Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

Abstract

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 þ ) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of ALK þ 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 þ and 215 ALKÀ 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 þ 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 þ 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 þ and 49 ALKÀ) with a sensitivity of 88% and a specificity of 45%. In conclusion, ALK þ 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 þ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment.

CCR 20th Anniversary Commentary: Molecular Pathology of ALK-Rearranged Lung Tumors

“…Research published subsequent to our study has clearly corroborated our findings, including the correlation of ALK fusions with young age, nonsmoking status, advanced stage, mutual exclusivity from other major driver genes, and signet ring cell morphology (9)(10)(11)(12)(13). Recently several meta-analyses have been published that have firmly established these findings, although some minor differences have been noted in the morphology of ALK-positive tumors in Asia (14).…”

Biomarker testing in advanced non-small-cell lung cancer: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

“…With all these considerations, it is recommended that the tumour be re-biopsied when any of the following circumstances apply: (1) whenever molecular tests yield uninformative results or there is not enough tumour material to do them, and the clinicopathological features of patient and tumour point to the possible presence of a therapeutic target. Examples of this might be patients below the usual age of disease presentation or who have never smoked, or suggestive pathology such as signetring cells [30] or a lepidic or micropapillary patterns [31];…”

Actualización de las recomendaciones para la determinación de biomarcadores en el carcinoma de pulmón avanzado de célula no pequeña. Consenso Nacional de la Sociedad Española de Anatomía Patológica y de la Sociedad Española de Oncología Médica

“…Por todo ello, será fundamental informar adecuadamente al paciente de los pros y contras de la nueva toma de material tumoral, y las razones y objetivos que llevan a esa decisión. Con todas estas consideraciones, se recomienda hacer una re-biopsia del tumor cuando existen algunas de las siguientes circunstancias: a) siempre que el resultado del análisis molecular no haya sido informativo o no se disponga de material tumoral suficiente para su realización, y las características clínico-patológicas del paciente y del tumor orienten a la posible presencia de una diana terapéutica; ejemplos de ello pueden ser pacientes que nunca hayan sido fumadores o con edad inferior a la presentación habitual de la enfermedad, o características patológicas sugestivas, como la presencia de células en anillo de sello 30 o un patrón micropapilar 31 , y b) cuando exista discrepancia entre el perfil clínico del paciente y el resultado anatomopatológico obtenido. Así, cuando el diagnóstico sea de un carcinoma de tipo escamoso o de células pequeñas en un paciente que nunca haya sido fumador o de edad muy joven, habría que revisar el estudio anatomopatológico o valorar, en cualquier caso, la realización de los estudios moleculares establecidos para los tumores de histología no escamosa.…”