About the Author
Maxwell B. Sauder, MD, FRCPC
Dr. Sauder is currently an assistant professor in the division of dermatology at the University of Toronto. He is an onco-dermatologist at Princess Margaret Cancer Centre as well as the research director at Toronto Research Centre. He earned his Doctor of Medicine degree at McMaster University, completed a residency in dermatology at The University of Ottawa and completed fellowship training in Cutaneous Oncology at Harvard Medical School.
Canadian Dermatology Today, Volume 3, Issue 2, May 2022
Cutaneous Squamous Cell Carcinoma: risk stratification and staging
Non-melanoma skin cancer (NMSC) is one of the most common forms of cancer in Canada with an estimated 76,100 cases in 2014, accounting for approximately 28% of all new cancer cases1. Cutaneous squamous cell carcinoma (cSCC) is the second most common type of NMSC and has a greater risk of metastases and death compared with the more common NMSC, basal cell carcinoma (BCC). The vast majority of cSCC are primary low risk; however, higher risk primary, locally advanced, regional or distant metastatic cases can result in a significant decrease in survival (Figure 1). In 2019, the first systemic therapy for cSCC, cemiplimab, was approved in Canada. The aim of this article is to review the epidemiology, risk stratification and available staging systems for cSCC to help clinicians better identify patients that may benefit from further work-up or treatment.
Statistics regarding incidence, prevalence, morbidity, and mortality of cSCC is limited. Most Canadian cancer registries do not track cSCC. Additionally, BCC and SCC as well as some other NMSC are often coded together making it difficult to separate individual types of cancers2.
In 2014, it was estimated that of all the cases of NMSC diagnosed in Canada, approximately 77% were BCC and 23% were SCC1. Another study from approximately the same period showed that the ratio of patients treated for BCC and SCC in a cohort of United States Medicare beneficiaries was 1:13. Studies consistently demonstrate that the incidence rate of cSCC is rising. A recent population-based study of incidence and mortality rates of keratinocyte carcinoma in Ontario identified that the incidence rate increased by 30% over a 14-year period from 2003 to 2017 to 369 per 100 000 males and 345 per 100 000 females in 2017 (AAPC [average annual percentage change] 1.9%, 95% confidence interval [CI] 1.7 to 2.1 from 2003 to 2017). Concurrently, the mortality rate from NMSC rose 4.8-fold between 1997 and 2017 (AAPC 8.9%, 95% CI 6.4 to 11.4 in males; 8.0%, 95% CI 5.3–10.8 in females) with the majority of deaths likely from cSCC4.
Most cases of NMSC are associated with a complete response to treatment. cSCC may have a 3% risk of local recurrence and a 4% risk of metastases. A prospective study analysing the risk factors determining prognosis of local recurrence or metastasis of cSCC, observed tumours with a depth of 2.0 mm or less did not metastasize whereas 4% of tumours (12 out of 308) 2.1 mm to 6.0 mm and 16% of tumours (14 out of 90) greater than 6.0 mm metastasized5. The mortality risk for metastatic cSCC is high with multiple studies reporting rates greater than 70%6. More specifically, the 5-year survival rate for regional metastatic cSCC was 58.3%7 versus distant metastatic cSCC of 11%8.
Tumour Characteristic Risk Factors
Predictive characteristics of tumours for local recurrence or metastasis may be valuable for management to improve survival. Multiple variables that are associated with ‘higher-risk’ have been identified including: tumour diameter, tumour thickness, perineural invasion, location, invasion beyond subcutaneous fat, histological differentiation, and immunosuppression. The National Cancer Comprehensive Network (NCCN) developed clinical guidelines in 2020 that identified high-risk features9. Similar guidelines with similar criteria were developed by the British Association of Dermatologists (BAD)10 and the European Association of Dermato Oncology (EADO)11 (Table 1). Meta-analyses in 201612 and 202013 identified the relative risk of each of the high-risk factors for local recurrence, metastases, and disease-specific death (Table 2). For the Canadian dermatologist, the presence of one or more of these risk factors should prompt consideration of aggressive treatment, further work-up and/or increased frequency of surveillance.
The two main staging systems for cSCC are: American Joint Committee on Cancer (AJCC) and Brigham and Women’s Hospital (BWH) tumor staging system (Table 3). The AJCC system is used specifically for cSCC of the head and neck and requires information on tumor (T), lymph node involvement (N) and metastasis (M) for full staging. The BWH system only assesses tumor features. A comparison between the two systems demonstrated higher specificity (93%) and positive predictive values (30%) for the BWH staging system in identifying cases at risk for metastasis and death14. The AJCC system has a better negative predictive value (99.2%)15. The BWH system may provide better prognostication for patients with localized cSCC whereas the AJCC 8th edition may be superior at addressing nodal and metastatic classifications16.
It has been estimated that cSCC mortality rates are equal to those of renal and oropharyngeal carcinomas and melanomas17. The difference between cSCC and these other malignancies is that other malignancies have consistent staging systems and care pathways already established and identified. Unfortunately, there is no universally accepted or consistently applied system for cSCC. The 2018 American Academy of Dermatology cSCC guidelines recommended the BWH system for prognostication and the NCCN stratification for practical clinical guidance16. In Canada, there are now immunotherapies such as cemiplimab and pembrolizumab that have been approved for locally advanced or metastatic cSCC. Further work is required to develop a Canadian approach to cSCC. In the interim, using any of the risk factors or staging systems for cSCC discussed in this article will assist in the identification of tumours that are at risk for deleterious outcomes and patients that may benefit from further lymph node evaluation or therapies14.
- Public Health Agency of Canada (phac). Non melanoma skin cancer [Web page]. Ottawa, ON: phac; 2014. [Available at https://www.canada.ca/en/public-health/services/chronic-diseases/cancer/non-melanoma-skin-cancer.html; cited 06 Mar 2022]
- Dessinioti C, Pitoulias M, Stratigos AJ. Epidemiology of advanced cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol. 2022 Jan;36(1):39-50. doi: 10.1111/jdv.17709. Epub 2021 Oct 11. PMID: 34592000.
- Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatol. 2015 Oct;151(10):1081-6. doi: 10.1001/jamadermatol.2015.1187. PMID: 25928283.
- Tang E, Fung K, Chan AW. Incidence and mortality rates of keratinocyte carcinoma from 1998-2017: a population-based study of sex differences in Ontario, Canada. CMAJ. 2021 Oct 4;193(39):E1516-E1524. doi: 10.1503/cmaj.210595. PMID: 34607845; PMCID: PMC8568084.
- Brantsch KD, Meisner C, Schönfisch B, Trilling B, Wehner-Caroli J, Röcken M, Breuninger H. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008 Aug;9(8):713-20. doi: 10.1016/S1470-2045(08)70178-5. Epub 2008 Jul 9. PMID: 18617440.
- Burton KA, Ashack KA, Khachemoune A. Cutaneous Squamous Cell Carcinoma: A Review of High-Risk and Metastatic Disease. Am J Clin Dermatol. 2016 Oct;17(5):491-508. doi: 10.1007/s40257-016-0207-3. PMID: 27358187.
- Eisemann N, Jansen L, Castro FA, Chen T, Eberle A, Nennecke A, Zeissig SR, Brenner H, Katalinic A; GEKID Cancer Survival Working Group. Survival with nonmelanoma skin cancer in Germany. Br J Dermatol. 2016 Apr;174(4):778-85. doi: 10.1111/bjd.14352. Epub 2016 Mar 22. PMID: 26676514.
- Brunner M, Veness MJ, Ch’ng S, Elliott M, Clark JR. Distant metastases from cutaneous squamous cell carcinoma–analysis of AJCC stage IV. Head Neck. 2013 Jan;35(1):72-5. doi: 10.1002/hed.22913. Epub 2012 Jan 20. PMID: 22266877.
- SchmultsCB,R. AasiSZ, AlamM, AndersenJS, BordeauxJ, BowenGM, Carson W, et al. Squamous cell skin cancer. Version 2.2020- July 14, 2020. NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines). Accessed 06 Mar 2022. 2020; https://www.nccn.org/professionals/ physician_gls/pdf/squamous.pdf.
- Keohane SG, Botting J, Budny PG, Dolan OM, Fife K, Harwood CA, Mallipeddi R, Marsden JR, Motley RJ, Newlands C, Proby C, Rembielak A, Slater DN, Smithson JA, Buckley P, Fairbrother P, Hashme M, Mohd Mustapa MF, Exton LS; British Association of Dermatologists’ Clinical Standards Unit. British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020. Br J Dermatol. 2021 Mar;184(3):401-414. doi: 10.1111/bjd.19621. Epub 2021 Jan 18. Erratum in: Br J Dermatol. 2021 Sep;185(3):686. PMID: 33150585.
- Stratigos AJ, Garbe C, Dessinioti C, Lebbe C, Bataille V, Bastholt L, Dreno B, Fargnoli MC, Forsea AM, Frenard C, Harwood CΑ, Hauschild A, Hoeller C, Kandolf-Sekulovic L, Kaufmann R, Kelleners-Smeets NW, Malvehy J, Del Marmol V, Middleton MR, Moreno-Ramirez D, Pellecani G, Peris K, Saiag P, van den Beuken-van Everdingen MHJ, Vieira R, Zalaudek I, Eggermont AMM, Grob JJ; European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC). European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 1. epidemiology, diagnostics and prevention. Eur J Cancer. 2020 Mar;128:60-82. doi: 10.1016/j.ejca.2020.01.007. Epub 2020 Feb 26. PMID: 32113941.
- Thompson AK, Kelley BF, Prokop LJ, Murad MH, Baum CL. Risk Factors for Cutaneous Squamous Cell Carcinoma Recurrence, Metastasis, and Disease-Specific Death: A Systematic Review and Meta-analysis. JAMA Dermatol. 2016 Apr;152(4):419-28. doi: 10.1001/jamadermatol.2015.4994. PMID: 26762219; PMCID: PMC4833641.
- Zeng S, Fu L, Zhou P, Ling H. Identifying risk factors for the prognosis of head and neck cutaneous squamous cell carcinoma: A systematic review and meta-analysis. PLoS One. 2020 Sep 29;15(9):e0239586. doi: 10.1371/journal.pone.0239586. PMID: 32991600; PMCID: PMC7523977.
- Ruiz ES, Karia PS, Besaw R, Schmults CD. 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. 2019 Jul 1;155(7):819-825. doi: 10.1001/jamadermatol.2019.0032. PMID: 30969315; PMCID: PMC6583833.
- Venables ZC, Tokez S, Hollestein LM, Mooyaart AL, van den Bos RR, Rous B, Leigh IM, Nijsten T, Wakkee M. Validation of Four Cutaneous Squamous Cell Carcinoma Staging Systems Using Nationwide Data. Br J Dermatol. 2021 Dec 3. doi: 10.1111/bjd.20909. Epub ahead of print. PMID: 34862598.
- Work Group; Invited Reviewers, Kim JYS, Kozlow JH, Mittal B, Moyer J, Olenecki T, Rodgers P. Guidelines of care for the management of cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2018 Mar;78(3):560-578. doi: 10.1016/j.jaad.2017.10.007. Epub 2018 Jan 10. PMID: 29331386; PMCID: PMC6652228.
- Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013 Jun;68(6):957-66. doi: 10.1016/j.jaad.2012.11.037. Epub 2013 Feb 1. PMID: 23375456