we investigated 383 consecutive classical ptmc patients from the department of pathology , kangbuk samsung hospital , sungkyunkwan university school of medicine ( seoul , korea ) from january 1 , 2010 to december 31 , 2011 . the correlations between multifocality and clinicopathological characteristics including age , sex , tumor size , extrathyroidal extension , lymph node metastasis , ptnm stage , and us findings were evaluated by reviewing medical charts , pathology records , and glass slides and based on the seventh edition ajcc tnm classification system . patients had undergone either total thyroidectomy ( n = 237 ) or lobectomy ( including hemithyroidectomy ) ( n = 146 ) with lymph node dissection . the decisions to perform lymph node dissection and the extent of dissection were made by the surgeon based on ata management guidelines   and various risk - evaluation systems . the mean age of patients was 45.4  10.4 years , the mean tumor size of the largest dominant tumor was 0.65  0.20 cm , and the sex ratio ( male : female ) was 1:3.85 . by ajcc stage grouping , there were 295 cases in stage i , 0 cases in stage ii , 86 cases in stage iii , and two cases in stage iv . the study protocol was approved by the institutional review board ( irb ) of kangbuk samsung hospital ( irb no . kbc12202 ) , who confirmed informed consents . sections were cut to a thickness of 0.2 cm for postoperative pathological examination . all tumors detected during inspection were histologically examined . for evaluation of extrathyroidal extension , peritumoral parenchyma with thyroidal in addition , one section with normal - appearing parenchyma was included from each lobe . mptmcs were defined as tumors with an intertumoral distance greater than 0.5 cm in the ipsilateral lobe or contralateral lobe of the primarytumor . the number of tumors ranged from two to six ( mean , 2.36  0.70 ) , and we designated ptmcs other than the largest tumor as supplemental tumors . the first group included suspicious mptmcs , the second group included uptmcs accompanied by benign or indeterminate nodules , and the third group included suspicious uptmcs . within the second and third groups , incidental mptmcs were defined as those discovered on pathological examination , which were not detected on preoperative us . us evaluation was performed by radiologists at our institution , and results were reported according to standard criteria . relevant articles were obtained by searching pubmed and medline databases up to january 15 , 2015 . searches were performed using the keywords  papillary thyroid carcinoma  and  multifocal . search results were then scanned according to the following inclusion and exclusion criteria : ( 1 ) ptc investigated in human tissue , ( 2 ) available information regarding tumor recurrence in uptmc and mptmc , ( 3 ) case reports or non - original articles were excluded , and ( 4 ) non - english language publications were excluded . the following data were extracted from each of the eligible studies : the first author s name , year of publication , number of patients analyzed , and number of patients with tumor recurrence . the significance of tumor multifocality and correlations with clinicopathological parameters were determined by either chi - squre test or the fisher exact test ( two - sided ) . the relationship between tumor multifocality and tumor size was analyzed using a two - tailed student s t test . linear regression analysis was conducted to investigate correlations between primary tumor size and tumor multifocality , number of tumor , and supplemental tumor size . in addition , multivariate logistic regression analysis was performed to identify the most influential variables associated with tumor multifocality . to perform the meta - analysis , comprehensive meta - analysis ver . odds ratio ( or ) with a 95% confidence interval ( ci ) was calculated by fixed - effect and random - effect models and used to evaluate the correlation between tumor multifocality and recurrence . heterogeneity between studies was evaluated with the q test , i , and p - values . we investigated 383 consecutive classical ptmc patients from the department of pathology , kangbuk samsung hospital , sungkyunkwan university school of medicine ( seoul , korea ) from january 1 , 2010 to december 31 , 2011 . the correlations between multifocality and clinicopathological characteristics including age , sex , tumor size , extrathyroidal extension , lymph node metastasis , ptnm stage , and us findings were evaluated by reviewing medical charts , pathology records , and glass slides and based on the seventh edition ajcc tnm classification system . patients had undergone either total thyroidectomy ( n = 237 ) or lobectomy ( including hemithyroidectomy ) ( n = 146 ) with lymph node dissection . the decisions to perform lymph node dissection and the extent of dissection were made by the surgeon based on ata management guidelines   and various risk - evaluation systems . the mean age of patients was 45.4  10.4 years , the mean tumor size of the largest dominant tumor was 0.65  0.20 cm , and the sex ratio ( male : female ) was 1:3.85 . by ajcc stage grouping , there were 295 cases in stage i , 0 cases in stage ii , 86 cases in stage iii , and two cases in stage iv . the study protocol was approved by the institutional review board ( irb ) of kangbuk samsung hospital ( irb no . sections were cut to a thickness of 0.2 cm for postoperative pathological examination . all tumors detected during inspection in addition , one section with normal - appearing parenchyma was included from each lobe . mptmcs were defined as tumors with an intertumoral distance greater than 0.5 cm in the ipsilateral lobe or contralateral lobe of the primarytumor . the number of tumors ranged from two to six ( mean , 2.36  0.70 ) , and we designated ptmcs other than the largest tumor as supplemental tumors . the first group included suspicious mptmcs , the second group included uptmcs accompanied by benign or indeterminate nodules , and the third group included suspicious uptmcs . within the second and third groups , incidental mptmcs were defined as those discovered on pathological examination , which were not detected on preoperative us . us evaluation was performed by radiologists at our institution , and results were reported according to standard criteria . relevant articles were obtained by searching pubmed and medline databases up to january 15 , 2015 . searches were performed using the keywords  papillary thyroid carcinoma  and  multifocal . search results were then scanned according to the following inclusion and exclusion criteria : ( 1 ) ptc investigated in human tissue , ( 2 ) available information regarding tumor recurrence in uptmc and mptmc , ( 3 ) case reports or non - original articles were excluded , and ( 4 ) non - english language publications were excluded . the following data were extracted from each of the eligible studies : the first author s name , year of publication , number of patients analyzed , and number of patients with tumor recurrence . statistical analyses were conducted using spss ver . 18.0 software ( spss inc . , chicago , il , usa ) . the significance of tumor multifocality and correlations with clinicopathological parameters were determined by either chi - squre test or the fisher exact test ( two - sided ) . the relationship between tumor multifocality and tumor size was analyzed using a two - tailed student s t test . linear regression analysis was conducted to investigate correlations between primary tumor size and tumor multifocality , number of tumor , and supplemental tumor size . in addition , multivariate logistic regression analysis was performed to identify the most influential variables associated with tumor multifocality . to perform the meta - analysis , comprehensive meta - analysis ver . odds ratio ( or ) with a 95% confidence interval ( ci ) was calculated by fixed - effect and random - effect models and used to evaluate the correlation between tumor multifocality and recurrence . heterogeneity between studies was evaluated with the q test , i , and p - values . we initially investigated the correlations between tumor multifocality and clinicopathological parameters in 383 resected classical ptmcs . tumor multifocality was noted in 103 of 383 ptmcs ( 26.9% ) , and nodal metastasis occurred at significantly higher rates in mptmcs than in uptmcs ( p=.003 ) . patients who underwent total thyroidectomy showed a higher incidence of tumor multifocality than patients who underwent lobectomy ( p<.001 ) . for the 83 mptmcs in which total thyroidectomy was undertaken , tumor bilaterality was 62.7% ( 52 of 83 ) . there were no significant differences with respect to age , sex , tumor size , or extrathyroidal extension ( table 1 ) . on multivariate analysis , tumor multifocality was significantly correlated with lymph node metastasis ( p=.002 ) but not age ( 45 years ) , sex , or extrathyroidal extension . on preoperative us , tumor multiplicity was found in 180 cases including 54 suspicious mptmc cases . among suspicious mptmcs , 41 cases were confirmed as mptmcs ( non - incidental mptmcs ) on pathological examination . for the remaining 126 suspicious uptmcs accompanied by benign or indeterminate nodules , nineteen cases ( three suspicious mptmc cases and 16 non - suspicious mptmc cases ) involved incidentally found ptmcs ( incidental mptmcs ) that were not identified preoperatively . in 203 cases regarded as uptmcs on preoperative us , 23 supplemental ptmcs were incidentally discovered on pathological examination ( incidental mptmcs ) . in total , 103 mptmcs ( 61 non - incidental and 42 incidental ) of 383 ptmcs were identified ( fig . the distribution of mptmcs based on primary tumor size was investigated and is shown in fig . the rate of mptmc occurrence was 0%34.4% and was shown to increase with increasing primary tumor size on linear regression analysis ( r=0.519 and p=.019 ) . ptmcs were divided with a cutoff of 0.3 cm , and the mptmc rate was 5.9% in ptmcs smaller than 0.3 cm and 27.9% in ptmcs larger than 0.3 cm . in addition , the number of tumors and supplemental tumor size were significantly increased according to primary tumor size ( r=0.014 , p=.021 and r=0.117 , p=.023 , respectively ) ( fig . forty - two cases ( 40.8% ) were incidentally diagnosed as mptmc via postoperative pathological examination . to understand the significance of incidentally discovered supplemental tumors in mptmc , we compared clinicopathological characteristics between incidental and non - incidental mptmcs . the mean sizes of supplemental tumors were 0.23  0.12 cm in incidental mptmcs and 0.41  0.17 cm in non - incidental mptmcs . as expected , supplemental tumor size was significantly smaller in incidental mptmcs than in non - incidental mptmcs ( p<.001 ) , even though the largest tumor size did not differ ( p=.870 ) . the rate of extrathyroidal extension was higher in incidental mptmcs than in non - incidental mptmcs ( p=.016 ) , but there was no difference in lymph node metastasis ( p=.199 ) ( table 2 ) . we performed a systematic review and meta - analysis to confirm the difference of tumor recurrence between uptmc and mptmc . one hundred fifty - six studies were identified through a database search and were screened ( fig . 3 ) ; 148 of these studies were excluded due to no or insufficient information ( 123 ) , studies on other disease ( 10 ) , case reports or non - original articles ( 13 ) , and non - english - language articles ( 2 ) . eight eligible studies and 5,665 patients were included in the current meta - analysis [ 15 - 22 ] . tumor multifocality was found in 1,844 of 5,665 overall ptmcs ( 32.6% ) . in the eligible studies , the rates of tumor multifocality were 24.0%42.5% . our meta - analysis showed significant correlation between tumor recurrence and mptmcs in fixed - effect ( or , 2.002 ; 95% ci , 1.475 to 2.719 ; p<.001 ) and random - effect ( or , 2.118 ; 95% ci , 1.323 to 3.390 ; p=.002 ) models ( fig . 4 ) . on sensitivity analysis , or ranges were 1.7362.277 and 1.9072.417 in fixed - effect and random - effect models , respectively , and estimated ors were not affected by eligible studies . there was no definite asymmetry in begg s funnel plot ( data not shown ) . we initially investigated the correlations between tumor multifocality and clinicopathological parameters in 383 resected classical ptmcs . tumor multifocality was noted in 103 of 383 ptmcs ( 26.9% ) , and nodal metastasis occurred at significantly higher rates in mptmcs than in uptmcs ( p=.003 ) . patients who underwent total thyroidectomy showed a higher incidence of tumor multifocality than patients who underwent lobectomy ( p<.001 ) . for the 83 mptmcs in which total thyroidectomy was undertaken , tumor bilaterality was 62.7% ( 52 of 83 ) . there were no significant differences with respect to age , sex , tumor size , or extrathyroidal extension ( table 1 ) . on multivariate analysis , tumor multifocality was significantly correlated with lymph node metastasis ( p=.002 ) but not age ( 45 years ) , sex , or extrathyroidal extension . on preoperative us , tumor multiplicity was found in 180 cases including 54 suspicious mptmc cases . among suspicious mptmcs , 41 cases were confirmed as mptmcs ( non - incidental mptmcs ) on pathological examination . for the remaining 126 suspicious uptmcs accompanied by benign or indeterminate nodules , nineteen cases ( three suspicious mptmc cases and 16 non - suspicious mptmc cases ) involved incidentally found ptmcs ( incidental mptmcs ) that were not identified preoperatively . in 203 cases regarded as uptmcs on preoperative us , 23 supplemental ptmcs were incidentally discovered on pathological examination ( incidental mptmcs ) . in total , 103 mptmcs ( 61 non - incidental and 42 incidental ) of 383 ptmcs were identified ( fig . the distribution of mptmcs based on primary tumor size was investigated and is shown in fig . 2a . the rate of mptmc occurrence was 0%34.4% and was shown to increase with increasing primary tumor size on linear regression analysis ( r=0.519 and p=.019 ) . ptmcs were divided with a cutoff of 0.3 cm , and the mptmc rate was 5.9% in ptmcs smaller than 0.3 cm and 27.9% in ptmcs larger than 0.3 cm . in addition , the number of tumors and supplemental tumor size were significantly increased according to primary tumor size ( r=0.014 , p=.021 and r=0.117 , p=.023 , respectively ) ( fig . forty - two cases ( 40.8% ) were incidentally diagnosed as mptmc via postoperative pathological examination . to understand the significance of incidentally discovered supplemental tumors in mptmc , we compared clinicopathological characteristics between incidental and non - incidental mptmcs . the mean sizes of supplemental tumors were 0.23  0.12 cm in incidental mptmcs and 0.41  0.17 cm in non - incidental mptmcs . as expected , supplemental tumor size was significantly smaller in incidental mptmcs than in non - incidental mptmcs ( p<.001 ) , even though the largest tumor size did not differ ( p=.870 ) . the rate of extrathyroidal extension was higher in incidental mptmcs than in non - incidental mptmcs ( p=.016 ) , but there was no difference in lymph node metastasis ( p=.199 ) ( table 2 ) . we performed a systematic review and meta - analysis to confirm the difference of tumor recurrence between uptmc and mptmc . one hundred fifty - six studies were identified through a database search and were screened ( fig . 3 ) ; 148 of these studies were excluded due to no or insufficient information ( 123 ) , studies on other disease ( 10 ) , case reports or non - original articles ( 13 ) , and non - english - language articles ( 2 ) . eight eligible studies and 5,665 patients were included in the current meta - analysis [ 15 - 22 ] . tumor multifocality was found in 1,844 of 5,665 overall ptmcs ( 32.6% ) . in the eligible studies , our meta - analysis showed significant correlation between tumor recurrence and mptmcs in fixed - effect ( or , 2.002 ; 95% ci , 1.475 to 2.719 ; p<.001 ) and random - effect ( or , 2.118 ; 95% ci , 1.323 to 3.390 ; p=.002 ) models ( fig . 4 ) . on sensitivity analysis , or ranges were 1.7362.277 and 1.9072.417 in fixed - effect and random - effect models , respectively , and estimated ors were not affected by eligible studies . there was no definite asymmetry in begg s funnel plot ( data not shown ) . multifocal ptcs are associated with loco - regional recurrence and lymph node metastasis ; however , the clinicopathological significance and appropriate treatment modalities for mptmc remain unclear . in addition , little is known about the clinicopathological characteristics of incidental mptmcs . to the best of our knowledge , this is the first report showing the clinicopathological significance of incidental mptmcs and the correlation between tumor recurrence and mptmcs using meta - analysis . the incidence of ptmcs has rapidly increased in recent years [ 23 - 25 ] . it is debated whether ptmc is a normal finding , equivalent to disease , or a precursor of overt ptc . reported that the rate of ptmc enlargement without unfavorable features was 6.4% at 5 years and 15.9% at 10 years . in previous reports , distant metastasis and mortality occurred more rarely in ptmc than in overt ptc . however , there are many reports showing that ptmcs show similar rates of extrathyroidal extension and nodal metastasis ( 40.3% to 64.1% ) [ 23 - 25,28,29 ] . in addition , a recent meta - analysis showed that total thyroidectomy was significantly correlated with lower recurrence and mortality rates in ptmc . patients who underwent total thyroidectomy showed a higher incidence of tumor multifocality than patients who underwent lobectomy ( p<.001 ) . in 83 mptmcs that underwent total thyroidectomy , still , the unfavorable factors that can result in aggressive behavior and impact prognosis in ptmcs remain unclear . tumor multifocality is not considered a high - risk factor in systems including ages ( age , grade , extent , size ) , ames ( age , distant metastasis , extent , size ) , macis ( distant metastasis , age , completeness of resection , local invasion , size ) , and games ( grade , age , distant metastasis , extent , size ) . our data showed that tumor multifocality was significantly associated with nodal metastasis in 26.9% of total ptmcs , as in previous studies [ 15,17 - 19 ] . however , in the ptmcs of some previous studies , the correlation between tumor multifocality and recurrence wascontroversial [ 15 - 22 ] . further cumulative prospective studies or meta - analysis should be performed to determine the clinicopathological significance of mptmc . our meta - analysis showed that tumor recurrence was significantly higher in mptmc than in uptmc ( fig . regrettably , our data could not be included in the meta - analysis due to limitations including no recurrence cases during follow - up and short follow - up period ( 3 years ) . in addition , the current meta - analysis did not allow subgroup analysis based on positive or negative resection margins due to insufficient information provided in the eligible studies . kuo et al .   reported that mptmc was associated with worse survival than uptmc but reported no difference in survival between multifocal overt ptc ( > 1 cm ) and mptmc . our results and earlier studies suggest that tumor multifocality in ptmcs , regardless of tumor size , is a useful predictive factor of aggressive tumor behavior , such as lymph node metastasis and tumor recurrence . it might be appropriate to manage patients with mptmc differently than patients with uptmc having no unfavorable factors . incidental ptmc is defined as ptmc incidentally discovered and confirmed by gross and/or microscopic examination from surgical specimens resected for the evaluation of other disease entities . however , no clear definition for incidental mptmc has been previously provided . in this study , we defined incidental mptmc as supplemental tumors not detected on preoperative us that were discovered on pathological examination . although these supplemental tumors are important for diagnosis of multifocality , the characteristics of supplemental tumors have not been previously described . in the present study , however , the lower limit of tumor size detectable on us is unclear , and more controlled and careful histological examination for entirely submitted cases is needed to identify tumor multifocality . the mean size of incidentally discovered supplemental tumors was 0.27  0.15 cm , which was significantly smaller than non - incidental tumors ( p<.001 ) . 2 ) . the smaller size explains the lack of detection during preoperative us . however , there was no difference in nodal metastasis rate between incidental and non - incidental mptmc . this finding suggests that tumor multifocality itself , rather than the manner of detection , is related to lymph node metastasis . in addition , the detection rate of incidental mptmc might influence the rate of mptmc . if these supplemental tumors are missed in pathological examination , cases are diagnosed as uptmc and not mptmc . therefore , detailed examination for multiple tumors using preoperative us study and adequate postoperative pathological examination is essential in the diagnosis of ptmc . we previously reported that evaluation of tumor multifocality based on total surface area is useful to distinguish aggressive mptmc from less aggressive mptmc and uptmc . on that basis , we concluded that careful detection of multifocal tumors is important despite discrepant reporting on multifocality . the discrepancies largely seem to result from different manners of pathological examination and the number of sections analyzed . although radiological tools have improved , tumors smaller than 0.3 cm are not easily detected via radiological examination . in the present study , only four of 383 ptmcs were smaller than 0.3 cm . among them , two cases were 0.2 cm on histological examination , after appearing larger than 0.3 cm on preoperative us . suspicious nodules on preoperative us in the remaining two cases were confirmed as benign nodules on histological examination . another two incidentally detected nodules ( 0.2 cm and 0.1 cm ) were diagnosed as ptmc . in addition , it is difficult to confirm ptmc in preoperative fine - needle aspiration for tumors smaller than 0.5 cm , which require thin sections in postoperative gross examination for non - detected small nodules . because it is difficult to cut 0.2-cm - thick slices of specimens prior to fixation , thin sectioning after proper fixation is required for assessment of tumor multifocality . in conclusion , this study demonstrates that tumor multifocality in ptmc is significantly correlated with lymph node metastasis . our meta - analysis revealed a positive correlation between tumor multifocality and tumor recurrence in ptmc . therefore , careful attention should be paid to detection of mptmc , which behaves differently from uptmc , on preoperative and postoperative examination .