Factors Associated with Dysplastic Changes in Sinonasal Inverted Papilloma: Study of Tumor Infiltrating Lymphocytes (TILs) FOXP3, CD4, CD8, and expression of p53.

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.

Decreased Expressions of CK1α and PTEN 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.

Fluorescence grid analysis for the evaluation of piecemeal surgery in sinonasal inverted papilloma: a proof-of-concept study.

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 (FImean), with SNIP tissue showing a median FImean 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.

Increase in IL-17-positive cells in sinonasal inverted papilloma.

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.

Human papillomavirus and infiltration of CD8- and Foxp3-positive immune cells in sinonasal inverted papillomas.

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.

ErbB1 and ErbB2 overexpression in patients with sinonasal inverted papilloma and inverted papilloma with squamous cell carcinoma in China.

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.

Putative biomarkers of malignant transformation of sinonasal inverted papilloma into squamous cell carcinoma.

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.

Clinical Implications of Incidental Sinonasal Positive FDG Uptake on PET-CT.

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.

Distinctive expression profiles of Caveolin-1 and Notch-1 protein in patients with nasal polyps or sinonasal inverted papillomas.

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.

The analysis of expression of p16 protein in group of 53 patients treated for sinonasal inverted papilloma / Análise da expressão da proteína p16 em um grupo de 53 pacientes tratados para papiloma invertido nasossinusal

Abstract 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.

Resumo Introdução: Papiloma invertido nasossinusal constitui um problema terapêutico relevante devido ao caráter destrutivo do crescimento, a tendência à recorrência e a possibilidade de transformação maligna. Assim, muitas tentativas têm sido realizadas para identificar fatores de risco para ocorrência de papiloma invertido, bem como pesquisas para encontrar marcadores que permitam a detecção precoce de tumores e a utilização de terapia adequada. Um fator de risco amplamente conhecido de papiloma invertido é a infecção pelo HPV. Um dos marcadores da infecção por HPV e do efeito contínuo dessa alteração (embora suscite alguma controvérsia) é a expressão da proteína p16. Objetivo: Analisar a correlação entre a expressão de p16 como um substituto da infecção pelo HPV no material histopatológico analisado e as variáveis epidemiológicas, recorrências ou transformação maligna. Método: O estudo retrospectivo inclui um grupo de 53 pacientes (18 mulheres e 35 homens) submetidos a tratamento para papiloma invertido nasossinusal de 2002 a 2012. A intensidade da expressão da proteína p16 no material histopatológico foi pontuada como: 0 - sem expressão, 1 - expressão difusa (limite) e 2 - expressão positiva; ou 0 - sem expressão/expressão difusa (limite); 1 - expressão positiva. O Comitê de Ética aprovou o estudo (1.089/12; 245/13). Resultados e conclusão: Não houve relação estatisticamente significante entre a expressão de p16 e a idade dos pacientes, o tabagismo, a localização tumoral e o estadiamento tumoral de acordo com a classificação de Krouse e Cannady, presença de displasia ou ocorrência de recidiva.

The analysis of expression of p16 protein in group of 53 patients treated for sinonasal inverted papilloma.

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.

Expression of P53 and isoforms in bening and malignant lesions of the head and neck.

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.

Roles of human papillomavirus infection and stathmin in the pathogenesis of sinonasal inverted papilloma.

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.

A clinical and molecular review of inverted papilloma of the urinary tract: how to handle?

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.

[Expression and significance of C/EBPα and CK10 in nasal inverted papilloma].

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.

Conjunctival inverted squamous papilloma: a case report with immunohistochemical analysis and review of the literature.

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.

[The expression and significance of programmed cell death 5 and Bcelllymphoma/lewkmia-2 in sinonasal squamous cell carcinoma].

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.

[Expression and significance of PTEN and HIF-1α proteins in sinonasal inverted papilloma].

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.

Galectin fingerprinting in naso-sinusal diseases.

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.

The immunoexpression of CD34, Bcl-2, and Ki-67 antigens in sinonasal inverted papillomas.

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.