Penile Cancer

Penile cancer is a relatively rare squamous cell carcinoma. It usually originates in the epithelium of the inner prepuce and glans.^[1]There is a tendency for early signs to be ignored so that they often present late and conservative surgery is impossible. The psychological impact of the disease is highly significant. The cause of penile squamous cell carcinoma is unclear but human papillomavirus (HPV) appears to be an important causative factor.

Epidemiology^[1]

95% of penile cancers are squamous cell carcinomas.^[2]Other rare histological variants include malignant melanoma, basal cell carcinoma, extra-mammary Paget's disease and sarcoma.^[3]

• In Western countries, primary malignant penile cancer is uncommon, with an incidence of less than 1 per 100,000 males in Europe.
• The incidence increases with age. The peak incidence is in the sixth decade of life.
• However, a prospective study of 100 consecutive patients from one institution in the UK suggested that 25% of men were under 50 years of age at diagnosis.^[3]
• In the non-Western world, the incidence of penile cancer is much higher and can represent 10-20% of malignant diseases in men.
• Early circumcision reduces the risk of penile cancer by 3-5 times. Adult circumcision does not protect against penile cancer.

Risk factors^{[1, 3]}

• Phimosis is strongly associated with penile cancer.
• HPV infection plays a role in the development of penile cancer. About 50% of cancers are associated with HPV, with the main subtypes being HPV-16 and HPV-18.
• Genital warts.
• Multiple sexual partners and early age of first intercourse.
• HIV infection.
• Smoking.
• Psoralen plus ultraviolet light A (PUVA) treatment for psoriasis.
• Penile injury (small tears or abrasions).
• Other dermatological conditions: the role of such conditions as lichen planus and leukoplakia is disputed.
• Other risk factors include exposure to chemicals such as insecticides, fertilisers, styrene and acrylonitrile.

Premalignant conditions^[3]

Carcinoma in situ (CIS) may progress to invasive carcinoma in 10-30% of cases. The problem is knowing which will progress.

HPV-related premalignant penile lesions include:

• Erythroplasia of Queyrat (penile intraepithelial neoplasia (PIN) III; non-keratinising CIS). Velvety red plaques on the glans penis and inner prepuce. Tends to affect elderly, uncircumcised men.
• Bowen's disease (PIN III; keratinising CIS): pigmented lesions affecting follicle-bearing areas of the penile shaft and scrotum. Bowen's disease is rare and most often occurs in elderly men. Ulceration or papillomatous growth suggests that it has turned invasive.
• Bowenoid papulosis: multiple brown-red maculopapular areas. Occurs mostly on the shaft of the penis in circumcised young men. Lesions may remain static, spontaneously regress, or progress to Bowen's disease.
• Buschke-Löwenstein 'tumour' (giant condyloma acuminatum): confluence of warty exophytic cauliflower-like growths.

Non-HPV-related premalignant lesions include:

• Penile lichen sclerosus (balanitis xerotica obliterans): white sclerotic patches affecting the prepuce, glans, or meatus; often result in phimosis.^[4]
• Leukoplakia: white verrucous plaques on mucosal surfaces.
• Cutaneous penile horn: conical and exophytic lesion associated with areas of chronic inflammation.

Presentation

Around half of presenting patients have had the lesion for six months or more. Most men present with a lump, ulcer or erythematous lesion. Men may also present with bleeding or discharge from a lesion concealed by a phimotic foreskin. Tumours are most commonly seen on the glans (48%) or prepuce (21%).^[3]

• It can occur anywhere on the penis but about 50% start on the glans, 20% on the prepuce and 10% on both
• Itching or a burning sensation especially under the prepuce is a common feature. There may be ulceration of the glans or prepuce and this may progress to a mass.
• Tumours may be papillary and single or multiple and likely to coalesce, raised and possibly necrose or ulcerate. Flat lesions appear as small superficial ulcers.
• If ignored, the tumour will destroy the glans and prepuce and invade the shaft of the penis. It may obstruct the urethra and cause fistulae.
• Lymphatic spread is first to the deep and superficial inguinal nodes and then the pelvic nodes. Distant metastasis is usually to the liver or lung.
• Enlarged lymph nodes may also be due to secondary infection and a foul, purulent discharge may be noted.
• Verrucous carcinoma tends to grow and infiltrate rather than to produce distant spread.

About 20% of patients in Western countries present with palpable inguinal lymph nodes, which almost always signify metastatic disease. About 80% of patients present with clinically impalpable inguinal lymph nodes but 20-25% of these patients will have occult metastasis.^[3]

Once metastatic disease involves the inguinal lymph nodes, further spread of metastatic cells occurs to the pelvic lymph nodes, then distant sites such as the lungs, bone, and para-aortic lymph nodes.^[3]

Differential diagnosis

Metastatic skin cancer and genital warts.

Investigations^[3]

• Premalignant conditions only require biopsy to confirm the diagnosis and exclude invasive elements. Invasive tumours require staging of the primary penile lesion and inguinal and pelvic lymph nodes.
• Local staging can be performed using magnetic resonance imaging (MRI). Ultrasound of the glans penis can also be used to identify involvement of the corpus cavernosum.
• Techniques for lymph node staging include clinical examination, CT and MRI, ultrasound combined with fine-needle aspiration cytology and positron emission tomography-CT.
• Bilateral dynamic sentinel lymph node biopsy is used in some specialist centres for detecting lymph node metastasis.^[5]

Staging

Staging uses the tumour, node and metastasis (TNM) classification of malignant tumours:^[3]

Primary tumour (T):

• TX: primary tumour cannot be assessed.
• T0: no evidence of primary tumour:
  • Tis: CIS.
  • Ta: non-invasive verrucous carcinoma, not associated with destructive invasion.
• T1: tumour invades subepithelial connective tissue.
• T2: tumour invades corpus spongiosum or corpora cavernosa.
• T3: tumour invades urethra.
• T4: tumour invades other adjacent structures.

Regional lymph nodes (N):

• NX: regional lymph nodes cannot be assessed.
• N0: no regional lymph node metastasis.
• N1: intranodal metastasis in a single inguinal lymph node.
• N2: metastasis in multiple or bilateral inguinal lymph nodes.
• N3: metastasis in pelvic lymph node(s); unilateral, bilateral, or extranodal extension of regional lymph node metastasis.

Distant metastasis (M):

• M0: no distant metastasis.
• M1: distant metastasis.

Management^[6]

Surgery

Surgical techniques include:

• For small volume and superficial penile lesions: circumcision, wide local excision and epithelial ablative techniques are mainstay treatments. Local recurrences over time may occur and re-treatment may be required.
• For glanular and distal penile tumours: it is now possible to preserve much more length, and cosmetic and functional results are far superior to conventional partial penectomy.
• Preservation techniques: studies are assessing both less resection for superficial tumours and more penile reconstruction (phalloplasty) for more advanced tumours suitable only for total penectomy.

Radiotherapy

• Radiotherapy is not often used for the treatment of penile cancer and is most appropriate for small lesions in patients unfit or unwilling to undergo surgery.
• Radiotherapy as treatment of the primary tumour may be delivered either by external beam treatment or brachytherapy.
• Radiotherapy for the management of regional lymph node metastases:
• In penile cancer, elective radiotherapy has never been widely used. The role of adjuvant postoperative radiation is controversial.
• Adjuvant radiation to the inguinal lymphatic area has been advocated by some but there is no strong evidence of benefit.
• Chemoradiotherapy: a few retrospective studies suggest some benefit of radiotherapy with concurrent cisplatin-based chemotherapy in locally advanced unresectable disease but further research is needed.

Chemotherapy

• Penile cancer has only a limited response to chemotherapy. Cisplatin has been the cornerstone of combination regimens.
• Cytoreductive neoadjuvant chemotherapy has been applied to allow surgery or radiotherapy to obtain local control but there are no prospective trials of adjuvant chemotherapy, only small retrospective series. Cisplatin combination chemotherapy regimens are the most widely used and seem to be the most effective.
• Chemotherapy for advanced disease: cisplatin has been used in combination with agents such as 5-FU or irinotecan. The chemotherapy combination ifosfamide, paclitaxel and cisplatin may also be considered for metastatic disease. Paclitaxel in combination with carboplatin may provide an alternative regimen in patients who are ineligible for cisplatin treatment.

Choice of treatment

• Primary tumour: the choice of treatment is influenced by the size and position of the tumour on the glans or in the corpora. For superficial and glans confined tumours, a penile-preserving strategy is recommended.
• Regional lymph nodes: lymphadenectomy is the standard treatment of patients with inguinal lymph node metastases.
• Recurrence: local recurrence rate after conservative surgery does not seem to have a negative impact on long-term survival.
• Metastatic disease: patients who present with metastatic disease have a very poor prognosis and early consideration of palliative care is recommended.

Premalignant disease^[3]

• If an excisional biopsy indicates that the lesion was excised completely then circumcision (remove a preputial lesion, it also aids surveillance) and close supervision are recommended.
• After incisional biopsy, further treatment will be needed to eradicate the lesion completely. Topical chemotherapy is most effective for solitary lesions in immunocompetent patients.
• The most common first-line topical treatment used is 5% 5-fluorouracil.
• Persistent lesions can be treated with second-line immunotherapy using topical 5% imiquimod.
• Lasers and potassium titanyl phosphate have also been used with good functional and cosmetic results.
• Surgical excision is reserved for refractory cases or for patients who have developed extensive CIS of the glans penis.

Prognosis

• The overall cure rate for penile cancer has improved from 50% in the 1990s to 80% in recent years.^[1]
• Penile cancer can have devastating mutilating and psychological consequences for those affected.^[7]

Prevention

• Penile cancer is rare in circumcised men, particularly if they are circumcised as newborns.^[6]
• Other preventative measures include prevention of phimosis, treatment of chronic inflammatory conditions, smoking cessation, the use of condoms and prevention of HPV infection (including male vaccination).^[8]
• Lesions should be reported early and the possibility of malignancy given due consideration. Presentation is often delayed because of embarrassment about the lesion.