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
  • Record the presence, number, laterality and characteristics of any palpable/suspicious inguinal 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
  • Indications (2)
    1. Uncertainty if the tumour invades the cavernosal bodies (cT3)
    2. Organ-sparing treatment options (e.g., glansectomy) are considered
  • Magnetic resonance imaging with and without artificial erection showed similar accuracy in local staging
• Penile ultrasound
  • Can be considered, if MRI not available

Distant

• Indications
  • Clinically node-positive patients
• Modality
  • 18FDG-PET/CT
    • Imaging with 18FDG-PET/CT is likely to be more accurate than CT alone
    • CT and MRI have similar sensitivity and specificity for lymph node metastasis

Penile biopsy

• Indications
  • Absolute
    • When malignancy is not clinically obvious, or when non-surgical treatment of the primary lesion is planned (e.g., topical agents, laser, radiotherapy).
  • Relative
    • All suspected cases of penile cancer
      • 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
  • 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
      • High-risk tumors: T1b or higher
    • Optional for intermediate-risk (pT1a G2)
      • Surveillance is an alternative to surgical staging in patients willing to comply with strict follow-up
  • Options
    • Dynamic sentinel node biopsy (DSNB) (preferred)
      • Developed to avoid resecting unnecessary LNs and thereby minimizing the morbidity of surgical staging
      • A sentinel node (SN) is defined as the first LN on a direct drainage pathway from the primary tumour.
        • Based on this concept, it is assumed that if the SN is negative, this indicates the absence of lymphatic tumour spread in the corresponding inguinal basin. In case histopathology identifies SN (micro)metastasis, ipsilateral completion ILND is indicated
      • High diagnostic accuracy and low complication rates, especially when performed in experienced centres (sensitivity 92–96%, false negative rates 4–8%, complication rate 6–14%)
      • Technique
        • 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
      • If DSNB is not available, and referral to a centre with experience with DSNB is not feasible, or if the patient does not want to run the risk of a false-negative procedure, ILND (modified/superficial/video-endoscopic) can be considered after informing the patient of the inherent risk of higher morbidity associated with these procedures.
    • 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

Clinically node-positive patients (cN+)

• Lymph node metastasis should preferably be histopathologically confirmed by image-guided biopsy (e.g., US or CT) before initiating treatment.

Management

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

Primary Tumour

• Aims of the treatment of the primary tumour is complete tumour removal with as much organ preservation as possible (without compromising oncological control)
  • Fully functional penis is central to
    • Sexual functioning
    • Urination
    • Sense of wholeness, desirability and masculinity
• No RCTs or observational comparative studies for any of the treatment options for localised penile cancer
• Penile preservation appears to be superior in functional and cosmetic outcomes as compared to partial or total penectomy and is considered to be the primary treatment method for localised penile cancer
• With surgical treatment, negative surgical margins for invasive carcinoma must be obtained.
• Local treatment modalities for small and localised penile cancer include
  • Topical therapy
  • Laser ablation
  • Excisional surgery
  • External beam radiotherapy (EBRT)
  • Brachytherapy

Treatment of superficial non-invasive disease (PeIN, Ta)

• Most PeIN lesions are located on the mucosal surfaces of the glans or prepuce whilst lichen sclerosus also affects the prepuce
• Management
  • Circumcision should be the primary surgical option
    • Following circumcision, the glans mucosa keratinizes over a period of 3–6 months and any residual PeIN or lichen sclerosus may resolve. Close monitoring before starting additional therapy has been advocated
  • Topical therapies
    • Options
      • Imiquimod
        • Commonly used 3 times per week for 12 weeks
      • 5-fluorouracil
        • Although no standard protocol exists, leaving the 5-FU ointment on for 12 hours every 48 hours during a 4 to 6-week treatment course is often recommended
      • Discontinuation of topical agents due to side effects observed in 12% of cases
      • Insufficient responses and recurrences may signify underlying invasive disease, hence, if topical treatment fails, it should not be repeated
  • Laser ablation
    • Options
      • Neodymium:Yttrium-Aluminium-Garnet (Nd:YAG, penetration 4–6 mm, wavelength 1064 nm)
      • Carbon dioxide (CO2, penetration < 1 mm, wavelength 10600 nm) lasers
      • Photodynamic therapy
  • Surgery
    • Extensive PeIN, residual PeIN in resection margins or recurrent disease after ablative or topical therapy, can be treated by surgical excision
    • Glans resurfacing consists of full thickness removal of the glandular epithelium followed by reconstruction with a graft
• Despite treatment, penile intra-epithelial neoplasia can progress to invasive lesions in 2.6–13% of patients

Treatment of invasive disease confined to the glans (cT1/T2)

• Treatment choice depends on tumour size, histology, stage and grade, localisation and patient preference.
  • When feasible, small and localised invasive lesions should receive organ-sparing treatment.
    • Organ-sparing surgery associated with higher recurrence rates than amputative surgery
• Foreskin tumours
  • Treated by ‘radical’ circumcision.
    • In addition to treating preputial penile cancer, circumcision combined with topical treatment, laser therapy or brachytherapy, facilitates follow-up examinations
• For glandular and coronal lesions
  • Surgical options
    • Wide local excision
    • Partial glansectomy
    • Total glansectomy with reconstruction
    • Additional circumcision is advised in glandular tumours.
  • Non-surgical options
    • External beam radiotherapy and brachytherapy
    • Laser therapy of small lesions has been reported but the risk of invasive disease must be recognised, and the recurrence risk is high, possibly as a result of the limited tissue penetration depth of laser ablation.
• Width of negative surgical margins
  • Macroscopic margins can indeed be minimal, specifically in smaller and less aggressive lesions
    • Standard excision must include a margin of clinically normal-appearing skin around the tumour and surrounding erythema. However, for bulky or higher-grade lesions where local recurrence may have an impact on survival, adoption of a wider margin or partial penectomy may be prudent
• Use of intra-operative frozen section assessment
  • Not routinely recommended
  • Helpful tool to achieve definitive tumour-free margin in cases of doubt on the radicality of the resection
• Laser ablation
  • An option for smaller invasive lesions
    • Likely best limited to T1 tumours
  • Options
    • CO2 laser
    • Nd:YAG laser
• Moh’s micrographic surgery
  • A surgical technique by which tissue is excised and processed with en face histological margins in real time to give a complete circumferential and deep margin
    • Aims at maximal organ-preservation by adopting margin-guided excision
  • As data are very limited, it is not routinely recommended
• Surgical
  • Wide local excision and circumcision
  • Glans resurfacing
  • Glansectomy
  • Partial penectomy
• Radiotherapy for T1 and T2 disease

Locally advanced disease (T3–T4)

• Resectable disease
• Non-resectable disease

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