Variations in Anatomic Locations of Squamous Cell Carcinoma Stratified by Histologic Risk: A Single‐Center Retrospective Study

Cutaneous squamous cell carcinoma (SCC) is the second most common cancer worldwide, following basal cell carcinoma [1]. In the United States, the incidence of SCC and SCC in situ (SCC-IS) is calculated to be approximately 200,000 to 400,000 new cases annually [2]. However, the estimate varies widely as SCC is not included in national cancer registries [2]. The main driver of SCC pathogenesis is ultraviolet radiation, but information on how SCC characteristics vary between sun-exposed and sun-protected areas is lacking [1]. This retrospective study compares the anatomic distributions for SCC-IS and invasive SCC, further broken down by histologic tumor aggressiveness. These findings provide valuable insights regarding the epidemiology of SCC, which may aid clinical decision-making. This study was approved by the Minneapolis VA Institutional Review Board (IRB#1594484-6). Data from all invasive SCC and SCC-IS biopsies and patient demographics were compiled from the Minneapolis VA Health Care System from October 1, 1999, to September 1, 2020. Patients were 18 years of age or older with at least one biopsy-proven diagnosis of invasive SCC or SCC-IS. Invasive SCC was subdivided into two categories based on histopathology: well-differentiated, low-risk invasive SCC (LR-SCC), and moderately to poorly differentiated high-risk invasive SCC (HR-SCC). Prevalence and relative tumor densities (RTD) were determined across anatomical locations for SCC-IS, LR-SCC, and HR-SCC. RTD was defined as the ratio of tumors in an anatomical site to the total SCCs of that type, divided by the skin surface area at that location [3]. Ratios were calculated for SCC-IS to LR-SCC and HR-SCC to LR-SCC for each anatomical location standardized by total SCCs of the respective histologic subtype. Bootstrapping (2000 resamples of size 13,887 randomly selected with replacement) was utilized to produce 95% confidence intervals for these ratios. Analysis was conducted using SAS Software Version 9.4 (Cary, North Carolina, US). A total of 13,887 invasive SCCs and SCC-IS were identified in 5843 individuals in a population of majority White (98.7%), non-Hispanic (99.0%) men (98.4%) with a mean age of 74.1 years (Table 1). The most common sites for all SCC types by RTD were the ears, face, and scalp. HR-SCC were more common than LR-SCC on the face and scalp, and less common on the lower legs, arms, hands, and back/buttocks (Table 2). This may be unsurprising given that the head and neck are UV-exposed areas, but the hands, which are also UV-exposed, had a lower proportion of HR-SCC to LR-SCC, even when compared to UV-protected areas like the trunk. This may suggest that characteristics of the anatomic location, rather than UV exposure alone, contribute to the rate of aggressive SCCs on the head and neck. The higher risk of metastasis from SCCs in these sites may be partly related to the higher proportion of moderately to poorly differentiated tumors in these locations [1]. Previous studies have shown that more SCC-IS biopsies on the head/neck are upgraded to invasive SCC following excision or Mohs micrographic surgery (6%–28%) compared to the trunk and extremities (2%) [4, 5]. Surprisingly, the proportion of SCC-IS to LR-SCC was one-to-one on the head and neck. This is the first large-scale, retrospective study evaluating the anatomic location of SCC in relation to histologic risk, but the generalizability may be limited by the study population of predominantly White male Veterans between 42° and 49° North latitude. Additionally, this study is limited by the use of tumor differentiation as a sole measure to stratify LR-SCC versus HR-SCC, while factors such as perineural invasion, tumor diameter, and invasion into subcutaneous fat are also associated with poor SCC outcomes [1]. A study is currently underway to evaluate the contribution of epigenetic mechanisms to the pathogenesis of aggressive SCC across varying anatomic locations. This study was approved by the Minneapolis VA Institutional Review Board (IRB#1594484-6). Waiver of patient consent was obtained from the IRB of record. This manuscript contains no patient photos or other identifiable information. Dr. John Meisenheimer discloses a patent pending application on a medical device for use in Mohs surgery. Dr. Noah Goldfarb has participated in clinical trials with Novartis, Sonoma Biotherapeutics, Incyte, and DeepX Health. He has received grants from the HS foundation as well as VA Merit Award and VA CSP Award. He receives royalties from UpToDate. He receives consulting fees from Sonoma Biotherapeutics. He has also served on advisory boards and consulted for Novartis and UCB. Dr. Julie Lynch reports grants from Alnylam Pharmaceuticals Inc., AstraZeneca Pharmaceuticals LP, Biodesix Inc., Janssen Pharmaceuticals Inc., Novartis International AG, Parexel International Corporation through the University of Utah or Western Institute for Veteran Research outside the submitted work. The other authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.