Penile Cancer: Squamous Penile Cancer

Benign Tumours

• Pearly penile papules
  • Also known as papillomas
  • Normal and generally found on the glans penis or corona
  • Insert figure
• Zoon balanitis
  • Also called plasma cell balanitis and balanitis plasmacellularis
  • Occurs in uncircumcised men from the 3rd decade onward
  • Appearance: smooth, moist, erythematous, well-circumscribed plaques on the glans penis; shallow erosions are often present and lesions can be quite large (up to 2cm); difficult to distinguish from carcinoma in situ
    • See Figure
  • Pathology:
    • Angiofibromas, similar to the lesions seen on the face in tuberous sclerosis
    • Plasma cell infiltrate
  • Diagnosis and evaluation: biopsy
    • Malignancy and extra-mammary Paget’s disease must be excluded
  • Management
    • Circumcision
      • Curative in the majority of cases
      • Prevents against development of the disease
      • For patients wanting to avoid circumcision, topical corticosteroids may provide symptomatic relief; topical calcineurin inhibitors (tacrolimus or pimecrolimus) and laser therapy may also play a role

Premalignant cutaneous lesions

• Classified as HPV-related vs. non-HPV related§
  • HPV related (3): bowenoid papulosis, verrucous carcinoma, CIS
    1. Bowenoid papulosis
       • Appearance: multiple reddish-brown verrucous papules on the penile skin; occurs on the shaft of young men in most cases
         • See Figure
       • Histologically similar to low-grade carcinoma in situ [Bowen’s disease]
       • HPV 16 has been suspected as a cause
       • Progression rate to invasive cancer: 1%
       • Diagnosis: biopsy (gold standard)
       • Management: options include excision, electrocautery, cryotherapy, laser, or 5-fluorouracil topical therapy
    2. Verrucous carcinoma (also known as classic Buschke-Löwenstein Tumor and giant condyloma)
       • DNA from HPV types 6 and 11 has been identified in these tumors
       • Progression rate to invasive cancer: 30%
         • Exhibits progressive local growth but does not metastasize
         • Results in invasion and destruction of adjacent tissues by compression
           • Buschke-Löwenstein tumor differs from condyloma acuminatum in that condylomata, regardless of size, always remain superficial and never invade adjacent tissue.
       • Management: often requires surgical excision for definitive treatment; radiation is ineffective
       • INSERT FIGURE
    3. CIS
       • Erythroplasia of Queyrat
         • CIS of the glans or foreskin
         • Progression rate to invasive cancer: 30%
       • Bowen’s disease
         • CIS the penile shaft or the remainder of the genitalia or perineal region
         • Progression rate to invasive cancer: 5%
         • See Figure
       • Metastasis extremely rare
       • Not associated with visceral malignancies
  • Non-HPV related (5):
    1. Penile Kaposi sarcoma
       • Often associated with herpes-virus 8
       • Should prompt an investigation into whether patient is also infected with HIV or otherwise immunosuppressed
       • Appears as a raised, painful, bleeding papule or ulcer with bluish discolouration
         • See Figure
       • Categories of Kaposi sarcoma (4):
         1. Classic: occurs in patients without known immunodeficiency and typically has an indolent course
         2. Immunosuppressive treatment-related: occurs in patients undergoing immunosuppression for organ transplantation or other reasons
         3. African Kaposi sarcoma: occurs in young men and can be indolent or aggressive
         4. Epidemic or HIV-related: occurs in patients with AIDS
         • The classic and immunosuppressive forms of the disease are considered non-epidemic
           • Non-epidemic Kaposi sarcoma limited to penile involvement should be aggressively treated because it is rarely associated with diffuse organ involvement
       • Management
         • The first step in treatment of Kaposi's sarcoma in patients with HIV is to initiate HAART or to optimize the HAART regimen, which generally results in remission of Kaposi's sarcoma.
         • Local treatment can include laser therapy, cryotherapy, surgical excision, application of topical retinoids.
         • Disseminated or visceral Kaposi's sarcoma is treated with combination chemotherapy.
    2. Penile cutaneous horn
       • Rare
       • Usually develops over a pre-existing skin lesion (wart, nevus, traumatic abrasion, or malignant neoplasm)
       • Characterized by overgrowth and cornification of the epithelium, which forms a solid protuberance
         • See Figure
       • May recur and may demonstrate malignant change on subsequent biopsy, even when initial histological appearance is benign. As a result, careful histological evaluation of the base and close follow-up of the excision site are essential
    3. Leucoplakia
    4. Lichen sclerosis (see Penis and Urethra Surgery Chapter Notes)
    5. Pseudoepitheliomatous micaceous and keratotic balanitis

Squamous Cell Carcinoma of the Penis

• Accounts for > 95% of penile malignancies

Epidemiology

• Invasive Squamous Cell Carcinoma of the Penis
  • 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. Phimosis
3. Lichen sclerosus, chronic penile inflammation
4. HPV (subtype 16 most frequently; oncologic subtypes: 16 and 18, non-oncologic subtypes: 6 and 11)
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

• Most common sites of distant metastasis are lung, bone, 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:

• H+P (including exam of inguinal nodes)
• Laboratory (1): serum calcium
• Imaging (2):
  • Local: penile US for large/invasive lesions
  • Metastasis: if indicated (see below)
• Other (1): biopsy

History and physical exam

• History
  • Delay in seeking medical attention is common
  • Pain is uncommon
• Physical exam
  • Assess penile lesion for 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
  • 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

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 scintigraphy; or 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 (4):
    1. High-grade disease
    2. Depth of invasion [pT stage]
    3. Perineural invasion
    4. Vascular invasion

Differential diagnosis of penile cancer

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 of penile cancer

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
      6. 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
      7. 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.
      8. Because recurrence rates are higher with organ-preserving strategies, compliance with follow-up is also a consideration in recommending organ preservation versus amputation Indications for partial or total penectomy (3):
      9. High grade (grade ≥ 3) lesions
      10. [stage ≥ T2]; deep invasion into the glans urethra or corpora cavernosa
      11. Tumours >4cm