Erythroplasia of Queyrat

Erythroplasia of Queyrat is squamous cell carcinoma in situ (penile intraepithelial neoplasia) of the glans penis, coronal sulcus or inner prepuce. It is the mucosal counterpart of Bowen disease of the penile shaft. It is a premalignant lesion, and untreated disease progresses to invasive squamous cell carcinoma in roughly 10 to 33%.

Epidemiology:

• Mainly uncircumcised men, with a mean age around 50 to 60 years. It is rare in circumcised men, particularly those circumcised in the neonatal period.
• It makes up the majority of penile carcinoma in situ and is a small fraction of penile neoplasia overall.

Risk factors:

• Phimosis and poor genital hygiene, with chronic inflammation and smegma retention.
• High-risk HPV infection (types 16 and 18 in a majority of lesions, via the HPV-dependent pathway).
• Lichen sclerosus, which drives an HPV-independent, p53-associated pathway.
• Smoking, HIV and other immunosuppression, multiple sexual partners, history of genital warts, and psoralen with UVA therapy.

Pathology:

• Full-thickness epidermal atypia with loss of maturation, enlarged hyperchromatic nuclei, mitoses and a basement membrane that is intact. Basaloid and warty patterns are HPV-related, and differentiated type is HPV-independent. p16 is positive in HPV-driven lesions.
• Lack of a keratin layer on mucosal surfaces explains the moist, velvety red appearance.

Associated conditions: Bowen disease of the shaft, bowenoid papulosis (multiple pigmented HPV-related papules in younger men, usually benign), and field change with multifocal disease in the urethral meatus.

Presentation:

• A solitary (sometimes multiple), well-demarcated, bright red, velvety or shiny plaque on the glans, coronal sulcus or inner foreskin, usually 0.5 to 3 cm.
• Slow growth over months to years, and often misdiagnosed for months as balanitis, candidiasis or eczema that does not respond to topical steroids or antifungals.
• Symptoms are often minimal: itching, burning, soreness, mild discharge or bleeding on contact. Pain is uncommon until ulceration.

Signs that raise concern for invasion:

• Induration, nodularity, ulceration, warty or papillary change, bleeding, fixed lesion, and inguinal lymphadenopathy.

Differential diagnosis:

• Zoon plasma cell balanitis (orange-red, multiple, with "cayenne pepper" spots, benign, histology of plasma cells).
• Candida balanitis, psoriasis, lichen planus, lichen sclerosus, contact or fixed drug eruption, reactive arthritis (circinate balanitis), and balanitis xerotica obliterans.
• Invasive squamous cell carcinoma, extramammary Paget disease, melanoma in situ, and Kaposi sarcoma.

Red flags: any penile lesion persisting beyond 3 to 4 weeks of appropriate topical therapy, new induration, and palpable groin nodes.

Diagnosis requires histology. Clinical appearance alone cannot be relied on.

• Biopsy under local anaesthetic (lidocaine 1%): 3 to 4 mm punch biopsy or incisional biopsy of the most abnormal area, including the edge, with additional samples from multiple areas in extensive disease. Excisional biopsy or circumcision with histology is acceptable for small lesions. Report depth of invasion and grade.
• Immunohistochemistry (p16, Ki-67, p53) and HPV testing help to subtype.
• Examine the whole glans, meatus, foreskin, perianal and perineal skin, and the groin for lymphadenopathy.
• Urethroscopy for lesions extending to the meatus or when intraurethral involvement is suspected.
• Imaging is not needed for carcinoma in situ with no suspicion of invasion. If invasion is possible: MRI with artificial erection (prostaglandin E1 injection) or ultrasound to assess depth and corporal invasion, and pelvic CT or PET CT for suspected nodal disease.
• Check HIV, syphilis serology and other sexually transmitted infections. Screen for anogenital HPV disease and cervical screening for female partners.
• Fine needle aspiration of palpable nodes only when invasive disease is suspected.

Aims are complete eradication, preservation of penile structure and function, and detection of invasion.

Topical therapy (first line for superficial disease)

• Imiquimod 5% cream applied 3 to 5 times weekly at night for 4 to 16 weeks, washed off after 6 to 10 hours. Local inflammation and erosions are expected. Response rate about 50 to 70%.
• 5-fluorouracil 5% cream applied once or twice daily for 4 to 6 weeks (or 2 to 3 times weekly for longer), complete clearance in about 50 to 80%. Causes marked erythema, pain and ulceration, and requires supervision.
• Both need review at 4 to 6 weeks, with biopsy of any residual disease.

Procedural and surgical options

• Circumcision for lesions confined to the foreskin or with phimosis. It treats the field of risk and is often combined with other methods.
• Laser ablation: CO2 or Nd:YAG laser vaporisation, with depth control, shows cure of about 75 to 90% with good cosmetic and functional result. Biopsy is needed before ablation.
• Mohs micrographic surgery or wide local excision with 5 mm margin and frozen section control for localised disease.
• Glans resurfacing: removal of the epithelium of the glans with split-thickness skin graft (from the thigh) for extensive or multifocal disease, with recurrence under 10% and sexual function mostly preserved.
• Photodynamic therapy: 5-aminolevulinic acid or methyl aminolevulinate with red light, as an organ-sparing alternative.
• Radiotherapy (brachytherapy or external beam) is rarely used for in situ disease.
• Partial glansectomy or partial penectomy for invasive carcinoma, with inguinal lymph node assessment (dynamic sentinel node biopsy or modified inguinal lymphadenectomy) per risk, and cisplatin-based chemotherapy in advanced disease.

Adjunctive measures

• Treat concurrent balanitis, candidiasis or lichen sclerosus (clobetasol 0.05% ointment for lichen sclerosus), and improve hygiene.
• Smoking cessation, safer sexual practices, HPV vaccination in eligible men (the vaccine reduces new HPV-related lesions and may reduce recurrence), and HIV optimisation.
• Pain control with paracetamol and topical lidocaine 2% gel during topical therapy.

Follow-up

• Review at 3 months after treatment, then every 3 to 6 months for 2 years and annually thereafter, with examination of the glans, meatus and groin. Repeat biopsy for any suspicious area or persistent erythema.
• Recurrence occurs in 5 to 30% depending on treatment (higher after topical therapy). Educate patients on self-examination and prompt reporting of new lesions.
• Prognosis is excellent when treated at the in situ stage, with near-100% disease-specific survival.