Characterization and clinicopathological significance of circulating tumour cells in patients with oral squamous cell carcinoma.

Circulating tumour cells (CTCs) are cancer cells released by cancer into the peripheral circulation. Haematogenous tumour spread is a hallmark of metastatic malignancy and a key factor in cancer recurrence and prognosis. CTCs have diagnostic and prognostic significance for a number of adenocarcinomas and melanoma. A review of the published peer-reviewed literature was performed to determine the clinical relevance of CTCs as a biomarker in the management of oral squamous cell carcinoma (OSCC). Fourteen studies met the eligibility criteria. With regard to patients with OSCC, this review found the following: (1) CTCs have been detected using multiple techniques; (2) the presence of CTCs does not appear to be related to tumour differentiation or size; (3) CTCs may be detected without lymph node involvement; (4) the detection of CTCs may be prognostic for both disease-free survival and overall survival; (5) quantification of CTCs may reflect the efficacy of therapy; (6) CTCs may be of value for ongoing patient monitoring. Preliminary evidence suggests that CTCs have diagnostic and prognostic potential as a biomarker for oral cancer management and warrant further investigation to determine their appropriate place in the management of OSCC patients.

Anti-Ro52/TRIM21 is independently associated with pulmonary arterial hypertension and mortality in a cohort of systemic sclerosis patients.

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement.Method: The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses.Results: Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications.Conclusion: Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

Predictors of oropharyngeal cancer survival in Europe.

OBJECTIVES: HPV16-positive oropharyngeal cancer (OPC) patients experience better outcomes compared to HPV16-negative patients. Currently, strategies for treatment de-escalation are based on HPV status, smoking history and disease stage. However, the appropriate cut-point for smoking and the role of other non-clinical factors in OPC survival remains uncertain. MATERIALS AND METHODS: We examined factors associated with OPC outcome in 321 patients recruited in a large European multi-center study. Seropositivity for HPV16 E6 was used as a marker of HPV16 positive cancer. Hazard ratios (HR) and confidence intervals (CI) were estimated using Cox proportional models adjusted for potential confounders. RESULTS: Overall 5-year survival following OPC diagnosis was 50%. HPV16-positive OPC cases were at significantly lower risk of death (aHR = 0.51, 95% CI: 0.32-0.80). A significant effect on OPC survival was apparent for female sex (aHR 0.50: 95% CI: 0.29-0.85) and being underweight at diagnosis (aHR: 2.41, 95% CI: 1.38-4.21). A 10 pack year smoking history was not associated with overall survival. Higher stage at diagnosis appeared as the only factor significantly associated with OPC recurrence (aHR: 4.88, 95% CI: 2.12-11.21). CONCLUSION: This study confirms that HPV16 status is an independent prognostic factor for OPC survival while female sex lowers risk of death and being underweight at diagnosis increases the risk of death. Smoking was not an independent predictor of OPC survival.

Perspectives on oral squamous cell carcinoma prevention-proliferation, position, progression and prediction.

Squamous cell carcinoma arising from oral mucosal epithelium remains a lethal and deforming disease due to tumour invasion, oro-facial destruction, cervical lymph node metastasis and ultimate blood-borne dissemination. Worldwide, 300 000 new cases are seen each year, with a recent and significant rise in incidence affecting particularly the young. To rationalize perspectives on preventive strategies in oral cancer management, this study addresses a number of fundamental questions regarding carcinogenesis: proliferation-what epithelial cell changes precede tumour development? Position-why are certain oral sites so predisposed to cancer? Progression-why do some precursor lesions progress to invasive carcinoma and others do not? Prediction-how can we predict individual patient and/or lesion behaviour to prevent disease progression? By improving our understanding of oral carcinogenesis, can we thereby facilitate more effective primary, secondary and tertiary preventive strategies and ultimately reduce the global burden of oral squamous cell carcinoma (OSCC)?

Treatment resistance in potentially malignant disorders-'Nature' or 'Nurture' ?

BACKGROUND: Contemporary potentially malignant disorder management is based upon provisional histological diagnosis followed by interventional surgery to excise or ablate 'high-risk' mucosal lesions. Although the majority of patients achieve disease-free status post-treatment, others develop further or persistent disease unresponsive to intervention. METHODS: A detailed, retrospective clinico-pathological review of treatment resistant potentially malignant lesions, from a 590 patient cohort treated by CO2 laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was determined at study census date (31 December 2014). RESULTS: A total of 87 patients (15%) exhibited PMD disease resistant to treatment: 34 (6%) became disease free following further treatment, whilst 53 (9%) had persistent disease despite intervention. Disease-free patients were younger, changed lesion appearance from erythroleukoplakia to leukoplakia (P = .004), developed further lesions at new sites, demonstrated reduction in dysplasia severity with time and required multiple treatments to achieve disease-free status (P = .0005). In contrast, persistent disease patients were older, male, often presented with proliferative verrucous leukoplakia (PVL) on gingival and alveolar sites, displayed less severe dysplasia initially and underwent laser ablation rather than excision (P = .027). CONCLUSION: Despite clinico-pathological profiling of treatment resistant patients, the precise inter-relationship between the inherent nature of potentially malignant disease and the external influence of treatment intervention remains obscure.

Potentially malignant disorders-The case for intervention.

Potentially malignant disorders (PMD) are recognisable mucosal conditions preceding invasive squamous carcinoma development. Established oral cancer remains a lethal and deforming disease, with a rising incidence. Management techniques for identifiable oral precursor lesions have traditionally been polarised between observational and interventional surgical techniques. By defining salient management goals for treating potentially malignant disease, and examining the evidence supporting the efficacy of treatment intervention, this paper presents the case for interventional laser surgery as a definitive diagnostic and treatment modality.

Profiling cancer risk in oral potentially malignant disorders-A patient cohort study.

BACKGROUND: Oral potentially malignant disorders harbour variable and unpredictable risk for squamous carcinoma development. Whilst current management strategies utilise histopathological diagnoses, dysplasia grading and targeted intervention for "high-risk" lesions, clinicians are unable to predict malignant potential. METHODS: Detailed, retrospective clinico-pathological analysis of potentially malignant lesions undergoing malignant transformation, from a 590 patient cohort treated by interventional laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was documented at study census date (31 December 2014). RESULTS: A total of 99 patients (16.8%) developed cancer: 71 (12%) seen "unexpectedly" upon excision and 28 (4.8%) progressing to malignancy at a median of 87.3 months post-surgery. Thirty "unexpected" excisions were micro-invasive (42.3%) arising primarily in severely dysplastic precursors (75%) at ventro-lateral tongue and floor of mouth sites (54.5%); 1 patient (1.4%) had a cancer-related death, whilst 58 (81.7%) were disease free. A total of 19 of 28 "progressive" cancers (67.9%) arose at new sites, with erythroleukoplakia a significant predictor of malignancy (P = .0019). Nine (32.1%) developed at the same precursor site, with 6 (77.7%) on the ventro-lateral tongue and floor of mouth. Three (10.7%) were micro-invasive, 9 patients (32.1%) died from metastatic disease and 12 (42.9%) were disease free (P < .001). CONCLUSION: Squamous carcinoma may arise at the site of a precursor lesion as transformation or new-site development via field cancerisation. Whilst interventional surgery facilitates early diagnosis and treatment of occult disease, thus reducing risk from same-site transformation, new-site cancer is a significant long-term risk for patients with potentially malignant disorder.

Efficacy of oral brush biopsy in potentially malignant disorder management.

BACKGROUND: Oral potentially malignant disorders (PMD) harbour unpredictable risk for squamous cell carcinoma development. Current management requires tissue biopsy for histopathology characterisation, dysplasia grading and targeted intervention to "high-risk" lesions, although evidence-based guidelines are limited and diagnoses subjective. This study investigated the use of adjunctive oral brush biopsy techniques during the management of PMD in a UK hospital population. METHODS: Retrospective review of a 310 PMD patient cohort presenting to Maxillofacial Surgery in Newcastle upon Tyne with new, single-site lesions between December 2009 and May 2014. Patients underwent Orcellex® brush biopsy and liquid-based cytology examination in addition to conventional biopsy techniques, with management proceeding along established care pathways. Patient demographics, cytology data, most significant histopathology diagnoses and clinical outcome were all documented at the study census date (31.12.15). RESULTS: A total of 170 male & 140 female patients (age range 18-91 years), exhibiting primarily leukoplakia (86.5%) at floor of mouth and ventrolateral tongue sites (44.9%), were identified. Management comprised: observation (49.7%), laser surgery (44.9%), antifungal treatment (3.5%) and Head & Neck clinic referral following cancer diagnosis (1.9%). Clinical outcomes were as follows: disease free (51.3%), persistent PMD (42.3%) and malignant transformation (6.4%). Histology and cytology diagnoses strongly correlated (r = .305). Treatment modality, lesion site, histology and cytology diagnoses were the best predictors of clinical outcome. CONCLUSIONS: Orcellex® brush cytology provides reliable diagnoses consistent with conventional histopathology and offers less invasive, adjunctive assessment appropriate for long-term monitoring of patients in specialist clinics.

Interventional laser surgery for oral potentially malignant disorders: a longitudinal patient cohort study.

Oral squamous cell carcinoma (OSCC) is a lethal disease, with rising incidence. There were 6767 new OSCC cases and 2056 deaths in the UK in 2011. Cancers are preceded by oral potentially malignant disorders (PMDs), recognizable mucosal diseases harbouring increased SCC risk, offering clinicians a 'therapeutic window' to intervene. Contemporary practice remains unable to predict lesion behaviour or quantify malignant transformation risk. No clear management guidelines exist and it is unclear from the literature whether early diagnosis and intervention prevents cancer. Between 1996 and 2014, 773 laser treatments were performed on 590 PMD patients in Newcastle maxillofacial surgery departments. The efficacy of the intervention was examined by review of the clinicopathological details and clinical outcomes of the patients (mean follow-up 7.3 years). Histopathology required up-grading in 36.1% on examining excision specimens. Seventy-five percent of patients were disease-free, mostly younger patients with low-grade dysplasia; 9% exhibited persistent disease and were generally older with proliferative verrucous leukoplakia. Disease-free status was less likely for erythroleukoplakia (P=0.022), 'high-grade' dysplasia (P<0.0001), and with lichenoid inflammation (P=0.028). Unexpected OSCC was identified in 12.0%, whilst 4.8% transformed to malignancy. Interventional laser surgery facilitates definitive diagnosis and treatment, allows early diagnosis of OSCC, identifies progressive disease, and defines outcome categories. Evidence is lacking that intervention halts carcinogenesis. Multicentre, prospective, randomized controlled trials are needed to confirm the efficacy of surgery.

To treat...or not to treat? Clinicians' views on the management of oral potentially malignant disorders.

Oral potentially malignant disorders (PMD) are recognisable mucosal conditions that have a variable and unpredictable risk of transformation to invasive squamous cell carcinoma (SCC). Modern management relies initially on clinical recognition of suspicious lesions and histopathological assessment and grading after incisional biopsy. However, it then varies from wide excision to observation and review, and depends not only on the severity of dysplasia but also on the clinician's preference as there is no high-level evidence to support best practice. We invited clinicians from oral and maxillofacial surgery, oral medicine, ear, nose, and throat (ENT), and plastic surgery, to complete an online questionnaire on current practice, which included 3 fictitious cases, to ascertain their views on the management of PMD and to find out whether they would be interested in becoming involved in a proposed future randomised controlled trial (RCT). Of the 251 who replied, 178 (71%) were oral and maxillofacial surgeons, and 99 (39%) expressed an interest in participating in a future RCT. Most respondents (n=164 or 99%) would always treat severely dysplastic lesions by excision or laser ablation, whereas only 8% (n=13) would always excise mild dysplasia. The greatest equipoise among those interested in taking part in a RCT was found in the case of moderate dysplasia for which 27% (n=27) favoured observation compared with surgical excision or laser ablation. This study shows that there is support for a multicentre, prospective RCT that compares observation with resection and laser ablation in patients with moderate dysplasia.

Oral precursor lesions and malignant transformation--who, where, what, and when?

Oral potentially malignant disorders (PMD) are recognisable mucosal conditions that have an unpredictable risk of transformation to squamous cell carcinoma (SCC), a lethal and deforming disease of rising incidence. Contemporary management is based on clinical recognition of suspicious lesions and incisional biopsy to enable histopathological assessment and grading of dysplasia, together with excision of high-risk lesions and long-term surveillance. However, it is impossible to predict clinical outcome or risk of malignant transformation. Our aim was to evaluate the relevance of previously identified oral precursor lesions for the development of SCC and staging of disease. We therefore retrospectively reviewed 1248 cases of SCC diagnosed in oral and maxillofacial surgery units at Newcastle upon Tyne and Sunderland hospitals between 1996 and 2009. Of them, 58 identifiable precursor lesions became malignant but only 25 had been dysplastic on initial biopsy; 19 of 33 non-dysplastic lesions exhibited lichenoid inflammation only. SCC arose most often on the ventrolateral tongue and floor of the mouth, with a mean transformation time of 29.2 months. Transformation time was significantly shorter in men (p=0.018) and those over 70 years of age (p=0.010). Patients who consumed more than 21 units of alcohol/week and those who had had interventional laser surgery to treat precursor lesions, had higher-staged tumours (p=0.048). Although retrospective, this study shows that the results of incisional biopsy and grading of dysplasia have limited use as predictive tools, and supports the view that cancer may arise in the absence of recognisable epithelial dysplasia. Our findings confirm the importance of clinical vigilance and active surveillance in the management of all patients with clinically suspicious oral lesions, irrespective of the histological findings.

Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.

OBJECTIVE: To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort. METHODS: Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data. RESULTS: A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures. CONCLUSION: Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.

Clinical outcome following oral potentially malignant disorder treatment: a 100 patient cohort study.

Oral potentially malignant disorders (PMDs) are at risk of transforming to invasive squamous cell carcinoma (SCC), but controversy exists over their management and the precise role of interventional treatment. In this study, a cohort of 100 patients presenting with new, single oral dysplastic PMD lesions were followed for up to 10 years following laser excision. PMDs presented primarily as homogeneous leukoplakias on floor of mouth and ventrolateral tongue sites and showed mainly high-grade dysplasia following analysis of excision specimens. Sixty-two patients were disease-free at the time of the most recent followup, whilst 17 experienced same site PMD recurrence, 14 developed further PMDs at new sites, 5 underwent same site malignant transformation, and 2 developed SCC at new oral sites. Whilst laser excision is an effective therapeutic tool in PMD management, prolonged patient followup and active mucosal surveillance together with clear definitions of clinical outcomes are all essential prerequisites for successful interventional management. Multicentre, prospective, and randomised trials of PMD treatment intervention are urgently required to determine optimal management strategies.

Complications following interventional laser surgery for oral cancer and precancerous lesions.

Interventional carbon dioxide laser surgery is the preferred method to treat oral precancerous lesions and early invasive squamous cell carcinomas (SCCs). Little is known, however, about the complications that patients experience after such treatment. We retrospectively reviewed the hospital records of 82 patients with new dysplastic oral lesions or early invasive oral SCCs treated by laser surgery in the maxillofacial unit at Newcastle General Hospital. The most common postoperative complications were pain for more than two weeks after operation (n=28), bleeding (n=4), difficulties with speech (n=5), paraesthesia of the lingual nerve (n=17), difficulty swallowing (n=2), obstructive swelling of the submandibular gland (n=22), and tethering of the tongue (n=10). Overall, 78% of patients had one or more complication. In the absence of randomised controlled trials, this study provides the best available evidence for complication rates following interventional surgery. In addition to aiding in the preoperative counselling of patients, the data will help to inform and advise patients particularly during the immediate postoperative period.

Stochastic processes in the aetiopathogenesis of scleroderma.

We review the aetiology of scleroderma from an epidemiological perspective examining genetic, environmental and stochastic risk factors. The presence of familial clustering (but with low twin concordance) suggests a genetic contribution, and this has been confirmed with recent candidate gene and genome-wide association screening demonstrating both major histocompatibility complex and non-major histocompatibility complex genetic linkage. In contrast, environmental associations are weak or inconsistent. An examination of the age-adjusted incidence curve of scleroderma is consistent with a stochastic process involving five to eight random events. In pathogenesis, scleroderma is best considered as an autoimmune disorder where genetic and environmental factors are both important variables, but random events are also likely to play a pivotal role. We suggest that these random events might result in acquired somatic mutations or epigenetic alterations involving genes coding for immune receptors, tolerogenic gates or proteins involved in immune regulation, inflammation and/or repair that, over time, might summate to form a requisite cassette (of genetic changes), which allows the initiation and progression of the autoimmune process.

Clinical heterogeneity and prognostic features of South Australian patients with anti-synthetase autoantibodies.

AIM: To determine the clinical, serological and prognostic features of patients with autoantibodies against three aminoacyl-transfer RNA synthetases (ARS), namely Jo-1 (histidyl-tRNA synthetase), PL-7 (threonyl-tRNA synthetase) and PL-12 (alanyl-tRNA synthetase) in South Australia. METHODS: Patients with autoantibodies against ARS detected by line immunoassay (anti-Jo1, anti-PL7, anti-PL12) or enzyme-linked immunosorbent assay (anti-Jo1) were identified from existing laboratory databases for the period 1994-2009. Demographic, clinical and serological data were obtained by retrospective review of patients' medical records and laboratory databases. RESULTS: Forty-two patients with autoantibodies were identified (anti-Jo1 = 37, anti-PL7 = 4, anti-PL12 = 1). Females were more commonly affected than males (M : F = 12:30). Twenty-one patients had polymyositis (anti-Jo1 = 17, anti-PL7 = 4), seven dermatomyositis (anti-Jo1 = 6, anti-PL12 = 1), 10 overlap syndrome (anti-Jo1 = 10; lupus = 4, scleroderma = 3, Sjögren's syndrome = 2 and rheumatoid arthritis = 2) and four had interstitial lung disease (ILD) only (anti-Jo1 = 4). ILD was present in 69%, polyarthritis in 59% and positive anti-nuclear antibody (ANA) in 43% of patients. Concurrence of autoantibodies against Ro-52 with Jo-1 was seen in 12 patients. The mean follow-up period was 8.3 years (95% CI 5.8-10.8) with 12 deaths. Poor prognostic indicators were age of onset >60 years (P= 0.001), cancer (P= 0.002), negative ANA (P= 0.006) and negative autoantibodies to extractable nuclear antigens (P= 0.02). CONCLUSION: Patients with autoantibodies against ARS present with varied clinical features and occasionally with isolated lung involvement (amyopathic ILD). Older age of onset, malignancy and negative immunologic tests are predictors of poor prognosis. Concurrence of autoantibodies against Jo-1 and Ro-52 may reflect a coupling effect during generation of autoimmunity.

Survival in scleroderma: results from the population-based South Australian Register.

AIM: To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR). METHODS: The SASR is a population-based register, which was commenced in 1993 and has actively sought to recruit all scleroderma patients diagnosed in SA over a 15-year period. Clinical and serological details have been accessed from questionnaires or from clinical and laboratory files. Standardized mortality ratio (SMR) was calculated and survival analyses performed on all living and deceased patients listed on this SASR (n = 786). RESULTS: Patients with scleroderma had increased mortality compared with the general SA population (SMR 1.46 (95% confidence interval (CI) 1.28-1.69)). Factors that adversely altered survival included older age at onset, male gender, diffuse skin involvement, presence of scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer and anti-topoisomerase (Scl-70) and anti-U1 RNP antibodies, while a trend was observed with increased nailfold capillary dropout. Mean age of death for patients with limited scleroderma was 74.1 years (95% CI 72.5-75.7), diffuse scleroderma 62.9 years (95% CI 59.4-66.4) and overlap disease 57.8 years (95% CI 48.7-66.9). Survival improved over the 15-year study period. CONCLUSIONS: Scleroderma substantially reduces life expectancy. Survival is influenced by age at onset, gender, diffuse involvement of skin fibrosis, visceral involvement, development of cancer, extent of microvascular capillary damage and by the presence of scleroderma-associated antibodies, Scl-70 and RNP. Scleroderma renal crisis continues to carry high mortality. Survival improved over the 15-year study period.

Management of oral carcinoma: benefits of early precancerous intervention.

Management of oral precancerous lesions remains polarised between interventional surgery and conservative treatment. We have previously shown the efficacy of carbon dioxide laser excision for both diagnosis and treatment of oral precancerous lesions. The aim of this study was to review the clinicopathological details of a group of patients in whom pre-existing but occult invasive carcinoma was diagnosed histopathologically in specimens excised by laser. We retrospectively reviewed 169 patients who attended the Maxillofacial Dysplasia Clinic at Newcastle General Hospital with single, new oral premalignant lesions over a 5-year period (2004-2008). They were all treated by laser excision of lesions that were confirmed to be dysplastic from examination of preoperative incisional biopsy specimens. There was a significant correlation between the results of diagnostic incisional, and laser excision, biopsy specimens (p < 0.01), but 15 patients had signs of occult invasive carcinoma in the excision specimens (9%). In all cases the carcinomas were completely excised by the laser. Carbon dioxide laser excision is not only an effective treatment of precancerous lesions, but also facilitates early diagnosis and management of oral carcinoma at a stage when it is otherwise clinically undetectable.