Interpretation of Optical Coherence Tomography Images for Breast Tissue Assessment.

PURPOSE: Initial studies have shown that optical coherence tomography (OCT) is an effective margin-evaluation tool for breast-conserving surgery, but methods for the interpretation of breast OCT images have not been directly studied. In this work, breast pathologies were assessed with a handheld OCT probe. OCT images and corresponding histology were used to develop guidelines for the identification of breast tissue features in OCT images. METHODS: Mastectomy and breast-conserving surgery specimens from 26 women were imaged with a handheld OCT probe. During standard pathology specimen dissection, representative 1-cm × 1-cm tissue regions were grossly identified, assessed with OCT, inked for orientation and image-matching purposes, and processed. Histology slides corresponding to the OCT image region were digitally photographed. OCT and histology images from the same region were paired by selecting the best structural matches. RESULTS: In total, 2880 OCT images were acquired from 26 breast specimens (from 26 patients) and 48 matching OCT-histology image pairs were identified. These matched image pairs illustrate tissue types including adipose tissue, dense fibrosis, fibroadipose tissue, blood vessels, regular and hyperplastic ducts and lobules, cysts, cyst, fibroadenoma, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, calcifications, and biopsy cavities. Differentiation between pathologies was achieved by considering feature boundaries, interior appearance, posterior shadowing or enhancement, and overall morphologic patterns. CONCLUSIONS: This is the first work to systematically catalog the critical features of breast OCT images. The results indicate that OCT can be used to identify and distinguish between benign and malignant features in human breast tissue.

Margin Assessment in Renal Surgery Using a Handheld Optical Coherence Tomography Probe.

OBJECTIVE: To assess the use of a handheld optical coherence tomography (OCT) probe for the evaluation of intraoperative surgical margins during partial nephrectomy (PN). METHODS: In an initial feasibility study, a radical nephrectomy specimen with a 9-cm tumor was cut into 19 sections, exposing 0 mm (n = 8), 1 mm (n = 6), and 2 mm (n = 5) gross margins. OCT was used to determine the margin width in each specimen. Second, a prospective ex vivo assessment of 15 PN tumor specimens was performed with OCT to determine margin status and to measure the attenuation coefficient of tumor and renal parenchyma. RESULTS: Median OCT margin width measurements for sectioned samples were 0 mm, 0.9 mm (range 0.7-2.9 mm), and 2.7 (range 1.65-2.8 mm) for grossly 0 mm (positive), 1 mm, and 2 mm margins, respectively. The difference between measurements from all margin groups was statistically significant (P <.04). The sensitivity and specificity for identifying positive margins were both 100%. In the PN specimens, OCT correctly found that all specimens had negative margins (within <.0001). CONCLUSION: We have demonstrated the feasibility of using a handheld OCT probe to assess margins ex vivo during PN. OCT may reduce the need for intraoperative frozen section and aid in minimizing parenchymal excision.

Filtering for unwrapping noisy Doppler optical coherence tomography images for extended microscopic fluid velocity measurement range.

In this Letter, we report the first application of two phase denoising algorithms to Doppler optical coherence tomography (DOCT) velocity maps. When combined with unwrapping algorithms, significantly extended fluid velocity dynamic range is achieved. Instead of the physical upper bound, the fluid velocity dynamic range is now limited by noise level. We show comparisons between physical simulated ideal velocity maps and the experimental results of both algorithms. We demonstrate unwrapped DOCT velocity maps having a peak velocity nearly 10 times the theoretical measurement range.

Real-time Imaging of the Resection Bed Using a Handheld Probe to Reduce Incidence of Microscopic Positive Margins in Cancer Surgery.

Wide local excision (WLE) is a common surgical intervention for solid tumors such as those in melanoma, breast, pancreatic, and gastrointestinal cancer. However, adequate margin assessment during WLE remains a significant challenge, resulting in surgical reinterventions to achieve adequate local control. Currently, no label-free imaging method is available for surgeons to examine the resection bed in vivo for microscopic residual cancer. Optical coherence tomography (OCT) enables real-time high-resolution imaging of tissue microstructure. Previous studies have demonstrated that OCT analysis of excised tissue specimens can distinguish between normal and cancerous tissues by identifying the heterogeneous and disorganized microscopic tissue structures indicative of malignancy. In this translational study involving 35 patients, a handheld surgical OCT imaging probe was developed for in vivo use to assess margins both in the resection bed and on excised specimens for the microscopic presence of cancer. The image results from OCT showed structural differences between normal and cancerous tissue within the resection bed following WLE of the human breast. The ex vivo images were compared with standard postoperative histopathology to yield sensitivity of 91.7% [95% confidence interval (CI), 62.5%-100%] and specificity of 92.1% (95% CI, 78.4%-98%). This study demonstrates in vivo OCT imaging of the resection bed during WLE with the potential for real-time microscopic image-guided surgery.

Intraoperative Assessment of Final Margins with a Handheld Optical Imaging Probe During Breast-Conserving Surgery May Reduce the Reoperation Rate: Results of a Multicenter Study.

BACKGROUND: A multicenter, prospective, blinded study was performed to test the feasibility of using a handheld optical imaging probe for the intraoperative assessment of final surgical margins during breast-conserving surgery (BCS) and to determine the potential impact on patient outcomes. METHODS: Forty-six patients with early-stage breast cancer (one with bilateral disease) undergoing BCS at two study sites, the Johns Hopkins Hospital and Anne Arundel Medical Center, were enrolled in this study. During BCS, cavity-shaved margins were obtained and the final margins were examined ex vivo in the operating room with a probe incorporating optical coherence tomography (OCT) hardware and interferometric synthetic aperture microscopy (ISAM) image processing. Images were interpreted after BCS by three physicians blinded to final pathology-reported margin status. Individual and combined interpretations were assessed. Results were compared to conventional postoperative histopathology. RESULTS: A total of 2,191 images were collected and interpreted from 229 shave margin specimens. Of the eight patients (17 %) with positive margins (0 mm), which included invasive and in situ diseases, the device identified all positive margins in five (63%) of them; reoperation could potentially have been avoided in these patients. Among patients with pathologically negative margins (>0 mm), an estimated mean additional tissue volume of 10.7 ml (approximately 1% of overall breast volume) would have been unnecessarily removed due to false positives. CONCLUSIONS: Intraoperative optical imaging of specimen margins with a handheld probe potentially eliminates the majority of reoperations.

A computational model to generate simulated three-dimensional breast masses.

PURPOSE: To develop algorithms for creating realistic three-dimensional (3D) simulated breast masses and embedding them within actual clinical mammograms. The proposed techniques yield high-resolution simulated breast masses having randomized shapes, with user-defined mass type, size, location, and shape characteristics. METHODS: The authors describe a method of producing 3D digital simulations of breast masses and a technique for embedding these simulated masses within actual digitized mammograms. Simulated 3D breast masses were generated by using a modified stochastic Gaussian random sphere model to generate a central tumor mass, and an iterative fractal branching algorithm to add complex spicule structures. The simulated masses were embedded within actual digitized mammograms. The authors evaluated the realism of the resulting hybrid phantoms by generating corresponding left- and right-breast image pairs, consisting of one breast image containing a real mass, and the opposite breast image of the same patient containing a similar simulated mass. The authors then used computer-aided diagnosis (CAD) methods and expert radiologist readers to determine whether significant differences can be observed between the real and hybrid images. RESULTS: The authors found no statistically significant difference between the CAD features obtained from the real and simulated images of masses with either spiculated or nonspiculated margins. Likewise, the authors found that expert human readers performed very poorly in discriminating their hybrid images from real mammograms. CONCLUSIONS: The authors' proposed method permits the realistic simulation of 3D breast masses having user-defined characteristics, enabling the creation of a large set of hybrid breast images containing a well-characterized mass, embedded within real breast background. The computational nature of the model makes it suitable for detectability studies, evaluation of computer aided diagnosis algorithms, and teaching purposes.

Nondestructive volumetric imaging of tissue microstructure with benchtop x-ray phase-contrast tomography and critical point drying.

The in vitro investigation of many optically opaque biological microstructures requires 3D analysis at high resolution over a large field of view. We demonstrate a new nondestructive volumetric imaging technique that eliminates the structural and computational limitations of conventional 2D optical microscopy by combining x-ray phase-contrast tomography with critical point drying sample preparation. We experimentally demonstrate the enhancement of small features afforded by phase-contrast imaging and show the contrast improvement afforded by the drying of a hydrated specimen. We further demonstrate the biological application of this technique by imaging the microstructure of the accommodative apparatus in a primate eye using a benchtop phase-contrast tomography system.

Imaging of poly(α-hydroxy-ester) scaffolds with X-ray phase-contrast microcomputed tomography.

Porous scaffolds based on poly(α-hydroxy-esters) are under investigation in many tissue engineering applications. A biological response to these materials is driven, in part, by their three-dimensional (3D) structure. The ability to evaluate quantitatively the material structure in tissue-engineering applications is important for the continued development of these polymer-based approaches. X-ray imaging techniques based on phase contrast (PC) have shown a tremendous promise for a number of biomedical applications owing to their ability to provide a contrast based on alternative X-ray properties (refraction and scatter) in addition to X-ray absorption. In this research, poly(α-hydroxy-ester) scaffolds were synthesized and imaged by X-ray PC microcomputed tomography. The 3D images depicting the X-ray attenuation and phase-shifting properties were reconstructed from the measurement data. The scaffold structure could be imaged by X-ray PC in both cell culture conditions and within the tissue. The 3D images allowed for quantification of scaffold properties and automatic segmentation of scaffolds from the surrounding hard and soft tissues. These results provide evidence of the significant potential of techniques based on X-ray PC for imaging polymer scaffolds.

Framework for computing the spatial coherence effects of polycapillary x-ray optics.

Despite the extensive use of polycapillary x-ray optics for focusing and collimating applications, there remains a significant need for characterization of the coherence properties of the output wavefield. In this work, we present the first quantitative computational method for calculation of the spatial coherence effects of polycapillary x-ray optical devices. This method employs the coherent mode decomposition of an extended x-ray source, geometric optical propagation of individual wavefield modes through a polycapillary device, output wavefield calculation by ray data resampling onto a uniform grid, and the calculation of spatial coherence properties by way of the spectral degree of coherence.

Adaptation of a clustered lumpy background model for task-based image quality assessment in x-ray phase-contrast mammography.

PURPOSE: Since the introduction of clinical x-ray phase-contrast mammography (PCM), a technique that exploits refractive-index variations to create edge enhancement at tissue boundaries, a number of optimization studies employing physical image-quality metrics have been performed. Ideally, task-based assessment of PCM would have been conducted with human readers. These studies have been limited, however, in part due to the large parameter-space of PCM system configurations and the difficulty of employing expert readers for large-scale studies. It has been proposed that numerical observers can be used to approximate the statistical performance of human readers, thus enabling the study of task-based performance over a large parameter-space. METHODS: Methods are presented for task-based image quality assessment of PCM images with a numerical observer, the most significant of which is an adapted lumpy background from the conventional mammography literature that accounts for the unique wavefield propagation physics of PCM image formation and will be used with a numerical observer to assess image quality. These methods are demonstrated by performing a PCM task-based image quality study using a numerical observer. This study employs a signal-known-exactly, background-known-statistically Bayesian ideal observer method to assess the detectability of a calcification object in PCM images when the anode spot size and calcification diameter are varied. RESULTS: The first realistic model for the structured background in PCM images has been introduced. A numerical study demonstrating the use of this background model has compared PCM and conventional mammography detection of calcification objects. The study data confirm the strong PCM calcification detectability dependence on anode spot size. These data can be used to balance the trade-off between enhanced image quality and the potential for motion artifacts that comes with use of a reduced spot size and increased exposure time. CONCLUSIONS: A method has been presented for the incorporation of structured breast background data into task-based numerical observer assessment of PCM images. The method adapts conventional background simulation techniques to the wavefield propagation physics necessary for PCM imaging. This method is demonstrated with a simple detection task.

Analysis of ideal observer signal detectability in phase-contrast imaging employing linear shift-invariant optical systems.

Phase-contrast imaging methods exploit variations in an object's refractive index distribution to permit the visualization of subtle features that may have very similar optical absorption properties. Although phase-contrast is often viewed as being desirable in many biomedical applications, its relative influence on signal detectability when both absorption- and phase-contrast are present remains relatively unexplored. In this work, we investigate the ideal Bayesian observer signal-to-noise ratio in phase-contrast imaging for a signal-known-exactly/background-known exactly detection task involving a weak signal. We demonstrate that this signal detectability measure can be decomposed into three contributions that have distinct interpretations associated with the imaging physics.

Transport of intensity and spectrum for partially coherent fields.

Transport-of-intensity and transport-of-spectrum equations are derived using the coherent mode decomposition for paraxial fields having an arbitrary state of coherence. We give a simple example that demonstrates the difference between a partially coherent and a fully coherent transport of intensity or spectrum. The results presented here may be used to estimate the intensity response in a variety of phase-contrast imaging modalities and may form the basis for improved phase-retrieval techniques.

Optical coherence tomography: the intraoperative assessment of lymph nodes in breast cancer.

During breast-conserving surgeries, axillary lymph nodes draining from the primary tumor site are removed for disease staging. Although a high number of lymph nodes are often resected during sentinel and lymph-node dissections, only a relatively small percentage of nodes are found to be metastatic, a fact that must be weighed against potential complications such as lymphedema. Without a real-time in vivo or in situ intraoperative imaging tool to provide a microscopic assessment of the nodes, postoperative paraffin section histopathological analysis currently remains the gold standard in assessing the status of lymph nodes. This paper investigates the use of optical coherence tomography (OCT), a high-resolution real-time microscopic optical-imaging technique, for the intraoperative ex vivo imaging and assessment of axillary lymph nodes. Normal (13), reactive (1), and metastatic (3) lymph nodes from 17 human patients with breast cancer were imaged intraoperatively with OCT. These preliminary clinical studies have identified scattering changes in the cortex, relative to the capsule, which can be used to differentiate normal from reactive and metastatic nodes. These optical scattering changes are correlated with inflammatory and immunological changes observed in the follicles and germinal centers. These results suggest that intraoperative OCT has the potential to assess the real-time node status in situ, without having to physically resect and histologically process specimens to visualize microscopic features.

Intraoperative evaluation of breast tumor margins with optical coherence tomography.

As breast cancer screening rates increase, smaller and more numerous lesions are being identified earlier, leading to more breast-conserving surgical procedures. Achieving a clean surgical margin represents a technical challenge with important clinical implications. Optical coherence tomography (OCT) is introduced as an intraoperative high-resolution imaging technique that assesses surgical breast tumor margins by providing real-time microscopic images up to 2 mm beneath the tissue surface. In a study of 37 patients split between training and study groups, OCT images covering 1 cm(2) regions were acquired from surgical margins of lumpectomy specimens, registered with ink, and correlated with corresponding histologic sections. A 17-patient training set used to establish standard imaging protocols and OCT evaluation criteria showed that areas of higher scattering tissue with a heterogeneous pattern were indicative of tumor cells and tumor tissue in contrast to lower scattering adipocytes found in normal breast tissue. The remaining 20 patients were enrolled into the feasibility study. Of these lumpectomy specimens, 11 were identified with a positive or close surgical margin and 9 were identified with a negative margin under OCT. Based on histologic findings, 9 true positives, 9 true negatives, 2 false positives, and 0 false negatives were found, yielding a sensitivity of 100% and specificity of 82%. These results show the potential of OCT as a real-time method for intraoperative margin assessment in breast-conserving surgeries.

Clinical feasibility of microscopically-guided breast needle biopsy using a fiber-optic probe with computer-aided detection.

Needle biopsy of small or nonpalpable breast lesions has a high nondiagnostic sampling rate even when needle position is guided by stereotaxis or ultrasound. We assess the feasibility of using a near-infrared fiber optic probe and computer-aided detection for the microscopic guidance of needle breast biopsy procedures. Specimens from nine consented patients undergoing breast-conserving surgery were assessed intraoperatively using a needle device with an integrated fiber-optic probe capable of assessing two physical tissue properties highly correlated to pathology. Immediately following surgical resection, specimens were probed by inserting the optical biopsy needle device into the tissue, simulating the procedure used to position standard biopsy needles. Needle positions were marked and correlated with histology, which verified measurements obtained from 58 needle positions, including 40 in adipose and 18 in tumor tissue. This study yielded tissue classifications based on measurement of optical refractive index and scattering. Confidence-rating schemes yielded combined sensitivity of 89% (16/18) and specificity of 78% (31/40). Refractive index tests alone identified tumor tissue with a sensitivity of 83% (15/18) and specificity of 75% (30/40). Scattering profiles independently identified tumor tissue with a sensitivity of 61% (11/18) and specificity of 60% (24/40). These results show that a biopsy needle with an integrated fiber optic probe can be used to identify breast tumor tissue for sampling. Integration of this probe into current practices offers the potential to reduce nondiagnostic sampling rates by directly evaluating in situ microscopic tissue properties in real-time, before removal.

Group refractive index reconstruction with broadband interferometric confocal microscopy.

We propose a novel method of measuring the group refractive index of biological tissues at the micrometer scale. The technique utilizes a broadband confocal microscope embedded into a Mach-Zehnder interferometer, with which spectral interferograms are measured as the sample is translated through the focus of the beam. The method does not require phase unwrapping and is insensitive to vibrations in the sample and reference arms. High measurement stability is achieved because a single spectral interferogram contains all the information necessary to compute the optical path delay of the beam transmitted through the sample. Included are a physical framework defining the forward problem, linear solutions to the inverse problem, and simulated images of biologically relevant phantoms.

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.