Controversies in the management of cystic lung disease
Andrew Bush MB BS (Hons) MA MD FRCP FRCPCH
Professor of Paediatric Respirology, Imperial School of Medicine at National Heart and Lung
Institute; and Honorary Consultant Paediatric Chest Physician, Royal Brompton Hospital.
Correspondence: Department of Paediatric Respiratory Medicine, Royal Brompton Hospital,
Sydney Street, London SW3 6NP, UK.
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Tel: -207-351-8232
Fax: -207-351-8763
e mail:- a.bush@rbh.nthames.nhs.uk
Keywords: Sequestration, bronchogenic cyst, congenital cystic adenomatoid malformation, fetal
surgery, hydrops, sarcoma, pleuropulmonary blastoma,
Abstract The antenatal diagnosis of a congenital thoracic malformation (CTM) leads to anxiety and
uncertainty as to best management. CTM comprises congenital cystic adenomatoid malformation,
sequestration, congenital lobar emphysema, enteric and bronchogenic cysts, and bronchial atresia.
Most require only observation antenatally, and reduce in size substantially in the third trimester. If
fetal hydrops develops, then antenatal intervention, usually surgical, is required, because untreated
mortality is high. If the baby is symptomatic in the newborn period, then surgical intervention is
clearly needed. The treatment of the asymptomatic baby is the major controversial area. Advocates
of early surgery point to the complications of CTM, which include infection, pneumothorax, bleeding
and malignant transformation. The proponents of conservative management retort that some CTMs
disappear postnatally, and that the complication rate is unknown; many children appear never to
need surgery. Furthermore, excision of a CTM does not totally eliminate the risk of a subsequent
malignancy. Counselling of the family on a case by case basis is needed, both antenatally and
postnanatally, stressing the limitations of present evidence.
Introduction There is not enough evidence to give definite opinions to parents of a foetus in whom a
congenital thoracic malformation (CTM) has been discovered. We do know that:
1. Many antenatally diagnosed CTMs will regress spontaneously before birth. Thus any fetal
intervention runs the risk of being unnecessary and meddlesome. Rare cases of true
spontaneous postnatal regression of a CTM have been recorded [1]
2. If the child is significantly symptomatic in the newborn period despite medical management,
then surgery is indicated. However, an asymptomatic infant who is offered surgery will be
being exposed to a small risk of iatrogenic complications
3. There are late complications of CTMs, including infection, pneumothorax, malignant
transformation, high output cardiac failure and air embolism, but the risk is unkown.
Malignant transformation is not always preventable by resection.
This review focuses briefly on the ante- and post-natal nomenclature to use in discussions, the
antenatal presentations of CTMs, and the ante- and post-natal options with their advantages and
disadvantages, concluding with a suggested practical approach to parents. These may be contrasted
with other recent reviews [2, 3]. Amongst the problems of making sense of the literature are the
diversity of the histological patterns, and the rarity of the lesions, estimated at between 1 in 2030,000 live births [4]. Later post-natal presentations of CTMs, and a detailed account of their
pathology, are discussed in detail elsewhere [5].
Nomenclature of CTMs
The nomenclature of congenital lung disease has been confusing for the following reasons.
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Sequestration and cystic adenomatoid malformation (CCAM) are often assumed to be
separate identities, and pathologically have distinct features, but histological features of
both may be found within the same lesion (‘Hybrid lesions’).
There is inconsistent use of nomenclature before and after birth. For example, the term
CCAM is used by perinatologists to describe a lesion that may well disappear before birth,
but is used postnatally to describe an abnormality which often but not invariably requires
lobectomy.
No matter how sophisticated the imaging modality used, the clinician can only see shades of
grey, and should not make unwarranted pathological assumptions from these pictures. The
same clinical appearance (e.g., a multicystic mass) may have one of several different
histological appearances when excised.
The pathologist who can examine the excised lesion, and can provide a precise account of
what it contains, quite different from the clinician.
It is suggested that the following principles should be followed when looking at clinical images,
either antenatally or postnatally [6]:
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) has been proposed to replace the old nomenclature in clinical discussions [6], because this
makes no pathological assumptions. The spectrum of CTM includes CCAM, sequestration,
bronchogenic and foregut cysts, and bronchial atresia with distal cystic degeneration [7].
Postnatally at least, a congenital large hyperlucent lobe (CLHL, “congenital lobar emphysema” is
separated off, because late complications are almost unknown; antenatally, CLHL may be
impossible to distinguish from other pathological causes of CTM
b) The description should be in simple clear language. Thus a CTM could described (antenatally 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) they contain air should also be
noted. Speculating about pathology from antenatal ultrasound scans often leads to a revision of
the diagnosis once the lesion has been resected [8]
c) The rest of the respiratory system should be described in a systematic manner as far as possible,
in particular the arterial and venous trees.
d) Other organs should be considered systematically, because associated lesions will be missed
unless carefully sought.
Antenatal presentations of CTMs
Most abnormalities are detected around 20 weeks’ gestation, at the routine fetal anomaly scan,
either from an abnormality of amniotic fluid volume or the discovery of a mass. CTMs can cause
polyhydramnios in isolation as a result of compression of the fetal esophagus preventing the
swallowing of amniotic fluid, or as part of fetal hydrops. A mass (cystic or solid) may be directly
identified in the fetal thorax or its presence may be suspected because of mediastinal shift.
Increasingly, fetal MRI is being used further to image suspected lesions and the surrounding lung [913]. MRI can confirm the presence of the mass, delineate the blood supply, and help to assess the
residual lung parenchyma [9, 10], although the place of this technique remains to be determined.
Cystic CTMs usually occur alone, although other associated abnormalities have been described,
including bronchopulmonary sequestration, congenital diaphragmatic hernia and extrapulmonary
malformations including renal and cardiac anomalies, but not aneuploidy [14, 15]. A so-called fetal
sequestrated lobe is most often identified as an echogenic mass of uncertain origin in the chest or
sub-diaphragmatic area; demonstration of an aortic blood supply, usually by colour flow Doppler, is
not diagnostic, because a CCAM may also have an aortic blood supply (above). The results of
investigation may result in fetal therapy being offered (below), or more usually, identifies fetuses
that should be delivered in a centre offering high level neonatal intensive care where early postnatal
surgery can be performed if needed. Where any lesion has persisted or increased in size and
mediastinal shift persists in the third trimester, delivery in such a centre is advisable.
Options for antenatal management of CTMs: a paediatric perspective
The first big question is, is any antenatal intervention warranted at all? The prognosis for a fetus
with a cystic CTM (“CCAM”) is generally good; the lesion tends to peak in size at 25 weeks, and then
regress [16]. One series of 48 CTMs [17] reported that in 22 cases, the lesions disappeared, and only
6 became severe. Another group reported that 64 of 67 fetuses with an antenatally diagnosed CTM
were born alive, of whom 42 underwent postnatal surgery [18]. Accurate prediction of outcome can
be difficult on a single scan, and serial scans should be undertaken to detect lesions which are not
regressing. Antenatal ultrasound features which were predictive of hydrops were MTR (ratio of mass
size to thorax size), cystic predominance, and diaphragmatic eversion; these fetuses need
particularly careful follow-up [19]. Protocols for ultrasound follow-up have been described [20]. MRI
can be used to calculate CTM volume to head ratio (CVR) [21]; a ration of > 1.6 is 80% predictive of
progression to hydrops, whereas CVR < 1.6 had a good prognosis (only 2% becoming hydropic).
CTMs with a single dominant cyst may behave unpredictably, and MRI should be interpreted with
caution in this context. However, all the series to 2007, which were summarised in [22], and
additional series published since then [2, 20, 23] have confirmed the key message, that only a tiny
minority of antenatally diagnosed CTMs will require antenatal intervention. However, equally clear is
that if the fetus becomes hydropic, mortality without intervention is close to 100% [24], but this can
be improved by a number of interventions [25, 26]. It should be noted that there are rare but well
documented cases of CTMs causing hydrops which have resolved spontaneously [27]. A very rare
complication is ‘maternal mirror syndrome’ [28-30], in which rapid development of pre-eclampsia,
proteinuria and pulmonary oedema herald maternal death unless fetus and placenta are urgently
delivered.
If intervention is needed, the options which have been proposed include cyst decompression or
pleuro-amniotic shunting for in particular isolated pleural effusion, intra-uterine surgery or
sclerotherapy, embolization of collateral vessels, radiofrequency ablation, and maternal steroid
therapy. For the most part, experience is limited to small case series, and there are no controlled
clinical trials. There are anecdotal reports of the use of maternal injections of betamethasone in fetal
CTM with better outlook than historical controls [31, 32]. Around 50% of hydropic fetuses may
respond to maternal betamethasone [33]. However, an unexpected intra-uterine death has been
reported after resolution of hydrops following betamethasone therapy [34]. Furthermore, the
response is very variable, and, if the CTM progresses despite a first course of steroids, then further
courses are not useful, and surgical management is required [33], although this is disputed [34];
clearly more data are needed. There are many surgical options. Where there are single or multiple
large cysts with associated hydrops or polyhydramnios improvement has been reported with inutero decompression by thoracocentesis or the insertion of a pleuro-amniotic shunt [20, 36, 37].
Shunting is only beneficial in the setting of antenatal CTM when there is pleural effusion or fetal
hydrops [37]. The prognosis for shunted CTMs containing a dominant large cyst is good, even if there
is hydrops, with around 75% survival [38]. It may be complicated by later chest deformity,
particularly if shunting is performed at less than 21 weeks gestation [36]. This contrasts with the
results of fetal surgery, also occasionally used in these lesions [20], where the incision heals in utero
without leaving a scar. Other techniques reported in small series include sclerotherapy of abnormal
feeding vessels, and sclerotherapy of the mass under ultrasound control [39, 40]. If the feeding
vessel is occluded by fetal sclerotherapy, around half the fetuses will need no further postnatal
treatment [2]. A case in which radiofrequency ablation was used [19] to ablate a large CTM resulted
in fetal death, presumed to be due to hemorrhage into the necrotic mass. This case would suggest
cautious use of any procedure, either ante- or post-natal, which results in infarction of the mass.
Options for postnatal management of CTMs: a paediatric perspective
At the most dramatic end of the spectrum, a fetus with a huge malformation severely compromising
the airway will require ex-utero, intrapartum treatment (EXIT procedure) [41]. Similarly, the baby
who is symptomatic with a large CTM or CLHL will require treatment in the neonatal period; very
occasional big malformations require EXIT to resection on placental support [41]. If less severely
affected babies nonetheless remain too tachypnoeic to feed, or are severely stridulous because the
airway is compressed by the CTM, or are less severely tachypnoeic but fail to thrive, then surgical
treatment is inevitable. For many abnormalities, surgery is the best and definitive treatment;
occasionally a lesser procedure such as embolization of a feeding vessel may be all that is needed
[42]. If pulmonary hypertension complicates a CTM, then stabilization prior to surgery is preferable
[43]. Symptomatic babies undergoing surgery in the newborn period have a higher complication rate
than asymptomatic infants [44]. For all but the smallest, sickest infants, lobectomy is a safe and well
tolerated procedure, with few if any significant sequelae. Increasingly, this is performed
thoracoscopically; the inpatient stay and duration of placement of chest drains is shorter [45];
however preceding pneumonia may mandate conversion of thoracoscopy to formal thoracotomy
[46], which is a consideration when deciding whether to defer surgery in the asymptomatic child
(below). The minimal possible resection should be performed [47]. However, pneumonectomy
carries a significant mortality in infancy. There is also considerable long term morbidity, in particular
scoliosis which may worsen dramatically during the pubertal growth spurt.
What to do for the baby who is well and thriving, but who has been given an antenatal diagnosis of a
CTM, is completely unclear. They should have a CXR prior to discharge. In many it will be normal, but
subsequent, more detailed imaging may reveal malformations; CXR was only 61% sensitive for
malformations, compared with the gold standard of HRCT [48]. There were no false positive
diagnoses on HRCT. However the unanswerable and related questions that arise are (1) what further
imaging should be performed; and (2) should such infants be submitted to surgery, and if so, when?
The question of surgery has to be dealt with first, because clearly here is little point in requesting a
HRCT in a very young child if no action will be taken on the results.
Surgery for asymptomatic CTMs is a really controversial area. If the lesion is cystic, then it is likely
(but unproven) that infection will occur sooner or later, and some would advise prophylactic excision
[49]. It is said that all lesions should be excised to prevent malignant transformation, but there
definitive evidence against this view (below). Other rare complications, which would definitely be
prevented by surgery include bleeding into or from the cysts, pneumothorax, and air embolism [5054]. Whether an asymptomatic malformation should be resected to facilitate normal lung growth is
not clear. The advocates of an aggressive approach argue that an asymptomatic CTM merits surgery
because it is likely that there will be a complicating infection of the cyst eventually, which may make
the operation more difficult, sometimes mandating conversion of VATS to a thoracotomy [46, 49].
Furthermore, in one series, 50% of CTMs resected after the age of six months were thought to show
evidence of chronic infection [48], a higher prevalence than I have seen in my practice. Anecdotally, I
have seen a single child who was thought to be asymptomatic, and had a large CTM removed which
on histology showed evidence of chronic infection. Post-operatively, the child was much happier and
healthier than before, and the parents realized that in fact the child had been a lot less well prior to
surgery than they had thought. However, this has been the exception in my experience. Another
challenging observation is that there is evidence of chronic inflammation even in most CTMs, even
those which were resected very early in life [52]. Again, the practical significance of this is hard to
determine. Finally, in one very small series (as with all others, uncontrolled) those initially treated
conservatively, and then subsequently undergoing surgery had a longer operation time and greater
blood loss, but were not otherwise disadvantaged [55].
Surgery is generally uncomplicated [56]. In favor of conservative management is the fact that some
lesions may regress completely post-natally [1, 53]. Furthermore, data presented briefly in a letter to
the Editor suggested that in more than 100 malformations, 10% required surgery in the newborn
period, a further 5% became infected and subsequently had an operation, and 85% remained
symptom free with no surgery; the detailed duration of follow-up is not stated [576]. Others report a
much higher proportion of children requiring surgery [50, 51], many as an emergency. These
children tended to need larger resections, although whether this was because of emergency
presentation is not clear. A Canadian survey highlighted that even among surgeons there was no
consensus about whether to operate on an asymptomatic CTM, what procedure to do and when to
do it. Of interest, 80% of CTMs managed conservatively initially eventually underwent surgery;
however, it is not clear from the manuscript what proportion became symptomatic, and how many
underwent surgery because of peer or parental pressure [58].
If the risk of these lesions becoming infected is unknown, still less do we know the risk of malignant
transformation. The following facts are clear.
 Primary pulmonary malignancy in childhood is very rare, and the evidence that there is in
fact an increased risk in most types of CTM is tenuous [3]
 There are case reports and case series of co-existence of CTM and a variety of primary
pulmonary malignancies [59-71]. These include bronchioloalveolar carcinoma and Type 1
CCAM [61, 68, 71]; pleuropulmonary blastoma (PPB) and Type 4 CCAM [62], and PPB and a
congenital lung cyst [65]; CCAM (type unspecified) and rhabdomyosarcoma [66, 67]. Further
information on the relationship between CCAM and PPB can be found at
www.ppbregistry.org.
 Even complete removal of a CTM cannot prevent the development of malignant disease
elsewhere in the lung [69, 72, 73], implying that the malformation is merely a marker of
increased malignant potential throughout the lungs, in which case removing the
malformation would not deal with the underlying problem.
Thus although one group [74] suggested on the basis of cytogenetic and p53 profiles that CCAM was
not a premalignant condition, the rest of the literature is less reassuring. It is suggested that a higher
incidence of suspicion is justified in those with bilateral disease, a family history of pleuropulmonary
blastoma, pulmonary cysts or renal anomalies, or a close relative with a childhood malignancy,
especially Wilm’s tumour or medulloblastoma. The registry data on the relationship of
pleuropulmonary blastoma and CTM has been reviewed [75]. Malignant transformation is rare, but
more evidence is needed.
Thus we do not know the risk of infection or malignant transformation. Surgery prevents infection,
although cysts recurrence has been described [50], but it does not always prevent pulmonary
malignancy. If surgery is contemplated, it is essential to delineate the anatomy of the CTM, and in
particular the blood supply. HRCT scanning after contrast, with modern reconstruction techniques is
used to delineate the blood supply and venous drainage CTM [76]. MRI may also be used.
What to say to the parents: a practical approach
If a large CTM is discovered at the 20 week anomaly scan, then parental anxiety is likely to be huge;
almost paradoxically parents worry more about the uncertainty around a usually benign prognosis
CTM than about definitively bad prognosis lesions such as congenital diaphragmatic hernia [77].
Parents should be advised that the vast majority of CTMs require no antenatal intervention, and the
likeliest outcome is the safe delivery of a healthy infant, for whom an elective operation may need to
be considered at some stage. Early consultation with respiratory paediatricians and paediatric
surgeons is helpful. Progress is followed with serial ultrasound scans. Parents of the rare fetus
requiring antenatal intervention should receive counselling from a specialist perinatologist.
My personal, non-evidence based practice is to recommend post-natal surgery for all but trivial
CTMs, so that an elective, low risk procedure can be performed at a convenient time, rather than the
possibility of having to deal as an emergency with an infected malformation. If the child is well and
thriving, I perform HRCT without contrast in the first few weeks of life; if the CTM has truly
involuted, or of trivial size, then no further action is needed. If the size is significant, then timing of
surgery is a trade-off between allowing the baby to grow, and not allowing time for complications to
develop. Since complications are rare before age 2 years [55] (although definitely described [78]) I
advise surgery towards the end of the second year of life. However, there is recent, albeit indirect
evidence from post-operative nuclear medicine studies that lung growth postoperatively may be
better if surgery is performed before a year of age, in uninfected children [79]. Interestingly, the size
of resection was apparently irrelevant. In preparation for surgery, I recommend a second HRCT scan
with contrast at 18 months of age; if the mass has involuted, surgery is cancelled. Immediate surgery
in the postnatal period may mean some children will undergo an unnecessary operation. It could be
argued that the first HRCT is unnecessary, but it allows some infants to be discharged immediately;
furthermore, if the CTM is in fact a CLHL (“congenital lobar emphysema”) and the child is
asymptomatic, then the family can be reassured that surgery is highly unlikely ever to be necessary,
since these lesions do not become infected, and no further imaging is required.
In summary, given the lack of evidence, at all stages the paediatrician would do well to share with
the parents the little that is known, and the large amount that is unknown, and discuss the lesions
with the family on a case by case basis [80]. Reassuringly, whatever options are chosen, the long
term outlook for the vast majority is excellent.
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