What I did before
Thyroid nodules found on physical examination are common. It is estimated that up to 7% of adults in the United States have a palpable thyroid nodule (1). Fewer than 5% of these nodules are malignant (2). In accordance with the most recent guidelines of the American Thyroid Association (3), I obtain a TSH in patients with a thyroid nodule. If the TSH is low, the patient should be investigated for hyperthyroidism using a radioactive iodine scan. In absence of any worrisome features on history or physical exam (Table 1), a hyper functioning nodule on a scan has a very low probability of being malignant (4). However, patients with palpable nodules and normal or high TSH require an ultrasound and a great deal of useful information can be gained from the imaging.
|Table 1. Clinical Findings Suggesting the Diagnosis of Thyroid Carcinoma in a Solitary Nodule, According to the Degree of Suspicion (4)|
Fine needle aspiration (FNA) of the thyroid nodule should be performed under ultrasound guidance in all patients with nodules of >1 cm or in patients with features on history, physical examination, or ultrasound which suggest an increased risk of malignancy (Tables 1 and 2) regardless of nodule size. While some FNA’s will definitely be benign and some positive for thyroid cancer – in which case patients should be referred to a surgeon for removal. Approximately 15-30% of FNA’s will yield indeterminate results (3). These indeterminate findings are one of “atypia (or follicular lesion) of undetermined significance,” “follicular neoplasm or suspicious for follicular neoplasm,” and “suspicious for malignancy” (5, 6).
Indeterminate results present a diagnostic dilemma: based on history (see Table 1) and other ultrasound or pathological findings, some patients are referred for surgery while others are monitored. It is inevitable that some patients with indeterminate results may undergo surgery and be found to have benign pathology. However, the rate of unnecessary surgery can be reduced using ultrasound and genetic tools.
What changed my practice
Ultrasound can be a powerful tool in distinguishing thyroid nodules with malignant potential from benign ones. I look for the ultrasound to answer the following questions: 1) How many nodules are there and how big is each one? 2) Is the nodule a simple cyst? 3) Is there increased vascularity? 4) Are there micro calcifications in the nodule? 5) Is the nodule hyper/hypo-echoic? 6) Is the lesion taller than wide on transverse view? 7) Is there suspicious cervical lymphadenopathy?
Numerous studies have evaluated predictive value of ultrasound findings in determining malignant features. In a study done by Bastin et al (8), microcalcifications were 84% and ill-defined or lobulated margins were 89% specific for nodules associated with thyroid cancer. A recent review article, in World Journal of Surgery, identified features that have been consistently found to be significantly associated with malignancy (9). Thus, these ultrasound characteristics can be very useful in making decisions about surgery in patients with indeterminate cytology.
|Table 2. Ultrasonographic features significantly associated with malignancy|
|Margin: Blurred or ill-definedIrregular ShapeSolid structureHypoechoic
Vascular pattern: intranodular or hypervascular
Gene mutations can be identified in 60-70% of cases of thyroid cancer (7). Genetic testing on FNA samples shows promise in further characterizing thyroid nodules that have indeterminate FNA results. In August 2012, Alexander and colleagues (10) reported their findings on using Afirma® Gene-Expression Classifier (Veracyte©) in pre-operative diagnosis of thyroid nodules with indeterminate cytology. The gene-expression classifier used 167 genes to classify the aspirated material. Of the final 265 indeterminate fine-needle aspirates used in the analysis, based on histopathological review, 85 (32%) were identified to be malignant. The gene-expression classifier correctly identified 78/85 of the samples as “suspicious” (sensitivity 92%, 95% Confidence Interval [CI], 84-97). Conversely, of the remaining 180 samples, 93 were correctly identified to be non-malignant by the assay (specificity 52%, 95% CI, 44-59). This corresponded to a negative predictive value (NPV) 93% (86-97) and a positive predictive value (PPV) 47% (40–55). Overall, the assay had 100% sensitivity (29-100) and 70% specificity for cytopathologically benign samples.
What I do now
Evaluation and work-up of a thyroid nodule is a relatively common presentation. I continue to follow the American Thyroid Association guidelines (3) in seeing these patients. It is nevertheless important, however, to have relevant radiological findings reported to aid in further management of these nodules (see above). Your ultrasound reports may not contain all of this information. If they do not, talk to the radiologist as these ultrasound characteristics are very useful in determining risk of malignancy, especially in samples with indeterminate cytology. Application is being made to have molecular testing on FNA specimens be a funded service in British Columbia (personal communication, B. Gilks M.D., Department of Pathology, Vancouver General Hospital), and thus available for patients in BC. However, the use of molecular diagnostic techniques should be limited to those samples in whom history, physical, and detailed ultrasound analysis do not provide sufficient information to guide surgical management. Additional note: There is not a role for nuclear scanning in the evaluation of thyroid nodules in the euthyroid patient. The nuclear scan will show a nodule as being hot, normal or cold. If the nodule is hot, it is unlikely to be malignant but if the nodule is hot, the TSH will be suppressed. While cold nodules are more likely than normal nodules to be malignant, most cold nodules are benign and not all malignant nodules are cold. Thus, the nuclear scan has little discriminatory power.
References (Note: Article requests might require a login ID with CPSBC or UBC):
- Singer PA, Cooper DS, Daniels GH, et al. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med. 1996;156(19):2165-72. (View article with CPSBC or UBC)
- Wong CKM, Wheeler MH. Thyroid nodules: rational management. World J Surg. 2000;24:934-41. (View article with CPSBC or UBC)
- 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;19:1167-214. (View article with CPSBC or UBC) [Erratum, Thyroid 2010;20:674-5.] (View article with CPSBC or UBC)
- Hegedus L. Thyroid Nodule. N Eng J Med. 2004;351:1764-71. (View article with CPSBC or UBC)
- Baloch ZW, Cibas ES, Clark DP, et al. The National Cancer Institute thyroid fine needle aspiration state of the science conference: a summation. Cytojournal 2008; 5:6. (View article)
- Cibas ES, Syed AZ. The Bethesda Sys- tem for reporting thyroid cytopathology. Am J Clin Pathol. 2009;132:658-65. (View article with CPSBC or UBC)
- Moses W, Weng J, Sansano I, et al. Molecular testing for somatic mutations improves the accuracy of thyroid fine- needle aspiration biopsy. World J Surg. 2010;34:2589-94. (View article)
- Bastin S, Bolland MJ, Croxson MS. Role of ultrasound in the assessment of nodular thyroid disease. J Med Imaging Radiat Oncol. 2009;53(2):177-87. (View article with CPSBC or UBC)
- Morris LF, Ragavendra N, Yeh MW. Evidence-based assessment of the role of ultrasonography in the management of benign thyroid nodules. World J Surg. 2008;32(7):1253-63. (View article with CPSBC or UBC)
- Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367:705-15. (View article with CPSBC or UBC)