Longitudinal outcomes of trismus release with free-flap reconstruction in primary and secondary oral submucous fibrosis-related trismus.

BACKGROUND: Oral submucous fibrosis is a global health concern associated with betel quid use and results in trismus, which can be either primary or secondary in origin. Severe cases often require trismus release with free-flap reconstruction. This study examined longitudinal outcome trends following trismus release and compared the outcomes of patients with primary and secondary oral submucous fibrosis-related trismus. METHODS: We conducted a retrospective cohort study by including patients who underwent trismus release between 2013 and 2022. All procedures were performed by a single surgical team to ensure technique standardisation. We measured the maximum mouth opening, the interincisal distance, perioperatively and 1, 2, 3, 4, 6 and 12 months post-operatively. Data were analysed using generalised estimating equations. RESULTS: A total of 35 patients were included in the study, 17 with primary and 18 with secondary oral submucous fibrosis-related trismus. Initially, patients with primary oral submucous fibrosis-related trismus had greater interincisal distance gains than those with secondary oral submucous fibrosis-related trismus (p = 0.015 and p = 0.025 at 3 and 4 months post-operatively, respectively). However, after 12 months, this initial advantage faded, with comparable interincisal distance improvements in patients with primary and secondary disease, despite the more complex surgical procedures required in secondary cases. CONCLUSION: Surgeons should carefully consider the benefits of trismus release procedures for patients with secondary oral submucous fibrosis-related trismus by recognising the changes in post-operative outcomes.

Proliferative verrucous leukoplakia/multifocal leukoplakia in patients with and without oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) and proliferative verrucous leukoplakia (PVL) are established as oral potentially malignant disorders. Dual pathology of the two conditions is not commonly encountered in clinical practice. This study aims to present a case series of multifocal leukoplakia in patients with and without OSF to outline the clinical behavior and challenges in the management of this high-risk group in clinical practice. MATERIAL AND METHODS: We retrospectively analyzed cases of six Indian patients (four with OSF) managed over a period of 5.5 to 13 years at the Government Dental College, Nagpur. Patient data consisting of age, gender, medical history, habits, clinical findings, and biopsy reports were recorded at the initial visit. During follow-up visits, the clinicopathological data were reassessed. When surgical intervention failed to arrest the disease or when surgery was contraindicated metronomic therapy with Folitrax 15 mg once a week and Celecoxib 100mg twice daily was initiated. RESULTS: All patients developed PVL after the initial pathology diagnosis of OSF or oral leukoplakia. Initial lesions were either homogenous or non-homogenous leukoplakia. All patients developed multiple recurrences, regional or systemic metastasis. Despite thorough interventions, the patients died of, or with the disease. CONCLUSIONS: The occurrence of two or more oral potentially malignant disorders poses challenges in patient management and possibly presents a higher risk of malignant transformation. More clinical trials are necessary to assess the benefits of metronomic therapy for patients diagnosed with aggressive PVL concurrently found with OSF.

Etiology of Oral Potentially Malignant Disorders and Squamous Cell Carcinoma Based on Cellular Stress Regulation and Matrix Stiffness.

The oral cavity serves as the initial segment of the digestive system and is responsible for both nutritional supplementation and the mechanical breakdown of food. It comprises distinct hard and soft tissues; the oral mucosa is subject to mechanical stress and interaction with microbiota. In oral cancer, tumors exhibit abnormal cellular networks and aberrant cell-cell interactions arising from complex interplays between environmental and genetic factors. This presents a challenge for clinicians and researchers, impeding the understanding of mechanisms driving oral cancer development and treatment strategies. Lesions with dysplastic features are categorized under oral potentially malignant disorders, including oral leukoplakia, erythroplakia, oral submucous fibrosis, and proliferative verrucous leukoplakia, carrying a high malignancy risk. In this review, we discuss oral cancer cell characteristics and the stiffness of the surrounding matrix. We also discuss the significance of stiffness equilibrium in oral potentially malignant disorders, particularly oral submucous fibrosis, possibly triggered by mechanical stress such as betel quid chewing.

5-aminolevulinic acid photodynamic therapy for extensive oral leukoplakia with concomitant oral submucous fibrosis: A case report.

BACKGROUND: Oral leukoplakia and oral submucous fibrosis are potentially malignant disorders of the oral cavity, with high rates of recurrence and malignant transformation. Notably, the malignant transformation rate of oral leukoplakia with concomitant oral submucous fibrosis is significantly higher than that of oral submucous fibrosis or oral leukoplakia alone. However, the management of these conditions is not well defined. Photodynamic therapy is a minimally invasive treatment modality that effectively targets oral potentially malignant disorders, such as oral leukoplakia, erythroleucoplakia, and verrucous hyperplasia, with the advantages of being repeatable and leaving no scarring. CASE PRESENTATION: We report the case of a 42-year-old man with concomitant oral leukoplakia and oral submucous fibrosis almost involving the entire right buccal mucosa, who underwent six sessions of topical 5-aminolevulinic acid-mediated photodynamic therapy. RESULTS: Photodynamic therapy successfully eradicated whitish plaques and improved mouth opening without any adverse effects. Although photodynamic therapy failed to completely reverse the pathological changes, grading of epithelial dysplasia did not progress and clinical recurrence was not found during the 10-month follow-up. CONCLUSION: In conclusion, topical 5-aminolevulinic acid-mediated photodynamic therapy appears safe and has excellent clinical efficacy against oral leukoplakia-concomitant oral submucous fibrosis, but long-term follow-up is necessary.

Paediatric Ulcerative Colitis Is a Fibrotic Disease and Is Linked with Chronicity of Inflammation.

BACKGROUND AND AIMS: Intestinal fibrosis has recently been characterised in adult ulcerative colitis and may affect motility, diarrhoea, and the symptom of urgency. We aimed to charactersze the presence of fibrosis in paediatric patients with ulcerative colitis, and its link to severity and chronicity of mucosal inflammation, as well as clinical factors of severity. METHODS: We performed a single-centre cross-sectional study in children ages 1-18 years with ulcerative colitis, undergoing colectomy or proctocolectomy. Tissue cross-sections were derived from proximal, mid, and distal colon and rectum, and inflammation and fibrosis were graded based on previously developed scores. Clinical data were collected prospectively. RESULTS: From 62 patients, 205 intestinal sections were evaluated. Median age at diagnosis was 13 years, 100% had extensive colitis, and all resections were done for refractory disease. The presence, chronicity, and degree of inflammation were linked with the presence of fibrosis. Thickness of the muscularis mucosa was also linked with presence and chronicity of inflammation. The overall submucosal fibrosis burden was associated with prior anti-tumour necrosis factor use. CONCLUSIONS: Paediatric patients with ulcerative colitis exhibit colorectal submucosal fibrosis and muscularis mucosa thickening, which correlate with the presence, chronicity, and degree of mucosal inflammation. Fibrosis should be recognised as a complication of paediatric ulcerative colitis, and ulcerative colitis should be considered a progressive disease.

Oral submucous fibrosis stimulates invasion and epithelial-mesenchymal transition in oral squamous cell carcinoma by activating MMP-2 and IGF-IR.

Oral submucous fibrosis (OSF) involves a high risk of malignant transformation and has been implicated in oral cancer. Limited studies have been conducted on the role of OSF in relation to the invasive capabilities and epithelial-mesenchymal transition (EMT) in oral cancer. Herein, we investigated the effects of OSF on the microenvironment of human oral cancer cells. The results showed that the conditioned medium (CM) of fibrotic buccal mucosal fibroblasts (fBMFs) strongly induced the invasion of oral cancer cells and increased the activities of matrix metalloproteinase-2. OSF significantly induced the EMT in oral cancer cells and downregulated epithelial markers, such as E-cadherin, but significantly elevated vimentin, fibronectin, N-cadherin, RhoA, Rac-1 and FAK. Insulin-like growth factor-1 (IGF-1) was elevated in OSF. The protein levels of the IGF-1R were upregulated specifically in fBMF CM treatment for oral cancer cells, and the IGFR gene was confirmed by The Cancer Genome Atlas patient transcriptome data. The Kaplan-Meier curve analysis revealed that patients with oral squamous cell carcinoma and high IGFR expression levels had poorer 5-year survival than those with low IGFR expression (p = 0.004). The fBMF-stimulated EMT cell model may recapture some of the molecular changes during EMT progression in clinical patients with oral cancer.

Differential expression of programmed death-1 and its ligand, programmed death ligand-1 in oral squamous cell carcinoma with and without oral submucous fibrosis.

OBJECTIVE: The aim of our study was to investigate the expression of programmed death ligand-1 (PD-L1)/programmed death-1 (PD-1) between oral squamous cell carcinoma (OSCC) patients with and without oral submucous fibrosis (OSF), and its correlation with clinic-pathologic features and its prognostic value. METHODS: PD-L1 and PD-1 expression was evaluated by immunohistochemical staining, double immunofluorescent staining and real-time PCR, and the correlation of PD-L1/PD-1 expression with clinical outcome was assessed. RESULTS: The level of PD-L1 expression was significantly higher in OSCC with OSF than in OSCC without OSF (p = 0.006). Moreover, PD-L1 expression was strongly correlated with lymph node metastasis (p = 0.016), and advanced tumor stage (p = 0.030). Increased PD-L1 expression was positively correlated with the incidence of OSCC with OSF (p = 0.006, p = 0.008, respectively). PD-L1 expression was an independent marker of unfavorable prognosis (p = 0.035, p = 0.048, respectively). High PD-L1 expression had a significantly worse outcome in OSCC patients with OSF (p = 0.014). Double immunofluorescent staining showed that OSCC with OSF were more strongly expressed both PD-L1 and PD-1 than OSCC without OSF. Moreover, the expression of PD-L1 were upregulated in OSCC tissues than normal control (p = 0.0422), and both PD-L1 and PD-1 was significantly higher in OSCC with OSF than OSCC without OSF tissues (p = 0.0043 and, p = 0.0012, respectively). CONCLUSIONS: The present study suggested that PD-L1 may be an unfavorable indicator for prognosis. PD-L1/PD-1 signaling might play an important role in the malignant transformation of OSF, and targeting PD-L1/PD-1 signaling may be a new therapeutic strategy for OSCC, especially in OSCC patients with OSF.

Impact of socioeconomic inequalities on quality of life in oral submucous fibrosis patients.

AIM: The purpose of this study was to analyze the impact of socioeconomic characteristics on oral health-related quality of life (OHRQoL) in patients with oral submucous fibrosis (OSF). METHODS:  A total of 300 OSF patients' quality of life (QoL) data were obtained using OHRQoL-OSF and global self ratings of oral health and overall wellbeing. The socioeconomic status (SES) of participants was analyzed by using modified Kuppuswamy scale. RESULTS: OSF patients with lower SES had worse OHRQoL as compared with those with middle and upper SES (p < 0.001). The household income of the family was found to be strongly associated with poor OHRQoL. CONCLUSION: Socioeconomic characteristics should be considered in the holistic management of OSF as it has been strongly associated with the OHRQoL of these patients.

Mouth-opening device as a treatment modality in trismus patients with head and neck cancer and oral submucous fibrosis: a prospective study.

OBJECTIVES: This study investigated the clinical effectiveness of intervention with an open-mouth exercise device designed to facilitate maximal interincisal opening (MIO) and improve quality of life in patients with head and neck (H&N) cancer and oral submucous fibrosis (OSF). MATERIALS AND METHODS: Sixty patients with H&N cancer, OSF, and trismus (MIO < 35 mm) participated in the functional rehabilitation program. An open-mouth exercise device intervention group and conventional group, each consisting of 20 patients, underwent a 12-week training and exercising program and follow-up. For the control group, an additional 20 patients were randomly selected to match the demographic characteristics of the aforementioned two groups. RESULTS: The patients' MIO improvements in the aforementioned three groups were 14.0, 10.5, and 1.3 mm, respectively. CONCLUSION: Results of this study confirm the significant improvement in average mouth-opening range. In addition, according to patient feedback, significant improvements in health-related quality of life and reductions in trismus symptoms occurred in the open-mouth exercise device group. CLINICAL RELEVANCE: This newly designed open-mouth exercise device can facilitate trismus patients with H&N cancer and OSF and improve mouth-opening range and quality of life.

"Introducing Modified Dakkak and Bennett Grading System for Indian Food in Oral Submucous Fibrosis": A Dharwad Study.

Oral submucous fibrosis (OSMF) is one of the "diseases of civilization" because of the large differences in prevalence among races, geographic areas, and individuals at different socioeconomic levels. It is a premalignant condition strongly associated with the habit of chewing areca nuts. This study is to compare the scoring system in relation to the burning sensation of mouth and dysphagia using the visual analog scale (VAS) and Dakkak and Bennett grading system for Indian food, respectively, in OSMF patients. This study was a randomized clinical trial incorporating a total of 50 cases of OSMF divided into a control group (antioxidant therapy) and pentoxifylline test cases. Values for burning sensation of the mouth using the VAS and modified Dakkak and Bennett grading system for Indian food were recorded. Statistical analyses were done using t test, Mann -Whitney U test, and one-way analysis of variance (ANOVA) test. Patients subjected to pentoxifylline when compared to the control group showed significant reduction in dysphagia for Indian food. Burning sensation was recorded according to the visual analogue scale. Significant reduction in burning sensation was seen in the pentoxifylline group when compared to the control group. This grading system provides quantitative and qualitative parameters in patients with OSMF.

Development and validation of oral health-related quality of life measure in oral submucous fibrosis.

OBJECTIVE: The aim of this study was to develop and assess the validity and reliability of disease-specific oral health-related quality of life (OHRQoL) instrument for oral submucous fibrosis (OSF). MATERIALS AND METHODS: Items for the OHRQoL-OSF were generated from personal interviews and focus group discussions, the existing questionnaires, reviews of literature and inputs from expert's panel. Item reduction was performed by clinical impact method followed by pretesting of the developed questionnaire. The validity and reliability of the instrument were then examined. RESULTS: Forty-five items were generated from qualitative data and item pooling from various sources. After item reduction, 17 items were finalized with four domain-structure having Eigenvalues greater than 1. OHRQoL-OSF was shown to be valid in distinguishing patients with varying degrees of OSF severity. For the concurrent validity, the observed impact of OSF based on OHRQoL-OSF significantly correlated with Oral Health Impact Profile and global self-ratings of oral health and overall well-being. OHRQoL-OSF and all its domains demonstrated good internal consistency reliability with Cronbach's alpha ˃0.7 and excellent test-retest reliability (ICC = 0.96). CONCLUSION: The first disease-specific OHRQoL-OSF instrument appeared to be highly reliable and valid measure for assessing impact of OSF on life quality.

Simultaneous double free radial forearm flaps combined with coronoidectomy and myotomy to release bilateral severe trismus: A case report.

Oral cancers associated with submucosal fibrosis-induced trismus are common. They may affect the patients' quality of life, cause nutritional deficits, and interfere with postoperative cancer surveillance. In such cases, locating desirable recipient vessels in the head and neck can be difficult. This report presents a 47-year-old man with severe trismus caused by recurrent head and neck cancer, who had received multiple free-flap reconstructions after cancer ablation. Reconstruction was successfully achieved for the bilateral defects and releasing the trismus by using simultaneous double free radial forearm flaps as a chained flow-through pattern with one residual recipient vessel combined with the bilateral myotomy of the medial pterygoid and masseter muscles, and coronoidectomy. Both flaps survived without any postoperative complication. The maximal mouth opening measured by interincisal distance was 38 mm intraoperative and 32 mm during the 3-year follow-up period. This approach may be an effective option for releasing trismus when recipient vessels are lacking.

Limited mouth opening in oral submucous fibrosis: reasons, ramifications, and remedies.

Limited mouth opening (LMO) in oral submucous fibrosis (OSF) has been attributed to both the submucosal and muscle fibrosis (MF). While reflectory trismus was proposed before as an auxiliary mechanism by another group, the stretch-mediated muscle damage (MSD), histopathological changes in blood vessels (such as endothelial dysfunction, endothelial hypertrophy, and endarteritis obliterans), and upregulated anaerobic isoforms of lactate dehydrogenase (LDH) have been proposed by us as complementary events leading to MF. Additionally, the amount of hypoxia-mediated upregulation of anaerobic isoforms of LDH determines the extent of MF. Radiotherapy (RT)-mediated release of reactive oxygen species causes vascular damage thereby worsening hypoxia. While the alteration in LDH levels secondary to hypoxia enhances fibrosis, RT worsens it. Oral squamous cell carcinoma occurring in the background of OSF is an absolute contraindication for RT as it augurs unfavorable prognosis. An algorithm to demonstrate this with evidence is clearly depicted. The role of HIF-1α in the progression of OSF and its malignant transformation, and the consideration of hyperbaric oxygen therapy as a therapeutic remedy in OSF are underscored.

Versatility of nasolabial flaps for the management of severe trismus in oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSMF) is a chronic insidious disease affecting any part of the oral cavity and sometimes the pharynx. It is a collagen-related disorder predominantly associated with tobacco/areca nut chewing habit and characterized by progressive hyalinization of the submucosa. Prevalence of OSMF is 2.01%, and malignant transformation rate of 2.3%-7.6% has been reported in the literature. Measures such as forcing the mouth open and cutting the fibrotic bands have resulted in more fibrosis and disability. AIM: Various surgical treatment modalities have been advocated in the surgical management of OSMF with variable results. This retrospective study evaluates the efficacy of nasolabial flap in the surgical treatment of OSMF. MATERIALS AND METHODS: Retrospective analysis of 42 patients who underwent surgical management of OSMF with mouth opening <20 mm by nasolabial flap at authors center from 2000 to 2015. Only the cases diagnosed as advanced OSMF based on long-standing positive history of habits (chewing tobacco, betel nut, etc.), clinical and histopathological examination. OSMF due to other causes such as nutritional deficiency, immunological diseases, and systemic illness with medically compromised patients were excluded from the study. Inferiorly based nasolabial flaps were raised in the supramuscular plane and transferred intraorally through a transbuccal tunnel. RESULTS: The study groups consist of 42 cases of clinical and histopathologically proven cases of OSMF treated by nasolabial flap. Out of 42 cases, 39 (92.85%) were males and 3 (7.15%) were females which showed a male predominance and the ratio was 13:1. The mean (standard deviation [SD]) preoperative mouth opening was 14.60 mm (3.06). After release of fibrotic bands, a mean forced intraoperative mouth opening of 36.27 (2.11) mm was achieved. The mean (SD) postoperative mouth opening was 33.05 mm (2.40) at the end of 2-year follow-up. The mean (SD) increase in mouth opening after surgical management at the end of 2-year follow-up is 18.46 mm (1.89). Sixteen out of 42 patients' histopathological report turned out to be dysplastic. The mean (SD) follow-up was 2.79 years (1.08). There was no incidence of infection in the transferred flap and the recipient site in all cases except one case with malignant transformation. All flaps healed without evidence of infection, dehiscence, or necrosis. Results were assessed by comparing the pre- and post-operative maximum mouth opening. CONCLUSION: The nasolabial flap is a versatile flap, which can be successfully used in the reconstruction of defects created after the release of fibrotic bands in OSMF. The versatility of the nasolabial flap has been attributed to its reliable vascularity derived from numerous vessels in the vicinity. Major advantage is the ease of elevation, proximity to the defect, suitable size for coverage of defect, minimal swallowing and speech difficulties, and a relatively cosmetic result as scar is in natural crease. All the cases treated for OSMF using bilateral nasolabial flaps showed adequate mouth opening at 2-year follow-up postoperatively, recommending its use.

Estimation of serum malondialdehyde and assessment of DNA damage using comet assay in patients with oral submucous fibrosis.

AIM: To quantify the level of serum malondialdehyde and extent of DNA damage using comet assay in patients with oral submucous fibrosis (SMF) in comparison to normal individuals and to correlate the extent of DNA damage with MDA levels. METHODS: Study included 30 cases of SMF (n = 30) and equal number of healthy volunteers. Serum malondialdehyde was measured using the thiobarbituric-trichloroacetitic acid (TBA-TCA) method. Comet assay was used to assess the DNA damage. Association between the extent of DNA damage and serum MDA levels was analyzed in SMF statistically. RESULTS: Comet assay results showed that there was an increase in tail length, percentage of tail DNA and tail moment among SMF subjects (P < 0.05). Serum MDA levels were elevated in SMF patients compared with healthy subjects. A significant positive correlation was observed between serum MDA levels and comet tail length in SMF group (r = 0.56; P < 0.05). CONCLUSIONS: Patients with SMF have increased DNA damage and elevated levels of lipid peroxidation compared with healthy controls. Evaluation of MDA levels as an oxidative biomarker along with comet assay analysis will serve as a diagnostic tool to identify patients with high risk of malignant potential in SMF.

Lichenoid Features and Fibrosis: Coexistence in Quid-induced Oral Lesions.

BACKGROUND: Oral submucous fibrosis (OSF) and quid associated oral lichenoid lesions (QOLL) are caused because of areca nut chewing and both show very characteristic histological changes. The present study aims to determine the histopathological presence of lichenoid features in cases of OSF as well as to determine the presence of fibrosis in cases of QOLL. MATERIALS AND METHODS: The study involved the retrospective analysis of hematoxylin and eosin stained slides of OSF (n = 50) and QOLL (n = 16). RESULTS: Seven cases of OSF revealed histopathological features of lichenoid reaction and four cases of QOLL revealed the presence of fibrosis in the underlying connective tissue. CONCLUSION: This study put forths a new finding that is, the presence of concomitant disease processes seen in the same patient at a histological level. It thus, stresses the need to evaluate all cases of OSF and QOLL for additional features which may be induced by areca nut chewing.