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The recurrent sinonasal inverted papilloma (IP) could be transformed to sinonasal squamous cell carcinoma. We use protein expression patterns by immunohistochemical method to see whether the expression of p53, p16, p21, and p27 belongs to cell-cycle-regulators and PCNA (proliferating cell nuclear antigen) and Ki-67 the proliferation markers in sixt...
Citations
... Previous studies have shown that the correlation between Ki-67 and Proliferating Cell Nuclear Antigen (PCNA) interacting with CDK1 could lead to malignant transformation. Elevated palate, lung, and nasal epithelium clone protein (PLUNC) expression in SIPs was related to multiple recurrences in humans [34]. The expression of cell cycle-related proteins, including p53, p21, p16, and p63, was also evaluated here [35]. ...
Background: This study aimed to explore candidate genes involved in the pathogenesis of sinonasal inverted papilloma (SNIP) using bioinformatic analysis and experimental verification.
Methods: For this, gene expression profiles (GSE193016) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) being used to analyze the functions and pathways of DEGs. Co-expression networks were established using single-sample gene set enrichment analysis (GSEA). Furthermore, Search Tool for the Retrieval of Interacting Genes (STRING), Cytoscape, Molecular Complex Detection (MCODE), and Cytohubba were used to construct protein–protein interaction (PPI) networks, screen hub DEGs, and identify hub genes, with a miRNA-TF-hub gene regulatory network also being constructed. Finally, expression levels of identified hub genes were verified using RT-qPCR.
Results: As a result, 985 DEGs were identified, including 343 upregulated and 642 downregulated genes. Functional enrichment analyses showed that upregulated DEGs were significantly enriched in epidermal development, cornification, keratinocyte differentiation, epidermal cell differentiation, and skin development. Meanwhile, downregulated DEGs were significantly enriched in muscle contraction, extracellular structure organization, muscle system process, extracellular matrix organization, and regulation of membrane potential. The top eight hub genes were MAD2L1, CDC20, CCNB2, CCNB1, AURKB, NDC80, KIF11, and DLGAP5. During the validation stage, the expression of MAD2L1 was significantly higher in patients with SNIP than in those with normal nasal mucosa.
Conclusions: Overall, this study identified key genes associated with SNIP and their biological functions. Furthermore, a variety of predicted genes involved in the cell cycle were found to be connected to SNIP pathogenesis and malignant transformation. MAD2L1may play an important role in SNIP pathogenesis, providing novel insights into the occurrence and development of SNIP.
... Increased cell proliferation unopposed by programmed cell death, as seen in many other malignancies, is one proposed mechanism behind IP transformation. All studies on the subject agree on increased expression of Ki-67, a known marker of cell proliferation, during this process [5][6][7][8][9][10][11][12][13][14]. However, due to heterogeneity in the tissues analyzed and the interpretation of immunostaining, these results cannot be sum-marized together. ...
... Increased cell proliferation unopposed by programmed cell death, as seen in many other malignancies, is one proposed mechanism behind IP transformation. All studies on the subject agree on increased expression of Ki-67, a known marker of cell proliferation, during this process [5][6][7][8][9][10][11][12][13][14]. However, due to heterogeneity in the tissues analyzed and the interpretation of immunostaining, these results cannot be summarized together. ...
... For instance, expression of the CDKI p27 was observed to be lower in both primary SNSCC and IP-derived SNSCC with respect to IP alone [5,10,11]. ...
Sinonasal neoplasms are uncommon diseases, characterized by heterogeneous biological behavior, which frequently results in challenges in differential diagnosis and treatment choice. The aim of this review was to examine the pathogenesis and molecular mechanisms underlying the regulation of tumor initiation and growth, in order to better define diagnostic and therapeutic strategies as well as the prognostic impact of these rare neoplasms. A systematic review according to Preferred Reporting Items for Systematic Review and Meta-Analysis criteria was conducted between September and November 2022. The authors considered the three main histological patterns of sinonasal tumors, namely Squamous Cell Carcinoma, Intestinal-Type Adenocarcinoma, and Olfactory Neuroblastoma. In total, 246 articles were eventually included in the analysis. The genetic and epigenetic changes underlying the oncogenic process were discussed, through a qualitative synthesis of the included studies. The identification of a comprehensive model of carcinogenesis for each sinonasal cancer subtype is needed, in order to pave the way toward tailored treatment approaches and improve survival for this rare and challenging group of cancers.
... "Nasal-type Natural Killer/T-cell Lymphoma Occurring at the Site from Which a Sinonasal Inverted Papilloma was Previously Schneiderian papillomas. The sinonasal tract, middle ear, kidney, ureter, bladder, and urethra are all possible areas for IP occurrence [3,4]. The annual incidence of sinonasal inverted papillomas (SNIPs) is between 0.2 and 1.5 per 100,000 population [1,2]. ...
... At present, the specific mechanisms of SNIP-associated malignancy remain unclear [5]. Tsou., et al. indicated that Ki-67 and proliferating cell nuclear antigen interacted with cyclin-dependent kinase 1, which might lead to the malignant transformation of SNIPs [3]. Udager., et al. proposed that the activation of epidermal growth factor receptor mutations play an essential role in the pathogenesis of SNIPs and associated SCC [9]. ...
... Histologically, the most common malignancy associated with SNIPs is SCC. In recent studies, malignant transformation to SCC has been observed in 11% of SNIPs [2][3][4][5]. Compared with pure primary SCC, malignant trans-51 Nasal-type Natural Killer/T-cell Lymphoma Occurring at the Site from Which a Sinonasal Inverted Papilloma was Previously Resected: A Rare Case Report Citation: Bo-Nien Chen. "Nasal-type Natural Killer/T-cell Lymphoma Occurring at the Site from Which a Sinonasal Inverted Papilloma was Previously formed SCC has a better therapeutic outcome. ...
... Moreover, Liu et al. reported that high CDK1 expression is closely associated with poor clinical prognosis in breast cancer [28]. In HNSCC, some studies have demonstrated that high CDK1 expression at both the mRNA and protein levels may occur during the early stages of carcinogenesis [29]，and that CDK1 overexpression is related to tumorigenesis [30] and malignant transformation [31]. Furthermore, some research has suggested that CDK1 is related to anti-cancer activity and enhanced sensitivity to radiotherapy and anti-cancer drugs in HNSCC cells [32,33]. ...
Head and neck squamous cell carcinoma (HNSCC) is the most common subtype of head and neck cancer; however, its pathogenesis and potential therapeutic targets remain largely unknown. In this study, we analyzed three gene expression profiles and screened differentially expressed genes (DEGs) between HNSCC and normal tissues. The DEGs were subjected to gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), protein–protein interaction (PPI), and survival analyses, while the connectivity map (CMap) database was used to predict candidate small molecules that may reverse the biological state of HNSCC. Finally, we measured the expression of the most relevant core gene in vitro and examined the effect of the top predicted potential drug against the proliferation of HNSCC cell lines. Among the 208 DEGs and ten hub genes identified, CDK1 and CDC45 were associated with unfavorable HNSCC prognosis, and three potential small molecule drugs for treating HNSCC were identified. Increased CDK1 expression was confirmed in HNSCC cells, and menadione, the top predicted potential drug, exerted significant inhibitory effects against HNSCC cell proliferation and markedly reversed CDK1 expression. Together, the findings of this study suggest that the ten hub genes and pathways identified may be closely related to HNSCC pathogenesis. In particular, CDK1 and CDC45 overexpression could be reliable biomarkers for predicting unfavorable prognosis in patients with HNSCC, while the new candidate small molecules identified by CMap analysis provide new avenues for the development of potential drugs to treat HNSCC.
... Even the current WHO classification has not included "carcinoma ex sinonasal papilloma" among its topics, which might negatively affect the precise diagnosis of such a category [28]. It should also be noted that the IHC profile of this group is yet to be established, despite several IHC studies conducted in this context [27,[29][30][31][32][33][34][35][36][37][38][39][40]. ...
Sinonasal inverted papilloma (IP) has a propensity for malignant transformation. Although the IP-associated squamous cell carcinoma (SCC) is rare, it has a poor prognosis. To the best of our knowledge, this is the first study to assess IMP3 immunohistochemical (IHC) expression in sinonasal tumors and to compare it to the Ki-67 IHC expression and to other established clinicopathological parameters. A retrospective study was conducted on three groups which consisted of 72 cases of sinonasal IP, 20 age-matched samples of normal respiratory epithelium, and 15 cases of sinonasal SCC associated with IP, which were obtained from the archives of the Pathology Lab of Ain Shams University Specialized and Ain Shams University Hospitals during the period from January 2012 to December 2019. An IHC study was performed to evaluate IMP3 and Ki-67 expression in the three groups, with correlation of IMP3 expression to established clinicopathological parameters of sinonasal SCC on top of IP. Both IMP3 and Ki-67 showed a sharp rise in expression in the sinonasal SCC group. In addition, there were statistically significant differences in expression values between the 3 groups (). Receiver Operating Characteristic (ROC) analysis revealed that IMP3 and Ki-67 could be used to discriminate sinonasal SCC from control and IP lesions, with sensitivity and specificity of 100% and 81.5% for IMP3, respectively, and 100% and 62.5% for Ki-67, respectively. Spearman’s rho revealed that both IMP3 and Ki-67 were significantly related to the lymph node and tumor stages but not to the tumor grade. ROC analysis was performed to select cut-off scores for progression and survival for IMP3, and accordingly, Kaplan-Meier analysis showed correlation between IMP3 and overall survival, local recurrence-free survival, and metastasis-free survival in sinonasal SCC cases at the selected cut-off values. Based on our results, IMP3 could serve as a promising diagnostic, prognostic, and therapeutic marker for IP-associated sinonasal SCC.
1. Introduction
Sinonasal inverted papilloma (IP) is one of the most common nonmalignant lesions in the nasal cavity and paranasal sinuses. Although benign, it has a high recurrence rate (up to 78% of cases), destroys surrounding structures (including bone erosion and orbital wall involvement), and may undergo malignant transformation (in 5–15% of cases). In fact, sinonasal IPs are concomitantly diagnosed in 1.7–56% of patients with sinonasal squamous cell carcinoma (SCC). Moreover, malignant transformation in such lesions has worse long-term clinical outcomes that include metastasis, postoperative disfigurement, and/or death [1–3]. Thus, precise and early diagnosis, thorough follow-ups, and discovering new prognostic and therapeutic indicators have become necessary in the management of sinonasal IP.
The oncofetal RNA-binding protein insulin-like growth factor 2 mRNA binding protein 3 (IMP3) is expressed during the early stages of embryogenesis and plays a role in cell growth and migration. These functions are mediated by posttranscriptional regulation of cell proliferation via regulation of IGF-2 transcription. After birth, IMP3 becomes epigenetically silenced, such that normal adult tissues show no detectable expression of this protein. However, its reexpression was noted in a series of human malignancies but not in the adjacent normal epithelium [4–6]. Moreover, several studies have demonstrated a prognostic role for IMP3 in several malignancies and their progression [7–13].
Only a few studies have assessed the immunohistochemical (IHC) expression of IMP3 in head and neck SCC [6, 14–18], and none have been conducted on sinonasal tumors. Thus, the primary objectives of the current study were to evaluate the IHC expression of IMP3 in the normal sinonasal epithelium, sinonasal IP, and IP-associated sinonasal SCC and to analyze its expression in relation to Ki-67 being an established biomarker. A secondary objective is comparing the IHC expression of IMP3 to established clinicopathological parameters of SCC on top of IP.
2. Materials and Methods
2.1. Tissue and Patient Data
The current study was a retrospective study conducted on three groups: 72 cases of sinonasal IP, 20 age-matched samples of normal respiratory epithelium obtained from cases with inflammatory/allergic nasal polypi and cases submitted to exclude fungal infection that proved to be free of fungal infection by periodic acid Schiff, and 15 cases of sinonasal SCC associated with IP. They were obtained from the archives of the Pathology Lab of Ain Shams University Specialized and Ain Shams University Hospitals. These were received and diagnosed during the period from January 2012 to December 2019. All cases underwent surgical intervention such as transnasal endoscopic resection and open surgical resection. The archival files were reviewed to determine the age and sex of patients. Hematoxylin and Eosin (H&E) stained slides were examined to reevaluate and verify the histopathologic diagnosis and histologic grade according to the World Health Organization (WHO) tumor differentiation [19–21]. TNM staging was performed according to the American Joint Committee on Cancer (AJCC) [22]. Normal sinonasal respiratory epithelial samples were also confirmed by histology.
ENT reports of the patients of the third group of IP-associated SCC were reviewed to determine (a) survival time, which was calculated based on the date of major surgery and the date of last follow-up or death, and (b) progression-free survival time, which was calculated based on the date of major surgery or last session of adjuvant postoperative radiotherapy and the date of relapse (local recurrence/distant metastasis) at the last follow-up.
2.1.1. Ethics Statement
Signed written and informed consent was obtained from all participants prior to surgery. The study was approved by the Research Ethical Committee at the Faculty of Medicine, Ain Shams University.
2.1.2. Immunohistochemical Staining
Four-micrometer sections of formalin-fixed and paraffin-embedded samples of normal respiratory epithelium, sinonasal IP, and sinonasal SCC associated with IP were prepared. IHC staining was performed on samples of the three groups using rabbit monoclonal anti-IMP3 (Clone: EP286; Cell Marque, Sigma-Aldrich Co., California, USA; 1 : 100 dilution) and rabbit monoclonal anti-Ki-67 (Clone: SP6; Cell Marque, Sigma-Aldrich Co., California, USA; 1 : 200 dilution). Avidin-Biotin immunoperoxidase complex technique was used by applying the sensitive detection kit (BioGenex, Fermont, California, USA) [23]. This was followed by fixation on poly-L-lysine-coated slides overnight at 37° C. They were then deparaffinized and rehydrated using graded alcohol series. Heating of the sections in a microwave oven in 10 mM citrate buffer (pH 6.0) was performed for 20 minutes. Blocking of endogenous peroxidase, incubation in Protein Block Serum-Free Solution (DakoCytomation, Glostrup, Denmark) for 20 minutes, then incubation overnight at 4°C with primary antibodies were done. Addition of biotinylated anti-mouse immunoglobulin and streptavidin conjugated to horseradish peroxidase was then performed. Finally, 3,3-diaminobenzidine as the substrate or chromogen was used to form an insoluble brown product. The sections were counterstained with hematoxylin and mounted. Sections of pancreatic ductal adenocarcinoma samples were used as positive control for IMP3 while sections of tonsillar tissue were used as positive control for Ki-67, with each run of every staining procedure performed. Negative control sections of each lesion were incubated with normal mouse serum instead of each of the primary antibodies.
2.1.3. Interpretation of Immunohistochemical Staining
IHC analysis of IMP3 and Ki-67 were blindly performed by three pathologists (the authors). Cytoplasmic staining of IMP3 and nuclear staining of Ki-67 in cells in any of the lesions of the three groups were regarded as positive staining. Slides were scanned by three pathologists at 20x magnification to identify representative hot spots for counting positive cells. The counting of cells with cytoplasmic positivity for IMP3 and cells with nuclear positivity for Ki-67 was performed at 400x magnification. Next, the proportion of positive cells over the total number of counted cells was independently estimated by each of the three pathologists, and the average was calculated. A multiheaded microscope was used to resolve any discrepancies.
The assessment of the intensity of cytoplasmic staining of IMP3 and the nuclear staining of Ki-67 was carried out by subjective consideration of staining intensity, which was scored as follows: 0: negative, 1: weak positivity, 2: moderate positivity, and 3: strong positivity. Any discrepancies were resolved by consensus using a multiheaded microscope [6].
All readings were performed independently and without any prior knowledge of the clinical or histopathological characteristics of the cases.
2.2. Statistical Analysis
Data was tested for normality with a Shapiro-Wilk test and expressed as for parametric numerical data or median (interquartile range) for nonparametric numerical data. Categorical variables were expressed as frequencies and percent. Student’s test or Mann-Whitney test was used to compare quantitative data between two groups according to data distribution. ANOVA or Kruskal-Wallis tests with post hoc test were used to compare quantitative data between two and more than 2 group tests according to data distribution. Spearman correlation analysis was used to test the strength of correlation between two variables. The ROC curve was used to evaluate the sensitivity and specificity of IMP3 and Ki-67 in predicting SCC. Multivariate logistic regression analysis was performed for determining the predictors of SCC. A significance level of was used in all tests. All statistical procedures were carried out using SPSS version 20 for Windows (SPSS Inc., Chicago, IL, USA).
3. Results
3.1. Patients
Data describing age and gender of the three studied groups are demonstrated in Table 1.
Group
Normal epithelium
Inverted papilloma
SCC
Mean
±SD
Mean
±SD
Mean
±SD
Age
47.95
6.03
48.43
5.42
57.80
9.30
Gender
Male
9
45.0%
49
68.1%
13
86.7%
Female
11
55.0%
23
31.9%
2
13.3%
SD: standard deviation; SCC: squamous cell carcinoma.
... Ki-67 initiated IP entry into the G1 cell cycle and influences CDK1 in causing malignant transformation. 16 Conclusion of this study found that (1) Expression of EGFR, KRAS and ERK were related to Ki-67 in IP and SCC. ...
Background: Inverted papilloma (IP) is benign tumor of the nasal cavity and paranasal sinuses epithelium. Sinonasal squamous cell carcinoma (SCC) is epithelial malignancy of nasal cavity and paranasal sinuses. HPV increases epidermal growth factor receptor (EGFR) expression mediated by E5. RAS is part of the RAS-RAF-MEK-ERK pathway that regulates various cell functions. Ki-67 serves as a molecular marker of tumor proliferation. Early malignant transformation often goes unnoticed. It is important to know the roles of EGFR, RAS, ERK and Ki-67 as predictor for tumor markers in IP and Sinonasal SCC. Objective: To find out the correlation of EGFR, RAS, ERK expressions towards Ki-67 expression as predictor of sinonasal IP transformation into sinonasal SCC. Method: A cross sectional study taking samples from the medical record of Dr.Saiful Anwar Hospital. The expression of EGFR, RAS, ERK and Ki-67 were examined with immunohistochemistry. Result: The estimated inner model results for direct influence of EGFR, RAS, ERK and Ki-67 towards IP and SCC were 2.352, 2.019, 2.625, and 2.213. The estimated inner model results for direct influence of EGFR, RAS and ERK towards Ki- 67 were 2.386, 3.811, and 3.00. Discussion: Previous research had reported an increase in Ki-67 index indicated the role of Ki-67 in cell tranformation of IP with dysplasia into SCC. Conclusion: EGFR, RAS and ERK expressions related to Ki-67 on IP and SCC. Increased expressions of EGFR, RAS, ERK and Ki-67 on IP indicated risk of malignant transformation. EGFR, RAS, ERK and Ki-67 could become predictors of IP transformation into SCC. ABSTRAKLatar belakang: Papiloma inverted (PI) merupakan tumor jinak epitel kavum nasi dan sinus paranasal. Karsinoma sel skuamosa (KSS) sinonasal merupakan keganasan yang berasal dari epitel mukosa kavum nasi dan sinus paranasal. HPV meningkatkan ekspresi EGFR yang dimediasi oleh E5. RAS merupakan bagian dari jaras RAS–RAF–MEK–ERK yang mengatur berbagai fungsi sel. Ki-67 berfungsi sebagai penanda molekuler proliferasi tumor. Diagnosis dini transformasi keganasan pada papiloma inverted seringkali luput dari pengamatan. Penting mengetahui peran EGFR, RAS, ERK dan Ki-67 sebagai cikal bakal penanda tumor pada IP dan KSS sinonasal. Tujuan: Mengetahui hubungan ekspresi EGFR, RAS, ERK terhadap Ki-67 sebagai prediksi transformasi keganasan PI sinonasal menjadi KSS sinonasal. Metode: Penelitian cross sectional, sampel penelitian diambil dari arsip rekam medis rawat jalan yang masih didapatkan preparat histopatologi papiloma inverted dan karsinoma sel skuamosa sinonasal di laboratorium Patologi Anatomi, dan dilakukan pemeriksaan ekspresi EGFR, RAS, ERK dan Ki-67 dengan imunohistokimia. Hasil: Hasil estimasi inner model untuk pengaruh langsung EGFR, RAS, ERK dan Ki-67 terhadap PI dan KSS sebesar 2,352, 2,019, 2,625 dan 2,213. Hasil estimasi inner model untuk pengaruh langsung EGFR, RAS dan ERK terhadap Ki-67 sebesar 2,386, 3,811 dan 3,00. Diskusi: Penelitian terdahulu membuktikan peningkatan indeks Ki-67 merupakan pertanda adanya peran Ki-67 pada perubahan PI dengan displasia menjadi SCC. Kesimpulan: Ekspresi EGFR, RAS dan ERK berhubungan terhadap Ki-67 pada IP dan KSS. Peningkatan ekspresi EGFR, RAS, ERK dan Ki-67 pada PI menandakan adanya risiko terjadi transformasi keganasan. EGFR, RAS, ERK dan Ki-67 dapat menjadi cikal bakal prediktor transformasi keganasan PI menjadi KSS.
... Ki-67 is a marker of cell proliferation, in immunohistochemical studies of protein expression, Tsou et al. observed significantly greater Ki-67 staining in IP-SCC as compared with non-recurrent IP [67]. Ki-67 was considered a signal of poor prognosis and malignant transformation [67]. ...
... Ki-67 is a marker of cell proliferation, in immunohistochemical studies of protein expression, Tsou et al. observed significantly greater Ki-67 staining in IP-SCC as compared with non-recurrent IP [67]. Ki-67 was considered a signal of poor prognosis and malignant transformation [67]. ...
Background:
Inverted papilloma (IP) is an unusual type of benign tumor that has high recurrence rates and the potential to transform into squamous cell carcinomas (SCC). The mechanism of the transformation process from IP to IP-SCC is uncertain and there is no consensus regarding the best practice for IP-SCC detection. The goal of this study is to identify the best clinical methods to detect for IP-SCC.
Methods:
An evidence-based review was performed using Medline and Ovid to obtain all articles up to October 10th, 2019 pertaining to identification of IP malignant transformation. All manuscripts discussing clinical methods or biomarkers were included.
Results:
Based on clinical research studies, convoluted cerebriform pattern and apparent diffusion coefficient values on Magnetic Resonance Imaging (MRI) can help differentiate benign IP from SCC and increased SUVmax on PET/CT is associated with higher probability of malignancy although not as specific. No consensus about the best biomarker for IP-SCC has been reached among researchers and continues to be exploratory.
Conclusion:
Endoscopy with biopsy is the gold standard practice to identify IP-SCC; however, MRI is the preferred imaging modality to recognize malignant transformation in cases where biopsy is difficult. Multiple biomarkers have shown positive results, but no single indicator with clinical significance for monitoring malignant transformation process has been found.
... Recent data suggests that Ki-67 may have biological significance as a proliferative index in head and neck malignances [34,35]. Some authors found an increased proliferative activity of tumor cells (significantly higher Ki-67), an elevated expression of PCNA (proliferating cell nuclear antigen), and a decreased expression of p27 in SNIPs with severe dysplasia and invasive SCC [36]. The PCNA, Ki-67 and p27 could interact with CDK1 (Cyclindependent kinase 1-a key player protein in cell cycle regulation) and promote the cell entry into the cell cycle with consequent proliferation and cancerization. ...
... The PCNA, Ki-67 and p27 could interact with CDK1 (Cyclindependent kinase 1-a key player protein in cell cycle regulation) and promote the cell entry into the cell cycle with consequent proliferation and cancerization. Tsou et al. [36] in a recent study on a cohort of 70 patients observed significantly elevated levels of Ki-67, p27, and PCNA in SNIPs with sinonasal SCC transformation compared with SNIPs without malignancy. Other authors have revealed that the nuclear immunoexpression of the inhibitor of apoptosis protein survivin and Bcl-2 oncoprotein immunoexpression are significantly higher in SNIP, suggesting that survivin and Bcl-2 may be involved in sinonasal tumorigenesis [37]. ...
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.
... To date, many studies have aimed to resolve this issue (Tables II and III CCAAT enhancer binding proteins (71), cyclooxygenase-2 (COX-2) (72), angiomotin (73), phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase (PTEN) (74), hypoxia-inducible factor 1-α (HIF-1α) (74), HPV infection and stathmin (75). Malignant transformation of SIP may be associated with the following factors: HPV 16/18 infection (76), epidermal growth factor receptor (EGFR) 1 (77,78); cell cycle proteins [p21 (79); p16 (79,80); p53 (80,81); p63 (79,81); p27; cyclin D1 (82); proliferating cell nuclear antigen reverse transcription (65,83); Ki-67 (65,84); metallothionein-2-5A/G (reference single nucleotide polymorphisms cluster ID, 28366003) (85); TFPI-2 (86); fascin (87); matrix metallopeptidase-2 (76); sex determining region Y-box 2 (88); topoisomerase II-α (84,89,90); OPN (91); homeobox protein MSX-2 (89-91); desmoglein 3 (92); survivin (83,93); cathepsin S (94); stefin A (94); E-cadherin (95); β-catenin (82,95); COX-2 (96,97); deleted in lung and esophageal cancer protein 1 (98); IQ motif containing GTPase activating protein 1 (99); Smac (93); PTEN (74); HIF-1α (74); Dvl-1 (82); retinoblastoma protein (100); and regulatory T cells (101). However, there were several key limitations in these studies. ...
... To date, many studies have aimed to resolve this issue (Tables II and III CCAAT enhancer binding proteins (71), cyclooxygenase-2 (COX-2) (72), angiomotin (73), phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase (PTEN) (74), hypoxia-inducible factor 1-α (HIF-1α) (74), HPV infection and stathmin (75). Malignant transformation of SIP may be associated with the following factors: HPV 16/18 infection (76), epidermal growth factor receptor (EGFR) 1 (77,78); cell cycle proteins [p21 (79); p16 (79,80); p53 (80,81); p63 (79,81); p27; cyclin D1 (82); proliferating cell nuclear antigen reverse transcription (65,83); Ki-67 (65,84); metallothionein-2-5A/G (reference single nucleotide polymorphisms cluster ID, 28366003) (85); TFPI-2 (86); fascin (87); matrix metallopeptidase-2 (76); sex determining region Y-box 2 (88); topoisomerase II-α (84,89,90); OPN (91); homeobox protein MSX-2 (89-91); desmoglein 3 (92); survivin (83,93); cathepsin S (94); stefin A (94); E-cadherin (95); β-catenin (82,95); COX-2 (96,97); deleted in lung and esophageal cancer protein 1 (98); IQ motif containing GTPase activating protein 1 (99); Smac (93); PTEN (74); HIF-1α (74); Dvl-1 (82); retinoblastoma protein (100); and regulatory T cells (101). However, there were several key limitations in these studies. ...
Sinonasal inverted papilloma (SIP) is a benign tumor of the nasal cavity and sinus. SIP is characterized by aggressive malignant transformation and a high rate of recurrence. Inadequate removal of the tumor during surgery is one of the most significant contributors to SIP recurrence. A growing body of evidence suggests that molecular alteration in SIP, including human papilloma virus infections, single nucleotide polymorphisms of key genes, deregulation of signaling pathways and immunological changes, may lead to SIP occurrence and malignant transformation. However, the extent to which these molecular mechanisms contribute to SIP pathology and transformation remains unclear due to limited research. Further studies are warranted to elucidate the primary dependent factors that contribute to SIP etiology. The present article reviewed risk factors of progression and recurrence of SIP, including outdoor and industrial occupational exposure, smoking, septal deviation, SIP location, recurrent cases, stage of SIP-associated squamous cell carcinoma and choice of surgical method.
... Ultimately, a total of 17 studies fulfilled the above select criteria and were included in the current meta-analysis. [9,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] Among the 17 articles published in English, the publication years ranged from 1998 to 2015. Sixteen studies including 229 SNSCC and 675 benign papilloma patients evaluated the relationship between p53 expression and SNSCC in cancer versus benign sinonasal papillomas. ...
... Sixteen studies including 229 SNSCC and 675 benign papilloma patients evaluated the relationship between p53 expression and SNSCC in cancer versus benign sinonasal papillomas. [9,[23][24][25][26][27][28][29][30][32][33][34][35][36][37][38] Five studies involving 112 SNSCC patients and 73 normal sinonasal mucosa estimated the relationship between p53 expression and SNSCC in cancer versus normal sinonasal mucosa. [30,34,35,37,38] Three studies with 72 SNSCC patients evaluated the correlation between p53 expression and tumor differentiation in cancer. ...
... 22 (4.5) ----->10% Yoon et al [25] Korea Asians IHC Tissue 5 (100) 68 (8.8) ----->10% Lin et al [24] USA Mix IHC Tissue 21 (61.9) 135 (33.3) ----->5% Tsou et al [23] China Asians IHC Tissue 10 (100) 60 (58.3) ----->10% Yamashita et al [9] Japan that p53 expression was significantly higher in moderately or poorly differentiated SNSCC than in well-differentiated SNSCC (OR = 3.51, 95% CI = 1.21-10.18, P = 0.021) (Fig. 6A). ...
Background
The level of p53 protein expression in sinonasal squamous cell carcinoma (SNSCC) has been estimated, but the results remain inconsistent and the point of consensus has not been reached. This study was first determined to evaluate the clinical effects of p53 expression in SCC of the sinonasal tract.
Methods
According to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria, the potential literature was searched from diverse databases. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess the strength of association between p53 expression and SNSCC.
Results
Final 17 eligible studies were included in a total of 258 cases and 748 controls. The result of p53 expression was shown to be notably higher in SNSCC than in benign sinonasal papillomas and normal sinonasal mucosa (OR?=?26.93, P?<?0.001; OR?=?39.79, P?<?0.001; respectively). Subgroup analyses of ethnicity revealed that p53 expression had significant association with SNSCC in Asian and Caucasian populations in cancer versus benign sinonasal papillomas or normal sinonasal mucosa. The expression of p53 was notably higher in moderately or poorly differentiated SNSCC than in well-differentiated SNSCC (OR?=?3.51, P?=?0.021), while p53 expression was not associated with histological type.
Conclusion
The results suggested that p53 overexpression may be correlated with the carcinogenesis and progression of SNSCC. The p53 gene may become a novel drug target of SNSCC. Additional studies on the correlation of p53 expression with clinicopathological features are needed.
