Eur J Pediatr (2017) 176:1559–1571
https://doi.org/10.1007/s00431-017-3032-7
REVIEW
Congenital pulmonary airway malformations: state-of-the-art
review for pediatrician’s use
Claire Leblanc 1 & Marguerite Baron 1 & Emilie Desselas 1 & Minh Hanh Phan 1 &
Alexis Rybak 1 & Guillaume Thouvenin 1,2 & Clara Lauby 1 & Sabine Irtan 2,3
Received: 4 July 2017 / Revised: 30 September 2017 / Accepted: 4 October 2017 / Published online: 19 October 2017
# Springer-Verlag GmbH Germany 2017
Abstract Congenital pulmonary airway malformations or
CPAM are rare developmental lung malformations, leading
to cystic and/or adenomatous pulmonary areas. Nowadays,
CPAM are diagnosed prenatally, improving the prenatal and
immediate postnatal care and ultimately the knowledge on
CPAM pathophysiology. CPAM natural evolution can lead
to infections or malignancies, whose exact prevalence is still
difficult to assess. The aim of this Bstate-of-the-art^ review is
to cover the recently published literature on CPAM manage-
ment whether the pulmonary lesion was detected during preg-
nancy or after birth, the current indications of surgery or sur-
veillance and finally its potential evolution to pleuro-
pulmonary blastoma.
Conclusion: Surgery remains the cornerstone treatment of
symptomatic lesions but the postnatal management of asymp-
tomatic CPAM remains controversial. There are pros and cons
of surgical resection, as increasing rate of infections over time
renders the surgery more difficult after months or years of
Communicated by Peter de Winter
* Sabine Irtan
sabine.irtan@gmail.com; sabine.irtan@aphp.fr
Claire Leblanc
claire.leblanc@aphp.fr
Marguerite Baron
margueritebaron2@gmail.com
Emilie Desselas
emilie.desselas@yahoo.fr
Minh Hanh Phan
mhanh.phan@gmail.com
Alexis Rybak
alexis.rybak@gmail.com
evolution, as well as risk of malignancy, though exact inci-
dence is still unknown.
What is known:
• Congenital pulmonary airway malformations (CPAM) are rare devel-
opmental lung malformations mainly antenatally diagnosed.
• While the neonatal management of symptomatic CPAM is clear and
includes prompt surgery, controversies remain for asymptomatic
CPAM due to risk of infections and malignancies.
What is new:
• Increased rate of infection over time renders the surgery more difficult
after months or years of evolution and pushes for recommendation of
early elective surgery.
• New molecular or pathological pathways may help in the distinction of
type 4 CPAM from type I pleuropulmonary blastoma.
Keywords CPAM . State of the art . Pleuropulmonary
blastoma
Guillaume Thouvenin
guillaume.thouvenin@aphp.fr
Clara Lauby
lauby.clara@gmail.com
1
Department of Pediatric Pulmonology, APHP Hôpital Armand
Trousseau, Paris, France
2
UPMC Univ Paris 06, Centre de Recherche St Antoine Inserm
UMRS.938, Sorbonne Universités, Paris, France
3
Department of Pediatric Surgery, APHP Hôpital Armand Trousseau,
26 avenue du Dr Arnold Netter, 75012 Paris, France
1560 Eur J Pediatr (2017) 176:1559–1571

Abbreviations Embryology and molecular regulations

BAC bronchio-alveolar carcinoma of the embryonic lung development process
BC bronchogenic cysts
BMP4 bone morphogenic protein 4 The lung development is classically divided into five histo-
BPS bronchopulmonary sequestration logical stages, namely embryonic, pseudo glandular, canalic-
CCAM congenital cystic adenomatoid malformation ular, saccular, and alveolar stages. The embryologic process
CC10 clara cell 10 starts first with a separation of the trachea from the foregut, the
CLE congenital lobar emphysema lung bud appearing as an out pouching of respiratory epithe-
CPAM Congenital pulmonary airway malformation lium from the ventral part of the foregut. The players known to
CT computer tomography be involved in this early stage of development are expressed in
CVR CPAM volume ratio the endoderm (Nkx2-1 is a gene encoding for a thyroide tran-
EFS event free survival scription factor TTF1 that lies in the ventral wall of the ante-
EXIT ex utero intrapartum treatment rior foregut, while sex determining region Y-box 2 gene, Sox2,
FABP7 fat acid binding protein 7 and Hox gene 5, Hoxb5, are in the dorsal wall of the anterior
FEV1 forced expiratory volume in 1 s foregut), and in the surrounding mesenchyme (with bone mor-
FGF10 fibroblast growth factor-10 phogenic protein 4, BMP4, and its antagonists Noggin, fibro-
FGFR2b fibroblast growth factor receptor blast growth factor-10 (FGF10), and Wnt) [22, 64].This prim-
FVC forced vital capacity (FVC) itive formation extends and divides into branches, creating the
MRI magnetic resonance imaging primitive bronchi, between the 4th and 7th week of gestation.
PDGF-B platelet-derived growth factor B Pulmonary arteries develop at this stage from the 6th aortic
PPB pleuro-pulmonary blastoma arches; they will grow into the mesenchyme to form a vascular
OS overall survival plexus around the lung tubules. During the pseudo glandular
SPRY2 Sprouty 2 stage, between the 8th and 16th week of gestation, the lung
SSH Sonic Hedghog buds elongate caudally and sprout into the surrounding mes-
TGF β growth factor β enchyme [65]. This pattern depends on FGF10 expression in
US ultrasound scan the distal mesoderm through its receptor fibroblast growth
YY1 Yin Yang 1 factor receptor (FGFR2b) in the adjacent epithelium that leads
to bud extension and growth [1, 81, 87]. Negative feedback
loops to inhibit the bud outgrowth are mediated by Sprouty 2
(SPRY2), Sonic hedgehog (SHH), the transforming growth
Introduction factor β (TGFβ), and Wnt signaling pathways [7]. By the
end of the pseudo glandular stage, all branches of the tracheo-
Congenital pulmonary airway malformations or CPAM (for- bronchial tree (from the trachea to the preacinar airways) are
merly congenital cystic adenomatoid malformation or formed. Epithelial cell differentiation leads to the onset of
CCAM) [84, 86] are rare developmental lung malformations. ciliated cells, goblet, and basal cells while the mesoderm dif-
They are characterized by an abnormal airway pattern occur- ferentiates into early cartilage, connective tissue, smooth mus-
ring during lung branching morphogenesis and can possibly cle, lymphatic, and vascular cells. In the canalicular stage
lead to cystic and/or adenomatous pulmonary areas. The prev- (from the 17th to the 24th week of gestation), blood-air inter-
alence is estimated at 0.81/10,000 fetuses according to a face is prepared through formation of the acinus (gas exchang-
European registry [31]. CPAM is the most common congeni- ing unit) and of capillaries leaning against the epithelium. The
tal lung malformation (30–40%). CPAM differential diagno- pulmonary epithelium continues its differentiation into type II
ses are bronchopulmonary sequestration (BPS), bronchogenic pneumocytes (surfactant-producing cells) and type I
cysts (BC), and congenital lobar emphysema (CLE). Hybrid pneumocytes (responsible for the thin barrier at the blood-air
lesions are defined as a combination of CPAM and BPS [19]. interface). The ensuing saccular stage (from the 25th to 35th
Today, CPAM are often antenatally diagnosed and managed weeks of gestation) corresponds to the earliest period of lung
by the pediatric surgeon in early life. The surgical treatment of viability with saccule formation at airways end. The produc-
CPAM is a contentious subject because of the lack of infor- tion of pulmonary surfactant starts into the primitive alveoli.
mation regarding the natural evolution of CPAM with respect The blood air barrier gets thinner and capillaries rapidly grow
to its infectious and degenerative risks. In this Bstate-of-the- in the surrounding mesenchyme preparing the beginning of air
art^ review, we aim to cover the recently published literature exchange. Primitive saccular septation and interstitial tissue
on CPAM genetics and pathophysiological hypothesis, prena- thinning increase the gas exchange surface. The alveolar stage
tal and post-natal diagnosis and treatment and finally its po- continues until 4–5 years old, with the establishment of sec-
tential evolution to pleuro-pulmonary blastoma (PPB). ondary septa that subdivide the saccules into smaller units
Eur J Pediatr (2017) 176:1559–1571
called alveoli. The lung and thorax growth carries on until the
end of adolescence.
Genetics and pathophysiological hypotheses
for CPAM formation
The lung formation is a well-organized process, involving the
coordination of regulatory factors orchestrated by mesenchy-
mal and epithelial interactions in all the stages of develop-
ment. However, their potential involvement with congenital
cystic lung disease remains misunderstood.
Two different theories have been put forward to explain the
pathophysiological mechanisms of CPAM. The environmen-
tal hypothesis states that a persistent expression of early lung
development markers caused by potential genetics defects
would lead to a focal and temporary interruption of the lung
morphogenesis.
More recently, histological studies of lung malformations
have suggested an obstructive hypothesis: focal obstruction of
the air tree, either functional (peristalsis abnormality) or or-
ganic (bronchial stenosis), would generate an increase of me-
diators and engender the abnormalities of CPAM [56]. The
modes and timing of obstructive events are currently poorly
understood [53].
Table 1 summarizes the key genes and molecules known or
potentially involved to play a role in early lung formation. The
main studies use mouse lungs and human fetal resected
CPAM tissues to try to discern how the disturbance of their
expression can interfere with normal lung morphogenesis.
Overall, these significant progresses in the identification of
potential molecular and gene factors involved in CPAM con-
firm the multifactorial and complex physiopathology of
CPAM.
CPAM classification
CPAM classification is mainly based on the proposition
made by Stocker on the histology of lung lesions obtained
from surgery. Stocker et al. initially identified three stages
through gross and microscopic description resulting in the
first classification (type 1, the most frequent form, with
large cysts containing mucus cells, type 2 with multiple
small sized cysts and possibly other anomalies associated,
type 3 with bulky lesions with solid appearance and often
mediastinal shift) [86]. Later, the classification was up-
dated after new types were described [77] such as type 0
or acinar dysplasia, often lethal and type 4. Type 4 CPAM
is an acinar malformation lesion that consists of varying
sized cysts, all lined by type 1 and 2 alveolar cells with no
mucous cells [85].
1561
CPAM diagnosis
Antenatal diagnosis
In 2016, due to sonographic improvements, the antenatal di-
agnosis of congenital cystic lung lesions reaches 85.7% in an
8-year retrospective review [37]. The mean gestational age for
sonography detection is the second trimester of gestation (21–
24 weeks). CPAM appears as an echogenic mass within the
fetal lungs. CPAM has been antenatally categorized into three
types: type I (25% of the cases) a macrocystic and multicystic
mass characterized by one or more cysts of variable size, up to
10 cm; type II (25% of the cases) a mixed mass with cysts and
adjacent area of increased echogenicity on ultrasound; and
type III (50%) a microcystic (< 5 mm) anechogenic mass
within the fetal lungs [49]. The hyperechogenicity is not spe-
cific and does not predict the histological diagnosis [36]. The
sensitivity and specificity of prenatal ultrasound scan (US)
reach 90 and 77%, respectively. Pulmonary sequestration,
the main differential diagnosis, can be identified by the visu-
alization of a vessel coming directly from the aorta in Doppler
mode [27].
The place for prenatal magnetic resonance imaging (MRI)
increases over time for antenatal detection of all kinds of fetal
malformations. The sensitivity and specificity of MRI to de-
tect lung lesions reaches at least 95% [69], but MRI does not
show any real benefit in terms of diagnosis and prognosis
compared to US [32]. Both prenatal MRI and US exhibit high
accuracy in the detection of isolated lung malformations. In
complex cases (CPAM associated with another lung malfor-
mation, i.e., hybrid lesion), MRI seems the best technique
even though the additional information provided do not influ-
ence postnatal management [4].
It is unusual that CPAM continue to grow over the 28 weeks
of gestation. The spontaneous sonographic antenatal evolution
may be resolution (disappearance) (11–49%), regression (mal-
formation shrink) (18–42%), or progression (33–44%) [18, 36,
59, 83]. Cavoretto et al. showed that only 34 (44.7%) of 76 cases
with prenatal sonographic resolution were confirmed postnatally
[18]. Vanishing lung lesions seem to be relatively common es-
pecially with microcystic and low volume lesions and are less
symptomatic at birth than persistent antenatal lesions [51]. Even
though vanished during the pregnancy, systematic imaging is
recommended at birth to characterize CPAM appropriately. A
chest X-ray may be performed first, but even if normal, one
would not be able to confirm the complete disappearance of
the antenatally detected lung lesion. To avoid high-dose radia-
tion, one could choose to repeat chest X-ray at 6 months of life
or to perform a computer tomography angiography (CTA)-scan
later to definitively confirm the absence of pulmonary lesion.
The detection of antenatal complications such as mediasti-
nal shift, hydrops, hydramnios, and finally fetal death is cru-
cial [83]. To detect fetuses at risk of complications,
Table 1 Key genes and molecules involved to play a role in early lung formation
Genes and molecules controlling airway formation
Thyroide transcription factor gene (Nkx2)
Sex determining region Y)-box 2 gene (Sox2)
Hox gene (Hoxb-5)
Yin Yang 1 gene (Yy1)
Fatty Acid Binding protein-7 gene (FABP-7)
Elevated Platelet-Derived Growth Factor B gene
(PDGF-B)
Function
• Encodes a protein identified as a thyroid-specific
transcription factor (TTF1)
• During embryogenic stage:
- Expression of Nkx2–1 in the ventral wall of the anterior
foregut,
- Regulates the appearance of the two primary lungs buds
• During embryogenic stage:
- Expression dorsally in the anterior foregut
- Role in foregut separation between a dorsal esophagus
and a ventral trachea
• During pseudoglandular stage:
- Expressed, in the undifferentiated proximal cells of the
foregut,
- Involved in the differentiation of endoderm epithelium
cells to basal cells by regulating the expression of Trp63, a
transcription factor
• Expression in the mesenchyme, surrounding the anterior
foregut, during embryogenic stage and expression at
pseudoglandular stage during branching morphogenesis
• Encodes for a zinc finger transcription factor YY1
• Known to plays function in embryogenesis in regulating
a multitude of genes (by selectively activating or
repressing transcription)
• Encodes for FABP-7, which decreases the concentration
of fatty acid in the cytoplasm.
• Encodes for platelet-derived growth factor-BB, during
the canalicular stage
• Induces lung development by increasing cells proliferation
• During embryogenic stage:
1562
Pathophysiological hypotheses for CPAM formation from mouse models or
humans resected CPAM tissues
Morotti et al.: compared TTF-1 expression in CPAM post-natal lungs
and fetal lungs at varying gestational ages.
In the fetal lungs, TTF-1 decreased in bronchial, bronchiolar, and alveolar
epithelia with advancing gestational age and cytodifferentiation whereas
in CPAM types 1, 2, and 3, TTF-1 was expressed in a majority of the
bronchiolar-like epithelial cells of the cysts. [63]
Ochieng et al.: observed on developing mouse lung that the appearance
of cystic structure, similar to CPAM, can be explained by an abnormal
expression of Sox2 in the epithelial cells.
The cysts could be induced by:
- The premature differentiation of epithelial tip cells, unable to respond to
FGF10 and subsequently explaining an arrest in the branching of the
epithelium.
- The overexpression of GATA-binding factor 6 (GATA6) a zinc finger
transcription factor, regulated by Sox2 and known to be involved in
broncho-alveolar stem cells emergence, causing cellular changes. [68]
Volpe et al.: found persistent high-level expression of Hoxb-5 in human
CPAM lung tissues during the saccular and alveolar stage of lung de-
velopment. Maintained Hoxb-5 expression may alter downstream
genes involved in cell adhesiveness. Altered adhesive properties
epithelial cells may form abnormal airways leading to CPAM by pro-
liferating and migrating through the surrounding mesenchyme
[88, 89].
Boucherot et al.: showed that YY1 inactivation impairs tracheal cartilage
formation, alters cell differentiation, abrogate lung branching and cause
airway dilation similar to human CPAM in mouse mutants. YY1 impacts
on SHH expression which represses FGF10 expression. Also analysis of
human lung tissues revealed decreased YY1 expression in children with
pleuropulmonary blastoma, associated with DICER1 mutations, but no
major changes in YY1 expression of CPAM patients [11, 12].
Wagner et al.: analyzed fetal and postnatal resected CPAM tissues:
FABP-7, was under-expressed. FABP-7 decreases the concentration of
fatty acid
in the cytoplasm. Fatty acids inhibit the binding of glucocorticoids to
their intracytoplasmic receiver. The involvement of glucocorticoids in
the lung maturation explains why a lack of FABP-7 expression could
play a part in the pathogenesis of CPAM [90].
Liechty et al.: showed that the CPAM fetal subtype, which is rapidly
growing and progressing to hydrop, has an increased mesenchymal
growth factor PDGF-B gene expression and elevated PDGF-BB
protein. CPAM abnormalities can be explained by the persistence of
PDGF-B production at inappropriate time, leading to incessant
stimulation of the adjacent epithelium [58].
Eur J Pediatr (2017) 176:1559–1571
Eur J Pediatr (2017) 176:1559–1571 1563

Pathophysiological hypotheses for CPAM formation from mouse models or

fetal and post-natal CPAM human samples, using microarray analysis

Jancelewicz et al.: did not find an alteration of FGF10 expression in the
the development stage and the location of the injection, cystic lesions
Crombleholme et al. developed a measure of CPAM volume

Gonzaga et al.: showed it could produce cystic lesions when injecting

FGF10 protein in fetal rat lung by trans-uterine way. According to
normalized for gestation age, named CPAM volume ratio

A very temporary overexpression of FGF10 might explain these

(CVR). CVR represented the ratio between the CPAM esti-
mated volume at antenatal ultrasound (CPAM was considered
as an ellipse and its volume was calculated by the formula
length*height*width*0.52) and the head circumference. The

of laser dissected epithelium and mesenchyme.

authors showed that a CVR greater than 1.6 at presentation
was highly predictive of hydrops [23]. A recent study showed
that a CVR over 0.84, polyhydramnios, and ascites increased
the risk of severe respiratory distress [78]. Other formulas
such as fetal MRI lung volumes, mass-to-thorax-ratio, and
lung-to-head ratio using ultrasound have been tested subse-
humans resected CPAM tissues

contradictory findings [42].

quently [40, 93]. The main purpose to establish a predictive
marker for life-threatening complications is to give parents
accurate counseling based on risk stratification and the thera-
peutic resources required and available. Among antenatally
differed [35].

diagnosed patients, 70% of CPAM are asymptomatic at birth;

the other 30% have neonatal respiratory distress. Ten percent
have severe respiratory distress necessitating assisted ventila-
tion [27]. Therefore, the birth must be handled by specialized
maternity wards, especially when antenatal risk factors (shift,
high CVR, hydrops) of postnatal respiratory distress are pres-
ent. Otherwise, these neonates may be delivered in general
• During pseudoglandular stage: - Negative feedback
loop of FGF 10 expression inhibit bud outgrowth

• Through its epithelium receiver FGFR2b, leads to

- Role in the early differentiation of the trachea and
- Expression in the endoderm and in the mesoderm

hospitals.

Treatment of antenatal complications

bud extension and growth of the air tree
during bronchial ramification process
Fibroblast growth factors 10, 9, 7 (FGF10, FGF9, FGF7) • During the pseudoglandular phase:

The indications of prenatal treatment for CPAM complications

- Expression in the mesenchyme

require a correct characterization of the lesion and the addition

of cardiac echocardiography to evaluate cardiac conse-
quences. The indication for fetal surgery is based on fetal
echocardiogram. Significant valvar regurgitation, decreased
ventricular function, or Doppler changes on fetal echocardio-
gram seem predictive of adverse outcome [16]. Treatments
(TGFβ)

ranging from maternal steroid administration to minimally

Function

lung

invasive or open fetal surgery can be offered. Steroid admin-

istration to the mother has been used with reasonable success
for microcystic lesions associated to hydrops fetalis, with a
Sonic Hedghog (SHH), Bone Morphogenetic protein 4

lower risk of prematurity, less ventilator requirement, and a

pathways, transforming growth factor β (TGFβ)
(BMP4), Sprouty 2 (SPRY2), and Wnt signaling

better outcome, compared to open fetal surgery [3, 60]. The

Genes and molecules controlling airway formation

exact number of courses needed is still debatable, the absence

of microcystic lesions decreases after the first course being a
risk factor of fetal surgery [26, 72]. Percutaneous sclerothera-
py by ethanolamine injection for CPAM type 2 or 3 has been
reported in three children with success [55]. In macrocystic
lesions, thoracocentesis can be a useful tool for both diagnosis
(cell count, viral screen, and culture) and treatment of
Table 1 (continued)

hydrops. Though, the most appropriate treatment approach is

thoracoamniotic shunting because thoracocentesis will be al-
most inevitably followed by fluid re-accumulation. Wilson
et al. reported 13 survivals after prenatal shunting among 18
hydropic babies with large cysts [92]. For fetuses with large
masses inducing mediastinal shift who survive to the end of
1564 Eur J Pediatr (2017) 176:1559–1571

gestation and when lung development is compatible with life,

the ex utero intrapartum treatment (EXIT) procedure is an
option that has showed good results in highly specialized cen-
ters [17]. When treatment possibilities are overcome, a thera-
peutic abortion can be discussed [78, 80].

Post-natal diagnosis

Post-natal diagnosis is mainly made after pneumonia in pa-

tients with no antenatal diagnosis, while wheezing is found in
one third of patients antenatally diagnosed and not operated
during the first month of life [25]. CPAM usually appears as a
hyperlucent mass with sometimes a radio-opaque component
(depending on the CPAM type) on chest X-ray. Incidental
findings on postnatal chest X-ray lead to the diagnosis of
CPAM in 50 to 60% of cases (Fig. 1) [8, 71] whereas almost
100% of CPAM are detected by CTA-scan with contrast in-
travenous injection as well as their potential complications [8,
13, 71, 94]. Large lesions can impact the mediastinum with
trachea deviation and mediastinal shift (Fig. 2) or be respon-
sible for pneumothorax. CTA images can also detect vascular
anomalies that have to be checked [19, 47]. Differential diag-
noses, such as pulmonary sequestration, congenital lobar em- Fig. 2 Chest X-ray of an asymptomatic newborn antenatally diagnosed
physema, and bronchogenic cyst, can be excluded [18]. with CPAM (dark hyperlucent mass of the left lower lobe) and
corresponding images on chest CTA, illustrating type 2 CPAM

However, CTA-scan is not fully reliable for the diagnosis

and does not replace specimen pathologic analysis [19, 71],
especially because of potential misdiagnosis with PPB for
type 4 CPAM. Finally, the good resolution of pictures and
3D reconstructions make CTA-scan essential to the preopera-
tive assessment [79]. The CPAM symptoms at birth and the
intended surgical procedure determine the timing of imaging.
There is consensus that imaging has to be done emergently
after respiratory stabilization in case of symptomatic lesions;
otherwise, it can be performed between the age of 1 to
6 months for symptomatic lesions at birth [52, 71]. The exact
timing and modalities of neonatal imaging for asymptomatic
lesions are still under debate, but CTA-scan is proposed within
the first 6 months of life even for authors who favor surveil-
lance rather than surgery [21].

Post-natal treatment

The surgical management in neonates and infants is consen-

Fig. 1 Normal chest X-ray at birth of a newborn antenatally diagnosed
with CPAM and CTA scan performed at 1 month of life showing
macrocystic lesion in the right lower lobe consistent with type 1 CPAM
sual for symptomatic patients. Commonly reported symptoms
include cyst infection, hemorrhage, dyspnea, pneumothorax,
nutritional difficulties, sudden respiratory compromise (20%
of children under 1 year old), and malignant transformation
(1–3%) [20, 71, 82]. The prognosis after surgery is good,
whatever the age at surgery [91].
Eur J Pediatr (2017) 176:1559–1571
By contrast, the postnatal management of asymptomatic
patients remains challenging, as the natural postnatal history
of CPAM is still unclear. Antenatal and postnatal radiological
features are useless in distinguishing a lesion that will finally
disappear from a lesion that should be removed. The decision
to undergo surgery is based on the clinical evolution (appear-
ance of symptoms) and/or to prevent common and rare com-
plications (malignancies). In a systematic review with meta-
analysis of 1070 patients, symptoms developed in 3.2% of
asymptomatic cases and at a median age of 7 months [83].
In a more recent systematic review and meta-analysis includ-
ing 168 patients with longer follow-up (3 versus 1 year), only
36% of patients who were managed non-surgically remained
asymptomatic at last follow-up [45]. However, this review
was not designed to properly assess the percentage of asymp-
tomatic patients at birth that will become symptomatic at long-
term follow-up, potentially overestimating the real rate of pa-
tients becoming symptomatic. Another systematic review
dedicated to compare thoracoscopy versus thoracotomy for
asymptomatic cases exhibited a rate of symptoms onset before
surgery at 12% (195 out of 1626 patients who were operated
on at an average age of 17 months for the thoracoscopy group
and 13 months for the thoracotomy group developed symp-
toms before surgery) [2]. Late symptoms can appear at any
time during life, as shown in a large retrospective study of 102
adult patients (mean age 47 years) surgically treated for
CPAM, where 84 (82.3%) required resection for symptoms
often suggestive of recurrent pneumonia (n = 33), or other
symptoms such as dyspnea, cough, or chest pain. Only 18
patients who underwent surgery were asymptomatic, for
whom surgery was indicated for establishing diagnosis.
None of the lesions removed were malignant (histological
findings were bronchogenic cysts and pulmonary sequestra-
tions) [61]. All of the studies described above advocate early
surgery, symptomatic patients being more than likely to expe-
rience surgical complications and to require extensive and
open thoracotomy resections at adult age. Complications of
surgery for patients operated on when becoming symptomatic
include longer hospital stay, longer pleural drainage and inva-
sive ventilation, higher rate of postoperative complications
(fistula, hemorrhage, second surgery) but with no difference
in mortality [20]. Elective surgery, eliminating CPAM com-
plications, is thus considered to provide better outcome than
emergency surgery [83].
Another argument in favor of surgery is the absence of
absolute concordance between radiological and pathological
findings. Type 4 CPAM is indistinguishable from type I PPB
at imaging. The other malignancies to consider in the context
of CPAM are bronchio-alveolar carcinoma (BAC) now
reclassified as adenocarcinoma and rhabdomyosarcoma
(now viewed as cystic PPB). Typically, BAC is a slowly grow-
ing tumor in adults, but cases of neonatal occurrence have
been published [57]. A single example of mucoepidermoid
1565
carcinoma in a 19-year-old male patient arising from a large
multicystic lesion in the right upper lobe has been reported
[38].
The best timing for surgery of asymptomatic infants is still
debated, but seems to be between 6 months and 2 years old
because anesthetic and surgical risks decrease after the first
months of life [30]. More importantly, the lung maintains the
capacity to expand and develop until 4 years of age allowing
better compensation when early surgery [24, 44]. On the con-
trary, Rothenberg et al. advocate less pulmonary tissue inflam-
mation if operation is performed before 6 months of life [77].
Figure 3 proposes a decision-tree for CPAM management.
Surgical management
The standard technique has been open approach since
years, but thoracoscopy approach is nowadays gaining
increasing experience among surgeons [76, 77]. A recent
s t u d y o f 11 2 0 A m e r i c a n s a m p l e c h i l d r e n , t h e
thoracoscopic approach, is significantly increasing
(32.2% in 2008 to 48.2% in 2012) with similar postoper-
ative complications or length of hospital stay [73].
Thoracoscopic and open resection provide comparable
30-day outcomes and safety in a review of 258 patients
[50]. Comparing open vs thoracoscopy technique, a meta-
analysis performed in 2012, has shown no differences
concerning complication rates and operative time, but
the chest tube duration and hospital stay seemed longer
with the open approach [66]. A recent meta-analysis in-
cluding 1626 patients (versus 216 in the previous review)
showed a lower surgical complication rate after
thoracoscopy (16 versus 18% with thoracotomy) with a
shorter length of stay (1.4 days) despite a longer operative
time (37 mn more for thoracoscopic resection) [2].
If a thoracotomy is performed, the muscle-splitting ap-
proach, which preserves the serratus anterior and lattisimus
dorsi together with their nerve supply, is favored. This tech-
nique may not only decrease postoperative pain but may also
decrease the incidence of scoliosis and muscle dysfunction
found in children having undergone thoracotomies as infants
[54, 75].
The thoracoscopic intervention is difficult in neonates be-
cause of the small exposure space. However, video-assisted
thoracoscopic surgery was reported to be safe and effective,
even in infants less than 3 months of age when performed in
experienced centers. Indeed, there is a very small rate of con-
version to thoracotomy (from 3 to 12.2%) [66, 77].
The choice between lobectomy and segmentectomy is
guided by the need to both completely remove the lesion
and preserve as much lung parenchyma as possible.
Elective lobectomy appears to be very well tolerated and
is the most prevalent surgical method [30]. But
segmentectomy, defined as an anatomical resection, or
1566
Fig. 3 Guidance of CPAM antenatal and postnatal management
wedge-resection defined as a non-anatomical resection, is
gaining experience with safe outcome [48]. No differ-
ences have been found in terms of early postoperative
complication incidence, length of hospital stay, chest tube
duration, and late morbidities (length of follow-up,
pulmonary infection) in patients who had a parenchyma-
saving resection [5, 48, 73]. Sparing-lung surgery seems
as effective as lobectomy regarding risks of leaving resid-
ual disease or of recurrence [43]. Surgical risks are the
lowest for asymptomatic patients with small lesions [33].
We still need further prospective studies to determine the
best way to operate CPAM.
In order to characterize the potential of CPAM for infection
and malignancy, Durell et al. have reviewed 69 pathological
specimens, 34 were CPAM. Seven of the pathological speci-
mens showed microabscesses, 9 had neutrophil/macrophage
infiltration, and 2 were tumors. Twenty-six percent of asymp-
tomatic antenatally diagnosed CPAM showed a risk of infec-
tion or malignancy [29]. This information favors surgery and
is useful to share with parents confronted with difficult deci-
sion about their child.
Eur J Pediatr (2017) 176:1559–1571
Evolution of operated CPAM from children to adults
Concerning the long-term assessment of respiratory function
of children who underwent surgery for lung resection, the
literature is rare with opposite results. Keijzer et al. studied
the forced vital capacity (FVC) and forced expiratory volume
in 1 s (FEV(1)) on children operated on before or after 2 years
old, at a median of 10 years. This study has shown no signif-
icant difference in long-term respiratory function [46]. But a
restrictive syndrome can develop if the resection is not made
soon enough to benefit from the lung compensatory growth
[74]. The best age to have the lowest operative risk and the
best chances of lung recuperation seems to be around
6 months. Lung function test, usually done around 3 to 4 years
old, may help identify children with decreased pulmonary
compliance and increased respiratory rates that could benefit
from early surgery [6]. Complications in adulthood are tho-
racic malformations (thorax growth asymmetry, scoliosis,
pectus excavatum) related to the size of the malformation
[74]. Abnormalities of the mammary gland can also be seen
[74]. A very recent study comparing the respiratory outcome
Eur J Pediatr (2017) 176:1559–1571 1567

of patients operated on by thoracotomy for congenital lung
malformations (including CPAM, BPS, and congenital alveo-
lar overdistension) to control patients operated on for inguinal
hernia showed that patients operated on for lung lesions had a
higher prevalence of wheezing, lower respiratory tract infec-
tions, and needed more inhaled bronchodilatators and system-
ic steroids in their first years of life, but these sequelae tended
to disappear after 4 years of age [14].
Evolution to PPB
PPB is a rare but very aggressive intrathoracic tumor, usually
diagnosed before the age of 6 years. It is classified into three
types: type I (cystic), type II (both cystic and solid), and type
III (solid only). The clinical signs leading to its diagnosis are
most of the time unspecific: repeated pulmonary infections,
pneumothorax without identified triggers, or unspecific le-
sions on chest X-ray (Fig. 4) [28].
Its incidence is difficult to establish, because of its
rarity, and because PPB type I is usually confounded with
CPAM type 4.
Until very recently, no clinical, radiological, or biological
criteria that can distinguish PPB type I from type 4 CPAM
were established and PPB diagnosis relied on the histological
examination of the lesion showing a multilocular cyst with
proliferation of primitive mesenchyme cells into underlying

Fig. 4 Type I pleuro pulmonary

blastoma chest X-Ray in a 4-year-
old boy (a), diagnosed after
respiratory distress. The
corresponding CTA scan shows a
macrocystic lesion with healthy
lung parenchyma atelectasis and
septa seen on X-ray. Left type II
(b) and type III pleuro pulmonary
blastoma (c) showing trachea and
heart deviation on the right side of
the thorax
1568
stroma filling the cyst progressively (explaining the continu-
um from type I to type III PPB). After comparing 103 CPAM
to 112 type I PPB, Feinberg et al. propose a new algorithm
based on clinical and radiological data to distinguish CPAM
from type I PPB [34]. Pulmonary lesions that are antenatally
detected and post-natally asymptomatic with hyperinflation
and a feeding vessel are more likely CPAM [34]. If there is a
doubt on the final diagnosis between type 4 CPAM and PPB
type I, an evaluation of the expression of FGF 10 can be of
help, an overexpression of FGF 10 in the epithelium and the
stroma being in favor of type 4 CPAM [18].
Cases of malignancy emerging from CPAM have been
described in the literature. Hartman et al. reported that 4%
of pulmonary tumors were associated with congenital cys-
tic malformations [39]. Nasr et al. reveal a 2% incidence
o f P P B i n p r e e x i s t i n g s u s p e c t e d C PA M [ 6 7 ] .
Papagiannopoulos et al. report seven patients who were
diagnosed with pulmonary cystic lesions and later devel-
oped PPB in the same lung region. All these patients,
when diagnosed of CPAM, had a surgical resection. In
six of the seven patients, the tumor developed in the area
of the cysts [70]. A systematic review by Casangre et al.
analyzed lung tumor cases, in children and adults, associ-
ated with CPAM. No limit of age for malignant progres-
sion or definitive order for malignant transformation of
CPAM could be found. The evolution of CPAM is unpre-
dictable as no specific time delay has been determined
between the diagnosis of CPAM and the emergence of a
tumor [15].
PPB is known to be part of the spectrum of DICER1
mutation-related tumors including sex cord stromal tumors,
medulloepithelioma, thyroid carcinoma, and cystic nephroma
[10, 41]. A genetic counseling should be proposed to all pa-
tients and families having PPB or disease from DICER1 spec-
trum. Abdominal and pelvic US should be performed to as-
sure the absence of associated cystic nephroma and/or ovarian
tumor after a PPB diagnosis.
Only two large international studies analyzed the treatment
and prognostic factors of PPB and reported similar outcome
results. The 5-year event free survival (EFS) was 82% for the
American study and 83.3% for the European study, while the
5-year overall survival (OS) was 91% in both studies [9, 62].
Type II and III PPB seemed to have poorer prognosis. Bisogno
et al. showed a 5-year EFS up to 42.9% and 5-year OS of
57.2%, with no difference between types II and III [41].
Messinger et al. found a 5-year EFS of 59% for type II versus
37% for type III and a 5-year OS of 71% for type II versus
53% for type III [62]. Prognostic factors were extent of tumor
resection at diagnosis, tumor invasiveness, and parietal pleural
involvement [9]. No difference was found between age, sex,
chemotherapy and radiotherapy, countries, and tumor’s size in
terms of prognosis [9]. DICER1 mutation status did not seem
to be associated to the outcome [62].
Eur J Pediatr (2017) 176:1559–1571
Conclusion
Useful improvements have been made over the years in the
understanding of CPAM genetics and pathophysiology. Its clin-
ical detection is nowadays preferably done prenatally, and CTA-
scan gives high-resolution images of postnatal CPAM. Surgery
remains the cornerstone treatment of symptomatic lesions, but
the postnatal management of asymptomatic CPAM remains
controversial. There are pros and cons of surgical resection, as
increasing rate of infections over time renders the surgery more
difficult after months or years of evolution, as well as risk of
malignancy, though exact incidence is still unknown. When
surgical treatment has been chosen, remaining questions con-
cern the best surgical approach, timing, and extent of resection.
Further large, multicentric, and prospective studies are strongly
needed to improve our knowledge of both the pathophysiology
and the accurate management of CPAM.
Acknowledgements The authors want to gratefully thank Emily
Barrios for her kind review of English editing.
Authors’ contributions Claire Leblanc: collect data, write the draft,
approve final manuscript.
Marguerite Baron: collect data, write the draft, approve final manuscript.
Emilie Desselas: collect data, write the draft, approve final manuscript.
Minh Hanh Phan: collect data, write the draft, approve final manuscript.
Alexis Rybak: collect data, write the draft, approve final manuscript.
Guillaume Thouvenin : critical analysis of the manuscript, approve
final manuscript.
Clara Lauby: collect data, write the draft, approve final manuscript.
Sabine Irtan: design the study, critical analysis of the manuscript, ap-
prove final manuscript.
Funding The authors have no funding to declare.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Informed consent No informed consent was needed for this article.
This article does not contain any studies with human participants or
animals performed by any of the authors.
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