EAU & ASCO: Penile Cancer 2023

See Original Guidelines

See Penile Cancer: Squamous Penile Cancer Chapter Notes

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/Western/developed countries countries, but increasing in incidence
  • Increasing incidence most likely due to higher infection rates of HPV
• 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.

Pathophysiology

Risk factors (8)

1. 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
   • HPV vaccination
     • 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
2. 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 (PeIN)
3. Chronic penile inflammation
4. Lichen sclerosus
5. Ultraviolet A phototherapy
6. Cigarette smoking
7. Low level of education
8. 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 foreskin/prepuce or the glans

Classification

• 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

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
• Classification (4)
  • Grade 1
  • Grade 2
  • Grade 3
  • Sarcomatoid
    • Grade 3 and sarcomatoid are considered poorly differentiated

Penile intraepithelial neoplasia (PeIN)

• Considered the precursor lesion of penile SCC
• Clinical terms such as ‘Erythroplasia of Queyrat, Bowenoid papulosis and Bowen’s disease’ are discouraged
• Also classified as HPV-independent and HPV-associated

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 based on imaging, unilateral or bilateral
• Pathological
  • pN0 No regional lymph node metastasis
  • pN1 Metastasis in 1-2 inguinal lymph nodes
  • pN2 Metastasis in >2 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

UrologySchool.com Summary

Recommended

• History and Physical Exam
  • History
    • Risk factors for penile cancer
  • Physical exam
    • Penis
    • Inguinal lymph nodes
• Other
  • Penile biopsy

Optional

• Imaging
  • Regional
    • Penile MRI
      • Indications (2)
        1. Uncertainty if the tumour invades the cavernosal bodies (cT3)
        2. Organ-sparing treatment options (e.g., glansectomy) are considered
  • Distant
    • 18FDG-PET/CT
      • Indications (1)
        1. Clinically node positive disease

History and Physical Exam

History

• Risk factors for penile cancer (see above)

Physical exam

Penis/foreskin

• Often presents as raised or ulcerous lesions which can be locally destructive
  • Can sometimes be hidden under the foreskin/prepuce in case of phimosis
  • Most PeIN lesions are located on the mucosal surfaces of the glans or prepuce
    • Lichen sclerosus also affects the foreskin/prepuce
• Note the dimensions, anatomic location, and extent of local invasion
• Examine entire penis to identify potential skip lesions
• Assess stretched penile length

Inguinal lymph nodes

• False-negative
  • Reliable physical examination can be challenging in case of obesity and in patients with previous inguinal surgery
• False-positive
  • Enlarged LNs secondary to infection of the primary tumour (rather than metastasis) can occur
    • 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 (2)
  • 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

Local

• 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
• Modalities
  • MRI (preferred)
    • MRI with and without artificial erection showed similar accuracy in local staging
  • Penile ultrasound, if MRI not available

Regional/Distant

• Indications (1)
  1. 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

Management

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

Primary Tumour

• Aims of primary tumour treatment (2)
  1. Complete tumour removal with
  2. 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

Options

• Non-surgical (4)
  1. Topical therapy (2)
     1. Imiquimod
     2. 5-fluorouracil
  2. Laser therapy
  3. Radiation
     • Brachytherapy
     • External beam radiation
• Surgical
  • Organ-sparing (3)
    1. Circumcision
    2. Wide local excision
    3. Partial or total glansectomy, with or without reconstruction
  • Amputative (2)
    1. Partial amputation
    2. Radical amputation
• Organ-sparing approaches are considered to be the primary treatment method for localised penile cancer
  • Generally, penile-preserving surgery preserves superior functional, erectile and cosmetic outcomes compared to partial or total penectomy (amputation)
    • Glans sensation and orgasm can be affected in penile-preserving surgery
  • Patients should be informed about the higher risk of local recurrence with organ-sparing treatments, compared to amputative surgery
• No RCTs or observational comparative studies for any of the treatment options for localised penile cancer

Non-surgical

Topical

• Indications
  • Biopsy-confirmed PeIN
• Options
  1. Imiquimod
  2. 5-fluorouracil
• Dosing
  • Imiquimod
    • Commonly used 3 times per week for 12 weeks
  • 5-fluorouracil
    • No standard protocol exists
    • 5-FU ointment on for 12 hours every 48 hours during a 4 to 6-week treatment course is often recommended
• Adverse events
  • Discontinuation of topical agents due to side effects observed in 12% of cases

Laser

• Options
  • Neodymium:Yttrium-Aluminium-Garnet (Nd:YAG, penetration 4–6 mm, wavelength 1064 nm)
  • Carbon dioxide (CO2, penetration < 1 mm, wavelength 10600 nm)
• Indications
  • Biopsy-confirmed PeIN, Ta, or T1 lesions

Radiation

• Efficacy
  • 5-year recurrence-free survival improved with brachytherapy compared to EBRT (≈80% vs. ≈55%)
• Indications
  • Biopsy-confirmed T1 or T2 lesions

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
• Not routinely recommended as data are very limited

Surgical

• Pre-operative planning requires taking into consideration the
  • Size of the mass
  • Involvement of surrounding structures
  • Anticipated skin and soft tissue defects (as well as plastic surgical consultation (as appropriate))
• Organ-sparing
  • Options (3)
    1. Circumcision
       • Standard treatment for foreskin/preputial penile cancer
       • Facilitates follow-up in patients treated with topical treatment, laser therapy or brachytherapy, facilitates follow-up examinations
    2. Wide local excision
    3. Partial or total glansectomy, with or without reconstruction
       • Glans resurfacing
         • Consists of full thickness removal of the glandular epithelium followed by reconstruction with a graft
  • Indications
    • Lesions confined to the glans and prepuce (PeIN, Ta, T1–T2) and patient willing to comply with strict follow-up
• Amputative surgery (2)
  1. Partial penectomy
     • Indications
       1. Invasion of the corpora cavernosa (T3)
       2. Patient not willing to undergo organ-sparing surgery or not willing to comply with strict follow-up.
     • Efficacy
       • Risk of local recurrence ≈4–5%
  2. Total penectomy with perineal urethrostomy
     • Indications
       • Large invasive tumours not amenable to partial amputation
• With surgical treatment, negative surgical margins for invasive carcinoma must be obtained.
  • Width of negative surgical margin (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
  • Perform intra-operative frozen section analysis of resection margins in cases of doubt on the completeness of resection.
    • 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

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

• Options
  • Non-surgical
    • Topical therapies
      • Imiquimod
      • 5-fluorouracil
      • Insufficient responses and recurrences may signify underlying invasive disease, hence, if topical treatment fails, it should not be repeated
    • Laser ablation
  • Surgical
    • 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
    • Local excision
      • Extensive PeIN, residual PeIN in resection margins or recurrent disease after ablative or topical therapy, can be treated by surgical excision
      • Glans resurfacing
• 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.
• Glandular and coronal tumors
  • Non-surgical options
    • External beam radiotherapy and brachytherapy
      • Can be given as external radiotherapy with a minimum dose of 60 Gy combined with a brachytherapy boost or as brachytherapy alone
      • Brachytherapy has been studied only for lesions < 4 cm hence its use should be limited to tumours not exceeding this size
      • In the few studies comparing surgical treatment and radiotherapy, results of surgery were slightly better.
      • Complications of radiotherapy for penile cancer
        • Meatal/urethral stenosis
        • Glans necrosis
        • Late fibrosis of the corpora cavernosa
        • Pain with sexual intercourse
        • Dysuria
      • Local recurrence after radiotherapy can be salvaged by surgery
    • Laser ablation
      • Option for smaller invasive lesions (likely best limited to T1 tumours)
        • Laser therapy of small lesions has been reported but the risk of invasive disease must be recognized, and the recurrence risk is high, possibly as a result of the limited tissue penetration depth of laser ablation.
  • Surgical options
    • Wide local excision (and circumcision)
      • Lesions located on the corona or glans, limited in size, may be treated with wide local excision which should include a margin of clinically normal-appearing skin around the tumour and surrounding erythema
      • Additional circumcision is advised in glandular tumours.
    • Glansectomy (with or without reconstruction)
      • Patients with tumours confined to the glans and prepuce that are not eligible for wide local excision or glans resurfacing are good candidates for glansectomy
      • Split-thickness skin graft is commonly used to reconstruct a neo-glans
        • Poor candidates for graft application:
          • Poor vascular function
          • Diabetes
          • Immunosuppression,
          • Previous radiation to the groin area
    • Amputation
      • Reserved for more advanced disease

Locally advanced disease (T3–T4)

Resectable disease

• Pre-operative MRI or US can assist in surgical planning
• cT2 (corpus spongiosum): gGlansectomy (partial or total), with or without reconstruction
  • If doubt of corporeal or tunica albuginea invasion, rather than continuing the dissection over Buck’s fascia to perform glansectomy combined with distal corporectomy, dissection superficial to the tunica albuginea can be adopted after dividing the neurovascular bundle.
    • Frozen sections of the corporeal tips and urethra may be helpful in assessing the radicality of the procedure peri-operatively.

• cT3 (corpus cavernosum): partial amputation
  • Reconstructive options can be offered, such as (2)
    1. Urethral centralisation and/or
    2. Neo-glans formation with the use of a graft
    3. Total phallic reconstruction in patients undergoing total/subtotal amputation
  • In patients undergoing total/subtotal amputation, a total phallic reconstruction may be offered
  • Patients should be informed that a wider resection provides a lower risk of local recurrence at the cost of functionality of the penis
  • Radical amputation and diversion of urination with a perineal urethrostomy is reserved for those patients in whom a resection with a safe margin would result in the inability to void standing upright or without wetting the scrotum.
  • In case of locally-advanced and ulcerated cases which are resectable, composite myocutaneous flaps or advancement flaps may be needed to cover the surgical defect

• Radiotherapy for locally-advanced penile lesions should be undertaken with concurrent chemotherapy.

Non-resectable disease

• Induction chemotherapy
  • Offers the ability to downstage disease and may enable surgical resection among responders
    • Several retrospective studies have evaluated combination regimens using paclitaxel or docetaxel with cisplatin and ifosfamide or 5-FU
• If inadequate response, consider palliative chemo-radiotherapy

Local recurrence after organ-sparing surgery

• If there is no corpus cavernosum invasion, a second organ-sparing procedure can be performed
• For large or high-stage recurrence (involving corpora cavernosa), partial or total amputation is required, unless unresectable or concurrent with nodal or distant metastatic recurrence

Regional Lymph Nodes

• Penile cancer metastasizes in a stepwise manner from the primary tumor through the lymphatic system
  • Initially to the superficial inguinal nodes (which can occur on both or either side
    • Superficial nodes are located under the subcutaneous fascia and above the fascia lata within Scarpa’s triangle
  • Then to the deep inguinal nodes (which can occur on both or either side)
    • Deep nodes lie within the region of the fossa ovalis where the superficial saphenous veins anastomose with the femoral vein at the saphenofemoral junction.
    • The Cloquet’s node (or Rosenmuller’s node) is located medial to the femoral vein around the entrance to the femoral canal and marks the transition between inguinal and pelvic regions.
  • Then the pelvic nodes (which can only occur with ipsilateral inguinal LN metastasis)
    • Crossover metastatic spread, from one groin to the contralateral pelvis, is rare
  • And finally to distant nodes
    • Lymphatic spread from the pelvic nodes to retroperitoneal nodes (para-aortic, para-caval) is classified as systemic metastatic disease
• Detecting lymphatic spread as early as possible is a crucial element in penile cancer management

Clinically node-negative patients (cN0)

• ≈20-25% of cN0 patients may harbour occult metastases
  • Additional staging is warranted
  • initial LN staging is focused on identifying (micro)metastatic disease in the inguinal LNs as early as possible

Staging in cN0

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

• Surgical staging
  • Invasive/surgical staging remains indispensable to identify micro-metastasis before nodal metastases become palpable/visible.
  • Approaches (2)
    1. Dynamic sentinel node biopsy (DSNB) (preferred)
       • 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.
         • If histopathology identifies SN (micro)metastasis, ipsilateral completion ILND is indicated
       • Test characteristics
         • Sensitivity 92–96% (in experienced centres)
         • False negative rates 4–8% (in experienced centres)
       • 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
       • Adverse events
         • Complication rate 6–14% (in experienced centres)
           • Developed to avoid resecting unnecessary LNs and thereby minimizing the morbidity of surgical staging
       • 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.
    2. Inguinal lymph node dissection (ILND)
       • Radical inguinal lymph node dissection (ILND)
         • Most accurate surgical staging method
         • Associated with the highest complication rates
       • Modified ILND
         • Lowers morbidity
         • Maintains sufficient sensitivity
         • Modifications in modified ILND
           1. Shorter skin incision
           2. No dissection lateral to the femoral artery
           3. No dissection caudal to the fossa ovalis
           4. Preservation of the saphenous vein
       • Video-endoscopic/robot-assisted radical LND
         • 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
• 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).

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.
• Cure can be achieved in limited LN-disease confined to the regional LNs
• Complete surgical inguinal and pelvic nodal management within 3 months of diagnosis (unless the patient has undergone prior neoadjuvant chemotherapy).
  • Delay in nodal management of more than three to six months may affect disease-free survival.

Options

Radical inguinal lymph node dissection

• Standard of care for patients with cN1–2 (or cN0 patients with a tumour positive sentinel node at DSNB)
• No widespread adoption of lymph node yield or density as quality marker
• Adverse events
  • Significant morbidity due to impaired lymph drainage from the legs and scrotum
    • Overall complication rate: 21–55%
    • Most common complications
      • Wound infections (2–43%)
      • Skin necrosis (3–50%)
      • Lmphoedema (3.1–30%)
      • Lymphocele formation (1.8–26%)
      • Seroma (2.4–60%)
• Approaches (2)
  1. Open
     • Standard for cN1–2 disease
       • In patients with cN1 disease offer either ipsilateral:
         • Fascial-sparing inguinal lymph node dissection (ILND)
         • Open radical ILND; sparing the saphenous vein, if possible
       • In patients with cN2 disease offer ipsilateral open radical ILND; sparing the saphenous vein, if possible
  2. Minimally-invasive
     • Offer minimally-invasive ILND to patients with cN1–2 disease only as part of a clinical trial.
     • Although operative time is longer, LN yields can be similar to open ILND, length of hospital stay shorter in VEIL/RAVEIL and wound complications lower, though lymphocele and readmission rates were equivalent

Neoadjuvant chemotherapy

• Alternative approach to upfront surgery to selected patients who are candidates for cisplatin and taxane-based chemotherapy with (2):
  1. Bulky mobile inguinal nodes or
  2. Bilateral disease (cN2)

Prophylactic pelvic lymph node dissection

• In most cases represents a staging procedure that can thus identify candidates for early adjuvant therapy, although in select patients may also provide a therapeutic benefit
• Indications (2)
  1. ≥3 inguinal nodes are involved on one side on pathological examination
  2. Extranodal extension is reported on pathological examination

Clinical N3 Disease (fixed inguinal nodal pass or pelvic lymphadenopathy)

• Neoadjuvant chemotherapy (NAC) using a cisplatin- and taxane-based combination should be offered to chemotherapy-fit patients with pelvic lymph node involvement or those with extensive inguinal involvement (cN3), in preference to up front surgery.
  • Bulky inguinal LN enlargement indicates extensive lymphatic metastatic disease for which few patients will benefit from surgery alone.
  • Surgery as the initial treatment in patients with a fixed inguinal mass or clinically evident pelvic adenopathy (cN3) at presentation or recurrence is discouraged in routine management.
    • Surgery alone will rarely cure patients with cN3 disease.
    • Even when technically feasible, upfront surgery often results in large skin/soft tissue defects, the need for myocutaneous flap reconstruction, prolonged hospital stays and is associated with high overall complication rates
  • If responding to NAC and resection is feasible, offer surgery
    • ≈50% with advanced (cN2–cN3) penile cancer respond to combination chemotherapy.
    • Responders that subsequently undergo consolidative inguinal/PLND have an OS chance of ≈50% at 5 years.
• If not candidate for conventional multi-agent chemotherapy, pre-operative chemo-radiation/radiation can be offered in an attempt to downsize tumours to improve resectability.
• Surgical resection
  • Timing
    • should proceed 5–8 weeks after completion of chemotherapy to provide time for haematologic recovery and other therapy related symptoms to improve.
  • Technique
    • Inguinal LND in cN3 patients often requires resection of overlying skin to effectively remove a fixed bulky nodal mass
  • Approach (1)
    • Open
      • Minimally-invasive techniques (i.e., robotic-, laparoscopic ILND) are considered inappropriate in cN3 inguinal metastases
  • Pelvic lymph node dissection
    • Simultaneous PLND should be performed at the time of ILND if pelvic LN metastases were clinically evident at diagnosis.
    • Ipsilateral PLND should also be performed in a simultaneous (preferred) or delayed fashion in the setting of advanced bulky inguinal metastases without clinically evident pelvic metastases as well (i.e., prophylactic).

Multimodal Chemotherapy/Radiotherapy in the management of regional lymph nodes

Chemotherapy

• Adjuvant chemotherapy
  • Have a balanced discussion of risks and benefits with high-risk patients with surgically resected disease, in particular with those with pathological pelvic LN involvement (pN3)

Radiotherapy

• Adjuvant radiation (with or without chemo sensitisation)
  • Indications
    • pN2/N3 disease (including those who received prior neoadjuvant chemotherapy)
• Definitive radiotherapy (with or without chemo sensitisation)
  • Indications
    • Patients unwilling or unable to undergo surgery
    • cN3 patients who are not candidates for multi-agent chemotherapy

Advanced disease

• Offer patients with distant metastatic disease, platinum-based chemotherapy as the preferred approach to first-line palliative systemic therapy.
• Offer radiotherapy for symptom control (palliation) in advanced disease.

Prognosis

• Overall 5-year survival: 67%
  • Localized disease: 81%
  • Distant metastasis: 18%

Prognostic Factors

1. Presence and extent of nodal metastases (most important)
   • Extra-capsular extension in even one single LN carries a poor prognosis and is denoted as pN3
2. Depth of invasion
3. Grade in the primary tumour
4. Pathological subtype
5. Peri-neural invasion
6. Lymphovascular invasion

Follow-up

Recurrence

• Local or regional nodal recurrences usually occur within 2-3 years of primary treatment
  • Local recurrence is easily detected by physical examination, by the patient himself or his physician.
  • Regional recurrence requires timely treatment by rILND with (neo)adjuvant chemotherapy/chemoradiotherapy.
• Follow-up also depends on the primary treatment modality
  • Histology from the glans should be obtained to confirm disease-free status following laser ablation or topical chemotherapy
• After local treatment with negative inguinal nodes
  • Follow-up should include physical examination of the penis and groins for local and/or regional recurrence. Additional imaging has no proven benefit

Lymphedema

• Following nodal surgery, ideally, refer to specialist lymphoedema services for assessment and management before any significant lymphoedema occurs.
  • Specialist lymphoedema services offer a range of made-to-measure compression garments or multi-layer lymphoedema bandaging for lower limb and genital lymphoedema
• Assess for genital and lower limb lymphoedema at each outpatient clinic appointment
• Advise good skin care, compression, exercise, massage, and elevation when resting as the mainstay of treatment.
  • For lower limb compression adjustable Velcro garments also exist.
  • Good skin care is critical to prevent infection that can damage remaining lymphatic channels.
  • Prophylactic antibiotics should be used following any episode of cellulitis
    • Penicillin V, erythromycin or clindamycin recommended, except in genital lymphoedema where prophylactic trimethoprim can be used

References

Brouwer, Oscar R., et al. "European Association of Urology-American Society of Clinical Oncology collaborative guideline on penile cancer: 2023 update." European urology 83.6 (2023): 548-560.