Dysgerminoma vs. Poorly Differentiated Carcinoma Charles Zaloudek, M.D. Department of Pathology, University of California San Francisco, CA

Clinical History 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. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Microscopic Findings 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 Discussion 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. [1, 2] The 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 and OCT4. [3, 4] 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: Stain Result Anticipated in Dysgerminoma Result in the Tumor Cytokeratin cocktail Negative Positive CD117 Positive Negative PLAP Positive Negative OCT-4 Positive Negative 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. Transitional cell carcinoma (TCC) has become a more popular diagnosis in recent years and it now accounts for 5-10% of primary ovarian cancers. [5] Some authors have observed that TCC is more likely to respond to chemotherapy and has better survival than other high grade advanced stage ovarian cancers, [5, 6, 7, 8] 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 ovaries. [7, 9] 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. [6, 7, 10, 11] 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. [9] 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. [9, 12] Admixtures of other types of surface epithelial tumors, including serous, endometrioid, and undifferentiated carcinoma, are common, [7] 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. [7] Immunohistochemical studies show positive staining of TCC for cytokeratin, epithelial membrane antigen, and cytokeratin 7. [13] While TCC somewhat resembles urothelial carcinoma, its immunophenotype does not suggest urothelial differentiation. It is negative for uroplakin III, thrombomodulin and cytokeratin 20, [13, 14] and usually stains for estrogen receptors, WT-1, and CA-125. [15, 16, 17] 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: 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 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. References Asadourian LA,Taylor HB. Dysgerminoma. An analysis of 105 cases. Obstet Gynecol. 1969; 33:370-379. Bjorkholm E, Lundell M, Gyftodimos A, Silfversward C. 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