Enriched NKX2-1 Mutations in Bronchiolar Adenoma Variants: Evidence for Malignant Transformation or an Indolent Entity

Abstract

Objective

Bronchiolar adenoma (BA) is a peripheral pulmonary neoplasm characterized by a bilayered cell structure composed of basal cells and luminal cells. Owing to its low incidence and limited research data, clinicians and pathologists still have an insufficient understanding of this disease. This study aims to characterize the morphological, immunohistochemical, and genetic features of BA and its variants, and to determine whether BA can progress to a malignancy.

Methods

Among these 33 cases, 21 were histologically characterized by double-layered tumors with continuous basal cell layers. Six patients exhibited a partial classic bilayer, transitioning from a bilayer to a monolayer in certain lesion areas (mixed-type BAs). Six other BA-like tumors with monolayered components might represent the early stage of malignant transformation of BA. Next-generation sequencing analysis was conducted on 33 cases to elucidate the genetic spectrum.

Results

All the cellular components exhibited a relatively mild morphology. Immunohistochemical analysis revealed that basal cells coexpressed p40 and cytokeratin 5/6. Thyroid transcription factor 1 was expressed in the double-cell layer, which consists of ciliated columnar epithelial cells, basal cells, nonciliated columnar epithelial cells, and cuboidal epithelial cells. The pan-cancer gene panel was used to observe driver alterations in 9 of 21 classic bilayered BAs (43%), 2 of 6 mixed-type BAs (33%), and 3 of 6 monolayered BA-like lesions (50%). Genetically, monolayered BA-like lesions shared some alterations with classic BAs in mutational signatures, whereas NKX2-1 mutations were enriched only in monolayered BA-like lesions.

Conclusion

These findings underscore the histopathological and genetic characteristics of BA and its variants, suggesting that monolayered BA-like lesions have the potential to develop into lung adenocarcinoma. In the future, more cases should be recruited to further explore the malignant transformation of this specific entity via the multidimensional spectrum.

Keywords

Bronchiolar adenoma / Monolayered BA-like lesions / Histopathology / Genomic analysis / NKX2-1 mutation / Lung adenocarcinoma / Next-generation sequencing / TTF-1

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Funding

Xi'an Jiaotong University Medical Development Fund (XJYG2025-SFJJ011)

Natural Science Foundation of Inner Mongolia Autonomous Region(2023LHMS08027)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology