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Warning: These guidelines may change over time according to new data. The local clinician

remains responsible for the care of his patient. The EXPeRT members are not responsible for

results or complications related to their use. If necessary, medical discussions are possible with

members of these groups via the eSIOP website (http://www.XXX.eu).

Coordinators of these guidelines: Daniel Orbach, M.D (Pediatric-adolescent-young adult

department, Institut Curie, Paris, France), Gianni Bisogno, M.D (Pediatric Hematology and

Oncology Division, Padova University, Padova, Italy), Sabine Sarnacki, M.D, Ph.D (Department

of Pediatric Surgery, Hôpital Necker-Enfants-Malades and Assistance Publique Hôpitaux de

Paris, Université Paris Descartes, Paris, France), Teresa Stachowicz-Stencel, M.D (Department

of Pediatrics, Medical University, Gdansk, Poland) and EK (Germany).

Definitive validation: XXX. Validate by: EXPeRT members, Version n° 3.2

Background

Pleuropulmonary blastoma (PPB) is a very rare and highly aggressive neoplasm arising in

the lungs and presenting in early childhood, with most cases diagnosed in children less than 6

years of age. It is a dysembryonic malignancy believed to arise from the pleuropulmonary

mesenchyme. PPB is classified into 3 interrelated clinico-pathologic entities occurring from birth

to 6 years. Type I PPB presented as an air-filled multilocular cyst in the peripheral lung

parenchyma. Type II PPB occurs latter and has both type I cysts or cysts remnants with grossly

visible thickened cyst wall, solid mural nodules or larger tumor excrescences. Type III PPB is a

completely solid mixed-pattern including high grade sarcoma elements (1-3).

PPB in children is characterized by symptoms often mistaken for respiratory infection,

pneumothorax or lung malformation. The tumor is usually located in the lung periphery, but it

may be extra pulmonary with involvement of the mediastinum, diaphragm and/or parietal pleura.

Rarely, Types II-III PPB may present with metastases, most frequently located in the brain and

lung parenchyma. This tumor is already known to be part of the spectrum of the DICER1

mutation related tumors which includes at least Sex cord stromal tumors, medulloepithelioma,

thyroid carcinoma and cystic nephroma (4, 5). Results from the Expert group suggest that at least

types II-III are chemosensitive (6).

PULMONARY PNEUMOBLASTOMA  

 p. 3 

No prospective or comparative studies have been conducted in PPB. All guidelines presented

here are based on a grade III level of evidence.

PULMONARY PNEUMOBLASTOMA  

 p. 4 

Guidelines

Standard:

Initial tumor assessment:

- This step should take into account the respiratory difficulties that PPB generally present

with. Management of any pneumothorax or pleural effusion should be done initially. It is

recommended not to leave a chest tub in order to minimize the contamination of the

pleura.

- Type I is usually diagnosed and treated as a cystic lung malformation, i.e. with primary

surgical resection. This should be a complete resection with adequate tumour margins.

Indication for a total pneumonectomy should be exceptional, and as for any lung

malformation, should be discussed in a multidisciplinary team (MDT) after biopsy.

For types II-III, a biopsy first to allow histological examination is recommended. Initial

surgery should only be discussed in small tumors that can be easily resected with adequate

tumour margins, and without functional consequences. Core-needle (18 or 16 Gauge) or

open surgical biopsies are both possible options, but they must be large enough to allow

histological, biological and genetic tests. Cytology of pleural fluid is not enough for

diagnosis. Histology is mandatory to distinguish PPB from other paediatric sarcomas as

rhabdomyosarcoma.

- Loco-regional evaluation is initially performed by Chest Computed Tomography (CT)

- Distant metastasis evaluation needs a brain MRI.

Therapies:

Surgery

- MDT discussion is mandatory, at diagnosis and during therapy. All PPB surgeries must

follow guidelines for sarcomas surgery.

- Special attention when general anaesthesia is required is needed

- Type I PPB should initially have a total resection. The recommended surgical approach is

for a thoracotomy but some small lesions thought to be cystic lung malformation could

have been resected by a thoracoscopic approach. The operative report should mention

any mediastinal, diaphragmatic or pleural extension and any rupture of the lesion. All

residues should be resected to prevent later transformation to types II-III.

PULMONARY PNEUMOBLASTOMA  

 p. 5 

- For types II-III, primary surgery should only be considered in small tumors that can easily

and completely resected without any functional consequences, and if there is no clear

radiological evidence of lymph node or metastatic disease. In all other cases, tumor

resection should occur following neo-adjuvant chemotherapy. Complete pneumonectomy

is discouraged at diagnosis.

- In case of life-threatening situation, up-front surgery may be discussed in order to allow,

if possible, a complete resection of the tumor. In this case, if a total pneumonectomy is

the only way to remove all lesions, a debulking surgery is acceptable with a planned

second look surgery after adjuvant chemotherapy in order to resect all remaining parts of

the tumor.

- After neoadjuvant chemotherapy, second look surgery is highly recommended even if no

lesion is identified on the post-treatment CT scan because the absence of viable cells in

resected lesions could minimize the doses of radiotherapy or avoid it. The pleural cavity

and the pulmonary parenchyma should be carefully analysed. Remaining pleural effusion

should be collected for a cytological analysis. All remaining pleural or lung nodules should

be resected or biopsied, eventually indicated by positioning a clip by an interventional

radiologist prior the operation. It could imply non-anatomical lung resection or

lobectomy and associated removal of suspicious pericardium and/or diaphragm and/or

parietal pleura. All tissues resected should be histologically analysed in order to guide the

adjuvant radiotherapy fields. A non-anatomical lung resection or lobectomy and

associated removal of suspicious pericardium and/or diaphragm and/or parietal pleura

could be performed depending on the peroperative findings. If initial lesion or pre-

operative lesion suggests that a total pneumonectomy after neoadjuvant chemotherapy

could be required, it should be balanced with the possibilities of local treatment with

radiotherapy. If a complete pneumonectomy is chosen, a complete parietal pleurectomy

should be associated.

Chemotherapy

- All patients with types II-III PPB should receive chemotherapy.

- For types II-III :

o In case of R0 or R1 surgery, 9 courses of IVA are recommended

o In case of R1, R2 surgery or biopsy only, a total of 4 courses of IVADo and 5

courses of IVA are recommended.

- Specific attentions should be paid to the management of chemotherapy in very young

infants: central venous access insertion, slow increasing of chemotherapy dosages for first

PULMONARY PNEUMOBLASTOMA  

 p. 6 

courses and specific attention to hepatic, renal, cardiac and neuropathic toxicity are

strongly recommended.

Radiotherapy

- The role of external radiotherapy is unclear in PPB. Recommendation is to deliver

radiotherapy only in the case of residual tumor after chemotherapy that contains viable

cells incompletely resected despite a second look surgery. In this case the advantages and

risks of the external radiotherapy should be balanced with a total pleuro-

pneumonectomy. Fields should be focused and restricted to residual tumor volume after

chemotherapy (or tumor volume bed) (see recommendation section).

Genetic

- A genetic counselling should be proposed to all patients and family in order to screen all

diseases associated with DICER1 mutation. At diagnosis, abdominal and pelvic US may

be useful to verify the absence of cystic nephroma and/or ovarian tumor. Systematic

radiological and clinical screening in case of constitutional DICER1 mutation

recommendations could not be done currently.

Optional:

- Adjuvant therapy for type I :

o In case of complete surgery (R0 resection), or microscopic incomplete resection

(R1 resection), adjuvant chemotherapy with VA is recommended. NB: Surgery

that allows a complete resection of the tumor, even after core needle biopsy (< 18

G) or fine needle aspiration, should be considered as a definitive R0 resection.

Initial intra-thoracic cyst puncture should also be defined as R0 procedure

provided that the entire tumor is then completely resected.

o In case of macroscopic incomplete surgery (R2 resection), adjuvant chemotherapy

with IVA is recommended except if the initial imaging and/or the surgical report

let think that a complete resection could have been done. A second surgery

should then be proposed.

o No radiotherapy is recommended for type I.

- New-borns or young infants <3 months with type I PPB may not receive adjuvant

chemotherapy provided that initial surgery was at least macroscopically complete and that

a strict follow-up is possible.

PULMONARY PNEUMOBLASTOMA  

 p. 7 

- Patients should have the proposition to be enrolled in all prospective protocols or

collecting national or international databases.

Recommendations:

Radiotherapy:

- In case of needed radiotherapy, total dosage should be between 45 Gy (R1 margins) to 54

Gy (R2 margins), with 1.8 Gy daily fractions. Even in case of initial pleural effusion at

diagnosis, in the absence of remaining pleural tumor cells after chemotherapy during the

second look surgery, radiotherapy on the hemi-thorax may be avoid.

- Unilateral thorax irradiation may be restricted only to old patients with remaining pleural

“viable” tumor that could not be resected during the second look surgery. Specific

attention should be done to myocardial irradiation after anthracyclin exposure. MDT

discussion should balance irradiation risks with those of a total pleuro-pneumonectomy.

Surgery:

- Total pleuro-pneumonectomy should only be discussed in case of persistent tumor in the

absence of tumor regression after chemotherapy that seems unresectable otherwise

and/or in case of residual tumor that contains viable cells incompletely resected despite a

second look surgery. In this latter situation, an option should be an external unilateral

pulmonary irradiation. Long term effects of this mutilating surgery must be balanced with

the ones of a unilateral pulmonary irradiation in such young patients.

- For types II-III PPB, in case of insufficient response to first line therapy, second line with

etoposide-carboplatin could be delivered.

- Metastatic tumors should be discussed within the EXPeRT Committee. As a general

principle, neurosurgical resection of brain metastases followed by local radiotherapy in

association of IVADo/IVA protocol may be considered up to 9 courses. Local tumor

resection should also be done. Maintenance chemotherapy up to 6-12 months may be

discussed.

- In case of relapse after chemotherapy, discussion should be made within the EXPeRT

Committees. As a principle, etoposide-carboplatin regimen could be first used.

 

 p. 8 

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PULMONARY PNEUMOBLASTOMA  

 p. 11 

Ifosfamide: Day 1 and 2, IV 3 hours, with hydration 100 ml/kg/d G5% dextrose and uromitexan (120% of ifosfamide dosage) from day 1 to 3. Maximum: 6 g/m²/course.

Hyper-hydration and diuresis should be strictly followed at diagnosis in the context of a respiratory distress with compressive pleural effusions.

No alkylating agent before the age of 1 month

- For children 1- 3 months or < 5 kg: 40 mg/kg/injection/d for the 2 first cycles (2 injections) then if good tolerance 60 mg/kg/injection/d for further injections and 80 mg/kg/injection/d only when age > 6 months and weight > 8 kg;

- For children 3- 6 months and 5-8 kg: 60 mg/kg/injection/d for the 2 first cycles (2 injections) then if good tolerance 80 mg/kg/injection/d for further injections and 100 mg/kg/injection/d only when age > 6 months and weight > 8 kg;

- For children 6-12 months and 8-10 kg: 80 mg/kg/injection/D for the 2 first cycles (2 injections) then if good tolerance 100 mg/kg/injection/d for further injections until age > 12 months and weight > 10 kg;

- For children > 12 months and > 10 kg: 3000 mg/m²/injection/d.

Vincristine: Day 1 of each course (+ D8 and D15 for the 2 first courses), see dosages above.

Actinomycin-D: Day 1, see dosages above.

IVADo regimen (ifosfamide, vincristine, actinomycin-D, doxorubicine): a course every 21 days. A central line is essential and mandatory for the administration of doxorubicin over 4 hours. Maximum: 4 cycles.

Ifosfamide: Day 1 and 2, IV 3 hours, with hydration 100 ml/kg/d G5% dextrose and uromitexan (120% of ifosfamide dosage) from day 1 to 3. Maximum: 6g/m²/course. See dosage adaptations above.

Vincristine: Day 1 of each course (+ D8 and D15 for 2 first courses), see dosages above.

Actinomycin-D: Day 1, see dosages above.

Doxorubicin: in 0.9% saline IV 4 hours, day 4 and 5

- For children < 3 months or < 5 kg: No doxorubicin

- For children 3- 6 months and 5-8 kg: 0.6 mg/kg/injection for the 2 first cycles (2 injections) then if good tolerance 0.8 mg/kg/injection for further injections and 1 mg/kg/injection only when age > 6 months and weight > 8 kg;

- For children 6-12 months and 8-10 kg: 0.8 mg/kg/injection for the 2 first cycles (2 injections) then if good tolerance 1 mg/kg/injection for further injections until age > 12 months and weight > 10 kg;

- For children > 12 months and > 10 kg: 30 mg/m²/injection.

 

 p. 12 

1. P

pleuropu

J Clin O

2. P

metastas

Blood C

3. P

Pleurop

61.

4. B

associati

from the

5. H

mutation

Priest JR, H

ulmonary bl

Oncol. 2006 S

Priest JR, M

sis and othe

Cancer. 2007

Priest JR, M

ulmonary bl

Boman F, H

ion of pleur

e Internation

Hill DA, Iva

ns in familia

Hill DA, Will

lastoma: a re

Sep 20;24(2

Magnuson J, W

r central ner

7 Sep;49(3):2

McDermott M

lastoma: a cl

Hill DA, Will

ropulmonary

nal Pleuropu

anovich J, P

al pleuropulm

PULMONA

R

iams GM, M

eport from t

7):4492-8.

Williams GM

rvous system

266-73.

MB, Bhatia S

linicopathol

liams GM, C

y blastoma w

ulmonary Bl

Priest JR, Gu

monary blas

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ICER1

PULMONARY PNEUMOBLASTOMA  

 p. 13 

6. Bisogno G, Brennan B, Orbach D, Stachowicz-Stencel T, Cecchetto G, Indolfi P, et al.

Treatment and prognostic factors in pleuropulmonary blastoma: an EXPeRT report. Eur J

Cancer. 2014 Jan;50(1):178-84.