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Original Investigation
March 3, 2015

The Natural History of Benign Thyroid Nodules

Author Affiliations
  • 1Dipartimento di Medicina Interna e Specialità Mediche, Università di Roma Sapienza, Roma, Italy
  • 2Dipartimento di Scienze della Salute, Università di Catanzaro Magna Graecia, Catanzaro, Italy
  • 3Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy
  • 4Unità di Endocrinologia, Ospedale di Tinchi-Pisticci, Matera, Italy
  • 5Unità Operativa Semplice Dipartimentale di Endocrinologia, Ospedale di Bentivoglio, Bologna, Italy
  • 6Dipartimento di Medicina, Università di Perugia, Perugia, Italy
  • 7Unità Operativa di Endocrinologia, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • 8Dipartimento di Medicina Clinica e Sperimentale, Università di Catania, Catania, Italy
  • 9Unità Operativa di Endocrinologia, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
  • 10Dipartimento di Scienze Mediche di Base, Neuroscienze ed Organi di Senso, Università di Bari Aldo Moro, Bari, Italy
JAMA. 2015;313(9):926-935. doi:10.1001/jama.2015.0956

Importance  Detection of asymptomatic thyroid nodules has increased. Consensus is lacking regarding the optimal follow-up of cytologically proven benign lesions and sonographically nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and reassessment of cytology if significant growth is observed.

Objective  To determine the frequency, magnitude, and factors associated with changes in thyroid nodule size.

Design, Setting, and Participants  Prospective, multicenter, observational study involving 992 consecutive patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid-disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed.

Main Outcomes and Measures  Baseline nodule growth (primary end point) was assessed with yearly thyroid ultrasound examinations. Size changes were considered significant for growth if an increase of 20% or more was recorded in at least 2 nodule diameters, with a minimum increase of 2 mm. Baseline factors associated with growth were identified. Secondary end points were the sonographic detection of new nodules and the diagnosis of thyroid cancer during follow-up.

Results  Nodule growth occurred in 153 patients (15.4% [95% CI, 14.3%-16.5%]). One hundred seventy-four of the 1567 original nodules (11.1% [95% CI, 10.3%-11.9%]) increased in size, with a mean 5-year largest diameter increase of 4.9 mm (95% CI, 4.2-5.5 mm), from 13.2 mm (95% CI, 12.1-14.2 mm) to 18.1 mm (95% CI, 16.7-19.4 mm). Nodule growth was associated with presence of multiple nodules (OR, 2.2 [95% CI 1.4-3.4] for 2 nodules; OR, 3.2 [95% CI, 1.8-5.6 for 3 nodules; and OR, 8.9 [95% CI, 4.4-18.0] for 4 nodules), main nodule volumes larger than 0.2 mL (OR, 2.9 [95% CI, 1.7-4.9] for volumes >0.2 to <1 mL and OR, 3.0 [95% CI, 1.8-5.1] for volumes ≥1 mL), and male sex (OR, 1.7 [95% CI, 1.1-2.6]), whereas an age of 60 years or older was associated with a lower risk of growth than age younger than 45 years (OR, 0.5 [95% CI 0.3-0.9]). In 184 individuals (18.5% [95% CI, 16.4%-20.9%]), nodules shrank spontaneously. Thyroid cancer was diagnosed in 5 original nodules (0.3% [95% CI, 0.0%-0.6%]). Only 2 had grown. An incidental cancer was found at thyroidectomy in a nonvisualized nodule. New nodules developed in 93 patients (9.3% [95% CI, 7.5%-11.1%]), with detection of one cancer.

Conclusions and Relevance  Among patients with asymptomatic, sonographically or cytologically benign thyroid nodules, the majority of nodules exhibited no significant size increase during 5 years of follow-up and thyroid cancer was rare. These findings support consideration of revision of current guideline recommendations for follow-up of asymptomatic thyroid nodules.