Case 34

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 34

A patient of yours has just undergone surgery at your local hospital for cancer of the colon. You agreed to act as a surgical assistant for this operation. After completion of the surgery, the surgeon reminds you to draw a carcinoembryonic antigen (CEA) level. Why did the surgeon do this? What is this measurement? What is the significance of measuring this in this population?

QUESTIONS FOR GROUP DISCUSSION

1. What are the two most common colorectal cancers in which heredity plays a role? Explain why a mutation in a gene encoding proteins that play a role in DNA mismatch repair might make a person more susceptible to colon cancer.
2. Describe the clinical manifestations of colon cancer and the screening tests that are used for early detection.
3. What is the underlying assumption behind the concept of tumor immunology?
4. Explain the term tumor-specific antigen and give examples.
5. Explain the term tumor-associated antigen (oncofetal antigen). Give three examples.
6. Carcinoembryonic antigen (CEA) is an oncofetal antigen. What is its function? Given its function, what role might it play in embryogenesis? What role might it have in adults when it is re-expressed in malignant tissues?
7. Explain why CEA cannot be used as a specific marker for the detection of colon cancer.
8. Explain the term magic bullet as it refers to tumor therapy. Describe approaches that are used in attempts to achieve this.
9. Describe, in general terms, the assay for measuring CEA levels in a patient. Discuss why there is, to date, no well-described cell-mediated immune assay available for CEA detection. How might you approach this problem to develop an assay?
10. Regarding the patient in this case, if CEA has no value in the specific diagnosis of the tumor, of what value is it to measure CEA in this patient?

RECOMMENDED APPROACH

Implications/Analysis of Family History

Individuals with a family history of colorectal cancer or polyps in a parent or sibling (diagnosed before the sixth decade) are at increased risk for colon and rectal cancer. Most cases of colorectal cancer occur sporadically; however, about 7% of cases are hereditary. The two most common colorectal cancers in which heredity plays a role include (1) hereditary nonpolyposis colorectal cancer (HNPCC) and (2) familial adenomatous polyposis (FAP). Patients with HNPCC have mutations in hMH1, hMSH2, hPMS1, or hPMS2 proteins, which play a role in the repair of DNA mismatches. Because DNA mismatches are not repaired, mutations occur more frequently. When these mutations are in growth-regulatory genes, cancer can arise. Individuals with FAP have hundreds/thousands of polyps at an early age, and, generally, some of these polyps will result in colorectal cancer.

Implications/Analysis of Clinical History

Common symptoms of colorectal cancer include (1) a change in bowel habits, irrespective of whether it is diarrhea or constipation; (2) blood in the stool; (3) stomach cramps; (4) decreased appetite; and (5) fatigue/weight loss.

Implications/Analysis of Laboratory Investigation

Colorectal cancer is often detected during screening procedures that include (1) digital rectal examination, (2) fecal occult blood test, and (3) either a colonoscopy, sigmoidoscopy, or barium enema.

Additional Laboratory Tests

A positive result from a fecal occult blood test should be followed by a complete blood cell count to check for anemia.

DIAGNOSIS

This patient was diagnosed with colon cancer. A staging system from O to IV is used to report the degree of spread through the colon/rectal wall and then through the body. Also, serum levels of CEA are determined after resection. This is done after resection because CEA levels have no diagnostic value (elevated levels are expressed in a number of malignant and nonmalignant conditions, including in heavy smokers and cirrhotics). CEA is a cell surface glycoprotein that occurs in high levels on colon epithelial cells during embryonic development, but expression is downregulated in adults. The sera of patients with colorectal cancer typically have elevated levels of the oncogenic tumor-associated antigen, CEA. Although there are a number of different tests that may be used to detect serum CEA, the enzyme-linked immunosorbent assay (ELISA) is used most often.

Why Measure CEA Expression?

To return to the patient of interest, one might now ask, if CEA has no value in the specific diagnosis of the tumor or as a therapeutic “tool” (specific killing of the tumor), then what indeed is the value of measurement of CEA levels in this case? It has become apparent that, along with a number of oncofetal antigens, CEA has significant value in monitoring early recurrence (before it becomes clinically detectable). These measurements can be made in a very sensitive and cost-effective manner, saving use of other more expensive (and often less sensitive) imaging procedures. The case of another oncofetal marker (β-human chorionic gonadotropin [β-hCG] in choriocarcinoma) is a prime example of the value of such measurements. This tumor is normally treated effectively with high doses of methotrexate. However, the sensitivity of a rising β-hCG level in the presence of methotrexate therapy is sufficiently convincing of failure of therapy that such a measurement alone is sufficient to demand an alteration in therapy.

THERAPY

Colon resection, chemotherapy, internal radiation, or external radiation are all potential therapies. In internal radiation therapy a radioisotope is injected or implanted directly into the tumor; in external radiation high levels of radiation are emitted by a machine and directed at the tumor.

Tumor-Associated Antigens

The driving thesis behind the concept of tumor immunology is that tumors have cell surface molecules that are preferentially expressed (with respect to the normal tissue) and that can be recognized by the host immune system. As such, they are referred to as antigens. Antigens may be tumor specific (TSA) or tumor associated (TAA). (See Tumor Immunology, Section IV.) TAAs can be used to characterize tumors but are not necessarily unique to the tumor as opposed to other (normal) host tissues.

Oncofetal Antigens

TAAs are often molecules (antigens) that are expressed at stages of normal cell differentiation, although the tumor cell expression is either qualitatively or quantitatively different from normal cells at that particular stage of maturation/differentiation. An important class of TAAs is the so-called oncofetal antigens (OFAs). Oncofetal antigens, of which CEA is an example, are not unique to tumor cells but are in general not expressed at high levels in perfectly normal adult tissue. They tend to be, as the name implies, molecules expressed preferentially during normal fetal development but molecules for which transcriptional silencing of gene expression occurs during adult life. However, it has become apparent as we understand more about these OFAs that there are a number of nonmalignant conditions (for different tissues) in adulthood in which re-expression does occur. In addition to CEA, α-fetoprotein and β-hCG are also recognized oncofetal antigens (Fig. 34-1).

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FIGURE 34-1 Oncofetal antigen, β-human chorionic gonadotropin (β-hCG). Choriocarcinoma, showing typical neoplastic syncytial cells and cytotrophoblast cells stained reddish brown using immunoperoxidase staining for hCG (the hormone synthesized in the syncytiotrophoblast of the placenta). (Immunoperoxidase for hCG, ×200.)

Carcinoembryonic Antigen

CEA itself is thought to be one of a family of cell:cell/matrix adhesion molecules. It probably thus subserves an essential role in normal tissue development during embryogenesis, ensuring that the appropriate cellular architecture develops in the gut. In adult (malignant) tissue, re-expression of this molecule may have profound effects on altering the manner in which cells interact with one another and with their environment, and thus expression on tumor cells is likely important in the regulation of metastatic spread.

Re-expression of CEA

As an example of other conditions in which high levels of CEA are found, in addition to in patients with gastrointestinal malignancies (of the colon), increases have been observed in cigarette smokers and in alcoholic cirrhosis. Increased levels have also been described in nongastrointestinal malignancies (e.g., breast cancer). It is because of these numerous exceptions (false-positive results) that simple marked increased expression of CEA cannot be used as a specific marker for the detection of colon cancer.

Anti-CEA Antibodies

In the early stages after CEA was discovered it was hoped that the molecule could be used to develop a so-called magic bullet (anti-CEA antibody) to kill tumor cells. The principle behind this (and essentially any case in which expression of a molecule exists, against which a specific antibody can be made) is that infusion of “tagged” antibodies could now be used both to detect and even eliminate the tumor specifically (without affecting normal tissue). Labeling of antibodies with radioactive tracers (e.g., 125I) should enable use of a gamma camera to “see” tumor in the intact patient. Labeling with a toxin (e.g., diphtheria toxin) would serve as a specific way to deliver a high dose of toxin (too toxic if given systemically to all cells in the body) only to tumor cells.

Cell-Mediated Assays to Detect CEA Expression

There is to date no well-described cell-mediated immune assay used for the detection of CEA on a cell surface. This is not surprising, given its postulated cell surface expression and its putative role thereby in regulating cell/cell and cell/matrix interactions. It may be instructive, nevertheless, to consider what immune responses might be measured to study the effect of CEA expression on a particular function? Development of assays to examine whether the immune response of antigen-challenged T (or B) cells (reactive with a conventional antigen) is altered in the presence of overexpression of CEA might be of interest. The assumption here is that CEA may play an auxiliary role in regulating a primary stimulus delivered to the lymphocyte-specific receptor. Increased CEA expression might also result in altered histopathology assessment of a tumor biopsy, altering both evidence for tumor cell/matrix interactions and also the incidence of, or interaction with, other immune cells within the tumor.

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