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A 34-year-old man with a complaint of testicular enlargement was seen by an urologist. An ultrasound revealed a testicular mass. An orchiectomy was performed. The removed testis measured up to 5.5 cm and was partially replaced by a fairly homogenous 5.0 cm tan-pink tumor with a central area of necrosis. The tumor grossly appeared to be confined to the testis.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 16 and is a seminoma.
Criteria for Diagnosis and Comments:
This is a pure seminoma. In its classic form seminoma accounts for almost 50% of testicular germ cell tumors in adults; the remainder are taken up mostly by mixed germ cell tumors with a small percentage of solid embryonal carcinoma, yolk sac tumor, teratoma and choriocarcinoma. Embryonal carcinoma occurs in a pure form in 2-10% of adult germ cell tumors (it is also seen in more than 80% of mixed germ cell tumors). Choriocarcinoma is distinctly rare in its pure form (<1% of adult germ cell tumor) and an uncommon component in mixed germ cell tumors (8%). In order to be certain a particular case is pure seminoma, generous sampling of the tumor is required in order to exclude the presence of other nonseminomatous germ cell components. The average age of a patient with seminoma is 41 years, about ten years older than patients with nonseminomatous germ cell tumors. Other germ cell tumors that are of one histologic type include yolk sac tumor; mostly in children (average age 18 months) and spermatocytic seminoma (average age 54 years).
Seminoma is composed of large cells with abundant clear to lightly eosinophilic granular cytoplasm, well-defined cell borders and central large nuclei. The nuclei are hyperchromatic with irregularly thickened nuclear membranes, granular chromatin and 1-2 prominent nucleoli. The cytoplasm is fairly abundant resulting in almost no nuclear overlapping or crowding. Their cytoplasm is rich in glycogen so they are strongly PAS positive and diastase sensitive. The tumor cells are commonly compartmentalized into small groups or nests by a fibrovascular stroma that is infiltrated by mature lymphocytes. Some of the lymphocytes are admixed with the tumor cells. The lymphocytic infiltrate is characteristic of seminoma varying only in degree from sparse to dense. Many times there are multinucleated giant cells and occasionally well formed granulomas. The adjacent testicular parenchyma commonly shows tubular atrophy. As in most cases of adult testicular germ cell tumors, intratubular germ cell neoplasia of the unclassified type (IGCNU) is found in 63-99%.
Other histologic patterns, not represented in this case, include a tubular, microcystic or cribriform and intertubular growth pattern. These usually do not cause much of a diagnostic problem since they are commonly focal and typically present in conjunction with the more classical pattern. However, on occasion these patterns may dominate the histology of an individual case resulting in the potential for misinterpretation. Therefore, awareness of these histologic variants is important. Usually careful evaluation of multiple sections, will resolve the dilemma. However, immunohistochemistry may be helpful in some case and confirm the initial impression.
The microcystic or cribriform pattern in seminoma is in part created by edema fluid accumulating within the tumor and pushing tumor cells aside forming a pseudoglandular pattern. If this pattern dominates the histology of a particular case the concern for yolk sac tumor may arise; the first hint that this is seminoma may be the recognition of the lymphocytic infiltrate that accompanies almost all seminomas. Additionally, the cystic spaces filled with eosinophilic material are lined by cuboidal epithelial cells (more characteristic of seminoma) rather that flattened lining cells with compressed nuclei (more characteristic of yolk sac tumor). The presence of the cytologic features of seminoma and the lack of the characteristic features of yolk sac tumor also help to differentiate these two lesions. Lastly, immunostains negative for cytokeratin AE1/AE3 and AFP, and positive staining for OCT3/4 can help confirm a diagnosis of seminoma and rule out yolk sac tumor in this setting (see Table 1).
A seminoma with a solid tubular pattern may be confused with a Sertoli cell tumor. The tumor cell nests are elongate resulting in a tubular pattern, sometimes with palisading nuclei at the periphery. A careful search for areas typical of seminoma, a lymphocytic infiltrate or focal areas of IGCNU are all clues to recognizing this tubular pattern as seminoma and not Sertoli cell tumor. More importantly, nuclear features of the cells lining the tubules are characteristic of seminoma. If the lesion is composed of solid tubules and lacks focal areas characteristic of seminoma, immunohistochemical stains for PLAP and OCT3/4 (positive in seminoma and negative in Sertoli cell tumor), and inhibin (negative in seminoma and positive in most Sertoli cell tumors) will be very helpful.
Embryonal carcinoma is also in the differential diagnosis of seminoma since they are commonly found side by side in mixed germ cell tumors. This distinction is critical since the prognosis, therapy and follow-up are different for seminoma and nonseminomatous germ cell tumors. This becomes a challenging problem when trying to identify small scattered foci of embryonal carcinoma within a seminoma. Any areas with definite epithelial differentiation, glands or papilla formation should be considered as a good indication of embryonal carcinoma. If definite epithelial differential is lacking, but there are foci of nuclear pleomorphism, nuclear crowding and irregularity, dense cytoplasm and indistinct cell borders, consideration of embryonal carcinoma is warranted. Immunohistochemistry for CD30 and AE1/AE3 could prove very useful in this setting. The areas considered to be embryonal carcinoma should be strongly positive for CD30 and AE1/AE3 in contrast to non-reactivity in the areas of typical seminoma. Additionally, seminomas may be confused for solid pattern of embryonal carcinoma, especially in poorly fixed tumors, which results in groups of cells with dense eosinophilic cytoplasm and nuclear crowding with nuclear irregularity and loss of distinct cell borders. Good tissue fixation and processing will help avoid some of these problems.
An intertubular infiltrate of seminoma can be seen at the periphery in many cases of seminoma. Usually this does not cause a difficult problem. However, it rarely may not only dominate, but essentially represent the entire lesion. The tumor cells of seminoma can be sparse and overshadowed by interstitial Leydig cells or by the usual concomitant lymphocytic infiltrate. On routine H&E, the lymphocytic infiltrate, the presence of IGCNU and tubular atrophy aid in the recognition of this intertubular pattern as seminoma. Appropriate immunostains can also be used to highlight the tumor cells, i.e. PLAP, CD117(c-kit).
Spermatocytic seminoma can be confused with seminoma, classic type. It has an excellent prognosis, almost never metastasizes and occurs in a distinctly older age group. Spermatocytic seminoma also has a distinctive histology of densely packed polymorphous tumor cells, which are composed of three distinct sizes: small (lymphocyte like), medium (15-20 µm) and large (50-100 µm). In contrast to classic seminoma, it is not associated with IGCNU. Additionally, immunohistochemical stains for PLAP and OCT3/4 are negative in spermatocytic seminoma whereas classic seminoma is positive.
Syncytiotrophoblasts are seen in up to 7% of classic seminomas (25% if utilizing immunostains for hCG). This finding does not affect the overall prognosis. The syncytiotrophoblasts are usually widely dispersed but occasionally form clusters associated with hemorrhage, which may raise the possibility of choriocarcinoma. However, the diagnosis of choriocarcinoma is made only by identifying syncytiotrophoblasts closely associated with cytotrophoblasts. Careful morphologic evaluation is the key.
A dense lymphocytic infiltrate may sometimes obscure the tumor cells of seminoma. In difficult cases, immunostains for PLAP and CD117 will help identify them. Additionally, the dense lymphocytic infiltrate can make one consider the diagnosis of lymphoma, which usually occurs in an older age group (average age 54 years) and are bilateral in 20% as opposed to only 2% of seminomas. Lymphomas have an intertubular growth pattern. The tubules are preserved and IGCNU is not present. Most lymphomas involving the testis are of the B-cell phenotype so immunostains for PLAP, CD117, leucocyte common antigen and CD20 are useful in this differential diagnosis.
The diagnosis of pure seminoma is usually straightforward. The difficulties arise from a number of factors including poor tissue fixation and unusual morphologic patterns that may dominate the tumor histology and make one seriously consider nonseminomatous germ cell tumors. Good tissue fixation/processing and tissue sampling will obviate many of these problems. However, sometimes it may be necessary to confirm the diagnosis of a pure seminoma with positive staining for PLAP and CD117 and negative staining for inhibin, alpha-fetoprotein and CD30.