statements and recommendations were given a strength of recommendation according to SORT criteria (Table 3).
Statement 1: There is data to support that specific genes influence cSCC clinical behavior. (SORT Level A)
Several studies have demonstrated a correlation between the upregulation or downregulation of certain genes and aggressive clinicopathologic features, poor outcomes, or both.43-52 Campos et al retrospectively evaluated 162 cases of cSCC and found that RAS mutations were more frequently associated with an infiltrative than expansive pattern of invasion and were also associated with features of local aggressiveness.49 Additionally, p53 overexpression was shown to be a predictor of recurrence in the univariate analysis, although not in the multivariate analysis.49 Canueto et al analyzed podoplanin expression in a series of 94 cSCCs and found that moderate-to-intense expression was associated with the presence of desmoplasia, an infiltrative growth pattern, the presence of lymphovascular invasion, and the presence of ulceration.43 These higher levels of expression were also associated with a higher risk of nodal metastasis during follow-up and shorter periods of disease-free relapse.43 Additional studies have shown that overexpression of p300 correlates with decreased recurrence-free survival (RFS) and overall survival (OS),44 and that high CD133 expression is greater in patients with advanced tumor stage and it also correlated with decreased RFS and OS.47
Statement 2: The data supports the 40-GEP test's ability to identify a subset of cSCCs that are at high risk for metastasis. (SORT Level A)
The original validation study for the 40-GEP test consisted of a prospective cohort of 321 primary cSCC cases, all of which had 1 or more clinicopathologic risk factors, of which 52 had documented regional or distant metastasis vs 269 that did not. Regarding metastatic risk, the test designated 203 cases as Class 1 (low risk), 93 as Class 2A (high risk), and 25 as Class 2B (highest risk). Kaplan-Meier survival analysis then demonstrated that the 3-year metastasis-free survival (MFS) rates were 91.6% for Class 1, 80.6% for Class 2A, and 44.0% for Class 2B.28 Furthermore, the hazard ratios for metastasis for the Class 2A and 2B cases were 2.44 and 10.15, respectively.28
Since that original study, several others have demonstrated that the 40-GEP test can accurately identify a subset of cSCCs at high risk for metastasis. Arron et al used the test to assess 278 cases of cSCC of the head and neck and found that 3-year MFS rates were 92.1% for Class 1, 76.1% for Class 2A, and 44.4% for Class 2B.29 Ibrahim et al used the 40-GEP test to analyze a retrospective cohort of 420 cases of cSCC without at least 1 high-risk feature as defined by NCCN guidelines or AJCC or BWH staging systems.11 In this study, 3-year MFS rates for Class 1, Class 2A, and Class 2B were 93.9%, 80.5%, and 47.8%, respectively.11 All 3 studies demonstrated concordant 3-year MFS rates for each 40-GEP class and verified the ability of the test to predict the risk of metastasis.
Statement 3: The 40-GEP test provides clinically useful data for cSCC prognosis independent of the AJCC8 and BWH staging systems. (SORT Level A)
The utility of the 40-GEP test depends on its ability to accurately assess cSCC prognosis independent of established staging systems such as AJCC8 and BWH. Several studies compared the 40-GEP test to these staging systems and found that the test is an independent predictor of risk. In the original validation study, a 40-GEP Class 2B result had a PPV of 60% compared to 32.8%, 35.1%, and 16.7% for the AJCC, BWH, and NCCN high-risk groups, respectively.28 Furthermore, a Class 1 result
