Page 429 - Concise Pathology for Exam Preparation ( PDFDrive )

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414 SECTION II Diseases of Organ Systems

• A minimum number of 100 are required for the diagnosis.
• Adenomas may also be present in other parts of the intestine, eg, duodenum.
• Polyps manifest as early as adolescence or early adulthood.
• Conversion to colonic cancer is 100% by middle age.
• Specific APC mutations are also seen in variants such as Gardner syndrome (oste-
oma of mandible, skull and long bones, epidermal cysts, desmoid tumours and thy-
roid tumours) and Turcot syndrome (intestinal adenomas and tumours of central
nervous system).
• The morphology of the polyps is same as any sporadic adenoma.
2. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch Syndrome:
• HNPCC is an autosomal dominant condition in which patients have an earlier onset
of colorectal cancer as compared to sporadic cases. The cancer is usually found in
right colon and is nonaggressive despite being mucinous on histology.
• Though the name suggests absence of adenomas; adenomas do develop in HNPCC,
although few.
• HNPCC is associated with germline mutations in DNA mismatch repair (MMR) genes
which encode enzymes responsible for repair of sequence errors which may occur
during DNA replication. An important diagnostic feature of MMR-deficient tumours
is the high rate of mutations that accumulate in repetitive nucleotide regions and
these mutations are known as microsatellite instability (MSI).
• Extracolonic cancers associated with HNPCC include: cancers of stomach, small in-
testine, endometrium, ovary and urinary bladder.

Q. Write briefly on colorectal carcinogenesis/adenoma–carcinoma
sequence.
Ans. The following are the salient features of colorectal cancer:

Aetiology
Dietary factors
• High content of refined carbohydrate and low content of dietary fibre reduces bulk,
increases transit time, thereby increasing the duration of exposure of colonic epithelium
to possible carcinogens in diet and altering the normal intestinal bacterial flora.
• Intake of red meat (high cholesterol and hence high bile acid secretion, whose bacterial
byproducts in the colon are considered to be irritants)
• Decreased intake of protective micronutrients (less vitamins A, C and E)
Geographical Variation
More common in North America and Northern Europe rather than South America, Africa
and Asia
Familial History
Only in 1–3% cases; most cases are sporadic

Previous Bowel Conditions
Inflammatory bowel disease, adenomas and diverticular diseases
It has been noted that aspirin and other NSAIDs may have a protective role in colorectal
carcinogenesis as they inhibit cyclooxygenase-2 (COX-2) which is expressed in 90% colorectal
cancers. COX-2 is instrumental in production of PGE-2 which is thought to be responsible for
epithelial proliferation.
Two distinct molecular pathways have been implicated in colonic cancer and
they are
1. Adenoma-carcinoma sequence (APC b-catenin pathway; Flowchart 14.2):
• This pathway is responsible for 80% sporadic colonic cancers and involves a series
of genetic alterations accompanying the progressive conversion of normal mucosa to
malignancy.

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