Assistance Publique-Hôpitaux de Paris (APHP), Pathology Department, Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, F-94010, France.
Département Hospitalo-Universitaire (DHU), Virus-Immunité-Cancer (VIC), Université Paris-Est-Créteil, (UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Equipe 7 Translational Research of Genito-Urinary Oncogenesis, INSERM U 955, Créteil, F-94010, France.
Mod Pathol. 2018 Aug;31(8):1270-1281. doi: 10.1038/s41379-018-0023-9. Epub 2018 Feb 21.
Although human epidermal growth factor receptor 2 (HER2) may represent a therapeutic target, its evaluation in urothelial carcinoma of the bladder does not rely on a standardized scoring system by immunohistochemistry or fluorescent in situ hybridization (FISH), as reflected by various methodology in the literature and clinical trials. Our aim was to improve and standardize HER2 amplification detection in bladder cancer. We assessed immunohistochemical criteria derived from 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAPs) guidelines for breast cancer and investigated intratumoral heterogeneity in a retrospective multicentric cohort of 188 patients with locally advanced urothelial carcinoma of the bladder. Immunohistochemistry was performed on 178 primary tumors and 126 lymph node metastases, eligible cases (moderate/strong, complete/incomplete membrane staining) were assessed by FISH. HER2 overexpression was more frequent with 2013 ASCO/CAP than 2007 ASCO/CAP guidelines (p < 0.0001). The rate of positive HER2 FISH was similar between primary tumor and lymph node metastases (8%). Among positive FISH cases, 48% were associated with moderate/strong incomplete membrane staining that were not scored eligible for FISH by 2007 ASCO/CAP criteria. Among 3+ immunohistochemistry score cases, 67% were associated with HER2-positive FISH. Concordance between primary tumors and matched lymph node metastases was moderate for immunohistochemistry (κ = 0.54 (CI 95%, 0.41-0.67)) and FISH (κ = 0.50 (CI 95%, 0.20-0.79)). HER2-positive FISH was more frequent in micropapillary carcinomas (12%) and carcinoma with squamous differentiation (11%) than in pure conventional carcinoma (6%). Intratumoral heterogeneity for HER2 immunohistochemistry was observed in 7% primary tumor and 6% lymph node metastases; 24% positive HER2 FISH presented intratumoral heterogeneity. Our study suggests that HER2 evaluation should include an immunohistochemistry screening step with eligibility for FISH including incomplete/complete and moderate/strong membrane staining. Spatial or temporal intratumoral heterogeneity prompts to perform evaluation on both tumor and lymph node, and for each histological variant observed.
尽管人类表皮生长因子受体 2（HER2）可能代表一个治疗靶点，但在膀胱癌中的评估并不依赖于免疫组织化学或荧光原位杂交（FISH）的标准化评分系统，这反映了文献和临床试验中各种方法的差异。我们的目的是改进和标准化膀胱癌中 HER2 扩增的检测。我们评估了源自 2013 年美国临床肿瘤学会（ASCO）/美国病理学家协会（CAPs）乳腺癌指南的免疫组织化学标准，并在 188 例局部晚期膀胱癌患者的回顾性多中心队列中研究了肿瘤内异质性。对 178 例原发性肿瘤和 126 例淋巴结转移进行了免疫组织化学检查，合格病例（中度/强，完整/不完整膜染色）通过 FISH 进行评估。与 2007 年 ASCO/CAP 指南相比，2013 年 ASCO/CAP 指南中 HER2 过表达更为常见（p<0.0001）。原发性肿瘤和淋巴结转移之间的阳性 HER2 FISH 率相似（8%）。在阳性 FISH 病例中，48%与中度/强不完整膜染色相关，根据 2007 年 ASCO/CAP 标准，这些病例未被评分合格进行 FISH。在 3+免疫组织化学评分病例中，67%与 HER2 阳性 FISH 相关。原发性肿瘤和匹配的淋巴结转移之间的免疫组织化学一致性为中度（κ=0.54（95%CI，0.41-0.67））和 FISH（κ=0.50（95%CI，0.20-0.79））。微乳头状癌（12%）和具有鳞状分化的癌（11%）中 HER2 阳性 FISH 的发生率高于纯常规癌（6%）。在 7%的原发性肿瘤和 6%的淋巴结转移中观察到 HER2 免疫组织化学的肿瘤内异质性；24%的阳性 HER2 FISH 表现出肿瘤内异质性。我们的研究表明，HER2 评估应包括免疫组织化学筛选步骤，包括不完整/完整和中度/强膜染色的 FISH 资格。空间或时间上的肿瘤内异质性提示对肿瘤和淋巴结进行评估，并对观察到的每种组织学变体进行评估。
