Initial Evaluation of Thyroid Nodules

Management Recommendations

1. Clinical Background

A. Past Medical History^​1–3​

ATA // AACE // JAES

In patients with confirmed or suspected thyroid nodules, the following personal and family history should be elicited:

• Family history for pheochromocytoma, hyperparathyroidism, and thyroid cancer in a first degree relative,
• Personal history of other malignancies, 
• Childhood head and neck radiation therapy, 
• Total body radiation for bone marrow transplant, 
• Exposure to ionizing radiation, 
• Symptoms of hoarseness, difficulty swallowing, and compression in the neck.

B. Physical Exam^​1–3​

ATA // AACE // JAES

In patients with risk factors for thyroid cancer or thyroid nodule related symptoms, a physical examination should be performed that focuses on the thyroid gland and adjacent cervical lymph nodes.

2. Laboratory Tests

A. Evaluation of TSH, TG & Calcitonin

ATA // ESMO // JAES

Measuring TSH is recommended to evaluate newly diagnosed thyroid nodules. Hyperfunctional nodules are more likely to be benign than non-hyperfunctional nodules.^​1,2​

Serum thyroglobulin measurement before total thyroidectomy is not an accurate test to assess for thyroid malignancy. Therefore, in patients with thyroid nodules, serum thyroglobulin measurement is not recommended.^​1,2​

Serum calcitonin may help identify patients with thyroid nodules harboring medullary thyroid cancers.^​4​

• However, because medullary thyroid cancer is rare, and calcitonin levels could be falsely elevated, guidelines are discordant in regard to routine measurement of serum calcitonin in patients with thyroid nodules.^​1,4​

3. Imaging Studies

A. Ultrasound (US) in Thyroid Nodule Assessment

ATA // NCCN // TIRADS

It is recommended to perform a thyroid ultrasound with cervical lymph node assessment in all patients suspected to have a thyroid nodule, or for whom a nodule has been previously identified through physical exam or incidentally on other imaging modalities.

It is recommended to evaluate and record ultrasound characteristics such as composition, echogenicity, shape, characteristics of the nodule’s margins and presence of echogenic foci.^​1,5,6​

It is recommended to assess the entirety of a nodule in order to describe characteristics including size, location, composition, echogenicity, margins, shape, and presence or absence of calcifications. These features help classify the risk of malignancy and guide FNA decision making.

There is agreement between guidelines regarding the sonographic features that should be assessed. However, mild discordance exists in the use of classification systems used to aid FNA decision making. The two most commonly used classification systems are based on:^​1,5,6​

• Ultrasound pattern recognition.
• Point-scoring systems based on sonographic features.

i. Sonographic Pattern-based Approach

ii. Scoring Systems Based on Individual Sonographic Characteristics

Recommendations for FNA biopsy are based on a nodule’s sonographic characteristics (TIRADS level) and the nodule’s maximum diameter. In levels TR3 to TR5, this system suggests size thresholds for which FNA is recommended, as well as lower size limits for which follow-up ultrasound examinations are recommended.^​6​

B. US for FNA Decision Making^​1,5,6​

ATA // NCCN // TIRADS

• Fine needle aspiration, with ultrasound guidance (UG-FNA), is the gold standard for diagnostic evaluation of clinically relevant thyroid nodules. Clinical relevance is determined by measurement of nodule size and analysis of the following sonographic features: microcalcifications, echogenicity, margins, cystic content, and shape.
• UG-FNA is not recommended when nodule diameter is < 1 cm regardless of sonographic features.

4. Management of Benign Thyroid Nodules^​1​

ATA

Surgery may be considered for benign thyroid nodules when > 4 cm in diameter, especially if a pattern of growth is detected or if there are compressive symptoms.

5. Molecular Testing^​1​

ATA // NCCN

• Molecular testing may help guide clinical management in patients having an indeterminate thyroid FNA result (Bethesda III or IV) without a high level of clinical or radiologic concern for malignancy.^​5​
• Molecular testing may also be considered for patients with a suspicious for malignancy (Bethesda V) thyroid FNA result if the results of such testing would impact surgical management.
• Such molecular testing should be performed in appropriately certified laboratories (CLIA or CAP in the US).
• Patients should be counselled regarding the benefits and limitations of molecular testing and the uncertainty regarding the significance of molecular testing results.
• Although not explicitly stated by ATA guidelines, there is concordance that if molecular testing results (in conjunction with clinical and radiologic findings) suggest a benign lesion, nodule surveillance as per guidelines for a benign FNA result is recommended.^​5​
• If molecular testing is suggestive of malignancy, diagnostic excision (lobectomy or total thyroidectomy) is recommended.^​5​
• If molecular testing indicates a high likelihood of papillary carcinoma (particularly a BRAF^V600E mutation, RET/PTC translocation), management should be as per guidelines for a diagnosis of papillary carcinoma by FNA.

  Related: Initial Thyroid Cancer Management

• No specific molecular test is endorsed as being preferred.

6. Management Based on Cytological Findings

ATA // NCCN // TIRADS

A. Non-diagnostic (Bethesda I)

Risk of Malignancy

5–10%

Included Histology

• Nondiagnostic or Unsatisfactory Cyst fluid only, • Virtually acellular specimen, • Other (obscuring blood, clotting artifact, drying artifact, etc).

• An initial non-diagnostic result of a solid nodule should prompt repeat FNA with ultrasound guidance and on-site cytology evaluation if available.^​1,5​
• If cystic, repeat FNA should be performed if any sonographically concerning areas are identified, Repeatedly non-diagnostic nodules that are not sonographically suspicious may be treated with continued surveillance or diagnostic excision.^​1,5​
• Surgical excision should be considered if: ^​1,6​
  • The nodule is sonographically highly suspicious,
  • Growth of > 20% in 2 dimensions is identified, or
  • There is high clinical concern for malignancy.

B. Benign (Bethesda II)

Risk of Malignancy

0–3%

Included Histology

• Benign, • Consistent with a benign follicular nodule (includes adenomatoid nodule, colloid nodule, etc), • Consistent with chronic lymphocytic (Hashimoto) thyroiditis in the proper clinical context, • Consistent with granulomatous (subacute) thyroiditis, • Other

No immediate treatment is needed for a benign FNA.^​1​

Nodule surveillance should be performed in accordance with sonographic imaging risk stratification, as defined by:^​1,5,6​

• High suspicion: repeat ultrasound and FNA biopsy within 12 months.
• Low-intermediate suspicion: repeat ultrasound at 12–24 months and consider repeat FNA for growth of > 20% in 2 dimensions (at least 2 mm or > 50% volume increase) or new concerning imaging findings.
• Very low suspicion: no surveillance or imaging after 24 months.
• If 2 benign FNA results are obtained on the same nodule, no further surveillance is needed for that nodule.

C. AUS/FLUS (Bethesda III)^​1,5​

Risk of Malignancy

10–30%

Included Histology

• Atypia of Undetermined Significance • Follicular Lesion of Undetermined Significance

Diagnostic lobectomy or nodule surveillance (guided by clinical and radiologic risk factors and patient preference) may be considered after an initial or repeat AUS/FLUS diagnosis, or if molecular testing is not performed or is uninformative.

Diagnostic lobectomy or total thyroidectomy is indicated if molecular testing yields a suspicious result.

Total thyroidectomy may be appropriate for diagnostic excision depending on imaging and clinical concerns, such as:

• Large nodule size (> 4 cm),
• Family history,
• History of radiation exposure,
• Patient preference, or
• Molecular testing results.

If molecular testing results (in conjunction with clinical and radiologic findings) suggest a benign lesion, nodule surveillance as per guidelines for a benign FNA result is recommended.

D. Suspicious for a Follicular (or Hürthle Cell) Neoplasm (Bethesda IV)^​1,5​

Risk of Malignancy

25–40%

Included Histology

• Follicular Neoplasm, or • Suspicious for a Follicular Neoplasma, including Oncocytic (Hürthle cell) type

If clinically or radiographically concerning for malignancy, diagnostic lobectomy or total thyroidectomy should be performed.

Otherwise, molecular testing may be considered to inform further decision making.

Diagnostic excision is indicated if molecular testing is not performed, is uninformative, or yields a suspicious result.

Nodule surveillance may be considered if the nodule is low-risk or there is patient preference for surveillance.

Total thyroidectomy may be appropriate for diagnostic excision depending on imaging and clinical concerns, such as:

• large nodule size (> 4 cm),
• family history,
• history of radiation exposure,
• patient preference, or
• molecular testing results.

If molecular testing results (in conjunction with clinical and radiologic findings) suggest a benign lesion, nodule surveillance as per guidelines for a benign FNA result is recommended.

E. Suspicious for Malignancy (Bethesda V)

Risk of Malignancy

50–75%

Included Histology

• Suspicious for Malignancy, • Suspicious for papillary thyroid carcinoma, • Suspicious for medullary thyroid carcinoma, • Suspicious for metastatic carcinoma, • Suspicious for lymphoma, • Other

• FNA diagnosis of suspicious for malignancy should be managed similarly to a malignant cytologic diagnosis.^​1,5​
• Molecular mutational testing may be considered for patients with a suspicious for malignancy (Bethesda V) thyroid FNA result if the results of such testing would impact surgical management.^​1​

F. Malignant (Bethesda VI)^​1​

Risk of Malignancy

97–99%

Included Histology

• Malignant, • Papillary thyroid carcinoma, • Poorly differentiated carcinoma, • Medullary thyroid carcinoma, • Undifferentiated (anaplastic) carcinoma, • Squamous cell carcinoma, • Carcinoma with mixed features (specify), • Metastatic malignancy, • Non-Hodgkin lymphoma, • Other

• Surgery is generally indicated for a diagnosis of papillary carcinoma in nodules ≥ 1 cm.^​5​
• Lobectomy may be appropriate for low-risk papillary carcinomas between 1–4 cm with:^​5​
  • No evidence of distant or nodal metastasis.
  • No evidence of extrathyroidal extension.
  • No prior radiation exposure.
• Otherwise, total thyroidectomy is preferred.^​5​
• Surgery may not be indicated if:
  • Patient has a short life expectancy.
  • Patient has significant comorbidities increasing surgical risk.
  • Patient has other urgent health concerns.
• Surgery is generally indicated for a diagnosis of medullary carcinoma regardless of size.
• Anaplastic carcinoma needs further evaluation to assess tumor resectability.^​5​

7. Thyroid Nodule Evaluation During Pregnancy^​1​

ATA

• FNA of clinically relevant thyroid nodules should be performed in euthyroid and hypothyroid pregnant women.^​7​
• For women with suppressed serum TSH levels that persist beyond 16 weeks gestation, FNA may be deferred until after pregnancy and cessation of lactation. At that time, a radionuclide scan can be performed to evaluate nodule function if the serum TSH remains suppressed.
• PTC discovered by cytology in early pregnancy should be monitored sonographically. If it grows substantially before 24–26 weeks gestation, or if the US reveals cervical lymph nodes that are suspicious for metastatic disease, surgery should be considered during pregnancy. However, if the disease remains stable by midgestation, or if it is diagnosed in the second half of pregnancy, surgery may be deferred until after delivery.

8. Thyroid Nodule Evaluation During Childhood^​1​

ATA

Children with DTC should be cared for by teams of physicians experienced in the management of DTC in children. This will facilitate interdisciplinary decisions regarding optimal therapy and will help to reduce the possibility that treatment and long-term follow-up will be either overly aggressive or inadequate 

The evaluation and treatment of thyroid nodules in children should be the same as in adults with the exceptions that:

1. US characteristics and clinical context should be used, rather than size alone, to identify nodules that warrant FNA, 
2. All FNAs in children should be performed under US guidance,
3. Preoperative FNA of a hyperfunctioning nodule in a child is not warranted as long as the lesion is removed, 
4. A diffusely infiltrative form of PTC may occur in children and should be considered in a clinically suspicious gland, and 
5. Surgery (lobectomy plus isthmusectomy) is favored over repeat FNA for most nodules with indeterminate cytology.

A positive mutational test appears highly likely to be associated with malignancy. Conversely, insufficient data exist in children to rely on negative genetic studies to reliably exclude malignancy. Although molecular studies hold promise for complementing the results of FNA, particularly for nodules that yield indeterminate cytology, they have not yet been sufficiently validated in children and cannot be recommended in routine clinical practice until further studies are conducted.