Prevalence of Malignant Tumors and Adenomatous Lesions Detected by Ultrasonographic Screening in Patients with Autoimmune Thyroid Diseases

Abstract

Background:

Thyroid ultrasonography (US) is the most sensitive method for detecting thyroid nodules, and US-guided aspiration biopsy is the most accurate diagnostic procedure for thyroid nodules. We performed this retrospective study to establish the prevalence of thyroid nodules in Graves' disease and patients with Hashimoto's thyroiditis at the time of their initial visit.

Methods:

We performed thyroid US as routine screening in 1652 patients with Graves' disease and 2036 Hashimoto's thyroiditis and performed US-guided fine-needle aspiration biopsy when the diameter of a nodule >1 cm or a nodule was suspected of being malignant.

Results:

The prevalence of papillary carcinoma in the patients with Hashimoto's thyroiditis was higher than in the patients with Graves' disease (1.77% vs. 0.97%), and two patients with Hashimoto's thyroiditis (0.098%) were found to have malignant lymphoma. Adenomatous lesions were observed more frequently in the patients with Hashimoto's thyroiditis than in the patients with Graves' disease. The prevalence of adenomatous lesions increased in an age-dependent manner in both the patients with Graves' disease and those with Hashimoto disease; and adenomatous lesions were more frequent in younger patients with Hashimoto’ s thyroiditis than in those with Graves' disease.

Conclusions:

The prevalence of both thyroid papillary cancer and adenomatous lesions was greater in the patients with Hashimoto's thyroiditis than in those with Graves' disease; and adenomatous lesions were more frequent in younger patients with Hashimoto's thyroiditis. We recommend performing US at the time of the initial visit in patients with autoimmune thyroid disease, who have a high prevalence of thyroid papillary carcinoma, to detect malignant thyroid tumors and adenomatous lesions.

Introduction

T hyroid nodules constitute a common clinical problem in the general population. The prevalence of palpable nodules in iodine-sufficient areas has been found to be between 3.2% and 21% (1). Epidemiological studies of general populations by ultrasonography (US) have found prevalences of thyroid nodules ranging from 25% to 67% owing to the much greater sensitivity of US than palpation (1,2), and the prevalence of such nodules increases with age (3). Since increasing numbers of patients undergo imaging studies for medical evaluations, more thyroid nodules are being detected.

The prevalence of thyroid nodules by US in Graves' disease has been reported to be 33.6% (4), at least twice their prevalence in the general population. The authors also reported that most of the nodules actually developed during the course of their study, suggesting an association between Graves' disease and nodule development (4). Moreover, the reported prevalence of malignant thyroid tumors in Graves' disease has varied widely (4), and the prevalence of thyroid nodules in Hashimoto's thyroiditis is not well known in Japan, which is known to be an iodine-sufficient country.

Adenomatous lesions are benign changes characterized by the presence of hyperplasia and various pathological changes such as cyst formation, necrosis, hemorrhage, and calcification. The formation of adenomatous lesions may be caused by iodine deficiency, dietary goitrogens, and inherited defects in thyroid hormone synthesis; and their most common cause is iodine deficiency. However, the prevalence of adenomatous lesions in patients with Graves' disease and Hashimoto's thyroiditis in Japan has never been thoroughly investigated.

Since thyroid US is the most sensitive method for detecting thyroid nodules (5,6), US-guided cytological examinations have greater diagnostic accuracy than palpation (7). Although the diagnostic accuracy of fine-needle aspiration biopsy of thyroid nodules is greater than that of ultrasonographic diagnosis (8), thyroid US has been accepted as useful, including for identification of nonpalpable nodules and for determination of the size of thyroid nodules during follow up. Its noninvasiveness and instant availability are major benefits for evaluation of nodular thyroid disease.

We performed this retrospective study to establish the prevalence of thyroid tumors and adenomatous lesions in patients with Graves' disease and in those with Hashimoto's thyroiditis during routine screening by US at the patients' initial visit.

Patients and Methods

Patients

We enrolled 1652 patients with Graves' disease and 2036 patients with Hashimoto's thyroiditis who came to Ito Hospital for the first time between January 5, 2006 and December 29, 2006 in this study. Subjects with a history of earlier treatment for thyroid diseases, neck irradiation, or neck surgery were excluded from this study. A diagnosis of Graves' disease was made when a patient was found to have diffuse goiter and increased iodine uptake by thyroid scintigraphy and/or a positive serum thyrotropin (TSH)-binding inhibitor immunoglobulin (TBII) value. A diagnosis of Hashimoto's thyroiditis was made when a patient was found to have a diffuse goiter, euthyroidism, or hypothyroidism and to be positive for anti-thyroglobulin (TgAb) and/or anti-thyroid peroxidase antibody (TPOAb). This study was approved by the ethics committee of our institution, and we obtained informed consent with document from all the patients.

Assays

All patients underwent a physical examination that included thyroid palpation, blood sampling, and evaluation of their serum-free triiodothyronine (fT3), free thyroxine (fT4), TSH, TBII, TgAb, and TPOAb levels. TSH, fT3, and fT4 were measured by chemiluminescence assay (Eclusis TSH, Eclusis fT3, and Eclusis fT4; Roche Diagnostics, Tokyo, Japan), and their normal ranges at our hospital are TSH, 0.2–4.5 mU/L; fT3, 3.37–6.58 pmol/L; and fT4, 10.3–20.6 pmol/L. TBII was measured by radioimmunoassay (TRAb Cosmic III; Cosmic Corp., Tokyo, Japan), and a TBII value >10% was considered positive. TgAb and TPOAb were measured by radioimmunoassay (TgAb Cosmic and TPOAb Cosmic; Cosmic Corp.), and a serum concentration of TgAb and TPOAb >2.6 and 6.7 U/mL, respectively, was considered positive.

Imaging and aspiration biopsy

During their initial visit, the patients also underwent thyroid US with a Voluson730 machine (GE Health Care, Tokyo, Japan) having 7- to 15-MHz linear transducers that was performed by trained technicians and whose results were interpreted by radiologists. Echo structure (solid, cystic, or mixed), echogenicity (hyperechoic, isoechoic, hypoechoic, or mixed), calcification (punctuate, coarse, egg-shell, or absent), and the characteristics of nodule margins (well-defined or ill-defined) were assessed according to the criteria described elsewhere (9). If the patients were suspected of having a malignant thyroid tumor based on the criteria, the nodule was evaluated by US-guided fine-needle aspiration biopsy (USGFNAB).

USGFNAB was performed with a 23-gauge needle attached to a 10 mL syringe. Ultrasonographic guidance was used to confirm the placement of the needle in the nodule. At least two passes were made per nodule. Specimens were immediately smeared on slides, fixed in 95% ethanol, and stained. Cytodiagnosis was performed by experienced pathologists, and all patients diagnosed as having evidence of a malignancy were referred for surgery.

Statistical analysis

Age, TSH, and TBII are shown as the median and range. Differences between the frequency of thyroid nodules were analyzed by the chi-square test. Comparisons of continuous variables were made by using Student's t-test for TBII and Wilcoxon's test for other variables. A p-value <0.05 was considered statistically significant. The statistical analyses were performed by using JMP programs for Windows (SAS Institute, Cary, NC).

Results

Characteristics of the thyroid nodules detected by US and the patients' clinical parameters

The characteristics of the patients in each group are shown in Table 1. Thyroid nodules were detected by US in 294 of the patients with Graves' disease (17.8%) and in 634 of the patients with Hashimoto disease (31.1%). The prevalence of nodules detected by US was significantly higher in the female patients than in the male patients with both Hashimoto's thyroiditis (31.9% vs. 22.4%, p = 0.009) and Graves' disease (19.3% vs. 11.5%, p = 0.001). In the Graves' disease group, the TBII value was significantly lower in the patients with a nodule than in the patients without a nodule (Table 1). In the Hashimoto's thyroiditis group, the TSH level was significantly higher in the patients without adenomatous lesions than in those with adenomatous lesions (p < 0.001).

Table 1.

Existence of Nodules and Patient Characteristics at Initial Visit

	Graves' disease (n = 1652)		Hashimoto's thyroiditis (n = 2036)
Nodule	+	−	+	−
N	294	1358	634	1402
M/F	37/257^a	285/1073	36/598^b	125/1277
Age (years old)	49.0 ± 15.1^c	37.9 ± 13.2	51.3 ± 14.7^d	43.1 ± 15.7
TSH (μU/L)	n.a.	n.a.	7.12 ± 22.3^e	14.6 ± 40.8
TBII (%)	53.0 ± 25.4^f	60.8 ± 23.5	n.a.	n.a.

Data are expressed as the mean ± standard deviation.

p = 0.009 versus nodule without Graves' disease.

p = 0.009 versus nodule without Hashimoto disease.

p < 0.0001 versus nodule without Graves' disease.

p < 0.0001 versus nodule without Hashimoto disease.

p < 0.0001 versus nodule without Graves' disease.

n.a., not accessible; TBII, thyrotropin-binding inhibitor immunoglobulin; TSH, thyrotropin.

Cytological and histological evaluation of malignant tumors

USGFNAB was performed in 50 of the 294 patients with Graves' disease with a thyroid nodule, and 17 had a malignant tumor (papillary carcinoma in 16, and follicular carcinoma in 1, Table 2). Of the 634 patients with Hashimoto's thyroiditis with a thyroid nodule, 177 were suspected of having a malignant tumor based on the screening echography findings and they underwent USGFNAB. In the Hashimoto's thyroiditis group, 579 patients had an adenomatous lesion and 38 patients had a malignant tumor. There were no major complications of USGFNAB.

Table 2.

Details of Thyroid Nodules in Patients with Graves' Disease and Hashimoto's Thyroiditis

	Graves' disease	Hashimoto's thyroiditis
Adenomatous lesion	273 (16.5%)	579 (28.4%)
Papillary carcinoma	16 (0.97%)	36 (1.77%)
Follicular carcinoma	1	0
Follicular adenoma	4	15
Malignant lymphoma	0	2

All of the patients who underwent surgery due to suspicion of papillary carcinoma (n = 52) were diagnosed with papillary carcinoma; and prevalence of histologically proved thyroid papillary carcinoma was 0.97% in the patients with Graves' disease and 1.77% in the patients with Hashimoto's thyroiditis at the time of the initial visit (Table 2).

The prevalence of malignant lymphoma was 0.098% in the patients with Hashimoto's thyroiditis, and no patients with Graves' disease had thyroid malignant lymphoma.

Prevalence of adenomatous lesion in patients with Graves' disease and Hashimoto's thyroiditis

The prevalence of adenomatous lesions increased in an age-dependent manner in both the Graves' disease group and the Hashimoto's thyroiditis patients group; and the prevalence of adenomatous lesions was greater in Hashimoto's thyroiditis than in Graves' disease, especially in the younger population (Fig. 1).

FIG. 1.

Prevalence of adenomatous lesion in patients with Graves' disease and Hashimoto's thyroiditis. The prevalence of adenomatous lesions increased in an age-dependent manner in both groups, and the prevalence of adenomatous lesions was greater in patients with Hashimoto's thyroiditis than in the younger population.

Discussion

The aim of this study was to determine the prevalence of thyroid nodules in patients with Graves' disease and Hashimoto's thyroiditis by US. All of the patients underwent thyroid US to detect nodules, and bias due to patient selection seems to have been negligible.

Thyroid cancer is relatively uncommon in the general population, accounting for <2% of all cancers, with an annual incidence of 2.0–3.8 per 100,000 women and 1.2–2.6 per 100,000 men (10). The prevalence of thyroid cancer in Graves' disease remains a matter of controversy despite being thoroughly investigated over the past several decades. A large part of the controversy stems from the widely disparate results of the various studies on the subject, many of which have been confounded by ascertainment bias. The reported frequency of thyroid cancer in Graves' disease has ranged from 0% to 9.8% (4,11,12), and the wide range is attributable to a variety of reasons. Maruchi et al. reported a prevalence of thyroid cancer of 1.3 per 1000 subjects examined based on their population surveys in a nonendemic region of Japan (13).

Some investigators have reported that the prevalence of thyroid nodules and cancers in patients with Graves'disease is higher than in the general population (4,14,15), and their reports are consistent with the results of our study. In this study, the prevalence of papillary cancer was higher in the patients with Hashimoto's thyroiditis than in the patients with Graves' disease.

Recommendations for USGFNAB have been limited to patients with incidentally detected impalpable thyroid nodules on examination, and we performed the aspiration cytology only when the patients were suspected of having a malignant tumor or the diameter of a nodule was >1 cm, and that may have caused subclinical thyroid malignancies to be missed. However, the American Association of Clinical Endocrinologists has recommended fine-needle aspiration of all thyroid nodules, in which the possibility of malignancy is appreciable; and Shimura et al. reported a high sensitivity and specificity of the ultrasonographic criteria for detection of papillary carcinoma (9), which we used to make the diagnosis.

The best way to screen for thyroid nodules in patients with Graves' disease and Hashimoto's thyroiditis has been discussed. Palpation by an experienced endocrinologist is frequently cited as adequate to detect any sizeable, clinically important thyroid cancer, but the sensitivity of thyroid palpation is quite poor. Although many authors have demonstrated the high sensitivity of ultrasound, it can yield a very high percentage of smaller nodules of less clinical significance. To avoid increasing false-negative pathology results, we applied the ultrasonographic criteria suggested in a multicenter study (9), and USGFNAB was performed if a nodule was suspected of being malignant based on the criteria.

In this study, the prevalence of adenomatous lesions was significantly higher in women than in men. This evidence is being reported, although the reason for it is poorly understood. One possible pathogenesis is a direct impact of sex steroid hormones. Higher estrogen receptor expression has been reported in adenomatous lesions and papillary cancer than in the normal thyroid (16), and a growth-promoting effect of estrogen has been described in vitro in rat FRTL-5 cells and thyroid cancer cell lines as a possible contributing factor (17,18).

The prevalence of adenomatous lesions in the patients with Hashimoto's thyroiditis was higher than in the patients with Graves' disease, and this study is the first to report such a finding. In this study, there was little difference between the prevalence of adenomatous lesions in the patients with Hashimoto's thyroiditis and Graves' disease over 60 years of age; and this finding may support the effect of estrogen, although further study is needed. Recently, Rajoria et al. have provided evidence that the metastatic phenotype is regulated by estrogen in thyroid cells (19).

In areas of iodine deficiency with a high prevalence of goiter, many prepubertal children have diffuse goiters, although the goiters sometimes regress in early adolescence. In areas with a lower prevalence of goiter, goitrogenesis usually starts at an older age. In a cross-sectional study of patients with nontoxic goiter, evidence of thyroid growth and nodule formation with age was found (20). However, epidemiological studies of adenomatous lesions have focused on middle-aged women and the elderly, and only a few have documented the prevalence of adenomatous lesions in a population-based manner (21). In the present study, we found that the average age of the patients in the Hashimoto's thyroiditis group was higher than in the Graves' disease group; but adenomatous lesions were more common among the younger patients in the Hashimoto's thyroiditis group than in the Graves' disease group, even though iodine intake is rather high in Japan. The pathogenesis of adenomatous lesions in Hashimoto's thyroiditis may be different from their pathogenesis in Graves' disease, and the reason for these findings is unknown and requires further study.

TSH is the main extrathyroidal thyroid growth-stimulatory factor (22), and TSH stimulation may play an important role in the pathogenesis of adenomatous lesions. However, in this study, the TSH level of the Hashimoto's thyroiditis group without adenomatous lesions was significantly higher than in those with adenomatous lesions. These findings suggest that other thyroid growth-stimulatory factors, such as insulin-like growth factor-1 (23) and fibroblast growth factor (24), may be involved in the development of adenomatous lesions in young patients with Hashimoto's thyroiditis.

In conclusion, the prevalences of thyroid papillary cancer and adenomatous lesions were greater in the patients with Hashimoto's thyroiditis than in the patients with Graves' disease; and adenomatous lesions were more frequent in younger patients with Hashimoto's thyroiditis. If a patient with an autoimmune thyroid disease is found to have a diffuse goiter by palpation during the initial visit, US is recommended to detect a malignant tumor and adenomatous lesions.

Disclosure Statement

The authors declare that no competing financial interests exist.

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