远处转移性甲状腺乳头状癌生化进展的影响因素研究

Factors Influencing Biochemical Progression in Distant Metastatic Papillary Thyroid Carcinoma

背景晚期甲状腺乳头状癌(PTC),尤其是远处转移性甲状腺乳头状癌(DM-PTC)的病情变化主要从甲状腺球蛋白(Tg)等血清学指标和CT等影像学两方面进行监测。由于CT等影像学手段本身的局限性如辐射、价格昂贵及转移病灶分布的复杂性,实体瘤疗效评估标准(RECIST 1.1)常无法及时捕捉DM-PTC患者的病情变化,而整合了时间维度的Tg倍增时间(TgDT)已显示其在灵敏监测PTC疾病变化中的作用。目的以TgDT为结局变量,探索DM-PTC的生化进展及其影响因素。方法回顾性纳入2018年1月—2023年6月北京协和医院核医学科就诊的61例DM-PTC患者为研究对象,通过门诊病历系统收集研究对象的基线资料并进行基因突变检测,基因突变检测内容包括鼠类肉瘤滤过性毒菌致癌同源体B1(BRAF)突变、端粒酶反转录酶(TERT)突变、转染重排(RET)融合、大鼠肉瘤病毒(RAS)突变。末次^(131)I治疗后4个月到1年时间内行外周血T细胞亚群、自然杀伤细胞(NK细胞)及淋巴细胞检测。计算TgDT,以TgDT 3年为界,将研究对象分为<3年组(n=16)和≥3年组(n=45)。末次^(131)I治疗后4个月到1年时间内,计算TgDT的初次Tg时间点的T细胞亚群、NK细胞百分比及淋巴细胞绝对值被定义为淋巴细胞亚群的初始值,计算TgDT的末次Tg时间点的T细胞亚群、NK细胞百分比及淋巴细胞绝对值被定义为淋巴细胞亚群的末次值,淋巴细胞亚群随时间纵向变化情况以淋巴细胞亚群变化率表示,淋巴细胞亚群变化率=(末次值-初始值)/初始值×100%。比较两组淋巴细胞亚群初始值及变化率的差异情况。采用多因素Logistic逐步向后回归分析探究DM-PTC生化进展的影响因素。结果≥3年组确诊年龄、末次^(131)I治疗前局部手术次数、碘难治(RAIR)、TERT突变、BRAF与TERT共同突变比例低于<3年组,RET融合比例高于<3年组(P<0.05)。≥3年组CD_(3)^(+)T细胞百分比、CD_(8)^(+)T细胞百分比高于<3年组,NK细胞百分比、CD4/CD8低于<3年组(P<0.05)。多因素Logistic回归分析结果显示CD_(8)^(+)T细胞百分比降低(OR=0.879,95%CI=0.792~0.975)、BRAF与TERT共同突变(OR=7.044,95%CI=1.368~36.265)是DM-PTC生化进展的影响因素(P<0.05)。结论低CD_(8)^(+)T细胞比例的免疫状态、BRAF与TERT共同突变等多种因素可影响DM-PTC的生化进展,淋巴细胞亚群及多基因联合检测对于DM-PTC病情监测及预后评价具有重要意义。

Background In advanced papillary thyroid carcinoma(PTC),particularly distant metastatic PTC(DM-PTC),disease progression is primarily monitored through serum markers like thyroglobulin(Tg)and imaging modalities such as computed tomography(CT).Due to limitations inherent in imaging techniques,such as radiation exposure,high cost,and complexity of metastatic lesion distribution,Response Evaluation Criteria In Solid Tumors version 1.1(RECIST 1.1)often fail to timely capture disease changes in DM-PTC patients.The integration of Tg doubling time(TgDT)has demonstrated its efficacy in sensitively monitoring PTC disease progression.Objective To explore the biochemical progression and its influencing factors in DM-PTC using TgDT as the outcome variable.Methods This retrospective study included 61 DM-PTC patients treated at the Department of Nuclear Medicine,Peking Union Medical College Hospital from January 2018 to June 2023.Baseline data and genetic mutation analyses(including BRAF mutation,TERT mutation,RET fusion,and RAS mutation)were collected.Peripheral blood T cell subsets,natural killer(NK)cells,and lymphocyte counts were measured 4 months to 1 year post-last^(131)I treatment.Patients were categorized into two groups based on TgDT<3 years(n=16)and≥3 years(n=45).The initial and final values of T cell subsets,NK cell percentages,and lymphocyte counts were defined at the first and last Tg measurement points,respectively.The lymphocyte subset change rate was calculated as[(final value-initial value)/initial value]×100%.Differences in initial values and change rates of lymphocyte subsets between the two groups were compared.Multivariate Logistic regression analysis was performed to identify factors influencing biochemical progression in DM-PTC.Results The≥3 years group had a lower age at diagnosis,fewer local surgeries before the last^(131)I treatment,lower RAIR,TERT mutation,and co-occurrence of BRAF and TERT mutations,but a higher RET fusion rate compared to the<3 years group(P<0.05).The≥3 years group exhibited higher percentages of CD_(3)^(+)and CD_(8)^(+)T cells and lower percentages of NK cells and CD4/CD8 ratio compared to the<3 years group(P<0.05).Multivariate Logistic regression analysis indicated that a decrease in CD_(8)^(+)T cell percentage(OR=0.879,95%CI=0.792-0.975)and co-occurrence of BRAF and TERT mutations(OR=7.044,95%CI=1.368-36.265)were factors influencing biochemical progression in DM-PTC(P<0.05).Conclusion An immune status characterized by a low proportion of CD_(8)^(+)T cells and the co-occurrence of BRAF and TERT mutations are influential factors in the biochemical progression of DM-PTC.Lymphocyte subset analysis and combined genetic testing are crucial for disease monitoring and prognosis evaluation in DM-PTC.