Colorectal tumours

Colorectal tumours, especially colorectal carcinomas, are very common. They are the bread and butter of GI pathology. Non-tumour colon is dealt with in the colon article.

An introduction to gastrointestinal pathology is in the gastrointestinal pathology article. The precursor lesion of colorectal carcinoma (CRC) is, typically, an adenomatous polyp. Polyps are discussed in the intestinal polyps article.

Classification

Most common

• Colon & rectum - most common = adenocarinoma.

Others

Other tumours - many (incomplete list):

• Mucinous carcinoma.
  • Need > 50% mucinous component.
• Adenosquamous carcinoma.
• Signet-ring carcinoma.
• Squamous carcinoma.
• Neuroendocrine neoplasms (carcinoid tumours).
• Lipoma.
• Leiomyoma.
• Gastrointestinal stromal tumour (GIST) - dealt with in a separate article.
• Angiosarcoma.
• Lymphoma (Non-Hodgkin's lymphoma).

Notes:

• Mucinous carcinoma - percentage required to call varies by site:

Squamous carcinoma

Main article: Squamous carcinoma

• Rare.
  • In the context of a rectal tumour, retrograde growth from the anus should be considered.

Staging of colorectal cancer

Main article: Colorectal cancer staging

Pathogenesis of colorectal carcinoma

Overview

Colorectal carcinoma is thought to arise from one of two pathways:

1. APC (adenomatous polyposis coli) gene mutation pathway, AKA classic adenoma-carcinoma pathway.
2. Serrated pathway, AKA mutator pathway, mismatch repair pathway.

Syndromes

Both of the above described pathways are associated with syndromes:

1. Familial adenomatous polyposis (FAP) or familial polyposis coli (FPC).
2. Lynch syndrome (AKA hereditary non-polyposis colorectal cancer syndrome (HNPCC)).

Pathways

APC gene mutation pathway

Microscopic:

• Adenomatous polyps.

Mismatch repair pathway

• Associated with microsatellite instability (MSI).

Other ancillary studies

• BRAF V600E missense mutation found in ~10% CRC.
• KRAS mutation status.

BRAF V600E mutation

Main article: BRAF V600E mutation

Features:

• Independently associated with BRAF V600E:
  • Usually older (>70 years old).
  • Female gender.
  • Right-sided tumour location.
• Worse prognosis - in the context of metastatic disease.

KRAS mutation

Main article: KRAS mutation

Features:

• Patient must have wild type KRAS to get drugs; KRAS mutation predicts resistance to cetuximab (Erbitux) and panitumumab (Vectibix).
  • Cetuximab and panitumumab are EGFR inhibitors.

Microsatellite instability cancers

• Abbreviated MSI cancers.

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.

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:

• The MSHs are paired together.
  • MSH (Mount Sinai Hospital) is where they started it in the city.
  • 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!).

Specific entities

Colorectal adenocarcinoma

• AKA colorectal adenocarcinoma not otherwise specified.
• AKA colorectal carcinoma, abbreviated CRC.

Main article: Colorectal adenocarcinoma

See also

• Anus - covers anal cancer and anal intraepithelial neoplasia.
• Colon.
• Gastrointestinal pathology.
• Tumour budding.