| Objectives:The potential overdiagnosis and overtreatment of the low-risk papillary thyroid microcarcinoma(PTMC)has become a clinical and social issue.The active surveillance(AS)approach provides an effective shunting mechanism for patients with low-risk thyroid cancer.With continuous ultrasound monitoring,only a small proportion of patients would require delayed surgery for tumor progression.The AS management has substantively reduced overtreatment on thyroid cancer and has also significantly reduced the burden of disease on society and individuals.With the safety and effectiveness constantly being proven,AS approach has become a first-line recommendation by many guidelines.However,due to the differences in long-term clinical practices and concepts,there are no prospective studies and clinical practices of AS management have been reported in China.Many Chinese experts widely believe that(i)numerous clinical low-risk PTMCs(cN0)were pathologically diagnosed as pN1 disease,and a paradox seems to exist between extremely high micro-lymph node metastasis(m-LNM)and observation for the low-risk PTC.(ii)Chinese patient visits are usually not conducted in a fixed hospital,and follow-up adherence is poor,thus AS management may have potential safety issues.(iii)the culture between Chinese and west is different obviously,the traditional philosophy of Chinese patients is not consistent with the notion of "living with a tumor".(iv)there is a serious imbalance in the doctor-patient ratio in China,constructing an ideal AS and follow-up team is difficult.Therefore,eliminating these presuppositions in Chinese patients may be critical to the development of AS management in China.In this study,we aimed(ⅰ)to construct a probabilistic model to evaluate the risk of false negative lymph nodes(LNs),and to verify the long-term survival effect of residual m-LNM in body in patients with PTMC.(ⅱ)to evaluate whether the observation increased the incidence of m-LNM and multifocality in patients with asymptomatic PTC.(ⅲ)to investigate the epidemiological and clinical characteristics of patients who underwent AS management,and to evaluate the feasibility,safety and effectiveness of AS approach,and to explore and optimize the AS approach based on the characteristics of Chinese patients and medical environment.Methods:(ⅰ)Patients diagnosed with PTMC who underwent thyroidectomy with at least one LN examined were identified from the First Affiliated Hospital of Kunming Medical University database between 2007 and 2020.Based on the distribution characteristics of LNMs from this retrospective cohort,a probabilistic model for the risk of residual m-LNM was established.A β-binomial distribution was used to estimate the probability of missing nodal disease as a function of the number of LNs examined.Overall survival(OS)probabilities of groups with adequacy and inadequacy LNs examined were estimated using the Kaplan-Meier method in the Surveillance,Epidemiology,and End Results(SEER)database(n=15,340).A multivariable model with restricted cubic splines was also used to verify the association of OS with the numbers of LN examined.(ⅱ)Patients with asymptomatic PTC who underwent thyroidectomy with prophylactic central lymph node dissection(CLND)and tumor size≤1.5 cm on pathology examination were retrospective analysis(n=5,287).Patients were divided non-observation(immediate surgery)and observation groups which were further divided six subgroups according to different observation duration.The prevalence trend of LNM,LNM>5,multifocality,and bilateral multifocality were evaluated using the Mann-Kendall trend test.A multivariable logistics regression was used to evaluate the odds ratio of above four outcome variables between the observation and non-observation groups.(ⅲ)We construct a prospective cohort of cT1aM0M0 stage PTMC patients who performed AS management.Patient adherence was compared in patients with or without cytological diagnosed PTMC.Tumor progression,progression surgery and non-progression surgery rates were further evaluated in cytological diagnosed PTMC patients.A Cox multivariable regression was used to analyze the clinical factors which associated with tumor progression.Results:(i)The risk of m-LNM residual in body(missed nodal disease)is from 31.3%to 10.0%if LNs examined number between 1 and 7 in patients with PTMC.with 7 LNs examined as the cut-off value,the intergroup comparison showed residual positive LNs did not affect OS both across all patients and aged≥ 55 group(P=0.72 and P=0.112).After adjusting of patients and clinical characteristics,the multivariate model was also showed the slight effect between LN examined numbers and OS.(P=0.69).(ii)All patients with asymptomatic low-risk PTC were divided into observation(n=3,427)and non-observation(n=1,860)groups.Trend test showed that a decreasing trend with the observation time on the prevalence of central LNM and central LNM>5,but there was no significant difference(Z=-1.608,P=0.108 and Z=-0.901,P=0.368);and showed that significantly decreasing trends both on the prevalence of multifocal and bilateral multifocal PTC(both Z=-3.004,P=0.003).After adjustment,there were no significant differences in the above four outcome variables between the observation and nonobservation groups.(iii)From March 2020 to February 2022,89.7%of patients who met the inclusion criteria were willing to performed AS management to avoid immediate surgery.A total of 202 patients with low-risk(or highly suspected)PTMC were included.The median age was 40(IQR:32-48)years,with 48.0%of patients were under 40 years old.The median baseline diameter of the index tumors was 4.3(IQR:3.2-5.2)mm,with 74.8%of tumors being≤5 mm.One hundred and eighteen(58.4%)patients performed FNAB at beginning or during AS,of which 48.5%were diagnosed as PTMC by cytology(Bethesda Ⅴ/Ⅵ and BRAF mutation)and up to 16.1%and 49.2%of cases were diagnosed with unsatisfactory or uncertain cytology(Bethesda I or III,IV,V),respectively.Patient adherence of PTMC group significantly better than that of suspected PTMC group(P=0.003).After a median 22(IQR:12-44)months follow-up for patients with cytological diagnosed PTMC,tumor growth≥ 3mm and tumor volume increase≥ 50%occurred in 11(11.2%)and 50(51.0%)patients,respectively,and no new LNM,distant metastasis,and death occurred.Five(5.1%)patients were determined to need delayed surgery intervention,and other surgeries performed in 5 patients because of patient preferences rather than disease progression.The Cox regression analyses showed that less than 12 months of observation before enrollment were independently associated with the risk of both tumor growth≥ 3mm(OR:36.24,95%CI:3.52～372.90)and tumor volume increase ≥50%(OR:23.06,95%CI:8.64～61.55).The tumor doubling rates(TDRs)were reduced in 75.0%of tumor growth≥3mm patients and 84.6%of tumor volume increase≥ 50%patients,respectively.The median post-tumor progression TDRs was significantly lower than that of pre-tumor progression TDRs(-0.09/year[-0.12/year～0.48/year]vs.0.91/year[0.86/year～1.25/year],P=0.014 for size and 0.29/year[-0.14/year～0.70/year]vs.1.04/year[0.66/year～2.17/year],P<0.001 for volume).After tumor size and volume progression,62.5%and 43.6%of tumors were remained stable or shrank,respectively.Conclusions:The present study confirmed the feasibility,safety,and effectiveness of AS approach alternatives immediate surgery in management in Chinese patients with low-risk PTMC,based on a large sample retrospective and a first prospective AS cohort study in China.The concerns regarding m-LNM during observation should not be an obstacle to the development of AS.The AS can be used as a management strategy for low-risk PTMC in China,and is expected to significantly reduce the disease burden of both the government and individuals through the shunting of AS and surgery in patients with low-risk PTMC.Given the differences in epidemiological and clinical characteristics,Chinese institutions should fully consider the features of the Chinese population when developing candidate criteria,surveillance intervals,and follow-up strategies for AS. |
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