Long-Term Follow-up of Thyroid Nodule Growth

Summary

Benign thyroid nodules are common in iodine deficient countries. Although many recent studies have addressed the molecular basis and short-term outcome of treatment in nodular thyroid disease, data on the long-term follow-up of thyroid nodule growth are widely lacking. The aim of the present study was to evaluate the long-term behaviour of benign thyroid nodules growth.

We followed 109 consecutive patients seen at yearly intervals in our Outpatient Clinic for at least 3 years (range 3-12 years, mean 4.9 ± 2.6 years) presenting with 139 benign nodules in uni- or multinodular goiters. The size of the nodules and thyroid glands was analysed retrospectively. The study included a spectrum of benign thyroid nodules, 86 functioning and 53 non-functioning. 27 patients were treated with levothyroxine, 8 with iodide and 16 with a combination of both. 58 patients were not treated mainly because of thyroid functional autonomy. Patients with overt hyperthyroidism or suspected malignancy by fine-needle aspiration were excluded from the study. The nodules and glands were assessed by ultrasonography at yearly intervals and documented by photoprints. Relevant growth was defined as an increase in nodule volume of at least 30%. For statistical analyses, Cox Proportional Hazard Model and life-table analyses according to Kaplan-Meier were performed. Most thyroid nodules grew slowly but continously during follow-up. After about 3 years, half of the nodules had increased their volume by at least 30%. Growth of the nodules was significantly faster than of the corresponding thyroid glands (p < 0.0001).

Age and sex of the patients and size or function of the nodules at initial presentation were not significantly related to their growth. Suppression of TSH did not affect growth of the nodules irrespective of the source of thyroid hormones, endogenous or by administration of levothyroxine. In conclusion, benign thyroid nodules have a slow intrinsic growth potential, which is apparently higher than that of the non-nodular tissue. In this study, not only nodular but even non-nodular goiter growth continues in the majority of patients. Exogeneous factors, including therapy with levothyroxine and/or iodide, appear to have little effect on the growth behaviour.

Thyroid nodules - goiter - levothyroxine - ultrasonography - TSH

References

• 1 Bennedbaek F N, Nielsen L K, Hegedus L. Effect of percutaneous ethanol injection therapy versus suppressive doses of L-thyroxine on benign solitary solid cold thyroid nodules: a randomized trial.  J Clin Endocrinol Metabol. 1998;  83 830-835
• 2 Brix T H, Kyvik K O, Hegedus L. Major role of genes in the etiology of simple goiter in female: a population based twin study.  J Clin Endocrinol Metabol. 1999;  84 3071-3075
• 3 Brunn J, Block U, Bos U, Kunze W P, Scriba P C. Volumetrie der Schilddrüsenlappen mittels Real-Time-Sonographie.  Dtsch Med Wochenschrift. 1981;  106 1338-1340
• 4 Burgi H, Supersaxo Z, Selz B. Iodine deficiency diseases in Switzerland one hundred years after Theodor Kocher's survey: a historical review with some new goitre prevalence data.  Acta Endocrinol. 1990;  123 577-590
• 5 Celani M F, Mariani M, Mariani G. On the usefulness of levothyroxine suppressive therapy in the medical treatment of benign solitary, solid or predominantly solid thyroid nodules.  Acta Endocrinol. 1990;  123 603-608
• 6 Cheung P S, Lee J M, Boey J H. Thyroxine suppressive therapy of benign solitary thyroid nodules: a prospective randomized study.  World J Surg. 1989;  13 818-822
• 7 Csako G, Byrd D, Wesley R A, Sarlis N J, Skarulis M C, Nieman L K, Pucino F. Assessing the effects of thyroid suppression on benign solitary thyroid nodules. A model for using quantitative research synthesis.  Medicine. 2000;  79 9-26
• 8 Delange F. The disorders induced by iodine deficiency.  Thyroid. 1994;  4 107-128
• 9 Derwahl M. Molekulare Aspekte in der Pathogenese von Knoten und Adenomen der Schilddrüse.  Schweiz Med Wochenschrift. 1994;  124 1613-1618
• 10 Derwahl M, Broecker M, Kraiem Z. Clinical Review 101: Thyrotropin may not be the dominant growth factor in benign and malignant thyroid tumors.  J Clin Endocrinol Metab. 1999;  84 829-834
• 11 Dunn J T, Medeiros-Neto G A. Endemic goiter and cretinism: Continuing threats to the world health. Pan American Health Organization, WHO, Scientific Publication No. 292 1974
• 12 Gharib H, James E M, Charboneau J W, Naessens J M, Offord K P, Gorman C A. Suppressive therapy with levothyroxine for solitary thyroid nodules: A double-blind controlled clinical study.  N Engl J Med. 1987;  317 70-75
• 13 Gharib H. Changing concepts in the diagnosis and managment of thyroid nodules.  Endocrinol Metab Clin North Am. 1997;  26 777-800
• 14 Gharib H, Mazzaferri E L. Thyroxine suppressive therapy in patients with nodular thyroid disease.  Ann Intern Med. 1998;  128 386-39
• 15 Gullu S, Gursus M A, Baskal N, Uysal A R, Kamel A N, Erdogan G. Suppressive therapy with levothyroxine for euthyroid diffuse and nodular goiter.  Endocr J. 1999;  46 221-226
• 16 Gutekunst R, Smolarek H, Hasenpusch U, Stubbe P, Friedrich H J, Wood W G, Scriba P C. Goitre epidemiology: thyroid volume, iodine excretion, thyroglobulin and thyrotropin in Germany and Sweden.  Acta Endocrinol. 1986;  112 494-501
• 17 Hamburger J I, Miller J M, Kini S R. Diagnosis of thyroid nodules by needle biopsy. In: Ingbar SH, Bravermann LE (eds), Werner's the thyroid JB Lippincott Company, Philadelphia 1986: 592-604
• 18 Hamburger J I, Hamburger S W. Diagnosis and management of large toxic multinodular goiters.  J Nucl Med. 1985;  26 888-892
• 19 Hampel R, Kuhlberg T, Klein K, Jerichow J U, Pichmann E G, Clausen V, Schmidt I. Strumaprävalenz in Deutschland ist größer als bisher angenommen.  Med Klinik. 1995;  90 342-349
• 20 Knudsen N, Bols B, Bulow I, Jorgensen T, Perrild H, Ovesen L, Laurberg P. Validation of ultrasonography of the thyroid gland for epidemiological purposes.  Thyroid. 1999;  9 1069-1074
• 21 Knudsen N, Perrild H, Christiansen E, Rasmussen S, Dige-Petersen H, Jorgensen T. Thyroid structure and size and two-year follow-up of solitary cold thyroid nodules in an unselected population with borderline iodine deficiency.  Eur J Endocrinol. 2000;  142 224-230
• 22 Kopp P, Kimura E T, Aeschimann S, Oestreicher M, Tobler A, Fey M F, Studer H. Polyclonal and monoclonal thyroid nodules coexist within human multinodular goiters.  J Clin Endocrinol Metab. 1994;  79 134-139
• 23 Kuma K, Matsuzuka F, Kobayashi A, Hirai K, Morita S, Miyauchi A, Katayama S, Sugawara M. Outcome of long standing solitary thyroid nodules.  World J Surg. 1992;  16 583-588
• 24 Kuma K, Matsuzuka F, Yokozawa T, Miyauchi A, Sugawara M. Fate of untreated benign thyroid nodules: results of long-term follow-up.  World J Surg. 1994;  18 495-499
• 25 La Rosa G L, Ippolito A M, Lupo L, Cercabene G, Santonocito M G, Vigneri R, Belfiore A. Cold thyroid nodule reduction with L-thyroxine can be predicted by initial nodule volume and cytological characteristics.  J Clin Endocrinol Metab. 1996;  81 4385-4387
• 26 Lima N, Knobel M, Cavaliere H, Sztejnsznajd C, Tomimori E, Medeiros-Neto G. Levothyroxine suppressive therapy is partially effective in treating patients with benign, solid thyroid nodules and multinodular goiters.  Thyroid. 1997;  7 691-697
• 27 Mainini E, Martinelli I, Morandi G, Villa S, Stefani I, Mazzi C. Levothyroxine suppressive therapy for solitary thyroid nodule.  J Endocrinol Invest. 1995;  18 797-799
• 28 Paggi A, Persegani-Trimarchi C, Russo P, Mastropasqua M, Mosetti M A, Losi T, Leri O. Solitary nodular disease and multinodular goiter: a retrospective study on suppressive versus replacement levothyroxine therapy.  Endocr Res. 1999;  25 229-238
• 29 Papini E, Bacci V, Panunzi C, Pacella C M, Fabbrini R, Bizzarri G, Petrucci L, Giammarco V, La Medica P, Masala M. et al . A prospective randomized trial of levothyroxine suppressive therapy for solitary thyroid nodules.  Clin Endocrinol. 1993;  38 507-513
• 30 Papini E, Petrucci L, Guglielmy R, Panunzi C, Rinaldi R, Bacci V, Crescenci A, Nardi F, Fabbrini R, Pacella C M. Long-term changes in nodular goiter: a 5-year prospective randomized trial of levothyroxine suppressive therapy for benign cold thyroid nodules.  J Clin Endocrinol Metab. 1998;  83 780-783
• 31 Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont J, Vassart G. Somatic mutation in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas.  Nature. 1993;  365 649-651
• 32 Parma J, Duprez L, Van Sande J, Paschke R, Tonacchera M, Dumont J, Vassart G. Constitutively active receptors as a disease-causing mechanism.  Mol Cell Endocrinol. 1994;  100 159-162
• 33 Paschke R, Ludgate M. The thyrotropin receptor in thyroid diseases.  N Engl J Med. 1997;  337 1675-1681
• 34 Peter H J, Gerber H, Studer H, Smeds S. Pathogenesis of heterogenity in human multinodular goiter. A study on growth and function of thyroid tissue transplantated onto nude mice.  J Clin Invest. 1985;  76 1992-2002
• 35 Reverter J L, Lucas A, Salinas I, Audi L, Foz M, Sanmarti A. Suppressive therapy with levothyroxine for solitary thyroid nodules.  Clin Endocrinol. 1992;  36 25-28
• 36 Scriba P C, Beckers. et al . Goitre and iodine deficiency in Europe. Report of the subcommitte for the study of endemic goitre and iodine deficiency of European Thyroid Association.  Lancet. 1289-1293 1985; 
• 37 Smeds S, Peter J H, Jortso E, Gerber H, Studer H. Naturally occurring clones of cells with high intrinsic proliferation potential within the follicular epitheelium of mouse thyroids.  Cancer Res. 1987;  47 1646-1651
• 38 Studer H, Peter H J, Gerber H. Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth.  Endocr Rev. 1989;  10 125-135
• 39 Studer H, Derwahl M. Mechanisms of nonneoplastic endocrine hyperplasia - a changing concept: a review focused on the thyroid gland.  Endocr Rev. 1995;  16 411-426
• 40 Tunbridge W M, Evered D C, Hall R, Appleton D, Brewis M, Clark F, Evans J G, Young E, Bird T, Smith P A. The spectrum of thyroid disease in a community: the Whickham survey.  Clin Endocrinol. 1977;  7 481-493
• 41 Vanderpump M P, Tunbridge W M, French J M, Appleton D, Bates D, Grimley Evans J, Hasan D M, Rodgers H, Tunbridge F. et al . The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey.  Clin Endocrinol. 1995;  43 55-68
• 42 Zelmanovitz F, Genro S, Gross J L. Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study and cumultative meta-analysis.  J Clin Endocrinol Metab. 1998;  83 3881-3885