Pleuropulmonary blastoma type I might arise in congenital pulmonary airway malformation type 4 by acquiring a Dicer 1 mutation

Abstract

Congenital pulmonary airway malformation (CPAM) occurs most commonly in infants. It is divided into 5 types. The most common types 1 and 2 are cystic, type 0 presents as bronchial buds without alveolar tissue, most likely corresponding to alveolar dysgenesis, while type 3 is composed of branching bronchioles and appears as a solid lesion. A defect in the epithelialmesenchymal crosstalk might be the underlying mechanism for all. Type 4 is a peripheral cystic lesion with a thin cyst wall covered by pneumocytes. CPAM 4 has been mixed up with pleuropulmonary blastoma (PPB) type I and some authors question its existence. We investigated five cases of CPAM type 4 for the presence or absence of rhabdomyoblasts, and for markers associated with CPAM development. In addition, all cases were evaluated for mutations within the Dicer gene and for mutations of the RAS family of oncogenes. All five cases showed smooth muscle actin and desmin-positive cells; however, only one case showed a few cells positive for MyoD. The same case showed a mutation of Dicer 1. All cases were negative for mutations of the RAS family of genes. Fibroblast growth factor 10 was similarly expressed in all cases, and thus cannot be used to differentiate CPAM4 from PPB-I. Low expression of the proliferation marker Ki67 was seen in our CPAM 4 cases and the probable PPB-I case. YingYang-1 protein seems to play an active role in the development of PPB-I. CPAM 4 can be separated from PPB-I based on the presence of rhabdomyoblasts and mutations in Dicer 1 gene. These cells might not be numerous; therefore, all available tissue has to be evaluated. As CPAM 4 morphologically looks very similar to PPB-I, it might be speculated, that there exists a potential for progression from CPAM 4 to PPB-I, by acquiring somatic mutations in Dicer 1.

Application of second-generation sequencing in congenital pulmonary airway malformations

“…NGS has been applied in kidney disease 18 , neurological disease 19 and several cancers 20 . Although some studies have identified genes associated with congenital pulmonary airway malformations by NGS, the results are not consistent 11 , 12 , implying that research in this area is still insufficient.…”

“…Variety of genes have also been implicated in this process of CPAM such as sex-determining region Y- box 2 gene (Sox2), hyroid transcription factor gene (Nkx2), Hox gene (Hoxb-5), fatty acid-binding protein-7 gene (FABP-7) and Ying Yang 1 gene (Yy1) 1 , 9 , 10 . In another study, all type 4-CPAM patients possessed the mutation of Dicer 1 11 . In addition, KRAS mutation was demonstrated in the mucinous proliferations and adjacent nonmucinous CPAM tissue 12 .…”

Congenital Pulmonary Airway Malformations With a Reconsideration and Current Perspective on the Stocker Classification

“…[74][75][76][77] The emergence of PPB type I has introduced a cautionary note into the approach of any CCPL, requiring a thorough pathologic examination. [78][79][80][81] Studies on DICER1 detection by ctDNA are ongoing. 82…”

Neonatal and Infant Lung Disorders

“…Management of asymptomatic CPAMs is somewhat controversial due to underlying risks for infection and arguably malignancy. Further investigation into genetic mutations, such as a germline DICER1 mutation present in two-thirds of patients with PPB, may provide an additional layer of information for clinical management 77 …”

“…Further investigation into genetic mutations, such as a germline DICER1 mutation present in two-thirds of patients with PPB, may provide an additional layer of information for clinical management. 77 Bronchopulmonary Sequestration (BPS) BPS, sometimes referred to as pulmonary sequestration, is a rare aberrant mass of nonfunctional lung tissue with anomalous vascular and absent bronchial connections. There are 2 types of BPS: intralobar and extralobar.…”