Penile cancer: causes, symptoms, diagnosis and treatment

Penile cancer is a rare malignancy that in the great majority of cases (about 95%) is a squamous cell carcinoma, arising from the epithelium of the glans or foreskin. In Europe it accounts for less than 1% of all male cancers and mainly affects older men. When diagnosed early it has a favourable natural history and most patients can be cured: this is why self-examination and prompt assessment of any suspicious lesion are decisive.

Types of penile cancer

About 95% of penile cancers are squamous cell carcinomas, presenting in two forms:

• Forms that grow outward, forming a polypoid mass, located mainly on the glans
• Infiltrating forms, developing in the foreskin or glans and more rarely on the shaft; these are more often responsible for lymph-node metastases

The remaining 5% consists of sarcomas (including Kaposi's sarcoma), melanomas, basal cell carcinomas, Paget's disease and lymphomas. Metastases to the penis from other tumours (prostate, bladder, colon-rectum, kidney, testis) are rare.

Precancerous lesions and carcinoma in situ

Some lesions can precede malignant transformation: leukoplakia, balanitis xerotica obliterans (lichen sclerosus) and giant condyloma acuminatum. When the tumour is confined to the surface epithelium (carcinoma in situ) it takes specific names by site: erythroplasia of Queyrat on the glans, foreskin or shaft; Bowen's disease on the shaft, scrotum or perineum. Bowen's disease can progress to invasive carcinoma in 5-10% of cases, erythroplasia of Queyrat in about 10-33%.

How common it is

In Europe penile carcinoma is a rare tumour, less than 1% of all male cancers, with an incidence below 1 new case per year per 100,000 men. The risk varies enormously between countries: in Brazil, Uganda and Thailand the incidence is 20-30 times higher (2-3 new cases/year per 100,000) than in industrialised countries. In Europe the peak is seen above the age of 75.

Risk factors

A risk factor is a condition that increases the probability of developing a disease, without making it certain. For penile cancer the main ones are:

• Phimosis: the most important risk factor
• Absence of circumcision: neonatal circumcision appears to have a protective role
• HPV infection (Human Papillomavirus), although infection alone is probably not enough, in a healthy, immunocompetent man, to cause the tumour
• History of sexually transmitted diseases
• Cigarette smoking: increases the risk 2-3 fold, with a greater effect in current than in former smokers
• Immunosuppression and infection with other microbial agents
• Chronic inflammatory conditions such as balanoposthitis and lichen sclerosus, and some dermatological treatments (psoralen, UVA phototherapy)

Symptoms

The most common symptoms, in order of frequency, are a nodule, pain or itching, bleeding, palpable masses in the groin and urinary disturbances. The most frequent site is the glans, followed by the foreskin. Note: phimosis can hide the lesion and delay diagnosis. A palpable inguinal mass is common at diagnosis, but in about half of cases it is due to inflammation (from an ulcerated or infected lesion), which can resolve with 4-6 weeks of antibiotics.

Diagnosis

Diagnosis starts with a careful clinical examination of the lesion (size, site, mobility, degree of infiltration, involvement of the corpora cavernosa) and of the groin. Supporting imaging includes ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI).

Assessment of the inguinal lymph nodes is central but difficult: about 50% of patients have palpable inguinal nodes at diagnosis, but in half of these it is only inflammation, resolving with 4-6 weeks of antibiotics. If the enlargement persists, a fine-needle aspiration is performed. PET/CT has been proposed to assess extent: in some studies it showed high sensitivity and specificity for inguinal nodal metastases (80% and 100% respectively). The diagnosis is confirmed histologically, by biopsy (excisional for small lesions, incisional for larger ones).

Staging

Defining the stage is essential to plan treatment and estimate prognosis. The TNM classification is mainly used, considering three parameters: T (tumour size), N (regional lymph-node involvement), M (distant metastases). TNM has a pre-treatment clinical version (cTNM) and a post-surgical pathological one (pTNM), which underpins the prognostic assessment. An older system is the Jackson classification.

Treatment

The rarity of the tumour has prevented the definition of a standard approach based on randomised trials. When diagnosed early, however, most patients can be cured. Treatment is based on surgical removal of the primary tumour and, where indicated, of the regional lymph nodes, aiming to combine oncological radicality with preservation of sexual and urinary function where possible. This matters particularly in younger patients (under 40, about 20% of cases), for whom radical surgery such as total penectomy can have a major psychological impact.

Treatment of the primary tumour

• Carcinoma in situ (Tis): surgery, topical chemotherapy with 5-fluorouracil cream, or laser ablation (Nd:YAG or CO2), with periodic checks and regular self-examination
• T1 tumour confined to the foreskin: wide local excision with circumcision; circumcision alone requires clear margins and careful follow-up (recurrence risk up to 32% in proximal sites)
• T1 tumour involving the glans: depending on size and aggressiveness, partial amputation (with 1.5-2 cm margins, excellent local control and 0-8% recurrence), microscopically-controlled surgery, radiotherapy (external beam or brachytherapy) or laser therapy in small superficial lesions
• T2-T4 (invasive) tumours: conservative treatment is rarely applicable; amputation (partial or total, with perineal urethrostomy in more extensive forms) is the standard option

Treatment of the regional lymph nodes

Survival depends decisively on the presence and extent of nodal metastases, and their removal (lymphadenectomy) can be curative in about half of patients with metastases. Because the lymphatic drainage of the penis is crossed, a lesion on one side can metastasise to the nodes on both sides.

In patients with clinically negative nodes (N0), the choice is between surveillance (“wait and see”) and a prophylactic lymphadenectomy, which seems reasonable in invasive (T2 or more), high-grade or vascular-invasion tumours. To reduce morbidity, sentinel lymph-node biopsy has been proposed. In node-positive disease (N1-N2), the standard is bilateral removal, possibly with postoperative radiotherapy.

Advanced disease and chemotherapy

In advanced (unresectable N3) or metastatic disease there is no curative treatment and management is essentially palliative (surgery or radiotherapy for local control, chemotherapy). Neoadjuvant chemotherapy (before surgery, often with cisplatin and 5-fluorouracil) can render about 50% of patients with fixed metastatic inguinal nodes operable; adjuvant chemotherapy is used after surgery in at-risk patients. The role of these approaches is still under study.

Prognosis

Prognosis depends chiefly on the stage at diagnosis. Penile carcinoma begins as a superficial lesion on the glans, foreskin or shaft and often remains localised for a long time; if untreated it can invade the corpora cavernosa and the urethra, spread to the inguinal and then iliac nodes, and give distant metastases (liver, lungs, bone). The main prognostic factors are the extent of the primary lesion and lymph-node involvement: nodal metastases are present in 20% of T1 tumours and 47-66% of T2-T4. Tumour grade and vascular invasion also matter.

Follow-up

After treatment a follow-up of at least 5 years is planned, with periodic visits and checks to detect any recurrence early. Most relapses occur within the first 2 years, but late recurrences are possible, so long-term monitoring is recommended and should be entrusted to a team experienced in this rare malignancy.

Frequently asked questions about penile cancer

Is penile cancer caused by HPV?

HPV infection is one of the risk factors, but on its own it is not enough, in a healthy, immunocompetent man, to cause the tumour: other cofactors are needed. Penile cancer shares this mechanism with other HPV-related cancers (cervix, anus, oropharynx). Because of the role of HPV, preventing sexually transmitted infections is relevant to this cancer too.

Does circumcision protect against penile cancer?

Neonatal circumcision appears to have a protective role, as suggested by the low incidence of the tumour in populations that practise it at birth. The most important risk factor is phimosis, which circumcision removes and which can also hide a lesion, delaying diagnosis.

What are the first signs of penile cancer?

The most common sign is a nodule or lesion on the glans or foreskin, often with pain or itching, sometimes bleeding. Any lesion, red area or nodule that does not heal should be shown promptly to a specialist. Phimosis can hide the lesion, which is why self-examination is important.

Can penile cancer be cured?

Yes, especially when diagnosed early: in that case the natural history is favourable and most patients are cured. Prognosis depends on the stage at diagnosis and on any lymph-node involvement. Modern treatments aim, where possible, to preserve the organ and sexual and urinary function.

Can penile cancer be operated on while preserving the penis?

In many early cases, yes. Organ-preserving techniques exist (wide local excision, microscopically-controlled surgery, laser therapy, radiotherapy), indicated for small superficial lesions. In more invasive forms (T2-T4), partial or total amputation often becomes necessary. The choice depends on the size, site and stage of the tumour.

Noticed a lesion, a nodule or an area that will not heal on the penis? Do not wait: ask Prof. Natali for a consultation or book an appointment at his practices in Florence and Empoli, Italy.

The information on this page is provided for general educational purposes and does not replace a medical examination, which remains the only diagnostic tool for correct and effective treatment.