Understanding Cutaneous Squamous Cell Carcinoma: A Comprehensive Patient Guide

Table of Contents

• Introduction: The Prevalence of Skin Cancer
• Epidemiology and Clinical Presentation
• Environmental, Clinical, and Genetic Risk Factors
• Staging, Workup, and Prognosis
• Treatment Approaches
• Prevention and Sun Protection
• Clinical Implications for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Introduction: The Prevalence of Skin Cancer

Skin cancer represents the most frequently diagnosed cancer in the United States and worldwide, affecting approximately one in five Americans during their lifetime. Among skin cancers, nonmelanoma skin cancers (also called keratinocyte carcinomas) are the most common type treated in the United States, with more than 5 million new cases occurring each year.

Cutaneous squamous cell carcinoma (cSCC) specifically ranks as the second most common type of skin cancer, with over 1 million new cases annually. This number actually exceeds the combined total of all top five reportable cancers treated in the United States. The condition is not routinely tracked in national cancer registries, which makes precise incidence estimates challenging.

Most patients with cSCC have excellent outcomes, but certain high-risk groups face significant challenges. The cancer spreads to lymph nodes in 1.9% to 5.2% of cases, with overall mortality rates ranging from 1.5% to 3.4%. However, patients who develop metastases tend to have much poorer outcomes.

Immunosuppressed patients face particularly elevated risks, with their chance of developing cSCC increased by a factor of 65 to 250 compared to the general population. Among these patients, 6% to 15% experience local recurrence and metastasis. Notably, cSCC accounts for an increasing number of skin cancer deaths in the United States, with absolute numbers of patients with nodal metastasis and deaths now equaling or exceeding those for melanoma or leukemia.

Epidemiology and Clinical Presentation

Cutaneous squamous cell carcinoma accounts for approximately 20% of all skin cancers. The incidence has been increasing worldwide over recent decades among White populations, which researchers attribute to multiple factors including an aging population, increased sun exposure, tanning bed use, and better skin cancer detection practices.

The disease shows distinct demographic patterns, affecting men three times more frequently than women. Risk increases dramatically with age, with incidence rates among people over 75 years old being 5 to 10 times higher than those under 55. Patients typically present with scaly, red, or bleeding lesions, most often appearing on sun-exposed areas.

The distribution of cSCC varies significantly by race and ethnicity:

• Most common skin cancer in Black persons
• Second most common in White, Asian, and Hispanic persons
• Overall incidence among Black persons: approximately 3 cases per 100,000 people
• Incidence among non-Hispanic White persons: 150 to 360 cases per 100,000 people

In non-White populations, cSCC more frequently appears on areas not exposed to the sun, including the palms, soles, nails, anogenital regions, and areas of chronic inflammation or scarring. Most cases remain localized to the skin without spreading to other areas.

Environmental, Clinical, and Genetic Risk Factors

Multiple factors increase patient risk for developing cutaneous squamous cell carcinoma. The most significant risk factors include cumulative ultraviolet (UV) radiation exposure, age, and systemic immunosuppression.

UV radiation represents the most important environmental risk factor. Specific patterns of total and cumulative UV exposure lead to the highest rates of cSCC development. Ultraviolet B (UVB) causes direct DNA damage through the formation of dipyrimidine dimers that lead to malignant transformation. Ultraviolet A (UVA) also contributes through indirect DNA damage and free radical formation.

Notable environmental risk factors include:

• Indoor tanning: People who have undergone indoor tanning of any duration have a 1.67 times higher risk compared to those who never tanned indoors
• Psoralen plus UVA treatments
• Tanning beds (primary emitters of UVA)
• Exposure to ionizing radiation
• Exposure to arsenic or radon

Genetic factors also play significant roles in cSCC development. Inherited characteristics such as light skin, red or blonde hair, and light-colored eyes increase risk. A family history of cSCC associates with a two to four times higher risk. Specific genetic disorders including xeroderma pigmentosum, epidermolysis bullosa, albinism, and other rare syndromes dramatically increase risk, often with earlier age of onset.

Genomewide association studies have identified germline mutations (single-nucleotide polymorphisms) that may increase risk. cSCC typically shows a high tumor mutational burden, with common mutations in TP53, NOTCH1 or NOTCH2, CDKN2A, PI3K, and cell-cycle pathways.

Immunosuppression significantly elevates risk, whether innate, acquired, or medication-induced. Acquired immunosuppression, most commonly from organ transplantation, HIV infection, chronic lymphocytic leukemia, lymphoma, or long-term immunosuppressive therapy, substantially increases risk. Organ transplant recipients show 5 to 113 times higher incidence compared to immunocompetent individuals.

Additional risk factors include:

• Chronic inflammation (from burn scars, chronic ulcers, sinus tracts, or inflammatory skin conditions)
• Smoking
• Hypothyroidism
• Certain medications (voriconazole, hydrochlorothiazide, BRAF inhibitors, tumor necrosis factor inhibitors)
• Human papillomavirus (HPV), particularly for periungual and anogenital squamous cell carcinoma

Staging, Workup, and Prognosis

Staging of cutaneous squamous cell carcinoma has evolved significantly over the past decade, with several refinements that integrate clinical and pathological risk factors for local recurrence and metastasis. This improved risk stratification helps identify patients who might benefit from enhanced workup, management, and surveillance strategies.

Four tumor staging systems use clinical and pathological features to predict outcomes including local recurrence and metastasis development. The National Comprehensive Cancer Network (NCCN) also stratifies cSCC into risk categories to guide management and surveillance, though it doesn't provide prognostic information.

The American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition, represents the most widely used staging system for solid-organ tumors. However, the Brigham and Women's Hospital (BWH) and Salamanca refinements of the AJCC definition of T3 tumors have demonstrated improved risk stratification in both single-center and population-based studies.

The BWH refinement shows the highest specificity, positive predictive value, and concordance index among staging systems. BWH stage T2a, T2b, and T3 tumors associate with increased risk of nodal metastasis, showing 10-year cumulative incidence rates of 5%, 24%, and 60% respectively. In one validation study, BWH stage T2b tumors accounted for only 5% of cases but represented 72% of nodal metastases and 83% of cSCC-related deaths.

Immunosuppressed patients face increased metastasis risk, with a systematic review showing pooled risk estimates for metastasis among organ transplant recipients of 7.3% (95% CI: 6.2 to 8.4) on the body and 11.0% (95% CI: 7.7 to 14.8) in head and neck areas. A population study of over 11,000 patients showed that immunosuppression in organ transplant recipients and patients with hematologic cancer associated with multivariable hazard ratios of 5.0 and 2.7 respectively for metastasis.

Additional risk factors not included in current staging systems but relevant for predicting poor outcomes include recurrence, lymphovascular invasion, and in-transit metastasis. Current staging systems based solely on clinical and pathological features may have limitations in accurately stratifying all patients.

Gene expression profiling has emerged as an independent predictor of metastatic risk, showing significantly improved positive predictive value compared to traditional staging while maintaining similar negative predictive value, sensitivity, and specificity. A 40-gene expression profile test has been developed and validated to stratify primary cSCC into three classes with 3-year metastasis rates of 8.9%, 20.4%, and 60.0% respectively.

No evidence-based or consensus guidelines currently exist for imaging in cSCC. Clinical indications for radiologic imaging at baseline include assessment of primary tumor extent (bony invasion, orbital invasion, or involvement of muscle, fascia, or other critical structures) and evaluation for potential perineural spread or metastatic disease.

All patients with cSCC, particularly those with high-risk features, should undergo clinical nodal staging. Retrospective studies suggest that patients with BWH stage T2b or higher tumors may benefit from baseline imaging of draining nodal basins, as 59% to 65% show abnormal results, with management altered in 24% to 33% of cases.

Nodal staging follows AJCC classification based on size, number of nodes involved, and presence or absence of extranodal extension. Pathological nodal staging is likely underutilized in high-risk cSCC, with systematic reviews showing sentinel lymph node biopsy positivity rates of 13% to 21%, and rates of subclinical lymph node metastasis as high as 30% in BWH T2b tumors.

Treatment Approaches

Treatment approaches for cutaneous squamous cell carcinoma vary based on tumor characteristics and patient factors. The National Comprehensive Cancer Network provides guidelines outlining general management approaches.

For the primary tumor, most localized, low-risk cases can be managed with destructive or surgical techniques performed under local anesthesia in outpatient settings. Curettage and electrodessication represents a destructive technique used for small, low-risk lesions (excluding terminal hair-bearing areas), achieving cure rates as high as 95% for appropriately selected lesions.

Standard wide local excision can be performed with surgical margins of 4 to 6 mm, yielding cure rates of 90% to 98%. Surgery remains the mainstay for localized, high-risk cSCC, though wider surgical margins (6 to 10 mm) and more exhaustive histologic assessment are recommended.

Specifically, Mohs micrographic surgery or resection with peripheral and deep exhaustive margin assessment is recommended to achieve local control for high-risk and very-high-risk cSCC. Mohs surgery demonstrates high effectiveness for primary cSCC control, with very low local recurrence rates (1.2% to 4.1%), nodal metastasis, and disease-specific death.

High-risk features such as positive margins, extensive perineural involvement, or involvement of large or named nerves warrant multidisciplinary consultation and consideration of adjuvant therapy.

Radiation therapy may be considered for patients who are not surgical candidates. The use of adjuvant radiation therapy in patients with cSCC, particularly with clear histologic margins, remains debated due to limited consensus guidelines and lack of long-term prospective data.

The NCCN and American College of Radiology recommend considering adjuvant radiation therapy to the tumor basin after multidisciplinary consultation for patients with positive margins after Mohs surgery with exhaustive margin assessment and for patients with extensive peripheral-nerve involvement, involvement of large nerves (≥0.1 mm diameter) or named nerves, or other high-risk features.

Data on adjuvant radiation therapy benefits remain limited. A retrospective study of head and neck cSCC showed adjuvant radiation therapy associated with improved overall survival (hazard ratio: 0.59; 95% CI: 0.38 to 0.90) and improved disease-free survival in tumors with peripheral-nerve involvement (hazard ratio: 0.47; 95% CI: 0.23 to 0.93).

Another retrospective study of 508 patients with high-T-stage cSCC showed adjuvant radiation therapy after surgery with clear margins resulted in lower 5-year cumulative incidence of both local recurrence (3.6% vs. 8.7%) and locoregional recurrence (7.5% vs. 15.3%) compared to clear-margin surgery alone. However, other studies showed no benefit of adjuvant radiation therapy over surgical monotherapy in cohorts with clear histologic margins.

For nodal metastasis limited to a solitary, small lymph node (≤3 cm diameter) without extranodal extension, surgery alone may be sufficient. Radiation therapy represents the standard of care for nodal disease that is inoperable, not fully resected, or involves multiple nodes or nodes larger than 3 cm with extracapsular extension. Adjuvant radiation therapy for nodal disease has demonstrated improved both disease-free and overall survival.

Systemic therapy (conventional chemotherapy, immunotherapy, and targeted therapies) is not recommended for most primary tumors unless neither curative surgery nor radiation therapy is feasible. However, immunotherapy has dramatically changed the systemic treatment landscape for cSCC in recent years with FDA approval of cemiplimab (2018) and pembrolizumab for advanced disease.

Prevention and Sun Protection

Prevention represents a crucial component in managing cutaneous squamous cell carcinoma risk. Given that ultraviolet radiation serves as the most important environmental risk factor, comprehensive sun protection strategies are essential for all patients, particularly those with additional risk factors.

Effective sun protection includes:

1. Regular use of broad-spectrum sunscreen with SPF 30 or higher
2. Protective clothing including wide-brimmed hats and long sleeves
3. Seeking shade during peak sun hours (10 AM to 4 PM)
4. Avoiding tanning beds and artificial UV exposure
5. Regular skin self-examinations
6. Professional skin examinations based on individual risk factors

For high-risk patients, including those with previous skin cancers, immunosuppression, or genetic susceptibility, more frequent monitoring and enhanced protective measures are recommended. Patient education about recognizing early signs of cSCC, such as new, changing, or non-healing lesions, facilitates earlier detection and treatment.

Clinical Implications for Patients

This comprehensive review has several important implications for patients with or at risk for cutaneous squamous cell carcinoma. Understanding your personal risk profile helps guide appropriate prevention, screening, and treatment decisions.

Key takeaways for patients include:

• Most cSCC cases have excellent outcomes with proper treatment
• Early detection significantly improves treatment success and reduces complications
• Patients with immunosuppression require more vigilant monitoring and protection
• Multiple treatment options exist, ranging from office-based procedures to advanced surgical techniques
• New immunotherapies offer hope for patients with advanced disease
• Regular follow-up care is essential, particularly for high-risk patients

Patients should discuss their individual risk factors with their dermatologist to develop personalized surveillance and protection plans. Those with high-risk features may benefit from referral to specialized centers with experience managing complex cSCC cases.

Study Limitations

While this review article synthesizes current evidence about cutaneous squamous cell carcinoma, several limitations should be acknowledged. The article primarily relies on retrospective studies and systematic reviews rather than prospective randomized controlled trials, which represent the gold standard in medical evidence.

Specific limitations include:

• Incomplete cancer registry data since cSCC is not routinely reported to national registries
• Limited prospective data on optimal treatment approaches, particularly for adjuvant therapies
• Evolving staging systems that require further validation in diverse patient populations
• Gene expression profiling based on retrospective cohorts needing prospective validation
• Limited long-term data on newer immunotherapies
• Potential publication bias in the available literature

These limitations highlight areas where additional research is needed to optimize care for patients with cSCC, particularly those with high-risk disease features.

Patient Recommendations

Based on the current evidence, patients should consider the following recommendations:

1. Sun Protection: Implement comprehensive sun protection strategies regardless of skin type or previous sun exposure history
2. Skin Self-Exams: Perform regular self-examinations to identify new or changing lesions early
3. Professional Evaluation: Seek prompt evaluation for any concerning skin changes, particularly non-healing sores or growing bumps
4. Risk Assessment: Discuss personal risk factors with a dermatologist to determine appropriate screening frequency
5. Treatment Compliance: Complete recommended treatments and follow-up care, especially for high-risk lesions
6. Multidisciplinary Care: For complex cases, seek care at centers offering multidisciplinary management
7. Education: Learn to recognize the signs of cSCC and understand your individual risk profile

Patients with immunosuppression, previous skin cancers, or genetic risk factors should establish regular care with a dermatologist and may require more frequent monitoring.

Source Information

Original Article Title: Squamous-Cell Carcinoma of the Skin
Authors: Ashley Wysong, M.D.
Publication: The New England Journal of Medicine, June 15, 2023
DOI: 10.1056/NEJMra2206348

This patient-friendly article is based on peer-reviewed research published in The New England Journal of Medicine. It maintains the full content and data from the original scientific review while making the information accessible to patients and caregivers.