Tips for Management of Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies encountered in dermatologic practice. Current treatment guidelines for cSCC provide recommendations based largely on tumor risk classification, while emphasizing the importance of clinical judgment and patient-specific factors when selecting management strategies. Although surgical excision remains the cornerstone of treatment for most eligible tumors, real-world decision-making often requires consideration of factors such as patient age, comorbidities, functional status, and treatment preferences. In this article, we highlight practical strategies to help dermatologists navigate the management of cSCC across a range of clinical scenarios, incorporating recent advances and evolving evidence in the field.

Tip 1: For low-risk elderly patients, consider performing a narrow margin scoop removal at the time of biopsy.

Management of cSCC should be individualized, particularly in older adults. In elderly patients without significant risk factors obtaining a wider and deeper specimen at the time of biopsy can sometimes serve both diagnostic and therapeutic purposes. Significant risk factors would include, but are not limited to, immunosuppression, prior aggressive SCC, or other high-risk clinical features. The goal of performing a scoop removal would be to achieve clear margins at the time of biopsy, thus eliminating the need for additional surgical procedures.

This approach may be particularly useful for patients who are less concerned about cosmetic outcomes and more focused on minimizing the burden of multiple appointments or procedures. When treating older adults, clinicians must take an approach guided by the principle of nonmaleficence, particularly in oncologic care.¹ One retrospective cohort study of frail patients undergoing skin cancer excision reported a 21% mortality rate within 6 months, which was largely attributable to comorbidities and frailty rather than the procedure or malignancy itself.¹ This is mentioned not to argue against treatment but to highlight the importance of tailoring management to the patient’s overall health and goals of care. For carefully selected patients, a therapeutic biopsy with close clinical follow-up may represent a reasonable and pragmatic approach.

Tip 2: For patients with SCC in situ, consider topical therapy as an alternative to surgical management.

Although surgical excision and Mohs micrographic surgery remain highly effective treatments for squamous cell carcinoma in situ (SCCis), topical therapies can be an appropriate alternative in selected patients. With SCCis being confined to the epidermis, the risk of metastasis and poor oncologic outcomes is essentially zero, allowing clinicians greater flexibility in treatment selection. As a result, topical therapy should at least be considered when managing superficial lesions, particularly in patients who are surgery-averse, where there are ill-defined lesions as part of broader field cancerization, or in clinical scenarios where surgery may be less desirable.

Topical 5-fluorouracil (5-FU) is one of the most commonly used nonsurgical treatments for SCCis and has demonstrated variable but meaningful response rates in the literature. Reported complete clinical response rates are up to 85%, reflecting differences in treatment duration, lesion characteristics, and study design.² Shorter treatment duration and larger lesion size have been identified as more likely to be associated with treatment failure, whereas immunosuppression and anatomic location have not consistently predicted poorer outcomes.² These findings support the versatility of topical therapy across a range of clinical scenarios. Emerging evidence suggests that combination therapy with 5-FU and calcipotriene may help address some of these limitations, allowing for shorter treatment durations while maintaining reliable response and clearance.³ Although optimal treatment regimens are still being defined, this approach has the potential to reduce treatment courses from the traditional 4 weeks to as little as 1-2 weeks.³

Topical therapy may be particularly useful for large lesions, areas of field cancerization, or highly mobile anatomic areas in situ (SCCis), topical therapies can be an appropriate alternative in selected patients. With SCCis being confined to the epidermis, the risk of metastasis and poor oncologic outcomes is essentially zero, allowing clinicians greater flexibility in treatment selection. As a result, topical therapy should at least be considered when managing superficial lesions, particularly in patients who are surgery-averse, where there are ill-defined lesions as part of broader field cancerization, or in clinical scenarios where surgery may be less desirable.

Although cSCC often can be successfully treated with surgery alone, some tumors fall into a gray area where resection is technically feasible but may require extensive surgery or complex reconstruction, or carry a higher risk of recurrence. The tumors that often fall into this category are >4 cm, poorly differentiated, in challenging anatomic locations, or have potentially extensive or larger-caliber perineural invasion. For these high-risk, borderline resectable tumors, clinicians should consider neoadjuvant immunotherapy prior to surgery.

Among available options, PD-1 inhibition with cemiplimab has the most robust evidence supporting its use in this setting. In a phase 2 pilot trial evaluating two doses of neoadjuvant cemiplimab for locally advanced cSCC, investigators reported a pathologic complete response (pCR) rate of 55% and a major pathologic response (MPR) rate of 20%, with disease-free survival of 89.5% and overall survival of 95%.⁴ A larger phase 2 study in stage II to IV tumors confirmed similarly strong results, demonstrating 51% pCR and 13% MPR, with a manageable safety profile.⁵ Therapy was well tolerated and did not delay definitive surgery.

Beyond improving surgical outcomes, neoadjuvant immunotherapy may also allow for treatment de-escalation. In clinical studies, nearly half of treated patients were able to avoid adjuvant immunotherapy or radiation, highlighting the potential for reduced treatment burden.⁴ Real-world data have similarly demonstrated high pathologic response rates and 1-year recurrence-free survival approaching 90%, reinforcing the reproducibility of these results outside of clinical trials.

Other immune checkpoint inhibitors such as nivolumab and pembrolizumab, as well as combination regimens, have been explored in the neoadjuvant setting, but cemiplimab currently has the strongest body of evidence and has been increasingly incorporated into treatment pathways for high-risk disease. For patients with tumors that are technically resectable but biologically aggressive, early referral to oncology for consideration of neoadjuvant immunotherapy may improve outcomes while simplifying subsequent surgical management.

Tip 3: For patients with high-risk, borderline resectable tumors, consider neoadjuvant immunotherapy.

Adjuvant radiation therapy (ART) is often recommended for patients with cSCC who have high-risk clinicopathologic features. However, current guidelines encompass a broad spectrum of risk factors, which can make it challenging to determine which patients are most likely to benefit from additional treatment. In these situations, gene expression profiling (GEP) may provide useful prognostic information to help guide treatment decisions.

The 40-gene expression profile (40-GEP) test stratifies tumors into three risk categories based on the likelihood of nodal or distant metastasis: class 1 (low risk), class 2A (higher risk), and class 2B (highest risk).⁵ By more precisely identifying patients at elevated metastatic risk, this test may help clinicians determine which individuals are most likely to benefit from adjuvant radiation therapy as well as who may safely avoid additional treatment. Data suggest that the benefit of ART may be largely confined to patients with class 2B tumors, with ART-treated class 2B patients demonstrating significantly improved disease progression outcomes and delayed time to metastasis compared with untreated cohorts, whereas no significant benefit was observed in class 1 or 2A disease.⁵ These findings suggest that incorporating 40-GEP testing into clinical decision-making may help identify the class 2B patients most likely to benefit from ART, while also supporting the consideration of avoiding radiation in lower-risk groups. In this way, gene expression profiling may provide greater specificity than clinicopathologic features alone and help personalize treatment decisions for patients with high-risk cSCC.

Tip 4: For patients being considered for adjuvant radiation therapy, consider gene expression profiling.

Patients with high-risk cSCC, particularly those with tumors classified as Brigham and Women’s Hospital (BWH)

Tip 5: For patients with T2b or greater tumors, consider preoperative imaging.

Several retrospective studies evaluating computed tomography (CT) imaging in high-risk cSCC have demonstrated that early imaging can lead to changes in therapeutic approach through the identification of previously unrecognized disease. Smith et al.⁶ Early identification of nodal or metastatic disease not apparent on physical examination can greatly influence decisions regarding surgical planning, further lymph node evaluation, radiation therapy, or systemic immunotherapy treatment. These findings highlight the importance of considering imaging in patients with tumors that carry an elevated risk of metastasis.

Emerging evidence suggests that imaging can detect subclinical regional or distant metastatic disease, which may significantly alter treatment planning and ultimately affect patient outcomes. Patients with a history of high-risk locally advanced cSCC remain at substantial risk for recurrence even after definitive surgery and radiation therapy. Recent clinical trial data evaluating immune checkpoint inhibition in the adjuvant setting are beginning to reshape the management of these high-risk cSCC patients.

The phase 3 C-POST trial evaluated adjuvant cemiplimab in patients with resected locally advanced cSCC with specific factors at high risk for recurrence.⁷ In this study, patients who received cemiplimab experienced significantly improved disease-free survival compared with placebo, with a 68% reduction in the risk of recurrence or death.⁷ At 24 months, the estimated disease-free survival was 87.1% in the cemiplimab group compared with 64.1% in the placebo group, with lower rates of both locoregional and distant recurrence observed in the treatment arm.⁶

Based on these findings, the US Food and Drug Administration (FDA) approved adjuvant cemiplimab in October 2025 for patients with cSCC at high risk of recurrence following surgery and radiation. High-risk features were defined by this study as extracapsular nodal extension, involvement of three or more lymph nodes, in-transit metastases, T4 primary tumors with bone invasion, perineural involvement of named nerves, or locally recurrent tumors with additional adverse features.⁸ For dermatologists managing patients with a history of a previously resected high-risk tumor, early collaboration with medical oncology may be appropriate to discuss whether adjuvant immunotherapy could help reduce the risk of recurrence.

Recent guidelines now recommend performing imaging such as ultrasound and/or contrast-enhanced CT for patients with high-risk cSCC, including those with T2b or greater tumors or other significant risk factors, even when clinical examination is negative. Imaging modality should be tailored to the suspected extent of disease. MRI may be particularly useful for evaluating deep invasion, perineural spread, or involvement of the skull, parotid gland, or central nervous system, whereas PET or body CT may be considered when lymph node involvement is present to assess for distant metastasis.

Tip 6: For postoperative high-risk patients, consider adjuvant immunotherapy.

Management of cSCC should be individualized at every stage of care, from the initial biopsy through treatment and post-treatment surveillance. As new diagnostic tools and therapies emerge, dermatologists play a central role in integrating clinical judgment with evolving evidence to determine the best approach for each patient.

1. Thakker S, Minkis K, Lipner SR, Gulati N, Patel VA, Al-Mondhiry J. An ethical framework for managing neglected skin tumors in older patients. J Am Acad Dermatol. 2026;94(1):395-396. doi:10.1016/j.jaad.2025.02.027
2. Lin CP, Kibbi N, Bandali T, Hirotsu K, Aasi SZ. 5-fluorouracil 5% cream for squamous cell carcinoma in situ: factors impacting treatment response. J Am Acad Dermatol. 2025;92(3):473-479. doi:10.1016/j.jaad.2024.10.066
3. Patel RT, Fagan KK, Quan EY, et al. Combination topical 5-fluorouracil 5%/calcipotriene 0.005% cream for the treatment of cutaneous in situ squamous cell carcinoma: a pilot study. J Am Acad Dermatol. 2024;91(6):1277-1278. doi:10.1016/j.jaad.2024.08.039.
4. Sun KH, Thakker S, Greenzaid J, Belzberg M, Miller DM, Patel VA. Perioperative treatment strategies for advanced melanoma and nonmelanoma skin cancers. J Am Acad Dermatol. 2026;94(2):557-566. doi:10.1016/j.jaad.2025.09.098
5. Arron ST, Cañueto J, Siegel J, Fitzgerald A, Prasai A, Koyfman SA, Yom SS. Association of a 40-gene expression profile with risk of metastatic disease progression of cutaneous squamous cell carcinoma and specification of benefit of adjuvant radiation therapy. Int J Radiat Oncol Biol Phys. 2024;120(3):760-771. doi:10.1016/j.ijrobp.2024.05.022
6. Comune R, Ruggiero A, Portarapillo A, et al. Cutaneous squamous cell carcinoma: from diagnosis to follow-up. Cancers (Basel). 2024;16(17):2960. doi:10.3390/cancers16172960
7. Rischin D, Porceddu S, Day F, et al. Adjuvant cemiplimab or placebo in high-risk cutaneous squamous-cell carcinoma. N Engl J Med. 2025;393(8):774-785. doi:10.1056/NEJMoa2502449
8. Lim AM, Porceddu S, Rischin D. Impact of adjuvant cemiplimab in high-risk cutaneous squamous cell carcinoma. Curr Oncol. 2025;32(8):459. doi:10.3390/curroncol32080459.

VISHAL ANIL PATEL, MD

• Director of Cutaneous Oncology, GW Cancer Center
• Director of Dermatologic Surgery, GW Department of Dermatology
• Associate Professor of Dermatology & of Medicine (Oncology)
• George Washington University School of Medicine & Health Sciences

Washington, DC

AMANDA STINES, CCMA

• Medical Assistant
• George Washington Medical Faculty Associates
• Department of Dermatology

Washington, DC