Carcinoma of the Penis

Penile cancer is a rare malignancy, with an incidence in Europe and North America of about 0.3 to 1 per 100,000 men per year, and higher rates in parts of South America, Africa and Asia (up to 10 per 100,000). More than 95% are squamous cell carcinomas. It typically occurs at ages 50 to 70.

Risk factors:

• Lack of neonatal circumcision, phimosis (present in 25 to 75% of patients), and poor hygiene with smegma retention.
• High-risk HPV infection (types 16 and 18 in about 30 to 50% of cases).
• Lichen sclerosus (a major HPV-independent risk factor, in 20 to 50%), chronic balanitis, smoking (a 3 to 4 fold risk), HIV, psoralen with UVA therapy, and low socioeconomic status.

Pathology and precursors:

• Precursor lesions: penile intraepithelial neoplasia (including erythroplasia of Queyrat and Bowen disease), giant condyloma (Buschke-Löwenstein tumour), and lichen sclerosus.
• HPV-related subtypes (basaloid, warty, warty-basaloid, clear cell) have a better prognosis than HPV-independent usual-type and verrucous types in many series. Sarcomatoid and basaloid carcinomas behave aggressively.
• Verrucous carcinoma is well-differentiated, locally invasive and rarely metastasises.
• Rarer tumours: melanoma, Paget disease, basal cell carcinoma, sarcoma, lymphoma, and metastasis.

Spread: local to the glans, prepuce and shaft, with the urethra, corpora spongiosum and cavernosum involved later. Lymphatic spread occurs to the superficial and deep inguinal nodes, then the pelvic nodes. Distant metastasis is uncommon at presentation (about 5%).

TNM staging (AJCC 8th):

• Tis: carcinoma in situ. Ta: non-invasive verrucous carcinoma.
• T1a: invades subepithelial connective tissue, no lymphovascular invasion, not poorly differentiated. T1b: lymphovascular invasion or perineural invasion, or poorly differentiated.
• T2: invades corpus spongiosum, with or without urethra. T3: invades corpus cavernosum. T4: invades adjacent structures such as scrotum, prostate or pubic bone.
• N stages: palpable mobile unilateral (cN1) and bilateral nodes (cN2), fixed nodes (cN3), and pelvic nodal involvement.

Prognosis: 5-year survival is above 90% for localised disease, about 50 to 80% with inguinal node involvement, and under 10 to 30% with pelvic nodes or distant metastases. Nodal status is the strongest predictor.

Presentation:

• A lesion on the glans (about 50%), prepuce (about 20%), or both, and less often the coronal sulcus or shaft. It may be a nodule, papular, ulcerated, fungating, verrucous, flat erythematous, or a hardened plaque.
• Itching, discharge, bleeding, foul odour, pain, and phimosis that hides the lesion. Many patients delay seeking care for over 6 months because of shame, fear or denial.
• Late: penile destruction, urethral obstruction, fistula, and fungating mass.

Lymph node features:

• Inguinal nodes enlarge from true metastasis, or from infection in the primary lesion (reactive nodes in about half of palpable cases). Metastatic nodes are hard, fixed, matted, and may ulcerate through skin or erode the femoral vessels.
• Lower limb and scrotal lymphoedema indicates bulky disease.

Systemic signs: weight loss, bone pain, and hypercalcaemia (paraneoplastic parathyroid-hormone-related peptide).

Differential diagnosis: balanitis, genital warts, syphilitic chancre, chancroid, lymphogranuloma venereum, lichen sclerosus, lichen planus, Zoon balanitis, Kaposi sarcoma, pyoderma gangrenosum, and tuberculosis.

Red flags: persistent penile lesion beyond 3 weeks after treatment of balanitis, induration, ulceration, nodular growth, phimosis with discharge or bloody discharge, and palpable inguinal nodes.

Biopsy confirms diagnosis and is needed before treatment:

• Punch, incisional or excisional biopsy including the edge of the lesion and the depth of invasion. Circumcision may serve as both biopsy and treatment for lesions confined to the foreskin.
• Pathology must report histological subtype, grade, depth of invasion in millimetres, lymphovascular and perineural invasion, margins, and urethral and corporal involvement. HPV and p16 status are recorded.

Local staging:

• Clinical examination, with photography and measurement.
• Ultrasound or MRI with artificial erection (alprostadil 10 to 20 micrograms intracavernosal, or phenylephrine) to define invasion of the corpus spongiosum and cavernosum for tumours of T2 or higher or when organ-sparing surgery is planned.

Nodal staging:

• Palpable inguinal nodes: examine groin, and send ultrasound with fine needle aspiration cytology or core biopsy. Pelvic and abdominal CT or PET CT for node-positive disease.
• Non-palpable nodes: risk stratification by pathological features:
• Low risk (Tis, Ta, T1a G1 to G2): surveillance.
• Intermediate risk (T1b or G3, no lymphovascular invasion): dynamic sentinel node biopsy or modified inguinal lymphadenectomy.
• High risk (T2 or higher, grade 3, lymphovascular invasion): bilateral inguinal lymphadenectomy or sentinel node biopsy.
• Dynamic sentinel node biopsy uses technetium-99m nanocolloid with blue dye (or indocyanine green) and has a false-negative rate of about 5 to 10%.

Distant staging: CT chest, abdomen and pelvis (or PET CT) in node-positive or locally advanced disease. Bone scan for bone pain or raised alkaline phosphatase. Check calcium, renal function and CBC.

Baseline testing: HIV, syphilis, and other sexually transmitted infections.

Treatment aims at cure with maximal penile preservation without compromising oncological control, and optimal nodal management is the major determinant of survival.

Primary tumour

• Tis, Ta and T1a (low-risk, superficial) disease:
• Topical imiquimod 5% or 5-fluorouracil 5% for Tis only, laser ablation (CO2 or Nd:YAG), circumcision, wide local excision with 3 mm margin (adequate for most), Mohs micrographic surgery, or glans resurfacing.
• T1b and T2 limited to the glans:
• Glansectomy with split-skin graft reconstruction, or partial penectomy with a surgical margin of 5 to 10 mm (margins as small as 3 to 5 mm are acceptable for lower-grade tumours), with frozen section control. Radiotherapy (external beam 60 to 74 Gy, or brachytherapy for lesions under 4 cm) is an organ-sparing choice with local control in about 70 to 85%, and strictures in some.
• T2 to T3 involving the shaft or corpora: partial penectomy with a 1 to 2 cm margin where a functional stump can be kept (voiding standing). Total penectomy with perineal urethrostomy for extensive disease or when the stump is inadequate (less than 2 to 3 cm).
• T4: total penectomy, emasculation, or neoadjuvant chemotherapy followed by surgery.
• Reconstruction: phalloplasty may be considered, and psychosexual support is vital.

Inguinal lymph node management

• cN0 disease: dynamic sentinel node biopsy or modified inguinal lymphadenectomy for intermediate and high-risk tumours. Surveillance for low risk. Positive nodes: completion radical inguinal lymphadenectomy.
• Palpable nodes (cN1 to cN2): bilateral inguinal lymphadenectomy, with pelvic lymphadenectomy when two or more inguinal nodes are positive, extranodal extension is present, or the pelvic nodes are suspicious on imaging. Minimally invasive (video endoscopic or robotic) approaches reduce wound complications.
• Fixed or bulky nodes (cN3): neoadjuvant chemotherapy, then consolidative surgery in responders.
• Adjuvant therapy after lymphadenectomy with pN2 or pN3, or extranodal extension: cisplatin-based chemotherapy (docetaxel, cisplatin and 5-fluorouracil, or paclitaxel, ifosfamide and cisplatin) with or without adjuvant chemoradiation to the pelvis and groins.
• Complications of lymphadenectomy: skin necrosis (up to 30%), wound infection, lymphocele, seroma, lymphoedema (30 to 60%), and thromboembolism. Reduce risk with sartorius muscle transposition, saphenous vein preservation, prophylactic antibiotics (cefazolin 2 g IV), enoxaparin 40 mg daily, compression stockings, and closed suction drains.

Systemic therapy for advanced disease

• Neoadjuvant: paclitaxel 175 mg/m2, ifosfamide 1200 mg/m2 days 1 to 3, cisplatin 25 mg/m2 days 1 to 3 (TIP), every 3 to 4 weeks for 4 cycles, with G-CSF and mesna. This yields a survival benefit in N2 or N3 disease, with response in about 50% and 5-year survival of about 50% for responders who go on to surgery.
• First-line metastatic: TIP or docetaxel with cisplatin and 5-fluorouracil, or carboplatin-based regimens for those who are cisplatin ineligible.
• Second-line: paclitaxel, docetaxel or vinflunine 320 mg/m2 every 3 weeks, EGFR inhibitors (panitumumab, cetuximab 400 mg/m2 then 250 mg/m2 weekly) and checkpoint inhibitors (pembrolizumab 200 mg every 3 weeks for MSI-high or tumour mutational burden-high tumours), with limited evidence.
• Palliative radiotherapy for pain, bleeding or bone metastases (8 Gy single fraction or 20 Gy in 5 fractions), and hypercalcaemia treated with IV hydration and zoledronic acid 4 mg.

Supportive and psychosexual care

• Psychological counselling, sexual rehabilitation, erectile aids after partial penectomy, and specialist input in penile cancer centres (multidisciplinary care improves outcome).
• Stoma and urethrostomy care, wound management, and lymphoedema therapy with compression and manual lymph drainage.
• Prevention: neonatal circumcision, hygiene, treatment of phimosis and lichen sclerosus, HPV vaccination, smoking cessation.

Follow-up

• Frequent follow-up in the first 2 years, when most recurrences occur: every 3 months for years 1 and 2, every 6 months in years 3 to 5 (less frequent for low-risk disease). Examination of the penis and groin, with imaging (ultrasound, CT or MRI) in node-positive and high-risk patients. Local recurrence after organ-sparing treatment occurs in 5 to 30% and is usually salvageable by surgery.
• Teach self-examination of the penis and groin.