Features and outcome of differentiated thyroid carcinoma associated with Graves’ disease: results of a large, retrospective, multicenter study



Whether differentiated thyroid cancer (DTC) occurring concomitantly with Graves’ disease (GD) is more aggressive and bound to a less favorable outcome is controversial.


Aim of this multicenter retrospective study was to compare baseline features and outcome of DTC patients with GD (DTC/GD+) or without GD (DTC/GD−).


Enrolled in this study were 579 patients referred to five endocrine units (Cagliari, Pavia, Pisa, Siena, and Varese) between 2005 and 2014: 193 patients had DTC/GD+ , 386 DTC/GD−. Patients were matched for age, gender and tumor size. They underwent surgery because of malignancy, large goiter size, or relapse of hyperthyroidism in GD.


Baseline DTC features (histology, lymph node metastases, extrathyroidal extension) did not differ in the two groups, except for multifocality which was significantly more frequent in DTC/GD+ (27.5% vs. 7.5%, p < 0.0001). At the end of follow-up (median 7.5 years), 86% of DTC/GD+ and 89.6% DTC/GD− patients were free of disease. Patients with persistent or recurrent disease (PRD) had “biochemical disease” in the majority of cases. Microcarcinomas were more frequent in the DTC/GD+ group (60% vs. 37%, p < 0.0001) and had an excellent outcome, with no difference in PRD between groups. However, in carcinomas ≥ 1 cm, PRD was significantly more common in DTC/GD+ (24.4% vs. 11.5%; p = 0.005). In the whole group, univariate and multivariate analyses showed that GD+ , lymph node involvement, extrathyroidal invasion, multifocality and tall cell histotype were associated with a worse outcome. Female gender and microcarcinomas were favorable features. No association was found between baseline TSH-receptor antibody levels and outcome. Graves’ orbitopathy (GO) seemed to be associated with a better outcome of DTC, possibly because patients with GO may early undergo surgery for hyperthyroidism.


GD may be associated with a worse outcome of coexisting DTC only if cancer is ≥ 1 cm, whereas clinical outcome of microcarcinomas is not related to the presence/absence of GD.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Pacini F, Basolo F, Bellantone R, Boni G, Cannizzaro MA, De Palma M, Durante C, Elisei R, Fadda G, Frasoldati A, Fugazzola L, Guglielmi R, Lombardi CP, Miccoli P, Papini E, Pellegriti G, Pezzullo L, Pontecorvi A, Salvatori M, Seregni M, Vitti P (2018) Italian Consensus on diagnosis and treatment of differentiated thyroid cancer: joint statements of six Italian societies. J Endocrinol Invest 41(7):849–876

  2. 2.

    Hegedus L, Bonnema SJ, Bennedbaek FN (2003) Management of simple nodular goiter: current status and future perspectives. Endocr Rev 24(1):102–132

  3. 3.

    Russ G, Leboulleux S, Leenhardt L, Hegedus L (2014) Thyroid incidentalomas: epidemiology, risk stratification with ultrasound and workup. Eur Thyroid J 3(3):154–163

  4. 4.

    Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L (2016) 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 26(1):1–133

  5. 5.

    Liang L, Zheng XC, Hu MJ, Zhang Q, Wang SY, Huang F (2019) Association of benign thyroid diseases with thyroid cancer risk: a meta-analysis of prospective observational studies. J Endocrinol Invest 42(6):673–685

  6. 6.

    Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R (2013) Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol 2013:965212

  7. 7.

    Davies L, Morris LG, Haymart M, Chen AY, Goldenberg D, Morris J, Ogilvie JB, Terris DJ, Netterville J, Wong RJ, Randolph G, AACE Endocrine Surgery Scientific Committee (2015) American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: the increasing incidence of thyroid cancer. Endocr Pract 21(6):686–696

  8. 8.

    Kitahara CM, Sosa JA (2016) The changing incidence of thyroid cancer. Nat Rev Endocrinol 12(11):646–653

  9. 9.

    La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F, Negri E (2015) Thyroid cancer mortality and incidence: a global overview. Int J Cancer 136(9):2187–2195

  10. 10.

    Vaccarella S, Dal Maso L, Laversanne M, Bray F, Plummer M, Franceschi S (2015) The impact of diagnostic changes on the rise in thyroid cancer incidence: a population-based study in selected high-resource countries. Thyroid 25(10):1127–1136

  11. 11.

    Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, Dal Maso L (2016) Worldwide thyroid-cancer epidemic? The increasing impact of overdiagnosis. N Engl J Med 375(7):614–617

  12. 12.

    Miccoli P, Minuto MN, Galleri D, D’Agostino J, Basolo F, Antonangeli L, Aghini-Lombardi F, Berti P (2006) Incidental thyroid carcinoma in a large series of consecutive patients operated on for benign thyroid disease. ANZ J Surg 76(3):123–126

  13. 13.

    Bartalena L (2013) Diagnosis and management of Graves’ disease: a global overview. Nature Rev Endocrinol 9(12):724–734

  14. 14.

    Bartalena L, Chiovato L, Vitti P (2016) Management of hyperthyroidism due to Graves’ disease: frequently asked questions and answers (if any). J Endocrinol Invest 39(10):1105–1114

  15. 15.

    Brito JP, Schilz S, Singh Ospina N, Rodriguez-Gutierrez R, Maraka S, Sangaralingham LR, Montori VM (2016) Antithyroid drugs-the most common treatment for Graves’ disease in the United States: a nationwide population-based study. Thyroid 26(8):1144–1145

  16. 16.

    Masiello E, Veronesi G, Gallo D, Premoli P, Bianconi E, Rosetti S, Cusini C, Sabatino J, Ippolito S, Piantanida E, Tanda ML, Chiovato L, Wiersinga WM, Bartalena L (2018) Antithyroid drug treatment for Graves’ disease: baseline predictive models of relapse after treatment for a patient-tailored management. J Endocrinol Invest 41(12):1425–1432

  17. 17.

    Belfiore A, Garofalo MR, Giuffrida D, Runello F, Filetti S, Fiumara A, Ippolito O, Vigneri R (1990) Increased aggressiveness of thyroid cancer in patients with Graves’ disease. J Clin Endocrinol Metab 70(4):830–835

  18. 18.

    Chen YK, Lin CL, Chang YJ, Cheng FT, Peng CL, Sung FC, Cheng YH, Kao CH (2013) Cancer risk in patients with Graves’ disease: a nationwide cohort study. Thyroid 23(7):879–884

  19. 19.

    Jia Q, Li X, Liu Y, Li L, Kwong JS, Ren K, Jiang Y, Sun X, Tian H, Li S (2018) Incidental thyroid carcinoma in surgery-treated hyperthyroid patients with Graves’ disease: a systematic review and meta-analysis of cohort studies. Cancer Manag Res 10:1201–1207

  20. 20.

    Pellegriti G, Belfiore A, Giuffrida D, Lupo L, Vigneri R (1998) Outcome of differentiated thyroid cancer in Graves patients. J Clin Endocrinol Metab 83(8):2805–2809

  21. 21.

    Pellegriti G, Mannarino C, Russo M, Terranova R, Marturano I, Vigneri R, Belfiore A (2013) Increased mortality in patients with differentiated thyroid cancer associated with Graves’ disease. J Clin Endocrinol Metab 98(3):1014–1021

  22. 22.

    Hales IB, McElduff P, Crummer P, Clifton-Bligh P, Delbridge L, Hoschl R, Poole A, Reeve TS, Wilmshurst E, Wiseman J (1992) Does Graves’ disease or thyrotoxicosis affect the prognosis of thyroid cancer? J Clin Endocrinol Metab 75(3):886–889

  23. 23.

    Yano Y, Shibuya H, Kitagawa W, Nagahama M, Sugino K, Ito K (2007) Recent outcome of Graves’ disease patients with papillary thyroid cancer. Eur J Endocrinol 157:325–329

  24. 24.

    Belfiore A, Russo D, Vigneri R, Filetti S (2001) Graves’ disease, thyroid nodules and thyroid cancer. Clin Endocrinol 55(6):711–718

  25. 25.

    Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML, Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E, Pinchera A (1998) Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 338:73–78

  26. 26.

    Filetti S, Belfiore A, Amir SM, Daniels GH, Ippolito O, Vigneri R, Ingbar SH (1988) The role of thyroid-stimulating antibodies of Graves’ disease in differentiated thyroid cancer. N Engl J Med 318(12):753–759

  27. 27.

    Boutzios G, Vasileiadis I, Zapanti E, Charitoudis G, Karakostas E, Ieromonachou P, Karatzas T (2014) Higher incidence of tall cell variant of papillary thyroid carcinoma in Graves’ disease. Thyroid 24(2):347–354

  28. 28.

    Bartalena L, Tanda ML (2009) Clinical practice. Graves’ ophthalmopathy. N Engl J Med 360(10):994–1001

  29. 29.

    Cho A, Chang Y, Ahn J, Shin H, Ryu S (2018) Cigarette smoking and thyroid cancer risk: a cohort study. Br J Cancer 119:638–645

  30. 30.

    Kitahara CM, Linet MS, Beane Freeman LE, Check DP, Church TR, Park Y, Purdue MP, Schairer C, Berrington de Gonzalez A (2012) Cigarette smoking, alcohol intake, and thyroid cancer risk: a pooled analysis of five prospective studies in the United States. Cancer Causes Control 23:1615–1624

  31. 31.

    Bartalena L, Macchia PE, Marcocci C, Salvi M, Vermiglio F (2015) Effects of treatment modalities for Graves’ hyperthyroidism on Graves’ orbitopathy: a 2015 Italian Society of Endocrinology Consensus Statement. J Endocrinol Invest 38(4):481–487

Download references


This study was supported by grants from the Ministry of Education, University and Research (MIUR, Rome) to Luigi Bartalena, Luca Chiovato, Rossella Elisei, Stefano Mariotti, Furio Pacini, and Paolo Vitti. Giovanni Veronesi carried out the statistical analyses.

Author information

Correspondence to L. Bartalena.

Ethics declarations

Conflict of interest

All authors state that they have no conflict of interest.

Ethical approval

All procedures performed in human participants during this retrospective study were in accordance with the ethical standards of institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The ethical committee approval is not required for retrospective studies.

Informed consent

For this type of retrospective study, formal consent is not required. Data were anonymized.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Premoli, P., Tanda, M.L., Piantanida, E. et al. Features and outcome of differentiated thyroid carcinoma associated with Graves’ disease: results of a large, retrospective, multicenter study. J Endocrinol Invest 43, 109–116 (2020) doi:10.1007/s40618-019-01088-5

Download citation


  • Thyroid carcinoma
  • Graves’ disease
  • Outcome
  • Thyroidectomy
  • Graves’ orbitopathy
  • TSH-receptor antibody
  • Radioiodine