Occupational exposure and risk clusters in malignant transformation of inverted sinonasal papilloma.

Inverted sinonasal papilloma (ISP) is a benign epithelial neoplasm with potential for malignant transformation into squamous cell carcinoma (ISP-SCC). While high-risk HPV infection has been studied as a possible driver, other factors, including occupational exposures, may play a role. Thirty-two cases (n = 32) of ISP and ISP SCC were retrospectively analysed. These cases had been diagnosed between 2010 and 2022. We assessed their occupational history through the Italian Sino-Nasal Cancer Registry questionnaire and performed p16/p53 immunohistochemistry, HPV DNA and RNA testing. Overall, 41% of ISP and 40% of ISP-SCC cases reported exposure to IARC Group 1–2 A carcinogens, and 69% had a history of smoking. Transcriptionally active HPV was detected in only one case (3.1%). Conventional bivariate analyses did not reveal significant associations between occupational exposure and malignant transformation. However, hierarchical cluster analysis identified three distinct phenotypes. Cluster 1 included predominantly male smokers with high cumulative occupational and non-occupational exposure, with ISP-SCC in 17%. Cluster 2, characterized by the highest occupational exposure and lowest smoking prevalence, consisted exclusively of ISP-SCC cases (100%), suggesting occupational carcinogens as a possible independent driver. Cluster 3 had minimal exposure, inflammatory features, and no malignant transformation. These findings highlight the potential of multidimensional analytical approaches to identify high-risk subgroups and inform targeted preventive and surveillance strategies in exposed populations.