Download Colon carcinoma

Carcinoma Colon
Dr Sowmya Uthaiah
Assistant Professor
Dept Of Pathology
Introduction
 Adenocarcinoma of the colon is the most common malignancy of the
GI tract
 Major cause of morbidity and mortality worldwide
Epidemiology
 Apprx 1.2 million new cases
 600,000 associated deaths/year (10% of all cancer deaths)
 High incidence -North America, Australia, New Zealand, Europe,
japan
 Low incidence - South America, India, Africa, and South Central
Asia
 Age group- 60 to 70 years
Dietary factors
 Low intake of unabsorbable vegetable fiber
reduced fiber
content decreased stool bulk and altered composition of the
intestinal microbiota
increase synthesis of potentially toxic
oxidative by-products of bacterial metabolism
remain in
contact with the colonic mucosa for longer periods of time.
 High intake of refined carbohydrates and fat
of cholesterol and bile acids
intestinal bacteria.
hepatic synthesis
converted into carcinogens by
Protective effect - aspirin or other NSAIDs
 NSAIDs cause polyp regression in FAP patients
 Inhibition of the enzyme cyclooxygenase-2 (COX-2)
 COX-2
 highly expressed in 90% of colorectal carcinomas and 40% to 90% of
adenomas.
 production of prostaglandin E2, which promotes epithelial proliferation
Pathogenesis
 Genetic and epigenetic abnormalities.
 Apc/β-catenin pathway – classic adenoma-carcinoma sequence
 Microsatellite instability pathway - defects in DNA mismatch repair
and accumulation of mutations in microsatellite repeat regions of the
genome
Classic adenoma-carcinoma sequence –APC gene
 80% of sporadic colon tumors
 Early event
 Both copies of the APC gene must be functionally inactivated
 Key negative regulator of β-catenin, a component of the Wnt
signaling pathway
 APC protein normally binds to and promotes degradation of β-
catenin
 loss of APC function
β-catenin accumulates and translocates to
the nucleus forms a complex with the DNA-binding factor TCF
activates the transcription of genes- MYC and cyclin D1
promote proliferation
Activating mutations in KRAS
 Promote growth and prevent apoptosis
 Late event
 Fewer than 10% of adenomas less than 1 cm in diameter
 50% of adenomas greater than 1 cm in diameter
 50% of invasive adenocarcinomas
Mutations in other tumor suppressor genes
 Encoding SMAD2 and SMAD4 - effectors of TGF-β signaling
 TGF-β signaling normally inhibits the cell cycle
 Tumor suppressor gene TP53
 70% to 80% of colon cancers
 later stages of tumor progression
Microsatellite instability (MSI)
 DNA mismatch repair deficiency
 Mutations accumulate in microsatellite repeats
 MSI high, or MSI-H, tumors
 Microsatellite sequences are located in the coding or promoter
regions of genes involved in regulation of cell growth
 Type II TGF-β receptor and the pro-apoptotic protein BAX
CpG island hypermethylation phenotype (CIMP)
 Subset of microsatellite unstable colon cancers
 Without mutations in DNA mismatch repair enzymes
 MLH1 promoter region is hypermethylated
reducing
MLH1 expression and repair function
 Activating mutations in the oncogene BRAF
CpG island methylation in the absence of microsatellite
Instability
 KRAS mutations
Clinical Features
 Insidiously and may go undetected for long periods
 Ceacal and other right-sided colon cancers- fatigue and weakness
due to iron deficiency anemia
 Left-sided colorectal adenocarcinomas
 occult bleeding
 changes in bowel habits
 cramping and left lower quadrant discomfort
Morphology
Gross : Proximal colon - polypoid, exophytic masses, extend along
one wall of the large-caliber cecum and ascending colon (rarely cause
obstruction)
Distal colon – annular lesions - produce “napkin-ring” constrictions
and luminal narrowing (obstruction)
Both forms grow into the bowel wall over time.
Microscopy
 Tall columnar cells that resemble dysplastic epithelium found in
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adenomas
Invasion-stromal desmoplastic response-firm consistency
poorly differentiated tumors form few glands
abundant mucin that accumulates within the intestinal wall
signet-ring cells
neuroendocrine differentiation
Well-differentiated adenocarcinoma. Note the elongated, hyperchromatic nuclei.
Necrotic debris, present in the gland lumen, is typical.
Poorly differentiated adenocarcinoma forms a few glands, largely composed of
infiltrating nests of tumor cells.
Mucinous adenocarcinoma with signet-ring cells and
extracellular mucin pools.
Prognostic factors
 Depth of invasion and the presence of lymph node metastases
 Invasion into the muscularis propria- reduced survival
 Metastases -the liver ,regional lymph nodes, lungs and bones
 Five-year survival rates :overall 5-year survival rate in the united
states is 65%, and ranges from 90% to 40% depending on stage.
China, India, the Philippines, and Thailand (30% to 42%).
Metastatic colorectal carcinoma. A, Lymph node metastasis.
Note the glandular structures within the subcapsular sinus.
Solitary subpleural nodule of colorectal carcinoma metastatic to
the lung.
Liver containing two large and many smaller metastases. Note the central necrosis
within metastases.