Characteristic Morphology and Immunoprofile of Lung Adenocarcinoma with KRAS Mutations: Propensity for Solid Growth Pattern and Correlation with TTF-1 Expression
DC Ang, MF Zakowski, M Ladanyi, AL Moreira, N Rekhtman. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: KRAS mutations in lung adenocarcinoma (AD) define a distinctive clinical subgroup of patients who are resistant to not only to EGFR-targeted therapies, but also to conventional chemotherapy. Compared to EGFR-mutant tumors, KRAS mutations are strongly associated with smoking, and are predictive of poor prognosis. However, whether KRAS mutations define a morphologically and immunophenotypically distinctive subtype of AD has not been established.
Design: 82 resected lung AD were analyzed for KRAS and EGFR mutations, and classified histologically based on the presence or predominance (>50%) of solid vs other (bronchioloalveolar, acinar, papillary, micropapillary) patterns. All tumors were evaluated by immunohistochemistry for TTF-1 as positive (any reactivity) or negative.
Results: Of 82 tumors, 27 (33%) harbored KRAS mutations, 17 (21%) EGFR mutations, and 38 (46%) neither KRAS nor EGFR mutations. KRAS mutations were strongly associated with solid-predominant growth pattern: 16/25 (64%) of solid-predominant tumors were KRAS-mutant compared to 11/57 (19%) of non-solid predominant tumors (P=0.0002). Even tumors with a minor solid component had more frequent KRAS mutations (21/45, 46%) than tumors without any solid component (6/37, 16%; P=0.004). In contrast, none of solid-predominant tumors had EGFR mutations (0/25) as compared to tumors with other patterns (17/57, 30%; P=0.001). TTF-1 was expressed in 26/27 (96%) of KRAS-mutant tumors, 17/17 (100%) of EGFR-mutant tumors, and 31/38 (82%) of non-mutant tumors. Presence of either KRAS or EGFR mutations was significantly associated with TTF-1 expression (P=0.02).
|Histologic Type||KRAS-mutant||EGFR-mutant||KRAS and EGFR non-mutant|
|All types combined (n=82)||27 (33%)||17 (21%)||38 (46%)|
|Solid predominant (n=25)||16 (64%)||0 (0)||9 (36%)|
|Any solid (n=45)||21 (47%)||7 (15%)||17 (38%)|