Search

Background: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Objectives: Sinonasal inverted papilloma (SNIP) is a noncancerous tumor that develops in the mucous membrane of the nasal sinuses. Many malignancies are tightly linked to autophagy, an intracellular self-degradation mechanism. HMGB1 has demonstrated its ability to modulate autophagy in many pathological conditions. This work investigates how HMGB1 and other genes involved in autophagy contribute to SNIP., Material and Methods: The study included 45 patients with SNIP and a control group consisting of 28 individuals. In each group, qPCR was employed to examine the mRNA expression levels of genes correlated with autophagy and HMGB1. HMGB1 and genes associated with autophagy were examined for protein expression levels via Western Blot and immunohistochemical staining assays. At the same time, the association between HMGB1 and genes involved in autophagy was discovered through correlation analysis. Furthermore, Krouse staging was utilized for investigating the expression levels of HMGB1 and other autophagy-related genes at various stages in clinically staged SNIP patients., Results: LC3B, ATG5, and Beclin1 autophagy-related genes and HMGB1 were substantially expressed in SNIP. Additionally, there was a positive correlation between HMGB1 and these genes. During various phases of SNIP, the levels of HMGB1 expression and autophagy-related genes were notably elevated at stage T4 compared with stage T2., Conclusion: Clinical staging in SNIP is correlated with HMGB1 expression in conjunction with autophagy-related genes LC3B, ATG5, and Beclin1, suggesting the possibility of novel prognostic indicators., Level of Evidence: NA Laryngoscope, 134:3941-3946, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

The mechanism and predictive biomarkers of sinonasal inverted papilloma (IP) transformation into squamous cell carcinoma (SCC) are still unclear. We investigated the genetic mutations involved and the predictive biomarkers. Fourteen patients with SCC arising from IP and six patients with IPs without malignant transformation (sIP) were included. DNA was extracted separately from areas of normal tissue, IP, dysplasia, and SCC. Whole exome sequencing and immunohistochemistry was performed. Major oncogenic mutations were observed in the progression from IP to SCC. The most frequently mutated genes were TP53 (39%) and CDKN2A (27%). Mutations in TP53 and/or CDKN2A were observed in three of six IPs with malignant transformation (cIP); none were observed in sIPs. Tumor mutational burden (TMB) increased from IP to SCC (0.64/Mb, 1.11/Mb, and 1.25 for IP, dysplasia, and SCC, respectively). TMB was higher in the cIPs than in the sIPs (0.64/Mb vs 0.3/Mb). Three cIPs showed a diffuse strong or null pattern in p53, and one showed a total loss of p16, a distinct pattern from sIPs. Our result suggests that TP53 and CDKN2A status can be predictive markers of malignant transformation of IP. Furthermore, immunohistochemistry of p53 and p16 expression can be surrogate markers for TP53 and CDKN2A status., (© 2024. The Author(s).)

Objective: This study examine FOXP3, CD4, CD8 and p53 expression in the transformation of the Sinonasal Inverted Papilloma (SIP) malignancy into sinonasal carcinoma., Materials and Methods: This study used a cross-sectional approach. The research sample from thirty-six paraffin block preparations with the diagnosis of SIP. Then, immunohistochemical staining was performed using FOXP3 mouse monoclonal antibody (236A/E7), CD8 rabbit monoclonal antibody (CD8/1179R), CD4 mouse monoclonal antibody (4B12) and p53 rabbit monoclonal antibody.  Results: There was a significant difference between Foxp3 expression in SIP without dysplasia and SIP with dysplasia (p= 0.013). There was no significant difference between the expression of CD4 and CD8 in the two groups with p-values 0.1 and 0.062, respectively. The mean percentage of positive p53 expression in SIP without dysplasia was 0.45+0.63 and in the SIP with dysplasia 29.31+38.96. There was a significant difference between the two groups (p<0.001)., Conclusion: FOXP3 and p53 were overexpressed in SIP with malignant transformation. FOXP3 together with p53 status is associated with dysplastic changed in the SIP. FOXP3 and p53 status could be potential biomarker of malignant transformation in sinonasal inverted papilloma.

To investigate the diagnostic value of casein kinase 1α (CK1α) and phosphatase and tensin homolog (PTEN) in sinonasal inverted papilloma (SNIP), 42 control subjects and 56 SNIP patients were recruited in this study. Demographic and clinical characteristics, computerized tomography scans and endoscopic examinations were analyzed according to the Krouse staging system. Real-time quantitative-polymerase chain reaction and Western blotting were performed to detect CK1α and PTEN expression levels in different subgroups. Receiver operating characteristic and correlation analyses were conducted to assess their clinical significance in SNIP diagnosis. The expression levels of CK1α and PTEN were decreased in SNIP patients. Interestingly, the declined mRNA levels were consistent with the elevated Krouse staging and closely associated with the pathophysiological characteristics. Their expression levels also negatively correlated with neutrophil counts and positively correlated with lymphocyte counts in the blood of SNIP patients. This study suggests that CK1α and PTEN might be useful biomarkers for the occurrence and recurrence diagnosis of SNIP., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Local recurrence occurs in ~ 19% of sinonasal inverted papilloma (SNIP) surgeries and is strongly associated with incomplete resection. During surgery, it is technically challenging to visualize and resect all SNIP tissue in this anatomically complex area. Proteins that are overexpressed in SNIP, such as vascular endothelial growth factor (VEGF), may serve as a target for fluorescence molecular imaging to guide surgical removal of SNIP. A proof-of-concept study was performed to investigate if the VEGF-targeted near-infrared fluorescent tracer bevacizumab-800CW specifically localizes in SNIP and whether it could be used as a clinical tool to guide SNIP surgery., Methods: In five patients diagnosed with SNIP, 10 mg of bevacizumab-800CW was intravenously administered 3 days prior to surgery. Fluorescence molecular imaging was performed in vivo during surgery and ex vivo during the processing of the surgical specimen. Fluorescence signals were correlated with final histopathology and VEGF-A immunohistochemistry. We introduced a fluorescence grid analysis to assess the fluorescence signal in individual tissue fragments, due to the nature of the surgical procedure (i.e., piecemeal resection) allowing the detection of small SNIP residues and location of the tracer ex vivo., Results: In all patients, fluorescence signal was detected in vivo during endoscopic SNIP surgery. Using ex vivo fluorescence grid analysis, we were able to correlate bevacizumab-800CW fluorescence of individual tissue fragments with final histopathology. Fluorescence grid analysis showed substantial variability in mean fluorescence intensity (FI mean ), with SNIP tissue showing a median FI mean of 77.54 (IQR 50.47-112.30) compared to 35.99 (IQR 21.48-57.81) in uninvolved tissue (p < 0.0001), although the diagnostic ability was limited with an area under the curve of 0.78., Conclusions: A fluorescence grid analysis could serve as a valid method to evaluate fluorescence molecular imaging in piecemeal surgeries. As such, although substantial differences were observed in fluorescence intensities, VEGF-A may not be the ideal target for SNIP surgery., Trial Registration: NCT03925285., (© 2021. The Author(s).)

Objective: Neutrophil infiltration in patients with sinonasal inverted papilloma (SNIP) is significantly high. Whether IL-17, which is a potent factor mediating neutrophilic inflammation, is involved in the neutrophilic phenotype of SNIP is investigated in the current study., Study Design: Laboratorial study., Participants: Nasal papilloma and inferior turbinate were collected from patients with SNIP (n = 50) and control subjects with septal deviation (n = 15)., Methods: IL-17 + cells were evaluated in tissues obtained from patients with SNIP and control subjects with septal deviation, by immunohistochemistry and flow cytometry., Main Outcome Measures: The IL-17 + cells were mainly localised in mononuclear cells and neutrophils, and were up-regulated in the SNIP samples compared with those in the controls. The IL-17 + T-cell subsets mainly included CD4+ (Th17, 60.0%) and CD8+ (Tc17, 30.0%), and both subsets were enhanced in the SNIP samples than controls. The total level of IL-17 + cells was significantly correlated with neutrophil infiltration in the SNIP tissues. Furthermore, the SNIP homogenates could significantly promote IL-17 production in peripheral blood mononuclear cells., Conclusions: An increase in IL-17 + cells is evident in SNIP and may be involved in neutrophil infiltration in local tissues. IL-17 could be a potential therapeutic target to relieve the neutrophilic pathological change in SNIP., (© 2019 John Wiley & Sons Ltd.)

Background: Currently, the expression patterns of epidermal growth factor receptor (EGFR) family genes in sinonasal inverted papilloma (SNIP) and inverted papilloma with squamous cell carcinoma (IPwSCC) are not clear. Objective: This study aimed to investigate the expression of EGFR family members and their ligands in SNIP and IPwSCC and to analyze their correlations with SNIP histological grade and Krouse stage. Materials and methods: Data from 25 cases of inverted papilloma patients in China were collected and divided into 16 cases in the SNIP group and 9 in the IPwSCC group. In addition, eight cases of normal nasal mucosa (NNM) were collected and used as the control group. The expression levels of EGFR family members and their ligands in the NNM and SNIP groups and EGFR family members in the IPwSCC group were evaluated using immunohistochemistry and qRT-PCR. In addition, their correlations with the SNIP histological grade and Krouse stage were analyzed. The statistical analysis was performed using the GraphPad Prism 7.0 statistical software. Results: The ErbB1 and ErbB2 mRNA and protein expression levels were significantly higher in the SNIP group than in the NNM group ( p  < .01). The ErbB1 and ErbB2 protein expression levels were significantly higher in the IPwSCC group than those in the NNM and SNIP groups ( p  < .01). The ErbB1 and ErbB2 mRNA and protein expression levels in the SNIP group were positively correlated with the SNIP dysplasia grade. Conclusion: Upregulation of ErbB1 and ErbB2 expression may be associated with SNIP pathogenesis and carcinogenesis.

Background: Sinonasal inverted papilloma (IP) is a benign tumor with a high risk of local recurrence and a potential to malignify and Human papillomavirus (HPV) has been suggested an etiological factor. p16INK4a (p16) overexpression is considered a surrogate marker for HPV, but whether p16 and HPV correlate to IP is uncertain. Besides, a prognostic role of tumor infiltrating lymphocytes (TILs) are observed in many tumors, however their role in IP is sparsely studied. Aims/objectives: We hence analyzed IPs for the presence and the prognostic role of HPV and p16 overexpression together with CD8+ and FoxP3+ TILs in a population-based study. Material and methods: 98 IP patients diagnosed 2001-2010 were identified from the Swedish Cancer Registry and analyzed for HPV by PCR and p16, CD8 and FoxP3 was by immunohistochemistry. Results: In total, 12.2% of the IPs were HPV-positive (nine HPV-11, two HPV-6 and one HPV-45). Patients with HPV-positive lesions were younger ( p =  .003) and tended to present with more dysplasia. No correlation was observed between TILs and prognosis. Conclusions and significance: Our data suggests that patients with HPV-positive IPs present with different clinical characteristics, suggesting possibly different disease entities. Moreover, recurrences may occur >5 years, which should be considered in the follow-up.

Objective: To compare genome-wide DNA methylation between samples of sinonasal inverted papilloma (SNIP) and squamous cell carcinoma (SCC) samples in order to identify aberrantly methylated genes that might be involved in malignant transformation., Methods: Tissue samples were collected from patients. DNA methylation in C-phosphate-G islands and gene promoters was analysed using a DNA methylation microarray kit. The levels of mRNA or protein from aberrantly methylated genes were measured using real-time polymerase chain reaction or Western blot analysis., Results: A total of 27 tissue samples were included in this study; 15 SNIP samples and 12 SCCs arising in SNIPs. A total of 11 201 nominally differentially methylated sites were observed between SNIP and SCC arising in SNIPs. Six sites were significantly different at P < 0.01 and contained three genes ( MIR661, PLEC and OPA3). These three genes were hypermethylated. In addition, the levels of mature miR-661 mRNA and PLEC protein were significantly upregulated in SCC tissues compared with SNIP samples. The levels of OPA3 protein were downregulated in SCC tissues compared with SNIP samples., Conclusions: This study demonstrated hypermethylation and abnormal expression of the MIR661, PLEC and OPA3 genes, suggesting a role for their involvement in the malignant transformation of SNIP.

Objectives: Fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) has been increasingly used in the past decade. Incidental FDG-avid findings are encountered in these studies, several of which with clinical significance. However, the significance of incidental FDG-avid sinonasal findings has not been studied to date., Study Design: Retrospective cohort study., Setting: A single tertiary medical center., Materials and Methods: The medical records were reviewed of patients with incidental sinonasal positive FDG uptake between 2007 and 2016 who referred for further otolaryngological diagnostic workup., Results: A total of 26 patients were identified, all of whom underwent a diagnostic surgical procedure. Histopathology revealed chronic inflammation (n = 12, 46.1%), malignancy (n = 7, 26.9%), inverted papilloma (n = 4, 15.5%), and fungal infections (n = 3, 11.5%). A unilateral maxillary sinus with FDG uptake was documented for 16 (61.5%) patients. CT evidence of bilateral disease and mucosal or sinus wall thickening correlated with inflammatory disease., Conclusions: Incidental lesions with positive FDG uptake in the sinonasal cavities are at a high risk (40%) of being neoplastic. A diagnostic biopsy is advocated in these cases.

Background: Nasal polyposis (NP) and sinonasal inverted papillomas (SIP) are considered benign lesions capable of recurrence or malignant transformation although not with the same prevalence. Since fluctuations of Caveolin-1 and Notch-1 proteins expression have been reported in many pathologies, the current study aimed to investigate their involvement in the epithelial transformation observed in SIPs compared to NP., Methods: Immunohistochemical expression of Caveolin-1 and Notch-1 proteins was assessed in 104 patients with sinonasal lesions (45 NP, 45 SIP and 14 NP with SIP), semiquantively (percentage times intensity). Proteins expression profiles were evaluated statistically for their correlation with patients demographic and clinicopathological variables (grade of dysplasia, inflammation, recurrence) as well as with markers of proliferation (Ki67) and apoptosis (7-AAD) as determined by flow cytometry analysis., Results: SIP lesions presented increased Caveolin-1 immunopositivity compared to NP (62.2%, vs 40.9%; p = 0.045). Cytoplasmic staining was observed only in epithelium's basal and suprabasal layers. Caveolin-1 positivity was not related to Ki67 expression, apoptosis, inflammation or dysplasia, eventhough 81.8% of highly immunopositive lesions were dysplastic (p = 0.03). Also, smokers presented significantly increased immunopositivy (p = 0.03). In contrast SIP lesions presented reduced Notch-1 expression compared to NP (68.9% vs 100%; p < 0.001). Dysplastic lesions presented low Notch-1 immunopositivity (p < 0.001). Enhancement of Notch-1 gene expression was also associated with inflammation., Conclusions: The herein presented data suggest that the expression profiles of Caveolin-1 and Notch-1 proteins in sinonasal pathologies are distinctive and that could be explored as potential targets for the development of alternative therapeutic approaches., (Copyright © 2018. Published by Elsevier GmbH.)

Introduction: Sinonasal inverted papilloma constitute relevant therapeutic problem due to destructive character of growth, tendency to recur and the possibility of malignant transformation. Therefore, many attempts to identify risk factors for inverted papilloma occurrence have been undertaken, as well as research to find markers that would allow for the earlier detection of tumors and the application of adequate therapy. A widely known risk factor of inverted papilloma is HPV infection. One of the markers of HPV infection and the ongoing effect of this change (although arousing some controversy) is the expression of the p16 protein., Objective: The aim of the study was to analyze the correlation between the expression of p16 as a surrogate of HPV infection in analyzed histopathological material and epidemiological variables, recurrences or malignant transformation., Methods: The retrospective study includes a group of 53 patients (18 women and 35 men) undergoing treatment for sinonasal inverted papilloma in the period of 2002-2012. The intensity of the p16 protein in histopathological material was scored as: 0 - no expression, 1 - diffuse expression (borderline) and 2 - positive expression; or 0 - no expression/diffuse expression (borderline); 1 - positive expression. The Ethics Committee agreement was obtained (1089/12; 245/13)., Results and Conclusion: There was no statistically significant relationship between the expression of p16 and the age of patients, cigarette smoking, tumor location, tumor staging according to the Krouse and Cannady classification, the presence of dysplasia or the occurrence of relapse., (Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Background: P53, a crucial suppressor of tumor formation, generates multiple isoforms, whose role in disease is still being defined., Methods: By immunohistochemistry, we studied the expression of P53 protein and relative isoforms in benign papillomas (PA, n=9), inverted papilloma (IPA, n=10) and squamous cell carcinomas (SCC, n=21)., Results: In all lesions, P53 isoforms were significantly more expressed than P53. Immunoexpression of P53 matched with P53 isoforms in IPA as well as in SCC. Simultaneous immunoexpression of P53 and related isoforms was double in SCC compared to IPA (10% vs 24%), while expression of P53 isoforms was strongly reduced (70% vs 43%). IPA showed the highest percentage of both reactive cases and immunostained cells expressing P53 isoforms., Conclusions: We found the higher expression of P53 isoforms in IPA and SCC compared to PA, suggesting their role in local aggressiveness and malignant proliferation in head-neck lesions.

Background: The purpose of this study was to investigate roles of human papillomavirus (HPV) infection and stathmin in sinonasal inverted papilloma (SNIP)., Methods: HPV DNA detection was performed by the fluorescence-based polymerase chain reaction (PCR) method. Stathmin protein expression was investigated by the immunohistochemistry method and mRNA expression of stathmin, Kif2a, and cyclin D1 were assessed by real-time PCR in SNIP and control subjects., Results: The positive rate of HPV DNA detected in SNIP was about 53.6% (15 of 28). Recurrent cases showed a higher rate of HPV infection compared with initial cases and higher Krouse stage (T3 + T4) cases showed higher rate of HPV infection than lower Krouse stage (T1 + T2) cases. Stronger expression of stathmin, Kif2a, and cyclin D1 were observed in SNIP, especially HPV(+) SNIP., Conclusion: HPV infection was closely associated with recurrence and progression of SNIP. Stathmin is a valuable prognostic marker and could be considered as a therapeutic target in patients with SNIP., (© 2015 Wiley Periodicals, Inc.)

Inverted papilloma (IP) of the urinary tract is classified by the World Health Organisation as a non-invasive urothelial tumour with normal to minimal cytological atypia of the neoplastic cells. During the 1980s, it came under suspicion of having a premalignant or malignant potential and of being concurrent with urothelial cell carcinoma (UCC). This quandary has been proven difficult to solve, due to the fact that IP is very rare and literature mostly consists of case reports with varying levels of information, making strong meta-analyses problematic. New immunohistochemical techniques and genetic approaches are more frequently being used in the attempt to achieve better classifications, prognosis and treatment of lesions hereunder IP. This review will, in our awareness, be the first to combine the knowledge from retrospective studies with these new approaches for determining a possible premalignant potential and concurrency with UCC and subsequently outline a recommendation for follow-up., (© 2015 APMIS. Published by John Wiley & Sons Ltd.)

A 63-year-old man presented with an asymptomatic papillary, sessile lesion of the juxtalimbal bulbar conjunctiva that was surgically excised with cryotherapy. Histopathologically, the lesion created some diagnostic confusion as it displayed an endophytic, or inverted, growth pattern-with squamous cells pushing into the substantia propria around fibrovascular cores, but without significant cytologic atypia, consistent with a conjunctival inverted papilloma (IP). Unlike previously reported cases of conjunctival IP, there were no goblet cells or cysts within the tumor. Immunostaining was diffusely positive for cytokeratin (CK) 7, and CK14 stained the basilar and suprabasilar cells, as in normal conjunctiva. CK17 weakly and non-uniformly stained the tumor, ruling out a dysplasia, which is usually strongly positive. The lesion's cytokeratin profile therefore paralleled that of normal conjunctiva. The proliferation index with Ki67 nuclear staining was extremely low (<1%), as was p53 nuclear staining (10-20%), both in contrast to squamous cell dysplasias or carcinomas that have a much higher percentage of positive cells. The lesion was negative for human papillomavirus subtypes associated with squamous neoplasias including carcinomas. We review the previous literature devoted to this comparatively rare condition and contrast its benign clinical course with that of inverted papillomas of the sinonasal, lacrimal drainage, and genitourinary systems and provide a set of criteria for establishing the diagnosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The expression of C/EBPα, CK10 in nasal inverted papilloma (NIP) were detected in the study. Further discussed their significance in genesia, development and recurrence of NIP., Method: Three groups including nasal cavity mucosae (NM 10 cases), nasal polyp (NP 20 cases) and NIP (30 cases) were selected in the study. Expretion of C/EBPα, CK10 were detected by immunohistochemisty PV-6000 method., Result: (1) The different expression of C/EBPα and CK10 in the group of NM, NP and NIP was statistically significant (P < 0.05). (2) The different expression of C/EBPα, CK10 in the group of benign NIP and NIP with atypical hyperplasia was statistically significant (P < 0.05). (3) The different expression of C/EBPα and CK10 in the group of NIP with recurrence and NIP with no recurrence was statistically significant, P < 0.05, respectively. (4) Our result indicate that the relationship of C/EBPα and CK10 (r = 0.578, P < 0.01) was direct correlation. The difference was statistically significant., Conclusion: In conclusion, the present results describe C/EBPα, CK10 expression in NIP and their possible implication in the regulation of tumor growth and differentiation. C/EBPα and CK10 production may prove useful in terms of a prognostic marker for the recurrence in nasal inverted papilloma.

Objective: To explore the expression and significance of programmed cell death 5 (PDCD5) and Bcelllymphoma/lewkmia-2(Bcl-2) in sinonasal squamous cell carcinoma (SNSCC)., Method: Immunohistochemical method and Western Blot method was used to determine the expression of PDCD5 and Bcl-2 in specimen of SNSCC in thirty cases, sinonasal inverted papillomas (SNIP) in thirty-eight cases, and normal nasal mucosa in twenty cases., Result: (1) The expression of PDCD5 protein in SNSCC significantly decreased compared with SNIP and normal nasal mucosa. (2) The expression of Bcl-2 protein in SNSCC up-regulated obviously compared with SNIP and normal nasal mucosa. (3) Positive rate of PDCD5 protein and Bcl-2 protein in well, moderate and low differentiatied group is respectively 100.00%, 83.33%, 38.89% and 50.00%, 70.83% and 100.00%, the difference was statistically significant (P < 0.05). (4) In the follow-up cases, the survival rate of the patients with higher expression of PDCD5 protein was higher, but that with lower expression of Bcl-2 protein was higher., Conclusion: The inactivation of PDCD5 protein and the activation of Bcl-2 protein may play an important role in the development of SNSCC, and there are a positive correlation between PDCD5 and Bcl-2 protein in SNSCC, which may be identified as a new therapeutic target.

Galectins, a family of endogenous lectins, are multifunctional effectors that act at various sites and can be used in immunohistochemical localization studies of diseased states. Since they form a potentially cooperative and antagonistic network, we tested the hypothesis that histopathological fingerprinting of galectins could refine the molecular understanding of naso-sinusal pathologies. Using non-cross-reactive antibodies against galectin-1, -3, -4, -7, -8 and -9, we characterized the galectin profiles in chronic rhinosinusitis, nasal polyposis, inverted papillomas and squamous cell carcinomas. The expression, signal location and quantitative parameters describing the percentage of positive cells and labeling intensity were assessed for various cases. We discovered that inverted papillomas showed a distinct galectin immunohistochemical profile. Indeed, epithelial overexpression of galectin-3 (p=0.0002), galectin-4 (p<10-6), galectin-7 (p<10-6) and galectin-9 (p<10-6) was observed in inverted papillomas compared to non-malignant diseases. Regarding carcinomas, we observed increased expression of galectin-9 (p<10-6) in epithelial cells compared to non-tumor pathologies. Our results suggest that galectin-3, -4, -7 and -9 could be involved in the biology of inverted papillomas. In addition, we observed that the expression of galectin in naso-sinusal diseases seems to be affected by tumor progression and not inflammatory or allergic phenomena.

Objective: To investigate the expression and clinical significance of phosphatase and tensin homology deleted on chromosome ten (PTEN) and hypoxia-inducible factor 1 alpha (HIF-1α) in sinonasal inverted papilloma (SNIP) of different pathological grades., Methods: Fifty-five paraffin samples from patients with SNIP and a control group of 10 paraffin samples of patients with normal nasal cavity mucosa (NM) who underwent inferior turbinectomy were consisted in this study. Among the 55 cases of SNIP, 30 cases were without dysplasia subtypes, 11 cases were with dysplasia subtypes, and 14 cases with canceration to squamous cell carcinoma (SCC) subtypes. PTEN and HIF-1α expression in SNIP was detected by immunohistochemistry. The differences between NM and SNIP, and among the three subtypes were analyzed, and the relationship between PTEN, HIF-1α expression and SNIP recurrence and the correlation between PTEN expression and HIF-1α expression were also analyzed. SPSS 16.0 software was used to analyze the data., Results: The positive expression rate of PTEN in NM and SNIP was 100% and 65.5%, the difference was significant (U = 147, P = 0.014), while HIF-1α was 0 and 30.9%, the difference was significant (U = 190, P = 0.045). The positive expression rate of PTEN in SNIP without dysplasia, SNIP with dysplasia and NSCC was 83.3%, 63.6%, 28.6%, respectively, the difference was significant (H = 12.644, P = 0.002); while HIF-1α was 16.7%, 45.5%, 50.0%, respectively, the difference was significant (H = 8.292, P = 0.016). A total of 22 SNIP patients recurred. PTEN had lower expression in recurrent SNIP (45.5%) than that in non-recurrent SNIP (82.8%), and the difference was significant(χ² = 7.834, P = 0.005). However, the expression of HIF-1α had no significant difference between recurrent SNIP and the SNIP which had no recurrence (χ² = 0.901, P = 0.343). The expression of PTEN protein was negatively correlated with that of HIF-1α protein (r = -0.503, P = 0.001)., Conclusions: PTEN expression decreased graduately with the severity of malignancy of SNIP, but HIF-1α increased. The expression of HIF-1α was induced by hypoxia, which may negatively effect the expression of PTEN, and both HIF-1α and PTEN may play critical roles in the progress of SNIP. PTEN is one of the factors responsible for the postoperative recurrence of SNIP.

The expression profiles of 14-3-3β and θ isoforms, known to exert both oncogenic and antiapoptotic effects, were assessed in different entities of nasal pathophysiology. Flow cytometry and immunohistochemistry were used on paraffin-embedded sections of 51 inverted papillomas (IP), 26 nasal polyps (NP), 9 polyps with IP (NPIP) and 10 specimens of normal epithelium (NE). 14-3-3β expression was significantly upregulated in IP as compared with both NP (p=0.015) and NE (p=0.002). 14-3-3β was also increased in NPIP as compared with NE (p=0.008). 14-3-3β cytoplasmic staining was more pronounced in basal cells of the respiratory epithelium although serous glands and the vascular system were often positive as well. High 14-3-3β immunopositivity in IP patients concurred with increased proliferative activity shown by PCNA immunostaining (p=0.04). Expression of 14-3-3θ was also found increased in IP and NPIP patients, compared to NP (p=0.005, p=0.002 respectively) and NE (p=0.004 and p=0.001 respectively). 14-3-3θ cytoplasmic immunopositivity was detected in columnar epithelium, particularly in basal and subluminal cells, whereas no immunoreactivity was observed in NP and NE. Our results demonstrate differential expression of 14-3-3β and θ isoforms in sinonasal pathophysiology, supporting their implication, respectively, in the proliferative and inflammatory process engaged in the formation of IP., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Background: Numerous molecular markers of sinonasal inverted papillomas (IP) were investigated in the past; however, significance of angiogenesis and inhibition of apoptosis were not well documented. This study was designed to determine expression of angiogenic marker CD34 antigen, antiapoptotic marker Bcl-2 oncoprotein, and proliferative marker Ki-67 antigen in the group of patients with IP. We matched up these findings to the group of patients with sinonasal carcinoma (SNC) and used chronic rhinosinusitis (CRS) patients as control group. In addition, we compared expression of the markers among IP patients who displayed distinctly different patterns of clinical behavior., Methods: Tissue samples were obtained from 46 surgically treated patients; 18 of them had a diagnosis of IP, 9 had documented SNC, and the remaining 19 patients had CRS. All specimens were stained using immunohistochemistry techniques for CD34 (mean vessel density [MVD]), Bcl-2, and Ki-67 antigens. Morphometry was evaluated by computer image analysis system., Results: We noted statistically significant differences in expression of CD34 antigen, Bcl-2 protein, and Ki-67 antigen (for all groups, ANOVA p < 0.001) among the investigated groups. The mean value of CD34 antigen was significantly higher in the IP group than in the CRS group, but it was below the levels of the SNC group. Compared with the cases not complicated by recurrence, the patients with recurrent IP exhibited higher MVD levels, while levels of bcl-2 and Ki67 protein expression did not differ in a significant way between recurrent and nonrecurrent cases. The significant positive correlations were observed between Bcl-2 protein and Ki-67 antigen in IP and SNC groups and between Bcl-2 protein and CD34 antigen in the CRS group., Conclusion: Our findings underscore importance of angiogenesis in the development and prognosis of IP and support further investigation of this aspect of IP tumor growth.

Background: Inverted papilloma (IP) is a benign, but locally aggressive neoplasm of the nasal cavity and paranasal sinuses. The mainstay of treatment of IP is surgical resection, but high rates of tumor recurrence have been reported. Cyclo-oxygenase-2 (COX-2) has been found to be overexpressed in many tumors and has been used successfully as a therapeutic target. The goal of this study is to highlight COX-2 expression in IP., Methods: Immunohistochemistry for COX-2 was performed on IP samples obtained during surgical resection between January 2012 and June 2013. The intensity of staining was evaluated by 2 head and neck pathologists blinded to the clinical features and outcomes. A positive stain was defined as having 10% or more of tumor cells exhibiting immunoreactivity., Results: The study includes 13 tumor samples from 7 females and 6 males. Mean age was 54.5 (range, 18-81) years. Tumor locations included: nasal septum (1), ethmoid (3), sphenoid (4), and maxillary (5) sinuses. No tumors demonstrated malignancy or dysplasia. Five (38%) of the 13 IP samples stained strongly positive for COX-2, and 3 of 13 (23%) stained weakly positive. There were no clinical differences in patients that stained strongly or weakly for COX-2., Conclusion: COX-2 overexpression was identified in 62% of cases of IP in this study, and strongly positive in 38% of cases. Larger studies are necessary to identify the true incidence of COX-2 expression for this tumor. Pharmaceuticals targeting COX-2 may eventually provide an additional therapeutic option for select cases of recurrent or unresectable IP., (© 2013 ARS-AAOA, LLC.)

Objective: To investigate the expression level and significance of osteopontin (OPN) and muscle segment homeobox2 (Msx2) in sinonasal inverted papilloma (SNIP), and the relationship with the process of SNIP malignant transfomation., Method: Immunohistochemical method was used to detect the expression of osteopontin and Msx2 in 32 cases of sinonasal inverted papilloma (SNIP), 30 cases of inflammatory nasal polyp paraffin tissue (INP) and 30 cases of sinonasal inverted papilloma with carcinoma. According to the pathology results SNIP were divided into mild dysplasia, moderate dysplasia, severe dysplasia. All the datas were analyzed by SPSS13.0., Result: The positive expression of OPN and Msx2 in the SNIP with carcinoma were all 100% (30/30), were significantly higher than the SNIP and INP, and the pairwise comparisons were all statistically significant (P < 0.05). The expression of OPN and Msx2 in the SNIP were divided according to pathological. There was significant difference between mild dysplasia and severe dysplasia group (P < 0.05), while there were not significant difference between light degree of dysplasia and moderate dysplasia group, moderate dysplasia and severe dysplasia group. And the expression of OPN and Msx2 was positively correlated in SNIP (P < 0.01)., Conclusion: OPN and Msx2 may play an important role in the pathway of progression of SNIP, which may be identified as the new therapeutic targets.

Objective: To explore the expression of Smac(second mitochondria-derived activator of caspase)and survivin on the growth, development, recurrence and carcinogenesis of the sinonasal inverted papilloma(NIP)., Method: Immunohistochemical method was used to detective the expression of Smac and survivin in 10 cases of (nasal cavity mucosae, NM), 45 cases of NIP. The NIP group including 25 cases of NIP without dysplasia, 11 cases of NIP with dysplasia, and 9 cases of NIP with malignant transformation to squamous cell carcinoma(SCC)., Result: The intensity of the positive expression of Smac in NIP was lower than NM, the intensity of the positive expression decreased with the decreasing degree of histological differentiation. There was significantly difference between NIP without dysplasia and SCC. The expression of survivin was negative in the control group, the expression intensity of NIP was enhanced. The degree of histological differentiation was lower, the intensity of the positive expression was higher. The expression between NIP without dysplasia and SCC had significantly differences. Smac negatively correlated with survivin(rs = -0.403, P<0.01)., Conclusion: Smac and survivin were associated with the growth and carcinogenesis of NIP.

Objective: To explore the expression and significance of survivin and proliferating cell nuclear antigen (PCNA) on the occurrence, proliferation, recurrence and carcinogenesis of the sinonasal inverted papilloma (SNIP)., Method: Immunohistochemical method was used to detect the expression of survivin and PCNA in 10 cases of nasal cavity mucosal (NM), 45 cases of SNIP and 9 cases of canceration SNIP., Result: The positive expression of survivin and PCNA increased gradually in NM,SNIP and canceration PCNA group, and there were significant difference between the three groups. But there was no correlation between survivin and PCNA in the tissue of SNIP (r = 0.135, P > 0.05)., Conclusion: Survivin and PCNA are involved in the growth and carcinogenesis of SNIP.

Sinonasal inverted papilloma (SIP) is a rare benign tumor featuring increased cell proliferation, a tendency toward squamous differentiation, recurrence and malignant transformation. The CCAAT enhancer binding proteins, C/EBPs, are transcription factors regulating the proliferation and differentiation of various types of cells, including epithelial cells. We prospectively investigated the production of these transcription factors and the related proliferation and differentiation targets, keratin-10, keratin-15 and cyclin-D1, in 26 SIP patients and 8 sinonasal polyposis cases suspected for SIP. Ten of these patients had one or more recurrences over follow-up periods of one to eight years. C/EBP-alpha and C/EBP-beta proteins were not found in normal-looking sinonasal epithelial cells. The proteins and RNAs were detected in SIP and, occasionally, in polyposis tissues. The production of these factors was not significantly correlated with age, sex, site, tumor size or medical history. By contrast, correlations were found between the levels of C/EBP-alpha and keratin-10 levels and between those of C/EBP-beta and keratin-15. C/EBP-alpha levels were also significantly correlated with cyclin-D1 levels. These data suggested that the C/EBPs are implicated in the regulation of cell proliferation and differentiation in SIP. Finally, recurrent SIP produced significantly larger amounts of C/EBP-alpha than non- recurrent tumors. These results implicate CCAAT enhancer binding proteins in the pathogenesis of SIP and highlight the role of C/EBP-alpha as a candidate marker for tumor recurrence.

Inverted urothelial carcinoma (UC) without papillary areas is very rare; only 31 cases of three papers have been reported. The author herein reports three additional cases, and proposes the term "inverted variant" (IV) of UC. The materials were 3 cases of IV of UC, 5 cases of inverted papilloma (IP), and two cases of nested variant (NV) of UC. The three cases of IV of UC consisted of 56-year-old woman, 63-year-old man, and 78-year-old man. Presenting symptoms were hematuria in all cases. The cystoscopic findings were elevated tumors without papillary proliferations in all cases. The treatment was transurethral tumor resection (TUR-BT) in all cases. The sizes was 0.6 cm, 0.5 cm, and 3 cm. Microscopically, IV of UC showed inverted growth of atypical cells without papillary proliferations. Compared to IP, the inverted growth pattern was similar, but cytological atypia and thick trabeculae were noted in IV of UP while they were absent in IP. Compared to NV of UC, the growth pattern is different; NV of UC showed nested and vague tubular pattern. The cellular atypia is more pronounced in IV of UC than NV of UC. Immunohistochemically, p53 expression was seen in all the cases of IV of UC and in all the cases of NV of UC, while p53 expression was negative in all the cases of IP. Ki-67 labeling index was 25, 30 and 40% in IV of UC, 15 and 30% in NV of UC, and 3, 5, 6, 7, 9% in IP. Invasive features were seen in 1 case of IV of UC and 2 cases of NV of UC. In all cases of IV of UC, IP, and NV of UC, the TUR-BT, but one case of IV of UC, showed no recurrence after TUR-BT, while one case of IV of UC showed a recurrence. In conclusion, the IV and UC were structurally and cytologically very different from the NV of UC. The IV of UC was structurally similar to IP, but cellular atypia and thickened trabeculae were seen in IV and UC. p53 expression and Ki-67 labeling status were entirely different between in IV of UC and IP. The author proposes the term of IV of UC as a new clinicopathological entity.

Purpose: This study examined the early events in the neoplastic progression of the sinonasal inverted papilloma to squamous cell carcinoma from the viewpoint of chronic inflammation and apoptosis., Materials and Methods: In total, 118 archival slides stained with hematoxylin and eosin from 45 patients were graded according to histopathology (grades I-IV). Their representative portions were transferred to a tissue microarray, sections of which were stained immunohistochemically for cyclooxygenase-2, p53, bax, bcl-2, and nuclear factor κB., Results: Cyclooxygenase-2 expression was positively correlated with histopathologic grade, with higher expression in advanced grades. p53s were detected in all cores from advanced grades (III, IV), but not in early grades (I, II). The expressions of nuclear factor κB, bax, and bcl-2 were not correlated with the grade., Conclusions: A p53 mutation seems be a critical event for the malignant transformation of the sinonasal inverted papilloma. Cyclooxygenase-2-mediated inflammatory signals, activated as a consequence of the p53 mutation, may contribute to promoting the proliferation of the advanced sinonasal inverted papilloma., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: The scaffold protein IQGAP1 is a ubiquitously expressed 190 kDa protein that participates in protein-protein interactions, integrating diverse signaling pathways. In this study, we examined the expression of IQGAP1 in sinonasal inverted papillomas (IP) and sinonasal squamous cell carcinomas (SCC), which include IP with SCC (IPcSCC) and SCC alone. We also tried to elucidate whether the amount of IQGAP1 expression is related with any clinicopathologic features of sinonasal SCCs., Study Design: This was a retrospective study., Methods: The expression of IQGAP1 was analyzed by means of immunohistochemistry. The degrees of IQGAP1 expression and subcellular localization (rim formation) were analyzed with respect to the following clinicopathologic variables: age, gender, T stage, histologic differentiation, local recurrence, and distant metastasis., Results: The expression of IQGAP1 was significantly higher in patients with IPcSCC (3.62 ± 0.14), and SCC (2.93 ± 0.34) compared with IP (1.43 ± 0.26). The rim formation scale was significantly higher in IPcSCC (2.39 ± 0.24) compared with IP (1.68 ± 0.15). Distant metastasis in patients with SCC significantly correlated with an increased IQGAP1 rim formation (p = 0.011). Histologic differentiation was also significantly correlated with a positive staining scale for IQGAP1 in IPcSCCs (p = 0.038)., Conclusion: These results indicated that IQGAP1 expression is associated with both the histologic differentiation of IPcSCCs and is present in SCC cases where distant metastasis has occurred., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Objective: To evaluate the apurinic/apyrimidinic endonuclease 1 (APE1) expression in sinonasal squamous cell carcinomas (SCC) and to examine the correlation between APE1 expression patterns and various clinicopathological factors associated with sinonasal SCC that include SCC with inverted papilloma (SCCwIP) and SCC alone., Study Design: Case-control study., Setting: Chungnam National University Hospital., Subjects and Methods: The expressions of APE1 were analyzed by means of immunohistochemistry in 30 sinonasal SCC, including 14 SCC patients associated with IP and 16 patients with SCC alone. A total of 19 patients who had been diagnosed with chronic rhinosinusitis with nasal polyposis and who required endoscopic sinus surgery were used as the control group. The degrees of APE1 expression were analyzed with respect to the following clinicopathologic variables: age, sex, T stage, histologic differentiation, distant metastasis, and recurrence., Results: Cytoplasmic staining of APE1 was significantly higher in SCC compared with SCCwIP (68.75% vs 14.29%). Cytoplasmic staining of APE1 was significantly associated with T stage (P = .044) in SCC and histologic grade (P = .0025) in sinonasal SCC. Nuclear staining of APE1 was significantly associated with distant metastasis (P = .022) in SCC., Conclusion: These results suggest that the nuclear and cytoplasmic expression of APE1 may be related to tumor invasiveness and prognosis in sinonasal SCC. The suppression of APE1 expression can potentially be a new target for future sinonasal SCC therapies.

Objective: To investigate the expression of Fascin in sinonasal inverted papilloma (SNIP) and the relationship between Fascin expression and microvessel density (MVD)., Method: The expression of Fascin and CD34 were determined by immunohistochemistry in 30 cases of SNIP, 12 cases of nasal squamous cell carcinoma (NSCC) and 10 cases of normal inferior turbinate (IT) tissues. Meanwhile, CD34, measure of MVD, was counted at the same time., Result: Fascin was expressed in 17 of 30 (56.6%) cases of SNIP, 10 of 12 (83.3%) cases of NSCC and 2 of 10 (20.0%) cases of normal IT tissues. Expression of Fascin was significantly increased in SNIP and NSCC compared to normal tissues (P < 0.01). MVD counts was 23.64 +/- 2.74, 45.10 +/- 5.45, 74.76 +/- 7.32, respectively (P < 0.01). There was a positive correlation between the expression of Fascin and MVD counts., Conclusion: The high expression of Fascin and angiogenesis are significantly associated with biological behaviour of SNIP. Fascin may play an important role in the pathogenesis of SNIP and NSCC and synergic role with angiogenesis in progression of SNIP.

Objective: To explore the expression and significance of second mitochondria derived activator of caspase (Smac), X-linked inhibitor of apoptosis protein (XIAP)and cysteine containing aspartate specific protease 3 (caspase-3) in the growth, development and carcinogenesis of the nonnasal inverted papilloma (NIP)., Method: Immunohistochemical method was used to detect the expression of Smac, XIAP, caspase-3 in 10 cases of nasal cavity mucosae (NM) and 45 cases of NIP, the group of NIP including 25 cases of NIP without dysplasia, 11 cases of NIP with dysplasia, and 9 cases of NIP with malignant transformation to squamous cell carcinoma (SCC)., Result: The intensity of the positive expression of Smac, Caspase-3 in NIP were lower than NM, the intensity of the positive expression decreased with the decreasing degree of histological differentiation. There was a significant difference between NIP without dysplasia and SCC. It was presented with a progressive tendency for the expression of XIAP in the group of NM and NIP. The lower degree of histological differentiation, the higher intensity of the positive expression. The expression between NIP without dysplasia and SCC had a significant difference. Smac negatively correlated with XIAP (r(s) = -0.323, P < 0.05), XIAP negatively correlated with caspase-3 (r(s) = -0.408, P < 0.01), Smac positively correlated with caspase 3 (r(s) = 0.424, P < 0.01)., Conclusion: Smac, XIAP, caspase 3 might be associated with the growth and carcinogenesis of NIP.

Background: Gelsolin is an actin-binding protein with multiple cellular functions including apoptosis and is reported to be down-regulated in various cancers and premalignant lesions. The objective of this study was to identify gelsolin and caspase-3 expression in inverted papilloma (IP) and investigate the role of gelsolin in the progression of IP related to apoptosis., Methods: Specimens from 30 patients with nondysplastic IP were retrieved. The percentage of surface epithelium covered with squamous metaplastic epithelium was assessed. Immunohistochemically demonstrated gelsolin and caspase-3 expression were compared between IP and adjacent control mucosa. We analyzed the correlations among gelsolin expression, caspase-3 expression, and the degree of squamous metaplasia in IP., Results: The degree of squamous metaplasia of surface epithelium was inversely correlated with gelsolin (r = -0.610; p < 0.001) and caspase-3 expression (r = -0.433; p = 0.017). Gelsolin expression in IP was significantly lower than that in the control when >50% of surface epithelium showed squamous metaplasia (p = 0.015). Caspase-3 also showed diminished expression when >50% of surface epithelium had undergone squamous metaplasia (p = 0.035). Gelsolin and caspase-3 expression showed no significant differences when the degree of squamous metaplasia was ≤50%. Gelsolin and caspase-3 expression levels in IP had a positive relationship (r = 0.557; p = 0.001)., Conclusion: Progression of IP may be related to an insidious decrease in caspase-3-mediated apoptosis, and down-regulated gelsolin expression may be correlated with the decrease in apoptosis, especially in more highly progressed IP in which >50% of surface epithelium has undergone squamous metaplasia.

Background: The purpose of this study of human papillomavirus (HPV), Epstein-Barr virus (EBV), p21, and p53 in sinonasal inverted papilloma (IP) was to help elucidate its pathogenesis., Methods: Seventy-three IPs, 48 nasal polyps, and 85 hypertrophied turbinates were subjected to HPV polymerase chain reaction (PCR) study. Seventy-three IPs, 30 nasal polyps, and 32 hypertrophied turbinates were subjected to EBV in situ hybridization (ISH), p21, and p53 immunohistochemical (IHC) studies., Results: HPV was positive in 3 of 73 IPs (4.1%). All specimens were EBV negative. In all, 99% of IPs showed strong and diffuse p21 nuclear reactivity. Most nasal polyps and hypertrophied turbinates showed weak to moderate immunoreactivity of the basal and parabasal cells. Only focal p53 immunoreactivity of the basal and parabasal cells was found in 19% of IPs and 40% of nasal polyps., Conclusions: HPV prevalence of our IP is low. EBV is not present in IP. High p21 and low p53 expression in IP suggests a non-p53-dependent regulation pathway., (Copyright © 2011 Wiley Periodicals, Inc.)

Objective: Inverted papilloma is associated with sinonasal squamous cell carcinoma. This study aimed to investigate the epigenetic regulation of the tumour suppressor gene DLEC1 in inverted papilloma and sinonasal squamous cell carcinoma., Methods: DLEC1 gene expression was investigated by quantitative real-time polymerase chain reaction (QRT-PCR) in normal mucosa, inverted papilloma, and squamous cell carcinoma tissues. Methylation-specific PCR and subsequent autosequencing were also used to examine the methylation status of DLEC1 promoter and the involved mechanism. DLEC1 expression in a large validation set was evaluated by immunohistochemistry (n  =  25 in each group)., Results: DLEC1 was downregulated in inverted papilloma and squamous cell carcinoma tissues compared to normal mucosa (p < .01 in QRT-PCR and immunohistochemistry), with squamous cell carcinoma more repressed (p < .05 in QRT-PCR and immunohistochemistry) than inverted papilloma tissues. DLEC1 promoter hypermethylation was found in squamous cell carcinoma tissues., Conclusion: Repression of DLEC1 in squamous cell carcinoma tissues is associated with promoter hypermethylation. DLEC1 is downregulated in sinonasal squamous cell carcinoma and inverted papilloma and has a distinct mechanism.

Objective: To investigate the expression and significance of muscle segment homeobox2 (Msx2) and topo II-alpha in sinonasal inverted papilloma (SNIP), and the relationship in the process of malignant transformation of SNIP., Method: Immunohistochemical method was used to detect the expression of Msx2 and topo II-alpha in 32 cases of SNIP, 30 cases of inflammatory nasal polyp (INP) and 30 cases of SNIP with carcinoma. According to the pathology results, SNIP were divided into mild atypical hyperplasia, moderate atypical hyperplasia and severe atypical hyperplasia., Result: The mean optical density of Msx2 in SNIP and SNIP with carcinoma tissues were 0.2183 +/- 0.0598 and 0.2521 +/- 0.0761,which were significantly higher than 0.1878 +/- 0. 0372 in the INP tissue (P<0.05 or 0.01). The mean optical density of topo II-alpha in SNIP and SNIP with carcinoma tissues were 0.2303 +/- 0.0397 and 0.2666 +/- 0.0483, which were significantly higher than 0.1978 +/- 0.0388 in the NIP tissue (P<0.01). There were significant difference of Msx2 and topo II-alpha in SNIP between any two of the three groups divided according to pathological morphology (P<0.01 or 0.05). The expression of Msx2 and topo II-alpha in SNIP were positively correlated (P<0.05)., Conclusion: Msx2 and topo II-alpha may play an important role in the occurrence and development of SNIP. So it can be used as new therapeutic targets.

Objective: To study the expressions of FSCN1 and HGF in nasal inverted papilloma (NIP) and explore their role in occurrence and development of this disease., Method: Immunohistochemical method was used to determine the expression of FSCN1 and HGF in 12 cases of chronic hypertrophic rhinitis, 40 cases of NIP and 14 cases of NIP with malignant transformation., Result: FSCN1 was expressed in 52.5% of NIP, 78.6% of NIP with malignant transformation and 8.3% of inferior turbinate of chronic hypertrophic rhinitis. Expression of FSCN1 was significantly higher in NIP and NIP with malignant transformation than in inferior turbinate (P<0.05). HGF was expressed in 85.7% of NIP with malignant transformation and 8.3% of inferior turbinate. Expression of HGF was significantly higher in NIP with malignant transformation than in inferior turbinate (P<0.05). HGF was expressed in 40.0% of NIP,which was higher than that of inferior turbinate. Expression of HGF was positively related to expression of FSCN1 in NIP and NIP with malignant transformation., Conclusion: The abnormal expression of FSCN1 and HGF may be closely correlated with NIP and its malignant process. Analysis of FSCN1 and HGF expression in NIP may be useful in predicting malignant transformation.

Objective: To determine the expression of vascular endothelial growth factor (VEGF) and their receptor in nasal inverted papillomas (NIP) and to clarify the function of VEGF in the occurrence of NIPs and the correlation with malignant phenotype., Method: VEGF and its receptor (flk-1), expression were examined by immunohistochemistry using LSAB method in sections of NIP from 48 patients and squamous carcinoma from 8 patients., Result: All the epithelium together with the adjacent vascular and stroma,expressed increased positive staining of VEGF and flk-1 with the degree of atypical hyperplasia in epithelium. The VEGF/flk-1 expression in epithelium was significantly stronger in severe atypical hyperplasia than that in mild atypical hyperplasia, and same in mild atypical hyperplasia than in NIPs (P<0.01)., Conclusion: VEGF/flk-1 participate in the growth of NIPs. The enhanced VEGF/flk-1 in the epithelium may be identified as one of the parameters in judging malignant transformation of NIPs.

Background: E-cadherin and &#946;-catenin are molecules that mediate cell-cell adhesion in normal epithelium. Aberrant expression of these adhesion molecules results in the loss of intercellular adhesion, with possible cell transformation and tumour progression. We determined the role of E-cadherin and &#946;-catenin in the pathogenesis of sinonasal inverted papilloma (IP) and its malignant transformation., Methods: We determined the expression of E-cadherin and &#946;-catenin by immunohistochemistry in paraffin-embedded tissue of 21 subjects with nasal polyps, 56 with IPs, 7 IPs with dysplasia and 18 IPs with squamous cell carcinoma (SCC). The clinicopathological variables of the IPs with SCC correlated with the degree of expression of E-cadherin and &#946;-catenin., Results: The degree of expression of E-cadherin and &#946;-catenin in the cell membrane was significantly lower in IPs with SCC than in nasal polyps and IPs. The degree of expression of &#946;-catenin was significantly lower in IPs with SCC with a malignant proportion &gt; 50% compared to a malignant proportion &#8804; 50%. However, there was no significant association between the degree of expression of E-cadherin and &#946;-catenin and clinicopathological variables, such as age, gender, T stage, tumour differentiation, or SCC type (metachronous vs. synchronous). In addition, there was no significant relationship between recurrence or survival rate in IPs with SCC and the degree of expression of E-cadherin or &#946;-catenin in the cell membrane or nuclear &#946;-catenin., Conclusion: Decreased expression of E-cadherin and &#946;-catenin in the cell membrane may be associated with carcinogenesis of IPs and help predict malignant transformation in sinonasal IPs.

Background: The purpose of this study was to investigate the presence of CD4(+) CD25(+) FOXP3(+) regulatory T (Treg) cells both in peripheral blood and local tumors in patients with nasal inverted papilloma (NIP)., Methods: By using flow cytometry, the frequencies of CD4(+) CD25(+) FOXP3(+) Treg cells in both peripheral blood and tissues from 18 patients with NIP and 8 control subjects were determined. CCL22 and CCL17 proteins in NIP tumors were analyzed by using enzyme-linked immunosorbent assay. The suppressive capacity of Treg cells was estimated by WST-8 and enzyme-linked immunosorbent assay (ELISA; interferon-gamma [IFN-γ] and interleukin-4 [IL-4]) analysis., Results: Patients with NIP showed increased CD4(+) CD25(+) FOXP3(+) Treg cell frequencies in tumor tissues and CD4(+) T cell fraction rather than in peripheral blood. CCL22 increased in NIP tumors. Phytohemagglutinin (PHA)-induced proliferation and cytokine production of CD4(+) CD25(-) T cells were suppressed equally well by CD4(+) CD25(high) cells from both patients with NIP and controls., Conclusion: Our study demonstrated the increased frequencies of CD4(+) CD25(+) FOXP3(+) Treg cells in NIP tumors, which might be influenced by CCL22., (Copyright © 2010 Wiley Periodicals, Inc.)

Objective: To study the clinicopathologic features of urothelial hyperplastic lesion with an endophytic growth pattern and the role of immunohistochemistry and multitargeted fluorescence in situ hybridization (FISH) in the differential diagnosis., Methods: Forty-one cases of urothelial lesions exhibiting endophytic growth patterns were reviewed and reclassified as inverted papilloma, urothelial carcinoma with an endophytic growth pattern, and florid von Brunn nest. The gains of chromosomes 3, 7, and 17 and loss of 9p21 was detected by FISH, and performed immunohistochemical staining for CK20, p53, and Ki-67. Follow-up data of 12 cases were obtained., Results: (1) Twelve inverted papillomas sized 1.2 cm in average, consisted of anastomosing cords and nests with uniform width distribution involving the lamina propria, the central portion contained streaming cells with squamous metaplasia, and the periphery showed palisading. No or rare atypia and mitosis were found. Focal exophytic papillary component lined by less than 6 layers of normal urothelium were observed in 4 cases. (2) Twenty-four urothelial carcinomas with an endophytic growth pattern sized 2.1 cm in average, demonstrated the similar architecture with inverted papilloma, but exhibited thick columns and variable thickness of the cords, irregular size and shape of large nests with transition into solids. Mild to moderate cytologic atypia was shown, and mitotic figures ranged 1 to 8 per 10 HPFs. Exophytic papillary component was not observed in 3 cases, but the superficial urothelium showed dysplasia, while coexisted exophytic component in other cases was associated with low malignant potential or low grade tumor. (3) Five florid von Brunn nests sized 0.9 cm in average, had normal or hyperplastic urothelium, variable nests with cysts compacted in lamina propria, no cytologic atypia and mitosis. Twenty-one of 24 (79.1%) urothelial carcinomas with an endophytic growth pattern displayed abnormally positive results by multitargeted FISH, whereas all inverted papillomas and florid von Brunn nests were negative. Immunohistochemically, CK20 was weakly positive in 2 cases of urothelial carcinoma with an endophytic growth pattern, and negative in all inverted papillomas and florid von Brunn nests. p53 weakly stained 5% to 50% nuclei of the tumor cells in 16 cases of urothelial carcinomas with an endophytic growth pattern and 1 inverted papilloma. 1%-5% tumor cells expressed Ki-67 in urothelial carcinoma with an endophytic growth pattern, and less than 1% in inverted papilloma and florid von Brunn nests. Follow-up study revealed that 2 cases of urothelial carcinoma with an endophytic growth pattern had developed invasive carcinoma, underwent cystectomy, and metastasized remotely. No recurrence occurred in cases of inverted papilloma., Conclusions: Benign and malignant urothelial lesions with an endophytic growth pattern present histologic overlapping. Urothelial carcinoma with an endophytic growth pattern displays unique characteristics in morphology and immunohistochemistry. Multitargeted FISH analysis is helpful in the differential diagnosis.

Background: It has been suggested that sinonasal inverted papilloma (IP) can progress to squamous cell carcinoma (SCC); however, mechanisms of malignant transformation are not fully understood. This study investigated alterations in the expression of cell cycle-related proteins in a multistep process of malignant transformation of IPs., Methods: The expression of cell cycle-related proteins, including p53, p21, p16, and p63, was evaluated by immunohistochemistry in 21, 56, 7, and 18 cases of nasal polyps, IPs, IPs with dysplasia, and IPs with SCC, respectively. Furthermore, we determined the possible correlation between the expression of these proteins and clinicopathological variables in patients with IPs with SCC., Results: Expression of p53 was found only in 8 of 18 IPs with SCC (44.4%). The frequency of p21 positivity was significantly higher in IPs with dysplasia (71.4%) and IPs with SCC (77.8%) compared with nasal polyps (0%) and IPs (12.5%). A p16 positivity was observed in 82.1% of IPs and 57.1% of IPs with dysplasia, whereas 83.3% of IPs with SCC showed an apparent loss of p16 protein expression. A p63 positivity was found in all specimens, but the percentage of positive cells was significantly increased in IPs with dysplasia and IPs with SCC compared with nasal polyps and IPs. There was no significant correlation between the expression of these proteins and clinicopathological variables, such as tumor stage, histological differentiation, and the proportion of malignant areas in patients with IPs with SCC., Conclusion: Alteration of cell cycle-related proteins may contribute importantly to the malignant transformation from IP to SCC.

Schneiderian papillomas are uncommon benign tumors of the sinonasal area. They are prone to local aggressiveness and recurrence, and some undergo malignant progression. We analyzed specimens obtained from 67 Chinese patients who had presented to the ENT department of a regional hospital with biopsy-proven schneiderian papilloma. Seven of these patients had either synchronous or metachronous carcinoma, 1 of whom had pure carcinoma in situ. For each case, we documented the morphology, immunohistochemical expression of tumor suppressor genes p53 and p16, and any association with human papillomavirus (HPV) infection as detected by either polymerase chain reaction or in situ hybridization techniques. We found that severe dysplasia and p53 positivity were strongly associated with malignant progression. Association with HPV was demonstrated in 22 of the 67 patients (33%); the association was strongest among patients with exophytic papillomas and carcinomas. The effect of HPV in papilloma oncogenesis probably begins during the early phase, while other factors are responsible for progression to carcinoma. We conclude that p53-positive, dysplastic schneiderian papillomas warrant aggressive surgical treatment.

Background: Dysregulation of cysteinyl cathepsins and their inhibitors, cystatins (stefins), were implied in progression of tumorgenesis; nevertheless, their role in sinonasal inverted papilloma (IP) is still unrecognized., Methods: The differential expression of cathepsins and stefins in IP and normal tissues were revealed by data of human Affymetrix U133A gene chips, real-time polymerase chain reaction (PCR) and immunohistochemistry., Results: Among the cathepsins and stefins family, expression of cathepsin S and stefin A were most differentially expressed (down- and up-regulated, respectively) in IP tissue as compared with normal tissues. Their expression levels were validated by real-time PCR, which showed the expression level of cathepsin S was significantly down-regulated, whereas the expression of stefin A was significantly up-regulated in IP tissue compared to normal sinus mucosa. Using immunohistochemistry, expression of cathepsin S was observed in stromal and epithelial area macrophages of normal sinus mucosa, but no obvious expression of cathepsin S was found in IP tissue. In contrast, over-expression of stefin A was present in nearly all layers of the proliferative squamous cells of IP, but expression of stefin A was only detected in a scattered area of normal sinus mucosa., Conclusion: Down-regulation of cathepsin S and up-regulation of its endogenous inhibitor, stefin A, were found in IP tissues as compared with their expression level in normal sinus mucosa tissues. The biological significance of inverse expression of both stefin A and cathepsin S in sinonasal IP need further investigation in the future.

This study investigated the role of human papillomavirus (HPV) in Schneiderian papillomas (SPs) to determine whether HPV is associated with the pathogenesis of particular histologic subtypes and whether p16(INK4a) can be used as a surrogate marker for HPV detection. Twenty-seven papilloma specimens (19 inverted [IPs], 6 exophytic [EPs], 1 oncocytic [OP] and 1 mixed) were collected from 23 patients. Purified SP DNA extracts were tested for HPV by PCR using GP5 +/GP6 + primers; HPV genotyping was performed by dot blot hybridization. PCR positive specimens were screened for HPV by biotinyl-tyramide-based chromogenic in situ hybridization (CISH). Immunohistochemsistry (IHC) for the HPV L1 capsid protein and for p16(INK4a) was performed on all specimens. HPV was detected by PCR in 16/27 (59.3%) SPs; 9/19 (47.4%) IPs; 6/6 (100%) EPs [p = 0.051], and 1/1 (100%) mixed SP. HPV was not detected in the single OP. High risk genotypes were detected in 4/9 IPs (44.4%) and 0/6 EPs (0%) [p = 0.10]. Seven of 16 PCR positive SPs were also CISH positive for HPV: 5/6 EPs (83.3%) and 1/9 IP (11.1%) [p = 0.01]. IHC for the L1 capsid protein was positive in 2 SPs (1 EP and 1 mixed). p16(INK4a) staining was seen in 14/16 (87.5%) PCR positive SPs and in 10/11 (90.9%) PCR negative SPs (p = 1.00). In summary, this study demonstrates a strong association between HPV and EPs, however, its role in IPs remains less well-defined. Further, p16(INK4a) is not a useful surrogate marker for HPV detection across the various SPs.

Objective: Proteomics-based approach was applied to analyze and compare the difference of proteins among human nasal inverted papilloma (NIP), nasal polyposis and normal nasal mucosa, in order to screen different proteins as marker., Methods: The total proteins of NIP, nasal polyposis and normal nasal mucosa were separated by two-dimensional gel electrophoresis (2-DE). Protein image obtained by using the gel of Calibrated GS-800 Densitometer system, and determined different protein spots., Results: Six differential proteins between NIP and nasal polyp tissue were identified, which were galectin-1, Manganese-superoxide dismutase, galectin-7, trichostatin A, prohibitin and transferring. All of them were increased in NIP., Conclusions: Six differential proteins were possibly involved in NIP, which provided a new way for discriminating NIP from nasal polyposis. The data would be good for the establishment of NIP protein 2-DE map.

Objectives/hypothesis: We sought to investigate the role of desmoglein 3 in pathogenesis of sinonasal inverted papilloma (IP) and its malignant transformation., Methods: 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., Results: 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)., Conclusions: 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.