these numbers are primarily estimated by retrospective cohort studies, which cite a rate between 2% to 6%.7-10 Furthermore, disease-specific mortality is typically estimated to be 1.5% to 3%.4,9,11,12 Despite this relatively low mortality rate, the absolute number of deaths attributable to cSCC in the US was estimated to be between 3932 and 8971 in 2012 and may already exceed deaths from cutaneous melanoma.3,12-14 The vast majority of these deaths arise in patients with metastasis, at which point the 5-year survival rate can drop to 50% to 83% for regional metastasis and even below 40% for distant metastasis.8,9,11
There are several staging systems for cSCC designed to stratify patients based on the risk of recurrence and metastasis. The most commonly used systems include the individual risk factor-based National Comprehensive Cancer Network (NCCN) system, American Joint Committee on Cancer Eighth Addition (AJCC8) staging system, and the Brigham and Women's Hospital (BWH) classification.15-17 These systems are based on clinical and/or pathological features, such as tumor size and thickness, perineural invasion, cell differentiation, and tumor location. However, these factors may be limited in their utility, as biopsy specimens are often transected, precluding accurate measurement of tumor depth.9,12 Additionally, interobserver variability in dermatopathology has been reported throughout the literature,18-20 with one study identifying discrepancies in 22% of the 405 cases reviewed, 40% of which related to nonmelanocytic neoplasms.18 The combination of these limitations have resulted in a low sensitivity (23-46%) and positive predictive value (PPV) (12-13%) for these staging systems.16,17,21,22
Given these relatively low sensitivity and PPV values, more precise methods of predicting the risk of recurrence, metastasis, and mortality are needed for skin cancer. Precision medicine has already become commonplace throughout many specialties, including dermatology. Genomic testing with the use of gene expression profile (GEP) assays is a validated and commonly used tool to aid in diagnosis and prognostic assessment for cutaneous malignancies.23-27 For cSCC, there is one commercially available GEP test, the 40-gene expression profile test (40-GEP), that uses formalin-fixed paraffin-embedded (FFPE), primary cSCC tissue to stratify tumors into low (Class 1), high (Class 2A), and highest (Class 2B) risk for regional or distant metastasis at 3 years after diagnosis.14 The test was initially validated by Wysong et al in 2020,28 but several other studies since then have demonstrated the test's analytical validity, clinical validity, accuracy, and clinical utility.11,14,28-36 Despite the abundant data, limited guidelines exist on how to incorporate this test into clinical practice. The purpose of this study was for a panel of experts in cSCC diagnosis and management to review the available literature and produce appropriate use recommendations for dermatology practitioners for GEP testing for this cancer.
MATERIALS AND METHODS
Literature Search and Study Selection
A comprehensive literature search of PubMed, EMBASE, and Scopus was completed on December 2, 2022, using the keywords cutaneous squamous cell carcinoma, prognosis, and gene expression along with the Boolean term AND for English-language original research articles, systematic reviews, and meta-analyses without date restrictions. Articles were screened for relevance to the topic of measuring gene expression to assess prognosis in cSCC. The studies that met the inclusion criteria were then distributed to the panelists. Each member of the panel reviewed the selected articles and assigned them a level of evidence based on Strength of Recommendation Taxonomy (SORT) criteria.37 These levels include level 1 (good-quality patient-oriented evidence, such as systematic reviews or meta-analyses of good-quality cohort studies or a prospective cohort study with good follow-up), level 2 (limited-quality patient-oriented evidence, such as retrospective cohort studies or prospective cohort studies with poor follow-up), or level 3 (other evidence, such as consensus guidelines, usual practice, opinion, or disease-oriented evidence).37 Of note, a level 2 or 3 designation does not necessarily indicate a deficient study, but is requisite for retrospective studies or basic science articles that focus on disease states, respectively.
Development of Consensus Statements
The panel consisted of 8 dermatologists with expertise in diagnosing and managing cSCC. They convened on January 13, 2023, to review and discuss the studies and create consensus statements to guide clinicians on the use of GEP testing to assess prognosis for cSCC. A modified Delphi process was used to reach a consensus for each statement.38 This process requires supermajority approval to adopt a recommendation through multiple rounds of real-time voting and has been utilized frequently to create expert recommendations in dermatology.39-42
RESULTS
Literature Search and Study Selection
The initial literature search produced 157 articles that met the search criteria. A thorough screening of the studies for relevance to the research question resulted in 21 articles that were distributed to the panelists for review prior to the roundtable discussion.
Levels of Evidence Designation
Of the 21 articles that were reviewed, the panel assigned level 1 evidence to 2 articles,28,35 level 2 evidence to 8 articles,11,14,29,43-47 and level 3 evidence to 11 articles30-34,36,48-52 (Tables 1 and 2).
Consensus Statements
The panel created seven consensus statements related to cSCC and the use of GEP testing to assess prognosis. All 7 statements received a unanimous (8/8) vote for adoption. Each of the
