Penile Cancer

Benign Penile Lesions

• Papilloma (pearly penile papules) → no treatment
• Condyloma acuminatum → HPV (6 & 11); stays superficial, never invades
• Zoon's balanitis (plasma cell balanitis) → uncircumcised men, 3rd decade+; mimics CIS → circumcision (curative)

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Premalignant Lesions

• Non-HPV also includes: penile Kaposi sarcoma (HHV-8 → screen HIV; start HAART first), leucoplakia, pseudoepitheliomatous keratotic balanitis
  • Kaposi sarcoma → 2nd most common penile malignancy after SCC (HIV prevalence); also with transplant or other immunosuppression
  • Kaposi in a transplant recipient → reduce immunosuppression first (often regresses) → if it fails: local excision, laser ablation or radiotherapy; no partial penectomy
• Giant condyloma vs condyloma acuminatum → condyloma acuminatum stays superficial regardless of size; giant condyloma still shows no malignant change on histology
• CIS naming = location only → glans/prepuce = erythroplasia of Queyrat; shaft skin, rest of genitalia or perineum = Bowen disease
• BXO / lichen sclerosus → chronic scarring inflammatory disease; may be premalignant (esp. HPV-independent SCC); late stage → penile urethral strictures
  • Histology: flattened/lost rete pegs (epidermal atrophy) = classic hallmark; plus basal cell vacuolation, dermal collagen homogenization
  • Diagnosis: clinical appearance or confirmatory biopsy; skin disease → topical steroids (treatment of choice)
  • Meatal stenosis (weak stream) + non-healing glans ulcer → dilate the meatus + biopsy the ulcer (rule out malignancy)

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Squamous Cell Carcinoma (SCC) of the Penis

• >95% of penile malignancies; abrupt incidence rise in 6th decade

Risk factors

• Uncircumcised
• Premalignant lesions
• HPV 16 & 18
  • HPV 16 = most common genotype → 68.3% of HPV-positive tumors; next, low-risk HPV 6 (~8%)
• Chronic inflammation (lichen sclerosus, phimosis)
• Tobacco, poor hygiene/low SES, multiple partners, PUVA

Circumcision: before puberty lowers invasive cancer risk; does NOT lower risk of CIS. Adult circumcision offers little/no protection.

• Adult circumcision = after age 21 → too late, as etiologic exposure likely already occurs by puberty
• Prevention (besides prepubertal circumcision): HPV vaccination, daily genital hygiene, tobacco avoidance

Presentation

• Painless penile lesion (pain uncommon; care-seeking delay common)
• Site frequency: Glans (48%) > prepuce (21%) > shaft
• ~50% present with a palpable inguinal node (of palpable nodes, only ~43% are truly metastatic — rest inflammatory)
• Metastasis to the penis → priapism = most frequent sign; also penile swelling, nodularity, ulceration

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Primary Urethral Carcinoma

• Male — site: bulbomembranous (60%) > penile (30%) > prostatic (10%)
  • Commonest risk factor = urethral stricture → concentrated in the bulbar urethra
• Male — histology varies by site: anterior → up to 80% SCC; posterior → mostly urothelial; adenocarcinoma commoner in the bulbar urethra
• Female — proposed risk factors: leukoplakia, glandular metaplasia, chronic irritation, stricture, recurrent UTIs, caruncles, HPV, diverticula
• Female — histology (roughly even split): urothelial 28–45%, squamous 19–29%, adenocarcinoma 28–38%
  • 6–10% of urethral diverticula harbor malignancy → adenocarcinoma predominates
• Locally advanced (T3 = invades corpora cavernosa), non-metastatic:
  • SCC → curative chemoradiotherapy (genital preservation):
    • 2 cycles 5-FU + mitomycin C + concurrent external beam radiotherapy → ~80% complete response, 52% 5-yr overall survival
  • Urothelial → cisplatin-based chemotherapy before surgery

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Staging (TNM, AJCC 8th)

T stage

• Why spongiosum = T2 but cavernosum = T3: spongiosum invasion → lower rate of inguinal node metastasis and better survival
• Urethral invasion no longer sets the T stage on its own (formerly T3) → now T2 or T3 by the corpus invaded
  • A tumor near the meatus can reach the distal urethra through the spongiosum without a worse outcome

N stage

• Note: clinically, N3 = fixed mass; pelvic nodes are captured as pN3 pathologically — AJCC separates these. Node >4 cm often = extranodal extension.
• cN3 = fixed inguinal mass regardless of size or laterality → neoadjuvant chemotherapy before node dissection

M stage

• M1 — distant metastasis (node mets outside true pelvis, or visceral/bone).
  • Most common sites: lung, bone, liver (late).
  • Untreated → death in majority within 2 years.

Pathology variants

• Classic
• Verrucous → excellent prognosis (does not metastasize; observe)
  • Exam answer: verrucous (Buschke–Löwenstein) rarely metastasizes → a palpable groin node is likely reactive → observe
    • Biopsy only if it persists or grows
    • Lymphadenectomy only for biopsy-proven metastases
• HPV-related
  • HPV prevalence by subtype: basaloid 84% > warty-basaloid 75.7% > warty 58.7%
  • p16 immunohistochemistry = surrogate marker of HPV activity → prognostic
• Sarcomatoid → very aggressive

Strongest prognostic factor for survival → extent of lymph node metastasis.

• Outranks primary tumor stage, grade and vascular invasion
• Best survival after attempted curative resection of inguinal metastases → unilateral involvement · minimal nodal disease (≤2 nodes, pN1) · no extranodal extension

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Lymphatic Spread & Inguinal Anatomy

Pattern of spread

• Most common metastasis = inguinal lymph nodes (ILN):
  • Penis → sentinel node → superficial nodes → deep nodes → pelvic nodes → distant mets
• Penile lymphatics can cross the midline → superficial and deep inguinal nodes → a unilateral tumor can seed contralateral nodes → bilateral inguinal nodal management is standard
• Scrotal lymphatics do not cross the median raphe → ipsilateral superficial inguinal nodes only → scrotal cancer lymphadenectomy can be ipsilateral

Inguinal anatomy (lateral → medial): "NAVEL"

• Fascia lata divides superficial from deep lymph nodes
• Node of Cloquet = most cephalad deep node; marks the inguinal/pelvic boundary

ILND

• Sartorius transposition (ILND): iliac origin detached and sutured to the inguinal ligament → covers the femoral vessels and stops a superficial wound infection spreading
• Modified ILND (Catalona) → less lymphedema
  • No dissection lateral to the femoral artery or caudal to the fossa ovalis · saphenous vein preserved
  • Positive frozen section → mandatory conversion to standard dissection
• Number of nodes removed = main predictor of lymphatic complications → videoendoscopic and robot-assisted ILND mainly reduce wound complications, not lymphatic ones

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Workup

• History & physical (incl. inguinal node exam — number, fixed vs mobile per side)
• Biopsy → assess depth, vascular invasion, grade (Broder 1–4; G1-2 = 70-80% at dx)
• Imaging →
  • Small glanular lesion = none
  • Larger/invasion = US (Doppler US > MRI for corporal invasion)
  • CT/PET for pelvic nodes
  • CT C/A/P + bone scan for distant
• Non-palpable inguinal node → DSNB (dynamic sentinel node biopsy) if ≥pT1b
  • DSNB = Tc-99m nanocolloid lymphoscintigraphy + patent blue dye + intraop gamma probe
    • Target false-negative rate ≤5%
    • Preferred for cN0 staging.
    • ~20% of cN0 groins harbor occult mets.
  • Standard for detecting microscopic inguinal mets: superficial ILND or DSNB (DSNB at experienced centers)
  • Sentinel node biopsy directed to a specific anatomic area (not dynamic) → unreliable for micromets, no longer recommended
• Palpable inguinal node → FNAC/biopsy (see node algorithm)

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Management of the Primary Tumor

Before choosing, identify:

• T stage: Tis/Ta · T1a/T1b · T2/T3 · T4
• Node status: non-palpable · palpable mobile <4 cm · fixed or >4 cm or N3 (= pelvis)
• Penile-sparing desired? Yes / No
• Lesion location: glans · distal · proximal

• PeIN (biopsy-proven) → first line = topical 5-FU 5% cream (or imiquimod)
  • 5-FU inhibits thymidylate synthase; typically applied 12 h every 48 h × 4–6 wk
  • Failed topical → don't repeat it — poor response or recurrence may signal underlying invasion
  • PeIN progresses to invasive disease in 2.6–13% despite treatment (median 13 mo)
• Glans CIS, positive excision margin → treat around the scar: scar excision, laser, or topical 5-FU / imiquimod (penectomy and radiation = too aggressive)
• Foreskin SCC, pT1a (subepithelial invasion, no LVI/PNI, negative margins) → circumcision alone is definitive → surveil the glans + both groins
• Primary radiotherapy suits:
  • Young men with small (2–4 cm), superficial, exophytic, noninvasive glans / coronal sulcus lesions
  • Men refusing surgery
  • Distant or inoperable mets needing local control

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Inguinal Lymph Node Management Algorithm

Primary risk: Tis/Ta · T1a = low | T1b–T4 = high · then examine both groins (none · mobile <4 cm · fixed/>4 cm) and note laterality

POSITIVE pathway = ipsilateral radical ILND (superficial + deep) → add ipsilateral pelvic LND if ≥ 3 positive nodes on one side or extranodal extension (EAU 2026)

• AUA vs EAU: AUA adds pelvic LND at ≥ 2 positive inguinal nodes or extranodal extension

Palpable node also means a node positive on imaging (inguinal US ± FNAC, CT or PET) — treat it as cN+.

• Dissection extent: for a palpable (cN+) node, or superficial nodes +ve on frozen section in a cN0 groin → superficial + deep inguinal dissection
  • Exam answer: late palpable node on surveillance (after partial penectomy, CT negative) → superficial + deep dissection on the affected side only; no antibiotics without infection concern (vs + contralateral DSNB for a unilateral node in the table below)
• Single resectable node, CT negative → dissection, not chemotherapy (no distant or unresectable disease)

Low-risk primary (Tis / Ta · T1a)

Click the algorithm to open it full size.

• pT1a G1 (grade 1 pT1, no LVI), impalpable groins → <10% inguinal met risk → observe
  • Surgical nodal staging not justified — no sentinel node biopsy, no prophylactic groin radiotherapy, no lymphadenectomy
• pT1a G2 → 6–8% micrometastasis risk → surveillance can be discussed · pT1b upward → DSNB mandatory

High-risk primary (T1b–T4)

Click the algorithm to open it full size.

• T1b or higher = high risk → ~20–25% occult mets in cN0 → offer bilateral DSNB after inguinal US + FNAC; ILND only if neither DSNB nor referral is available
• Early vs delayed nodal surgery: 84% vs 35% 3-yr survival · extranodal extension 20% vs 95%

Bilateral ILND

• Exam answer: bilateral ILND is generally reserved for pT2 or high-grade tumors (vs bilateral DSNB for cN0 in the table below)
  • Low-grade pT1 with LVI → consider it immediately (LVI strongly suggests occult mets)
  • pT2 → bilateral ILND whether or not nodes are palpable — superficial + deep on the suspicious side, superficial on the other
  • pT2: antibiotics lower the risk of inguinal wound infection, but nodal response to them should not influence the decision to stage surgically

Text version

• EAU 2026 differs on antibiotics: an antibiotic trial to shrink enlarged nodes delays staging and is not recommended — EAU goes straight to FNAC.

FNAC outcome (low-risk primary: Tis/Ta, T1a)

• Node still palpable after 4 wk of antibiotics following excision of low-grade pT1 → FNAC (sensitivity and specificity >90%) — not observation, not immediate lymphadenectomy
  • Exam answer: FNAC +ve → complete ILND on that side + superficial ILND on the opposite side

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Adjuvant Chemotherapy — Indications

Consider adjuvant or neoadjuvant chemo with surgery (ilioinguinal lymphadenectomy) for:

• ≥2 positive nodes
  • Exam answer: >2 positive nodes → two unilateral inguinal nodes with focal metastases is not an indication
• Bilateral metastases
• Pelvic nodes
• Extranodal extension
• Fixed inguinal masses
• Single 6-cm inguinal node

Evidence (one center): adjuvant vincristine-bleomycin-methotrexate after surgery for node-positive disease → 82% 5-year survival vs 37% with surgery alone (25 vs 31 patients)