Co-authored by Akshay V. Patel, DO MA & Roshansa Singh, MD
We have seen the rise of cutaneous squamous cell carcinoma (cSCC) and it is now situated as the second most common skin cancer world-wide1. In conjunction with basal cell carcinoma (BCC), these cancers are classified as keratinocyte carcinoma, or colloquially as nonmelanoma skin cancer. While previously seen at a lower frequency as compared to BCC, the aging population and increased cumulative ultraviolet radiation exposure has led to a rise in numbers of patients diagnosed with cSCC2. A majority of patients with cSCC have favorable outcomes, with low local recurrence (3-5.2%), nodal metastasis (1.5-4%), and disease specific death (1.5-2.8%) rates2,3,4. Surgical excision of these lesions with negative margins portends a favorable prognosis. Patients with locally advanced or recurrent disease are high risk and in the setting of metastasis, prognosis is poor4,5,6. The ability to prognosticate outcomes and thereby model treatments in these patients is an invaluable tool in our armamentarium. Having the capability to provide early estimates of prognosis affords physicians the opportunity to describe varied treatment options with expected outcomes and can alter the approach to treatment.
The key features of an ideal staging system incorporate distinctiveness, homogeneity, and monotonicity2. Distinctiveness refers to the difference in disease-related outcomes based on stage. Homogeneity, on the other hand, implies that patients within the same stage have similar outcomes. Monotonicity represents worsening outcomes with increasing stage. The increasing incidence of cSCC has fostered interest in the development of an applicable, accurate staging system that can be implemented in these patients with reproducible outcomes. The systems reviewed include the American Joint Committee on Cancer (AJCC) seventh edition, AJCC eight edition, and the Brigham and Woman’s Hospital (BWH) system.
Developments in our understanding of the mechanisms at play with cSCC has allowed for steady appreciation of risk factors that contribute to the progression of this disease. This has stimulated an ever-evolving slew of staging systems, with each iteration undertaking the goal to address and incorporate the key points lacking from the previous proposal. Immunosuppression surfaced early as a significant risk factor for the development of cSCC, with patients who underwent solid organ transplantation experiencing 65-250 times the risk of developing carcinoma as compared to the general population and a higher risk for metastasis4,7.
The 7th edition of the AJCC staging system was published in 2010, taking into account tumor diameter and high-risk factors shown to predict adverse outcomes (tumor thickness, Clark level, differentiation, perineural invasion, location) to establish a T grade8. Critics of this staging system cite low specificity and variable complexity as reasons for inapplicability in a clinical setting2,6. Next on the stage was the Brigham and Women’s Hospital system, which assigned T grade based on the number of high-risk factors (tumor diameter, invasion beyond subcutaneous fat, differentiation, quantified perineural invasion). The relative ease of applicability of this staging system has often rendered it the frontrunner in the field. Studies that compared AJCC 7th edition to BWH attribute improved distinctiveness, homogeneity, and monotonicity in the latter3,9. BWH includes invasion beyond subcutaneous fat and perineural invasion of large-caliber nerves (>0.1 mm) as two of its risk factors, both of which have been thought to be too exhaustive for the general clinic setting6. The AJCC published the eighth edition in 2016, which went into effect on 2018. With regards to cSCC, a head and neck subset was designed and high-risk factors now included deep invasion, bony erosion, and perineural invasion. This system proved to have better homogeneity and monotonicity as compared to AJCC 7, however, distinctiveness continued to lag behind, proving to be a minor setback to this system2,3,10.
A desired goal of these staging systems is the ability to predict patients at risk for nodal metastasis and provide a stratified paradigm in which to guide treatment. The overall risk of metastasis in this disease cohort is quoted at 4%4,10,11. There is a significantly increased rate of mortality in those with nodal metastasis, with 5-year survival rates reported at 27% as compared to 98% in those without nodal metastasis2,9. Initial studies of cSCC staging systems and their relation to nodal disease demonstrated high risks of nodal metastasis with increasing T stage, primarily with the BWH system11. Most recently, Upton et al. reviewed patients with cSCC at their institution from 2006-2017 and evaluated the ability of the AJCC 7, AJCC 8, and BWH systems to predict nodal spread12. Keeping their limited sample size in mind, BWH was demonstrably most reliable with increasing T stage corresponding to higher risk of nodal disease.
Their results were compared to the current literature in a letter to the editor by Barriera‐Silvestrini and Knackstedt, who quoted significantly lower rates of nodal spread in each T stage when incorporating studies with larger sample sizes13. Upton et al. depicted that many of the T2 staged tumors in AJCC 7 were upstaged to T3 when utilizing AJCC 8, with a corresponding increase in rate of nodal disease. Similarly, a change was seen between BWH stages T2a and T2b, with T2b tumors representing higher risk of nodal metastases. Their team suggests use of these thresholds to drive discussion regarding nodal management, i.e. those with AJCC 8 T3 or BWH T2b disease to consider concurrent elective neck dissection. Interestingly, Barriera‐Silvestrini and Knackstedt offer a decision point as opposed to the proposition of neck dissection in these patients. They present 3 options: further radiological evaluation, sentinel lymph node biopsy, and primary tumor risk assessment.
These studies reiterate that staging systems should not be utilized in isolation. In its entirety, evaluation of cSCC presents a challenge due to its rarity, further exacerbated by the primarily favorable outcomes in this disease process. With increasing sample sizes from a multitude of studies, the ability to test the robustness of these staging systems continues to steadily improve. Discussions with patients presenting with higher stages, regardless of system, may include consideration of management of neck disease. In addition, given patient risk factors and subsequent to histological analysis, further evaluation with radiological evaluation and genetic classification remains a viable next step. CT continues to be the most commonly used modality for detecting nodal disease, especially in the face of high costs associated with PET/CT2, 14.
The inherent pathogenesis of cSCC development involves a high burden of mutations secondary to ultraviolet radiation, driven primarily by inactivation of tumor suppressor genes, and at higher rates than other tumors7,15. Critically, the role of programmed cell death ligand (PD-L1) expression was evaluated, prompting the approval of cemiplimab in 2018, currently awaiting phase II trial results2,16. The availability of immunotherapy and preference over chemoradiation therapy, especially with regards to treatment sequelae, posits that genetic contribution should be deliberated in the treatment planning.
A desire for a reliable, predictive staging system for cutaneous squamous cell carcinoma has garnered much research over the past decade. Successive recapitulations of the staging systems, with both patient and pathological factors coming to the foreground seem to place the BWH and AJCC 8th edition as the preferred paradigms. The sensitivity and specificity of these staging systems, related not only to survival but also propensity for nodal disease, continues to evolve and may ultimately improve prognostication abilities. The importance of incorporating genetic factors in the setting of a tumor that is highly susceptible to mutation secondary to its etiology should not be undervalued. At the current point, these systems can prove to be effective with regards to patient discussions of management and promote discourse between physician and patient with regards to available options.
At our institution, we prefer to use the BWH staging system, using it as a guide during our tumor board discussions and patient care. Given the relative abundance of Mohs surgeons in our area, we commonly meet patients with large tumors favoring elective nodal dissection to facilitate complex reconstruction or patients with delayed metastatic disease to the parotid gland and neck. In patients who present with delayed metastatic disease, we review the initial pathology from prior resections and apply the BWH staging system, commonly finding that many of these patients had advanced local disease and high risk factors at their initial presentation, predictive of their risks for nodal disease.
Which staging system do you prefer and why?
- Rogers HW, Weinstock MA, Feldman SR, et al. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol 2015;151(10):1081–6.
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- Haisma MS, Plaat BE, Bijl HP, Roodenburg JL, Diercks GF, Romeijn TR, Terra JB. Multivariate analysis of potential risk factors for lymph node metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. Journal of the American Academy of Dermatology. 2016 Oct 1;75(4):722-30.
- Alam M, Armstrong A, Baum C, Bordeaux JS, Brown M, Busam KJ, Eisen DB, Iyengar V, Lober C, Margolis DJ, Messina J. Guidelines of care for the management of cutaneous squamous cell carcinoma. Journal of the American Academy of Dermatology. 2018 Mar 1;78(3):560-78.
- Fox M, Brown M, Golda N, Goldberg D, Miller C, Pugliano-Mauro M, Schmults C, Shin T, Stasko T, Xu YG, Nehal K. Nodal staging of high-risk cutaneous squamous cell carcinoma. Journal of the American Academy of Dermatology. 2019 Aug 1;81(2):548-57.
- Upton M, Kita A, Scapa J, St. John M. Prognostic Value of Tumor Staging: Predicting Nodal Metastases in Cutaneous Squamous Cell Carcinoma. The Laryngoscope. 2021 Jan;131(1):E170-5.
- Barriera‐Silvestrini P, Knackstedt T. In Reference to Prognostic Value of Tumor Staging: Predicting Nodal Metastases in Cutaneous Squamous Cell Carcinoma. The Laryngoscope. 2021 Feb;131(2):E443-.
- Liao LJ, Lo WC, Hsu WL, Wang CT, Lai MS. Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck—a meta-analysis comparing different imaging modalities. BMC cancer. 2012 Dec;12(1):1-7.
- Abraham I, Curiel-Lewandrowski C. Staging systems to predict metastatic cutaneous squamous cell carcinoma: unsatisfactory for clinical use, but some less so?. JAMA dermatology. 2018 Dec 1;154(12):1391-2.
- Migden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, Chung CH, Hernandez-Aya L, Lim AM, Chang AL, Rabinowits G. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. New England Journal of Medicine. 2018 Jul 26;379(4):341-51.
Roshansa Singh, MD obtained her Bachelor of Arts from Cornell University and pursued medicine at Rutgers New Jersey Medical School. She is currently in her Otolaryngology – Head and Neck Surgery residency at the University of Connecticut.