Accepted Manuscript

Thyroid carcinoma in graves’ disease: A meta-analysis

Joy U.L. Staniforth, Senarath Erdirimanne, Guy D. Eslick, Associate Professor

PII: S1743-9191(15)01343-6
DOI: 10.1016/j.ijsu.2015.11.027
Reference: IJSU 2334

To appear in: International Journal of Surgery

Received Date: 7 September 2015

Accepted Date: 11 November 2015

Please cite this article as: Staniforth JUL, Erdirimanne S, Eslick GD, Thyroid carcinoma in graves’
disease: A meta-analysis, International Journal of Surgery (2015), doi: 10.1016/j.ijsu.2015.11.027.

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 ACCEPTED MANUSCRIPT
To be considered for publication in:
International Journal of Surgery

25 November 2015

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THYROID CARCINOMA IN GRAVES’ DISEASE: A META-ANALYSIS

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Joy U. L. Staniforth

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Senarath Erdirimanne

Guy D. Eslick

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The Whiteley-Martin Research Centre, Discipline of Surgery, The University of
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Sydney, Nepean Hospital, Penrith, New South Wales, Australia.

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Address for correspondence: Associate Professor Guy D. Eslick

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Discipline of Surgery
The University of Sydney
Nepean Hospital
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Level 5, South Block

P.O. Box 63
Penrith, NSW 2751
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Australia
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Tel: +61 2 47 341 373

Fax: +61 2 47 343 432
E-mail: guy.eslick@sydney.edu.au

Word count: 3247 (excluding references); 4519 (with references)

Conflict of Interest: None

Key words

Graves’ disease, thyroid carcinoma, hyperthyroidism, thyroid nodules, surgery.

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Abstract

Background: The incidence of thyroid carcinoma is increasing worldwide. Graves’

disease is the most common hyperthyroid disease. Studies have suggested an

increased risk of thyroid malignancy in Graves’ disease: there has not yet been a

meta-analysis to allow quantitative comparison. The purpose of this study was to

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determine the risk of thyroid carcinoma in Graves’ disease, and to gather information

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on the histological subtypes of carcinoma and the co-existence of thyroid nodules.

Methods: Several databases and article reference lists were searched. Inclusion

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criteria included appropriate diagnostic criteria for thyroid conditions and a diagnoses

of carcinoma based on histology.

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Results: 33 studies were selected, all reporting on surgically-resected specimens.
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The event rate of thyroid carcinoma in Graves’ disease was 0.07 (95% CI 0.04 to
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0.12). There was no data to allow comparison with patients without hyperthyroid

diseases. There was no increase in the odds of developing carcinoma in Graves’

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disease compared to toxic multinodular goitre and toxic uninodular goitre. 88% of
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thyroid carcinomas in Graves’ disease were papillary, with solitary papillary micro-

carcinoma (diameter 10mm or less) comprising 23% of all detected thyroid

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carcinomas. Patients with Graves’ disease and co-existing thyroid nodules were
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almost 5 times more likely to be diagnosed with thyroid carcinoma than those without
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nodules.

Conclusion: Thyroid malignancy in Graves’ disease requiring surgical treatment

should be considered as likely as in other hyperthyroid diseases needing surgical

treatment. Clinicians should consider screening selected patients with Graves’

disease for nodules whilst being aware of potentially over-diagnosing papillary micro-

carcinoma.
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Introduction

Graves’ disease is an immune-mediated thyrotoxicosis and is the underlying cause

of 50 to 80% of all cases of hyperthyroidism [1]. Thyrotoxcosis results from the

binding of circulating antibodies to the G-protein coupled thyrotropin receptor, which

activate the downstream signalling pathways to induce hypertrophy and hyperplasia

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of the thyroid follicles and increases the production of thyroid hormone. Remaining

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common causes of hyperthyroidism are toxic multinodular goitre, in which multiple

autonomously-functioning thyroid nodules secrete excess thyroid hormone, and toxic

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adenoma, in which there is a single hyper-functioning thyroid nodule.

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Thyroid carcinoma is the most common endocrine cancer [2] and is a neoplasm of
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the thyroid epithelium. Arising from the follicular cells are papillary carcinomas (80%
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of cases), follicular carcinomas (14%, of which 3% is the Hürthle cell subtype), and

anaplastic or undifferentiated carcinomas (2%). Medullary carcinoma (4%) arises

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from the medullary cells [2]. Papillary micro-carcinoma is a papillary lesion less than
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or equal to 10mm in diameter [3]; it occurs incidentally in otherwise benign thyroid

tissue in 5% to 12% of cases [4]. Papillary micro-carcinoma nearly always gives an

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extremely good clinical outcome [4] and, as such, the value of its diagnosis and
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treatment is controversial [5].

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Thyroid carcinoma is a significant health issue. Worldwide, thyroid cancer was the

9th most common cancer to be diagnosed in females in the year of 2008 [6]. The

worldwide mortality rate is 0.5 per 100 000 [6].

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Thyroid carcinoma in Graves’ disease was originally thought to be a rare

phenomenon [7], even “insurance against cancer of the thyroid” [8]. However, a

number of recent primary studies have individually indicated that the opposite may

be true, reporting an increased prevalence of differentiated thyroid cancer compared

to the normal population [7]. Current hypotheses of the mechanism of

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carcinogenesis centre around pathways activated by the binding of thyroid-

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stimulating antibodies, which as well as stimulating growth may also promote

invasion and angiogenesis [9] and activate insulin-like growth factor pathways [7].

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The American Thyroid Association states that thyroid cancer occurs in Graves’

disease with a frequency of 2% or less [10].

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Thyroid carcinoma may be associated with a thyroid nodule, which are detectable on
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ultrasound in 30% to 70% of the population [4, 5] and clinically important for their

malignant potential (4% to 6% of biopsied nodules [5]). The American and British
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Thyroid Association recommend fine needle aspiration of all ultrasound-detected

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nodules in patients with a clinical history that is high risk for thyroid carcinoma [4, 11]

For nodules of a size 10mm or less in patients without a high risk history, case-by-
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case clinical judgement is recommended to avoid the over-treatment of clinically

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insignificant papillary micro-carcinoma [4].

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The relative incidence of histologically-confirmed thyroid carcinoma in patients with

Graves’ disease versus control individuals with no thyroid pathology is not well

reported in the literature. There is a reasonable amount of data regarding the

incidence of thyroid carcinoma in patients with Graves’ disease and other forms of

hyperthyroidism (toxic uninodular goitre or toxic adenoma, TUG, and toxic

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multinodular goitre, TMG), allowing comparison between these two populations in

this meta-analysis. From the located information, we were also able to review the

histological subtypes of thyroid carcinoma in patients with Graves’ disease and the

association of thyroid carcinoma and thyroid nodules in Graves’ disease.

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Methods

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Literature search strategy

We followed the Preferred Reporting Items for Systematic reviews and Meta-

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Analyses (PRISMA) guidelines [12, 13]. A systematic search of the databases

MEDLINE (from 1950), PubMed (from 1946) and EMBASE (from 1949), through to

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the 19th of February 2015 was carried out by JS to identify relevant articles. The
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search used the terms ‘Graves’ disease’ AND ‘thyroid cancer’ OR 'thyroid
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carcinoma', which were searched as text word and as exploded medical subject

headings where possible. The reference lists of relevant articles were also searched
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for appropriate studies. No language restrictions were used in either the search or
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study selection. A search for unpublished literature was not performed.

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Study selection
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We included studies that met the following inclusion criteria:

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(a) Graves’ disease, and thyroid disease of comparison groups, was named explicitly

or sufficient information was provided in the study as to ensure the diagnosis fit the

relevant ICD-10 criteria; where toxic multinodular goitre (TMG) and toxic adenoma or

toxic uninodular goitre (TUG) could not be further specified, these were included as a

“mixed” control group of “unspecified toxic nodular goitre” (uTNG); figures for which

were calculated separately;

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(b) thyroid cancer was confirmed histologically, and the study either (i) reported the

histology in accordance with the WHO classification of thyroid carcinoma [2, 14], or

(ii) was published after 1974 when the first edition of the WHO classification was

published (so as to ensure confidence in the interpretation of the histological report);

(c) the study did not exclude any type of thyroid carcinoma or condition in which

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thyroid carcinoma was found (for example, studies reporting on only a certain

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histological subtype of carcinoma, or only carcinoma associated with nodules, or

only incidental carcinoma, were excluded);

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(d) the study did not pre-select any specific group of patients with Graves’ disease

(for example, solely those with thyroid nodules);

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(e) where a comparison group was used, the risk point estimate was reported as an
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odds ratio (OR), or the data was presented such that an OR could be calculated;
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(f) where a comparison group was used, the 95% confidence interval (CI) was

reported, or the data was presented such that the CI would be calculated;
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(g) where the study used a comparison group, this group was internal.
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We excluded studies that did not meet these inclusion criteria.

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Data extraction
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The data extraction was performed using a standardized data extraction form,
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collecting information on the publication year, study design, country, and continent.

The number of cases (patients with Graves’ disease), if applicable, the number of

controls (patients with TUG, TMG, or uTNG), and the total number of diagnoses of

thyroid cancer made in each of these groups was extracted. Where available, data

was collected on the histological types of carcinoma diagnosed in Graves’ disease

patients and on co-existing thyroid nodules in patients with Graves’ disease (for this,
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methods of nodule detection, the number of patients with nodules, and thyroid

carcinoma detected in patients with nodules was extracted if given in the study). The

quality of the studies was not assessed and the authors were not contacted for

missing data.

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Risk estimates and CIs were calculated from the available data and included in the

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extraction form. Adjusted ratios were extracted in preference to non-adjusted ratios,

however, where ratios were not provided, unadjusted ORs and CIs were calculated.

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Where multiple risk estimates were available in the same study, for example due to

the use of different comparator groups, they were included as separate risk

estimates.
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Statistical analysis

Pooled odds ratios and 95% confidence intervals were calculated for the effect of
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hyperthyroid disease on carcinoma risk using a random effects model [13]. We

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tested heterogeneity with Cochran’s Q statistic, with P<0.10 indicating heterogeneity,

and quantified the degree of heterogeneity using the I2 statistic, which represents
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the percentage of the total variability across studies which is due to heterogeneity. I2
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values of 25, 50 and 75% corresponded to low, moderate and high degrees of
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heterogeneity respectively [15]. We quantified publication bias using the Egger’s

regression model [16], with the effect of bias assessed using the fail-safe number

method. The fail-safe number was the number of studies that we would need to have

missed for our observed result to be nullified to statistical non-significance at the

p<0.05 level. Publication bias is generally regarded as a concern if the fail-safe

number is less than 5n+10, with n being the number of studies included in the meta-
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analysis [17]. All analyses were performed with Comprehensive Meta-analysis

(version 2.0), Biostat, Englwood, NJ, USA.

Results

Fig 1. A flow diagram showing the process reached to identify the 33 studies

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included in the meta-analysis, following the identification of approximately 50 000

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citations by database search

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The 33 identified studies [18 – 50] shown in Figure 1 and Table 1 were retrospective

reviews carried out in a variety of geographical regions. They examined the cases of

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patients with Graves’ disease who had undergone the surgical removal of all or part
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of their thyroid gland (total of sub-total thyroidectomy) for a variety of reasons. 14
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studies [20, 21, 24, 26, 27, 31, 36, 38, 41, 42, 44, 46, 47, 50] also included

participants with other hyperthyroid diseases. Reasons given for surgery included
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failures or side-effects of medical therapy and the presence of suspicious nodules;

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these were not consistently linked to all study participants in any study. No studies

reported thyroid carcinoma in patients without thyroid disease. No studies included

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information on TSH antibody status for all of the study participants.

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Table 1. Study characteristics. Shown are the number of cases of Graves’ disease,

GD; toxic multinodular goitre, TMG; toxic uninodular goitre TUG, and unspecified

toxic nodular goitre, uTNG. Numbers of cases of carcinoma, Ca, in each group are

shown in brackets

As shown by the funnel plot in Figure 2, no publication bias was detected (p = 0.98).
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Fig 2. A funnel plot demonstrating no detected publication bias

As demonstrated in Figure 3, the overall event rate of thyroid carcinoma in Graves’

disease, utilising regional comparison, was 0.07 (95% confidence interval 0.04 to

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0.12).

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Fig 3. The event rate of thyroid carcinoma in Graves’ disease. CI, confidence interval

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28 studies [20 – 23, 25 – 40, 42 – 46, 48 – 50] reported the histological subtypes of

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thyroid cancer diagnosed in Graves’ disease: this data is presented in Table 2. 325
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of the 498 reported cases of thyroid carcinoma in Graves’ disease included a
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histological diagnosis. In 88% of cases this was papillary, 10% follicular, 0.6% mixed

papillary-follicular, 0.6% medullary, and 0.3% anaplastic. 254 of the reported cases
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also included the size of the lesion in addition to the histological subtype. 29% of all
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papillary carcinomas were micro-carcinomas of less than or equal to 10mm in

diameter, and 23% of all thyroid carcinoma was papillary micro-carcinoma. There
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were no recorded cases of lymphoma.

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Table 2. Numbers of histological subtypes reported (total 325 thyroid carcinomas).

Ca, carcinoma; -, not stated

20 studies [18, 20, 22, 23, 25, 26, 28 – 30, 33, 35 – 37, 40, 43 – 46, 48, 50] provided

some data on the co-existence of thyroid nodules in studied patients: this is shown in

Table 3. Overall, where thyroid nodules were reported 51% of reported carcinomas
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were found in patients with Graves’ disease and thyroid nodules. In the 10 studies

[22, 25, 29, 35 – 37, 40, 43, 45, 48] that reported the total number of patients with

Graves’ disease and co-existing nodules, 23% of patients had nodules and

carcinoma occurred in 23% of these patients with nodules; for patients with Graves’

disease and no detected nodules, the proportion of carcinoma was only 5%. 10

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studies [20, 22, 23, 25, 26, 28, 36, 43, 45, 46] in which carcinoma was discovered in

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patients with co-existing nodules reported the size and type of lesion; 38% of

malignancy associated with nodules was papillary micro-carcinoma.

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Table 3. Thyroid cancer diagnosed in the presence of clinically-detectable thyroid

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nodules. Ca, carcinoma; P, palpation; U, ultrasound; S, scintigraphic identification of
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cold nodule(s); -, not stated. The studies did not record whether the carcinoma was
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found within the detected nodules, unless otherwise stated in the table
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As demonstrated in Figure 4, the pooled odds ratio of developing thyroid carcinoma

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in Graves’ disease compared to any type of toxic nodular goitre is 0.89 (95% CI 0.63

to 1.26). There was no statistically significant heterogeneity (I2 = 28.57, p = 0.10).

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Fig 4. Odds ratios of thyroid carcinoma in Graves’ disease compared to all toxic
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nodular goitres. b, toxic uninodular goitre; TNG, unspecified toxic nodular goitre;

remaining studies toxic multinodular goitre; CI, confidence interval

Ten studies [20, 24, 31, 36, 41, 42, 44, 46, 47, 50] reported thyroid carcinoma in both

Graves’ disease and toxic multinodular goitre; the odds ratio of developing

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carcinoma in Graves’ disease compared to toxic multinodular goitre was 1.24 (95%

CI 0.81 to 1.90), and there was no statistically significant heterogeneity (I2 = 0.00, p

= 0.82). Ten studies [20, 24, 31, 36, 41, 42, 44, 46, 47, 50] reported thyroid

carcinoma in both Graves’ disease and toxic uninodular goitre; the odds ratio was

0.96 (95% CI 0.58 to 1.57), and there was again no statistically significant

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heterogeneity (I2 = 5.13, p = 0.39). Four studies [21, 26, 27, 38] reported thyroid

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carcinoma in both Graves’ disease and unspecified toxic nodular goitre; the odds

ratio was 0.43 (95% CI 0.14 to 1.33), and in this case there was statistically

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significant heterogeneity (I2 = 71.73, p = 0.01) which likely results from the small

sample size.

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Discussion
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Although no data are reported on the incidence of thyroid carcinoma in euthyroid

controls in this study, the incidence rate of thyroid carcinoma in Graves’ disease
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seen here is roughly 2.5 times the overall global figures. This is likely due to a higher
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detection rate in the surgically-resected specimens of this study, and indeed our

incidence rate is approximately in concordance with that observed in developed

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countries [51]. Our event rate of 0.07 of thyroid carcinoma in Graves’ disease (95%
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CI 0.04 to 0.12) is at least double the 2% figure quoted by the American Thyroid
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Association [10]. A recent review [52] noted that thyroid carcinoma incidence is

increasing worldwide, and this represents both an apparent increase due to more

sensitive diagnostic procedures, and a true increase.

The proportion of thyroid carcinoma histological types does not appear to differ

widely from the literature [51]. The proportion of papillary carcinoma is slightly
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increased (88% compared to 80% expected). The occurrence of papillary micro-

carcinoma is in direct concordance with the reported proportion of papillary micro-

carcinoma in malignant and benign thyroid disease; 23% [51]. The elevated

proportion of papillary carcinoma is therefore likely due to incidental findings of

papillary micro-carcinoma in these surgically-resected specimens, and indeed

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diagnosis of papillary micro-carcinoma has doubled in two decades [51].

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Correspondingly, in a recent study of papillary thyroid carcinoma in Hashimoto’s

thyroiditis [54] it was observed that studies in which thyroidectomy was performed for

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clinical reasons generated a statistically significant positive correlation between

Hashimoto’s disease and papillary carcinoma, whereas population-based fine needle

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aspiration studies did not find a correlation. The detection of incidental lesions that
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are not clinically important is not cost-effective and can cause direct harm to the
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patient in terms of anxiety, as well as the side-effects of further investigation and

treatment [53].
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The 23% co-incidence of Graves’ disease and thyroid nodules found here is in

agreement with a previous review [7], which found palpable thyroid nodules to occur
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in 10% to 15% of patients with Graves’ disease. The use of ultrasonography and
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scintigraphy as methods of nodule detection in the studies used in this analysis is the
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likely cause of the increased detection rate compared to palpation alone. The

previous review [7] also found a malignancy rate of 2% to 46% in patients with

Graves’ disease and palpable nodules, in-keeping with our figure of 23%. Only 3

studies commented specifically on whether the carcinoma was found to be actually

within a nodule; this occurred in 55% to 100% of cases. The 38% proportion of

papillary micro-carcinoma in malignancies associated with nodules is in-keeping with

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the observation that routine ultrasonography in Graves’ disease identifies more

nodules and carcinoma than palpation and scintigraphy, with most of these

carcinomas being papillary micro-carcinomas [10].

A 2012 review [9] found that the incidence and prognosis of thyroid cancer

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associated with hyperthyroidism was highly variable between studies. Pooling the

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available data, our meta-analysis shows no increase in the odds of thyroid

carcinoma being diagnosed in Graves’ disease compared to nodular thyrotoxic

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disease; this is relatively consistent between studies, as shown in Figure 3.

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The mechanisms driving thyroid carcinoma in Graves’ disease may not be entirely
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antibody-mediated given the similar odds of developing thyroid carcinoma in nodular
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thyrotoxic diseases, or there may be different mechanisms of carcinogenesis in

nodular thyrotoxic disease, or there may be an alternative mechanism common to

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both, such as elevated serum insulin-like growth factor 1 [55].

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There are a number of limitations in this study. Selection bias will be present as all
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patients undergoing surgical treatment, and for a variety of reasons which were not
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linked directly to the patients studied. Overall, this could mean greater severity of
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hyperthyroid disease, with a greater degree hyperplasia and potentially atypia, than

in other hyperthyroid patients. Surgery varied from partial to total thyroidectomy, so

not all of the thyroid tissue was examined. There is a likely over-reporting of papillary

micro-carcinoma which may well have been otherwise clinically insignificant. Patient

data including demographics and family history of thyroid carcinoma were not linked

to the patients, so we cannot perform quantitative analysis to account for pre-existing

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risk factors. No case-control matching was attempted in studies examining other

hyperthyroid diseases. There is potential diagnostic error, especially in older studies,

as recommended practice changes through time. Detailed features of detected

nodules were not given, so the presence or absence of high-risk features is not

known, and there were a variety of diagnostic tests performed for nodules with

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reasons for their deployment not clearly stated.

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Conclusions

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The event rate of thyroid cancer in Graves’ disease is at least double the currently-

accepted 2% of the American Thyroid Association [10]. This may, however, be due

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to the increased detection of papillary micro-carcinoma in the surgical patients who
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comprise the studies.
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Graves’ disease requiring surgical management is not protective against thyroid

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carcinoma compared to other thyrotoxic diseases which also require surgical

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management.
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For surgical Graves’ disease patients with nodules there should be a clinical
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suspicion of thyroid cancer, as its risk is increased approximately fivefold in these

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patients. Clinicians may wish to consider the screening of selected patients for

nodules, but must bear in mind the resulting possibility of over-treatment of cases of

clinically insignificant papillary micro-carcinoma.

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Funding

None.

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No.
No. Author Time period GD (Ca) TMG (Ca) TUG (Ca) uTNG (Ca)
centres
18 Behar et al. (1986) 1971-81 1 194 (10)
19 Bradley and Leichty (1983) 1971-83 2 166 (5)

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20 Cappellli et al. (2006) 1985-2001 1 145 (9) 339 (13) 207 (10)
21 Chou et al. (1993) 1980-91 1 674 (10) 27 (4)
22 Erbil et al. (2008) 1996-2005 1 150 (18)

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23 Farbota et al. (1985) 1961-84 1 117 (6)
24 Gabriele et al. (2003) 1980-2000 2 64 (0) 241 (4) 120 (3)

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25 Gerenova et al. (2003) 1990-2000 1 95 (7)
26 Hales et al. (1992) 1966-89 1 886 (16) 322 (5)

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27 Hancock et al. (1977) 1960-72 1 457 (7) 92 (3)
28 Kasuga et al. (1993) 1965-90 1 847 (36)

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29 Kraimps et al. (2000) 1991-97 5 557 (21)
30 Lin et al. (2003) 1989-2000 1 42 (4)
31 Linos et al. (1997) 1982-91 1 112 (6) 226 (16) 62 (5)

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32 Miccoli et al. (1996) 1986-94 1 140 (13)
33 Mssrouri et al. (2008) 1995-2005 1 547 (6)

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34 Ozaki et al. (1990) 1983-85 1 739 (15)

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35 Ozoux et al. (1988) 1971-84 1 88 (4)
36 Pacini et al. (1988) 1970-85 1 86 (6) 21 (4) 40 (1)
37 Phitayakorn et al. (2013) 1985-2010 1 300 (35)
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38 Pomorski et al. (1996) 1974-94 1 704 (3) 2762 (18)
39 Razack et al. (1997) 1982-92 1 62 (3)
40 Ren et al. (2014) 2002-12 1 423 (58)
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41 Rieger et al. (1989) 1970-86 1 64 (0) 676 (11) 1108 (3)

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42 Ruggieri et al. (1999) 1994-99 1 8 (1) 54 (5) 20 (0)

43 Tameata et al. (2012) 2001-11 1 117 (8)
44 Terzioğlu et al. (1993) 1986-91 1 33 (2) 80 (4) 25 (2)
45 Thakur et al. (1995) 1989-93 1 49 (4)
46 Vaiana et al. (1999) 1984-98 1 108 (7) 251 (10) 153 (8)
47 Wahl et al. (1982) 1962-79 1 178 (2) 317 (10) 207 (6)
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48 Weber et al. (2006) 1993-2005 1 48 (8)

49 Yano et al. (2007) 1994-2004 1 2356 (166)
50 Zanella et al. (2001) 20 years 4 38 (2) 119 (2) 41 (8)
Totals 423 years 42 10594 (498) 2324 (79) 1983 (46) 3203 (30)

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Other Ca
Ref. All papillary Ca
Study P, papillary; PF, mixed papillary-follicular;
no. (single papillary micro-Ca)
F, follicular; M, medullary; A, anaplastic
Cappellli et al. (2006) 20 9 (4) 0
Chou et al. (1993) 21 9 (-) 1F
Erbil et al. (2008) 22 18 (14) 0
Farbota et al. (1985) 23 4 (1) 2F
Gerenova et al. (2003) 25 7 (6) 0
Hales et al. (1992) 26 15 (11) 1F
Hancock et al. (1977) 27 3 (-) 3 F, 1 PF

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Kasuga et al. (1993) 28 30 (20) 6F
Kraimps et al. (2000) 29 20 (-) 1F
Lin et al. (2003) 30 1 (-) 3F
Linos et al. (1997) 31 5 (-) 1M

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Miccoli et al. (1996) 32 13 (≥ 5) 0
Mssrouri et al. (2008) 33 3 (-) 2 F, 1 PF
Ozaki et al. (1990) 34 11 (6) 4F

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Ozoux et al. (1988) 35 4 (4) 0
Pacini et al. (1988) 36 2 (1) 4F
Phitayakorn et al (2013) 37 34 (≥ 22) 1F
Pomorski et al. (1996) 38 1 (-) 2F

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Razack et al. (1997) 39 3 (3) 0
Ren et al. (2014) 40 56 (-) 1 F, 1 A
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Ruggieri et al. (1999) 42 1 (1) 0
Tameata et al. (2012) 43 7 (4) 1F
Terzioğlu et al. (1993) 44 2 (-) 0
Thakur et al. (1995) 45 3 (2) 1F
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Vaiana et al. (1999) 46 7 (3) 0

Weber et al. (2006) 48 8 (-) 0
Yano et al. (2007) 49 8 (-) 1M
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Zanella et al. (2001) 50 2 (0) 1F

Totals 286 (≥ 107) 34 F, 2 PF, 2 M, 1 A
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No. cases Ca diagnosed

Nodule Total no. GD patients
No. Reference in GD patients with nodules
detection with nodules
(no. isolated papillary micro-carcinomas)
18 Behar et al. (1986) - 4 (-) -

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20 Cappelli et al. (2006) U 7 (2) -
22 Erbil et al. (2008) U 11 (4), of which 6 (4) in a nodule 80
23 Farbota et al. (1985) S 2 (0) -

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25 Gerenova et al. (2003) P +/ U +/ S 6 (5) 46
26 Hales et al. (1992) S 5 (4) -

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28 Kasuga et al. (1993) - 7 (2) -
29 Kraimps et al. (2000) P +/ U +/ S 21 (-), all in a nodule 140
30 Lin et al. (2003) U +/ S 4 (-) -

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33 Mssrouri et al. (2008) P 3 (-) -

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35 Ozoux et al. (1988) S 0 9
36 Pacini et al. (1988) P +/ S 4 (1), of which ≥ 3 (0 to 1) in a nodule 18
37 Phitayakorn et al. (2013) S 3 (-) 24

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40 Ren et al. (2014) P +/ U 46 (-) 96
43 Tameata et al. (2012) - ≥ 1 (0) ≥ 2*

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44 Terzioğlu et al. (1993) S 0 -
45 Thakur et al. (1995) S 2 (0) 7

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46 Viana et al. (1999) U +/ S 3 (0) -
48 Weber et al. (2006) P+S 5 (-) 12
50 Zanella et al. (2011) P+S 1 (-) -
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Highlights

The incidence of thyroid carcinoma is increasing worldwide.

Studies have suggested an increased risk of thyroid malignancy in Graves’ disease.

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Thyroid malignancy in Graves’ disease requiring surgical treatment is important.

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