Wynes Murry W, Sholl Lynette M, Dietel Manfred, Schuuring Ed, Tsao Ming S, Yatabe Yasushi, Tubbs Raymond R, Hirsch Fred R
*Department of Medicine, Division of Medical Oncology, University of Colorado, Aurora, Colorado; †Department of Pathology Brigham and Women's Hospital, Boston, Massachusetts; ‡Institute of Pathology, Charité University Hospital Berlin, Germany; §Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, The Netherlands; ‖Princess Margaret Hospital, University Health Network, University of Toronto, Ontario, Canada; ¶Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Kanokoden, Chikusa-ku, Nagoya, Japan; #Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio; ** Department of Pathology, University of Colorado, Aurora, Colorado; and ††University of Colorado Comprehensive Cancer Center, Aurora, Colorado.
J Thorac Oncol. 2014 May;9(5):631-8. doi: 10.1097/JTO.0000000000000115.
The goal of personalized medicine is to treat patients with a therapy predicted to be efficacious based on the molecular characteristics of the tumor, thereby sparing the patient futile or toxic therapy. Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK-positive non-small-cell lung cancer (NSCLC) tumors, but to date the only approved companion diagnostic is a break-apart fluorescence in situ hybridization (FISH) assay. Immunohistochemistry (IHC) is a clinically applicable cost-effective test that is sensitive and specific for ALK protein expression. The purpose of this study was to assemble an international team of expert pathologists to evaluate a new automated standardized ALK IHC assay.
Archival NSCLC tumor specimens (n =103) previously tested for ALK rearrangement by FISH were provided by the international collaborators. These specimens were stained by IHC with the anti-ALK (D5F3) primary antibody combined with OptiView DAB IHC detection and OptiView amplification (Ventana Medical Systems, Inc., Tucson, AZ). Specimens were scored binarily as positive if strong granular cytoplasmic brown staining was present in tumor cells. IHC results were compared with the FISH results and interevaluator comparisons made.
Overall for the 100 evaluable cases the ALK IHC assay was highly sensitive (90%), specific (95%), and accurate relative (93%) to the ALK FISH results. Similar results were observed using a majority score. IHC negativity was scored by seven of seven and six of seven evaluators on three and two FISH-positive cases, respectively. IHC positivity was scored on two FISH-negative cases by seven of seven readers. There was agreement among seven of seven and six of seven readers on 88% and 96% of the cases before review, respectively, and after review there was agreement among seven of seven and six of seven on 95% and 97% of the cases, respectively.
On the basis of expert evaluation the ALK IHC test is sensitive, specific, and accurate, and a majority score of multiple readers does not improve these results over an individual reader's score. Excellent inter-reader agreement was observed. These data support the algorithmic use of ALK IHC in the evaluation of NSCLC.
精准医疗的目标是根据肿瘤的分子特征，采用预计有效的疗法治疗患者，从而避免患者接受无效或有毒的治疗。间变性淋巴瘤激酶（ALK）抑制剂对ALK阳性非小细胞肺癌（NSCLC）肿瘤有效，但迄今为止唯一获批的伴随诊断方法是一种分离式荧光原位杂交（FISH）检测。免疫组织化学（IHC）是一种临床适用、性价比高的检测方法，对ALK蛋白表达敏感且特异。本研究的目的是组建一个国际专家病理学家团队，评估一种新的自动化标准化ALK IHC检测方法。
国际合作者提供了之前通过FISH检测ALK重排的存档NSCLC肿瘤标本（n = 103）。这些标本用抗ALK（D5F3）一抗进行IHC染色，结合OptiView DAB IHC检测和OptiView扩增（Ventana Medical Systems, Inc., Tucson, AZ）。如果肿瘤细胞中存在强颗粒状细胞质棕色染色，则标本二元评分为阳性。将IHC结果与FISH结果进行比较，并进行评估者间比较。
总体而言，对于100例可评估病例，ALK IHC检测对ALK FISH结果具有高度敏感性（90%）、特异性（95%）和相对准确性（93%）。使用多数评分观察到类似结果。在3例和2例FISH阳性病例中，分别有7名评估者中的7名和7名中的6名将IHC阴性评分。在2例FISH阴性病例中，7名读者中有7名对IHC阳性进行了评分。在审查前，7名读者中的7名和7名中的6名分别对88%和96%的病例达成一致，审查后，7名读者中的7名和7名中的6名分别对95%和97%的病例达成一致。
基于专家评估结果，ALK IHC检测敏感、特异且准确，与单个读者评分相比，多个读者的多数评分并未改善这些结果。观察到评估者间的高度一致性。这些数据支持在NSCLC评估中采用ALK IHC的算法应用。
