Haeryoung Kim · Wei-Qiang Leow · Regina Lo · Paulo Giovanni L. Mendoza · Anthony Wing-Hung Chan Atlas of Hepatocellular Carcinoma Pathology 123 Atlas of Hepatocellular Carcinoma Pathology Haeryoung Kim • Wei-Qiang Leow • Regina Lo Paulo Giovanni L. Mendoza Anthony Wing-Hung Chan Atlas of Hepatocellular Carcinoma Pathology Haeryoung Kim Wei-Qiang Leow Department of Pathology Department of Anatomical Pathology Seoul National University Hospital Singapore General Hospital Seoul National University College of Medicine Singapore Seoul Singapore Korea (Republic of) Paulo Giovanni L. Mendoza Regina Lo Pathology and Laboratory Department Department of Pathology and State Key Cardinal Santos Medical Center Laboratory of Liver Research (HKU) San Juan The University of Hong Kong Philippines Hong Kong China Anthony Wing-Hung Chan Department of Anatomical and Cellular Pathology The Chinese University of Hong Kong Shatin Hong Kong ISBN 978-981-16-8499-9 ISBN 978-981-16-8500-2 (eBook) https://doi.org/10.1007/978-981-16-8500-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore My mentor, Young Nyun Park, for guiding me into this beautiful world of liver pathology. My parents, CK and BH, for their love and support. HAERYOUNG KIM My wife, Audrey, for being the bedrock of my life. My children: Sean, Jeanne, Ean, and Leanne, for giving me the impetus to work hard. My mentors, Swan, Tony, and Puay Hoon, for showing me what excellence is. WEI-QIANG LEOW All mentors at different stages of my life who enlightened and encouraged me with a kind heart. REGINA LO My wife, Angela, for being my inspiration and companion in this journey. My folks: Dolly, Victor; My siblings: Carlo and Dessa for being the constant strength that binds. My mentors, Neil, Isabel and Tony, for the dedication to share what they do best. To our patients who continue to drive us to be excellent and persevering. PAULO GIOVANNI L. MENDOZA My wife, Joanna, and my aunt, PC, for their unreserved love, support, and encouragement. My mentors, Alastair, Fernand, and KF, for shepherding me into the amazing world of pathology. ANTHONY WING-HUNG CHAN Preface This fledging group, based in different parts of Asia such as Hong Kong, Philippines, Singapore, and South Korea, shares a common love and passion for liver pathology. Having been schooled by some of the world’s most eminent hepatopathologists: Professors Alastair Burt, Irene Ng, Young Nyun Park, Neil Theise, and Swan Thung, the group members grew in knowledge and confidence through robust discussion, sharing of the current literature and evidence. It wasn’t long before when a name for this group was contemplated, and inspired by the impact of suc- cessful liver pathology study groups such as the Gnomes (International Liver Pathology Group) and Elves (International Liver Pathology Study Group); the name “smurfs” emerged. The steady cultivation of this academic kinship resulted in endeavors for the smurfs to meet in-person, with soirees in the springtime of the 2019 United States and Canadian Academy of Pathology (USCAP) Annual Meeting and 2019 Hong Kong International Academy of Pathology (HKIAP) Fall Scientific Meeting. It was in the midst of the COVID- 19 pandemic that the proposal to compile an Atlas of Hepatocellular Carcinoma (HCC) Pathology originated from our doyen Dr. Anthony Wing-Hung Chan. This proposal was met with enthusiasm and it is this critical moment that represents the smurfs’ first step into such a formal academic pursuit. The incidence of liver cancer is growing worldwide and it is the 3rd leading cause of cancer- associated deaths globally. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for up to 85% of primary liver cancers. Of note, about three quarters of liver cancer patients are Asian, resulting in a wealth of cases in the backyards of the smurfs, whose practices include university hospitals, academic medical centers as well as private labo- ratories. Furthermore, the spotlight on the various subtypes of HCCs in the 2019 Digestive System Tumours of the 5th edition WHO Classification of Tumours, makes it timely for prac- ticing pathologists to take a deeper dive into the various histomorphologies and nuances of HCCs, in order to render an updated modern diagnosis. Against this backdrop, the Atlas of HCC Pathology is a visual smorgasbord with over 550 high-quality photos and concise synopses. It also strives to be holistic by encompassing not only chapters of the various HCC subtypes, but also chapters that illustrate the value of gross morphology, tackle the challenging aspects of precursor lesions, and clarify the controversial combined hepatocellular-cholangiocarcinoma entity. In this era of rapid locoregional and sys- temic therapy advances, the Atlas also covers post-treatment changes. To equip pathologists with the knowledge to yield the armamentarium of ancillary histochemical and immunohisto- chemical stains, a comprehensive chapter illustrating the use of stains is included. And lastly, in line with the spirit of the smurfs’ sharing and discussion of challenging cases, a chapter that highlights the dilemmas and differential diagnoses of HCC concludes the Atlas’s offerings. The authors hope that the Atlas of HCC Pathology will be a useful reference not only for vii viii Preface pathologists and pathologists-in-training striving to refine their diagnoses of liver cancer but also for the established field of liver cancer researchers who work tirelessly to uncover the secrets of this enigmatic cancer. Seoul, Republic of Korea Haeryoung Kim Singapore, Singapore Wei-Qiang Leow Hong Kong, China Regina Lo San Juan, Philippines Paulo Giovanni L. Mendoza Shatin, Hong Kong Anthony Wing-Hung Chan Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2 Precursor Lesions of Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1 Dysplastic Foci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1.1 Large Cell Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1.2 Small Cell Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1.3 Iron-Free Foci . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.2 Dysplastic Nodules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2.1 Low-Grade Dysplastic Nodule. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2.2 High-Grade Dysplastic Nodule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.3 Early Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.4 Hepatocellular Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.4.1 β-Catenin-Activated HCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 3 Gross Morphology of Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3.1 Gross Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4 General Histopathological Features of Hepatocellular Carcinoma . . . . . . . . . . . . 31 4.1 Architectural Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.2 Cytological Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.3 Differentiation and Grading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4.4 The Tumour Microenvironment of HCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 4.5 Other Histopathological Features of HCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 4.6 Multiplicity: Intrahepatic Metastasis Versus Multicentric Occurrence . . . . . . . . 45 4.7 Prognostic Factors of HCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 5 Fibrolamellar Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 5.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 5.2 Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 6 Steatohepatitic Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 6.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 6.2 Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 7 Clear Cell Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 7.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 7.2 Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 ix x Contents 8 Macrotrabecular-Massive Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . 61 8.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 8.2 Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 9 Scirrhous Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 9.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 9.2 Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 10 Lymphocyte-Rich Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 10.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 10.2 Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 11 Other Uncommon Histological Variants of Hepatocellular Carcinoma . . . . . . . . 77 11.1 Chromophobe Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 11.2 Neutrophil-Rich Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 11.3 Sarcomatoid Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 11.4 Cirrhotomimetic Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 11.5 Myxoid Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 12 Hepatocellular Carcinoma with Cytokeratin 19 Expression . . . . . . . . . . . . . . . . . 85 12.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 12.2 Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 13 Combined Hepatocellular- Cholangiocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 13.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 13.2 Synopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 14 Post-treatment Changes of Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . 97 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101 15 Ancillary Tests for Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103 15.1 Differentiation Between Hepatocellular Carcinoma and Benign Hepatic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103 15.2 Determination of Hepatocellular Differentiation . . . . . . . . . . . . . . . . . . . . . . . .108 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .142 16 Tumour Staging for Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . .145 16.1 American Joint Committee on Cancer Tumour-Node-Metastasis Staging . . . .145 16.2 Assessment of Liver Functional Reserve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .145 16.3 Barcelona Clinic Liver Cancer Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148 16.4 Hong Kong Liver Cancer Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .151 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .152 17 Differential Diagnoses of Hepatocellular Carcinoma . . . . . . . . . . . . . . . . . . . . . . .155 17.1 Focal Nodular Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .155 17.2 Hepatocellular Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .157 17.3 Angiomyolipoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .160 17.4 Cholangiocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .163 Contents xi 17.5 Hepatoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .166 17.6 Neuroendocrine Neoplasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169 17.7 Hepatoid Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .173 17.8 Metastatic Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .176 17.9 Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .178 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .192