What is the best treatment approach for an older male patient with penile extra-mammary Paget's disease (EMPD) with invasive adenocarcinoma?

Treatment of Penile Extramammary Paget's Disease with Invasive Adenocarcinoma

For penile extramammary Paget's disease (EMPD) with invasive adenocarcinoma, surgical resection with curative intent is the preferred treatment, requiring wide local excision or partial penectomy with negative margins confirmed by intraoperative frozen section analysis. 1

Primary Treatment Approach

Surgical Management (First-Line)

Surgical excision remains the definitive treatment for invasive EMPD. 1, 2 The surgical approach must be tailored to the depth of invasion and extent of disease:

• For invasive disease: Wide local excision or partial penectomy is required depending on the depth of invasion and involvement of penile structures 1, 2
• Surgical margins: 5-10 mm margins are adequate for tumor control, contrary to older recommendations requiring 2 cm margins 3, 4
• Intraoperative frozen section analysis: This is critical to achieve negative margins at the time of initial surgery 3, 4
• If corpora cavernosa invasion (T3): Partial or total penectomy is necessary 3

Mohs Micrographic Surgery Consideration

Mohs surgery is the surgical treatment of choice when feasible, as it allows precise margin control while minimizing tissue sacrifice 2. However, this technique requires specialized expertise and may not be available in all centers 5.

Lymph Node Management

Inguinal lymph node assessment is essential given the metastatic potential of invasive EMPD. 1

• Clinical examination: Assess for palpable inguinal lymphadenopathy bilaterally 3
• Routine sentinel lymph node biopsy or lymph node dissection is NOT recommended for EMPD unless there is clinical evidence of nodal involvement 1
• If palpable nodes present: Fine-needle aspiration should be performed, and if positive, inguinal lymph node dissection (ILND) is indicated 3
• For bulky nodal disease (≥4 cm): Consider neoadjuvant chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP regimen) prior to ILND 3

Non-Surgical Options (For Unresectable or Medically Inoperable Cases)

If the patient cannot undergo surgery due to medical comorbidities or extensive unresectable disease:

• Chemoradiation therapy: External beam radiation (45-50.4 Gy to the penile shaft and inguinal nodes, with boost to 60-70 Gy to the primary lesion) combined with chemotherapy 3, 6
• Systemic chemotherapy: For distant metastatic disease, platinum-based chemotherapy or individualized targeted approaches 1
• Alternative modalities (for intraepidermal disease only): Imiquimod, photodynamic therapy, CO2 laser therapy, or radiotherapy alone 1, 2, 7

Important caveat: These non-surgical approaches have inferior cure rates compared to surgical resection for invasive disease 1. One case report documented complete clinical response with chemoradiation followed by systemic chemotherapy in stage III perianal EMPD, but this requires ongoing surveillance 6.

Screening for Secondary EMPD

Malignancy screening appropriate for age and anatomical site must be performed at baseline to distinguish primary from secondary EMPD, as secondary EMPD (associated with internal malignancies) accounts for approximately 25% of cases 6, 1. This includes:

• Colonoscopy for perianal/penile lesions
• Cystoscopy if urethral involvement suspected
• Age-appropriate cancer screening

Surveillance Protocol

Close follow-up is mandatory for at least 5 years given high recurrence rates. 1

• Years 1-2: Clinical examination every 3 months 3, 1
• Years 3-5: Clinical examination every 6 months 3, 1
• Beyond 5 years: Annual examination 3
• Imaging: For invasive disease, chest imaging (CT or X-ray) and abdominopelvic imaging (CT or MRI) should be performed every 3-6 months for the first 2 years 3

Critical Pitfalls to Avoid

• Inadequate initial margins: EMPD has ill-defined borders that can extend beyond clinical boundaries, leading to positive margins and recurrence 5. Always use frozen section analysis intraoperatively 3
• Underestimating invasion depth: Multiple skin biopsies, including any nodular areas, are critical for accurate diagnosis and staging 1
• Delaying surgery: While non-surgical modalities exist, cure rates are superior with surgical approaches for invasive disease 1
• Inadequate follow-up: Local recurrence rates are significant even after wide excision, necessitating lifelong surveillance 7, 5

Prognostic Factors

Poor prognostic indicators include: nodule formation, tumor thickness, dermal invasion, lymphovascular invasion, and perianal location 5. Tumor thickness (depth of invasion) correlates more strongly with prognosis than tumor size 5.