Cutaneous Squamous Cell Carcinoma: risk stratification and staging

Introduction 

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.

Figure 1: Classification of cSCC – adapted from Dessinioti C, et al.

Epidemiology

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.

Area L: trunk and extremities (excluding hands, nail units, pretibial, ankles, and feet).
Area M: cheeks, forehead, scalp, neck and pretibial.
Area H: ‘mask areas’ of face (central face, eyelids, eyebrows, periorbital, nose, lips [cutaneous and vermillion], chin, mandible, preauricular and postauricular skin/sulci, temple and ear), genitalia, hands, and feet.
CLL, chronic lymphocytic leukaemia.
Table 1: High-risk factors for recurrence and metastasis in the UK BAD, European EADO and US NCCN guidelines; adapted from Dessinioti C et al.

From the meta-analyses of Thompson et al. 2016 including 36 studies, and Zeng et al. 2020 including 43 studies (the multivariate estimate for each factor was not consistently available in included studies).
NR, not reported.
DSD, disease-specific death; LR, local recurrence; NM, nodal metastasis; ns, not statistically significant; RR, risk ratio.
*Statistically significant (P < 0.05).
**Only one included study on immunosuppression and DSD.
Table 2: Quantification of the risk conferred by the presence of high-risk factors for recurrence, metastasis and disease-specific death; adapted from Dessinioti, C et al.

Staging systems

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 8^th edition may be superior at addressing nodal and metastatic classifications¹⁶.

N, number; NCRAS, National Cancer Registration and Analysis Service
Table 3: Studies reporting the population-based incidence and mortality of advanced cSCC; adapted from Dessinioti, C et al.

Conclusion

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.