development of lung, congenital malformations of lung

1. Development of lung,
Congenital malformations
of lung
Dr Susruth Reddy,
Moderator: Dr N Saravanan.

2. Embryonic period
• An understanding of lung development and maturation is
central to the care of preterm infants.
• The 1st lung appears as a ventral bud off esophagus just
caudal to laryngotracheal sulcus.
• Groove between lung and esophagus deepens and bud
elongates within surrounding mesenchyme and divides to
form mainstem bronchi.
• Subsequent dichotomous branching gives rise to
conducting airways.
• Branching of endodermal endothelium is controlled by
underlying mesenchyme.

4. Pseudoglandular stage
 The 15-20 generations of airway branching occur in
psuedoglandular stage from 7th to 18th week.
 The developing airways are lined with simple cuboidal
cells that contain large amounts of glycogen.
 Neiroepithelial bodies and cartilage appears by 9-10
weeks.
 Ciliated cells, goblet cells and basal cells are in
epithelium of proximal airways by 13 weeks.

5.  Epithelial differentiation is centrifugal in general.
 Regulators of branching morphogenesis are FGF-10, FGF-7,
TGF-alpha, EGF.
 Upper lobar development occurs earlier.
 In early stage, airways are surrounded by loose
mesenchyme with developing vasculature and capillaries.
 Pulmonary arteries grows in conjunction with airways.
 Pulmonary venous development occurs in parallel but with
a different pattern that demarcates lung segments and
sub-segments.

7. Canalicular stage
 Occurs between 16 and 25 weeks.
 Represents transformation of previable lung to potentially
viable lung that can exchange gas.
 Bronchial tree has completely branched and respiratory
bronchioles are forming.
 Major events are appearance of acinus, epithelial
differentiation with the development of potential air-
blood barrier, and the start of surfactant synthesis with
type-II cells.

8.  The acinus in the mature lung is the tuft of about 6
branching generations of respiratory bronchioles, alveolar
ducts, and alveoli originating from a terminal bronchiole.
 This saccular branching is the first step for the
development of future gas exchange surface of the lung.
 Mesenchyme surrounding the lung becomes more vascular
and more closely approximated to the airway epithelial
cells.

9.  Capillaries initially form as a double capillary network
between future airspaces and subsequently fuse to form a
single capillary .
 A structure comparable to future adult air-blood barrier
forms, with fusion of vascular and epithelial basement
membranes.
 If the double capillary network fails to fuse, it may lead
to alveolar capillary dysplasia.
 By the end of canalicular stage, surface area occupied by
air-blood barrier begins to increase exponentially.

10.  Epithelial differentiation is characterized by proximal to
distal thinning of epithelium by transformation of cuboidal
cells into thin cells that line the tubes.
 Tubes grow in length and width with attenuation of
mesenchyme, which simultaneously becomes vascularized.
 Many of the cells are characterized as intermediary cells.
 These epithelial cells develop attenuated extensions as
well as some characteristics of mature type-II cells such as
lamellar bodies.

11.  After 20 weeks in human fetus, cuboidal cells rich in
glycogen begin to have lamellar bodies in their cytoplasm.
 TTF-1, FOXa1, FOXa2, GATA6 mediate type-II cell
differentiation.
 Glycogen in type-II cells provides substrate for surfactant
synthesis as lamellar body content increases.

12. Saccular and alveolar stages
 Saccular stage encompasses the period of lung
development during the potentially viable stages of
prematurity from 24 weeks to term.
 Terminal sac or saccule is the developing respiratory
bronchiole or alveolar duct that is elongating, branching
and widening prior to initiation of alveolarization at about
32 weeks in fetal human lung.
 Alvelolarization is initiated fro these terminal saccules by
the appearance of septa in association with capillaries,
elastin fibers, and collagen fibers.
 Shallow alveolar structures can be identified by 28 weeks
of gestation.

13.  Alveolar numbers increase rapidly from about 32 weeks of
gestation to term when human lung contains about 50-150
million alveoli.
 Adult human being has about 500 million alveoli.
 Potential lung gas volume and surface area increases from
25 weeks to term.
 Traditional view was that alveolar development was
completed by early childhood.
 Narayanan et al. demonstrated that alveolar formation
occurs till 20 years of age.

17. Congenital lung malformations
 Congenital lung abnormalities or bronchopulmonary
malformations are increasingly identified in perinatal
setting.
 Use of ultrasonography with improved resolution for
antenatal screening, along with supplementary fetal MRI
has increased detection of pulmonary lesions.
 A large percentage of these lesions will remain
asymptomatic in neonatal period and later.

18.  Embryonic phase is critical for development of
rudimentary tracheobronchial tree and lung buds.
 Interruption of this process may result in lung
abnormalities.
 Pseudoglandular phase disruption may result in formation
of formation of congenital pulmonary airway
malformations type 1,2 and 3.
 Bronchopulmonary sequestrations, with abnormal lobar
budding creating a supernumary lobe termed intralobar
sequestration or extralobar sequestration.

19.  Bronchomalacia or dysplastic cartilage formation may
occur during this phase and contribute to congenital lobar
emphysema.
 During saccular and alveolar phase, compromise to
respiratory bronchioles and alveoli can result in
pulmonary hypoplasia.
 Endoluminal obstruction from mucosal hyperproliferation
or thick mucus can result in hyperexpansion of a lobe and
lead to CLE.
 Large lesions may result in hydrops and fetal death.

20. Congenital pulmonary airway
malformation(CPAM)
 CPAM previously called congenital cystic adenomatoid
malformations(CCAM), is the most common of pulmonary
abnormalities.
 More prevalent in lower lobes with equal left to right-
sided distribution.
 Cyst formation occurs at terminal bronchioles.
 There is proliferation of mucosa, increased smooth muscle
and elastin in the walls, mucus-producing cells, absence
of inflammation.

21.  Classified by Stoker into 3 types, now been expanded to include
5 subtypes:
• Type 0(rare):limited to upper tracheobronchial tree.
• Type 1(70%): Macrocystic with size more than 2 cms, with
dominat single or multiple cysts.
• Type 2(20%): Multicystic cyst with size less than 2 cms.
• Type 3(10%): Microcystic adenomatoid solid without cystic
elements and associated anomalies. Worse prognosis.
• Type 4(rare):Hamartomatous malformation in distal acini with
peripheral cysts. Difficult to distinguish from type 1
pleuropulmonary blastoma.

22.  Morotti et al, divided CPAM into 2 major subtypes
 One subtype consisting of type 1,2,3 that show a
bronchiolar-type epithelial differentiation.
 Other subtype consisting of CPAM type 4 showing acinar-
alveolar epithelial differentiation.

23.  CPAM is caused by focal arrest in lungs at different stages
of branching of pulmonary tree.
 1st subtype(CPAM bronchiolar types 1,2 and 3) at
pseudoglandular stage and 2nd subtype at type 4 at
saccular stage.
 Several molecular mechanisms have been identified and
contributed to understand pathogenesis of CPAM.

25.  A more clinically applicable classification delineates 2
groups:
• Macrocystic cysts->5mm cysts.
• Microcystic cysts-<5mm cysts.
Macrocystic lesions communicate with airways which can
lead to air trapping

27. Bronchopulmonary sequestration
 Abnormal arterial inflow from systemic circulation rather
than pulmonary.
 A large feeding artery often arises from aorta and supplies
sequestration.
 This arterial branch can arise from above or below
diaphragm.
 Classified into 2 types:
• Intralobar sequestration(ILS)
• Extralobar sequestration(ELS)

28.  Venous return is variable with ILS draining via pulmonary
venous channels and ELS draining into systemic veins,
frequently azygous veins.
 ILS pleura is contiguous with adjacent lung, essentially
sharing same visceral pleura, and ELS has its own
independent pleural covering.
 Arise due to formation of supernumerary lobe during lobar
budding.
 ILS budding being proximal to the main lung bud and ELS
budding being distal to lung bud.

29.  They do not connect to the tracheobronchial tree, but ILS
may entrap air by communicating with the pores of Kohn
in normal lung tissue.
 BPS is usually located in the lower thorax.
 ELS can be found below the diaphragm.
 Hybrid lesions composed of both sequestrations and type 2
CPAM components also occur.

31. Congenital lobar emphysema
 Occurs as a result of over distension of one or more lobes
that impair ventilation and can result in life-threatening
compromise.
 This can result in air entrapment and ball-valve effect.
 Also, external compression by other tracheobronchial
lesions or abnormal vasculature have been implicated.
 Occurs more commonly in upper lobe in 40-45% cases,
right upper in 20% cases.

32.  Right middle lobe is involved in 30-40% cases.
 Lower lobes are les frequently affected.
 If not diagnosed antenatally, 25% cases present after
delivery, 50% by 1 month of age.
 In large lesions or aggressive positive pressure ventilation,
infants present with life-threatening complications.

34. Bronchogenic cyst
 Primarily abnormalities related to tracheal and foregut
budding and occur in mediastinum in 85% of time.
 Can occur in lung at interparenchymal location at 12% of
time.
 Located in lower lobes with equal distribution on both
sides.
 Histologically thin walled cysts with a bronchial epithelial
lining and mucus secretion, and do not communicate with
the tracheobronchial tree.
 An initially large cyst, haemorrhage into cyst, pr infection
with rapid expansion can occur and may cause acute
respiratory or cardiovascular compromise.

36. Antenatal imaging
 Antenatal/prenatal diagnosis has evolved over years.
 Ultrasound can identify echogenic lesions in lung
parenchyma and application of B-mode Doppler allows for
examination of blood supply.
 Antenatal MRI can also be used for detection of lesion.
 USG reveals fetal lung and identifies normal appearance
and then determines homogenous versus heterogenous
areas.

37.  CPAM
• Today, routine USG complemented with MRI has become
increasingly valuable in detecting CPAM’s.
• CPAM’s can be identified at 18-21 weeks of gestation,
increase in size upto 28 weeks of gestation.
• Some CPAM’s undergo regression and vanish later.
• Before the advent of prenatal USG, CPAM’s were
diagnosed only in symptomatic infants or as an incidental
finding.

38. • USG is the imaging modality of choice to screen CPAM.
• MRI is an excellent option for morphological and
volumetric evaluation of fetal lung.
• CPAM’S shows hyperechoic heterogenous parenchyma with
hyperechoic cystic areas.
• Fetal MRI shows T2-hyperintense lesions, helpful in
differentiating surrounding normal tissue.

39.  When the USG findings are equivocal or images are
difficult to interpret, sucha as in late pregnancy or
inaccessible fetal position, MRI is the choice.
 Colour Doppler is used to investigate systemic arterial
blood supply.
 CVR predicts increased risk for hydrops fetalis.

40. Bronchopulmonary sequestration:
• Appear hyperechoeic and generally homogenous, Doppler
USG will identify feeding systemic artery frequently from
aorta.
• On MRI, appearance of BPS is similar to CPAM, with
hyperintense lung parenchyma.

41.  CLE
• Difficult to identify on antenatal examination.
• MRI will show a hyperintense lesion indistinguishable from other
CLA’s.
 Bronchogenic cysts
• Typically located near carina but can be found in lung
parenchyma.
• USG reveals anechoic well defined mass.
• MRI reveals homogenous hyperintense lesion on T2 imaging.

42. Treatment
 Antenatal diagnosis allows treatment strategy to be
planned before delivery.
 Lesions that produce severe respiratory compromise may
require emergency intervention.
 Asymptomatic lesions will follow elective approach.
 Of primary concern in the management is risk of
malignancy developing in the lesion.
 Recommendation for an observational approach includes
follow-up and imaging studies to assess any changes in the
lesion.

43.  CPAM:
• Prenatal management includes maternal steroids,
minimally invasive procedures or open fetal surgery.
• These interventions aim to allievate mass effect, prevent
progression of complications, to improve fetal outcome.
• In macrocystic lesions, decompression can be attempted
by permanent drainage via TAS by USG or single needle
thoracocentesis.

44. • In microcystic lesions, open fetal surgery may be
indicated.
• Maternal betamethasone has been suggested to have
beneficial effects on large microcystic CPAM’s.
• Before prenatal intervention, it is recommended to
characterize the lesion, and to identify associated
anomalies by USG, MRI, Echocardiogram.

45. • EXIT procedure was initially used for reversing tracheal
occlusion in CDH.
• Hallmark is prolonged intrauterine relaxation with deep
inhalational anesthesia, leading to preservation of
uteroplacental blood flow and gas exchange.
• Major indications are fetal lung mass with mediastinal
shift, hydrops associated with persistently elevated CVR.

47.  Postnatal evaluation should begin with clinical assessment
of respiratory status and chest radiography.
 Radiography-hyperlucent cystic areas in type-1 and 2
lesions.
 Type-3 may be radio opaque.
 There may be mediastinal shift and rarely pneumothorax.

48.  CT scan of the chest with IV contrast should be performed
for surgical planning.
 If infant is asymptomatic, CT scan should be obtained
after 6 and 8 weeks of delivery.
 Surgical treatment to resect the lesions is current
standard of treatment.
 Timing is variable, traditionally performed at 1 year age,
some recommend at 3 months of age.

50.  Complications are pneumonia and infection of cystic
elements.
 Repeated infections may cause scarring and adhesions.
 Spontaneous pneumothorax and malignancies can occur.

52.  Bronchopulmonary sequestration:
• Initial approach is similar to CPAM.
• Lesions are rarely symptomatic.
• Need for emergency surgery is rare.
• Some lesions may be safely observed.

53.  Congenital lobar emphysema:
• Initial approach is similar to other CLA’s.
• CT evaluation can be performed in early neonatal period,
with plan for early surgical intervention.
• Therapeutic intervention should be aimed at avoiding
subsequent catastrophic respiratory decompensation.

55.  Bronchogenic cyst:
• Lesions are identified on chest radiography and CT in
postnatal period.
• Symptomatic lesions require immediate surgery, where as
asymptomatic lesions are noted and evaluated.
• May undergo malignant transformation.

56. References
 Fanaroff textbook of neonatology.
 Congenital lesions of lung, Neoreview article 2016.
 Prenatal and postnatal management of CPAM, Neonatology
article 2016.

57. THANK YOU