Histologic Multivariate Model for Predicting Presence of ALK-Rearrangement in Lung Adenocarcinoma
Michiya Nishino, Veronica E Klepeis, Beow Yeap, Kristin Bergethon, Mark J Mark, A John Iafrate, Mari Mino-Kenudson. Massachusetts General Hospital, Boston
Background: The identification of ALK rearrangement is emerging as an important pathology analysis of lung cancers. However, it is currently impractical for most pathology laboratories to screen all lung adenocarcinomas for ALK rearrangement using FISH. Thus, recognizing distinctive pathologic features of ALK-rearranged (ALK+) tumors may help us enrich for cases most likely to be positive for ALK rearrangement for molecular testing. Our previous study has shown the association of ALK rearrangement with a solid histology with numerous signet ring cells; however, experience of others, especially with lung resections, appears to be different. Thus, we sought to evaluate the histologic characteristics of ALK+ lung adenocarcinomas on various types of specimens from a large cohort of patients and develop a scoring system to predict ALK rearrangement.
Design: We examined resection, excision, and small biopsy specimens from 104 patients with ALK+ lung adenocarcinomas. The predominant histologic patterns and distinctive cytomorphologic features were assessed in each case and were compared with 215 lung adenocarcinomas negative for ALK rearrangement (ALK-). Based on the analysis, we developed a multivariate model for predicting ALK rearrangement in lung adenocarcinomas and tested its performance on a validation cohort (n =78).
Results: Compared to the ALK- tumors, ALK+ primary lung adenocarcinomas were associated with solid (47% vs. 16%) and micropapillary (22% vs. 9%) patterns, any signet ring cells (71% vs. 15%), and oncocytic cells (31% vs. 5%). Multivariate analysis further identified a significant association of papillary-predominant histology with ALK rearrangement. Among metastatic tumors and small tumor samples, the only morphologic feature distinguishing ALK+ from ALK- tumors was the presence of any signet ring cells (70% vs. 21%). Our morphologic scoring system based on signet ring cells, oncocytic cells, predominant histologic patterns and specimen types predicted the presence of ALK rearrangement with a sensitivity of 76% in the validation cohort.
Conclusions: The results of the current study confirm the association of ALK+ lung adenocarcinomas with distinctive morphologic features. In particular, the presence of signet ring cells predicts ALK rearrangement irrespective of specimen types. Our scoring system appears to be useful in predicting the majority of ALK+ tumors. However, additional screening methodology such as ALK immunohistochemistry scoring is warranted since morphologic analysis alone is not sufficiently sensitive to identify all patients who may be eligible for targeted therapy.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 308, Tuesday Morning