Risk and Prognosis of Thyroid Cancer in Patients with Graves’ Disease: An Umbrella Review
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Umbrella Review Methods
2.2. Search Strategy and Selection Criteria
2.3. Eligibility Criteria
2.4. Data Extraction
2.5. Evaluation of the Strength of Evidence
2.6. Quality Assessment
2.7. Statistical Analysis
3. Results
3.1. Search Strategy Outcome
3.2. Quality Assessment and Bias
3.3. Risk and Prognosis (Mortality and Recurrence/Persistence) of Thyroid Cancer in Patients with Graves’ Disease
3.3.1. Risk of Thyroid Cancer in Patients with Graves’ Disease by Comparison Groups
Risk of Thyroid Cancer in Patients with Graves’ Disease vs. Multinodular Toxic Goiter (MTG), Uninodular Toxic Goiter (UTG), or Unspecified Toxic Nodular Goiter (uTNG)
Risk of Thyroid Cancer in Patients with Graves’ Disease with Nodular vs. Those without Nodules
Number of Thyroid Nodules in Graves’ Disease Patients and Risk of Differentiated Thyroid Cancer
3.3.2. Prognosis (Mortality) of Thyroid Cancer in Patients with Graves’ Disease by Comparison Groups
Graves’ Disease vs. No Graves’ Disease Hyperthyroid Patients
Graves’ Disease Hyperthyroid Patients Compared with Euthyroid Subjects
Graves’ Disease Patients Compared with Those without Graves’ Disease (Including Both Euthyroid and Hyperthyroid Patients)
3.3.3. Prognosis (Recurrence/Persistence) of Thyroid Cancer in Patients with Graves’ Disease by Comparison Groups
Graves’ Disease Compared to Non-Graves’ Disease Hyperthyroid Patients
Patients with Graves’ Disease Compared with Euthyroid Patients
Patients with Graves’ Disease Compared to Non-Graves’ Disease Patients (Including Both Euthyroid and Hyperthyroid Patients)
4. Discussion
4.1. Main Findings and Interpretation Considering Evidence
- “Strong” evidence of thyroid cancer risk in patients with GD and thyroid nodules compared to patients with GD without nodules.
- “Modest” evidence of thyroid cancer risk in GD patients compared to MTG patients and in GD patients with solitary nodules compared with GD patients with multiple nodules.
- “Strong evidence of increased thyroid cancer risk mortality in GD patients compared with non-GD patients (including both euthyroid and hyperthyroid patients) that increased after excluding the low-rate incidental cancers and also after stratifying by continent (Europe higher than Asia) [41].
- “Moderate” evidence of higher risk of recurrence/persistence among patients with GD compared to those without GD (including both euthyroid and hyperthyroid patients) by continents (Europa and America vs. Asia).
4.2. Strengths and Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Evidence | Criteria Used |
---|---|
Strong | OR * > 2; p ** < 10−6; >1000 cases; p < 0.05 of largest study in meta-analysis; I2 *** < 50%; no small study effect; prediction interval excludes null value **; no excess significance bias |
Moderate | OR > 1.5; p * < 10−6; >1000 cases; p < 0.05 of largest study in meta-analysis |
Modest | OR >1.2; p * < 10−3 |
Weak | OR > 1; p < 0.05 |
Mekraksakit et al., 2019 [38] | Papanastasiou et al., 2019 [39] | Staniforth et al., 2015 [40] | Song et al., 2019 [41] | Jia et al., 2018 [42] | |
---|---|---|---|---|---|
| Yes | Yes | Yes | Yes | Yes |
| Partial Yes | Partial Yes | Partial yes | Partial Yes | Partial Yes |
| Yes | No | Yes | Yes | Yes |
| Partial Yes | Partial Yes | Partial Yes | Partial Yes | Partial Yes |
| Yes | Yes | No | Yes | Yes |
| Yes | Yes | No | Yes | Yes |
| No | No | No | No | No |
| Yes | Partial Yes | No | Yes | Partial Yes |
| Yes | Yes | Yes | Partial Yes | Partial Yes |
| Yes | Yes | Yes | Yes | Yes |
| Yes | Yes | Yes | Yes | Yes |
| Yes | Yes | Yes | Yes | Yes |
| Yes | Yes | Yes | Yes | Yes |
| Yes | Yes | Yes | Yes | No |
| Yes | Yes | Yes | No | Yes |
| Yes | Yes | Yes | Yes | Yes |
Total of yes | 13/16 (75.0%) | 11/16 (68.7%) | 10/16 (75.0%) | 11/16 (68.7%) | 10/16 (62.5%) |
Rating overall confidence | Moderate | Moderate | Low | Low | Moderate |
Author, Year | N. and Study Design in Meta-Analyses | Graves’ Patients (GD) (Number of Thyroid Cancer Cases) | Sex by Comparison Groups | Comparison Groups (N) | Age (Years) | Type of Thyroid Cancer | Country | Period of Primary Studies’ Publication | Exposure Time Period/ Follow-Up | Effect Size by Comparing Group (Thyroid Cancer Risk in GD Patients, Mortality, Recurrence/Persistence) | Heterogenicity (p-Value) * | Publication Bias |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Mekraksakit et al., 2019 [38] | 15 retrospective cohorts 9 case-control 1 prospective cohort | GD: 2892(2892) | F: 1320 M: 1572 | -DTC patients with non-Graves’ hyperthyroidism -DTC patients with euthyroidism -Non-specified DTC patients -DTC with TNMG -DTC with TA | from 5 to 81 | 2662 PTC, 213 FTC, 16 mixed PTC and FTC 1 CCC | 1 Germany, 4 USA, 7 Italy, 2 Taiwan, 2 Turkey, 1 Oman, 1 Greece, 1 U.K., 1 Spain, 1 Australia, 2 Japan, 1 India | from 1988 to 2018 | from 1 to 30 years | GD vs. no GD hyperthyroidism | Yes | |
OR for mortality = 0.79 (95% CI 0.17–3.67) | 0.0% (0.50) | |||||||||||
OR for recurrence/persistence 2.66 (95% CI 0.94–7.54) | 1.8% (0.41) | |||||||||||
GD vs. euthyroid | ||||||||||||
OR for mortality = 2.69 (95%CI 0.70–10.40) | 22.9% (0.27) | |||||||||||
OR for recurrence/persistence = 1.39 (95% CI 0.52–3.76) | 64.2% (0.04) | |||||||||||
GD vs. Non-specified DTC OR for recurrence/persistence = 0.91 (95% CI 0.18–4.58) | 73.3% (0.01) | |||||||||||
Papanastasiou et al., 2019 [39] | 7 retrospectivecohorts | GD:2582(297) | F: 1368 M: 517 (this number is partly due to the lack of data in some of the included studies) | -GD patients without thyroid nodules -GD patients without thyroid nodules (without malignant or suspicious cytology) -GD patients with multiple nodules | from 27 to 58 | 297 DTC | 1 France, 4 Turkey, 1 USA, 1 China | from 1988 to 2018 | Notapplicable | GD with thyroid nodules vs. GD without thyroid nodules OR incidence for thyroid cancer risk = 5.30 (95% CI 2.43–11.59) | 83%(0.00) | Not evaluated because of the insufficient number of included studies |
GD with thyroid nodules vs. GD without malignant or suspicious cytology OR incidence for thyroid cancer risk = 4.02 (95% CI 1.24–12.99) | 89% (0.00) | |||||||||||
GD with thyroid nodules vs. number of nodules OR incidence for thyroid cancer risk = 1.39 (95% CI 0.85–2.29) | 0% (0.76) | |||||||||||
Staniforth et al., 2015 [40] | 28 retrospective 1 cohort 3 prospective 1 case-control | GD: 10,594 (498) | GD: 451 M, 2456 F UTG: 674 M, 791 F MTG: 276 M, 491 F Hyperthyroidism/Thyrotoxicosis: 199 M, 573 F Goiter: 1613 M, 12,887 F (this number is partly due to the lack of data in some of the included studies) | Patients with non-Graves’ hyperthyroidism: -Any type of toxic nodular goiter -Toxic multinodulargoiter-Toxic uninodulargoiter-Unspecified toxic nodular goiter | from 3 to 82 | 325 out of 498 cases had the histological diagnosis: Papillary: 286 (88%) Follicular: 34 (10%) Mixed papillary-follicular: 2 (0.6%) Medullary: 2 (0.6%) Anaplastic: 1 (0.3%) | 7 Asia, 18 Europe, 2 Pacific Area, 6 USA | 1977–2014 | from 2 to 25 years | GD vs. any type of toxic nodular goiter OR incidence = 0.89 (95% CI 0.63–1.26) | 28.57% (0.10) | No publication bias (p = 0.98) |
GD vs. toxic multinodular goiter OR incidence= 1.24 (95% CI 0.81–1.90) | 0.0% (0.82) | |||||||||||
GD vs. toxic unimodular goiter OR incidence = 0.96 (95% CI 0.58–1.57) | 5.13% (0.39) | |||||||||||
GD vs. unspecified toxic nodular goiter OR incidence = 0.43 (95% CI 0.14–1.33) | 71.73% (0.01) | |||||||||||
Song et al., 2019 [41] | 12 retrospective | GD: 882 (36) | GD: 189 M, 1345 F UTG: 23 M, 141 F MTG: 166 M, 929 F Hyperthyroidism: 15 M, 68 F DTC: 22 M, 117 FEuthyroidism: 28 M, 181 F Thyroidectomy not GD and PTC: 104 M, 405 F Thyroidectomy not GD and STC: 33 M, 476 F (this number is partly due to the lack of data in some of the included studies) | -Non-Graves’ DTC patients (N: 2201) -Non-Graves’ hyperthyroidism DTC patients (N: 118) -Euthyroidism DTC patient (N: 697) | from 15 to 51 (meanage) | 2708 PTC 31 FTC 159 DTC | 3 Italy, 2 Greece, 2 USA, 1 India, 2 Japan, 1 U.K., 1 China | from 1988 to 2018 | Notapplicable | GD patients vs. not GD patients OR(recurrence/disease progress/persistence) = 1.07 (0.51–2.22) | 65% (0.00) | Not reported |
Moderate–high quality subgroup OR(recurrence/disease progress/persistence) = 1.50 (95% Cl 0.60–3.79) | 64% (0.00) | |||||||||||
Weak quality subgroup OR (recurrence/disease progress/persistence) = 0.53 (0.20–1.43) | 51% (0.13) | |||||||||||
By K-M curves OR(recurrence/disease progress/persistence) = 2.02 (95% Cl 1.04–3.90) | 0% (0.04) | |||||||||||
Europe OR (recurrence/disease progress/persistence) = 1.77 (95% Cl 0.99–3.16) | 0% (0.47) | |||||||||||
Europe and America OR (recurrence/disease progress/persistence) = 1.74 (95% Cl 1.02–2.98) | N.A. | |||||||||||
Asia OR (recurrence/disease progress/persistence) = 0.43 (95% Cl 0.25–0.77) | 80% (0.00) | |||||||||||
Retrospective not randomized studies with subgroup OR(recurrence/disease progress/persistence) = 0.50 (95% Cl 0.30–0.85) | 76% (0.00) | |||||||||||
Retrospective randomized studies subgroup OR(recurrence/disease progress/persistence) = 1.79 (95% Cl 1.01–3.18) | 0% (0.47) | |||||||||||
High incidental carcinoma rate studies OR(recurrence/disease progress/persistence) = 1.75 (95% Cl 1.04–2.95) | 0% (0.81) | |||||||||||
GD vs. not GD hyperthyroidism OR(recurrence/disease progress/persistence) = 3.56 (95% Cl 1.18–10.75) | 5% (0.37) | |||||||||||
GD vs. euthyroid OR(recurrence/disease progress/persistence) = 0.86 (95% Cl 0.42–1.77) | 93% (0.00) | |||||||||||
GD vs. not GD OR for mortality = 2.93 (95% Cl 1.17–7.37) | 33% (0.20) | |||||||||||
High incidental carcinoma rate studies OR for mortality = 7.17 (95% Cl 2.14–24.02) | 0% (0.51) | |||||||||||
Europe OR for mortality = 4.89 (95% Cl 1.52–15.75) | 38% (0.20) | |||||||||||
Asia OR for mortality = 1.13 (95% Cl 0.21–6.13) | 0% (0.34) | |||||||||||
Retrospective not randomized studies with subgroup OR for mortality = 3.75 (95% Cl 1.29–10.90) | 57% (0.10) | |||||||||||
Retrospective randomized studies subgroup OR for mortality = 1.36 (95% Cl 0.19–9.82) | 0% (0.43) | |||||||||||
GD vs. euthyroid OR for mortality = 3.99 (95% Cl 1.19–13.39) | 78% (0.03) | |||||||||||
GD vs. not GD hyperthyroidism OR for mortality= 1.36 (95% Cl 0.19–9.82) | 0% (0.43) | |||||||||||
Jia et al., 2018 [42] | 11 cohorts | 10743 (207) | GD patients with PTC GD: 1065 F, 9678 M (this number is partly due to the lack of data in some of the included studies) | TA patients with TC TNG patients with TC non-GD patients with PTC | from 17 to 76 | 207 DTC | 2 USA, 1 Oman, 1 Greece, 1 Turkey, 1 India, 3 Italy, 1 Germany, 1 France | from 1946 to 2013 | Not reported | Surgery-hyperthyroid incidental thyroid cancer patients with GD vs. not GD OR incidence: 1.0 (0.68–1.46 p = 0.98). | 12% (0.33) | No publication bias (p = 0.77) |
GD vs. toxic adenoma patients OR incidence: 0.53 (0.21–1.36 p = 0.18) | 40% (0.17) | |||||||||||
GD vs. TNG patients OR incidence: 1.01 (0.65–1.57 p = 0.95) | 5% (0.39) | |||||||||||
GD patients and non-GD patients OR incidence: 0.79 (0.24–2.64 p = 0.70) | 0% (0.97) | |||||||||||
GD vs. Toxic multinodular goiter OR incidence = 1.24 (95% CI 0.81–1.90) | 0.0% (0.82) | |||||||||||
GD vs. Toxic unimodular goiter OR incidence = 0.96 (95% CI 0.58–1.57) | 5.13% (0.39) | |||||||||||
GD vs. unspecified toxic nodular goiter OR incidence = 0.43 (95% CI 0.14–1.33) | 71.73% (0.01) |
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Palella, M.; Giustolisi, F.M.; Modica Fiascaro, A.; Fichera, M.; Palmieri, A.; Cannarella, R.; Calogero, A.E.; Ferrante, M.; Fiore, M. Risk and Prognosis of Thyroid Cancer in Patients with Graves’ Disease: An Umbrella Review. Cancers 2023, 15, 2724. https://doi.org/10.3390/cancers15102724
Palella M, Giustolisi FM, Modica Fiascaro A, Fichera M, Palmieri A, Cannarella R, Calogero AE, Ferrante M, Fiore M. Risk and Prognosis of Thyroid Cancer in Patients with Graves’ Disease: An Umbrella Review. Cancers. 2023; 15(10):2724. https://doi.org/10.3390/cancers15102724
Chicago/Turabian StylePalella, Marco, Francesca Maria Giustolisi, Adriana Modica Fiascaro, Martina Fichera, Antonella Palmieri, Rossella Cannarella, Aldo E. Calogero, Margherita Ferrante, and Maria Fiore. 2023. "Risk and Prognosis of Thyroid Cancer in Patients with Graves’ Disease: An Umbrella Review" Cancers 15, no. 10: 2724. https://doi.org/10.3390/cancers15102724