Simultaneous coaxial widefield imaging and reflectance confocal microscopy for improved diagnosis of skin cancers in vivo

1皮肤科医生依赖于皮肤病变的视觉（临床宽视野）和皮肤镜检查来指导需要 2例活检。通过这种方法，灵敏度很高，但特异性往往变化很大且较低，导致 每年百万分之三的良性病变活检。为了提高特异性， 4正在开发非侵入性检测皮肤癌。其中，反射共焦显微镜（RCM）是 5、临床应用最先进，被证明用于诊断皮肤癌具有高灵敏度和特异性。 6皮肤镜引导下的RCM成像检测皮肤癌的特异性为2倍上级， 7良恶性活检率较单纯皮肤镜检查提高2倍。2016年，中心 8项医疗保险和医疗补助服务授予RCM的现行程序术语（CPT）报销代码 9皮肤的图像RCM成像与皮肤镜相结合，现在正在推进到临床实践中， 10例为不必要的良性病变活检。然而，为了得到广泛的接受和采用， 11个关键挑战是，临床宽视野检查，皮肤镜和RCM成像目前进行， 12个单独的手术，使用单独的器械。临床医生并不确切知道RCM图像的位置- 相对于临床宽视野检查所见的周围背景病变形态， 14皮肤镜检查，导致较低和更多的可变诊断准确性（特别是，敏感性，阳性和 15个阴性预测值）。我们提出了一种新的解决方案：（i）一种新的物镜透镜与集成微 16照相机，用于传送RCM成像位置周围的皮肤表面的同时宽视场图像; 17（ii）一种新的软件算法，用于皮肤镜内RCM图像位置的宽视野图像跟踪， （iii）一种新的诊断方法，将主动使用宽视野成像来定位RCM图像， 19张皮肤镜照片。我们打算提供这种集成的宽视野临床，皮肤镜和RCM成像应用程序， 20进入临床，朝着更准确，一致和更快的RCM成像的新标准，以指导 21病人护理在台式装置上用"模拟"物镜透镜和微型照相机进行的初步研究 22个证明了RCM成像的出色光学切片（~2 µ m）和分辨率（~1 µ m）， 23宽视场图像内RCM视场的可重复位置。RCM图像显示良好的细胞 24和体内形态学细节。我们的具体目标是：（1）开发一种手持式反射式共焦显微镜， （2）开发用于实时宽视场成像的图像处理算法， 26皮肤镜视野内RCM图像位置的老化引导跟踪;（3）测试和验证性能 100个病人中有27个。虽然我们的主张是针对皮肤病变，但这项研究肯定会产生更广泛的影响， 28在其他设置中的成像，特别是使用小型化共焦显微镜和内窥镜，其具有 29个小视野我们是来自蒙大拿州立大学纪念斯隆的一个高度协同的团队 30 Kettering Cancer Center，Northeastern University and Caliber Imaging and Diagnostics（formerly，Lucid Inc.）.

1 Dermatologists rely on visual (clinical widefield) and dermoscopic examination of skin lesions to guide the need 2 for biopsy. With this approach, sensitivity is high, but specificity tends to be quite variable and lower, resulting 3 in millions of biopsies of benign lesions every year. To improve specificity, several optical technologies are 4 being developed to noninvasively detect skin cancer. Of these, reflectance confocal microscopy (RCM) is the 5 furthest advanced in clinical utility, proven for diagnosing skin cancers with high sensitivity and specificity. 6 RCM imaging, guided by dermoscopy, detects skin cancers with 2 times superior specificity, and reduces the 7 benign-to-malignant biopsy rate by 2 times, compared to that with dermoscopy alone. In 2016, the Centers for 8 Medicare and Medicaid Services granted current procedural terminology (CPT) reimbursement codes for RCM 9 imaging of skin. RCM imaging combined with dermoscopy is now advancing into clinical practice, sparing pa- 10 tients from unnecessary biopsies of benign lesions. However, toward widespread acceptance and adoption, a 11 key challenge is that clinical widefield examination, dermoscopy and RCM imaging are currently performed as 12 three separate procedures with separate devices. Clinicians do not precisely know the location of RCM imag- 13 es relative to the surrounding contextual lesion morphology that is seen with clinical widefield examination and 14 dermoscopy, resulting in lower and more variable diagnostic accuracy (particularly, sensitivity, positive and 15 negative predictive values). We propose a novel solution: (i) a new objective lens with an integrated micro- 16 camera, to deliver a concurrent widefield image of the skin surface surrounding the location of RCM imaging; 17 (ii) a new software algorithm for widefield image-based tracking of the location of RCM images within a dermoscopic 18 field of view; (iii) a new diagnostic approach that will proactively use widefield imaging to locate RCM images in 19 dermoscopic images. We intend to deliver this integrated widefield clinical, dermoscopic and RCM imaging ap- 20 proach into the clinic, toward a new standard for more accurate, consistent and faster RCM imaging to guide 21 patient care. Preliminary studies with a “mock” objective lens and micro-camera on a bench-top set-up 22 demonstrated excellent optical sectioning (~2 µm) and resolution (~1 µm) for RCM imaging, and accurate and 23 repeatable location of RCM fields-of-view within the widefield image. RCM images showed excellent cellular 24 and morphologic detail in vivo. Our specific aims are (1) to develop a handheld reflectance confocal micro- 25 scope with integrated widefield camera; (2) to develop image processing algorithms for real-time widefield im- 26 aging-guided tracking of RCM image locations within dermoscopic fields; (3) to test and validate performance 27 on 100 patients. Although our proposition is for skin lesions, the research will surely have wider impact for 28 imaging in other settings, particularly, with miniaturized confocal microscopes and endoscopes, which have 29 very small fields-of-view. We are a highly synergistic team from Montana State University, Memorial Sloan 30 Kettering Cancer Center, Northeastern University and Caliber Imaging and Diagnostics (formerly, Lucid Inc.).