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EAU & ASCO: Penile Cancer 2023: Difference between revisions

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See [https://pubmed.ncbi.nlm.nih.gov/36906413/ Original Guidelines]
'''See [https://pubmed.ncbi.nlm.nih.gov/36906413/ Original Guidelines]'''
 
'''See [[Penile Cancer: Squamous Penile Cancer]] Chapter Notes'''


== Background ==
== Background ==
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* Pathological
* Pathological
** pN0 No regional lymph node metastasis
** pN0 No regional lymph node metastasis
** pN1 Metastasis in one or two inguinal lymph nodes
** pN1 Metastasis in 1-2 inguinal lymph nodes
** pN2 Metastasis in more than two unilateral inguinal nodes or bilateral 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
** pN3 Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis


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=== Regional Lymph Nodes ===
=== Regional Lymph Nodes ===


*'''<span style="color:#ff0000">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'''
*'''<span style="color:#ff0000">Penile cancer metastasizes in a stepwise manner from the primary tumor through the lymphatic system'''
*'''Detecting lymphatic spread as early as possible is a crucial element in penile cancer management.'''
**'''<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) ====
==== Clinically node-negative patients (cN0) ====
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====== Options ======
====== Options ======


* '''Surgical staging'''
* '''<span style="color:#ff0000">Surgical staging'''
** '''Invasive/surgical staging remains indispensable to identify micro-metastasis before nodal metastases become palpable/visible.'''
** '''Invasive/surgical staging remains indispensable to identify micro-metastasis before nodal metastases become palpable/visible.'''
** '''Approaches (2)'''
** '''<span style="color:#ff0000">Approaches (2)'''
*** '''Dynamic sentinel node biopsy (DSNB) (preferred)'''
**# '''<span style="color:#ff0000">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.'''
**** 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.
***** 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
**#** If 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%)
**#* Test characteristics
**** '''Technique'''
**#** Sensitivity 92–96% (in experienced centres)
***** '''Inguinal US is obtained prior to DSNB'''
**#** False negative rates 4–8% (in experienced centres)
****** 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
**#* '''Technique'''
******* 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
**#** '''Inguinal US is obtained prior to DSNB'''
****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.
**#*** 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
*** '''Inguinal lymph node dissection (ILND)'''
**#**** 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
**** Radical inguinal lymph node dissection (ILND) is the most accurate surgical staging method, but is associated with the highest complication rates
**#*Adverse events
**** Modified ILND lowers morbidity while maintaining sufficient sensitivity
**#**Complication rate 6–14% (in experienced centres)
***** Modifications in modified ILND
**#***Developed to avoid resecting unnecessary LNs and thereby minimizing the morbidity of surgical staging
****** Shorter skin incision
**#*'''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.'''
****** No dissection lateral to the femoral artery
**# '''<span style="color:#ff0000">Inguinal lymph node dissection (ILND)'''
****** No dissection caudal to the fossa ovalis
**#* '''Radical inguinal lymph node dissection (ILND)'''
****** Preservation of the saphenous vein
**#** Most accurate surgical staging method
****Video-endoscopic/robot-assisted radical LND has been introduced more recently
**#** Associated with the highest complication rates
*****Similar lymph node yield compared to open
**#* '''Modified ILND'''
*****Reduces wound-related complications compared to open ILND, but no significant reduction in lymphatic complications
**#** Lowers morbidity  
******Main predictor of lymphatic complications is the number of lymph nodes removed
**#** Maintains sufficient sensitivity
* '''Non-surgical staging'''
**#** Modifications in modified ILND
** '''Imaging'''
**#**# Shorter skin incision
*** '''Not reliable to evaluate clinically node-negative patients'''
**#**# 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
**** 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
****18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) does not detect LN metastases < 10 mm
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==== Clinically node-positive patients (cN+) ====
==== 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.
* '''Lymph node metastasis should preferably be histopathologically confirmed by image-guided biopsy (e.g., US or CT) before initiating treatment.'''
 
*
*
* 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
* Cure can be achieved in limited LN-disease confined to the regional LNs
* 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 ====
==== Options ====
'''Radical inguinal lymph node dissection'''


===== Radical inguinal lymph node dissection =====
* '''Standard of care for patients with cN1–2 (or cN0 patients with a tumour positive sentinel node at DSNB)'''
* '''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
* No widespread adoption of lymph node yield or density as quality marker
* Significant morbidity due to impaired lymph drainage from the legs and scrotum
* '''Adverse events'''
** 21–55% of men will suffer a complication
** '''Significant morbidity due to impaired lymph drainage from the legs and scrotum'''
** Most reported complications in recent series were
*** '''Overall complication rate: 21–55%'''
*** Wound infections (2–43%)
*** '''Most common complications'''
*** Skin necrosis (3–50%)
**** '''Wound infections (2–43%)'''
*** Lmphoedema (3.1–30%)
**** '''Skin necrosis (3–50%)'''
*** Lymphocele formation (1.8–26%)
**** '''Lmphoedema (3.1–30%)'''
*** Seroma (2.4–60%)
**** '''Lymphocele formation (1.8–26%)'''
** Minimally-invasive approaches have been introduced
**** '''Seroma (2.4–60%)'''
*** 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
* '''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


===== cN1–N2 disease: radical inguinal lymph node dissection =====
===== Neoadjuvant chemotherapy =====
* Open radical ILND is the standard for cN1–2 disease
* '''Alternative approach to upfront surgery to selected patients who are candidates for cisplatin and taxane-based chemotherapy with (2):'''
** In patients with cN1 disease offer either ipsilateral:
*# '''Bulky mobile inguinal nodes or'''
*** Fascial-sparing inguinal lymph node dissection (ILND)
*# '''Bilateral disease (cN2)'''
*** 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
* Offer minimally-invasive ILND to patients with cN1–2 disease only as part of a clinical trial.
* 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.


====== Prophylactic pelvic lymph node dissection ======
====== 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
* 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
* '''Indications (2)'''
**Three or more inguinal nodes are involved on one side on pathological examination
*#'''≥3 inguinal nodes are involved on one side on pathological examination'''
**Extranodal extension is reported on pathological examination
*#'''Extranodal extension is reported on pathological examination'''
* Complete surgical inguinal and pelvic nodal management within three months of diagnosis (unless the patient has undergone neoadjuvant chemotherapy).


===== Clinical N3 Disease =====
===== Clinical N3 Disease (fixed inguinal nodal pass or pelvic lymphadenopathy) =====
* 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.
* '''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.
** 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 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.
*** 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
*** 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
* Offer surgery to patients responding to NAC in whom resection is feasible.
** '''If responding to NAC and resection is feasible, offer surgery'''
** 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.
*** ≈50% with advanced (cN2–cN3) penile cancer respond to combination chemotherapy.
* 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.
*** Responders that subsequently undergo consolidative inguinal/PLND have an OS chance of ≈50% at 5 years.
* Surgical resection should proceed 5–8 weeks after completion of chemotherapy to provide time for haematologic recovery and other therapy related symptoms to improve.
* 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.
** Inguinal LND in cN3 patients often requires resection of overlying skin to effectively remove a fixed bulky nodal mass
* Surgical resection  
* Minimally-invasive techniques (i.e., robotic-, laparoscopic ILND) are considered inappropriate in cN3 inguinal metastases
** Timing
* Pelvic lymph node dissection
*** should proceed 5–8 weeks after completion of chemotherapy to provide time for haematologic recovery and other therapy related symptoms to improve.
** Simultaneous PLND should be performed at the time of ILND if pelvic LN metastases were clinically evident at diagnosis.  
** Technique
** 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).
*** 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 ===
=== Multimodal Chemotherapy/Radiotherapy in the management of regional lymph nodes ===


==== Systemic therapy ====
==== Chemotherapy ====


* 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)
* 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 ====
==== Radiotherapy ====


* Offer adjuvant radiotherapy (with or without chemo sensitisation) to patients with pN2/N3 disease, including those who received prior neoadjuvant chemotherapy.
* '''Adjuvant radiation (with or without chemo sensitisation)'''
* Offer definitive radiotherapy (with or without chemo sensitisation) to patients unwilling or unable to undergo surgery.
** '''Indications'''
* Offer radiotherapy (with or without chemo sensitisation) to cN3 patients who are not candidates for multi-agent chemotherapy.
*** '''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 ===
=== Advanced disease ===
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** Localized disease: 81%
** Localized disease: 81%
** Distant metastasis: 18%
** Distant metastasis: 18%
*'''Prognostic factors'''
 
**'''Presence and extent of nodal metastases'''
=== Prognostic Factors ===
***'''Most important prognostic factor for survival'''
#'''<span style="color:#ff0000">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'''
#*'''<span style="color:#ff0000">Extra-capsular extension in even one single LN carries a poor prognosis and is denoted as pN3'''
**'''Depth of invasion'''
#'''<span style="color:#ff0000">Depth of invasion'''
**'''Grade in the primary tumour'''
#'''<span style="color:#ff0000">Grade in the primary tumour'''
**'''Pathological subtype'''
#'''<span style="color:#ff0000">Pathological subtype'''
**'''Peri-neural invasion'''
#'''<span style="color:#ff0000">Peri-neural invasion'''
**'''Lymphovascular invasion'''
#'''<span style="color:#ff0000">Lymphovascular invasion'''


== Follow-up ==
== Follow-up ==


* Local or regional nodal recurrences usually occur within two to three years of primary treatment
=== Recurrence ===
* 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 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.
** 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.
** Regional recurrence requires timely treatment by rILND with (neo)adjuvant chemotherapy/chemoradiotherapy.
* 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.
* 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
** Specialist lymphoedema services offer a range of made-to-measure compression garments or multi-layer lymphoedema bandaging for lower limb and genital lymphoedema
*** For lower limb compression adjustable Velcro garments also exist.  
* Assess for genital and lower limb lymphoedema at each outpatient clinic appointment
*** Good skin care is critical to prevent infection that can damage remaining lymphatic channels.
* Advise good skin care, compression, exercise, massage, and elevation when resting as the mainstay of treatment.
*** 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
** 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 ==
== 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.
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.
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