Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Australian Dental Journal The official journal of the Australian Dental Association Australian Dental Journal 2013; 58:(1 Suppl): 85–94 doi: 10.1111/adj.12054 Minimum intervention dentistry in oral medicine CS Farah,*† N Bhatia,*† K John,*† BW Lee*† *UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, Australia. †School of Dentistry, The University of Queensland, Brisbane, Queensland, Australia. ABSTRACT Oral medicine sits at the interface of medicine and dentistry. Minimum intervention dentistry (MID) borrows a medical model of disease control by oral health professionals. As an oral physician, the oral medicine specialist practices MID on a daily basis. With the advent of sophisticated early detection and diagnostic technology, and the growing understanding of oral diseases at the microscopic and molecular levels, all oral health practitioners can contribute to the practice of oral medicine from a MID perspective. MID in oral medicine allows the practice of comprehensive oral care where the patient is fully engaged in their own healthcare, with the use of advanced diagnostic technology, the application of medicines and therapeutics depending on disease processes, important risk assessment of both the oral disease and the affected patient with identification of those at high risk, monitoring of compliance, and patient recall. In this article we highlight minimum intervention in oral medicine by exploring oral cancer as the most significant disease we encounter and are involved with. Advances in patient care, particularly in relation to minimum intervention, are underpinned by high calibre cutting edge translational research. It is this research that allows us to positively transform our patients’ lives. Keywords: Minimum intervention dentistry, oral medicine, oral cancer, early detection. Abbreviations and acronyms: AF = autofluorescence; CT = computerized tomography; HPV = human papillomavirus; IMRT = intensity modulated radiation therapy; IPCL = intrapapillary capillary loops; LED = light emitting diode; MID = minimum intervention dentistry; miRNA = microRNA; MRI = magnetic resonance imaging; NBI = narrow band imaging; OHT = oral health therapist; OSCC = oral squamous cell carcinoma; PET = positron emission tomography; SNP = single nucleotide polymorphism. INTRODUCTION Minimum intervention dentistry – otherwise known as MID – has been defined as a philosophy of professional care concerned specifically with three strategies, namely: (1) disease risk assessment; (2) early disease detection and diagnosis; and (3) minimally invasive treatment. Although this philosophy has mainly focused on assessment and management of dental caries, minimum intervention in oral medicine is an equally developed strategy although it has received less widespread attention, and has used different nomenclature and terminology to define its activities over time. The definition of oral medicine, as approved by the Oral Medicine Academy of Australasia, is ‘The branch of dentistry concerned with the diagnosis, prevention and predominantly non-surgical management of medically-related disorders and conditions affecting the oral and maxillofacial region, in particular oral mucosal disease and oro-facial pain, as well as the oral health care of medically complex patients’. Given the © 2013 Australian Dental Association scope of conditions and diseases oral medicine specialists deal with, it could perhaps appear too difficult to discuss minimum intervention strategies and philosophies that cover the broad aspects of this specialty. Nevertheless, with the particular importance of minimum intervention as a paradigm shift in oral healthcare, and the near complete absence of open discussion of issues pertinent to oral medicine in this growing field of dentistry, here we highlight particular aspects of oral medicine where minimum intervention plays a prominent role. It is interesting that minimum discussion has occurred around the importance of MID in oral medicine, given that MID borrows a medical model of disease control by oral health professionals, and oral medicine sits at the interface of medicine and dentistry. As an oral physician, the oral medicine specialist practises MID on a daily basis. Here we argue that with the advent of sophisticated early detection and diagnostic technology available in this field, and the growing understanding of oral diseases at the microscopic and molecular levels, all oral health practitioners 85 CS Farah et al. can contribute to the practice of oral medicine from a MID perspective. MID in oral medicine allows the practice of comprehensive oral care where the patient is fully engaged in their own healthcare, with the use of advanced diagnostic technology, the application of medicines and therapeutics depending on disease processes, important risk assessment of both the oral disease and the affected patient with identification of those at high risk, monitoring of compliance, and patient recall. Recent and future advances in technology used for early detection of oral mucosal pathology and the rapid development of point-of-care oral-based diagnostics, will put the oral health professional centre stage in the management of chronic oral diseases such as oral precancerous and cancerous conditions. However, these advancements will also call on significant understanding of risk, assessment of that risk, and the use of saliva, and other oral fluids and tissues for monitoring of disease and disease risk. Fundamentally, this necessitates upskilling the oral health workforce and comprehensive utilization of oral health professionals such as oral health therapists (OHTs). Oral health therapists are uniquely positioned to assist in the long-term maintenance of oral medicine conditions, many of which are chronic in nature, given their training in health promotion and provision of preventive clinical services. Indeed, one can argue that with the development of point-of-care oral-based diagnostics, both dentists and OHTs need to be even more familiar and competent with systemic diseases affecting their patients and the ramifications of detection and potential diagnosis of these conditions using technology. This is not as futuristic as it might seem. MID in oral medicine supports the argument that OHTs need to be better utilized in the context of oral health prevention and health promotion, and that dentists need to view themselves more as oral ‘physicians’ and less as oral ‘surgeons’ or indeed oral ‘engineers’. With the future of ‘personalized medicine’ upon us, it is vital that all oral health practitioners engage with MID as it lies at the heart of personalized medicine, particularly in the context and framework of oral medicine. Many oral diseases or oral manifestations of systemic diseases could be used to highlight the application of MID in oral medicine. These include, but are not limited to, oral cancer and potentially malignant mucosal pathology; head and neck cancer treatment and long-term dental follow-up; mucocutaneous diseases; tooth erosion and salivary dysfunction; temporomandibular joint disorders and orofacial pain conditions. Inasmuch as disease processes can be used to highlight MID in oral medicine, technology can also be used to frame this philosophy in everyday 86 practice. Autofluorescence (AF) imaging, narrow band imaging (NBI), oral spectroscopy, exfoliative brush biopsy, endoscopy/endomicroscopy, point-of-care saliva-based diagnostic, cone beam volumetric tomography, molecular diagnostics, cancer stem cell therapy, and molecular imaging are but some of these varied technologies at different stages of penetration and performance in oral medicine which are important to the true practice of MID in oral medicine. At the heart of MID in oral medicine though, is an appreciation of people rather than diseases or technology, and proper training in disease recognition/ diagnosis. ‘People’ in this context though does not only pertain to health practitioners, but more importantly to the patients we serve, consult, diagnose, care for, manage, treat and educate. There can be no real patient and disease risk assessment without a fundamental engagement with the patient at risk. There cannot be minimum intervention without an understanding of risk factors, lifestyle risks, genetic risks, health behaviour management strategies, the importance of monitoring and long-term maintenance and compliance. Patient engagement and education is core to MID in oral medicine as it is in minimum intervention broadly. Long gone are the days where the practitioner dispenses treatment or a script for medication without truly engaging the patient and explaining the need, mode of operation, expected outcomes, and adverse effects of therapeutics. And long gone are the days where a patient is referred for diagnostic services without truly comprehending the expected outcomes, health risks and benefits. If MID in oral medicine is to grow and flourish, and if oral medicine as a specialty is to do the same, then practitioner and patient engagement and education are paramount. From our perspective, MID in oral medicine highlights an opportunity for integrated comprehensive oral healthcare where the oral medicine specialist, dentist, oral health therapist and others work as a team to deliver healthcare of the highest standard, through a well-formulated treatment plan that is executed based on accurate diagnostic information, and delivered in accordance with an evidence-based agenda at precise time points for distinct benefits. In the context set above, we will explore these concepts as they apply to the most important and deadly of oral diseases: oral cancer. Here we will use oral cancer as an example to highlight the practical aspects of MID in oral medicine. We will reflect on early detection technology such as AF and NBI, molecular and salivary diagnostics, and molecular imaging in head and neck cancer. In doing so, we will highlight personalized medicine in the context of oral cancer and also the shifting aetiology, changes to our understanding of the pathogenesis, and management strategies for this important disease. © 2013 Australian Dental Association MID in oral medicine DISEASE RISK ASSESSMENT Molecular and salivary diagnostics Populations at high risk of developing oral cancer are predominantly older, male, heavy users of alcohol and tobacco, often associated with a poor diet and low socio-economic status. Human papillomavirus (HPV) has emerged as a major aetiological factor, creating a new and enlarging subset of head and neck cancers, predominantly arising from the tonsil, base of tongue and oropharynx. With the increase in the incidence of HPV-related oral squamous cell carcinoma (OSCC), the demographics of the typical high risk patient are likely to change as these lesions are diagnosed at younger ages than non-HPV related SCC. Since the prevalence of disease is higher in high risk groups, risk assessment should be focused on these populations in order to better utilize human resources, but also to affect better outcomes for the populations involved. HPV-related OSCC has emerged as a new and growing subset of head and neck cancers, with HPV status greatly influencing clinical features and prognosis.1 The aetiology and epidemiology of this group is different to that of non-HPV related OSCC and management of this disease should be customized so as to effectively treat patients, improving the prognosis and patients’ quality of life. In order to achieve this, on par with current scientific knowledge, it is important to profile the molecular pathogenic mechanisms underlying HPV-related OSCC, to aid in early diagnosis and appropriate treatment. It has been shown that 16–62% of OSCC develop from potentially malignant oral leukoplakia.2 A potentially malignant lesion is defined as ‘a morphologically altered tissue in which cancer is more likely to occur than in its normal counterpart’ – i.e. the lesion itself can undergo malignant transformation. Leukoplakia and erythroplakia are examples of potentially malignant lesions. Leukoplakia is the most common potentially malignant lesion of the oral cavity and may be clinically homogenous or non-homogenous, nodular or speckled, including Candidaassociated lesions and proliferative verrucous leukoplakia. Erythroplakia carries the greatest threat of malignant transformation, with 50% of cases already being malignant at the time of diagnosis. Dysplastic lesions may be graded histologically as mild, moderate or severe; however, this is highly subjective with low interpersonal and intrapersonal reproducibility. Dysplasia is considered to be ‘the histopathological expression of genomic and molecular alterations in a field of keratinocytes’ with a reported prevalence of 5% to 25% of epithelial dysplasia in oral leukoplakia.3 © 2013 Australian Dental Association HPV has been detected in 26.2% of leukoplakia with dysplasia and other precancerous intraepithelial oral cancers.4 Up to 30% of oral leukoplakia may recur,5 and oral cancer may develop in 12% of treated sites of leukoplakia.6 It is clear that some treated leukoplakias will recur or undergo malignant transformation, but there are no current diagnostic methods, clinical, histological, or molecular, to predictably identify these cases.4 HPV-related OSCC is non-keratinizing and more common in non-smoking and non-drinking 40–60 year old males, a category distinctly separate to non-HPV related OSCC, and has been termed a sexually transmitted disease.1,7 The viral particle gains access into the basal cells (consisting of stem cells and transit-amplifying cells) through microabrasions of the epithelial tissue.8 The stem cells need to be infected for the infection to be maintained since it is these cells that continuously divide to replace the lost superficial layer cells through desquamation.8 The viral early genes are expressed while the keratinocyte is in the basal or parabasal layer, while the late genes are expressed as the keratinocyte reaches the upper spinous, stratified or cornified layers.9 Persistent infection, which the host immune system has been incapable of clearing, has been deemed a causal factor for cervical cancer.10 The reason for the presence of HPV DNA in the oropharynx has been attributed to changing sexual behaviour, multiple sexual partners, and earlier sexual debut.11 MicroRNAs (miRNAs) have emerged with a great potential as diagnostic and therapeutic aids. miRNAs belong to a family of small, non protein-coding RNAs that have been shown to regulate up to 60% of all mRNAs.12 To date, there are 2042 mature miRNAs and 1600 precursor miRNAs.13 In normal function, miRNAs control important cellular processes such as cell division, differentiation and apoptosis14 in a network of interlaced processes that are tightly controlled and coordinated with large co-expression patterns.15 However, in cancer these networks are reprogrammed, forming smaller, disjointed networks that form cliques with over or under-expression of miRNAs. These miRNAs may function either as oncogenes that drive tumour growth or as tumour-suppressor genes that normally serve as protective mechanisms against carcinogenesis but are down-regulated, allowing tumour initiation and progression.16 miRNA expression dysregulation is central in its role in carcinogenesis. miRNAs involved in cancers are frequently located in genomic loci known to be fragile,17 with chromosomal alterations shown to affect miRNA levels and carcinogenesis.18 Single nucleotide polymorphisms (SNPs) in the miRNA gene have also been shown to cause aberrant miRNA formation and under/over expression.19 87 CS Farah et al. miRNAs in saliva are thought to be derived from tumour tissues through studies which reported decreases in miRNA levels following cancer resection surgery.20,21 However, there is a gap in our knowledge comparing miRNA expression profiles in tumour tissues to that in saliva. There are currently nearly 45 miRNAs that have been quantified as being involved in oral cancer. The discovery of miRNAs and its role in cancer has allowed a greater understanding of the molecular basis of oral cancer tumourigenesis. Although the field is relatively new, it is maturing at a rapid pace, with continual refinements in research methodology allowing for more comparable data to be found. Saliva is an attractive medium for oral cancer biomarker detection due to the non-invasive nature of collection and the fact that it is in constant contact with the oral epithelium.22 Previous research into saliva as a source for biomarkers focused on proteomics,23 which has proved to be difficult for a myriad of reasons. However, salivary miRNA has been found to be remarkably stable, and able to resist degradation much better than non-salivary miRNA. The use of saliva as a biomarker may potentially allow for non-invasive salivary diagnostics to be conducted for oral cancer, providing another tool that the clinician may employ in the detection of these lesions and their precursors. It is anticipated that the discovery of comparable miRNA signatures in saliva and in tumour tissues, as well as changes in salivary miRNA signatures will allow the development of non-invasive salivary diagnostic biomarker panels. Given the rapid speed with which our understanding of the role of HPV in oral/oropharyngeal cancers is developing, the explosion of new molecular targets to assay, and the developing pace of saliva-based point of care diagnostics, it is no wonder that a radical re-think/paradigm shift is occurring in the way we approach oral cancer risk assessment. With this new information that is available to us, there is more responsibility on us as a profession to educate our patients about the emerging role of oral sexual behaviour as a means for transmission of HPV, and to undertake sexual histories. Although saliva based diagnostic tests are available for determining HPV genotypes in the ease of the dental surgery (OraRisk® HPV Salivary Diagnostic Test, OralDNA Labs), the usefulness of these in patient management is yet to be determined. EARLY DISEASE DETECTION AND DIAGNOSIS Early detection technology The poor prognosis for oral malignancies can largely be attributed to the late diagnosis of these cancers. Patients with a delayed diagnosis of oral or 88 oropharyngeal carcinoma are 30% more likely to present with an advanced stage tumour compared to those without a delayed diagnosis.24–26 There is a significant decrease in prognosis with a more advanced TNM stage at initial presentation. The five-year survival rates for Stage I and II tumours are 85% and 66% respectively, while the survival rates decrease for Stage III and IV tumours to 41% and 9%.27 Alarmingly, almost half of all oral cancers are diagnosed at Stage III or IV.24 As such, emphasis is being placed on increased public awareness and earlier detection of oral cancer to improve patient survival rates. It is well established that the majority of oral cancers are preceded by potentially malignant lesions. However, many of these same lesions may remain benign in nature or resemble other benign mucosal abnormalities. Leukoplakia and erythroplakia are the most common lesions to precede oral cancer although others such as oral lichen planus and submucous fibrosis may also progress to malignancy. Current practice for the detection of malignant or potentially malignant lesions involves a visual and tactile mucosal examination under an incandescent overhead light by a dental practitioner. White or red lesions exhibiting induration or fixation may be indicative of malignancy.28 These lesions are typically referred to an oral medicine specialist for biopsy and a definitive diagnosis. A conventional oral examination may not necessarily detect or identify all potentially malignant or malignant lesions. While screening programmes to identify malignant lesions have been trialled, their cost-effectiveness in the general population is uncertain and the onus has fallen on primary care providers to screen patients for such lesions.29–32 A number of diagnostic aids have recently been developed to assist the general dental and medical practitioner in detecting premalignant and malignant lesions, and to differentiate these from benign lesions. Light based systems have been developed for this purpose,33–36 although these, on the whole, have not proven to be beneficial in providing the practitioner with useful information to assist in identification or diagnosis of suspicious lesions. Microlux/DLTM (AdDent Inc) is a handheld battery operated light emitting diode (LED) white light device which can be used on patients for assessment of an oral lesion. McIntosh et al. have used this device following a conventional oral examination under incandescent overhead light for examination of suspicious oral mucosal lesions.37 While lesion visibility was enhanced compared to a regular incandescent light, Microlux/DLTM did not help uncover any new lesions or alter the provisional diagnosis or biopsy site. It was also poor in helping discriminate between benign and malignant or potentially malignant lesions. A LED headlight displayed similar properties to Microlux/DLTM in increasing © 2013 Australian Dental Association MID in oral medicine lesion visibility and allowed for an even greater field of view. They found that white light was more beneficial compared to routine incandescent operatory light in the detection of oral mucosal lesions and have been advocating more widespread use of LED headlights for examination of oral mucosal pathology since. In contrast to devices that utilize white light and the properties of reflectance, several diagnostic aids utilize the features of AF. These include handheld devices designed for use in dental practice such as VELScopeTM (LED Dental Inc)35 and IdentafiTM (StarDental)33 and endoscopic devices such as the Wolf Diagnostic Auto-fluorescence Endoscope. These devices use AF to differentiate benign mucosa from malignant and potentially malignant lesions. They typically emit blue/violet light in the 400–460 nm wavelength range, causing the oral mucosa to fluoresce due to the presence of intrinsic fluorophores, collagen and cross-links between collagen.38 The AF profile of a tissue is altered by absorption and scattering events in the tissue. Normal oral mucosa is associated with a pale green fluorescence while abnormal tissue is associated with a loss of AF in this wavelength, largely due to changes in the concentration of fluorophores and structural modifications such as increased epithelial thickness, altered collagen content and nuclear size distribution.38 These visual changes can be used in vivo to differentiate normal oral mucosa from dysplasia, carcinoma in situ and invasive carcinoma.39 AF has also proven to be a valuable tool in demarcating margins of established tumours where the malignant tissue may extend beyond what is otherwise clinically visible.40 Only recently have trials become available evaluating the use of AF in a clinical environment. Mehrotra et al. reported the detection of 11 cases of dysplasia and 1 case of oral cancer of which 6 demonstrated loss of AF providing a sensitivity of 50%.41 Among the 144 benign lesions evaluated, 88 lesions demonstrated a loss of AF giving an overall specificity of 38.9% and a positive predictive value of 6.4%. Awan et al. conducted a prospective study evaluating the accuracy of AF compared to a clinical and subsequently histological exam at specialist oral medicine clinics.42 When correlated with histology, 44 lesions proved to be dysplastic of which only 7 retained AF, giving a sensitivity of 84.1%. However, the specificity was relatively low at 15.3% with 61 out of the 72 non-dysplastic lesions also exhibiting some loss of AF. A similar study by Scheer et al. on a high risk population reported a sensitivity and specificity of 100% and 80.8% respectively.43 The authors found that lesions presented along a spectrum ranging from marked decrease in AF to an increase in fluorescence. While the above studies evaluated the diagnostic capabilities and accuracy of AF without taking into © 2013 Australian Dental Association account clinical characteristics in the diagnosis, it should be remembered that the main function of these devices is to be an adjunctive aid to, rather than a replacement for, a conventional oral examination. For this reason, Farah et al. prospectively evaluated what additional benefits AF provided when used in conjunction with an oral examination by oral medicine specialists.44 The accuracy of a conventional oral examination, an AF examination, and both in combination were compared. In addition, the study evaluated whether AF altered the biopsy site or provisional diagnosis. They also tested for diascopic fluorescence of lesions with those displaying complete blanching on pressure being deemed negative for loss of AF. A histopathological gold standard was used. While the diagnostic accuracy increased with the use of AF in conjunction with clinical examination, the rate of false positives also increased. This confirmed findings from previous trials on the poor diagnostic accuracy of AF findings without proper clinical interpretation.42,43 AF enhanced the visualization of 34.74% of lesions and helped uncover 5 clinically occult lesions of which one was moderately dysplastic. Further, the use of AF altered the provisional diagnosis in 22 cases and altered the biopsy site of 4 lesions. It was observed that blanching of lesions was difficult to perform accurately, and partial blanching in particular may complicate interpretation. Like Scheer et al., Farah et al. expressed concerns regarding clinical interpretation and stated that advanced knowledge of mucosal pathology was required to accurately interpret the findings of AF.43,44 The study by Farah et al. showed that although AF could provide useful information to assist in the identification and diagnosis of lesions when used in conjunction with a conventional oral examination under white light, its use may be more suitable to a specialist oral oncology setting due to the difficulties in accurate interpretation of findings, without proper training and skill. AF is able to differentiate between normal mucosa and mucosal abnormalities; however, it is not highly specific in detecting potentially malignant lesions, giving rise to a high rate of false positives. The sensitivity varies among studies and this could be due to interoperator variability in what constitutes loss of AF. It has been reported that there is a large spectrum of fluorescence, and more definitive criteria in what constitutes loss of AF may be required before this technology can gain widespread use. Further, it is suggested that significant understanding of mucosal pathology is required to make correct clinical interpretations of AF findings. This may be lacking in a general dental practice although the onus is on us, as a profession, to improve our detection and interpretation 89 CS Farah et al. of mucosal changes for the benefit of our patients. Overall, the evidence suggests that AF technology has difficulty in differentiating benign lesions from potentially malignant and malignant lesions, and a significant level of training in its use and interpretation is required if it is to become a useful adjunctive aid in general dental practice. In the meantime we await the results of properly designed large scale studies currently underway investigating its use by general oral health practitioners. To better differentiate between oral epithelial lesions, a new device, IdentafiTM has been released utilizing the properties of both reflectance and AF although clinical data is currently unavailable. IdentafiTM combines the essential properties of tissue reflectance and AF in one streamlined multi-spectral handheld device. It consists of a white light source, a violet light source and also an amber light source. Tissue is examined firstly with the white light source, and then with the use of the clinician’s photosensitive glasses, abnormal areas lose AF and appear dark under violet light. The amber light is designed to help with the visualization of tissue vasculature to assist in the interpretation of abnormalities of the mucosa. IdentafiTM is a small handheld battery-operated device, which is used intraorally as opposed to the VELScopeTM which is used extraorally. At this stage no results from large scale studies showing the utility of IdentafiTM are available, although several of these are currently underway in clinics around the world including our own. NBI is a newer endoscopic imaging modality that applies 2 narrow bands of filtered light in the blue (400–430 nm) and green (525–555 nm) spectrum to only minimally penetrate the superficial mucosa and mimic the waveform of haemoglobin to detect early abnormal angiogenesis seen in premalignant and malignant lesions. It has been shown to be superior to white light in detecting head and neck cancers and precancers,45,46 and it has also been used for surgical margin detection but mainly in superficial head and neck cancers.47 NBI has been reported to improve the sensitivity, diagnostic accuracy, and negative predictive value for the detection of early head and neck squamous cell carcinomas compared with white light inspection.48 Well-characterized changes can be seen that correspond to an early increase in vascularization of lesions of severe dysplasia or worse; these include intrapapillary capillary loops (IPCLs) and tortuosity of vessels.49 Nguyen et al. have used AF and NBI in patients with head and neck cancer planned for panendoscopy as part of their diagnostic workup. The aim was to screen for additional lesions to the primary head and neck cancer, and to determine how these had an 90 impact on overall management. Furthermore, they wanted to determine if the addition of NBI improved the poor specificity of AF without influencing overall sensitivity. In the head and neck region there were 42 extra biopsies taken because of abnormal AF or NBI findings. Histopathology of these showed 17 normal/ inflammatory lesions (40.5%), 1 mild dysplasia (2.4%), 6 moderate dysplasias (14.3%), 11 severe dysplasias (26.2%), and 7 carcinomas in situ (16.7%).50 For lesions of moderate dysplasia or worse, sensitivity of WL was 0.375 and the specificity was 0.95. AF and NBI had the same sensitivity: 0.96. The specificity of AF was 0.26, whereas for NBI it was 0.79. Both AF and NBI were significantly more sensitive than WL (p = 0.003). The specificities of WL and NBI were not significantly different, with both modalities being more specific than AF compared with WL and NBI, respectively. In addition, there were 66 random biopsies that were negative for dysplasia or malignancy and also negative at the time of AF and NBI inspection. The results confirm that NBI is more specific than AF without compromising sensitivity. NBI inspection adds to WL and AF evaluation in patients with head and neck cancer, and NBI improves specificity and can have a direct positive impact on patient management. Given the excellent results observed in this study, the usefulness of NBI is currently being assessed on precancerous lesions in our oral medicine outpatient clinic for assessment of new lesions, surveillance of existing and previously removed lesions, and surgical margin delineation. This technology promises more than AF alone, and appears to suffer less from the subjective interpretation of results, although skill in utilizing the technology and interpretation of the results is still paramount. Although this technology may not find its way into general dental practice due to the size of the equipment and the associated expense, it is another example of advanced technology driving early detection and diagnosis in oral medicine. MINIMALLY INVASIVE TREATMENT Head and neck cancer imaging At present the most advanced and relevant multimodal system used in head and neck cancer imaging is the combination of positron emission tomography (PET) and computerized tomography (CT).51 However, the combination of the high soft tissue contrast provided by magnetic resonance imaging (MRI) and the molecular and metabolic information provided by PET shows promise especially in the evaluation of tumours of the head and neck.52 © 2013 Australian Dental Association MID in oral medicine PET with 18-F-flurodeoxyglucose (FDG) has shown promising results for the assessment of lymph node involvement in cancer, the identification of distant metastasis and synchronous and metasynchronous tumours, and the evaluation of tumour recurrence or carcinoma of an unknown primary.52 MRI has several advantages compared with CT for morphologic imaging in the head and neck region due to the superior soft tissue contrast and fewer artefacts. MRI also allows functional imaging such as the assessment of perfusion with dynamic contrast enhanced MRI. Studies with sequential PET/MRI have shown that patients with head and neck cancer would benefit from additional high definition MRI sequences providing soft tissue characterization not possible with CT images from traditional PET/CT scanners. The published data to date regarding image fusion, although in its infancy, indicates that this is beneficial in the evaluation of potential metastatic lymph nodes and in assessment of recurrence of head and neck cancer. However, PET can deliver more information than is available from 18 FDG and can provide imaging biomarkers of specific biological processes, which may be relevant for therapy planning, assessment of prognosis and evaluation of the treatment response, beyond the traditional applications in staging assessment of tumour extent and metastatic spread.52, 53 Fully integrated PET/MRI systems allow for simultaneous whole-body PET and MRI imaging. This allows the simultaneous acquisition of high resolution PET and MRI images which is significantly beneficial in head and neck cancer imaging given the complexity of the anatomy of this region, and the soft tissue nature of its pathology.54 Simultaneous acquisition of PET and MRI sequences is advantageous not only because it decreases examination time compared to sequential scanning, but also because PET/MRI co-registration has the potential to be a useful tool in the planning of image-based surgery and radiotherapy, image-guided radiotherapy, and the determination of the level of follow up in the treatment of head and neck cancer. Potential benefits of combined PET/MRI technology in head and neck cancer management include, but are not limited to: (1) Usefulness and applicability of PET/MRI in head and neck cancer staging and detection. PET is more superior to clinical examination and CT in staging primary tumour with similar sensitivity but higher specificity.55 The sensitivity of PET is hampered by its lower resolution than CT or MRI, but with the inclusion of hybrid PET/MRI, this should be resolved. MRI is useful for determination of perineural spread, and typically PET alone is unable to resolve these because of partial volume averaging effects. The com© 2013 Australian Dental Association bination of PET/MRI has the potential to improve this. In addition to detection of primary disease, PET/ MRI has the potential to uncover unknown primary tumours. The reported incidence of unknown primary tumours in the head and neck area range between 3% to 10% with negative clinical examination and CT and/or MRI studies.56 Panendoscopy in combination with FDG-PET has been shown to be valuable in the work-up of such patients. PET staging also has the significant benefit of yielding smaller tumour volumes and tends to be closely correlated with the pathological specimen. There is a significant advantage in coupling this with MRI, as this might facilitate focused treatment options such as intensity modulated radiation therapy (IMRT). In addition, some patients with small tumour volumes and stage exhibit aggressive growth patterns despite appropriate therapy, and it is thought that the functional data from PET can be used to identify and stratify these cases.57,58 (2) Assessment of sentinel lymph nodes. The combination of PET/MRI not only has the ability to localize disease even in small subcentimetre nodes, but also has the ability to alter planned neck dissection, and monitor nodal involvement post-surgery/radiotherapy in surveillance patients. The benefit of PET/MRI has not been determined in N0 patients, and this requires attention given the rates of occult nodal metastasis in some head and neck cancer groups such as oral cavity. Early evidence supports superior performance of PET over CT/MRI in nodal metastasis determination, and up to 5.2% altered treatment planning based on PET findings compared to CT/MRI in discordant TNM staging. Extra-capsular nodal spread is another important prognostic factor, which requires MRI enhancement accompanied with PET to increase sensitivity and specificity, compared to PET alone, or even contrast enhanced CT. In addition to detection of nodal involvement in staging treatment, PET has a role in post-treatment evaluation of nodal disease, and appears to be beneficial in patients undergoing radiochemotherapy. (3) Correlation of biomarkers for head and neck cancer and resection margins. Autofluorescence and narrow band imaging have recently been introduced to examine patients with head and neck cancer, and our group has been the first to show conclusively that panendoscopy with narrow band imaging increases sensitivity and specificity of detection compared with white light panendoscopy, but also improves surgical margin delineation.50 PET has also more recently been shown to be of value in detection of recurrence in up to 25% of patients with clinically unsuspected disease. PET/ MRI can be useful in surveillance of patients post-surgery or radiation treatment. Given that the changes noted under AF and NBI are limited to epithelium and 91 CS Farah et al. superficial connective tissue, it is anticipated that coupling of these technologies with PET/MRI will allow better determination of algorithms for detection of superficial tumours, given the ability of PET to capture metabolic rates in earlier detection of recurrent tumour, even in clinically disease-free patients. (4) Development of drug/molecular targets discovered through next generation sequencing for possible radionuclide tracer development. We are currently undertaking genome wide sequencing of head and neck tumours in an effort to produce a diagnostic molecular biomarker panel for early detection and more accurate diagnosis. Molecular targets in head and neck cancer, coupled with novel targeted anticancer therapeutics, labelled with positron emitters could be used to guide patient selection protocols, further drug development, and hence advance efforts into personalized medicine. Use of non-FDG PET with emitters such as zirconium-89 or gallium-68, coupled to monoclonal antibodies against target molecules, has great potential in guiding both patient treatment and surveillance. PET imaging of tyrosine kinase inhibitors may also prove useful.59 CONCLUSIONS The concept of minimum intervention dentistry in the context of oral medicine may seem foreign to some, but in fact oral medicine specialists practise minimum intervention daily. As oral diagnosticians we have a duty of exploring the most effective and efficient early detection approaches to unravel disease, and as oral physicians we undertake minimally invasive interventions to affect positive outcomes for our patients, many of whom live with chronic conditions that require regular care. Underlying this is a deep understanding of disease risk, aetiopathogenesis, health behaviour patterns, and effective patient communication strategies. In this article we have tried to highlight minimum intervention in oral medicine by exploring oral cancer as the most significant disease we encounter and are involved with. Advances in patient care, particularly in relation to minimum intervention, are underpinned by high calibre cutting edge translational research. It is this research that allows us to positively transform our patients’ lives. ACKNOWLEDGEMENTS CSF would like to thank Dr Pauline Ford from the UQ School of Dentistry for fruitful discussions while conceptualizing this article, and Dr Anastasia Georgiou, Oral Medicine Specialist and President-Elect of the Oral Medicine Academy of Australasia, for critical review of the manuscript. 92 DISCLOSURE The authors declare that they have no conflicts of interest in relation to this work. CSF is a registered specialist in Oral Medicine and Oral Pathology, current President of the Oral Medicine Academy of Australasia, and Head of the Oral Oncology Research Program at the UQCCR where he undertakes clinical practice and research into head and neck cancer early detection, diagnosis and imaging. NB, KJ and BWL are dental student members of the Oral Oncology Research Program. REFERENCES 1. Lajer CB, Von Buchwald C. The role of human papillomavirus in head and neck cancer. APMIS 2010;118:510–519. 2. Lee JJ, Hong WK, Hittelman WN, et al. Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res 2000;6:1702–1710. 3. Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E. Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. J Oral Pathol Med 2008;37:127–133. 4. Feller L, Lemmer J. Oral leukoplakia as it relates to HPV infection: a review. Int J Dent 2012;2012:540561. 5. Lodi G, Porter S. Management of potentially malignant disorders: evidence and critique. J Oral Pathol Med 2008;37: 63–69. 6. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol 2006;42:461–474. 7. Cardesa A, Nadal A. Carcinoma of the head and neck in the HPV era. Acta Dermatovenerol Alp Panonica Adriat 2011;20:161–173. 8. Conway MJ, Meyers C. Replication and assembly of human papillomaviruses. J Dent Res 2009;88:307–317. 9. Zheng ZM, Wang X. Regulation of cellular miRNA expression by human papillomaviruses. Biochim Biophys Acta 2011;1809:668–677. 10. Li B, Hu Y, Ye F, Li Y, Lv W, Xie X. Reduced miR-34a expression in normal cervical tissues and cervical lesions with high-risk human papillomavirus infection. Int J Gynecol Cancer 2010;20:597–604. 11. Joseph AW, D’Souza G. Epidemiology of human papillomavirus-related head and neck cancer. Otolaryngol Clin North Am 2012;45:739–764. 12. Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009;19:92–105. 13. Griffiths-Jones S, Grocock RJ, Van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006;34(Database issue): D140–144. 14. Miska EA. How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev 2005;15:563– 568. 15. Volinia S, Galasso M, Costinean S, et al. Reprogramming of miRNA networks in cancer and leukemia. Genome Res 2010;20:589–599. 16. Babu JM, Prathibha R, Jijith VS, Hariharan R, Pillai MR. A miR-centric view of head and neck cancers. Biochim Biophys Acta 2011;1816:67–72. © 2013 Australian Dental Association MID in oral medicine 17. Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 2004;101:2999– 3004. 37. McIntosh L, McCullough MJ, Farah CS. The assessment of diffused light illumination and acetic acid rinse (Microlux/DL) in the visualisation of oral mucosal lesions. Oral Oncol 2009;45: e227–231. 18. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99:15524–15529. 38. De Veld DC, Witjes MJ, Sterenborg HJ, Roodenburg JL. The status of in vivo autofluorescence spectroscopy and imaging for oral oncology. Oral Oncol 2005;41:117–131. 19. He L, Thomson JM, Hemann MT, et al. A microRNA polycistron as a potential human oncogene. Nature 2005;435:828– 833. 20. Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP, Wei WI. Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res 2008;14: 2588–2592. 21. Liu CJ, Lin SC, Yang CC, Cheng HW, Chang KW. Exploiting salivary miR-31 as a clinical biomarker of oral squamous cell carcinoma. Head Neck 2012;34:219–224. 22. Patel RS, Jakymiw A, Yao B, et al. High resolution of microRNA signatures in human whole saliva. Arch Oral Biol 2011;56:1506–1513. 23. Schulz BL, Cooper-White J, Punyadeera CK. Saliva proteome research: current status and future outlook. Crit Rev Biotechnol. 2012 May 21 [Epub ahead of print]. 24. Gomez I, Seoane J, Varela-Centelles P, Diz P, Takkouche B. Is diagnostic delay related to advanced-stage oral cancer? A metaanalysis. Eur J Oral Sci 2009;117:541–546. 25. Pitchers M, Martin C. Delay in referral of oropharyngeal squamous cell carcinoma to secondary care correlates with a more advanced stage at presentation, and is associated with poorer survival. Br J Cancer 2006;94:955–958. 26. Lo WL, Kao SY, Chi LY, Wong YK, Chang RC. Outcomes of oral squamous cell carcinoma in Taiwan after surgical therapy: factors affecting survival. J Oral Maxillofac Surg 2003;61: 751–758. 27. Sciubba JJ. Oral cancer. The importance of early diagnosis and treatment. Am J Clin Dermatol 2001;2:239–251. 28. Farah CS, McCullough MJ. Oral cancer awareness for the general practitioner: new approaches to patient care. Aust Dent J 2008;53:2–10. 29. Downer MC, Evans AW, Hughes Hallet CM, Jullien JA, Speight PM, Zakrzewska JM. Evaluation of screening for oral cancer and precancer in a company headquarters. Community Dent Oral Epidemiol 1995;23:84–88. 30. Lim K, Moles DR, Downer MC, Speight PM. Opportunistic screening for oral cancer and precancer in general dental practice: results of a demonstration study. Br Dent J 2003;194:497–502. 31. Brocklehurst P, Kujan O, Glenny AM, et al. Screening programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev 2010;(11):CD004150. 32. Sankaranarayanan R, Ramadas K, Thomas G, et al. Effect of screening on oral cancer mortality in Kerala, India: a cluster-randomised controlled trial. Lancet 2005;365:1927– 1933. 33. Identafi. StarDental. URL: ‘http://www.identafi.net/’. Accessed 26 October 2012. 34. Microlux/DL product information. AdDent, Inc. URL: ‘http:// www.addent.com/prod-microlux2.html’. Accessed 26 October 2012. 35. VELscope Vx. LED Dental Inc. URL: ‘http://www.velscope. com/default.aspx’. Accessed 26 October 2012. 36. ViziLite Plus Product Information. Zila Pharmaceuticals Inc. URL: ‘http://www.zila.com/40/VIZILITE%26REG%3B%20PLUS/’. Accessed 26 October 2012. © 2013 Australian Dental Association 39. Lane PM, Gilhuly T, Whitehead P, et al. Simple device for the direct visualization of oral-cavity tissue fluorescence. J Biomed Opt 2006;11:024006. 40. Poh CF, Zhang L, Anderson DW, et al. Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients. Clin Cancer Res 2006;12:6716–6722. 41. Mehrotra R, Singh M, Thomas S, et al. A cross-sectional study evaluating chemiluminescence and autofluorescence in the detection of clinically innocuous precancerous and cancerous oral lesions. J Am Dent Assoc 2010;141:151–156. 42. Awan KH, Morgan PR, Warnakulasuriya S. Evaluation of an autofluorescence based imaging system (VELscope) in the detection of oral potentially malignant disorders and benign keratoses. Oral Oncol 2011;47:274–277. 43. Scheer M, Neugebauer J, Derman A, Fuss J, Drebber U, Zoeller JE. Autofluorescence imaging of potentially malignant mucosa lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:568–577. 44. Farah CS, McIntosh L, Georgiou A, McCullough MJ. Efficacy of tissue autofluorescence imaging (VELScope) in the visualization of oral mucosal lesions. Head Neck 2012;34: 856–862. 45. Piazza C, Cocco D, Del Bon F, et al. Narrow band imaging and high definition television in evaluation of oral and oropharyngeal squamous cell cancer: a prospective study. Oral Oncol 2010;46:307–310. 46. Muto M, Minashi K, Yano T, et al. Early detection of superficial squamous cell carcinoma in the head and neck region and esophagus by narrow band imaging: a multicenter randomized controlled trial. J Clin Oncol 2010;28:1566– 1572. 47. Katada C, Tanabe S, Koizumi W, et al. Narrow band imaging for detecting superficial squamous cell carcinoma of the head and neck in patients with esophageal squamous cell carcinoma. Endoscopy 2010;42:185–190. 48. Tan NC, Herd MK, Brennan PA, Puxeddu R. The role of narrow band imaging in early detection of head and neck cancer. Br J Oral Maxillofac Surg 2012;50:132–136. 49. Watanabe A, Taniguchi M, Tsujie H, Hosokawa M, Fujita M, Sasaki S. The value of narrow band imaging endoscope for early head and neck cancers. Otolaryngol Head Neck Surg 2008;138:446–451. 50. Nguyen P, Bashirzadeh F, Hodge R, et al. High specificity of combined narrow band imaging and autofluorescence mucosal assessment of patients with head and neck cancer. Head Neck 2013;35:619–625. 51. Beyer T, Townsend DW, Brun T, et al. A combined PET/CT scanner for clinical oncology. J Nucl Med 2000;41:1369– 1379. 52. Loeffelbein DJ, Souvatzoglou M, Wankerl V, et al. PET-MRI fusion in head-and-neck oncology: current status and implications for hybrid PET/MRI. J Oral Maxillofac Surg 2012;70: 473–483. 53. Weber WA. Positron emission tomography as an imaging biomarker. J Clin Oncol 2006;24:3282–3292. 54. Platzek I, Beuthien-Baumann B, Schneider M, et al. PET/MRI in head and neck cancer: initial experience. Eur J Nucl Med Mol Imaging 2012 Sep 28 [Epub ahead of print]. 93 CS Farah et al. 55. Sigg MB, Steinert H, Gratz K, Hugenin P, Stoeckli S, Eyrich GK. Staging of head and neck tumors: [18F]fluorodeoxyglucose positron emission tomography compared with physical examination and conventional imaging modalities. J Oral Maxillofac Surg 2003;61:1022–1029. 59. Heuveling DA, De Bree R, Van Dongen GA. The potential role of non-FDG-PET in the management of head and neck cancer. Oral Oncol 2011;47:2–7. 56. Subramaniam RM, Truong M, Peller P, Sakai O, Mercier G. Fluorodeoxyglucose-positron-emission tomography imaging of head and neck squamous cell cancer. AJNR Am J Neuroradiol 2010;31:598–604. Address for correspondence: Associate Professor Camile Farah Oral Medicine Specialist UQ Centre for Clinical Research The University of Queensland Building 71/918 Royal Brisbane and Women’s Hospital Campus Herston QLD 4029 Email: [email protected] 57. Higgins KA, Hoang JK, Roach MC, et al. Analysis of pretreatment FDG-PET SUV parameters in head-and-neck cancer: tumor SUVmean has superior prognostic value. Int J Radiat Oncol Biol Phys 2012;82:548–553. 58. Kubicek GJ, Champ C, Fogh S, et al. FDG-PET staging and importance of lymph node SUV in head and neck cancer. Head Neck Oncol 2010;2:19. 94 © 2013 Australian Dental Association