Cutaneous squamous cell carcinoma arises from keratinocytes due to cumulative UV damage and other carcinogens. It ranges from low-risk lesions curable with excision to high-risk tumors with metastatic potential, especially in immunosuppressed patients. Variants include in situ SCC (Bowen disease), keratoacanthoma-type, and invasive cSCC with diverse histologies. Accurate risk stratification (tumor size, depth, differentiation, location, perineural invasion, host factors) guides management and surveillance.
Epidemiology and Risk Factors
- Second most common skin cancer; incidence rising.
- Risks: chronic UV, fair skin, older age, actinic keratoses/field damage, immunosuppression (solid organ transplant recipients have 65–250× risk), radiation scars/burns, HPV (periungual/genital), arsenic, chronic wounds.
- In skin of color, cSCC often arises in scars, ulcers, or areas of inflammation; later presentation and worse outcomes.
Clinical Features
- Hyperkeratotic papule/plaque or nodule with scale/crust; can ulcerate or be tender.
- cSCC in situ (Bowen): well-demarcated erythematous scaly patch/plaque.
- Keratoacanthoma-type: rapid-growing crateriform nodule with keratin plug; many behave as low-grade SCC but treat as SCC.
- High-risk sites: ear, lip, central face, hands, genitalia; tumors on scars/chronic ulcers (Marjolin).
Diagnosis and Staging
- Biopsy: shave or punch to confirm SCC and assess differentiation.
- High-risk features: thickness >2 mm or Clark IV/V, poor differentiation, perineural invasion, ear/lip location, size thresholds (e.g., >2 cm trunk/extremities; lower thresholds on face), immunosuppression.
- Staging: AJCC 8th (head/neck) and BWH staging systems incorporate size, depth, and perineural invasion; useful for nodal risk.
- Imaging: ultrasound/CT/MRI for high-risk tumors to assess nodes or perineural spread.
Management
- Surgical
- Standard excision with 4–6 mm margins for low-risk cSCC; wider for high-risk.
- Mohs micrographic surgery for high-risk locations, recurrent tumors, poorly defined borders, perineural involvement.
- Sentinel lymph node biopsy: consider in select very high-risk cases; evidence evolving.
- Destructive/field treatments
- cSCC in situ: C&E, cryosurgery, topical 5-FU or imiquimod, or PDT on non–hair-bearing skin; surgery preferred for hair-bearing or thick lesions.
- Invasive cSCC: destructive methods generally avoided unless low-risk and superficial.
- Radiation therapy
- Primary treatment for nonsurgical candidates; adjuvant for positive margins, extensive perineural invasion, or nodal disease.
- Systemic/advanced disease
- PD-1 inhibitor cemiplimab (first-line) and pembrolizumab for unresectable/metastatic cSCC; high response rates and durability.
- EGFR inhibitors (cetuximab) when immunotherapy unsuitable.
- Multidisciplinary management for nodal or advanced disease (surgery + adjuvant RT ± systemic).
- Special populations
- Solid organ transplant recipients: reduce immunosuppression if feasible (switch to mTOR inhibitors), intensive surveillance, field therapy, and chemoprevention (acitretin).
- Periungual/anogenital SCC: evaluate for HPV; margin-controlled surgery.
- Follow-up and Prevention
- Regular skin and nodal exams (every 3–6 months initially for high-risk).
- Treat field cancerization; sun protection; nicotinamide 500 mg bid may reduce NMSC burden.
- Educate on self-exams and early signs.
References (recent guidelines and key reviews)
- NCCN/AAD guidelines for cSCC, 2022–2024.
- AJCC/BWH risk stratification and outcomes studies, 2021–2024.
- Immunotherapy in advanced cSCC trials and real-world data, 2021–2024.