Changes are stirring in the management of thyroid cancers, from molecular testing to surveillance in select cases, and from nerve monitoring to the choice between total thyroidectomy over hemi-thyroidectomy for certain tumors. An expert panel reviewed the main points in a session at the Triological Society Combined Sections Meeting, held in Coronado, Calif., January 24–26, 2019.
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March 2019Robert Witt, MD, professor of otolaryngology–head and neck surgery at Thomas Jefferson University in Philadelphia, said molecular tests are becoming increasingly important in the diagnosis and exclusion of thyroid
cancer. “We are, I believe, at the beginning of a renaissance in the management of thyroid disease,” he said. “And I think it’s spearheaded by molecular testing.”
There are four main commercial testing options: the Genetic Sequencing Classifier; ThyroSeqv3; ThyGenX & ThyraMIR; and RosettaGX Reveal. The value of the testing on indeterminate thyroid nodules (Bethesda Grade 3 or 4) stems from their ability either to improve accuracy of ruling in thyroid cancer, with positive predictive values that can cut down on the number of completion thyroidectomies, or to rule out thyroid cancer, with negative predictive values that can reduce unnecessary surgery on indeterminate thyroid nodules that would ultimately be found to be benign if they underwent operation.
Positive predictive values (PPV) with the available tests stand at 47% to 82%. Negative predictive values (NPV) are much better, ranging from 91% to 99%. “This is the real stronghold of molecular testing today,” Dr. Witt said, referring to NPV. “I think the positive predictive values are a little bit wanting.” But he added that a lot of nodules labeled suspicious, but not certain for cancer by these tests, and treated with diagnostic lobectomy, will be low-grade, such as follicular variant papillary thyroid cancer, and many don’t require completion thyroidectomy.
“I’m expecting in the next year—or two or three—that the PPV on all of these tests is going to bump up with advancements in mutation identifications and microRNA analysis,” he said.
Ultimately, on the question of whether molecular testing for indeterminate thyroid nodules improves specificity analysis and positive predictive value, the answer, Dr. Witt said, is “maybe.” For BRAF or RET/PTC mutations, the answer is yes, but discovery of other mutations might not eliminate completion thyroidectomy if a diagnostic lobectomy was performed. But, he added, completion thyroidectomy, depending on clinical evaluation and ultrasound, is not mandated by American Thyroid Association guidelines for differentiated thyroid cancers smaller than 4 cm.
The Option of Active Surveillance
Whether to choose active surveillance or immediate intervention for certain low-risk thyroid cancers can be a difficult decision, but it’s an option that is being taken increasingly seriously in the face of data showing the benefits. “At first glance,” said Marilene Wang, MD, professor of otolaryngology–head and neck surgery at the University of California, Los Angeles, “this concept seems to fly in the face of every oncologic principle that we know.
Early diagnosis and timely treatment have always been the standards for best practice management of cancer.”
But the evidence is hard to ignore. In the last three decades, the incidence of thyroid cancer diagnoses has almost tripled, but the death rate hasn’t changed, according to the latest data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. That, Dr. Wang said, is because many of these cancers that account for the increased incidence are very small papillary microcarcinomas found on routine ultrasound.
The American Thyroid Association 2015 guidelines say that very low-risk tumors “can be” considered for active surveillance—based on two Japanese studies that followed patients for a decade and found low frequency of enlargement and no recurrence or death after surgery when progression was discovered.
More recently, Memorial Sloan Kettering researchers found that, among 291 patients who underwent active surveillance for a median of 25 months, growth of 3 mm or more was seen in just 3.8% of patients, with no regional or distant metastases seen during surveillance. They also found that 3D measurements of tumor volume were better at finding growth than tumor diameter, discovering it a median of 8.2 months earlier. (JAMA Otolaryngol Head Neck Surg. 2017;143:1015–1020).
Nonetheless, SEER data for 1998 to 2010 show that 98% of those with papillary thyroid microcarcinoma undergo surgery, and 75% receive a total thyroidectomy.
Active surveillance is a good option, said Dr. Wang, when only patients considered low-risk are selected, when a multi-disciplinary team with a high level of expertise is available, and when patients are compliant.
A study out of Kuma Hospital in Japan found that the cost of immediate surgery was 4.1 times higher than surveillance even with the costs of salvage surgery for recurrence factored in (Endocr J. 2017;64:59–64).
The level of patient anxiety also is a big factor, Dr. Wang said. “If the patient is highly anxious and they’re going to live a long time, it’s probably better for them to have a hemithyroidectomy,” she said. “If they don’t have much anxiety and their life expectancy is not great, hemithyroidectomy is probably not cost-effective.”
Hemithyroidectomy vs. Total Thyroidectomy
Eric Genden, MD, MHCA, Isidore Friesner Professor and Chair of otolaryngology-head and neck surgery at the Icahn School of Medicine at Mount Sinai in New York, tackled the sometimes difficult question of hemithyroidectomy or total thyroidectomy for well-differentiated stage T2 tumors.
Because of the limitations inherent in assessing the extent of disease, patients should be given full explanations of the nuances at work, Dr. Genden said. “It is important to explain to patients that there are limitations to imaging and pathology in determining the presence of extrathyroidal extension, a contraindication to hemithyroidectomy,” he said. “Understanding these limitations is absolutely critical to shared decision-making.”
Dr. Genden surveyed a variety of practitioners, including 19 endocrinologists, head and neck surgeons, and pathologists regarding their approach to clinical management of patients with T2 disease and he found the responses were “quite disparate.” Pathologists expressed the concern that accuracy rates for ultrasound and CT scans are not great for predicting extrathyroidal extension preoperatively. That’s because, they say, the popular concept that the thyroid gland is well-encapsulated is erroneous. Not uncommonly, pathologists will identify normal thyroid tissue that has escaped through the pseudocapsule and into the surrounding muscle, suggesting that imaging may be misleading. “Extracapsular extension exists in a fair number of benign etiologies,” Dr. Genden said.
Also, he said, ultrasound is limited in its ability to detect peritracheal nodal disease, and those he queried during his informal survey repeatedly emphasized that ultrasound is operator-dependent. He added that nodules in the contralateral lobe were a strong indication to pursue a total thyroidectomy.
Regarding active surveillance, he said “very few endocrinologists were comfortable sitting tight, even with the most benign-looking tumors.”
Also, Hashimoto’s disease, glandular irregularity, and multifocal disease were typically an impetus for total thyroidectomy, particularly for endocrinologists who say the more aggressive procedure makes surveillance easier. Surgeons tend to be split, Dr. Genden said, but added, “Everybody agreed across the board that it’s a multi-disciplinary disease. It requires endocrinology evaluation.”
Dr. Genden also emphasized that in the face of imperfect imaging and limitations regarding pathological confirmation of extrathyroidal extension, patients should be made aware of these limitations to support the shared-decision making process. Dr. Genden said that the “management of T2 thyroid disease remains an imperfect science; it is still an art.”
Loss of Signal
When signal is lost on one side after surgery for thyroid cancer, it is a serious situation, as borne out by statistics, said Gregory Randolph, MD, professor of otolaryngology-head and neck surgery and the Clair and John Bertucci Chair in thyroid surgical oncology at Harvard Medical School in Boston, who helped lead the International Neural Monitoring Study Group’s (INMSG) most recent thyroid guidelines, which looked at incidence of vocal cord paralysis, cost effectiveness of neural monitoring during thyroid surgery, and monitoring methods.
The expected rate of paralysis on the second side should be—all things being equal—about half a percent or one percentage point. But actually, in the world’s literature, the group found, it’s 17%. “It is a high stakes situation once you lose that ipsilateral signal,” Dr. Randolph said.
It is important to explain to patients that there are limitations to imaging and pathology in determining the presence of extrathyroidal extension, a contraindication to hemithyroidectomy. Understanding these limitations is absolutely critical to shared decision-making. —Eric Genden, MD
The group found that the cause of the loss of signal matters a great deal. Thermal and clamping injuries lead to the highest rates of permanent paralysis, while traction and compression, while they have high initial rates of paralysis, have comparatively low rates of permanent paralysis.
When performing neural monitoring, a baseline reading is essential, Dr. Randolph said. During surgery, when the amplitude and latency stay within a normative range, there is virtually no risk of vocal cord paralysis. The INMSG guideline lays out changes in signal that bring different levels of risk, underscoring the importance of respecting changes in electromyography (EMG) signal during the case as these are the warning signs of vocal cord paralysis, he said.
“A surgeon,” the group wrote, “should prioritize concern for the obvious significant medical and psychological morbidity of bilateral vocal cord paralysis and possible tracheotomy over perceived surgical convenience, the routine of doing the ‘planned procedure,’ or the potential perceived impact on surgical reputation by openly acknowledging the surgical complication of ipsilateral loss of signal.”
Gady Har-El, MD, chair of otolaryngology-head and neck surgery at Lenox Hill Hospital in New York City, said using active surveillance raises an ethical question: Since it is a new approach that departs from what has been considered standard for many years, independent review board (IRB) approval might be necessary.
“If I see tomorrow a 40-year-old lady with a small thyroid cancer who meets all of the criteria that are deemed appropriate for active surveillance—and I would like to do active surveillance—can I do it, without IRB approval?” he said. “This obviously has implications, both ethical and medical-legal.”
Dr. Wang and other panelists said IRB approval would be appropriate. “Ideally, an IRB is best for any medical intervention that is not considered standard,” she said. “The question is, is this considered standard of care? And probably not. It is a recommendation if you look in the ATA guidelines, but it’s very vague.”
Thomas R. Collins is a freelance medical writer based in Florida.