Right- vs Left-sided Colorectal Cancer

Colorectal cancer is the third most common cancer in the US, affecting roughly 1 in 23 men and 1 in 25 women. It is also the second leading cause of cancer-related deaths in men and in women.

However, despite colorectal cancer impacting men and women at seemingly similar rates, colorectal cancers are not made equal. The colon and rectum makes up the lower gastrointestinal (GI) tract, and the colon alone spans about 5 feet long. Multiple studies have found differences in how cancer develops in different parts of the colon, affecting the detection and diagnosis of colorectal cancer.

Distinguishing between the right and left colon is not as simple as drawing a line down the middle of the body and calling it a day. The cells in the right and left colon have different embryological origins, but what does that mean, exactly?

After an egg is fertilized, it undergoes cellular division to form an embryo, which is implanted into the uterus. The cells in the embryo continuously divide and grow, at the same time differentiating into different types of cells that eventually make up different tissues and organs.

The colon forms from cells that make up the midgut and hindgut, which are formed in the embryo through two distinctly different development pathways. From the midgut, the ascending colon and proximal two-thirds of the transverse colon make up the right side of the colon. Conversely, the hindgut results in the distal one-third of the transverse colon, descending and sigmoid colon and rectum, making up the left-side.

Given that different parts of the colon are not quite “cut from the same cloth,” it stands to reason that the resultant cancers that develop also tend to be different.

Right-side colon cancer can occur when tumors show high microsatellite instability (MSI). Microsatellites are sections of repeated DNA that change in length and become unstable if repair of damaged DNA does not work properly. Tumor tissue samples can be screened for MSI by observing if certain DNA microsatellites have increased or decreased in length.

On the other hand, left-side colon and rectal cancers often result from chromosomal instability (CIN), where tumor cells have missing or extra chromosomes, or an entire copy of a gene is lost or missing (known as loss of heterozygosity). These tumors are considered more genetically unstable and also more aggressive.

Under a microscope, tumors in the left and right side of the colon also appear different. Tumors that form in the right side are typically either sessile serrated adenomas or mucinous adenocarcinomas — malignant tumors that originate from the epithelial lining and result in abnormal mucous secretion. Left-side tumors are more typical adenocarcinomas that have tubular or villous growth patterns and are polypoid in appearance. Consequently, right-side tumors appear flat morphologically, while left tumors have more obvious protrusions in the intestinal lumen.

Anything that sticks out like a proverbial sore thumb is easier to spot, and the same goes for left-sided colorectal cancer.

With a polypoid appearance that protrudes from the intestinal lining, these polyps or tumors are easier to identify at earlier stages of cancerous growth during a colonoscopy. Right-sided colorectal cancer, on the other hand, is harder to detect due to its flatter appearance, which is less conspicuous and harder to spot during a standard colonoscopy that doesn’t use narrow band imaging (NBI) or blue light imaging (BLI) technologies.

The difficulty in detecting right-sided tumors often means that these tend to be more advanced and larger by the time they are detected, and the cells are also poorly differentiated or difficult to distinguish from other cancer cell types.

The development of late-stage cancer also changes depending on where the primary colorectal cancer is found. Right-side cancers are more likely to metastasize into the abdominal cavity, a process known as peritoneal carcinomatosis. In this instance, the cancerous cells spread into the space between organs in the abdomen, reaching other abdominal organs such as the pancreas or stomach. Conversely, late-stage left-sided colorectal cancer is more likely to metastasize to the liver and lungs. In particular, rectal cancer often spreads to the lungs due to venous drainage patterns.

How quickly and easily a cancer can be detected changes not only the prognosis, but also the treatment and survival rate, and the same applies to left- and right-sided colorectal cancers.

While researchers debate if these cancers should be treated as separate entities due to the various differences, perhaps there is enough justification to do so if it ensures better evaluation of right- and left-sided tumors and designing of therapy regimens.