Genetic Features,Risk Factors And Surgical Strategies For Aggressive Papillary Thyroid Microcarcinoma

Objective:The study aimed to determine genetic features and risk factors associated with aggressiveness in papillary thyroid microcarcinoma(PTMC),and to investigate the surgical strategies for PTMC patients with lateral lymph node metastasis(LLNM).Methods:1.16 PTMCs were divided into aggressive and non-aggressive groups according to whether the primary lesions had extrathyroidal extension(ETE)and lymph node metastasis.They were performed by whole-exome sequencing,and GO/KEGG analysis was used to study the characteristics of somatic mutation and biological functions.Then sequenced these genes using target sequencing approach in the validation cohort of 70 PTMCs.2.A total of 3,686 patients with PTMC who underwent initial surgery in the last ten years,were retrospectively analyzed.Chi-squared test and multivariate logistic regression analysis were conducted to identify risk factors associated with cervical lymph node metastasis.3.Patients with PTMC who underwent initial surgery in the last nine years,were retrospectively reviewed.Finally,129 unilateral PTMC patients with ipsilateral LLNM without gross ETE were enrolled in this study and classified into two groups:those who underwent unilateral lobectomy(Group 1)and those who underwent total thyroidectomy(GroupⅡ).Surgical outcomes and recurrence-free survival during the follow-up period were compared between the two groups.Results:1.254 somatic mutations of 234 genes,for which 178 mutations in 168 genes were found in the aggressive group,and 76 mutations in 74 genes were found in the non-aggressive group.Several recurrent mutations in BRAF、VCAN、ALDH1L1 and MUC5B were identified,and many novel but infrequent mutations in other genes were also found.The aggressive cohort had more mutational burdens than the non-aggressive group(P=0.004).The enrichment analysis of GO/KEGG pathway showed that non-synonymous mutations of 13 genes(MUC5B、TNN、SSPO、PPFIA1、PCDHGA2、ITGA8、ITGA4、DCHS1、CRNN、ROCK1、RELN、LAMC2 and AEBP1)were involved in cell adhesion,and these were only present in the aggressive group Targeted sequencing of these genes revealed significant enrichment in the aggressive group(P=0.000004).2.Multivariate analyses demonstrated that male gender,age<55 years,tumor size>6.5mm,lymphovascular invasion,multifocality,ETE and LLNM served as independent risk factors of central lymph node metastasis(CLNM).Moreover,male gender,tumor size>6.5mm,lymphovascular invasion,Hashimoto’s thyroiditis and CLNM served as independent risk factors of LLNM.3.There were 62 patients in Group Ⅰ and 67 patients in Group Ⅱ.Cases in Group Ⅱ had a longer median operation time(150 min vs 120 min,P<0.001)and a higher incidence of postoperative hypoparathyroidism(P<0.001),than cases in Group Ⅰ.But the RFS showed no statistically significant difference(P=0.6005)between the two groups during a median follow-up period of 60 monthsConclusions:The genetic features of aggressiveness for PTMC are cell-adhesion related somatic mutations;the independent risk factors of aggressiveness include male gender,age<55 years,tumor size>6.5mm,ETE,lymph node metastasis and so on;clinical treatment should be performed individually according to related risk factors,and thyroid lobectomy alone plus lymph node dissection may be an optimum initial procedure for unilateral PTMC patients with ipsilateral LLNM without gross ETE.