Lung Cyst

The most common fetal cystic lung lesions are congenital cystic adenomatoid malformation (CAM), and bronchogenic cyst; and are considered a developmental lung anomaly with dysplastic lung tissue and abnormal bronchoalveolar structures.

Fetal cystic lung lesions complicate about 1 in 3,000 live births. The incidence of CCAM is estimated at 1 in 6,000 births¹.  

As previously demonstrated by several histological studies, CCAM lung tissue is associated with an increased cell proliferation, decreased apoptosis and aberrant cell adhesion molecule expression ^{2, 3}. Inmunohystochemical studies have demonstrated an over expression of different growth factors that enhance cell proliferation and proteins that down-regulate apoptosis such as the keratinocyte growth factor and the platelet-derived growth factor ^{4, 5}. Likewise, genetic and molecular studies suggest that over expression of Fgf7 gene is involved in the pathogenesis of CCAM⁶. 

Cystic lung lesions arise from the arrested maturation of bronchiolar cells resulting from immature bronchioles during early stages of lung morphogenesis.

CCAM is characterized by a lack of normal alveoli and an adenomatoid excessive proliferation and cystic dilatation of terminal respiratory bronchioles ranging in diameter from 1 mm to over 10 cm and that usually arise from one lobe of the fetal lung ⁷.

Histologically, CCAM is characterized by mucous secreting cells, polypoid projections of the mucosa, increase in smooth muscle and elastic tissue within cyst walls, and absence of cartilage and inflammation. Histological studies have classified them as pseudoglandular and canalicular⁸. Stocker et al have classified CCAMs according to the size of the lung cysts;  Type 1, when the cysts size is above 2cm; type 2 where the lesions are below 2cm; and  type 3 which are predominantly solid lesions with cysts sizes below 0.5cm⁷. The clinical and current classification is based primarily on sonographiccharacteristics as macrocystic, microcystic (solid mass), and a mixed component of both solid and macrocystic types⁹.

Fetuses with cystic lung lesions are in general not associated with chromosomal abnormalities or genetic causes¹⁰. However, it could be associated with other congenital malformations such as congenital diaphragmatic hernia and tracheoesophageal fistula in up to 10%⁶, and congenital heart diseases in up to 2%¹¹ of occurances. In the presence of any of these associated malformations, the risk of chromosomal abnormalities increases to 40-50% and dictates the need for karyotype analysis. 

In euploid fetuses the recurrence risk is below 1%. Genetic consultation is not recommended due to the lower recurrence rate, and that association with genetic syndromes is infrequent.

Prenatal diagnosis is based on the sonographic demonstration of an intrathoracic anechoic lesion that appears as single well-defined, unilocular, cystic mass within the lung parenchyma (bronchogenic cyst) or multicystic tumor (macrocystic CCAM) with or without echogenic stroma (solid-cystic mass), usually unilateral and involving one lobe of the lung ⁹.

Some indirect signs could be found in the sonographic examination as a complication of the lung masses. The presence of large lung lesions could induce hydrops fetalis (that is manifests as fetal ascitis, pleural and pericardial effusions, skin and scalp edema) either secondary to obstruction of the inferior vena cava return or direct cardiac compression by the cystic mass¹². Mediastinal and large cysts tend to induce tracheal and esophageal compression with subsequent polyhydramnios.

Other anomalies that have to be considered in the differential diagnosis of cystic lung lessions include congenital diaphragmatic hernia (if a single intrathoracic cytstic mass is observed in left side), thoracic lynphangioma, and enteric duplication cysts.

It is easy to recognize cystic lung lesions during fetal ultrasound since they appear as anechoic lesions due to the presence of liquid in the cysts. Once a lung cyst is identified, the location, size, and blood supply must be evaluated using conventional spectral or power Doppler ultrasound. CCAMs usually have their blood supply arising from the pulmonary artery. However, a small proportion of cases may have systemic blood supply from the descending aorta mimicking a bronchopulmonary sequestration. Such cystic lesions with systemic blood supply are known as hybrid lesions. Fetal echocardiography must be performed in the screening for potential congenital heart malformations. Depending on the type and size of the lung mass, sonographic surveillance should be performed weekly to assess the mass volume, amniotic fluid volume, and cervical length. Additionally, evaluation of cardiac function parameters such as Doppler of the ductus venosus and tricuspid regurgitation should also be performed in the monitoring of these fetuses to identify the early occurrence of hydrops.

The clinical spectrum of severity is very variable extending from cases with a rapidly growing intrathoracic mass resulting in hydrops and stillbirth, to lesions which despite achieving a significant size, show a spontaneous disappearance throughout the pregnancy. The behavior of this pathology has a huge variability. While in a few cases (30%), an increasing CCAM size is observed, 2D and 3D ultrasound examinations have demonstrated decreasing CCAM volume in up to 90% of  cases with a complete spontaneous prenatal image disappearance in about 50%  when the lung mass is small. However with large lung tumors, spontaneous regression of the mass rarely occurs during prenatal follow-up ^{13, 14}.

Consensus exsists that the best prenatal predictor of prognosis is firstly, the relative size of the thoracic mass, and secondly, the development of fetal pleural effusion or hydrops as a complication⁹. Additionally, in the presence of hydrops the mortality rate increases above 95% primary due to fetal heart failure and could be also associated with extremely severe pulmonary hypoplasia. The lung mass size could be calculated using the CCAM volume-to-head ratio (CVR) which is obtained by dividing the CCAM volume (cm²) = (length (cm) x height (cm) x width (cm) x 0.52) by the head circumference (cm). ¹⁵ Those cases with a CVR >1.6 show an increased risk for developing hydrops (75%) in comparison with those with less than 1.6 (3%) ¹⁵. Recent evidence has demonstrated that a CVR above 1.0 is associated with a higher risk of adverse perinatal outome and neonatal morbidity¹⁶. Another prenatal finding associated with bad prognosis is the presence of polyhydramnios, which may appear as a consequence of esophageal compression by the cystic mass producing difficulties in fetal amniotic fluid swallowing. The available prenatal series of macrocystic CCAM consistently indicate polyhydramnios (with subsequent higher risk for preterm labor), and mediastinal shifting as prenatal findigns associated with bad prognosis.

Expectant management with continuing ultrasonographic follow-up seems to be a reasonable recommendation for small, nonhydropic lung mass lesions. Although subsequent postnatal spontaneous resolution is very uncommon, it has also been documented in about 4% of cases¹⁷. Despite antenatal resolution of CCAMs on ultrasound, postnatal examination with chest radiography and computed tomography scan is necessary for further follow-up.

Small-case series have reported a potential negative effect of prenatal steroid management on the growth of CCAM with a substantial positive effect in hydrops resolution and survival ^18-20. They reported a CCAM volume decrease in >70%, resolution of hydrops above 80% and on average 30 days later, and survival rate >90% in cases managed with maternal betamethasone (12mg intramuscularly, 2 doses, 24-hours apart).

Since cases with large cystic lung lesions complicated with hydrops has a very poor prognosis due to the risk of perinatal death; in countries where termination of pregnancy is legal, this could be a reasonable option if the couple requested. For such poor prognositic cases, when the termination of pregnancy is not an option, fetal therapy has demonstrated an improvement in survival probability after in utero decompression with the placement of a thoracoamniotic shunt. Clinical series have reported overall survival rates ranging from 50-74%, which compare favorably with historical controls managed expectantly ^{6, 21}. In utero pulmonary drainage may be associatged with a temporary decrease in lung mass size but fluid tends to increae rapidily at an exponential rate,  requiring further interventions and thererfore is not a good option in comparison with a thoraco-amniotic shunt.

Preliminary evidence has demonstrated that laser coagulation of the feeding artery by ultrasound guidance may improve neonatal prognosis and decreased neonatal morbilidy in fetuses with cystic lung lessions with systemic blood supply (hybrids) at risk of perinatal death, i.e those with hydrops or massive pleural effusions²².

Cases diagnosed above 32 weeks of gestation may benefit with planned delivery, prenatal steroid therapy and the use of ex utero intrapartum therapy (EXIT) rather than fetal invasive therapy ²³.

Neonatal thoracotomy and lobectomy for congenital lung cysts is often indicated by the size of the mass or by symptoms such as respiratory distress, hydrothorax or pneumothorax. However, several studies have reported that 10% of CCAMs could be associated with an increased risk to develop pleuropulmonary blastoma.  This underlines the need to perform timely surgical interventions even in asymptomatic newborns to prevent the potential risk of malignancy ²⁴.

1.         Burge D and Wheeler R. Increasing incidence of detection of congenital lung lesions. Pediatr Pulmonol 2010; 45: 103; author reply 104.

2.         Cass DL, Crombleholme TM, Howell LJ, Stafford PW, Ruchelli ED and Adzick NS. Cystic lung lesions with systemic arterial blood supply: a hybrid of congenital cystic adenomatoid malformation and bronchopulmonary sequestration. J Pediatr Surg 1997; 32: 986-990.

3.         Volpe MV, Chung E, Ulm JP, Gilchrist BF, Ralston S, Wang KT and Nielsen HC. Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation. Am J Physiol Lung Cell Mol Physiol 2009; 297: L143-152.

4.         Liechty KW, Crombleholme TM, Quinn TM, Cass DL, Flake AW and Adzick NS. Elevated platelet-derived growth factor-B in congenital cystic adenomatoid malformations requiring fetal resection. J Pediatr Surg 1999; 34: 805-809; discussion 809-810.

5.         Simonet WS, DeRose ML, Bucay N, Nguyen HQ, Wert SE, Zhou L, Ulich TR, Thomason A, Danilenko DM and Whitsett JA. Pulmonary malformation in transgenic mice expressing human keratinocyte growth factor in the lung. Proc Natl Acad Sci U S A 1995; 92: 12461-12465.

6.         Wilson RD, Hedrick HL, Liechty KW, Flake AW, Johnson MP, Bebbington M and Adzick NS. Cystic adenomatoid malformation of the lung: review of genetics, prenatal diagnosis, and in utero treatment. Am J Med Genet A 2006; 140: 151-155.

7.         Stocker JT, Madewell JE and Drake RM. Congenital cystic adenomatoid malformation of the lung. Classification and morphologic spectrum. Hum Pathol 1977; 8: 155-171.

8.         Cha I, Adzick NS, Harrison MR and Finkbeiner WE. Fetal congenital cystic adenomatoid malformations of the lung: a clinicopathologic study of eleven cases. Am J Surg Pathol 1997; 21: 537-544.

9.         Adzick NS. Management of fetal lung lesions. Clin Perinatol 2009; 36: 363-376.

10.       Adzick NS, Harrison MR, Crombleholme TM, Flake AW and Howell LJ. Fetal lung lesions: management and outcome. Am J Obstet Gynecol 1998; 179: 884-889.

11.       Husler MR, Wilson RD, Rychik J, Bebbington MW, Johnson MP, Mann SE, Hedrick HL and Adzick S. Prenatally diagnosed fetal lung lesions with associated conotruncal heart defects: is there a genetic association? Prenat Diagn 2007; 27: 1123-1128.

12.       Mahle WT, Rychik J, Tian ZY, Cohen MS, Howell LJ, Crombleholme TM, Flake AW and Adzick NS. Echocardiographic evaluation of the fetus with congenital cystic adenomatoid malformation. Ultrasound Obstet Gynecol 2000; 16: 620-624.

13.       Laberge JM, Flageole H, Pugash D, Khalife S, Blair G, Filiatrault D, Russo P, Lees G and Wilson RD. Outcome of the prenatally diagnosed congenital cystic adenomatoid lung malformation: a Canadian experience. Fetal Diagn Ther 2001; 16: 178-186.

14.       MacGillivray TE, Harrison MR, Goldstein RB and Adzick NS. Disappearing fetal lung lesions. J Pediatr Surg 1993; 28: 1321-1324; discussion 1324-1325.

15.       Crombleholme TM, Coleman B, Hedrick H, Liechty K, Howell L, Flake AW, Johnson M and Adzick NS. Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung. J Pediatr Surg 2002; 37: 331-338.

16.       Hellmund A, Berg C, Geipel A, Bludau M, Heydweiller A, Bachour H, Muller A and Gembruch U. Prenatal Diagnosis and Evaluation of Sonographic Predictors for Intervention and Adverse Outcome in Congenital Pulmonary Airway Malformation. PLoS One 2016; 11: e0150474.

17.       Butterworth SA and Blair GK. Postnatal spontaneous resolution of congenital cystic adenomatoid malformations. J Pediatr Surg 2005; 40: 832-834.

18.       Curran PF, Jelin EB, Rand L, Hirose S, Feldstein VA, Goldstein RB and Lee H. Prenatal steroids for microcystic congenital cystic adenomatoid malformations. J Pediatr Surg 2010; 45: 145-150.

19.       Peranteau WH, Wilson RD, Liechty KW, Johnson MP, Bebbington MW, Hedrick HL, Flake AW and Adzick NS. Effect of maternal betamethasone administration on prenatal congenital cystic adenomatoid malformation growth and fetal survival. Fetal Diagn Ther 2007; 22: 365-371.

20.       Tsao K, Hawgood S, Vu L, Hirose S, Sydorak R, Albanese CT, Farmer DL, Harrison MR and Lee H. Resolution of hydrops fetalis in congenital cystic adenomatoid malformation after prenatal steroid therapy. J Pediatr Surg 2003; 38: 508-510.

21.       Adzick NS, Harrison MR, Flake AW, Howell LJ, Golbus MS and Filly RA. Fetal surgery for cystic adenomatoid malformation of the lung. J Pediatr Surg 1993; 28: 806-812.

22.       Cruz-Martinez R, Martinez-Rodriguez M, Bermudez-Rojas M, Magana-Abarca C, Narvaez-Dominguez V, Rojas-Macedo A, Bautista-Garcia N and Alcocer-Alcocer M. Fetal laser ablation of feeding artery of cystic lung lesions with systemic arterial blood supply. Ultrasound Obstet Gynecol 2017; 49: 744-750.

23.       Hedrick HL, Flake AW, Crombleholme TM, Howell LJ, Johnson MP, Wilson RD and Adzick NS. The ex utero intrapartum therapy procedure for high-risk fetal lung lesions. J Pediatr Surg 2005; 40: 1038-1043; discussion 1044.

24.       Priest JR, Williams GM, Hill DA, Dehner LP and Jaffe A. Pulmonary cysts in early childhood and the risk of malignancy. Pediatr Pulmonol 2009; 44: 14-30.