Current Methods and Caveats to Risk Factor Assessment in Cutaneous Squamous Cell Carcinoma (cSCC): A Narrative Review

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, and the number of deaths due to cSCC is estimated to be greater than the number attributed to melanoma. While the majority of cSCC tumors are resectable with clear margins by standard excision practices, some lesions exhibit high-risk factors for which there is evidence of their association with recurrence, metastasis, and disease-specific death. The most commonly used staging systems and guidelines in the USA for cSCC are based on these clinical and pathologic high-risk factors; however, these are limited in their ability to predict adverse events, thus posing a challenge for implementing risk-directed patient management. Since the development of local recurrence and/or metastasis has a profound impact on the survival of patients with cSCC, accurate identification of patients at high risk for poor outcomes is critical, potentially allowing for early and appropriate adjuvant therapy. This review summarizes the current cSCC literature with a focus on how differing clinical assessments within each of the five selected risk factors (perineural invasion, differentiation, depth of invasion, size, and location) can influence the evaluation of patient outcomes, along with summarizing the utility of staging and guidelines, and highlighting the potential for molecular tools to improve upon cSCC risk assessment.

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“…Indeed, metastatic disease can develop in individuals whose tumors have highrisk factors. Once metastases develop, survival rates drop [82][83][84].…”

“…The clinical risk factor is a tumor diameter of 2 cm or larger; pathologic risk factors include a poorly differentiated histology, perineural invasion, and tumor invasion beyond the subcutaneous fat (however, if there is bone invasion, the tumor is categorized as T3). The NCCN stratification incorporates additional clinical (such as location, poorly defined or well-defined borders, primary or recurrent, presence or absence of immunosuppression, rapid or slow growth rate, and presence or absence of neurologic symptoms) and pathologic (such as histologic subtype, depth, and lymphatic or vascular involvement) tumor parameters to those included by the BWH system [82][83][84].…”

“…For example, some of the cutaneous SCC patients who were initially classified as low risk developed metastatic disease. In addition, other patients with cutaneous SCC who are classified as high-risk do not develop metastases [82][83][84][85][86][87][88][89][90][91][92].…”

“…The test can be used for a cutaneous SCC patient with one or more risk factors (Table 2) [82,[85][86][87][88][89][90][91][92]. Indeed, when it is used in combination with traditional risk factors, the result provides additional risk prediction of metastasis and death for the patient [82][83][84][85][86][87][88][89][90][91][92].…”

“…RNA is extracted after macrodissection of the cutaneous SCC tumor tissue (including tumor stroma) from the formalin-fixed, paraffin-embedded tissue biopsy specimen. Subsequently, qRT-PCR is used to generate complementary DNA so that the expression of the 40 genes can be quantified and the tumor's risk for metastasis can be classified [82][83][84][85][86][87][88][89][90][91][92].…”