Novel genetic characteristics in low‐grade fetal adenocarcinoma of the lung

BACKGROUND: Low‐grade fetal adenocarcinoma of the lung (L‐FLAC) is a rare subtype of lung adenocarcinoma with undetermined histological features and genetic abnormalities. In this study, we attempted to investigate the pathological characteristics and genomic profiles of L‐FLAC. METHODS: Among 9839 cases of primary lung adenocarcinoma resected at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2011 and June 2016, three cases diagnosed with L‐FLAC were selected. An immunohistochemical profile and whole exome sequencing (WES) using tumor and normal tissues was conducted. The last follow‐up date of patients was January 2021. RESULTS: Three cases diagnosed with L‐FLAC were finally screened, suggesting a percentage of 0.03%. All three patients were male and diagnosed as stage I following radical lobectomy. The missense variant was found to be the major gene mutation type using WES. CTNNB1 and DICER1 were the two most frequent gene mutations. All cases demonstrated positive TTF‐1 expression. In addition, two patients showed positive expression of β‐catenin (nuclear/cytoplasmic expression), CgA and Sny. Negative expression of PD‐L1 in tumor cells was observed in all three cases. One case with a relatively high tumor mutation burden (TMB) (2.18 mut/Mb) had an inferior overall survival of 11.5 months. However, the other two cases with a lower TMB (0.12 and 0.74 mut/Mb) still acquired disease‐free status up to the last follow‐up date. CONCLUSIONS: L‐FLAC has a specific molecular background which is different from lung adenocarcinoma. Furthermore, gene heterogeneity was found and might be the reason for a dramatically different prognosis in these L‐FLAC patients.