Editing EAU & ASCO: Penile Cancer 2023 (section)

=== Regional Lymph Nodes ===

*'''<span style="color:#ff0000">Penile cancer metastasizes in a stepwise manner from the primary tumor through the lymphatic system'''
**'''<span style="color:#ff0000">Initially to the superficial inguinal nodes  (which can occur on both or either side'''
***'''<span style="color:#ff0000">Superficial nodes are located under the subcutaneous fascia and above the fascia lata within Scarpa’s triangle'''
**'''<span style="color:#ff0000">Then to the deep inguinal nodes  (which can occur on both or either side)'''
***'''<span style="color:#ff0000">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.'''
**'''<span style="color:#ff0000">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
**'''<span style="color:#ff0000">And finally to distant nodes'''
***Lymphatic spread from the pelvic nodes to retroperitoneal nodes (para-aortic, para-caval) is classified as systemic metastatic disease
*'''<span style="color:#ff0000">Detecting lymphatic spread as early as possible is a crucial element in penile cancer management'''

==== Clinically node-negative patients (cN0) ====

* '''<span style="color:#ff0000">≈20-25% of cN0 patients may harbour occult metastases''' 
** '''<span style="color:#ff0000">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 ======

*'''<span style="color:#ff0000">Recommended'''
** '''<span style="color:#ff0000">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 ======

* '''<span style="color:#ff0000">Surgical staging'''
** '''Invasive/surgical staging remains indispensable to identify micro-metastasis before nodal metastases become palpable/visible.'''
** '''<span style="color:#ff0000">Approaches (2)'''
**# '''<span style="color:#ff0000">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.'''
**# '''<span style="color:#ff0000">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
**#**# 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'''
**#**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
* '''<span style="color:#ff0000">Non-surgical staging'''
** '''<span style="color:#ff0000">Imaging'''
*** '''<span style="color:#ff0000">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)'''
*# '''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
*# '''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):'''
*# '''Bulky mobile inguinal nodes or'''
*# '''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)'''
*#'''≥3 inguinal nodes are involved on one side on pathological examination'''
*#'''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).