What are the risk factors for squamous cell carcinoma?

Risk Factors for Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) development is primarily driven by ultraviolet radiation exposure, with additional critical risk factors including immunosuppression, chronic inflammation, specific anatomic locations, and certain genetic syndromes. 1, 2

Primary Environmental and Host Risk Factors

Ultraviolet Radiation Exposure

• Solar UV exposure is the principal external cause of cutaneous SCC, with the disease occurring predominantly on sun-exposed sites 1, 2
• Occupational sunlight exposure independently increases risk even after adjusting for non-occupational sun exposure 3
• Sunbed use is associated with increased SCC risk 1
• Fair-skinned individuals with light eye color, light hair color, and fair complexion face elevated risk 3

Immunosuppression

• Organ transplant recipients demonstrate dramatically elevated SCC rates, making immunosuppression one of the two established major risk factors alongside UV radiation 4, 1
• Immunosuppressive states predispose individuals to NMSC formation 4

Genetic and Hereditary Factors

• Certain genetic syndromes greatly predispose to SCC development, including:
  • Albinism (absent skin pigment) 4
  • Xeroderma pigmentosum (defective UV-induced DNA repair) 4
  • Nevoid basal cell carcinoma syndrome 4
• Burdened family history of first-degree relatives with skin cancer increases risk 5
• Mutations in tumor suppressor gene p53 appear to be an early common event in cutaneous SCC development 4

Chemical and Environmental Exposures

• Exposure to arsenic, insecticides, and pesticides increases malignant transformation risk 6
• Tobacco smoking is associated with increased SCC risk 3
• Prior radiation therapy to a site predisposes to subsequent SCC development 4

Clinical Risk Factors for Aggressive Behavior

Anatomic Location

High-risk locations include:

• The "mask area" of the face (central face, periorbital, nose, lips, chin, mandible, preauricular and postauricular areas, temple, ear) 4
• Genitalia 4
• Mucosal surfaces 4
• Ear 4
• Head and neck region generally carries higher recurrence risk than trunk and extremities 4

Tumor Size

• Tumors ≥6 mm in high-risk facial locations indicate increased recurrence risk 4
• Tumors ≥10 mm in middle-risk locations indicate increased recurrence risk 4
• Tumors ≥20 mm on trunk and extremities indicate high-risk behavior 4

Tumor Characteristics

• Poorly defined or ill-defined tumor borders indicate high-risk behavior 4
• Recurrent tumors carry significantly higher risk than primary tumors 4
• Rapidly growing tumors indicate high-risk behavior with increased metastasis and mortality risk 4

Site of Chronic Inflammation

• SCC arising in chronic scarring or chronic inflammatory processes demonstrates substantially increased metastasis rates 4

Neurologic Symptoms

• Any neurologic symptoms (pain, burning, stinging, anesthesia, paresthesia, facial paralysis, diplopia, blurred vision) in the region of an SCC places it in the high-risk category, as these may indicate perineural involvement occurring in up to 40% of cases 4

Histologic Risk Factors

Degree of Differentiation

• Poor differentiation is associated with worse outcomes and increased risk 7, 2

Perineural Involvement

• Perineural involvement significantly increases risk of recurrence and metastasis 7

Aggressive Histologic Subtypes

• Adenoid (acantholytic) squamous cell carcinoma indicates increased recurrence/metastasis risk 4
• Adenosquamous (mucin-producing) squamous cell carcinoma indicates increased risk 4
• Desmoplastic squamous cell carcinoma poses greatly increased risk of both recurrence and metastasis 4, 7

Depth of Invasion

• Invasion into deep reticular dermis or subcutaneous fat (Clark level IV or V) is associated with aggressive behavior 4, 7
• Tumor depth measured in millimeters (similar to Breslow depth in melanoma) has prognostic value 4

Precursor Lesions

Actinic Keratoses

• The presence of actinic keratoses on sun-damaged skin is one of the strongest predictors of SCC in unaffected individuals 1
• A very small proportion of AKs are SCC precursors, though the true malignant transformation rate remains unknown 1

Important Clinical Pitfalls

• Not using sun-protection preparations significantly increases risk 5
• Patients who develop one SCC often develop multiple primaries over time, substantially increasing disease burden 1
• Associations with human papillomavirus infection and high body weight are not established 1
• Basosquamous carcinomas should be conceptualized as squamous cell cancers rather than basal cell cancers, as their metastatic capacity resembles SCC 4