Abstract
.Significance: Early detection of epithelial cancers and precancers/neoplasia in the presence of benign lesions is challenging due to the lack of robust in vivo imaging and biopsy guidance techniques. Label-free nonlinear optical microscopy (NLOM) has shown promise for optical biopsy through the detection of cellular and extracellular signatures of neoplasia. Although in vivo microscopy techniques continue to be developed, the surface area imaged in microscopy is limited by the field of view. FDA-approved widefield fluorescence (WF) imaging systems that capture autofluorescence signatures of neoplasia provide molecular information at large fields of view, which may complement the cytologic and architectural information provided by NLOM.Aim: A multimodal imaging approach with high-sensitivity WF and high-resolution NLOM was investigated to identify and distinguish image-based features of neoplasia from normal and benign lesions.Approach: In vivo label-free WF imaging and NLOM was performed in preclinical hamster models of oral neoplasia and inflammation. Analyses of WF imaging, NLOM imaging, and dual modality (WF combined with NLOM) were performed.Results: WF imaging showed increased red-to-green autofluorescence ratio in neoplasia compared to inflammation and normal oral mucosa (). In vivo assessment of the mucosal tissue with NLOM revealed subsurface cytologic (nuclear pleomorphism) and architectural (remodeling of extracellular matrix) atypia in histologically confirmed neoplastic tissue, which were not observed in inflammation or normal mucosa. Univariate and multivariate statistical analysis of macroscopic and microscopic image-based features indicated improved performance (94% sensitivity and 97% specificity) of a multiscale approach over WF alone, even in the presence of benign lesions (inflammation), a common confounding factor in diagnostics.Conclusions: A multimodal imaging approach integrating strengths from WF and NLOM may be beneficial in identifying oral neoplasia. Our study could guide future studies on human oral neoplasia to further evaluate merits and limitations of multimodal workflows and inform the development of multiscale clinical imaging systems.
Highlights
Oral squamous cell carcinoma (OSCC) accounts for almost 94% of all oral cancers with ∼53;000 new diagnoses every year solely in the United States (US).[1]
A multimodal imaging approach integrating strengths from widefield fluorescence (WF) and nonlinear optical microscopy (NLOM) may be beneficial in identifying oral neoplasia
The choice of WF imaging with NLOM in this work was motivated by the fact that WF imaging is already a clinical, FDA-approved approach for oral cancer screening adjunct to conventional oral examination (COE) and has relatively high sensitivity; multiphoton microscopy (MPM)/second harmonic generation microscopy (SHGM) has been shown in the previous studies to have high sensitivity and specificity in preclinical tests and can provide cellular and extracellular atypia metrics.[36]
Summary
Oral squamous cell carcinoma (OSCC) accounts for almost 94% of all oral cancers with ∼53;000 new diagnoses every year solely in the United States (US).[1] The five-year survival rate of patients with advanced OSCC involving regional lymph node invasion or beyond is ∼47% (regional) and 20% (distant) but can be as high as 84% when cancers are diagnosed and treated when detected in the localized primary site.[2] It is estimated that the percent of cases diagnosed at advanced stages, defined as regional or distant cancers, range from 64 to beyond 70%, motivating approaches that facilitate early detection and intervention.[3,4] The most comprehensive US source is the SEER Cancer Statistics Review (CSR) 1975–2016, which indicates 31% of cases are diagnosed at early stage (local), 64% at advanced stages (regional or distant), and 5% at unknown stages.[5] OSCCs, primarily oral epithelial dysplasia (OED), have potential to develop from neoplasia, an abnormal growth of the epithelium due to a malignant or a benign precancerous lesion.[6,7] With grade of OEDs remaining the key factor to assess risk for transformation of such lesions, there have been increased efforts to detect OEDs harbored in lesions to aid in clinical decisions.[8,9] There remains a need for methods that more effectively support detection efforts
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