Aetna considers oral lesion identification systems (ViziLite-Blue and VELscope) experimental and investigational for early detection of oral cancer and other indications because their effectiveness has not been established.

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.  Recent data from the Surveillance, Epidemiology, and End Results Program suggested that 28,900 new cases of oral cancer will be identified and 7400 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.

ViziLite-Blue:

The U.S. 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 squamous cell carcinoma (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 standard visual examination, 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 standard visual examination.  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 the standard visual oral examination, 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-minute 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 (2007) 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 four 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 squamous cell carcinoma.  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.

VELscope:

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 U.S. 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 one 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.