Pediatrics

Congenital Cystic Adenomatoid Malformation

Overview: What every practitioner needs to know.Are you sure your patient has congenital cystic adenomatoid malformation?

Congenital cystic adenomatoid malformation (CCAM) is now known as congenital pulmonary airway malformation (CPAM) because not all types of CPAM are cystic and adenomatoid. CPAM is the most common congenital cystic lung lesion; they are rare but clinically significant (Figure 1).

Figure 1.

Congenital pulmonary airway malformation in the right lung.

Routine prenatal ultrasonography and advances in imaging technology have led to an increase in prenatal diagnosis of these congenital lung lesions.

It is very important for obstetricians, radiologists, neonatologists, surgeons, pediatricians, and pulmonologists to be aware of these lung lesions, their natural history, management options, prognosis, and possible outcomes. This information is crucial to aid parents or expectant parents in making an informed care decision.

The presentation of CPAM is highly variable. CPAM can present with respiratory distress or can remain asymptomatic. The clinical presentation is usually at birth but can occur in the prenatal period, neonatal period, childhood, or during adulthood. The most common symptom of (CPAM) is difficulty breathing. Respiratory distress and its severity usually increases with the size of the CPAM.

Additional signs and symptoms

Tachypnea

Grunting respirations

Labored breathing accompanied by chest wall retractions

Cyanosis

History

A family history of tumors and/or cystic lesions should be obtained irrespective of the patient's age, presenting signs, and symptoms. A history of renal cystic disease, small bowel polyps, childhood malignancies, or dysplasia should be obtained. A history of spontaneous pneumothorax might suggest pleuropulmonary blastoma syndrome (PPB).

In older patients presenting with recurrent pneumonia it is very important to obtain history regarding presenting symptoms, location of pneumonia, course of the disease, images and their reports, management and their outcomes, as this may be a presentation of CPAM. A detailed history for possible immunodeficiency disorder should also be obtained.

Physical examination

In a symptomatic patient, physical findings can include respiratory distress, abnormal anatomy of the thorax, decreased aeration, or hyperresonance of the chest. Type, location, and size of the CPAM lesion determines the physical findings. In patients without clinical symptoms, the physical examination is usually normal.

Prenatal presentation

The appearance of CPAM on prenatal ultrasonography ranges from an incidental finding of small cystic lesions to numerous lesions involving the majority of the lung. Fetal hydrops is common with severe lesions, and based on one study, it may complicate as many as 40% of cases. In another study, 14% of infants with CPAM were stillborn. After 28 weeks of gestation, lesions may become smaller; which lesions will regress and to what extent cannot be predicted. Complete spontaneous resolution in the postnatal period has been reported in a small number of cases. Remaining abnormalities may not be seen in postnatal plain radiographs and require computed tomography (CT) to confirm complete resolution.

Neonatal presentation

The most common presentation of CPAM during the newborn period and infancy is respiratory distress. The majority of CPAMs presenting in neonates are type 1. Typical presenting signs include tachypnea, respiratory distress including grunting, chest retractions, and cyanosis.

Childhood presentation

Thirty percent of CPAMs are diagnosed after the neonatal period. Typically lesions are smaller and are usually type 1 or type 4. Recurrent pneumonia is a common presentation in older children and adolescents. Common presenting symptoms include cough, dyspnea, and cyanosis. Patients can also present with lung abscess, pneumothorax, asthma, failure to thrive, and malignant transformation. Congenital anomalies are associated with CPAM. Renal agenesis, neural tube defects, cleft lip and palate, and cardiac defects all represent potential comorbidities. Type 4 CPAM can present with pneumothorax and is associated with malignancy. It is important to obtain a good history, physical examination, and necessary work-up to evaluate for malignancy.

Asymptomatic presentation

About half of the of patients with a prenatal diagnosis of CPAM are asymptomatic at birth. Compared with symptomatic patients, fewer asymptomatic patients have mediastinal shift, polyhydramnios, or hydrops.

Classification of CPAM:

In 1977 Stocker identified three histopathologic subtypes of "CCAM" (types 1-3). It was classified based on postnatal lung resections or stillborn infants at autopsy. Later two additional , less frequent subtypes (types 0 and 4) were added. The designation of CCAM was changed to CPAM to reflect the fact that lesions are cystic in only three of the five types and adenomatoid in only one type (type 3).

Type 0: Type 0 is rare, composing less than 5%. It originates from tracheal or bronchial tissue. The cystic lesions are small and are lined with ciliated pseudostratified epithelium. The malformation is usually diffuse and involves the entire lung. Gas exchange is poor in these patients, and almost all infants with type 0 CPAM die at birth.

Type 1: Type 1 CPAM composes two thirds of cases of CPAM and is the most common form. These lesions likely originate from the distal bronchi or proximal bronchioles. Cysts are lined with ciliated pseudostratified epithelium and the walls contain smooth muscle and elastic tissue. In most cases (approximately 95%) only one lobe is involved and lung parenchyma surrounding the CPAM is essentially normal.

The clinical presentation of type 1 CPAM depends primarily on the size of the cysts. Large cysts can compress adjacent normal lung causing respiratory distress in the neonate, mediastinal shift to the contralateral side, and flattening of the ipsilateral diaphragm (Figure 2). Smaller cysts may remain asymptomatic for varying periods. They may be picked up as an incidental finding or present as a focus of recurrent infection. Type 1 CPAM has malignant potential, but the magnitude of the risk is not known.

Figure 2.

Chest CT showing multiple large cysts in the right lung.

Type 2: Type 2 lesions compose 15% to 20% of CPAM. Cysts resemble dilated terminal bronchioles and are lined with ciliated cuboidal or columnar epithelium. There can be minimal mass effect on the adjacent lung. Extralobar sequestration may have a similar appearance, but unlike type 2 CPAM, a systemic blood supply can may be visualized with the use of contrast CT.

Type 2 CPAM is associated with congenital anomalies in more than half of the cases. Anomalies include esophageal atresia, tracheoesophageal fistula, renal agenesis or dysgenesis, and intestinal atresia. Anomalies can also be seen in the cardiac, central nervous, and skeletal systems. This association with other congenital malformations suggest that the insults resulting in type 2 CPAM probably occur during the early first trimester. It is important to note that in many cases the associated anomalies can be the presenting feature, and CPAM is detected as a secondary finding. Type 2 CPAMs are not at risk for malignant transformation.

Type 3:Type 3 CPAMs compose 5% to 10% of cases. They usually involve multiple lobes and are large. They are acinar in origin and consist of adenomatoid proliferation in the distal airways or air spaces. Lesions can be solid tissue or a combination of cystic and solid tissue. As type 3 CPAMs are typically large and lack differentiation, they are thought to result from an insult in the third or fourth week of gestation. Most infants present in utero or at birth with severe respiratory distress. Type 3 CPAM has not been associated with malignancy.

Type 4: Type 4 lesions comprise 10%-15% of CPAM cases. Cysts consist of nonciliated, flattened, alveolar lining cells, with no mucus cells or skeletal muscle. Type 4 CPAMs may present at birth or in childhood. Older patients can present with tension pneumothorax or recurrent respiratory infection. Type 4 CPAM has increased malignant potential and is strongly associated with PPB.

What other disease/condition shares some of these symptoms?

In patients with identified lesions prenatally, the differential diagnosis includes the following, as they share similar clinical symptoms and can have similar findings on prenatal ultrasonography.

Congenital lobar emphysema

Bronchopulmonary sequestration

Bronchogenic cysts

In older children and adolescents, the differential diagnosis includes the following in addition to those listed above:

Uncontrolled asthma

Cystic fibrosis

Immunodeficiency disorder

Aspiration disorder

Tuberculosis

Foreign body

Evaluation

Radiologic imaging is the most important modality to help with the diagnosis of CPAM, and definitive diagnosis is made by histopathologic analysis. Evaluation will be divided into prenatal and postnatal evaluation for convenience in this chapter.

Prenatal evaluation

Ultrasonographic imaging: Prenatal diagnosis is typically made by ultrasonography. Ultrasonography in the second trimester is a reliable tool for detecting echogenic pulmonary lesions and assessing lung size and mediastinal shift if present. Ultrasonography can also detect the presence of polyhydramnios and hydrops. With current data, it is not possible to predict which lesions will grow and result in hydrops versus those that will stabilize or regress. CPAM volume-to-head circumference ratio (CVR) can be determined by an ultrasonogram. This allows a gestational age–corrected volume ratio to be used prognostically when CPAMs are identified.

Color Doppler ultrasonography: Color Doppler ultrasonography can differentiate CPAM from bronchopulmonary sequestration by identifying the presence of a systemic feeding vessel.

Magnetic resonance imaging (MRI): The combination of MRI and high-resolution ultrasonography can now establish a radiographic diagnosis in the majority of lung lesions. These combined imaging techniques are used to identify the location and size of lesions, their imaging characteristics, and any associated structural features of lung, heart, and mediastinal vasculature. Some studies have demonstrated a poor correlation between a diagnosis made by prenatal ultrasonography and definitive tissue diagnosis at autopsy. Hence, a prenatal ultrasonographic diagnosis of CPAM should not be considered definitive.

CPAM volume-to-head circumference

Crombleholme and colleagues found that a CVR less than or equal to 1.6 was predictive of an increased risk of hydrops, with hydrops developing in 80% of these fetuses with CPAM. There is a 2% risk of hydrops developing in fetuses with a CVR less than or equal to 1.6. The major exception to this rule is that CPAMs with a dominant cyst may be unpredictable in their growth and expansion. CVR is thus useful in distinguishing fetuses at low versus high risk for hydrops. Fetuses at high risk can undergo close surveillance and if required fetal intervention can be planned.

Postnatal evaluation

The urgency and extent of a postnatal evaluation depends on the newborn's clinical status. In a symptomatic patient, urgent radiologic evaluation with chest radiography and CT should be obtained, followed by surgical excision if warranted. In asymptomatic cases, postnatal investigation should consist of plain chest radiography in the first week of life and chest CT within the first few months after birth, even if regression or resolution is noted on prenatal scanning. Plain radiography should not be relied on, as it can miss and underestimate lesions.

Common radiographic findings include mediastinal shift, compression of adjacent normal lung, and flattening of the ipsilateral diaphragm (Figure 1). CPAMs often are not detected on a chest radiograph even when clearly seen on prenatal ultrasonography.

Chest CT : All patients with a prenatal diagnosis of lung lesions should have CT of the chest, even if subsequent ultrasonography showed no evidence of lung lesions or even if the postnatal chest radiograph was normal. It is important to note that serial ultrasonograms may suggest that the cystic lesion has resolved even while fetal MRI or postnatal CT scan may readily redemonstrate the lesions. Older children who present with infectious complications may also require radiography, ultrasonography, and CT of the chest for diagnosis.

Prenatal management

Serial ultrasonograms are recommended to monitor the development of fetal hydrops. Most of these cystic lesions involute after 28 weeks of gestation, but complete resolution is rare. Only a small percentage of cases need fetal intervention. A large cystic mass or fetal hydrops are two important indications for fetal intervention. Such intervention is considered in patients with normal karyotype and absence of other detected anomalies. The type of fetal intervention chosen will depend on clinical findings and severity of the lesion. Options for intervention include therapeutic amniocentesis, thoracoamniotic shunt placement, percutaneous laser ablation, and open fetal surgical resection. Prenatal interventions are not without risk. Associated complications are premature labor, sepsis, and shunt displacement. Maternal steroid administration has been reported to have a beneficial effect on some CCAMs, although the mechanism is unclear.

Postnatal management

Postnatal management is determined by clinical presentation at birth.

Symptomatic patients: If there is a prenatal diagnosis of CPAM and the newborn is symptomatic at birth, urgent radiologic evaluation with chest radiography and CT is required, followed by surgical intervention. Outside of the neonatal age group, CPAM can act as a focus of malignancy or infection, resulting in recurrent pneumonia, lung abscess, empyema, or a lung mass. The management of the symptomatic lesions carries a higher morbidity.

Asymptomatic patients: In asymptomatic patients, postnatal investigation consists of chest radiography and CT within the first few months after birth, even if regression or resolution is noted on prenatal scanning. Plain radiography should not be relied on, as it can miss and underestimate lesions. Surgical excision of postnatal asymptomatic lesions remain controversial, with some centers opting for conservative management. The approach to treating this asymptomatic group has evolved in some centers, where CT is performed within 1 month postnatally, followed by surgery before 6 months of age, because of the inherent risk of infection and malignant transformation. Small lesions less than or equal to1 cm may be managed expectantly, bearing in mind that true resolution of these lesions is exceptional. Successful outcomes greater than 90% have been reported for surgically managed asymptomatic lung lesions.

CPAMs are thought to result from abnormal branching of the bronchioles during lung development. CPAMs represent about one third of the developmental lung bud anomalies and are diagnosed both antenatally and postnatally. Mechanisms and timing of embryonic insult are unclear. There is some evidence suggesting that these lesions arise in the first and early second trimester of gestation, resulting in a broad spectrum of pathologic and radiologic presentations.

CPAM is not related to race, maternal age, or exposure. The incidence is approximately 1/11,000-1/35,000 live births. These numbers likely underestimate the true incidence. Most lesions occur with equal frequency in the right and left lungs and have a slight male predominance. Single-lung lobe disease is far more common (85%-95%) than multilobar disease. Any lobe of the lung can be affected, but CPAM has a predilection for the lower lobes.

What causes this disease and how frequent is it?

CPAM is thought to result from abnormal branching of the bronchioles during lung development. CPAM malformation represents about one third of the developmental lung bud anomalies and is diagnosed both antenatally and postnatally. Mechanisms and timing of embryonic insult are unclear. There is some evidence that suggests that these lesions arise in the first and early second trimester of gestation, resulting in a broad spectrum of pathologic and radiologic presentations.

CPAM is not related to race, maternal age, or exposure. The incidence is approximately 1/11,000-1/35,000 live births. These numbers likely underestimate the true incidence. Most lesions occur with equal frequency in the right and left lungs and have a slight male predominance. Single lung lobe disease is far more common (85%-95%) than multilobar disease. Any lobe of the lung can be affected, but CPAM has a predilection for the lower lobes.

How do these pathogens/genes/exposures cause the disease?

Genes HOXB5, Fibroblast growth factor 7 (FGF7), and platelet derived growth factor B may contribute to the pathogenesis.

What is the evidence?

Adzick, NS, Harrison, MR, Crombleholme, TM. "Fetal lung lesions: management and outcome". Am J Obstet Gynecol. vol. 179. 1998. pp. 884-9.

(This is s a retrospective review of 175 fetal lung lesions diagnosed by antenatal ultrasonography. They concluded that the natural history of prenatally diagnosed lung masses is variable, and associated anomalies are rare. Most CCAM lesions can be managed with maternal transport, planned term delivery, and postnatal resection.)

Lakhoo, K. "Management of congenital cystic adenomatous malformations of the lung". Arch Dis Child Fetal Neonatal Ed. vol. 94. 2009. pp. F73-6.

(This review article discusses pathogenesis, classification, prenatal and postnatal diagnosis, and management.)

Fitzgerald, DA. "Congenital cyst adenomatoid malformations: resect some and observe all". Paediatr Respir Rev. vol. 8. 2007. pp. 67-76.

(This review article discusses the clinical course, options of surgical management, and conservative management of congenital cystic lung lesions.)

Stocker, JT, Madewell, JE, Drake, RM. "Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum". Hum Pathol. vol. 8. 1977. pp. 155-71.

(In this study, 38 cases of congenital cystic adenomatoid malformation of the lung are described, and a classification based on the clinical, gross, and microscopic criteria is proposed.)

Sundararajan, L, Parikh, DH. "Evolving experience with video-assisted thoracic surgery in congenital cystic lung lesions in a British pediatric center". J Pediatr Surg. vol. 42. 2007. pp. 243-50.

(The study aimed to evaluate the efficacy of video-assisted thoracic surgery and its outcome in both antenatally and postnatally detected congenital lung lesions. They concluded that video-assisted thoracic surgery is a safe and effective option for asymptomatic congenital cystic lung lesions.)

Wilson, RD, Hedrick, HL, Liechty, KW. "Cystic adenomatoid malformation of the lung: review of genetics, prenatal diagnosis, and in utero treatment". Am J Med Genet A,. vol. 140. 2006. pp. 151-5.

(Genetics, prenatal evaluation, and treatment of lung abnormalities with CCAM is reviewed.)

Priest, JR, Williams, GM, Hill, DA. "Pulmonary cysts in early childhood and the risk of malignancy". Pediatr Pulmonol. vol. 44. 2009. pp. 14-30.

(Malignancy in childhood lung cysts and their management controversies are discussed in this article.)

Calvert, JK, Boyd, PA, Chamberlain, PC. "Outcome of antenatally suspected congenital cystic adenomatoid malformation of the lung: 10 years' experience 1991-2001". Arch Dis Child Fetal Neonatal Ed. vol. 91. 2006. pp. F26-8.

Davenport, M, Warne, SA, Cacciaguerra, S. "Current outcome of antenally diagnosed cystic lung disease". J Pediatr Surg. vol. 39. 2004. pp. 549-56.

Calvert, JK, Lakhoo, K. "Antenatally suspected congenital cystic adenomatoid malformation of the lung: postnatal investigation and timing of surgery". J Pediatr Surg. vol. 42. 2007. pp. 411-4.

(Retrospective study to document the optimal postnatal investigation and timing of surgery.)

Ongoing controversies regarding etiology, diagnosis, treatment

Surgical management of asymptomatic lesions are controversial.

Pros:

Surgery may be technically more difficult and carry higher morbidity in the setting of an infected CPAM.

Infections are the most common presentation of CPAM after the neonatal period.

Significant or rapid enlargement of the lesion and/or pneumothorax may lead to respiratory distress or failure and further complicate surgical intervention.

Surgical resection can allow compensatory lung growth. Animal studies suggest that after pneumonectomy, the lung increases in both volume and weight because of growth of the tissue.

There is a risk of malignancy in association with CPAM. This may be a presenting feature of the diagnosis or may be diagnosed as a later complication. The risk of malignancy is difficult to predict. The presence of malignant spread (either locally or systemically) may preclude an exclusively surgical cure.

In general, postoperative recovery tends to be more rapid in the pediatric population. However, neonates may be at increased risk for surgical complications. Specific recommendations are provider dependant but most will opt for surgery in the time frame of 1-6 months after birth.

Cons:

The natural history of CPAM is not well defined, as most of these lesions have been removed after diagnosis.

The aggressive treatment of CPAM as a premalignant lesion may not be necessary in all patients, as malignant transformation may be of higher likelihood in particular clinical settings.

A conservative approach includes regular follow-up with chest CT. In this setting, the associated risk of a secondary malignancy related to repeated radiation exposure must be considered.

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