Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma is a malignant proliferation of keratinocytes and the second most common skin cancer, with an incidence of about 100 to 300 per 100,000 people a year in fair-skinned populations. The median age is 70 years. It arises from precursors (actinic keratosis, with a transformation rate of 0.1 to 10% a year, and Bowen disease, which is in situ carcinoma) and from chronic wounds, scars (Marjolin ulcer), burns and radiodermatitis.

Risk factors

• Cumulative ultraviolet exposure
• Immunosuppression, notably organ transplantation (a 65 to 250 times higher risk)
• Chronic lymphocytic leukemia
• Human papillomavirus infection
• Arsenic exposure
• Xeroderma pigmentosum and epidermolysis bullosa

Genomic features: TP53 mutations in over 90%, and NOTCH, CDKN2A and RAS mutations.

High-risk features: diameter over 2 cm, thickness over 6 mm or invasion beyond subcutaneous fat, perineural invasion (especially of nerves 0.1 mm or larger), poorly differentiated histology, location on the lip, ear, temple or scalp, recurrence, and immunosuppression. Nodal metastasis occurs in 2 to 5% overall, and up to 10 to 15% for lip and ear tumors, with 5-year survival of about 35 to 50% once nodes are involved.

Keratoacanthoma is a variant that is treated as a carcinoma. Complications: local destruction, perineural spread with cranial neuropathy, nodal and distant metastasis (lung, liver, brain, bone).

• A firm, scaly, crusted or ulcerated nodule or plaque on sun-exposed skin (the scalp, ears, lips, face and the dorsum of the hands), with a tender or bleeding surface
• A rapidly growing dome-shaped nodule with a keratin core (keratoacanthoma-like)
• Lip lesions: a nonhealing ulcer or crusted area
• Perineural spread: pain, tingling, numbness or facial weakness along a nerve distribution
• Regional lymph node enlargement
• Red flags: a nonhealing ulcer on a scar, deep fixation, new neurological symptoms, nodal swelling and rapid growth in a transplant recipient

1. Biopsy: deep shave, punch or incisional biopsy, reaching the reticular dermis or deeper, with histology giving differentiation, depth in millimetres, perineural and lymphovascular invasion.
2. Ultrasound of the regional nodes for tumors with high-risk features, and fine-needle aspiration of suspicious nodes.
3. CT or MRI for tumors invading bone or nerve, and for tumors with nodal disease. MRI of the skull base with cranial nerve imaging in suspected perineural invasion.
4. CT chest for staging in advanced disease.
5. Sentinel lymph node biopsy is considered only for very high-risk tumors in selected patients.

Differentials: basal cell carcinoma, actinic keratosis, Merkel cell carcinoma, melanoma, amelanotic melanoma, wart, hypertrophic lichen planus, pseudoepitheliomatous hyperplasia.

1. Excision with margins: 4 mm for low-risk tumors under 2 cm, and 6 to 10 mm for high-risk tumors, taken to the fascia. Anesthesia with lidocaine 1% with adrenaline 1:100,000 (maximum 7 mg/kg of lidocaine). Cefazolin 2 g IV before incision for flaps and grafts.
2. Mohs micrographic surgery for the head and neck, hands, genitals, and for recurrent or high-risk tumors.
3. Curettage and electrodesiccation for small, low-risk lesions on the trunk and limbs.
4. Radiotherapy for inoperable tumors, for adjuvant treatment in perineural invasion and positive margins, and in frail patients: 60 to 66 Gy in 30 to 33 fractions, or 50 to 55 Gy in 20 fractions. Nodal basin 50 to 66 Gy after dissection.
5. Nodal disease: therapeutic neck or axillary or groin dissection, followed by adjuvant radiotherapy for extracapsular spread or multiple positive nodes.
6. Advanced, unresectable or metastatic disease: cemiplimab 350 mg IV every 3 weeks for up to 24 months, or pembrolizumab 200 mg IV every 3 weeks. Monitor thyroid function, liver tests, glucose and cortisol every 4 to 6 weeks, and manage immune adverse events with prednisolone 1 mg/kg orally daily, tapered over 4 to 6 weeks. Chemotherapy (carboplatin AUC 5 IV every 21 days, or cisplatin 75 mg/m2) or cetuximab 400 mg/m2 IV load then 250 mg/m2 weekly for patients who cannot receive immunotherapy.
7. Actinic keratosis: fluorouracil 5% cream twice daily for 2 to 4 weeks, cryotherapy with a freeze time of 5 to 10 seconds, and imiquimod 3.75% cream daily for two 2-week cycles.
8. Organ transplant recipients: reduce the immunosuppression where possible, change to sirolimus (trough 5 to 8 ng/mL), and use acitretin 10 to 25 mg orally daily for chemoprevention (teratogenic, so effective contraception is needed during treatment and for 3 years after, with monitoring of lipids and liver tests).
9. Chemoprevention: nicotinamide 500 mg orally twice daily in high-risk patients, and sunscreen SPF 30 or higher.

Follow-up: skin and node examination every 3 to 6 months for 2 years, then every 6 to 12 months for life. Counsel on sun protection, self-examination and early reporting of new lesions.