Weatherly's Woes - Colon Cancer

POLYPS

Polyps are blobs of tissue that grow into the lumen of the gut. They’re frequently found during colonoscopies (30% of Americans in their 60s). Since some of them are precancerous, the gastroenterologist will remove the polyp and send it to a pathologist. You may not realize this, but polyps are the main reason why adults get screening colonoscopies beginning at age 50. Polyps are an early sign of colon cancer. By removing those polyps early, we prevent them from evolving further into big bad cancers. Although the majority of polyps won’t become cancerous, studies have shown that regular surveillance and removal leads to better health outcomes! Note that polyps are mostly asymptomatic, although larger ones tend to bleed (occult bleeding leading to iron deficiency anemia). Polyps can be a bit frustrating to learn about because they can be classified in many different ways: shape, location, histology, malignancy potential and underlying cause. Keep in mind that polyp size is the biggest predictor of malignancy. Cancer is pretty darn rare below 1cm, but growths that are 4 or 5 cm are usually cancerous.

Hyperplastic polyps are always benign. They have zero cancer potential. They are common in old age. They probably occur because of cellular overcrowding, which leads to a “pile up” of different cells. Grossly, they usually look like small buttons of tissue. On histology there will often be a sawtooth pattern of the villi. They don’t require any further monitoring or intervention.

Hamartomatous polyps are often associated with an underlying systemic condition. See the next page for more info.

Adenomatous polyps are precancerous. They can vary quite a lot in terms of appearance. Some of them are small little pedunculated blobs, while others form dramatic sessile structures. Microscopically, colorectal adenomas are defined by epithelial dysplasia. There are two subtypes:

Tubular adenomas are usually benign. They’re called tubular because you’ll see a proliferation of glands (lots of circles) on histology

Villous adenomas have a very high cancer potential. Their villi are very long, like an octopus. Villous is Villainous

Sessile serrated polyps are short, wide growths found in the right half of the colon. These fellows are also precancerous.

POLYPOSIS SYNDROMES

There are two conditions that cause hamartomatous polyps in kids. Hamartomas are clusters of different cells that are all growing simultaneously. Unlike cancer, which is the disorganized growth from a single progenitor cell, in hamartomas there is a big group of cells all growing haphazardly together. It’s often due to some underlying systemic condition. An isolated hamartoma is nothing to worry about, but when there are many hamartomatous polyps you should evaluate them for one of the polyposis syndromes.

Juvenile Polyposis Syndrome is an autosomal dominant condition causing kids to get tons of polyps (up to 100). This confers a risk of colorectal cancer (roughly 30% increased risk) necessitating more frequent colonoscopies.

Peutz-Jeghers Syndrome is another autosomal dominant condition that looks like JPS plus dark spots around the lips (melanin hyperpigmentation). It’s associated with increased colorectal cancer risk, with a lifetime GI cancer rate of around 45%.

Familial Adenosis Polyposis (FAP) is an autosomal dominant condition that causes thousands of adenomatous polyps. The cause is a mutation of the APC gene, a tumor suppressor (continue reading for more information of APC). FAP carries a 100% risk of colorectal cancer, necessitating a prophylactic pancolectomy as soon as possible.

Gardner syndrome is a variant of FAP that also features osteomas of the skull, extra teeth and retinal problems.

Turcot syndrome is a variant of FAP that also features brain cancer.

Lynch Syndrome (also called Hereditary Non-Polyposis Colorectal Cancer Syndrome) is an inherited condition that predisposes to a particular pattern of cancers. Lynch syndrome is caused by a mutation of genes involved in mismatch repair enzymes (MRE) like MLH1 and MSH2, which look for errors during DNA transcription (like a T being paired to a C). MRE enzymes can remove and replace those mistakes once found. Kind of like a spell checker. For reasons beyond my understanding, MRE mutations lead to something called microsatellite instability. Microsatellites are little clusters of nucleotides 1 to 6 base pairs long that repeat over and over again (for example, ACACACAC). In healthy people, microsatellites stay the same size their whole lives, neither shrinking nor growing. But with MRE mutations, these microsatellites “destabilize” and become much longer which can throw off nearby genes. Some of these microsatellites are located in important spots, like in the promoter regions for genes that regulate cell growth. That’s why this can lead to cancer. Lynch syndrome predisposes to cancers of the right colon, endometrium, ovaries and pancreas (among others).

COLORECTAL CANCER

Colon Cancer (CC) is the 3rd most common cancer in America, and it is also the 3rd deadliest cancer. It almost exclusively happens in old people (50 and older). That's why colonoscopy screening starts around age 50 and is repeated every 10 years. High risk groups (polyps, family history, IBD, Lynch Syndrome) get more frequent scopes. During a colonoscopy, the doc is looking for polyps or lesions, which they will snip out and send to the friendly neighborhood pathologist. A cheaper (but less effective) screening method is to use hemoccult tests, since CC often causes some slight rectal bleeding. However, this is much less sensitive and specific. The Carcinoembryonic Antigen (CEA) tumor marker is helpful with trending CC over time, but it isn’t helpful for diagnosing or screening. The Deleted-in-Colorectal-Cancer (DCC) gene is mutated in advanced / aggressive cases, and it confers a poor prognosis. CC likes to metastasize to the liver (following the path of the portal vein). Keep in mind that CC can weaken mucosal defense, allowing gut flora like Strep bovis to enter the circulation and cause endocarditis.

There are two genetic pathways that cause Colon Cancer

IBD causes colon cancer along the Chromosomal Instability pathway, but with a few key differences. (a) The p53 mutation happens earlier than the APC mutation, (b) the tumors are less likely to be associated with polyps, and (c) tends to arise in multiple different locations.