40-Gene expression profile test predicting metastatic risk in localized,high-risk cutaneous squamous cell carcinoma for peer review

Introduction

The annual incidence of cutaneous squamous cell carcinoma (cSCC) in the United States is estimated to be 1.8 million cases. ¹ Moreover, deaths from cSCC are believed to surpass those from melanoma. ¹ The potential for invasion makes early detection crucial to better enhance patient outcomes in patients with high-risk cSCC. Given the unpredictable nature of cSCC when diagnosed at later stages, early detection is critical. Detecting metastasis early enables the timely start of suitable treatments and screening protocols, thereby enhancing patient survival. ² Currently, several types of staging and categorization are utilized to guide the management of treatment options for cutaneous cancers. Treatment decisions for patients with cSCC are primarily guided by assessing the patient’s risk of adverse outcomes. Clinicopathologic factor-based risk assessment approaches include the appropriate use criteria for Mohs surgery, the American Joint Committee on Cancer’s eighth edition (AJCC8) staging manual, and the Brigham and Women’s Hospital (BWH) staging for cSCC. ² Recent studies have indicated that these approaches often incorrectly label patients who will eventually experience disease progression as low risk while categorizing patients as high risk who do not go on to experience relapse. ³ The 40-gene expression profile (40-GEP) test effectively determines the metastatic risk in patients with cSCC who have one or more risk factors. ³ It provides prognostic information that is independent of known high-risk factors and traditional staging systems. ³ In addition, this test offers a more accurate evaluation of metastatic risk in patients with high-risk cSCC. ² Our case report demonstrates the effective use of the 40-GEP test as an independent predictor of metastatic risk.

Case Report

A 75-year-old man with a history of non-melanoma skin cancer and chronic lymphocytic leukemia visited the clinic for a Mohs surgery to treat a cSCC on his left cheek (Figure 1). His medical history included cSCC, hyperlipidemia, hypertension, and Benign Prostatic Hyperplasia (BPH). The patient had no prior history of melanoma or non-melanoma skin cancer. Initially, the lesion presented with a large hyperkeratotic tumor on the left central malar cheek for 2 months. The pathology results of the biopsy showed well-differentiated squamous cell carcinoma. He was referred for Mohs surgery, which met the appropriate use criteria for the M-zone, moderate risk zone. The pathology results on frozen sections showed stage III deeply infiltrative, moderate to poorly differentiated SCC with a preoperative tumor size of approximately 2.8 × 2.0 cm. There was a perineural invasion of a large caliber nerve, measuring 0.11 mm in diameter. This finding classified the tumor as T3 according to the AJCC8 staging system, while the BWH staging identified it as T2b. However, his 40-GEP staging fell into Class 1 (low risk), indicating a low probability of metastasis within 3 years. ⁴ The patient underwent Mohs surgery (Figure 2); however, due to poor differentiation and perineural invasion exceeding 0.1 mm, the patient is classified as having high-risk SCC. The patient received thorough counseling on the National Comprehensive Cancer Network (NCCN) guidelines and the potential benefits of adjuvant radiation therapy. Ultimately, the patient chose not to proceed with radiation therapy. He was advised to undergo a PET-CT scan for complete staging to check for any suspicious regional nodal involvement. Nine months following the Mohs procedure, the PET-CT scan showed no evidence of nodal involvement or distant metastatic disease. Although he was classified as high risk by standard staging systems, gene expression profile testing indicated a low risk of metastasis.

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Figure 1.

Cutaneous squamous cell carcinoma circled on the left central malar cheek.

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Figure 2.

Mohs surgical defect after successful removal of cutaneous squamous cell carcinoma on the left central malar cheek.

Discussion

Our case reveals a discrepancy between current staging techniques and the results of 40-GEP testing. The 40-GEP test categorizes primary cSCC patients with one or more clinicopathologic risk factors into three biological risk groups, according to their likelihood of regional, nodal, or distant metastasis: low risk as Class 1, higher risk as Class 2A, and highest risk as Class 2B. ² While the AJCC8 and BWH staging systems categorized the patient’s tumor as T3 and T2b, respectively, suggesting higher risks, the 40-GEP staging placed our patient in Class 1, which indicates low risk. His 40-GEP staging being Class 1, demonstrates a <7% risk of metastasis within 3 years. ² The AJCC8 staging system estimates the nodal metastatic risk at approximately 13% for the T2 and T3 groups, compared to a higher 24% for BWH T2b. ²

While the NCCN guidelines for cSCC offer a framework for patient stratification, the diverse characteristics of cSCC make it difficult to accurately assess risk using only clinicopathologic factors, resulting in an incomplete picture. ³ In addition, the subjective evaluation of clinicopathologic factors such as “degree of differentiation” and “rapidly growing tumor,” along with the use of multiple measurements for depth of invasion (such as Breslow depth or Clark level), and the broad range of patients considered immunosuppressed have introduced further uncertainty into the field. ³ Previous research has indicated that using 40-GEP results to direct adjunctive radiation therapy can significantly reduce Medicare healthcare costs, with savings estimated between $140 million and $970 million. ⁵ This reduction in expenses primarily comes from preventing the unnecessary use of adjunctive radiation therapy in patients who have low-risk 40-GEP profiles and from the careful selection of treatments for patients based on molecular risk assessments. ⁵

Genetic expression profile testing in oncology is an evolving field that holds promise for improving outcome predictions. We aim for this case to contribute to the ongoing dialogue and expand research on using gene expression profiling to assess patient metastatic risk more accurately. In our case, the independent predictive capability of the 40-GEP test differed from the risks identified by traditional staging methods.