Pathophysiology of Colorectal Cancer
How does colorectal cancer develop?
The pathogenesis of colon cancer is complex. Colon cancer results from the accumulation of multiple genetic alterations that happen in a specific sequence over a period of time. The genetic alterations may result from sporadic mutations or from mutations that are inherited as discussed under risk factors for rectal and colon cancer.
The APC gene, which has an essential role in the regulation of the growth of intestinal epithelial cells, and is frequently mutated resulting in FAP. APC mutations can lead to accumulation of a type of oncogene in the cells, which can promote cancer development.
The right-sided tumors usually grow as polypoid masses that bleed. The bleeding can often be in the form of occult bleeding. The right-sided tumors rarely cause obstruction, while the carcinomas of the left side (distal colon) usually lead to bowel obstruction due to constriction of the bowel as the lesions are generally annular shaped. The tumors of the distal colon may also present with bleeding.
Majority of colon cancers are left-sided, but of late there has been a steady increase in the incidence of right-sided colon cancer in the US, Europe and Asia. The anatomic shift probably results from response to carcinogens, increased longevity, or genetic factors with defects in mismatch repair genes.
Histological grading of colon cancer has important prognostic value. It depends on the cellular pleomorphism, glandular architecture, and the prominent pattern of mucin secretion. Most of the staging systems divide tumors into :
- Grade I – well differentiated
- Grade II – moderately differentiated
- Grade III – poorly differentiated
- Grade IV – undifferentiated
A simpler approach to grading employs only the two divisions of low grade (includes well differentiated and moderately differentiated grades) and high-grade (includes poorly differentiated and undifferentiated grades).
Types of Colorectal Cancers
Adenocarcinoma is the most common type of colon cancer accounting for more than 95% of colon cancers. These malignant epithelial tumors arise from glandular structures and are further classified according to its microscopic appearance as signet ring cell adenocarcinoma and mucinous adenocarcinoma. The signet ring cell adenocarcinoma carries slightly more adverse prognosis than mucinous adenocarcinoma. Medullary carcinoma is a type of undifferentiated cancer characterized by absence of glands and distinctive growth pattern and is infiltrated with lymphocytes.
The less frequent types of cancers affecting the colon and rectum are leiomyosarcoma, malignant melanoma, neuroendocrine tumors (NET), and lymphomas.
Leiomyosarcomas are soft tissue tumors that can occur in colon and they account for less than 2% of all colon cancers. It usually presents with pain and bleeding.
Malignant melanoma accounts for about 2% of all colon cancers and manifests with weight loss, nausea, vomiting, diarrhea, bleeding per rectum and abdominal pain.
Neuroendocrine tumors (NETs) arise from the argentaffin cells in the glands of intestine and accounts for less than 1% of all colon cancers. NETs can be aggressive or indolent (carcinoid) type. Aggressive NETs like small cell or extrapulmonary oat cell tumors have poor prognosis. Indolent NETs or carcinoids usually cause carcinoid syndrome.
Lymphomas can develop in colon and non-Hodgkins lymphoma is most common form seen in the colon. Lymphomas account for 0.5% of all colon cancers.
Signs and Symptoms of Colorectal Cancer
The early stages of colorectal cancer may be asymptomatic. The major clinical features of symptomatic colon cancer include :
- bleeding from the lower gastrointestinal tract
- abdominal pain and/or pain during a bowel movement
- unintentional weight loss
- unexplained fatigue
- change in appetite
- change in bowel habits
Carcinoid syndrome results from release of various substances from cancer cells and manifests with symptoms like flushing, diarrhea, headache, asthma and heart failure. It is more prominent with indolent neuroendocrine tumors (NETs) of the colon.
The complications of colon cancer can present with acute gastrointestinal bleeding, bowel obstruction, bowel perforation, and complications related to distant metastasis like ascites, bladder dysfunction and sacral nerve pain.
Symptoms based on different location of colon cancer
The symptoms of colon cancer typically vary depending upon the location of lesions.
Lesions in proximal colon (first part of the colon) often ulcerate and cause chronic blood loss leading to symptoms like melena (black tarry stools), fatigue, palpitations and characteristic features of iron deficiency anemia. These patients usually do not suffer from abdominal pain or change in bowel habits.
Lesions in distal colon (latter part of the colon) usually present with intestinal obstruction, abdominal distension, abdominal cramping, change in bowel habits with increasing constipation, and straining at stools. Rectal bleeding may be prominent with the passage of fresh, bright red blood in stools (hematochezia).
Spread of Colon Cancer
The adenomatous colon cancers can produce mucin that may help in the direct spread of cancer to the adjacent organs. The cancer cells can also enter the lymphatic system and spread to regional lymph nodes. Colon cancer can directly spread into peritoneal cavity or invade the pericolonic fat and the surrounding structures like liver, renal pelvis, bladder, or ureters. It can spread into the lungs or bone marrow through the blood stream (hematogenous spread). A host of signs and symptoms may arise depending on the metastatic spread and the extent to which the various sites are affected.