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Testicular Cancer

Medical Oncology·GU Cancer·2024
Testicular Cancer (Germ Cell Tumors)

Introduction

  • 1% of all solid tumors in men; most common solid ca in men 15 to 35; ~9K new cases/yr in the US. Incidence is ↑ and mortality is ↓.
  • 95% are seminomas or NSGCT.
  • Children: NSGCT > seminoma. Adults: seminoma > NSGCT.
  • MRI brain if clinically indicated or beta-HCG >5000, AFP >10,000, non-pulmonary visceral mets, or extensive lung mets.
  • PET/CT: not beneficial in NSGCT; only used to assess residual masses in seminoma.
  • Do NOT biopsy the testis. Do NOT remove the testis through the scrotum.

Risk factors

  • Germ cell neoplasia in situ (GCNIS; formerly ITGCN): found adjacent to GCT in >90% of adult cases. Risk of progression to malignancy is 50% at 5 years if untreated.
  • Cryptorchidism (RR ~3 to 5 times; higher with intra-abdominal testis or later orchiopexy).
  • History of GCT.
  • Family history: brother (RR 8 to 10 times), father (RR 4 times).
  • Isochromosome 12p present in most GCT; familial role unclear.
    • i(12p) characterizes invasive postpubertal (GCNIS-related) GCTs, including primary extragonadal tumors; GCNIS/CIS itself usually lacks it, as do prepubertal-type teratoma/yolk sac and spermatocytic tumor. The remaining 20% have excess 12p copy number, tandem duplication, or transposition, indicating one or more genes on 12p are involved in malignant transformation.
  • Most GCTs are hyperdiploid, often triploid or tetraploid, implying endoreduplication is important early in malignant transformation.

Presentation

  • Painless nodule; dullness, heavy sensation, rarely painful; gynecomastia (↑ beta-HCG, rare); hyperthyroidism from homology between beta-HCG and TSH; SVC syndrome from primary mediastinal tumors; supraclavicular adenopathy; hemoptysis from extensive lung mets.

Anatomy (lymphatic drainage)

  • Right testicular artery originates from the aorta and the right testicular vein drains into the IVC → spread to the interaortocaval LNs immediately below the renal vessels.
  • Left testicular artery originates near the left renal artery and the left testicular vein terminates in the left renal vein → left-sided tumors spread to the para-aortic LNs immediately below the left renal artery and vein.
  • Lymphatic spread is common in all GCTs except choriocarcinoma → vascular dissemination.

Diagnosis

  • Testicular biopsy or trans-scrotal orchiectomy is contraindicated because it disturbs normal vascular and lymphatic drainage.
  • Scrotal US is usually diagnostic; if a solid mass is identified, no biopsy is needed, and the dx is testicular cancer until proven otherwise.
  • Proceed with imaging (CT TAP) and tumor markers (AFP, beta-HCG, LDH) to complete staging.
  • Proceed with radical orchiectomy.
  • Repeat tumor markers 4 weeks postop.
  • Obtain brain MRI if beta-HCG >5,000, AFP >10,000, or extensive lung mets.

Histology (IHC)

  • Seminoma: OCT-3/4 (POU5F1) +, CD117 (c-kit) +, D2-40 (podoplanin) +, CD30 neg, SALL4 +.
  • Embryonal carcinoma: OCT-3/4 +, CD117 neg, CD30 +.
  • Yolk sac tumor: OCT-3/4 neg, CD117 neg, CD30 neg, glypican-3 +, AFP +/-, EMA neg.
  • Choriocarcinoma: OCT-3/4 neg, glypican-3 +/-, AFP neg, beta-HCG +.
  • FISH + for isochromosome 12p.

Serum Tumor Markers (STMs)

  • Two tumor markers: AFP and beta-HCG. LDH is important but not specific to testicular cancer.
  • AFP (alpha-fetoprotein)
    • Produced in liver, GI tract, and fetal yolk sac; also increased with heavy alcohol use, viral hepatitis, hereditary tyrosinemia, ataxia telangiectasia, cirrhosis, other cancers (HCC, gastric, biliary, pancreatic, bronchial), antiepileptic and anesthetic drugs, and hereditary persistence of AFP (usually 15 to 30 ng/mL).
    • Limited to NSGCT. Pure choriocarcinoma and pure seminoma do NOT produce AFP.
    • Half-life ~5 to 7 days; check levels 4 weeks (4 half-lives) after orchiectomy; if ↑ (>20), treat as residual disease.
    • If elevated, treat as non-seminoma even if pathology reports "pure seminoma."
  • Beta-HCG
    • Produced by syncytiotrophoblasts; secreted by pituitary (false positive); marijuana use is listed (NCCN) as a possible cause of false-positive hCG, though evidence is limited; if elevated, evaluate for tumor, pituitary hCG in hypogonadism, or assay interference or from LH stimulation (in hypogonadism; testosterone administration can exclude hypogonadism as a cause).
    • Half-life ~24 to 36 hours (up to 3 days in some references).
  • LDH
    • Level correlates with tumor burden, growth rate, and cellular proliferation.
    • Increased in the majority of metastatic NSGCTs and seminomas.
    • Very nonspecific; not recommended for post-orchiectomy surveillance.

Classification of GCT

  • Seminoma (SGCT)
    • Presents as a single histology (seminoma only); makes beta-HCG and LDH.
    • Never AFP; if AFP is ↑, the dx is likely non-seminoma even if path reports "pure seminoma."
    • RadioSensitive; surgery rarely plays a role (unlike non-seminoma).
    • More likely localized, more indolent; if it spreads, uses the lymphatic system.
    • 80% limited to testis (stage I), 15% to RP LN (stage II), and <5% beyond RP LN (stage III).
  • Non-seminoma
    • One or many histologies: embryonal, seminoma, yolk sac, teratoma, choriocarcinoma.
    • Makes AFP, LDH, and/or beta-HCG (or none).
    • More aggressive; likely to present with metastasis; spreads via the bloodstream (especially choriocarcinoma).
    • Non-radiosensitive.
    • TeRatoma → Resistant to chemo and RT → surgery often needed; composed of somatic cells from two or more germ cell layers; can be mature or immature, or de-differentiate to sarcoma or carcinoma.
    • Embryonal carcinoma is the most undifferentiated.
    • Yolk sac tumors most common in infants/children; ↑ AFP; chemotherapy sensitive.
    • Choriocarcinoma mets to lungs and brain; ↑ beta-HCG.
  • Mediastinal primary: mediastinal seminoma has a very good outcome (5 yr OS ~90%); mediastinal non-seminoma 5 yr OS ~50% (associated with 2nd malignancies: AML, MDS, histiocytic sarcoma, other sarcomas; Klinefelter). Primary mediastinal (extragonadal) GCT should be referred to experienced centers; mediastinal nonseminoma: treat with VIP x4 (avoid bleomycin given planned thoracic surgery) followed by resection of residual masses.
  • Sex cord stromal tumors are non-germ cell testicular tumors; very rare. Leydig cell tumors (most common) show a hypoechoic hypervascular mass on US, associated with activating LHCGR (LH/hCG receptor) mutations in a subset (especially pediatric tumors). STMs (AFP, LDH, hCG) are normal. IHC: inhibin + and Melan-A +. Tx with surgery; unclear role of chemo/RT. Sertoli cell and granulosa cell tumors are extremely rare.
  • Spermatocytic tumor (formerly spermatocytic seminoma): rare, older men (median ~50 to 55), usually indolent; metastasis rare but possible, especially with sarcomatous transformation. Normal STMs. Tx orchiectomy f/b surveillance.

Treatment

Pathway: testicular pain → US of testicles → STMs / CT-TAP → radical orchiectomy → repeat STMs 4 weeks postop.

Testicular GCT: T stage and stage I groupsAJCC 8th
GroupStageDefinition
T stagepT1Limited to testis, rete testis and tunica albuginea
pT2LVI, or invasion of tunica vaginalis, epididymis or hilar soft tissue
pT3Invasion of spermatic cord
pT4Invasion of scrotum
Stage IIApT1, N0, M0, markers normal
IBpT2 to pT4, N0, M0, markers normal
ISAny pT, N0, M0, markers persistently elevated after orchiectomy
Tumor size does not change T stage for NSGCT; for pure seminoma, pT1a <3 cm vs pT1b >=3 cm (AJCC 8th).

Treatment by stage and IGCCCG risk

Testicular germ cell tumors: treatment by stageNCCN / EAU; IGCCCG update 2021. Risk group uses post-orchiectomy markers
StageDefinitionSubgroupSeminomaNon-seminoma (NSGCT)
Stage IConfined to testis Seminoma: ~85% cured by orchiectomy alone NSGCT: ~70% cured by orchiectomy alone T stage
  1. pT1: testis and rete testis, no LVI
  2. pT2: LVI, or hilar soft tissue, epididymis, tunica vaginalis
  3. pT3: spermatic cord
  4. pT4: scrotum
N0 M0. Workup: scrotal US, AFP / hCG / LDH, CT chest, abdomen, pelvis; radical inguinal orchiectomy; repeat markers after orchiectomy. Never biopsy or remove the testis through the scrotum (changes lymphatic drainage). 		Stage IMarkers normalize after orchiectomy

Relapse risk factors: tumor >4 cm, rete testis invasion.

  • Surveillance: preferred; relapse ~15 to 20%
  • Carboplatin AUC 7 ×1 to 2: relapse ~5%
  • RT 20 Gy para-aortic: rarely used (second cancers)

Main risk factor: LVI (relapse ~50% if present, ~15% if absent).

  • Surveillance: preferred, especially LVI negative
  • BEP ×1: relapse ~2 to 3%; option if LVI positive
  • Nerve-sparing RPLND: relapse ~10 to 15%; teratoma-predominant
NSGCT is not radiosensitive: no RT in stage I.
Stage ISMarkers stay elevated after orchiectomy

Rare. Treat as metastatic per IGCCCG risk using post-orchiectomy markers: good risk (usual) BEP ×3 or EP ×4; intermediate/poor risk BEP ×4 or VIP ×4.

BEP ×3 or EP ×4.

Confirm true persistence using half-lives (AFP 5 to 7 days, hCG 1 to 3 days); exclude false AFP (liver disease) and false hCG (hypogonadism, marijuana).
Stage IIRetroperitoneal nodes Markers S0 to S1 Cure >90% By node size
  1. IIA: node ≤2 cm
  2. IIB: node 2 to 5 cm
  3. IIC: node >5 cm
Landing zones: right tumors to interaortocaval nodes; left tumors to para-aortic nodes below the left renal vein. Residual mass after chemo: seminoma, PET/CT ≥6 weeks after chemo if >3 cm; NSGCT, resect all residual masses ≥1 cm (teratoma is chemo resistant). 		IIANode ≤2 cm
  • RT 30 Gy para-aortic + ipsilateral iliac, or
  • EP ×4 or BEP ×3
  • Primary RPLND in selected patients (SEMS, PRIMETEST)
  • Markers normal: nerve-sparing RPLND or chemo
  • Markers elevated: BEP ×3 or EP ×4
  • After RPLND: pN1 surveillance; pN2 EP ×2 or surveillance; pN3 full chemo
IIBNode 2 to 5 cm

BEP ×3 or EP ×4 preferred; RT 36 Gy an option for non-bulky disease.

BEP ×3 or EP ×4; RPLND only if markers normal and nodes within the landing zone.
IICNode >5 cm

Treat as good-risk metastatic: BEP ×3 or EP ×4.

Chemotherapy per IGCCCG risk group (see stage III).
Stage IIIDistant or non-regional Treat by IGCCCG risk group 5-yr OS 67 to 96% Any of
  1. Non-regional nodes or lung mets (M1a)
  2. Non-pulmonary visceral mets: liver, bone, brain (M1b)
  3. Nodes with markers S2 to S3
Markers: AFP ng/mL, hCG mIU/mL, LDH ×ULN. Brain MRI if hCG >5,000, AFP >10,000, NPVM or extensive lung mets. Pure seminoma never makes AFP: an elevated AFP means NSGCT, whatever the pathology says. 		Good~90% of seminoma
~56% of NSGCT

Any primary, no NPVM, normal AFP, any hCG or LDH.

BEP ×3 or EP ×4. 5-yr PFS 89%, OS 95%

LDH >2.5× ULN predicts worse outcome within good risk.

Testis or RP primary, no NPVM, AFP <1,000, hCG <5,000, LDH <1.5× ULN.

BEP ×3 or EP ×4. 5-yr PFS 89%, OS 96%
Intermediate~10% of seminoma
~28% of NSGCT

NPVM present (liver, bone, brain).

BEP ×4 or VIP ×4. 5-yr PFS 79%, OS 88%

No NPVM; AFP 1,000 to 10,000, or hCG 5,000 to 50,000, or LDH 1.5 to 10× ULN.

BEP ×4 or VIP ×4. 5-yr PFS 78%, OS 89%
PoorNSGCT only
~16% of NSGCT

No poor-risk category for seminoma.

Mediastinal primary, or NPVM, or AFP >10,000, hCG >50,000, or LDH >10× ULN.

BEP ×4 (VIP ×4 if bleomycin unsafe) at a high-volume center. 5-yr PFS 54%, OS 67%
Relapse: TIP or VeIP, or high-dose carboplatin + etoposide with autologous stem cell rescue. Never delay, dose-reduce, or swap carboplatin for cisplatin in first-line therapy.
BEP = bleomycin, etoposide, cisplatin; EP = etoposide, cisplatin; VIP = etoposide, ifosfamide, cisplatin; NPVM = non-pulmonary visceral metastases. Avoid bleomycin with age >50, reduced CrCl, lung disease or heavy smoking (use EP ×4 or VIP). Survival: IGCCCG Update Consortium (Gillessen JCO 2021; Beyer JCO 2021).

Stage III substages

  • Stage III definitions:
    • IIIA: mets to lungs and/or non-RP LN, STMs S0 or S1.
    • IIIB: at least one STM = S2, none >S2; mets limited to any LN and/or lungs.
    • IIIC: N1 to N3/M0/S3, or M1a/S3, or M1b (non-pulmonary visceral mets) with any marker level. (Primary mediastinal NSGCT is IGCCCG poor risk, not AJCC stage IIIC.)
  • Markers used for risk classification are post-orchiectomy.

General principles of chemotherapy

  • First-line options: BEP (bleomycin, etoposide, cisplatin), EP (etoposide, cisplatin), or VIP (etoposide, ifosfamide, cisplatin).
  • Preserve dose intensity: do not delay or reduce cisplatin (100 mg/m2/cycle) or etoposide (500 mg/m2/cycle in BEP/EP, 375 mg/m2/cycle in VIP), except for protocol-defined toxicity. Do not substitute carboplatin for cisplatin.
  • Neutropenia management: ANC 0.9 on C2D1 → proceed with EP/BEP at same doses; proceed with any ANC, but if WBC <2.5 on D4, hold etoposide on D5 (Indiana); proceed if ANC ≥ 0.5, otherwise delay 1 week (MSKCC).
  • Cr increase from 1.0 to 1.5 on C2D1 → proceed at same doses with ↑ fluids.
  • Bleomycin toxicity: skin toxicity, Raynaud, and pulmonary toxicity (↑ risk with age >50, smoking, high-flow O2, ↓ CrCl). Consider alternatives such as EP for good-risk or VIP for intermediate/high-risk. Association between growth factor use and bleomycin pulmonary toxicity is controversial.
  • Long-term complications: CVD (HLD and ↑ risk of MI, VTE); secondary malignancies after RT and chemo (GI, GU, thyroid, soft tissue sarcomas, AML, MDS); infertility (oligospermia/azoospermia, retrograde ejaculation, prevent with sperm banking); ototoxicity, neuropathy, renal impairment, pulmonary toxicity.
  • Relapse: early (<2 yr), salvage chemo (TIP/VeIP or high-dose chemo) then resect residual masses; late (>2 yr), relatively chemoresistant, complete surgical resection preferred when resectable, chemo reserved for unresectable disease.
  • Second-line conventional chemo: TIP (paclitaxel, ifosfamide, cisplatin) x4 → CR ~70%; VeIP (vinblastine, ifosfamide, cisplatin) x4 → CR ~50%, durable CR ~25%.
  • High-dose chemo with ASCT rescue can be used in 2L or 3L:
    • 2L (including HDCT) is for relapsed or platinum-refractory disease (rising or inadequately falling markers, or viable GCT); a marker-negative residual mass is managed with resection (NSGCT) or PET-directed surveillance (seminoma), not salvage chemo.
    • 3L for relapsed/refractory disease after 2L chemo.
    • ASCT rescue after high-dose carbo/etoposide: TICE (MSKCC; CR 50%, PR 8%, 5 yr DFS 47%, 5 yr OS 52%) or tandem high-dose carboplatin + etoposide (Indiana).
    • Alliance 031102 / EORTC 1407 (TIGER): TIP vs TICE (see updates below).
  • Oligorecurrence can be managed with surgery in select cases.
Chemotherapy regimens for germ cell tumorsConventional regimens (BEP, EP, VIP, TIP, VeIP) repeat every 21  days at full dose intensity; high-dose TI-CE is 2 TI mobilization cycles then 3 high-dose CE cycles with stem-cell rescue
LineRegimenAgents and dosingWhen used
First line BEPBleomycin 30 units IV days 1, 8, 15; etoposide 100 mg/m2 IV days 1 to 5; cisplatin 20 mg/m2 IV days 1 to 5×3 good risk; ×4 intermediate or poor risk. Growth factor from day 6.
EPEtoposide 100 mg/m2 IV days 1 to 5; cisplatin 20 mg/m2 IV days 1 to 5×4 good risk (avoids bleomycin); pathologic stage II; viable GCT at surgery after first-line chemo
VIPEtoposide 75 mg/m2 IV days 1 to 5; ifosfamide 1,200 mg/m2 days 1 to 5 (with mesna); cisplatin 20 mg/m2 IV days 1 to 5×4 intermediate or poor risk when bleomycin is unsafe
Second lineConventional dose TIPPaclitaxel 250 mg/m2 IV over 24 h day 1; ifosfamide 1,500 mg/m2 IV days 2 to 5 (with mesna); cisplatin 25 mg/m2 IV days 2 to 5×4; CR ~70% in favorable relapse
VeIPVinblastine 0.11 mg/kg IV days 1 to 2; ifosfamide 1,200 mg/m2 IV days 1 to 5; cisplatin 20 mg/m2 IV days 1 to 5×4; CR ~50%, durable CR ~25%
High doseWith autologous stem cell rescue CECarboplatin 700 mg/m2 IV days 1 to 3; etoposide 750 mg/m2 IV days 1 to 3; ×2 cycles (tandem, Indiana)Second line if no CR to first-line chemo, or third line after conventional salvage
TICEPaclitaxel 200 mg/m2 IV over 24 h day 1; ifosfamide 2,000 mg/m2 IV over 4 h days 2 to 4; carboplatin AUC 7 to 8 IV days 1 to 3; etoposide 400 mg/m2 IV days 1 to 3MSKCC regimen; TIP vs TICE tested in TIGER
Later OtherGemcitabine + oxaliplatin (GemOx) ± paclitaxelRefractory disease; surgery for oligorecurrence
Do not delay or reduce cisplatin doses, and never substitute carboplatin in first-line therapy. Bleomycin: skin toxicity, Raynaud, pneumonitis (risk rises with age >50, smoking, reduced CrCl, high FiO2).

Residual Mass After Chemotherapy

  • Seminoma: residual mass >3 cm on CT with normal AFP and beta-HCG → PET-CT (6 weeks or more after chemo).
    • If negative → surveillance.
    • If positive, confirm with repeat imaging and/or biopsy (PET has low PPV); treat only if viable seminoma is shown (necrosis or fibrosis needs no further chemo).
  • Non-seminoma: residual mass ≥ 1 cm → surgery for all pts, because there may be teratoma, which can grow or transform and must be removed.
    • ~10% to 15% may harbor viable germ cell tumor (residual embryonal, yolk sac, choriocarcinoma, or seminoma element); if found at RPLND, consider 2 additional cycles of chemo (VeIP, VIP, TIP, or EP x2).
    • Still resect residual NSGCT masses >=1 cm at any involved site (lung, mediastinum); routine RPLND may be omitted only if the retroperitoneum was and remains uninvolved.
    • NSGCT cannot be reliably assessed with PET. Most residual masses are simply necrotic tissue; a substantial subset are teratoma; ~10 to 15% are viable GCT.
    • For visible RP LN but no residual mass ≥1 cm: RPLND (avoids CT A/P surveillance) vs surveillance (avoids surgery, requires long-term CT A/P imaging).

Relapse Treatment

  • Approximately 2% to 3% of pts relapse after a DFS of 2 to 3 years.
  • Consider: isolated elevated tumor markers, second primary, pseudo-nodules on CXR/CT, growing teratoma syndrome.
  • Treatment options: VeIP x4 (~30% cure in NSGCT, ~50% in seminoma); TIP x4; high-dose chemo + autologous SCT; salvage surgery.
  • Early relapse (<2 years): aggressive systemic therapy (eg, paclitaxel/ifosfamide/cisplatin, response rate ~60%, 2 yr PFS 36% to 65%) +/- surgery. High-dose chemo with autologous stem cell rescue is an alternative (long-term DFS ~40% to 70%).
  • Late relapse (>2 years): uncommon; tumors tend to be slow-growing and more chemoresistant; systemic therapy plus surgery.

2024 to 2025 Updates

  • TIGER trial (Alliance A031102; NCT02375204): phase 3 in relapsed/refractory GCT after 1L platinum, conventional-dose TIP x4 vs high-dose chemo (TI-CE with tandem ASCT); primary endpoint OS. Accrual complete, results pending; conventional-dose TIP and HDCT with ASCT both remain acceptable first salvage options.
  • IGCCCG 2021 update: Gillessen (NSGCT) and Beyer (seminoma) JCO 2021 refined first-line prognostic groups (eg, LDH >2.5× ULN adverse in good-risk seminoma); full-dose, on-schedule BEP/EP remains standard and reduced-intensity BEP is not recommended.
  • Post-chemo residual mass surgery (RPLND) remains a cornerstone in NSGCT with residual mass ≥ 1 cm on CT with normalized markers (rising AFP/hCG indicates active disease and prompts salvage chemo, not RPLND). Robotic/laparoscopic RPLND is increasing at high-volume centers with equivalent oncologic outcomes.
Veli Bakalov MD, Board Review Notes 2026