Journal Article
. 2016 Aug;7().
doi: 10.4103/2153-3539.186902.

Deep learning for digital pathology image analysis: A comprehensive tutorial with selected use cases

Andrew Janowczyk 1 Anant Madabhushi 1 
  • PMID: 27563488
  •     27 References
  •     145 citations


Background: Deep learning (DL) is a representation learning approach ideally suited for image analysis challenges in digital pathology (DP). The variety of image analysis tasks in the context of DP includes detection and counting (e.g., mitotic events), segmentation (e.g., nuclei), and tissue classification (e.g., cancerous vs. non-cancerous). Unfortunately, issues with slide preparation, variations in staining and scanning across sites, and vendor platforms, as well as biological variance, such as the presentation of different grades of disease, make these image analysis tasks particularly challenging. Traditional approaches, wherein domain-specific cues are manually identified and developed into task-specific "handcrafted" features, can require extensive tuning to accommodate these variances. However, DL takes a more domain agnostic approach combining both feature discovery and implementation to maximally discriminate between the classes of interest. While DL approaches have performed well in a few DP related image analysis tasks, such as detection and tissue classification, the currently available open source tools and tutorials do not provide guidance on challenges such as (a) selecting appropriate magnification, (b) managing errors in annotations in the training (or learning) dataset, and (c) identifying a suitable training set containing information rich exemplars. These foundational concepts, which are needed to successfully translate the DL paradigm to DP tasks, are non-trivial for (i) DL experts with minimal digital histology experience, and (ii) DP and image processing experts with minimal DL experience, to derive on their own, thus meriting a dedicated tutorial.

Aims: This paper investigates these concepts through seven unique DP tasks as use cases to elucidate techniques needed to produce comparable, and in many cases, superior to results from the state-of-the-art hand-crafted feature-based classification approaches.

Results: Specifically, in this tutorial on DL for DP image analysis, we show how an open source framework (Caffe), with a singular network architecture, can be used to address: (a) nuclei segmentation (F-score of 0.83 across 12,000 nuclei), (b) epithelium segmentation (F-score of 0.84 across 1735 regions), (c) tubule segmentation (F-score of 0.83 from 795 tubules), (d) lymphocyte detection (F-score of 0.90 across 3064 lymphocytes), (e) mitosis detection (F-score of 0.53 across 550 mitotic events), (f) invasive ductal carcinoma detection (F-score of 0.7648 on 50 k testing patches), and (g) lymphoma classification (classification accuracy of 0.97 across 374 images).

Conclusion: This paper represents the largest comprehensive study of DL approaches in DP to date, with over 1200 DP images used during evaluation. The supplemental online material that accompanies this paper consists of step-by-step instructions for the usage of the supplied source code, trained models, and input data.

Keywords: Classification; deep learning; detection; digital histology; machine learning; segmentation.

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JCO Clin Cancer Inform, 2020 Mar 11; 4. PMID: 32155093    Free PMC article.
Glioma Grading via Analysis of Digital Pathology Images Using Machine Learning.
Saima Rathore, Tamim Niazi, Muhammad Aksam Iftikhar, Ahmad Chaddad.
Cancers (Basel), 2020 Mar 07; 12(3). PMID: 32131409    Free PMC article.
Computationally Derived Image Signature of Stromal Morphology Is Prognostic of Prostate Cancer Recurrence Following Prostatectomy in African American Patients.
Hersh K Bhargava, Patrick Leo, +11 authors, Anant Madabhushi.
Clin Cancer Res, 2020 Mar 07; 26(8). PMID: 32139401    Free PMC article.
Artificial intelligence driven next-generation renal histomorphometry.
Briana A Santo, Avi Z Rosenberg, Pinaki Sarder.
Curr Opin Nephrol Hypertens, 2020 Mar 25; 29(3). PMID: 32205581    Free PMC article.
Validation of machine learning models to detect amyloid pathologies across institutions.
Juan C Vizcarra, Marla Gearing, +3 authors, David A Gutman.
Acta Neuropathol Commun, 2020 Apr 30; 8(1). PMID: 32345363    Free PMC article.
Accurate diagnosis of lymphoma on whole-slide histopathology images using deep learning.
Charlotte Syrykh, Arnaud Abreu, +7 authors, Pierre Brousset.
NPJ Digit Med, 2020 May 08; 3. PMID: 32377574    Free PMC article.
Enhancing the Value of Histopathological Assessment of Allograft Biopsy Monitoring.
Michelle A Wood-Trageser, Andrew J Lesniak, Anthony J Demetris.
Transplantation, 2019 Feb 16; 103(7). PMID: 30768568    Free PMC article.
Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.
Mohamed Amgad, Elisabeth Specht Stovgaard, +66 authors, International Immuno-Oncology Biomarker Working Group.
NPJ Breast Cancer, 2020 May 16; 6. PMID: 32411818    Free PMC article.
Artificial Intelligence and Digital Microscopy Applications in Diagnostic Hematopathology.
Hanadi El Achi, Joseph D Khoury.
Cancers (Basel), 2020 Apr 01; 12(4). PMID: 32224980    Free PMC article.
Deep-Learning-Based Characterization of Tumor-Infiltrating Lymphocytes in Breast Cancers From Histopathology Images and Multiomics Data.
Zixiao Lu, Siwen Xu, +5 authors, Kun Huang.
JCO Clin Cancer Inform, 2020 May 27; 4. PMID: 32453636    Free PMC article.
Computer-aided diagnosis in the era of deep learning.
Heang-Ping Chan, Lubomir M Hadjiiski, Ravi K Samala.
Med Phys, 2020 May 18; 47(5). PMID: 32418340    Free PMC article.
Cardiac tissue engineering: state-of-the-art methods and outlook.
Anh H Nguyen, Paul Marsh, +4 authors, Hung Cao.
J Biol Eng, 2019 Jul 13; 13. PMID: 31297148    Free PMC article.
Dataset of segmented nuclei in hematoxylin and eosin stained histopathology images of ten cancer types.
Le Hou, Rajarsi Gupta, +5 authors, Joel H Saltz.
Sci Data, 2020 Jun 21; 7(1). PMID: 32561748    Free PMC article.
Impact of pre-analytical variables on deep learning accuracy in histopathology.
Andrew D Jones, John Paul Graff, +8 authors, Hooman H Rashidi.
Histopathology, 2019 Feb 26; 75(1). PMID: 30801768    Free PMC article.
Learning from irregularly sampled data for endomicroscopy super-resolution: a comparative study of sparse and dense approaches.
Agnieszka Barbara Szczotka, Dzhoshkun Ismail Shakir, +3 authors, Tom Vercauteren.
Int J Comput Assist Radiol Surg, 2020 May 18; 15(7). PMID: 32415459    Free PMC article.
Deep Learning With Sampling in Colon Cancer Histology.
Mary Shapcott, Katherine J Hewitt, Nasir Rajpoot.
Front Bioeng Biotechnol, 2019 Apr 12; 7. PMID: 30972333    Free PMC article.
Automated histologic diagnosis of CNS tumors with machine learning.
Siri Sahib S Khalsa, Todd C Hollon, +7 authors, Daniel A Orringer.
CNS Oncol, 2020 Jul 01; 9(2). PMID: 32602745    Free PMC article.
Artificial intelligence in digital breast pathology: Techniques and applications.
Asmaa Ibrahim, Paul Gamble, +4 authors, Emad A Rakha.
Breast, 2020 Jan 15; 49. PMID: 31935669    Free PMC article.
Deep learning-based image analysis methods for brightfield-acquired multiplex immunohistochemistry images.
Danielle J Fassler, Shahira Abousamra, +10 authors, Joel Saltz.
Diagn Pathol, 2020 Jul 30; 15(1). PMID: 32723384    Free PMC article.
Relevant Applications of Generative Adversarial Networks in Drug Design and Discovery: Molecular De Novo Design, Dimensionality Reduction, and De Novo Peptide and Protein Design.
Eugene Lin, Chieh-Hsin Lin, Hsien-Yuan Lane.
Molecules, 2020 Jul 28; 25(14). PMID: 32708785    Free PMC article.
Clinical-grade computational pathology using weakly supervised deep learning on whole slide images.
Gabriele Campanella, Matthew G Hanna, +7 authors, Thomas J Fuchs.
Nat Med, 2019 Jul 17; 25(8). PMID: 31308507    Free PMC article.
Highly Cited.
Non-disruptive collagen characterization in clinical histopathology using cross-modality image synthesis.
Adib Keikhosravi, Bin Li, +3 authors, Kevin W Eliceiri.
Commun Biol, 2020 Aug 02; 3(1). PMID: 32737412    Free PMC article.
Time Series Analysis and Forecasting with Automated Machine Learning on a National ICD-10 Database.
Victor Olsavszky, Mihnea Dosius, Cristian Vladescu, Johannes Benecke.
Int J Environ Res Public Health, 2020 Jul 16; 17(14). PMID: 32664331    Free PMC article.
Deep Learning in Medical Image Analysis.
Heang-Ping Chan, Ravi K Samala, Lubomir M Hadjiiski, Chuan Zhou.
Adv Exp Med Biol, 2020 Feb 08; 1213. PMID: 32030660    Free PMC article.
Clinically applicable histopathological diagnosis system for gastric cancer detection using deep learning.
Zhigang Song, Shuangmei Zou, +21 authors, Huaiyin Shi.
Nat Commun, 2020 Aug 29; 11(1). PMID: 32855423    Free PMC article.
Artificial Intelligence in Pathology.
Hye Yoon Chang, Chan Kwon Jung, +4 authors, Tae-Yeong Kwak.
J Pathol Transl Med, 2019 Jan 03; 53(1). PMID: 30599506    Free PMC article.
Highly Cited.
Artificial Intelligence and Digital Pathology: Challenges and Opportunities.
Hamid Reza Tizhoosh, Liron Pantanowitz.
J Pathol Inform, 2019 Jan 05; 9. PMID: 30607305    Free PMC article.
Highly Cited. Review.
The Use of Screencasts with Embedded Whole-Slide Scans and Hyperlinks to Teach Anatomic Pathology in a Supervised Digital Environment.
Mary Wong, Joseph Frye, Stacey Kim, Alberto M Marchevsky.
J Pathol Inform, 2019 Jan 05; 9. PMID: 30607306    Free PMC article.
Twenty Years of Digital Pathology: An Overview of the Road Travelled, What is on the Horizon, and the Emergence of Vendor-Neutral Archives.
Liron Pantanowitz, Ashish Sharma, +3 authors, Joel Saltz.
J Pathol Inform, 2019 Jan 05; 9. PMID: 30607307    Free PMC article.
Computer-Aided Laser Dissection: A Microdissection Workflow Leveraging Image Analysis Tools.
Jason D Hipp, Donald J Johann, +12 authors, Michael A Tangrea.
J Pathol Inform, 2019 Jan 10; 9. PMID: 30622835    Free PMC article.
Quantitative Characterization of CD8+ T Cell Clustering and Spatial Heterogeneity in Solid Tumors.
Chang Gong, Robert A Anders, +7 authors, Aleksander S Popel.
Front Oncol, 2019 Jan 23; 8. PMID: 30666298    Free PMC article.
Detection and classification of cancer in whole slide breast histopathology images using deep convolutional networks.
Baris Gecer, Selim Aksoy, +3 authors, Joann G Elmore.
Pattern Recognit, 2019 Jan 27; 84. PMID: 30679879    Free PMC article.
Blinded Visual Scoring of Images Using the Freely-available Software Blinder.
Steven D Cothren, Joel N Meyer, Jessica H Hartman.
Bio Protoc, 2019 Feb 15; 8(23). PMID: 30761327    Free PMC article.
Convolutional neural network initialized active contour model with adaptive ellipse fitting for nuclear segmentation on breast histopathological images.
Jun Xu, Lei Gong, +4 authors, Anant Madabhushi.
J Med Imaging (Bellingham), 2019 Mar 07; 6(1). PMID: 30840729    Free PMC article.
Introduction to Digital Image Analysis in Whole-slide Imaging: A White Paper from the Digital Pathology Association.
Famke Aeffner, Mark D Zarella, +11 authors, Douglas Bowman.
J Pathol Inform, 2019 Apr 16; 10. PMID: 30984469    Free PMC article.
Highly Cited. Review.
Construction and Utilization of a Neural Network Model to Predict Current Procedural Terminology Codes from Pathology Report Texts.
Jay J Ye.
J Pathol Inform, 2019 May 07; 10. PMID: 31057982    Free PMC article.
Rapid and robust whole slide imaging based on LED-array illumination and color-multiplexed single-shot autofocusing.
Shaowei Jiang, Zichao Bian, +4 authors, Guoan Zheng.
Quant Imaging Med Surg, 2019 Jul 10; 9(5). PMID: 31281778    Free PMC article.
Segmentation of Glomeruli Within Trichrome Images Using Deep Learning.
Shruti Kannan, Laura A Morgan, +9 authors, Vijaya B Kolachalama.
Kidney Int Rep, 2019 Jul 19; 4(7). PMID: 31317118    Free PMC article.
Otorhinolaryngology and Artificial Intelligence.
Turgut Karlıdağ.
Turk Arch Otorhinolaryngol, 2019 Jul 31; 57(2). PMID: 31360921    Free PMC article.
Staining Invariant Features for Improving Generalization of Deep Convolutional Neural Networks in Computational Pathology.
Sebastian Otálora, Manfredo Atzori, +2 authors, Henning Müller.
Front Bioeng Biotechnol, 2019 Sep 12; 7. PMID: 31508414    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.
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.
Application of Big Data Technology for COVID-19 Prevention and Control in China: Lessons and Recommendations.
Jun Wu, Jian Wang, +2 authors, Qiuyan Fan.
J Med Internet Res, 2020 Oct 02; 22(10). PMID: 33001836    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.
Automated detection of COVID-19 using ensemble of transfer learning with deep convolutional neural network based on CT scans.
Parisa Gifani, Ahmad Shalbaf, Majid Vafaeezadeh.
Int J Comput Assist Radiol Surg, 2020 Nov 17; 16(1). PMID: 33191476    Free PMC article.
Joint reconstruction and classification of tumor cells and cell interactions in melanoma tissue sections with synthesized training data.
Alexander Effland, Erich Kobler, +6 authors, Martin Rumpf.
Int J Comput Assist Radiol Surg, 2019 Feb 20; 14(4). PMID: 30779021    Free PMC article.
Direct Cellularity Estimation on Breast Cancer Histopathology Images Using Transfer Learning.
Ziang Pei, Shuangliang Cao, Lijun Lu, Wufan Chen.
Comput Math Methods Med, 2019 Jul 10; 2019. PMID: 31281408    Free PMC article.
Automated detection and delineation of hepatocellular carcinoma on multiphasic contrast-enhanced MRI using deep learning.
Khaled Bousabarah, Brian Letzen, +7 authors, MingDe Lin.
Abdom Radiol (NY), 2020 Jun 06; 46(1). PMID: 32500237    Free PMC article.
Reimagining T Staging Through Artificial Intelligence and Machine Learning Image Processing Approaches in Digital Pathology.
Kaustav Bera, Ian Katz, Anant Madabhushi.
JCO Clin Cancer Inform, 2020 Nov 10; 4. PMID: 33166198    Free PMC article.
Artificial Intelligence Tools for Refining Lung Cancer Screening.
J Luis Espinoza, Le Thanh Dong.
J Clin Med, 2020 Dec 03; 9(12). PMID: 33261057    Free PMC article.
The Utility of Deep Learning in Breast Ultrasonic Imaging: A Review.
Tomoyuki Fujioka, Mio Mori, +10 authors, Ukihide Tateishi.
Diagnostics (Basel), 2020 Dec 10; 10(12). PMID: 33291266    Free PMC article.
Deep learning for digital pathology image analysis: A comprehensive tutorial with selected use cases.
Andrew Janowczyk, Anant Madabhushi.
J Pathol Inform, 2016 Aug 27; 7. PMID: 27563488    Free PMC article.
Highly Cited.
Artificial intelligence in automatic classification of invasive ductal carcinoma breast cancer in digital pathology images.
Mohammad Abdolahi, Mohammad Salehi, Iman Shokatian, Reza Reiazi.
Med J Islam Repub Iran, 2021 Jan 14; 34. PMID: 33437736    Free PMC article.
Artificial intelligence neuropathologist for glioma classification using deep learning on hematoxylin and eosin stained slide images and molecular markers.
Lei Jin, Feng Shi, +10 authors, Jinsong Wu.
Neuro Oncol, 2020 Jul 15; 23(1). PMID: 32663285    Free PMC article.
Feature-driven local cell graph (FLocK): New computational pathology-based descriptors for prognosis of lung cancer and HPV status of oropharyngeal cancers.
Cheng Lu, Can Koyuncu, +8 authors, Anant Madabhushi.
Med Image Anal, 2020 Dec 23; 68. PMID: 33352373    Free PMC article.

;. PMID: 33574288
Deep learning in cancer pathology: a new generation of clinical biomarkers.
Amelie Echle, Niklas Timon Rindtorff, +3 authors, Jakob Nikolas Kather.
Br J Cancer, 2020 Nov 19; 124(4). PMID: 33204028    Free PMC article.
A comprehensive survey of image segmentation: clustering methods, performance parameters, and benchmark datasets.
Himanshu Mittal, Avinash Chandra Pandey, +3 authors, Garv Modwel.
Multimed Tools Appl, 2021 Feb 16;. PMID: 33584121    Free PMC article.
Deep learning powers cancer diagnosis in digital pathology.
Yunjie He, Hong Zhao, Stephen T C Wong.
Comput Med Imaging Graph, 2021 Jan 17; 88. PMID: 33453648    Free PMC article.
Deep Learning in Head and Neck Tumor Multiomics Diagnosis and Analysis: Review of the Literature.
Xi Wang, Bin-Bin Li.
Front Genet, 2021 Mar 02; 12. PMID: 33643386    Free PMC article.
A multi-phase deep CNN based mitosis detection framework for breast cancer histopathological images.
Anabia Sohail, Asifullah Khan, +2 authors, Saranjam Khan.
Sci Rep, 2021 Mar 20; 11(1). PMID: 33737632    Free PMC article.
Deep Multi-Magnification Networks for multi-class breast cancer image segmentation.
David Joon Ho, Dig V K Yarlagadda, +6 authors, Thomas J Fuchs.
Comput Med Imaging Graph, 2021 Jan 24; 88. PMID: 33485058    Free PMC article.
Deep Learning-Based Image Classification in Differentiating Tufted Astrocytes, Astrocytic Plaques, and Neuritic Plaques.
Shunsuke Koga, Nikhil B Ghayal, Dennis W Dickson.
J Neuropathol Exp Neurol, 2021 Feb 12; 80(4). PMID: 33570124    Free PMC article.
Application of Single-Cell Approaches to Study Myeloproliferative Neoplasm Biology.
Daniel Royston, Adam J Mead, Bethan Psaila.
Hematol Oncol Clin North Am, 2021 Mar 02; 35(2). PMID: 33641869    Free PMC article.
Digital diagnostics and artificial intelligence in prostate cancer treatment in 5 years from now.
Alessia Cimadamore, Liang Cheng, +2 authors, Rodolfo Montironi.
Transl Androl Urol, 2021 Apr 15; 10(3). PMID: 33850784    Free PMC article.
A review and comparison of breast tumor cell nuclei segmentation performances using deep convolutional neural networks.
Andrew Lagree, Majidreza Mohebpour, +8 authors, William T Tran.
Sci Rep, 2021 Apr 15; 11(1). PMID: 33850222    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.