Thyroid Disorders
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Thyroid Nodules – Management Dilemmas and Theraputic Considerations

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Published Online: Jun 6th 2011 US Endocrinology, 2005;(1):68-70 DOI:
Authors: M Regina Castro
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Thyroid nodules are very common in clinical practice, with an overall prevalence that varies from 4% by palpation to 67% by ultrasonography. The annual incidence by palpation has been estimated at 0.09% by the Framingham study,1 which translates into approximately 300,000 new nodules in the US in 2005. Despite their high frequency, only a small fraction (~5%) of thyroid nodules harbor cancer. Because only malignant or large, symptomatic nodules will require surgical excision, a systematic approach to their evaluation is important to avoid unnecessary surgery. Certain aspects in the evaluation and management of thyroid nodules remain controversial or represent clinical dilemmas.


‘ Non – diagnostic ’ Smear

‘ Non – diagnostic ’ Smear
Fine needle aspiration (FNA) biopsy is the most costeffective and accurate method of distinguishing benign from malignant thyroid nodules. This procedure has led to a substantial reduction of unnecessary surgeries, while doubling or tripling the malignancy yield at thyroidectomy. Despite its overall excellent accuracy, approximately 15% of all specimens will be classified as ‘non-diagnostic’ or ‘insufficient’, a diagnosis that poses a management dilemma. Repeat aspiration, preferably under ultrasound guidance, can significantly reduce the rate of non-diagnostic smears. However, when repeat aspiration fails to provide an adequate specimen, the clinician must decide whether to follow the patient clinically or refer for surgical excision. Certain clinical features (history of head or neck irradiation, rapid nodule growth, a hard nodule with fixation to surrounding tissues, compressive symptoms such as dysphagia or persistent hoarseness) increase the likelihood of malignancy in a nodule and may be considered an indication for surgery. However, many patients who lack such clinical features are often found to have thyroid cancer on subsequent evaluation. It is important to recognize that ‘nondiagnostic’ is not synonymous with benign disease, as shown in a study where a 9% incidence of malignancy and a 52% rate of neoplasia was seen after surgical excision of nodules with repeatedly non-diagnostic cytopathology.2 In the presence of ‘high-risk’ clinical features, surgical excision should be considered to definitively exclude malignancy, while observation and re-evaluation in six to 12 months may be appropriate for low-risk patients. ‘ Suspicious ’ or ‘ Indeterminate ’ Cytology
The finding of ‘indeterminate’ or ‘suspicious’ cytologyon FNA biopsy of thyroid nodules is one of the most challenging diagnostic dilemmas for the endocrinologist, and the best management strategy remains controversial. This category includes cytologic findings commonly referred to as ‘follicular neoplasms’ that include hyperplastic nodules, follicular adenomas and carcinomas, and follicular variants of papillary carcinoma.3 The microscopic distinction is difficult, leading most clinicians to recommend surgical excision for a definitive diagnosis. Due to the fact that only 15% to 20% of these lesions will ultimately be found to represent cancer,4,5 up to 85% of patients in this subgroup may undergo unnecessary surgery, with its attendant high cost and potential morbidity. Many studies have attempted to determine factors predictive of malignancy in patients with cytologic findings ‘suspicious for follicular neoplasm’.6,7 Although certain clinical findings (large nodule diameter, fixation to surrounding tissue,male gender, and younger age of the patient) were associated with increased risk of malignancy in some studies,6,7 others found that no cytological,3 clinical, scintigraphic, or ultrasonographic characteristics were predictive of malignancy.8 Other techniques, such as the use of electron microscopy, flow cytometry, and several genetic markers, have been evaluated, but have not improved diagnostic reliability. However, two immunohistochemical markers (HBME- 1 and galectin-3) have shown promise in their ability to predict malignancy and their potential for ease of use in any surgical or cytopathology laboratory, in academic or community settings.9,10 Bartolazzi et al. conducted a retrospective analysis of 618 tissue specimens and 165 cell blocks, as well as a prospective analysis of 226 ultrasound guided (UG)-FNA specimens.9 In the retrospective review of their surgical specimens, 94% of 311 malignant cases stained positive for galectin-3. Less than 3% of papillary carcinomas failed to express this marker.Thirty-seven (93%) minimally invasive follicular thyroid carcinomas were positive for galectin-3, and this marker was not expressed in any case of nodular hyperplasia or thyroiditis. More importantly, the prospective analysis focussed on 90 cases in which conventional cytology was inconclusive. In these cases, the addition of galectin-3 allowed the correct identification of all malignancies, including five minimally invasive follicular carcinomas.

Evaluation of the Patient with Multinodular Goiter
The evaluation of a patient with a palpable solitary nodule is generally straightforward and will usually include FNA biopsy with or without ultrasound guidance. It is important to recognize that in up to 48% of patients with a clinically palpable solitary nodule, ultrasonography will often demonstrate the presence of one or more additional nodules.11 The evaluation and management of patients with multinodular goiters (MNG) represents a much more difficult problem in the clinical setting. It had been suggested that, in the setting of multi-nodularity, a dominant palpable thyroid nodule is most often benign,12 but a study by Belfiore et al.13 found that the frequency of thyroid cancer in patients with a solitary nodule (4.7%) does not differ from that in patients with a non-toxic MNG (4.1%). Because no single clinical or ultrasonographic feature has been found to reliably confirm or exclude the presence of malignancy, selection of the nodule(s) that will require biopsy needs careful consideration. It is generally recommended that in the setting of a multinodular goiter, the dominant nodule should be biopsied. However, certain ultrasonographic features of thyroid nodules, such as hypoechogenicity, the presence of microcalcifications, increased vascular flow, or irregular borders, are associated with increased risk of malignancy14 and, when present, should help the clinical in selecting the target of the FNA biopsy (see Figures 1 and 2). In the absence of these features malignancy cannot definitively be excluded, therefore patients with MNG should be followed with periodic neck

examination and ultrasonography and a repeat biopsy should be considered if significant growth of a nodule is noted or other worrisome clinical (persistent hoarseness, dysphagia, adenopathy, etc.) or sonographic features develop on follow-up.


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