9.4 Penile Cancer: Staging, Organ-Sparing & Lymphadenectomy

9.4 Penile Cancer: Staging, Organ-Sparing & Lymphadenectomy

Penile cancer is a relatively rare malignancy in Western and European nations, with an annual incidence of 0.5 to 1.6 cases per 100,000 men. However, it presents a substantial healthcare challenge in developing regions of South America, sub-Saharan Africa, and parts of Asia, where incidence is substantially higher than in many European populations. The disease typically manifests in men between the sixth and eighth decades of life. Embarrassment, fear and failure to recognize symptoms can delay presentation for months; encourage prompt examination of persistent penile lesions. The overarching clinical principle in penile cancer management is balancing organ-sparing primary tumour control with aggressive, risk-stratified regional lymph node staging and dissection, because regional lymphatic metastasis represents the single most important prognostic determinant of patient survival.

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1. Epidemiology, Etiological Risk Factors & Premalignant Lesions

Major Etiological Risk Factors

• Human Papillomavirus (HPV): High-risk oncogenic HPV types (predominantly HPV 16 and HPV 18) are detected in approximately 30% to 50% of invasive penile squamous cell carcinomas. Viral oncoproteins E6 and E7 drive malignant transformation by binding and inactivating the tumour suppressors p53 and retinoblastoma protein (pRb), respectively, triggering secondary cellular accumulation of p16INK4a (a reliable surrogate immunohistochemical marker for HPV-driven disease).
• Phimosis & Chronic Inflammation: Phimosis is strongly associated with invasive penile cancer and can conceal a lesion. Chronic balanoposthitis contributes to the inflammatory setting; smegma itself is not an established carcinogen.
• Cigarette Smoking: Smoking is an established, modifiable risk factor for invasive penile cancer; counsel cessation alongside assessment of HPV and chronic inflammatory risk factors.
• Chronic Dermatoses: Lichen sclerosus (formerly known as balanitis xerotica obliterans, BXO) is present in up to 30% to 40% of penile cancer specimens, driving non-HPV-associated neoplastic pathways.
• Circumcision Timing: Neonatal circumcision reduces invasive penile cancer risk but does not provide complete lifelong protection or eliminate PeIN risk. Protection is linked substantially to prevention of phimosis.

Premalignant Penile Lesions

Use the current penile intraepithelial neoplasia (PeIN) categories: HPV-associated and HPV-independent/differentiated. Historical clinical names remain useful for recognizing appearances but are not the modern pathological classification:

• Erythroplasia of Queyrat: Carcinoma in situ (CIS) involving the glans penis or inner mucosal prepuce. It characteristically presents as a solitary, velvety, shiny, erythematous, non-healing plaque. Biopsy is needed to exclude invasion; classify the lesion pathologically as PeIN and treat with appropriate follow-up.
• Bowen Disease: Carcinoma in situ involving the keratinized shaft skin or perianal region. Appears as a crusted, scaling, discrete, hyperkeratotic plaque with well-defined margins. Histological assessment distinguishes PeIN from invasive SCC; appearance alone does not supply a fixed progression probability.
• Bowenoid Papulosis: Manifests as multiple small, reddish-brown, pigmented verrucous papules on the penile shaft in young, sexually active men. While histopathologically indistinguishable from carcinoma in situ (full-thickness cellular atypia, high mitotic rate), it runs a clinically benign, often self-limiting course with minimal risk of malignant transformation.
• Non-HPV-Associated Lesions: Cutaneous horn (hyperkeratotic excrescence overlying underlying SCC in 30%), pseudoepitheliomatous micaceous and verrucous balanitis, and leukoplakia.

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2. Histopathology & AJCC 8th Edition Staging

Over 95% of all penile malignancies are Squamous Cell Carcinomas (SCC) arising from the squamous epithelium of the glans (48%), prepuce (21%), coronal sulcus (10%), or penile shaft (<2%).

Histological Subtypes & Pathological Grading

• Usual / Conventional SCC (50–60%): Keratinizing, moderately differentiated SCC forming epithelial pearls and intercellular bridges. Intermediate metastatic risk.
• Verrucous Carcinoma (5–10%): Exophytic, slow-growing, cauliflower-like, well-differentiated tumour with a blunt, pushing deep border. HPV-negative. Locally destructive but virtually zero risk of regional lymphatic metastasis.
• Basaloid SCC (5%): Highly aggressive, solid sheets of small, uniform, hyperchromatic cells. Strongly HPV-associated (p16+). Exhibits high rates of early vascular and lymphatic invasion.
• Warty (Condylomatous) SCC (10%): Papillary architecture with hyperkeratosis and prominent koilocytosis. HPV-associated with an intermediate, favorable prognosis.
• Sarcomatoid SCC (1–2%): Biphasic tumour with spindle-cell morphology. Exceptionally aggressive, refractory to therapy, with early hematogenous dissemination and a fatal outcome in over 75% of patients.
• Pathological Grading (ISUP / WHO): Grade 1 (well-differentiated, mature keratinization), Grade 2 (moderately differentiated), Grade 3 (poorly differentiated, marked cellular pleomorphism, diffuse anaplasia).

Primary Tumour (T) Staging (AJCC 8th / UICC 9th Edition)

The relevant penile T categories are unchanged in UICC TNM9 compared with the eighth edition:

• Tis: Carcinoma in situ (flat, non-invasive).
• Ta: Non-invasive localized verrucous carcinoma.
• T1: Tumour invades subepithelial connective tissue (lamina propria):
  • T1a: Invades subepithelial connective tissue WITHOUT lymphovascular invasion (LVI) or perineural invasion (PNI) AND is well or moderately differentiated (Grade 1 or 2).
  • T1b: Invades subepithelial connective tissue WITH lymphovascular invasion (LVI) or perineural invasion (PNI) OR is poorly differentiated/undifferentiated (Grade 3).
• T2: Tumour invades corpus spongiosum (with or without urethral invasion).
• T3: Tumour invades corpus cavernosum (with or without urethral invasion).
• T4: Tumour invades adjacent structures (e.g., scrotum, prostate, pubic bone, or abdominal wall).

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3. Primary Tumour Management: Organ-Sparing vs Penectomy

Historically, primary penile surgery mandated a rigid 2 cm macroscopic surgical margin, necessitating routine partial or total penectomy. Aim for histologically negative invasive-cancer margins. Selected smaller lesions can be excised with narrow margins; macroscopic margins of 5–10 mm have yielded acceptable control. There is no universal safe microscopic width, and organ preservation may carry higher local recurrence than amputation. Contemporary management emphasizes organ-sparing surgery (OSS) to maximize functional urinary length and preserve sexual health.

Organ-Sparing Modalities for Superficial & Localized Disease

• Carcinoma in Situ (Tis):
  • Topical Medical Therapy: After biopsy confirmation, examples include 5% 5-FU left on for about 12 hours every 48 hours over 4–6 weeks, or 5% imiquimod three times weekly for about 12 weeks. Protocols and responses vary; assess toxicity and response, biopsy uncertainty, and investigate failure rather than simply repeating ineffective topical therapy.
  • Laser Ablation: CO2 or Nd:YAG laser photocoagulation for localized superficial lesions.
  • Preputial Circumcision: Curative if CIS or localized verrucous carcinoma is strictly confined to the foreskin.
• Invasive Lesions Confined to Glans (Ta, T1a, selected T1b/T2):
  • Wide Local Excision / Partial Glansectomy: For small lesions (<1 cm) confined to the glans periphery.
  • Total Glansectomy: The workhorse organ-sparing oncological operation for glanular SCC. The entire glans penis is excised from the tips of the corpora cavernosa and distal corpus spongiosum. The exposed corporal tips are covered with a split-thickness skin graft (STSG) harvested from the thigh, and the urethra is spatulated and matured onto the neoglans. Preserves penile length and potential erectile function, but requires strict surveillance for local recurrence; reported five-year recurrence-free rates vary rather than guaranteeing >95% control.

Amputative Resection for Advanced Local Tumours

• Partial Penectomy: Indicated for tumours invading the distal corpus cavernosum (T3) or extensive T2 tumours not amenable to glansectomy. Resection must achieve negative margins while leaving a functional stump that permits acceptable voiding; required residual length is individualized rather than a universal numerical cutoff.
• Total Penectomy with Perineal Urethrostomy: Required for proximal penile shaft tumours, extensive T3/T4 disease, or cases where partial penectomy leaves an inadequate stump. The entire penis is excised down to the pubic rami, the corporal crura are ligated, and the mobilized bulbar urethra is transposed to the perineum as a permanent spatulated perineal urethrostomy.

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4. Regional Lymph Nodes: The Critical Prognostic Determinant

Regional lymph node status is the single most critical prognostic factor governing long-term survival in penile cancer. EAU cites approximate five-year cancer-specific survival of 95%, 80%, 65% and 35% for N0, N1, N2 and N3 disease, respectively. These are population estimates, not an individual prognosis.

Anatomical Drainage Pathways & Crossover

Penile lymphatic drainage occurs in an orderly, stepwise, anatomical cascade:

1. Superficial Inguinal Lymph Nodes: Reside in subcutaneous tissue between Camper's fascia and the fascia lata, arranged in five anatomical quadrants (Daseler quadrants) around the saphenofemoral junction.
2. Deep Inguinal Lymph Nodes: Located beneath the fascia lata in the fossa ovalis, medial to the femoral vein. The highest deep inguinal node is Cloquet's node (Rosenmüller's node), situated beneath the inguinal ligament in the femoral canal.
3. Pelvic Lymph Nodes: Follow the external iliac, internal iliac (hypogastric), and obturator nodal basins.

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5. Management of Clinically Node-Negative (cN0) Groins

In patients with non-palpable inguinal lymph nodes (cN0), physical examination and conventional imaging (CT, MRI, ultrasound) fail to detect occult micrometastatic disease in 20% to 25% of patients. Historically, "watchful waiting" was practiced; however, non-randomized comparative evidence supports timely nodal management: one study reported three-year survival of 84% with early surgery versus 35% with delayed surgery. This supports early detection, not routine radical dissection of every cN0 groin.

Risk-Stratified cN0 Decision Pathway (EAU Guidelines)

Management of the cN0 groin is dictated strictly by the primary tumour's pathological risk profile:

1. Low Risk (Tis, Ta, T1a G1 without LVI/PNI): Nodal risk is too low to justify routine surgical staging. Use clinical surveillance, generally three-monthly for two years then six-monthly to five years.
2. Intermediate Risk (T1a G2): Occult nodal risk is about 6–8%. Balance staging morbidity and risk individually; discuss surveillance in selected, particularly frail, patients who can comply with strict follow-up.
3. High Risk (T1b or higher): Offer surgical nodal staging even with normal imaging. T1b includes LVI, PNI or poor differentiation; a T1b G2 tumour has an estimated 22–30% nodal risk.

Modalities for Invasive Staging of cN0 Groins

• Dynamic Sentinel Node Biopsy (DSNB): The gold standard in high-volume tertiary centers. Preoperatively, technetium-99m labeled nanocolloid is injected intradermally around the primary tumour, and lymphoscintigraphy identifies drainage pathways. Intraoperatively, patent blue dye or indocyanine green (ICG) fluorescence and a handheld gamma probe identify the primary landing sentinel nodes. In experienced centres, DSNB sensitivity is approximately 92–96%, with false-negative rates 4–8%, while sparing 80% of node-negative men the morbidity of a full lymphadenectomy. If the sentinel node is pathologically positive, a complete radical inguinal lymph node dissection is performed.
• Inguinal Lymph Node Dissection (ILND): If DSNB is unavailable and referral is not feasible or the informed patient prefers dissection, offer an appropriate ILND approach. Modified templates preserve the saphenous vein and avoid dissection lateral to the femoral artery or below the fossa ovalis. They still carry substantial morbidity and false-negative risk; they do not reduce complications universally below 10%. A positive sentinel node requires ipsilateral completion therapeutic ILND.

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6. Management of Clinically Node-Positive Groins & Pelvic Lymphadenectomy

Palpable nodes may be inflammatory or metastatic; obtain image-guided confirmation where indicated rather than using empirical antibiotics to delay staging. cN1 denotes mobile unilateral inguinal disease, cN2 multiple or bilateral mobile nodes, and cN3 fixed inguinal nodes or pelvic adenopathy.

Pathological categories differ: pN1 is one or two unilateral inguinal metastases, pN2 ≥3 unilateral or any bilateral inguinal metastases, and pN3 extranodal extension or pelvic nodal metastasis.

Diagnostic & Surgical Pathway

1. Ultrasound-Guided Fine-Needle Aspiration Cytology (FNAC): Use image-guided biopsy to confirm suspicious mobile nodes and stage the pelvis/distant sites. Known penile cancer with an unequivocal fixed cN3 mass may proceed through the advanced-disease pathway without another nodal biopsy.
2. Radical Inguinal Lymph Node Dissection (Radical ILND):
   • Anatomical Boundaries: Inguinal ligament superiorly, sartorius muscle laterally, adductor longus muscle medially, and the apex of the femoral triangle (where sartorius crosses adductor longus) inferiorly.
   • Procedure: Resection of all superficial nodal packets above the fascia lata and deep nodal packets within the fossa ovalis surrounding the femoral vein, including Cloquet's node. For cN1, fascial-sparing or open radical ILND may be used; cN2 usually requires open radical ILND. Preserve the saphenous vein when possible. Sartorius transposition is not universally mandatory, and fascial-sparing approaches can reduce morbidity.
3. Indications for Pelvic Lymph Node Dissection (PLND): Offer ipsilateral PLND when ≥3 inguinal nodes on that side are positive or there is ENE. The recommendation is based on limited evidence; bilateral inguinal positivity alone does not automatically require bilateral PLND. The principal purpose is staging and selection for further treatment, with possible therapeutic benefit in selected patients.

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7. Systemic Chemotherapy in Advanced Disease

• Neoadjuvant Chemotherapy (TIP Regimen): Indicated for patients with fixed, bulky, ulcerated inguinal lymph nodes (cN3) to achieve downstaging and resectability. Regimen consists of 4 cycles of TIP (paclitaxel 175 mg/m2 day 1, ifosfamide 1,200 mg/m2 days 1–3, cisplatin 25 mg/m2 days 1–3, supported by mesna and G-CSF). Neoadjuvant TIP yields an objective response rate of ~50%, and 22 of 30 patients (73.3%) underwent surgery in the phase II study; this does not mean every treated patient becomes resectable. Offer consolidation when responsive or non-progressive disease can be completely resected.
• Adjuvant Chemotherapy: Discuss risks and benefits individually in high-risk resected disease, particularly pN3/pelvic involvement if neoadjuvant chemotherapy was not given. A survival benefit is not established for all pN2/pN3 patients. Postoperative radiotherapy with or without sensitizing chemotherapy is another specialist option for pN2/pN3 disease.

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EAU Penile Cancer Regional Nodal Management Algorithm

Primary Urethral Carcinoma

Primary urethral carcinoma is a distinct malignancy with urothelial, squamous and adenocarcinoma histologies. Do not apply penile skin-cancer staging or treatment solely because a male tumour lies in the penile urethra. Predisposing contexts include stricture and chronic urethral irritation; female urethral diverticula are another association.

Consider malignancy in persistent bloody urethral discharge, haematuria, an indurated urethral mass or progressive obstruction. Examine the urethra/external genitalia and groins; perform a pelvic examination in women. Urethrocystoscopy with biopsy establishes site, extent and histology and assesses the bladder. Cytology is useful but a negative result does not exclude cancer. Pelvic MRI assesses local and regional nodal extent; CT of the chest, abdomen and pelvis assesses distant disease.

For the general urethral TNM system, T1 invades subepithelial connective tissue, T2 may invade spongiosum, periurethral muscle or prostate, and T3 may invade cavernosum, anterior vagina or extend beyond the prostatic capsule. Prostatic urothelial carcinoma has a separate staging scheme. Distinguish grade from anatomical stage.

Treatment depends on site, stage and histology. Selected localised distal tumours can undergo urethra-preserving surgery if negative margins are achievable. Refer locally advanced disease for specialist multidisciplinary treatment: perioperative systemic therapy follows histology, and radiosensitising chemoradiotherapy is an organ-preserving option for locally advanced urethral SCC. Suspicious regional nodes need assessment; prophylactic dissection of every clinically negative groin is not a universal rule.

Worked decision: An obstructing urethral lesion proves to be SCC on biopsy. Stage its local, nodal and distant extent before selecting specialist treatment; neither repeated stricture dilation nor automatic application of a penile-cancer algorithm is adequate.

Primary references: EAU Primary Urethral Carcinoma pathology, diagnosis, staging and treatment.