To the Editor,
A male fetus was diagnosed antenatally with large left CPAM. It was
identified at the anomaly scan, and noted to be unusually large with
mediastinal shift. (Figure 1) This persisted throughout the
antenatal period with no regression. He was born by induced vaginal
delivery at 38+4 weeks, weighing 3.09kg. He immediately required
mechanical respiratory support. Further instability in his respiratory
function led to several escalating modalities, including inhaled nitric
oxide iNO at 20ppm. He also developed circulatory failure, mixed
acidosis and hypotension thus was commenced on adrenaline up to
0.3mcg/kg/min. The Chest X-ray (figure2A) showed a large lesion
occupying the entire left hemithorax with significantly right-shifted
mediastinum. A chest CT (Figure2B) confirmed a likely CCAM
multicystic lesion with air-fluid levels in LUL. On cardiac
echocardiography a small muscular ventricular septal defect was
detected. The respiratory and circulatory dysfunction continued to make
his condition parlous and surgical treatment was considered to reduce
mediastinal shift. Surgery (left upper lobectomy) was performed on day 1
with good post-operative recovery. There was prolonged air leak from
chest drain, that was removed after 14 days. His functional lung reserve
appeared initially low and he was supported with non-invasive
ventilation for a prolonged period to support growth and recovery. He
was discharged at 8 weeks of age, supported by nocturnal non-invasive
ventilation (CPAP) and NG tube feeding.
Histology confirmed type 1 CPAM (with focal areas of type 2 histology)
and highlighted multiple foci of mucinous cells lining the wall of the
cysts and focally showing lepidic growth pattern, best regarded as
mucinous BAC arising in a CPAM (figure 3) , however the lesion
was completely resected. Cytogenetic study on DNA extracted from the
sample tested by MALDI-TOF mass array spectrometry for 28 activating
variants in KRAS identified the KRAS c.35G>A p.(Gly12Asp)
variant.
Following the diagnosis, the paediatric oncology team were consulted.
Modified staging was undertaken and no evidence of metastatic spread was
seen. A repeat CT at six weeks of age showed no contemporaeous lesions
in the other lung. The oncology team recommended no further adjunctive
therapy and considered the lesions curatively treated. Long term follow
up with regular imaging will be required.
Congenital pulmonary airway malformations (CPAM) consist of a spectrum
lung malformations affecting different portions of the tracheobronchial
tree. The incidence of CPAM is estimated at 1/25000–1/35000 births.
CPAM is often diagnosed antenatally by ultrasound, allowing prompt and
appropriate medical and surgical management after birth. The natural
history and clinical spectrum of CPAM is highly variable. This can range
from complete regression antenatally to life-threatening hydrops
fetalis. It may present significant cardiorespiratory compromise at
birth as seen in our patient. Moreover, the potential for malignant
transformation is recognized in CPAM. The most commonly used
classification in the pathology literature is the revised Stocker
classification1 who described five types of CPAM
(types 0-4) based on cyst size and histology. Stocker proposed changing
the name from CCAM to CPAM since the lesions are cystic in only three of
the five types, and adenomatoid in only one type. The distinction
between histological subgroups remains important, as some types of
cancer are more common in some histologic types of CPAMs. Almost all
reported cases in the literature arise in type 1 CPAM. The suggested BAC
incidence is approximately 1% of type 1 CPAM 2. The
majority of patients developed BAC in an older age. There are only a few
patients under age of 16 with type 1 CPAM who developed BAC, with the
reported youngest age being 6 years3. Occasional
neonatal or infant BAC in CPAM has been reported. Clusters of mucogenic
cells are believed to be the precursor cells of mucinous BAC and are
described in type 1 CPAM. Mutation of KRAS has been reported in cases of
BAC arising in CPAM4. However, the molecular mechanism
of CPAM malignant transformation is still largely unknown. KRAS mutation
occurs most frequently in codon 12 and 13 in exon 15,
which were observed in the previously reported BAC cases in type 1 CPAM
as well as this case. Some authors suggest that.malignant transformation in type 1 CPAM may be strongly associated with
this mutation2. Therefore, the concept of malignant
transformation in the sequence from type 1 CPAM to mucous cell
hyperplasia to atypical adenomatous hyperplasia to BAC and invasive
adenocarcinoma due to K-ras mutation has been proposed. Surgical
excision remains controversial in children with practice varying widely
between services. It is recognised that excision prevents complications
including recurrent infections, pneumothorax and malignancy, in addition
to treating the morbidity of CPAM itself, even in asymptomatic cases.
In conclusion, CPAM is a rare congenital pulmonary malformation that may
cause respiratory distress in the newborn. Diagnosis by prenatal US
allows better parental information, fetal supervision, and detection of
associated malformations as well as medical and surgical management
immediately after birth, including early surgery. The potential for
malignant transformation, usually mucinous BAC, is recognized in type 1
CPAM. The case supports the relationship between type 1 CPAM and lung
mucinous BAC/KRAS mutant, and highlights that malignant transformation
can occur in very early stage of the infancy in patients with CPAM. In
light of these rare cases, the presence of mucinous epithelium in CPAM
and completeness of resection should be documented for follow-up
purposes.