Congenital Pulmonary Airway Malformation

Etiology

The etiology of CPAM remains multifactorial, involving complex disruptions in normal pulmonary development. CPAM arises from abnormalities in lung formation across the 5 stages of embryogenesis, including the embryonic, pseudoglandular, canalicular, saccular, and alveolar phases, each contributing to the structural and functional maturation of the respiratory system.

Multiple genes involved in early lung development have been implicated in CPAM pathogenesis. These include the thyroid transcription factor gene (Nkx2), sex-determining region Y-box 2 gene (Sox2), Hox gene (Hoxb-5), Ying Yang 1 gene (Yy1), fatty acid-binding protein-7 gene (FABP-7), acyl-CoA synthetase 5 (ACSL5), platelet-derived growth factor B gene (PDGF-B), sonic hedgehog (SHH), bone morphogenetic protein 4 (BMP4), sprouty 2 (SPRY2), Wnt2B, transforming growth factor beta (TGFB), and fibroblast growth factors 10, 9, and 7 (FGF10, FGF9, FGF7). These genes regulate key processes, eg, cellular proliferation, differentiation, and apoptosis, and abnormal expression patterns may contribute to the development of congenital lung malformations, including CPAM.[2][3][4] Additional research has also explored a potential association with KRAS mutations, suggesting a possible role for oncogenic signaling pathways in lesion formation.[5]

Epidemiology

Although rare, CPAM accounts for about 95% of congenital cystic lung disease. The incidence of CPAM is reported to range from 1 in 10,000 to 1 in 35,000 births.[3]

Pathophysiology

CPAM is differentiated into 5 major types by the Stocker classification. Each type originates from a different part of the bronchial tree, resulting in distinct histopathological features, clinical manifestations, malignant potential, and overall prognosis.[1][2][6][7] CPAM is mostly unilateral, involving 1 lobe, and has an intact blood supply from the pulmonary arteries, and maintains communication with the tracheopulmonary tree.[1][6] The Stocker classification divides CPAM into 5 types based on the following features:

• Type 0: This type is rare (1%-3%) and originates in the trachea or bronchi with histology showing bronchial-type airways with cartilage, smooth muscles, and glands separated by mesenchyme. Type 0 involves both lungs as a diffuse malformation, leading to no gas exchange and therefore is considered lethal or incompatible with life.

• Type 1: This type accounts for the majority of CPAM cases (50%-70%) and originates in the bronchi. The cysts in this type are usually single or multiloculated, located primarily within 1 lobe, and have a lining of pseudo-stratified columnar epithelium. Type 1 has a good prognosis following resection and rarely undergoes malignant transformation (bronchiolo-alveolar carcinoma). The clinical presentation depends on the size of the cysts and could lead to respiratory distress after birth.

• Type 2: This is the second most frequent type (10%-40%), originating in the bronchiolar regions and often associated with bronchial atresia and other anomalies (renal agenesis, cardiovascular defects, diaphragmatic hernia, skeletal defects, esophageal atresia). Usually, type 2 presents as multiple small cysts with no mass effect. The prognosis is variable and has no malignant potential.

• Type 3: This type is less common (5%-10%) and originates in the alveolar regions. Type 3 typically involves an entire lobe, causing compression of the other lobes. These lesions are usually solid versus cystic. The prognosis is poor, as type 3 CPAM can cause fetal hydrops with lung hypoplasia and can present as severe respiratory distress at birth. Furthermore, this type has no malignant potential.

• Type 4: This type is also less common (10%-15%) and originates in the acinar structures of the lung. Type 4 consists of single or multifocal peripheral thin-walled cysts filled with air and can present as a pneumothorax. Type 4 CPAM has a high malignant potential, similar to that of type 1 pleuropulmonary blastomas. Prognosis can be good with timely surgical intervention.

History and Physical

CPAM demonstrates a broad spectrum of clinical presentations (see Table 1). At one extreme, CPAM may present with severe disease incompatible with life or manifest as significant respiratory distress immediately after birth. At the opposite end of the spectrum, affected infants may remain completely asymptomatic throughout infancy and into childhood, with no overt clinical manifestations.

Advances in fetal imaging, particularly the widespread use of prenatal ultrasonography for the evaluation of fetal lung abnormalities, have increased the rate of antenatal diagnosis. This shift toward earlier detection has contributed to a relative decrease in the proportion of symptomatic CPAM cases at birth. Despite the absence of early symptoms, asymptomatic neonates remain at risk for later complications during childhood, including recurrent respiratory infections and rare malignant transformation. Symptomatic neonates typically present with respiratory distress, with severity closely related to lesion size and the degree of compression on adjacent airways and mediastinal structures. Each CPAM subtype demonstrates distinct clinical and radiologic characteristics that further define presentation patterns and prognostic implications.[8][9]

Table 1. Clinical Presentations of Congenital Pulmonary Airway Malformation

Evaluation

CPAM is the most common lung malformation diagnosed prenatally. A second-trimester fetal ultrasound is the primary imaging modality for detecting CPAM, as they appear more echogenic than the rest of the lung tissue, and can be classified as either microcystic or macrocystic based on the size.[1] For further characterization of the lesion, fetal magnetic resonance imaging (MRI) is recommended due to its high sensitivity and specificity for delineating the type and extent of lung lesions, especially in more complex cases.[3] 

A significant prognostic indicator is the CPAM Volume Ratio (CVR), which is calculated by dividing the CPAM lesion volume by the head circumference at that gestational age. A CVR of more than 1.6 is strongly associated with fetal hydrops and inferior clinical outcomes, with few studies suggesting a CVR of greater than 2 as a more critical threshold.[10] CVR value helps guide early referral to a high-risk fetal center. A fetal echocardiogram should be performed to evaluate cardiac function in severe cases.[2]

If an infant has a diagnosis of CPAM from a prenatal ultrasound and is symptomatic after birth, an initial chest radiograph is usually performed as a part of management.[11] For diagnostic imaging, a computed tomography (CT) scan is considered the gold standard. Postnatal MRI can be performed, but its accuracy is limited, and evidence of its superiority over the CT scan is lacking.[3][10] In asymptomatic infants, CT of the lungs is recommended by 3 months of age.[3] In infants with the absence of a prenatal diagnosis of CPAM due to no prenatal imaging, infection, eg, pneumonia, requiring a chest x-ray often leads to the diagnosis of CPAM, while in many cases, CPAM is detected as an incidental finding in a postnatal chest x-ray showing hyperlucency with a possible radio-opaque component.[2]

Treatment / Management

Management of congenital pulmonary airway malformation can be performed in the prenatal and postnatal period, depending on the severity and presentation (see Table 2).[6] In the prenatal period, if the risk of nonimmune fetal hydrops is identified, interventions, eg, maternal corticosteroids (betamethasone) are indicated to potentially reduce CPAM size and improve hydrops.[10] For cases with worsening hydrops, procedures like cyst drainage, thoracoamniotic shunt, or open resection can be considered to improve prenatal outcomes.[6] In selected cases with large lung masses and mediastinal shift, ex utero intrapartum (EXIT) procedures can be performed at specialized centers.[2] The presence of a high CVR ratio, fetal hydrops, and mediastinal shift can guide delivery at a higher-level center with adequate facilities (eg, pediatric surgery) and extracorporeal membrane oxygenation (ECMO), to manage affected newborns.[6][10] (B3)

In infants presenting with symptomatic CPAM after birth, immediate respiratory support within the neonatal intensive care unit remains essential to stabilize respiratory function and address hypoxemia or respiratory distress. Surgical resection represents the definitive management strategy for symptomatic cases.[6] Lobectomy constitutes the most frequently performed operative approach, although lung-sparing procedures such as segmentectomy may be appropriate in selected cases to preserve functional pulmonary tissue while ensuring complete lesion removal.[1][10](B3)

In asymptomatic patients, no universally preferred strategy exists for determining the optimal timing of surgical intervention. Early elective resection, commonly performed between 6 and 12 months of age, offers potential benefits including enhanced compensatory lung growth, reduction in infection risk, mitigation of potential malignant transformation, and decreased cumulative exposure to diagnostic radiation. Alternatively, a conservative management strategy emphasizes close clinical and radiologic surveillance, with delayed surgical intervention reserved for patients who develop symptoms or complications. This approach considers the possibility of spontaneous lesion regression, the generally low malignant potential in many CPAM cases, and the feasibility of timely intervention if clinical deterioration occurs. Management decisions require individualized assessment by the multidisciplinary care team in collaboration with the patient’s family, weighing risks and benefits of both operative and nonoperative strategies.[6][10][12][13] Following surgical resection or during conservative management of stable asymptomatic CPAM, longitudinal follow-up with periodic computed tomography imaging supports ongoing surveillance for recurrence, residual disease, or late-onset complications, with imaging intervals tailored to clinical status and risk profile.[3](B2)

Table 2. Congenital Pulmonary Airway Malformation Prenatal Diagnosis and Management

Differential Diagnosis

The primary differential diagnoses for CPAM include other congenital lung malformations (CLMs), particularly bronchopulmonary sequestration, bronchogenic cyst, and congenital lobar emphysema.[2] Bronchopulmonary sequestration can also be detected prenatally by ultrasonography and typically appears as a well-defined, solid, homogeneous mass. These lesions remain nonfunctional and, unlike CPAM, lack communication with the tracheobronchial tree. Their vascular supply originates from the systemic circulation through an anomalous systemic artery rather than from the pulmonary circulation.

Bronchogenic cyst, commonly referred to as a foregut duplication cyst, presents as a fluid-filled cystic lesion without communication with the tracheobronchial tree. Congenital lobar emphysema, also termed congenital lobar overinflation, causes hyperinflation of a pulmonary lobe and commonly appears hyperlucent on chest radiography with increased echogenicity on prenatal ultrasonography.[1][6] Additional prenatal differential diagnoses include congenital diaphragmatic hernia and other fetal thoracic masses, all of which require careful imaging evaluation to establish an accurate diagnosis and guide appropriate perinatal management.[14]

Prognosis

The overall prognosis of CPAM varies considerably and largely depends on the specific CPAM subtype. Several reported cases have demonstrated prenatal regression of the lesion, particularly with close fetal monitoring and appropriate perinatal management. The presence of fetal hydrops significantly worsens outcomes and correlates with decreased survival rates. Surgical resection during the neonatal period has been shown to improve survival and often provides definitive treatment. Studies have also suggested that, in carefully selected patients, conservative management may achieve outcomes comparable to surgical intervention.[13]

Among the CPAM subtypes classified by the Stocker system, type 1 CPAM carries the most favorable prognosis. The prognosis of type 2 CPAM depends largely on the severity and extent of associated congenital anomalies. Type 3 CPAM commonly involves hypoplasia of an entire lobe, which can contribute to serious complications, eg, pulmonary hypertension due to compromised lung development and mass effect on adjacent structures. Type 4 CPAM generally demonstrates an excellent prognosis following surgical resection; however, this subtype maintains a strong association with pleuropulmonary blastoma, necessitating careful long-term surveillance and clinical follow-up.[1][2][6]

Complications

Infection, particularly pneumonia, and development of pneumothorax represent common complications of CPAM and most frequently occur during the first few years of life, especially when conservative management delays surgical resection. Patients managed nonoperatively require close clinical surveillance because recurrent respiratory infections and progressive pulmonary complications may develop over time. Following surgical resection, potential postoperative complications include residual lesions, infection, bleeding, spontaneous pneumothorax, persistent air leak, and other procedure-related pulmonary complications.[15]

Pleuropulmonary blastoma (PPB) remains the most common malignant complication associated with CPAM. Risk factors for PPB include CPAM type 4, multifocal or bilateral cystic lesions, and a family history of associated tumors.[11][15] CPAM type 1 rarely undergoes malignant transformation into bronchioloalveolar carcinoma. Pulmonary hypoplasia with subsequent pulmonary hypertension may occur in CPAM type 3 because the lesion can involve an entire lobe or even the entire lung.[6] One study suggested an increased risk for reduced lung function and diminished exercise tolerance in children with CPAM requiring surgical intervention.[16] Another study demonstrated no significant difference in long-term respiratory function between infants undergoing surgery before or after 2 years of age.[17]