Undifferentiated Carcinoma
of Nasopharyngeal Type of Tonsil
Jerzy Klijanienko, MD; Christian Micheau, MD; Nacer Azli, MD; Esteban Cvitkovic, MD; Fran\l=c;\oisEschwege, MD;
Patrick Marandas, MD; Jean-Pierre Armand, MD; Odile Casiraghi, MD; Guy Schwaab, MD; Florent de Vathaire, PhD
\s=b\ A review of 2262 squamous cell car-
cinomas of the tonsillar region seen at the
Institut Gustave-Roussy, Villejuif, France,
from 1970 to 1986 showed 1837 well- and
poorly differentiated squamous cell
carcinomas and 425 undifferentiated
squamous cell carcinomas. Eighteen pa-
tients with undifferentiated squamous cell
carcinomas presented histologic charac-
teristics of undifferentiated carcinomas of
nasopharyngeal type. Radiosensibility and
radiocurability (complete sterilization with
70 Gy administered) was found in this
group with an excellent long-term control
of local disease (77% at 10 years actuar-
ial). Epstein-Barr virus\p=n-\relatedserologic
tests were performed for seven patients.
Four of them presented the serologic
anti\p=n-\Epstein-Barrvirus titer patterns,
generally associated with undifferenti-
ated carcinomas of nasopharyngeal type
(1280 to 5120 for viral capsid antigen /lgG
and 40 to 320 for viral capsid antigen/
IgA). These observations confirm that un-
differentiated carcinomas of the nasopha-
ryngeal type may arise outside the naso-
pharynx.
(Arch Otolaryngol Head Neck Surg.
1989;115:731-734)
Undisopharyngeal
fferentiated type
carcinoma
(UCNT) is
of na¬
a nasopharynx; the possibility of includ¬
tumor linked both to endemic geo-
Accepted for publication November 29, 1988.
From the Departments of Pathology (Drs Kli-
janienko, Micheau, and Casiraghi), Radiotherapy
(Drs Azli and Eschwege), Medicine (Drs Cvitkovic
and Armand), Ear, Nose, and Throat Surgery
(Drs Marandas and Schwaab), and Statistics (Dr
Vathaire), Institut Gustave-Roussy, Villejuif,
France.
Reprints not available.
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graphie areas and to the Epstein-Barr
virus (EBV).1 This association has
been confirmed worldwide by serologie
studies of EBV antibodies in cases of
nasopharyngeal carcinomas, by detec¬
tion of EBV genomes in the malignant
epithelial cells, and by demonstration
of EBV nuclear antigen.24 The same
entity has been described outside these
classic endemic geographic areas, and
carcinomas of similar appearance
have been found in other epithelial and
lymphoepithelial organs (salivary
glands, thymus, larynx, tonsil, and
lung), but the presence of EBV in the
tumor cells has not always been stud¬
ied.
We present 18 cases of undifferenti¬
ated carcinomas of the tonsillar region
with a histologie pattern of UCNT,
several associated with characteristic
anti-EBV serologie levels usually seen
in patients with UCNT. To investigate
these cases, all the patients with
UCNT of the tonsillar region seen at
our institution were reviewed. The re¬
sults were compared with the other
tonsillar squamous cell carcinomas
(SCC) and the UCNT arising in the
ing all of the localizations of undiffer¬
entiated carcinoma with heavily reac¬
tive EBV serologie findings and the
same biological behavior in a single
histoclinical entity is described.
MATERIALS AND METHODS
The Institut Gustave-Roussy (IGR,
Villejuif, France) is an important European
referral center for UCNT and a major ref¬
erence point for the diagnosis and treat¬
ment of this disease. It also has one of the
largest oncologie ear, nose, and throat sur¬
gical and pathologic services in the world,
with more than 1000 new patients a year. In
a retrospective analysis from 1970 to 1986,
2262 consecutive patients with histologi¬
cally proven carcinoma of the tonsillar re¬
gion were seen at the IGR. We found
1837 well- and poorly differentiated SCC
and 425 undifferentiated SCC. Among these
425 cases a selected group of 18 patients
presented histologie characteristics5-6 of
UCNT recognized on biopsy specimens
of the tonsil or metastatic lymph nodes,
and constitute the material for this analy¬
sis.
The criteria for selection were as follows:
(1) the histologie characteristics of UCNT
on tonsillar biopsy specimen; (2) no evi¬
dence of disease in the nasopharynx at time
of onset; and (3) histologie slides reviewed
by the same histopathologists (CM. and
J.K.).
The clinical findings are summarized in
Table 1. Patients with UCNT consisted of 13
men and 5 women. Most of then (10 pa¬
tients) were French. The age distribution
ranged from 24 to 73 years, the mean age
being 55.5 years.
They were all retrospectively reclassified
according to the clinical TNM classification
recommended by the International Union
Against Cancer (1986).7
Specimens for EBV serologie tests were
not routinely drawn before 1980. Serum
samples from 7 of the 18 patients were an¬
alyzed and sent for assessment of anti¬
bodies to the International Agency for Re¬
search on Cancer in Lyon, France. These
were measured according to the method of
Henle et al8 and Reedman and Klein.9 Anti-
 EBV titers in these 7 patients are shown in
Table 1.—Patients' Characteristics*
Table 2. Four (patients 1 to 4) had the sero¬
logie pattern of UCNT and their clinical, Case No./ Serology Follow-up,
biological, and therapeutic features are de¬ Age,y/Sex Nationality TNM Done Status y/mo
scribed in the case reports. The other 3 pa¬ 1/70/M French T1, N2b, MO NED
tients had only elevation of the IgG anti¬ 2/54/M Algerian T4, N2b, MO NED 0/5t
viral capsid antigen (VCA) titer. 3/79/M Algerian T2, NO, MO NED 5/6
All patients were treated by radiation 4/73/M Italian T3, N2b, MO NED
therapy only (70 Gy for 7 weeks, 4 to 5 frac¬ 5/24/F French* T1, N2b, MO NED 10/6
tions a week), which was administered to 6/55/M French T2, N2b, MO DOD
the primary tumor; 65 Gy was administered French T3, NO, MO NED
to the metastatic lymph nodes in the neck; 8/31/M Senegallan T3, N3, MO NED 0/7t
and 50 Gy was administered to the clini¬ 9/58/M French T2, N2b, MO ARD 6/3
cally negative cervical areas. All but one 10/49/F Algerian T1, N3, MO NED
patient has been followed up every 3 French T3, N2b, MO NED 16/3
months. 12/70/M Italian T1, N1, MO NED 0/10t
Survival analysis of all cases has been 13/60/F French T2, N2b, MO 9/11
monitored using the Kaplan-Meier's French T4, N2a, MO ARD
method for censored data'0 employing the 15/54/F Italian T1, NO, MO NED
time of real follow-up. Survival curves were 16/28/M Tunisian T1, N1, MO NED 10/3
compared with the log rank test." French T2, NO, MO NED
18/73/F French* T2, NO, MO ARD 17/4
REPORT OF CASES *
NED indicates no evidence of disease; DOD, dead of disease; ARD, another reason of death; plus sign, se-

Case 1.—A 70-year-old French man, non- rology done; and minus sign, serology not done.
tUnavailable for follow-up.
smoker, had enjoyed good health until Sep¬ in Algeria.
tember 1982 when a right tonsillar tumor
and submandibular, subdigastric, and pos-
tauricular metastatic lymph nodes were Table 2.—Available Anti-Epstein-Barr Virus Serologie Titers*
discovered. Results of the nasopharyngeal
mucosa were normal on examination. Serologie Findings
A biopsy of the tonsil was performed and
VCA
the diagnosis of UCNT was made. The
Case Evolution,
tumor was staged Tl, N2b, MO according to No. IgA
IgG IgA IgG mo
the American Joint Committee on Cancer 1280 40 320 40
and International Union Against Cancer 5120 320 <5
classification. 67
Radiation treatment was started 1 month 1280 40 <160 10
later and 70 Gy were administered to the
primary tumor and 65 Gy were adminis¬ 15 160 <5
tered to the metastatic lymph nodes. Lo- te 320 20
coregional control was excellent and the VCA indicates viral capsid antigen; EA, early antigen.
patient is alive and disease free 5 years
later, despite severe radiation-induced se¬
quelae. tumor. uation of postauricular and subdigastric
Initial EBV serologie levels were high Case 3.—A 79-year-old Algerian man, nodes associated with a large tonsillar tu¬
(Table 2) and compatible with the diagno¬ nonsmoker, was first seen in July 1981 with mor (T3, N2b, MO). The sections of the pri¬
sis. an ulcerated right tonsillar tumor without mary and lymph node specimens were re¬
Case 2.—A 54-year-old French man with clinical adenopathy (Tl, NO, MO). Results viewed and the diagnosis of UCNT was
a long history of heavy smoking was ad¬ of a nasopharyngeal examination were nor¬ maintained. The EBV serologie titers were
mitted to IGR in July 1981 for evaluation of mal and EBV serologie levels were high high (Table 2).
a large left tonsillar tumor and subdigastric (Table 2). Histologie examination revealed Radiotherapy consisted of 70 Gy admin¬
lymph node metastasis (T4, N3, MO). Re¬ a UCNT. Radiotherapy resulted in a com¬ istered to the tonsil and 65 Gy administered
sults of clinical and radiologie nasopharyn¬ plete tumoral disappearance with doses of to the metastatic lymph node area. Six
geal examinations were normal. Anti-EBV 70 and 50 Gy administered prophylactically years later, the patient is alive and well
titers were high (Table 2). to cervical nodes. Local recurrence was ob¬ with no evidence of disease.
Histologie diagnosis of the tonsillar tu¬ served 36 months later, and the tumor was
mor was that of UCNT. Radiotherapy (70 treated by surgery with clear-cut exci¬ RESULTS
Gy) was administered to the primary tumor sion.
Hematoxylin-eosin and Giemsa-
and (65 Gy) to the subdigastric node. Peri¬ After radiotherapy EBV serologie levels stained sections of paraffin-embedded
odic examinations during the radiation dropped to normal, but increased prior to material of all 18 cases showed fea¬
treatment revealed a high radiosensitivity surgery, and dropped again to normal af¬
with disappearance of the tonsillar lesion terward. The patient is alive and well 66 tures typical of UCNT.12 This revealed
a monomorphic cell population dif¬
after the administration of 23 Gy. The pa¬ months after the first diagnosis.
tient was unavailable for follow-up 5 Case 4.—A 73-year-old Italian man, non- fusely replacing lymphoid tissue of the
months after a complete regression of his smoker, was first seen at the IGR for eval- tonsils and/or the neck lymph node.

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Fig 1.—Case 3. Undifferentiated carcinomas of nasopharyngeal type of
tonsillar fossa with positive serologie findings. The tumor is composed
of a mixture of clear, syncytial mononucleate cells with huge nuclei,
mixed with eosinophils and lymphocytes. Several histiocytelike cells are
also noted (hematoxylin-eosin, original magnification X63).
Fig 2.—Case 16. Undifferentiated carcinomas of nasopharyngeal type
of tonsillar fossa with negative serologie findings. Histologie appearance
is similar to four positive cases of Epstein-Barr virus. Several atypical
mitoses are evident on tonsil biopsy specimen (hematoxylin-eosin, orig¬
inal magnification X100).

Plasma cells and lymphocytes were
intermingled with large tumor cells of
carcinomatous origin. The tumor cells
had oval or round vesicular nuclei and
prominent nucleoli. The cell margins
were indistinct and the tumor exhib¬
ited a syncytial rather than a paved
appearance. Spindle-shaped tumor
cells, some with hyperchromatic nu¬
clei, were occasionally present (Figs 1
and 2).
Because of the small number of
cases, we did not attempt to subgroup
the cases according to the prognostic
value of differently proposed histologie
classifications.12
The results of anti-EBV antibody tí¬
tere are shown in Table 1. Four of the
seven patients had EBV serologie lev¬
els typical for patients with UCNT
(Table 2) and an elevated IgG/VCA.
A high proportion of these patients
are alive without disease (from 5
months to 208 months; mean, 110
months), of whom three were unavail¬
able for follow-up. Three patients are
dead of noncancerous pathologic con¬
ditions and one patient died of poly-
metastatic dissemination (case 6).
Treatment results of the 18 cases of
UCNT of tonsillar origin have been ex¬
cellent. Ten years overall survival was
77% (standard error, 0.1197), which is
better when compared with the other
histologie types of tonsillar carcino¬
mas. The 3-year overall survival rate
was better for undifferentiated SCC
(74%) than for differentiated SCC
(47% ). The 5-year overall survival rate
was also better for undifferentiated
SCC than for differentiated SCC (60%
and 29.5%, respectively).13
Undifferentiated carcinoma of the
nasopharynx is a highly malignant
disease, generally locally advanced at
presentation, with a higher incidence
of distant métastases to lungs, liver,
and bone marrow than other head and
neck carcinomas.114 Survival rates are
about 63 % at 3 years for Tl and T2, and
38% for T3.1·13
COMMENT
Among the recommendations given
to the participants of all Nasopharyn¬
geal Carcinoma International Con¬
gresses, one of the most important was
the identification of UCNT cases out¬
side the nasopharynx in association
with elevated EBV serologie levels.
Such tumors, identical to UCNT, which
are recognized by histologie, clinical,
and, sometimes, by EBV serologie
findings, have been already described
in the salivary glands of Eskimos and
Southeast Chinese, in the thymus, the
larynx, and the lung. Krishnamurthy
et al15 reported 18 cases of malignant
low- and high-grade salivary malig¬
nant lymphoepithelial neoplasms in
Alaskan natives and they suggested
that this lesion shows histologie simi¬
larities to nasopharyngeal UCNT.
Lanier et al,16 Saemundsen et al,w and
Hanji and Gohao18 also suggested a re¬
lation between EBV and salivary ma¬
lignant lymphoepithelial neoplasms.
The analysis of cell-free material in
saliva of parotid secretions and throat
washings from patients with acute in¬
fectious mononucleosis suggested that
the salivary glands were the site of
EBV production in the oropharynx and
that epithelial buccal cells were a ma¬
jor source of viral replication.1922
Some types of primary thymic car¬
cinomas were diagnosed as lymph-
oepithelioma.2326 The nosology of thy¬
mic neoplasms has undergone consid¬
erable change with several tumor
entities formerly included among the
thymomas shown to be pathologically
and clinically distinct. Another case of
thymic carcinoma histologically com¬
patible with a patient's nasopharyn¬
geal homologue was observed in 1980
at the IGR. The patient's serologie
findings were IgG/VCA, 2560; IgG/
early antigen, 640; IgA/VCA, 20; and
IgG/early antigen, 10. In 1979,
Micheau et al27 reported three cases of
UCNT in relation with laryngoceles,
but EBV serologie findings were not
assessed. This histologie type of carci¬
noma is infrequent in the larynx
(0.02% ). Another case of UCNT of the
vocal cord was reported in 1978.28 Des-
granges and de The,29 Ringborg et al,30
and Begin et al31 reported some cases of
bronchopulmonary carcinomas that
were IgA/VCA positive, but others32·33
have reported some cases of poorly
differentiated SCC of different head
and neck localizations that were also
associated with moderately positive
EBV serologie findings. Review of all
these series shows that these tumors
have clinical features and evolution

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 similar to classic UCNT.114 The prog¬
nosis and radiocurability appear to be
better than other histologie types of
primitive SCC, in keeping with the
well-known radiosensitivity of UCNT.
Serologie EBV data, however, are not
specific, and various cancers and their
associated therapies have immunosup¬
pressive effects, and a latent EBV in¬
fection may be reactivated, resulting
in increased antibody Liters.34
Oropharyngeal localizations of
UCNT may be explained by the strong
biological and clinical similarity
among nasopharyngeal, palatine, and
base of tongue mucosa, ie, "Waldeyer's
ring." Lymphoepithelial tissue is con-
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2. Neel BH, Pearson GR, Weiland LH, et al.
Anti-EBV serologic tests for nasopharyngeal car-
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3. Andersson-Anvret M, Forsby N, Klein G,
Henle W, Bj\l=o"\rklundA. Relationship between the
Epstein-Barr virus genome and nasopharyngeal
carcinoma in Caucasian patients. Int J Cancer.
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4. Ringborg U, Henle W, Henle G, et al. Ep-
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5. Micheau C, Rilke F, Pilotti S. Proposal for a
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7. TNM International Union Against Cancer.
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sidered to be a prerequisite for the oc¬
currence of UCNT. Patients with ton¬
sillar UCNT seem to be from the same
Mediterranean region (Algerians,
southern Italians, French, Portuguese,
and others).
Furthermore, prognosis appears to
be better for tonsillar UCNT because
the locoregional conditions are differ¬
ent. This diagnosis of a tumoral pro¬
cess in the tonsil is easier to establish
than is a diagnosis of nasopharyngeal
tumor, which is often delayed. Tonsil¬
lar tissue is surrounded by a capsule,
and the first cervical metastasis ap¬
pears in the subdigastric node, while
the nasopharyngeal area is more com-
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