Available online 16 November 2022, 151228

Author links open overlay panelAbstract

Congenital lung malformations comprise a diverse group of anomalies including congenital pulmonary airway malformation (CPAM, previously known as congenital cystic adenomatoid malformation or CCAM), bronchopulmonary sequestration (BPS), congenital lobar emphysema (CLE), bronchogenic cysts, and hybrid lesions. Little is known about the signaling pathways that underlie the pathophysiology of these lesions and the processes that may promote their malignant transformation. In the last decade, the use of transgenic/knockout animal models and the implementation of next generation sequencing on surgical lung specimens have increased our knowledge on the pathophysiology of these lesions. Herein, we provide an overview of normal lung development in humans and rodents, and we discuss the current state of knowledge on the pathophysiology and molecular pathways that are altered in each congenital lung malformation.

Section snippetsLung development

The airway epithelium (trachea, bronchi, and alveoli) arises from the endoderm, and differentiates into specialized epithelial cells, such as alveolar type 1 (ATI) and 2 (ATII), club, ciliated, and goblet cells.7 The airway mesenchyme derives from the mesoderm and gives rise to a broad spectrum of cells, including endothelial precursor, smooth muscle, cartilage, lymphatic, and mesothelial cells, as well as pericytes.8 The formation of blood vessels in the lung depends on both angiogenesis and

Congenital Pulmonary Airway Malformation

Within the group of congenital lung malformations, CPAM is the most frequent anomaly that usually affects a single lobe, with only occasional multi-lobar presentation.5,70,71 According to the most updated classification proposed by Dr. Stocker and based on histopathology72, 73, 74:

- type 0 is referred to as acinar dysplasia consistent with tracheal or bronchial like structures, associated with severe pulmonary hypoplasia;

- type 1 is the most frequent subtype characterized by multiple cysts or

Bronchopulmonary Sequestration

BPS is the second most common pulmonary lesion in the spectrum of congenital lung malformation. BPS is classified as intralobar (ILS, 75%) and extralobar (ELS, 25%), with a tendency to occur in the lower lobes of the lung.71 Some groups have reported cases of familial BPS and association with other congenital anomalies, such as CDH.129, 130, 131, 132

Congenital Lobar Emphysema

CLE represents the third most common congenital lung malformation and is usually located in the left upper lobe.5,71 A prenatal diagnosis is rare, as these lesions tend to be isoechoic on ultrasonography. Postnatally, about 60% of neonates are symptomatic due to air trapping and lung expansion leading to compression of the heart and/or contralateral lung.71,138 Air trapping may be caused by intrinsic or extrinsic factors such as bronchial stenosis, bronchomalacia, and bronchial narrowing.5,139

Bronchogenic Cysts

Bronchogenic cyst is a rare congenital lung malformation thought to results from abnormal budding of the primitive foregut.8,71 Typically, the cysts are localized in the proximal mediastinum arising from the trachea or mainstem bronchi. Although, they also occur within the lung parenchyma and other regions including the abdomen, the tongue and the head/neck region.143, 144, 145 Proximal bronchogenic cysts are thought to develop early, whereas more distal lesions develop later during lung

Final remarks

In the last decade, the characterization of normal lung development has been further established through advancements in basic science techniques such as RNA-sequencing and lineage-tracing experiments. Similarly, the use of transgenic/knockout animal models and the implementation of next generation sequencing on surgical lung specimens have increased our knowledge on the pathophysiology of congenital lung malformations. However, relatively little is known about the signaling pathways that

Acknowledgements

The figures were made with BioRender.

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