Congenital pulmonary airway malformation

INTRODUCTION — Congenital pulmonary airway malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a rare developmental anomaly of the lower respiratory tract [1,2]. Affected patients may present with respiratory distress in the newborn period or may remain asymptomatic until later in life. Many cases are now detected by routine prenatal ultrasound examination. Surgical resection is the definitive treatment.

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 — Congenital pulmonary airway malformation (CPAM) is a developmental malformation of the lower respiratory tract. Although rare, it is the most common congenital lung lesion. The widespread use of antenatal ultrasound examination has resulted in an increase in the prenatal diagnosis of CPAM [3,4]. Data from large population registries suggest an incidence of congenital lung cysts in the range of 1 per 8300 to 35,000 live births [5,6]. Large-cyst subtypes account for approximately 70 percent of CPAMs, or 2 to 8 per 100,000 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 — Congenital pulmonary airway malformations (CPAMs) result from abnormalities of branching morphogenesis of the lung. The different types of CPAMs are thought to originate at different levels of the tracheobronchial tree and at different stages of lung development, possibly influenced by in utero airway obstruction and/or atresia [5,13,14]. (See 'Pathology' below.)

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

●Histopathology – Congenital pulmonary airway malformations (CPAMs) are hamartomatous lesions that are comprised of cystic and adenomatous elements arising from tracheal, bronchial, bronchiolar, or alveolar tissue. Large lesions can compromise alveolar growth and development by compressing adjacent normal tissue.

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].

●Types – CPAMs were previously known as congenital cystic adenomatoid malformations (CCAMs) which were divided into three major types based upon the size of the cysts and their cellular characteristics (predominantly bronchial, bronchiolar, or bronchiolar/alveolar duct cells) [22-24]. Under this classification scheme, more than 65 percent of CPAMs were type 1, while type 2 comprised 20 to 25 percent and type 3 comprised 8 percent [22,23].

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].

Each type of CPAM has distinct pathologic characteristics [24-27].

•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).

Type 1 lesions are comprised of distinct thin-walled cysts 2 to 10 cm in diameter (picture 1). The cysts are usually single but may be multiloculated. They are lined with ciliated pseudostratified columnar epithelium (picture 2), and the walls contain smooth muscle and elastic tissue. Mucus-producing cells are present in approximately one-third of cases, and a thin fibromuscular layer may be present under the epithelium. Small islands of abnormal cartilage are found in 5 to 10 percent of lesions. The adjacent alveoli are relatively normal, and in 95 percent of cases, only one lobe of the lung is involved [5].

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 2 – Type 2 lesions comprise 15 to 20 percent of CPAMs. They consist of multiple cysts 0.5 to 2 cm in diameter and solid areas that blend into adjacent normal tissue (picture 3). The cysts resemble dilated terminal bronchioles and are lined with ciliated cuboidal or columnar epithelium (picture 4). Type 2 lesions may also have a thin fibromuscular layer with an increase in elastic tissue. Mucus-secreting cells and cartilage are absent. There is usually little mass effect on the adjacent lung. Extralobar pulmonary sequestrations may have a similar appearance, but unlike type 2 CPAM, these have a systemic blood supply. Hybrid forms, with features of both type 2 CPAM and extralobar pulmonary sequestrations, have been described [2]. (See "Bronchopulmonary sequestration".)

Other congenital anomalies are observed in patients with type 2 CPAM in up to 60 percent of cases [5,28]. These malformations include esophageal atresia with tracheoesophageal fistula [29]; bilateral renal agenesis or dysgenesis [30]; intestinal atresia; other pulmonary malformations; and diaphragmatic, cardiac, central nervous system, and bony anomalies. This association with other congenital malformations suggests that insults resulting in type 2 CPAMs occur during the third week of gestation. In many cases, the associated anomalies are the presenting feature and the CPAM is detected as a secondary finding. Type 2 CPAMs are not at risk for development of malignancy.

•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.

•Type 4 – Type 4 lesions comprise 5 to 10 percent of CPAMs [5,27,31]. The cysts have a maximum diameter of 7 cm and consist of nonciliated, flattened, alveolar lining cells, with no mucus cells or skeletal muscle.

Type 4 CPAMs may present at birth or in childhood, often with tension pneumothorax or infection, but they may also be identified as incidental findings in asymptomatic patients. Importantly, this type of CPAM is strongly associated with malignancy, especially with pleuropulmonary blastoma (PPB). (See 'Association with malignancy' below.)

CLINICAL FEATURES — The presentation of congenital pulmonary airway malformation (CPAM) is variable. Many are identified by routine prenatal ultrasound examination. Early reviews indicated that up to two-thirds of infants with prenatally diagnosed CPAM are symptomatic at birth [12]. More recent references suggest that only approximately 25 percent of affected newborns are symptomatic [2,32]. This discrepancy may reflect improvements in prenatal ultrasound technology, such that smaller lesions are now identified, and these tend to be asymptomatic.

Prenatal presentation — The appearance of CPAMs on prenatal ultrasound ranges from incidental findings of cystic-appearing lesions to massive pulmonary involvement [3,7,33-35]. Lesions regress and appear to resolve during the course of gestation in approximately 50 percent of cases as determined by fetal ultrasonography [36], but most of these will still be detectable on postnatal imaging [37]. Among lesions present at birth, complete spontaneous resolution in the postnatal period has been reported in a small number of cases [38,39]. A retrospective review suggested that peak CPAM size occurred at approximately 25 weeks gestational age and that regression in size led to favorable outcomes unless severe hydrops was present [40]. Prenatal diagnosis, course, and management of CPAM are discussed in a separate topic review. (See "Congenital pulmonary airway malformation: Prenatal diagnosis and management".)

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.

Development of hydrops — Fetal hydrops develops in 5 to 40 percent of cases due to hemodynamic alterations from vena cava obstruction and cardiac displacement and compression [2,36,43]. The risk of hydrops is highest in fetuses with large lesions, lesions that persist into the third trimester, and microcystic lesions. In particular, the CVR, which is a measure of CPAM volume referenced to the fetal head, predicts an increased risk of hydrops. (See "Congenital pulmonary airway malformation: Prenatal diagnosis and management", section on 'Hydrops with abnormal fetal echocardiography'.)

Neonatal period

Asymptomatic — Approximately three-quarters of patients with a prenatal diagnosis of CPAM are asymptomatic at birth [32,38,45,46].

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.)

Symptomatic — The remaining 25 percent of patients with a prenatal diagnosis of CPAM are symptomatic at birth [38,45,46]. As an example, in a series of 89 infants with prenatally diagnosed CPAM, 22 had abnormal breathing, including 12 with severe respiratory distress [45]. The likelihood of respiratory distress, and its severity, increases with the size of the lesion (eg, CVR >0.84) [45]. Other sonographic predictors of respiratory distress at birth include mediastinal shift, polyhydramnios, and ascites.

Some clinical features are associated with CPAM type:

●Type 0 CPAMs are associated with severely impaired gas exchange, and affected infants die at birth [5].

●Type 1 CPAMs comprise the majority of CPAMs presenting in newborns. When symptomatic, typical signs include tachypnea, increased respiratory effort with 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.)

Childhood presentation — Approximately one-third of CPAMs are diagnosed after the neonatal period. These lesions typically are CPAM types 1, 2, or 4 and tend to be smaller than CPAMs that present with respiratory symptoms at birth.

●A common presentation in older children is recurrent pneumonia [48,49]. Other presenting complaints include cough, dyspnea, and/or cyanosis [49]. Findings on physical examination include decreased breath sounds over the lesion, hyperresonance, and chest wall asymmetry with a bulge on the affected side.

●CPAMs can also present with spontaneous pneumothorax. Because pneumothorax is most often associated with type 4 CPAMs, and type 4 CPAM is associated with malignancy, there should be a strong suspicion for malignancy in any child presenting with pneumothorax and CPAM [5]. (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.)

Imaging — The diagnosis of congenital pulmonary airway malformation (CPAM) is made by radiographic imaging. A minority of lesions detected by fetal ultrasonography will resolve during gestation, but most lesions that are present at birth will persist [2]. (See 'Prenatal presentation' above and "Congenital pulmonary airway malformation: Prenatal diagnosis and management", section on 'Prenatal course'.)

Suggested protocol — We suggest the following approach to imaging:

●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.

●Symptomatic newborns should be further evaluated with advanced thoracic imaging (contrast-enhanced computed tomography [CT] or MRI) to further define the lesion and distinguish it from other developmental anomalies of the lung, as part of preoperative planning. The use of intravascular contrast may be helpful to delineate the vascular supply of the lesion. (See 'Differential diagnosis' below and "Radiographic appearance of developmental anomalies of the lung".)

●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, a family history of PPB-associated conditions, or pneumothorax) (algorithm 1). For infants without these characteristics, we perform the advanced thoracic imaging by six months of age.

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].

Radiographic appearance — CPAM types 1, 2, and 4 are characterized by air-filled cysts. Radiography does not reliably distinguish among them. However, types 1 and 4 tend to appear as a single lesion, with one or a few large cysts that may be entirely air-filled or have air-fluid levels (image 3 and image 4) [5]. In type 2, the numerous small cysts appear more homogenous, with a "bubbly" appearance (image 5 and image 6). In contrast, type 3 CPAM often appears as a large, solid, homogeneous mass. There is usually a marked shift of the mediastinal contents to the contralateral side with hypoplasia of the ipsilateral lung due to mass effect. The presence of pneumothorax, or bilateral or multifocal cysts, strongly suggests CPAM type 4 [5]. These distinctions are clinically important because type 4 is associated with malignancy (PPB). (See 'Pleuropulmonary blastoma' below.)

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.)

Differential diagnosis — The differential diagnosis of CPAM includes bronchopulmonary sequestration (BPS). On prenatal ultrasound, BPS appears as a well-defined, homogeneous, echodense mass [42]. In contrast to CPAM, BPS usually has no connection to the tracheobronchial tree and is supplied by an anomalous systemic artery rather than the pulmonary circulation. The systemic arterial supply can be demonstrated by color flow Doppler. However, hybrid lesions with histologic characteristics of CPAM and a systemic arterial supply have been reported [58]. In a series of 50 patients with BPS, 50 percent of the cases were associated with CPAMs [59]. (See "Bronchopulmonary sequestration".)

In addition to BPS, the differential diagnosis of CPAM includes congenital diaphragmatic hernia, bronchogenic cyst, congenital lobar emphysema, and localized pulmonary interstitial emphysema that may arise in patients receiving mechanical ventilation, and pneumatoceles (which can be sequelae of bacterial pneumonia, especially due to staphylococcal infection). These disorders usually can be distinguished from CPAM based on the radiographic appearance and clinical history. (See "Congenital lobar emphysema" and "Radiographic appearance of developmental anomalies of the lung".)

MANAGEMENT

Prenatal management — Management of fetuses with prenatally diagnosed congenital pulmonary airway malformation (CPAM) includes assessment for associated abnormalities and serial ultrasound examinations to monitor changes in the CPAM and development of hydrops. Fetuses with large CPAMs and/or hydrops have a poor prognosis [2]. In this case, treatment options include antenatal corticosteroids, drainage procedures, fetal surgery, or early delivery. These considerations are discussed in detail in a separate topic review. (See "Congenital pulmonary airway malformation: Prenatal diagnosis and management".)

Postnatal management — The postnatal management of CPAM depends on whether the patient has respiratory distress or is asymptomatic [60].

Symptomatic patients — In symptomatic patients, CPAM is treated by surgical resection [2,12,61-65]. Resection is frequently required in newborns with significant respiratory distress, but it is often done electively in older children who present with less acute symptoms. In older children, resection is usually performed to prevent recurrent infection and to eliminate concerns regarding malignancy. (See 'Pleuropulmonary blastoma' below.)

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, increased morbidity associated with partial resections in some reports, and possibility of leaving residual disease [2,66,67]. (See 'Outcome' below.)

Asymptomatic patients — Close observation during the neonatal period is important because some infants are asymptomatic immediately after birth but then become symptomatic as the cystic lung lesions expand due to replacement of the fluid with air [32]. For infants and children who remain completely asymptomatic, the decision between surgical management and observation and the optimal timing for surgical excision are controversial and there is a significant lack of consistency reported among pediatric surgeons [68-70]. Efforts to identify a "core outcome set," using Delphi methodology, to inform decisions regarding surgical intervention for asymptomatic children with CPAM did not demonstrate a high degree of concordance among European practices [71].

The main rationale for surgery is that it eliminates the risks of future infection and the potential for malignant transformation [2,72-74]. 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) [75]. 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 [76,77]. (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) [78,79] and point out that only one case has been reported of pleuropulmonary blastoma (PPB) arising in an asymptomatic, antenatally diagnosed CPAM [68]. 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 [38,80]. 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):

●Large lesion (occupying >20 percent of the hemithorax)

●Bilateral or multifocal cysts

●Pneumothorax

●Family history of DICER1 syndrome or PPB-associated conditions (including lung cysts, spontaneous pneumothorax, and several specific childhood cancers or dysplasias (table 1)) (see 'Pleuropulmonary blastoma' below)

●Pathogenic DICER1 variants

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 surgical resection is chosen for an asymptomatic, low-risk patient, it is usually performed after the neonatal period and before 12 months of age, but the optimal timing has not been established and practice varies [81,82]. We and others prefer to do the surgery when the infant is between 6 and 12 months of age [32]. Other groups have suggested earlier timeframes for elective surgery, between three and six months of age [80,83-85] or even between one and two months of age [86]. Minimally invasive surgery for asymptomatic patients with CPAM during infancy is now commonly performed in many centers, and most reports have high success rates without significant postoperative complications [87-91].

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 — The most common complication of congenital pulmonary airway malformation (CPAM) is recurrent pulmonary infection. In some cases, this may be the presenting sign. A rare complication is spontaneous hemopneumothorax [92]. The development of malignancy in some patients with previously unrecognized CPAM, while extremely rare, is another reason for the recommendation to resect the lesions, even in asymptomatic patients.

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 [45,46,78,93,94]. Another case series report that symptoms developed in only 3 percent at median follow-up of five years [95]. 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 [96].

Association with malignancy — Reported associations with CPAM include pleuropulmonary blastoma (PPB) and bronchoalveolar carcinoma (BAC) [97]. Rhabdomyosarcomas originating in a CPAM have been reported [98,99], but these are now thought to have been cases of PPB [100].

Pleuropulmonary blastoma — PPB is a rare lung tumor of childhood but is more common in children with CPAM and especially those in whom the lung lesion is first detected postnatally [101,102]. In a large case series, PPB was identified in 15 of 177 (9 percent) of children with lung lesions that were not identified prenatally, compared with none of the 344 children with prenatally identified lung lesions [102]. Fewer than 500 cases have been reported, most presenting in children younger than six years of age [68,103]. Most reported cases of PPB have presented after birth, and there are only a few case reports of PPB arising in children with cystic lung lesions identified antenatally. In one study, factors favoring a diagnosis of CPAM rather than PPB included prenatal detection (odds ratio [OR] 89.4), presence of a systemic feeding vessel (OR 61.7), asymptomatic (OR 8.0), and hyperinflated lung (OR 6.6) [104]. Thus, a neonate with an asymptomatic CPAM identified prenatally has a low risk of PPB, unless there are additional risk factors, as described below.

Risk factors suggesting a substantial risk of malignancy are [5]:

●DICER1 syndrome or a family history of PPB or related diseases – PPB can be associated with DICER1 syndrome (MIM #601200), a hereditary cancer predisposition syndrome related to mutations in the DICER1 gene [105]. The inheritance pattern is autosomal dominant with decreased penetrance, and screening is summarized in a review article [56]. Affected family are predisposed to PPB, ovarian or renal tumors, or a variety of other malignancies, most of which arise during childhood or early adulthood (table 1) [103,106,107]. Other associated features may include cystic lesions (including renal cystic disease), small bowel polyps, thyroid disease (multinodular goiter and cancer [108]), and macrocephaly [109]. (See "Thyroid nodules and cancer in children", section on 'Genetic predisposition' and "Prenatal sonographic diagnosis of cystic kidney disease", section on 'Cystic tumors' and "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis", section on 'Inherited syndromes'.)

●Type 4 CPAM – Type 4 CPAM should be considered malignant lesions because approximately 30 percent of PPB present in a purely cystic form that is indistinguishable from nonmalignant cysts [5,110-112]. Indeed, there is increasing evidence that all type 4 CPAMs are actually cystic PPB [5]. Because it is difficult to distinguish between CPAM types 1 and 4, some cases classified as CPAM type 1 are actually cystic PPB. As noted above, the presence of a systemic feeding vessel identified on CT supports a diagnosis of CPAM rather than PPB (OR 61.7) [104]. However, this information has limited clinical utility because systemic feeding vessels are identified on only approximately 25 percent of infants with CPAM.

●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.

●Pneumothorax – Pneumothorax is a prominent feature of type 4 CPAM, occurring in approximately 40 percent of cases later diagnosed as PPB [5].

Bronchoalveolar carcinoma — There is a weak association of CPAM type 1 with bronchoalveolar carcinoma (BAC), also known as adenocarcinoma in situ [97,113,114]. In patients with CPAM, BAC is usually discovered incidentally in cysts resected during adolescence or adulthood (range 6 months to 75 years of age) [5]. It has been estimated that BAC eventually develops in approximately 1 percent of unresected CPAM type 1 [106], but the true rate of this malignancy and its clinical significance remains unclear.

OUTCOME — Among congenital pulmonary airway malformation (CPAM) diagnosed prenatally, the overall survival rate is more than 95 percent and the presence of fetal hydrops is an important predictor of mortality. For most symptomatic or asymptomatic infants with CPAM, surgical excision in the neonatal period is curative and the prognosis for survival is excellent [2,96,115,116]. Although the remaining lung parenchyma undergoes compensatory growth and development [117], the pulmonary function outcomes vary across different reports, probably reflecting differences in patient selection [76,118-122]. As examples, in a series of infants with congenital lung malformations who were mostly asymptomatic and underwent elective surgical resection before one year of age, more than 80 percent had normal pulmonary function testing during childhood [77]. In a different series in which surgery was performed for symptomatic lung lesions, patients who were managed surgically had mildly impaired exercise tolerance by eight years, and one-half had pulmonary function testing abnormalities, most of which were mild [121]. In this same cohort, patients who were asymptomatic and managed conservatively generally had normal pulmonary function tests but still had mildly reduced exercise tolerance.

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 [7,9,10,123-125]. 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 [126,127].

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.)

SUMMARY AND RECOMMENDATIONS

●Definition and types – Congenital pulmonary airway malformation (CPAM), previously known as congenital cystic adenomatoid malformation (CCAM), is a developmental anomaly of the respiratory tract. CPAMs are categorized as types 0 through 4, which are defined pathologically and have different clinical presentations and prognoses. Type 1 CPAM is most common, and type 4 CPAM has high malignant potential. (See 'Pathology' 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.)

●Pleuropulmonary blastoma (PPB) – PPB is a rare lung tumor of childhood but is more common in children with CPAM (especially bilateral, multifocal, or presenting with pneumothorax), pathogenic DICER1 variants, and/or a family history of PPB or related conditions (DICER1 syndrome) (table 1). (See 'Pleuropulmonary blastoma' above.)

●Evaluation – For all infants with a prenatal diagnosis of CPAM, the postnatal evaluation should include (algorithm 1) (see 'Evaluation' above):

•Chest radiograph – Perform in the neonatal period, even if the infant is asymptomatic and even if the lesion appeared to resolve on serial prenatal ultrasounds.

•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

•Symptomatic infants – In patients with CPAM that is causing any respiratory symptoms (respiratory distress or tachypnea), we recommend surgical resection rather than observation (Grade 1A) (algorithm 1). All resected cysts should be carefully examined for evidence of malignancy. (See 'Symptomatic patients' above.)

•Asymptomatic infants – Asymptomatic infants with a prenatal diagnosis of CPAM should be evaluated with a chest radiograph in the neonatal period. Subsequent management depends on whether there are characteristics that suggest a high risk of complications (algorithm 1):

-For infants and children with high-risk characteristics (large lesions on chest radiograph, bilateral or multifocal cysts, pneumothorax, pathogenic DICER1 variants, or a family history of PPB-associated conditions (table 1)), we suggest early surgical resection rather than observation (Grade 2C). These infants should be evaluated with CT or MRI prior to surgery to confirm the diagnosis and further evaluate the lesion. (See 'High risk' above.)

-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.)