Squamous cell carcinoma of the penis

Squamous cell carcinoma (SCC) of the penis is an uncommon condition that often presents at an advanced stage. Imaging is more often used for staging than for the initial diagnosis. It is the commonest histological subtype of penile cancer.

Epidemiology

Penile cancer is a relatively infrequent condition, encountered in about 0.001% of the world’s male population every year ². 95% of penile cancers are squamous cell carcinomas ¹. It occurs more commonly in developing countries and this is thought to be due to poor socioeconomic status and low rates of circumcision in neonates ⁴.

Risk factors

• HPV (human papillomavirus) infection in almost 4 out of 10 affected individuals. The virus may

  • exploit the squamous epithelium for producing its virions, thus favoring low-grade lesions or

  • integrate its genome into the host’s DNA, overexpressing oncogenes which in turn favor unrestrained proliferation of infected cells) ^4,6

• uncircumcised penis ⁴

• phimosis (inability to retract the foreskin from the tip of the penis, leading to smegma accumulation and chronic inflammation) ^4,7

• balanitis (inflammation of the glans/head of the penis) ⁴

• obesity (BMI over 30) ⁴

• lichen sclerosis (thinning and whitening of the skin, more commonly on the genitals) ⁴

• smoking (tobacco products concentrate in smegma, which becomes carcinogenic) ^4,5

• PUVA (psoralen UV-A) therapy (the germinative layer is exposed to much more UV radiation than other parts of the body due to the thinner and poorly tanning skin of the foreskin and glans) ^8-10

Diagnosis

­­The diagnosis of penile cancer is based on clues from mandatory physical examination and histopathologic analysis, and additional imaging information ¹¹. The disease is commonly diagnosed belatedly, as psychological reasons hinder patients’ visits to their physicians for clinical assessment, often rendering therapies limited in terms of satisfactory results ¹.

Clinical presentation

Penile cancer most commonly appears as a palpable penile nodule or a lesion on the skin (usually on the glans, coronal sulcus, or prepuce) ¹, an ulcer or a painless lump ¹⁸. The skin may swell and change in color, and other symptoms include pruritus, secretions, dyspareunia, oliguria, and visible inflammatory changes ¹⁹. Metastatic disease is more often initially observed at the inguinal lymph nodes ³.

Although useful for estimating an initial malignancy, ultrasonography is not valuable for staging penile cancers ¹¹.

Pathology

Classification

Squamous cell carcinoma can be histologically subclassified into:

• usual type SCC (majority of cases)

• papillary carcinoma

• warty condylomatous tumors

• basaloid carcinoma

• verrucous carcinoma

• spindle cell (sarcomatoid) carcinoma

Usual type SCC, demonstrates a variable mitotic activity, keratinization, and the presence of epithelial pearl formations. If the malignancy is invasive, the basement membrane and structures around the tumor are visibly infiltrated. Broder classification can be used to assess cellular differentiation considering nuclear pleomorphism, mitoses and keratinization; this system defines SCCs as low-grade (grade I and II) lesions (well-differentiated with hyperkeratosis at the epidermis, from which atypical squamous cells emerge perpendicularly in cords, in 7 to 8 out of 10 patients) and high-grade (grade III and IV) lesions (metastases to surrounding regional lymph nodes and possible vascular and/or perineural invasion, in 2 to 3 out of 10 patients) ¹.

When the diagnosis is confirmed, the lesion's depth of invasion is assessed along with vascular infiltration and the malignancy’s grade is estimated in accordance with the TNM system ². Basaloid cell tumors (appearing “blue”) are usually HPV-positive, whereas those with “pink” cells (eosinophilic), which are mostly keratinized, are usually HPV-negative ¹⁶.

Markers

Markers have been shown to predict survival. Positive p53 is associated with a poor prognosis. Cyclin D1 and p21 do not seem to affect prognosis, however, p21 can increase model quality regarding survival prediction when incorporated into multivariable cox models ²⁰. Concerning invasive SCCs, p16 (INK4a) was found to be strongly correlated to good prognosis, excellent reproducibility, and increased cancer-specific survival (CSS) overall ²¹.

Radiographic features

Penile cancer is usually imaged using ultrasonography, MRI, and PET-CT

Ultrasound

• lesions are most commonly hypoechoic, heterogeneous, and poorly defined ^13,22,23 

• color Doppler reveals increased intratumoral vasculature and lobulated contours concerning con-absorbent lesions ²⁴

MRI

• T1 and T2: solitary, poorly-defined lesions are observed, hypointense on both ²⁴

• T1 +C: while tumor enhancement is observed, it appears to enhance less when compared to the corpora cavernosa ²⁴

MRI is often used for staging of penile cancer ¹⁴ and helps determine whether there is an invasion of the tunica albuginea ¹⁵. Some consider that evaluation is improved when prostaglandins are injected intracavernosal, for the induction of an artificial erection ¹¹.

Nuclear medicine

PET-CT

• primary tumors uptake F-18-FDG cellularly at elevated rates due to profound glycolysis induction ²⁶

• metastatic lymph nodes are also FDG-avid ¹⁷

Treatment and prognosis

Numerous therapeutic approaches can be employed, ranging from surgical and radiotherapeutic interventions for advanced cases, to chemotherapeutic agent administration for pre-malignant alterations (penile intraepithelial neoplasia (PeIN)) ³.