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SECTION III: MALIGNANT NEOPLASMS XXI SINONASAL SQUAMOUS CELL CARCINOMA A De novo sinonasal squamous cell carcinoma 1 Background and epidemiology Malignancies of the nasal cavity and paranasal sinuses are rare, representing only 3%–5% of cancers originating within the head and neck. 1048 In a review of 13,295 patients with SNM from the National Cancer Institute’s SEER database between 1973 and 2011, Dutta et al. report the overall incidence of sinonasal cancer to be 0.83 cases per 100,000 patients. 29 Of all SNM, sinonasal squamous cell carcinoma (SNSCC) is the most common histologic sub type across all subsites of the sinonasal tract, representing an estimated 41.9%–51.6% of all sinonasal cancers. 29,30,1048 This section serves as a standalone assessment of the cur rent evidence for SNSCC and also as an update to the ICSB 2019 section on this topic (Section VIII.B). In a SEER database analysis of 4994 patients with SNSCC between 1973 and 2009, Sanghavi et al. report the overall average incidence of SNSCC to be 0.36 cases per 100,000 patients. 1049 Importantly, however, trend analysis over the last 30 years demonstrates a statistically sig nificant decline in the SNSCC incidence rate over that same time period. In 1973, the overall incidence rate of SNSCC was 0.41 cases per 100,000. While this incidence rate peaked in 1986, with an average incidence of 0.50 cases per 100,000, by 2009 that incidence rate fell to just 0.32 cases per 100,000. This translates to an annual per centage change between 1973 and 2009 of –2.21%, a trend that was reflected in both male and female populations independently (–2.63% and –1.69%, respectively). 1049 The rate and incidence of SNSCC vary greatly by patient demographic factors. This is an important consideration, given oncologic outcome disparities between patients of various socioeconomic backgrounds. In an NCDB review of 6155 patients with SNSCC, Black, Asian, and Pacific Islanders and those with Medicaid or uninsured were found more likely to present with advanced-stage disease. Of these, Black patients had the lowest OS rates (31.9% at 5 years). Additionally, older age was independently asso ciated with worse OS when presenting with an advanced stage. 1050 The average age of diagnosis for SNSCC is estimated to be 62.3 years, with approximately 80% of patients diag nosed over the age of 55 and only 4.3% of patients diagnosed under the age of 40. 29,32,1049 Further 64.44% of SNSCC presents in males. 1049 This translates to an estimated male

incidence of SNSCC of 0.52 cases per 100,000 patients, a female incidence of just 0.23 cases per 100,000 patients, and a male-to-female incidence ratio of 1.82–2.26:1. 1048,1049 These data are corroborated by Ansa et al., who identify 63.6% of patients with SNSCC as male and 75% as White. 32 Lastly, SNSCC presents much more commonly in Cau casians than in other races. An estimated three quarters of SNSCC presents in Caucasian patients, while only 12.9% present in African American patients. 1048 Interestingly, the incidence of SNSCC arising as a sec ond primary in head and neck cancer patients is very low (estimated to be approximately 0.2%). 1051 This is likely attributable to the fact that the common etiologies of SCC arising at other subsites of the head and neck are not strong causative risk factors for SNSCC. a Etiologies and risk factors A number of etiologies have been proposed, including environmental and occupational exposures. While alcohol consumption and smoking are primary etiologies recog nized in the development of SCC at other subsites of the aerodigestive tract, the causal relationship is not as clear for SNSCC. Alcohol consumption has never been impli cated as a risk factor toward the development of SNSCC, and, although many historic case–control studies support smoking (and secondhand smoke exposure) as a risk fac tor for the development of SNSCC based on dose–response relationships and a decrease in risk associated with time since quitting, the evidence is dated and may be con founded by the inclusion of nasal vestibular SCC in those historic studies. 58,92,231,1052–1055 Even by the most liberal estimates, smoking only increases the risk of SNSCC devel opment by two to three times, far less than that at other subsites of the aerodigestive tract. 98 The most oft-cited occupational exposure is softwood dust, which is purported to confer a 20 times increase in risk of developing SNSCC compared with the general population and other sinonasal tumors. Additional occu pational exposures that have been identified as etiologic risk factors in the development of SNSCC include leather dust, glues, formaldehyde, chrome, nickel, arsenic, and welding fumes. 55,101,1056–1059 These chemical substances and industrial compounds are attributed in up to 30% of SNSCC. 88,1049,1058,1059 There are additional reports of SNSCC in hairdressers and rubber workers, although these reports are limited. 1060 Another proposed etiology is viral oncogenesis. While the causative role of HPV on tumorigenesis is well estab lished, its role in the tumorigenesis of SNSCC is not as well defined as at other subsites of the head and neck. Lawson et al. found HPV DNA by polymerase chain reac tion (PCR) in 20% (46/230 cases) of SNSCC. 657 However, this study did not distinguish between transcriptionally