Clinicopathologic features of KRAS G12C-mutated non-small cell lung carcinomas:insights from 279 retrospective cases

KRAS G12C-mutated non-small cell lung carcinoma (NSCLC), caused by a glycine-to-cysteine substitution at codon 12, is associated with poor prognosis and is now targetable with specific inhibitors. We retrospectively analyzed 279 KRAS G12C-mutated NSCLC cases (2017-2023) from our registry with available histologic, immunohistochemical, and molecular data. The cohort included 279 patients (125 females, 151 males; mean age 67 years, range 29-91). Most tumors were primary lung carcinomas (n = 229, 82%), while 45 (16%) were metastatic at presentation. Morphologic evaluation was available in 240 tumors: 37% showed solid squamous cell carcinoma (SCC)-like features, 61% rhabdoid/plasmacytoid morphology, and 17% sarcomatoid features. Adenocarcinoma-associated patterns were present in 67 cases, often mixed, and focal solid growth occurred in 77%. TTF1, Napsin A, and CK7 were positive in 86%, 87%, and 98%, respectively, whereas squamous markers were infrequent (p40/p63 7%, CK5/6 8%). PD-L1 expression was detected in 65%. Co-mutations most commonly involved TP53 (n = 27) and STK11 (n = 12); IDH1/2, PIK3CA, and CTNNB1 mutations occurred in four cases each, MET in two cases, and BRAF, FGFR2, FGFR3, and GNAS in one case each. Two gene fusions were identified (LRP12::NRG1, FGFR3::TACC3). Mean survival was 1.89 years, with one- and five-year survival rates of 54% and 25%. KRAS G12C-mutated NSCLC is clinically aggressive and frequently shows solid growth with rhabdoid, plasmacytoid, or SCC-like morphology, which may lead to misclassification and missed genetic testing. Immunohistochemistry and molecular profiling are essential for accurate classification and enabling targeted therapy.