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

 	 

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  
Carcinoma in�situ: intraepithelial or invasion of lamina propria. 
pT1  
Tumour invades submucosa. 
pT2  
Tumour invades muscularis propria. 
pT3  
Tumour invades through muscularis propria into subserosa or into nonperitonealised pericolic or perirectal tissues. 
pT4 
Tumour directly invades other organs or structures (pT4a) and/or perforates visceral peritoneum (pT4b). 

 
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:  
Tumour invades submucosa but not muscularis propria. 
pT2:  
Tumour invades into, but not through muscularis propria. 
pT3:  
Tumour invades through muscularis propria into subserosa or into nonperitonealised pericolic or perirectal tissues. 
pT3 indicates spread in continuity beyond the bowel wall. The microscopic presence of tumour cells confined within the lumen of lymph vessels or veins does not qualify as local spread in the T classification [16]. Occasionally cancer has spread as far as the outer edge of the muscularis propria but not beyond. If no muscle separates the cancer from the mesenteric tissue then the muscle coat should be interpreted as breached (pT3) [25].  
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 
No margin involvement (or residual disease). 
R1  
Microscopic but not macroscopic margin involvement. 
R2  
Macroscopic margin involvement. 

 
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. 
20. Hamilton SR, Vogelstein B, Kudo S, Riboli E, Nakamura S, Hainaut P, Rubio CA, 
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. 
21. Halvorsen TB, Seim E: Degree of differentiation in colorectal adenocarcinomas: a multivariate analysis of the influence on survival. Journal of Clinical Pathology 1988;41:532-537. 
22. Chapuis PH, Dent OF, Fisher R, Newland RC, Pheils MT, Smyth E, Colquhoun K: A multivariate analysis of clinical and pathological variables in prognosis after resection of large bowel cancer. British Journal of Surgery 1985;72:698-702. 
23. Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, Hammond ME, Henson DE, Hutter RV, Nagle RB, Nielsen ML, Sargent DJ, Taylor 
CR, Welton M, Willett C: Prognostic factors in colorectal cancer. College of 
American Pathologists Consensus Statement 1999. Archives of Pathology & Laboratory Medicine 2000;124:979-994. 
24. Prall F: Tumour budding in colorectal carcinoma. Histopathology 2007;50:151162. 
25. Jass J, O'Brien M, Riddell R, Snover D: Recommendations for the reporting of surgically resected specimens of colorectal carcinoma. Virchows Archiv 2007;450:1-13. 
26. Wittekind CH, Henson DE, Hutter RVP, Sobin LH (eds): TNM Supplement: a commentary on uniform use. New York, Wiley-Liss, 2001. 
27. Adam IJ, Mohamdee MO, Martin IG, Scott N, Finan PJ, Johnston D, Dixon MF, Quirke P: Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 1994;344:707-711. 
28. Birbeck KF, Macklin CP, Tiffin NJ, Parsons W, Dixon MF, Mapstone NP, Abbott CR, Scott N, Finan PJ, Johnston D, Quirke P: Rates of circumferential resection margin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Annals of Surgery 2002;235:449-457. 
29. de Haas-Kock DF, Baeten CG, Jager JJ, Langendijk JA, Schouten LJ, Volovics A, Arends JW: Prognostic significance of radial margins of clearance in rectal cancer. British Journal of Surgery 1996;83:781-785. 
30. Martling A, Holm T, Bremmer S, Lindholm J, Cedermark B, Blomqvist L: Prognostic value of preoperative magnetic resonance imaging of the pelvis in rectal cancer. British Journal of Surgery 2003;90:1422-1428. 
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. 
32. Ng IO, Luk IS, Yuen ST, Lau PW, Pritchett CJ, Ng M, Poon GP, Ho J: Surgical lateral clearance in resected rectal carcinomas. A multivariate analysis of clinicopathologic features. Cancer 1993;71:1972-1976. 
33. Quirke P, Durdey P, Dixon MF, Williams NS: Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet 1986;2:996-999. 
34. Wibe A, Rendedal PR, Svensson E, Norstein J, Eide TJ, Myrvold HE, Soreide O: Prognostic significance of the circumferential resection margin following total mesorectal excision for rectal cancer.[see comment]. British Journal of Surgery 2002;89:327-334. 
35. Quirke P, Morris E: Reporting colorectal cancer. Histopathology 2007;50:103112. 
36. Bateman AC, Carr NJ, Warren BF: The retroperitoneal surface in distal caecal and proximal ascending colon carcinoma: the Cinderella surgical margin? Journal of Clinical Pathology 2005;58:426-428. 
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. 
40. Michael-Robinson JM, Biemer-Huttmann A, Purdie DM, Walsh MD, Simms LA, Biden KG, Young JP, Leggett BA, Jass JR, Radford-Smith GL: Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut 2001;48:360-366. 
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. 
 
 




 	- 2 -

 	- 2 -









 	- 2 -

 	- 2 -



 	- 2 -





 	- 2 -

 	- 2 -



 	- 2 -





 	- 2 -

 	- 2 -



 	- 2 -





 	- 2 -





 	- 2 -





 	- 2 -

 	- 2 -



 	- 2 -