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


The impact of coexistent HT on the risk of developing thyroid cancer has been unclear. Building on a sound hypothesis and extensive preliminary data, we performed a large, prospective cohort analysis investigating this question. Using a highly translatable and broad clinical definition of HT, our data confirm a 45% increased risk that a clinically relevant thyroid nodule will prove malignant when in the presence of this chronic inflammatory process. The risk of a nodule being cancerous in the setting of HT was nearly one in four, substantially higher than in patients without the disease. Furthermore, the diagnostic evaluation of thyroid nodules is affected by the presence of HT, even when the nodule is nonmalignant, and a significantly higher risk of indeterminate cytology should be expected. Together, these data provide evidence that HT can be viewed as a risk factor for the development of thyroid cancer. Easily obtainable variables, such as measurement of TPOAb levels and/or identification of a diffusely heterogeneous parenchyma on ultrasound, should be sought at the time of initial thyroid nodule evaluation. The large-scale, prospective nature of this 20-year cohort analysis supports the translatability and durability of these findings, though multivariate analysis is required to better understand if this risk factor remains independent of other variables.

We used the broadest and most practical definition of HT. This proved important to our study, because histopathology alone remains an impractical end point. Patients recommended for surgery typically represent a highly selected group, and routine thyroidectomy of all patients in any study would be deemed unacceptable. The association of an elevated TPOAb level with HT is well established. Furthermore, a diffuse heterogeneous parenchyma on sonographic imaging is highly suggestive of a diffuse inflammatory process, most notable HT.[21] Others have similarly used broad-based, holistic diagnostic criteria for HT, such as in our study.[17,22]

Together, one or more of these findings confirming HT was present in 27% of our population. Although many population estimates of HT (typically using only TPOAb measurement to identify HT) are lower,[4,23,24] we note that our study cohort was unique. Our population of 9851 consecutive patients were all being evaluated for clinically relevant thyroid nodules. As expected in such a cohort, most were women, and the mean age was older than 52 years. Together, such a group would be expected to have a higher rate of autoimmune thyroid disease than a broad epidemiologic sampling. It is also well documented that a hypoechoic sonographic pattern or irregular echogenic parenchyma may precede TPOAb positivity in autoimmune thyroid disease and thus may not be detected in up to 20% of individuals with HT.[25] Furthermore, our data indicate a higher rate of cancer among patients with HT and known nodules. Stemming from this, it is equally plausible that HT itself may predispose to nodule formation. If so, a much higher rate of HT would be expected in any nodule population subsequently studied. In support of our methodology, we note a separate postmortem histopathologic thyroid analysis on thyroid disease–free individuals that detected evidence of chronic autoimmune thyroiditis in 27% of adult women, a percentage strikingly similar to our findings.[1]

Notable to our study were several findings. First, the increased risk of cancer attributable to HT was detected in those with solitary nodules as well as in nodules that were part of a multinodular gland. This supports the rationale that inflammation imparts a field effect through the gland itself. Second, the type, size, and aggressiveness of the cancer detected did not differ from those with or without HT. Thus, although malignant transformation or formation appears affected by HT, papillary thyroid carcinoma (by far the most common cancer subtype) remains generally low risk and indolent. Finally, although an increased RR of thyroid lymphoma has long been associated with the presence of HT, our data speak to an increase in well-differentiated thyroid cancer, and lymphoma is most certainly not responsible for the full increase in RR of malignancy as a whole.

There has been an increase worldwide in differentiated thyroid cancer. According to the Surveillance, Epidemiology, and End Results database, the number of new cases of thyroid cancer was 14.5 per 100,000 men and women per year during the period of 2011 to 2015.[26] Enhanced thyroid nodule detection has been implicated in this but appears to not fully explain this increase. The concomitant increase in the incidence of HT worldwide (perhaps following iodine supplementation) presents another plausible explanation and reinforces the concept that thyroid chronic inflammation may lead to neoplastic processes.[1,5]

The impact of HT on nodule diagnostic evaluation is also perhaps not surprising. HT may result in reactive atypia that mimics papillary thyroid cancer, such as increased nuclear size and nuclear contour irregularities and grooves, which can result in an indeterminate diagnosis of FNA samples.[27] Also, the differentiation between follicular neoplasms and HT can be difficult because some cytological features, such as hyperplastic follicular cells and Hürthle cells, are encountered in both scenarios.[28] Studies have attempted to link the presence of HT to FNA accuracy, with conflicting results. HT is related to a higher rate of false-negative and false-positive FNA results.[27,29] Others have demonstrated that the presence of HT significantly decreased the accuracy and increased the indeterminate rate of cytological results of ultrasound-FNA in subcentimeter nodules,[30] though data are variable.[31]

We acknowledge limitations to our investigation. First, we studied only those patients with at least one thyroid nodule >1 cm; thus, our findings are not generalizable to a general population nor do they reflect epidemiologic data regarding HT or thyroid cancer in a broad population. Nonetheless, our data are translatable to the real-world clinical environment, allowing preoperative data such as TPOAb level or ultrasound appearance to inform individualized risk assessment during thyroid nodule care. Second, we did not measure TPOAb level in all patients; thus, we cannot assess the overlap of sonographic and serologic findings of HT. Third, ultrasound interpretation was performed by only a single expert radiologist for most patients. This precludes assessment of interrater variability, which is known to exist. And finally, different TPOAb assays were used over the course of 20 years, possibly introducing some variability in defining low-level positive results.

In conclusion, HT adversely affects the diagnostic evaluation of, and increases the risk of thyroid malignancy in, any patient being seen for nodule evaluation. The presence of a diffusely heterogeneous sonographic pattern or of TPOAb positivity may be used for thyroid malignancy risk assessment at the time of nodule evaluation. Future investigations should work to elucidate the relative impact of this finding in relation to other known risk factors such as age and sex.[32,33]