Residency · Residency · Urology

Penile Cancer and Premalignant Lesions

Epidemiology and Risk Factors

Penile cancer is a rare malignancy in developed countries, with an incidence of approximately 1 in 100,000 men in the United States. However, its occurrence is notably higher in regions such as South America, Africa, and Southeast Asia. The peak incidence typically occurs in the sixth to seventh decades of life. Several major risk factors contribute to the development of penile cancer. Phimosis, a condition characterized by the inability to retract the foreskin, increases the relative risk by three to five times. Human papillomavirus (HPV) infection, particularly with types 16 and 18, is detected in about half of penile squamous cell carcinomas (SCC). Chronic inflammatory conditions such as lichen sclerosus or balanitis xerotica obliterans (BXO) also predispose to malignancy. Tobacco use, poor hygiene, and lack of circumcision further elevate risk. Exposure to ultraviolet phototherapy (PUVA) has been implicated as well. Neonatal circumcision is protective against penile cancer, whereas adult circumcision offers less benefit.

Premalignant Lesions

Penile Intraepithelial Neoplasia (PeIN)

Penile intraepithelial neoplasia (PeIN) represents premalignant epithelial changes and is classified into two main types. Differentiated PeIN, which is not related to HPV infection, is often associated with lichen sclerosus and carries a lower risk of progression to invasive cancer. In contrast, undifferentiated PeIN, which includes basaloid and warty subtypes, is HPV-related and has a higher risk of malignant transformation. Historically, these lesions were described by different names depending on their location and appearance: erythroplasia of Queyrat refers to lesions on the glans, Bowen disease to those on the penile shaft, and bowenoid papulosis to multiple papules seen in younger patients.

Specific Premalignant Conditions

Several specific premalignant conditions warrant attention. Leukoplakia presents as a white plaque on the penile skin and carries a 15-20% risk of malignant transformation. Cutaneous horns are keratinized, exophytic growths, with approximately 30% harboring underlying malignancy. Giant condyloma, also known as Buschke-Lowenstein tumor, is a verrucous, locally destructive lesion caused by HPV types 6 and 11.

Evaluation of Premalignant Lesions

Any persistent, atypical, or treatment-resistant penile lesion mandates biopsy to establish a definitive diagnosis. Preferred biopsy techniques include punch biopsies measuring 4 to 6 millimeters or excisional biopsies when feasible. Treatment options depend on the extent of the lesion and may include topical agents such as 5-fluorouracil (5-FU) or imiquimod, laser ablation, or wide local excision.

<image>Clinical photographs of premalignant penile lesions including erythroplasia of Queyrat and Bowen disease</image>

Pathology of Penile Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) accounts for over 95% of penile malignancies. Histologically, SCC is classified into several subtypes. The usual type is the most common, comprising approximately 50-70% of cases. Basaloid SCC is aggressive and HPV-related, while the warty subtype is also HPV-related but generally has a better prognosis. Verrucous carcinoma is well-differentiated and rarely metastasizes. Sarcomatoid carcinoma is aggressive and associated with poor outcomes. Mixed histologies can also occur. Tumor grading ranges from G1 (well-differentiated) to G3 (poorly differentiated). The presence of lymphovascular invasion (LVI) is a critical adverse prognostic factor, and perineural invasion similarly predicts worse clinical outcomes.

TNM Staging (AJCC 8th Edition)

The TNM staging system for penile cancer categorizes tumors based on depth of invasion and nodal involvement. T1a tumors are characterized by the absence of LVI and are graded G1 or G2. T1b tumors exhibit either LVI or are graded G3. T2 tumors invade the corpus spongiosum, while T3 tumors extend into the corpus cavernosum. T4 tumors invade adjacent structures such as the urethra, prostate, or pubic bone. Nodal staging is based on clinical examination: cN0 indicates no palpable nodes; cN1 denotes a palpable, mobile, unilateral inguinal node; cN2 refers to palpable, mobile bilateral or multiple inguinal nodes; and cN3 describes fixed nodal masses or pelvic lymphadenopathy.

<image>Diagram of penile cancer TNM staging system showing depth of invasion through penile structures</image>

Primary Tumor Management

Organ-Sparing Approaches (Preferred When Feasible)

Organ-sparing treatments are preferred when oncologically appropriate to preserve penile function. Topical therapies such as 5-FU and imiquimod are suitable for carcinoma in situ (Tis) and selected superficial tumors (Ta). Laser ablation using Nd:YAG or CO2 lasers can be employed for Tis, Ta, and T1a lesions on the glans. Glans resurfacing involves removal of the glans epithelium followed by split-thickness skin grafting and is indicated for carcinoma in situ or superficial tumors of the glans. Wide local excision aims for a negative surgical margin of 5 millimeters, a reduction from historically larger margins based on recent evidence. Glansectomy with reconstruction is appropriate for T1 to T2 tumors confined to the glans.

Penectomy

Partial penectomy is reserved for T2 or higher tumors, with a 5-millimeter histologic margin considered adequate. The residual penile stump must be sufficient to allow standing voiding, ideally exceeding 3 centimeters in length. Total penectomy with perineal urethrostomy is indicated for extensive T3 to T4 tumors or when the remaining stump is too short for functional voiding.

Margin Assessment

Intraoperative frozen section analysis is recommended to ensure negative surgical margins. Positive margins are associated with a high local recurrence rate of approximately 30%.

Inguinal Lymph Node Management

The status of the inguinal lymph nodes is the most important prognostic factor for survival in penile cancer. Patients with node-negative disease have a 5-year cancer-specific survival (CSS) rate of about 85-90%, whereas those with positive nodes have a significantly lower survival rate of 30-50%.

Clinically Node-Negative (cN0)

For patients with low-risk tumors—defined as Tis, Ta, or T1a G1-G2 without LVI—surveillance is appropriate. However, those with intermediate or high-risk features, including T1b or higher, G3 grade, or presence of LVI, require invasive inguinal staging. Dynamic sentinel node biopsy (DSNB), which involves technetium-99m and blue dye injection, has a sensitivity of approximately 90-95% in experienced centers and is recommended by the European Association of Urology (EAU) for intermediate-risk cN0 patients. Modified inguinal lymph node dissection involves limited dissection within Daseler zones, which are medial to the femoral artery and bounded superiorly and inferiorly. The boundaries of superficial inguinal dissection include the inguinal ligament superiorly, the adductor longus muscle medially, the sartorius muscle laterally, and the apex of the femoral triangle inferiorly.

Clinically Node-Positive (cN+)

In patients with palpable inguinal nodes, fine needle aspiration (FNA) or core biopsy is performed to confirm metastasis. If positive, radical inguinal lymph node dissection is indicated, with bilateral dissection if nodes are palpable on both sides. Pelvic lymph node dissection is recommended if there are two or more positive inguinal nodes or evidence of extranodal extension. Neoadjuvant chemotherapy using the TIP regimen—paclitaxel, ifosfamide, and cisplatin—is administered for fixed or bulky (cN3) nodal disease prior to surgery.

<image>Anatomical diagram of inguinal lymph node dissection boundaries showing superficial and deep compartments</image>

Complications of Inguinal Lymphadenectomy

Inguinal lymphadenectomy carries a high risk of complications. Wound infection and dehiscence occur in 30-50% of cases, as does lymphedema. Skin flap necrosis and deep vein thrombosis (DVT) are additional concerns. Techniques such as sparing the saphenous vein can reduce morbidity. Transposition of the sartorius muscle is commonly performed to cover and protect the femoral vessels.

Systemic Therapy

Neoadjuvant chemotherapy with the TIP regimen is indicated for patients with cN3 or bulky nodal disease, achieving response rates of 40-50%. Adjuvant chemotherapy may be considered for patients with pN2 or pN3 disease following lymphadenectomy. Palliative chemotherapy, typically cisplatin-based regimens, offers modest response rates in advanced disease. Immunotherapy with agents such as pembrolizumab and other checkpoint inhibitors is under investigation, with early data showing promise in PD-L1 positive tumors. Targeted therapies, including epidermal growth factor receptor (EGFR) inhibitors like cetuximab, have been studied in small series.

HPV and Prevention

HPV type 16 is the most common oncogenic strain associated with penile SCC. Vaccination with the nonavalent HPV vaccine is recommended for males aged 9 to 26 years and may reduce the incidence of HPV-related penile cancer. Circumcision also reduces the risk of acquiring HPV infection.

<image>Algorithm for the management of penile cancer from diagnosis through primary treatment and inguinal node management</image>

Clinical Pearls

Any persistent penile lesion in an uncircumcised male should prompt biopsy rather than empirical treatment beyond four to six weeks, as early diagnosis is critical. Surgical margins of 5 millimeters are oncologically adequate for penile SCC, a standard supported by multiple series, and larger margins unnecessarily compromise function. The introduction of dynamic sentinel node biopsy has revolutionized the management of clinically node-negative patients by reducing the morbidity associated with unnecessary full lymphadenectomy while maintaining accurate staging. Importantly, the status of the inguinal lymph nodes, rather than the primary tumor stage, is the strongest predictor of survival. Wound complications following inguinal lymphadenectomy are extremely common, necessitating meticulous skin flap management and careful drain care. Current EAU guidelines recommend offering invasive staging procedures, such as DSNB or modified lymphadenectomy, to all intermediate and high-risk clinically node-negative patients instead of surveillance alone.

References

• EAU Guidelines on Penile Cancer, 2024 Update
• AUA/ASTRO Guidelines on Penile Cancer
• Hakenberg OW, et al. "EAU Guidelines on Penile Cancer." Eur Urol. 2015;67(1):142-150.
• Djajadiningrat RS, et al. "Dynamic sentinel node biopsy in penile carcinoma." Eur Urol. 2014;66(6):1055-1063.
• Pagliaro LC, et al. "Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer." J Clin Oncol. 2010;28(24):3851-3857.
• Campbell-Walsh-Wein Urology, 12th Edition, Chapter on Penile Cancer

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