Multidisciplinary management of a large microcystic congenital pulmonary airway malformation: case report and literature review

Abstract Introduction Congenital pulmonary airway malformations (CPAMs) are rare sporadic lesions frequently associated with poor fetal prognosis. Type 3 CPAMs are characterized by small hyperechogenic cysts (<5 mm). Hydrops often develops secondarily, and the fetal survival rate is approximately 5% in this setting. Case presentation We present a case of a large type 3 CPAM complicated by fetal hydrops. The lesion was detected at 19 gestational weeks (GW) and confirmed by fetal MRI at 29 GW. At 22 GW, a course of maternal steroids was given as a possible treatment of type 3 CPAM. Peritoneal-amniotic shunt was placed twice to reduce fetal ascites, with unsatisfactory results. Similarly, polyhydramnios was relieved by two amnioreductions, but redeveloped soon after. A baby girl was delivered spontaneously at 33 GW and received a two-stage partial lobectomy in the first three months of life. Desaturations necessitated challenging invasive oscillatory ventilation between stages. Her outcome is unexpectedly positive and she may expect a good quality of life. She now approaches one year of age, with near-to-normal growth and developmental milestones. Discussion Type 3 CPAMs complicated by fetal hydrops are associated with high perinatal mortality. While open fetal surgery remains a viable option in select specialist centers, antenatal interventions are typically ineffective. The survival of this infant can be attributed to prenatal management and early postnatal surgical intervention. The lack of guidelines for ventilation in this setting was a significant challenge for neonatal intensivists. Multidisciplinary vigilance and collaboration with frequent specialist follow ups were the key to success for both mother and child.


Introduction
Congenital pulmonary airway malformations (CPAMs) are the most common congenital lung malformations (CLMs).With a prevalence ranging from 1/11,000 to 1/33,000 live births they are rare overall [1].It is thought that developmental deficiencies occurring in early embryogenesis lead to abnormal lung morphogenesis, resulting in cystic and non-cystic multilevel malformations of the broncho-pulmonary tree [1][2][3].The prognosis for the child is frequently poor.Twentyfive to 30% of neonates with antenatally diagnosed CPAMs will present with respiratory distress, pneumothorax, and infection, and perinatal mortality may reach 50% [1].Furthermore, the development of fetal hydrops is a devastating complication that is associated with a less than 5% survival rate [4][5][6].With advancements in the quality of fetal ultrasonography (US), CPAMs are increasingly detected in the prenatal period [7] which has led to the evolution of management strategies that continue to improve peri-and postnatal prognosis [8].

Case presentation
A 23-year old primigravida presented at the clinic in April 2020.Her routine ultrasound (US) at 19 gestational weeks (GW) revealed a fetus with ascites and a large hyperechogenic, homogenous lesion (5.25 Â 3.58 cm) that occupied the left lung.A hypoplastic contralateral lung measuring 1.0 Â 1.5 cm and extreme cardiac dextroposition was visualized.Fetal US revealed typical features of type 3 CPAM (Figure 1).Routine screening for cytomegalovirus, toxoplasmosis, rubella, and parvovirus B19 was negative.Intrauterine paracentesis was performed and 80 ml of peritoneal fluid was aspirated from the fetal peritoneal cavity.Amniocentesis performed concurrently revealed a normal karyotype (46, XX).
At 22 GW, due to the re-accumulation of peritoneal fluid, 80 ml was drained in a second fetal paracentesis.During this stay, a course of steroids (Dexamethasone 4 Â 6 mg) was given as a possible treatment of type 3 CPAM.The presentation of CPAM in US did not change and there were no signs of fetal heart failure.The CPAM-volume ratio (CVR) was 3.02.
At 25 GW, due to increasing ascites, a peritonealamniotic shunt was placed twice but was displaced both times, and the effect was thus unsatisfactory.At the same time, polyhydramnios was detected (Amniotic Fluid Index [AFI] 33 cm) and amnioreduction (2000 ml) was performed.
At 28 GW, the patient was readmitted for fetal assessment and observation.Fetal hydrops was diagnosed at this time with the presence of ascites, mild hydrothorax and subcutaneous edema (Figure 2).There were no sonographic or Doppler signs of fetal heart insufficiency.A second amnioreduction (2000 ml) was performed but polyhydramnios redeveloped soon after (AFI 36 cm).Fetal MRI was performed at 29 GW to rule out bronchial atresia and confirm the diagnosis of type 3 CPAM (Figure 3).At 33 GW, soon after premature rupture of membranes, the patient naturally delivered a baby girl (2814 g, Apgar 2,6,6).
After birth, the baby girl presented with respiratory distress and was placed immediately on invasive oscillatory ventilation.General poor condition with oxygen delivery 1.0-0.4necessitated total parenteral nutrition.Later, poor sucking and swallowing justified PEG placement.Plain film radiography and neonatal computed tomography (CT) were obtained in the next three days (Figures 4 and 5).CT confirmed the absence of arterial systemic feeding vessels, and she was qualified for a two-stage partial left lobectomy.The first surgery was performed on day 14, removing the lower 45% of the left upper lobe (Figure 6).Closure of the left upper lobe bronchi led to significant desaturations, which demonstrated that this lobe did in fact contain viable lung tissue.As a result, only the lower 45% of the left upper lobe could be safely removed, and the problem of restricted thoracic volume remained.Ventilation between the two stages was a significant challenge for neonatal intensivists, as it was necessary to balance ventilation of a cystic and noncompliant upper left lobe, an atelectatic lower left lobe, and a hypoplastic right lung.The only way to avoid severe barotrauma was to place her on oscillatory ventilation with deep sedation and use of paralytic agents, where she remained for five weeks.There are no neonatological guidelines dictating the longterm use of ventilation and sedation in such a unique  situation.This strategy appeared to be effective, and it was possible to reduce oxygen delivery from 100 to 40% during this period.
The second surgery was performed shortly after to remove necrotic portions of the left upper lobe.Plain films from February 2021 revealed significant anatomic improvement (Figure 7).Histopathology of excised tissue confirmed cysts <2 cm.As of the time of writing, the baby has achieved her first year of life.Her growth and developmental milestones are delayed by approximately 3 months.This is attributed to poor abdominal tone, leading to difficulties with crawling and sitting.She is followed up frequently with specialists including otolaryngology, physiotherapy, speech therapy, and pediatrics.
Written informed consent was obtained from the patient for the publication of this case.

Natural history of CPAMs
CPAMs typically peak in size at 28-30 GW [9].Spontaneous prenatal regression occurs in approximately 8-49% [10] and always during the third trimester.These range from shrinkage of the malformation by up to 90%, or complete resolution of the lesion on US prior to birth [11].Because of premature delivery, it is not known whether this large CPAM would have regressed had the pregnancy come to term, but generally, the size of the lesion in our case remained stable, measuring 5.25 Â 3.58 at 23 GW and 5.84 Â 4.44 at 31 GW.Approximately 15% of CPAMs regress after birth [2,9] which we did not observe due to early surgical resection.
Fetal clinical presentation varies according to lesion size, and affected fetuses may suffer from mediastinal shift, hydrops, polyhydramnios, and fetal death [5].Large symptomatic lesions are associated with high in utero mortality.Because of the potential for dynamic lesion growth, serial US assessment throughout pregnancy is the standard of care [8].The CVR was developed as a predictive marker for life-threatening complications, and is determined by ultrasonographic assessment of lesion volume to head circumference.CVR !1.6 was shown to be highly predictive of fetal hydrops [12]; however, there is no international consensus of CVR thresholds for the prediction of fetal/ neonatal outcomes, and its utility should be established in further studies [13].The CVR of 3.02 in our patient is nevertheless a significant finding that suggested a significant risk of respiratory distress within 24 h of birth, and is associated with the need for surgical intervention within 2 years [14].

Diagnosis and radiologic imaging
CPAMs occur sporadically, and there are no known direct associations with any genetic or maternal risk factors [1].The association of CPAMs with chromosomal abnormalities has been reported to occur in the setting of other congenital malformations such as diaphragmatic hernia and congenital heart disease [15].A case of CPAM was diagnosed in a fetus with mosaic Kleinfelter syndrome [16], and a recent case described CPAM in mosaic trisomy 5 [17].
Traditionally, CPAMs are classified using the Stocker criteria [18].Based on radiologic and pathologic data, the modified Stocker criteria differentiate CPAM into five subtypes, with type 1 (large cysts, 2-10 cm) and type 2 (small cysts, <2 cm) occurring with greater frequency.However, the basis of this classification remains a point of contention [3].It is clinically more useful in the antenatal period to apply ultrasonographic criteria, with Adzick et al. [19] differentiating CPAMs into macrocystic (>5 mm) and microcystic (solid, echogenic masses in proximity to normal lung tissue) [20,21].Furthermore, a descriptive approach outlined by Langston can aid identification.For example, Langston describes Stocker type 3 as a CPAM that expands to occupy the whole lobe or lung, leading to compression of surrounding anatomy and fetal hydrops [22].This aligns closely with the clinical presentation of our case, despite the histopathological finding of Stocker 2 cysts.Our clinical decisions have been made with this in mind.It is our view that traditional and alternate classifications, together with clinical judgment, should be applied carefully to improve management and prognosis [22].In fetal US, a CPAM appears as an obstructive lung mass that is first suspected at 16-20 GW [23].The sensitivity and positive predictive value demonstrated by US for the detection of CPAMs is 93 and 76%, respectively [7], and in many cases, US is sufficient to confirm prenatal diagnosis [2].Furthermore, US is the main modality for the assessment of fetal hydrops, thus has high prognostic value as well as being a reliable diagnostic tool.
However, because of overlapping ultrasonographic features, CPAMs may be hard to distinguish from other CLMs, as many lung lesions on fetal US are known to cause mediastinal shift, diaphragmatic eversion, and fetal hydrops [24].The sensitive detection of systemic feeding vessels to the lesion is also low [7].Prenatal MRI was shown by Pacharn et al. [25] to accurately reflect postnatal imaging and pathological findings in 98% of cases.This modality is increasingly implemented as part of the diagnostic work-up [7] and in the decision-making surrounding in utero interventions and delivery [26].Furthermore, the clarity of MR imaging is not limited by maternal body habitus, amniotic fluid volume, or fetal positioning.Due to the rarity of type 3 CPAM, a prenatal MRI was obtained from our patient as part of differential diagnosis.Notably, MRI alone does not appear to provide any diagnostic or prognostic advantages over US, and does not influence postnatal management [5].
Computed tomography (CT) has the highest diagnostic specificity of the three modalities, and is the gold standard in the postnatal detection of CPAMs [27].The baby received a postnatal CT on the third day of birth as part of preoperative counseling [7], and a control CT was also performed between the two stages of the partial lobectomy.
Operative fetoscopy may be another diagnostic tool in the arsenal of maternal-fetal medicine.In a single patient report, Chon et al. successfully utilized fetal tracheobronchoscopy for both CPAM diagnosis and therapeutic disimpaction of bronchial debris.This invasive procedure is not without substantial risks to the fetus, and very few cases utilizing fetal tracheobronchoscopy have been published in the literature [24,[28][29][30].

Treatment strategies
In CPAM types 1 and 2, treatment can be initiated in utero, and these include the placement of peritonealamniotic shunts and cyst aspirations [9].Large macrocystic lesions typically respond well to these interventions.In contrast, type 3 CPAMs invariably require surgical resection.Fetal surgery is a high risk procedure that is only attempted in select institutions [5,31]; morbidity and mortality are high, with studies documenting a 50% survival rate [6,20].Open fetal surgery is not performed at our specialist center.
Type 3 CPAM in our patient led us to take conservative measures.A peritoneal-amniotic shunt was placed twice to reduce fetal ascites, though the results were unsatisfactory.A course of maternal steroids was given at 22 GW.Other than stimulating the growth of the hypoplastic right lung, steroids have been shown to significantly increase fetal survival by reducing the size of microcystic (but not macrocystic) CPAMs (CVR !1.6), which may lead to the resolution of hydrops [20,32].The pharmaco-mechanism of steroids on CPAMs is unknown and steroid-prescribing practices among obstetricians vary widely [10,20].In our patient, the therapeutic effect of steroids was only minimal.
Percutaneous sclerotherapy is a developing intervention that has been shown to be successful in four patients with CPAM types 2 and 3, and its safety and efficacy remains open to study [21].

Postnatal care
Surgical resection is the standard of care for symptomatic neonates in order to prevent lung infections, allow for compensatory lung growth and reduce future complications [3,5].The prognosis after surgery appears to be good [33].Ben-Ishay et al. [9] performed life-saving pneumonectomies for a series of giant CPAMs, but lobectomy via thoracoscope (including video-assisted thoracoscopic surgery) or thoracotomy remains the most prevalent surgical method [34].Lung sparing techniques such as segmentectomy and wedge-resection are also proving to be safe and efficacious, with excellent early and late outcomes [35].In our baby girl, respiratory distress and desaturations prompted an immediate surgical consultation and qualification for partial lobectomy.Completion within 2 months of birth has led to rapid anatomic improvement and only minor delay in developmental milestones.

Conclusion
Type 3 CPAMs complicated by fetal hydrops are associated with high perinatal mortality.While open fetal surgery remains a viable option at select specialist centers, antenatal interventions are typically ineffective and survival is less than 5%.The CVR of 3.02 was a significant predictor of neonatal respiratory distress and prompted the consideration of early surgical intervention.Partial lobectomy allowed for the compensatory growth of healthy lung tissue, but the lack of guidelines for ventilation in this setting was a significant challenge for neonatal intensivists.The baby's positive outcome can be attributed to prenatal management and early postnatal surgical intervention; furthermore, she may expect a good quality of life.Multidisciplinary vigilance and collaboration with frequent specialist follow ups were the key to success for both mother and child.

Figure 3 .
Figure 3. Fetal MRI performed at 29 gestational weeks.T2-Weighted images in axial (a), coronaloblique (b, c) and sagittal oblique (d) planes.Enlarged left lung ( Ã ) compressing the fetal heart (H) and displacing it to the right side.Vestigial right lung (arrow).Free fluid in the abdomen.

Figure 4 .
Figure 4. Plain film radiographs obtained July 2020 (Day 1).AP projection.Right-sided deviation of the trachea (T), endotracheal tube in situ.Hypoplastic right lung RL.Coarse opacities in left lung (LL).Protuberant abdomen due to ascites secondary to fetal hydrops.

Figure 6 .
Figure 6.Chest CT (sagittal) obtained in August 2020 between the first and second partial left lobectomies.Left lung (LL) measuring 4.28 cm.Endothoracic tube in situ after post-lobectomy air leak.

Figure 7 .
Figure 7. Plain film radiographs obtained in February 2021.Anatomical improvement of thorax compared to previous study.Trachea at midline, endotracheal tube in situ.Resolution of abdominal ascites.