Bronchiolar adenoma and glandular papilloma/mixed squamous cell and glandular papilloma represent a continuous disease spectrum: revelations from combined histological and genetic analysis

AIMS: Despite their common bronchial/bronchiolar origin, the relationship between glandular/mixed papillomas (GPs/MPs) and bronchiolar adenomas (BAs) remains uncertain; therefore, this study aimed to elucidate it. METHODS AND RESULTS: We performed a combined clinicopathological and next-generation sequencing analysis of 6 GP/MP and 14 BA cases. The cases were classified into three groups based on histopathological features: Group A (classic GP/MP), Group B (transitional morphology) and Group C (glandular predominant BA, lacks papillary structure). Analysis revealed a morphological continuum from Group A to Group C, characterized by a gradual transition from endobronchiolar papillary growth to alveolar glandular structures and a shift in the lining epithelium from pseudostratified ciliated columnar to cuboidal/flat. Clinically, compared with Group C, Group A showed a higher proportion of males and larger tumour size, while Group B exhibited intermediate features. Genetically, GP/MP frequently harboured BRAF (83.3%) and AKT1 (66.6%) mutations, whereas BAs displayed a more diverse profile, including BRAF (28.5%), AKT1 (21.4%), EGFR (28.5%) and KRAS (14.2%) mutations. BRAF and AKT1 mutations were predominantly found in Groups A and B, whereas EGFR and KRAS mutations were more common in Group C. CONCLUSION: GP/MP and BA represent the same disease spectrum, showing a continuous histomorphological change along the proximal-to-distal bronchial tree. BRAF and AKT1 mutations are more frequently observed in GP/MP and proximal-type BA with papillary architecture, whereas BA lacking papillary structures is mainly characterized by EGFR or KRAS mutations. However, the BRAF mutation rate in BA varies across geographical regions and appears to be associated with factors such as smoking.