~Colorectal Cancer, Part 2 - Classifications and Stages

Cellular Classification

Cancer is classified as to where it is found in the layers of the colon. Of all colorectal cancers, 95% are adenocarcinomas. There are less common forms of cancer as well.

Adenocarcinoma. Adenocarcinoma of the colon and rectum develops in the glands of the inner lining or mucosa of the intestine and makes up 95% of colorectal cancer cases.

Subtypes of adenocarcinoma of the colon are:
  • Mucinous (colloid): Mucinous adenocarcinomas are adenocarcinomas that produce mucus and may arise from several primary sites including the colon and ovaries.
  • Signet ring: A signet ring is an adenocarcinoma whose nuclei are often pushed to the side of the cells. These signet ring tumors often have a propensity to metastasize to the ovary.
Other types include:
  • Neuroendocrine
  • Lymphomas
  • Melanomas
  • Squamous cell
  • Sarcomas
  • Carcinoids
Regional Lymph Nodes. Lymph nodes are small clumps of immune cells acting as filters for the lymphatic system. Like the circulatory system, the lymphatic system runs throughout the body carrying fluid, cells, and other material. When colon cancer spreads, the first place it usually travels is to regional lymph nodes located proximally to the large intestine in the abdomen. Regional lymph node involvement is determined postoperatively by a pathologist, who will microscopically examine the nodes to determine whether or not they contain cancer. The best prognosis is when the cancer remains localized within the colorectal area.

Stage Information
  • TNM definitions
  • Regional lymph nodes
  • Distant metastasis
  • Modified Duke Staging System
Treatment decisions should be made with reference to the TNM classification, rather than the older Duke's or the Modified Astler-Coller (MAC) classification schema. The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification (Anon. 1995; Yarbro et al. 1999).

TNM Definitions
  • T: Primary tumor
  • TX: Primary tumor cannot be assessed
  • T0: No evidence of primary tumor
  • Tis: Carcinoma in situ, intraepithelial or invasion of the lamina propria*
  • T1: Tumor invades submucosa
  • T2: Tumor invades muscularis propria
  • T3: Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic or perirectal tissues
  • T4: Tumor directly invades other organs or structures and/or perforates visceral peritoneum
  • This includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.
  • Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa, for example, invasion of the sigmoid colon by a carcinoma of the cecum.
Regional lymph nodes (N)
  • NX: Regional nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis in 1 to 3 regional lymph nodes
  • N2: Metastasis in 4 or more regional lymph nodes
A tumor nodule greater than 3 mm in diameter in the perirectal or pericolic fat, without histologic evidence of a residual node in the nodule, is classified as regional perirectal or pericolic lymph node metastasis. A tumor nodule of 3 mm or less in diameter is classified in the T category as a noncontiguous extension, that is, T3.

Distant metastasis (M)
  • MX: Distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant me4tastasis
Stage 0
  • Tis, N0, M0
Stage 1
  • T1, N0, M0
  • T2, N0, M0
Stage III
  • Any T, N1, M0
  • Any T, N2, M0
Stage IV
  • Any T, any N, M1
Modified Duke Staging System
  • Modified Duke A - The tumor penetrates into the mucosa of the bowel wall but not further.

  • Modified Duke B
    • B1: Tumor penetrates into but through the muscularis propria (the muscular layer) of the bowel wall.
    • B2: Tumor penetrates into and through the muscularis propria of the bowel wall.
  • Modified Duke C
    • C1: Tumor penetrates into but not through the muscularis propria of the bowel wall; there is pathologic evidence of colon cancer in the lymph nodes.
    • C2: Tumor penetrates into and through the muscularis propria of the bowel wall; there is pathologic evidence of colon cancer in the lymph nodes.
  • Modified Duke D Tumor which has spread beyond the confines of the lymph nodes (to organs such as the liver, lung, or bone).
p53 Gene Mutation

The p53 protein is a tumor suppressor encoded by the p53 gene whose mutation is associated with approximately 50-60% of human cancers. The p53 gene acts as the guardian of DNA, and in the event of DNA damage it performs several crucial functions. The p53 gene acts as a checkpoint in the cell cycle, inducing growth arrest (halting the cell cycle) by increasing the expression of the p21 gene. It initiates DNA repair. If the DNA can be repaired, the p53 gene prevents apoptosis (programmed cell death). If the DNA cannot be repaired, p53 initiates desirable apoptosis. The p53 protein also plays a major role in the transcription ("reading") factor of DNA by binding to and initiating the expression of multiple genes.

When a mutation in the p53 gene occurs, one amino acid is substituted for another and p53 loses its ability to block abnormal cell growth. Indeed, some mutations produce a p53 molecule that actually stimulates cell division and promotes cancer, and these cancers are more aggressive, more apt to metastasize, and more often fatal.

A person inheriting only one functional copy of the p53 gene from their parents is predisposed to cancer in early adulthood. Usually several independent tumors develop in a variety of tissues. This is a rare condition known as Li-Fraumeni syndrome. The p53 gene has been mapped to chromosome 17p13, and mutations in the p53 gene are found in most tumor types and contribute to the molecular events that lead to tumor formation.

Since the hallmark of cancer is the unchecked proliferation (growth) of cells, p53's role is critical. The question becomes, if the p53 gene is a built-in tumor suppressor, why does cancer still develop? The answer is the p53 molecule can be inactivated in several ways. In human families, for example, p53 mutations are inherited, and family members have a high incidence of cancer. More often, the molecule is inactivated by an outside source.

In the cell, p53 protein binds DNA that in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 binds with cdk2, the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and, as a consequence, the p21 protein is not made available to act as the stop signal for cell division. Thus, cells divide uncontrollably and form tumors. DNA tumor viruses such as the human adenovirus and the human papilloma virus can bind to and inactivate the p53 protein function, altering cells and initiating tumor growth. In addition, some sarcomas amplify another gene, called mdm-2, which produces a protein that binds to p53 and inactivates it, much the way the DNA tumor viruses do.

The amount of information that exists on all aspects of p53 normal function and mutant expression in human cancers is now vast, reflecting its key role in the pathogenesis of human cancers. It is clear that p53 is just one component of a network of events that culminate in tumor formation.

Protecting genes from mutation may be the most effective way of preventing colon cancer. Since folic acid is one of the most effective DNA protecting agents known, this helps explain why in one study that women taking folic acid supplements for at least 15 years showed a 75% reduction in colon cancer incidence (Giovannucci et al. 1998).

Other Emerging Genetic Factors

Over the last 15 years, pioneering work by Bert Vogelstein and colleagues has identified approximately 19 genetic alterations that have been found to contribute to the development of colorectal cancer (Vogelstein et al. 1988). It is important to note that there is not a specific order of genetic changes leading from benign adenoma to carcinoma. Rather, it is the total accumulation of these changes that leads to the progression of the neoplastic process.

As discussed previously in this protocol, individuals affected by familial adenomatous polyposis (FAP) were found to have APC (adenomatous polyposis coli) gene alterations in even the earliest tumors (0.05 cm) that were removed and analyzed (Powell et al. 1992). The protein encoded by the APC gene targets the degradation (breakdown) of beta-catenin, a protein component of a transcriptional complex that activates growth-promoting oncogenes, such as cyclin D1 or c- myc, which contribute to the unabated growth of cancer cells. APC mutations are very common in sporadic colorectal cancer and beta-catenin mutations.

DNA methylation changes are a relatively early event in colorectal cancer development and have been detected at the polyp stage. Colorectal cancers and polyps have an imbalance in genomic DNA methylation with global hypomethylation (decreased methylation) and regional hypermethylation (excessive methylation) occurring simultaneously within the body. Hypomethylation can lead to oncogene activation contributing to the production of myc and tyrosine kinase gene products involved in cancer cell proliferation (Feinberg et al. 1983; Lengauer et al. 1997). Folic acid protects against hypomethylation.

Interestingly, Ras gene mutations are observed commonly in larger polyps but not in smaller polyps, suggesting a role for this oncogene in polyp growth (Vogelstein et al. 1988). Additionally, Ras gene mutations are observed in more dysplastic adenomas and are believed to be related to the conversion of cells bearing these mutations into carcinomas.

Chromosome arm 18q deletions are a later event associated with cancer development. This region is deleted in 50% of late adenomas and in more than 70% of carcinomas (Vogelstein et al. 1988). These deletions likely involve the targets DPC4 (a gene involved in the transforming growth factor [TGF-beta] growth-inhibitory signaling pathway) and DCC (a gene frequently deleted in colon cancer). Also 18q deletions detected in Duke's Stage B colon cancers have been associated with an increased risk of recurrence following surgery, and studies are in progress to determine whether patients with 18q deletions might benefit from more aggressive adjuvant chemotherapy.

Chromosome arm 17p losses and tumor suppressor p53 mutations are common late events in colon cancer. 17p loss is infrequently observed in adenomas at any stage but is observed in over 75% of colorectal carcinomas.

Another predisposing condition is hereditary nonpolyposis colon cancer in which affected individuals inherit a mutation in one of several genes involved in DNA mismatch repair, including MSH2, MLH1, and PMS2.

Poor prognostic indicators include:
  • Five or more lymph nodes involved
  • Tumor spread to regional lymph nodes
  • Tumor penetration through the bowel wall
  • Perforation of colon
  • Tumor adherence to adjacent organs
  • Metastasis to distant organs
Prognostic indicators 1 through 6 put the patient in a more advanced staging category. Some other poor prognostic signs not reflected directly by staging are:
  • Poorly differentiated histology
  • Venous invasion of tumor
  • Preoperative elevation of CEA titer greater than 5.0 nanograms/mL
  • p53 mutation found in tumor
  • DNA aneuploidy  
Metastasis

Cancer cells have the ability to leave the original tumor site, travel to distant locations, and metastasize in organs such as the liver, lungs, or bones. Colorectal cancer has a propensity for metastasizing to the liver. This process of metastasis is a dynamic process which requires an optimal environment in order for a tumor cell to proliferate in the large intestine, establish its own blood supply (angiogenesis), invade into surrounding tissues, be released into the circulation, adhere to the blood vessels of the liver, invade into the liver (invasion), proliferate, and again acquire its own blood supply. This complex process requires that the tumor cell interact with the microenvironment of the liver to the extent that the tumor cell can utilize the growth factors and blood vessels of the liver in order to grow.

To date, vascular endothelial growth factor (VEGF) has been established as the most potent angiogenic factor leading to metastasis of colorectal cancer. Since VEGF is an important factor in the cancer's metastasis to the liver, various strategies have been utilized to inhibit VEGF activity so as to diminish growth and metastasis of the colorectal cancer. Studies have demonstrated that blocking VEGF activity decreases the number of colon cancer metastasis, the size of colon cancer metastasis, and the number of blood vessels within that metastasis.

In order for a tumor cell to divide, it must possess the appropriate growth factor receptors to be able to respond to growth factors released by the liver. These growth factor receptors are not only involved in tumor cell division, but are also involved in tumor cell survival. The tumor growth factors important in regulating tumor cell proliferation and survival are epidermal growth factor receptors, hepatocyte growth factor receptors, and insulin-like growth factor receptors. Numerous strategies are being investigated to inhibit activity of these receptors, including monoclonal antibodies and enzymes that inhibit the activity of these receptors as well as supplementation and diet modification. Preliminary analysis suggests that these strategies can slow the growth of these tumors. Further analysis will be necessary to determine if these agents can prolong survival.

Tumor cells frequently receive outside signals that are then transmitted through the interior of the cell to the nucleus where genes are activated. This process, signal transduction, is an active area of investigation. In colon cancers that metastasize to the liver, specific enzymes (Src, MAP kinase, and others) have found to be associated with increases in tumor aggressiveness. Furthermore, these signal transduction pathways activate genes that lead to angiogenesis, cell survival, or proliferation. Therefore, these signal transduction molecules are very important mediators in the formation of colon cancer metastasis and must therefore be inhibited as well.

Tests for Distant Metastases

In addition to tests for prognostic and predictive factors, patients diagnosed with colorectal cancer will require a number of tests to confirm that the cancer has not metastasized or spread to other organs, such as the lungs, liver, and bone. Distant metastasis is one of the worst prognostic signs because this places the patient in the most advanced staging category.

Cancer cells spread by breaking through a barrier called the basement membrane that surrounds all tissues in the body. This allows cancer cells to migrate into the bloodstream or the lymph system and be carried to distant areas of the body. Although most cancer cells die en route to other parts of the body, some survive the turbulence of the bloodstream and the body's immunological defenses to reach the lungs, brain, liver, and kidneys. Once the cell settles in new tissue, it can then grow into secondary tumors.

Cancers of the large bowel generally spread through the lymphatics or through the portal venous system to the liver. The liver is the most frequent visceral site of metastatic dissemination. It is the initial site of metastasis in one-third of recurring colon cancers, with two-thirds of patients having cancerous cells in the liver at the time of death. Other common sites for metastatic spread when the liver is involved are the lungs, bones, and brain. Rarely does cancer spread to the lungs, bone, or brain without first spreading to the liver.

Median survival after the detection of distant metastasis ranges from 6-9 months (with heavy liver involvement) to 24-30 months (with initially small liver nodules). The process to detect metastatic spread after a primary colon tumor is diagnosed may include blood tests that check for liver and bone metastasis; x-ray/CT scans to test for chest, abdomen, and liver metastasis; and a bone scan to test for bone metastasis.

X-rays. An x-ray is a test in which an image is created using moderate doses of radiation reflected on film paper or fluorescent screens providing an image of specific areas. The films created by x-rays show different features of the body in various shades of gray. The darkest images are those areas that do not absorb x-rays well; the lighter images are dense areas (e.g., bones) that absorb more of the x-rays. To enhance visibility, some x-ray exams will use a contrasting solution that can be swallowed, injected intravenously into the circulatory system, or given by an enema to locate or confirm possible metastases.

Blood tests. A variety of blood tests can assess the health of different organs and systems in your body. Cancer marker tests can detect possible cancer activity in the body. If cancer is present, it can produce specific protein in the blood that can serve as a marker for the cancer. A carcinoembryonic antigen (CEA) level can be helpful in the clinical management of colorectal cancer. Usually both pre- and postoperative CEA levels are obtained. If the CEA level is elevated preoperatively, it can be monitored for evidence of recurrence. It is important to remember that CEA may be elevated for reasons other than colon cancer, such as pancreatic disease or hepatobiliary disease, and that elevation does not always reflect cancer or disease recurrence. Also, recurrence remains a possibility when CEA is not elevated, even if CEA was elevated preoperatively. Findings of other tests, such as CT scans and colonoscopy, must be incorporated in detection of recurrence. However, if the CEA is elevated in recurrent or metastatic colorectal cancer, the CEA level may be helpful to monitor response. The real value of monitoring CEA after initial resection is that it can allow early identification of patients who may benefit from additional surgery with curative intent. Other blood laboratory tests may include tumor marker test CA 19-9 and CA 125, standard complete blood counts, and electrolyte and chemistry panels.

CT scan. This procedure combines the use of a digital computer together with a rotating x-ray device to create detailed cross sectional images or "slices" of the different organs and body parts. This procedure may or may not involve injecting an IV contrasting solution into the circulatory system. It does, however, always involve exposure to ionizing radiation. A CT scan has the unique ability to image a combination of soft tissue, bone, and blood vessels and can assist in locating possible metastasis.

Ultrasound. Very high-frequency sound waves are used to produce an image of many of the internal structures in the body without exposure to ionizing radiation.

Bone scan. This procedure uses a radioisotope tracer (Technetium-99m MDP or HDP) injected intravenously into the circulatory system. This radioactive compound localizes in the bone and is recorded by the radionuclide scanner (better known as a gamma or scintillation camera), producing an image of the tracer's distribution in the skeletal system. This recording can reveal the presence of bone metastases.

Magnetic resonance imaging (MRI). An MRI is a diagnostic imaging tool that produces detailed images, using a large magnet, radio waves, and a computer system that processes the data. MRIs involve no ionizing radiation and can be used for precise imaging of any organ suspected of having metastases.

Continued . . .


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