Hashimoto's Thyroiditis Is Not Associated with Increased Risk of Thyroid Cancer in Patients with Thyroid Nodules: A Single-Center Prospective Study

Abstract

Background:

The risk of thyroid carcinoma in patients with thyroid nodules associated with Hashimoto's thyroiditis (HT) is a debatable issue. The studies defining the true risk of thyroid malignancy are scanty and mainly depend on retrospective series. To eliminate inherent bias of retrospective studies, this prospective study was carried out to evaluate the true malignancy rate of unselected thyroid nodules in patients with HT who underwent fine-needle aspiration cytology (FNAC).

Methods:

These prospective data were gathered on all patients newly diagnosed with thyroid nodules who were sent for FNAC between May 2006 and August 2009. All patients were evaluated for the presence of HT diagnosis by measuring thyroid autoantibodies. If a patient had at least one positive thyroid autoantibody, then the patient was defined as HT with thyroid nodules. There were 164 patients (147 women and 17 men) with thyroid nodules associated with HT (HT group). There were 551 patients (432 women and 119 men) with thyroid nodules without HT (control group). All patients underwent FNAC and ultrasonography (US).

Results:

The malignancy rate was 1.0% in HT group (2 out of 191 nodules) and 2.7% in the control group (19 out of 713 nodules), a not significant (p = 0.19) difference. In the two cytologically malignant nodules in HT group and 19 in the control group, papillary thyroid carcinoma was diagnosed after thyroidectomy and histopathological examination. US features of nodule echogenicity, structure, margin, and Doppler flow were similar between the two groups. US features of microcalcification and absence of peripheral halo were more prominent in the nodules of the control group (p = 0.002 and p < 0.001, respectively).

Conclusions:

On the basis of cytopathological criteria, thyroid nodules in patients with HT are no more likely to be malignant than in those without HT. Many of the US features of benign thyroid nodules are similar in patients with and patients without HT.

Introduction

T hyroid nodules are frequently observed in patients with Hashimoto's thyroiditis (HT) as in nonautoimmune thyroid glands (1,2). The linkage between HT with thyroid nodules and thyroid malignancy was first proposed by Dailey et al. in 1955 (3). Since that time, many studies were launched that focused on the risk of malignancy in patients with thyroid nodules associated with HT (2,4 –9). However, whether the risk of malignancy for a given thyroid nodule is different in patients with HT compared to patients without thyroid autoimmunity remains a highly debated and controversial issue. Some studies have reported an increased risk of malignancy in thyroid nodules associated with HT; others have failed to find an association (4,5,10 –14). The observed lack of consistency among the studies can be largely attributed to the retrospective analyses of surgical series and the type of study design.

In most of the previous retrospective studies, there was a support for a significant association between thyroid malignancy and HT (3,4,6,7,10,12 –14). The recently revised American Thyroid Association guidelines for thyroid nodules and thyroid cancer have reported that the rate of malignancy in nodules in thyroid glands involved with HT is possibly higher (15). However, it is noteworthy that most of the series that reported increased risk were focused on the recognition of autoimmune pathological features associated with thyroid malignancy after surgery (3,4,6,7,10,12). The lack of a true control group in these studies is an issue of concern.

Data about the association of HT and thyroid cancer based on fine-needle aspiration cytology (FNAC) results are more limited (16 –18). Only one properly designed retrospective controlled trial evaluated the frequency of malignant nodules in patients with HT and comparing the results those obtained in thyroid nodules without HT (16). This prospective study was therefore undertaken to compare the rate of malignancy by cytological criteria in patients with thyroid nodules with and without HT.

Materials and Methods

This was a single-center prospective study in patients with or without HT having one or more thyroid nodules. The Baskent University Ethics Committee for Human Studies approved the protocol. All participants provided informed consent. One hundred sixty-four patients newly diagnosed with thyroid nodules with HT (age range, 18–84 years) who had 10 mm or larger thyroid nodule(s) were included. Patients were attendees for regular follow-up at the Endocrinology Department of Baskent University Faculty of Medicine in Ankara, Turkey, between May 2006 and August 2009, and were consecutively recruited in the study. As a control group, 551 subjects newly found as euthyroid with single or multiple thyroid nodules at least 10 mm in diameter and with no thyroid autoimmunity were recruited from patients admitting to the same center during the same period.

Euthyroidism was defined as sensitive thyroid-stimulating hormone (reference range, 0.35–4.0 mIU/L) and free T₃ (FT3; reference range, 1.71–4.71 pg/mL) and free T₄ (FT4; reference range, 0.8–1.9 ng/dL) within the normal reference range. Subclinical hypothyroidism was defined as elevated sensitive TSH levels (>4.0 mIU/L) in the presence of normal FT4.

All patients who were scheduled for ultrasonography (US)-guided FNACs for the first time were included in the study in a prospective manner. At study entry, HT was diagnosed for those who had either overt or subclinical hypothyroidism with moderate or prominent heterogeneous thyroid parenchyma sonographically and at least one positive thyroid autoantibody (anti-thyroglobulin [anti-Tg] >40 U/mL; anti-thyroid peroxidase [anti-TPO] >50 U/mL). Patients with thyroid nodule(s) who had euthyroidism on admission were tested for thyroid autoantibody positivity. If a patient had at least one positive thyroid autoantibody, then the patient was defined as HT with thyroid nodules. A flow diagram of the protocol with all subjects was depicted in Figure 1. Overall 164 patients (147 women and 17 men) had at least positive thyroid autoantibody. Of those patients, 128 patients had either overt or subclinical hypothyroidism. Thirty-six patients had euthyroidism. All patients had US signs of HT. Patients with newly diagnosed thyroid nodules without thyroid autoantibody positivity were assigned to the control group (n = 551; 432 women and 119 men). Subjects with any of the following characteristics were excluded from the study: those with history of different thyroid disease, overt or subclinical hyperthyroidism (as defined by suppressed TSH levels), previous L-thyroxine suppression therapy at any time, or history of neck irradiation or surgery.

FIG. 1.

Flow diagram of the protocol. FNAC, fine-needle aspiration cytology; HT, Hashimoto's thyroiditis.

US and US-guided fine-needle aspiration biopsy

Thyroid US was performed by a single physician (A.G.) using a 10-MHz linear probe (Logiq 5 Pro; GE Medical Systems, WI). In heterogeneous thyroid parenchyma of HT, a three-dimensional discrete lesion within the thyroid gland that was ultrasonographically distinct from the surrounding thyroid parenchyma was considered as a nodule. The presence, location, size, and margin characteristics of each nodule within the thyroid gland were clearly defined. All US features of thyroid nodules, including structure, echogenicity, calcification, margin, and Doppler flow, were documented. Nodule structure was defined as solid, mixed, or cystic. The echogenicity of each thyroid nodule was defined according to its brightness compared to the normal thyroid parenchyma. Nodule echogenicity was classified as hyperechoic/isoechoic/hypoechoic. In case of cystic nodules, the classification of echogenicity was made by examination of the solid component. The vascularization patterns of each nodule were evaluated by color flow Doppler sonography. Using color flow Doppler sonography, nodule vascularity was categorized as absent (type I), perinodular (type II), or peri- and intranodular (type III).

According to the standard practice at our institution, four aspirations were made with four different 25-gauge needles at different sites in each nodule. The same endocrinologist (A.G.) performed all ultrasonographically guided FNACs. All patients with thyroid nodules >1 cm were offered to undergo FNAC unless it was a purely cystic nodule. All of the FNAC evaluations were carried out by a single experienced cytopathologist from the Department of Pathology, Faculty of Medicine, Baskent University, who was blinded to the clinical and laboratory features of the patients. FNAC results were repored in four categories: nondiagnostic, malignant, indeterminate or suspicious, and benign.

Laboratory analysis

Each venous sample was drawn after a minimum fasting period of 12 hours. All samples were collected between 08:00 and 09:00 hours. Thyroid function was evaluated by measuring FT4, FT3, and TSH using immunochemoluminescent assays by an automated analyzer (Immulite 2000; Diagnostic Products Corporation, Los Angeles, CA). Thyroid antibodies (anti-TPO [normal range: <50 U/mL] and anti-Tg [normal range: <40 U/mL]) were measured by immunochemoluminescent assays employing commercial kits (Diagnostic Products Corporation).

Statistical analysis

All continuous data were expressed as the mean ± standard deviation. Data were analyzed with SPSS software (Statistical Package for the Social Sciences, version 11.0; SSPS, Chicago, IL). Statistical comparisons were performed by means of independent-samples t-tests for data with a normal distribution and χ ²-tests for percentages. Continuous variables with non-normal distribution were expressed as median (interquartile range), and analyzed by Mann–Whitney U-test. Categorical variables were expressed as percent, and analyzed by Pearson's χ ²-test or Fisher exact test, where appropriate. A p-value of < 0.05 was considered significant.

Results

The demographic, laboratory, and US features of two study groups are summarized in Table 1. The female–male distribution in the two groups was significantly different; 89.6% of the patients in HT group and 78.4% of patients in control group were women (p = 0.001). Mean TSH levels were significantly higher in HT group. In HT group, 30.5% of patients had positive anti-TPO alone, 19.5% had anti-Tg alone, and 50% had positive anti-TPO and anti-Tg. Distribution and a comparison of gray scale and Doppler US features of the nodules in the study groups are also depicted in Table 1.

Table 1.

Demographic, Laboratory, and Ultrasonographic Features of the Study Groups

	Hashimoto group	Control group	p-Value
Case number (female/male)^a	164 (147/17)	551 (432/119)	0.001
Age, mean ± SD^b	53.4 ± 12.4	52.3 ± 13.0	>0.05
sTSH (mIU/mL), median (IQR)^c	1.5 (2.2)	0.9 (1.0)	<0.001
Nodule number	191	713
Single/multinodularity
Uninodular (%)	28.3	25.6	>0.05
Multinodular (%)^a	71.7	74.4
Maximum nodule size (mm), median (IQR)^c	15 (10)	17 (11)	0.032
Nodule echogenicity, n (%)^a
Hyperechoic	24 (12.5)	71 (10.0)	>0.05
Isoechoic	126 (66.0)	459 (64.4)
Hypoechoic	41 (21.5)	183 (25.6)
Nodule structure, n (%)^a
Predominantly solid	168 (88)	623 (87.4)	>0.05
Predominantly cystic	23 (12)	90 (12.6)
Calcification, n (%)^a
Absent	110 (57.6)	332 (46.6)	0.002
Microcalcification	23 (12.0)	157 (22.0)
Coarse	58 (30.4)	224 (31.4)
Doppler features, n (%)^a
Type 1	49 (25.7)	163 (22.8)	>0.05
Type 2	132 (69.1)	494 (69.3)
Type 3	10 (5.2)	56 (7.9)
Irregular margin, n (%)^a
Absent	169 (88.5)	620 (87.0)	>0.05
Present	22 (11.5)	93 (13.0)
Peripheral halo, n (%)^a
Absent	38 (19.9)	253 (35.5)	<0.001
Present	153 (80.1)	460 (64.5)

χ ²-test.

t-test.

Mann–Whitney U-test.

SD, standard deviation; sTSH, sensitive thyroid-stimulating hormone; IQR, interquartile range.

A total of 191 nodules in 164 HT cases and 713 nodules in 551 euthyroid control cases were included. Maximum nodule size was slightly higher in the control group at a significance level (15 mm vs. 17 mm, p = 0.032). No difference was determined between the two groups as far as single/multinodularity, nodule echogenicity, Doppler features, and margin irregularity were concerned. Microcalcifications existed significantly more often in the control group than in the HT group (p = 0.002). Peripheral halo was determined to be presenting significantly more frequently around the nodules of the HT group (p < 0.001). FNAC results are depicted in Table 2. Percent distribution among four groups of cytological results revealed no difference between the two study groups. The malignancy rate of the nodules in HT group was 1.0%, and that of the nonautoimmune control group was 2.7%, which was not significant. One patient had overt hypothyroidism and the other had subclinical hypothyroidism receiving L-thyroxine therapy. The two cytologically malignant cases in HT group were papillary thyroid carcinoma after the pathological examination of thyroidectomy specimens. Sonographically, those two malignant nodules were hypoechoic and exhibited microcalcifications and irregular margins and intranodular blood flow on Doppler examination. The six patients with indeterminate cytology results in HT group were benign on histopathological assessment. The repeat FNACs of nondiagnostic nodules were benign.

Table 2.

Distribution of Nodules in Each Group According to Fine-Needle Aspiration Cytology Results

	Hashimoto group (n = 191)	Control group (n = 713)	p-Value
Nondiagnostic, n (%)	6 (3.1)	22 (3.1)
Malignant, n (%)	2 (1.0)	19 (2.7)
Indeterminate, n (%)	6 (3.1)	45 (6.3)	>0.05
Benign, n (%)	177 (92.8)	627 (87.9)

Results were determined using χ ²-test.

Discussion

Thyroid nodules develop in patients with and without HT. On the basis of some publications, it is not clear if the rate of malignancy in thyroid nodules is greater in patients with HT than in those without HT (1,2). Since Dailey et al. (3) reported that the risk of malignancy was greater in patients with thyroid nodules who had thyroidectomy if they also had HT, numerous retrospective studies have been performed to clarify the relationship between HT and thyroid carcinoma (4 –14,19,20). This was confirmed in many, but not all, retrospective studies (4,6,7,9,10,12 –14).

In our prospective study, patients with thyroid nodules associated with HT and euthyroid controls with thyroid nodules without HT were evaluated during the same study period. As expected, the percentage of women in the HT group was significantly greater than that in the group without HT. Although there has been an impression that the US evaluation of thyroid nodules is more difficult in patients with HT, we noted similar US features of structure and echogenicity in our control and HT groups. Because of the relatively small numbers of thyroid cancers diagnosed, we cannot comment on whether concomitant HT influences the US features of thyroid malignancy.

The important finding of this prospective study is that the rate of malignancy, at least as ascertained by FNAC, was similar in thyroid nodule patients with and without HT. In fact it was lower, though not significantly lower, in HT patients compared to patients without HT (1.0% and 2.7%, respectively). Prospective studies of this nature are few. Crile et al., however, did not diagnose a single case of malignancy during their 3000 patient-years observation of 373 HT cases (5). In this study, the percent of patients who had thyroid nodules was not specified. In another prospective study, HT cases (46.4% of patients had thyroid nodules) were followed for more than 10 years and the incidence of malignancy was found to be 6.3% (11). Both studies had no control group. The authors have concluded that this rate was not higher than the incidence for thyroid cancer among thyroid nodules in the population.

In retrospective studies, the rates of malignancy in thyroid nodules in patients having HT ranged from 0.5% to 53%; in many (2,6,9,12 –14,16,19), but not all (17,21,22), the rate of malignancy in thyroid nodules was considered to be higher if there was concomitant HT than if there was not HT. One factor that may explain the high incidence of carcinoma in these retrospective studies is that many focused on patients who were surgically treated. The majority of patients who are sent to thyroid surgery have at least one feature placing them at high risk for malignancy.

A possible limitation of our study was that only 4.9% of our HT group and 10% of our control group had thyroidectomy for their thyroid nodule(s). Therefore malignant nodules may have been missed, but it seems unlikely that the proportion that were missed would be greatly different in the two groups. Certainly, it is likely that those that were missed were less clinically relevant that the ones that had FNAC and ultrasound features suggestive of malignancy. This is important because of the very high frequency of incidental thyroid cancer in autopsy and other series (23 –27).

Data about the association of HT and thyroid cancer based on FNAC results are limited and not always controlled. To the best of our knowledge, only three retrospective studies assessed the association between thyroid autoimmunity and thyroid cancer (16 –18). Erdogan et al. retrospectively evaluated FNAC results in patients with HT. In their study, FNAC of the nodules had been performed in 207 patients (198 women and 9 men), and none of those biopsies were diagnosed as malignant. After surgery for suspicious cytology, they found that 2% (n = 4) of all patients with HT had a final diagnosis of papillary carcinoma (17). Carson et al. reviewed the data about FNAC results from 90 patients with HT. Only two patients (2.2%) were thought to have papillary thyroid carcinoma (18). Boi et al. (16), in contrast to the prior two studies, did perform a study with controls though it was retrospective. In this study, US-guided FNACs were obtained from 590 unselected consecutive patients with single thyroid nodules (anti-thyroid antibody positive [n = 197] and anti-thyroid antibody negative [n = 393]). A higher prevalence of indeterminate cytology (28.9% vs. 21.4%, p < 0.05) and suspected or malignant cytology (18.8% vs. 9.2%, p < 0.001) were found in anti-thyroid antibody–positive group compared to anti-thyroid antibody–negative group. On the basis of FNAC results, thyroidectomy was carried out in 106 patients. Histologically proven thyroid cancer was observed in a higher proportion of anti-thyroid antibody–positive nodules (13.7%) compared to anti-thyroid antibody–negative nodules (8.4%) (p = 0.044). Notably, 47.7% and 30.6% of thyroid nodules (including indeterminate and suspicious/malignant cytologies) in anti-thyroid antibody–positive group and anti-thyroid antibody–negative group, respectively, had a clear indication for thyroidectomy. These percentages are quite high with almost half of the nodular thyroid glands in patients with thyroid autoimmunity requiring thyroid surgery. This is not consistent with our study nor does it seem consistent with routine clinical experience. The reason for this is not clear, but it should be noted that the criteria for selection of patients with thyroid nodules for FNAC were not specified in the study of Boi et al. (16).

The usefulness of US features in selecting lesions for FNAC is well known. It may be challenging to differentiate asymmetric involvement of the thyroid by HT from a discrete thyroid nodule since identification of these qualitative ultrasound features is highly operator dependent. In our study, all three-dimensional discrete lesions within the thyroid gland that were ultrasonographically distinct from the surrounding thyroid parenchyma were considered as a nodule. Regarding US features in our study, there was no difference between the two groups in respect to single/multinodularity, nodule echogenicity, and structure. Our study design and ability to perform US maximized the homogeneity of study groups and the comparability of the findings.

In summary, we found that the rate of malignancy in thyroid nodules is similar in patients with or without HT. On the basis of our findings, we do not advocate a more aggressive role for surgical intervention for patients with HT.

Footnotes

Acknowledgment

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Disclosure Statement

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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