Endocrinology – Thyroid Nodules

Focused summary of Thyroid Nodules relevant to Primary Care

Thyroid nodules may be found during a physical examination or incidentally on imaging of the neck. The majority of thyroid nodules are benign, however, approximately 5% may be malignant.

General examination of the thyroid gland may be a part of the routine physical examination, however risk factors for thyroid malignancy include a history of head and neck radiation, a family history of thyroid cancer or rare inherited diseases such as MEN- 2. In these patients a baseline thyroid ultrasound would be warranted to screen for thyroid cancer.

Differential diagnosis of thyroid mass noted on physical examination include a thyroglossal duct cyst, thyroid hemorrhagic cyst, lymph nodes or a parathyroid adenoma. A dedicated thyroid ultrasound is the first line test for differentiation of a thyroid mass. Final work up will be determined by the results of the ultrasound and clinical picture.

Thyroid nodule guidelines recommend that a thyroid/neck ultrasound be conducted on all patients with a suspected thyroid nodule or goiter or an incidental abnormality of the thyroid gland noted on another imaging modality (e.g. MRI, CT, PET scan etc.). The ultrasound report should characterize the nodule by outlining the following features: size, location, composition, echogenicity, margins, calcifications, shape if taller than wide and vascularity. Based on the American Thyroid Association guidelines, these features should then be summarized in the report in the form of risk stratifying each nodule for malignancy and guiding FNA decision making.

Checklist to Guide your In-Clinic Review of the Patient with a Thyroid Nodule

  • Absence of red flag features (change in voice or hoarseness, difficulty swallowing or dysphagia, rapid growth, obstructive symptoms, stridor)
  • Assess for risk factors for malignancy (history of head and neck radiation, a family history of thyroid cancer or rare inherited diseases such as MEN-2)
  • Clinical assessment of patient to determine if hyperthyroid, hypothyroid (uncommon) or euthyroid and request TSH
  • Clinical assessment of nodule (fixed vs. mobile, tender, cervical lymph nodes, skin changes)
  • Dedicated thyroid ultrasound requesting malignancy risk stratification based on the American Thyroid Association guidelines

Links to Additional Resources for Physicians and Patients

For Physicians:American Thyroid Association guidelines: www.thyroid.org/
Link to Endo website: http://www.calgaryendocrinology.com/
American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules – 2016 Update: www.aace.com/files/thyroid-nodule-guidelines.pdf
For Patients:www.mythyroid.com/
Up to date Patient Education: Thyroid nodules (Beyond the Basics): www.uptodate.com/contents/thyroid-nodules-beyond-the-basics

Clinical Flow Diagram with Expanded Detail

This AHS Calgary Zone Pathway has been developed with consideration of the most current evidence based clinical guidelines for diagnosis and management of Thyroid Nodules from both Endocrinology and Primary Care literature.

The following is a best-practice clinic pathway for the management of Thyroid Nodules in the primary care medical home. Included is a flow diagram and expanded detail explanation to determine which nodules may be followed in the primary care medical home and which require referral and specialist management.

Thyroid Nodule Pathway Flow Diagram
*If biopsy required for further work up of the nodule, a community ultrasound guided biopsy by radiology may be ordered at the same timeas Endocrine referral or biopsy will be done/ordered at initial Endocrine appointment.

1. Thyroid Nodule on Physical Exam or Ultrasound

Commonly thyroid nodules are found incidentally on physical exam of the neck or imaging of the neck (US, CT or MRI). The presence of a thyroid nodule should be confirmed with a dedicated ultrasound of the neck and thyroid as this will help to characterise the nodule and detect any other associated nodules or lymph nodes.

2. Alarm Features

When a thyroid nodule or other neck mass is noted, it is important to screen for alarm features or red flags (although rare). These include: stridor, that may suggest compression of the airway; hoarseness, that may suggest compression of the vocal cords by the lesion (a poor prognostic sign); or dysphagia that may suggest compression of the esophagus. Other concerning features include obstructive symptoms or a rapidly growing nodule (may suggest an aggressive malignancy or hemorrhage into a mass).

3. Risk Factors for Thyroid Cancer

While most cases of papillary thyroid cancer (PTC) are spontaneous, there are several risk factors that increase an individual’s risk. These include a history of head or neck radiation (e.g. treated for lymphoma at a younger age) or radiation fallout from power plant accidents or nuclear weapons (e.g. Chernobyl, Fukushima etc.)

There are several hereditary conditions that are associated with an increased risk of papillary thyroid cancer.

  1. Cowden syndrome
  2. Familial Adenomatous Polyposis
  3. Carney complex, type 1
  4. Familial non-medullary thyroid carcinoma (strong family history of papillary thyroid cancer)

There are several hereditary conditions that are associated with an increased risk of medullary thyroid cancer.

About 2 out of 10 medullary thyroid carcinomas (MTCs) are hereditary. The combination of MTC and tumors of other endocrine glands is called multiple endocrine neoplasia type 2 (MEN 2). In MEN 2a, MTC occurs along with pheochromocytomas and with parathyroid gland adenomas. In MEN 2b, MTC is associated with pheochromocytomas and with benign neuromas. This subtype is much less common than MEN 2a.

4. Laboratory Investigation

When investigating a thyroid nodule a TSH should be requested at baseline. This helps to distinguish if a nodule is non-functional, which the majority are, or possibly functional (i.e. hot). A TSH alone is a good screen for baseline thyroid function and if >0.2 with a clinically euthyroid patient, there is a high probability that the free T4 will be normal and therefore does not need to be ordered. If a TSH is <0.2 there is a possibility the nodule is functional (i.e. hot) (see Step 6).

5. TSH Normal or Elevated

A normal or elevated TSH is suggestive of a non-functional adenoma. The risk of malignancy in a non-functional adenoma is approximately 5%. Therefore, if the TSH is normal or elevated and the nodule meets criteria for a biopsy, a fine needle aspiration under ultrasound guidance should be arranged. A technicium (Tc) thyroid scan is not needed in these cases.

6. TSH <0.2

A TSH below 0.2 (despite values between 0.1-0.2 being within the normal range) may indicate that the thyroid nodule is functional (i.e. hot; shows increased uptake of technicium or radioactive iodine). The risk of malignancy in functional (i.e. hot) nodules is very low.

A technicium (Tc) thyroid scan provides a qualitative picture of radioiodine distribution within the gland. If there is increased uptake in the area of the nodule (correlated with the ultrasound findings) with suppression of iodine uptake elsewhere this is in keeping with a functional (i.e. hot) nodule.

In an otherwise non suspicious nodule, biopsy of a hyperfunctional / hot nodule is not indicated. The follicular cells in a hot nodule may be interpreted as highly abnormal as they can resemble thyroid cancer cells when seen under the microscope. However, hot nodules that are suspicious (e.g., irregular borders) should be considered for possible biopsy via fine needle aspiration.

7. U/S Guided Biopsy

Ultrasound guided biopsies are recommended for several reasons:

  • In nodules that have both a cystic and a suspicious solid component, ultrasound helps to ensure that the suspicious solid component of the nodule is biopsied.
  • Ultrasound allows for visualization of the needle and surrounding structures (eg. carotid artery, jugular vein and associated lymph nodes)
8. If Malignancy Risk Stratification not Provided on U/S

Please contact radiology group to provide a detailed report of each nodule’s risk for malignancy as outlined above. If the radiologist is unable to provide risk stratification for thyroid cancer, consider Endocrinology referral for recommendations. This will allow a specific patient plan to be formulated with consideration of
the current ATA guidelines, thus ensuring appropriate further investigation, follow up and management of patients.

9. Using ATA Thyroid Nodule Ultrasound Malignancy Risk Stratification

Using the American Thyroid Association thyroid nodule ultrasound malignancy risk stratification as a guide, patients with the sole recommendation of clinical and U/S follow up may continue to be managed in the medical home without the need for specialist referral.

Revised Calgary Lobectomy Protocol: July 2017

Patients to consider offering lobectomy as an option to a total thyroidectomy should have all the following criteria:
  • Age below 55 years (age where new AJCC/TNM v. 8 staging changes).
  • No family history of thyroid cancer and no past radiation exposure.
  • Patient choice and ability to understand nuances, risks and benefits of a new practice. The information discussed with the patient should include a discussion about surgical complications of a total thyroidectomy (RLN injury and hypoparathyroidism).
  • The patient must prepared for the possibility that he or she may have to undergo a completion thyroidectomy particularly when the final surgical pathology reveals features suggesting an intermediate or high risk of recurrence. The current paucity of long term surveillance data for lobectomy in PTC > 1 cm should be outlined and discussed with the patient.
  • Patient realization that lifelong post-op L-thyroxine treatment may still be needed.
  • A solitary lesion biopsy proven to show malignant cells consistent with papillary thyroid cancer (Bethesda VI).
  • Papillary thyroid cancer Size: 1-4 cm without extra-thyroidal extension or clinical evidence of lymph node metastasis.
  • Contralateral lobe is ideally free of nodules on ultrasound. If any nodules in contralateral lobe, evaluate US malignancy risk characteristics, consider FNAB or change to total thyroidectomy.
Post-lobectomy evaluation:
  • Detailed review of surgical pathology report (second opinion by thyroid pathology group prn) and intra-operative findings.
  • Patient must meet all the criteria post-op to classify as ATA Low risk of recurrence. Patients who are classified as ATA Intermediate or ATA High risk of recurrence should have a completion thyroidectomy to allow the possibility for treatment with radioactive iodine, when indicated.
  • Patients who have persistent high titer anti-Tg antibodies may merit consideration for a completion thyroidectomy only if the clinician feels that the ability to do nuclear medicine imaging or radioiodine reatment may provide better follow-up care or reassurance for the patient.
Surveillance recommendations post-lobectomy:
  • Target TSH 0.2-2.0 treating with L-thyroxine, if necessary.
  • Measure serum thyroglobulin (Tg) and anti-thyroglobulin antibodies at 6-8 weeks post-op.
  • Detailed thyroid/neck ultrasound at 6-12 months post-op.
  • TSH, Tg, anti-Tg antibodies at 6-12 months post-op.
  • At 6-12 months post-op: Apply dynamic re-staging using the response to therapy criteria

Thyroid Ultrasound: Standard Ultrasound Assessment & Reporting

Epidemiology

Thyroid nodules are a common clinical problem. An autopsy study found 50% of patients with no clinical history of thyroid disease had thyroid nodules, and the majority were multiple [1]. Diagnostic imaging can also reveal subclinical thyroid nodules. The prevalence rate of these thyroid incidentalomas is 18- 25% with MRI and CT imaging [2,3,4], up to 67% with ultrasound (US) imaging [5,6], and 1-2 % on FDG positron emission tomography (PET) [4,7]. In the absence of clinical risk factors, the risk of malignancy is between 5-13% when discovered by US, CT, or MRI [8,9] and 30% if based on PET [10]. Largely due to the widespread use of imaging, the yearly incidence of thyroid cancer has almost tripled from 4.9 per 100,000 in 1975 to 14.3 per 100,000 in 2009, with increasing proportion of cancers measuring < 1cm [11]. This increased diagnosis of small thyroid cancers has not resulted in more favourable outcomes. In fact, over the last thirty years, mortality rates from thyroid malignancy have remained stable [11]. In light of the evidence, a recent report from South Korea describes the increased detection of small relatively indolent thyroid cancers as a “thyroid cancer epidemic” [12], an experience also seen in Western countries [13]. To compound the problem, the diagnosis and treatment of thyroid cancer is not without its own inherent risks. Total thyroidectomy may be complicated by hypocalcemia from parathyroid gland damage and vocal cord dysfunction from inadvertent sectioning of the recurrent laryngeal nerve. To reduce overdiagnosis and overtreatment, recently revised guidelines (ATA, AACE/AME)* advocate thyroid nodule malignancy risk assessment and risk stratified de-escalated treatment strategies. These guidelines have been adopted by the Provincial Endocrine Tumour Team and are endorsed by the University of Alberta and University of Calgary thyroid cancer tumour groups.

Initial Management

Thyroid nodules are usually assessed with clinical parameters followed by diagnostic ultrasound. Patients in which the TSH is subnormal may also benefit from a radionuclide thyroid scan to determine if the nodule is autonomously functioning and therefore likely benign. If the TSH is normal or elevated, a radionuclide imaging should not be performed as an initial evaluation [14]. Ultimately, the decision to biopsy a thyroid nodule is generally determined by the sonographic features with less consideration given to the size of the lesion.

Characterization of Thyroid Nodules with Ultrasound

The goal of US risk stratification is to detect those lesions at highest risk of malignancy and to select which nodules should undergo FNA biopsy. The consensus by the Provincial Endocrine Tumour Team and AMA Endocrinology Section has been to use the American Thyroid Association (ATA) 2015 Guidelines to characterize thyroid nodules. The most critical step is the evaluation of US features that may be associated with increased malignant risk. Features assessed include internal content (solid vs. cystic), shape, margins, echogenicity, and calcifications. Vascularity is evaluated but has not been shown to help predict malignancy. The vast majority of thyroid cancers are solid (82-91%) [15-20] and the decision to biopsy partially cystic nodules must take into account their lower malignant risk. The solid components of the lesion are evaluated for suspicious features which include: taller-than-wide shape, spiculated/microlobulated margins, markedly hypoechoic echogenicity, microcalcifications, and disrupted rim calcifications (+/- extra-nodular soft tissue component) [14, 21-24]. The presence of a single suspicious feature elevates the risk to high suspicion; however, multiple suspicious features are additive and increase the malignant risk [14, 15, 25]. Just as there are sonographic features which have a high suspicion pattern, there are several distinct forms which are strongly correlated with benignity. A spongiform nodule is the aggregation of multiple cysts comprising >50% of nodule volume, with a malignant risk < 3 % [14]. As such, FNA biopsy for spongiform nodules is generally not recommended. Simple cysts are considered benign and require no intervention unless for symptomatic reasons. US features are the most important imaging factor in assessing malignant risk; however, nodule size and volume should also be assessed. Ongoing research is examining whether or not size is truly relevant, and there is a paucity of good data to suggest that even statistically significant size change predicts the risk of malignancy. Nevertheless, current ATA 2015 Guidelines suggest that size should factor into management decisions. In fact, each malignant risk category has a maximum size (usually based on the largest dimension of a nodule) above which FNA should be considered. Interestingly, biopsy is generally not recommended for lesions less than 1 cm regardless of the sonographic characteristics. Changes in nodule volume of ≥ 50% can be interpreted as growth or regression, and changes of ˂ 50% may be attributable to inter-observer variability [26]. It should be noted that determining volume change for very small nodules is challenging as small statistical variation in measurement may mathematically overestimate change. Volume change in lesions measuring <10 mm should therefore be interpreted with caution.

American Thyroid Association Risk Stratification System

The ATA 2015 Guidelines combine US features into several categories with a definable malignant risk and anagement strategy [figure 1 & 2]. Please note that biopsy is generally not recommended for lesions < 1 cm regardless of their sonographic features and malignant risk assessment [12,13, 25].

Figure 1: American Thyroid Association Classification (pictorial).17

American Thyroid Association Classification

Figure 2:
Standard Biopsy Recommendations - Thyroid Nodules

  • High Suspicion Nodules
    • If > or = 10 mm, Endocrine referral and Urgent biopsy.
    • If < 10 mm, Endocrine referral only (bx to be determined by Endocrinology)
  • Intermediate suspicion nodules
    • If > or = 10 mm, non-urgent biopsy +/- Endocrine referral.
    • If < 10 mm and no clinical risk factors, US surveillance q 12-14 months
  • Low suspicion
    • If > or = 1.5 cm, Endocrinology referral.
    • If < 1.5 cm, US surveillance q 12-14 months
  • Very low suspicion and Benign
    • Clinical follow-up and US in 2 years
    • Consider Endocrine referral if > 2cm and growing
ETA Guidelines on Cerivical Lymph Nodes

The European Thyroid Association (ETA) Guidelines for cervical lymph node assessment have been adopted to assess lymph node malignant risk in the setting of current or previous thyroid nodules or cancer. These guidelines stratify nodes into normal, indeterminate, or suspicious based on US features and size. The usefulness of these guidelines was confirmed by a recent evaluation by Lamartina et al [27], but is beyond the scope of this review.

Standardized Patient Management Recommendations

Using sonographic risk stratification, standard management strategies are recommended based on ATA (2015) Guidelines and with the endorsement of the U of C Division of Endocrinology. Small nodules < 5mm in size may not be characterized due to their small size, but generally require no intervention other than clinical and/or US follow-up. If a nodule has any suspicious features, subspecialty Endocrinology assessment is recommended.** High suspicion lesions ≥ 1cm also generally go on to urgent FNA biopsy. Guidelines recommend against biopsy for lesions < 1 cm regardless of the US appearance unless there are strong clinical risk factors or abnormal cervical lymph nodes. Intermediate risk lesions ≥ 1 cm and low risk lesions ≥1.5 cm generally undergo elective biopsy +/- Endocrinology referral. Current recommendations for very low risk or spongiform lesions with a high likelihood of benignity (>97%) suggest clinical follow-up in two years. For lesions that do not meet currently accepted size thresholds for biopsy, clinical and US follow-up is generally advised in 1-2 years. Recommendations should take into account results from prior FNA biopsy and/or clinical risk factors (such as a positive family history of medullary thyroid cancer, MEN2 syndrome, radiation exposure, and young age).

Synoptic Reporting of Thyroid Ultrasound

In an effort to improve quality and decrease variability of radiology reports, structured thyroid US reporting has been adopted by EFW Radiology. A sample report is included [figure 3].

Figure 3: EFW Sample Report

EFW Sample Report

Abbreviations:
*ATA = American Thyroid Association; AACE = American Association of Clinical Endocrinologists; AME = Associazione Medici
Endocrinologi
** = The standardized thyroid ultrasound reporting system was developed as a collaboration between EFW Radiology and the University of Calgary Division of Endocrinology (consultation for your patients is available at RRDTC or TBCC through Endocrinology Central Triage ph.# 403-955-8633 fax#: 403-955-8634).

Thyroid Ultrasound Summary
  • Thyroid nodules are very common and often discovered incidentally
  • Thyroid US is used to characterize nodules with regard to sonographic malignancy criteria, size, volume, and interval growth/regression
  • Sonographic malignancy criteria are more important than size and growth in determining malignant risk;
  • Proper sonographic malignancy risk assessment and risk stratified (deescalated) treatment strategies are aimed at reducing overdiagnosis and overtreatment;
  • EFW is working in collaboration with the University of Calgary Division of Endocrinology to promote improved Thyroid Nodule Malignancy Risk Assessment.

Hard copies are available for the content of this page as well as the Revised Calgary Lobectomy Protocol and the Standard Ultrasound Assessment and Reporting EFW Radiology Medical Brief.