The Role Of Tumor Multifocality In Clinical Outcomes Of Papillary Thyroid Carcinoma

Part Ⅰ The Role of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid CarcinomaBackground and PurposeThyroid cancer is the most common malignancy of the endocrine system with a rapid rise in incidence in recent decades.But thyroid cancer mortality had been stable.Papillary thyroid carcinoma(PTC)is the main type of thyroid cancer.Tumor multifocality is frequently observed and often empirically treated as a prognostic risk factor in PTC,prompting more aggressive treatments,but its role in clinical outcomes of PTC remained controversial and was investigated here.the prognostic value of multifocality of PTC remains controversial,creating a major confusion and dilemma in the current clinical management of PTC.As such,overtreatment or undertreatment of PTC may occur depending on how a clinician understands and uses multifocality as a prognostic risk factor.In the present study,we took advantage of a large international multicenter cohort of patients with PTC as well as the Surveillance,Epidemiology and End Results(SEER)database to investigate the role of tumor multifocality in clinical outcomes of PTC and its prognostic value in the management of this cancer.MethodsWith the approval of institutional review boards of the participating institutions and,where required,informed written subject consents,data from 2638 patients with PTC on clinicopathological characteristics,tumor recurrence,and PTC-specific patient death were pooled from 11 medical centers in 6 countries.These patients included 623(23.6%)men and 2015(76.4%)women,with median(interquartile range[IQR])age of 46(35-58)years at the diagnosis of PTC and median(IQR)follow-up time of 58(26-107)months after the initial surgery.All the patients were treated with total or near-total thyroidectomy for PTC.Clinicopathological characteristics examined at the initial surgical treatment included patient sex and age,tumor foci(unifocality versus multifocality—defined as ≥ two tumor foci),tumor size,extrathyroidal extension,lymph node metastasis,distant metastasis,tumor stages,and histopathological variant type.The greatest dimension of the largest tumor focus was used as the tumor size in the analysis.Histopathological diagnoses of PTC variants were established following the World Health Organization criteria.Neck dissection and postsurgical therapies,including radioiodine ablation and thyrotropin suppression.Statistical analysesComparisons of categorical variables were performed by Pearson chi-square test or,for small numbers,Fisher’s exact test.Wilcoxon-Mann-Whitney test was used to compare independent continuous variables.Recurrence-free probability and PTC-specific patient survival probability were estimated by Kaplan-Meier(K-M)analysis with follow-up time censored,in which log-rank test was used for comparison between multifocality and unifocality.Cox regression and Cox proportional hazard analyses were performed to examine the independent effects of clinicopathological characteristics on the recurrence-free survival and disease-specific survival probabilities using hazard ratio(HR)and 95%confidence interval(CI).A two-tailed P value<0.05 was considered significant.Data were analyzed using Statistical Package for Social Science version 17.0(SPSS,Inc,New York,NY,USA).Result1.Clinicopathological characteristics of PTC in three main variantsAmong the total of 2638 cases of PTC,the most common three variants were CPTC(1893 cases,71.8%),FVPTC(525 cases,19.9%),and TCPTC(100 cases,3.8%),collectively accounting for 95.5%of the entire PTC cohort.Other variants were rare(collectively 120 cases,4.5%).The prevalence of high-risk parameters was significantly different among the three variants,including extrathyroidal invasion,lymph node metastasis,stages III/IV,distant metastasis,disease recurrence,mortality,and the use(need)of radioiodine treatment,BRAF mutation status(all P<0.001),being highest in TCPTC,lowest in FVPTC,and intermediate in CPTC,following an order of TCPTC>CPTC>FVPTC.Tumor recurrence rate occurred in 320/1893(16.9%)CPTC,53/525(13.2%)FVPTC,and 30/100(30.0%)TCPTC,being highest in TCPTC,lowest in FVPTC,and intermediate in CPTC.Patient mortality occurred in 41/1893(2.2%)CPTC,5/525(1.0%)FVPTC,and 9/100(9.0%)TCPTC,being also highest in TCPTC,lowest in FVPTC,and intermediate in CPTC.Multifocality and sex(male)was not significantly different among the three PTC variants(respectively P=0.203,P=0.731).2.Association between multifocality and high-risk clinicopathological characteristics of PTC in univariate analysesMultifocality was seen in 1000/2624(38.1%)all PTC,731/1888(38.7%)CPTC,183/524(34.9%)FVPTC,and 42/100(42.0%)TCPTC,with no difference among them(P=0.203).On the overall analysis of the 2638 patients of all PTC,when compared with unifocality of PTC,multifocality was associated with extrathyroidal extension,lymph node metastasis and,correspondingly,advanced tumor stage Ⅲ/Ⅳ.Multifocality was also associated with more frequent use and higher dosage of radio iodine-131(I131)in the treatment of PTC.There was no difference between multifocality and unifocality in patient age,tumor size,and BRAF mutation status(P>0.05 in all).The recurrence of PTC was moderately higher in multifocality compared with unifocality,being 198/1000(19.8%)in the former versus 221/1624(13.6%)in the latter(P<0.001).This pattern was also seen when examining papillary thyroid microcarcinoma(PTMC)and non-PTMC(e.g.,tumors>1.0 cm)separately,with the recurrence in multifocal versus unifocal PTMC and non-PTMC being 35/297(11.8%)versus 24/484(5.0%)(P<0.001)and 162/699(23.2%)versus 190/1121(16.9%)(P=0.001),respectively.There was no association between multifocality and mortality in any of these PTC settings.There was no association between multifocality and distant metastasis in any of the PTC settings investigated in this study.3.Lack of an independent role of multifocality in clinical outcomes of papillary thyroid carcinomaOn univariate analyses,moderately significant HRs of multifocality for recurrences were observed in several settings of PTC.However,on multivariate adjustment for classical clinicopathological risk factors of patient age,male sex,tumor size,extrathyroidal extension,and lymph node metastasis,the significance of HRs of multifocality for recurrence was lost in all the PTC settings.In contrast,the HRs of patient age,male sex,tumor size,extrathyroidal extension,and lymph node metastasis for PTC recurrence remained significant in most of these settings after multivariate adjustment,consistent with their well-established role in poor clinical outcomes of PTC.Similar results were obtained when the three PTC variants—CPTC,FVPTC and TCPTC—were individually analyzed.These results strongly suggested that multifocality had no independent role in PTC recurrence,and its association with recurrence observed on univariate analyses reflected the effects of coexisting classical high-risk factors,such as lymph node metastasis and extrathyroidal extension.To definitively test this,we identified and examined a special cohort of 1423 patients with intrathyroidal PTC defined as tumors lacking extrathyroidal extension,lymph node metastasis and distant metastasis.Among these patients,455/1422(32.0%)cases had multifocality.The overall rate of intrathyroidal multifocality among all PTC was 455/2624(17.3%).Even on univariate analysis,no association between multifocality and disease recurrence was observed in patients with intrathyroidal PTC.Specifically,recurrence in multifocal versus unifocal PTC in these patients were 20/455(4.4%)versus 41/967(4.2%)(P=0.892),with a HR of 1.08(95%CI,0.63-1.84),which remained insignificant at 1.14(95%CI,0.66-1.95)after multivariate adjustment.Lack of association between multifocality and recurrence of intrathyroidal PTC was similarly observed in CPTC,FVPTC,and TCPTC,with insignificant HRs.There was no association between multifocality and PTC-related patient mortality in any of the PTC settings examined in this study,whether on univariate or multivariate analyses.These results were replicated and validated in the analysis of 89 680 patients with PTC in the SEER database.4.Lack of independent effects of multifocality on Kaplan-Meier survival curves of patients with PTCCompared with unifocality,multifocality was associated with a moderate decline in recurrence-free survival curves of patients either in the analysis of the entire cohort of patients or CPTC or FVPTC.In striking contrast,there was no difference in recurrence-free survival curves in patients between multifocality and unifocality when intrathyroidal PTC was analyzed,either in intrathyroidal PTC of all variants or intrathyroidal CPTC or intrathyroidal FVPTC.There was no difference in PTC-specific survival curves of patients between multifocality and unifocality,either in general PTC of all variants,intrathyroidal PTC of all variants,general CPTC,or general FVPTC.Thus,these results clearly demonstrated that multifocality had no effects on the survival curves of patients with PTC.Conclusion1.The aggressiveness order of TCPTC>CPTC>FVPTC is shown clearly in this study.The accurate pathologic diagnosis of PTC histological variants is critical in helping define appropriate treatments of PTC.2.While multifocality is associated with lymph node metastasis,extrathyroidal invasion and advanced tumor stage Ⅲ/Ⅳ,it could therefore be potentially useful in facilitating preoperative surgical decision making for PTC.3.Multifocality had no independent role in PTC recurrence,and its association with recurrence observed on univariate analyses was lost in all the PTC settings on multivariate adjustment for classical clinicopathological risk factors.4.Multifocality did not affect the PTC-related mortality on univariate and multivariate analyses.Significances1.This large comprehensive international multicenter study,complemented by the SEER data analyses,provides definitive evidence reconciling the controversies on the role and prognostic value of tumor multifocality in clinical outcomes of PTC.2.This study will likely have a broad impact on the current clinical management of PTC.Part Ⅱ Risk Factors Of Central Lymph Node Metastasis in Papillary Thyroid MicrocarcinomaBackgroundThe incidence of papillary thyroid microcarcinoma(PTMC)has risen rapidly in recent years,and PTMC patients with central lymph node metastasis(CLNM)usually have poor prognosis.Independent risk factors predicting CLNM in PTMC have not been well understood.PurposeThe aim of our study was to identify useful clinicopathological risk factors predicting CLNM in PTMC patients.MethodsThis study included 1,227 patients with PTC who underwent surgery at the Department of Thyroid Surgery in the Affiliated Hospital of Qingdao University from January 2014 to December 2015.917 patients were finally enrolled in the study.The study was approved by the ethical review commit-tee in our hospital.Clinicopathologic characteristics of included patients were collected,such as gender,age at diagnosis,outcomes of ultrasonography,tumor size,main complications,thyroid functions and thyroid autoantibodies.Because several main guidelines used the age of 45 as the cut-point to divide patients,we thus divided our patients at the age of 45 into younger group(age<45 years)and older group(age ≥45 years).Previous studies suggested Hashimoto’s thyroiditis had possible influence on the occurrence of lymph node metastasis in PTMC patients,and we thus examined two thyroid autoantibodies including thyroglobulin antibody(TgAb)and anti-thyroid peroxidase antibody(TPOAb)to investigate their roles in predicting CLNM among PTMC patients.Main complications included transient hypoparathyroidism,permanent hypoparathyroidism,permanent palsy of the recurrent laryngeal nerve,and temporary palsy of the recurrent laryngeal nerve.Statistical analysesResults were expressed as mean±standard deviation(SD)on continuous data that were in normal distribution.Comparisons of such data were performed using Student t test.Comparisons of categorical variables were performed using chi-square test or,for small number of cases,Fisher’s exact test.Logistic regression was performed with univariate and multivariate analyses to identify predictive risk factors for CLNM.Odds ratios(OR)with 95%confidence intervals(95%CI)were also reported.All statistical analyses were performed using SPSS 17.0 software.Difference was considered significant when a P value was<0.05.All P values were two-tailed.ResultAmong the 917 patients(218 male and 699 female)analyzed,344(37.5%)had CLNM confirmed by intraoperative frozen-section examinations.CLNM was only found in 10.5%of all patients by preoperative ultrasonography,and another 27%of all patients were found to have CLNM by intraoperative frozen-section examinations.In the analysis for predictive risk factors of CLNM by univariate logistic regression analysis,CLNM was significantly associated with male sex(OR=2.00,95%CI 1.47-2.72;P<0.001),younger age(<45years)(OR=1.55,95%CI 1.19-2.03;P=0.001),positive CLNM on preoperative ultrasonography(OR=9.75,95%CI 5.65-16.79;P<0.001),mulifocality(OR=1.77,95%CI 1.31-2.39;P<0.001),larger tumor size(>5 mm)(OR=3.02,95%CI 2.29-4.00;P<0.001),bilaterality of tumor(OR=1.83,95%CI 1.27-2.63;P=0.001),and thyroid capsular invasion(OR=2.31,95%CI 1.23-4.32;P=0.009).There were no significant associations between CLNM and surgical types(P>0.05)and thyroid function test results(P>0.05).Multiple logistic regression analysis showed that there were independent associations of CLNM with most of the significant clinicopathological factors found in the univariate analysis.Of particular importance,clinicopathological risk factors that can be available preoperatively,including male patient sex,younger age(<45years),positive CLNM on preoperative ultrasonography,mulifocality,and larger tumor size(>5 mm),had significant independent association with CLNM(P=0.006,P=0.002,P<0.001,P=0.04 and P<0.001,respectively).The ORs for the association with CLNM were 1.75(95%CI 1.17-2.61),1.69(95%CI 1.20-2.38),10.20(95%CI 5.51-18.88),1.69(95%CI 1.00-2.85),and 2.80(2.01-3.91)for male patient sex,younger age(<45years),positive CLNM on preoperative ultrasonography,mulifocality,and larger tumor size(>5 mm),respectively.Conclusion1.The findings of our study suggest that CLNM is very common in PTMC patients;and male gender,younger age,multifocality,and larger tumor size are useful independent risk factors predicting CLNM in PTMC patients.2.Combinational use of these risk factors of CLNM together with preoperative ultrasonography will help clinicians to precisely estimate the probability of the existence of CLNM in PTMC patients,which is helpful to the management for PTMC patients.