《中国恶性肿瘤学科发展报告（2021）》——肿瘤病理研究进展篇

2021年是肿瘤病理学科蓬勃发展的一年。肿瘤病理诊断始终是肿瘤诊治中最关键的环节之一。过去一年里，许多病理同仁投入了大量的精力，从不同层面对不同瘤种进行了深入且细致的研究：一方面，传统的形态学分析继续焕发着勃勃的生机，不断给病理医师带来新的思考及认识；另一方面，新技术的出现及应用给病理学科注入了新的活力，极大地丰富了病理诊断的内涵。许多研究取得了卓越的成绩，研究结论具有较高的临床应用价值，为临床医师提供了更多的信息，为患者提供了更多的选择，相关论著也得到了国际同行的一致认可。本报告收集整理了2021年度肿瘤病理学科的主要进展及研究成果，抛砖引玉，以期提供给读者更多的启发和思考。

1.精益求精 常见肿瘤的精细诊断

形态学诊断是病理诊断的基础。精准诊断的核心内涵之一是对常见肿瘤的精细化诊断。虽然辅助诊断技术日新月异，但通过细致的形态学观察总结能提供丰富生物学行为信息。该方向相关研究可分为以下三个方面。

一，对常见肿瘤的特殊生长方式的回顾性总结，如：①研究发现，具有掐丝样（filigree）结构的肺腺癌预后类似甚至更差于普通微乳头型肺腺癌，支持了掐丝样结构作为微乳头型的一种特殊类型[1]；②部分早期胃癌表现为高级别乳头状癌的组织学形态，这些病例更容易有脉管瘤栓及淋巴结转移，预后不良，可能不适合内镜治疗[2]；③有研究总结分析了17例窦性生长方式的大B细胞淋巴瘤（SLBCL），这些病例具有类似的生长方式及间变性形态，免疫表型上主要为非生发中心型且常有BCL2和MYC双表达，大部分PD-L1阳性，预后明显比其它弥漫性大B细胞淋巴瘤差[3]。

二，对常见肿瘤的特殊亚型的回顾性总结：①与低级别胎儿型腺癌（FLL）相比，肺的高级别FLL更常同时具有普通型肺腺癌的成分，且免疫组化蛋白表达及基因突变方面与其内的普通型肺腺癌成分类似而不同于低级别FLL [4]；②胃肠胰混合性神经内分泌-非神经内分泌肿瘤的淋巴结转移灶与远处转移灶的分析发现，多数淋巴结内为单一成分（神经内分泌或非神经内分泌成分）转移，而多数远处转移灶为纯的神经内分泌成分[5]。

三，对常见肿瘤的非常见年龄及部位的回顾性总结，如：①通过对236例成人颅内室管膜瘤（EPN）的回顾分析发现，43.1%的幕上型EPN有RELA融合，融合者预后较差，有88.1%的后颅窝EPN有H3K27me3染色阳性，阳性者预后较好[6]；②对23例儿童脂肪肉瘤的回顾分析发现，发病年龄11-21岁，好发部位为四肢，主要组织学类型为黏液样脂肪肉瘤（均有DDIT3重排），其次为高分化脂肪肉瘤及去分化脂肪肉瘤（均有MDM2扩增）[7]。

另外，鉴别诊断始终是病理诊断的关键之一，怎样有效地避免误诊是许多病理医师非常关心的问题，比如：①在冰冻诊断中，硬化性肺细胞瘤常常容易和腺癌等其它恶性肿瘤混淆，有研究回顾分析了230例硬化性肺细胞瘤病例，总结可能支持其诊断的线索有大体形态、存在两种细胞及存在泡沫细胞、出血、含铁血黄素等[8]；②除了经典形态，少数甲状腺髓样癌可表现为梭形细胞形态，这也需要在诊断中予以关注[9]。

2.求真求确 少见肿瘤的准确诊断

部分肿瘤发病率较低，临床特征不明显，常常难以准确诊断。作为诊断的金标准，对这些肿瘤的准确病理诊断往往是诊断的“最后一道门槛”。许多研究对少见肿瘤进行了回顾性总结，如：①对20例单形性上皮性肠道T细胞淋巴瘤的回顾分析发现，多数病例位于空肠或回肠，大部分CD3、CD8、CD43、CD56阳性而CD5阴性，常有STAT5B及TP53突变[10]；②通过对5例乳头状涎腺瘤及文献报道病例的回顾发现，这种良性肿瘤好发于老年硬腭，具有复杂乳头状结构，且伴有BRAF V600E突变[11]；③有研究总结了6例形态类似于低度恶性潜能的多房囊性肾细胞肿瘤的Xp11异位的肾细胞癌[12]；④还有部分研究总结了具有特殊分子改变的间叶源性肿瘤，比如BCOR重排肉瘤[13]以及RAF1融合的梭形细胞肿瘤[14]等。

临床诊断中更为棘手的情况是不常见的肿瘤发生于不常见的部位，此时往往更容易“想不到”，造成漏诊和误诊。多项研究进行了回顾性总结：①对8例宫颈尤文肉瘤的回顾分析发现，虽然极其少见，但宫颈的小圆细胞肿瘤应考虑到尤文肉瘤可能，并且EWSR1基因检测有助于确诊[15]；②对9例肝脾外EBV阳性的炎性滤泡树突细胞肉瘤回顾分析发现，肝脾外的主要好发部位为结肠并常表现为带蒂息肉，患者以女性为主，预后良好[16]；③对13例咽淋巴环的滤泡辅助T细胞源性的外周T细胞淋巴瘤回顾性分析发现，组织形态大多数表现为炎性背景中的弥漫性肿瘤细胞浸润，常见血管增生，所有病例均表达至少两种TFH标志物尤其是PD-1及BCL6，NGS检测的突变主要为TET2及RHOA[17]。

3.见微知著 肿瘤预后的病理线索

除了明确肿瘤类型，病理诊断的另一个重要作用是提示肿瘤预后。许多研究从不同方面进行了病理与预后的相关研究。一方面是主要基于形态学特点的研究，如：①有研究入组了部分高级别腺样囊性癌（ACC），其中包括7例只能满足部分经典的高级别转化的诊断标准，但都伴有基底细胞/肌上皮细胞免疫组化标记物低表达或不表达，预后同样更差，因此认为这些病例也应归入高级别转化的范围[18]；②对398例宫颈腺癌手术标本进行回顾性分析并根据肿瘤出芽、肿瘤细胞大小以及分化等建立了一种三级分类系统，通过这种分级系统可以很好的将宫颈腺癌的总生存率进行分层[19]；③在胰腺神经内分泌肿瘤中，高级别、胰管扩张和神经侵犯是独立预后因素，将其与TNM分期结合可以显著提高预后预测准确性[20]；④有研究发现，梭形细胞形态及TIL＞30%可作为小细胞肺癌的负性预后因素[21]；⑤通过对大宗甲状腺乳头状癌数据的回顾性分析，在肿瘤直径≤ 5 mm时中央区淋巴结转移与BRAF V600E突变明显相关，是独立危险因素[22]。

另一方面是通过免疫组化标记提示预后，如：①有研究对257个早期胃癌进行黏蛋白表型分类发现，胃型表型更具有侵袭性生物学行为[23]；②在早期胃癌病例中，原始肠上皮表型（AFP、GPC3、SALL4）的表达有助于提示淋巴结转移风险[24]；③相对于低级别胶质瘤，高级别胶质瘤中的YAP1和STAT3被显著激活[25]；④HER2阳性的乳腺癌中，P63表达与组织学的高级别、异常P53表达相关[26]；⑤FRGs的表达情况有助于提示食管鳞状细胞癌的预后[27]；⑥预后标志物SLC2A3与结直肠癌中的EMT相关[28]。

随着新辅助治疗的广泛开展，对治疗后残存肿瘤情况与预后的关系引起了广泛关注。病理评价是评估肿瘤缓解情况的最重要标准之一：①有研究总结发现，对于预测新辅助治疗后的非小细胞肺癌病例的预后，残存肿瘤百分比在鳞癌和腺癌原发灶中的最佳截断值分别为12%和58%，在鳞癌的淋巴结转移灶中为8%，因此支持在临床病理工作中对鳞癌使用10%的截断值用于预后评价[29]；②对新辅助治疗后乳腺癌非完全缓解的病例，临床分期、HER2状态、残存肿瘤负荷及TIL分级与预后相关[30]。

4.知病明理 肿瘤的分子特征研究

分子检测是重要的辅助诊断方法，同时也是与临床治疗最紧密结合的检查结果之一。随着大量分子检测项目的开展，首先面临的是技术的规范化问题。基于多年的检测结果分析，去年有几项重要的多中心分子检测项目共识发表，如非小细胞肺癌中的ALK检测[31, 32]、乳腺癌患者的BRCA1/2基因检测[33]等。这些共识为分子检测的规范开展及质控提供了详实的数据支持。

另外，大量研究通过测序等高通量技术分析肿瘤的分子特点，如：①PHF8和FOXA2水平可单独或联合作为前列腺神经内分泌癌的生物标志物，且PHF8或FOXA2可能成为其治疗的潜在靶点[34]。②对甲状腺未分化癌的WES结果显示，常见的分子改变有TP53、BRAF、PIK3CA和TERT启动子突变以及NOTCH2NL拷贝数增加[35]。③宫颈胃型黏液腺癌中突变频率较高的基因有TP53、STK11、CDKN2A等[36]。④卵巢透明细胞癌的NGS结果显示同源重组缺陷的发生率非常低[37]，有6%的病例免疫组化检测为错配修复缺陷型（dMMR），且多数存在ARID1A表达的缺失[38]。⑤FH缺陷型肾细胞癌的分子特征在于CpG岛甲基化，且该类病例可能对免疫治疗效果较好[39]；另一项对TFE3融合的肾癌研究发现该类病例常有低PD-L1表达和T细胞浸润，且一些体细胞拷贝数改变与侵袭性特征和不良结果有关[40]。⑥一组涎腺黏膜相关组织型结外边缘区淋巴瘤的病例研究发现其最常见的分子改变是3号染色体三体[41]。⑦纤维瘤病样梭形细胞癌病例常存在致病性的PIK3CA H1047R突变以及TERT启动子的-124C>T突变[42]。⑧中国人胰头癌有更多的KRAS G12V突变[43]。⑨错配修复缺陷型结直肠癌中可存在多种致癌的基因融合[44]。⑩有研究分别对食管和肺的小细胞癌进行WES检测，发现食管小细胞癌驱动基因突变明显低于肺小细胞癌。在食管小细胞癌中，13个频发驱动突变是肿瘤发生早期阶段的克隆性突变；而在肺小细胞癌中，存在16个克隆性驱动突变。NOTCH1/3、PIK3CA和ATM是食管小细胞癌的特异性克隆性突变基因，而TP53为肺小细胞癌的特异性克隆性突变基因[45]。另一项研究通过多组学分析，认为原发食管小细胞癌的基因组改变、转录组特征和分子亚型与肺小细胞癌高度相似[46]。

分子检测也可以为鉴别诊断提供一定的线索。如一项基于多中心对肝转移瘤的分子检测研究显示，基因检测可以较好的提示原发灶来源[47]。

5.追本溯源 肿瘤致病机制研究

病理学是临床医学与基础医学的重要桥梁，多项研究通过某些基因入手研究其如何影响常见致癌通路进而调控肿瘤的发生发展，如：①乳腺癌中Mortalin通过Wnt/β-Catenin通路调节EMT[48]。②膀胱癌中HBXIP通过AKT/mTOR通路减少细胞中的糖酵解从而阻断血管生成[49]。③鼻型结外NK/T细胞淋巴瘤中，p-ATM/CHK2通过ATM通路影响预后及耐药性[50]。④Luminal-A型乳腺癌中FGFR1通过Akt/Erk-ER通路促进乳腺癌耐药性[51]。⑤结直肠癌中CCT8通过TP53及EMT通路调控肿瘤进展[52]。⑥胶质瘤中CAPS通过调节细胞周期促进肿瘤增殖[53]。

另外还有一些研究探索了表观遗传学等其他影响机制，如：①m6A去甲基化酶ALKBH5通过靶向铁代谢调节剂预防胰腺导管腺癌[54]。②结直肠癌肿瘤细胞产生的SPON2通过激活PYK2促进M2极化的肿瘤相关巨噬细胞浸润和癌症进展[55]。③弥漫性大B细胞淋巴瘤中NEK2通过磷酸化调节PKM2丰度来促进细胞增殖和糖酵解[56]。④结直肠癌中抑制源自Mo-MDSCs的CCL7可防止肿瘤转移进展[57]。

非编码RNA是近几年机制研究的热点，过去一年同样有较多关于非编码RNA的机制研究。如：①lncRNA 00473通过调节AQP3以及miR-16-5p/CCND2轴促进胃癌的增殖和迁移[58]。②piRNA-14633通过METTL14 依赖的m6A RNA甲基化促进宫颈癌细胞进展[59]。

6.开拓蓝海 免疫治疗/免疫微环境分析

随着PD-1/PD-L1抑制剂获批后的广泛临床应用，PD-L1检测逐渐成为免疫治疗中最重要的检测指标，多项研究分析了不同肿瘤中的PD-L1表达情况，如肺非小细胞癌[60]、肺肉瘤样癌[61]、胃癌[62]、宫颈小细胞癌[63]、间变性弥漫性大B细胞淋巴瘤[64]、甲状腺乳头状癌[65]等，这些研究对扩大以及精准筛选免疫治疗的适应症有重要帮助。

另外，免疫微环境中其它标志物也可能对肿瘤的治疗和预后产生重要的影响，如：①对发生局部进展期直肠癌患者，CD8+细胞毒性T淋巴细胞可能改善对新辅助放化疗的反应，而CD163+肿瘤相关巨噬细胞则具有相反的效果[66]。②另一项结直肠癌的研究显示，肿瘤中央的细胞毒性CD4+T细胞对于提示肿瘤预后有意义[67]。③一项研究分析了B7家族成员在宫颈癌的表达情况，发现在PD-L1阴性的宫颈癌中B7-H4和VISTA共表达提示预后良好[68]。④对胰腺神经内分泌肿瘤的分析发现，高密度肥大细胞浸润与CD4+T细胞和CD15+中性粒细胞计数相关，并且是无进展生存延长的独立预测因子，可能对该肿瘤具有保护作用[69]。

还有部分研究基于高通量数据对肿瘤的免疫微环境进行分子分型，分析不同免疫亚型之间的生物学特点。比如：①对TCGA数据库的胰腺导管腺癌数据进行聚类分析发现，约31%的样本（免疫激活型）具有更多的免疫细胞浸润与更高的肿瘤突变负荷(TMB)，这是一个对总生存有利的独立预后因子，且可能对PD-1抑制剂有较好疗效[70]。②通过对食管癌TCGA等公共数据库中的数据分析发现，M2巨噬细胞[71]、m6A调节因子[72]、TP53突变相关基因[73]对应着不同的免疫微环境及预后，可能对治疗产生不同反应。

7.深耕红海 免疫组化的丰富应用

免疫组化是最常用的辅助诊断技术，如何恰当地选择抗体、判读结果从而辅助诊断是病理医师每天都面临的问题。大量研究对此做出了卓有成效的工作。一方面是对经典免疫组化的诊断回顾性总结，如：①GATA3、CR、WT1的组合有助于鉴别肉瘤样恶性间皮瘤与组织性胸膜炎[74]。②相对于其它前列腺间质肿瘤，恶性孤立性纤维肉瘤的STAT6、PR和Ki67表达率更高[75]。③CD117阴性且CD7阳性的低级别嗜酸性肾肿瘤有相似的形态学特点且预后较好[76]。④神经内分泌标志物表达是黑色素瘤的常见现象且并没有预后意义[77]。⑤SSTR2a在鳞状分化的淋巴上皮瘤样癌中表达，而在腺样分化的淋巴上皮瘤样中不表达[78]。⑥胃/肠腺癌的原发灶、淋巴结转移灶及库肯勃瘤中的HER2、c-MET、FGFR2表达整体阳性率都较低[79]。⑦少部分间变性大细胞淋巴瘤也可以有弥漫的CD56表达[80]。另一方面是探索验证一些新抗体、少见抗体的诊断价值，如脂肪肉瘤中的FRS2[81]、高级别神经内分泌癌的INSM1[82]、肾嫌色细胞癌的FOXI1[83]、施旺细胞及黑色素细胞标志的Nek9[84]等。

另外，有研究通过不同抗体之间以及免疫组化与分子检测结果之间的比对探讨了免疫组化结果的一致性问题，如多瘤种中的TP53[85, 86]、三阴性乳腺癌的NTRK[87]、非小细胞肺癌的ALK[88]、黑色素瘤的cyclinD1[89]等。

8.百花齐放 新技术与新方法开展

多重免疫荧光技术可以实现同一张切片上多个免疫荧光标记的显色，相对于传统单一标记的免疫荧光及免疫组化，可以极佳地展示肿瘤及肿瘤微环境的空间分布特点，具有较好的科研及临床应用价值，多项研究应用该技术进行了研究：①在结直肠癌标本中检测多种免疫标记物，结果显示M2巨噬细胞中CMTM6的表达是预测PD-1/PD-L1抑制剂反应性的最佳标志[90]。②有研究发现NK/T淋巴瘤中VISTA主要在CD68+巨噬细胞中表达，高表达VISTA或PD-L1与预后差、高密度的CD8+TILs有关，高表达VISTA还与高密度FOXP3+TILs显著相关。VISTA联合PD-L1是独立预后因素，高表达VISTA的患者对PD-1抑制剂反应较差[91]。VISTA可能成为NK/T淋巴瘤理想的免疫治疗靶点。③对HPV相关的口咽癌进行免疫微环境检测及基因检测发现，高PD-L1表达与免疫活性状态如TMB、CD8+毒性T淋巴细胞及免疫相关基因组改变相关[92]。④对比肺非小细胞癌的原发灶和转移灶的免疫微环境，发现PD-L1表达、淋巴细胞浸润差异与治疗史的时间异质性、EGFR突变相关，提示预测存在转移的患者的免疫治疗效果可能需要采集转移样本进行评估[93]。

在人工智能领域的进展可以分为以下三个方面：①辅助识别肿瘤与非肿瘤，如细胞学的宫颈液基薄层细胞涂片[94]、组织学的胰腺癌识别[95]等；②提示可能的治疗效果及预后，如提示肾透明细胞癌的预后[96]、预测乳腺癌治疗后病理缓解程度[97]等；③对免疫微环境相关因素的识别判读，这也是近两年的新兴热点，如对非小细胞肺癌、乳腺癌中的PD-L1判读[98, 99]，以及结直肠癌中克罗恩样淋巴反应的识别[100]等。

    另外，还有部分研究应用循环肿瘤标志物检测[101, 102]、RNA原位杂交[103]等新技术方法进行了新颖的研究。细胞学领域也进行了大宗病例回顾性研究总结[104]。

【主编】

应建明   中国医学科学院肿瘤医院

刘艳辉   广东省人民医院

【副主编】

王   哲   空军军医大学西京医院

王   坚   复旦大学附属肿瘤医院

云径平   中山大学附属肿瘤医院

孟   斌   天津医科大学肿瘤医院

周   桥   四川大学华西医院

薛丽燕   中国医学科学院肿瘤医院

【编委】（按姓氏拼音排序）

冯晓莉   中国医学科学院肿瘤医院

郭嫦媛   中国医学科学院肿瘤医院

李文斌   中国医学科学院肿瘤医院

刘尚梅   中国医学科学院肿瘤医院

鲁海珍   中国医学科学院肿瘤医院

石素胜   中国医学科学院肿瘤医院

宋   艳   中国医学科学院肿瘤医院

王炳智   中国医学科学院肿瘤医院

张宏图   中国医学科学院肿瘤医院

张智慧   中国医学科学院肿瘤医院

郑   波   中国医学科学院肿瘤医院

郑   闪   中国医学科学院肿瘤医院

邹霜梅   中国医学科学院肿瘤医院

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