Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Mod Pathol. 2012 Nov;25(11):1462-72. doi: 10.1038/modpathol.2012.109. Epub 2012 Jun 29.
Chromosomal rearrangements leading to constitutive activation of anaplastic lymphoma receptor tyrosine kinase (ALK) define a category of lung adenocarcinomas that may be amenable to targeted therapy with the ALK inhibitor crizotinib. Defining distinctive features of ALK-rearranged (ALK+) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of ALK+ lung adenocarcinomas are conflicting and are primarily based on analysis of resected primary lung tumors. It is unclear whether the findings from prior studies are applicable to metastatic lung tumors or to small biopsy/cytology specimens. To address these issues, we examined resection, excision, small biopsy, and cytology cell block specimens from 104 ALK+ and 215 ALK- lung adenocarcinomas from primary and metastatic sites. All cases were evaluated for ALK rearrangements by fluorescence in situ hybridization. The predominant histologic subtypes and distinctive cytomorphologic features were assessed in each case. Primary ALK+ lung adenocarcinomas showed a significant association with solid, micropapillary, and papillary-predominant histologic patterns and tumor cells with a signet ring or hepatoid cytomorphology. Among metastatic lung tumors and small biopsy/cytology specimens, the only distinguishing morphologic feature of ALK+ tumors was the presence of signet ring cells. Based on these results, we developed a morphology-based scoring system for predicting ALK rearrangements in lung adenocarcinomas. The scoring system predicted ALK rearrangements in a new cohort of 78 lung adenocarcinomas (29 ALK+ and 49 ALK-) with a sensitivity of 88% and a specificity of 45%. In conclusion, ALK+ lung adenocarcinomas have distinctive morphologic features, with signet ring cells showing a significant association with ALK rearrangements irrespective of tumor site (primary vs metastatic) or specimen type. However, morphologic screening alone will not detect a minority of ALK+ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment.
导致间变性淋巴瘤激酶酪氨酸激酶（ALK）组成性激活的染色体重排定义了一类肺腺癌，这些肺腺癌可能对 ALK 抑制剂克唑替尼的靶向治疗有效。确定 ALK 重排（ALK+）肺腺癌的独特特征可能有助于确定需要进行分子检测的病例。然而，描述 ALK+肺腺癌形态特征的数据存在冲突，并且主要基于对切除的原发性肺肿瘤的分析。尚不清楚先前研究的结果是否适用于转移性肺肿瘤或小活检/细胞学标本。为了解决这些问题，我们检查了来自原发性和转移性部位的 104 例 ALK+和 215 例 ALK-肺腺癌的切除、切除、小活检和细胞学细胞块标本。所有病例均通过荧光原位杂交评估 ALK 重排。在每个病例中评估了主要组织学亚型和独特的细胞形态特征。原发性 ALK+肺腺癌与实体、微乳头状和乳头状为主的组织学模式以及具有印戒细胞或肝细胞样细胞形态的肿瘤细胞显著相关。在转移性肺肿瘤和小活检/细胞学标本中，ALK+肿瘤唯一的形态学特征是存在印戒细胞。基于这些结果，我们开发了一种基于形态学的评分系统，用于预测肺腺癌中的 ALK 重排。该评分系统在一组新的 78 例肺腺癌（29 例 ALK+和 49 例 ALK-）中预测 ALK 重排，敏感性为 88%，特异性为 45%。总之，ALK+肺腺癌具有独特的形态学特征，印戒细胞与 ALK 重排显著相关，无论肿瘤部位（原发性与转移性）或标本类型如何。然而，单独的形态学筛查不会发现少数 ALK+肺腺癌，可能需要常规使用辅助研究来识别所有可能从克唑替尼治疗中受益的患者。
