P&S Journal: Spring 1997, Vol.17, No.2
Diagnosis Made Easier for Metastatic Thyroid Cancer
P&S researchers have developed a simple blood test that can identify postoperative thyroid cancer patients at risk for metastatic disease. The test was described in the December 1996 issue of the journal Surgery.
The test involves a technique called reverse transcriptase-polymerase chain reaction (RT-PCR), which allows scientists to isolate minute amounts of genetic material (messenger RNA), transcribe the material into DNA, and then clone enough copies that can be detected using standardized tests. In this application, RT-PCR is used to isolate and clone the mRNA for thyroglobulin, a protein secreted only by thyroid cells. Normally, thyroid cells are found only in the thyroid gland, explains Dr. Beth Ann Ditkoff, assistant professor of surgery in the Thyroid Center and co-leader of the research team. "So if thyroglobulin RNA is found in the peripheral blood, this is an indication that thyroid cells are being shed from metastatic tumors," she says. The thyroid is a small, butterfly-shaped gland that lies over the trachea and below the larynx. The gland produces thyroid hormone, which affects the rate of virtually all metabolic processes in the body. Millions of Americans have thyroid problems, such as hypothyroidism, in which the gland produces too little hormone, or hyperthyroidism (such as Grave's disease), in which it produces too much.
Cancer also can strike the thyroid. About 14,000 new cases of thyroid cancer are diagnosed each year in the United States, says Dr. Ditkoff. Most can be treated successfully with surgery, but patients need to be closely monitored because metastases can occur many years after the operation. "Right now, there's no perfect way to monitor thyroid cancer patients postoperatively," says Dr. Paul Lo Gerfo, co-director of the Thyroid Center and co-leader of the research team.
One existing method is radioiodine scanning, which is expensive and time-consuming and requires the patient to stop taking thyroid replacement hormone for at least two weeks. "It's often very difficult for patients to endure this hypothyroid state, which causes extreme lethargy and sometimes depression," says Dr. Lo Gerfo. The only other method, serum thyroglobulin measurement, is much simpler, but it too has major drawbacks. False positive results are common, since thyroglobulin is sometimes found in the blood of disease-free individuals, in patients with benign thyroid disease, and, especially, in thyroid cancer patients who have had only part of their glands removed. Serum thyroglobulin testing is also plagued by false negative results. "Not every tumor makes a significant amount of thyroglobulin," says Dr. Lo Gerfo. "In addition, the body produces antibodies to thyroglobulin, which can make the test difficult to interpret."
The RT-PCR test, in contrast, is simple, inexpensive, and accurate. Since the test detects the presence of thyroglobulin mRNA--instead of thyroglobulin protein--it provides a clear indication that thyroid cells are present in the blood and that the patient is at risk for metastatic disease. The RT-PCR test is most accurate when conducted more than three weeks after surgery because surgery can temporarily release both benign and malignant thyroid cells into the bloodstream, producing a false positive result. After three weeks, and possibly sooner, however, these wayward cells disappear from the blood. Says Dr. Ditkoff: "We're in the process of taking serial blood samples from patients to see when these cells clear after the operation and to see when positives are indeed true positives. It looks right now that about three weeks afterward, the test is accurate."
Dr. Ditkoff and her colleagues evaluated the accuracy of the RT-PCR test in a clinical trial involving 100 patients, including 78 with localized thyroid cancer, nine with metastatic thyroid cancer, six with benign thyroid disease, and a control group of seven disease-free individuals. Investigators conducting the RT-PCR tests were blinded to the patients' actual clinical status. All patients with benign disease and all controls tested negative for circulating thyroglobulin mRNA. All patients with metastatic disease tested positive. And significantly, seven of the 78 patients with localized cancer also tested positive. "Five of these seven patients had a past history of metastatic thyroid cancer that had been successfully treated with surgery," says Dr. Ditkoff. "We know that patients like these are at risk for a recurrence of metastatic disease, so their positive tests suggest that they have circulating thyroid cancer cells that could take root and form tumors. This is a subset of patients who are at risk for metastatic disease."
Further research on the RT-PCR test is now in progress, including tests of accuracy both preoperatively and postoperatively, studies about whether the test can be used in place of radioiodine scanning for long-term follow-up, and a study of additional markers for metastatic disease. The investigators are also exploring a possible link between the quantity of circulating thyroid cells and a patient's prognosis. "First, we would have to develop a way to quantitate how many thyroid cells are in the peripheral blood," Dr. Ditkoff says. "Then we can examine whether that number influences staging and prognosis." The other members of the research team are Drs. Michael Marvin, John Chabot, and Carl Feind.