Deep Learning Classification of Breast Cancer Tissue from Terahertz Imaging Through Wavelet Synchro-Squeezed Transformation and Transfer Learning.

Terahertz imaging and spectroscopy is an exciting technology that has the potential to provide insights in medical imaging. Prior research has leveraged statistical inference to classify tissue regions from terahertz images. To date, these approaches have shown that the segmentation problem is challenging for images of fresh tissue and for tumors that have invaded muscular regions. Artificial intelligence, particularly machine learning and deep learning, has been shown to improve performance in some medical imaging challenges. This paper builds on that literature by modifying a set of deep learning approaches to the challenge of classifying tissue regions of images captured by terahertz imaging and spectroscopy of freshly excised murine xenograft tissue. Our approach is to preprocess the images through a wavelet synchronous-squeezed transformation (WSST) to convert time-sequential terahertz data of each THz pixel to a spectrogram. Spectrograms are used as input tensors to a deep convolution neural network for pixel-wise classification. Based on the classification result of each pixel, a cancer tissue segmentation map is achieved. In experimentation, we adopt leave-one-sample-out cross-validation strategy, and evaluate our chosen networks and results using multiple metrics such as accuracy, precision, intersection, and size. The results from this experimentation demonstrate improvement in classification accuracy compared to statistical methods, an improvement to segmentation between muscle and cancerous regions in xenograft tumors, and identify areas to improve the imaging and classification methodology.

Hyperspectral terahertz imaging and optical clearance for cancer classification in breast tumor surgical specimen.

Purpose: We investigate the enhancement in terahertz (THz) images of freshly excised breast tumors upon treatment with an optical clearance agent. The hyperspectral imaging and spectral classifications are used to quantitatively demonstrate the image enhancement. Glycerol solution with 60% concentration is applied to excised breast tumor specimens for various time durations to investigate the effectiveness on image enhancement. Approach: THz reflection spectroscopy is utilized to obtain the absorption coefficient and the index of refraction of untreated and glycerol-treated tissues at each frequency up to 3 THz. Two classifiers, spectral angular mapping (SAM) based on several kernels and Euclidean minimum distance (EMD) are implemented to evaluate the effectiveness of the treatment. The testing raw data is obtained from five breast cancer specimens: two untreated specimens and three specimens treated with glycerol solution for 20, 40, or 60 min. All tumors used in the testing data have healthy tissues adjacent to cancerous ones consistent with the challenge faced in lumpectomy surgeries. Results: The glycerol-treated tissues showed a decrease in the absorption coefficients compared with untreated tissues, especially as the period of treatment increased. Although the sensitivity metric of the classifier presented higher values in the untreated tissues compared with the treated ones, the specificity and accuracy metrics demonstrated higher values for the treated tissues compared with the untreated ones. Conclusions: The biocompatible glycerol solution is a potential optical clearance agent in THz imaging while keeping the histopathology imaging intact. The SAM technique provided a good classification of cancerous tissues despite the small amount of cancer in the training data (only 7%). The SAM exponential kernel and EMD presented classification accuracy of ∼ 80 % to 85% compared with linear and polynomial kernels that provided accuracy ranging from 70% to 80%. Overall, glycerol treatment provides a potential improvement in cancer classification in freshly excised breast tumors.

Mammary tumors in Sprague Dawley rats induced by N-ethyl-N-nitrosourea for evaluating terahertz imaging of breast cancer.

Purpose: The objective of this study is to quantitatively evaluate terahertz (THz) imaging for differentiating cancerous from non-cancerous tissues in mammary tumors developed in response to injection of N-ethyl-N-nitrosourea (ENU) in Sprague Dawley rats. Approach: While previous studies have investigated the biology of mammary tumors of this model, the current work is the first study to employ an imaging modality to visualize these tumors. A pulsed THz imaging system is utilized to experimentally collect the time-domain reflection signals from each pixel of the rat's excised tumor. A statistical segmentation algorithm based on the expectation-maximization (EM) classification method is implemented to quantitatively assess the obtained THz images. The model classification of cancer is reported in terms of the receiver operating characteristic (ROC) curves and the areas under the curves. Results: The obtained low-power microscopic images of 17 ENU-rat tumor sections exhibited the presence of healthy connective tissue adjacent to cancerous tissue. The results also demonstrated that high reflection THz signals were received from cancerous compared with non-cancerous tissues. Decent tumor classification was achieved using the EM method with values ranging from 83% to 96% in fresh tissues and 89% to 96% in formalin-fixed paraffin-embedded tissues. Conclusions: The proposed ENU breast tumor model of Sprague Dawley rats showed a potential to obtain cancerous tissues, such as human breast tumors, adjacent to healthy tissues. The implemented EM classification algorithm quantitatively demonstrated the ability of THz imaging in differentiating cancerous from non-cancerous tissues.

Terahertz Imaging and Characterization Protocol for Freshly Excised Breast Cancer Tumors.

This manuscript presents a protocol to handle, characterize, and image freshly excised human breast tumors using pulsed terahertz imaging and spectroscopy techniques. The protocol involves terahertz transmission mode at normal incidence and terahertz reflection mode at an oblique angle of 30°. The collected experimental data represent time domain pulses of the electric field. The terahertz electric field signal transmitted through a fixed point on the excised tissue is processed, through an analytical model, to extract the refractive index and absorption coefficient of the tissue. Utilizing a stepper motor scanner, the terahertz emitted pulse is reflected from each pixel on the tumor providing a planar image of different tissue regions. The image can be presented in time or frequency domain. Furthermore, the extracted data of the refractive index and absorption coefficient at each pixel are utilized to provide a tomographic terahertz image of the tumor. The protocol demonstrates clear differentiation between cancerous and healthy tissues. On the other hand, not adhering to the protocol can result in noisy or inaccurate images due to the presence of air bubbles and fluid remains on the tumor surface. The protocol provides a method for surgical margins assessment of breast tumors.

Breast Cancer Detection with Low-dimension Ordered Orthogonal Projection in Terahertz Imaging.

This paper proposes a new dimension reduction algorithm based on low-dimension ordered orthogonal projection (LOOP), which is used for cancer detection with terahertz (THz) images of freshly excised human breast cancer tissues. A THz image can be represented by a data cube with each pixel containing a high dimension spectrum vector covering several THz frequencies, where each frequency represents a different dimension in the vector. The proposed algorithm projects the high-dimension spectrum vector of each pixel within the THz image into a low-dimension subspace that contains the majority of the unique features embedded in the image. The low-dimension subspace is constructed by sequentially identifying its orthonormal basis vectors, such that each newly chosen basis vector represents the most unique information not contained by existing basis vectors. A multivariate Gaussian mixture model is used to represent the statistical distributions of the low-dimension feature vectors obtained from the proposed dimension reduction algorithm. The model parameters are iteratively learned by using unsupervised learning methods such as Markov chain Monte Carlo or expectation maximization, and the results are used to classify the various regions within a tumor sample. Experiment results demonstrate that the proposed method achieves apparent performance improvement in human breast cancer tissue over existing approaches such as one-dimension Markov chain Monte Carlo. The results confirm that the dimension reduction algorithm presented in this paper is a promising technique for breast cancer detection with THz images, and the classification results present a good correlation with respect to the histopathology results of the analyzed samples.

Terahertz tomographic imaging of freshly excised human breast tissues.

Terahertz imaging and spectroscopy characterization of freshly excised breast cancer tumors are presented in the range 0.15 to 3.5 THz. Cancerous breast tissues were obtained from partial or full removal of malignant tumors while healthy breast tissues were obtained from breast reduction surgeries. The reflection spectroscopy to obtain the refractive index and absorption coefficient is performed on experimental data at each pixel of the tissue, forming tomographic images. The transmission spectroscopy of the refractive index and absorption coefficient are retrieved from experimental data at few tissue points. The average refractive index and absorption coefficients for cancer, fat, and collagen tissue regions are compared between transmission and reflection modes. The reflection mode offers the advantage of retrieving the electrical properties across a significantly greater number of points without the need for sectioning or altering the freshly excised tissue as in the transmission mode. The terahertz spectral power images and the tomographic images demonstrated good qualitative comparison with pathology.

Cancer detection in excised breast tumors using terahertz imaging and spectroscopy.

Terahertz imaging and spectroscopy has demonstrated a potential for differentiating tissue types of excised breast cancer tumors. Pulsed terahertz technology provides a broadband frequency range from 0.1 THz to 4 THz for detecting cancerous tissue. Tumor tissue types of interest include cancer typically manifested as infiltrating ductal or lobular carcinomas, fibro-glandular (healthy connective tissues) and fat. In this work, images of breast tumors excised from human and animal models are reviewed. In addition to alternate fresh tissues, breast cancer tissue phantoms are developed to further evaluate terahertz imaging and the potential use of contrast agents. Terahertz results are successfully validated with pathology images, showing strong differentiation between cancerous and healthy tissues for all freshly excised tissues and types. The advantages, challenges and limitations of THz imaging of breast cancer are discussed.

Pulsed Terahertz Reflection Imaging of tumors in a spontaneous model of breast cancer.

We report the use of reflection-mode terahertz (THz) imaging in a transgenic mouse model of breast cancer. Unlike tumor xenografts that are grown from established cell lines, these tumors were spontaneously generated in the mammary fat pad of mice, and are a better representation of human breast cancer. THz imaging results from 7 tumors that recapitulate the compartmental complexity of breast cancer are presented here. Imaging was first performed on freshly excised tumors within an hour of excision and then repeated after fixation with formalin and paraffin. These THz images were then compared with histopathology to determine reflection-mode signals from specific regions within tumor. Our results demonstrate that the THz signal was consistently higher in cancerous tissue compared with fat, muscle, and fibrous tissue. Almost all tumors presented in this work demonstrated advanced stages where cancer infiltrated other tissues like fat and fibrous stroma. As the first known THz investigation in a transgenic model, these results hold promise for THz imaging at different stages of breast cancer.