THYROID CANCER STRUCTURED REPORTING PROTOCOL (2Nd Edition 2020)

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THYROID CANCER STRUCTURED REPORTING PROTOCOL (2nd Edition 2020)

Incorporating the: International Collaboration on Cancer Reporting (ICCR) Carcinoma of the Thyroid Dataset www.ICCR-Cancer.org

Core Document versions: • ICCR dataset: Carcinoma of the Thyroid 1st edition v1.0 • AJCC Cancer Staging Manual 8th edition • World Health Organization (2017) Classification of Tumours of Endocrine Organs (4th edition). Volume 10

2 Structured Reporting Protocol for Thyroid Cancer 2nd edition ISBN: 978-1-76081-423-6

Publications number (SHPN): (CI) 200280

Online copyright

This work (Protocol) is copyright. You may download, display, print and reproduce the Protocol for your personal, non-commercial use or use within your organisation subject to the following terms and conditions:

1. The Protocol may not be copied, reproduced, communicated or displayed, in whole or in part, for profit or commercial gain.

2. Any copy, reproduction or communication must include this RCPA copyright notice in full.

3. With the exception of Chapter 6 - the checklist, no changes may be made to the wording of the Protocol including any Standards, Guidelines, commentary, tables or diagrams. Excerpts from the Protocol may be used in support of the checklist. References and acknowledgments must be maintained in any reproduction or copy in full or part of the Protocol.

4. In regard to Chapter 6 of the Protocol - the checklist:

• The wording of the Standards may not be altered in any way and must be included as part of the checklist.

• Guidelines are optional and those which are deemed not applicable may be removed.

• Numbering of Standards and Guidelines must be retained in the checklist, but can be reduced in size, moved to the end of the checklist item or greyed out or other means to minimise the visual impact.

• Additional items for local use may be added but must not be numbered as a Standard or Guideline, in order to avoid confusion with the RCPA checklist items.

• Formatting changes in regard to font, spacing, tabulation and sequencing may be made.

• Commentary from the Protocol may be added or hyperlinked to the relevant checklist item.

Apart from any use as permitted under the Copyright Act 1968 or as set out above, all other rights are reserved. Requests and inquiries concerning reproduction and rights should be addressed to RCPA, 207 Albion St, Surry Hills, NSW 2010, Australia.

First published: June 2020, 2nd Edition (version 2.0)

3 Structured Reporting Protocol for Thyroid Cancer 2nd edition Disclaimer

The Royal College of Pathologists of Australasia ("College") has developed these protocols as an educational tool to assist pathologists in reporting of relevant information for specific cancers. While each protocol includes “standards” and “guidelines” which are indicators of ‘minimum requirements’ and ‘recommendations’, the protocols are a first edition and have not been through a full cycle of use, review and refinement. Therefore, in this edition, the inclusion of “standards” and “guidelines” in each document are provided as an indication of the opinion of the relevant expert authoring group. It should not be regarded as definitive or as widely accepted peer professional opinion. The use of these standards and guidelines is subject to the clinician’s judgement in each individual case.

The College makes all reasonable efforts to ensure the quality and accuracy of the protocols and to update the protocols regularly. However subject to any warranties, terms or conditions which may be implied by law and which cannot be excluded, the protocols are provided on an "as is" basis. The College does not warrant or represent that the protocols are complete, accurate, error-free, or up to date. The protocols do not constitute medical or professional advice. Users should obtain appropriate medical or professional advice, or where appropriately qualified, exercise their own professional judgement relevant to their own circumstances. Users are responsible for evaluating the suitability, accuracy, currency, completeness and fitness for purpose of the protocols.

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4 Structured Reporting Protocol for Thyroid Cancer 2nd edition Contents

Scope ...... 6

Abbreviations ...... 7

Definitions ...... 8

Introduction...... 11

Authority and development ...... 15

1 Pre-analytical ...... 18

2 Specimen handling and macroscopic findings ...... 23

3 Microscopic findings ...... 27

4 Ancillary studies findings ...... 39

5 Synthesis and overview ...... 41

6 Structured checklist ...... 43

7 Formatting of pathology reports ...... 58

Appendix 1 Pathology request form for thyroid tumours ...... 59

Appendix 2 Guidelines for formatting of a pathology report ...... 63

Appendix 3 Example of a pathology report ...... 64

Appendix 4 WHO histological classification of tumours of the thyroid gland ...... 66

Appendix 5 Histological tumour type...... 68

Appendix 6 AJCC Staging Grouping ...... 71

References ...... 72

5 Structured Reporting Protocol for Thyroid Cancer 2nd edition Scope

This protocol contains standards and guidelines for the preparation of structured reports for thyroid resection specimens for carcinoma. Core needle biopsies and metastasis to the thyroid gland are not included. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), tumours of uncertain malignant potential (UMP), thyroid carcinomas arising from struma ovarii, thyroid carcinomas arising in thyroglossal duct cysts are included in this protocol. Sarcomas and lymphomas are dealt with in separate protocols.

This protocol is designed for the reporting of a total thyroidectomy or a single laterality specimen i.e. left or right. If both are submitted separately or if surgeries are done at different time points (e.g. completion thyroidectomy after initial lobectomy), then separate protocols should be completed. If multiple carcinomas are found in the same specimen, the protocol should be completed for the most clinical relevant tumour which is the one with the highest T stage and/or the one that has the most aggressive histologic features. For example, in the case of a papillary thyroid carcinoma with gross extension into muscle associated with a papillary carcinoma without adverse histologic features, the protocol should be filled for the tumour with gross extra-thyroid extension. The less aggressive tumour should be reported with a description limited to basic histopathologic features (such as size and location) under the tumour focality element. If tumours of different lineage coincide in the same specimen, then a protocol should be completed for each of these tumours. For example, if a lobectomy contains separate medullary and papillary carcinoma, a protocol should be completed for each of these carcinomas.

Structured reporting aims to improve the completeness and usability of pathology reports for clinicians, and improve decision support for cancer treatment. The protocol provides the framework for the reporting of any thyroid cancer, whether as a minimum data set or fully comprehensive report.

6 Structured Reporting Protocol for Thyroid Cancer 2nd edition Abbreviations

AJCC American Joint Committee on Cancer ATA American Thyroid Association CAP College of American Pathologists CD Cluster of differentiation CEA Carcinoembryonic antigen CI Capsular invasion ENE Extranodal extension ETE Extrathyroidal extension FC Follicular carcinoma FNA Fine needle aspiration FTC Follicular thyroid carcinoma HPF High power field ICCR International Collaboration on Cancer Reporting IHI Individual Healthcare Identifier LIS The laboratory information system LVI Lymphovascular invasion MEN Multiple endocrine neoplasia mm Millimetres MRN MedicalS Standard Record Number NCCN National Comprehensive Cancer Network G Guide NHI New Zealand National Health Identifier NHMRC National Health and Medical Research Council NIFTP Non-invasive follicular thyroid neoplasm with papillary-like nuclear features PAX8 Paired box 8 PBS Pharmaceutical Benefits Scheme PDTC Poorly differentiated thyroid carcinomas PTC Papillary thyroid carcinoma RAI Radioiodine RCPA Royal College of Pathologists of Australasia RCPath UK Royal College of Pathologists United Kingdom RET Rearranged during transfection proto-oncogene SI International System of Units TNM tumour-node-metastasis TTF Thyroid transcription factor-1 UICC International Union Against Cancer UK United Kingdom UMP Uncertain malignant potential VI Vascular invasion WHO World Health Organization

7 Structured Reporting Protocol for Thyroid Cancer 2nd edition Definitions

The table below provides definitions for general or technical terms used in this protocol. Readers should take particular note of the definitions for ‘standard’, ‘guideline’ and ‘commentary’, because these form the basis of the protocol.

Ancillary study An ancillary study is any pathology investigation that may form part of a cancer pathology report but is not part of routine histological assessment.

Clinical Patient information required to inform pathological assessment, information usually provided with the specimen request form, also referred to as ‘pre-test information’.

Commentary Commentary is text, diagrams or photographs that clarify the standards (see below) and guidelines (see below), provide examples and help with interpretation, where necessary (not every standard or guideline has commentary).

Commentary is used to:

• define the way an item should be reported, to foster reproducibility • explain why an item is included (e.g. how does the item assist with clinical management or prognosis of the specific cancer).

• cite published evidence in support of the standard or guideline • state any exceptions to a standard or guideline. In this document, commentary is prefixed with ‘CS’ (for commentary on a standard) or ‘CG’ (for commentary on a guideline), numbered to be consistent with the relevant standard or guideline, and with sequential alphabetic lettering within each set of commentaries (e.g. CS1.01a, CG2.05b).

General General commentary is text that is not associated with a specific commentary standard or guideline. It is used:

• to provide a brief introduction to a chapter, if necessary

• for items that are not standards or guidelines but are included in the protocol as items of potential importance, for which there is currently insufficient evidence to recommend their inclusion. (Note: in future reviews of protocols, such items may be reclassified as either standards or guidelines, in line with diagnostic and prognostic advances, following evidentiary review).

8 Structured Reporting Protocol for Thyroid Cancer 2nd edition Guideline Guidelines are recommendations; they are not mandatory, as indicated by the use of the word ‘should’. Guidelines cover items that are unanimously agreed should be included in the dataset but are not supported by National Health and Medical Research Council (NHMRC) level III-2 evidence.1 These elements may be clinically important and recommended as good practice but are not yet validated or regularly used in patient management.

Guidelines include key information other than that which is essential for clinical management, staging or prognosis of the cancer such as macroscopic observations and interpretation, which are fundamental to the histological diagnosis and conclusion e.g. macroscopic tumour details, block identification key, may be included as either required or recommended elements by consensus of the expert committee. Such findings are essential from a clinical governance perspective, because they provide a clear, evidentiary decision-making trail.

Guidelines are not used for research items.

In this document, guidelines are prefixed with ‘G’ and numbered consecutively within each chapter (e.g. G1.10).

Macroscopic Measurements, or assessment of a biopsy specimen, made by the findings unaided eye.

Microscopic In this document, the term ‘microscopic findings’ refers to histo- findings morphological assessment.

Predictive factor A predictive factor is a measurement that is associated with response or lack of response to a particular therapy.

Prognostic A prognostic factor is a measurement that is associated with factor clinical outcome in the absence of therapy or with the application of a standard therapy. It can be thought of as a measure of the natural history of the disease.

Standard Standards are mandatory, as indicated by the use of the term ‘must’. Standards are essential for the clinical management, staging or prognosis of the cancer. These elements will either have evidentiary support at Level III-2 or above (based on prognostic factors in the NHMRC levels of evidence1 document). In rare circumstances, where level III-2 evidence is not available an element may be made a Standard where there is unanimous agreement in the expert committee. An appropriate staging system e.g. Pathological TNM staging would normally be included as a required element. These elements must be recorded and at the discretion of the pathologist included in the pathology report according to the needs of the recipient of the report.

The summation of all standards represents the minimum dataset for the cancer.

9 Structured Reporting Protocol for Thyroid Cancer 2nd edition In this document, standards are prefixed with ‘S’ and numbered consecutively within each chapter (e.g. S1.02).

Structured A report format which utilises standard headings, definitions and report nomenclature with required information.

Synoptic report A structured report in condensed form (as a synopsis or precis).

Synthesis Synthesis is the process in which two or more pre-existing elements are combined, resulting in the formation of something new.

The Oxford dictionary defines synthesis as ‘the combination of components or elements to form a connected whole’.

In the context of structured pathology reporting, synthesis represents the integration and interpretation of information from two or more modalities to derive new information.

10 Structured Reporting Protocol for Thyroid Cancer 2nd edition Introduction

Thyroid cancer

Thyroid cancer is the most common endocrine cancer in Australia and in other parts of the world. This malignancy is more common in women than in men and occurs primarily in young and middle-aged adults, with approximately 122,000 new cases per year worldwide.1

Thyroid cancers, like benign thyroid diseases, usually present as a thyroid nodule and/or enlargement of the thyroid gland. In many instances, it is very difficult to differentiate them from benign thyroid lesions clinically. Thyroid nodules are common clinically (prevalence of approximately 5%) and even more common on ultrasound examination (prevalence of approximately 25%).2 About 1% of thyroid nodules are malignant.

Pathological reporting of resection specimens for thyroid cancer provides information both for the clinical management of the affected patient, for research, and for the evaluation of the health care system. In thyroid cancer, there are many different histological types. Papillary carcinoma is the most common type, accounting for more than 80-90% of thyroid malignancies.2, 33 Many subtypes of papillary carcinoma have been described and some are known to have prognostic significance. Also, follicular lesions including follicular carcinoma, minimally invasive follicular carcinoma, Hürthle cell carcinoma, follicular variant of papillary carcinoma, follicular adenoma, Hürthle cell carcinoma and adenomatous nodule often are difficult to differentiate. Some patients with thyroid cancer can progress to a more aggressive metastatic form of thyroid cancer with a high mortality.4 Therefore, recognition of pathological parameters in thyroid cancer is very important for the management of these patients.

Benefits of structured reporting

The pathology report lays the foundation for a patient’s cancer journey and conveys information which:

• Provides the definitive diagnosis • Includes critical information for Tumour-Node-Metastasis (TNM) staging • Evaluates the adequacy of the surgical excision • Provides morphological and biological prognostic markers which determine personalised cancer therapy

However, the rapid growth in ancillary testing such as immunohistochemistry, flow cytometry, cytogenetics, and molecular studies, have made the task of keeping abreast of advances on specific cancer investigations extremely difficult for pathologists. The use of structured reporting checklists by pathologists ensures that all key elements are included in the report specifically those which have clinical management, staging or prognostic implications. Consequently, minimum or comprehensive datasets for the reporting of cancer have been developed2,4 around

11 Structured Reporting Protocol for Thyroid Cancer 2nd edition the world. Both the United Kingdom,5 and United States6 have produced standardised cancer reporting protocols or ‘datasets’ for national use for many years.

The use of cancer reporting checklists improves completeness and quality of cancer reporting and thereby ensures an improved outcome for cancer patients. This has long term cost implications for public health by ensuring the most effective and timely treatment based on accurate and complete information.

The use of a structured reporting format also facilitates easy extraction of the necessary information by secondary users of the information i.e. cancer registries.

International Collaboration on Cancer Reporting

The International Collaboration on Cancer Reporting (ICCR), founded in 2011 by the Royal College of Pathologists of Australasia (RCPA), United States College of American Pathologists (US CAP) and Royal College of Pathologists United Kingdom (RCPath UK) Colleges of Pathology and the Canadian Association of Pathology - Association Canadienne des Pathologistes (CAP-ACP) in association with the Canadian Partnership Against Cancer (CPAC), was established to explore the possibilities of a collaborative approach to the development of common, internationally standardised and evidence-based cancer reporting protocols for surgical pathology specimens.

The ICCR, recognising that standardised cancer datasets have been shown to provide significant benefits for patients and efficiencies for organisations through the ease and completeness of data capture7-10 undertook to use the best international approaches and the knowledge and experience of expert pathologists, and produce cancer datasets which would ensure that cancer reports across the world will be of the same high quality – ensuring completeness, consistency, clarity, conciseness and above all, clinical utility.

Representatives from the four countries participating in the initial collaboration undertook a pilot project in 2011 to develop four cancer datasets - Lung, Melanoma, Prostate (Radical Prostatectomy), and Endometrium. Following on from the success of this pilot project, the ICCR was joined by the European Society of Pathology (ESP) in 2013 and in 2014 incorporated a not-for-profit organisation focussed on the development of internationally agreed evidence-based datasets developed by world leading experts. The ICCR Datasets are made freely available from its website www.ICCR-Cancer.org

Design of this protocol

This structured reporting protocol has been developed using the ICCR dataset on Carcinoma of the Thyroid as the foundation.

This protocol includes all of the ICCR cancer dataset elements as well as additional information, elements and commentary as agreed by the RCPA expert committee. It provides a comprehensive framework for the assessment and documentation of pathological features of Carcinoma of the Thyroid.

12 Structured Reporting Protocol for Thyroid Cancer 2nd edition ICCR dataset elements for Carcinoma of the Thyroid are included verbatim. ICCR Core elements are mandatory and therefore represented as standards in this document. ICCR Non-core elements, that is, those which are not mandatory but are recommended, may be included as guidelines or upgraded to a standard based on the consensus opinion of the local expert committee.

The ICCR elements are identified in each chapter with the ICCR logo placed before the Standard or Guideline number or bullet and the ICCR element description and commentary is boarded by a grey box as shown below:

S3.01 The histological tumour type must be recorded.

Additional commentary by the RCPA expert committee may be added to an ICCR element but is not included in the grey bordered area nor indicated with an ICCR logo e.g.

G2.03 If present, the laterality of the lymph nodes submitted may be recorded as central, left lateral, right lateral or bilateral.

CS2.03a If present, record site and number. All lymph node tissue should be submitted for histological examination.

Further information on the ICCR is available at www.iccr-cancer.org

Checklist

Consistency and speed of reporting is improved by the use of discrete data elements recorded from the checklist. Items suited to tick boxes are distinguished from more complex elements requiring free text or narrative. A structured or discrete approach to responses is favoured, however the pathologist is encouraged to include free text or narrative where necessary to document any other relevant issues, to give reasons for coming to a particular opinion and to explain any points of uncertainty.

Report format

The structure provided by the following chapters, headings and subheadings describes the elements of information and their groupings, but does not necessarily represent the format of either a pathology report (Chapter 7) or checklist (Chapter 6). These, and the structured pathology request form (Appendix 1) are templates that represent information from this protocol, organised and formatted differently to suit different purposes.

13 Structured Reporting Protocol for Thyroid Cancer 2nd edition Key documentation

• ICCR dataset: Carcinoma of the Thyroid 1st edition v1.0 • Guidelines for Authors of Structured Cancer Pathology Reporting Protocols, Royal College of Pathologists of Australasia, 200911 • World Health Organization (2017) Classification of Tumours of Endocrine Organs (4th edition). Volume 1012

Changes since the last edition Inclusion of ICCR Core and Non-core elements.

14 Structured Reporting Protocol for Thyroid Cancer 2nd edition Authority and development This section provides information about the process undertaken to develop this protocol.

This 1st edition of the protocol is an amalgam of two separate processes:

• This protocol is based on the ICCR dataset – Carcinoma of the Thyroid 1st edition v1.0. All ICCR elements from this dataset, both core (mandatory) and non-core (optional), are included in this protocol, verbatim. (It should be noted that RCPA feedback from all Anatomical Pathology fellows and specifically the local expert committee was sought during the development process of the ICCR dataset.) Details of the ICCR development process and the international expert authoring committee responsible for the ICCR dataset are available on the ICCR website: iccr-cancer.org. 1. Additional elements, values and commentary have been included as deemed necessary by the local expert committee. In addition, the standard inclusions of RCPA protocols e.g. example reports, request information etc., have also been added.

Expert committee

Prof Jane Dahlstrom (Lead Author, Chair of Head and Neck and Endocrine Group), Pathologist Dr John Turchini Pathologist A/Prof Ruta Gupta, Pathologist Prof Alfred Lam (Lead author 1st edition), Pathologist Prof Anthony J. Gill, Pathologist Prof Klaus-Martin Schulte, Endocrine Surgeon A/Prof Michael Elliott, Head and Neck Surgeon A/Prof Rory Clifton-Bligh, Endocrinologist Prof Christopher J. Nolan, Endocrinologist

Editorial manager

Christina Selinger, PhD, Royal College of Pathologists of Australasia

Acknowledgements

The Thyroid expert committee wish to thank all the pathologists and clinicians who contributed to the discussion around this document.

15 Structured Reporting Protocol for Thyroid Cancer 2nd edition Stakeholders

ACT Cancer Registry ACT Health Anatomical Pathology Advisory Committee (APAC) Australian and New Zealand Endocrine Surgeons (ANZES) Australian Commission on Safety and Quality in Health Care Australian Digital Health Agency (ADHA) Australian Institute of Health and Welfare (AIHW) Australian Pathology Cancer Australia Cancer Council ACT Cancer Council Australia and Australian Cancer Network (ACN) Cancer Council NSW Cancer Council Queensland Cancer Council SA Cancer Council Tasmania Cancer Council Victoria Cancer Council Western Australia Cancer Institute NSW Cancer Services Advisory Committee (CanSAC) Cancer specific expert groups – engaged in the development of the protocols Cancer Voices Australia Cancer Voices NSW Clinical Oncology Society of Australia (COSA) Department of Health, Australian Government Endocrine Society of Australia (ESA) Health Informatics Society of Australia (HISA) Independent Review Group of Pathologists Medical Oncology Group of Australia (MOGA) Medical Software Industry Association (MSIA) National Pathology Accreditation Advisory Council (NPAAC) New Zealand Cancer Control Agency New Zealand Cancer Registry Northern Territory Cancer Registry Public Pathology Australia

16 Structured Reporting Protocol for Thyroid Cancer 2nd edition Queensland Cooperative Oncology Group (QCOG) Representatives from laboratories specialising in anatomical pathology across Australia Royal Australasian College of Physicians (RACP) Royal Australasian College of Surgeons (RACS) Royal Australian and New Zealand College of Radiologists (RANZCR) Royal Australian College of General Practitioners (RACGP) Royal College of Pathologists of Australasia (RCPA) South Australia Cancer Registry Southern Cancer Network, Christchurch, New Zealand Standards Australia Tasmanian Cancer Registry Victorian Cancer Registry Western Australia Clinical Oncology Group (WACOG) Western Australian Cancer Registry

Development process

This protocol has been developed following the ten-step process set out in Guidelines for Authors of Structured Cancer Pathology Reporting Protocols.11

Where no reference is provided, the authority is the consensus of the local expert group for local inclusions and the ICCR Dataset Authoring Committee for ICCR components denoted with the ICCR logo.

17 Structured Reporting Protocol for Thyroid Cancer 2nd edition 1 Pre-analytical This chapter relates to information that should be recorded on receipt of the specimen in the laboratory. The pathologist is reliant on the quality of information received from the clinicians or requestor. Some of this information may be received in generic pathology request forms; however, the additional information required by the pathologist specifically for the reporting of thyroid tumours is outlined in Appendix 1. Appendix 1 also includes a standardised request information sheet that may be useful in obtaining all relevant information from the requestor. Surgical handling procedures affect the quality of the specimen and recommendations for appropriate surgical handling are included in Appendix 1.

S1.01 All demographic information provided on the request form and with the specimen must be recorded.

CS1.01a The Royal College of Pathologists of Australasia (RCPA) The Pathology Request-Test-Report Cycle — Guidelines for Requesters and Pathology Providers must be adhered to.13 This document specifies the minimum information to be provided by the requesting clinician for any pathology test.

CS1.01b Ideally the laboratory information system (LIS) should include documentation as to whether the patient identifies as Aboriginal and/ or Torres Strait Islander in Australia, or Māori in New Zealand. This is in support of government initiatives to monitor the health of those who identify as indigenous, particularly in relation to cancer.

CS1.01c The patient’s health identifiers may include the patient’s Medical Record Number as well as a national health number such as a patient’s Medicare number (Australia), Individual Healthcare Identifier (IHI) (Australia) or the National Healthcare Index (New Zealand).

S1.02 All clinical information as documented on the request form must be recorded verbatim.

CS1.02a The request information may be recorded as a single text (narrative) field or it may be recorded in a structured format.

CS1.02b In most cases all clinical information should be transcribed: however, in a small number of cases the pathologist may exercise discretion regarding the inclusion of provided clinical information, for instance, possibly erroneous information or information that may impact on patient privacy. In such case reference should be made as to the location of the complete clinical information e.g. ‘Further clinical information is available from the scanned request form.’

18 Structured Reporting Protocol for Thyroid Cancer 2nd edition G1.01 The copy doctors requested on the request form should be recorded.

S1.03 The pathology accession number of the specimen must be recorded.

S1.04 The principal clinician involved in the patient’s care and responsible for investigating the patient must be recorded.

CS1.04a The principal clinician can provide key information regarding the clinical presentation of the patient. Follow up may be required with the principal clinician for a number of reasons: • The clinical assessment and staging may be incomplete at the time of biopsy. • The pathology request is often authored by the clinician performing the biopsy rather than the clinician who is investigating and managing the patient. • The identity of this clinician is often not indicated on the pathology request form In practice therefore, it is important in such cases that the reporting pathologist should be able to communicate with the managing clinician for clarification.

CS1.04b The Australian Healthcare identifiers i.e. Healthcare Provider Identifier - Individual (HPI-I) and Healthcare Provider Identifier - Organisation (HPI-O) should be included, where possible, to identify the principal clinician involved in the patient's care.

G1.02 Any clinical information received in other communications from the requestor or other clinicians should be recorded together with the source of that information.

19 Structured Reporting Protocol for Thyroid Cancer 2nd edition

Figure 1. Anatomy of the thyroid gland. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th Edition (2017) published by Springer Science and Business Media LLC, www.springerlink.com.14

Figure 2. Topological definition of lymph node levels in the neck. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th Edition (2017) published by Springer Science and Business Media LLC, www.springerlink.com.14

20 Structured Reporting Protocol for Thyroid Cancer 2nd edition

Figure 3. Two views of T3: on the left, tumour more than 4 cm in greatest dimension limited to the thyroid (categorised as T3a); on the right, a tumour of any size with gross extrathryroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid or omohyoid muscles) (categorised as T3b). Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th Edition (2017) published by Springer Science and Business Media LLC, www.springerlink.com.14

Figure 4. T4a is defined as gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, oesophagus, or recurrent laryngeal nerve from a tumour of any size. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th Edition (2017) published by Springer Science and Business Media LLC, www.springerlink.com.14

21 Structured Reporting Protocol for Thyroid Cancer 2nd edition

Figure 5. Cross-sectional diagram of three different parameters of T4a: tumour invading subcutaneous soft tissues; tumour invading trachea; tumour invading oesophagus. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th Edition (2017) published by Springer Science and Business Media LLC, www.springerlink.com.14

Figure 6. T4b is defined as gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumour of any size. Cross-sectional diagram of two different parameters of T4b: tumour encases carotid artery; tumour invades vertebral body. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th Edition (2017) published by Springer Science and Business Media LLC, www.springerlink.com.14

22 Structured Reporting Protocol for Thyroid Cancer 2nd edition 2 Specimen handling and macroscopic findings This section relates to the procedures required after the information has been handed over from the requesting clinician, and the specimen has been received in the laboratory. Tissue banking

➢ Pathologists may be asked to provide tissue samples from fresh specimens for tissue banking or research purposes. The decision to provide tissue should only be made if the pathologist is sure that the diagnostic process will not be compromised. As a safeguard, research use of the tissue samples may be put on hold until the diagnostic process is complete.

➢ If tissue is sampled for banking or research, then this should be done in consultation with a pathologist and recorded in the report.

Specimen handling

➢ Detailed fixation and specimen handling instructions are available from the RCPA online Cut-up Manual:

https://www.rcpa.edu.au/Manuals/Macroscopic-Cut-Up-Manual

➢ The specimen must be handled in a systematic and thorough fashion to ensure completeness and accuracy of pathological data.

Macroscopic findings

S2.01 The labelling of the specimen(s) must be clearly recorded.

S2.02 Clinical information must be recorded.

CS2.02a Any clinical information relevant to the thyroid disease should be recorded. If a pre-operative fine needle aspiration (FNA) or core biopsy has been performed, this should be recorded, and the results of that biopsy briefly stated. If imaging has been performed, this should be recorded, and the results briefly stated. Previous thyroid surgery or medical treatments like anti- thyroid drug or radioactive iodine should be noted. Previous exposure of the neck to radiotherapy (e.g. for treatment of Hodgkin lymphoma) should be noted. The indication for performing the surgery should be recorded as many thyroid

23 Structured Reporting Protocol for Thyroid Cancer 2nd edition cancers are found incidentally in thyroid specimens removed for a purpose other than cancer. Family history of thyroid cancers or features of other endocrine tumours or syndromes should be recorded. (Refer to ICCR guidelines for full commentary.) Clinical or biochemical evidence of hyperthyroidism or hypothyroidism should be noted.

S2.03 The operative procedure must be recorded.

CS2.03a Cases with lobectomy followed by completion thyroidectomy in the same operative procedure should be classified as total thyroidectomies. Other procedures include completion thyroidectomy, central compartment resection or lateral neck node dissection. (Refer to ICCR guidelines for full commentary.)

CS2.03b Surgical management of thyroid tumours consists of either enucleation, lobectomy (removal of a lobe), a hemithyroidectomy (resection of lobe and isthmus), subtotal thyroidectomy (leaving 2 g of tissue on one side), near total thyroidectomy (leaving 0.5-2.0 g tissue on one side) or total thyroidectomy.

S2.04 Any operative findings should be recorded.

CS2.04a It is expected that the surgeon will provide information in regard to the presence or absence of gross extrathyroidal extension (ETE) at the time of the surgical procedure, as well as to the completeness of excision. Gross ETE is a crucial element in staging systems.15,16 The pathologist should indicate if the intra-operative data on gross ETE or margin completeness is not available at the time of pathology reporting.

S2.05 The specimen(s) submitted and laterality must be recorded.

CS2.05a The nature of the specimen and laterality (in lobectomy specimens and node dissection) must be reported.

G2.01 The specimen should be weighed and findings recorded.

S2.06 Tumour focality must be recorded.

CS2.06a Multifocal lesions (defined as more than one tumour focus) are not uncommon in patients with papillary carcinoma and medullary carcinoma. They must be reported.

S2.07 The tumour sites must be recorded, where possible.

CS2.07a The thyroid may give rise to more than 1 or multiple foci of the same type of carcinoma, designated as per the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) guidelines with the descriptor ‘(m)’.15,16 The designation of the tumour site and

24 Structured Reporting Protocol for Thyroid Cancer 2nd edition this protocol are applicable to the dominant excised carcinoma. The dominant tumour is defined as the most clinically relevant tumour because of its aggressiveness and/or its higher T stage. As such, it is often, but not necessarily, the largest tumour. In cases of multiple lesions, the tumour characteristics of a second focus may be relevant and contribute to patient management, particularly if they are of a different histologic type (i.e. tumour 1 is papillary carcinoma and tumour 2 is medullary carcinoma). A second protocol should be generated for these instances. For additional tumour foci that do not alter management, only basic histopathological features (such as size and location) may be reported at the pathologist’s discretion.

S2.08 The macroscopic description of any lesion(s) in the specimen must be recorded.

CS2.08a Where there are multiple lesions, the total number of lesions must be recorded, and each lesion should be identified and described.

CS2.08b For each lesion, the location, appearance, the borders (encapsulated or infiltrative), size (greatest dimension), and distance from the nearest excision margin must be recorded.

CS2.08c Thyroid cancer can be an incidental finding in thyroid glands surgically removed for reasons other than thyroid cancer.

G2.02 The appearance of the thyroid other than the lesion(s) detected should be documented.

S2.09 A block identification key listing the nature and origin of all tissue blocks must be recorded.

CS2.09a The origin/designation of all tissue blocks should be recorded and it is preferable to document this information in the final pathology report. This is particularly important should the need for internal or external review arise. The reviewer needs to be clear about the origin of each block in order to provide an informed specialist opinion. If this information is not included in the final pathology report, it should be available on the laboratory computer system and relayed to the reviewing pathologist. Photography of macroscopic specimens is considered best practice. Annotation of captured images can be very helpful and aids with review of the case later. It can also provide useful information in the context of multidisciplinary meetings. Recording the origin/designation of tissue blocks also facilitates retrieval of blocks, for example for further immunohistochemical or molecular analysis, research studies or clinical trials.

25 Structured Reporting Protocol for Thyroid Cancer 2nd edition Because of the importance of resection margin status, it is recommended that all surgical surfaces are painted prior to specimen dissection. Occasionally different colours can be used to identify specific surgical margins. This information should also be recorded in the block key.

G2.03 A descriptive or narrative field should be provided to record any macroscopic information that is not recorded in the above standards and guidelines, and that would normally form part of the macroscopic description.

CG2.03a The traditional macroscopic narrative recorded at the time of specimen dissection is often reported separately from the cancer protocol. Although this remains an option, it is recommended that macroscopic information be recorded within the overall structure of this protocol.

CG2.03b Much of the information recorded in a traditional macroscopic narrative is covered in the standards and guidelines above and in many cases, no further description is required.

26 Structured Reporting Protocol for Thyroid Cancer 2nd edition 3 Microscopic findings

Microscopic findings relate to purely histological (morphological) assessment. Information derived from multiple investigational modalities, or from two or more chapters, is described in Chapter 5.

S3.01 The histological tumour type must be recorded.

CS3.01a All tumours of the thyroid should be given a type based on the most recent edition of the World Health Organization (WHO) Classification of Tumours of Endocrine Organs.17 (See also Appendix 4).

CS3.01b The more common types are papillary carcinoma, follicular carcinoma, Hürthle cell carcinoma, medullary carcinoma, anaplastic carcinoma and poorly-differentiated carcinoma. It is important to note that other types of benign and malignant tumours can occur in the thyroid gland.

CS3.01c For follicular carcinoma and Hürthle cell carcinoma, it is important to define the carcinoma based on the extent of capsular and/or vascular invasion. Follicular carcinomas and Hürthle cell carcinomas are divided into widely invasive and minimally invasive type. Widely invasive follicular and Hürthle cell carcinomas show infiltration of thyroid cancer cells outside the capsule of the lesion. Minimally invasive (encapsulated) follicular and Hürthle cell carcinoma show significant focal invasion of the tumour capsule. It is important to indicate whether there is capsular invasion, vascular invasion or both. The number of foci of capsular or vascular invasion should be noted. (See figures 7, 8, and 9). Invasion must be differentiated from entrapments of follicles in the capsule and the pseudo-invasive changes following fine needle aspiration.

CS3.01d Minimally invasive follicular or Hürthle cell carcinomas with capsular invasion alone behave like benign tumours. The

presence of vascular invasion should be noted.14,18

CS3.01e For poorly-differentiated carcinoma, the pattern should be dominant for the carcinoma to be placed in this category, but foci of poor differentiation should also be reported.19

CS3.01f For papillary, follicular/Hürthle cell or poorly-differentiated thyroid carcinomas, the presence of even a minor undifferentiated component should be noted as having a component of anaplastic carcinoma as this confers a poorer prognosis.4

27 Structured Reporting Protocol for Thyroid Cancer 2nd edition CS3.01g For papillary carcinoma, there are 15 histological variants documented by WHO.14 Some variants have prognostic significance, while others do not. Papillary microcarcinoma (≤10 mm in diameter), is not thought to have a significant risk of recurrence or metastasis.16 On the other hand, tall cell and columnar cell variants may show more aggressive clinical behaviour than conventional papillary thyroid carcinoma. Some variants, in particular, encapsulated follicular variant, oncocytic variant, etc. may be difficult to differentiate from other tumours. It is recommended that expert opinion be sought if there are uncertainties.

CS3.01h For carcinomas of follicular differentiation, the carcinoma is classified as Hürthle cell carcinoma if more than 75% of the carcinoma is composed of oncocytic cells.14 The 4th edition WHO classification defines this carcinoma as Hürthle cell carcinoma as they have different clinical and genetic features from follicular carcinoma.

CS3.01i For poorly differentiated and undifferentiated anaplastic carcinomas, minor components of papillary, follicular or Hürthle cell carcinoma should be mentioned.

CS3.01j In familial medullary carcinoma, the tumour is preceded by expansion of the C cell population, termed familial C cell hyperplasia that is thought to be neoplastic.17 The C cells are normally found in the upper and middle thirds of the lobes, so immunostaining of sections from these areas may be helpful in suggesting familial disease, although the thresholds for diagnosis are a matter of debate.18-19 From a practical point of view, the presence of multiple groups or nodules of C cells in sections that do not contain the main tumour is suggestive of C cell hyperplasia. It should be noted, however, that secondary C cell hyperplasia may occur in several other circumstances such as hyperparathyroidism,20 Hashimoto’s thyroiditis19 and around tumours of follicular origin.21 It remains important for the pathologist to identify C cell hyperplasia, as it remains one of the clinical settings in which patients should have genetic testing for mutations in the RET protooncogene.22

S3.02 The tumour dimensions must be recorded.

CS3.02a The dimension is that of the microscopically proven dominant tumour, based upon a reconciliation of the imaging, macroscopic and microscopic findings. The dominant tumour (largest tumour) is defined as the most clinically relevant tumour because of its aggressiveness and/or its higher T stage (such as extension to outside thyroid). As such, it is often, but not necessarily, the largest tumour. Tumour size has an impact on prognosis and is a

28 Structured Reporting Protocol for Thyroid Cancer 2nd edition component of TNM staging. For example, papillary carcinomas measuring 10 mm or less are associated with an excellent prognosis, while tumours measuring over 40 mm are associated with a worse prognosis.20 If the exact tumour size cannot be measured, the report should mention the reason such as specimen fragmentation or a grossly positive margin.

CS3.02b For multifocal tumours, the mm measurements of each foci must not be combined, as this would artificially increase the ‘T’ stage.

CS3.02c The size of each lobe of the thyroid and isthmus (if present) must be determined.

S3.03 Mitotic activity must be recorded in poorly-differentiated thyroid carcinoma.

CS3.03a The mitotic status should be reported in every thyroid carcinoma since it is an essential defining criterion for poorly differentiated thyroid carcinomas (PDTC) regardless of the definition used for this entity.21,22 The vast majority of thyroid carcinomas have a very low mitotic rate and a mitotic count is required only in those cases with elevated mitotic activity (≥3 mitoses/2 mm2). Mitotic count (using mm2) should be performed in the area of highest mitotic activity in 10 consecutive high power fields (HPFs).23,24 The Ki-67 proliferation rate has been shown to correlate with outcome.25,26 It has not been utilized in the commonly used definitions of poorly differentiated thyroid carcinomas and thus is not a required element. It can however guide the pathologist to the area of highest mitotic activity.

G3.01 The histological tumour grade should be recorded.

CG3.01a The grade in thyroid carcinomas of follicular cell origin (including both papillary and follicular carcinoma) impacts outcome significantly. It can, however, be deduced from the histologic type along with increased mitotic activity and tumour necrosis, therefore this item is designated as non- core.

S3.04 Whether the capsule of the thyroid is intact or not must be recorded.

CS3.04a The presence of a fibrous capsule or a well demarcated tumour border (i.e. well circumscribed tumour edge directly adjacent to benign thyroid parenchyma with no intervening capsule) is a crucial element in thyroid carcinomas. In follicular and Hürthle cell tumours, the invasion of the capsule and its vessels define malignancy.17 Even in biologically aggressive carcinomas such as poorly differentiated carcinoma, the presence of a capsule was

29 Structured Reporting Protocol for Thyroid Cancer 2nd edition shown to convey a better outcome.22 When a tumour infiltrates the surrounding non-neoplastic parenchyma and is not completely encapsulated/well demarcated, it should be labelled as infiltrative. Infiltrative papillary carcinomas are different from their encapsulated counterparts with regard to metastatic spread (propensity for nodal rather than distant metastasis) and genetic mutations (BRAF V600E rather than RAS mutations).27

S3.05 The presence of capsular invasion must be recorded.

CS3.05a There is no consensus as to the definition of capsular invasion (CI). While there is universal agreement that complete transgression of the capsule constitutes CI,28 complete as opposed to partial transgression of the capsule may suffice for diagnosis of CI.29 Figure 7 depicts the various histologic appearances associated with the presence or absence of CI. According to Chan (2007),28 a given neoplasm should not be diagnosed as carcinoma if complete capsular penetration cannot be proven after extensive sampling except in the following circumstance. This situation occurs when a satellite tumour nodule, morphologically similar to the main tumour, is lying just outside the tumour capsule (Figure 7e). This appearance results from failure to identify the point of capsular penetration. It is noteworthy that not all authors agree that these satellite nodules represent CI.30 In equivocal cases of CI, the entire capsule, irrespective of tumour size, should be processed in the attempt to clarify whether CI is present. Deeper sections (at least three levels) of the representative paraffin block(s) should be performed in the areas of concern in order to exclude CI.28 Despite enhanced histologic examination, there are cases where the presence of CI is questionable. In this instance the term uncertain CI should be used. There is no need to report on the number of foci of CI since it has not been shown to have clinical value.

S3.06 The presence of lymphatic and blood vessel invasion must be recorded.

CS3.06a The majority of authors agree that blood vessel invasion (BVI), also termed angioinvasion, should involve capsular or extra-capsular vessels in encapsulated tumours (Figure 8). In infiltrative tumours partially encapsulated or totally lacking a capsule, BVI can be present within the tumour nodule. These images (Figure 8) depict intracapsular BVI with tumour thrombus attached to the vessel wall, covered by endothelium or associated with fibrin. Tumour thrombus covered by endothelial cells qualifies as BVI (Figure 8b). However, endothelialization is not a requirement if the tumour is attached to the vessel wall (Figure 8c) or admixed with a fibrin thrombus (Figure 8d). If the tumour is encapsulated, intra-tumoural or subcapsular vessels do not

30 Structured Reporting Protocol for Thyroid Cancer 2nd edition qualify for BVI and should not be interpreted as such (Figure 8a). One study has raised the caveat that tumour cells within vascular lumina unassociated with thrombus, and tumour cells underlying intact endothelium could represent ‘pseudoinvasion’ given the fenestrated endothelial network of endocrine organs.31 When this more stringent criterion of BVI is applied, the incidence of BVI in differentiated thyroid carcinoma decreased drastically from 7-62%32-36 to 3%,31 while the risk of distant metastasis in association with the mere existence of BVI becomes 35%. This latter approach has not been validated by additional studies and may fail to identify a significant proportion of thyroid tumours with BVI, focal or extensive, that should be classified as carcinoma based on the presence of invasion, and that may benefit from appropriate risk stratification and/or additional therapies. The consensus opinion is that the criteria used in Figure 8 to define BVI should be utilised. In regard to the extent of BVI, several papers have shown that the presence of 4-5 foci of BVI in encapsulated follicular/Hürthle cell carcinoma confers a much worse outcome than lower number of LVI foci.18,37,38 The 2015 American Thyroid Association (ATA) guidelines classify a patient in a high risk category, if having 4 foci or more of vascular invasion (VI), while focal BVI (<4 foci) in an intrathyroidal follicular carcinoma will put the patient in low risk group.39 More importantly, the National Comprehensive Cancer Network (NCCN) 2019 guidelines have defined minimal vascular invasion as a few foci (1-4) of VI, and does not mandate radioiodine (RAI) administration in an intrathyroidal, well defined, follicular or Hürthle cell carcinoma, with minimal VI.40 Consequently, it is important to report the extent of BVI in encapsulated thyroid carcinoma by counting the foci of BVI. It is noteworthy that most papers that validated the importance of BVI cut-offs have counted individual vessel sections invaded by tumour separately, as different foci. In regard to papillary thyroid carcinoma (PTC), the presence of BVI was shown to impart poorer outcome.35 Furthermore any focus of VI in PTC will put the patient in an intermediate risk category according to the 2015 ATA guidelines.39 It is therefore mandatory to report on the status of BVI in PTC (i.e. core item). There is no evidence that the number of BVI foci impact on prognosis in non-encapsulated PTC. Counting the BVI foci in non- encapsulated PTC is therefore not a core item. It is however a core item in those PTC who are completely encapsulated. (Refer to ICCR guidelines for full commentary.)

S3.07 The presence of necrosis must be recorded.

CS3.07a Tumour necrosis should be reported in every thyroid carcinoma since it is an essential defining criterion for PDTC regardless of the definition used for this entity.21,22 Tumour

31 Structured Reporting Protocol for Thyroid Cancer 2nd edition necrosis is defined as coagulative or comedo-necrosis and should be differentiated from infarct-like necrosis related to previous FNA or ischemic changes within the tumour. Reactive changes seen in the latter two situations such as hyalinization or fibrosis, haemorrhage, hemosiderin laden macrophages, cholesterol clefts or calcification, should be separated from coagulative necrosis.

S3.08 The presence of extrathyroidal extension must be recorded.

CS3.08a Extrathyroidal extension (ETE), defined as tumour extension beyond the thyroid capsule into the adjacent soft tissue, is a common pathologic finding in papillary thyroid carcinomas.41 ETE has long been considered as an adverse prognostic factor with an increased risk of recurrence and mortality.41-44 It can be further subdivided into two categories: 1) minimal (or microscopic) ETE, identified in roughly half of all PTC45 which is invasion into the immediate perithyroidal soft tissue, detected solely at microscopic level and not appreciated clinically or grossly at the time of surgery; and 2) extensive (or gross) ETE, present in around 10% of cases45 that is defined as gross direct extension of the carcinoma into strap muscles (e.g. sternohyoid, sternothyroid, thyrohyoid, and omohyoid muscles), subcutaneous tissue, adjacent viscera (e.g. larynx, trachea, and oesophagus), or recurrent laryngeal nerve, and is typically established clinically by imaging or during the operation. These two categories of ETE bear different prognostic values: the risk of recurrence associated with minor extrathyroidal extension is approximately 3 to 9%,46-52 compared with 23 to 40% risk of recurrence in patients with gross ETE.46,47,49-51,53,54 Furthermore, several studies have shown that microscopic ETE is not an independent predictor for persistent disease, recurrence free survival and disease specific survival.45,48,49,52,54-56 NCCN 2019 guidelines recommend completion thyroidectomy and post-operative RAI for lesions with gross ETE, while low-dose RAI using 30 mCi of iodine 131 is optional for patients with a primary tumour of <4 cm, clinical M0 and minor ETE.40 Histologically, the thyroid gland is devoid of a well-defined capsule in many areas along its periphery, and the follicles are often intermingled with adipose tissue or even skeletal muscle.57 Therefore, the very definition of microscopic ETE is problematic and subjective, and a universally accepted pathologic criterion for ETE is lacking. The fact that microscopic ETE is associated with poor interobserver agreement57 and does not affect recurrence and survival raise concerns of whether microscopic ETE alone is sufficient to upstage a patient. Because of all the above, in the 8th edition AJCC and UICC staging systems, microscopic ETE has been removed entirely from the staging system of differentiated thyroid carcinoma.15,16 Gross ETE invading strap muscles only, by a tumour of any size, will be staged

32 Structured Reporting Protocol for Thyroid Cancer 2nd edition as pT3b, while gross ETE with invasion into subcutaneous soft tissue, larynx, trachea, oesophagus, or recurrent laryngeal nerve will be staged as pT4a. In view of the above, the pathologists’ role is 1) to mention in their report the ETE seen histologically (whether microscopic or gross) and 2) communicate with the surgeon in regards to staging, since the determination of gross ETE is done intra- operatively.

CS3.08b The pathological staging (T stage) depends on the size of the cancer and the extent of involvement of thyroid gland and adjacent tissues. The extension into peri-thyroid soft tissue and the sternohyoid muscles is recorded as T3, regardless of the size of the cancer. Cancer extending beyond the thyroid capsule into subcutaneous soft tissue, larynx, trachea, oesophagus or recurrent laryngeal nerve, etc. should be recorded as T4.

S3.09 The margin status must be recorded.

CS3.09a The margin status of a surgical resection for thyroid carcinoma is a core element and can be divided into three categories: R0 resection (microscopically negative margin), R1 resection (grossly complete resection with microscopically positive margin), and a R2 resection (grossly positive margin or incomplete resection).15 The surgeon should communicate macroscopic status of the margins to the pathologist. Histologically, a positive margin is defined by the presence of tumour cells at the inked tissue border and/or the outer aspect of the thyroid gland.58-61 Several studies have shown that microscopically positive margin is not an independent predictor for recurrence and disease free survival, especially after adjusting for tumour stage and ETE.59-61 Taken these into consideration, the current ATA guideline has only included incomplete R2 resection into the risk stratification as a feature of high risk lesions.39 In contrast, the NCCN 2019 guideline has included any positive resection margin as one of the criteria to recommend completion thyroidectomy.40 (Refer to ICCR guidelines for full commentary.)

S3.10 The presence, location and status of lymph nodes must be recorded.

CS3.10a Increasing evidence has shown that various characteristics of nodal metastases, e.g. number, size, and extranodal extension (ENE), may provide additional prognostic information. Thus, detailed features of nodal disease ought to be included in the pathology report, and be considered in

33 Structured Reporting Protocol for Thyroid Cancer 2nd edition risk stratification and staging systems.55,62-69 A meta-analysis by Randolph et al (2012) has shown that small volume subclinical microscopic pathologic N1 disease, i.e. five or fewer subcentimeter metastatic lymph nodes, conveys little prognostic impact on recurrence free survival and disease specific survival in patients with PTC, compared with clinically evident macroscopic nodal disease involving more than 5 lymph nodes, especially those with ENE.62 The greatest dimension of the largest metastatic deposit in a lymph node should be measured. It is accepted it can be difficult to distinguish multiple small metastases in one large deposit. Many authors recommend measuring the greatest dimension end to end in a single slide including discontinuous deposits.70 Taking this data into consideration, the NCCN 2019 guidelines no longer recommend completion thyroidectomy and post-operative RAI in small volume pN1a disease, i.e. <5 involved nodes with metastasis <2 mm in largest dimension.40 Histologic features of the nodal metastasis that have been incorporated in the ATA initial risk stratifications included number of involved lymph nodes (>5 is considered as intermediate risk) and size of the metastatic lymph nodes (≥3 cm as high risk). The presence of psammoma bodies alone in a node is subject to controversy. While some practicing pathologists do not consider these as metastasis, we are in agreement with the College of American Pathologists in considering these lymph nodes as positive for metastatic carcinoma.23 Extranodal extension is not an uncommon finding, being reported in up to 12% of PTC overall and 33% of nodal metastatic PTC.55,66 Similar to ETE, a well-defined, consensus, histologic diagnostic criterion for ENE is currently lacking.23,71 A study by Du et al (2016) has shown that involvement of perinodal adipose tissue appears to be the most consistent diagnostic criteria of ENE, being considered by eleven participating endocrine pathologists as ENE.71 However, the overall agreement in diagnosing ENE is only fair among expert pathologists.71 Nevertheless, studies have repeatedly demonstrated the association between ENE and persistent and/or recurrence disease.55,62-68 Hence, it is important to document ENE in the pathology report of a differentiated thyroid carcinoma. A seven-compartment nomenclature is used to define anatomic lymph nodes compartments. Central neck refers to level VI (peri-thyroidal, paralaryngeal, paratracheal, and prelaryngeal (Delphian)) and VII (upper mediastinal). Lateral neck refers to level I (submental/submandibular), II (upper jugular), III (mid jugular), IV (lower jugular) and V (posterior triangle).72 At the current time, no additional special techniques should be used other than routine histology for the assessment of nodal metastases (i.e. sentinel lymph node-type protocols

34 Structured Reporting Protocol for Thyroid Cancer 2nd edition are not advocated). However, confirmation by immunohistochemical staining, including thyroglobulin or Thyroid transcription factor-1 (TTF-1) for papillary carcinoma and calcitonin and neuroendocrine markers (e.g. chromogranins, synaptophysin, carcinoembryonic antigen (CEA), CD56) for medullary carcinoma, may be required.

CS3.10b If regional lymph nodes are identified, the location must be specified.

CS3.10c The total number of lymph nodes sampled must be stated.

CS3.10d The number of lymph nodes containing metastatic tumour must be stated.

CS3.10e The presence and sites of lymph node metastases of thyroid carcinoma, affect the pathological staging (N stage) of thyroid cancer.

G3.02 The presence of C-cell hyperplasia should be recorded.

CG.02a The presence of C-cell hyperplasia may suggest hereditary disease and should therefore be reported in specimens harbouring medullary thyroid carcinoma.

S3.11 The parathyroid gland status must be recorded.

CS3.11a The number and status of the parathyroid glands in the specimen should be stated to support surgical quality assurance.

CS3.11b The presence of parathyroid tissue may provide correlation with the clinical data on calcium status.

S3.12 The presence or absence of histologically confirmed distant metastases must be recorded.

CS3.12a The presence of histologically confirmed distant metastasis is a key component of staging.2,3

S3.13 The presence or absence of coexistent pathological abnormalities in the thyroid gland should be recorded.

CS3.13a The presence of chronic lymphocytic thyroiditis, follicular adenoma, Hürthle cell adenoma, NIFTP and nodular hyperplasia for example can help explain the clinical/imaging/cytologic findings.

CS3.13b Hashimoto’s thyroiditis, lymphocytic thyroiditis, diffuse parenchymatous goitre and nodular hyperplasia, etc. are common additional findings and may help elucidate the aetiological relationship or the differential diagnosis.

35 Structured Reporting Protocol for Thyroid Cancer 2nd edition G3.03 Any additional relevant microscopic comments should be recorded.

Figure 7. Capsular invasion (CI)

Schematic drawing for the interpretation of the presence or absence of CI. The diagram depicts a follicular neoplasm (orange) surrounded by a fibrous capsule (green). a) bosselation on the inner aspect of the capsule does not represent CI; b) sharp tumour bud invades into but not through the capsule suggesting invasion requiring deeper sections to exclude; c) tumour totally transgresses the capsule invading beyond the outer contour of the capsule qualifying as CI; d) tumour clothed by thin (probably new) fibrous capsule but already extending beyond an imaginary (dotted) line drawn through the outer contour of the capsule qualifying as CI; e) satellite tumour nodule with similar features (architecture, cytomorphology) to the main tumour lying outside the capsule qualifying as CI; f) Follicles aligned perpendicular to the capsule suggesting invasion requiring deeper sections to exclude g) follicles aligned parallel to the capsule do not represent CI; h) mushroom-shaped tumour with total transgression of the capsule qualifies as CI; i) mushroom-shaped tumour within but not through the capsule suggests invasion requiring deeper sections to exclude; j) neoplastic follicles in the fibrous capsule with a degenerated appearance accompanied by lymphocytes and siderophages does not represent CI but rather capsular rupture related to prior fine needle aspiration.

36 Structured Reporting Protocol for Thyroid Cancer 2nd edition

Modified from Chan JKC; Chapter 18 Tumours of the thyroid and parathyroid glands. Diagnostic Histopathology of Tumours. 3rd ed. Fletcher CDM, editor. London, England: Churchill Livingston; 2007. p. 997–1078. Reproduced with permission.

Figure 8. Vascular invasion (VI): Schematic drawing for the interpretation of the presence or absence of VI.

The diagram depicts a follicular neoplasm (green) surrounded by a fibrous capsule (blue). a) Bulging of tumour into vessels within the tumour proper does not constitute VI. b) Tumour thrombus covered by endothelial cells in intracapsular vessel qualifies as VI. c) Tumour thrombus in intracapsular vessel considered as VI since it is attached to the vessel wall. d) Although not endothelialized, this tumour thrombus qualifies for VI because it is accompanied by a fibrin thrombus. e) Endothelialized tumour thrombus in vessel outside the tumour capsule represents VI. f) Artefactual dislodgement of tumour manifesting as irregular tumour fragments into vascular lumen unaccompanied by endothelial covering or fibrin thrombus.

37 Structured Reporting Protocol for Thyroid Cancer 2nd edition Figure 9. Encapsulated Hürthle cell carcinoma

Encapsulated Hurtle cell carcinoma with multiple foci of microscopic vascular invasion (VI) and no gross invasion.

In some classification schemes, these tumours are labelled as minimally invasive while others will use terms such as encapsulated angioinvasive Hürthle cell carcinomas or encapsulated Hürthle cell carcinomas with extensive angioinvasion to stress their potential for aggressive behaviour. This 50 year old patient developed bone metastases 10 years after thyroidectomy.

A. Low power view showing multiple microscopic foci of VI in tumour capsule (arrow) and immediately outside the capsule.

B. High power view of a tumour thrombus (arrow) attached to vessel wall and covered by endothelial cells.

Reproduced with permission from Springer Science+Business Media: Ghossein R. Update to the College of American Pathologists Reporting on Thyroid Carcinomas Head and Neck Pathol (2009) 3:86–93.73

38 Structured Reporting Protocol for Thyroid Cancer 2nd edition 4 Ancillary studies

Ancillary studies may be used to determine lineage, clonality or disease classification or subclassification; as prognostic biomarkers; or to indicate the likelihood of patient response to specific biologic therapies.

G4.01 The findings of any ancillary studies, where performed, should be recorded.

CG4.01a Ancillary studies may be used to determine lineage, disease classification or subclassification; as prognostic biomarkers; or to indicate the likelihood of patient response to specific biological therapies. In cases in which the diagnosis is suspected to be medullary carcinoma, immunostaining for calcitonin, chromogranin, synaptophysin, CEA and thyroglobulin may be performed to confirm the diagnosis. The calcitonin, CEA, chromogranin and synaptophysin immunostains are also helpful to identify C-cell hyperplasia. Thyroglobulin, TTF-1 and paired box 8 (PAX8) may indicate that a tumour is of follicular cell origin. TTF-1 is more sensitive than thyroglobulin however, TTF-1 can be positive in other cancers such as lung adenocarcinoma and small cell carcinoma of any primary site. Anaplastic thyroid carcinoma is negative for thyroglobulin, positive focally for TTF-1 in a small percentage of cases, but labels for PAX-8 in a substantial number of cases.74 It is not possible to differentiate benign and malignant thyroid tumours by using immunohistochemistry. (Refer to ICCR guidelines for full commentary.) Molecular analyses are currently being performed to identify targets in tumour refractory to radioactive iodine therapy. An immunostain for the BRAF V600E mutation is an easy to perform, robust and rapid assay to select patients for BRAF inhibitor therapy as well as confirm diagnosis of some papillary thyroid carcinomas.

CG4.01b Uncommon tumours (e.g. angiosarcoma, carcinoma showing thymus-like differentiation, paraganglioma, etc.) can occur in the thyroid gland. Immunohistochemistry (CD31, CD5, GATA-3, etc.) can help with a definitive diagnosis.

G4.02 Results of any molecular investigation should be incorporated into the pathology report.

CG4.02a Molecular investigation can be useful in the management of patients with medullary thyroid carcinoma.

39 Structured Reporting Protocol for Thyroid Cancer 2nd edition Germline mutations of the rearranged during transfection proto-oncogene (RET) gene identify patients at risk for mutation-specific thyroidal and extrathyroidal manifestations, in particular MEN2a and MEN2b. The strong genotype-phenotype correlation guides management and prognosis of germline carriers. Somatic RET mutations occur in up to 70% of sporadic medullary thyroid carcinoma patients.

CG4.02b Ancillary tests performed externally may contain information needed for compliance with National Pathology Accreditation Advisory Council (NPAAC) and RCPA requirements, that are not relevant to cancer reporting protocols. The specific elements of an ancillary study report needed for cancer reporting include the following: • laboratory performing the test, • substrate (e.g. cytology smears, fluid in special media, paraffin block, fresh tissue, etc.), • method (where relevant), • results,

• conclusion (usually a text field), and • person responsible for reporting the ancillary test.

CG4.02c Documentation of all relevant ancillary study findings is essential for overarching commentary (see Synthesis and Overview, Chapter 5), in which the significance of each finding is interpreted in the overall context of the case.

40 Structured Reporting Protocol for Thyroid Cancer 2nd edition 5 Synthesis and overview

Information that is synthesised from multiple modalities and therefore cannot reside solely in any one of the preceding chapters is described here.

For example. tumour stage is synthesised from multiple descriptors – clinical, macroscopic and microscopic.

By definition, synthetic elements are inferential rather than observational, often representing high-level information that is likely to form part of the report ‘Summary’ or ‘Diagnosis’ section in the final formatted report.

Overarching case comment is synthesis in narrative format. Although it may not necessarily be required in any given report, the provision of the facility for overarching commentary in a cancer report is essential.

S5.01 The tumour stage and stage grouping must be recorded according to the most recent TNM staging system of the AJCC Cancer Staging Manual. (See Appendices 5 and 6).

CS5.01a The staging applies to all tumour types, including anaplastic carcinoma, which hitherto had automatically been staged as stage 4 irrespective of all other details. The UICC TNM 8th edition staging applies to carcinomas and includes papillary, follicular, poorly differentiated, Hürthle cell (oncocytic), anaplastic, and medullary carcinoma.16 Multifocal tumours (≥2 foci) of all histological types should be designated (m), with the largest and/or most invasive focus determining the classification, e.g. pT2(m).

CS5.01b In thyroid cancer, staging is also informed by patient age and cancer type.

CS5.01c A dedicated staging system is employed in young patients (age <55) with differentiated thyroid cancer, i.e. papillary and follicular carcinoma.

CS5.01d Anaplastic thyroid carcinoma is stage IV but being subdivided to stage IVA, IVB and IVC based on the criteria of AJCC TNM 8th edition.14

S5.02 The year of publication and edition of the cancer staging system used in S5.01 must be included in the report.

G5.01 The ‘Diagnostic summary’ section of the final formatted report should include: a. Specimen type b. Tumour laterality and site

41 Structured Reporting Protocol for Thyroid Cancer 2nd edition c. Tumour type d. Tumour stage e. Completeness of excision

S5.03 The reporting system must provide a field for free text or narrative in which the reporting pathologist can give overarching case comment.

CS5.03a This field may be used, for example, to: – list results of any relevant ancillary tests, – document any noteworthy adverse gross and/or histological features, – express any diagnostic subtlety or nuance that is beyond synoptic capture, and – document further consultation or results still pending.

CS5.03b Use of this field is at the discretion of the reporting pathologist.

G5.02 The edition/version number of the RCPA protocol on which the report is based should be included on the final report.

CG5.02a For example, the pathology report may include the following wording at the end of the report: ‘the data fields within this formatted report are aligned with the criteria as set out in the RCPA document ‘ XXXXXXXXXX’ XXXX Edition dated XXXXXXX’.

42 Structured Reporting Protocol for Thyroid Cancer 2nd edition 6 Structured checklist

The following checklist includes the standards and guidelines for this protocol which must be considered when reporting, in the simplest possible form. The summation of all ‘standards’ is equivalent to the ‘minimum data set’ for thyroid cancer. For emphasis, standards (mandatory elements) are formatted in bold font. S6.01 The structured checklist provided may be modified as required but with the following restrictions: a. All standards and their respective naming conventions, definitions and value lists must be adhered to. b. Guidelines are not mandatory but are recommendations , and where used, must follow the naming conventions, definitions and value lists given in the protocol. G6.01 The order of information and design of the checklist may be varied according to the LIS capabilities and as described in Functional Requirements for Structured Pathology Reporting of Cancer Protocols.75 CG6.01a Where the LIS allows dissociation between data entry and report format, the structured checklist is usually best formatted to follow the pathologist’s workflow. In this situation, the elements of synthesis or conclusions are necessarily at the end. The report format is then optimised independently by the LIS. CG6.01b Where the LIS does not allow dissociation between data entry and report format, (for example where only a single text field is provided for the report), pathologists may elect to create a checklist in the format of the final report. In this situation, communication with the clinician takes precedence and the checklist design is according to principles given in Chapter 7. G6.02 Where the checklist is used as a report template (see G6.01), the principles in Chapter 7 and Appendix 2 apply. CG6.02a All extraneous information, tick boxes and unused values should be deleted. G6.03 Additional comment may be added to an individual response where necessary to describe any uncertainty or nuance in the selection of a prescribed response in the checklist. Additional comment is not required where the prescribed response is adequate.

43 Structured Reporting Protocol for Thyroid Cancer 2nd edition

Item descriptions in italics are conditional on previous responses.

Values in all caps are headings with sub values.

S/G Item description Response type Conditional Pre-analytical S1.01 Demographic information provided S1.02 Clinical information provided Text on request form OR Information not provided OR Structured entry as below: CLINICAL INFORMATION Previous history of thyroid Text tumour or related abnormality Relevant biopsy/cytology Text results Imaging findings Text Previous surgery/therapy Text Relevant family history Text Presence of clinical Text syndrome G1.01 Copy To doctors recorded Text S1.03 Pathology accession number Alpha-numeric S1.04 Principal clinician Text

G1.02 Other clinical information Text received Macroscopic findings S2.01 Specimen labelled as Text S2.02 Clinical information Text S2.03 Operative procedure Not specified If partial excision, specify the type if possible. OR Multi selection value list (select all that apply): • Total thyroidectomy • Near total thyroidectomy • Hemithyroidectomy • Lobectomy • Isthmusectomy • Partial excision* • Lymph node dissection • Other, specify *Note: Anything less than a lobectomy excluding isthmusectomy, including substernal excision. Type of partial excision Text S2.04 Operative findings Single selection value list: If intra-operative macroscopic evidence of extrathyroidal • Not specified extension is present, specify • Intra-operative macroscopic evidence of location and tissue invaded. extrathyroidal extension If R2 excision is observed, specify the location.

o Yes, specify location and tissue invaded o No o Information not available • Intra-operative impression of completeness of excision o R0/R1 o R2, specify location o Information not available • Other, specify S2.05 Specimen(s) submitted Single selection value list: • Not specified OR Multi selection value list (select all that apply): • Thyroid gland o Left o Right o Isthmus • Parathyroid gland(s) • Lymph node(s), specify site(s) and laterality • Other, specify site(s) and laterality G2.01 Specimen weight Numeric: ___g

S2.06 Tumour focality Single selection value list: If multifocal, specify the number of tumours (if >5 state such, but • Cannot be assessed, specify no need to specify the number) • Unifocal • Multifocal Number of tumours in Numeric: ____ specimen S2.07 Tumour site Single selection value list: Describe tumour focality for the most clinically relevant tumour. • Not specified OR Multi selection value list (select all that apply): • Lobe o Left o Right • Isthmus • Pyramidal lobe • Soft tissue or muscle, specify site(s) and laterality • Other, specify site(s) and laterality S2.08 Macroscopic description Text G2.02 Thyroid appearance Text S2.09 Block identification key Text G2.03 Other macroscopic comments Text Microscopic findings

S3.01 Histological tumour type Single selection value list from WHO Classification of Tumours: Pathology and

Genetics of Tumours of Endocrine Organs (2017). Single selection value list: • Papillary thyroid carcinoma o Classic (usual, conventional) o Cribriform-morular variant o Diffuse sclerosing variant o Encapsulated variant o Encapsulated/well-demarcated follicular variant with invasion o Infiltrative follicular variant o Hobnail variant o Microcarcinoma o Oncocytic variant o Solid variant o Tall cell variant o Warthin-like variant o Other variant, specify • Follicular thyroid carcinoma (FTC) o FTC, minimally invasive o FTC, encapsulated angioinvasive o FTC, widely invasive • Hürthle (oncocytic) cell tumours

o Hürthle cell carcinoma, minimally invasive o Hürthle cell carcinoma, encapsulated angioinvasive o Hürthle cell carcinoma, widely invasive • Poorly differentiated thyroid carcinoma • Anaplastic thyroid carcinoma • Squamous cell carcinoma • Medullary thyroid carcinoma • Mixed medullary and follicular thyroid carcinoma • Mucoepidermoid carcinoma • Sclerosing mucoepidermoid carcinoma with eosinophilia • Mucinous carcinoma • Spindle epithelial tumour with thymus-like differentiation • Intrathyroid thymic carcinoma • Other, specify S3.02 Microscopic tumour Single selection value list: dimension • Cannot be assessed, specify

OR Numeric: ___mm maximum tumour dimension (largest tumour) OR

Additional dimensions (largest tumour) ____mm x ____mm S3.03 Mitotic activity Single selection value list: If high mitoses, specify number of mitoses per 2 mm2 • Not identified/low (<3 mitoses/2 mm2) • High (>3 mitoses/2 mm2) • Cannot be assessed, specify Note: 2 mm2 approximates 10 high power fields on some microscopes Numeric: ___ mitotic figures/2 mm2 G3.01 Histological grade Single selection value list: • Well differentiated • Poorly differentiated • Undifferentiated/anaplastic S3.04 Tumour encapsulation / Single selection value list: circumscription • Encapsulated • Infiltrative • Other, specify S3.05 Capsular invasion Single selection value list: • Not applicable • Uncertain • Not identified • Present • Cannot be assessed, specify S3.06 Lymphatic invasion Single selection value list: • Cannot be assessed, specify • Not identified

• Present Vascular invasion Single selection value list: • Not identified • Present, for encapsulated neoplasms o Focal, <4 foci o Extensive, >4 foci • Extrathyroidal blood vessel invasion o Not identified o Present • Small vessel, not otherwise classifiable • Cannot be assessed, specify S3.07 Necrosis Single selection value list: • Not identified • Present S3.08 Extrathyroidal extension Single selection value list: • Cannot be assessed • Not identified OR Multi selection value list (select all that apply): • Invasion into perithyroid fibroadipose tissue • Invasion into skeletal muscle

• Invasion into subcutaneous soft tissue, larynx, trachea, oesophagus or recurrent laryngeal nerve • Invasion into prevertebral fascia or encasing the carotid artery or mediastinal vessel S3.09 Margin status Single selection value list: If not involved by invasive carcinoma record the distance of • Not involved tumour to closest margin • Involved, specify (anterior or posterior) If involved by invasive • Cannot be assessed, specify carcinoma specify the anterior or posterior margin, if possible Distance to closest margin Numeric: __mm Margin (anterior or posterior) Text

S3.10 LYMPH NODE STATUS No nodes submitted or found OR Single selection value list: Record the number of LN examined. • Not involved If involved, specify the number • Involved of positive LN

Number of lymph Number cannot be determined nodes examined OR Numeric: ___

Number of positive Numeric: ___ Not required if number cannot lymph nodes be determined is entered above. Location of involved lymph Text nodes

Greatest dimension of Numeric: __mm largest lymph node with metastasis Greatest dimension of Numeric: __mm largest metastatic focus in lymph node Extranodal extension (ENE) Single selection value list: If ENE present, specify number of nodes • Not identified • Present • Cannot be determined G3.02 C-cell hyperplasia Single selection value list: • Not identified • Present • Unilateral • Bilateral S3.11 Parathyroid gland status Single selection value list: If present, specify the number of parathyroid gland(s) found and • Not identified the location of any removed • Present parathyroid glands (e.g. right upper or lower lobe). o Normal o Involved by carcinoma o Hypercellular/enlarged

Number of parathyroid Numeric: __ gland(s) S3.12 Distant metastases Single selection value list: • Not identified

• Not assessed • Present, specify site(s) S3.13 Coexistent pathological None identified abnormalities OR Multi select value list : • Nodular hyperplasia • Diffuse hyperplasia • Dyshormonogenetic goitre • Chronic lymphocytic thyroiditis • Follicular adenoma • Hürthle cell adenoma • Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) • Other, specify G3.03 Additional microscopic comment Text Ancillary findings G4.01 Ancillary studies Single selection value list: • Not performed • Performed, specify Results Text G4.02 Molecular studies Text Synthesis and overview S5.01 PATHOLOGICAL STAGING (AJCC 8TH EDITION)

TNM descriptors Multi select value list : • m - multiple primary tumours • r – recurrent • y – post therapy Primary tumour (pT)* Single select value list : All categories may be subdivided: (s) solitary tumour TX Primary tumour cannot be assessed and (m) multifocal tumour (the T0 No evidence of primary tumour largest tumour determines the T1 Tumour <2 cm in greatest dimension classification). limited to the thyroid T1a Tumour <1 cm in greatest dimension limited to the thyroid T1b Tumour >1 cm but <2 cm in greatest dimension limited to the thyroid T2 Tumour >2 cm but <4 cm in greatest dimension limited to the thyroid T3 Tumour >4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles T3a Tumour >4 cm limited to the thyroid T3b Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohoid, or omohyoid muscles) from a tumour of any size T4 Includes gross extrathyroidal extension beyond the strap muscles T4a Gross extrathryroidal extension invading subcutaneous soft tissues, larynx, trachea, oesophagus, recurrent laryngeal nerve from a tumour of any size T4b Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumour of any size

Regional lymph node (pN) Single selection value list: NX Regional lymph nodes cannot be assessed N0 No evidence of locoregional lymph node metastasis N0a One or more cytologically or histologically confirmed benign lymph nodes N0b No radiologic or clinical evidence of locoregional lymph node metastasis N1 Metastasis to regional nodes N1a Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease. N1b Metastasis to unilateral, bilateral or contralateral lateral neck lymph nodes (levels I, II, III, IV or V) or retropharyngeal lymph nodes S5.02 Year and edition of staging Numeric: year system AND Text: Edition e.g. 1st, 2nd etc. G5.01 Diagnostic summary Text Include: a. Operative procedure b. Tumour site c. Histological tumour type d. Tumour stage e. Margin status S5.03 Overarching comment Text

G5.02 Edition/version number of the Text RCPA protocol on which the report is based

7 Formatting of pathology reports

Good formatting of the pathology report is essential for optimising communication with the clinician, and will be an important contributor to the success of cancer reporting protocols. The report should be formatted to provide information clearly and unambiguously to the treating doctors, and should be organised with their use of the report in mind. In this sense, the report differs from the structured checklist, which is organised with the pathologists’ workflow as a priority.

Uniformity in the format as well as in the data items of cancer reports between laboratories makes it easier for treating doctors to understand the reports; it is therefore seen as an important element of the systematic reporting of cancer. For guidance on formatting pathology reports, please refer to Appendix 2. An example of a pathology report is shown in Appendix 3.

Appendix 1 Pathology request form for thyroid tumours

This appendix describes the information that should be collected before the pathology test. Some of this information can be provided on generic pathology request forms; any additional information required specifically for the reporting of thyroid tumour specimens may be provided by the clinician on a separate request information sheet. An example request information sheet is included below. Elements which are in bold text are those which pathologists consider to be required information. Those in non-bold text are recommended.

Also included in this appendix are the procedures that are recommended before handover of specimens to the laboratory. Patient information

• Adequate demographic and request information should be provided with the specimen.

• Items relevant to cancer reporting protocols include: • patient name

• date of birth • gender • identification and contact details of requesting doctor • date of request • Document whether or not the patient identifies as Aboriginal and/ or Torres Strait Islander in Australia, or Māori in New Zealand. This is in support of government initiatives to monitor the health of those who identify as indigenous, particularly in relation to cancer.

• The patient’s health identifiers should be provided.

➢ The patient’s health identifiers may include the patient’s Medical Record Number as well as a national health number such as a patient’s Individual Healthcare Identifier (IHI) (Australia) or the National Healthcare Index (New Zealand).

➢ The Australian Healthcare identifiers i.e. Healthcare Provider Identifier - Individual (HPI-I) and Healthcare Provider Identifier - Organisation (HPI- O) should be used, where possible, to identify the requesting doctor.

Clinical Information

➢ Surgical handling procedures affect the quality of the specimen.

• The specimen should be fixed in 10% neutral buffered formalin as soon as possible after resection or after tissue banking (if applicable). • It is useful for the surgeon to identify the anatomical orientation of the thyroid.

➢ Any previous history of thyroid/endocrine tumour or related abnormality must be recorded.

➢ • Clinical or biochemical evidence of hyperthyroidism or hypothyroidism should be noted.

➢ • Clinical features associated with thyroid lesion such as change in size, presence of hoarse voice, stridor, swallowing difficulties, presence of pain.

➢ If a pre-operative biopsy, or cytology has been performed, this must be recorded.

➢ • If a pre-operative FNA or core biopsy has been performed, this should be recorded and the results of that biopsy briefly stated. .

Any imaging findings must be recorded.

• If imaging has been performed, this should be recorded and the results briefly stated.

➢ Any previous surgery or therapy should be recorded.

➢ • Previous thyroid surgery or medical treatments like anti-thyroid drug or radioactive iodine should be noted. Previous exposure of the neck to radiotherapy (e.g. for treatment of Hodgkin lymphoma) should be noted. The indication for performing the surgery should be recorded as many thyroid cancers are found incidentally in thyroid specimens removed for a purpose other than cancer.

➢ Any relevant family history should be recorded.

➢ • Family history of thyroid cancers or features of other endocrine tumours or syndromes should be recorded. It is worth noting that gastrointestinal manifestations of an endocrine syndrome may present before identification of an endocrine tumour.

➢ The presence of the clinical syndrome be recorded.

• Relevant clinical information suggestive of the presence of clinical syndromes, in pargicular multiple endocrine neoplasia type 2A and type 2B that are associated with increased risk of medullary cancer of thyroid (e.g. phaeochromocytoma, hyperparathyroidism, neuromas) and any evidence (clinical or biochemical) of endocrine hyperfunction or hypofunction should be included.

➢ Any other clinical information should be included, if appropriate.

• Space for free text should be included to encourage reporting of ambiguity, or for the addition of other comments.

Example Request Information Sheet

The above Request Information Sheet is also available on the RCPA Cancer Protocols webpage.

Appendix 2 Guidelines for formatting of a pathology report Layout

Headings and spaces should be used to indicate subsections of the report, and heading hierarchies should be used where the LIS allows it. Heading hierarchies may be defined by a combination of case, font size, style and, if necessary, indentation. • Grouping like data elements under headings and using ‘white space’ assists in rapid transfer of information.76

Descriptive titles and headings should be consistent across the protocol, checklist and report.

When reporting on different tumour types, similar layout of headings and blocks of data should be used, and this layout should be maintained over time. • Consistent positioning speeds data transfer and, over time, may reduce the need for field descriptions or headings, thus reducing unnecessary information or ‘clutter’.

Within any given subsection, information density should be optimised to assist in data assimilation and recall. The following strategies should be used: • Configure reports in such a way that data elements are ‘chunked’ into a single unit to help improve recall for the clinician.76

• Reduce ‘clutter’ to a minimum.76 Thus, information that is not part of the protocol (e.g. billing information or SNOMED codes) should not appear on the reports or should be minimised.

• Reduce the use of formatting elements (e.g. bold, underlining or use of footnotes) because these increase clutter and may distract the reader from the key information.

Where a structured report checklist is used as a template for the actual report, any values provided in the checklist but not applying to the case in question must be deleted from the formatted report.

Reports should be formatted with an understanding of the potential for the information to ‘mutate’ or be degraded as the report is transferred from the LIS to other health information systems. As a report is transferred between systems: • text characteristics such as font type, size, bold, italics and colour are often lost • tables are likely to be corrupted as vertical alignment of text is lost when fixed font widths of the LIS are rendered as proportional fonts on screen or in print • spaces, tabs and blank lines may be stripped from the report, disrupting the formatting • supplementary reports may merge into the initial report.

Appendix 3 Example of a pathology report

Appendix 4 WHO histological classification of tumours of the thyroid gland

Follicular adenoma 8330/0

Hyalinizing trabecular tumour 8336/1*

Other encapsulated follicular-patterned thyroid tumours Follicular tumour of uncertain malignant potential 8335/1* Well-differentiated tumour of uncertain malignant potential 8348/1* Non-invasive follicular thyroid neoplasm with papillary-like nuclear features 8349/1*

Papillary thyroid carcinoma (PTC) Papillary carcinoma 8260/3 Follicular variant of PTC 8340/3 Encapsulated variant of PTC 8343/3 Papillary microcarcinoma 8341/3 Columnar cell variant of PTC 8344/3 Oncocytic variant of PTC 8342/3

Follicular thyroid carcinoma (FTC), NOS 8330/3 FTC, minimally invasive 8330/3 FTC, encapsulated angioinvasive 8339/3* FTC, widely invasive 8330/3

Hürthle (oncocytic) cell tumours Hürthle cell adenoma 8290/0 Hürthle cell carcinoma 8290/3

Poorly differentiated thyroid carcinoma 8337/3

Anaplastic thyroid carcinoma 8020/3

Squamous cell carcinoma 8070/3

Medullary thyroid carcinoma 8345/3

Mixed medullary and follicular thyroid carcinoma 8346/3

Mucoepidermoid carcinoma 8430/3

Sclerosing mucoepidermoid carcinoma with eosinophilia 8430/3

Mucinous carcinoma 8480/3

Ectopic thymoma 8580/3

Spindle epithelial tumour with thymus-like differentiation 8588/3

Intrathyroid thymic carcinoma 8589/3

Paraganglioma and mesenchymal/stromal tumours Paraganglioma 8693/3 Peripheral nerve sheath tumours (PNSTs) Scwannoma 9560/0

Malignant PNST 9540/3 Benign vascular tumours Haemangioma 9120/0 Cavernous haemangioma 9121/0 Lymphangioma 9120/0 Angiosarcoma 9120/3 Smooth muscle tumours Leiomyoma 8890/0 Leiomyosarcoma 8890/3 Solitary fibrous tumour 8815/1

Haematolymphoid tumours Langerhans cell histiocytosis 9751/3 Rosai-Dorfman disease Follicular dendritic cell sarcoma 9758/3 Primary thyroid lymphoma

Germ cell tumours Benign teratoma (grade 0 or 1) 9080/0 Immature teratoma (grade 2) 9080/1 Malignant teratoma (grade 3) 9080/3

Secondary tumours

The morphology codes are from the International Classification of Diseases for Oncology (ICD-O).77 Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; and /3 for malignant tumours. The classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

*These new codes were approved by the IARC/WHO Committee for ICD-O.

From WHO Classification of Tumours Pathology and Genetics. Tumours of Endocrine Organs 2017, Volume 10, 4th Edition. IARC.17

Appendix 5 Histological tumour type

Papillary carcinoma Papillary carcinoma is the most common carcinoma type and consists of numerous named variants, though only a few of these currently have sufficient evidence to be considered clinically and biologically relevant. Thus efforts should be made to flag or document the following variants when present: • Classic (usual, conventional) • Encapsulated/well demarcated follicular variant with invasion • Infiltrative follicular variant • Tall cell variant • Cribriform-morular variant • Diffuse sclerosing variant • Encapsulated variant • Microcarcinoma

Classical papillary thyroid carcinoma (PTC), tall cell and microcarcinoma variants Classic (usual, conventional) papillary carcinoma is the most common and ‘default’ variant of papillary carcinoma. Tall cell variant of papillary carcinoma is a more aggressive variant that has a higher prevalence of BRAF mutations and is more frequently refractory to radioactive Iodine therapy.78-80 Papillary microcarcinomas are defined by their size (≤1 cm) and are extremely indolent and often incidental.17 In this protocol, it is recommended but not required that they are subtyped according to their cytoarchitectural features (e.g. papillary microcarcinoma, classical)

Follicular variant and related lesions Follicular variant of papillary carcinoma is important to document because it has recently been substratified based on outcome into completely encapsulated/well demarcated and infiltrative follicular variants which completely or partially lack a capsule. Infiltrative follicular variants have a behaviour similar to classic papillary carcinoma, particularly in terms of propensity for nodal metastasis, while the behaviour of encapsulated/well circumscribed follicular variant is more indolent, especially if non-invasive.81,82 Many non-invasive encapsulated/well circumscribed follicular variants of papillary thyroid carcinoma can now be reclassified under the new designation NIFTP. This shift in nomenclature arose as an effort to encourage conservative management of these lesions given their extremely low risk of structural recurrence.83 It is noteworthy that the impact of this change worldwide varies according to countries. For example, many cases designated as NIFTP today were labelled in parts of Asia including Australia, as follicular adenomas and thus this new designation will have little effect on the practice of these pathologists. NIFTP remains an actionable surgical disease, albeit with a more conservative approach. As NIFTP is not overtly malignant, it is technically not required to report these under this cancer protocol. However it is encouraged to include them in the overall pathology report, though only limited parameters are relevant, namely size, laterality, and margin status. It must be noted that not all tumours previously designated as non-invasive follicular

variant of papillary thyroid carcinoma would qualify as NIFTP.83 Several exclusionary criteria have been put forth in the initial publication of this entity in order to ensure that the NIFTP category remains indolent83 and are as follows: solid/trabecular or insular growth ≥30%, ≥1% true papillary growth (for more explanation see below), psammoma bodies, tumour necrosis, ≥3 mitosis/10 HPFs at 400x magnification, tall cell, columnar, or cribriform morular morphology. A key requirement for a NIFTP diagnosis is that the entire lesional border has been submitted for histologic evaluation. When a tumour fulfils these inclusion and exclusion criteria, NIFTP designation is appropriate. Of note, subcentimeter NIFTP and NIFTP with oncocytic features have been shown to have an outcome similar to NIFTP.84,85 Multifocal NIFTP has not been well validated yet. In view of the small number of articles on these NIFTP scenarios, some pathologists do not label these unusual forms of this entity as NIFTP. In these situations, our opinion is that the designation, NIFTP, is not absolutely contraindicated. NIFTP is still an evolving diagnosis, and certain problematic areas have already been noted such as the quantification of true papillae. Because the initial criterion of <1%83 papillae was noted to be subjective and difficult to apply, there was a suggestion that even 1 well-formed papilla as defined above should be considered exclusionary.86 Studies are underway to resolve this issue. When an encapsulated non- invasive follicular patterned lesion with PTC nuclei does not fulfil the NIFTP inclusion criteria, they can be labelled as encapsulated variant. This variant is defined in the most recent WHO as an architecturally and cytologically typical PTC that is totally encapsulated but in the opinion of this expert panel it can be used to label encapsulated non-invasive follicular patterned lesions with PTC nuclei that do not meet the NIFTP criteria.17 If an encapsulated follicular patterned tumour has questionable capsular/vascular invasion, the term of uncertain malignant potential (UMP) is used as a qualifier. These tumours are not required to be reported using this thyroid cancer protocol since their malignant potential has not been demonstrated yet. When the nuclear features of PTC are absent, these lesions are labelled as follicular tumour of uncertain malignant potential (FTUMP) while if PTC nuclei are questionable or present the designation well differentiated tumour of uncertain malignant potential (WTUMP) is used.17

Diffuse sclerosing variant and cribriform-morular variants The cribriform morular variant is a biologically distinct variant characterised by APC or beta-catenin mutations and shows an association with familial adenomatous polyposis coli, in some cases preceding recognition of colon polyps or other extracolonic manifestations.87 Diffuse sclerosing variant is a locoregionally aggressive variant with a high rate of nodal metastasis and locoregional recurrence, though overall survival is good possibly because of the young age of the patients. Nonetheless, this variant appears to necessitate more aggressive initial surgical management including more extensive node dissection.88 Other variants that may have prognostic and therapeutic value but are rare and not well validated include: • Clear cell • Hobnail variant • Oncocytic or oxyphilic • Solid Follicular and Hürthle (oncocytic) cell carcinomas Follicular carcinoma is a well-differentiated carcinoma type defined by invasiveness in the absence of diagnostic nuclear features of papillary thyroid carcinoma. The diagnosis of follicular carcinoma and its distinction from follicular adenoma primarily depends on

the identification of invasion of the tumour capsule and/or vascular spaces. The most recent WHO classification subdivide these carcinomas into minimally invasive (capsular invasion only), encapsulated angioinvasive (any focus of vascular invasion) and widely invasive. The latter is defined as grossly apparent extensive invasion of the thyroid and/or extra-thyroid tissue with often prominent vascular invasion.17 These widely invasive carcinomas are often characterised by loss of encapsulation and multiple invasive fronts radiating from the epicenter of the tumour. Hürthle cell carcinoma is defined as a tumour composed of 75% of oncocytes lacking the nuclear features of papillary carcinoma demonstrating capsular and/or vascular invasion.17 In the most recent WHO classification of endocrine tumours, Hürthle cell carcinoma is no longer considered a variant of follicular carcinoma because of different (overall more aggressive) behaviour, different molecular profile and less radioactive iodine avidity.17 The definition of minimally invasive, angioinvasive and widely invasive Hürthle cell carcinoma mirrors those of follicular carcinoma. Although pathologists can diagnose benign from malignant thyroid tumours with very high accuracy, there are extremely rare cases with distant metastasis in a setting of non-invasive follicular and Hürthle cell carcinoma even after complete sampling of the tumour capsule.89 There are also very rare instances of regional nodal metastases without primary thyroid carcinoma found.90 While the majority of thyroid cancers are well differentiated, a subset are poorly differentiated (historically known as insular, or trabecular, carcinoma) or undifferentiated (anaplastic). These tumour types represent progression to a more aggressive phenotype and are often seen with co-existent or antecedent well-differentiated carcinoma. While detailed histomorphologic review is beyond the scope of this protocol, salient features of both tumour types are listed below.

Poorly differentiated thyroid carcinomas (PDTC) Poorly differentiated thyroid carcinomas (PDTC) have a prognosis in between the well differentiated indolent papillary thyroid carcinoma and the often fatal anaplastic carcinoma. According to the most recent WHO classification, poorly differentiated carcinomas are tumours that display a solid, trabecular, and/or insular growth pattern, and show 1 or more of the following: 3 or more mitoses per 10 HPF, tumour necrosis, and nuclear convolution (without other nuclear features seen in papillary carcinoma).17,21 As defined, PDTC is not the only tumour type that has prognostic features intermediate between well- differentiated and undifferentiated (anaplastic) carcinoma.17 Other tumour types, including tall cell papillary carcinoma, can have guarded prognosis. Grading (based on high mitotic count and necrosis as used at Memorial Sloan-Kettering Cancer Center) identifies aggressive thyroid tumours of intermediate prognosis, regardless of their cytoarchitectural features.17,22 Of note, encapsulated poorly differentiated thyroid carcinomas appear to have a more favourable prognosis than unencapsulated tumours, particularly if they show no capsular or vascular invasion with adequate sampling.22,24

Anaplastic (undifferentiated) carcinoma Undifferentiated carcinoma represents the most extreme form of tumour progression and consists of a high-grade malignancy with spindled, pleomorphic, squamoid, or even rhabdoid morphology.91 Undifferentiated carcinoma is almost invariably rapidly lethal. A better differentiated component such as PTC or Hürthle cell carcinoma may be found and its presence should be mentioned.

Appendix 6 AJCC Staging Grouping

Separate stage groupings are recommended for papillary or follicular (differentiated), medullary, and anaplastic (undifferentiated) carcinoma. Differentiated Stage And T is… And N is… And M is… When age at diagnosis is… Stage I Any T Any N M0 <55 years Stage II Any T Any N M1 <55 years 55 YEARS AND OLDER Stage I T1 N0/NX M0 >55 years Stage II T1 N1 M0 >55 years Stage I T2 N0/NX M0 >55 years Stage II T2 N1 M0 >55 years Stage II T3a/T3b Any N M0 >55 years Stage III T4a Any N M0 >55 years Stage IVA T4b Any N M0 >55 years Stage IVB Any T Any N M1 >55 years Anaplastic carcinoma Stage IVA T1-T3a N0/NX M0 Stage IVB T1-T3a N1 M0 Stage IVB T3b Any N M0 Stage IVB T4 Any N M0 Stage IVC Any T Any N M1 Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 8th Edition (2017) published by Springer Science and Business Media LLC, www.springerlink.com.

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