and Laboratory Medicine, David Geffen
School of Medicine at UCLA, 10833 Le Conte
Avenue, A7-149 CHS, Los Angeles, CA 90095-
1732, USA. E-mail: spullarkat@mednet.ucla.edu
Key words: myeloid sarcoma, fluorescent in situ
hybridization, t(8;21) acute myelogenous
leukemia.
Contributions: TH, drafting the article; FS, acqui-
sition of photos, revision of article; NR, cytoge-
netics; STP, drafting, revision, and final approval
of article.
Conflict of interest: the authors report no con-
flict of interests.
Received for publication: 23 September 2009.
Accepted for publication: 4 November 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright T. Ho et al., 2009
Licensee PAGEPress, Italy
Rare Tumors 2009; 1:e51
doi:10.4081/rt.2009.e51
monocytes.4,5 Hematopoietic and non-hema-
topoetic neoplasms that express CD56 can
involve the skin. Cutaneous non-hematopoiet-
ic tumors that are CD56 positive include
Merkel cell carcinomas and metastases to the
skin from other primary neuroendocrine carci-
nomas. Merkel cell carcinomas present as der-
mal nodules mainly involving the head and
neck regions, with a characteristic salt-and-
pepper nuclear chromatin histologically.6-8 The
tumors are CD45 negative and stain for cytok-
eratin 20 (CK20), CAM 5.2, and CD56.
Metastatic neuroendocrine tumors to the skin
have an immunophenotype similar to the pri-
mary tumor and frequently express CD56.
A review of CD56 positive hematological
neoplasms presenting in the skin, conducted
by the Cutaneous Lymphoma Task Force of the
European Organisation for Research and
Treatment of Cancer,1 recognizes four different
subtypes of proliferations with CD56 expres-
sion: (i) CD4+/CD56+ hematodermic neo-
plasms (previously designated as blastic NK-
cell lymphomas); (ii) skin infiltration by CD56
positive acute myelogenous leukemia (myeloid
sarcoma); (iii) nasal-type extranodal NK/T cell
lymphomas; and (iv) “classical” cases of cuta-
neous T-cell lymphoma (CTCL) with coexpres-
sion of the CD56 molecule.
CD4 and CD56 positive hematodermic neo-
plasm is a recently recognized entity that orig-
inates from plasmacytoid dendritic cells
(pDC), has a high incidence of skin involve-
ment and leukemic dissemination, an aggres-
sive clinical course, and a dismal prognosis.
 Case Report
Article

CD43, CD4, CD31, and chloroacetate esterase.

The initial biopsy was reviewed and was found
to be a myeloid sarcoma and not a T-cell lym-
phoma.
A recent report by Pileri et al. reviewing 92
cases of myeloid sarcomas in adults has
heightened our knowledge on myeloid sarco-
mas. They have illustrated that the tumor cells
in myeloid sarcomas most commonly
expressed CD68/KP1 (100%), followed in
A D decreasing order by myeloperoxidase (83.6%),
CD117 (80.4%), CD99 (54.3%), CD68/PG-M1
(51%), CD34 (43.4%), CD56 (13%), CD61
(2.2%), CD30 (2.2%), and glycophorin A and
CD4 (1.1%).12 Chromosomal abberations were
detected in about 54% of cases and monosomy
7 (10.8%), trisomy 8 (10.4%), and mixed line-
age leukemia-splitting (8.5%) were the com-
monest abnormality.
Since detection of genetic lesions is critical
B E for classification, prognostic stratification, and
monitoring of AML, it is very important that
FISH studies on the paraffin-embedded tissue
for chromosomal abnormalities, namely mono-
somy 7, trisomy 8, 11q23 rearrangement, and
t(8;21), are performed to aid in further prog-
nostication when myeloid sarcoma is the sole
manifestation of acute myeloid leukemia. This
is mainly owing to the fact that since the diag-
nosis of myeloid sarcoma frequently is unex-
pected, fresh cells are not available usually for
cytogenetic and/or molecular studies.
C F In summary, myeloid sarcoma should be
considered in the differential diagnosis of
Figure 1. (A) Skin lesion from the left ear, showing intact epidermis with large mononu- cutaneous CD56 positive tumors that are CD45
clear cells within the dermis (hematoxylin and eosin stain, 40X). (B) Skin lesion from the positive and lack expression of cytokeratin and
left ear, showing large mononuclear cells with fine chromatin, and moderate amounts of other neural markers.
granular cytoplasm (hematoxylin and eosin stain, 400X). (C) Cytochemical staining for
myeloperoxidase shows cytoplasmic positivity in the malignant cells (400X). (D) CD34
immunohistochemical staining shows strong positivity in the malignant cells (400X). (E)
CD56 immunohistochemical staining identifies the neoplastic cells (100X). (F) FISH
studies of the skin lesion 8q22 (red); 21q22 (green); fusion (yellow) signals consistent References
with t(8;21)(q22;22).
1. Assaf C, Gellrich S, Whittaker S, et al. CD
56-positive haematological neoplasms of
Extranodal NK/T cell lymphoma most common- lymphoid antigens. Kurata et al.10 have the skin: a multicentre study of the
ly occurs in the nasopharngeal area and fre- described a case of a 39-year-old man who pre- Cutaneous Lymphoma Project Group of the
quently shows an angiocentric growth pattern sented with a forehead cutaneous nodule that European Organisation for Research and
with prominent necrosis, and once was was positive for CD45 and CD56, and negative Treatment of Cancer. J Clin Pathol 2007;
referred to as lethal midline granuloma. Most for CD3, CD20, CD34, TIA-1, and TdT. Only a 60:981-9.
cases are associated with Epstein Barr Virus limited panel of immunostains was performed, 2. Rappaport, H. Tumors of Hematopoetic
(EBV) and express cytotoxic molecules such as hence leading to a misdiagnosis of NK cell lym- System. Washington DC, Armed Forces
perforin, granzyme B, and TIA-1. Occasionally, phoma. The initial biopsy specimen when re- Institute of Pathology, 1966, Atlas of Tumor
CD56 may be expressed also by cutaneous T- evaluated showed expression of myeloid anti- Pathology, 1st series, fascicle 8.
cell lymphoma such as primary cutaneous gens, namely myeloperoxidase (MPO), and the 3. Mellinghoff IK, Wang MY, Vivanco I, et al.
CD30+ lymphoproliferations, anaplastic large diagnosis of myeloid sarcoma was made final- Molecular determinants of EGFR kinase
cell lymphomas (ALCL), and subcutaneous ly. Beswick et al.11 described a case of a 65- inhibitor response in glioblastoma. N Engl
panniculitis-like T-cell lymphomas. Results year-old man who presented with a nodule on J Med 2005;353:2012-24.
from this study showed that CD56+ cutaneous the back that was diagnosed as high-grade T- 4. Chan JK, Sin VC, Wong KF, et al. Nonnasal
lymphoproliferative disorders, with the excep- cell lymphoma by virtue of CD3 expression. He lymphoma expressing the natural killer
tion of CD56+ CTCL, have a very poor progno- received chemotherapy and three years later cell marker CD56: a clincopathologic study
sis. developed violaceous nodules over his trunk of 49 cases of an uncommon aggressive
Previous reports have highlighted the diffi- and limbs. Biopsy of this mass and a detailed neoplasm. Blood 1997;89:4501-13.
culty in the diagnosis of cutaneous myeloid immunohistochemistry panel revealed a 5. Suzuki R, Yamamoto K, Seto M, et al.
sarcomas owing to the aberrant expression of myeloid sarcoma that was positive for CD45, CD7+ and CD56+ myeloid/natural killer

[Rare Tumors 2009; 1:e51] [page 157]

ArticleReport
Case
cell precursor acute leukemia: a distinct
hematolymphoid disease entity. Blood
1997;90:2417-28.
6. Skelton HG, Smith KJ, Hitchcock CL, et al.
Merkel cell carcinoma: analysis of clinical,
histologic and immunohistologic features
of 132 cases with relation to survival. J Am
Acad Dermatol 1997;37:734-9.
7. Tai PT, Yu E, Tonita J, et al. Merkel cell car-
cinoma of the skin. J Cutan Med Surg
2000;4:186-95.
8. Sur M, Alardati H, Ross C, et al. Tdt expres-
[page 158]
sion in Merkel cell carcinoma: potential
diagnostic pitfall with blastic hematologi-
cal malignancies and expanded immuno-
histochemical analysis. Mod Pathol 2007;
20:1113-20.
9. Bekkenk MW, Jansen PM, Meijer CM, et al.
CD56+ hematological neoplasms present-
ing in the skin: a retrospective analysis of
23 cases and 130 cases from the literature.
Ann Oncol 2004;15:1097-108.
10. Kurata H, Okukubo M, Fukuda E, et al.
Myeloid markers should be undertaken in
[Rare Tumors 2009; 1:e51]
cases of CD 56 positivity to exclude granu-
locytic sarcoma. Br J Dermatol 2002;147:
609-11.
11. Beswick SJ, Jones EL, Mahendra P, et al.
Chloroma (aleukaemic leukaemia cutis)
initially diagnosed as cutaneous lym-
phoma. Clin Exp Dermatol 2002;27:272-4.
12. Pileri SA, Ascani S, Cox MC, et al. Myeloid
sarcoma: clinico-pathologic, phenotypic
and cytogenetic analysis of 92 adult
patients. Leukemia 2007;21:340-50.

The epidemiology of malignant
giant cell tumors of bone:
an analysis of data from the
Surveillance, Epidemiology
and End Results Program
(1975–2004)
Jennifer L. Beebe-Dimmer,1
Karynsa Cetin,2 Jon P. Fryzek,3
Scott M. Schuetze,4 Kendra Schwartz5
1
Karmanos Cancer Institute and Wayne State
University Department of Internal Medicine,
Detroit, MI; 2Amgen Inc., Department of
Global Epidemiology, Thousand Oaks, CA;
3
Medimmune Inc., One MedImmune Way,
Gaithersburg, MD; 4University of Michigan
Department of Internal Medicine, Ann Arbor,
MI; 5Karmanos Cancer Institute and Wayne
State University Department of Family
Medicine, Detroit, MI, USA
Abstract
Malignant giant cell tumor (GCT) of bone is
a rare tumor with debilitating consequences.
Patients with GCT of bone typically present
with mechanical difficulty and pain as a result
of bone destruction and are at an increased
risk for fracture. Because of its unusual occur-
rence, little is known about the epidemiology
of malignant GCT of bone. This report offers
the first reliable population-based estimates of
incidence, patient demographics, treatment
course and survival for malignancy in GCT of
bone in the United States. Using data from the
National Cancer Institute’s Surveillance,
Epidemiology and End Results (SEER) pro-
gram, we estimated the overall incidence and
determinants of survival among patients diag-
nosed with malignant GCT of bone from 1975-
2004. Cox proportional hazards regression was
used to evaluate demographic and clinical
determinants of survival among malignant
GCT cases. Based on analyses of 117 malig-
nant GCT cases, the estimated annual inci-
dence in the United States was 1.6 per
10,000,000 persons per year. Incidence was
highest among adults aged 20 to 44 years (2.4
per 10,000,000 per year) and most patients
were diagnosed with localized (31.6%) or
regional (29.9%) disease compared to distant
disease (16.2%). Approximately 85% of
patients survived at least 5 years, with survival
poorest among older patients and those with
evidence of distant metastases at time of diag-
nosis. The current study represents the largest
systematic investigation examining the occur-
rence and distribution of malignancy in GCT of
bone in the general U.S. population. We con-
Rare Tumors 2009; volume 1:e52
firm its rare occurrence and suggest that age
and stage at diagnosis are strongly associated Correspondence: Jennifer L. Beebe-Dimmer,
with long-term survival. Karmanos Cancer Institute, Prentis Center, 110
E. Warren Avenue #1115, Detroit, Michigan , USA
E-mail: dimmerj@karmanos.org
Introduction
Key words: giant cell tumor of bone, surveil-
lance, epidemiology and end results, descriptive
epidemiology, incidence, survival, osteosarcoma.
Giant cell tumors (GCTs) of bone occur
infrequently, comprising just 5% of all bone Acknowledgements: project funded by Amgen
tumors, both benign and malignant.1 Inc, Thousands Oaks, CA.
However, the disease can be incapacitating, as
Received for publication: 12 October 2009.
patients with GCT of bone typically present
Revision received: 4 November 2009.
with mechanical difficulty and pain resulting Accepted for publication: 5 November 2009.
from bone destruction and are at an increased
risk for fracture.1-3 GCTs are observed predom- This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
inantly at the ends of long bones, most com-
monly located in and around the knee (distal
©Copyright J.L. Beebe-Dimmer et al., 2009
femur, proximal tibia) and wrist (distal
Licensee PAGEPress, Italy
radius).1 They are categorized according to the Rare Tumors 2009; 1:e52
Enneking staging system, where the patholog- doi:10.4081/rt.2009.e52
ic spectrum ranges from static and confined to
the bone (Stage 1) to aggressive, extending
into the surrounding soft tissue (Stage 3).4 A tend to have poorest outcomes, suggesting that
radiographic grading system developed by rigorous follow-up of patients treated for
Campanacci et al. grades lesions from 1 to 3, benign tumors even decades after initial diag-
with Grade 1 lesions having well-defined mar- noses is crucial to insuring long-term survival.
gins and an intact cortex, and Grade 3 having Because of the rarity of the malignant vari-
irregular margins and cortical destruction.5
ety, there are limited sources which can be
Metastases can develop from both benign and
used to characterize incidence and survival fol-
malignant GCTs; and lung is the most frequent
lowing a diagnosis of malignancy in GCT of
metastatic site.6
bone. Most published data on its epidemiology
Histologically, GCTs are a heterogeneous
have been generated from hospital-based
mix of multinucleated giant cells resembling
patient series, which may not accurately trans-
osteoclasts, spindle-shaped stromal cells
late to the larger population in terms of patient
exhibiting features of osteoblast precursors
and tumor characteristics and frequency of
and CD-68 positive mononuclear cells.7,8 The
occurrence in the general population.
neoplastic cell of origin has not been identified
To better understand the epidemiology of
conclusively. Recently, expression of the ligand
malignancy in GCT of bone, we consulted data
for receptor activator of nuclear factor κB
from the National Cancer Institute’s (NCI)
(RANKL), a factor critical in the development
Surveillance, Epidemiology and End Results
and activation of osteoclasts, was detected in
(SEER) Program, which represents the most
GCT, raising the possibility of controlling bone
comprehensive and complete source of infor-
lysis from GCT by inhibition of the RANKL-
mation available on the diagnosis, demograph-
RANK axis.9
ics, treatment and follow-up of cancer patients
While GCTs account for approximately 20%
in the United States (U.S.).14 To our knowl-
of all benign bone tumors,1 malignancies in
edge, this study represents the first systematic
GCT of bone are much rarer and are typically
U.S. investigation of the descriptive epidemiol-
classified as primary or secondary according to
ogy of this rare tumor using a large, popula-
specific criteria.10,11 A primary malignant GCT
tion-based dataset.
of bone will most often arise concurrently and
closely with a benign tumor; however, sponta-
neous neoplasm may occur in the absence of
benign growth. Secondary malignant GCTs are Materials and Methods
more common than primary malignant GCTs
and arise after treatment of a previously
benign tumor and more often in patients Surveillance, Epidemiology and End
undergoing radiation therapy with or without Results registry and study population
curettage.6 While GCT is typically associated We used data gathered as part of the
with a favorable prognosis, the long-term prog- National Cancer Institute’s SEER Program.
nosis for malignant transformation of a previ- SEER currently consists of 18 statewide and
ously benign-appearing tumor is poor. Further, regional tumor registries spread throughout
reports.3,11-13 indicate that those patients with a the U.S., covering approximately 26% of the
history of radiation treatment for benign GCT population (http://seer.cancer.gov/registries/
[Rare Tumors 2009; 1:e52] [page 159]
Article
data.html). The individual registries are geo-
graphically located to over-sample minority
populations, including African Americans,
Hispanics, Asian Pacific Islanders, and Native
Americans. SEER routinely collects data on
patient demographics (age at diagnosis, gen-
der, race/ethnicity and geographic residence at
the time of diagnosis), tumor characteristics
(size, grade, stage), first course of treatment,
as well as follow-up documentation of vital sta-
tus (date and cause of death). Based on the
rare occurrence of malignancy in GCT of bone,
coupled with our initial goal of assessing epi-
demiologic time trends, we limited our analy-
ses to the longest running SEER registries
(Connecticut, Detroit, Hawaii, Iowa, New
Mexico, San Francisco-Oakland, Utah, Seattle-
Puget Sound, and Atlanta), all of which have
collected information on invasive cancers
diagnosed from 1975 through 2004 and repre-
sent nearly 10% of the U.S. population.
Patients included in the current study were
those diagnosed with malignant giant cell
tumors of bone (ICD-O-3 codes, M-9250/1, M-
9250/3, M-8003/3, and primary site codes
C40.0-C41.9) between January 1, 1975 and
December 31, 2004. Classification of tumors
was based upon SEER summary staging crite-
ria. SEER summary stage is produced using
the extent of disease information from medical
records and pathology reports reviewed at the
time of diagnosis. A localized tumor is defined
as an invasive neoplasm a.) confined to the
cortex of the bone; or b.) extends beyond the
cortex into the periosteum (with no break in
the periosteum). Regional stage is defined as
a neoplasm that has a.) extended beyond the
periosteum into adjacent bone, cartilage or
skeletal muscle; or b.) into regional lymph
nodes by way of the lymphatic system; or c.) a
combination of extension and regional lymph
node involvement. A distant classification
would include a neoplasm that has spread to
parts of the body remote from the primary
tumor either by direct extension or by metasta-
sis to distant organs, tissues or the distant
lymph nodes via the lymphatic system
(http://seer.cancer.gov/tools/ssm/muscu-
loskel.pdf).
Statistical methods
Patient (age at diagnosis, gender, race/eth-
nicity), tumor (stage), and treatment (receipt
of surgery and/or radiation) characteristics
were described for all individuals diagnosed
with malignant GCT of bone across the study
period (1975-2004). Annual crude and age-
adjusted incidence rates per 10,000,000 per-
sons were calculated using SEER*Stat v. 6.36
and then averaged over the entire study period
and for 5-year periods using U.S. county popu-
lation estimates. Estimates were age-adjusted
using the 2000 U.S. population as the standard
population. Chi-square tests were conducted to
[page 160]
determine differences in incidence rates 10,000,000 persons (in 1975-1979 and 1985-
across the study period by age at diagnosis, 1989). The average annual malignant GCT
gender, race/ethnicity (white, black, other incidence across the entire study period did
race) and SEER summary stage (localized, not differ significantly by gender or race/eth-
regional, distant). nicity. However, the annual incidence did dif-
SEER*Stat was also used to calculate rela- fer depending upon age, with the highest inci-
tive survival rates for the entire study cohort. dence observed among those aged 20 to 44
SAS software version 9.1 (SAS Institute, Cary, years (2.4 per 10,000,000 persons), with esti-
N.C., USA) was used to build Cox proportional mates ranging from 1.6 in 2000-2004 to 3.2 in
hazards (PH) regression models to estimate 1975-1979 across the study period. Metastatic
the relation of select factors and survival fol- GCT of bone was exceedingly rare; its inci-
lowing a diagnosis of malignant GCT of bone. dence was lower than that of either localized or
Individuals were censored at the date of death, regional disease (P=0.04).
the date last known to be alive (if lost to follow- The mean survival time for patients diag-
up), or December 31, 2004, whichever came
nosed with malignant GCT of bone was 11
first. Variables included in the final Cox PH
years and 11 months, with a 5-year relative
model were: age at diagnosis (in 5-year age
survival of 84.2%. As would be expected, Cox
groups), year of diagnosis, gender, race, stage
proportional hazards modeling indicated that
at diagnosis, and receipt of first-line treatment
older age and more advanced stage at time of
(none, surgery, radiation, or a combination of
surgery and radiation). diagnosis were associated with an increased
risk of death after controlling for other poten-
tial important determinants (Table 3). More
specifically, for each 5-year increase in age at
Results diagnosis, the risk of death increased by 41%
(P<0.0001). Likewise, for patients with distant
From 1975 through 2004, a total of 117 indi- metastases detected at the time of diagnosis,
viduals were identified as having been diag-
nosed with “primary” malignant GCT of bone
in the SEER 9 registry regions (Table 1). Table 1. Characteristics of patients diag-
nosed with malignant giant cell tumors
“Primary” in this context means that the (GCT) of bone (SEER† 1975-2004)
tumor is the first and/or only invasive cancer (N=117).
diagnosed, not to be confused with the afore-
mentioned definitions of primary versus sec- Characteristic N (%)
ondary malignancy in GCT. Most patients diag- Age at diagnosis
nosed were between the ages of 20 and 44 <20 years 12 (10.2)
years (57.3%), female (53.9%), and white 20-44 years 67 (57.3)
(74.4%). Of these patients, nearly one-third 45+ years 38 (32.5)
(31.6%) were diagnosed with disease confined Gender
to the bone, 29.9% were diagnosed with cancer Female 63(53.9)
with evidence of extension into the surround- Male 54(46.1)
ing soft tissue, 16% were diagnosed with dis- Race
tant metastasis, and 22% were of unknown White 87 (74.4)
stage. The primary treatment for most patients Black 14 (12.0)
(69.3%) was surgical removal of the tumor Other 16 (13.6)
either with (12.0%) or without (57.3%) radia- Stage at diagnosis
tion therapy. First-line treatment was associat- Localized 37(31.6)
ed with stage at diagnosis; as most patients Regional 35(29.9)
with localized disease received surgery where- Distant 19 (16.2)
as patients with more advanced disease Treatment
received radiation therapy (with or without Surgery only 67 (57.3)
surgery) as primary treatment (P<0.0001). Surgery + radiation 14 (12.0)
Radiation only 15 (12.8)
The incidence of malignant GCT of bone
None 15 (12.8)
was extremely low for the thirty-year study Unknown 6 (5.1)
period (1.6 per 10,000,000 persons per year)
SEER Region at diagnosis
(Table 2). As one of the initial aims of the
Detroit, MI 24 (20.5)
investigation was to examine trends in occur-
Connecticut 23 (19.7)
rence over time, incidence was estimated for San Francisco-Oakland, CA 21 (17.9)
5-year time periods. However, because of the Seattle-Puget Sound, WA 15 (12.8)
small number of cancers reported for each Hawaii 9 (7.6)
time period, no formal tests of trend over time New Mexico 7 (6.0)
were conducted. Annual incidence estimates Atlanta, GA 6 (5.2)
varied from 1.0 per 10,000,000 in the most Iowa 5 (4.3)
recent time period (2000-2004) to 2.2 per Utah 7 (6.0)
[Rare Tumors 2009; 1:e52]
 Article

the risk of death was 5.2 times higher com- Table 2. Incidence of malignant GCTs of bone (in 5-year intervals), 1975-2004, accord-
pared to those diagnosed with tumor confined ing to age at diagnosis, gender, race and stage.
to the bone (P=0.007). However, there was no Incidence per 10,000,000 persons
significant difference in risk of death between 1975-2004 1975-79 1980-84 1985-89 1990-94 1995-99 2000-04
patients with regional and localized disease
(P=0.49). Year of diagnosis, gender and Overall 1.6 2.2 1.4 2.2 2.1 1.2 1.0
race/ethnicity were not significantly related to Age(years)
survival. <20 0.6 1.6 -- 1.0 0.3 0.3 0.3
20-44 2.4 3.2 2.3 2.9 2.2 2.2 1.6
45+ 1.7 1.7 1.2 2.4 3.6 0.5 1.0
p† <0.01
Discussion Gender
Male 1.5 2.0 1.1 2.1 1.8 1.1 1.3
To our knowledge, this represents the first Female 1.7 2.4 1.6 2.4 2.4 1.2 0.7
investigation of malignancy in GCT of bone p 0.53
conducted in the general U.S. population. Our Race
results confirm that malignant GCT of bone is White 1.5 2.4 1.4 2.1 1.9 0.9 0.9
a rare occurrence in the United States (less Black 1.8 - - 3.4 2.9 0.2 1.8
than one case per million persons per year). Other 2.5 3.2 2.6 2.6 3.5 2.2 1.3
While we observed a decrease in incidence p 0.17
over the decades from 2.2 cases per 10 million Stage
persons in the 1970’s to 1.0 case per 10 million Localized 0.5 0.8 0.3 0.9 0.5 0.5 0.3
persons in the 2000’s, the rarity of the tumor Regional 0.5 0.9 0.5 0.2 0.8 0.3 0.2
prevented any formal test of trend in incidence Distant 0.3 0.3 0.1 0.3 0.3 0.2 0.4
p 0.04
over time. Results reported in an analysis of 75
malignant GCT of bone cases from a Swedish †
Corresponding p of χ2 test to detect difference in incidence rates for period (1975-2004) between age, gender, race and stage groupings.
population-based national cancer registry
showed an average annual incidence of 0.63
Table 3. The association between patient, treatment and tumor characteristics and risk of
per million from 1958 to 1968, a somewhat death after diagnosis of malignant GCT of bone using Cox proportional hazards regres-
higher estimate than our own.15 However, sion.
based on the small number of cases identified
Characteristic Hazard ratio† p
in both the Swedish report and our current
‡
investigation, it is possible that the observed Age at diagnosis 1.41 <0.01
trends in incidence over time and/or difference Year of diagnosis 1.03 0.84
in incidence rates between these reports may
Gender
not be meaningful but merely a reflection of Female 1.00
chance variability in the populations studied. Male 0.73 0.46
The current investigation is also the first to
Race
examine racial/ethnic differences in the inci- White 1.00
dence and survival associated with this rare Black 0.45 0.17
disease. Our results suggest no significant Other 0.55 0.41
racial difference in the incidence of malignant Stage at diagnosis
GCT of bone. Survival estimates suggest a Localized 1.00
reduction in risk of death among non-white Regional spread 1.41 0.49
compared with white patients, but the results Distant metastases 5.20 <0.01
were not statistically significant. And although Stage unknown 0.20 0.14
a slightly greater proportion of cases diag- Treatment
nosed were females compared to males, there None 1.00
was no significant difference in the overall Surgery 0.99 0.15
incidence of malignant GCT by gender. We Radiation 0.76 0.69
found most malignant GCT cases are typically Surgery + radiation 1.04 0.94
diagnosed in the third and fourth decades of †
Estimate of relative risk adjusted for all other variables in the final multivariable model (age, year of diagnosis, gender, race, stage, treat-
life, a finding supported by most case- ‡
ment). Hazard Ratio represents an estimate of the increase in risk of death with each increase from one 5-year age group to the next
series.2,3,5,16-19 starting with and including the following age groupings (10-14 years, 15-19 years, …,>85 years)
The average 5-year relative survival rate for
patients with malignant GCT of the bone in our race, or treatment. Our survival rates are information on first line treatment, but no sub-
study was 84.2%. As seen with other cancer improved over hospital-based case-series in sequent treatment information is collected on
types, older age and metastatic disease at diag- malignant GCT, possibly reflecting advances in patients. Anract et al. observed a 5-year rela-
nosis were associated with poorer survival. treatment of these tumors over time and/or tive survival rate of 50% in a case-series of 29
However, we did not observe any significant geographic differences in referral patterns to malignant GCT patients diagnosed between
difference in risk of death among patients specific institutions as well as availability and 1954 and 1993.3 Case ascertainment in this
diagnosed with regionally advanced disease. access to medical care for these patients. study began approximately twenty years prior
No significant differences in risk of death However, these are difficult theories to prove to the establishment of the SEER registry and
were detected by year of diagnosis, gender, with existing data. The SEER registry records ended a decade prior to our patient follow-up.

[Rare Tumors 2009; 1:e52] [page 161]

Article
Bertoni et al. showed that 59% of all patients
diagnosed with malignancy in GCT at a single
institution eventually died, most of metastatic
disease.12 The authors also indicated a survival
disparity between patients diagnosed with pri-
mary and secondary malignant GCT, though
not formally tested because of the small num-
ber of patients in the series (n=17). Of notable
importance, there was variability in the num-
ber of patients diagnosed with primary versus
secondary malignant GCT in these studies as
less than one-third of patients included in the
Italian study12 were diagnosed with primary
malignant GCT, while nearly 60% of patients in
the French investigation were similarly diag-
nosed.3 A limitation of SEER with respect to
this investigation is the inability to classify
patients as having primary or secondary malig-
nant GCT, as the SEER database does not
record medical history of benign lesions. This
information might have been useful in our
evaluation of patient survival. If survival is
improved among patients diagnosed with pri-
mary malignant GCT and the proportion of
patients diagnosed with primary versus sec-
ondary malignant GCT is higher among
patients in SEER, this might explain some of
the variability in survival rates between stud-
ies. As our study demonstrates, surgery is the
preferred treatment choice for most patients,
particularly if the tumor appears indolent and
confined to the bone. For biologically aggres-
sive or recurrent tumors, curettage has been
coupled with adjuvant chemotherapy or radia-
tion.6 The typical treatment for patients with
non-resectable GCT has been a course of mod-
erate-dose radiation therapy.20,21 Reported rates
of recurrence of benign, primary malignancy
in GCT or secondary malignancy in GCT are
variable and dependent on tumor characteris-
tics and treatment.1,22 Wide resection and the
adjuvant use of polymethymethacrylate follow-
ing intralesional curettage have been associat-
ed with reduced recurrence rates.23,24 The use
of intravenous and oral bisphosphonates may
also reduce risk of local recurrence in patients
with soft tissue extension of GCT.25
The treatment of recurrent and metastatic
GCT has been mostly surgical. Metastasectomy
of lung nodules may result in long-term sur-
vival.26-28 Chemotherapy is generally of margin-
al benefit in advanced GCT, but may provide
palliative treatment of primary or secondary
malignancy in GCT. Results of a phase II trial
of the fully human monoclonal antibody to
RANKL, denosumab, in patients with recurrent
or unresectable giant cell tumor of bone indi-
cate nearly 90% of cases had a positive
response to the agent (either elimination of
giant cells or no radiographic progression of
the target lesion) and nearly 85% of patients
reported reduced pain and/or improvement in
functional status,29 suggesting that denosumab
is a viable treatment approach for patients
[page 162]
with advanced or metastatic GCT not amenable
to surgery.
Our investigation does have a few limita-
tions which necessitate some caution in eval-
uating our results. As previously mentioned,
our sample size prohibits the detection of sta-
tistically significant differences in incidence
across the study period and determinants of
long term survival amonng various subgroups.
Therefore, analyses relating demographic dif-
ferences in malignant GCT incidence as well
as demographic and clinical determinants of
survival must be interpreted with prudence,
particularly if the observed disparities between
these subsets of the population are modest.
Additionally, formal review of the histopatholo-
gy of patients in this investigation was not pos-
sible because of the unavailability of historical
medical records on all patients through the
individual SEER registries.
Nevertheless, the current investigation rep-
resents the largest population-based and most
comprehensive examination of the descriptive
epidemiology of malignancy in GCT of bone
and the first of its kind conducted in the
United States. Based on the rare nature of
malignancy in GCT, only a large cancer data-
base such as NCI’s SEER has the ability to
accrue an adequate number of cases to esti-
mate rates of incidence and survival. An impor-
tant strength of the SEER cancer registry is the
active tracking of cases for vital status (over
97%) regardless of migration out of the reg-
istries catchment areas. Because losses to fol-
low-up in our patient population are minimal,
the calculated survival rates are an accurate
representation of the survival experience of
these patients. In the future, we would recom-
mend that the SEER registries consistently and
routinely collect information on cases of
benign GCT of bone as well. Benign GCT of
bone is unique in that it is considered to be a
borderline neoplasm because of its potential to
metastasize. Obtaining information on the
diagnosis, treatment and follow-up of both
benign and malignant GCT cases would
enhance our understanding of the determi-
nants of risk and survival among those diag-
nosed with this disease.
References
1. Turcotte RE. Giant cell tumor of bone.
Orthop Clin North Am 2006;37:35-51.
2. Tunn PU, Schlag PM. Giant cell tumor of
bone. An evaluation of 87 patients. Z
Orthop Ihre Grenzgeb 2003;141:690-8.
3. Anract P, de PG, Cottias P, Pouillart P,
Forest M, Tomeno B. Malignant giant-cell
tumours of bone. Clinico-pathological
types and prognosis: a review of 29 cases.
[Rare Tumors 2009; 1:e52]
Int Orthop 1998;22:19-26.
4. Enneking WF. A system of staging muscu-
loskeletal neoplasms. Clin Orthop Relat
Res 1986;204:9-24.
5. Campanacci M, Baldini N, Boriani S,
Sudanese A. Giant-cell tumor of bone. J
Bone Joint Surg Am 1987;69:106-14.
6. Mendenhall WM, Zlotecki RA, Scarborough
MT, Gibbs CP, Mendenhall NP. Giant cell
tumor of bone. Am J Clin Oncol 2006;
29:96-9.
7. Morgan T, Atkins GJ, Trivett MK, Johnson
SA, Kansara M, Schlicht SL, et al.
Molecular profiling of giant cell tumor of
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tor kappaB. Am J Pathol 2005;167:117-28.
8. Golding SR, Roelke MS, Petrison KK, Bhan
AK. Human giant cell tumor of bone: iden-
tification and characterization of cell
types. J Clin Invest 1987;79:483-91.
9. Huang L, Xu J, Wood DJ, Zheng MH. Gene
expression of osteoprotegerin ligand,
osteoprotegerin, and receptor activator of
NF-kappaB in giant cell tumor of bone:
possible involvement in tumor cell-
induced osteoclast-like cell formation. Am
J Pathol 2000;156:761-7.
10. Hutter RV, Worchester JN Jr., Francis KC,
et al. Benign and malignant giant cell
tumors of bone. A clinicopathological
analysis of the natural history of the dis-
ease. Cancer 1962;15:653-90.
11. Dahlin DC, Cupps RE, Johnson EW, Jr.
Giant-cell tumor: a study of 195 cases.
Cancer 1970;25:1061-70.
12. Bertoni F, Bacchini P, Staals EL.
Malignancy in giant cell tumor of bone.
Cancer 2003;97:2520-9.
13. Unni K.K. Dahlin's bone tumor: general
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tion: Philadelphia. Lippincott-Raven
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14. Fritz A. The SEER Program's Commitment
to Data Quality. J Registry Manag 2001;28:
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15. Larsson SE, Lorentzon R, Boquist L. Giant-
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recorded in the Swedish Cancer Registry
for the years 1958 through 1968. J Bone
Joint Surg Am 1975;57:167-73.
16. Boutou-Bredaki S, Agapios P, Papachristou
G. Prognosis of giant cell tumor of bone.
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Schachar N, Masri BA, et al. Giant cell
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[page 163]
Rare Tumors 2009; volume 1:e53
Temsirolimus in the treatment
of renal cell carcinoma
associated with Xp11.2
translocation/TFE gene
fusion proteins: a case report
and review of literature
1 2
Jigarkumar Parikh, Teresa Coleman,
Nidia Messias,3 James Brown4
1 able for patients with stage 4 disease.3-9 The
Department of Medicine;
2 prognosis in adult onset translocation renal
Department of Medicine, Section of
Hematology/Oncology; 3Department of
Pathology; 4Department of Surgery,
Section of Urologic Surgery; Medical
College of Georgia, Augusta, GA, USA
Abstract
Xp11.2 translocation renal cell carcinomas
(TRCCs) are a rare family of tumors newly
recognized by the World Health Organization
(WHO) in 2004. These tumors result in the
fusion of partner genes to the TFE3 gene
located on Xp11.2. They are most common in
the pediatric population, but have been
recently implicated in adult renal cell carcino-
ma (RCC) presenting at an early age. TFE3-
mediated direct transcriptional upregulation
of the Met tyrosine kinase receptor triggers
dramatic activation of downstream signaling
pathways including the protein kinase B
(Akt)/phosphatidylinositol-3 kinase (PI3K)
and mammalian target of rapamycin (mTOR)
pathways. Temsirolimus is an inhibitor of
mammalian target of rapamycin (mTOR)
kinase, a component of intracellular signaling
pathways involved in the growth and prolifer-
ation of malignant cells. Here we present a
case of a 22-year old female who has been
treated with temsirolimus for her Xp11.2/TFE3
gene fusion RCC.
Introduction
Renal cell carcinoma predominantly mani-
fests after the age of 60 with most cases being
sporadic. Most are clear cell carcinomas, with
papillary subtypes representing a minority of
cases.1 Abnormalities of the Von Hipple Lindau
(VHL) gene are found in 40-50% of patients
with sporadic RCC, suggesting that the VHL
gene has a role in pathogenesis.2 The recently
recognized Xp11.2 translocation renal cell car-
cinomas are accepted as a distinctive entity in
the 2004 World Health Organization's renal
tumor classification.1 All bear gene fusions
involving the TFE3 transcription factor gene
[page 164]
and comprise approximately one-third of pedi-
atric RCCs.3Fusion partners for the TFE3 gene
include the papillary renal cell carcinoma
(PRCC) gene at 1q21, the splicing factor PSF
gene at 1p34.1, the splicing factor NonO gene
at Xp12, and the alveolar soft part sarcoma
(ASPL) gene at 17q25.3
Prognosis in children with TRCC is difficult
to ascertain from the literature, but would
appear to be favorable for patients with Stage
1-3 surgically resected disease and unfavor-
cell carcinoma is especially poor. Argani et al.
analyzed 28 Xp11 translocation RCCs in
patients over the age of 20 years.8 All cases
were confirmed by TFE3 immunohistochem-
istry. Patients ranged in age from 22 to 78
years, with a strong female predominance
(female:male ratio 22:6). These cancers tend-
ed to present at advanced stage with 14 of the
28 patients presenting with stage 4 disease.
Lymph nodes were involved with metastatic
carcinoma in 11 of 13 cases in which they were
resected.8 Meyers et al. studied 5 cases of
translocation carcinoma in adult patients, 18
years or older (mean age 32.6 years). Patients
were again diagnosed with advanced disease,
and most with distant metastases. Various
treatments met with minimal success. Unlike
pediatric patients, the adult patients followed a
rapidly terminal course, with a mean survival
of 18 months after diagnosis in the 3 patients
with follow-up data (range 10-24 months).9
Here we report the successful treatment of
adult onset TRCC with an inhibitor of the
mammalian target of rapamycin.
Case Report
A 22-year old African American female pre-
sented to our institution with a two month his-
tory of hematuria, lower extremity swelling,
and a 25 lbs (11%) weight loss. On physical
examination she had tachycardia, pale oral
mucosa, and a palpable mass in the left upper
and lower quadrants of the abdomen.
A CT scan of the abdomen and pelvis
revealed a 14x14x20 cm necrotic mass in the
left kidney with extension through the capsule,
tumor invasion into the left renal vein, renal
hilar and celiac lymphadenopathy, and four ill
defined lesions in the right lobe of the liver
measuring 3.3x3.2 cm, 2.4x2.5 cm, 1.6x2.6 cm,
and 2.1x1.8 cm, respectively. A CT scan of the
chest revealed a 4 mm left lower lobe lung nod-
ule and a small left pleural effusion. A bone
scan and brain MRI were negative for metasta-
sis. A subsequent ultrasound guided biopsy of
the kidney revealed scant fragments of an
epithelioid tumor diagnosed as a renal cell car-
cinoma. Further classification and grading of
the tumor were deferred to the permanent
resection. The patient underwent an ultra-
sound guided alcohol embolization of the left
[Rare Tumors 2009; 1:e53]
Correspondence: Jigarkumar Parikh, 1120 15th
Street BAA-5407, Augusta, GA 30912, USA.
E-mail: jparikh@mcg.edu
Key words: renal cell carcinoma; Xp11.2 translo-
cation, temsirolimus.
Received for publication: 12 October 2009.
Accepted for publication: 16 October 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright J. Parikh et al., 2009
Licensee PAGEPress, Italy
Rare Tumors 2009; 1:e53
doi:10.4081/rt.2009.e53
kidney prior to a left nephrectomy, periaortic
lymphadenectomy, and caval thrombectomy. At
the time of nephrectomy, grossly, a 21x13x12.5 cm
mass was noted extending from the hilum of
the left kidney to the cortex. Pathological
examination of the tumor confirmed a
21x13x12.5 cm mass which occupied the upper
pole and middle of kidney extending from the
cortex into the renal hilum. The mass grossly
extended into the pelvic sinus, involved the
renal vein and artery, and invaded into the per-
inephric fat and Gerota’s fascia. The tumor
was a mostly solid red/brown to white/tan
mass, with a variegated appearance, showing
areas of hemorrhage and necrosis, as well as
multiple calcified areas. Periaortic lymph node
excision revealed that seven of thirty-seven
lymph nodes were involved with tumor. The
liver lesions were not biopsied intraoperative-
ly due to the highly vascular nature of the
tumor. Histopathological examination of the
tumor revealed a renal cell carcinoma with a
heterogeneous appearance consisting of cells
with clear to eosinophilic cytoplasm, arranged
in nests and papillary cores, with extensive
associated necrosis and hemorrhage.
Extensive areas of ossification and focal calci-
fication were also identified. Immunohisto-
chemical analysis of the primary tumor speci-
men demonstrated the expression of the
Xp11.2 translocation/TFE gene fusion product,
with intense and diffuse positivity. The pri-
mary tumor was also focally positive for pan-
cytokeratin, vimentin, CD-10 and negative for
EMA. The final pathological staging reported a
pT3bpN2pMX TRCC, Fuhrman grade G3, with
lymphovascular invasion. Surgical margins
were positive at the renal vein and artery, as
well as Gerota’s fascia. Unfortunately, the
patient’s post-operative course was complicat-
ed by a prolonged hospitalization due to a
wound infection.
Eight weeks post operatively the patient
began chemotherapy with temsirolimus 25 mg
intravenously every week. Before starting
chemotherapy the patient developed shortness

of breath due to a worsening pleural effusion
demonstrated by chest X-ray. Her pleural effu-
sion was presumed to be malignant from
metastasis from her primary RCC. The patient
unfortunately declined a thoracentesis. The
patient responded exceptionally well to tem-
sirolimus clinically and her pleural effusion
completely resolved on chest X-ray after four
doses of temsirolimus. Significant clinical
improvement was also noted with an improve-
ment in appetite, weight gain, resolution of
her left flank pain, and a marked improvement
in her overall performance status.
Unfortunately after five months of tem-
sirolimus, the patient demonstrated disease
progression by CT scanning and recurrence of
her pleural effusion. A follow-up CT scan
revealed recurrence of her left pleural effu-
sion, a hilar mass, subcarinal lymphadenopa-
thy, and too numerous to count liver lesions.
She expired four weeks later after surviving 12
months from the time of diagnosis.
Discussion
Translocation renal call carcinomas are usu-
ally considered pediatric carcinomas with a
strong female predominance.1-7,10 The WHO
describes these cancers as papillary renal cell
carcinomas demonstrating translocations
involving the TFE3 gene on chromosome
Xp11.2. The histopathological appearance is
usually that of a typical papillary carcinoma
with clear cells and cells with granular
eosinophilic cytoplasm.1 Early adult onset
translocation RCC is associated with an
advanced stage at presentation and, most of
the time, with metastatic lesions.9 A mutated
TFE3 gene leads to upregulation of the mes-
enchymal-epithelial transition (MET) tyrosine
kinase receptor that triggers dramatic activa-
tion of downstream signaling pathways lead-
ing to a neoplastic cascade in normal cells.
Thus a therapy that blocks this pathway could
represent a reasonable approach to treatment
based on biological rationale.
The gene of interest, located at Xp11.2, is
TFE3, a member of the microphthalmia tran-
scription factor (MiTF) family. Members of this
family of genes code for basic-helix-loop-helix
leucine-zipper transcription factors that bind
DNA as homodimers or heterodimers. TFE3-
mediated direct transcriptional upregulation of
the Met receptor tyrosine kinase triggers dra-
matic activation of downstream signaling
pathways. The depletion of MET by RNA inter-
ference or its functional inhibition by a selec-
tive inhibitor abolishes hepatocyte growth fac-
tor (HGF) stimulated signaling pathways, lead-
ing to loss of various tumorigenic phenotypes
in TFE3-associated renal carcinoma cells,
including cell proliferation, adhesion, cell
Figure 1. Pro-posed schema of ASPL-TF3-mediated MET activation and downstream effects
in ASPL-TFE3-containing human cancers.
motility, and matrigel invasion 11 (Figure 1).
Many recent publications have linked MET
activation to PI3K/Akt signaling.12-15 PI3K stim-
ulation leads to the activation of mTOR and
changes the translation rates of mRNA
through the intermediates 4E-BP1 and p 70s6k
ribosomal proteins.13 It has been shown in vitro
that PI3K activation by growth factors leads to
Akt dependant phosphorylation of the E3 ubiq-
uitin ligase Mdm2 and degradation of p53.14 In
vitro data also suggest that inhibition of either
Mdm2 or mTOR is sufficient to block MET
induced cell survival.13
Temsirolimus is an inhibitor of mammalian
target of rapamycin (mTOR) kinase, a compo-
nent of intracellular signaling pathways
involved in the growth and proliferation of
cells and the response of such cells to hypoxic
stress. Temsirolimus binds to an abundant
intracellular protein, FKBP-12, and in this way
forms a complex that inhibits mTOR signal-
ing. The disruption of mTOR signaling sup-
presses the production of proteins that regu-
late progression through the cell cycle and
angiogenesis.15
We believe that our patient’s improvement
with temsirolimus is due to its inhibitory
action on mTOR kinase leading to downregula-
tion of cell proliferation and cell growth
through two downstream pathways: p70S6K
and 4E-BP1.14 To date, and to our knowledge,
there has been no prior report of the use of
temsirolimus in Xp11.3/TFE3 fusion transloca-
tion renal cell carcinomas. In our case report
we showed resolution of a presumed malig-
nant pleural effusion, weight gain, and a
marked improvement in the performance sta-
tus of the patient after four doses of tem-
sirolimus. We hypothesize that mTOR
inhibitors interfere with effects of the TFE3
gene fusion proteins leading to blockade of
[Rare Tumors 2009; 1:e53]
Case Report
some of their prooncogenic effects through the
MET receptor tyrosine kinase signaling path-
way. In vitro data suggest that MEK inhibition
enhances rapamycin inhibition of growth in
kidney cancer cell lines,16 and several trials of
MET inhibitors and mTor inhibitors are in
phase I clinical trials.
TRCCs are usually identified according to
their distinct morphology, which is that of a
carcinoma organized in nests and papillae
lined by clear cells, along with other features
such as psammomatous type calcifications.1
Then, usually only in the setting of a pediatric
RCC or an adult who has disease onset at a
young age, are TRCCs suspected and immuno-
histochemical testing for TFE3 carried out. We
note with interest that several authors have
recently identified TRCCs by TFE3 testing on
unusual clinical presentations of RCC that pre-
sented with classical clear cell histology.3,5-7,9 If
mTOR/MEK inhibition is proven to be effective
in this subclass of renal cell carcinomas, we
would ask whether TFE3 testing would be war-
ranted in all cases of RCC in younger patients
given the current poor prognosis of patients
presenting with advanced stage disease.
References
1. Lopez-Beltran A, Scarpelli M, Montironi R,
Kirkail Z. 2004 WHO Classification of the
renal tumors of adults. Eur Urol 2006;49:
798-805.
2. Cohen H, McGovern F. Renal cell carcinoma.
N Engl J Med 2005;353:2477-90.
3. Altinock G, Kattar M, Mohamed A, et al.
Pediatric renal carcinoma associated with
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[page 165]
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4. Camparo P, Vasiliu V, Molinie V, et al. Renal
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immunohistochemical, and gene expres-
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review of the literature. Am J Surg Pathol
2008; 32:656-70.
5. Perot C, Boccon-Gibod L, Bouvier R, et al.
Five new cases of juvenile renal cell carcino-
ma with translocations involving Xp11.2: a
cytogenic and morphologic study. Cancer
Genet Cytogenet 2003;143:93-9.
6. Ramphal R, Pappo A, Zielenska M, et al.
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pathologic, and molecular abnormalities
associated with the members of the MiT
transcription factor family. Am J Clin Pathol
2006;126:349-64.
7. Carcao M, Taylor G, Greenberg M, et al.
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8. Argani P, Olgac S, Tickoo S, et al. Xp11
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adults: Expanded clinical, pathological and
genetic spectrum. Am J Surg Pathol
2007;31:1149-60.
9. Meyer P, Clark J, Flanigan R, Picken M.
Xp11.2 Translocation renal cell carcinoma
with very aggressive course in five adults.
Am J Clin Pathol 2007;128:70-9.
10. MC Hintzy, Camparo P, Vasiliu V, et al. Renal
carcinoma associated with MiTF/ TFE
translocation: report of six cases in young
adults. Prog Urol. 2008;18:275-80.
11. Tsuda M, Davis I, Argani P, et al. TFE fusions
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Metastasizing pleomorphic
adenoma presenting as an
asymptomatic kidney tumor
twenty-nine years after
parotidectomy – urological
viewpoint and overview of
the literature to date
Jan Ebbing,1 Carolin Blind,2 Harald Stein,2
Kurt Miller,1 Christoph Loddenkemper2
1
Department of Urology, and 2Institute of
Pathology, Charité–Universitätsmedizin
Berlin, Campus Benjamin Franklin, Berlin,
Germany
Abstract
Pleomorphic adenomas (benign mixed
tumors) are the most common tumors of glan-
dular origin in the head and neck and are one
of the few benign neoplasms that can undergo
malignant transformation.1 Mixed tumors that
are seemingly benign at the microscopic level
but metastasize have been termed metastasiz-
ing mixed tumors (MZMTs). The entity of
metastasizing benign mixed tumors has been
reported since the early 1940s, with up to
approximately 50 cases described in the liter-
ature to date. Despite their bland morphologic
appearance, MZMTs have been associated
with an overall mortality rate of about 20-40%.
We report the case of a MZMT of the kidney
almost 30 years after lateral parotidectomy
owing to the same tumor entity. For benign
mixed tumors, we are unaware of more than
two other cases of metastasis to the kidney
that have been published, whereas metastases
to the bone, lung, and lymph nodes are more
common. Parotidectomy is widely accepted as
the first choice of treatment,13 but once metas-
tases have occurred the therapeutic strategy
is uncertain with surgery being the only cura-
tive option in cases with resectable disease.
This case report provides information about
the rare event of metastatic disease to the kid-
ney and points out therapeutic strategies.
However, in view of the general lack of ade-
quate information in the literature, the best
therapy for systemic disease still remains
unresolved.
Case Report
A 49-year-old woman suffered from a car
accident and was brought to our clinic. A rou-
tine ultrasound scan of the abdomen in the
emergency unit detected a kidney tumor on
the right side. The patient did not report any
symptoms that would point to a disease of the
urogenital tract. The physical examination
was without pathological findings. A comput-
erized tomography (CT) scan of the abdomen
revealed the presence of two suspect cortical
tumors (20 mm and 50 mm in diameter) in
the right kidney. In addition, the CT scan was
suspicious for pulmonary metastases and a CT
scan of the chest confirmed the presence of
multiple pulmonary lesions in both lungs, with
a maximal diameter of 11 mm in the right
lower lobe. The right kidney was removed by
laparoscopic radical nephrectomy as clinically
renal cell carcinoma was suspected, without
complications.
Pathological Findings
Gross findings
On sectioning the cut surface of the kidney
revealed a white, solid, lobulated, well-circum-
scribed tumor in the middle third of the
parenchyma, which measured 55x55x50 mm
and penetrated the capsule (Figure 1A).
Another smaller, similar focus of 10 mm in
diameter was found in the surrounding
parenchyma close to the hilus.
Histological findings
The microscopic features of both tumors
showed a mixed cell composition with mes-
enchymal elements demonstrating chondroid
differentiation embedded in a myxoid matrix,
as well as epithelial components consisting of
[Rare Tumors 2009; 1:e54]
Rare Tumors 2009; volume 1:e54
Correspondence: Jan Ebbing, Department of
Urology, Campus Benjamin Franklin, Charité –
Universitätsmedizin Berlin, Hindenburgdamm
30, 12200 Berlin, Germany.
E-mail: jan.ebbing@charite.de
Key words: carcinoma ex-mixed tumor, metasta-
sizing mixed tumor, metastasizing pleomorphic
adenoma, kidney metastasis, kidney tumor.
Contributions: JE was the main author and initia-
tor of the case report; CB worked on the patholog-
ical findings; HS approved the pathological find-
ings; KM was responsible for the patient´s urolog-
ical treatment; CL was responsible for the patho-
logical findings and proofread the article.
Received for publication: 18 October 2009.
Accepted for publication: 30 November 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright J. Ebbing et al., 2009
Licensee PAGEPress, Italy
Rare Tumors 2009; 1:e54
doi:10.4081/rt.2009.e54
ductal structures without atypia (Figure 1B).
Immunohistochemical studies showed that
the epithelial component stained positive for
pan-cytokeratin AE1/AE3 with partial expres-
sion of the myoepithelial markers p63
(Figure 1C) and a very low Ki-67 proliferation
rate (Figure 1D).
Figure 1. (A) Gross appear-
ance of the dissected
nephrectomy specimen
showing a well-defined
tumor with a homoge-
neous tan cut surface. (B)
Histology displays the typ-
ical features of a benign
(metastasizing) pleomor-
phic adenoma in the right
kidney with a mesenchy-
mal cartilaginous compo-
nent and an epithelial duc-
tal component within renal
tissue (left lower corner).
(C) The myoepithelial cells
showing expression of p63.
(D) The Ki-67+ prolifera-
tive index is seen as
extremely low (<1%). (E)
Macroscopy of the paraffin
block from 1978 showing
a small nodular tumor of
the parotid gland with a
white-to-tan cut surface.
(F) The identical morphol-
ogy of a pleomorphic ade-
noma in the salivary gland
tissue is demonstrated (left
lower corner).
[page 167]
Case Report
Statement of the pathologist
The histopathological features of the tumors
disclosed a mixed tumor of salivary gland ori-
gin, in particular for a metastasizing pleomor-
phic adenoma, but were not typical of a pri-
mary tumor of the kidney.
The past history of the patient revealed that
a lateral parotidectomy on the left side had
been performed 29 years previously because of
a tumor mass of the parotid gland diagnosed as
a pleomorphic adenoma. The pathological
report described a 45x35x28 mm gland with a
tumor 22 mm in diameter. It was possible to
retrieve the old paraffin blocks from the
archives of the Institute of Pathology of the
Charité–Campus Benjamin Franklin, which
showed a white cut surface of the tumor
(Figure 1E). On histology, even in retrospect,
no signs of malignancy were detected and the
tumor was still classified as a pleomorphic ade-
noma with characteristic epithelial and mes-
enchymal composition (Figure 1F) and great
morphological similarity to the kidney metas-
tasis 29 years later.
Discussion
We report the case of a metastasizing
“benign” pleomorphic adenoma of the kidney
almost 30 years after a lateral parotidectomy
owing to the same tumor entity. A CT scan
revealed suspect pulmonary masses in both
lungs that have remained stable over a period
of three months. After discussion with an
oncologist a surveillance strategy of the
asymptomatic patient was agreed.
Mixed tumors of the salivary glands general-
ly are divided into benign mixed tumors and
malignant mixed tumors, represented by carci-
nosarcomas (true malignant mixed tumors)
and so-called carcinoma ex-mixed tumors,
which can develop within a benign mixed
tumor over an extended period of time.1 Rarely
will a mixed tumor that is seemingly benign at
the microscopic level metastasize. These
tumors have been termed metastasizing mixed
tumors (MZMTs) and have been classified as
metastasizing pleomorphic adenomas within
the category of malignant epithelial tumors of
the salivary gland by the WHO. Some authors
suggest that a MZMT could be the intermediate
link in the transformation of a pleomorphic
adenoma into a carcinoma ex-mixed tumor.2-5 A
published case report from Czader et al. under-
lined the suggestion that MZMT and carcinoma
ex-mixed tumor could represent different
stages along a common biological pathway.2
Histopathological and clinical criteria to dif-
ferentiate metastatic mixed tumors from non-
metastatic mixed tumors are lacking. There
are no predictive factors available to determine
[page 168]
which mixed tumor may have the potential to
metastasize and which patient may die of
metastatic disease.6 However, the probability
that a benign mixed tumor will become malig-
nant depends on the period of time it has been
allowed to develop without treatment. The risk
of malignant transformation – usually into a
carcinoma ex-pleomorphic tumor – ranges
from 1.5% in the first five years to 9.5% after
15 years.7 It is estimated that approximately
20-40% of patients with MZMT will die from
the disease eventually.6 Surgical manipula-
tions are thought to create a metastatic poten-
tial but do not truly explain the occurrence of
metastases.8 Metastases were discovered from
6 to 52 years after the primary tumor was
removed.9 About 40-50% of patients suffering
from carcinoma ex-pleomorphic adenoma
develop local recurrence and up to 70% develop
local or distant metastases.10 Systematic data
for MZMTs concerning recurrence and
metastatic rates are lacking. In contrast to our
case, the patients normally have at least one
episode of tumor recurrence at the primary
site before the development of metastases,
which may occur many years after the presen-
tation of the primary mixed tumor. The
metastatic potential of mixed tumors is related
to the accumulation of key genetic alterations.
The development of a carcinoma ex-mixed
tumor apparently could be, in part, the conse-
quence of the accumulative loss of chromoso-
mal loci at 3p, 9p, and 17p.11 A number of case
reports describe the simultaneous appearance
of benign and malignant components of mixed
tumors in the same tumor manifestation.2,5,12
The order of genetic alterations along tumor
progression seems to be variable and may dif-
fer for each salivary tumor, but for MZMT no
recurrent genetic defect has been reported.
Parotidectomy is widely accepted as the first
choice of treatment,13 but once metastases
have occurred, the therapeutic strategy is
uncertain with surgery being the only curative
option in cases with resectable disease.
Conclusions
Metastatic pleomorphic adenoma of the
salivary gland to the kidney is a very rare neo-
plasm, which requires a careful patient histo-
ry and knowledge of the lesion for patholo-
gists and clinicians to reach the correct diag-
nosis. There is no approved hypothesis as to
how a morphologically benign tumor may
metastasize. Surgery of resectable disease
with curative intent should be attempted
whenever possible. In view of the general lack
of adequate information in the literature, the
best therapy for systemic disease still
remains unresolved.
[Rare Tumors 2009; 1:e54]
References
1. Klijanienko J, El-Naggar AK, Servois V, et al.
Clinically aggressive metastasizing pleomor-
phic adenoma: report of two cases. Head
Neck 1997;19:629-33.
2. Czader M, Eberhart CG, Bhatti N, et al.
Metastasizing mixed tumor of the parotid:
initial presentation as a solitary kidney
tumor and ultimate carcinomatous transfor-
mation at the primary site. Am J Surg Pathol
2000;24:1159-64.
3. Li X, Lu XY, Zhu XZ, et al. Metastasising pleo-
morphic adenoma of the parotid presenting
as a solitary kidney mass. Pathology 2008;40:
87-9.
4. Fujimura M, Sugawara T, Seki H, et al.
Carcinomatous change in the cranial metas-
tasis from a metastasizing mixed tumor of
the salivary gland - case report. Neurol Med
Chir (Tokyo) 1997;37:546-50.
5. Minic AJ. Unusual variant of a metastasizing
malignant mixed tumor of the parotid gland.
Oral Surg Oral Med Oral Pathol 1993;76:330-
2.
6. Batsakis JG. Malignant mixed tumor. Ann
Otol Rhinol Laryngol 1982;91:342-3.
7. Seifert G, Sobin LH. The World Health
Organization's Histological Classification of
Salivary Gland Tumors. A commentary on the
second edition. Cancer 1992;70: 379-85.
8. Ellis G. Tumors of the Salivary Glands. In:
Tumors of the Salivary Glands. Ellis GL,
Auclair PL, eds. Washington, DC: 1996, pp
155-373.
9. Wenig BM, Hitchcock CL, Ellis GL, et al.
Metastasizing mixed tumor of salivary glands.
A clinicopathologic and flow cytometric analy-
sis. Am J Surg Pathol 1992; 16:845-58.
10. Bradley P. Metastasizing pleomorphic sali-
vary adenoma should now be considered a
low-grade malignancy with a lethal potential.
Curr Opin Otolaryngol Head Neck Surg
2005;13:123-6.
11. Johns MM 3rd, Westra WH, Califano JA, et al.
Allelotype of salivary gland tumors. Cancer
Res 1996;56:1151-4.
12. Hellquist H, Michaels L. Malignant mixed
tumour. A salivary gland tumour showing
both carcinomatous and sarcomatous fea-
tures. Virchows Arch A Pathol Anat
Histopathol 1986;409:93-103.
13. Paris J, Facon F, Chrestian MA, et al.
Recurrences of pleomorphic adenomas of
the parotid: changing attitudes. Rev Laryngol
Otol Rhinol (Bord) 2003;124:229-34.

A case of primary mucosa-
associated lymphoid tissue
lymphoma of the prostate
Noriko Koga,1 Masanori Noguchi,1,3
Fukuko Moriya,1,2 Kouichi Ohshima,2
Nobuyuki Yoshitake,4 Kei Matsuoka1
Departments of 1Urology, 2Pathology, and
3
Clinical Research Division of Research
Center for Innovative Cancer Therapy,
Kurume University School of Medicine,
Kurume, Japan; 4Yoshitake Urological
Clinic, Kurume, Japan
Abstract
We report a case of primary mucosa-associat-
ed lymphoid tissue (MALT) lymphoma of the
prostate. A 67-year-old man presented with uri-
nary obstruction and an elevated prostate-spe-
cific antigen (PSA) level. A physical examina-
tion revealed mild prostate enlargement and no
lymphadenopathy. A needle biopsy and immu-
nohistochemical studies of the prostate were
performed, which revealed marginal zone B-cell
MALT-type lymphoma. A bone marrow aspira-
tion and biopsy did not show involvement by
lymphoma. Magnetic resonance imaging (MRI)
of the abdomen and the pelvis revealed no lym-
phadenopathy or ascites. There was no involve-
ment of other sites by lymphoma. The patient
was diagnosed and staged as extranodal mar-
ginal zone B-cell MALT-type lymphoma of the
prostate, low grade and stage I. The patient
received external beam radiation therapy to the
prostate with a total dose of 3600cGy in 22 frac-
tions, and became free of disease within the fol-
lowing 15 months.
Introduction
Low-grade B-cell mucosa-associated lym-
phoid tissue (MALT) lymphoma rarely presents
as a primary tumor in extranodal sites other
than in the stomach, which is the most common
site.1 To date only seven cases of primary prosta-
tic MALT lymphoma have been reported in the
literature to our knowledge.2-8 We report here a
new case that had an elevated prostate-specific
antigen (PSA) level and was treated successful-
ly by external beam radiation therapy alone.
Case Report
A 67-year-old man presented with urinary
obstruction. A physical examination revealed
Rare Tumors 2009; volume 1:e55
mild prostate enlargement and no lymph-
adenopathy or hepatosplenomegaly. Trans- Correspondence: Masanori Noguchi, Department
rectal ultrasonography showed a 4.3x3.2 cm of Urology, and Clinical Research Division of
prostate with high echoic spots in the transi- Research Center for Innovative Cancer Therapy,
tion zone. The laboratory data showed that the Kurume University School of Medicine, 67
Asahi-machi, Kurume 830-0011, Japan.
serum PSA level was 7.53 ng/mL (normal: <4.0
E-mail: noguchi@med.kurume-u.ac.jp
ng/mL). A transrectal ultrasound-guided
prostate needle biopsy was performed and the Key words: mucosa-associated lymphoid tissue
prostatic tissues of the biopsy demonstrated lymphoma, prostate, prostate-specific antigen,
radiation therapy.
diffuse lymphoid infiltrations extending in
most areas in 12 of 12 biopsy specimens. The Received for publication: 18 October 2009.
lymphoid cells invaded the prostate glandular Accepted for publication: 30 November 2009.
epithelium and the characteristic lympho-
This work is licensed under a Creative Commons
epithelial lesions were seen (Figure 1).
Attribution 3.0 License (by-nc 3.0).
The lymphoid cells in these areas were uni-
form in size and shape. They were each char- ©Copyright N. Koga et al., 2009
acterized by a scanty, clear cytoplasm and a Licensee PAGEPress, Italy
Rare Tumors 2009; 1:e55
round, slightly cleaved nucleus. The morpho-
doi:10.4081/rt.2009.e55
logic features were those of centrocyte-like
cells (Figure 2).
In addition, cells with plasma cell differenti-
ation were seen. The immunohistochemical
analysis showed that the lymphoid cells were
positive for CD79a and partially positive for
CD20, and that a small number of cells were
positive for CD3. These histological results
confirmed a low-grade MALT lymphoma of the
prostate. A bone marrow aspiration and biopsy
did not show involvement by lymphoma.
Magnetic resonance imaging (MRI) of the
abdomen and pelvis revealed no lym-
phadenopathy or ascites. Positron emission
Figure 1. Lymphoid cells invading the
tomography (PET) images showed abnormal prostate gland-ular epithelium.
uptake only in the prostate. There was no
involvement of other sites by lymphoma. The
patient was diagnosed and staged as a margin-
al zone B-cell MALT-type of non-Hodgkin’s lym-
phoma of the prostate, low grade and stage I.
The patient received external beam radia-
tion therapy to the prostate with a total dose of
3600cGy in 22 fractions. A follow-up biopsy of
the prostate was performed 12 months after
the radiation therapy. The immunohistochemi-
cal analysis showed that a small number of lym-
phocytes were more dominantly positive for CD3
than CD20 and CD79a, and negative for CD10,
Bcl2, and CD20. Light chain restriction staining Figure 2. Cells with scanty clear cytoplasm
also showed no κ- and λ-reactivity. These find- and a round, slightly cleaved nucleus.
ings confirmed no recurrence of MALT lym-
phoma of the prostate. The patient was free of
disease within the following 15 months.
Primary prostatic MALT lymphoma is extreme-
ly rare and its clinicopathological features are
not well clarified. To our knowledge only seven
Discussion cases have been reported previously. Clinical
features of these seven cases, as well as that
The criteria for primary prostatic lymphoma of our case, are shown in Table 1. The patients
includes disease limited to the prostate and were elderly men with a mean age of 73 years
adjacent soft tissue, absence of lymph node (57-87 yr). The most frequent symptom was
involvement, and a systemic lymphoma-free urinary tract obstruction. Three patients had
interval of at least one month.9 Primary prosta- elevated PSA levels (>4.0 ng/mL). The diagno-
tic lymphoma is rare. It accounts for 0.1% of sis of prostatic MALT lymphoma was made by
newly diagnosed lymphomas and comprises transurethral resection (TUR) in seven
less than 0.09% of all prostate neoplasms.10 patients and a trans-rectal needle biopsy in
[Rare Tumors 2009; 1:e55] [page 169]
Case Report

Table 1. Clinical features of eight primary prostatic MALT lymphoma.

Case Age Symptom Laboratory Clinical Treatment Response Outcome Follow-up Reference
(years) findings stage (months)
1 75 Hematuria, pyuria Normal II TUR, Cx CR AW 12 2
2 57 Urinary obstruction Normal I TUR, Cx CR AW 18 3
3 84 Urinary obstruction Elavated PSA I TUR CR DOC 24 4
4 67 Prostatism Normal I TUR, Rx CR AW 36 5
5 87 Urinary obstruction Normal I TUR NR NR NR 6
6 79 Urinary obstruction Normal I TUR CR AW 108* 7
7 70 Disuria Elevated PSA I TUR, Cx CR AW 5 8
8 67 Urinary obstruction Elevated PSA I Rx CR AW 15 Present case
*Relapse was noted 7 years after the initial treatment; AW, alive and well; CR, complete remission; Cx, chemotherapy; DOC, died of other causes; MALT, mucosa-associated lymphoid tissue; NR, not recorded; PSA,
prostate-specific antigen; Rx, radiotherapy; TUR, transurethral resection.

one patient. All patients had clinical stage I
disease except for one case with tumor
involvement in the epididymis and spermatic
cord. Seven patients underwent TUR, three
had additional chemotherapy, and one had
additional radiotherapy. Our patient was treat-
ed by radiotherapy alone according to the non-
Hodgkin’s lymphoma (NHL) medical guide-
line. The clinical course in each case was
favorable, although one patient died of other
causes. Another site of marginal zone B-cell
lymphoma of the MALT type was characterized
by a high frequency of localized extranodal
disease and a prolonged survival, whereas
nodal marginal zone (monocytoid) B-cell lym-
phoma more often occurred with advanced-
stage disease and had a worse survival rate.1
However, in case 2, a tumor relapse was
detected seven years after the initial TUR. It
seems that long-term follow-ups and more
reports are needed to clarify the clinical char-
acteristics and pathogenesis of this disease.
References
1. The Non-Hodgkin’s Lymphoma Classifica-
tion Project. A clinical evaluation of the
international lymphoma study group: clas-
sification of Non-Hodgkin’s lymphoma.
Blood 1997;89:3909-18.
2. FrancoV, Florena AM, Quinini G, et al.
Monocytoid B-cell lymphoma of the
prostate. Pathologica 1992;84:411-7.
3. Tomikawa S, Okumura H, Yoshida T, et al.
Primaly prostatic lymphoma of mucosa-
associated lymphoid tissue. Intern Med
1998;37:628-30.
4. Tomaru U, Ishikura H, Kon S, et al.
Primary lymphoma of the prostate with
features of low grade B-cell lymphoma of
mucosa-associated lymphoid tissue: a rare
cause of urinary obstruction. J Urol 1999;
162:496-7.
5. Jhaver S, Agerwal JP, Naresh KN, et al.
Primaly extranodal mucosa-associated
lymphoid tissue (MALT) lymphoma of the
prostate. Leuk Lymphoma 2001;41:445-9.
6. Tissier F, Badoual C, Saporta F, et al.
Prostatic lymphoma of mucosa-associated
lymphoid tissue: an uncommon location.
Histopathology 2002;40:111-3.
7. Li C, Hibino M, Komatsu H, et al. Primary
mucosa-associated lymphoid tissue lym-
phoma of the prostate: tumor relapse 7
years after local therapy. Pathol Int 2008;
58:191-5.
8. Kawamoto K, Takeshita T, Iwasaki H, et al.
Extranodal marginal zone B-cell lym-
phoma of mucosa-associated lymphoid tis-
sue (MALToma) of prostate; a case report.
J Diag Pathol 2008;25:43-6.
9. Mermershtain W, Benharroch D,
Lavrenkov K, et al. Primary malignant lym-
phoma of the prostate: a report of three
cases. Leuk Lymphoma 2001;42:809-11.
10. Sarris A, Dimopoulos M, Pugh W, et al.
Primary lymphoma of the prostate: good
outcome with doxorubicin-based combi-
nation chemotherapy. J Urol 1995;53:
1852-4.

[page 170] [Rare Tumors 2009; 1:e55]


Re: Koga et al. A case of
primary mucosa-associated
lymphoid tissue lymphoma
of the prostate
Damien C. Weber
Geneva University Hospital, Radiation
Oncology Department, Geneva,
Switzerland
In the review of MALT of the prostate per-
formed in the case report published by Koga et
al1., the overall majority of these low-grade
tumours seems to be of clinical stage IE.
Conversely, primary non-Hodgkin lymphomas
of the prostate of non-MALT histology appear
to have a much higher rate of extraprostatic
involvement. Botstwick et al. reported on 22
primary prostate NHL and observed a 50% and
19% of lymph node and spleen involvement,
respectively.2
Moreover, the reported 1-year lymphoma spe-
cific survival in this series is in heavy contrast
of the favourable outcome of MALT prostate
patient reported by Koga et al.1 Definitive con-
clusions about the importance of histology on
staging and prognosis cannot however be
inferred from these studies, because of the
small sample size. Further research regarding
the outcome of these patients is justified in the
framework of future retrospective studies. As
such, the Rare Cancer Network (http://www.
rarecancer.net) is currently undertaking a large
study of primary low- and high-grade lymphoma
of the prostate. Inclusion criteria are the follow-
ing: i) biopsy-proven non-Hodgkin’s lymphoma
(NHL) extra nodal of the prostate gland; ii) neg-
ative work-up (abdominal-pelvic CT with or
without bone marrow aspirate) and iii) mini-
mal follow-up of 6 months.
We invite all investigators to participate to
this study that aims to more comprehensively
investigate and clarify the staging features and
outcome of these exceptional patients.
[Rare Tumors 2009; 1:e56]
Rare Tumors 2009; volume 1:e56
Correspondence: Damien C. Weber, Geneva
University Hospital, Radiation Oncology
Department, Geneva, Switzerland.
E-mail:damien.weber@hcuge.ch
Received for publication: 22 December 2009.
Accepted for publication: 23 December 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright D.C. Weber, 2009
Licensee PAGEPress, Italy
Rare Tumors 2009; 1:e56
doi:10.4081/rt.2009.e56
References
1. Koga N, Noguchi M, Moriya F, et al. A case
of primary mucosa-associated lymphoid
tissue lymphoma of the prostate. Rare
Tumors 2009;1e55.
2. Bostwick DG, Iczkowski KA, Amin MB, et
al. Malignant lymphoma involving the
prostate: report of 62 cases. Cancer 1998;
83:732-8.
[page 171]
Rare Tumors 2009; volume 1:e57
A clinical and molecular project
on gonadoblastoma needs
international collaboration
Nicolas Kalfa,1,3 Olivier Maillet,1
Charles Sultan1,2
1 Moreover, GB can be a precursor of dysgermi-
Service d'Hormonologie, Hôpital
Lapeyronie, CHU de Montpellier et UM1,
Montpellier, France; 2Unité
d’Endocrinologie et Gynécologie
Pédiatriques, Service de Pédiatrie,
Hôpital Arnaud de Villeneuve et UM1,
CHU de Montpellier, France; 3Service de
Chirurgie et Urologie Pédiatrique, Hôpital
Lapeyronie, CHU de Montpellier et UM1,
Montpellier, France
Gonadoblastoma (GB) is a specific and
unusual tumor developed by patients present-
ing a disorder of sex development (DSD). The
term gonadoblastoma was first introduced in
19531 to designate a steroid hormone-secret-
ing gonadal tumor. This name was chosen
because the neoplasm appeared to recapitulate
gonadal development more completely than
any other type of tumor. In 1970, Scully2 report-
ed 74 cases of GB and precisely defined it as
the association of embryonic germ cells and
supportive cells that resemble immature
Sertoli/granulosa cells in a context of gonadal
dysgenesis (GD).
First, the natural history of GB remains
unclear. Patient phenotypes are often female
but some degree of masculinization is possi-
ble.3 Diagnosis is frequently made during con-
sultation for primary amenorrhea with the dis-
covery of Swyer syndrome. Tumor secretion
may also induce the development of secondary
sexual characteristics and diagnosis after sec-
ondary amenorrhea has been described.
Patients with true hermaphroditism can also
present with GB.
Second, the predictive factors of GB develop-
ment are largely unknown. Although Page4
hypothesized that GB development is depend-
[page 172]
ent on the presence of part of the Y chromo-
some, known as the GBY region, tumor occur-
rence remains multi-factorial. The overall
tumor risk is evaluated at 30% for complete
gonadal dysgenesis and is variable for other
cases of dysgenesis. Apart from the presence of
Y material, no other risk factor has been found.
noma, but the predictive factor for the transfor-
mation into an aggressive cancer is again
unknown.3,5 An early prophylactic gonadectomy
has thus been advocated for many patients
with GD. In order to provide better guidelines
for making therapeutic decisions about
patients with DSD and to prevent abusive
gonadectomy, we plan to perform a clinical,
immunohistochemical and genetic study on
gonadoblastoma. Hence, we here present an
international call to perform a multicenter
analysis of this rare tumor. The first objective
is to characterize in detail the epidemiological
factors, the diagnostic circumstances, and the
hormonal profiles of patients with GB. This
data collection will define the specific charac-
teristics of these patients, guide subsequent
research, and enable us to test the correlation
of these characteristics with histological crite-
ria. Then, analysis of the molecular profile of
this tumor will focus on sexual determination
factors (SOX9, FOXL2), pluripotency and dif-
ferentiation factors (OCT3/4). Both expression
of candidate genes inside the tumor and their
direct sequencing on tumor DNA (SOX9,
FOXL2, TSPY) could provide new pathophysio-
logical insights into GB.
For this purpose, we would appreciate
receiving the following: (i) a short report of
the patient history recorded on a specific
patient form and (ii) ten uncolored slides of
the tumor, with if possible frozen tissue.
Overall, the pathophysiology of GB develop-
ment is unknown. A collaborative internation-
al study will bring much needed information
on the connections between tumorogenesis
and developmental abnormalities, and could
improve the follow-up of patients with DSD,
while reducing the rate of prophylactic
gonadectomy.
[Rare Tumors 2009; 1:e57]
Correspondence: Charles Sultan, Unité
d’Endocrinologie-Gynécologie Pédiatriques,
Service de Pédiatrie 1 Hôpital Arnaud de
Villeneuve, CHU Montpellier, 34295 Montpellier,
France. E-mail: c-sultan@chu-montpellier.fr
Received for publication: 21 December 2009.
Accepted for publication: 23 December 2009.
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright N. Kalfa et al., 2009
Licensee PAGEPress, Italy
Rare Tumors 2009; 1:e57
doi:10.4081/rt.2009.e57
References
1. Scully RE. Gonadoblastoma; a gonadal
tumor related to the dysgerminoma (semi-
noma) and capable of sex-hormone pro-
duction. Cancer 1953;6:455-63.
2. Scully RE. Gonadoblastoma. A review of 74
cases. Cancer 1970;25:1340-56.
3. Hersmus R, de Leeuw BH, Wolffenbuttel
KP, Drop SL, Oosterhuis JW, Cools M, et al.
New insights into type II germ cell tumor
pathogenesis based on studies of patients
with various forms of disorders of sex
development (DSD). Mol Cell Endocrinol
2008;291:1-10.
4. Page DC. Y chromosome sequences in
Turner's syndrome and risk of gonadoblas-
toma or virilisation. Lancet 1994;343:240.
5. Hersmus R, Kalfa N, de Leeuw B, Stoop H,
Oosterhuis JW, de Krijger R, et al. FOXL2
and SOX9 as parameters of female and
male gonadal differentiation in patients
with various forms of disorders of sex
development (DSD). J Pathol 2008;215:
31-8.

Primary NK/T cell lymphoma
nasal type of the stomach with
skin involvement: a case report
Sebastian Kobold,1 Hartmut Merz,2
Markus Tiemann,3 Carolina Mahuad,1
Carsten Bokemeyer,1 Irmtraut Koop,4*
Walter Fiedler1*
1
Department of Oncology/Hematology/
Bone Marrow Transplantation/
Pneumology, University Medical Center
Eppendorf; 2Department of Pathology,
University of Lübeck; 3Institute for
Hematological Pathology, Hamburg;
4
Department of Internal Medicine,
Amalie-Sieveking Hospital, Hamburg
*both authors share senior authorship,
Germany
Abstract
Since nasal NK/T cell lymphoma and NK/T
cell lymphoma nasal type are rare diseases,
gastric involvement has seldom been seen. We
report a unique case of a patient with a pri-
mary NK/T cell lymphoma nasal type of the
stomach with skin involvement. The patient
had no history of malignant diseases and was
diagnosed with hematemesis and intense
bleeding from his gastric primary site. Shortly
after this event, exanthemic skin lesions
appeared with concordant histology to the pri-
mary site. Despite chemotherapy, the patient
died one month after the first symptomatic
appearance of disease.
Introduction
According to the WHO classification of lym-
phoma, the NK cell type can be classified into
3 subgroups: NK/T cell lymphoma nasal/nasal
type, NK cell leukemia and chronic lymphopro-
liferative disorders of NK cells.1,2 Among non-
Hodgkin’s lymphomas, NK/T cell lymphoma
nasal type is a very rare subtype, predominant-
ly found in East Asia. There it makes up 2-10%
of NHL (non-Hodgkin’s lymphoma).3 It is pri-
marily located in the nasal/nasopharyngeal
region (75%), the skin (4%), the gastrointesti-
nal tract (6%), the bone marrow and the
spleen.4 NK/T cell lymphoma nasal type is diag-
nosed by immunophenotyping. The typical
phenotype has been described as CD2+,
CD3/Leu4–, CD3ε+, CD3–, CD56+, TCR germline
and generally EBV+.5 Based on histological cri-
teria, angiocentric and/or angiodestructive
behavior with mixed in cell morphology (small,
medium and large cells) is often found.6 This
type is known to be highly aggressive and asso-
ciated with a very poor prognosis in dissemi-
nated disease.7 Primary gastric lymphomas are
rare, especially of the NK/T cell nasal type.8
According to literature only 2 cases of primary
gastric NK/T cell lymphoma nasal type have
been reported.9,10 These patients did not show
involvement of other sites except stomach.
They died shortly after diagnosis.
Case Report
A 69-year old Caucasian man was first hos-
pitalized with hematemesis and melena. The
endoscopic examination revealed a bleeding
duodenal ulcer, Forrest 1a and a second ulcer
in the antrum of the stomach (Figure 1).
Biopsies were taken from the gastric ulcer. The
pathological examination revealed a high-
grade lymphoma of the stomach. Roughly, the
histo-morphology showed an angiocentric and
angiodestructive growth pattern with a mixed
cell population accompanied by a heavy admix-
ture of inflammatory cells. Immunohisto-
chemistry revealed positivity for CD2, CD56,
and a weak expression of CD20, as well as a
negative stain for CD4, CD5, CD7, CD8, CD30,
CD33, CD34, CD79a, CD103, CD117 and CD138
(Figure 2). A CD3ε, stain on a fresh tissue
sample was also positive. The neoplastic cells
showed strong granular staining for the cyto-
toxic molecules granzyme B, perforin and
TIA1. The immunostaining with a monoclonal
antibody for the anaplastic lymphoma kinase
(ALK) was negative. The molecular analysis of
the TCR γ-chain-locus showed a germline con-
figuration. By analyzing the samples for IgH
gene rearrangement by PCR analysis, no clon-
al rearrangement could be found.11 Although
EBER (EBV encoded small nuclear RNAs)
expression was negative which is an unususal
finding for nasal NK-T-cell lymphoma; we per-
formed an LMP-1 stain, revealing strong cyto-
plasmatic and surface membrane expression
in almost all lymphoma cells. Therefore, pres-
ence of an EBV-related lymphoma could be
concluded. A NK/T cell lymphoma, nasal type
with partial aberrant expression of CD20 was
diagnosed. The patient underwent the usual
staging examinations with clinical exam, com-
putertomographic assessment of the chest, the
abdomen and the pelvis, a bone marrow biopsy
and a positron emission tomography. None of
these assessments uncovered another involved
site. In particular, the nasal and nasopharyn-
geal regions as well as the bone marrow, were
free of disease. No lymphadenopathy was
found. The patient had no history of celiac dis-
ease and serological analysis was negative for
specific antibodies. The LDH was 865U/L at
time of diagnosis. The patient’s medical histo-
[Rare Tumors 2009; 1:e58]
Rare Tumors 2009; volume 1:e58
Correspondence: Sebastian Kobold,
Universitätsklinikum Hamburg Eppendorf,
Klinik für Hämatologie, Onkologie, Pneumologie
und Knochenmarkstransplantation,
Martinistrasse 52, 20246 Hamburg, Germany
E-mail: sebastian.kobold@hotmail.de
Key words: NK/T cell lymphoma nasal type, pri-
mary intestinal lymphoma, skin involvement.
Conflict of interest: the authors report no con-
flicts of interest.
Contributions: the original manuscript was writ-
ten by SK. All authors participated in drafting and
editing the manuscript. IK and WF share senior
authorship. All authors read and approved the
final manuscript. The authors all provide special-
ized multidisciplinary clinical care for cancer
patients in Hamburg, Germany.
Consent: the patient’s wife, as his legal supervi-
sor, has provided informed consent for the publi-
cation of this case report and accompanying
images.
Received for publication: 17 October 2009.
Revision received: 14 December 2009.
Accepted for publication: 14 December 2009
This work is licensed under a Creative Commons
Attribution 3.0 License (by-nc 3.0).
©Copyright S. Kobold et al., 2009
Licensee PAGEPress, Italy
Rare Tumors 2009; 1:e58
doi:10.4081/rt.2009.e58
ry was insignificant apart from newly diag-
nosed diabetes and the loss of 10% body weight
in the previous four months rated as B-symp-
toms. The patient met the Dawson criteria for
primary intestinal lymphoma.12
In addition, shortly after the symptomatic
appearance of his disease, the patient devel-
oped exanthemic non-pruriginous skin
lesions. A biopsy was performed and the
immunohistochemical assessment showed the
same expression profile as described above
(Figure 3). Dermal spread of the NK/T cell lym-
phoma nasal type was concluded. It can be
deducted that the patient had a stage IVB dis-
ease before the start of the therapy.
Chemotherapy using the CHOP-protocol
(cyclophosphamid, hydroxydaunorubicin, onco-
vin, prednison) was applied and well tolerated
by the patient. About a week later, the patient
developed grade IV hematoxicity, becoming
aplastic and septic. Supportive care was pro-
vided with antibiotic escalation and parenteral
support. Meanwhile skin infiltration increased
with several new lesions. Despite all efforts,
the patient died of septic complications, most-
ly due to a severe pneumonia. The patient’s
relatives declined autopsy.
[page 173]
Case Report

Discussion
The presence of this rare tumor lead us to
various differential diagnoses. First, an
anaplastic large cell lymphoma (ALCL) was dis-
cussed. According to the latest WHO classifica-
tion, these lymphomas are CD30 positive, and
are in 80% of all cases ALK positive. As the
present lymphoma completely lacked expres-
sion of these markers, an ALCL could be exclud-
ed. Enteropathy-associated T-cell lymphoma
(EATL) was then taken into consideration. The
WHO1 defines the polymorphic form (type I) of
EATL as CD3+, CD5–, CD7–, CD8+/-, CD4–,
CD103+, TCRβ+/- and cytotoxic proteins positive.
The monomorphic form (type II) is defined as Figure 1. Endoscopic appearances of primary gastric NK–/T−cell lymphoma: ulcerative
type.
CD3+, CD4–, CD8+, CD56+ and TCRβ+. The lym-
phoma cells were completely negative for these
markers except CD56 and the cytotoxic pro-
teins. These markers are insufficient for the
diagnosis of EATL.1 A primary cutaneous γ-d T-
cell lymphoma was excluded because of the
negativity for CD3 and the TCR germline con-
figuration, required for diagnosis by the WHO
classification.1 Finally, a peripheral T-cell lym-
phoma not otherwise specified was considered
due to the typical involvement of skin and stom-
ach.1 CD4+ and clonal TCR gene rearrangement
is most frequently seen, in contrast to the pres-
ent case, albeit a false negative TCR rearrange-
ment and a negative stain for CD4 have been
described before.1 In addition, a peripheral T-
cell lymphoma not otherwise specified could
only be diagnosed if other lymphoma types are Figure 2. Immunostain-ing with monoclonal antibody directed against CD56 (A) and
ruled out. As the morphology didn’t match the CD2 (B). Nearly all the stomach infiltrating cells were positive.
typical morphology of such a peripheral T-cell
lymphoma we didn’t favor this diagnosis.
Because of the CD20 positivity, a B-cell lym-
phoma was considered, but given the negativi-
ty for CD79a and a lack of clonal IgH gene
rearrangement associated with the above men-
tioned immunohistochemical profile, a B-NHL
seemed very unlikely. An aberrant expression
of CD20 was concluded.
We compared the findings in the present
patient with a recent analysis on the largest
series of NK/T-cell lymphoma.13 As was seen in
this collective, CD2, CD3ε, TIA-1, granzyme B
and CD56 stainings were positive. Although
CD30 was negative in our extranasal case, it
was negative in 37% of cases in this series and
it is not a prerequisite according to WHO clas-
Figure 3. Immunostain-ing with monoclonal antibody directed against CD56 (A) and
sification. The germline configuration of TCR CD2 (B). About 80% of the skin infiltrating cells were positive.
fits into the findings of this series, as most
extranasal cases were found negative for TCR
rearrangement. The EBER positivity was an ular tumor concurred only with an extranodal and LMP-1 analysis to assess EBV status of
obligatory inclusion criteria in this study. The NK/T-cell lymphoma nasal type. The EBER-neg- lymphomas, as is recommended in Hodgkin’s
strong LMP-1 expression of the present case, ativity could be explained by a low quality of lymphomas.16
which points towards an EBV-associated lym- preservation of the paraffin wax-embedded Several authors have advocated the estab-
phoma, can easily weigh out the EBER negativ- blocks14 or by a lack of expression of EBER-1, as lishment of a prognostic model for NK/T cell
ity for EBV diagnosis. has been reported in other tumors.14,15 Our find- lymphoma nasal type that is more reliable than
Finally the immunophenotype of this partic- ings argue in favor of the combination of EBER IPI1,7,17,18 (International Prognostic Index).

[page 174] [Rare Tumors 2009; 1:e58]


Factors significantly associated with a worse
prognosis are male gender, the presence of B-
symptoms, high LDH, advanced stage and
CD30 negativity. In our case, the patient pos-
sessed all negative prognostic factors and died
shortly after diagnosis.
Past experiences with the CHOP-regi-
menindicated that it might not be an adequate
therapeutic approach for advanced stage dis-
ease.19 Some authors have suggested high-
dose chemotherapy associated with autologous
or allogeneic transplantation for patients with
NK/T cell lymphoma nasal type and poor prog-
nosis.20,21 In this case, the general condition of
the patient at the start of the therapy did not
allow such an aggressive approach. Therefore,
the standard CHOP therapy was chosen in
order to improve the overall condition of the
patient.22
To our knowledge, this patient is a unique
case of a primary NK/T cell lymphoma of the
stomach with skin involvement. To date, no
conclusive theory has been described to
explain why this type of lymphoma remains
confined to these unusual locations.22 We hope
that our experience might help in the under-
standing of this very rare disease.
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