Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population

Abstract

Purpose: The anaplastic large cell kinase gene (ALK) is rearranged in approximately 5% of lung adenocarcinomas within the Asian population. We evaluated the incidence and the characteristics of ALK-rearranged lung adenocarcinomas within the western population and the optimal diagnostic modality to detect ALK rearrangements in routine clinical practice.

Experimental design: We tested 358 lung adenocarcinomas from three institutions for ALK rearrangements by fluorescent in situ hybridization (FISH) and immunohistochemistry with and without tyramide amplification. The clinicopathologic characteristics of tumors with and without ALK rearrangements were compared.

Results: We identified 20 (5.6%) lung adenocarcinomas with ALK rearrangements within our cohort of western patients. ALK rearrangement was associated with younger age (P = 0.0002), never smoking (P < 0.0001), advanced clinical stage (P = 0.0001), and a solid histology with signet-ring cells (P < 0.0001). ALK rearrangement was identified by FISH in 95% of cases and immunohistochemistry with and without tyramide amplification in 80% and 40% of cases, respectively, but neither FISH nor immunohistochemistry alone detected all cases with ALK rearrangement on initial screening. None of the ALK-rearranged tumors harbored coexisting EGFR mutations.

Conclusions: Lung adenocarcinomas with ALK rearrangements are uncommon in the western population and represent a distinct entity of carcinomas with unique characteristics. For suspected cases, dual diagnostic testing, with FISH and immunohistochemistry, should be considered to accurately identify lung adenocarcinomas with ALK rearrangement.

Figure 1

ALK-rearranged NSCLC have distinct histologic characteristics. Representative examples of ALK-rearranged NSCLC showing the distinct solid growth pattern (A, C, E, 400x original magnification), and ≥10% signet-ring cells (B, D, F, 1000x original magnification). An ALK-rearranged adenocarcinoma with focal squamous differentiation (G, 400x), and an ALK-rearranged adenocarcinoma with the typical acinar histologic features (H, 400x).

Figure 2

Standard diagnostic techniques are not optimal for the routine detection of ALK-rearranged NSCLC. Representative ALK-rearranged (A-F) and ALK germline (G-I) tumors analyzed by fluorescent in-situ hybridization using probes flanking the ALK gene (A, D, G), standard immunohistochemical staining for ALK protein (B, E, H), and tyramide amplified immunohistochemical staining for ALK protein (C, F, I). Red arrows: split FISH probes characteristic of an ALK rearrangement. Yellow arrows: non-split FISH probes characteristic of ALK germline.