High-Risk Cutaneous Squamous Cell Carcinomas: The Present and Future

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Cutaneous squamous cell carcinoma is the second most common type of skin cancer, with more than 1 million cases diagnosed in the United States annually.1 Historically, cutaneous squamous cell carcinoma is grouped together with basal cell carcinoma and collectively referred to as nonmelanoma skin cancer. Nonmelanoma skin cancer has become an epidemic in this country, with an annual incidence three to four times higher than all other types of cancer combined. Although these two types of skin cancer share some risk factors for development, they can have very different biologic behavior.

Traditional teaching has been that nonmelanoma skin cancer has a low metastatic potential. Although this is true for most basal cell carcinomas, this teaching fails to address the significant morbidity and mortality that can be seen with cutaneous squamous cell carcinomas. Nodal metastasis with cutaneous squamous cell carcinoma is estimated at between 3.7 and 5.2%.2-5 More than 15,000 people die of cutaneous squamous cell carcinoma each year, a number almost twice that of melanoma.6 Because cutaneous squamous cell carcinomas are not publicly reported cancers, this number could be an underestimate of the true burden of the disease.

Adam Sutton, MD, MBA

Adam Sutton, MD, MBA

Ashley Wysong, MD, MS

Ashley Wysong, MD, MS

Currently, there are several unanswered questions about cutaneous squamous cell carcinoma. Specifically, which patients should undergo nodal staging, who should be surgically treated with comprehensive margin assessment, and which patients would benefit from early adjuvant therapy.

Older and Newer Staging Systems

Staging of cutaneous squamous cell carcinoma is critical, as early identification of regional or distant metastasis leads to better outcomes. Newly developed and updated staging systems over the past decade have significantly improved risk stratification of cutaneous squamous cell carcinomas. Historical staging systems failed to reliably predict poor outcomes, including local recurrence, nodal metastasis, and disease-specific death. With the American Joint Committee on Cancer 7th edition (AJCC 7), the majority of poor outcomes occurred in patients with low tumor stages (T1/T2). The Brigham and Women’s Hospital (BWH) Tumor Staging System for Cutaneous Squamous Cell Carcinoma was introduced in 2014 and was a major step forward for the stratification of cutaneous squamous cell carcinomas.

The BWH staging system stratifies cutaneous squamous cell carcinomas by four risk factors: size > 2 cm; poorly differentiated histology; perineural invasion > 0.1 mm; and tumor invasion beyond subcutaneous fat. With BWH staging, 72% of node metastases and 83% of disease-specific deaths occurred in patients with cutaneous squamous cell carcinomas who had two or more risk factors, despite making up just 5% of cutaneous squamous cell carcinomas.7

In 2019, a study compared cutaneous squamous cell carcinoma staging with the AJCC 8th edition (AJCC 8) and BWH staging systems. The study found that the BWH staging system had a higher specificity and positive predictive value than AJCC 8, identifying the same number of poor outcomes with a subset of 9% of cutaneous squamous cell carcinomas vs 23% with AJCC 8 and minimizing inappropriate upstaging of low-risk disease.8 Despite this improved stratification, there is no standard workup recommended for patients with high-risk cutaneous squamous cell carcinomas.

Although lymph node staging beyond clinical examination is becoming more prevalent, guidance as to which patients will benefit from imaging or sentinel lymph node biopsy is lacking. Studies have shown a greater predictive value for nodal metastasis with sentinel lymph node biopsy than with other modalities such as imaging.9 A quantitative review of the positivity rate of sentinel lymph node biopsy with cutaneous squamous cell carcinoma in the literature was found to be 14.6%.10 The high positivity rate reported in this study suggests possible underutilization of sentinel lymph node biopsy for cutaneous squamous cell carcinomas; however, sentinel lymph node biopsy has not been shown to be cost-effective to date for cutaneous squamous cell carcinomas of the head and neck.11

Risk Factors

“Beyond tumor and patient characteristics, treatment modality has a significant impact on outcomes for patients with cutaneous squamous cell carcinomas.”
— Adam Sutton, MD, MBA, and Ashley Wysong, MD, MS

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Despite improved risk stratification for cutaneous squamous cell carcinoma, there are several well-known risk factors for poor outcomes that are not included in the current staging systems. These risk factors include, but are not limited to, recurrent tumors, immunosuppression, and lymphovascular invasion.7 Although these risk factors may not be included in staging, they should be considered when treating patients.

Beyond clinicopathologic features, a novel 40-gene–expression profile test was recently developed and validated in high-risk cutaneous squamous cell carcinomas for prediction of metastatic risk utilizing tumor biology.12 Results are stratified from a low to a high risk of metastatic potential, with the class 2b signature representing the highest risk. This gene-expression profile test was found to be an independent predictor of metastasis. Early data suggest a positive predictive value of 60% for patients with the class 2b signature gene-expression profile, outperforming AJCC, BWH, and National Comprehensive Cancer Network® (NCCN®) high-risk cohorts. In the validation cohort, those with class 2b signature tumors had a 60% event rate and a 3-year metastasis-free survival rate of 44%.

Impact of Treatment Modality on Outcomes

Beyond tumor and patient characteristics, treatment modality has a significant impact on outcomes for patients with cutaneous squamous cell carcinomas. Surgical management for cutaneous squamous cell carcinoma is typically accomplished with wide local excision or Mohs micrographic surgery. Local recurrence rates with high-risk cutaneous squamous cell carcinomas treated with wide local excision have been shown to be high, with some studies reporting more than 15%.13 Mohs micrographic surgery is a specialized technique for skin cancer surgery whereby the surgeon is also the pathologist and performs real-time comprehensive margin assessment of both peripheral and deep margins. Mohs micrographic surgery has been shown to offer excellent local tumor control and low rates of nodal metastasis and disease-specific death for patients with high-risk cutaneous squamous cell carcinomas.14

The use of adjuvant therapy for high-risk cutaneous squamous cell carcinoma is also advancing. Radiation therapy continues to be utilized locally in tumors excised with positive margins and in tumors with extensive perineural or named nerve involvement or in the case of nodal metastasis. However, there is a need for prospective studies to identify which patients would most benefit from adjuvant radiation therapy.

Historically, systemic therapies for cutaneous squamous cell carcinoma were limited to cytotoxic chemotherapeutics, however, there has been recent success utilizing molecular inhibitors off-label and immunomodulators for locally advanced or metastatic disease. Specifically, retrospective reviews have found that cetuximab improved the overall response rate and median disease-free survival when compared with cisplatin.15 Two new drugs targeting the PD-1 pathway, cemiplimab and pembrolizumab, have received U.S. Food and Drug Administration approval for the treatment of locally advanced or metastatic squamous cell carcinoma, with overall response rates of approximately 40% to 50% and higher rates of response seen in patients with a higher mutational burden.16,17

The morbidity, mortality, and economic burden of cutaneous squamous cell carcinoma are only increasing. As our ability to accurately identify and stratify high-risk tumors and patients continues to improve, we have the opportunity to improve outcomes for patients and to provide standardized and data-driven management and surveillance guidelines. 

Dr. Sutton is Assistant Professor and Director of Mohs and Dermatology Surgery at the University of Nebraska Medical Center and Nebraska Medicine, Omaha. Dr. Wysong is Department of Dermatology Founding Chair and William W. Bruce MD Distinguished Chair of Dermatology at the University of Nebraska Medical Center, Omaha.

DISCLOSURE: Dr. Sutton reported no conflicts of interest. Dr. Wysong  has received institutional research funding from Castle Biosciences.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views
of ASCO or The ASCO Post.


1. Skin Cancer Foundation: Squamous cell carcinoma overview. Available at Accessed December 16, 2020.

2. Mourouzis C, Boynton A, Grant J, et al: Cutaneous head and neck SCCs and risk of nodal metastasis: UK experience. J Craniomaxillofac Surg 37:443-447, 2009.

3. Brantsch KD, Meisner C, Schönfisch B, et al: Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: A prospective study. Lancet Oncol 9:713-720, 2008.

4. Schmults CD, Karia PS, Carter JB, et al: Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: A 10-year, single-institution cohort study. JAMA Dermatol 149:541-547, 2013.

5. Brougham NDLS, Dennett ER, Cameron R, et al: The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors. J Surg Oncol 106:811-815, 2012.

6. Mansouri B, Housewright CD: The treatment of actinic keratoses: The rule rather than the exception. JAMA Dermatol 153:1200, 2017.

7. Karia PS, Jambusaria-Pahlajani A, Harrington DP, et al: Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol 32:327-334, 2014.

8. Ruiz ES, Karia PS, Besaw R, et al: Performance of the American Joint Committee on Cancer Staging Manual, 8th Edition vs the Brigham and Women’s Hospital Tumor Classification System for Cutaneous Squamous Cell Carcinoma. JAMA Dermatol 155:819-825, 2019.

9. Relic A, Aletsee C, Brors D, et al: [Sentinel node mapping in head and neck squamous cell carcinoma]. Laryngorhinootologie 85:897-902, 2006.

10. Ahadiat O, Higgins S, Sutton A, et al: SLNB in cutaneous SCC: A review of the current state of literature and the direction for the future. J Surg Oncol 116:344-350, 2017.

11. Quinn PL, Oliver JB, Mahmoud OM, et al: Cost-effectiveness of sentinel lymph node biopsy for head and neck cutaneous squamous cell carcinoma. J Surg Res 241:15-23, 2019.

12. Wysong A, Newman JG, Covington KR, et al: Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol. April 25, 2020 (early release online).

13. Marrazzo G, Zitelli JA, Brodland D: Clinical outcomes in high-risk squamous cell carcinoma patients treated with Mohs micrographic surgery alone. J Am Acad Dermatol 80:633-638, 2019.

14. Tschetter AJ, Campoli MR, Zitelli JA, et al: Long-term clinical outcomes of patients with invasive cutaneous squamous cell carcinoma treated with Mohs micrographic surgery: A 5-year, multicenter, prospective cohort study. J Am Acad Dermatol 82:139-148, 2020.

15. Trodello C, Pepper JP, Wong M, et al: Cisplatin and cetuximab treatment for metastatic cutaneous squamous cell carcinoma: A systematic review. Dermatol Surg 43:40-49, 2017.

16. In GK, Vaidya P, Filkins A, et al: PD-1 inhibition therapy for advanced cutaneous squamous cell carcinoma: A retrospective analysis from the University of Southern California. J Cancer Res Clin Oncol. November 18, 2020 (early release online).

17. Migden MR, Rischin D, Schmults CD, et al: PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 379:341-351, 2018.