Epidemiology and Etiology

The incidence of penile cancer varies depending on geographic area and ethnicity. In industrialized countries, it is relatively rare, with an incidence of about 0.9 per 100,000 in Europe and 0.5 in the United States. In contrast, the incidence is much higher in South America, Asia, and Africa. In recent decades, there has been a slight increase in cases, likely linked to higher rates of HPV infection; nearly half of the cases are attributed to HPV-associated carcinogenesis.

Risk Factors

Penile cancer is associated with numerous risk factors:

• – Phimosis, along with poor hygiene and chronic inflammation, is strongly associated with the onset of invasive cancer. Circumcision appears to have a protective effect, reducing the risk of invasive cancer.
• – The incidence of lichen sclerosus is very high in patients with penile cancer.
• – Smoking and low education levels are other risk factors.
• – However, the primary risk factor is HPV infection. This virus can induce carcinogenesis by interacting with various oncogenes and tumor suppressor genes once its DNA integrates with the host’s DNA.

More than 95% of these tumors are squamous cell carcinomas (SCC) that originate from the foreskin or glans. Penile intraepithelial neoplasia (PeIN) is considered the precursor lesion of SCC; PeIN is classified into HPV-independent and HPV-associated types. Terms such as “Queyrat erythroplasia” or “Bowen’s disease” are no longer used based on the 2022 WHO classification. Other malignant lesions of the penis include melanocytic lesions, mesenchymal tumors, lymphomas, or metastases.

Diagnosis

PHYSICAL EXAMINATION

A thorough physical examination is vital: penile cancer manifests with lesions that are often raised or ulcerated.

BIOPSY

A biopsy of the lesion should always be performed, even in clinically obvious cases, as the histological information obtained can guide therapeutic choices. The quality of the biopsy is crucial for confirming the diagnosis; smaller lesions should be completely excised, while incisional biopsies may suffice for larger lesions.

MAGNETIC RESONANCE IMAGING (MRI)

MRI is not superior to simple clinical examination when it comes to distinguishing a T1 stage (tumor invading subepithelial connective tissue) from a T2 stage (tumor invading the spongy body with or without urethral invasion). However, it shows 80% sensitivity in assessing cavernous body invasion (T3).

LYMPH NODE STAGING

Penile cancer metastasizes via lymphatics, initially spreading to inguinal lymph nodes and then to pelvic nodes. The presence of lymph node metastases is the most important prognostic factor for survival in penile cancer: at 5 years, survival rates drop from 95% for N0 (no palpable lymph nodes) to 35% for N3 (fixed inguinal mass or pelvic lymphadenopathy).
For patients suspected of having penile cancer, palpation of both inguinal regions should always follow the physical examination of the penis.

• Clinically Negative Patients

Unfortunately, when it comes to penile cancer, there are no tumor markers available that can predict lymph node involvement, and imaging techniques such as MRI or CT are unable to detect micro-metastases, making them unsuitable for routine use in clinically negative patients. Given that non-invasive staging options are currently unreliable, the only way to identify lymph node micro-metastases before they become palpable is through surgical staging, which involves dissection of the inguinal lymph nodes. This is, of course, an invasive procedure and is not performed arbitrarily on all patients but only on those with tumors considered high-risk, while intermediate-risk tumors are evaluated case by case, balancing the risk of micro-metastases against the morbidity associated with surgical staging.

• Clinically Positive Patients

Patients with palpable lymph nodes should undergo additional imaging techniques to exclude the presence of distant metastases. CT and MRI are valid staging modalities, reporting similar sensitivity and specificity, while 18-FDG PET-CT has proven superior.

Management of the Disease

The treatment goal should be to preserve the organ as much as possible without compromising oncological radicality.

• Superficial Non-Invasive Disease

While there is no consensus on treatment protocols, topical therapy with 5-fluorouracil and imiquimod is a valid therapeutic alternative. Cases of extensive PeIN, or those recurring after topical therapy, may be treated surgically with glans resurfacing.

• – Localized Invasive Disease Confined to the Glans

The therapeutic choice depends on tumor size, histology, and patient preferences. In recent years, there has been an increased preference for surgical approaches, which have a lower recurrence rate compared to other alternatives like radiotherapy and brachytherapy. In such cases, surgery entails glandulectomy with subsequent reconstruction: if the neoplasm only involves the glans without affecting the cavernous bodies, dissection can be performed above the Buck fascia. The neo-glans is then reconstructed with a full-thickness graft. This procedure ensures the patient a satisfactory aesthetic result and good erections. It is essential to discuss with the patient the possibility of a less conservative and more radical surgery in these cases, represented by partial penectomy, considering the effects this may have on the patient’s quality of life and sexuality.

• Locally Advanced Disease

In cases of resectable disease with evident cavernous body involvement, partial penectomy is standard. For non-resectable disease, neoadjuvant chemotherapy offers the possibility of reducing the tumor mass to make it surgically resectable. Among the most used drug combinations are those utilizing paclitaxel or docetaxel with cisplatin and ifosfamide or 5-fluorouracil.

Lymph Nodes

For patients with positive lymph nodes, open radical dissection of the inguinal lymph nodes is the standard approach. In patients with advanced disease and the presence of a fixed inguinal mass or pelvic lymphadenopathy, chemotherapy followed by surgery is a reasonable strategy. Major complications from inguinal lymph node dissection include lymphocele, dehiscence, necrosis, venous thrombosis, and pulmonary embolism.

FOLLOW-UP

Patient surveillance is crucial because early diagnosis of potential recurrences increases the likelihood of curative treatment. Follow-up should last a minimum of 5 years, with surveillance intervals of about 3 months for the first two years, as most recurrences manifest in this time frame. Subsequently, consideration can be given to transitioning to semiannual and then annual checks. Follow-up is essential not just from an oncological perspective, but also to assess the physical and psychological impact of treatments. The diagnosis of cancer often generates significant anxiety and, in some cases, depression in patients. This is even truer for penile cancer. Such pathology and the associated treatments can be functionally and sexually debilitating, significantly negatively impacting the patient’s quality of life. This can affect the patient’s self-perception, as they may feel inadequate or deprived of their masculinity, leading to isolation. For this reason, it is essential that these patients receive psychological support at every stage of managing their condition: open communication with partners, psychological therapy, and sexual counseling can help manage the psychological repercussions of this condition and improve the patient’s quality of life.

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