ELEVATED RISK OF PAPILLARY THYROID CANCER IN KOREAN PATIENTS WITH HASHIMOTO S THYROIDITIS

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1 ORIGINAL ARTICLE ELEVATED RISK OF PAPILLARY THYROID CANCER IN KOREAN PATIENTS WITH HASHIMOTO S THYROIDITIS Kyung Won Kim, PhD, 1,2 Young Joo Park, PhD, 1,3 Eun Hye Kim, RN, 3 So Yeon Park, PhD, 4,5 Do Joong Park, PhD, 6,7 Soon-Hyun Ahn, PhD, 8,9 Do Joon Park, PhD, 1 Hak C. Jang, PhD, 1,3 Bo Youn Cho, PhD 1 1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. yjparkmd@snu.ac.kr 2 Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea 3 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Korea 4 Department of Pathology, Seoul National University College of Medicine, Seoul, Korea 5 Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Korea 6 Department of Surgery, Seoul National University College of Medicine, Seoul, Korea 7 Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Korea 8 Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Korea 9 Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam-si, Korea Accepted 12 May 2010 Published online 10 November 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: /hed Abstract: Background. Hashimoto s thyroiditis (HT) and higher levels of thyroid-stimulating hormone (TSH) have been proposed as risk factors for papillary thyroid cancer (PTC), but this issue is still being debated. The purpose of this study was whether HT was related to the risk of PTC over TSH. Methods. We enrolled 1329 patients (1028 with PTC, 52 with follicular thyroid cancer, and 249 with benign disease) of 1490 patients who underwent thyroidectomy. Results. The TSH concentration was not different among patients with PTC or benign disease. Our study showed that men (odds ratio [OR] ¼ 1.54; p ¼.049) and the presence of HT (OR ¼ 2.96; p <.001) increased the risk of PTC. Moreover, HT was associated with multifocal cancer (p ¼.005) and smaller tumor size (p ¼.031), but it did not influence the extrathyroidal invasion or nodal metastasis. Conclusion. Clinicians who deal with thyroid nodules should pay particular attention to HT because it is a stronger predictor for PTC than other risk factors. VC 2010 Wiley Periodicals, Inc. Head Neck 33: , 2011 Keywords: Hashimoto s thyroiditis; thyroid cancer; thyrotropin; thyroid-stimulating hormone; papillary thyroid cancer Chronic inflammation is thought to predispose an individual to neoplastic transformation, 1 and autoimmune diseases are associated with several kinds of cancers. 2 Hashimoto s thyroiditis (HT) is a chronic autoimmune disorder that causes hypothyroidism in Correspondence to: Y. J. Park Contract grant sponsor: Korea Research Foundation; contract grant number: KRF E This Abstract was presented at the 33rd Annual Meeting of the European Thyroid Association, Thessaloniki, Greece, September 20 24, VC 2010 Wiley Periodicals, Inc. iodine-sufficient areas. 3 In 1955, Dailey et al 4 reported a causal association between papillary thyroid cancer (PTC) and HT. Since that report, clinical studies have focused on this link. Some have reported a positive correlation, 4 8 whereas others have not observed a correlation Recently, several articles have reported that thyroid-stimulating hormone (TSH) concentrations were higher in patients with thyroid cancers compared with those who had a benign thyroid nodule. 9,13 15 Interestingly, higher TSH concentrations in white populations were associated with advanced-stage cancer in patients with a differentiated thyroid cancer (DTC). 9,14,16 Because HT is associated with the progression from a euthyroid state to overt hypothyroidism, HT might influence carcinogenesis through TSH activity and inflammation; however, this aspect has not yet been investigated. Haymart et al, 9,16 which initially showed the association between TSH concentration and DTC, reported an association between HT and PTC using a similar cohort, but they showed only borderline significance (p ¼.051). 17 This report implied that the influence of TSH on tumorigenesis was not mediated through HT. Other studies 6,18 showing an association between HT and PTC did not analyze the association of TSH. Those studies raise important questions of whether it is the TSH level or inflammation that causes the PTC. Because HT is closely related to elevated TSH concentrations, HT could be associated with an elevated risk of PTC, possibly through higher serum TSH concentrations. The purpose of our study was to investigate whether the presence of HT increased the risk of PTC independent of preoperative Hashimoto s Thyroiditis and Thyroid Cancer HEAD & NECK DOI /hed May

2 Table 1. Patient characteristics. Variables (No. of patients) Benign disease (n ¼ 249) PTC (n ¼ 1028) Total (n ¼ 1028) >1 cm(n ¼ 453) 1 cm(n ¼ 575) FTC (n ¼ 52) Hashimoto s thyroiditis 24 (9.6%) 307 (29.9%) 123 (27.2%) 184 (32.0%) 5 (9.6%) Male 38 (15.3%) 207 (20.1%) 91 (20.1%) 116 (20.2%) 20 (38.5%) Age at operation, y Tumor size, cm TSH, miu/l* Free T4, pmol/l* TPO Ab positivity 26 (14.0%) 120 (16.4%) 50 (15.8%) 70 (16.9%) 13 (28.3%) Tg Ab positivity 50 (22.5%) 266 (29.5%) 112 (28.4%) 154 (30.4%) 2 (5.9%) Abbreviations: PTC, papillary thyroid cancer; FTC, follicular thyroid cancer; TPO Ab, thyroid peroxidase antibody; Tg Ab, thyroglobulin antibody. *Patients who were administered levothyroxine were excluded. p <.001 compared with patients with benign disease. p <.05 compared with patients with benign disease. TSH levels. We also wanted to determine whether HT influenced the pathologic characteristics of PTC. MATERIALS AND METHODS Patients. Between May 2003 and December 2007, thyroidectomy was recommended for the indicated patients according to current guidelines Of the 1490 patients who underwent thyroid surgery, 154 patients were excluded because their preoperative thyroid function was not available. A total of 1329 patients (1028 with PTC, 52 with follicular thyroid cancer [FTC], and 249 with a benign thyroid nodule) were included for further analysis. Among them, 142 patients (11%) were prescribed levothyroxine (LT4) preoperatively. The preoperative serum TSH and free thyroxine (T4) concentrations were measured from 1 day to 3 months before surgery. Other malignancies besides PTC or FTC were excluded in this analysis (n ¼ 7). The Institutional Review Board of the Seoul National University Bundang Hospital approved the study protocol. All subjects in this study were Korean nationals. Serum Measurements of Thyroid Function. The serum TSH and free T4 concentrations were measured by immunoradiometric assays using commercial kits (TSH; Cisbio International, Gif-sur-Yvette, France; free T4, DiaSorin S.P.A, Saluggia, Italy). The Central Laboratory of Seoul National University Bundang Hospital reported that the normal ranges of TSH and free T4 were 0.4 to 4.1 miu/l and pmol/ L, respectively. Histopathology. Resected surgical specimens were cut at 3-mm intervals and fixed in 10% formalin. One to 3 representative sections of the tumor and all suspicious lesions were submitted for microscopy. All sections were fixed in formalin, embedded in paraffin wax, and stained with hematoxylin and eosin. Hashimoto s thyroiditis was diagnosed by the presence of diffuse lymphoplasmacytic infiltrations with germinal centers, parenchymal atrophy with oncocytic changes, and variable amounts of stromal fibrosis throughout the thyroid gland. We examined and recorded any coexisting HT in all of the patients included in the study. Statistical Analysis. Differences in the frequency of single variables were tested by the chi-square test or independent-samples t test. Univariate and multivariate logistic regression analyses were used to identify the preoperative factors associated with thyroid malignancy. Univariate and multivariate logistic regression analyses were also used to investigate the influence of HT on the pathologic characteristics of PTC. Values are either reported as the mean SD or odds ratio (OR) and 95% confidence intervals (CI). In all instances, p <.05 was considered significant. All data were analyzed using SPSS for Windows (version 17.0, SPSS Corp, Chicago, IL). RESULTS Patient and Tumor Characteristics. The study group included more women (n ¼ 1064; age years) than men (n ¼ 265; age years; Table 1). However, the men showed a higher rate of malignancy (n ¼ 227; 85.7%) than benign disease (n ¼ 38; 14.3%; p ¼.04). The male sex showed borderline significance in predicting PTC (p ¼.08), but significance in predicting FTC (p <.001). In addition, men were diagnosed with PTC at an earlier age than women ( vs years; p ¼.013). Nodules were larger in patients with benign nodules than in patients with PTC ( cm vs cm; p <.001). This finding may reflect a bias because patients with a large benign tumor underwent the operation because of a fear of malignancy. For patients with FTCs, the tumors were larger than benign nodules ( cm vs cm; p ¼.035), which indicated that the size of any nodule is an important risk factor. Coexisting HT was more frequent in the PTC group (29.9%; p <.001), and the same pattern was maintained when the patients with papillary microcarcinomas were removed from the analysis. 692 Hashimoto s Thyroiditis and Thyroid Cancer HEAD & NECK DOI /hed May 2011

3 Table 2. Independent risk factors for diagnosing differentiated thyroid cancer identified by univariate and multivariate logistic regression analysis. PTC FTC Variable Unadjusted OR (95% CI) Adjusted OR** (95% CI) Unadjusted OR (95% CI) Adjusted OR** (95% CI) Male 1.40 ( ) 1.54 ( ) 3.47 ( ) 3.28 ( ) Age 45 y 0.93 ( ) 0.92 ( ) 0.57 ( ) 0.64 ( ) HT 3.99 ( ) 2.96 ( ) 1.00 ( ) 1.22 ( ) Tumor size 1 cm 0.16 ( ) 0.18 ( ) 8.07 ( ) 4.58 ( ) TSH*, miu/l 1.10 ( ) 1.06 ( ) 0.71 ( ) 0.70 ( ) Abbreviations: PTC, papillary thyroid cancer; FTC, follicular thyroid cancer; OR, odds ratio; CI, confidence interval; HT, Hashimoto s thyroiditis; TSH, thyroid-stimulating hormone. *Patients who were administered levothyroxine were excluded. **Adjusted ORs were calculated using logistic regression analysis with all risk factors entered as covariates simulation. p <.001. p <.05. HT was also associated with papillary microcarcinomas (p <.001). Both thyroid peroxidase antibody and thyroglobulin antibody levels were associated with HT, but only thyroglobulin antibody was associated with a higher rate of PTC (p ¼.039). However, TSH and free T4 concentrations were not different between patients with benign or malignant diseases. Independent Risk Factors for Papillary Thyroid Cancer Defined by Multivariate Logistic Regression. Multivariate logistic regression analysis including sex, age, preoperative TSH levels, tumor size, and the presence of HT was used to assess whether these factors were significantly associated with PTC. Male sex (OR ¼ 1.54; 95% CI, ; p ¼.049), the presence of HT (OR ¼ 2.96; 95% CI, ; p <.001), and smaller tumor size (OR ¼ 0.18; 95% CI, ; p <.001) were independently associated with PTC (Table 2). Multivariate logistic regression analysis including sex, age, preoperative TSH levels, larger tumor size (>1 cm), and the presence of HT was also used to assess whether these factors were significantly associated with FTC. In FTC, only the male sex was an independent risk factor (OR ¼ 3.28; 95% CI, ; p ¼.003). Comparison of Clinical Characteristics in Relation to the Presence of Hashimoto s Thyroiditis. Men were less likely to have HT (6.1% of men vs 30.6% of women; p <.001; Table 3). Tumor size was smaller in patients with PTC with HT compared with patients with PTC without HT (p ¼.004). HT was associated with a higher TSH level ( vs miu/l; p ¼.051) than those patients without HT. However, TSH was not elevated in patients with PTC with HT (TSH miu/l) compared with patients with PTC without HT (TSH miu/l; p ¼.141). In the group of patients with HT, TSH concentrations and the rates of positive thyroid peroxidase antibody or thyroglobulin antibody were not different between patients with a benign disease and PTC (data not shown). Hashimoto s Thyroiditis and Histologic Characteristics. We investigated whether HT was associated with poor pathologic findings as a surrogate marker for prognosis. HT was positively associated with multifocality (p ¼.005; Table 4) and smaller size (p ¼.031) but not with extrathyroidal invasion, nodal metastasis, or TNM stage. DISCUSSION In this study, we found a very strong association between PTC and HT (OR ¼ 2.96; 95% CI, ; p <.001) that was independent of serum TSH concentration. The rate of HT was higher in patients with PTC (29.9%) compared with benign cases (9.6%). Because we defined HT on histopathology, we could not know the exact prevalence in our study. However, the reported prevalence of HT in the general population is 8% to 14% in Japanese and white Table 3. Comparison of clinical characteristics according to the presence of Hashimoto s thyroiditis. PTC with HT PTC without HT Benign with HT Benign without HT No. of patients Male 13* Age at operation, y Tumor size, cm *, TSH, miu/l Free T4, pmol/l Abbreviations: PTC, papillary thyroid cancer; HT, Hashimoto s thyroiditis; TSH, thyroid-stimulating hormone; T4, thyroxine. *p <.05, compared with HT (-) PTC group. p <.05, compared with HT (þ) benign group. Patients who were administered levothyroxine were excluded. Hashimoto s Thyroiditis and Thyroid Cancer HEAD & NECK DOI /hed May

4 Table 4. Associations between pathologically aggressive features and Hashimoto s thyroiditis in patients with papillary thyroid cancer. PTC without HT, No. of patients PTC with HT, No. of patients Unadjusted OR (95% CI) Adjusted OR (95% CI)* Nodule >1 cm 330/649 (46%) 123/266 (40%) 0.74 ( ) 0.72 ( ) Extrathyroidal invasion 429/717 (60%) 177/307 (58%) 0.91 ( ) 1.12 ( ) Lymph node metastasis 296/692 (43%) 118/295 (40%) 0.89 ( ) 0.98 ( ) Multifocality 243/681 (36%) 124/283 (44%) 1.41 ( ) 1.52 ( ) TNM stages III and IV 312/719 (43%) 118/307 (38%) 0.81 ( ) 0.77 ( ) Abbreviations: PTC, papillary thyroid cancer; HT, Hashimoto s thyroiditis; OR, odds ratio; CI, confidence interval. *Adjusted ORs were calculated using logistic regression analysis with all risk factors entered as covariates simulation. p <.05. populations, 22,23 which is similar to the prevalence in our benign cases. Thus, it is clear that HT was a strong risk factor for developing PTC in this study. This positive association was maintained regardless of the size of the PTC (>1 cmvs1 cm). This suggests that the pathophysiology of HT in tumorigenesis was similar among PTCs regardless of tumor size. In addition to coexisting HT, the male sex showed an association with PTC but old age did not. Tumor size is a well-known risk factor of thyroid cancer; however, there was a bias in our study in that we usually recommended thyroidectomy if the patient had a large (usually >4 cm) or growing tumor regardless of its cytology. Therefore, we could not assess the effects of tumor size in this study. Although tumor size of patients with FTC was larger than that of benign disease, only male sex remained as an independent risk factor for FTC after multivariate logistic regression analysis. TSH has a trophic effect on thyroid cancer growth, which is most likely mediated by TSH receptors on tumor cells. 24,25 This is consistent with clinical results showing that TSH suppression is an independent predictor of relapse-free survival from DTC. 26 Therefore, the increased prevalence of hypothyroidism (ie, elevated TSH levels) in HT could be 1 possible explanation for the association of PTC with HT. Our study showed that a higher TSH level was not associated with PTC in univariate and multivariate logistic regression analysis. This is different from the findings of previous reports in white patients. 9,13,14 The mean TSH concentration was not higher in our patients with PTC compared with patients with benign thyroid nodules. Although we cannot fully explain this difference, there are some possible explanations. In our study, there were fewer pathologically proven benign cases than malignant cases, which could result in a selection bias. In addition, the mean serum TSH concentration was higher in our study than in other reports, 9,13 which might have masked the diagnostic value of an elevated TSH concentration. The reported mean TSH concentration range was 1.72 to ,28 in euthyroid Asian subjects (similar to our unpublished data on Koreans), which is higher than the range of 1.45 to 1.48 miu/l in white populations. 22,29 The mean TSH concentration in our patients with benign thyroid disease ( miu/l) was similar to that for Asian populations but higher than the study by Haymart et al 9 ( miu/l). The reason for higher TSH concentrations in our subjects is not clear; however, it is possible that iodine consumption in Asians is different from other ethnic groups. Teng et al 30 reported that the cumulative incidence of hypothyroidism in subjects with euthyroidism increases with increasing iodine intake in areas with sufficient to excessive iodine. The reported urinary excretion rate of iodine is 640 to 3800 lg/l in healthy Koreans, which is similar to the values from areas with excessive iodine. However, this value is 2 or 3 times higher than the urinary excretion rate of iodine in whites in the United States and the United Kingdom The mechanisms that can lead to PTC in patients with HT are still unclear, but several possible mechanisms have been proposed. Harach and Ceballos 34 reported the incidence of PTC after dietary iodine supplement and proposed a relationship between thyroiditis and iodine intake, thyroiditis and PTC. Our country is 1 of the most iodine-sufficient areas, so the iodinerelated HT and PTC could be 1 candidate for explanation; however, this needs to be confirmed. The PI3K/ Akt or RET/RAS/ERK pathways were also suggested as possible molecular mechanisms of carcinogenesis in HT, butthisalsoneedstobeconfirmed. 35,36 We analyzed various clinicopathological features to predict whether coexisting thyroiditis could influence the prognosis for patients. However, conventional prognostic factors, such as advanced age, extrathyroidal invasion, and nodal metastasis, were not associated with HT. Multifocality and smaller tumor size were the pathological features that showed a difference between patients with PTC with or without HT. The presence of a smaller cancer in HT is likely to show a protective effect on tumor progression. However, we did not investigate the recurrence rate or mortality rate in this study. These findings suggest that patients with PTC with HT are more likely to have other tumor foci in the thyroid gland. The pathologists should make an effort not to miss a coexisting lesion that was not detected preoperatively. In summary, univariate and multivariate analysis showed that male sex and the presence of HT were important predictors for the risk of developing PTC in the Korean population. Therefore, we should watch 694 Hashimoto s Thyroiditis and Thyroid Cancer HEAD & NECK DOI /hed May 2011

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