Use of topical methylene blue to image nuclear morphometry with a low-cost scanning darkfield microendoscope.

Significance: Fiber-optic microendoscopy is a promising approach to noninvasively visualize epithelial nuclear morphometry for early cancer and precancer detection. However, the broader clinical application of this approach is limited by a lack of topical contrast agents available for in vivo use. Aim: The aim of this study was to evaluate the ability to image nuclear morphometry in vivo with a novel fiber-optic microendoscope used together with topical application of methylene blue (MB), a dye with FDA approval for use in chromoendoscopy in the gastrointestinal tract. Approach: The low-cost, high-resolution microendoscope implements scanning darkfield imaging without complex optomechanical components by leveraging programmable illumination and the rolling shutter of the image sensor. We validate the integration of our system and MB staining for visualizing epithelial cell nuclei by performing ex vivo imaging on fresh animal specimens and in vivo imaging on healthy volunteers. Results: The results indicate that scanning darkfield imaging significantly reduces specular reflection and resolves epithelial nuclei with enhanced image contrast and spatial resolution compared to non-scanning widefield imaging. The image quality of darkfield images with MB staining is comparable to that of fluorescence images with proflavine staining. Conclusions: Our approach enables real-time microscopic evaluation of nuclear patterns and has the potential to be a powerful noninvasive tool for early cancer detection.

Multiscale Optical Imaging Fusion for Cervical Precancer Diagnosis: Integrating Widefield Colposcopy and High-Resolution Endomicroscopy.

OBJECTIVE: Early detection and treatment of cervical precancers can prevent disease progression. However, in low-resource communities with a high incidence of cervical cancer, high equipment costs and a shortage of specialists hinder preventative strategies. This manuscript presents a low-cost multiscale in vivo optical imaging system coupled with a computer-aided diagnostic system that could enable accurate, real-time diagnosis of high-grade cervical precancers. METHODS: The system combines portable colposcopy and high-resolution endomicroscopy (HRME) to acquire spatially registered widefield and microscopy videos. A multiscale imaging fusion network (MSFN) was developed to identify cervical intraepithelial neoplasia grade 2 or more severe (CIN 2+). The MSFN automatically identifies and segments the ectocervix and lesions from colposcopy images, extracts nuclear morphology features from HRME videos, and integrates the colposcopy and HRME information. RESULTS: With a threshold value set to achieve sensitivity equal to clinical impression (0.98 [p = 1.0]), the MSFN achieved a significantly higher specificity than clinical impression (0.75 vs. 0.43, p = 0.000006). CONCLUSION: Our findings show that multiscale optical imaging of the cervix allows the highly sensitive and specific detection of high-grade precancers. SIGNIFICANCE: The multiscale imaging system and MSFN could facilitate the accurate, real-time diagnosis of cervical precancers in low-resource settings.

Scanning darkfield high-resolution microendoscope for label-free microvascular imaging.

Characterization of microvascular changes during neoplastic progression has the potential to assist in discriminating precancer and early cancer from benign lesions. Here, we introduce a novel high-resolution microendoscope that leverages scanning darkfield reflectance imaging to characterize angiogenesis without exogenous contrast agents. Scanning darkfield imaging is achieved by coupling programmable illumination with a complementary metal-oxide semiconductor (CMOS) camera rolling shutter, eliminating the need for complex optomechanical components and making the system portable, low-cost (<$5,500) and simple to use. Imaging depth is extended by placing a gradient-index (GRIN) lens at the distal end of the imaging fiber to resolve subepithelial microvasculature. We validated the capability of the scanning darkfield microendoscope to visualize microvasculature at different anatomic sites in vivo by imaging the oral cavity of healthy volunteers. Images of cervical specimens resected for suspected neoplasia reveal distinct microvascular patterns in columnar and squamous epithelium with different grades of precancer, indicating the potential of scanning darkfield microendoscopy to aid in efforts to prevent cervical cancer through early diagnosis.

Multimodal optical imaging with real-time projection of cancer risk and biopsy guidance maps for early oral cancer diagnosis and treatment.

Significance: Despite recent advances in multimodal optical imaging, oral imaging systems often do not provide real-time actionable guidance to the clinician who is making biopsy and treatment decisions. Aim: We demonstrate a low-cost, portable active biopsy guidance system (ABGS) that uses multimodal optical imaging with deep learning to directly project cancer risk and biopsy guidance maps onto oral mucosa in real time. Approach: Cancer risk maps are generated based on widefield autofluorescence images and projected onto the at-risk tissue using a digital light projector. Microendoscopy images are obtained from at-risk areas, and multimodal image data are used to calculate a biopsy guidance map, which is projected onto tissue. Results: Representative patient examples highlight clinically actionable visualizations provided in real time during an imaging procedure. Results show multimodal imaging with cancer risk and biopsy guidance map projection offers a versatile, quantitative, and precise tool to guide biopsy site selection and improve early detection of oral cancers. Conclusions: The ABGS provides direct visible guidance to identify early lesions and locate appropriate sites to biopsy within those lesions. This represents an opportunity to translate multimodal imaging into real-time clinically actionable visualizations to help improve patient outcomes.

Optical imaging technologies for in vivo cancer detection in low-resource settings.

Cancer continues to affect underserved populations disproportionately. Novel optical imaging technologies, which can provide rapid, non-invasive, and accurate cancer detection at the point of care, have great potential to improve global cancer care. This article reviews the recent technical innovations and clinical translation of low-cost optical imaging technologies, highlighting the advances in both hardware and software, especially the integration of artificial intelligence, to improve in vivo cancer detection in low-resource settings. Additionally, this article provides an overview of existing challenges and future perspectives of adapting optical imaging technologies into clinical practice, which can potentially contribute to novel insights and programs that effectively improve cancer detection in low-resource settings.

Mildly dysplastic oral lesions with optically-detectable abnormalities share genetic similarities with severely dysplastic lesions.

OBJECTIVE: Optical imaging studies of oral premalignant lesions have shown that optical markers, including loss of autofluorescence and altered morphology of epithelial cell nuclei, are predictive of high-grade pathology. While these optical markers are consistently positive in lesions with moderate/severe dysplasia or cancer, they are positive only in a subset of lesions with mild dysplasia. This study compared the gene expression profiles of lesions with mild dysplasia (stratified by optical marker status) to lesions with severe dysplasia and without dysplasia. MATERIALS AND METHODS: Forty oral lesions imaged in patients undergoing oral surgery were analyzed: nine without dysplasia, nine with severe dysplasia, and 22 with mild dysplasia. Samples were submitted for high throughput gene expression analysis. RESULTS: The analysis revealed 116 genes differentially expressed among sites without dysplasia and sites with severe dysplasia; 50 were correlated with an optical marker quantifying altered nuclear morphology. Ten of 11 sites with mild dysplasia and positive optical markers (91%) had gene expression similar to sites with severe dysplasia. Nine of 11 sites with mild dysplasia and negative optical markers (82%) had similar gene expression as sites without dysplasia. CONCLUSION: This study suggests that optical imaging may help identify patients with mild dysplasia who require more intensive clinical follow-up. If validated, this would represent a significant advance in patient care for patients with oral premalignant lesions.

Development of a multimodal mobile colposcope for real-time cervical cancer detection.

Cervical cancer remains a leading cause of cancer death among women in low-and middle-income countries. Globally, cervical cancer prevention programs are hampered by a lack of resources, infrastructure, and personnel. We describe a multimodal mobile colposcope (MMC) designed to diagnose precancerous cervical lesions at the point-of-care without the need for biopsy. The MMC integrates two complementary imaging systems: 1) a commercially available colposcope and 2) a high speed, high-resolution, fiber-optic microendoscope (HRME). Combining these two image modalities allows, for the first time, the ability to locate suspicious cervical lesions using widefield imaging and then to obtain co-registered high-resolution images across an entire lesion. The MMC overcomes limitations of high-resolution imaging alone; widefield imaging can be used to guide the placement of the high-resolution imaging probe at clinically suspicious regions and co-registered, mosaicked high-resolution images effectively increase the field of view of high-resolution imaging. Representative data collected from patients referred for colposcopy at Barretos Cancer Hospital in Brazil, including 22,800 high resolution images and 9,900 colposcope images, illustrate the ability of the MMC to identify abnormal cervical regions, image suspicious areas with subcellular resolution, and distinguish between high-grade and low-grade dysplasia.

Cervical lesion assessment using real-time microendoscopy image analysis in Brazil: The CLARA study.

We conducted a prospective evaluation of the diagnostic performance of high-resolution microendoscopy (HRME) to detect cervical intraepithelial neoplasia (CIN) in women with abnormal screening tests. Study participants underwent colposcopy, HRME and cervical biopsy. The prospective diagnostic performance of HRME using an automated morphologic image analysis algorithm was compared to that of colposcopy using histopathologic detection of CIN as the gold standard. To assess the potential to further improve performance of HRME image analysis, we also conducted a retrospective analysis assessing performance of a multi-task convolutional neural network to segment and classify HRME images. One thousand four hundred eighty-six subjects completed the study; 435 (29%) subjects had CIN Grade 2 or more severe (CIN2+) diagnosis. HRME with morphologic image analysis for detection of CIN Grade 3 or more severe diagnoses (CIN3+) was similarly sensitive (95.6% vs 96.2%, P = .81) and specific (56.6% vs 58.7%, P = .18) as colposcopy. HRME with morphologic image analysis for detection of CIN2+ was slightly less sensitive (91.7% vs 95.6%, P < .01) and specific (59.7% vs 63.4%, P = .02) than colposcopy. Images from 870 subjects were used to train a multi-task convolutional neural network-based algorithm and images from the remaining 616 were used to validate its performance. There were no significant differences in the sensitivity and specificity of HRME with neural network analysis vs colposcopy for detection of CIN2+ or CIN3+. Using a neural network-based algorithm, HRME has comparable sensitivity and specificity to colposcopy for detection of CIN2+. HRME could provide a low-cost, point-of-care alternative to colposcopy and biopsy in the prevention of cervical cancer.

Cervical cancer prevention in El Salvador: A prospective evaluation of screening and triage strategies incorporating high-resolution microendoscopy to detect cervical precancer.

Cervical cancer remains a leading cause of cancer death for women in low- and middle-income countries. The goal of our study was to evaluate screening and triage strategies, including high-resolution microendoscopy (HRME), to detect cervical abnormalities concerning for precancer at the point of care. Women (n = 1824) were enrolled at the Instituto de Cáncer de El Salvador. All underwent screening by both human papillomavirus (HPV) testing using careHPV and visual inspection with acetic acid (VIA). Screen-positives, along with 10% of screen-negatives, were invited to return for a follow-up examination that included triage with VIA, colposcopy and HRME imaging. Biopsies were taken of any abnormalities identified. If no abnormalities were identified, then the worst scoring site by HRME was biopsied. The sensitivities of HPV testing and VIA to screen for cervical intraepithelial neoplasia Grade 2 or more severe diagnoses (CIN2+) were 82.1% and 75% (P = .77), while the specificities were 90.4% and 80.9% (P < .001), respectively. The sensitivities of VIA, colposcopy and HRME as triage tests for CIN2+ were 82.1%, 82.1% and 71.4%, respectively (P ≥ .38). HRME had a significantly higher specificity (66.7%) than VIA (51.9%) (P < .001) and colposcopy (53.3%) (P < .001). When evaluating different theoretical screening and triage strategies, screening with HPV testing followed by triage with HRME would result in more women receiving appropriate care (97%) compared to screening with VIA (75%) or HPV alone (90%). Our findings demonstrate that screening with HPV is superior to VIA, and that triage with HRME imaging increases the specificity of detecting CIN2+ at the point of care in a low-resource setting.

Initial Results of First In Vivo Imaging of Bladder Lesions Using a High-Resolution Confocal Microendoscope.

Purpose: Conventional cystoscopy plays an important role in detection of bladder cancer; however, it is difficult to differentiate benign and neoplastic lesions based on cystoscopic appearance alone. Advanced microscopic modalities, such as confocal laser endomicroscopy and optical coherence tomography, have been shown to provide critical histopathologic information to help identify neoplastic bladder lesions in real time, but their availability and clinical adoption are limited due to a high cost. In this study, we present the first use of a novel and low-cost ($ <5000) confocal high-resolution microendoscope (confocal HRME) for in vivo imaging of bladder lesions. Materials and Methods: In a cohort of 15 patients undergoing white light cystoscopy as part of their standard of care, high-resolution images of proflavine-stained bladder lesions were acquired in vivo using the confocal HRME. Based on these images, we evaluated the ability of the confocal HRME to visualize uroepithelium with subcellular resolution and high contrast. Furthermore, we analyzed the cellular architecture and staining patterns of benign and neoplastic bladder lesions in confocal HRME images and compared results to that of standard cystoscopy and histopathology. Results:In vivo imaging in the pilot study demonstrates that the confocal HRME resolved subcellular structures of bladder uroepithelium with high contrast. In a wide range of clinical conditions from normal bladder wall to benign and neoplastic lesions, confocal HRME images revealed important diagnostic features that correlated to histopathology. Conclusions: The confocal HRME provides an affordable, portable, and easy-to-use tool to allow real-time and high-contrast subcellular characterization of bladder lesions, well suited for bladder cancer detection in community and resource-constrained settings. The ClinicalTrials.gov Identifier: NCT02340650.

Algorithm to quantify nuclear features and confidence intervals for classification of oral neoplasia from high-resolution optical images.

Purpose: In vivo optical imaging technologies like high-resolution microendoscopy (HRME) can image nuclei of the oral epithelium. In principle, automated algorithms can then calculate nuclear features to distinguish neoplastic from benign tissue. However, images frequently contain regions without visible nuclei, due to biological and technical factors, decreasing the data available to and accuracy of image analysis algorithms. Approach: We developed the nuclear density-confidence interval (ND-CI) algorithm to determine if an HRME image contains sufficient nuclei for classification, or if a better image is required. The algorithm uses a convolutional neural network to exclude image regions without visible nuclei. Then the remaining regions are used to estimate a confidence interval (CI) for the number of abnormal nuclei per mm 2 , a feature used by a previously developed algorithm (called the ND algorithm), to classify images as benign or neoplastic. The range of the CI determines whether the ND-CI algorithm can classify an image with confidence, and if so, the predicted category. The ND and ND-CI algorithm were compared by calculating their positive predictive value (PPV) and negative predictive value (NPV) on 82 oral biopsies with histopathologically confirmed diagnoses. Results: After excluding the images that could not be classified with confidence, the ND-CI algorithm had higher PPV (65% versus 59%) and NPV (78% versus 75%) than the ND algorithm. Conclusions: The ND-CI algorithm could improve the real-time classification of HRME images of the oral epithelium by informing the user if an improved image is required for diagnosis.

A PIK3CA transgenic mouse model with chemical carcinogen exposure mimics human oral tongue tumorigenesis.

Oral cancer causes significant global mortality and has a five-year survival rate of around 64%. Poor prognosis results from late-stage diagnosis, highlighting an important need to develop better approaches to detect oral premalignant lesions (OPLs) and identify which OPLs are at highest risk of progression to oral squamous cell carcinoma (OSCC). An appropriate animal model that reflects the genetic, histologic, immunologic, molecular and gross visual features of human OSCC would aid in the development and evaluation of early detection and risk assessment strategies. Here, we present an experimental PIK3CA + 4NQO transgenic mouse model of oral carcinogenesis that combines the PIK3CA oncogene mutation with oral exposure to the chemical carcinogen 4NQO, an alternate experimental transgenic mouse model with PIK3CA as well as E6 and E7 mutations, and an existing wild-type mouse model based on oral exposure to 4NQO alone. We compare changes in dorsal and ventral tongue gross visual appearance, histologic features and molecular biomarker expression over a time course of carcinogenesis. Both transgenic models exhibit cytological and architectural features of dysplasia that mimic human disease and exhibit slightly increased staining for Ki-67, a cell proliferation marker. The PIK3CA + 4NQO model additionally exhibits consistent lymphocytic infiltration, presents with prominent dorsal and ventral tongue tumours, and develops cancer quickly relative to the other models. Thus, the PIK3CA + 4NQO model recapitulates the multistep genetic model of human oral carcinogenesis and host immune response in carcinogen-induced tongue cancer, making it a useful resource for future OSCC studies.

Prospective evaluation of oral premalignant lesions using a multimodal imaging system: a pilot study.

BACKGROUND: Multimodal optical imaging, incorporating reflectance and fluorescence modalities, is a promising tool to detect oral premalignant lesions in real-time. METHODS: Images were acquired from 171 sites in 66 patient visits for clinical evaluation of oral lesions. An automated algorithm was used to classify lesions as high- or low-risk for neoplasia. Biopsies were acquired at clinically indicated sites and those classified as high-risk by imaging, at the surgeon's discretion. RESULTS: Twenty sites were biopsied based on clinical examination or imaging. Of these, 12 were indicated clinically and by imaging; 58% were moderate dysplasia or worse. Four biopsies were indicated by imaging evaluation only; 75% were moderate dysplasia or worse. Finally, four biopsies were indicated by clinical evaluation only; 75% were moderate dysplasia or worse. CONCLUSION: Multimodal imaging identified more cases of high-grade dysplasia than clinical evaluation, and can improve detection of high grade precancer in patients with oral lesions.

Autofluorescence Imaging to Monitor the Progression of Oral Potentially Malignant Disorders.

Patients with oral potentially malignant disorders (OPMD) must undergo regular clinical surveillance to ensure that any progression to malignancy is detected promptly. Autofluorescence imaging (AFI) is an optical modality that can assist clinicians in detecting early cancers and high-grade dysplasia. Patients with OPMD undergoing surveillance for the development of oral cancer were examined using AFI at successive clinic visits. Autofluorescence images acquired at 133 clinical visits from sites in 15 patients who met inclusion criteria were analyzed quantitatively using an algorithm to calculate the red-to-green pixel intensity (RG ratio). A quantitative AFI threshold for high risk of progression was defined based on the RG ratio and was compared with expert clinical impression and with histopathology when available. Patients were divided into two groups based on their endpoint: surveillance (n = 6) or surgery (n = 9). In the surveillance group, 0 of 6 (0%) of patients were clinically identified as high risk for progression prior to the study endpoint, whereas 1 of 6 (17%) of patients were deemed at high risk for progression based on AFI during the same time period. In the surgery group, 9 of 9 (100%) of patients were clinically identified as high risk prior to the study endpoint, whereas 8 of 9 (89%) of patients were at high risk for progression based on AFI during the same time period. AFI results tracked over time were comparable with expert clinical impression in these patient groups. AFI has the potential to aid clinicians in noninvasively monitoring oral precancer and evaluating OPMDs that require increased surveillance.

Advances in technologies for cervical cancer detection in low-resource settings.

Introduction: Cervical cancer mortality rates remain high in low- and middle-income countries (LMICs) and other medically underserved areas due to challenges with implementation and sustainability of routine screening, accurate diagnosis, and early treatment of preinvasive lesions. Areas covered: In this review, we first discuss the standard of care for cervical cancer screening and diagnosis in high- and low-resource settings, biomarkers that correlate to cervical precancer and cancer, and needs for new tests. We review technologies for screening and diagnosis with a focus on tests that are already in use in LMICs or have the potential to be adapted for use in LMICs. Finally, we provide perspectives on the next five years of technology development for improved cervical cancer screening and diagnosis in LMICs. Expert opinion: Innovation toward improved molecular and imaging tests is needed to enable effective, affordable see-and-treat approaches to detect and treat cervical precancer in a single visit. Current molecular tests remain too complex and/or costly for widespread use. Especially with imaging tests, decision support may improve performance of new technologies.

Low-cost, high-resolution imaging for detecting cervical precancer in medically-underserved areas of Texas.

OBJECTIVE: Cervical cancer rates in the United States have declined since the 1940's, however, cervical cancer incidence remains elevated in medically-underserved areas, especially in the Rio Grande Valley (RGV) along the Texas-Mexico border. High-resolution microendoscopy (HRME) is a low-cost, in vivo imaging technique that can identify high-grade precancerous cervical lesions (CIN2+) at the point-of-care. The goal of this study was to evaluate the performance of HRME in medically-underserved areas in Texas, comparing results to a tertiary academic medical center. METHODS: HRME was evaluated in five different outpatient clinical settings, two in Houston and three in the RGV, with medical providers of varying skill and training. Colposcopy, followed by HRME imaging, was performed on eligible women. The sensitivity and specificity of traditional colposcopy and colposcopy followed by HRME to detect CIN2+ were compared and HRME image quality was evaluated. RESULTS: 174 women (227 cervical sites) were included in the final analysis, with 12% (11% of cervical sites) diagnosed with CIN2+ on histopathology. On a per-site basis, a colposcopic impression of low-grade precancer or greater had a sensitivity of 84% and a specificity of 45% to detect CIN2+. While there was no significant difference in sensitivity (76%, p = 0.62), the specificity when using HRME was significantly higher than that of traditional colposcopy (56%, p = 0.01). There was no significant difference in HRME image quality between clinical sites (p = 0.77) or medical providers (p = 0.33). CONCLUSIONS: HRME imaging increased the specificity for detecting CIN2+ when compared to traditional colposcopy. HRME image quality remained consistent across different clinical settings.

Development of an integrated multimodal optical imaging system with real-time image analysis for the evaluation of oral premalignant lesions.

Oral premalignant lesions (OPLs), such as leukoplakia, are at risk of malignant transformation to oral cancer. Clinicians can elect to biopsy OPLs and assess them for dysplasia, a marker of increased risk. However, it is challenging to decide which OPLs need a biopsy and to select a biopsy site. We developed a multimodal optical imaging system (MMIS) that fully integrates the acquisition, display, and analysis of macroscopic white-light (WL), autofluorescence (AF), and high-resolution microendoscopy (HRME) images to noninvasively evaluate OPLs. WL and AF images identify suspicious regions with high sensitivity, which are explored at higher resolution with the HRME to improve specificity. Key features include a heat map that delineates suspicious regions according to AF images, and real-time image analysis algorithms that predict pathologic diagnosis at imaged sites. Representative examples from ongoing studies of the MMIS demonstrate its ability to identify high-grade dysplasia in OPLs that are not clinically suspicious, and to avoid unnecessary biopsies of benign OPLs that are clinically suspicious. The MMIS successfully integrates optical imaging approaches (WL, AF, and HRME) at multiple scales for the noninvasive evaluation of OPLs.

Is Proflavine Exposure Associated with Disease Progression in Women with Cervical Dysplasia? A Brief Report.

Proflavine is an acridine dye used with high-resolution microendoscopy for in vivo diagnostic evaluation of cervical epithelial cells. However, there are concerns that even short-term exposure of cervical tissue to dilute proflavine may increase cervical cancer risk. We performed a retrospective analysis of women referred for colposcopy to Barretos Cancer Hospital comparing the risk of cervical disease progression in those whose cervical tissue was (n = 232) or was not exposed (n = 160) to proflavine. Patients in both groups underwent treatment and follow-up based on histopathologic results and per the local standards of care. Progression of disease was evaluated by comparing histopathology from the initial visit to the worst subsequent histopathology result from all follow-up visits. Mean duration of follow-up was 18.7 and 20.1 months for the proflavine-exposed and controls groups, respectively. There were no significant differences in disease progression from normal/CIN1 to CIN2/3 or from any initial diagnosis to invasive cancer between the proflavine exposed and control groups overall. Risks of cervical dysplasia progression observed in this study are in agreement with those of the natural history of cervical cancer. Our results suggest that cervical exposure to dilute proflavine does not increase the risk of cervical precancer and cancer.

In Vivo Multimodal Optical Imaging: Improved Detection of Oral Dysplasia in Low-Risk Oral Mucosal Lesions.

Early detection of oral cancer and oral premalignant lesions (OPL) containing dysplasia could improve oral cancer outcomes. However, general dental practitioners have difficulty distinguishing dysplastic OPLs from confounder oral mucosal lesions in low-risk populations. We evaluated the ability of two optical imaging technologies, autofluorescence imaging (AFI) and high-resolution microendoscopy (HRME), to diagnose moderate dysplasia or worse (ModDys+) in 56 oral mucosal lesions in a low-risk patient population, using histopathology as the gold standard, and in 46 clinically normal sites. AFI correctly diagnosed 91% of ModDys+ lesions, 89% of clinically normal sites, and 33% of benign lesions. Benign lesions with severe inflammation were less likely to be correctly diagnosed by AFI (13%) than those without (42%). Multimodal imaging (AFI+HRME) had higher accuracy than either modality alone; 91% of ModDys+ lesions, 93% of clinically normal sites, and 64% of benign lesions were correctly diagnosed. Photos of the 56 lesions were evaluated by 28 dentists of varied training levels, including 26 dental residents. We compared the area under the receiver operator curve (AUC) of clinical impression alone to clinical impression plus AFI and clinical impression plus multimodal imaging using k-Nearest Neighbors models. The mean AUC of the dental residents was 0.71 (range: 0.45-0.86). The addition of AFI alone to clinical impression slightly lowered the mean AUC (0.68; range: 0.40-0.82), whereas the addition of multimodal imaging to clinical impression increased the mean AUC (0.79; range: 0.61-0.90). On the basis of these findings, multimodal imaging could improve the evaluation of oral mucosal lesions in community dental settings. Cancer Prev Res; 11(8); 465-76. ©2018 AACR.