Quick Reference Handbook for Surgical Pathologists PDF

Quick Reference Handbook for Surgical Pathologists Natasha Rekhtman Justin A. Bishop Quick Reference Handbook for Surgical Pathologists 123 Natasha Rekhtman, MD, PhD Assistant Attending Memorial Sloan-Kettering Cancer Center Department of Pathology New York, NY USA [email protected] Justin A. Bishop, MD Assistant Professor The Johns Hopkins Medical Institutions Department of Pathology Baltimore, MD USA [email protected] ISBN 978-3-642-20085-4 e-ISBN 978-3-642-20086-1 DOI 10.1007/978-3-642-20086-1 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011932990 © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, speciﬁcally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microﬁlm or in any other way, and storage in data banks. 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Natasha Rekhtman To Ashley, Riley, and Avery. Justin Bishop v Preface About this book This book is a compilation of high-yield at-a-glance summaries for various topics frequently needed in a quick reference for- mat at the microscope (or when cramming for the boards). As recently minted pathologists, we compiled this book from the perspective of pathologists-in-training and we gathered topics which we wanted to have in quick summary format during our recent residency and fellowships. Although written with the trainees in mind, the book may also be of interest to practicing pathologists as a practical quick reference by the microscope. The book has a unique layout in that most of the information is presented in tables and diagrams accompanied by minimal explanatory text. Our motto for this book was to boil the information down to the essentials and key elements but with just enough commentary to be accessible to a newcomer to pathology. This book is not intended as a substitute for original re- sources or authoritative texts, but rather its purpose is to bring under one roof compact summaries for various types of informa- tion that trainees and practicing pathologists now search for in many different sources, and give the conceptual “lay of the land” with emphasis on “must know” facts. Certainly decisions about what constitutes “must know” and “high-yield” are highly subjective, and we apologize for any omissions which are inevitable by the nature of this book. Our other main objective was to make the format of the book as user-friendly and easy to navigate as possible, such that one can quickly find the needed information. We thank our Springer editors for agreeing to publish this book in a non-standard format to help achieve this goal. Contents The focus is not organ-based morphologic criteria for which there are many excellent quick-summary resources, but rather the focus is everything else that helps a pathologist make a diagnosis (and pass the boards) with emphasis on the vast and fast- growing fields of immunohistochemistry (IHC) and molecular markers. The book starts with unique introductory “primers” – at-a-glance 1-page summaries with diagrams on the main types of marker applications and high-yield facts (such as peculiar principles of cytokeratin designation). We highlighted the rules and biologi- cal principles behind various immunostains and special stains to help residents reason through a problem rather than having to resort to memorized panels. The other part of the IHC section contains a large compilation of general and organ-based applica- tions of IHC with numerous immunopanels. This includes the classics (such as lung adenocarcinoma versus mesothelioma) and more recent applications (such as the work-up for mismatch repair proteins). Other sections of the book contain various quick references that are often needed at the microscope but require frequent re- minders. This includes a compilation of grading systems, common prognostic systems, and other criteria that are difficult to keep committed to memory (such as size cut-points for various micro-entities like thyroid papillary microcarcinoma). Also included are summaries for tumor syndromes with a particularly practical “slide-to-syndrome” summary where we highlighted which diagnoses or features should trigger consideration of a syndrome. In tumor genetics and cytogenetics we highlighted which tumors have unique molecular characteristics that can aid in the diagnosis or are used in prognostic/predictive testing. Another high-yield section that is not usually covered in most pathology books is a compilation of quick clinical references geared for pathologists. This section contains resources that help pathologists interpret clinical information that may be highly informative in the differential diagnosis of tumors, including a primer on metastasis (what metastatic patterns are classic vs. exceptional for certain tumors) and serologic tumor markers. We also included a brief summary of targeted therapies for which pathologists may be asked to perform predictive marker testing. Even though the focus of the book is not organ-based morphologic criteria, we included several sections with differentials that cut across all organs. For example, this section includes at-a-glance differentials for small round blue cell tumors, and classic differentials for certain morphologic features (such as which tumors are classically associated with granulomas or have stag- horn vessels). We also included an illustrated guide to microorganisms. Finally, we compiled an illustrated glossary of histo- pathologic descriptors with illustrations of common objects these terms are said to resemble (such as storiform or palisaded, and what Orphan Annie’s eyes actually look like!). Keep this by your side as you begin to tackle the large pathology books! We are also very excited to include a handy guide for pathology web resources by Terina Chen and a user-friendly CPT coding summary by Diana Molavi. Sources We used a variety of sources, including standard books and mountains of primary literature. However, most importantly our “world view” of pathology this early in our careers comes primarily from our outstanding teachers at The Johns Hopkins Hos- pital and Memorial Sloan-Kettering Cancer Center. From them we learned the approaches and principles that come only after years of experience but cannot be learned by reading books and papers. We were fortunate to learn pathology from these bril- vii viii Preface liant diagnosticians and generous educators, who shared their knowledge with us through sign outs, lectures and weekly un- knowns during our residency at Johns Hopkins. We therefore can only take credit for organizing and presenting this stream of knowledge in a format easily accessible to a newcomer to pathology, and we give all credit for the many useful pearls and principles in this book to our teachers. On the other hand, we take full responsibility for any inaccuracies that may have inad- vertently escaped our attention. In conclusion It is our hope that this book will be your best friend both at the microscope and in the late night hours of studying for the boards. Because the type of information covered in this book is rapidly evolving, please be sure to check the most current sources. Natasha Rekhtman and Justin Bishop How this book came about – part 1 I started working on this book in my second year of residency at The Johns Hopkins Hospital, although at that time I did not yet know that this was what I was doing. Like many pathologists, I am a very visual learner, and I firmly believe that a good table or diagram is worth many pages of text. Therefore I was desperately looking for resources that succinctly summarized the mountains of information I was trying to absorb, particularly in a format that was tabular or diagrammatic and was amenable to quick learning of the essentials. While there were many great resources for histologic criteria, what I felt was missing were quick references for the new and fast growing fields of immunostains and molecular markers, as well as other types of material frequently needed in pathologists’ daily work but not available in a single source. I therefore started compiling these summa- ries and diagrams for my own use, and later started sharing them with my co-residents. After getting feedback that others were findings these summaries useful, and after I realized that creating them was an incredible motivator to learn and digest the information, I put together a small handbook which was generously printed by the Department of Pathology at Johns Hopkins as a Resident Manual in 2004 and 2007. Now in collaboration with Justin Bishop as my coeditor and main coauthor and with contributions from many former and current Hopkins residents and fellows and my current colleagues at Memorial Sloan- Kettering Cancer Center, this book has morphed into what it is today. Justin joined forces with me in the last two years, and I could not have dreamt of a more dedicated and talented collaborator, who made it possible to get this project completed. Natasha Rekhtman How this book came about – part 2 My first interaction with this book (universally known as the “Green Book” at Hopkins) was in 2006. The more senior resi- dents had copies of a magical book that had all the answers I was seeking as a pathology intern. Desperate for something to boil down the massive amounts of information into one resource, my fellow first-year residents and I assembled crude bootleg copies of it. At the end of that year as she left Hopkins, Natasha distributed a new edition which remains a fixture at my micro- scope to this day. However, as the years passed and new waves of residents entered our program, original copies of the Green Book became increasingly scarce, and the quality of copies became increasingly poor as they became 2nd and 3rd generation. My chief resident year, I was frequently confronted with a question from the junior residents: “Where can I get a copy of that Green Book?” We had heard rumors about the possibility of it being published, but no one at Hopkins knew the status of the now-mythical Green Book. Intent on getting an answer, I contacted Natasha. As luck would have it, she needed a collaborator to push the project past the finish line, and that collaborator became me. Initially a great way to study for my boards, working on the book then became a means to stay on top of the newest information as I started signing out surgical pathology. Al- though perhaps it was a bigger commitment than I initially realized, it was well worth the effort, and I am extremely grateful to Natasha for allowing me to be a part of this very special project. Justin Bishop Acknowledgements We were fortunate to learn pathology as residents and assistants in surgical pathology from the brilliant diagnosticians and dedicated educators of The Johns Hopkins surgical pathology team and other divisions. We are most grateful to all our teachers for sharing with us their knowledge and wisdom that serves as the foundation of this book. We would like to sincerely thank all coauthors and reviewers for contributing their brainpower to this project with special thanks to Ashlie Burkart, Terina Chen, Amy Duffield, Diana Molavi and Janis Taube for lead-authoring various sections of this book. Very special thanks to Ashlie Burkart, Shien Michelli and Diana Molavi for reviewing various portions of this book, and penciling in multiple suggestions and question marks (as well as smiley faces…) and for being the constant source of en- couragement over the years. We are most grateful to all Hopkins faculty and trainees for making suggestions/corrections and enthusiastic support over the years. This book would not be what it is today if it had not been vetted by several generations of keen Hopkins residents. We also want to thank our publishing team Gabriele Schroeder, Sandra Lesny, and Ellen Blasig at Springer and Patrick Waltemate at le-tex for all their efforts on behalf of this book. Natasha also thanks her colleagues at Memorial Sloan-Kettering Cancer Center for their support and for generously sharing their knowledge and expertise. Natasha Rekhtman and Justin Bishop ix Editors and Main Authors: Justin A. Bishop, MD Assistant Professor Department of Pathology Surgical Pathology The Johns Hopkins Medical Institutions Baltimore, MD Natasha Rekhtman, MD, PhD Assistant Attending Department of Pathology Memorial Sloan-Kettering Cancer Center New York, NY Coauthors and Contributors: Jennifer Broussard, MD Franklin Square Hospital Center Baltimore, MD Ashlie L. Burkart, MD, CM Assistant Professor Department of Pathology, Anatomy and Cell Biology Jefferson Medical College of Thomas Jefferson University Philadelphia, PA Terina S. Chen, MD Good Samaritan Hospital of Maryland Baltimore, MD Amy S. Duffield, MD, PhD Assistant Professor Department of Pathology Hematopathology Division The Johns Hopkins Medical Institutions Baltimore, MD Tara Nikole Miller, MD Pathology Resident and Clinical Instructor Sanford School of Medicine of the University of South Dakota Sioux Falls, SD Ross Allen Miller, MD Pathology Resident and Clinical Instructor Sanford School of Medicine of the University of South Dakota Sioux Falls, SD Diana Weedman Molavi, MD, PhD Sinai Hospital of Baltimore Baltimore, MD Janis M. Taube, MD Assistant Professor Departments of Dermatology and Pathology The Johns Hopkins Medical Institutions Baltimore, MD Kathryn Villa, MD Assistant Faculty in Surgical Pathology Department of Pathology The Johns Hopkins Medical Institutions Baltimore, MD xi xii List of Contributors Reviewers: Meera Hameed, MD Attending Pathologist Memorial Sloan-Kettering Cancer Center, New York, NY Professor of Pathology and Laboratory Medicine Weil-Cornell Medical College New York, NY Jason T. Huse, MD, PhD Assistant Attending Department of Pathology Memorial Sloan-Kettering Cancer Center New York, NY Peter B. Illei, MD Assistant Professor Director, Immunopathology laboratory Department of Pathology The Johns Hopkins Medical Institutions Baltimore, MD Anna Yemelyanova, MD Assistant Professor Department of Pathology Gynecologic Surgical Pathology Division The Johns Hopkins Medical Institutions Baltimore, MD Illustrator (for lymph node diagram in chapter 2 and non-microscopy objects in chapter 12) Terry Helms Medical Illustrator Department of Media Services Memorial Sloan-Kettering Cancer Center New York, NY Table of Contents – At a Glance 1 Immunostains: Introduction............................................................................................................................................... 1 Natasha Rekhtman and Justin Bishop 2 Immunostains: Organ Systems.......................................................................................................................................... 23 Natasha Rekhtman, Ashlie Burkhart, Amy Duffield, Janis Taube, Justin Bishop 3 Immunostains: Antibody Index.......................................................................................................................................... 55 Justin Bishop, Amy Duffield, Diana Molavi, Natasha Rekhtman 4 Special Stains....................................................................................................................................................................... 69 Justin Bishop, Jennifer Broussard, Natasha Rekhtman 5 Grading (and Classification) Systems................................................................................................................................ 77 Justin Bishop, Amy Duffield, Diana Molavi, Natasha Rekhtman 6 Potpourri of Quick Morphologic References.................................................................................................................... 99 Natasha Rekhtman and Justin Bishop 7 Tumor Syndromes............................................................................................................................................................... 109 Justin Bishop, Ashlie Burkart, Natasha Rekhtman 8 Tumor Genetics and Cytogenetics..................................................................................................................................... 119 Justin Bishop, Amy Duffield, Ashlie Burkhart, Natasha Rekhtman 9 Quick Clinical References for Pathologists....................................................................................................................... 125 Justin Bishop and Natasha Rekhtman 10 Pathology Web Resources................................................................................................................................................... 131 Terina Chen 11 CPT (Current Procedural Terminology) Coding Quick Reference................................................................................ 135 Diana Molavi 12 It Looks Like WHAT? An Illustrated Glossary of Histopathologic Descriptors........................................................... 139 Natasha Rekhtman and Kathryn Villa References...................................................................................................................................................................................... 161 Subject Index................................................................................................................................................................................. 171 xiii Detailed Table of Contents 1 Immunostains: Introduction............................................................................................................................................... 1 Natasha Rekhtman and Justin Bishop General Background...................................................................................................................................................................................... 1 Applications of Immunohistochemistry in Anatomic Pathology................................................................................................................. 1 Markers of Differentiation at a Glance........................................................................................................................................................ 2 Location, Location, Location! Primer on Location of Antigens.................................................................................................................. 3 Primer on Cytokeratins............................................................................................................................................................................... 4 CK7 and CK20 Expression Profiles Diagram............................................................................................................................................. 7 CK7 and CK20 Expression Profiles............................................................................................................................................................ 8 Expression of EMA, CEA and Vimentin in Carcinomas............................................................................................................................ 9 Primer on Markers of Muscle Differentiation............................................................................................................................................. 10 Primer on Markers of Neuroendocrine Differentiation............................................................................................................................... 11 Primer on Markers of Melanocytic Differentiation..................................................................................................................................... 12 Primer on Markers of Neuroglial Differentiation........................................................................................................................................ 13 Primer on Markers of Vascular Differentiation........................................................................................................................................... 14 Primer on Assessment of Invasion.............................................................................................................................................................. 15 General Panels................................................................................................................................................................................................ 15 Differential Diagnosis of Undifferentiated Malignant Neoplasm................................................................................................................ 16 Carcinoma of Unknown Primary: Site-Specific Markers............................................................................................................................ 17 Differential Diagnosis of Small Round Blue Cell Tumors.......................................................................................................................... 18 Differential Diagnosis of Spindle Cell Tumors........................................................................................................................................... 19 Differential Diagnosis of Neuroendocrine and Neuroectodermal Neoplasms............................................................................................. 20 Predictive Markers......................................................................................................................................................................................... 20 Semiquantitative assessment (ER/PR, HER2, EGFR)................................................................................................................................. 21 2 Immunostains: Organ Systems.......................................................................................................................................... 23 Natasha Rekhtman, Ashlie Burkhart, Amy Duffield, Janis Taube, Tara Miller, Ross Miller, Justin Bishop Breast.............................................................................................................................................................................................................. 23 Breast: Key Markers at a Glance................................................................................................................................................................. 23 Markers for Myoepithelial Cells (and what else they stain)........................................................................................................................ 23 Breast: Immunoprofiles at a Glance............................................................................................................................................................ 23 DDx of In Situ Proliferations...................................................................................................................................................................... 24 DDx of Papillary Lesions............................................................................................................................................................................ 24 DDx of Low Grade Spindle Cell Proliferations in the Breast...................................................................................................................... 24 DDx of Pagetoid Proliferations in the Nipple............................................................................................................................................. 24 Genitourinary Tract....................................................................................................................................................................................... 25 Prostate and Bladder................................................................................................................................................................................... 25 Prostate: Key Markers at a Glance.............................................................................................................................................................. 25 Prostate: Immunoprofiles at a Glance......................................................................................................................................................... 25 Reactive Urothelial Atypia vs. Carcinoma in Situ....................................................................................................................................... 26 Dx of the Depth of Invasion by Urothelial Carcinoma................................................................................................................................ 26 DDx of Adenocarcinoma Involving the Bladder......................................................................................................................................... 26 Adenocarcinoma of Bladder and Prostate vs. Mimics................................................................................................................................. 26 Urothelial Carcinoma vs. High-Grade Prostate Carcinoma......................................................................................................................... 26 Kidney and Adrenal.................................................................................................................................................................................... 27 Kidney: Key Markers at a Glance............................................................................................................................................................... 27 Kidney: Immunoprofiles at a Glance.......................................................................................................................................................... 27 Adrenal: Immunoprofiles at a Glance......................................................................................................................................................... 27 DDx of Main Types of Renal Cortical Neoplasms...................................................................................................................................... 28 DDx of Cytologically Bland Renal Tumors with Tubulo-papillary Architecture........................................................................................ 28 DDx of Renal Tumors with Clear Cells...................................................................................................................................................... 28 Renal Cell Carcinoma vs. Adrenocortical Neoplasm.................................................................................................................................. 28 xv xvi Table of Contents Testis............................................................................................................................................................................................................. 29 Testicular Neoplasms: Key Multipurpose Markers at a Glance.................................................................................................................. 29 Testicular Neoplasms: Immunoprofiles at a Glance.................................................................................................................................... 29 Head and Neck............................................................................................................................................................................................... 29 Thyroid, Parathyroid, and Sinonasal Tract.............................................................................................................................................. 30 Thyroid and Parathyroid Neoplasms: Immunoprofiles at a Glance............................................................................................................. 30 DDx of Poorly Differentiated Neoplasms in the Sinonasal Tract................................................................................................................ 30 DDx of Basaloid Carcinomas of the Head and Neck.................................................................................................................................. 30 Salivary Gland............................................................................................................................................................................................. 31 Salivary Gland Neoplasms: Immunoprofiles (and Special Stains) at a Glance........................................................................................... 31 DDx of Salivary Gland Tumors with Clear Cells....................................................................................................................................... 31 Gastrointestinal Tract.................................................................................................................................................................................... 31 Pancreas....................................................................................................................................................................................................... 32 Pancreas: Immunoprofiles at a Glance........................................................................................................................................................ 32 DDx of Pancreatic Neoplasms with Cellular (no desmoplastic stroma) Acinar/Solid Growth Pattern....................................................... 32 Tubular Gastrointestinal Tract.................................................................................................................................................................. 33 DDx for the Site of Origin of Intestinal Metaplasia at the GE junction...................................................................................................... 33 Evaluation of Dysplasia in IBD.................................................................................................................................................................. 33 Diagnosis of Autoimmune Metaplastic Atrophic Gastritis/ “Pernicious Anemia”...................................................................................... 33 Testing of DNA Mismatch Repair Proteins by Ashlie Burkart................................................................................................................... 34 Liver............................................................................................................................................................................................................. 35 Hepatocellular carcinoma vs. Cholangiocarcinoma vs. Metastatic Adenocarcinoma................................................................................. 35 Hepatocellular carcinoma vs. Benign Hepatocellular Nodule..................................................................................................................... 35 Thoracic.......................................................................................................................................................................................................... 35 Lung and Thymus....................................................................................................................................................................................... 35 Lung: Immunoprofiles at a Glance............................................................................................................................................................. 36 DDx of Neuroendocrine Neoplasms of the Lung........................................................................................................................................ 36 Carcinoid Tumorlet vs. Minute Meningothelial-like Nodule...................................................................................................................... 36 DDx of Thymic Epithelial Neoplasms........................................................................................................................................................ 36 Mesothelioma............................................................................................................................................................................................... 37 Mesothelioma vs. Adenocarcinoma............................................................................................................................................................ 37 DDx Malignant vs. Reactive Mesothelial Proliferations............................................................................................................................. 37 Soft Tissue....................................................................................................................................................................................................... 38 Select Mesenchymal Tumors: Immunoprofile at a Glance......................................................................................................................... 38 Central Nervous System................................................................................................................................................................................ 39 Lesions of Central Nervous System at a Glance......................................................................................................................................... 39 Astrocytoma vs. Oligodendroglioma.......................................................................................................................................................... 39 DDx of Clear Cell Nested Tumors in CNS................................................................................................................................................. 39 DDx of Dural-Based Spindle Cell Tumors................................................................................................................................................. 39 DDx of Myxoid and Chondromyxoid Lesions of the CNS/Coverings........................................................................................................ 39 Gynecologic Tract.......................................................................................................................................................................................... 40 Gynecologic Tract: Key Markers at a Glance............................................................................................................................................. 40 Gynecologic Tract: Immunoprofiles at a Glance........................................................................................................................................ 40 Ovarian Germ Cell Tumors at a Glance...................................................................................................................................................... 40 DDx of Dysplastic vs. Reactive Squamous Intraepithelial Lesions of the Cervix....................................................................................... 41 DDx of Uterine Carcinomas....................................................................................................................................................................... 41 Endometrial vs. Endocervical Adenocarcinoma......................................................................................................................................... 41 DDx of Uterine Spindle Cell Neoplasms.................................................................................................................................................... 41 DDx of Serous Tubal Intraepithelial Carcinoma......................................................................................................................................... 41 DDx of Ovarian Tumors with Tubular/Trabecular Pattern......................................................................................................................... 41 DDx of Trophoblastic Tumors.................................................................................................................................................................... 42 DDx of Hydatidiform Moles....................................................................................................................................................................... 42 Skin by Janis Taube, Natasha Rekhtman, Justin Bishop.................................................................................................................................. 43 General......................................................................................................................................................................................................... 43 Key Melanocytic Markers at a Glance........................................................................................................................................................ 43 Select Skin Lesions: Immunoprofiles at a Glance....................................................................................................................................... 43 DDx of Melanocytic Lesions...................................................................................................................................................................... 43 Table of Contents xvii DDx of Cutaneous Storiform Spindle Cell Lesions..................................................................................................................................... 44 DDx of Cutaneous High-Grade Neuroendocrine Carcinomas..................................................................................................................... 44 DDx of Ugly-Looking Spindle Cell Neoplasms of the Skin....................................................................................................................... 44 DDx of Pagetoid Proliferations in the Skin................................................................................................................................................. 44 DDx of Mammary vs. Extra-mammary Paget’s Disease............................................................................................................................. 44 Cutaneous Lymphomas by Janis Taube...................................................................................................................................................... 45 Classification of Cutaneous T Cell Lymphomas......................................................................................................................................... 45 Classification of Primary Cutaneous B-cell Lymphomas............................................................................................................................ 45 Hematopoietic System by Amy Duffield, Justin Bishop, Tara Miller, Ross Miller, Natasha Rekhtman.......................................................... 46 General......................................................................................................................................................................................................... 46 Hematopoietic Markers at a Glance............................................................................................................................................................ 46 Markers for Identification of Blasts............................................................................................................................................................ 46 Cytochemistry for Identification of Blasts.................................................................................................................................................. 46 Stages of Lymphocyte Differentiation and Corresponding Lymphomas..................................................................................................... 47 B cell Lymphomas....................................................................................................................................................................................... 49 Reactive Hyperplasia versus Follicular Lymphoma.................................................................................................................................... 49 Low-grade B cell lymphomas..................................................................................................................................................................... 49 Hodgkin Lymphoma................................................................................................................................................................................... 50 DDx of Plasma Cell-Rich Neoplasms......................................................................................................................................................... 50 Immunoprofiles of Select Hematopoietic Disorders.................................................................................................................................. 51 B-cell and Plasma Cell Neoplasms............................................................................................................................................................. 51 T-cell Neoplasms........................................................................................................................................................................................ 52 Other (Extranodal NK/T-cell lymphoma, Myeloid sarcoma, Paroxysmal Nocturnal hemoglobinuria)....................................................... 52 DDx of Post-transplant lymphoproliferative disorders................................................................................................................................ 53 Histiocytic and Dendritic Cell Lesions....................................................................................................................................................... 54 3 Immunostains: Antibody Index.......................................................................................................................................... 55 Justin Bishop, Amy Duffield, Diana Molavi, Natasha Rekhtman Common Multipurpose Immunostains at a Glance..................................................................................................................................... 55 Alphabetical Antibody Index......................................................................................................................................................................... 56 4 Special Stains....................................................................................................................................................................... 69 Justin Bishop, Jennifer Broussard, Natasha Rekhtman Quick Primer on Mucins............................................................................................................................................................................... 69 Special Stains at a Glance.............................................................................................................................................................................. 70 Carbohydrates: Glycogen and mucosubstances........................................................................................................................................... 70 Connective Tissue....................................................................................................................................................................................... 70 Other Common Applications...................................................................................................................................................................... 70 Microorganisms.......................................................................................................................................................................................... 71 Alphabetical Index of Special Stain by Jennifer Broussard, Natasha Rekhtman, Justin Bishop................................................................... 72 5 Grading (and Classification) Systems................................................................................................................................ 77 Justin Bishop, Amy Duffield, Diana Molavi, Natasha Rekhtman General............................................................................................................................................................................................................ 77 Grading of Adenocarcinoma, NOS............................................................................................................................................................. 77 Grading of Squamous Cell Carcinoma, NOS.............................................................................................................................................. 77 Breast.............................................................................................................................................................................................................. 78 Elston Grading of Infiltrating Breast Cancer............................................................................................................................................... 78 Nuclear Grading of Ductal Carcinoma in Situ............................................................................................................................................ 78 Grading of Phyllodes Tumor....................................................................................................................................................................... 78 Genitourinary Tract....................................................................................................................................................................................... 78 Prostate and Kidney.................................................................................................................................................................................... 79 Gleason Grading of Prostate Cancer........................................................................................................................................................... 79 Grading of Prostatic Intraepithelial Neoplasia............................................................................................................................................ 79 Fuhrman Nuclear Grading of Renal Cell Carcinoma.................................................................................................................................. 79 xviii Table of Contents Bladder and Wilms Tumor......................................................................................................................................................................... 80 The WHO (2003)/ISUP Consensus Classification of Non-invasive (In Situ) Papillary Urothelial Neoplasms........................................... 80 The WHO (2003)/ISUP Consensus Classification of Flat In Situ Urothelial Neoplasms........................................................................... 80 Wilms tumor: Criteria for Anaplasia (unfavorable histology)..................................................................................................................... 80 Head and Neck............................................................................................................................................................................................... 81 Grading of Thyroid Carcinomas................................................................................................................................................................. 81 Grading of Salivary Gland Carcinomas...................................................................................................................................................... 81 Mucoepidermoid Carcinoma, AFIP Grading System.................................................................................................................................. 81 Evaluation of Autoimmune Sialiadenitis (Sjögren’s Disease) in Labial Biopsy......................................................................................... 81 Gastrointestinal Tract.................................................................................................................................................................................... 82 Grading of Pancreatic Intraepithelial Neoplasia and Pancreatic Cystic Mucinous Neoplasms (IPMN and MCN)..................................... 82 Grading of Dysplasia in Barrett’s Mucosa.................................................................................................................................................. 83 Grading and Staging of Chronic Viral Hepatitis......................................................................................................................................... 83 Criteria for Acute Liver Allograft Rejection............................................................................................................................................... 83 Sarcoma Grading (not for the Faint of Heart!)........................................................................................................................................... 84 Neuroendocrine and Neuroectodermal Neoplasms..................................................................................................................................... 85 Pulmonary Neuroendocrine Neoplasms, WHO 2004 Classification........................................................................................................... 85 Gastroenteropancreatic Neuroendocrine Neoplasms, WHO 2010 Classification........................................................................................ 85 Neuroblastoma, Revised Shimada Grading System.................................................................................................................................... 86 Olfactory Neuroblastoma/Esthesioneuroblastoma, Hyams Grading System............................................................................................... 86 Central Nervous System................................................................................................................................................................................ 87 Meningioma, WHO Grading System.......................................................................................................................................................... 87 Gliomas, WHO Grading System................................................................................................................................................................. 87 Gynecologic Tract.......................................................................................................................................................................................... 88 Endometrioid Carcinoma, FIGO Grading................................................................................................................................................... 88 Smooth Muscle Neoplasms of the Uterus................................................................................................................................................... 88 Epithelioid Smooth Muscle Neoplasms of the Uterus................................................................................................................................. 88 Grading of Immature Ovarian Teratomas................................................................................................................................................... 88 Dating of Endometrium by Diana Molavi................................................................................................................................................... 89 Grading and Staging of Infections in the Placenta...................................................................................................................................... 89 Hematopoietic System by Amy Duffield......................................................................................................................................................... 90 Follicular Lymphoma, WHO Grading System............................................................................................................................................ 90 Diagnostic Criteria for Plasma Cell Disorders, 2009 Update...................................................................................................................... 90 Myelodysplastic Syndromes, WHO Classification..................................................................................................................................... 91 Acute Myeloid Leukemia NOS, WHO Classification................................................................................................................................. 92 Myeloproliferative Disorders, WHO Classification.................................................................................................................................... 93 Classification of Post-transplant Lymphoproliferative Disorders............................................................................................................... 94 Transplant Pathology.................................................................................................................................................................................... 95 Grading of Lung Allograft Rejection, ISHLT system................................................................................................................................. 95 Grading of Acute Graft-versus-Host Disease in Intestinal Biopsy.............................................................................................................. 95 Grading of Acute Graft-versus-Host Disease in Skin Biopsy..................................................................................................................... 95 The Good the Bad and the Ugly: Prognostic Features in Neoplasms with Difficult-to-Predict Behavior............................................... 96 Adrenocortical Neoplasms, Pheochromocytoma, Solitary Fibrous Tumor................................................................................................. 96 Gastrointestinal Stromal Tumor, Parathyroid Neoplasms, Sertoli and Leydig Cell Tumors....................................................................... 97 Criteria for “Micro-entities” in Various Organs......................................................................................................................................... 98 6 Potpourri of Quick Morphologic References.................................................................................................................... 99 Natasha Rekhtman and Justin Bishop Tumor Differentials 101................................................................................................................................................................................ 99 Generic Tumor Types................................................................................................................................................................................. 99 Tumors by Cell Type.................................................................................................................................................................................. 100 Tumors by Architectural Pattern................................................................................................................................................................. 100 Potpourri of Differentials............................................................................................................................................................................ 101 Benign Mimics of Malignancy 101 – watch out!........................................................................................................................................ 101 Small Round Blue Cell Tumors of Adulthood............................................................................................................................................ 102 Small Round Blue Cell Tumors of Childhood............................................................................................................................................ 103 Table of Contents xix Quick Guide to Identification of Microorganisms in Tissue....................................................................................................................... 103 There’s Fungus among us! Quick Reference for Histologic Identification of Fungi................................................................................... 104 Quick Reference for Histological Identification of Viruses........................................................................................................................ 107 Reference for Tumors with Viral Associations........................................................................................................................................... 108 7 Tumor Syndromes............................................................................................................................................................... 109 Justin Bishop, Ashlie Burkart, Natasha Rekhtman Quick Summary of Tumor Syndromes......................................................................................................................................................... 109 Multiple Endocrine Neoplasia Syndromes, Neurocutaneous Syndromes.................................................................................................... 109 Syndromes Associated with Renal Neoplasms, Syndromes Associated with Tumors of Bone................................................................... 110 Syndromes Associated with GI Polyps and Neoplasms by Ashlie Burkart and Natasha Rekhtman............................................................ 111 Syndromes Associated with Breast Cancer, Syndromes Associated with Skin Tumors.............................................................................. 113 Other........................................................................................................................................................................................................... 114 “Slide to Syndrome” by Justin Bishop, Ashlie Burkart, Natasha Rekhtman................................................................................................... 115 Lynch Syndrome: Clinicopathologic predictors and testing algorithms by Justin Bishop, Ashlie Burkhart, Natasha Rekhtman.............. 117 8 Tumor Genetics and Cytogenetics..................................................................................................................................... 119 Justin Bishop, Amy Duffield, Ashlie Burkhart, Natasha Rekhtman Molecular Associations at a Glance.............................................................................................................................................................. 119 Cytogenetic and Genetic Changes in Leukemia/Lymphoma by Amy Duffield............................................................................................ 120 B Cell Leukemia/Lymphoma...................................................................................................................................................................... 120 T Cell Leukemia/Lymphoma...................................................................................................................................................................... 120 Myeloid Leukemia and Myelodysplastic Syndrome................................................................................................................................... 121 Cytogenetic and Genetic Changes in Solid Tumors by Justin Bishop, Ashlie Burkhart, Natasha Rekhtman............................................... 122 Select Solid Tumors with Recurrent Genetic Alterations............................................................................................................................ 122 Brain and Meninges.................................................................................................................................................................................... 123 Recurrent Genetic Alterations in Select Carcinomas.................................................................................................................................. 123 9 Quick Clinical References for Pathologists....................................................................................................................... 125 Justin Bishop and Natasha Rekhtman Metastasis “To and From”: a Quick Reference............................................................................................................................................. 125 General principles....................................................................................................................................................................................... 125 Metastasis “From → To”............................................................................................................................................................................ 126 Metastasis “To → From”............................................................................................................................................................................ 127 Serologic Tumor Markers: Common Associations....................................................................................................................................... 128 Targeted Therapies and Predictive Markers – Welcome to the Future!...................................................................................................... 129 Solid Tumors............................................................................................................................................................................................... 129 Selected Hematopoietic Tumors................................................................................................................................................................. 130 10 Pathology Web Resources................................................................................................................................................... 131 Terina Chen 11 CPT (Current Procedural Terminology) Coding Quick Reference................................................................................ 135 Diana Molavi 12 It Looks Like WHAT? An Illustrated Glossary of Histopathologic Descriptors........................................................... 139 Natasha Rekhtman and Kathryn Villa References...................................................................................................................................................................................... 161 Subject Index................................................................................................................................................................................. 171 Unless otherwise specified, subsection authors are Justin Bishop and Natasha Rekhtman. Abbreviations, Acronyms, and Designations **See IHC index for alternative designations of antibodies/antigens AFIP – Armed Forces Institute of Pathology HTLV – Human T-lymphotropic virus AJCC – American Joint Committee on Cancer ID – identification or identify ALL – acute lymphoblastic leukemia/lymphoma IHC – immunohistochemistry AML – acute myeloid leukemia IPMN – intraductal papillary mucinous neoplasm BAC – bronchioloalveolar carcinoma ISH – in situ hybridization Bx – biopsy JHH – Johns Hopkins Hospital CA – carcinoma LMWCK – low molecular weight cytokeratins CD – cluster of differentiation (as in CD3, CD20, etc.) LN – lymph node CHR – chromogranin MCL – mantle cell lymphoma CIS – carcinoma in situ MCN – mucinous cystic neoplasm CK – cytokeratin(s) MD – moderately differentiated CLL/SLL – chronic lymphocytic leukemia/small lymphocytic ME – myoepithelial lymphoma MEC – myoepithelial cells CMV – cytomegalovirus Met – metastasis CNS – central nervous system MPNST – malignant peripheral nerve sheath tumor CRC – colorectal carcinoma MSKCC – Memorial Sloan-Kettering Cancer Center CT – computed tomography MZL – marginal zone lymphoma Derm – dermatopathology NE – neuroendocrine DNA – deoxyribonucleic acid NK – natural killer DDx – differential diagnosis NLPHL – nodular lymphocyte predominant Hodgkin Lymphoma DLBCL – diffuse large B cell lymphoma NOS – not otherwise specified Dx – diagnosis PCR – polymerase chain reaction EBV – Epstein-Barr virus PD – poorly differentiated EM – electron microscopy PEComa – perivascular epithelioid cell tumor ER – estrogen receptor PET – positron emission tomography FL – follicular lymphoma PNET – primitive neuroectodermal tumor GI – gastrointestinal PR – progesterone receptor GIST – gastrointestinal stromal tumor PTC – papillary thyroid carcinoma GU – genitourinary RBC – red blood cell GYN – gynecologic RCC – renal cell carcinoma HCC – hepatocellular carcinoma R-S cell – Reed Sternberg cell H&E – hematoxylin and eosin Rx – therapy, treatment H&N – head and neck SmCC – small cell carcinoma Heme – hematopathology SqCC – squamous cell carcinoma HHV8 – Human Herpesvirus 8 SRBCT – small round blue cell tumor HMWCK – high molecular weight cytokeratins SYN – synaptophysin HPF – high-power field (40X) TB – tuberculosis HPC – hemangiopericytoma vs. – versus HPV – human papillomavirus WD – well differentiated HSV – herpes simplex virus WHO – World Health Organization Immunohistochemistry reactivity code +++ Overexpressed or consistently diffuse + Positive +/– Usually positive –/+ Usually negative – Negative xxi Chapter 1 Immunostains: Introduction Immunostains: Introduction by Natasha Rekhtman and Justin Bishop Applications of Immunohistochemistry (IHC) in Anatomic Pathology (select examples) 1. DIAGNOSIS OF TUMORS: a. Classification of poorly differentiated neoplasms: carcinoma (cytokeratin+) vs. lymphoma (CD45+) vs. melanoma (S100+, Melan-A+, HMB45+) b. Diagnosis of carcinoma of unknown primary: colon (CDX2+) vs. lung (TTF-1+) vs. prostate (PSA+) c. Diagnosis of invasion: loss of myoepithelial cells (breast cancer) loss of basal cells (prostate cancer) loss of basement membrane/collagen type IV (various carcinomas, rarely used) 2. ASSESSMENT OF MARKERS REFLECTING PROGNOSIS (“PROGNOSTIC” MARKERS”): Ki67/MIB1 (general proliferation marker) p53 (general marker of apoptosis)1 HER2 (adverse prognosis in breast cancer) CD38 (adverse prognosis in chronic lymphocytic leukemia) 3. ASSESSMENT OF MARKERS REFLECTING A THERAPEUTIC RESPONSE (“PREDICTIVE” OR “THERANOSTIC” MARKERS): ER/PR (Tamoxifen for breast cancer) HER2 (Herceptin for breast cancer) c-kit (Gleevec for GIST, CML, other; mutations more predictive than IHC) 4. DETECTION OF MICROMETASTASES: melanoma (melanocytic markers) breast cancer (cytokeratins) 5. IDENTIFICATION OF INFECTIOUS ORGANISMS2: viruses (HSV, CMV) other organisms (Toxoplasma, Pneumocystis) 1. It may appear counterintuitive that p53, a well-known tumor-suppressor, is overexpressed in various tumors. This occurs because inactivating mutations in p53 also disable protein degradation and lead to a robust p53 overexpression. In essence, robust overexpression of p53 is used as a surrogate marker for p53 gene mutation. 2. Currently IHC is not widely used to identify bacteria and fungi (this is likely to change). These organisms are primarily evaluated by special stains (such as GMS), and some viruses may be identified by in situ hybridization (EBV, HPV). N. Rekhtman, J.A. Bishop, Quick Reference Handbook for Surgical Pathologists, 1 DOI:10.1007/978-3-642-20086-1_1, © Springer-Verlag Berlin Heidelberg 2011 2 1 Immunostains: Introduction. General Background. Markers of Differentiation at a Glance Immunostains: Introduction Differentiation Markers Mesenchymal Vimentin Epithelial Cytokeratins, EMA [see “epithelial primer”] Smooth muscle Desmin, muscle-specific actin, smooth muscle actin, Calponin, h-Caldesmon, smooth muscle myosin heavy chain [see “muscle primer”] Skeletal muscle Desmin, muscle-specific actin, myogenin, MyoD [see “muscle primer”] Myofibroblastic Partial smooth muscle phenotype: actins (MSA, SMA) in “tram-track” distribution, calponin, but not h-caldesmon [see “muscle primer”] Myoepithelial Polyphenotypic markers: smooth muscle (complete phenotype – smooth muscle actin, calponin, other), neural (S100), glial (GFAP), epithelial (CK), and basal/stem cell factor (p63) [see “muscle primer”] Endothelial CD34, CD31, Factor VIII, Ulex europaeus I, CD141, Fli-1, D2-40 [see “vascular primer”] Lipomatous S100 (immunos generally not used) Melanocytic S100, HMB45, Melan-A/MART-1, MITF, Tyrosinase [see “melanocytic primer”] Neuroendocrine SYN, CHR, NSE, CD56, CD57 [see “neuroendocrine primer”] Glial GFAP [see “neuroglial primer”] Neuronal Neurofilament, NeuN, SYN, CHR [see “neuroglial primer”] Nerve Sheath (Schwannian) S100 [see “neuroglial primer”] Serous Acinar Cells PAS (general), Trypsin, Chymotrypsin, and Lipase (pancreas) Hematopoietic CD45/LCA (pan-hematopoietic), CD3 (pan-T cell), CD20, CD79a, PAX5 (pan-B cell), CD138 & κ/λ light chains (plasma cell) [see hemepath section] Histiocytic CD68, CD163, HAM56, MAC 387, enzymes (Lysozyme/Muramidase, α1-antitrypsin) [see hemepath section] 1 Immunostains: Introduction. General Background. 3 Location, Location, Location! Immunostains: Introduction Primer on Location of Antigens. In order to properly interpret immunoreactivity, it is important to know the expected location of the antigen of interest. Knowing the biological function of a molecule of interest can be very helpful in intuitively anticipating the site of reactivity. Transcription factors (TTF-1, CDX2, Myogenin, PAX2, WT1, p53, p63) and steroid hormone receptors (ER, PR) function in the nucleus, and therefore the expected IHC signal is nuclear. Ki67, a molecule with still unelucidated function, is also nuclear (except for peculiar membra- nous/cytoplasmic reactivity in hyalinizing trabecular adenoma of thyroid). In contrast, cytoskeletal, contractile, and other functional proteins are cytoplasmic. In fact, the majority of antigens in current use are cytoplasmic. This category includes all intermediate filaments (CK, Desmin, Vimentin, GFAP, Neurofilament), contractile proteins (Actin), melanosome- associated proteins (HMB45, Melan-A), secretory products (ACTH, Trypsin), and various other functional molecules. Membranous reactivity is expected for receptors (EGFR), adhesion molecules (E-Cadherin) and other surface molecules. This category includes virtually all CD (cluster of differentiation) antigens, such as CD3 (T cell marker) and CD20 (B cell marker). Occasionally, membranous reactivity may be difficult to distinguish from cytoplasmic signal; this distinction is important for several molecules where only membranous but not cyto- plasmic reactivity counts as specific (HER2, EGFR). Although rare, several antigens have a characteristic combined nuclear AND cytoplasmic reactivity. This category most notably includes S100 and Calretinin. β-catenin is cytoplasmic in most cell types. However, it is a shift to nuclear reactivity that is a specific feature of several tumor types associated with mutations in adenomatosis polyposis coli /β-catenin pathway, such as deep fibromatosis and colon cancer. Granular reactivity usually indicates localization to cytoplasmic organelles (mitochondria, Golgi, secretory vesicles, etc). Distinctive granular cytoplasmic reactivity is typical of Racemase (mitochondrial/peroxisomal), Prostein/P501S (Golgi), and Napsin A (lysosomal). Dot-like CD30 in ALCL and classical HL, and CD15 in classical HL are attributed to Golgi staining, and are seen in conjunction with typical membranous staining generating the so-called “targetoid” or “ball and chain” appearance. Finally, “punctate” (aka peri-nuclear dot-like) reactivity is typical of some antigens that aggregate in the cytoplasm, most notably CK pattern in neuroendocrine carcinomas, including small cell carcinoma (pan-CK) and Merkel cell carcinoma (CK20). This occurs due to formation of CK tangles. Note that there are some instances in which the lack of immunoreactivity is what is significant. One example is the loss of DPC4, a protein deleted in 55% of pancreatic carcinomas, which supports the diagnosis of a pancreatic primary. Other examples are the loss of E-cadherin in lobu- lar carcinoma of the breast and loss of INI1 in rhabdoid tumors and AT/RT. Beware of classic false-positives (tissue edge-effect, non-specific staining of hepatocytes due to high albumin content), and classic false negative as a result of failed IHC (always check controls, particularly normal structures serving as internal positive controls). Also beware of non-specific cytoplasmic reactivity for antigens with expected nuclear localization (such as TTF-1 or ER) – this should not be accepted as a specific signal! Nuclear Reactivity: Transcription factors (TTF-1, CDX2, Myogenin, WT1, p53, p63) Steroid hormone receptors (ER, PR) Other (Ki67) Membranous Reactivity: Cytoplasmic Reactivity: CD anything (CD3, CD20, etc) Intermediate Filaments (CK, Desmin, Vimentin, etc) Surface receptors (HER2, EGFR) Contractile proteins (Actin) Adhesion molecules (E-cadherin) Secretory products (ACTH) Other functional proteins Nuclear AND Cytoplasmic Reactivity: S100, Calretinin, Cytoplasmic Granular Reactivity: β-catenin (only nuclear reactivity is specific) Racemase, Prostein (P501S), Napsin A, HepPar1 Cytoplasmic Dot-like Reactivity: CD30 and CD15 in Hodgkin Lymphoma, CKs in neuroendocrine tumors Abbreviations: ALCL anaplastic large cell lymphoma, HL Hodgkin lymphoma, CK cytokeratins 4 1 Immunostains: Introduction. General Background. Primer on Cytokeratins Immunostains: Introduction Cytokeratins (CK) are cytoskeletal proteins that belong to a family of intermediate filaments (IFs). CKs are present in epithelial cells and are regarded as the most fundamental markers of epithelial differentiation. Other members of IF family are also used as markers of differentiation, in- cluding Vimentin (for mesenchyme), GFAP (for glia), Desmin (for muscle) and Neurofilament (for neurons). There are 20 distinct types of CKs (plus hair and nail-specific CKs). CKs were characterized by Moll et al. and the currently used CK designation system is known as the “Moll’s catalogue.” CKs are designated in a somewhat non-intuitive fashion based their migration pattern in a two-dimensional (2D) gel electrophoresis, which sepa- rates proteins based on size and charge. Based on the 2D gel migration, CKs fall into two categories: basic (CK1 through 8) and acidic (CK9 through 20). Within each group, CKs are numbered in order of decreasing size, from high molecular weight (HMW) to low molecular weight (LMW), as diagramed below. Basic CK Acidic CK (Type B / Class II): (Type A / Class I): CK1 HMW CK 9 CK2 CK10 HMWCK “squamous CK3 CK11 (Ab: CK903, keratins” CK4 : CK5/6) CK5 CK16 CK6 CK17 CK7 CK18 “simple/non-squamous CK8 CK19 LMWCK LMW keratins” CK20 (Ab: Cam 5.2) Basic CKs Acidic CKs (Ab: AE3) (Ab: AE1) In a cell, CKs exist as heterodimers, composed of acidic + basic subunits of a similar size. Therefore certain pairs of CKs (such as CK8/18, CK1/10) are expressed jointly. For diagnostic purposes, CKs are divided as LMWCK and HMWCK, as indicated on the diagram. This division corresponds to a distinctive distribution of these two groups of CKs in normal tissues: − HMWCKs are expressed predominantly in squamous epithelia (and in basal cells), and they are known as “squamous keratins”. HMWCKs are large, and they are able to form a dense cytoplasmic network of filaments, accounting for resistance to mechanical stress of the surface epi- thelia. Large bundles of HMWCKs are known ultrastructurally (by electron microscopy) as “tonofilaments”, and these structures are the hall- mark of squamous epithelia and SqCC. − In contrast, LMWCKs are loosely distributed in the cytoplasm and are unable to bundle. They are therefore characteristic of visceral organs, which experience little mechanical stress (such as liver, kidney, and various glandular epithelia). LMWCK are known as “non-squamous or simple keratins”. LMWCK are expressed in all epithelial tissues with the exception of keratinizing squamous epithelium. Note that some glandular epithelia (such as breast) do co-express HMWCK in addition to LMWCK, and HMWCK can be induced in non-squamous epithelia as a result of reactive conditions (such as inflammation). So the rule of thumb “squamous epithelium=HMWCK” vs. “non-squamous epithe- lium=LMWCK” is not 100%. − A designation of “intermediate molecular weight CKs” is occasionally applied, which refers to the lighter CKs within the HMWCK group (CK 5,6,17). These are also known as “basal keratins” because they are expressed preferentially in basal cells. The above patterns of CKs are generally retained in corresponding carcinomas, and can serve as useful diagnostic tools. As a word of caution – some carcinomas deviate from CK patterns of their parent epithelia. For example, high-grade SqCC frequently co-expression LMWCKs in addi- tion to HMWCKs. In addition, some adenocarcinomas are well-known to co-express HMWCKs (such as carcinomas of pancreas, endometrium, and subset of breast). To increase the yield of diagnostic IHC, expression of CKs is usually analyzed by mixtures of various CK antibodies (Abs), known as “Ab cock- tails”. The commonly used Ab cocktails include: Antibody Cocktail What it detects AE1 All acidic CKs except CK 9, 12, 17, 18 AE3 All basic CKs (CK1–8) AE1/AE3 (pan-CK) All types of CKs OSCAR, PANK (MNF-116) Broad-spectrum CK cocktail (similar to AE1/AE3) Cam 5.2 (34βH11) LMWCKs (CK 8, 18) CK903 (K903; 34βE12) HMWCKs (CK 1, 5, 10, 14) CK5/6 HMWCKs (detects primarily CK5) 1 Immunostains: Introduction. General Background. 5 Immunostains: SUMMARY Introduction Epithelium Type Corresponding Carcinoma CK profile Antibody Reactivity Squamous & basal cells Squamous cell carcinoma CK903 HMWCK1 CK5/6 Glandular epithelia (bowel, prostate, etc) & Colon adenocarcinoma Pan-CK visceral parenchyma (liver, kidney, etc)

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