. 2016 Jul; 33:170-175.
doi: 10.1016/

Image analysis and machine learning in digital pathology: Challenges and opportunities

Anant Madabhushi 1 George Lee 2 
  • PMID: 27423409
  •     27 References
  •     126 citations


With the rise in whole slide scanner technology, large numbers of tissue slides are being scanned and represented and archived digitally. While digital pathology has substantial implications for telepathology, second opinions, and education there are also huge research opportunities in image computing with this new source of "big data". It is well known that there is fundamental prognostic data embedded in pathology images. The ability to mine "sub-visual" image features from digital pathology slide images, features that may not be visually discernible by a pathologist, offers the opportunity for better quantitative modeling of disease appearance and hence possibly improved prediction of disease aggressiveness and patient outcome. However the compelling opportunities in precision medicine offered by big digital pathology data come with their own set of computational challenges. Image analysis and computer assisted detection and diagnosis tools previously developed in the context of radiographic images are woefully inadequate to deal with the data density in high resolution digitized whole slide images. Additionally there has been recent substantial interest in combining and fusing radiologic imaging and proteomics and genomics based measurements with features extracted from digital pathology images for better prognostic prediction of disease aggressiveness and patient outcome. Again there is a paucity of powerful tools for combining disease specific features that manifest across multiple different length scales. The purpose of this review is to discuss developments in computational image analysis tools for predictive modeling of digital pathology images from a detection, segmentation, feature extraction, and tissue classification perspective. We discuss the emergence of new handcrafted feature approaches for improved predictive modeling of tissue appearance and also review the emergence of deep learning schemes for both object detection and tissue classification. We also briefly review some of the state of the art in fusion of radiology and pathology images and also combining digital pathology derived image measurements with molecular "omics" features for better predictive modeling. The review ends with a brief discussion of some of the technical and computational challenges to be overcome and reflects on future opportunities for the quantitation of histopathology.

Keywords: Deep learning; Digital pathology; Omics; Radiology.

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Riccardo Scodellaro, Margaux Bouzin, +5 authors, Laura Sironi.
Front Oncol, 2019 Jul 06; 9. PMID: 31275857    Free PMC article.
Physician perspectives on integration of artificial intelligence into diagnostic pathology.
Shihab Sarwar, Anglin Dent, +4 authors, Phedias Diamandis.
NPJ Digit Med, 2019 Jul 16; 2. PMID: 31304375    Free PMC article.
The revolving door for AI and pathologists-docendo discimus?
Simone L Van Es, Anant Madabhushi.
J Med Artif Intell, 2019 Aug 03; 2. PMID: 31372599    Free PMC article.
A bird's-eye view of deep learning in bioimage analysis.
Erik Meijering.
Comput Struct Biotechnol J, 2020 Oct 01; 18. PMID: 32994890    Free PMC article.
Recognition of Cutaneous Melanoma on Digitized Histopathological Slides via Artificial Intelligence Algorithm.
Francesco De Logu, Filippo Ugolini, +6 authors, Marco Laurino.
Front Oncol, 2020 Oct 06; 10. PMID: 33014803    Free PMC article.
Generating Region of Interests for Invasive Breast Cancer in Histopathological Whole-Slide-Image.
Shreyas Malakarjun Patil, Li Tong, May D Wang.
Proc COMPSAC, 2020 Oct 09; 2020. PMID: 33029594    Free PMC article.
Morphometric Cell Classification for Single-Cell MALDI-Mass Spectrometry Imaging.
Klára Ščupáková, Frédéric Dewez, +2 authors, Benjamin Balluff.
Angew Chem Int Ed Engl, 2020 Jul 16; 59(40). PMID: 32668069    Free PMC article.
Optimization of Deep Learning Network Parameters Using Uniform Experimental Design for Breast Cancer Histopathological Image Classification.
Cheng-Jian Lin, Shiou-Yun Jeng.
Diagnostics (Basel), 2020 Sep 05; 10(9). PMID: 32882935    Free PMC article.
Immune contexture analysis in immuno-oncology: applications and challenges of multiplex fluorescent immunohistochemistry.
Reshma Shakya, Tam Hong Nguyen, Nigel Waterhouse, Rajiv Khanna.
Clin Transl Immunology, 2020 Oct 20; 9(10). PMID: 33072322    Free PMC article.
Integrative Data Augmentation with U-Net Segmentation Masks Improves Detection of Lymph Node Metastases in Breast Cancer Patients.
Yong Won Jin, Shuo Jia, Ahmed Bilal Ashraf, Pingzhao Hu.
Cancers (Basel), 2020 Oct 16; 12(10). PMID: 33053723    Free PMC article.
PyHIST: A Histological Image Segmentation Tool.
Manuel Muñoz-Aguirre, Vasilis F Ntasis, Santiago Rojas, Roderic Guigó.
PLoS Comput Biol, 2020 Oct 20; 16(10). PMID: 33075075    Free PMC article.
Attitudes Toward Artificial Intelligence Within Dermatopathology: An International Online Survey.
Sam Polesie, Phillip H McKee, +4 authors, John Paoli.
Front Med (Lausanne), 2020 Nov 17; 7. PMID: 33195357    Free PMC article.
The Role of Telehealth During the COVID-19 Pandemic Across the Interdisciplinary Cancer Team: Implications for Practice.
Catherine Paterson, Rachel Bacon, +10 authors, Sandra C Hayes.
Semin Oncol Nurs, 2020 Nov 22; 36(6). PMID: 33218886    Free PMC article.
Breast cancer outcome prediction with tumour tissue images and machine learning.
Riku Turkki, Dmitrii Byckhov, +8 authors, Nina Linder.
Breast Cancer Res Treat, 2019 May 24; 177(1). PMID: 31119567    Free PMC article.
Lateral lymph node dissection for low rectal cancer: Is it necessary?
Niki Christou, Jeremy Meyer, +2 authors, Nicolas Christian Buchs.
World J Gastroenterol, 2019 Sep 10; 25(31). PMID: 31496614    Free PMC article.
Deep neural network models for computational histopathology: A survey.
Chetan L Srinidhi, Ozan Ciga, Anne L Martel.
Med Image Anal, 2020 Oct 14; 67. PMID: 33049577    Free PMC article.
Pathological Cluster Identification by Unsupervised Analysis in 3,822 UK Biobank Cardiac MRIs.
Qiao Zheng, Hervé Delingette, +2 authors, Nicholas Ayache.
Front Cardiovasc Med, 2020 Dec 15; 7. PMID: 33313075    Free PMC article.
Deep learning networks reflect cytoarchitectonic features used in brain mapping.
Kai Kiwitz, Christian Schiffer, +2 authors, Katrin Amunts.
Sci Rep, 2020 Dec 18; 10(1). PMID: 33328511    Free PMC article.
Digital image analysis in pathologist-selected regions of interest predicts survival more accurately than whole-slide analysis: a direct comparison study in 153 gastric carcinomas.
You Jeong Heo, Taebum Lee, +6 authors, Kyoung-Mee Kim.
J Pathol Clin Res, 2020 Sep 05; 7(1). PMID: 32885920    Free PMC article.
The ImageJ ecosystem: Open-source software for image visualization, processing, and analysis.
Alexandra B Schroeder, Ellen T A Dobson, +3 authors, Kevin W Eliceiri.
Protein Sci, 2020 Nov 10; 30(1). PMID: 33166005    Free PMC article.
Artificial Intelligence in Dermatology: A Practical Introduction to a Paradigm Shift.
Bell R Eapen.
Indian Dermatol Online J, 2020 Dec 22; 11(6). PMID: 33344334    Free PMC article.
Potential for Standardization and Automation for Pathology and Endoscopy in Inflammatory Bowel Disease.
Sana Syed, Ryan W Stidham.
Inflamm Bowel Dis, 2020 Sep 02; 26(10). PMID: 32869844    Free PMC article.
Artificial intelligence and computational pathology.
Miao Cui, David Y Zhang.
Lab Invest, 2021 Jan 18; 101(4). PMID: 33454724    Free PMC article.
Can Contrast-Enhanced Ultrasound Increase or Predict the Success Rate of Testicular Sperm Aspiration in Patients With Azoospermia?
Heng Xue, Shou-Yang Wang, Li-Gang Cui, Kai Hong.
AJR Am J Roentgenol, 2019 Feb 27;. PMID: 30807223    Free PMC article.
Automated immunohistochemical assessment ability to evaluate estrogen and progesterone receptor status compared with quantitative reverse transcription-polymerase chain reaction in breast carcinoma patients.
Taesung Jeon, Aeree Kim, Chungyeul Kim.
J Pathol Transl Med, 2020 Dec 03; 55(1). PMID: 33260290    Free PMC article.
Harnessing non-destructive 3D pathology.
Jonathan T C Liu, Adam K Glaser, +4 authors, Anant Madabhushi.
Nat Biomed Eng, 2021 Feb 17; 5(3). PMID: 33589781    Free PMC article.
Image-based consensus molecular subtype (imCMS) classification of colorectal cancer using deep learning.
Korsuk Sirinukunwattana, Enric Domingo, +22 authors, S:CORT consortium.
Gut, 2020 Jul 22; 70(3). PMID: 32690604    Free PMC article.
Boosted EfficientNet: Detection of Lymph Node Metastases in Breast Cancer Using Convolutional Neural Networks.
Jun Wang, Qianying Liu, +2 authors, Hefeng Zhou.
Cancers (Basel), 2021 Feb 11; 13(4). PMID: 33562232    Free PMC article.
Hidden Variables in Deep Learning Digital Pathology and Their Potential to Cause Batch Effects: Prediction Model Study.
Max Schmitt, Roman Christoph Maron, +14 authors, Titus Josef Brinker.
J Med Internet Res, 2021 Feb 03; 23(2). PMID: 33528370    Free PMC article.
Human-interpretable image features derived from densely mapped cancer pathology slides predict diverse molecular phenotypes.
James A Diao, Jason K Wang, +19 authors, Amaro Taylor-Weiner.
Nat Commun, 2021 Mar 14; 12(1). PMID: 33712588    Free PMC article.
Association of the imaging characteristics of desmoplasia on digital breast tomosynthesis and the Ki-67 proliferation index in invasive breast cancer.
Kristina Samaržija, Zoran Jurjević.
Croat Med J, 2021 Mar 05; 62(1). PMID: 33660962    Free PMC article.
The frontier of live tissue imaging across space and time.
Qiang Huang, Aliesha Garrett, +4 authors, Xiling Shen.
Cell Stem Cell, 2021 Apr 03; 28(4). PMID: 33798422    Free PMC article.
Quantitative X-ray phase contrast computed tomography with grating interferometry : Biomedical applications of quantitative X-ray grating-based phase contrast computed tomography.
Lorenz Birnbacher, Eva-Maria Braig, +2 authors, Julia Herzen.
Eur J Nucl Med Mol Imaging, 2021 Apr 14;. PMID: 33846846
A deep learning model for the classification of indeterminate lung carcinoma in biopsy whole slide images.
Fahdi Kanavati, Gouji Toyokawa, +6 authors, Masayuki Tsuneki.
Sci Rep, 2021 Apr 16; 11(1). PMID: 33854137    Free PMC article.
Computational Image Analysis Identifies Histopathological Image Features Associated With Somatic Mutations and Patient Survival in Gastric Adenocarcinoma.
Jun Cheng, Yuting Liu, +7 authors, Jie Zhang.
Front Oncol, 2021 Apr 20; 11. PMID: 33869007    Free PMC article.
Histopathological Classification of Canine Cutaneous Round Cell Tumors Using Deep Learning: A Multi-Center Study.
Massimo Salvi, Filippo Molinari, +7 authors, Luca Aresu.
Front Vet Sci, 2021 Apr 20; 8. PMID: 33869320    Free PMC article.
A deep learning model to detect pancreatic ductal adenocarcinoma on endoscopic ultrasound-guided fine-needle biopsy.
Yoshiki Naito, Masayuki Tsuneki, +25 authors, Hirohisa Yano.
Sci Rep, 2021 Apr 21; 11(1). PMID: 33875703    Free PMC article.
Assessment of Immunological Features in Muscle-Invasive Bladder Cancer Prognosis Using Ensemble Learning.
Christos G Gavriel, Neofytos Dimitriou, +5 authors, Peter D Caie.
Cancers (Basel), 2021 May 01; 13(7). PMID: 33915698    Free PMC article.
Role of AI and Histopathological Images in Detecting Prostate Cancer: A Survey.
Sarah M Ayyad, Mohamed Shehata, +7 authors, Ayman El-Baz.
Sensors (Basel), 2021 May 01; 21(8). PMID: 33917035    Free PMC article.
Deep learning in histopathology: the path to the clinic.
Jeroen van der Laak, Geert Litjens, Francesco Ciompi.
Nat Med, 2021 May 16; 27(5). PMID: 33990804
SPIE-AAPM-NCI BreastPathQ challenge: an image analysis challenge for quantitative tumor cellularity assessment in breast cancer histology images following neoadjuvant treatment.
Nicholas Petrick, Shazia Akbar, +7 authors, BreastPathQ Challenge Group.
J Med Imaging (Bellingham), 2021 May 15; 8(3). PMID: 33987451    Free PMC article.
Ensemble of transfer learnt classifiers for recognition of cardiovascular tissues from histological images.
Shubham Mittal.
Phys Eng Sci Med, 2021 May 21;. PMID: 34014495
Application of Machine Learning in Translational Medicine: Current Status and Future Opportunities.
Nadia Terranova, Karthik Venkatakrishnan, Lisa J Benincosa.
AAPS J, 2021 May 20; 23(4). PMID: 34008139    Free PMC article.
A generalized deep learning framework for whole-slide image segmentation and analysis.
Mahendra Khened, Avinash Kori, +2 authors, Balaji Srinivasan.
Sci Rep, 2021 Jun 04; 11(1). PMID: 34078928    Free PMC article.
Multiview boosting digital pathology analysis of prostate cancer.
Jin Tae Kwak, Stephen M Hewitt.
Comput Methods Programs Biomed, 2017 Mar 23; 142. PMID: 28325451    Free PMC article.
Hybrid AI-assistive diagnostic model permits rapid TBS classification of cervical liquid-based thin-layer cell smears.
Xiaohui Zhu, Xiaoming Li, +31 authors, Yanqing Ding.
Nat Commun, 2021 Jun 12; 12(1). PMID: 34112790