Microsatellite instability in colorectal cancer

Intratumoural lymphocytic response in colorectal carcinoma, as may be seen in microsatellite instability. H&E stain. (WC)

Microsatellite instability in colorectal cancer, often abbreviated MSI, is recognized as an important predictor of outcome in colorectal adenocarcinoma, and may be seen in the context of Lynch syndrome.

General

• Can be sporadic, i.e. non-syndromic.
• Strong association with Lynch syndrome.

Features:

• Prognosis: slightly better than other CRC without MSI.
• Treatment implication: different response to chemotherapy.

When to test

• National Comprehensive Cancer Network (NCCN) in the USA recommends testing all individual with colorectal cancer that are under the age of 70 years.
• A draft document (written in 2015) from CAP, ASCO and others suggests testing all colorectal cancer cases for MSI.
• In Canada, the guidelines vary by the province. Some use the Bethesda criteria (see below) and others have their own set of criteria.

Bethesda criteria of 2004 for MSI testing

MSI testing should be done if any of the following apply:

• Colorectal cancer in patient <50 years old.
• Colorectal cancer with MSI-H histology <60 years old.
  • MSI-H histology (any of the following): mucinous differentiation, signet ring differentiation, medullary growth pattern, TILs, Crohn's like reaction.
• Regardless of age - any of the following:
  • HNPCC-associated tumours.†
  • Synchronous colorectal cancer.
  • Metachronous colorectal cancer.
• Colorectal cancer in an individual with:
  • One or more first degree relatives with a HNPCC-related tumour diagnosed when <50 years old.
  • Two or more first- or second degree relatives with HNPCC-related tumours (diagnosed at any age).

Notes:

• Formally known as Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability.
• †Includes: colorectum, endometrium, stomach, ovary, pancreas, ureter and renal pelvis, biliary tract and brain (usu. glioblastoma), sebaceous gland adenomas and keratoacanthoma in Muir-Torre syndrome and small bowel carcinoma.

MSI classification

MSI associated cancers can be classified into:

• MSI-H >= 30% of loci have abnormality.
• MSI-L <30% of loci have abnormality.

Note:

• In the context of no chemotherapy, individuals with MSI-H tumours have a superior outcome to those with MSI-L tumours.
  • With chemotherapy the outcomes are similar.

Gross

Features:

• Location: proximal colon, i.e. right-sided, predominance.

Microscopic

Features:

• Lymphocytic infiltrate - see intratumoural lymphocytic response.
• Large peritumoural collections of lymphocytes - see peritumoural lymphocytic response.
• Pushing border.
• Histomorphology:
  • Poorly differentiated.
  • Mucinous.
  • Signet ring.
  • Medullary.

Molecular

Commonly associated abnormalities in the genes:

1. MLH1.
2. PMS2.
3. MSH2.
4. MSH6.

Less common abnormalities:

1. PMS1.
2. MLH3.
3. MSH3.

IHC

Immunostains are commonly done for:

• MLH1.
• PMS2.
• MSH2.
• MSH6.

Note:

• MSI testing (in the context of suspect Lynch syndrome) can be done on adenomatous polyps; however, dysplasia should be present.
  • Sessile serrated adenomas without dysplasia should not be tested.

IHC interpretation

• Loss of nuclear staining in nuclei of the tumour implies a mutation.
  • Nuclear staining = normal.
• Patchy MSH6 is considered normal.^{[citation needed]}

MSI staining loss patterns:

• MLH1 and PMS2 are often lost together, as MLH1 loss results in PMS2 loss.
• MSH2 and MSH6 are often lost together, as MSH2 loss results in MSH6 loss.

Implication of MSI staining loss patterns:

• PMS2 & MSH6 can be used as a screen.

Etiology/significance loss of staining

• MSH2 mutations (IHC stain -ve) - often associated with a germline mutation, while mutations in MLH1 are usually sporatic.
• PMS2 mutations (IHC stain -ve) - often associated with a germline mutation.

How to remember the more important MSI stuff:

• Groupings:
  • The MSHs are paired together.
  • PMS sucks... it's with the other one (MLH).
• The higher numbers in the pairings (PMS2, MSH6) are the screening tests (High Screen Pass).
• The 2s (MSH2, PMS2) are associated with germline mutations (Four legs good two legs bad!).

See also

• Colorectal tumours.
• Colorectal adenocarcinoma.