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Seminars in Fetal & Neonatal Medicine (2007) 12, 477e481

Antenatal diagnosis and management of congenitalcystic adenomatoid malformation

Stephanie Mann a,b,*, R. Douglas Wilson a,b, Michael W. Bebbington a,b,N. Scott Adzick a,b, Mark P. Johnson a,b

a Center for Fetal Diagnosis and Treatment, Children’s Hospital of Philadelphia, 34th Streetand Civic Center Boulevard, Wood Center 5113, Philadelphia, PA 19104, USAb University of Pennsylvania School of Medicine, 34th Street and Civic Center Boulevard,Philadelphia, PA 19104, USA

KEYWORDSCongenital cysticadenomatoidmalformation;CCAM volume ratio;EXIT procedure

Summary One of the most enigmatic pulmonary lesions encountered in the prenatal period isthe congenital cystic adenomatoid malformation (CCAM). This review presence current think-ing on pathogenesis, prenatal assessment, fetal intervention, and management for this pulmo-nary malformation. Careful delivery planning by utilizing a multidisciplinary approach willoptimize neonatal outcomes.ª 2007 Elsevier Ltd. All rights reserved.

Classification

A congenital cystic adenomatoid malformation (CCAM) ischaracterized as a bronchopulmonary malformation pre-senting as an intrapulmonary mass that is usually localizedto one lung lobe. A congenital cystic adenomatoid malfor-mations (CCAMs) is characterized by a lack of normal alveoliand an excessive proliferation and cystic dilatation ofterminal respiratory bronchioles.1 Historically, classificationschemes for CCAMs reflect the size and histology of the cystswithin these lesions. Hence, the initial pathologic classifica-tion of CCAMs was based on the size of the cysts and the mi-croscopic appearance of lesions evaluated at autopsy.1 Inthis classification scheme, type I lesions are characterized

* Corresponding author. Center for Fetal Diagnosis and Treatment,Children’s Hospital of Philadelphia, 34th Street and Civic CenterBoulevard, Wood Center 5113, Philadelphia, PA 19104, USA.Tel.: þ1 215 590 8771; fax: þ1 215 590 2447.

E-mail address: manns@email.chop.edu (S. Mann).

1744-165X/$ - see front matter ª 2007 Elsevier Ltd. All rights reservedoi:10.1016/j.siny.2007.06.009

by large cysts of varying sizes (measuring >2 cm in diame-ter), type II lesions typically contain cysts of a more variablesize (�2 cm in diameter), and type III lesions contain micro-scopic cysts.

Recently, this classification scheme has been revisited,as several studies suggest that Stocker’s classification maynot accurately describe the histopathology of CCAMsdetected antenatally.2e6 Analysis of specimens obtainedfrom fetal resections suggests that the antenatal ultra-sound features are poorly correlated with the histologicalfindings.7 Cha et al. identified two histologic patterns offetal CCAM thought to represent the stage of lung develop-ment at which the arrest in pulmonary development oc-curred.3 Kreiger et al.4 proposed a tripartite classificationbased on the histologic features of the parenchyma be-tween the cysts. The results of these evaluations suggestthat there is a histologic difference between CCAMs ob-served in prenatal versus postnatal life.

Recent studies have also shown that there are hybridlesions, i.e., masses that not only histologically and

d.

478 S. Mann et al.

sonographically appear as CCAMs but also contain a systemicarterial blood supply similar to that of a bronchopulmonarysequestration (BPS).8,9 The natural history of these intralo-bar hybrid lesions appears to be dependent on the size ofthe mass and the resultant physiologic sequelae.8

Prenatal assessment

As imaging modalities have become more sophisticated androutine, prenatal identification of these lesions has in-creased. Once a lung mass is identified on ultrasound, thelocation, volume, size/appearance (i.e. microcystic versusmacrocystic) and blood supply must be evaluated. Addi-tionally, color Doppler should be used to evaluate the originof the blood supply of the CCAM to exclude the diagnosis ofBPS. The initial evaluation should include fetal echocardi-ography, as there is an increased incidence of structuraland functional cardiac anomalies associated with theselesions. It has also been shown that a baseline assessmentof cardiac function is useful in monitoring physiologicchanges as the pregnancy progresses.10

Once the diagnosis of CCAM has been made, carefulserial antenatal observation is necessary to monitor thedevelopment of hydropic changes in the fetus. Although thelarge CCAM mass can cause mediastinal shift and esopha-geal compression, resulting in polyhydramnios, the singlebest predictor of fetal death is hydrops.11,12 Depending onthe size of the CCAM and associated sequelae, ultrasono-graphic surveillance should be performed once or twicea week through mid-gestation to monitor the volumechanges of the CCAM. Approximately 15% of CCAMs will de-crease in size during gestation2,5,6; the exact mechanismand reason for the reduction in size is unclear. Peak CCAMgrowth is expected to occur by 28 weeks, and regressionin CCAM volume has been observed in 20% of cases after29 weeks.5 In addition to growth, it is also important tomonitor the amniotic fluid volume (DVP, AFI), cardiac func-tion, mediastinal shift, measurement of placental thickness

(measured at the cord insertion site),13 and Doppler assess-ment of the ductus venosus and umbilical vessels for evi-dence of hemodynamic alterations secondary to theintrathoracic mass effect.

While the majority of fetuses with antenatally detectedCCAMs have a good outcome, ongoing surveillance isnecessary due to the unpredictable growth patterns forthese lesions, and to identify the early occurrence ofhydrops. The natural history of CCAMs can be variable, assome lesions increase in size and others will at leastpartially regress spontaneously. For those lesions thatremain small and do not significantly change in size aftera 3-week observation period or beyond 28 weeks, expec-tant obstetrical management and postnatal evaluation andresection are recommended.

To enhance the ability to predict CCAM behavior, wedeveloped a sonographic measurement based on CCAMvolume to predict the growth patterns of CCAMs andidentify fetuses at risk for progressing to fetal hydrops.14

The CCAM volume ratio (CVR) is a volumetric ratio basedon the elliptical volume of the CCAM [height (cm)�width(cm)� depth (cm)� 0.523 Z cm3] divided by head circum-ference (cm) for gestational normalization. Specifically,a retrospectively derived CVR� 1.6 is correlated witha 94% survival rate and a <3% risk of developing hydrops.This study also analyzed gestational changes in CCAMgrowth and showed that peak CCAM growth occurs at 25weeks, and that most lesions reach a growth plateau at28 weeks. An important caveat to the use of CVR is thatits predictive utility is most applicable to predominantlysolid CCAMs without a dominant cyst. Therefore, the CVRappears to be a useful modality for stratifying patientsinto categories of high and low risk of hydrops, but is notintended to specifically select fetuses that should have in-utero treatment or surgery prior to developing secondarycomplications such as hydrops.

Magnetic resonance imaging (MRI; Fig. 1) has been shownto be a useful tool for imaging fetal chest masses, not onlyfor distinguishing CCAMs from other intrathoracic lesions

Figure 1 Magnetic resonance imaging (MRI) of (A) a microcystic congenital cystic adenomatoid malformation (CCAM), and(B) a macrocystic CCAM.

Congenital cystic adenomatoid malformation 479

but also indicating lobe location and for accurately visualiz-ing and determining the presence of compressed normallung.15,16

Management

Aspiration and drainage of the dominant cyst has been usedas a temporizing tool for the management of macrocysticCCAMs.17e19 However, a simple thoracocentesis is usuallyineffective as a definitive therapy, as cyst fluid will usuallyrapidly reaccumulate depending on gestational age. How-ever, initial macrocyst aspiration can provide helpful clini-cal information as it will determine the percentage massvolume decrease if the cyst were chronically drained, andidentifies drainage of multiple cystic connections, thus pro-viding information in planning for possible thoracoamnioticshunt placement (Fig. 2).

Another in-utero technique that has been attempted fordebulking a large, microcystic CCAM is percutaneous laserablation.7,20,21 The concept behind this technique is thatlaser is used to eliminate blood supply to the mass. Ofthe three fetuses described in these reports, there wasone neonatal survivor,21 one fetal death after the lasertherapy,20 and one neonatal death that was attributed tosepsis.7 Further study and refinements are necessary beforethis therapy is considered as a viable therapeutic option.

Currently, the options available for non-invasive treat-ment of fetuses that have become hydropic due to a CCAMare limited. However, there is evidence to suggest thatprenatal betamethasone may be an option for the manage-ment of these patients.22,23 Tsao et al.22 reviewed threecases of large, unilateral, and microcystic CCAMs that hadprogressed to hydrops; after maternal treatment with beta-methasone, the hydrops were resolved and the neonateswere delivered at term without respiratory distress. Simi-larly, encouraging results were found in a recent study eval-uating a cohort of fetuses with poor-prognosis CCAMs (i.e.presence of hydrops, CVR> 1.6) in whom maternal betame-thasone was given.23 When this group of 11 fetuses wascompared to untreated historical controls, survival was

significantly improved after betamethasone had beengiven. These data highlight the need for additional random-ized studies investigating the utility of antenatal steroidsfor the management of large CCAMs.

The development of fetal hydrops necessitates interven-tion, as expectant management in this scenario results infetal death.2 The exact gestational age cut-off for deliveryand postnatal resection versus in-utero intervention hasnot been definitively established. The experience at our cen-ter suggests that for those fetuses with normal chromosomesand no other associated anomalies in whom hydrops occurs ator after 30e32 weeks, betamethasone with early deliveryand immediate postnatal resection has improved survival.22

The optimal time for pursuing in-utero therapy versuscontinuing expectant management is not well defined. Priorto 30e32 weeks, management of the fetus with a CCAM is inpart determined by the cystic characteristics of the CCAMas well as the risk of preterm delivery due to polyhydram-nios, developing hydrops, or pulmonary hypoplasia (i.e.<24 weeks, significant mass effect with mediastinal shiftand bilateral lung compression). CCAMs with a large,dominant cyst respond favorably to the placement ofa thoracoamniotic shunt.2,12,24,25 A recent review of the ex-perience at the Children’s Hospital of Philadelphia showedthat CCAM volumes were reduced by an average of 70% andresulted in an overall 74% survival rate by the placement ofa thoracoamniotic shunt in the presence of hydrops or poly-hydramnios, or in those fetuses at increased risk for devel-oping pulmonary hypoplasia.25 Though this procedure cansignificantly improve outcome, there are several potentialcomplications, including catheter displacement, malfunc-tion of the catheter, catheter occlusion from thrombusmaterial, fatal fetal hemorrhage, procedure-related abrup-tion, premature rupture of membranes, or preterm labor.26

One interesting postnatal complication that has been re-ported is rib deformities adjacent to the shunt placementsite.27 This finding may have been developmentally-relatedto the increased pliability of the fetal rib cage and increasedsusceptibility to rib deformation when shunts are placed tooearly in gestation (�21 weeks). Therefore, given the smallbut potential risks associated with shunt placement, it has

Figure 2 (A) This axial image demonstrates a macrocystic congenital cystic adenomatoid malformation (CCAM) in the right thoraxprior to placement of a thoracoamniotic shunt. This fetus had signs of hydrops; there was cardiac compression (arrow). (B) Threeweeks after shunt placement (thin arrow) the hydrops had resolved and the heart is less compressed (thick arrow).

480 S. Mann et al.

been suggested that an invasive procedure not be offeredunless there is hydrops or recurrent polyhydramnios thatplaces the pregnancy at very high risk for preterm labor.11,28

For large solid CCAMs with macrocysts that do notrespond to thoracoamniotic shunting or for predominantlysolid lesions, open fetal surgery may be an option.2 Generalanesthesia is used to ensure uterine relaxation. A laparot-omy/hysterotomy is performed followed by a fetal thora-cotomy and resection of the involved lobe. In a review of22 open maternal fetal cases complicated by fetal hydrops,the overall neonatal survival rate was 50%. Hydrops resolvedwithin 1e2 weeks with normal postnatal pulmonary devel-opment in surviving children. Analysis of the unsuccessfulresections reveals both maternal and fetal causes for thelosses. Three of the cases were attributed to maternal is-sues, i.e. mirror syndrome, preterm labor, and chorioamnio-nitis, respectively. Fetal complications included six cases ofintraoperative fetal cardiovascular collapse during resec-tion, and two cases of unexplained fetal bradycardia. Theseearly complications have identified the need to establish in-travenous access in the fetus to allow aggressive volumeloading with intravenous fluid or blood prior to and duringthe mass resection based on continuous fetal echocardio-graphic surveillance during these procedures. Since utilizingthis volume loading approach, there have been no subse-quent losses from cardiovascular collapse. The above experi-ence demonstrates the stressing the need for intraoperativefetal cardiac assessment and monitoring.

For those fetuses with large CCAMs who are likely tohave difficulty with oxygenation after birth, the ex-uterointrapartum therapy (EXIT) delivery approach is an option.At the time of cesarean section, a hysterotomy isperformed using a special stapling device to establish abloodless uterine incision, as the fetus is partially exterior-ized from the uterine cavity and maintained on maternaleplacental support. At this time, an airway and intravenousaccess are established in the fetus.29 A recent study30 hasshown that, in the appropriate maternal candidate, a fetuswith severe mediastinal shift associated with a persistentlyelevated CVR due to a large intrathoracic mass effect canbenefit from an EXIT delivery and lung mass resection whileon maternaleplacental support. The overall survival in thisstudy of 22 infants was 89%. An EXIT delivery with controlledresection of the large CCAM helps to avoid the clinicalscenario of an unstable, persistently hypoxic neonaterequiring immediate and emergent thoracotomy and massreduction. The benefits of an EXIT delivery results fromavoiding the acute respiratory decompensation due tohemodynamic consequences of impaired venous return frommediastinal shift, lung compression from a space-occupyingmass effect, potential mass expansion from air-trappingwithin the larger cysts, or spontaneous pneumothorax.

Summary

In the majority of fetuses diagnosed with CCAMs in theprenatal period, the outcome is generally favorable. How-ever, outcome is based on a definitive diagnosis and closeultrasonographic surveillance dependent on volume andgestational age. Fetuses for large macrocystic lesions maybe the candidates for minimally invasive thoracoamniotic

shunt placement. Fetuses with large solid CCAMs thatdevelop hydrops or severe polyhydramnios remote fromterm may benefit from in-utero resection. Careful deliveryplanning is crucial to optimize neonatal outcome. Neonatalprognosis is favorable when fetuses are carefully evaluatedand managed by a multidisciplinary team and undergopostnatal CCAM resection because of the risks of recurrentinfection, air-trapping, or malignant transformation.

References

1. Stocker JT, Madewell JE, Drake RM. Congenital cystic adeno-matoid malformation of the lung. Classification and morpho-logic spectrum. Hum Pathol 1977;8(2):155e71.

2. Adzick NS. Management of fetal lung lesions. Clin Perinatol2003;30(3):481e92.

3. Cha I, Adzick NS, Harrison MR, Finkbeiner WE. Fetal congenitalcysticadenomatoidmalformationsofthe lung:aclinicopathologicstudy of eleven cases. Am J Surg Pathol 1997;21(5):537e44.

4. Kreiger PA, Ruchelli ED, Mahboubi S, et al. Fetal pulmonarymalformations: defining histopathology. Am J Surg Pathol2006;30(5):643e9.

5. MacGillivray TE, Harrison MR, Goldstein RB, Adzick NS. Disap-pearing fetal lung lesions. J Pediatr Surg 1993;28(10):1321e4[Discussion 1324e1325].

6. Miller JA, Corteville JE, Langer JC. Congenital cystic adenoma-toid malformation in the fetus: natural history and predictorsof outcome. J Pediatr Surg 1996;31(6):805e8.

7. Davenport M, Warne SA, Cacciaguerra S, et al. Current out-come of antenally diagnosed cystic lung disease. J PediatrSurg 2004;39(4):549e56.

8. Cass DL, Crombleholme TM, Howell LJ, et al. Cystic lung lesionswith systemic arterial blood supply: a hybrid of congenital cys-tic adenomatoid malformation and bronchopulmonary seques-tration. J Pediatr Surg 1997;32(7):986e90.

9. Hirose R, Suita S, Taguchi T, Koyanagi T, Nakano H. Extralobarpulmonary sequestration mimicking cystic adenomatoid

Practice points

� If a CCAM is suspected, the initial evaluationshould include color Doppler to evaluate the originof the blood supply to the mass.� CCAMs usually demonstrate peak growth between

25 and 28 weeks.� The CVR is useful for stratifying fetuses with re-

spect to the risk of developing hydrops.

Research directions

� The precise etiology of the abnormal cell prolifer-ation in CCAMs remains to be determined.� Further studies are necessary to determine the

utility of prenatal betamethasone as a potentialtherapeutic option for CCAMs.

Congenital cystic adenomatoid malformation 481

malformation in prenatal sonographic appearance and histo-logical findings. J Pediatr Surg 1995;30(9):1390e3.

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21. Ong SS, Chan SY, Ewer AK, et al. Laser ablation of foetal micro-cystic lung lesion: successful outcome and rationale for its use.Fetal Diagn Ther 2006;21(5):471e4.

22. Tsao K, Hawgood S, Vu L, et al. Resolution of hydrops fetalis incongenital cystic adenomatoid malformation after prenatalsteroid therapy. J Pediatr Surg 2003;38(3):508e10.

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25. Wilson RD, Hedrick HL, Liechty KW, et al. Cystic adenomatoidmalformation of the lung: review of genetics, prenataldiagnosis, and in utero treatment. Am J Med Genet 2006;140(2):151e5.

26. Smith RP, Illanes S, Denbow ML, Soothill PW. Outcome of fetalpleural effusions treated by thoracoamniotic shunting. Ultra-sound Obstet Gynecol 2005;26(1):63e6.

27. Merchant AM, Peranteau W, Wilson RD, et al. Case report: post-natal chest wall deformities after fetal thoracoamniotic shunt-ing for congenital cystic adenomatoid malformation. FetalDiagn Ther, [in press].

28. Dommergues M, Louis-Sylvestre C, Mandelbrot L, et al. Congen-ital adenomatoid malformation of the lung: when is activefetal therapy indicated? Am J Obstet Gynecol 1997;177(4):953e8.

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30. Hedrick HL, Flake AW, Crombleholme TM, et al. The ex uterointrapartum therapy procedure for high-risk fetal lung lesions.J Pediatr Surg 2005;40(6):1038e43.