. 2019 Aug;16(11).
doi: 10.1038/s41571-019-0252-y.

Artificial intelligence in digital pathology - new tools for diagnosis and precision oncology

Kaustav Bera 1 Kurt A Schalper 2 David L Rimm 2 Vamsidhar Velcheti 3 Anant Madabhushi 4 
  • PMID: 31399699
  •     125 References
  •     67 citations


In the past decade, advances in precision oncology have resulted in an increased demand for predictive assays that enable the selection and stratification of patients for treatment. The enormous divergence of signalling and transcriptional networks mediating the crosstalk between cancer, stromal and immune cells complicates the development of functionally relevant biomarkers based on a single gene or protein. However, the result of these complex processes can be uniquely captured in the morphometric features of stained tissue specimens. The possibility of digitizing whole-slide images of tissue has led to the advent of artificial intelligence (AI) and machine learning tools in digital pathology, which enable mining of subvisual morphometric phenotypes and might, ultimately, improve patient management. In this Perspective, we critically evaluate various AI-based computational approaches for digital pathology, focusing on deep neural networks and 'hand-crafted' feature-based methodologies. We aim to provide a broad framework for incorporating AI and machine learning tools into clinical oncology, with an emphasis on biomarker development. We discuss some of the challenges relating to the use of AI, including the need for well-curated validation datasets, regulatory approval and fair reimbursement strategies. Finally, we present potential future opportunities for precision oncology.

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JCO Clin Cancer Inform, 2019 Apr 17; 3. PMID: 30990737    Free PMC article.
Development and validation of a deep learning algorithm for improving Gleason scoring of prostate cancer.
Kunal Nagpal, Davis Foote, +16 authors, Martin C Stumpe.
NPJ Digit Med, 2019 Jul 16; 2. PMID: 31304394    Free PMC article.
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Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images.
Joel Saltz, Rajarsi Gupta, +14 authors, Vésteinn Thorsson.
Cell Rep, 2018 Apr 05; 23(1). PMID: 29617659    Free PMC article.
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A deep learning based strategy for identifying and associating mitotic activity with gene expression derived risk categories in estrogen receptor positive breast cancers.
David Romo-Bucheli, Andrew Janowczyk, +2 authors, Anant Madabhushi.
Cytometry A, 2017 Feb 14; 91(6). PMID: 28192639    Free PMC article.
Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers.
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Improved automatic detection and segmentation of cell nuclei in histopathology images.
Yousef Al-Kofahi, Wiem Lassoued, William Lee, Badrinath Roysam.
IEEE Trans Biomed Eng, 2009 Nov 04; 57(4). PMID: 19884070
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Cancer Digital Slide Archive: an informatics resource to support integrated in silico analysis of TCGA pathology data.
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J Am Med Inform Assoc, 2013 Jul 31; 20(6). PMID: 23893318    Free PMC article.
High-throughput adaptive sampling for whole-slide histopathology image analysis (HASHI) via convolutional neural networks: Application to invasive breast cancer detection.
Angel Cruz-Roa, Hannah Gilmore, +6 authors, Fabio González.
PLoS One, 2018 May 26; 13(5). PMID: 29795581    Free PMC article.
Accuracy of computer diagnosis of melanoma: a quantitative meta-analysis.
Barbara Rosado, Scott Menzies, +4 authors, Harald Kittler.
Arch Dermatol, 2003 Mar 08; 139(3). PMID: 12622631
The analysis of cell images.
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Prediction of recurrence in early stage non-small cell lung cancer using computer extracted nuclear features from digital H&E images.
Xiangxue Wang, Andrew Janowczyk, +5 authors, Anant Madabhushi.
Sci Rep, 2017 Oct 21; 7(1). PMID: 29051570    Free PMC article.
Light-sheet microscopy for slide-free non-destructive pathology of large clinical specimens.
Adam K Glaser, Nicholas P Reder, +6 authors, Jonathan T C Liu.
Nat Biomed Eng, 2018 May 12; 1(7). PMID: 29750130    Free PMC article.
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Computational pathology analysis of tissue microarrays predicts survival of renal clear cell carcinoma patients.
Thomas J Fuchs, Peter J Wild, Holger Moch, Joachim M Buhmann.
Med Image Comput Comput Assist Interv, 2008 Nov 06; 11(Pt 2). PMID: 18982583
New Trends of Emerging Technologies in Digital Pathology.
Gloria Bueno, M Milagro Fernández-Carrobles, Oscar Deniz, Marcial García-Rojo.
Pathobiology, 2016 Apr 23; 83(2-3). PMID: 27100343
Opportunities for Artificial Intelligence in Advancing Precision Medicine.
Fabian V Filipp.
Curr Genet Med Rep, 2019 Dec 25; 7(4). PMID: 31871830    Free PMC article.
Spatially multiplexed RNA in situ hybridization to reveal tumor heterogeneity.
Lena Voith von Voithenberg, Anna Fomitcheva Khartchenko, +2 authors, Govind V Kaigala.
Nucleic Acids Res, 2019 Dec 20; 48(3). PMID: 31853536    Free PMC article.
Editorial: Digital Interventions in Mental Health: Current Status and Future Directions.
Elias Aboujaoude, Lina Gega, Michelle B Parish, Donald M Hilty.
Front Psychiatry, 2020 Mar 17; 11. PMID: 32174858    Free PMC article.
Deep learning pathological microscopic features in endemic nasopharyngeal cancer: Prognostic value and protentional role for individual induction chemotherapy.
Kuiyuan Liu, Weixiong Xia, +4 authors, Xing Lv.
Cancer Med, 2019 Dec 21; 9(4). PMID: 31860791    Free PMC article.
Introduction to digital pathology and computer-aided pathology.
Soojeong Nam, Yosep Chong, +5 authors, Heounjeong Go.
J Pathol Transl Med, 2020 Feb 13; 54(2). PMID: 32045965    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.
Emerging role of deep learning-based artificial intelligence in tumor pathology.
Yahui Jiang, Meng Yang, +2 authors, Yan Sun.
Cancer Commun (Lond), 2020 Apr 12; 40(4). PMID: 32277744    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.
Multiresolution Application of Artificial Intelligence in Digital Pathology for Prediction of Positive Lymph Nodes From Primary Tumors in Bladder Cancer.
Stephanie A Harmon, Thomas H Sanford, +8 authors, Baris Turkbey.
JCO Clin Cancer Inform, 2020 Apr 25; 4. PMID: 32330067    Free PMC article.
Classification and mutation prediction based on histopathology H&E images in liver cancer using deep learning.
Mingyu Chen, Bin Zhang, +6 authors, Xiujun Cai.
NPJ Precis Oncol, 2020 Jun 19; 4. PMID: 32550270    Free PMC article.
From Patient-Controlled Analgesia to Artificial Intelligence-Assisted Patient-Controlled Analgesia: Practices and Perspectives.
Rui Wang, Shaoshuang Wang, Na Duan, Qiang Wang.
Front Med (Lausanne), 2020 Jul 17; 7. PMID: 32671076    Free PMC article.
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.
Deep HT: A deep neural network for diagnose on MR images of tumors of the hand.
Xianliang Hu, Zongyu Liu, +2 authors, Hui Lu.
PLoS One, 2020 Aug 17; 15(8). PMID: 32797089    Free PMC article.
Digital pathology and computational image analysis in nephropathology.
Laura Barisoni, Kyle J Lafata, +2 authors, Ulysses G J Balis.
Nat Rev Nephrol, 2020 Aug 28; 16(11). PMID: 32848206    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.
Multiparametric MRI and Whole Slide Image-Based Pretreatment Prediction of Pathological Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer: A Multicenter Radiopathomic Study.
Lizhi Shao, Zhenyu Liu, +13 authors, Jie Tian.
Ann Surg Oncol, 2020 Jul 31; 27(11). PMID: 32729045    Free PMC article.
Prognostic value of histopathological DCIS features in a large-scale international interrater reliability study.
Emma J Groen, Jan Hudecek, +29 authors, Grand Challenge PRECISION consortium.
Breast Cancer Res Treat, 2020 Aug 01; 183(3). PMID: 32734520    Free PMC article.
Artificial intelligence (AI) and big data in cancer and precision oncology.
Zodwa Dlamini, Flavia Zita Francies, Rodney Hull, Rahaba Marima.
Comput Struct Biotechnol J, 2020 Oct 01; 18. PMID: 32994889    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.
Use of Steroid Profiling Combined With Machine Learning for Identification and Subtype Classification in Primary Aldosteronism.
Graeme Eisenhofer, Claudio Durán, +11 authors, Martin Reincke.
JAMA Netw Open, 2020 Sep 30; 3(9). PMID: 32990741    Free PMC article.
A Regulatory Science Initiative to Harmonize and Standardize Digital Pathology and Machine Learning Processes to Speed up Clinical Innovation to Patients.
Hetal Desai Marble, Richard Huang, +14 authors, Jochen K Lennerz.
J Pathol Inform, 2020 Oct 13; 11. PMID: 33042601    Free PMC article.
In the literature: October 2020.
Valentina Gambardella, Gema Bruixola, Clara Alfaro, Andrés Cervantes.
ESMO Open, 2020 Oct 11; 5(5). PMID: 33037034    Free PMC article.
Integration of geoscience frameworks into digital pathology analysis permits quantification of microarchitectural relationships in histological landscapes.
Timothy J Kendall, Catherine M Duff, Andrew M Thomson, John P Iredale.
Sci Rep, 2020 Oct 18; 10(1). PMID: 33067578    Free PMC article.
Multiple Primary Lung Cancers: A New Challenge in the Era of Precision Medicine.
Lishu Zhao, Chaoyuan Liu, +2 authors, Chunhong Hu.
Cancer Manag Res, 2020 Oct 30; 12. PMID: 33116891    Free PMC article.
A prognostic model for overall survival of patients with early-stage non-small cell lung cancer: a multicentre, retrospective study.
Cheng Lu, Kaustav Bera, +14 authors, Anant Madabhushi.
Lancet Digit Health, 2020 Nov 10; 2(11). PMID: 33163952    Free PMC article.
Exploring the Limits of Combined Image/'omics Analysis for Non-cancer Histological Phenotypes.
Paul Gallins, Ehsan Saghapour, Yi-Hui Zhou.
Front Genet, 2020 Nov 17; 11. PMID: 33193632    Free PMC article.
A novel deep learning-based point-of-care diagnostic method for detecting Plasmodium falciparum with fluorescence digital microscopy.
Oscar Holmström, Sebastian Stenman, +10 authors, Johan Lundin.
PLoS One, 2020 Nov 18; 15(11). PMID: 33201905    Free PMC article.
New insights into the interaction of the immune system with non-small cell lung carcinomas.
Paul Hofman.
Transl Lung Cancer Res, 2020 Nov 20; 9(5). PMID: 33209644    Free PMC article.
A narrative review of digital pathology and artificial intelligence: focusing on lung cancer.
Taro Sakamoto, Tomoi Furukawa, +8 authors, Junya Fukuoka.
Transl Lung Cancer Res, 2020 Nov 20; 9(5). PMID: 33209648    Free PMC article.
Experimental Assessment of Color Deconvolution and Color Normalization for Automated Classification of Histology Images Stained with Hematoxylin and Eosin.
Francesco Bianconi, Jakob N Kather, Constantino Carlos Reyes-Aldasoro.
Cancers (Basel), 2020 Nov 15; 12(11). PMID: 33187299    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.
The importance of introducing artificial intelligence to the medical curriculum - assessing practitioners' perspectives.
Ivo Dumić-Čule, Tin Orešković, +2 authors, Stjepan Orešković.
Croat Med J, 2020 Nov 06; 61(5). PMID: 33150764    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.
SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.
Siwen Hu-Lieskovan, Srabani Bhaumik, +14 authors, Holden T Maecker.
J Immunother Cancer, 2020 Dec 04; 8(2). PMID: 33268350    Free PMC article.
The Application of Artificial Intelligence in the Genetic Study of Alzheimer's Disease.
Rohan Mishra, Bin Li.
Aging Dis, 2020 Dec 04; 11(6). PMID: 33269107    Free PMC article.
Comparing Deep Learning and Immunohistochemistry in Determining the Site of Origin for Well-Differentiated Neuroendocrine Tumors.
Jordan Redemann, Fred A Schultz, +4 authors, Joshua A Hanson.
J Pathol Inform, 2020 Dec 22; 11. PMID: 33343993    Free PMC article.
Single-Cell Spatial Analysis of Tumor and Immune Microenvironment on Whole-Slide Image Reveals Hepatocellular Carcinoma Subtypes.
Haiyue Wang, Yuming Jiang, +3 authors, Ruijiang Li.
Cancers (Basel), 2020 Dec 03; 12(12). PMID: 33260561    Free PMC article.
Identifying Cross-Scale Associations between Radiomic and Pathomic Signatures of Non-Small Cell Lung Cancer Subtypes: Preliminary Results.
Charlems Alvarez-Jimenez, Alvaro A Sandino, +3 authors, Eduardo Romero.
Cancers (Basel), 2020 Dec 11; 12(12). PMID: 33297357    Free PMC article.
A 'Real-Life' Experience on Automated Digital Image Analysis of FGFR2 Immunohistochemistry in Breast Cancer.
Marcin Braun, Dominika Piasecka, +3 authors, Hanna M Romanska.
Diagnostics (Basel), 2020 Dec 11; 10(12). PMID: 33297384    Free PMC article.
Deep learning-enabled medical computer vision.
Andre Esteva, Katherine Chou, +7 authors, Richard Socher.
NPJ Digit Med, 2021 Jan 10; 4(1). PMID: 33420381    Free PMC article.
A deep-learning-based prognostic nomogram integrating microscopic digital pathology and macroscopic magnetic resonance images in nasopharyngeal carcinoma: a multi-cohort study.
Fan Zhang, Lian-Zhen Zhong, +12 authors, Hong Shan.
Ther Adv Med Oncol, 2021 Jan 07; 12. PMID: 33403013    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.
Machine Learning in Rheumatic Diseases.
Mengdi Jiang, Yueting Li, +3 authors, Peter E Lipsky.
Clin Rev Allergy Immunol, 2020 Jul 19; 60(1). PMID: 32681407
Machine learning analysis using 77,044 genomic and transcriptomic profiles to accurately predict tumor type.
Jim Abraham, Amy B Heimberger, +12 authors, David Spetzler.
Transl Oncol, 2021 Jan 20; 14(3). PMID: 33465745    Free PMC article.
Designing deep learning studies in cancer diagnostics.
Andreas Kleppe, Ole-Johan Skrede, +3 authors, Håvard E Danielsen.
Nat Rev Cancer, 2021 Jan 31; 21(3). PMID: 33514930
Pathway-Based Drug-Repurposing Schemes in Cancer: The Role of Translational Bioinformatics.
Enrique Hernández-Lemus, Mireya Martínez-García.
Front Oncol, 2021 Feb 02; 10. PMID: 33520715    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.
Artificial Intelligence for Histology-Based Detection of Microsatellite Instability and Prediction of Response to Immunotherapy in Colorectal Cancer.
Lindsey A Hildebrand, Colin J Pierce, +2 authors, Asaf Maoz.
Cancers (Basel), 2021 Jan 27; 13(3). PMID: 33494280    Free PMC article.
Dual energy imaging in cardiothoracic pathologies: A primer for radiologists and clinicians.
Amit Gupta, Elias G Kikano, +7 authors, Kai R Laukamp.
Eur J Radiol Open, 2021 Feb 04; 8. PMID: 33532519    Free PMC article.
PD-L1 as a biomarker of response to immune-checkpoint inhibitors.
Deborah Blythe Doroshow, Sheena Bhalla, +7 authors, Fred R Hirsch.
Nat Rev Clin Oncol, 2021 Feb 14;. PMID: 33580222
Transpathology: molecular imaging-based pathology.
Mei Tian, Xuexin He, +8 authors, Hong Zhang.
Eur J Nucl Med Mol Imaging, 2021 Feb 16;. PMID: 33585964
Gut microbiome, big data and machine learning to promote precision medicine for cancer.
Giovanni Cammarota, Gianluca Ianiro, +5 authors, Giampaolo Tortora.
Nat Rev Gastroenterol Hepatol, 2020 Jul 11; 17(10). PMID: 32647386
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
Protein-based immune profiles of basal-like vs. luminal breast cancers.
Andrea Walens, Linnea T Olsson, +11 authors, Benjamin C Calhoun.
Lab Invest, 2021 Feb 25;. PMID: 33623115
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.
The Role of the Pathologist in the Next-Generation Era of Tumor Molecular Characterization.
Valentina Angerilli, Francesca Galuppini, +3 authors, Matteo Fassan.
Diagnostics (Basel), 2021 Mar 07; 11(2). PMID: 33670699    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.
Establishment and Clinical Application of an Artificial Intelligence Diagnostic Platform for Identifying Rectal Cancer Tumor Budding.
Shanglong Liu, Yuejuan Zhang, +6 authors, Yun Lu.
Front Oncol, 2021 Mar 26; 11. PMID: 33763362    Free PMC article.
Point-of-Care Digital Cytology With Artificial Intelligence for Cervical Cancer Screening in a Resource-Limited Setting.
Oscar Holmström, Nina Linder, +9 authors, Johan Lundin.
JAMA Netw Open, 2021 Mar 18; 4(3). PMID: 33729503    Free PMC article.
Can artificial intelligence overtake human intelligence on the bumpy road towards glioma therapy?
Precilla S Daisy, T S Anitha.
Med Oncol, 2021 Apr 04; 38(5). PMID: 33811540
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.
Computerized spermatogenesis staging (CSS) of mouse testis sections via quantitative histomorphological analysis.
Jun Xu, Haoda Lu, +6 authors, Eugene Yujun Xu.
Med Image Anal, 2021 Mar 07; 70. PMID: 33676102    Free PMC article.
Interpretable survival prediction for colorectal cancer using deep learning.
Ellery Wulczyn, David F Steiner, +20 authors, Craig H Mermel.
NPJ Digit Med, 2021 Apr 21; 4(1). PMID: 33875798
Artificial Intelligence-based methods in head and neck cancer diagnosis: an overview.
Hanya Mahmood, Muhammad Shaban, Nasir Rajpoot, Syed A Khurram.
Br J Cancer, 2021 Apr 21;. PMID: 33875821
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.