Final Diagnosis: Germ Cell Tumor with Spermatocytic Differentiation
In the current case, the differential diagnosis includes both a spermatocytic tumor and seminoma.
The findings which favor a spermatocytic tumor include a tripartite cytology/morphology, absence of germ cell neoplasia in situ (GCNIS), and absence of significant lymphocytic infiltrates. Supporting immunophenotypes include SALL4+, c-kit+, PLAP-, OCT 3/4-; however, the tumor cells are negative for NUT (not shown) and OCT2. The over-representation of 12p via FISH is not typical of spermatocytic tumor and is associated with post-pubertal malignant germ cell tumors with associated intratubular germ cell neoplasia (e.g. classical seminoma and malignant non-seminomatous germ cell tumors). Absence of PLAP (not shown) and OCT 3/4 expression are uncharacteristic for classical seminoma.
Discussion
Clinical Presentation and Significance
Spermatocytic tumors are an uncommon, germ cell-derived tumor, which represent less than 1% of germ cell tumors (Ghazarian, et al). These tumors are unrelated to GCNIS. Spermatocytic tumors typically present as an incidental finding of a testicular mass. Similarly to the current case, it is expected that the serum markers are within normal limits. Also similar to the current case, patients often present in their sixth or seventh decade of life (Ghazarian, et al).
The correct identification of a spermatocytic tumor from GCNIS-associated tumors is important, as it has significant clinical implications, including increased frequency of bilateral tumors being present (Hu, et al), as well as only rare metastasis, with the exception of when high-grade sarcomatous components are present within the spermatocytic tumor (Grogg, et al).
Histopathologic Findings
The most distinguishing morphologic feature is the presence of three distinct tumor cell sizes and chromatin patterns, i.e., a tripartite morphology. The small cells often show round, basophilic nuclei, and with small amounts of cytoplasm. Cell of intermediate size classically have nuclei with more granular cytoplasm and the presence of nucleoli (ranging from inconspicuous to conspicuous). Finally, the large or ‘giant’ cells may present with similar nuclear features as the intermediate-sized cells, but can additionally have multinucleate cells, as well increased amounts of cytoplasm, from which they derive their overall size. Other common histologic features which can be appreciated include frequent mitotic figures and/or associated apoptosis. Spermatocytic tumors can have several architectural patterns, including multinodular, pseudoglandular, cystic, trabecular, nested, or seen as single cells. The tumor is often associated with stromal edema.
Also similar to the current case, spermatocytic tumors are not associated with GCNIS; however, intratubular components of spermatocytic tumors can be present. In contract to seminoma, spermatocytic tumors lack any prominent lymphocytic infiltrates. While beyond the current discussion, it is also important to rule out the presence of any sarcomatous components within a spermatocytic tumor, as these tumors are higher-grade and demonstrate a more aggressive phenotype with higher likelihood of metastasis (WHO).
Immunohistochemistry and Ancillary Studies
As is discussed in the differential above, spermatocytic tumors are typically immunoreactive to SALL4, and OCT2, but are not immunoreactive to many common markers of germ cell tumors, including AFP, beta-HCG, CD30, PLAP, and OCT3/4. Some keratins may be expressed, notably CAM5.2 (Cummings, et al).
Cytogenetic and Molecular Ancillary Studies
Cytogenetic findings can help differentiate between seminomas and spermatocytic tumors. Spermatocytic tumors are associated with over-representation of chromosome 9p (including the DMRT1 gene). In contrast, seminoma germ cell tumors are associated with chromosome 12p over-representation. Similar findings can be seen in molecular studies, with spermatocytic tumors demonstrating gains of chromosome 9 (e.g., amplification of DMRT1).
Given the overall morphologic, immunohistochemical and cytogenetic findings, the differential diagnosis for this malignant germ cell tumor with spermatocytic differentiation include both a spermatocytic tumor and seminoma. Additional cytogenetic studies assessing the presence of chromosome 9p could also be informative in the current case.
References
- Ghazarian AA, Rusner C, Trabert B, Braunlin M, McGlynn KA, Stang A. Testicular cancer among US men aged 50 years and older. Cancer Epidemiol. 2018 Aug;55:68-72. doi: 10.1016/j.canep.2018.05.007. PMID: 29807233; PMCID: PMC6668029.
- Hu R, Ulbright TM, Young RH. Spermatocytic Seminoma: A Report of 85 Cases Emphasizing Its Morphologic Spectrum Including Some Aspects Not Widely Known. Am J Surg Pathol. 2019 Jan;43(1):1-11. doi: 10.1097/PAS.0000000000001001. PMID: 29280854.
- Grogg JB, Schneider K, Bode PK, Wettstein MS, Kranzbühler B, Eberli D, Sulser T, Beyer J, Hermanns T, Fankhauser CD. A systematic review of treatment outcomes in localised and metastatic spermatocytic tumors of the testis. J Cancer Res Clin Oncol. 2019 Dec;145(12):3037-3045. doi: 10.1007/s00432-019-03056-1. Epub 2019 Oct 23. PMID: 31646373.
- WHO Classification of Tumours Editorial Board. Urinary and male genital tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022 [cited 2025 Feb 02]. (WHO classification of tumours series, 5th ed.; vol. 8). Available from: https://tumourclassification.iarc.who.int/chapters/36.
- Cummings OW, Ulbright TM, Eble JN, Roth LM. Spermatocytic seminoma: an immunohistochemical study. Hum Pathol. 1994 Jan;25(1):54-9. doi: 10.1016/0046-8177(94)90171-6. PMID: 7508884.