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Objectives: Oral submucous fibrosis (OSMF) is a potentially malignant disorder (PMD) characterized by a high rate of malignant transformation (MT). OSMF exhibits atrophic epithelium yet has a high proliferation rate. Both p53 and Ki67 are nuclear proteins associated with cell proliferation, detectable in the early stages of oral cancer (OC). This study aimed to analyze the efficacy of p53 and Ki67 immuno-expression as tools for predicting malignant transformation in OSMF cases. The objective was to correlate the expression of p53 and Ki67 with demographic and chewing habits data., Materials and Methods: The study group consisted of 60 histopathologically diagnosed cases of OSMF, 60 cases of OC as positive controls, and 60 cases of NOM as negative controls. Immunohistochemistry was performed on neutral-buffered formalin-fixed, paraffin-embedded tissue sections of 3 μm thickness, using ready-to-use anti-human p53 protein (clone DO-7) and monoclonal antibody for Ki67 antigen (clone MIB-1). Statistical analysis was conducted using SPSS software version 21, employing the chi-square test (p < 0.05)., Results: The expression of p53 and Ki67 was significantly higher in OSMF samples compared to NOM samples, but lower than in OC samples. When the expression levels of both p53 and Ki67 were correlated with demographic and chewing habits data, the results were statistically significant., Conclusion: The overexpression of p53 and Ki67 may contribute to the progression of MT in OSM. Early detection of these biomarkers is crucial for preventing MT, which also helps reduce the morbidity and mortality of OC. Therefore, both p53 and Ki67 can serve as predictive biomarkers for the early detection of MT in high-risk OSMF patients.

Objectives: The M1/M2 macrophage framework is crucial in organ fibrosis and its progression to malignancy. This study investigated the possible role of M1/M2 macrophage interplay in the pathogenesis of oral submucous fibrosis (OSF) and its malignant transformation by analysing immunohistochemical expression of CD11c (M1) and CD163 (M2) markers., Methods: Immunohistochemistry was performed using primary antibodies against CD11c and CD163 on ten formalin-fixed paraffin-embedded tissue blocks for each group: (i) Stage 1 OSF, (ii) Stage 2 OSF, (iii) Stage 3 OSF, (iv) Stage 4 OSF, (v) well-differentiated squamous cell carcinoma (WDSCC) with OSF, and (vi) WDSCC without OSF. Ten cases of healthy buccal mucosa (NOM) served as controls., Results: Epithelial quick scores of M1 (CD11c) in NOM, Stages 1-4 OSF, and WDSCC with and without OSF were 0, 1.8, 2.9, 0.4, 0, 0, and 0, while connective tissue scores were 0, 3.2, 4.3, 2.7, 0.5, 1.2, and 2.4, respectively. Epithelial scores for M2 (CD163) were 0, 0.8, 0.8, 2.1, 0.6, 0.8, and 0.2, and connective tissue scores were 0, 1.8, 2.6, 3.9, 2.2, 5, and 4.4, respectively. Stages 3 and 4 OSF, WDSCC with and without OSF exhibited higher M2/M1 ratios compared to NOM and Stages 1-2 OSF., Conclusion: The interaction between M1 (CD11c) and M2 (CD163) macrophages, leading to M2 polarisation, plays a crucial role in the pathogenesis of OSF and its potential malignant transformation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Telocytes are interstitial cells widely distributed in the extracellular matrix of numerous tissues distinguished by their long, thin, and moniliform projections. Telocytes have a role in the stimulation of angiogenesis and contribute to the development and progression of fibrosis., Aim: The current study aimed to assess and compare the telocyte distribution in normal mucosa, oral submucous fibrosis (OSF), and OSCC associated with OSF (OSCCOSF)., Materials and Methods: Formalin-fixed and paraffin-embedded tissue blocks of 30 OSF cases, 15 OSCCOSF cases, and 15 normal oral mucosae were obtained. Immunohistochemical staining was done with antibodies to CD34 to assess the vasculature and telocytes. The mean vascular density (MVD) and mean telocyte density were compared between the groups using the Kruskal-Walli test., Results: A statistically significant high MVD (3.4 ± 1.22) and mean telocyte density (3.8 ± 1.35) was observed in OSCCOSF cases while it was lowest in advanced OSF cases. MVD was higher in early OSF cases than in normal mucosa., Conclusion: This study showed a decrease in CD34-positive telocytes in OSF, indicating that telocyte loss promotes the development of fibrosis.Increased angiogenesis coexisted with an increase in telocytes in OSCCOSF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Pathogenesis and malignant potential of Oral submucous fibrosis(OSMF) have always been a topic of interest among the researchers. Despite OSMF being a collagen metabolic disorder, the alterations occurring in the connective tissue stroma affects the atrophic surface epithelium in later stages and progresses to malignant phenotypes. The present review aims to summarize the role of stem cells in the pathogenesis and malignant transformation of oral submucous fibrosis., Materials and Methods: A literature search was carried out using data banks like Medline and Embase, google scholar and manual method with no time frame, pertinent to the role of mucosal stem cells in OSMF and its malignisation. The relevant literature was reviewed, critically appraised by all the authors and compiled in this narrative review., Results: Critical appraisal and evaluation of the data extracted from the selected articles were compiled in this review. The collated results highlighted the upregulation and downregulation of various stem cell markers during the progression and malignisation of OSMF were depicted in a descriptive and detail manner in the present review., Conclusion: We highlight the potential of mucosal stem cells in the regulation and malignisation of OSMF. However, future large-scale clinical studies will be needed to support whether manipulation of this stem cells at molecular level will be sufficient for the treatment and preventing the malignant transformation of OSMF., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: An umbrella review is a systematic review of systematic reviews, which provides a tertiary level of evidence. This umbrella review of systematic reviews and meta-analysis (SR-MA) aimed to determine the proportion of oral cancer (OC) development in oral submucous fibrosis (OSF) patients., Materials and Methods: We searched electronic databases including PubMed, Scopus, Web of Science, Cochrane and grey literature. Two reviewers independently screened abstracts and assessed for eligible papers. The methodological quality of SR-MA was evaluated using AMSTAR2, and we also checked the quality of evidence of the included papers., Results: Out of 454 papers identified in the primary search, 105 underwent eligibility screening. Inclusion criteria were met by four SR-MA. OC ratios ranged between 4.2% and 6% for OSF. Substantial heterogeneity was observed for this outcome in all four MA (I 2  = 71.31% to 86.37%). None of the SRs assessed the quality of evidence, and half of them were judged to be of critically low methodological quality., Conclusion: There is lack of quality of evidences and critically low methodological quality among SRs and MA leading to substantial heterogeneity. However, due to potentially malignant nature, OSF patients should be monitored carefully for early detection of OC., (© 2023 Wiley Periodicals LLC.)

Background: Oral submucous fibrosis (OSF) is a precancerous lesion, with oral squamous cell carcinoma (OSCC) being the most prevalent malignancy affecting the oral mucosa. The malignant transformation of OSF into OSCC is estimated to occur in 7-13% of cases. Myofibroblasts (MFs) play pivotal roles in both physiological and pathological processes, such as wound healing and tumorigenesis, respectively. This study aimed to explore the involvement of MFs in the progression of OSF and its malignant transformation., Materials and Methods: In total, 94 formalin-fixed paraffin-embedded tissue blocks were collected, including normal oral mucosa (NOM; n = 10), early-moderate OSF (EMOSF; n = 29), advanced OSF (AOSF; n = 29), paracancerous OSF (POSF; n = 21), and OSCC (n = 5) samples. Alpha-smooth muscle actin was used for the immunohistochemical identification of MFs., Results: NOM exhibited infrequent expression of MFs. A higher staining index of MFs was found in AOSF, followed by EMOSF and NOM. Additionally, a significant increase in the staining index of MFs was found from EMOSF to POSF and OSCC. The staining index of MFs in NOM, EMOSF, AOSF, POSF, and OSCC was 0.14 ± 0.2, 1.69 ± 1.4, 2.47 ± 1.2, 3.57 ± 2.6, and 8.86 ± 1.4, respectively. All results were statistically significant (P < 0.05)., Conclusions: The expression of MFs exhibited a gradual increase as the disease progressed from mild to malignant transformation, indicating the contributory role of MFs in the fibrogenesis and potential tumorigenesis associated with OSF., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

Connective tissue growth factor (CTGF), a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins, is highly expressed in various organ fibrosis and several malignant tumors. Although a few studies have been conducted using CTGF in oral submucous fibrosis (OSF) and oral squamous cell carcinoma, no study has demonstrated its relation with various stages of OSF and its malignant transformation. The present study investigated the possible role of CTGF in the pathogenesis of OSF and its malignant transformation by using immunohistochemistry. Ten formalin-fixed paraffin-embedded tissue blocks, each of Stage 1 OSF, Stage 2 OSF, Stage 3 OSF, Stage 4 OSF, well- differentiated squamous cell carcinoma (WDSCC) with OSF and WDSCC without OSF were stained for CTGF by immunohistochemistry. Ten cases of healthy buccal mucosa (NOM) were included as controls. The present study demonstrated a statistically significant expression of CTGF in the epithelium and connective tissue of OSF and WDSCC with and without OSF cases against its complete absence in NOM. We observed an upregulation of CTGF expression from NOM to various stages of OSF to WDSCC with or without OSF. A gradual upregulation of the CTGF expression in various stages of OSF to WDSCC (with and without OSF) against its complete absence in NOM suggests that CTGF plays an important role in the pathogenesis of OSF and its malignant transformation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Introduction: Tobacco contains several genotoxic agents including N-nitrosamine which has the potential to cause significant nuclear damage. Nuclear blebbing is a form of protrusion on the nuclear membrane and could potentially be caused by tobacco-induced genotoxicity and is closely associated with malignancy. Thus, the present study aimed to assess if tobacco-associated oral potentially malignant disorders including oral submucous fibrosis (OSF) and oral leukoplakia have a higher nuclear blebbing frequency than patients with normal oral mucosa with no history of tobacco use., Methods: The sample consisted of patients with OSF (n = 30) and oral leukoplakia (n = 10) and normal oral mucosa (n = 10). Exfoliated cells collected from the study groups were smeared on a clean microscopic slide and stained by May-Grunwald-Giemsa stain. A baseline frequency of nuclear blebbing was evaluated using a bright-field microscope with a ×100 objective. The number of nuclear blebbing per 1,000 epithelial cells was recorded and expressed in percentage. ANOVA, the Mann-Whitney U test, and Spearman's correlation were used to analyze the data., Results: The mean rank of distribution of nuclear blebbing showed significant difference between all 3 groups, with the highest frequency noted in leukoplakia, followed by oral submucous and normal oral mucosa. Within OSF, the frequency of nuclear blebbing significantly increased from early stage to advanced stage. In OSF, a statistically significant positive linear correlation was noted between duration (in years), frequency (per day) of tobacco use, clinical grading, and nuclear blebbing., Discussion/conclusions: The frequency of nuclear blebbing was significantly higher in oral potentially malignant disorders than normal mucosa. Nuclear blebbing also exhibited a strong dose- and time-dependent correlation with tobacco usage and clinical staging in OSF. The nuclear blebbing frequency could be a noninvasive, economic tool to assess malignant risk in tobacco-induced oral potentially malignant disorders., (© 2021 S. Karger AG, Basel.)

Oral potentially malignant disorders refer to oral mucosal disorders with increased risk for malignant transformation, primarily to oral squamous cell carcinoma (SCC). Leukoplakia and erythroplakia are the most common of these disorders, but others have been identified. Transformation rates to oral cancer vary based on multiple factors. Healthcare providers should be aware of risk factors and clinical manifestations of these disorders and should intervene early to monitor and/or treat them to reduce the potential for malignant transformation.

Oral submucous fibrosis (OSMF), the most commonly encountered potentially premalignant oral epithelial lesion, is a chronic disorder associated with areca nut chewing. It has a relatively high potential for malignant transformation resulting into oral squamous cell carcinoma (OSCC), the most common oral malignancy with high mortality rate. Paymaster first described the malignant potential of OSMF in 1956, the rate of which had been estimated to be 7-13%. The pathogenesis of OSMF in itself is quite varied, and hence, its transformation to malignancy is also open to many varied mechanisms. The early diagnosis and sequentially, early treatment of OSMF is desirable so that the progression towards malignancy can be controlled. There are various theories that have been put forward explaining the probable pathway of malignant transformation of OSMF such as hypoxia, areca nut as a carcinogen or epithelial-mesenchymal transitions. Many recent molecular advances have also highlighted few biomarkers and genes that play a pivotal role in transformation of OSMF to OSCC. The purpose of this systematic review is to discuss all the possible mechanisms of malignant transformation of OSMF. Further research is still needed to establish the exact mechanism responsible for transformation of OSMF to OSCC and to reduce the mortality by newer interventions.

The integrity of the basal stem cell layer is critical for epithelial homoeostasis. In this paper, we review the expression of oral mucosal stem cell markers (OM-SCMs) in oral submucous fibrosis (OSF), oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) to understand the role of basal cells in potentiating cancer stem cell behaviour in OSF. While the loss of basal cell clonogenicity triggers epithelial atrophy in OSF, the transition of the epithelium from atrophic to hyperplastic and eventually neoplastic involves the reactivation of basal stemness. The vacillating expression patterns of OM-SCMs confirm the role of keratins 5, 14, 19, CD44, β1-integrin, p63, sex-determining region Y box (SOX2), octamer-binding transcription factor 4 (Oct-4), c-MYC, B-cell-specific Moloney murine leukaemia virus integration site 1 (Bmi-1) and aldehyde dehydrogenase 1 (ALDH1) in OSF, OPMDs and OSCC. The downregulation of OM-SCMs in the atrophic epithelium of OSF and their upregulation during malignant transformation are illustrated with relevant literature in this review.

Background: The associations between malignant transformation of oral potentially malignant disorders (OPMDs), oral cancer development and prognosis, and apurinic/apyrimidinic endonuclease 1 (APE1) functional polymorphisms are unclear., Methods: Patients with OPMDs, patients with oral cancer, and healthy controls from the community were recruited to determine the effects of APE1 polymorphisms on malignant transformation, overall survival, and genetic susceptibility, respectively., Results: The APE1 Asp148Glu polymorphisms significantly correlated with a high hazard ratio for OPMD malignant transformation (adjusted hazard ratio [AHR] = 2.29; 95% confidence interval [CI] = 1.44-3.74) and low overall survival in oral cancer patients (AHR = 1.71, 95% CI = 1.11-2.56) according to follow-up and survival analysis. However, APE1 polymorphisms did not significantly correlate with development of oral cancer in the case-control study and logistic regression analysis., Conclusions: These results indicate that APE1 Asp148Glu polymorphisms may have indirect roles in increasing the OPMD malignant transformation rate and in decreasing overall survival in oral cancer patients., (© 2019 Wiley Periodicals, Inc.)

Oral potentially malignant disorders (OPMDs) have a statistically increased risk of progressing to cancer, but the risk varies according to a range of patient- or lesion-related factors. It is difficult to predict the risk of progression in any individual patient, and the clinician must make a judgment based on assessment of each case. The most commonly encountered OPMD is leukoplakia, but others, including lichen planus, oral submucous fibrosis, and erythroplakia, may also be seen. Factors associated with an increased risk of malignant transformation include sex; site and type of lesion; habits, such as smoking and alcohol consumption; and the presence of epithelial dysplasia on histologic examination. In this review, we attempt to identify important risk factors and present a simple algorithm that can be used as a guide for risk assessment at each stage of the clinical evaluation of a patient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Oral potentially malignant disorders (OPMDs) are conditions that precede the onset of invasive cancers of the oral cavity. The term embraces precancerous lesions and conditions referred to in earlier World Health Organization (WHO) definitions. Leukoplakia is the most common OPMD; erythroplakia, although rare, is more serious. Several variants of leukoplakia are recognized, and clinical subtyping may help determine the prognosis to a limited extent. Biopsy is essential to confirm the provisional clinical diagnosis, and timely referral to a specialist is indicated. Certain OPMDs, such as oral submucous fibrosis, are encountered particularly in population groups from Asia with specific lifestyle habits. This review provides clinical descriptions of the wide range of potentially malignant disorders encountered in the oral cavity as a prelude to the topics discussed in this focus issue., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The term oral potentially malignant disorders, proposed at the World Health Organization workshop in 2005, has now been renamed potentially premalignant oral epithelial lesions (PPOELs). It is important to differentiate among PPOELs, which is a broad term to define a wide variety of clinical lesions, and oral epithelial dysplasia, which should be reserved specifically for lesions with biopsy-proven foci of dysplasia. PPOELs encompass lesions that include leukoplakia, erythroplakia, erythroleukoplakia, lichen planus, and oral submucous fibrosis. The primary goal of management of dysplasia includes prevention, early detection, and treatment before malignant transformation. The aim of this article is to inform the clinician about management of PPOELs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The term oral potentially malignant disorders (OPMDs) describes a recognizable group of mucosal diseases that have a risk of progressing to squamous cell carcinoma. Oral leukoplakia, the most common OPMD, has a 1% prevalence and reported malignant transformation rates of 2% to 5%. Other OPMDs include erythroplakia, erythroleukoplakia, submucous fibrosis, lesions of reverse smokers, and inherited genetic disorders, such as Fanconi anemia. The histopathologic assessment of OPMDs is an area of subjectivity, and oral epithelial dysplasia (OED) is fraught with both interrater variability and intrarater variability. Both architectural and cytologic changes are utilized when developing criteria for grading OED. However, the concept of atypical verrucous lesions, particularly as it pertains to proliferative verrucous leukoplakia, suffers from lack of histopathologic diagnostic criteria. Histopathologic mimics of OPMDs, including reactive/regenerative epithelium, frictional keratosis, and infection, can result in patient mismanagement. This review will focus specifically on the histologic features of OED, including human papillomavirus-associated dysplasia, as well as the histologic features of atypical verrucous keratoses/hyperplasia, particularly those that arise in the setting of proliferative verrucous leukoplakia along with OPMD mimics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Oral submucous fibrosis (OSF) is one of the well-recognized oral potentially malignant disorders. In this study, we investigated the malignant transformation of OSF in a Taiwanese population., Methods: A retrospective cohort study was analyzed from Taiwan's National Health Insurance Research Database. A comparison cohort was randomly frequency-matched with the OSF cohort according to age, sex, and index year. Oral leukoplakia (OL) was further stratified to evaluate for the possible synergistic effects of OSF-associated malignant transformation., Results: In this cohort, 71 (9.13%) of 778 cases of OSF were observed to transform into oral cancer. The malignant transformation rate was 29.26-fold in the OSF cohort than in the comparison cohort after adjustment (95% confidence intervals 20.55-41.67). To further stratify with OL, OSF with OL (52.46%; 95% confidence intervals 34.88-78.91) had higher risk of malignant transformation rate than OSF alone (29.84%; 95% confidence intervals 20.99-42.42). The Kaplan-Meier plot revealed the rate free of malignant transformation was significant over the 13-year follow-up period (log-rank test, P<.001). The mean duration of malignant transformation was 5.1, 2.7, and 2.2 years for non-OSF, OSF alone, and OSF with OL, respectively., Conclusion: Oral submucous fibrosis patients exhibited a significantly higher risk of malignant transformation than those without OSF. OL could enhance malignant transformation in patients with OSF., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Oral submucous fibrosis (OSMF) is a potentially malignant condition associated with areca nut chewing. Formerly confined to the Indian subcontinent, it is now often seen in Asian populations of the United Kingdom, USA and other developed countries, and is therefore a serious problem for global health. What makes it more sinister is the malignant transformation rate, which has been reported to be around 7.6% over a 17-year period. In this concise article, we review the current trends in the pathophysiology of malignant transformation of OSMF., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Oral submucous fibrosis (OSF) is a chronic progressive disease of the oral cavity that is considered a common potentially malignant disorder in South Asia. Areca nut chewing is the main etiological factor, but its carcinogenic mechanism has yet to be proven. The purpose of this study was to identify the useful biomarkers in predicting high-risk patients with OSF., Methods: Thirty-six cases of OSF and six cases of normal oral mucosa (NOM) were used for this study. Immunohistochemical staining was performed for Ki67, cyclin D1, p16, p53, β-catenin, c-Jun, c-Met, and insulin-like growth factor II mRNA-binding protein 3 (IMP3). The expression patterns of NOM served as guidelines for the scoring system., Results: The expression of Ki67, cyclin D1, c-Met, IMP3, and β-catenin showed a significant difference between OSF and NOM samples. The combined biomarkers of Ki67 and p16 showed significantly different expression between the transformation and non-transformation groups. With discriminant analysis, we proposed a noble formula and cutoff value for predicting high-risk patients with OSF., Conclusion: The notable biomarkers in our present study were Ki67 and p16 showing significantly different expression levels between the transformation and non-transformation groups. With the identification of high-risk patients with OSF, we can expect to develop more intensive treatment modalities, leading to the reduction in cancer transformation rate from OSF., (© 2016 The Authors. Journal of Oral Pathology & Medicine Published by John Wiley & Sons Ltd.)

Worldwide estimates of oral submucous fibrosis (OSMF) show a confinement to Indians and Southeast Asians. In India, the prevalence of OSMF has increased over the past four decades from 0.03% to 6.42%. The condition is well recognized for its malignant potential rate of 7-30%. The condition has a multifactorial etiology and may remain either stationary or become severe, leaving an individual physically challenged both physically and psychologically. Hence, the study aims at reviewing studies done on various etiological factors leading to its onset. Their analysis may serve as an adjunct in defining the broad spectrum of the causation of this potentially malignant disorder.

Objective: To determine the relationship of age, gender and other associated risk factors linked with malignant transformation of oral submucous fibrosis into oral squamous cell carcinoma., Methods: This cross-sectional, multi-centre study was conducted at both public and private tertiary care hospitals and clinics of Karachi, Pakistan, from 2004 to 2012, and comprised patients with oral submucous fibrosis and/or oral squamous cell carcinoma. Out of the total sample, malignant transformations of oral submucous fibrosis to oral squamous cell carcinoma were included. Cases of oral squamous cell carcinoma without clinical evidence of pre-existing oral submucous fibrosis were excluded. Sample selection was based on non-probability convenience sampling. SPSS 18 was used for data analysis., Results: Of the 1774 cases, 765(43.12%) were of oral submucous fibrosis alone, 472(26.60%) were reported as malignant transformation of oral submucous fibrosis into oral squamous cell carcinoma and 537(30.27%) were of oral squamous cell carcinoma without clinically visible oral submucous fibrosis. Of the malignant transformation cases,370(78.4%) involved women and 102(21.6%)men.Besides,5(1.1%)patients were aged below 25 years, 266(56.4%)were 26-50 years and 201(42.6%)were aged 51 years or above, with the mean age of 21.80±3.1, 34.02±2.1 and 40.28±13.1 years, respectively (p=0.001).Moreover, 228(48.3%)patients used betel quid with tobacco, 108(22.9%) consumed areca nut only, 55(11.7%) chewed betel quid without tobacco, 36(7.6%)used naswar, while 45(9.5%)had no chewing habits (p=0.001).., Conclusions: The risk of developing oral squamous cell carcinoma was high, especially women.

Research studies focusing on various aspects of carcinogenesis in the background of fibrosis have advanced significantly in the recent past, allowing us to understand the mechanisms involved in malignant transformation of oral submucous fibrosis (OSF), the most prevalent potentially malignant oral disorder in South Asia. The role of areca nut as a carcinogen has been proven beyond doubt, with a large number of animal studies demonstrating its carcinogenicity, mutagenicity, and genotoxicity. Studies on the molecules implicated in cell cycle regulation, hypoxia, processes leading to DNA double-strand breaks, senescence, and many other pathways related to carcinogenesis have shown ample evidence for the malignant transformation in OSF induced by areca nut. More importantly, the understanding of the mechanisms of malignant transformation may lead to early diagnosis of oral squamous cell carcinoma arising in the background of OSF, which is now considered to constitute a clinicopathologically distinct disease, and the differences are believed to arise from the differential mechanisms of areca nut carcinogenesis. Therefore, the objective of this study is to review the literature on the various mechanisms leading to the malignant transformation of OSF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Oral submucous fibrosis (OSF), first described in 1952, is a potentially malignant disorder associated with betel quid and areca nut chewing, mostly prevalent in the population of the Indian subcontinent and South East Asia. Malignant transformation of OSF to squamous cell carcinoma (SCC) has been estimated to be between 2% and 8%. Our study aimed to review the histopathologic changes that contribute to the understanding of the malignant transformation of OSF. Changes in epithelial thickness and dysplasia characterized by micronuclei, altered AgNOR counts and distribution, keratin protein alteration, and alteration of P63 and E-cadherin characterize the epithelial changes during the transformation of OSF to SCC. Common mechanisms have been proposed to be involved in OSF and SCC, through collagen maturation and their interaction with myofibroblasts and mast cells. Fibrosis-driven vascular constriction that results in epithelial hypoxia has also been proposed as an important mechanism for the malignant transformation of OSF. However, reassessment of the classical view is required, because with demonstration of large blood vasculature in the connective tissue stroma of OSF, the hypothesis associated with tissue hypoxia-induced malignant transformation of OSF can be questioned., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Oral submucous fibrosis (OSF), a common disease in South Asia, is a chronic disorder, and there is a lack of proper scientific understanding about many aspects of the disease. Carcinogenesis in the background of dense fibrosis is considered the most significant aspect of the disease that needs investigation, as the transformation rate is also remarkable compared with other oral potentially malignant disorders. Verrucous growths are a common finding in patients with OSF. We highlight a group of patients who presented with clinically malignant verrucous growths. However, despite the highly suspicious clinical appearance, there was no histologic evidence of invasion. This subgroup of patients with OSF and the inability of the lesion to invade the underlying corium need to be investigated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Oral submucous fibrosis (OSF) is prevalent mostly in Southeast Asia, particularly in the Indian subcontinent. Chewing betel nuts and betel leaves, with or without tobacco, has been associated with OSF. Betel quid contents including guvacine, arecoline, guvacoline, arecaidine, and chavibetol are considered to play an important part in the occurrence of OSF. Transformation of OSF to squamous cell carcinoma (SCC) is variable, but up to 13% conversion of OSF to SCC has been reported. Various genetic and molecular mechanisms impact the malignant transformation of OSF, causing changes in the cell cycle, DNA, keratinocytes, and keratin; tumor-cell proliferation and survival; angiogenesis; fibrosis through epithelial-mesenchymal transitions (EMTs), and tissue hypoxia. All are reviewed here, including potential biomarkers for malignant transformation of OSF. These interactions are not fully understood, but a critical mass of knowledge is building up to ultimately allow the understanding of all mechanisms involved.

Objective: Problems in pre-cancer diagnosis complicate cancer theragnosis as well as life expectancy. There is uncertainty regarding malignant transformation of oral submucous fibrosis (OSF), an oral pre-cancer with dysplastic (OSFWD) and non-dysplastic (OSFWT) subtypes. Understanding the structural, molecular and physical aspects of epithelial homeostasis may be useful., Materials and Methods: Histopathological grading of biopsy sections was performed using H&E staining. Alterations in epithelial surface architecture in different groups was evaluated using scanning electron microscopy (SEM). The expression of crucial epithelial genes (p63, CK-5/6, CK-10, E-cadherin and β-catenin) was studied by immunohistochemistry, Western blot and RT-PCR analysis., Results: SEM observations revealed that the surface epithelial ridge pattern became thick and dense, and pit pattern gradually decreased in OSFWD and oral squamous cell carcinoma (OSCC). p63, ΔNp63 and CK-5/6 were up-regulated in OSFWD and OSCC but down-regulated in OSFWT. CK-10 was down-regulated in OSFWD compared to OSFWT. Cytoplasmic expression of E-cadherin and β-catenin was elevated in dysplastic and cancerous conditions. Moreover, statistical correlation between SEM features (ridges and pits) and molecular attributes demonstrated a significant positive relationship between the ridge-to-pit ratio and p63 population density (r=0.85) and the ridge-to-pit ratio and CK-5/6 intensity (r=0.63)., Conclusions: Molecular changes related to epithelial progressive maturation and cellular proliferation are correlated with concomitant alteration of epithelial surface architecture which helps to predict the malignant potentiality of OSF., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Oral cancers can be preceded by clinically evident oral potentially malignant disorders (OPMDs). The current study evaluated the rate and the time of malignant transformation in the various OPMDs in a cohort of patients from southern Taiwan. Parameters possibly indicative for malignant transformation of OPMDs, such as epidemiological and etiological factors, and clinical and histopathological features were also described., Methods: We followed-up 5071 patients with OPMDs-epithelial dysplasia with oral submucous fibrosis, epithelial dysplasia with hyperkeratosis/epithelial hyperplasia, hyperkeratosis/epithelial hyperplasia, oral submucous fibrosis, lichen planus, and verrucous hyperplasia-between 2001 and 2010 for malignant transformation., Results: Two hundred nineteen of these 5071 OPMD patients (202 men, 17 women; mean age: 51.25 years; range: 30-81 years) developed oral cancers (179 squamous cell carcinomas; 40 verrucous carcinomas) in the same sites as the initial lesions at least 6 months after their initial biopsies. The overall transformation rate was 4.32% (mean duration of transformation: 33.56 months; range: 6-67 months). Additionally, the mean time of malignant transformation was significantly shorter for lesions with than without epithelial dysplasia. The risk of malignant transformation was 1.89 times higher for epithelially dysplastic than non-dysplastic lesions. The anatomical site of OPMD and the presence of epithelial dysplasia were significantly associated with malignant transformation. The hazard rate ratio was 1.87 times larger for tongue lesions than for buccal lesions., Conclusion: Patients with OPMDs require long-term follow up.

Mast cells (MCs) expressing serine proteases; tryptase and chymase, are associated with fibrosis in various diseases. However, little is known about their involvement in oral submucous fibrosis (OSF). Our goal was to evaluate the role of MC tryptase and chymase in the pathogenesis of OSF and its malignant transformation. Immunohistochemical expression of MC tryptase and chymase was evaluated in 20 cases of OSF, 10 cases of oral squamous cell carcinoma (OSCC) and 10 cases of healthy controls. Subepithelial zone of Stage 1 and 2 while deep zone of Stage 3 and 4 OSF demonstrated increased tryptase positive MCs. OSCC revealed a proportionate increase in tryptase and chymase positive MCs irrespective of areas of distribution. An altered balance in the subepithelial and deep distribution of tryptase and chymase positive MCs play an important role in the pathogenesis of OSF and its malignant transformation.

Background: Oral cancer (OC) is the leading cause of death from cancer in men between the ages of 25 and 44 in Taiwan. The survival rate for the last stage of OC is <20% while that for the earliest stage is >75%, which suggests the importance of the diagnosis of oral precancerous lesions (OPLs) in reducing OC mortality. The aim of this study was to analyze the time to OC event after OPL diagnosis, and to suggest the surveillance period necessary according to OPL type., Materials and Methods: This was a retrospective cohort study based on 1.0 million people randomly selected from the Taiwan National Health Insurance Database, which provided data on 3058 adult male patients aged ≥20 years who were diagnosed with OPL for the first time between 1996 and 2009. The patient population was divided into two groups according to the type of lesion: oral submucous fibrosis (OSF) or oral leukoplakia (OLE). Age-standardized incidence rate (ASIR) and hazards rate (HR) were then estimated., Results: The ASIR for OPL showed an increasing trend over the study period, the main contributor to this being OSF. The OSF group demonstrated a higher OC incidence rate than the OLE group., Conclusion: Patients with both OLE and OSF carry a higher risk for OC than those with either OLE or OSF alone, and they may also experience malignant transformation at an earlier date (mostly within 5 years). The 5- and 10-year OC rate for both OLE and OSF was found to be 5% and around 10%, respectively. However, 10 years after the diagnosis of OPL, OSF carries a higher risk of developing into OC than OLE., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Oral submucous fibrosis (OSMF) is a chronic debilitating disease and a premalignant condition of the oral cavity characterized by generalized submucosal fibrosis. Despite its precancerous nature, the molecular biology regarding its malignant potential has not been extensively studied. PTEN, a known tumor suppressor gene is mutated in a majority of human cancers and has also been implicated in several fibrotic disorders. The present study aims to evaluate the expression of PTEN in OSMF and oral squamous cell carcinoma (OSCC) and correlate it with the pathogenesis and malignant transformation of OSMF. 60 cases total of OSMF (30) and OSCC (30) were subjected to immunohistochemistry using PTEN antibody. Ten normal oral mucosa (NOM) specimens were also stained as controls. There was progressive loss of PTEN expression from normal mucosa to OSMF and OSCC (p ≤ 0.001). Significant differences were observed for PTEN expression between NOM and OSMF, OSMF and OSCC as well as NOM and OSCC. Though a progressive loss of PTEN was noticed between early OSMF and advanced OSMF, the variation did not reach statistical significance (p ≥ 0.001). Data suggest that there is a significant loss of PTEN expression in OSMF as compared to normal oral mucosa and that this trend increased from OSMF to OSCC. Thus, alteration of PTEN is likely an important molecular event in OSMF pathogenesis and oral carcinogenesis.

Objective: To investigate the clinical characteristics, pathological and biological behaviors of oral squamous cell carcinomas (OSCC) originated from oral submucous fibrosis (OSF)., Methods: A total of 528 patients with OSCC treated at Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University from 2002 to 2010 were divided into two groups, OSCC originated from OSF and OSCC not originated from OSF. The clinical data regarding age, gender, location, pathological type, metastasis and recurrence rate of these patients were analyzed retrospectively., Results: The mean age of the group of OSCC originated from OSF (45.8 years) was younger than that of the group of OSCC not originated from OSF (55.9 years). The male female ratio of the group of OSCC originated from OSF (32.3:1) was higher than that of the group of OSCC not originated from OSF (2.3:1). The metastasis and recurrence rate of the group of OSCC originated from OSF (13.5%, 39.1%) was higher than that of the group of OSCC not originated from OSF (7.6%, 27.8%.)., Conclusions: OSCC originated from OSF occurs at younger age and more in male, and is clinically more invasive and metastatic.

Oral submucous fibrosis (OSF), a chronic progressive disorder, is regarded as the premalignant lesion of oral squamous cell carcinoma (OSCC). Its distribution is associated with chewing betel quid (BQ). The objective of the present study was to investigate risk factors for the carcinogenesis of OSF in mainland China. A case-control study was performed in 42 patients with OSCC that originated from OSF and 40 OSF controls. Epidemiological data and information related to risk factors were collected using a short structured questionnaire. Odd ratios (OR) and 95% confidence intervals (CI) were derived from logistic regression analysis. In multivariate analysis, only age, duration of BQ chewing, duration of cigarette smoking, and OSF accompanied by oral leukoplakia or oral lichen planus were associated with significantly increased risk for the malignant transformation of OSF. These findings contribute to current knowledge on the prevention of carcinogenesis of OSF in mainland China.

Background: Oral submucous fibrosis (OSF) is a high-risk pre-cancerous condition where 7-13% of these patients develop head and neck squamous cell carcinoma (HNSCC). To date there is no cancer predictive markers for OSF patients. Genomic instability hallmarks early genetic events during malignant transformation causing loss of heterozygosity (LOH) and chromosomal copy number abnormality. However, to date there is no study on genomic instability in OSF. Although this condition is known as a high-risk pre-cancerous condition, there is no data regarding the genomic status of this disease in terms of genetic susceptibility to malignant transformation., Methods: In this study, we investigated the existence of genetic signatures for carcinogenesis in OSF. We employed the high-resolution genome-wide Affymetrix Mapping single nucleotide polymorphism microarray technique to 'fingerprint' global genomic instability in the form of LOH in 15 patient-matched OSF-blood genomic DNA samples., Results: This rapid high-resolution mapping technique has revealed for the first time that a small number of discrete hot-spot LOH loci appeared in 47-53% of the OSF tissues studied. Many of these LOH loci were previously identified regions of genomic instability associated with carcinogenesis of the HNSCC., Conclusion: To our knowledge, this is the first evidence that genomic instability in the form of LOH is present in OSF. We hypothesize that the genomic instability detected in OSF may play an important role in malignant transformation. Further functional association studies on these putative genes may reveal potential predictive oral cancer markers for OSF patients.

Background: Although the effect of betel quid chewing and smoking on oral cancer has been well documented, both influences, dose and duration during life time, on multistate progression of oral pre-malignancy are hardly addressed., Methods: By recruiting a group of male chewers from different occupation groups, we modeled the effects of both duration and quantity of betel quid chewing and smoking on annual incidence rate of developing leukoplakia and average dwelling times (ADTs) staying in leukoplakia and erythroleukoplakia., Results: The annual incidence rate (per year) of leukoplakia was estimated as 0.35% (95% CI: 0.22-0.48%). The ADTs were 24 years for leukoplakia and 7 years for erythroleukoplakia. Annual incidence rate of leukoplakia with high consumption and long duration of betel quid and smoking was higher. Both quantity and duration of smoking and betel quid chewing play minor roles in the influence of ADT. The risks of developing oral cancer after 20 years of follow-up were 42.2% for leukoplakia and 95.0% for erythroleukoplakia., Conclusion: The effects of betel quid chewing and smoking on multistate progressions between oral pre-malignancies were elucidated. These results can be applied to predict long-term risk of malignant transformation varying with different duration and quantity of betel quid and cigarette.

Background: Oral submucous fibrosis (OSF) is a precancerous condition showing extensive fibrosis of the submucosa and affects most parts of the oral cavity, including pharynx and upper third of the oesophagus. The molecules involved in the biological pathways of the fibrotic process appeared to be either down- or upregulated at different stages of the disease. Despite the precancerous nature, malignant transformation of the epithelium in the background of fibrosis has not been studied in detail. HIF-1alpha is a known transcription factor that is induced by hypoxia., Aims: To test the hypothesis that hypoxia plays a role in malignant transformation and progression of OSF., Materials and Methods: We used both formalin-fixed and frozen samples of OSF and normal mucosa to investigate the relationship between HIF-1alpha and epithelial dysplasia using immunohistochemistry and RT-PCR., Conclusions: Our data indicate that HIF-1alpha is upregulated at both protein and mRNA levels in OSF and the correlation with epithelial dysplasia is statistically significant (P < 0.001). We propose that HIF-1alpha may play a role in malignant transformation of OSF. Further, over-expression of HIF-1alpha may contribute to the progression of fibrosis. It may be possible to use HIF-1alpha as a marker for malignant transformation of OSF.

Background: It is generally accepted that the development of cancer in the oral mucosa is preceded by an identifiable non-invasive precursor lesion. The aim of this follow-up study was to estimate the rate and the time to transformation in a group of patients from southern Taiwan with potentially malignant oral epithelial lesions., Methods: The follow-up time is defined as the duration between the onset of the initial diagnosis and the occurrence of confirmed oral cancer. A total of 1458 patients with histological diagnoses of various pre-malignant oral lesions were followed up between 1991 and 2001. The average age at initial diagnosis was 47.5 years. The histological diagnoses were divided into six categories: epithelial dysplasia with hyperkeratosis/epithelial hyperplasia (8.85%); epithelial dysplasia with submucous fibrosis (2.54%); submucous fibrosis (27.57%); hyperkeratosis/epithelial hyperplasia (29.01%); lichen planus (9.80%) and verrucous hyperplasia (22.22%)., Results: Within the cohort of 1458 patients, 44 patients progressed to oral cancer in the same site as the initial lesions with an overall transformation rate of 3.02% and a mean follow-up time of 42.64 months. Eight of the 166 patients with dysplastic lesions and 15 of 423 patients with hyperkeratosis/epithelial hyperplasia progressed to malignancy. The other patients with malignant transformation originated from various pre-cancerous oral lesions and conditions (submucous fibrosis, eight of 402; lichen planus, three of 143; verrucous hyperplasia, 10 of 324)., Conclusion: These results indicate that patients with pre-malignant oral lesions need long-term follow up.

Sixty-six patients with oral submucous fibrosis were followed-up for a period of 17 yr (median observation 10 yr) in Ernakulam District, Kerala, India. Oral cancer developed in five (7.6%) patients. The malignant transformation rate in the same sample was 4.5% over a 15-yr observation period (median 8 yr). These findings impart a high degree of malignant potential to this condition.