EAU & ASCO: Penile Cancer 2023

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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.

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

References

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