Malignant Transformation Of Inverted Papilloma Research Articles

Matrix metalloproteinase-11 regulates inverted papilloma epithelial cell migration and invasion.

Inverted papilloma (IP) is a benign tumor characterized by epithelial proliferation, which has the potential for malignant transformation. However, the mechanisms driving this transformation are poorly defined. Matrix metalloproteinase-11 (MMP-11), a regulator of the tumor microenvironment that degrades extracellular matrix, is upregulated in IP with dysplasia. Here, we aim to investigate the role of MMP-11 in IP epithelial migration and invasion. Human IP and contralateral normal sinus mucosa (control) samples were obtained. IP-derived epithelial cultures and normal mucosa-derived epithelial cultures were grown in air‒liquid interface, followed by immunostaining to assess MMP-11 expression in IP. Migration and invasion assays were used to evaluate the role of an anti-MMP-11 antibody on IP and control epithelial cultures. IP-derived cultures demonstrated strong MMP-11 expression compared to controls. Treatment with anti-MMP-11 blocking antibody significantly reduced epithelial migration only in IP-derived cells compared to non-treated IP cells, as seen by incomplete wound closure and reduced transepithelial resistance. In addition, inhibition of MMP-11 reduced IP epithelia's ability to invade through collagen-coated transwells, suggesting that MMP-11 plays a role in invasion. We established an in vitro model to study IP-derived epithelial cells. MMP-11 is uniquely expressed in IP epithelial cultures compared to control epithelial cultures. Inhibition of MMP-11 limits IP epithelial migration and invasion to levels similar to that of normal sinus mucosa. MMP-11 does not appear to have a functional role in normal sinus epithelium, suggesting that MMP-11 has a role in malignant transformation of IP.

Overexpression of FoxM1 in Sinonasal Inverted Papilloma and Associated Squamous Cell Carcinoma.

BackgroundSinonasal inverted papilloma (IP) is a rare tumor of nasal cavity and paranasal sinuses. Its etiology and factors associated with tumor progression remains unclear. Forkhead Box M1 (FoxM1) has also been suggested to serve as an oncogene due to its pivotal roles in cell proliferation and cell cycle regulation. The aim of this study was to characterize the expression pattern of FoxM1 in IP and IP with associated squamous cell carcinoma (IPwSCC).MethodsThe study included 8 subjects with IPwSCC, 17 subjects with sinonasal IP, and 8 normal uncinate tissue (UT) mucosa. Real-time polymerase chain reaction (PCR) and immunohistochemistry were used to assess the expression and distribution of FoxM1, polo-like kinase 1 (PLK1), cyclin B1, and cyclin D1 in IP tissues and normal control. The expression of FoxM1, PLK1, cyclin B1, and cyclin D1 in IPwSCC was evaluated using immunohistochemistry.ResultsThe messenger RNA (mRNA) expression of FoxM1, PLK1, cyclin B1, and cyclin D1 was significantly upregulated in IP tissues versus normal UT by real-time PCR (all P values < .05). Using immunohistochemistry, the expression of FoxM1 was observed in the tumor cells of sinonasal IP and IPwSCC, but scarce positive cells in normal UT mucosa. The percentage of positive FoxM1-staining cells was statistically higher in IPwSCC than IP and normal UT mucosa (both P < .05). Both mRNA and protein expression of FoxM1 in IP with or without associated squamous cell carcinoma was correlated with tumor histological grades (both P < .05).ConclusionFoxM1, a proliferation specific transcription factor, was overexpressed in sinonasal IP and IPwSCC. FoxM1 might be a key molecule associated with growth of IP and malignant transformation of IP into IPwSCC.

Genetic mutation analysis of the malignant transformation of sinonasal inverted papilloma by targeted amplicon sequencing.

The mechanism underlying the malignant transformation of inverted papilloma (IP) has not yet been elucidated. To clarify the genes responsible for the malignant transformation, we analyzed 10 cases of IP, 8 of IP with dysplasia, and 11 of squamous cell carcinoma (SCC) by targeted amplicon sequencing. The number of mutant genes increased in the order of IP < dysplasia < SCC. Significant differences were observed in the mutation rates of three genes (KRAS, APC and STK11) in particular. TP53 was altered frequently in each group and might be involved in malignant transformation based on to the site of the mutation. A comparison of the genetic variants by region of IP tissue among patients with IP alone, and those with dysplasia or SCC revealed significant differences in the mutation rate of the KRAS gene. Identification of genetic mutations in KRAS is effective for predicting the malignant transformation of IP.

Multiparametric MRI in differentiation between sinonasal inverted papilloma and malignant transformation of inverted papilloma

Objective To identify the value of multiparametric MR imaging features including diffusion weighted (DW) and dynamic contrast-enhanced (DCE) MR imaging features in differentiation between inverted papilloma and malignant transformation of inverted papilloma in the sinonasal region. Methods Seventy-seven patients were included in this study, including 12 malignant transformation of inverted papilloma and 65 inverted papillomas. Conventional MRI including nonenhanced and static contrast-enhanced imaging, DCE-and the DW-MRI were analyzed. Differences in conventional MRI features, ADCs and DCE-MRI parameters between the two entities were determined by Fisher exact test, independent samples t-test and Mann-Whitney U test, respectively. Results There were significant differences in convoluted cerebriform pattern (P=0.045), necrosis (P=0.003) and orbit involvement (P<0.01) between inverted papilloma and malignant transformation of inverted papilloma in the sinonasal region. The ADCs of inverted papilloma were significantly lower than those of malignant transformation of inverted papilloma (P<0.01). There were significant differences in time to peak enhancement (P<0.01), maximum contrast index (P=0.004) and time intensity curve types (P<0.01) between the two entities. Conclusions A multiparametric approach using conventional MR imaging with added ADCs and DCE-MRI parameters had the potential to improve the differentiation between inverted papilloma and malignant transformation of inverted papilloma in the sinonasal region. Key words: Nasal cavity; Sinus; Neoplasms; Multiparametric MR imaging

Role of microRNA-296-3p in the malignant transformation of sinonasal inverted papilloma.

Inverted papilloma (IP) is a benign tumor occurring in the nasal cavity and paranasal sinuses. It is reported that 5-15% of IPs undergo malignant transformation into squamous cell carcinoma (SCC), and the role of microRNAs (miRNA/miR) in this process remains to be elucidated. In the present study, whole miRNA profiles using samples of IP and SCC were investigated, in order to detect the function of miRNA in the carcinogenesis of IP. Samples from IPs (n=5) and SCC lesions (n=5), which arose from IPs, were used for miRNA analysis. A total of 200 miRNAs exhibited a >2-fold differential expression between IP and SCC. miR-296-3p was markedly upregulated in SCC with a 23-fold difference. Computational analysis indicated that miR-296-3p targeted PTEN, which regulates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and PTEN is involved in the carcinogenesis of SCC. miR-296-3p directly regulated PTEN expression in head and neck cancer cells, with PTEN protein levels decreased in 4/19 the SCCs (21.0%), as compared with those in the IPs (76.4%). Positive p21 staining was observed in 64.7% of IPs; this was a significantly increased rate compared with that for SCCs (26.3%, P=0.0086). The results of the present study indicated that there were marked changes in the miRNA expression signature during the malignant transition. miR-296-3p may serve an important role in the malignant transformation of IPs via the regulation of PTEN, combined with the subsequent inhibition of the PI3K/Akt signaling pathway, and may be a novel agent for cancer prevention.

Role of Wnt signaling pathway in progression of sinonasal inverted papilloma to squamous cell carcinoma.

Sinonasal inverted papilloma (IP) is one of the most common benign tumors of the sinonasal area and malignant transformation has frequently been reported. However, the exact mechanism of the transition from benign lesion to malignancy is not known. The Wnt signaling pathway involves a network of multiple signaling glycoproteins that are known to play an important role in embryogenesis and carcinogenesis. The purpose of this study was to evaluate the role of the Wnt pathway and signaling proteins in malignant transformation of IP to dysplasia and squamous cell carcinoma. Expression of the Wnt signaling pathway proteins, including Wnt-1, beta-catenin, cyclin D1, and Dishevelled-1 (Dvl-1), were detected by immunohistochemistry by using 3-mm tissue core microarrays that consisted of 115 cores of IP tissue. Each of the IP cores was graded as I (prominent squamous metaplasia), II (inverted pattern), III (dysplasia), or IV (squamous cell carcinoma). The expression pattern of each protein and the correlation between the expression of each target protein and IP grade were evaluated. Membranous staining of beta-catenin showed a significant positive correlation with IP grade (ρ = 0.247, p < 0.001), as did staining of cyclin D1 (ρ = 0.365, p < 0.001), which showed a nuclear pattern and staining of Dvl-1 (ρ = 0.380, p < 0.001), which showed a membranous, cytoplasmic, and nuclear pattern. For Dvl-1, a nuclear expression pattern was more frequently observed in grade III and IV IP (p = 0.036). In the case of Wnt-1, cytoplasmic expression was observed; however, it did not show a significant correlation with IP grade (ρ = 0.141, p = 0.130). Wnt signaling proteins, including beta-catenin, cyclin D1, and Dvl-1, may play crucial roles in the malignant transformation of IP.

Importance of Human Papillomavirus Integration in Malignant Transformation of Inverted Papilloma

Objectives: This study investigated the role of human papillomavirus (HPV) in malignant transformation of paranasal inverted papilloma (IP). Methods: HPV presence and viral load and physical status of HPV-16 were examined by polymerase chain reaction-based methods using fresh frozen samples or paraffin-embedded samples obtained from 17 patients with IP (IP group), 5 with IP and squamous cell carcinoma (IP+SCC group), 16 with SCC (SCC group), and 67 with chronic inflammatory lesions (inflammatory group). Results: The presence of the HPV genome was detected in 29.4%, 40.0%, 25.0%, and 6.0% of patients in the IP, IP+SCC, SCC, and inflammatory groups, respectively. The IP group showed significantly higher HPV-positive rates than the inflammatory group. All types of HPV detected were high-risk HPV, especially HPV-16. The relative HPV-16 copy numbers varied from 2.5 to 7953 per 50 ng genomic DNA. Viral load was higher in the IP+SCC group than in the inflammatory group. In the IP group, no significant relationship was found between HPV-16 viral load and clinical characteristics. All patients with IP+SCC and SCC showed integration of HPV-16. Conclusions: High viral load and integration of HPV have an important role in malignant lesion in association with IP.

Desmoglein 3 is overexpressed in inverted papilloma and squamous cell carcinoma of sinonasal cavity

We sought to investigate the role of desmoglein 3 in pathogenesis of sinonasal inverted papilloma (IP) and its malignant transformation. Fifteen subjects with sinonasal IP and 15 subjects of normal sphenoid sinus mucosa were enrolled. Each specimen was divided into two portions: one for mRNA expression analysis by real-time polymerase chain reaction, and the other for detection of targeted proteins by immunohistochemistry analysis. In addition, another 10 cases of IP with squamous cell carcinoma (SCC) were added for immunohistochemistry analysis. The mRNA expression level of desmoglein 3 was significantly higher in IP tissues than in the normal sinus mucosa (P < .001). In immunohistochemistry study, desmoglein 3 was detected in plasma membrane areas of IP and IP with SCC tissues, but no obvious expression was found in normal sinus mucosa (total score; both P < .001). Positive desmoglein 3 staining was strongly present in nearly all malignant transformation areas of IP with SCC cases (90%), but only in scattered areas of some cases of IP (53%) (total score; P < .001). Desmoglein 3 was overexpressed in IP and IP with SCC, and the overexpression was correlated with malignant transformation of IP. It may provide valuable insight into the pathobiology of this disease, and can potentially provide a venue to predict malignant transformation in sinonasal IP.