Value of Immunohistochemistry in Gynecological Pathology
Moderator: Dr. W. Glenn McCluggage
Case 4 -
Dysgerminoma vs. Poorly Differentiated Carcinoma
Charles Zaloudek, M.D.
Department of Pathology, University of California
San Francisco, CA
The patient was a 73-year-old woman. She underwent surgery
with a preoperative diagnosis of uterine leiomyomas. At operation, the gynecologist discovered a 9 cm
ovarian mass that obliterated the left fallopian tube and superficially invaded into the uterus, to which
it was adherent. The tumor was mainly firm and gray-white, although there were red brown areas and areas
of cystic degeneration. Following microscopic study of the tumor, the pathologist made a diagnosis of
dysgerminoma with an anaplastic or mixed germ cell component.
Case 4 - Figure 1
The tumor has several growth patterns. In places, a chronic inflammatory cell infiltrate separates
rounded aggregates of tumor cells. In these areas, the tumor cells are cohesive with well-defined cell
borders. The cytoplasm is clear to granular and amphophilic. The nuclei are large and relatively
uniform with moderately coarse chromatin and small to indistinct nucleoli. Mitotic figures are readily
identified. In other parts of the tumor, the cells form epithelial like nests that invade through
fibrous stroma. The nests range from large and irregular to rounded and surrounded by clefts. The tumor
cells are cohesive, and polygonal or fusiform with variably dense, amphophilic cytoplasm. The nuclei
have fine to moderately coarse chromatin, inconspicuous nucleoli, and there are numerous mitotic
figures. This aspect of the tumor is more carcinoma like. The tumor involves the serosal surface of the
uterus and invades into the myometrium. Lymphovascular space invasion is present. The submitting
pathologist preformed the following immunostains:
|Stain ||Result ||Comment|
|CK7 ||Positive ||Should be negative in dysgerminoma|
|CD15 ||Negative |
|CD117 ||Negative ||There was significant cytoplasmic staining, but only membranous staining is a positive result for germinoma|
|CD30 ||Negative |
|HCG ||Negative |
|PLAP ||Focal positive staining ||Carcinomas can be PLAP positive|
|Calretinin ||Negative |
|Chromogranin ||Negative |
|NSE ||Negative |
|TTF-1 ||Negative. |
Differential Diagnosis: Dysgerminoma vs. poorly differentiated carcinoma
This case brings up an interesting differential diagnostic problem that must be resolved correctly,
as the treatment and prognosis for dysgerminoma is quite different from that of an ovarian carcinoma.
Dysgerminoma is an uncommon ovarian tumor that occurs mainly in children and young women.
average age is 22 years, and 90% of patients are less than 30. Dysgerminoma is rarely diagnosed in a
woman older than 50. Dysgerminoma responds well to chemotherapy and radiotherapy. The cure rate is >
90% for patients with tumors confined to the ovary and is high even when extraovarian spread is present.
Dysgerminoma tends to be large and solid with a fleshy, homogeneous or nodular tan or white cut surface.
Hemorrhage and necrosis are common in large tumors. Microscopically, dysgerminoma cells are rounded or
polygonal and have distinct cell membranes and abundant clear or granular cytoplasm. The nuclei are
central, round, and vesicular, and they contain prominent nucleoli. Mitotic figures are usually
numerous. The cells grow in nests that are separated by fibrous septae. A lymphocytic infiltrate in the
septae and among the tumor cells is a characteristic finding. Epithelioid cells and multinucleated
Langhans giant cells can be present and sometimes form sarcoid-like granulomas. Syncytiotrophoblastic
giant cells are found in about 3% of dysgerminomas; their presence has no prognostic significance, but
serum levels of human chorionic gonadotropin (HCG) can be elevated in such patients.
Dysgerminoma has a characteristic immunophenotype and immunostains can help confirm the
diagnosis. There is positive staining of tumor cells for placental alkaline phosphatase (PLAP), CD117
Staining for PLAP and CD117 is membranous and is generally strong and diffuse. OCT4 is
the protein product of a nuclear transcription factor, so staining is nuclear. Dysgerminoma is generally
thought of as being keratin negative, and the type of diffuse strong positive staining that is
characteristic of carcinomas virtually never occurs in dysgerminoma. However, with modern antibodies and
antigen retrieval techniques, there is often patchy weak staining for keratin, usually in a dot or rim
pattern. CK7 and EMA stains are negative. The syncytiotrophoblastic giant cells that are occasionally
noted in dysgerminoma stain for HCG.
Is this tumor a dysgerminoma? This patient's age of 74 years places her far outside the usual age
range for dysgerminoma. In parts of the tumor the light microscopic appearance does bear a resemblance
to a dysgerminoma, but even in the areas that most suggest a dysgerminoma the nuclei have more granular
chromatin (i.e., not vesicular), smaller nucleoli and exhibit greater nuclear pleomorphism than is
typical of a dysgerminoma. In addition, areas of more cohesive growth and a fibrous stromal reaction are
more in keeping with a carcinoma than a dysgerminoma. Finally, immunostains answer the question of
whether or not this is a dysgerminoma. We performed the following immunostains:
The diagnosis of dysgerminoma is excluded by the clinical findings, the H&E appearance of the
tumor, and its immunophenotype. If this is not a dysgerminoma, what is it? Although parts of the tumor
mimic a dysgerminoma, other parts suggest a poorly differentiated surface epithelial carcinoma.
Pathologists do not always agree on the classification of high grade ovarian carcinomas, and one might
consider designating this simply as a poorly differentiated or undifferentiated carcinoma. However, the
presence of large nests of cells arranged in a pavement like fashion with focal squamoid features is
compatible with a transitional cell carcinoma.
|Stain ||Result Anticipated in Dysgerminoma ||Result in the Tumor|
|Cytokeratin cocktail ||Negative ||Positive|
|CD117 ||Positive ||Negative|
|PLAP ||Positive ||Negative|
|OCT-4 ||Positive ||Negative|
Transitional cell carcinoma (TCC) has become a more popular diagnosis in recent years and it now
accounts for 5-10% of primary ovarian cancers.  Some authors have observed that TCC is more likely to
respond to chemotherapy and has better survival than other high grade advanced stage ovarian
but not all authors have been able to confirm this.
TCC tends to be partly cystic and it is usually unilateral when it is limited to the
The average diameter is about 10 cm. There are two main microscopic patterns in TCC. The
most common one is reminiscent of a papillary urothelial carcinoma in that thick papillae lined by
stratified transitional cells grow into cystic spaces.
The tumor cells have moderate amounts
of eosinophilic cytoplasm and atypical nuclei with one or more nucleoli. Mitotic figures are numerous.
Nests of malignant transitional cells invade the stroma in solid portions of the tumor. Microspaces and
slit like clefts are commonly present among the tumor cells, both in papillae and in areas of solid
growth.  Foci of mucinous and squamous differentiation, spindle cell differentiation, and irregular
gland formation can be present. A second, less common pattern is one in which the growth is more solid,
with nests and cords of malignant transitional cells invading a prominent fibrous stroma.
Admixtures of other types of surface epithelial tumors, including serous, endometrioid, and
undifferentiated carcinoma, are common,  but the transitional cell carcinoma pattern must predominate
(i.e., > 50%) for a diagnosis of TCC. The microscopic appearance of extraovarian metastases, if any
are present, may be important in transitional cell carcinoma. In one study, patients whose metastases
had a TCC like pattern had better survival than those whose metastases resembled serous carcinoma. 
Immunohistochemical studies show positive staining of TCC for cytokeratin, epithelial
membrane antigen, and cytokeratin 7.  While TCC somewhat resembles urothelial carcinoma, its
immunophenotype does not suggest urothelial differentiation. It is negative for uroplakin III,
thrombomodulin and cytokeratin 20,
and usually stains for estrogen receptors, WT-1, and
TCC tends to be a high grade carcinoma and the presence of serous carcinoma areas in many
TCC's, the serous appearance of the metastases in some cases, and the immunophenotype with positive
staining for WT-1 suggests that TCC of the ovary is a surface epithelial carcinoma that is closely
related to serous carcinoma.
As noted above, dysgerminoma is ruled out by absence of staining for any of the
dysgerminoma markers. Additional immunostains that we performed indicate that the tumor is an ovarian
carcinoma and help to classify it:
Diffuse strong positive staining for cytokeratin is indicative of a carcinoma. The strong positive
staining for CK7 and WT-1 favors a primary epithelial neoplasm, such as a high grade serous or
transitional cell carcinoma. The histologic pattern of growth suggests that transitional cell carcinoma
is the best diagnosis. Absence of staining for NSE, synaptophysin and chromogranin excludes a large cell
neuroendocrine carcinoma. The negative stain for TTF-1 excludes a metastasis from the lung.
|Stain ||Result Anticipated in TCC ||Result in the Tumor|
|Cytokeratin cocktail ||Positive ||Positive|
|CK7 ||Positive ||Positive|
|WT-1 ||Positive ||Positive|
|CA-125 ||Positive ||Positive|
|Chromogranin ||Negative ||Negative|
|Synaptophysin ||Negative ||Negative|
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