INTRODUCTION
Current Staging Methods and the Need for Gene Expression Profiling
Skin cancer is the most prevalent malignancy in the United States.1 By current estimations, 1 in 5 Americans will develop skin cancer by the age of 70.2 Skin cancers are broadly divided into melanoma and non-melanoma skin cancers (NMSC), with melanoma, considered the deadliest - a predicted 7,180 deaths in the United States in 2021.3
The 5-year survival rate for pathologically staged I-II melanoma is approximately 82% to 99%, and rates plummet with more advanced stages.4 Staging of melanoma using the American Joint Committee on Cancer (AJCC) criteria classifies tumors as stage 0 through IV based on tumor thickness (T in-situ to T4), ulceration status, sentinel lymph node involvement, and distant metastasis.4 However, this widely used staging system still presents limitations. Despite progression to later stages having a worse prognosis for patients, early-stage melanoma still represents the highest mortality burden; and subdividing this category into tumor depth quartiles did not present an expected worsening prognosis with increased depth.5 When using the AJCC guidelines, these conflicting outcomes and the inherent variability between pathologists when analyzing tumor histopathology indicate the need for additional avenues for the diagnosis and prognosis of melanoma and evaluation of tumor biology.6
For non-melanoma skin cancers, there were an estimated 3.3 million patients treated in 2012,1 and about 20% to 50% represent cutaneous squamous cell carcinoma (cSCC).7 The AJCC and the Brigham Women’s Hospital (BWH) are 2 main staging systems that use clinicopathologic criteria and high-risk factors for classifying cSCC (T1 to T4 in the AJCC and T1 to T3 in the BWH), but they too possess limitations.7,8 The AJCC 7 staging criteria was criticized for its high percentage of poor outcomes in earlier stages since its higher stages were too narrow in criteria. While the newer AJCC 8 has shown improvement in identifying higher stage cSCC that was not previously classified, the system still displays the limitation of having equivalent risks of nodal metastasis and disease-specific death in patients with stage T2 and T3, resulting in a heterogeneous T2/T3 group that has proved hard to differentiate by prognosis.8 BWH classifies