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Bronchopulmonary foregut malformations: embryology, radiology and quandary

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Received: 28 January 2002 Revised: 24 October 2002 Accepted: 6 December 2002 Published online: 12 February 2003 © Springer-Verlag 2003 Abstract Bronchopulmonary fore- gut malformations (BPFM) are a het- erogeneous group of pulmonary de- velopmental anomalies that present at varying ages and with overlapping symptoms, signs and radiology. This article discusses the embryology of these lesions with reference to possi- ble common origins and the link be- tween aetiology and radiological ap- pearance. The radiology of each le- sion, both antenatally and postnatal- ly, is described and illustrated. A number of quandaries exist in the prediction of prognosis and subse- quent treatment of BPFM. We dis- cuss the radiological features that may help to elucidate an individual prognosis and aid in the planning of treatment. The treatment options available for BPFM are briefly dis- cussed. Finally, the link between BPFM, in particular cystic adenoma- toid malformations and malignancy, is discussed. We aim to provide a comprehensive overview of the em- bryology, radiology, prognosis and treatment highlighting contentious issues of BPFM. Keywords Bronchopulmonary foregut malformation · Cystic adenomatoid malformation · Bronchopulmonary sequestration · Bronchogenic cyst · Radiological diagnosis/diagnostic Eur Radiol (2003) 13:2659–2673 DOI 10.1007/s00330-002-1812-5 PEDIATRIC N. A. Barnes D. W. Pilling Bronchopulmonary foregut malformations: embryology, radiology and quandary Introduction Congenital cystic lung lesions are an apparently hetero- geneous group of rare lung abnormalities of pulmonary development. They can present in a number of ways from severe respiratory distress at birth, to an inciden- tal finding on a chest radiograph. In recent years improvements in imaging, particularly in fetal ultra- sound, have allowed earlier detection and discovery of smaller masses. Improvements in fetal intervention and surgery, combined with a desire to reduce the number of terminations in affected fetuses, have necessarily led to further consideration of the antenatal progress and prognosis of cystic lung lesions. In addition, sever- al authors have reported cases of malignancy that appeared to arise from congenital cystic lung lesions [1, 2, 3, 4, 5, 6]. The radiological diagnosis and assess- ment of these lesions has therefore become ever more important. The radiological features of bronchopulmonary fore- gut malformations (BPFM) are often distinct. The le- sions have therefore often been thought of as distinct entities, but it is now recognised that they have a similar embryological aetiology. The group of abnormalities, as a whole, are best classified according to their embryo- logical origin as BPFM; these are listed in Table 1. The lesions as a group are rare and studies show variation in the relative number of malformations in the population. The studies, where comparable figures are available, are summarised in Table 2. Aetiology, embryology and histology In order to understand the radiological appearances of this group of conditions, together with their prognosis, it is useful to comprehend the normal development of the lung in utero. In the fourth week of gestation, the tracheo- bronchial bud develops from the foregut as a diverticu- N. A. Barnes · D. W. Pilling ( ) Department of Radiology, Royal Liverpool Children’s Hospital Alder Hey, Eaton Road, West Derby, L12 2AP UK e-mail: [email protected] Tel.: +44-151-2525432 Fax: +44-151-2525533
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Page 1: Bronchopulmonary foregut malformations: embryology, radiology and quandary

Received: 28 January 2002Revised: 24 October 2002Accepted: 6 December 2002Published online: 12 February 2003© Springer-Verlag 2003

Abstract Bronchopulmonary fore-gut malformations (BPFM) are a het-erogeneous group of pulmonary de-velopmental anomalies that presentat varying ages and with overlappingsymptoms, signs and radiology. Thisarticle discusses the embryology ofthese lesions with reference to possi-ble common origins and the link be-tween aetiology and radiological ap-pearance. The radiology of each le-sion, both antenatally and postnatal-ly, is described and illustrated. Anumber of quandaries exist in theprediction of prognosis and subse-quent treatment of BPFM. We dis-cuss the radiological features thatmay help to elucidate an individual

prognosis and aid in the planning oftreatment. The treatment optionsavailable for BPFM are briefly dis-cussed. Finally, the link betweenBPFM, in particular cystic adenoma-toid malformations and malignancy,is discussed. We aim to provide acomprehensive overview of the em-bryology, radiology, prognosis andtreatment highlighting contentiousissues of BPFM.

Keywords Bronchopulmonary foregut malformation · Cystic adenomatoid malformation · Bronchopulmonary sequestration ·Bronchogenic cyst · Radiological diagnosis/diagnostic

Eur Radiol (2003) 13:2659–2673DOI 10.1007/s00330-002-1812-5 P E D I AT R I C

N. A. BarnesD. W. Pilling

Bronchopulmonary foregut malformations: embryology, radiology and quandary

Introduction

Congenital cystic lung lesions are an apparently hetero-geneous group of rare lung abnormalities of pulmonarydevelopment. They can present in a number of waysfrom severe respiratory distress at birth, to an inciden-tal finding on a chest radiograph. In recent years improvements in imaging, particularly in fetal ultra-sound, have allowed earlier detection and discovery ofsmaller masses. Improvements in fetal intervention andsurgery, combined with a desire to reduce the numberof terminations in affected fetuses, have necessarily led to further consideration of the antenatal progressand prognosis of cystic lung lesions. In addition, sever-al authors have reported cases of malignancy that appeared to arise from congenital cystic lung lesions [1, 2, 3, 4, 5, 6]. The radiological diagnosis and assess-ment of these lesions has therefore become ever moreimportant.

The radiological features of bronchopulmonary fore-gut malformations (BPFM) are often distinct. The le-sions have therefore often been thought of as distinct entities, but it is now recognised that they have a similarembryological aetiology. The group of abnormalities, asa whole, are best classified according to their embryo-logical origin as BPFM; these are listed in Table 1. Thelesions as a group are rare and studies show variation inthe relative number of malformations in the population.The studies, where comparable figures are available, aresummarised in Table 2.

Aetiology, embryology and histology

In order to understand the radiological appearances ofthis group of conditions, together with their prognosis, itis useful to comprehend the normal development of thelung in utero. In the fourth week of gestation, the tracheo-bronchial bud develops from the foregut as a diverticu-

N. A. Barnes · D. W. Pilling (✉)Department of Radiology,Royal Liverpool Children’s Hospital Alder Hey,Eaton Road, West Derby, L12 2AP UKe-mail: [email protected].: +44-151-2525432Fax: +44-151-2525533

Page 2: Bronchopulmonary foregut malformations: embryology, radiology and quandary

lum surrounded by splanchnic mesoderm. From 5 to17 weeks gestation the laryngotracheal tube develops,followed by two lung buds and progressive branching ofthe pulmonary tree, eventually forming blind-ending ter-minal bronchioles. Segmental bronchi are formed by6 weeks [7]. From the thirteenth week, respiratory bron-chioles and primitive alveoli form so that gas exchangeis possible by 24–25 weeks of gestation. From term, thenumber of alveoli increases in the lung from approxi-mately one sixth the adult number to reach maturity by8 years of age [7, 8, 9].

A number of theories relating to the aetiology ofBPFM exist [9]. Although most lesions are often de-scribed in discrete histological terms, a number of casesof mixed lesions, such as cystic adenomatoid malforma-tion (CCAM) occurring in bronchopulmonary sequestra-tion (BPS) and congenital lobar emphysema (CLE) witha systemic arterial supply, have been described [3, 4, 8,9, 10, 11, 12, 13]. Therefore, most authors agree that thisgroup of abnormalities has common origins starting inthe first weeks of lung development; however, the typeand timing of the insult is less well understood, and anumber of causes have been postulated including trauma,ischaemia, infection and adhesions.

Clements and Warner [9] propose a unifying theorythat encompasses a cause for all the major bronchopul-monary malformations. This depends on the relativegrowth and development of the pulmonary tree and pul-monary vessels. The early bronchial buds are suppliedby capillaries from the primitive systemic circulation,

but as the lung grows these vessels regress and the pul-monary artery supply becomes dominant. Interruption ofthis process at different times and sites during the devel-opment of the fetus will result in varying abnormal de-velopment in the affected area of lung. Complete arrestof the pulmonary artery supply and arrest of early bron-chial development will result in agenesis of a lung, lobeor segment. A localised interruption in blood supply,with continued distal development of lung tissue, will re-sult in tracheal/bronchial stenosis or a bronchial cyst. Anearly interruption in the development of the pulmonaryarterial tree could result in continued development of theprimitive systemic capillary supply to a region of lungwith resultant abnormal development of the supplied re-gion. Therefore, the size of the insult would determinethe exact development of the affected lung tissue and final blood supply resulting in pulmonary sequestration,cystic adenomatoid malformation or a mixture of the twolesions.

The pathology and histology of BPFM is again usefulin understanding their varied radiological appearances.

The CCAM presents as a mixed solid and cysticmass apparently resulting from failure of the pulmonarymesenchyma to develop fully [14], and as such contains disorganised and dilated distal components of the respi-ratory tract with varying cell types. The lesion can com-municate normally with the bronchial tree and tends torapidly inflate with air at birth [15, 16]. A number ofclassification systems for CCAM exist, but most ofthese are based on work first published by Stocker et al.in 1977 [14]. This work is referred to by several authors[17]. Stocker et al. described three subtypes based onhistological and pathological appearance. Type-1CCAM is most common and is seen in 65% of CCAMlesions (Table 3). Type-1 lesions feature a predominantcyst measuring >2 cm in size with surrounding smallercysts. The cysts are lined with mucin-secreting epitheli-um and can contain cartilage plates. Type-2 CCAM oc-cur in 25% of cases and are characterised by multiplesmall cysts <1 cm in diameter. Type-2 CCAM cysts arelined by ciliated columnar epithelium [14]. They do not

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Table 1 Bronchopulmonary foregut malformations

Lesion Abbreviation

Tracheal stenosis TSBronchogenic cyst BCBronchopulmonary sequestration BPSCongenital cystic adenomatoid malformation CCAMBronchial atresia/stenosis BACongenital lobar emphysema CLE

Table 2 Relative incidence of bronchopulmonary foregut malformations. S surgical study

Malformation Reference

[35] [32] [37] [38] [8] (S) [15] (S) [64] (S) Total

Bronchogenic cyst – 8 – – 13 13 6 40 (20)Congenital lobar emphysema – 37 – – 3 5 10 55 (27)Bronchopulmonary sequestration 4 5 2 2 6 16 20 55 (27)Congenital cystic adenomatoid malformation – 7 9 7 4 14 5 46 (23)Bronchial atresia/stenosis – – 1 1 – – 4 6 (3)Tracheal stenosis 1 – – – – – – 1 (0.5)Total 5 57 12 10 26 48 45 203

Reference [35] also noted eight congenital diaphragmatic herniasNumbers in parentheses are percentages

Page 3: Bronchopulmonary foregut malformations: embryology, radiology and quandary

possess cartilage and have the appearance of bronchi-oles [14, 18]. Stocker et al.’s [14] original description oftype-3 CCAM is of a non-cystic bulky mass containingbronchiole-like structures and alveolar ducts lined bycuboidal epithelium; however, type-3 CCAM is oftenreferred to as microcystic due to its hyperechoic appear-ance on antenatal ultrasound. The ultrasound appear-ance is produced by the dilated bronchioles and alveolarducts, giving rise to an effect similar to that of the cystsof autosomal-recessive polycystic kidney disease [19,20]. Recently, two further rare subtypes (4 and 0) havebeen described [18]. Type-4 CCAM feature a large cystlined predominantly with alveolar type cells [18, 22],and type-0 CCAM appear to originate from tracheo-bronchial structures. At the cellular level there is, there-fore, some evidence that the different types of CCAMare caused by injury to the developing lung at differentgestational ages, resulting in different cellular compo-nents and pathological and radiological appearance [22].

BPS is classically defined as a bronchopulmonarymass separate from the normal bronchial system with ananomalous systemic arterial supply [9]. Clement andWarner’s theory, as discussed earlier, attempts to explainthe large variation in anatomy and often mixed histologyseen in these lesions. The systemic arterial supply ismost commonly derived from the thoracic aorta; howev-er, the arterial supply has also been noted to arise fromthe abdominal aorta, coeliac trunk, intercostal artery,subclavian artery and renal artery [15]. BPS is dividedfurther into intralobar BPS (ILS) and extralobar BPS(ELS) [21]. ILS is the more common of the two and iscontained within the normal visceral pleura with normalpulmonary venous drainage (Table 3) [21]. ELS is sepa-rated from normal lung by its own discrete pleural layerand has venous drainage into the systemic circulation.ELS have a close association with the gastrointestinaltract, and up to 5–10% are located within the abdomenbelying their common embryological origin [15, 18, 19,23]. Occasionally, ELS are known to possess connec-tions with the upper gastrointestinal tract [9].

Histological changes of CCAM and BPS can occurwithin the same lesion, and cases of both ILS and ELScontaining CCAM have been published [3, 4, 8, 10, 11,12, 13, 16, 24, 25]. The reported incidence of CCAMwithin BPS varies widely from study to study but can beas much as 50% [3]. CCAM has also been described insubdiaphragmatic BPS [16]. Most CCAM found withinBPS is histological type 2, although cases of type 1 andtype 3 have been documented [8, 26]. CCAM and EPShave been reported in to occur simultaneously, but sepa-rately, within the same lung [27].

ILS often presents in childhood or adulthood ratherthan in the neonatal period, with infection, cough orhaemoptysis. ELS, if it does not present in the neonatalperiod, is usually clinically silent [8, 15, 19, 46]. ILSwas thought to be an acquired lesion [21], but the factthat ILS is associated with CCAM and has been identi-fied in asymptomatic infants [11] with associated anoma-lies, such as Scimitar syndrome, suggests that the lesionis congenital.

Both CCAM and BPS are associated with otheranomalies. In particular cases of CCAM, type 2 have anincreased incidence of cardiac, renal and chromosomalabnormalities [19]. BPS has been associated with cardiacanomalies, diaphragmatic hernias, and gastric duplica-tion [19], and these may occur in up to 50% of ELS [21].These linked anomalies lend further evidence to an un-derlying event early in embryological development lead-ing to the evolution of several associated abnormalities.

Bronchial atresia (BA) is the local obliteration of thelumen of a bronchus [28] resulting initially in a fluid-filled mass. The bronchial tree, distal to the obstruction,undergoes normal branching. Shortly after birth, the alveoli of the involved lung become overinflated due tocollateral air drift leaving a central mucous plug in thebronchus distal to the obstruction [7]. The aetiology ofBA can, to an extent, be explained by the theory of Clements and Warner [9], although the timing of the vas-cular incident is not clear and may occur between 5 to15 weeks gestation [19]. McAlister et al. present a case ofBA in which antenatal ultrasound was normal at 15 and20 weeks but abnormal at 24 weeks gestation suggestingthat the causal event may arise after 15 weeks [7]. Otherproposed causes include separation of the growing bron-chial bud from the main bronchial tree, with subsequentcontinued development of the bud [28]. Similar theoriescould explain the aetiology of tracheal atresia.

CLE is overinflation of the alveoli in a segment orlobe of lung due to obstruction of the supplying bron-chus [15, 29]. The obstruction can be primary in origin,such as a defect of the cartilaginous rings or endobron-chial obstruction due to mucosal folds [30], or secondarydue to compression. Bronchial cysts, bronchial atresia,lymph nodes, mucous plugs, aberrant vessels and cyto-megalovirus infection have all been implicated in thecause of secondary bronchial obstruction [15, 31].

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Table 3 Relative incidence of types of CCAM and BPS

Type Reference

[22] [44] [36] [8] (S) [15] (S) Total

CCAM type 1 17 12 4 3 9 45 (65)CCAM type 2 2 4 6 – 5 17 (25)CCAM type 3 1 2 1 1 – 5 (7)CCAM type 4 2 – – – – 2 (3)Total 69

Intralobar BPS – – 4 9 13 (57)Extralobar BPS – – 3 7 10 (43)Total 23

Numbers in parentheses are percentages

Page 4: Bronchopulmonary foregut malformations: embryology, radiology and quandary

Bronchogenic cysts (BC) are usually located withinthe mediastinum or more rarely are found peripherally inthe lung parenchyma [8, 30]. Histologically, the cyst isthin walled and lined with columnar ciliated epitheliumor squamous epithelium [8, 30]. The contents of the cystvary from fluid density or greater and can contain anair–fluid level. BC could be caused by an early eventwhich involves the lung bud resulting in the separate de-velopment of an abnormal bronchial structure. The for-mation of a bronchial cyst, rather than BPS or CCAM,would seem to be a matter of exact timing.

Symptoms, radiology and prognosis

The outcome of BPFM varies widely, from death in utero to recurrent infection in adults and an asymptomat-ic incidental finding on imaging. On the whole, those in-fants and neonates who become symptomatic at less than1 year of age present with respiratory distress of varyingdegrees. In contrast, those presenting later in life attendwith recurrent infection [8]. More specifically, the pre-sentation of BPFM can be divided into five categorieswith each category presenting a different radiologicaland management challenge:

1. Prenatal, i.e. fetuses that are in difficulty before birthand have lesions large enough to cause compressionof the superior vena cava (SVC) and induce non-im-mune fetal hydrops (NIFH). Most lesions that causethese appearances have the appearance of CCAM onultrasound, although BPS can also produce these fea-tures. Fetuses in this group require close monitoringso that a decision as to whether surgical interventionis necessary or a termination is the best course of ac-tion.

2. Birth, i.e. fetuses that present immediately or soon after at birth. These neonates have large lesions orrapidly expanding lesions that cause compression ofadjacent structures such as the heart, SVC and pulmo-nary vessels. The size of these lesions means that theyare also associated with significant pulmonary hypo-plasia and thus cause significant respiratory distress.Neonates in this group often need immediate surgeryonce they have been stabilised. Extralobar BPS canpresent with high-output cardiac failure, secondary toshunting of blood through the lesion.

3. Infancy to childhood, i.e. patients with moderate tomild symptoms that do not require immediate treat-ment. This group includes infants with symptomssuch as wheezing, coughing and bronchiectasis [32,38], and those older children and adults who presentwith infection. Some patients of this group requiresurgery to prevent recurrent or serious infection, andin others with mild symptoms the necessary course ofaction is less clear.

4. Large lesion, no symptoms, i.e. a large lesion but onethat is asymptomatic in the neonate or infant. Most ofthese lesions, however, need surgery, but the optimumtime to perform such surgery is not yet apparent, al-though it is generally considered ideal to remove suchmasses electively before the onset of a potentiallylife-threatening infection. Possibly, cystic lesions aremore likely to become infected than a solid lesionand, therefore, merit removal at an earlier stage.

5. Small lesion, no symptoms, i.e. a small lesion thatcauses no symptoms and thus is most likely to befound incidentally after birth or to represent those lesions that apparently resolve on ultrasound. Thisgroup is the focus of more recent discussions as to thetreatment and management pertaining to the small pos-sible incidence of malignant tumours within BPFM.

The different BPFM can present at any stage in life frombirth to adulthood, although some tend to present earlierthan others. Large lesions or those causing compressionof mediastinal structures, typical of a large CCAM, willbe symptomatic before or at birth. The number of lesionsthat are symptomatic at birth varies depending on thestudy. Table 4 summarises the data from studies examin-ing the number of provisionally diagnosed CCAM thatare symptomatic at birth. This suggests that only around24% of lesions with antenatal ultrasound appearances ofCCAM will produce symptoms at birth. Other lesionsare more likely to be symptomatic at birth. Fifty-sevenpercent of patients with CLE will be symptomatic short-ly after birth, as the affected lobe inflates causing dys-pnoea, cyanosis and recurrent respiratory tract infections[34]. Sixty-three percent of ELS will present in the first3 months of life, although some ELS are not discovereduntil adulthood [3]. The early presentation of ELS mayalso be related to the high incidence of other congenitalanomalies such as congenital diaphragmatic hernia. ILSis much less likely to become symptomatic in the neona-

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Symptomatic chest lesions at birth Reference

[12] [39] [44] [59] [64] [38] Total

Total in study 17 25 18 21 9 23 120Survived to birth 12 16 17 N/S N/S 19 –Respiratory symptoms at birth 4 5 6 6 2 6 29 (24%)

Table 4 Symptomatic chest lesions at birth. N/S number offetuses surviving to birth notspecifically stated

Page 5: Bronchopulmonary foregut malformations: embryology, radiology and quandary

tal period and often presents later in life with infection.BCs produce symptoms usually by compressing otherstructures to cause bronchiectasis, haemoptysis, pulmo-nary artery stenosis or airway obstruction, and the exactlocation and size of the lesion will determine how symp-tomatic it is.

Antenatal ultrasound

The gradual improvement in and use of antenatal ultra-sound has led to an increase in the pre-natal diagnosis ofBPFM. Ultrasound is not only useful in diagnosis, butcan also offer some pointers to the prenatal and immedi-ately post-natal courses. Most of the lesions are discov-ered on ultrasound at around the end of the second trimester (range 16–36 weeks) [12, 35, 36, 37, 40], al-though the time of discovery often depends on the dateof the first antenatal scan. Ultrasound can then be used tomonitor the intra-uterine course of the lesion. The earlydiagnosis of a lesion allows transfer to a specialist re-gional unit for assessment of the fetus and counselling ofthe parents. Some centres now offer in utero interventionand surgery for lesions with poor prognosis. The role ofultrasound has become ever more important in decidingwhen intervention may be appropriate.

Normal lung has approximately the same echotextureas liver and spleen on antenatal ultrasound [24]. The ap-pearances of BPFM on ultrasound can be divided intotwo groups:

1. Hyperechoic apparently solid lesion, i.e. a hyper-echoic region is seen within the lung. The region canbe focal or it can involve a whole lung. It may or maynot have a degree of mass effect on the mediastinalstructures. The hyperechoic appearances seen on ul-trasound can be related to the pathology of the lesionsthat cause them, so that lesions with this appearanceare microcystic or solid in nature. Classically, CCAMtype 3 and BPS produce hyperechoic appearances(Fig. 1a), but a small number of cases of proven bron-chial atresia [7, 38] and CLE have been noted to pro-duce this appearance (Fig. 2a) [38]. Hyperechoic lesions are usually unilateral, although bilateral hy-perechoic lungs have been seen in tracheal stenosis[38], laryngeal atresia as part of Fraser’s syndromeand bilateral CCAM (Fig. 3a). The hyperechogenicityseen in bronchial and tracheal stenosis perhaps repre-sents fluid or mucous trapped within the alveoli pro-ducing a “microcystic” picture.

2. Cystic mass or mixed cystic/solid lesions, i.e. lesionsin this category consist of one or more fluid-filled

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Fig. 1a–d Bronchopulmonarysequestration (BPS). a Antena-tal ultrasound showing a hyper-echoic lesion containing bloodvessels corresponding to a BPS(arrows indicate colour Dopp-ler flow). b Chest radiograph of the same patient with a sub-tle opacity in the right lowerlobe corresponding to the lesion seen on antenatal ultra-sound. c T2-weighted axialmagnetic resonance scanthrough the same with a cysticlesion and surrounding densityin the right lower lobe. d Sagit-tal magnetic resonance of thesame lesion showing the arteri-al supply of the BPS arisingfrom the lower thoracic aorta(arrowhead)

Page 6: Bronchopulmonary foregut malformations: embryology, radiology and quandary

cysts plus or minus a solid hyperechoic component.The size of the cyst can be classified according to thecriteria suggested by Stocker et al. for CCAM intothose with a predominant cyst >2 cm and those withmultiple cysts <1 cm in size [14]. CCAM types 1 and2 and BPS can produce a mixed appearance with avariable sized-associated solid component (Fig. 3b).Bronchogenic cysts tend to appear as a single cysticstructure with a thin wall.

The overlap of ultrasound appearances of all the BPFMmeans that making an accurate diagnosis is difficult. Anumber of studies, mostly of lesions thought to beCCAM or BPS on ultrasound, show that pathology of le-sions is difficult to predict accurately and is correct inapproximately 81% of cases (see Table 5). Often lesionsthought to CCAM or BPS are in fact other BPFM, suchas BC, BA or CLE, or of a more diverse pathology suchas teratoma, oesophageal duplication [39] or thoracicneuroblastoma [39]. Carrol et al. document a hyper-echoic lesion seen on antenatal ultrasound with associat-

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Fig. 2a, b Congenital lobar emphysema (CLE). a Antenatal ultra-sound demonstrating a hyperechoic left lung corresponding toCLE. b Chest radiograph of the same demonstrating marked hy-

perinflation of the left upper lobe with compression of the rest ofthe left lung and midline herniation

Fig. 3 a Coronal oblique antenatal ultrasound of bilateral hyper-echoic lungs of tracheal stenosis in Fraser’s syndrome. b Antena-tal ultrasound of a large type-1 cystic adenomatoid malformation

(CCAM) containing a large central cyst and surrounding hyper-echogenicity corresponding to the non-cystic part of the lesion andcompressed adjacent lung

Page 7: Bronchopulmonary foregut malformations: embryology, radiology and quandary

ed polyhydramnios and mediastinal shift that proved tobe CLE on removal (Fig. 2a) [31]. This lesion wouldhave traditionally been labelled as CCAM type 3 andgiven a poor prognosis. Magnetic resonance imaging(Fig. 1) offers a more accurate diagnosis and should beused.

The differentiation of lung masses from a congenitaldiaphragmatic hernia (CDH) is of importance but can bedifficult particularly in the case of multicystic lesions[24]. Features that may help distinguish congenital diaphragmatic hernia are the demonstration of a normalintra-abdominal stomach and a normally positioned dia-phragm [24]. Abnormal rotation of the abdominal con-tents with fetal breathing movement suggests CDH.

A number of secondary features of BPFM on ultra-sound have been noted, some of which have been associ-ated with a poor prognosis:

1. Non-immune fetal hydrops (NIFH) is an importantfactor in predicting prognosis and is the only antena-tal ultrasound sign associated consistently with a poorprognosis [12, 24, 36, 39, 40, 41, 42, 43, 45]. Thosefetuses without NIFH have been shown to have an inutero survival >90% [41]. NIFH is associated withlarge lesions and may be due to the compression ofthe SVC resulting in soft tissue oedema, pleural effu-sions and ascites. In a large retrospective study in-volving 175 congenital cystic lung lesions by Evrardet al. 25 fetuses developed NIFH, all of whom died[15]. More importantly, however, some studies haveshown that NIFH can resolve spontaneously. Barret etal. noted a 30% resolution of NIFH once seen on anoriginal scan in fetuses with echogenic lung [41].Winters et al. presented a case, within their series,with marked mediastinal shift and ascites that re-solved spontaneously [4]. The number of fetuses withBPFM that develop NIFH varies greatly from study tostudy with most of the small studies finding no evi-dence of NIFH. Only a small number develop NIFHif it is not present on the initial scan (6%) [41].

2. Polyhydramnios, probably secondary to compressionof oesophagus, is seen in a proportion of BPFM cases(5–29%) [12, 36, 39, 44]. From study to study surviv-al of fetuses with polyhydramnios varies greatly from

50% mortality [39] to no association (12, 43, 45];therefore, polyhydramnios in isolation should be usedwith caution as a prognostic indicator.

3. Mediastinal shift, due to mass effect of the lesions, isnoted in some studies as an indicator of poor outcomein the antenatal period [36, 39, 41, 45]. In contrast,other studies indicate that it is not [4, 12, 45]. In theseries published by Sapin et al. mediastinal shift wasseen to some degree in all patients with CCAM [44].In the studies that do show a link with mediastinalshift and poor prognosis, this finding is often linkedwith other features such as increasing mediastinalshift [39] or NIFH [24]. It would appear, therefore,that minor degrees of mediastinal shift are unimpor-tant, but large or increasing degrees of mediastinalshift are likely to involve compression of mediastinalstructures and result in NIFH and have associated pul-monary hypoplasia.

4. Bunduki et al. positively identify CCAM type 3 as in-dicating a poor antenatal outcome [45]. CCAM type 3has been traditionally associated with a poor progno-sis, but most recent studies do not make this distinc-tion.

5. The size of lesion is not identified specifically as anindicator of poor prognosis in several studies [12, 35];however, in Van Leeuwen et al.’s series, a mass filling>50% of the hemithorax with mediastinal shift wasassociated with significant postnatal symptoms [36].Kamata et al. demonstrated that serial measurementsof lung/thorax transverse area ratio could assist inpredicting the post-natal respiratory condition of aneonate [46].

6. The finding of bilateral lung hyperechogenicity isvery rare but can be caused with tracheal atresia and,therefore, can be associated with a poor prognosis[38, 45]; however, cases with bilateral lesions, such as CCAM, surviving to term, have been published.Lipshutz et al. published a series of three antenatallyidentified bilateral lesions two of whom survived toterm [47].

Most prognostic studies are to determine antenatal sur-vival and not outcome after birth. It seems that large le-sions with NIFH and mediastinal shift will do poorlysecondary to lung hypoplasia and heart failure; however,some lesions will improve and cases of apparently hope-less outcome have resolved and to some degree im-proved their prognosis. It may be that the underlying pathology of the lesions can be used to predict the outcome, but ultrasound alone is only 72% specific incorrectly identifying histology. The individual prognosticfeatures associated with BPFM must be carefully consid-ered when counselling and accurate prediction can bevery difficult in an individual case.

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Table 5 Accuracy of prenatal ultrasound in identifying correctBPFM

Accuracy of prenatal ultrasound Reference

[35] [37] [33] [36] Total

Total in study 17 13 9 16 68Pathology identified correctly 13 7 7 14 55Percentage identified correctly 76 54 78 88 81

All studies initially identified the lesions as CCAM or BPS

Page 8: Bronchopulmonary foregut malformations: embryology, radiology and quandary

Doppler ultrasound

Doppler has been used in a number of ways in antenatalultrasound of BPFM, most commonly in the search for asystemic blood supply in demonstrating BPS, which ispossible, but in most cases is difficult (Fig. 1a). Other in-teresting possibilities for the use of Doppler includeanalysis of pulmonary blood flow in determining lunghypoplasia [48].

Reported regression of BPFM on antenatal ultrasound

The regression in the size of BPFM identified on antena-tal ultrasound has been widely noted and lesions havebeen found to disappear completely prior to delivery.The incidence of reported regression varies considerablyfrom 15 to 68% depending on the study. Table 6 summ-arises papers that noted regression of lesions identifiedon antenatal ultrasound. The pathology of these lesionsis not always proven histologically as not all lesions areremoved to enable a histological diagnosis, and the diag-nosis is therefore made on ultrasound criteria alone. Lesions with ultrasound criteria of both CCAM and BPShave been noted to regress in size.

McCullagh et al. present two cases of complete re-gression with normal postnatal investigations in their series of 13 antenatally diagnosed presumed to beCCAM [37]. There are a number of studies of BPFM inwhich apparent resolution on antenatal ultrasound hasshown residual changes on post-natal computerised to-mography, although these lesions were not always visi-ble on chest radiograph [4, 36]. A lesion that had re-solved on antenatal ultrasound was demonstrated to beclearly identifiable on prenatal magnetic resonance im-aging by Hubbard et al. [50].

Lesions can regress in size during gestation comparedwith the fetal thorax, but most authors conclude that thisis due to the differential growth rate between the thoraxand the mass. A small study by Winters et al. measuredcross-sectional area of eight masses with features ofCCAM types 1–3 and found a favourable outcome inthose fetuses where thoracic growth exceeded that of the

mass [49]. The apparent decrease in size of lesions couldbe secondary to a change in the fluid/ tissue interface sothat the mass becomes isoechoic with normal lung [4].Achiron et al. presented four cases with echogenic lungmasses that resolved on antenatal ultrasound [51]. Oneof these died in utero. The autopsy diagnosis was pneu-monia; the remaining three were normal at birth. Theysuggested that a hyperechoic appearance on antenatal ultrasound can be secondary to bronchial obstructioncausing mucoid impaction which may then resolve dur-ing gestation.

Complete or partial regression in size, especially accompanied by a reduction or reversal of NIFH, hasbeen linked with a reduction in symptoms at birth [36].

Fetal magnetic resonance imaging

Fetal magnetic resonance imaging is now possible withthe advent of fast magnetic resonance sequences that reduce the degradation produced by movement [50].Hubbard et al. recently confirmed magnetic resonanceimaging to be useful in accurately characterising antena-tally discovered lesions [50]. Using the rapid acquisitionand relaxation enhancement (RARE) sequences type-1and type-2 CCAM appear as very high-signal masseswith cysts as small as 3 mm being identifiable. TheCCAM type 3 is seen as a moderately high-signal ho-mogenous lesion mass. BPS is shown as a well-definedhigh-signal mass. Fast magnetic resonance sequencesproved accurate in distinguishing congenital diaphrag-matic hernia from cystic lung lesions [50]. Tracheal ste-nosis can be seen as a homogenous high signal with a dilated fluid-filled trachea distal to the obstruction. Compressed lung has a sufficiently distinct signal fromnormal lung to identify its extent. This raises the possi-bility of calculating the volume of affected and unaffect-ed lung and thus the degree of pulmonary hypoplasia,and this could be useful as a post-natal prognostic guide.

In general, magnetic resonance can provide an accu-rate diagnosis and produce information on anatomy andpathology aiding in prenatal counselling and planning offuture treatment.

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Table 6 “Regression” of lesions seen on antenatal ultrasound

Lesions on antenatal ultrasound Reference

[40] [10] [37] [42] [39] [44] [33] [36] [38]

No. of lesions regressing 28 2 2 9 13 7 4 6 9Total in study 41 6 13 50 25 18 9 14 23Percentage 68 33 15 18 53 39 44 43 39Pathology ELS Mixed Variable Presumed CCAM/ CCAM CCAM CCAM Hyperechoic (not all proven histologically) CCAM/ CCAM plus CCAM BPS lesion on antenatal

BPS other pathology ultrasound

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Postnatal imaging

A plain chest radiograph is the initial investigation ofchoice in neonates with pre-diagnosed lung lesions orthose presenting with respiratory distress. The chest radiograph can be diagnostic where the appearances areclassical, and can monitor pathological effect of the lesion, e.g. mediastinal shift (Fig. 2b); however, lesionscan often appear similar, particularly CCAM and BPS,which can both produce an air-filled cystic appearancewith an associated mass. If an antenatally diagnosed lesion is not visible on chest radiograph after birth, acomputerised tomogram should be performed. Althoughcomputerised tomography is the preferred method ofcross-sectional imaging, magnetic resonance imagingcan be used to visualise lesions within the lung (Fig. 1c).Magnetic resonance can be particularly useful in identi-fying blood supply to a lesion (Fig. 1d); those with novisible lesion on chest radiograph are more than likely tobe asymptomatic at birth [36]. The abdominal contentsshould be identified in their correct position to excludecongenital diaphragmatic hernia.

The appearance of CCAM on chest radiograph de-pends on the histological type of the lesion and its size.The appearance of a solid mass of soft tissue density,which may contain air or fluid-filled cysts, is typical(Fig. 4). CCAM can be found in any lobe of the lungsbut is most commonly located in the lower lobes on theleft side [4, 8, 32, 36, 44]. A large lesion will producemediastinal shift to the contralateral side with compres-sion of adjacent lung (Fig. 5). A small resolving lesionmay only be seen as a subtle focal increase in lucency(Fig. 6a) [4]. Spontaneous pneumothorax has been noted[52]. If a CCAM becomes infected, a previously hyper-

lucent lesion can become more solid [4]. The presence ofcystic changes on the antenatal chest radiograph hasbeen shown to predict symptoms in the newborn period[36].

Like CCAM, a BPS, if small enough, may not beidentified on chest radiograph, and computerised tomog-raphy will be required to image such a lesion (Fig. 6). Incontrast, if the BPS is large enough, mediastinal shift canoccur. Ultrasound can be used to examine lesions adja-cent to the chest wall and may identify feeding vessels inBPS. Classically, ILS will be seen as a soft tissue masswith a cystic structure containing air–fluid levels. Thelung within the ILS can be aerated by collateral drift viathe pores of Köhn. Dilated bronchii may be visualisedwithin the lesion. ELS produces an airless mass with flu-id-filled cysts often lying adjacent to the diaphragm. On

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Fig. 4 Chest radiograph of a large right-sided CCAM type III

Fig. 5 Chest radiograph of a large hyperinflated CCAM in theright lower lobe of a neonate causing midline shift and compres-sion of the opposite lung. This CCAM was removed at a fewmonths of age

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chest radiograph this appears as a well-defined triangularmass with no air bronchograms. Air in an ELS may indi-cate communication with the gastrointestinal tract. Simi-lar to CCAM, BPS can be found in any part of the lungbut most commonly in the postero-basal segments on theleft side [3, 8].

CLE can be initially fluid filled after birth producingthe appearance of a distended fluid-filled lobe with ahazy soft tissue opacity [53]. Once the fluid is absorbedthe lobe becomes hyperinflated and therefore hyperlu-cent [18, 34] with attenuation of the pulmonary vascula-ture. The distended lobe will compress the adjacent lungand can cause mediastinal shift (Fig. 2b) [18, 53]. UnlikeCCAM and BPS, CLE is seen in the left upper lobe in upto two-thirds of cases, followed in order of frequency bythe right middle and then upper lobes.

BC produces a well defined soft tissue density mostcommonly within the mediastinum often causing com-pression and distortion of surrounding structures such astrachea or oesophagus. Intrapulmonary BCs are well de-fined round lesions and may occasionally contain an airfluid level. Eighty-six percent of BCs are mediastinal,most often pericarinal (52%). When peripherally locatedBCs are most commonly located in the upper lobes [30].

Bronchial atresia can produce a similar plain-film ap-pearance to CLE with initial opacification of the affectedlung secondary to fluid. The affected lung will then grad-ually inflate secondary to collateral air drift and becomehyperlucent with attenuated vasculature [7]. Classically,a “finger-like” opacity extending from the hilum, whichrepresents the mucous-filled bronchus distal to the ob-struction, with surrounding hyperinflated lung, is seen[28].

Computerised tomography

Computerised tomography is important in assessing lesions, particularly those that are difficult to identify onplain films or where surgery is not immediately neces-sary at birth. It can provide important information onsize, location and possible pathology of BPFM, allowingconfirmation of a provisional diagnosis and helping toexclude the rare but important causes of hyperlucent an-tenatal ultrasound lesions such as thoracic neuroblasto-ma. The computerised tomography appearances ofBPFM are similar to the classical appearances on chestradiography but will be seen with greater clarity.

The computerised tomography features of CCAMcorrelate well with histology and the CCAM components[54]. A typical type-1 or type-2 CCAM may consist ofmultiple air-filled cysts with interposed soft tissue densi-ty and adjacent hyperinflated lung (Fig. 6b, 7) [4, 52].Cysts within CCAM are readily identified and can con-tain air, fluid or both. Areas of “consolidation” seenwithin the lesion have been correlated histologically torepresent areas of glandular or bronchial structures. Inaddition, low-attenuation regions within the mass corre-spond to microcysts blended with normal lung [54].

BPS can have very similar appearances to CCAM oncomputerised tomography. An ILS appears as a cysticstructure with single or multiple cysts containing air orfluid. Characteristically, mucous-impacted bronchii canbe identified with surrounding emphysematous changes[4]. ELS appears as a triangular well-circumscribed mass[21]. Feeding vessels may be identified when intrave-nous contrast is given, although a vessel cannot be dem-onstrated in most cases [4]. Magnetic resonance imagingis better at identifying feeding vessels and their source.Computerised tomography or magnetic resonance imag-ing is useful in identifying and characterising intra-ab-dominal ELS, which needs to be differentiated from le-sions such as neuroblastoma.

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Fig. 6 a Chest radiograph of a CCAM in the right lower lobe seenas a subtle density. b Computerised tomography of the same lesionshowing a cluster of thin-walled cystic structures posteromediallyin the right lung corresponding to a CCAM

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CLE appears as a hyperlucent lobe with peripheral at-tenuation of vessels with associated compression of adja-cent lung and contralateral mediastinal shift [18]. Com-puterised tomography is useful for identifying bronchialanatomy to exclude bronchial stenosis or atresia and ab-normal vasculature [31]. Intravenous contrast may helpwith discerning underlying vascular anomalies that areobstructing the bronchus [18]. BC appear as thin-walled,unilocular cysts containing fluid or slightly denser con-tents [30]. BS can be identified on computerised tomog-raphy by the central mucous plugged bronchus with sur-rounding hyperinflated lung.

Angiography

Angiography and interventional techniques have a small,but potentially useful, role to play in the diagnosis andmanagement of BPFM. If necessary, angiography willidentify supplying and draining vessels in BPS. If thevessels in ELS are large enough to cause a left-to-rightshunt and high-output cardiac failure, it is possible to em-bolise them prior to surgical removal of the lesion [18].

Nuclear imaging

Perfusion and ventilation scanning has been used in theassessment of congenital lung lesions. Lesions such asCCAM and BPS show ventilation defects. CLE willdemonstrate an area of decreased perfusion [34]. Addi-tionally, ventilation-perfusion scanning also has a role toplay in quantifying the function of unaffected lung [31].

Treatment

The treatment of BPFM can be divided into two groups,namely pre- and post-natal. Advances in antenatal tech-niques have allowed for intrauterine intervention to beused in an attempt to reverse the poor prognosis of thoseinfants with large BPFM and NIFH. Thoracocentesis andthoracoamniotic shunts have been successfully used todrain large cysts causing mediastinal shift and pleural ef-fusions [37, 45, 55]. Unfortunately, cysts that are simplydrained tend to re-accumulate fluid and so thoracocente-sis can provide a short-term measure only. Thoracoamni-otic shunts can be difficult to place and tend to block[15]. Fetal surgery has been used successfully in a smallnumber of cases. In a study by Adzick et al., 13 fetusesunderwent surgery for masses causing severe NIFH, ofwhich 8 survived with resolution of their NIFH [40].Surgery does appear to offer improvement in prognosisin fetuses predicted to have a fatal antenatal outcome,but at present its use is limited to a small number of cen-tres worldwide [56].

All lesions diagnosed antenatally should be trans-ferred to a tertiary centre for assessment. A significantnumber of neonates with BPFM need removal of the le-sion soon after birth and require respiratory support andoften ventilation. High-frequency oscillatory ventilation(HFO) and extracorporeal membranous oxygenation(ECMO) have been used successfully in neonates withBPFM [57, 58]. Those neonates with larger lesions whoare mildly symptomatic or asymptomatic tend to havethe lesions removed to prevent serious infection later inlife. Any lesion with doubt over its diagnosis, such as in-tra-abdominal ELS, should also be removed [23]. Theexact timing of surgery in these cases will depend on thechild and preferences of the surgeons involved.

Whether small or residual lesions should be removedis a matter for debate. There are a small number of pub-lished cases of malignancy associated with presumedcongenital cystic lung disease [5, 6, 59, 60, 61]. It hasbeen postulated because of this that BPFM possess pre-malignant potential and in some centres all lesions withthe appearance of CCAM are removed because of this.Tagge et al. [61] reviewed cases of malignancy associat-ed with previously diagnosed cystic lung disease in chil-dren and found only 17 cases in the literature between1977 and 1996 including their own case. Most premalig-nant lesions were classified in a number of non-specificways as cystic lung disease, pneumatocoele, congenitallung cyst and pneumothorax [61]. Included in this serieswere three cases published by Murphy et al., two ofwhich demonstrated malignancy arising with cyststhought to be CCAM [5]. There is some confusion in theliterature over the type or naming of the malignancy thatmay occur in relation to congenital cystic lung disease.Pleuro-pulmonary blastoma (PPB) probably accounts forall the tumours reported in case studies as “pulmonary

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Fig. 7 Computerised tomography of a large CCAM in the rightmiddle lobe causing midline shift compression of the remainingnormal right lung and left lung

Page 12: Bronchopulmonary foregut malformations: embryology, radiology and quandary

blastoma”, rhabdomyosarcoma and mesenchymal sarco-ma [60]. Certainly PPB is a rare tumour and histologicalfeatures seem to overlap with those of other tumourssuch as rhabdomyosarcoma [60]. PPB has three morpho-logical types. Type-1 PPB are entirely multi-cystic,whereas type 2 are mixed cystic solid lesions and type 3are entirely solid lesions [60]. Priest et al. present a se-ries of children with proven PPB of which 19 had cysticchanges [60]. Of these 19 children, 12 had cystic lesionsonly diagnosed a month before the final diagnosis, but 7had lesions known for >1 month. All the cystic lesionsseen in this study were visible on plain radiography andmost of the 50 children were symptomatic at presenta-tion, most commonly with respiratory distress or featuresof infection. Only one case was associated with CCAM,and in this case the CCAM was in the contralateral lung[60]. In the 17 cases reviewed by Tagge et al. the knowncystic lesions had been present for up to 4 years beforethe diagnosis of malignancy was made [61].

There are radiological and histological similarities be-tween CCAM and type-1 PPB. It has been suggested thatthe rarity of PPB could lead to a diagnosis of type-1 PPBpresent as a focus of PPB in a CCAM rather than thewhole lesion being recognised as the PPB [16, 60].There is, however, some evidence of the possibility ofpremalignant change in BPFM. The BC have been asso-ciated with bronchogenic carcinoma in adults [62]. Wanget al. identified glandular tissue, similar to adenomatouspolyps and bronchoalveolar carcinoma within CCAM[1], and Cass et al. found increased cell proliferation anddecreased apoptosis within CCAM [2] suggesting thepossibility for premalignant change in BPFM. Conranand Stocker [3] identified rhabdomyomatous degenera-tion in 48% of combined ELS/CCAM lesions that theyexamined. Significantly, however, McManus and O’Harafound that striated muscle occurred rarely in CCAM[16]. Interestingly, no prenatally diagnosed lesion has yetbeen noted to progress to malignancy and no histologi-cally proven BPFM has been seen to progress to PPB[61].

From this evidence cystic lesions can be divided intothree risk categories:

1. It is clear that the diagnosis of PPB should be consid-ered in infants and young children presenting withrespiratory or infective symptoms and cystic or solidlesions on plain radiography of the chest. Childrenthat presented in this way all had surgery in the studyby Priest et al. either for a chest mass, pneumothorax,presumed or confirmed infection, and in 4 childrenbecause of lung cysts only [60]

2. Small asymptomatic lesions, either cystic or solid,found incidentally after birth on plain radiographywith benign features do have a very small risk of ma-lignancy as demonstrated by the cases collected fromthe literature by Tagge et al. [61]. Whether the cystic

lesions seen in this type of case truly represent aBPFM, such as CCAM, is of less importance if theycannot be radiologically distinguished. Careful as-sessment of these lesions should be carried out, and ifnot removed for other reasons, such as infection,close follow-up is required. Although lobectomy iswell tolerated [63], whether all such lesions should beremoved is a matter of balancing the risks of surgeryversus the risk of leaving such a lesion.

3. Lesions diagnosed on antenatal ultrasound that arenot significant enough to require surgery at birth, inparticularly those that regress, present more of a prob-lem. As no lesion discovered in this way has been as-sociated with a malignant lesion, a balance of riskwould suggest that surgery purely on the grounds ofremoving a very small malignant risk would be im-prudent. It is possible that those lesions visible onchest radiograph at birth need closer follow up thanthose that are small and cystic with thin walls and only seen on CT. Surgery in these lesions may be required for more common occurrences such as pre-venting possible life-threatening infection

There is, perhaps, only a fine distinction between thoselesions that fall into groups 2 and 3 and further researchis necessary to clarify the management further. It may bethat the radiological appearances of lesions associatedwith PPB need reassessing to distinguish potentially ma-lignant lesions from benign lesions that present no risk.Priest et al. [60] suggest a PPB phenotype with associat-ed familial or intra-patient dysplasia. Possibly future ge-netic analysis will help to decide the malignant potentialof apparently benign cystic chest lesions.

Conclusion

BPFM are an apparently disparate group of conditionsthat are likely to have a common embryological origin.Improvements in antenatal imaging have meant thatmore lesions are discovered prior to birth. When aBPFM is found on antenatal ultrasound, a thorough scanof the fetus should be performed to exclude any other associated abnormalities including congenital diaphrag-matic hernia. The exact pathology of BPFM can be determined, to some extent by antenatal ultrasound, butcaution should be exercised when using ultrasound topredict prognosis. Antenatal magnetic resonance has anincreasing role in differentiating lesions found on ante-natal ultrasound. Serial ultrasound at a tertiary centre isappropriate to allow assessment of prognostic factors,the most important of which is NIFH, and also in regres-sion in size which may indicate an improved prognosis.A significant number of antenatally diagnosed lung le-sions, presumed to be CCAM or BPS, may reduce insize. If facilities are available, then intrauterine interven-

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tion, such as thoracocentesis, or fetal surgery, does seemto offer improved prognosis in those with an otherwiseprobable fatal outcome. A significant proportion of neo-nates with BPFM require immediate respiratory supportand resection of the lesion soon after birth. Modern sup-port techniques, such as HFO and ECMO, have somerole to play in those with severe respiratory distress atbirth. Those neonates with asymptomatic lesions, whomay have minimal or no changes on chest radiograph,require further work-up with computerised tomographyor magnetic resonance imaging. Occasionally, lesions

found on antenatal ultrasound may not be found at fol-low-up and could represent the clearing of impacted mucous from the bronchial tree, but most lesions areidentified by cross-sectional imaging. Most centreswould remove large lesions, as these tend to present withinfection in later life. The need to remove small and re-sidual lesions is still unclear, and evidence both that con-firms and refutes the occurrence of malignancy in trueBPFM, except perhaps bronchoalveolar carcinoma inadults, exists. Larger collaborative studies may be theonly way to answer this important question.

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