Practical Diagnostic Approaches in Non- Gynaecologic Cytology

Min En Nga

Practical Diagnostic Approaches in Non-Gynaecologic Cytology

ISBN 978-981-15-2960-3 ISBN 978-981-15-2961-0 (eBook)https://doi.org/10.1007/978-981-15-2961-0

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Min En NgaDepartment of PathologyNational University HospitalSingapore

To my husband, Tony, for always inspiring me to be better.

To my mentors Felicity Frost, Greg Sterrett and Priyanthi Kumarasinghe, not only for schooling me in cytology but also for showing me the meaning of service and humility.

And to my parents, Been Hen and Cheng Choo, who made me want to teach.

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Although there are many comprehensive cytology texts, there are not many that give a broad approach to cytopathology with practical tips. Such teaching is inherently difficult and is built on a very deep understanding of the ‘art and science’ of cytopathology in the back drop of very sound clinical knowledge. This book fills that void. It covers aspects that are beyond standard interpreta-tion, and yet essential in achieving the final goal of cytopathology practice which is patient care. Thyroid, lymph node, salivary gland, effusion cytology and cytopathology of endoscopic ultrasound-guided (EUS) aspirates are given special attention with the novel slant of pre- and post-analytical issues.

The absolute value of cytopathology as one of the most cost-effective diagnostic techniques ever invented, both in the developed and developing world has been established beyond doubt for decades. Notwithstanding that, the honest acceptance of what you can not do is absolutely well illustrated in Chap. 1. The reader is introduced to a humble beginning of the journey of cytopathology with self-learning along the way. This is an essential part of mastering cytopathology along with the essential requirement of in-depth clinical knowledge. Chapter 2 covers an integral part of pathology practice—writing a meaningful, clinically useful cytopathology report. All the hard work would be lost with a confusing report as the final cytopathology report is often the only communication with the clinician. Chapter 3 deals compre-hensively with the triple approach which comprises clinical, cytological eval-uation and ancillary testing, and Chap. 4 describes Rapid On-site Evaluation (ROSE).

The system-based chapters expand on the basic essentials covered in Chaps. 1–4. The many figures and charts provide details and clues to differ-ential diagnosis and cytopathological features. Thyroid cytopathology is cov-ered in Chap. 5 with emphasis on terminology and new and evolving concepts. A useful description of architectural patterns is beautifully presented with very clear illustrations. Similarly, the other systemic chapters are covered in a manner that can be readily understood even by the uninitiated.

Chapter 8, on EUS-guided aspiration of the gastrointestinal tract and pan-creas, provides excellent practical tips. The value and limitations of ROSE are discussed with honesty, with reference to the role of telecytology. In pan-creatic cytology, the Papanicolaou Society of Cytopathology Guidelines for Reporting of Pancreaticobiliary Cytology appears to be the flavour in the text. This system has earned its deserved recognition with the useful categories especially the category of ‘Neoplasm’. Here again, approaches in the

Foreword

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foundational chapters are elaborated on with a very comprehensive discus-sion on site-specific neoplasms, non-neoplastic lesions and potential diagnos-tic pitfalls.

In the time that I have known Dr Nga, she has never hidden her keen inter-est in unravelling the mysteries of the cells. The intricate details have always made her curious. Over time, she has practised and taught cytopathology with the same undiluted passion. She has keenly embraced and refined all the prac-tical tips gathered throughout her practice, and this text is a fine testimony to her journey. This book will no doubt fill a void that is needed in the overall understanding of cytopathology that is not only restricted to the interpretation of material. I congratulate Dr Nga for undertaking such a task.

Priyanthi KumarasingheConsultant Pathologist, Department of Anatomical PathologyPathWest Laboratory Medicine, Queen Elizabeth II Medical CentreNedlands, WA, Australia

Clinical Professor, Discipline of Pathology and Laboratory MedicineUniversity of Western AustraliaPerth, WA, Australia

Director, Western Australia, International Academy of Pathologists, Australasian DivisionPerth, WA, Australia

Foreword

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The practice of cytopathology is very much like detective work. It is akin to peering through a keyhole, gathering minute and sometimes peripheral clues, meticulously studying them, and, hopefully, solving the mystery that each case presents.

This is a book of approaches. It is written with the busy practicing patholo-gist and cytotechnologist in mind. It is not a comprehensive tome that system-atically highlights the diagnostic features of specific entities in every organ system—this has been amply and beautifully covered in many excellent texts today, many of which have been my own silent teachers past and present. Instead, it is a practical guide on how to best combine the knowledge of cyto-morphology with clinical knowledge and an understanding of ancillary tests, in order to obtain the most accurate and clinically helpful diagnosis.

In these pages, practice-driven approaches will be provided, focusing on the salient, most distinguishing and unique cytomorphologic features of com-mon and challenging entities. In tandem with this, relevant clinical aspects will be highlighted, hand in hand with ancillary tests. The algorithmic approaches provided here are not comprehensive; indeed, they are only a start—a template—on which you can build your own improved and tailor- made versions.

As you read, you are encouraged to actively think of each case in its full clinical context, incorporating relevant clinical findings into the cytologic evaluation where possible. This practical guide also touches on the optimal use of limited cytologic material for ancillary testing, and how to maximise the tissue for diagnostic use, prognostication and prediction of response to therapy.

I hope that you will find this to be a helpful companion in your journey to uncover the mysteries that each and every cell holds.

Min En Nga

Preface

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I would like to express my sincere thanks to many who have, in one way or another, helped to make this book a reality. For your generous and inspired suggestions and comments—Tony Lim, Siaw Ming Chai, Gwyneth Soon, Yingting Mok, Nicholas Tan, Li Yin Ooi, Hui Min Tan, Jaslyn Lee, Gideon Tan, Noel Chia and Fredrik Petersson. For so kindly and willingly hunting down suitable illustrative cases—Zhen Qin Tan and Gaik Lan Lim. For so patiently guiding me through the murky waters of formatting—Darren Chua.

For your immense support, friendship and incisive opinions, and for being our steadfast and able cytology director, Shaun Goh. To my other colleagues in cytopathology who provide unstinting support in the practice and teaching of cytology, Ju Ee Seet and Qasim Ahmed.

For always putting the patient first and for being the absolute backbone of our cytopathology service—my thanks to our wonderful cytotechnologists—Hua Cheng Kee, Xu Xia, Vanessa Soh, Gaik Lan Lim, Zhen Qin Tan, Irene Lee, Li Yin Lim, Jocelycn Chung and Bridget Wong.

For being a joy to teach and learn with, all trainees past and present in the Department of Pathology, National University Hospital—you are the motiva-tion for this book, and the future of cytopathology.

To all colleagues in the Department of Pathology, National University Hospital and National University of Singapore, my sincere thanks for your support and for the generous sharing of cases and knowledge in this ever fascinating discipline of Pathology.

And, finally, my sincere thanks to Barbro Nilsson, who was my first teacher of cytology and who taught me how to ‘talk’ to the cells!

Acknowledgements

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This book is written in two main parts—Part I, the foundational chapters, and Part II, the system-based chapters.

Part I (Chaps. 1–4) comprises the foundational elements of the practice of cytology, with a strong emphasis on practice-based aspects. It highlights active ways in which to maximise learning from each case and provides a general approach (the triple approach) to the diagnostic process. The three elements of this approach are clinical information, cytology and ancillary tests. These chapters aim to equip one with the mindset of how to formulate the most helpful diagnosis for optimal clinical management. It also provides practical tips on the writing of a cytology report such as how to craft a thor-ough, concise and clear report. The question of when and how to write com-ments in the diagnostic report is also discussed.

In Part II (Chaps. 5–9), several specific body systems will be covered, applying the approaches and methods laid out in Part I. The chapters begin with laying out the spectrum of common and important conditions that may be encountered in that system, followed by a discussion on the limitations of cytology. Thereafter, a framework is provided in terms of the triple approach, with a particular focus on morphological aspects. Morphology is covered in a step-wise fashion, moving from low-power (cellularity, architecture) to high-power analysis (nuclear and cytoplasmic features) and, finally, background material. In some chapters, for example, endoscopic ultrasound- guided (EUS) FNA, basic imaging correlates are also described. Thereafter, specific algo-rithmic approaches to challenging areas, as well as pitfalls and danger zones are discussed, with practical tips and clues to help avoid misinterpretation.

The focus of this book is on problem-solving from the perspective of clini-cal and morphological clues, rather than a detailed description of the cyto-logic features of specific entities. For more comprehensive morphological descriptions, the reader is referred to many excellent texts such as The Art and Science of Cytopathology (Richard Dr May, Am Soc Clinical Pathology, Chicago, IL.), Orell and Sterrett’s Fine Needle Aspiration Cytology (Edited by Svante R Orell and Gregory F.  Sterrett Elsevier, 5th edition 2012), Cytology: Diagnostic Principles and Clinical Correlates (Edmund S. Cibas and Barbara S. Ducatman, Saunders, 4th edition, 2014).

These texts form the basis of the appreciation of diagnostic cytologic fea-tures of a wide spectrum of diagnostic entities, as well as an understanding of sound laboratory practices, complementing the clinical approaches provided in this book.

About the Book

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Part I Foundational Approaches in Cytopathology

1 Basic Principles in Cytopathology: Things I Wish I Knew at the Start . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2 Four Principles in Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1.2.1 Know What Cytology Can and Can’t Do . . . . . . . . . . 4 1.2.2 Have a Morphological Approach . . . . . . . . . . . . . . . . . 4 1.2.3 Know the Major Classification Systems . . . . . . . . . . . 5 1.2.4 Accept That There Will Always Be Cells

You Can’t Figure Out . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1.3 The Triple Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.3.1 Cytomorphologic Evaluation . . . . . . . . . . . . . . . . . . . . 6 1.3.2 Clinical Information . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1.3.3 Ancillary Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1.4 Four Tips for Improving Diagnostic Proficiency . . . . . . . . . . . 7 1.4.1 Compare, Compare, Compare . . . . . . . . . . . . . . . . . . . 7 1.4.2 Seek Out the Equivocal Cells on

Immunohistochemistry . . . . . . . . . . . . . . . . . . . . . . . . 7 1.4.3 Create a Mental or Photographic Archive . . . . . . . . . . 7 1.4.4 Curiosity Is a Good Thing: Follow That Case Up! . . . 8

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

2 The Cytology Report: Practical Tips. . . . . . . . . . . . . . . . . . . . . . . . 11 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.2 Three Important Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.2.1 What Is the Reason for the Biopsy/Sample? . . . . . . . . 12 2.2.2 How Can I Provide the Most Accurate

Information in the Clearest Manner Possible? . . . . . . . 12 2.2.3 When Should I Include a Comment? . . . . . . . . . . . . . . 13

2.3 The Cytology Report: What Goes In? . . . . . . . . . . . . . . . . . . . 14 2.4 Levels of Diagnostic Certainty . . . . . . . . . . . . . . . . . . . . . . . . 14

2.4.1 Brief Scenario . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 2.5 Example Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

2.5.1 Conveying Uncertainty as to Whether the Sample Is Representative . . . . . . . . . . . . . . . . . . . . 15

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2.5.2 Conveying Correlation with Relevant Past Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.5.3 Recommendations for Further Management . . . . . . . . 16

3 The Triple Approach in Cytopathology: Its Practical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 3.2 Elements of the Triple Approach . . . . . . . . . . . . . . . . . . . . . . . 19

3.2.1 Clinical Information . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.2.2 Cytology (Gross and Microscopic Evaluation) . . . . . . 21 3.2.3 Ancillary Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

3.3 Applying the Triple Approach . . . . . . . . . . . . . . . . . . . . . . . . . 29 3.3.1 Start with the Most Basic Clinical Information . . . . . . 29 3.3.2 Form a Quick Diagnostic Impression . . . . . . . . . . . . . 29 3.3.3 Perform a Careful Check of the Relevant

Clinical History If Necessary . . . . . . . . . . . . . . . . . . . . 29 3.3.4 Carefully Screen All Slides . . . . . . . . . . . . . . . . . . . . . 29 3.3.5 If Additional Material Is Available,

Decide on Whether Ancillary Tests Are Required . . . . 29 3.3.6 Consult a Colleague If Necessary . . . . . . . . . . . . . . . . 29 3.3.7 Craft the Cytology Report . . . . . . . . . . . . . . . . . . . . . . 30

3.4 Outline of a Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

4 On-Site Evaluation and the Provisional Report . . . . . . . . . . . . . . . 33 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4.2 Sample Adequacy and Triage . . . . . . . . . . . . . . . . . . . . . . . . . . 33

4.2.1 Sample Adequacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4.2.2 Specimen Triage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

4.3 Provisional Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.3.1 Information That a Provisional Report

May Include . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.4 Sample Case for Provisional Report . . . . . . . . . . . . . . . . . . . . 36References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Part II System-Specific Approaches in Cytopathology

5 Approach to Thyroid Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 5.2 Main Diagnostic Entities and Classification Systems . . . . . . . 42

5.2.1 Main Diagnostic Entities . . . . . . . . . . . . . . . . . . . . . . . 42 5.2.2 NIFTP: A Recently Defined Entity . . . . . . . . . . . . . . . 43 5.2.3 Major Classification Systems in Thyroid Cytology . . . 43

5.3 The Bethesda System for Reporting Thyroid Cytology. . . . . . 44 5.3.1 Non-diagnostic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 5.3.2 Benign . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 5.3.3 Atypia of Undetermined Significance

(AUS)/Follicular Lesion of Undetermined Significance (FLUS) . . . . . . . . . . . . . . . . . . . . . . . . . . 45

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5.3.4 Follicular Neoplasm (FN)/Suspicious for Follicular Neoplasm (SFN) . . . . . . . . . . . . . . . . . . 45

5.3.5 Suspicious for Malignancy (SM) . . . . . . . . . . . . . . . . . 45 5.3.6 Malignant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

5.4 What Cytology Can’t Diagnose in the Thyroid . . . . . . . . . . . . 46 5.5 Brief Technical Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

5.5.1 Needle Gauge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 5.5.2 Ultrasound Guidance . . . . . . . . . . . . . . . . . . . . . . . . . . 48 5.5.3 Collecting Material for Ancillary Tests . . . . . . . . . . . . 48

5.6 Triple Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 5.6.1 Clinical Information . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 5.6.2 Cytology (Gross and Microscopic Evaluation) . . . . . . 51 5.6.3 Ancillary Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

5.7 Specific Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 5.7.1 Cystic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 5.7.2 Hurthle Cell-Rich Lesions . . . . . . . . . . . . . . . . . . . . . . 68 5.7.3 Lymphoid-Rich Lesions

(When to Diagnose Lymphoid Atypia?) . . . . . . . . . . . 69 5.7.4 The Atypical FNA: When to Call

Something FLUS/AUS? . . . . . . . . . . . . . . . . . . . . . . . . 70 5.8 Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

5.8.1 False Negatives/Undercalls . . . . . . . . . . . . . . . . . . . . . 73 5.8.2 False Positives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 5.8.3 Mimics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

6 Approach to Lymph Node Cytology . . . . . . . . . . . . . . . . . . . . . . . . 81 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 6.2 Main Diagnostic Entities and a Working

Classification System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 6.2.1 Main Diagnostic Entities . . . . . . . . . . . . . . . . . . . . . . . 82 6.2.2 Working Classification System . . . . . . . . . . . . . . . . . . 83

6.3 Lymphomas: Role of Cytology . . . . . . . . . . . . . . . . . . . . . . . . 85 6.4 Brief Technical Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

6.4.1 Needle Gauge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 6.4.2 Personal Protective Equipment . . . . . . . . . . . . . . . . . . 86 6.4.3 Collecting Material for Ancillary Tests . . . . . . . . . . . . 86

6.5 Triple Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 6.5.1 Clinical Information . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 6.5.2 Cytology (Gross and Microscopic Evaluation) . . . . . . 90 6.5.3 Ancillary Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

6.6 A Sequential, Pattern-Based Diagnostic Approach . . . . . . . . . 102 6.6.1 Is This a Lymphoid Population? . . . . . . . . . . . . . . . . . 103 6.6.2 What Is the Main Architectural Pattern? . . . . . . . . . . . 104 6.6.3 In a Lymphoid Lesion, What Is the Main

Cell Make-Up? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 6.6.4 If This Is a Non-lymphoid Lesion, Could

This Be a Non-nodal Lesion? . . . . . . . . . . . . . . . . . . . 108

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6.6.5 Is There Any Relevant Clinical Finding that Ties in with the Lymphadenopathy? . . . . . . . . . . . 108

6.7 Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 6.7.1 False Positives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 6.7.2 False Negatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 6.7.3 Mimics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

7 Approach to Salivary Gland Cytology . . . . . . . . . . . . . . . . . . . . . . 123 7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 7.2 Main Diagnostic Entities and the Milan System . . . . . . . . . . . 124

7.2.1 Non-diagnostic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 7.2.2 Non-neoplastic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 7.2.3 Atypia of Undetermined Significance (AUS) . . . . . . . 126 7.2.4 Neoplasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 7.2.5 Suspicious for Malignancy . . . . . . . . . . . . . . . . . . . . . 127 7.2.6 Malignant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

7.3 Salivary Gland FNA: What Cytology Can and Cannot Do . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

7.4 What Do Clinicians Need from Us? . . . . . . . . . . . . . . . . . . . . 128 7.5 Triple Approach, with a Pattern-Based

Morphologic Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 7.5.1 Clinical Information . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 7.5.2 Alarming/Red Flag Clinical Findings . . . . . . . . . . . . . 130 7.5.3 Cytology (Gross and Microscopic Evaluation) . . . . . . 130 7.5.4 Ancillary Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

7.6 Specific Challenging Areas . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 7.6.1 Cystic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 7.6.2 Lymphoid-Rich Lesions . . . . . . . . . . . . . . . . . . . . . . . . 141 7.6.3 Basaloid Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . 143 7.6.4 Oncocytic/Oncocytoid Lesions . . . . . . . . . . . . . . . . . . 144 7.6.5 Low-Grade Malignancies . . . . . . . . . . . . . . . . . . . . . . . 146

7.7 Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 7.7.1 False Positives and Negatives . . . . . . . . . . . . . . . . . . . 151 7.7.2 Mimics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

8 Approach to Endoscopic Ultrasound-Guided FNA of the Gastrointestinal Tract and Pancreas . . . . . . . . . . . . . . . . . . 157 8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 8.2 EUS FNA: What’s Good to Know . . . . . . . . . . . . . . . . . . . . . . 158

8.2.1 Needle Route . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 8.2.2 ROSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 8.2.3 Specimen Triage for Ancillary Testing . . . . . . . . . . . . 160

8.3 GIT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 8.3.1 Triple Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 8.3.2 Specific Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 8.3.3 Pitfalls (False Positives, False Negatives, Mimics) . . . 170

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8.4 Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 8.4.1 Spectrum of Diagnostic Entities

and the Papanicolaou Society of Cytopathology Guidelines . . . . . . . . . . . . . . . . . . . . 175

8.4.2 What Pancreatic Cytology Can and Cannot Diagnose . . . . . . . . . . . . . . . . . . . . . . 176

8.4.3 Technical Issues in Pancreatic EUS FNA . . . . . . . . . . 177 8.4.4 A Systematic Approach: Key Questions . . . . . . . . . . . 179 8.4.5 Triple Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 8.4.6 Specific Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 8.4.7 Pitfalls (False Positives, False Negatives

and Mimics) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

9 Approach to Effusion Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 9.2 Spectrum of Conditions and Classification Systems . . . . . . . . 207

9.2.1 Cytologic Classification Systems . . . . . . . . . . . . . . . . . 208 9.3 Technical Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

9.3.1 Collection Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 9.3.2 Fluid Volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 9.3.3 Optimising Cellular Yield . . . . . . . . . . . . . . . . . . . . . . 210 9.3.4 Sample Triage for Ancillary Testing . . . . . . . . . . . . . . 210

9.4 Triple Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 9.4.1 Clinical Information . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 9.4.2 Cytology (Gross and Microscopic Evaluation) . . . . . . 213 9.4.3 Ancillary Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

9.5 Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 9.5.1 False Negatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 9.5.2 False Positives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 9.5.3 Mimics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

Index � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 245

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Min En Nga, FRCPath, FRCPA, FIAC is an alumnus of the Faculty of Medicine at the National University of Singapore (NUS). She was awarded fellowships by the Royal College of Pathologists of both the United Kingdom and Australasia, as well as the International Academy of Cytology. She has been practicing anatomical pathology at the National University Hospital’s Department of Pathology since 2005 and has previously served as the Director cytology section and quality assurance program in cytology. She is also an Associate Professor at the Department of Pathology at the Yong Loo Lin School of Medicine at the National University of Singapore. She is currently a council member of the Singapore Society of Cytology and editor of its CytoPage newsletter. Dr Nga received the Singapore Society of Pathology’s Becton Dickinson Research Award in 2012, as well as numerous NUS teach-ing excellence awards, and was included in the NUS Teaching Excellence Honour Roll in 2016. In 2019, she was selected by NUS as the recipient of the university’s Outstanding Educator Award. She is currently the supervisor of postgraduate cytology training in NUH and a frequent invited speaker at cyto-pathology workshops, including the Australian Society of Cytology Annual Scientific Meetings; International Academy of Pathology Cytology Companion Meetings. She also addressed the Indian Academy of Cytologists in November 2017 as the IAC Oration Lecturer.

About the Author

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ACC Acinic cell carcinomaAcCC Acinar cell carcinomaAdCC Adenoid cystic carcinomaAITL Angioimmunoblastic T-cell lymphomaALCL Anaplastic large cell lymphomaATC Anaplastic thyroid carcinomaAUS Atypia of undetermined significanceBCA Basal cell adenomaBCAC Basal cell adenocarcinomaBCC Basal cell carcinomaBCN Basal cell neoplasmBFN Benign follicular noduleBL Burkitt lymphomaBRMs Benign/reactive mesothelial cellsCEPA Carcinoma ex pleomorphic adenomaCHL Classical Hodgkin lymphomaDDx Differential diagnosisDLBCL Diffuse large B-cell lymphomaDQT DeQuervain’s thyroiditisEBUS Endobronchial ultrasoundEMC Epithelial-myoepithelial carcinomaEMR Electronic medical recordsEUS Endoscopic ultrasoundEUS FNA Endoscopic ultrasound-guided FNAFA Follicular adenomaFDCs Follicular dendritic cellsFISH Fluorescent in situ hybridisationFL Follicular lymphomaFLUS Follicular lesion of undetermined significanceFNA Fine needle aspirationFVPTC Follicular variant papillary thyroid carcinomaGEC Gene expression classifierGIST Gastrointestinal stromal tumourGMS Grocott methenamine silverHCA Hurthle cell adenomaHCC Hurthle cell carcinomaHCN Hurthle cell neoplasm

Abbreviations

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HL Hodgkin lymphomaHPF High-power fieldI-131 Radioactive iodineIHC ImmunohistochemistryIMS Infectious mononucleosis syndromeIMT Inflammatory myofibroblastic tumourIPCHT Intraperitoneal chemotherapyIPMN Intraductal papillary mucinous neoplasmITPN Intraductal tubulopapillary neoplasmKFD Kikuchi–Fujimoto diseaseLBCL Large B-cell lymphomaLBL Lymphoblastic lymphomaLELC Lymphoepithelioma-like carcinomaLGBs Lymphoglandular bodiesLGFL Low-grade follicular lymphomaLGMEC Low-grade mucoepidermoid carcinomaLH aggregates Lymphohistiocytic aggregatesLM LeiomyomaLMS LeiomyosarcomaLOH Loss of heterozygosityLBC Liquid-based cytologyMAC Mycobacterium avium complexMALT lymphoma Mucosa-associated lymphoid tissue lymphomaMCN Mucinous cystic neoplasmME MyoepitheliomaMEC Mucoepidermoid carcinomaMECA Myoepithelial carcinomaMM Malignant mesotheliomaMPD Main pancreatic ductMSRSGC Milan System for Reporting Salivary Gland

CytopathologyMTC Medullary thyroid carcinomaMZL Marginal zone lymphomaND Non-diagnosticNEC Neuroendocrine carcinomaNET Neuroendocrine tumourNF Nodular fasciitisNHL Non-Hodgkin lymphomaNIFTP Non-invasive follicular thyroid neoplasm with papillary-

like nuclear featuresNLPHL Nodular lymphocyte predominant Hodgkin lymphomaNMC Neoplastic mucinous cystNPC Nasopharyngeal carcinomaNSHL Nodular sclerosing Hodgkin lymphomaPA Pleomorphic adenomaPC PseudocystPDAC Pancreatic ductal adenocarcinomaPDTC Poorly differentiated thyroid carcinoma

Abbreviations

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PEL Primary effusion lymphomaPLAC Polymorphous adenocarcinomaPMX PilomatrixomaPSGPBC Papanicolaou Society of Cytopathology Guidelines for

Reporting Pancreaticobiliary CytologyPTC Papillary thyroid carcinomaPTCL Peripheral T-cell lymphomaRA Rheumatoid arthritisRBCs Red blood cellsRCC Renal cell carcinomaROM Risk of malignancyROSE Rapid on-site evaluationRS cells Reed–Sternberg cellsSC Secretory carcinomaSCA Serous cystadenomaSCC Squamous cell carcinomaSDC Salivary duct carcinomaSFN Suspicious for follicular neoplasmSG Salivary glandSLE Systemic lupus erythematosusSM Suspicious for malignancySmCC Small cell carcinomaSPN Solid pseudopapillary neoplasmSUMP Salivary gland neoplasm of Uncertain Malignant

PotentialTBMs Tingible body macrophagesTBSRTC The Bethesda System for Reporting Thyroid CytopathologyTCRBCL T-cell-rich B-cell lymphomaUS UltrasoundWT Warthin tumourZN Ziehl–Neelsen

Abbreviations

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Chart 5.1 Thyroid—main diagnostic entities . . . . . . . . . . . . . . . . . . . . . . 42Chart 5.2 Common architectural patterns with diagnostic

correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Chart 5.3 Approach to cystic thyroid nodules . . . . . . . . . . . . . . . . . . . . . 67Chart 5.4 Approach to Hurthle cell-rich lesions . . . . . . . . . . . . . . . . . . . 69Chart 5.5 Approach to lymphoid-rich lesions . . . . . . . . . . . . . . . . . . . . . 70Chart 5.6 Atypical lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71Chart 6.1 Lymph nodes—main diagnostic entities . . . . . . . . . . . . . . . . . 82Chart 6.2 Lymph node FNA: pattern-based approach . . . . . . . . . . . . . . . 95Chart 7.1 Salivary gland aspirates—main diagnostic entities . . . . . . . . . 125Chart 7.2 Salivary gland cytology—broad approach according

to clinical/imaging characteristics . . . . . . . . . . . . . . . . . . . . . . 131Chart 7.3 Approach to cystic lesions with Milan categories . . . . . . . . . . 140Chart 7.4 Approach to lymphoid-rich lesions . . . . . . . . . . . . . . . . . . . . . 141Chart 7.5 Approach to basaloid neoplasms . . . . . . . . . . . . . . . . . . . . . . . 144Chart 7.6 Approach to oncocytic lesions with Milan categories . . . . . . . 145Chart 8.1 Spectrum of common/important EUS FNA lesions . . . . . . . . . 158Chart 8.2 Common/important pancreatic lesions . . . . . . . . . . . . . . . . . . 175Chart 8.3 Pancreas—key questions in the cytologic evaluation

of solid vs. cystic lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Chart 8.4 Triple approach to pancreatic cystic lesions . . . . . . . . . . . . . . 192Chart 9.1 Spectrum of conditions encountered in serous effusions . . . . . 207Chart 9.2 Broad morphologic approach to effusion cytology . . . . . . . . . 215Chart 9.3 Approach to atypical epithelioid cells . . . . . . . . . . . . . . . . . . . 216

List of Charts

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Table 2.1 Subjective Levels of Diagnostic Certainty . . . . . . . . . . . . . . . 15Table 3.1 Types of Material for Ancillary Testing . . . . . . . . . . . . . . . . . 28Table 5.1 Major Classification Systems in Thyroid Cytology . . . . . . . . 44Table 5.2 Entities That are Not Readily Diagnosable on Cytology . . . . 47Table 5.3 Nuclear Features of Various Thyroid Entities . . . . . . . . . . . . . 58Table 5.4 Thyroid—Helpful Immunohistochemical Panels . . . . . . . . . . 65Table 6.1 Lymphoma Diagnosis on Cytology:

What Cytology Can and Cannot Do . . . . . . . . . . . . . . . . . . . . 85Table 6.2 Metastases With Origin-specific Morphological

Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Table 6.3 Metastases Without Origin-specific Morphological

Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Table 6.4 Specific Morphologic Features of Common

B-Cell Lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Table 6.5 Specific Morphologic Features of Other Lymphomas . . . . . . 94Table 6.6 Ancillary Tests in Lymph Node FNA . . . . . . . . . . . . . . . . . . 101Table 7.1 The Milan System for Reporting Salivary

Gland Cytopathology with Risk of Malignancy (ROM) . . . 125Table 7.2 Benign and Malignant Neoplasms that are

Readily Diagnosable on Cytology . . . . . . . . . . . . . . . . . . . . . 128Table 7.3 Main Morphologic Cell Types in SG Neoplasms . . . . . . . . . 133Table 7.4 Stromal Features of Basaloid Tumours . . . . . . . . . . . . . . . . . 134Table 7.5 IHC Profiles of Specific SG Neoplasms . . . . . . . . . . . . . . . . 138Table 7.6 Common False-Negative and -Positive Diagnoses . . . . . . . . 152Table 8.1 Most Common Mesenchymal Lesions by Location . . . . . . . 161Table 8.2 Salient Morphologic Features of Gut

Wall or Extramural Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . 166Table 8.3 Useful Ancillary Tests in Gut Wall Lesions . . . . . . . . . . . . . 169Table 8.4 The Papanicolaou Society of Cytopathology

Guidelines for Reporting Pancreaticobiliary Cytology . . . . . 176Table 8.5 Cytologic Diagnoses of Pancreatic Lesions . . . . . . . . . . . . . 177Table 8.6 Imaging Findings in Solid Pancreatic Lesions . . . . . . . . . . . 182Table 8.7 Clinical, EUS and Cytological Findings

and Ancillary Tests in Pancreatic Cystic Lesions . . . . . . . . . 191

List of Tables

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Table 8.8 Ancillary Tests in PDAC vs. Benign Ductal Cells . . . . . . . . 196Table 9.1 Specific Gross Appearances of Effusion Fluid . . . . . . . . . . . 214Table 9.2 Salient Morphologic Features—Mesothelial cells,

Adenocarcinoma, Macrophages . . . . . . . . . . . . . . . . . . . . . . 217Table 9.3 Cells with a Signet Ring Appearance

in Effusion Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223Table 9.4 Ancillary Tests for Benign vs. Malignant

Mesothelial Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

List of Tables