National Program for Nodular Goiter (PRONBONO). Multicenter study of single palpable thyroid nodules

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1 National Program for Nodular Goiter (PRONBONO). Multicenter study of single palpable thyroid nodules Corino M., Faure E., Deutsch S. and other members of the Thyroid Department of SAEM: Abalovich M., Alcaraz G., Balzaretti M., Becerra H., Brenta G.,Cabezón C. Ferreiro, L., Frascaroli G., Gauna A., Gutiérrez S., Iorcansky S., Lowenstein A., Maza Puig C., Melado G., Niepomniszcze H., Orlandi A., Puscar A., Reyes A., Rezzónico J., Ridruejo C., Roccatagliata G., Sartorio G., Schnitman M., Silva Croome M. del C., Storani M.E., Vázquez G. FASEN (Argentine Federation of Endocrinology Societies) Thyroid Department of SAEM. (Argentine Society of Endocrinology and Metabolism) ABSTRACT Introduction: the presence of palpable thyroid nodules in the general population is one of the most common clinical signs of thyroid disease in daily practice. Objectives: 1) To assess the prevalence of pathologies, clinical and cytological findings of single palpable thyroid nodules (SPTN) in Argentina. 2) To analyze regional differences in Argentina. Methods: Prospective study of 739 patients with STPN who were evaluated at centres in Buenos Aires, Bahía Blanca, Mendoza, and La Pampa between 1/1/00 and 12/31/01. Clinical examination, thyroid ultrasound scan (US), TSH, TPOAb and fine needle aspirations (FNA) were performed. Statistics: Pearson Correlation, X2 & Fisher Tests. Results: Age (X ± SD) 46 ± 14ys: 93.1 % were women. Previous history of neck radiation & familial thyroid disease were found in 1.6 and 29.9 %, respectively. Clinical findings: dysphagia: 7.9 %; dysphonia: 3.5%; nodule growth: 19.2 %; hard consistence: 24.7 %; fixation to adjacent structure: 1.5 % and lymphadenopathies (ADP): 3 %. Biochemical findings: TSH was normal in 81.2 % & TPOAb+ in 30.3 %. US features: solid: 53.1 %; hypoechoic: 63.8 %; microcalcifications: 10.3 %; incomplete halo: 15 %; more than 1 nodule: 30.5 %; thyroid heterogeneity: 60.2 % and ADP: 3.8 %. Cytology: Only 1 FNA was needed in 86.8%. Unsatisfactory (excluding cysts): 3.2 %; benign: 77.2%; suspicious: 12.6 % and cancer: 7 % (42 papillary, 2 medullary and 3 non-specified). A significant correlation (p<0.02) was established between malignant nodules and rapid growth, hard, fixed, solid nodule, incomplete halo and ADP, though these parameters were more frequent (in absolute number) in benign nodules. Surgery was mainly indicated based on FNA results. Histological diagnosis of 96 patients who underwent surgery showed 51 carcinomas, of which only 2 were cytologically benign, and 31 adenomas. Conclusion: Palpable single nodules were more frequent in middle aged euthyroid women. One third had familial thyroid pathology, similar to the presence of TPOAb. On US, nodules were predominantly solid, hypoechoic, single with heterogeneous thyroid gland. FNA was predominantly benign. Rapid growth, hard, fixed, solid nodule, incomplete halo and ADP were associated with malignancy, but benignity was more common. In most patients, surgery was recommended based on cytological findings. Our results are similar to those reported in other geographic areasno financial conflicts of interest exist. Key words: single palpable thyroid nodules; thyroid cytology and ultrasound INTRODUCTION The presence of palpable thyroid nodules in the general population is commonly found in daily practice. Fine needle aspiration has been accepted as the diagnostic method of choice in the initial evaluation of thyroid nodules. The clinical and ultrasound features of nodules are a supplementary factor to make a proper diagnosis. Nodular thyroid disease has a prevalence ranging between 2.5% and 7 % (1-3), predominantly in women in iodine-sufficient areas. Thus, nodular thyroid disease involves a diagnosis dilemma for specialists to differentiate malignant nodules. Post-surgical findings have shown that between 5 and

2 15% of all nodules which underwent surgery are malignant (4-5). Factors such as age, gender, radiation exposure and family history lead to suspect malignancy when a thyroid nodule is found. However, it is not clear if there are other parameters to predict malignancy. As a consequence of that, members of the FASEN decided to study the predictive malignancy value of the clinical and ultrasound features of single palpable nodular goiter. The Thyroid Department of SAEM prepared a study protocol known as National Program of Nodular Goiter (PRONBONO) whose objectives were: 1) to establish the prevalence of different pathologies through fine needle aspiration in single palpable nodular goiter and analyze its features and correlation with cytological findings and histology in patients who underwent surgery; 2) to analyze the existence of regional differences. Study Author Year n Prevalence Age Women Men Framingham (US) Whickham (UK) Vander % % 1.5% Tunbridge % % 0.8% MATERIAL AND METHODS Study design: prospective, cross-sectional and multicenter. We prospectively studied patients with single palpable nodular goiter who presented between 1/JAN/2000 and 31/DEC/2001 at 19 sites: 16 in the city of Buenos Aires and Greater Buenos Aires, 1 in the city of Bahía Blanca, 1 in Mendoza and 1 in Santa Rosa, La Pampa. The inclusion criteria for this study were: patients presenting for the first time with a single palpable nodule, who underwent fine needle aspiration, with or without prior treatment for thyroid disease. The exclusion criteria were multi-nodular goiter or diffuse goiter found by palpation. Medical records of all patients were prepared including history of neck radiation, prior thyroid treatment as well as surgeries; non-thyroid autoimmune disease and family history of thyroid disease and Multiple Endocrine Neoplasia. Patients were questioned about nodule evolution, growth in the last 6 months and presence of local symptoms such as pain, dysphagia and dysphonia. Neck examination included nodule palpatory findings: longitudinal and transverse diameters, consistency (hard, soft, firm and/or elastic), adherence to deep planes, pain on palpation and features of the rest of the gland. In patients with enlarged lymph nodes, their number, location and size were reported. Laboratory parameters included TSH levels (with ultrasensitive methodology depending on each site) and the presence of antithyroid antibodies (ultrasensitive TPOAb or anti-m by hemagglutination test) considering them either positive or negative depending on the reference range of each method. The US scan had to be performed by a thyroid-experienced operator using a mhz transducer. The operator had to fill in a form with information about nodule size (specifying three diameters: AP-T-L); characteristics: solid, cystic or mixed; echogenicity, presence or absence of posterior enhancement or acoustic shadow, calcifications (micro, macro or egg shell); presence of nodular halo; number of nodules;

3 type of nodular and glandular contour; features of the rest of the thyroid parenchyma, as well as the presence of lymph nodes. For the cytological study, a group of recognized cytologists specialized in thyroid pathology previously determined the protocol methodology and established consistent criteria. The number of FNA repetitions necessary to reach a diagnosis, gross (liquiddrops or volume, solid) and microscopic description were recorded. The material was classified as unsatisfactory, benign, unspecified cyst, follicular proliferation, Hürthle Cell Tumor, malignant and tumor not originated in thyroid epithelium. The histological report of patients who had to undergo surgery was the statistical analysis of data, we used: The statistical analysis was performed using Pearson correlation, Chi Square Test and Fisher s Exact Test. RESULTS The data obtained from 739 patients with single palpable nodular goiter were analyzed. The proportion of patients evaluated at the above-mentioned sites is detailed in Table I. The group studied included 688 women (93%) and 51 men (7%), woman to man ratio: 13/1, age ( ± SD): 46.3 ± 14 years old (range: 16 to 81 years old). Twenty-nine point nine per cent (n=219) of patients had a family history of thyroid disease and one patient, of multiple endocrine neoplasia (MEN). Eighteen per cent (n=121) had received prior treatment with thyroid hormones, while 4.3% (n=31) had undergone thyroid surgery. 12 (1.6%) patients had been exposed to neck radiation. The patient-reported duration of goiters (expressed in months) ranged from 0.1 to 480 (40 years), with a mean of 25.8 months. As regards symptoms, 19.2% of patients reported nodule growth in the last six months; 7.9%, dysphagia; 6.4%, pain and 3.5% dysphonia. On thyroid palpation, nodules had a longitudinal diameter of 23.7 mm (± 12.5) (5-80 range) and mm (± 11) (4-60 range) in transverse diameter. In terms of consistence, 43.1% of nodules were firm, 24.7% were hard, 20.8% were elastic and 11.4% were soft. The rest of the gland was normal in 67.5% of patients. On neck palpation, we found tender nodules in 6.5% of patients, fixed nodules in 1.5% and lymph node enlargement in 3%. TSH levels were measured in 675 patients. The mean was 2.9 miu/l with a SD of ± 8.7 ( ). In 81.9% of patients (553/675), TSH levels were within the normal range. In 10.1% (68/675), above the highest limit and in 8% (54/675), below the lowest limit, based upon the methodology used and the range applied. The presence of anti-thyroid antibodies was evaluated in 638 patients, 30.3% of which were positive (n=193). In the ultrasound scan, nodule diameters expressed in mm ± SD were: anteroposterior: 18.3 ± 10.3; transverse 17.2 ± 10.4; longitudinal 21.6 ± 12.5; there being a highly significant linear correlation between palpation and ultrasound both in transverse (r 0.620) and longitudinal measurements (r 0.703) (p<0.0001). Pearson correlation coefficients were calculated and a highly significant linear correlation was found between Palpation and Ultrasound both in transverse and longitudinal measurements. (P<0.0001). Figure 1. When analyzing the ultrasound scan variables studied, we found that 53.1% of nodules were solid, 33.3% were mixed and 13.6% were cysts. Regarding echogenicity, 63.8% of nodules were hypoechoic, 17.9% were hyperechoic and 18.4% were isoechoic

4 compared to the remaining parenchyma. Calcifications were found in 27.3% of nodules (microcalcifications in 10.3% and macrocalcifications in 7%), complete halo (CH) in 17.1% and incomplete halo (IH) in 15% of cases. Single nodules were found on ultrasound in 69.5% of patients and multiple nodules, in 30.5%. The remaining thyroid parenchyma was heterogeneous in 60.2% of patients and nodular contour was regular in 77.7% of patients. Enlarged lymph nodes were reported in 3.8% of patients and muscular planes were free in 100% of patients. As regards fine needle aspiration, cytological diagnosis was made in 86.8% of nodules through a single procedure, and in 13.2% of cases, repeat aspiration was necessary to reach a diagnosis. The cytological material was macroscopically solid in 59.6% of patients and liquid material was obtained in 40.4% of cases. Cytological reports showed that 77.2% of samples were benign, 7% were malignant, 12.6% were doubtful and 3.2% were unsatisfactory. Table II shows the different cytological diagnoses found and their rates. In our population, benign cytology was more common between 40 and 60 years of age (68.64%). By contrast, malignancy was more common between 30 and 50 years of age (72.2%), in younger patients. Figure 2. Table I. Proportion of patients from the different participating sites Site Rate Percentage Alvarez Bazterrica Británico Churruca Clínicas Cpe Durand Fernandez Frances Inst megan Italiano Militar Penna Perinat Posadas Ramos Rivadavia San Isidro Total Sites of the city of Buenos Aires; 2 Sites of Greater Buenos Aires. CPE of Mendoza, Instituto MEGAN of La Pampa, Hospital PENNA of Bahía Blanca.

5 Transverse ultrasound (mm) Longitudinal ultrasound (mm) Transverse palpation (mm) Longitudinal palpation (mm) Figure 1. Correlation between palpation and ultrasound diameters. Pearson correlation coefficients were calculated and there was a highly significant linear correlation between Palpation and Ultrasound both in transverse and longitudinal measurement. (P<0.0001). TABLE II. Cytological findings and rates Cytological report N % Colloid goiter Thyroiditis Epithelial hyperplasia Colloid cyst Benign 77.2% benign Unspecified Colloid cyst Benign Unspecified Epithelial hyperplasia and hyperfunction Follicular proliferation doubtful Hürthle cell tumor Papillary carcinoma Medullary carcinoma % malignant Malignant unspecified Unsatisfactory % unsatisfactory

6 Age Age Age distribution of patients with benign cytology Age distribution of patients with malignant cytology Figure 2. Age distribution in benign and malignant cytology. TABLE III. Nodule features associated with malignant cytology Clinical US Fine Needle Aspiration Recent growth (p<0.02) Solid (p<0.01) Solid macroscopy (p<0.001) Hard consistency (p<0.001) Fixed nodule (p<0.01) Incomplete halo (p<0.01) Single nodule (p<0.01) Enlarged lymph nodes (p<0.04) Statistical Results In the population studied, we did not find a statistically significant correlation between malignancy and gender. (p = NS). Nodular growth in the last 6 months (p<0.02); hard consistency (p<0.001) and adherence to surrounding structures (p<0.01) were the clinical features associated with malignancy. (Table III). In 83.3% of smears with malignant cytology, the material obtained was solid, in correlation with malignancy. (p<0.001) (Table III). The presence of a single solid nodule with incomplete halo on US correlated with malignancy (p<0.01), as well as the presence of enlarged lymph nodes. (p<0.04) (Figure 3). According to the medical and/or cytological criterion, 96 patients underwent surgery. Histological findings were as follows (Figure 4): - 25 follicular adenomas - 6 Hürthle cell adenomas - 6 colloid goiters - 4 follicular cell hyperplasia - 2 thyroiditis - 1 colloid cyst - 40 papillary carcinomas - 6 follicular carcinomas - 2 medullary carcinomas - 3 without histological report

7 Of the 48 carcinomas that underwent surgery, cytology was negative in 4 cases (8.3% FALSE NEGATIVE). In 47 malignant cytological findings that underwent surgery, 2 had benign histology (4.2% FALSE POSITIVE). As regards the 41 patients with cytology consistent with follicular proliferation and/or Hürthle cell tumor with indication for surgery, histological findings were as follows: - 24 follicular adenomas - 6 Hürthle cell adenomas - 2 hyperplasias of follicular cells - 2 colloid goiters - 4 papillary carcinomas - 3 follicular carcinomas That is, 17.07% of follicular proliferation and/or Hürthle cell tumor were carcinomas according to their histological findings. Yes Yes Yes Yes Solid IH SN Lymph node enlargement Benign Malignant Figure 3. US features associated with malignancy. There is a significant correlation between malignant cytology and solid nodules on US: P<0.01; incomplete nodular halo (HI); P<0.06; single nodule on US; p <0.06 and the presence of neck lymph nodes; P<0.08. (References: Quiste coloide = Colloid cyst; Tiroiditis = Thyroiditis; Adenomas foliculares = follicular adenomas; Bocio hiperplasia = hyperplasia goiter; Sin datos = No data; Maligno = malignant) Figure 4: Percentage of histological findings in 96 cases where surgery was recommended.

8 DISCUSSION This cross-sectional, prospective and multicenter study conducted in the Argentine Republic enabled us to establish the features of the population with single palpable thyroid nodule, and their correlation with the clinical parameters evaluated, US findings, cytology and histology of patients who were operated on. In clinical practice, risk assessment for malignancy of a thyroid nodule is based upon a set of multiple features: gender, age, personal history, family history, growth, gland features, enlarged lymph nodes, nodule size, laboratory test such as TSH level, determination of antibodies and fine needle aspiration considered the most reliable parameter to rule out malignancy in thyroid nodule. The contribution made by Gharib- Goelner (6) in 1993, (18163 patients) and Mazzaferri-Caruso (7) in 1995 (9119 patients) reaffirm the importance of the cytological findings in nodular pathology. In the epidemiological data of our study, most nodules occurred in women, with a female/male ratio of 13:1 and an age range corresponding to middle age. In consistency with these findings, Hagag et al (8) reported in 254 patients a mean age of 44±9.5 years and the same ratio for gender (13:1). In 542 patients participating in a study at Hospital de Clinicas, Niepomniszcze et al (3) reported a female/male ratio of 4:1 with a wide age range (2-85 years). These data show a high prevalence of nodular pathology in women. Thirty percent of our patients had a family history of thyroid disease or positive antibodies. In consistency with these data, Hagag et al (8) reported 29.7% of positive thyroid autoimmunity in their population. Eighty-nine percent of the 151 patients studied by Gerry et al (9) were euthyroid. We found that TSH levels were within normal ranges in 82% of the population. As regards nodule size, in recent studies, Lubitz et al (10) analyzed cytological and clinical findings in 144 patients with nodules suspicious for malignancy. Women accounted for 75% of the population with nodule; the mean age was 55 years; nodules > 4 cm were significantly associated with malignancy. In our study, nodular size had no statistical correlation with malignancy. As regards symptoms associated with malignancy, we found that nodular growth in the last 6 months was one of the most representative signs. However, neither spontaneous pain nor tenderness to palpation, or dysphagia or dysphonia was indicative of nodules with malignant cytology. Our findings are consistent with the classification made by Hamming in 1990 (11), and which is currently in effect. This classification establishes risk groups defined by clinical findings, where rapid growth and nodule hardness are included as highly suspicious for malignancy. According to his data, such features are associated with 71% of histological prevalence of carcinoma. In this study, clinical signs associated with cytological malignancy were rapid growth, fixation and hardness, in agreement with other authors such as Tuttle et al (12). It should be noted that the American Thyroid Association takes into account these data to prepare the recommendations for the management of patients with nodules and differentiated thyroid carcinoma. ATA 2006 (13) and 2009 (14). Ultrasound is a diagnostic method commonly used to evaluate thyroid nodules. It should be noted that the combination of different US features have a strong predictive value for malignancy as shown by Hyun Jung et al (15). Such authors describe several US properties associated with suspicion for malignancy, such as single, solid, hypoechoic nodule, calcifications and enlarged lymph node. In a group of cases in Argentina, in ultrasound-guided FNA, Capriata, Orlandi et al (16) found that 51% of solid and hypoechoic nodules were associated with malignancy. In 2002, in the study of non palpable nodules, Papini et al (17) assessed the value of US and color Doppler in thyroid nodules and agreed that microcalcifications,

9 hypoechogenicity and irregular nodular margins were predictors of malignancy, as well as the presence of multiple intranodular newly-formed vessels on Doppler ultrasound. In our study, the presence of a single, solid nodule with incomplete halo on US correlated with malignant cytology in 93.2% of patients. In malignant pathology, enlarged lymph nodes occurred in 25% of cases. As regards cytological findings, in patients, Gharib et al (6) found benignity in 69%, follicular proliferation in 10%, malignancy in 3.5% and inadequate specimen in 17%, with this being one of the first published studies with a large sample size. Lubitz et al (10) reported in 144 patients malignancy in 11% and benignity in 88.9%. In 2008, Baloch et al (18) reported in aspirated nodules, 5 to 10% risk of malignancy and 15 to 30% risk of follicular neoplasm. In PRONBONO, diagnosis was made with a single procedure in 87% of patients. Benign pathology was the most frequent result; the percentage of unsatisfactory material was low (3%) and malignancy accounted for 7%. According to age, carcinoma occurred at 30 to 50 years of age and there was no statistical correlation between gender and malignancy. In a national study performed by Gutiérrez, Capriata et al (19), 352 patients who underwent fine needle aspiration were evaluated; the percentage of cancer in patients who underwent surgery was 7.6%, similar to our findings. In 2004, Ylagan et al (20) established a cyto-histological correlation in nodules > 4 cm and found 5% of false negatives. Our pathology results determined that 4.2% were false positives and 8.3% were false negatives. Gagneten et al (21) reported cyto-histological correlation in 107 patients and found the following histology in 21 follicular proliferations: 33% adenoma, 28.6% carcinoma, 33.3% hyperplasia and 4.8% chronic thyroiditis. In PRONBONO, in the 41 patients operated on with cytology of follicular proliferation, benign pathology (adenoma) was the most common, and 17% carcinomas were diagnosed: 4 papillary and 3 follicular. CONCLUSIONS Most nodules occurred in middle-aged, asymptomatic, euthyroid female patients. The presence of 30% of family thyroid pathology was similar to the presence of positive antibodies. On US, most single, solid and incomplete halo nodules were associated with malignancy. Even if the percentage of false positives and negatives is consistent with the literature, the number of false negatives should tend to decrease. The low percentage of unsatisfactory material and the good correlation between palpation and ultrasound measurement should be highlighted. These results at population level do not imply diagnostic accuracy at individual patient level. In this multicenter study, we could not achieve the objective of establishing regional differences in nodular pathology, probably due to the low number or absence of data from all geographic areas in the country. REFERENCES

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