Human papillomavirus infection and immunohistochemical expression of cell cycle proteins pRb, p53, and p16INK4a in sinonasal diseases

Abstract

BackgroundWe aimed to clarify the possible role of human papillomavirus (HPV) infection in the malignant transformation of sinonasal inverted papilloma (IP).MethodsSubjects comprised 32 patients with chronic rhinosinusitis (CRS), 17 with IP, 5 with IP and squamous cell carcinoma (IP + SCC), and 16 with primary sinonasal SCC. HPV presence, viral loads, and physical status were investigated using polymerase chain reaction. Retinoblastoma (pRb), p53, and p16INK4a gene products were investigated by immunohistochemistry.ResultsHPV DNA was detected in 6.3 % of cases with CRS, 29.4 % with IP, 40 % with IP + SCC, and 25 % with SCC. IP cases had significantly higher HPV presence than CRS cases (p = 0.04). High-risk HPV-16 was the most frequently encountered subtype (10/13, 76.9 %). HPV-16 viral loads varied from 2.5 to 7953 E6 copies/50 ng genomic DNA. Patients in the SCC and IP + SCC groups had significantly higher viral loads than those in the IP and CRS groups (p < 0.01). All SCC and IP + SCC patients with HPV-16 demonstrated mixed-type integration, whereas 4 of 5 HPV-16 patients in the IP and CRS groups showed episomal type infection (p = 0.04). Positivity to pRb was found in 78.1 % of CRS, 35.3 % of IP, and 68.8 % of SCC cases. The presence of HPV DNA negatively correlated with pRb expression in SCC (p = 0.029) and IP (P = 0.049) groups. Although 62.5 % of SCC cases exhibited p53 positivity, only 5.9 % of IP, and no CRS cases were positive. Regardless of HPV status, p16INK4a positivity was frequently detected in IP cases (82.4 %), less in SCC (12.5 %) cases, and was not detected in the CRS group. Neither the IP nor SCC cohorts showed any correlation between HPV presence and the expression of either p53 or p16INK4a.ConclusionsHPV infection was more frequent in the IP, IP + SCC, and SCC groups than the CRS group. Higher viral loads and integration observed in the IP + SCC and SCC groups, and an inverse correlation between HPV presence and positive pRb indicated that persistent infection and integration play a part in tumorigenesis and malignant transformation in certain IP cases. However, p16INK4a is not a reliable surrogate marker for HPV infection in IP.

Significance of human papillomavirus positivity in sinonasal squamous cell carcinoma

“…A relationship between HPV and SN‐SCC was first reported in 1989 in a study of sinonasal papillomas; two thirds of the papillomas were HPV‐positive, including all of the cases that progressed to SN‐SCC . Since then, numerous studies have detected HPV in exophytic, inverted, and fungiform sinonasal papillomas. Furthermore, HPV positivity has been identified in 40% to 100% of SN‐SCC that transformed from inverted papillomas .…”

“…Since then, numerous studies have detected HPV in exophytic, inverted, and fungiform sinonasal papillomas. Furthermore, HPV positivity has been identified in 40% to 100% of SN‐SCC that transformed from inverted papillomas . Therefore, involvement of the virus in the papilloma‐to‐carcinoma transition is one possible mechanism by which HPV may cause SN‐SCC.…”

Clinical effects of p53 overexpression in squamous cell carcinoma of the sinonasal tract

“…Ultimately, a total of 17 studies fulfilled the above select criteria and were included in the current meta-analysis. [9,23–38] Among the 17 articles published in English, the publication years ranged from 1998 to 2015. Sixteen studies including 229 SNSCC and 675 benign papilloma patients evaluated the relationship between p53 expression and SNSCC in cancer versus benign sinonasal papillomas.…”

“…Sixteen studies including 229 SNSCC and 675 benign papilloma patients evaluated the relationship between p53 expression and SNSCC in cancer versus benign sinonasal papillomas. [9,23–30,32–38] Five studies involving 112 SNSCC patients and 73 normal sinonasal mucosa estimated the relationship between p53 expression and SNSCC in cancer versus normal sinonasal mucosa. [30,34,35,37,38] Three studies with 72 SNSCC patients evaluated the correlation between p53 expression and tumor differentiation in cancer.…”

“…[8] Recently, accumulating evidence suggests that a number of genetic alterations may contribute to the initiation and progression of SNSCC. [9–12] The p53 gene is a tumor suppressor gene mapped to chromosome 17p13, encodes the p53 protein, which involves in the regulation of the cell cycle, the inhibition of DNA synthesis, the function of DNA repair and apoptosis. [13–15] The p53 mutation is the most commonly found genetic alterations in various human carcinomas, [16,17] and the overexpression of p53 detected by immunohistochemistry (IHC) in most of cases (85%) is consistent with an underlying mutation.…”