College of American Pathologists

2013 — January Case of the Month

Posted January 28, 2013


CAP Foundation Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 45-year-old man noticed enlargement of his right testicle; a subsequent ultrasound confirmed the presence of a testicular mass. He had no other symptoms. A right radical orchiectomy was performed. Preoperative blood tests for human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) were normal.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2010, case 2, and is a seminoma.

Criteria for Diagnosis and Comments:
This is a seminoma. In its classic form seminoma accounts for almost 50% of testicular germ cell tumors in adults; the remainder is 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 and an uncommon component in mixed germ cell tumors. 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 nonseminomatous germ cell components. The average age of patients with seminoma is 41 years, about 10 years older than patients with non-seminomatous 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 cytoplasm is fairly abundant resulting in almost no nuclear overlap or crowding. The cytoplasm is rich in glycogen and therefore strongly PAS positive and diastase sensitive. The nuclei are hyperchromatic with irregularly thickened nuclear membranes, granular chromatin and 1-2 prominent nucleoli. The tumor cells are characteristically compartmentalized into small groups by a delicate fibrovascular stroma that is infiltrated by mature lymphocytes. The lymphocytic infiltrate is characteristic of seminoma varying only in degree from sparse to dense. Other tumors that imitate seminoma lack this characteristic stroma and lymphocytic infiltrate making it an important differential diagnostic feature. Multinucleated giant cells and occasionally well formed granulomas are not uncommon. The adjacent testicular parenchyma commonly shows tubular atrophy and as in most cases of adult testicular germ cell tumors, intratubular germ cell neoplasia of the unclassified type (IGCNU) is frequently found.

Other histologic patterns include a tubular, microcystic or cribriform and intertubular growth patterns. These usually do not cause diagnostic problems since they are commonly focal and present in conjunction with the more classical pattern. However, these patterns may dominate the histology on occasion resulting in the potential for misinterpretation. Careful evaluation of multiple sections will usually resolve this dilemma. Immunohistochemistry may be helpful in some cases.

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. This pattern may cause concern for yolk sac tumor. The first hint that it is seminoma may be the recognition of the lymphocytic infiltrate that accompanies almost all seminomas. Additionally, the cystic spaces are lined by cuboidal epithelial cells (more characteristic of seminoma) rather than flattened lining cells with compressed nuclei (more characteristic of yolk sac tumor). Lastly, immunostains negative for cytokeratin AE1/AE3 and AFP, and positive staining for OCT3/4 (POU5F1) and/or podoplanin (D2-40) 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. Areas typical of seminoma, a lymphocytic infiltrate or IGCNU are clues to recognizing this tubular pattern as seminoma and not Sertoli cell tumor. Additionally, the nuclear features of the cells lining the tubules are 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 a 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 may be particularly challenging when trying to identify small scattered foci of embryonal carcinoma within a seminoma. Any areas of definite epithelial differentiation, glands or papilla formation should be considered a good indication of embryonal carcinoma. If epithelial differentiation 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 of embryonal carcinoma should be strongly positive for CD30 and AE1/AE3, while negative in the areas of typical seminoma. Lastly, seminomas may be confused for a solid pattern of embryonal carcinoma especially in poorly fixed tissue. Good tissue fixation and processing will help avoid some of these problems.

An intertubular pattern of seminoma can be seen at the periphery of most cases of seminoma. Rarely, it may not only dominate, but essentially represent the entire lesion. The tumor cells may 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 help us in the recognition of this intertubular pattern as seminoma. Immunostains can also be used to highlight the tumor cells, i. e. PLAP and CD117.

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 cells which are composed of three distinct types: small (lymphocyte like), medium (15 - 20 µm) and large (number 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 5% of classic seminoma (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 may make one consider the possibility of lymphoma, which usually occurs in an older age group(average age 54 years) and are bilateral in 20% as opposed only 2% of seminoma. Lymphomas have an intertubular growth pattern. Tubules are preserved and IGCNU is not present. Most lymphomas involving the testis are of the B cell phenotype; therefore, immunostains for PLAP, podoplanin, CD117, leukocyte common antigen and CD20 are useful in this differential diagnosis.

The diagnosis of classic seminoma is usually straightforward. The difficulties arise from a number of factors including poor tissue fixation and unusual morphologic features which may dominate the tumor histology. Good tissue fixation and sampling will avert many of these problems. However, sometimes it may be necessary to confirm the diagnosis of classic seminoma with immunohistochemistry.

Supplementary Questions: For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. An important morphologic feature differentiating classic seminoma from spermatocytic seminoma or Sertoli cell tumor is that classic seminoma is associated with intratubular germ cell neoplasia of the unclassified type (IGCNU). A. True
B. False
2. The delicate fibrovascular stroma with lymphocytic infiltrate as seen in classic seminoma is not seen in other testicular germ cell tumors or Sertoli cell tumor. A. True
B. False
3. An important difference between classic seminoma, yolk sac tumor and embryonal carcinoma is that seminoma is negative for PLAP, podoplanin and CD117, but positive for AE1/AE3 and CAM5.2. A. True
B. False


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  2. Emerson RE and Ulbright TM. The use of immunohistochemistry in the differential diagnosis of tumors of the testis and paratestis. Semin Diagn Pathol. 2005;22;33-50.
  3. Ulbright TM, Amin MB, Young RH. Tumors of the Testis, Adnexa, Spermatic Cord and Scrotum. Atlas of Tumor Pathology. 3rd Series, Fascicle 25. Washington DC: Armed Forces Institute of Pathology; 1999:59-85.
  4. Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005:S61-S79.
  5. Young RH. Testicular Tumors –Some New and a Few Perennial Problems. Arch Pathol Lab Med. 2008;132:548-564.

Robert H. Knapp, MD
Surgical Pathology Committee
Pathology Laboratory, PC
Grandville, MI