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摘要: 甲状腺未分化癌(anaplastic thyroid cancer,ATC)是一种罕见的甲状腺肿瘤,约占甲状腺恶性肿瘤的1%~2%,是最具侵袭性的甲状腺癌,可导致显著的发病率和死亡率。高龄、男性、双侧肿瘤、局部浸润和(或)远处转移等是多数ATC患者预后欠佳因素。ATC最佳治疗方案尚未明确,目前虽以手术、放疗、化疗、靶向治疗、免疫治疗等综合治疗为主,然而治疗现状不容乐观。本文通过整理国内外ATC的相关研究,就目前的诊断、治疗方案、近期临床试验结果,以及今后的研究方向等进行综述,为ATC的诊疗决策提供参考。Abstract: Anaplastic thyroid cancer (ATC) is a rare thyroid tumor, accounting for approximately 1%-2% of all thyroid malignancies. It is the most aggressive type of thyroid cancer, resulting in significant morbidity and mortality. Older age, male, bilateral tumors, local invasion, and/or distant metastasis are adverse prognostic factors for most patients with ATC. The best treatment strategy for ATC remains unknown. Currently, comprehensive treatments such as surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy are mainly used; however, the current treatment status remains unclear. By reviewing relevant studies on ATC in China and other countries, this review summarizes the current diagnosis, treatment plans, recent clinical trial results, and future research directions to provide references for ATC diagnosis and treatment decision making.
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甲状腺未分化癌(anaplastic thyroid cancer,ATC)在甲状腺癌中所占比例不足2%,与分化良好的甲状腺癌相比更具侵袭性,是造成甲状腺恶性肿瘤死亡的主要原因。67%的ATC患者年龄>70岁,其中女性占70%,男性占30%。近30年ATC发病率趋势稳定,中位生存时间为3.16个月,生存率无明显改善;患者预后可能与年龄、社会经济状况、远处转移、手术和化疗等有关[1]。ATC目前尚无标准的治疗方案。本文就目前的诊断、治疗方案、近期临床试验结果,以及今后的研究方向进行综述,为ATC的诊疗决策提供参考。
1. ATC的诊断与分期
1.1 临床表现
ATC主要表现为快速增长的颈部肿块并伴有呼吸困难、吞咽困难、声音嘶哑等压迫症状,70%ATC患者伴有甲状腺外周组织浸润和淋巴结转移,而最常见的远处转移部位包括肺、骨、脑等[2-3]。
1.2 美国癌症联合会TNM分期
美国癌症联合会(AJCC)提出ATC患者一经确诊,临床分期即为Ⅳ期:肿瘤局限于甲状腺内并可行根治性切除即为ⅣA期(cT4a AnyN M0)、肿瘤超出甲状腺而无法根治性切除即为ⅣB期(cT4b AnyN M0)、伴有远处转移即为ⅣC期(c AnyT AnyN M1)。
1.3 组织病理学诊断
Dustin等[4]研究显示,细针穿刺细胞学检查(fine needle aspiration cytology,FNAC)是诊断ATC的一种快速有效的方法,具有较高的敏感性(100%)和阳性预测价值(89%)。Manjusha等[5]也支持FNAC可作为早期诊断ATC的可靠工具。因活检组织可能伴有坏死或感染,建议用粗针抽吸或手术活检取材。远处转移灶的活检,应在原发病灶手术后进行。ATC多来源于异常的甲状腺,尤其是侵袭性较高的甲状腺癌中常伴有ATC成分[6]。同一甲状腺癌中同时存在分化型和未分化型癌成分,该部分患者归入未分化癌类型,ATC所占比例将影响患者治疗和预后。ATC的组织学起源尚未明确,一般认为可能是分化型甲状腺癌去分化的终末阶段[7]。PI3K信号通路、TP53和TERT启动子是ATC转化所必需的基因改变[8]。ATC的病理组织学取决于梭形细胞、巨细胞、鳞状或上皮样细胞3种成分,细胞多形性明显,核分裂像、坏死、出血、血管浸润多见,主要表现为肉瘤样、表皮样或鳞状形态改变。肿瘤细胞多表达上皮性标记物如细胞角蛋白、EMA、CEA、PAX- 8、甲状腺转录因子(TTF-1)[9-11],而甲状腺球蛋白(Tg)、降钙素多呈阴性或弱阳性[12]。
1.4 实验室及影像学检查
颈部CT、MRI、B超和PET-CT均有助于ATC诊断。有气管受压导致呼吸不畅者可行纤维气管镜检查,声音嘶哑患者可行电子喉镜、声带功能检查,疑有食管受侵、可行电子胃镜检查。因ATC常伴甲状腺功能亢进、甲状旁腺及肺转移等,也需检查血清甲状腺激素水平、血钙、血清中CA19-9和GM-CSF水平。有报道[13]ATC伴有肺和其他器官转移患者血清中CA19-9和GM-CSF水平较高。
2. ATC的治疗
对于ATC患者,尚无最佳的治疗标准,目前临床治疗方法主要为手术、放化疗等综合治疗,晚期患者以全身治疗为主。新的治疗策略包括针对驱动基因突变的分子靶向治疗、免疫治疗等。
2.1 手术治疗
手术治疗包括甲状腺全切或次全切手术、减瘤术、活检术和气管切开术。甲状腺全切术优于其他方法,有利于延长患者生存期,提高总生存率(中位生存期10个月,6个月生存率达59.26%。由于ATC患者常伴广泛转移,手术通常被排除,然而对于局限性病灶,建议完整手术切除。当肿瘤局限于腺体内、未侵及包膜,应行根治性甲状腺切除术。但仅约10% ATC患者可行根治性切除术,大部分患者仍不能完全切除,或行减瘤术连同全部或部分甲状腺切除。手术是ⅣA、ⅣB期可切除患者治疗的基础,术后可辅以放疗和(或)化疗。根据手术范围可分为单纯原发灶切除术和甲状腺切除+淋巴结清扫术,伴有淋巴结清扫术者预后较好。手术切缘R0、R1较R2可明显提高生存率。ATC确诊时常伴气管、食管等周围组织器官受侵,甚至出现颈部淋巴结和远处转移。对于手术无法完整切除的ⅣB、ⅣC期ATC患者,可行新辅助放化疗使得部分患者获得手术机会。手术联合放化疗的综合治疗模式可在一定程度上提高疗效,延长患者生存期[14]。当肿瘤侵及气管、食管导致呼吸困难、进食梗阻时,可行气管切开术或行手术解除压迫。
2.2 放疗
因缺乏钠碘共体,放射性碘(131I)消融术治疗ATC效果不佳。ⅣA期和ⅣB期ATC患者,术后放疗可生存获益,而对于ⅣC期患者意义不大。放疗联合手术和(或)化疗可改善局部控制率,还可延长总生存时间、提高总生存率。目前,适形放疗技术尤其调强放疗,可同时保证肿瘤区域高剂量,邻近正常组织器官低剂量,从而减少了严重放疗相关不良反应的发生。放疗的范围因手术瘤床、双侧颈部淋巴结和前纵隔等的定位不同而有所不同。在局部晚期ATC患者中,放疗似乎显示出剂量依赖性,可能使部分ATC患者获得持续的局部无进展生存(locoregional progression-free survival,LPFS)和总生存(overall survival,OS)获益,多因素分析显示放疗剂量≥60 Gy可改善患者预后[15]。一项来自美国国家癌症数据库(NCDB)1 288例ATC患者的Meta分析显示,不可切除ATC患者可能受益于较高照射剂量[(60~75 Gy)vs.(45~59.9 Gy)]的多模式局部治疗[16]。术后辅助放化疗且放疗剂量>40 Gy是重要的预后因素[17]。亦有研究显示放疗方式采用常规分割(1.5~2 Gy/次,1次/天)或加速超分割(1~2 Gy/次,2次/天)且总放疗剂量≥ 45 Gy的ATC患者总生存期更长[18]。而一项研究在多变量分析中显示,接受2 Gy分量(EQD2)≥50 Gy等效剂量的患者OS显著改善(P=0.016),并且大分割放疗(≥5 Gy)降低了局部复发的死亡率(P=0.025)[19]。大分割放疗ATC可能优于常规分割放疗。
2.3 化疗
ATC确诊时常伴有淋巴结转移,约50%患者伴有远处转移。化疗是全身治疗的重要手段之一,但ATC对单纯化疗敏感性较低。研究显示[20],多药耐药基因1(multidrug resistance gene1,mdr1)及其基因产物P-糖蛋白(P-glycoprotein,P-GP)的过表达被认为是ATC化疗耐药的部分原因。研究表明[21],肿瘤干细胞(cancer stem cell,CSC)表型主要与ATC的侵袭性有关。另外也有研究推测目前化疗无法阻止ATC进展,可能因为化疗药物不能有效针对肿瘤干细胞[22]。有研究表明[23],KLF5在ATC细胞中的表达高于正常甲状腺细胞,KLF5沉默导致磷酸化(p)-c-Jun N末端激酶(JNK)表达下调,从而可显著抑制ATC细胞增殖、迁移、侵袭,诱导ATC细胞凋亡,并可增加ATC的化疗敏感性。目前,治疗ATC常用的化疗方案包括多柔比星、顺铂、紫杉醇、多西紫杉醇、吉西他滨和长春新碱等单药或其中两药联合。ATC患者病情发展迅速且多为合并其他基础疾病的老年人,常不可耐受化疗药物的不良反应,因此根据患者身体状况制定合适的化疗方案尤为重要。有研究显示44例ATC患者(66%患者伴有远处转移)接受化疗的中位生存期明显长于未接受化疗者(8.5个月vs. 1.3个月,P=0.002)。总之,化疗可能对部分ATC患者有效,单用化疗效果可能不佳,与手术、放疗联合应用可能会使ATC患者获益。
2.4 靶向治疗
目前,ATC分子靶向治疗主要以抑制肿瘤细胞增殖和抗血管生成治疗为主。截至目前,已被发现与ATC发生发展有关的突变基因主要包括BRAF、RAS、ALK、PIK3CA、TP53、NF1、ATRX、PTEN、APOBEC、CDKN2A、CDKN2B、CCNE1、KDR、KIT、PDGFRA、CD274、PDCD1LG2、JAK2、RAC1、TERT、NTRK1、DNMT3A、E1F1AX等,其中同时发生BRAF、RAS、TERT突变的ATC患者预后更差[24-26]。涉及ATC基因突变的信号转导途径主要有PI3K/mTOR/AKT[27]和RAF/ RAS/MEK/ERK信号通路[28]。
小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)已用于治疗ATC,如仑伐替尼、索拉非尼、吉非替尼、伊马替尼、帕唑帕尼、舒尼替尼、阿西替尼等单药或联合紫杉类等化疗药物有望提高ATC患者疾病控制率、延长生存期。安罗替尼(anlotinib)是中国自主研发的小分子多靶点酪氨酸激酶抑制剂,体内及体外实验[29]显示其可抑制ATC细胞增殖,并可抑制体外甲状腺癌细胞迁移和小鼠移植瘤生长,其可能会为ATC患者提供一种有效的治疗策略。
BRAF基因抑制剂如达拉非尼、维莫非尼可使BRAFV600E突变的ATC患者获益。雷帕霉素衍生物依维莫司可通过阻断细胞PI3K/AKT/mTOR信号转导通路,在ATC中具有抗肿瘤活性。依维莫司单药治疗ATC有效率低,其联合周期蛋白依赖性激酶(cyclindependent kinase,CDK)抑制剂或联合ALK抑制剂克唑替尼可能对ATC有效[30]。达拉非尼联合MEK抑制剂曲美替尼治疗BRAFV600E突变ATC具有良好的临床疗效且耐受性好[31],二者联合新辅助治疗初治不可切除的BRAFV600E突变ATC后,可行完整手术切除。阿帕替尼是中国自主研发的小分子抗血管生成靶向药,是血管内皮生长因子受体-2(vascular endothelial growth factor receptor-2,VEGFR-2)抑制剂,其通过AKT/mTOR通路下调p-AKT和p-mTOR信号,可诱导人ATC细胞自噬和凋亡。组蛋白去乙酰化酶(histone deacetylase,HDAC)在ATC相关基因的转录调控中发挥着重要作用,这使得HDAC抑制剂(histone deacetylase inhibitors,HDACIs)有望用于抗ATC癌药物[32]。ATC分子靶向治疗的发展有赖于在分子和细胞水平解释各个靶点在ATC发生发展中的作用机制,从而开发出针对各靶点有效的靶向药物和治疗方案。
2.5 免疫治疗
利用荧光多重免疫组织化学(multiplex fluorescence immunohistochemistry,F-MIHC)和多光谱成像(multispectral imaging,MSI)来检测伴远处转移的分化型甲状腺癌(differentiated thyroid carcinoma,DTC)和ATC的免疫概况,结果显示ATC中程序死亡配体-1(PD-L1)阳性肿瘤细胞明显多于DTC样本,且与DTC相比,ATC的淋巴细胞浸润明显增加,ATC中PD-L1或PD-L1同源受体PD-1阳性淋巴细胞明显多于DTC样本,PD-L1的TPS和CPS在所有的DTC样本中均为阴性,在ATC样本中多为阳性。肿瘤细胞以PD-1/PD-L1相互作用为机制而实现免疫逃逸,PD-1/PD-L1通路抑制剂通过阻断PD-1/PD-L1的相互作用,使得细胞毒性T细胞激活,促进肿瘤细胞的死亡和清除。上述研究均表明免疫治疗可作为ATC治疗选择之一。高PD-1表达(>40%炎症细胞染色)整体OS下降(P < 0.05)并具有较差的无进展生存(progression-free survival,PFS),而高PD-L1表达(>33%肿瘤细胞染色)具有更差的PFS和OS,表明PD-1/ PD-L1在ATC中起到关键作用[33]。
免疫治疗单独或联合BRAF抑制剂在治疗ATC中显示出良好的前景。ATC中BRAFV600E突变与PD- 1/PD-L1表达有强相关性,在原位ATC免疫小鼠模型中,BRAF抑制剂和抗PD-L1或抗PD-1抗体联合可协同抑制肿瘤生长[34-35]。纳武利尤单抗(一种针对PD-1受体的人源化IgG4亚型单克隆抗体)联合维莫非尼对于BRAF突变和PD-L1阳性的ATC效果明显[36]。有研究显示[37],抗PD-1/PD-L1治疗可通过改变ATC小鼠的免疫微环境,从而增强仑伐替尼的疗效,提示抗PD-1/PD-L1治疗联合酪氨酸激酶抑制剂可能同样是提高ATC疗效、减少耐药的潜在手段。在激酶抑制剂治疗ATC耐药时,帕博利珠单抗可能是一种有效的挽救治疗。一些免疫检查点抑制剂的临床试验正在进行中,期待更高质量的数据来证明免疫治疗对部分ATC患者是一种选择。
2.6 姑息治疗
2012年美国甲状腺协会抗ATC指南提出,在ATC确诊后应在患者及其家属共同参与下决定治疗目标,若考虑姑息治疗,包括姑息性减瘤术、解除肿瘤压迫所致的呼吸困难、进食梗阻,或者针对颈部或其他转移病灶低剂量姑息性放和(或)化疗、营养支持治疗等,以缓解病痛、延长无症状生存时间、提高患者生存质量。
3. 结语
综上所述,目前暂无标准治疗ATC的方法。根治性手术可明显改善预后,适形放疗优于常规放疗,而手术、放疗、化疗、分子靶向、生物免疫等综合应用可能提高治疗疗效。肿瘤局限于甲状腺体内或部分腺体局限性浸润患者,可先行手术,术后辅助放化疗;对于腺体外浸润明显而无法手术者,可先行放化疗或靶向治疗,再评估手术可行性;对于局部浸润广泛且常规治疗无效或伴有远处转移者,结合患者及其家属意愿,给予姑息性治疗或系统性药物治疗。当肿瘤侵及气管、食管导致呼吸困难、进食梗阻时,可行气管切开术或行手术解除压迫,后再行系统性治疗。靶向治疗、免疫治疗可单药或联合治疗作为难治性ATC患者的选择方案之一。
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