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Authors: Dr. Jagadish V. Hosmani(Senior Lecturer), Dr. Deepa Hugar (Senior Lecturer), Dr. Ramakant Nayak, (Professor & H.O.D.)

The World Health Organization has clearly indentified prevention and early detection as major objectives in the control of the oral cancer burden worldwide. At the present time, screening of oral cancer and its pre-invasive intra-epithelial stages, as well as its early detection, is still largely based on visual examination of the mouth. There is strong available evidence to suggest that visual inspection of the oral mucosa is effective in reducing mortality from oral cancer in individuals exposed to risk factors. Simple visual examination, however, is well known to be limited by subjective interpretation and by the potential, albeit rare, occurrence of dysplasia and early OSCC within areas of normal-looking oral mucosa. As a consequence, adjunctive techniques have been suggested to increase our ability to differentiate between benign abnormalities and dysplastic/malignant changes as well as to identify areas of dysplasia/early OSCC that are not visible to naked eye.

In the past decades, adjunctive techniques have emerged with claims of enhancing oral mucosal examinations and facilitating the detection of and distinctions between oral benign and oral premalignant and malignant lesions . Clinicians who use these tools may be unaware of the state of the evidence supporting their effectiveness. Techniques that are promoted or assessed to improve earlier detection and diagnosis of oral malignancy include toluidine blue , ViziLite Plus with TBlue , ViziLite , Microlux DL , Orascoptic DK ,VELscope and OralCDx brush biopsy.In developing countries such as India, where there is a high prevalence of disease, the focus is on downstaging oral cancer at diagnosis from advanced to earlier disease. In the United States, by contrast,these adjunctive techniques are marketed to facilitate the detection of premalignant disease. It is assumed that if a premalignant lesion is detected and treated, the lesion may not progress to cancer.
The World Health Organization has clearly indentified prevention and early detection as major objectives in the control of the oral cancer burden worldwide. At the present time, screening of oral cancer and its pre-invasive intra-epithelial stages, as well as its early detection, is still largely based on visual examination of the mouth. There is strong available evidence to suggest that visual inspection of the oral mucosa is effective in reducing mortality from oral cancer in individuals exposed to risk factors. Simple visual examination, however, is well known to be limited by subjective interpretation and by the potential, albeit rare, occurrence of dysplasia and early OSCC within areas of normal-looking oral mucosa. As a consequence, adjunctive techniques have been suggested to increase our ability to differentiate between benign abnormalities and dysplastic/malignant changes as well as to identify areas of dysplasia/early OSCC that are not visible to naked eye.

In the past decades, adjunctive techniques have emerged with claims of enhancing oral mucosal examinations and facilitating the detection of and distinctions between oral benign and oral premalignant and malignant lesions . Clinicians who use these tools may be unaware of the state of the evidence supporting their effectiveness. Techniques that are promoted or assessed to improve earlier detection and diagnosis of oral malignancy include toluidine blue , ViziLite Plus with TBlue , ViziLite , Microlux DL , Orascoptic DK ,VELscope and OralCDx brush biopsy.In developing countries such as India, where there is a high prevalence of disease, the focus is on downstaging oral cancer at diagnosis from advanced to earlier disease. In the United States, by contrast,these adjunctive techniques are marketed to facilitate the detection of premalignant disease. It is assumed that if a premalignant lesion is detected and treated, the lesion may not progress to cancer.

THE DETECTION TECHNIQUES
Vital tissue staining. Tolonium chloride, more commonly referred to as TB, has been used for more than 40 years to aid in detection of mucosal abnormalities of the cervix and the oral cavity.TB is a metachromatic vital dye that may bind preferentially to tissues undergoing rapid cell division (such as inflammatory, regenerative and neoplastic tissue), to sites of DNA change associated with OPML or both. The binding results in the staining of abnormal tissue in contrast to adjacent normal mucosa. Toluidine blue (TB), also known as tolonium chloride, is a vital dye that is believed to stain nucleic acids.

Hence, it has been used for many years as an aid to the identification of clinically occult mucosal abnormalities and as a useful way of demarcating the extent of a potentially malignant lesion prior to excision . Several studies on TB have been performed in the past years but the majority of them present significant limitations and methodological biases . Analysis of current evidence suggests that TB is good at detecting carcinomas, but its sensitivity in detecting dysplasias is significantly lower . Furthermore, there remain a high percentage of false positive stains which impairs its use in primary care settings as a valid screening mean . In addition, controversy exists regarding the subjective interpretation of mucosal staining and criteria for positive results (e.g. dark royal blue versus pale blue staining). Visualization adjuncts. Several visualization adjuncts, described below, are intended for use as adjuncts to the standard visual and tactile oral examination under incandescent light. They function under the assumption that mucosal tissues undergoing abnormal metabolic or structural changes have different absorbance and reflectance profiles when exposed to various forms of light or energy.

Described as a chemiluminescent light detection system, ViziLite was developed from predicate devices to detect cervical neoplasia. Clinical inspection of oral mucosa with the aid of chemiluminescent blue/white light was recently suggested to improve the identification of mucosal abnormalities with respect to the use of normal incandescent light The relevant technology involves the use of an oral rinse with a 1% acetic acid solution for 1 minute followed by the examination of the oral mucosa under diffuse chemiluminescent blue/white light (wavelength of 490 to 510 nm). The theory behind this technique is that the acetic acid removes the glycoprotein barrier and slightly desiccates the oral mucosa, the abnormal cells of the mucosa then absorbing and reflecting the blue/white light in a different way with respect to normal cells. Hence normal mucosa appears blue, whereas abnormal mucosal areas reflect the light (due to higher nuclear/cytoplasmic ratio of epithelial cells) and appear more acetowhite with brighter, sharper and more distinct margins.More recently, the ViziLite system was modified in order to include the use of TB and a new chemiluminescence device (MicroLux DL) was introduced.

Several studies have been performed with the Vizilite system with the attempt to demonstrate its efficacy in to enhance the identification of mucosal abnormalities. It should be highlighted that no study has demonstrated that the chemiluminescence can help in differentiating dysplasia/carcinoma from benign lesions . Hence, the majority of studies have investigated how chemiluminescence enhances subjective clinical evaluation of intra-oral lesions including brightness, sharpness and texture with respect to routine clinical examination. As these parameters are highly subjective, it is not surprising that results have been contradictory . Whilst some authors report that this technique can improve the detection of intra-oral abnormalities (regardless their nature), other reports suggest that the overall detection rate was not significantly improved and the chemilumi nescent light produced reflections that made visualization even more difficult than with incandescent light Furthermore, the majority of the studies are limited by methodological flaws such as lack of histopathological diagnosis or clear objectives (screening device versus case-finding device) . Some studies suggest that chemiluminescence may help identifying occult lesions that cannot be seen with incandescent light but this, however, is not supported by any strong evidence.

Tissue Fluorescence Imaging

Tissue autofluorescence has been used in the screening and diagnosis of precancers and early cancer of the lung, uterine cervix, skin and, more recently, of the oral cavity. The concept behind tissue autoflorescence is that changes in the structure (e.g., hyperkeratosis, hyperchromatin and increased cellular/nuclear pleomorphism) and metabolism (e.g. concentration of flavin adenine dinucleotide [FAD] and nicotinamide adenine dinucleotide [NADH]) of the epithelium, as well as changes of the subepithelial stroma (e.g. composition of collagen matrix and elastin), alter their interaction with light . Specifically, these epithelial and stromal changes can alter the distribution of tissue fluorophores and as a consequencethe way they emit fluorescence after stimulation with intense blue excitation (400 to 460 nm) light, a process defined autoflorescence. The autoflorescence signal is finally visualized directly by a human observer. With regards to the oral cavity, normal oral mucosa emits a pale green autofluorescence when viewed through the instrument handpiece whilst abnormal tissue exhibits decreased autofluorescence and appears darker with respect to the surrounding healthy tissue. Autoflorescence technology for inspection of the oral mucosa has been developed by LED Medical Diagnostics Inc. in partnership with the British Columbia Cancer Agency and is marketed as VELscope system. Effectiveness of the VELscope system as an adjunct to visual examination for(i) improving the distinction between between normal and abnormal tissues (both benign and malignant malignant changes), (ii) differentiating between benign and dysplatic/malignant changes, (iii) and identifying dysplastic/ malignant lesions (or lesion's margins) that are not visible to the naked eye under white light. Overall the quality of available studies is significantly higher than that of studies upon chemiluminescence and TB as the technology's sensitivity and specificity was compared to gold standard (histopathology) in all patients studied .With regard to the first aspect, autofluorescence imaging of the oral mucosa has been reported to possibly improve lesions' contrast and therefore increase the ability to distinguish between mucosal lesions and healthy mucosa, although further research on different patients population is needed . The ability of autofluorescence to differentiate between different lesion types has been investigated in a few studies and overall the technique seems to show high sensitivity, but low specificity. However, the VELscope system seems to be very promising due to its ability and effectiveness in identifying lesions and lesions' margins that are occult to visual examination under white light. Using histology as the gold standard, VELscope demonstrated high sensitivity and specificity in identifying areas of dysplasia and cancers that extended beyond the clinically evident tumors . A direct clinical application consists of assessing lesion margins in patients with potentially malignant oral disorders therefore improving surgical management .However, it should be highlighted that these results are from case series and case reports rather than clinical trials and that no published studies have assessed the VELscope system as a diagnostic adjunct in screening lower-risk populations (e.g. without a history of dysplasia/OSCC) or in patients seen by primary care providers.

Tissue Fluorescence Spectroscopy

In addition to visual autofluorescence, a technique called autofluorescence spectroscopy has been recently tested in oral oncology research . The autofluorescence spectroscopy system consists of a small optical fiber that produces various excitation wavelengths and a spectrograph that receives and records on a computer and analyzes, via a dedicated software, the spectra of reflected fluorescence from the tissue. This technique has the clear advantage of eliminating the subjective interpretation of tissue fluorescence changes. However, the downside is that more variables (e.g. combination of wavelengths, methodology of fluorescence analysis etc) have to be tested and considered and this has led to controversial and often unclear results. Overall, autofluorescence spectroscopy seems to be very accurate for distinguishing lesions from healthy oral mucosa, with high sensitivity and specificity, especially when malignant tumors are compared to healthy mucosa. However, the ability of the technique to distinguish and classify different types of lesion has been reported to be low. Moreover autofluorescence spectroscopy is for practical reasons not suitable to detect new lesions or to demarcate large lesions as the optical fiber can sample only a small mucosal area . This limits the use of spectroscopy to the evaluation of a well defined small mucosal lesion that has been already identified through visual inspection, with the attempt to clarify its benign or (pre)malignant nature. Further research is needed to support this clinical application of autofluorescence spectroscopy. After receiving application of acetic acid, sites of epithelial proliferation, having cells with altered nuclear structure, are purported to preferentially reflect the low energy blue-white light emitted by a device generating an “acetowhite” change. The ViziLite system no longer is available as a single product, but is a part of the ViziLite Plus withTBlue system .The Microlux DL system is a multiuse system developed from a blue-white light-emitting diode and a diffused fiber-optic light guide that generates a lowenergy blue light.The Orascoptic DK system is sold as a three-in one, battery-operated, hand-held LED instrument with an oral lesion screening instrument attachment that is used in concert with a mild acetic acid rinse promoted to improve visualization of oral lesions. The VELscope system is a multiuse device with a handheld scope through which the clinician can scan the mucosa visually for changes in tissue fluorescence. The proposed mechanism of tissue fluorescence is that mucosal tissues have a reflective and absorptive pattern based on naturally occurring fluorophores in the tissue. Tissue fluorescence in the oral cavity is variable and isaffected by structural changes, metabolic activity, the presence of hemoglobin in the tissue, vessel dilatation and, possibly, inflammation. This variability has not been defined. Exposure to blue light spectra (400-460 nanometers) may maximize a differential profile in areas undergoing neoplastic change in which a loss of fluorescence visualization is reported.

Cytopathology is the microscopic study of cell samples collected from mucosal surfaces (via smears, scrapings orlavage) or from internal sites via fine-needle aspiration. The oral brush biopsy, also known as OralCDx Brush Test system, consists of a method of collecting a trans-epithelial sample of cells from a mucosal lesion with representation of the superficial, intermediate and parabasal/basal layers of the epithelium .

This test was specifically designed to investigate mucosal abnormalities that would otherwise not be subjected to biopsy because of low-risk clinical features . A specially designed brush is the non-lacerational device used for epithelial cell collection and samples are eventually fixed onto a glass slide, stained with a modified Papanicolaou test and analyzed microscopically via a computer-based imaging system. Results are reported as "positive" or "atypical" when cellular morphology is highly suspicious for epithelial dysplasia or carcinoma or when abnormal epithelial changes are of uncertain diagnostic significance respectively. Results are defined as negative when no abnormalities can be found. The test is considered an intermediate diagnostic step as a scalpel biopsy must follow when an abnormal result is reported (atypical or positive). Biopsy. The gold standard diagnostic test for oral mucosal lesions that are suggestive of premalignancy or malignancy remains tissue biopsy and histopathological examination.

The World Health Organization has clearly indentified prevention and early detection as the major targets in thebattle to control the oral cancer burden worldwide .

Prevention and early detection of OSCC and its pre-invasive intra-epithelial stages is still largely based on visual examination of the mouth, although a variety of molecular techniques have been tested and are likely to represent the ultimate goal of oral cancer research . A 9-year randomized controlled trial has shown that screening via visual examination of the oral mucosa under white light is effective in reducing mortality in individuals exposed to risk factors. Simple visual examination, however, is well known to be limited by subjective interpretation and by the potential, albeit rare, occurrence of dysplasia and early OSCC within areas of normal-looking oral mucosa. As a consequence, adjunctive techniques have been suggested to increase our ability to differentiate between benign abnormalities and dysplastic/malignant changes as well as identify areas of dysplasia/early OSCC that are not visible to naked eye. Chemiluminescence and autofluorescence are two relatively new techniques that have been investigated with variable results. Available studies have shown promising results, but strong clear evidence to support their effectiveness is still lacking. Major limitations include analysis of small sample sizes, lack of methodologically sound clinical trials, insufficient use of histologic and molecular mapping of optically altered mucosa, need of more detailed analysis of factors rather than cancer that can affect the optical qualities of the oral mucosa (e.g. inflammation, previous chemo- or radio-therapy), and also direct comparison with other detection methods. Toluidine Blue has been used by clinicians for many years, yet a clear demonstration of TB indications, limitations, as well as strong evidence from methodologically sound clinical trials is still lacking. Brush biopsy is another example of promising novel diagnostic technique that unfortunately has not been supported by robust evidence. Clinical trials have been performed but in the majority of cases results should be read with caution due to biases, variations in research objectives and methodological inconsistencies. At present, the utilization of these techniques in clinical practice is largely anedoctal and is principally directed to help experienced clinicians at improving their ability to detect dysplasia and early OSCC in high-risk individuals attending secondary and tertiary centers. Moreover, experienced surgeons use some of the described optic aids to improve the identification of a lesion's margins and extensions in the operatory setting, although it is not know then impact these techniques have on a patient's survival and risk of disease recurrence.

At present, molecular and genetic analysis is not a routine procedure for oral lesions in which biopsy is performed in daily practice. New methods under investigation that involve examination of molecular markers in exfoliated cells and in oral fluids and new imaging methodologies may contribute to future advances in diagnosis evaluation of response to treatment interventions and determination of prognosis of oral mucosal lesions. The future is promising for further development and evolution of oral-cancer diagnostic aids to enhance the quality of patient care provided by all clinicians.

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