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

Abstract and Introduction


Context: The impact of Hashimoto thyroiditis (HT) on the risk of thyroid cancer and its accurate detection remains unclear. The presence of a chronic lymphocytic infiltration imparts a logical mechanism potentially altering neoplastic transformation, while also influencing the accuracy of diagnostic evaluation.

Methods: We performed a prospective, cohort analysis of 9851 consecutive patients with 21,397 nodules ≥1 cm who underwent nodule evaluation between 1995 and 2017. The definition of HT included (i) elevated thyroid peroxidase antibody (TPOAb) level and/or (ii) findings of diffuse heterogeneity on ultrasound, and/or (iii) the finding of diffuse lymphocytic thyroiditis on histopathology. The impact of HT on the distribution of cytology and, ultimately, on malignancy risk was determined.

Results: A total of 2651 patients (27%) were diagnosed with HT, and 3895 HT nodules and 10,168 non-HT nodules were biopsied. The prevalence of indeterminate and malignant cytology was higher in the HT vs non-HT group (indeterminate: 26.3% vs 21.8%, respectively, P < 0.001; malignant: 10.0% vs 6.4%, respectively, P < 0.001). Ultimately, the risk of any nodule proving malignant was significantly elevated in the setting of HT (relative risk, 1.6; 95% CI, 1.44 to 1.79; P < 0.001), and was maintained when patients with solitary or multiple nodules were analyzed separately (HT vs non-HT: 24.5% vs 16.3% solitary; 22.1% vs 15.4% multinodular; P < 0.01).

Conclusion: HT increases the risk of thyroid malignancy in any patient presenting for nodule evaluation. Diffuse sonographic heterogeneity and/or TPOAb positivity should be used for risk assessment at time of evaluation.


Hashimoto thyroiditis (HT) is the most common autoimmune disease and the most frequent cause of hypothyroidism, affecting between 2% and 15% of the global population, depending on their age.[1–4] The pathogenesis of HT involves a chronic inflammatory infiltrate in the thyroid gland as a consequence of a breakdown in immune tolerance. This leads to activation of cellular and humoral immune responses.[5] Histologically, HT is characterized by diffuse lymphocytic infiltration of the gland, with numerous lymphoid follicles and germinal centers, fibrosis, and, ultimately, parenchymal atrophy.[6,7] Genetic and environmental factors, such as dietary iodine uptake, have been shown to contribute to the development of HT.[8]

In 1893, Rudolf Virchow first proposed an association between chronic inflammation and the formation of cancer. Over the ensuing century, this hypothesis has been verified through our understanding of a multitude of human illnesses. Classic examples of this adverse effect of inflammation on malignancy risk include the predisposition of patients with ulcerative colitis to adenocarcinoma of the colon and the impact of chronic hepatitis on development of hepatocellular carcinoma.[9,10]

Given the well-established cause-and-effect relationship between chronic inflammation and risk of malignancy, it has long been postulated that HT, a chronic thyroid inflammatory disease, would also be associated with an increased risk of thyroid cancer. Although numerous studies have since investigated this hypothesis, nearly all have been confounded by substantial selection bias, imprecise metrics, and/or retrospective analysis.[11–16] For these reasons, the association between HT and papillary thyroid cancer continues to remain controversial. To date, no large, unbiased, and prospective analysis has been performed to examine this important question, to our knowledge.

By definition, HT is a histological diagnosis. However, it is clinically impractical to necessitate surgical intervention when other means of preoperative diagnosis have proven highly predictive of the disease. These include the presence of antibodies to thyroid peroxidase (TPOAbs), as well as the identification of a diffusely heterogeneous parenchyma upon sonographic imaging of the gland.[17] It follows, therefore, that all three means of identifying HT (i.e., histopathologic, biologic, and sonographic) should be applied to any investigation seeking the broadest inclusion of patients with evidence of inflammation.

Thus, using a large, prospectively tracked database of consecutive patients seen for nodule evaluation, we evaluated the association between HT and thyroid cancer. Separately, we also sought to determine the impact of HT on diagnostic nodule evaluation, specifically on the distribution of preoperative cytology.