Thyroid Nodules as a Risk Factor for Thyroid Cancer in Patients With Graves' Disease

A Systematic Review and Meta-Analysis of Observational Studies in Surgically Treated Patients

Anastasios Papanastasiou; Konstantinos Sapalidis; Dimitrios G. Goulis; Nikolaos Michalopoulos; Evangelia Mareti; Stylianos Mantalovas; Isaak Kesisoglou


Clin Endocrinol. 2019;91(4):571-577. 

In This Article

Abstract and Introduction


Objective: Graves' disease (GD) is an autoimmune thyroid disorder characterized by hyperthyroidism. The incidence of thyroid cancer in patients with GD varies from 0.15% to 15%. There is conflicting evidence on the role of thyroid nodules as a risk factor for thyroid cancer in patients with GD.

Design: Three electronic databases (PubMed, Cochrane Library, Scopus) as well as grey literature sources were searched, from inception until 25 February 2019, for observational studies about the prevalence of thyroid cancer in patients with GD.

Patients: Clinical and ultrasonographic examination was necessary preoperatively for all patients to be classified depending on the presence/absence of thyroid nodules.

Measurements: Primary outcome was the incidence of thyroid cancer. The latter was determined after total or near-total thyroidectomy by the histopathologic report. Statistical analysis was performed with REVMAN 5.3 software.

Results: The systematic review and meta-analysis included 7 studies with 2582 patients overall. The prevalence of any thyroid cancer was 11.5%. The presence of at least one thyroid nodule in patients with GD was associated with higher risk for thyroid cancer (odds ratio [OR] 5.3, 95% confidence interval [CI] 2.4-11.6, I 2 83%). A subgroup analysis showed no difference in thyroid cancer risk in patients with GD according to the number of nodules (solitary versus multiple) (OR 1.4, 95% CI 0.9-2.3, I 2 0%).

Conclusions: The presence of thyroid nodules is positively associated with the prevalence of thyroid cancer in surgically treated patients with GD. However, further prospective research is needed as the heterogeneity among the studies is high.


Graves' disease (GD) is an autoimmune disorder, constituting the most common cause of hyperthyroidism. Although its causes are not clear, GD has been associated with genetic and environmental factors. Its annual incidence is 20-50 per 100 000 people. The diagnosis of GD is set more often in people between 30 and 50 years old. Women have a sixfold higher risk to develop GD compared with men.[1]

The presence of one (solitary) or more (multiple) thyroid nodules is a frequent finding in patients with thyroid disorders. The widespread use of ultrasonography in the screening of thyroid disorders has increased the incidence of detected thyroid nodules.[2] An increased risk of thyroid cancer has been reported in patients with thyroid nodules.[3]

It was previously thought that disorders characterized by hyperthyroidism, such as GD, were protective against thyroid cancer (0.15%-2.5%). However, recent studies demonstrate an increased prevalence of thyroid cancer in patients with GD (2.6%-15%).[4] In addition, the natural history of thyroid cancer in patients with GD is controversial: some studies report a higher rate of lymph node metastasis and mortality,[3,5] while others report the contrary.[6]

The current systematic review and meta-analysis aimed to investigate if the presence of thyroid nodules in patients with GD is associated with a higher risk of thyroid cancer. The confirmation of such an association would have profound clinical implications for the diagnosis and treatment of thyroid cancer.