Colorectal cancer

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. 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, may be 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
  • Hereditary non-polyposis colorectal cancer
  • Familial adenomatous polyposis
• 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.

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.

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. Other common sites of metastasis are bone and ovary.

Clinical features

The most important symptoms are those of lower GI bleeding (haematochezia, melena, or occult bleading leading to iron-deficiency anaemia) or altered bowel habits. Altered bowel habits is more common for left-sided cancers compared to right-sided, due to the smaller lumen of the left-sided colon. Alternating diarrhoea and constipation is a typical sign. Abdominal pain is a less frequent symptom. Rectal cancers cause tenesmus and incomplete defecation.

Metastases are present at presentation in 20% of cases. Distal rectal cancers may be palpated on DRE.

Diagnosis and evaluation

Colonoscopy is the gold standard investigation for CRC, as it not only allows for diagnosis but also for biopsy (and sometimes complete removal) of the lesion. If a suspicious lesion is found, the whole colon must still be examined, because of the relatively high chance of synchronous primary tumours.

CT colonography (virtual colonoscopy) is an alternative to colonoscopy, but it does not allow for biopsy or removal.

Once the diagnosis of colon cancer has been made, a CT of the chest, abdomen, and pelvis is required for staging. For rectal cancers, MRI is used, and a transrectal ultrasound may be necessary to determine the T and N stage.CEA is the tumour marker most specific for CRC and should be measured upon diagnosis. Elevated CEA is associated with a worse prognosis, and CEA which doesn’t normalise postoperatively is indicative of persistent disease. Microcytic or normocytic anaemia (due to chronic GI blood loss) or faecal occult blood are typical findings in CRC.

Staging

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)

Treatment

The gold standard treatment for CRC is radical surgery. CRC is one of the few cancers in which M1 cancers can be cured, as surgical resection of liver and/or lung metastases (metastasectomy) may allow for cure.

Stages I-III can usually be attempted cured, with surgical resection with or without chemotherapy. Some stage IV CRCs may be cured, if there are only a few metasases in the liver or lung which can be removed surgically, although complete cure is rare. In most cases of stage IV disease, treatment is only palliative.

Surgical treatment

Options include left or right hemicolectomy, sigmoid colectomy, or total or subtotal colectomy. This may be performed open, laparoscopically, robot-assisted, etc. At least 12 regional lymph nodes must be removed for proper surgical staging. Rectal cancer is treated with total mesorectal excision (TME) in most cases, or more modern techniques like transanal endoscopic microsurgery (TEM).

Surgery may also be used palliatively, either by resection, bypass operation, stoma formation, or by stenting.

Systemic treatment

Chemotherapy (usually FOLFOX or FOLFIRI) may be used neoadjuvant or adjuvant in stages II-IV. Biological therapy may be used palliatively and include anti-VEGF and anti-EGFR antibodies. Targeted therapy, with multi-tyrosine kinase inhibitors like regorafenib, may also be used palliatively.

Radiotherapy

Radiation is not used for colon cancer (or any intraabdominal cancer) because the small bowel is very sensitive to radiation. Radiotherapy may be used for rectal cancer, as it lies in the pelvic region.

Screening

Screening is important to reduce the incidence of CRC, as most CRCs develop from adenomatous polyps which take years to develop into cancer. 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. ‎