Most cases of colorectal cancer risk factors develop from non-cancerous adenomatous polyps through a process called adenoma-carcinoma sequence, and the risk of developing colorectal cancer increases with the increase in size.
The term polyp of the colon refers to a protuberance into the lumen from the normally flat colonic mucosa. Polyps are usually asymptomatic but may ulcerate and bleed, cause tenesmus if in the rectum, and, when very large, produce intestinal obstruction.
They may be of following types-
- Neoplastic (adenomas and carcinomas),
- Non-neoplastic, and
- Submucosal (neoplastic / non-neoplastic).
High Risk Factors
Risk of cancer is highest with Villous histology, increasing polyp size and High-grade dysplasia.
Polyps have three variants – tubular(75-87%), tubulovillous (8-15%) and Villous(5-10%). Tubulovillous and villous polyps have most increased risk of cancer, 20% and 40% respectively. Villous polyps are at a higher risk of transformation into malignant neoplasm compared to tubular and tubulovillous polyps.
Increasing polyp size
The proportion of adenomas showing advanced histologic features (high-grade dysplasia or >25 percent villous histology) increases from 1% in small adenomas (<5 mm) to 7 to 12 % for medium-sized adenomas (5 to 10 mm) upto 20 % for large adenomas (>1 cm).
Older age is also associated with high-grade dysplasia within an adenoma, independent of size and histology
Are all Colon Polyps Pre-cancerous?
No, all colon polyps are not precancerous. Polyps are classified as neoplastic (adenomatous) or malignant, and non neoplastic (hyperplastic, mucosal, inflammatory, hamartomatous).
Adenomatous polyps are found in 33% of people by age 50 and 50% by age 70. Most lesions are <1cm, 60% being single and 40% multiple. Invasive cancer will develop in 24% when untreated.
These are mostly located in the rectosigmoid, less than 5 mm in size and rarely, if ever, develop into colorectal cancers
Hyperplastic polyposis syndrome
(HPS) refers to a condition characterized by multiple, large and/or proximal hyperplastic polyps and, occasionally, smaller numbers of serrated adenomas adenomas, or mixed hyperplastic / adenomatous polyps.
WHO criteria for HPS
- At least five hyperplastic polyps proximal to the sigmoid colon, of which two are greater than 1 cm in diameter, or
- Any number of hyperplastic polyps occurring proximal to the sigmoid colon in an individual who has a first degree relative with hyperplastic polyposis, or
- Greater than 30 hyperplastic polyps distributed throughout the colon.
Mucosal polyps are small (usually <5 mm) excrescences of tissue that endoscopically resemble the adjacent flat mucosa and histologically are normal mucosa. They have no clinical significance
Inflammatory pseudopolyps are irregularly shaped islands of residual intact colonic mucosa that are the result of the mucosal ulceration and regeneration that occurs in inflammatory bowel disease (IBD).
Typically multiple, these are often filiform and scattered throughout the colitic region of the colon. They may also be more isolated and semi-pedunculated in areas of more active recent inflammation, and have mucus adherent to their apices.
Some of the common types of submucosal polys are as follows-
- Lymphoid aggregates,
- Pneumatosis cystoid intestinalis,
- Metastatic lesions
Adenoma-Carcinoma Sequence of Colonic Polyps
Adenoma carcinoma sequence refers to the sequence of malignant changes that take place in a dyspalstic polypoid lesion (adenoma) for it’s transformation into a carcinoma. It involves activation of oncogenes and/or suppression of tumor suppressor genes.
Some common molecular changes in pathogenesis of colon cancer are discussed below.
Microsatellite Instability (MSI-H)
Two distinct mutational pathway can give rise to colorectal cancer, the microsatellite pathway and the chromosomal instability pathway.
Microsatellites are DNA sections in which short sequences of nucleotides (most commonly dinucleotides) are repeated multiple times. When microsatellite has gained or lost repeat units and has undergone change in length resulting in frame shift mutation and/or base pair substitutions, it is called as Microsatellite Instability (MSI). Appoximately 15% cases harbour this and it is typically associated With DNA mismatch repair function.
MSI-H (high) colonic tumors are those in which there is high incidence of microsatellite instability. These are more frequently right sided, high grade, mucinous type, diploid, with increased peritumoural lymphocytic infiltration, have large primary at diagnosis, more node negative and better prognosis and treatment with 5FU did not improve survival.
On the otehr hand, MSI-L (low) colonic tumors are those in which there is low incidence of microsatellite instability.
Majority of colon cancer have chromosomal instability pathway (LOH, chromosomal amplification and tanslocation). They are known as MSS (microsatellite stable). MSS & MSI-L behave similarly. They are aneuploid and have poor prognosis as compared to MSI-H.
DCC gene loss (allelic loss of 18q)
It occurs in nearly 70% of colon cancer, rarely in adenomas (exception being large villous adenomas). But it is more common in patient with liver metastasis, and it’s prevalence rises to nearly 90% to 100% in such cases.
Product of DCC is netrin-1. DCC induces apoptosis and binding of netrin blocks apoptosis. So loss of DCC leads to impaired apoptosis. It has prognostic value, more so in stage II & III disease.
Hereditary Polyp Disorders
Lynch syndrome or hereditary non-polyposis colorectal cancer
It is an autosomal dominant disorder, accounting for 3% of colon cancers. It occurs five times more frequently than familial adenomatous polyposis.
Lynch Syndrome I just involves colon, whereas Lynch II also involves endometrium, ovary, stomach, small bowel, biliary, pancreas, ureter, renal pelvis. It is called as non-polyposis syndrome as the number of polyps seen are few, upto 100 colonic polyps.
MSH2 and MLH1 (60%) are the most common mutations seen in HNPCC, less common ones are MSH5, MSH6, PMS1 and PMS2.
There is 85% lifetime risk of colon cancer, more right sided cancers (60-70%), earlier are of presentation (before 45 years), accelerated rate of progression, lower stage, better survival. There is a 20% risk of metachronous (one cancer after the other) or synchronous (tweo cancers at the same time) lesions. Risk for endometrial is 40% and < 10% for all other cancer.
It is caused by mutations in the APC gene. It is an autosomal dominant disorder with 100% penetrance. It affects 1 in 8000 individuals and accounts for 0.5% of all colorectal cancer.
Extracolonic manifestations include benign conditions (osteomas, retinal epithelium hypertrophy, epidermal cysts, adrenal adenomas, desmoid tumours) and other malignant conditions (thyroid tumours, ampullary adeno carcinoma and brain tumours).
Caused by mutation in LKB1.
Caused by germline mutations in PTEN, SMAD4, BMPR1, or other genes yet to be identified.