Thyroid FNA Cytology: Differential Diagnoses and Pitfalls [3 ed.] 9819967813, 9789819967810

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Zhiyan Liu · DanielKennichi Kakudo · J. Mollura Chan Kwon Jung · Matthew P. Lungren Mitsuyoshi Hirokawa · Andrey Bychkov · Michael R.B. Evans Chiung-Ru Lai   Editors Editors

ThyroidMedicine FNA Clinical Covertemplate Cytology Subtitle for Differential Diagnoses and Pitfalls Clinical Medicine Covers T3_HB Third Edition Second Edition

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Thyroid FNA Cytology

Kennichi Kakudo  •  Zhiyan Liu Chan Kwon Jung  •  Mitsuyoshi Hirokawa Andrey Bychkov  •  Chiung-Ru Lai Editors

Thyroid FNA Cytology Differential Diagnoses and Pitfalls Third Edition

Editors Kennichi Kakudo Department of Pathology Cancer Genome Center & Thyroid Disease Center, Izumi City General Hospital Izumi, Osaka, Japan Chan Kwon Jung Department of Pathology Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Seoul, Korea (Republic of) Andrey Bychkov Department of Pathology Kameda Medical Center Kamogawa, Japan

Zhiyan Liu Department of Pathology Shanghai Sixth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China Mitsuyoshi Hirokawa Department of Diagnostic Pathology and Cytology Kuma Hospital Kobe, Japan Chiung-Ru Lai Department of Pathology and Laboratory Medicine Taipei Veterans General Hospital Taipei, Taiwan

ISBN 978-981-99-6781-0    ISBN 978-981-99-6782-7 (eBook) https://doi.org/10.1007/978-981-99-6782-7 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2019, 2023 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 Paper in this product is recyclable.

Preface to the Third Edition

The first edition of Thyroid FNA Cytology: Differential Diagnoses and Pitfalls was published in 2016. It was the first textbook on thyroid fine needle aspiration (FNA) cytology from Asia, written in English. The second edition, published in 2019, was inspired by new developments and received contributions from many more international authors. Due to several breakthrough events in the field of thyroid pathology and cytopathology, such as the wider implementation of ancillary techniques, molecular studies, and the publication of the fifth edition WHO Classification of Thyroid Tumors along with the upcoming release of the Bethesda System, the editors are urged to publish the third edition. In recent years, the editors were reassured that diagnostic criteria for specimen adequacy, malignancy, and clinical management guidelines vary significantly among countries and continents. While most pathologists follow the WHO classification and rely on international clinical guidelines, there are marked differences between reports published by Asian and European/ North American pathologists. These regional differences may be due to epidemiological variances, socioeconomic conditions, available medical resources, different insurance systems, national clinical practice guidelines developed by specific countries, and medical expenses. This phenomenon along with the national and international reporting systems of thyroid FNA and the new edition of the WHO Classification of Thyroid Tumors will be discussed in the first part of the book. In the second part, the diagnostic criteria, differential diagnosis, and pitfalls for each cytologic category of benign, borderline, and malignant thyroid lesions will be thoroughly discussed. This will emphasize the divergent opinions of the international expert authors. The next part of the book will cover the techniques and ancillary tests used for thyroid FNA specimens. Readers will be introduced to various technologies, from the preparation of conventional FNA samples, liquid-based preparations, and cell blocks to rapid on-site evaluation, and molecular studies. By understanding these new technologies, readers will better understand how to achieve a more precise cytologic diagnosis. The final part of the book will cover the clinical management guidelines and rationales in thyroid nodule practice. It is crucial for cytopathologists and clinicians to communicate effectively. The chapters in this section will help both pathologists and clinicians provide the best management for patients with thyroid nodules or tumors. The third edition of Thyroid FNA Cytology: Differential Diagnoses and Pitfalls is the only textbook that emphasizes regional differences in the practice of thyroid FNA.  The editors intentionally included divergent opinions so that readers can select the most appropriate strategy for their own thyroid practice after understanding the merits and demerits of each. The third edition is significantly expanded to cover a wide range of topics related to thyroid FNA cytology and consists of 95 richly illustrated chapters authored by international experts from 20 countries. This book utilizes a case-based approach simulating real-world situations. The readers will learn how to interpret thyroid FNA, narrow the differential diagnosis, and arrive at a correct diagnosis.

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Preface to the Third Edition

The editors express deep appreciation to all authors who contributed to this edition and hope that it will serve as a handbook for daily thyroid practice, not only for cytopathologists but also for other thyroid specialists such as cytotechnologists, endocrinologists, surgeons, radiologists, and nuclear medicine doctors. Taipei, Taiwan Kamogawa, Japan  Shanghai, China  Seoul, Republic of Korea  Kobe, Japan  Izumi, Japan 

Chiung-Ru Lai Andrey Bychkov Zhiyan Liu Chan Kwon Jung Mitsuyoshi Hirokawa Kennichi Kakudo

Preface to the First eBook Edition

Thyroid fine needle aspiration (FNA) cytology is the most widely used clinical test for patients with thyroid nodules. This can be attributed to its accuracy and reliability in identifying high-­ risk patients who should undergo surgical treatments. It has been nearly 10 years since the National Cancer Institute of the United States proposed a reporting system for thyroid FNA cytology [1]. Following this recommendation, Italy, England, and Japan developed their own reporting systems comparable with the American (Bethesda) system [2–4]. These diagnostic systems have contributed to significantly better performance in thyroid cytology and improved communication among the different cytology practices. All four diagnostic systems focused on the standardization of (1) diagnostic terminologies, (2) clinical management, and (3) risks of malignancy. However, there remain a few pitfalls that are important to address for cytopathologists to achieve a good performance in their practice. This eBook, Thyroid FNA Cytology, Differential Diagnoses and Pitfalls, focuses on how to avoid such pitfalls in thyroid FNA cytology. Good performance in your practice can only be achieved when you become familiar with these pitfalls and differential diagnoses in detail. The thyroid experts included in this eBook demonstrate how to bypass these pitfalls using beautiful case presentations and detailed differential diagnoses based on their rich experiences and evidence from the literature. We believe this approach is essential for establishing high-level performance in thyroid FNA cytology, regardless of the diagnostic system used. This eBook is the first English textbook of thyroid FNA cytology published from Asia, and all authors are of Asian background. The editors thank all contributors and appreciate their great efforts in helping publish this eBook. References 1. Ali SZ, Cibas ES, editors. The Bethesda system for reporting thyroid cytopathology. Definitions, criteria and explanatory notes. New York: Springer; 2010. 2. Fadda G, Basolo F, Bondi A, Bussolati A, Crescenzi O, et al. Cytological classification of thyroid nodules. Proposal of the SIAPEC-IAP Italian consensus working group. Pathologica. 2010;102:405–6. 3. Lobo C, McQueen A, Beale T, Kocjan G. The UK Royal College of Pathologists thyroid fine-needle aspiration diagnostic classification is a robust tool for the clinical management of abnormal thyroid nodules. Acta Cytol. 2011;55:499–506. 4. Kakudo K, Kameyama K, Miyauchi A, Nakamura H. Introducing the reporting system for thyroid fine-needle aspiration cytology according to the new guidelines of the Japan Thyroid Association. Endocr J. 2014;61:539–52.

Izumi, Japan Shanghai, China  Kobe, Japan 

Kennichi Kakudo Zhiyan Liu Mitsuyoshi Hirokawa

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Preface to the First Print Edition

We are happy to provide you a print edition of Thyroid FNA Cytology: Differential Diagnoses and Pitfalls. As there is a file size limit in the eBook edition, some important illustrations were deleted, and the quality of all illustrations was reduced. To circumvent these issues, the print edition was published. In the print edition, we provide you with all of the original illustrations in high quality, and we have incorporated additionally illustrations that were deleted from the eBook edition. The editors proudly announce that this is the first and only textbook for thyroid FNA cytology that incorporates borderline tumor categories in thyroid tumor classification, which are hyalinizing trabecular adenoma identified by Carney et  al. [1], well-differentiated tumor of uncertain malignant potential and follicular tumor of uncertain malignant potential proposed by Williams [2], the recent reclassification of some indolent tumors currently classified as carcinoma into the borderline tumor category proposed by Kakudo et al. [3–7] and noninvasive follicular thyroid neoplasm with papillary-like nuclear features, a nomenclature revision of noninvasive encapsulated follicular variant papillary thyroid carcinoma proposed by Nikiforov et al. [8–15]. The eBook edition was the first English-language thyroid FNA cytology textbook published in Asia. In the print edition, we invited additional authors, and we would like to highlight the new supplementary chapters only available in this print edition. Finally, this print edition is a more comprehensive and international textbook than our eBook edition. The editors of the print edition thank all authors sincerely and acknowledge their great efforts and contributions to this book. References 1. Carney JA, Hirokawa M, Lloyd RV, et al. Hyalinizing trabecular tumors of the thyroid gland are almost all benign. Am J Surg Pathol. 2008;32:1877–89. 2. Williams ED. Guest editorial: two proposals regarding the terminology of thyroid tumors. Int J Surg Pathol. 2000;8:181–3. 3. Kakudo K, Bai Y, Katayama S, et  al. Classification of follicular cell tumors of thyroid gland: analysis involving Japanese patients from one institute. Pathol Int. 2009;59:359–67. 4. Liu Z, Zhou G, Nakamura M, et al. Encapsulated follicular thyroid tumor with equivocal nuclear changes, so-called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal. Cancer Sci. 2011;102:288–94. 5. Kakudo K, Bai Y, Liu Z, et al. Classification of thyroid follicular cell tumors: with special reference to borderline lesions. Endocrine J. 2012;59:1–12. 6. Kakudo K, Bai Y, Liu Z, et al. Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer. Pathol Int. 2012;62:155–60. 7. Nishigami K, Liu Z, Taniguchi E, et al. Cytological features of well-differentiated tumors of uncertain malignant potential: indeterminate cytology and WDT-UMP.  Endocrine J. 2012;59:483–7.

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8. Liu J, Singh B, Tallini G, et al. Follicular variant of papillary carcinoma. A clinicopathologic study of a problematic entity. Cancer. 2006;107:1255–64. 9. Rivera M, Ricarte-Filho J, Knauf J, et  al. Encapsulated papillary thyroid carcinoma: A clinic-pathologic study of 106 cases with emphasis on its morphologic subtypes (histologic growth pattern). Mod Pathol. 2010;23:1191–200. 10. Ganly I, Wang L, Tuttle RM, et al. Invasion rather than nuclear features correlates with outcome in encapsulated follicular tumors: further evidence for the reclassification of the encapsulated papillary thyroid carcinoma follicular variant. Hum Pathol. 2015;46:657–64. 11. Nikiforov Y, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016. https://doi.org/10.1001/jamaoncol.2016.0386. [Epub ahead of print]. 12. Strickland KC, Howitt BE, Marquesee E, et al. The impact of non-invasive follicular variant of papillary thyroid carcinoma on rates of malignancy for fine-needle aspiration diagnostic categories. Thyroid. 2015;25:987–92. 13. Liu X, Medici M, Kwong N, et al. Bethesda categorization of thyroid nodule cytology and prediction of thyroid cancer type and prognosis. Thyroid. 2015. [Epub ahead of print]. 14. Faquin WC, Wong LQ, Afrogheh AH, et al. Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in the Bethesda system for reporting thyroid cytopathology. Cancer Cytopathol. 2015. https://doi.org/10.1002/ cncy.21631. [Epub ahead of print]. 15. Maletta F, Massa F, Torregrossa L et al. Cytological features of “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” and their correlation with tumor histology. Hum Pathol. 2016. https://doi.org/10.1016/j.humpath.2016.03.014. [Epub ahead of print].

Izumi, Japan Shanghai, China  Kobe, Japan 

Kennichi Kakudo Zhiyan Liu Mitsuyoshi Hirokawa

Preface to the Second Edition

There were several breakthrough events in thyroid fine needle aspiration (FNA) cytology recently, which included the introduction of borderline tumors in the fourth edition World Health Organization (WHO) Classification of thyroid tumors [1–6]. In addition, the second edition of the Bethesda diagnostic system changed the diagnostic criteria of papillary thyroid carcinoma (PTC) to incorporate this new tumor entity in thyroid FNA cytopathology [7–12]. We will soon come to the end of a historic period in thyroid pathology, when pathologists have had only two diagnostic choices (benign and malignant) for thyroid tumors and enter a new era with three choices (benign, borderline, and malignant) similar to other organ systems [5, 13–16] (Fig.  1). The second edition of Thyroid FNA Cytology, Differential Diagnoses and Pitfalls accepted and incorporated these modifications in the newest WHO classification and established strategies on how to solve newly identified issues appeared after 2017. The editor believes that this textbook is the only one that is prepared for the paradigm shift occurring in thyroid tumor classification. Furthermore, after publication of the first edition in 2016, the editor found significant differences among practices [17–20]. One of the best examples was how molecular tests were available and accessible in practice because these were not covered by health insurance systems in the majority of countries. Readers can find how developed countries apply molecular tests in thyroid nodule practice in Chap. 60 by Ohori (an example from North American practice) and more cost-effective methods in Chap. 59 by Bongiovanni (in European practice) and Chap. 61 by Pyo (in Korean practice). Without molecular tests, you can find in Chap. 10 by Ito and Miyauchi, Chap. 22 by Kakudo and Chaps. 42 and 43 by Kameyama (in Japanese practice), how risk stratification of patients with indeterminate nodules for surgery can be achieved as an active surveillance (close follow-up without immediate diagnostic

Fig. 1  Changing concepts in thyroid cytology and histology correlation study. Traditional view (upper) based on the 3rd edition WHO classification with only two diagnostic choices, benign and malignant tumors, and current view (lower) based on the 4th edition WHO classification with three diagnostic choices, benign, borderline, and malignant tumors. Borderline/Precursor lesions include neoplastic lesions without clear evidence of invasion or minimally invasive, with or without papillary-like nuclear features. The AUS and FN categories are not “indeterminate” but clear-cut categories aimed to accommodate thyroid borderline/precursor tumors (equivalent to dysplasia/carcinoma in situ). AUS atypia of undetermined significance, FN follicular neoplasm xi

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surgery to identify high-risk nodules for progression). As a consequence, all of these thyroid FNA practices identify thyroid carcinomas effectively, which may prevent unnecessary invasive tests in patients with benign nodules or low-risk thyroid carcinoma. For the purpose of providing individualized guides to readers who are practicing in various geographic areas with different medical settings and social resources, the second edition tries to cover more than those provided by the first edition, and authors from 15 countries (Australia, Canada, China, Korea, Japan, Italy, Philippines, Portugal, Switzerland, Taiwan, Thailand, Turkey, Ukraine, the United Kingdom, the United States) invited to participate. The editor of Thyroid FNA Cytology, Differential Diagnoses and Pitfalls has intentionally provided several topics in duplicate chapters by different authors to show you how they are handled differently, so that readers may select the most suitable and appropriate one related to each reader’s thyroid practice and FNA cytology. The editor hopes that readers will enjoy reading these topics and compare the differences among them, as in any other existing textbooks on thyroid FNA cytology focusing on only one country. To understand others is thought-­ provoking and can provide surprises on how thyroid FNA cytology is operated on differently among countries. The editor believes that this approach can increase knowledge and broaden perspectives. The editor thanks all the authors who have contributed to this textbook—Thyroid FNA Cytology, Differential Diagnoses and Pitfalls—for their valuable contributions from all over the world, which make this textbook truly international. References 1. Lloyd RV, Osamura RY, Klöppel G, Rosai J, editors. WHO classification of tumours of endocrine organs. 4th ed. Lyon: IARC; 2017. 2. Carney JA, Hirokawa M, Lloyd RV, et al. Hyalinizing trabecular tumors of the thyroid gland are almost all benign. Am J Surg Pathol. 2008;32:1877–89. 3. Williams ED. Guest editorial: two proposal regarding the terminology of thyroid tumors. Int J Surg Pathol. 2000;8:181–3. 4. Liu Z, Zhou G, Nakamura M, Koike E, et al. Encapsulated follicular thyroid tumor with equivocal nuclear changes, so-called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal. Cancer Sci. 2011;102:288–94. 5. Kakudo K, Bai Y, Liu Z, et al. Classification of thyroid follicular cell tumors: with special reference to borderline lesions. Endocr J. 2012;59:1–12. 6. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2:1023–9. 7. Pusztaszeri M, Rossi ED, Auger M, et al. The Bethesda system for reporting thyroid cytopathology: proposed modifications and updates for the second edition from an international panel. Acta Cytol. 2016;60:399–405. 8. Ali SZ, Cibas ES. The Bethesda system for reporting thyroid cytopathology: definitions, criteria and explanatory notes. New York: Springer; 2018. 9. Krane JF, Alexander EK, Cibas ES, et al. Commentary: Coming to terms with NIFTP: A provisional approach for cytologists. Cancer Cytopathol. 2016;124:767–72. 10. Baloch ZW, Seethala RR, Faquin WC, et al. Commentary: noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): a changing paradigm in thyroid surgical pathology and implications for thyroid cytopathology. Cancer Cytopathol. 2016;124:616–20. 11. Ibrahim AA, Wu HH. Fine-needle aspiration cytology of noninvasive encapsulated follicular variant of papillary thyroid carcinoma is cytomorphologically distinct from the invasive counterpart. Am J Clim Pathol. 2016;146:373–7.

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12. Layfield LJ, Baloch ZW, Esebua M, et al. Impact of the reclassification of the noninvasive follicular variant of papillary carcinoma as benign on the malignancy risk of the Bethesda system for reporting thyroid cytopathology: a meta-analysis study. Acta Cytol. 2017;61:187–93. 13. Kakudo K. How to handle borderline/precursor thyroid tumors in management of patients with thyroid nodules. Gland Surg. 2017. https://doi.org/10.21037/gs.2017.0802. 14. Kakudo K, Higuchi M, Horokawa M, et al.: Thyroid FNA cytology in Asian practice – active surveillance for indeterminate thyroid nodules reduces overtreatment of thyroid carcinomas. Cytopathology. 2017;28:455–66. 15. Kakudo K, Bai Y, Liu Z, et al. Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer. Pathol Int. 2012;62:155–60. 16. Kakudo K, Wakasa T, Ohta Y, et al. Borderline and precursor lesions of thyroid carcinomas. J Basic Clin Med. 2015;4:2–7. 17. Bychkov A, Hirokawa M, Jung CK, et al. Low rate of noninvasive follicular thyroid neoplasm with papillary-like nuclear features in Asian practice. Thyroid. 2017;27(7):983–4. https://doi.org/10.1089/thy.2017.0079. Epub 2017 Jun 5. 18. Bychkov A, Keelawat S, Agarwal S, et al. Impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on risk of malignancy for the Bethesda categories: a multi-institutional study in five Asian countries. Pathology. 2018. pii: S0031-3025(17)30494-4. https://doi.org/10.1016/j.pathol.2017.11.088. [Epub ahead of print]. 19. Bychkov A, Jung CK, Liu Z, et al. Noninvasive follicular thyroid neoplasm with papillary-­ like nuclear features in Asian practice: perspectives for surgical pathology and ­cytopathology. Endocr Pathol. 2018. https://doi.org/10.1007/s12022-018-9519-6. [Epub ahead of print] Review. 20. Hirokawa M, Carney JA, Goellner JR, et al. Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol. 2002;26:1508–14.

Izumi, Japan

Kennichi Kakudo

Contents

Part I Why Are There Significant Differences Among Us in Thyroid Nodule Practices? 1 Addressing  the Impact of International Variation in Thyroid Cytology: Which Reporting System Is Best for Patients? �������������������������������������������������������   3 Kennichi Kakudo, Andrey Bychkov, Mitsuyoshi Hirokawa, Chan Kwon Jung, Chiung-Ru Lai, and Zhiyan Liu 2 Diagnostic  Criteria of Papillary Thyroid Carcinoma (PTC)-Type Nuclear Features Impacting Thyroid Fine Needle Aspiration (FNA) Cytology�����������������������������������������������������������������������������������������������������������������������   7 Kennichi Kakudo, Zhiyan Liu, Andrey Bychkov, Mitsuyoshi Hirokawa, Chiung-Ru Lai, and Chan Kwon Jung 3 Differences  Among Thyroid FNA Practices Elucidated by Meta-analyses of the Literature ���������������������������������������������������������������������������������������������������������  15 Chanchal Rana and Huy Gia Vuong 4 International  Comparison Study of Thyroid Fine Needle Aspiration (FNA) Cytology Reporting System���������������������������������������������������������������������������  21 Chiung-Ru Lai and Chien-Chin Chen 5 Thyroid  FNA Terminology: Progress Towards a Single Unified International System for Thyroid FNA Reporting �������������������������������������������������  27 David N. Poller Part II Reporting Systems of Thyroid FNA Cytology 6 Introduction  to the Third Edition of the Bethesda System for Reporting Thyroid Cytopathology�����������������������������������������������������������������������������������������������  33 Paul A. VanderLaan and Diana Esther Rossi 7 The  2014 Italian Reporting System for Thyroid Cytology: Present and Future���������������������������������������������������������������������������������������������������������������������������  37 Cristina Pizzimenti and Guido Fadda 8 The  UK Royal College of Pathologists (RCPath) Thy Terminology for Reporting Thyroid FNA Cytology�����������������������������������������������������������������������������  43 David N. Poller 9 Australian  System for Reporting Thyroid Cytology�����������������������������������������������  51 Marian Priyanthi Kumarasinghe 10 The  Japanese System Recommended by the Japan Thyroid Association�������������  59 Kaori Kameyama and Eiji Sasaki

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11 Risk  Classification of Follicular-­Patterned Lesions in Thyroid FNA���������������������  63 Kaori Kameyama and Eiji Sasaki 12 The  Japanese Reporting System for Thyroid Aspiration Cytology (JRSTAC)���������������������������������������������������������������������������������������������������������������������  67 Mitsuyoshi Hirokawa, Ayana Suzuki, Akira Miyauchi, and Takashi Akamizu 13 Clinical  Management for Follicular Neoplasm Without Molecular Testing �������������������������������������������������������������������������������������������������������������������������  75 Mitsuyoshi Hirokawa, Ayana Suzuki, Takumi Kudo, and Akira Miyauchi Part III Classification of Thyroid Tumors 14 Histological  Classification of Thyroid Tumors by the New Fifth Edition of the WHO Classification�����������������������������������������������������������������������������������������  83 Chan Kwon Jung 15 Low-Risk  Neoplasms in the Fifth Edition of the WHO Classification of Thyroid Tumors�����������������������������������������������������������������������������������������������������������  91 Kennichi Kakudo, Yaqion Li, Yanhua Bai, and Zhiyan Liu 16 Clinically  Insignificant Papillary Thyroid Carcinoma and Self-limiting Carcinoma that Do Not Harm Patients��������������������������������������������������������������������� 103 Kennichi Kakudo and Toru Takano 17 Whole  Tumor Capsule Is Prognostic of Very Good Outcome in the Classic Papillary Thyroid Cancer����������������������������������������������������������������������������� 109 Fulvio Basolo, Clara Ugolini, and Agnese Proietti 18 A  Framework for Approaching Cytologically Indeterminate Thyroid Nodules with RAS Mutations: A North American Perspective������������������������������� 111 Andrea D. Olivas, Tatjana Antic, and Nicole A. Cipriani 19 Clinical  Advantages and Limitations of Tumors Displaying Minimal and Extensive Vascular Invasion��������������������������������������������������������������������������������������� 119 Catarina Eloy, José Manuel Cameselle-Teijeiro, Ihab Abdulkader-Nallib, Isabel Amendoeira, and Manuel Sobrinho-Simões 20 High-Grade Follicular Cell-Derived Non-­anaplastic Thyroid Carcinomas ����������������������������������������������������������������������������������������������������������������� 131 Minh-Khang Le, Yan Xiong, and Tetsuo Kondo 21 Molecular  Classification of Thyroid Tumors and Key Molecular Features to Identify High-Grade Thyroid Carcinomas������������������������������������������� 139 Yi Wang, Likun Zhang, and Zhiyan Liu Part IV Criteria for Each Cytological Category 22 Specimen  Adequacy and Nondiagnostic Thyroid Nodules������������������������������������� 149 Andrey Bychkov and Pichet Sampatanukul 23 Cyst  Fluid Only Samples ������������������������������������������������������������������������������������������� 161 Risa Kanematsu, Ayana Suzuki, and Mitsuyoshi Hirokawa 24 Cytology of Benign Thyroid Aspirates ��������������������������������������������������������������������� 167 Agustina D. Abelardo and Andrey Bychkov 25 AUS/FLUS  in the Third Edition of the Bethesda System��������������������������������������� 175 Marc Pusztaszeri, Beatrix Cochand-Priollet, and Massimo Bongiovanni

Contents

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26 Cytological  Diagnosis of Follicular Neoplasm ��������������������������������������������������������� 183 SoonWon Hong 27 Diagnostic  Criteria of Suspicious for Malignancy��������������������������������������������������� 191 Sue Youn Kim and Chan Kwon Jung 28 Cytological  Diagnoses of Malignancy and Nuclear Features of PTC ������������������� 199 Chan Kwon Jung Part V Cytological Features of Thyroid Lesions 29 Diagnostic  Clues for Thyroid Aspiration Cytology������������������������������������������������� 207 Aki Tanaka, Ayana Suzuki, and Mitsuyoshi Hirokawa 30 False  Positive in Thyroid FNA: Causes and How to Avoid Them��������������������������� 233 Fernando Schmitt and Ricella Souza da Silva 31 Papillae in Thyroid Aspirates������������������������������������������������������������������������������������� 245 Shipra Agarwal, Xin Jing, Claire W. Michael, Zhiyan Liu, and Kennichi Kakudo 32 Papillary  Thyroid Carcinoma on LBC Preparations ��������������������������������������������� 253 Ayana Suzuki 33 Spindle Cells in Thyroid Aspirates ��������������������������������������������������������������������������� 257 Shurong He, Xuedong Zhang, and Aixia Hu Part VI Benign Lesions, Differential Diagnoses and Pitfalls 34 Thyroglossal  Duct Cyst and Other Ectopic Thyroid Tissue in the Neck��������������� 273 Andrey Bychkov 35 Benign  Follicular-Patterned Lesions (Thyroid Follicular Nodular Disease)������������������������������������������������������������������������������������������������������������������������� 285 Shoko Kure and Iwao Sugitani 36 Infectious Thyroiditis������������������������������������������������������������������������������������������������� 291 Shipra Agarwal, Claire W. Michael, Xin Jing, Mitsuyoshi Hirokawa, and Kennichi Kakudo 37 Diagnostic  Considerations for Thyroid Nodules in Graves’ Disease��������������������� 299 Jen-Fan Hang 38 Subacute  Thyroiditis or Papillary Carcinoma��������������������������������������������������������� 305 Tiesheng Wang and Yun Zhu 39 Hashimoto’s  Thyroiditis or Papillary Carcinoma��������������������������������������������������� 313 Yun Zhu and Tiesheng Wang Part VII Low Risk Neoplasms, Differential Diagnoses and Pitfalls 40 NIFTP in Asian Practice��������������������������������������������������������������������������������������������� 321 Andrey Bychkov, Chanchal Rana, Zhiyan Liu, Chan Kwon Jung, and Kennichi Kakudo 41 Role  of FNA Cytology in Preoperative Prediction of NIFTP: Practical Experiences in North America����������������������������������������������������������������������������������� 335 Madelyn Lew and Xin Jing

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42 Hyalinizing Trabecular Tumor ��������������������������������������������������������������������������������� 341 Naoki Yamao, Ayana Suzuki, Seiji Kuma, and Mitsuyoshi Hirokawa Part VIII Papillary Thyroid Carcinoma, Differential Diagnoses and Pitfalls 43 Cystic Papillary Thyroid Carcinoma ����������������������������������������������������������������������� 349 Aparna Harbhajanka, Claire W. Michael, and Jay Wasman 44 Tall  Cell Subtype of Papillary Thyroid Carcinoma������������������������������������������������� 357 Lan Chen 45 Papillary  Carcinoma, Columnar Cell Variant: Diagnostic Pitfalls and Differential Diagnoses������������������������������������������������������������������������������������������������� 361 Chiung-Ru Lai 46 Hobnail Papillary Thyroid Carcinoma��������������������������������������������������������������������� 365 Andrey Bychkov and Chan Kwon Jung 47 Solid/Trabecular  Subtype of Papillary Thyroid Carcinoma����������������������������������� 377 Ryuji Ohashi 48 Aggressive  Subtypes of PTC: How to Handle Them in FNA Cytology����������������� 383 Annette Salillas Part IX High-Grade Carcinomas, Differential Diagnoses and Pitfalls 49 High-Grade  Follicular-Derived Carcinomas in FNA Cytology ����������������������������� 391 Minh-Khang Le, Yan Xiong, and Tetsuo Kondo 50 Poorly  Differentiated Carcinoma and Anaplastic Carcinoma of the Thyroid������������������������������������������������������������������������������������������������������������������������� 397 Francesca Maletta, Elena Vissio, Marco Volante, and Mauro Papotti 51 Anaplastic Thyroid Carcinoma��������������������������������������������������������������������������������� 407 Andrey Bychkov, Shipra Agarwal, and Somboon Keelawat 52 Metastasis to Thyroid������������������������������������������������������������������������������������������������� 427 Radhika Srinivasan, Shipra Agarwal, and Andrey Bychkov Part X Other Thyroid Lesions, Differential Diagnoses and Pitfalls 53 Cribriform-Morular Thyroid Carcinoma���������������������������������������������������������������� 437 Zhiyan Liu, Chunyan Zhang, Qianqian Wang, Ayana Suzuki, and Mitsuyoshi Hirokawa 54 Oncocytic  Cell Neoplasms in Hematoxylin-Eosin-Stained Samples ��������������������� 447 Yun Zhu and Tiesheng Wang 55 Hürthle  Cell Neoplasms in Papanicolaou- and Romanowsky-­Stained Specimens��������������������������������������������������������������������������������������������������������������������� 457 Eleni Thodou and Sule Canberk 56 Medullary  (C Cell) Thyroid Carcinoma or Oncocytic Follicular Neoplasms ������������������������������������������������������������������������������������������������������������������� 465 Yun Zhu, Tiesheng Wang, and Kennichi Kakudo 57 Diagnosis  of Medullary (C Cell) Thyroid Carcinoma��������������������������������������������� 475 Chih-Yi Liu and Chien-Chin Chen

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58 Primary Thyroid Lymphoma������������������������������������������������������������������������������������� 487 Ayana Suzuki and Mitsuyoshi Hirokawa 59 Rare  Hematolymphoid Neoplasms of the Thyroid�������������������������������������������������� 493 Radhika Srinivasan and Andrey Bychkov 60 Intrathyroid Thymic Carcinoma������������������������������������������������������������������������������� 505 Deepali Jain, Andrey Bychkov, and Mitsuyoshi Hirokawa 61 Parathyroid  Adenoma and Its Differential Diagnoses��������������������������������������������� 513 Min En Nga Part XI How to Improve Diagnostic Performance in Thyroid FNA Cytology 62 Aspiration  Methods and Optimal Smear Preparation Techniques ����������������������� 525 Miyoko Higuchi, Ayana Suzuki, and Mitsuyoshi Hirokawa 63 Staining  Methods in Thyroid Cytology��������������������������������������������������������������������� 533 Annette L. Salillas and Ayana Suzuki 64 Fine  Needle Aspiration Biopsy Complications��������������������������������������������������������� 539 Yasuhiro Ito and Mitsuyoshi Hirokawa 65 Liquid-Based  Cytology Technique for Thyroid Cytology��������������������������������������� 543 Claire W. Michael 66 Rapid  On-Site Evaluation (ROSE)��������������������������������������������������������������������������� 557 Xin Jing, Kennichi Kakudo, and Claire Michael 67 Mobile  Rapid On-Site Evaluation����������������������������������������������������������������������������� 563 Toshitetsu Hayashi and Noriko Akiyama 68 Low-Cellularity  Thyroid Fine Needle Aspiration Specimens: Differential Diagnosis, the Role of Ancillary Testing and Associated Diagnostic Challenges������������������������������������������������������������������������������������������������������������������� 567 Syed M. Gilani 69 The  Role of Repeat FNA in Indeterminate Thyroid Nodules��������������������������������� 573 Pablo Valderrabano 70 Frozen  Section and Intraoperative Imprint Cytology��������������������������������������������� 579 Bozidar Kovacevic, Snezana Cerovic, and Vesna Skuletic 71 Core  Needle Biopsy for the Diagnosis of Thyroid Nodules: Pathologic Aspects������������������������������������������������������������������������������������������������������������������������� 587 Chan Kwon Jung 72 Biochemical  Test of Fine-Needle Aspirate as an Adjunct to Cytological Diagnosis in Patients with Thyroid Cancer or Primary Hyperparathyroidism������������������������������������������������������������������������������������������������� 599 Shinya Satoh, Hiroyuki Yamashita, Kennichi Kakudo, and Masahiro Nakashima 73 Quality  Control for Cytology Laboratory in the USA��������������������������������������������� 607 Aparna Harbhajanka and Claire W. Michael 74 Infection  Control in Cytology Practice and the COVID-19 Pandemic ����������������� 615 Elena Vigliar, Claudio Bellevicine, and Giancarlo Troncone

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Part XII Immunohistochemistry in Thyroid Nodule Practice 75 Cell  Blocks in Cytopathology and Their Role in Evaluation of Thyroid Aspirates ��������������������������������������������������������������������������������������������������������������������� 621 Rimlee Dutta, Manish Rohilla, Radhika Srinivasan, and Deepali Jain 76 European  Experience and Recommendations for Immunocytochemistry on Cytological Thyroid Fine-Needle Aspiration Specimens����������������������������������� 637 Beatrix Cochand-Priollet, Irena Srebotnik Kirbis, and Benedicte Royer 77 Application  of Immunocytochemistry in Thyroid Aspiration Cytology ��������������� 643 Ayana Suzuki and Mitsuyoshi Hirokawa Part XIII Molecular Tests in Thyroid Nodule Practice 78 Practice  of Molecular Detection of Thyroid Fine-Needle Aspiration Specimen in China ����������������������������������������������������������������������������������������������������� 653 Zhiyan Liu, Qiong Jiao, and Kennichi Kakudo 79 Experience  in Molecular Testing Using FNA Cytology in EU Countries ������������� 661 Sara Coluccelli, Thais Maloberti, Federico Chiarucci, Antonio De Leo, Dario de Biase, and Giovanni Tallini 80 Molecular  Testing for Thyroid Nodules: The Experience at McGill University Teaching Hospitals in Canada����������������������������������������������������������������� 675 Marc Pusztaszeri, Mohannad Rajab, and Richard J. Payne 81 Thyroid  Fine Needle Aspiration Cytology Molecular Testing in the USA������������� 685 N. Paul Ohori and Michiya Nishino 82 Molecular  Target Therapy for Pathologists in Advanced Thyroid Carcinoma������������������������������������������������������������������������������������������������������������������� 697 Young Shin Song and Young Joo Park Part XIV Image Technology in Thyroid Nodule Practice 83 Pathologic  Basis for Thyroid Ultrasound����������������������������������������������������������������� 717 Grace C. H. Yang and Chiung-Ru Lai 84 Ultrasonography  of the Thyroid Gland ������������������������������������������������������������������� 731 So Lyung Jung 85 Nuclear  Imaging of the Thyroid Gland��������������������������������������������������������������������� 743 Joo Hyun O and Seunggyun Ha Part XV Clinical Guidelines in Thyroid Nodule Practice 86 International  Comparison of Thyroid Nodule Workup ����������������������������������������� 751 Elizabeth E. Cottrill, Erin Buczek, Lauren Schlegel, Tanya Fancy, Aarti Agarwal, Amr H. Abdelhamid Ahmed, and Gregory Randolph 87 How  to Follow FNA-Confirmed Benign Thyroid Nodules ������������������������������������� 759 Minoru Kihara 88 Management  of Papillary Microcarcinoma of the Thyroid ����������������������������������� 761 Yasuhiro Ito, Akira Miyauchi, Makoto Fujishima, and Takahiro Sasaki

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89 Active  Surveillance for Low-Risk Small Papillary Thyroid Cancer in North America������������������������������������������������������������������������������������������������������������� 771 Marc P. Pusztaszeri, Michael Tamilia, and Richard J. Payne Part XVI Thyroid Nodule in Children and Young Adults 90 Thyroid  Nodules in Children and Adolescents��������������������������������������������������������� 783 Young Ah Lee 91 Thyroid  Carcinoma of Young Adults and Children������������������������������������������������� 791 Chanchal Rana and Huy Gia Vuong 92 The  Role of Thyroid FNA Cytology in Pediatric Malignant Lesions: Case Illustrations and Literature Review����������������������������������������������������������������� 797 Esther Diana Rossi Part XVII Patient Oriented Thyroid Nodule Practice 93 One-Stop  Clinic for Thyroid Nodules����������������������������������������������������������������������� 809 Voichita Suciu, Livia Lamartina, and Philippe Vielh 94 Caring  for Patients with Thyroid Nodules: Preventing Overdiagnosis as a Harm of FNA Cytological Examinations��������������������������������������������������������������� 817 Sanae Midorikawa and Akira Ohtsuru 95 Consideration  of Patients’ Viewpoint and the Role of Pathologists in Reporting Diagnosis of Thyroid Carcinomas����������������������������������������������������������� 823 Naomi Kitayama, Zhiyan Liu, and Kennichi Kakudo Index������������������������������������������������������������������������������������������������������������������������������������� 829

Part I Why Are There Significant Differences Among Us in Thyroid Nodule Practices?

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Addressing the Impact of International Variation in Thyroid Cytology: Which Reporting System Is Best for Patients? Kennichi Kakudo, Andrey Bychkov, Mitsuyoshi Hirokawa, Chan Kwon Jung, Chiung-Ru Lai, and Zhiyan Liu

1.1 Introduction The first edition of Thyroid FNA Cytology: Differential Diagnoses and Pitfalls was published in 2016. It was the first textbook of thyroid fine needle aspiration (FNA) cytology from Asia written in the English language. Following collaborations and exchanges among the international authors of the first and second editions [1, 2] and among member experts of the Asian Thyroid Working Group [3, 4], the author found that diagnostic criteria of malignancy by pathologists [5–14] and clinical guidelines varied greatly from country to country [14–20]. Although most pathologists follow the WHO classification and most clinicians follow international clinical guidelines, there are enormous differences in reports produced by Asian pathologists compared to those reported from Europe and North America. (See Chap. 3.) The author finds all of the following factors, both scientific and non-scientific, impact each other and contribute to those heterogeneities in clinical approach to patients [10–20]: K. Kakudo (*) Department of Pathology, Cancer Genome Center and Thyroid Disease Center, Izumi City General Hospital, Izumi, Osaka, Japan e-mail: [email protected] A. Bychkov Department of Pathology, Kameda Medical Center, Kamogawa, Chiba, Japan M. Hirokawa Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe, Japan C. K. Jung Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea C.-R. Lai Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Z. Liu Department of Pathology, Shanghai Sixth People’s Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China

1. Epidemiological differences (such as ethnicity, environment, lifestyle, food, climate, religion, etc.) in the patient population. 2. Variable social economic conditions and available medical resources among countries. 3. Particularly, medical specialist supply in clinical practice differs among countries significantly [21]. 4. Different health insurance systems and insurance coverage among countries. 5. Clinical practice guidelines are set defensively in some countries where physicians may be litigated against for malpractice; on the other hand, defensive medicine is not welcomed in other countries as it increases social costs and patients’ expenses. 6. Medical expense differs among countries and is extraordinarily high in North America. Immediate surgery is often selected to minimize the cost to patients. In contrast, risk stratification for surgery and life-long clinical follow-up is usually less expensive than surgery in the rest of the world and is favored.

1.2 Understanding Differences Among Us Is the Start to Improving the Situation As a result, there are regional differences in the clinical guidelines and treatment recommendations in thyroid nodule practice [19, 20]. (See Chap. 86.) The author found that there were two types of clinical guidelines and thyroid tumor classifications: one for practice in countries with a high rate of malpractice claims where the priority is given to avoiding malpractice litigation and another based on scientific evidence where the priority is not given to avoiding malpractice litigation [10, 12–16]. In thyroid FNA cytology reporting systems, the most typical example of this is the treatment of the so-called cyst fluid-only samples, whether in the inadequate or benign category. (See Chaps. 6, 7, 8, 9, 10, and 12.) Cyst fluid-only thyroid specimens have been found to have a significant risk of a false-negative diagnosis caused by cystic

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 K. Kakudo et al. (eds.), Thyroid FNA Cytology, https://doi.org/10.1007/978-981-99-6782-7_1

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papillary thyroid carcinoma (PTC); however, the risk is usually very low, almost equal to or less than that of the benign category. (See Chaps. 23, 30, and 43.) Therefore, this risk is acceptable in some practices to reduce unnecessary invasive tests or costly molecular tests on the patients; thus, it is classified as benign when there is no suspicious clinical finding. In contrast, some cytopathologists do not accept this classification, and they are classified in the inadequate category, leading clinicians to apply repeat FNAs and further examinations on patients to rule out missing cystic PTC. To solve this heterogeneity on how to diagnose cyst fluid-only samples, several reporting systems introduced a cyst fluid-only subcategory in the inadequate category to prevent malpractice litigation from a false-negative diagnosis while at the same time emphasizing the very low risk of malignancy, which is equal to or less than that of a benign diagnosis. (See Chaps. 4, 5, 23, 30, and 43.) The author wishes to emphasize this international consensus in this third edition of Thyroid FNA Cytology: Differential Diagnoses and Pitfalls.

1.3 Diagnostic Criteria of PTC Differ Between the Third Edition and the Fifth Edition of the WHO Classification of Thyroid Tumors and Between Eastern and Western Thyroid Nodule Practice Another critically important controversy among pathologists is the diagnostic criteria of RAS-like PTC [5–9], which is caused by the factors mentioned above, including the defensive attitude of North American pathologists who may be litigated against for malpractice [10–16]. (See Chaps. 14, 15, 27, and 28.) The low threshold of PTC-type malignancy for RASlike follicular pattern thyroid tumors was recommended in the third edition of the WHO classification of thyroid tumors [22], but it was revised and downgraded to the borderline tumor category when encapsulated and noninvasive in the previous fourth edition of the WHO classification [23] and low-risk neoplasm category in the current fifth edition of the WHO classification [24]. Diagnosis of a nuclear score 2–3 of delicate nuclear changes of papillary-like nuclear features (the socalled RAS-like dysplasia) in histological and cytological samples varies among countries [25–27]. (See Chaps. 2, 3, 4, 25, 26, 27, 28, and 41.) This is an essential point emphasized in the current third edition of Thyroid FNA Cytology because a complete solution has not been established yet.

1.4 Molecular Tests The author believes it may also be linked to which molecular tests are available and accessible in thyroid nodule practice, as health insurance systems do not cover all of the different

K. Kakudo et al.

kinds of tests in most countries. The characteristic cytological diagnosis of suboptimal samples with BRAF-like PTC-­ type nuclear features in the Bethesda III (AUS) and Bethesda V (SM) categories in Asian practice was established before the era of gene panel tests [14–16, 28–31]. This strategy helps concentrate BRAF-like classic PTCs in the AUS and SM categories, which can be confirmed with repeat FNAs or BRAF single gene tests cost-efficiently [14–18, 28–37]. (See Chaps. 21, 78, 79, 80 and 81.) The Asian approach to the indeterminate nodules [to classify suboptimal samples with suspicion for BRAF-like nuclear features in AUS or SM categories and cases with possible RAS-like nuclear dysplasia in the Bethesda IV (FN) category] also makes it possible to reduce the essential needs of costly gene panel tests. This is one of the significant merits of morphological distinction between BRAF-like and RAS-like nuclear features in thyroid nodule practice [14, 15, 28–31]. It also means that such effort may be less essential in countries where gene panel tests are affordable for the patient. The morphological distinction between BRAF-like and RAS-like nodules is not encouraged, and both nuclear features are called with a single morphological term, PTC-type nuclear feature, in the Bethesda reporting system and North American thyroid practice [22– 25, 38]. Even accurate distinction between Bethesda III (low-risk indeterminate) and Bethesda IV (high-risk indeterminate) categories is not essential in practices where gene panel tests are readily accessible. Furthermore, these two indeterminate categories can be combined into one gray zone (indeterminate) category, and then a gene panel test is used to provide a more conclusive diagnosis such as benign or suspicious. The diversity of social economic, healthcare, and health insurance systems may lead North American physicians to a different conclusion from that of the rest of the world. Nicholson et al. concluded that molecular testing was considerably more cost-effective than diagnostic lobectomy [39]. However, Khan and Zeiger highlighted the limitations regarding diagnostic accuracy, the impact on surgical decision-­making and outcomes, and the cost-effectiveness of molecular testing [40].

1.5 Why Low Resection Rate and High Risk of Malignancy can be Achieved on Indeterminate Nodules in Most Asian Countries Without Molecular Tests The above conclusions by North America researchers may not apply to other thyroid practices where gene panel tests are only sporadically used. The author believes the clinical follow-up of FN nodules without the aid of a gene panel test reduces surgery for patients with benign or borderline n­ odules because only patients with high-risk clinical features are

1  Addressing the Impact of International Variation in Thyroid Cytology: Which Reporting System Is Best for Patients?

advised to undergo surgery. (See Chaps. 11 and 13.) This clinical approach to the indeterminate nodule, which consists of watchful follow-up using ultrasound examination, is available in most countries and is more cost-efficient. As a result, more patients with benign and borderline nodules can be spared from unnecessary diagnostic surgery in most Asian countries [41–43]. (See Chaps. 3, 13, and 87.) While, in North America thyroid practice, where a life-long clinical follow-up is expensive and often not affordable for patients, immediate diagnostic surgery is often favored by the patient; however, this may cause increased expenses due to the risk of treatment-­ related complications. (See Chap. 88.) The author must add one more evidence that many cytopathologists in the world modify their diagnostic criteria in their practice. Delman et al. analyzed the National Surgical Quality Improvement Program database and reported that the national rate of malignancy is higher than the implied ROMs of Bethesda III, IV, and V thyroid nodules on resection [44]. It is evident that most cytopathologists in the world, even in North America, often tune their diagnostic criteria for the patients’ sake.

References 1. Kakudo K, editor. Thyroid FNA cytology: differential diagnoses and pitfalls. 1st ed. Himeji: BookWay Global; 2016. 2. Kakudo K, editor. Thyroid FNA cytology: differential diagnoses and pitfalls. 2nd ed. Singapore: Springer; 2019. 3. Bychkov A, Kakudo K, Hong SW. Current practices of thyroid fine-­ needle aspiration in Asia: a missing voice. J Pathol Transl Med. 2017;51:517–20. 4. Jung CK, Hong SW, Bychkov A, Kakudo K. The use of fine-­needle aspiration (FNA) cytology in patients with thyroid nodules in Asia: a brief overview of studies from the Working Group of Asian Thyroid FNA Cytology. J Pathol Transl Med. 2017;51:571–8. 5. Hirokawa M, Carney JA, Goellner JR, et  al. Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol. 2002;26:1508–14. 6. Kakudo K, Katoh R, Sakamoto A, et  al. Thyroid gland: international case conference. Endocr Pathol. 2002;13:131–4. 7. Lloyd RV, Erickson LA, Casey MB, et al. Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol. 2004;28:1336–40. 8. Cipriani NA, Nagar S, Kaplan SP, et al. Follicular thyroid carcinoma: how have histologic diagnoses changed in the last half-century and what are the prognostic implications? Thyroid. 2015;25:1209–16. 9. Poller DN, Johnson SJ, Bongiovanni M. Measures to reduce diagnostic error and improve clinical decision making in thyroid FNA aspiration cytology: a proposed framework. Cancer Cytopathol. 2020;128:917–27. 10. Renshaw AA, Gould EW. Why there is the tendency to “overdiagnose” the follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;117:19–21. 11. Chan J. Strict criteria should be applied in the diagnosis of encapsulated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;117:16–8. 12. Kakudo K, Bychkov A, Abelardo A, Keelawat S, Kumarasinghe P. Malpractice climate is a key difference in thyroid pathology practice between North America and the rest of the world. Arch Pathol Lab Med. 2019;143:1171.

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13. Warrick J, Lengerich E. Thyroid cancer overdiagnosis and malpractice climate. Arch Pathol Lab Med. 2019;143:414–5. 14. Kakudo K, Higuchi M, Hirokawa M, et al. Thyroid FNA cytology in Asian practice—active surveillance for indeterminate thyroid nodules reduces overtreatment of thyroid carcinomas. Cytopathology. 2017;28:455–66. 15. Kakudo K. Asian and Western practice in thyroid pathology: similarities and differences. Gland Surg. 2020;9:1614–27. 16. Kakudo K. Different threshold of malignancy for RAS-like thyroid tumors causes significant differences in thyroid nodule practice. Cancers (Basel). 2022;14:812. 17. Nguyen TPX, Truong VT, Kakudo K, et  al. The diversities in thyroid cytopathology practices among Asian countries using the Bethesda system for reporting thyroid cytopathology. Gland Surg. 2020;9:1735–46. 18. Vuong HG, Ngo HTT, Bychkov A, et  al. Differences in surgical resection rate and risk of malignancy in thyroid cytopathology practice between Western and Asian countries: a systematic review and meta-analysis. Cancer Cytopathol. 2020;128:238–49. 19. Hay ID. Managing patients with a preoperative diagnosis of AJCC/ UICC stage I (T1N0M0) papillary thyroid carcinoma: east versus west, whose policy is best? World J Surg. 2010;34:1291–3. 20. Takami H, Ito Y, Okamoto T, Onoda N, Noguchi H, et al. Revisiting the guidelines issued by the Japanese Society of Thyroid Surgeons and Japan Association of Endocrine Surgeons: a gradual move towards consensus between Japanese and western practice in the management of thyroid carcinoma. World J Surg. 2014;38:2002–10. 21. Bychkov A, Schubert M.  Constant demand, patchy supply. Pathologist. 2023;88:18–27. 22. DeLellis RA, Lloyd RV, Heitz PU, et  al., editors. World Health Organization Classification of Tumours: pathology and genetics of tumours of endocrine organs. 3rd ed. Lyon: IARC Press; 2004. 23. Lloyd RV, Osamura RY, Kloppel G, et  al., editors. World Health Organization Classification of tumours of endocrine organs. 4th ed. Lyon: IARC Press; 2017. 24. IARC. The WHO Classification of endocrine and neuroendocrine tumors. 5th ed. Lyon: IARC Press; 2022. (in press) 25. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2:1023–9. 26. Kakudo K, Liu Z, Bychlov A, et al. Nuclear features of papillary thyroid carcinoma (BRAF-like tumors), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (RAS-like tumors), and follicular adenoma/follicular thyroid carcinoma (RAS-like tumors). In: Kakudo K, editor. Thyroid FNA cytology. Differential diagnoses and pitfalls. 2nd ed. Springer; 2019. p. 173–80. 27. Kakudo K, El-Naggar AK, Hodak SP, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in thyroid tumor classification. Pathol Int. 2018;68:327–33. 28. Kakudo K, Kameyama K, Miyauchi A, et al. Introducing the reporting system for thyroid fine-needle aspiration cytology according to the new guidelines of the Japan Thyroid Association. Endocr J. 2014;61:539–52. 29. Kakudo K, Kameyama K, Hirokawa M, et  al. Subclassification of follicular neoplasms recommended by the Japan Thyroid Association reporting system of thyroid cytology. Int J Endocrinol. 2015;2015:938305. 30. Satoh S, Yamashita H, Kakudo K. Thyroid cytology: the Japanese system and experience at Yamashita Thyroid Hospital. J Pathol Transl Med. 2017;51:548–54. 31. Ooi LY, Nga ME.  Atypia of undetermined significance/follicular lesion of undetermined significance: Asian vs. non-Asian practice and the Singapore experience. Gland Surg. 2020;9:1764–87. 32. Zhu Y, Wu H, Huang B, et  al. BRAFV600E mutation combined with American College of Radiology thyroid imaging report and data system significantly changes surgical resection rate and risk

6 of malignancy in thyroid cytopathology practice. Gland Surg. 2020;9:1674–84. 33. Lee EJ, Song KH, Kim DL, et  al. The BRAF(V600E) mutation is associated with malignant ultrasonographic features in thyroid nodules. Clin Endocrinol. 2011;75:844–50. 34. Zhao H, Zhang ZH, Zhou B, et al. Detection of BRAF c.1799T > A (p.V600E) mutation using residual routine fine-needle aspiration specimens of papillary thyroid carcinoma. Diagn Cytopathol. 2015;43:786–90. 35. Lee ST, Kim SW, Ki CS, et al. Clinical implication of highly sensitive detection of the BRAF V600E mutation in fine-needle aspirations of thyroid nodules: a comparative analysis of three molecular assays in 4585 consecutive cases in a BRAF V600E mutation-­ prevalent area. J Clin Endocrinol Metab. 2012;97:2299–306. 36. Jinih M, Foley N, Osho O, et al. BRAFV600E mutation as a predictor of thyroid malignancy in indeterminate nodules: a systematic review and meta-analysis. Eur J Surg Oncol. 2017;43:1219–27. 37. Trimboli P, Scappaticcio L, Treglia G, et  al. Testing for BRAF (V600E) mutation in thyroid nodules with fine-needle aspiration (FNA) read as suspicious for malignancy (Bethesda V, Thy4, TIR4): a systematic review and meta-analysis. Endocr Pathol. 2020;31:57–66.

K. Kakudo et al. 38. Ali S, Cibas E, editors. The Bethesda system for reporting thyroid cytopathology: definitions, criteria, and explanatory notes. 2nd ed. New York: Springer; 2018. 39. Nicholson KJ, Roberts MS, McCoy KL, et  al. Molecular testing versus diagnostic lobectomy in Bethesda III/IV thyroid nodules: a cost-effectiveness analysis. Thyroid. 2019;29:1237–43. 40. Khan TM, Zeiger MA. Thyroid nodule molecular testing: is it ready for prime time? Front Endocrinol (Lausanne). 2020;11:590128. 41. Cohen DS, VandeGriend ZP, Yoo GH, et  al. Risk stratification based on thyroid cytology: can we rely on national data? Am J Otolaryngol. 2014;35:362–5. 42. Smulever A, Pitoia F. Active surveillance in small cytological indeterminate thyroid nodules: a call to common sense? Endocrine. 2021;72:505–12. 43. Hirokawa M, Suzuki A, Kawakami M, et  al. Criteria for follow­up of thyroid nodules diagnosed as follicular neoplasm without molecular testing—the experience of a high-volume thyroid centre in Japan. Diagn Cytopathol. 2022;50:223–9. 44. Delman AM, Turner KM, Ammann AM, Sisak S, Farooqui Z, Holm TM. The national rate of malignancy among Bethesda III, IV, and V thyroid nodules is higher than expected: a NSQIP analysis. Surgery. 2023;173:645–52.

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Diagnostic Criteria of Papillary Thyroid Carcinoma (PTC)-Type Nuclear Features Impacting Thyroid Fine Needle Aspiration (FNA) Cytology Kennichi Kakudo, Zhiyan Liu, Andrey Bychkov, Mitsuyoshi Hirokawa, Chiung-Ru Lai, and Chan Kwon Jung

2.1 Introduction

2.2 Papillary-Like Nuclear Features (Score 2–3 Nuclear Features Defined by As discussed in the preface to the third edition and Chap. 1, Nikiforov et al. [1]) and the So-Called there are several factors significantly impacting quality meaRAS-Like Dysplasia (Fig. 2.1) sures of thyroid FNA cytology. The author focused on two of them in this chapter: 1) different handling of papillary-like nuclear features [the so-called RAS-like dysplasia or score 2–3 of papillary-like nuclear features] in follicular-patterned tumors among pathologists [1–6] and 2) different diagnostic criteria for cytologically indeterminate (AUS and FN) categories among cytopathologists [7–11]. Furthermore, the author introduces a histological type-oriented cytology reporting system suitable for selecting further ancillary tests, such as immunohistochemistry, biochemical assays, and cost-efficient BRAF single-gene molecular test, in addition to repeat FNA for a more definitive diagnosis. (See Chaps. 69, 72, 76, 77, and 78.)

K. Kakudo (*) Department of Pathology, Cancer Genome Center and Thyroid Disease Center, Izumi City General Hospital, Izumi, Osaka, Japan e-mail: [email protected] Z. Liu Department of Pathology, Shanghai Sixth People’s Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China A. Bychkov Department of Pathology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand M. Hirokawa Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe, Japan C.-R. Lai Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan C. K. Jung Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea

The author termed papillary-like nuclear features characteristic of NIFTP (score 2–3 nuclear features defined by Nikiforov et al. [1]) as dysplastic nuclear changes of RAS-­ like tumors (RAS-like dysplasia), which are observed in RAS-like tumors [follicular adenoma (FA) (score 0–1), NIFTP (score 2–3), well-differentiated thyroid tumor of uncertain malignant potential (WDT-UMP) (score 2–3), follicular thyroid carcinoma (FTC) (score 0–1), well-­ differentiated carcinoma not otherwise specified (WDC-NOS) (score 2–3), follicular variant of PTC (FV-PTC) (score 2–3), high-grade well-differentiated carcinomas (score 0–3), and poorly differentiated thyroid carcinoma (PDC) (score 0–1)] [6, 12, 13]. The papillary-like nuclear features (worrisome nuclear features of PTC) were previously accepted as evidence of PTC-type malignancy such as in the third edition of WHO classification [14]. This central dogma (cases with PTC-type nuclear features are malignant regardless of invasive growth even if it is subtle) was significant in thyroid cytology because the nuclear features alone were diagnostic for malignancy [14], which was paramount in cytological preparations. However, the noninvasive (NIFTP) and questionable invasive (UMP) counterparts were downgraded to borderline (not cancer) category by the fourth edition of WHO classification [15] and lowrisk neoplasm category in the fifth edition of WHO classification [16]. The fifth edition of WHO classification further clarified the definition of malignant counterpart as follows: “invasive encapsulated FV-PTC is a malignant well-differentiated follicular cell-derived neoplasm that is encapsulated, has an exclusive or almost exclusive follicular architecture, nuclear features of PTC, and capsular or vascular invasion [16].” The diagnostic criteria for malignant FV-PTC now require capsular or vascular invasion (invasive encapsulated FV-PTC) [16]. From the revision by the fifth

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 K. Kakudo et al. (eds.), Thyroid FNA Cytology, https://doi.org/10.1007/978-981-99-6782-7_2

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a

b

c

d

Fig. 2.1  Nuclear features of four follicular-patterned thyroid tumors. (a) Follicular adenoma with nuclear score 1 (nuclear enlargement 1 + nuclear membrane irregularity 0 + chromatin clearing 0), (b) NIFTP with nuclear score 3 (nuclear enlargement 1 + nuclear membrane irregularity 1 + chromatin clearing 1), (c) BRAFV600E-mutated noninvasive encapsulated follicular subtype of PTC with nuclear score 3 (nuclear enlargement 1 + nuclear membrane irregularity 1 + chromatin clearing

1), and (d) BRAFV600E-mutated invasive encapsulated FV-PTC (nuclear enlargement 1 + nuclear membrane irregularity 1 + chromatin clearing 1). Please note fully developed PTC-type nuclear features in (d) suggesting BRAFV600E mutation. The blue arrow in (c) indicates nuclear cytoplasmic pseudo-inclusion suggesting BRAFV600E mutation. (HE staining, ×20)

edition of WHO classification, most encapsulated RAS-like thyroid nodules become benign follicular adenomas (FAs) or low-risk neoplasms (NIFTP, NEPRAS, FT-UMP, and WDT-UMP), and only the minority (less than 5%) is malignant tumors (invasive encapsulated FV-PTC, WDC-NOS, FTC, and PDC) [1, 17–25]. This means the papillary-like nuclear feature (RAS-like dysplasia) is no longer evidence of malignancy as the noninvasive counterpart was reclassified from cancer (noninvasive encapsulated FV-PTC) to a low-risk neoplasm (NIFTP) [1, 15]. Therefore, the discrimination of delicate nuclear change (papillary-like nuclear features) of RAS-like tumors from florid nuclear features of

classic PTC of BRAFV600E gene mutation becomes paramount in thyroid cytology (Fig. 2.2), as only florid nuclear features of BRAF-like PTCs are diagnostic for PTC-type malignancy and papillary-like nuclear features (RAS-like dysplasia) are no longer evidence of malignancy by the fifth edition of WHO classification [1, 16]. (See Chap. 18.) Thus, downgrading cases with papillary-­like nuclear features from definite malignancy to indeterminate (AUS, FN, and SM) categories is of key importance to reduce false-positive cytological diagnoses, as recommended by the second and third edition of the Bethesda reporting system [26, 27]. (See Chaps. 3–6 and 30.)

2  Diagnostic Criteria of Papillary Thyroid Carcinoma (PTC)-Type Nuclear Features Impacting Thyroid Fine Needle Aspiration (FNA…

a

b

9

c

Fig. 2.2  Nuclear features of three thyroid tumors in cytological smears. (a) Follicular adenoma with nuclear score 1 (nuclear enlargement 1 + nuclear membrane irregularity 0 + chromatin clearing 0), (b) NIFTP with nuclear score 3 (nuclear enlargement 1  +  nuclear mem-

brane irregularity 1 + chromatin clearing 1), and (c) BRAF-like PTC with fully developed PTC-type nuclear features. The blue arrow in (c) indicates a nuclear cytoplasmic pseudo-inclusion suggesting BRAFV600E mutation. (Papanicolaou stain, ×40)

2.3 Diagnostic Criteria for Indeterminate Cytological Categories in Asia Are Different from Those in Western Practice

probably because the second edition of the Bethesda reporting system stated that focal cytologic atypia is a diagnostic criterion of AUS nodules, which was followed by a statement that cytologic atypia for AUS diagnosis was rare in cells with nuclear enlargement, pale chromatin, and irregular nuclear contours [26]. Although it further added that this cytologic atypia is common in patients with Hashimoto thyroiditis and nuclear pseudo-inclusions are typically absent [26], cases with florid nuclear features of BRAF-like PTC are often classified as either AUS (when suboptimal specimen), SM (when not conclusive for malignancy), or M (when conclusive) [6– 13] (Fig.  2.3) in most Asian practice without knowing the Bethesda recommendation that cases with BRAF-like PTC nuclear changes should be excluded from the AUS category and classified in SM or M categories [26]. (See Chaps. 3–6, 10, 12, and 25.) As distinction of BRAF-like PTC nuclear features and RAS-like nuclear features is possible at acceptable concordance [29–35], the cytological distinction of these two genetically different lineage tumors (a selective diagnosis of BRAF-like nodules in either AUS or SM categories and RAS-like nodules in the FN category) helps to confirm classic PTCs accurately using inexpensive repeat FNA (see Chap. 69) or cost-saving BRAF single-gene tests on inadequate, AUS, and SM nodules (see Chaps. 3 and 78).

In Western practice, cases with papillary-like nuclear features in follicular-patterned cytological samples are classified in AUS or FN categories, and florid nuclear features of PTC are classified in the SM or M category, as recommended by the second and third edition of the Bethesda reporting system [26, 27]. (See Chaps. 6, 25, and 26.) On the other hand, the Japanese reporting system recommended by the Japan Thyroid Association (JTA) emphasized a distinction of florid nuclear features (often seen in classic PTC with BRAFV600E mutation) and delicate nuclear changes (often seen in RAS-like tumors such as FA, NIFTP, UMP, FTC, WDC-NOS, FV-PTC, and PDC) [6–13]. It recommends classifying cases with papillary-like nuclear features as indeterminate A and risk-stratifying cases with florid nuclear features often seen in BRAF-like PTC in indeterminate B, SM, and M categories [6–13] (Fig. 2.3). (See Chaps. 1, 3, 10, 11, and 26.) Most Asian cytopathologists often translate the indeterminate B (suboptimal specimens with BRAF-like PTC nuclear changes) to AUS nodules [8–13, 28, 29]. This is

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Fig. 2.3  Diagnostic algorithm of thyroid FNA cytology in the Japanese system [8]. BRAF-like florid nuclear features of papillary thyroid carcinoma (PTC) are risk-stratified in either indeterminate B (when questionable), suspicious for malignancy (when not conclusive), or definite malignancy (when conclusive). Rare atypical cells in poor-quality spec-

imens are also classified as indeterminate B. Cases with delicate nuclear changes in RAS-like tumors or architectural abnormality are classified as indeterminate A.  The indeterminate A category is further risk-­ stratified into favor benign, borderline, and malignant morphologically (see Chap. 10)

This morphological identification of suspicious BRAF-like PTCs makes it possible to replace costly gene panel tests with either repeat FNAs or BRAF single-gene tests, which helps reduce healthcare costs for society and the patient in countries where gene panel tests are not affordable by the patients.

line cancer risk (8–15%) of all thyroid nodules estimated by Alexander [37] and within a range of the implied ROM (10– 30%) of AUS nodules reported by the second edition of the Bethesda reporting system [26, 36]. Guan et al. reported that RAS mutations are not helpful markers to identify malignancy among AUS and FN nodules [38]. Guan et al. and Soares et al. correctly concluded in their excellent papers that the most prevalent molecular alterations in follicular-­ patterned thyroid tumors are RAS mutations and they do not carry prognostic significance [38, 39]. (See Chap. 18.) However, a significant number of patients with benign nodules still underwent surgery in a recent meta-analysis by Valderrabano et al. [40]. The resection rate (RR) of AUS nodules was 50% and that of FN nodules was 62% using the Afirma gene expression classifier (GEC). The benign call rate of 1158 (combined AUS and FN) nodules was low at 45%, and the RR of GEC-benign nodules was high at 20%. They reported that the prevalence of carcinoma among resected AUS nodules was 39% and that among resected FN nodules was 38% [40]. There was only a slight improvement in the RR of FN nodules (62% vs. 69.7%) when compared with an old (before gene panel tests) meta-analysis by Bongiovanni et al. [41]. However, this improvement was not observed for AUS nodules (50% vs. 39.2%) [40, 41]. (See Chaps. 18 and 78–81.)

2.4 The Current Gene Panel Tests Are Unable to Accurately Distinguish Benign and Malignant Tumors in AUS and FN Nodules The current gene panel tests are unable to accurately distinguish benign and malignant tumors in AUS and FN nodules in Western patient cohorts, and the quality measures for multigene panel tests to indeterminate nodules have poor performance because BRAF-like PTCs, RAS-like tumors, and oncocytic follicular tumors are mixed together in AUS and FN categories in the current Western reporting system. Gilani et al. demonstrated the RAS mutation-associated overall ROM in their AUS nodules was 29% (with or without any other molecular alterations) [36], whereas the ROM of RAS mutation-only nodules was 19% [36], which was only slightly above the base-

2  Diagnostic Criteria of Papillary Thyroid Carcinoma (PTC)-Type Nuclear Features Impacting Thyroid Fine Needle Aspiration (FNA…

2.5 The ATA Clinical Guidelines Recommend Surgery for NIFTP, Whereas the Asian Clinical Approach Favors Clinical Follow-Up Furthermore, most NIFTPs (not a malignant tumor) are found among GEC-suspicious nodules [40, 42], and the ATA clinical guidelines recommend surgery because they are precursor tumors [43, 44]. This approach recommended by the ATA clinical guidelines made the resection rate (RR) greater than 50% and the ROM of the indeterminate nodules less than 40% in North America [40–43, 45–47]. This was confirmed even in an eminent academic center in the USA [42], although a newer version (Afirma genomic sequencing classifier: GSC) reported an improved specificity and sensitivity [45–47]. Zhang et  al. reported a substantially improved benign call rate (77.3% vs. 52%), rate of subsequent surgery (31.4% vs. 51.2%), and rate of histology-confirmed malignancy (29% vs. 9.8%) in 137 AUS thyroid nodules when compared with 127 AUS nodules tested with GSC [47]. These quality measures in Western countries were not satisfactory for Asian physicians where the RR of most indeterminate nodules was less than 50% and the ROM was greater than 40% without gene panel tests [10, 11, 13, 28, 29]. (See Chaps. 3, 11, and 13.)

2.6 The Distinction Between Papillary-­ Like Nuclear Features (RAS-Like Dysplasia) and Florid Nuclear Features (BRAF-Like PTC Nuclear Features) Is Essential in Thyroid FNA Cytology when Gene Panel Tests Are Not Freely Accessible As BRAF single-gene tests are available in Korean thyroid practice, researchers reported high ROMs (41.7–86.6%, average 68.7%) and low resection rates (5.5–38.7%, average of 20.2%) for AUS nodules in 15 Korean institutes [48], and a similar decrease in RR and increase in ROM were reported with the BRAF gene test for inadequate and AUS nodules by Zhu et  al. from China [49]. They reported that the RR of inadequate (21.6% vs. 39.1%) and AUS (16.7% vs. 36.1%) categories significantly decrease after implementing the American College of Radiology Thyroid Imaging Reporting and Data System and the BRAFV600E mutation analysis [49]. In addition, their ROMs increased to 80.0% vs. 41.5% and 50.0% vs. 34.6%, respectively [49]. As the author’s personal view in this chapter, most Asian pathologists and cytopathologists regard and estimated ROM 60% of the cell component), with moderate to severe cytological atypia suggestive for a “follicular neoplasm” (FN) (Fig. 7.2). Samples composed almost exclusively of oncocytes (Hürthle cells) are included in the TIR3B category without taking into consideration either the architectural or the cytological atypia (Figs. 7.3 and 7.4). TIR3B category also includes specimens characterized by nuclear alterations suggestive of PTC that do not permit to reliably exclude malignancy but are too mild or focal to be included in the TIR4 category (Fig. 7.5). Fig. 7.3  High-risk indeterminate lesion (TIR 3B)—Oncocytic type The TIR3B category has an expected ROM between 40 (ThinPrep, Papanicolaou, 1000×) and 55% [31] compared to the ROM of the FN/SFN category of the TBSRTC [12] (25–40%) and to the ROM of the Thy3f category of the UK RCPath (31%) [30]. However, the above-­ mentioned study observed a significant difference in ROM in this category between follicular cell lesions and Hürthle cell lesions, showing a ROM of 59% for the former group and 9% for the latter, respectively [27]. This finding suggests that Hürthle cell lesions, most of which are non-neoplastic nodules, might be included in the indeterminate low-risk category (TIR3A) to reduce the amount of inappropriate surgical treatments. Surgery is the recommended action for TIR3B highrisk indeterminate lesions. However, the surgical or conservative management of these indeterminate categories depends on both the cytological and clinical data and requires the consultation between cytopathologists and clinicians. Fig. 7.4  High-risk indeterminate lesion (TIR 3B)—Oncocytic type (Papanicolaou, 500×)

Fig. 7.2  High-risk indeterminate lesion (TIR 3B) showing a microfollicle lined by follicular cells with mild to moderate atypia (ThinPrep, Papanicolaou, 1000×)

Fig. 7.5  Papillary thyroid carcinoma (TIR 5) (ThinPrep, Papanicolaou, 500×)

7  The 2014 Italian Reporting System for Thyroid Cytology: Present and Future

References 1. Hossein G.  Changing trends in thyroid practice: understanding nodular thyroid disease. Endocr Pract. 2004;10(1):31–9. 2. Poller DN, Baloch ZW, Fadda G, et  al. Thyroid FNA: new classifications and new interpretations. Cancer Cytopathol. 2016;124(7):457–66. 3. Yassa L, Cibas ES, Benson CB, et al. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer. 2007;111(6):508–16. https://doi.org/10.1002/cncr.23116. 4. Baloch ZW, Fleisher S, LiVolsi VA, Gupta PK. Diagnosis of follicular neoplasm? A gray zone in thyroid fine-needle aspiration cytology. Diagn Cytopathol. 2002;26(1):41–4. https://doi.org/10.1002/ dc.10043. 5. Nardi F, Basolo F, Crescenzi A, et al. Italian consensus for the classification and reporting of thyroid cytology. J Endocrinol Investig. 2014;37(6):593–9. 6. Ali SZ, Cibas ES. The Bethesda system for reporting thyroid cytopathology II. Acta Cytol. 2016;60(5):397–8. 7. Cross P, Chandra A, Giles T, et  al. Guidance on the reporting of thyroid cytology specimens January 2016. R Coll Pathol. 2016; https://www.rcpath.org/uploads/assets/uploaded/9ddf3c1d-­c58f-­ 4b8c-­b89b63e0704f5a50.pdf 8. Hirokawa M, Suzuki A, Higuchi M, et al. The Japanese reporting system for thyroid aspiration cytology 2019 (JRSTAC2019). Gland Surg. 2020;9(5):1653–62. 9. VanderLaan PA, Marqusee E, Krane JF.  Usefulness of diagnostic qualifiers for thyroid fine-needle aspirations with atypia of undetermined significance. Am J Clin Pathol. 2011;136(4): 572–7. 10. Castro MR, Espiritu RP, Bahn RS, et al. Predictors of malignancy in patients with cytologically suspicious thyroid nodules. Thyroid. 2011;21(11):1191–8. https://doi.org/10.1089/thy.2011.0146. 11. Johnson DN, Cavallo AB, Uraizee I, et al. A proposal for separation of nuclear atypia and architectural atypia in Bethesda category III (AUS/FLUS) based on differing rates of thyroid malignancy. Am J Clin Pathol. 2019;151(1):86–94. 12. Vuong HG, Ngo HTT, Bychkov A, et  al. Differences in surgical resection rate and risk of malignancy in thyroid cytopathology practice between Western and Asian countries: a systematic review and meta-analysis. Cancer Cytopathol. 2020;128(4): 238–49. 13. Trimboli P, Fulciniti F, Paone G, et al. Risk of malignancy (ROM) of thyroid FNA diagnosed as suspicious for malignancy or malignant: an institutional experience with systematic review and meta-­ analysis of literature. Endocr Pathol. 2020;31(1):52–6. 14. Na DG, Kim J, Sung JY, et  al. Core-needle biopsy is more useful than repeat fine-needle aspiration in thyroid nodules read as nondiagnostic or atypia of undetermined significance by the Bethesda system for reporting thyroid cytopathology. Thyroid. 2012;22(5):468–75. https://doi.org/10.1089/thy.2011.0185. 15. Nasrollah N, Trimboli P, Guidobaldi L, et  al. Thin core biopsy should help to discriminate thyroid nodules cytologically classified as indeterminate. A new sampling technique. Endocrine. 2013;43(3):659–65. https://doi.org/10.1007/s12020-­012-­9811-­z. 16. Fadda G, Rossi ED.  Liquid-based cytology in fine-needle aspiration biopsies of the thyroid gland. Acta Cytol. 2011;55(5):389–400. https://www.karger.com/Article/FullText/329029 17. Fadda G, Rossi ED, Raffaelli M, et al. Follicular thyroid neoplasms can be classified as low- and high-risk according to HBME-1 and Galectin-3 expression on liquid-based fine-needle cytology. Eur J Endocrinol. 2011;165(3):447–53. 18. Renshaw AA.  Subclassification of atypical cells of undetermined significance in direct smears of fine-needle aspirations of the thy-

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roid: distinct patterns and associated risk of malignancy. Cancer Cytopathol. 2011;119(5):322–7. 19. Faquin WC, Baloch ZW.  Fine-needle aspiration of follicular patterned lesions of the thyroid: diagnosis, management, and follow-up according to National Cancer Institute (NCI) recommendations. Diagn Cytopathol. 2010;38:731–9. https://doi.org/10.1002/ dc.21292. 20. Trimboli P, Crescenzi A, Giovanella L.  Performance of Italian Consensus for the Classification and Reporting of Thyroid Cytology (ICCRTC) in discriminating indeterminate lesions at low and high risk of malignancy. A systematic review and meta-­ analysis. Endocrine. 2018;60(1):31–5. https://doi.org/10.1007/ s12020-­017-­1382-­6. 21. Haugen BR, Alexander EK, Bible KC, et  al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1–133. 22. Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, Barletta JA, Wenig BM, Al Ghuzlan A, Kakudo K, Giordano TJ.  Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors Yuri. JAMA Oncol. 2016;2:1023–9. 23. Parente DN, Kluijfhout WP, Bongers PJ, et  al. Clinical safety of renaming encapsulated follicular variant of papillary thyroid carcinoma: is NIFTP truly benign? World J Surg. 2018;42(2):321–6. 24. Kopczyński J, Suligowska A, Niemyska K, et al. Did introducing a new category of thyroid tumors (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) decrease the risk of malignancy for the diagnostic categories in the Bethesda system for reporting thyroid cytopathology? Endocr Pathol. 2020;31(2):143–9. 25. Ventura M, Melo M, Fernandes G, Carrilho F. Risk of malignancy in thyroid cytology: the impact of the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Endocr Pract. 2019;25(7):642–7. 26. Torregrossa L, Poma AM, Macerola E, et al. The Italian consensus for the classification and reporting of thyroid cytology: cytohistologic and molecular correlations on 37,371 nodules from a single institution. Cancer Cytopathol. 2022;130(11):899–912. 27. Straccia P, Santoro A, Rossi ED, et al. Incidence, malignancy rates of diagnoses and cyto-histological correlations in the new Italian reporting system for thyroid cytology: an institutional experience. Cytopathology. 2017;28(6):503–8. 28. Trimboli P, Ferrarazzo G, Cappelli C, Piccardo A, Castellana M, Barizzi J.  Thyroid nodules with indeterminate FNAC according to the Italian classification system: prevalence, rate of operation, and impact on risk of malignancy. An updated systematic review and meta-analysis. Endocr Pathol. 2022;33(4):457–71. https://doi. org/10.1007/s12022-­022-­09729-­x. 29. Straccia P, Rossi ED, Bizzarro T, et al. A meta-analytic review of the Bethesda system for reporting thyroid cytopathology: has the rate of malignancy in indeterminate lesions been underestimated? Cancer Cytopathol. 2015;123(12):713–22. 30. Poller DN, Bongiovanni M, Trimboli P. Risk of malignancy in the various categories of the UK Royal College of Pathologists thy terminology for thyroid FNA cytology: a systematic review and meta-­ analysis. Cancer Cytopathol. 2020;128(1):36–42. 31. Trimboli P, Crescenzi A, Castellana M, Giorgino F, Giovanella L, Bongiovanni M.  Italian consensus for the classification and reporting of thyroid cytology: the risk of malignancy between indeterminate lesions at low or high risk. A systematic review and meta-analysis. Endocrine. 2019;63(3):430–8. https://doi. org/10.1007/s12020-­018-­1825-­8.

8

The UK Royal College of Pathologists (RCPath) Thy Terminology for Reporting Thyroid FNA Cytology David N. Poller

8.1 Introduction The UK Royal College of Pathologists (RCPath) ‘Thy’ thyroid FNA reporting terminology was first published in 2009 [1]. It was preceded by an earlier terminology system developed under the auspices of the British Thyroid Association [2]. The UK terminology enables consistent and reproducible reporting of thyroid cytology, which is essential for effective clinical management of thyroid nodules [3, 4]. The UK terminology emphasises the value of the multidisciplinary team (MDT) and MDT meetings. Cytology reports use full free-text descriptions to explain the reason(s) for the chosen diagnostic category together with a ‘Thy’ numeric category. Thyroid cytology categories are also used for coding, audit and comparison.

8.2 Main Features of the UK RCPath Thy FNA Reporting Terminology The UK system is similar to other international terminology systems [4]. Table 8.1 summarises the main features of the UK terminology and the other international terminology systems. The UK guidance stipulates that aspirators must be suitably trained, that the number of staff who perform aspiration cytology should be minimised to maintain skill levels and quality and that each aspirator should be subject to periodic audit of their results. Aspirators with repeatedly high (>15%) non-diagnostic Thy1 rates (but excluding Thy1c cystic specimens) should be identified and remedial action taken if necessary. (See Chap. 62.) The UK guidance also recommends that full details of the clinical and radiological information are provided at the time of reporting. MDT meetings are integral to the use of the terminology, providing an opportunity to share clinical, radiological and pathological information and to assist in the clinical decision-making process. The diagnostic criteria for the UK RCPath terminology are as follows [4]:

D. N. Poller (*) Department of Pathology, Queen Alexandra Hospital, Portsmouth, UK e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 K. Kakudo et al. (eds.), Thyroid FNA Cytology, https://doi.org/10.1007/978-981-99-6782-7_8

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D. N. Poller

44 Table 8.1  Comparison of international thyroid cytology classifications RCPath Thy1 Non-diagnostic for cytological diagnosis Thy1c Non-diagnostic for cytological diagnosis— cystic lesion Thy2 Non-neoplastic Thy2c Non-neoplastic, cystic lesion

Thy3a Neoplasm possible— atypia/present

Thy3f Neoplasm possible, suggesting follicular neoplasm Thy4 Suspicious for malignancy

Thy5 Malignant

Bethesda I. Non-diagnostic or unsatisfactory Virtually acellular specimen Others (obscuring blood, clotting artefact, etc.) Cyst fluid only

Italian TIR 1 Non-diagnostic TIR 1c Non-diagnostic cystic

Australian 1 Non-diagnostic

Japanese 1 Unsatisfactory

II. Benign Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodule, etc.) Consistent with lymphocytic (Hashimoto) thyroiditis in the proper clinical context Consistent with granulomatous (subacute) thyroiditis Others III. Atypia of undetermined significance

TIR 2 Non-malignant

2 Benign

2 Benign Cyst fluid

TIR 3A Low-risk indeterminate lesion (LRIL)

3 Undetermined significance

IV. Follicular neoplasm or suspicious for a follicular neoplasm Specify if Hürthle cell (oncocytic) type

TIR 3B High-risk indeterminate lesion (HRIL) TIR 4 Suspicious for malignancy

3 Indeterminate OR follicular lesion of undetermined significance 4 Suggestive of a follicular neoplasm

5 Suspicious for malignancy

4 Suspicious for malignancy

6 Malignant

5 Malignant

V. Suspicious for malignancy Suspicious for papillary carcinoma Suspicious for medullary carcinoma Suspicious for metastatic carcinoma Suspicious for lymphoma Others VI. Malignant Papillary thyroid carcinoma Poorly differentiated carcinoma Medullary thyroid carcinoma Undifferentiated (anaplastic) carcinoma Squamous cell carcinoma Carcinoma with mixed features (specify) Metastatic carcinoma Non-Hodgkin lymphoma Others

8.3 Non-diagnostic for Cytological Diagnosis: Thy1/Thy1c This category includes Thy1 and Thy1c specimens. The cytological cellularity criterion is essentially the same in other international systems. (See Chap. 22.) The reason for the non-diagnostic sample should be clearly stated in the cytology report. If there is uncertainty as to whether or not a sample is adequate for diagnostic purposes, this should be stated in the report. A sample of adequate epithelial cellularity from a solid lesion should have ‘at least six groups of thyroid follicular epithelial cells across all the submitted slides, each with at least ten well-visualised epithelial cells’. But the UK guidance also states that a second more practi-

TIR 5 Malignant

3 Follicular neoplasm

cal specimen adequacy criterion is preferable, which fully takes into account all the clinical and radiological information although this latter criterion is only to be used if this information is available to the reporting cytologist. Use of second opinions is suggested if there is uncertainty as to whether or not a sample is adequate for diagnostic purposes.

8.3.1 Thy1 Thy1 samples are most likely related to the operator or the technique. These are all classed as Thy1 for audit and clinical purposes. Examples of Thy1 include specimens that:

8  The UK Royal College of Pathologists (RCPath) Thy Terminology for Reporting Thyroid FNA Cytology

• Consist entirely of blood or are so heavily bloodstained that the epithelial cells and/or colloid cannot be visualised • Are acellular or have too low a follicular epithelial cellularity to allow diagnosis (i.e. do not reach the adequacy criterion stated above) • Are technically unable to be evaluated (e.g. poorly spread, delayed air drying or fixation artefact, prominent crush artefact, cells trapped in fibrin)

8.3.2 Thy1c These are samples that are most likely related to the lesion characteristics. In category Thy1c, ‘c’ means ‘cystic lesion’. • These are cystic lesion fluid specimens that do not reach the follicular epithelial cell adequacy criterion described above and which contain mostly macrophages but without abundant colloid. Suggestions for report phrasing can be used, e.g. ‘the sample is in keeping with fluid from a cyst but there are no/too few epithelial cells and insufficient colloid to confirm cyst type’. The UK guidance notes that assessment of thyroid cysts can be particularly problematic and there is a recognised risk of non-­ representative sampling, especially in cystic papillary thyroid carcinomas. The UK guidance takes account of this, stating that it is important for auditing results that any samples of insufficient epithelial cellularity that are cyst fluid specimens are separated from those that are non-diagnostic for other reasons. The UK guidance also states that it is important not to offer false reassurance on suboptimal epithelial cellularity, although stating that the risk of malignancy in these cases must not be overstated and that careful assessment is needed, with MDT meeting discussion if this is required.

8.3.3 Non-neoplastic: Thy2/Thy2c 8.3.3.1 Thy2 Samples in this category should have sufficient epithelial cellularity to allow diagnosis and should be consistent with the clinical information. The specific diagnosis should be stated in the report when a specific diagnosis can be made. All of the entities below are classed as Thy2 for audit and clinical purposes. The non-neoplastic category includes: • Colloid nodules—these samples will contain abundant easily identifiable colloid with cytologically bland follicular epithelial cells sufficient for diagnosis, with or without the presence of cyst macrophages. • Hyperplastic nodules.

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• Thyroiditis, e.g. Hashimoto’s thyroiditis. • Samples of benign thyroid tissue with an element of oncocytic change. Specimens almost exclusively or exclusively oncocytic in appearance would be classed within the Thy3f category (see below). • Other non-neoplastic conditions including normal thyroid.

8.3.3.2 Thy2c This category is coded as Thy2c (‘c’ for ‘cyst’). These are cystic lesion specimens that consist predominantly of abundant colloid and macrophages, and even if too few follicular epithelial cells are present to meet the adequacy criterion outlined above for solid lesions, these can be considered to be ‘consistent with a colloid cyst’ in the appropriate clinical setting. The suggested wording of reports for these samples is ‘the sample is in keeping with fluid from a cystic colloid nodule but there are no/too few epithelial cells for confirmation’.

8.3.4 Neoplasm Possible: Thy3a and Thy3f Owing to the limitations of FNA cytology, MDT meeting discussion is often necessary to decide further management in these cases. There is also some evidence that subclassification of Thy3a cases may help with better diagnostic allocation and improve risk stratification [5]. The UK guidance states that the free-text report should identify the nature of the cytological concern and that the differential diagnosis should be made clear. It is important that the free-text wording explains clearly why the individual aspirate falls within the Thy3a or Thy3f subcategory. The Thy3a and Thy3f categories are separate groups and are not meant to imply any direct progression between themselves or any other Thy category. Thy3a and Thy3f reflect cytological diagnostic problem area(s), although there is inevitably some overlap and subjectivity in interpretation and categorisation. There is no ‘Thy3’ category without the suffix ‘a’ or ‘f’. Accurate and complete clinical and radiological information is vitally important to allow for cytological interpretation. If there is a problem with categorisation of the sample, then this should be stated in the report and the reason(s) given.

8.3.5 Thy3a (‘a’ for ‘Atypia’) The UK guidance states that these are samples that exhibit cytological nuclear or cytological architectural atypia or other features that raise the possibility of neoplasia, but which are insufficient to enable confident placement into any other category. The text of the report should describe the nature of the problem. These specimens should form only a minority of cases

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overall, and this category should only be used if the sample cannot be confidently allocated to another category. There is evidence of the usefulness of this atypical category from publications that use RCPath terminology [6], the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) [7, 8] and the Italian TIR terminology for the Thy3a or their equivalent categories [9, 10]. Cytological nuclear atypia is more highly predictive of malignancy; hence, the UK guidance recommends that the presence or absence of cytological nuclear atypia should always be commented on. In the Italian TIR system, indeterminate FNAs with cytological nuclear atypia are categorised in the higher-risk TIR 3B subgroup rather than the lower-risk TIR 3A subgroup [9, 10]. The UK guidance comments that the accompanying free-text wording is crucial to explain which specific cytological features are present with a statement that if atypical nuclear features are present, then these have a higher risk of malignancy [4]. Pre-existing conditions (such as thyroiditis) can cause difficulty with diagnosis, even leading to overcalls, and these difficulties should be identified within the cytology report. Complete and accurate clinical and radiological information is vital to the correct interpretation of thyroid cytology samples. In many cases, a repeat thyroid cytology enables placement into a more definitive category. Thy3a samples include those in which there is • Cytological architectural atypia in the form of a mixed micro- and macro-follicular pattern and/or little colloid or sparsely cellular samples containing predominantly microfollicles, where a definite distinction between a follicular neoplasm and hyperplastic nodule is difficult, but there is insufficient material or features for the Thy3f category. Suggested wording could be that ‘the appearances may represent a cellular colloid nodule but a follicular neoplasm is not excluded’. • Focal cytological nuclear atypia or other features, which are most probably benign but where a papillary ­carcinoma cannot be confidently excluded and the features are insufficient for the Thy4 category. • A compromised specimen (e.g. obscured by blood or a poorly spread smear), where some cells appear to be mildly abnormal but are not obviously from a follicular neoplasm or suspicious for, or diagnostic of, malignancy. • Cyst lining cells that are not normal, but which are not able to be characterised otherwise. • Predominance of lymphoid cells with very scanty epithelium, provided a lymphocytic thyroiditis has been excluded.

8.3.6 Thy3f (‘f’ for ‘Follicular’) • Samples suggesting follicular or oncocytic neoplasms. Samples suggestive of follicular neoplasm or consisting

D. N. Poller

entirely or almost entirely of oncocytic cells should be categorised as Thy3f. Marked nuclear cytological atypia is also a feature of oncocytic thyroid neoplasms and can be mistaken for other thyroid tumours, including thyroid cancers. The histological possibilities therefore include hyperplastic or other cellular but non-neoplastic nodules, as well as neoplasms, including follicular or oncocytic adenomas and follicular or oncocytic carcinomas. These entities cannot be reliably distinguished on cytology alone. Follicular variants of papillary thyroid carcinoma (FVPTC) and non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) may also be represented in this category, especially if the nuclear features are subtle. The cytological interpretation must be clearly stated in the report, which may mean listing the likely differential diagnoses. Some of these problematic cases may reflect poor aspiration/cellularity, and a repeat aspirate may help clarify the exact diagnostic category. Review of the cytology and/or MDT discussion locally or centrally may be of use to help with patient management.

8.3.7 Suspicious for Malignancy: Thy4 This category includes those samples that are suspicious for malignancy, but which do not allow confident diagnosis of malignancy. This will include specimens of low cellularity and mixed cell types (normal and abnormal). The tumour type suspected should be clearly stated if at all possible and will often be a papillary carcinoma. This category should not be used for samples that exhibit mild atypia or the types of features described earlier, which should be categorised as Thy3a, or for follicular or oncocytic neoplasms, which should be categorised as Thy3f. Cases of definite malignancy, but where a specific diagnosis cannot be made (e.g. lymphoma versus anaplastic carcinoma), should be placed in the Thy5 category.

8.3.8 Malignant: Thy5 These are samples that can be confidently diagnosed as malignant. The tumour type should be clearly stated if possible, for example: • • • • •

Papillary thyroid carcinoma Medullary thyroid carcinoma Anaplastic thyroid carcinoma Lymphoma Other malignancy, including potentially non-thyroid/metastatic malignancy

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8  The UK Royal College of Pathologists (RCPath) Thy Terminology for Reporting Thyroid FNA Cytology Table 8.2  Risk of malignancy of the UK RCPath, Bethesda and Italian terminology systems Terminology system Bethesda (Western) Bethesda (Eastern) UK RCPath Italian TIR

Pooled risk of malignancy III/Thy3a/TIR 3A 21.5 45.0 25 17

Pooled risk of malignancy IV/Thy3f/TIR 3B 27.3 32.8 31 47

Sometimes it may be possible to be confident of malignancy but not of tumour type. This should then be clearly stated and a differential diagnosis given, e.g. between anaplastic carcinoma and lymphoma or anaplastic carcinoma and metastatic malignancy. NIFTP can be a particular problem.

8.4 Diagnostic Accuracy of UK ‘Thy’ Terminology A detailed meta-analysis of published studies (both in the UK and internationally) of thyroid surgical outcomes following cytology reported using the RCPath Thy terminology shows the following pooled risk of malignancy rates based on surgical excision: Thy3a, 25% (95% CI 20–31%); Thy3f, 31% (95% CI 24–39%); Thy4, 79% (95% CI 70–87%); and Thy5, 98% (95% CI 97–99%) [6]. These figures are similar to figures recently reported for the Western patient cohort in another large meta-analysis of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The ROM for AUS/FLUS [equivalent to Thy3a] was 21.5%, ROM for FN/ SFN [equivalent to Thy3f] was 27.3%, ROM for suspicious for malignancy [equivalent to Thy4] was 75.1%, and ROM for malignant [equivalent to Thy5] was 99.2%, see Table 8.2 [8]. There are some differences noted in the ROM rates in some of the higher TBSRTC categories between Asian and Western patient cohorts, which are likely to be due to differences in multidisciplinary management, resection rates and diagnostic thresholds. Some but not all publications from the UK show comparatively high rates for non-diagnostic FNA (Thy1) [11], and the UK RCPath terminology also classifies cysts in a slightly different way to TBSRTC. Worldwide, TBSRTC is the single most utilised terminology for thyroid FNA reporting. TBSRTC emphasises specific management for each diagnostic category [12]. The UK RCPath system takes a less prescriptive attitude, stating that the patient management decisions should be made by multidisciplinary teams and that all patients with higher-risk, e.g. Thy4 and Thy5, FNA (equivalent to TBSRTC category V/Italian TIR 4 and TBSRTC category VI/Italian TIR 5) should be discussed within the multidisciplinary setting, whereas the need for multidisciplinary discussion of lower-risk fine needle aspirates is at the discretion of multidisciplinary teams [4]. Metaanalyses of TBSRTC, UK RCPath and TIR terminologies

Pooled risk of malignancy V/Thy4/TIR 4 75.1 88.1 79 85

Pooled risk of malignancy VI/Thy5/TIR 5 99.2 98.6 98 99

[6–10] show that the system that demonstrates the most progressive incremental risk of malignancy (ROM) in the indeterminate categories is the Italian system as cases without cytological atypia are placed in a lower-risk indeterminate category, TIR 3A (pooled ROM 17%), while cases with cytological atypia are placed in a higher-risk category of the Italian system, TIR 3B (pooled ROM 47%). The TIR 3A and TIR 3B categories are designed to separate indeterminate nodules according to differing risks of malignancy into lower-risk and higher-risk lesions. By contrast, TBSRTC and UK RCPath in Western patient cohorts have pooled ROMs of 21.5% and 25% for Cat III/Thy3a and pooled ROMs of 27.3% and 31% for Cat IV/Thy3f.

8.5 Ancillary Testing In the UK, use of ancillary tests is not widespread. Immunohistochemistry (IHC) is more readily available than molecular testing. Ancillary immunocytochemical techniques are helpful for diagnosis of specific thyroid lesions although they are dependent on the type of sample preparation used. (See Chaps. 75, 76 and 77.) IHC is useful for confirming the diagnosis in problematic cases such as in suspected metastatic disease, e.g. well-differentiated papillary thyroid carcinoma that is typically thyroglobulin-­positive, TTF1-positive, PAX8-positive, HBME1-positive, CK19-positive and CD56negative; assisting in the diagnosis of medullary thyroid carcinoma that is typically calcitonin-­positive, CEA-positive, chromogranin-positive, synaptophysin-­positive, TTF1positive and thyroglobulin-­negative; and distinguishing lymphoma versus anaplastic thyroid carcinoma and/or other rarer primary thyroid lesions or tumours metastatic to the thyroid gland (e.g. head and neck squamous cell carcinoma, other metastatic carcinomas or melanoma). Immunocytochemistry can be performed on cytology or cell blocks if available.

8.6 UK Recommendations for Clinical Actions The UK guidance considers it advisable not to include clinical recommendations in cytology reports as not all the relevant clinical and/or radiological information may be available to the cytopathologist at the time of reporting [4]. Ideally,

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decisions about patient management should rest on a multidisciplinary assessment of the patient. It is expected that any thyroid cytology case categorised as Thy4 or Thy5 will be reviewed by a cyto-/histopathologist core member of the thyroid MDT meeting and discussed in the MDT meeting setting. Other cases, such as Thy3a and Thy3f, and even cases classed as Thy1/Thy1c or Thy2/Thy2c can benefit from MDT meeting discussion, especially if there is any concern. Depending on local arrangements, these may be reviewed or discussed locally or as part of a network MDT meeting approach.

8.7 UK Recommendations for Audit The UK guidance states that it is essential that reporting categories and outcomes are audited [4], although noting that the proportion of cases reported in each category will vary depending on the local case mix and aspirating protocols, commenting also that the most valid audit of accuracy is proven clinical outcomes, which are predominantly in those cases where histology is available. (See Chap. 73.) The risk of malignancy can be calculated locally for each cytology reporting category, and the correlation between cytology and histology should be with the FNA targeted lesion, as pickup of co-incidental malignant lesions can skew the correlation. The use of the reporting categories should be monitored to ensure their correct use and also to allow any changes to future thyroid cytology reporting guidance to be made based on robust evidence. Other aspects of the thyroid cytology service that can be audited may include quantity and accuracy of clinical information given on the request forms, the use of reporting codes and SNOMED codes compared with the text report, rates of insufficient samples per individual aspirator and proportion of benign/malignant nodules undergoing surgery. It is recommended that audit(s) are undertaken at least annually and that the data is discussed with MDT members and shared with other relevant interested parties as necessary. The Royal College of Pathologists has produced a template for thyroid cytology audit, which is posted on the RCPath website. The suggested audit standards are: • 100% thyroid cytology reports include a ‘Thy’ category as well as a free-text explanation of the findings • The percentage of all thyroid cytology cases that fall into each ‘Thy’ category is appropriate (as per national data) • The positive predictive value (PPV) for malignancy for Thy5 is 97–99% (although rates of 100% can be fully achievable) • 100% of Thy4/Thy5 cases undergo discussion at thyroid cancer MDT meetings • The number of Thy3 (Thy3a and/or Thy3f) cases that undergo discussion at thyroid cancer MDT meetings is appropriate (as per local preferences)

D. N. Poller

8.8 Summary As of late 2022, the UK RCPath Thy terminology is a well-­ established and extensively validated national terminology system for thyroid FNA reporting used primarily in the UK and Ireland but also in some other English-speaking parts of the world. This terminology will necessarily evolve in the future with advances in preoperative molecular testing and diagnostic categorisation of thyroid nodules, including the use of artificial intelligence. Acknowledgments  The author would like to acknowledge the major input of other UK colleagues who are members of the UK RCPath Thyroid Cytology Guideline Group in the development and formulation of these guidelines, specifically to the group chair, Dr. Paul Cross, for all three editions from 2009 to 2022, and also to Dr. A Chandra, Dr. T Giles and Dr. SJ Johnson. Thanks are also due to Dr. G Kocjan and Prof T Stephenson for their input to earlier editions of the UK RCPath terminology.

References 1. Cross PCA, Giles T, Johnson S, Kocjan G, Poller D, Stephenson T. Guidance on the reporting of thyroid cytology specimens. Royal College of Pathologists; 2009. 2. Guidelines for the Management of Thyroid Cancer. 2007. http:// www.british-­thyroid-­association.org/news/Docs/Thyroid_cancer_ guidelines_2007.pdf. 3. Cross P, Chandra A, Giles T, Johnson S, Kocjan G, Poller D, et al. Guidance on the reporting of thyroid cytology specimens. 2nd ed. Royal College of Pathologists; 2016. 4. Cross P, Chandra A, Giles T, Johnson S, Poller D. Guidance on the reporting of thyroid cytology specimens. 3rd ed. Royal College of Pathologists; 2022. 5. van der Horst C, Wright S, Young D, Tailor H, Clark L.  What is Thy3a? A study of 336 Thy3a (AUS/FLUS) thyroid FNAs with histology compares UK RCPath with other reporting systems and shows how Thy3a subclassification can improve risk stratification and help address overuse of this category. Cytopathology. 2020;32:29. https://doi.org/10.1111/cyt.12910. 6. Poller DN, Bongiovanni M, Trimboli P. Risk of malignancy in the various categories of the UK Royal College of Pathologists thy terminology for thyroid FNA cytology: a systematic review and meta-­ analysis. Cancer Cytopathol. 2019;128:36. https://doi.org/10.1002/ cncy.22201. 7. Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW.  The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytol. 2012;56(4):333–9. https://doi. org/10.1159/000339959. 8. Vuong HG, Ngo HTT, Bychkov A, Jung CK, Vu TH, Lu KB, et al. Differences in surgical resection rate and risk of malignancy in thyroid cytopathology practice between Western and Asian countries: a systematic review and meta-analysis. Cancer Cytopathol. 2019;128:238–49. https://doi.org/10.1002/cncy.22228. 9. Trimboli P, Crescenzi A, Castellana M, Giorgino F, Giovanella L, Bongiovanni M.  Italian consensus for the classification and reporting of thyroid cytology: the risk of malignancy between indeterminate lesions at low or high risk. A systematic review and meta-analysis. Endocrine. 2019;63(3):430–8. https://doi. org/10.1007/s12020-­018-­1825-­8. 10. Trimboli P, Fulciniti F, Paone G, Barizzi J, Piccardo A, Merlo E, et al. Risk of malignancy (ROM) of thyroid FNA diagnosed as suspi-

8  The UK Royal College of Pathologists (RCPath) Thy Terminology for Reporting Thyroid FNA Cytology cious for malignancy or malignant: an institutional experience with systematic review and meta-analysis of literature. Endocr Pathol. 2020;31(1):52–6. https://doi.org/10.1007/s12022-­019-­09602-­4. 11. Poller DN, Doyle V, Trimboli P, Bongiovanni M.  Rates of thy 1-non-diagnostic thyroid fine needle aspiration using the UK Royal College of Pathologists thy terminology. A systematic review of the

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literature comparing patients who undergo rapid on-site evaluation and those who do not. Cytopathology. 2020;31:502. https://doi. org/10.1111/cyt.12804. 12. Ali SZ, Cibas ES. The Bethesda system for reporting thyroid cytopathology. Definitions, criteria, and explanatory notes. 2nd ed. Cham: Springer; 2017.

9

Australian System for Reporting Thyroid Cytology Marian Priyanthi Kumarasinghe

9.1 Introduction

sification system for reporting thyroid FNAs, 53 used the Bethesda system, and 14 used other systems for reporting Australasian guidelines for thyroid cytology were prepared thyroid cytology. Findings of the survey showed an overas the first step to standardize non-gynecological cytology whelming consensus for a uniform reporting system suitable reporting [1]. This document can be accessed freely. This for Australasia. was a joint effort by the structured pathology reporting projAs the majority of the aspirations are performed by the ect of the Royal College of Pathologists of Australasia and radiologists in this region, the quality and the quantity of Australian Society of Cytology. Standardization of gyneco- smears and other material provided to the pathologist are logical cytology reporting in Australia has proven to be a largely dependent on the skills of radiologists performing the great success. The aim was to achieve similar success in non-­ procedure and others who are involved in sample preparation gynecological cytology to standardize the practice, improve before the specimen arrives in the laboratory. (See Chaps. 22 quality of the final cytopathology report, and introduce and 62.) appropriate and cost-effective ancillary testing to improve Considering the above background, it was decided that accuracy. Ultimately, the protocol was aimed at improving guidelines should include some aspects of FNA techniques the clinical decisions for management of thyroid lesions. It and smear preparation without restricting to terminology and was hoped that a standard approach to all aspects of thyroid interpretation alone. Therefore, Australasian guidelines cytology would allow optimal management of thyroid lesions include standards and guidelines for preparation, interpretaby clinicians. tion, and reporting of thyroid cytology material obtained by The guidelines were prepared based on several needs in fine-needle aspiration (FNA) biopsy not limited to reporting Australasia. They include the local state-funded health-care and terminology only. delivery system and judicious use of government rebates and Standard approach to all the above areas is expected to reimbursements for investigations. These needs were recog- improve the quality of the material and therefore interpretanized and discussed by a working party comprising cytopa- tion and final diagnosis. This approach would allow enhancethologists, cytologists, and clinicians with an interest and ment of laboratory quality assurance programs and expertise in the field of thyroid cytology as a joint project of performance measures as well as facilitate education and the Royal College of Pathologists of Australasia (RCPA) and research with regard to thyroid nodules. the Australian Society of Cytology (ASC). About 5% of the population is found to have thyroid A survey done by RCPA QA program had demonstrated nodules on clinical examination. This number increases up that radiologists perform approximately 65% of aspirations, to 25%, if the thyroid gland is examined by ultrasound while only 11% is done by pathologists. The survey also examination. About 5% of thyroid nodules are likely to be showed that thyroid fine-needle aspirations (FNAs) consti- malignant [2, 3]. The incidence of thyroid cancer is increastute between 0 and 62% of the total workload of cytology ing, particularly in women, where it is among the top 10 laboratories. Of 143 labs surveyed, 60 used no defined clas- cancers diagnosed in Australia. At the time of preparation of the first edition, according to the statistics available in 2007, 1787 new cases of thyroid cancer were reported comM. P. Kumarasinghe (*) Department of Anatomical Pathology, PathWest, QEII Medical pared to 859 new cases in 1997—a twofold increase in Centre, Nedlands, WA, Australia 10 years [4]. Discipline of Pathology and Laboratory Medicine, University of Similar to the rest of the world, in Australasia, fine-neeWestern Australia, Crawley, WA, Australia dle aspiration is currently considered as the best tool for trie-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 K. Kakudo et al. (eds.), Thyroid FNA Cytology, https://doi.org/10.1007/978-981-99-6782-7_9

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M. P. Kumarasinghe

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aging thyroid nodules. It is well-established that if stringent diagnostic criteria are used, the majority of thyroid nodules can be safely and accurately categorized by cytological assessment. Often a specific diagnosis, such as a colloid goiter, thyroiditis, or a specific thyroid malignancy (e.g., papillary, medullary, or anaplastic carcinoma), can be made. The use of ancillary techniques may enhance diagnostic accuracy in some cases. Some aspirates are non-diagnostic due to technical issues such as insufficient cellularity, poor quality of sample preparation, or technical artifacts due to blood staining, ultrasound gel, etc. In others, the distinction between benign and malignant nodules may not be possible due to interpretative difficulties. To ensure the best possible assessment of thyroid nodules, some guidance on sampling, preparation of material, interpretation, and reporting were warranted. The role of the cytopathologist and cytologist in the management of thyroid nodules is to provide guidance to clinicians in planning further management. While accurate assessment of cytology material is vital, translation of the pathological assessment and interpretation into a report is an equally important exercise. The reporting categories, systems, and terminology should be reproducible and predictive of outcome and translate to clear management guidelines. The “inconclusive/gray” area should thus be within an acceptable range. At the time of preparation of the guidelines, at least three published Australian systems were in use in Australasia to consider [5–7]. The recently introduced Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) together with the other systems such as the Papanicolaou Society classification and British Thyroid Association terminology was also critically analyzed by the group (Table  9.1) [8–10]. Advantages and disadvantages of each system were considered by the expert committee.

A combination of the most widely utilized system, the Bethesda system and local terminology, was incorporated to prepare Australasian reporting guidelines. These guidelines were expected to evolve further when evidence and data on their merits and shortcomings become available. Structured pathology protocol project by RCPA determines that standards are mandatory, as indicated by the use of the term “must.” Their use is reserved for core items essential for the clinical management and key information (including observations and interpretation), which is fundamental to the diagnosis and conclusion. The summation of all standards represents the minimum dataset for a report [1, 11]. The first edition was completed and published in 2014, and a subsequent review was published in Pathology (the official journal of RCPA) [12].

9.2 Australasian Guidelines The guidelines deal with five important areas of thyroid cytology and are not restricted to microscopic evaluation and terminology. These areas are discussed below.

9.2.1 Pre-analytical Clinical information is a prerequisite for accurate diagnosis. Some of this information may be received on generic pathology request forms prepared by the clinician. In the case of a nodular goiter, it is imperative that the nodule to be sampled is indicated clearly. Knowledge of the radiological findings was considered helpful if not essential. A standard request form especially aimed at obtaining radiology details was prepared and recommended.

Table 9.1  Terminologies used in Australia in the past British Thyroid Association Thy 1—Inadequate Thy 2—Benign Thy 3—Follicular lesion/suspected follicular neoplasm

Thy 4—Suspicious for malignancy Malignant

Papanicolaou Society 2007 Bethesda (TBSRTC) 2009 Unsatisfactory Non-diagnostic/ unsatisfactory Benign Benign Atypical cellular Atypia of undetermined lesion significance/follicular lesion of undetermined significance Follicular neoplasm Follicular neoplasm or suspicious for follicular neoplasm Suspicious for Suspicious for malignancy papillary thyroid carcinoma Malignant Malignant

Orell and Phillips 2000 (Australia) Unsatisfactory Benign Indeterminate (further subdivided)

PathWest (Western Australia: from mid-2000s) Non-diagnostic

RCPA/ASC (2014) Non-diagnostic

Benign Indeterminate

Benign Indeterminate

Atypical

Suspicious for malignancy

Suspicious for malignancy

Suggestive of a follicular neoplasm Suspicious for malignancy

Malignant

Malignant

Malignant

9  Australian System for Reporting Thyroid Cytology

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9.2.2 FNA Collection and Preparation of Material

Therefore, a standard report was expected to include: 1. The general classification (category descriptor) using RCPA/ASC terminology with the optional use of the category number. 2. A summary of the cytological findings, a conclusion, and comments and any recommendations as appropriate.

Both direct and ultrasound-guided aspirations with and without rapid on-site evaluation (ROSE) are practiced in Australasia. Direct smears are critical for on-site evaluation to provide essential information that would guide triaging specimens for ancillary studies at the time of the aspiration. Liquid-based cytology (LBC) is used in some centers, mostly in New Zealand. LBC techniques may be useful if material is collected by inexperienced staff with no exposure to cytology techniques. Important diagnostic cytological features are often lost in LBC preparations, and cytology staff needs retraining. The committee was of the opinion that LBC technology should not be mandated until there is strong evidence of its superiority locally [13, 14]. (See Chaps. 32, 63, and 65.) The aspiration utilizing a syringe, with or without a pistol-­ grip device, or without aspiration by needle alone was recommended. Some are of the opinion that non-aspiration technique provides increased tactile sensation of the lesions and causes less bleeding [15].

9.2.3 Terminology, Microscopic Findings, Interpretation, and Recommendations The terminology is based on an adaptation of the two main systems that were in existence in Australia almost over two decades [5, 6]. This adaptation was aligned with the Bethesda system (Table 9.1—columns 4 and 5) [8]. This approach was necessary in Australia to streamline standardization while maintaining well-established and “time-tested” systems yet embracing positive aspects of the TBSRTC. Australasian guidelines recommend six cytology categories similar to TBSRTC and PathWest system in Western Australia [6, 8]. RCPA/ASC categories are: • Non-diagnostic—Category 1 • Benign—Category 2 • Indeterminate or follicular lesion of undetermined significance—Category 3 • Suggestive of a follicular neoplasm—Category 4 • Suspicious for malignancy—Category 5 • Malignant—Category 6 A category descriptor is considered standard, while the category number was considered optional. Category number was recommended for comparison with other systems, in particular, the TBSRTC.

Table 9.2 shows a comparison of the Bethesda system and Australasian (RCPA/ASC) guidelines highlighting the similarities and differences. There were several aspects and issues highlighted and emphasized in the first edition of Australasian guidelines. • Category 1—Non-diagnostic: A uniform approach for the statement “non-diagnostic” was recommended as standard. It was essential that the reason for the “non-­ diagnostic” category be clearly stated in the report as this was considered to be an important reflection of pre-­ analytical issues. The “non-diagnostic” category is commonly associated with poor techniques of aspiration and smear preparation and less commonly with the nature of the lesion, resulting in inadequate or unsatisfactory smears. Adequacy criteria used were similar to those recommended by TBSRTC and the British Thyroid Association. It was acknowledged that criteria were driven by expert opinion than scientific evidence (Level V evidence). (See Chap. 22.) • Category 3—Indeterminate/Follicular Lesion of Undetermined Significance: One major emphasis is to advice against using the term “atypical” as a general diagnostic category. The word atypia/atypical in the Australasian cytology practice (as well as around the world) may be used with different connotations. Similarly, the term “atypical” may convey a degree of concern for neoplasia and may be misinterpreted by clinicians and general practitioners, the latter group being the predominant primary care physicians in the local setting. This may lead to unwarranted anxiety in the patient and may even be a trigger for surgery, which is likely to be inappropriate. The word atypia may be used in the microscopic description or to describe a cellular or architectural feature. The choice of recommended term is dependent on the circumstances. Some laboratories prefer to use the simple phrase “indeterminate” than follicular lesions of undetermined significance (Table  9.3) [6, 16]. Both follicular and non-­ follicular lesions (e.g., autoimmune thyroiditis, spindle cell reactions) may fall into this category. Most cases will have a benign follow-up, and the risk of malignancy is low (5–13%) in our experience locally [6]. (See Chap. 25.)

M. P. Kumarasinghe

54 Table 9.2  Comparison of the Bethesda system and Australasian (RCPA/ASC) guidelines Category number 1 2 3

RCPA/ASC (2014) Non-diagnostic Benign Indeterminate/follicular lesion of undetermined significance

Suggestive of a follicular lesion Suspicious for malignancy

4

Malignant

6

5

Comments and recommendations The reason for non-diagnostic category should be mentioned Suggested benign diagnosis should be mentioned  • The use of the term atypia as the diagnostic category is not recommended  • These lesions include follicular and non-follicular lesions in which most features suggest a benign lesion; however, a definite benign diagnosis cannot be rendered  • The choice of the term depends on the circumstances, e.g., if a non-follicular lesion such as thyroiditis is suspected, the term “indeterminate” is an option The use of the term suspicious is not recommended Use of stringent criteria to maintain a high rate of risk of malignancy approaching 80% or above is recommended

Bethesda Non-diagnostic/unsatisfactory Benign Atypia of undetermined significance/follicular lesion of undetermined significance

Follicular neoplasm or suspicious for follicular neoplasm Suspicious for malignancy Malignant

Table 9.3  Australasian nomenclature with recommendations RCPA category (Bethesda) Category % of total cases no. Specific diagnosis Non-diagnostic 1 1. Insufficient material for (non-diagnostic/ diagnosis unsatisfactory) 10–20%

Benign (benign) 40–60%

2

2. Cyst/hemorrhage with no epithelium, no colloid, and no info about whether a mass remained. Cystic neoplasm not excluded 1. Colloid nodule

2. Cyst aspirated to dryness. No residual mass by palpation or US and no atypia 3. Thyroiditis (Hashimoto or de Quervain) Indeterminate (atypia of undetermined significance AUS/ follicular lesion of undetermined significance FLUS) 15–20%

Suggestive of follicular neoplasm (follicular neoplasm or suspicious for FN) 10%

3

4

Satisfactory sample. Unable to distinguish between colloid nodule and neoplasm and thyroiditis and neoplasm

Suggests a follicular neoplasm

The term “follicular lesion” or “follicular nodule” is not recommended in reports because of low specificity

Recommendation 1. Repeat sample, e.g., 6–8 weeks

2. Repeat if recurs or refer to specialist thyroid opinion

Risk of Explanatory notes/follow-up malignancy data Low 1. If a satisfactory sample is not obtained on repeat FNA, refer for specialist thyroid/ endocrine opinion