EAU & ASCO: Penile Cancer 2023

See Original Guidelines

Background

• Penile cancer negatively impacts quality of life through
  • Physical and emotional changes
  • Feelings of mutilation
  • Loss of masculinity
  • Voiding and sexual dysfunction, which in turn can result in relationship breakdowns and withdrawal from society
  • Lymphedema

Epidemiology

• Uncommon in industrialized countries
• More common in South America, Southeast Asia, and parts of Africa
• Race
  • Highest incidence in white Hispanics, followed by Alaskans and Native American Indians, African Americans, white non-Hispanics.
• Increasing incidence in Western/developed countries most likely due to higher infection rates of HPV

Pathophysiology

Risk factors

• Human papilloma virus (HPV)
  • Most important risk factor
  • Most frequent HPV genotypes: HPV16 followed by HPV6
  • Risk of penile cancer is increased in patients with condyloma acuminata
  • Female sexual partners of patients with penile cancer have not been found to have an increased incidence of cervical cancer
  • No general recommendation (except in a few countries) for HPV vaccination in males because of the different HPV-associated risk patterns in penile- and cervical cancer
    • Since up to 50% of invasive penile carcinomas and 80% of preneoplastic lesions are HPV-associated, HPV vaccination is encouraged
• Phimosis
  • Strongly associated with invasive penile cancer, due to associated chronic infections
  • Smegma is not a carcinogen
  • Neonatal circumcision reduces the incidence of penile cancer, but does not reduce the risk of Penile Intraepithelial Neoplasia
• Chronic penile inflammation
• Lichen sclerosus
• Ultraviolet A phototherapy
• Cigarette smoking
• Low level of education
• Low socio-economic status

Pathology

• >95% of penile cancers are squamous cell carcinomas (SCCs)
• Other malignant lesions of the penis
  • Melanoma
  • Mesenchymal tumors
  • Lymphomas
  • Metastases
    • Penile metastases are frequently of prostatic, urinary bladder or colorectal origin
  • Sarcoma

Penile Squamous Cell Carcinoma

• Usually arises from the epithelium of the inner prepuce or the glans
• Subtypes
  • HPV-independent
    • Usual
    • Pseudohyperplastic
    • Pseudoglandular
    • Verrucous
    • Caniculatum
    • Papillary
    • Sarcomatoid (Most aggressive and worse prognosis)
    • Mixed
  • HPV-associated
    • Basaloid (most common among HPV-associated penile carcinomas)
    • Warty
    • Clear cell
    • Lymphoepithelioma-like
    • Mixed
• Penile intraepithelial neoplasia is considered the precursor lesion of penile SCC
  • Clinical terms such as ‘Erythroplasia of Queyrat, Bowenoid papulosis and Bowen’s disease’ are discouraged
  • Penile intraepithelial neoplasia is also classified as HPV-independent and HPV-associated

Grading

• The tumour, node, metastasis (TNM) classification for penile cancer includes tumour grade based on its prognostic relevance
• Highly observer-dependent and can be problematic, especially in large tumours which may be heterogeneous
• Based on
  • Cytological atypica
  • Keratinisation
  • Intercellular bridges
  • Mitotic activity
  • Tumour margin
• Classified into
  • Grade 1
  • Grade 2
  • Grade 3
  • Sarcomatoid
    • Grade 3 and sarcomatoid are considered poorly differentiated

TNM Staging

• Based on 8th edition of AJCC, last updated in 2017

Primary Tumor (T)

• TX: Primary tumour cannot be assessed
• T0: No evidence of primary tumour
• Tis: Carcinoma in situ (Penile Intraepithelial Neoplasia – PeIN)
• Ta: Non-invasive verrucous carcinoma
• T1: Tumour invades subepithelial connective tissue
  • T1a: without lymphovascular invasion or perineural invasion and is not poorly differentiated
  • T1b: with lymphovascular invasion or perineural invasion or is poorly differentiated
• T2: Tumour invades corpus spongiosum with or without invasion of the urethra
• T3: Tumour invades corpus cavernosum with or without invasion of the urethra
• T4: Tumour invades other adjacent structures

Regional Lymph Nodes (N)

• Clinical
  • cN0: No palpable or visibly enlarged inguinal lymph nodes
  • cN1: Palpable mobile unilateral inguinal lymph node
  • cN2: Palpable mobile multiple or bilateral inguinal lymph nodes
  • cN3: Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral
• Pathological
  • pN0 No regional lymph node metastasis
  • pN1 Metastasis in one or two inguinal lymph nodes
  • pN2 Metastasis in more than two unilateral inguinal nodes or bilateral inguinal lymph nodes
  • pN3 Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis

Distant Metastasis (M)

• M0: No distant metastasis
• M1: Distant metastasis

Diagnosis and Evaluation

Penile biopsy

• In most cases, acquiring a punch biopsy (e.g., 2–3 mm) under local anaesthesia is sufficient to confirm the diagnosis.
• in cases where assessment of depth of invasion is necessary, an incisional biopsy which is deep enough to properly assess the degree of invasion and stage is preferable.
• Tissue sections determine the accuracy of histological diagnosis.
  • Small lesions should be fully included
  • Bigger lesions should have at least 3-4 blocks of tumour with the anatomical landmarks
• Second-opinion pathology review is recommended given the rarity of this cancer
• The pathology report must include
  • Surgical procedure
  • Anatomical site of the primary tumour
  • Size of tumour
  • Maximum thickness
  • Histological type of SCC
  • Grade
  • Depth and extent of invasion
  • Vascular invasion (venous/lymphatic)
  • Perineural invasion
  • Surgical margins
  • HPV assessment

Management

• Patients should be referred to comprehensive referral centers for penile cancer

Prognosis

• Overall 5-year survival: 67%
  • Localized disease: 81%
  • Distant metastasis: 18%
• Prognostic factors
  • Pathological subtype
  • Peri-neural invasion
  • Lymphovascular invasion
  • Depth of invasion
  • Grade in the primary tumour
  • Extent of LN metastasis and extracapsular spread
    • Extra-capsular extension in even one single LN carries a poor prognosis and is denoted as pN3