Malignant Transformation of Sinonasal Papilloma: Assessment of Clinicopathologic Features, p16 and p53 Expression, Transcriptionally Active HPV Status and Underlying Molecular Alterations.

PURPOSE: Sinonasal papilloma (SP) has a recognized potential for malignant transformation, most commonly into squamous cell carcinoma (SCC). Well-established criteria for malignancy are lacking in SP and often depends on subjective features, such as stromal invasion without desmoplasia or assessment of dysplastic epithelium-to-stroma ratio, which can lead to under- or over-diagnosis, particularly in small biopsies. Additionally, emerging entities that mimic dysplastic papillomas necessitate re-evaluation of previously diagnosed “atypical/dysplastic SP” cases.

METHODS

We conducted a retrospective study of 270 SP cases (226 patients) from 01/2010 to 06/2024. Three patients initially reported as “atypical and/or dysplastic SP”, “low-grade papillary sinonasal carcinoma”, and “papillary SCC”, were later found to harbor a DEK::AFF2 fusion were excluded from the study.

RESULTS

In all, malignant transformation was identified in 17/226 (7.5%) SP patients (including 14/202 (6.9%) inverted papilloma and 3/12 (25%) oncocytic papilloma), of which nine were synchronous and eight were metachronous transformations. Resultant malignancies comprised of SCC (14/17; 82.3%), sinonasal adenocarcinoma (SNAC) (1/17; 5.9%), dedifferentiated squamous cell carcinoma (1/17; 5.9%), and adenosquamous carcinoma (ASC) (1/17; 5.9%). Molecular profiling identified EGFR and KRAS as primary driver mutations, with additional TP53 and CDKN2A loss-of-function alterations implicated in malignant transformation. Immunohistochemical patterns of p53 (overexpression/null) and loss of p16 expression correlated with underlying genetic alterations (TP53 and/or CDKN2A), suggest these can act as surrogate markers for malignant transformation and may aid in risk stratification. Interestingly in our study, among the three oncocytic papillomas with malignant transformation, one showed ASC with transcriptionally active high-risk HPV and a concurrent KRAS mutation, and another transformed into non-intestinal-type SNAC.

CONCLUSION

Malignant transformation in SP occurs almost exclusively in IP and OP, warranting comprehensive evaluation of dysplastic SPs to exclude unsampled malignancy and newly defined molecular subsets. HPV appears to play role in malignant transformation. p53 and p16 immunostaining may help in dysplastic SP and guide closer clinical surveillance.