Role of mast cells in the pathogenesis of oral submucous fibrosis: a systematic review and meta-analysis.

BACKGROUND: Oral Submucous Fibrosis (OSMF) is an oral potentially malignant disorder (OPMD) that commonly occurs in the South Asian population as there is high usage of areca nut. There has been extensive research on the pathogenesis and treatment of this condition. It is well-established in the scientific literature that mast cells (MC) have a definitive role in several inflammatory disorders. OSMF being a chronic inflammatory disorder, is also expected to have increased MCs. Hence, this review aims to evaluate the role of MCs in the pathogenesis of OSMF. METHODS: A systematic search of articles was performed by two of the authors independently in PubMed, Scopus, Embase, Web of Science, and Google Scholar using the appropriate keywords and Boolean terms. The risk of bias was assessed using the Modified Newcastle-Ottawa Scale. The meta-analysis was performed with R studio software (Version: 4.4.0, Year: 2024, Company: The R foundation for statistical computing). RESULTS: The search retrieved 36 studies, of which 16 were suitable for the review. There is evidence for a marked increase in the number of MCs in OSMF than the normal mucosa upon analyzing the retrieved articles. However, when comparing the grades of OSMF, there are variations in the reports. As all the retrieved articles were case-control studies, the risk of bias was analyzed using the Modified New Castle Ottawa Scale. All the studies scored in the good category (Score 6-9). The pooled effect size shows the Standard Mean Deviation (SMD) to be 0.09, 95% confidence interval (CI) [-0.18;0.37] to lie on either side of no effect. Hence the role of MCs in OSMF has not been established because of homogeneity and consistent sampling error. CONCLUSION: Our systematic review does suggest a definitive role of mast cells in the progression of OSMF. However, there is a lack of methodological rigor in the included studies. This may contribute to diluting the results.

Novel role of CD34+ stromal cells/telocytes in oral submucous fibrosis development and its malignant transformation.

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.

Areca nut-induced oral fibrosis - Reassessing the biology of oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) is a pathological condition characterized by excessive tissue healing resulting from physical, chemical, or mechanical trauma. Notably, areca nut consumption significantly contributes to the development of oral fibrosis. The current definition of OSF, recognizing its potential for malignant transformation, necessitates a more comprehensive understanding of its pathophysiology and etiology. HIGHLIGHTS: Areca nut induces fibrotic pathways by upregulating inflammatory cytokines such as TGF-ß and expressing additional cytokines. Moreover, it triggers the conversion of fibroblasts to myofibroblasts, characterized by α-SMA and γSMA expression, resulting in accelerated collagen production. Arecoline, a component of areca nut, has been shown to elevate levels of reactive oxygen species, upregulate the expression of various cytokines, and activate specific signaling pathways (MEK, COX2, PI3K), all contributing to fibrosis. Therefore, we propose redefining OSF as "Areca nut-induced oral fibrosis" (AIOF) to align with current epistemology, emphasizing its distinctive association with areca nut consumption. The refined definition enhances our ability to develop targeted interventions, thus contributing to more effective prevention and treatment strategies for oral submucous fibrosis worldwide. CONCLUSION: Arecoline plays a crucial role as a mediator in fibrosis development, contributing to extracellular matrix accumulation in OSF. The re-evaluation of OSF as AIOF offers a more accurate representation of the condition. This nuanced perspective is essential for distinguishing AIOF from other forms of oral fibrosis and advancing our understanding of the disease's pathophysiology.

[Oral squamous cell carcinoma in the background of oral submucous fibrosis - a systematic review]. / Skvamozno-kletochnaya kartsinoma polosti rta na fone podslizistogo fibroza polosti rta - sistematicheskii obzor.

Oral squamous cell carcinoma (OSCC) in the background of oral submucous fibrosis (OSMF) is one of the most common presentations of oral cancer among Asian population. OSCC arising in the background of OSMF (OSCC with OSMF) has been a topic of interest among researchers recently and a few studies have considered this to be a distinct clinicopathological entity. This systematic review analyses the demographic and clinicopathological variations of OSCC with OSMF from conventional OSCC to evaluate the distinctiveness of OSCC with OSMF. A comprehensive search from PubMed, Google scholar and manual search were carried out and 4 articles were retrieved and analysed systematically. Out of the total 377 OSCC with OSMF cases and 542 conventional OSCC, males were found to be predominantly affected (82.7% and 73.6%). 47% of the OSCC with OSMF cases were well differentiated squamous cell carcinomas as against 33.4% in conventional OSCC. Lymph node metastases were seen predominantly in conventional OSCC (49.1%) than OSCC with OSMF cases (40.7%). OSCC with OSMF were more prevalent in males and showed better tumour differentiation and lesser lymph node metastasis. Even though the present results inculpate OSCC with OSMF as a distinct clinicopathological entity, there is a dire need for thorough investigation.

Serum and salivary Cu/Zn ratio as a diagnostic biomarker for oral submucosal fibrosis: an analysis of trace metals and LOX gene variants.

This study aimed to analyze the serum and salivary levels of copper (Cu), zinc (Zn), iron (Fe), chromium (Cr), manganese (Mn) and the Cu/Zn ratio and investigate the association between LOX gene variants (rs18800449 and rs2288393) and oral submucosal fibrosis (OSMF). A total of 250 subjects were included in the study: OSMF patients (n = 50), areca nut chewers without OSMF (n = 100) and controls (n = 100). Trace metals were measured using an atomic absorption spectrophotometer, while LOX gene variants were genotyped using the tetra primer amplification refractory mutation system (tetra ARMS) polymerase chain reaction (PCR) method. The results showed significant variations in serum and salivary Cu, Zn, Fe and Cr levels and serum Mn concentrations among the three groups (p < 0.0001). Serum Cu levels were significantly higher in OSMF patients, while serum Zn levels were significantly lower. Both serum and salivary Cu/Zn ratios demonstrated a statistically significant difference (p < 0.0001) and diagnostic potential to differentiate OSMF from chewers and controls. However, LOX gene variants did not show an association between OSMF and chewers, except for rs1800449 genotypes, which showed a significant and increased risk with the AA genotype in OSMF patients compared to controls (OR = 7.58; 95%CI 2.30-24.97). The study suggests that trace elements and genetic variants may impact the etiology of OSMF. The findings may aid in early diagnosis, suitable treatment, and as a prognostic indicator for disease progression.

Jiawei Danxuan Koukang Alleviates Arecoline Induced Oral Mucosal Lesions: Network Pharmacology and the Combined Ultra-High Performance Liquid Chromatography (UPLC) and Mass Spectrometry (MS).

Purpose: Arecoline is one of the main toxic components of arecoline to cause oral mucosal lesions or canceration, which seriously affects the survival and life quality of patients. This study analyzed the mechanism of Jiawei Danxuan Koukang (JDK) in alleviating arecoline induced oral mucosal lesions, to provide new insights for the treatment of oral submucosal fibrosis (OSF) or cancerosis. Methods: Metabolomics was applied to analyze the composition of JDK and serum metabolites. The active ingredients of JDK were analyzed by the combined ultra-high performance liquid chromatography and mass spectrometry. The target network of JDK, metabolites and OSF was analyzed by network pharmacology, and molecular docking. Oral mucosal lesions and fibrosis were analyzed by HE and Masson staining. Cell differentiation, proliferation and apoptosis were detected. The expressions of α-SMA, Collagen I, Vimentin, Snail, E-cadherin, AR and NOTCH1 were detected by Western blot. Results: Arecoline induced the gradual atrophy and thinning of rat oral mucosal, collagen accumulation, the increase expressions of fibrosis-related proteins and Th17/Treg ratio. JDK inhibited arecoline-induced oral mucosal lesions and inflammatory infiltration. Arecoline induced changes of serum metabolites in Aminoacyl-tRNA biosynthesis, Alanine, aspartate and glutamate metabolism and Arginine biosynthesis pathways, which were reversed by M-JDK. Quercetin and AR were the active ingredients and key targets of JDK, metabolites and OSF interaction. Arecoline promoted the expression of AR protein, and the proliferation of oral fibroblasts. Quercetin inhibited the effect of arecoline on oral fibroblasts, but was reversed by AR overexpression. Arecoline induced NOTCH1 expression in CAL27 and SCC-25 cells, and promoted cell proliferation, but was reversed by M-JDK or quercetin. Conclusion: JDK improved the arecoline-induced OSF and serum metabolite functional pathway. Quercetin targeted AR protein to improve arecoline-induced OSF. JDK and quercetin inhibited arecoline-induced NOTCH1 protein expression in CAL27 and SCC-25 cells to play an anti-oral cancer role.

Clinicopathological characteristics of oral squamous cell carcinoma arising from oral submucous fibrosis: A systematic review.

Introduction: Oral submucous fibrosis (OSMF) is considered to be a potentially malignant oral disorder with high risk of malignant transformation. Oral squamous cell carcinoma (OSCC) arising from OSMF has peculiar clinical and histopathological features. Aim: To assess the clinicopathological features of OSCC arising in the background of OSMF in an attempt to identify the patients with OSMF who are at increased risk of developing OSCC. Methodology: A systematic review was performed based on PRISMA guidelines to include articles published until May 2021 in English, relating the clinicohistopathological characteristics of OSCC arising from OSMF (OSMF-OSCC) or OSMF associated with OSCC (OSCC-OSMF). All the eligible articles were analyzed and relevant data were extracted. Results: Seventeen articles were included for systematic review after following strict inclusion and exclusion criteria. The malignant transformation rate of OSMF-OSCC ranged from 1.9 to 9.13 and the prevalence of OSCC-OSMF ranged from 2.8 to 66. The mean age of the patients ranged from 36.6 years to 47.2 years and buccal mucosa was the common site to be affected. Majority of the OSCC-OSMF was well-to-moderately differentiated and majority of them did not metastasize to the lymph nodes. Conclusion: OSCC associated with OSMF presents at a younger age with early tumor stage, better differentiation, and better prognosis when compared to OSCC not associated with OSMF. However, more multicentric prospective studies with large sample size are required to determine the true biologic behavior of OSCC arising in the background of OSMF to establish less aggressive treatment strategies considering them as a separate entity.

Left colonic localization, non-granular morphology, and pit pattern independently predict submucosal fibrosis of naïve colorectal neoplasms before endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) represents the method of choice for removal of large colorectal neoplasms with suspected submucosal invasion. Presence and degree of submucosal fibrosis increases ESD duration and technical complexity, reduces the rate of curative resection and reduces safety profile. The aim of the study was to identify pre-procedural predictive factors of submucosal fibrosis in naïve colorectal neoplasms and to assess the impact of fibrosis on technical and clinical ESD outcomes. METHODS: All consecutive ESD performed between 2014 and 2021 were retrieved from a prospectively collected database. For each patient, pre-procedural, procedural, and post-procedural data were recorded. Logistic regression was used to identify pre-procedural predictive factors for submucosal fibrosis. The study was approved by Institutional Reviewer Board and registered on ClinicalTrials.gov (NCT04780256). RESULTS: One hundred-74 neoplasms (46.6% rectum, 21.8% left colon, 31.6% right colon; size 34.9 ± 17.5 mm) from 169 patients (55.0% male; 69.5 ± 10.4-year-old) were included. 106 (60.9%) neoplasms were granular type laterally spreading tumor (LST-G), 42 (24.1%) non-granular (LST-NG), and 26 (14.9%) sessile; invasive pit pattern was observed in 90 (51.7%) lesions. No fibrosis (F0) mild (F1) and severe (F2) were observed in 62 (35.6%), 92 (52.9%), and 20 (11.5%), respectively. Left colonic localization [OR 3.23 (1.1-9.31)], LST-NG morphology [OR 5.84 (2.03-16.77)] and invasive pit pattern [OR 7.11 (3.11-16.23)] were independently correlated to submucosal fibrosis. Lower curative resection rate (59.8% vs. 93.5%, P < 0.001) was observed in case of fibrosis; the incidence of adverse events was higher in case of severe fibrosis (35.5%) compared to no (3.2%) and mild fibrosis (3.3%; P < 0.001). Procedure time was significantly impacted by presence and degree of fibrosis (P < 0.001). CONCLUSIONS: Left colonic localization, LST-NG morphology, and invasive pit pattern are independent predictors of fibrosis, affecting technical and clinical ESD outcomes. Pre-procedural stratification is pivotal to estimate procedure time, required operator's experience and advanced dissection techniques. Cecinato P et al. Left colonic localization, non-granular morphology, and pit pattern independently predict submucosal fibrosis of colorectal neoplasms before endoscopic submucosal dissection. Surg Endosc. 2023.

Evaluation of Copper Levels in Dental Calculus of OSF Patients with Chewing Dried Areca-Nut Quids in Hunan Province of Mainland China.

Dental calculus is a potential material that can be used for assessing chronic exposure to trace heavy metals in oral cavity as it is a long-term reservoir. The aim of this study was to investigate the correlation between dental calculus copper levels and risk of oral submucous fibrosis (OSF) due to chewing dried areca-nut quids in Mainland China. This study included 34 OSF (grade 1) sufferers with dried areca-nut quids chewing as the patient group and 23 healthy individuals without areca-nut chewing as the control group. The dental calculus sample was obtained from all 57 participants and evaluated by inductively coupled plasma mass spectrometry (ICP-MS) for dental calculus level of copper. This work revealed that the mean copper level of dental calculus was significantly higher in OSF (grade 1) sufferers with areca-nut chewing than those in healthy individuals without areca-nut chewing (p < 0.001). This work provided an evidence to support that there may be a positive correlation between elevated levels of copper in dental calculus caused by chewing dried areca-nut quids and an increased risk of developing OSF in Mainland China.

Clinicopathological Evaluation of Tobacco-related Oral Mucosal Lesions.

AIM: To clinically evaluate the nature of precancerous and cancerous lesions associated with tobacco consumption habit and to correlate clinical profile with the histopathological findings of clinically suspected precancerous and cancerous lesions. MATERIALS AND METHODS: These included the examination of patients who visited the outpatient department (OPD) of the institute that includes 1,500 patients who had tobacco chewing habits were classified into the following two groups according to their characteristics. The study group comprised 270 patients, of which 170 gave consent for biopsy and 100 patients who not gave consent were counseled for tobacco cessation. RESULTS: Among 270 patients, the highest number of patients, 146 (54.07%) patients, were found to be smokeless tobacco consumers followed by 65 (24.07%) patients who were smoked tobacco consumers while 59 (21.85%) patients were found to have both the habits. Wide variation was noted in duration and frequency of habit. Most prevalent site was the buccal mucosa affected in 138 (51.11%) patients who consumed both smoked as well as smokeless tobacco. And on clinical examination, 138 (51%) patients had leukoplakia followed by 54 (20%) patients with oral squamous cell carcinoma and 40 (15%) patients with oral submucous fibrosis (OSMF). Other patients were tobacco pouch keratosis 17 (6%), smoker's melanosis 8 (3%), smoker's palate 7 (3%), and erythroplakia 6 (2%). The patients who gave consent (170 patients) were evaluated histopathologically to correlate with clinical findings. CONCLUSION: Tobacco-related oral lesions are also high, which brings an alarming signal toward the development of cancer. Our contribution as healthcare providers can be made by conducting more oral health education programs and educating the general population about the adverse effects of tobacco. The appropriate clinical assessment and categorization of all these lesions aided us in motivating patients to undergo necessary treatments and also to discontinue their habits in order to prevent deterioration of their conditions. CLINICAL SIGNIFICANCE: Set up de-addiction centers in dental colleges and help tobacco users in discontinuing their habits. Interestingly, this study also served as a mirror for those patients who were unaware of the lesions they were giving abode to in their oral cavities.

Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics.

Oral submucous fibrosis (OSF) belongs to a group of potentially malignant disorders that are characterized by the progressive fibrosis of the lining mucosa as well as an increasing loss of tissue mobility [...].

Factors for conversion risk of colorectal endoscopic submucosal dissection: a multicenter study.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become a widely accepted treatment method for colorectal tumors; however, there are some persistent problems. This multi-center study aimed to characterize the risk factors for incomplete resection and perforation in standardized colorectal ESD procedures. METHODS: This study included 2423 consecutive patients who underwent ESD for 2592 colorectal tumors between August 2013 and December 2018 at 11 institutions (1 academic hospital and 10 affiliated hospitals) from the Hiroshima GI Endoscopy Research Group. We evaluated the risk factors for interruption, piecemeal resection, and perforation of standardized colorectal ESD in relation to clinicopathologic and endoscopic characteristics. RESULTS: The incidences of interruption, piecemeal resection, and perforation were 0.7%, 2.9%, and 3.0%, respectively. Multivariate analysis identified the following risk factors for interruption: perforation during the procedure, deep submucosal invasion (> 1000 µm), poor scope operability, and severe submucosal fibrosis. The risk factors for piecemeal resection included poor scope operability, severe submucosal fibrosis, and procedure time (≥ 85 min). The risk factors for perforation during the procedure were severe submucosal fibrosis, poor scope operability, procedure time (≥ 85 min), and tumor size (≥ 40 mm). Independent risk factors for severe submucosal fibrosis included a history of biopsy and lesions located on the fold or flexure. CONCLUSIONS: Severe submucosal fibrosis and poor scope operability are the common risk factors for interruption, piecemeal resection, and perforation in standardized colorectal ESD.

Oral submucous fibrosis induced by graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is one of the most common and serious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). About 45%∼83% of patients develop GVHD in the oral cavity. There has no medical records of oral submucous fibrosis (OSF) induced by GVHD after allo-HSCT, which should be brought to the attention of dentists.

Correlation of Clinical Features in Oral Submucous Fibrosis: A 9-Year Retrospective Study.

BACKGROUND: Oral Submucous Fibrosis is a chronic debilitating disease and potentially malignant disorder of the oral cavity known in medical literature for a long time. The study aims to correlate the clinical staging of Oral Submucous Fibrosis with various clinical findings of the oral mucosa like hyperpigmentation, erosions, ulcerations, VAS score, tongue protrusion, and cheek flexibility. METHODS: A retrospective observational study was undertaken and records of 1267 clinically diagnosed cases of OSMF were included in the study. Clinical grading was done as per criteria by Lai DR et al. The observations were tabulated and subjected to statistical analysis using SPSS software. RESULTS: In our study, the incidence of hyperpigmentation, erosions, and ulcerations was higher in Group C OSMF. Visual analog scores in the range of 5-6 was noted in 40.9% of the total subjects, out of which 36.2% belonged to Group C OSMF. Tongue protrusion of less than 25 mm was seen in 10.65% of the subjects. Cheek flexibility of less than 0.6 cm was seen in 19.62% of the subjects, most of which belonged to Group D. CONCLUSION: In our study, we found an increase in the occurrence and severity of symptoms with an increase in grades of OSMF, but this increase was not observed to be consistent. Hence classification based on a single clinical entity cannot be sufficient and correlations to other clinical findings should be studied over a large population and a multi-tier classification could be proposed in the future.

Immunopathogenesis of oral submucous fibrosis by chewing the areca nut.

Oral submucous fibrosis (OSF) is a chronic, progressive, scarring, and premalignant disease of the oral mucosa. Its pathogenic factors are complex and include chewing areca nuts or other spicy food items, nutrition, and genetic and immune factors. Recently, immune factors have become the focus of medical research, with increased attention being paid to the role of immune regulation in diseases, particularly tumors. OSF is accompanied by obvious changes in the immune microenvironment. The aim of this review is to discuss the potential relationship of OSF and areca nuts genetic with the immune system, including lymphocytes, macrophage, Langerhans cell, mast cell, and substances released by activated immune cells, to determine the pathogenesis and treatment of OSF from an immunologic viewpoint.

Why do Only Certain Cases of Oral Submucous Fibrosis Undergo Malignant Transformation?

Oral submucous fibrosis (OSMF) causes desmoplasia and rigidity of submucosa of the oral cavity, resulting in reduced mouth opening, and in advanced stage causes difficulty in swallowing. OSMF has poor morbidity in terms of oral function as well as general health due to loss of oral function, such as eating. In severe conditions, it can cause dysphagia and hearing loss. Various clinicians have tried the different treatment modalities to reverse the disease process, but with limited success and that too in alleviating the associated symptoms.

Predictors of the severity of oral submucous fibrosis among gutka consumers: a regression analysis.

Oral submucous fibrosis (OSMF) is an insidious chronic disease of the oral mucosa that is characterised by severely limited mouth opening, blanching of the oral mucosa, and a burning sensation in the oral cavity. Consumption of betel nut and/or gutka are the known risk factors. We undertook this study to correlate the frequency and duration of gutka intake with the severity of OSMF and to determine the predictors of severe OSMF (mouth opening <20mm). A cross sectional study was conducted on 300 participants (who were known gutka chewers) selected at the Baqai Dental College and Fatima Hospital, Karachi, Pakistan. Participants' medical and dental histories were recorded. Informed consent was obtained, and clinical oral examination was done. Information regarding the extent of mouth opening, chewing habits, frequency and duration of gutka intake, the site of placing gutka, duration of chewing, and whether they swallowed or spat out the gutka were collected. A standardised questionnaire was used to document the findings. Binary logistic regression was applied using the severity of OSMF (mouth opening <20mm) as an outcome variable. Out of 300 participants, 172 (57.3%) were males; mean (SD) age of the sample was 38.2 (12.3) years. A total of 156 (52%) participants had the habit of chewing gutka, of which 213 (71%) had clinical stage I OSMF, 75 (25%) had stage II, and 12 (4%) had stage III. As per functional staging, 18 (6%) subjects had mouth opening <20mm. Nearly 144 (48%) participants were consuming other forms of tobacco in addition to the gutka. Patients with palpable bands = 232 (77.3%), ulcerative lesions = 212 (70.7%), altered taste sensation = 210 (70%) and altered hunger = 252 (85.7%) were common findings. The duration of gutka intake was found to be positively correlated with the severity of OSMF; however; its frequency was not. Among intraoral findings, the presence of red and white lesions inside the mouth was the most significant predictor of the severity of OSMF.

Oral submucous fibrosis presenting with histopathological lichenoid changes as predominant feature: Report of five cases and review of the literature.

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity associated with habitual chewing of quid, with a high incidence among populations of the Indian subcontinent and Southeast Asia. Clinically, its initial manifestation may mimic oral lichen planus or lichen sclerosus. If the habit is not halted, the mucosa gets leathery and thickened, and fibrous bands form causing significant morbidity. Microscopically, it is characterized by atrophic epithelium, loss of rete ridges, and hyalinization of lamina propria. Of note, these hallmark histopathological features may be overlooked in the unusual presence of lichenoid interface changes, which may lead to the wrong diagnosis. We present herein five cases in which the rare joint appearance of OSF and lichenoid reaction features posed a diagnostic challenge. Due to its progressive nature and malignant potential, the presence of oral lichenoid changes overlying submucous hyalinization, in the right clinical and demographic setting, should raise suspicion of OSF and prompt actions directed at quid-chewing discontinuation.