Residency · Residency · Pathology

Testicular and Ovarian Germ Cell Tumors

Introduction

Germ cell tumors (GCTs) arise from primordial germ cells and represent a diverse group of neoplasms occurring in gonadal and extragonadal sites. They are the most common solid malignancy in males aged 15 to 35 and account for approximately 20 to 25 percent of ovarian neoplasms. Understanding their classification, morphology, and immunohistochemical profiles is essential for accurate diagnosis.

Embryology and Pathogenesis

Primordial germ cells migrate from the yolk sac to the gonadal ridge during embryogenesis. Germ cell neoplasia in situ (GCNIS) is the precursor lesion in the testis, found in nearly all adult-type GCTs. Isochromosome 12p, designated i(12p), is a hallmark cytogenetic abnormality in testicular GCTs. Risk factors include cryptorchidism, disorders of sex development, and prior contralateral GCT.

Classification of Testicular Germ Cell Tumors

Seminoma

Seminoma is the most common pure testicular GCT, accounting for approximately 50 percent. It consists of sheets of uniform cells with clear cytoplasm and prominent nucleoli, accompanied by a lymphocytic infiltrate. The immunoprofile is positive for OCT3/4, PLAP, D2-40, SALL4, and c-KIT, while CD30 is negative. A granulomatous reaction is common.

Non-Seminomatous Germ Cell Tumors (NSGCTs)

Embryonal carcinoma is composed of primitive epithelial cells with marked pleomorphism and is positive for OCT3/4, CD30, and SALL4. Yolk sac tumor characteristically shows Schiller-Duval bodies along with reticular and microcystic patterns, and is positive for AFP, glypican-3, and SALL4. Choriocarcinoma displays a biphasic pattern of syncytiotrophoblast and cytotrophoblast with markedly elevated beta-hCG. Teratoma contains mature or immature elements from all three germ layers; in the postpubertal testis, teratoma is considered malignant regardless of the degree of maturity.

Classification of Ovarian Germ Cell Tumors

Dysgerminoma

Dysgerminoma is the ovarian counterpart of seminoma and represents the most common malignant ovarian GCT. It has identical morphology and immunophenotype to seminoma. Prognosis is excellent due to high chemosensitivity.

Immature Teratoma

Immature teratoma of the ovary is graded 1 through 3 based on the amount of immature neuroepithelium. The grade correlates directly with prognosis and the need for adjuvant chemotherapy.

Yolk Sac Tumor

Yolk sac tumor is the most common ovarian GCT in children. Elevated serum alpha-fetoprotein (AFP) is a reliable tumor marker for diagnosis and monitoring.

Staging and Serum Tumor Markers

AFP is elevated in yolk sac tumor and some embryonal carcinomas, with a half-life of approximately 5 days. Beta-hCG is elevated in choriocarcinoma and some seminomas, with a half-life of 24 to 36 hours. LDH is non-specific but correlates with tumor burden. Staging follows the AJCC TNM system, which includes an S category for serum markers in testicular tumors.

Mixed Germ Cell Tumors

Approximately 30 to 40 percent of testicular GCTs are mixed, containing more than one histologic component. Each component must be reported with its percentage. The presence of even small amounts of non-seminomatous elements changes management from seminoma-directed to NSGCT-directed therapy.

Immunohistochemistry Summary

Clinical Pearls

All components and their percentages must be reported in mixed GCTs because the presence of any non-seminomatous element dictates therapy. GCNIS identified in a testicular biopsy warrants close surveillance or treatment of the contralateral testis given the high risk of subsequent tumor development. Post-chemotherapy retroperitoneal lymph node dissection specimens should be carefully sampled to quantify viable tumor, teratoma, and necrosis, as each carries different prognostic and therapeutic implications. Serum markers that fail to decline appropriately after orchiectomy suggest residual or metastatic disease and should prompt further investigation.

References

1. Moch H, et al. WHO Classification of Tumours: Urinary System and Male Genital Organs. 5th ed. Lyon: IARC Press; 2022.
2. Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005;18(Suppl 2):S61-S79.
3. Nogales FF, et al. Germ cell tumours of the ovary: an update. Adv Anat Pathol. 2014;21(3):178-192.
4. Williamson SR, et al. The World Health Organization 2016 classification of testicular germ cell tumours: a review and update. Histopathology. 2017;70(3):335-346.

For the intern

At 3am, if you're called about a young man with testicular mass or elevated AFP/beta-hCG, order urgent imaging and consult urology—delays worsen outcomes. Similarly, a child with ovarian mass and elevated AFP needs immediate surgical evaluation. Check tumor markers (AFP, beta-hCG, LDH) stat and trend them; they guide diagnosis and monitor response. For post-orchiectomy specimens, ensure proper sampling—missing a small focus of embryonal carcinoma or choriocarcinoma in an otherwise pure seminoma completely changes chemotherapy planning. If markers don't decline appropriately post-surgery (AFP half-life 5 days, beta-hCG 24-36 hours), this signals residual disease. Everything else—detailed grading of immature teratoma, quantifying mixed tumor percentages, and finalizing immunostains—can wait for morning rounds when you're alert.

Common pitfalls

• Calling every testicular GCT "seminoma": Approximately 30-40% are mixed. Even 5% embryonal carcinoma changes management from seminoma protocols to more aggressive NSGCT therapy. Sample thoroughly and report all percentages.
• Ignoring GCNIS in background: Nearly all adult testicular GCTs arise from germ cell neoplasia in situ (GCNIS). Document its presence—it affects contralateral testis surveillance.
• Forgetting that postpubertal teratoma is malignant: Unlike prepubertal or ovarian mature teratoma, any teratoma in postpubertal testis behaves malignantly regardless of maturity.
• Misinterpreting post-chemotherapy specimens: Viable tumor, mature teratoma, and necrosis each have different implications. Don't call everything "treatment effect."

<image>Simple flowchart for testicular mass workup. Panel 1: Young male with testicular mass → Check AFP, beta-hCG, LDH. Panel 2: Orchiectomy specimen → Look for seminoma (uniform cells, lymphocytes, OCT3/4+, CD30-) versus non-seminomatous components. Panel 3: If any embryonal carcinoma (OCT3/4+, CD30+), yolk sac (AFP+, Schiller-Duval bodies), or choriocarcinoma (beta-hCG+, biphasic) present → Label as mixed GCT, quantify each component → NSGCT protocols. Panel 4: Pure seminoma → Seminoma-directed therapy.</image>

Make it stick

You're a junior resident on a busy day, signing out a testicular germ cell tumor case. The preliminary report shows seminoma, and you're ready to finalize. But then, you remember Dr. Smith's lecture: "Always look for the bad actor." You scroll through the slides one last time and, in a small corner, spot a few haphazardly arranged, pleomorphic cells with prominent nucleoli. A quick immunostain for CD30 lights up these cells—it's a small focus of embryonal carcinoma, perhaps only 5% of the tumor. You update the diagnosis to "Mixed germ cell tumor with predominant seminoma and minor embryonal carcinoma component." This seemingly minor detail completely shifts the patient's treatment from single-agent carboplatin to a multi-agent chemotherapy regimen. Your meticulousness potentially saved this young patient's life.

If you remember one thing

The presence of any non-seminomatous component in a testicular germ cell tumor, even a small percentage, dictates management as a non-seminomatous germ cell tumor (NSGCT), which generally requires more aggressive chemotherapy. Always meticulously sample and report all components of mixed germ cell tumors.

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