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2007-08-29-guidelines-for-colorectal-cancer-reporting.txt

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+TABLE OF CONTENTS 
+SCOPE OF DOCUMENT .............................................................................................................. 5 
+How to use this document ........................................................................................................ 5 
+INTRODUCTION ......................................................................................................................... 6 
+Authors .................................................................................................................................. 6 
+MACROSCOPIC DESCRIPTION .................................................................................................... 7 
+Site of tumour ........................................................................................................................ 7 
+  Definition of the rectum .................................................................................................... 7 Maximum tumour diameter .................................................................................................. 8 
+Distance of tumour to nearer cut end ................................................................................... 8 Presence of tumour perforation ........................................................................................... 8 
+Relationship of rectal tumours to the anterior peritoneal reflection ................................... 9 
+MICROSCOPIC DESCRIPTION ................................................................................................... 11 
+Tumour type ........................................................................................................................ 11 
+Differentiation by predominant area .................................................................................. 12 Local invasion ...................................................................................................................... 13 
+Non-peritonealised circumferential margin in rectal tumours ........................................... 14 The non-peritonealised margin in the colon ....................................................................... 15 
+Lymphocytic infiltration....................................................................................................... 15 
+Lymph nodes ....................................................................................................................... 16 
+Guidelines for small tumour deposits in lymph nodes .................................................... 16 
+A note on TNM 5th edition versus TNM 6th edition ......................................................... 17 
+Lymphovascular invasion .................................................................................................... 18 Perineural invasion .............................................................................................................. 18 
+Histologically confirmed distant metastases ....................................................................... 19 
+Background abnormalities................................................................................................... 19 Residual tumour status ....................................................................................................... 20 Summary - TNM staging ..................................................................................................... 20 
+Mismatch repair deficiency status ...................................................................................... 21 
+Appendix A - Minimum dataset proforma for colorectal cancer resections .......................... 22 
+Appendix B - Colorectal cancer surgical request .................................................................... 24 
+Useful Website ........................................................................................................................ 26 
+REFERENCES ............................................................................................................................ 26 
+ 
+ 	 
+
+SCOPE OF DOCUMENT 
+This document should be read in conjunction with the minimum dataset proforma for colorectal cancer resections, which was developed by the NSW Oncology Group for Colorectal Cancer. It is based on information contained within multiple international publications and datasets and has been developed in consultation with local practising pathologists, oncologists, surgeons, radiologists and interested national bodies.  
+ 
+HOW TO USE THIS DOCUMENT 
+
+To facilitate accurate and complete reporting of colorectal carcinomas, a proforma for the reporting of colorectal cancer resection specimens has been created from a set of minimum data items (Appendix A). To aid in the collection of all essential data items, a colorectal cancer surgical request form has also been prepared (Appendix B). This document is a working guide to help in the accurate reporting of the dataset items contained in the proforma. The data items are listed in the way that they would usually be reported in current laboratory practice. These guidelines reference relevant literature for each data item, including their prognostic significance or relevance to case management.    
+It is important to highlight that the data items presented here form a "minimum" dataset. The report is formatted with tick boxes for ease of presentation.  Individual departments can alter the format to suit their working practices, add areas of free text, or incorporate the items into a free text document with the minimum dataset serving as their template.   
+This minimum dataset for colorectal cancer was developed after lengthy consultation with interested parties and it is hoped that all those good ideas and comments have been taken on board. It may not please everyone and is a work in progress, but it is an important first step towards the objective of improving the way we report colorectal cancer.  
+ 	 
+
+INTRODUCTION 
+Colorectal cancer is currently the most common cancer diagnosed in Australia and has the second highest incidence of cancer related deaths [1].  Recent advances have been made with regard to the biological understanding of this disease and its treatment, with new surgical, chemotherapeutic and radiotherapeutic strategies now available.  
+Histopathological reporting of resection specimens for colorectal cancer provides important information both for the clinical management of the affected patient and for the evaluation of health care as a whole.  For the patient it confirms the diagnosis and describes the variables that will affect prognosis, all of which will inform future clinical management.  For health care evaluation, pathology reports provide information for cancer registration and clinical audit for ensuring comparability of patient groups in clinical trials, and for assessing the accuracy of new diagnostic tests and preoperative staging techniques.  In order to fulfil all of these functions, the information contained within the pathology report must be accurate and complete. 
+Guidelines, datasets and various documents on best practice in pathology are nothing new.  There are large differences however, between available versions. Within existing datasets there is variability in the amount of information required, ranging from those that encompass vast lists of every possible data item, many without proven relevance, to the more focussed and pragmatic evidence-based minimum datasets. 
+Several studies have highlighted deficiencies in the content of colorectal cancer resection reports, including elements that are considered crucial for patient management [2]. Many studies have shown that adherence to a minimum dataset proforma for colorectal cancer reporting significantly improves the rate of inclusion of these crucial features [3].  
+ 
+AUTHORS 
+
+ 
+This document was written by Dr Jill Farmer, Dr Sian Munro and Associate Professor Nicholas Hawkins from the Colorectal Cancer Research Consortium. The document should be read in conjunction with the minimum dataset proforma for colorectal cancer resections, which was developed in collaboration with Dr Andrew Kneebone, the NSW Oncology Group for Colorectal Cancer and local pathologists. The Colorectal Cancer 
+Research Consortium is supported by a Strategic Research Partnership Grant from the 
+Cancer Council NSW. 	 
+MACROSCOPIC DESCRIPTION 
+All measurements should be made in millimetres 
+ 
+SITE OF TUMOUR 
+
+The site of the tumour should be recorded. 
+It is important to record the correct anatomical site of a tumour for the following reasons:  
+* It determines the appropriate staging system. 
+* It indicates whether a non-peritonealised (circumferential) margin is present. 
+* It defines the presence of regional lymph nodes versus non-regional lymph nodes. 
+ 
+
+In 1999 representatives of the American Society of Colon and Rectal Surgeons and the Association of Coloproctology of Great Britain and Ireland met with their Australian counterparts to define the rectum and the procedures to treat cancer of the rectum [4]. 
+The treatment of rectal cancer differs from the treatment of colonic cancer in some important respects, particularly in the areas of surgery and radiotherapy. It is thus essential to have a clear anatomical definition of the rectum. 
+Strictly the rectum is that part of the large bowel distal to the sigmoid colon and its upper limit is indicated by the end of the sigmoid mesocolon.  Standard anatomical texts put this at the level of the 3rd sacral vertebra [5], but it is generally agreed by surgeons that the rectum starts at the sacral promontory [6].  It was agreed by the Expert Advisory Committee that any tumour whose distal margin is seen at 15cm or less from the anal verge using a rigid sigmoidoscope should be classified as rectal.  Clearly, in the excised specimen these anatomical landmarks are not available for the pathologist, hence the importance of the site of the tumour being stated by the surgeon on the clinical request form. 
+ 	 
+MAXIMUM TUMOUR DIAMETER 
+The maximum tumour diameter should be recorded.  The diameter is measured from the luminal aspect of the bowel. The thickness of the tumour is ignored for this measurement. 
+The definitive determination of tumour size is made on gross pathological examination. 
+Several studies have shown that tumour size is of no prognostic significance in colorectal cancer [7,8].  However, it is recorded for purposes of documentation and for correlation with measurements made by various imaging modalities. 
+ 
+DISTANCE OF TUMOUR TO NEARER CUT END 
+
+This is the measurement from the nearer cut end of the specimen and not the nonperitonealised (circumferential, radial) margin.   
+Tumour at a longitudinal margin has always been considered a poor prognostic feature but it occurs very rarely [9,10]. The necessity of sampling this margin has therefore been questioned [11-13].  It may be prudent to sample this margin if the tumour is close to the margin, or if the tumour is found by histology to have an exceptionally infiltrative growth pattern, to show extensive vascular invasion or lymphatic permeation or to be a pure signet ring, small cell or undifferentiated carcinoma [11]. 
+NB. It is useful to have normal tissue for control purposes and uninvolved margins can provide this. 
+ 
+PRESENCE OF TUMOUR PERFORATION 
+
+The presence or absence of tumour perforation should be recorded.  
+Tumour perforation is defined as a macroscopically visible defect through the tumour, such that the bowel lumen is in communication with the external surface of the intact resection specimen.  Perforation through the tumour into the peritoneal cavity is a well established adverse prognostic factor in colonic [14] and rectal cancer [15].  It is suggested that a block be taken from the area of perforation for histological confirmation. If perforation is present then this is regarded as pT4 in the TNM staging system, regardless of other factors [16]. 
+Perforation of the proximal bowel as a result of a distal obstructing tumour should not be recorded as tumour perforation. 
+ 
+ 	 
+
+RELATIONSHIP OF RECTAL TUMOURS TO THE ANTERIOR PERITONEAL REFLECTION 
+
+The relationship of rectal tumours to the anterior peritoneal reflection should be recorded. 
+Rectal tumours are classified according to whether they are 
+a. Entirely above the level of the peritoneal reflection anteriorly. 
+b. Astride (or at) the level of the peritoneal reflection anteriorly. 
+c. Entirely below the level of the peritoneal reflection anteriorly. 
+ 
+ 
+
+The non-peritonealised margin is also known as the radial or circumferential resection margin.  It represents the "bare" area in the connective tissue at the surgical plane of excision that is not covered by a serosal surface.  Low rectal tumours will be completely surrounded by a non-peritonealised margin (the circumferential margin), while upper rectal tumours have a non-peritonealised margin posterolaterally and a peritonealised (serosal) surface anteriorly. Tumours below the peritoneal reflection have the highest rates of local recurrence [15,17-19]. 
+
+ 
+Anteriorly the rectum is covered by peritoneum down to the peritoneal reflection.  Posteriorly the non�peritonealised margin extends upwards as a triangular shaped bare area containing the rectal arteries, which then continues up to the start of the sigmoid mesocolon. 
+MICROSCOPIC DESCRIPTION 
+
+TUMOUR TYPE 
+
+The tumour type should be described according to WHO International Histological Classification of Tumours ICD�10 (the "Blue Book") [20]. 
+Virtually all colorectal cancers are adenocarcinomas.  The term "Adenocarcinoma NOS" on the proforma is used in this instance to indicate conventional adenocarcinoma without any of the special features of the tumour types listed below it. 
+For convenience the tumour types are summarised: 
+* Adenocarcinoma 
+* Mucinous adenocarcinoma 
+* Signet-ring carcinoma 
+* Small cell carcinoma 
+* Squamous cell carcinoma 
+* Adenosquamous carcinoma ? 	Medullary carcinoma 
+* Undifferentiated carcinoma 
+For most tumours, histologic type is not prognostically significant.  Exceptions include tumour types that are, by definition, high grade e.g. small cell carcinoma;  and the medullary subtype, which is invariably associated with high microsatellite instability (MSI-H) and has a favourable prognosis when compared to other poorly differentiated and undifferentiated colorectal carcinomas [20]. 
+ 
+ 
+ 
+ 
+DIFFERENTIATION BY PREDOMINANT AREA 
+
+The assessment of differentiation should be based on the predominant degree of differentiation present in the primary tumour [21]. 
+Assessment of differentiation should be based on the percentage of tumour showing the formation of glands, as described in WHO International Histological Classification of 
+Tumours [20]: 
+* Well differentiated adenocarcinoma shows glands in 95% of the tumour. 
+* Moderately differentiated adenocarcinoma shows 50-95% glands. 
+* Poorly differentiated adenocarcinoma shows 5-50% glands.  
+* Undifferentiated carcinoma shows <5% glands. 
+Histologic grade is a stage independent prognostic factor [17,22].  Multiple grading systems with variation in the number of strata within them have been suggested over the past few years. The distinction between well and moderately differentiated adenocarcinoma (low grade) versus poorly differentiated or undifferentiated carcinoma (high grade) has been shown to be prognostically useful [23].  The terms well, moderate and poor differentiation are equivalent to Grades 1-3 in the TNM staging system [16].   
+For the most part the pathological distinction between moderately and poorly differentiated or undifferentiated tumours is consistent and interobserver variability is small. Distinction between well and moderately differentiated carcinomas is less reproducible and associated with significant interobserver variability. Thus, a two tiered grading system that eliminates this distinction is recommended: 
+* Well differentiated and moderately differentiated - low grade 
+* Poorly differentiated and undifferentiated - high grade 
+Small foci of apparent poor differentiation are not uncommon at the advancing edge of tumours but these are insufficient to classify the tumour as poorly differentiated [21].   
+There is recent interest in the phenomenon of tumour budding at the advancing margin of colorectal cancers with accumulating evidence that it might have prognostic significance [24]. However, this is not yet considered sufficient to justify the inclusion of this item the minimum dataset. 
+ 
+LOCAL INVASION 
+
+The maximum degree of local invasion into or through the bowel wall should be recorded.  This is based on the T component of the TNM staging system. 
+pTis  
+ 
+pTis:  The TNM classification includes a level pTis to represent either in-situ carcinoma or carcinoma showing invasion of the lamina propria (intramucosal carcinoma).  This practice is based primarily on the aim of achieving a uniform staging system across all organ systems.  Colorectal neoplasia has not been shown to have metastatic potential until it has invaded through the muscularis mucosae.  The term pTis is thus avoided in the lower gastrointestinal tract and the term high grade dysplasia is preferred.  pTis tumours should be regarded as adenomas and not as carcinomas for the purpose of diagnosis and cancer registration. 
+pT1:  
+pT4a:  Tumour directly invades other organs or structures AND/OR    pT4b:  Tumour invades through serosa with tumour cells on the peritoneal surface or free in the peritoneal cavity. Cases showing perforation should be classified as pT4b. 
+Direct invasion in pT4 includes invasion of other segments of the colorectum by way of the serosa, e.g. invasion of sigmoid colon by a carcinoma of the caecum [16,26].  Intramural or longitudinal extension of tumour into an adjacent part of the bowel e.g. extension of a caecal tumour into the terminal ileum does not affect the pT stage. 
+Serosal involvement through direct continuity with the primary tumour (pT4) is recorded differently from peritoneal tumour deposits that are separate from the primary. These latter deposits are regarded as distant metastases (pM1).   
+NON-PERITONEALISED CIRCUMFERENTIAL MARGIN IN RECTAL TUMOURS 
+
+In rectal tumours the minimum distance in millimetres between the tumour and the non�peritonealised, (circumferential, radial) margin should be recorded from the histological slides.  
+Tumour frequently (5-36%) involves the non-peritonealised surgical circumferential resection margin (CRM) in the rectum and is associated with significantly higher rates of local recurrence and cancer-related death [27-34]. 
+The frequency of involvement of the CRM depends on the quality of surgery, advancing 
+TNM stage and whether the patient has undergone preoperative neoadjuvant therapy. The closer the tumour is to the CRM the worse the prognosis [35]. The vast majority of studies, including clinical trials and population studies, have used a cut off of 1mm or less to define margin involvement. The Dutch total mesorectal excision (TME) study suggests this measurement should be 2mm [31].   
+CRM involvement may be through direct continuity with the main tumour, by tumour deposits discontinuous from the main tumour or by tumour in veins, lymphatics or lymph nodes. All types of involvement confer a poor prognosis [28,31].  
+ 
+
+ 
+Confusingly, the residual tumour status (R) used in the TNM staging system requires that tumour be identified at the resection margin for the margin to be considered involved [16].  Thus, in TNM staging if tumour is not actually seen at this margin it is coded as R0.  Therefore, recording the distance between the tumour and the CRM will alert the clinician to those patients who may benefit from being treated as though they were margin positive. 
+ 
+ 	 
+THE NON-PERITONEALISED MARGIN IN THE COLON 
+
+The importance of non-peritonealised margin involvement in colonic tumours, particularly those of caecum and ascending colon has recently been recognised [14,36].   Studies indicate the frequency of margin involvement is 7-10% [36]. It is recommended that tumour involvement of the non-peritonealised resection margin in colonic tumours should be recorded when this is present as this may facilitate the selection of patients with colonic tumours for postoperative adjuvant therapy [11]. 
+ 
+LYMPHOCYTIC INFILTRATION 
+
+Intraepithelial lymphocytes (IEL) are those that are in direct contact with tumour cells or are located directly between tumour cell clusters. For standardised detection, routine histological methods should be used. Only a high density of lymphocytes (=5 IEL per hpf) should be considered significant. It has been suggested that a minimum of 10 standard fields including both the centre and periphery of the tumour should be included in the count [37].   
+Intraepithelial lymphocytes are thought to be indicative of a host immune response against cancer cells. They are also associated with a favourable outcome in terms of both recurrence and overall survival [38-40].  
+While the extent of lymphocytic infiltrates at the margins of the tumour 
+(peritumoural lymphocytes) and the prominence of lymphoid follicles (Crohn's-like reaction) in adjacent tissues are also features of MMR deficient tumours, most studies have found the strongest correlation between IELs and MMR deficiency [41,42]. IEL counts are therefore not necessary if MMR deficiency status is to be 
+assessed formally, by MMR immunohistochemistry or MSI testing.  
+
+LYMPH NODES 
+All lymph nodes should be harvested from the specimen and examined histologically. 
+The finding of positive lymph nodes is a major determinant of whether the patient receives adjuvant therapy.  The probability of finding a positive node increases with the number of nodes found although this probability curve flattens out after finding 12-15 nodes [43,44]. However, for practical purposes all lymph nodes present should be harvested from the specimen. 
+The AJCC recommendations state that if the examined lymph nodes are negative, but only a small number of nodes has been found, then the case should be classified as pN0 rather than pNX [16].  
+The N3 staging category, which described cases with a positive apical node, has been shown not to be prognostic [45] and so has been removed from the 6th edition of the AJCC guidelines. 
+Direct extension of a colorectal tumour into a lymph node is considered nodal metastasis. Metastasis in any lymph nodes other than regional nodes is classified as distant metastasis [16].  
+There is no consensus that occult metastatic disease detected by immunohistochemistry or other methods discriminates between high- and low-risk groups of patients.  Data are thus insufficient to recommend routine use of tissue levels or ancillary special techniques [23,25].  
+ 
+GUIDELINES FOR SMALL TUMOUR DEPOSITS IN LYMPH NODES 
+Isolated tumour deposits are single tumour cells or small cell clusters, generally less than 0.2mm in diameter, present within a lymph node. They may be visible in H&E stained sections or detected by immunohistochemistry. The literature suggests that the finding of s ch cells is not a marker of an adverse prognosis for the patient [46-48]. u
+The TNM 6th edition recommends that cases in which isolated tumour cells are the only form of nodal involvement should be classified as pN0, although the presence of the isolated tumour cells should be noted. Optional designation as pN0(i+) is suggested for this situation [26],  although a free-text description might provide clearer communication. 
+Micrometastasis refers to nodal metastatic deposits less than 2 mm in diameter. Such deposits differ from isolated tumour cells not only in size, but also in that they show evidence of growth, for example glandular differentiation, distension of the sinus or a stromal desmoplastic reaction [25]. 
+The TNM 6th edition suggests that cases where micrometastasis is the only form of metastatic spread, be classified as pN1(mi), although again some explanatory free text would be advisable in this situation.  
+ 
+A NOTE ON TNM 5TH EDITION VERSUS TNM 6TH EDITION 
+Isolated tumour deposits in the pericolic or perirectal fat, separate from the main tumour and lacking evidence of pre-existing lymph node or vessel, are common. TNM 5th edition classified such deposits as involved lymph nodes if they were >3mm in diameter. TNM 6th edition replaced this criterion with another, namely that such deposits were classified as involved lymph nodes if they showed a rounded contour, regardless of size. 
+Deposits of irregular shape are to be coded as T3 and recorded as vascular invasion. This change has been the subject of some criticism, as it has replaced a relatively objective criterion (a measurement) with a subjective one (assessment of shape). The assessment of the nodal contour has been shown to be poorly reproducible [49] and it has therefore been suggested that the 5th edition criteria should be adhered to. 
+Other commentators [50] have pointed out that, reproducible or not, both criteria are essentially arbitrary and that such deposits may derive from nodes, vascular invasion, perineural invasion or a combination of these within a single case. Most examples occur in situations where there are unequivocally involved nodes anyway (in only 8% of cases were they the only form of deposit) and, where present, are in themselves associated with an adverse prognosis. It would therefore seem reasonable to adhere to the TNM 6th edition criteria, stating in free-text if isolated tumour deposits are the only form of nodal deposits identified. 
+ 
+ 
+ 
+ 
+ 
+LYMPHOVASCULAR INVASION 
+For all tumours, including malignant polyps, venous and lymphatic invasion should be reported as present or absent and its anatomic location specified as mural or extramural. 
+Venous invasion by tumour has been repeatedly shown by multivariate [17,51,52] and univariate analyses to be a stage independent adverse prognostic factor.  However some studies identifying venous invasion as an adverse factor on univariate analysis have failed to confirm its independent impact on prognosis on multivariate breakdown [5254].  Similar disparate results have also been reported for lymphatic invasion [54]. In other reports vascular invasion as a general feature was prognostically significant, but no distinction between lymphatic and venous vessels was made.  In a few studies the location as well as the type of the involved vessels (e.g. extramural veins) were both considered strong determinants of prognostic impact [23,55].  Data from existing studies are difficult to amalgamate but nevertheless, the importance of venous and lymphatic invasion by tumour is strongly suggested and largely confirmed.  
+Some groups have recommended that only extramural vascular invasion be recorded [11], while others have recommended that the site of any vascular invasion should be recorded, along with its location, intra or extramural [23].  Both intramural and extramural vascular invasion have been shown to have similar prognostic value [14]. Evidence is also lacking or is inconclusive for preferential recording of vascular versus lymphatic invasion. It is thus recommended that both items are combined as lymphovascular invasion and a comment made on its location.  
+It is debatable whether special techniques, such as histochemical and immunohistochemical stains, to identify elastic tissue or endothelium increase the ease or accuracy of evaluation.  Because these techniques are also labour intensive and time consuming they are not performed routinely.  Accordingly, special stains are not recommended.  
+The prognostic importance of involvement of small (thin-walled, presumably lymphatic) vessels in the submucosa has been well documented with respect to polypectomies of malignant polyps. Such involvement has been shown to be associated with an increased risk of regional lymph node metastasis [56]. 
+ 
+PERINEURAL INVASION 
+
+Perineural invasion should be reported as present or absent.  
+There is some evidence that perineural infiltration by tumour is an important indicator of spread, particularly in rectal tumours where it may involve the sacral plexus and this may be an indication for radiotherapy [57].   
+The presence or absence of perineural invasion should be assessed using routine histology alone.  
+HISTOLOGICALLY CONFIRMED DISTANT METASTASES 
+
+The presence of histologically confirmed distant metastases and their site should be recorded.  
+Pathological M staging can only be based on distant metastases that are submitted for histological assessment by the surgeon and will therefore tend to underestimate the true (clinical) M stage.  Pathologists will only be able to use pM1 (distant metastases present) or pMX (distant metastases unknown).  However at the request of the oncologists, a box marked cM has been included in the staging summary to record the presence of clinically diagnosed metastases as stated by the submitting surgeon and captured by the clinical request form. 
+Disease classifiable as distant metastasis may sometimes be present within the primary tumour resection specimen, e.g. a serosal or mesenteric deposit that is distant from the primary tumour mass.  
+ Metastatic deposits in lymph nodes distant from those surrounding the main tumour or its main artery in the specimen will usually be submitted separately by the surgeon (e.g. deposits in para-aortic nodes or nodes surrounding the external iliac or common iliac arteries).  Metastatic deposits in lymph nodes distant from those surrounding the main tumour or its main artery in the specimen are regarded as distant metastases (pM1) [26]. 
+ 
+BACKGROUND ABNORMALITIES 
+
+The presence of any pathological abnormalities in the background bowel should be recorded.  Those listed are particularly of note. 
+If the resection specimen contains two or more carcinomas (as indicated by the term "synchronous carcinomas" on the minimum dataset proforma) then a separate minimum dataset should be completed for each primary carcinoma.  Where possible lymph nodes should be assigned and assessed for each cancer separately, based on topographical distribution. 
+ 
+ 
+RESIDUAL TUMOUR STATUS 
+The completeness of resection should be recorded. 
+R0 
+ 
+Residual tumour classification (R status) is not limited to the primary tumour.  The R classification not only considers locoregional residual tumour, but also distant residual tumour in the form of unresected or incompletely resected metastases (R2) [58]. 
+For example, a metastasis in the liver from a primary colorectal carcinoma would be M1 and R0 if the metastasis was solitary and resected with tumour-free margins.  This case would be M1 and R2 if the metastasis was not resected. 
+The resection status rule also applies to lymph nodes.  If a clinically positive lymph node is left behind it is classified as R2. 
+Tumour cells that are confined to the lumen of blood vessels or lymphatics at the resection margin are classified as R0 [58].  
+Peritoneal involvement alone is not a reason to categorise the tumour as incompletely excised. 
+With regard to the presence of residual disease in areas which have not been resected (e.g. involvement of other organs by trans-coelomic spread), it is the responsibility of the surgeon to recognise and report these deposits.  Such information will be collected by the surgical request form. 
+ 
+SUMMARY - TNM STAGING 
+
+TNM 6th edition is used. 
+The prefix "p" is used to indicate pathological staging. 
+If neoadjuvant chemotherapy or radiotherapy has been given, the prefix "yp" should be used to indicate that the original p stage may have been modified by therapy.  Tumour remaining in a resection specimen following neoadjuvant therapy should always be classified by ypTNM to distinguish it from untreated tumour [26]. 
+MISMATCH REPAIR DEFICIENCY STATUS 
+
+A mutation in mismatch repair genes (mainly MLH1, PMS2, MSH2 and MSH6) can cause an accumulation of DNA mutations that result in the initiation of cancer.  Mismatch repair deficient (MMRD) cancers occur either sporadically (~12%) or less commonly (~2%) because the individual suffers from hereditary non-polyposis colorectal cancer (HNPCC).  Tumours which show loss of MMR proteins by immunohistochemistry are almost always characterised by microsatellite instability (MSI), which is determined by analysis of tumour DNA.  This finding is important for the following reasons: 
+MMRD has been shown to be a favourable prognostic factor in colorectal cancer, in terms of both recurrence-free survival and overall survival [41,59,60].  
+MMRD tumours may be less responsive to adjuvant chemotherapy compared to other colorectal cancers [61-63] although this has not been shown conclusively in all studies [64-66].  
+In 2% of cases MMRD is associated with underlying HNPCC which raises cancer issues for all family members. 
+Immunohistochemical (IHC) analysis of mismatch repair proteins  is used to detect MMRD in colorectal cancer, with an absence of one or more of the mismatch repair proteins considered an abnormal result [67,68].  MMRD can also be determined by microsatellite analysis, which is the amplification and analysis of selected microsatellite loci within the genome of the tumour cells.  However, this later technique is not used routinely in diagnostic pathology settings.  MMR testing is currently recommended for all cases of colorectal cancer arising in individuals less than 50 years of age, although this cut off is arbitrary.   
+ 	 
+
+APPENDIX A - MINIMUM DATASET PROFORMA FOR COLORECTAL CANCER RESECTIONS 
+
+
+
+ 
+ 	- 23 -
+APPENDIX B - COLORECTAL CANCER SURGICAL REQUEST 
+
+
+
+ 
+ 	 
+
+USEFUL WEBSITE 
+
+http://www.uicc.org/ 
+The UICC website has a dedicated TNM page, which includes a frequently asked questions (FAQ) section and a link to a helpdesk, for questions not covered by the FAQ.  
+ 
+REFERENCES 
+
+ 
+1. Australian Institute of Health and Welfare and the Australasian Association of 
+Cancer Registries: Cancer in Australia. In 2004 AIoHaWAAAoCRA (ed), AIHW Canberra, Australia, 2004. 
+2. Bull AD, Biffin AH, Mella J, Radcliffe AG, Stamatakis JD, Steele RJ, Williams GT: 
+Colorectal cancer pathology reporting: a regional audit. Journal of Clinical Pathology 1997;50:138-142. 
+3. Cross SS, Feeley KM, Angel CA: The effect of four interventions on the informational content of histopathology reports of resected colorectal carcinomas. Journal of Clinical Pathology 1998;51:481-482. 
+4. The association of Coloproctology of Great Britian and Ireland (ed): Guidelines for the management of colorectal cancer. London, The association of Coloproctology of Great Britian and Ireland, 2001. 
+5. Williams PL, Warwick R (eds): Gray's anatomy. London [England], Churchill Livingstone, 1980. 
+6. UKCCCR (ed): Handbook for the clinicopathological assessment and staging of colorectal cancer. London, UKCCCR, 1989. 
+7. Miller W, Ota D, Giacco G, Guinee V, Irimura T, Nicolson G, Cleary K: Absence of a relationship of size of primary colon carcinoma with metastasis and survival. Clinical & Experimental Metastasis 1985;3:189-196. 
+8. Morris M, Platell C, de Boer B, McCaul K, Iacopetta B: Population-based study of prognostic factors in stage II colonic cancer. British Journal of Surgery 2006;93:866-871. 
+9. Guillou PJ, Quirke P, Bosanquet N, Smith A, Thorpe H, Walker J, Bell SE, Brown 
+JM: The MRC CLASICC trial: results of short term endpoints. British Journal of Cancer 2003;88(Suppl 1):S11 - S24. 
+10. Guillou PJ, Quirke P, Thorpe H, Walker J, Jayne DG, Smith AMH, Heath RM, Brown JM, group MCt: Short-term endpoints of conventional versus laparoscopicassisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet 2005;365:1718-1726. 
+11. The Royal College of Pathologists Working Group on Cancer Services: UK Guidelines. Minimum data set for colorectal cancer histopathology reports. InLondon, Royal College of Pathologists, 1998. 
+12. Compton CC: Colorectal carcinoma: diagnostic, prognostic, and molecular features. Modern Pathology 2003;16:376-388. 
+13. Cross SS, Bull AD, Smith JH: Is there any justification for the routine examination of bowel resection margins in colorectal adenocarcinoma? Journal of Clinical Pathology 1989;42:1040-1042. 
+14. Petersen VC, Baxter KJ, Love SB, Shepherd NA: Identification of objective pathological prognostic determinants and models of prognosis in Dukes' B colon cancer. Gut 2002;51:65-69. 
+15. Nagtegaal ID, van de Velde CJH, Marijnen CAM, van Krieken JHJM, Quirke P, Dutch Colorectal Cancer G, The Pathology Review C: Low rectal cancer: a call for a change of approach in abdominoperineal resection. Journal of Clinical Oncology 2005;23:9257-9264. 
+16. Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M (eds): AJCC Cancer Staging Manual. New York, Springer, 2002. 
+17. Freedman LS, Macaskill P, Smith AN: Multivariate analysis of prognostic factors for operable rectal cancer. Lancet 1984;2:733-736. 
+18. Bentzen SM, Balslev I, Pedersen M, Teglbjaerg PS, Hanberg-Sorensen F, Bone J, Jacobsen NO, Sell A, Overgaard J, Bertelsen K, et al.: Time to loco-regional recurrence after resection of Dukes' B and C colorectal cancer with or without adjuvant postoperative radiotherapy. A multivariate regression analysis. British Journal of Cancer 1992;65:102-107. 
+19. Pilipshen SJ, Heilweil M, Quan SH, Sternberg SS, Enker WE: Patterns of pelvic recurrence following definitive resections of rectal cancer. Cancer 
+1984;53:1354-1362. 
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+Sobin LH, Fogt F, Winawer SJ, Goldgar DE, Jass JR: Tumours of the Colon and Rectum. in Hamilton SR, Aaltonen LA (eds): Pathology and Genetics of Tumours of the Digestive System. World Health Organisation Classification of Tumours. Lyon, France: IARC Press, 2000, 101-142. 
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+CR, Welton M, Willett C: Prognostic factors in colorectal cancer. College of 
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+31. Nagtegaal ID, Marijnen CAM, Kranenbarg EK, van de Velde CJH, van Krieken JHJM, Pathology Review C, Cooperative Clinical I: Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: not one millimeter but two millimeters is the limit. American Journal of Surgical Pathology 2002;26:350-357. 
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+37. Nagtegaal ID, Marijnen CA, Kranenbarg EK, Mulder-Stapel A, Hermans J, van de Velde CJ, van Krieken JH: Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect--a histopathological and immunohistochemical study. BMC Cancer 2001;1:7. 
+38. Hakansson L, Adell G, Boeryd B, Sjogren F, Sjodahl R: Infiltration of mononuclear inflammatory cells into primary colorectal carcinomas: an immunohistological analysis. British Journal of Cancer 1997;75:374-380. 
+39. Jass JR, Atkin WS, Cuzick J, Bussey HJ, Morson BC, Northover JM, Todd IP: The grading of rectal cancer: historical perspectives and a multivariate analysis of 
+447 cases. Histopathology 1986;10:437-459. 
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+41. Guidoboni M, Gafa R, Viel A, Doglioni C, Russo A, Santini A, Del Tin L, Macri E, Lanza G, Boiocchi M, Dolcetti R: Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. American Journal of Pathology 2001;159:297-304. 
+42. Ward RL, Cheong K, Ku S-L, Meagher A, O'Connor T, Hawkins NJ: Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. Journal of Clinical Oncology 2003;21:3729-3736. 
+43. Goldstein NS: Lymph node recoveries from 2427 pT3 colorectal resection specimens spanning 45 years: recommendations for a minimum number of recovered lymph nodes based on predictive probabilities. American Journal of Surgical Pathology 2002;26:179-189. 
+44. Pheby DFH, Levine DF, Pitcher RW, Shepherd NA: Lymph node harvests directly influence the staging of colorectal cancer: evidence from a regional audit. Journal of Clinical Pathology 2004;57:43-47. 
+45. Vaccaro CA, Bonadeo FA, Benati ML, Quintana GMO, Rubinstein F, Mullen E, Telenta M, Lastiri JM: Colorectal cancer staging: reappraisal of N/PN classification. Diseases of the Colon & Rectum 2004;47:66-69. 
+46. Hara M, Hirai T, Nakanishi H, Kanemitsu Y, Komori K, Tatematsu M, Kato T: Isolated tumour cell in lateral lymph node has no influences on the prognosis of rectal cancer patients. Int J Colorectal Dis 2007;In press. 
+47. Hermanek P, Hutter RV, Sobin LH, Wittekind C: International Union Against 
+Cancer. Classification of isolated tumor cells and micrometastasis. Cancer 1999;86:2668-2673. 
+48. Messerini L, Cianchi F, Cortesini C, Comin CE: Incidence and prognostic significance of occult tumor cells in lymph nodes from patients with stage IIA colorectal carcinoma. Human Pathology 2006;37:1259-1267. 
+49. Howarth SM, Morgan JM, Williams GT: The new (6th edition) TNM classification of colorectal cancer - a stage too far. Gut 2004;53:A1-A123. 
+50. Nagtegaal ID, Quirke P: Colorectal tumour deposits in the mesorectum and pericolon; a critical review. Histopathology 2007;In press. 
+51. Knudsen JB, Nilsson T, Sprechler M, Johansen A, Christensen N: Venous and nerve invasion as prognostic factors in postoperative survival of patients with resectable cancer of the rectum. Diseases of the Colon & Rectum 1983;26:613617. 
+52. Wiggers T, Arends JW, Volovics A: Regression analysis of prognostic factors in colorectal cancer after curative resections. Diseases of the Colon & Rectum 1988;31:33-41. 
+53. Chan CLH, Chafai N, Rickard MJFX, Dent OF, Chapuis PH, Bokey EL: What pathologic features influence survival in patients with local residual tumor after resection of colorectal cancer? Journal of the American College of Surgeons 2004;199:680-686. 
+54. Fujita S, Shimoda T, Yoshimura K, Yamamoto S, Akasu T, Moriya Y: Prospective evaluation of prognostic factors in patients with colorectal cancer undergoing curative resection. Journal of Surgical Oncology 2003;84:127-131. 
+55. Talbot IC, Ritchie S, Leighton M, Hughes AO, Bussey HJ, Morson BC: Invasion of veins by carcinoma of rectum: method of detection, histological features and significance. Histopathology 1981;5:141-163. 
+56. Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD: Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology 1985;89:328-336. 
+57. Ueno H, Hase K, Mochizuki H: Criteria for extramural perineural invasion as a prognostic factor in rectal cancer. British Journal of Surgery 2001;88:994-1000. 
+58. Wittekind C, Compton CC, Greene FL, Sobin LH: TNM residual tumor classification revisited. Cancer 2002;94:2511-2516. 
+59. Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, Slattery ML: Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiology, Biomarkers & Prevention 2001;10:917-923. 
+60. Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP: Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology 1996;110:682-687. 
+61. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR: Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004;126:394-401. 
+62. Claij N, te Riele H: Microsatellite instability in human cancer: a prognostic marker for chemotherapy? Experimental Cell Research 1999;246:1-10. 
+63. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S: 
+Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. New England Journal of Medicine 2003;349:247-257. 
+64. Hemminki A, Mecklin JP, Jarvinen H, Aaltonen LA, Joensuu H: Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 2000;119:921-928. 
+65. Storojeva I, Boulay J-L, Heinimann K, Ballabeni P, Terracciano L, Laffer U, Mild G, Herrmann R, Rochlitz C: Prognostic and predictive relevance of microsatellite instability in colorectal cancer. Oncology Reports 2005;14:241-249. 
+66. Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R, Haller DG, Benson AB, 3rd, Hamilton SR: Molecular predictors of survival after adjuvant chemotherapy for colon cancer. New England Journal of Medicine 2001;344:1196-1206. 
+67. Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, Walsh-Vockley C, Petersen GM, Walsh MD, Leggett BA, Young JP, Barker MA, Jass 
+JR, Hopper J, Gallinger S, Bapat B, Redston M, Thibodeau SN: 
+Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. Journal of Clinical Oncology 2002;20:1043-1048. 
+68. Ward RL, Turner J, Williams R, Pekarsky B, Packham D, Velickovic M, Meagher A, O'Connor T, Hawkins NJ: Routine testing for mismatch repair deficiency in sporadic colorectal cancer is justified. Journal of Pathology 2005;207:377-384. 
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Dataset_for_Pathology_Reporting_of_Colorectal.35.txt

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+
+     
+REVIEW PAPER
+
+Dataset for Pathology Reporting of Colorectal Cancer
+Recommendations From the International Collaboration on Cancer Reporting (ICCR)
+Maurice B. Loughrey, MRCP, FRCPAth, MD,y Fleur Webster,z Mark J. Arends, MD, PhD, FRCPath,�
+Ian Brown, MBBS, BGEN, FRCPA, Lawrence J. Burgart, MD,jj
+Chris Cunningham, BSC (Hons), MBChB, MD, FRCSEd, Jean-Francois Flejou, MD, PhD,yy
+Sanjay Kakar, MD,zz Richard Kirsch, MBChB, PhD, FRCPath(SA), FRCPC,�� Motohiro Kojima, MD, PhD,
+Alessandro Lugli, MD,jjjj Christophe Rosty, MD, PhD, FRCPA,yyyzzz
+Kieran Sheahan, MB, FRCPI, FRCPath,��� Nicholas P. West, MBChB, PhD, FRCPath,
+Richard H. Wilson, MD,jjjjjj and Iris D. Nagtegaal, MD, PhDY
+     
+Objective: The aim of this study to describe a new international dataset for pathology reporting of colorectal cancer surgical specimens, produced under the auspices of the International Collaboration on Cancer Reporting (ICCR).
+Background: Quality of pathology reporting and mutual understanding between colorectal surgeon, pathologist and oncologist are vital to patient management. Some pathology parameters are prone to variable interpretation, resulting in differing positions adopted by existing national datasets.
+     
+From the Centre for Public Health, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK; yDepartment of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK; zInternational Collaboration on Cancer Reporting, Sydney, NSW, Australia; �Division of Pathology, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK; Envoi Pathology, Kelvin Grove, QLD, Australia; jjDepartment of Pathology, Virginia Piper Cancer Institute, Abbott Northwestern Hospital, Minneapolis, MN; Department of Colorectal Surgery, Churchill Hospital, Oxford University Hospitals NHSFT, Oxford, UK; yyDepartment of Pathology, Saint-Antoine Hospital, Sorbonne University, Paris, France; zzDepartment of Pathology, University of California San Francisco, San Francisco, CA; ��Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Kashiwa, Japan; jjjjInstitute of Pathology, University of Bern, Bern, Switzerland; Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia; yyyEnvoi Specialist Pathologists, Brisbane, QLD, Australia; zzzDepartment of Pathology, University of Melbourne, Melbourne, VIC, Australia; ���Department of Pathology, St Vincent's University Hospital & University College, Dublin, Ireland; Pathology and Data Analytics, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK; jjjjjjInstitute of Cancer Sciences, University of Glasgow, Glasgow, UK; and Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
+Iris.Nagtegaal@radboudumc.nl.
+Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
+Declarations of interest: none.
+Authorship justification: This manuscript describes the creation of a new International Collaboration on Cancer Reporting dataset for pathology reporting of colorectal cancer surgical resection specimens. This first internationally agreed dataset for colorectal cancer pathology reporting represents the culmination of a series of web meetings and protracted e-mail exchanges over several years discussing, agreeing and finalising content amongst an international authorship, representing four continents and nine countries. All authors were deeply involved in this process, (a) making substantial contributions to one or more dataset items (b) participating in either drafting specific manuscript sections or reviewing critically for intellectual content; and (c) approving the final version for publication.
+The authors report no conflicts of interest.
+This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
+Copyright  2021 The Author(s). Published by Wolters Kluwer Health, Inc.
+ISSN: 0003-4932/21/27503-e549
+DOI: 10.1097/SLA.0000000000005051
+Annals of Surgery  Volume 275, Number 3, March 2022
+Methods: The ICCR, a global alliance of major pathology institutions with links to international cancer organizations, has developed and ratified a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Here we describe the production of a dataset for colorectal cancer resection specimens by a multidisciplinary panel of internationally recognized experts.
+Results: The agreed dataset comprises eighteen core (essential) and seven non-core (recommended) elements identified from a review of current evidence. Areas of contention are addressed, some highly relevant to surgical practice, with the aim of standardizing multidisciplinary discussion. The summation of all core elements is considered to be the minimum reporting standard for individual cases. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or non-core.
+Conclusions: This first internationally agreed dataset for colorectal cancer pathology reporting promotes standardization of pathology reporting and enhanced clinicopathological communication. Widespread adoption will facilitate international comparisons, multinational clinical trials and help to improve the management of colorectal cancer globally.
+Keywords: colorectal cancer, dataset, guidelines, ICCR, protocol, structured report, synoptic report
+(Ann Surg 2022;275:e549-e561)
+P
+athology reporting of cancer resection specimens, through provision of histological subtype, grade, stage, and other clinically relevant information, impacts on individual patient management and prognosis. At a population level, it provides data for cancer registrations, epidemiological audits, and research including clinical trials.1,2 Tissue-based cancer research also partly relies on histopathological stage, the presence high-risk features, and molecular pathological subtypes. Standardization of pathology evaluation of cancer resection specimens and reporting of individual features is essential, to allow valid comparison of data between cohorts and countries, to allow assessment of the impact of new screening programs and to allow participation in multicenter trials. However, some pathology parameters are prone to variable or evolving interpretation, resulting in differing positions adopted by various national
+     
+datasets in existence or an inability to reach consensus, manifest as a lack of clearly expressed guidance for certain contentious areas. This is evidenced by regular changes made to TNM staging systems as new evidence and new interpretations emerge. For some issues, clear guidance is simply unavailable.
+     Alloftheseprinciplesapplytocolorectalcancer(CRC)andsome such issues impact directly on surgical practice and staging. For example, the minimum distance of tumor from a margin required to label as ''clear,'' the interpretation of regional, discontinuous ''tumor deposits,'' and the interpretation of surgical resection margin status when this is involved by tumor not continuous with the primary tumor.3 If there is limited evidence, clear consensus-based guidelines, based on best available evidence and expert opinion, are helpful to assist pathologists in case by case reporting and surgeons and oncologists in clinical management of their patients. Close liaison between surgeon and pathologist, and good surgical understanding of pathology reporting guidelines and practice are key to maximizing the quality of pathology reports and their value to the surgeon and ultimately the patient.
+     Pathology protocols and datasets are well established in some countries and have been independently developed at national level by organizations including the College of American Pathologists (CAP), USA, the Royal College of Pathologists (RCPath), United Kingdom (UK), and the Royal College of Pathologists of Australasia (RCPA). Although these organizations' protocols broadly align, there are significant differences in structure, content and terminology and some subtle differences in interpretation that could hinder international comparison. Standardization of existing national cancer reporting datasets would also have the added benefits of reducing the global burden of regular dataset production and of providing a single benchmarking reference available to other countries.
+     Withthisinmind,in2011,anumberofpathologyorganizations including the CAP, RCPath, and RCPA formed the International Collaboration on Cancer Reporting (ICCR) and successfully piloted the developmentofdatasets for pathologyreporting ofa selectnumber of cancers. The subsequent ICCR development has been described previously in detail.4 The ICCR has developed important strategic alliances with other international cancer organizations including the International Agency forResearch onCancer (IARC)whichisresponsible for producing the World Health Organization (WHO) monographs or ''Blue Books'' on tumor classification and the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC). These partnerships facilitate the co-ordination of dataset production with new classifications and staging systems. The ICCR datasets are freely available from the ICCR website (http:// www.iccr-cancer.org/datasets). Here we describe the production of such a dataset for CRC surgical resection specimens by a panel of internationally recognized expert pathologists and other clinicians, supported by the ICCR. Areas of contention or divergence are addressed, with the aim of offering a consensus position to standardize interpretation and multidisciplinary discussion.
+METHODS
+     TheICCRhas developed a rigorous processfor theproduction of individual datasets (http://www.iccr-cancer.org/datasets/dataset-development). This process has been described in detail in previous publications (http://www.iccr-cancer.org/articles/publications). The ICCR quality framework dictates both content and presentation and the roles and responsibilities of all involved are clearly outlined. In brief, the Dataset Steering Committee (DSC) of the ICCR appointed a ''Series Champion'' (IN) to coordinate the simultaneous development of a related suite of five datasets all pertaining to gastrointestinal and pancreaticobiliary tract cancers, and a Chair (M.B.L.) to oversee productionoftheCRCresectiondataset.Afurther11expertgastrointestinal pathologists, comprising 2 each from the United States (L.B., S.K.), UK (M.A.,N.W.),andAustralia (I.B.,C.R.)and 1 eachfromCanada(R.K.), Japan (M.K.), France (J.F.), Ireland (K.S.), and Switzerland (A.L.), together with a colorectal surgeon (C.C.) and a colorectal oncologist (R.W.) comprised the 15 members of the Dataset Authoring Committee (DAC). Lead authors of the current CAP, RCPath, and RCPA CRC datasets were included.5-7 The group was coordinated by an ICCR Project Manager (F.W.), assuring optimal communication within the international group and adherence to agreed timelines.
+     Regarding scope, this dataset was developed for the reporting of pathology specimens resulting from major surgical resection of primary carcinomas arising within the colon and rectum. This includes neuroendocrine carcinomas (NECs) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs).2 It is not applicable to carcinomas of the small intestine, appendix or anus, nor to neuroendocrine tumors (NETs) or nonepithelial malignancies, as these are subject to different classifications and staging systems. Furthermore, primary CRC treated by local excision are the subject of a separate ICCR dataset, as specimen handling and reporting of these differ from major surgical resection specimens.
+     An initial draft document was produced by the Project Manager and Chair after scrutiny of core and non-core data items within existing CAP, RCPath, and RCPA CRC datasets and review of present published evidence. This draft was circulated and individual dataset items discussed among the DAC at a coordinated series of teleconferences, following which an agreed draft dataset was posted for open international consultation on the ICCR website for a period of 2 months. All comments received were discussed by the DAC and, where agreed, resultant changes incorporated into the final dataset, which was ratified by the DSC before publication. The final agreed dataset is available at http://www.iccr-cancer.org/datasets/publisheddatasets/digestive-tract/colorectal.
+     The ICCR dataset style lists a set of reporting elements and value lists (responses) accompanied by a commentary for each, explaining the element and categorization, offering guidance for reporting, citing relevant evidence, and, where applicable, definitions for the value lists. Each element is categorized as either core or noncore. Core elements are those unanimously agreed by the expert panel to be essential for diagnosis, prognostication and/or patient management. These generally required evidentiary support at Level III-2 or above [based on prognostic factors in the National Health and Medical Research Council (NHMRC) levels of evidence document, and defined as ''Analysis of prognostic factors amongst persons in a single arm of a randomized controlled trial''].8 Non-core elements were those that did not meet the above criterion but were considered by the panel to be clinically important, representing good practice but not currently fully validated for routine clinical practice. Specific levels of evidence were not assigned to each core or non-core element. The summation of all core elements is considered to be the minimum reporting standard for individual cases.
+RESULTS
+     A summary of the agreed core and non-core elements is presented in Table 1 and each is described in further detail below:
+Clinical Information
+     Knowledge of relevant clinical information, such as an underlying polyposis syndrome, Lynch syndrome or chronic inflammatory bowel disease, is essential for optimal specimen sampling and histological interpretation. However, as it is beyond the control of the pathologist to ensure this information is available, it is considered a non-core rather than a core item.
+     Two specific items represent exceptions to this rule, given their importance, and are considered core. Firstly, information on neoadjuvant therapy, including type and duration, is a core item and must always be provided to the pathologist, as response to therapy can influence stage and tumor morphology, potentially altering interpretation. Staging should be provided with a ''y'' prefix.
+     Secondly, the nature of the operative procedure is a core item (Table 1), and additional information may be provided clinically, such as the attempted dissection plane in an abdominoperineal excision. Distinction of high from low anterior resection, the latter defined by inclusion of the peritoneal reflection within the specimen, is considered non-core. If the operative specimen includes any additional tissue or organs, for example en bloc resection of a separate segment of intestine or abdominal wall connective tissue or a more extensive anterior exenteration specimen (Fig. 1), details of
+TABLE 1. Core and Non-Core Elements for Reporting
+Operative procedure
+Tumor site
+Tumor dimensions (maximum)
+Perforation
+Relation of tumor to anterior peritoneal reflectionPlane of mesorectal excision Histological tumor type
+Histological tumor grade
+Extent of invasion
+Lymphatic and venous invasion
+Perineural invasion
+Lymph node status
+Tumor deposits
+Response to neoadjuvant therapy
+Margin status
+Histologically confirmed distant metastases
+Pathological staging
+Ancillary studies
+Plane of sphincter excision
+Plane of mesocolic excision
+Measurement of invasion beyond muscularis propria
+Tumor budding
+Coexistent pathology
+Ancillary studies
+These items are only relevant to certain specimen types-see text for details.
+Tumor Site
+     If a specimen contains multiple tumors, these should all be documented individually and separate datasets completed for each. Tumor location is a core item, stated in the clinical information provided and confirmed by macroscopic specimen examination. It can be difficult to identify specific location in the colon within an ex vivo specimen, particularly in relation to the flexures. If clinical and pathological tumor locations are discordant, this should be documented by photography and discussed with the clinical team. Recording the anatomical site allows
+     
+FIGURE 1. A fresh anterior exenteration specimen comprising abdominoperineal excision of the rectum and anus with en bloc levator ani muscles, prostate, seminal vesicles and bladder.
+
+FIGURE 2. Rectal anatomy and possible relationships of rectal cancers to the peritoneal reflection. Adapted by permission from
+Nicholas P. West and Philip Quirke: Springer Multidisciplinary Treatment of Colorectal Cancer (G. Baatrup, ed.); Quality of Surgery
+     
+by Nicholas P. West and Philip Quirke (2021).
+correlation with prior endoscopic and radiological investigations, indicates whether or not a nonperitonealized margin is likely to be present andpermitsclassificationoflymphnodesasregionalversusnonregional. Distinction ofcolonic from rectalorigin is ofimportance, given different biology, clinical features, management, and risks of peritoneal versus local recurrence. This classification can be subjective, especially for moreadvanced stagetumors.Ifatumorstraddles2sites,thesitewiththe greatest tumor bulk should be recorded. The rectosigmoid boundary is markedbyfusionofthethreetaeniaecoliofthesigmoidcolontoformthe circumferentiallongitudinalmuscleoftherectalwall.Ifadvancedtumor growth obliterates these anatomical landmarks, the tumor site should be retrieved from available clinical and radiological information.9 Classification as rectosigmoid should be reserved for cases in which an accurate determination between rectum and sigmoid cannot be made by above methods.
+Tumor Dimensions
+     Tumor size has no prognostic significance for CRC and does not directly influence staging. Despite this, maximum dimension is considered a core data item, as it is baseline information which allows correlation with preoperative clinical, endoscopic, and radiological assessments. It should be based on a combination of macroscopic and microscopic assessment and, if possible, exclude any associated inflammatory component or preinvasive lesion, which may be noted in a comment for clinicopathological correlation. Additional tumor dimensions may be provided as non-core data.
+Perforation
+     Tumor perforation into the peritoneal cavity is a well-established adverseprognosticfactorinCRC 10,11 anditspresenceorabsenceshould be recorded as a core item. Tumor perforation is defined as a macroscopicallyvisiblefullthicknessdefect,suchthatthebowellumenwithin the segment involved by tumor is in communication with the external surface of the resection specimen or with the lumen of another organ. Cases with tumor perforation are regarded as pT4a.12,13 Note that tumor perforation requires penetration of the serosal surface. Peritumoral abscess cavity, for example, within the mesentery, that is contained anddoesnotdemonstratebreachoftheserosalsurface,isnotconsidered perforation and is considered pT3 rather than pT4a. This may be commonly encountered in the setting of sigmoid diverticular disease complicated by CRC. Perforation of the colon resulting from a more distal obstructing tumor is distinct from tumor perforation and is not interpretedaspT4disease.However,thisshouldstillberecordedasnontumor perforation is associated with higher mortality risk.
+     Some confusion can be introduced when using the term perforation for other settings, such as when a full thickness defect arises intraoperatively. We consider the term perforation is best reserved for the biological setting, as the clinical impact is likely different depending on the scenario. If an iatrogenic full thickness tumor defect arises whilst the specimen is in situ within the abdominal cavity, there is likely some risk of tumor seeding the peritoneal cavity and we consider this is best regarded as pT4a disease. This interpretation is however offered without good evidence. In contrast, if such an iatrogenic defect occurs once the specimen is outside the abdominal cavity, this should not influence pT classification. Interpretation therefore requires close clinicopathological correlation and this should always be explained in the pathology report.
+Relation of Tumor to Anterior Peritoneal Reflection
+     For rectal cancers, the relationship of the tumor to the anterior peritoneal reflection is reported as a core item, as this predicts the risk of local recurrence in addition to peritoneal recurrence (Fig. 2).14 The anterior aspect of the rectum has a peritoneal covering to the level of the peritoneal reflection. Posteriorly, the nonperitonealized margin is represented by a triangular-shaped bare which extends superiorly in continuity with the mesentery of the sigmoid colon.
+Plane of Mesorectal Excision
+     Prospective randomized controlled trials have demonstrated that, in patients with rectal cancer, use of total mesorectal excision (TME) surgery improves local recurrence rates and the survival by up to 20%.15,16 Furthermore, objective macroscopic assessment by pathologists of the surgical plane of excision predicts margin involvement, local recurrence and survival.14,17 This grading is therefore considered a core item for reporting. The optimal plane is that of the mesorectal fascia (complete TME) whilst excision extending onto the muscularis propria (incomplete TME) is associated with the worst outcomes. Overall macroscopic assessment of the intact specimen, with grading based on the worst area, is as described in Table 2 and illustrated in Figure 3.
+Plane of Sphincter Excision
+     In considering management of rectal cancer, abdominoperineal excision for lower tumors has been associated with poorer outcomes compared to anterior resection for higher tumors, due to increased rates of circumferential resection margin (CRM) involvement and intraoperative full thickness defects, referred to as perforation in this literature.18 More radical surgery to remove more tissue around low rectal tumors by en bloc resection of the levator muscles, extralevator abdominoperineal excision, reduces the risk of CRM involvement and intraoperative full thickness defects leading to better long term outcomes.19,20 Using staging magnetic resonance imaging (MRI), radiologists are able to predict the optimal dissection plane for abdominoperineal excision surgery.21 Subsequent correlation with pathological assessment of the intact
+TABLE 2. Pathological Assessment of Rectal and Colonic Cancer Surgical Resection Specimens
+Intact bulky mesorectum with a smooth surface
+Only minor irregularities of the mesorectal surface
+No surface defects >5 mm in depth
+No coning towards the distal margin of the specimen
+Moderate bulk to the mesorectum
+Irregularity of the mesorectal surface with defects >5mm, but none extending to the
+muscularis propria
+Moderate coning may be evident distally
+No areas of visibility of the muscularis propria except at the insertion site of the levator ani muscles
+Little bulk to the mesorectum
+Defects in the mesorectum down to the muscularis propria
+After transverse sectioning, the circumferential margin appears very irregular and is formed by muscularis propria in areas.
+Dissection plane lies external to the external sphincter and levator ani muscles, which are removed en bloc with
+the mesorectum and anal canal
+Cylindrical-shaped specimen with the levators forming an extra protective layer above the sphincters
+No significant defects into the sphincter muscles or levators
+Dissection plane lies on the surface of the sphincter muscles
+No levator ani muscle attached or only a very small cuff leading to coning or surgical waisting at the level of puborectalis
+No significant defects into the sphincter muscles
+Dissection plane lies within the sphincter muscles or even deeper into the submucosa
+Full thickness iatrogenic defect of the specimen at any point below the peritoneal refection.
+Smooth surface to the mesocolon (mesocolic fascia and peritoneum)
+Only minor irregularities
+No surface defects >5mm in depth
+Irregularity of the mesocolic surface with defects >5mm, but none extending to the muscularis propria
+Defects in the mesocolon down to the muscularis propria
+After transverse sectioning, the mesocolic margin is irregular and formed by muscularis propria in areas.
+Plane of Mesocolic Excision
+     Beyond assessment of rectal cancer surgery, the quality of surgical technique for colonic cancer, evaluating the plane of mesocolic excision, has been shown, in retrospective observational studies and 1 randomized clinical trial, to predict outcomes.22 Surgery in the mesocolic plane is associated with a lower rate of local recurrence and better survival when compared to surgery in the muscularis propria plane. Complete mesocolic excision, where surgery occurs in the mesocolic plane with a high vascular ligation, is associated with better plane of surgery and higher lymph node yield, although the effect of the high ligation on long term outcomes is uncertain and subject to further study.23 Pathological evaluation of mesocolic surgery is considered a non-core data item, as its application requires further validation in clinical practice. Overall assessment is based on theworst area, as described in Table 2 and illustrated in Figure 3.22
+FIGURE 3. Planes of colorectal cancer surgery for the mesorectum (A-C), sphincters (D-F) and mesocolon (G-I). For the mesorectum, applicable to all rectal cancer specimens, the planes include the mesorectal plane, with intact mesorectum (A), intramesorectal plane, with mesorectal defect (B) and muscularis propria plane, with little bulk to mesorectum and exposure of muscularis propria (C). For the sphincters, applicable to all abdominoperineal excisions in addition to the mesorectal plane, the planes include the extralevator plane (D), sphincteric plane (E) and intrasphincteric plane (F). The extralevator specimen includes en bloc resection of the levator ani muscles and coccyx thus preventing the creating of a surgical waist (D). The intrasphincteric plane specimen includes a large anterior perforation (F). For the mesocolon, applicable to all colon cancer specimens, the planes include the mesocolic plane, with intact mesocolon (G), intramesocolic plane, with mesocolic defect (H) and muscularis propria plane, with ragged mesocolon and exposure of muscularis propria (I). Adapted by permission from Nicholas P. West and Philip Quirke: Springer Multidisciplinary Treatment of Colorectal Cancer (G. Baatrup, ed.); Quality of Surgery by Nicholas P. West and Philip Quirke (2021).
+     The WHO Classification of Tumors of the Digestive System is recommended for tumor typing as a core item.2 Almost all CRC are adenocarcinomas, most of which are of no specific type or ''not otherwise specified'' (NOS). Specific subtypes of adenocarcinoma are recognized and defined as follows:
+     Mucinous adenocarcinoma has >50% of the tumor comprised of pools of extracellular Mucin, containing malignant glands, or individual tumor cells. Microsatellite instability is more common, as is the presence of an activating BRAF V600E mutation.
+     Signet-ring cell adenocarcinoma has >50% of the tumor demonstrating signet-ring cell morphology, in the form of malignant cells with intracytoplasmic mucin, displacing and typically indenting the nuclei. Signet-ring cell adenocarcinoma is associated with worse stage-for-stage survival relative to conventional adenocarcinoma.2 Like mucinous adenocarcinoma, there is a strong association with microsatellite instability and BRAF V600E mutation.2
+     Medullary carcinoma demonstrates solid sheets of malignant cells with indistinct cell boundaries, vesicular nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and prominent intratumoral and peritumoral inflammatory infiltrates. Almost invariably these tumors demonstrate microsatellite instability and are associated with a good prognosis.2
+     Serrated adenocarcinoma by definition demonstrates glandular serrations, often slit-like, and tumor cells usually have low nuclear to cytoplasmic ratio with abundant eosinophilic or clear cytoplasm and sometimes accompanied by areas of mucinous differentiation.2 BRAF or KRAS activating mutations are common.
+     Micropapillary adenocarcinoma is characterized by small, rounded clusters of tumor cells lying within stromal spaces mimicking vascular channels. At least 5% of the tumor should demonstrate this feature for this classification. There is an association with adverse pathological features including extramural venous invasion and lymph node metastatic disease.2
+     Adenoma-like adenocarcinoma is a subtype of adenocarcinoma in which at least 50% of the invasive tumor has an adenomalike appearance with villous architecture, low-grade cytology, a pushing growth pattern, and minimal desmoplastic stromal reaction.2 Demonstration of invasion is difficult on endoscopic biopsy. This subtype is associated with a good prognosis.
+     Neuroendocrine neoplasms of the gastrointestinal tract are currentlyclassifiedintoNETs,NECsandMiNENs.2 ThetermMiNEN incorporatestheprevioustermmixedadenoneuroendocrinecarcinoma (MANEC), in recognition that occasionally the non-neuroendocrine componentofmixedtumorsmay not beanadenocarcinoma. NETsare now graded 1 to 3 on the basis of mitotic count and Ki-67 proliferation index, with NET grade 3 recognizing a subset of tumors previously meeting criteria for NEC, but found to be less responsive to platinumbased chemotherapy, yet have better survival compared to other NECs.24 Grade 3 NETs are better differentiated than NECs and the primary distinction is morphological. MiNENs are usually composed of a poorly differentiated NEC component and a conventional adenocarcinomaNOScomponentandeachshouldarbitrarilyconstitute30% ofthetumorforthisdesignation.ThisdatasetisapplicabletoNECsand MiNENs but, given different staging and grading systems applied, NETs should not be reported using this dataset.
+     Other epithelial tumors rarely encountered include adenosquamous carcinoma, carcinoma with sarcomatoid components, undifferentiated carcinoma, squamous cell carcinoma, and non-signetring cell poorly cohesive adenocarcinoma.
+Histological Tumor Grade
+     Although subject to poor interobserver agreement,25 histological grade of CRC, based on gland formation, is an independent prognostic factor and is a core item.26,27 A 2-tiered grading system is more reproducible and favored over a 4-tiered grading system. Aligning with the latest WHO classification,2 grading is based on the least differentiated component, rather than predominant pattern, although this is recommended without good evidence and a minimum area of high-grade tumor required for classification as highgrade has not been defined. Tumor buds or poorly differentiated clusters, most commonly seen at the invasive front, should not be considered in the evaluation of grade. Grading based on poorly differentiated clusters may be superior to conventional grading with respect to both prognostic value and reproducibility but further studies are required in this regard.28
+     According to the latest WHO classification, only adenocarcinoma NOS and mucinous adenocarcinoma should be graded.2 Grading is not applicable to other subtypes of adenocarcinoma, as assessment of gland formation is difficult to apply to subtypes and most subtypes are associated with their own clinical prognosis independent of grade. Mucinous adenocarcinoma should be graded on glandular formation and epithelial maturation.2
+Extent of Invasion
+     Local invasion depth of CRC is categorized by the pT classification. This is the most important prognostic factor in CRC and is a core data item, using UICC and AJCC 8th edition criteria.12,13 The onlyexceptionisthatpTinsituisnotrecognizedinthis dataset.Thisis somewhat contentious and rare cases of colorectal neoplasia confined to invasion of the lamina propria (intramucosal invasive neoplasia or intramucosal carcinoma) are acknowledged but, given the negligible metastatic potential ofsuch neoplasms,29 the consensus position ofthe DAC was that these should be classified under the same category as high grade dysplasia/high grade noninvasive neoplasia.
+     Given the clear anatomical delineation of the muscularis propria at most sites, defining pT1-pT3 tumors, classification of this extent of invasionisnotoftenproblematic.Anexceptionisthelowrectum,where complexities of sphincter anatomy make accurate assessmentof level of invasionchallenging.Theinternalsphincterrepresents acontinuation of the muscularis propriaandinvasion ofthisalso constitutes pT2.Skeletal muscle fibers can cross-over from external to internal sphincter and therefore invasion of skeletal muscles fibers may only represent pT2 disease if these fibers are from the internal sphincter. Invasion beyond internal sphincter into the intrasphincteric plane, but not involving the external sphincter, is considered pT3. Note that in some areas of the sphincter complex the internal and external sphincter muscles are directly apposed with only a theoretical space between.
+     pT4 includes tumor infiltration of the peritoneal surface (pT4a) or involvement of an adjacent organ or structure (pT4b). Peritoneal involvement has been demonstrated by multivariate analysis to have a negative impact on prognosis.30 Data from a cohort of >100,000 colon cancer cases indicate that pT4a carcinomas have on average a 10% to 20% better 5-year survival than pT4b carcinomas for each pN category.31 Involvement of the peritoneal surface requires tumor breaching the serosa with tumor cells visible either on the peritoneal surface, free in the peritoneal cavity or separated from the peritoneal surface by inflammatory cells only.10 If tumor passes close to the serosal surface and elicits a mesothelial reaction without clear invasion, this is categorized as pT3, although additional sections and/or multiple levels should be examined to look deeper invasion. This setting is prone to interobserver variation however.32 Elastic stains to identify peritoneal elastic lamina invasion are advocated in some studies, as a staging or prognostic tool.33,34 Cases with tumor perforation are classified as pT4a, without the need to document tumor cells on the peritoneal surface.
+     It is important to distinguish peritoneal involvement through direct continuity with the primary tumor from discontinuous peritoneal deposition. The former indicates pT4a disease, whereas the latter is regarded as distant metastatic disease, pM1c. It is also important to distinguish involvement of a peritoneal surface from involvement of a nonperitonealized resection margin. Peritoneal involvement is a risk factor for peritoneal metastases whilst margin involvement is a risk factor for local recurrence.
+     Adjacent organ involvement by tumor (pT4b) may follow peritoneal invasion or, for example in low rectal tumors, represent direct extraperitoneal invasion. If a tumor is macroscopically adherent to another organ, microscopic invasion must be demonstrated to classify as pT4b; otherwise, the adherence is considered inflammatory in nature. Longitudinal tumor extension into the wall of an adjacent segment of the intestine does not influence pT classification. Rectal tumors invading skeletal muscle of the external sphincter and/ or levator ani are classified as pT4b.
+Measurement of Invasion Beyond Muscularis Propria
+     Prognosis of patients with pT3 tumors can be stratified accordingly to their extent of invasion of the primary tumor beyond the muscularis propria, with 5 mm an accepted cut-off for higher risk in some studies.29 Based on the level of existing evidence, this is considered a non-core item for reporting. The distance beyond the muscularis propria is measured to the nearest mm from the outer margin of the muscularis propria. In the event of local tissue destruction by tumor, reconstruction of this outer margin may be required for the purposes of measurement. The measurement should be performed macroscopically and refined microscopically if appropriate.
+Lymphatic and Venous Invasion
+     The presence or absence of lymphovascular invasion has strong prognostic implications for CRC and this should be reported as a core item. Classification is required according to the type of vessels involved (Fig. 4) and, for veins, their intramural or extramural location, as the vessel type and location have different clinical and prognostic implications. Extramural venous invasion, present beyond the muscularis propria, has the greatest clinical significance, having been demonstrated on multivariate analysis in multiple studies to be a stage-independent adverse prognostic factor.35 Intramural venous invasion, identified within the submucosa or muscularis propria but not beyond, is also of prognostic importance but the evidence is much weaker than for extramural venous invasion.10,36,37
+     The minimum criteria for calling venous invasion are debatable. The longstanding definition of Talbot et al (1981) is approved, whereby venous invasion is defined as tumor present within an endothelium-lined space that is either surrounded by a rim of muscle or contains red blood cells.38 Proximity of a rounded or elongated deposit of tumor beside an artery should raise suspicion of venous invasion but is not diagnostic without identification of a residual venous wall. Examination of further levels and additional stains may help interpretation.39,40 A circumscribed tumor nodule surrounded by a smooth muscle wall or an identifiable elastic lamina is considered sufficient to classify as venous invasion.
+     Small vessel invasion is defined as 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, and invasion of these should be distinguished from large vessel (venous) invasion. D2-40 immunohistochemistry, which only stains lymphatic endothelial cells, not venular, can be used to classify small vessel invasion further but this is not in routine use in this setting. Small vessel invasion of all forms is considered under the ''L'' classification under UICC/AJCC TNM 8th editions.12,13 The identification of small vessel invasion has been reported in some but not all studies to be associated with lymph node metastatic disease and represent an independent prognostic factor.36,41-43 The relative importance of intramural and extramural anatomic location with respect to small vessel invasion has not been well established.36
+Perineural Invasion
+     The presence of perineural invasion in CRC (Fig. 4) has adverse prognostic implication, particularly in stage II disease.41,44,45 Although the importance of anatomic location in perineural invasion is not well established, 1 large multicenter study, reported adverse prognostic significance for both intramural and extramural locations.44 The presence or absence of any perineural invasion is therefore considered a core item but it is not necessary to specify anatomical location.
+Lymph Node Status
+     Regional lymph node status determines the need for adjuvant chemotherapy and is a core item. Nonregional lymph node involvement is distant metastatic (pM1) disease. If a specimen contains synchronous primary tumors in distinct anatomic regions, attempt should be made to assign lymph nodes by regional status and each cancer assessed for nodal status separately.
+     It is important to perform a diligent pathological dissection to identify all lymph nodes in a specimen as lymph nodes containing metastatic disease may be very small. Individual dissectors and departments should aim for a median lymph node yield of at least 12 per case. Low lymph node harvest is an adverse prognostic factor in stage II disease.46 This reflects a combination of inadequate nodal retrieval and unfavorable patient immunology.
+     Micrometastases (size between 0.2mm and 2mm) are associated with recurrence in stage I/II CRC compared to tumor-negative nodes, but there is no increased risk of disease recurrence in the presence of ''isolated tumor cells'' (single tumor cells or groups <0.2mm in maximum dimension) compared to tumor-negative nodes.47 Therefore, any lymph nodes containing micrometastatic or larger tumor foci are considered as positive nodes whereas isolated tumor cells, identified on H&E or immunohistochemical staining, when representing the only form of nodal involvement should be classified as pN0, with a comment indicating the presence of isolated tumor cells and optional designation as pN0(i�).
+     Following neoadjuvant therapy, only the identification of viable tumor constitutes nodal involvement (ypN1/2). Necrosis, fibrosis or acellular mucin within lymph nodes in this setting is not considered nodal tumor involvement. Nevertheless, a descriptive comment of these findings indicates likely response to therapy and allows correlation with initial staging MRI.
+Tumor Deposits
+     The term tumor deposit, or satellite, was introduced in the UICC/AJCC TNM 7th editions48,49 and the concept refined in UICC/ AJCC TNM 8th editions: discrete macroscopic or microscopic nodules of cancer in the pericolorectal adipose tissue's lymph drainage area of a primary carcinoma that are discontinuous from the primary and without histological evidence of residual lymph node or identifiable vascular or neural structures (Fig. 4).12,13 If a vessel wall is identifiable on H&E, elastic or other stains, it should be classified as venous invasion or lymphatic invasion and if neural structures are identifiable in association with the tumor, the lesion should be classified as perineural invasion rather than as a tumor deposit. A minimum size of deposit or minimum distance of separation from the primary tumor, or further other deposits, is not specified. Neither is guidance on how to classify mesenteric tumor which demonstrates lymphatic, venous or perineural invasion, but where the bulk of the tumor appears unrelated to the vascular or neural structure. The identification of a tumor deposit is considered under the node (N) rather than primary tumor (T) status for the purposes of staging and tumor deposits in the absence of lymph node metastases are classified as pN1c. In the presence of lymph node metastases, tumor deposits are discounted for staging purposes. However, there is evidence from meta-analysis of the adverse prognostic significance of tumor deposits in the presence of lymph node metastatic disease, based on the UICC/AJCC TNM 7th editions48,49 definition, and therefore the presence and number of identified tumor deposits should be recorded in all cases, as a core item.50
+     Mesenteric tumor, without evidence of origin, which is discontinuous from the primary tumor and predominantly subserosal in location but which penetrates the serosal surface of the mesentery, should be classified as a tumor deposit rather than as distant metastatic (pM1c) disease. This does not influence the pT category, which should be based on extent of local invasion of the primary tumor only. However, given serosal involvement by the tumor deposit may equate clinically to pT4a disease, a comment may be usefully added to this effect. Guidance on this interpretation is offered without good evidence. pM1c disease should be reserved for cases where the tumor appears to have arisen from metastatic spread via the peritoneal cavity.
+     In the setting of tumor regression following administration of neoadjuvant therapy, the distinction of discontinuous residual primary tumor foci from tumor deposit is difficult and subjective. To facilitate uniform interpretation, it is recommended that designation as tumor deposit should necessitate the presence of intervening normal tissue, rather than just fibrosis or acellular mucin.
+     
+
+FIGURE4. Metastatic pathways in colorectal cancer. A, Obvious extramural venous invasion (EMVI, black arrows), including a focus extending perpendicularly from muscularis propria (white arrow) (H&E). B, Lymph node metastatic disease (white arrows) and EMVI (black arrow,) confirmed by identification of an elastic lamina in the vein wall (inset) on histochemical staining (H&E, elastic van gieson). C, Lymphatic invasion, malignant glands (arrow) lying within a thin-walled lymphatic channel, surrounded by lymphoid cells (H&E). D, Perineural invasion, malignant glands infiltrating thickened neural bundles (arrows), highlighted by S100 immunohistochemical staining (Upper, H&E; Lower, S100). E indicates tumor deposit, defined by the absence of features of any identifiable metastatic pathway (ancillary stains noncontributory).
+     
+Tumor Budding
+     There is considerable interest in tumor budding, considered to be a morphological manifestation of epithelial mesenchymal transition.51 A tumor bud is defined as a single tumor cell or cluster of up to 4 tumor cells at the invasive front of carcinomas. Budding is of potential clinical relevance to CRC in 2 distinct settings. First, multiple studies have shown that pT1 CRC with greater budding (tumor budding scores Bd2 and Bd3) are associated with an increased risk of lymph node metastatic disease compared to those with lesser budding (tumor budding score Bd1).52-54 Second, in stage II CRC, tumor budding score Bd3 is associated with an increased risk of recurrence and mortality.55
+     As recommended from the International Tumor Budding Consensus Conference (ITBCC) of 2016,56 tumor budding is scored using a 3-tier system according to the number of buds evident in the highest countafterscanning10separatefields(at20objectivelens)alongthe invasive front of the tumor or the entire lesion for malignant polyps (''hotspot'' approach). The number of tumor buds is based on haematoxylin and eosin (H&E) assessment, although pan-cytokeratin immunohistochemistry can be used to help identify hotspots.57 This may be of particular value when the invasive front is obscured by inflammatory cells. A correction for microscope eyepiece field diameter is required, the bud count normalized to a field area of 0.785 mm2 (equivalenttoanobjectivelens20witheyepiecediameterof20mm).
+     Tumor budding, applying the above system to assess tumor budding score (Bd1-Bd3) and actual number of buds, is considered a non-core item for reporting, pending the emergence of further evidence of reproducibility of assessment and clinical significance. Note that budding should only be reported in nonmucinous and nonsignet-ring cell adenocarcinoma areas of tumor and budding should not be reported in cancers resected after neoadjuvant therapy.
+Response to Neoadjuvant Therapy
+     Any form of neoadjuvant therapy may result in morphological tumor response in the form of fibrosis, necrosis or acellular mucin. The presence of complete or marked tumor regression in rectal cancer resection specimen is associated with a better outcome.58,59 For grading of regression, a 4-tier system is recommended, based on a modification of the system described by Ryan et al.60 This is a core item for reporting. Assessment of regression is based on evaluation of the primary tumor site. Similar features may be evident within regional lymph nodes involved by metastatic tumor, or at any distant metastatic sites. Although findings at metastatic sites do not influence tumor regression score, a descriptive comment in the pathology report is recommended to allow correlation with imaging. Overall designation as a complete pathological response requires the absence of viable tumor locally (ypT0) and in lymph nodes (ypN0). The entire tumor bed should be processed for histological examination in this situation.
+Margin Status
+     Assessment of surgical margin status is a core item. In particular, circumferential or nonperitonealized margin involvement in rectal cancer is strongly predictive of local recurrence and poor survival.61,62 Margin involvement in colon cancer is much less common and there is less evidence of its significance.63,64 The definition of margin involvement is somewhat contentious but it is generally accepted that any circumferential margin 1mm should be regarded as involved. The precise distance to the margin should be recorded, to the nearest 0.1mm, if less than 1mm, and to the nearest 1mm, if <10mm. This assessment may require a combination of macroscopic and microscopic evaluation. Any separately submitted anastomotic rings should be taken into consideration in measuring the distance to longitudinal margins.
+
+FIGURE 5. A, Posterior aspect of a right hemicolectomy specimen highlighting an intact, enlarged lymph node (rectangle) abutting the posterior specimen margin. B, Histology of a horizontal section through this lymph node shows metastatic mucinous adenocarcinoma. Although tumor extends to the surgical margin (painted black at base of image), tumor is confined to the intact lymph node and therefore NOT considered to represent margin involvement.
+     There is some evidence to suggest that margin involvement due to discontinuous or intravascular tumor is associated with a similar risk of local recurrence to that of margin involvement by primary tumor.61,62 Margin involvement by tumor within a lymph node, however, was reported in 1 study not to be associated with a significant risk of local recurrence.62 Therefore, if a lymph node containing tumor is present at the resection margin, and the lymph node capsule is intact, the circumferential margin should not be reported as involved (Fig. 5). A comment should be added to the pathology report describing the interpretation. In the setting of margin involvement by discontinuous tumor, this should be clearly reported and a separate measurement provided of distance from the primary tumor.
+Coexistent Pathology
+     Any background colonic or rectal pathological abnormalities, such as polyps, chronic inflammatory bowel disease, effects of neoadjuvant therapy, diverticular disease, or obstructive changes should be recorded as non-core information. In the event of 2 synchronous primary carcinomas, individual datasets should be completed as appropriate.
+Ancillary Studies
+     Clinical applications of ancillary testing applied to CRC are limited but expanding. Reflex testing for defective mismatch repair (MMR)/microsatellite instability (MSI) status is now widely recommended for the detection of Lynch syndrome,65,66 caused by either a constitutional pathogenic mutation in one of the MMR genes, or sporadic MMR deficient CRC, usually caused by hypermethylation of the MLH1 MMR gene promoter region. Defective MMR (dMMR) associated with MLH1 loss, or a MSI-high result, triggers algorithmic testing, including somatic BRAF mutation testing and/or MLH1 promoter methylation testing, to distinguish between sporadic dMMR cancers and Lynch syndrome. Absence of BRAF V600 mutation and/or absent MLH1 promoter hypermethylation should prompt a recommendation of referral to clinical genetics for appropriate counseling before germline mutation screening of the relevant MMR genes, as should loss of PMS2, MSH2, and/or MSH6 immunohistochemical expression. MMR status also informs patient management with MMR deficiency associated with good prognosis, poorer response to 5-fluorouracil-based chemotherapy and potential response to immune checkpoint blockade therapy.67
+     Patients with metastatic CRC should be tested for RAS (KRAS and NRAS) and BRAF mutations when treatment with anti-epidermal growth factor receptor (anti-EGFR) therapy is considered.66,68 Similarly, it is likely that the presence of the V600E BRAF mutation confers resistance to anti-EGFR therapy, though this may be modified by addition of a BRAF and/or MEK inhibitor.69,70 Most modern guidelines therefore recommend also testing metastatic CRC for the V600E BRAF mutation.66
+     Although the above indications for focused ancillary testing are now well established, facilities for such testing are not globally available. As such, these are currently considered non-core items for reporting. It is inevitable that further clinical applications of ancillary testing will emerge and this will be kept under review.
+Histologically Confirmed Distant Metastases
+     It is occasionally possible to designate a case as having histologically confirmed distant metastatic disease (pM1) on examination of either the main surgical resection specimen, for example when a peritoneal or omental deposit is identified, or of a separately submitted biopsy or resection specimen, for example from the liver or a nonregional lymph node.
+     UICC/AJCC 8th edition staging systems recognize prognostic stratification according to the pattern of organ involvement by distant metastatic disease and have subclassified pM1 into pM1a indicating metastatic disease in 1 distant organ (excluding metastatic peritoneal disease), pM1b indicating metastatic disease in 2 distant organsand pM1c indicating metastatic peritoneal disease (regardless of other organ involvement).12,13 It is therefore important for pathologists to accurately document such disease and this is considered a core item for reporting. It should be noted that pathologists can only make a positive statement regarding distant metastatic disease, their assessment based on selected specimens submitted to them for examination, and therefore the terms ''pM0'' or ''pMX'' should no longer be used. cM1 and cM0 can be applied according to best radiological and intraoperative evidence available.
+Pathological Staging
+     The agreed criteria of the UICC and AJCC 8th editions are applied to derive TNM stage.12,13 The only exception is that this dataset does not advocate the use of pT in situ, as discussed above.
+     If completion surgery follows a diagnosis of carcinoma made in a local excision specimen, the pathological findings within both specimens should be considered in providing a single, overall TNM stage. Similarly, if a resection specimen contains synchronous primary carcinomas, each should be separately assessed and individual datasets completed, but a single overarching stage provided, following the conventions of TNM.
+DISCUSSION
+     Quality of pathology reporting and mutual understanding between colorectal surgeon and pathologist is vital to management and outcomes of CRC patients. It is well established that adoption of structured pathology reporting is associated with greater clinician satisfaction and improved access to pathology information relevant to patient management, as well as ease of returning pathology data for central registration purposes.71,72 Adoption of structured reporting helps ensure data is complete and it has been demonstrated for CRC to reduce the risk of missing assessment of important pathology features when compared to narrative reporting, especially for nonspecialist pathologists, thereby impacting patient care.72-74 There remains an important role, however, for a narrative component to pathology reports, explaining any areas of uncertainty or unusual pathological findings which may be pertinent to individual patient management and offer useful feedback to the surgeon.
+     Herein we have described the process of creation of such a dataset for CRC surgical resection specimens, involving an international panel of expert gastrointestinal pathologists from 9 countries and with representation from colorectal surgery and oncology. There was strong representation of authors of equivalent existing CRC datasets from the US, UK, and Australasia. A key aim of ICCR is to minimize the workload involved in production and regular update of such datasets in addition to standardization of reporting to facilitate international comparisons. Scrutiny of these existing national datasets illustrates the current problem of lack of uniformity.5-7 Although most of the content is uniform between datasets, there are subtle but important differences pertaining to numerous data items, which would hinder comparison. This is the first agreed international dataset for CRC pathology reporting. It is hoped that the various national datasets align with this ICCR version in the future.
+     This dataset is more extensive than the UICC/AJCC TNM cancer staging systems, which provide primarily a classification of anatomical extent of disease and represent the most powerful predictor of clinical outcome for many cancers. Incorporation of additional prognostically relevant morphological features into TNM staging is challenging. Some, specifically venous, lymphatic, and perineural invasion, can already be optionally recorded under the UICC/AJCC systems, not impacting the summary stage. However, as a result the prognostic impact of these features may not be fully considered in the clinical management of individual cases. More prominent integration of newly defined prognostic features into the TNM system will be complex, for example as described above for tumor deposits. Nevertheless, international discussion of such features is necessary to further the goals of reproducible consensus definitions and standardization of interpretation.
+     The ICCR aspires towidespread uptake of this freely available dataset by those countries currently lacking such a strategy, to improve the standard of pathology reporting of CRC globally. The greatest effect may be in low- and middle-income countries, where incidence of CRC has risen significantly.75 Standardized reporting will allow comparison of relative proportions of CRC subtypes between countries, assessment of the impact of new screening programs and participation in international trials targeting a specific molecular subset of CRC and requiring a minimum standard of pathology reporting.
+     To conclude, this internationally agreed freely available dataset provides a structured template for the pathological reporting of CRC surgical resection specimens. The ICCR initiative streamlines the dataset production process, both for new datasets and for regular updates as new evidence emerges. Such international collaborative efforts become more important with rapid progress in the fields of molecular pathology, digital pathology, and image analysis, allowing rapid translation of new developments, many relevant to surgical practice, into routine pathology reporting.
+ACKNOWLEDGMENTS
+     The authors thank Christina Selinger and the wider project team at ICCR for assistance in the production of this dataset and manuscript.
+REFERENCES
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+7. Royal College of Pathologists of Australasia. Colorectal cancer structured reporting protocol. 2016. Available from: https://www.rcpa.edu.au/getattachment/730b9fad-3228-4601-9009-b3d671818bd6/Protocol-colorectal-cancer.aspx. Accessed April 22, 2020.
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+34. Puppa G, Shepherd NA, Sheahan K, et al. Peritoneal elastic lamina invasion incolorectal cancer: the answer to a controversial area of pathology? Am J Surg Pathol. 2011;35:465-468.
+35. Freedman LS, Macaskill P, Smith AN. Multivariate analysis of prognosticfactors for operable rectal cancer. Lancet. 1984;2:733-736.
+36. Betge J, Pollheimer MJ, Lindtner RA, et al. Intramural and extramuralvascular invasion in colorectal cancer: prognostic significance and quality of pathology reporting. Cancer. 2012;118:628-638.
+37. Knijn N, van Exsel UEM, de Noo ME, et al. The value of intramural vascularinvasion in colorectal cancer-a systematic review and meta-analysis. Histopathology. 2018;72:721-728.
+38. Talbot IC, Ritchie S, Leighton M, et al. Invasion of veins by carcinoma ofrectum: method of detection, histological features and significance. Histopathology. 1981;5:141-163.
+39. Howlett CJ, Tweedie EJ, Driman DK. Use of an elastic stain to show venousinvasion in colorectal carcinoma: a simple technique for detection of an important prognostic factor. J Clin Pathol. 2009;62:1021-1025.
+40. Kirsch R, Messenger DE, Riddell RH, et al. Venous invasion in colorectalcancer: impact of an elastin stain on detection and interobserver agreement among gastrointestinal and nongastrointestinal pathologists. Am J Surg Pathol. 2013;37:200-210.
+41. Santos C, Lopez-Doriga A, Navarro M, et al. Clinicopathological risk factorsof Stage II colon cancer: results of a prospective study. Colorectal Dis. 2013;15:414-422.
+42. Lim SB, Yu CS, Jang SJ, et al. Prognostic significance of lymphovascularinvasion in sporadic colorectal cancer. Dis Colon Rectum. 2010;53:377-384.
+43. vanWykHC,RoxburghCS,HorganPG,etal.Thedetection androleof lymphaticand blood vessel invasion in predicting survival in patients with node negative operable primary colorectal cancer. Crit Rev Oncol Hematol. 2014;90:77-90.
+44. Ueno H, Shirouzu K, Eishi Y, et al. Characterization of perineural invasion as acomponentofcolorectalcancerstaging.AmJSurgPathol.2013;37:1542-1549.
+45. Knijn N, Mogk SC, Teerenstra S, et al. Perineural invasion is a strongprognostic factor in colorectal cancer: a systematic review. Am J Surg Pathol. 2016;40:103-112.
+46. Chang GJ, Rodriguez-Bigas MA, Skibber JM, et al. Lymph node evaluationand survival after curative resection of colon cancer: systematic review. J Natl Cancer Inst. 2007;99:433-441.
+47. Sloothaak DA, Sahami S, van der Zaag-Loonen HJ, et al. The prognostic valueof micrometastases and isolated tumour cells in histologically negative lymph nodes of patients with colorectal cancer: a systematic review and metaanalysis. Eur J Surg Oncol. 2014;40:263-269.
+48. Sobin LH, Gospodarowicz MK, Wittekind C, eds. Union for International Cancer Control. TNM Classification of Malignant Tumours. 7th ed, USA: Wiley-Blackwell; 2009.
+49. Edge SE, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed., New York: Springer; 2010.
+50. Nagtegaal ID, Knijn N, Hugen N, et al. Tumor deposits in colorectal cancer: improving the value of modern staging-a systematic review and meta-analysis. J Clin Oncol. 2017;35:1119-1127.
+51. Zlobec I, Lugli A. Epithelial mesenchymal transition and tumor budding inaggressive colorectal cancer: tumor budding as oncotarget. Oncotarget. 2010;1:651-661.
+52. Beaton C, Twine CP, Williams GL, et al. Systematic review and meta-analysisof histopathological factors influencing the risk of lymph node metastasis in early colorectal cancer. Colorectal Dis. 2013;15:788-797.
+53. Bosch SL, Teerenstra S, de Wilt JH, et al. Predicting lymph node metastasis inpT1 colorectal cancer: a systematic review of risk factors providing rationale for therapy decisions. Endoscopy. 2013;45:827-834.
+54. Cappellesso R, Luchini C, Veronese N, et al. Tumor budding as a risk factor fornodal metastasis in pT1 colorectal cancers: a meta-analysis. Hum Pathol. 2017;65:62-70.
+55. van Wyk HC, Park J, Roxburgh C, et al. The role of tumour budding inpredicting survival in patients with primary operable colorectal cancer: a systematic review. Cancer Treat Rev. 2015;41:151-159.
+56. Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumorbudding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol. 2017;30:1299-1311.
+57. Koelzer VH, Assarzadegan N, Dawson H, et al. Cytokeratin-based assessmentof tumour budding in colorectal cancer: analysis in stage II patients and prospective diagnostic experience. J Pathol Clin Res. 2017;3:171-178.
+58. Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patientswith a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835-844.
+59. Rodel C, Martus P, Papadoupolos T, et al. Prognostic significance of tumorregression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005;23:8688-8696.
+60. Ryan R, Gibbons D, Hyland JM, et al. Pathological response following longcourse neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology. 2005;47:141-146.
+61. Nagtegaal ID, Quirke P. What is the role for the circumferential margin in themodern treatment of rectal cancer? J Clin Oncol. 2008;26:303-312.
+62. Birbeck KF, Macklin CP, Tiffin NJ, et al. Rates of circumferential resectionmargin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Ann Surg. 2002;235:449-457.
+63. Scott N, Jamali A, Verbeke C, et al. Retroperitoneal margin involvement byadenocarcinoma of the caecum and ascending colon: what does it mean? Colorectal Dis. 2008;10:289-293.
+64. Bateman AC, Carr NJ, Warren BF. The retroperitoneal surface in distalcaecal and proximal ascending colon carcinoma: the Cinderella surgical margin? J Clin Pathol. 2005;58:426-428.
+65. National Institute for Health and Care Excellence. Molecular testing strategies for Lynch syndrome in people with colorectal cancer. 2017. Available from: https://www.nice.org.uk/guidance/dg27. Accessed August 28, 2020.
+66. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines() Colon Cancer. 2020. Available from: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed August 28, 2020.
+67. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predictsresponse of solid tumors to PD-1 blockade. Science. 2017;357:409-413.
+68. National Institute for Health and Care Excellence. Cetuximab and panitumumab for previously untreated metastatic colorectal cancer. Technology appraisal guidance. 2017. Available from: https://www.nice.org.uk/guidance/ta439/chapter/1-Recommendations. Accessed August 28, 2020.
+69. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations inpatients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51:587-594.
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+71. Lankshear S, Srigley J, McGowan T, et al. Standardized synoptic cancerpathology reports - so what and who cares? A population-based satisfaction survey of 970 pathologists, surgeons, and oncologists. Arch Pathol Lab Med. 2013;137:1599-1602.
+72. Srigley JR, McGowan T, Maclean A, et al. Standardized synoptic cancerpathology reporting: a population-based approach. J Surg Oncol. 2009;99: 517-524.
+73. Messenger DE, McLeod RS, Kirsch R. What impact has the introduction of asynoptic report for rectal cancer had on reporting outcomes for specialist gastrointestinal and nongastrointestinal pathologists? Arch Pathol Lab Med. 2011;135:1471-1475.
+74. Sluijter CE, van Workum F, Wiggers T, et al. Improvement of care in patientswith colorectal cancer: influence of the introduction of standardized structured reporting for pathology. JCO Clin Cancer Inform. 2019;3:1-12.
+75. Arnold M, Abnet CC, Neale RE, et al. Global burden of 5 major types ofgastrointestinal cancer. Gastroenterology. 2020;159:335-349.e315.
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+Loughrey et al	Annals of Surgery  Volume 275, Number 3, March 2022
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+Annals of Surgery  Volume 275, Number 3, March 2022	ICCR Colorectal Cancer Dataset
+     
+e550 |	www.annalsofsurgery.com	 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
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+ 2021 The Author(s). Published by Wolters Kluwer Health, Inc.	www.annalsofsurgery.com	| e551
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+Loughrey et al	Annals of Surgery  Volume 275, Number 3, March 2022
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+e550 |	www.annalsofsurgery.com	 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
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Dataset_for_Pathology_Reporting_of_Colorectal_Canc.txt

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+See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/352762126
+Dataset for Pathology Reporting of Colorectal Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR)
+Article  in  Annals of Surgery � June 2021
+DOI: 10.1097/SLA.0000000000005051
+
+CITATIONS	READS
+16	485
+The University of Edinburgh
+	415 PUBLICATIONS   15,887 CITATIONS   	201 PUBLICATIONS   5,505 CITATIONS   
+Oxford University Hospitals NHS Trust	French Institute of Health and Medical Research 262 PUBLICATIONS   9,524 CITATIONS   	290 PUBLICATIONS   8,006 CITATIONS   
+Some of the authors of this publication are also working on these related projects:
+Construction and analysis of tissue microarrays in the era of digital pathology: A pilot study targeting CDX1 and CDX2 in a colon cancer cohort of 612 patients View project
+Cancer Stem Cells View project
+All content following this page was uploaded by Mark Arends on 01 August 2022.
+The user has requested enhancement of the downloaded file.
+     
+REVIEW PAPER
+
+Dataset for Pathology Reporting of Colorectal Cancer
+Recommendations From the International Collaboration on Cancer Reporting (ICCR)
+Maurice B. Loughrey, MRCP, FRCPAth, MD,y Fleur Webster,z Mark J. Arends, MD, PhD, FRCPath,�
+Ian Brown, MBBS, BGEN, FRCPA, Lawrence J. Burgart, MD,jj
+Chris Cunningham, BSC (Hons), MBChB, MD, FRCSEd, Jean-Francois Flejou, MD, PhD,yy
+Sanjay Kakar, MD,zz Richard Kirsch, MBChB, PhD, FRCPath(SA), FRCPC,�� Motohiro Kojima, MD, PhD,
+Alessandro Lugli, MD,jjjj Christophe Rosty, MD, PhD, FRCPA,yyyzzz
+Kieran Sheahan, MB, FRCPI, FRCPath,��� Nicholas P. West, MBChB, PhD, FRCPath,
+Richard H. Wilson, MD,jjjjjj and Iris D. Nagtegaal, MD, PhDY
+
+     
+Objective: The aim of this study to describe a new international dataset for pathology reporting of colorectal cancer surgical specimens, produced under the auspices of the International Collaboration on Cancer Reporting (ICCR).
+Background: Quality of pathology reporting and mutual understanding between colorectal surgeon, pathologist and oncologist are vital to patient management. Some pathology parameters are prone to variable interpretation, resulting in differing positions adopted by existing national datasets.
+     
+
+From the Centre for Public Health, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK; yDepartment of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK; zInternational Collaboration on Cancer Reporting, Sydney, NSW, Australia; �Division of Pathology, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK; Envoi Pathology, Kelvin Grove, QLD, Australia; jjDepartment of Pathology, Virginia Piper Cancer Institute, Abbott Northwestern Hospital, Minneapolis, MN; Department of Colorectal Surgery, Churchill Hospital, Oxford University Hospitals NHSFT, Oxford, UK; yyDepartment of Pathology, Saint-Antoine Hospital, Sorbonne University, Paris, France; zzDepartment of Pathology, University of California San Francisco, San Francisco, CA; ��Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Kashiwa, Japan; jjjjInstitute of Pathology, University of Bern, Bern, Switzerland; Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia; yyyEnvoi Specialist Pathologists, Brisbane, QLD, Australia; zzzDepartment of Pathology, University of Melbourne, Melbourne, VIC, Australia; ���Department of Pathology, St Vincent's University Hospital & University College, Dublin, Ireland; Pathology and Data Analytics, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK; jjjjjjInstitute of Cancer Sciences, University of Glasgow, Glasgow, UK; and Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
+Iris.Nagtegaal@radboudumc.nl.
+Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
+Declarations of interest: none.
+Authorship justification: This manuscript describes the creation of a new International Collaboration on Cancer Reporting dataset for pathology reporting of colorectal cancer surgical resection specimens. This first internationally agreed dataset for colorectal cancer pathology reporting represents the culmination of a series of web meetings and protracted e-mail exchanges over several years discussing, agreeing and finalising content amongst an international authorship, representing four continents and nine countries. All authors were deeply involved in this process, (a) making substantial contributions to one or more dataset items (b) participating in either drafting specific manuscript sections or reviewing critically for intellectual content; and (c) approving the final version for publication.
+The authors report no conflicts of interest.
+This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
+Copyright  2021 The Author(s). Published by Wolters Kluwer Health, Inc.
+ISSN: 0003-4932/21/27503-e549
+DOI: 10.1097/SLA.0000000000005051
+Annals of Surgery  Volume 275, Number 3, March 2022
+Methods: The ICCR, a global alliance of major pathology institutions with
+links to international cancer organizations, has developed and ratified a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Here we describe the production of a dataset for colorectal cancer resection specimens by a multidisciplinary panel of internationally recognized experts.
+Results: The agreed dataset comprises eighteen core (essential) and seven non-core (recommended) elements identified from a review of current evidence. Areas of contention are addressed, some highly relevant to surgical practice, with the aim of standardizing multidisciplinary discussion. The summation of all core elements is considered to be the minimum reporting standard for individual cases. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or non-core.
+Conclusions: This first internationally agreed dataset for colorectal cancer pathology reporting promotes standardization of pathology reporting and enhanced clinicopathological communication. Widespread adoption will facilitate international comparisons, multinational clinical trials and help to improve the management of colorectal cancer globally.
+Keywords: colorectal cancer, dataset, guidelines, ICCR, protocol, structured report, synoptic report
+(Ann Surg 2022;275:e549-e561)
+P
+athology reporting of cancer resection specimens, through provision of histological subtype, grade, stage, and other clinically relevant information, impacts on individual patient management and prognosis. At a population level, it provides data for cancer registrations, epidemiological audits, and research including clinical trials.1,2 Tissue-based cancer research also partly relies on histopathological stage, the presence high-risk features, and molecular pathological subtypes. Standardization of pathology evaluation of cancer resection specimens and reporting of individual features is essential, to allow valid comparison of data between cohorts and countries, to allow assessment of the impact of new screening programs and to allow participation in multicenter trials. However, some pathology parameters are prone to variable or evolving interpretation, resulting in differing positions adopted by various national datasets in existence or an inability to reach consensus, manifest as a lack of clearly expressed guidance for certain contentious areas. This is evidenced by regular changes made to TNM staging systems as new evidence and new interpretations emerge. For some issues, clear guidance is simply unavailable.
+     Alloftheseprinciplesapplytocolorectalcancer(CRC)andsome such issues impact directly on surgical practice and staging. For example, the minimum distance of tumor from a margin required to label as ''clear,'' the interpretation of regional, discontinuous ''tumor deposits,'' and the interpretation of surgical resection margin status when this is involved by tumor not continuous with the primary tumor.3 If there is limited evidence, clear consensus-based guidelines, based on best available evidence and expert opinion, are helpful to assist pathologists in case by case reporting and surgeons and oncologists in clinical management of their patients. Close liaison between surgeon and pathologist, and good surgical understanding of pathology reporting guidelines and practice are key to maximizing the quality of pathology reports and their value to the surgeon and ultimately the patient.
+     Pathology protocols and datasets are well established in some countries and have been independently developed at national level by organizations including the College of American Pathologists (CAP), USA, the Royal College of Pathologists (RCPath), United Kingdom (UK), and the Royal College of Pathologists of Australasia (RCPA). Although these organizations' protocols broadly align, there are significant differences in structure, content and terminology and some subtle differences in interpretation that could hinder international comparison. Standardization of existing national cancer reporting datasets would also have the added benefits of reducing the global burden of regular dataset production and of providing a single benchmarking reference available to other countries.
+     Withthisinmind,in2011,anumberofpathologyorganizations including the CAP, RCPath, and RCPA formed the International Collaboration on Cancer Reporting (ICCR) and successfully piloted the developmentofdatasets for pathologyreporting ofa selectnumber of cancers. The subsequent ICCR development has been described previously in detail.4 The ICCR has developed important strategic alliances with other international cancer organizations including the International Agency forResearch onCancer (IARC)whichisresponsible for producing the World Health Organization (WHO) monographs or ''Blue Books'' on tumor classification and the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC). These partnerships facilitate the co-ordination of dataset production with new classifications and staging systems. The ICCR datasets are freely available from the ICCR website (http:// www.iccr-cancer.org/datasets). Here we describe the production of such a dataset for CRC surgical resection specimens by a panel of internationally recognized expert pathologists and other clinicians, supported by the ICCR. Areas of contention or divergence are addressed, with the aim of offering a consensus position to standardize interpretation and multidisciplinary discussion.
+METHODS
+     TheICCRhas developed a rigorous processfor theproduction of individual datasets (http://www.iccr-cancer.org/datasets/dataset-development). This process has been described in detail in previous publications (http://www.iccr-cancer.org/articles/publications). The ICCR quality framework dictates both content and presentation and the roles and responsibilities of all involved are clearly outlined. In brief, the Dataset Steering Committee (DSC) of the ICCR appointed a ''Series Champion'' (IN) to coordinate the simultaneous development of a related suite of five datasets all pertaining to gastrointestinal and pancreaticobiliary tract cancers, and a Chair (M.B.L.) to oversee productionoftheCRCresectiondataset.Afurther11expertgastrointestinal pathologists, comprising 2 each from the United States (L.B., S.K.), UK (M.A.,N.W.),andAustralia (I.B.,C.R.)and 1 eachfromCanada(R.K.), Japan (M.K.), France (J.F.), Ireland (K.S.), and Switzerland (A.L.), together with a colorectal surgeon (C.C.) and a colorectal oncologist (R.W.) comprised the 15 members of the Dataset Authoring Committee (DAC). Lead authors of the current CAP, RCPath, and RCPA CRC datasets were included.5-7 The group was coordinated by an ICCR Project Manager (F.W.), assuring optimal communication within the international group and adherence to agreed timelines.
+     Regarding scope, this dataset was developed for the reporting of pathology specimens resulting from major surgical resection of primary carcinomas arising within the colon and rectum. This includes neuroendocrine carcinomas (NECs) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs).2 It is not applicable to carcinomas of the small intestine, appendix or anus, nor to neuroendocrine tumors (NETs) or nonepithelial malignancies, as these are subject to different classifications and staging systems. Furthermore, primary CRC treated by local excision are the subject of a separate ICCR dataset, as specimen handling and reporting of these differ from major surgical resection specimens.
+     An initial draft document was produced by the Project Manager and Chair after scrutiny of core and non-core data items within existing CAP, RCPath, and RCPA CRC datasets and review of present published evidence. This draft was circulated and individual dataset items discussed among the DAC at a coordinated series of teleconferences, following which an agreed draft dataset was posted for open international consultation on the ICCR website for a period of 2 months. All comments received were discussed by the DAC and, where agreed, resultant changes incorporated into the final dataset, which was ratified by the DSC before publication. The final agreed dataset is available at http://www.iccr-cancer.org/datasets/publisheddatasets/digestive-tract/colorectal.
+     The ICCR dataset style lists a set of reporting elements and value lists (responses) accompanied by a commentary for each, explaining the element and categorization, offering guidance for reporting, citing relevant evidence, and, where applicable, definitions for the value lists. Each element is categorized as either core or noncore. Core elements are those unanimously agreed by the expert panel to be essential for diagnosis, prognostication and/or patient management. These generally required evidentiary support at Level III-2 or above [based on prognostic factors in the National Health and Medical Research Council (NHMRC) levels of evidence document, and defined as ''Analysis of prognostic factors amongst persons in a single arm of a randomized controlled trial''].8 Non-core elements were those that did not meet the above criterion but were considered by the panel to be clinically important, representing good practice but not currently fully validated for routine clinical practice. Specific levels of evidence were not assigned to each core or non-core element. The summation of all core elements is considered to be the minimum reporting standard for individual cases.
+RESULTS
+     A summary of the agreed core and non-core elements is presented in Table 1 and each is described in further detail below:
+Clinical Information
+     Knowledge of relevant clinical information, such as an underlying polyposis syndrome, Lynch syndrome or chronic inflammatory bowel disease, is essential for optimal specimen sampling and histological interpretation. However, as it is beyond the control of the pathologist to ensure this information is available, it is considered a non-core rather than a core item.
+     Two specific items represent exceptions to this rule, given their importance, and are considered core. Firstly, information on neoadjuvant therapy, including type and duration, is a core item and must always be provided to the pathologist, as response to therapy can influence stage and tumor morphology, potentially altering interpretation. Staging should be provided with a ''y'' prefix.
+     Secondly, the nature of the operative procedure is a core item (Table 1), and additional information may be provided clinically, such as the attempted dissection plane in an abdominoperineal excision. Distinction of high from low anterior resection, the latter defined by inclusion of the peritoneal reflection within the specimen, is considered non-core. If the operative specimen includes any additional tissue or organs, for example en bloc resection of a separate segment of intestine or abdominal wall connective tissue or a more extensive anterior exenteration specimen (Fig. 1), details of
+TABLE 1. Core and Non-Core Elements for Reporting
+Operative procedure
+Tumor site
+Tumor dimensions (maximum)
+Perforation
+Relation of tumor to anterior peritoneal reflectionPlane of mesorectal excision Histological tumor type
+Histological tumor grade
+Extent of invasion
+Lymphatic and venous invasion
+Perineural invasion
+Lymph node status
+Tumor deposits
+Response to neoadjuvant therapy
+Margin status
+Histologically confirmed distant metastases
+Pathological staging
+Ancillary studies
+Plane of sphincter excision
+Plane of mesocolic excision
+Measurement of invasion beyond muscularis propria
+Tumor budding
+Coexistent pathology
+Ancillary studies
+These items are only relevant to certain specimen types-see text for details.
+Tumor Site
+     If a specimen contains multiple tumors, these should all be documented individually and separate datasets completed for each. Tumor location is a core item, stated in the clinical information provided and confirmed by macroscopic specimen examination. It can be difficult to identify specific location in the colon within an ex vivo specimen, particularly in relation to the flexures. If clinical and pathological tumor locations are discordant, this should be documented by photography and discussed with the clinical team. Recording the anatomical site allows
+     
+FIGURE 1. A fresh anterior exenteration specimen comprising abdominoperineal excision of the rectum and anus with en bloc levator ani muscles, prostate, seminal vesicles and bladder.
+
+FIGURE 2. Rectal anatomy and possible relationships of rectal cancers to the peritoneal reflection. Adapted by permission from
+Nicholas P. West and Philip Quirke: Springer Multidisciplinary Treatment of Colorectal Cancer (G. Baatrup, ed.); Quality of Surgery
+     
+by Nicholas P. West and Philip Quirke (2021).
+correlation with prior endoscopic and radiological investigations, indicates whether or not a nonperitonealized margin is likely to be present andpermitsclassificationoflymphnodesasregionalversusnonregional. Distinction ofcolonic from rectalorigin is ofimportance, given different biology, clinical features, management, and risks of peritoneal versus local recurrence. This classification can be subjective, especially for moreadvanced stagetumors.Ifatumorstraddles2sites,thesitewiththe greatest tumor bulk should be recorded. The rectosigmoid boundary is markedbyfusionofthethreetaeniaecoliofthesigmoidcolontoformthe circumferentiallongitudinalmuscleoftherectalwall.Ifadvancedtumor growth obliterates these anatomical landmarks, the tumor site should be retrieved from available clinical and radiological information.9 Classification as rectosigmoid should be reserved for cases in which an accurate determination between rectum and sigmoid cannot be made by above methods.
+Tumor Dimensions
+     Tumor size has no prognostic significance for CRC and does not directly influence staging. Despite this, maximum dimension is considered a core data item, as it is baseline information which allows correlation with preoperative clinical, endoscopic, and radiological assessments. It should be based on a combination of macroscopic and microscopic assessment and, if possible, exclude any associated inflammatory component or preinvasive lesion, which may be noted in a comment for clinicopathological correlation. Additional tumor dimensions may be provided as non-core data.
+Perforation
+     Tumor perforation into the peritoneal cavity is a well-established adverseprognosticfactorinCRC 10,11 anditspresenceorabsenceshould be recorded as a core item. Tumor perforation is defined as a macroscopicallyvisiblefullthicknessdefect,suchthatthebowellumenwithin the segment involved by tumor is in communication with the external surface of the resection specimen or with the lumen of another organ. Cases with tumor perforation are regarded as pT4a.12,13 Note that tumor perforation requires penetration of the serosal surface. Peritumoral abscess cavity, for example, within the mesentery, that is contained anddoesnotdemonstratebreachoftheserosalsurface,isnotconsidered perforation and is considered pT3 rather than pT4a. This may be commonly encountered in the setting of sigmoid diverticular disease complicated by CRC. Perforation of the colon resulting from a more distal obstructing tumor is distinct from tumor perforation and is not interpretedaspT4disease.However,thisshouldstillberecordedasnontumor perforation is associated with higher mortality risk.
+     Some confusion can be introduced when using the term perforation for other settings, such as when a full thickness defect arises intraoperatively. We consider the term perforation is best reserved for the biological setting, as the clinical impact is likely different depending on the scenario. If an iatrogenic full thickness tumor defect arises whilst the specimen is in situ within the abdominal cavity, there is likely some risk of tumor seeding the peritoneal cavity and we consider this is best regarded as pT4a disease. This interpretation is however offered without good evidence. In contrast, if such an iatrogenic defect occurs once the specimen is outside the abdominal cavity, this should not influence pT classification. Interpretation therefore requires close clinicopathological correlation and this should always be explained in the pathology report.
+Relation of Tumor to Anterior Peritoneal Reflection
+     For rectal cancers, the relationship of the tumor to the anterior peritoneal reflection is reported as a core item, as this predicts the risk of local recurrence in addition to peritoneal recurrence (Fig. 2).14 The anterior aspect of the rectum has a peritoneal covering to the level of the peritoneal reflection. Posteriorly, the nonperitonealized margin is represented by a triangular-shaped bare which extends superiorly in continuity with the mesentery of the sigmoid colon.
+Plane of Mesorectal Excision
+     Prospective randomized controlled trials have demonstrated that, in patients with rectal cancer, use of total mesorectal excision (TME) surgery improves local recurrence rates and the survival by up to 20%.15,16 Furthermore, objective macroscopic assessment by pathologists of the surgical plane of excision predicts margin involvement, local recurrence and survival.14,17 This grading is therefore considered a core item for reporting. The optimal plane is that of the mesorectal fascia (complete TME) whilst excision extending onto the muscularis propria (incomplete TME) is associated with the worst outcomes. Overall macroscopic assessment of the intact specimen, with grading based on the worst area, is as described in Table 2 and illustrated in Figure 3.
+Plane of Sphincter Excision
+     In considering management of rectal cancer, abdominoperineal excision for lower tumors has been associated with poorer outcomes compared to anterior resection for higher tumors, due to increased rates of circumferential resection margin (CRM) involvement and intraoperative full thickness defects, referred to as perforation in this literature.18 More radical surgery to remove more tissue around low rectal tumors by en bloc resection of the levator muscles, extralevator abdominoperineal excision, reduces the risk of CRM involvement and intraoperative full thickness defects leading to better long term outcomes.19,20 Using staging magnetic resonance imaging (MRI), radiologists are able to predict the optimal dissection plane for abdominoperineal excision surgery.21 Subsequent correlation with pathological assessment of the intact
+TABLE 2. Pathological Assessment of Rectal and Colonic Cancer Surgical Resection Specimens
+Intact bulky mesorectum with a smooth surface
+Only minor irregularities of the mesorectal surface
+No surface defects >5 mm in depth
+No coning towards the distal margin of the specimen
+Moderate bulk to the mesorectum
+Irregularity of the mesorectal surface with defects >5mm, but none extending to the
+muscularis propria
+Moderate coning may be evident distally
+No areas of visibility of the muscularis propria except at the insertion site of the levator ani muscles
+Little bulk to the mesorectum
+Defects in the mesorectum down to the muscularis propria
+After transverse sectioning, the circumferential margin appears very irregular and is formed by muscularis propria in areas.
+Dissection plane lies external to the external sphincter and levator ani muscles, which are removed en bloc with
+the mesorectum and anal canal
+Cylindrical-shaped specimen with the levators forming an extra protective layer above the sphincters
+No significant defects into the sphincter muscles or levators
+Dissection plane lies on the surface of the sphincter muscles
+No levator ani muscle attached or only a very small cuff leading to coning or surgical waisting at the level of puborectalis
+No significant defects into the sphincter muscles
+Dissection plane lies within the sphincter muscles or even deeper into the submucosa
+Full thickness iatrogenic defect of the specimen at any point below the peritoneal refection.
+Smooth surface to the mesocolon (mesocolic fascia and peritoneum)
+Only minor irregularities
+No surface defects >5mm in depth
+Irregularity of the mesocolic surface with defects >5mm, but none extending to the muscularis propria
+Defects in the mesocolon down to the muscularis propria
+After transverse sectioning, the mesocolic margin is irregular and formed by muscularis propria in areas.
+Plane of Mesocolic Excision
+     Beyond assessment of rectal cancer surgery, the quality of surgical technique for colonic cancer, evaluating the plane of mesocolic excision, has been shown, in retrospective observational studies and 1 randomized clinical trial, to predict outcomes.22 Surgery in the mesocolic plane is associated with a lower rate of local recurrence and better survival when compared to surgery in the muscularis propria plane. Complete mesocolic excision, where surgery occurs in the mesocolic plane with a high vascular ligation, is associated with better plane of surgery and higher lymph node yield, although the effect of the high ligation on long term outcomes is uncertain and subject to further study.23 Pathological evaluation of mesocolic surgery is considered a non-core data item, as its application requires further validation in clinical practice. Overall assessment is based on theworst area, as described in Table 2 and illustrated in Figure 3.22
+FIGURE 3. Planes of colorectal cancer surgery for the mesorectum (A-C), sphincters (D-F) and mesocolon (G-I). For the mesorectum, applicable to all rectal cancer specimens, the planes include the mesorectal plane, with intact mesorectum (A), intramesorectal plane, with mesorectal defect (B) and muscularis propria plane, with little bulk to mesorectum and exposure of muscularis propria (C). For the sphincters, applicable to all abdominoperineal excisions in addition to the mesorectal plane, the planes include the extralevator plane (D), sphincteric plane (E) and intrasphincteric plane (F). The extralevator specimen includes en bloc resection of the levator ani muscles and coccyx thus preventing the creating of a surgical waist (D). The intrasphincteric plane specimen includes a large anterior perforation (F). For the mesocolon, applicable to all colon cancer specimens, the planes include the mesocolic plane, with intact mesocolon (G), intramesocolic plane, with mesocolic defect (H) and muscularis propria plane, with ragged mesocolon and exposure of muscularis propria (I). Adapted by permission from Nicholas P. West and Philip Quirke: Springer Multidisciplinary Treatment of Colorectal Cancer (G. Baatrup, ed.); Quality of Surgery by Nicholas P. West and Philip Quirke (2021).
+     The WHO Classification of Tumors of the Digestive System is recommended for tumor typing as a core item.2 Almost all CRC are adenocarcinomas, most of which are of no specific type or ''not otherwise specified'' (NOS). Specific subtypes of adenocarcinoma are recognized and defined as follows:
+     Mucinous adenocarcinoma has >50% of the tumor comprised of pools of extracellular Mucin, containing malignant glands, or individual tumor cells. Microsatellite instability is more common, as is the presence of an activating BRAF V600E mutation.
+     Signet-ring cell adenocarcinoma has >50% of the tumor demonstrating signet-ring cell morphology, in the form of malignant cells with intracytoplasmic mucin, displacing and typically indenting the nuclei. Signet-ring cell adenocarcinoma is associated with worse stage-for-stage survival relative to conventional adenocarcinoma.2 Like mucinous adenocarcinoma, there is a strong association with microsatellite instability and BRAF V600E mutation.2
+     Medullary carcinoma demonstrates solid sheets of malignant cells with indistinct cell boundaries, vesicular nuclei, prominent nucleoli, abundant eosinophilic cytoplasm, and prominent intratumoral and peritumoral inflammatory infiltrates. Almost invariably these tumors demonstrate microsatellite instability and are associated with a good prognosis.2
+     Serrated adenocarcinoma by definition demonstrates glandular serrations, often slit-like, and tumor cells usually have low nuclear to cytoplasmic ratio with abundant eosinophilic or clear cytoplasm and sometimes accompanied by areas of mucinous differentiation.2 BRAF or KRAS activating mutations are common.
+     Micropapillary adenocarcinoma is characterized by small, rounded clusters of tumor cells lying within stromal spaces mimicking vascular channels. At least 5% of the tumor should demonstrate this feature for this classification. There is an association with adverse pathological features including extramural venous invasion and lymph node metastatic disease.2
+     Adenoma-like adenocarcinoma is a subtype of adenocarcinoma in which at least 50% of the invasive tumor has an adenomalike appearance with villous architecture, low-grade cytology, a pushing growth pattern, and minimal desmoplastic stromal reaction.2 Demonstration of invasion is difficult on endoscopic biopsy. This subtype is associated with a good prognosis.
+     Neuroendocrine neoplasms of the gastrointestinal tract are currentlyclassifiedintoNETs,NECsandMiNENs.2 ThetermMiNEN incorporatestheprevioustermmixedadenoneuroendocrinecarcinoma (MANEC), in recognition that occasionally the non-neuroendocrine componentofmixedtumorsmay not beanadenocarcinoma. NETsare now graded 1 to 3 on the basis of mitotic count and Ki-67 proliferation index, with NET grade 3 recognizing a subset of tumors previously meeting criteria for NEC, but found to be less responsive to platinumbased chemotherapy, yet have better survival compared to other NECs.24 Grade 3 NETs are better differentiated than NECs and the primary distinction is morphological. MiNENs are usually composed of a poorly differentiated NEC component and a conventional adenocarcinomaNOScomponentandeachshouldarbitrarilyconstitute30% ofthetumorforthisdesignation.ThisdatasetisapplicabletoNECsand MiNENs but, given different staging and grading systems applied, NETs should not be reported using this dataset.
+     Other epithelial tumors rarely encountered include adenosquamous carcinoma, carcinoma with sarcomatoid components, undifferentiated carcinoma, squamous cell carcinoma, and non-signetring cell poorly cohesive adenocarcinoma.
+Histological Tumor Grade
+     Although subject to poor interobserver agreement,25 histological grade of CRC, based on gland formation, is an independent prognostic factor and is a core item.26,27 A 2-tiered grading system is more reproducible and favored over a 4-tiered grading system. Aligning with the latest WHO classification,2 grading is based on the least differentiated component, rather than predominant pattern, although this is recommended without good evidence and a minimum area of high-grade tumor required for classification as highgrade has not been defined. Tumor buds or poorly differentiated clusters, most commonly seen at the invasive front, should not be considered in the evaluation of grade. Grading based on poorly differentiated clusters may be superior to conventional grading with respect to both prognostic value and reproducibility but further studies are required in this regard.28
+     According to the latest WHO classification, only adenocarcinoma NOS and mucinous adenocarcinoma should be graded.2 Grading is not applicable to other subtypes of adenocarcinoma, as assessment of gland formation is difficult to apply to subtypes and most subtypes are associated with their own clinical prognosis independent of grade. Mucinous adenocarcinoma should be graded on glandular formation and epithelial maturation.2
+Extent of Invasion
+     Local invasion depth of CRC is categorized by the pT classification. This is the most important prognostic factor in CRC and is a core data item, using UICC and AJCC 8th edition criteria.12,13 The onlyexceptionisthatpTinsituisnotrecognizedinthis dataset.Thisis somewhat contentious and rare cases of colorectal neoplasia confined to invasion of the lamina propria (intramucosal invasive neoplasia or intramucosal carcinoma) are acknowledged but, given the negligible metastatic potential ofsuch neoplasms,29 the consensus position ofthe DAC was that these should be classified under the same category as high grade dysplasia/high grade noninvasive neoplasia.
+     Given the clear anatomical delineation of the muscularis propria at most sites, defining pT1-pT3 tumors, classification of this extent of invasionisnotoftenproblematic.Anexceptionisthelowrectum,where complexities of sphincter anatomy make accurate assessmentof level of invasionchallenging.Theinternalsphincterrepresents acontinuation of the muscularis propriaandinvasion ofthisalso constitutes pT2.Skeletal muscle fibers can cross-over from external to internal sphincter and therefore invasion of skeletal muscles fibers may only represent pT2 disease if these fibers are from the internal sphincter. Invasion beyond internal sphincter into the intrasphincteric plane, but not involving the external sphincter, is considered pT3. Note that in some areas of the sphincter complex the internal and external sphincter muscles are directly apposed with only a theoretical space between.
+     pT4 includes tumor infiltration of the peritoneal surface (pT4a) or involvement of an adjacent organ or structure (pT4b). Peritoneal involvement has been demonstrated by multivariate analysis to have a negative impact on prognosis.30 Data from a cohort of >100,000 colon cancer cases indicate that pT4a carcinomas have on average a 10% to 20% better 5-year survival than pT4b carcinomas for each pN category.31 Involvement of the peritoneal surface requires tumor breaching the serosa with tumor cells visible either on the peritoneal surface, free in the peritoneal cavity or separated from the peritoneal surface by inflammatory cells only.10 If tumor passes close to the serosal surface and elicits a mesothelial reaction without clear invasion, this is categorized as pT3, although additional sections and/or multiple levels should be examined to look deeper invasion. This setting is prone to interobserver variation however.32 Elastic stains to identify peritoneal elastic lamina invasion are advocated in some studies, as a staging or prognostic tool.33,34 Cases with tumor perforation are classified as pT4a, without the need to document tumor cells on the peritoneal surface.
+     It is important to distinguish peritoneal involvement through direct continuity with the primary tumor from discontinuous peritoneal deposition. The former indicates pT4a disease, whereas the latter is regarded as distant metastatic disease, pM1c. It is also important to distinguish involvement of a peritoneal surface from involvement of a nonperitonealized resection margin. Peritoneal involvement is a risk factor for peritoneal metastases whilst margin involvement is a risk factor for local recurrence.
+     Adjacent organ involvement by tumor (pT4b) may follow peritoneal invasion or, for example in low rectal tumors, represent direct extraperitoneal invasion. If a tumor is macroscopically adherent to another organ, microscopic invasion must be demonstrated to classify as pT4b; otherwise, the adherence is considered inflammatory in nature. Longitudinal tumor extension into the wall of an adjacent segment of the intestine does not influence pT classification. Rectal tumors invading skeletal muscle of the external sphincter and/ or levator ani are classified as pT4b.
+Measurement of Invasion Beyond Muscularis Propria
+     Prognosis of patients with pT3 tumors can be stratified accordingly to their extent of invasion of the primary tumor beyond the muscularis propria, with 5 mm an accepted cut-off for higher risk in some studies.29 Based on the level of existing evidence, this is considered a non-core item for reporting. The distance beyond the muscularis propria is measured to the nearest mm from the outer margin of the muscularis propria. In the event of local tissue destruction by tumor, reconstruction of this outer margin may be required for the purposes of measurement. The measurement should be performed macroscopically and refined microscopically if appropriate.
+Lymphatic and Venous Invasion
+     The presence or absence of lymphovascular invasion has strong prognostic implications for CRC and this should be reported as a core item. Classification is required according to the type of vessels involved (Fig. 4) and, for veins, their intramural or extramural location, as the vessel type and location have different clinical and prognostic implications. Extramural venous invasion, present beyond the muscularis propria, has the greatest clinical significance, having been demonstrated on multivariate analysis in multiple studies to be a stage-independent adverse prognostic factor.35 Intramural venous invasion, identified within the submucosa or muscularis propria but not beyond, is also of prognostic importance but the evidence is much weaker than for extramural venous invasion.10,36,37
+     The minimum criteria for calling venous invasion are debatable. The longstanding definition of Talbot et al (1981) is approved, whereby venous invasion is defined as tumor present within an endothelium-lined space that is either surrounded by a rim of muscle or contains red blood cells.38 Proximity of a rounded or elongated deposit of tumor beside an artery should raise suspicion of venous invasion but is not diagnostic without identification of a residual venous wall. Examination of further levels and additional stains may help interpretation.39,40 A circumscribed tumor nodule surrounded by a smooth muscle wall or an identifiable elastic lamina is considered sufficient to classify as venous invasion.
+     Small vessel invasion is defined as 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, and invasion of these should be distinguished from large vessel (venous) invasion. D2-40 immunohistochemistry, which only stains lymphatic endothelial cells, not venular, can be used to classify small vessel invasion further but this is not in routine use in this setting. Small vessel invasion of all forms is considered under the ''L'' classification under UICC/AJCC TNM 8th editions.12,13 The identification of small vessel invasion has been reported in some but not all studies to be associated with lymph node metastatic disease and represent an independent prognostic factor.36,41-43 The relative importance of intramural and extramural anatomic location with respect to small vessel invasion has not been well established.36
+Perineural Invasion
+     The presence of perineural invasion in CRC (Fig. 4) has adverse prognostic implication, particularly in stage II disease.41,44,45 Although the importance of anatomic location in perineural invasion is not well established, 1 large multicenter study, reported adverse prognostic significance for both intramural and extramural locations.44 The presence or absence of any perineural invasion is therefore considered a core item but it is not necessary to specify anatomical location.
+Lymph Node Status
+     Regional lymph node status determines the need for adjuvant chemotherapy and is a core item. Nonregional lymph node involvement is distant metastatic (pM1) disease. If a specimen contains synchronous primary tumors in distinct anatomic regions, attempt should be made to assign lymph nodes by regional status and each cancer assessed for nodal status separately.
+     It is important to perform a diligent pathological dissection to identify all lymph nodes in a specimen as lymph nodes containing metastatic disease may be very small. Individual dissectors and departments should aim for a median lymph node yield of at least 12 per case. Low lymph node harvest is an adverse prognostic factor in stage II disease.46 This reflects a combination of inadequate nodal retrieval and unfavorable patient immunology.
+     Micrometastases (size between 0.2mm and 2mm) are associated with recurrence in stage I/II CRC compared to tumor-negative nodes, but there is no increased risk of disease recurrence in the presence of ''isolated tumor cells'' (single tumor cells or groups <0.2mm in maximum dimension) compared to tumor-negative nodes.47 Therefore, any lymph nodes containing micrometastatic or larger tumor foci are considered as positive nodes whereas isolated tumor cells, identified on H&E or immunohistochemical staining, when representing the only form of nodal involvement should be classified as pN0, with a comment indicating the presence of isolated tumor cells and optional designation as pN0(i�).
+     Following neoadjuvant therapy, only the identification of viable tumor constitutes nodal involvement (ypN1/2). Necrosis, fibrosis or acellular mucin within lymph nodes in this setting is not considered nodal tumor involvement. Nevertheless, a descriptive comment of these findings indicates likely response to therapy and allows correlation with initial staging MRI.
+Tumor Deposits
+     The term tumor deposit, or satellite, was introduced in the UICC/AJCC TNM 7th editions48,49 and the concept refined in UICC/ AJCC TNM 8th editions: discrete macroscopic or microscopic nodules of cancer in the pericolorectal adipose tissue's lymph drainage area of a primary carcinoma that are discontinuous from the primary and without histological evidence of residual lymph node or identifiable vascular or neural structures (Fig. 4).12,13 If a vessel wall is identifiable on H&E, elastic or other stains, it should be classified as venous invasion or lymphatic invasion and if neural structures are identifiable in association with the tumor, the lesion should be classified as perineural invasion rather than as a tumor deposit. A minimum size of deposit or minimum distance of separation from the primary tumor, or further other deposits, is not specified. Neither is guidance on how to classify mesenteric tumor which demonstrates lymphatic, venous or perineural invasion, but where the bulk of the tumor appears unrelated to the vascular or neural structure. The identification of a tumor deposit is considered under the node (N) rather than primary tumor (T) status for the purposes of staging and tumor deposits in the absence of lymph node metastases are classified as pN1c. In the presence of lymph node metastases, tumor deposits are discounted for staging purposes. However, there is evidence from meta-analysis of the adverse prognostic significance of tumor deposits in the presence of lymph node metastatic disease, based on the UICC/AJCC TNM 7th editions48,49 definition, and therefore the presence and number of identified tumor deposits should be recorded in all cases, as a core item.50
+     Mesenteric tumor, without evidence of origin, which is discontinuous from the primary tumor and predominantly subserosal in location but which penetrates the serosal surface of the mesentery, should be classified as a tumor deposit rather than as distant metastatic (pM1c) disease. This does not influence the pT category, which should be based on extent of local invasion of the primary tumor only. However, given serosal involvement by the tumor deposit may equate clinically to pT4a disease, a comment may be usefully added to this effect. Guidance on this interpretation is offered without good evidence. pM1c disease should be reserved for cases where the tumor appears to have arisen from metastatic spread via the peritoneal cavity.
+     In the setting of tumor regression following administration of neoadjuvant therapy, the distinction of discontinuous residual primary tumor foci from tumor deposit is difficult and subjective. To facilitate uniform interpretation, it is recommended that designation as tumor deposit should necessitate the presence of intervening normal tissue, rather than just fibrosis or acellular mucin.
+     
+
+FIGURE4. Metastatic pathways in colorectal cancer. A, Obvious extramural venous invasion (EMVI, black arrows), including a focus extending perpendicularly from muscularis propria (white arrow) (H&E). B, Lymph node metastatic disease (white arrows) and EMVI (black arrow,) confirmed by identification of an elastic lamina in the vein wall (inset) on histochemical staining (H&E, elastic van gieson). C, Lymphatic invasion, malignant glands (arrow) lying within a thin-walled lymphatic channel, surrounded by lymphoid cells (H&E). D, Perineural invasion, malignant glands infiltrating thickened neural bundles (arrows), highlighted by S100 immunohistochemical staining (Upper, H&E; Lower, S100). E indicates tumor deposit, defined by the absence of features of any identifiable metastatic pathway (ancillary stains noncontributory).
+     
+Tumor Budding
+     There is considerable interest in tumor budding, considered to be a morphological manifestation of epithelial mesenchymal transition.51 A tumor bud is defined as a single tumor cell or cluster of up to 4 tumor cells at the invasive front of carcinomas. Budding is of potential clinical relevance to CRC in 2 distinct settings. First, multiple studies have shown that pT1 CRC with greater budding (tumor budding scores Bd2 and Bd3) are associated with an increased risk of lymph node metastatic disease compared to those with lesser budding (tumor budding score Bd1).52-54 Second, in stage II CRC, tumor budding score Bd3 is associated with an increased risk of recurrence and mortality.55
+     As recommended from the International Tumor Budding Consensus Conference (ITBCC) of 2016,56 tumor budding is scored using a 3-tier system according to the number of buds evident in the highest countafterscanning10separatefields(at20objectivelens)alongthe invasive front of the tumor or the entire lesion for malignant polyps (''hotspot'' approach). The number of tumor buds is based on haematoxylin and eosin (H&E) assessment, although pan-cytokeratin immunohistochemistry can be used to help identify hotspots.57 This may be of particular value when the invasive front is obscured by inflammatory cells. A correction for microscope eyepiece field diameter is required, the bud count normalized to a field area of 0.785 mm2 (equivalenttoanobjectivelens20witheyepiecediameterof20mm).
+     Tumor budding, applying the above system to assess tumor budding score (Bd1-Bd3) and actual number of buds, is considered a non-core item for reporting, pending the emergence of further evidence of reproducibility of assessment and clinical significance. Note that budding should only be reported in nonmucinous and nonsignet-ring cell adenocarcinoma areas of tumor and budding should not be reported in cancers resected after neoadjuvant therapy.
+Response to Neoadjuvant Therapy
+     Any form of neoadjuvant therapy may result in morphological tumor response in the form of fibrosis, necrosis or acellular mucin. The presence of complete or marked tumor regression in rectal cancer resection specimen is associated with a better outcome.58,59 For grading of regression, a 4-tier system is recommended, based on a modification of the system described by Ryan et al.60 This is a core item for reporting. Assessment of regression is based on evaluation of the primary tumor site. Similar features may be evident within regional lymph nodes involved by metastatic tumor, or at any distant metastatic sites. Although findings at metastatic sites do not influence tumor regression score, a descriptive comment in the pathology report is recommended to allow correlation with imaging. Overall designation as a complete pathological response requires the absence of viable tumor locally (ypT0) and in lymph nodes (ypN0). The entire tumor bed should be processed for histological examination in this situation.
+Margin Status
+     Assessment of surgical margin status is a core item. In particular, circumferential or nonperitonealized margin involvement in rectal cancer is strongly predictive of local recurrence and poor survival.61,62 Margin involvement in colon cancer is much less common and there is less evidence of its significance.63,64 The definition of margin involvement is somewhat contentious but it is generally accepted that any circumferential margin 1mm should be regarded as involved. The precise distance to the margin should be recorded, to the nearest 0.1mm, if less than 1mm, and to the nearest 1mm, if <10mm. This assessment may require a combination of macroscopic and microscopic evaluation. Any separately submitted anastomotic rings should be taken into consideration in measuring the distance to longitudinal margins.
+
+FIGURE 5. A, Posterior aspect of a right hemicolectomy specimen highlighting an intact, enlarged lymph node (rectangle) abutting the posterior specimen margin. B, Histology of a horizontal section through this lymph node shows metastatic mucinous adenocarcinoma. Although tumor extends to the surgical margin (painted black at base of image), tumor is confined to the intact lymph node and therefore NOT considered to represent margin involvement.
+     There is some evidence to suggest that margin involvement due to discontinuous or intravascular tumor is associated with a similar risk of local recurrence to that of margin involvement by primary tumor.61,62 Margin involvement by tumor within a lymph node, however, was reported in 1 study not to be associated with a significant risk of local recurrence.62 Therefore, if a lymph node containing tumor is present at the resection margin, and the lymph node capsule is intact, the circumferential margin should not be reported as involved (Fig. 5). A comment should be added to the pathology report describing the interpretation. In the setting of margin involvement by discontinuous tumor, this should be clearly reported and a separate measurement provided of distance from the primary tumor.
+Coexistent Pathology
+     Any background colonic or rectal pathological abnormalities, such as polyps, chronic inflammatory bowel disease, effects of neoadjuvant therapy, diverticular disease, or obstructive changes should be recorded as non-core information. In the event of 2 synchronous primary carcinomas, individual datasets should be completed as appropriate.
+Ancillary Studies
+     Clinical applications of ancillary testing applied to CRC are limited but expanding. Reflex testing for defective mismatch repair (MMR)/microsatellite instability (MSI) status is now widely recommended for the detection of Lynch syndrome,65,66 caused by either a constitutional pathogenic mutation in one of the MMR genes, or sporadic MMR deficient CRC, usually caused by hypermethylation of the MLH1 MMR gene promoter region. Defective MMR (dMMR) associated with MLH1 loss, or a MSI-high result, triggers algorithmic testing, including somatic BRAF mutation testing and/or MLH1 promoter methylation testing, to distinguish between sporadic dMMR cancers and Lynch syndrome. Absence of BRAF V600 mutation and/or absent MLH1 promoter hypermethylation should prompt a recommendation of referral to clinical genetics for appropriate counseling before germline mutation screening of the relevant MMR genes, as should loss of PMS2, MSH2, and/or MSH6 immunohistochemical expression. MMR status also informs patient management with MMR deficiency associated with good prognosis, poorer response to 5-fluorouracil-based chemotherapy and potential response to immune checkpoint blockade therapy.67
+     Patients with metastatic CRC should be tested for RAS (KRAS and NRAS) and BRAF mutations when treatment with anti-epidermal growth factor receptor (anti-EGFR) therapy is considered.66,68 Similarly, it is likely that the presence of the V600E BRAF mutation confers resistance to anti-EGFR therapy, though this may be modified by addition of a BRAF and/or MEK inhibitor.69,70 Most modern guidelines therefore recommend also testing metastatic CRC for the V600E BRAF mutation.66
+     Although the above indications for focused ancillary testing are now well established, facilities for such testing are not globally available. As such, these are currently considered non-core items for reporting. It is inevitable that further clinical applications of ancillary testing will emerge and this will be kept under review.
+Histologically Confirmed Distant Metastases
+     It is occasionally possible to designate a case as having histologically confirmed distant metastatic disease (pM1) on examination of either the main surgical resection specimen, for example when a peritoneal or omental deposit is identified, or of a separately submitted biopsy or resection specimen, for example from the liver or a nonregional lymph node.
+     UICC/AJCC 8th edition staging systems recognize prognostic stratification according to the pattern of organ involvement by distant metastatic disease and have subclassified pM1 into pM1a indicating metastatic disease in 1 distant organ (excluding metastatic peritoneal disease), pM1b indicating metastatic disease in 2 distant organsand pM1c indicating metastatic peritoneal disease (regardless of other organ involvement).12,13 It is therefore important for pathologists to accurately document such disease and this is considered a core item for reporting. It should be noted that pathologists can only make a positive statement regarding distant metastatic disease, their assessment based on selected specimens submitted to them for examination, and therefore the terms ''pM0'' or ''pMX'' should no longer be used. cM1 and cM0 can be applied according to best radiological and intraoperative evidence available.
+Pathological Staging
+     The agreed criteria of the UICC and AJCC 8th editions are applied to derive TNM stage.12,13 The only exception is that this dataset does not advocate the use of pT in situ, as discussed above.
+     If completion surgery follows a diagnosis of carcinoma made in a local excision specimen, the pathological findings within both specimens should be considered in providing a single, overall TNM stage. Similarly, if a resection specimen contains synchronous primary carcinomas, each should be separately assessed and individual datasets completed, but a single overarching stage provided, following the conventions of TNM.
+DISCUSSION
+     Quality of pathology reporting and mutual understanding between colorectal surgeon and pathologist is vital to management and outcomes of CRC patients. It is well established that adoption of structured pathology reporting is associated with greater clinician satisfaction and improved access to pathology information relevant to patient management, as well as ease of returning pathology data for central registration purposes.71,72 Adoption of structured reporting helps ensure data is complete and it has been demonstrated for CRC to reduce the risk of missing assessment of important pathology features when compared to narrative reporting, especially for nonspecialist pathologists, thereby impacting patient care.72-74 There remains an important role, however, for a narrative component to pathology reports, explaining any areas of uncertainty or unusual pathological findings which may be pertinent to individual patient management and offer useful feedback to the surgeon.
+     Herein we have described the process of creation of such a dataset for CRC surgical resection specimens, involving an international panel of expert gastrointestinal pathologists from 9 countries and with representation from colorectal surgery and oncology. There was strong representation of authors of equivalent existing CRC datasets from the US, UK, and Australasia. A key aim of ICCR is to minimize the workload involved in production and regular update of such datasets in addition to standardization of reporting to facilitate international comparisons. Scrutiny of these existing national datasets illustrates the current problem of lack of uniformity.5-7 Although most of the content is uniform between datasets, there are subtle but important differences pertaining to numerous data items, which would hinder comparison. This is the first agreed international dataset for CRC pathology reporting. It is hoped that the various national datasets align with this ICCR version in the future.
+     This dataset is more extensive than the UICC/AJCC TNM cancer staging systems, which provide primarily a classification of anatomical extent of disease and represent the most powerful predictor of clinical outcome for many cancers. Incorporation of additional prognostically relevant morphological features into TNM staging is challenging. Some, specifically venous, lymphatic, and perineural invasion, can already be optionally recorded under the UICC/AJCC systems, not impacting the summary stage. However, as a result the prognostic impact of these features may not be fully considered in the clinical management of individual cases. More prominent integration of newly defined prognostic features into the TNM system will be complex, for example as described above for tumor deposits. Nevertheless, international discussion of such features is necessary to further the goals of reproducible consensus definitions and standardization of interpretation.
+     The ICCR aspires towidespread uptake of this freely available dataset by those countries currently lacking such a strategy, to improve the standard of pathology reporting of CRC globally. The greatest effect may be in low- and middle-income countries, where incidence of CRC has risen significantly.75 Standardized reporting will allow comparison of relative proportions of CRC subtypes between countries, assessment of the impact of new screening programs and participation in international trials targeting a specific molecular subset of CRC and requiring a minimum standard of pathology reporting.
+     To conclude, this internationally agreed freely available dataset provides a structured template for the pathological reporting of CRC surgical resection specimens. The ICCR initiative streamlines the dataset production process, both for new datasets and for regular updates as new evidence emerges. Such international collaborative efforts become more important with rapid progress in the fields of molecular pathology, digital pathology, and image analysis, allowing rapid translation of new developments, many relevant to surgical practice, into routine pathology reporting.
+ACKNOWLEDGMENTS
+     The authors thank Christina Selinger and the wider project team at ICCR for assistance in the production of this dataset and manuscript.
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+Loughrey et al	Annals of Surgery  Volume 275, Number 3, March 2022
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+Annals of Surgery  Volume 275, Number 3, March 2022	ICCR Colorectal Cancer Dataset
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+e550 |	www.annalsofsurgery.com	 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
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+ 2021 The Author(s). Published by Wolters Kluwer Health, Inc.	www.annalsofsurgery.com	| e551
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