Penile Cancer: Epidemiology, Risk Factors & Pathology

• Penile cancer has a significant impact on quality of life, with many unmet needs

Introduction

• The guideline panel stresses the importance of addressing emotional, social, and physical needs early through a holistic, multidisciplinary approach

Epidemiology

• Penile cancer incidence increases with age, peaking in the sixth decade, but can occur in younger patients
• Most common in regions with high HPV prevalence
• Approximately one third to half of cases are attributed to HPV-related carcinogenesis
• Slight increase in incidence in Western/developed countries, likely due to higher HPV infection rates

Risk Factors

• HPV infection is the primary risk factor
• Other risk factors include:
  • Phimosis
  • Chronic penile inflammation
  • Lichen sclerosus
  • Smoking
  • Ultraviolet A phototherapy
  • Low socio-economic status

Pathology

• Squamous cell carcinoma (SCC) accounts for over 95% of penile malignancies
• There are different histological subtypes of SCC with distinct growth patterns, clinical aggressiveness, and HPV associations
• Numerous mixed forms exist, with warty-basaloid being the most common (50-60%)
• Penile Intraepithelial Neoplasia (PeIN) is considered a precursor lesion
• Other malignant lesions (melanocytic, sarcomatoid, mesenchymal tumours, lymphomas, metastases) are extremely rare in comparison to SCC

Pathology Report

• International Collaboration on Cancer Reporting (ICCR) dataset template should be used for standardization and data collection
• Report must include:
  • Anatomical site of the primary tumour
  • Histological type of SCC
  • Grade
  • Perineural invasion
  • Depth of invasion
  • Vascular invasion (venous/lymphatic)
  • Irregular growth pattern and front of invasion
  • Urethral invasion
  • Invasion of corpus spongiosum/cavernosum
  • Surgical margins
  • P16 immunohistochemistry (IHC) results

Staging and Classification Systems

• The 8th edition of the UICC/AJCC TNM should be used
• Clinical classifications:
  • TX: Primary tumour cannot be assessed
  • T0: No evidence of primary tumour
  • Tis: Carcinoma in situ (PeIN)
  • Ta: Non-invasive localized squamous cell carcinoma
  • T1: Tumour invades subepithelial connective tissue
    • T1a: Tumour invades subepithelial connective tissue without lymphovascular/perineural invasion and is not poorly differentiated
    • T1b: Tumour invades subepithelial connective tissue with lymphovascular/perineural invasion or is poorly differentiated
  • T2: Tumour invades corpus spongiosum with or without urethral invasion
  • T3: Tumour invades corpus cavernosum with or without urethral invasion
  • T4: Tumour invades other adjacent structures
• Additional classifications are:
  • N - Regional lymph nodes
  • M - Distant metastasis
  • Pathologic classifications
  • pN - Regional Lymph nodes
  • pM - Distant metastasis
  • G - Histopathological grading

Diagnosis and Staging

• Physical examination should include inspection and palpation of the entire penis and groins, noting dimensions, anatomic location, and local invasion extent
• Physical examination is key for estimating penile tumour size and clinical T stage
• Careful palpation of both groins for enlarged/pathologic inguinal lymph nodes (LNs) must be part of initial exam
• Penile biopsy of the primary tumour is necessary for histological confirmation to guide management

Imaging of the primary tumour

• Magnetic resonance imaging (MRI) is used in case of uncertainty if the tumour invades the cavernosal bodies (cT3), and if organ-sparing treatment options are considered.
• Ultrasound (US) can be considered if MRI is not available.

Lymph Node Staging

• Presence and extent of LN metastasis is the most important prognostic factor
• Survival is better when LN metastases are removed in a micro-metastatic state (before they become palpable (cN0))
• Surgical staging is recommended in cN0 patients at high risk of having occult LN involvement (≥ pT1b)
• pT1a G2 tumours are considered intermediate-risk; surgical staging is not justified if low risk.
• Inguinal lymph node dissection (ILND) is most reliable, but has the highest morbidity
• Dynamic sentinel node biopsy (DSNB) has high diagnostic accuracy and low morbidity in high-volume centres
• Inguinal US + fine needle aspiration cytology (FNAC) of sonographically abnormal nodes can reduce the need of DSNB when tumour is positive
• Obtaining pathological confirmation by biopsy and additional imaging for staging pelvic LNs and distant sites is recommended for cN+ patients
• 18FDG-PET/CT imaging shows higher sensitivity/specificity than CT alone

Treatment of Primary Tumour

• Main aims are complete tumour removal balanced against organ preservation, without compromising oncological control
• Circumcision should be the first surgical option, with close monitoring, for superficial non-invasive disease (PeIN, Ta)
• Topical therapy with imiquimod (IQ) or 5-fluorouracil (5-FU) are effective non-invasive first-line treatment options
• Laser ablation is an alternative treatment option
• Surgical excision/glans resurfacing may be necessary for extensive PeIN, residual PeIN in resection margins, or recurrent disease after ablative therapy
• Treatment choice for invasive disease confined to the glans (cT1/T2)
  • Depends on tumour size, histology, stage, grade, localisation, and patient preference
  • Minimal resection margins (>1 mm) have to be oncologically safe
  • Organ sharing should be recommended when feasible
• Glansectomy is good for patients with tumours confined to the glans and prepuce not eligible for wide local excision or glans resurfacing
• Partial amputative surgery generally reserved for more advanced disease (≥ T3)
• Radiotherapy, either external beam or brachytherapy, is an alternative organ-preserving approach in selected patients with T1-2 lesions
  • Local recurrence after organ-sparing surgery may need a second procedure if no corpus cavernosum invasion For patients with locally advance disease (T3-T4) partial or total amputative surgery is the standard

Treatment of cN1-2 Disease

• Management of regional LNs is the most important prognostic factor
• Open radical ILND remains the standard of care for patients with cN1-2 disease, but carries significant morbidity
  • Minimally-invasive approaches have emerged

Prophylactic Pelvic Lymph Node Dissection (PLND)

• PLND in most cases represents a staging procedure, and if you have the following symptoms should be administered if
  • Three or more inguinal nodes are involved on one side on pathological examination,
  • extranodal extension is reported on pathological examination

Clinical N3 Disease

• Defined as a fixed inguinal mass or pelvic lymphadenopathy
• Surgery alone will not often cure patients with cN3 disease
• Inguinal LND in cN3 patients will often need, resection of overlying akin to effectively remove a fixed bulky nodal mass

Multimodal Chemotherapy/Radiotherapy

• Systemic therapy: platinum-based chemotherapy preferred for first-line palliative treatment
• Neoadjuvant chemotherapy (NAC) is suitable for patients with pelvic- and/ or extensive/fixed inguinal LN involvement or selected patients with bilateral involvement
• No strong data supporting adjuvant chemotherapy to improve OS
• Primary (definitive) and adjuvant radiotherapy for node-positive penile cancer remains controversial

Palliative Therapies for Advanced Disease

• Systemic therapy: low-level data supports platinum-based chemotherapy as preferred approach
• Role of radiotherapy in palliation is necessary for palliation of penile cancer, and customized for unique presentations

Follow-Up and Quality of Life

• Surveillance is important as early detection of recurrence may increase the likelihood of curative treatment
• Local or regional nodal recurrences usually occur within two years of primary treatment
• Penile cancer requires an extended multi-disciplinary team (urologists, specialists, nurses, pathologists, etc.)
• Follow-up three-monthly for 2 years, then less frequently
• Discuss the psychological impact of penile cancer and offer support and counselling services
• Discuss the negative impact of treatment for primary tumour so the patient is prepared for the challenges they may face
• Discuss lymphoedema impact and refer to therapists early