DISCUSSION
Alveolar growth abnormalities (AGA) usually present after birth and can occur as a result of multiple factors. They may be related to 1) pulmonary hypoplasia seen in situations limiting in utero lung growth, 2) prematurity-related chronic lung disease, 3) term infants with early onset chronic lung disease, 4) children with congenital heart disease who have a normal karyotype, and 5) children with chromosomal abnormalities (including trisomy 21 with or without associated congenital heart disease, and other chromosomal abnormalities).
Regardless of the underlying etiology, AGAs share the common feature of alveolar growth arrest leading to alveolar simplification on histopathology. This simplified alveolar pattern is reminiscent of the rudimentary lung in fetal life, which has dilated alveolar sacculi. The overall reduced alveolar density results in a smaller gas-exchange surface area. Ancillary changes may occur in the surrounding interstitium, including pulmonary interstitial glycogenosis (PIG) and hypertensive arteriopathy in the pulmonary artery branches (11,12,13).
Cystic lung disease in Trisomy 21 was first reported by Joshi et al (14) in the autopsy specimens of two infants with AVSD. These were evident as multiple 2-4 mm sized cysts lining the subpleural surfaces of the lungs anteromedially, with cystic dilatation of the alveoli on microscopic examination. In a postmortem study by Gonzales et al (4), subpleural cysts were described in specimens of 18/89 (25%) children with Trisomy 21 (9 stillborn fetuses and 80 infants). Interestingly, none of the stillborn fetuses had subpleural cysts and only one neonate (3.5 weeks of age) was found to have subpleural cysts. The authors concluded that formation of the subpleural cysts occur due to immaturity/dysmaturity of alveoli in their later stages of development (phase of alveolarization). As such these changes were not present in fetal and neonatal life.
While this entity became reasonably well documented in association with Trisomy 21, our cohort shows subpleural cysts can be present in other conditions as well. Subpleural cysts are described with ancillary findings including interstitial glycogenosis and interstitial thickening in the regional interstitium, that can also be associated with alveolar growth abnormalities (12). However, the exact pathophysiological significance of subpleural cysts remains uncertain. Histopathological correlation places these cysts within the final stage of lung development of alveolarization, suggesting they are a form of altered alveolar growth. (2). The phase of alveolarisation is further divided into an ‘early phase’ of rapid alveolar growth that occurs from 36 weeks’ gestation to 3 years of age, and a slower phase that continues into later childhood. This stage also holds importance in laying an effective gas-exchange unit. with thinning of the intervening mesenchyme and further apposition of the alveolar walls (1,9,15,16).
Interestingly, we observed 4 cases for whom an initial scan demonstrated no cysts, but subsequent scans showed the interval development of cysts. This supports the observations by Gonzales et al that these cysts can develop due to abnormalities affecting the alveolar development beyond their fetal stage of development.
Previous studies have demonstrated the youngest children with subpleural cysts to be as young as 2 weeks and 3 months of age, respectively (5,7). The youngest child with subpleural cysts in our study was an 8-day old infant with antenatally detected pulmonary lymphangiectasia.
From their large database of 8000 cases, Gonzales et al could find only two cases with subpleural cysts who did not have Trisomy 21, one of which had CHD. By contrast, Trisomy 21 was not the most common clinical entity in our study population. In fact, we found that most cases (67%) did not have Trisomy 21. This might be related to improved contemporary genetic analytic capabilities as compared to previous studies, or to CT related factors including improved spatial resolution and accessibility. Gyves et al (17) were the first to report that subpleural cysts in children with Trisomy 21 can be seen on CT alone, and not chest radiographs. We anecdotally found a similar low sensitivity of radiographic detection of subpleural cysts, suggesting a higher true incidence of these cysts given the limited indications for CT.
The size of these subpleural cysts has been described as 1-2 mm (4,7). This correlates with our findings of cysts between 1-2 mm in most cases at initial CT. Interestingly however, cysts did enlarge in subsequent CT’s in children with follow-up imaging.
As can be seen in Table 2, bilateral lung involvement predominated. This is in concordance with the literature, where Biko et al. reported unilateral involvement in only one of the nine (11%) cases and Lim et al described unilateral involvement in only three of their ten cases (30%) with Trisomy 21. Bilaterality would be expected in children with an abnormality of alveolar development, diffusely affecting the concomitantly developing lungs.
Pneumothorax was not observed in any of our cohort, despite the precarious subpleural location of these cysts, especially in the presence of positive-pressure ventilation. We also could not find any report of pneumothorax complicating these cysts in the literature. Microscopically, these cysts have definable walls of varying thickness, which may prevent their rupture. Histopathological findings from our study, as well as existing evidence from cases of Trisomy 21 (2) and Trisomy 18 (10), suggest that these abnormal alveoli indeed have thick walls. The intervening interstitium is also thickened in these cases due to the presence of a primitive capillary network. We believe that these features of dysplastic alveoli and rudimentary capillary network confer them with relative protection against the subsequent development of pneumothorax.
Although 66% of our cohort had a history of prematurity, the distribution of cysts did not suggest that these are attributable to prematurity alone. Parenchymal cysts in chronic lung disease of prematurity are more randomly distributed within the lungs. Paradoxically in our cases, these cysts predominantly or exclusively involved the subpleural lungs, thereby suggesting an alternate etiology.
The exact impact of these cysts on lung function remains elusive as their impact on the cardiopulmonary status is often difficult to ascertain. There remains ambiguity for the potential role, if any, of these alveolar growth abnormalities in the development of PAH.
We believe that these subpleural cysts represent dysplastic alveoli and alveolar ducts. The extent to which they contribute to respiratory compromise is likely variable and partially dependent on other underlying co-morbidities, particularly congenital heart disease. Limited cardio-respiratory reserve and vulnerable conditions could theoretically unmask the inability of these immature and dysplastic alveoli to provide an efficient gas-exchange unit. It has been proposed that this could worsen a hypoxemic state, which sets a vicious cycle of worsening PAH that in turn affects alveolar ventilation and vice-a-versa (2,11).
Our study demonstrates the non-specificity of subpleural cysts to Trisomy 21. As such, we believe that these cysts represent a growth abnormality of the lung that can be seen in other conditions, consisting of, in part, alveolar simplification, peripheral acinar enlargement and resultant overall pulmonary alveolar hypoplasia. CT can be performed to identify subpleural cysts as evidence of underlying lung maldevelopment.
The most significant limitation of our study is the small number of children who manifest subpleural cysts at CT. Due to a small sample size, we could not establish a definitive association of these cysts with co-morbidities and long -term outcome. Subsequent studies of larger sample sizes could help to clarify the role of this degree of pulmonary dysmaturity in cardio-respiratory compromise.