Journal of Molecular Pathology · Published 2025-11-17 · DOI 10.3390/jmp6040028
Targetable gene alterations have become increasingly important in the treatment of cancers. Thirty <i>STK11</i>-mutated lung cancers from 199 cases with molecular profiling performed during 2016–2024 were studied for clinical, morphologic, immunohistochemical (IHC) and molecular features. Of the 30 <i>STK11</i>-mutated lung cancers, 29 were lung adenocarcinomas (LADCs) and 1 was large cell neuroendocrine carcinoma (LCNEC). <i>STK11</i> mutation was not found in other subtypes of lung cancers. Of the 29 <i>STK11</i>-mutated LADCs, 6 (21%) were mucinous and 23 (79%) were non-mucinous. Of the 19 non-mucinous LADCs with sufficient material for IHC, 9 (47%) displayed acinar/papillary/lepidic patterns, 8 (42%) were poorly differentiated (solid/trabecular/basaloid/complex glandular), and 2 (11%) had mixed solid and acinar patterns. The most common concurrent altered genes were <i>KRAS</i> (52%), followed by <i>TP</i>53 (38%), <i>KEAP1</i> (34%), and DNA repair genes (<i>BRCA2/ATM</i>) (21%). A total of 6/15 (40%) LADCs with a <i>KRAS</i> mutation presented with mucinous morphology. Concurrent <i>EGFR</i><i>, ROS</i>, or <i>ALK</i> alterations with <i>STK11</i> mutation were rare or non-existent. Of the 3 LADCs with SMARCA4 deficiency, 2 were mucinous and 1 had basaloid/adenoid cystic-like features. All the cases were microsatellite stable (MSS). The majority (55%) had low TMB (<10). Most (86%) had PD-L1 TPS 0 or <5%. Among the 14 non-mucinous LADCs with IHC performed, 5 (36%) were TTF-1-negative and all displayed poorly differentiated morphology. Overall, 8/10 (80%) of poorly differentiated components in non-mucinous LADCs were negative for TTF-1. In contrast, all LADCs with better differentiated patterns (acini/papillary/lepidic) were positive for TTF-1. The majority (14/21, 67%) of patients with available follow-up presented with metastasis.
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