Salivary transforming growth factor beta in oral submucous fibrosis: A diagnostic and predictive marker.

CONTEXT: Growth factors and cytokines like transforming growth factor beta (TGF-ß) play a key role in the pathogenesis of oral submucous fibrosis. AIMS: To elucidate the role of Salivary TGF-ß isoforms as a predictive and diagnostic marker for oral submucous fibrosis. SETTINGS AND DESIGN: A total of 30 OSMF and 10 control patients were included in this study, and their clinic-epidemiological data was recorded. METHODOLOGY: The expression of TGF-ß genes-TGF-ß1, TGF-ß2, TGF-ß3-was studied by a real-time polymerase chain reaction in tissue and saliva. Patients were given medicinal intervention for 12 weeks along with jaw-opening exercises. Expression of salivary TGF-ß genes was studied at 12 weeks. STATISTICAL ANALYSIS USED: SPSS software version 20. RESULT: Expression of salivary TGF beta isoforms in OSMF was more than in the control group. There was an increase in salivary TGF-ß1, ß2, ß3 expressions with increasing clinical grades of OSMF and advancing the stage of the disease. Expression of all the TGF beta isoforms was decreased after treatment with statistically significant results. Statistically significant correlations were found between the mean difference of TGF-ß1 and the mean difference between mouth opening and tongue protrusion. CONCLUSION: Salivary TGF-ß isoforms may be used in diagnosis, risk assessment, and screening of the entire population at risk of OSMF after its clinical validation. However, adequate sample size and segmental assessment of the expression of TGF-ß isoforms are needed for further evaluation.

Guideline for the Diagnosis and Clinical Management of Oral Submucous Fibrosis.

Oral submucous fibrosis (OSF) is a chronic, progressive and potentially malignant oral mucosal disease. Patients often have a habit of chewing betel nuts. Areca catechu has been listed as a Class 1 carcinogen by the International Agency for Research on Cancer (IARC), and its main active component, arecoline, is classified as a Group 2B carcinogen by the IARC. The World Health Organization (WHO) categorises OSF as an oral potentially malignant disorder (OPMD). The present guideline describes the risk factors, clinical symptoms and clinical signs of OSF. Clinical staging, auxiliary examination methods, basis for diagnosis and differential diagnosis and the need to improve bad lifestyle habits are proposed and addressed, and local treatment drugs, therapies, dosage and course of treatment, possible adverse reactions, and oral treatment drugs, dosage and course of treatment are proposed. The guideline also addresses the indications for surgical treatment, alternative non-drug treatment methods, selection of treatment plans for different clinical stages, criteria for efficacy evaluation, and preventive measures.

Salivary Lactate Dehydrogenase as a Potential Biomarker in Oral Potentially Malignant Disorders and Head & Neck Cancer- A Systematic Review and Meta-analysis.

BACKGROUND: The prognosis of head &neck cancer (HNC) depends on its early detection, diagnosis, and treatment, which has advocated a search for a simple, reliable, noninvasive, cost-effective tool to aid in the same. Salivary lactate dehydrogenase has gained interest in recent years, meeting the above requisite. OBJECTIVES: To evaluate the levels of salivary lactate dehydrogenase in patients with oral potentially malignant disorders (OPMD), HNC, and in the healthy control group (CG); to find the correlation, grade-wise and genderwise difference between them; and to assess whether it can be used as a potent biomarker in OPMD and HNC. MATERIALS AND METHODS: A comprehensive search of the specialized 14 databases and 4 institutional repositories was performed for including the studies evaluating salivary lactate dehydrogenase in OPMD and HNC patients either comparing or not comparing to the healthy control group in the systematic review process. The meta-analysis was performed with the eligible study data with the STATA version 16, 2019 software with 95% CI and p ≤ 0.05 in the random-effects model. RESULTS: Twenty-eight studies of case-control, interventional, or uncontrolled non-randomized design evaluating salivary lactate dehydrogenase were included. A total of 2074 subjects were included, involving HNC, OPMD, and CG. The salivary lactate dehydrogenase levels were significantly higher in HNC than in CG & oral leukoplakia (OL) (p=0.00); in OL & oral submucous fibrosis (OSMF) than CG (p=0.00); and higher in HNC than OSMF, however not significant (p=0.49). Also, the salivary lactate dehydrogenase levels had no significant difference between males and females in CG, HNC, OL, and OSMF groups(p> 0.05). DISCUSSION: It is evident that the epithelial transformations in the various OPMD and HNC, and the proceeding necrosis in the case of HNC, raises the LDH levels. It's also worth noting that when degenerative alterations continue, the SaLDH levels rise correspondingly, which are higher in HNC than in OPMD. Hence, it is essential to determine the cut-off values for SaLDH for establishing that the patient may have HNC or OPMD. It would be easy to follow-up frequently and perform investigations such as biopsy for the cases with high SaLDH levels, thereby aiding in the early detection and improving the prognosis of HNC. Moreover, the increased SaLDH levels were indicative of a lower degree of differentiation and an advanced disease leading to a poor prognosis. Salivary sample collection is less invasive, simple, and more acceptable to the patient; however, saliva collection is a time-consuming procedure as it is mostly collected by the passive spit method. Also, it is more feasible to repeat the SaLDH analysis during the follow-up, but the method has recently gained interest for over a decade. CONCLUSION: Salivary lactate dehydrogenase can be a potential biomarker for the screening, early detection, and follow-up of OPMD or HNC being simple, noninvasive, cost-effective, and readily acceptable modality. However, more studies with new standardized protocols are recommended to determine the precise cut-off levels for HNC and OPMD. Keywords (MeSH): L-Lactate dehydrogenase; Saliva; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck; Oral; Precancerous conditions.

Expression of Ki67 as potential biomarker in oral submucous fibrosis: An immunohistochemical study.

Background: Oral submucous fibrosis (OSMF) is a potentially malignant disorder (PMD) known to transform into oral cancer. One of the important hallmarks of malignant transformation is the uncontrolled growth rate, commonly reflected as increased cell proliferation which can be significantly detected by proliferative markers such as a high Ki-67 index. Aim: The aim of this study is to evaluate the degree and pattern of expression of Ki67 in OSMF, oral squamous cell carcinoma (OSCC) and in normal mucosal (NOM) patients and to correlate the Ki67 expression with clinical and histological grading of OSMF and OSCC patient. Materials and Methods: A prospective cross-sectional study was conducted over a duration of two years. An immunohistochemical study was performed for Ki76 expression on 35 cases of OSMF, 10 cases of OSCC and 10 normal mucosal patients. Statistical Analysis: Data were analysed using SPSS version 21. Chi-squared test was used to analyse the differences between the intensity levels in OSMF, OSCC and NOM. Results: Expression of Ki67 was significantly higher in OSMF than that of NOM samples but less than that of OSCC samples. Expression of Ki67 increased with increasing grade of clinical and histological stages. Conclusion: The study demonstrated a high incidence of Ki67 overexpression in OSMF and OSCC and showed a correlation between clinical and histological grading of OSMF and OSCC. Identification of high-risk oral PMDs and intervention at premalignant stages could constitute one of the key steps in reducing the mortality, morbidity and cost of treatment associated with malignant transformation of these diseases.

The prevalence of oral squamous cell carcinoma with oral submucous fibrosis.

OBJECTIVE: The objective of the study was to find out the prevalence of oral squamous cell carcinoma (OSCC) with oral submucous fibrosis (OSF) in patients with OSF. MATERIALS AND METHODS: Of 48,757 patients, we found 300 OSF subjects. Three hundred patients of OSF were checked for OSCC. Both OSF and OSCC with OSF (OSCCwOSF) were diagnosed histopathologically. The prevalence of OSCCwOSF was calculated. Descriptive analysis was done. Chi-square test and t-test were calculated for proportions and mean, respectively, to check any difference among OSF and OSCCwOSF groups. Age-specific relative risk was calculated in OSF and OSCCwOSF groups. Multiple logistic regression analysis was done among odd ratios of the different variable between OSF and OSCCwOSF groups. RESULTS: The prevalence of OSCCwOSF among OSF was 13.7% over a period of 1 year. The mean age of OSCCwOSF group was 43.95 ± 10.22 years in comparison to the OSF group that was 35.51 ± 11.26 years (P < 0.00). The mean habit duration was significantly less in the OSF group when compared to OSCCwOSFgroup for mishri (P = 0.002). Age-specific adjusted relative risk of OSCC in OSF patient increases from 0.33 (18-34 years) to 3.86 (≥65 years). CONCLUSION: It could be concluded that a 13.7% prevalence rate of OSCCwOSF in OSF patients should alert the clinician. Clinicians should, therefore, anticipate OSSC in OSF patients. This awareness could lead to the early diagnosis and management of such OSCC.

Saliva based non invasive screening of Oral Submucous Fibrosis using ATR-FTIR spectroscopy.

Oral Submucous Fibrosis (OSMF) is a type of precancerous condition of Oral cancer and considered to have the greatest malignant potential. Biopsy is an ultimate option for the conformation of the malignancy. But the invasiveness of the procedure makes it interdict. Therefore, there is an urgent need to identify effective screening and diagnostic methods which would be less invasive, rapid, more accurate and cost effective. Here, we used Attenuated Total Reflection- Fourier transform infrared spectroscopy (ATR-FTIR) with Chemometric analysis coupled with estimation of total salivary protein to discriminate OSMF and Healthy Control (HC). The present study showed the specific Infrared spectrum for OSMF patients, which was specifically differentiated from HC based on the spectral shift of proteins/amide II, carbohydrate and nucleic acid using Principal Component Analysis (PCA) and Hierarchical Clustering Analysis (HCA) with small data sets. ATR-FTIR spectroscopy of saliva coupled with total protein estimation can be used to discriminate between OSMF and HC. However, large sample size should be needed to evaluate the ATR-FTIR for consideration as a screening tool for an early diagnosis OSMF.

Oral submucous fibrosis: An overview of a challenging entity.

The oral cavity is considered to be a mirror of the body's health, as it reflects the manifestations of various systemic disorders. Most of the oral mucosa is derived embryologically from an invagination of ectoderm and thus, like other similar orifices, it may become involved in the disorders that are primarily associated with the skin. Oral submucous fibrosis is one of the commonest precancerous conditions of the oral mucosa involving any part of the oral cavity resulting in tissue scarring, dysphagia and trismus. It is a collagen-related disorder characterized by excessive fibrosis in the oral submucosa, hyalinization and degenerative changes in the muscles. This disease has become a challenging entity for dermatologists due to resemblance of its features to various mucocutaneous conditions. An improper diagnosis can lead to wrong treatment and additional complications. Dermatologists need to be aware of the characteristic features of this disease which can distinguish it from other similar conditions. This review aims to focus on the detailed aspects of oral submucous fibrosis including its historical background, etiological factors, pathogenesis, clinical features, differential diagnosis, investigations, management and future perspectives.

Oral submucous fibrosis in children: an alarming condition and challenges in management.

Oral submucous fibrosis (OSF) is a well-documented potentially malignant condition. It affects most commonly the adult patients of India and Indian subcontinent, only few cases affecting children have been reported in the literature. This paper presents three cases of OSF below the age of 12 years and reviews the aetiology, clinical presentation, treatment modalities in children with improved follow-up results. Clinical features like restricted mouth opening, burning sensation and history of betel nut chewing helps in the diagnosis of the patients, which can be confirmed by histopathological examination. Conservative management and oral physiotherapy in children help in improved mouth opening. Counselling the children, their friends and parents also plays a vital role. The present paper highlights that children on a larger scale are using tobacco products and further studies are required with larger sample size.

Common benign and malignant oral mucosal disease.

BACKGROUND: Mucosal diseases of the oral cavity are relatively common, and patients often seek initial assessment from their general practitioner. OBJECTIVE: The aim of this article is to provide an overview of common oral mucosal diseases to help with formulating a differential diagnosis and stratifying the urgency of referral. DISCUSSION: Pathological mucosal conditions of the oral cavity and jaws commonly present as a mucosal ulcer or a white, red or pigmented lesion. In this review, the authors outline the most common conditions organised according to their clinical presentation and describe their typical appearance and management.

Ki67, CD105, and α-SMA Expression Supports Biological Distinctness of Oral Squamous Cell Carcinoma Arising in the Background of Oral Submucous Fibrosis.

BACKGROUND: The clinicopathological distinctness of oral squamous cell carcinoma arising in the background of oral submucous fibrosis (OSCC-OSF) is well known; however, the molecular distinctness of this unique OSCC-OSF has not been investigated to date. With this in mind, we compared the expression of Ki67, CD105, and α-SMA between OSCC-OSF and oral squamous cell carcinoma (OSCC). METHODS: Formalin-fixed paraffin-embedded tissues of 105 OSCC-OSF and 112 OSCC cases were subjected to immunohistochemistry for evaluation of Ki67, CD105, and α-SMA expression. RESULTS: Ki67 (labeling index) LI, MVD and α-SMA expression were significantly higher in OSCC compared to OSCC-OSF. Ki67 LI and MVD was significantly higher in OSCC compared to OSCC-OSF in parameters such as well-differentiated, early TNM stage, non-metastatic, and more than 3-year survival. α-SMA expression was significantly higher in OSCC compared to OSCC-OSF in parameters such as moderate differentiation, metastatic lesions, and survival less than 3 years. Ki67 LI, MVD and α-SMA showed significant positive correlation with each other in OSCC and OSCC-OSF. CONCLUSION: Proliferation, neoangiogenesis and myofibroblast differentiation were significantly higher in the OSCC group compared to the OSCC-OSF group. This suggests the biological distinctness of OSCC-OSF, which could help the future development of targeted therapies.

DNA content abnormality in oral submucous fibrosis concomitant leukoplakia: A preliminary evaluation of the diagnostic and clinical implications.

Oral submucous fibrosis (OSF) is an insidious chronic oral and oropharyngeal potentially malignant disorder. Our previously studies reported that DNA image cytometry (ICM) using brushing added in the diagnosis of high-grade dysplasia and staging of oral leukoplakia (OLK). This preliminary study aimed to investigate the abnormal rate of DNA content in 30 cases of OSF including three cases of OSF concomitant OLK and evaluate their the diagnostic and clinical implications with special emphasis on the OSF concomitant OLK. Brushing and biopsy sample form each patient was processed by DNA-ICM and histological examination, respectively. The results of DNA-ICM analysis showed that all the lesions from the 27 patients with OSF only were identified as normal DNA content. Strikingly, two of three cases of OSF concomitant OLK were identified as abnormal DNA content, and one case of whom progressed to early oral squamous cell carcinoma at the follow-up of 31 months. Collectively, this preliminary evaluation revealed that DNA content abnormality was hardly observed in OSF only; however, it may be usually observed in OSF concomitant OLK, whom should be monitored on a priority basis for early detection of carcinoma. Multicenter large studies are needed to validate the findings of the current study.

Histo-Blood Group Antigens in Oral Cancer and Potentially Malignant Disorders.

BACKGROUND: Early detection of oral cancer is of critical importance because survival rates markedly improve when oral lesions are identified at an early stage. Aim of the present study is to investigate the expression of ABO (H) antigens in tissue specimens of oral cancer and potentially malignant disorders and to determine the role of ABO (H) antigens in tumour staging. MATERIALS AND METHODS: A prospective study was conducted on 60 cases of oral cancer and potentially malignant diseases. Specific red cell adherence test (SRCA-test) was used for studying A, B and O (H) antigens in tissue specimens and iso-antigenicity of epithelium was graded according to degree of adherence of indicator red blood cells. RESULTS: Among OSMF group, grade II adherence was seen in 53.3% cases, grade III in 33.3% cases, grade IV in 13.3% cases. In leukoplakia group, grade II adherence was seen in 26.7% cases, grade III adherence in 53.3% cases, grade IV adherence in 20% cases. Within the leukoplakia group, cases with dysplasia showed decreased adherence, compared with cases without dysplasia. Oral cancer group, negative adherence was seen in 13.3% cases, grade I adherence in 46.7% cases, grade II in 40% cases. In oral cancer group, antigen reactivity was less in poorly and moderately differentiated carcinoma, compared to well differentiated carcinoma. CONCLUSIONS: Antigen adherence and degree of loss of ABO (H) antigens in tissue specimens can be used for staging of the tumour.

Oral submucous fibrosis: a contemporary narrative review with a proposed inter-professional approach for an early diagnosis and clinical management.

Oral Submucous fibrosis (OSMF) has traditionally been described as "a chronic, insidious, scarring disease of the oral cavity, often with involvement of the pharynx and the upper esophagus". Millions of individuals are affected, especially in South and South East Asian countries. The main risk factor is areca nut chewing. Due to its high morbidity and high malignant transformation rate, constant efforts have been made to develop effective management. Despite this, there have been no significant improvements in prognosis for decades. This expert opinion paper updates the literature and provides a critique of diagnostic and therapeutic pitfalls common in developing countries and of deficiencies in management. An inter-professional model is proposed to avoid these pitfalls and to reduce these deficiencies.

Oral submucous fibrosis in Asian countries.

Oral submucous fibrosis (OSF) is a chronic, insidious, and progressive oral mucosal disease that affects entire oral cavity and sometimes pharynx. This oral potentially malignant disorder has a high rate of malignant transformation (7%-30%) to oral squamous cell carcinoma (OSCC), posing global problems for public health. Due to enormous efforts dedicated to this disease in the past decades, there have been significant advances in identification of its etiology and pathogenesis as well as development of corresponding therapeutic approaches, in spite of several challenges. This study reviewed the existing literature concerning OSF in Asian countries, encompassing its etiology, histopathology, pathogenesis, clinical manifestations, diagnosis and differential diagnosis, and treatments. For improving treatment of OSF, the multifactorial etiology analysis, incorporation of effective molecular pathways, cytokines and cells for mechanism illustration, and integration of multidisciplinary modalities were also expounded to guide future research and clinical practice.

p16 as an independent marker for detection of high-risk HPV in oral submucous fibrosis and oral squamous cell carcinoma.

BACKGROUND: An alarming increase in incidence of high-risk human papillomavirus (HPV) positive tumors in head and neck squamous cell carcinoma (HNSCC) by 25% and 70% in oropharyngeal HNSCC cannot be ignored. The early oncogenes of HPV, E6, and E7 play a key role in carcinogenesis. HPV associated tumors have a better clinical outcome and a favorable prognosis. The p16 expression has high concordance with other methods of HPV detection, ascertaining p16 as a surrogate marker for HPV. OBJECTIVE: To assess the immunohistochemical expression of p16 in oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC) with and without coexistent OSF as a marker for high-risk HPV detection. Materials and. METHODS: Tissue blocks of 70 cases including normal, OSF, OSCC with and without OSF were subjected to IHC staining with a p16INK4A monoclonal antibody. (Biogenex, San Roman). The p16 expression was noted according to percent positivity and pattern. The data were tabulated, statistically analyzed using the Chi-square test and the P value was assessed. RESULTS: The percentage of p16 positive cells raised from normal to OSF to OSCC with and without OSF. In addition, a shift from nuclear to cytoplasmic expression from normal to OSCC was noted with a statistical significance (P < 0.001). However, no statistical significance was established with any clinicopathologic parameters except age (P = 0.012) and habits (P= 0.023). CONCLUSION: The presence of HPV using p16 was not detected in OSF but was positive in OSCC. Altered pattern of expression from normal to OSF to OSCC indicates promising use of p16 as a diagnostic marker.

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy.

Oral submucous fibrosis (OSF) is characterized by abnormal collagen deposition. It is a precancerous disorder and transforms into a malignant tumor in 1.5-15% of all cases. Symptoms include submucous fibrosis, ulceration, xerostomia, a burning sensation, and restricted mouth opening. All of these greatly interfere with patient quality of life. The present review introduces OSF from a molecular perspective and summarizes what is known about its underlying mechanisms, diagnostic biomarkers, and therapeutic interventions. In addition to the aggressive treatment of OSF, its prevention is also important. Future research should, therefore, focus on improving the oral health literacy of the patients susceptible to OSF.

Oral Submucous Fibrosis in Pediatric Patients: A Systematic Review and Protocol for Management.

AIM: To conduct a systematic review evaluating the cases of oral submucous fibrosis in pediatric patients. MATERIAL AND METHOD: Systematic review was conducted using PRISMA guidelines. The article focused on oral submucous fibrosis in pediatric patients were included. A total of five manuscripts were included in our systematic review. The prevalence of OSMF in pediatric patients, gender distribution, causes, and clinical presentation were reviewed. RESULTS: On systematically reviewing, a total of 10 cases of OSMF in pediatric patients were found. The youngest patient reported to be diagnosed with OSMF was of 2.5 years of age. Female preponderance was noticed. All the patients had the habit of areca nut chewing which subsequently led to fibrosis. CONCLUSION: Such a rapid increase in the rate of OSMF among pediatric population is a potential danger to the society. The habit of areca nut chewing is the major cause for this dreadful condition. Lack of health consciousness and low level of education are the major factors for initiation of this habit among children. Therefore it is imperative for the parents and school as well as government authorities to take serious actions.