Morphological, immunohistochemical, and genetic analyses of bronchiolar adenoma and its putative variants

We collected 26 cases of bronchiolar adenoma (BA) and its variants, and performed a comprehensive characterization using a combination of morphological, immunohistochemical, and genetic assessments. Of these 26, 13 were classic bilayered cases, including 10 proximal and 3 distal-type BAs. Of note, we also identified 13 cases that lacked a continuous basal cell layer. In five cases, the adenomas were partially classic bilayered, leaving a single layer of columnar or cuboidal epithelial cells in some areas of the lesion (BA with monolayered cell lesions). In the other eight cases, the glandular or papillary structures were entirely composed of monolayered columnar or cuboidal epithelial cells, which were morphologically identical to the luminal epithelial cells of classic BA (monolayered BA-like lesions). Immunohistochemical analysis revealed thyroid transcription factor 1 expression by ciliated columnar epithelial cells, basal cells, and nonciliated columnar and cuboidal epithelial cells. Basal cells also expressed p40 and p63. Twenty-five cases underwent next-generation sequencing using a 422-cancer-gene panel (GeneseeqPrime). Oncogenic driver mutations were detected in 23 cases, including 13 (52%) with EGFR mutations, 4 (16%) with KRAS G12D/V mutations, 3 (12%) with BRAF V600E mutations, 2 (8%) with ERBB2 exon 20 insertions, and 1 (4%) with a RET fusion. EGFR exon 20 insertions were present in 100% of BAs with monolayered cell lesions, 37.5% of monolayered BA-like lesions, and 8% of classic BA (Fisher's exact test, p = 0.002, false discovery rate = 0.014). Collectively, our study revealed a gradual morphological transition between BA and its variants. The genetic composition of BAs with monolayered structures differed significantly from those of classic BAs or lung adenocarcinoma.