EAU & ASCO: Penile Cancer 2023: Difference between revisions

See [https://pubmed.ncbi.nlm.nih.gov/36906413/ Original Guidelines]

* '''Usually arises from the epithelium of the inner foreskin/prepuce or the glans'''

* '''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'''

** '''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'''

** pN1 Metastasis in one or two inguinal lymph nodes

** pN2 Metastasis in more than two unilateral inguinal nodes or bilateral inguinal lymph nodes

* Risk factors for penile cancer (see above)

** '''Most PeIN lesions are located on the mucosal surfaces of the glans or prepuce'''

*** Lichen sclerosus also affects the prepuce

*** '''Can sometimes be hidden under the foreskin in case of phimosis'''

* Dimensions, anatomic location, and extent of local invasion should be noted

* 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+).  

==== Regional ====

* '''MRI'''

** '''Not routinely indicated'''

*** Physical examination is a reliable method for estimating penile tumour size and clinical T stage

** '''Indications (2)'''

**# '''Uncertainty if the tumour invades the cavernosal bodies (cT3)'''

**# '''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'''

** 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).

* 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

* '''Non-surgical'''

** '''Topical'''

*** '''Imiquimod'''

*** '''5-fluorouracil'''

** '''Laser'''  

** '''Moh's surgery'''

** '''Radiation'''

*** '''Brachytherapy'''

*** '''External beam radiation'''

* '''Surgical'''

** '''Organ-sparing'''

*** '''Circumcision'''

*** '''Wide local excision'''

*** '''Glansectomy'''

*** '''Glans resurfacing'''

** '''Amputative'''  

*** '''Partial amputation'''

*** '''Radical amputation'''

* 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'''

** '''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'''

** '''Wide local excision'''

** '''Glansectomy'''

** '''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'''

** Partial penectomy

*** Indications

**** Invasion of the corpora cavernosa (T3)

**** Patient not willing to undergo organ-sparing surgery or not willing to comply with strict follow-up.

***Efficacy

****Risk of local recurrence ≈4–5%

**Total penectomy with perineal urethrostomy

***Indications

****Large invasive tumours not amenable to partial amputation

*'''Options'''

** '''Non-surgical'''

*** '''Topical therapies'''

**** '''Imiquimod'''

**** '''5-fluorouracil'''

***'''Laser ablation'''

**'''Surgical'''

***'''Circumcision'''  

****'''Should be the primary surgical option'''

***'''Local excision'''

**** Glans resurfacing  

* '''Despite treatment, penile intra-epithelial neoplasia can progress to invasive lesions in 2.6–13% of patients'''

* 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.

* For glandular and coronal lesions

** 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

***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.

**Glans resurfacing

***Total or partial glans resurfacing has been used for superficially-invasive lesions combined with deeper resection at the site of invasion

**Glansectomy

***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.

***A split-thickness skin graft is commonly used to reconstruct a neo-glans

****Patients with poor vascular function, diabetes, immunosuppression, or previous radiation to the groin area are less suitable for graft application

**Partial penectomy

***Amputative and partial amputative surgery is reserved for more advanced disease

*Radiotherapy for T1 and T2 disease

**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.

**Local recurrence after radiotherapy can be salvaged by surgery

**Complications of radiotherapy for penile cancer

***Meatal/urethral stenosis

***Glans necrosis

***Late fibrosis of the corpora cavernosa

***Pain with sexual intercourse

***Dysuria

* Pre-operative MRI or US can assist in surgical planning

* In cT2 disease where there is 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. In these instances, frozen sections of the corporeal tips and urethra may be helpful in assessing the radicality of the procedure peri-operatively.

* For cT3 patients with obvious involvement of the corpora cavernosa, partial amputation is standard.

** Patients can be offered reconstructive options such as urethral centralisation and/or neo-glans formation with the use of a graft.

** A total phallic reconstruction may be offered to patients undergoing total/subtotal amputation.

** 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.

* Induction chemotherapy offers the ability to downstage disease and thereby enable surgical resection among responders, even among men with advanced penile cancer

** Several retrospective studies have evaluated combination regimens using paclitaxel or docetaxel with cisplatin and ifosfamide or 5-FU

* In case of not obtaining a response sufficient for resection, palliative chemo-radiotherapy is an option.

* Route of anatomical drainage from the primary tumour:

** Superficial and then deep inguinal LNs (which can occur on both or either side)

** Followed by the ipsilateral pelvic LNs

* The superficial nodes are located under the subcutaneous fascia and above the fascia lata within Scarpa’s triangle.

* The 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.

* Pelvic nodal disease does not occur without ipsilateral inguinal LN metastasis.

* Crossover metastatic spread, from one groin to the contralateral pelvis, is rare

* Lymphatic spread from the pelvic nodes to retroperitoneal nodes (para-aortic, para-caval) is classified as systemic metastatic disease

* Significant morbidity due to impaired lymph drainage from the legs and scrotum

** 21–55% of men will suffer a complication

** Most reported complications in recent series were

*** Wound infections (2–43%)

*** Skin necrosis (3–50%)

*** Lmphoedema (3.1–30%)

*** Lymphocele formation (1.8–26%)

*** Seroma (2.4–60%)

** Minimally-invasive approaches have been introduced

*** 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

==== cN1–N2 disease: radical inguinal lymph node dissection ====

 

* Offer neoadjuvant chemotherapy as an alternative approach to upfront surgery to selected patients with bulky mobile inguinal nodes or bilateral disease (cN2) who are candidates for cisplatin and taxane-based chemotherapy

* Complete surgical inguinal and pelvic nodal management within three 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.

 

* Indications

**Three or more inguinal nodes are involved on one side on pathological examination

**Extranodal extension is reported on pathological examination

=== Clinical N3 Disease ===

 

* Offer neoadjuvant chemotherapy (NAC) using a cisplatin- and taxane-based combination to chemotherapy-fit patients with pelvic lymph node involvement or those with extensive inguinal involvement (cN3), in preference to up front surgery.

* Offer surgery to patients responding to NAC in whom resection is feasible.

** About half of the patients with advanced (cN2–cN3) penile cancer respond to combination chemotherapy. Responders that subsequently undergo consolidative inguinal/PLND have an OS chance of about 50% at 5 years.

* Among cN3 patients who are not candidates for conventional multi-agent chemotherapy, pre-operative chemo-radiation/radiation can be offered in an attempt to downsize tumours to improve resectability.

* Surgical resection should proceed 5–8 weeks after completion of chemotherapy to provide time for haematologic recovery and other therapy related symptoms to improve.

** Inguinal LND in cN3 patients often requires resection of overlying skin to effectively remove a fixed bulky nodal mass

* 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).

==== Systemic therapy ====

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

* Offer adjuvant radiotherapy (with or without chemo sensitisation) to patients with pN2/N3 disease, including those who received prior neoadjuvant chemotherapy.

* Offer definitive radiotherapy (with or without chemo sensitisation) to patients unwilling or unable to undergo surgery.

* Offer radiotherapy (with or without chemo sensitisation) to cN3 patients who are not candidates for multi-agent chemotherapy.

*'''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'''

* Local or regional nodal recurrences usually occur within two to three years of primary treatment

* 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

* 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

* Local recurrence is easily detected by physical examination, by the patient himself or his physician.

* Men should be assessed for genital and lower limb lymphoedema at each outpatient clinic appointment, advised about good skin care, compression, exercise, massage, and elevation when resting as the mainstay of treatment. Following nodal surgery, ideally, they would be referred to specialist lymphoedema services for assessment and management before any significant lymphoedema occurs.

*** 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, with penicillin V, erythromycin or clindamycin recommended, except in genital lymphoedema where prophylactic trimethoprim can be used