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Thyroid nodule evaluation

last modified on: Mon, 06/05/2017 - 19:31

Thyroid Nodule Evaluation

return to: Thyroidectomy and Thyroid Lobectomy

see also: I131 sialadenitis (Radioiodine Sialadenitis) and Thyroid Cancer (Evaluation and Management)

See: Thyroid Ultrasound



This guideline reflects the collaborative approach of the departments of Endocrinology, Pathology and Otolaryngology, and the Division of Surgical Oncology and Endocrine Surgery at the University of Iowa.

December 7, 2013

Thyroid Nodule Evaluation


Thyroid nodules are defined as radiologically distinct lesions within the thyroid regardless of whether they are palpable or not. The diagnosis of a thyroid nodule made by palpation must be confirmed with ultrasound (US) or other imaging. The prevalence of palpable nodules in the United States is approximately 4-7% (F>M). With examination by high resolution US the prevalence increases to 20-65% of individuals (F>M). The increasing incidence of identified thyroid nodules and malignancies is clearly related to the increasing frequency of US and other imaging of the neck over the last 20 years.


Between 5 -10% of thyroid nodules are malignant. The fundamental purpose of nodule evaluation in the majority of cases is to determine the probability that the nodule is malignant and from this probability develop a definitive management plan. The recommendations in this protocol largely follow the American Thyroid Association Clinical Practice Guidelines For Patients With Thyroid Nodules and Differentiated Thyroid Cancer,1 with deviations from those guidelines related to our pattern of thyroid fine needle aspiration (FNA) cytopathologic diagnoses at the University of Iowa Hospitals and Clinics (UIHC), and the evolving role of molecular diagnostics in thyroid FNA evaluation. The use of this protocol should be done with a clear understanding of the pattern and use of cytopathologic diagnoses and their implications at the reader’s institution. Over the last 10 years there has been a substantial evolution in the cytopathologic, molecular, and imaging characterization of thyroid nodules, and this work is evolving. As this work progresses, the substance of this management guideline is likely to change as well.1,2,3,4

Evaluation of thyroid nodules

  1. History
    • History of diagnosed thyroid disease (Hashimoto’s, Graves, Autoimmune thyroid disease)
    • History of thyroid cancer in a first degree relative or a number of more distant relatives who developed thyroid cancer before age 30 yrs.
    • History of ionizing radiation to the neck (particularly as a child or adolescent < 15yrs of age)5
    • Duration of known nodule(s) and noted change in size including changes based on prior US evaluations
    • Symptoms of: pain, hoarseness or change in voice, dysphagia, dyspnea
    • Symptoms of hypo or hyperthyroidism
  2. Physical Examination
    • Size, location and character of palpable thyroid nodules
    • Size and location of palpable neck nodes
    • The thyroid mass evaluation may warrant including an examination of the larynx to assess the vocal fold mobility
  3. Laboratory and imaging studies
    • High resolution US of the thyroid and neck (high risk findings regardless of nodule size include : nodule calcifications, particularly microcalcifications; vascular and solid; irregular margins; associated cervical adenopathy)
    • TSH
  4. Further work up based on the US and TSH
    • Low TSH (suggesting hyperfunctioning nodule)
      • A technetium scan may be done to determine nodule activity. If the nodule is hot, then the patient should be managed for hyperthyroidism. The prevalence of malignancy in hyperfunctioning nodules is very low and FNA is not generally indicated. These patients require work up of the hyperthyroidism, possible medical management and may ultimately require radioiodine or surgical treatment.
    • Normal TSH, Nodule < 1 cm in greatest dimension.
      • If there are no high risk US findings (see above), there is nothing in the medical history of concern, and the exam is otherwise negative, these patients should be advised to return in 12 months for a repeat US to evaluate any progression in size.
    • Normal TSH, Nodule >1 cm and < 3-4 cm.
      • These patients should be further evaluated with FNA
      • Our preference is to perform ultrasound guided fine needle aspiration (USGFNA). However, if the nodule is easily palpable, solitary, and the patient has not had a prior non-diagnostic FNA, the FNA may be done by palpation.
      • Immediate, on-site, cytologic evaluation to assure adequacy of the specimen will significantly improve the yield of diagnostic FNA material.
      • USGFNA as opposed to FNA by palpation is indicated in cases of: multiple nodules, nodules not easily palpable, posterior nodules, mixed solid and cystic nodules and prior non-diagnostic FNA.
    • Normal TSH and multiple nodules (>1 cm, < 3 cm)
      • All nodules with any high risk features should undergo USGFNA
      • In the case of multiple coalescent nodules, FNA assessment is done for at least the largest 3 nodules and the patient is followed closely with serial US to evaluate changes in any of the nodules with aspiration of any nodules demonstrating an increase in size.
    • Normal TSH, Nodule(s) larger than 3-4 cm.
      • Once nodules reach a size of 4 cm, the potential to find a clinically significant cancer within the thyroid increases to approximately 16% (13% within the suspect nodule and a 3% rate of clinically relevant, multifocal, micro-papillary cancer).6 Management of a nodule that is 3 – 4 cm in maximal dimension requires tailoring the treatment to all of the patient-mix variables and the patient’s preferences. With nodules larger than 3-4 cm it is reasonable to have a discussion with the patient about diagnostic surgery, most frequently a lobectomy, even in the event of a benign FNA. In the presence of any high risk history, physical exam (PE) or US findings, diagnostic surgery should be strongly considered. If diagnostic surgery is planned, and an FNA has yet to be done, the cytology may help in planning for either a diagnostic or definitive, therapeutic surgery.
      • If the nodule is larger than 4 cm, the patient should be offered the option of diagnostic surgery.
  5. Many patients are evaluated with PET/CT for a variety of malignancies. A thyroid nodule identified on PET/CT as a discrete area of FDG uptake should be worked up with an US and USGFNA. Up to 30 % of FDG avid, discrete thyroid nodules are malignant.7  


Interpretation of the FNA cytopathology


  1. The most commonly accepted classification for thyroid nodule cytopathology evolved from the NCI Thyroid FNA State of the Science Conference.2 This classification scheme requires that all thyroid FNA diagnoses be placed into one of four major categories, each with an associated (risk of malignancy). The indeterminate category is further subdivided into three categories.


  1. Benign Thyroid Nodule (<1%)
  2. Non-diagnostic (NA)
  3. Malignant (~100%)
  4. Indeterminate
    1. Follicular lesion or atypia of undetermined significance (5-10%)
    2. Follicular or Hurthle cell neoplasm or suspicious for follicular or Hurthle cell neoplasm (20-30%)
    3. Suspicious for malignancy (50-75%)


The diagnostic categories above with their associated prevalence of malignancy are consensus categories with approximate malignancy prevalences derived from the literature.2 These diagnostic categories, the cytologic features that result in their being used, and the associated prevalence of cancer associated with each one is likely to be institution specific.

For the most accurate and useful information, it is imperative that the managing physician be familiar with the diagnostic categories preferentially utilized by the cytopathologists at their institution, and the prevalence of cancer associated with each one.

At the UIHC, the category of follicular lesion or atypia of undetermined significance is very sparingly used because it is not felt to be an actionable diagnosis, and in that regard is not substantially more helpful than a non-diagnostic FNA. Based on a review of 2216 thyroid FNAs read at the UIHC, our indeterminate category made up 11.9% of FNA diagnoses overall. Of the remaining FNAs, 6.5% were malignant, 76.2% were benign nodules, and 5.4% were non-diagnostic. Within the indeterminate category three subcategories were primarily used, and these follow the Bethesda classification scheme.2 However, at the UIHC, a diagnosis of “atypical follicular cells” clearly implies that the pathologist identified follicular cells of concern. In this regard, this category does not directly mirror the Bethesda classification of “follicular lesion of undetermined significance” or “atypia of undetermined significance.” These categories are listed below with their associated prevalence of malignancy at the UIHC:

  1. Follicular lesion or Hurthle cell neoplasm or suspicious for follicular lesion or Hurthle cell neoplasm (27%)
  2. Atypical follicular cells (39%)
  3. Suspicious for malignancy (92%)

Our recommendations for definitive management are based on these prevalence figures, history, clinical findings, patient preference, global patient health status, and the selected use of molecular diagnostics.


  1. General recommendations based on the FNA cytopathology are outlined below. These recommendations should not replace mature clinical wisdom in the management of individual patients which takes into account all of the clinical variables and not just the FNA cytopathology.


Recommendations based on FNA Cytopathology at the University of Iowa

  1. Benign Thyroid Nodule:
    1. In the majority of cases, these patients are asked to return for a follow-up US in 12 months
    2. If the nodule is greater than 3-4 cm or the patient has concerning US or clinical factors, the potential utility of diagnostic surgery is discussed with the patient
  2. Non-Diagnostic Aspirate: At the UIHC, the overwhelming majority of these are FNA specimens obtained without US guidance and sent in for cytopathologic consultation. We repeat an US and USGFNA with on-site pathologic evaluation of specimen adequacy.
  3. Suspicious for malignancy: These individuals almost certainly have a malignancy (92%), they undergo an appropriate diagnostic work up (neck node evaluation) and therapeutic surgery (most frequently thyroidectomy and appropriate neck dissection).
  4. Malignant: Appropriate diagnostic work up (neck node evaluation) and therapeutic surgery (most frequently thyroidectomy and appropriate neck dissection).
  5. Indeterminate “Atypical Follicular Cells” present: At our institution this indicates that the cytopathologist has identified cells with concerning features and the prevalence of malignancy in this group is 39%. These patients are counseled to have, at a minimum, a diagnostic hemi-thyroidectomy. In selected cases, A BRAF​ V600E mutation evaluation may be ordered on the FNA material. If this is positive, the patient is managed as a papillary thyroid cancer.8
  6. Indeterminate “Follicular lesion or Hurthle cell neoplasm or suspicious for follicular lesion or Hurthle cell neoplasm.”

The prevalence of malignancy in this group is 27%. These patients are in general counseled to have a diagnostic hemi-thyroidectomy. Within the context of the entire clinical situation, the potential for further nodule characterization with BRAF V600E mutation testing and/or the Afirma gene-expression classifier (produced by Veracyte) may be discussed with them (see below).


The Evolving use of Molecular Markers in the evaluation of thyroid FNA analysis


  1. A number of molecular diagnostic interventions are now available to augment the routine cytopathologic characterization of thyroid FNA biopsies. One of the most well studied is the B-isoform of the Raf kinase (BRAF) mutation BRAF V600E which is present in approximately 50% of papillary thyroid cancers (PTC). This marker has a very high (99%) specificity for PTC. Therefore, a positive result should be regarded as diagnostic of PTC. Unfortunately, because it is not expressed in all PTCs, the sensitivity for diagnosing cancer in an indeterminate nodule is approximately 50%. In addition to its diagnostic utility, the BRAF V600E mutation appears to be more prevalent in tumors with an aggressive behavior. The evaluation for BRAF V600E may be done using material obtained with the FNA biopsy.3,9,10   
  2. Based on our cytopathology results and the prevalence of malignancy in the different categories of indeterminate nodules diagnosed at the UIHC, the BRAF V600E mutation may be used to further characterize indeterminate nodules. The primary utilities of the BRAF V600E mutation evaluation are: 1) If it is positive, then the diagnosis of cancer is made and 2) A positive result allows the surgery to be designed as a therapeutic not a diagnostic intervention which may eliminate the need for completion thyroidectomy and prompt a level VI node dissection in selected cases.
  3. The Afirma gene-expression classifier is a proprietary microarray assay done on material obtained from a thyroid FNA biopsy. The Assay was designed to provide additional information regarding the probability of malignancy within an indeterminate nodule. The potential utility of this gene-expression classifier lies in the potential to identify as benign or malignant, a lesion that has an indeterminate cytopathology. Across all categories of indeterminate nodules, and when evaluated based on intent to treat, the test has an 87% sensitivity and a 90% negative predictive value.11 The gene-expression classifier kit requires that diagnostic material be sent to Veracyte for cytopathologic evaluation and then if an indeterminate diagnosis is made, the gene-expression classifier is utilized to characterize the FNA as suspicious (surgery recommended) or benign (observation recommended). The gene-expression classifier has an approximately 50% false discovery rate (benign pathology with a suspicious Afirma result), and so this evaluation does not eliminate the potential for unnecessary surgery.     
  4. In populations with a high prevalence of cancer such as our “atypical follicular cells” (prevalence = 39%) and “suspicious for malignancy” (prevalence = 92%) the negative predictive value of the Afirma gene-expression classifier is unacceptably low, 88% and 42%, respectively (NPVs calculated based on the sensitivity and specificity of the Afirma gene-expression classifier11). However, in selected cases of “follicular lesion” this evaluation may add information that would sway the decision regarding diagnostic surgery. In cases of follicular lesion or Hurthle cell neoplasm or suspicious for follicular lesion or Hurthle cell neoplasm, the use of the Afirma gene-expression classifier may be discussed with patients. For this group of patients at the UIHC our NPV with Afirma is calculated to be 93%. It is important for patients to understand that although this test may provide further characterization of the nodule, 7% of cancers will be missed, and the false discovery rate is 50%.   

Selected clinical findings that influence the approach to thyroid nodules

  1. Patients with a thyroid nodule and a first degree family relative with known thyroid cancer should have the thyroid nodule(s) worked up with USGFNA regardless of size.
  2. A history of ionizing radiation to the neck in early childhood should prompt an aggressive workup of any thyroid nodules. Patients with larger nodules and this history, should be offered surgery as a management option.
  3. Microcalcifications within a thyroid nodule should prompt USGFNA regardless of the nodule size.
  4. Patients with an otherwise unexplained vocal cord paralysis and an ipsilateral thyroid nodule should be worked up with USGFNA and in most cases offered surgery.


This brief outline provides a framework within which to approach patients presenting with thyroid nodules. The information should be used within the context of all the historical, clinical, radiographic and cytopathologic information available to the practitioner.

The utility of molecular classification of thyroid nodules for both diagnostic and therapeutic decision making is rapidly evolving. As new algorithms are developed it is certain that the approaches outlined above will evolve. This evolution will be based on the available diagnostic tests and will continue to reflect the prevalence of malignancy found in the classes of cytopathologic diagnoses made at this institution.


  1. Cooper DS, Doherty GM, Haugen BR et al,  Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2009;19 (No.11):1167-1214.
  2. Blaloch AW, LiVolsi VA, ASA SL et al, Diagnostic Terminology and Morphologic Criteria for Cytologic Diagnosis of Thyroid Lesions: A Synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol. 2008;36:425-437.
  3. Xing M, Alazahrani AS, Carson KA et al, Association Between BRAF V600E Mutation and Mortality in Patients With Papillary Thyroid Cancer. JAMA. 2013;309(14):1493-1501.
  4. Nikiforov YE, Ohori NP, Hodak SP et al. Impact of Mutational Testing on the Diagnosis and Management of Patients with Cytologically Indeterminate Thyroid Nodules: A Prospective Analysis of 1056 FNA Samples. J Clin Endocrinol Metab. 2011;96:3390-3397.
  5. Schneider AB, Sarne DH, Long-Term Risks for Thyroid Cancer and Other Neoplasms After Exposure to Radiation. Endocrinology & Metabolism. 2005;1(2):82-91.
  6. McCoy KL, Jabbour N, Ogilvie JB et al, The Incidence of Cancer and Rate of False-Negative Cytology in Thyroid Nodules Greater Than or Equal to 4 cm in Size. Surgery. 2007;142:837-44.
  7. Are C, Hsu JF, Ghossein RA et al, Histological Aggressiveness of Fluorodeoxyglucose Positron-Emission Tomogram (FDG-PET)-Detected Incidental Thyroid Carcinomas. Ann Surg Oncol. 2007;14:3210-3215.
  8. Nikiforov YE, Yip L, Nikiforov MN, New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers. Clin Cancer Res. 2013:19(9);2283-2288.
  9. Adeniran AJ, Theoharis C, Hui P et al, Reflex BRAF Testing in Thyroid Fine-Needle Aspiration Biopsy With Equivocal and Positive Interpretation: A Prospective Study. Thyroid. 2011;21(7):717723.
  10. O’Neill CJ, Bullock M, Chou A et al, BRAFV600E Mutation is Associated With and Increased Risk of Nodal Recurrence Requiring Reoperative Surgery in Patients With Papillary Thyroid Cancer. Surgery. 2010;148:1139-46.
  11. Alexander EK, Kennedy GC, Baloch ZW et al, Preoperative Diagnosis of Benign Thyroid Nodules With Indeterminate Cytology. NEJM. 2012;23:705-715.