Morphologic Features in Congenital Pulmonary Airway Malformations and Pulmonary Sequestrations Correlate With Mutation Status

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.

Neonatal and Infant Lung Disorders

“…Ongoing discoveries of the features that overlap between CPAM and other congenital lung lesions have raised controversy surrounding the Stocker classification system. Furthermore, a subset of CPAM harboring KRAS mutations is emerging as a distinctly different subtype, histologically and etiologically 72 …”

“…Furthermore, a subset of CPAM harboring KRAS mutations is emerging as a distinctly different subtype, histologically and etiologically. 72 CPAM may be first identified on prenatal screening ultrasound as heterogeneous hyperechoic masses with or without cysts. 65 In BA-CPAM, further characterization by fetal MRI typically demonstrates a corresponding lesion with T2 hyperintensity due to retained fluid, again with or without cysts depending on its type.…”

Selection of potential targets for stratifying congenital pulmonary airway malformation patients with molecular imaging: is MUC1 the one?

“…KRAS mutations were found in all mucinous proliferation tissue, whereas the surrounding healthy lung tissue did not contain this mutation [ 24 – 26 ]. Specifically, KRAS mutations located on exon 2 G12V and G12D were found in both CPAM and mucinous AIS [ 17 , 25 , 27 – 31 ]. Because KRAS mutations found in lung tissue in adults supports the diagnosis of malignancy, we hypothesised that KRAS-positive CPAM patients ( i.e.…”

RAS-MAPK Pathway Mutations in Congenital Pulmonary Airway Malformations

“…Congenital pulmonary airway malformations (CPAMs) are developmental anomalies of the lung that lead to respiratory complications and are rarely associated with adenocarcinoma ( 1 , 2 ). Stocker developed a classification system using cyst size and histology to distinguish five CPAM subtypes, CPAM Types 0–4, according to the affected tracheobronchial system segment ( 1 , 3 ). CPAM Type 0, now called acinar dysplasia, has a complex molecular pathogenesis with disruption of TBX4-FGF10 signaling playing a key role ( 1 , 2 ).…”

“…The most distal lesion, pleuropulmonary blastoma (PPB) Type 1, formerly referred to as CPAM Type 4, is associated with germline DICER1 variants ( 2 , 4 ). The most common subtype, CPAM Type 1, is believed to originate from a major proximal bronchus and is characterized by large cysts and frequent mucinous cell clusters that may transform into mucinous adenocarcinoma ( 2 , 3 ). Recently, it was shown that CPAM Type 1 results from somatic KRAS mutations that are detected primarily in lesional mucinous and nonmucinous epithelial cells ( 5 ).…”