Diagnosis and Discussion - Case 1118

Final Diagnosis

Mixed malignant germ cell tumor consisting of yolk sac tumor, postpubertal-type (85%); embryonal carcinoma (10%); choriocarcinoma (<5%); and teratoma, postpubertal-type (<5%), with prominent hemorrhage and necrosis.

Discussion

Testicular tumors are a complex and diverse group of tumors that exhibit a wide range of histologic features. Among these tumors, more than 90% are of germ cell origin, which can be either highly aggressive or benign, ultimately depending on classification1.

The overall incidence of testicular germ cell tumors (TGCTs) is relatively low, and they predominantly affect young men between the ages of 15 and 45. The incidence rates vary geographically, with the highest rates observed in Western Europe, Northern Europe, and Australia/New Zealand2. TGCTs have shown a progressive increase in incidence during the 20th century, although some recent evidence suggests stabilization3. Higher socioeconomic groups4 and individuals with certain syndromes, such as Marfan syndrome5 and Down syndrome6, are also more prone to developing TGCTs.

Seminomas account for approximately 50% of germ cell tumors7. The majority of the remaining tumors are either pure forms of other subtypes or mixed germ cell tumors referred to as "non-seminomatous germ cell tumors" (NSGCTs), which includes subtypes such as yolk sac tumor; embryonal carcinoma; trophoblastic tumors, including choriocarcinoma; and teratoma, postpubertal-type8. Approximately 90% of TGCTs are associated with germ cell neoplasia in situ (GCNIS), considered to be embryonic germ cells arrested at the gonocyte stage9. The genetic alterations in TCGTs are complex and many are variable, however, gains or rearrangements of chromosome 12p, including 12p overrepresentation and isochromosome 12p, are present in almost all GCNIS-related TCGTs. As such, fluorescence in situ hybridization (FISH) detection of chromosome 12p alterations can be used to confirm germ cell origin10. Non-GCNIS-related TGCTs make up the remaining 10% and include subtypes such as teratoma, prepubertal-type; yolk sac tumor, prepubertal-type; and spermatocytic tumor1. The etiology of these tumors is comparatively poorly understood.

Given that the clinical behavior of germ cell tumors is highly dependent on their classification, so too is their clinical management. NSGCTs are more aggressive than seminomas, and mixed germ cell tumors that contain a seminomatous component are classified and clinically considered as NSGCTs. In addition to histologic classification, clinical stage and post-orchiectomy serum biomarker levels, including serum lactate dehydrogenase (LDH), β-human chorionic gonadotropin (β-hCG), and alpha-fetoprotein (AFP), are important for management decisions11,12. Clinical staging is currently based on the eighth edition of the AJCC cancer staging manual, with non-metastatic tumors representing stage I, tumors with metastasis to nearby lymph nodes representing stage II, and tumors with systemic metastasis or metastasis above the diaphragm regarded as stage III. At the time of diagnosis, approximately 80% of seminoma patients and 60% of NSGCTs patients are clinical stage I. For stage I seminomas, the need for adjuvant chemotherapy or radiation is still a controversial topic. Chemotherapy has been shown to reduce the risk of relapse; however, the prognosis of stage I seminoma patients with no risk factors is excellent without chemotherapy and the possibility of chemotherapy-related side effects has led to debate about treating these patients13. Chemotherapy is the standard treatment for seminomas of clinical stage II or III1. In NSGCTs, surveillance after orchiectomy is a possibility for stage I disease if additional risk factors for metastasis are not present. In the setting of stage I disease with risk factors or low stage II disease, retroperitoneal lymph node dissection (RPLND) or one cycle of platinum-based chemotherapy may be utilized1. For high stage II disease and stage III disease, multiple cycles of chemotherapy is standard 14.    

Seminomas usually present as a self-identified mass and may show elevations in serum LDH and β-hCG. Elevations in LDH are present in approximately 80% of advanced-stage seminomas15, while β-hCG is elevated in approximately 10-20% of cases, although not usually above 1000 IU/L16. Grossly, seminomas are usually solid to partially cystic tumors with a greyish white to tan cut surface. They may have a myxoid appearance and can exhibit hemorrhage and necrosis17. Histologically the cells are usually large and polygonal with clear to eosinophilic cytoplasm, distinct cell membranes, vesicular chromatin, and prominent nucleoli. The most common growth pattern is a diffuse sheet-like pattern with interspersed fibrous septa, almost always associated with a prominent lymphocytic infiltrate. Approximately 10-20% of seminomas, particularly pure seminomas, also contain syncytiotrophoblasts 18. In 85-90% of cases, GCNIS is present in adjacent seminiferous tubules19. Immunohistochemically, seminomas express OCT3/4, SALL4, PLAP, c-KIT, SOX17, and D2-40. They are typically negative for cytokeratin AE1/AE3, CD30, AFP, and EMA12.

Embryonal carcinoma is the second most common TCGT20 and the most frequent component of mixed germ cell tumors21. Similar to seminoma, syncytiotrophoblasts are not infrequently seen in embryonal carcinoma, which can lead to elevated β-hCG levels. Serum LDH levels may also be elevated22.  Grossly, embryonal carcinoma is typically a solid lesion with poorly defined borders and a soft, fleshy consistency. The tumor may exhibit areas of hemorrhage and necrosis22. Histologically, the cells are large, pleomorphic, and crowded with vesicular nuclei, prominent nucleoli, frequent mitotic figures, and amphophilic cytoplasm. Growth patterns are often mixed and common patterns include solid, glandular, and papillary21. Immunohistochemically, embryonal carcinoma expresses CD30, OCT3/4, SALL4, and AE1/AE3. PLAP, D2-40, and c-KIT are typically negative or weak and patchy22.

Yolk sac tumor, postpubertal-type is rare in pure form23, but is a common component of mixed germ cell tumor24. Serum AFP is frequently elevated in yolk sac tumor25. Histologically, yolk sac tumor demonstrates numerous possible growth patterns, often combined within the same tumor. The most common growth pattern is the microcystic/reticular pattern, which consists of the heavily vacuolated tumor cells forming a honeycomb-like meshwork. The endodermal sinus/perivascular pattern is considered a hallmark of yolk-sac tumor and consists of fibrovascular cores with peripheral mantles of cuboidal tumor cells and surrounded by a cystic space, termed Schiller Duval bodies26. However, this distinctive pattern is only present in approximately 25% of cases27. Independent of growth pattern yolk sac tumors often demonstrate the presence of intracytoplasmic and/or extracellular hyaline globules and irregular, intercellular basement membrane deposits26. Immunohistochemically, Glypican-3, AFP, SALL4, AE1/AE3, CDX2, and GATA3 are frequently expressed, while CK7, EMA, and OCT3/4 are often negative or only focally positive26.

Choriocarcinoma is an uncommon component of mixed germ cell tumors and is exceedingly rare in pure form (approximately 0.6% of TGCTs)28. Patients commonly present with distant metastases, frequently to the liver, lungs, and/or brain29. Serum β-hCG levels are often markedly elevated (>50,000 IU/L), above the more mild elevations sometimes seen in seminoma and embryonal carcinoma28. The primary choriocarcinoma is often small, with many patients with established metastatic disease only showing a small area of scar in the testis30. When grossly present, the cut surface is nodular, commonly with cystic degeneration, extensive necrosis and hemorrhage, and a peripheral rim of solid grey-to-tan tumor. Histologically, choriocarcinoma is composed of malignant mononuclear trophoblasts (the intermediate trophoblasts and cytotrophoblasts) and multinucleated syncytiotrophoblasts. Background necrosis and hemorrhage is often extensive. Immunohistochemically, the syncytiotrophoblasts express β-hCG, hPL, inhibin, GATA3, and glypican-3. The cytotrophoblasts typically express SALL4, p63, GATA3, and GDF331.

Teratoma, postpubertal-type are composed of tissue arising from one or more germ layers, i.e. the endoderm, mesoderm, or ectoderm. An incredible amount of heterogeneity can be seen in these tumors, ranging the spectrum from mature, well-differentiated tissue to immature, embryonic-type tissue32. Postpubertal teratomas are a relatively common component of mixed germ cell tumors33, but are somewhat rare in their pure forms, accounting for only 3-7% of TGCTs32. Serum tumor markers may be elevated, particularly AFP32. Given the wide range of tissue types that can be present, the gross appearance of postpubertal teratomas is very heterogenous. Most tumors have both solid and cystic components, and mature cartilage or bone may be identified 32. Histologically, virtually any tissue type can be seen, although multiple cysts lined by glandular or squamous epithelium are common. Immature neuroectodermal structures are also frequently identified. Syncytiotrophoblasts may also be present32. Immunohistochemically, differentiated tissue within the teratoma expresses the immunohistochemical profile of the given tissue type.

As in this case, any of the described germ cell tumor components that are derived from GCNIS can occur together, resulting in a mixed germ cell tumor. The histologic and immunohistochemical features of the different components are identical to those seen in the pure forms. Two forms of mixed germ cell tumor have a distinct categorization and nomenclature:  polyembryoma and diffuse embryoma. Both are composed of yolk sac tumor and embryonal carcinoma, with polyembryoma resembling an embryo prior to day 18 of development and diffuse embryoma composed of generally equal proportions of yolk sac tumor and embryonal carcinoma in parallel flat layers34.

References

  1. World Health Organization. Tumours of the testis: Introduction. WHO Classification of Tumours online. Accessed March 30, 2023. https://tumourclassification.iarc.who.int/chapters/63
  2. Globocan 2020. Testis. Accessed October 14, 2023. https://gco.iarc.fr/today/data/factsheets/cancers/28-Testis-fact-sheet.pdf
  3. Znaor A, Skakkebaek NE, Rajpert-De Meyts E, et al. Testicular cancer incidence predictions in Europe 2010-2035: A rising burden despite population ageing. Int J Cancer. 2020;147(3):820-828. doi:10.1002/ijc.32810
  4. McDowall ME, Balarajan R. Testicular cancer mortality in England and Wales 1971-80: variations by occupation. J Epidemiol Community Health. 1986;40(1):26-29. doi:10.1136/jech.40.1.26
  5. Dexeus FH, Logothetis CJ, Chong C, Sella A, Ogden S. Genetic abnormalities in men with germ cell tumors. J Urol. 1988;140(1):80-84. doi:10.1016/s0022-5347(17)41492-3
  6. Braun DL, Green MD, Rausen AR, et al. Down’s syndrome and testicular cancer: a possible association. Am J Pediatr Hematol Oncol. 1985;7(2):208-211.
  7. Mortensen MS, Lauritsen J, Gundgaard MG, et al. A nationwide cohort study of stage I seminoma patients followed on a surveillance program. Eur Urol. 2014;66(6):1172-1178. doi:10.1016/j.eururo.2014.07.001
  8. Daugaard G, Gundgaard MG, Mortensen MS, et al. Surveillance for stage I nonseminoma testicular cancer: outcomes and long-term follow-up in a population-based cohort. J Clin Oncol. 2014;32(34):3817-3823. doi:10.1200/JCO.2013.53.5831
  9. Hanna NH, Einhorn LH. Testicular cancer--discoveries and updates. N Engl J Med. 2014;371(21):2005-2016. doi:10.1056/NEJMra1407550
  10. Cheng L, Davidson DD, Montironi R, et al. Fluorescence in situ hybridization (FISH) detection of chromosomal 12p anomalies in testicular germ cell tumors. Methods Mol Biol. 2021;2195:49-63. doi:10.1007/978-1-0716-0860-9_4
  11. Lempiäinen A, Stenman U-H, Blomqvist C, Hotakainen K. Free beta-subunit of human chorionic gonadotropin in serum is a diagnostically sensitive marker of seminomatous testicular cancer. Clin Chem. 2008;54(11):1840-1843. doi:10.1373/clinchem.2008.108548
  12. Milose JC, Filson CP, Weizer AZ, Hafez KS, Montgomery JS. Role of biochemical markers in testicular cancer: diagnosis, staging, and surveillance. Open Access J Urol. 2011;4:1-8. doi:10.2147/OAJU.S15063
  13. Honecker F, Aparicio J, Berney D, et al. ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up. Ann Oncol. 2018;29(8):1658-1686. doi:10.1093/annonc/mdy217
  14. Bagrodia A, Pierorazio P, Singla N, Albers P. The Complex and Nuanced Care for Early-stage Testicular Cancer: Lessons from the European Association of Urology and American Urological Association Testis Cancer Guidelines. Eur Urol. 2020;77(2):139-141. doi:10.1016/j.eururo.2019.10.003
  15. Fosså A, Fosså SD. Serum lactate dehydrogenase and human choriogonadotrophin in seminoma. Br J Urol. 1989;63(4):408-415. doi:10.1111/j.1464-410x.1989.tb05228.x
  16. Ro JY, Dexeus FH, el-Naggar A, Ayala AG. Testicular germ cell tumors. Clinically relevant pathologic findings. Pathol Annu. 1991;26 Pt 2:59-87.
  17. World Health Organization. Seminoma. WHO Classification of Tumours online. Accessed October 13, 2023. https://tumourclassification.iarc.who.int/chaptercontent/36/119
  18. Mostofi FK, Sesterhenn IA. Pathology of germ cell tumors of testes. Prog Clin Biol Res. 1985;203:1-34.
  19. Coffin CM, Ewing S, Dehner LP. Frequency of intratubular germ cell neoplasia with invasive testicular germ cell tumors. Histologic and immunocytochemical features. Arch Pathol Lab Med. 1985;109(6):555-559.
  20. Lobo J, Costa AL, Vilela-Salgueiro B, et al. Testicular germ cell tumors: revisiting a series in light of the new WHO classification and AJCC staging systems, focusing on challenges for pathologists. Hum Pathol. 2018;82:113-124. doi:10.1016/j.humpath.2018.07.016
  21. Kao C-S, Ulbright TM, Young RH, Idrees MT. Testicular embryonal carcinoma: a morphologic study of 180 cases highlighting unusual and unemphasized aspects. Am J Surg Pathol. 2014;38(5):689-697. doi:10.1097/PAS.0000000000000171
  22. World Health Organization. Embryonal carcinoma . WHO Classification of Tumours online. Accessed October 14, 2023. https://tumourclassification.iarc.who.int/chaptercontent/36/121
  23. Krag Jacobsen G, Barlebo H, Olsen J, et al. Testicular germ cell tumours in Denmark 1976-1980. Pathology of 1058 consecutive cases. Acta Radiol Oncol. 1984;23(4):239-247. doi:10.3109/02841868409136019
  24. Talerman A. Endodermal sinus (yolk sac) tumor elements in testicular germ-cell tumors in adults: comparison of prospective and retrospective studies. Cancer. 1980;46(5):1213-1217. doi:10.1002/1097-0142(19800901)46:5<1213::aid-cncr2820460522>3.0.co;2-z
  25. Talerman A, Haije WG, Baggerman L. Serum alphafetoprotein (AFP) in patients with germ cell tumors of the gonads and extragonadal sites: correlation between endodermal sinus (yolk sac) tumor and raised serum AFP. Cancer. 1980;46(2):380-385. doi:10.1002/1097-0142(19800715)46:2<380::aid-cncr2820460228>3.0.co;2-u
  26. World Health Organization. Yolk sac tumour, postpubertal-type. WHO Classification of Tumours online. Accessed October 14, 2023. https://tumourclassification.iarc.who.int/chaptercontent/36/122
  27. Jacobsen GK. Histogenetic considerations concerning germ cell tumours. Morphological and immunohistochemical comparative investigation of the human embryo and testicular germ cell tumours. Virchows Arch A Pathol Anat Histopathol. 1986;408(5):509-525. doi:10.1007/BF00705305
  28. Alvarado-Cabrero I, Hernández-Toriz N, Paner GP. Clinicopathologic analysis of choriocarcinoma as a pure or predominant component of germ cell tumor of the testis. Am J Surg Pathol. 2014;38(1):111-118. doi:10.1097/PAS.0b013e3182a2926e
  29. Shabani S, Pritchard N, Padhya TA, Mifsud M. Head and neck cutaneous metastasis of testicular choriocarcinoma. BMJ Case Rep. 2020;13(2). doi:10.1136/bcr-2019-233337
  30. El-Sharkawy MS, Al-Jibali AS. Burned-out metastatic testicular tumor: Choriocarcinoma. Int J Health Sci (Qassim). 2017;11(2):81-82.
  31. World Health Organization. Choriocarcinoma. WHO Classification of Tumours online. Accessed October 14, 2023. https://tumourclassification.iarc.who.int/chaptercontent/36/124
  32. World Health Organization. Teratoma, postpubertal-type. WHO Classification of Tumours online. Accessed October 14, 2023. https://tumourclassification.iarc.who.int/chaptercontent/36/316
  33. von Hochstetter AR, Hedinger CE. The differential diagnosis of testicular germ cell tumors in theory and practice. A critical analysis of two major systems of classifiction and review of 389 cases. Virchows Arch A Pathol Anat Histol. 1982;396(3):247-277. doi:10.1007/BF00431386
  34. World Health Organization. Mixed germ cell tumours. WHO Classification of Tumours online. Accessed October 14, 2023. https://tumourclassification.iarc.who.int/chapters/36