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.