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ORIGINAL ARTICLE

Clear Cell Carcinoma of the Penis: An HPV-related


Variant of Squamous Cell Carcinoma
A Report of 3 Cases
Diego F. Sanchez, MD,*w Ingrid M. Rodriguez, MD,*w Adriano Piris, MD,z Sofı´a Cañete, MD,*
Cecilia Lezcano, MD,y Elsa F. Velazquez, MD,8 Maria J. Fernandez-Nestosa, PhD,z
Javier E. Mendez-Pena, HT,# Mai P. Hoang, MD,# and Antonio L. Cubilla, MD*w

inates in the penile mucosal surface and is probably related to


Abstract: Penile clear cell carcinoma originating in skin adnexal warty carcinomas.
glands has been previously reported. Here, we present 3 mor-
phologically distinctive penile tumors with prominent clear cell Key Words: clear cell carcinoma, penile carcinoma, HPV
features originating not in the penile skin but in the mucosal (Am J Surg Pathol 2016;40:917–922)
tissues of the glans surface squamous epithelium. Clinical and
pathologic features were evaluated. Immunohistochemical stains
were GATA3 and p16. Human papilloma virus (HPV) detection
by in situ hybridization was performed in 3 cases, and whole-
tissue section-polymerase chain reaction was performed in 1
T here are several subtypes of penile squamous cell
carcinomas according to the new WHO classification
of tumors of the male genital system.1 Because of their
case. Patients’ ages were 52, 88, and 95 years. Tumors were large
morphologic distinctiveness and sufficient evidence for a
and involved the glans and coronal sulcus in all cases. Micro-
bimodal etiopathogenesis of penile cancer2 the subtypes
scopically, nonkeratinizing clear cells predominated. Growth
were grouped into human papilloma virus (HPV) and
was in solid nests with comedo-like or geographic necrosis.
non-HPV-related carcinoma. In the first category are the
Focal areas of invasive warty or basaloid carcinomas showing in
basaloid, warty (condylomatous), warty-basaloid, papil-
addition warty or basaloid penile intraepithelial neoplasia were
present in 2 cases. There was invasion of corpora cavernosa,
lary basaloid, and lymphoepithelioma-like carcinomas.3–5
The importance of identifying these tumors is not only
lymphatic vessels, veins, and perineural spaces in all cases. p16
etiological or morphologic but has to do with the better
was positive, and GATA3 stain was negative in the 3 cases. HPV
prognoses reported for tumors associated with HPV in
was detected in 3 cases by in situ hybridization and in 1 case by
the penis and other sites.6–15 Some studies found no
polymerase chain reaction. Differential diagnoses included other
prognostic difference in HPV-positive and HPV-negative
HPV-related penile carcinomas, skin adnexal tumors, and
patients.16,17 Here we report 3 patients with penile clear
metastatic renal cell carcinoma. Features that support primary
cell squamous cell carcinomas associated with HPV,
penile carcinoma were tumor location, concomitant warty and/
adding to the list of morphologically distinctive HPV-
or basaloid penile intraepithelial neoplasia, and HPV positivity.
related penile squamous cell carcinomas.
Clinical groin metastases were present in all cases, pathologi-
cally confirmed in 1. Two patients died from tumor dissem-
ination at 9 and 12 months after penectomy. Clear cell
carcinoma, another morphologic variant related to HPV, orig-
MATERIALS AND METHODS
Clinical and pathologic materials from 3 patients
diagnosed at the Instituto de Patologı́a e Investigación
From the *Instituto de Patologı́a e Investigación; wSchool of Medicine,
National University of Asunción, Asunción, Paraguay; zPolytechnic
were evaluated. Pathologic specimens consisted of 3 pe-
School, National University of Asunción, San Lorenzo, Paraguay; nectomies (2 total and 1 partial). An average of 15 sec-
zMihm Cutaneous Pathology Consultative Service, Brigham and tions per case were studied.
Women’s Hospital, Harvard Medical School; 8Miraca Life Sciences Immunohistochemical studies and in situ hybrid-
and Tuft University; #Department of Pathology, Harvard Medical
School and Massachusetts General Hospital, Boston, MA; and
ization were performed at the Department of Pathology,
yUniversity of Pittsburgh Medical Center, Pittsburgh, PA. Massachusetts General Hospital, Boston, MA, on 5-mm-
Conflicts of Interest and Source of Funding: The authors have disclosed thick tissue sections in a Bond III automated im-
that they have no significant relationships with, or financial interest munostainer (Leica Microsystems, Bannockburn, IL),
in, any commercial companies pertaining to this article. using primary antibodies against GATA3 (L50-823, 1:250;
Correspondence: Antonio L. Cubilla, MD, Instituto de Patologia e
Investigacion, Cap. Manuel Brizuela 325 and Ayala Velazquez, Biocare Medical, Concord, MA) and p16 (16P04, 1:4;
Asuncion, Paraguay 1584 (e-mail: antoniocubillaramos@gmail.com). Ventana Medical Systems, Tucson, AZ) and DNA in situ
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved. hybridization probes against HPV16 and 18 (prediluted,

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Sanchez et al Am J Surg Pathol  Volume 40, Number 7, July 2016

Leica Microsystems). Appropriate positive and negative hyperchromatic, rounded, ovoid, or wrinkled nuclei. Bi-
controls were included. nucleated forms were also present. There were prominent
Whole-tissue section-polymerase chain reaction cytoplasmic clear cell features (Figs. 2C, D). The second
(PCR) was performed in 1 case. This case was part of a growth pattern was characterized by a tumoral nest with
previous study correlating morphology with presence of comedo necrosis. At low power, confluent nests showed
the virus.3 Follow-up ranged from 12 to 18 months. prominent central and geographical-like necrosis
(Fig. 2E). At higher power necrosis was comedo-like, and
RESULTS central cells were poorly differentiated and had mostly
centrally located hyperchromatic nuclei with some mitotic
Clinical Features figures and prominent clear cell cytoplasm (Fig. 2F). In 1
Patients’ ages ranged from 52 to 95 years (average, case there was great nuclear pleomorphism.
78.3 y). All of them were uncircumcised (Table 1). Pre- Areas of the tumor showed morphologic features
senting clinical sign was that of a self-appreciated large indistinguishable from those of classical warty and basa-
tumor mass in the distal part of the penis. One patient loid carcinomas in 2 cases: the warty component was
presented with a concomitant penile mass and metastases found predominantly at the surface component of the
in the lungs and cervical lymph nodes. Physical exami- tumor (Fig. 3A), and the basaloid component was present
nation showed tumors to involve preferentially the glans as deeply invasive nests (Fig. 3B). These changes were
with extension to the coronal sulcus in all cases. In 1 case focal, comprising <5% of the total volume of invasive
the foreskin was focally compromised. The skin of the tumor. Warty and warty-basaloid penile intraepithelial
penile shaft was not affected in any of the cases. neoplasia (PeIN) (Figs. 3C, D) was found in the adjacent
glans squamous epithelium of these 2 cases, one of which
Gross Features was associated with lichen sclerosus. The third tumor was
Tumors were large, white to gray, granular, firm, entirely composed of clear cells in a nesting pattern
irregular masses with ulceration of the glans epithelial without in situ lesions. A metastatic renal cell carcinoma
surface. The cut surface showed a replacement of the was considered. Images revealed no kidney tumor.
normal anatomic architecture of the glans, with massive
tumor occupation of erectile tissues, up to the corpora
cavernosa in the 3 specimens. Cut surface was white to Pathologic Prognostic Factors
tan and showed minute yellow foci related to tumor ne- Adverse pathologic prognostic factors including
crosis (Figs. 1A, B). They measured 5.5 to 7.5 cm in high histologic grade, tumor thickness averaging 40 mm,
largest dimensions; the average size was 6.5 cm (Table 1). deep invasion of the corpora cavernosa, and vascular and
perineural invasion were found in all cases.
Microscopic Features
We found a distinctive nesting growth divided into 2
different patterns, solid and with comedo necrosis. Solid Immunohistochemistry and HPV Studies
growth was characterized by rounded or irregular sheets Immunohistochemical staining showed p16 pos-
of non-necrotic tumor cells with a finely lobulated ar- itivity in all cases (Fig. 3E). GATA3 stain was negative in
chitecture and sharp tumor boundaries infiltrating erectile the 3 cases. In situ hybridization for DNA of HPV16 and
tissues (Fig. 2A). A closer view would reveal solid lobules 18 was positive in all cases (Fig. 3F). HPV16 was detected
of tumor cells separated by a delicate strand of fibrous by PCR in 1 case, previously published.3 This was the
tissue (Fig. 2B). At high power, the neoplastic cells had case resembling renal cell carcinoma.

TABLE 1. Clinicopathologic Features


Features Case 1 Case 2 Case 3
Age (y) 52 88 95
Circumcision No No No
Site Glans, COS Glans, COS Glans, COS, foreskin
Size (cm) 6.5 7.5 5.5
Grade III III III
Thickness (mm) 21 75 25
Level of invasion CC, urethra CC, urethra CC, urethra
Vascular invasion Positive Positive Positive
Perineural invasion Positive Positive Positive
Lymph nodes Positive Positive (clinical) Positive (clinical)
Follow-up DOD, 12 mo AWD, 15 mo DOD, 9 mo
Associated lesions
PeIN No Warty/basaloid Warty/basaloid
Lichen sclerosus No No Yes
AWD indicates alive with disease; CC, corpora cavernosa; COS, coronal sulcus; DOD, dead of disease.

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Am J Surg Pathol  Volume 40, Number 7, July 2016 Clear Cell Carcinoma of the Penis

FIGURE 1. A and B, Cut surface of a partial penectomy specimen and diagrammatic representation. There is a massive tumor
replacement of the lamina propria and corpus spongiosum of glans surrounding the urethra. There is focal infiltration of corpus
cavernosum (tumor in blue). White spots correspond to necrotic foci.

Inguinal Nodal Status and Outcome glands within penile epithelial mucosal compartments. Ad-
Inguinal node metastasis was confirmed pathologi- nexal glands normally do not occur in the penile mucosae,
cally in 1 patient. Clear cell features were prominent in which include the epithelium and lamina propria of the
the metastasis as well. The other 2 had inguinal adenop- glans, coronal sulcus, and foreskin.21 Occasionally, seba-
athy clinically consistent with nodal metastasis. Both, ceous glands may be noted near the coronal sulcus in pre-
because of age, refused lymphadenectomy. Two patients viously circumcised patients, probably resulting from
died from disseminated disease 9 and 12 months after surgical and repair displacement. They may be the origin of
penectomy. The third patient was alive with disease at last the unusually reported cases of penile sebaceous gland car-
follow-up 15 months after surgery. cinomas.22–25
The differential diagnosis of clear cell carcinoma of
DISCUSSION the penis involves other HPV-related penile squamous cell
We report a new type of HPV-related penile squamous carcinomas, skin adnexal tumors,25,26 urethral clear cell
cell carcinoma, the clear cell variant. The relation of HPV, in adenocarcinomas,27,28 and metastatic renal cell carcino-
addition to the morphology of the tumor, is based on the ma.29 Clear cell carcinomas may be confused with the more
detection of HPV by PCR and in situ hybridization and on common HPV-related tumors, warty and basaloid carci-
the positivity of p16. This immunostain is believed to be an nomas,30 because of the presence of 2 features: clear cells,
adequate immunohistochemical surrogate for HPV de- typical in warty carcinomas; and nesting solid or comedo-
tection.13 The first series of 5 cases of clear cell carcinoma in like growth pattern, frequent in basaloid carcinomas.
the penis was published in 2004 by Liegl and Regauer18 from However, warty carcinomas are exophytic and papil-
Viena. Unlike our cases, preferentially affecting the glans, lomatous, simulating condylomas, features not present in
theirs were located in the foreskin. According to these au- clear cell carcinomas. Nesting and comedo-like necrosis is
thors those were originated in adnexal glands located in the prominent in both clear cell and classical basaloid carci-
intersection of the foreskin with the skin of the shaft. One of nomas, but the latter lacks the presence of clear cells. Be-
the microphotographs showed in situ carcinoma in sweat nign or malignant sweat and sebaceous gland tumors with
glands from adjacent skin. It was the opinion of the authors clear cell features may involve the distal penis primarily or
that, unlike the tumors we are reporting, these characteristics secondarily. However, these tumors are negative for HPV
would indicate their cases to be primary skin tumors and not and p16 immunostaining. They usually originate in the skin
mucosal. However, the microscopic features of the tumors of the shaft and rarely in the penile mucosae.22,23 The lack
described in the Austrian paper are similar to our 3 cases, of GATA3 expression disfavor the possibility of a ur-
suggesting that some of their cases may represent the same othelial origin.31 Metastatic renal cell carcinoma to the
tumor entity. The in situ carcinoma within sweat glands may penis accounts for 7% of all malignant tumors secondarily
correspond to pagetoid spread from a penile carcinoma. affecting the penis, after prostate, urinary bladder, and
Pagetoid variants of PeIN have been reported.19 We had colon. It preferentially affects the corpora cavernosa, and it
observed pagetoid spread of penile carcinomas extending to is usually multicentric.29 One of our cases presented with
the skin of the shaft or proximal penile urethra to reach the systemic metastasis, and the primary tumor had no evi-
resection margin.20 Furthermore, their cases, like ours, were dence of in situ changes. A kidney primary was suspected,
positive for HPV by PCR or p16, which are usually negative but imaging studies were negative. Immunostaining for
in skin adnexal tumors. We have not seen adnexal-type renal carcinoma may be useful in difficult cases.

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Sanchez et al Am J Surg Pathol  Volume 40, Number 7, July 2016

FIGURE 2. A, Low-power view of a solid invasive nodule in the corpus spongiosum of the glans. Outlines are well demarcated.
HPV16 was found in this case by PCR. B, Solid sheets of invasive tumor composed of clear cells separated by a delicate strand of
fibrous tissue imprinting a lobulated architecture. C, Solid clear cell carcinoma. Note the prominent clear cytoplasm of the tumor
cells. D, Solid clear cell carcinoma. Higher power view showing hyperchromatic, rounded, ovoid, or wrinkled nuclei some of them
with duplication. E, Comedo carcinoma nesting pattern. Tumor proliferation with a distinctive nesting pattern separated by
fibromuscular erectile tissues. F, Comedo carcinoma nest. Higher power view of a nest showing central comedo necrosis. Cells are
uniform and the cytoplasm shows clear cell features.

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Am J Surg Pathol  Volume 40, Number 7, July 2016 Clear Cell Carcinoma of the Penis

FIGURE 3. A, Surface papillomatous lesion composed of clear cells, undistinguishable from classical warty carcinoma. B, In this
case there were focal areas with invasive carcinoma nests consistent with classical basaloid carcinomas. C, PeIN, warty type,
with clear cell features. D, PeIN, warty-basaloid type. E, Nesting pattern with central necrosis, positive for p16. F, DNA in situ
hybridization for HPV16 and 18. The test was positive in tumor cells.

Pathologic adverse prognostic factors predominated in pathologic stage, they were associated with inguinal nodal
our cases. They were histologically high grade, deeply invasive metastasis and tumor dissemination. The presence of these
into the corpora cavernosa, and had vascular and perineural adverse pathologic prognostic factors may be the consequence
invasion. As in other subtypes of penile carcinomas at this of the advanced clinical stage at the time of presentation after

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Sanchez et al Am J Surg Pathol  Volume 40, Number 7, July 2016

years of patient neglect. More cases with earlier stages need carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;
to be evaluated for a definitive prognostic comment of this 100:261–269.
12. Friedman JM, Stavas MJ, Cmelak AJ. Clinical and scientific impact
unusual penile neoplasm. of human papillomavirus on head and neck cancer. World J Clin
The clear cell features, the nested pattern with comedo Oncol. 2014;5:781–791.
necrosis, the foci of warty and basaloid invasive carcinoma, 13. Cubilla AL, Lloveras B, Alejo M, et al. Value of p16(INK)(4)(a) in
positivity for p16 and HPV, and the identification of ad- the pathology of invasive penile squamous cell carcinomas: a report
jacent PeIN (warty or basaloid subtypes) are sufficient evi- of 202 cases. Am J Surg Pathol. 2011;35:253–261.
14. Hernandez BY, Goodman MT, Unger ER, et al. Human
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carcinoma that is characteristically composed of clear cells. and genotyping of human papillomavirus in a Spanish cohort of
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