Morphologic Features in Congenital Pulmonary Airway Malformations and Pulmonary Sequestrations Correlate With Mutation Status: A Mechanistic Approach to Classification

Abstract

Congenital pulmonary airway malformations (CPAMs) have a range of morphologies with varying cyst sizes and histologic features (types 1 to 3). Evidence suggested they arise secondary to bronchial atresia, however, we recently showed that cases with type 1 and 3 morphology are driven by mosaic KRAS mutations. We hypothesized that 2 distinct mechanisms account for most CPAMs: one subset is secondary to KRAS mosaicism and another is due to bronchial atresia. Cases with type 2 histology, similar to sequestrations, would be related to obstruction and therefore negative for KRAS mutations regardless of cyst size. We sequenced KRAS exon 2 in type 2 CPAMs, cystic intralobar and extralobar sequestrations, and intrapulmonary bronchogenic cysts. All were negative. Most sequestrations had a large airway in the subpleural parenchyma adjacent to the systemic vessel, anatomically confirming bronchial obstruction. We compared morphology to type 1 and 3 CPAMs. On average, type 1 CPAMs had significantly larger cysts, but there remained substantial size overlap between KRAS mutant and wild-type lesions. Features of mucostasis were frequent in sequestrations and type 2 CPAMs, while their cysts were generally simple and round with flat epithelium. Features of cyst architectural and epithelial complexity were more common in type 1 and 3 CPAMs, which rarely showed mucostasis. Similarity in histologic features among cases that are negative for KRAS mutation support the hypothesis that, like sequestrations, the malformation of type 2 CPAMs is related to obstruction during development. A mechanistic approach to classification may improve existing subjective morphologic methods.