Comprehensive morphological, immunohistochemical, and molecular characterization of congenital pulmonary airway malformation (CPAM).

Abstract

Congenital pulmonary airway malformation (CPAM) is among the most common congenital lung disorders. Possible findings are foci of mucinous cell clusters (MCCs), harboring KRAS mutations. Studies combining morphology, immunohistochemistry (IHC), and molecular data are scarce. A total of. 46 CPAM lesions were assessed by conventional histomorphology. IHC was performed to analyze lung-specific markers, transcription factors, and epithelial markers reflecting the structural composition of the bronchial tree and alveolar system. Next-generation sequencing (NGS) was conducted to identify mutations and fusions. CPAM type 1 was found in 50%, type 2 in 22%, and type 3 in 6%. A mixed pattern of types 1 and 2 was observed in 22%. The epithelial lining was strongly positive for CK7 and TTF-1 in all samples. Expression for Napsin A, Surfactant A, p40, CK5/6, and CK20 varied within and between subtypes. P40 and CK5/6 were more enriched in type 1 compared to type 2. MCCs occurred in 17%. Mutations were found in 24% (9 × KRAS; 2 × FGFR2). Besides classical KRAS mutations (G12D, G12V), two cases showed a double-mutation pattern (G12D/G12V; G12D/TP53). In all MCC cases, the same mutation with comparable allele frequencies was found in mucinous and non-mucinous areas. No fusions were detected. The presence of mixed-type patterns supports the hypothesis that CPAM represents a continuum of developmental disturbances occurring at various stages of lung branching morphogenesis. This is further corroborated by the divergent protein expression patterns. Our study confirms recent findings that the same KRAS mutations occur in mucinous and non-mucinous areas. The identification of additional mutations, including potential co-mutations, underscores the need for further investigation into molecularly defined CPAM subtypes.