Title: Fast diagnosis of basal cell carcinoma during Mohs micrographic surgery
Funder: Department of Health (England)

Abstract: Basal cell carcinoma (BCC) accounts for 80% of the non-melanoma skin cancers worldwide and more than 60,000 new patients are diagnosed each year in the UK [2]. Mohs micrographic surgery (MMS) is the best treatment option for the high-risk BCCs as sequential layers of skin tissue are excised and diagnosed by frozen-section pathology to ensure complete removal of tumour cells while sparing as much healthy tissue as possible. However, the diagnosis of BCC by frozen-section pathology requires time-consuming and costly tissue preparation steps as well as manual diagnosis (1-2 hours per tissue layer), which have limited the availability of MMS within NHS and led to an inequitable healthcare provision. Recently, our team has developed a novel technique called multimodal spectral histopathology (MSH) that can eliminate the need to prepare and manually diagnose frozen tissue sections [1]. MSH relies on tissue auto-fluorescence imaging and Raman spectroscopy to measure molecular differences between healthy tissue and BCC. Compared to previous studies using raster-scanning Raman spectroscopy, MSH is based on a selective sampling approach that achieves a drastic decrease in the number of Raman spectra required to obtain accurate diagnosis of BCC, from ~100,000-200,000 to only 500-1500. Using our prototype instrument requiring acquisition times of 2 s per Raman spectrum, we showed that MSH can provide accurate diagnosis of BCC in skin sample in 20-60 minutes (Appendix Figures 2 and 3) [1]. In this project we will focus on increasing the speed of the new MSH technique to achieve diagnosis of BCC in only 5 minutes, then build an optimise instrument to be tested on samples from 150 new patients. The main objective of the first two years will be the develop and development of the optimized MSH instrument. To reduce the diagnosis time to 5 minutes we will integrate auto-fluorescence imaging based on structured illumination (allows high quality imaging on thick tissue samples) with the Raman skin analyzer Gen2-SCA developed by RiverD International. We have already showed that the Gen2-SCA instrument can measure individual Raman spectra of skin and other tissue samples in only 0.1 seconds, which is 20 times faster than the Raman spectrograph integrated on the MSH prototype in dr Notingher’s laboratory (Appendix Figure 4). As the diagnosis of a typical sample requires 500-1500 Raman spectra, the acquisition time for all spectra will be 1-3 minutes. The acquisition and processing time for the auto-fluorescence images will be reduced to less than 1 minuted by integrating faster detectors and hardware processing (field-programable array). After completion of the instrument design by the Nottingham team in collaboration with RiverD, RiverD International will be sub-contracted to build the MSH instrument. In the third year, the the MSH instrument will be tested against the gold-standard diagnosis by frozen-section histopathology for 150 skin samples removed during Mms We will include a range of BCCs (nodular, infiltrative and superficial) as well as tissue structures that can be confused with BCC (inflammation, especially lymphocytic, trichoblastoma and trichoepithelioma). The prediction accuracy will also be estimated for each type of BCC, as this may affect the applicability of this technology based on the pre-operatory information obtained from biopsy. The performance results obtained in this task will be used to complete our health-economics model to determine the cost-effectiveness of MMS using MSH compared to conventional MMS based of frozen-section histopathology. Milestones: i) Establish diagnosis performance of MSH compared to frozen-section pathology (month 36); ii) Establish cost-effectiveness of MSH (month 36).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS