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CRC: CLASSIFICATION AND PATHOLOGY
Slides last updated: March 2015
Adenocarcinomas make up more than 95% of CRC1
Adenocarcinomas start
in gland cells that make
mucus to lubricate the
inside of the colon and
rectum
Less common types of
CRC:
• Carcinoid tumours
• Gastrointestinal
stromal tumours
(GISTs)
• Lymphomas
• Sarcomas
CRC
(100%)
Adenocarcinoma
(>95%)
1. American Cancer Society. Colorectal Cancer Detailed Guide, 2014. Available online from
http://www.cancer.org/acs/groups/cid/documents/webcontent/003096-pdf.pdf, last accessed on 17/03/2015.
Less common types of CRC1
Carcinoid tumours start from specialised hormone-producing cells in the
intestine
Gastrointestinal stromal tumours (GISTs) start from specialised cells in
the colon wall called the interstitial cells of Cajal. They can be found
anywhere in the digestive tract, and are rare in the colon
Lymphomas are cancers of the immume system that usually start in
lymph nodes, but may also start in the colon, rectum and other organs
Sarcomas start in blood vessels or in the muscle and connective tissue
in the wall of the colon and rectum. Colorectal sarcomas are rare
1. American Cancer Society. Colorectal Cancer Detailed Guide, 2014. Available online from
http://www.cancer.org/acs/groups/cid/documents/webcontent/003096-pdf.pdf, last accessed on 17/03/2015.
Most CRCs develop slowly over several years1
Before a cancer develops, growth of tissue or tumour usually begins as a
non-cancerous polyp on the inner lining of the colon or rectum
Some polyps can become malignant (cancerous), but some remain benign
(not cancerous)
The two main types of polyps are:
•
Adenomas (adenomatous polyps) – develop into cancer
•
Hyperplastic polyps and inflammatory polyps – not pre-cancerous but
might be considered as a sign of having a greater risk of developing
adenomas
Dysplasia is a pre-cancerous condition often seen in patients with
inflammatory bowel disease. Cells in the lining of the colon or rectum may
look abnormal under a microscope and develop into cancer over time
1. American Cancer Society. Colorectal Cancer Detailed Guide, 2014. Available online from
http://www.cancer.org/acs/groups/cid/documents/webcontent/003096-pdf.pdf, last accessed on 17/03/2015.
Loss of genomic stability can drive CRC1
Chromosomal instability:
•
Causes physical loss of a wild-type copy of tumour-suppressor genes
such as APC, TP53 and SMAD4
•
Unlike some other cancers, CRC does not commonly involved
amplification of gene copy number or gene rearrangement
DNA-repair defects:
•
Inactivation of genes required for repair of base-base mismatches in
DNA, known as mismatch-repair genes
•
Can be inherited (HNPCC) or acquired
•
Leads to microsatellite instability (MSI)
Aberrant DNA methylation:
•
Leads to gene inactivation
•
A methylated form of cytosine is observed in 15% of CRC cases
1. Markowitz SD, et al. N Eng J Med 2009;361:2449-60.
Sequencing of CRC has shown its wide heterogeneity1
The average stage IV CRC genome has 15 mutated candidate cancer
genes, and 61 mutated passenger genes (very low frequency mutational
events)
In the progression of CRC, genetic alterations target the following genes to
either turn on oncogenic mediators or turn off tumour-suppressor factors:
MSI
(MMR mutation)
(MLH1 methylation)
Normal
epithelium
APC,
-Catenin
Chromosomal
instability
(eg, CDC4)
Small
adenoma
KRAS,
BRAF
PIK3CA,
PTEN
Large
adenoma
TP53,
BAX
SMAD4,
TGFBR2
Cancer
Growth factors:
•
Oncogenic mediators that are turned on in CRC are COX-2 and EGFR
•
Tumour-suppressor factors that are turned off are 15-PGDH and TGF-
1. Markowitz SD, et al. N Eng J Med 2009;361:2449-60.
Key pathways in CRC1
•
APC mutations are present n 85% of CRCs
•
Result in the activation of the Wnt signalling pathway, regarded as the
initiating event in CRC
•
TP53 mutations are present in 35-55% of CRCs
•
Lead to inactivation of the p53 pathway, which often coincides with the
transition of large carcinomas into invasive carcinomas
•
KRAS and BRAF mutations are present in 37% and 13% of CRCs,
respectively
•
The mitogen-activated protein kinase (MAPK) pathway is activated
•
BRAFV600E activating mutation is present in 8-12% of CRCs
•
PI3KCA activating mutations are present in one third of CRC cases
•
PTEN inactivating mutations lead to identical results (activation of PI3K)
1. Markowitz SD, et al. N Eng J Med 2009;361:2449-60.
Key pathways in CRC1
•
TGFBR2 is inactive in one third of CRCs, inactivating the TGF- pathway
(mediator of growth arrest and apoptosis)
•
TGF- pathway inactivation coincides with the transition of an adenoma
to high grade dysplasia or carcinoma
•
Approximately two-thirds of CRC cases show increased levels of COX2, an enzyme involved in the activation of prostaglandin signalling
•
This signalling pathways is a critical step in the development of an
adenoma
•
The vascular endothelial growth factor (VEGF) and its receptor (VEGFR)
stimulate angiogenesis
•
Angiogenic pathways appear to be involved in the growth and lethal
potential of CRC
1. Markowitz SD, et al. N Eng J Med 2009;361:2449-60.