Progress in Re-differentiating Therapy of Radioiodine-refractory Differentiated Thyroid Cancer
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摘要:
分化型甲状腺癌（DTC）大多进展缓慢，经手术、促甲状腺素抑制治疗和（或）放射性碘（RAI）等规范化治疗后总体预后好，但仍有部分患者治疗后出现复发或远处转移，并可能在自然病程或治疗过程中丧失摄碘能力，不能从后续RAI治疗中获益，成为碘难治性分化型甲状腺癌（RAIR-DTC）。RAIR-DTC患者可选择的治疗方法有限，且效果欠佳。近年来，随着对RAIR-DTC分子机制研究的不断深入，诱导再分化联合RAI治疗在RAIR-DTC中展现出一定的应用前景。本文综述了信号通路抑制剂、组蛋白去乙酰化酶抑制剂（HDACi）、DNA甲基化酶抑制剂、维甲酸类药物及过氧化物酶体增殖物激活受体（PPAR）激动剂在RAIR-DTC诱导再分化治疗中的进展。
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关键词:
- 碘难治性分化型甲状腺癌 /
- 再分化 /
- 碘摄取 /
- 放射性碘治疗
Abstract:The majority patients of differentiated thyroid carcinoma (DTC) with indolent progression have general good prognosis after standard primary treatments including surgery, thyroid stimulating hormone (TSH) suppression and radioactive iodine (RAI) therapy. However, there are still some patients suffered from recurrence or distant metastasis after initial treatment. They may lose the ability of uptaking iodine during their natural course of disease or treatment and could not benefit from subsequent RAI treatment, which will result in radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). Options are very limited for RAIR-DTC patients, which is associated with a poor prognosis. Recently, with the research advances on the molecular mechanism of RAIR-DTC, redifferentiation combined with RAI therapy have been increasingly used to treat RAIR-DTC, and some outcomes are quite encouraging. This paper reviews the progress of signaling pathway inhibitors, histone deacetylase inhibitors, DNA methyltransferase inhibitors, retinoids and peroxisome proliferator-activated receptor agonists in redifferentiating therapy of RAIR-DTC.
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0 引言
原发性纵隔大B细胞淋巴瘤（primary mediastinal B-cell lymphoma, PMBL）是一种侵袭性B细胞淋巴瘤，占非霍奇金淋巴瘤（non-Hodgkin lymphoma, NHL）的2%~3%，多见于30~40岁女性[1]。尽管采用了免疫治疗方案，10%~30%的PMBL患者仍有复发。难治性（relapsed/refractory, RR）疾病需要挽救治疗，且效果并不令人满意[2]。PMBL利用PD-1/PD-L轴抑制抗肿瘤反应[3]，抗CD30单抗（brentuximab vedotin, BV）在CD30阳性PMBL患者中表现出较好的疗效[4]。文献报道60%~85%的PMBL表达CD23，而在非纵隔DLBCL和结外DLBCL中表达率较低[5]。GATA3是鉴别PMBL和纵隔经典霍奇金淋巴瘤（classic Hodgkin’s lymphoma, CHL）的最有帮助的标志物[6]，BCL-2在静息B细胞和T细胞上表达而在正常生发中心细胞上不表达，相反BCL-6在生发中心内的B和CD4+T细胞中表达，MUM1/IRF4和CD138反映了生发中心内B细胞成熟为浆细胞的最后步骤，但有关PMBL中的BCL-6和MUM1表达情况的研究还较少。与其他淋巴瘤不同，PMBL缺乏预后生物标志物，并且当非纵隔原发的非特指型弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma, not otherwise specified, DLBCL-NOS）累及纵隔时，临床上很难与原发性纵隔大B细胞淋巴瘤进行区分，因此我们选取了非纵隔DLBCL-NOS作为对照组，运用免疫组织化学法对诊断为PMBL、DLBCL-NOS组织中的治疗相关标志物PD-L1、PD-L2、CD30及CD23、BCL-2、BCL-6、MUM1、GATA3的表达进行检测及分析，探讨上述8种蛋白在PMBL诊断和预后评估中的应用价值，寻求更具特异性的免疫组织化学指标，提高对该病的诊断，以期为判断PMBL预后提供理论参考进而指导临床个体化治疗。
1 资料与方法
1.1 临床资料
选取2000—2019年中国医学科学院肿瘤医院病理科确诊的34例PMBL，对照组为随机抽取的同期31例非纵隔原发的DLBCL-NOS，取材涵盖了常见发病部位。34例PMBL患者有完整的随访资料，所有切片均由两位有经验的临床病理医师独立阅片，病理诊断依据WHO标准（2017版），结合临床特点、组织学形态、免疫表型及分子诊断，均已明确诊断。本研究所有患者均知情同意。
1.2 病理形态学观察及分级
1.2.1 制备组织切片
34例PMBL和31例DLBCL-NOS的肿瘤组织用4%的中性甲醛固定4~6 h，取1.5 cm×1.5 cm×0.3 cm的组织块，5~10倍固定液中固定3~24 h，脱水、过夜（水洗、脱水、透明、浸蜡），石蜡包埋，切片厚度为3~5 μm，烘烤。
1.2.2 免疫组织化学染色
采用4 μm厚FFPE组织切片进行免疫组织化学染色，免疫组织化学采用EnVision法。切片经过脱蜡、水化、抗原修复后滴加一抗，主要一抗为PD-L1、PD-L2、CD30、CD23、GATA3、BCL-2、BCL-6和MUM1，一抗来源及阳性表达部位见表 1。按厂家说明书操作，温浴30~60 min后滴加二抗，DAB显色，苏木精对比染色，常规脱水、透明、封片。染色时每批均包括阴性对照和阳性对照。
表 1 免疫组织化学检测一抗来源及其染色部位Table 1 Source and staining site of immunohistochemical antibody
1.2.3 结果判读
PD-L1和PD-L2细胞膜染色肿瘤细胞的百分比，见表 2。针对抗体CD23、CD30和GATA3，选取代表区域计数10个高倍视野下阳性肿瘤细胞占细胞总数的百分比， < 10%阳性细胞判为阴性（-），阳性细胞数≥10%且染色弱阳性为（+），阳性细胞数≥10%且染色中等阳性为（++），阳性细胞数≥10%且染色强阳性为（+++），按照（+）（-）进行记录并分析。抗体BCL-2、BCL-6和MUM1的截断值为30%[7]，结果记录见表 3。本研究中染色细胞百分率主要由两位有经验的临床病理专家评分，平均阳性细胞百分率用于分析，有争议的病例由第三位临床病理专家确认。标志物的诊断指标计算公式：敏感度=真阳性/（真阳性+假阴性），特异性=真阴性/（真阴性+假阳性），阳性预测值=真阳性/所有阳性，阴性预测值=真阴性/所有阴性。
表 2 PD-L1、PD-L2和CD30蛋白在PMBL和DLBCL-NOS中的阳性肿瘤细胞百分比[M (P25, P75), %]Table 2 Percentage of positive tumor cells with PD-L1, PD-L2 and CD30 expression in PMBL and DLBCL-NOS [M (P25, P75), %]
表 3 CD23、CD30、GATA3、BCL-2、BCL-6和MUM1蛋白在PMBL和DLBCL-NOS中的表达Table 3 Expression of CD23, CD30, GATA3, BCL-2, BCL-6 and MUM1 proteins in PMBL and DLBCL-NOS groups
1.3 随访
通过常规的复诊或电话对患者进行回顾性随访。主要研究终点是总生存期（overall survival, OS），其定义为从最初确诊到死亡或最后一次随访的时间（2020年11月）。记录以下随访内容：病程、治疗和预后情况、随访结束时的状况（死亡、存活或失访）、死亡原因和存活时间。
1.4 统计学方法
所有数据采用统计学软件SPSS20.0进行统计分析，检验水准α=0.05，P < 0.05为差异有统计学意义。各蛋白表达与PMBL和DLBCL-NOS患者临床及病理因素的关系采用卡方检验；PD-L1、PD-L2和CD30在PMBL和DLBCL-NOS中的阳性肿瘤细胞百分比组间比较采用非参数秩和检验；Kaplan-Meier法进行单变量生存分析并绘制生存曲线，Log rank检验比较生存差异。所有指标采用GraphPad Prism 8及SPSS20.0进行作图。
2 结果
2.1 临床特点
PMBL患者34例，其中男性19例（55.88%），女性15例（44.12%），中位年龄28岁（15~47岁）。随机选择非纵隔原发的DLBCL-NOS患者31例作为对照组，其中男20例（64.52%），女性11例（35.48%），中位年龄63岁（年龄17~84岁）。两组年龄分布差异有统计学意义（P < 0.01）。在PMBL组中，由纵隔压迫引起的症状是最主要的症状，全部34例病例均有大小不等的纵隔肿块。
2.2 PMBL病理特征
形态上PMBL肿瘤细胞弥漫分布，被纤细或粗大致密胶原分割，呈簇状、巢团状或结节状排列。肿瘤细胞中等大或稍大，胞质淡染，细胞核较圆或卵圆形，部分病例中可见Reed-Sternberg样细胞，见图 1A、B。PMBL组织形态上与累及纵隔的DLBCL-NOS有重叠，见图 1C、D，鉴别诊断需要免疫组织化学标志物的辅助。PMBL组中进行Ki-67标记，阳性细胞比例为30%~80%，其中64.71%（22/34）的病例表达超过60%，DLBCL-NOS组表达相似。
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图 1 PMBL(A, B)与DLBCL-NOS(C, D)的HE染色(A, C: ×200; B, D: ×400)Figure 1 HE staining of PMBL(A, B) and DLBCL-NOS (C, D) (A, C: ×200; B, D: ×400)2.3 PMBL与DLBCL-NOS的免疫表型
PMBL组和非纵隔原发的DLBCL-NOS组中PD-L1、PD-L2、CD30、CD23、BCL-2、BCL-6、MUM1和GATA3的表达见图 2。PD-L1、PD-L2和CD30在PMBL组阳性肿瘤细胞百分比的中位数分别为70%（30%, 90%）、25%（0, 70%）和17.5%（0, 60%），显著高于DLBCL-NOS组，差异有统计学意义（均P < 0.05），见表 2。PMBL组CD30阳性表达率为61.76%（21/34），DLBCL-NOS组为12.90%（4/31），差异有统计学意义（P=0.000）。与DLBCL-NOS组比较，CD30诊断PMBL的特异性为76.47%（13/17），阳性预测值为84%（21/25），阴性预测值为32.50%（13/40）。PMBL组CD23阳性率为76.47%（26/34），在DLBCL-NOS组中阳性表达率为9.68%（3/31），差异有统计学意义（P=0.000）。与DLBCL-NOS组比较，CD23诊断PMBL的特异性为72.73%（8/11），阳性预测值为89.66%（26/29），阴性预测值为22.22%（8/36）。GATA3（P=0.414）、BCL-2（P=0.480）、BCL-6（P=0.659）和MUM1（P=0.601）的表达在PMBL和DLBCL-NOS组之间差异均无统计学意义，见表 3。
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图 2 CD23(A)、CD30(B)、GATA3(C)、BCL-2(D)、BCL-6(E)、MUM1(F)、PD-L1(G)和PD-L2(H)在PMBL中的阳性表达(×200)Figure 2 Positive expression of CD23(A), CD30(B), GATA3(C), BCL-2(D), BCL-6(E), MUM1(F), PD-L1(G) and PD-L2(H) in PMBL group (×200)2.4 PMBL的随访与治疗
PMBL组有完整随访资料的患者28例，失访6例，随访率82.4%。死亡6例（6/28，21.43%），中位生存期为30.5月（4.2~166.1月），总体生存曲线见图 3。5例（5/28，17.86%）单纯采用CHOP方案化疗，16例（16/28，57.14%）常规化疗结合利妥昔单抗，1例（1/28，3.57%）PD-1抑制剂联合常规化疗4周期后达到完全缓解（complete response, CR），13例（13/28，46.43%）接受过放射治疗。伴有CD30或BCL-6表达的PMBL患者其生存曲线尽管P > 0.05，但仍显示出预后差的趋势，见图 4。
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图 3 原发性纵隔大B细胞淋巴瘤患者总体生存曲线Figure 3 Overall survival curve of patients with primary mediastinal large B-cell lymphoma![]()
图 4 伴有CD30(A)或BCL-6(B)表达的PMBL患者的生存曲线Figure 4 Survival curves of PMBL patients with CD30(A) or BCL-6(B) expression3 讨论
原发性纵隔大B细胞淋巴瘤起源于胸腺髓质B细胞，是一种发病率较低但并不罕见的淋巴造血系统疾病，男女比约为1:3。本研究结果显示PMBL发病高峰年龄段为28岁左右，男女性别无差异，与既往文献女性患者居多的特点有所不同，而DLBCL-NOS患者多集中于老年人。组织学上，PMBL的肿瘤细胞多呈透明细胞或R-S（Reed-Sternberg）样细胞形态，且穿刺活检标本易挤压、固定不佳，致使难以识别而漏诊误诊，免疫组织化学可以协助诊断。PMBL表达B细胞抗原（如CD20，CD79α）和B细胞转录因子（如PAX-5、BOB.1、Oct-2等），不表达表面免疫球蛋白（Ig）和κ、λ[8]。PMBL在形态学和细胞学上不同病例间具有较大的变异，CD30阳性率约为80%，个体差异较大且通常染色强度较弱，CD23阳性率约为70%，BCL-2阳性率约为55%~80%，BCL-6阳性率约为45%~100%[9]。免疫组织化学研究对于PMBL和DLBCL-NOS的鉴别诊断必不可少，在本研究中我们探讨了治疗相关标志物PD-L1、PD-L2、CD30及CD23、BCL-2、BCL-6、MUM1和GATA3在PMBL诊断和预后评估中的应用价值，以期为判断PMBL预后提供理论参考进而指导临床的个体化治疗。
PD-L1和PD-L2经常由于特定的遗传突变而过度表达。PD-L1的表达具有时空异质性，PD-L1阴性肿瘤复发时可能变成PD-L1阳性肿瘤（反之亦然）。Ventana的sp263 PD-L1用于免疫组织化学检测时，建议病理学家的报告结果包括阳性肿瘤细胞百分比。对于PD-L2蛋白到目前为止还没有得到广泛的研究。9p24.1染色体异常多见于PMBL，相比之下这种异常在DLBCL中很少见[10-12]。一些研究已经表明，PD-L1位点的畸变是PMBL的一个特征，并且PD-L1的表达与9p24.1的扩增相关[13]。我们在PMBL中的研究结果表明，PD-L1和PD-L2在PMBL组的表达水平较高，与DLBCL-NOS组间差异有统计学意义（P < 0.05），因此PD-L1和PD-L2免疫组织化学检测可作为鉴别PMBL和DLBCL-NOS的辅助实验手段，有助于识别更多对免疫检查点抑制剂有反应的患者，但尚需进一步的前瞻性测试和验证，以确定免疫检查点抑制剂在淋巴瘤亚型中的疗效。基于KEYNOTE-170研究，帕博利珠单抗获得美国食品药品监督管理局（food and drug administration, FDA）复发/难治性（R/R）PMBL适应证批准。KEYNOTE-170研究中，应用帕博利珠单抗治疗R/R PMBL，中位随访43.1月后，76%的患者治疗反应持续时间（duration of response, DOR）超过36月，36月无进展生存（progress free survival, PFS）率达34.2%。因此，帕博利珠单抗单药治疗R/R PMBL显示出持久的抗肿瘤效应且安全可控[3]。另外纳武利尤单抗联合CD30单抗治疗R/R PMBL的Ⅱ期临床研究也显示出纳武利尤单抗与维布妥昔单抗BV（brentuximab vedotin）的协同效应，其可作为桥接治疗方案[4]。这些发现强调了PD-1/PD-L1轴在调节抗肿瘤免疫方面的重要性，以及在临床实践中靶向这一信号通路的好处。
CD30在临床中是一个非常重要的指标，除了淋巴造血系统肿瘤，CD30在非淋巴造血系统肿瘤中也可以表达。CD30能够帮助鉴别多种淋巴肿瘤，如霍奇金淋巴瘤（Hodgkin’s lymphoma, HL）、间变大细胞淋巴瘤（anaplastic cell lymphoma, ALCL）[14]。除此之外，CD30在一些T细胞淋巴瘤和B细胞淋巴瘤中都可以表达，但CD30的专一性、特异性不强，给淋巴瘤的病理诊断带来困难，需要结合形态以及其他免疫组织化学标记进行诊断。PMBL肿瘤细胞存在CD30高表达，本组试验结果亦显示CD30表达在PMBL与DLBCL-NOS组之间差异有统计学意义（P < 0.01），因此治疗相关标志物PD-L1、PD-L2和CD30均有助于区分PMBL与DLBCL-NOS。BV是一类CD30抗体偶联药物，可通过抑制微管蛋白合成和细胞分裂，诱导CD30阳性肿瘤细胞凋亡。BV联合纳武利尤单抗治疗R/R PMBL显现出良好的协同抗肿瘤活性，客观缓解率（objective response rate, ORR）达73%，完全缓解（complete response, CR）率为37%[4]。CD23是一种低亲和力的IgE受体，还可作为成熟滤泡B细胞、活化巨噬细胞、嗜酸性粒细胞和滤泡树突状细胞上的淋巴细胞生长因子。CD23在PMBL中的表达率为70%~85%[5, 15]，与本研究在PMBL中观察到的76.47%相符。本研究表明CD23阳性有助于PMBL与DLBCL-NOS的鉴别诊断，与既往的结果[16]一致。PMBL的分子遗传学特征中BCL-2和BCL-6基因重排少见，而有研究表明BCL-2表达是DLBCL的预后标志物[17]。MUM1/IRF4是干扰素和细胞因子介导基因表达的重要调节剂，在既往的研究中，MUM1与DLBCL的不良预后相关[18]，但本研究结果显示MUM1表达对PMBL的总体生存无影响，可能与本研究队列较小有关。CD30和BCL-6的预后价值值得下一步在更大的患者队列中进行验证。
综上所述，PMBL是一种起源于胸腺的成熟的侵袭性大B细胞淋巴瘤，具有独特的临床、免疫表型、基因型和分子特征。PMBL中治疗相关标志物PD-L1、PD-L2和CD30的表达水平较高，有助于识别更多可能对免疫或靶向治疗有反应的患者。免疫组织化学标记PD-L1、PD-L2、CD30和CD23有助于PMBL与DLBCL-NOS鉴别诊断，CD30和BCL-6在PMBL的预后方面显示了一定的趋势，但要作为PMBL的候选预后指标应该在更大量的样本中进一步研究。
Competing interests: The authors declare that they have no competing interests.作者贡献：张亚奇、朱锡群、樊倩妤：文献检索、论文撰写陈健：指导及修改论文 -
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图 1 RAIR-DTC诱导再分化治疗药物及作用途径
Figure 1 Drugs and relevant pathways involved in the re-differentiating therapy of RAIR-DTC
表 1 用于临床诱导RAIR-DTC再分化治疗的靶向药物
Table 1 Targeted drugs for re-differentiating therapy of RAIR-DTC
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