1. Journal Club Dr. Ronly Har-Even Cohn Pulmonology Fellow (PGY 6),
Cross Canada rounds Nov 2017
Division of Pediatric Pulmonology
Stollery Children’s Hospital, Edmonton, Alberta, Canada

2. An article that was published in archives of diseases in childhood in June 2017.
And I choose it because I think that it presents a very important and a relevant topic.

3. objectives
Learn about CLM, CPAM, PS- presentation, complications and management.
Review the study-” The natural history of prenatally diagnosed congenital cystic lung lesions: long term follow-up of 119 cases”.
Appraisal of the above study
JAMA critical review.
Review of the editorial.
Future directions.
Discussion.

4. The importance of this study
Continue debate regarding postnatal management of asymptomatic CPAM/ PS.
One of the largest case series of CPAM and PS following prenatal diagnosis.
The conservative treatment has the longest median length of follow up that has been published so far.
this study is

5. Intervention- Children were conservatively treated.
PICO Evaluation
Patients-Children born between diagnosed with CPAM/PS on prenatal US, confirmed by postnatal CT imaging, referred to GOSH and followed up ≥5y.
Intervention- Children were conservatively treated.
Comparator- Surgical treatment electively/urgently.
Outcome- Malignant transformation, respiratory infections and pneumothorax.
Study-Descriptive, cohort prospective study from database on fetuses with CLM.
Great Ormond Street Hospital in London
CPAM/PS

6. CLm: congenital lung malformation
A heterogenous group of rare disorders that include:
CPAM-Congenital pulmonary airways malformations
PS-pulmonary sequestrations
Bronchogenic cyst,
Bronchial atresia,
Congenital lobar emphysema,
Hybrid form of these lesions.
What is CLM?

7. prenatally DETECTION of CLM increased with Technology improvement
Prevalence of prenatal detection of CLM per 10,000 births. Smaller asymptomatic lesions can be identified. The first CLM that was diagnosed antenatally was CPAM in 1975 in Australia.
As technology improves, our ability to identify CLM prenatally improved.
In fact the first CLM

8. CPAM: congenital pulmonary airways malformation
Nonfunctioning cystic lesion.
Prevalence at birth 1:8,300-1:35,000
>80% diagnosed antenatally.
Most common congenital lung lesion 25-30% of all.
M>F
Mostly Sporadically
Previously called CCAM- congenital cystic adenomatoid malformation.
Replacement of a portion of the lung by nonfunctioning cystic lesion.
Results from failure of the pulmonary mesenchyme to develop fully.
Although rare

9. CPAM: congenital pulmonary airways malformation
Lesions are hamartomatous:
contain cystic and adenomatous elements.
connected to the tracheobronchial tree
have blood supply from the pulmonary circulation.
usually unilateral and limited to one lobe

10. Question CPAM are classified according to their:
Location of the lesion in the airway
Radiologic features
Pathological characteristics
None of the above
a+c

11. CPAM-classification
There are 5 types of CPAM (types 0-4). (Stoker classification)
Classified pathologically, according to the level of the insult to the airways and the different stages of lung development.
This classification was not universally accepted, many pathologists classify CPAM as type 1 and 2.

12. CPAm- 5 types pathologically
Percentage
Location in the airways
Lesion description
Prognosis
Comments
Type 0
1-3%
From the trachea/bronchi and involve the whole lung
Solid, lungs are small and firm
Fatal- incompatible with life.
Type 1
60-70%
From distal bronchi or proximal bronchioles
One Large cyst 2-10cm, presentation may be late
Most common type –good prognosis
Associated with malignancy BAC (rare)
Type 2
15-20%
Bronchiolar origin
Multiple small cysts 0.5-2cm
Neonatal period
Poor prognosis
Associated with other anomalies
Type 3
5-10%
Alveolar origin
Small cystic area with solid tissue. Solid appearance
Respiratory distress in neonatal period/death
Severe
Type 4
10-15%
Acinar origin
Thin walled Large fluid filled/ air filled cysts up to 10cm.
Good prognosis
Associated with pneumothorax and PPB
Other anomalies for type 2- renal agenesis, Cardiovascular defects, CDH, syringomyelia
PPB-pleuropulmonary blastoma

13. CPAM -Imaging
A CXR in 1y old child who ingested a coin with an incidental finding of RUL large cystic lesion –type 1 CPAM.
A Chest CT of this 1y old child with a single large air filled cyst in the RUL- type 1 CPAM.

14. CPAM -Imaging
A CXR of a newborn with multiple small cysts in the RUL- CPAM type 2.
A Chest CT of a newborn with multiple small cysts in the apex of the RUL –CPAM type 2.

15. CPAM- clinical presentation
33% Diagnosed later in childhood
d/t complications
Prenatal presentation incidental/ pulmonary involvement
5-40% fetal hydrops
66% Asymptomatic at birth
25% -Symptoms at birth (resp distress)
variable
Respiratory distress due to mass effect compression of the CCAM and associated pulmonary hypoplasia.

16. cpam Diagnosis-recommendations
Family history of cancers/ cystic lesions (type 4-genetic predisposition).
Prenatal US+/- prenatal MRI.
CXR (all patients)
single lesions of large air filled cysts (type 1,4),
small numerous air filled cysts (type 2),
large solid mass (type 3)
Plain CXR often fail to detect CPAM in asymptomatic patients.

17. cpam Diagnosis-recommendations
Chest CT /chest MRI-for symptomatic patients-preoperative or for asymptomatic patients at 6m of age or earlier if in high risk for complications.
High risk for complications: large lesions, bilateral/multifocal cysts, family history of PPB, pneumothorax.
Definitive diagnosis- by histological examination.
Reference: Antenatal and postnatal management of congenital cystic adenomatoid malformation”. Kotecha S, et al. Paediatric respiratory reviews reviews 2012; 13:

18. Question What are the complications of CPAM ? infections pneumothorax
malignancy
all of the above
none of the above

19. PULMONARY sequestration- PS
A pulmonary tissue ,isolated from normal functioning lung , has blood supply from aberrant systemic arteries. It can have histology of CPAM- type 2 in 60%.
Can be infected/bronchiectatic/atelectatic
Intrapulmonary-
posterior basal segment of the LLL.
diagnosed late, after adolescence.
associated with other malformations.
Extrapulmonary-
beneath the LLL. 15% are abdominal.
diagnosed in infancy because of associated malformation.
M:F 4:1.
Intrapulmonary-within the lung parenchyma
Extrapulmonary-accessory to the lung.

20. PULMONARY sequestration
A CXR of a 4y old child with intralobar sequestration in the LLL.
A CT of a 2m old infant with bronchopulmonary sequestration (BPS). The top images demonstrate abnormal lung tissue (arrows), consistent with BPS, in the posterior right lower lobe. The lower two images demonstrate an extremely large feeding artery arising from the thoracic aorta just above the diaphragm (arrowhead).

21. Question
What is the current management suggested for treating CPAM/PS?
Surgery for all lesions
Conservative treatment and observation for all lesions
Surgery for symptomatic lesions and watch and wait for asymptomatic lesions.
None of the above
I cannot answer the question, further studies are needed.

22. Management of CPAM/PS
Symptomatic lesions in the neonatal period- surgical resection.
The surgery is curative.
Lobectomy preferred over segmentectomy and VATS preferred over open surgery.
Controversy about how to manage asymptomatic lesions.
Uncertainty about
The risk of recurrent infections
The risk of malignancy
If an elective surgery is done- it is done before the age of 1y.
If a surgery is done in asymptomatic lesions it is done before the age of 1y to avoid the majority of infectious complication.
Thoracoscopy is safe. Operative time is longer with that, however length of stay, analgesia requirements and long term cosmetic results improved.
What do surgeons do? Canadian survey in 2008 showed that 33% plan observation for asymptomatic lesions, however most of them later underwent resection.
UK survey showed that 24% don’t resect asymptomatic lesions, 20% always resect. The rest operate selected cases based on size.
Worldwide 70% of lesions underwent excision.

23. Management of asymptomatic CPAM/PS -controversy Surgical treatment versus Conservative treatment

24. Surgical versus Conservative treatment
Arguments for conservative treatment
Arguments for surgical treatment
In the past, lesions had been rarely diagnosed as pathogenic
Low risk of complications (low frequency of infections, extremely low risk of malignancy).
Can resolve spontaneously
No exposure to unnecessary surgical and anesthetic risks.
Prevention of complications such as malignant transformation, recurrent infections and pneumothorax.
Better compensatory lung growth in early age.
Fewer postoperative complications for elective surgery.
No exposure to repeated CT and long term follow up.
Psychological effect- “to do something”
Prior to fetal US development,

25. An article that was published in archives of diseases in childhood in June 2017.

26. Study question
Whether a conservative management is a reasonable option to treat asymptomatic patients with CPAM and PS?
from

27. Methods
Descriptive, cohort prospective study from database of fetus with CLM on prenatal US (CPAM/PS) that were confirmed by Chest CT.
Data collected:
Demographic details,
Postnatal CT imaging results,
Date of last clinic attended
Follow up status: continued/lost to follow up/discharged from follow up.
Surgical treatment if done: indications/age at surgery/histologic features.
Diagnosis of CLM made on prenatal US at the University College Hospital in London UK and referred to GOSH (Great Ormond Street Hospital).

28. Inclusion/exclusion criteria
Inclusion criteria:
CLM on prenatal US and Radiological confirmation of CPAM/PS on postnatal CT imaging.
Follow up for ≥ 5y (5-18y, median 9.9y).
Exclusion criteria: not reported
Exclusion criteria?

29. (36%) beyond neonatal period (9.2%) Recurrent infections
RESULTS
119 cases CPAM/PS
F (52%) M (48%)
Conservative tx
(57%)
Surgical tx
(43%)
(10%)
Discharged
(76%)
Asym, Continu F/U-9.9y
(12.5%) Lost to F/U
(6.7%) Emergency- neonatal period
(36%) beyond neonatal period
57%-68 patients
(17%) Elective consult
5.1 % Concern CT
(5.9%) Spont resolution
(9.2%) Recurrent infections
(0.8%) Severe LRTI
(4.2%)
Unclear

30. Results The only complication - recurrent infections.
Resection due to respiratory infections decreased >2y of age.
Resection due to respiratory infections disappear >5y of age.
No features of malignancy.
4 patients had spontaneous resolution.
In (53%) of the resected lesions, no evidence of inflammation.
Post operatively- no death recorded following elective surgery.
1 lesion (CPAM –Type 1) of the resected lesions showed an area of mucinous proliferation.
Other postoperative complications were not recorded.

31. Indication for surgery>neonatal period
Age of surgery for recurrent infections
Figure 1- the most common indication for surgery is elective advise followed by recurrent infections.
Figure 2- The median age to surgery for recurrent infection is 1.6y.

32. Radiologic/histologic diagnosis
119 patients CLM
Conservative FU (57%) –CT
CPAM-
(53%)
PS- (39%)
Hybrid lesion- (7.4%)
Surgical resection (43%)
CPAM (70.8%)
PS- (13%)
Hybrid lesion- (2%)
Others
Others: bronchial atresia, lobar emphysema, bronchogenic cyst..

33. Discussion
Arguments for surgical approach in all asymptomatic patients 1.Prevent malignancy 2. Prevent complications (infection/pneumothorax) 3.Early resection allow compensatory lung regrowth. 4.Elective resection decrease postoperative complications.

34. Complications –the Risk of malignancy-background
2 types of malignancy associated with cystic lung lesions:
PPB-Pleuropulmonary blastoma
BAC-bronchioloalveolar carcinoma
Picture of gross morphology of adenocarcinoma of the lung.

35. PPB- Pleuropulmonary blastoma
Rare lung tumor of childhood <500 cases worldwide.
Incidence 1:300,000.
3 types- type 1 is cystic, type 2-cystic+solid, type 3-solid.
Appeared before 6.8y but after birth. Only few identified antenatally.
30% are cystic form, resemble nonmalignant CPAM cysts.
Distinct lesion- Not a malignant transformation of CPAM/PS,
There is still a debate whether PPB is a distinct pathological entity or a malignant transformation of type 4 CPAM although most of the studies support distinct lesion.

36. PPB- Pleuropulmonary blastoma
Risk factors that support the diagnosis of PPB
Positive family history of associated tumors or cystic lesions.
Genetic diagnosis- mutation in DICER1 gene in 66%.
Bilateral and multifocal cysts.
Pneumothorax, pleural effusions.
Type 4 CPAM histologically overlap with grade 1 PPB (cystic lesion)
PPB-Can develop following prior resection of cystic lesion.
(ovarian, thyroid, renal tumors and renal cystic disease).

37. BAC-bronchioloalveolar carcinoma
BAC- Extremely rare in childhood. Usually in young adult/adult.
Transformation of cells within CPAM Type 1 in 1% of lesions.
No report of BAC diagnosed antenatally.
Discovered incidentally following resection of cystic lesion.
Chromosomal aberrations (K-RAS mutation) in the mucinous cell of type1.
Can occur following previous resection of CPAM in early life.
Mucinous cells hyperplasia within the cyst can extend into alveolar parenchyma consider as atypical adenomatous hyperplasia and then transform into BAC (non invasive) and then into adenocarcinoma (invasive).
Mucinous cell hyperplasia
Atypical adenomatous hyperplasia
BAC non invasive
BAC- invasive

38. Risk of malignancy- in this article
The results were similar to previous studies.
No evidence of malignancy was found in the resected lesions.
No concerns about malignancy in the asymptomatic patients.
Support the assumption that the risk of malignant transformation in early life is rare.
A risk of approximately 1% of malignancy in adolescence and adults cannot be ruled out.

39. Complications-Recurrent pulmonary infections -background
Recurrent infections is the most common complication. Can be the presenting sign or can occur later in the first few years of life. Frequency –varies: In some case series: 10-30% of infants developed infection within 1y versus other that showed only 3% risk of infection in the first 5y.
will develop infection

40. Risk of Respiratory infections-in this article
In this study:
Severe neonatal complications are rare- only 6.7% had emergency surgery due to respiratory compromise.
In post neonatal period, only 9.2% had surgery due to respiratory infections.
The risk of resection due to RI decreased>2y of age.
The risk of resection due to RI disappeared >5y of age.
Infection is not predominant indication for surgery
RI- respiratory infections

41. Risk of complications- pneumothorax in this article
There were no complications of pneumothorax.

42. Potential for compensatory lung growth following early resection
Arguments against :
New alveolar growth occur into adolescence and not only in early life.
The majority of the lesions are small and reduce in size as the lung grows.
4 lesions disappeared on CT during postnatal period.
Other studies -minimal change in lung function after resection in infancy.

43. Postoperative complications
Not recorded in this study.
However, a large meta analysis of 9 case series showed an increased risk of postoperative complication (X2) in symptomatic patients compared to asymptomatic and support elective surgery.

44. GOSH approach to asymptomatic CPAM/PS
Assessment of asymptomatic CPAM
Prenatal period: detection of CLM
Neonatal period: clinical assessment +CXR
Within 6m: CT scan+/- Echo
Clinical follow up every 6-12m
At the age of 5y: CT scan and follow up every12m.
Features triggering potential intervention
Hydrops
Respiratory distress, large mass, mediastinal shift
Multifocal lesions, large lesion, solid tissue, family history of PPB, respiratory infections
Respiraotory Infections, pneumothorax, parental concern or change on CT
GOSH-Great Ormond Street Hospital-approach to assessment and follow up of asymptomatic patients.
At the age of 16y prior to transition to repeat the CT.

45. Conclusion of the study
Conservative approach in asymptomatic CPAM/PS is possible.
Explanation to parents and antenatal counselling is recommended,
The need for surgery due to RI decreases >2y of age.
Spontaneous resolution can occur in some cases.
Malignancy is rare during pediatric period.
A long term follow up is needed.
RI-respiratory infection

46. Appraisal of the STUDY- Jama
Are the results valid?
Was there a representative and well defined sample of patients at a similar point in the course of the disease? No. The inclusion criteria was representative for the target population (CLM pt), however along the disease there were selection bias. Many families chose to have an elective resection due to medical advice.
Was follow up sufficiently long and complete? No. The follow up was not long enough regarding the risk for malignancy and wasn’t complete because12.5% of the asymptomatic patients were lost for follow up.
Were objective and unbiased outcome criteria used? Yes. Outcomes were defined at the begining of the study, however not enough time was given to assess the risk for malignancy.
Descriptive, cohort prospective study

47. Appraisal of the STUDY What are the results?
How likely are the outcomes over times? We don’t know. Follow up was not sufficient long enough for the outcome regarding for the risk of malignancy.
How precise are the estimates of likelihood (confidence intervals)? We don’t know. No statistical analysis was done.
We assume that no analysis was done because they didn’t have sufficient power of the results.

48. Appraisal of the STUDY Will the results help me care my patients?
Can the results be applied to my patients? No. No information was reported about the patients’ demographics ,co morbidities, and their imaging results.
Will the results lead directly to selecting therapy? No. The sample size was not large enough (only 119 pt , out of which only 68 patients were conservatively followed up) and the validity of the results is questionable.
Are the results useful for reassuring the patients? No. The study cannot rule out the possibility of malignancy which is most concerning for the families.

49. editorial about the study
Published on Aug 2017 in archives of diseases in childhood

50. Support the article
The results of the study are similar to previous studies.
The study provides a median of about 10y of follow up for 68 pt managed conservatively.
Severe neonatal complications are rare-6.7%.
Infection is not the predominant indication for surgery post neonatally.
Spontaneous resolution of CPAM is rare-5.9%.

51. Article weaknesses-No phenotypic description
CPAM are highly heterogenous in size and appearance.
Prenatal and postnatal imagining of CPAM provides phenotypic information.
The impact of phenotype on complication rate is unknown.
In this study there was no phenotypic description , only pathological diagnosis that is poorly predicted by imaging.
More studies are needed in that matter.
The impact of phenotype in complication rate in unknown and this series is not informative on this issue.

52. Article weaknesses- Risk for malignant transformation
The study neither has sufficient power nor a long enough duration of follow up to rule out the possibility of malignancy.
BAC can develop from K-RAS mutation in mucinous cells of CPAM.
More information is needed about the rate of K-RAS mutation in CPAM and the associated phenotype in CPAM.
Although rare, parents won’t like to take this risk.
The study cannot ruled out the possibility of malignancy

53. Article weaknesses- parents’ approach
The prenatal diagnosis of a CPAM is stressful for the parents.
Parents can act in a disproportional way- prohibit activities.
Some parents will be uncomfortable with an indeterminate long term prognosis for their child’s malformation.
Some parents will prefer to have surgical excision of the CPAM which cure the condition completely.

54. Future directions prenatal management Antenatal steroids
Thoracocentesis
Cyst aspiration/Thoracoamniotic shunt
Early delivery/partial delivery- exit procedure
In utero resection
Sclerotherapy
Laser ablation
Prenatal management- for symptomatic cases
Steroids- reverse hydrops and improve prognosis.
Thoracocentesis –prevent pulmonary hypoplasia
Cyst aspiration/Thoracoamniotic shunt- for large cysts
In utero surgical resection- for solid component
Laser ablation- for solid lesion
Sclerotherapy-percutaneous injection of Ethamolin/polidocanol under US
Early delivery
Exit procedure-with intubation and no umbilical cord clamping. While uteroplacental blood flow maintained and provide time for lung resection/ECMO cannulation.
Intervention has serious complications and reaccumulation of fluid is common.

55. Future directions Conservative tx Research Long F/U
Research directions to determine long term outcomes, assessment of lung growth and function and risk for malignancy.
Research to identify if genetic factors affect risks of complications.

56. Take home message
As technology develops our ability to identify CLM antenatally improves.
CPAM is a rare congenital pulmonary airways malformation
CPAM- clinical presentation can be asymptomatic.
There is controversy about how to manage asymptomatic patients.
Conservative approach is possible.
A long term follow up and further studies are needed.

57. Discussion
What is the current management of CPAM/PS in your hospital?

58. Questions?

59. References
Cook J, et al. The natural history of prenatally diagnosed congenital cystic lung lesions: long term follow-up of 119 cases. Archives of disease in childhood 2017; 102:
Delacourt C, et al. Postnatal management of asymptomatic congenital pulmonary malformation: moving towards evidence-based decisions. Archives of disease in childhood 2017 editorial letter: 102:
Kapralik J, et al. Surgical versus conservative management of congenital pulmonary airway malformation in children: A systemic review and meta-analysis. Journal of pediatric surgery 2016; 51:
Stanton M, et al. Systemic review and meta-analysis of the postnatal management of congenital cystic lung lesions. Journal of pediatric surgery 2009; 44:
Kotecha S, et al. Antenatal and postnatal management of congenital cystic adenomatoid malformation. Paediatric respiratory reviews 2012; 13:
Oermann CM, Congenital pulmonary airway (cystic adenomatoid) malformation. Uptodate 2017: 1-22.
Stanton M. The argument for a non operative approach to asymptomatic lung lesions. Seminars in Pediatric Surgery 2015; 24 :
Singh R. The argument for operative approach to asymptomatic lung lesions. Seminar in Pediatric Surgery 2015; 24:
Kendig and Chernick’s. Congenital cystic lesions. Disorders of the Respiratory Tract in Children. Eighth Edition 2012:
Hull Jeremy, et al. Congenital lung anomalies. Pediatric Respiratory Medicine, Oxford specialist handbook in pediatrics, second edition 2015;
Dusmet Michael. Adult lung tumors of childhood origin. Seminars in Pediatric Surgery 2015: 24:

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