Penile Cancer: Squamous Penile Cancer

Epidemiology

• Invasive Squamous Cell Carcinoma of the Penis
  • Accounts for > 95% of penile malignancies
  • Abrupt increase of incidence in the 6th decade of life

Risk factors

1. Lack of circumcision
   • Neonatal circumcision
     • Almost eliminates risk of invasive penile cancer
       • The controversial discussion about neonatal circumcision should take into account that circumcision removes approximately half the tissue that can develop into penile cancer
     • Does not demonstrate the same level of protection for CIS
   • Adult circumcision
     • Offers little to no protection
2. HPV (subtype 16 most frequently; oncologic subtypes: 16 and 18, non-oncologic subtypes: 6 and 11)
3. Phimosis
4. Lichen sclerosus, chronic penile inflammation
5. Tobacco exposure (smoking, chewing tobacco)
6. Poor hygiene, rural areas, low socioeconomic status, unmarried
7. Number of sexual partners, early age of sexual intercourse
8. Penile trauma
9. Sporalene and ultraviolet A phototherapy (PUVA) for various dermatological conditions such as psoriasis
   • PUVA is a combination treatment which consists of Psoralens (P) and then exposing the skin to UVA (long wave ultraviolet radiation)

TNM Staging

• AJCC 8th edition

Primary tumour (T)

• TX: Primary tumour cannot be assessed
• T0: No evidence of primary tumour
• Tis: Carcinoma in situ
• Ta: non-invasive squamous cell carcinoma types including basaloid, warty, verrucous, papillary, and mixed types
• T1: invades subepithelial connective tissue
  • T1a: WITHOUT lymphovascular invasion, perineural invasion, and is not high grade (i.e. grade 3-4 or sarcomatoid)
  • T1b: WITH lymphovascular invasion, perineural invasion, or high grade (i.e. grade 3-4 or sarcomatoid)
• T2: invades corpora spongiosum
• T3: invades corpus cavernosum
• T4: invades other adjacent structures

Lymph nodes (N)

• Clinical
  • cNX: Regional nodes cannot be assessed
  • cN0: No palpable or visibly enlarged inguinal lymph nodes
  • cN1: unilateral, solitary, mobile inguinal lymph node
  • cN2: ≥2 unilateral, mobile inguinal lymph nodes or bilateral inguinal lymph nodes
  • cN3: fixed nodal mass, regardless of the size or unilateral/bilateral involvement
• Pathological
  • pNX: Regional nodes cannot be assessed
  • pN0: No regional lymph node metastasis
  • pN1: up to 2 unilateral positive inguinal lymph nodes
  • pN2: ≥3 unilateral lymph nodes or bilateral inguinal lymph nodes
  • pN3: extra-nodal extension or pelvic lymph node(s)
    • A lymph node > 4 cm is often associated with extranodal extension of cancer.

Distant metastasis (M)

• M0: No distant metastasis (no pathologic M0; use clinical M to complete staging group)
• M1: Distant metastasis: lymph node metastasis outside the true pelvis, or to visceral or bone sites

Natural history

• Tumour architecture
  • Flat tumours are associated with earlier nodal metastasis and worse survival than papillary tumours
• Earliest route of dissemination is metastasis to the regional inguinal and pelvic nodes
  • Superficial lymphatic system
    • Drains the foreskin and skin of the penile shaft
    • Empties into the right and left superficial inguinal nodes
  • Deep lymphatic system
    • Drains the glans penis
    • Empties into the superficial inguinal nodes and the deep inguinal nodes of the femoral triangle
  • Penile cancer can metastasize to contralateral inguinal nodes because of crossover in the symphyseal region
  • Drainage subsequently proceeds from the inguinal nodes to the ipsilateral pelvic lymph nodes (external iliac, internal iliac, and obturator)
  • Metastatic enlargement of the regional nodes eventually leads to skin necrosis, chronic infection, and death from sepsis, or hemorrhage secondary to erosion into the femoral vessels

• Distant Metastasis
  • Most common sites (3):
    1. Lung
    2. Bone
    3. Liver
  • Clinically detectable distant metastatic lesions to the lung, liver, bone, or brain are uncommon
  • Usually occur late in the course of the disease after the local lesion has been treated
• Death occurs in the majority of untreated patients within 2 years

Diagnosis and Evaluation

UrologySchool.com Summary

• History and Physical exam (including exam of inguinal nodes)
• Laboratory (1): serum calcium, HPV status
• Imaging (2):
  • Primary tumour
    • For small-volume glanular lesions, imaging studies are not needed
    • For larger lesions/lesions suspicious for invasion, US can provide information about infiltration of the corpora
  • Metastasis: if indicated (see below)
• Other (1): biopsy

History and Physical Exam

• History
  • Delay in seeking medical attention is common
  • Signs and Symptoms
    • Pain is uncommon
• Physical exam
  • Penile lesion
    • Size, location, fixation, and involvement of corporeal bodies
      • Lesions are most commonly on the glans (48%) and foreskin (21%)
      • Physical exam incorrectly establishes pathologic tumour stage in 26% of cases
  • Inguinal area
    • Careful palpation of the inguinal area for adenopathy is important
      • EAU Guidelines: Palpably enlarged lymph nodes are highly indicative of lymph node metastases. Physical examination should note the number of palpable nodes on each side and whether these are fixed or mobile. Additional imaging does not alter management and is not required

Laboratory

• Serum calcium
  • Hypercalcemia may occur without detectable osseous metastases from elevated PTH and related substances produced by tumour
• HPV status
  • Mandatory to determine HPV status when a patient is diagnosed with penile cancer[1]

Imaging

Primary tumour

• For small-volume glanular lesions, imaging studies are not needed
• For larger lesions/lesions suspicious for invasion, US can provide information about infiltration of the corpora
  • Penile Doppler US has been reported to have a higher staging accuracy than an MRI in detecting corporal infiltration
    • MRI with an artificially induced erection can be used to detect corporal invasion but is very unpleasant for the patient
    • CT has poor soft-tissue resolution and is not useful for imaging the extent of the primary tumour

Metastases

• Regional
  • Physical exam of the inguinal region remains the clinical gold standard for evaluating the presence of metastasis in the non-obese patients
    • EAU Guidelines: Imaging studies are not helpful in staging clinically normal inguinal regions; however, CT or MRI should also be performed in obese patients and those who have had prior inguinal surgery, whose physical examination findings may be unreliable
    • EAU Guidelines: A pelvic CT/PET scan can be used to assess the pelvic lymph nodes
    • Campbell's: some patients may have a challenging inguinal nodal examination because of body habitus or lymphedema from prior procedures. In these patients ultrasound can be used. The role of computed tomography (CT), positron emission tomography (PET)-CT, or magnetic resonance imaging (MRI) is not well defined
• Distant
  • CT scan of the chest, abdomen, pelvis
  • Bone scan
  • CT/PET scan

Other

• Biopsy
  • Before initiation of therapy, biopsy is necessary to (4):
    1. Confirm the diagnosis of penile carcinoma
    2. Evaluate the depth of invasion
    3. Evaluate presence of vascular invasion
    4. Evaluate histologic grade
       • Squamous cell carcinomas are graded (1 to 4) using Broder classification
         • Low-grade lesions (grade 1 and 2) represent majority (70-80%) of cases at diagnosis
  • Risk factors for nodal metastases (5):
    1. High-grade disease
    2. Depth of invasion [pT stage]
    3. Sarcomatoid tumors
    4. Perineural invasion
    5. Vascular invasion

Differential diagnosis

1. Condyloma acuminatum (HPV warts)
2. Verrucous carcinoma (Buschke-Lowenstein tumour)
3. Lichen sclerosis
4. STI lesion: Chancre, chancroid, herpes, lymphogranuloma venereum, granuloma inguinale
5. Tuberculosis

Management

CIS

• Non-surgical
  • Topical
    • EAU: Circumcision is advisable prior to the use of topical agents
    • Options (2):
      1. 5-fluorouracil cream (5% concentration BID x 6 weeks)
      2. Imiquimod 5% cream
    • 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.
  • Ablation with lasers
    • Two commonly used laser mediums are carbon dioxide (CO2) and Nd:YAG; conflicting literature regarding their efficacy for cancerous lesions
• Surgical
  • Foreskin lesion
    • Circumcision or excision with a 5-mm margin is adequate
  • Glans lesion
    • Excisional strategies while maintaining normal penile anatomy
• Radiation
  • Can be used for tumours that are resistant to topical treatment, especially among patients who are not surgical candidates
• Moh's surgery

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

• Organ-sparing or glans-sparing surgical procedures
  • Goal is to preserve glans sensation and maximize shaft length
    • Options (5):
      1. Moh's surgery
      2. Laser ablation
      3. Radiation therapy
      4. Limited excision strategies
      5. Glansectomy
         • 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): =

1. High grade (grade ≥ 3) lesions
2. [stage ≥ T2]; deep invasion into the glans urethra or corpora cavernosa
3. Tumours >4cm

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

• Lymph node involvement is most important prognostic factor for survival
  • 5-year survival: lymph node involvement vs. without: 73% vs. 60% (range 0-86% depending on extent of lymph node involvement)

Clinically negative groins

• ≈20% of patients with clinically nonpalpable inguinal nodes harbor occult metastases
  • 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
• Surgical staging
  • Indications
    • Recommended (1):
      • High-risk tumor (≥pT1b)
    • Optional (1):
      • T1a G2 disease
        • Surveillance is an alternative to surgical staging with patients willing to comply with strict follow-up
  • Options (2)
    1. Dynamic sentinel node biopsy (DNSB) (preferred)[2]
       • 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):
             1. Preoperative inguinal US with needle biopsy of any suspicious nodes
             2. Routine inguinal exploration even in the absence of radiotracer visualization
             3. Intraoperative palpation of the wound for abnormal nodes
             4. 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
    2. Bilateral inguinal lymph node dissection (ILND)
       • Lymphatic spread of penile carcinoma can be unilateral or bilateral to the inguinal lymph nodes
       • Approaches (2):
         • Open
         • Video-endoscopic surgery

Palpable adenopathy

• 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
  • The superficial lymph node dissection should be bilateral even if adenopathy is unilateral at presentation
  • 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.
• 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.

Fixed inguinal lymph nodes (cN3)

• Neoadjuvant chemotherapy followed by radical inguinal lymphadenectomy in responders

Lymph node involvement (pN+)

• Prognosis
  • Pathologic criteria associated with improved long-term survival after attempted curative surgical resection of inguinal metastases include:
    1. Unilateral involvement
    2. Minimal nodal disease (≤2 involved nodes in most series (pN1))
    3. No evidence of extra nodal extension of cancer (pN3)
    4. Absence of pelvic nodal metastases (pN3)
       1. 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[3]
• Indications for pelvic lymph node dissection in patients undergoing inguinal lymph node dissection for curative intent (no pelvic adenopathy) (2):
  1. ≥2 positive inguinal lymph nodes
  2. Extra-nodal extension is present
     1. PLND in this setting serves as staging tool to identify patients who should be considered for adjunctive therapy
     2. PLND includes the distal common iliac, external iliac, and obturator groups of nodes.

Summary of treatment strategies for nodal metastases

Lymph node status	Management
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

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015
• Brouwer, Oscar R., et al. "European association of urology-american society of clinical oncology collaborative guideline on penile cancer: 2023 update." European urology (2023).