Cutaneous Squamous Cell Carcinoma

UV-driven keratinocyte malignancy — actinic keratosis precursors, high-risk features, Mohs surgery, and cemiplimab for advanced disease

Key Points

• Cutaneous SCC (cSCC) is the second most common skin cancer (~1 million new cases/year in the US) and accounts for ~15,000 deaths annually.
• Chronic UV exposure, immunosuppression (solid organ transplant recipients have up to 100× increased risk), and actinic keratoses are the primary risk factors.
• High-risk features include tumor diameter ≥2 cm, depth >6 mm, perineural invasion, poor differentiation, and immunosuppressed host.
• Mohs micrographic surgery is the treatment of choice for high-risk or head/neck cSCC.
• Cemiplimab (PD-1 inhibitor) is FDA approved (2018) for locally advanced and metastatic cSCC — ORR ~47%; pembrolizumab is also approved.
• Actinic keratoses (AKs) are the precursor lesion — treatment with topical 5-FU, imiquimod, or PDT reduces future cSCC risk.

Epidemiology & Incidence

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer after basal cell carcinoma, with approximately 700,000 to 1,000,000 new cases per year in the United States. Deaths from cSCC number approximately 15,000 annually — higher than melanoma in some estimates — largely attributable to cSCC arising in immunosuppressed patients, those with perineural invasion, and head/neck primaries. Unlike BCC, cSCC carries a meaningful metastatic potential (~3–5% of cases overall; up to 15–20% for high-risk tumors in immunosuppressed patients). The vast majority of cSCC arises on…

Risk Factors & Pathogenesis

Ultraviolet radiation (primarily UVB at 290–320 nm) is the dominant carcinogen in cSCC: • UVB causes characteristic C→T (and CC→TT) transition mutations at dipyrimidine sites in TP53 and other tumor suppressor genes — the UV "signature" mutation. • TP53 mutations are found in >90% of cSCC, often early in the AK→cSCC progression. • Additional drivers: CDKN2A loss, PIK3CA mutations, NOTCH1/2 mutations (particularly in immunosuppression-associated cSCC), EGFR overexpression (~90% of cSCC). • cSCC does not harbor BRAF, NRAS, or KIT mutations seen in melanoma, limiting targeted therapy options.…

Clinical Presentation & Staging

cSCC presents as a firm, flesh-colored to erythematous papule, plaque, or nodule on sun-damaged skin. Key features: • Ulceration, crusting, or bleeding: Characteristic of more advanced or poorly differentiated lesions. • Indurated base: Unlike BCC, cSCC often has a firm, infiltrated base on palpation. • Rapid growth: More typical of cSCC than BCC. • Actinic keratosis precursor: Often identifiable in the surrounding skin (field cancerization). • Bowen's disease (cSCC in situ): Well-demarcated, erythematous plaque; any thickness; may resemble psoriasis or eczema. • Perineural invasion (PNI):…

Treatment

Local treatment (primary approach): • Mohs Micrographic Surgery (MMS): Gold standard for high-risk cSCC — head/neck location, large tumors, poorly defined margins, perineural invasion, recurrent tumors, or immunosuppressed patients. Provides complete circumferential margin assessment, highest cure rates (~97% for primary, ~92% for recurrent cSCC). • Standard excision: 4 mm margins for low-risk, well-defined cSCC; 6–10 mm margins for high-risk disease. Recommended when Mohs is not available. • Adjuvant radiation: Indicated for pathologic perineural invasion, positive/close margins not…