Testicle

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 27, and is diffuse large B-cell lymphoma, germinal center B-cell type found in the testicle.

The information provided in this case was accurate and correct at the time of publication in 2021.

Any changes in terminology since the time of publication may not be reflected in this case.

Histologic sections demonstrate a diffuse and non-cohesive proliferation of large lymphoid cells with little cytoplasm, enlarged nuclei, and increased mitotic activity. The nuclei show vesicular chromatin and focally prominent nucleoli. Some tumor cell aggregation around blood vessels is seen. Occasional lymphoid cells show multiple nuclei. Background fibrosis can be seen, and rare sections show zonal necrosis. A significant population of smaller lymphoid cells is not identified. The neoplastic cells are post germinal center B cells, positive for CD19, CD20, PAX5, BCL2, BCL6, ​MUM1, ​and negative for CD10. Positive CD10 should raise suspicion of disseminated diffuse large B-cell lymphoma from another location, rather than a PT-LBCL. PT-LBCLs have approximately 50% MUM1 expression. Cyclin D1, SOX11, CD5, CD30, and ALK immunostains are negative. Ki67 index is 80%, and EBV is negative by in-situ hybridization. Flow cytometry shows a monotypic B-cell lymphoproliferative disorder without CD5 or CD10 expression. Fluorescence in situ hybridization (FISH) fails to show MYC or BCL2 gene rearrangements; however, BCL6 is rearranged. These findings are consistent with primary testicular large B-cell lymphoma (PT-LBCL), a de novo lymphoma which is a subtype of primary large B-cell lymphoma of immune-privileged sites ​(IP-LBCL) ​in the WHO 5 edition (Beta on line). The International Consensus Classification (ICC) has classified this as primary diffuse large B-cell lymphoma (DLBCL) of the testis. PT-LBCL characteristically demonstrates mature germinal center (post​-​​germinal center) immunophenotype, as seen in this case.

As with many lymphoid neoplasms, morphologic assessment should be coupled with flow cytometry, cytogenetic analysis, targeted FISH studies, and sometimes next-generation sequencing (NGS). B symptoms are rare in PT-LBCL. PT-LBCL​s​ comprise fewer than 2% of all NHL but are the most common testicular malignancy in men older than 60 years. They represent 5% of all testicular malignancies, and present most often as a unilateral testicular mass, however 6% to 10% are bilateral at diagnosis. PT-LBCL is a de novo lymphoma of an “immune-privileged” site not normally subject to autoimmune surveillance. Macroscopically, ​it​​ involves testicular parenchyma and adjacent structures. Histologically, the neoplastic infiltrates can show geographic necrosis and prominent single cell apoptosis. PT-LBCL is similar to other DLBCL as described above. High proliferation rates are usual. Rarely a starry-sky pattern may be present. Bone marrow involvement is rare in PT-LBCL.

Prognosis of PT-LBCL is similar to systemic nodal DLBCL. Common molecular finding​s​ in PT-LBCL include ​concordant ​MYD88 ​(p.L265P) ​and CD79b mutations. FISH often shows translocations of IG or BCL6. PT-LBCL often relapse in the central nervous system (CNS) or contralateral testis.

Diffuse large B-cell lymphoma/High-grade B-cell lymphoma (HGBCL) with MYC and BCL2 rearrangements, along with high-grade B-cell lymphoma, not otherwise specified; represent the two main types of high-grade B-cell lymphomas. HGBCL is more aggressive than DLBCL and does not respond as well to treatment with chemotherapy. HGBCL is also known as “double hit” lymphomas for their specific number of gene rearrangements, high-grade B-cell lymphoma with MYC and BCL2 rearrangements represent 1% - 2% of all NHL. An additional BCL6 rearrangement may be present (“triple hit”) but “high-grade lymphoma with MYC and BCL6 rearrangements” is no longer recognized in the WHO 5e. DLBCL and this entity share similar histologic features, but the diagnosis rests solely on the demonstration of these specific gene rearrangements; thus MYC and BCL2 FISH gene rearrangement tests should be performed on all large B-cell lymphomas.

Embryonal carcinoma presents in the 3rd or 4th decades as a unilateral testicular mass, most often as a component of a mixed-germ cell tumor. Embryonal carcinoma shows multiple histologic patterns, including solid, pseudoglandular, alveolar, or tubular. Some variants show more cellular discohesion mimicking other undifferentiated malignancies. Immunostains easily separate embryonal carcinoma from lymphomas, as cytokeratins will be positive, along with SALL4, OCT3/4, and CD30. It should be noted that some lymphomas may also be OCT4 and CD30 positive.

Embryonal rhabdomyosarcoma is a rare tumor of children and young adults. It is the most common childhood malignant tumor of the spermatic cord and presents with a rapidly growing painless mass. Histologically, embryonal rhabdomyosarcoma shows undifferentiated primitive malignant cells with little cytoplasm in a myxoid or fibrous background. Usually, some cells with skeletal muscle differentiation can be seen, which is a helpful clue to the diagnosis. Cases without definitive skeletal muscle differentiation can mimic lymphoma, but would be positive for desmin, myogenin, and myo-D1, and negative for CD45.

Seminoma, the most common type of germ cell tumor, usually presents in the 4th and 5th decades. Seminomas are composed of sheets and lobules of large polygonal tumor cells, often with one or more prominent nucleoli. Cytoplasmic clearing and edema may be present, giving the impression of discohesive cells. A brisk lymphocytic infiltrate can be present. SALL4, OCT 3/4, CD117, D2-40, and PLAP are positive in seminoma. Elevated serum LDH, hCG, and PLAP levels can also be helpful clues to the diagnosis.

1. Which of the following is true regarding primary testicular large B-cell lymphomas (PT-LBCL)?
   1. PT-LBCL of the testes commonly involves the bone marrow.
   2. PT-LBCL commonly recurs in the central nervous system.
   3. PT-LBCL arises as a transformation of a low-grade lymphoma.
   4. PT-LBCL is a common type of non-Hodgkin lymphoma (NHL).
   5. PT-LBCL is commonly positive for CD30.
2. The following stains including desmin, myogenin, and myo-D1 are positive in the following lesion:
   
   
   1. Seminoma
   2. Embryonal carcinoma
   3. Primary testicular large cell lymphoma
   4. Embryonal rhabdomyosarcoma
   5. High-grade B-cell lymphoma with MYC and BCL2 rearrangements
3. Diffuse large B-cell lymphoma/High-grade B-cell lymphoma with MYC and BCL2 gene rearrangements:
   
   
   1. Has an overall prognosis and survival rate comparable to usual DLBCL
   2. Is a morphologic subtype of DLBCL in the 2022 World Health Organization 5th edition lymphoma classification system
   3. Is diagnosed by demonstrating “double hit” gene rearrangements
   4. Must have BCL6 rearrangements for diagnosis
   5. Responds well to R-CHOP chemotherapy regimens

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5. Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classifications of Tumours of Hematopoietic and Lymphoid Tissues. Revised 4th Ed. IARC Press; 2017:291-298, 335-338.
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7. 5th edition WHO hematopoietic neoplasms [online publication beta version].

1. PT-LBCL commonly recurs in the central nervous system (b)
2. Embryonal rhabdomyosarcoma​​ (​d​​)
3. Is diagnosed by demonstrating “double hit” gene rearrangements (c)