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

Disclosures

Clin Endocrinol. 2019;91(4):571-577.

Abstract and Introduction

Abstract

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.

Introduction

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.

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Next Section

Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Basic characteristics of the selected studies
First author	Year	Country	Mean age (years)	F/M ratio	Year of surgery	Scintigraphy	Malignant/suspicious FNAB (n)	Diagnosis of thyroid cancer	Lymph node metastasis (n)	Non-DTC (n)
Kraimps⁹	2000	France	N/A	N/A	1991–1997	All patients	0	21/557 (3.8%)	1	0
Erbil¹⁷	2007	Turkey	37 (27–47)	105/45	1996–2005	N/A	5	18/150 (12.0%)	N/A	0
Gul¹⁸	2009	Turkey	44.3 (30.6-58.0)	N/A	2005–2008	All patients	15	20/159 (12.6%)	1	1
Ren¹⁹	2013	China	34.9	336/87	2002–2012	N/A	0	58/423 (13.7%)	N/A	1
Ergin¹⁰	2014	USA	40 (30–53)	211/34	2005–2013	Not for all patients	0	66/226 (29.2%)	6	0
Tam²⁰	2014	Turkey	41.2 (28.8-53.6)	352/174	2006–2013	N/A	2	42/526 (8.0%)	3	0
Dirikoc²¹	2017	Turkey	45.4	364/177	2007–2014	All patients	N/A	72/541 (13.3%)	3	0

Abbreviations: DTC, Differentiated thyroid cancer; F/M, Females/Males; FNAB, Fine-needle aspiration biopsy; N/A, Not available.

Table 2. Design of the included studies
First author	Type of study	Inclusion criteria	Exclusion criteria	Classification to patients with/without thyroid nodules	Type of surgery	Primary outcome
Kraimps⁹	Retrospective multicenter cohort	Consecutive patients who had thyroidectomy for GD	Previous neck irradiation Previous RAI TMG	Preoperative clinical and ultrasonographic evaluation	TT/near TT	Prevalence of thyroid nodules and thyroid cancer in surgically treated patients with GD
Erbil¹⁷	Retrospective cohort	Consecutive patients with GD who underwent surgical treatment	Previous neck irradiation Previous RAI	Preoperative thyroid ultrasonographic findings	TT/near TT	Association of thyroid nodules and thyroid cancer in surgically treated patients with GD
Gul¹⁸	Retrospective cohort	Hyperthyroid patients who were treated surgically (159 of them with GD)	Previous neck irradiation Previous RAI	Preoperative thyroid ultrasonographic findings	TT	Prevalence of thyroid cancer in patients with surgically treated hyperthyroidism Evaluation of FNAB in diagnosis of thyroid cancer
Ren¹⁹	Retrospective cohort	Patients with GD who underwent surgical treatment	Previous neck irradiation Family history of TC or autoimmune thyroid disease	Preoperative thyroid ultrasonographic findings	TT/near TT	Prevalence of thyroid cancer in surgically treated patients with GD
Ergin¹⁰	Retrospective cohort	Patients with GD and EG who underwent TT (245 of them with GD)	Previous suspected or diagnosed MPTC	Preoperative thyroid ultrasonographic findings when available (226 patients)	TT	Prevalence of IDTC in patients with GD and EG Evaluation of factors that may predict IDTC
Tam²⁰	Retrospective cohort	Patients who underwent thyroidectomy because of GD	Previous neck irradiation Previous RAI Previous thyroid surgery	Preoperative thyroid ultrasonographic findings	TT/near TT	Prevalence of thyroid nodules and thyroid cancer in surgically treated patients with GD
Dirikoc²¹	Retrospective cohort	Patients who underwent thyroidectomy	Previous neck irradiation Previous thyroid surgery Percutaneous invasive procedure for thyroid nodule	Preoperative thyroid ultrasonographic findings	TT/near TT	Evaluation of thyroid cancer risk in various surgically treated thyroid diseases

Abbreviations: EG, Euthyroid goitre; GD, Graves' disease; IDTC, Incidental differentiated thyroid cancer; MPTC, Micropapillary thyroid cancer; RAI, Radioactive iodine; TMG, Toxic multinodular goitre; TT, Total thyroidectomy.

Supplementary Table 1. Indications of thyroidectomy of the selected studies.
First author	Contraindications for ATDs	Contraindications for RAI therapy	Failure of ATDs	Failure of RAI therapy	Recurrence of HT	Single/multiple nodules detected	Large goiter with/without compressive symptoms	Malignant cytology	Suspicious cytology	Suspicious clinical/US findings	Severe opthalmopathy	Substernal goiter	Patient's request
Kraimps⁹					√	√
Erbil ¹⁷			√		√		√	√	√		√		√
Gul ¹⁸		√	√		√		√	√	√	√			√
Ren ¹⁹			√		√		√			√
Ergin¹⁰	√	√	√	√		√	√				√	√
Tam ²⁰			√				√		√		√		√
Dirikoc²¹					√		√	√	√	√

ATDs: Antithyroid drugs, RAI: Radioactive iodine, HT: Hyperthyroidism, US: Ultrasonographic.

Supplementary Table 2. Quality assessment of the selected studies.
First author	Bias due to confounding	Bias in selection of participants into the study	Bias in classification of interventions	Bias due to deviations from intended interventions	Bias due to missing data	Bias in measurement of outcomes	Bias in selection of the reported result	Overall bias
Kraimps	Moderate	Low	Low	Low	Low	Low	Low	Moderate
Erbil	Moderate	Low	Low	Low	Low	Low	Low	Moderate
Gul	Moderate	Low	Low	Low	Low	Low	Low	Moderate
Ren	Moderate	Low	Low	Low	Low	Low	Low	Moderate
Ergin	Moderate	Serious	Low	Low	Moderate	Low	Low	Moderate
Tam	Moderate	Low	Low	Low	Low	Low	Low	Moderate
Dirikoc	Moderate	Low	Low	Low	Low	Low	Low	Moderate

Overall bias
Low: The study is judged to be at low risk of bias for all domains. The study is comparable to a well-performed randomized trial.
Moderate: The study is judged to be at low or moderate risk of bias for all domains. The study provides sound evidence for a non-randomized study but cannot be considered comparable to a well-performed randomized trial.
Serious: The study is judged to be at serious risk of bias in at least one domain, but not at critical risk of bias in any domain. The study has some important problems.
Critical: The study is judged to be at critical risk of bias in at least one domain. The study is too problematic to provide any useful evidence and should not be included in any synthesis.
No information: There is no clear indication that the study is at serious or critical risk of bias and there is a lack of information in one or more key domains of bias (a judgement is required for this) ⁷.