Surgical removal of head and neck cancers presents challenges to the surgeon as they seek to remove cancerous tissue, preserve normal tissues and function, and prevent disfigurement. For this purpose, assessment of tissue status at the margins is critical for effective intervention. The pathologic examination of margins for tumors and the determination of "clean margins" is currently based on traditional frozen section methods that routinely examine less than 0.2% of the tissue removed.
The aims of the proposed studies are to improve the assessment of tumor margins by developing tools that effectively move the microscopic examination closer to the patient in both time and space, and that provide improved guidance for tissue selection. This will be accomplished by developing, and deploying, arrays of miniaturized microscopes that reveal tissue histopathology at a resolution approaching that of conventional microscopes, and offer large coverage of tissue samples, and high speed scanning. These arrays serve as rapid screening tools, and are enabled by developments in integrated optics, and lithographic fabrication techniques such as MOEMS (micro-opto-electro-mechanical systems), and high- resolution, high-speed digital image capture and sophisticated image-processing algorithms to accelerate acquisition and refine quality of pathology images. We propose to use these arrays at the cutting bench in the surgical pathology suite to increase the amount of tissue analyzed in gross pathology, link macroscopic inspection of tissue to microscopic examination and provide more information, more rapidly, than conventional approaches. We will construct arrays of dual axis confocal (DAC) microscopes, advance rapid fluorescent surface staining, and develop image reconstruction software to enable rapid, microscopic inspection of large surface areas of resected tissue. The arrayed dual axis confocal (ADAC) device will be approximately the size of a cell phone and will provide cellular-level images of tissue architecture and molecular signatures at 1-5um resolution, and will be applied to the pathologic assessment of tumor margins. Although this study is limited to head and neck cancers, the full potential of ADAC is substantial. The margins of resection specimens are, in many cases, inadequately sampled due to the inefficiency of current sampling methods. The ADAC device could allow comprehensive en face examination of the entire lumpectomy specimen, and will have utility in selection of tissue for processing at the surgical pathology bench. As these tools advance, the histology lab could be circumvented for many specimens, which would provide a significant cost savings to the healthcare system, and increase the speed at which pathology could be reported.

Public Health Relevance

Precision in surgical removal of cancer is guided by pathological assessment of resected tissues, and there is a dire need to reduce the time and distance between the critical diagnostic events and the surgical procedure. Here we propose to develop tools that reveal histopathology with cellular resolution, and eventually molecular specificity, on fresh resected tissues that can be used on the cutting bench in the surgical pathology suite. The core technology is a series of arrayed miniaturized confocal microscopes that allow rapid examination of tissue margins to guide the pathologist and inform the surgeon ensuring complete removal of the cancer and preservation of normal tissue. We will first apply these tools to surgical removal of head and neck cancers where microscopic techniques are current used. Although this is a relatively limited context, the future potential for microscope arrays is substantial. There are many resection specimens where margins are inadequately sampled due to the inefficiency of current sampling methods. Arrays of mini-microscopes could allow comprehensive en face examination of the entire lumpectomy specimen. These tools could be present at surgical pathology bench to provide instant feedback and prospective quality control for specimens submitted for microscopic evaluation. In the future we envision the images so faithfully reproducing the H&E image that no further processing would need to be done on some (or eventually most) specimens. Such a process could eliminate the histology lab from evaluation of most specimens leading to a significant savings in time and cost.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZCA1-GRB-P (M1))
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Ossandon, Miguel
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Stanford University
Schools of Medicine
United States
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