69. STK11 mutation with negative TTF-1 staining in mucinous adenocarcinomas of the lung: A single institution experience

Mucinous adenocarcinoma of the lung has been previously linked with TTF-1 negative staining. However, TTF-1 negative mucinous adenocarcinoma of the lung has not been definitively linked to STK11 mutations. This study aims to evaluate the potential mechanisms of the relationships between negative TTF-1 immunohistochemical (IHC) staining and mucinous adenocarcinoma histology as well as between STK11 variants and TTF-1 negativity. A retrospective study of 30 patients diagnosed with lung adenocarcinoma with STK11 mutations from Keck Hospital of University of Southern California was performed. The age, gender, histologic and IHC features, mucicarmine IHC status, PD-L1/tumor percentage score, tumor mutational burden, microsatellite status, and follow-up clinical features were compared among the 30 patients. Eight out of thirty cases have mucinous morphology. Of these cases, 2 showed positive TTF-1 staining, 3 showed negative TTF-1 staining, and 3 did not have TTF-1 staining performed. TPS score was positive in ten cases, three of them with mucinous features. TMB score was high in fourteen cases, two with mucinous features. Microsatellite status was stable in all thirty cases. TTF-1 stains were negative in five cases, three with mucinous features. Mucicarmine IHC was performed on three out of thirty cases, all of them having mucinous morphology. Two out of the three cases showed positive mucicarmine staining. Correlation among age, gender, clinical follow-up, and the other findings listed above were negligible. STK11 LOF mutations would activate mTOR , which would lead to an decrease in AKT expression, which would decrease the inhibition of RAF via PI3K-AKT-mTOR and RAS-RAF-MEK-ERK pathway interactions. This would lead to a subsequent downstream increase in ERK expression. ERK normally inhibits TTF-1 via phosphorylation, so with an increase in ERK , more inhibition of TTF-1 would potentially occur. However, in our study, both positive and negative TTF-1 stains were seen in mucinous adenocarcinomas. Epigenetic factors such as methylation and acetylation can potentially affect TTF-1 expression. The increased mucin in mucinous adenocarcinoma could potentially be due to the interactions among the STK11 , PI3K-AKT-mTOR and MUC-1C pathways. Since STK11 loss of function mutation causes an increase in mTOR proteins, we postulate that this increase in mTOR will decrease PI3K via negative feedback, which will subsequently increase MUC-1C expression through positive feedback. This will result in an increase in mucin production in these patients with STK11 variants. This correlates with our results comparing mucinous adenocarcinoma morphology and mucicarmine IHC stains. There are potential links found between STK11 mutations and TTF-1 negative IHC stains in mucinous lung adenocarcinoma. Also, potential links are found between TTF-1 negative IHC stains and mucicarmine status in mucinous lung adenocarcinoma.