Neoplasms originating from skin keratinocytes are increasing in frequency in the United States and include a spectrum of diseases culminating in the development of invasive cutaneous squamous cell carcinoma. Although most cases of cutaneous squamous cell carcinoma can be treated conservatively with excellent outcomes, a significant number of patients present with advanced disease requiring aggressive treatment associated with considerable morbidity. Moreover, cutaneous squamous cell carcinoma can be lethal, leading to over 4,000 deaths annually in the United States.1
The challenge has been to identify at presentation patients with cutaneous squamous cell carcinoma who are at risk for local recurrence, metastasis, and death. This has proved difficult, as the disease is common and often treated without definitive histopathologic diagnosis, and failures can develop long after treatment of the index case.
Accordingly, cancer registries have not captured the outcomes of the disease adequately. Absence of large, high-quality, comprehensive, and prospectively derived data sets has led to development of staging systems based on expert consensus by the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC). However, the validity of the current staging systems has been questioned by clinicians.2
Novel Staging System
Karia and colleagues conducted a detailed analysis of a large cohort of patients to develop a modified staging system that is a better predictor of outcomes than the AJCC system currently in use.1 The investigators assessed associations between patient, clinical, and pathologic variables and clinical outcomes, including local recurrence, regional lymph node metastasis, disease-specific death, and overall death in univariate and multivariate models.
They identified five parameters that significantly predicted worse outcomes on multivariate analysis (poor differentiation, diameter ≥ 2 cm, perineural invasion, depth beyond subcutaneous fat, and immunosuppression). These findings were used to develop a novel staging system for cutaneous squamous cell carcinoma3; the number of poor prognostic factors was used to define the T stage rather than size and/or anatomic disease extent in the AJCC staging system.
The recent publication by this group in the Journal of Clinical Oncology, reviewed in this issue of The ASCO Post, compares AJCC and UICC systems with this system, the Brigham and Women’s Hospital (BWH) tumor staging system. Retrospective analysis of patients with cutaneous squamous cell carcinoma presenting to a single institution between 2000 and 2009 was performed.
In total, 974 patients with 1,818 cutaneous squamous cell carcinomas were analyzed, after excluding 162 cases (8.1%) located in the anogenital region, eyelid, or tumors with insufficient information for analysis. The authors concluded that the BWH staging system was associated with greater distinctiveness (outcomes differ between staging groups), homogeneity (outcomes are similar between staging groups), and monotonicity (outcomes worsen with increasing stage) compared to the AJCC and UICC staging systems.
Strengths and Limitations
The BWH system has several strengths, including inclusion of clinical factors (immunosuppression) and outcomes-based derivation from a well-defined patient population. However, several issues need to be considered when evaluating the generalizability of the BWH system.
Its derivation from a single patient cohort opens the possibility of introducing biases based on referral patterns and therapy selected. It is also unclear how tissue sampling was achieved and whether this influenced results. It is conceivable that some patients underwent a partial superficial biopsy, while others underwent definitive excision with more histopathologic variables for analysis, such as perineural invasion, differentiation, and depth of invasion.
In most contemporary staging systems, there is a clinical staging (based on biopsy) and pathologic staging (based on definitive surgical excision). Moreover, in patients undergoing biopsy alone, the biopsy technique used (shave vs punch) could affect the ability to detect certain pathologic features incorporated into the BWH system.
National guidelines suggest that when biopsying cutaneous squamous cell carcinoma, “inclusion of the deep reticular dermis is preferred” for “more than [a] superficial lesion.”4 Additionally, imaging studies are recommended to complete clinical staging. Among patients studied, it is unclear what imaging studies were performed and when. National guidelines on cutaneous squamous cell carcinoma staging suggest “imaging studies as indicated for suspicion of extensive disease,” including “deep structural involvement such as bone, perineural disease, and deep soft tissue.”4
Design and Statistical Issues
Finally, there are some study design and statistical issues that may influence the findings. In this study, multiple cutaneous squamous cell carcinomas from the same patient were studied. This is problematic if an individual has two tumors with different characteristics resulting in two very different outcomes. Typically in study design, only the first incident case is taken in a given individual. Multiple tumors may also reflect tumor biology or host status that can further confound study results.
Additionally, the authors reported on 10-year outcomes, with a median follow-up that is considerably shorter (50 months [range, 2–142] in the study text, and 44 months [range, 2–130] in Table 2 of the article). This leads to broad confidence intervals in the estimations of the rare events reported by the investigators.
In a prospective analysis of risk factors associated with cutaneous squamous cell carcinoma outcomes, with a median follow-up of a similar duration, local recurrence and metastasis were noted to occur up to 4 and 6 years after diagnosis.5 The patterns and time interval to recurrence after treatment of cutaneous squamous cell carcinoma have not been well-characterized and have significant bearing on the current results, as well as implications for patient follow-up practices.
Staging Systems Compared
Are we ready, then, to abandon the AJCC TNM staging system on the basis of the reported results? The TNM-based AJCC/UICC staging system is uniformly applicable across disease sites. This uniformity makes the AJCC staging system easy to apply in a consistent manner.
The TNM system has also remained a reproducible predictor of cancer behavior across disease sites. The TNM staging system was intended to be used in combination, rather than individually as T, N, or M for staging. The combined approach is what makes the TNM system so reproducible and relatively stable over time. Yet, the significance of individual parameters that contribute to T stage is lost when N and M status are incorporated into the staging.
For example, tumor differentiation has been shown to be a significant predictor of outcomes for many cancer types, but its inclusion does not add to TNM staging, as poorly differentiated tumors more readily metastasize. Available data suggest that approximately 2% of patients with cutaneous squamous cell carcinoma present with regional and/or distant metastasis. It would be informative to learn whether the addition of N and M status to the BWH system would make it perform better. Moreover, the factors included in the BWH system may not be easily defined on biopsy samples.
A basic premise of clinical TNM staging is that it aids in therapeutic decision-making. Clinical staging systems require that information for staging is available before definitive therapy begins. As such, the BWH system may be valuable as a pathologic system, but may have limited value as a clinical staging system.
In summary, cutaneous squamous cell carcinoma is often managed with a simple therapeutic approach, with excellent outcomes. However, there is a pressing need to identify patients at high risk for treatment failure, given the morbidity and mortality associated with the disease. Modifications in the current staging systems may be necessary to allow for better risk stratification. Application of specialized multidisciplinary care, development of novel therapies, and execution of clinical trials using a more accurate staging system will be vital for decreasing morbidity and mortality and improving outcomes in patients with high-risk cutaneous squamous cell carcinoma. ■
Disclosure: Drs. Barker, Singh, and Nehal reported no potential conflicts of interest.
Dr. Barker is Assistant Attending Physician in the Department of Radiation Oncology; Dr. Singh is Director of the Laboratory of Epithelial Cancer Biology and Attending Surgeon in the Head and Neck Service; and Dr. Nehal is Director of Mohs and Dermatologic Surgery and Attending Physician in the Dermatology Service at Memorial Sloan Kettering Cancer Center, New York.
References
1. 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 68:957-966, 2013.
2. Warner CL, Cockerell CJ: The new seventh edition American Joint Committee on Cancer staging of cutaneous non-melanoma skin cancer: a critical review. Am J Clin Dermatol 12:147-154, 2011.
3. 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.
4. NCCN Clinical Practice Guidelines in Oncology. Basal cell and squamous cell skin cancers. Version 1.2014.
5. 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.
