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Upcoming Guidelines for Differentiated Thyroid Cancer Expected to Stress Risk Stratification

Lindsey, Heather

doi: 10.1097/01.COT.0000445628.94663.07

Clinicians are eagerly anticipating updates to the American Thyroid Association's guidelines for the treatment of differentiated thyroid cancer (DTC), which will likely put more emphasis on comprehensive ultrasound screening and risk stratification for the management of patients. That was the consensus of several thyroid cancer specialists who presented at the American Association of Clinical Endocrinologists (AACE) Advances in Medical and Surgical Management of Thyroid Cancer meeting earlier this year.



Published guidelines are tentatively slated for later this spring, according to the ATA.

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Ultrasound Screening

Ultrasound has to be carefully and thoughtfully performed before a patient's first thyroid surgery, said Mira Milas, MD, FACS, Professor of Surgery and Director of Endocrine Surgery at Oregon Health and Sciences University. “Ultrasound remains the single most important action to perform in order to achieve the best kind of surgery at the first time of surgery,” she said, adding that comprehensive imaging of the thyroid and parathyroid region, and cervical lymph nodes in the central and lateral neck is needed.

The goal is for the first surgery to be the last surgery, she said. With this in mind, ultrasound can detect lymph node metastases, allowing surgeons to remove these growths when they perform a thyroidectomy, explained Milas, speaking to what has recently become part of routine care and may be reflected in the upcoming ATA guidelines for DTC, although she could not comment on what the specific recommendations will ultimately be.

Guidelines recently published by the AACE and the American Institute of Ultrasound in Medicine (J Ultrasound Med. 2013;32:1319-1329) recommend that ultrasound evaluation of cervical lymph nodes be performed the first time imaging is done to evaluate a thyroid nodule, even before biopsy or any surgery takes place. “Doing this at the initial point of ultrasound may help us make management down the road be more optimal,” she explained.

The new ATA guidelines will likely emphasize the interpretation of thyroid nodules on ultrasound, allowing for risk stratification for the likelihood of thyroid cancer being present, Milas said.

Interpreting which nodule features on ultrasound favor malignant or benign findings can help to determine whether nodules require biopsy and which ones can forego biopsy. “This really means that physicians who are performing ultrasound will need to have ongoing education on the interpretation of images to make biopsy recommendations,” she said.

“It used to be that everybody who had a thyroid nodule greater than 1 cm received a biopsy. Now, though, comprehensive criteria based on nodule features and cancer risk guide physicians as to what growths should be biopsied. “Sometimes even nodules up to 2.5 cm can avoid biopsy, and those below 1 cm should be biopsied, based on these criteria.”

While this approach was included in the 2009 guidelines, it will likely be further emphasized in the 2014 publication, she said.

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Treating MRD

Over the last 10 to 15 years, the ability to detect minimal residual disease has greatly advanced, said R. Michael Tuttle, MD, Professor of Medicine at Memorial Sloan-Kettering Cancer Center. Thyroglobulin can be read down to minuscule levels, and ultrasound allows physicians to find small metastases in the lymph nodes.



“The big question is: Does minimal residual disease need to be treated?” he said.

Treatment associated with minimal residual disease can lead to side effects and does not always eradicate the cancer. Still, some patients do require treatment. With the 2014 ATA guidelines “we're going to do a better job of describing when small growths can possibly be observed. The challenge is that not a lot of data exist on this topic.

“We're not completely ignoring low-level thyroid cancer. Rather, the guidelines will open the door to say that in cases of low-level thyroid cancer and small metastases, a cautious period of observation is certainly an alternative to treatment.”

Observation is important because patients can have low-level thyroid cancer that never becomes clinically apparent. “These low-risk patients have a 99 percent survival rate,” he noted.

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Structural Disease Risk Recurrence

When assessing patients, physicians need to consider the risks of disease-specific mortality, persistent or recurrent disease, additional therapies, and observation, Tuttle continued.

He described a recent approach to risk assessment of structural disease recurrence, the details of which are being discussed for possible incorporation into the guidelines, he said.

This system defines high-risk patients as having gross extrathyroidal extension, incomplete tumor resection, or distant metastases. Specifically, this group includes patients with follicular thyroid cancer with extensive vascular invasion and individuals with stage pT4a disease with gross extrathyroidal extension.

Also at high-risk are patients with pN1 lymph nodes more than 3 cm, those with clinical N1 disease, individuals with BRAF mutations with non-intrathyroidal malignancy, patients with papillary thyroid carcinoma with vascular invasion, and those with more than 5 pN1 lymph nodes, he said.



Intermediate-risk patients are described as having N1 disease, minor extrathyroidal extension, vascular invasion, or aggressive histology. This category includes patients with BRAF mutations and intrathyroidal tumors of less than 4 cm, those with stage pT3 disease and minor extrathyroidal extension, and individuals with pN1 lymph nodes less than 0.2 cm or less than 5 pN1 lymph nodes.

Also included are patients with intrathyroidal papillary thyroid carcinoma of 2 to 4 cm, multifocal papillary microcarcinoma or minimally invasive follicular thyroid cancer.

At low risk for structural disease recurrence are patients with intrathyroidal DTC, specifically those with growths of less than 4 cm and with BRAF wild-type or intrathyroidal unifocal papillary microcarcinoma with BRAF mutations. Also at low risk are individuals with the intrathyroidal, encapsulated follicular variant of papillary thyroid carcinoma or unifocal papillary microcarcinoma, he said.

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Classifying Response

The risk of recurrence may change over time and depends on the response to therapy, Tuttle noted. Consequently, patients require ongoing assessment. Based on the available literature, he has developed a new categorization of patients that includes four possible clinical outcomes: excellent response, biochemical incomplete response, structural incomplete response, or indeterminate response.

Patients demonstrating an excellent response have a one to four percent recurrence risk and less than a one percent risk of disease-specific mortality. For these patients, physicians can decrease the intensity and frequency of follow-up and the degree of TSH suppression.

Generally, a yearly non-stimulated serum thyroglobulin (Tg) test and ultrasound screenings every few years is warranted.

In patients with a biochemical incomplete response, 30 percent are expected to have disease that spontaneously resolves, 20 percent will develop structural disease, and less than one percent will die from progressive thyroid cancer.

Patients generally have stable or decreasing Tg and Tg antibody (TgAb) and require observation. Further investigation is required in patients with increasing Tg or TgAb. Tuttle said he recommends non-stimulated Tg testing and ultrasound every six to 12 months in this group of patients. Physicians may also want to consider stimulated Tg testing and a diagnostic whole body scan during follow-up, he said.

In patients with a structural incomplete response, 50 to 80 percent will have persistent disease despite additional treatments. The majority of deaths from thyroid cancer occur in this group of patients. Some individuals will require ongoing treatment, while others can be observed depending on the specific characteristics of their disease.



Tuttle recommends non-stimulated Tg testing and ultrasound every six to 12 months in addition to risk-appropriate functional and cross-sectional imaging.

Of the patients who are categorized as having an indeterminate response, 20 percent will develop structural disease. The risk of death is less than one percent. Continued clinical observation with mild TSH suppression is warranted. Tuttle recommends yearly nonstimulated Tg testing, quarterly ultrasound for one to three years, and consideration of stimulated Tg testing.

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Radioiodine Therapy—Less is More

Probably the most pressing new recommendation pertaining to radioiodine use occurs in what the ATA 2009 guidelines describe as DTC low- to intermediate-risk groups, said Bryan Haugen, MD, Professor of Medicine and Pathology Head of the Division of Endocrinology, Metabolism & Diabetes, and the Mary Rossick Kern and Jerome H. Kern Chair in Endocrine Neoplasms Research at the University of Colorado School of Medicine, Anschutz Medical Campus.

“Especially in low-risk patients, we're moving away from using radioiodine,” he said. “Physicians aren't terribly concerned about side effects because they are minimal with small doses of radioiodine. However, based on an increasing number of studies, RAI does not provide a treatment benefit in low-risk patients so any small morbidity risk isn't worth it,” he said.

Specifically, almost all patients with thyroid cancer less than 1 cm can forego RAI. “And even in those with cancers 1 to 4 cm, you need to think long and hard about why patients are getting it,” said Haugen. So, overall, physicians should be using RAI in fewer patients.

Additionally, while cervical lymph node metastases are classified as intermediate risk, according to the 2009 ATA guidelines, not all of these metastases are created equal, he noted. As demonstrated by the literature and Tuttle's system, “the more it seems that in patients with few or very small tumors in the lymph nodes, the risk of a recurrence isn't very high.” Despite the growing body of data, “if you ask the average doctor, if any lymph node is involved, then RAI is needed.”

Also of note in RAI therapy, the 2009 guidelines recommend thyroid hormone withdrawal or using rhTSH (Thyrogen) before RAI for remnant ablation. Physicians are now moving toward giving Thyrogen with a lower dose of RAI, so patients don't have to come off their thyroid hormone, Haugen said.

“We used to give 100 mCi, then 75 and 50, and now we're using 30 with Thyrogen,” he said, citing a recent study in the Journal of Clinical Endocrinology & Metabolism (2013;98:1353-1360).

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New Management Tool

Mira Milas, MD, FACS, said that of particular value to physicians who treat thyroid cancer is a treatment-management website platform under development by the Thyroid Cancer Care Collaborative (TCCC). The website acts as an electronic health record to connect patients and all of their treating physicians from the point of a thyroid nodule being identified via ultrasound, to capturing all of the nodule features by risk stratification, through the next step on needle biopsy, diagnosis, thyroid surgery, and follow-up care if cancer is present

“Any doctor who is predominantly or exclusively taking care of patients with thyroid nodules and thyroid cancer will likely find this an incredibly helpful tool,” she said.

The system was developed with the Thyroid, Head and Neck Cancer Foundation ( and is now being beta tested at Oregon Health and Sciences University and Stanford University, with an expected launch date later this year.

© 2014 by Lippincott Williams & Wilkins, Inc.
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