[Congenital lung malformations: natural history and pathophysiological mechanisms]. / Malformations pulmonaires congénitales: histoire naturelle et hypothèses pathogéniques.

INTRODUCTION: Congenital lung lesions comprise a broad spectrum of various malformations including congenital cystic adenomatoid malformation (CCAM), bronchopulmonary sequestration (BPS), congenital lobar emphysema, bronchial atresia and bronchogenic cyst. This review aims at the description of their natural history, and of the underlying pathophysiological mechanisms. STATE OF THE ART: Congenital lung lesions are frequently diagnosed antenatally and many remain asymptomatic after birth. In the absence of antenatal identification, they are usually revealed by the occurrence of infection. In some cases, spontaneous resolution of the malformation can occur. Different pathogenic hypotheses are discussed for the origin of these abnormalities, and common processes appear likely to all of these malformations. Factors involved in the process of branching seem to play a particularly important role. PERSPECTIVES: Prospective follow-up of operated and unoperated children would complete our knowledge about the natural history of these lesions. The contribution of experimental models has led to advances in the understanding of pathogenic mechanisms. Further studies are needed to identify the factors initiating the malformative process.

MUC5AC, cytokeratin 20 and HER2 expression and K-RAS mutations within mucinogenic growth in congenital pulmonary airway malformations.

AIMS: To analyse the expression of several mucins (MUC1, MUC2, MUC3, MUC5AC and MUC6), epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukaemia viral oncogene homologue 2 (HER2), thyroid transcription factor-1 (TTF-1), caudal type homeobox 2 (CDX2) and cytokeratin 20 (CK20), and the presence of mutations of EGFR, KRAS and HER2 in congenital pulmonary airway malformations (CPAM). METHODS AND RESULTS: Forty-one cases of CPAM and six pulmonary sequestrations were included. TTF-1 expression was observed in all cases but was not seen in mucinogenic growths in CPAM. CDX2 expression was completely negative. MUC1 expression was noted in 12 (29%) CPAM and in 33% sequestrations. MUC5AC was noted in only five cases (26%) by immunohistochemistry and was found in the mucinogenic proliferations of type 1 CPAM. No immunolabelling was noted for the other mucins. EGFR was expressed variably in almost all cases, while HER2 and CK20 was seen exclusively in the mucinogenic proliferations. All mucinous growths were characterized by KRAS mutations. No EGFR and HER2 gene alterations were identified. CONCLUSIONS: KRAS mutations and MUC5AC, CK20 and HER2 expression was seen in all mucinogenic proliferations, supporting the neoplastic nature of these cytologically bland growths. These findings emphasize the importance of complete surgical resection of such lesions.

Extending the phenotypes associated with DICER1 mutations.

DICER1 is crucial for embryogenesis and early development. Forty different heterozygous germline DICER1 mutations have been reported worldwide in 42 probands that developed as children or young adults, pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian sex cord-stromal tumors (especially Sertoli-Leydig cell tumor [SLCT]), and/or multinodular goiter (MNG). We report DICER1 mutations in seven additional families that manifested uterine cervix embryonal rhabdomyosarcoma (cERMS, four cases) and primitive neuroectodermal tumor (cPNET, one case), Wilms tumor (WT, three cases), pulmonary sequestration (PS, one case), and juvenile intestinal polyp (one case). One carrier developed (age 25 years) a pleomorphic sarcoma of the thigh; another carrier had transposition of great arteries (TGA). These observations show that cERMS, cPNET, WT, PS, and juvenile polyps fall within the spectrum of DICER1-related diseases. DICER1 appears to be the first gene implicated in the etiology of cERMS, cPNET, and PS. Young adulthood sarcomas and perhaps congenital malformations such as TGA may also be associated.

Familial case of prenatally diagnosed intralobar and extralobar sequestrations with cystadenomatoid change.

Hybrid lesions are part of a spectrum of rare pulmonary diseases that are characterized as having elements of both congenital pulmonary airway malformation and bronchopulmonary sequestration. Fetal thoracic masses arise from alterations during lung development that are separated by timing of the inciting event and are often associated with an underlying degree of bronchial atresia. There are a handful of documented reports of sequestrations occurring in siblings, but no known reports of prenatally diagnosed lesions occurring in families. We present a case of 2 siblings diagnosed prenatally with fetal thoracic lesions who underwent postnatal resection revealing hybrid lesions on pathologic examination. Newer radiologic techniques have increased our ability to detect these masses prenatally, as well as follow them throughout pregnancy to determine their natural history. Ongoing laboratory investigation into the etiology of congenital lung lesions has brought forth more questions and suggested a familial component at a cellular level that has not yet been fully discovered. We reviewed the current literature of factors contributing to the development of congenital lung lesions and suggest that there is a familial link in certain patient populations where screening may be indicated.

Role of phosphatidylinositol 3-kinase-gamma in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis.

We addressed the in vivo role of phosphatidylinositol 3-kinase-gamma (PI3K-gamma) in signaling the sequestration of polymorphonuclear leukocytes (PMNs) in lungs and in the mechanism of inflammatory lung vascular injury. We studied mice with deletion of the p110 catalytic subunit of PI3K-gamma (PI3K-gamma(-/-) mice). We measured lung tissue PMN sequestration, microvascular permeability, and edema formation after bacteremia induced by intraperitoneal Escherichia coli challenge. PMN infiltration into the lung interstitium in PI3K-gamma(-/-) mice as assessed morphometrically was increased 100% over that in control mice within 1 h after bacterial challenge. PI3K-gamma(-/-) mice also developed a greater increase in lung microvascular permeability after E. coli challenge, resulting in edema formation. The augmented lung tissue PMN sequestration in PI3K-gamma(-/-) mice was associated with increased expression of the PMN adhesive proteins CD47 and beta(3)-integrins. We observed increased association of CD47 and beta(3)-integrins with the extracellular matrix protein vitronectin in lungs of PI3K-gamma(-/-) mice after E. coli challenge. PMNs from these mice also showed increased beta(3)-integrin expression and augmented beta(3)-integrin-dependent PMN adhesion to vitronectin. These results point to a key role of PMN PI3K-gamma in negatively regulating CD47 and beta(3)-integrin expression in gram-negative sepsis. PI3K-gamma activation in PMNs induced by E. coli may modulate the extent of lung tissue PMN sequestration secondary to CD47 and beta(3)-integrin expression. Therefore, the level of PI3K-gamma activation may be an important determinant of PMN-dependent lung vascular injury.

Identical twins concordant for pulmonary sequestration communicating with the esophagus and discordant for the VACTERL association.

Communicating bronchopulmonary foregut malformations (CBPFMs) are unusual congenital structures composed of a segment of lung tissue connected to the foregut. We present what we believe is the first reported case of identical twins concordant for CBPFM who are discordant for the VACTERL association. Their nonfunctional lung tissue was successfully removed and the fistulae were corrected, and they are expected to live normal life spans. We review the literature concerning these malformations and the proposed theories of their etiology. This case report of concordance in identical twins suggests that a possible genetic component to CBPFMs cannot be ruled out. The discordance for the VACTERL association implies that the etiology is most likely multifactorial.

A familial case of pulmonary arterial sequestration.

The cases of a mother and infant son are reported, both with a rare type of pulmonary sequestration where the arterial supply to the lung arises from the systemic circulation. This is a familial case of arterial sequestration. In both patients, the lung parenchyma was radiologically normal.

Familial recurrence of pulmonary sequestration.

BACKGROUND: Pulmonary sequestration is not believed to be familial. We report two male infants with this anomaly who were born to the same parents. CASES: The prenatal diagnosis of pulmonary sequestration was made in a woman's two consecutive pregnancies by demonstrating systemic arterial supply to an echogenic mass located in the left lower lung of each fetus. Postnatal radiographic evaluation confirmed the prenatal diagnoses. CONCLUSION: Recurrent pulmonary sequestration in two male offspring from the same parents raises the possibility of a genetic predisposition for this condition.