Antenatal and Postnatal Management of Congenital Cystic Adenomatoid Malformation

Paediatric Respiratory Reviews 13 (2012) 162–171

Contents lists available at SciVerse ScienceDirect

Paediatric Respiratory Reviews

CME article

Antenatal and Postnatal Management of Congenital Cystic Adenomatoid Malformation S. Kotecha 1,*, A. Barbato 2, A. Bush 3, F. Claus 4, M. Davenport 5, C. Delacourt 6, J. Deprest 7, E. Eber 8, B. Frenckner 9, A. Greenough 10, A.G. Nicholson 11, J.L. Anto´n-Pacheco 12, F. Midulla 13 1

Department of Child Health, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom Department of Pediatrics, University of Padova, Padua, Italy Department of Paediatrics, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Division, Imperial College, London, United Kingdom 4 Department of Radiology, University Hospitals Leuven, Leuven, Belgium 5 Department of Paediatric Surgery, King’s College Hospital, London, United Kingdom 6 Service de Pneumologie Pe´diatrique, hoˆpital Necker, Universite´ Paris Descartes, Paris, France 7 Department of Obstetrics and Gynaecology University Hospitals Leuven, Leuven, Belgium 8 Department of Paediatrics, University Children’s Hospital, Medical University of Graz, Graz, Austria 9 Department of Paediatric Surgery, Astrid Lindgren Children’s, Karolinska Institutet, Stockholm, Sweden 10 Division of Asthma, Allergy and Lung Biology, King’s College London, London, United Kingdom 11 Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust and National Heart and Lung Division, Imperial College, London, United Kingdom 12 Division of Pediatric Surgery, Hospital U. 12 de Octubre, Universidad Complutense, Madrid, Spain 13 Paeditric Department, Sapienza University of Rome, Rome, Italy 2 3

EDUCATIONAL AIMS  To review diagnostic terminology for congenital cystic thoracic lesions  To discuss the clinical course of congenital cyst adenomatoid malformations (CCAMs) and its related condition pulmonary sequestration from the time of diagnosis to resection or spontaneous resolution  To discuss the limited evidence for prophylactic surgery versus conservative management of asymptomatic CCAMs in infants  To underline the importance of longitudinal clinical follow-up of all patients with CCAMs

A R T I C L E I N F O

S U M M A R Y

Keywords: Congenital thoracic malformation Congenital lung malformations Pulmonary sequestration Pleuropulmonary blastoma Bronchial atresia

Congenital thoracic malformations (CTMs) are a heterogeneous group of rare disorders that may involve the airways or lung parenchyma. The authors have focused on the condition that causes the most controversy, namely, congenital cystic adenomatoid malformation (CCAM). The reported incidence is 3.5 and 0.94 per 10,000 live births for CTMs and CCAMs respectively. Ultrasound is the antenatal imaging modality of choice for screening for CCAMs whilst magnetic resonance imaging is complimentary for morphological and volumetric evaluation of the foetal lung. Most CCAMs are detected antenatally with only a small proportion presenting postnatally. Only a few CCAMs cause foetal problems, with foetal hydrops being the best predictor of death. Although many CCAMs regress during pregnancy, most remain detectable postnatally by CT scans. Surgical excision of symptomatic lesions is relatively straightforward, but management of asymptomatic lesions is controversial. Some surgeons adopt a ‘‘wait and see’’ approach operating only on those patients who develop symptoms, but others operate on asymptomatic patients usually within the first year of life. Due to the potential of malignant transformation, children should have long term follow up. There is an urgent need to delineate the natural history of antenatally detected CCAMs to guide future management. ß 2012 Elsevier Ltd. All rights reserved.

INTRODUCTION * Corresponding author. Department of Child Health Cardiff University School of Medicine Cardiff CF14 4XN, United Kingdom. Tel.: +44 0 29 20 74 4187; fax: +44 0 29 20 74 4283. E-mail address: [email protected] (S. Kotecha). 1526-0542/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2012.01.002

Congenital thoracic malformations (CTMs) are a heterogeneous group of rare disorders that may involve the upper and lower airways or the lung parenchyma. Although CTMs are rare, they may

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171

lead to considerable morbidity and mortality. While the availability of new imaging modalities such as ultrasound (US) scanning and magnetic resonance imaging (MRI) have improved antenatal and postnatal diagnosis, they have also introduced complexities to the classification and management of CTMs. Although antenatally diagnosed lesions may spontaneously regress before birth, evidence-based information to advise parents about management options is lacking. Due to the complexity of congenital thoracic malformations, we have focussed on the condition that causes the most controversy, namely, congenital cystic adenomatoid malformation (CCAM), and the related malformation pulmonary sequestration (PS) although it is accepted that some conditions such as bronchogenic cysts and bronchial atresia may be difficult to distinguish until resection. We have reviewed antenatal presentations, the antenatal and postnatal therapeutic options, and prognosis. We have reviewed the problems of congenital diaphragmatic hernia elsewhere.1 NOMENCLATURE The nomenclature of CTMs is confusing with clinicians often trying to make a pathological diagnosis on grey scale imaging. However, the introduction of antenatal scanning necessarily involves attempts to identify the most likely diagnosis (Table 1) to guide management especially antenatally. There are excellent recent reviews covering classification and nomenclature of CTMs.2,3 It is suggested that the following principles should be adhered to when looking at clinical images, either ante- or postnatally3:

163

d) Important associated organs (in particular, the heart, great vessels, chest wall, and abdominal contents) should be considered in a systematic manner, because abnormalities are often multiple, and associated lesions will be missed unless carefully sought.

EPIDEMIOLOGY Epidemiology of CTMs needs unbiased population-based reporting which is not always available: in 1979, the European Community established the European Surveillance of Congenital Anomalies (EUROCAT), whose aim was to establish a network of populationbased registers for the epidemiological surveillance of congenital anomalies including CTMs. The robustness of the data depends on that (a) all pregnant women had an antenatal ultrasound scan, and (b) the scans were of diagnostic quality and properly interpreted. The data were collected from 43 European registries in 20 European countries.4 The individual registers were regional and not national in most cases, with EUROCAT capturing approximately 29% of Europe’s birth population.4 In 2008, EUROCAT reported 222 fetuses with CTMs giving an incidence of 4.44/10,000 (i.e. including live births, foetal deaths and terminations of pregnancy). Of the 222 fetuses, 52 had CCAM alone i.e. an incidence of 1.04/10,000. The incidence was 3.52 and 0.94 per 10,000 live births in 2008 for all CTMs and CCAMs respectively in EUROCAT countries. The reported annual incidence of pulmonary sequestration ranges between 0.15% and 6.45% of all CTMs.5–9 PATHOLOGY

a) What is actually seen should be described, without embryological or pathological speculation, which may later be proved wrong. A simple ‘catch-all’ term, congenital thoracic malformation (CTM) should replace the old nomenclature in clinical discussions.3 b) The description should be in clear language, not Latin, avoiding ambiguity. Thus a CTM could be described (ante- or postnatally) as solid or cystic; if cystic, the cysts should be described as single or multiple, whether large or small (ideally with the size measured rather than estimated), thin or thick walled, and whether the contents are purely fluid or (postnatally) contain air should be noted. c) The CTM should be described in the context of the rest of the respiratory system, and also any relevant extrathoracic features. Thus the rest of the respiratory system should as far as possible be described in a systematic manner. The lung is formed from six ‘‘trees’’: bronchial, arterial (systemic and pulmonary), venous (systemic and pulmonary) and lymphatic. There are no known abnormalities of bronchial venous drainage, so in practice, only five trees are considered. Table 1 Differential diagnosis of CTMs Congenital cystic adenomatoid malformation Congenital diaphragmatic hernia Tracheo-oesophageal fistula Pulmonary sequestration Cysts - bronchogenic - foregut Tumours - neuroblastoma - mediastinal teratoma - rhabdomyoma Atresia - bronchial with distal degeneration Congenital lobar emphysema Congenitally small lungs Lung agenesis Vascular abnormalities - vascular rings - pulmonary artery slings

Diagnostic terminology for congenital cystic lung lesions has varied considerably over the 20th century. Several unifying proposals have been made, such as ‘malinosculation’ and types 0-4 CCAM, but without universal uptake of usage.10–12 There is also increasing recognition of overlap between ‘entities’, for example features of CCAM in both sequestrations and bronchial atresia.12–14 Finally, recent advances in understanding how blastematous neoplasms behave in terms of regression have also influenced proposed classifications.15 Table 2 shows two proposals; discussion below follows that of Langston,12 other than reviewing sequestrations as a separate group. BRONCHIAL ATRESIA This anomaly (Figure 1) typically takes the form of a membrane, fibrous cord or gap in a bronchus, with the distal airway showing dilatation, often saccular or cyst-like, and the lumen filled with mucus or purulent exudate if infected. Atresia is most commonly seen in segmental bronchi. There may also be distal hyperinflation probably due to collateral ventilation and/or air trapping. PULMONARY SEQUESTRATION Pulmonary Sequestration (PS), divided into intralobar (Figure 2) and extralobar types, are localised lesions comprising lung parenchyma receiving their blood supply via aberrant systemic arteries and lacking continuity with the upper respiratory tract.12,13 Extralobar sequestrations have their own covering visceral pleura, whilst intralobar are localised lesions within otherwise normal lung. Intralobar sequestrations are typically located in the posterior basal segment of the left lower lobe and extralobar sequestrations beneath the left lower lobe. Microscopically, they show dilated airspaces, some lined by bronchiolartype epithelium, with or without inflammation and fibrosis.13 Features of type 2 CCAM are seen in up to 60% of cases.13,14 Rarely,

164

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171

Table 2 A comparison of two proposals for the classification of CCAMs. Congenital pulmonary airway malformation: a new name for and an expanded classification of congenital cystic adenomatoid malformation of the lung. (Ref 11)

New concepts in the pathology of congenital lung malformations. (Ref 12)

Type 0 CCAM – Acinar atresia

Bronchogenic cyst

Type 1 CCAM – Cysts up to 10 cm. The cysts are lined by pseudostratified ciliated cells that are often interspersed with rows of mucous cells

Type 2 CCAM – Sponge- like multiple small cysts (<2cm) and solid pale tumour- like tissue. The cysts resemble dilated bronchioles separated by normal alveoli. Striated muscle seen in 5%

Bronchial atresia  Isolated  With systemic arterial/venous connection (intralobar sequestration)  With connection to GI tract  Systemic arterial connection to normal lung CCAM, large cyst type (Stocker type 1)  Isolated  With systemic arterial/venous connection (hybrid/intralobar sequestration) CCAM, small cyst type (Stocker Type 2)  Isolated  With systemic arterial/venous connection (hybrid/intralobar sequestration

Type 3 CCAM – Solid. Excess of bronchiolar structures separated by small air spaces with cuboidal lining (foetal lung)

Type 4 CCAM – Cysts up to 10 cm. The cysts are lined by flattened epithelium resting upon loose mesenchymal tissue

Extralobar sequestration  Without connection to GI tract  With connection to GI tract Pulmonary hyperplasia and related lesions  Laryngeal atresia  Solid or adenomatoid CCAM (Stocker Type3)  Polyalveolar lobe Congenital lobar over-inflation Other cystic lesions  Lymphatic cysts, Enteric cysts, Mesothelial Cysts, Simple parenchymal cysts, Regressed type 1 pleuropulmonary blastoma

an ‘‘airway’’ may connect the sequestration to the oesophagus or stomach,16; or ectopic pancreatic tissue may be present within the sequestration.17 PS, especially extralobar, can be associated with other malformations. CONGENITAL CYSTIC ADENOMATOID MALFORMATION CCAM encompasses a spectrum that remains the subject of research and argument. Although recognised for over a century,

Figure 1. Bronchial atresia. The cut surface of the lung shows dilated airways with surrounding microcystic changes. Dissection showed atresia within a segmental bronchus.

the term CAM was introduced in 194918 with ‘cystic’ added in later publications that described types 1-3.19,20 Types 0 and 4 were subsequently proposed, the hypothesis being that these lesions range from type 0 being an essentially tracheobronchial defect to type 4 being an alveolar defect.11,20 On this basis the term congenital pulmonary airway malformation was proposed instead of CCAM as only types 1-3 were adenomatoid and only types 1, 2 and 4 were cystic.11 However, as seen from Table 2, this classification has not been universally accepted and it seems more likely that types 0, 3 and 4 represent different pathogenetic processes. Type 0 is better viewed as congenital acinar dysplasia and type 3 as pulmonary hyperplasia. Type 4 is more controversial as its features overlap with type 1 pleuropulmonary blastoma, the distinguishing feature being a lack of blastema in type 4 CCAM,

Figure 2. Intralobar sequestration. The lung contains a cystic mass-like lesion filled with mucoid material. Adjacent to the cyst, a prominent systemic artery can be seen.

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171

165

Figure 4. Type 2 Cystic adenomatoid malformation. In contrast to the type 1 CCAM, the cut surface is more spongiform, with smaller more uniform cystic spaces.

by simplified alveolar parenchyma.11 Occasionally, striated muscle may be seen.11,27,28 Figure 3. Type 1 Cystic adenomatoid malformation. (A) A cystic lesion fills most of the lower lobe. An arrow highlights a barely visible area of consolidation at its lower aspect. (B) Further sectioning of this area shows a mucinous adenocarcinoma of lepidic pattern.

leading to some viewing such lesions as ‘regressed’ pleuropulmonary blastomas.15 Such complexities show the inadvisability of embryological speculation from pathological appearances. Type 1 CCAM This is the commonest type, with a good prognosis, as it is a relatively localised lesion that typically affects only part of a lobe (Figure 3a). The cysts range widely in size, arbitrarily defined as at least one cyst being more than 2 cm in diameter and, to emphasise the overlap between CCAMs, atretic bronchi may be identifiable.21,22 Cysts are lined by pseudostratified ciliated columnar epithelium, sometimes interspersed with rows of mucous cells.11 It is estimated that 1-2% of type 1 lesions are complicated by malignant change (Figure 3b), nearly always a mucinous adenocarcinoma of lepidic pattern.23–25 Both the intracystic mucinous cells and those within adenocarcinomas show genetic abnormalities (such as k-ras mutations) similar to those seen in mucinous adenocarcinomas arising ‘de novo’.24,26 Atypical adenomatous hyperplasia has also been seen in background lung, suggesting genetic instability in both CCAMs and surrounding lung.23 Type 2 CCAM Rarer than type 1 CCAMs and often seen within sequestrations,13,14 this lesion is sponge-like, consisting of multiple small cysts measuring up to two centimetres (Figure 4). Microscopically the cysts comprise dilated bronchiole-like structures interspersed

PULMONARY HYPERPLASIA AND RELATED LESIONS Hyperplastic lungs, especially in the context of laryngeal atresia, are grossly enlarged and compress adjacent structures. Microscopically, bronchiolar structures are separated by small air spaces with cuboidal lining resembling late foetal lung. There are virtually no arteries within the lesion.11 These changes are also those of the type 3 CCAM, these maybe reflecting airway atresia at a lower level. Polyalveolar lobe is a further type of hyperplastic lung lesion where there are a normal number of conductive airways, but an increased numbers of alveoli per acinus.29 The affected lobe, usually left upper, is enlarged and air-filled, clinically resembling congenital lobar emphysema, but individual alveoli are not increased in size. The aetiology is obscure but partial or sporadic airway obstruction may lead to a lesser degree of hyperplasia when compared to the hyperplasia associated with laryngeal atresia. OTHER CYSTIC LESIONS Regressed type 1 pleuropulmonary blastoma versus type 4 CCAM This rare lesion typically presents as infantile respiratory distress or repeated pneumonia in childhood, but may occasionally present in adults.23 The cysts are peripheral and thin-walled, and lined by alveolar or bronchiolar epithelial cells resting upon loose mesenchymal tissue.11 Morphologically, this description encompasses both type 4 CCAM and type 1 pleuropulmonary blastoma other than type 4 CCAMs lack foci of hypercellular blastema, hence the view that type 4 CCAMs are regressed neoplasms (Figure 5). This remains a contentious area but there is agreement that any lesion with type 4 CCAM morphology that shows hypercellularity should be classified as type 1 pleuropulmonary blastoma.15,23,30 Identification of a specific gene mutation (DICER-1) related to pleuropulmonary blastomas may help elucidate the true nature of these lesions.31,32

166

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171

most cases normal delivery with postnatal evaluation is sufficient.37–40 Only few CCAMs cause foetal problems, with foetal hydrops being the best predictor of death. When the CVR is >1.6, the risk for hydrops ranges between 15–75%. Proposed ante- and peri-natal interventions include steroid administration, intra-uterine puncture or shunting of macrocystic masses, alcohol embolisation or lasering of the feeding vessel, lobectomy via hysterotomy for more solid masses and resection while on placental circulation.41–49 Foetal pleural effusions may be treated with pleura-amniotic shunt. The evidence base for these interventions is currently poor. CLINICAL PRESENTATION OF CCAMS

Figure 5. Type 4 Cystic adenomatoid malformation (regressed cystic pleuropulmonary blastoma). These cysts are multiloculated and lined by native pneumocytes with loose cytologically bland stroma comprising their walls (care needs to be taken to ensure that no blastematous elements are present, which would then indicate a diagnosis of pleuropulmonary blastoma).

ANTENATAL MANAGEMENT OF CCAMS Antenatal presentation and imaging characteristics of CCAMs Ultrasound (US) is the antenatal imaging modality of choice to screen for CCAMs and magnetic resonance imaging (MRI) is an excellent modality for morphological and volumetric evaluation of the foetal lung. Both modalities may complement each other especially for equivocal findings and are discussed further in the ERS Task Force document on congenital diaphragmatic hernia.1 It is important to describe the lesions in detail after imaging and to provide a differential diagnosis (Table 1) to guide management. CCAMs may ‘‘resolve’’ i.e. are not observed by ultrasound during pregnancy but are often detectable postnatally by computed tomography (CT) scans; they may also increase in size during pregnancy. Larger lesions can cause mediastinal shift and hydrops. Polyhydramnios may be caused by swallowing problems or by oesophageal compression or atresia. Normal lung may become compressed, leading to pulmonary hypoplasia. MRI may discriminate small lesions, and detect cystic CTMs. Pulmonary sequestrations are lung masses lacking communication with the rest of the airways with their own blood supply. The mass has an increased echogenicity or MRI signal intensity by fluid entrapment, similar to type III CCAM lesions. It may be difficult to differentiate the lesion from bronchial atresia if the normal part of the lung becomes compressed. Although differentiation is often made between CCAM and pulmonary sequestration on the basis of a separate blood supply, CCAMs can also have a separate blood supply on occasions. Hybrid cases have also been described.33–35 Extra-thoracic sequestration has been described.

Clinical presentation of CCAMs and other CTMs is discussed in detail elsewhere.2,50–53 Briefly, most CCAMs are detected antenatally, with few presenting postnatally either asymptomatically, detected on routine chest x-rays, or symptomatically, especially with respiratory distress in the neonatal period. Infants with large lesions may have such respiratory insufficiency. They will require intubation and ventilation until surgery. Infrequently such patients may have pulmonary hypertension. Infants with smaller lesions may be too tachypnoeic to feed or be stridulous because their airway is compressed, such infants will require surgery. Later symptomatic presentation of CCAMs include repeated chest infections, bronchiectasis, lung abscess, haemoptysis, pneumothorax, air embolism, haemothorax, pyopneumothorax, steroid resistant asthma, high output cardiac failure (if there is a large systemic arterial blood supply) or rarely with malignant transformation. INVESTIGATIONS FOR SUSPECTED CCAMS In infants with a CCAM, the chest radiograph will demonstrate a cystic, solid or mixed lesion in the affected lobe(s); mediastinal shift is common. HRCT is useful to elucidate associated lung masses and bronchopulmonary foregut malformations.54 Doppler ultrasonography, CT scanning or MR angiography can be used to determine the arterial supply and venous drainage in pulmonary sequestrations.55–58 Aortography is now rarely, if ever, required.58 POSTNATAL SURGICAL MANAGEMENT OF CCAMS Indications for surgical excision

Antenatal management of CCAMs

All CCAMs should be evaluated for surgery. If the infant is symptomatic, the choice is easy. Appropriate management of the child with suspected CCAM, but no symptoms is controversial. This area was addressed in a systematic review and meta-analysis,59 which reviewed English-language literature from 1996 – 2008, identifying 41 series (total cases, n = 1070). The rate of complications occurring in asymptomatic infants beyond the neonatal period was estimated at 3.2% occurring at a median of seven months of age. Nevertheless, in some of those formerly asymptomatic infants, complications could be life-threatening.59,60 Elective surgery was also associated with significantly less post-operative complications than emergency surgery. There are four possible justifications for ‘‘prophylactic’’ surgery

A CCAM acts as space occupying lesion. If large, it causes pulmonary hypoplasia and mediastinal shift, with subsequent hydrops foetalis and polyhydramnios. Growth accelerates from 20 weeks onwards and is maximal around 28 weeks, thereafter the majority decrease in size. Crombleholme proposed using the ratio of lesion mass to the head circumference, the CCAM Volume Ratio (CVR) for follow up and/or to predict foetal demise.36 For

 Prevent chest infection and sepsis, and other rarer complications such as bleeding and pneumothorax  Prevention of malignancy  Early, rather than delayed, surgery may encourage compensatory lung growth  Reduction in post-operative complications (compared to emergency surgery)

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171

A further legitimate reason for surgery in older children is to determine the nature of an undiagnosed lesion which may be congenital or an acquired malignancy. Some surgeons adopt a ‘‘wait and see’’ approach for all their patients,61–63 and operate only on those who develop symptoms. In one series of 56 children61 with an antenatal diagnosis of CCAM over a 7-year period, two CCAMs spontaneously resolved postnatally and 10 had resolved antenatally suggesting ante- and postnatal resolution rates of 18% and 4%, although the series are too small to be dogmatic. One lesion occupying the whole hemithorax antenatally which decreased substantially before birth was reported.61 CT Scanning at 9 months showed a lesion measuring 2 cm which disappeared completely by 37 months. Timing of surgery This is dictated by severity of symptoms, with some large lesions requiring emergency surgery on the first day of life. Wherever possible, such infants should be medically stabilized and assessed urgently (ideally by CT scan). The aim of resection is to salvage adjacent viable lung parenchyma and reverse any mediastinal displacement. If resection is advised in asymptomatic cases, then most would schedule surgery between the neonatal period and the first birthday. The lung continues to grow and develop until at least two years of age and there is some suggestion that there is better catchup lung growth following early thoracotomy. However, no difference was noted in long-term lung function by age at thoracotomy (two years was used as cut-off) in a study of 14 children.64 Conventional thoracotomy and lung resection The aim is for complete excision usually by lobectomy. Smaller lesions may be resected by segmentectomy to preserve parenchyma and if the CCAM involves multiple lobes then this is a better option. Resection of extralobar sequestration is usually straightforward, but special care needs to be taken with the vasculature. Early postoperative complications such as atelectasis, prolonged air leak, pleural effusion, chylous effusion, pneumothorax and broncho-pleural fistula are rare.65–69 In the longer term, scoliosis and chest wall deformities are possible sequelae but their prevalence is unknown. Surgery on patients with symptomatic CCAMs marginally increases complications including increased length of stay.70 Thoracoscopy and minimally invasive resection The largest video-assisted thoracoscopic surgery (VATS) series describes 97 lobectomies over a 10 year period.71 The technique requires single lung ventilation and is possible even in neonates. Although most lung pathology can be treated thoracoscopically, some lesions such as lobar emphysema can cause difficulty because of the hyperinflated lobe and difficult access in a small chest cavity.71,72 Caution is advised in those with a history of pneumonia because of the risk of adhesions and loss of fissure anatomy.71,72 VATS resection of CCAMs results in longer operative times but shorter hospital stay, better cosmesis and decreased post-operative pain.72–74 There are no good studies comparing VATS with conventional thoracotomy. Other therapeutic options Embolization of the systemic feeding vessel has been used in some cases of pulmonary sequestration and other lesions with an arterial supply as an alternative to surgery.75 Probably there is no

167

advantage over operative treatment because general anaesthesia is also needed (although post-operative pain may be decreased) and on the other hand, long-term results are lacking. The two techniques have not been formally compared. SHORT- AND LONG-TERM PROGNOSIS OF CCAM The natural history of CCAMs is still not well defined. A recent systematic review comparing risk of adverse outcomes after elective and emergency surgery, also reported outcomes for antenatally diagnosed CCAMs.59 Many CCAMs decrease in size over time with 18% and 11% respectively regressing or resolving on antenatal ultrasound.59 Although some ‘‘disappear’’ on serial antenatal ultrasound scans or postnatal chest xrays6,37,40,60,61,63,65,69,76–83 the majority can be detected by CT or MR imaging.40,61,64,68,70,81,82 For children who are asymptomatic in the neonatal period,6,84,85 the subsequent development of symptoms has been poorly evaluated (partly because many asymptomatic CCAMs are resected). In the above systematic review,59 from 505 asymptomatic antenatally diagnosed lesions who survived the perinatal period without surgery, 16 (3.2%) developed symptoms by 7 months of age (range 2.5 – 10 months) but only included 4 publications but overall from 13 included studies, 10% developed symptoms by 10 months of age (with a range of 2 months to 8.5 years). In a more recent study, 18 out of 21 patients who were asymptomatic at birth subsequently developed symptoms at a median age of two years (range: 1 month – 13 years).85 Given the relatively short follow-up in these series, the true incidence of complications is likely to be higher. The latter is particularly true for the risk of malignant transformation.11,15,23,26,86–103 CCAM has been shown to predispose to the development of lung neoplasms. Rhabdomyosarcoma or pleuropulmonary blastoma arising within a CCAM is commonest in children.26,86,89,91,99,100,104 Bronchioloalveolar carcinoma may develop in CCAM type 1, in young adulthood.23,87,88,90,92,96,101 CCAM may be a preinvasive lesion for mucinous bronchioloalveolar carcinoma, which may be very slow-growing.101 Prophylactic resection of CCAMs may not prevent the development of pleuropulmonary blastoma.105The long-term respiratory outcome after surgery depends on the extent of lung resection. The possibility of compensatory lung growth in infants and young children is one of the main arguments for resecting asymptomatic CCAMs.106 The potential for alveolar growth and thus the ability of infants and very young children to replace lost lung parenchyma is thought to decrease with age,44,106 although definitive evidence is lacking. In humans, this increase in alveolar number continues at least for the first two years of life.107–110 Older studies employing lung function testing as a surrogate to assess compensatory lung growth early in life have produced conflicting results. One study reported reduced lung volumes and diffusing capacity, approximately by the amount predictable from the size of lung resected.111 Others found evidence for some compensatory growth, but no normalisation of physiological measurements,112 and yet another group reported complete normalisation of lung volumes after lobectomy for congenital lobar emphysema (CLE) in infancy.113 Larger lung volumes than expected from the amount of remaining lung tissue, however, do not necessarily indicate the presence of adequate lung growth in the remaining lung; the mild-to-moderate elevation of residual volume (RV) and functional residual capacity (FRC) commonly found after lobectomy suggests that overexpansion of residual lung contributes to compensation for volume loss.114–116 This is supported by the scintigraphic finding of decreased perfusion in the resected area.116 One study indeed showed more compensatory lung growth in younger patients, especially those under four

168

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171

years of age at operation.117 Recently, however, a retrospective study showed that age at the time of lobectomy (surgery before versus after two years of age) did not influence forced vital capacity (FVC) or forced expiratory volume in 1 sec (FEV1) at a mean age of 10 years.118 Another small study of CCAM reported mild airway obstruction without respiratory symptoms in the first year of life, with no difference between patients treated conservatively or surgically.119 More work is needed to resolve this issue and should include measurements of surrogate markers of alveolar-capillary membrane (e.g. DLco). LONG-TERM FOLLOW UP FOR CCAMS Stable lesions should be followed up long-term. The interest in repeated CT scans needs to be balanced against risks of radiation, sedation or general anaesthesia and potential loss to follow up. Further work is required to investigate if MRI scans are suitable. Thus, whatever approach is employed, patients with CCAMs should be followed up into adulthood. How best to achieve this, including optimal investigations, requires further study. CONCLUSIONS Our Task Force focused on the management of CCAMs as this condition causes the greatest controversy especially for its management after birth in asymptomatic patients and have made recommendations for management (Table 3) and for Future Research Directions (Table 4). Although CCAMs are rare, they may be associated with morbidity especially from repeated infections but also have the potential for developing malignancy. Its removal in asymptomatic patients needs to be balanced with the need for repeated CT scans and equally importantly the Table 3 Summary and Recommendations  The term congenital thoracic malformation (CTM) is recommended for all congenital lung and thoracic malformations  Antenatal ultrasound scanning is an excellent screening modality. Antenatal MR imaging is complementary to assess foetal lesion morphology and volume, but is not a routine investigation  Antenatal ultrasound screening detects >80% of lesions  What is actually seen on antenatal scans should be described and a differential diagnosis formulated  Hybrid lesions of CCAM and pulmonary sequestration (PS) are common, thus differentiation between these conditions should be avoided  CCAM Volume Ratio (CVR) of >1.6 predicts a 15-75% risk of developing foetal hydrops  Few affected foetuses develop symptoms, but foetal hydrops is an independent risk factor for mortality  Many antenatally detected lesions appear to ‘‘resolve’’ but most are detectable on postnatal CT scans  Obstetric decisions should guide choice of delivery mode  Postnatal evaluation is essential for all suspected CCAMs including a chest radiograph after birth and a CT scan within six months of birth. Other investigations may be necessary including Doppler ultrasonography and MR angiography  Surgery is necessary for symptomatic lesions after imaging with CT scanning wherever possible  Some CCAMs have a potential risk for malignancy, but the relative risk is unknown  Close postnatal follow up is essential as symptoms may develop in infancy or in later childhood in previously asymptomatic patients, but accurate rates of affected patients are unknown  Surgery for asymptomatic lesions is controversial, but needs to be balanced against repeated CT scans, loss to follow up and the risk of malignancy  If surgery is considered, most surgeons opt for excision of the lesion during the first year after birth  Wherever surgery is performed expert pathology review of the excised specimen is essential; genetic analysis should be considered where appropriate  Long term follow up is essential especially for patients with asymptomatic lesions

Table 4 Future Research Directions  To accurately determine the population-based epidemiology of CTMs including CCAMs  To accurately delineate the natural history of CCAMs, especially: * rates of complete (if any) resolution of lesions * rates and risk factors for developing symptoms * the relative risk of malignancy  To determine if surgery decreases the risk of future malignancy  To determine if genetic factors affect risks of developing symptoms or malignancy  To understand the genetic basis, if any, for the development of CCAMs (ref 120)  To identify antenatal and postnatal biomarkers, if any, for specific CTMs to aid diagnosis and management  To determine if MR imaging is the imaging modality of choice during long term follow up  To determine long term outcomes including assessments of lung growth and function for those undergoing or not undergoing surgery

potential loss to follow up. Furthermore, the natural history of CCAMs is unclear and it is vital that longer-term follow-up data is available in the future. It is vitally important that congenital anomalies registers such as EUROCAT are supported to provide accurate data on incidence and prevalence of these lesions. Whether surgery is performed or not, standardised protocols are necessary to follow up these children in the longer term. Of greatest importance is the need for multi-disciplinary approach to the management of these rare but important lesions. Acknowledgements The participants were partially funded by the European Respiratory Society to convene the group to write to article. A Bush and AG Nicholson were supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. CONFLICTS OF INTEREST No conflicts of interest to report. References 1. Kotecha S, Barbato A, Bush A, et al. European Respiratory Society Task Force on Congenital Diaphragmatic hernia. Eur Respir J 2012;39(4):820–9. 2. Bush A, Hogg J, Chitty LS. Cystic lung lesions – prenatal diagnosis and management. Prenat Diagn 2008;28:604–11. 3. Bush A. Congenital lung disease: a plea for clear thinking and clear nomenclature. Pediatr Pulmonol 2001;32:328–37. 4. EUROCAT: European Surveillance of Congenital Anolmalies (www.eurocatnetwork.eu accessed Jan 2011). 5. Halkic N, Cuenoud PF, Corthesy ME, Ksontini R, Boumghar M. Pulmonary sequestration: a review of 26 cases. Eur J Cardiothorac Surg 1998;14: 127–33. 6. Adzick NS, Harrison MR, Crombleholme TM, Flake AW, Howell LJ. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998;179:884–9. 7. Carter R. Pulmonary sequestration (collective review). Ann Thorac Surg 1969;7:68–88. 8. Savic B, Birtel F-J, Knoch CR, Tholen W, Schild H. Pulmonary sequestration. In: Frick HP, Harnack GA, Martini EA, Praeder A, editors. Advances in Internal Medicine and Paediatrics. New York: Springer-Verlag; 1979. p. 58–92. 9. Weinbaum PJ, Bors-Koefoed R, Green KW, Prenatt L. Antenatal sonographic findings in a case of intra-abdominal pulmonary sequestration. Obstet Gynecol 1989;7(5 Pt 2):860–2. 10. Clements BS, Warner JO. Pulmonary sequestration and related congenital bronchopulmonary-vascular malformations: nomenclature and classification based on anatomical and embryological considerations. Thorax 1987 Jun;42:401–8. 11. Stocker JT. Congenital pulmonary airway malformation-a new name for an expanded classification of congenital cystic adenomatoid malformation of the lung. Histopathology 2002;41(Supplement 2):424–58. 12. Langston C. New concepts in the pathology of congenital lung malformations. Semin Paediatr Surg 2003;12:17–37. 13. Stocker JT. Sequestration of the lung. Semin Diagn Pathol 1986;3:106–21.

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171 14. Desai S, Dusmet M, Ladas G, Pomplun S, Padley SPG, Griffin N, Badreddine J, Goldstraw P, Nicholson AG. Secondary vascular changes in pulmonary sequestrations. Histopathology 2010;57:121–7. 15. Hill DA, Jarzembowski JA, Priest JR, Williams G, Schoettler P, Dehner LP. Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry. Am J Surg Pathol 2008; 32:282–95. 16. Gerle RD, Jaretzkia A, Ashley CA, Berne AS. Congenital bronchopulmonryforegut malformation: pulmonary sequestration communicating with the gastrointestinal tract. N Engl J Med 1968;278:1413–9. 17. Corrin B, Danel C, Allaway A, Warner JO, Lenney W. Intralobar pulmonary sequestration of ectopic pancreatic tissue with gastro-pancreatic duplication. Thorax 1985;40:637–8. 18. Ch’in KY, Tang MY. Congenital adenomatoid malformation of one lobe of a lung with general anasarca. Arch Pathol 1949;48:221–9. 19. Van Dijk C, Wagenvoort CA. The various types of congenital adenomatoid malformation of the lung. J Pathol 1973;110:131–4. 20. Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatoid malformation of the lung. Hum Pathol 1977;8:155–71. 21. Cachia R, Sobonya RE. Congenital cystic adenomatoid malformation of the lung with bronchial atresia. Hum Pathol 1981;12:947–50. 22. Imai Y, Mark EJ. Cystic adenomatoid change is common to various forms of cystic lung diseases of children: a clinicopathologic analysis of 10 cases with emphasis on tracing the bronchial tree. Arch Pathol Lab Med 2002;126: 934–40. 23. MacSweeney F, Papagiannopoulos K, Goldstraw P, Sheppard MN, Corrin B, Nicholson AG. An assessment of the expanded classification of congenital cystic adenomatoid malformations and their relationship to malignant transformation. Am J Surg Pathol 2003;27:1139–46. 24. Lantuejoul S, Nicholson AG, Sartori G, Piolat C, Danel C, Brabencova E, Goldstraw P, Brambilla E, Rossi G. Mucinous cells in type 1 pulmonary congenital cystic adenomatoid malformation as mucinous bronchioloalveolar carcinoma precursors. Am J Surg Pathol 2007;31:961–9. 25. Lantuejoul S, Ferretti GR, Goldstraw P, Hansell DM, Brambilla E, Nicholson AG. Metastases from bronchioloalveolar carcinomas associated with long-standing type 1 congenital cystic adenomatoid malformations. A report of two cases. Histopathology 2006;48:204–6. 26. Stacher E, Ullmann R, Halbwedl I, Gogg-Kammerer M, Boccon-Gibod L, Nicholson AG, Sheppard MN, Carvalho L, Franca MT, Macsweene F, Morresi-Hauf A, Popper HH. Atypical goblet cell hyperplasia in congenital cystic adenomatoid malformation as a possible preneoplasia for pulmonary adenocarcinoma in childhood: a genetic analysis. Hum Pathol 2004;35:565–70. 27. Fraggetta F, Davenport M, Magro G, Cacciaguerra S, Nash R. Striated muscle cells in non-neoplastic lung tissue: a clinicopathologic study. Hum Pathol 2000;31:1477–81. 28. Lienicke U, Hammer H, Schneider M, Heling K, Wauer RR, Mau H, Vogel M. Rhabdomyomatous dysplasia of the newborn lung associated with multiple congenital malformations of the heart and great vessels. Pediatr Pulmonol 2002;34:222–5. 29. Hislop A, Reid L. New pathological findings in emphysema in childhood: 1. Polyalveolar lobe with emphysema. Thorax 1970;25:682–90. 30. Hill DA, Dehner LP. A cautionary note about congenital cystic adenomatoid malformation (CCAM) type 4. Amer J Surg Pathol 2004;28:554–5. 31. Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ. DICER1 mutations in familial pleuropulmonary blastoma. Science 2009 Aug 21;325:965. 32. Slade I, Bacchelli C, Davies H, Murray A, Abbaszadeh F, Hanks S, Barfoot R, Burke A, Chisholm J, Hewitt M, Jenkinson H, King D, Morland B, Pizer B, Prescott K, Saggar A, Side L, Traunecker H, Vaidya S, Ward P, Futreal PA, Vujanic G, Nicholson AG, Sebire N, Turnbull C, Priest JR, Pritchard-Jones K, Houlston R, Stiller C, Stratton MR, Douglas J, Rahman N. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet 2011 Apr;48:273–8. 33. Chen HW, Hsu WM, Lu FL, Chen PC, Jeng SF, Peng SS, Chen CY, Chou HC, Tsao PN, Hsieh WS. Management of congenital cystic adenomatoid malformation and bronchopulmonary sequestration in newborns. Pediatr Neonatol 2010; 51: 172–7. 34. Farrugia MK, Raza SA, Gould S, Lakhoo K. Congenital lung lesions: classification and concordance of radiological appearance and surgical pathology. Pediatr Surg Int 2008;24:987–91. 35. Laje P, Liechty KW. Postnatal management and outcome of prenatally diagnosed lung lesions. Prenat Diagn 2008;28:612–8. 36. Crombleholme TM, Coleman B, Hedrick H, Liechty K, Howell L, Flake AW, Johnson M, Adzick NS. Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung. J Pediatr Surg 2002;37:331–8. 37. Calvert JK, Boyd PA, Chamberlain PC, et al. Outcome of antenatally suspected congenital cystic adenomatoid malformation of the lung: 10 years’ experience 1991–2001. Arch Dis Child Fetal Neonatal Ed 2006;91:F26–8. 38. Kamata S, Usui N, Kamiyama M, et al. Long-term outcome in patients with prenatally diagnosed cystic lung disease: special reference to ventilation and perfusion scan in the affected lung. J Pediatr Surg 2006;41:2023–7. 39. Kunisaki SM, Barnewolt CE, Estroff JA, et al. Large fetal congenital cystic adenomatoid malformations: growth trends and patient survival. J Pediatr Surg 2007;42:404–10.

169

40. Ierullo AM, Ganapathy R, Crowley S, et al. Neonatal outcome of antenatally diagnosed congenital cystic adenomatoid malformations. Ultrasound Obstet Gynecol 2005;26:150–3. 41. Liechty K. Ex Utero Intrapartum Therapy. Sem Neonatal Matern Med 2010 Feb;15:34–9. 42. Wilson RD, Baxter JK, Johnson MP, et al. Thoracoamniotic shunts: fetal treatment of pleural effusions and congenital cystic adenomatoid malformations. Fetal Diagn Ther 2004 Sep-Oct;19:413–20. 43. Knox EM, Kilby MD, Martin WL, Khan KS. In utero pulmonary drainage in the management of primary hydrothorax and congenital cysti lung lesion: a systematic review. Ultrasound Obstet Gynecol 2006;28:726–34. 44. Adzick NS. Management of fetal lung lesions. Clin Perinatol 2003;30:481–92. 45. Curran PF, Peranteau WH, Wilson RD, Liechty KW, et al. Effect of maternal betamethasone administration on prenatal congenital cystic adenomatoid malformation growth and fetal survival. Fetal Diagn Ther 2007;22:365–71. 46. Salomon LJ, Audibert F, Dommergues M, Vial M, Frydman R. Fetal thoracoamniotic shunting as the only treatment for pulmonary sequestration with hydrops: favorable long-term outcome without postnatal surgery. Ultrasound Obstet Gynecol 2003;21:299–301. 47. Nicolini U, Cerri V, Groli C, Poblete A, Mauro F. A new approach to prenatal treatment of extralobar pulmonary sequestration. Prenat Diagn 2000;20: 758–60. 48. Oepkes D, Devlieger D, Lopriore E, Klumper F. Successful ultrasound-guided laser treatment of fetal hydrops caused by pulmonary sequestration. Ultrasound Obstet Gynecol 2007;29:457–9. 49. Abel RM, Bush A, Chitty LS, Harcourt J, Nicholson AG. Congenital Lung Diseases. In: Chernick V, Boat TF, Wilmott RW, Bush A, editors. Kendig’s Disorders of the Respiratory Tract. 7th Edn, S Philadelphia: Elsevier; 2006. p. 280–316. 50. Azizkhan RG, Crombleholme TM. Congenital cystic lung disease: contemporary antenatal and postnatal management. Pediatr Surg Int 2008;24:643–57. 51. Biyyam DR, Chapman T, Ferguson MR, Deutsch G, Dighe MK. Congenital lung abnormalities: embryologic features, prenatal diagnosis, and postnatal radiologic-pathologic correlation. Radiographics 2010;30:1721–38. 52. Bush A. Prenatal presentation and postnatal management of congenital thoracic malformations. Early Hum Dev 2009;85:679–84. 53. Epelman M, Kreiger PA, Servaes S, Victoria T, Hellinger JC. Current imaging of prenatally diagnosed congenital lung lesions. Semin Ultrasound CT MR 2010; 31:141–57. 54. Hang JD, Guo QY, Chen CX, Chen LY. Imaging approach to the diagnosis of pulmonary sequestration. Acta Radiol 1996;37:883–8. 55. Manson DE, Daneman A. Pitfalls in the sonographic diagnosis of juxtadiaphragmatic pulmonary sequestrations. Pediatr Radiol 2001;31:260–4. 56. Wang S, Ruan Z, Liu F, Huang H, Song K. Pulmonary sequestration: angioarchitecture evaluated by three-dimensional computed tomography angiography. Thorac Cardiovasc Surg 2010;58:354–6. 57. Abbey P, Das CJ, Pangtey GS, Seith A, Dutta R, Kumar A. Imaging in bronchopulmonary sequestration. J Med Imaging Radiat Oncol 2009;53:22–31. 58. Mata JM, Ca´ceres J, Lucaya J, Garcı´a-Conesa JA. CT of congenital malformations of the lung. Radiographics 1990;10:651–74. 59. Stanton M, Njere I, Ade-Ajayi N, Patel S, Davenport M. Systematic review and meta-analysis of the postnatal management of congenital cystic lung lesions. J Pediatr Surg 2009;44:1027–33. 60. Davenport M, Warne SA, Cacciaguerra S, Patel S, Greenough A, Nicolaides K. Current outcome of antenally diagnosed cystic lung disease. J Pediatr Surg 2004;39:549–56. 61. Butterworth SA, Blair GK. Postnatal spontaneous resolution of congenital cystic adenomatoid malformations. J Pediatr Surg 2005;40:832–4. 62. Chow PC, Lee SL, Tang MH, Chan KL, Lee CP, Lam BC, Tsoi NS. Management and outcome of antenatally diagnosed congenital cystic adenomatoid malformation lung. Hong Kong Medical Journal 2007;13:31–9. 63. Hsieh CC, Chao AS, Chang YL, Kuo DM, Hsieh TT, Hung HT. Outcome of congenital cystic adenomatoid malformation of the lung after antenatal diagnosis. Int J Gynaecol Obstet 2005;89:99–102. 64. Kijzer R, Chiu PP, Ratjen F, Langer JC. Pulmonary function after early vs late lobectomy during childhood: a preliminary study. J Pediatr Surg 2009;44:893–5. 65. Lopoo JB, Goldstein RB, Lipshutz GS, Goldberg JD, Harrison MR, Albanese CT. Fetal pulmonary sequestration: a favorable congenital lung lesion. Obstet Gynecol 1999;94:567–71. 66. Papagiannopoulos K, Hughes S, Nicholson AG, Goldstraw P. Cystic lung lesions in the pediatric and adult population: surgical experience at the Brompton Hospital. Ann Thorac Surg 2002;73:1594–8. 67. Khosa JK, Leong SL, Borzi PA. Congenital cystic adenomatoid malformation of the lung: indications and timing of surgery. Pediatr Surg Int 2004;20:505–8. 68. Kim YT, Kim JS, Park JD, Kang CH, Sung SW, Kim JH. Treatment of congenital cystic adenomatoid malformation: does resection in the early postnatal period increase surgical risk? Eur J Cardiothorac Surg 2005;27:658–61. 69. Kunisaki SM, Fauza DO, Nemes LP, Barnewolt CE, Estroff JA, Kozakewich HP, Jennings RW. Bronchial atresia: the hidden pathology within a spectrum of prenatally diagnosed lung masses. J Pediatr Surg 2006;41:61–5. 70. Aziz D, Langer JC, Tuuha SE, Ryan G, Ein SH, Kim PCW. Perinatally diagnosed asymptomatic congenital cystic adenomatoid malformation: to resect or not? J Pediatr Surg 2004;39:329–34. 71. Rothenberg SS. First decade’s experience with thoracoscopic lobectomy in infants and children. J Pediatr Surg 2008;43:40–5. 72. Rahman N, Lakhoo K. Comparison between open and thoracoscopic resection of congenital lung lesions. J Pediatr Surg 2009;44:333–6.

170

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171

73. Vu LT, Farmer DL, Nobuhara KK, Miniati D, Lee H. Thoracoscopic versus open resection for congenital cystic adenomatoid malformations of the lung. J Pediatr Surg 2008;43:35–9. 74. Zeidan S, Hery G, Lacroix F, Gorincour G, Potier A, Dubus JC, Guys JM, de Lagausie P. Intralobar sequestration associated with cystic adenomatoid malformation: diagnostic and thoracoscopic pitfalls. Surg Endosc 2009; 23:1750–3. 75. Tokel K, Boyvat F, Varan B. Coil embolization of pulmonary sequestration in two infants: a safe alternative to surgery. AJR Am J Roentgenol 2000;175:993–5. 76. Bromley B, Parad R, Estroff JA, Benacerraf BR. Fetal lung masses: prenatal course and outcome. J Ultrasound Med 1995;14:927–36. 77. King SJ, Pilling DW, Walkinshaw S. Fetal echogenic lung lesions: prenatal ultrasound diagnosis and outcome. Pediatr Radiol 1995;25:208–10. 78. Lacy DE, Shaw NJ, Pilling DW, Walkinshaw S. Outcome of congenital lung abnormalities detected antenatally. Acta Paediatr 1999;88:454–8. 79. Roggin KK, Breuer CK, Carr SR, et al. The unpredictable character of congenital cystic lung lesions. J Pediatr Surg 2000;35:801–5. 80. Laberge JM, Flageole H, Pugash D, et al. Outcome of the prenatally diagnosed congenital cystic adenomatoid lung malformation: a Canadian experience. Fetal Diagn Ther 2001;16:178–86. 81. Blau H, Barak A, Karmazyn B, et al. Postnatal management of resolving fetal lung lesions. Pediatrics 2002;109:105–8. 82. Pumberger W, Ho¨rmann M, Deutinger J, Bernaschek G, Bistricky E, Horcher E. Longitudinal observation of antenatally detected congenital lung malformations (CLM): natural history, clinical outcome and long-term follow-up. Eur J Cardiothorac Surg 2003;24:703–11. 83. Borsellino A, Zaccara A, Nahom A, et al. False-positive rate in prenatal diagnosis of surgical anomalies. J Pediatr Surg 2006;41:826–9. 84. Rocha G, Fernandes PC, Proenc¸a E, Quintas C, Martins T, Azevedo I, Guimara˜es H. Congenital cystic adenomatoid malformation of the lung – the experience of five medical centres. Rev Port Pneumol 2007;13:511–23. 85. Wong A, Vieten D, Singh S, Harvey JG, Holland AJA. Long-term outcome of asymptomatic patients with congenital cystic adenomatoid malformation. Pediatr Surg Int 2009;25:479–85. 86. Ueda K, Grupps R, Unger F. Rhabdomyosarcoma of lung arising in congenital cystic adenomatoid malformation. Cancer 1977;40:383–8. 87. Prichard MG, Brown PJ, Sterret GF. Bronchioloalveolar carcinoma arising in longstanding lung cysts. Thorax 1984;39:545–9. 88. Sheffield EA, Addis BJ, Corrin B, McCabe MM. Epithelial hyperplasia and malignant change in congenital lung cysts. J Clin Pathol 1987;40:612–4. 89. Shariff S, Thomas JA, Shetty N, D’Cunha S. Primary pulmonary rhabdomyosarcoma in a child, with a review of literature. J Surg Oncol 1988;38: 261–4. 90. Benjamin DR, Cahill JL. Bronchioloalveolar carcinoma of the lung and congenital cystic adenomatoid malformation. Am J Clin Pathol 1991;95:889–92. 91. Murphy JJ. Rhabdomyosarcoma arising within congenital pulmonary cysts: Report of three cases. J Pediatr Surg 1992;27:1364–7. 92. Ribet ME, Copin MC, Soots JG, Gosselin BH. Bronchioloalveolar carcinoma and congenital cystic adenomatoid malformation. Ann Thorac Surg 1995;60:1126– 8. 93. Cuypers P, De Leyn P, Cappelle L, Verougstraete L, Demedts M, Deneffe G. Bronchogenic cysts: a review of 20 cases. Eur J Cardiothorac Surg 1996;10:393– 6. 94. Kaslovsky RA, Purdy S, Dangman BC, McKenna BJ, Brien T, Ilves R. Bronchioloalveolar carcinoma in a child with congenital cystic adenomatoid malformation. Chest 1997;112:548–51. 95. Priest JR, McDermott MB, Bhatia S, Watterson J, Manivel JC, Dehner LP. Pleuropulmonary blastoma: a clinicopathologic study of 50 cases. Cancer 1997;80:147–61. 96. Granata C, Gambini C, Balducci T, et al. Bronchioloalveolar carcinoma arising in congenital cystic adenomatoid malformation in a child: a case report and review of malignancies originating in congenital cystic adenomatoid malformation. Pediatr Pulmonol 1998;25:62–6.

CME SECTION This article has been accredited for CME learning by the European Board for Accreditation in Pneumology (EBAP). You can receive 1 CME credit by successfully answering these questions online. (A) Visit the journal CME site at http://www.prrjournal.com. (B) Complete the answers online, and receive your final score upon completion of the test. (C) Should you successfully complete the test, you may download your accreditation certificate (subject to an administrative charge).

97. Endo C, Imai T, Nakagawa H, Ebina A, Kaimori M. Bronchioloalveolar carcinoma arising in a bronchogenic cyst. Ann Thorac Surg 2000;69:933–5. 98. de Perrot M, Pache JC, Spiliopoulos A. Carcinoma arising in congenital lung cysts. Thorac Cardiovasc Surg 2001;49:184–5. 99. Federici S, Domenichelli V, Tani G, et al. Pleuropulmonary blastoma in congenital cystic adenomatoid malformation: report of a case. Eur J Pediatr Surg 2001;11:196–9. ¨ zcan C, Celik A, Ural Z, Veral A, Kandiloglu G, Balik E. Primary pulmonary 100. O rhabdomyosarcoma arising within cystic adenomatoid malformation: a case report and review of the literature. J Pediatr Surg 2001;36:1062–5. 101. Ioachimescu OC, Mehta AC. From cystic pulmonary airway malformation, to bronchioloalveolar carcinoma and adenocarcinoma of the lung. Eur Respir J 2005;26:1181–7. 102. Jakopovic M, Slobodnjak Z, Krizanac S, Samarzija M. Large cell carcinoma arising in bronchogenic cyst. J Thorac Cardiovasc Surg 2005;130:610–2. 103. Ramos SG, Barbosa GH, Tavora FR, Jeudy J, Torres LAGM, Tone LG, Trad CS. Bronchioloalveolar carcinoma arising in a congenital pulmonary airway malformation in a child: case report with an update of this association. J Pediatr Surg 2007;42:E1–4. 104. Pai S, Eng HL, Lee SY, Hsiao CC, Huang WT, Huang SC. Rhabdomyosarcoma arising within congenital cystic adenomatoid malformation. Pediatr Blood Cancer 2005;45:841–5. 105. Papagiannopoulos KA, Sheppard M, Bush AP, Goldstraw P. Pleuropulmonary blastoma: is prophylactic resection of congenital lung cysts effective? Ann Thorac Surg 2001;72:604–5. 106. Laberge JM, Bratu I, Flageole H. The management of asymptomatic congenital lung malformations. Paediatr Respir Rev 2004;5(Suppl A):S305–12. 107. Thurlbeck WM. Postnatal human lung growth. Thorax 1982;37:564–71. 108. Zeltner TB, Caduff JH, Gehr P, Pfenninger J, Burri PH. The postnatal development and growth of the human lung,I: Morphometry. Respir Physiol 1987; 67:247–68. 109. Zeltner TB, Burri PH. The postnatal development and growth of the human lung, II: Morphology. Respir Physiol 1987;67:269–82. 110. Joshi S, Kotecha S. Lung Growth and Development. Ear Hum Develop 2007;83:789–94. 111. Cook CD, Bucci G. Studies of respiratory physiology in children. IV. The late effects of lobectomy on pulmonary function. Pediatrics 1961;27:234–42. 112. Frenckner B, Freyschuss U. Pulmonary function after lobectomy for congenital lobar emphysema and congenital cystic adenomatoid malformation. Scand J Thorac Cardiovasc Surg 1982;16:293–8. 113. McBride JT, Wohl MEB, Strieder DJ, et al. Lung growth and airway function after lobectomy in infancy for congenital lobar emphysema. J Clin Invest 1980;66:962–70. 114. Cagle PT, Thurlbeck WM. Postpneumonectomy compensatory lung growth. Am Rev Respir Dis 1988;138:1314–26. 115. Holschneider AM, Schlachtenrath R, Knoop U. Follow-up study results and lung function changes following lung resection in childhood. Z Kinderchir 1990;45:349–59. 116. Werner HA, Pirie GE, Nadel HR, et al. Lung volumes, mechanics, and perfusion after pulmonary resection in infancy. J Thorac Cardiovasc Surg 1993;105: 737–42. 117. Nakajima C, Kijimoto C, Yokoyama Y, Miyakawa T, Tsuchiya Y, Kuroda T, Nakano M, Saeki M. Longitudinal follow-up of pulmonary function after lobectomy in childhood: factors affecting lung growth. Pediatr Surg Int 1998;13:341–5. 118. Keijzer R, Chiu PPL, Ratjen F, Langer JC. Pulmonary function after early versus late lobectomy during childhood: a preliminary study. J Pediatr Surg 2009;44:893–5. 119. Spoel M, Ijsselstijn H, Nieuwhof EM, et al. Respiratory morbidity and lung function in congenital cystic adenomatoid malformation of the lungs in the first year of life. Am J Respir Crit Care Med 2008;177:A699. 120. Correia-Pinto J, Gonzaga S, Huang Y, Rottier R. Congenital lung lesions–underlying molecular mechanisms. Semin Pediatr Surg 2010;19:171–9.

Educational questions Answer true or false to the following questions: 1. What is the incidence of congenital cystic adenomatoid malformations for all pregnancies and for live births only? a. 5/10,000 and 3/10,000 b. 1.04 /10,000 and 0.94/10,000 c. 0.2/ 10,000 and 3/10,000 d. 10/10,000 and 4/10,000 e. 3/10,000 and 1.04/10,000 2. Which of the following may predict death for antenatally detected congenital cyst adenomatoid malformations (CCAMs)?

S. Kotecha et al. / Paediatric Respiratory Reviews 13 (2012) 162–171

a. b. c. d. e. 3. a. b. c. d. e. 4. a.

Oligohydramnios CCAM volume ratio (CVR) Hydrops foetalis Mediastinal shift Lung hypoplasia Which of the following is NOT a sign of antenatal presentation of congenital cystic adenomatoid malformations? Mediastinal shift Pulmonary Hypoplasia Hydrops foetalis Oligohydramnios Polyhydramnios With regard to Type 1 congenital cystic adenomatoid malformation: It is the commonest type

b. The lesion is sponge-like, consisting of multiple small cysts (<2 cm). c. It is estimated that 1-2% of type 1 lesions are complicated by malignant change d. The cyst are lined by pseudostratified ciliated cells e. Cysts are more than 2 cm of diameter 5. What are the possible justifications for ‘‘prophylactic’’ surgery in infants with asymptomatic congenital cystic adenomatoid malformations (CCAMs)? a. Prevent chest infection, bleeding and pneumothorax b. Prevention malignancy c. Early surgery may encourage compensatory lung growth d. CCAMs never spontaneously resolve after birth e. Reduction in post-operative complications (compared to emergency surgery)

171