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Congenital Pulmonary Airway Malformation
Congenital Pulmonary Airway Malformation
Alison G Hoppin, MD
D E P U T Y E D I TO R :
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
INTRODUCTION
The clinical presentation and postnatal management of CPAM are discussed below.
Prenatal diagnosis, course, and management of CPAM are discussed in a separate topic
review. (See "Congenital pulmonary airway malformation: Prenatal diagnosis and
management".)
EPIDEMIOLOGY
live births.
CPAMs occur sporadically. Their formation is not related to maternal factors such as race,
age, or exposures. In some series, lesions that present in infancy have a slight male
preponderance [7-10], although others found no sex predilection [11,12]. There is no
known genetic predisposition, with the exception of type 4 malformations, which have been
associated with a familial pleuropulmonary blastoma (PPB) syndrome. (See
'Pleuropulmonary blastoma' below.)
PATHOGENESIS
The molecular mechanisms resulting in CPAM formation remain largely unknown but may
include an imbalance between cell proliferation and apoptosis during organogenesis [15-
18]. Disorders of the HOXB5 gene have been implicated in this process [19]. One study
found that CPAMs resected from fetuses and newborns had twice as much cell proliferation
and five times the number of apoptotic bodies as did normal fetal and neonatal lung tissue
[15]. Advances in the development of transgenic/knockout animal models and the
widespread use of next-generation genetic sequencing on surgical tissue specimens have
led to a much more robust, though incomplete, understanding of the molecular
mechanisms involved in the development of CPAM [20].
This process may be mediated in part by glial cell-derived neurotrophic factor (GDNF), a
growth factor that is widely expressed in organs with development characterized by
epithelial-mesenchymal interaction. In one report, GDNF was detected in epithelial and
endothelial cells from normal fetal lung and in epithelial cells from CPAMs, while none was
found in normal lung tissue obtained from older infants and children (four months to three
years of age) [16]. Vascularity was also reduced in CPAMs compared with normal lung
tissue [17].
PATHOLOGY
CPAMs have connections with the tracheobronchial tree, although the connecting
bronchi usually are not normal. The arterial supply and venous drainage from the
lesion are almost always from the pulmonary circulation, though vascular connections
to the systemic circulation have been reported.
CPAMs are equally distributed between the right and left lungs and can arise in all
lobes. Lesions are usually limited to one lobe, but infrequently, they can involve
multiple lobes [7,9,10]. The CPAMs that present during adulthood tend to be in the
lower lobes [21].
In the present classification scheme, these congenital cystic lung lesions are now
called CPAM, and two additional types (0 and 4) were added. Type 0 arises from the
trachea, and type 4 lesions have alveolar/distal acinar origins [25-27].
• Type 0 – Type 0 is the rarest form, comprising only 1 to 3 percent of cases, and
originates from tracheal or bronchial tissue. The cysts are small, with a maximum
diameter of 0.5 cm, and are lined with ciliated pseudostratified epithelium [27].
Mucus cells and cartilage are present, but skeletal muscle is absent. This is a
diffuse malformation that involves the entire lung. Gas exchange is severely
impaired, and affected infants die at birth [5].
• Type 1 – Type 1 is the most common form of CPAM, comprising 60 to 70 percent
[5]. This type is thought to originate from the distal bronchi or proximal
bronchioles. Because there is well-differentiated tissue within the lesions, this type
probably originates relatively late during embryogenesis (7 to 10 weeks).
This type of CPAM has malignant potential, but the magnitude of the risk is not
well delineated. Care must be taken not to misclassify type 4 lesions as type 1,
because type 4 lesions have a high malignant potential. (See 'Association with
malignancy' below.)
The clinical presentation of type 1 CPAMs depends primarily on the size of the
cysts. Large cysts may be detected on prenatal ultrasound. If they compress
adjacent normal lung, they can cause respiratory distress in the neonate,
mediastinal shift to the contralateral side, and flattening of the ipsilateral
diaphragm. Smaller cysts may present months or years after birth as incidental
lesions or a focus of infection.
• Type 3 – Type 3 CPAMs comprise 5 to 10 percent of CPAMs. They are often very
large and can involve an entire lobe or several lobes. They have an acinar origin
and consist of adenomatoid proliferation of distal airways or airspaces. They can
be a mixture of cystic and solid tissue or be entirely solid. Because of their large
size and lack of differentiation, type 3 CPAMs are thought to originate early in
gestation (26 to 28 days). The numerous small cysts are less than 0.5 cm in
diameter and are lined with nonciliated cuboidal epithelium. They have a thin
fibromuscular layer and increased elastic tissue, similar to type 2 lesions. Mucus-
secreting cells and cartilage are absent.
Affected infants present in utero or at birth, usually with severe respiratory distress
or death in the neonatal period [5]. This type of CPAM has not been associated
with malignancy.
CLINICAL FEATURES
Prenatal imaging — CPAM is one of the most common lung lesions diagnosed prenatally,
although the birth prevalence is quite low. Prenatal diagnosis is typically made by
ultrasonography ( image 1A-B and image 2). CPAMs presenting prenatally are
classified by their ultrasound findings and gross anatomy [41,42]. Microcystic lesions
consist of cysts <5 mm in diameter and appear echogenic and solid, while macrocystic
lesions contain one or more cysts >5 mm in diameter. The CPAM volume ratio (CVR) is an
index of CPAM volume referenced to the fetal head ( image 1A-B) and is a useful
prognostic indicator [2,38,43]. (See "Congenital pulmonary airway malformation: Prenatal
diagnosis and management", section on 'Prenatal diagnosis'.)
Additional evaluation with prenatal magnetic resonance imaging (MRI) is useful for
distinguishing CPAM from other pulmonary anomalies, including bronchopulmonary
sequestration (BPS), congenital diaphragmatic hernia, and congenital lobar emphysema.
Approximately 25 percent of infants with CPAM detected prenatally also have other
structural anomalies; most of these cases are associated with type 2 CPAM [44]. In patients
with such anomalies, a fetal karyotype should be obtained. Isolated CPAMs typically are not
associated with chromosomal abnormalities.
Neonatal period
The natural history of CPAMs that are asymptomatic at birth is not well described. It is clear
that some of these infants will develop complications (primarily infection) during the first
few years of life, but the frequency varies markedly among different case series. The risk of
malignancy is extremely low, except in type 4 CPAMs, although type 1 lesions may also have
some malignant potential. The uncertainty about the risk of infection and malignancy is the
basis for controversy about how to manage these patients, as discussed below. (See
'Complications' below and 'Asymptomatic patients' below.)
● Type 0 CPAMs are associated with severely impaired gas exchange, and affected
infants die at birth [5].
grunting and retractions, and cyanosis. Depending upon the extent of air trapping,
large cysts may expand, which leads to respiratory distress.
● Type 2 CPAMs are often diagnosed soon after birth because of their association with
other congenital anomalies, which are present in up to 60 percent of affected
patients. Presenting respiratory signs and symptoms are similar to those noted with
type 1 CPAMs.
● Type 3 CPAM is the most severe form (other than type 0, which is uniformly lethal at
birth). Type 3 lesions are large and can involve the entire lung, and fetal hydrops and
pulmonary hypoplasia are typical. Infants may be stillborn or present immediately
after birth with severe, progressive respiratory distress, cyanosis, and respiratory
failure. Historically, there has been a strong male predominance [22].
● Type 4 CPAMs can present in the neonatal period and may be difficult to distinguish
from type 1 lesions. Presentation with spontaneous pneumothorax has been reported
in several cases [5,47]. Because many type 4 lesions are probably due to
pleuropulmonary blastoma (PPB), there should be a strong suspicion for malignancy
in any infant presenting with pneumothorax and CPAM. (See 'Association with
malignancy' below.)
In a report of 12 patients who were diagnosed with CPAM between 6 months and 23 years
of age (mean age 6.7 years), nine presented with recurrent pulmonary infections, one
presented with pneumothorax, and two were discovered as incidental findings [50]. Among
the 11 patients who underwent surgical resection of CPAM, type 1 CPAMs were identified in
seven patients and type 2 CPAMs were identified in four patients.
EVALUATION
History — Regardless of the patient's age and presenting signs and symptoms, the family
history should be explored in detail for cancers and cystic lesions that might suggest
familial pleuropulmonary blastoma (PPB) syndrome. These include renal cystic disease,
small bowel polyps, childhood cancers or dysplasias, and a history of spontaneous
pneumothorax ( table 1). (See 'Pleuropulmonary blastoma' below.)
● All infants with a prenatal diagnosis of CPAM should have a chest radiograph in the
neonatal period, even if they are asymptomatic and even if the lesion appeared to
resolve on serial prenatal ultrasounds.
● Asymptomatic infants also should have advanced thoracic imaging to confirm the
diagnosis and further evaluate the lesion, but the timing depends on risk
characteristics (symptoms and results of chest radiography). We perform the
advanced imaging immediately for infants with characteristics suggesting increased
risk for complications (large lesions on chest radiograph, bilateral or multifocal cysts,
The CT or MRI should be performed even in infants with normal chest radiographs
because plain radiographs often fail to detect CPAM in asymptomatic neonates. As an
example, in one case series of asymptomatic infants with prenatally diagnosed CPAM,
the chest radiograph appeared normal at birth in 12 of 29 patients (41 percent) [38].
However, when CT scan was performed at 45 days of age, cystic lung abnormalities
were seen on CT scan in 11 of the 12 infants who had normal chest radiographs at
birth. Chest ultrasound has also been used to monitor these lesions, but CT and MRI
are better validated [51].
● If CPAM is not diagnosed prenatally and first presents in the newborn or child, the
diagnosis usually can be made on a plain radiograph, though CT or MRI of the chest is
still recommended [7,52-54].
CT scans of the chest correlate with pathologic findings. In one report, preoperative CT
findings were compared with pathologic findings [54]. CT accurately identified both small
(<2 cm in diameter) and large cysts and whether they were filled with air and/or fluid. Areas
of consolidation corresponded to glandular or bronchiolar structures; this was observed in
43 percent of the scans. The area around cystic lesions where attenuation was lower than
normal lung represented microcysts blending into normal lung parenchyma; this feature
was seen in 29 percent of the CT scans.
CT has poor diagnostic accuracy for distinguishing PPB from benign cystic lung lesions
(sensitivity 58 percent, specificity 83 percent [55]). As a result, surgical involvement for
diagnosis and management is important for any patient with risk factors for PPB, including
pathogenic DICER1 variants, or any imaging findings suspicious for PPB. (See
'Pleuropulmonary blastoma' below.)
Genetic testing — We suggest genetic testing for pathogenic variants in the DICER1
gene for all infants and children with CPAM to help identify those at increased risk for PPB
[56]. Genetic testing is especially important for those with multiseptated, multiple, or
bilateral cysts or other risk factors for PPB, described below. A list of laboratories that
perform DICER1 testing is available at the Genetic Testing Registry website. Approximately
70 percent of PPBs are associated with pathogenic germline DICER1 variants [57], and early
identification of at-risk individuals is important in their management. (See
'Pleuropulmonary blastoma' below.)
MANAGEMENT
The surgery is curative and has few complications. Lobectomy is generally preferred to
wedge resection because of the technical difficulty in identifying planes of dissection with
some lesions and the increased morbidity associated with partial resections [2,66]. (See
'Outcome' below.)
The main rationale for surgery is that it eliminates the risks of future infection and the
potential for malignant transformation [2,71-73]. However, the magnitude of these risks is
poorly established. The estimated frequency of infection developing in an infant who is
asymptomatic at birth and does not undergo surgery is probably approximately 5 to 10
percent, as discussed below (see 'Infection' below). In addition, there are fewer
postoperative complications in patients undergoing elective surgery compared with those
undergoing surgery after infectious symptoms develop (10 percent versus 32 percent in
one meta-analysis) [74]. The risk of malignancy is extremely low, except in type 4 CPAMs,
although type 1 lesions may also have some malignant potential (see 'Association with
malignancy' below). A secondary consideration is that early surgery may have advantages
for compensatory lung growth. However, the available small case series of infants with
congenital lung malformations have demonstrated little or no correlation between age at
lobectomy and pulmonary function, perhaps because pulmonary function outcomes are
good in most patients [75,76]. (See 'Outcome' below.)
The main rationale in favor of observation is that surgery may be entirely avoided for some
patients. The drawbacks of the observation strategy are the risk of infection developing
within the cysts, the low but present risk of malignant transformation, and radiation
exposure. Proponents of this approach cite the relatively low rate of infection (5 to 13
percent) [77,78] and point out that only one case has been reported of pleuropulmonary
blastoma (PPB) arising in an asymptomatic, antenatally diagnosed CPAM [67]. Nonetheless,
they acknowledge that surgery should be considered for infants with high-risk features (see
'High risk' below). In some reports, spontaneous regression has been reported in up to 20
percent of asymptomatic infants with congenital cystic lesions confirmed by CT scan in the
neonatal period [38,79]. However, such cases are not well documented and are probably
rare or represent cases of extralobar pulmonary sequestration rather than CPAM.
For asymptomatic infants and children, our management depends on the initial evaluation,
including whether the chest radiograph has features suggesting an increased risk for
developing complications, as discussed in the following sections.
High risk — We suggest surgical resection for asymptomatic infants and children
with any the following features ( algorithm 1):
For such patients, we perform advanced thoracic imaging (CT or MRI) immediately to
confirm the diagnosis and further evaluate the lesion. This is followed by early surgical
resection during the index hospitalization, if practical, or by six months of age at the latest.
Low risk — For asymptomatic infants and children with small lesions and none of the
high-risk features outlined above, either elective surgical resection or conservative
management with observation are reasonable options ( algorithm 1) [2]. We choose
among these options after a detailed discussion with the family about the relative
advantages and disadvantages of each approach. In particular, the family should
understand that children who do not undergo surgery have a risk of developing infection in
the cyst, and that outcomes of surgery are generally excellent. (See 'Infection' below and
'Outcome' below.)
If observation is chosen, we suggest close clinical follow-up during the first year of life to
monitor for the development of symptoms of respiratory distress or infection. In addition,
we suggest routine imaging at least annually. Both chest radiographs and advanced
thoracic imaging (CT or MRI) have been recommended for monitoring of these patients,
and there is no consensus on the optimal strategy for imaging.
COMPLICATIONS
Infection — For infants who are asymptomatic at birth, the risk of developing infection is
not well described. It is clear that some of these infants will develop infection during the
first few years of life if surgery is not performed. The most reliable estimates are that
infection probably develops in 5 to 10 percent of those managed conservatively, and that
most of these infections occur within the first three years of life [45,46,77,92,93]. Another
case series report that symptoms developed in only 3 percent at median follow-up of five
years [94]. These estimates reflect series in which all or most cases were identified on
prenatal ultrasound. Older case series in which more infants were diagnosed postnatally
report rates of infection as high as 35 percent [95].
● Cysts that are bilateral or multifocal – There is a substantial risk of malignancy for a
child presenting with bilateral or multifocal lung cysts because type 4 CPAMs often
have this appearance and carry a malignancy risk. Type 4 CPAMs also may present as
a large, air-filled cyst. Type 1 and 2 lesions can also be large and air-filled; type 1
lesions are rarely associated with malignancy, and type 2 lesions have no malignancy
risk.
OUTCOME
The good overall prognosis described above reflects the predominance of the type 1 lesion.
The prognosis for type 2 and 3 CPAMs is not as favorable, although recovery is possible
[7,9,10,122-124]. Outcomes in infants with type 2 lesions may be influenced by the severity
of the accompanying congenital anomalies. Infants with type 3 lesions frequently have
severe hypoplasia of the contralateral lung and are at risk for developing pulmonary
hypertension [125,126].
The outcome of type 4 CPAM is also quite good with surgical resection. However, because
this lesion probably represents cystic pleuropulmonary blastoma (PPB), oncologic
consultation and complete surgical resection is essential. (See 'Pleuropulmonary blastoma'
above.)
● Clinical presentation – Many infants with CPAM are identified by routine prenatal
ultrasound examination. Approximately one-quarter of these infants have symptoms
at birth, including mild or severe respiratory distress, and some have associated
congenital anomalies. Approximately one-third of CPAM are identified later in infancy
or childhood, presenting with recurrent pneumonia or spontaneous pneumothorax.
(See 'Clinical features' above.)
● Evaluation – For all infants with a prenatal diagnosis of CPAM, the postnatal
evaluation should include ( algorithm 1) (see 'Evaluation' above):
• Advanced imaging – The timing depends on symptoms and on the results of the
initial chest radiograph. Advanced imaging should be performed even in infants
with normal chest radiographs because plain radiographs often fail to detect CPAM
in asymptomatic neonates. (See 'Suggested protocol' above.)
• Genetic testing – Test for pathogenic DICER1 variants. (See 'Genetic testing'
above.)
● Management
- For infants and children with small lesions and none of the other high-risk
features outlined above, either elective surgical resection or conservative
management with observation are reasonable options. If surgical resection is
chosen for such patients, it is usually performed after the neonatal period but
before 12 months of age. If observation is chosen, infants should have close
follow up during the first year of life to monitor for the development of
symptoms of respiratory distress or infection, as well as imaging with CT or
MRI by six months of age and annually thereafter. (See 'Low risk' above.)
For infants who are asymptomatic at birth, the risk of developing infection is not
well delineated. It is clear that some of these infants will develop infection during
the first few years of life if surgery is not performed, but the estimates of the risk
for infection ranges from 3 to 30 percent. (See 'Infection' above.)
● Outcome – For the majority of infants with CPAM, surgical excision in the neonatal
period is curative and the prognosis excellent. (See 'Outcome' above.)
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