Testicular Cancer¶

Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Part 4 – Oncology: Solid Tumors · Chapter 93

Key Clinical Points¶

Testicular germ cell tumors (GCTs) represent 95% of all testicular neoplasms and are the most common malignancy in adolescent and young adult males (age 15–39 years).
Radical inguinal orchiectomy is the gold standard initial treatment; transscrotal biopsy or aspiration is contraindicated due to risk of tumor seeding.
Seminomas are exquisitely sensitive to chemotherapy and radiation; nonseminomatous GCTs are chemotherapy sensitive but teratomas are chemoresistant.
Serum tumor markers (AFP, hCG, LDH) are essential for diagnosis and staging; AFP is never elevated in seminoma.
Active surveillance is the preferred management for Stage I seminoma, while Stage I nonseminomatous GCTs may be managed with surveillance or adjuvant therapy depending on risk features.
Cisplatin-based chemotherapy (BEP or EP) is the standard for metastatic disease; fertility preservation via sperm banking is recommended prior to treatment.
Postchemotherapy residual masses often represent necrosis or teratoma; resection is indicated for viable nonteratomatous GCT or masses >3 cm.
Relapse occurs in 20–30% of patients with metastatic GCT; prognosis is determined by the International Germ Cell Consensus Classification System.
Extragonadal GCTs occur in ~5% of cases, commonly in the mediastinum, retroperitoneum, or pineal gland.
Risk factors include cryptorchidism, history of testicular GCT, and germ cell neoplasia in situ (GCNIS).

1. DEFINITION & OVERVIEW¶

• Overview: Testicular germ cell tumors (GCTs) represent 95% of all testicular neoplasms. ◦ Non-GCTs of the testis are much less common. ◦ Approximately 5% of GCTs arise in extragonadal locations, including the mediastinum, retroperitoneum, and pineal gland. ◦ High cure rate: ~95% of newly diagnosed patients with testicular GCTs will be cured; considered a "model for a curable neoplasm."

• Classification: GCTs are categorized as either seminomas or nonseminomas. ◦ Seminoma: To be considered a seminoma, the tumor must be 100% seminoma. ◦ Nonseminomatous GCT (NSGCT): Any mixed GCT should be approached as a nonseminomatous GCT. ◦ Prevalence: Seminomas represent ~50% of cases; NSGCTs are most commonly diagnosed in the third decade of life. ◦ NSGCT Histologic Subtypes: - Embryonal carcinoma: Most undifferentiated nonseminomatous GCT subtype with potential to differentiate into other subtypes; may secrete AFP, hCG, both, or neither. - Yolk sac tumor: Often secretes AFP. - Choriocarcinoma: Aggressive subtype, often secreting hCG at very high levels. - Teratoma: Composed of somatic cell types derived from ≥ 2 germinal layers (endoderm, mesoderm, and ectoderm); classified as mature, immature, or malignant.

Definition (Harrison's 22e): Teratoma is composed of somatic cell types derived from two or more germinal layers (endoderm, mesoderm, and ectoderm).

2. EPIDEMIOLOGY¶

• Demographics: ◦ Most common malignancy in adolescent and young adult males (age 15–39 years). ◦ Incidence is increasing in patients over 50. ◦ Highest incidence: Scandinavia, Western Europe, Australia/New Zealand. ◦ Lowest incidence: Africa and Asia. ◦ Prevalence: More common in Caucasians; much less commonly seen in African Americans.

• Trends: ◦ No distinct biology related to geography is apparent, but several countries report a migration to earlier stage disease (partially due to public awareness and earlier diagnosis).

2.1 Risk Factors¶

• Primary Risk Factors: - Prior history of testicular GCT: 1–2% risk of developing a contralateral GCT (more commonly metachronous than synchronous). - Cryptorchidism: Approximately a four- to sixfold increased risk. - Germ cell neoplasia in situ (GCNIS): Significant risk when identified during infertility evaluation.

• Mitigation & Other Factors: - Orchidopexy before puberty: Decreases but does not eliminate the risk of GCT. - Contralateral descended testis: Also at risk for this disease. - Environmental factors: No conclusive causal links established.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Origin: The primordial germ cell is the cell of origin for GCTs. • Development: Most malignant GCTs arise from in situ neoplasia. • Genetics: - Genetic analysis shows an excess copy number of isochromosome 12p (i[12p]) in most cases. - KITLG (KIT ligand) locus on chromosome 12: The strongest identified independent locus associated with testicular GCT risk.

3.1 Serum Tumor Markers¶

• General Utility: AFP, hCG, and LDH are essential for diagnosis, staging, and monitoring response to therapy.

• AFP (alpha-fetoprotein): - Elevated in ~60–70% of patients with nonseminomatous GCTs. - Seminomas never secrete AFP. - If a seminoma shows elevated AFP → approach as having a nonseminomatous GCT. - Half-life: 5–7 days. - False positives: Seen in hepatic disease or hereditary persistence of AFP (baseline levels may be mildly elevated).

• hCG (beta-human chorionic gonadotropin): - Elevated in both nonseminomatous GCTs and seminomas. - Choriocarcinoma → markedly elevated levels of hCG. - Half-life: 24–36 h. - False positives: Hypogonadism, marijuana use, or interference from substances measured by the assay.

• LDH (lactate dehydrogenase): - Nonspecific marker for GCT. - Primary use: Assessment of risk classification in patients with metastatic disease.

• Other: Serum microRNA (miR)-371a-3 is a promising biomarker; validation studies are ongoing.

3.2 Pathology¶

• Seminoma: - Most common in patients in the fourth decade of life. - May contain syncytiotrophoblastic cells (may secrete β-human chorionic gonadotropin). - Never secrete α-fetoprotein (AFP). - Exquisitely sensitive to both chemotherapy and radiation therapy.

• NSGCT Subtypes: - Embryonal carcinoma: Most undifferentiated; can differentiate into other subtypes; may secrete AFP, hCG, both, or neither. - Yolk sac tumor: Often secretes AFP. - Choriocarcinoma: Aggressive subtype, often secreting hCG at very high levels. - Teratoma: Chemotherapy resistant; must be treated surgically.

4. CLINICAL FEATURES¶

• Presentation: - Primary: Painless testicular mass (most common). Other symptoms include swelling, firmness, or discomfort.

• Metastatic Symptoms: - Retroperitoneal metastases → back or flank pain. - Lung metastases → cough, shortness of breath, or hemoptysis. - High serum hCG → gynecomastia may be present.

• Physical Exam: - Evaluation of the affected testis and the contralateral normal testis. - Assessment for testicular atrophy. - Examination for supraclavicular lymphadenopathy, gynecomastia, and abdominal mass.

5. DIFFERENTIAL DIAGNOSIS¶

• Primary Differentials: - Epididymitis - Orchitis - Note: A trial of antibiotics may be considered for these conditions.

5.1 Diagnostic Clues¶

• Imaging Findings: - A solid mass identified on ultrasound should be considered malignant until otherwise proven. - GCT appearance: Hypoechoic and may be multifocal.

• Contraindications: - Transscrotal aspiration or biopsy → NEVER PERFORMED due to risk of tumor seeding of the scrotum or inguinal lymph nodes.

6. INVESTIGATIONS & DIAGNOSIS¶

• Initial Workup: - If a firm testicular mass is identified → perform scrotal ultrasound (include both testicles). - Patients with suspected epididymitis/orchitis who do not respond to antibiotics should also undergo scrotal ultrasound.

• Imaging for Staging: - New diagnosis → CT scan of the abdomen and pelvis. - If retroperitoneal metastases or lung nodules are identified → Chest X-ray and CT scan of the chest. - Bone scan and MRI of the brain: Not routinely performed unless clinically indicated. - PET: Little role in initial staging.

• Procedures: - Transscrotal aspiration or biopsy is contraindicated due to risk of tumor seeding.

6.1 Diagnostic Algorithm¶

Identify Mass: If a firm testicular mass is identified → perform scrotal ultrasound.
Assess Ultrasound: If ultrasound shows a solid mass → consider malignant until proven otherwise.
Laboratory Workup: Measure serum tumor markers (AFP, hCG, LDH).
Referral: Prompt referral to urology if testicular GCT is suspected.
Primary Treatment: Radical inguinal orchiectomy (removal of testicle and spermatic cord to the level of the internal inguinal ring).
Metastatic Management: If metastatic disease is certain → orchiectomy may be deferred until completion of chemotherapy.
Post-operative Monitoring: Serum tumor markers should be obtained before and after orchiectomy.

7. MANAGEMENT & TREATMENT¶

• Decision Logic: Treatment is based on (1) histology (Seminoma vs. NSGCT) and (2) stage.

• Risk Stratification (Table 93-1): - Good Risk: - Seminoma: Any primary site; normal AFP, any hCG, any LDH; nonpulmonary visceral metastases absent. - NSGCT: Gonadal or retroperitoneal primary; nonpulmonary visceral metastases absent; AFP <1000 ng/mL; hCG <5000 mIU/mL; LDH <1.5 imes ULN. - Intermediate Risk: - Seminoma: Any primary site; normal AFP, any hCG, any LDH; nonpulmonary visceral metastases absent; plus one of (hCG 5000–50,000 mIU/mL; or AFP 1,000–10,000 ng/mL; or LDH 1.5–10 imes ULN). - NSGCT: Gonadal or retroperitoneal primary; nonpulmonary visceral metastases absent; plus one of (hCG 5000–50,000 mIU/mL; or AFP 1,000–10,000 ng/mL; or LDH 1.5–10 imes ULN). - Poor Risk: - Seminoma: N/A. - NSGCT: Mediastinal primary; OR nonpulmonary visceral metastases present; OR one of (AFP >10,000 ng/mL; or hCG >50,000 mIU/mL; or LDH >10 imes ULN).

• Stage-Based Management (Table 93-2 & 93-3): - Stage IA / IB: - Seminoma: Active surveillance; OR adjuvant carboplatin imes 1 or 2 cycles; OR adjuvant para-aortic RT. - NSGCT: Active surveillance; OR nerve-sparing RPLND; OR adjuvant BEP imes 1 cycle. - Stage IS (Elevated markers post-orchiectomy): - Seminoma/NSGCT: BEP imes 3 cycles; OR EP imes 4 cycles. - Stage IIA (N1: nodes ≤ 2 cm): - Seminoma: Para-aortic and ipsilateral iliac RT; OR BEP imes 3 cycles or EP imes 4 cycles; OR nerve-sparing RPLND in select patients. - NSGCT: Nerve-sparing RPLND; OR BEP imes 3 cycles or EP imes 4 cycles. - Stage IIB (N2: nodes > 2 to 5 cm): - Seminoma: BEP imes 3 cycles or EP imes 4 cycles; OR para-aortic and ipsilateral iliac RT. - NSGCT: BEP imes 3 cycles or EP imes 4 cycles ± postchemotherapy RPLND. - Stage IIC (N3: nodes > 5 cm): - Seminoma: BEP imes 3 cycles or EP imes 4 cycles. - NSGCT: BEP imes 3 cycles or EP imes 4 cycles ± postchemotherapy RPLND. - Stage IIIA (Good-risk): - Seminoma/NSGCT: BEP imes 3 cycles; OR EP imes 4 cycles; ± Postchemotherapy surgery. - Stage IIIB (Intermediate-risk): - Seminoma/NSGCT: BEP imes 4 cycles; OR VIP imes 4 cycles. - Stage IIIC (Poor-risk): - NSGCT: BEP imes 4 cycles; OR VIP imes 4 cycles.

• Chemotherapy Regimens: - BEP: bleomycin, etoposide, cisplatin. - EP: etoposide, cisplatin. - VIP: etoposide, ifosfamide, cisplatin.

• Special Considerations for NSGCT: - If residual viable nonteratomatous GCT is suspected → 2 additional cycles of chemotherapy may be considered. - Postchemotherapy RPLND: Standard for NSGCT if nodes are >1 cm. If ≤ 1 cm, often foregone unless viable nonteratomatous GCT is suspected. - Management of growing teratoma syndrome (markers normalize but tumors enlarge) → surgery.

8. PROGNOSIS & COMPLICATIONS¶

• Survival: - Stage III Good-risk: >90% will be cured. - Stage III Intermediate-risk: ~80% 5-year survival. - Stage III Poor-risk: ~50% 5-year survival.

• Relapse: - 20–30% of patients with metastatic GCTs treated with cisplatin-based chemotherapy will not achieve durable disease control. - Most of these patients will experience disease progression within 2 years following completion of chemotherapy. - Factors for worsened prognosis: NSGCT histology, extragonadal primary, incomplete response to first-line chemotherapy, time to relapse of 3 months or less, level of serum tumor markers at relapse, and the presence of nonpulmonary visceral metastatic disease.

• Fertility: - Cisplatin-based chemotherapy is associated with sterility. - Approximately 30% of newly diagnosed testicular GCT patients have severe oligospermia or azoospermia. - For the remainder with normal baseline spermatogenesis who receive cisplatin-based chemotherapy, all will be azoospermic at the completion of therapy. - Approximately 80% of these patients will recover spermatogenesis over a period of several years. - Action: Prechemotherapy sperm banking should be offered to all patients treated with chemotherapy.

9. SPECIAL CONSIDERATIONS¶

• Postchemotherapy Findings: - Approximately 50% of postchemotherapy residual masses represent necrosis or fibrosis. - Approximately 40% are teratoma (no additional treatment required). - Approximately 10% are viable nonteratomatous GCT → requires resection (e.g., RPLND, potentially thoracotomy or neck dissection).

• Clinical Rule: - If a solid mass is identified on ultrasound, it should be considered malignant until proven otherwise. - Absolute Contraindication: Transscrotal biopsy/aspiration must never be performed due to risk of seeding. - Marker Logic: Serum markers are essential for diagnosis and staging; remember that seminomas never secrete AFP.

KEY PEARLS & HIGH-YIELD POINTS¶

• Rule of Thumb: If a solid mass is on ultrasound, assume malignancy until proven otherwise. • Absolute Contraindication: Never perform transscrotal biopsy/aspiration (risk of seeding). • Marker Logic: AFP eq Seminoma. High hCG = Choriocarcinoma suspicion. • Fertility: Sperm banking is mandatory before cisplatin-based therapy. • Teratoma Rule: Teratomas are chemoresistant; management is surgical.

Reference Tables¶

TABLE 93-1 International Germ Cell Consensus Classification System¶

Harrison's 22e, p.708

RISK GROUP	SEMINOMA	NSGCT
Good	Any primary site; and normal AFP, any hCG, any LDH; and nonpulmonary visceral metastases absent	Gonadal or retroperitoneal primary; and nonpulmonary visceral metastases absent; and AFP <1000 ng/mL; and hCG <5000 mIU/mL; and LDH <1.5 × ULN
	Any primary site; and normal AFP, any hCG, any LDH; and nonpulmonary visceral metastases present
Poor	N/A	Mediastinal primary; or nonpulmonary visceral metastases present; or one of the following: AFP >10,000 ng/mL HCG >50,000 mIU/mL LDH >10 × ULN