AACE 27th Annual Scientific & Clinical Congress:

Evolving Care of Thyroid Nodules: Improving Cancer Detection, Determining Need for Active Surveillance

With Fan Zhang, MD, PhD, and  Stephanie L. Lee, MD, PhD

In the evolving care of patients with thyroid nodules, two key recommendations were highlighted to promote improved detection and treatment of thyroid cancer during the AACE 2018, the 27th Annual AACE Scientific and Clinical Congress held from May 17 to 20, 2018, in Boston, Massachusetts. pertaining to thyroid assessment and length of time needed for monitoring.

The two new strategies for clinical consideration: the location of malignancy in the thyroid gland and which thyroid nodules necessitate monitoring.1,2

Location of nodule in the thyroid gland offers strong clue to potential for malignancy.

               Nodule Location in Thyroid Gland Establishes Risk for Malignancy

In assessing thyroid nodules for risk of malignancy, findings from a ground-breaking study utilizing ultrasound imaging offered compelling evidence that the location of nodule was predictive of malignancy,1 according to poster author, Fan Zhang, MD, PhD, a resident in internal medicine at Brookdale University Hospital and Medicine Center in Brooklyn, New York.

The results of a retrospective study of 219 patients who had undergone biopsy with fine needle aspiration suggested that thyroid nodules found in the superior pole appeared to confer a four-fold higher risk of cancer than other regions of the thyroid gland.1 Thirty-one patients with benign (Bethesda II) nodules were followed for observation but excluded from the final analysis.

A Closer Look at the Study Design and Methodology  

Although certain imaging characteristics in thyroid nodules, including micro-calcifications, hypoechoic nodules, infiltrative margins, increased vascularity, and nodules that are taller than wider, have had some evidence for increased risk of malignancy the association between malignancy and location of thyroid nodules in the thyroid gland, said Dr. Zhang.

Dr. Zhang and her colleagues examined clinic charts of patients—of which 86% were female— from July 2016 to June 2017.1 Demographics collected on the patients included: sex, ethnicity, body mass index. Thyroid nodules were assessed for the following characteristics:

  • Laterality of nodule location: left, isthmus, right
  • Polarity of nodule location: superior lobe, middle, lower
  • Size: height, length, width
  • Presence of microcalcifications
  • Number of nodules present

Nodules were evenly distributed between the right lobe (47 percent) and left lobe (50.5 percent), with the rest of the nodules located in the isthmus (2 percent). Most nodules (79 percent) were located in the inferior poles with just 7% in the middle pole. Some 40% of the patients had multiple nodules.1

Nodule in Upper Pole May Confer Malignancy Risk  

Malignancy was observed most often in the superior region of the thyroid gland with 22% of nodules found in the upper lobes as compared to 14% in the middle pole, and just 5% in the inferior poles.1 Using a multiple logistic regression model to adjust for the number of thyroid nodules, age, sex, BMI, and laterality, a strong association between nodule location and presence of cancer was confirmed.

“This study demonstrates that nodules located in the upper pole present a higher malignancy risk factor and, therefore, location of thyroid nodules may need to be included in ultrasound classification guidelines to enhance the predictive value of malignancy, diagnostic accuracy and reliability as an indicator to perform FNA,” said Dr. Zang, in presenting his results.1

The investigators proposed that the reason for the increased risk of malignancy in the superior poles may be due to anatomy. For example, venous drainage is slower, which might cause a delay in clearing normal byproducts of metabolism, said Dr. Zang.

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                     Benign Thyroid Nodules: How Long Should We  Follow?

Thyroid nodules are commonly detected among 65% of the US population. With the population aging, clinicians will likely find 50-75 million thyroid nodules of which 500,000 will be biopsied, and 90% will be benign and 95% will be benign and remain asymptomatic.2

Given that most thyroid nodules are benign, the clinical challenge becomes one of discerning when to maintain surveillance of a nodule and when to stop,2 said Stephanie L. Lee, MD, PhD, professor of medicine and director of the Thyroid Health Center at Boston Medical Center in Boston, Massachusetts in a pre-conference symposium on Clinical thyroidology—Beyond the Basics, at AACE 2018 in Boston, Massachusetts.

The goal of thyroid nodule management is to design an optimal, personalized, risk-based approach that minimizes testing and unnecessary clinical intervention so active surveillance with ongoing imaging is reserved for suspicious thyroid nodules, she said.

Considering the Clinical Approach to Surveillance

For the patient with a benign thyroid nodule, what criteria will best inform the need to discontinue active surveillance?  Dr. Lee offered four factors to inform clinical decision-making:

  • Results of fine needle aspiration (FNA) biopsy (1, 2 or more benign findings?)
  • Lack of growth defined as >50% change in volume or >20% increase in at least 2 dimensions of a solid nodule or solid portion of a cystic nodule (How many years…1, 2, 5?)
  • Indeterminate cytology and benign molecular test findings
  • How does presence multiple nodes change the course of surveillance?

In doing an initial assessment of thyroid nodules, certain imaging features such as spongiform or cystic appearance suggest a benign nodule whereas solid composition, irregular margins, the presence of microcalcifications or solid formation would suggest the need for further cytological evaluation, 3,4 said Dr. Lee. The estimated risk of malignancy and the presence of symptoms, particularly compressive symptomatology are indicative of the need for further management.

“Medical management of goiters and benign cytology on ultrasound and molecular markers rule out malignancy with a risk of error of 1-3% with errors. Those patients rarely have thyroid cancer, and 80% of nodules over five years are stable or smaller with growth a very poor predictor of malignancy,” she told EndocrineWeb.   

“The trick is not to mistake spongiform nodules, which make up about 10% of thyroid nodules and are benign, with microcalcifications,” Dr. Lee said. “In addition, for non-suspicious nodules—such as those with an absence of hypoechogenicity, irregular margins, taller than wider shape, asymmetry, these warrant observation without biopsy as a reasonable option.”  

For nodules deemed spongiform or pure cyst on ultrasound, less than 1 cm with no suspicious features, the new recommendation is not to biopsy at all, and do not require routine ultrasound surveillance.5,6,

Size Should Not Inform Management Strategy But Symptoms Warrant Action

For multiple nodules, the recommendation is to follow the guidelines for ultrasound evaluation. Importantly, size is a poor predictor for large nodules, particularly those that extend beyond the screen. If all nodules are similar on sonography, biopsy the largest one; however, it’s more important to identify the highest risk nodule (ie, diffuse goiter, indistinct margins) to biopsy rather than the largest one. Another caveat: rule out a substernal goiter (ie, thyroid extension inferior to the sternal notch), which should be referred for surgery.4

Nontoxic goiter with symptoms such as globus sensation (increased pressure on trachea/esophagus, particularly on neck flexion), respiratory symptoms (shortness of breath, cough) dyspnea on exertion, or dysphasia or those with positional stridor, Pemberton’s sign, superior vena cava syndrome, or result in voice changes should be referred to surgery,4 Dr. Lee said.

Treatment for simple, nontoxic goiter will depend on the presence of any symptoms, if any, size, location, any compression of trachea but when with concerns, management should be to monitor for growth and development of hyperthyroidism.7

Treatment of goiter with levothyroxine is no longer recommended as results have been mixed and there is significant risk of TSH suppression with adverse effects on bone, particularly in postmenopausal women, and increased risk for cardiovascular disease.7 Of note, diffuse goiters appeared to respond more favorably to treatment than discrete nodules.

Radioactive iodine may be considered to manage lesser symptoms and for those who are not candidates for surgery.8 Recent radiograph studies support the use of iodinated contrast dye.

Response to Suspicious Appearance on Ultrasound

Despite benign biopsy (Bethesda II) findings, those thyroid nodules with “high suspicion” should have a repeat ultrasound and FNA biopsy within one year for indeterminate nodules or those with some suspicion of malignancy,5  the recommendation is to repeat the biopsy or continue active surveillance for growth or detection of new suspicious feature at 12 to 24 months. As for nodules with a very low level of suspicion, the value of surveillance ultrasound is limited at best,2 said Dr. Lee.

If the second biopsy returns a benign cytology, then a repeat ultrasound is no longer indicated;2 however, “in my patients, I would likely follow the nodule for growth around 18 to 24 months,” Dr. Lee said.

Tumor Growth and Compressive Symptoms

“Growth is not associated with thyroid cancer,”3,4 said Dr. Lee. A rule of thumb, is “thyroid nodules that tend not to grow are usually those which are small (< 1 cm) or large (> 4 cm or > 30 mL).3,4 Also, spongiform characteristics predict a benign nodule (Bethesda II) in comparison to nodules with suspicious features, based on results of a four-year, retrospective study in which 10 nodules were found to be cancerous out of a total of 854 evaluated.4

“In fact, suspicious features on imaging offer the best indicator of a missed malignancy,” she said, with further evaluation needed when a nodule shows irregular margins on non-contrast CT scan that is located below the trachea,” she said. “We can now wait longer (2-4 years) with less frequent intervals of surveillance. In fact, no follow-up is necessary for nodules smaller than 1 cm according to the American College of Radiology guidelines.” If there is any tracheal obstruction with symptoms, refer for surgery.

Another important tip for clinicians. “Stay connected to your scans to better advise your patient,” said Dr. Lee. The tech does the radiography, and the radiologist may read the findings but neither has ever met your patient so by viewing the scan yourself, you can more confidently respond to patients questions and address any concerns directly, she said.

Assessment of Complicated Nodules

“The first question to ask the patient: where is the problem?  Pulmonary function tests should be ordered to rule out asthma. Symptoms such as throat clearing, difficulty swallowing, or a light cough following a change in position are often the first sign of malignancy,” Dr. Lee said.

Goiters that present with no tracheal compression or extension into the trachea need no intervention. However, should the patient complain of discomfort, cough, hoarseness, treatment for a non-toxic goiter is surgical removal, she said.

“Don’t biopsy the largest nodule, rather biopsy the most suspicious, she said. Treatment for nontoxic goiter will depend on the size, location, and presence of symptoms (respiratory or causing patient discomfort).

Table 1: Recommendations for Management of Benign Thyroid Nodules

Determining if and how long to follow a patient with a benign thyroid nodule.

“While substantial evidence supports the use of rhTSH stimulated I-131 treatment rather than I-131 alone, this approach remains off-label in the US,” Dr. Lee said.

In effect, we should operate with the understanding that risk of thyroid cancer in cytologically benign nodules— (eg, cysts, nodules > 1 cm, spongiform, or those with 2 benign cytology reports) with no suspicious characteristics  3-5%. Therefore, follow-up is not necessary for thyroid cancer, just for growth, according to Dr. Lee.

Neither Dr. Zhang nor Dr. Lee had any financial conflicts to report. 

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