Biology of Disease

the age of 25 years. The development of colorectal cancer is also associated

with both hypomethylation and hypermethylation of DNA and this has been

detected at the polyp stage. Methylation of DNA is involved in switching

genes off, hence hypomethylation can result in activation of oncogenes,

whereas hypermethylation could lead to inactivation of tumor suppressor

genes. Deletions in the long arm of chromosome 18 and in the short arm of

chromosome 17 are also seen in colorectal cancers. Mutations in the RAS gene

have been detected in cells in the feces of patients with colorectal cancer and

it is possible that this may be used as the basis for a noninvasive diagnostic

procedure.

The condition, hereditary nonpolyposis colorectal cancer (HNPCC) is

associated with inherited mutations in a number of genes involved in

DNA repair that also predispose an individual to colon cancer. Hereditary

nonpolyposis colorectal cancer is estimated to cause between 2 and 5% of

colorectal cancers and is linked to 40% of cases of colorectal cancer occurring

in people below the age of 30 years. Other risk factors for colorectal cancer

include being diabetic (Chapter 7) and being of Ashkenazi Jewish origin.

This group also have a higher incidence of mutated BRCA1 and BRCA2 genes

(Section 17.5) and are therefore also more likely to develop breast cancer. The

genetic link to colorectal cancer has not been fully elucidated.

Signs, symptoms, diagnosis and staging of colorectal cancers

Patients with colorectal cancer may present with symptoms that include

loss of weight, bleeding from the rectum and/or blood in the feces, anemia

resulting in fatigue and breathlessness, changes in bowel habits, including

increased diarrhea, and pain in the abdomen. The tumor may cause a bowel

obstruction and if this occurs the patient suffers abdominal pain, nausea

and constipation. An initial detection of a lump in the abdomen or rectum

means that the patient must be referred for further specialist examination.

Colonoscopy is used to examine the whole colon and to obtain a biopsy for

further investigation. An alternative to colonoscopy is flexible sigmoidoscopy,

an endoscopic technique which examines only the lower part of the colon

and the rectum. The concentration of CEA (Section 17.6) in the blood can be

measured although increased values are not entirely specific for cancer and

a poorly differentiated tumor may not produce CEA. This measurement may,

however, be useful for monitoring disease progress and treatment. Abdominal

CT scans are helpful in diagnosis of metastatic spread to the lymph nodes and

liver, and chest X-rays are routinely used to detect metastases in the lungs.

Prognosis is poor for patients with metastatic spread to these two organs.

Several staging systems have been used for colorectal cancer. The Dukes system

is shown in Table 17.11 which also documents the proportion of patients who

present at this stage, together with the survival rates at five or two years.

The TNM staging system is also used increasingly for colorectal cancers

(Figure 17.35). T1, T2 and T4 are equivalent to Dukes A, B and D respectively.

T3 describes the situation if the tumor has broken the outermost membrane

of the GIT. The lymph nodes are classified as N0 if there are none containing

cancer cells, N1 where between one and three nearby lymph nodes are

involved, and N3, where there are cancer cells in four or more lymph nodes

that are more than 3 cm from the main tumor, or where there are cancer cells

in lymph nodes connected to the main blood vessels around the GIT.

Treatment of colorectal cancer

The usual treatment for colorectal cancer is surgery. Various procedures may

be used but, if possible, a resection, in which the length of GIT containing the

tumor is excised and the two cut ends are stapled together to reinstate the

integrity of the GIT, will be performed. The advantage of resection is that

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Precancerous

stage

T 1

T 2

T 3

T 4

Mucosa

Serosa

Submucosa

Muscularis

Lymph node

Figure 17.35A diagram illustrating the four

stages (TNM) of colorectal cancer.