[PDF Download] Thyroid fna cytology: differential diagnoses and pitfalls, third edition kennichi kak
Thyroid FNA Cytology: Differential Diagnoses and Pitfalls, Third Edition
Kennichi Kakudo
Visit to download the full and correct content document: https://textbookfull.com/product/thyroid-fna-cytology-differential-diagnoses-and-pitfalls -third-edition-kennichi-kakudo/
More products digital (pdf, epub, mobi) instant download maybe you interests ...
Thyroid and Parathyroid Ultrasound and Ultrasound Guided FNA 4th Edition Daniel S. Duick
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, specifcally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microflms 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 specifc 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 affliations.
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 frst edition of Thyroid FNA Cytology: Differential Diagnoses and Pitfalls was published in 2016. It was the frst textbook on thyroid fne 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 feld of thyroid pathology and cytopathology, such as the wider implementation of ancillary techniques, molecular studies, and the publication of the ffth edition WHO Classifcation 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 signifcantly among countries and continents. While most pathologists follow the WHO classifcation 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 specifc countries, and medical expenses. This phenomenon along with the national and international reporting systems of thyroid FNA and the new edition of the WHO Classifcation of Thyroid Tumors will be discussed in the frst 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 fnal 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 signifcantly 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.
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
Chiung-Ru Lai Kamogawa, Japan Andrey Bychkov Shanghai, China Zhiyan Liu Seoul, Republic of Korea
Chan Kwon Jung Kobe, Japan Mitsuyoshi Hirokawa Izumi, Japan Kennichi Kakudo Preface
Preface to the First eBook Edition
Thyroid fne 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 highrisk 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 signifcantly 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 frst 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. Defnitions, criteria and explanatory notes. New York: Springer; 2010.
2. Fadda G, Basolo F, Bondi A, Bussolati A, Crescenzi O, et al. Cytological classifcation 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 fne-needle aspiration diagnostic classifcation 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 fne-needle aspiration cytology according to the new guidelines of the Japan Thyroid Association. Endocr J. 2014;61:539–52.
Izumi, Japan
Kennichi Kakudo Shanghai, China Zhiyan Liu Kobe, Japan Mitsuyoshi Hirokawa
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 fle 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 frst and only textbook for thyroid FNA cytology that incorporates borderline tumor categories in thyroid tumor classifcation, which are hyalinizing trabecular adenoma identifed 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 reclassifcation of some indolent tumors currently classifed 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 frst 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. Classifcation 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. Classifcation 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.
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 reclassifcation 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 fne-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 Kennichi Kakudo Shanghai, China Zhiyan Liu Kobe, Japan Mitsuyoshi Hirokawa
Preface to the Second Edition
There were several breakthrough events in thyroid fne needle aspiration (FNA) cytology recently, which included the introduction of borderline tumors in the fourth edition World Health Organization (WHO) Classifcation 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 modifcations in the newest WHO classifcation and established strategies on how to solve newly identifed 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 classifcation. Furthermore, after publication of the frst edition in 2016, the editor found signifcant 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 fnd 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 fnd in Chap. 10 by Ito and Miyauchi, Chap. 22 by Kakudo and Chaps. 42 and 43 by Kameyama (in Japanese practice), how risk stratifcation 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 classifcation with only two diagnostic choices, benign and malignant tumors, and current view (lower) based on the 4th edition WHO classifcation 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 signifcance, FN follicular neoplasm
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 frst 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 thoughtprovoking 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 classifcation 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. Classifcation 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 modifcations 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: defnitions, 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.
12. Layfeld LJ, Baloch ZW, Esebua M, et al. Impact of the reclassifcation 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 fve 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 papillarylike 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
Part I Why Are There Signifcant Differences Among Us in Thyroid Nodule Practices?
1 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
3
2 Diagnostic Criteria of Papillary Thyroid Carcinoma (PTC)-Type Nuclear Features Impacting Thyroid Fine Needle Aspiration (FNA) Cytology 7
61 Parathyroid Adenoma and Its Differential Diagnoses
Min En Nga
Part XI How to Improve Diagnostic Performance in Thyroid FNA Cytology
62 Aspiration Methods and Optimal Smear Preparation Techniques
Miyoko Higuchi, Ayana Suzuki, and Mitsuyoshi Hirokawa
63 Staining Methods in Thyroid Cytology
Annette L. Salillas and Ayana Suzuki
64 Fine Needle Aspiration Biopsy Complications
Yasuhiro Ito and Mitsuyoshi Hirokawa
65 Liquid-Based Cytology Technique for Thyroid Cytology
Claire W. Michael
66 Rapid On-Site Evaluation (ROSE)
Xin Jing, Kennichi Kakudo, and Claire Michael
67 Mobile Rapid On-Site Evaluation .
Toshitetsu Hayashi and Noriko Akiyama
68 Low-Cellularity Thyroid Fine Needle Aspiration Specimens: Differential Diagnosis, the Role of Ancillary Testing and Associated Diagnostic Challenges
Syed M. Gilani
69 The Role of Repeat FNA in Indeterminate Thyroid Nodules
Pablo Valderrabano
70 Frozen Section and Intraoperative Imprint Cytology
Bozidar Kovacevic, Snezana Cerovic, and Vesna Skuletic
71 Core Needle Biopsy for the Diagnosis of Thyroid Nodules: Pathologic Aspects
Chan Kwon Jung
72 Biochemical Test of Fine-Needle Aspirate as an Adjunct to Cytological Diagnosis in Patients with Thyroid Cancer or Primary Hyperparathyroidism
Shinya Satoh, Hiroyuki Yamashita, Kennichi Kakudo, and Masahiro Nakashima
73 Quality Control for Cytology Laboratory in the USA
Aparna Harbhajanka and Claire W. Michael
74 Infection Control in Cytology Practice and the COVID-19 Pandemic
Elena Vigliar, Claudio Bellevicine, and Giancarlo Troncone
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 . .
Sara Coluccelli, Thais Maloberti, Federico Chiarucci, Antonio De Leo, Dario de Biase, and Giovanni Tallini
661
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
Young Shin Song and Young Joo Park
Part XIV Image Technology in Thyroid Nodule Practice
83 Pathologic Basis for Thyroid Ultrasound
Grace C. H. Yang and Chiung-Ru Lai
84 Ultrasonography of the Thyroid Gland
697
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
89 Active Surveillance for Low-Risk Small Papillary Thyroid Cancer in North America
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 .
Young Ah Lee
91 Thyroid Carcinoma of Young Adults and Children
Chanchal Rana and Huy Gia Vuong
92 The Role of Thyroid FNA Cytology in Pediatric Malignant Lesions: Case Illustrations and Literature Review
Esther Diana Rossi
Part XVII Patient Oriented Thyroid Nodule Practice
93 One-Stop Clinic for Thyroid Nodules
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
Part I
Why Are There Signifcant Diferences Among Us in Thyroid Nodule Practices?
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 frst edition of Thyroid FNA Cytology: Differential Diagnoses and Pitfalls was published in 2016. It was the frst textbook of thyroid fne needle aspiration (FNA) cytology from Asia written in the English language. Following collaborations and exchanges among the international authors of the frst 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 classifcation 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 fnds all of the following factors, both scientifc and non-scientifc, 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: kakudo@thyroid.jp
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 Affliated 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 signifcantly [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 stratifcation 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 Diferences 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 classifcations: 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 scientifc 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 fuid-only samples, whether in the inadequate or benign category. (See Chaps. 6, 7, 8, 9, 10, and 12.)
Cyst fuid-only thyroid specimens have been found to have a signifcant risk of a false-negative diagnosis caused by cystic
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 classifed as benign when there is no suspicious clinical fnding. In contrast, some cytopathologists do not accept this classifcation, and they are classifed 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 fuid-only samples, several reporting systems introduced a cyst fuid-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 Difer
Between the Third Edition and the Fifth Edition of the WHO Classifcation 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 classifcation 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 classifcation [23] and low-risk neoplasm category in the current ffth edition of the WHO classifcation [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
kinds of tests in most countries. The characteristic cytological diagnosis of suboptimal samples with BRAF-like PTCtype 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 confrmed with repeat FNAs or BRAF single gene tests cost-effciently [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 signifcant 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 nodules because only patients with high-risk clinical features are
K. Kakudo
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-effcient. 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 treatmentrelated 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.
3. Bychkov A, Kakudo K, Hong SW. Current practices of thyroid fneneedle 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 fne-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.
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 signifcant 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 Classifcation 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 Classifcation of tumours of endocrine organs. 4th ed. Lyon: IARC Press; 2017.
24. IARC. The WHO Classifcation 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 classifcation. Pathol Int. 2018;68:327–33.
28. Kakudo K, Kameyama K, Miyauchi A, et al. Introducing the reporting system for thyroid fne-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. Subclassifcation 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 signifcance/follicular lesion of undetermined signifcance: 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 signifcantly changes surgical resection rate and risk 1 Addressing
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 fne-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 fne-needle aspirations of thyroid nodules: a comparative analysis of three molecular assays in 4585 consecutive cases in a BRAF V600E mutationprevalent 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 fne-needle aspiration (FNA) read as suspicious for malignancy (Bethesda V, Thy4, TIR4): a systematic review and meta-analysis. Endocr Pathol. 2020;31:57–66.
38. Ali S, Cibas E, editors. The Bethesda system for reporting thyroid cytopathology: defnitions, 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 stratifcation 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.
K. Kakudo et al.
2.1 Introduction
Diagnostic Criteria of Papillary Thyroid Carcinoma (PTC)-Type Nuclear Features Impacting Thyroid Fine Needle Aspiration (FNA) Cytology
As discussed in the preface to the third edition and Chap. 1, there are several factors signifcantly impacting quality measures 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-effcient BRAF single-gene molecular test, in addition to repeat FNA for a more defnitive diagnosis. (See Chaps. 69, 72, 76, 77, and 78.)
2.2
Papillary-Like Nuclear Features
2
K. Kakudo (*)
Department of Pathology, Cancer Genome Center and Thyroid Disease Center, Izumi City General Hospital, Izumi, Osaka, Japan e-mail: kakudo@thyroid.jp
Z. Liu
Department of Pathology, Shanghai Sixth People’s Hospital
Affliated 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
(Score 2–3 Nuclear Features Defned by Nikiforov et al. [1]) and the So-Called RAS-Like Dysplasia (Fig. 2.1)
The author termed papillary-like nuclear features characteristic of NIFTP (score 2–3 nuclear features defned by Nikiforov et al. [1]) as dysplastic nuclear changes of RASlike 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), welldifferentiated carcinoma not otherwise specifed (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 classifcation [14]. This central dogma (cases with PTC-type nuclear features are malignant regardless of invasive growth even if it is subtle) was signifcant 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 classifcation [15] and lowrisk neoplasm category in the ffth edition of WHO classifcation [16]. The ffth edition of WHO classifcation further clarifed the defnition 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 ffth
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
edition of WHO classifcation, 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 reclassifed 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 forid nuclear features of
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)
classic PTC of BRAFV600E gene mutation becomes paramount in thyroid cytology (Fig. 2.2), as only forid 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 ffth edition of WHO classifcation [1, 16]. (See Chap. 18.) Thus, downgrading cases with papillary-like nuclear features from defnite 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.)
K. Kakudo et al.
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-
2.3 Diagnostic Criteria for Indeterminate
Cytological Categories in Asia Are Diferent from Those in Western Practice
In Western practice, cases with papillary-like nuclear features in follicular-patterned cytological samples are classifed in AUS or FN categories, and forid nuclear features of PTC are classifed 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 forid 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 forid 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
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)
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 forid nuclear features of BRAF-like PTC are often classifed 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 classifed 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 confrm 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). 2
Fig. 2.3 Diagnostic algorithm of thyroid FNA cytology in the Japanese system [8]. BRAF-like forid nuclear features of papillary thyroid carcinoma (PTC) are risk-stratifed in either indeterminate B (when questionable), suspicious for malignancy (when not conclusive), or defnite malignancy (when conclusive). Rare atypical cells in poor-quality spec-
This morphological identifcation 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.
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-
imens are also classifed as indeterminate B. Cases with delicate nuclear changes in RAS-like tumors or architectural abnormality are classifed as indeterminate A. The indeterminate A category is further riskstratifed into favor benign, borderline, and malignant morphologically (see Chap. 10)
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 signifcance [38, 39]. (See Chap. 18.) However, a signifcant 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 Afrma gene expression classifer (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.)
K. Kakudo et al.
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 confrmed even in an eminent academic center in the USA [42], although a newer version (Afrma genomic sequencing classifer: GSC) reported an improved specifcity 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-confrmed 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 PapillaryLike 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 signifcantly 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 <50% as insuffcient to advise patients to undergo diagnostic surgery. Asian physicians usually feel guilty if the patient is found to have a
benign nodule on resection [50, 51]. Asian physicians often advise surgery to patients when the estimated ROM is greater than 80%, which is a different climate from Western physicians, where diagnostic surgery is usually recommended to all FN (high-risk indeterminate) nodules and even to biologically benign (not malignant) NIFTPs [43, 44]. This approach recommended by the ATA clinical guidelines is not acceptable by most physicians practicing outside of North America [10, 13, 50, 51]. Asian physicians often advise watchful follow-up (no immediate surgery) to patients with indeterminate thyroid nodules after confrming benign ultrasound features [8, 10, 11, 13, 52] because the vast majority of cases with indeterminate cytology are benign or borderline tumors, and the majority of thyroid carcinomas in indeterminate categories are low risk [53–55]. (See Chaps. 3 and 13.) Clinical follow-up of these nodules is one method recommended by the JTA clinical guidelines as long as they have benign clinical features [8–12, 52] (See Chaps. 3, 13, and 86.)
In conclusion of this subsection, the distinction between cases with BRAF-like nuclear features and cases with RASlike dysplasia in cytological samples is essential in most countries where gene panel tests are not freely accessible. The accurate identifcation of BRAF-like PTCs in AUS and SM categories can be achieved with repeat FNA or BRAF single-gene tests without the aid of costly gene panel tests. This clinical management helps signifcantly reduce healthcare costs for society and the patients.
2.7 Which Do You Prefer, Over-Diagnosis or Under-Diagnosis, when You Are Uncertain?
Another marked difference in cytology practice in Asian countries is that most cytopathologists prefer under-diagnosis rather than over-diagnoses when the diagnosis is uncertain, as malpractice litigation occurs more often in cases with a false-positive diagnosis in Asia [50, 51], where the Hippocratic Oath “Primum Non Nocere (frst, do not harm patients.)” is essential [56, 57]. As a result, indeterminate nodules with malignant clinical features undergo immediate surgery (not for diagnostic purposes but as treatment) in Asian countries [8–13, 50, 52]. With this conservative clinical approach, the rate of surgery for benign lesions, low-risk neoplasms (NIFTP, NEPRAS, and UMP), and low-risk minimally invasive encapsulated FTC and minimally invasive encapsulated FV-PTC, in addition to low-risk small PTCs, is reduced without an increased risk of mortality to the patients. (See Chaps. 3, 11, 13, 15, and 87–89.) Of note, some Western pathologists/cytopathologists are also concerned about overtreatment of thyroid nodules in current Western thyroid nodule practice [57–61].
Another random document with no related content on Scribd:
