POLYPECTOMY and LOCAL RESECTIONS of the COLORECTUM STRUCTURED REPORTING PROTOCOL (2Nd Edition 2020)

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POLYPECTOMY AND LOCAL RESECTIONS OF THE COLORECTUM STRUCTURED REPORTING PROTOCOL (2nd Edition 2020)

Incorporating the: International Collaboration on Cancer Reporting (ICCR) Colorectal Excisional Biopsy (Polypectomy) Dataset www.ICCR-Cancer.org

Core Document versions:

• ICCR dataset: Colorectal Excisional Biopsy (Polypectomy) 1st edition1 • AJCC Cancer Staging Manual 8th edition2 • World Health Organization (2019) Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System (5th edition).3

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

ISBN: 978-1-76081-426-7

Publications number (SHPN) : (CI) 200283

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:

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

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

o 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.

o 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.

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

o 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: November 2020, 2nd Edition (Version 2.0)

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, but 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 particular circumstances. Users are responsible for evaluating the suitability, accuracy, currency, completeness and fitness for purpose of the protocols.

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Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Contents Scope ...... 6

Abbreviations ...... 7

Definitions ...... 9

Introduction ...... 12

Authority and development ...... 16

1 Pre-analytical ...... 20

2 Specimen handling and macroscopic findings ...... 22

3 Microscopic findings ...... 29

4 Ancillary studies findings ...... 47

5 Synthesis and overview ...... 49

6 Structured checklist ...... 51

7 Formatting of pathology reports ...... 68

Appendix 1 Pathology request information and surgical handling procedures ...... 69

Appendix 2 Guidelines for formatting of a pathology report ...... 76

Appendix 3 Examples of a pathology report ...... 77

Appendix 4 WHO Classification of tumours of the colon and rectum 5th edition ...... 81

Appendix 5 Polyp types ...... 83

Appendix 6 Polyposis syndromes ...... 103

Appendix 7 Colonoscopy surveillance guidelines ...... 107

Appendix 8 Risk of residual disease following malignancy ...... 110

Appendix 9 Practice audits ...... 112

References ...... 114

Scope

This protocol contains standards and guidelines for the preparation of structured reports for local excisions of the colon and rectum. These include polypectomies, endoscopic mucosal resections (EMR), endoscopic submucosal dissections (ESD), endoscopic full thickness resections (EFTR), transanal submucosal excisions, transanal minimally invasive surgery (TAMIS) and transanal endoscopic microsurgery (TEMS) specimens. It is not intended to apply to tumours of the appendix, small bowel and anus. It does not cater for full resection specimens including neuroendocrine carcinomas (NECs) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs), as these specimens are covered by a separate protocol.

Structured reporting aims to improve the completeness and usability of pathology reports for clinicians and improve decision support for cancer treatment. This protocol can be used to define and report the minimum dataset, but the structure is scalable and can equally accommodate a maximum dataset or fully comprehensive report.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Abbreviations

AJCC American Joint Committee on Cancer

CRC Colorectal cancer

EFTR Endoscopic full thickness resections

EMR Endoscopic mucosal resection

ESD Endoscopic submucosal dissection

FAP Familial adenomatous polyposis

GCHP goblet cell hyperplastic polyp

HGD High grade dysplasia

HP Hyperplastic polyp

IBD Inflammatory bowel disease

ICCR International Collaboration on Cancer Reporting

LIS Laboratory information system

LST Lateral spreading tumours

MAP MUTYH-associated polyposis

MCP Malignant colorectal polyp

MiNEN Mixed neuroendocrine-non-neuroendocrine neoplasm

MMR Mismatch repair

MSI Microsatellite instability

MPHP Mucin-poor hyperplastic polyp

MVHP Microvesicular hyperplastic polyp

NEC Neuroendocrine carcinoma

NET Neuroendocrine tumour

NHMRC National Health and Medical Research Council

NOS Not otherwise stated

PJS Peutz Jegher syndrome

PSC Primary sclerosing cholangitis

RCPA Royal College of Pathologists of Australasia

SSL Sessile serrated lesion

SSLD Dysplasia in sessile serrated lesion

TAMIS Transanal minimally invasive surgery

TEMS Transanal endoscopic microsurgery

TNM Tumour-node-metastasis

TSA Traditional serrated adenoma

UICC Union for International Cancer Control

WHO World Health Organization

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 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).

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 the National Health and Medical Research Council (NHMRC) level III-2 evidence.4 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 factor A prognostic factor is a measurement that is associated with 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 evidence4 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 tumour-node-metastasis (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. In this document, standards are prefixed with ‘S’ and numbered consecutively within each chapter (e.g. S1.02).

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Structured report A report format which utilises standard headings, definitions and 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.

Introduction

Colorectal cancer

Colorectal cancer is currently one of the most common cancers diagnosed in Australia and has the second highest incidence of cancer-related deaths after lung cancer.5 Recent advances have been made in the biological understanding of this disease, which have resulted in new surgical, chemotherapeutic and radiotherapeutic strategies.

Colonoscopy is the first-line investigation for assessing the colon and rectum, and has a sensitivity of 95% for detection of colorectal cancer.6 Colonoscopy allows biopsy and histologic confirmation of the diagnosis of cancer as well as identification and immediate removal of synchronous polyps.

Precursor lesions to colorectal carcinoma fall into 2 main types – conventional adenoma (tubular, tubulovillous and villous) and serrated adenomas (sessile serrated lesion and traditional serrated adenoma). Conventional adenoma pathway are the precursor to approximately 70% to 80% of colorectal cancers (CRCs). They are mostly found in the left colon and rectum and approximately 25% of the population develop at least one by age 50 years, and half the population have a conventional adenoma by age 70 years.7 Progression to CRC occurs in a limited number of conventional adenomas; one study estimated a 10% to 15% chance of progression during 10 years for a 10 mm conventional adenoma,8 while another review puts the risk of developing cancer at 3- 5%.9 If progression of a conventional adenoma to CRC occurs it takes approximately 15 years.10 There is good evidence that the endoscopic removal of conventional adenomas decreases the incidence of subsequent CRC.11,12 Serrated lesions are the precursors for approximately 20% to 30% of all CRCs.13-16 Most of these are sessile serrated lesions (SSLs) and are mainly identified in the right colon. The progression risk of SSL to CRC is unknown, however, it is unlikely to be higher than for a similar sized conventional adenoma and the time for progression is approximately 15 years on average.17 The development of dysplasia within these polyps marks a rapid acceleration point in carcinogenesis.16,18-20 Colonoscopic screening programs have been less effective at reducing right-sided CRC, in large part because of the difficulty in appreciating serrated precursors.21

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

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

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 developed22,23 around the world. Both the United Kingdom,24 and United States25 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 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 capture26-29 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 Colorectal excisional biopsy (polypectomy) 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 Colorectal excisional biopsies (polypectomies).

ICCR dataset elements for colorectal excisional biopsy (polypectomy) specimens are included verbatim. ICCR Required elements are mandatory and therefore represented as standards in this document. ICCR Recommended 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:

G3.02 The intraglandular extent should be recorded as a percentage.

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 left, right 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. Key documentation

• Clinical Practice Guidelines for Surveillance Colonoscopy – in adenoma follow-up; following curative resection of colorectal cancer; and for cancer surveillance in inflammatory bowel disease, developed by the Colonoscopy Surveillance Working Party, Cancer Council Australia.30

• Guidelines for Authors of Structured Cancer Pathology Reporting Protocols, Royal College of Pathologists of Australasia, 200931

• The Pathology Request-Test-Report Cycle — Guidelines for Requesters and Pathology Provider28

• World Health Organization Classification of Tumours, Digestive System Tumours. 5th Edition, 20193

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

• AJCC Cancer Staging Manual 8th edition, American Joint Committee on Cancer, 20162

• ICCR dataset: Colorectal excisional biopsy (Polypectomy) dataset 1st edition v1.0

Changes since last edition

Inclusion of ICCR Core and Non-core elements.

Authority and development This section provides information about the process undertaken to develop this protocol.

This 2nd edition of the protocol is an amalgam of three separate processes:

1. This protocol is based on the ICCR dataset – Colorectal excisional biopsy (polypectomy) 1st edition. All ICCR elements from this dataset, both required (mandatory) and recommended (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.

2. 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.

3. This protocol was developed by an expert committee, with assistance from relevant stakeholders.

Authorship – 2nd edition (2020) Dr Ian Brown (Lead author 1st and 2nd editions), Pathologist Prof Priyanthi Kumarasinghe (Gastrointestinal Series Chair), Pathologist A/Prof Christophe Rosty, Pathologist A/Prof David Ellis, Pathologist A/Prof Andrew Ruszkiewicz, Pathologist Dr Julie Lokan, Pathologist Dr Duncan McLeod, Pathologist Dr Nicole Kramer, Pathologist Conjoint Prof Stephen Ackland, Medical Oncologist Dr Spiro Raftopoulos, Gastroenterologist

Authorship – 1st edition Dr Ian Brown, Pathologist (Chair and lead author), Pathologist Conjoint Professor Stephen Ackland, Medical Oncologist Prof Michael Bourke, Gastroenterologist A/Prof Bastiaan deBoer, Pathologist Associate Professor Robert Eckstein, Pathologist Professor Nicholas Hawkins, Pathologist Dr Andrew Hunter, Colorectal Surgeon Dr Andrew Kneebone, Radiation Oncologist

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Clinical Prof Priyanthi Kumarasinghe, Pathologist A/Prof Andrew Ruszkiewicz, Pathologist Dr Mee Ling Yeong, Pathologist

Editorial manager

Christina Selinger, PhD, Royal College of Pathologists of Australasia

Acknowledgements

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

Stakeholders ACT Cancer Registry ACT Health Anatomical Pathology Advisory Committee (APAC) Australasian Gastro-Intestinal Trials Group (AGITG) 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) Colorectal Surgical Society of Australia and New Zealand (CSSANZ) Department of Health, Australian Government Gastroenterological Society of Australia (GESA) 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 New Zealand Committee of Pathologists New Zealand Society of Gastroenterology (NZSG)

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Northern Territory Cancer Registry Public Pathology Australia 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 seven-step process set out in Guidelines for Authors of Structured Cancer Pathology Reporting Protocols.31

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.

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 local resection of the colon 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.32 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 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.

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.’

G1.01 The copy doctors requested on the request form should be recorded.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

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 should 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 surgical excision/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 clinician should be recorded together with the source of that information.

CG1.02a There should be a free text field so that the referring doctor can add anything that is not addressed by the above points, such as previous cancers, risk factors, investigations, treatments and family history.

2 Specimen handling and macroscopic findings

This chapter 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. It is good practice to specify a paraffin block that is ideal for future ancillary testing or research purposes, if possible. 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 Polyp identification label and number per container must be recorded.

CS2.01a Polyp number is an essential component used in bowel screening registries and for surveillance guidelines. Preferably, the endoscopist should submit tissue piece(s) from each polyp resection in a separate container, so that each specimen jar will contain only one polyp sample for histological evaluation.

When multiple polyps or an unknown number of polyps are received in a specimen container, this may preclude accurate assessment of i) the number of polyps received; ii) polyp classification; iii) the number of positive polyps if carcinoma is present in more than one fragment. As polyps are often resected in multiple fragments (piecemeal resection), the number of fragments does not necessarily reflect the number of polyps removed.

In the event that fragments are received from multiple polyps in a specimen container from multiple sites, the ability to

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

accurately record polyp features corresponding to the polyp site of origin may be compromised. This may have impacts for bowel screening registry follow up.

CS2.01b The total number of polyps may be unreliable especially if there are large numbers of polyps submitted and/or numerous fragmented specimens, however an estimate of the total number can be used as an indicator of polyposis syndrome.

CS2.01c The term ‘polyp’ is used throughout this protocol as a generic designation for all lesions presenting as an elevated mucosal abnormality. It is recognised that uncommon neoplastic lesions may be entirely flat or even depressed. Since this protocol is relevant to the designation and reporting of such lesions, the term ‘polyp’ is still used as a generalisation.

S2.02 Clinical information must be recorded.

CS2.02a Clinical information can be provided by the clinician on the endoscopy report or the pathology request form. Pathologists could search for additional information from possible previous pathology reports.

The presence of a known polyposis syndrome, Lynch syndrome, chronic inflammatory bowel disease (IBD) or any other relevant gastrointestinal disorder should be recorded and provided to the pathologist as awareness of such underlying conditions may influence histological interpretation.

The diagnosis of conventional adenoma or advanced serrated polyp in a patient with IBD raises the possibility of IBD- associated dysplasia in the involved segment.

S2.03 The type of endoscopic procedure must be recorded.

CS2.03a The type of endoscopic procedure is important as it may affect histological analysis, including the evaluation of resection margins.

Polypectomy removes polyps using a snare without or with submucosal injection of a solution to lift the lesion (EMR). Diminutive (1-5 millimetres (mm)) polyps and small (6-9 mm) sessile polyps are usually removed by cold snare or sometimes hot snare (mechanical transection without or with electrocautery). Hot snare polypectomy may be used for larger (10-19 mm) sessile polyps and pedunculated polyps. Depending on polyp size and configuration, en bloc or piecemeal removal is performed.33

CS2.03b Cold snare polypectomy is utilised for most sessile polyps, irrespective of size. However, any lesion <10 mm should utilise cold snare technique as standard.34

CS2.03c Endoscopic submucosal dissection (ESD) consists of en bloc resection of superficial lesions of any size after submucosal injection of a solution, using specialised endoscopic knives. It

is more commonly used in the upper gastrointestinal tract and sometimes performed in the large bowel for suspected superficial invasive carcinomas. One of the main advantages of ESD compared with EMR is an accurate evaluation of resection margins.

Transanal endoscopic microsurgery (TEMS) is a minimally invasive surgical procedure for en bloc removal of large rectal lesions and early rectal carcinomas not amenable to colonoscopic resection. For malignant lesions, the muscular layer of the rectum is removed with the specimen.

Transanal minimally invasive surgery (TAMIS) is a crossover procedure between laparoscopic surgery and TEMS for resection of benign and early-stage malignant lesions in the lower and mid rectum. The TAMIS technique can also be used for non-curative intent surgery of more advanced lesions in patients who are not candidates for radical surgery.

Endoscopic full thickness resection (EFTR) is a recent minimally invasive endoscopic technique that can be performed in the large bowel resulting in the full transection of all layers of the bowel. EFTR can be used for the management of challenging epithelial and subepithelial lesions that are not amenable to conventional endoscopic resection methods and previously required a surgical approach.

S2.04 The specimen sites of the polyps submitted must be recorded if provided by the clinician.

CS2.04a Determination of specimen site is based on clinical information provided on the container label, the pathology request form or the endoscopy report. Any discrepancy should be discussed with the endoscopist.

CS2.04b Ideally, when polyps are resected from different sites, they should be placed in separate, clearly labelled containers indicating number of polyps and resection site. If container contains piecemeal resected polyp, this should be clearly stated by the clinician.

CS2.04c To facilitate best practice, it is advantageous for the pathologist to have access to a comprehensive endoscopy report. This may be available online or alternately should accompany the pathology request form.

CS2.04d Particular factors apply to the polyps arising in the right colon versus the left colon, underlying the importance of site of polyp origin to subsequent colorectal carcinoma risk.

There is an increased risk for both metachronous adenomas with high grade dysplasia and colorectal cancer if multiple adenomas are found in the right colon at baseline 35-38 colonoscopy. Increasing age is associated with an increase in the number of adenomas in the right colon.39 Other factors that may be responsible for the increased risk of

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

metachronous lesions include of the finding of sessile polyps (e.g. sessile serrated adenoma/polyps/lesions [SSA/P/L]), more anatomical ‘blind spots’ and more difficulty achieving adequate bowel preparation.

S2.05 For specimens other than TEMS, record if polyps are received intact or fragmented.

CS2.05a Many large sessile polyps are removed by piecemeal EMR.40,41 This can make histological evaluation of the completeness of excision difficult or impossible.

S2.06 For specimens other than TEMS, record the diameter of each intact polyp.

CS2.06a Adenomas are classified based on their diameter.30 Refer CG2.02a for further detail.

CS2.06b The probability of developing future advanced adenomas or cancers increases with the size of adenoma found at index examination, and ranges, depending on the study, from 1.5- 7.7% for adenomas less than 5 mm, through 3-15.9% for adenomas of 5-20 mm, to 7-19.3% for adenomas >20 mm.35,42-47 Size is usually considered a more robust marker of risk than histological characteristics of advanced polyps such as higher grades of villosity or dysplasia, with which it is closely associated.36,42,48

CS2.06c Grossly, measurement of the size can be done from the formalin-fixed specimen, excluding the stalk, if present.

CS2.06d Note that the macroscopic diameter may not correspond to the diameter seen at microscopy due to the finding at microscopy that the lesion represents only a proportion of the specimen, the remainder being a cuff of normal mucosa. The microscopic size is more reflective of lesional risk in this situation.

G2.01 When received in a fragmented fashion or where multiple tissue pieces are placed in a single specimen jar, the diameter of the largest fragment should be recorded.

CG2.01a An aggregate measure of the total tissue submitted in 3 dimensions may be useful for the pathologist.

G2.02 A description of each polyp is recommended.

CG2.02a Polyp size is associated with risk of metachronous polyp and colorectal carcinoma, and is used to determine colonoscopy surveillance intervals. Conventional adenomas <10 mm are considered as low-risk lesions while conventional adenomas ≥10 mm are classified as advanced lesions. Polyps <10 mm in size are further divided into small (6-9 mm) and diminutive (1-5 mm) lesions. The size of conventional adenoma correlates with other advanced histologic features (villosity >25% of the polyp and high- grade dysplasia). Sessile serrated lesions (formerly known as sessile serrated adenoma/polyp) and hyperplastic polyps ≥10 mm are

considered advanced lesions.

Information on endoscopic appearances of polyps should be recorded for endoscopy/histology correlation. This may be helpful to pathologists who may request deeper levels in tissue blocks when the first histologic impression does not match the endoscopic appearance (optical diagnosis).

Superficial and early neoplasms of the gastrointestinal tract can be assessed on the basis of their endoscopic appearance. Various classifications are used.

Using the Paris classification, type 0 neoplastic lesions are classified as polypoid (Ip and Is), non-polypoid (IIa, IIb and IIc), and non-polypoid and excavated (III) (Figure 1).49

Lateral spreading tumours (LSTs) are a subgroup of the type IIa lesions, larger than 10 mm in diameter, and classified into 2 groups: granular and non-granular LSTs.50 Granular LSTs are subclassified into homogenous and nodular mixed types. Non-granular LSTs have a higher malignant potential than the granular LST and are subclassified into flat, elevated and pseudo-depressed types.

For direct optical diagnosis of colorectal lesions, usually both high-definition white light as well as image-enhanced endoscopy, are becoming increasingly used. Various strategies and classifications exist, including the Narrow-band imaging (NBI) International Colorectal Endoscopic (NICE), the Japanese NBI Expert Team (JNET) and the Workgroup serrAted polypS and Polyposis (WASP) classifications.51-53 The endoscopist’s optical diagnosis can be reported as a specific type of the classification used or as histologic category: serrated lesions/polyps (hyperplastic polyp, sessile serrated lesion, sessile serrated adenoma with dysplasia), adenoma, early adenocarcinoma, advanced adenocarcinoma, submucosal lesion, others.

CG2.02b NICE classification:53

1 – serrated/hyperplastic lesion

2 – conventional adenoma

3 – advanced dysplastic lesion/early cancer

S2.07 For all en bloc resections, the dimensions of the specimen must be recorded.

CS2.07a The dimensions of large en bloc resection specimens (large EMR, ESD, TEMS, TAMIS, EFTR) need to be recorded. If possible, a photograph should be taken and recorded. When the specimen contains normal tissue and the polyp is macroscopically clearly visible, the maximum diameter of the polyp (without the stalk if pedunculated) should be given.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

For polyps resected in piecemeal fashion, a measurement of the aggregated tissue fragments with a dimension of the largest piece of tissue can be given to provide some information about the amount of tissue submitted.

Resection specimens of sessile polyps usually include various amounts of normal surrounding colonic mucosa. The dimension of these specimens does not reflect the actual size of the polyp. The microscopic size may be more appropriate for these cases.

Various studies demonstrated some discordance between polyp sizes determined by endoscopy and pathology, with a tendency for larger endoscopy than pathology sizing.54 For all polyps resected in piecemeal fashion, the endoscopic size is used for determining surveillance intervals. For en bloc resection specimens, the pathology size may be more accurate; however, these lesions are often large with little impact of size differences for determining colonoscopy surveillance intervals.

G2.03 For all en bloc resections, a detailed description should be recorded.

CG2.03a The description should include:

o Dimensions of the lesion

o Colour

o Surface contour e.g. villiform, nodular, granular

o Presence of ulceration

CG2.03b Ideally the specimen should be photographed.

S2.08 The nature and sites of all blocks must be recorded.

Figure 1. Schematic representation of the major variants of type 0 neoplastic lesions of the digestive tract: polypoid (Ip and Is), non-polypoid (IIa, IIb, and IIc), non-polypoid and excavated (III). Terminology as proposed in a consensus macroscopic description of superficial neoplastic lesions. Reproduced with permission from Paris workshop participants (2003). The Paris endoscopic classification of superficial neoplastic lesions: oesophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 58(6 Suppl):S3-43.49

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

3 Microscopic findings

Microscopic findings relate to purely histological or morphological assessment. Information derived from more than one type of investigation (e.g. clinical, macroscopic and microscopic findings), are described in Chapter 5.

S3.01 The histological type of polyps must be recorded.

CS3.01a Each polyp should be classified according to the World Health Organization (WHO) Classification of Tumours of the Digestive System 5th edition, 2019.55

Conventional adenomas are divided based on the proportion of villous component: tubular adenoma (villous component <25% of the polyp), villous adenoma (villous component >75% of the polyp) and tubulovillous adenoma for all other cases. Conventional adenomas with a significant villous component (>25%) are advanced lesions. The presence of high grade dysplasia is reported. Conventional adenomas with high grade dysplasia are regarded as advanced lesions in colonoscopy surveillance guidelines. High grade dysplasia is characterised by marked architectural changes visible at low magnification (complex crowding, irregularity of glands, cribriform architecture, intraluminal necrosis), associated with cytological features (loss of cell polarity, enlarged nuclei with prominent nucleoli, often with atypical mitotic figures). Epithelial misplacement of adenomatous glands into the head or stalk of the polyp can be present in usually large pedunculated polyps. This should be recorded as a separate value in addition to the main histological subtype of polyp.

Dysplasia in sessile serrated lesion (SSLD), formerly known as sessile serrated adenoma/polyp, shows greater morphological heterogeneity than conventional adenoma. The dysplasia should not be graded because biologically advanced SSLDs may show mild morphological changes.56

Traditional serrated adenoma is considered as a low-grade dysplastic lesion with different morphology than the usual dysplasia in conventional adenomas. However, superimposed dysplasia can develop as these lesions progress. Only when high grade dysplasia is present, this be should recorded as traditional serrated adenoma (TSA), high grade.

Serrated adenoma unclassified can be used for lesions that are difficult to classify as either TSA or SSLD, not for SSL versus hyperplastic polyp.

Some advanced conventional adenomas or serrated lesions/polyps may demonstrate histological features suspicious but not definite for the diagnosis of adenocarcinoma. This can be due to limited amount of tissue, cautery artefact or cases difficult to distinguish between epithelial misplacement of adenomatous glands and invasive adenocarcinoma. Such cases should be recorded as an additional value ‘Suspicious for adenocarcinoma’. The clinical behaviour of these lesions is not clear. The pathologist should

comment in the report when an invasive carcinoma cannot be excluded but should not complete the elements for adenocarcinoma if the diagnosis of adenocarcinoma is not definite.

Neuroendocrine neoplasms are classified into neuroendocrine tumours (NETs), NECs and MiNENs. NETs are graded 1-3 using the mitotic count and Ki-67 proliferation index (Table 1).55 If the two proliferation indicators suggest different grades, the higher grade is assigned. Most NETs of the gastrointestinal tract are grade 1 or 2.

For adenocarcinoma in a polyp, NEC or MiNEN, refer to additional elements specific to malignant polyps (see S3.01 Histological type).

Other benign polyps (hamartomatous polyps, inflammatory polyps) do not have dysplasia. If superimposed dysplasia is identified in a hamartomatous polyp or if a particular subtype of hamartomatous polyp is identified (e.g., juvenile polyp, Peutz-Jeghers polyp), it should be recorded as an additional feature. Dysplasia arising in an inflammatory polyp raises the possibility of IBD-associated dysplasia.

Various types of mesenchymal polyp can be identified in polypectomy specimens, including perineurioma, Schwann cell hamartoma, schwannoma, neurofibroma, ganglioneuroma, lipoma, granular cell tumour, inflammatory fibroid polyp or gastrointestinal tumour. This should be recorded under the ‘other’ category.

CS3.01b For each location from which specimens have been received and recorded in S2.04, record the type of polyp (refer to Appendix 5) and the number of polyps of that type.

CS3.01c If carcinoma, follow protocol for malignant polyp outlined below from S3.04-G3.04.

S3.02 If present, the grade of dysplasia must be recorded.

CS3.02a This should be recorded as low or high grade which replaces previous terms such as mild, moderate and severe. Most dysplastic lesions will have low grade dysplasia. Features of high grade dysplasia are listed in Appendix 5. High grade dysplasia is an indicator of an advanced polyp, and hence a shorter surveillance interval (Appendix 7). As discussed in CS3.01a, all dysplasia, even when subtle, developing in a SSL represents a biologically advanced lesion and hence should not be graded.

Polypoid dysplastic lesions arising in a setting of inflammatory bowel disease should also be graded as low or high grade.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Figure 2. High grade adenoma example

Figure 3. High grade adenoma example

Figure 4. High grade adenoma example

S3.03 The presence of a significant component of villous architecture must be recorded in conventional adenoma.

CS3.03a The significance of villous architecture in other polyp types e.g. TSA or sessile serrated lesion with dysplasia (SSL/D) is unknown. The presence of villous architecture in such lesions may be recorded, but is not a requisite to guide subsequent follow up.

G3.01 Evidence of polyposis syndrome should be recorded.

CG3.01a The pathologist should be cognisant of the presence of

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

polyposis syndromes (refer to Appendix 6). These include:

• Familial Adenomatous Polyposis (FAP)

• Hyperplastic (serrated ) polyposis syndrome

• MUTYH-associated polyposis (MAP)

• Juvenile polyposis

• Peutz–Jeghers syndrome

• Cowden syndrome (PTEN hamartoma tumour syndrome)

• Hereditary mixed polyposis syndrome

CG3.01b For these syndromes the polyps suggestive of the syndrome can be and often are cumulative over time. The pathologist may need to review previous reports of specimens accessioned from the patient if available.

G3.02 The adequacy of resection of non-malignant polyp should be reported where the polyp is received intact and where the margin of resection is unequivocally seen.

CG3.02a This is typically only able to be done in a small percentage of specimens. Malignant Polyps A malignant colorectal polyp (MCP) is a malignant process developing from an adenoma (conventional or serrated) or less commonly without an identifiable precursor (polypoidal carcinoma) within which the malignant cells have breached the muscularis mucosa and invaded the submucosa (stage pT1). This process provides the potential for spread to regional lymph nodes or distant organs.57 Adenocarcinoma is found in 0.5 to 5.6% of colorectal adenomas (closer to the lower end of this range in large volume practices). There is a higher prevalence of adenocarcinoma in adenomas detected as part of a faecal blood screening program.57-60 MCP’s account for 10% of all the CRC’s detected in these screening programs61 and approximately half of all stage 1 CRCs.60,62,63 The importance of this lesion lies in the clinical decision as to whether a patient should precede to subsequent surgery or whether endoscopic polypectomy alone is sufficient treatment, given that the vast majority of malignant polyps are not associated with residual disease. Histological adverse features including large invasive tumour size, high tumour grade, tumour budding, lymphovascular invasion, greater depth of invasion and resection margin involvement, are associated with increased risk for residual carcinoma and regional or distant spread57,64-68 and are generally considered indications for surgery. While it is generally agreed that in the absence of adverse features, endoscopic resection alone, with adequate margin clearance, is sufficient for disease control and optimal overall patient outcome.

S3.04 The specific tumour type must be recorded.

CS3.04a Colorectal cancers should be typed according to the WHO Classification of Tumours of the Digestive System, 5th edition, 2019.55 This applies only in the setting of a malignant polyp and not of an endoscopic biopsy specimen. If identified, the precursor polyp/lesion from which the adenocarcinoma arose should be recorded. Some endoscopic resection specimens

following a large biopsy or neoadjuvant therapy may only show a scar but no residual tumour.

Most colorectal adenocarcinomas are of no specific type (not otherwise specified (NOS)) but some subtypes of adenocarcinoma are defined as follows:

Mucinous adenocarcinoma classification requires greater than 50% of the tumour to comprise pools of extracellular mucin containing malignant glands or individual tumour cells. Microsatellite instability is present in a higher proportion compared to adenocarcinoma NOS. Tumours with less than 50% mucinous content are described as having a mucinous component.

Signet-ring cell adenocarcinoma classification requires greater than 50% of the tumour to demonstrate single malignant cells with intracytoplasmic mucin, displacing and typically indenting the nuclei, imparting signet-ring cell morphology. Signet-ring cell adenocarcinoma has stage-independent adverse prognostic significance relative to adenocarcinoma NOS.69 There is a strong association with microsatellite instability and with Lynch syndrome.70 Tumours with less than 50% signet- ring cell content are described as having a signet-ring cell component.

Medullary carcinoma is characterised by sheets of malignant cells with indistinct cell boundaries, vesicular nuclei, prominent nucleoli, abundant eosinophilic cytoplasm and prominent intratumoural lymphocytes and neutrophils. These tumours almost invariably demonstrate microsatellite instability and are associated with a good prognosis.71

Serrated adenocarcinoma shares morphological similarities with precursor serrated polyps, demonstrating glandular serrations, which are often slit-like, abundant eosinophilic or clear cytoplasm, minimal necrosis and sometimes areas of mucinous differentiation.72

Micropapillary adenocarcinoma is characterised by small, rounded clusters of tumour cells lying within stromal spaces mimicking vascular channels. At least 5% of the tumour should demonstrate this feature to classify as micropapillary adenocarcinoma. This pattern is most frequently encountered alongside adenocarcinoma NOS. There is a strong association with adverse pathological features including a high risk of lymph node metastatic disease.73

Adenoma-like adenocarcinoma is defined as an invasive adenocarcinoma in which at least 50% of the invasive tumour has an adenoma-like appearance with villous architecture, low grade cytology, a pushing growth pattern and minimal desmoplastic stromal reaction.74 Diagnosis of adenocarcinoma on endoscopic biopsy is exceedingly difficult. This variant is associated with a good prognosis.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Neuroendocrine carcinomas (NECs) show marked cytological atypia, brisk mitotic activity, and are subclassified into small cell and large cell subtypes. NECs are considered high-grade by definition. A Ki-67 proliferation index <55% is associated with better overall survival.75 MiNENs are usually composed of a poorly differentiated NEC component and an adenocarcinoma component. If a pure or mixed NEC is suspected on morphology, immunohistochemistry is required to confirm neuroendocrine differentiation, usually applying synaptophysin and chromogranin A as a minimum.

Other epithelial tumours rarely encountered include adenosquamous carcinoma, carcinoma with sarcomatoid components, undifferentiated carcinoma, squamous cell carcinoma and non-signet-ring cell poorly cohesive adenocarcinoma. Many of these are extremely rare.

If multiple primary tumours are present, separate datasets should be used to record histological tumour type and all following elements for each primary tumour.

CS3.04b The description must be based on the WHO Histological Classification of Tumours of the Colon and Rectum (refer to Appendix 4).55

CS3.04c Virtually all colorectal cancers are adenocarcinomas. The term ‘Adenocarcinoma NOS’ on the reporting checklist is used to indicate conventional adenocarcinoma without any of the special features of the tumour types listed below it.

S3.05 The histological tumour grade must be recorded.

CS3.05a Grading applies only to malignant polyps not to endoscopic biopsy specimens. Despite low level of interobserver agreement,76 histological grade is associated with nodal status and is an independent prognostic factor used in risk assessment models for colorectal carcinoma.77-79

Various grading systems have been used over the years. A two-tiered grading system is more reproducible and more prognostically relevant than a four-tiered grading system. For consistency with the latest WHO classification,55 grading should be based on gland formation: low grade (formerly well to moderately differentiated) and high grade (formerly poorly differentiated). Grading is based on the least differentiated component of the tumour, although there is no good evidence to support this stance and a minimum area of high grade tumour required for this classification has not been defined. Grading may not be applicable if the adenocarcinoma is very small.

Tumour buds most commonly seen at the invasive tumour front, should not be considered in the evaluation of grade. Refer to ICCR dataset for full commentary.

Emerging data suggests that grading based on poorly differentiated clusters is superior to conventional grading with

respect to both prognostic value and reproducibility.80,81

Only adenocarcinoma NOS and mucinous adenocarcinoma should be graded. Grading is not applicable to other subtypes of adenocarcinoma, as grading by gland formation is difficult to apply to subtypes and most of these are associated with their own clinical prognosis e.g., bad for signet-ring cell adenocarcinoma, micropapillary adenocarcinoma, serrated adenocarcinoma and good for medullary carcinoma and adenoma-like adenocarcinoma. Mucinous adenocarcinoma should be graded on gland formation and epithelial maturation.55 Tumour mismatch repair (MMR) status is likely to influence clinical behaviour of some histological tumour types, including mucinous adenocarcinoma, but some studies have found morphological grading superior to MMR status for prognostication of mucinous adenocarcinomas.82,83 A cribriform pattern of invasive adenocarcinoma is associated with greater risk of nodal metastasis in malignant polyps.68

CS3.05b Histological grading of invasive colorectal adenocarcinoma is based on a balance of the different levels of differentiation. The 8th edition American Joint Committee on Cancer (AJCC) staging system provides a classification grading scheme (see Table 2).

Ideally pathologists should designate the differentiation of adenocarcinoma arising in a polyp by at least one grading system descriptor. Because most studies on the prognosis of early carcinomas arising in malignant polyps have used tumour differentiation rather than tumour grade, it is advisable for clarity that a designation of high grade is spelt out as being equivalent to poor differentiation (or rarely, undifferentiated).

S3.06 The presence of any degree of poor differentiation/ undifferentiated tumour must be recorded.

CS3.06a Several studies have specifically examined the relevance of poor differentiation of any extent and have identified this as an adverse prognostic feature associated with an average approximate 10% risk of lymph node or systemic metastasis.

CS3.06b Poor differentiation is often seen at the advancing edge and associated with a prominent desmoplastic stromal reaction. It is identified to variable extent in 6-9% of malignant polyps. In addition to the conventional grading system, the following patterns are indicative of poor differentiation.

1. Signet ring cells

2. Small tumour nests with ≥5 cells (termed ‘poorly differentiated clusters’).84 This pattern forms a continuum with micropapillary carcinoma.

3. Tight cribriform arrangements characterised by small closely associated gland lumina and/or fused

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

chain like arrangements. This pattern is often reminiscent of Gleason pattern 4 prostatic adenocarcinoma.

Tumour budding (invasive groups of <5 cells) does not equate with poor differentiation but represents an independent adverse prognostic feature (see below).

Poor differentiation remains a subjective feature and hence has less interobserver agreement than other features listed below.

G3.03 The presence of any amount of tumour budding should be recorded.

CG3.03a Tumour budding is defined as single cells or clusters of up to 4 tumour cells at the invasive front of invasive carcinomas. It is considered to be the morphological manifestation of epithelial mesenchymal transition.85 Tumour budding is different from tumour grade (based on gland formation) and poorly differentiated clusters (≥5 cells).

There is increasing evidence that tumour budding is an independent adverse prognostic factor in colorectal carcinoma. Several studies have shown that pT1 colorectal carcinomas, including malignant polyps, with tumour budding score Bd2 and Bd3 (≥5 buds) are associated with an increased risk of lymph node metastasis.67,86-89 For stage II colorectal carcinomas, tumour budding score Bd3 is associated with increased risk of recurrence and mortality.90-92

Tumour budding is reported as the number of buds and scored using a three-tiered system. According to the recommendations from a consensus conference on tumour budding,93 the number of tumour buds is the highest count after scanning 10 separate fields (20x objective lens) along the invasive front of the tumour or the entire lesion for malignant polyps (‘hotspot’ approach). The count of tumour buds is only performed in non-mucinous, non-signet-ring cell adenocarcinoma areas. The number of tumour buds is counted on H&E. If the invasive front of the tumour is obscured by inflammatory cells, immunohistochemistry using pan-cytokeratin can be used to help identifying the buds, but the final count is performed on H&E. Depending on the eyepiece field number diameter of the microscope, the number of buds may need to be normalised to represent the number for a field of 0.785 mm2 (objective lens 20x with eyepiece diameter of 20 mm).

Tumour budding should only be reported in non-mucinous and non-signet-ring cell adenocarcinoma areas.94

S3.07 Lymphatic and venous invasion must be reported.

CS3.07a For colorectal cancer, it is important to report the presence or absence of lymphovascular invasion and to classify this further according to the type of vessels involved and, for veins, their intramural or extramural location, as these features may have different clinical and prognostic

implications.

Small vessel invasion should be reported separately from venous (large vessel) invasion. Small vessel invasion is defined as tumour involvement of thin-walled structures lined by endothelium, without an identifiable smooth muscle layer or elastic lamina. Small vessels may represent lymphatics, capillaries or post-capillary venules. Lymphatics and venules may be distinguished by D2-40 immuno-histochemistry, which only stains lymphatic endothelial cells, not venular, but this is not routinely recommended in reporting polypectomy specimens. All forms of small vessel invasion are considered under the ‘L’ classification under Union for International Cancer Control (UICC)/AJCC TNM 8th editions.2,95 Small vessel invasion is associated with lymph node metastatic disease and has been shown to be an independent indicator of adverse outcome in several studies.96-98 A higher prognostic significance of extramural small vessel invasion has been suggested, but the importance of anatomic location in small vessel invasion is not well established.97 In malignant polyps, lymphatic invasion is associated with an increased risk of lymph node metastasis.65,67

Venous invasion is defined as tumour present within an endothelium-lined space that is either surrounded by a rim of muscle or contains red blood cells.99 It should be suspected in the presence of a rounded or elongated deposit of tumour beside an artery. Interpretation of such features is subjective and can be improved by the application of immunohistochemical and histochemical stains, in particular elastic staining to identify venous elastic lamina.100,101 A circumscribed tumour nodule surrounded by a smooth muscle wall or an identifiable elastic lamina, evident on haematoxylin & eosin (H&E) or elastic stains, is considered sufficient to classify as venous invasion. Examination of multiple levels in blocks showing features suspicious of venous invasion can also be helpful in borderline cases.

Extramural (beyond muscularis propria) venous invasion has been demonstrated by multivariate analysis in multiple studies to be a stage independent adverse prognostic factor for colonic and rectal cancer.97,102 However, it would only be identified in TAMIS or EFTR specimens. There is also evidence from several studies that intramural (intramuscular or submucosal) venous spread is also of prognostic importance but the evidence is much weaker than for extramural venous invasion.103

S3.08 Perineural invasion must be reported.

CS3.08a Multiple independent studies and one meta-analysis have demonstrated the adverse prognostic implication of perineural invasion in colorectal cancer, particularly in stage II disease.104,105 One large multicentre study reported adverse prognostic significance of both intramural and extramural

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

perineural invasion.104 However, the importance of anatomic location in perineural invasion is not well established.

In malignant polyps, perineural invasion is extremely rare. It can sometimes be found in endoscopic resection or TEMS/TAMIS for early rectal carcinomas.

S3.09 The margin status must be recorded.

CS3.09a The margin status is an essential component of the histological examination. Assessment of margins can only be done for en bloc polypectomy, ESD, EFTR, TAMIS and TEMS specimens. Margins cannot be reliably assessed for specimens resected in piecemeal fashion.

An involved (positive) deep resection margin is a predictor for adverse outcome.106 However, if no other adverse histological features are present, an involved deep margin is associated with a risk of local recurrence but not lymph node or distant metastasis. Various cut-offs have been used to define an involved deep margin. Most studies have shown that a clearance of <1 mm should be regarded as a positive margin.107,108 Pathologists should report the deep margin as either involved if carcinoma cells are present directly at the margin, or record the clearance distance to nearest 0.1 mm between the deep margin and the closest invasive carcinoma. If the invasive carcinoma is within a diathermy zone, the distance between the outer aspect of the diathermy zone and the closest carcinoma should be reported if possible. In cases for which extensive diathermy artefacts obscure the presence of possible carcinoma at the margin, immunohistochemistry for CDX2 or pancytokeratin may be helpful in this assessment. If measurement is not possible, the margin status should be reported as non-assessable.

Lateral margin is less critical for patient management but needs to be recorded. A positive lateral margin does not influence local recurrence rate.109 The status of the lateral margin should be recorded as either involved or by measuring the distance to nearest 0.1 mm between the closest lateral margin and the neoplasm (dysplasia or carcinoma). If possible, the component of the malignant polyp present at the margin (carcinoma or benign precursor polyp/lesion) should be specified. However, this distinction is not always possible.

CS3.09b Margins cannot be reliably assessed for specimens resected in piecemeal fashion, however, it is good practice to comment on clearance to a deep margin in this situation, particularly if the invasive carcinoma is present in one or a limited number of pieces.

It is recommended to record the distance of invasive carcinoma to the cauterized/deep margin, even in piecemeal resections.

G3.04 Where possible record whether the malignant polyp had a pedunculated or sessile morphology. Pedunculated polyps require the presence of a

stalk.

CG3.04a This may require correlation with the macroscopic and/or endoscopic appearance.

CG3.04b This may be difficult in poorly orientated or fragmented specimens.

CG3.04c In pooled analysis, sessile polyps containing malignancy are associated with an approximately 10 times increased mortality risk over pedunculated polyp with malignancy.110 This appears to be largely related to the increased frequency of a positive polypectomy margin, although increased rate of vascular invasion and other factors may contribute. Because positive margin seems to be the most significant feature, further treatment is not usually warranted in a sessile polyp with malignancy where there is a clear resection margin at polypectomy and no other adverse factors.

S3.10 The extent of invasion must be recorded.

CS3.10a The anatomic extent of tumour invasion, based on a combination of macroscopic and microscopic assessment of an excision specimen, is the most important prognostic factor in colorectal cancer. pT classification indicates the extent of invasion of the primary tumour in the absence of application of neoadjuvant therapy. Criteria of the UICC95 and AJCC2 8th editions are applied, with the exception that pT in situ is not recognised. Rare cases of colorectal neoplasia confined to invasion of the lamina propria (intramucosal carcinoma) are acknowledged but, given the negligible metastatic potential of such neoplasms, including those with a poorly differentiated morphology,111,112 these should be classified under high grade dysplasia/non-invasive neoplasia.

Some rare polyps will remain difficult to classify as either invasive or non-invasive neoplasia, in particular when epithelial misplacement is present. Some adenomas may involve submucosal lymphoglandular complexes, mimicking invasive carcinoma,113 but the distinction with an adenocarcinoma invading the submucosa can be challenging. In other cases, signet-ring cells limited to the mucosa may be identified in an adenoma.114 The clinical behaviour of such lesions is not clear. The pathologist should comment in the report when an invasive carcinoma cannot be excluded or for rare cases with unknown clinical behaviour.

For endoscopic resection of early colorectal carcinoma, tumours are usually invading no deeper than into the submucosa (pT1). For rectal carcinoma removed by TEMS/TAMIS, invasion into the muscularis propria (pT2) or the perirectal fat tissue (pT3) can be present. Further consideration of colorectal carcinoma invading beyond the submucosa is provided in a separate surgical resection

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

dataset.

S3.11 The maximum depth or width of invasive tumour must be recorded.

CS3.11a Depth of invasion is one of the main histological risk factors associated with clinical outcome and used for patient management.115,116 Submucosal invasion ≥1 mm is associated with an increased risk of lymph node metastasis.67,86,117 Depth of invasion is the maximum thickness of invasive carcinoma, measured in mm, from the deepest aspect of the invasive tumour in the submucosa to either the overlying muscularis mucosae or from the Haggitt line (Haggitt level 2; the neck of the polyp) in a pedunculated polyp or the surface of the polyp, if the carcinoma is ulcerated or has overgrown the precursor polyp. This requires well-oriented sections perpendicular to the surface. If the resection is piecemeal, the maximum depth of invasion in any fragment is used.

The maximum width of invasive carcinoma can also be recorded. Tumours with an invasive component ≥4 mm are more likely to be associated with lymph node metastasis.64,68 If the resection is piecemeal, the maximum width of invasion in any fragment is used.

Refer to ICCR dataset for full commentary.

CS3.11b A semi-quantitative evaluation of the depth of invasion into 3 or 4 levels may still be used in some parts of the world as follows:

- Haggitt levels 1 (head), 2 (neck), 3 (stalk) and 4 (beyond stalk) for pedunculated polyps. Level 1,2 and superficial (≤1mm) level 3 invasion is not associated with any risk for lymph node metastases unless there is vascular invasion present. There is a significant increased risk of lymph metastasis for level 3 with invasion ≥3 mm and for level 4 polyps.116,118 This requires intact polyp with well- oriented sections from the head to the base.119,120

- Kikuchi levels sm1 (superficial submucosa), sm2 (mid submucosa) and sm3 (deep submucosa) for sessile polyps, with significant increased risk of nodal metastasis for sm3 polyps.121,122 This requires the presence of the muscularis propria to define the deep boundary of the submucosa, which is often absent in endoscopic resection specimens. The Kikuchi system can be more reliably applied in TEMS, TAMIS and EFTR specimens.

Refer to Figures 5-8.

S3.12 The presence of other relevant coexistent pathological abnormalities in the bowel must be recorded.

CS3.12a The presence and type of chronic inflammatory bowel disease (Crohn disease, ulcerative colitis, primary sclerosing cholangitis (PSC) related colitis) and any other clinically relevant pathology is important information that needs to be

recorded.

CS3.12b In both ulcerative colitis and Crohn disease, patients with more extensive disease and duration of disease >10 years are at increased risk of colorectal cancer.123,124 Ulcerative colitis patients with co-existing primary sclerosing cholangitis are especially at risk of developing colorectal neoplasia.125

The following text may be added to the report to allow clarification of colorectal carcinoma risk:

‘Dysplastic lesions arising in an area affected by inflammatory bowel disease are a heterogeneous group. Many are adenoma–like and are not progressive. Conservative management may be warranted if the following conditions are met: Macroscopically adenoma – like in appearance; excised with clear margins; no flat dysplasia of surrounding mucosa and/or polyp stalk. If these criteria are not met, the lesion should be regarded as having a significant risk for associated or subsequent colorectal carcinoma.’

G3.05 A comment on the likelihood of residual disease post polypectomy may be included.

CG3.05a The pathologist can provide clinical guidance based on published studies and meta-analysis to the likelihood of residual disease post polypectomy. This can be considered as low risk or high risk. Appendix 8 provides a summary of useful prognostic data.

G3.06 Any additional relevant information should be recorded.

CG3.06a There must be a free text field so that the pathologist can add any essential information that is not addressed by the above points.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Figure 5. Levels of invasion of colorectal adenomas.

Adapted from Haggitt RC, Glotzbach RE, Soffer EE and Wruble LD (1985). Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology 89(2):328–336. Reproduced with permission.

Figure 6. Measurement in a sessile polyp

Figure 7. Measurement in a pedunculated polyp

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

0.2-0.3mm

sm1: slight submucosal invasion from the muscularis mucosae.

sm2: intermediate between sm1 and sm 3

sm3: carcinoma invasion near the inner surface of the muscularis propria

Figure 8. Sessile polyps

Table 1. Classification and grading for neuroendocrine neoplasms.

Terminology Differentiation Grade Mitotic count Ki-67 index (mitoses/2 mm2)

NET, grade 1 Low <2 <3% Well NET, grade 2 Intermediate 2-20 3-20% differentiated NET, grade 3 High >20 >20%

NEC, small cell >20 >20% type Poorly High differentiated NEC, large cell >20 >20% type

MiNEN Well or poorly Variable Variable Variable differentiated

Reproduced with permission from Klimstra DS et al (2019). Classification of neuroendocrine neoplasms of the digestive system. In: World Health Organization Classification of Digestive System Tumours. 5th ed. IARC Press, Lyon. © World Health Organization/International Agency for Research on Cancer126

Table 2. AJCC 8th edition tumour grading system2

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

4 Ancillary studies findings

Ancillary studies are being increasingly used to aid diagnosis as prognostic biomarkers or to indicate the likelihood of patient response to specific biologic therapies.

S4.01 Ancillary studies for mismatch repair by immunohistochemistry must be performed on appropriate specimens.

CS4.01a Testing colorectal carcinoma for MMR protein deficiency is standard of care for Lynch syndrome screening and provides therapeutic decision information for patient management.127 MMR deficiency is associated with good prognosis, poor response to 5-Fluorouracil and predicts response to immune checkpoint blockage therapy.128,129

CS4.01b Immunohistochemistry for mismatch repair markers (MLH-1, MSH-2, MSH-6 and PMS-2) can help identify an adenoma as originating in Lynch syndrome.

CS4.01c Approximately 70% of adenomatous polyps in patients with Lynch syndrome demonstrate an absence of immunoreaction for one or four common mismatch repair markers.130 Adenomas in Lynch syndrome are often large, villous, right sided and demonstrate high grade dysplasia.131,132 Adenomas with these features are more likely to demonstrate an immunohistochemical abnormality. The incidental occurrence of sporadic adenomas in patients with Lynch syndrome probably accounts for the approximately 30% of adenomas that exhibit preservation of mismatch repair markers. Hence, the presence of preserved MMR expression/staining does not exclude that a patient has Lynch Syndrome, making routine testing for MMR deficiency in adenomas, of limited clinical use.

The original Bethesda criteria133 recommended investigation for Lynch syndrome in ‘Individuals with adenomas diagnosed at age less than 40’. Currently no universal testing guideline exists and the use of MMR immunohistochemistry in adenomas should be restricted to specific clinical situations.

CS4.01d The identification of Lynch syndrome may affect subsequent treatment decisions.

G4.01 Ancillary studies for microsatellite instability, BRAF (V600E) mutation testing, MLH1 promoter methylation testing, RAS mutation testing should be documented.

CG4.01a BRAF mutation testing and MLH1 promoter methylation analysis are performed to help distinguish sporadic MLH1- deficient colorectal carcinomas from Lynch syndrome associated tumours, caused by constitutional MLH1 mutation. The presence of either BRAF V600E mutation or MLH1 promoter methylation effectively excludes Lynch syndrome. BRAF mutation status may also have predictive/therapeutic value.

CG4.01b Immunohistochemistry for MLH1 can help confirm the presence of dysplasia in a SSLD.

Loss of staining in an area with morphological atypia suggestive of dysplasia confirms SSLD. Loss of expression of MLH1 is seen in approximately 80% of SSLD. Isolated crypts in an otherwise morphologically normal SSL may also show loss of MLH1 expression, however, in the absence of a morphological abnormality, this does not equate with SSLD.

G4.02 Special stains may aid detection of lymphatic and venous invasion in malignant polyps

CG4.02a Lymphatic invasion – use of the lymphatic endothelium marker D2-40 can highlight that a space containing tumour is lined by lymphatic endothelium

Venous invasion – the use of elastic stains such as VVG and Orcein can aid identification of veins containing tumour. A Desmin immunohistochemical stain may highlight smooth muscle in the wall of a compressed vein.

G4.03 Any additional studies for colorectal carcinoma should be performed.

CG4.03a If a pure or mixed neuroendocrine neoplasm is suspected on morphology, immunohistochemistry is required to confirm neuroendocrine differentiation, usually applying synaptophysin and chromogranin A as a minimum. As with other gastrointestinal tract and pancreatic neuroendocrine neoplasms, assessment of proliferation index by Ki-67 immunohistochemistry is fundamental to grading of the neuroendocrine component. A Ki-67 proliferation index <55% is associated with better overall survival in NECs.75

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 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 classes of information – clinical, macroscopic and microscopic. Overarching case comment is synthesis in narrative form. 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.

By definition, synthetic elements are inferential rather than observational, often representing high-level information that is likely to form part of the ‘Diagnostic summary’ section in the final formatted report (see G5.01).

G5.01 The ‘Diagnostic summary’ section of the final formatted report should include:

For carcinoma:

a. Specimen site(s)

b. Polyp type

c. Degree of differentiation

d. Lymphatic and venous invasion

e. Depth of invasion

f. Margin status

For conventional adenoma*:

a. Polyp identification and number

b. Specimen site of polyp

c. Polyp type

d. Diameter

e. Presence or absence of high grade dysplasia

f. Villous component

g. Evidence of polyposis syndrome

h. Adequacy of excision

For sessile serrated lesions/adenoma/polyps:

a. Polyp identification and number

b. Specimen site of polyp

c. Diameter

d. Presence or absence of dysplasia

e. Evidence of polyposis syndrome

f. Adequacy of excision

For hyperplastic polyps:

a. Polyp identification and number

b. Specimen site of polyp

*A table may be advantageous to report on large numbers of polyps.

S5.01 A field for free text or narrative in which the reporting pathologist can give overarching case comment must be provided.

CS5.01a This field may be used, for example, to:

• list any relevant ancillary tests

• document any noteworthy adverse gross and/or histological features

• express any diagnostic subtlety or nuance that is beyond synoptic capture

• document further consultation or results still pending.

CS5.01b 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’.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 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 dataset’ for polypectomies and local resections of the colorectum. 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.134

CG6.01a Where the LIS allows dissociation between data entry and report format, the structured checklist is usually best formatted to follow pathologist 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.

CG6.01c To aide implementation of Level 6 structured reporting (where each reporting element is digitally captured using a discrete data field), some reporting elements may require repeating, such as in the case of synchronous primary tumours. For this scenario, the superscript r is indicated next to the element ID (e.g. S2.05r) to assist with coding of the protocol template.

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.

Values in italics are conditional on previous responses. Values in all caps are headings with sub values. S/G Item description Response type Conditional Pre-analytic S1.01 Demographic information provided S1.02 Clinical information provided Text on request form OR Information not provided OR Structured entry as below: Multi select value list (select all that apply): • Screening colonoscopy • Known polyposis syndrome o Familial adenomatous polyposis (FAP) o MUTYH-associated polyposis (MAP) o Serrated polyposis o Other, specify • Lynch syndrome • Chronic inflammatory bowel disease o Ulcerative colitis o Crohn disease • Previous polyp(s)

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

S/G Item description Response type Conditional • Previous colorectal cancer 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 S2.01r Clinical information Text S2.02r Endoscopic procedure Single selection value list: • Not specified OR Multi select value list(select all that apply): • Polypectomy / Endoscopic mucosal resection (EMR) o Cautery ▪ Not specified ▪ Used ▪ Not used o Submucosal injection ▪ Not specified ▪ Used (EMR) ▪ Not used o Resection type

S/G Item description Response type Conditional ▪ Not specified ▪ En bloc ▪ Piecemeal • Endoscopic submucosal dissection (ESD) • Transanal endoscopic microsurgery (TEMS) • Transanal minimally invasive surgery (TAMIS) • Endoscopic full thickness resection (EFTR) • Other, specify S2.03 Polyp identification Not specified / not assessable Record the polyp label, number of polyps and polyp location for OR each container Label Note: For each specimen submitted record: how the specimen is labelled, the number of polyps/tissue pieces, the polyp site location, polyp conformation and intact polyp diameter. Number per container:___ S2.04r Specimen sites of polyps • Not specified If other, specify the site • Caecum • Ileocaecal valve • Appendiceal orifice • Ascending colon • Hepatic flexure • Transverse colon

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

S/G Item description Response type Conditional • Splenic flexure • Descending colon • Sigmoid colon • Rectosigmoid junction • Rectum • Anorectal junction • Numeric: __mm from anal verge • Other, specify Note: this will be repeated for each specimen noted in S2.01 For large numbers of polyps a table may assist to present this in a clearer format. S2.05r Polyp conformation Single selection value list: • Intact • Fragments Note: this will be repeated for each polyp noted in S2.02 S2.06 Intact polyp diameter Numeric: ___mm Note: this will be repeated for each intact polyp noted in S2.02. G2.01 Diameter of the largest Numeric: ___mm fragment OR Numeric: __x__x__mm aggregate tissue G2.02r Description of polyp (e.g. colour, Text shape, contour, ulceration etc.)

S/G Item description Response type Conditional Note: this will be repeated for each polyp noted in S2.02 Single selection value list: • Not specified • Numeric: ___mm • Size range: __mm to __mm • Size category: o Diminuitive o Small o Large Classification Not given OR Paris Classification Text Lateral spreading tumour Text classification Optical diagnosis Text S2.07 Specimen dimensions Conditional on a TEM being submitted. Maximum dimension of intact Numeric: __x__mm specimen Maximum diameter of intact Numeric: __mm polyp Aggregated dimensions for Numeric: __x__mm

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

S/G Item description Response type Conditional fragmented polyps Maximum dimension of largest Numeric: __mm piece for fragmented polyps G2.03 TEMS SPECIMEN Lesion dimensions Numeric: __x__x__mm Colour Text Surface contour Text Ulceration Single selection value list: • Absent • Present S2.08 Nature and site of blocks Text

Microscopic findings S3.01 Polyp type and number Note: For each location from which If carcinoma, S3.05 – S3.11 specimens have been received and recorded must be recorded, and consider in S2.02, record the type of polyp from the recording G3.03-4. list below and the number of polyps/tissue

pieces of that type.

Single select value list if intact polyps received. Multi select where a location has polyp fragments: • No polyp identified (normal mucosa) • Tubular adenoma • Tubular adenoma, high grade • Tubulovillous adenoma

S/G Item description Response type Conditional • Tubulovillous adenoma, high grade • Villous adenoma • Villous adenoma, high grade • Hyperplastic polyp • Sessile serrated lesion • Sessile serrated lesion with dysplasia • Traditional serrated adenoma • Traditional serrated adenoma, high grade • Serrated adenoma unclassified • Suspicious for adenocarcinoma • Adenocarcinoma* • Neuroendocrine tumour o Grade 1 o Grade 2 o Grade 3 • Neuroendocrine carcinoma o Small cell type o Large cell type • Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) • Hamartomatous polyp • Inflammatory polyp

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

S/G Item description Response type Conditional • Mucosal prolapse polyp • Other, specify Additional features Not applicable For neuroendocrine neoplasms only Mitotic count Numeric:___ / 2 mm2 AND/OR Ki-67 proliferation index Numeric:___ % S3.02 Dysplasia Single selection value list: If present, record the grade of dysplasia. Note: If sessile • Cannot be assessed serrated adenoma with dysplasia • Absent (SSLD) selected in S3.01, S3.02 is not required. • Present Note: this should be recorded for each polyp or fragments per location recorded in S3.01. Grade of dysplasia Single selection value list: Conditional on the presence of dysplasia • Low grade • High grade • Not specified Note: this should be recorded for each polyp recorded in S3.01. If fragments received, the highest grade of dysplasia should be recorded. S3.03 Significant villous Single selection value list: Conditional on conventional architecture adenoma being selected in S3.01 • Absent • Present Note: this should be recorded for each

S/G Item description Response type Conditional conventional adenoma recorded in S3.01. G3.01 Evidence of polyposis syndrome Single selection value list: If present provide details • Absent • Present Details Text G3.02 Polyp resection (non-malignant) Single selection value list: • Adequate • Inadequate S3.04 Tumour type Single selection value list: • Not applicable • No evidence of residual tumour • Adenocarcinoma not otherwise specified (NOS) • Mucinous adenocarcinoma • Signet ring cell carcinoma • Medullary carcinoma • Serrated adenocarcinoma • Micropapillary adenocarcinoma • Adenoma-like adenocarcinoma • Neuroendocrine carcinoma o Small cell type o Large cell type

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

S/G Item description Response type Conditional • Mixed neuroendocrine-non-neuroendocrine • Other, specify Note: this should be recorded for each polyp classified as malignant in S3.01 Precursor polyp/lesion Single selection value list: • Absent • Present, specify type# Note: Refer to S3.01 Type of polyp. S3.05 Histological tumour grade Single selection value list: Only adenocarcinoma NOS and mucinous adenocarcinoma • Not applicable should be graded • Low grade (formerly well to moderately differentiated) • High grade (formerly poorly differentiated) Note: this should be recorded for each polyp classified as malignant in S3.01 S3.06 Poor differentiation Single selection value list: (undifferentiated) tumour • Absent • Present Note: this should be recorded for each polyp classified as malignant in S3.01 G3.03 Tumour budding Cannot be assessed If present, consider recording the number of foci OR Number of tumour buds*: ___ *Note: After scanning 10 fields on a 20x objective lens, the hotspot field normalised to

S/G Item description Response type Conditional represent a field of 0.785 mm2. Tumour budding score Single selection value list: • Bd1 – low budding (0-4 buds) • Bd2 – intermediate budding (5-9 buds) • Bd3 – high budding (>10 buds) Note: this should be recorded for each polyp classified as malignant in S3.01 S3.07 Lymphatic and venous Single selection value list: invasion • Not identified • Present o Small vessel (lymphatic, capillary or venular) o Large vessel (venous) o Intramural o Extramural Note: this should be recorded for each polyp classified as malignant in S3.01 S3.08 Perineural invasion Single selection value list: • Not identified • Present Note: this should be recorded for each polyp classified as malignant in S3.01 S3.09r Margin status Note: this should be recorded for each polyp If involved, record the involved

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

S/G Item description Response type Conditional classified as malignant in S3.01 margin(s)

If not involved, record the clearance from deep margin and clearance from nearest peripheral margin Deep margin Single selection value list: • Cannot be assessed • Involved • Not involved, specify distance to invasive carcinoma Distance to invasive Numeric: ___mm carcinoma Lateral margin Single selection value list: • Cannot be assessed • Involved, specify • Not involved, specify distance to neoplasia Involved margin(s) Text Distance to neoplasia Numeric: ___mm G3.04 Morphology Single selection value list: • Pedunculated • Sessile • Indeterminate Note: this should be recorded for each polyp

S/G Item description Response type Conditional classified as malignant in S3.01 S3.10 Extent of invasion Single selection value list: • Non-invasive neoplasia/high grade dysplasia • Invasion into submucosa • Invasion into muscularis propria • Invasion through the muscularis propria into pericolorectal connective tissue • Invasion into the surface of the visceral peritoneum • Invasion into the adjacent structure(s)/organ(s), specify S3.11 Invasive carcinoma Cannot be assessed dimensions OR Maximum depth of invasion: ___ mm Cannot be assessed OR Maximum width of invasion: ___ mm S3.12r Coexistent abnormalities Multi select value list (select all that apply): If ‘Other’ is selected, provide details. • None noted If Ulcerative colitis, Crohn • Ulcerative colitis disease, Primary sclerosing • Crohn disease cholangitis (PSC) or Inflammatory bowel disease, not • Primary sclerosing cholangitis (PSC) otherwise specified is selected • Inflammatory bowel disease, not otherwise the following text may be added

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

S/G Item description Response type Conditional specified to allow clarification of colorectal carcinoma risk • Other, specify ‘Dysplastic lesions arising in an area affected by inflammatory bowel disease are a heterogeneous group. Many are adenoma – like, and are not progressive. Conservative management may be warranted if the following conditions are met: Macroscopically adenoma – like in appearance; excised with clear margins; no flat dysplasia of surrounding mucosa and/or polyp stalk. If these criteria are not met, the lesion should be regarded as having a significant risk for associated or subsequent colorectal carcinoma.’ G3.05 Comment on risk for residual Text disease G3.06 Additional microscopic comment Text Ancillary test findings S4.01 Mismatch repair (MMR) Single selection value list: status by • Not tested immunohistochemistry • Not interpretable • MMR proficient • MMR deficient o MLH1/PMS2 loss o MSH2/MSH6 loss

S/G Item description Response type Conditional o MSH6 loss o PMS2 loss o Other, specify Note: Mismatch repair enzyme immunohistochemistry results may be recorded for each malignant polyp recorded in S3.01. Mismatch repair (MMR) status Single selection value list: by microsatellite instability • Not tested (MSI) testing • Test failed • MSI-high • MSI-low • MS-stable G4.01 Additional ancillary studies BRAF (V600E) mutation testing Single selection value list: • Not tested • Test failed • Mutated • Wild type MLH1 promoter methylation Single selection value list: testing • Not tested • Test failed • Methylated

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

S/G Item description Response type Conditional • Not methylated • Inconclusive RAS mutation testing Single selection value list: • Not tested • Test failed • Mutated, specify • Wild type G4.02 Special stains Text G4.03 For neuroendocrine neoplasm Single selection value list: For neuroendocrine neoplasms neuroendocrine markers only Not applicable Neuroendocrine markers Text Ki-67 proliferation index Numeric: ___ % Other Text Synthesis and overview G5.01 Diagnostic summary Text S5.01 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.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Appendix 1 Pathology request information and surgical handling procedures

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 local resections of the colon 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. Patient information

➢ Adequate demographic and request information must be provided with the specimen.

• Items relevant to cancer reporting protocols include:

• patient name

• date of birth

• sex

• identification and contact details of requesting doctor

• date of request

• The patient’s ethnicity should be recorded, if known. In particular whether the patient is of aboriginal or Torres Strait islander origin. This is in support of a government initiative to monitor the health of indigenous Australians 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 Medicare number (Australia), Individual Healthcare Identifier (IHI) (Australia) or the National Healthcare Index (New Zealand). Clinical Information

The presence of a known polyposis syndrome, Lynch syndrome, chronic inflammatory bowel disease or any other relevant gastrointestinal disorder should be recorded.

• Clinical information can be provided by the clinician on the endoscopy report or the pathology request form. Pathologists could search for additional information from possible previous

pathology reports.

• The presence of a known polyposis syndrome, Lynch syndrome, chronic IBD or any other relevant gastrointestinal disorder should be recorded and provided to the pathologist as awareness of such underlying conditions may influence histological interpretation.

• The diagnosis of conventional adenoma or advanced serrated polyp in a patient with IBD raises the possibility of IBD-associated dysplasia in the involved segment.

➢ The proceduralist’s identity and contact details should be recorded.

• Name of operating surgeon, contact details, and date of operation.

➢ The number of specimens submitted should be recorded.

The endoscopic tumour morphology should be recorded in accordance with the Paris Classification of superficial neoplastic lesions.135

This information is attained at time of colonoscopy by the requesting clinician.

Select all that apply:

• Polypoid

o 0-Ip (protruded, pedunculated)

o 0-Is (protruded, sessile; >2.5 mm above baseline)

• Non-Polypoid

o 0-IIa (superficial, elevated; <2.5 mm above baseline)

o 0-IIb (flat)

o 0-IIc (superficial shallow, depressed)

o 0-III (excavated/ulcerated)

Refer to Figures 1 and 7.

The Paris classification provides a means of distinguishing sessile polypoid lesions (Type 0-Is, protruding above 2.5 mm) from the non-polypoid ones (Type 0-IIa protruding below 2.5 mm), the distinction being crucial given the highly significant differences in cancer rates between non-polypoid and sessile polypoid (adenomatous and serrated) lesions.136

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Figure 9. Neoplastic lesions with ‘superficial’ morphology

Terminology as proposed in a consensus macroscopic description of superficial neoplastic lesions. Reproduced with permission from Paris workshop participants (2003). The Paris endoscopic classification of superficial neoplastic lesions: oesophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 58(6 Suppl):S3-43.49

➢ The location in the large bowel from which each specimen has been taken should be recorded.

• Choose from one of the following:

• Not specified

• Caecum

• Ileocaecal valve

• Appendiceal orifice

• Ascending colon

• Hepatic flexure

• Transverse colon

• Splenic flexure

• Descending colon

• Sigmoid colon

• Rectosigmoid junction

• Rectum

• Anorectal junction

• Numeric: __mm from anal verge

• Other, specify

➢ The diameter of each resected polyp should be recorded.

• The diameter may be measured either in situ or after retrieval.

➢ The presence of multiple unexcised polyps should be recorded.

• In some cases polyps are too numerous to excise all lesions, and only a sample is taken. The presence of numerous polyps is considered high risk for future high grade adenomas and may be indicative of FAP.30

➢ The reason for the procedure should be provided.

• Options include:

• Initial screening colonoscopy (baseline or index procedure)

• Surveillance – no previous history of adenoma or malignancy

• Surveillance – high risk e.g. FAP, other polyposis syndromes,

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Lynch syndrome

• Surveillance – previous adenoma/high grade dysplasia (HGD)/malignant polyps

• Positive faecal occult blood test (FOBT)

• Other, specify

• If the reason for the procedure is surveillance following previous findings of adenoma or malignancy, the date and results of that previous encounter should be provided.

➢ Any relevant patient or family history should be provided.

• Of particular relevance is a family history of colorectal cancer; FAP or other polyposis syndromes; Lynch syndrome, ulcerative colitis, inflammatory bowel disease or Crohn disease.

➢ Any previous colorectal surgery should be detailed.

• Details regarding when the previous procedure has occurred and relevant results will be important.

➢ Any other relevant issues noted during the procedure.

• Information such as the presence of inflammatory conditions; dysplasia etc. is of importance to the pathologist.

Example Request Information Sheet

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

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

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.137 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.137 • Reduce ‘clutter’ to a minimum.137 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.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Appendix 3 Examples of a pathology report

Adenoma polyp – example report

Malignant polyp – example report

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Multiple polyp – example report

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Appendix 4 WHO Classification of tumours of the colon and rectum 5th edition

Benign epithelial tumours and precursors

8213/0* Serrated dysplasia, low grade 8213/2* Serrated dysplasia, high grade Hyperplastic polyp, microvesicular type Hyperplastic polyp, goblet cell 8210/0* Adenomatous polyp, low-grade dysplasia 8210/2* Adenomatous polyp, high-grade dysplasia 8211/0* Tubular adenoma, low grade 8211/2* Tubular adenoma, high grade 8261/0* Villous adenoma, low grade 8261/2* Villous adenoma, high grade 8263/0* Tubulovillous adenoma, low grade 8263/2* Tubulovillous adenoma, high grade Advanced adenoma 8148/0 Glandular intraepithelial neoplasia, low grade 8148/2 Glandular intraepithelial neoplasia, high grade

Malignant epithelial tumours

8140/3 Adenocarcinoma NOS 8213/3 Serrated adenocarcinoma 8262/3* Adenoma-like adenocarcinoma 8265/3 Micropapillary adenocarcinoma 8480/3 Mucinous adenocarcinoma 8490/3 Poorly cohesive carcinoma 8490/3 Signet-ring cell carcinoma 8510/3 Medullary adenocarcinoma 8560/3 Adenosquamous carcinoma 8020/3 Carcinoma, undifferentiated, NOS 8033/3* Carcinoma with sarcomatoid component 8240/3 Neuroendocrine tumour NOS 8240/3 Neuroendocrine tumour, grade 1 8249/3 Neuroendocrine tumour, grade 2

8249/3 Neuroendocrine tumour, grade 3 8152/3 L-cell tumour 8152/3 Glucagon-like peptide-producing tumour 8152/3 PP/PYY-producing tumour 8241/3 Enterochromaffin-cell carcinoid 8241/3 Serotonin-producing tumour 8246/3 Neuroendocrine carcinoma NOS 8013/3 Large cell neuroendocrine carcinoma 8041/3 Small cell neuroendocrine carcinoma 8154/3 Mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN)

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2).138 Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries.

This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

* Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD- O at its meeting in April 2019.

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Appendix 5 Polyp types

Polyps are classified as:

• No polyp identified (normal mucosa) • Tubular adenoma • Tubular adenoma, high grade • Tubulovillous adenoma • Tubulovillous adenoma, high grade • Villous adenoma • Villous adenoma, high grade • Hyperplastic polyp • Sessile serrated lesion • Sessile serrated lesion with dysplasia • Traditional serrated adenoma • Traditional serrated adenoma, high grade • Serrated adenoma unclassified • Suspicious for adenocarcinoma • Adenocarcinoma* • Neuroendocrine tumour o Grade 1 o Grade 2 o Grade 3 • Neuroendocrine carcinoma o Small cell type o Large cell type • Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) • Hamartomatous polyp • Inflammatory polyp • Mucosal prolapse polyp • Other, specify

CONVENTIONAL ADENOMA

Conventional adenomas are neoplastic lesions characterised by the presence of dysplasia. Most are polypoid, but they may be flat or even depressed.

Dysplasia is evidenced by nuclear enlargement, hyperchromasia, stratification and loss of polarity. Increased mitotic activity and apoptosis are easily appreciated. All adenomas are regarded as having malignant potential. ‘Advanced adenoma’ is a term used for lesions at much higher risk for malignant progression. Advanced adenoma is characterised by one or

more of the following: 1) size >10mm, 2) villous architecture and 3) high grade dysplasia. Increased number of adenomas is also associated with an increased risk for colorectal adenocarcinoma.

1) Number

The number of individual adenomas identified at the baseline colonoscopy correlates with an increased likelihood of finding an advanced adenoma at that time or in subsequent colonoscopies.36,37,139,140 Analysis of pooled data from several prospective studies indicates that risk for metachronous advanced adenomas increased with the number of adenomas at base line and was 8.6% (1 adenoma), 12.7% (2 adenomas), 15.2% (3 adenomas), 19.6% (4 adenomas) and 24.1% (5 adenomas).36 In another study the risk of developing colorectal cancer/advanced adenoma was double in patients with ≥3 adenomas (0.8-1.1%) than with ≤3 adenomas (0.5%) at baseline colonoscopy.141

Current NHMRC guidelines (2011) recommend follow up colonoscopy 12 months after the identification of ≥5 adenomas and sooner in patients with ≥10 adenomas. If the number of polyps found at baseline colonoscopy is ≥10, then FAP or MAP may be the cause.41,142-144 Pathologists should highlight this in the report (See S3.03).

From the above it can be concluded that two objective criteria namely adenoma size and adenoma number, are strong predictive factors for a subsequent finding of advanced adenoma or colorectal carcinoma, and in multivariate analyses are typically more important than degree of villous architecture or dysplasia.17

Adenoma size ≥20 mm and/or ≥4 adenomas, identified at baseline colonoscopy, are associated with a 20% risk of finding either advanced adenoma or colorectal carcinoma on subsequent colonoscopy.

2) Villous architecture

While a strict universal definition of what defines a villous structure is lacking,145 most studies have identified villosity as a risk factor for metachronous advanced adenoma and colorectal carcinoma. Villous pattern has been defined as fronds covered by neoplastic cells. These may appear to be floating free on tangential section or to be connected to the main body of the polyp by a narrow stalk.146

Some studies have identified villosity as an independent risk factor, while in other studies it correlates with adenoma size which is easier to measure, and less prone to inter-observer variation amongst pathologists.35,36,42-48,147-155

Adenomas with a villous component have more malignant potential and are usually larger than the more common tubular adenomas. The 2019 WHO defines tubular adenomas as having <25% villous component, tubulovillous as 25-75% and villous as >75% villous component.55

3) Degree of dysplasia

Dysplasia is an unequivocal neoplastic transformation in the epithelium. In conventional adenoma it is characterised by evidence of epithelial proliferation - multilayering, variable gland complexity and increased mitotic and apoptotic activity. Epithelial cells display nuclear hyperchromasia and nuclear enlargement.

Dysplasia is classified on the basis of its severity. A progression from low grade to high grade has been demonstrated in some (but not all cases) before malignancy develops.156,136

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At present, the degree of dysplasia is not reported for serrated pattern lesions as any degree of unequivocal cytological dysplasia is regarded as evidence of an advanced lesion.

Reparative changes in the superficial aspect of polyps due to trauma or erosion may mimic HGD and could be over interpreted as such.136 Pathologists should take this into account if there is evidence of erosion, torsion or other trauma in the adenoma.

Although not verified in all multivariate studies, HGD in adenomas at index colonoscopy increases the risk for advanced metachronous adenomas.36

High grade dysplasia (HGD) is diagnosed when architectural and/or cytological abnormality is marked. Only one or two glands with HGD that are identifiable at low power examination are needed to classify an adenoma as high grade. Significant interobserver variability in the diagnosis of HGD has been reported.145 Gland architectural abnormality is more easily identified and has more importance to the diagnosis of HGD. The following are features diagnostic of HGD:

1. Architecture

Glandular complexity typified by:

o Crowding and irregularity o Prominent glandular budding o Cribriform pattern with ‘back to back’ glands o Prominent intraluminal papillary tufting 2. Cytology

o Loss of cell polarity o Nuclear stratification - at least 2–5 nuclear rows o variable number of rows within individual glands o The nuclei are haphazardly distributed within all three thirds of the height of the epithelium o No maturation towards the luminal surface o Abnormal goblet cell forms (retronuclear/dystrophic goblet cells) o Nuclei - vesicular , enlarged, irregular thickened nuclear membranes, prominent nucleolus, loss of polarity, atypical mitotic figures o Prominent apoptosis o Focal cell debris and necrosis - ‘dirty necrosis pattern’ Usually more than one of the above features is present in an adenoma with HGD.

3. Size

The probability of developing future advanced adenomas or cancers increases with the size of adenoma found at index examination, and ranges, depending on the study, from 1.5- 7.7% for adenomas less than 5 mm, 3-15.9% for adenomas of 5-20 mm and 7-19.3% for adenomas >20 mm.35,36,42-45,48 As an objective feature, size is a more robust marker of risk than histological characteristics (i.e. higher grades of villosity and dysplasia) which are subjective.36,42,48

Neoplastic invasion into the submucosa through the muscularis mucosae into submucosa is diagnostic of invasive adenocarcinoma (pT1).136

Rarely polyps are encountered that are completely excised and contain invasive adenocarcinoma in the lamina propria with or without extension into but not completely through the muscularis mucosae. Some pathologists may prefer the technically correct term ‘intramucosal carcinoma’ for this abnormality. This abnormality may be associated with submucosal invasion in deeper levels. If submucosal invasion is not identified then this lesion has negligible risk for metastatic spread (presumably, because of the absence of communicating lymphatics in the colorectal lamina propria).The term ‘high grade dysplasia’ is therefore adequate and recommended. Caution may be warranted in the setting of intramucosal carcinoma with poor differentiation since metastatic spread has been reported.157

Figure 10. High grade adenoma example

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Figure 11. High grade adenoma example

Figure 12. High grade adenoma example

HYPERPLASTIC POLYP

Hyperplastic polyps (HP) account for 25-30% of resected polyps in most series.158-162 and have an estimated prevalence of 10-20% in Western populations. These lesions frequently harbour BRAF or KRAS mutations, supporting a neoplastic nature.

Three HP subtypes are recognised 1) microvesicular hyperplastic polyp (MVHP); 2) goblet cell hyperplastic polyp (GCHP) and 3) mucin-poor hyperplastic polyp (MPHP). MVHPs and GCHPs are the most common.163 This subdivision remains only of theoretical interest at this time and its use in routine reporting is not required.

Microvesicular hyperplastic polyps are characterised by a serrated gland profile and an ordered ‘test-tube’ arrangement of the crypts which taper toward the muscularis mucosae.164 Microvesicular mucin droplets impart a faint basophilic quality to the

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cytoplasm. Superficial goblet cells are usually found.163 The subepithelial basement membrane and muscularis mucosae are thicker than in the adjacent normal mucosa.163,165

Figure 13. Typical appearance of microvesicular hyperplastic polyp

Goblet cell hyperplastic polyps display crowded crypts163 containing an increased number of mature goblet cells.163 Serration is often minimal or limited to the upper third of the crypt, but tufting of the epithelial surface is frequent. Thickening of the basement membrane and muscularis mucosae is minimal.

Mucin poor hyperplastic polyp is poorly categorised potential sub-group which has been dropped as a subcategory from the 5th edition of the WHO.

Hyperplastic polyps of all types are currently regarded as innocuous lesions with no significant malignant potential and therefore no requirement for follow up.

SERRATED ADENOMA/POLYP/LESION

Classification schema for these polyps are still evolving and histological interpretation of these serrated polyp types differs between pathologists.47,166,167

The 2019 WHO classification scheme divides this group into sessile serrated lesion (SSL) (also known as sessile serrated adenoma and sessile serrated polyp) and traditional serrated adenoma (TSA).

The majority of studies suggest that both TSA and SSL have malignant potential and are associated with subsequent development of metachronous neoplasia.152-155,166,168 There is variability and uncertainty as to the extent of the risk.169-172 It has been estimated that 1 in 25 SSLs progress to malignancy,40 a rate approximately equivalent to that of a conventional adenoma.

A retrospective follow-up study of patients with SSLs found all but one patient had further polyps/tumours (including one CRC). This supports surveillance colonoscopies in patients with SSL.173

1) SSL

The emergence of SSL as an entity distinct from HP is based on 1) epidemiologic evidence of CRC risk and 2) morphologic and 3) biological differences.174,175 When examined carefully, SSL has a prevalence of 9% of resected polyps. 75% occur on the right colon and polyp size is variable - 36% ≤5mm, 47% 6-10 mm and 17% ≥11 mm.

The lesions are sessile and often coated by thick mucus making them difficult to appreciate at colonoscopy.

At low power the typical features of SSL reflect asymmetric proliferation. Most characteristic are the dilated crypts as well as crypts with basal horizontal growth of crypts in L or inverted T shapes along the muscularis mucosae.165,176 The 2019 WHO recommends one such crypt is adequate for diagnosis.177 Crypts are irregularly spaced and may display branching.163,165,178 Crypt serration extends into the crypt base. Increased intraluminal mucin is common and displaced crypts can be seen herniating into the submucosa.179 At higher power, disturbance to proliferation and maturation is evident,163,165 with asymmetric proliferative zones178 and maturation towards both the luminal and basal aspects of the crypts. This means that mature goblet cells extend toward both the luminal and basal aspects of the crypt.179 Dystrophic goblet cells may be prominent. A minor degree of nuclear atypia characterised by nuclear enlargement (with small nucleoli) is allowable, particularly in the crypt bases.163 SSL’s (and also HPs) may be associated with a perineural proliferation in the stroma (previously known as ‘fibroblastic polyp’). SSLs may also be associated with a submucosal lipomatous proliferation and with inversion into the submucosa that should not be mistaken for invasion.

Figure 14. Typical appearance of sessile serrated lesion

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Figure 15. SSL with associated perineural cell proliferation

Figure 16. SSL with subjacent lipomatous proliferation

The natural history of SSLs remains to be defined.180 A 2017 study has found a lead time of approximately 15 years based on differenced in the median age of patients with SSL and MLH-1 deficient CRC.17

2) Traditional serrated adenoma

163 Named by Torlakovic et al in 2003 , TSAs account for around 1% of colorectal polyps (range 0.6-1.9%).160,162,181 They occur throughout the large bowel but have a predilection for the distal colon and rectum. Right sided lesions may arise from a sessile serrated lesion and have BRAF mutation. Left sided lesions have a KRAS mutation and are occasionally seen to arise in continuity with a goblet cell rich hyperplastic polyp.

The histopathological features of TSAs are characteristic resulting in high diagnostic reproducibility.178 They usually display tubulovillous architecture, eosinophilic tall columnar epithelium with prominent serration and ectopic crypt foci. The epithelial cells are most characteristic with abundant pink cytoplasm and centrally located palisaded, pencillate nuclei with dispersed chromatin.178,181 TSA may present as a flat lesion, especially in the distal rectum. True dysplasia is characterised by similar features to those described for high grade dysplasia in a conventional adenoma. Development of dysplasia in a TSA represents an advanced neoplastic progression. Dysplasia arising in a TSA is characterised by loss of cytoplasmic eosinophilia and nuclear and architectural changes that are equivalent to high grade dysplasia in conventional adenomas. This should be separated from lesions that show combination features of low grade conventional adenoma and TSA. These lesions should be considered as conventional adenoma if ≤50% of the lesion is of conventional pattern and TSA if >50% of the lesion has a TSA pattern. The follow up implications are usually the same regardless. These combined lesions are sometimes identified in the distal rectum and appear to have a higher recurrence risk because the margins are often ill defined.

Figure 17. Typical appearance of traditional serrated adenoma

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Figure 18. Traditional serrated adenoma arising from a background of hyperplastic polyp.

Filiform serrated adenoma182,183 reportedly accounts for 4% of TSAs, occurs distally and is characterised by very long (filiform) villi and marked lamina propria oedema.

Figure 19. Filiform traditional serrated adenoma

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Figure 20. Traditional serrated adenoma with high grade dysplasia

Figure 21. Traditional serrated adenoma with high grade dysplasia

Figure 22. Traditional serrated adenoma with high grade dysplasia – cytological atypia

3) Sessile serrated lesion with dysplasia (SSLD)

Dysplastic sessile serrated adenoma represents most of what in past was termed ‘mixed hyperplastic polyp/adenomatous polyps’. The development of dysplasia in SSL is believed to herald a more aggressive lesion with possible risk of rapid progression to CRC. This is suggested by the similar median age of patients with SSLD and MLH-1 deficient CRC.17

In a large population based study, 13.2% of SSLs showed dysplasia, accounting for 0.17% of all colorectal polyps.184

Two types of dysplasia are described in the 5th edition WHO:185,186

1) ‘conventional adenomatous dysplasia’ - similar to that of conventional adenomatous polyps with increased nuclear hyperchromasia, stratification and variable loss of polarity, increased mitoses and basophilic cytoplasm. The changes extend to the polyp surface; Caution is warranted in poorly oriented sections where there is risk of over-interpretation of the proliferative zone as dysplastic. This pattern can rarely be mimicked by a collision lesion comprising a SSL and a conventional adenoma.187 This should always be considered if MLH1 staining is retained in the dysplastic area.

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Figure 23. Sessile serrated lesion with dysplasia – conventional adenomatous pattern.

2) ‘serrated dysplasia’ in which the glands frequently retain serration, the cells have ample eosinophilic cytoplasm and the nuclei are vesicular and basally located.

Figure 24. Sessile serrated lesion with development of serrated pattern dysplasia.

Sometimes dysplasia arising in a SSL may be subtle, with only mild cytoarchitectural change. The term ‘minimal deviation’ has been applied to this pattern.56 Loss of expression of MLH1 in the abnormal area confirms the diagnosis.

Figure 25. MLH1 loss in SSL with dysplasia. The lower lesion displays a minimal deviation pattern in the left hand side of the lesion.

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Development of dysplasia in a SSL is a marker of particularly high risk for invasive carcinoma and pathologists should indicate this in their reports. While the mean age of patients with SSL is approximately 20 years younger than the mean age of patients with sporadic MLH1 deficient colorectal carcinoma, the means age of SSLD is identical, indicating that a rapid pathway to colorectal carcinogenesis may proceed once dysplasia develops.17

MLH-1 is lost in dysplastic foci of SSLD in approximately 80% of cases and can be a useful adjunct investigation to confirm this high grade lesion.

A local study of SSLD identified four major morphological patterns of dysplasia; minimal deviation (19%), serrated (12%), adenomatous (8%) and not otherwise specified (79%) respectively. Minimal deviation dysplasia has only minor architectural and cytological changes that usually requires loss of MLH1 immunohistochemical expression to support the diagnosis. Serrated dysplasia and adenomatous dysplasia have distinctive histological features and are less frequently associated with loss of MLH1 expression (13% and 5%, respectively). Dysplasia not otherwise specified encompasses most cases and shows a diverse range of morphological changes that do not fall into the other subgroups and are frequently associated with loss of MLH1 expression (83%).56

MALIGNANT POLYP (see Appendix 8)

EPITHELIAL MISPLACEMENT (PSEUDOINVASION)

Epithelial misplacement is seen in 2-10% of pedunculated polyps. There is predilection for the left colon (sigmoid), presumably due to increased intraluminal forces leading to polyp torsion. As dysplastic epithelium is displaced into the submucosa, the pattern may be misinterpreted as invasive carcinoma. It is important to be aware that invasive carcinoma may coexist with pseudoinvasion.

Distinction from invasive carcinoma relies on assessment of:

1. Architecture

o Narrow gap in muscularis mucosae188 o Rounded appearance to focus o Rounded appearance of glands within focus

2. Stromal change

o Lamina propria surrounds glands o Dense fibrosis (not desmoplasia) o Smooth muscle hypertrophy (and ‘fibromuscular’) o Haemosiderin o Chronic inflammation

o Extravasated mucin o Either no epithelium or epithelium at periphery of the mucin. Epithelium floating within mucin pools is indicative of adenocarcinoma.

3. Cytology

This is the same as the overlying epithelium and may incorporate some non dysplastic epithelium. High grade nuclear abnormality should raise concern that the abnormality may represent invasive adenocarcinoma.

Figure 26. Example of pseudoinvasion with herniation of the mucosa through narrow gaps in the muscularis mucosae.

NEUROENDOCRINE TUMOURS

Neuroendocrine tumours are occasionally removed as polypoid lesions. Most are low grade lesions (previously referred to as carcinoid tumour). There is an increasing recognition of tumours with mixed adenoma/neuroendocrine features.189,190

WHO Classification:

• Neuroendocrine tumour NOS (‘carcinoid tumours’)

o EC cell ‘carcinoid’ tumours – right colon; like ileal tumours

o L cell ‘carcinoid’ tumour – rectum

o (Microcarcinoid in colorectal adenoma)

• Neuroendocrine carcinoma NOS (poorly differentiated)

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o Seldom presents as a polyp amenable to local resection. May be small cell or large cell type.

• Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) o Need 2 distinct recognisable malignant components (>30% glandular)191

o Seldom presents as a polyp amenable to local resection.

• Other specified malignant neoplasms of colon

POLYPOID LESIONS IN THE SETTING OF INFLAMMATORY BOWEL DISEASE189,192-195

Polyps arising in the setting of IBD may be inflammatory (‘inflammatory pseudopolyp’) or neoplastic in nature. The neoplastic lesions may be any from the list provided above.

There is a predilection for hyperplastic polyp like lesions to develop in the setting of longstanding IBD. The significance of this is unknown but is likely to be limited.196 The term ‘serrated epithelial change’ is widely used for this process. Broad serrated lesions (with or without dysplasia) may also occur and have not been specifically studied but possibly portend a significant risk for CRC.

Sporadic adenomas may arise in patients with IBD either in areas never involved by disease or in the setting of active or quiescent disease.

Most attention has focused on polypoid dysplastic lesions in areas involved by colitis (current or past). For polyps harbouring dysplasia, knowledge of the endoscopic polyp appearance and most importantly, the adequacy of endoscopic resection is required. Biopsies from the mucosa surrounding the polyp and/or the polyp stalk must also be examined. These features are required to determine appropriate follow up as discussed below.

Polypoid lesions are of 2 types: endoscopically resectable (adenoma like lesion) and non- endoscopically resectable (non adenoma like lesion).The latter are usually non resectable because of a variable combination of large size, margin irregularity, sessile areas and ulceration. Endoscopically resectable polyps can be followed up as per sporadic adenoma (which most in fact are) as long as no dysplasia is found in the surrounding mucosa, elsewhere in the colon or in the polyp stalk (in the case of a pedunculated lesion).

Nonresectable polypoid dysplastic lesions are associated with high risk (>40%) of identifying invasive adenocarcinoma in a subsequent resection specimen and hence a colectomy is typically performed.195,197

Because the reporting pathologist may not be made aware of the appearance and resection status of a dysplastic lesion in a setting of inflammatory bowel disease, the following comment should be applied to such lesions:

‘Dysplastic lesions arising in an area affected by inflammatory bowel disease are a heterogeneous group. Many are adenoma – like, and are not progressive. Conservative management may be warranted if the following conditions are met: Macroscopically adenoma – like in appearance; excised with clear margins; no flat dysplasia of surrounding mucosa and/or polyp stalk. If these criteria are not met, the lesion should be regarded as having a significant risk for associated or subsequent colorectal carcinoma.’

101

While many polypoidal dysplastic lesion arising in chronic inflammatory bowel disease have features similar to conventional adenoma, non conventional patterns are increasingly being recognised. In a recent study six morphologic patterns were recognized. Hypermucinous dysplasia (n = 15; 42%) presented as either a 'pure type' (n = 5; 14%) or a 'mixed type' with either conventional or another nonconventional subtype (n = 10; 28%). Serrated lesions, as a group, were equally common (n = 15; 42%) and included three variants: traditional serrated adenoma-like (n = 10; 28%), sessile serrated lesion-like (n = 1; 3%), and serrated lesion, not otherwise specified (n = 4; 11%). Dysplastic lesions with increased Paneth cell differentiation (n = 4; 11%) and goblet cell deficient dysplasia (n = 2; 6%) were rare.198 It remains to be determined to what extent these morphological patterns affect the prognosis of the lesion.

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Appendix 6 Polyposis syndromes

A number of inherited genetic defects can give rise to syndromes characterised, at least in part, by the formation of multiple polyps within the large bowel. Increasingly, these syndromes are becoming defined by the inherited genetic defect, and there is often considerable overlap in phenotypic expression between syndromes, making morphological distinctions challenging. The notes below provide accepted phenotypic definitions, though these may change as the underlying genetics become better understood. Pathologists should make mention of the possibility of an underlying genetic syndrome whenever multiple polyps are encountered. Often the nature of the polyps indicates the most likely syndrome, however, definitive diagnosis requires formal genetic screening which is accomplished by next generation sequencing panels. Pathologists should include a comment in reports to the effect of - ‘the number and/or combination of polyp types encountered in this patient raise the possibility of an underlying genetic syndrome. Referral to a genetics service should be considered’.

In all polyposis syndromes, the polyp count is cumulative over time and the pathologist should also refer to previous patient specimens reported in their laboratory.

Hyperplastic (serrated) polyposis syndrome

While it remains a poorly understood syndrome with no known biological basis, the WHO has revised the previous diagnostic criteria for hyperplastic (serrated) polyposis syndrome and simplified these into either of two diagnostic requirements:

1) five or more serrated polyps proximal to the rectum with two or more being larger than 10 mm in diameter and all being at least 5 mm in size;

2) more than 20 serrated polyps of any size distributed throughout the large bowel, with at least five being proximal to the rectum.

Familial adenomatous polyposis (FAP)

Affected individuals usually develop hundreds to thousands of adenomatous polyps of the colon and rectum, a small proportion of which will progress to colorectal carcinoma if not surgically treated. Gardner syndrome is a variant of FAP in which desmoid tumours, osteomas, and other neoplasms occur together with multiple adenomas of the colon and rectum. See http://omim.org/entry/175100.

Peutz Jegher syndrome (PJS)199

One of the following:

• Two or more PJS polyps of the small intestine.

• One hamartomatous polyp in a patient who has a characteristic pigmentation of the mouth, lips, nose, eyes, genitalia, or fingers.

• One hamartomatous polyp in a patient who has a family history of PJS

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See http://omim.org/entry/175200

Juvenile polyposis syndrome199

One of the following:

• At least three–five juvenile polyps of the colon.

• Multiple juvenile polyps found throughout the gastrointestinal tract.

• Any number of juvenile polyps in an individual with a family history of JPS.

See http://omim.org/entry/174900

Cowden syndrome (PTEN hamartoma tumour syndrome)199 International consortium criteria have been established and are weighted heavily to the presence of the characteristic mucocutaneous lesions.

Gastrointestinal tract (GIT) manifestations occur in 60% of Cowden Syndrome patients and comprise the following lesions:

i. Hamartomatous polyps

• <10-20 mm

• lamina propria fibrosis

• gland/crypt elongation and dilatation

• found throughout GIT

ii. Nodular lymphoid hyperplasia

iii. Adipose tissue in the lamina propria/true lipomas

iv. Ganglioneuromas (ganglioneuromatous hamartoma)

v. Glycogenic acanthosis in the oesophagus

vi. Probably colorectal carcinoma (not universally accepted)

See http://omim.org/entry/601728

MUTYH-associated polyposis (MAP)

A cumulative lifetime count of >15 adenomatous polyps (or 10 adenomatous polyps before age 50 years) has been suggested a threshold for genetic testing200: Serrated polyps may co-exist with adenomatous polyps in MAP. Extra intestinal manifestations identical to those of familial adenomatous polyposis can occur.

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See http://omim.org/entry/608456

Hereditary Mixed Polyposis syndrome (HMPS)201,202

An autosomal dominant condition characterised by presence of mixed hyperplastic- adenomatous polyps as well as conventional adenomatous polyps (up to 100) throughout the colon and rectum.

See http://omim.org/entry/601228

Many polyposis syndromes have a genetic basis. The table below highlights the features of familial syndromes associated with colorectal polyps.

Table 3. Familial syndromes associated with increased risk of colorectal cancer203

Extracolonic Syndrome Gene responsible Inheritance Typical phenotype manifestations

Early onset colorectal cancer, particularly in the proximal colon Endometrial, ovarian,

EPCAM deletion gastric, pancreatic, The incidence of leading to epigenetic urothelial, renal pelvic, Lynch Autosomal adenomas is not high silencing of MSH2 , small intestine, biliary syndrome* dominant but those that do arise MLH1, MSH6 or tract, brain, sebaceous have a high risk of PMS2 gland adenomas and rapidly progressing to keratoacanthomas malignancy; Cancers display microsatellite instability Familial Duodenal, gastric, adenomatous Autosomal APC > 100 adenomas desmoid, brain, thyroid, polyposis dominant hepatoblastoma (FAP)* > 10 adenomas Attenuated Autosomal APC before age 30 years Duodenal, gastric FAP (AFAP) dominant or 20–100 adenomas MUTYH- Usually 20–100 Autosomal associated MUTYH adenomas but may Duodenal, gastric recessive polyposis have > 100 Polymerase proofreading- 10–100 adenomas Autosomal associated POLD1 or POLE and variable number Endometrial dominant polyposis of serrated polyps (PPAP) NTHL1- associated Autosomal 8–50 adenomatous NTHL1 Endometrial polyposis recessive polyps (NAP) Histologically Upper gastrointestinal Peutz-Jeghers Autosomal STK11 characteristic and small intestine, syndrome dominant hamartomatous breast, gynaecological,

105

polyps throughout pancreas gastrointestinal tract and mucocutaneous pigmentation Histologically characteristic Upper gastrointestinal hamartomatous and small intestine but Juvenile Autosomal polyps throughout no evidence of excess polyposis SMAD4 or BMPR1A dominant gastrointestinal tract; risk for extra- syndrome polyps of mixed gastrointestinal histology may also be cancers present At least 5 serrated polyps proximal to the sigmoid with ≥ 2 of Serrated Unclear and these > 10 mm or > polyposis Unknown low Nil known 20 serrated polyps of syndrome penetrance any size but distributed throughout the colon# Some patients develop adenomas and hyperplastic polyps in addition to colonic hamartomas. Breast, endometrial, thyroid, renal, skin There is no evidence lesions Cowden Autosomal that all families with (trichilemmoma, PTEN syndrome dominant PTEN are at high risk papilloma). Cowden of bowel cancer. Syndrome is often Families with a history associated with of colorectal cancer macrocephaly. should follow screening guidelines based on their family history.

*Note on nomenclature

Historically, eponymous names were used to refer to specific clinical phenotypes in an individual patient, but now that the genetic basis of FAP and LS is known they should be avoided. • Gardner Syndrome refers to classic FAP where intestinal polyposis is associated with extra- intestinal manifestations including osteomas (typically of the skull), fibromas, epidermoid cysts and desmoid tumours. • Muir-Torre syndrome refers to Lynch syndrome associated with sebaceous gland tumours such as sebaceous epitheliomas, sebaceous adenomas, sebaceous carcinomas and keratoacanthomas. • Turcot syndrome (brain tumour – polyposis syndrome) refers to the occurrence of multiple colorectal adenomas and a primary brain tumour. It can also be associated with cafe-au-lait spots. Turcot syndrome is associated with at least 2 distinct types of germline defects: o Type I is associated with a mutation in one of the mismatch repair genes and gliomas (predominantly astrocytomas) and accounts for about one third of cases. o Type 2, which accounts for two thirds of cases, is associated with a mutation in the APC gene (FAP variant) and medulloblastoma is the most common type of brain tumour. # any number of serrated polyps proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis syndrome Reproduced with permission from Leggett B, Poplawski N, Pachter NP, Rosty C, Norton I, Wright C, Win AK, Macrae F, Cancer Council Australia Colorectal Cancer Guidelines Working Party. [Version URL: https://wiki.cancer.org.au/australiawiki/index.php?oldid=173052, cited 2020 Apr 26]. Available from https://wiki.cancer.org.au/australia/Guidelines:Colorectal_cancer/High- risk_familial_syndromes.203

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Appendix 7 Colonoscopy surveillance guidelines

The general principles of surveillance are to ensure that the risk for CRC is matched by the pathology findings. The new NHMRC guidelines30 provide for considerable detail to allow appropriated risk stratification of patients. The role of the pathologist is more considerable than at any previous time.

The basic features are combinations of

1) Polyp type

2) Presence of high grade dysplasia (conventional adenoma) and any dysplasia (serrated lesions)

3) Number of polyps

4) Size of adenoma (10 mm being the cut off)

5) Age of patient

6) Number of the colonoscopy

Table 4. Summary of recommendations for first surveillance intervals following removal of conventional adenomas only

Surveillance recommendations should be made after the colon has been cleared of all significant neoplasia, once histology is known and in the context of individualised assessment of benefit to the patient. Villosity is defined in the First surveillance intervals following removal of high-risk conventional adenoma section.

Polyp/adenoma size as per the endoscopist documentation should be used for determining surveillance intervals. a Consider colonoscopy at an interval of 5 years (Y) in low risk individuals with clinical evidence of the metabolic syndrome b If a significant family history of CRC is present, use screening recommendation if the interval is shorter than 10Y (see the Clinical practice guidelines for the prevention, early detection and management of colorectal cancer) c Return to the NBCSP with FOBT after 4 years is also an appropriate option and should be discussed with the patient d Complete excision of lesions is required before surveillance intervals can be recommended

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e Adenomas ≥20 mm are more likely to be excised piecemeal and should be considered under the large and laterally spreading adenomas section (see section on Large and laterally spreading adenomas)

Reproduced with permission from Cancer Council Australia Surveillance Colonoscopy Guidelines Working Party. Clinical practice guidelines for surveillance colonoscopy. Sydney: Cancer Council Australia. [Version URL: https://wiki.cancer.org.au/australiawiki/index.php?oldid=208067, cited 2020 Jul 6]. Available from: https://wiki.cancer.org.au/australia/Guidelines:Colorectal_cancer/Colonoscopy_sur veillance.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Table 5. Summary of recommendations for first surveillance intervals following removal of clinically significant serrated polyps (± conventional adenomas)

Polyp/adenoma size as per the endoscopist documentation should be used for determining surveillance intervals. Clinically significant serrated polyp: sessile serrated adenoma, traditional serrated adenoma, large (≥10mm) hyperplastic polyp. Low-risk conventional adenoma: small (<10 mm) tubular adenoma without high-grade dysplasia. High-risk conventional adenoma: size ≥10 mm, high-grade dysplasia or villosity. TSA: traditional serrated adenoma; Y: years.

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Appendix 8 Risk of residual disease following malignancy

Endoscopically removed malignant polyps may be of two types:

1) Invasive carcinoma arising from a pre-existing adenoma or

2) Polypoid carcinoma without a pre-existing adenoma evident.

Features determining risk for locally recurrent or metastatic disease are the same in both situations. These factors can be considered as either qualitative (poor differentiation, vascular invasion, tumour budding) or quantitative (Haggitt level, depth of invasion, width of invasive tumour). The number of qualitative prognostic factors present in a malignant polyp appears to be synergistic for the risk of adverse outcome. In the Ueno paper (ref 33) the risk for lymph node metastases was 0.7% if none were present, 20.7% if one adverse factor was present and 36.4% if ≥2 factors were present.

Several studies have identified the rectum (particularly the distal one third) as a site of increased adverse behaviour with increased lymph node metastatic rate (one third) and increased risk of recurrent or residual disease (5-28%).118,204-206 The reason for this increased adverse behaviour is unclear.

A more aggressive treatment approach has been advocated for a distal rectal site.205

The following 3 tables have been developed as a result of meta-analyses of the published data and provide a useful clinical guidance that can be added as a comment to the histopathological report. The ultimate decision for further surgery is based on a weighted assessment of clinical and pathological aspects of the individual case.

Table 6. Scoring the risk of residual disease following resection of a malignant polyp.

Criteria Degree of Risk

Resection margin <1 mm* ++++

Resection margin 1-2 mm* +

Pedunculated polyp with invasion ≥3 mm +++ below the Haggitt line

Sessile invasion ≥2mm ++

Poor differentiation +++

Tumour budding +

Lymphovascular invasion +++

Combination of ≥2 of the above +++ to ++++

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

* Risk for residual carcinoma at the polypectomy site

Table 7. Risk stratification based on sum of risk factors

Total score Grade of Current estimate of Recommended course of action Risk potential % risk of to be discussed with patient residual cancer

0 Very low <3% Routine follow up

+ Low <5% Assess other factors - Careful follow up

++ Medium 5-10% Discussion of risks/benefit of surgery or follow up with patient

+++ High 8-15% Discuss risks with patient – recommend surgery

++++ (or more) Very high >20% Recommend surgery unless patient unfit

Criteria are based on histological description of endoscopically resected malignant polyp weighted for prognostic significance of each risk factor. Where more than one risk factor is present, the degree of risk is added together to give a total risk score.207

Table 8. Risk features in endoscopically resected malignant polyps

Feature Prevalence of Rate of lymph feature node metastasis* Sessile polyp depth ~60% ~5% ≥2mm Pedunculated polyp <10% ~10% with stalk invasion ≥3mm Vascular invasion ~20% ~10% Poor differentiation ~10% ~10% Tumour budding ~10-20% ~5% (BD2/3) Resection margin ~30% ~5% involvement+

• *Overall rate observed in studies with this feature reported. Does not account for the concurrent presence of other risk factors • + Margin directly involved or undefined

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Appendix 9 Practice audits

Structured reporting for polypectomies and local resections of the colorectum present an ideal opportunity to perform practice audits. This is because structured pathology reports are more likely to produce consistent data on the expected range of positive findings. High frequency polypectomies are ideal for performing practice audits.

In some jurisdictions58,208 the following parameters have been helpful for practice audit and cross practice correlation:

Table 9. Incidence of polyps in a study population using WHO diagnostic criteria

Polyp type Incidence in patients with at least 1 polyp identified*

Tubular adenoma with low grade dysplasia 55%

Tubular adenoma with high grade dysplasia 1%

Tubulovillous adenoma with low grade dysplasia 10%

Tubulovillous adenoma with high grade dysplasia 1.5%

Villous adenoma with low grade dysplasia 0.1%

Villous adenoma with high grade dysplasia 0.1%

Hyperplastic polyp 40%

Sessile serrated lesion 20%

Sessile serrated lesion with dysplasia 1%

Traditional serrated adenoma 1%

Adenocarcinoma arising in a polyp 0.5%

Audit data from Envoi pathology. Different patient populations may yield different data.

Polypectomy and Local Resections of the Colorectum Structured Reporting Protocol 2nd Edition

Table 10. Number, size and distribution of polyps208

Reproduced with permission from Bettington M, Walker N, Rahman T, Vandeleur A, Whitehall V, Leggett B and Croese J (2017). High prevalence of sessile serrated adenomas in contemporary outpatient colonoscopy practice. Intern Med J 47(3):318- 323.208

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