Optical coherence tomography (OCT) as a diagnostic tool for the real-time intraoperative assessment of breast cancer surgical margins

Background: The decrease in the number of breast cancer deaths has largely been attributed to increased awareness, earlier detection, and improved treatment options. However, as the number of breast-conserving surgeries rose over the years, the need for negative margins and little or no residual disease has become critical to help reduce the chances of local recurrence. OCT is a high resolution imaging modality that has been used to image tumor margins in an NMU-carcinogen-induced rat mammary tumor model. Due to the location of breast lesions, the use of needle-based imaging probes may be used to further extend the reach of the OCT imaging beam by incorporating an optical fiber into biopsy needle tips, providing real-time information to guide biopsies or to place localization wires.
Material & Methods: A clinical spectral domain OCT system was developed with a super luminescent diode light source centered at 1310 nm with a bandwidth of 92 nm yielding an axial resolution of 8.3 µm. The beam delivery sample arm uses a 60 mm achromatic lens to focus 4.75 mW of light to a 35.0 µm spot size (transverse resolution) with a confocal parameter of 1.47 mm. The patients included in this study had primary breast tumors diagnosed by needle-biopsy and were in need of surgical resection, as determined by their physicians. At Carle Foundation Hospital, the OCT system was placed inside the operating room during breast conserving surgical procedures to image the tissue specimens. The OCT images were evaluated by a single operator allowing for consistent classification based on the level of scattering intensity and heterogeneity, scattering profile, and physical extent of the highly scattering area.
Results: An initial training data set of OCT images from 17 patients was used to establish standard imaging protocols and standard evaluation criteria of the surgical margins. Of the 20 additional tissue specimen imaged for the feasibility study, 11 were identified as having a positive or close surgical margin and nine as a negative margin under OCT. In comparing to the H&E histology, there were 9 true positives, 9 true negatives, 2 false positives, and 0 false negatives yielding a sensitivity of 82% and specificity of 100%.
Discussion: With an imaging penetration depth of 2-3 mm, equivalent to that used for histological assessment, OCT provides unique real-time cellular-level imaging to identify positive and close margins. In these studies, areas of higher scattering tissue with an irregular or heterogeneous pattern were identified, differentiating them from the abundant adipose tissue found in normal breast tissue. The small nucleus to cytoplasm (N/C) ratio is observed with low-scattering adipocytes compared with the larger N/C ratio found from highly-scattering tumor cells. These intraoperative imaging studies have demonstrated the ability for OCT to identify positive surgical margins.

Coherent optical imaging and guided interventions in breast cancer: translating technology into clinical applications

Breast cancer continues to be one of the most widely diagnosed forms of cancer in women and the second leading type of cancer deaths for women. The metastatic spread and staging of breast cancer is typically evaluated through the nodal assessment of the regional lymphatic system, and often this is performed during the surgical resection of the tumor mass. The recurrence rate of breast cancer is highly dependent on several factors including the complete removal of the primary tumor during surgery, and the presence of cancer cells in involved lymph nodes. Hence, developing means to more accurately resect tumor cells, along with the tumor mass, and ensure negative surgical margins, offers the potential to impact outcomes of breast cancer. The use of diffuse optical tomography has been applied for screening optical mammography applications as an alternative to standard x-ray mammography. The use of coherence ranging and coherent optical imaging in breast tissue has also found numerous applications, including intra-operative assessment of tumor margin status during lumpectomy procedures, assessment of lymph node changes for staging metastatic spread, and for guiding needle-biopsy procedures. The development, pre-clinical testing, and translation of techniques such as low-coherence interferometry (LCI) and optical coherence tomography (OCT) into clinical applications in breast cancer is demonstrated in these feasibility studies.

Magnetic protein microspheres as dynamic contrast agents for magnetomotive optical coherence tomography

Optical coherence tomography (OCT) is an emerging biomedical imaging modality that has been developed over the last 15 years. More recently, OCT has been used for the intraoperative imaging of tumor margins in breast cancer and axillary lymph nodes providing a real time in-vivo assessment of the tissue morphology. Traditional OCT images are limited by only being able to observe morphological structures. As diagnostic medicine continues to push for earlier detection, one must develop functional imaging modalities that would detect molecular information in-vivo allowing a real-time microscopic analysis of the tissue specimen. A novel modality of OCT called magnetomotive-OCT (MMOCT) has been developed by our group, employing an induced modulated magnetic field with a magnetic contrast agent to create the added contrast to structural OCT images. Modified protein microspheres with a BSA protein shell functionalized with RGD peptide sequences for targeting and an oil core have been designed and synthesized. Magnetic nanoparticles (Fe3O4) and Nile Red dye have been encapsulated into its oil core. These microspheres have previously been demonstrated to target cancer cells by functionalizing them with a layer of RGD peptides and could be functionalized with monoclonal antibodies. Preliminary results show that these magnetic microspheres, which are 2.0- 5.0 microns in size, are readily detectable under MM-OCT when embedded in a 5% agarose gel, in a 3-D scaffold of macrophage cells previously incubated with the microspheres, and when injected in-vivo into a tumor from an NMUcarcinogen rat animal model for breast cancer.


Optical coherence tomography: a review of clinical development from bench to bedside

Since its introduction, optical coherence tomography (OCT) technology has advanced from the laboratory bench to the clinic and back again. Arising from the fields of low coherence interferometry and optical time- and frequency-domain reflectometry, OCT was initially demonstrated for retinal imaging and followed a unique path to commercialization for clinical use. Concurrently, significant technological advances were brought about from within the research community, including improved laser sources, beam delivery instruments, and detection schemes. While many of these technologies improved retinal imaging, they also allowed for the application of OCT to many new clinical areas. As a result, OCT has been clinically demonstrated in a diverse set of medical and surgical specialties, including gastroenterology, dermatology, cardiology, and oncology, among others. The lessons learned in the clinic are currently spurring a new set of advances in the laboratory that will again expand the clinical use of OCT by adding molecular sensitivity, improving image quality, and increasing acquisition speeds. This continuous cycle of laboratory development and clinical application has allowed the OCT technology to grow at a rapid rate and represents a unique model for the translation of biomedical optics to the patient bedside. This work presents a brief history of OCT development, reviews current clinical applications, discusses some clinical translation challenges, and reviews laboratory developments poised for future clinical application.


Needle-based refractive index measurement using low-coherence interferometry

We present a novel needle-based device for the measurement of refractive index and scattering using low-coherence interferometry. Coupled to the sample arm of an optical coherence tomography system, the device detects the scattering response of, and optical path length through, a sample residing in a fixed-width channel. We report use of the device to make near-infrared measurements of tissues and materials with known optical properties. The device could be used to exploit the refractive index variations of tissue for medical and biological diagnostics accessible by needle insertion.

Portable real-time optical coherence tomography system for intraoperative imaging and staging of breast cancer

Breast cancer continues to be one of the most widely diagnosed forms of cancer amongst women and the second leading type of cancer deaths amongst women. The recurrence rate of breast cancer is highly dependent on several factors including the complete removal of the primary tumor and the presence of cancer cells in involved lymph nodes. The metastatic spread and staging of breast cancer is also evaluated through the nodal assessment of the regional lymphatic system. A portable real-time spectral domain optical coherence tomography system is being presented as a clinical diagnostic tool in the intraoperative delineation of tumor margins as well as for real time lymph node assessment. The system employs a super luminescent diode centered at 1310 nm with a bandwidth of 92 nm. Using a spectral domain detection system, the data is acquired at a rate of 5 KHz / axial scan. The sample arm is a galvanometer scanning telecentric probe with an objective lens (f = 60 mm, confocal parameter = 1.5 mm) yielding an axial resolution of 8.3 μm and a transverse resolution of 35.0 μm. Images of tumor margins are acquired in the operating room ex vivo on freshly excised human tissue specimen. This data shows the potential of the use of OCT in defining the structural tumor margins in breast cancer. Images taken from ex-vivo samples on the bench system clearly delineate the differences between clusters of tumor cells and nearby adipose cells. In addition, the data shows the potential for OCT as a diagnostic tool in the staging of cancer metastasis through locoregional lymph node assessment.

Needle-probe system for the measurement of tissue refractive index

Needle-based devices, which are in wide clinical use for needle biopsy procedures, may be augmented by suitable optical techniques for the localization and diagnosis of diseased tissue. Tissue refractive index is one optical contrast mechanism with diagnostic potential. In the case of mammary tissue, for example, recent research indicates that refractive index variations between tissue types may be useful for the identification of cancerous tissue. While many coherence-based forward-sensing devices have been developed to detect scattering changes, none have demonstrated refractive index measurement capabilities. We present a novel needle-based device that is capable of simultaneously measuring refractive index and scattering. Coupled to the sample arm of an optical coherence tomography system, the needle device detects the scattering response and optical pathlength through tissue residing in a fixed-width channel. Near-infrared measurements of tissues and materials with known optical properties using a prototype device will be presented. This work demonstrates the feasibility of integrated in vivo measurement of refractive index and scattering in conjunction with existing clinical needle-based devices.


Optical biopsy of lymph node morphology using optical coherence tomography

Optical diagnostic imaging techniques are increasingly being used in the clinical environment, allowing for improved screening and diagnosis while minimizing the number of invasive procedures. Diffuse optical tomography, for example, is capable of whole-breast imaging and is being developed as an alternative to traditional X-ray mammography. While this may eventually be a very effective screening method, other optical techniques are better suited for imaging on the cellular and molecular scale. Optical Coherence Tomography (OCT), for instance, is capable of high-resolution cross-sectional imaging of tissue morphology. In a manner analogous to ultrasound imaging except using optics, pulses of near-infrared light are sent into the tissue while coherence-gated reflections are measured interferometrically to form a cross-sectional image of tissue. In this paper we apply OCT techniques for the high-resolution three-dimensional visualization of lymph node morphology. We present the first reported OCT images showing detailed morphological structure and corresponding histological features of lymph nodes from a carcinogen-induced rat mammary tumor model, as well as from a human lymph node containing late stage metastatic disease. The results illustrate the potential for OCT to visualize detailed lymph node structures on the scale of micrometastases and the potential for the detection of metastatic nodal disease intraoperatively.