Testicular Cancer and Germ Cell Tumors

Epidemiology and Etiology

Testicular cancers are uncommon tumors with an estimated 9610 new cases and 440 deaths in the US in 2020.¹ However, they are the most common tumors diagnosed in men aged 15-35.

Pathology

GCTs account for approximately 95% of all testicular tumors and may be divided into pure seminomas and nonseminomas, with the latter subdivided into embryonal carcinoma, choriocarcinoma, yolk sac tumor, teratoma, and mixed GCTs including seminoma and nonseminoma components. Sex cord tumors account for approximately 5% of the testicular cancers, including Sertoli cell tumor, Leydig cell tumor, granulosa cell tumor, mixed and unclassified tumors. GCTs may rarely originate in extragonadal sites including the retroperitoneum and mediastinum.²⁴

Clinical Presentation

The most common presentation is that of a painless testicular mass, but patients may also present with testicular pain, hydrocele, or gynecomastia. Advanced testicular cancer may present with back or flank pain, fevers, night sweats, and weight loss.

Diagnostic Testing

Patients with a palpable testicular mass should be evaluated for testicular cancer, initially with a testicular ultrasound and tumor markers (AFP, LDH [lactic dehydrogenase], and beta-hCG [human chorionic gonadotropin]). Testicular GCTs are usually heterogeneous, hypoechoic, and vascular. Patients with a heterogeneous, hypoechoic intratesticular lesion on ultrasound should undergo unilateral radical orchiectomy as the next evaluation step. Trans-scrotal biopsies should not be performed due to the increased risk of local or atypical recurrences. Patients with metastatic disease may undergo biopsy of the metastatic site rather than orchiectomy for diagnosis. Postdiagnostic workup includes CT of the abdomen and pelvis, chest radiograph, and repeat tumor markers.

Staging

Staging is based on TNM status and serum markers (S). In general, stage I represents disease confined to the scrotum (T1-4), stage II indicates lymph node involvement (N1-3), and stage III is defined by the presence of visceral/distant metastases (M1). There is no stage IV category for testicular cancers. The serum marker classification includes: S0 (normal markers), S1 (LDH lt;1.5 ULN and hCG lt;5000 [mIU/mL] and AFP lt;1000 [ng/mL]), S2 (LDH 1.5-10? ULN or hCG 5000-50,000 or AFP 1000-10,000), and S3 (LDH gt;10? ULN or hCG gt;50,000 or AFP gt;10,000).

TREATMENT

• Prior to starting treatment, patients should be offered sperm banking for fertility preservation.

• Seminomas: Patients with stage I seminomas are treated with orchiectomy followed by surveillance, single-agent carboplatin, or radiation. Patients with stages IIA or IIB (no lymph node larger than 5 cm) may be treated with chemotherapy or radiation therapy, whereas those with stage IIC (lymph node larger than 5 cm) or III with good risk (normal AFP, no nonpulmonary visceral metastases) are treated with chemotherapy including three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of EP. Patients with stage III and intermediate risk (normal AFP, nonpulmonary visceral metastases) are treated with four cycles of BEP or etoposide, ifosfamide, and cisplatin (VIP). No patient with pure seminoma is classified as poor risk.

• Nonseminomas: Patients with stage I are treated with orchiectomy and then surveillance, one cycle of BEP, or retroperitoneal lymph node dissection (RPLND). Patients with stage II are treated with nerve­sparing RPLND, three cycles of BEP, or four cycles of EP. Patients with stage IIC or good risk IIIA (no nonpulmonary visceral metastases and post-orchiectomy S1) are treated with three cycles of BEP or four cycles of EP. Patients with intermediate (no nonpulmonary visceral metastases, S2) or poor risk (nonpulmonary visceral metastases, mediastinal primary tumor, or S3) are treated with four cycles of BEP or VIP.

• Subsequent therapies: Treatment options for patients with GCTs who relapse after the initial treatment include alternative cisplatin-based regimens such as VeIP (vinblastine, ifosfamide, cisplatin) and TIP (paclitaxel, ifosfamide, cisplatin), pembrolizumab for MSI-high tumors and high-dose chemotherapy

with autologous stem cell transplant.²⁴