Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a new type of sinonasal tumour that frequently drops out of accurate diagnosis. Human papillomavirus related multiphenotypic sinonasal carcinoma was previously known as HPV-related sinonasal carcinoma with adenoid cystic characteristics, and it is connected to high-risk HPV (HR-HPV) strains whose prognosis is unknown. We aim to evaluate PI3K/Akt, pRb, and h telomerase reverse transcriptase (TERT) signalling pathway activation through the expression of proteins cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), ProEx-C, and TERT and their prognostic and clinicopathological value in HMSC patients. Sections of the 40 paraffin blocks of HMSC were recovered, and all samples were evaluated for the presence of a cocktail of HR-HPV, and the absence of MYB, NFIB, and MYBL1 fusions using fluorescence in situ hybridization; the presence of myoepithelial markers; S100, actin; the presence of squamous differentiation markers; calponin, p40, and p63 using PCR-based assays; and COX-2,VEGF, ProEx-C, and TERT using immunohistochemical staining. All patients were monitored for around 54 months, until death, or the last known surviving data (range 20–60 months). A statistically significant relationship exists between COX-2 expression was significantly related to the old age group, tumour extent, relapse, mortality, and poor DFS; (p = 0.001), (p = 0.01), (p = 0.002), and (p = 0.035), respectively. While VEGF, ProEx-C, and TERT expression with the old age group, tumour extent, lymph node metastasis, advancedstaging, relapse, mortality, poor disease free survival (DFS), and overall survival (p = 0.001).