Additional information on pathology reporting
Prognostic factors independent of stage[edit source]
The pathology report provides a histological confirmation of the diagnosis of colorectal cancer and summation of additional prognostic information that is used to guide further postsurgical clinical management of the patient. Apart from tumour stage, the importance of including information on a range of other variables in the histopathology report is recognised (see Table 8.6). These variables include the components of stage and some other factors that have been shown to have a statistically independent bearing on prognosis. The independent prognostic effects of many of these variables have been assessed within the ACPS system and have been demonstrated to be stage dependent. Those having independent prognostic significance have also been included in current pathology reporting protocols. These include histological tumour type, tumour grade/differentiation, non-peritonealised circumferential margin status, and lymphatic and vascular invasion. The extent of tumour spread beyond the bowel wall has been shown to have prognostic significance, and while subdivision of pT3 has not been adopted by the AJCC, the maximum distance of tumour extension beyond the muscularis propria may be reported as a measurement in millimetres. The true significance of other features, such as the presence of perineural invasion, tumour budding, and discontinuous extramural tumour deposits not associated with lymph nodes, is still to be fully resolved.
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Molecular markers[edit source]
Molecular research has greatly advanced the understanding of colorectal carcinogenesis, but its impact on routine clinical practice has so far been limited.
Microsatellite instability (MSI), DNA mismatch repair (MMR) and Lynch syndrome[edit source]
Up to 15% of colorectal cancers harbour multiple defects in repetitive non-coding regions of DNA known as microsatellites (microsatellite instability, MSI). This is the result of loss of DNA microsatellite mismatch repair (MMR) protein function. MMR deficiency is the genetic defect in Lynch syndrome (hereditary non-polyposis colorectal cancer) which accounts for 2-3% of colorectal cancers. MMR deficient CRCs are more frequently right-sided and show distinctive histological features including prominent tumour-infiltrating lymphocytes, a pushing invasive tumour front, and mucinous or poor differentiation. These tumours have been reported to be associated with higher risk of synchronous and metachronous tumours. Their relationship to prognosis and responsiveness to FU-based chemotherapy remains controversial.
Tumours that are right-sided, synchronous or metachronous, and/or show histological features described above should raise suspicion for MMR deficiency (sporadic or familial). Those that present under age 50, are associated with a strong family history or the presence of other Lynch syndrome associated cancers, further raise the possibility of Lynch syndrome.
Immunohistochemical testing for the four MMR proteins (MLH1, MSH2, MSH6 and PMS2) is now widely available, and universal testing of colorectal cancers (or at least in patients under the age of 70) has been recommended for the detection of Lynch syndrome. See Lynch syndrome. The identification of a MMR deficient colorectal cancer also may have implications for selection of patients for adjuvant 5-FU based chemotherapy, and long term post-operative follow up..
BRAF mutation[edit source]
Immunohistochemistry for the V600E mutated BRAF is now available, and is useful in distinguishing between sporadic and familial (Lynch syndrome) cases of MMR deficient colorectal cancer. Sporadic loss of MLH1 is commonly seen in elderly patients due to methylation of its promoter site, and BRAF mutation is commonly associated with hypermethylation. In the context of MLH1 loss, the presence of mutated BRAF almost certainly indicates that the loss is due to MLH1 promoter methylation, and can be used to virtually exclude the possibility of Lynch syndrome.
RAS mutation and anti-EGFR therapy[edit source]
KRAS mutation status has been reported to be associated with response to anti-epidermal growth factor receptor (EGFR) therapy. These agents have been shown to have a beneficial effect in some colorectal cancer patients with metastatic disease, and tumours harbouring mutations in KRAS and subsequently other genes in the RAS family have been found to be resistant to such treatment. Testing of tumour tissue for extended RAS (KRAS/NRAS) mutation status is recommended for patients with advanced colorectal cancer for whom anti-EGFR treatment is being considered.
DNA mismatch repair status studies should be performed on all cases of colorectal cancer for the detection of Lynch syndrome.
BRAF mutation studies should be performed in conjunction with DNA mismatch repair status studies to differentiate between sporadic and familial (Lynch syndrome) cases of DNA mismatch repair status-deficient colorectal cancer.
Structured reporting of colorectal cancer[edit source]
The use of structured reporting in synoptic format has been recommended to ensure the consistent quality and completeness of data. Each variable should be recorded individually and explicitly in pathology reports. The Royal College of Pathologists of Australasia has published a comprehensive protocol for structured reporting of colorectal cancer that outlines a number of standards (mandatory elements) and guidelines (optional elements), the details of which are summarised in Table 13.6.
Table 8.6. Reporting on colorectal cancer specimens[edit source]
|Demographic information provided on the request form||Name, date of birth, sex, identification and contact details of requesting doctor, date of request, medical record number|
|Clinical information documented on the request form||Operating surgeon name and contact details
Perforation, clinical obstruction, tumour location, synchronous tumours, distance from anal verge, type of operation, preoperative radiotherapy, surgeon’s opinion on the existence of residual cancer postsurgery , involvement of adjacent organs, new primary cancer or recurrence
|Pathology accession number of the specimen|
|ˆAny other clinical information received in other communications from the requestor or other clinician|
|Specimen length||Measurement in mm|
|Site of the tumour||Caecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, rectosigmoid junction, rectum|
|Maximal tumour diameter||Measurement in mm|
|Distance of tumour to nearer proximal or distal resection margin||Measurement in mm|
|Distance of the tumour to the circumferential margin||Measurement in mm|
|Presence or absence of tumour perforation|
|Relationship of the tumour to the anterior peritoneal reflection (for rectal tumours)||Entirely above, astride, entirely below|
|Intactness of the fascial envelope enclosing the perirectal fat (mesorectum)||Incomplete (grade 1), nearly complete (grade 2), complete (grade 3)|
|ˆAny involvement of the peritoneum||By direct spread, tumour nodule(s) discrete from the tumour mass|
|ˆNumber of lymph nodes placed in each cassette|
|ˆNumber, diameter and gross configuration of polyps|
|ˆAny other relevant macroscopic information|
|Nature and sites of all blocks|
|Tumour type||Adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, medullary carcinoma, neuroendocrine carcinoma, squamous carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, other (see WHO classification, 2010)|
|Histological grade||Low grade (well and moderately differentiated) |
High grade (poorly and undifferentiated)
|Maximal degree of local invasion into or through the bowel wall||Submucosa, muscularis propria, beyond muscularis propria, serosal surface, involves other organs/structures|
|Involvement of proximal or distal resection margins||Involved or not involved
Specify involved margin(s), microscopic clearance (specify in mm if less than 10mm)
|Status of nonperitonealised circumferential margin in rectal tumours||Involved or not involved, microscopic clearance in mm|
|Results of lymph node histopathology||Site(s) and numbers of lymph nodes (number of positive nodes/total number of nodes from this site)|
Isolated extramural tumour deposits
|ˆApical lymph node involvement if required where staging systems additional to TNM staging are in use||Required for ACPS and Dukes|
|Venous and small vessel invasion||Intramural vein invasion, extramural vein invasion, small vessel invasion (not identified, present or extensive)|
|ˆPerineural invasion||Not identified, present or extensive|
|Histologically confirmed distant metastases||Present or absent
|Relevant coexistent pathological abnormalities||Polyps, ulcerative colitis, Crohn’s disease, dysplasia, other|
|Microscopic residual tumour status (completeness of resection)||Text|
|Response to neoadjuvant therapy||Grade 0 (complete response): No viable cancer cells|
Grade 1 (moderate response): Single cells or small groups of (viable-appearing) cancer cells
|Ancillary test findings|
|ˆMismatch repair enzymes||MLH1, PMS2, MSH2, MSH6 immunohistochemistry|
Microsatellite instability (MSI)
|ˆRAS gene mutation||KRAS and NRAS (exons 2, 3, 4)|
|Synthesis and summary|
|Tumour stage||pTNM and Stage grouping
ACPS stage (substage)
|Year and/or edition of staging system||AJCC 2010, 7th edition
|Residual tumour status||R classification|
|ˆDiagnostic summary||Specimen type, tumour site, type, stage, completeness of excision|
|New primary cancer or recurrence||New primary, regional (local) recurrence, distant metastases, indeterminate|
|Overarching comment||Free text|
Source: RCPA 2016
Synoptic reporting is strongly recommended to capture the key variables to enable translation between major internationally recognised staging systems and facilitate multidisciplinary patient management.
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