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

Currently there is a global lack of consensus about the best treatment for asymptomatic congenital pulmonary airway malformation (CPAM) patients. The somatic KRAS mutations commonly found in adult lung cancer combined with mucinous proliferations are sometimes found in CPAM. For this risk of developing malignancy, 70% of paediatric surgeons perform a resection for asymptomatic CPAM. In order to stratify these patients into high- and low-risk groups for developing malignancy, a minimally invasive diagnostic method is needed, for example targeted molecular imaging. A prerequisite for this technique is a cell membrane bound target. The aim of this study was to review the literature to identify potential targets for molecular imaging in CPAM patients and perform a first step to validate these findings.A systematic search was conducted to identify possible targets in CPAM and adenocarcinoma in situ (AIS) patients. The most interesting targets were evaluated with immunofluorescent staining in adjacent lung tissue, KRAS+ CPAM tissue and KRAS- CPAM tissue.In 185 included studies, 143 possible targets were described, of which 20 targets were upregulated and membrane-bound. Six of them were also upregulated in lung AIS tissue (CEACAM5, E-cadherin, EGFR, ERBB2, ITGA2 and MUC1) and as such of possible interest. Validating studies showed that MUC1 is a potential interesting target.This study provides an extensive overview of all known potential targets in CPAM that might identify those patients at risk for malignancy and conducted the first step towards validation, identifying MUC1 as the most promising target.

Morphologic Features in Congenital Pulmonary Airway Malformations and Pulmonary Sequestrations Correlate With Mutation Status: A Mechanistic Approach to Classification.

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.

Extralobar Pulmonary Sequestration in Adrenal Mimicking Neuroblastoma: A Case Report.

Background: Extralobar pulmonary sequestration (ELS) is a malformation composed of bronchopulmonary tissue outside the lungs that is discontinuous from the main tracheobronchial tree. ELS can present as a suprarenal space occupying lesion. Case Report: A 1-day old girl presented with a right supra-adrenal mass, first detected in-utero at 34 weeks. The differential included congenital neuroblastoma, but the urinary VMA was normal. At resection, there was lung tissue composed of dilated and tortuous bronchioles lined by columnar epithelium present in a back- to- back arrangement along with thick-walled vessels, features of an ELS with congenital pulmonary airway malformation type II. Conclusion: ELS enters the differential diagnosis of neonatal suprarenal masses with normal urinary catecholamines, and can have the morphology of a type II congenital pulmonary airway malformation.

Malformación congénita de la vía aérea pulmonar: a propósito de un caso clínico / Congenital pulmonary airway malformation: a clinical case study / Malformação congênita das vias aéreas pulmonares: relato de caso

La malformación congénita de la vía aérea pulmonar (MVAP), antes llamada malformación adenomatoidea quística pulmonar, es una rara anormalidad del desarrollo de las vías respiratorias terminales. Las lesiones son de distribución y tamaños variables, usualmente unilaterales. El diagnóstico puede realizarse desde el período prenatal mediante ecografía gestacional, encontrándose, en ocasiones, graves repercusiones fetales. En los recién nacidos la enfermedad puede manifestarse con dificultad respiratoria aguda. En niños y adultos puede diagnosticarse ante infecciones pulmonares recurrentes u otras complicaciones. En pacientes sintomáticos está indicado el tratamiento quirúrgico para prevenir infecciones y la transformación neoplásica; sin embargo, sigue siendo controversial el tratamiento profiláctico frente al tratamiento expectante en pacientes asintomáticos. Se presenta el caso clínico de una lactante de 2 meses, que en el curso de una bronquiolitis se realizó una radiografía de tórax que evidenció una imagen radiolúcida del lóbulo medio. La tomografía computada visualizó gran imagen quística en pulmón derecho, que podría corresponder a una MVAP. Se decidió tratamiento quirúrgico coordinado. Se realizó una segmentectomía, confirmándose con anatomía patológica una MVAP tipo IV. Evolucionó favorablemente.

Congenital pulmonary airway malformation (CPAM), formerly called pulmonary cystic adenomatoid malformation, is a rare developmental abnormality of the terminal airways. Lesions are of variable size and distribution, usually unilateral. The diagnosis can be made from the prenatal period by means of gestational ultrasound, occasionally causing serious fetal repercussions. In newborns, the disease may manifest itself through acute respiratory distress. In children and adults it can be diagnosed through recurrent lung infections or other complications. In symptomatic patients, surgical treatment is indicated to prevent infections and neoplastic transformation. However, prophylactic versus expectant management in asymptomatic patients remains controversial. We present the clinical case of a 2-month-old infant who, during the course of bronchiolitis underwent a chest X-ray that revealed a radiolucent image of the middle lobe. The computed tomography scan showed a large cystic image in the right lung, which could be linked to an CPAM. The surgical treatment was carried out and the segmentectomy confirmed a pathological type IV CPAM. The patient evolved favorably.

A malformação congênita das vias aéreas pulmonares (MVAP), anteriormente chamada de malformação adenomatoide cística pulmonar, é uma anormalidade rara do desenvolvimento das vias aéreas terminais. As lesões são de tamanho e distribuição variáveis, geralmente unilaterais. O diagnóstico pode ser feito desde o pré-natal por meio da ultrassonografia gestacional, podendo encontrar repercussões fetais graves. Em recém-nascidos, a doença pode se manifestar com dificuldade respiratória aguda. Em crianças e adultos, pode ser diagnosticada com infecções pulmonares recorrentes ou outras complicações. Em pacientes sintomáticos, o tratamento cirúrgico é indicado para prevenir infecções e transformações neoplásicas; no entanto, o tratamento profilático versus expectante em pacientes assintomáticos permanece controverso. Apresentamos o caso clínico de uma criança de 2 meses que foi submetida a radiografia de tórax durante bronquiolite, que revelou imagem radiotransparente do lobo médio. A tomografia computadorizada mostrou grande imagem cística em pulmão direito, que poderia corresponder a uma MVAP. O tratamento cirúrgico foi realizado e a segmentectomia confirmou um tipo IV de MVAP com patologia. A criança evoluiu favoravelmente.

Fetal imaging of congenital lung lesions with postnatal correlation.

Congenital lung lesions are a rare group of developmental pulmonary abnormalities that are often first identified prenatally on routine second-trimester US. Congenital pulmonary airway malformation (CPAM) is the most common anomaly while others include bronchopulmonary sequestration, congenital lobar overinflation, bronchogenic cyst and bronchial atresia. Clinical presentation is highly variable, ranging from apparent in utero resolution to severe mass effect with resultant hydrops fetalis and fetal demise. Differentiation among these lesions can be challenging because overlapping imaging features are often present. The roles of the radiologist are to identify key imaging findings that help in diagnosing congenital lung lesions and to recognize any ominous features that might require prenatal or perinatal intervention. High-resolution US and complementary rapid-acquisition fetal MRI provide valuable information necessary for lesion characterization. Postnatal US and CT angiography are helpful for lesion evaluation and for possible surgical planning. This article reviews the embryology of the lungs, the normal prenatal imaging appearance of the thorax and its contents, and the prenatal and neonatal imaging characteristics, prognosis and management of various congenital lung lesions.

A case of juvenile systemic sclerosis and congenital pulmonary airway malformation related mucinous adenocarcinoma of the lung: paraneoplastic syndrome or just a coincidence?

BACKGROUND: Juvenile systemic sclerosis (JSS) is an extremely rarely seen auto-immune disease characterized by the increased fibrosis of skin and internal organs. Congenital pulmonary airway malformation (CPAM) is a developmental disorder of the lung, characterized by atypical cell hyperplasia which creates the ground for lung adenocarcinoma. In general, CPAM is diagnosed in early childhood, due to recurrent respiratory symptoms including cough, hemoptysis and respiratory infections. Although rare, there are some sporadic asymptomatic cases of CPAM that have been reported. We present a case with a coincidental presence of two rare diseases: JSS and CPAM. CASE: An adolescent female patient was admitted to hospital due to clinical signs of JSS. During the followup, the patient had been diagnosed with cystic adenoid malformation of the lung complicated by mucinous adenocarcinoma. The patient was previously healthy with an unremarkable history, including lack of respiratory symptoms. Left inferior lobectomy was performed. Considering the small size of malignant loci, the total resection of the tumor and absence of any sign for metastasis disease, adjuvant therapy was not scheduled. We haven`t found a pediatric case of CPAM associated adenocarcinoma of the lung presented by signs of JSS in the literature. In this case, the clinical signs of JSS possibly represent part of the paraneoplastic syndrome related to adenocarcinoma of the lung. CONCLUSIONS: Internal organ involvement, including respiratory system, should not be omitted even in asymptomatic patients with JSS. Auto-antibody negativity represents a clue for the possible underlying condition. Further studies with a higher number of patients would reveal more relevant data.

Global interpretation of novel alternative splicing events in human congenital pulmonary airway malformations: A pilot study.

Little is known about differentially expressed genes (DEGs) and alternative splicing (AS) landscapes in congenital lung malformations (CLMs). We applied reference-based assembly of sequencing reads from RNA sequencing (RNA-seq) libraries to identify DEGs and AS landscapes in the lesions and normal lung tissue from the most common types of CLMs, including congenital pulmonary airway malformation-Ⅰ (CPAM-Ⅰ), CPAM-Ⅱ, intralobar sequestration (ILS), and ILS with CPAM (ILS-CPAM). We analyzed the expression profiles and related biological functions of AS events (ASEs). We further constructed a co-expression regulatory network between RNA binding protein (RBP) genes and corresponding ASEs to explore the related pathways in the regulated network. Ten DEGs were identified in the four types of CLMs, including eight upregulated genes and two downregulated genes. Additionally, 16 differential ASEs were detected, including the genes MACF1, RFX2, and FBXL4. Gene ontology (GO) enrichment was mainly observed in embryonic visual malformation and apoptotic process, and the KEGG pathway mainly enriched in the PI3K/AKT signaling pathway. We also detected 13 differentially expressed RBPs among 1979 DEGs in CPAM-I, in which ASEs in the MACF1 gene and RBP genes TLR8 and PTRH1 were closely associated. Moreover, we confirmed that the expression levels of PTRH1, NSUN7, and DZIP1L abundantly increased and the expression levels of TLR8, MEF2A, and NIPBL decreased in the CPAM-I lung tissue compared with the controls. It is suggested that ASEs in different types of CLMs is prominently different from normal controls, and ASEs differences occurring in CPAM-I malformation tissue are dramatically different from other types, which demonstrates the complex pathogenesis of CLMs and provides foundations for future studies to elucidate the mechanisms of developing CLMs.

18FDG PET-Positive Congenital Pulmonary Airway Malformation Mimicking Lung Cancer.

ABSTRACT: Adult cases of type 2 congenital pulmonary airway malformation (CPAM) are extremely rare, and no PET/CT findings have been reported for CPAM. We encountered a case of 18FDG PET-positive CPAM mimicking lung cancer in a 45-year-old asymptomatic man. CT revealed a large cavitary mass in the left lower lobe. SUVmax measured by 18FDG PET was 3.5. The patient underwent video-assisted thoracoscopic lobectomy on suspicion of CPAM with/or lung cancer. Histologically, no neoplastic cells were present, and the lesion was consistent with type 2 CPAM. An adenomatoid proliferative pattern and granulomatous lesions may have contributed to a PET/CT false-positive result.

An Incidental Finding of Congenital Pulmonary Airway Malformation Type 3 During a Forensic Autopsy for a Sudden Infant Death: A Case Report With a Brief Literature Review.

ABSTRACT: Congenital pulmonary airway malformation (CPAM), previously known as congenital cystic airway malformation, is a developmental disorder of the lower respiratory tract. It is subdivided into 5 types based on clinical and pathologic features. Type 3, an adenomatoid type of CPAM, is the second rarest form of CPAM, occurring in approximately 5% of all CPAM cases. This article reports an autopsy of a nearly 11-week-old male infant, found unresponsive in bed with his mother. She had fallen asleep after breastfeeding a few hours prior. Although the autopsy and additional technical examinations did not uncover the exact cause of death, CPAM type 3 was eventually identified on histological examination. Taking into account the context of this case, in which accidental asphyxia/neglect could not be ruled out, it is thought that the presence of CPAM might have contributed to the demise of the infant. As CPAM is a rare congenital disorder, the diagnosis could easily be missed. Therefore, this article aims to raise awareness of this diagnosis and points out the clinical and pathologic features of this disorder.

Mucinous Adenocarcinoma With Intrapulmonary Metastasis Harboring KRAS and GNAS Mutations Arising in Congenital Pulmonary Airway Malformation.

OBJECTIVES: Mucinous adenocarcinoma arising in unresected congenital pulmonary airway malformation (CPAM) is rare. Underlying driver mutations in addition to KRAS gain-of-function mutations in this setting and the long-term outcomes of these patients are unknown. METHODS: We report a case of metastatic mucinous adenocarcinoma harboring both KRAS and GNAS mutations arising in a type 1 CPAM of a 14-year-old male. A literature review was performed. RESULTS: Next-generation sequencing revealed identical KRAS (G12V) mutations in both the CPAM and metastatic adenocarcinoma and a missense mutation in the GNAS (R201C) gene in the metastatic adenocarcinoma only. Median survival was 23 and 4 years for patients with localized (no or limited spread within the same lobe of CPAM) and distant involvement (spread to any different lobe of CPAM) of mucinous cells, respectively (95% confidence interval, 23-23 and 1.5-22 years, respectively; P = .017). CONCLUSIONS: Mucinous cell proliferation associated with type 1 CPAM has exceptionally good long-term outcomes if confined within the same lobe of CPAM. A second oncogenic mutation in the GNAS gene may be necessary for progression to malignancy and distant spread.

The prenatal ultrasonic character and postnatal follow-up of 227 microcystic and macrocystic congenital cystic adenomatoid malformations.

The objective of our study was to compare microcystic and macrocystic congenital cystic adenomatoid malformation (CCAMs) through prenatal characteristics, perinatal outcome, postnatal management and development after consultation in our prenatal diagnosis centre. We conducted a retrospective cohort study of 227 cases prenatally diagnosed as CCAM in our hospital within three years. One hundred and eighty-one cases continued their pregnancy and 46 pregnancies were terminated. One hundred and fifteen of 227 cases were microcystic and 112 were macrocystic. The prenatal ultrasound characteristics of two types showed no statistically significant differences, despite that CVR of macrocystic CCAMs was mildly greater than microcystic. None of recorded cases received surgical intervention in utero. Compared with healthy foetuses, CCAMs presented with higher percentage of polyhydramnios and male foetuses, larger amount of postpartum blood loss and longer duration of NICU hospitalisation. Compared with 46 legal abortions, continued pregnancy cases had a smaller CVR, less polyhydramnios, cardiac shift and hydrops. One hundred and seventy-nine cases were followed up after birth and 174 babies were asymptomatic. Thirty one cases received successful surgical resection. In conclusion, the prenatally diagnosed CCAMs have a good short-term prognosis and conservative management is a reasonable option in asymptomatic fetuses. Microcystic and macrocystic CCAMs both presented similar prenatal courses and perinatal prognoses. Conservative management, prenatally and postnatally, could be accepted in selected cases.Impact statementWhat is already known on this subject? Congenital cystic adenomatoid malformation is a well-known developmental abnormality of the lung. The prognosis for most CCAMs is good, but the prenatal and postnatal management remains controversial.What do the results of this study add? This study is one of the largest case cohorts to conclude that microcystic and macrocystic CCAMs both presented similar prenatal courses and perinatal prognoses. Conservative management is a reasonable option in asymptomatic babies.What are the implications of these findings for clinical practice and/or further research? A comprehensive assessment by an experienced multidisciplinary team is necessary to forbid blinding abortions of CCAMs. Conservative management prenatally and postnatally could be accepted in most asymptomatic cases.

Mucinous adenocarcinoma arising in congenital pulmonary airway malformation: clinicopathological analysis of 37 cases.

AIMS: Mucinous adenocarcinoma arising in congenital pulmonary airway malformation (CPAM) is a rare complication, with little being known about its natural course. The aims of this article are to describe a series of mucinous adenocarcinomas arising from CPAMs, and present their clinicopathological features, genetics, and clinical outcome. METHODS AND RESULTS: Thirty-seven cases were collected within a 34-year period, and the subtype of adenocarcinoma and CPAM, tumour location, stage, growth patterns, molecular data and follow-up were recorded. The cohort comprised CPAM type 1 (n = 33) and CPAM type 2 (n = 4). Morphologically, 34 cases were mucinous adenocarcinomas (21 in situ; 13 invasive), and three were mixed mucinous and non-mucinous adenocarcinoma. Seventeen cases showed purely extracystic (intra-alveolar) adenocarcinoma, 15 were mixed intracystic and extracystic, and five showed purely intracystic proliferation. Genetically, nine of 10 cases tested positive for KRAS mutations, four with exon 2 G12V mutation and five with exon 2 G12D mutation. Residual disease on completion lobectomy was observed in two cases, and three cases recurred 7, 15 and 32 years after the original diagnosis. Two patients died of metastatic invasive mucinous adenocarcinoma. CONCLUSIONS: Most adenocarcinoma that arise in type 1 CPAMs, are purely mucinous, and are early-stage disease. Intracystic proliferation is associated with lepidic growth, an absence of invasion, and indolent behaviour, whereas extracystic proliferation may be associated with more aggressive behaviour and advanced stage. Most cases are cured by lobectomy, and recurrence/residual disease seems to be associated with limited surgery. Long-term follow-up is needed, as recurrence can occur decades later.

Single-cell transcriptome profiling reveals the mechanism of abnormal proliferation of epithelial cells in congenital cystic adenomatoid malformation.

OBJECTIVES: Congenital cystic adenomatoid malformation (CCAM) is the most common congenital pulmonary anomaly with unknown etiology. Here, single-cell RNA sequencing (scRNA-seq) was used to map its cellular landscape and identify the underlying cellular and molecular events related to CCAM. METHODS: This study involved a 4.25 year old patient with grade Ⅱ-Ⅲ CCAM at the Children's Hospital of Fudan University. Samples of lesioned and non-lesioned areas were collected during surgery for scRNA-seq. RESULTS: In total, 19,904 cells were obtained with median UMI counts of 7032 per cell and 1995 median genes per cell. In terms of lesioned and non-lesioned areas, epithelial cells accounted for 27.23% and 17.85%, respectively, while mesenchymal cells accounted for 2.67% and 16.06%, respectively (P < 0.0001). Further clustering of epithelial cells revealed that the fractions of alveolar type 1 cells (AT1, N: 23.65%; L: 49.81%), AT2(N: 2.02%; L: 5.26%), club-1(N: 9.02%; L: 17.57%), club-3(N: 1.18%; L: 4.15%), and basal cells (N: 0.34%; L: 2.93%) were increased in lesioned samples (P < 0.0001). Pseudotime trajectory analysis showed tracks of club-1/basal cells→AT2→club-3→AT1 and club-1,2/basal→AT2. Mast cells (N: 0.63%; L: 2.48%) were also increased in lesioned samples and interactions of CD44 with HBEGF and FGFR2 were detected between mast and epithelial cells. CONCLUSIONS: AT1, AT2, club, and basal cells were increased in CCAM patients, and newly defined club-1/3 and basal cells might be the origin of proliferating AT1 and AT2 cells. Increased mast cells might promote epithelial cell proliferation through interactions of CD44 with HBEGF and FGFR2.

Early KRAS oncogenic driver mutations in nonmucinous tissue of congenital pulmonary airway malformations as an indicator of potential malignant behavior.

The potential for malignant degeneration is the most common reason for some practitioners to resect asymptomatic congenital pulmonary airway malformations (CPAMs). We aimed to investigate the potential of various immunohistochemical (IHC) and genomic biomarkers to predict the presence of mucinous proliferations (MPs) in CPAM. Archival CPAM tissue samples were re-assessed and underwent IHC analysis using a panel of differentiating markers (TTF1/CDX2/CC10/MUC2/MUC5AC/p16/p53/DICER1). In each sample, intensity of IHC staining was assessed separately in normal lung tissue, CPAM, and MP tissue, using a semiquantitative approach. Likewise, next-generation targeted sequencing of known adult lung driver mutations, including KRAS/BRAF/EGFR/ERBB2, was performed in all samples with MP and in control samples of CPAM tissue without MP. We analyzed samples of 25 CPAM type 1 and 25 CPAM type 2 and found MPs in 11 samples. They were all characterized by strong MUC5AC expression, and all carried a KRAS mutation in the MP and adjacent nonmucinous CPAM tissue, whereas the surrounding normal lung tissue was negative. By contrast, in less than half (5 out of 12) control samples lacking MP, the CPAM tissue also carried a KRAS mutation. KRAS mutations in nonmucinous CPAM tissue may identify lesions with a potential for malignant degeneration and may guide histopathological assessment and patient follow-up.

Mucinous Cell Clusters in Infantile Congenital Pulmonary Airway Malformations Mimic Adult Mucinous Adenocarcinoma But Are Not Associated With Poor Outcomes When Appropriately Resected.

Congenital pulmonary airway malformations (CPAMs) are abnormalities of the lung arising during development. At our institution the majority of type I infantile CPAMs contain mucinous cell clusters (MCCs). The overlapping histology of MCCs and adult in situ mucinous adenocarcinomas, as well as reports of metastatic mucinous adenocarcinoma arising in CPAMs resected later in childhood raise concerns about the malignant potential of these cells. However, after adequate surgical resection, malignant recurrence has not been reported in infants with CPAMs. Despite benign behavior, MCCs often have histologic features that, in an adult, would be consistent with a diagnosis of adenocarcinoma. Therefore, to assess the spectrum of features that may be seen in these presumed precursor lesions, we characterized the histology of 671 MCCs spread across 44 infantile CPAMs and compared them to 10 adult mucinous adenocarcinomas. MCCs in CPAMS were often numerous, widespread, and located outside of the large cysts. Mucinous and nonmucinous epithelium within CPAMs showed complex architecture, making application of adult adenocarcinoma architectural patterns difficult. The MCCs within CPAMs displayed nuclear features similar to adult mucinous adenocarcinomas. The proliferative index in infantile MCCs was higher than in adult mucinous adenocarcinomas but was also higher in uninvolved infantile lung tissue. This work illustrates that histologic features typically associated with adenocarcinoma frequently occur within CPAMs; however, this does not alter their benign behavior. Therefore, extreme caution should be used if adult lung cancer terminology is applied to avoid significant potential psychological and physical harms associated with the label of adenocarcinoma.

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

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 epithelial-mesenchymal 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.

Congenital cystic adenomatoid malformations of the lung: an epithelial transcriptomic approach.

BACKGROUND: The pathophysiology of congenital cystic adenomatoid malformations (CCAM) of the lung remains poorly understood. AIM: This study aimed to identify more precisely the molecular mechanisms limited to a compartment of lung tissue, through a transcriptomic analysis of the epithelium of macrocystic forms. METHODS: Tissue fragments displaying CCAM were obtained during planned surgical resections. Epithelial mRNA was obtained from cystic and normal areas after laser capture microdissection (LCM). Transcriptomic analyses were performed and the results were confirmed by RT-PCR and immunohistochemistry in independent samples. RESULTS: After controlling for RNA quality, we analysed the transcriptomes of six cystic areas and five control areas. In total, 393 transcripts were differentially expressed in the epithelium, between CCAM and control areas. The most highly redundant genes involved in biological functions and signalling pathways differentially expressed between CCAM and control epithelium included TGFB2, TGFBR1, and MAP 2 K1. These genes were considered particularly relevant as they have been implicated in branching morphogenesis. RT-qPCR analysis confirmed in independent samples that TGFBR1 was more strongly expressed in CCAM than in control tissues (p < 0.03). Immunohistochemistry analysis showed TGFBR1 (p = 0.0007) and TGFB2 (p < 0.02) levels to be significantly higher in the epithelium of CCAM than in that of control tissues. CONCLUSIONS: This compartmentalised transcriptomic analysis of the epithelium of macrocystic lung malformations identified a dysregulation of TGFB signalling at the mRNA and protein levels, suggesting a possible role of this pathway in CCAM pathogenesis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01732185.

Fetal lung interstitial tumor: Prenatal presentation of a rare fetal malignancy.

Fetal lung interstitial tumor (FLIT) is a rare fetal malignancy that is typically diagnosed in the postnatal period, or, if recognized prenatally can mimic a benign lesion such as congenital pulmonary airway malformation. We present the earliest case of a FLIT tumor described by ultrasound and MRI at 26 weeks of gestation. Our case highlights features suggestive of FLIT including presentation later in gestation in combination with findings on fetal MRI such as a solid appearance with radiating curved bands of high signal within and along the periphery of the lesion (not as intensely high signal as the typical CPAM), possibly detailing a radiographic signature for these tumors. The role of betamethasone for these tumors is not known.

Establishment of a biobank for human lung tissues of congenital diaphragmatic hernia and congenital pulmonary airway malformation.

BACKGROUND: Human tissue samples are an invaluable and little available source of information for translational studies of congenital lung diseases such as Congenital Diaphragmatic Hernia (CDH) or Congenital Pulmonary Airway Malformation (CPAM). PURPOSE: We aimed to establish a human lung tissue biobank of CDH and CPAM patients together with age-matched controls, coupled with a clinical database. METHODS: Pathology records from autopsies or surgical specimens for CDH and CPAM cases between 1980 and 2017 were reviewed. For surviving individuals, clinical patient data was obtained from corresponding pediatric surgery reports. Formalin-fixed, paraffin-embedded tissues of patients and age-matched controls were systematically stored for further translational studies. RNA integrity was determined on selected CDH blocks. RESULTS: A total of 16 CDH and 18 CPAM and age-matched control lung tissue blocks were included in our biobank. Ages ranged from 22 to 41 weeks of gestation (GA) in CDH (33.9 ±â€¯6.35 weeks) and 26 weeks (GA) and 12 years in CPAM (2.3 ±â€¯3.7 y). RNA isolation from CDH and control blocks yielded good RNA quality (OD 260/280 ratio: 2.01-2.09, OD 260/230 ratio: 2.04-2.09). CONCLUSION: We established a unique human biobank for CDH and CPAM tissues. The combination with clinical patient data will allow us to design future translational studies to improve our understanding of the disease pathogenesis of these congenital malformations.