Assessment Of Breast Tumor Margins Research Articles

Analysis of Deep Ultraviolet Fluorescence Images for Intraoperative Breast Tumor Margin Assessment.

Positive margin status after breast-conserving surgery (BCS) is a predictor of higher rates of local recurrence. Intraoperative margin assessment aims to achieve negative surgical margin status at the first operation, thus reducing the re-excision rates that are usually associated with potential surgical complications, increased medical costs, and mental pressure on patients. Microscopy with ultraviolet surface excitation (MUSE) can rapidly image tissue surfaces with subcellular resolution and sharp contrasts by utilizing the nature of the thin optical sectioning thickness of deep ultraviolet light. We have previously imaged 66 fresh human breast specimens that were topically stained with propidium iodide and eosin Y using a customized MUSE system. To achieve objective and automated assessment of MUSE images, a machine learning model is developed for binary (tumor vs. normal) classification of obtained MUSE images. Features extracted by texture analysis and pre-trained convolutional neural networks (CNN) have been investigated for sample descriptions. A sensitivity, specificity, and accuracy better than 90% have been achieved for detecting tumorous specimens. The result suggests the potential of MUSE with machine learning being utilized for intraoperative margin assessment during BCS.

Rapid assessment of breast tumor margins using deep ultraviolet fluorescence scanning microscopy.

.Significance: Re-excision rates for women with invasive breast cancer undergoing breast conserving surgery (or lumpectomy) have decreased in the past decade but remain substantial. This is mainly due to the inability to assess the entire surface of an excised lumpectomy specimen efficiently and accurately during surgery.Aim: The goal of this study was to develop a deep-ultraviolet scanning fluorescence microscope (DUV-FSM) that can be used to accurately and rapidly detect cancer cells on the surface of excised breast tissue.Approach: A DUV-FSM was used to image the surfaces of 47 (31 malignant and 16 normal/benign) fresh breast tissue samples stained in propidium iodide and eosin Y solutions. A set of fluorescence images were obtained from each sample using low magnification () and fully automated scanning. The images were stitched to form a color image. Three nonmedical evaluators were trained to interpret and assess the fluorescence images. Nuclear–cytoplasm ratio (N/C) was calculated and used for tissue classification.Results: DUV-FSM images a breast sample with subcellular resolution at a speed of . Fluorescence images show excellent visual contrast in color, tissue texture, cell density, and shape between invasive carcinomas and their normal counterparts. Visual interpretation of fluorescence images by nonmedical evaluators was able to distinguish invasive carcinoma from normal samples with high sensitivity (97.62%) and specificity (92.86%). Using N/C alone was able to differentiate patch-level invasive carcinoma from normal breast tissues with reasonable sensitivity (81.5%) and specificity (78.5%).Conclusions: DUV-FSM achieved a good balance between imaging speed and spatial resolution with excellent contrast, which allows either visual or quantitative detection of invasive cancer cells on the surfaces of a breast surgical specimen.

Abstract 1873: Intraoperative assessment of breast tumor margins using multimodal photoacoustic tomography (MarginPAT)

Abstract Radical mastectomies are progressively becoming a surgery of the past. Women today are increasingly opting for lumpectomies, a less invasive treatment option. Clinical data has shown no difference in survival or clinical outcomes between the two surgical groups in early stages of breast cancer. There is, however, an undesired outcome yet to be adequately addressed. Lumpectomies have, in some cases, failed to remove marginal malignant tumor cells left as a product from surgery. Following surgery, tumor biopsies are analyzed for marginal tumor cells. Biopsies are cut in, fixed, processed in a tissue processor, embedded into a paraffin block, and stained with H&E. After processing, presence of marginal cancerous tissue is determined by a pathologist. This process takes 3-5 days, ultimately requiring the patient to undergo reoperation if a positive margin is discovered. Presently, the reoperation rate is 20-30%. A device capable of imaging removed tissue to determine remaining marginal tumor during surgery would greatly reduce the reoperation rate. Multiple intraoperative imaging tools existing or are emerging for breast tumor margin assessment. Current devices fail to meet acceptable clinical specifications due to either long procedure time (15 mins+), or low sensitivity (~70%), and low specificity (~68%). An unmet need exists in developing an intraoperative margin assessment device that is rapid, sensitive, capable of measuring the entire tissue surface, and images a depth of 2mm+. The MarginPAT device presents a multi-modal photoacoustic/ultrasound imaging system for rapid and highly sensitive breast cancer margin assessment. After surgical removal of tumor, tissue is inserted, via cartridge, into MarginPAT for imaging. An automatic scan (<3 mins) provides 3D images of the excised tissue, providing margin status. Such immediate feedback allows the surgeon to re-operate immediately or allow the patient to return home based on the marginal results from MarginPAT. Our preliminary study on 40 patient samples, showed 93% sensitivity and 90% specificity in margin assessment by precise localization of adipose tissue using PA imaging and further RF spectrum analysis of ultrasound signaling. Other than the superior sensitivity and specificity, the unique features of MarginPAT include deep tissue sensing (>3 mm) and high surface scanning speed (20 cm2/per min). These achieved specifications meet the needs of intraoperative margin assessment, which are expected to surpass similar platforms. More importantly, MarginPAT supports conventional ultrasound imaging, allowing for use in ultrasound-guided wire localization. These multimodality functions allow MarginPAT to be utilized in multiple fields of breast cancer diseases, another advantage over other platforms. In conclusion, current clinical results show through both verification and validation that MarginPAT competently performs in the operating room. Citation Format: Kyle McElyea, George Sandusky, Rui Li, Lu Lan, Ji-Xin Cheng, Linda K. Han, Pu Wang. Intraoperative assessment of breast tumor margins using multimodal photoacoustic tomography (MarginPAT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1873. doi:10.1158/1538-7445.AM2017-1873

Abstract P1-16-05: Intra-operative imaging of surgical margins in breast conserving surgery using localized tissue dielectric response

Abstract INTRODUCTION: Breast conserving surgery (BCS) removes the tumor with a surrounding margin of normal breast tissue, and to reduce local recurrence clear margins are needed. Involved margins identified by pathology several days later require a second operation. Between 20-40% of BCS patients require re-excision. There is a clear unmet clinical need for effective and efficacious intra-operative, real time assessment of breast tumor margins. The handheld, battery operated TOUCH Imaging device displays spatially resolved images of margins based on tissue spectral dielectric response. This novel imaging device enables surgeons to assess in real-time the status of the excised tissue margins. AIM: To determine the efficacy and safety of TOUCH Imaging device as used by surgeons during BCS and its health economics. METHOD: The 1st study of the TOUCH Imaging device was run in the USA with freshly excised breast tissue as part of BCS. The study was run in the pathology lab to determine the efficacy and safety of using the device. The efficacy was determined by surgeons interpretation of device generated margin images compared with permanent section pathology. A follow up study in the UK is currently underway. Surgeons were trained to use the device in the operating room on freshly excised tissue. The imaging was performed after the surgery was completed with no subsequent intervention. The margins were scored as clear or positive and the localization of the abnormality was marked using special ink for specific pathology attention. In the learning phase 18 BCS cases were performed. The main study is being run in two phases and is currently underway. Phase-1 aimed to determine the accuracy of the device when used by individual surgeons in real time had been completed. Analysis is on the way, and phase-2 will start following the confirmation of device accuracy and will involve using the device to direct intra-operatively which margins require further excision. Phase 2 will provide insight to the potential health economics of using the TOUCH Imaging device. RESULTS: Data from the first study in the USA on 50 BCS specimens, imaging 214 distinct margins are shown in the table. The sensitivity of the device is high; the false negative rate low, the specificity and false positive rates are satisfactory. TOUCH Compared to Permanent Section Pathology Positive PathologyNegative PathologyPositive TOUCH66 ( 30.8%)50 (23.4%))Negative TOUCH5 ( 2.3%)93 ( 43.5%) % (95% CI)% (90% CI)Sensitivity92.96 (84.33, 97.67)92.96 ( 85.76, 97.18)Specificity65.03 (56.62, 72.81)65.03 (57.93, 71.66)False Positive Rate34.97 ( 27.19, 43.38)34.97 (28.34, 42.07)False negative Rate7.04 ( 2.33, 15.67)7.04 ( 2.82, 14.24) The training study in the UK on 18 BCS specimen results showed 50% True Positive, 39% True Negative, 11% False Positive, 6% False Negative rates. There were 5 cases (28%) of positive margins < 1 mm and the device images identified 4 with 1 case (6%) being missed. Results from the ongoing study will be presented. CONCLUSIONS: • The TOUCH Imaging device is safe and efficacious. • It is easy for surgeons to use in the operating room. • This device has the potential to reduce BCS re-operation rate. Citation Format: J Michael Dixon, Lorna Renshaw, Oliver Young, Dhananjay Kulkarni, Talha Saleem, Moshe Sarfaty, Ramaswamy Sreenivasam, Catherine Kusnick, Jeremy Thomas. Intra-operative imaging of surgical margins in breast conserving surgery using localized tissue dielectric response [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-16-05.

Assessing breast tumor margin by multispectral photoacoustic tomography.

An unmet need exists in high-speed and highly-sensitive intraoperative assessment of breast cancer margin during conservation surgical procedures. Here, we demonstrate a multispectral photoacoustic tomography system for breast tumor margin assessment using fat and hemoglobin as contrasts. This system provides ~3 mm tissue depth and ~125 μm axial resolution. The results agreed with the histological findings. A high sensitivity in margin assessment was accomplished, which opens a compelling way to intraoperative margin assessment.

Advancing Optical Imaging for Breast Margin Assessment: An Analysis of Excisional Time, Cautery, and Patent Blue Dye on Underlying Sources of Contrast

Breast conserving surgery (BCS) is a recommended treatment for breast cancer patients where the goal is to remove the tumor and a surrounding rim of normal tissue. Unfortunately, a high percentage of patients return for additional surgeries to remove all of the cancer. Post-operative pathology is the gold standard for evaluating BCS margins but is limited due to the amount of tissue that can be sampled. Frozen section analysis and touch-preparation cytology have been proposed to address the surgical needs but also have sampling limitations. These issues represent an unmet clinical need for guidance in resecting malignant tissue intra-operatively and for pathological sampling. We have developed a quantitative spectral imaging device to examine margins intra-operatively. The context in which this technology is applied (intra-operative or post-operative setting) is influenced by time after excision and surgical factors including cautery and the presence of patent blue dye (specifically Lymphazurin™, used for sentinel lymph node mapping). Optical endpoints of hemoglobin ([THb]), fat ([β-carotene]), and fibroglandular content via light scattering (<µs’>) measurements were quantified from diffuse reflectance spectra of lumpectomy and mastectomy specimens using a Monte Carlo model. A linear longitudinal mixed-effects model was used to fit the optical endpoints for the cautery and kinetics studies. Monte Carlo simulations and tissue mimicking phantoms were used for the patent blue dye experiments. [THb], [β-carotene], and <µs’> were affected by <3.3% error with <80 µM of patent blue dye. The percent change in [β-carotene], <µs’>, and [β-carotene]/<µs’> was <14% in 30 minutes, while percent change in [THb] was >40%. [β-carotene] and [β-carotene]/<µs’> were the only parameters not affected by cautery. This work demonstrates the importance of understanding the post-excision kinetics of ex-vivo tissue and the presence of cautery and patent blue dye for breast tumor margin assessment, to accurately interpret data and exploit underling sources of contrast.

Performance metrics of an optical spectral imaging system for intra-operative assessment of breast tumor margins

As many as 20-70% of patients undergoing breast conserving surgery require repeat surgeries due to a close or positive surgical margin diagnosed post-operatively [1]. Currently there are no widely accepted tools for intra-operative margin assessment which is a significant unmet clinical need. Our group has developed a first-generation optical visible spectral imaging platform to image the molecular composition of breast tumor margins and has tested it clinically in 48 patients in a previously published study [2]. The goal of this paper is to report on the performance metrics of the system and compare it to clinical criteria for intra-operative tumor margin assessment. The system was found to have an average signal to noise ratio (SNR) >100 and <15% error in the extraction of optical properties indicating that there is sufficient SNR to leverage the differences in optical properties between negative and close/positive margins. The probe had a sensing depth of 0.5-2.2 mm over the wavelength range of 450-600 nm which is consistent with the pathologic criterion for clear margins of 0-2 mm. There was <1% cross-talk between adjacent channels of the multi-channel probe which shows that multiple sites can be measured simultaneously with negligible cross-talk between adjacent sites. Lastly, the system and measurement procedure were found to be reproducible when evaluated with repeated measures, with a low coefficient of variation (<0.11). The only aspect of the system not optimized for intra-operative use was the imaging time. The manuscript includes a discussion of how the speed of the system can be improved to work within the time constraints of an intra-operative setting.

Optical assessment of tumor resection margins in the breast.

Breast conserving surgery, in which the breast tumor and surrounding normal tissue are removed, is the primary mode of treatment for invasive and in situ carcinomas of the breast, conditions that affect nearly 200,000 women annually. Of these nearly 200,000 patients who undergo this surgical procedure, between 20-70% of them may undergo additional surgeries to remove tumor that was left behind in the first surgery, due to the lack of intra-operative tools which can detect whether the boundaries of the excised specimens are free from residual cancer. Optical techniques have many attractive attributes which may make them useful tools for intra-operative assessment of breast tumor resection margins. In this manuscript, we discuss clinical design criteria for intra-operative breast tumor margin assessment, and review optical techniques appied to this problem. In addition, we report on the development and clinical testing of quantitative diffuse reflectance imaging (Q-DRI) as a potential solution to this clinical need. Q-DRI is a spectral imaging tool which has been applied to 56 resection margins in 48 patients at Duke University Medical Center. Clear sources of contrast between cancerous and cancer-free resection margins were identified with the device, and resulted in an overall accuracy of 75% in detecting positive margins.

Rapid Optical Imaging of Breast Tumor Margins: Final Results from a 100-Patient Clinical Study.

Abstract Background: Increasing attention has been given to the surgical margin status in primary breast conserving therapy (BCT) due to reports which indicate that 20-70% of patients undergoing BCT must undergo multiple surgeries for complete tumor resection. For the past 4 years, our multidisciplinary group has been working to address this clinical need via the development of an optically-based intraoperative breast tumor margin assessment device. This device, based on diffuse reflectance spectroscopy, is sensitive to biochemical and morphological changes associated with cancer and has a sensing depth of 1-2 mm which is compatible with widely used criteria for cancer-free margins. The device is capable of surveying the entire specimen surface intraoperatively in imaging mode. Here we report the results of a non-significant-risk study of the device in over 100 patients at Duke University Medical Center.Materials and Methods: Under an institutionally-approved protocol, we tested our device on consented patients undergoing a partial mastectomy at DukeUniversity Medical Center for invasive or in situ malignancies. Optical spectral images of tumor margins were recorded within 20 minutes of excision and converted into tissue compositional parameter maps that reflect the vascular density, fat content and cell density in the tissue. The pathologic status of the imaged margins was collected from standard post-operative surgical pathology reports. Intraoperative frozen section and touch prep analysis was not performed on these specimens. Margins were considered positive if residual malignancy was found within 2 mm of the tissue surface.Results and Discussion: BCT specimens from 121 patients have been imaged with the optical device. One to four margins were imaged on each BCT specimen. Data from 112 patients were retained for analysis (51 negative margins, and 47 margins containing cancer within 1mm). Images of negative margins from patients with at least one positive margin (9 patients) elsewhere on the specimen were excluded from analysis due to the potential for presence of margin positivity that was not identified pathologically. For each margin, a set of 8 tissue composition maps were generated, from which a set of 36 image-descriptive variables were obtained. Wilcoxon rank-sum tests were used to determine which of the variables best separated negative from positive margins. A predictive model was developed using conditional inference trees to identify the optimal partitions from all 36 image-descriptive variables. The model selected variables related to the light scattering properties, total hemoglobin content, and β-carotene content of the underlying tissue, which are related to tissue density and morphology, vascular volume, and fat content, respectively. This model resulted in a sensitivity of 80% for detecting cancer at the margin, a sensitivity of 73% for detecting residual disease within 1mm of the margin, and a specificity of 65%. These results are promising and a prospective validation trial of the device is under development. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5017.