CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Anne Paxton
April 2013—Faced with assessing one of the hundreds of thousands of patients who present with thyroid nodules each year, clinicians know that the initial diagnostic steps are straightforward. With fairly good reliability, using ultrasound examination, fine-needle aspiration, and cytologic examination, they can determine in about 70 to 80 percent of cases whether the nodule is benign or malignant. And good treatment options exist for those in the latter category.
It’s the 20 to 30 percent of patients with “indeterminate cytology”—not definitively benign and not definitively malignant—who preoccupy Yuri Nikiforov, MD, PhD, vice chair and director of the Division of Molecular and Genomic Pathology at the University of Pittsburgh. As Dr. Nikiforov describes in an article published Feb. 19 online in Clinical Cancer Research, “New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers,” by pinpointing new molecular markers, researchers at UPMC expect to make a profound impact on the management of patients with thyroid nodules.
Some mutational markers are already available to clinicians through academic pathology laboratories and commercial companies. “What is emerging and is really even more exciting is the use of next-generation DNA sequencing panels based on multiple known and new markers,” Dr. Nikiforov says. His institution, which is now conducting clinical validation of panels in the molecular lab, expects within two months to launch what he believes to be the first CLIA-validated laboratory-developed molecular test for thyroid nodules based on NGS. Soon, he predicts, academic pathology labs and eventually commercial companies will adopt and use the panel for diagnostic purposes.
“This is a huge advance in how we can risk-stratify patients with thyroid cancer,” he says. The panel is still not ideal and needs to be improved further, he adds, but with NGS, he is confident that improvements won’t be far behind.
There is a significant need for additional markers in thyroid nodules, says Dr. Nikiforov, who has been researching thyroid cancer for two decades and molecular markers for 15 years. “The biggest challenge is that thyroid nodules are extremely common and particularly that they increase as people age. Some population studies show by the age of 50 about five to 10 percent of all individuals have palpable thyroid nodules, and ultrasound screening tends to find 50 percent of people have such nodules by age 60.”
“So this is a very, very common condition. The cancer frequency in the nodules is low; less than five percent of the nodules are malignant. Therefore, the real challenge is to be sure we can separate benign from malignant nodules without performing a diagnostic surgery.”
Dr. Yuri Nikiforov at UPMC: “The more mutations we know, the more we can test for, and the more accurate the tests will be.”
Thyroid cancer incidence has been growing steadily in the U.S. and many other countries over the past four decades, and it is now the fastest growing cancer type in women in the United States. Why the incidence of thyroid cancer is rising remains unclear, although Dr. Nikiforov and colleagues have just submitted a paper for publication that discusses molecular genetic evidence pointing to probable chemical or dietary factors as a reason for the increase.
The introduction of fine-needle aspiration in the 1970s and 1980s has significantly reduced the number of unnecessary thyroid surgeries, Dr. Nikiforov notes.
“Approximately 75 percent of all FNAs can be reliably diagnosed through cytological examination as either benign (65 to 70 percent) or malignant (about five percent). So about 25 percent are indeterminate. And this is a large-scale problem.” In the U.S. about 150,000 FNA biopsies per year are indeterminate.
At the University of Pittsburgh, Dr. Nikiforov started using a limited panel of known molecular markers in 2007. Their big advantage, he says of the markers, is in significantly improving the algorithm for clinically managing patients with thyroid cancer. Even with the panel of seven markers, though, all patients with nodules that have indeterminate cytology cannot be triaged reliably. “Using NGS, we can input many more mutations and do it cheaply, so we are not limited any longer to the few most common mutations. The more mutations we know, the more we can test for, and the more accurate the tests will be,” Dr. Nikiforov says.
The new research initiatives and expanding knowledge have a twofold impact on clinical practice, he explains. One is the ability to find when nodules are benign and not have to subject those patients to unnecessary surgery. Second, many patients who have nodules with indeterminate cytology undergo lobectomy—removal of one of the two lobes of the thyroid—because the diagnosis is not clear, and 70 percent of those cases are benign. But if the diagnosis is cancer, “those patients have to come back for the second surgery to complete removal of the thyroid.”
No one likes that. “The surgeons hate it because you operate twice, and for the second surgery there is a higher probability of significant surgical complications such as recurrent laryngeal nerve injury and permanent hypoparathyroidism. The ideal approach is an up-front total thyroidectomy.” So the molecular markers are extremely helpful, he says, because if mutations are found, there is more than a 90 percent chance it is cancer, and those patients can avoid the surgical complications and expense of a two-step surgery and have a total thyroidectomy as the initial surgical approach.
In 2009 guidelines issued by the American Thyroid Association, the mutational markers BRAF, RAS, RET/PTC, and PAX8/PPARgamma were recommended for patients with indeterminate cytology on FNA to help guide management. “In our center, these markers are readily available, and I know in some other medical centers they are getting accepted as routine. Several commercial laboratories offer this panel too.” An ATA task force, of which Dr. Nikiforov is a member, is working now on the revision of the guidelines. “Use of the molecular markers is being carefully considered, and it is my hope that the revised guidelines will endorse even more strongly the use of these new diagnostic tools.”