Editing Penile Cancer: Squamous Penile Cancer (section)

== Management ==

=== CIS ===

* '''<span style="color:#ff0000">Non-surgical</span>'''
** '''<span style="color:#ff0000">Topical</span>'''
*** '''EAU: Circumcision is advisable prior to the use of topical agents'''
*** '''<span style="color:#ff0000">Options (2):</span>'''
***# '''<span style="color:#ff0000">5-fluorouracil cream (5% concentration BID x 6 weeks)</span>'''
***# '''<span style="color:#ff0000">Imiquimod 5% cream</span>'''
*** '''Patient adherence and strict follow-up is a must, and prompt re-biopsy is necessary for lesions that fail to respond'''
*** '''If topical treatment fails, it should not be repeated.'''
** '''<span style="color:#ff0000">Ablation with lasers</span>'''
*** '''Two commonly used laser mediums are''' '''carbon dioxide (CO2''') '''and Nd:YAG;''' conflicting literature regarding their efficacy for cancerous lesions
* '''<span style="color:#ff0000">Surgical</span>'''
** '''Foreskin lesion'''
*** '''Circumcision or excision with a 5-mm margin is adequate'''
** '''Glans lesion'''
*** '''Excisional strategies while maintaining normal penile anatomy'''
* '''<span style="color:#ff0000">Radiation</span>'''
** '''Can be used for tumours that are resistant to topical treatment, especially among patients who are not surgical candidates'''
* '''<span style="color:#ff0000">Moh's surgery</span>'''

=== Favourable histologic features (stage Ta, T1; grade 1 and 2) ===

* '''<span style="color:#ff0000">Organ-sparing or glans-sparing surgical procedures</span>'''
** '''<span style="color:#ff0000">Goal is to preserve glans sensation and maximize shaft length</span>'''
*** '''<span style="color:#ff0000">Options (5):</span>'''
***# '''<span style="color:#ff0000">Moh's surgery</span>'''
***# '''<span style="color:#ff0000">Laser ablation</span>'''
***# '''<span style="color:#ff0000">Radiation therapy</span>'''
***# '''<span style="color:#ff0000">Limited excision strategies</span>'''
***# '''<span style="color:#ff0000">Glansectomy</span>'''
***#* '''Moh's micrographic surgery'''
***#** '''Least invasive of the organ-sparing approaches, with favourable functional outcomes'''
***#** '''High recurrence rates have been reported during long-term follow-up'''.
***#** Due to the low radicality of the procedure, Moh’s surgery has greater benefit for small superficial shaft lesions, but '''should not be used for large or high-risk tumours'''
***#* '''Glansectomy'''
***#** '''Most radical of the organ-sparing procedures'''
***#** '''Has the highest local control rate'''
***#** The glans is separated from the corporal heads and urethra transected with a distal urethrostomy constructed. The shaft skin can be advanced or split, or a full-thickness skin graft used.
***'''Because recurrence rates are higher with organ-preserving strategies, compliance with follow-up is also a consideration in recommending organ preservation versus amputation''' 

=== Penectomy ===
==== Indications for partial or total penectomy (3):====
#'''<span style="color:#ff0000">High grade (grade ≥ 3) lesions</span>'''
#'''<span style="color:#ff0000">[stage ≥ T2]; deep invasion into the glans urethra or corpora cavernosa</span>'''
#'''<span style="color:#ff0000">Tumours >4cm</span>'''

=== Treatment of Primary Penile Tumour Summary ===
* Tis (glans): Laser therapy, glans resurfacing; alternative: topical therapy
* Ta, Tis (foreskin, shaft skin): Surgical excision to achieve negative margin; alternatives: laser therapy, topical therapy (Tis only)
* Ta, T1 grade 1-3
** Glans: Therapy based on size and position of lesion as well as potential side effects, excision, glans resurfacing procedures, glansectomy, radiotherapy (not indicated for Ta)
** Foreskin, shaft: Complete surgical excision to achieve negative margin
* T2 (glans) without gross cavernosum involvement: Total glansectomy with or without corpora cavernosa transection to achieve negative surgical margins, partial penectomy, radiotherapy
* T2 (corporeal invasion), T3: Partial or total penectomy
* '''T4 (adjacent structures): Consider neoadjuvant chemotherapy with surgical consolidation for responding patients if baseline resectability is a concern'''
* Local disease recurrence after conservative therapy: Complete surgical excision to achieve negative surgical margins; may require partial or total penectomy; select patients with superficial low-grade recurrences may be candidates for repeat penile-conserving procedure
* Radiotherapy: Select patients with T1-T2 tumors involving glans, coronal sulcus <4 cm

=== Treatment of Inguinal Nodes ===

* '''<span style="color:#ff0000">Lymph node involvement is most important prognostic factor for survival</span>'''
** 5-year survival: lymph node involvement vs. without: 73% vs. 60% (range 0-86% depending on extent of lymph node involvement)

==== <span style="color:#ff0000">Clinically negative groins</span> ====
* '''<span style="color:#ff0000">≈20% of patients with clinically nonpalpable inguinal nodes harbor occult metastases</span>'''
**Cross-sectional imaging studies such as CT and magnetic resonance imaging (MRI) are unable to accurately detect these cases and are only largely used to assess for the presence of pelvic lymph node involvement
**'''Immediate resection of clinically occult lymph node metastases is associated with improved survival when compared with delayed resection of involved nodes at the time of clinical detection'''
* '''<span style="color:#ff0000">Surgical staging</span>'''
**'''<span style="color:#ff0000">Indications</span>'''
***'''<span style="color:#ff0000">Recommended (1):</span>'''
****'''<span style="color:#ff0000">High-risk tumor (≥pT1b)</span>'''
***'''<span style="color:#ff0000">Optional (1):</span>'''
****'''<span style="color:#ff0000">T1a G2 disease</span>'''
*****'''<span style="color:#ff0000">Surveillance is an alternative to surgical staging with patients willing to comply with strict follow-up</span>'''
**'''<span style="color:#ff0000">Options (2)</span>'''
**#'''<span style="color:#ff0000">Dynamic sentinel node biopsy (DNSB) (preferred)[https://pubmed.ncbi.nlm.nih.gov/36906413/]</span>'''
**#* Sentinel lymph node biopsy is the technique to remove nodes that are first affected by the spread of metastatic disease.
**#**Based on the assumption that penile cancer cells will initially spread unilaterally or bilaterally to a single inguinal lymph node before disseminating to adjoining lymph nodes and that this sentinel lymph node can have a variable position among individuals
**#***The theory is that certain cancers typically do not spread to other lymph nodes without the necessary and stepwise involvement of the sentinel node first.
**#***The concept of orderly lymphatic progression of metastatic cells from the primary tumor to the sentinel node seems to be likely with regard to squamous cell carcinoma of the penis.
**#*Technique
**#**Inguinal ultrasound and fine-needle aspiration (FNA) cytology of suspect lymph nodes has been added as a preliminary step before lymphoscintigraphy. Patients with abnormal nodes on ultrasound undergo FNA, and only patients with negative FNA findings proceed to scintigraphy and DSNB.
**#*** Patients with positive FNA findings undergo inguinal lymph node dissection.
**#**DNSB involves preoperative lymphoscintigraphy using technetium-99m nanocolloid, preoperative patent blue dye injection, and intraoperative guidance with a gamma ray detection probe to visualize the individual drainage pattern and accurately identify the sentinel node, which is subsequently resected
**#*'''Advantages'''
**#**'''Significantly less morbid than modified inguinal lymph node dissection or a standard lymphadenectomy'''
**#***Can serve as an intermediary between noninvasive imaging modalities and surgical resection when identifying those patients with clinically negative groins who would benefit from inguinal lymphadenectomy
**#*'''Disadvantages'''
**#** '''Widespread use of DSNB remains limited and generally restricted to high-volume centers'''
**#***Dedicated experience is needed to gain optimal results
**#**** Should be performed with the goal of a false-negative rate at ≤5%
**#****Methods to increase the accuracy of DNSB (4):
**#***# Preoperative inguinal US with needle biopsy of any suspicious nodes
**#***# Routine inguinal exploration even in the absence of radiotracer visualization
**#***# Intraoperative palpation of the wound for abnormal nodes
**#***# Extended pathologic analysis of any excised lymph nodes
**#* '''Follow-up'''
**#** '''Strict follow-up is necessary to identify recurrences that can be managed surgically and potentially salvaged.'''
**#** '''It is important to stress that DSNB remains a diagnostic procedure, allowing some men to avoid a therapeutic IFLND.'''
**#*** '''Those with a positive DSNB should proceed to a full therapeutic lymphadenectomy. It is not appropriate for palpable lymphadenopathy and applies only to clinically negative nodes'''.
**#*** '''In patients with palpable lymphadenopathy'''
**#'''<span style="color:#ff0000">Bilateral inguinal lymph node dissection (ILND)</span>'''
**#*'''Lymphatic spread of penile carcinoma can be unilateral or bilateral to the inguinal lymph nodes'''
**#*Approaches (2):
**#**Open
**#**Video-endoscopic surgery

==== <span style="color:#ff0000">Palpable adenopathy</span> ====
* '''Associated with metastasis in 43% of cases, secondary to inflammation in the remainder'''; can consider fine-needle aspiration to differentiate
* '''Lymphadenectomy can be curative''' due to the prolonged locoregional phase before distant dissemination
* '''Inguinal lymphadenectomy is still recommended'''
** '''<span style="color:#ff0000">The superficial lymph node dissection should be bilateral even if adenopathy is unilateral at presentation</span>'''
** '''<span style="color:#ff0000">Complete ilionguinal lymph node dissection (removal of those nodes deep to the fascia lata contained within the femoral triangle as well as the pelvic nodes) is then performed if the superficial nodes are positive at surgery by frozen-section analysis.</span>'''
* '''Exception is verrucous carcinoma, also known as a Buschke-Lowenstein tumor'''
** Unlike penile squamous cell carcinoma, verrucous carcinoma of the penis has a very low likelihood of metastasis.
** Palpable adenopathy in the context of verrucous carcinoma is very likely to be reactive and should be initially observed. Biopsy should be reserved unless the node remains persistently enlarged or grows over time.
** '''Lymphadenectomy in the context of verrucous carcinoma should be reserved for cases of biopsy-proven metastases.'''

==== <span style="color:#ff0000">Fixed inguinal lymph nodes (cN3)</span> ====
* '''<span style="color:#ff0000">Neoadjuvant chemotherapy followed by radical inguinal lymphadenectomy in responders</span>'''

==== Lymph node involvement (pN+) ====
*'''Prognosis'''
**'''Pathologic criteria associated with improved long-term survival after attempted curative surgical resection of inguinal metastases include:'''
**# '''Unilateral involvement'''
**# '''Minimal nodal disease (≤2 involved nodes in most series (pN1))'''
**# '''No evidence of extra nodal extension of cancer (pN3)'''
**# '''Absence of pelvic nodal metastases (pN3)'''
**## '''i.e. pN1, and lack of features associated with pN2 and pN3'''
* '''No anatomic or lymphangiographic studies demonstrating direct lymphatic drainage to the pelvic lymph nodes from the penis, which is evidenced by the lack of metastatic spread to the pelvic lymph nodes from a primary penile tumor in the absence of metastatic spread to the inguinal lymph nodes[https://link.springer.com/book/10.1007/978-3-319-60858-7]'''
*'''<span style="color:#ff0000">Indications for pelvic lymph node dissection in patients undergoing inguinal lymph node dissection for curative intent (no pelvic adenopathy) (2):</span>'''
*# '''<span style="color:#ff0000">≥2 positive inguinal lymph nodes</span>'''
*# '''<span style="color:#ff0000">Extra-nodal extension is present</span>'''
*## '''PLND in this setting serves as staging tool to identify patients who should be considered for adjunctive therapy'''
*## '''PLND includes the distal common iliac, external iliac, and obturator groups of nodes.'''

==== Summary of treatment strategies for nodal metastases ====
{| class="wikitable"
|'''Lymph node status'''
|'''Management'''
|-
| rowspan="2" |'''No palpable inguinal nodes (cN0)'''
|'''Tis, Ta G1, T1G1: surveillance.'''
|-
|'''> T1G2 [2019 NCCN guidelines: T1b or ≥T2]: invasive lymph node staging by either bilateral modified inguinal lymphadenectomy''' (the medial superficial inguinal lymph nodes and those from the central zone are removed bilaterally, leaving the greater saphenous vein untouched) '''or dynamic sentinel node biopsy'''
|-
|'''Palpable inguinal nodes (cN1/cN2)'''
|'''Palpably enlarged groin lymph nodes should be surgically removed, pathologically assessed (by frozen section) and, if positive, a radical [bilateral?] inguinal lymphadenectomy should be performed'''
|-
|'''Fixed inguinal lymph nodes (cN3)'''
|'''Neoadjuvant chemotherapy followed by radical inguinal lymphadenectomy in responders'''
|-
|'''Pelvic lymph nodes'''
|'''Ipsilateral pelvic lymphadenectomy if ≥2 inguinal nodes are involved on one side or if extracapsular nodal metastasis (pN3) reported.'''
|-
|'''Adjuvant chemotherapy'''
|'''In pN2/pN3 patients after radical lymphadenectomy'''
|-
|'''Radiotherapy'''
|'''Not recommended for nodal disease except as a palliative option'''
|}
'''2018 EAU Penile Cancer Guidelines'''

=== Radiation ===

* '''An option for those with invasive SCC refusing surgical treatment'''
* '''May be delivered as brachytherapy with interstitial implant or external beam radiation'''
* '''Primary radiation therapy may be successfully applied to select patients with T1-2 tumours that are < 4cm; circumcision is necessary before'''
** Brachytherapy more likely to preserve erectile function compared to EBRT
* '''Adverse effects: desquamation, meatal stenosis, and soft-tissue ulceration'''
* Salvage penectomy may be required for persistent or recurrent disease after radiation
* '''For patients undergoing primary radiotherapy, surgical management of inguinal lymph nodes should be recommended by the same criteria as for patients selected for surgical management of the primary tumour'''
** '''Radiation to the inguinal area is not as effective as surgery for the treatment of inguinal nodes'''
* '''Prophylactic radiotherapy has not been shown to alter the natural history of inguinal metastases and is not recommended'''
* '''Palliative radiotherapy among patients with inoperable inguinal nodes may provide some benefit'''

=== Chemotherapy ===

* '''Treatment with a cisplatin-containing regimen in advanced metastatic penile cancer should be considered''' and this may facilitate curative resection. The optimal regimen has yet to be determined.
* Among patients whose tumour progresses through chemotherapy, surgery is not recommended