Transformation Of Sinonasal Inverted Papilloma Research Articles

Comprehensive analysis of DNA methylation gene expression profiles in GEO dataset reveals biomarkers related to malignant transformation of sinonasal inverted papilloma

BackgroundDNA methylation may be involved in the regulation of malignant transformation from sinonasal inverted papilloma (SNIP) to squamous cell carcinoma (SCC). The study of gene methylation changes and screening of differentially methylated loci (DMLs) are helpful to predict the possible key genes in the malignant transformation of SNIP-SCC.Materials and methodsMicroarray dataset GSE125399 was downloaded from the Gene Expression Omnibus (GEO) database and differentially methylated loci (DMLs) were analyzed using R language (Limma package). ClusterProfiler R package was used to perform Gene Ontology (GO) analysis on up-methylated genes and draw bubble maps. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and its visualization analysis were analyzed to speculate the possible key Genes in SNIP-SCC malignant transformation. Subsequently, SNIP cases archived in our department were collected, tissue microarray was made, and immunohistochemical staining was performed to analyze the expression levels of UCKL1, GSTT1, HLA-G, MAML2 and NRGN in different grades of sinonasal papilloma tissues.ResultsAnalysis of dataset GSE125399 identified 56 DMLs, including 49 upregulated DMLs and 7 downregulated DMLs. Thirty-one genes containing upregulated DNA methylation loci and three genes containing downregulated DNA methylation loci were obtained by methylation microarray annotation analysis. In addition, KEGG pathway visualization analysis of 31 up-methylated genes showed that there were four significantly up-methylated genes including UCKL1, GSTT1, HLA-G and MAML2, and one significantly down-methylated gene NRGN. Subsequently, compared with non-neoplasia nasal epithelial tissues, the expression of HLA-G and NRGN was upregulated in grade I, II, III and IV tissues, while the expression of MAML2 was lost. The protein expression changes of MAML2 and NRGN were significantly negatively correlated with their gene methylation levels.ConclusionsBy analyzing the methylation dataset, we obtained four up-regulated methylation genes UCKL1, GSTT1, HLA-G and MAML2 and one down-regulated gene NRGN. MAML2, a tumor suppressor gene with high methylation modification but loss of protein expression, and NRGN, a tumor gene with low methylation modification but upregulated protein expression, can be used as biological indicators to judge the malignant transformation of SNIP-SCC.

Microvessel barrier dysfunction in sinonasal inverted papilloma-associated squamous cell carcinoma and its manifestation in dynamic contrast-enhanced MRI.

To date, an effective means to preoperatively predict the malignant transformation of sinonasal inverted papilloma (SIP) remains lacking due to similarities in clinical appearance. This study aimed to retrospectively evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and microvessel structure in tumors with histologically confirmed SIP and inverted papilloma-associated squamous cell carcinoma (IP-SCC), as well as correlate DCE-MRI findings with angiogenesis biomarkers. Absolute quantitative DCE-MRI parameters (Ktrans, Kep, Ve) based on the Tofts model and model-free semi-quantitative indices (Tpeak, WR, MaxSlope) of SIP (n=22) and IP-SCC (n=20) were investigated. Regions of interest (ROIs) were oriented according to the tumor subsites in the surgical records. Micro-vessel density (MVD) counts and tight junction protein (claudin-5) expression were evaluated in tumor specimens obtained during surgery. Differences in the above data were compared between the two groups. Correlations between DCE-MRI parameters and angiogenic biomarkers were analyzed. Compared with SIP specimens, IP-SCC specimens were characterized by a significantly higher MVD and a leakier microvessel barrier. The values of Tpeak and Ve were significantly higher for SIP than those for IP-SCC, whereas WR, MaxSlope, and Kep were significantly lower, indicating early enhancement and a faster dispersion model in IP-SCC. MVD was positively correlated with WR and Kep and negatively correlated with Tpeak. Tpeak was slightly positively correlated to claudin-5 expression. DCE-MRI can serve as a noninvasive biomarker of angiogenesis in the malignant transformation from SIP to IP-SCC. DCE-MRI may assist in the differentiation of malignancies and treatment selection.

Preoperative Prediction of Malignant Transformation of Sinonasal Inverted Papilloma Using MR Radiomics.

PurposeAccurate preoperative prediction of the malignant transformation of sinonasal inverted papilloma (IP) is essential for guiding biopsy, planning appropriate surgery and prognosis of patients. We aimed to investigate the value of MRI-based radiomics in discriminating IP from IP-transformed squamous cell carcinomas (IP-SCC).MethodsA total of 236 patients with IP-SCC (n=92) or IP (n=144) were enrolled and divided into a training cohort and a testing cohort. Preoperative MR images including T1-weighted, T2-weighted, and contrast enhanced T1-weighted images were collected. Radiomic features were extracted from MR images and key features were merged into a radiomic model. A morphological features model was developed based on MR morphological features assessed by radiologists. A combined model combining radiomic features and morphological features was generated using multivariable logistic regression. For comparison, two head and neck radiologists were independently invited to distinguish IP-SCC from IP. The area under the receiver operating characteristics curve (AUC) was used to assess the performance of all models.ResultsA total of 3948 radiomic features were extracted from three MR sequences. After feature selection, we saved 15 key features for modeling. The AUC, sensitivity, specificity, and accuracy on the testing cohort of the combined model based on radiomic and morphological features were respectively 0.962, 0.828, 0.94, and 0.899. The diagnostic ability of the combined model outperformed the morphological features model and also outperformed the two head and neck radiologists.ConclusionsA combined model based on MR radiomic and morphological features could serve as a potential tool to accurately predict IP-SCC, which might improve patient counseling and make more precise treatment planning.

NGS-based miRNome identifies miR-449 cluster as marker of malignant transformation of sinonasal inverted papilloma

Objectiveidentification of the miRNA expression profile in sinonasal inverted papilloma (SNIP) as a tool to evaluate the risk of transformation into sinonasal squamous cell carcinoma (SNSCC). Materials and Methodspaired tumour tissues and adjacent normal tissues were obtained from SNIP and SNSCC patients who had undergone surgical resection and used for next-generation sequencing (NGS)-based miRNome analysis. SNIP tissues with concomitant dysplasia (SNIP-DISP) were used as malignant transition samples. By comparing the deregulated miRNAs in SNIP and SNSCC, an miRNA cluster was identified and its physio- and clinical-pathological value was predicted. ResultsNGS identified 54 miRNAs significantly down- and upregulated in SNIP. Among them, the miR-449 cluster was upregulated in SNIP and could differentiate the benign tumour from normal tissue. Notably, the miR-449 cluster was found to be significantly underexpressed in SNSCC, and the cluster markedly changed in SNIP during the malignant transition into SNSCC. miRNA enrichment analysis and GO analysis revealed that miR-449 is involved in apoptotic and cell proliferation pathways. ConclusionsOur findings suggest that miR-449 may be involved in the molecular pathogenesis of SNIP and its malignant transformation into SNSCC. miR-449 might therefore be a useful tumour biomarker in patients with SNIP and may also have the potential to be used as a tool for detecting and monitoring the course of the possible malignant transformation.

Risk factors of malignant transformation of sinonasal inverted papilloma

Objective:To explore the risk factors of malignant transformation of sinonasal inverted papilloma （SNIP）, and to improve the accuracy of preoperative diagnosis of tumor. Methods:The clinical data of 89 patients with sinonasal inverted papilloma （SNIP group, n=60） and malignant transformation of sinonasal inverted papilloma （IP-SCC, n=29） were analyzed retrospectively. Clinical symptoms, medical history, endoscopic examination, characteristic of sinonasal CT scan and MR imaging were collected and compared between two groups. Then the indicators with significant differences between the two groups were used for binary logistic regression analysis. The logistic regression model was established to predict the malignant transformation risk factors of inverted papilloma and the prediction ability of the regression model was estimated. Results:The significant differences between the two groups were: symptoms, including nasal obstruction, purulent mucus, blood in the nasal discharge; long-term smoking history; tumor attached with purulent mucus; CT scan showing bone destruction of the orbital wall and skull base; MR Imaging showing convoluted cerebriform pattern （CCP） sign, intraorbital involvement, and dural enhancement of the skull base. The results of logistic regression analysis showed that the risk factors of malignant transformation of SNIP were blood in the nasal discharge, long-term smoking history, tumor with purulent discharge, orbital wall destruction on CT scan, disappearance of CCP and orbital involvement on MRI. The accuracy rate of regression model for predicting malignant transformation of IP is 75.0%, and the accuracy rate for benign inverted papilloma is 96.7%, and the overall accuracy of the model is 89.8%. Conclusion:The risk factors for predicting malignant transformation of SNIP are blood in the nasal discharge, long-term smoking history, tumor with purulent discharge, orbital wall destruction on CT scan, and disappearance of CCP sign and orbital involvement on MRI. It's necessary to analyze all of clinical factors in order to improve the accuracy of preoperative diagnosis of sinonasal inverted papilloma.

Prediction of malignant sinonasal inverted papilloma transformation by preoperative computed tomography and magnetic resonance imaging.

Accurate preoperative prediction of the malignant transformation of sinonasal inverted papilloma (SNIP) is essential for radical resection of tumours and prevention of recurrence. We here explored the predictive value of preoperative computed tomography (CT) and magnetic resonance imaging (MRI). The study was performed on 268 patients with SNIP with (n = 78) or without (n = 190) coexistent malignant transformation. We used univariate and multivariate logistic regression analysis method to screen for independent risk factors, and established a nomogram model. Finally, using receiver operating characteristic curves, we assessed the diagnostic value of the independent risk factors for malignant transformation of SNIP. We identified bone erosion on CT, change in convoluted cerebriform pattern (CCP) on MRI, and washout-type time intensity curve (TIC) of dynamic contrast-enhanced (DCE)-MRI were independent predictors of malignant transformation of SNIP. The scores of these three independent risk factors from the nomogram model were 10, 7 and 8, respectively. The area under the receiver operating characteristic curve for predicting SNIP malignancy was 0.954 for the nomogram model, 0.826 for bone erosion, 0.776 for washout-type TIC, and 0.810 for CCP mutation. Of the independent risk factors and related combination identified, the nomogram model based on bone destruction on CT, CCP mutation on MRI, and washout-type TIC of DCE-MRI had the best predictive value for malignant transformation of SNIP.

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

ObjectiveTo 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.MethodsTissue 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.ResultsA 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.ConclusionsThis 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.

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

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

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

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

Malignant transformation of sinonasal inverted papilloma and related genetic alterations: a systematic review.

Schneiderian papillomas are uncommon tumors which may develop within the nasal cavity and comprise three well-defined histological types: sinonasal inverted papilloma (SNIP), exophytic papilloma, and oncocytic papilloma. It is well known the rate of Schneiderian papilloma may also present a malignant degeneration and SNIP represents the most important subgroup in consideration of its frequency and malignant propensity. Although HPV infection is always considered the first event favoring the development of SNIP, however, it is not established as an eventual connection between viral actions and malignant transformation. In fact, different molecular mechanisms are suspected to play a crucial role in this process and, currently, many authors agree that only by improving our knowledge about these mechanisms it will be possible to achieve new and effective targeted therapies. So the aim of this study was firstly to systematically review the literature focusing on different biomarkers that could be implicated in the stages of SNIP malignant degeneration. Secondly, a systematic review with meta-analysis was performed to better define the incidence of sinonasal malignancies originating from Schneiderian papilloma (SNIP, exophytic papilloma, and oncocytic papilloma). Twenty-nine studies comprising a total of 3177 patients were statistically analyzed. Results showed a 9% (95% CI=7-11) overall rate of malignant transformation from Schneiderian papilloma. In conclusion, this analysis confirmed that the potential malignancy of Schneiderian papilloma should not be underestimated. On the other hand, our review showed the paucity of studies investigating the molecular alterations which may be related with the malignant transformation of SNIP.

Risk Factors of Recurrence and Malignant Transformation of Sinonasal Inverted Papilloma.

Sinonasal inverted papilloma is a relatively rare disease; however, it is prevalent enough for every ENT practitioner to encounter it several times throughout medical routines. Despite the developments in experimental and clinical medicine as well as surgical techniques, our knowledge of this disease is still inadequate. With improved imaging and better diagnostic techniques, proper diagnosis and qualification for surgical approaches leave no doubt. Although the endoscopic approach seems to be the gold standard for such condition, some cases may additionally require an external approach. Regardless of the type of surgery, postoperative management is crucial for both healing and long-term follow-up. Unfortunately, the procedures are still lacking in explicit and standardized postoperative management guidelines. Moreover, an important issue is still the need for a biomarker indicative of inverted papilloma and its malignant transformation. Several particles, within the spotlight of the researchers, have been SCCA, Ki-67, Bcl-2, Wnt proteins, and many more. Nevertheless, the topic requires further investigations.

Human papillomavirus infection and immunohistochemical expression of cell cycle proteins pRb, p53, and p16(INK4a) in sinonasal diseases.

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

The role of tissue factor pathway inhibitor-2 in malignant transformation of sinonasal inverted papilloma

The aim was to evaluate the potential role of tissue factor pathway inhibitor-2 (TFPI-2) in the process of malignant transformation of sinonasal inverted papilloma (SIP). We evaluated the expression of TFPI-2 in 23 SIP and 8 SIP with squamous cell carcinoma (IPcSCC), compared to 9 normal sinonasal mucosa by means of Western blot and immunohistochemistry staining. In addition, angiogenesis, vascular endothelial growth factor (VEGF) expression and microvessel density marked by CD105 staining were assessed. Correlation of TFPI-2 expression and angiogenesis in the process of malignant transformation of SIP was investigated. Western blot results demonstrated that the protein level of TFPI-2 in IPcSCC was significantly lower than that in the control group (P < 0.01). In addition, significant difference in TFPI-2 protein expression between SIP and IPcSCC was detected (P < 0.01). Higher number of microvessel per unit area (MVNA) was observed in IPcSCC compared to SIP (P < 0.01). Correlational analysis indicated positive correlation of VEGF and MVNA (r = 0.735), inverse correlation of TFPI-2 and MVNA (r = -0.318). However, no significant correlation between TFPI-2 and VEGF was detected. We conclude that TFPI-2 might be a regulatory molecule in the malignant potential of SIP. Down regulation of TFPI-2 is associated with increased MVNA in IPcSCC, which may be involved in the process of malignant transformation of SIP.

Malignant transformation of sinonasal inverted papilloma: retrospective analysis of 32 cases

To investigate the clinicopathological features and prognosis of patients with the malignant transformation of sinonasal inverted papilloma. Thirty-two consecutive cases encountered between January 1991 and January 2008 were retrospectively reviewed. Survival rates and prognostic factors were calculated with SPSS 17.0 software using the Kaplan-Meier method and multivariate Cox model survival analysis. The malignancy accounted for 8.99% of all types of sinonasal inverted papilloma. There were 25 males and 7 females, the median age was 56.5 years. The sites of tumor included 22 cases in nasal cavity and ethmoid sinuses, 10 cases in maxillary sinuses. The tumors included 21 high grade tumors, 8 intermediate grade tumors and 3 low grade tumors. Thirty-two patients were staged as T1(3/32), T2(10/32), T3(16/32), T4(3/32). According to the percentage of the malignant cell in the entire tumor tissue, 5 patients were in grade I, 5 patients were in grade II, 8 patients were in grade III, 14 patients were in grade IV. There were 3 distant metastasis in 32 patients; 19 patients underwent surgery plus postoperative radiotherapy, 10 underwent surgery alone and 3 underwent radiotherapy alone. The 5-year overall survival were 72.5%, and the median overall survival time was 62.2 months. Kaplan-Meier univariate survival analysis indicated that the clinical stages and treatment modalities were prognostic factors, and multivariate Cox model survival analysis confirmed that the clinical stages and treatment modalities were independent factors for overall survival (HR were 4.211 and 0.312, all P < 0.05). The morbidity of sinonasal inverted papilloma-associated malignancy is low, the clinical features were not specificity. The clinical stages and treatment modalities may affect the prognosis. Surgery plus postoperative radiotherapy are main treatment means.

Inflammation and apoptosis in malignant transformation of sinonasal inverted papilloma: the role of the bridge molecules, cyclooxygenase-2, and nuclear factor κB

PurposeThis 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 methodsIn 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. ResultsCyclooxygenase-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. ConclusionsA 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.

Pattern of expression of cyclooxygenase-2 in malignant transformation of sinonasal inverted papilloma

ObjectiveCyclooxygenases (COXs) are enzymes that catalyze the conversion of arachidonic acid to prostaglandins. Many studies have suggested that COX-2, the inducible form of COX, is important in carcinogenesis. However, little is known about the pattern of expression of COX-2 in a multistep process of malignant transformation of sinonasal inverted papilloma (IP). In this study, we investigated COX-2 expression in IPs, IPs with dysplasia, IPs with squamous cell carcinoma (SCC), and primary SCCs of sinonasal tract. Study designA retrospective study was conducted. SettingThe setting was a tertiary care referral center. Subjects and methodsThe expression of COX-2 was evaluated by immunohistochemistry in 56, 7, 18, and 17 cases of IPs, IPs with dysplasia, IPs with SCC, and primary SCCs, respectively. Furthermore, we investigated the possible correlation between the expression of COX-2 and clinicopathologic variables in patients with IPs with SCC and primary SCC patients. ResultsPositive immunoreactivity for COX-2 was observed in 3 (5.4%) of 56 IPs, 7 (38.9%) of 18 IPs with SCC, and 7 (41.2%) of 17 primary SCCs, whereas it was not observed in IPs with dysplasia. The percentage of tumors with COX-2–positive immunostaining was significantly higher in IPs with SCC and primary SCCs compared with benign IPs. There was no significant correlation between the expression of COX-2 and clinicopathologic variables, such as tumor stage, histologic differentiation, and the proportion of malignant areas in patients with IPs with SCC. ConclusionCyclooxygenase-2 may play an important role in the process of malignant transformation from IP to SCC.

Pattern of Expression of Cell Cycle–related Proteins in Malignant Transformation of Sinonasal Inverted Papilloma

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. 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. 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. Alteration of cell cycle-related proteins may contribute importantly to the malignant transformation from IP to SCC.

Expression of Cell Cycle-Related Proteins and E-cadherin/^|^beta;-catenin in the Process of Malignant Transformation of Sinonasal Inverted Papilloma

Expression of Cell Cycle-Related Proteins and E-cadherin/^|^beta;-catenin in the Process of Malignant Transformation of Sinonasal Inverted Papilloma

Increased expression of fascin associated with malignant transformation of sinonasal inverted papilloma

Fascin, an actin binding protein, usually expressed at a low level in normal epithelium, but is significantly increased in transformed epithelial cells and several common carcinomas. In this study, we examined the expression of fascin by immunohistochemistry in sinonasal epithelium with chronic inflammation (control group), exophytic papilloma (EP), inverted papilloma (IP) with dysplasia and cancerated IP (including carcinoma in situ and invasive squamous cell carcinoma, SCC), and furthermore investigated the relationship between fascin expression and formation of malignant IP. Fascin expression was immunohistochemically detected using monoclonal antibody against fascin in 86 paraffin embedded tissues, including 10 cases of sinonasal mucosa with chronic inflammation, 10 of EP, 45 of IP with dysplasia (45 cases were divided into three groups: IP with mild dysplasia, IP with moderate dysplasia, and IP with severe dysplasia, 15 cases each), and 21 of cancerated IP. The level of fascin expression was significantly higher in the neoplastic tissue than that in control group. Fascin expression increased gradually with the progression from sinonasal epithelium with chronic inflammation, IP with mild dysplasia, IP with moderate dysplasia, IP with severe dysplasia, to cancerated IP, and significant difference of fascin expression was observed between any two groups of the five. Precancerous lesions of IP exhibit elevated levels of fascin that may be associated with carcinogenesis of IP. Fascin may play a role in the formation of IP and EP.

Cell proliferation, apoptosis, and apoptosis inhibition in malignant transformation of sinonasal inverted papilloma

Conclusion. Increasing cell proliferation seems to be a very important factor in the development of inverted papilloma (IP). Apoptosis that was increased but weakly inhibited by Bcl-2 did not cause imbalance in the cell proliferation. Further increased cell proliferation in IP with dysplasia was an important mechanism of growth in dysplastic areas. Objectives. The purpose of this study was to compare cell proliferation, apoptosis, and apoptosis inhibition by Bcl-2 in IP. Patients and methods. Cell proliferation and apoptosis inhibition were detected by immunohistochemical staining with monoclonal antibodies to Ki-67 and Bcl-2. Apoptosis was detected by the transferase-mediated dUTP nick end-labeling (TUNEL) method. Results. As regards the Ki-67 index (KI), a significant increase was observed in IP with severe dysplasia, IP with carcinoma and invasive squamous cell carcinoma (SCC) compared with EP and IP with mild and moderate dysplasia. For the apoptosis index (AI), a significant increase was observed in IP with mild and moderate dysplasia compared with IP with carcinoma, invasive SCC and EP. For the Bcl-2 index (BI), a significant increase in expression was observed in IP with severe dysplasia and carcinoma and invasive SCC compared with control, EP and IP with mild dysplasia. Among IP, the KI (average 18.2%) was much higher than the AI (6.4%) and BI (4.1%).