Nakamura Sayuri, Hayashi Kentaro, Imaoka Yuki, Kitamura Yuka, Akazawa Yuko, Tabata Kazuhiro, Groen Ruben, Tsuchiya Tomoshi, Yamasaki Naoya, Nagayasu Takeshi, Fukuoka Junya
Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
PLoS One. 2017 Oct 19;12(10):e0186192. doi: 10.1371/journal.pone.0186192. eCollection 2017.
Programmed cell death ligand-1 (PD-L1) expression may predict the response to both programmed cell death-1 and PD-L1 inhibitors in lung cancer. However, the extent of intratumoral heterogeneity of PD-L1 expression, which may cause false negative results, is largely unexplored. We aimed to assess the intratumoral heterogeneity of PD-L1 expression in surgically resected lung cancer specimens by applying a novel method of tissue microarray, namely Spiral Arrays, which enables us to observe the heterogeneity in spiral-shaped tissue cores. Adenocarcinoma and squamous cell carcinoma specimens were obtained from consecutive patients with lung cancer who had undergone surgical resection at Nagasaki University Hospital (Nagasaki, Japan) since 2009. Small cell lung cancer and large cell carcinoma specimens were selected from patients in the same archive who had undergone resection since 1998. Spiral Arrays were constructed of spiral-shaped cores, prepared from representative blocks of each case, which were subjected to immunohistochemistry using an anti-PD-L1 antibody. Each core was divided into 8 segments and each segment was classified as either PD-L1-positive or PD-L1-negative using thresholds of 1.0%, 5.0%, 10.0%, and 50.0%, respectively. In total, 138 specimens were selected, including 60 adenocarcinomas, 59 squamous cell carcinomas, 12 small cell lung cancers, and 7 large cell carcinomas. The majority of specimens with PD-L1-positive segments exhibited heterogeneous expression (i.e., had a mixture of PD-L1-positive and PD-L1-negative segments within a core) irrespective of the threshold (1.0%, 66.7%; 5.0%, 74.4%; 10.0%, 75.8%; and 50.0%, 85.7%]. Large variations in the ratios of PD-L1-positive segments were observed. At least 50.0% of the segments within a core were negative in no fewer than 50.0% (range, 50.0-76.0%) of cases with heterogeneous PD-L1 expression. In conclusion, intratumoral heterogeneity of PD-L1 expression was frequently observed in cases of lung cancer. Thus, multiple tumor biopsy specimens may be needed to accurately determine the PD-L1 expression status.
程序性细胞死亡配体1（PD-L1）表达可能预测肺癌对程序性细胞死亡蛋白1和PD-L1抑制剂的反应。然而，PD-L1表达的肿瘤内异质性程度可能导致假阴性结果，目前对此尚未充分研究。我们旨在通过应用一种新型组织微阵列方法，即螺旋阵列，来评估手术切除的肺癌标本中PD-L1表达的肿瘤内异质性，该方法使我们能够观察螺旋形组织芯中的异质性。腺癌和鳞状细胞癌标本取自自2009年以来在日本长崎大学医院接受手术切除的连续肺癌患者。小细胞肺癌和大细胞癌标本选自同一存档中自1998年以来接受切除的患者。螺旋阵列由螺旋形芯构建而成，从每个病例的代表性块制备，使用抗PD-L1抗体进行免疫组织化学检测。每个芯被分成8个部分，每个部分分别使用1.0%、5.0%、10.0%和50.0%的阈值分类为PD-L1阳性或PD-L1阴性。总共选择了138个标本，包括60例腺癌、59例鳞状细胞癌、12例小细胞肺癌和7例大细胞癌。无论阈值如何（1.0%，66.7%；5.0%，74.4%；10.0%，75.8%；50.0%，85.7%），大多数具有PD-L1阳性部分的标本表现出异质性表达（即芯内有PD-L1阳性和PD-L1阴性部分的混合）。观察到PD-L1阳性部分比例的巨大差异。在异质性PD-L1表达的病例中，至少50.0%的芯内部分在不少于50.0%（范围，（50.0-76.0%）的病例中为阴性。总之，在肺癌病例中经常观察到PD-L1表达的肿瘤内异质性。因此，可能需要多个肿瘤活检标本才能准确确定PD-L1表达状态。
