Risk Factors for Squamous Cell Carcinoma
The most significant risk factors for squamous cell carcinoma include chronic ultraviolet light exposure, immunosuppression, prior radiation therapy, chronic inflammatory processes, and specific histologic features that predict aggressive behavior. 1, 2
Primary Risk Factors
Environmental and Exposure Factors
- Ultraviolet radiation exposure: The most common cause of cutaneous SCC 1
- Cumulative sun exposure over lifetime
- History of sunburns, especially severe ones
- Use of tanning beds
- Tobacco use: Particularly important for head and neck SCC (accounts for 75-85% of these cases) 1
- Alcohol consumption: Works synergistically with tobacco for head and neck SCC 1
- Prior radiation therapy: Tumors developing in sites of previous radiation treatment for benign conditions 2
- Chemical carcinogens: Including arsenic exposure 1
Host Factors
- Age: Higher incidence in people over 75 years 1, 3
- Gender: More common in men 1, 3
- Skin type: Fair skin, light-colored eyes and hair, poor tanning ability 4
- Geographic location: Higher rates in southern and mid-western USA 1, 3
- Immunosuppression: Solid organ transplant recipients, chronic lymphocytic leukemia, HIV infection 2
Pre-existing Conditions
- Chronic inflammatory processes: Including:
- Previous skin cancer: History of basal cell or squamous cell carcinoma significantly increases risk of subsequent SCC 5
- Precancerous lesions: Actinic keratoses, Bowen's disease (intraepidermal SCC) 1
- Human papillomavirus (HPV) infection: Particularly important in oropharyngeal and cervical SCC 1
High-Risk Features for Aggressive Behavior
Tumor Characteristics
- Location: High-risk areas include 2, 3:
- Face (especially central face, "mask areas")
- Ears and periauricular region
- Genitalia
- Hands and feet
- Lips and mucosal surfaces
- Size: Larger tumors have higher risk 2
- ≥6 mm in high-risk locations
- ≥10 mm in medium-risk locations
- ≥20 mm in low-risk locations
- Depth of invasion: 2, 3
2 mm depth
- Invasion into deep reticular dermis or subcutaneous fat (Clark level IV or V)
- Rapid growth: Tumors that grow quickly have higher metastatic potential 2
Histologic Features
- Poor differentiation: Moderately or poorly differentiated tumors have higher risk 2
- Specific histologic subtypes: 2
- Adenoid (acantholytic)
- Adenosquamous (mucin-producing)
- Desmoplastic
- Basosquamous carcinoma
- Perineural involvement: Significantly increases risk of recurrence and metastasis 2
- May present with neurologic symptoms (pain, burning, stinging, anesthesia, paresthesia)
- Recurrent disease: Previously treated tumors that have recurred 2
Clinical Pitfalls and Caveats
Young age is not an independent risk factor: Despite common belief, the evidence does not support young age alone as a high-risk factor for aggressive SCC behavior 2
Multiple risk factors compound risk: Patients with multiple risk factors have substantially higher risk of recurrence and metastasis 2, 3
Immunosuppressed patients require heightened vigilance: These patients often develop more aggressive tumors and may present with atypical features 2
Neurologic symptoms near SCC sites: Any neurologic symptoms in the region of an SCC should raise immediate concern for perineural invasion and place the tumor in a high-risk category 2
Basosquamous carcinomas: Should be conceptualized and managed as squamous cell carcinomas rather than basal cell carcinomas due to their metastatic potential 2
Understanding these risk factors is essential for appropriate risk stratification, treatment planning, and follow-up to minimize morbidity and mortality from squamous cell carcinoma.