Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

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.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / enzymology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / secondary*
  • Adenocarcinoma of Lung
  • Adenocarcinoma, Papillary / enzymology
  • Adenocarcinoma, Papillary / genetics
  • Adenocarcinoma, Papillary / secondary
  • Adult
  • Aged
  • Aged, 80 and over
  • Anaplastic Lymphoma Kinase
  • Antineoplastic Agents / therapeutic use
  • Biopsy
  • Carcinoma, Signet Ring Cell / enzymology
  • Carcinoma, Signet Ring Cell / genetics
  • Carcinoma, Signet Ring Cell / secondary
  • Crizotinib
  • Female
  • Gene Rearrangement*
  • Genetic Predisposition to Disease
  • Humans
  • In Situ Hybridization, Fluorescence
  • Logistic Models
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology*
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Patient Selection
  • Phenotype
  • Precision Medicine
  • Predictive Value of Tests
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / therapeutic use
  • Pyridines / therapeutic use
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Young Adult


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases