病理诊断没那么简单，以胃胃食管交界处腺癌的HER2检测为例
胃食管交界处腺癌 HER-2 检测及临床决策主要内容
胃食管交界处腺癌HER-2 检测及临床决策主要内容胃食管交界处腺癌（GEA）HER2 检测与临床决策指南，由美国病理学家学会（CAP）、美国临床病理学会（ASCP）和美国临床肿瘤学会（ASCO）联合发布，刊登在近期的JCO 上。
GEA 发病率高，II 期和III 期患者经过治疗后的5 年生存率约为40%，但GEA 患者被确诊时往往已达晚期，此时的治疗手段极为有效，预后很差。
2010 年有研究发现，人表皮生长因子受体2（HER2）阳性的GEA 患者采用抗HER2 靶向治疗，能够显著延长生存时间。
HER2 是目前发现的治疗晚期GEA 的唯一生物学标志物，但尚无关于HER2 评估的共识指南，因此CAP、ASCP、ASCO 检索了2008 年至2015 年共计969 篇文献，从其中116 项研究中提取了数据进行荟萃分析，制定出该指南，用于指导晚期GEA 患者HER2 的检测。
给临床医师的建议1. 对于HER2 靶向治疗潜在候选晚期GEA 患者，临床医师应申请检测肿瘤组织的HER2 表达。
（类型：基于证据；证据质量：高；推荐强度：强）化疗联合曲妥珠单抗能够显著增强HER2 阳性晚期GEA 患者的应答率，并延长无进展生存（PFS）和总生存（OS）。
HER2 状态除了指导是否加用曲妥珠单抗治疗外，并无诊断和预测价值。
目前尚无证据证明HER2 靶向治疗可使非晚期GEA 患者获益。
ToGA 临床试验显示晚期GEA 患者中HER2 阳性率约为22.1%，心脏不良事件的发生率与单独化疗组相当，但曲妥珠单抗治疗可能更易导致患者出现腹泻、胃炎、贫血、疲劳和体重减轻。
NCCN 指南建议Karnofsky 体力评分≥60%，或ECOG 体力评分≤2 的患者可行化疗，HER2 阳性转移性GEA 患者首选化疗联合曲妥珠单抗治疗。
2. 在曲妥单抗治疗开始之前，临床医师或病理医师应申请检测肿瘤组织的HER2 表达，采用活检或手术切除样本（原发或转移）最佳，若无法获取，也可用细针穿刺样本替代。
胃癌组织中Her—2的表达及临床病理的价值体现
胃癌发病率在目前已知的恶性肿瘤中占第四位， 在世界范围内由癌症引起的相关死亡中占第二位[1]。目前Her2被广泛认为是人体实体瘤生长发育的一种关键因子， 尤其对于乳腺癌， 在20%～25%的乳腺癌患者中， Her2基因呈现过量表达， Her2已被认为是肿瘤治疗的预后和治疗的指标[2]。在我国胃癌为高发肿瘤， 由于胃组织重要的生理功能， 单纯手术治疗效果并不理想， 患者的术后5年生存率仍然不高[3]， 目前的治疗仍依赖于以化学治疗为主的综合治疗方法， 因而为胃癌的治疗寻找有效的生物学标记物成为目前研究的热点。本研究应用免疫组化法检测78例胃癌和39例正常胃组织中Her2的表达情况以及其与临床病理指标的关系， 为胃癌的靶向治疗提供理论依据。现将研究结果报告如下。
2016年在ASCO会议上公布了ToGA临床试验结果， 在ToGA试验中， 将Her2蛋白过表达的胃癌患者随机分为化疗组5氟尿嘧啶或卡陪他滨联合顺铂化疗以及化疗联合曲妥珠单抗治疗组进行治疗， 结果显示， 后者的治疗效果较好， 确立了曲妥珠单抗在胃癌治疗中的地位[9]， 曲妥珠单抗抑制Her2介导的信 传导途径， 阻断Her2受体细胞外区域分裂， 激活抗体依赖性细胞介导的细胞毒性作用， 抑制肿瘤的生长。检测Her2蛋白的表达， 可以为临床治疗提供一定的参考， 为胃癌的个体化治疗提供依据。
总之， 胃癌组织中Her2蛋白的检测有利于胃癌预后的判断， 对于胃癌患者的治疗有一定的指导意义， 检测Her2蛋白， 可能使患者从辅助靶向治疗中获益。
参考文献
[1]陆再英， 钟南山.内科学.第7版.北京 人民卫生出版社， 2016 396401.
[2]乔杉杉， 张静.乳腺癌HER2基因的研究进展及其靶点治疗.首都医科大学学报， 2016， 2911 9699.
HER2阳性胃癌的治疗现状
HER2阳性胃癌的治疗现状HER2是人表皮生长因子受体-2的缩写，实际上是一种原癌基因，临床上胃癌可按HER2检测分为阴性和阳性两种，其中HER2阳性胃癌更难治也更易复发。
根据临床统计显示，越有16%的转移性胃癌患者HER2基因呈阳性。
在一项针对200例胃癌患者的调查中，42例胃癌患者HER2过表达阳性率21.0%。
HER2阳性胃癌会根据发生部位的不同、分化程度的不同，胃癌患者所表达出的HER2阳性率也有所不同。
胃食道连接部癌（胃底、贲门）HER2阳性率为30.8%，胃部癌（胃体、胃窦）HER2阳性率为17.6%；肠型胃癌HER2阳性表达率28.5%，弥漫型胃癌HER2阳性率9.9%；高中分化型胃癌HER2阳性率30.6%，低分化型胃癌HER2阳性率15.6%。
HER2在胃食道连接部癌中表达高于胃体、胃窦部癌；HER2表达与胃癌组织分型相关，肠型胃癌HER2存在更高表达；高中分化型胃癌HER2表达高于低分化型胃癌。
有淋巴结转移的胃癌组织中HER2阳性率较无淋巴结转移的癌组织中HER2阳性率明显增高，24.5%vs12.7%，但统计学无显著性差异（p=0.056）；I/II期胃癌组织中，HER2表达阳性率为12.9%；III/IV期中，HER2阳性率25.4%。
有淋巴结转移的胃癌组织中HER2阳性表达率较高；III和IV期胃癌中HER2表达阳性率高于其他分期的胃癌。
早期胃癌也存在HER2过表达，阳性率17.8%，与进展期胃癌HER2阳性率（21.9%）相比无统计学差异；无淋巴结转移早期胃癌HER2表阳性率7.7%，有淋巴结转移的HER2表达阳性率1.8%。
有淋巴结转移的早期胃癌HER2阳性表达率显著高于无淋巴结转移的早期胃癌。
重庆新桥CTC肿瘤生物治疗专家指出，目前HER2基因检测虽未被列为胃癌的标准检测项目，但HER2作为胃癌重要的预后指标，HER2过度表现的患者虽然易复发、恶化较快速，但通过对治疗，可帮助患者规划最佳的个人化治疗方案。
HER2是胃癌患者是否接受放化疗的评价指标
HER2是胃癌患者是否接受放化疗的评价指标[导读]曲妥珠单抗已被批准用于人表皮生长因子受体2（HER2）阳性转移性胃癌患者。
然而，在这种疾病的自然病程中，我们对HER2基因的作用相对知之甚少。
Annals of Oncology最新在线发表了一项研究，旨在对胃或胃食管交界处的腺癌患者的HER2基因扩增进行评估。
Ann Once曲妥珠单抗已被批准用于人表皮生长因子受体2（HER2）阳性转移性胃癌患者。
然而，在这种疾病的自然病程中，我们对HER2基因的作用相对知之甚少。
Annals of Oncology最新在线发表了一项研究，旨在对胃或胃食管交界处的腺癌患者的HER2基因扩增进行评估。
Ann Oncol 2013 Mar 22.针对参加INT-0116/SWOG9008 III期胃癌临床试验的患者，通过其可用的组织标本进行回顾性检测，通过FISH检测HER2基因扩增以及免疫组化法（IHC）检测HER2过度表达。
原始试验的目的是评估术后放化疗与单纯手术相比的临床获益。
通过对258名患者的评估，FISH-HER2基因扩增率为10.9%,另外148例患者进行IHC 检测，HER2过表达率是12.2%,FISH和IHC之间有90%的一致性。
HER2扩增和治疗之间对于无病生存期（P = 0.020）和总生存（P = 0.034）都有显著的相互作用。
在HER-2无扩增癌症患者中，接受治疗的病人中位OS为44个月，相比手术组的24个月有显著提高（P = 0.003）。
在HER2扩增的肿瘤患者中，治疗组在生存方面没有显着差异。
在没有接受术后放化疗的患者中，HER2状态并不是一项预后指标。
通过以上研究结果可以看出，HER2无扩增的患者将从治疗中获益，包括无病生存期（DFS）和总生存（OS）。
病理检查结果解读
病理检查结果解读（篇幅扩展，注意段落分隔、适当引用实例）病理检查是一种重要的医学检查方法，通过对患者组织、细胞等进行显微镜下的观察，可以提供有关疾病诊断和治疗的关键信息。
然而，对于大部分患者来说，病理报告中的内容往往十分复杂和晦涩，很难直接理解。
因此，本文将从常见的病理检查结果入手，为大家解读和阐述其背后的含义。
1. 细胞学检查结果解读细胞学检查是通过对病人的细胞进行采样和分析，以确定细胞的形态、结构和功能是否异常。
常见的细胞学检查包括涂片染色和细胞脱落检查。
此类检查结果往往以细胞的形态特征和数量来描述，如细胞的大小、染色性质、核型等。
例如，在涂片染色中，常见的结果描述包括正常细胞、炎症细胞、上皮细胞异常等。
在解读时需要注意，细胞学检查结果属于初步筛查，通常需要进一步辅助检查或组织学检查来确诊。
2. 组织学检查结果解读组织学检查是通过对病变组织进行切片、染色和显微镜观察，以确定病变类型和性质。
组织学检查结果常以病变的形态特征和组织结构来描述，如细胞增生、细胞形态学改变等。
最常见的组织学检查结果解读是肿瘤病理学，其中涉及到良性和恶性肿瘤的鉴别和分级。
例如，乳腺癌的病理检查结果描述可能包括组织类型（如导管癌、小叶癌）、分级（如分化程度高低）和侵袭程度（如淋巴结转移）。
通过组织学检查结果的解读，可以帮助医生进行病情诊断和治疗方案制定。
3. 免疫组化检查结果解读免疫组化检查是一种常用的组织学检查技术，通过利用特定抗体与病变组织中的抗原结合，来检测目标抗原的存在和数量。
免疫组化检查结果常以阳性和阴性表示，描述目标抗原在病变组织中的表达情况。
例如，在乳腺癌的免疫组化检查中，HER2阳性表示HER2蛋白在癌细胞表面过度表达，这一结果可以指导HER2靶向治疗的应用。
需要注意的是，病理检查结果解读不仅需要依靠病理学家的经验和专业知识，还需要结合临床表现、病史和其他检查结果来进行综合分析。
对于患者来说，理解病理检查结果的含义和意义非常重要，可以帮助他们更好地了解自己的病情、制定治疗计划，并与医生进行有效的沟通和协作。
HER-2_联合血清肿瘤标志物检测在胃癌诊断中的临床价值
HER-2联合血清肿瘤标志物检测在胃癌诊断中的临床价值李 玲荆门市妇幼保健院检验科（荆门 448000）【摘 要】 目的 分析在胃癌诊断中应用人表皮生长因子受体2（HER-2）结合肿瘤标志物检测的意义。
方法 回顾性选取2019年6月—2021年6月我院收治的100例胃癌患者作为胃癌组，另选同期收治的60例胃良性肿瘤患者作为胃良性肿瘤组。
比较HER-2与多项肿瘤标志物检测的诊断效能等。
结果 胃癌组HER-2、糖类抗原（CA ）125、CA72-4及CA19-9浓度与阳性表达率高于胃良性肿瘤组（P ＜0.05）。
对于胃癌诊断，免疫组化指标HER-2检测的敏感度为72.00%，正确率为77.00%；多项肿瘤标志物检测的敏感度为77.00%，正确率为80.00%；二者联合检测的敏感度为89.00%，正确率为90.00%；相较于多项肿瘤标志物与HER-2单一检测，二者联合检验的正确率、敏感度更高（P ＜0.05）。
结论 HER-2结合血清肿瘤标志物检验对胃癌的诊断价值较高。
【关键词】 人表皮生长因子受体2；胃癌；阳性表达；肿瘤标志物DOI ：10. 3969 / j. issn. 1000-8535. 2023. 07. 005The value of HER-2 and tumor marker in the diagnosis of gastric cancerLI LingClinical laboratory ，Jingmen Women and Childrens Health ，Jingmen 448000，China【Abstract 】 Objective To analyze the significance of human epidermal growth factor receptor 2（HER-2）combined with tumor marker in the diagnosis of gastric cancer ．Methods A total of 100 patients with gastric cancer admitted to our hospital from June 2019 to June 2021 were retrospectively selected as the gastric cancer group ，and 60 cases of gastric benign tumor admitted to our hospital during the same period were also selected ．The diagnostic efficacy of HER-2 was compared with those of multiple tumor markers ．Results The concentration and positive expression rate of HER-2，carbohydrate antigen （CA ）125，CA72-4 and CA19-9 in gastric cancer group were higher than those in gastric benign tumor group （P ＜0.05）．For the diagnosis of gastric cancer ，the sensitivity of the immunohistochemical indicator HER-2 detection was 72.00%，and the accuracy rate was 77.00%．The sensitivity and accuracy of detecting multiple tumor markers were 77.00% and 80.00%，respectively ．The sensitivity of the combined detection of the two was 89.00%，and the accuracy was 90.00%．Compared to multiple tumor markers and HER-2 single detection ，the combined test of the two had a higher accuracy and sensitivity （P ＜0.05）．Conclusions The detection of HER-2 combined with serum tumor markers has high diagnostic value for gastric cancer ．【Key words 】 human epidermal growth factor receptor 2；gastric cancer ；positive expression ；tumor marker通信作者：李玲，E-mail ：ll1079205272@胃癌是最常见的消化系肿瘤，每年有140万胃癌及胃食管癌病例被诊断、110万患者死于胃癌，居恶性肿瘤死亡率的第2位［1-2］。
胃镜活检与外科病理诊断胃癌及HER2检测的对比研究
胃镜活检与外科病理诊断胃癌及HER2检测的对比研究目的：评估对比配对的胃腺癌活检标本及外科病理手术标本临床病理学特征及HER2表达，研究其异质性并评估临床意义。
方法：选取2011年1月-2013年1月本院诊断的胃食管交界区普通型腺癌内镜活检标本及相应的肿瘤手术切除标本患者98例，并收集相应的临床病理学资料，用免疫组化（IHC）及原位荧光杂交（FISH）法检测内镜活检标本及相应的肿瘤手术切除标本HER2蛋白过表达和基因扩增情况，观察并分析其异质性表达的情况，分析临床病理学特征，评估临床意义。
结果：98例胃腺癌患者中免疫组化HER2阳性16例（16.3%），FISH HER2阳性14例（14.3%），12例（75%）免疫组化HER2阳性胃腺癌组织中HER2呈现明显异质性，而FISH检测HER2阳性胃腺癌组织中仅有5例（41.7%）。
结论：HER2在胃癌组织中呈现明显的异质性；活检标本能良好地预测胃癌手术标本HER2表达，应该对活检标本进行HER2检测。
标签：胃镜活检；外科病理诊断；HER2；胃癌确诊胃癌是最常见的癌症之一，尽管胃癌在世界范围内的发病率有所下降，但它仍然是继肺癌之后死亡率居第二位的高发性肿瘤[1]。
我国和日本、智利、芬兰、冰岛等国家同是胃癌的高发区，发病率6～8倍于西方国家。
目前，手术切除仍然是治疗早期胃癌的主要手段。
但对晚期胃癌，尽管治疗方法很多，如手术、化疗、放疗等，但患者的存活率仍很低。
ToGA研究证实曲妥珠单抗联合化疗可改善HER-2/neu阳性晚期胃癌患者的生存[2]。
本研究的主要目的是评估对比配对的胃腺癌活检标本及外科病理手术标本临床病理学特征及HER2表达，研究其异质性并评估临床意义，因此选取2011年1月-2013年1月本院诊断的胃食管交界区普通型腺癌胃癌内镜活检标本及相应的肿瘤手术切除标本患者98例，具体报告如下。
1 资料与方法1.1 一般资料选取2011年1月-2013年1月在本院接受治疗的胃癌患者的胃镜活检标本及相应的肿瘤手术切除标本98例，并收集相应的临床病理学资料。
胃癌HER2判读及评分
胃癌HER2检测现状
2
胃癌与胃食管交界癌的 HER2 检测
• 晚期胃癌和乳腺癌的总体 HER2 过表达率相当
• 胃癌中 HER2 分布的异质性十分常见
– 胃食管交界癌的 HER2 过表达率高于胃癌 – 弥漫型胃癌的 HER2 过表达率低于肠型
• 检测流程需要反映出乳腺癌和胃癌之间的差异
• 采用 IHC 和 FISH 进行评估 • 将检测为 IHC 3+ 或 FISH+ 的患者进行随机分组
Van Cutsem E, et al. J Clin Oncol 2009;27:Abstract 4509. Bang YJ, et al. J Clin Oncol 2009;27:Abstract 4556.
IHC 2+ 染色范例
图片由 F. Hoffmann-La Roche Ltd. 提供
IHC 1+ 染色范例
图片由 F. Hoffmann-La Roche Ltd. 提供
胃癌 IHC 染色范例：活检标本
IHC 3+ 染色范例
胃癌中的 HER2 评分标准
手术标本 活检标本 分值 HER2过表达 情况评估
无反应或 <10% 肿瘤 细胞膜染色
任何肿瘤细胞无膜染色
0
阴性
肿瘤细胞团微弱或隐约可见膜染色 ≥10% 肿瘤细胞微弱或隐约可见 （不管着色的肿瘤细胞占整个组织 膜染色；仅有部分细胞膜染色 的百分比）
1+
阴性
肿瘤细胞团有弱到中度的基底侧膜、 ≥ 10% 肿瘤细胞有弱到中度的基 侧膜或完全性膜染色（不管着色的 底侧膜、侧膜或完全性染色 肿瘤细胞占整个组织的百分比，但 至少有5个成簇的肿瘤细胞着色）
胃癌胃镜活检标本HER-2检测中国专家共识(2023版)解读PPT课件
不同实验室采用的检测方法可能存在差异，如抗体选择、检测平台 等，这会导致结果的不一致性和可比性差。
结果判读主观性
HER-2检测结果的判读存在一定主观性，不同医生或实验室可能对 同一结果做出不同判断，影响临床决策的准确性。
如何进一步提高HER-2检测准确性和可靠性
加强标本质量控制
建立完善的标本采集、处理、保存和 运输规范，确保标本质量符合检测要 求。
01
标准化操作流程
02
统一评价标准
03
推动技术创新
专家共识提供了胃癌胃镜活检标本 HER-2检测的标准化操作流程，包括 标本处理、检测方法、结果判读等方 面，有助于提高检测的规范性和准确 性。
专家共识制定了HER-2检测结果的评 价标准，使得不同实验室之间的结果 具有可比性和一致性，便于临床医生 和患者理解和接受。
HER-2基因
位于人类17号染色体长臂上，编码 一种具有酪氨酸激酶活性的跨膜糖蛋 白。
HER-2蛋白结构
由胞外配体结合区、跨膜区和胞内酪 氨酸激酶区组成，属于受体酪氨酸激 酶家族成员。
HER-2在胃癌发生发展中的作用
HER-2扩增和过表达
在胃癌中，HER-2基因的扩增和蛋白的过表达与肿瘤的发生、发展密切相关。
FISH结果判读标准
HER-2/CEP17比值
当比值≥2.0时，视为HER-2阳性；当比值<2.0但平均HER-2拷贝数/细胞≥4.0时，也视 为HER-2阳性；否则为阴性。
注意事项
需确保足够的肿瘤细胞核被评估，至少计数20个细胞核；若信号重叠或模糊，需结合 IHC结果进行综合判断。
结果判读中需要注意的问题
THANKS
统一检测方法和标准
2024《胃癌临床实践指南》更新解读(全文)
2024《胃癌临床实践指南》更新解读（全文）摘要2024年3月7日美国国家综合癌症网络（NCCN）更新了2024年第一版《胃癌临床实践指南》，对于早期胃癌的内镜治疗、二代测序、胃癌腹膜转移的诊疗、系统治疗方案和术后营养缺乏监测等方面作出了更新。
特别是针对近年来晚期胃癌腹膜转移采用腹腔内化疗或腹腔热灌注化疗的热点问题，该指南较为详细地阐述了治疗适应证、综合治疗模式、疗效评估等内容。
在知识和信息迭代更新的时代，NCCN指南也不断地作出更新以适应新的挑战。
新的分子检测手段在胃癌精准诊疗中越来越占据重要的地位，而内镜治疗、腹腔镜手术、机器人手术在内的微创治疗手段也随着更多的循证医学证据和临床实践经验被纳入指南中，充分体现了外科医师对于病人长期生存和生存质量的无限追求。
同样，以免疫检查点抑制剂、靶向治疗药物、抗体药物偶联物为代表的新型抗肿瘤药物在胃癌系统治疗中的地位日益上升，也为病人提供了更多的治疗选择。
未来，秉承“以病人为中心”的治疗理念，积极推动多学科协作和全程化管理，才能真正追求实现所有治疗指南的终极目标。
美国国家综合癌症网络（National Comprehensive Cancer Network，NCCN）每年都会根据新出现的临床试验结果和循证医学证据对恶性肿瘤的临床实践指南适时进行更新，并发布不同版本，其更新速度之及时、收录证据之全面，提供信息之完整，远超其他各国的治疗指南和专家共识。
同时，不断进行纠错和调整也充分体现了其尊重客观试验结果、不盲从权威、不做主观臆断的科学精神。
2024年3月7日，2024年第一版《胃癌临床实践指南》（以下简称NCCN指南）发布，其中对于早期胃癌的内镜治疗、二代测序、胃癌腹膜转移的诊疗、系统治疗方案和术后营养缺乏监测等方面作出了更新。
本文将对该版指南中的主要更新内容变化和相关临床试验结果并加以解读和分析，以期把握胃癌诊疗的现状和最新进展。
1 首次增加了早期胃腺癌内镜治疗的流程随着早期胃癌（early gastric cancer，EGC）检出率的逐年升高，原在东亚地区较为普遍接受的内镜治疗理念和技术也逐渐为欧美学者所适应和接受，各版日本《胃癌治疗指南》的更新也为此发挥了积极推动作用，而美国和欧洲胃肠内镜协会也在近年相继发布了内镜黏膜下切除（endoscopic submucosal dissection，ESD）的治疗指南［1-2］，因此，NCCN指南也与时俱进地首次增加了早期胃腺癌的内镜治疗路径，指出首先需对EGC进行内镜的评估和活检，基于组织学类型进行分层，如分化较差或弥漫型，则属于非适宜内镜治疗的EGC而建议接受胃切除手术，反之则建议内镜治疗（优选ESD），术后由胃肠病理专业的病理科医师进行治愈性切除评估，其中治愈性切除是指黏膜下层浸润＜500 μm、非低分化或未分化类型、无淋巴及脉管浸润。
HER2检测在胃癌和胃食管结合部腺癌的检测情况-综述
HER2Testing in Gastric and GastroesophagealAdenocarcinomasEfsevia Vakiani,MD,PhDAbstract:The human epidermal growth factor receptor2(HER2)is overexpressed in10%to35%of gastric and gastroesophageal junction(GEJ)adenocarcinomas.In2010,the phase III Trastu-zumab for Gastric Cancer(ToGA)trial showed that addition of the anti-HER2monoclonal antibody trastuzumab to chemo-therapy significantly improved survival of patients with advanced or metastatic tumors that were positive for HER2overexpression. As a result,HER2testing is now recommended for all patients with advanced or metastatic disease,although there is still some debate as to the optimal methods of assessment.HER2expression in gastric and GEJ tumors shows several differences compared with breast tumors and,for this reason,the proposed criteria for scoring HER2expression in biopsies and resections of gastric and GEJ carcinomas differ from those used in breast carcinomas.This review discusses what is currently known about the patterns of HER2expression in gastric and GEJ adenocarcinomas,summa-rizes thefindings of the ToGA trial and its clinical implications, and provides an overview of the recommended guidelines for the most accurate evaluation of HER2status in gastric and GEJ cancer.Key Words:HER2,gastric cancer,gastroesophageal cancer, immunohistochemistry,in situ hybridization,ToGA trial(Adv Anat Pathol2015;22:194–201)HER2EXPRESSION IN GASTRIC AND GASTROESOPHAGEAL ADENOCARCINOMASThe human epidermal growth factor receptor2 (HER2,HER2/neu,ERBB2)is a protooncogene located on chromosome17q21,which encodes for a185kD trans-membrane tyrosine kinase receptor protein.It belongs to the human epidermal growth factor receptor superfamily, which is composed of4members sharing the same basic molecular structure:HER1(more commonly known as EGFR),HER2,HER3,and HER4.The binding of a ligand to the extracellular domain triggers homodimerization or heterodimerization,phosphorylation of the receptor,and initiation of signal transduction cascades that affect a variety of cellular processes including apoptosis,pro-liferation,and differentiation.1,2In contrast to the other family members,HER2does not bind to a known ligand.HER2is overexpressed in a number of different cancer types,where it promotes tumorigenesis,including breast, stomach,esophagus,colon,bladder,and ovary.3–8Amplifi-cation of the HER2gene and overexpression of the HER2 protein wasfirst described in gastric cancer in1986and these findings have been confirmed in multiple studies since that time.9–11The reported frequency of protein overexpression by immunohistochemistry(IHC)varies significantly among studies ranging from8.2%in one Japanese study to53.4%in one German study.12,13This high variation is likely secondary to different methodologies used,differences among ethnic groups,as well as different tumor histologies and locations among various cohorts.Results of studies using in situ hybridization(ISH)to look for HER2gene amplification have been somewhat more consistent with amplification being reported in10%to27%of cases.11Studies from the United States using both IHC and ISH have reported rates of HER2overexpression that are on the lower end of the spectrum.For example,Kunz et al14in their study of169 primary gastric and gastroesophageal(GEJ)adenocarcino-mas using tissue microarrays reported a HER2positivity rate of11.2%,whereas Tafe et al15in their study of135primary gastric and GEJ adenocarcinomas using mostly biopsy material found a HER2positivity rate of15%.HER2overexpression is significantly more frequent in intestinal-type adenocarcinomas compared with diffuse-type adenocarcinomas,afinding that seems to be consistent among studies.In one Finnish study of231gastric and GEJ tumors, HER2overexpression was seen in21.5%of intestinal-type adenocarcinomas compared with2%of diffuse-type adeno-carcinomas and5%of mixed-type adenocarcinomas.6An Australian study of178tumors reported HER2positivity in 30%of intestinal-type tumors compared with3.8%of diffuse-type tumors and9%of mixed-type tumors,whereas the study by Tafe et al15found positivity in22.1%of intestinal-type adenocarcinomas compared with2.7%of diffuse-type adeno-carcinomas.16HER2expression in unusual histologic types requires further study as there are only a few reports in the literature,sometimes with conflicting results.17–19For exam-ple,Yano et al19reported that all6tested papillary gastric adenocarcinomas showed strong HER2overexpression, whereas in another study all5papillary adenocarcinomas were HER2negative.17HER2overexpression appears to be more frequent among GEJ tumors compared with gastric tumors,although the difference has not been statistically sig-nificant in all studies and it is not known whether this may simply be a reflection of the fact that many gastric adeno-carcinomas are diffuse type.HER2overexpression in gastric/GEJ adenocarcinomas tends to show more heterogeneity compared with what is observed in breast adenocarcinomas.The frequency of het-erogeneity ranges among studies from5%to50%.This high variability is likely due to differences in the definition of heterogeneity.Hofmann et al20reported heterogeneity in 4.8%of cases referring to cases that showed strong positivity in<10%of tumor cells.In contrast,Wang et al21defined heterogeneity as between10%and60%of tumor cells showing2+or3+staining and reported that26%of all tested cases showed heterogeneity.Lee at al22found that 16.8%of322cases showed heterogenous HER2expressionFrom the Department of Pathology,Memorial Sloan-Kettering CancerCenter,New York,NY.The author has no NIH funding or conflicts of interest to disclose.Reprints:Efsevia Vakiani,MD,PhD,Department of Pathology,Memorial Sloan-Kettering Cancer Center,1275York Avenue,NewYork,NY10065(e-mail:vakianie@).Copyright r2015Wolters Kluwer Health,Inc.All rights reserved.R EVIEW A RTICLE194| Adv Anat Pathol Volume22,Number3,May2015where heterogeneity was defined as expression between5% and50%of tumor cells.In a study from Australia,hetero-geneity was defined as expression in<66%of tumor cells and was reported in50%(6/12)of cases.16Heterogeneity may be observed in the context of morphologic hetero-geneity,for example,in mixed carcinomas.In such cases, HER2expression is usually seen in the intestinal or better differentiated component,whereas it is absent in the more poorly differentiated component(Fig.1D).Heterogeneous expression can also be encountered in cases lacking mor-phologic heterogeneity,that is,the tumor areas showing HER2expression are similar histologically to those lacking expression.The relationship between HER2IHC and ISH has been somewhat controversial in gastric/GEJ cancer as early studies did not show a high concordance and reported a significant number of cases that showed protein overexpression but did not appear to have gene amplification.23,24This led to the hypothesis that,unlike breast cancer,in gastric cancer, mechanisms other than gene amplification may play an important role in protein overexpression.More recent studies have reported a high concordance between IHC and ISH in the range of86.9%to96.4%,19,20,25suggesting that an amplification in the gene drives protein overexpression in most cases.Despite the overall high concordance between IHC and ISH,the ToGA trial(see below)reported a sig-nificant number of cases that were positive by ISH but neg-ative by IHC.The molecular mechanisms underlying the different IHC and ISH results in these cases,as well as the clinical implications,are still unclear.The prognostic value of HER2overexpression in gastric/GEJ cancer has also been a controversial topic. Some studies have reported an association between HER2 overexpression and adverse clinical outcome,26,27however, others have failed to confirm such an association.14,25,28 This is in contrast to breast cancer where there is general acceptance of HER2overexpression as a marker of aggressive disease and poor prognosis.29HER2AS A THERAPEUTIC TARGET Gastric cancer is the second most common cause of cancer-related deaths worldwide.30In western countries where screening programs are absent,patients often present late with advanced disease and have a poor5-year survival with median overall survival being less than a year.31Fol-lowing the identification of HER2inhibition as an impor-tant therapeutic target in breast cancer patients,5a number of preclinical studies reported sensitivity of HER2-positive gastric cancer cell lines and xenografts to trastuzu-mab,6,32,33which is a humanized,recombinant monoclonal antibody that recognizes the extracellular portion of HER2. By binding HER2trastuzumab blocks HER2-mediated signaling and induces antibody-dependent cellular cyto-toxity.34Given the promising preclinical results and the good tolerability profile of trastuzumab in breast cancer patients,the Trastuzumab for Gastric Cancer(ToGA)trial was designed to assess the clinical efficacy and safety of trastuzumab added to chemotherapy forfirst-line treatment of advanced HER2-positive gastric/GEJ cancer.35 The ToGA trial was an international,randomized,open-label phase III trial that included24countries in Europe, Australia,South Africa,Central and South America,and Asia.A total of3803patients were screened for HER2pos-itivity by both IHC(HercepTest;Dako)andfluorescence ISH (HER2FISH pharmDx;Dako)in one single central labo-ratory.The majority(82%)of tumors were located in the stomach and were intestinal type(75%).Tumors were con-sidered to be HER2positive if they showed3+HER2 expression by IHC or if there was HER2amplification by FISH.In this study,22.1%of patients were HER2positive either by IHC or FISH.HER2positivity was more common in tumors with intestinal histology compared with those with diffuse histology(31.8%vs.6.1%)and in specimens from the GEJ compared with specimens from the stomach(32.2%vs.21.4%).Concordance between IHC and FISH after exclusion of IHC2+cases was92.8%;190patients were IHC0/1+ and FISH positive.Variability in HER2staining defined as r30%positively stained cells was observed in50.3%ofpatients.36A total of584patients were randomized to receive trastuzumab plus chemotherapy or chemotherapy alone. Patients receiving trastuzumab had a median overall sur-vival of13.8months compared with11.1months among patients who received only chemotherapy(HR=0.74;95% CI,0.6-0.91;P=0.0046).A post hoc exploratory analysis showed that those patients that had3+HER2expression by IHC or2+HER2expression by IHC and amplification by FISH derived the greatest survival benefit from trastu-zumab;these patients had a median overall survival of16 months when receiving trastuzumab compared with11.8 months with chemotherapy alone.There did not seem to be a benefit for patients with IHC0or1+and FISH-positive disease suggesting that IHC might be better suited in selecting patients for treatment with trastuzumab.35In a subsequent analysis of the ToGA trial data,Van Cutsem et al36noted that patients with IHC2+and3+scores seemed to derive benefit from trastuzumab regardless of staining variability,although the subgroups were small.The ToGA trial was thefirst phase III clinical trial to establish efficacy of a targeted therapy in gastric/GEJ can-cer and resulted in the approval of trastuzumab for the treatment of advanced HER2-positive gastric/GEJ adeno-carcinoma.On the basis of thesefindings,it is now rec-ommended that patients with gastric/GEJ adenocarcinoma have their tumors tested for HER2status.The European Medicines Agency guidelines recommend that IHC be used as the initial testing method and that ISH be performed in cases that are scored as2+by IHC.This is also done in many centers across the United States.Nonetheless,in the United States,the FDA has approved trastuzumab for HER2-positive tumors as defined by any FDA-approved test.For this reason some centers use both IHC and ISH on all samples and treat patients that might be1+by IHC but show amplification by ISH.37–39HER2IMMUNOHISTOCHEMISTRY PRACTICALCONSIDERATIONSA number of studies in breast cancer have highlighted the effect offixation and cold ischemia time on the accuracy of HER2testing.40–42On basis of such studies,the ASCO/ CAP guidelines for breast cancer recommendfixation of specimens with10%neutral buffered formalin and a length offixation between6and72hours.43Specimens should be placed infixative within<1hour from removal from patient.Similar studies have not been performed in gastric/ GEJ cancer,but it is generally assumed that similar guidelines should be applied.Ruschoffet al44recommended that biopsies should befixed immediately and surgicalAdv Anat Pathol Volume22,Number3,May2015HER2and Gastric Cancer Copyright r2015Wolters Kluwer Health,Inc.All rights |195Vakiani Adv Anat Pathol Volume22,Number3,May2015FIGURE1.Examples of HER2immunoreactivity in gastric or gastroesophageal junction(GEJ)specimens.A,GEJ biopsy showing faint, lateral membranous HER2reactivity(1+staining)clearly visible only at high power(Â400magnification).B,Gastric resection specimen showing weak to moderate basolateral,membranous HER2reactivity(2+)appreciated at medium power(Â200magnification).2+ staining was seen in>10%of tumor cells.C,GEJ resection specimen showing strong basolateral,membranous HER2reactivity(3+)seen even at low power(Â40magnification).D,Gastric biopsy showing a mixed adenocarcinoma with heterogeneous HER2reactivity. Strong membranous reactivity(3+)is seen in the intestinal-type adenocarcinoma on the right,whereas the diffuse-type adenocarci-noma on the left does not show HER2reactivity(Â40magnification).E,Gastric biopsy showing HER2reactivity in non-neoplastic epithelium(Â100magnification).F,Gastric biopsy showing cytoplasmic and nuclear staining in tumor cells.This was initially mis-interpreted as positive HER2staining and the case was subsequently correctly scored as IHC negative(Â200magnification).196| Copyright r2015Wolters Kluwer Health,Inc.All rights reserved.specimens within20minutes of excision and that thefix-ation time should be between8and48hours.A number of antibodies against HER2are available and there is no gold standard method for IHC.The CAP recommends that laboratories specify the test that was used to reach a certain conclusion about HER2status.45 Whichever test is used,it is also recommended that labo-ratories that had been using HER2IHC for breast cancer perform a small revalidation for gastric/GEJ adenocarci-nomas by testing25to50cases by both IHC and FISH aiming for a90%to95%concordance between the2tests (when equivocal2+cases are excluded).In general,there is good agreement between the avail-able antibodies,although there are some differences in the specific performance characteristics.Park et al46compared2 FDA-approved tests,the Dako HercepTest(using the rabbit polyclonal antibody A0485)and the Ventana Pathway method(using the rabbit monoclonal antibody4B5that recognizes the extracellular portion of HER2)and found a very high concordance(96.1%),although they observed a higher frequency of granular cytoplasmic staining with Her-cepTest compared with Pathway(23.4%vs.8.2%).In another study,comparing the4B5and A0485antibodies, Radu et al47reported that4B5showed a higher sensitivity in identifying cases that were amplified by FISH and,in general, the use of the4B5antibody resulted in a higher IHC score for a given case.In that study,the use of4B5resulted in the identification of6more cases eligible for trastuzumab com-pared with what was identified using A0485.Among these6 cases,1showed no amplification by FISH and3had low-level amplification,raising the possibility that the use of the more sensitive4B5to screen cases might result in the treat-ment of tumors that are less likely to respond.4B5was also reported to show higher sensitivity when compared with SP3, another rabbit monoclonal antibody that recognizes the intracellular portion of HER2.48Both biopsies and resection specimens may be used for HER2testing.Resection specimens usually contain larger amounts of tumor tissue but may not befixed properly. Currently,there are no guidelines regarding the number of tumor blocks to be tested for HER2expression and some authors have advocated the use of>1tumor block from gastrectomy specimens.16Asioli et al49reported that testing additional blocks increased both the sensitivity(from63% to83%)and the specificity(from91%to94%)of IHC compared with FISH.If1tumor block is used,as is done by many institutions,it is prudent to choose a block with representative histology and one that includes the better differentiated component of the tumor in cases where there are multiple components.Biopsies tend to befixed immediately and may have better antigen preservation,but may be more prone to crush and surface artifact and there is concern for false-negative results due to small amounts of tumor.Concerns for false-negative results on biopsies have been validated in some studies.In a relatively small study,Yan et al50 reported that5of11cases showing HER2positivity on a resection specimen had a negative result on the matched biopsy.Yang et al51found a higher percentage of HER2-positive cases(defined as FISH amplified)among surgical specimens compared with matched biopsies(96%vs.80%), although the overall concordance between IHC and FISH was high(93.2%).Similarly in a study of103cases by Grillo et al,52approximately10%of IHC-negative biopsies were IHC positive and FISH amplified at surgery.In the above studies,the number of tumor present on biopsies was not quantified so it is not possible to know the extent of tumor sampling on the studied biopsies.It is currently recommended that6to8biopsies be taken from a tumor during endoscopy.44Some recent studies have reported a high concordance rate between biopsies and resections with false-negative results being observed both in biopsies and resections.Wang et al21looked at paired biopsies and resections specimens from128patients and found an overall concordance of 96.1%.Discordant results were observed in5cases with2 cases showing a positive result only in the biopsy,whereas3 were positive only on the resection.Heterogeneity was observed in4of the5discordant cases.Watson et al53looked at paired biopsies and resection specimens from228patients, including135patients who received neoadjuvant therapy before resection.Overall they observed a concordance of 94%;in that study4treated cases that were HER2positive on biopsy were negative for HER2in the resection specimen, which showed a major histologic response in3of the4cases. The authors of that study suggested that HER2testing in resection specimens showing major histologic response might not be reliable and that in cases that are treated with neo-adjuvant therapy HER2status should be established on pretreatment biopsies.Heterogeneity in HER2overexpression also raises the question of whether testing should be performed on pri-mary tumor and/or a metastasis.A number of studies to date have tried to address this issue by looking at the concordance in the HER2status between primary tumors and matched metastases.25,54–58Most studies have reported a very high concordance,although there are some con-flicting data,and there are currently no guidelines on this issue.Marx et al25studied approximately50pairs of pri-mary tumors and lymph node metastases by IHC and FISH,and found100%concordance by FISH and only1 discordant case by IHC.Similarly,Bozzetti and colleagues in their study of72pairs of primary tumors and metastases found only1discordant case that was negative in the pri-mary tumor but showed protein overexpression and gene amplification in the metastasis.Kim et al57performed FISH testing using250paired primary and metastatic lesions on tissue microarrays and found7cases(2.8%)with discordant amplification.In6cases the metastasis showed amplification while the primary tumor did not,and the reverse was observed in1case.When the7discordant cases were reevaluated using whole sections,there was a heter-ogeneous pattern of amplification in6of the cases sug-gesting that heterogeneity was the underlying cause of the discordant results in most cases.In contrast to these stud-ies,Fusco et al56studied154primary adenocarcinomas and matched synchronous lymph node metastases using tissue microarrays and found discordant results in22(14%)cases, including16cases that showed positivity in the primary tumor and6cases that showed the reverse pattern.HER2IMMUNOHISTOCHEMISTRYSCORING CRITERIAThe scoring criteria for evaluating HER2expression in gastric/GEJ cancer are shown in Table1.These criteria werefirst proposed by Hofmann et al,20who validated a HER2IHC scoring system for the ToGA trial in168gastric cancer specimens,and were further refined by Ruschoffet al.59They differ from the HER2scoring criteria in breastAdv Anat Pathol Volume22,Number3,May2015HER2and Gastric Cancer Copyright r2015Wolters Kluwer Health,Inc.All rights |197carcinoma43in2important ways.First,gastric/GEJ tumor cells may only show HER2staining at the basolateral or lateral membrane regions.For this reason,complete membranous staining which is a requirement in breast cancer is not required in gastric/GEJ cancer.Second,due to the presence of heterogeneity,it was felt that the10%cutofffor the number of reactive cells would be retained for surgical specimens but would not be appropriate for biopsies.Hofmann and colleagues initially suggested that in biopsies the pattern of reactivity should be scored as pos-itive irrespective of the relative number of IHC-positive cells.Subsequently,Ruschoffand colleagues found that interobserver disagreement increased when few(<5)cells were evaluated on biopsies as such small cell groups tend to show nonspecific staining.They,therefore,proposed that the cutoffof immunoreactive cells on biopsies should be1 tumor cell cluster,the latter being defined as at least5 cohesive cells.Distinction between1+,2+,and3+IHC scores is based on the HER2staining intensity.Faint or barely perceptible staining corresponds to1+staining(Fig.1A), weak to moderate staining should be scored as2+ (Fig.1B),and moderate to strong staining is3+(Fig.1C). In an attempt to make intensity scoring more reproducible and increase interobserver agreement,Ruschoffand col-leagues suggested the magnification rule.According to this rule,if one can visualize unequivocal membranous staining at low power(Â2.5,Â5),then staining is considered “strong”and the case can be scored as3+if staining is present in10%of cells(surgical specimen)or in a tumor cell cluster(biopsy specimen).If the unequivocal mem-branous staining can only be appreciated at medium mag-nification(Â10toÂ20),the staining is considered weak to moderate and the case should be scored2+.Finally,if membranous staining can only be confirmed at high power (Â40),it is considered faint or barely perceptible and the case should be scored as1+.Interlaboratory agreement in the IHC scoring of gas-tric/GEJ tumors is generally good when following these criteria,although there seems to be room for improvement. In a study from Australia looking at the IHC assessment of 100tissue samples from9laboratories,Fox et al37found an overall agreement of84%when IHC0and1+cases were grouped together as negative.In a study from China, agreement in the IHC assessment of721samples between 11local laboratories and a central laboratory was86.7%.60 In the latter study,discordant results were attributed to misinterpretation of staining results due to unfamiliarity with scoring criteria and potential pitfalls.In a recent study from North America,Sheffield and colleagues reported excellent agreement among37laboratories in IHC3+ cases and very good agreement in IHC0or1+cases. Agreement was lower when scoring2+cases,nonetheless the overall sensitivity and specificity of HER2IHC were 99%and100%,respectively,when measured against expert review and consensus score.61HER2IMMUNOHISTOCHEMISTRY PITFALLS ANDSPECIAL SITUATIONSCytoplasmic background staining can be observed in normal or metaplastic mucosa and this is particularly common with the4B5antibody(Fig.1E).48This is usually not a problem as tumor cells can be readily distinguished from non-neoplastic epithelial cells under the microscope.A more common pitfall in IHC scoring is cytoplasmic and/TABLE1.Immunohistochemical Criteria for Scoring HER2Expression in Gastric and Gastroesophageal AdenocarcinomasScore Criteria for Gastric/GEJCancer(Biopsy)Criteria for Gastric/GEJCancer(ResectionSpecimen)Criteria for Breast Cancer Interpretation0No staining or no membranousstaining in any tumor cell No staining or membranousstaining in<10%oftumor cellsNo staining or incompletemembranous staining that isfaint/barely perceptible and inr10%of invasive tumor cellsNegative1+Tumor cell cluster with faint orbarely perceptible(visible onlyatÂ400magnification)staining irrespective ofpercentage of tumor cellsstained Faint or barely perceptiblemembranous staining inZ10%of tumor cells;tumor cells are reactive inonly part of theirmembraneIncomplete membranous stainingthat is faint/barely perceptibleand within>10%of tumor cellsNegative2+Tumor cell cluster with weak tomoderate(visible atÂ100toÂ200magnification)complete,basolateral,or lateralmembranous stainingirrespective of percentage oftumor cells stained Weak to moderate complete,basolateral,or lateralmembranous staining inZ10%of tumor cellsCircumferential membranousstaining that is incomplete and/or weak/moderate and within>10%of tumor cells;or strongand circumferentialmembranous staining withinr10%of tumor cellsEquivocal3+Tumor cell cluster with strong(visible atÂ25toÂ50)complete,basolateral,or lateralmembranous stainingirrespective of percentage oftumor cells stained Strong complete,basolateral,or lateralmembranous staining inZ10%of tumor cellsCircumferential membranousstaining that is complete,intense,and within>10%oftumor cellsPositiveGEJ indicates gastroesophageal junction.Vakiani Adv Anat Pathol Volume22,Number3,May2015 198| Copyright r2015Wolters Kluwer Health,Inc.All rights reserved.or nuclear staining in tumor cells(Fig.1F).This should not be misinterpreted as a positive result as only membranous staining should be scored.Tumor cells showing cytoplasmic and/or nuclear staining have not been found to show amplification by ISH,46,48nonetheless there might be cases where there is concern that cytoplasmic staining might obscure some membranous staining.In these cases,it would be prudent to subject the tumor to analysis by ISH.Assessment of HER2overexpression should be per-formed on invasive carcinoma.In some cases,however, particularly biopsies,there might be difficulty in dis-tinguishing morphologically between high-grade dysplasia and invasive carcinoma.HER2appears to be overexpressed in dysplastic lesions,but there are little data on the con-cordance between HER2status in dysplastic lesions and their corresponding invasive adenocarcinomas.16,56,62–64In a study by Lee et al,16there was no clear association between the HER2status of dysplastic and invasive components.The authors of that study encountered both cases where HER2 expression was seen in dysplasia but not in the invasive car-cinoma as well as cases where the dysplastic component was HER2negative,but the invasive component showed over-expression.In a more recent study,concordance between high-grade dysplasia and invasive carcinoma was seen only in 4/9(44%)cases.56Thesefindings raise the issue of false-positive results in biopsies due to HER2-positive dysplastic epithelium being misinterpreted as invasive carcinoma.Differentiating between weak2+and1+staining by IHC can also be challenging,especially in resection specimens where there might be a range of staining inten-sities.This can be an important distinction as a score of 1+is not sent for ISH testing in many institutions.If there is uncertainty,it is recommended that the case be scored as 1to2+and material sent for ISH analysis to prevent a false-negative result.As already mentioned,some cases show strong HER2 staining in<10%of tumor cells.On the basis of the criteria outlined in Table1,these cases would be scored as IHC negative.Nonetheless,an expert panel recommended that such cases should be subjected to ISH.44If such a sample shows amplification by ISH the tumor may be considered to be HER2positive similar to scoring biopsy samples.It should be noted that the response of such tumors to tras-tuzumab is not clear,although preliminary analysis from the ToGA trials seems to suggest that they might derive some benefit.36IN SITU HYBRIDIZATIONAmplification of the HER2gene is evaluated by ISH. Many institutions restrict this analysis for IHC equivocal (2+)cases,although as mentioned above some test all cases of gastric/GEJ adenocarcinoma.In general,ISH tends to be more reproducible but is more labor intensive and more expensive compared with IHC and may not be available in all laboratories.ISH can be performed by dark-field methods such as FISH or by bright-field techniques such as chromo-genic ISH(CISH)and silver ISH(SISH).Dual probes are often used one against the centromere of chromosome17 (CEP17)and one against HER2,although single-probe tests using only a probe against HER2are also available.The ISH method used in the ToGA trial and in many laboratories is dual-color FISH.Fluorescent-labeled DNA probes against the CEP17and against HER2are used and an average amplification ratio is calculated after measuring at least20nonoverlapping cells.The test is scored as pos-itive when the HER2/CEP17ratio is Z2.Unlike breast cancer,in gastric cancer there is no equivocal category for the FISH test.Nonetheless,for cases showing borderline amplification(ratio of1.8to2.2)it is recommended that20 to40additional cells be counted in a different area.44,65 Polysomy defined as Z3copies of the whole chro-mosome17can be a complicating factor when scoring ISH. It is not,however,considered to be common in gastric/GEJ cancer having been observed in only4%of cases in the screening population of the ToGA trial.36Although only a few studies have looked into the use of the HER2copy number,37,66an expert panel has recommended that>6 HER2gene copies should be considered a positive result. They suggested that copy number is an important consid-eration especially in cases showing borderline amplification. In a single-probe assay if there are4to6HER2gene copies then the use of a dual probe is recommended.Interestingly, a recent study correlating the level of HER2amplification and response to trastuzumab identified a HER2/CEP17 ratio of4.7as the optimal cutoffvalue discriminating sen-sitive and refractory patients.67Over the last few years,there is growing support for the use of bright-field ISH methods for the detection of HER2amplification.Such methods have several advan-tages over FISH,including use of a regular microscope instead of a dark-fieldfluorescence microscope,better sig-nal preservation over time,and better evaluation of mor-phology.Bright-field techniques may be particularly useful in the evaluation of gastric/GEJ tumors because of heter-ogeneity as they allow for alignment of IHC slides with the ISH slides.In this way it is easier to score by ISH specific areas showing focal HER2overexpression.CISH uses an IHC-like peroxidase reaction to detect DNA probes instead offluorescence.Several studies have reported very good concordance between FISH and CISH.27,50,55,68For example,Kiyose et al68used single-color CISH to study198gastric tumors and reported a con-cordance of99%between FISH and CISH.Two discordant cases were observed one of which showed polysomy.In another study,Yan et al50used a dual-color CISH assay in 199samples of gastric cancer and found a100%concordance with FISH results.A high level of agreement has also been reported between FISH and SISH,which is another bright-field ISH method that is based upon the deposition of silver at the target site after an enzymatic reaction.46,48,69In a study of166gastric cancer samples,96.4%of cases showed agreement between FISH and dual-color SISH.Six dis-cordant cases were SISH positive and FISH negative and all showed polysomy.69It is worth noting that the clinical sig-nificance of polysomy in gastric cancer is not known and in breast cancer polysomy has been reported in FISH-negative cases that responded to trastuzumab.70CONCLUSIONSHER2testing is now recommended for all patients with advanced gastric/GEJ adenocarcinoma to identify HER2-positive tumors that can be treated with trastuzumab.Many guidelines recommend that assessment of HER2status be performed usingfirst IHC,with ISH analysis being reserved for IHC equivocal cases.HER2expression in gastric/GEJ adenocarcinomas shows some differences compared with what is observed in breast adenocarcinomas,most notably baso-lateral or lateral membranous positivity and increasedAdv Anat Pathol Volume22,Number3,May2015HER2and Gastric Cancer Copyright r2015Wolters Kluwer Health,Inc.All rights |199。
食管胃交界处腺癌的临床研究进展
食管胃交界处腺癌的临床研究进展王龙;张雪(综述);刘巍(审校)【摘要】食管胃交界处腺癌（adenocarcinoma of esophagogastric junction，EGJA）有其独特的解剖学位置，同时又位于鳞状上皮与柱状上皮交界之处，其生物学特性不同于食管癌和胃癌，诊断分型一直存在众多的争议，治疗模式在学术界也始终没有公认的“金标准”，特别是局部进展期EGJA的治疗策略更是难以抉择。
随着影像学技术的发展和各项大型临床研究结果的公布，EGJA的治疗日益个体化，同时也凸显了多学科协作的重要性。
本文将针对以上问题对EGJA的最近进展做一综述。
%The adenocarcinoma of the esophagogastric junction (EGJA) is located in a unique anatomical position and at the junction of the squamous epithelium and the columnar epithelium. The biological characteristics of this disease are different from those of esophageal or gastric cancer. The diagnostic classification of EGJA has been subject to controversies, and no gold standard therapeu-tic regimens have been established, especially in the choice of treatment of locally advanced EGJA. Results from large-scale clinical tri-als and imaging technology development showed that the treatment of EGJA has been individualized. Furthermore, this problem high-lights the importance of multidisciplinary collaboration. This article focuses on current progress in studies on EGJA.【期刊名称】《中国肿瘤临床》【年(卷),期】2015(000)002【总页数】5页(P120-124)【关键词】胃食管交界处腺癌;治疗;诊断;进展【作者】王龙;张雪(综述);刘巍(审校)【作者单位】河北医科大学第四医院肿瘤内科石家庄市050011;河北医科大学第四医院肿瘤内科石家庄市050011;河北医科大学第四医院肿瘤内科石家庄市050011【正文语种】中文食管胃恶性肿瘤是一种颇具挑战性的疾病，特别是食管胃交界部腺癌（adenocarcinoma of esophagogastric junction，EGJA）近些年来发病率增长迅速，但是对于其诊断分型和治疗策略选择上的规范化还远远做不到，在具体的临床诊治层面，同一国家、地区，甚至同一家医院内部也有很大不同。
胃肠癌her2活检判读标准
胃肠癌her2活检判读标准英文回答：HER2 testing is an important aspect in the diagnosisand treatment of gastrointestinal cancer. The HER2 gene is known to be overexpressed in certain types of cancer, including gastric and colorectal cancer. HER2overexpression is associated with a more aggressive tumor behavior and poorer prognosis. Therefore, accurate HER2 testing is crucial in determining the most appropriate treatment options for patients.There are several methods available for HER2 testing in gastrointestinal cancer, including immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC is commonly used as a screening tool to assess HER2 protein expression, while FISH is used to detect gene amplification.The interpretation of HER2 testing results follows specific criteria. In IHC, the HER2 protein expression isevaluated on a scale of 0 to 3+. A score of 0 or 1+ indicates negative HER2 expression, while a score of 3+ indicates positive HER2 expression. A score of 2+ is considered equivocal and requires further testing using FISH.In FISH testing, gene amplification is assessed by comparing the ratio of HER2 gene copies to chromosome 17 copies. A HER2/CEP17 ratio of less than 2.0 is considered negative for gene amplification, while a ratio of 2.0 or greater is considered positive.It is important to note that HER2 testing should be performed on tumor tissue samples that are of good quality and sufficient quantity. Inadequate samples may lead to false-negative results. Additionally, it is recommended to have the HER2 testing performed in a certified laboratory with experienced pathologists who are familiar with the interpretation criteria.In conclusion, HER2 testing in gastrointestinal cancer plays a crucial role in determining the appropriatetreatment options for patients. The interpretation of HER2 testing results follows specific criteria, including IHCand FISH. Accurate and reliable HER2 testing is essentialfor providing personalized and targeted therapies for patients with gastrointestinal cancer.中文回答：胃肠癌中HER2活检是诊断和治疗的重要方面。
胃肠癌her2活检判读标准
胃肠癌her2活检判读标准英文回答：Her2 testing in gastric cancer is crucial for determining the appropriate treatment options for patients. The standard method for Her2 testing in gastric cancer is immunohistochemistry (IHC) combined with fluorescence in situ hybridization (FISH). These tests help determine the expression level and amplification status of the Her2 protein in tumor cells.The interpretation of Her2 testing in gastric cancer follows the guidelines established by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). The Her2 scoring system used in gastric cancer is based on the same criteria as breast cancer, but with some modifications.In gastric cancer, an IHC score of 0 or 1+ is considered negative for Her2 overexpression, while a scoreof 3+ is considered positive. A score of 2+ is considered equivocal and requires further testing with FISH to determine Her2 amplification status.If the FISH test shows a Her2/CEP17 ratio of 2.0 or higher, it is considered positive for Her2 amplification. A ratio below 2.0 is considered negative. The FISH test is crucial in cases where IHC score is 2+, as it helps confirm the presence of Her2 amplification.It is important to note that Her2 testing in gastric cancer can be challenging due to tumor heterogeneity. This means that different areas of the tumor may have different Her2 expression levels or amplification status. In such cases, it is recommended to sample multiple areas of the tumor to get a more accurate assessment of Her2 status.In addition to the IHC and FISH tests, other molecular methods such as next-generation sequencing (NGS) can also be used to assess Her2 status in gastric cancer. NGS allows for a more comprehensive analysis of multiple genes and can provide additional information about potential targetedtherapies.Overall, the interpretation of Her2 testing in gastric cancer follows the same principles as breast cancer, butwith some modifications. It is important to consider boththe IHC score and FISH results to determine the Her2 status accurately.中文回答：胃肠癌中的Her2检测对于确定患者的适当治疗方案至关重要。
胃癌HER2判读及评分
584
11.1对比13.8
0.74 0.60, 0.91
61 70 159 256 15
7.2 对比 10.6 对比 8.7 10.2 10.8 对比 12.3 12.3 对比 17.9 17.7 对比 17.5
0.92 1.24 0.75 0.58 0.83
0.48, 1.76 0.70, 2.20 0.51, 1.11 0.41, 0.81 0.20, 3.38
N=560 可估值 IHC 0 和 IHC 1+ 亚群主要由低水平
100
IHC 3+ 亚群主要由高水平 扩增病例组成
扩增病例组成
90
80 70 60 50 40
患者 (%)
30
20
10 0
0–<2 2–4 >4 0–<2 2–4 >4 0–<2 2–4 >4 0–<2 2–4 >4
IHC 0
FISH 比： 0–<2 = 无扩增；2–4 = 低水平扩增；>4 = 高水平扩增
• 采用 IHC 和 FISH 进行评估 • 将检测为 IHC 3+ 或 FISH+ 的患者进行随机分组
Van Cutsem E, et al. J Clin Oncol 2009;27:Abstract 4509. Bang YJ, et al. J Clin Oncol 2009;27:Abstract 4556.
图片摘自 Rüschoff J 等人 2010 年的资料，获得 Springer 允许。
胃癌IHC染色范例：手术标本
IHC 3+ 染色范例
图片由 F. Hoffmann-La Roche Ltd. 提供
Her—2在胃癌组织中的表达及其意义
Her—2在胃癌组织中的表达及其意义目的探讨Her-2蛋白在胃腺癌组织中的表达及其与胃腺癌各临床病理参数之间的相关性。
方法应用免疫组化法检测88例胃腺癌组织中Her-2表达状态，并采用χ2检验进行数据分析。
结果胃腺癌组织中Her-2蛋白阳性表达率为43.18% （38/88），Her-2蛋白表达与胃腺癌患者的性别、年龄、肿瘤部位、浸润深度无相关性（P>0.05），而与肿瘤分化程度及区域淋巴结转移有相关性（P ＜0.05）。
结论Her-2可以作为评估胃癌发展及预后的指标，并为曲妥珠单抗在Her-2过表达的胃腺癌中的临床应用提供理论依据。
标签：Her-2；胃癌；免疫组化；曲妥珠单抗胃癌占恶性肿瘤死亡率第2位，严重威胁人类健康。
手术治疗是已知的可完全治愈的疗法，但仍有多数患者在病灶完全切除后出现复发，即使再联合放化疗，5年生存率仍低至20%～30%。
更不幸的是，有约65%的胃癌患者在发现时就已达到中晚期[1]，预后差。
近年来，随着肿瘤分子生物学的发展，开展胃癌的靶向治疗已势在必行，人类表皮生长因子受体2（human epidermal growth factor receptor-2，Her-2）正是近来的研究热点之一。
本文通过免疫组化法检测88例胃腺癌组织中的Her-2蛋白表达，探讨其与患者各临床参数间的相关性，为胃癌的发展、预后及治疗提供理论依据。
1 资料与方法1.1一般资料病例材料收集2013年1月～2014年2月重庆医科大学附属第一医院胃癌手术病例88例，男性61例，女性27例，比例约为2.26：1，年龄28～86岁，中位年龄60.5岁，其中60岁以下41例，60岁及以上47例。
因纳入研究的病例数不大，将病例中肿瘤分化程度分为低分化（42例）、中高分化（46例）两组。
将肿瘤浸润深度分为浸润深度未及浆膜层组（31例）、浸润深度至浆膜及以外组（57例）。
有淋巴结转移53例，无淋巴结转移35例。
HER-2在胃腺癌中的表达及临床病理意义
HER-2在胃腺癌中的表达及临床病理意义温达雄;王军;温惠娟;黄慧敏;黄秀凡【摘要】目的:探讨胃腺癌组织中HER-2的表达及HER-2与胃癌各个临床病理特征之间的关系.方法:回顾性分析接受免疫组化学法检测的239例胃癌患者的胃腺癌组织中关于HER-2表达的临床资料,并选择215例胃正常者HER-2表达的临床资料进行对比,对胃腺癌组织中HER-2的表达及HER-2与胃癌各个临床病理特征之间的关系进行探讨.结果:胃正常者胃组织中未见HER-2表达,胃癌组织中HER-2的阳性表达率为10.5％ (25/239),两者相比差异明显(P＜0.05);胃癌患者HER-2表达与年龄、性别、淋巴结转移、肿瘤大小、静脉侵犯、TNM分期均无明显关系(P＞0.05);而与肿瘤部位、分化程度、Lauren分型关系明显(P＜0.05),有统计学意义.结论:胃腺癌组织中HER-2的表达与肿瘤部位、分化程度、Lauren分型相关,HER-2的表达对胃腺癌的发生、转移及早期发现具有重要意义.【期刊名称】《赣南医学院学报》【年(卷),期】2015(035)002【总页数】3页(P252-254)【关键词】胃腺癌组织;HER-2;免疫组织化学【作者】温达雄;王军;温惠娟;黄慧敏;黄秀凡【作者单位】广东省河源市人民医院病理科,广东河源517000;广东省河源市人民医院病理科,广东河源517000;广东省河源市人民医院病理科,广东河源517000;广东省河源市人民医院病理科,广东河源517000;广东省河源市人民医院病理科,广东河源517000【正文语种】中文【中图分类】R735.2胃癌是一种恶性肿瘤，临床发病率较高，一般预后很差［1］。
发现确诊时一般为Ⅲ～Ⅳ期患者，且胃癌对放疗、化疗的敏感性较差［2］。
HER-2(表皮生长因子受体2)是一种癌基因，位于17q21上，与胃癌的发生及发展有着密切的关系，其有望成为胃癌预后不良的一个指标，也有望成为胃癌治疗的新靶点［3］。
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病理诊断没那么简单，以胃胃食管交界处腺癌的HER2检测为例导读：胃及胃-食管交界处腺癌的HER2表达情况，对患者来说具有极重要的预后及治疗意义。
不过，相关文献中胃/胃-食管交界处腺癌的HER2阳性率自4.4%至53.4%不等！如此大的差异，说明很可能在相关检测过程中存在着诸多因素影响了最终的结果。
针对胃/胃-食管交界处腺癌的HER2检测相关问题，世界知名研究型大学-西澳大学（The University of Western Australia）专家Kumarasinghe等人进行了专门总结。
他山之石可以攻玉，我们结合该文要点、及相关文献，将其中的重点内容编译介绍如下，并希望可以借此文让相关专业人员有更深入的了解。
1．简介HER2基因扩增、导致HER2蛋白过表达，已确定是包括胃癌在内多种肿瘤的预后不良因素。
靶向治疗方面的研究进展也已表明，HER2是胃/胃-食管交界处腺癌的重要治疗靶点；相关研究已证实在HER阳性胃腺癌中，抗HER2制剂曲妥珠单抗加入标准化疗方案后，相关缓解率、无进展生存时间中位数、总生存时间等方面均有显著获益。
目前，FDA已批准将该药用于HER2阳性进展期胃腺癌的系统治疗。
综合上述资料，可见准确判定胃/胃-食管交界处腺癌的HER2状态具有极重要的预后及治疗意义。
2．HER2靶向治疗的患者筛选“HER2”阳性的进展期、及转移性胃和胃-食管交界处腺癌患者适用于抗HER2靶向治疗；而是否阳性，则可通过免疫组化评估蛋白表达情况、或通过原位杂交评估HER2扩增来确定。
至于具体检测方案，有人更推崇免疫组化、有人更欣赏原位杂交，还有人建议二者联合应用。
就原位杂交来说，也无具体方法以及相关解读方面的绝对共识。
更有意思的是，目前关于“HER2阳性”也并无广泛共识。
表1. 不同的“HER2阳性”定义3．HER2检测准确性之样本选择HER2检测标本主要分三类，分别是内镜活检标本、手术切除标本、转移灶（可以是活检标本，也可以是细胞学标本如浆膜腔积液、淋巴结转移灶的细针穿刺活检标本）。
内镜活检标本：目前HER2状态的确定大部分均是在原发肿瘤内镜活检标本中进行。
内镜活检标本中存在几个问题：大部分胃癌患者为进展期，已不适合手术，因此内镜活检可能是唯一可获取诊断性组织的方法。
不过，有时内镜活检所取标本可能并不适于HER2检测，如标本过少。
最近有研究表明，胃或胃-食管交界处腺癌内镜活检所取肿瘤碎片5块，即可在HER2检测中取得最高的敏感性和特异性；更多活检块数无助于敏感性和特异性的提高。
需要注意的是，取材数量一致时，不同研究中敏感性和特异性的差异颇大，这可能是由于并非所有活检标本中均为肿瘤组织。
ASCO/CAP、NCCN、澳大利亚的相关指南中，对取材数量的要求为最低5块，6-8块较合适。
当然，多取材还有助于减小肿瘤异质性对检测的影响。
就肿瘤异质性来说，HER2阳性结果一般见于有腺体形成、肠型腺癌部分，因此肿瘤异质性明显的标本中应注意选择这样的区域供HER2检测。
活检标本进行HER2检测的另一优点在于这类标本一般固定及时，且相对胃切除标本来说，固定的效果更好；此外，较小的活检标本相比较大的切除标本来说，试剂和耗材的耗费更少，相应费用更低。
手术切除标本：手术切除标本用于HER2检测时，需考虑的相关因素更多；最主要的是肿瘤固定是否到位，这对HER2检测影响巨大。
标本切除后固定不及时、或固定时间过长，均会影响HER2检测结果，固定剂的种类也会影响相应检测结果。
转移灶：有两项报道称转移灶和原发灶之间HER2结果的一致性分别为95%、98%，因此ASCO/CAP指南中提出对原发灶或转移灶进行HER2检测都是可以的。
由于出现转移的患者有时无法进行手术，因此相关细胞学标本如腹腔积液、胸腔积液、淋巴结细针穿刺标本可能是唯一可确定HER2情况的标本。
因此ASCO/CAP指南中提出细针穿刺标本（细胞块）进行HER2检测也是可以接受的。
不过，这种情况下对细胞学标本进行HER2检测的经验、以及结果的准确判读，是极为重要的，因此本文作者提出细胞学标本检测HER2仅用于无法进行活检、细胞学为唯一可得标本的情况下。
当然，用于证实转移存在的手术标本是最适合HER2检测的，因为这种情况下标本处理过程和内镜活检标本是一致的。
如原发灶和转移灶均可获得，对二者均进行HER2检测更为明智。
4．HER2检测准确性之技术问题检测前及检测中的重要因素有组织固定、试验方法的选择、是否了解相关临床信息等。
如前所述，目前常规应用于HER2检测的是免疫组化及原位杂交，因此本文并不涉及二代测序等其他分子检测方法。
原位杂交检测相关技术及方法有多种。
就原位杂交检测来说，有人推荐明视野相关检测方案、尤其是银染色原位杂交，因为这类方法有诸多优点，如已证实这一检测的结果与免疫组化结果一致性更好，且检测所需时间相对暗视野的FISH要短，而FISH检测对信号判读者的经验要求较高，且要求有荧光显微镜。
本文作者也认为明视野下的银染色原位杂交更好一些；但目前的指南并未强烈推荐这一方法。
组织固定是HER2检测中最重要的影响因素之一，可以说一定程度上决定着检测的成败与否。
目前国际上倾向于在实际工作中尽量将这一步骤标准化。
标本活检、或切除后至置于福尔马林固定液的时间间隔（冷缺血时间）也可影响HER2结果。
对于活检标本来说，建议切除后尽可能快的将其固定，并避免标本干燥；标本的冷缺血时间应短于20分钟。
所用固定液应为10%的中性缓冲福尔马林，固定时间8-48小时，过短或过长的固定时间均会影响检测结果。
图2. 不同固定时间对标本中HER2检测结果的影响：该图中所有结果均可判为3+，但相应固定时间分别为8小时（左上）、48小时（右上）、72小时（左下）、96小时（右下）；固定96小时者，免疫组化着色强度显著减弱。
原位杂交检测所需切片厚度应为4微米，甚至切片温度也会影响检测结果。
理想状态下，应在检测前才进行切片。
长时间存储的组织块可以降低免疫组化中的阳性率，这种情况下的检测可能需特殊处理。
5．HER2检测准确性之结果判读免疫组化及原位杂交中HER2结果的判读都需这方面的专业人士进行。
理想状态下，消化专业病理医师应接受过HER2检测分析前、分析中、分析后相关问题培训，当然也应接受HER2结果判读及报告方面的培训。
具体判读中还应注意区分浸润性癌细胞和癌前病变、反应性上皮、间质细胞，由此引出的诊断问题则超出了本文讨论范围。
免疫组化中的HER2结果判读胃癌中HER2的评分相关标准是由Hoffman等人提出的。
胃和胃-食管交界处腺癌的HER2评判标准是不同于乳腺癌相关标准的，如前者一般并无完整的细胞膜着色（而常表现为基底侧着色），活检标本中仅需有5个细胞的着色即可认为是阳性；两个细胞相邻的侧方细胞膜线状着色、或基底侧细胞膜着色而形成U型着色，均是胃和胃-食管交界处腺癌中特征性的表现。
图3. 免疫组化中HER2结果的判读：左上，低倍镜下即可见明确的膜着色，判为3+；右上，3+病例中，特征性的细胞相邻处、侧方着色；左下，需中倍镜下才可见细胞膜着色，判为2+；右下：需高倍镜下才可见细胞膜着色，判为1+。
图4. 胃癌标本中HER2检测的异质性。
低倍镜下即可见有强阳性、弱至中等阳性、低倍镜下几乎无着色区域，仔细判读，不同区域分别可以判为3+、2+、1+。
原位杂交中的HER2结果判读HER2是由17号染色体上的相应基因ERBB2编码的，因此可通过评估HER2基因拷贝数和/或HER2基因拷贝数与17号染色体着丝粒（CEP17）的比例来证实有无HER2基因的扩增。
对于明视野的银染原位杂交来说，黑色的HER2信号相比红色的CEP17信号要小、且更为离散；细胞核内大量信号的重叠可能无法单一计数，此时将其定义为簇状信号。
具体判读时，一般小簇状信号可计数为6，而较大的簇状信号可计数为12或更多。
建议在40倍（物镜）下至少计数20个无重叠的恶性肿瘤细胞信号；如拷贝数、或相应比例位于交界值时，则再多计数20个恶性肿瘤细胞信号。
荧光原位杂交中则应通过适当的滤镜计数至少40个肿瘤细胞的信号。
所有原位杂交检测方法中的评判阈值均相同。
ASCO/CAP指南中将阳性定义为HER2与CEP17的比值≥2，该比值＜2则视为阴性；不过对于比值＜2的病例，同时建议将HER2拷贝的绝对数作为评判标准，因为可能会存在17号染色体多体的情况。
对于免疫组化结果和原位杂交结果相关性不佳者，应重复检测并重新计数，也可由第二位专家进行评估。
原位杂交相关结果的解读、及原位杂交结果与免疫组化结果的相关性，详见下表。
6．HER2检测准确性之结果的报告曲妥珠单抗是一种单克隆抗体，针对的是过表达的蛋白产物，因此由该领域专家、使用经过验证的检测方法得出的免疫组化3+结果，即可视为HER2阳性。
不过，如前所述，很多客观因素会影响免疫组化检测的准确性，因此可通过原位杂交的方式来进一步证实有相关基因的扩增。
理想状态下，应该是对所有病例均同时进行免疫组化和原位杂交检测；但出于费用的考虑，目前大部分指南均仅建议对免疫组化2+的病例进行原位杂交检测，而结果可靠的0或1+者无需原位杂交证实；当然，也有人提出应用昂贵药物之前，免疫组化3+的病例最好也经原位杂交证实。
免疫组化及原位杂交结果均应在有阴性对照和阳性对照的情况下进行判读。
内部验证、外部验证、质控方案等均应强制实施，以确保HER2检测高标准的进行。
考虑到种族差异、不同组织学类型胃/胃-食管交界处腺癌发生率的差异，还应有全国性研究来确定本地区HER2阳性率的范围。
已证实集中检测才可以有最准确和最可靠的结果，因此胃/胃-食管交界处腺癌HER2的检测应在专业化实验室进行、由专业人员对结果进行准确判读。
这类检测中心每年应有一定的检测数量，这样才能保证其检测质量；同时还应有质控及对照方案。
应有强制性方案来保证HER2检测的质量，具体如相关检测中心所采用的检测方案需经验证，相关资质的连续评定，相关人员的培训等。
还应有相关质量改进方案，以确保整个检测过程及结果报告方面的一致性。
鉴于肿瘤异质性等因素，建议相关实验室应对自己的HER2阳性数据进行追踪，并对病理医师进行这方面的继续教育培训。
由于胃/胃-食管交界处腺癌患者大部分为进展期，因此HER2检测所需时间应尽量快，从最初确诊、至HER2结果报告的时间间隔不超过5个工作日为宜。
病理报告也应标准化，如注明标本是否充分、所用检测方法（所用抗体及探针信息）、明确指出HER2的检测结论、必要的备注等。
7．小结免疫组化检测没那么简单，HER2检测这一决定着患者是否适合曲妥珠单抗治疗的重要指标更是十分复杂。
由该文可知，HER2检测结果的准确与否，并非仅仅是病理科或病理医师的事情。