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人表皮生长因子受体2 (human epidermal growth factor receptor 2,HER2) 在尿路上皮癌的发生发展中起重要作用,HER2 高表达与尿路上皮癌预后差 有关-2]。抗HER2 抗体-偶联类药物在HER2 过表达尿路上皮癌治疗中表现出显著的临床疗效。因此,筛选出抗HER2 抗体-偶联类药物治疗潜在获益人群具有重要意义。目前,国内专家共识推荐对局部晚期、转移性尿路上皮癌及肌层浸润性尿路上皮癌患者进行HER2 蛋白表达检测。已有多项针对HER2在尿路上皮癌中表达的研究,然而其研究对象多为肌层浸润性膀胱癌,对不同类型组织学变异的HER2表达水平研究较少。此外,研究报道的尿路上皮癌中HER2 表达水平差异较大同。本研究回顾性分析836例尿路上皮癌HER2表达水平,探讨HER2与肿瘤T分期、肿瘤分级、组织学变异等临床病理特征之间的关系。
1 资料与方法
1.1 一般资料
1.2 研究方法
1.3 观察指标
1.4 统计学处理
2 结果
2.1 患者临床特征
2.2 HER2 在尿路上皮癌组织中的表达情况
2.3 HER2在尿路上皮癌伴组织学变异中的表达情况
3 讨论
尿路上皮癌是常见的泌尿系统恶性肿瘤,包括起源于肾盂或输尿管的UTUC、膀胱癌及尿道癌,超90%的尿路上皮癌为膀胱尿路上皮癌。文献所报道的尿路上皮癌中HER2表达水平存在较大差异。本研究回顾性分析尿路上皮癌中HER2表达情况,采用logistic回顾分析HER2阳性危险因素,结果显示膀胱癌、肿瘤高级别、伴有原位癌、CK20异常是尿路上皮癌HER2阳性的独立危险因素。既往研究显示,尿路上皮癌中HER2阳性的发生率为9.2%~61.1%-13。文献报道的HER2表达水平的差异可能与判读标准差异、检测流程差异及人种差异等因素有关。本研究参照专家共识进行判读,HER2阳性占31%,与BELLMUNT等报道一致,低于ZHOU等同报道的44%,可能与后者将HER22+/3+定义为阳性有关。GAN等认为原位癌是HER2阳性的独立危险因素。WAGNER等5报道原位癌患者中HER2阳性率55%。本研究结果与文献报道一致,乳头状肿瘤伴原位癌者HER2阳性率显著高于纯乳头状尿路上皮癌(52.4%vs.26.6%)。鉴于原位癌中HER2高表达,GUNIA等提出HER2蛋白可作为膀胱原位癌与反应性不典型性增生等组织学鉴别诊断的潜在标志物。肿瘤T分期与尿路上皮癌HER2表达水平的关系尚不明确。SORIA等7发现UTUC中HER2阳性与更高的T分期有关。LATTANZI等8认为肌层浸润性膀胱癌具有更高的HER2扩增水平。然而,CHAE等1发现T1、T2期膀胱癌HER2阳性率高于Ta期肿瘤,但T1与T2期肿瘤之间HER2阳性率无显著差异。张孟尼等0对166例尿路上皮癌根治性标本HER2表达水平进行分析,发现Ta、T1、T2、T3和T4之间HER2阳性率差异无统计学意义。本研究发现肿瘤T分期与HER2表达水平之间无显著相关性,这可能与膀胱癌及UTUC中HER2表达水平存在显著差异有关517。ZHOU等研究发现,在UTUC中,HER2阳性率为38%低于膀胱癌中的51%。SORIA等7的研究显示,在UTUC中,HER2阳性占其35.8%,与张孟尼等0的结果一致,但相较于本研究中15.2%的HER2阳性率较高。原因之一为HER2阳性的定义标准存在差异;HER2免疫组化染色2+但荧光原位杂交(fluorescence in situ hybridzation,FISH)阴性的患者不属于严格意义上的HER2过表达2。因此,上述研究中HER22+/3+均定义为阳性造成了HER2阳性率偏高。鉴于FISH检测对于明确HER2基因扩增情况及临床治疗指导意义,建议对HER2免疫组化为2+的患者行进一步的FISH检测4。一些诸如微乳头样变、巢状变异、肉瘤样癌等特殊类型的尿路上皮癌伴组织学变异患者预后显著较差,使用可靠的标志物可能对这类患者的分层管理具有重要意义2-24。研究显示,尿路上皮癌中HER2表达水平与组织学变异有关。BEHZATOGLU等报道HER2在微乳头样变中高表达(56%),阳性率高于纯尿路上皮癌的36%;在伴鳞状分化组织学变异中20%阳性、巢状变异中16%阳性,而在肉瘤样癌、伴腺样分化组织学变异中无HER2阳性。张孟尼等2发现微乳头样变患者HER2阳性率最高,达93%;其余依次为伴腺样分化(79%)、伴鳞状分化(17%)与纯尿路上皮癌HER2表达水平差异有统计学意义。本研究结果表明,尿路上皮癌伴有组织学变异的患者整体HER2表达水平与纯尿路上皮癌中一致。然而,不同类型的组织学变异在HER2表达水平方面差异有统计学意义。微乳头样变中HER2阳性率最高,肉瘤样癌患者无HER2阳性,结果与文献报道一致620.25-261因此,肉瘤样癌患者似乎无法从抗HER2抗体-偶联类药物中获益。浆细胞样变HER2表达水平尚未明确。MOKTEFI等7认为浆细胞样变HER2表达水平较低。然而,KOSSAI等2报道浆细胞样变中HER2阳性率显著高于纯尿路上皮癌。本研究观察到的浆细胞样变HER2阳性率高达60%(3/5),然而,由于样本量较少,这一结果可能受到限制。CK20表达水平与尿路上皮癌预后关系密切,29-30。BERTZ等”研究发现,CK20异常与肿瘤复发和疾病特异性死亡相关。HAGHAYEGHI等3研究发现,CK20、HER2及GATA结合蛋白3在管腔样细胞型中高表达,在基底样细胞型中表达量较低,可作为管腔样细胞型的标志物。因此,CK20与HER2可能是构成尿路上皮癌风险分层的潜在预后标志物。本研究存在局限性。首先,由于这是一项回顾性研究,可能存在一定的偏倚。其次,本研究未包括尿路上皮癌转移病灶及低度恶性潜能乳头状尿路上皮肿瘤,这可能限制了对尿路上皮癌HER2表达的全面展示。此外,本研究从蛋白水平评估HER2表达,对于HER2免疫组化为2+的病例未行进一步FISH检测,这可能在一定程度上影响了对HER2表达的准确性评估。综上所述,本研究呈现了尿路上皮癌HER2表达谱,研究显示HER2表达与肿瘤级别、肿瘤部位、CK20表达、伴有原位癌等多个因素密切相关,然而,与肿瘤T分期和淋巴血管侵犯并未观察到明显的相关性。不同类型的组织学变异在HER2表达方面差异有统计学意义。
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