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Congress Report: ENDO 2016

Congress Report: ENDO 2016
  • Endocrinology and metabolism
  • Thyroid disorder

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Article

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ENDO 2016
Endocrine Society
Management of thyroid disorders
thyroid nodules
thyroid cancer
Guidelines
thyroid dysfunction in pregnancy
Graves’ disease
hypothyroidism
hyperthyroidism
Graves’ orbitopathy
RAI-refractory disease

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Practical

Thyroid disorders and their management received major coverage at ENDO2016. Presentations featuring the key topics relating to thyroid disorder are summarized here, by Professor Ali S Alzahrani


Thyroid nodules: what molecular markers are most useful?

Steven Paul Hodak, MD

NYU Langone Medical Center, New York, NY

Bryan McIver, MB, ChB, PhD

Moffitt Cancer Center, Tampa, FL

In the evaluation of nodular thyroid disease, molecular testing should be undertaken in the context of the overall risk of disease progression. Evaluating the clinical and ultrasonographic features of thyroid tissue remains important.

Although study findings continue to be somewhat controversial, some genetic mutations appear to be associated with more aggressive types of thyroid tumour.

Genetic testing therefore has the potential to be helpful in deciding the surgery and surgical procedure in patients with nodular thyroid disease. This is especially true in patients with microcarcinoma, where observation rather than surgery is now considered as one of the management options. 

At least four commercially available molecular diagnostic tests are available for the evaluation of thyroid nodular disease:

  • mRNA-based classifier (Rosetta GX™)
  • 7 Gene Panel (BRAF, RAS, RET/PTC, PAX8/PPARy)
  • ThyroSeq®-enhanced gene panel
  • Afirma® gene expression classifier

mRNA-based testing (Rosetta GX™) involves taking a scraping of material from the stained cytology slide and characterizing the mRNA pattern of cells.  Based on the miRNA panel, nodules can be classified as benign, suspicious for malignancy or suspicious for medullary thyroid cancer (MTC). The negative predictive value (NPV) of mRNA-based testing is ~90–93% and the positive predictive value (PPV) is ~60–63%.

ThyroSeq® is a multigene panel that test over 290 hotspots in 14 cancer-related genes and 42 gene fusions. Risk of cancer can be determined, based on reported mutations: this has been validated in one institution. ThyroSeq® has an NPV of 94−96% and a PPV of 37−83%. ThyroSeq® has essentially replaced the 7 gene panel testing, which was mentioned during the presentation for historical completeness.

Afirma® is a 142 RNA expression array with 25 gene pre-screening; it indicates whether tissue samples are benign or suspicious, although suspicious results do not have a high degree of reliability. Afirma® has a high NPP (~95−97%) but relatively low PPV (38−77%), and the accuracy of testing is affected if tissue samples are contaminated with blood.

The average cost per patient of molecular diagnostic testing for thyroid disorder is estimated at between US$ 4000 and US$ 6000.

Pearls and pitfalls of thyroglobulin assays

Jonathan S Lopresti, MD, PhD

University of Southern California, Los Angeles, CA

Thyroglobulin antibodies (TgAb) are found much more frequently in people with thyroid cancer compared with normal populations.  Although mass spectrometry is more sensitive and accurate than immunometric assays (IMA) for measuring the thyroglobulin (Tg) level, radioimmunoassays are more sensitive than either mass spectrometry or IMA for detecting Tg in patients with thyroid disease. This is because radioimmunoassays have less TgAb interference than the other methods.

There is great variability between different assays, secondary to the heterogeneity of the circulating Tg level in patients with disseminated thyroid cancer and the use of monoclonal antibodies with different Tg epitopes. Consequently, one Tg assay should be used consistently for longitudinal patient follow up.  In patients with TgAbs, Tg levels may be underestimated if IMAs are used.

Tg is a glycoprotein synthesized by the thyroid and cosecreted with thyroid hormones.  Serum Tg levels may be high in patients with increasing thyroid tumour-related activity, such as neoplasms and goiter, injury, or high thyroid stimulating hormone level.

Post-thyroidectomy, Tg levels increase 10-fold and do not return to normal for ~2 weeks. Radioactive iodine (RAI) therapy also increases Tg levels by about the same amount, but following therapy a much longer period is required (~6 weeks) before Tg levels return to baseline. 

Although thyroid stimulating hormone (TSH) values < 0.5 have minimal effect on the Tg level, Tg values should always be interpreted in view of TSH values. First-generation assays have functional sensitivity down to 0.5 µg/l, and utilize radioimmunoassays and mass spectrometry.  Second-generation assays detect Tg levels as low as 0.05−0.1 µg/l; the typical methodologies used are immunometric assays (IMA). 

Ultrasound and thyroid cancer surveillance

Susan J Mandel, MD, MPH

Perelman School of Medicine, University of Pennsylvania, Ardmore, PA

Ultrasonography has a major role in the management of patients with disseminated thyroid carcinoma (DTC), preoperatively and during the first year following surgery. Thereafter, the response to therapy determines how frequently ultrasound and other follow-up measures should be performed in the individual patient.

Whether to intervene or continue observation when small lymph nodes are found during the follow up of a patient with DTC remains a challenging question. The decision should be made based on the predicted risk of progression versus the likely stability of disease.

  • Substantial nodular growth, features associated with a high risk of progression and a progressive increase in the serum thyroglobulin (Tg) level are all indications that favour intervention.
  • Conversely, observing stability in these measures suggests that observation and surveillance are the preferred options. 

Although cervical lymph node involvement is common in patients with DTC, the mortality rate remains low. In other words, a high proportion of patients are at low risk of death due to metastatic disease. 

Ultrasonography is very sensitive for detecting cervical lymph node involvement, and preoperative ultrasonography is recommended for every patient with DTC. This is because 14−22% of patients with DTC have nonpalpable lateral lymph node metastases that, if detected preoperatively, would change the surgical approach.

‘Recurrence’ of DTC is generally residual disease, rather than true recurrence.  Biochemical recurrence of DTC is defined as a suppressed Tg > 1 ng/dl or stimulated Tg > 10 ng/dl, as stated in current American Thyroid Association (ATA) guidelines. 

Ultrasonography should be performed 6−12 months after initial surgery. After the first year following treatment, if the patient remains free of DTC, the recurrence rate is only 0.8 % for low-risk patients and 2.5% for intermediate-risk patients.  Initial risk-recurrence estimates should be modified according to available data at 6−18 months postsurgery. 

The interval between ultrasonographic surveillance should be determined by the patient’s clinical risk of progression and serum Tg level:

  • Low-risk patients with excellent response can be followed-up with serum Tg analysis and clinical examination only
  • Other patients require periodic ultrasonography, in addition to serum Tg analysis and other imaging as needed based on their individual risk, together with biochemical and clinical findings. 

Thyroid dysfunction in pregnancy

Elizabeth N Pearce, MD MSC

Boston Medical Center, Boston, MA

During the first trimester of pregnancy, levels of human chorionic gonadotropin (hCG) normally increase whereas levels of thyroid stimulating hormone (TSH) decrease. TSH levels usually normalize in the second trimester. Trimester-specific TSH ranges are therefore used.

The measurement of free thyroxine (FT4) using analogue assays is an unreliable method during pregnancy: measuring total T3 and T4 levels, with upward adjustment of the normal ranges, is preferred.

Pregnant women with severe hyperemesis often present with heightened levels of hCG and reduced levels of TSH.  Such symptoms may be associated with gestational thyrotoxicosis. Although it can be difficult to differentiate gestational thyrotoxicosis from Graves’ disease, the former is usually transient (resolving spontaneously before the third trimester).

Compared with gestational thyrotoxicosis, in patients with Graves’ disease symptoms are more severe, ophthalmopathy may be present, thyroid peroxidase (TPO) and anti-TSH receptor antibody tests may be positive and ultrasonography may show increased vascularity in the thyroid.

Subclinical hyperthyroidism has not been shown to increase the rate of maternal or fetal complications.  According to a recent Danish registry study, birth defects affecting the infant’s face, neck and urinary system have been observed following propylthiouracil (PTU) administration in the mother during pregnancy.

Following methimazole treatment, birth defects are also observed in the infant: these are more severe and involve more systems compared with PTU.

Such treatments should therefore be used cautiously for the management of thyroid dysfunction during pregnancy, with the lowest therapeutically effective doses being administered, to maintain high-normal euthyroidism or even mild hyperthyroidism. PTU is the recommended treatment for the first trimester of pregnancy.

Hypothyroid women have higher thyroid hormone requirements than other pregnant women.  This is particularly true for the first trimester, although levels typically plateau around week 20 of pregnancy. Therefore, women with history of hypothyroidism should be counselled to increase their T4 dose by 25−30% as soon as pregnancy is confirmed.  This can be done by increasing their weekly dose by two tablets.

The target TSH is the lower half of the trimester-specific normal range.  If this range is unavailable, a target TSH < 2.5 µg/l is reasonable.  Measuring the maternal thyroid receptor antibody levels is recommended in early pregnancy for women with a history of Graves’ disease; of positive, tests should be repeated at ~22−28 weeks.

One UK−Italian trial showed no difference in the IQ at 3.2 years between babies of women treated vs. those not treated for a TSH in the high-normal range during pregnancy.  Another large trial from the National Institutes of Health is yet to be published, but appears to show similar results. Current recommendations are:

  • Treat all women who have TPO antibodies and TSH above the normal range (defined as 4 µg /l if no trimester-specific normal range is available)
  • Treat all women with TSH levels > 10 µg/l, regardless of TPO antibody status
  • Consider treating women who are TPO antibody positive who have TSH > 2.5 µg/l but in the normal range
  • Consider treating women who are TPO antibody negative who have TSH higher than the normal range
  • Do not treat women who are negative for TPO antibodies but have a normal TSH
  • All pregnant or breast-feeding women should receive daily iodine 150 µg supplements.

Graves’ orbitopathy: evaluation and management

Marius N Stan, MD

Mayo Clinic, Rochester, MN

Orbitopathy occurs in 30% of patients with thyroid dysfunction: ~5% of cases are associated with euthyroid state, and ~5% with hypothyroidism. The usual course is progression of orbitopathy for up to 1 year, followed by a static phase for 1−3 years and then remission, which is usually incomplete. 

Clinical assessment of orbitopathy involves establishing the level of disease activity. A clinical activity score can be calculated: this measure includes spontaneous retrobulbar pain, pain on eye movement, redness of the eyelids, redness of the conjunctiva, swelling of the eyelids, inflammation of the caruncle and conjunctival oedema.  Each of these observations scores 1 point; a score of ≥3 has a positive predictive value (PPV) of 80%, and a negative predictive value (NPP) of 64%, for response to therapy. 

Disease severity is another clinical assessment for orbitopathy.  This involves assessing the soft tissue for signs of inflammation, lid aperture, lagopthalmos, exophthalmos, subjective diplopia score, eye muscle involvement, corneal involvement and optic nerve involvement.   These features are categorized as mild, moderate, severe and sight threatening:

  • Mild does not justify immunosuppressive therapy
  • Moderate and severe justify immunosuppressive therapy
  • Sight threatening requires immediate action

In considering immunosuppressive therapy, also review disease activity and severity:

  • Activity predicts response to immunosuppressive therapy
  • Severity determines whether there is a need for immunosuppressive therapy

Intravenous methylprednisolone is effective for moderate to severe active Graves’ orbitopathy. Acute liver injury is a concern following this therapy, however. Predictors of injury are patient age >53 years, dose/infusion of 570 mg and cumulative dose of 8.5 g.

Hypothyroidism following radioactive iodine (RAI) treatment for Graves’ disease increases the risk of worsening or appearance of Graves’ orbitopathy. 

2015 ATA thyroid nodules/cancer guidelines

Ultrasound and molecular diagnostics in the evaluation of thyroid nodules

Jennifer Anne Sipos, MD

The Ohio State University Wexner Medical Center, Columbus, OH

Ultrasonographic evaluation is important for deciding the next diagnostic testing step, in patients with thyroid nodular disease or thyroid cancer:

  • Pure cysts have a < 15% risk of malignancy and need no further evaluation
  • Very low suspicion lesions carry a < 3% risk of malignancy and are mostly spongiform in nature
    • Fine-needle aspiration (FNA) is indicated for lesions ≥ 2 cm in diameter
  • Low suspicion lesions carry a 5−10% risk of malignancy
    • FNA is indicated for lesions ≥ 1.5 cm in diameter
    • Such lesions are usually hyperechoic or isoechoic with regular margins, or sometimes partially cystic
  • Intermediate suspicion lesions are usually hypoechoic and solid with regular margins
    • Malignancy risk is 10−20%
    • FNA is indicated in lesions ≥ 1 cm in diameter
  • High suspicion lesions are solid hypoechoic with irregular margins, microcalcification, a ‘taller than wider’ shape, disrupted rim
    • Lesions should be biopsied if ≥ 1 cm in diameter 
    • Such lesions have more aggressive features and are associated with extrathyroidal extension, lymph node metastases and higher stage disease

Lesions that have high suspicious features but negative FNA should be re-evaluated within 6−12 months of initial FNA. Low to intermediate suspicious lesions should undergo repeat FNA 12−24 months after initial FNA. If two FNA procedures are benign, further FNA is not required and ultrasound surveillance is not recommended. 

Radioactive iodine: to treat or not to treat low risk thyroid cancer

Megan R Haymart, MD

University of Michigan, Ann Arbor, MI

Low risk disease is defined in the 2015 ATA guidelines as papillary thyroid cancer (PTC) with all of the following features:

  • No local or distant metastases
  • All macroscopic tumour has been resected
  • No tumour invasion of locoregional tissue or structures
  • No aggressive histology
  • If 131I (sodium iodide) is given, no uptake outside the thyroid bed on post-treatment whole body scan, no vascular invasion, clinical N0 or < 5 palpable N1 micrometastases.

Low risk disease also includes intrathyroidal encapsulated follicular variant PTC, intrathyroidal follicular thyroid cancer with capsular or minimal (< 4cm) vascular invasion, and intrathyroidal papillary micro carcinoma (unifocal or multifocal, including BRAF-positive microcarcinoma). 

Patients with low risk disease who undergo total thyroidectomy should be evaluated postoperatively to assess residual disease, but for the most part, radioactive iodine (RAI) therapy is not indicated. If given, a dose of 30 mCi is usually adequate. 

Patients with low risk tumours who undergo lobectomy should not receive RAI but should be assessed postoperatively for their disease status. 

For intermediate risk patients, RAI should be considered although it should not be routine practice.    

Multikinase inhibitor therapy: when to pull the trigger

Naifa L Busaidy, MD

The University of Texas MD Anderson Cancer Center, Houston, TX

Radioiodine (RAI)-refractory disseminated thyroid cancer (DTC) is defined as known structural disease with no iodine uptake, confirmed disease progression within 6−12 months after RAI with confirmed uptake, and total cumulative dose of RAI > 600 mCi with disease progression.

A patient with RAI-refractory stable asymptomatic or minimally progressive disease should be maintained on TSH suppressive therapy.  Likewise, TSH suppression should always be maintained in cases of RAI-refractory DTC

Two drugs have been FDA approved for the treatment of RAI-refractory disease: sorafenib and lenvatinib. Both treatments improved progression-free survival but not disease-associated survival. 

Other drugs are being trialed:

  • Vemurafenib is in phase 2 trials for patients with BRAF-positive RAI-refractory DTC
  • Dabrafenib is in phase 1 trials
  • Everolimus, an mTOR inhibitor, is in phase 1 and phase 2 trials. 

Another concept in patients with RAI-refractive disease is to re-enhance RAI uptake. Two treatments, selumetinib and also dabrafenib, are in Phase 2 trials.

Treatment with multikinase inhibitors is commonly associated with side-effects, some of which can be serious. The most common side-effects observed in clinical trials to date are hypertension, skin lesions, diarrhoea, fatigue, bleeding and cardiac events.

Using these drug treatments for RAI-refractory disease should be carefully considered. Comorbidities, symptoms, performance status and patient preference all require evaluation. Tumour-related factors are also important, including sites and organs involved, disease burden, pace of progression and location especially near vital structures. 

Localized therapy might need to be considered before multikinase inhibitor therapy is initiated, to minimize the potential for side-effects (e.g. bleeding, fistulae, etc.). Larger tumours seem to benefit more from multikinase inhibitor therapy compared with smaller tumours.  Localized therapy has also an important role in the management of refractory DTC.

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