Whole Slide Imaging for Analytical Anatomic Pathology and Telepathology: Practical Applications Today, Promises, and Perils.

Whole slide imaging (WSI) offers a convenient, tractable platform for measuring features of routine and special-stain histology or in immunohistochemistry staining by using digital image analysis (IA). We now routinely use IA for quantitative and qualitative analysis of theranostic markers such as human epidermal growth factor 2 (HER2/neu), estrogen and progesterone receptors, and Ki-67. Quantitative IA requires extensive validation, however, and may not always be the best approach, with pancreatic neuroendocrine tumors being one example in which a semiautomated approach may be preferable for patient care. We find that IA has great utility for objective assessment of gastrointestinal tract dysplasia, microvessel density in hepatocellular carcinoma, hepatic fibrosis and steatosis, renal fibrosis, and general quality analysis/quality control, although the applications of these to daily practice are still in development. Collaborations with bioinformatics specialists have explored novel applications to gliomas, including in silico approaches for mining histologic data and correlating with molecular and radiologic findings. We and many others are using WSI for rapid, remote-access slide reviews (telepathology), though technical factors currently limit its utility for routine, high-volume diagnostics. In our experience, the greatest current practical impact of WSI lies in facilitating long-term storage and retrieval of images while obviating the need to keep slides on site. Once the existing barriers of capital cost, validation, operator training, software design, and storage/back-up concerns are overcome, these technologies appear destined to be a cornerstone of precision medicine and personalized patient care, and to become a routine part of pathology practice.

[1]  Tahsin Kurc,et al.  The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma. , 2012, The American journal of pathology.

[2]  S. Perkins,et al.  Web-based oil immersion whole slide imaging increases efficiency and clinical team satisfaction in hematopathology tumor board , 2014, Journal of pathology informatics.

[3]  Erwin G. Van Meir,et al.  Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma. , 2014, Cancer research.

[4]  Keith J Kaplan,et al.  Use of Robotic Telepathology for Frozen-Section Diagnosis: A Retrospective Trial of a Telepathology System for Intraoperative Consultation , 2002, Modern Pathology.

[5]  Alexis B. Carter,et al.  Reduced red blood cell transfusion in cardiothoracic surgery after implementation of a novel clinical decision support tool. , 2014, Journal of the American College of Surgeons.

[6]  Todd H. Stokes,et al.  Removing Batch Effects From Histopathological Images for Enhanced Cancer Diagnosis , 2014, IEEE Journal of Biomedical and Health Informatics.

[7]  Navid Farahani,et al.  Overview of Telepathology. , 2016, Clinics in laboratory medicine.

[8]  T. Gansler,et al.  Prognostic Indicators in Male Breast Carcinoma , 1998, The breast journal.

[9]  C. Cohen,et al.  Zonula Occludens-1 and HER-2/neu Expression in Invasive Breast Carcinoma , 2003, Applied immunohistochemistry & molecular morphology : AIMM.

[10]  M.D. Wang,et al.  Detecting and Quantifying Biomarkers of Risk for Colorectal Cancer Using Quantum Dots and Novel Image Analysis Algorithms , 2006, 2006 International Conference of the IEEE Engineering in Medicine and Biology Society.

[11]  William D. Dunn,et al.  MR imaging predictors of molecular profile and survival: multi-institutional study of the TCGA glioblastoma data set. , 2013, Radiology.

[12]  R. Lenox,et al.  Feasibility of dynamic telecytopathology for rapid on-site evaluation of endobronchial ultrasound-guided transbronchial fine needle aspiration. , 2013, Telemedicine journal and e-health : the official journal of the American Telemedicine Association.

[13]  Jerad M Gardner,et al.  Smart phone microscopic photography: a novel tool for physicians and trainees. , 2014, Archives of pathology & laboratory medicine.

[14]  Alexis B. Carter,et al.  Computational Pathology: A Path Ahead. , 2016, Archives of pathology & laboratory medicine.

[15]  Holger Lange,et al.  Trainable immunohistochemical HER2/neu image analysis: a multisite performance study using 260 breast tissue specimens. , 2011, Archives of pathology & laboratory medicine.

[16]  Jun Kong,et al.  Digital Pathology: Data-Intensive Frontier in Medical Imaging , 2012, Proceedings of the IEEE.

[17]  John D. Pfeifer,et al.  Review of the current state of whole slide imaging in pathology , 2011, Journal of pathology informatics.

[18]  John M S Bartlett,et al.  Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. , 2014, Archives of pathology & laboratory medicine.

[19]  V. Adsay Ki67 Labeling Index in Neuroendocrine Tumors of the Gastrointestinal and Pancreatobiliary Tract: To Count or Not to Count Is Not the Question, But Rather How to Count , 2012, The American journal of surgical pathology.

[20]  King La,et al.  A brief historical note on staining by hematoxylin and eosin. , 1986 .

[21]  Yinhai Wang,et al.  Virtual microscopy and digital pathology in training and education , 2012, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[22]  V. Deshpande,et al.  Autoimmune pancreatitis-related diabetes: quantitative analysis of endocrine islet cells and inflammatory infiltrate , 2010, Virchows Archiv.

[23]  M. Washington,et al.  Pathology Reporting of Neuroendocrine Tumors: Application of the Delphic Consensus Process to the Development of a Minimum Pathology Data Set , 2010, The American journal of surgical pathology.

[24]  Jesper Molin,et al.  Implementation of large-scale routine diagnostics using whole slide imaging in Sweden: Digital pathology experiences 2006-2013 , 2014, Journal of pathology informatics.

[25]  R. Colvin,et al.  Banff Fibrosis Study: Multicenter Visual Assessment and Computerized Analysis of Interstitial Fibrosis in Kidney Biopsies , 2014, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[26]  C. Cohen Image cytometric analysis in pathology. , 1996, Human pathology.

[27]  R. Dunstan,et al.  The Use of Immunohistochemistry for Biomarker Assessment—Can It Compete with Other Technologies? , 2011, Toxicologic pathology.

[28]  C. Cohen,et al.  Proliferation (Ki-67 and Phosphohistone H3) and Oncotype DX Recurrence Score in Estrogen Receptor-positive Breast Cancer , 2011, Applied immunohistochemistry & molecular morphology : AIMM.

[29]  C. Cohen,et al.  Bcl-2: bax and bcl-2: Bcl-x ratios by image cytometric quantitation of immunohistochemical expression in ovarian carcinoma: correlation with prognosis. , 2000, Cytometry.

[30]  Alexis B. Carter,et al.  Telepathology for Patient Care: What Am I Getting Myself Into? , 2010, Advances in anatomic pathology.

[31]  Daniel J Brat,et al.  Proliferation (MIB-1 Expression) in Oligodendrogliomas: Assessment of Quantitative Methods and Prognostic Significance , 2006, Applied immunohistochemistry & molecular morphology : AIMM.

[32]  Tahsin Kurc,et al.  Towards building computerized image analysis framework for nucleus discrimination in microscopy images of diffuse glioma , 2011, 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[33]  C. Lindskog,et al.  Garbage in, garbage out: A critical evaluation of strategies used for validation of immunohistochemical biomarkers , 2014, Molecular oncology.

[34]  A. Krasinskas,et al.  The High-grade (WHO G3) Pancreatic Neuroendocrine Tumor Category Is Morphologically and Biologically Heterogenous and Includes Both Well Differentiated and Poorly Differentiated Neoplasms , 2015, The American journal of surgical pathology.

[35]  Michael Goodman,et al.  Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies , 2015, Modern Pathology.

[36]  Clive R. Taylor,et al.  A brief history of pathology , 2010, Virchows Archiv.

[37]  Christina Appin,et al.  Tumor-Infiltrating Lymphocytes in Glioblastoma Are Associated with Specific Genomic Alterations and Related to Transcriptional Class , 2013, Clinical Cancer Research.

[38]  D. Sgoutas,et al.  Immunohistochemical progesterone receptor assay. Measurement by image analysis. , 1991, American journal of clinical pathology.

[39]  Liron Pantanowitz,et al.  Imaging file management to support international telepathology , 2015, Journal of pathology informatics.

[40]  Joel H. Saltz,et al.  The Proneural Molecular Signature Is Enriched in Oligodendrogliomas and Predicts Improved Survival among Diffuse Gliomas , 2010, PloS one.

[41]  May D. Wang,et al.  Semantic interpretation of robust imaging features for Fuhrman grading of renal carcinoma , 2014, 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[42]  C. Cohen,et al.  Epidermal growth factor (EGF) and EGF receptor in hypospadias. , 1997, British journal of urology.

[43]  Joel H. Saltz,et al.  Machine-Based Morphologic Analysis of Glioblastoma Using Whole-Slide Pathology Images Uncovers Clinically Relevant Molecular Correlates , 2013, PloS one.

[44]  Alton B Farris,et al.  Morphometric and visual evaluation of fibrosis in renal biopsies. , 2011, Journal of the American Society of Nephrology : JASN.

[45]  Jason Wang,et al.  Image Cytometric HER2 in Gastric Carcinoma: Is a New Algorithm Needed? , 2013, Applied immunohistochemistry & molecular morphology : AIMM.

[46]  Joel H. Saltz,et al.  Integrative, Multimodal Analysis of Glioblastoma Using TCGA Molecular Data, Pathology Images, and Clinical Outcomes , 2011, IEEE Transactions on Biomedical Engineering.

[47]  D. Sgoutas,et al.  Immunohistochemical estrogen receptor assay: quantitation by image analysis. , 1991, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[48]  B. Collins Telepathology in Cytopathology: Challenges and Opportunities , 2013, Acta Cytologica.

[49]  D. Sgoutas,et al.  Automated immunohistochemical estrogen receptor in fixed embedded breast carcinomas. , 1991, American journal of clinical pathology.

[50]  A. Nassar,et al.  Evaluation of new monoclonal antibodies in detection of estrogen receptor, progesterone receptor, and Her2 protein expression in breast carcinoma cell block sections using conventional microscopy and quantitative image analysis , 2009, Diagnostic cytopathology.

[51]  Alexis B. Carter Stepping across borders into the future of telepathology , 2011, Journal of pathology informatics.

[52]  C. Cohen,et al.  Image cytometric bcl-2:bax and bcl-2:bcl-x ratios in invasive breast carcinoma: correlation with prognosis. , 2002, Cytometry.

[53]  Jun Kong,et al.  In silico analysis of nuclei in glioblastoma using large-scale microscopy images improves prediction of treatment response , 2011, 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[54]  R. Bostick,et al.  Effects of Vitamin D and Calcium Supplementation on Markers of Apoptosis in Normal Colon Mucosa: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial , 2009, Cancer Prevention Research.

[55]  Rhona J. Souers,et al.  Immunohistochemistry validation procedures and practices: a College of American Pathologists survey of 727 laboratories. , 2013, Archives of pathology & laboratory medicine.

[56]  B F Boyce Whole slide imaging: uses and limitations for surgical pathology and teaching , 2015, Biotechnic & histochemistry : official publication of the Biological Stain Commission.

[57]  Joon Jeong,et al.  Current Issues and Clinical Evidence in Tumor-Infiltrating Lymphocytes in Breast Cancer , 2015, Journal of pathology and translational medicine.

[58]  Alexis B. Carter,et al.  Validating whole slide imaging for diagnostic purposes in pathology: guideline from the College of American Pathologists Pathology and Laboratory Quality Center. , 2013, Archives of pathology & laboratory medicine.

[59]  Jun Kong,et al.  Integrated morphologic analysis for the identification and characterization of disease subtypes , 2012, J. Am. Medical Informatics Assoc..

[60]  Jun Kong,et al.  A data model and database for high-resolution pathology analytical image informatics , 2011, Journal of pathology informatics.

[61]  Annie O Morrison,et al.  Microscopic Image Photography Techniques of the Past, Present, and Future. , 2015, Archives of pathology & laboratory medicine.

[62]  C. Cohen,et al.  Progesterone Receptor Immunohistochemical Quantitation Compared With Cytosolic Assay: Correlation With Prognosis in Breast Cancer , 2001, Applied immunohistochemistry & molecular morphology : AIMM.

[63]  Liron Pantanowitz,et al.  Experience with multimodality telepathology at the University of Pittsburgh Medical Center , 2012, Journal of pathology informatics.

[64]  Jun Kong,et al.  A comprehensive framework for classification of nuclei in digital microscopy imaging: An application to diffuse gliomas , 2011, 2011 IEEE International Symposium on Biomedical Imaging: From Nano to Macro.

[65]  S. Broderick,et al.  A Prospective Clinical Trial of Telecytopathology for Rapid Interpretation of Specimens Obtained During Endobronchial Ultrasound-Fine Needle Aspiration. , 2015, The Annals of thoracic surgery.

[66]  A. Krasinskas,et al.  Poorly Differentiated Neuroendocrine Carcinomas of the Pancreas: A Clinicopathologic Analysis of 44 Cases , 2014, The American journal of surgical pathology.

[67]  E. Rubin,et al.  Comparative image cytometric DNA ploidy of liver cell dysplasia and hepatocellular carcinoma. , 1994, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[68]  D. Sgoutas,et al.  Automated immunohistochemical estrogen receptor in fixed embedded breast carcinomas. Comparison with manual immunohistochemistry on frozen tissues. , 1989, American journal of clinical pathology.

[69]  Ramy Arnaout,et al.  The 2013 symposium on pathology data integration and clinical decision support and the current state of field , 2014, Journal of pathology informatics.

[70]  E. Unger,et al.  Image analysis for quantitation of estrogen receptor in formalin-fixed paraffin-embedded sections of breast carcinoma. , 1991, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[71]  C. Cohen,et al.  Image cytometric measurement of nuclear proliferation markers (MIB-1, PCNA) in astrocytomas. Prognostic significance. , 1998, American journal of clinical pathology.

[72]  Jun Kong,et al.  An Integrative Approach for In Silico Glioma Research , 2010, IEEE Transactions on Biomedical Engineering.

[73]  C. Cohen,et al.  Tumor angiogenesis as a prognostic factor in laryngeal cancer. , 1997, American journal of surgery.

[74]  C. Cohen,et al.  Comparison of cell proliferation in breast carcinoma using image analysis (Ki-67) and flow cytometric systems. , 1992, Analytical and quantitative cytology and histology.

[75]  Alton B Farris,et al.  Liver steatosis assessment: correlations among pathology, radiology, clinical data and automated image analysis software. , 2013, Pathology, research and practice.