Oral Dysplastic Lesions Research Articles

Effectiveness of Oral Surgeons Compared With OralCDx Brush Biopsy in Diagnosing Oral Dysplastic Lesions

To evaluate oral surgeons' effectiveness in diagnosing oral dysplastic lesions and compare it to OralCDx brush biopsy. In this cross-sectional study, the oral surgeon's ability to diagnose dysplasia among 152 consecutive cases (tissue samples) that had previously tested either "positive" (n = 3) or "atypical" (n = 149) for dysplasia by OralCDx brush biopsy was determined by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value using the scalpel biopsy as the gold standard. PPV for oral surgeons and atypical brush biopsy was compared stratified by age, gender, and lesion site. The PPV, negative predictive value, sensitivity, and specificity for oral surgeons were 10.3%, 100%, 100%, and 23.5%, respectively. After controlling for age, gender, and lesion site, oral surgeons were 19% to 58% more likely to diagnose a dysplastic lesion compared to OralCDx brush biopsy. Oral surgeons' effectiveness in diagnosing oral dysplastic lesions was slightly better than the OralCDx brush biopsy; hence, it is recommended that patients be referred to an oral surgeon for evaluation.

Abstract PR-10: Randomized placebo controlled trial of pioglitazone for oral premalignant lesions: A cross-consortium collaborative study in progress

Abstract There are currently no proven safe and effective oral cancer prevention treatments. Overall, approximately 5% of oral leukoplakias progress to squamous cell carcinoma and are therefore considered an important precursor lesion for cancer prevention intervention. Nuclear receptor agonists are agents that can affect cell maturation pathways in the oral cavity and other sites. The hypothesis of this National Cancer Institute/Division of Cancer Prevention (NCI/DCP)-sponsored trial is that 6 months of 45 mg pioglitazone daily will shrink oral premalignant lesions and favorably modulate surrogate endpoint biomarkers of cancer prevention. The study agent, pioglitazone, is a PPARγ agonist shown to modulate critical cellular pathways. There is preclinical evidence suggesting the potential efficacy of PPARγ ligands in prevention of cancer. Moreover, in an earlier nonrandomized phase IIa study, response rates of over 70% were achieved in patients with oral leukoplakia after 3 months of treatment. In this current study, 100 participants with dysplastic oral premalignant lesions are being recruited and randomized to active drug or placebo for a period of 6 months. The primary endpoint is lesion size reduction or histologic improvement after 6 months of drug intervention. The secondary endpoints are the following biomarkers: PPARγ, cyclin D1, p21, TUNEL assay for apoptosis, Ki-67 for proliferation, transglutaminase, involucrin, 15-PGDH, LOH, and the change in plasma level of CRP. Plasma drug levels and cotinine levels are also measured. Accrual and evaluation is planned for 24 months. Due to the large size of this study and the relative rarity of these lesions, an international interconsortium study was designed to facilitate accrual. The lead DCP Consortia institutions, University of Wisconsin Carbone Cancer Center (UWCCC) and University of Texas MD Anderson Cancer Center (MDACC), and their nine participating organizations, Memorial Sloan-Kettering Cancer Center, Columbia University Medical Center, Weill Medical College of Cornell University, University of Maryland, University of Minnesota, University of Iowa, University of Alabama, Roswell Park Cancer Institute, and European Institute of Oncology (EIO) in Milan, Italy, make up the 11 sites for accrual for this study. During the process of protocol development, a streamlined centralized pathology review system was developed to improve consistency in histological diagnosis utilizing a web-based Aperio system. Additionally, to insure high-quality data an extensive Manual of Procedures (MOP) delineating all protocol activities is used by all sites. Centralized data entry utilizing Westat-developed Remote Data Capture database is used. The data analysis will include stratification by group (UWCCC vs. MDACC vs. EIO) and severe vs. mild dysplasia. Study drug and placebo are encapsulated by Fisher BioServices. The repository for banked biological specimen for future studies is held at the Analytical Instrumentation Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics (3P) lab at UWCCC. In conclusion a large oral cancer prevention inter-consortium study has been designed and implemented at 10 U.S. sites and one Italian site to evaluate the efficacy of pioglitazone treatment in oral premalignant lesions. This talk is also presented as Poster A73. Citation Information: Cancer Prev Res 2010;3(12 Suppl):PR-10.

A Feasible Procedure in Dental Practice: The Treatment of Oral Dysplastic Hyperkeratotic Lesions of the Oral Cavity with the CO2 Laser

The aim of this work is to report some cases of surgical removal of hyperkeratotic lesions of the oral cavity with the CO(2) laser. Hyperkeratosis is an abnormal thickening of the stratum corneum caused by increased deposition of keratin, and its histopathologic features show wide variations. These changes are significant because they determine different biologic behavior. Several techniques are used to treat these lesions, including scalpel incision, electrosurgery, cryosurgery, photodynamic therapy, and some drugs. The use of surgical lasers has been proposed as an effective way of treating such lesions safely. The CO(2) laser is the most used laser on the oral cavity because of its affinity for water and high absorption by the oral mucosa. Several benefits of the use of the CO(2) laser are reported in the literature in regard to surgical procedures carried out on the oral cavity. All patients had histopathologic diagnosis of hyperkeratosis and mild epithelial dysplasia and were routinely prepared for surgery under local anesthesia. The surgical procedures were carried out by using a CO(2) laser (Sharplan 20 C; Laser Industries, Tel Aviv, Israel, λ10,600 nm, φ∼2 mm, CW/RSP). The beam was focused to delimit each lesion, and then lesions were excised, and the removed specimens were sent for histopathology. At the end of the surgery, the beam was used in a defocused manner to promote better hemostasis. Neither sutures nor dressings were used after the surgery. No medication but mouthwashes was prescribed to all patients in the postoperative period. The use of the CO(2) laser does not reduce the risk of relapses of the lesion, but it is an easy-to-use technique and results in both a quick surgical procedure and trouble-free postoperative period and may be safely used in dental practice.

CO2 laser ablation of oropharyngeal dysplasia

The use of CO2 laser in the management of oral dysplastic lesions have been put into practice for more than a few years now. The main advantage is the decrease in local tissue morbidity. Very few studies have evaluated recurrence, malignant transformation and overall outcome in patients undergoing such procedure.

Abnormal DNA content in oral epithelial dysplasia is associated with increased risk of progression to carcinoma

Background:Oral epithelial dysplasia (OED) is a histologically detectable lesion that may progress to carcinoma but there are no accurate markers that predict progression. This study examined the development of carcinoma from oral dysplastic lesions, and the association between abnormal DNA content and progression to carcinoma.Methods:Epithelial dysplasias from the Oral Pathology Diagnostic Service were matched against the Ontario Cancer Registry database to identify cases that progressed to carcinoma. A case–control study was conducted to compare DNA image cytometry of dysplasias that progressed with those that have not progressed. For a subset of the progressed dysplasias, DNA content of the carcinoma was also analysed.Results:A total of 8% of epithelial dysplasias progressed to carcinoma after 6–131 months. In all, 28 of 99 dysplasias showed abnormal DNA content by image cytometry. In multivariate analysis of time to progression, abnormal DNA content was a significant predictor with hazard ratio of 3.3 (95% confidence interval: 1.5–7.4) corrected for site and grade of dysplasia. Analysis of sequential samples of dysplasia and carcinoma suggested that epithelial cell populations with grossly abnormal DNA content were transient intermediates during oral cancer development.Conclusions:Abnormal DNA content is a significant biomarker of a subset of OED that progress to carcinoma.

The configuration of clinics and the use of biopsy and photography in oral premalignancy: a survey of consultants of the British Association of Oral and Maxillofacial Surgeons

Oral dysplastic lesions may have an increased chance of becoming oral squamous cell carcinoma, but to date their management remains controversial. The aim of this survey was to explore the current practical aspects of the management of patients with dysplasia by oral and maxillofacial consultants in the UK. In the survey we asked consultants about the numbers of patients they see with oral premalignant lesions, the frequency and specialty of designated hospital clinics, their use of photographs and biopsy, factors that influence their decision whether to biopsy a lesion at the first appointment, the procedure for treatment and follow-up and their use (if any) of chemopreventive agents. We found a wide variation in the practical aspects of managing patients with dysplasia, and the lack of consistency among clinicians supports the idea of an initiative to establish more robust national guidelines to use as a gold standard in the future.

The role of alcohol in oral precancer: observations from a North-East England population

Alcohol is known to be a risk factor for oral precancerous lesions, but evidence has been weakened by subjective estimates of alcohol intake from patients, and confounded by their use of tobacco. Red cell macrocytosis, assessed by calculation of mean corpuscular volume (MCV), may be a useful objective indicator of chronic alcohol intake. The aim of this study was to compare subjective and objective measures of alcohol intake in patients with oral precancerous lesions and assess the use of reported alcohol intake and MCV on assessing the degree of dysplasia at presentation and their role as markers of the behaviour of such lesions by assessing clinical outcome after treatment. Fifty-four new patients were recruited. All were smokers and had histologically confirmed single dysplastic oral precancerous lesions, but had had no previous treatment. Subjective data about their alcohol consumption were recorded, and blood samples taken for the assessment of MCV. All patients had laser excision of their lesions, which were assessed histopathologically for signs of dysplasia. Patients were followed up for 2 years. The significance of differences was assessed using Fisher's exact test. Alcohol intake of more than 28 units/week and MCV of over 100 were associated with increased dysplasia at presentation ( p = 0.01 and p = 0.03, respectively). Thirty-six patients were disease-free at 2 years, but 18 developed further disease, often at new sites. Alcohol intake of more than 28 units/week was significantly associated with an increased risk of further disease ( p = 0.03), particularly recurrence at the same site ( p = 0.02).

Clinicopathological behaviour of multiple oral dysplastic lesions compared with that of single lesions

Oral precancerous lesions may be solitary or multifocal, the latter being difficult to manage because of extensive field change. The aim of this study was to characterise differences in clinicopathological features, proliferative labelling indexes for cyclin A, cyclin B1, and Ki67, and clinical outcome 5 years after laser resection in a group of patients presenting with single and multiple oral precancerous lesions. Ninety-six patients with 132 lesions (78 single and 18 multiple) were recruited, and there were no significant differences between those with single and multiple lesions with respect to age, sex, smoking, or alcohol consumption, although multiple lesions were significantly more common in smokers who ate little fruit and vegetables ( p = 0.02). Clinically, most lesions were leukoplakia, with ulcerated or exophytic lesions appearing singly. There were significant differences in site, single lesions being most common on the floor of the mouth and the ventrolateral tongue, and multiple lesions preferring the buccal mucosa ( p = 0.0002). The most severe dysplasia was seen in single lesions ( p = 0.001) with labelling indexes for cyclin A and Ki67 being significantly higher in these ( p = 0.04 and p = 0.01, respectively). Oral squamous cell carcinoma developed in 3/78 single lesions and 4/18 multiple ones. There are distinct differences between single and multiple lesions that have implications for the prophylaxis and management of oral cancer.

Treatment and follow‐up of oral dysplasia — A systematic review and meta‐analysis

The aim of this study was to inform an evidence-based management policy for oral dysplastic lesions. Systematic review was performed with meta-analysis. Studies reporting follow-up of patients with histologically confirmed oral dysplasia were included. Outcome measures included malignant transformation rate (MTR) and time to malignant transformation (TMT). Subgroup analysis was performed by histologic grade, clinical risk factors, and treatment modality. Heterogeneity was assessed. Fourteen nonrandomized studies, reporting on 992 patients, were included. There was considerable heterogeneity between studies: mean overall MTR = 12.1% (confidence interval: 8.1%, 17.9%) and mean TMT = 4.3 years. Histologic grade significantly affected mean MTR (p < .008). Lesions that were not excised demonstrated considerably higher MTR than those that were excised (p = .003). Oral dysplasia showed a significant rate of transformation to cancer, which was related to grade and was decreased significantly but not eliminated by excision. This suggested the need for excision and continued surveillance.

Low positive predictive value of the oral brush biopsy in detecting dysplastic oral lesions

The authors evaluated the effectiveness of the oral brush biopsy technique as a diagnostic tool in detecting dysplastic oral lesions. In this cross-sectional study, pathologic reports (n = 152) from the scalpel biopsies (tissue samples) in patients who previously tested either "positive" (n = 3) or "atypical" (n = 149) for dysplasia by brush biopsy (OralCDx) were evaluated. Information on the age and sex of the patient, the site of the lesion, the brush biopsy results, and the histopathologic diagnosis of the scalpel biopsy was collected. The positive predictive values (PPVs) for "abnormal," "atypical," and "positive" brush biopsies were determined. Overall, the PPV of an abnormal brush biopsy was only 7.9% (95% confidence interval [CI], 4.2%-13.4%), and the PPV of an "atypical" brush biopsy was 7.4% (95% CI, 3.7%-12.8%). Of the 3 positive brush biopsies, only 1 was identified as dysplastic. The proportion of false-positive biopsy results was as high as 92.1% (95% CI, 86.6%-95.9%). The OralCDx technique overestimated dysplastic lesions and produced a high number of false-positive results.

Factors affecting carbon dioxide laser treatment for oral precancer: A patient cohort study

Although the benefits of CO(2) laser surgery in oral precancer management have been evaluated, little consideration has been given to the factors which may influence treatment outcome, especially amongst patients developing recurrence or malignant transformation. Seventy eight patients (51 males, 27 females; mean age 57.8 years) undergoing CO(2) laser excision of single, new dysplastic oral precancer lesions (OPLs) were followed up for a minimum of 2 years and the influence of clinico-pathological parameters, socio-demographic factors and the presence or absence of residual dysplasia in excision margins upon clinical outcome were examined. Seventy three percent of patients were smokers and 78% consumed alcohol regularly. The majority of lesions were leukoplakias arising in the floor of mouth and ventro-lateral tongue and moderate or severe dysplasia accounted for 86% of histopathological diagnoses. Patient follow up ranged from 24 to 119 months (mean 58 months). Sixty four percent of patients were disease free at most recent clinical follow up, whilst 32% developed local recurrent dysplasia or new site dysplasia with 4% developing oral squamous cell carcinoma (but at sites distinct from their initial OPL). Excision margins were clear in 55% of cases, but 19% showed mild, 21% moderate and 5% severe dysplasia on histopathological examination. No statistically significant associations were seen between patients' age, gender, lesion appearance, site of origin, histopathological grading, presence of dysplasia in resection margins, or alcohol consumption and clinical outcome. Smokers, however, were at significantly higher risk of dysplasia recurrence compared to ex-smokers or non-smokers (P = 0.04). In the absence of agreed treatment protocols for OPLs, we recommend CO(2) laser surgery as an effective treatment modality offering precise lesion excision, full histopathological assessment, minimal post-operative morbidity and a 64% disease free clinical outcome. Regular patient follow up is encouraged due to the persistence of field cancerisation effects.

DNA ploidy analysis by image cytometry helps to identify oral epithelial dysplasias with a high risk of malignant progression

Abnormal DNA content (aneuploidy) has been associated with malignant and premalignant epithelial lesions. The presence of aneuploidy in tumours at an early stage and in dysplastic lesions suggests that analysis of DNA content may be a useful marker for determination of prognosis in these lesions. The aim of this study was to use DNA image cytometry to evaluate aneuploidy in oral dysplastic lesions and to determine whether aneuploidy is associated with malignant progression. Forty-two lesions of oral epithelial dysplasias (OED) that had progressed to oral squamous cell carcinoma (OSCC) and 44 lesions that did not progress were analysed for DNA ploidy using image cytometry of nuclear monolayers prepared from paraffin-embedded tissue. Forty-two OSCC that had arisen from the OED cases and five samples of normal oral mucosa samples (NOM) were also examined. Aneuploidy was found in 14/42 (33.3%) of the OED that progressed, but in only 5/44 (11.3%) of OED that did not progress (p=0.01). A total of 19 OED were aneuploid of which 74% showed malignant progression compared to only 42% of the diploid lesions. The sensitivity and specificity of DNA image cytometry to detect cases with high risk of malignant progression was 0.33 and 0.88, respectively. The PPV and NPV were 0.74 and 0.58. We conclude that aneuploid oral dysplastic lesions have a high risk of malignant progression and that DNA image cytometry might help to identify those lesions most at risk.

Tissue engineering of oral dysplasia

Keratinocytes and fibroblasts isolated from dysplastic oral lesions were combined to provide a renewable source of epithelia. A dysplasia-scoring index was devised to compare the architectural and cytological features and used together with robust immunophenotyping to show that the engineered epithelia showed most of the characteristics of the clinical lesions. The strains of dysplastic oral keratinocytes with an extended or immortal lifespan provided a reproducible resource of epithelia showing mild (DOK), moderate (POE9n) or severe (D20) dysplasia when maintained under defined conditions. The dysplasia score was influenced by growth conditions, with KGF polarizing proliferation to the basal layer and reducing the severity of dysplasia. When compared to the normal counterparts, dysplasia-associated fibroblasts expressed MMP9, secreted more HGF, increased the dysplasia score for epithelia generated with mortal dysplastic keratinocytes and induced morphological changes in normal keratinocytes, highlighting the role of the microenvironment in determining the phenotype of dysplastic epithelia.

Lysis of Dysplastic but not Normal Oral Keratinocytes and Tissue-Engineered Epithelia with Conditionally Replicating Adenoviruses

There is no effective medical treatment for oral precancer, and surgery to remove these lesions is imprecise because abnormal mucosa extends beyond the visible lesion. Development of vectors for tumor-selective viral replication has been a significant advance, and viral lysis is well suited to destruction of oral precancerous mucosa. To facilitate evaluation of new treatments, we engineered dysplastic oral epithelium using keratinocytes isolated from dysplastic lesions. We show that these model systems recapitulate the key characteristics of the clinical lesions closely, and that topical delivery of the conditionally replicating adenovirus (CRAd) dl922-947 can lyse tissue-engineered epithelia that show mild, moderate, or severe dysplasia, but normal oral epithelia are very resistant to this treatment. The lytic effect is determined by various factors, including the grade and proliferation index of the dysplastic epithelia. The presence of suprabasal cycling cells, expression of the coxsackie adenovirus receptor (CAR), the transcription cofactor p300, and other aberrations that affect the regulation of the cell cycle or apoptosis and promote viral replication may also be important. The ability of dl922-947 to destroy engineered oral dysplasia was significantly greater than that observed using wild-type adenovirus, d/1520, or viruses modified to bypass cell entry dependent on the presence of CAR. Evidence of infection in clinical dysplastic lesions was also shown ex vivo using tissue explants. We conclude that dl922-947 may provide an efficient molecular cytotoxic to dissolve oral dysplastic lesions.

O28 Follow-up of oral dysplastic lesions a systematic review

O28 Follow-up of oral dysplastic lesions a systematic review

Effects of active non-smoking programmes on smoking behaviour in oral precancer patients

Smoking is the commonest risk factor for oral cancer and precancer. The objective of this study was to characterize smoking behaviour and attitude in a cohort of oral precancer patients in Newcastle upon Tyne, UK, and to determine changes in behaviour during diagnosis, treatment and follow-up. Twenty-seven consecutive, smoking patients with dysplastic oral lesions were recruited to the study and a detailed smoking history obtained, quantifying types and numbers of cigarettes smoked, length of smoking history, and changes in smoking behaviour during treatment episodes and long-term follow-up. All patients underwent an interventional management protocol comprising risk-factor education, histopathological diagnosis by incisional biopsy and laser excision of lesions. Patients were followed up for 5 years. Whilst there was a significant decrease in the number of cigarettes smoked at patients’ most recent follow-up compared with initial presentation ( p < 0.001), 74% continued to smoke. Patients received advice from a smoking cessation adviser on support available to them from the local NHS (National Health Service) Stop Smoking services. Six out of 10 patients who set a ‘quit date’ and attended a programme had quit at the 4-week follow-up but only 5 remained non-smokers. Smoking remains a considerable problem in oral precancer patients even after interventional treatment, with the risk of further precancerous lesions and malignant transformation.

Diagnostic Potential of Genomic and Proteomic Signatures in Oral Cancer

Oral cancer is a public health problem with increasing incidence and mortality rates worldwide. Despite rapid advances in treatment, 5year survival rates have not improved significantly. Major thrust is being laid on diagnosis of the disease in early stages, which is hampered by non-availability of specific diagnostic markers. Advances in genomics and proteomics have made global assessment of expressed genes and proteins in clinical samples feasible. Gene and protein expression profiles derived from clinical specimens have been used to distinguish differences between normal and malignant oral tissues, which are not obvious by clinical, or histologic characteristics. This review focusses on comprehensive analyses of gene expression patterns and proteomic signatures of oral dysplastic lesions and squamous cell carcinomas that have shown considerable promise to improve the discovery of biomarkers for progression of premalignant lesions, prediction of clincal outcome , identification of novel targets for therapy and future directions of molecular signatures of oral cancer in disease diagnosis and therapy.

Management of oral epithelial dysplasia: a review

One of the goals of the fourth meeting of The World Workshop on Oral Medicine (WWOM IV) included a review of the pathophysiology and future directions for the clinical management of patients with oral epithelial dysplasia, excluding the lips and oropharynx. In the pathophysiology review of dysplasia since WWOM III (1998-2006), a wide range of molecular changes associated with progression of dysplasia to squamous cell carcinoma were found. These include loss of heterozygosity, dysregulation of apoptosis, aberrant DNA expression, and altered expression of numerous tissue markers. Based on the literature search, no single molecular pathway has been identified as the primary factor in progression of dysplasia to squamous cell carcinoma. A systematic review of medical (i.e., nonsurgical) management strategies for the treatment of dysplastic lesions has shown promising results in short-term resolution of dysplasia in the small number of studies that met eligibility criteria for review. However, because of the limited periods of follow-up reported in these studies, it remains unclear as whether resolution of dysplasia would actually be a long-term benefit of these interventions. This question is particularly germane when it is considered in the context of prevention of future development of squamous cell carcinoma. Because of the lack of randomized controlled trials that have shown effectiveness in the prevention of malignant transformation, no recommendations can be provided for specific surgical interventions of dysplastic oral lesions either.

Expression of vascular endothelial growth factor (VEGF) in normal oral mucosa, oral dysplasia and oral squamous cell carcinoma

Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine implicated in tumour vasculogenesis. A significant increase in vascularity occurs during the transition from normal oral mucosa (NOM), through dysplasia, to squamous cell carcinoma (SCC). This study investigated the presence of VEGF in NOM, oral dysplasia and SCC. The correlation between VEGF expression and the grade of dysplasia or differentiation of SCC was also examined. Specimens consisting of NOM, oral dysplastic lesions and oral SCC were stained using standard immunohistochemistry methods to determine VEGF expression. Statistical analysis indicated an up-regulation of VEGF during the transition from NOM, through dysplasia to SCC. There was also a significant difference in expression according to differentiation of SCC, but not grade of dysplasia. As VEGF is a potent mediator of vascular development, these results suggest that VEGF may play an important role in the maintenance of a blood supply for developing pre-cancerous and invasive oral lesions.

Elastic scattering spectroscopy in the head &amp; neck

Objectives. To develop the a technique of optical biopsy of oral dysplastic lesions that will provide real‐time diagnosis, allow in situ monitoring, and which will be feasible in the clinical environment especially for patient follow‐up.Method. Ethics approval was granted. Ex‐vivo specimens were evaluated to determine the optimal protocol before use in vivo. 75 spectra were obtained from 25 patients with oral leukoplakia. The spectral readings were mapped, and the area was then biopsied. Photographic images were co‐registered with the histological specimen. The sensitivity and specificity of the technique was determined compared to the gold standard of histo‐pathological examination of paraffin sections.Results. The sensitivity and specificity in determining dysplastic from benign conditions were 70% and 78.6% respectively at 580 nm.Conclusions. The use of Elastic Scattering Spectroscopy may aid the differentiation of normal and dysplastic mucosal lesions in the head &amp; neck.References 1 Chung, A., Karlan, S., Lindsley, E., et al. (2006) In vivo cytometry: a spectrum of possibilities. Cytometry A. 69, 142–1462 Dhar, A., Johnson, KS., Novelli, MR., et al. (2006) Elastic scattering spectroscopy for the diagnosis of colonic lesions: initial results of a novel optical biopsy technique. Gastrointest Endosc.63, 257–261