High-Risk Cutaneous Squamous Cell Carcinoma: Staging, Prognostic Factors, and Treatment

Conclusions

• Depth of invasion and perineural invasion are the most consistently important predictors of poor outcomes in cutaneous squamous cell carcinoma.
• The Modified Brigham and Women’s staging system helps identify the intermediate-risk tumors that are most likely to develop nodal metastasis or disease-specific death.
• AJCC staging for cSCC captures some very high-risk disease but still misses several clinically important factors such as immunosuppression, tumor location, recurrence, and prior treatment.
• Mohs surgery is especially valuable in high-risk cSCC because it can better reveal depth and perineural invasion than routine biopsy or standard excision.
• Nerve caliber matters, with perineural invasion involving nerves of 0.1 mm or larger associated with especially poor prognosis and a lower threshold for adjuvant radiation.
• Larger, deeper, poorly differentiated, recurrent, ulcerated, and lip, ear, or scalp tumors have substantially higher risk of metastasis and death.
• Lymphovascular invasion and desmoplastic stroma emerge as major high-risk features that may be as important as traditional staging variables.
• Immunosuppressed patients, especially those with hematologic malignancies such as CLL, have disproportionately poor cSCC outcomes and warrant closer surveillance.
• Patients with cSCC and hematologic malignancy may have worse outcomes than transplant recipients, so immunosuppression should be treated as a major risk modifier.
• High-risk patients should be monitored more closely, often with frequent total-body skin exams and careful lymph node assessment.
• Adjuvant radiation is favored when high-risk features such as substantial perineural invasion, deep invasion, or poor differentiation are present.
• Field-directed therapies can be useful for widespread actinic damage, but they should not be used to intentionally shrink a suspected tumor before definitive staging or surgery.
• Acitretin and other preventive strategies may be considered in heavily sun-damaged or very high-risk patients, but require monitoring and patient counseling.
• Overall, current staging systems are useful but incomplete, and better risk stratification will likely require incorporating tumor biology and host factors into routine practice.