The Impact of Hashimoto Thyroiditis on Thyroid Nodule Cytology and Risk of Thyroid Cancer

Nathalie Silva de Morais; Jessica Stuart; Haixia Guan; Zhihong Wang; Edmund S. Cibas; Mary C. Frates; Carol B. Benson; Nancy L. Cho; Mathew A. Nehs; Caroline A. Alexander; Ellen Marqusee; Mathew I. Kim; Jochen H. Lorch; Justine A. Barletta; Trevor E. Angell; Erik K. Alexander


J Endo Soc. 2019;3(4):791-800. 

In This Article

Materials and Methods

We performed a prospective cohort analysis studying 10,054 consecutive adult patients (age ≥18 years) with thyroid nodules ≥1 cm who underwent nodule evaluation between 1995 and 2017 at the Brigham and Women's Hospital Thyroid Nodule Clinic.

All patients were referred for evaluation of a clinically relevant thyroid nodule and then underwent sonographic and clinical evaluation. Sonographic evaluation was performed by one of five radiologists with expertise in thyroid imaging, using a 5- to 17-mHz transducer. All thyroid nodules were evaluated as previously described,[18] and the background thyroid parenchyma was separately assessed. From the ultrasound report, HT was considered present if a diffusely heterogeneous parenchyma or the presence of HT was reported.[19] Clinical evaluation typically included a full medical history and physical examination, and assessment of serum TSH level. When the TSH level was elevated, or at the discretion of the clinician, measurement of serum TPOAbs was performed (n = 2551 patients). For the purposes of this study, a TPOAb test was considered positive when TPOAb level was elevated above the reference range at the time of blood sampling, as defined by the test manufacturer. For most patients in this study, one of three different assays was used over 20 years.

Thyroid nodules were treated per the clinical guidelines applicable to the time, typically performing fine-needle aspiration (FNA) on solid or partially cystic nodules ≥1 cm. FNA was performed by a thyroidologist under ultrasound guidance using a 25-gauge needle after local anesthesia was administered. Typically, three passes from different areas of the nodule constituted a single aspiration. Patients were submitted for surgery on the basis of abnormal cytologic findings concerning for, or supportive of, malignancy. Separately, a minority of patients had their thyroid surgically removed owing to large size, obstructive symptoms, or cosmetic reasons.

For each patient, age at the time of the first FNA and the total number of nodules ≥1 cm were documented. Aspiration specimens were processed using ThinPrep liquid-based cytology preparation (Hologic Corp., Marlborough, MA) and were examined by a cytopathologist with thyroid expertise. Although the period of study partially predates The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), cytologic classification through the entire study period uniformly used the same criteria and terminology later adopted by the TBSRTC.[20] Thyroid FNA cytology was reported as nondiagnostic, negative for malignant cells (benign), atypia of undetermined significance, suspicious for follicular or Hürthle cell neoplasm, suspicious for malignancy, or malignant. For patients with more than one nodule evaluated by ultrasound-guided FNA, the primary cytology was defined as the cytologic result that carried the highest risk of malignancy. Indeterminate cytology collective included those with atypia of undetermined significance, suspicious for follicular or Hürthle cell neoplasm, or suspicious for malignancy results. When a thyroidectomy was performed (n = 3186 patients), histopathologic data were also obtained, specifically documenting malignant or benign disease, as well as the histologic evidence of HT. A histologic diagnosis of HT was based on the presence of a diffuse lymphoplasmacytic infiltrate with germinal center formation, oncocytic change, and areas of atrophy or fibrosis.

To avoid selection bias while simultaneously applying the most translatable, real-world protocol, we used a holistic definition of HT that included (i) elevated TPOAb level, and/or (ii) findings of diffuse heterogeneity or HT on ultrasound, and/or (iii) diffuse lymphocytic thyroiditis on histopathology. The HT-negative population, therefore, included all other patients without a single positive finding. Given the decreased accuracy of ultrasound in assessing background thyroid parenchyma in the presence of extensive multinodularity, we excluded from our analysis those patients with more than six nodules each ≥1 cm. If sonographic reporting was unclear, images were reviewed by a blinded expert. Multinodularity was defined as two or more nodules each ≥1 cm. Incidental thyroid microcarcinoma (<1 cm) identified separately from the clinically relevant nodule(s) was not considered malignant nor was it included in our analysis.

Summary statistics are provided as mean ± SD for continuous, normally distributed variables; median with range and interquartile range for nonnormally distributed, continuous variables; or numbers and percentages for categorical variables. Comparisons were made using χ 2 or Fisher exact test for categorical variables and with the Student t or Mann-Whitney tests for continuous variables, according to the data distribution as evaluated by Kolmogorov-Smirnov test. For analysis, we calculated the relative risks (RRs), the 95% CIs, and the pooled effects. A two-sided Pvalue < 0.05 was considered significant. All calculations were performed using SPSS, version 25 (IBM, Armonk, NY). Permission for this study was granted by the Brigham and Women's Hospital institutional review board.