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.

Grading

• "Adenocarcinoma in situ" and "high-grade dysplasia" is used interchangeably by many in the colon and rectum.
  • Splitting hairs - adenocarcinoma in situ is invasion into the lamina propria, high-grade dysplasia does not have lamina propria invasion. Ergo, the difference (in my opinion) amounts to seeing a desmoplastic stroma (adenocarcinoma) or not seeing one (dysplasia).

Grading of tumours:

• Tis - in situ (intramucosal).
• T1 - into submucosa (through mucularis mucosae).
  • This is different than elsewhere, e.g. in the small bowel tumour cells in the lamina propria is defined as T1. The rationale for the T1 definition in CRC is that no lymphatics are present in the mucosa, ergo no risk of distant spread.
• T2 - into muscularis propria.
• T3 - into fat beyond musclaris propria.
• T4 - into something else.

Nodes:

• N0 - no positive nodes.
• N1 - 1-3 positive nodes.
• N2 - 4+ positive nodes.

Notes:

• Memory device for N2 = 4+ +ve LNs: the number four in chinese sounds like death.

Staging of colorectal cancer

Simple version

Tumour/node grade for stage:

• Stage I - T1 or T2 N0 M0.
• Stage II - T3 or T4 N0 M0.
• Stage III - Tx N1 or N2 M0.
• Stage IV - Tx Nx M1.

Complex version

Detailed tumour/node grade for stage:

• Stage I - T1 or T2.
• Stage IIA - T3.
• Stage IIB - T4.
• Stage IIIA - T1 N1 or T2 N1.
• Stage IIIB - T3 N1 or T4 N1.
• Stage IIIC - Tx N2.
• Stage IV - Tx Nx M1.

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).
• Common associated gene mutations:
  1. MLH1.
  2. PMS2.
  3. MSH2.
  4. MSH6.
• Less common gene mutations:
  1. PMS1.
  2. MLH3.
  3. MSH3.

IHC interpretation

• Loss of nuclear staining in nuclei of the tumour = mutation.
  • Nuclear staining = normal.

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!).

Other ancillary studies

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

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

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.

MSI cancers

General

Features:

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

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.
• Pushing border.
• Histomorphology:
  • Poorly differentiated.
  • Mucinous.
  • Signet ring.
  • Medullary.

Specific entities

Colorectal adenocarcinoma

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

General

• Very common.
• Rectum and sigmoid > proximal large bowel.

Presentation:

• Bright red blood per rectum (BRBPR).
• Constipation.
• Symptoms of bowel obstruction - nausea, vomiting.

Pathogenesis - see pathogenesis of colorectal carcinoma.

Gross

Often circumferential or near circumferential:

• These are referred to as "apple core lesion" or "napkin-ring" lesion.

Mucosa:

• Granular appearance.
• Raised (exophytic) or heaped edges with ulceration.

Note:

• Total mesorectal excisions should be assessed for completeness.
• The (soft tissue) radial margins, as present in TMEs and right hemicolectomies, should be inked.

Images

• 

  CRC - gross. (WC)

• 

  Rectum - anterior view. (WC)

• 

  Rectum - lateral view. (WC)

• 

  Rectum - inked. (WC)

• Rectum - opened (wikia.com).

Microscopic

Features:

• Nuclear atypia:
  • Nuclear pseudostratification.
  • Nuclear hyperchromasia.
  • Chromatin clearing or granularity.
• +/-Necrosis.
• Architecture - important for grading:
  • Glands.
  • Sheets.

Images

www:

• Colorectal adenocarcinoma (flickr.com/euthman).

• 

  Colorectal adenocarcinoma. (WC)

• 

  Mucinous adenocarcinoma of the colon - low mag. (WC/Nephron)

Grading

Based on component composed of glands:

• >=50% of tumour = low-grade (well-differentiated and moderately differentiated).
• <50% of tumour = high-grade (poorly-differentiated and undifferentiated).

Peritumour lymphocytic response

• AKA Crohn's-like lymphoid reaction.
• AKA Crohn's like reaction.
• AKA Crohn-like repsonse.

General

• Finding associated with improved survival in CRC.

Microscopic

Onlinepathology advocates use of the Ueno criteria. They have a better inter-rater reproducibility than the older Graham criteria and are less complicated.

Ueno criteria (2013)

Required criteria:

• Non-MALT lymphoid aggregates (peritumoural) >= 1 mm.

Ignore:

1. Muscosa-associated lymphoid tissue (MALT) = mucosal lymphoid aggregates, submucosal lymphoid aggregates adjacent to the musuclaris mucosae.
2. Lymph nodes - these have a (fibrous) capsule.
3. Irregular shape (not round).

Graham criteria (1990)

Required criteria:

• Peritumoral:
  1. Lymphoid aggregates with germinal centres focally.
  2. Stellate fibrosis.
  3. No previous clinical and pathologic evidence of Crohn's disease.

Note:

• Should not be confused with intratumoural lymphocytic response.
  • The intratumoural lymphocytic response is associated with MSI-H cancers.

Images:

• Peritumour lymphocytic response in endometrial carcinoma (bmjjournals.com).
• Peritumour lymphocytic response in CRC (ascpjournals.org).

Intratumoural lymphocytic response

• AKA tumour-infiltrating lymphocytes, abbreviated TILs.

General

• Finding is suggestive of microsatellite instabillity.
  • May be seen in the context of Lynch syndrome.

Microscopic

Features:

• Lymphocytes are between the tumour cells. †
  • Other lymphocytes do not count.

Note:

• † Definitions vary substantially - some authors consider lymphocytes adjacent to the tumour (in the stroma around the tumour cells) "intratumoural".

Images

• 

  TILs - high mag. (WC/Nephron)

• 

  TILs - very high mag. (WC/Nephron)

www:

• TILs in endometrial carcinoma (bmjjournals.com).
• TILs in CRC (ascpjournals.org).

IHC

• CK7 -ve.
• CK20 +ve.
• CEA +ve.
• CDX2 +ve.

Molecular

• KRAS mutation analysis.
  • Mutation present ~ 40% of CRC.
  • Mutations in codons 12 or 13 associated with failure of anti-EGFR therapy (e.g. cetuximab, panitumumab).
• BRAF mutation analysis.
  • V600E missense mutation found in ~10% CRC.

Note:

• KRAS mutations and BRAF mutations are considered mutually exclusive as they occur in the same pathway.

See also

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