Head and neck cancers account for 5 % of all tumors, and about 50 % of head and neck tumors occur specifically in the oral cavity. In 2000, 300,000 of the 615,000 new cases of oral cavity tumors reported worldwide were primary oral cavity squamous cell carcinomas (SCC). Recent data from the Surveillance, Epidemiology, and End Results Program suggested that 28,900 new cases of oral cancer will be identified and 7,400 deaths attributed to oral cancer each year in the United States. The 6th leading cause of cancer-related mortality, oral cancer accounts for 1 death every hour in the United States (Kademani, 2007). Since oral cancers are often detected in later stages, it is thought that early detection may lower the morbidity and mortality of oral cavity tumors.
The United States Food and Drug Administration (FDA) cleared ViziLite as an adjunct to visual examination of the oral cavity in November 2001. This chemiluminescent light technology has been used since 1995 for the identification of abnormalities in stratified squamous epithelium. The ViziLite-Blue oral examination kit, an oral lesion identification and marking system, is designed to be used as an adjunct to the conventional head and neck examination in patients at increased risk for oral cancer. It is comprised of a chemiluminescent light source (ViziLite) to improve the identification of lesions and a blue phenothiazine dye to mark those lesions identified by ViziLite. The ViziLite-Blue oral examination kit was cleared by the FDA through the 510(k) process in November 2004.
Ram and Siar (2005) examined the use of ViziLite as a diagnostic aid in the detection of oral cancer and potentially malignant epithelial lesions (PMELs) by comparing it against 1 % tolonium chloride mouth rinse. A total of 46 clinically identified lesions (14 primary SCC, 26 PMELs and 6 benign lesions) and 5 cases of normal oral mucosa from 40 subjects (including 10 previously treated SCC cases) were examined with ViziLite and tolonium chloride. Biopsy and histological verification of 31 lesions disclosed 14 SCC (45.2 %), 10 epithelial dysplasias (32.3 %), 5 lichen planus (16.1 %) and 2 benign lesions (6.4 %). For the remaining 15 lesions, a biopsy was not performed owing to patient's lack of consent or ill-health. The 5 cases of normal oral mucosa which tested negative for both tools were also not biopsied for ethical reasons. Sensitivity for ViziLite and tolonium chloride was 100 % and 70.3 %, respectively; and specificity was 14.2 % for ViziLite and 25 % for tolonium chloride. Their accuracy was 80.6 % and 64.5 %, respectively. The authors concluded that the present findings suggested that ViziLite is a more reliable diagnostic tool than tolonium chloride in the detection of oral cancer and PMELs, and for follow-up of patients treated for the same.
Kerr and associates (2006) examined the use of ViziLite as an adjunct to standard visual examination (SVE) to enhance visualization of mucosal lesions, particularly those "clinically suspicious" for oral pre-cancer or cancer. Individuals were considered at risk for oral cancer or pre-cancer if they have no a priori knowledge of the presence or absence of an oral lesion at the time of examination. A total of 501 consecutive consenting subjects, over 40 years of age and with a positive tobacco history, received a standard visual examination with conventional incandescent lighting, followed by chemiluminescent lighting. All lesions were recorded, and for lesions detected by both screening modalities, comparisons were made of the subjective parameters of lesion brightness, sharpness, surface texture, and relative size. A total of 410 epithelial lesions were detected in 270 subjects by SVE, of which 127 were clinically "suspicious" for oral cancer and pre-cancer. Ninety-eight lesions were also visualized by chemiluminescent lighting as "aceto-white" (CL+), in addition to 6 lesions not previously seen by SVE. Seventy-seven of the CL+ lesions (78.5 %) were clinically suspicious; all "suspicious" lesions with an ulcerative component and ulcerated lesions consistent with trauma were CL+. Leukoplakias were significantly more likely to be CL+ than erythroplakias (p < 0.01). Overall, those lesions illuminated by ViziLite appeared brighter, sharper, and smaller compared to incandescent illumination. The authors concluded that these findings suggested that oral chemiluminescent lighting, when used as a screening adjunct following SVE, provides additional visual information. Leukoplakias may be more readily visualized by chemiluminescence. Studies are underway to explore the clinical significance and predictive value of oral chemiluminescent lighting.
Epstein et al (2006) stated that early diagnosis of oral mucosal lesions has been advocated as a means of improving outcomes of cancer therapy. Improved visualization of mucosal lesions may aid in diagnosis by guiding tissue sampling or referral. This multi-center study reported the effect of chemiluminescent light (ViziLite) upon visualization of mucosal lesions. The chemiluminescent light did not appear to improve visualization of red lesions, but white lesions and lesions that were both red and white showed enhanced brightness and sharpness.
Farah and McCullough (2006) noted that conventional screening practice for oral lesions involves visual scrutiny of the oral tissues with the naked eye under projected incandescent or halogen illumination. Visualization is the principal strategy used to assess patients' lesions at risk for malignant transformation; hence, any procedure which highlights such lesions should aid the clinician. The aim of this pilot study was to examine the efficacy of acetic acid wash and chemiluminescent light (ViziLite) in enhancing visualization of oral mucosal white lesions, and its ability to highlight malignant and potentially malignant lesions. Fifty-five patients referred for assessment of an oral white lesion, were prospectively screened with ViziLite, and an incisional scalpel biopsy performed for a definitive diagnosis. The size, location, ease of visibility, border distinctness, and presence of satellite lesions were recorded. The ViziLite tool enhanced intra-oral visualization of 26 white lesions. Indeed, all lesions appeared "aceto-white", regardless of the definitive diagnosis. Examination of the oral tissues with ViziLite illumination did not change the provisional diagnosis, nor alter the biopsy site. ViziLite illumination does not discriminate between keratotic, inflammatory, malignant or potentially malignant oral mucosal white lesions and thus, a high index of suspicion, expert clinical judgment, and scalpel biopsy are still essential for proper patient care.
Oh and Laskin (2007) stated that early detection of oral cancer is crucial in improving survival rate. To improve early detection, the use of a dilute acetic acid rinse and observation under a chemiluminescent light (ViziLite; Zila Pharmaceuticals, Phoenix, AZ) has been recommended. However, to date, the contributions of the individual components of the system have not been studied. The present study was done to investigate the efficacy of the individual components of the ViziLite system in providing improved visualization of early oral mucosal lesions. A total of 100 patients, 39 males and 61 females, aged 18 to 93 years (mean age of 44 years), who presented to the Virginia Commonwealth University School of Dentistry for dental screening were examined. There were 58 Caucasians, 29 African-Americans, 5 Hispanics, 6 Asians, and 2 of mixed ethnicity. Thirty-five patients smoked, 53 used alcohol, and 25 both smoked and drank. After written consent, the oral cavity was examined under incandescent light for soft tissue abnormalities. After 1-min rinse with 1 % acetic acid, the mouth was re-examined for additional mucosal abnormalities. Then, the mouth was examined once again using the ViziLite system's chemiluminescent light. Any lesions detected by these 3 examinations that were clinically undiagnosable were brush biopsied (Oral CDx) for determination of cellular representation. In the original examination of the 100 patients, 57 clinically diagnosable benign lesions (e.g., linea alba, leukoedema) and 29 clinically undiagnosable lesions were detected. After the rinse, 6 additional diagnosable lesions (linea alba) and 3 undiagnosable lesions were found. No additional lesions were detected with the chemiluminescent light. Of the 32 undiagnosable lesions that were brush biopsied, 2 were positive for atypical cellular characterization and warranted further investigation with a scalpel biopsy. Neither of these lesions was found to be pre-malignant or malignant. The authors concluded that although the acid rinse accentuated some lesions, the overall detection rate was not significantly improved. The chemiluminescent light produced reflections that made visualization more difficult and thus was not beneficial.
Epstein et al (2008) examined the adjunctive value of ViziLite(R) and application of pharmaceutical grade toluidine blue to further evaluate lesions identified during the conventional oral soft tissue examination. Lesions deemed clinically suspicious by visual examination under incandescent light were further assessed under chemiluminescence and then application of toluidine blue stain. Differences between the conventional visual examination and chemiluminescent examination were noted on 4 characteristics that may aid in lesion identification. Tissue retention of toluidine blue stain was documented. Each suspicious lesion was biopsied and diagnosed based upon routine histopathology. Both adjunctive examinations were evaluated by comparing the histological diagnosis. The additive value of toluidine blue stain retention was assessed in lesions diagnosed as "serious pathology" defined as severe dysplasia, carcinoma in-situ and SCC. A total of 97 clinically suspicious lesions in 84 patients were identified. The chemiluminescent examination improved the brightness and/or sharpness of margin in 61.8 % of identified lesions. Biopsied lesions with toluidine blue stain retention reduced the false-positive rate by 55.26 % while maintaining a 100 % negative-predictive value (NPV). Vizilite was shown to increase the brightness and margins of mucosal lesions in a majority of cases and therefore may assist in identification of mucosal lesions not considered under traditional visual examination. Toluidine blue stain retention was associated with a large reduction in biopsies showing benign histology (false-positive biopsy results), while maintaining a 100 % NPV for the presence of severe dysplasia or cancer. The authors noted that practitioners may consider use of these adjuncts in practice, however the results presented are based upon experienced providers in referral centers for mucosal disease or cancer centers. Thus, positive findings may be an indication for referral to experienced providers.
McIntosh and colleagues (2009) evaluated the effectiveness of acetic acid mouthwash and diffused light illumination (Microlux/DL) as a diagnostic aid in the visualization of oral mucosal lesions and its ability to highlight malignant and potentially malignant lesions. A total of 50 patients referred for assessment of an oral white lesion were initially examined under routine incandescent operatory light. The location, size, ease of visibility, border distinctness and presence of satellite lesions were recorded. Clinical examination was repeated using the Microlux/DL diffused light illumination kit. An incisional biopsy was performed to provide a definitive histopathological diagnosis. Microlux/DL examination enhanced the visibility of 34 lesions, however, it did not help uncover any clinically undetected lesions, change the provisional diagnosis, or alter the biopsy site. Microlux/DL showed a sensitivity of 77.8 % and a specificity of 70.7 %, with a positive predictive value (PPV) of 36.8 %. The authors concluded that although Microlux/DL appears useful at enhancing lesion visibility, it is a poor discriminator for inflammatory, traumatic and malignant lesions.
VELscope received 510(k) market clearance in April 2006. It was deemed to be substantially equivalent to ViziLite. VELscope is intended to be used by dentists or health-care providers as an adjunct to traditional oral examination by incandescent light to enhance the visualization of oral mucosal abnormalities that may not be apparent or visible to the naked eye, such as oral cancer or pre-malignant dysplasia. It is further intended to be used by surgeons to help identify diseased tissue around a clinically apparent lesion and thus aid in determining the appropriate margin for surgical excision. VELscope uses visible light in the 430 nm wavelength in order to cause fluorescent excitation of certain compounds in the tissues.
Lane and associates (2006) described a simple hand-held device that facilitates the direct visualization of oral-cavity fluorescence for the detection of high-risk pre-cancerous and early cancerous lesions. Blue excitation light (400 to 460 nm) was employed to excite green-red fluorescence from fluorophores in the oral tissues. Tissue fluorescence was viewed directly along an optical axis collinear with the axis of excitation to reduce inter- and intra-operator variability. This device enables the direct visualization of fluorescence in the context of surrounding normal tissue. Results from a pilot study of 44 patients were presented. Using histology as the gold standard, the device achieves a sensitivity of 98 % and specificity of 100 % when discriminating normal mucosa from severe dysplasia/carcinoma in-situ (CIS) or invasive carcinoma.
In an article on a new technique for detecting oral cancer, Kois and Truelove (2006) stated that the VELscope can aid in patient assessment, and when added to a well-thought out clinical assessment process that takes into consideration the age of the patient and risk factors that include tobacco, alcohol, and immunological status, it increases the clinician's ability to detect oral changes that may represent pre-malignant or malignant cellular transformation. False-positive findings are possible in the presence of highly inflamed lesions, and it is possible that use of the scope alone may result in failure to detect regions of dysplasia, but it has been the authors' experience that use of the VELscope improves clinical decision-making about the nature of oral lesions and aids in decisions to biopsy regions of concern. Where tissue changes are generalized or cover significant areas of the mouth, use of the scope has allowed practitioners to identify the best region for biopsy. As with all clinical diagnostic activities, no single system or process is enough, and all clinicians are advised to use good clinical practice to assess patients and to recall and biopsy lesions that do not resolve within a pre-determined time frame. Lesions that are VELscope-positive and absorb light need to be followed with particular caution, and if they do not resolve within a 2-week period, then further assessment and biopsy are generally advised. It is much better to occasionally sample tissue that turns out to be benign than to fail to diagnose dysplastic or malignant lesions. It is unclear if the use of the VELscope would improve early detection and result in fewer deaths from oral cancer.
Poh and colleagues (2006) used a simple hand-held device in the operating room to directly visualize sub-clinical field changes around oral cancers, documenting alteration to fluorescence. A total of 122 oral mucosa biopsies were obtained from 20 surgical specimens with each biopsy being assessed for location, fluorescence visualization (FV) status, histology, and loss of heterozygosity (LOH; 10 markers on 3 regions: 3p14, 9p21, and 17p13). All tumors showed FV loss (FVL). For 19 of the 20 tumors, the loss extended in at least one direction beyond the clinically visible tumor, with the extension varying from 4 to 25 mm. Thirty-two of 36 FVL biopsies showed histological change (including 7 squamous cell carcinoma/CIS, 10 severe dysplasias, and 15 mild/moderate dysplasias) compared with 1 of the 66 FV retained (FVR) biopsies. Molecular analysis on margins with low-grade or no dysplasia showed a significant association of LOH in FVL biopsies, with LOH at 3p and/or 9p (previously associated with local tumor recurrence) present in 12 of 19 FVL biopsies compared with 3 of 13 FVR biopsies (p = 0.04). The authors concluded that these findings showed that direct FV can identify sub-clinical high-risk fields with cancerous and pre-cancerous changes in the operating room setting. These findings have little bearing in the primary care setting.
Poh et al (2007) presented 3 representative cases in which occult lesions were identified with fluorescence visualization during longitudinal follow-up, resulting in the diagnosis of a primary dysplasia in case 1, a second primary cancer in case 2, and cancer recurrence in case 3. The authors concluded that this was the first report of the diagnosis of occult oral disease using a simple non-invasive device. These early examples indicate the potential value of this technology to guide the management of patients with oral lesions, facilitating the detection of high-risk changes not apparent with white-light visualization.
The United States Preventive Services Task Force (2004) stated that the evidence is insufficient to recommend for or against routinely screening adults for oral cancer. In a Cochrane review, Kujan and colleagues (2006) evaluated the effectiveness of current screening methods in decreasing oral cancer mortality. The authors concluded that given the limitation of evidence (only 1 included randomized controlled trial) and the potential methodological weakness of the included study, it is valid to say that there is insufficient evidence to support or refute the use of a visual examination as a method of screening for oral cancer using a visual examination in the general population. Furthermore, no robust evidence exists to suggest that other methods of screening (e.g., toluidine blue, fluorescence imaging, and brush biopsy) are either beneficial or harmful. Future high quality studies to evalaute the effectiveness and costs of screening are needed for the best use of public health resources. In addition, studies to elucidate the natural history of oral cancer, prevention methods, and the effectiveness of opportunistic screening in high risk groups are needed.
In a systematic review, Patton et al (2008) evaluated the effectiveness of toluidine blue (TB), ViziLite Plus with TBlue, ViziLite, Microlux DL, Orascoptic DK, VELscope, and OralCDx brush biopsy for the early detection of oral premalignant and malignant lesions (OPML). These researchers abstracted data relating to study design, sampling and characteristics of the study group, interventions, reported outcomes and diagnostic accuracy of adjunctive aids from 23 articles meeting inclusion and exclusion criteria, including availability of histologic outcomes. The largest evidence base was for TB. A limited number of studies was available for ViziLite, ViziLite Plus with TBlue and OralCDx. Studies of VELscope have been conducted primarily to assess the margins of lesions in known OPML. The authors identified no studies of Microlux DL or Orascoptic DK. Study designs had various limitations in applicability to the general practice setting, including use of higher-risk populations and expert examiners. The authors concluded that there is evidence that TB is effective as a diagnostic adjunct for use in high-risk populations and suspicious mucosal lesions. OralCDx is useful in assessment of dysplastic changes in clinically suspicious lesions; however, there are insufficient data meeting the inclusion criteria to assess usefulness in innocuous mucosal lesions. Overall, there is insufficient evidence to support or refute the use of visually based examination adjuncts. These investigators noted that given the lack of data on the effectiveness of adjunctive cancer detection techniques in general dental practice settings, clinicians must rely on a thorough oral mucosal examination supported by specialty referral and/or tissue biopsy for OPML diagnosis.
Trullenque-Eriksson et al (2009) analysed publications that are related to examination techniques that might improve the visualization of suspicious lesions of the oral mucosa (ViziLite system and VELscope system) or that might facilitate the cytological identification of suspicious lesions (OralCDx). A literature search was performed, using the PubMed database and the key words "brush biopsy", "OralCDx", "ViziLite" and "Velscope", limiting the search to papers in English or Spanish published from 2002 to 2008. According to the results of studies identified, the ViziLite system has a sensitivity of 100 % and specificity ranging from 0 to 14.2 %, the VELscope system has a sensitivity of 98 to 100 % and specificity of 94 to 100 % and the Oral CDx system has a sensitivity of 71.4 to 100 % and specificity of 32 to 100 %. The authors concluded that clinical examination and histopathological confirmation with biopsy remain the gold standard for the detection of oral cancer. They stated that more randomized controlled studies are needed to confirm the positive cost-benefit relationship and the true usefulness of these "new diagnostic methods" in oral mucosal pathology.
Matsumoto (2011) examined if objective discrimination criteria can be set for the VELscope system when observing oral mucosal lesions. This investigator examined 74 cases with biopsy-confirmed oral mucosal lesions; 37 SCC lesions, 14 moderate-to-severe epithelial dysplasia lesions, 13 mild epithelial dysplasia lesions and 10 lichen planus lesions. Lesions were examined macroscopically under the conventional overhead light, and then, examined by this device. Each examination was recorded with a digital camera. The researcher contrasted findings with histopathological manifestation, and calculated the attenuation score. It is found that several conditions and sites, such as keratinization and the degree of inflammatory cell infiltration, were associated with detection sensitivity using this device. Based on the attenuation scores, a significant difference was seen between SCC and epithelial dysplasia. The author concluded that these findings suggested that the VELscope system might be a valuable adjunct in the early detection of potentially malignant and malignant lesions of the oral cavity.
Awan et al (2011) evaluated the accuracy of autofluorescence against conventional oral examination and surgical biopsy. A total of 126 patients, 70 males and 56 females (mean age of 58.5 +/- 11.9 years) who presented to the Oral Medicine Clinics at King's and Guy's Hospitals, London with oral white and red patches suspicious of oral potentially malignant disorders (OPMD) were enrolled. Following a complete visual and autofluorescence examination, all underwent an incisional biopsy for histopathological assessment. Seventy patients had oral leukoplakia/erythroplakia, 32 had oral lichen planus, 9 chronic hyperplastic candidiasis and rest frictional keratosis (13) or oral submucous fibrosis (2). Of 126 lesions, 105 (83 %) showed loss of fluorescence. Following biopsy, 44 had oral epithelial dysplasia (29 mild, 8 moderate and 7 severe). The sensitivity and specificity of autofluorescence for the detection of a dysplastic lesion was 84.1 % and 15.3 %, respectively. While VELscope was useful in confirming the presence of oral leukoplakia and erythroplakia and other oral mucosal disorders, the device was unable to discriminate high-risk from low-risk lesions.
Koch et al (2011) evaluated the sensitivity and specificity of the autofluorescence examination. A total of 78 patients were examined in this study. All of them suffered from suspicious oral mucosal lesions. Two different investigation methods were applied: (i) the standard examination by white light, and (ii) an examination by a novel light source of 400 nm that evoked a green light emission (greater than 500 nm) in normal mucosa. It was proposed that malignant oral mucosal lesions show different autofluorescence characteristics than the green autofluorescence of healthy mucosa. Red autofluorescence indicated SCC with a sensitivity of 20 % and a specificity of 98 %. The results showed that dysplasia and carcinoma could be identified with a sensitivity of 96 % and a specificity of 18 % by using the autofluorescence method. The sensitivity decreased according to the grade of mucosal keratosis and was influenced by the localization of the lesion. The authors concluded that benign as well as malignant oral lesions could not be distinguished by a diminished autofluorescence signal. A red autofluorescence signal, however, could indicate cancerous processes of the oral mucosa.
Lopez-Jornet and De la Mano-Espinosa (2011) reviewed papers published on autofluorescence imaging, a non-invasive technique that is used to identify neoplastic oral cavity lesions. A literature search was performed, using the PubMed database and the key words "autofluorescence" and "Velscope", limiting the search to papers in English or Spanish published from 2002 to June 2009. The Velscope system has a sensitivity of 98 to 100 % and specificity of 94 to 100 %. Autofluoresence is a supplementary tool used in the diagnosis of oral cancer, although other more reliable and robust studies are needed for confirmation. The authors concluded that there is insufficient evidence to demonstrate that its use as an adjunct to conventional oral screening provides additional benefit to conventional oral cancer screening alone.
The OraRisk HPV Test:
Human papillomavirus (HPV) infection is a significant risk factor for uterine cervical carcinoma. Moreover, there is increasing evidence that oral infection with HPV, particularly with high-risk genotypes, is a significant independent risk factor for oral SCC(OSCC). The OraRisk HPV is a salivary diagnostic test for oral cancer. It can be used in the dental office by the dental hygienist. Patients rinse with a saline solution and expectorate into a test vial that is sent to a laboratory for evaluation of the presence of HPV. However, there is insufficient evidence regarding the clinical value of the OraRisk test in detecting oral cancer.
Lee and Wong (2009) stated that saliva, a multi-constituent oral fluid, has high potential for the surveillance of general health and disease. To reach the above goal through saliva-based diagnostics, two prerequisites must be fulfilled: (i) discovering biomarker(s) for different diseases among the complicated components of saliva, and (ii) advancing sensitivity and specificity of biomarker(s) through persistent development of technologies. Under the support and research blueprint initiated by the National Institute of Dental and Craniofacial Research, salivary diagnostics has not only steadily progressed with respect to accuracy and availability, but has also bridged up-to-date nanotechnology to expand the areas of application. With collective efforts over several years, saliva has been demonstrated to be a promising bodily fluid for early detection of diseases, and salivary diagnostics has exhibited tremendous potential in clinical applications.
Pink et al (2009) noted that oral fluid is now systematically being researched and oral fluid analysis is being compared with the analysis of other diagnostic media such as blood and urine. A number of recent studies have focused on oncogenic marker detection and its monitoring in saliva. The latest clinical and laboratory findings on diagnostic markers of oropharyngeal carcinoma in oral fluid could be the beginning of their wider use as a diagnostic medium. The authors concluded that the diagnostic value of saliva, aided by current technological development will increase rapidly in the near future.
SahebJamee et al (2009) evaluated the presence of HPV in saliva rinses of patients with OSCC and analyzed the possibility of using saliva as a diagnostic method for screening high-risk patients. The saliva sample of 22 patients with OSCC and 20 age-and sex-matched healthy controls were obtained. The presence of HPV 6, 11, 16, 18, 31, and 33 was evaluated by polymerase chain reaction. In 40.9 % of the patients and in 25 % of the controls, the saliva was shown to be positive for HPV. In 27.3 % of the patients and in 20 % of the controls, the saliva was shown to be positive for HPV16; and none of the controls, except 1 patient was shown to be positive for HPV 18. Neither patients nor controls were positive for HPV 31 and 33. These differences were not statistically significant. The authors concluded that these findings were unable to support the detection of HPV in saliva rinses as a diagnostic method for OSCC.
Syrjanen et al (2011) calculated pooled risk estimates for the association of HPV with OSCC and OPMD when compared with healthy oral mucosa as controls. They also examined the effects of sampling techniques on HPV detection rates. Systematic review was performed using PubMed (January 1966 to September 2010) and Embase (January 1990 to September 2010). Eligible studies included randomized controlled, cohort and cross-sectional studies. Pooled data were analyzed by calculating odds ratios, using a random effects model. Risk of bias was based on characteristics of study group, appropriateness of the control group and prospective design. Of the 1,121 publications identified, 39 cross-sectional studies met the inclusion criteria. Collectively, 1,885 cases and 2,248 controls of OSCC and 956 cases and 675 controls of OPMD were available for analysis. Significant association was found between pooled HPV-DNA detection and OSCC (odds ration [OR] = 3.98; 95 % CI: 2.62 to 6.02) and even for HPV16 only (OR = 3.86; 95 % CI: 2.16 to 6.86). HPV was also associated with OPMD (OR = 3.87; 95 % CI: 2.87 to 5.21). In a subgroup analysis of OPMD, HPV was also associated with oral leukoplakia (OR = 4.03; 95 % CI: 2.34 to 6.92), oral lichen planus (OR = 5.12; 95 % CI: 2.40 to 10.93), and epithelial dysplasia (OR = 5.10; 95 % CI: 2.03 to 12.80). The authors concluded that these findings suggest a potentially important causal association between HPV and OSCC and OPMD.