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

History and Physical Exam

History

• Risk factors for penile cancer (see above)

Physical exam

• Penis
  • Often presents as raised or ulcerous lesions which can be locally destructive
    • Can sometimes be hidden under the foreskin in case of phimosis
  • Dimensions, anatomic location, and extent of local invasion should be noted
  • Examine entire penis to identify potential skip lesions
  • Assess stretched penile length
• Inguinal lymph nodes
  • Reliable physical examination can be challenging in case of obesity and in patients with previous inguinal surgery
  • Enlarged LNs secondary to infection of the primary tumour (rather than metastasis) can occur
    • The use of antibiotics with the aim to resolve enlarged nodes may delay further staging and treatment and is not recommended
  • Based on physical examination, patients can be divided into
    • Those without suspicious nodes at physical examination (clinically node-negative, cN0),
    • Those with suspicious palpable nodes (clinically node-positive, cN+).
      • In case of suspected pathologic LNs at palpation; the number, location, size and whether the node is fixed or mobile, should be noted.

Imaging

Regional

• MRI
  • Not routinely indicated
    • Physical examination is a reliable method for estimating penile tumour size and clinical T stage
  • When there is uncertainty if the tumour invades the cavernosal bodies (cT3), and if organ-sparing treatment options (e.g., glansectomy) are considered, MRI can be helpful
  • Magnetic resonance imaging with and without artificial erection showed similar accuracy in local staging
• Penile ultrasound
  • Can be considered, if MRI not available

Distant

• Only indicated in clinically node-positive patients

Penile biopsy

• Indications
  • Should be obtained when there is doubt about the exact nature of the lesion
  • Even in clinically obvious cases, histological information from a biopsy can facilitate treatment decisions (such as indications for surgical staging).
• Technique
  • 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

Lymph node staging

• Penile cancer metastasizes in a stepwise manner through the lymphatic system, initially to the inguinal nodes, then the pelvic nodes and finally to distant nodes
  • initial LN staging is focused on identifying (micro)metastatic disease in the inguinal LNs as early as possible
• Detecting lymphatic spread as early as possible is a crucial element in penile cancer management.

Clinically node-negative patients (cN0)

• Approximately 20-25% of cN0 patients may still harbour occult metastases, so additional staging is warranted
• Non-surgical staging options
  • Imaging
    • Not reliable to evaluate clinically node-negative patients
      • Conventional imaging modalities such as US, computed tomography (CT) or MRI cannot detect micrometastases
      • 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) does not detect LN metastases < 10 mm
      • These imaging modalities can be of value to detect enlarged/abnormal nodes in patients when physical examination is challenging (e.g., due to obesity).
• Surgical staging
  • Invasive/surgical staging remains indispensable to identify micro-metastasis before nodal metastases become palpable/visible.
  • Indications
    • Recommended for high-risk tumors
      • T1 with presence of
        • Lympho-vascular invasion OR
        • Peri-neural invasion OR
        • Poorly differentiated
      • T2–T4 with any grade
    • Optional for intermediate-risk (pT1a G2)
      • Risk of lymph node metastasis should be considered on a case-by-case basis
  • Options
    • Dynamic sentinel node biopsy (DSNB)
      • Inguinal US is obtained prior to DSNB
        • If sonographically suspicious nodes are detected, fine needle aspiration cytology (FNAC) can easily be performed in the same session to confirm the diagnosis of inguinal LN metastasis
          • if US + FNAC is positive, it can reduce the need for DSNB and allow for additional staging and therapeutic LN dissection at an earlier stage
    • Inguinal lymph node dissection (ILND)
      • Radical inguinal lymph node dissection (ILND) is the most accurate surgical staging method, but is associated with the highest complication rates
      • Modified ILND lowers morbidity while maintaining sufficient sensitivity
        • Modifications in modified ILND
          • Shorter skin incision
          • No dissection lateral to the femoral artery
          • No dissection caudal to the fossa ovalis
          • Preservation of the saphenous vein
      • Video-endoscopic/robot-assisted radical LND has been introduced more recently
        • Similar lymph node yield compared to open
        • Reduces wound-related complications compared to open ILND, but no significant reduction in lymphatic complications
          • Main predictor of lymphatic complications is the number of lymph nodes removed

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
  • Presence and extent of nodal metastases
    • Most important prognostic factor for survival
    • Extra-capsular extension in even one single LN carries a poor prognosis and is denoted as pN3
  • Depth of invasion
  • Grade in the primary tumour
  • Pathological subtype
  • Peri-neural invasion
  • Lymphovascular invasion