thyroid cancer is the most common endocrine malignancy worldwide , with a significant increase in global incidence [ 14 ] over the past decade . this is true both in the united states [ 2 , 5 ] and in eastern asia including china [ 69 ] . about 70% to 80% of thyroid cancers are papillary thyroid carcinoma ( ptc ) [ 9 , 10 ] . despite surgical advances and better long - term results hashimoto 's thyroiditis ( ht ) has been postulated to have a causative relationship to ptc , being suggested as a possible risk factor for developing ptc . this link was first proposed in 1955 with several subsequent retrospective studies showing similar results [ 1115 ] . some studies suggest that stimulating tsh concentrations ( often mildly elevated ) may be one responsible factor for this relationship . in support , treatment with l - t4 may reduce tsh levels and decreases the prevalence of clinically detectable ptc . however , other studies are contradictory finding tsh concentration similar among patients regardless of ptc or benign disease . it is well known that ptc represents a spectrum of disease inclusive of heterogeneity and severity in histologic patterns and/or tumor stages . occult or microscopic ptc ( mptc ) is frequently incidentally detected in histologic samples even when benign nodules are assumed . it is uncertain whether incidental micro - ptc ( mptc ) simply represents an early stage of overt ( or clinically relevant ) ptc or is actually a different subtype of ptc which seldom progresses . it is therefore reasonable to postulate that the analysis of ptc as a unified single group may in part be responsible for the conflicting published data . notably , most previous studies only evaluated clinically relevant ptc ( crptc , maximum diameter > 1  cm in size ) . we hypothesize that mptc might be the early stage of crptc with similar relationships existing between mptc and ht when compared to crptc and ht . however , some evidence suggests that the presence of ht may be associated with less risk of ptc lymph node metastasis ( lnm ) and an overall better prognosis [ 11 , 18 ] . to elucidate the uncertainty as to the influence of ht upon local tumor growth ( even from a very early stage ) , we conducted a retrospective study trying to clarify the relationship between ht and different stages of ptc . we collected data from the register and reporting system in department of pathology , the first affiliated hospital of nanjing medical university . particularly , we reviewed all consecutive thyroid histopathological reports from january 2008 to december 2013 . patient demographic data was obtained by chart review at a central location by xiaoyun liu , lijun zhu , dai cui , zhixiao wang , huanhuan chen , yu duan , xiaodong wang , and jiawei chen . generally , thyroidectomies were performed for the following reasons : ( a ) worrisome findings from ultrasonography and/or abnormal lymph node enlargement , ( b ) malignancy suspected from previous thyroid fna , or inconclusive fna results , ( c ) patients with multiple or bilateral nodules or symptoms of neck or throat compression , or enlargement during follow - up , and ( d ) concerning clinical or physical examination findings warranting consideration for removal . a small minority of patients chose thyroidectomy at their own wish , primarily for cosmetic reasons . malignancy , if present , was reported as one of the following subtypes : crptc , with the maximum diameter larger than 10  mm ; mptc , with the maximum diameter less than or equal to 10  mm [ 19 , 20 ] ; follicular thyroid carcinoma ( ftc ) ; medullary thyroid carcinoma ( mtc ) ; and anaplastic thyroid carcinoma ( atc ) . for each case , we collected data confirming the maximum diameter of the tumor , tumor multifocality , and other pathologic features . the impact of hashimoto 's thyroiditis upon mptc and crptc rates was the primary focus of this investigation . all pathological findings were confirmed by three experienced endocrine pathologists ( yunsong wu , rong rong , and zhihong zhang ) . lymph node dissection was performed at the discretion of the surgeon based upon clinical and other factors according to the guideline from the american thyroid association ( ata ) . most often , a neck ultrasound or computed tomography ( ct ) scan was performed prior to surgery allowing assessment of neck adenopathy . frozen sections were routinely used to guide the extent of the surgical procedures . if the nodule was found to be malignant by frozen section and no abnormal lymph nodes were identified on preoperative imaging ( or during the surgery ) , an ipsilateral central lymph node dissection ( clnd ) from level vi only when the tumor size was within 10  mm and no abnormal lymph node was found during the operation , clnd was not routinely performed . if abnormal lymph nodes were identified during preoperative ultrasound or intraoperatively , and the snap - frozen sample showed malignant lesion , a modified lateral lymph node dissection ( llnd ) was performed . all the samples were formalin fixed paraffin embedded ( ffpe ) for final histopathology confirmation . ht was defined as the presence of diffuse lymphocytic infiltration with the formation of lymphoid follicles and the presence of reactive germinal centers ; the infiltrate had to occur in a normal region of the thyroid gland , distinct from the site of the thyroid carcinoma . the antithyroglobulin and antithyroid peroxidase antibody levels were not routinely measured for the diagnosis of ht . we recruited 6,432 cases with valid pathology reports including all thyroidectomies performed over the six - year period . we next categorized each according to the histologic diagnosis of ht and separately for the identification of mptc and crptc ( or other cancer types ) . quantitative data are shown as mean  sd , compared using independent samples t - test , whereas numbers and percentage are provided for qualitative data . percentages were compared using the  test . the odds ratio ( or ) and the 95% confidence interval ( ci ) for relationships between each variable and ptc or positive lnm ( yes or no ) all tests were 2-sided , and a p value < 0.05 was considered statistically significant . statistical analyses were performed with spss software , version 13.0 for windows ( spss inc . , chicago , il , usa ) . this study was reviewed and deemed exempt from written informed consent by the institutional review board ( irb ) of the first affiliated hospital of nanjing medical university . demographic and pathologic details for all subjects are shown in table 1 . among this cohort , 20.6% ( 1,328/6,432 ) of our thyroidectomy population not surprisingly , those with ht were disproportionately female , consistent with other autoimmune illnesses . the mean age of the ht cohort was 46.2  13.6 years , significantly younger than the non - ht group . a total of 1,977 thyroidectomy specimens ( 30.7% of 6,432 ) were shown to harbor malignancy however , 823 cases ( 41.6% of all malignancy ) were best classified as mptc and 899 specimens ( 45.5% of all malignancy ) demonstrated a clinically relevant ( > 1  cm ) papillary thyroid carcinoma . a low but detectable rate of ftc , mtc , and atc was also identified , but these rates were not different in the ht cohort versus others ( table 1 ) . we next determined the prevalence of thyroid malignancy in thyroidectomy specimens with or without histologic evidence of ht . in the ht group , 46.9% specimens were found to also contain a thyroid malignancy of any pathological type , compared to 26.5% of those without ht ( p < 0.01 , table 1 ) . interestingly , however , the difference in malignancy rate was solely attributable to differences in the proportion of ptc in the two cohorts . of the 823 patients with mptc , 541 ( 10.6% ) patients were in the non - ht group while 282 ( 21.2% ) patients were in ht group ( table 1 ) . no difference was detected in the rate of ftc , mtc , or other malignancies ( table 1 ) . due to the gender and age discrepancy in non - ht and ht group , we divided the total population into four subcategories according to the sex and age differences . it was shown consistently that the prevalence of ptc was higher in all hashimoto 's cohorts in comparison with non - ht groups ( figure 1(a ) and supplementary table 1  in supplementary material available online at  http://dx.doi.org/10.1155/2014/769294 ) . nearly all subgroups analysis showed similar statistical findings for the prevalence of mptc with the exception of male under the age of 45 years ( figure 1(b ) and supplementary table 1 , p = 0.05 ) and for the prevalence of crptc with one exception in male 45 years ( figure 1(c ) and supplementary table 1 ) . we used univariate and multivariate analysis to determine whether the presence of ht would be an independent risk factor for ptc . as it was shown in table 2 , ht was a significant independent risk factor for ptc with odds ratio 2.725 ( 95% ci , 2.3903.109 ) . the age  45 years was a protective risk factor for ptc with odds ratio 0.474 ( 95% ci , 0.4230.532 ) . we next investigated the association of histologic ht upon local metastatic disease as defined by lymph node metastasis ( lnm ) . inclusive of all thyroid malignancy identified over 6 years , the presence of ht showed a neutral effect upon local lnm when thyroid cancer was present ( p > 0.05 , figure 2 and supplementary table 2 ) . as shown in table 3 , we found that male gender , age  <  45 years , foci of tumor , and maximum diameter were risk factors for lnm in ptcs , while ht was neither a protective nor risk factor for lnm in ptcs with or 0.978 , 95% ci ( 0.7721.239 ) ( table 3 ) . all cohorts evaluated with ptc demonstrated an association with younger age and female predominance in the hashimoto 's cohort compared with non - ht groups . no difference was noted in the number of positive lymph nodes or the number of specific tumor foci between ht and non - ht groups , respectively . interestingly , in all patients with hashimoto 's disease , the size of all identified clinically relevant ( crptc ) was generally smaller compared to those without hashimoto 's disease . in contrast , mptcs were more often bilateral ( though not more often multifocal ) in the ht cohort compared to non - ht cohort . differences in study design , selection bias , and standardized approaches have led to a mixed literature in this regard . arguably , to best investigate this important association , a large cohort of consecutive patients must be studied and all diagnoses  such as hashimoto 's disease and thyroid carcinoma  defined by expert histopathologic analysis . in this regard , we evaluated 6,432 consecutive thyroidectomies over 6 years from a single referral institution in china , revealing a unique association between hashimoto 's thyroiditis and ptc . particularly , hashimoto 's thyroiditis increases the risk of papillary thyroid carcinoma in affected subjects , though it appears to impart no risk factor upon lymph node metastasis and progressive disease . this association was true both for mptc and for crptc , though it was not detected for all other thyroid malignancies including follicular , medullary , and anaplastic thyroid carcinoma . these data support previous pilot findings and suggest those with ht may warrant increased attention for the development of clinically relevant thyroid nodules given their higher risk of malignancy . a recent meta - analysis of this topic similarly demonstrated that hashimoto 's thyroiditis is correlated to the presence of ptc , with carcinoma detected in 9.46~36.60% of patients with ht . in our study , the prevalence of ptc in the ht cohort was 43.8% , while in the non - ht group the prevalence was 22.4% . zhang showed in areas where the prevalence of ht was even higher the prevalence of ptc in ht was also higher , reaching 58.3% compared to 44.3% in non - ht group in the same region . this suggests a similar influence of hashimoto 's disease upon cancer risk across different populations despite variable incidence of malignancy . our study showed that ht was not only closely related to an increased risk of crptc , but also significantly related to the risk of mptc . this similar relationship to both crptc and mptc strengthens the translatability of our data and lessens concern for selection bias in our study population . beyond its clinical importance , our data also lends support to the hypothesis that microcellular dynamics ( such as inflammation ) impact the development of thyroid malignancy independent of nodule size . interestingly , although the coexistence of hashimoto 's disease appears related to increased risk of ptc , our results showed ht was not a risk factor for lnm in ptcs . and the maximum diameter of ptc seemed to be related to ht in mptc stage and conversely in the crptc stage . the mechanism behind this observation remains uncertain . in support , however , dvorkin has previously found that differentiated thyroid cancer is similarly associated with less aggressive disease and better outcome in patients with coexisting ht , while zhou has also found that ht is not a risk factor for occult contralateral carcinoma in patients with unilateral mptcs . increasingly , clinical and basic investigations appear to confirm the important influence of the body 's immune system in relation to malignant disease . while infection and immune response have been associated with an increased risk of malignancy in illnesses such as hepatitis , it is equally clear that immunologic influence can also positively influence malignant progression . this is perhaps best exemplified by melanoma or breast carcinoma , where numerous case reports have described unusual , prolonged remissions or late recurrences which implicate the immune system as a causative factor . thus , while speculative , it is not unreasonable to postulate that chronic inflammation of the thyroid may increase malignant transformation , while nonetheless stimulating an immunologic milieu in which tumor expansion and malignant growth are less favored . clinically , such a hypothesis would be nearly impossible to prove , as there currently exist no immunomodulating therapies for hashimoto 's disease by which one could study cancer prevalence and progression following a randomized intervention . however , it is also possible that ht may be the  response  to the tumor in genetically predisposed subjects and that this response may slow down cancer progression . regardless , these data nonetheless provide insight into the complex interactions of thyroid cellular biochemistry and immunology and provide a stimulus for further investigation . we did find that male gender , age  <  45 years , foci of tumor , and maximum diameter were risk factors for lnm in ptcs in accordance with another previous study . the strength of our study relates to the size and uniformity of our study cohort , as well as the strict histopathologic definitions used for both hashimoto 's thyroiditis and thyroid malignancy . we also analyzed ptc across the full spectrum of size , including evaluation of microcarcinomas no more than 1  cm in diameter . the similar relationship of ht to both mptc and crptc is notable and speaks against selection or sampling bias . we tried to eliminate further selection bias by subanalyzing our total cohort by gender , age , size of tumor , and using binary logistic regression method . we also note that a relatively large percent ( 69.3% ) of benign nodules was resected . most often , this was simply due to nodule size more than 3  cm or the presence of large multinodular goiters ( data not shown ) . while an ideal study would prospectively investigate thyroidectomy histopathology among all patients with nodular disease , it is unreasonable to routinely perform thyroidectomies on all low risk patients , or those with benign disease . recent data confirm modest interobserver variability in cancer diagnosis , which could reasonably suggest slight differences in translation of these data at other institutions . in conclusion , these data provide the most extensive consecutive analysis of the relationship between hashimoto 's thyroiditis and thyroid carcinoma , confirming an increased risk of ptc in the setting of ht . while this increased risk appears independent of ptc size , however , during more advanced stage , ht was no longer a risk factor suggesting a potential protective effect of the inflammatory milieu upon the progression of malignancy as defined by local lnm . these data support previous pilot findings and suggest that patients with ht may warrant increased attention for the development of clinically relevant thyroid nodules given their higher risk of malignancy .
purpose . to determine the relationship between hashimoto 's thyroiditis ( ht ) and all stages of papillary thyroid carcinoma ( ptc ) with or without local lymph node metastasis ( lnm ) 
 . methods . 
 we conducted a retrospective study of thyroidectomies from 20082013 in first affiliated hospital of nanjing medical university . 
 we categorized patients according to the presence of histopathologically proven ht . 
 the prevalence of mptc ( maximum diameter  10  mm ) and crptc ( clinical relevant ptc ) and local lnm rates were compared . 
 results . 
 we evaluated 6,432 consecutive thyroidectomies . in total , 
 1,328 specimens were confirmed as ht . 
 the prevalence of ptc in this ht cohort was 43.8% , significantly higher than non - ht group . 
 after adjustment of gender and age , the prevalence of ptc was still higher in ht group . 
 ht was a risk factor for ptc in multivariate analysis with odds ratio 2.725 ( 95% ci , 2.3903.109 ) ( p 
 < 0.001 ) . 
 however , no correlation was found between ht and lnm of ptc . 
 conclusion . 
 ht was associated with an increased prevalence of all stages of ptc , independent of tumor size , gender , and age . 
 in contrast , locally advanced disease defined by lnm was unrelated to ht . 
 these data suggest an association of ht with low risk ptc and a potential protective immunologic effect from further disease progression .