Doctor, what do you mean you can’t tell whether I have thyroid cancer?

Thyroid nodules or lumps are often found in the butterfly-shaped thyroid gland that sits low on the front of the neck below the Adam’s apple. Most times, these nodules are found by feeling the thyroid or by chance when radiologic imaging such as CAT Scan, MRI, or ultrasound are performed that include the neck. Many patients, especially women, will at some point in their lifetime be diagnosed with a thyroid nodule. The good news is that very few thyroid nodules are cancerous as five to 15 percent of nodules are malignant, at most.

Finding out whether a nodule is malignant or benign often starts with a trip to the endocrinologist or thyroid surgeon. An ultrasound is usually performed and then a small needle is used to retrieve cells from three or four different regions of the nodule. This procedure is called FNA or fine needle aspiration biopsy. The cells from the FNA are then sent to a cytopathologist, a specialist in analyzing cells and tissue samples to diagnose various conditions. The cytopathologist examines and evaluates the pattern of the cells under the microscope. This technique is the “gold standard test” for distinguishing whether a nodule is benign or malignant.

For most body parts (such as the breast, colon and skin), biopsy results are usually clearly defined; either the cells looks obviously cancerous or benign, and the treatment path forward is very clear. Unfortunately, however, in the case of endocrine organs (hormone-producing organs such as the thyroid, adrenal and pancreas) identifying distinctions between benign and cancerous cells can be challenging. In thyroid biopsies, approximately 20 percent of cases the test results will be “indeterminate,” that is, the pathologist is not able to definitively make a determination. Even if there are enough cells from which to make a diagnosis, the pattern is not clear. This so-called gray area or “indeterminate biopsy” often (and understandably) leads to extreme anxiety for patients and leads to a simple question: “What do you mean you can’t tell whether I have cancer?”

Experienced thyroid specialists realize that for patients “not knowing” the outcome of their biopsy is more anxiety-provoking than knowing, even when facing a diagnosis of thyroid cancer. Generally, a thyroid specialist would recommend patients in this situation have half of their thyroid removed, thus removing the nodule in its entirety along with surrounding healthy tissue. This was typically a difficult decision for both patients and doctors, because only one out of five patients turned out to have cancer.

To help make the difficult decision about whether or not to undergo surgery many new genetic and molecular tests have been developed and tested in the past few years to help patients in this gray zone. Many people are aware of the “DNA revolution,” which includes dramatic advances in using molecular genetics and genomic science, the study of all of a person’s genes (genome). These tools are now being used to help further categorize indeterminate thyroid nodules. Through the use of these new tools, some patients may find out they have thyroid cancer and can undergo definitive treatment while others may find out they have benign nodules and can be watched instead. These new tools are not perfect, and they do not provide a clear answer for every patient in the “gray zone” of thyroid biopsies, but almost half might be helped. Since molecular testing is so new, it is a rapidly-evolving technology. Thus, it’s important to discuss them in detail with your own doctor.

Generally, molecular tests are performed on a separate biopsy sample that preserves DNA and RNA, the genetic material that is present in the nuclei of thyroid cells. Therefore, your doctor may ask you to come in for a second biopsy.

Two kinds of tests are currently being used to help patients diagnosed with indeterminate nodules:

a) Since the National Institutes of Health’s multimillion dollar human genome project “Cancer Genome Atlas” has led to the discovery of genetic changes (mutations) in about two-thirds of thyroid cancers, it is now possible to test the DNA and RNA in thyroid cells to see if any of these important mutations are present. These special tests look for mutations and rearrangement in select important genes. It is important to note, the presence of mutations does not always equate to malignancy, but will lead to a recommendation to have surgery. Make sure to carefully discuss the results with your physician, including the extent of surgery (removing one or both sides of your thyroid) you should have.

b) Gene expression profiling uses computer analysis to identify “gene expression” patterns that are produced by the “code” of RNA material found in the cells of thyroid nodules. This complex analysis simultaneously looks at the products of numerous genes. Currently, the most widely known and clinically validated system is the Veracyte Afirma test, which compares the thyroid cells from an FNA to a bundle of 167 RNA codes that tend to “express” together when nodules are benign. When a “benign” expression pattern is found it will be accurate 92- 94 percent of the time. Only one large study of this technology has been performed, but it seems that about 40 to 50 percent of the indeterminate “gray zone” samples can be accurately classified as benign nodules, hence potentially avoiding unnecessary diagnostic surgeries in many patients. Unfortunately, this test is only helpful if the result is a benign expression pattern. If the tests comes back as “suspicious,” surgery may be needed. Keep in mind that does not necessarily mean a diagnosis of cancer in the patient.

With their recent development and validation, DNA, RNA and gene expression profiling systems are starting to be integrated into thyroid nodule evaluation as a viable option. This is an important new development for patients who find themselves without a definitive diagnosis. However, it is important to remember that molecular profiling is just one of many steps that might be undertaken in the evaluation of a thyroid nodule. Sometimes just a second biopsy without genetic testing will help pinpoint a diagnosis.

The best evidence suggests that these new molecular tests may improve the accuracy of current diagnostic standard FNA and minimize unnecessary surgeries. It’s important to remember that for now and the foreseeable future, the use of molecular testing can only supplement, and not replace, comprehensive evaluation which includes a thorough physical exam, ultrasound, cytopathologic evaluation and -- ultimately -- the treating physician’s experience and judgment.

Dr. Sareh Parangi is an endocrine surgeon at Massachusetts General Hospital and Assoicate Professor of Surgery at Harvard Medical School in Boston. She focuses her clinical efforts on endocrine surgery and applies her basic science knowledge and expertise to tumor progression in thyroid cancer. She is one of a handful of thyroid surgeons with expertise in molecular biology and has over 70 publications, many on thyroid cancer therapeutics. She has been a council member for the American Association of Endocrine Surgeons and is a member of American Association of Clinical Endocrinologist and The American Thyroid Association.