Autoimmune thyroiditis in benign and malignant thyroid nodules: 16-year results

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1 ORIGINAL ARTICLE Autoimmune thyroiditis in benign and malignant thyroid nodules: 16-year results Irene Giagourta, MD, Catherine Evangelopoulou, MD, Garyfallia Papaioannou, MD, Georgia Kassi, MD, PhD, Evangelia Zapanti, MD, PhD, Maria Prokopiou, MD, Konstantinos Papapostolou, MD, Helen Karga, MD, PhD* Second Division of Endocrinology, Alexandra Hospital, Athens, Greece. Accepted 8 February 2013 Published online 1 June 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. It is controversial whether autoimmune thyroiditis is associated with higher frequency of papillary thyroid carcinoma (PTC). Methods. This was a cross-sectional, retrospective study. PTCs were compared to benign nodules regarding the prevalence of autoimmune thyroiditis over 16 years. Results. A similar proportion of autoimmune thyroiditis was observed in both benign and/or malignant nodules. Mean nodule size in cases with autoimmune thyroiditis was smaller than those without autoimmune thyroiditis. Multivariate analysis showed a negative association between the coexistence of autoimmune thyroiditis and lymph node and/or distant metastases. Lymph nodes involvement and distant metastases were lower in the PTC with autoimmune thyroiditis compared to those without autoimmune thyroiditis. Capsular invasion was a strong predictor for distant metastases attenuated by the presence of autoimmune thyroiditis. Conclusion. Thyroid nodules with autoimmune thyroiditis are not more likely to be malignant than those without autoimmune thyroiditis. The coexistent autoimmune thyroiditis may be beneficial as a decreased incidence of lymph nodes involvement and distant metastasis was seen in those patients. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: autoimmune thyroiditis, thyroid nodules, papillary carcinomas INTRODUCTION There is evidence that autoimmune thyroiditis is associated with an increased prevalence of papillary thyroid carcinoma (PTC), suggesting a link between these 2 entities. 1,2 However, it is not clear if thyroiditis facilitates reactions toward neoplasia or if these 2 pathologies coexist in the same patient independently of each other. Although the typical clinical picture of autoimmune thyroiditis is characterized by a diffuse goiter, the coexistence of solitary or multiple thyroid nodules is not rare. The majority of these nodules have poor uptake of radioisotopes, raising the question of malignancy. Some studies have shown that patients with autoimmune thyroiditis are 3 times more likely to have thyroid cancer. 3,4 Consequently, some authors have recommended thyroidectomy for Hashimoto s thyroiditis. 5,6 On the other hand, in some studies, it was not found that an increased frequency of malignancy in patients with autoimmune thyroiditis and a similar frequency of coexisting autoimmune thyroiditis and PTC or benign goiter and autoimmune thyroiditis was observed. 7 Furthermore, the effect of the coexistent autoimmune thyroiditis on prognosis in patients with PTC remains controversial. For example, the PTC with autoimmune thyroiditis has less aggressive clinical presentation *Corresponding author: H. Karga, Alexandra Hospital, Vas Sofias at Lourou str, 11528, Athens, Greece. hkarga@yahoo.gr and better prognosis, a lower frequency of extrathyroidal invasion, nodal involvement, and absence of distant metastases. 8,9 However, coexistent autoimmune thyroiditis in patients with PTC was identified as a negative independent predictive factor for central metastatic lymph nodes, but not for the lateral lymph nodes involvement In contrast, in metastatic PTC, multifocality and bilaterality was more frequent in patients with autoimmune thyroiditis than those without autoimmune thyroiditis. 13 Few studies have investigated the prevalence of autoimmune thyroiditis between benign and malignant thyroid diseases. The purpose of this retrospective study was to determine the correlation between autoimmune thyroiditis and benign thyroid nodules in comparison with the correlation between autoimmune thyroiditis and PTC in a cohort of patients who underwent total thyroidectomy and had a final histological diagnosis. Several significant prognostic factors of the PTC included in the TNM classification 14 were compared between the cases with and without autoimmune thyroiditis. Our hospital medical ethics committee approved the protocol. PATIENTS AND METHODS This was a retrospective study of Greek patients who underwent total thyroidectomy over the last 16 years from 1996 to The medical records revealed a total of 1380 cases with histological diagnosed PTC and 824 cases with benign nodules. The higher rate of PTC compared to benign disease is expected given that we selectively operate on nodules with suspicious cytological HEAD & NECK DOI /HED APRIL

2 GIAGOURTA ET AL. biopsy findings or malignancy, with or without lymphocytic thyroiditis coexistence, or the cases with suspicious findings either on thyroid ultrasonography or on color flow-doppler. 15 Additionally, patients with rapidly growing nodules underwent surgery. A presence alone of autoimmune thyroiditis did not influence a decision to perform thyroidectomy. Operated cases with a history of prior head and neck radiation exposure were excluded. The criteria of histological classification of PTC were homogeneous over time according to the World Health Organization (WHO) 16 allowing comparable staging and grading among the samples. The pathologists are aware of the frequency of small carcinomas in the thyroid, and a large number of sections were examined from both cohorts. Additionally, all cases were subjected to central pathology review at our institution and the final evaluation was carried out by a senior cytopathologist with experience for more than 20 years in thyroid diseases to confirm the diagnosis and the extent of autoimmune thyroiditis was assessed. Thus, the interobserver variability was avoided. For the autoimmune thyroiditis, only the cases with the presence of dense or diffuse lymphocytic and plasma cell infiltration, oxyphilic cells, and formation of lymphoid follicles in the tissue of both lobes were included in this study, to avoid false positives. Peritumoral lymphocytic infiltration surrounding a nodule was not considered as autoimmune thyroiditis. For the PTC cases, age, female/male ratio, number of foci, tumor size, local invasion, distant metastases, and TNM classification were estimated. 14 For the benign lesions, age, the size of the nodules, and female/male ratio were documented. The tumor size was recorded taking into account the largest nodule diameter at gross pathological examination. Statistics Continuous variables are expressed as mean 6 SD. The Kolmogorov Smirnov test was applied to check normality of the variables. Discrete variables are presented as counts and percentages. Statistical comparisons were performed by chi-square test for percentages and by independent-sample t test for means with a normal distribution. Mann Whitney U test was used for variables with abnormal distribution. Regression analysis was applied appropriately. The relative importance of thyroiditis was presented as odds ratios (ORs) at 95% confidence intervals (CIs). Univariate and multivariate analysis was performed with incidence of lymph node and distant metastases as outcomes. TABLE 1. Clinical and histological characteristics in benign and malignant thyroid nodules associated with or without autoimmune thyroiditis at the initial histopathological diagnosis. Autoimmune thyroiditis presence Autoimmune thyroiditis absent p values Benign nodules, n ¼ 824 No. (%) 240 (29.0) 584 (70.8) Age, y <.01 Female/male ratio NS Nodule size, cm <.01 PTC nodules, n ¼ 1380 No. (%) 441 (31.9) 939 (68) Age, y <.05 Female/male ratio NS Nodule size, cm <.01 Cell type Papillary, no. (%) 282 (63, 9) 610 (64.9) NS Papillary/follicular, no. (%) 159 (36.0) 329 (35.1) NS Capsular invasion (%) 107 (24.4) 435 (46.4) <.01 Cervical nodes, no. (%) 38 (8.6) 240 (25.5) <.001 Multifocality, no. (%) 110 (24.9) 310 (33.5) <.05 Metastases, no. (%) 15 (3.4) 59 (6.3) <.05 TNM classification I, no. (%) 206 (46.7) 410 (43.6) NS TNM classification II, no. (%) 190 (43) 364 (38.8) NS High risk (TNM classification III, IVa, IVb, IVc), no. (%) 45 (10.2) 165 (17.6) <.05 Abbreviations: NS, nonsignificant; PTC, papillary thyroid carcinoma. RESULTS Benign thyroid nodules and autoimmune thyroiditis Table 1 shows the characteristics and histological findings between the cohorts with benign nodules with the presence and absence of autoimmune thyroiditis. Among the 824 patients with benign nodules, 240 (29%) had autoimmune thyroiditis. Patients who had benign nodules with autoimmune thyroiditis in pathology underwent operations at a younger age (mean age years vs years; p <.01) with a ratio female/male almost 5.7 (p <.01). The smaller mean size of the predominant nodule was shown in the cases with cytological autoimmune thyroiditis (p <.01; Table 1A). In the regression analysis model, the variables were the mean size of the primary nodule, the presence or absence of histological autoimmune thyroiditis, and the age at operation. It is worth noting that the variations in the nodule size could be correlated to the presence of autoimmune thyroiditis (by histopathologic criteria) in 0.8% (r approximately 0.008; b ¼ 1.71; SE ¼ 0.29; 95% CI, ; p <.049). Another 7% (r ¼ 0.069; b ¼ 3.33; SE ¼ 0.20; 95% CI, ) could be correlated to the age. Differentiated thyroid cancer and autoimmune thyroiditis A total of 1380 patients with PTC were diagnosed in the period between 1996 and 2012 in our hospital. Women had a 6 times higher frequency of autoimmune thyroiditis in comparison with men (ratio female/male was 6/1; p <.01; Table 1). Overall, 441 patients (31.9%) had autoimmune thyroiditis confirmed by histopathology. The accurate histological typing, according to the predominant cell type, show that in cases with autoimmune thyroiditis, 65% were classified papillary types, 35% were mixed papillary-follicular types, and almost the same proportion of these different types was found in the cases without autoimmune thyroiditis. It was a significant difference in the mean age among the patients with PTC and autoimmune thyroiditis compared to those with only PTC (p <.05; Table 1). The 3 major key variables in TNM staging (size, lymph nodes, and distant metastases) were reviewed in addition to the prevalence of autoimmune thyroiditis, as well as age, cell type, and the thyroid capsular invasion. In patients with PTC, those patients without autoimmune thyroiditis had larger tumors 532 HEAD & NECK DOI /HED APRIL 2014

3 AUTOIMMUNE THYROIDITIS IN THYROID NODULES TABLE 2. General linear model: univariate and multivariate analysis of the association of lymph node and distant metastases with various important parameters. Univariate Multivariate* Adjusted OR f Df p value f p value (95% CI) p value Lymph node metastases Tumor size < ( ) <.01 Capsular invasion < < ( ) <.001 Multifocality ( ).78 Autoimmune thyroiditis absence < < ( ) <.001 Distant metastases Tumor size ( ).1 Capsular invasion ( ).001 Multifocality ( ).24 Autoimmune thyroiditis absence ( ).01 Abbreviations: OR, odds ratio; f, f-distribution; df, degrees of freedom; CI, confidence interval. * Adjusted for age, sex, and cell types. compared to those with the presence of autoimmune thyroiditis (p <.01). The prevalence of cervical lymph node metastases with concurrent autoimmune thyroiditis was 8.6% (by histopathologic diagnosis). Again, the proportion of distant metastases was significantly higher in patients without autoimmune thyroiditis in comparison with those with autoimmune thyroiditis (p <.05; Table 1). Lung and bone were the most affected organs as it was diagnosed by high thyroglobulin levels and whole body scanning with 131-I. The prevalence of multiple tumor foci was increased in the absence of autoimmune thyroiditis (Table 1). Additionally, using the clinical status at the time of the initial diagnosis, stages III, IVA, IVB, and IVC were combined as a high-risk group. This high-risk group had a low prevalence of coexisting autoimmune thyroiditis, whereas the proportion of patients with T0/N0/M0 classification (stage I) was slightly higher (although not statistically significant) in the presence of autoimmune thyroiditis, but the proportion of T2/N0/M0 classification (stage II) was essentially equal, with or without autoimmune thyroiditis (Table 1). Multivariate analysis In order to identify the independent predictors of PTC spread, first, the interaction of autoimmune thyroiditis with each of the other independent variables on the dependent variables was tested by the univariate model and only the interactions with p <.2 were included in the final model. Therefore, age, sex, and the cell types (papillary, papillary/follicular) were removed from the model. We performed multivariate analysis with factors including (autoimmune thyroiditis as main exposure), nodule size, capsular invasion, and multifocality, and as outcome variables, the cervical node and distant metastases. The overall F value was significant for the model using lymph nodes and distant metastases as dependent variables, indicating that autoimmune thyroiditis and the other independent variables in the model had a statistically significant effect on each of the dependent variable when tested simultaneously (F ¼ 2.9; p ¼.002; 95% CI, for lymph nodes and F ¼ 8.0; p <.001; 95% CI, for distant metastases). Tumor size, the presence of capsular invasion, and the multifocality were significantly associated with lymph node metastases. The coexisting autoimmune thyroiditis was negatively associated with lymph node metastases. Additionally, the association of coexistence autoimmune thyroiditis with lymph node involvement did not get lost in multivariate analysis adjusted for tumor size, capsular invasion, and multifocality. The lymph nodes involvement was best (negatively) predicted by the presence of autoimmune thyroiditis at the time of diagnosis (OR ¼ 0.33; p <.001; 95% CI, ). As a result, patients without autoimmune thyroiditis had an OR ¼ 2.7; p <.001; (95% CI, ) for the development of lymph node metastases. The overall effect of autoimmune thyroiditis was also shown from the fact that patients without autoimmune thyroiditis had an OR ¼ 2.1; p ¼.003 (95% CI, ) to be classified as a high-risk patient (Table 2). The above results clearly show that in the absence of autoimmune thyroiditis there is an increased likelihood of the cervical lymph nodes to be affected. For the distant metastases, the capsular invasion had stronger predictive value than the autoimmune thyroiditis (Table 2), although it was a significant negative association between autoimmune thyroiditis and capsular invasion (data not shown). In the multivariate analysis, both capsular invasion and autoimmune thyroiditis had lost some of their predictive value, although the capsular invasion remained stronger (Table 2). This shows that the capsular invasion was another strong predictor for PTC metastases attenuated by the presence of autoimmune thyroiditis. DISCUSSION From this retrospective study, we were unable to find an increased prevalence of autoimmune thyroiditis in patients with PTC. The histopathologic findings of autoimmune thyroiditis were not differentially distributed between patients with PTC and benign nodules. Furthermore, it was shown that an association between the presence of autoimmune thyroiditis and good prognostic features in patients with PTC. The coexistence of autoimmune thyroiditis and PTC has been variously reported to range from low to 58% or higher. 11,12,17,18 In older studies, Pollock and Spronger 19 HEAD & NECK DOI /HED APRIL

4 GIAGOURTA ET AL. suggested that autoimmune thyroiditis is a premalignant lesion and should be treated by total thyroidectomy. Almost at the same period, Crile and Hazard 20 did not find an increased frequency of malignancy in patients with Hashimoto s disease. These controversies still exist. For example, Boi et al 21 found a quite high frequency of thyroid nodules to have indication for surgery because of suspicious cytologies in nodules of patients with high antithyroid antibody levels. The study of Kim et al 10 on 1329 patients who underwent thyroidectomy showed that the presence of autoimmune thyroiditis was the stronger predictor for PTC than other risk factors. In contrast, the results in the retrospective study of Erdogan et al 22 showed that after thyroidectomy, only 2% of all patients with autoimmune thyroiditis had a final diagnosis of PTC. A small proportion of PTC in patients with autoimmune thyroiditis was also found from the study of Carson et al. 23 Some authors recommend close observation of neoplastic changes of the nodules with autoimmune thyroiditis, whereas others suggest the necessity of lobectomy as minimal surgical intervention in autoimmune thyroiditis cases. 24 In our patients, the equal frequency of autoimmune thyroiditis between benign and malignant nodules shows that nodules with the diagnosis of autoimmune thyroiditis (alone) it is not a reason for surgery. The differences from various studies may be because of, at least in part, the differences in the evaluation of the extent of lymphocytic infiltration on pathologic examination. 25,26 It may be that some cases reported as autoimmune disease, in fact represent a lymphoid reaction surrounding the nodule rather than a true autoimmune disorder. The major strengths of our study were that the relatively large numbers of operated nodular goiters were referred to a central pathology review. Consequently our results were comparable. The fact that the significantly smaller size of the dominant nodules were in the presence of autoimmune thyroiditis indicates that the concurrent autoimmunity provides a reaction to control cell growth and proliferation. Although it is well known that the presence of autoimmune thyroiditis is associated with a smaller size of the primary PTC tumor at presentation, 10 the benign nodules have not yet been reported as an association between the size and the presence of autoimmune thyroiditis. Factors such as the consumption of macronutrients or micronutrients may also be involved in the size of goiter and consequently in the nodules size. 27,28 It is also suggested that the antithyroid antibodies are able to recognize either malignant or benign cells and destroy them in the same way, by inhibiting the rate of progression to larger tumors. 29 However, in our cases, by the regression analysis, a major part of the variation of nodules size was explained by the patient s age rather than by the presence of autoimmune thyroiditis. We can hypothesize that younger persons have a better nutritional status regarding the continuing exposure to iodine of foods, 30 which in some of them may precipitate the onset of thyroid autoimmunity. 25 Furthermore, we cannot entirely exclude the possibility that the smaller nodule size was because of the improved sensitivity for early detection of thyroid nodules in our younger patients, during a silent and intense strategy to apply thyroid ultrasound from most physicians for the prevention of goiter. In contrast, in many older persons, long-standing thyroid nodules are incidentally discovered during the examination for other diseases. 31 For patients with PTC, we believe that the findings from our study confirm earlier observations and provide strong evidences that in the presence of autoimmune thyroiditis there is a decreased frequency of nodal disease and decreased frequency of distant metastases. 11,32 The lower frequency of our high-risk cases was also associated with the presence of autoimmune thyroiditis. As a result, a shift of T0/N0/M0 classification toward stages I and II was observed in the presence of autoimmune thyroiditis, which is consistent with data published from different countries. 33,34 However, the influence of autoimmune thyroiditis on our cases of stages I and II was small and, again, our data may reflect an earlier detection of malignant lesion. 35 The above further strengthens the beneficial effect of autoimmune thyroiditis in the patients with PTC. Given the capsular invasion, which was also a strong predictor of metastases, it is important to identify as a potential contributor that it is attenuated by the presence of autoimmune thyroiditis. Controversial is the association of multifocality with autoimmune thyroiditis, 13,33 but in our cases, was lower frequency of multifocality in the presence of autoimmune thyroiditis compared to the cases without autoimmune thyroiditis, although in univariate and multivariate analysis, the multifocality did not remain as an indicator of poor prognosis. This study has a major limitation with the selection of the cases because the patients were surgically treated only if nodules were suspected of malignancy. Also, the choice for surgery was independent of the preoperative diagnosis of autoimmune thyroiditis. An additional limitation is that some malignant nodules may have been missed in patients who had not undergone thyroidectomy, particularly those cases with less clinical evidence of malignancy, such as microcarcinomas. In conclusion, in contrast with some studies and in agreement with others, this 16-year study clearly shows that autoimmune thyroiditis is not associated with high frequency of PTC. Consequently, it may be avoided by over-treating by thyroidectomy the cases with cytological findings of autoimmune thyroiditis and without any other evidence of malignancy. Additionally, autoimmune thyroiditis may have been beneficial by decreasing the frequency of PTC with nodes involvement and distant metastasis. Acknowledgment We thank Maria Psomas, MD, for the review of this manuscript. REFERENCES 1. Larson SD, Jackson LN, Riall TS, et al. Increased incidence of well-differentiated thyroid cancer associated with Hashimoto thyroiditis and the role of the PI3k/Akt pathway. 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