Additional information on pathology reporting

From Cancer Guidelines Wiki

Prognostic factors independent of stage

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

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

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

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

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

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

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

PathologyA medical specialty that determines the cause and nature of diseases by examining and testing body tissues, for instance from laboratory examination of samples of body tissue. 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 AdenocarcinomaA type of cancerous tumour that forms from glandular structures in epithelial tissue., 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 TNMA system that describes the amount and spread of cancer in a patient’s body. T describes the size of the tumour and its spread into nearby tissue; N describes the spread to nearby lymph nodes and M describes metastasis (spread of cancer to other parts of the body). 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

ACPS

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
ˆGuidelines
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

  1. Chapuis PH, Bokey L, Chan C, Dent OF. Colorectal cancer staging revisited: time for critical evaluation? ColorectalReferring to the large bowel, comprising the colon and rectum. Dis 2012 Sep;14(9):1043-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22909328.
  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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21199515.
  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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1912440.
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  6. College of American Pathologists. Protocol for Examination of Specimens From Patients With Primary Carcinoma of the Colon and Rectum. Version: ColoRectum 3.4.0.0. CAP; 2016.
  7. 7.07.17.27.3 Royal College of Pathologists of Australasia. Colorectal Cancer Structured Reporting Protocol (3rd edition). Royal College of Pathologists of Australasia; 2016 Available from: https://www.rcpa.edu.au/Library/Practising-Pathology/Structured-Pathology-Reporting-of-Cancer/Cancer-Protocols/Gastrointestinal/Protocol-colorectal-cancer.
  8. Royal College of Pathologists. Standards and Datasets for Reporting Cancers — Dataset for Colorectal Cancer Histopathology Reports. 3rd edition. London: RCP; 2014.
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  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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10631274.
  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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12867608.
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