Colorectal cancer

Additional information on pathology reporting

From Cancer Guidelines Wiki

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.[1][2] 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.[3][4][5] 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.[6][7][8] 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.[9][10][7] 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.[11]

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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.[12] 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.[13] These tumours have been reported to be associated with higher risk of synchronous and metachronous tumours.[14] Their relationship to prognosis and responsiveness to FU-based chemotherapy remains controversial.[15][16][17]

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.[18]

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.[19] 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.[20]

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.[21] 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.

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DNA mismatch repair status studies should be performed on all cases of colorectal cancer for the detection of Lynch syndrome.

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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.

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Extended RAS mutation testing should be carried out on all patients at the time of diagnosis of metastatic colorectal cancer. Note: RAS testing is not currently pathologist-determinable and therefore can only be performed for metastatic colorectal cancer following a request from a specialist (surgeon or oncologist).

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.[7]

Table 8.6. Reporting on colorectal cancer specimens[edit source]

Pre-analytical data
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
Macroscopic findings
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
Microscopic findings
Tumour type Adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, medullary carcinoma, neuroendocrine carcinoma, squamous carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, other (see WHO classification, 2010[22])
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

Specify sites

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
Grade 2 (minimal response): Residual cancer outgrown by fibrosis
Grade 3: (poor response): Minimal or no tumour kill; extensive residual cancer

Ancillary test findings
ˆMismatch repair enzymes MLH1, PMS2, MSH2, MSH6 immunohistochemistry

Microsatellite instability (MSI)
BRAF (V600E mutation)

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[7]

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Synoptic reporting is strongly recommended to capture the key variables to enable translation between major internationally recognised staging systems and facilitate multidisciplinary patient management.

Next section: Optimal molecular profiling of colorectal cancer

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References[edit source]

  1. Chapuis PH, Bokey L, Chan C, Dent OF. Colorectal cancer staging revisited: time for critical evaluation? Colorectal Dis 2012 Sep;14(9):1043-4 Available from:
  2. Chapuis PH, Chan C, Dent OF. Clinicopathological staging of colorectal cancer: Evolution and consensus-an Australian perspective. J Gastroenterol Hepatol 2011 Jan;26 Suppl 1:58-64 Available from:
  3. Fielding LP, Arsenault PA, Chapuis PH, Dent O, Gathright B, Hardcastle JD, et al. Clinicopathological staging for colorectal cancer: an International Documentation System (IDS) and an International Comprehensive Anatomical Terminology (ICAT). J Gastroenterol Hepatol 1991 Jul;6(4):325-44 Available from:
  4. Newland RC, Dent OF, Lyttle MN, Chapuis PH, Bokey EL. Pathologic determinants of survival associated with colorectal cancer with lymph node metastases. A multivariate analysis of 579 patients. Cancer 1994 Apr 15;73(8):2076-82 Available from:
  5. Newland RC, Dent OF, Chapuis PH, Bokey L. Survival after curative resection of lymph node negative colorectal carcinoma. A prospective study of 910 patients. Cancer 1995 Aug 15;76(4):564-71 Available from:
  6. College of American Pathologists. Protocol for Examination of Specimens From Patients With Primary Carcinoma of the Colon and Rectum. Version: ColoRectum CAP; 2016.
  7. 7.0 7.1 7.2 7.3 Royal College of Pathologists of Australasia. Colorectal Cancer Structured Reporting Protocol (3rd edition). Royal College of Pathologists of Australasia; 2016 Available from:
  8. Royal College of Pathologists. Standards and Datasets for Reporting Cancers — Dataset for Colorectal Cancer Histopathology Reports. 3rd edition. London: RCP; 2014.
  9. Compton CC. Key issues in reporting common cancer specimens: problems in pathologic staging of colon cancer. Arch Pathol Lab Med 2006 Mar;130(3):318-24 Available from:
  10. Washington MK. Colorectal carcinoma: selected issues in pathologic examination and staging and determination of prognostic factors. Arch Pathol Lab Med 2008 Oct;132(10):1600-7 Available from:
  11. Compton CC. Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol 2003 Apr;16(4):376-88 Available from:
  12. Liu B, Nicolaides NC, Markowitz S, Willson JK, Parsons RE, Jen J, et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 1995 Jan;9(1):48-55 Available from:
  13. Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillay SP, et al. Morphology of sporadic colorectal cancer with DNA replication errors. Gut 1998 May;42(5):673-9 Available from:
  14. Cawkwell L, Gray S, Murgatroyd H, Sutherland F, Haine L, Longfellow M, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut 1999 Sep;45(3):409-15 Available from:
  15. Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000 Jan 13;342(2):69-77 Available from:
  16. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003 Jul 17;349(3):247-57 Available from:
  17. Toh J, Chapuis PH, Bokey EL, Chan C, Spring KJ, Dent OF. Competing risks analysis of microsatellite instability as a prognostic factor in colorectal cancer. Br J Surg (in press).; 2017.
  18. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004 Feb 18;96(4):261-8 Available from:
  19. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006 Jul;38(7):787-93 Available from:
  20. Loughrey MB, Waring PM, Tan A, Trivett M, Kovalenko S, Beshay V, et al. Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer. Fam Cancer 2007;6(3):301-10 Available from:
  21. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008 Oct 23;359(17):1757-65 Available from:
  22. Bosman FT, Carneiro F, Hruban R H, Theise N. WHO classification of tumours of the digestive system, fourth edition. France: IARC; 2010 [cited 2018 Jul 10] Available from:

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