Testicular Cancer

Risk Factors

• White race
• HIV
• Family history — brother 8–12× | father 2–4×
• GCNIS/IGCN — ~50% develop GCT within 5 years
• Personal history of testicular cancer: 12×
• CHEK2 mutation: 4×
• Infertility: 2×
• Undescended testis (UDT) — 4–6× | reduced to 2–3× if orchiopexy pre-puberty
• Marijuana use — 3.5-fold more common among GCT patients than controls
• Pesticide exposure — higher levels found in men with testis cancer, and in their mothers
• SNP in KITLG — homozygosity for the dominant allele is associated with up to a 4.5-fold increase in the risk of GCT
• Disorders of sex development — variable risk, depending on the specific disorder
  • Complete androgen insensitivity (CAIS) — 46 XY, no functional androgen receptor; testes left in situ carry ~20% malignancy risk by age 30 → most likely tumor = seminoma
  • CAIS → gonadectomy recommended, typically after puberty
  • Gonadoblastoma is linked to partial or gonadal dysgenesis (46 XY or 46 XY/XO) — not to CAIS
• A history of extragonadal GCT also increases the risk of a metachronous testicular GCT

Not risk factors: microlithiasis, testicular atrophy, trauma

• Incidental testicular microlithiasis → reassurance only — no further tests or screening
  • Raises GCT risk only with another established risk factor → counseling, self-examination and clinician follow-up
• Microlithiasis vs burned-out primary — microlithiasis = many tiny scattered bright spots, no focal lesion; burned-out primary = discrete nodule, stellate scar or coarse calcification → radical orchiectomy (GCNIS and residual teratoma are often found)

Klinefelter syndrome is a risk factor for mediastinal primary NSGCT — not for testicular GCT.

Most common genetic abnormality: extra copy of short arm chromosome 12 (i12p)

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Tumor Classification

A. Germ Cell Tumors (~95%)

All adult GCT subtypes arise from GCNIS EXCEPT the spermatocytic tumor — embryonal carcinoma, choriocarcinoma, classic seminoma and teratoma all do.

1. Seminoma (52–56%)

• Age 20–30 (actually 4th–5th decade — older than NSGCT)
• 15% have ↑ β-hCG
  • Usually mild — <1,000 IU/L; seminoma does not raise AFP
• Chemo- and radiosensitive
• Histology: clear cytoplasm ("fried egg")
• Arises from GCNIS

2. NSGCT (44–48%)

→ Pure seminoma + ↑ AFP → treat as NSGCT

Comparison of germ cell tumors

• Syncytiotrophoblastic cells are present in choriocarcinoma, seminoma AND embryonal carcinoma — not choriocarcinoma alone

Choriocarcinoma

• Rare — pure < 1%, 10% as a mixed component
• Hematogenous spread — lung, liver and brain
• Prone to hemorrhage — spontaneously or after chemotherapy
  • Can be catastrophic — within days of starting chemotherapy, especially in lung or brain deposits
• hCG excess → hyperthyroidism and ↑ androgen output — the shared α-subunit stimulates TSH and LH receptors

Teratoma

• The pure form produces neither AFP nor β-hCG; pure teratoma is rare in adults
• Chemoresistant AND radioresistant
• Benign but unpredictable behavior — local growth and malignant transformation

Embryonal carcinoma

• Poorly differentiated, with the ability to differentiate into other NSGCT subtypes
• Aggressive, with a high rate of metastasis
• Syncytiotrophoblastic cells are scattered throughout the tumor
• ↑ AFP + ↑ hCG together → embryonal carcinoma — the only pure histology making both (yolk sac → AFP only; choriocarcinoma and 15% of seminomas → hCG only)

Yolk sac

• Schiller-Duval bodies are the classic pathognomonic finding
  • A central blood vessel ringed by tumor cells, resembling the endodermal sinus
• Cytoplasmic and extracellular eosinophilic hyaline globules are present in up to 84% of cases
• The most common testicular tumor in infants and children
  • Specifically the most common malignant one in infants and toddlers; 90% of prepubertal cases are stage I → radical orchiectomy alone (no RPLND, no chemotherapy)
• Markers (exam answer): almost always ↑ AFP, but not hCG (the comparison table above lists both as "Maybe")

Teratocarcinoma — a mixed tumor producing both AFP and β-hCG

3. GCNIS

• Formerly intratubular germ cell neoplasia unclassified
• Develops before birth from an arrested gonocyte → stays dormant until after puberty, when malignant progression occurs
• High risk of progression to invasive GCT
• Management options (3): orchiectomy | low-dose RT (18–20 Gy) | surveillance
• → Preserve fertility → surveillance
• → ↓ cancer risk → orchiectomy or testicular RT
  • RT advantage: Leydig cells radioresistant (less hypogonadism — 40% need TRT)
  • RT disadvantage: scatter to contralateral testis impairs spermatogenesis
  • Normal contralateral testis + future paternity desired → radical inguinal orchiectomy preferred over low-dose RT (avoids that scatter)
  • Paternity not desired → low-dose RT (20 Gy) preferred — controls GCNIS about as well as orchiectomy and may preserve endocrine function

B. Sex Cord–Stromal Tumors (~90% benign)

• Leydig cell — testosterone, gynecomastia; 10% bilateral; 40% need TRT post-op
  • Most common stromal tumor in both children and adults; pathognomonic Reinke crystals in ~40%
  • Boy with precocious puberty + solitary testicular lesion → Leydig cell tumor — benign before puberty → partial orchiectomy
• Sertoli cell — testosterone, estrogen; assoc. Peutz–Jeghers
• Gonadoblastoma — gonadal dysgenesis/intersex; bilateral orchiectomy (40% bilateral)

C. Non-Germ Cell

• Spermatocytic tumor — elderly; benign; no GCNIS, no i(12p), no cryptorchidism link
  • Formerly spermatocytic seminoma; <1% of GCTs; peak in the sixth decade
  • Unrelated to bilaterality; OCT3/4, PLAP and PAS negative
  • Pure form: only three documented metastases → orchiectomy alone is curative, no adjuvant therapy — provided no sarcomatous or anaplastic elements
• Testicular adrenal rest tumors (CAH) — ACTH-responsive adrenocortical tissue carried along the path of gonadal descent
  • Boy with precocious puberty + bilateral hypoechoic lesions near the mediastinum testis → congenital adrenal hyperplasia with adrenal rests
  • Reflect steroid undertreatment (high ACTH) → mostly respond to a higher steroid dose
  • CAH + bilateral lesions + normal tumor markers → observation with optimized glucocorticoid therapy — no surgery or biopsy
  • Bilaterality argues against GCT (GCT is bilateral in only 1–2%)

D. Secondary

• Lymphoma (most common testis tumor in men >50; 35% bilateral)
  • Non-Hodgkin lymphoma; 85% of cases occur in men >60
• Leukemia — usually appears in the testis after the patient is in remission; diagnosed by biopsy. Orchiectomy should NOT be done. Local control is radiotherapy 20 Gy, and the contralateral testis is included in the radiation field
• Mets: prostate, lung, melanoma, colon, kidney
  • Prostate = the most common primary source; deposits occur in older men, are often bilateral, and do not raise AFP or hCG

E. Paratesticular Tumors

• Adenomatoid tumor — of mesothelial origin; the most common paratesticular tumor
• Mesothelioma — arises from the tunica vaginalis; treated by orchiectomy and hemiscrotectomy

Sarcoma

• Usually arises from the cord. Do an MRI ± inguinal biopsy before wide-margin orchiectomy with high ligation of the cord. Some advocate local radiotherapy
• Systemic chemotherapy for retroperitoneal or distant metastases

When the metastatic workup is negative:

• Liposarcoma of the cord → radiotherapy

  • Removed unplanned at hernia repair → completion radical inguinal orchiectomy with high cord ligation + adjuvant radiotherapy — even with negative margins

• Other sarcomas (rhabdomyosarcoma, malignant fibrous histiocytoma, angiosarcoma) and mesothelioma → RPLND, with post-operative chemotherapy if the retroperitoneal nodes are involved

  • Paratesticular rhabdomyosarcoma — boys aged ≥10, or any age with enlarged nodes → nerve-sparing ipsilateral staging RPLND before chemotherapy (CT often misses retroperitoneal disease)
    • Staging RPLND: sample at least 7–13 nodes, dissecting up to the renal vessels → nodal findings set chemotherapy intensity

• In sarcoma the primary pattern of failure is LOCAL, particularly for liposarcoma — some advocate post-operative radiotherapy for all paratesticular sarcomas

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Special Notes

• 5% of GCTs are extragonadal (midline)
  • Retroperitoneum
  • Mediastinum — Klinefelter syndrome is a risk factor for mediastinal primary NSGCT, not for testicular GCT; poor prognosis, chemo-resistant
• Midline mass / metastatic GCT with a normal testicular exam
  • Scrotal ultrasound first — only ~1/3 of young men with a midline retroperitoneal mass truly have extragonadal GCT; most others have a burned-out primary or GCNIS
  • US nodule, stellate scar or coarse calcification → radical orchiectomy (GCNIS and residual teratoma often found)
  • Normal testes on both exam and US (advanced NSGCT) → primary extragonadal GCT → cisplatin-based induction chemo, cycles by IGCCCG group — systemic chemo supersedes diagnostic orchiectomy
  • Man <40 + midline retroperitoneal mass + raised AFP and/or hCG → diagnostic of GCT without biopsy → life-threatening bulky disease needs immediate systemic chemo
  • Life-threatening metastatic disease → orchiectomy of the likely primary (e.g. an impalpable UDT) is deferred, but still done after chemo — the testis is a sanctuary site (poor drug penetration)
• UDT patients: age 19–50 → orchiectomy | >50 → no surgery
  • Exam answer: healthy men (ASA I–II) aged 12–50 may have orchiectomy; also observe anyone at significant anesthetic risk — from age 50, operative mortality exceeds germ cell cancer mortality
  • Postpubertal UDT: no biopsy (a negative result can't exclude cancer elsewhere in the testis) | hCG therapy not recommended (no rigorous efficacy data)
• Orchitis → re-evaluate 2–4 weeks after antibiotics

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Metastatic Spread

• Lymphatic (70–80%)
  • Right testis → interaortocaval nodes
    • First landing zone below the renal vessels → then paracaval → then para-aortic
  • Left testis → para-aortic nodes
  • Crossover runs right → left — right-sided tumors may involve left-sided nodes; left → right is distinctly uncommon → shapes modified RPLND templates
  • Mediastinal and cervical nodal mets = lymphatic spread
• Inguinal nodes only if:
  • Prior inguinal/scrotal surgery
  • Tunica vaginalis invasion
• Exception: choriocarcinoma = hematogenous → lung, brain
  • Can bypass the retroperitoneum (the usual lymphatic landing site); β-hCG >10,000 IU/L usually signals it
• Pulmonary mets = hematogenous spread
  • Pediatric yolk sac tumors are also thought to spread hematogenously
• Mets at diagnosis: 33% NSGCT | 15% seminoma

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Tumor Markers & Half-Life

• β-hCG is secreted by syncytiotrophoblasts (not cytotrophoblasts) → the cell behind every β-hCG producer in the table (only some EC)
  • β-hCG >10,000 IU/L usually = choriocarcinoma
  • Very high levels can cause hyperthyroidism — hCG shares an identical α-subunit with TSH and LH
• AFP is physiologically high in newborns and declines over the first year of life → e.g. AFP 50 IU/mL at 11 months does not indicate yolk sac elements
• Repeat markers after 5 half-lives post-orchiectomy
  • Exam answer: markers should normalize after 4 half-lives → AFP back to normal 20–28 days after effective therapy → recheck at 1 month
  • An hCG that barely falls over 2 weeks after orchiectomy → persistent disease
  • Stage and treat on post-orchiectomy markers, not pre-orchiectomy values → repeat AFP and β-hCG before any treatment decision, even if earlier markers were normal
  • Metastatic NSGCT: repeat markers 7 days after orchiectomy, before chemo — the trajectory helps set the IGCCCG prognostic group and guides chemo selection
• False ↑ β-hCG — hCG immunoassays are directed at the beta subunit, so there is cross-reactivity with LH. This causes false-positive elevations in primary hypogonadism (including alcoholics and the anorchid) — they normalize within 48–72 hours of giving testosterone
  • Don't treat, re-image or order a brain MRI until a post-orchiectomy β-hCG rise is confirmed to be tumor-derived
• Marijuana use and hypogonadism cause a persistently high β-hCG
• Liver damage causes a persistently high AFP
  • From drugs, hepatitis or alcohol
• Renal insufficiency affects neither marker

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Work-Up

• History & physical exam
• Scrotal ultrasound (both testes — 2% bilateral) — high-frequency transducer (5–10 MHz)
• Tumor markers + LFTs + hormones
• CT chest / abdomen / pelvis (CXR acceptable for CS I seminoma)
  • In the landing zone, a 5 mm node is suspicious. In other zones, 10 mm is the cut-off.
  • Repeat imaging in 4–8 weeks applies only to equivocal retroperitoneal nodes <2 cm
  • FDG-PET/CT has no role before chemotherapy (including seminoma)
• Brain imaging if:
  • Neurologic symptoms
  • β-hCG >5,000
  • AFP >10,000
  • Extensive lung mets
  • Non-pulmonary visceral mets
• Use MRI with and without contrast. A CT brain is also warranted with a highly elevated β-hCG (> 10,000 mIU/mL), since those levels are often associated with metastatic choriocarcinoma
  • Image the brain before chemo — highly vascular choriocarcinoma spreads hematogenously and can hemorrhage catastrophically during treatment
• Contraindicated: testicular biopsy, trans-scrotal orchiectomy (scrotal violation ↑ local recurrence)

Contralateral biopsy is indicated when (the patient has already had a unilateral orchiectomy)

• History of undescended testis
• Atrophic contralateral testis
• Patient under 40
• Suspicious ultrasound finding

Radical Inguinal Orchiectomy — Ilioinguinal Nerve Injury

• The ilioinguinal nerve lies on top of the spermatic cord in the inguinal canal → at risk of entrapment during external oblique closure
• Presents weeks later: inguinal hyperesthesia + groin and hemiscrotal pain (delayed neuropathic pain)
• Management: neuropathic agents + local anesthetic or steroid blocks first → neurectomy only for refractory cases

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Fertility Considerations

• At diagnosis: 50% oligospermic | 10% azoospermic
  • 20–60% have abnormal semen analysis parameters at GCT diagnosis → this frequent infertility/subfertility can complicate pretreatment sperm banking
  • Parameters occasionally improve after orchiectomy (unclear why) — still factor baseline infertility in when judging fertility outcomes after treatment
• All patients become azoospermic after chemotherapy. Of those with normal semen parameters at diagnosis, 50% resume baseline at 2 years and 80% at 5 years
• Radiotherapy for seminoma affects spermatogenesis — recovery may take 2–3 years
• RPLND can cause ejaculatory dysfunction
• → Sperm bank before chemo/RT

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Testis-Sparing Surgery (Selective)

• Solitary testis
• Synchronous bilateral tumors
• Tumor <1 cm, <30% testicular volume, non-palpable, normal markers
  • Suspected GCT (exam answer): needs normal androgen production + tumor <2 cm in a solitary testis or bilateral synchronous tumors — not when the contralateral testis is normal
    • Solitary testis → inguinal partial orchiectomy, provided testosterone and LH are normal and >50% of parenchyma will remain
• 50–80% have concomitant GCNIS in ipsilateral testis
• Obtain a frozen section
• Biopsy the adjacent tissue for GCNIS — if positive, give radiotherapy 20 Gy
  • Take multiple biopsies of the surrounding parenchyma; adjuvant RT range 18–20 Gy
  • Fertility will be impaired, and testosterone will decline gradually — up to 40% will need testosterone replacement
  • If the patient already has a low testosterone, go for radical orchiectomy instead
    • Main goal of testis-sparing surgery (TSS) is preserving Leydig cell function → significant hypogonadism is a contraindication
• Not contraindications: infertility/subfertility (the primary goal is preserving testosterone production) | testicular microlithiasis
• Suspected benign lesions → TSS acceptable — e.g. epidermoid cyst, adenomatoid tumor arising from the tunica albuginea
• Prepubertal / peripubertal boy
  • Normal markers → testis-sparing partial orchiectomy
  • Elevated markers → radical inguinal orchiectomy + CT chest / abdomen / pelvis
  • Prepubertal mature teratoma is benign → partial orchiectomy after frozen-section confirmation — no serial ultrasounds, chemo, RT or RPLND

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Pathologic Risk Factors for Relapse (CS IA/IB )

Seminoma (2)

• Tumor size >4 cm
  • Best predictor of occult metastases on surveillance — more consistently reproduced than rete testis invasion
• Rete testis invasion

Surveillance relapse in CS I seminoma

• Overall 14.7–16% — rising to 44% at 5 years with size >5 cm + rete testis invasion + LVI
  • → Compliant, no risk factors → surveillance; non-compliant or risk factors → carboplatin or XRT (lower relapse)

NSGCT (5)

• LVI (most important)
  • Predicts occult metastases in CS I NSGCT — but is not associated with distant metastases in clinical or pathologic stage II
• Stage pT2 or higher
• > 40% embryonal cell carcinoma
• Proliferation rate > 70% on MIB-1
• Absence of yolk sac tumor

In CS IIA–B NSGCT, occult distant metastases are associated with

• Elevated post-orchiectomy tumor markers
• Bulky (>3 cm) retroperitoneal masses
• Lymphadenopathy outside the primary landing zone

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TNM Staging (AJCC 8th)

T Stage (pathologic — assigned after radical orchiectomy)

N Stage

• Regional nodes are the abdominal nodes: pre-aortic, para-aortic, retro-aortic, interaortocaval, pre-caval, para-caval, retro-caval, and along the spermatic vein
• Pelvic and inguinal nodes are NOT regional — unless there was scrotal violation

M Stage

• M1a: non-regional nodes or lung
• M1b: non-lung visceral mets

S Stage

• Testicular cancer is the only urological cancer whose stage grouping includes serum tumor markers
• The S category is set by the single worst marker → one S2-range value is enough for S2

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Stage Grouping

Stage I (N0, M0)

• IA: T1, S0
• IB: T2–T4, S0
• IS: Any T, S1–S3 (marker-positive post-orchiectomy)

Stage II (N+, M0, S0–1)

• IIA: N1
• IIB: N2
• IIC: N3

Stage III (Any N, M1 and/or higher S)

• IIIA: M1a, S0–S1
• IIIB: N1–3 + M0–M1a + S2
  • S2 = LDH 1.5–10 × ULN · hCG 5,000–50,000 mIU/mL · AFP 1,000–10,000 ng/mL — any one → any pT, N1–N3, M0 disease is IIIB, not stage II
  • Persistent S2 after orchiectomy (NSGCT) → IIIB — an AFP not falling at its 5–7 day half-life needs chemotherapy, not repeat markers; no primary RPLND with elevated markers
• IIIC: N1–3 + M0–M1a + S3, OR M1b any S

The short version

• Stage I — local tumor, no regional nodes, markers negative

• Stage II — regional nodes, markers negative, no metastases

• Stage III — metastases or markers positive

• Node-positive + S2 → IIIB · node-positive + S3 → IIIC

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Risk Stratification (IGCCCG)

• For IGCCCG risk, S stage is determined on the first day of chemotherapy — not at orchiectomy
  • e.g. NSGCT with post-orchiectomy AFP > 1,000 IU/mL (S2) on cycle 1, day 1 → intermediate risk → BEP ×4 (BEP ×3 or EP ×4 is for good-risk, S1 disease)
• NSGCT poor risk = any one of: non-pulmonary visceral metastases (e.g. liver) · mediastinal primary · AFP > 10,000 ng/mL · β-hCG > 50,000 IU/L · LDH > 10× ULN → BEP ×4
• Seminoma does not produce AFP — raised AFP with pure seminoma histology means an occult non-seminomatous component → stage and treat as NSGCT (IGCCCG has no poor-risk seminoma category)

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Management

Pure Seminoma

Stage I (CS IA/IB Seminoma)

• Choosing among the 3 — all valid, a physician–patient decision: compliant + no risk factors → surveillance; non-compliant or risk factors (size >4 cm, rete testis invasion) → carboplatin or XRT (lower relapse)
• Surveillance relapse (~15%) is retroperitoneal and within 2 years — nearly all salvageable in compliant patients; visceral, pulmonary or nonseminomatous relapse is extremely uncommon
• XRT → overall relapse ≤ 5%, but secondary malignancy (mainly leukemias and lymphomas) in ~18% at 25 years
  • Favored when non-compliant or with risk factors — seminoma is very radiosensitive and morbidity is low — despite the long-term secondary malignancy risk
• Carboplatin ×1 is the chemotherapy alternative to observation or XRT — efficacy similar to retroperitoneal radiation in the MRC randomized trial
• RPLND is not a standard option for stage I seminoma

Advantages of surveillance

• Avoids over-treating 80% of patients
• Avoids the toxicity of radiotherapy and chemotherapy
• Same cure rate

When to avoid XRT

• Inflammatory bowel disease · prior abdominal radiation · a kidney in the radiation field (horseshoe kidney, ectopic kidney, adenopathy near the kidney)
  • e.g. Crohn's disease + can't attend surveillance (leaving for a remote location) → single-dose carboplatin (radiation is relatively contraindicated in Crohn's)
• Shield the contralateral testis if it is not involved
• With scrotal violation, include the ipsilateral iliac and inguinal nodes in the field
• When the ipsilateral iliac nodes are not radiated, follow-up must include pelvic nodal imaging — the iliac nodes are then a common relapse site

Surveillance schedule — CS I seminoma

Stage II and beyond

• Stage IIA → XRT to para-aortic RPLN + ipsilateral iliac nodes, 30 Gy — relapse ~10%, usually in the thorax
  • Stage IIA dose range (exam answer): 30–36 Gy (vs 20 Gy for stage I)
• Stage IIB → 36 Gy if the RPLN mass is ≤ 3 cm; BEP ×3 or EP ×4 if > 3 cm
  • Low-volume IIB (exam answer): dog-leg XRT 30–36 Gy or good-risk chemo BEP ×3 or EP ×4 — Crohn's disease contraindicates radiation → BEP ×3
  • Bulky (> 3 cm) or multifocal retroperitoneal metastases → first-line platinum chemotherapy rather than radiation (regimen by IGCCCG risk, below)
• Stage IIC / III
  • Good risk → BEP ×3 or EP ×4
  • Intermediate → BEP ×4

Residual Masses Post-Chemo (Seminoma)

• 60–80% have radiologically detectable residuum
  • Most need no treatment — 50–60% resolve spontaneously over a median 13–18 months
• Histology: necrosis or fibrosis 80–90% · malignancy 10–20% · pure teratoma (rare)
  • Typically ~90% necrosis/fibrosis and ~10% viable tumor — vs NSGCT 40% necrosis · 45% teratoma · 15% viable
• → <3 cm: observe
  • With normal markers — only ~10% contain viable tumor
• → >3 cm: FDG-PET
  • Positive → post-chemo surgery
  • Negative → observe
  • PET is a useful adjunct to post-chemo staging CT — ~30% of discrete masses > 3 cm contain viable malignancy
• Perform the PET scan ≥ 6 weeks after chemotherapy — this reduces false positives. If indeterminate, repeat in 6–8 weeks
• Granulomatous disease (e.g. sarcoid) can cause a false-positive PET
• Malignancy is rare in residual masses ≤ 3 cm, but is present in 30–50% of residual masses > 3 cm
• Template RPLND is difficult here — chemotherapy for seminoma causes a desmoplastic reaction that obscures the tissue planes, so resection or biopsy of the residual mass is often performed instead
  • Complete resection is achieved in only 58–74% of seminoma cases — vs ≥ 85% after first-line chemotherapy for nonseminoma
• For FDG-PET-positive residual masses > 3 cm, give strong consideration to PC-RPLND — particularly after second-line chemotherapy
• Nodal mass growing after radiation despite normal markers → biopsy to exclude NSGCT transformation (open or laparoscopic if CT-guided is not feasible or nondiagnostic) — no RPLND before histologic confirmation

Post-chemotherapy relapse

• Early — could contain teratoma. If markers are normal, biopsy first; if there is no teratoma, give second-line chemotherapy
• Late — better prognosis. Treatment is chemotherapy (remember they probably had carboplatin). Biopsy first is not really needed — teratoma in late relapse is rare
• Radiotherapy has no role in a post-chemotherapy residual mass

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Non-Seminoma

• Stage I
  • Surveillance (compliant T1 only)
  • RPLND (unilateral) — preferred if teratoma in pathology
  • Chemo BEP ×1–2
    • Highest relapse-free survival, but does not treat retroperitoneal teratoma — relapses after it tend to be chemoresistant

• 60% of relapses occur in the retroperitoneum
• LVI-positive — relapse ~50% vs ~15% without LVI
  • Risk-adapted: surveillance, BEP ×1–2 or nerve-sparing RPLND after discussion
  • Stage IB with adjuvant chemo (physician–patient decision) → BEP ×1–2 — relapse only 2.7% after BEP ×2 at a median follow-up of ~7.9 years
• IA (LVI-negative) → guide toward surveillance; if adjuvant chemo is chosen, BEP ×1 is enough — 5-year relapse ~2%
• Non-compliant IA → nerve-sparing RPLND (modified or full bilateral template) or BEP ×1
  • BEP ×1 is preferred over surveillance if likely noncompliant, even at low risk — and may be preferable to RPLND with a transmissible infection (e.g. hepatitis C)
• Non-compliant IB → nerve-sparing RPLND or BEP ×1–2

Surveillance schedule — CS I NSGCT

• Stage IIA/B — RPLND (bilateral) only if S0; otherwise chemo BEP ×3
  • IIA with normal markers → nerve-sparing RPLND in an expert center; adjuvant chemo decided by pathology — max 2 cycles of BEP or EP
  • Pure seminoma histology + raised AFP = NSGCT → bulky 3 cm retroperitoneal nodes get induction cisplatin-based chemo (BEP ×3 or EP ×4) — not radiation or RPLND
• Stage IS → BEP ×3
  • Persistently raised post-orchiectomy markers with negative imaging (S1 disease) → BEP ×3 or EP ×4; RPLND is discouraged while markers are elevated
• Stage IIC / III
  • Good risk → BEP ×3 or EP×4
  • Poor risk → BEP ×4
  • Substitute VIP×4 if compromised pulmonary function or extensive chest surgery expected

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Post-RPLND (pre-chemo)

Relapse after primary RPLND, by pathologic stage

• Most relapses occur OUTSIDE the retroperitoneum — primarily in the lungs
• RPLND downstages up to 20% of marker-negative CS II NSGCT to pathological stage I
• Pathological stage II overall (exam answer): 12–40% recur without adjuvant chemo vs 0–4% with it

Residual Masses Post-Chemo (NSGCT)

Four response categories after chemotherapy

1. Complete response — markers normalize and radiographic disease resolves (residual masses < 1 cm)
2. Partial remission, marker negative — markers normalize but radiographic tumor persists
3. Partial remission, marker positive
4. Disease progression

• 5–15% fall into categories 3 and 4 and are managed with second-line (salvage) chemotherapy
• 38–68% have residual masses > 1 cm after first-line chemotherapy — clear consensus that these should undergo post-chemotherapy surgery

• Viable GCT after induction averages 15% (range 10–20%)

• Teratoma is the largest component (~45%) because it is chemoresistant — unresected, it risks growing teratoma syndrome, malignant transformation or late relapse

• Long-term survival ~90% with only fibrosis or teratoma vs 50–70% with viable GCT

• 6–8% of specimens show malignant transformation of teratoma — most often rhabdomyosarcoma

• Markers elevated: salvage chemo

  • Even if the mass has regressed or resolved — not RPLND or radiation; RPLND requires normal markers

• Markers normal:

  • >1 cm: → resection (full bilateral template PC-RPLND if RP)
    • > 1 cm in transaxial long axis on contrast-enhanced CT → resection is mandatory, as no test can accurately predict the histology
    • Bilateral PC-RPLND — not resection of that mass alone — even with coexisting regressing lung nodules
    • Applies to AFP-positive seminoma too → RPLND, not PET-CT, radiation or biopsy (PET cannot distinguish teratoma from fibrosis)
  • < 1 cm after primary chemotherapy — surveillance carries a 9% recurrence rate, but only 4% recur in the retroperitoneum. If every patient with a sub-centimeter residual mass had an RPLND, 96% would undergo unnecessary surgery
  • After SALVAGE chemotherapy the risk of residual malignancy is much higher — resection of a residual retroperitoneal mass is recommended regardless of size

• → Multiple sites → RPLND first (highest probability of residual; predicts other sites)

  • Fibrosis at RPLND → observe small residual lung and supraclavicular nodules — retroperitoneal necrosis strongly predicts necrosis elsewhere

• PC-RPLND histology:

  • Necrosis/teratoma → surveillance
  • Viable disease → 2 cycles chemo (EP, TIP, VIP, or VeIP)

• FDG-PET has NO role in NSGCT residual masses

  • Teratoma is not FDG-avid — even masses ≤ 20 mm still harbor teratoma in 30%

Parameters predicting fibrosis in the retroperitoneum after platinum-based chemotherapy

1. No teratoma in the primary tumor
2. 90% reduction in the size of the mass on CT
3. Pure embryonal cell carcinoma in the primary tumor
4. Size of the lymph node post-chemotherapy

• Pre-chemotherapy node size and marker levels do NOT predict fibrosis-only histology

• Post-chemotherapy, if a residual liver mass has shrunk (e.g. 5 cm → 2.5 cm) and the retroperitoneal nodes have nearly resolved (3 cm → 2 mm) with normalized markers → do the LIVER resection only. Adding an RPLND results in a high incidence of chylous ascites

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RPLND

Not only therapeutic — it gives accurate pathologic staging. Up to 30% of clinical stage I NSGCT have occult metastases, and up to 35% of clinical stage IIA are downstaged to stage I.

• The standard of care for PC-RPLND is a full, bilateral infrahilar retroperitoneal dissection with nerve sparing where technically feasible
  • Timing: within 6–8 weeks of the last chemotherapy cycle
  • An ipsilateral template is an option for residuals < 5 cm
  • Never a simple lumpectomy (excision of the mass alone)
• A predominance of teratoma in the orchiectomy specimen favors RPLND over chemotherapy — it increases the risk of teratoma in the retroperitoneum

Surgical Considerations

• Contralateral nodal involvement is more common in RIGHT-sided primary tumors — following right-to-left lymphatic drainage
  • Right primaries drain first to the interaortocaval and precaval nodes → the right template crosses the midline above the IMA
• Right modified template — left limit: the medial border of the left ureter above the IMA, narrowing to the medial border of the aorta below the IMA → preserves ejaculation
• The sympathetic trunks are bilateral paravertebral chains giving rise to postganglionic fibers posterior to the IC, anterior to the aorta, coalescing at the inferior hypogastric plexus caudal to the IMA
  • Exam answer: they converge in the superior hypogastric plexus
• For optimal preservation of ejaculation in a RIGHT-sided nerve-sparing RPLND, preserve the postganglionic sympathetic fibers POSTERIOR TO THE VENA CAVA
  • Usually 3–4 postganglionic trunks run behind the IVC and join the superior hypogastric plexus around and below the IMA
• On the LEFT, postganglionic fibers leave the sympathetic trunk and run lateral and anterior to the aorta to join the superior hypogastric plexus
• The most common site of sympathetic nerve injury during RPLND is the hypogastric plexus anterior to the aortic bifurcation
  • → Modified templates exclude the aortic bifurcation
• Postoperative tachycardia is common and is caused by sympathetic discharge
• IMA ligation → the sigmoid colon stays perfused: the middle hemorrhoidal (rectal) arteries from the internal iliac fill the superior hemorrhoidal and sigmoid branches retrograde
• Remove the spermatic cord remnant (contains the gonadal vein) at RPLND — in both the primary and post-chemotherapy settings

Steps

1. Midline incision
2. Find the cecum
3. Open the retroperitoneum
4. Dissect the white line of Toldt as far as the second part of the duodenum (from behind), then come from anterior-inferior and go superiorly to release the third part of the duodenum
5. Reflect the bowel into the bag
6. Split the aorta before the IVC → identifies right accessory lower-pole renal arteries missed on preoperative imaging (an IVC-first split may divide them → blood loss and renal parenchymal loss)
   • Downside: it risks dividing postganglionic sympathetic fibers → stop the aortic split at the IMA and identify the efferents before continuing caudally

Auxiliary Procedures

• Nephrectomy is the commonest — usually the left
• Prior chemotherapy is what makes RPLND technically difficult — the desmoplastic reaction obliterates the periaortic and pericaval planes → ↑ morbidity; adjunctive procedures such as nephrectomy are needed in 38–51%
• There is a common discordance between liver/thoracic pathology and retroperitoneal nodal pathology — one does not predict the other
• Thoracic masses should be managed AFTER the RPLND is completed. Masses > 1 cm should be considered for resection unless the retroperitoneum harbored only fibrosis

Complications

IVC injury

• If > 25% narrowing is expected, consider patch venoplasty or an interposition graft
• (Note the divergence: in the renal setting, 50% narrowing of the IVC lumen is accepted.)

Aortic injury

• Most common with subadventitial dissection of densely adherent masses, requiring aortic replacement with a PTFE or Dacron graft

Lymphocele

• A thin-walled cystic lesion in the resection bed
• Air within the lymphocele and/or a rim of enhancement raises concern for infection
• Percutaneous drainage for symptomatic or infected lymphoceles; antibiotics only if perceived to be infected
  • First step for a symptomatic collection (e.g., 2.5 cm) → ultrasound-guided percutaneous aspiration — decompresses it and confirms lymph (fluid creatinine close to plasma)
  • Recurs after aspiration → percutaneous sclerosis or unroofing into the peritoneum
  • Infected → leave an indwelling drain (not simple aspiration) + systemic antibiotics

Anejaculation

• Seminal emission and prostatic secretion, plus bladder neck closure, rely on postganglionic sympathetic fibers from L1 to L4, which coalesce at or below the IMA in the hypogastric plexus before traveling caudally in the interiliac space at the sacral promontory
• This is the superior hypogastric plexus, running from the caudal aorta to the anterior L5 vertebra over the aortic bifurcation → its disruption causes loss of seminal emission
• Nerve-sparing RPLND preserves antegrade ejaculation in 90–100%

Chylous ascites

• 0.2–2% in primary RPLND; 2–7% after post-chemotherapy RPLND
  • Holds for both open and laparoscopic primary RPLND (< 2%)
• Diagnosis — suspicion, CT abdomen, and paracentesis showing high protein (> 3 g/dL) and a triglyceride level 2–8× that of serum
• If symptomatic, escalate in this order:
  1. Paracentesis with no drain
  2. If it reaccumulates quickly, leave a drain and cap it off at intervals
  3. Very low fat, high protein diet with medium-chain triglyceride replacement
  4. IM octreotide
  5. NPO and TPN
  6. Observation or invasive intervention
• First step (exam answer): hydration + low-fat diet + drainage of the fluid; reoperation only after all else fails

Mesenteric ischemia

• Infarcted small bowel + normal colon after left-sided RPLND → SMA injury — the SMA alone supplies the jejunum and ileum; the colon survives via the marginal artery of Drummond
• Classic early sign: severe abdominal pain out of proportion to examination, without peritonism — peritoneal signs appear only after transmural infarction

Also: VTE, mortality

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Special Scenarios

Growing Teratoma Syndrome

• ↓ markers + ↑ mass during chemo
• → Complete chemo course, then resect
• Good-risk NSGCT progressing dramatically on first-line chemo despite normalized markers → growing teratoma syndrome or teratoma with malignant transformation
  • Enlarging purely cystic mass → growing teratoma syndrome
  • Enlarging solid mass + new disease sites → malignant transformation → CT-guided biopsy (the result may change the chemotherapy)

Brain Mets (choriocarcinoma)

• High hCG → bleed risk on chemo (death 4–10% ICH)
• → BEP ×4 → resection ± RT
  • Brain mets carry a poor prognosis; BEP ×4 first-line is also given for any hCG > 5000 mIU/mL when chemotherapy starts

Post-Chemotherapy Relapse (NSGCT)

Early (< 2 years)

• Second-line salvage chemotherapy — TIP, VIP or VeIP ×4; third line is high-dose chemotherapy
• If a residual mass remains after salvage chemotherapy → surgical resection; 50% contain viable cancer

Late (> 2 years)

• Rare (2–4%)
• Biopsy first
• Yolk sac is the most common histology; the majority are in the retroperitoneal nodes
  • → A rising AFP years after cure (> 24 months after a complete response) suggests late relapse
  • Teratoma is the second most common histology after yolk sac (relapse > 2 years after completing therapy with no evidence of disease) — prolonged doubling time + chemoresistance
• Generally chemoresistant — surgery is the better option
  • Resectable disease → RPLND is the first treatment; survival depends on complete surgical resection
• The best chemotherapy is TIP

Scrotal Violation

Scrotal violation alters the normal lymphatic drainage, redirecting it to the superficial inguinal nodes.

Optimal treatment is unclear, but consider:

• Stage T4 suspected at the time of orchiectomy → orchiectomy + en bloc excision of the involved portion of the scrotum
• After a trans-scrotal biopsy → radical inguinal orchiectomy + en bloc excision of the biopsy tract and the scrotal scar
• After a trans-scrotal orchiectomy — adjunctive therapy "may rarely be considered… for local control" [AUA]; scrotal scar excision depends on whether chemotherapy was given
  • No chemotherapy given → wide excision of the scrotal scar — e.g. CS I embryonal carcinoma with vascular invasion (scrotal contamination) → RPLND + wide excision of the scrotal scar and remnant cord; observation is not optimal
  • After chemotherapy → local scrotal relapse is very unlikely → no wide scar excision, hemiscrotectomy, scrotal radiation or inguinal node dissection; observe the scrotum on routine examination (the cord remnant is still removed at RPLND)
• Seminoma with scrotal violation going to radiation → modify the field to include the ipsilateral iliac and inguinal nodes

Bleomycin + RPLND

• Risk of post-op respiratory distress
• Obtain PFTs pre-operatively; the anesthetic team should be aware of bleomycin's pulmonary fibrosis risk
• → Low FiO₂ + conservative fluids

Chemotherapy — Agent-Specific Toxicity