Cytopathology Case 02

The modified Wright-Giemsa smears consist of large groups of cells in a background of hemorrhage and necrosis. (fig. 1) The groups are loosely cohesive and are composed of a two cell population. (fig. 2) The cells located centrally are moderate in size, round to polygonal in shape. Cell borders are somewhat distinct. Nuclei of these cells are single and bland with mild pleomorphism. The nuclei are centrally located in a pale to clear cytoplasm. (fig. 3) Nucleoli are indistinct in air dried smears. The second population of cell is peripherally located. These are giant cells that are multinucleated with nuclei that are large and atypical. (fig. 4) The cytoplasm is abundant and eosinophilic, vacuolations are occasionally present. The chromatin is smudged but prominent nucleoli can be seen. (fig. 5) The cell block highlights the multinucleated giant cells with eosinophilic cytoplasm. (fig. 6) Immunohistochemical stain is shown. (fig. 7)

DISCUSSION
Germ cell tumors of the testes are diagnosed at a rate of 8,000 cases annually in the United States. This reflects a worldwide increase in incidence for unexplained reasons. They affect whites more often than blacks (5:1) in the age range of 15-34 years, causing 10% of the cancer deaths in this age group. Pure forms occur in 40% of cases, with a pure choriocarcinoma accounting for less than 1% of all germ cell tumors. Choriocarcinomas are highly aggressive yet often form small lesions in the testes, causing no enlargement. The testicular tumor may also regress (although rarely completely) leaving behind only a small fibrous scar, making detection a challenge. These features account for the late stage of disease at the time of diagnosis. A primary choriocarcinoma of the lung would be very rare as extragonadal germ cell tumors occur at a small percentage with most occuring in the mediastinum (50-70%). A metastasis would always be more likely than a primary lesion, when found outside the testes, making it necessary to rule out a testicular primary in any male.

The morphology of choriocarcinoma is characterized by its biphasic architecture. Centrally located cytotrophoblasts form loose masses of somewhat uniform mononucleated round to polygonal cells with distinct cell borders. These groups are surrounded by large, pleomorphic, multinucleated giant cells with vacuolated, eosinophilic cytoplasm. These are syncytiotrophoblasts. This pattern mimics the structure of chorionic villi. Hemorrhage and necrosis are also common. Syncytiotrophoblasts may be scarce or difficult to identify. The large, pleomorphic, multinucleated giant cells need to be differentiated from similar cells found in giant cell/pleomorphic carcinoma of the lung, melanoma, anaplastic lymphoma, and other giant cell carcinomas. Some helpful clues may come from history, different or lack of architectural features, presence of additional cells, background substances, or finally immunohistochemical stains. Smears of giant cell carcinoma of the lung tend to contain single cells and may include spindle cells. Cells are keratin and epithelial membrane antigen (EMA) positive.

Melanoma may or may not have pigment associated and are more discohesive. A predominance of plasmacytoid cells with prominent nucleoli may help in this diagnosis as well as staining for S100, HMB45, or melanA. The cells of anaplastic lymphoma are also discohesive but may contain floret cells. The nuclear contours are irregular and cytoplasm is variable to clear. Lymphoglandular bodies in the background may be helpful. In these cases, positive immunohistochemical stains include CD30 and alkaline phosphatase (ALK). Syncytiotrophoblast can be present in both choriocarcinoma and seminoma. However, in addition to the absence of cytotrophoblasts, seminomas are known for their characteristic tigeroid background on modified Wright-Giemsa smears. Seminomas will tend to stain positively for CD117.

Immunocytochemical staining will strongly highlight hCG in the cytoplasm of syncytiotrophoblasts, and focally in cytotophoblastic cells. Cytokeratins are positive in all nonseminomatous germ cell tumors, however CK7 is more selective for choriocarcinoma. Epithelial membrane antigen (EMA) selectively stains syncytiotrophoblast rather than cytotrophoblasts. Choriocarcinoma also stains positively for human placental lactogen (HPL) and epidermal growth factor receptor. Inhibin is positive in 95%, placental alkaline phosphatase (PLAP) 50%, and carcinoembryonic antigen (CEA) in 20% of cases. Serum beta-HCG levels, which are can be detected in germ cell tumors, are especially elevated (>500 IU) in choriocarcinomas. Isochromosome, i(12p), is characteristic of all germ cell tumors, and can be performed on fresh tissue.

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