Background The role of HPV in sinonasal inverted papillomas (IP) is controversial. Determining the prevalence of HPV infection and its impact on the molecular biology of these tumors is critical to characterizing its role in the pathogenesis of inverting papillomas. Methods A total of 112 paraffin embedded IPs from 90 patients were studied. A tissue microarray was constructed and stained for p16, p53, EGFR and cyclin D1. HPV presence and type were determined using PGMY 09/11 primers and integration using HPV 11 DIPS-PCR. Results HPV was detected in 11/90(12%) of patients. HPV 11 was found in 9 samples. HPV 6 and HPV 27 were found in one sample each. EGFR staining proportion was higher in HPV positive IPs vs. HPV negative specimens (56.2 vs. 23.6%; p=0.009). Differences in p16, p53 and cyclin D1 staining were not significant. HPV positive lesions tend to progress to malignancy (p=0.064). Three samples were analyzed for integration. Viral integration was found in both malignant tumors but not in the precursor IP. Conclusions Degradation of p53 and p16/cyclin D1disregulation are not important mechanisms in low risk HPV related IP. The low prevalence of HPV in this series indicates it is not a main etiological factor for IPs, however, when present, low risk HPV may contribute to the biology of IPs through an increase of EGFR expression and a predisposition for malignant progression by integration into the cellular genome.

Introduction We aim to better characterize the staining patterns of inverted papilloma (IP) with and without carcinoma by performing immunohistochemistry for p16, EGFR (Epidermal Growth Factor Receptor), p53, and Cyclin D1 antibodies on a large patient cohort. Methods One hundred and sixty-two IP specimens from 122 patients treated at the University of Michigan between 1996 and 2011. Twenty-two specimens contained carcinoma. Tumor was extracted for construction of two tissue microarrays and stained for p16, EGFR, p53, and Cyclin D1. Tumor staining intensity and percentage staining were scored. Results Mean percentage staining for IP and IP with carcinoma was 12% versus 7% for p16 (no statistical significance, NS), 20% versus 34% for EGFR (NS), 4% versus 24% for p53 (p<0.001), and 17% versus 21% for Cyclin D1 (NS). Benign disease was positive for p16 in 64%, EGFR in 50%, p53 in 30%, and Cyclin D1 in 76%. Inverted papilloma with carcinomatous degeneration was positive for p16 in 14%, EGFR in 71%, p53 in 62%, and Cyclin D1 in 76%. This is statistically significant for differences between IP and IP carcinoma for p16 and p53 staining only. Conclusion Important characteristic staining pattern for inverted papilloma with and without carcinoma are highlighted in this study. Unlike recent trends in HPV-related head and neck malignancies, low expression of p16 is a marker for malignancy in this series. Positive staining for p53 correlates with the development of carcinoma in inverted papilloma.

OBJECTIVE Assess TP53 functional mutations in the context of other biomarkers in advanced larynx cancer. STUDY DESIGN Prospective analysis of pretreatment tumor TP53, HPV, Bcl-xL and cyclin D1 status in stage III and IV larynx cancer patients in a clinical trial. METHODS TP53 exons 4-9 from 58 tumors were sequenced. Mutations were grouped using three classifications based on their expected function. Each functional group was analyzed for response to induction chemotherapy, time to surgery, survival, HPV status, p16INK4a, Bcl-xl and cyclin D1 expression. RESULTS TP53 Mutations were found in 22/58 (37.9%) patients with advanced larynx cancer, including missense mutations in 13/58 (22.4%) patients, nonsense mutations in 4/58 (6.9%), and deletions in 5/58 (8.6%). High risk HPV was found in 20/52 (38.5%) tumors. A classification based on crystal Evolutionary Action score of p53 (EAp53) distinguished missense mutations with high risk for decreased survival from low risk mutations (p=0.0315). A model including this TP53 classification, HPV status, cyclin D1 and Bcl-xL staining significantly predicts survival (p=0.0017). CONCLUSION EAp53 functional classification of TP53 mutants and biomarkers predict survival in advanced larynx cancer.