Penile Cancer

Malignant lesions of the penis arise from the squamous epithelium of the glans, prepuce, or penile shaft. Penile cancer is rare in the United States, but there is a higher prevalence in lower socioeconomic regions. The most common histologic subtype is squamous cell carcinoma. Uncircumcised men and those with HPV infections are at highest risk of penile neoplasms. Diagnosis is a combination of physical exam, history, imaging studies, and tissue biopsy. Proper TNM staging is necessary to determine the correct treatment, which ranges from local topical therapy to multimodal surgery/radiation/chemotherapy.

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Overview

Epidemiology

  • Overall, penile malignancies are rare. 
  • Highest incidence: age group 50–70 years 
  • In the United States:
    • Estimated annual incidence of approximately 2000 new cases 
    • Average incidence: 1 in 100,000 men per year
  • In highly industrial countries (United States, Europe, Canada), annual incidence rates are lower. 
  • Prevalence rates are 5–10 times higher in nonindustrialized countries.

Risk factors

  • Uncircumcised males:
    • Greatest risk contributing to malignant penile lesions 
    • 22-fold increased risk versus circumcised males 
    • Maximal risk reduction of penile cancer with circumcision performed in the neonatal period  
  • History of HPV or HIV infection: 
    • 8-fold increase of penile lesions 
    • Up to 50% of penile cancers are associated with HPV serotypes 16 (most common), 6, and 18. 
    • Particularly increased risk of basaloid and warty penile carcinomas 
  • HIV
  • Lower socioeconomic status 
  • Poor genital hygiene (accumulation of smegma)
  • Smoking 
  • Psoralens and ultraviolet A photochemotherapy
  • Chronic inflammatory conditions: 
    • Phimosis 
    • Balanitis

Pathophysiology

Anatomy

  • Most cancers of the penis arise from the squamous epithelium of the epidermis and dermis. 
  • Two distinct fascial layers arise beneath the penile shaft skin:
    • Superficial dartos fascia 
    • Deep Bucks fascia 
  • Within Bucks fascia are the two cavernosal bodies dorsally and the solitary spongiosum ventrally. 
  • Lymphatic drainage of the penis is mainly via the inguinal lymph nodes in the groin:
    • No pattern of laterality for drainage, with much crossover 
    • Superficial and deep lymphatics, either above or below the fascia lata

Male reproductive anatomy (external)

Image: “Male Reproductive System” by Phil Schatz. License: CC BY 4.0

Cross section of the penis:
Image shows the form the erectile tissues take within the body of the penis. Here, note the tunica albuginea enclosing both types of erectile tissue as well as the urethra, which is fully within the corpus spongiosum.

Image: “Penis cross section” by Mcstrother. License: CC BY 3.0

Pathogenesis and pathology

  • Cancer growth:
    • Small lesions initially, often noted on the glans or prepuce
    • HPV-mediated penile carcinomas: 
      • Oncoproteins E6 and E7 produced by HPV infections can interfere with tumor suppressor gene function.
      • Alterations of the RB1 and p53 genetic pathways and cell-cycle regulators p21 and p16 occur.
  • Carcinoma in situ (CIS) or penile intraepithelial neoplasia: 
    • Bowen disease presents as lesions on the penile shaft.
    • Erythroplasia of Queyrat presents with lesions on the glans. 
  • Squamous cell carcinoma (SCC):
    • Common variant:
      • Comprises up to ⅔ of SCC cases
      • Typically invades the corpus spongiosum and grade II histology
      • Inguinal node metastases are present in 25%–40% of cases. 
    • Papillary carcinoma: 2%–15% of cases
      • Usually low grade or well differentiated but superficially invasive 
      • Microscopic evidence of hyperkeratosis and papillomatosis 
      • Not linked to HPV infection 
      • Not often associated with vascular or perineural invasion 
    • Warty (condylomatous): 7%–10% of cases 
      • Cauliflower-like lesions 
      • Prominent fibrovascular core with papillomatous formations 
      • Does not commonly reach vascular and neural structures
      • Linked to HPV infection 
      • Inguinal node metastasis in 17%–25% of cases 
    • Basaloid carcinoma: 4%–10% of cases 
      • Ulcerated irregular masses related to HPV
      • Histologically present as uniform and small hyperchromatic cells with central necrosis. 
      • Usually deeply invasive into the corpus cavernosum or spongiosum 
    • Verrucous carcinoma: 3%–7% of cases 
      • Usually low grade and exophytic
      • Histologically straight papillae lined by extremely well-differentiated neoplastic cells 
      • Hyperkeratotic surface with interpapillary keratin 
    • Sarcomatoid (spindle cell) carcinoma: 1%–6% of cases 
      • Most aggressive variant
      • Poorly differentiated, ulcerated, or rounded polypoid masses
      • Usually with vascular and perineural invasion 
  • Basal cell carcinoma: low risk of metastasis
  • Sarcoma (including Kaposi’s sarcoma, which is associated with HHV-8
  • Melanoma: most aggressive skin cancer
  • Metastasis to the penis is rare.

Clinical Presentation and Diagnosis

Presentation

  • Initially presents as a skin abnormality or palpable lesion on the penis: 
    • Majority arise from the glans penis, at the coronal sulcus or on the prepuce.
    • May be painful, but usually painless 
  • Lesions can vary in size and characteristics: 
    • Ulcerated lesions 
    • Infiltrative with progressive growth 
  • Inguinal adenopathy presents in about 30%–60% of cases. 
  • Distant metastasis: 
    • Usually means late disease presentation 
    • Affects adjacent genitourinary organs or distant organs 
    • Present in about 1%–10% of cases

Physical exam

  • Generalized constitutional exam (assess for overall performance status) 
  • Focused genitourinary exam: 
    • Penile exam: 
      • Determine circumcision status.
      • Characterize size, depth, location, and features of lesion.
      • Assess for discharge, erythema, and swelling.  
    • Inguinal exam: 
      • Assess for inguinal lymphadenopathy. 
      • Number of palpable inguinal nodes 
      • Fixed or mobile nodes

Penile squamous cell carcinoma

Image: “Cancer of the penis” by Service d’Urologie, CHU de Cocody, Abidjan, Ivory Coast, Africa. License: CC BY 4.0

Diagnostics

  • Tissue biopsy to confirm: 
    • Punch-type 
    • Incisional 
    • Excisional 
  • Imaging:
    • Options:
      • Ultrasonography
      • MRI/CT
    • Functions:
      • Assesses primary tumor stage and surgical approach 
      • Identifies invasion into the corpora cavernosa or spongiosa 
      • Determines regional lymph node involvement 
      • Imaging of other sites in case of metastasis
  • Staging of inguinal lymph nodes: 
    • Fine-needle aspiration: 
      • Performed under local anesthesia with 23-gauge needle 
      • Samples clinically palpable nodes 
    • Dynamic sentinel node biopsy: 
      • Involves injection of radioactive tracer dye 
      • Examines drainage of inguinal lymph nodes 
      • Allows for lymphatic mapping and sentinel node biopsy 
    • Superficial inguinal lymph node dissection:
      • Provides direct information regarding suspicious nodes 
      • Performed by experienced pelvic surgeons 
      • Higher overall complication rates

Staging

Table: Tumor, Node, Metastasis (TNM) Staging System for penile cancer (American Joint Committee on Cancer)
T: tumor
Primary tumor (T)Description
TxPrimary tumor cannot be assessed.
T0No evidence of tumor
TisCarcinoma in situ
T1
  • Glans: Tumor invades lamina propria.
  • Foreskin: Tumor invades dermis, lamina propria, or dartos fascia.
  • Shaft: Tumor invades connective tissue between epidermis and corpora.
T1aTumor without lymphovascular invasion or perineural invasion and not high grade
T1bTumor with lymphovascular invasion and/or perineural invasion or tumor is high grade
T2Tumor invades corpus spongiosum with or without urethral invasion.
T3Tumor invades corpora cavernosum with or without urethral invasion.
T4Tumor invades adjacent structures.
Table: Tumor, Node, Metastasis (TNM) Staging System for penile cancer (American Joint Committee on Cancer)
N: node
Regional lymph nodes (N)Description
cNxRegional lymph nodes cannot be assessed.
cN0No palpable or visibly enlarged inguinal lymph nodes
cN1Palpable mobile unilateral inguinal lymph node
cN2≥ 2 palpable mobile unilateral inguinal nodes or bilateral inguinal lymph nodes
cN3Palpable fixed inguinal nodal mass or pelvic lymphadenopathy unilateral or bilateral
Table: Tumor, Node, Metastasis (TNM) Staging System for penile cancer (American Joint Committee on Cancer)
M: metastasis
Distant metastasis (M)Description
M0No distant metastasis
M1Distant metastasis

Management

Management options

Table: Development of the tracheobronchial tree and lungs and clinical relevance
Treatment strategy for cancerous lesionsExplanation
Penis-preserving interventions
  • Local excision with reconstruction
  • Glansectomy
  • Laser therapy
  • Radiotherapy
  • Brachytherapy
Partial/total amputationPartial excision decision has to be exercised with great caution in selected patients with locally invasive tumors.
Surveillance for lymph node metastasisLow-risk patient with no vascular invasion
Early lymphadenectomyFor high-risk patients or with vascular invasion

Treatment approach

Carcinoma in situ or Tis–T1:

  • Topical therapy: 
    • Fluorouracil cream indicated for CIS 
    • Imiquimod cream for CIS 
  • Laser ablation: 
    • CO2 laser commonly used 
    • For local ablation of superficial lesions 
    • Usually successful for CIS 
  • Total glans resurfacing: 
    • Removes the skin and lamina propria layers of the glans penis 
    • Followed by skin graft placement 
    • Effective method for CIS 
  • Mohs micrographic surgery: 
    • Layer-by-layer excision of penile lesion 
    • Requires multiple procedures and coordination 
  • Radiation therapy: 
    • Via external-beam or interstitial brachytherapy 
    • Requires multiple sessions and high doses of radiation 
    • Significant side effects: urethral mucositis, edema, secondary infection risks

Bulky T2T4 tumors:

  • Limited excisions for distal, smaller T2 tumors 
  • Penile amputation: 
    • Determined by extent and location of primary tumor 
    • Partial amputation for distal invasive tumors 
    • Total amputation for extensively invasive tumors
  • Chemotherapy ± radiation therapy also used to shrink tumor or for large lymph nodes

Lymph nodes:

  • Nonpalpable:
    • Low risk (up to T1): surveillance for lymph node metastasis
    • High risk: confirm with node biopsy and if positive, proceed with lymphadenectomy
  • Palpable lymph nodes: inguinal lymphadenectomy

Differential Diagnosis

  • Angiokeratomas: uncommon benign, violaceous papules with an overlying scale: Angiokeratomas usually appear on the glans penis, but they can also be found on the scrotum. In most cases, the lesions are asymptomatic and do not require treatment. 
  • Lichen planus (penis): characterized by violaceous papules on the glans: Lichen planus is rarely symptomatic, although some patients may experience pruritus. Treatment will be for symptomatic control if needed. 
  • Condylomata acuminata: soft papillomatous growths that are highly associated with HPV infection: Most condylomata acuminata are benign and associated with low-risk HPV types 6 and 11. Treatment involves removal of lesions with laser treatment, topical agents, or surgical excision.
  • Genital psoriasis: erythematous plaques with well-defined margins in genital area: These lesions are often asymptomatic but can be pruritic. The presence of other psoriatic plaques on other parts of the body distinguishes this condition from penile cancer.

References

  1. Chipollni, J. (2021). Penile neoplasms. AUA Urology Core Curriculum. Retrieved April 3, 2021, from https://auau.auanet.org/core 
  2. Engelsgjerd J. S., LaGrange, C. A. (2020). Penile cancer. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK499930/
  3. Pagliaro L. C. (2016). Penile cancer. Kantarjian H. M., Wolff R. A. (Eds.), MD Anderson Manual of Medical Oncology, 3rd ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=1772&sectionid=121901369
  4. Pettaway, C. (2020). Carcinoma of the penis: Clinical presentation, diagnosis, and staging. UpToDate. Retrieved April 3, 2021, from https://www.uptodate.com/contents/carcinoma-of-the-penis-clinical-presentation-diagnosis-and-staging
  5. Pettaway, C. (2021). Carcinoma of the penis: epidemiology, risk factors, and pathology. UpToDate. Retrieved April 3, 2021, from https://www.uptodate.com/contents/carcinoma-of-the-penis-epidemiology-risk-factors-and-pathology
  6. Pettaway, C. (2021). Carcinoma of the penis: Surgical and medical treatment. UpToDate. Retrieved April 3, 2021, from https://www.uptodate.com/contents/carcinoma-of-the-penis-surgical-and-medical-treatment

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