Original Paper
HOR MON E RE SE ARCH I N PÆDIATRIC S
Received: November 16, 2009 Accepted: September 28, 2010 Published online: December 7, 2010
Horm Res Paediatr 2011;75:246–251 DOI: 10.1159/000321841
Levothyroxine Treatment in Pediatric Benign Thyroid Nodules Andrea Corrias a Alessandro Mussa a Malgorzata Wasniewska b Maria Segni c Alessandra Cassio d Mariacarolina Salerno e Roberto Gastaldi f Maria Cristina Vigone g Milva Bal d Patrizia Matarazzo a Giovanna Weber g Filippo De Luca b
a
Department of Pediatric Endocrinology and Diabetology, University of Turin, Turin, b Institute of Pediatrics, University of Messina, Messina, c Department of Pediatrics, 1st Faculty, La Sapienza University, Rome, d Department of Pediatrics, University of Bologna, Bologna, e Pediatric Endocrinology, Department of Pediatrics, University Federico II of Naples, Naples, f Department of Pediatrics, University of Genoa, Genoa, and g Department of Pediatrics, University of Milan, Milan, Italy
Key Words Thyroid nodule ⴢ Suppressive therapy ⴢ Childhood nodule ⴢ L-T4 treatment ⴢ Levothyroxine treatment
Abstract Aim: To evaluate the effectiveness of levothyroxine therapy in benign thyroid nodules in pediatrics. Methods: Data from 78 euthyroid children and adolescents with benign thyroid nodules were retrospectively collected. Subjects were divided into 2 groups: levothyroxine treated (n = 36) and nontreated (n = 42), and the clinical, laboratory and sonographic features of the 2 groups were compared. Nodules were considered benign according to histology, fine-needle aspiration biopsy or by features suggestive for benignity. The groups were followed up for 2.4 8 1.3 years, and treated patients received a mean dose of levothyroxine of 1.69 8 0.66 g/kg/day. Results: Patients in the treated and nontreated groups were comparable for age, sex and follow-up. A reduction in nodule diameter from 2.24 8 0.94 to 1.86 8 1.17 cm (p = 0.039) was observed in treated patients, whereas the
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nodule diameter increased from 1.66 8 0.86 to 1.78 8 0.91 cm in nontreated patients (p = 0.024). In the treatment group, 11 patients (30.6%) had a reduction greater than 50% and significantly decreased palpable nodules (p ! 0.001). A nonsignificant reduction in reported symptoms was observed, too. The change in nodule size was directly correlated with thyroid-stimulating hormone levels (r = 0.640, p ! 0.001) and inversely with levothyroxine dose (r = –0.389, p = 0.009). In nontreated subjects, both palpable nodules and symptoms increased. Conclusion: This study supports levothyroxine treatment effectiveness in shrinking benign nodules. Copyright © 2010 S. Karger AG, Basel
Introduction
Thyroid nodules are rare in childhood, with an estimated prevalence ranging from 0.05 to 1.8% [1–3]. Although they are more often malignant in children than in adults, approximately 75–80% of nodules are benign, resulting from thyroidal hyperplasia with or without goi-
Andrea Corrias, MD Division of Endocrinology, Department of Pediatric Endocrinology and Diabetology University of Turin, Regina Margherita Children’s Hospital Piazza Polonia 94, IT–10126 Torino (Italy) Tel. +39 011 313 5853, Fax +39 011 313 5347, E-Mail corrand @ libero.it
ter, adenomas, colloid cysts or abscesses [1]. Solitary thyroid nodules exist within a thyroid gland of normal dimensions, whereas multiple thyroid nodules (commonly with a dominant one) exist within a diffuse multinodular goiter. In solid nodules, possible therapeutic approaches include levothyroxine (L-T4) suppressive therapy. In adulthood, medical treatment has been extensively investigated, but its effectiveness is still controversial [4– 6]. Conversely, very little is known about the effectiveness of L-T4 treatment in pediatrics, owing to the lack of case series, although it has been hypothesized that young patients with relatively small and ‘new’ thyroid nodules might benefit the most [2, 7, 8]. In this study, we aimed to investigate the role of L-T4 treatment in childhood benign thyroid nodular disease by retrospectively comparing the clinical, laboratory and sonographic features of L-T4 treated and nontreated patients. Patients and Methods Patients We conducted a multicentric retrospective study on patients with benign thyroid nodules diagnosed in childhood or adolescence, gathering data from a series of consecutive cases diagnosed and followed up between 2000 and 2008, provided by 7 Italian pediatric endocrinology centers: the Department of Pediatric Endocrinology and Diabetology of the University of Turin, and the Pediatric Endocrinology Units of the Departments of Pediatrics of the Universities of Bologna, Genoa, Messina, Milan and Rome (1st Faculty, La Sapienza University), Italy. Institutional review board approval and patients’ informed consent was not required by the Institutions for retrospective studies involving the simple anonymous review of medical records of patients followed up at those institutions. Seventy-eight children and adolescents (60 female, 18 male, mean age at diagnosis 11.5 8 3.4 years) diagnosed with benign thyroid nodules were included. The following inclusion criteria were applied: (1) the presence of 1 or more thyroid nodules with a sonographically defined diameter greater than 1 cm, (2) a solid echogenic pattern or mixed pattern with a cystic component less than 20%, (3) at least 1 year of follow-up and (4) euthyroidism at diagnosis. Exclusion criteria were: (1) autoimmune thyroid diseases, (2) previous oncological diseases, (3) genetic/malformative disorders and (4) previous treatment with drugs affecting the thyroid metabolism. Nodules were considered benign according to histology (when submitted to surgery, n = 33) or to fine-needle aspiration biopsy cytology (n = 33) when not submitted to surgery, or according to clinical and sonographic features highly suggestive for benignity (n = 12; regular margins with no invasive growth, absence of lymph node alterations, absence of microcalcifications, homogeneity of the echogenic pattern, and normal intranodular flow at Doppler evaluation) [1]. In these latter cases, fine-needle aspiration biopsy was postponed and patients were followed up closely by clinical exam, ultrasound evaluation and laboratory investigations.
L-T4 in Pediatric Thyroid Nodules
Patients were divided into L-T4-treated (n = 36) and nontreated groups (n = 42). Clinical, laboratory, sonographic and treatment information was collected from medical records at the diagnosis and at each of the subsequent admissions. For both study groups, follow-up data were available every 6 months for the vast majority of the patients (with no follow-up interval longer than 12 months). Each patient was followed by the same clinician in the respective center. Nonblinded thyroid ultrasounds were always performed by the same skilled operator using high frequency Bmode 2-dimensional ultrasonography. Inter- and intraoperator variability was not controlled for in this study. For each patient, sex, age at diagnosis, follow-up period, presence of compression signs, TSH and FT4, maximum nodule diameter, and the number of nodules were registered. Each variable was recorded both at the diagnosis of the thyroid nodule and during the follow-up at the time of maximum nodule diameter variation with respect to baseline measurement. Initial treatment dosage was started following the recommended age-related substitutive doses. Treatment was subsequently titrated according to clinical, laboratory and sonographic findings in each patient. Dosages ranged from 0.7 to 3.5 g/kg/day (mean 1.69 8 0.66). TSH and FT4 were determined by high specific fluorometric or enzyme-linked immunoassays with intra- and interassay variations less than 10%. TSH reference values were 0.4–4.4 mU/l. In L-T4-treated patients, the mean dose used in the period between 2 echographies demonstrating a nodule variation was employed. This dosage was considered the most indicative of the presumptive effect of the therapy on nodule diameter. If there were no modifications in maximum nodule diameter, then the last available dosage was registered. Subjects who had clinical signs of compression of adjacent structures (discomfort, dysphagia, pain, breathing obstruction and hoarseness) were submitted to a tracheal X-ray. The maximum sonographic diameter of the nodule (the dominant nodule when there was multinodular disease) was considered as an index of treatment response. The difference in maximum nodule diameter was arbitrarily defined as a variation in a measurement of at least 10% compared to baseline. This cutoff was chosen as it roughly corresponded to a 30% volume modification in an ideal sphere with the maximum nodule diameter, a cutoff value frequently used in other studies [4, 9, 10]. A minimum 10% variation in the smallest nodule included (1 cm) seems, moreover, to approximate the average resolution limit of ultrasound imaging. We divided the series according to diameter change with respect to baseline: increased, unchanged, decreased 10–50%, decreased over 50%. Differences in the 2 groups’ characteristics were evaluated and correlations were sought among studied parameters in order to find factors associated with nodule modification. Statistical Analyses The Shapiro-Wilk test was used to check the normality of data distribution. Differences between the groups were established by Student’s t test. Pearson’s correlation coefficients were applied to check univariate associations. 2 and Fisher’s exact tests were employed to assess distributions. Calculations were considered statistically significant when the p value was less than 0.05. SPSS software (version 15.0; IBM, Chicago, Ill., USA) was used.
Horm Res Paediatr 2011;75:246–251
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Table 1. Clinical, laboratory and sonographic features of L-T4-treated and nontreated patients
Clinical and laboratory features
L-T4-treated (n = 36)
Nontreated (n = 42)
p
Age, years Female-to-male ratio Mean follow-up period, years Palpable vs. nonpalpable nodules at diagnosis Palpable vs. nonpalpable nodules at the end of follow-up Clinical signs of compression at diagnosis, yes/no Clinical signs of compression at the end of follow-up, yes/no L-T4 dosage at the time of maximum nodule variation, g/kg/day TSH at diagnosis, mU/l1 TSH at the time of maximum nodule variation, mU/l1 Sonographic features Nodule diameter at diagnosis, cm Nodule diameter at the end of follow-up, cm Nodule diameter variation, cm Percent modification with respect to diagnosis Diameter modification with respect to diagnosis (%) Reduced >50% with respect to diagnosis Reduced 10–50% with respect to diagnosis Unmodified Increased Uninodular vs. multinodular ratio at diagnosis Uninodular vs. multinodular ratio at the end of follow-up
12.282.5 26/10 2.581.3 33/3 20/163 12/24 6/30 1.6980.66 2.3181.10 1.3181.022
10.983.6 34/8 2.481.4 28/14 25/17 3/39 8/34 – 2.1880.79 2.1080.97
0.077 0.432 0.713 0.012 0.819 0.004 0.999 – 0.356
