Zakowski Maureen F, Hussain Sanaa, Pao William, Ladanyi Marc, Ginsberg Michelle S, Heelan Robert, Miller Vincent A, Rusch Valerie W, Kris Mark G
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
Arch Pathol Lab Med. 2009 Mar;133(3):470-7. doi: 10.5858/133.3.470.
A subset of lung adenocarcinomas appears preferentially sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). EGFR-activating mutations and never smoking are associated with response to TKIs.
To describe the morphology of adenocarcinomas responsive to TKIs, compare it to tumors in nonresponding patients, and correlate findings with EGFR mutations, gene copy number, and protein expression.
Material from 52 EGFR TKI-treated patients was studied: 29 responders and 23 nonresponders. Adenocarcinoma subtypes and morphologic features were defined in histologic and cytologic material. EGFR mutations were detected by sequencing, copy number by chromogenic in situ hybridization, and expression by immunohistochemistry.
Tumors from TKI responders tended to be better-differentiated adenocarcinomas with bronchioloalveolar carcinoma components. Nonresponders showed more heterogeneous morphology, higher grade, and more subtypes, and were more likely to show solid growth. In nonresponders, the only pure bronchioloalveolar carcinoma was mucinous, a subtype known to be negative for EGFR mutations. Using World Health Organization criteria, all tumors in both groups other than pure bronchioloalveolar carcinomas would be classified as adenocarcinomas, mixed subtype, thereby obscuring some of these distinctions. EGFR mutations were significantly more common in responders (22/29 vs 0/23; P < .001). Immunohistochemistry and chromogenic in situ hybridization results were not significantly correlated with EGFR mutations or response to TKIs in this study.
Overall, histologic differences exist between tumors that respond to TKIs and those that do not, although sampling affects classification, and there is significant histologic overlap between the 2 groups. Response is strongly associated with EGFR mutations.
一部分肺腺癌似乎对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）特别敏感。EGFR激活突变和从不吸烟与对TKIs的反应相关。
描述对TKIs有反应的腺癌的形态，将其与无反应患者的肿瘤进行比较，并将结果与EGFR突变、基因拷贝数和蛋白表达相关联。
研究了52例接受EGFR TKI治疗患者的材料：29例有反应者和23例无反应者。在组织学和细胞学材料中定义腺癌亚型和形态学特征。通过测序检测EGFR突变，通过显色原位杂交检测拷贝数，通过免疫组织化学检测表达。
TKI有反应者的肿瘤往往是分化较好的腺癌，伴有细支气管肺泡癌成分。无反应者表现出更异质的形态、更高的分级和更多的亚型，并且更有可能表现为实性生长。在无反应者中，唯一的纯细支气管肺泡癌是黏液性的，这是一种已知EGFR突变阴性的亚型。根据世界卫生组织标准，两组中除纯细支气管肺泡癌外的所有肿瘤都将被分类为腺癌，混合亚型，从而掩盖了其中一些差异。EGFR突变在有反应者中明显更常见（22/29对0/23；P <.001）。在本研究中，免疫组织化学和显色原位杂交结果与EGFR突变或对TKIs的反应无显著相关性。
总体而言，对TKIs有反应的肿瘤和无反应的肿瘤之间存在组织学差异，尽管取材会影响分类，并且两组之间存在明显的组织学重叠。反应与EGFR突变密切相关。
