Testicular Cancer

Overview & Pathology

Background & Epidemiology

Testicular tumours divide into germ cell tumours (GCTs) and non-GCTs:

• 95% are GCTs; 5% are non-germ cell (sex-cord stromal tumours, adenocarcinoma of the rete testis, lymphoma).
• 95% of GCTs originate in the testicle; 5% are primary extra-gonadal GCTs.

GCT is relatively rare overall but is the most common malignancy in males aged 20–39, accounting for 1–2% of male cancers in the US. Estimated incidence: ~74,458 worldwide and ~9,470 in the US (2020–2021). Mortality is low — ~9,334 worldwide and ~440 in the US — with a 5-year relative survival of 94.9% (vs prostate 97.5%, bladder 77.1%, kidney 75.6%).

Risk Factors

Inherited:

• Family history of GCT — brother 8–12×, father 2–4×.
• Germ cell neoplasia in situ (GCNIS) — formerly intratubular germ cell neoplasia (ITGCN), unclassified. It develops before birth from an arrested gonocyte, and all adult invasive GCTs arise from GCNIS except spermatocytic seminoma. Risk of invasive GCT is ≈50% at 5 years.
• Race — Caucasian risk > African-American.
• CHEK2 mutation — 4×.

Acquired:

• Cryptorchidism — ipsilateral relative risk 4–6× (falls to 2–3× if orchidopexy is performed before puberty); contralateral testis slightly increased (RR ~1.74×). Management of an undescended testis by age: 19–50 → orchiectomy; >50 → no surgery.
• Personal history of GCT — 12×.
• HIV.
• Klinefelter syndrome — especially mediastinal NSGCT.
• Infertility — 2×.

Not risk factors: testicular microlithiasis, testicular atrophy, trauma.

Genetics — an increased copy number of the short arm of chromosome 12 (i(12p)) is a universal finding in testicular and extra-gonadal GCTs.

Classification

• Pathological: GCNIS-derived vs non-GCNIS-derived.
• Clinical: seminoma vs non-seminoma GCT (NSGCT) — based on differences in management and outcome. Any tumour containing both seminoma and NSGCT elements is classified as NSGCT.

Histologic Subtypes

Seminoma — the most common GCT (52–56% of GCTs; NSGCT 44–48%). Occurs at an older average age (4th–5th decade), arises from GCNIS, and is the common precursor for the NSGCT subtypes. Histology shows clear cytoplasm ("fried egg").

Non-seminoma subtypes:

Subtype	Key features	Markers
Embryonal carcinoma (EC)	Most undifferentiated NSGCT, totipotent (can differentiate into other NSGCT types including teratoma); aggressive with a high metastatic rate, often despite normal markers	Usually normal
Choriocarcinoma	Rare, aggressive, spreads hematogenously; contains syncytiotrophoblasts	Markedly elevated hCG
Yolk sac tumour	Schiller-Duval bodies; occurs in infants; chemo-sensitive	Almost always elevated AFP; no hCG
Teratoma	Histologically benign; contains well- or incompletely-differentiated elements of ≥2 of 3 germ layers (endoderm, mesoderm, ectoderm); chemoresistant; no clinical distinction between mature and immature; rare somatic malignant transformation (rhabdomyosarcoma, adenocarcinoma, PNET)	Normal; may mildly elevate AFP

Spermatocytic seminoma — accounts for <1% of GCTs. It has a distinct pathogenesis and cell of origin: it does not arise from GCNIS, is not associated with cryptorchidism or bilaterality, does not demonstrate i(12p), and does not occur within mixed GCTs. It is benign and almost always cured with orchiectomy.

Natural History & Metastatic Spread

GCTs are rapidly growing. 70–80% of metastases spread lymphatically from the primary to the retroperitoneal lymph nodes (the most common site) and then to distant sites — the exception is choriocarcinoma, which favours hematogenous dissemination.

• Lymph nodes: retroperitoneal (most common) → supraclavicular, mediastinal; inguinal nodes only with prior scrotal violation.
• Visceral: lung is the second most common metastatic site overall and the most common visceral site. Pulmonary metastases reflect hematogenous spread, whereas mediastinal/cervical disease reflects lymphatic spread. Thoracic disease without retroperitoneal involvement or marker elevation is uncommon. Liver is also involved in advanced disease.

At diagnosis, metastasis (regional or distant) is present in 33% of NSGCT and 15% of pure seminoma.

Diagnosis & Tumour Markers

The mandatory workup for a scrotal mass suspicious for testicular neoplasm is: history and physical exam; serum tumour markers (AFP, hCG, LDH); and imaging — scrotal ultrasound with Doppler (primary), CT abdomen/pelvis (regional), and CT chest (distant; CXR may substitute for CS I seminoma).

Presentation & Physical Exam

• Most common presentation: a painless scrotal mass. Metastatic symptoms (e.g. dyspnea) are the presenting complaint in 10–20%.
• A firm intratesticular mass is malignant until proven otherwise and warrants scrotal ultrasound.
• Differential for a scrotal mass — painless: testicular neoplasm, paratesticular neoplasm (benign or malignant), hernia, varicocele, spermatocele; painful: torsion, hematoma, epididymo-orchitis. If orchitis is suspected, re-evaluate 2–4 weeks after antibiotics before assuming malignancy.
• Examine for metastatic sites — supraclavicular nodes, and inguinal nodes if prior inguinal/scrotal surgery.
• Gynecomastia occurs in 2% of males with GCT, from elevated hCG, decreased androgen production, and/or increased estrogen.

Tumour Markers

Mnemonic for which tumours secrete which marker — A·YET (AFP: Yolk sac, EC, Teratoma) and B·SEC (β-hCG: Seminoma, EC, Choriocarcinoma).

AFP

• Elevated in 50–70% of low-stage (CS I, IIA, IIB) and 60–80% of advanced (CS IIC, III) NSGCT.
• Produced by yolk sac, EC, and teratoma — not by choriocarcinoma or seminoma. A pure seminoma with elevated serum AFP must be treated as NSGCT.
• Upper limit <11 ng/mL. Although many labs flag AFP >8 ng/mL, some people reach 15–25 ng/mL without pathology — treating on a stable AFP <25 ng/mL alone is discouraged.
• Half-life 5–7 days. Other causes: non-malignant liver disease (infectious, drug/alcohol-induced, autoimmune), HCC, cancers of the stomach/pancreas/biliary tract/lung, ataxic telangiectasia, hereditary tyrosinemia, and hereditary persistence of AFP.

β-hCG

• Elevated in 20–40% of low-stage and 40–60% of advanced NSGCT.
• Produced by seminoma (~15% of cases), EC, and choriocarcinoma. Upper limit <5 mU/mL; levels >10,000 IU/L are usually choriocarcinoma.
• Half-life 24–36 hours (peds literature cites 24–48 h). Other causes: hypogonadism (elevated LH cross-reacts with the hCG assay — supplemental testosterone lowers LH and allows accurate hCG measurement); cancers of the liver, biliary tract, pancreas, stomach, lung, breast, kidney, and bladder; and cannabis use. (Assays target the β subunit because the α subunit is shared with pituitary tumours.)

LDH

• Elevated in ~20% of low-stage and 20–60% of advanced GCT. The least specific and least clinically useful marker; main role is the prognostic S-stage classification.
• Half-life ~1 day. Treating on LDH elevation alone with normal AFP/hCG is discouraged. Normal 48–115 IU/L; magnitude correlates with disease bulk. Also elevated by cancers (kidney, lymphoma, GI, breast) and non-cancer conditions (heart failure, anemia, HIV).

Interpreting Markers Around Orchiectomy

• Pre-orchiectomy markers support the diagnosis but must not decide whether to operate (normal AFP/hCG do not exclude GCT) and must not be used for clinical staging/risk stratification (risks over- or under-treatment).
• Post-orchiectomy markers should normalize after 4 half-lives (AFP typically normal 20–28 days after effective therapy). Track whether persistently elevated markers are declining by their half-lives or rising — this drives treatment. For borderline elevations (within 3× ULN), confirm a rising trend before acting (false positives occur). Also used to detect recurrence during surveillance and after therapy.

Imaging

Scrotal Ultrasound

• Scrotal US with Doppler; evaluate both testes (2% bilateral GCT — metachronous is the most common pattern). High-frequency transducers (5–10 MHz) distinguish intratesticular lesions of a few millimetres from extra-testicular pathology. Typical GCT is hypoechoic.
• Indications: a scrotal mass; suspected metastatic GCT with a normal testis exam (a small impalpable scar/calcification suggests a "burned-out" primary — a discrete nodule, stellate scar, or coarse calcification warrants orchiectomy, as GCNIS and residual teratoma are common); and suspected primary extra-gonadal GCT (advanced GCT with normal testes on exam and US). With normal markers and indeterminate findings, repeat imaging in 6–8 weeks.
• Testicular microlithiasis has unclear significance — with no GCT history, risk rises only if another established risk factor is present; with a GCT history, contralateral microlithiasis is associated with increased ITGCN risk. No further evaluation if incidental; if a risk factor coexists, counsel on self-examination and follow-up.
• MRI is an adjunct for lesions suspected to be benign but must not delay orchiectomy when malignancy is suspected.

Regional Staging (CT Abdomen/Pelvis)

• CT abdomen/pelvis with oral and IV contrast is the most effective modality for regional staging (MRI is an alternative). Regional nodes: inter-aortocaval, para-aortic, para-caval, pre-aortic, pre-caval, retro-aortic, retro-caval.
• Lymphatic drainage runs right → left: right-testis tumours drain first to the inter-aortocaval nodes (below the renal vessels), then paracaval/para-aortic; left-testis tumours drain first to the para-aortic nodes, then inter-aortocaval.
• Nodes 5–9 mm in the primary landing zone are suspicious, especially if anterior to the great vessels.
• Accuracy limits: understaging — 25–35% of CS I NSGCT with a "normal" CT have positive nodes at RPLND; overstaging — 12–40% of CS IIA/IIB have negative nodes at RPLND.

Chest & Other Imaging

• Chest imaging completes staging but must not delay orchiectomy. CXR is preferred for suspected CS I seminoma (with normal markers, thoracic skip metastasis is ~0%). CT chest is indicated for NSGCT (skip metastases more common), elevated/rising post-orchiectomy markers, or any metastasis on abdominal/pelvic imaging, CXR, or exam.
• Bone scan and CT brain have no routine role; obtain for CNS/bone symptoms or poor-prognosis disease. Specific triggers for brain imaging: neurologic symptoms, β-hCG >5,000, AFP >10,000, extensive lung metastases, or non-pulmonary visceral metastases (highly elevated hCG is associated with choriocarcinoma and brain metastases).
• FDG-PET has no role in routine staging of NSGCT or seminoma at diagnosis.

Scrotal Violation

Percutaneous testicular biopsy is contraindicated. Scrotal violation (trans-scrotal orchiectomy, open biopsy, FNA) increases the risk of pelvic/inguinal nodal metastasis (altered lymphatic drainage) and local recurrence. A systematic review (Capelouto, 1995) found local recurrence in 2.5% after scrotal violation vs 0% after radical inguinal orchiectomy, with viable GCT in 9% of excised scrotal scars, though no difference in metastatic disease or all-cause mortality.

Staging

Clinical stage (and therefore prognosis and initial management) is determined by the pT stage, regional N and distant M disease, and post-orchiectomy serum markers (S). Repeat AFP/hCG/LDH at appropriate half-life intervals after orchiectomy to establish the nadir for staging — monitoring to nadir before treatment is warranted only when the nadir would change management.

TNM (AJCC 8th edition)

T — Primary Tumour (pathologic)

Category	Definition
pTis	Germ cell neoplasia in situ (GCNIS)
pT1	Limited to testis (including rete testis) without LVI. Pure seminoma: pT1a <3 cm, pT1b ≥3 cm
pT2	Limited to testis with LVI, or invading hilar soft tissue, epididymis, or tunica vaginalis
pT3	Direct (continuous) spermatic cord soft-tissue invasion (LVI of the cord without soft-tissue invasion is not pT3)
pT4	Direct scrotal invasion

N — Regional Lymph Nodes

Stage	Clinical (cN)	Pathologic (pN)
N1	Node mass ≤2 cm, or multiple nodes each ≤2 cm	Node mass ≤2 cm and ≤5 positive nodes, none >2 cm
N2	Node mass >2 cm but ≤5 cm, or any node >2 cm but ≤5 cm	Node mass >2 cm but ≤5 cm, or >5 positive nodes (none >5 cm), or extranodal extension
N3	Node mass >5 cm	Node mass >5 cm

M — Distant Metastasis

• M1a: non-regional nodal (iliac, inguinal, pelvic) or lung metastasis.
• M1b: non-lung visceral metastasis.

S — Serum Markers (post-orchiectomy nadir)

Stage	LDH	hCG (mIU/mL)	AFP (ng/mL)
S1	<1.5× ULN and	<5,000 and	<1,000
S2	1.5–10× ULN or	5,000–50,000 or	1,000–10,000
S3	>10× ULN or	>50,000 or	>10,000

(S1 requires all three criteria; S2/S3 take the highest abnormal marker.)

Clinical Stage Groupings

Stage	pT	N	M	S
0	pTis	N0	M0	S0
IA	pT1	N0	M0	S0
IB	pT2–pT4	N0	M0	S0
IS	Any	N0	M0	S1–3
IIA	Any	N1	M0	S0–1
IIB	Any	N2	M0	S0–1
IIC	Any	N3	M0	S0–1
IIIA	Any	Any	M1a	S0–1
IIIB	Any	N1–N3 or M1a	M0/M1a	S2
IIIC	Any	N1–N3 or any	M0/M1a	S3; or any N, M1b, any S

In brief: CS I is confined to the testis; CS II has regional (retroperitoneal) nodal metastasis; CS III has non-regional nodal and/or visceral metastasis — and post-orchiectomy marker elevation (S2–S3) can upstage a patient from CS II to CS III.

Management: Principles, GCNIS & Modalities

General Principles

• Any post-pubertal male, regardless of age, is treated by adult guidelines.
• Manage in a multidisciplinary setting (urology, medical oncology, radiation oncology, pathology, radiology). Expert pathology review is recommended and changes the subtype in 1–4% of cases.
• Base decisions on imaging within the preceding 4 weeks and serum markers (hCG, AFP) within 10 days. Because GCTs (especially NSGCT) grow rapidly, risk-adapted decisions (e.g. RPLND for stage IIA) must use recent studies to avoid undertreatment.
• With normal markers and equivocal imaging, repeat imaging in 6–8 weeks before recommending treatment.

Pre-treatment Counselling

Before definitive treatment, counsel on three risks:

• Hypogonadism — over long-term follow-up, 10–15% develop low serum testosterone or require replacement. (In long-term survivors, testosterone is similar to controls but age-adjusted LH is higher — Nord, 2003.)
• Infertility — at diagnosis up to 50% have impaired semen parameters and 10% are azoospermic. Offer sperm cryopreservation: pre-orchiectomy if there is no normal contralateral testis or known subfertility; post-orchiectomy before any further (non-orchiectomy) treatment in those undecided or planning paternity. Nearly all men become azoospermic after chemotherapy, and 50–80% recover baseline parameters within 2 and 5 years respectively; recovery after seminoma radiotherapy may take 2–3 years or longer.
• Contralateral tumour — the risk of a second primary in the contralateral testis, though rare, is significantly increased.

Orchiectomy & Testis-Sparing Surgery

Radical inguinal orchiectomy is the standard — remove the testicle and spermatic cord to the internal inguinal ring; discuss a testicular prosthesis beforehand. (See the radical orchiectomy procedure page for operative detail.)

• Trans-scrotal orchiectomy is contraindicated (scrotal violation). If it has been performed for malignancy, counsel on the increased local-recurrence risk; adjunctive scar excision or radiotherapy is rarely needed, and after systemic therapy local relapse is rare and no adjuvant is required.
• In the rare case of a possibly benign tumour, perform excisional biopsy with frozen section before definitive orchiectomy to permit organ-sparing partial orchiectomy.
• Timing: orchiectomy precedes other treatment — except with life-threatening metastatic disease and unequivocally elevated AFP/hCG, where chemotherapy starts first and orchiectomy is deferred.

Testis-sparing surgery (TSS) is not recommended for a suspicious lesion with a normal contralateral testis (do radical orchiectomy). Indications: a patient wishing to preserve gonadal function with a mass <2 cm and one of — equivocal US/exam with negative markers; a congenital, acquired, or functionally solitary testis; or bilateral synchronous tumours. Counsel on higher local recurrence, the need for exam/US monitoring, the role and gonadal toxicity of adjuvant testicular radiotherapy, and risks of atrophy/TRT/subfertility. Take multiple biopsies of normal ipsilateral parenchyma to exclude GCNIS — 50–80% of TSS patients have concomitant GCNIS.

GCNIS Management

Treatment is justified by the high risk of progression to invasive GCT (≈50% at 5 years). GCNIS is diagnosed on biopsy (infertility workup, contralateral biopsy in a GCT patient, or within the affected testis during TSS).

Options: orchiectomy; low-dose radiotherapy (18–20 Gy); or close observation.

• If the patient prioritizes fertility/androgen production → surveillance (periodic US, deferring therapy until pregnancy is achieved and/or GCT develops; reasonable when semen is adequate for ART).
• If the patient prioritizes cancer-risk reduction → testicular radiotherapy (18–20 Gy) or orchiectomy.
• Radiation spares endocrine function more than orchiectomy (Leydig cells are radioresistant relative to germinal epithelium), but Leydig function declines over time and 40% later need supplemental testosterone; it causes permanent sterility of the treated testis (can be delayed for men wanting children). For a normal contralateral testis with a desire for paternity, radical orchiectomy is preferred because radiation scatter can impair contralateral spermatogenesis.
• If GCNIS is not found on biopsy, it is likely present in unsampled tissue — follow with self-exam, US, and markers; any ipsilateral local recurrence warrants completion radical orchiectomy. An open inguinal contralateral biopsy may be considered with risk factors or suspicious US.

Delayed orchiectomy: in widespread/symptomatic disease diagnosed by metastatic biopsy or empirically, systemic chemotherapy supersedes diagnostic orchiectomy; because of discordant intratesticular response, delayed orchiectomy is recommended for all NSGCT after induction chemotherapy — even with a complete retroperitoneal response. Its role is more controversial in presumed extra-gonadal GCT (favoured when retroperitoneal disease lateralizes to the expected testicular drainage).

Post-orchiectomy Principles

Subsequent management depends on histology (seminoma vs NSGCT) and clinical stage. Newly elevated or rising markers after orchiectomy indicate metastatic disease → induction chemotherapy. With a negative metastatic workup and slowly declining markers (not by half-life), monitor closely and recheck until levels normalize or begin to rise.

Treatment Modalities

Surveillance (Clinical Stage I)

Orchiectomy alone cures 80–85% of CS I seminoma and 70–80% of CS I NSGCT, and relapses are salvaged with excellent outcomes — so surveillance minimizes treatment-related toxicity by restricting therapy to those with proven need. Trade-offs: the highest relapse rate (vs adjuvant therapy), the need for long-term (>5 years) surveillance, second-malignancy risk from intensive CT imaging, and more intensive therapy if relapse occurs.

Radiotherapy

Seminoma is radiosensitive. Radiotherapy has no role in NSGCT, except for brain metastases.

Chemotherapy & IGCCCG Risk Classification

The IGCCCG risk classification (good / intermediate / poor) — not TNM — selects the chemotherapy regimen and number of cycles in advanced disease. It was developed for metastatic-at-diagnosis patients and does not apply to relapsed disease. NSGCT is classified by non-pulmonary visceral metastasis, primary mediastinal site, and marker levels at the start of chemotherapy (not pre-orchiectomy). Seminoma is classified by non-pulmonary visceral metastasis only and has no poor-prognosis category.

Histology	Good	Intermediate	Poor
Non-seminoma	Testis/retroperitoneal primary, no non-pulmonary visceral mets, and good markers (AFP <1,000 ng/mL, hCG <5,000 IU/L, LDH <1.5× ULN)	Testis/retroperitoneal primary, no non-pulmonary visceral mets, and intermediate markers (AFP 1,000–10,000, or hCG 5,000–50,000 IU/L, or LDH 1.5–10× ULN)	Mediastinal primary, or non-pulmonary visceral mets, or poor markers (AFP >10,000 ng/mL, or hCG >50,000 IU/L, or LDH >10× ULN)
Seminoma	Any primary site, no non-pulmonary visceral mets, normal AFP (any hCG/LDH)	Any primary site, with non-pulmonary visceral mets, normal AFP (any hCG/LDH)	— (none)

During chemotherapy, monitor with serial markers; afterward, radiologically restage all patients. If markers decline as expected, treat any residual mass appropriately; if they plateau at a low level, follow closely. Markedly elevated pre-treatment hCG may take longer to normalize or plateau.

Seminoma Management

CS IA and IB

Three options, with surveillance preferred (recommended by both 2019 AUA and 2010 CUA, with adjuvant therapy as an alternative); long-term survival approaches 100% with each:

Option	Detail
Surveillance (preferred)	Orchiectomy alone cures 80–85% of CS I seminoma
Adjuvant radiotherapy	20 Gy to the para-aortic region
Adjuvant chemotherapy	Single-agent carboplatin × 1 cycle

If adjuvant therapy is chosen, CUA prefers radiotherapy over chemotherapy, EAU recommends against radiotherapy, and SWONTECA uses radiotherapy only when chemotherapy is unsuitable.

Surveillance

Protocols vary (no consensus): history/physical and cross-sectional abdominal (± pelvic) imaging every 4–6 months for years 1–2, then every 6–12 months in years 3–5; chest imaging and markers as clinically indicated. Surveillance is harder than in NSGCT because markers have limited utility for detecting seminoma relapse. Risk factors for relapse: tumour size >4 cm and rete testis invasion. Relapses are fully restaged and treated by TNM-S status.

Adjuvant Radiotherapy

Delivered as a dog-leg field (retroperitoneum + ipsilateral pelvis) or para-aortic field:

• Dog-leg — in-field recurrence <1% (most recurrences in thorax and left supraclavicular fossa, nearly all cured with first-line chemotherapy); persistent oligospermia in 8%. Advantage: no serial follow-up CT needed.
• Para-aortic — smaller field and dose, but requires serial follow-up CT. An RCT found it non-inferior to dog-leg in CS I seminoma.

Adjuvant Chemotherapy

Carboplatin is superior to cisplatin for CS I seminoma; serial follow-up CT is required.

CS IIA and IIB

About 15–20% of seminoma is CS II at diagnosis, and 70% of those are IIA/IIB.

• CS IIA — CUA: dog-leg radiotherapy (25–35 Gy) preferred over first-line chemotherapy (BEP×3 or EP×4); AUA: radiotherapy or chemotherapy.
• CS IIB — CUA: radiation or chemotherapy by bulk/location, with first-line chemotherapy (good-risk BEP×3 or EP×4) for bulky (>3 cm) and/or multifocal retroperitoneal disease; AUA: node ≤3 cm → radiotherapy or chemotherapy, node >3 cm → chemotherapy.
• Routine surveillance CT is unnecessary after complete resolution.
• RPLND is an emerging option: the SEMS phase II trial (Daneshmand, 2023) treated 55 men with isolated 1–3 cm retroperitoneal nodes by open RPLND, achieving 2-year relapse-free survival of 81% (86% cN1 vs 64% cN2) and 2-year overall survival of 100%.

CS IIC and III

Regimen and cycles follow the IGCCCG classification — good-risk: BEP×3 or EP×4; intermediate-risk: BEP×4.

Residual Masses & Relapse

After chemotherapy, 60–80% have a radiologic residual mass, but histology is overwhelmingly necrosis (90%) vs viable malignancy (10%) — far more favourable than NSGCT (necrosis 40%, viable 15%, teratoma 45%). Most need no treatment: spontaneous resolution occurs in 50–60% (median 13–18 months), and post-chemotherapy surgery is technically difficult (desmoplastic reaction, higher morbidity). Teratoma/malignant transformation is much less of a concern than in NSGCT.

• Residual >3 cm → FDG-PET: positive → post-chemotherapy surgery; negative → observation.
• Residual <3 cm → observation.
• Post-chemotherapy radiotherapy has no role.

After radiotherapy, biopsy and confirm histology before acting — seminoma rarely transforms into NSGCT elements (consider this when metastatic seminoma fails conventional therapy). Open or robotic/laparoscopic biopsy of a para-aortic mass is acceptable if CT-guided biopsy is unfeasible or non-diagnostic, and RPLND should not be performed without histologic confirmation of NSGCT.

Relapse:

• Chemo-naïve — relapse on surveillance → primary radiotherapy; patients previously treated with radiotherapy (or surveillance relapse with bulky >3 cm retroperitoneal masses and systemic relapse) → first-line chemotherapy by IGCCCG. Salvage rates approach 100%.
• Early relapse after chemotherapy → salvage chemotherapy. Consider teratoma at the relapse site in advanced seminoma; with normal markers, biopsy before starting second-line chemotherapy.

NSGCT Management

CS IA and IB

Three options, each with long-term survival approaching 100%:

• Surveillance.
• Primary RPLND.
• Primary chemotherapy (BEP×1–2) — 2019 AUA: 1 cycle for CS IA, 2 cycles for CS IB; 2010 CUA: BEP×2.

Guidelines: 2010 CUA prefers surveillance for all CS I NSGCT; 2019 AUA recommends surveillance for CS IA and all three options for CS IB. RPLND is recommended if the primary contains a secondary somatic malignancy (rhabdomyosarcoma, adenocarcinoma, or PNET).

Surveillance

Orchiectomy alone cures 70–80% of CS I NSGCT. Risk factors for relapse: predominant embryonal carcinoma (definition varies, 45–90%) and lymphovascular invasion; other factors include advanced pT stage, absence of mature teratoma, absence of yolk sac tumour, presence of EC at any percentage, MIB-1 index, tumour size, and patient age.

Protocols vary by institution: H&P and markers (AFP, hCG ± LDH) every 2–3 months (year 1), 2–4 months (year 2), 4–6 months (year 3), then 6–12 months (years 4–5); imaging (CXR + abdomen ± pelvis) every 3–6 months in year 1 (from 3 months), 4–12 months in year 2, then once in year 3 and once in year 4 or 5. Image higher-risk men (e.g. LVI) more frequently. >90% of relapses occur within the first 2 years, with late relapse (>5 years) in ~1% (seminoma, by contrast, relapses later — 10–20% of relapses occur ≥4 years out — and needs longer surveillance). Relapses are fully restaged and treated by TNM-S; early and late relapses have similar prognosis.

Primary RPLND

Performed with curative (not staging) intent in all patients. A full bilateral template dissection gives the lowest abdominopelvic recurrence (<2%) and the highest antegrade ejaculation rate (>90%) with nerve-sparing. A multicentre RCT found chemotherapy had a lower relapse rate than primary RPLND (RPLND relapse 11%, higher than other series), underscoring that RPLND should be done at experienced centres.

Primary Chemotherapy

BEP×1–2. Advantages: highest relapse-free survival of any single modality; deliverable at community centres. Disadvantages: does not treat retroperitoneal teratoma; requires long-term surveillance CT of the retroperitoneum; late-toxicity risk (no clearly safe lower limit even for 2 cycles); and chemoresistant/late-relapse potential. Relapses after primary chemotherapy are less salvageable (chemoresistant), whereas relapses after RPLND or on surveillance are chemo-naïve and cured by chemotherapy in virtually all cases.

CS IS

Elevated markers after orchiectomy without clinical/radiographic metastasis. Treat like CS IIC/III — induction chemotherapy by IGCCCG.

CS IIA and IIB

• CS IIA marker-positive, or CS IIB regardless of markers → primary chemotherapy (both CUA and AUA). CUA notes that elevated AFP/hCG or bulky nodes (>3 cm) are recurrence risks after RPLND, so these patients receive induction chemotherapy. AUA permits RPLND as an alternative for select CS IIB with normal post-orchiectomy AFP/hCG.
• CS IIA without marker elevation — a substantial proportion are over-staged; the minority upstaged to pathologic IIB may get 2 cycles of adjuvant chemotherapy. CUA: RPLND (± adjuvant chemotherapy) or surveillance with surgery for stable/growing lesions (primary chemotherapy if it becomes marker-positive). AUA: RPLND or chemotherapy.

Management after Primary RPLND (2021 NCCN / 2019 AUA)

Pathology	Management
pN0	Surveillance
pN1	Surveillance (preferred) vs chemotherapy (BEP×2 or EP×2)
pN2	Chemotherapy (BEP×2 or EP×2, preferred) vs surveillance
pN3	Chemotherapy (BEP×3 or EP×4)
pN1–3 pure teratoma	Surveillance

Immediate vs deferred chemotherapy after RPLND-proven stage II (Williams, 1987, NEJM): 2-year relapse was 6% with immediate vs 49% with deferred chemotherapy, but with no significant difference in cancer-specific or overall survival.

Growing Teratoma Syndrome

Teratoma is chemoresistant, so RPLND is preferred as initial therapy for patients at risk of retroperitoneal teratoma but low systemic risk (normal markers, lymphadenopathy <3 cm) — unresected teratoma can grow rapidly, transform into malignancy, or relapse late. Suspect growing teratoma syndrome when markers decline as expected during chemotherapy but masses (often cystic) enlarge radiologically. Management: complete the full chemotherapy course and resect the growing/residual masses afterward; rarely, rapid progression despite falling markers requires resection before chemotherapy is finished. Complete resection carries a favourable long-term prognosis.

CS IIC and III

Induction cisplatin-based chemotherapy by IGCCCG:

• Good-risk: BEP×3 or EP×4 (5-year OS 91–94%).
• Intermediate/poor-risk: BEP×4 (5-year OS 79% intermediate, 48% poor).
• VIP×4 may replace BEP×4 with compromised pulmonary function or when extensive chest surgery for residual disease is anticipated.

Post-chemotherapy Residual Masses (PC-RPLND)

After first-line chemotherapy, 5–15% have a partial response with positive markers or progression.

• Markers elevated after induction → salvage chemotherapy.
• Markers normal, residual >1 cm → resection (full bilateral template RPLND if retroperitoneal). Residual <1 cm → controversial.

PC-RPLND histology: necrosis/fibrosis ≈40%, teratoma ≈45%, viable malignancy ≈15% (6–8% harbour non-GCT malignancy from teratoma transformation). Necrosis cannot be predicted reliably enough to skip surgery, though pure EC in the primary is the best predictor of fibrosis-only. Long-term survival is ~90% with fibrosis/teratoma only vs 50–70% with viable GCT. Management by PC-RPLND pathology (2021 NCCN): teratoma or necrosis/fibrosis → surveillance; viable disease (EC, yolk sac, choriocarcinoma, seminoma) → 2 cycles of chemotherapy (EP, TIP, VIP, or VeIP).

FDG-PET has no role in assessing NSGCT residual masses. With residual disease at multiple sites (retroperitoneum, chest, left supraclavicular fossa most common) and normal markers, resect all measurable disease — RPLND first, because retroperitoneal disease is most probable and its histology predicts the other sites (if the retroperitoneum is clear, other sites are unlikely involved). If RPLND shows viable malignancy → chemotherapy; fibrosis → surveillance or resection; teratoma → resection.

Relapse & Scrotal Exploration

Relapse management depends on prior treatment and location:

• Chemo-naïve → first-line chemotherapy by IGCCCG (cure >95%). Select CS I surveillance patients relapsing in the retroperitoneum with non-bulky (<3 cm) disease and normal markers may receive induction chemotherapy or RPLND (especially if teratoma was in the primary).
• Relapse after chemotherapy → salvage chemotherapy; resect residual masses after a serologic complete response. Viable malignancy in post-salvage specimens carries a poor prognosis not improved by postoperative chemotherapy. Late relapse is chemoresistant — outcome depends on complete surgical resection.

Scrotal exploration revealing NSGCT requires further treatment: low-stage → wide excision of the scrotal scar and removal of the spermatic cord; high-stage → systemic therapy is given, so hemiscrotectomy is unnecessary.

Advanced Disease & Sequelae

Treatment-related Sequelae

Early toxicity:

• Chemotherapy — cisplatin: fatigue, myelosuppression, infection, peripheral neuropathy, hearing loss, diminished renal function, and death; etoposide: myelosuppression.
• Radiation — fatigue, nausea/vomiting, leukopenia, dyspepsia.

Late toxicity:

• Hypogonadism — occurs in 10–20% after orchiectomy alone, 15–40% after radiation, and 20–25% after first-line chemotherapy. Measure AM testosterone and LH if symptomatic.
• Infertility — most men can father children, but paternity rates are lower after radiation and/or chemotherapy.
• Cardiovascular disease and secondary malignancy — both increased by subdiaphragmatic radiation or platinum-based chemotherapy; ensure primary-care follow-up for modifiable risk factors and appropriate cancer screening.

Chemotherapy-specific:

• Bleomycin — pulmonary complications (including pulmonary fibrosis), Raynaud phenomenon, mild myelosuppression at high doses.
• Cisplatin — nephrotoxicity, neurotoxicity, peripheral neuropathy, hearing loss.

Brain Metastases

Associated with choriocarcinoma — suspect in any patient with a very high serum hCG. Choriocarcinomas are highly vascular and tend to hemorrhage during chemotherapy, with death rates of 4–10% from intracranial hemorrhage.

• At diagnosis: BEP×4, then resection of residual masses.
• Brain relapse after first-line chemotherapy: second-line chemotherapy, then resection and/or radiotherapy.
• Brain relapse after a complete response carries a worse prognosis than brain involvement present at diagnosis.

Primary Extra-gonadal GCT

95% of GCTs are gonadal and 5% extra-gonadal, arising in midline locations — in descending frequency: mediastinum, retroperitoneum, sacrococcygeal region, and pineal gland.

• Primary mediastinal NSGCT (vs testicular/retroperitoneal NSGCT) more often has yolk sac components with elevated AFP, is associated with Klinefelter syndrome, is less chemosensitive, and carries a poor prognosis.
• Primary mediastinal seminoma has a prognosis similar to testicular seminoma.
• Primary retroperitoneal GCT behaves like, and carries the same prognosis as, testicular GCT.

Of patients with metastatic GCT and no testis mass, one-third each have: a true extra-gonadal primary, ITGCN in the testis, or sonographic evidence of a "burned-out" primary.

Diagnosis: consider GCT for any midline mass in a male <40. With elevated AFP and/or hCG, the diagnosis is established even if the testis is normal — no biopsy is needed before treatment; with normal markers, biopsy the midline mass to confirm first.

Inguinal orchiectomy is indicated in suspected extra-gonadal GCT when the metastatic pattern matches a right- or left-sided testicular primary, or there is a sonographic burned-out primary.

Small Impalpable Testicular Lesions

Small (<10 mm), impalpable intratesticular lesions without disseminated GCT or elevated markers are a diagnostic dilemma — most are benign (testicular cysts, small infarcts, small Leydig or Sertoli cell tumours), but 20–50% are small GCTs (usually seminoma), with malignancy risk rising with lesion size. Three options:

• Inguinal orchiectomy.
• Testis-sparing surgery — inguinal exploration and excision with frozen section to exclude GCT (intraoperative ultrasonography helps localize the lesion).
• Close observation with serial ultrasound, exploring any growing lesion.

Non-Germ Cell & Adnexal Tumours

Non-germ cell tumours comprise 5% of testicular tumours.

Sex-Cord Stromal Tumours

These contain Leydig, Sertoli, granulosa, or thecal cells. About 90% are benign and 10% malignant — the only reliable criterion for malignancy is metastatic disease (most often to the retroperitoneum and lung).

Leydig Cell Tumours

• Account for 75–80% of sex-cord stromal tumours; most occur in men aged 30–60, with no association with cryptorchidism.
• ~10% are bilateral (more often than GCT) and may cause gynecomastia (as with GCT).
• Radical inguinal orchiectomy is the initial treatment of choice. If suspected preoperatively, the 90% benign rate makes testis-sparing surgery reasonable for lesions <3 cm with intraoperative frozen section; perform completion orchiectomy if GCT histology (frozen or final) or malignant features appear.
• Persistent Leydig dysfunction/hypogonadism may follow excision — 40% require testosterone supplementation.

Sertoli, Granulosa & Gonadoblastoma

• Sertoli cell tumours — produce estrogen and are associated with Peutz–Jeghers syndrome. Like Leydig, TSS is reasonable for tumours <3 cm given ~90% benign histology.
• Granulosa cell tumours — exceedingly rare.
• Gonadoblastoma — occurs almost exclusively with gonadal dysgenesis and intersex syndromes; bilateral orchiectomy is required because of a 40% risk of bilateral tumours.

Miscellaneous Testicular Neoplasms

• Dermoid and epidermoid cysts — "onion-peel" appearance on ultrasound. Enucleation or partial orchiectomy is acceptable, but sample thoroughly to exclude GCT or ITGCN.
• Adenocarcinoma of the rete testis — rare but highly malignant, arising from the testicular collecting system; >50% present with metastasis and median overall survival is ~1 year.

Secondary Tumours

• Lymphoma — usually involves the testis by dissemination from extra-testicular sites; 85% occur in men >60, and non-Hodgkin lymphoma is the most common testicular neoplasm in men >50. Bilateral involvement in 35%. Treat with radical inguinal orchiectomy and refer to hematology-oncology.
• Leukemic infiltration — the testis is a frequent relapse site in boys with acute lymphocytic leukemia. Diagnosis is by biopsy (orchiectomy unnecessary); achieve local control with low-dose radiotherapy that includes the contralateral testis given the frequent bilateral risk.
• Metastases — most common primaries are prostate, lung, melanoma, colon, and kidney.

Tumours of the Testicular Adnexa

• Adenomatoid tumour — the most common paratesticular tumour, usually in the epididymis; asymptomatic and benign (no reported metastasis). Management: surgical excision.
• Cystadenoma — ~1/3 occur in von Hippel-Lindau disease and are usually bilateral.
• Paratesticular mesothelioma — arises from the tunica vaginalis.
• Sarcomas (spermatic cord, epididymis, testis) — the most common genitourinary sarcomas in adults; liposarcoma is the most common subtype in adults, and embryonal rhabdomyosarcoma is most common in men <30. Manage with wide resection via an inguinal approach (excise the testis and spermatic cord with high ligation), adding therapy by subtype and metastatic status. Liposarcomas rarely metastasize but recur locally — consider adjuvant radiotherapy (especially with positive margins or large tumours). With a normal metastatic workup, non-liposarcoma sarcomas (rhabdomyosarcoma, malignant fibrous histiocytoma, angiosarcoma) and mesothelioma warrant RPLND, with postoperative chemotherapy if retroperitoneal nodes are involved.

Operative Procedures

The two principal operations in testicular cancer have dedicated step-by-step references:

• Radical Orchiectomy — radical inguinal removal of the testicle and spermatic cord to the internal ring, plus testis-sparing partial orchiectomy for selected small lesions.
• Retroperitoneal Lymph Node Dissection (RPLND) — primary and post-chemotherapy nodal dissection, including templates, nerve-sparing, and minimally invasive approaches.