9.2 Management of Seminoma (Stage I to Metastatic)

9.2 Management of Seminoma (Stage I to Metastatic)

Pure seminoma accounts for approximately 50% of all testicular germ cell tumours (TGCTs). It characteristically arises in men approximately 5 to 10 years older than those affected by non-seminoma, with a median age at presentation of 35 years. Classical seminoma is an extraordinarily chemosensitive and radiosensitive disease. Through systematic risk stratification, early active surveillance, and modern cisplatin-based chemotherapy, long-term disease-specific survival for seminoma exceeds 99% in localized disease and approaches 90% even in advanced metastatic presentations.

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1. Histopathology & Immunohistochemistry of Pure Seminoma

Macroscopically, pure seminoma typically presents as a well-circumscribed, fleshy, homogeneous, lobulated, cream-to-pink or tan mass that bulges from the cut surface of the testis, typically lacking the extensive hemorrhage or cystic necrosis characteristic of non-seminomatous tumours.

Microscopically, classical seminoma exhibits distinct architectural and cytological hallmarks:

• Uniform Polygonal Cells: Large, round-to-polygonal cells arranged in sheets, cords, or well-defined lobules.
• Glycogen-Rich Cytoplasm: Abundant clear, pale, watery cytoplasm that stains strongly positive with Periodic Acid–Schiff (PAS) and is diastase-sensitive.
• Prominent Nuclei: Centrally located, hyperchromatic round nuclei with irregular nuclear membranes and one or two prominent eosinophilic nucleoli.
• Fibrovascular Septa with Lymphocytic Infiltrates: Thin, delicate fibrous trabeculae subdivide the tumour into lobules. These septa are densely infiltrated by mature host T-lymphocytes (CD3+). In approximately 20% to 30% of cases, a prominent non-caseating granulomatous giant-cell reaction is present, reflecting a robust anti-tumour host immune response.

Immunohistochemical (IHC) Profile

Correct pathological diagnosis requires a defined immunohistochemical panel:

• Positive Markers: OCT3/4, SALL4, c-KIT (CD117), D2-40 (podoplanin), and placental alkaline phosphatase (PLAP).
• Negative Markers: CD30 (positive in embryonal carcinoma), Cytokeratin (usually negative or focal in seminoma, commonly diffuse in embryonal carcinoma), and Alpha-fetoprotein (AFP) (never expressed in seminoma).

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2. Stage I Seminoma: Relapse Risk Stratification

Stage I seminoma (pT1–pT4 N0 M0 S0) has no regional nodal or distant metastases, although the primary may extend locally as far as the scrotum, accompanied by normal post-orchiectomy serum markers (S0) and completely negative staging cross-sectional CT imaging of the abdomen and chest. Approximately 80% to 85% of men with Stage I seminoma are permanently cured by radical inguinal orchiectomy alone.

Tumour size and stromal rete testis invasion are conventional relapse predictors, often using a 4-cm size threshold. They support counselling but are insufficient to dictate adjuvant treatment routinely. Contemporary studies also implicate hilar invasion, LVI and preoperative hCG/LDH; risk estimates depend on the model and population.

Unselected surveillance series show 12–20% relapse at five years. Contemporary estimates are approximately 6–8% without conventional risk factors and 15–20% with one or both. These are cohort estimates, not a fixed three-tier calculator. Most relapses occur in retroperitoneal nodes in the first two years. Surveillance remains preferred when follow-up and prompt treatment of relapse are feasible.

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3. Management of Stage I Seminoma: Surveillance vs Adjuvant Therapies

Following radical inguinal orchiectomy, three management options exist for Stage I seminoma:

Option 1: Active Surveillance (Standard Preferred Option per EAU Guidelines)

Active surveillance is the preferred standard of care for all patients with Stage I seminoma, regardless of tumour size or rete testis invasion, provided the patient is compliant with scheduled follow-up.

• Rationale: Because 80% to 85% of patients are already cured by surgery, routine adjuvant therapy unnecessarily over-treats the overwhelming majority of young men. When relapses do occur on surveillance, stage-adapted treatment is highly effective, giving the overall surveillance strategy >99% cancer-specific survival. Treatment at relapse depends on stage and may include cisplatin-based chemotherapy or radiotherapy.
• Surveillance Protocol: EAU minimum follow-up uses abdominopelvic MRI or CT twice in year 1, twice in year 2, then at 36 and 60 months, with clinical review and markers. Experienced interpretation is important when MRI replaces CT; routine PET is not surveillance imaging.

Option 2: Adjuvant Carboplatin Chemotherapy

An alternative after shared decision-making, including for patients declining surveillance or considering their individual relapse risk. Follow-up remains necessary after carboplatin.

• Dosing & Regimen: Delivered as a single cycle of carboplatin dosed at AUC 7 (Area Under the Concentration-time Curve calculated via the Calvert formula: $\text{Dose (mg)} = \text{AUC} \times [\text{GFR} + 25]$, using accurately measured GFR in mL/min, for example by 51Cr-EDTA; creatinine clearance is not interchangeable with measured GFR).
• Evidence & Efficacy: MRC TE19 / EORTC 30982 compared one carboplatin infusion AUC 7 with radiotherapy. Five-year relapse-free rates were 94.7% versus 96.0%, supporting non-inferiority; this was not a comparison with surveillance. Acute myelosuppression can occur. Available follow-up is reassuring, but it does not establish absence of all long-term malignancy or cardiovascular risks.
• Number of Cycles: EAU recommends one cycle AUC 7 if adjuvant chemotherapy is selected. Two-cycle series report low relapse, but two cycles are not the routine EAU standard.

Option 3: Adjuvant Radiotherapy (Discouraged / Largely Superseded)

Adjuvant radiotherapy consists of 20 Gy delivered in 10 fractions to an infradiaphragmatic para-aortic nodal field.

• Toxicity & Guideline Recommendation: Although highly effective in reducing relapse to ~3% to 4%, long-term survivorship data demonstrate that radiotherapy confers a 2- to 3-fold increased relative risk of secondary solid malignancies (e.g., gastric, pancreatic, colon, and bladder carcinomas) with a 10- to 20-year latency, as well as accelerated atherosclerosis and premature cardiovascular mortality. Consequently, EAU guidelines no longer recommend adjuvant radiotherapy as a standard option for Stage I seminoma.

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4. Management of Stage IIA & IIB Seminoma

Stage II seminoma is defined by the presence of retroperitoneal lymphadenopathy on cross-sectional CT imaging:

• Stage IIA: Metastatic regional nodal masses ≤2 cm (N1), without distant metastases.
• Stage IIB: A metastatic nodal mass >2 to ≤5 cm (N2), without distant metastases.

Therapeutic Strategy

For marker-negative equivocal nodes <2 cm, repeat staging after 6–8 weeks before treatment; some nodes are benign. Treat once metastasis is established by growth, biopsy or marker rise.

• Systemic Chemotherapy: 3 cycles BEP or 4 cycles EP when bleomycin is unsuitable are standard options for IIA/B. Discuss acute toxicity, fertility and long-term cardiovascular, renal and second-cancer risks.
• Radiotherapy: An accepted option for both stages: 30 Gy for IIA and 36 Gy for IIB, typically to a modified dog-leg field with nodal boost. It is not contraindicated in IIB. No randomized trial establishes superiority over chemotherapy; treatment choice balances disease volume and acute/late toxicity.
• Selected Low-Volume Disease: The 2026 EAU guideline permits expert-centre nerve-sparing RPLND for marker-negative IIA/small-volume IIB nodes ≤3 cm. Explain relapse risk and possible later chemotherapy; this is a specialized option rather than a universal replacement for chemotherapy or radiotherapy.

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5. Advanced / Metastatic Seminoma & The IGCCCG Classification

Patients with bulky retroperitoneal lymphadenopathy > 5 cm (Stage IIC) or metastatic spread to distant lymph nodes, lungs, or viscera (Stage III) are stratified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) consensus classification.

Crucial IGCCCG Principle: Seminoma Has NO Poor Risk Category

Unlike non-seminoma, advanced pure seminoma is stratified into only two prognostic categories:

1. Good Risk Seminoma (~90% of advanced cases):
   • Criteria: Primary tumour arising in any anatomical site (testicular or retroperitoneal), accompanied by absence of non-pulmonary visceral metastases (NPVM), normal serum AFP, any level of beta-hCG, and any level of LDH.
   • Exam Anchor: Pulmonary parenchymal metastases are explicitly permitted in Good Risk seminoma!
   • Prognosis: 5-year Progression-Free Survival (PFS) is ~89%; 5-year Overall Survival (OS) is ~95%.
   • Standard Regimen: 3 cycles of BEP or 4 cycles of EP. (Use EP when bleomycin is unsuitable, after assessing pulmonary and renal function and other toxicity risks; age or smoking alone is not an automatic regimen rule).
2. Intermediate Risk Seminoma (~10% of advanced cases):
   • Criteria: Presence of non-pulmonary visceral metastases (NPVM) (e.g., liver, bone, brain, gastrointestinal tract, or spleen), arising from any primary site, with normal AFP.
   • Prognosis: 5-year PFS is ~79%; 5-year OS is ~88%.
   • Standard Regimen: 4 cycles of BEP, or 4 cycles of VIP (etoposide, ifosfamide, cisplatin) if bleomycin is contraindicated.
3. Poor Risk Seminoma: DOES NOT EXIST. A patient with seminoma can never be classified as Poor Risk under IGCCCG criteria.

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6. Post-Chemotherapy Residual Mass Management: The 18F-FDG PET Algorithm

Following completion of induction chemotherapy, residual retroperitoneal masses are frequently identified on cross-sectional CT imaging (seen in up to 50% to 70% of bulky cases). In pure seminoma, the vast majority of these residual masses (>80%) represent harmless necrotic cellular debris and dense, desmoplastic fibrous tissue.

Retroperitoneal lymph node dissection (RPLND) in post-chemotherapy seminoma is notorious for severe, technically treacherous retroperitoneal fibrosis that obliterates natural tissue planes around the aorta, IVC, and renal vessels, carrying high rates of vascular injury and organ sacrifice. Therefore, surgery is avoided whenever possible.

Current EAU Residual Mass Algorithm

Initially monitor residual masses with cross-sectional imaging and serum markers. Most represent fibrosis or necrosis, and routine post-chemotherapy RPLND is avoided.

• Residual Mass ≤3 cm: Continue surveillance when markers are normal and the mass is stable or shrinking; PET is not routinely indicated.
• Residual Mass >3 cm: Consider 18F-FDG PET-CT at least two months after chemotherapy. Earlier imaging may show treatment-related inflammatory uptake rather than viable tumour.
  • PET-Negative Mass: A high NPV (>90%) supports surveillance rather than routine surgery.
  • PET-Positive, Stable Mass: PPV is limited and variable (23–69%). A single positive scan does not prove viable seminoma. If volume is not increasing, repeat PET after six weeks and review in the specialist multidisciplinary team.
  • Progression: Rising hCG warrants salvage chemotherapy. A growing mass without hCG progression requires histological verification before salvage chemotherapy. Select biopsy or expert surgery according to resectability and morbidity; complex residual masses may require systemic treatment. PET positivity alone does not justify RPLND.

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Seminoma Stage-Specific Management & Residual Mass Algorithm