Page created on February 22, 2019. Last updated on May 4, 2022 at 11:53

Written by ms. worldwide, edited by Nikolas.

Colorectal carcinoma

Introduction and epidemiology

Colorectal carcinoma (CRC) refers to all cancers that can affect the colon and rectum. Carcinomas in the colon are the most common malignancy in the GI-tract, accounting for 95% of all GI cancers. Paradoxically, the small intestine accounts for 75 % of the overall length of the whole GI-tract, but somehow the tumors accumulate in the colon anyway.

CRC is the third most common type of cancer, but it’s the second most common cause of cancer-related death. It accounts for 10% of the world’s cancers. It’s mostly a disease of elderly, affecting those in their 60s and 70s.

>90% of colorectal cancers develop from adenomatous polyps of the colon.

Screening is important to reduce the incidence of CRC. In Europe, screening programs for CRC are in development or recently launched. Generally, people above 50/55 should be screened with colonoscopy, or alternatively, with a faecal occult blood test.

Etiology

The diet is the major risk factor for CRC. A low intake of vegetable fiber and high intake of refined carbohydrates and fat increases the risk and is the reason why it’s so frequent in the western countries.

Other risk factors:

• Family history
• Older age
• Red meat
• Alcohol
• Processed meat
• Obesity
• Smoking
• Lack of physical activity

NSAIDs on the other hand, especially aspirin, are protective against colorectal cancers as they inhibit the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in the carcinomas.

We can distinguish multiple types of CRC according to cause:

• Sporadic CRC (95% of cases)
• Hereditary CRC
  • HNPCC
  • FAP
• IBD-associated CRC

Pathology

Adenocarcinoma is the most common type, accounting for 95% of cases. Other histological types include adenosquamous carcinoma, and spindle cell carcinoma.

Adenocarcinomas are usually solitary masses, either polypoid or ulcerated. These cancers are synchronous in a few percent of cases, meaning that more than one primary tumour is present at the same time.

Like all cancers they are graded based on their differentiation. Well differentiated tumors are low grade and form well-formed glands or tubules that somewhat resembles adenomatous epithelium. Moderately differentiated tumors are the most frequent type, where glands and tubules are irregular and abnormal. Poorly differentiates tumors produce few glands, and the majority of the tumor consists of sheets of cells without glands.

CRC is staged like this:

• Stage 0 – carcinoma in situ (cancer is in the mucosa)
• Stage I – cancer invades the muscularis mucosa
• Stage II – cancer invades beyond the muscularis mucosa
• Stage III – cancer has spread to regional lymph nodes
• Stage IV – cancer has spread distally (distant metastasis)

This type of cancer can metastasize by the lymphogenic way to regional lymph nodes. It can also spread by the portal circulation to the liver, or by the caval circulation to the lung if the tumor originated in the lower third of the rectum. Peritoneal seeding is uncommon.

Pathogenesis

There are two major molecular pathways involved in the development of colorectal carcinoma:

• Chromosomal instability pathway
• Microsatellite instability pathway

The chromosomal instability pathway occurs in 80% of cases and is the prototypic model for cancer development, as there is a clear progression from normal epithelium to an adenomatous polyp to invasive cancer through a well-studied multistep process called the adenoma-carcinoma sequence. Sporadic cancers result from the stepwise accumulation of multiple somatic mutations. This process takes 10 – 15 years. The APC gene is mutated and inactivated early in the adenoma-carcinoma sequence. This gene codes for the protein APC, which inhibits a proto-oncogene called β-catenin. Inactivation of k-RAS and p53 occurs late in the sequence.

In 15% of cases the so-called microsatellite instability pathway occurs (MSI). MSI is a condition where the DNA repair mechanism is impaired so that genes mutate more easily. Microsatellite instability in the case for colorectal carcinoma is commonly due to mutations in the genes MLH1 and MSH2. Both genes code for proteins involved in DNA repair. The presence of MSI can be shown with PCR.

These molecular changes are clinically important because we nowadays have drugs which may target the specific mutations, if present in that specific patient.

Clinical features

CRC may be asymptomatic in the early stages. In addition to constitutional cancer-related symptoms like weight loss, fever, night sweats, and fatigue, patients may develop specific symptoms such as:

• Occult or macroscopic lower GI bleeding (hematochezia or melena)
• Iron deficiency anaemia (due to long-term bleeding)
• Change in bowel habits (constipation, diarrhoea, or alternation between both)

The ascending colon has a larger lumen than the descending colon, so cancers in the ascending usually cause fewer symptoms and are therefore discovered later. For this reason, right-sided cancers usually present with bleeding. On the other hand, the left-sided colon has a smaller lumen, and so left-sided cancers usually present with changes in bowel habits.

Management

Surgical removal. There are some new immunotherapy treatments for different types of colorectal cancer. Nowadays specific drugs exist which target and bind to cell surface proteins like EGFR and PD-1, which are important for the cancer, if it expresses them.

Hereditary Nonpolyposis colorectal cancer (Lynch syndrome)

HNPCC is an autosomal dominant genetic disease which is associated with a very increased risk of colorectal cancer – they have an 80% risk of developing it in their lifetime. In addition to that, it’s also associated with cancer in endometrium, ovaries, small intestine, brain, ureters, hepatobiliary tract and skin. Patients with this disease tend to get colorectal cancer at much younger ages than for sporadic colon cancer and are often located in the right colon.

HNPCC is caused by germline mutations in the genes that code for proteins responsible for detection, excision and repair of errors during DNA replication. The majority of patients with HNPCC have mutations in the MSH2 and MLH1 genes, but the mutations can also happen in the MSH6 and PMS2 genes.

Despite the name of this disease, patients with this disease have a few polyps, but not as many as in FAP. Blood test can be taken to find out if a young person has these mutations. Some prevention of the disease can be achieved by taking small doses of aspirin every day. Prophylactic surgery is more used. Females with HNPCC are advised to perform a hysterectomy and remove the ovaries as well as the risk for cancer in these organs are very high.

Non-epithelial colorectal tumors

The same tumors discussed in the earlier topics of the GI-tract can occur in the colon and rectum as well. The most frequent one is the lipoma, which is most often submucous and benign. The others are rare, but can be:

• Leiomyomas
• GIST
• Leiomyosarcoma
• Angiosarcoma
• Kaposi sarcoma
• Lymphoma

Cancers from the stomach, lungs, the prostate, the breasts, ovaries can metastasize to the colon. Melanoma can also spread to the colon.

Tumors of the anal canal

Adenocarcinoma

Adenocarcinomas can appear in the upper part of the anal canal, where the mucosa is still the same as in the rectum.

Squamous cell carcinoma

The squamous cell carcinomas in the anal canal are induced by HPV and starts with a lesion just like in the CIN III slide of the cervix. Here it’s called anal intraepithelial neoplasia (AIN) and has the same staging.

Anorectal melanoma

Very rare and has a poor prognosis.