Is it Time for a Molecular-based Classification System for Sinonasal Squamous Cell Carcinoma?

Abstract

T he underlying processes leading to the majority of sinonasal squamous cell carcinomas (SNSCCs) are poorly understood, due in part to the dearth of foundational genomic data on these cancers and also the rarity of SNSCC overall (3% to 5% of all head and neck cancers). 1 As a result, SNSCCs have been clinically approached as one diagnostic entity, which has led to imprecise treatments with poor efficacy and, subsequently, unfavorable outcomes for patients. However, an emerging body of literature identifying and characterizing distinct molecular subtypes of SNSCC is bringing new understanding to the underlying etiologies of SNSCC and how we might leverage this understanding to improve patient outcomes. Here, we will summarize recent data and put forth what we see as an emerging, molecularly-based classification system for SNSCC comprised of 4 discrete subtypes: carcinogen-driven, human papillomavirus (HPV)-associated, epidermal growth factor receptor (EGFR)-altered, and gene fusion. We also suggest a fifth related category: poorly or undifferentiated carcinomas with squamous differentiation and/or squamous immunophenotype (Fig. 1). CARCINOGEN-DRIVEN SNSCCTraditionally, SNSCC has been described as arising from exposure to environmental carcinogens. For example, softwood dust and various industrial chemical compounds are well known to increase the risk of SNSCC; however, such exposures are rare. 2 While tobacco smoke exposure has been found to be associated with an increased risk of SNSCC, the relative risk is significantly less than for other cancers that have strong causal relationships to smoking, such as lung and laryngeal squamous cell carcinoma (SCC). 2 Data on underlying genomic alternations driving carcinogen-induced SNSCC is extremely limited. Similar to other head and neck SCCs, TP53 alterations appear to be common in carcinogen-induced SNSCCs and may portend a worse prognosis. 3,4 Recurrent mutations in genes such as KRAS have also been found in wood dust-induced sinonasal cancers. However, these mutations appear to be much more specific to intestinal-type adenocarcinomas, as opposed to SCCs. 5,6 Overall, the mutational landscape of carcinogen-induced SNSCCs remains poorly characterized. Regardless, in the modern era, with high-risk occupational exposures uncommon and smoking rates decreasing, most SNSCCs cannot be attributed to environmental carcinogen exposure.

Precision Medicine in the Treatment of Malignancies Involving the Ventral Skull Base: Present and Future

“…For instance, HPV-related sinonasal SCC has been associated with favorable prognosis by several groups [52][53][54][55][56][57]. Moreover, EGFR-mutated SCC might be targeted with some tyrosine kinase inhibitors [61]. Interestingly, DEK-AFF2 fusion-related SCC shows a relatively aggressive behavior, with high propensity to metastasize in the nodal basin and at distant site, thus suggesting the need for treatment intensification [63,64].…”

“…EGFR exon 19 or 20 mutation[61] Use of tyrosine kinase inhibitors NUT expression[48][49][50][51] Special escalation of locoregional treatment More stringent threshold to define resectable disease Use of BET inhibitors, histone deacetylase inhibitor or small molecules HPV detection[52-56, 61, 62] More propensity to indicate curative-intended treatment in borderline cases PD-L1 expression[76] …”

Molecular patterns and mechanisms of tumorigenesis in HPV-associated and HPV-independent sinonasal squamous cell carcinoma

“…Approximately 25% of SNSCC are associated with the human papillomavirus (HPV), compared to ~80% of oropharyngeal squamous cell carcinomas (OPSCC) (4,5). While HPV16 underlies ~90% of HPV-associated OPSCC, HPV-associated SNSCC is associated with HPV16 in only ~70% of cases, and other high-risk HPV subtypes are more frequently detected in SNSCC (5)(6)(7)(8)(9). HPV-associated SNSCC appears to behave differently than HPV-associated OPSCC in key aspects.…”

Epidemiologic Trends in Human Papillomavirus–Associated Sinonasal Squamous Cell Carcinoma

“…There are multiple oncogenic drivers for SNSCC, such as high-risk human papillomavirus (HPV), gene fusions including the DEK::AFF2 fusion, epidermal growth factor receptor alterations, or carcinogens . When considering HPV as an etiologic agent, HPV-associated SNSCC has a propensity to arise in the nasal cavity and ethmoid sinus, whereas HPV-independent SNSCC has a propensity for the maxillary sinus and other sinonasal subsites .…”

“…6,7 There are multiple oncogenic drivers for SNSCC, such as high-risk human papillomavirus (HPV), gene fusions including the DEK::AFF2 fusion, epidermal growth factor receptor alterations, or carcinogens. 8 When considering HPV as an etiologic agent, HPV-associated SNSCC has a propensity to arise in the nasal cavity and ethmoid sinus, whereas HPVindependent SNSCC has a propensity for the maxillary sinus and other sinonasal subsites. 9 Patients with HPV-associated SNSCC have an improved overall survival (OS) compared with patients with HPV-independent SNSCC, although to a lesser degree than patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC).…”