Cystic Pleuro-Pulmonary Blastoma – additional opinion
2-year-old girl was diagnosed with pleuropulmonary blastoma (PPB). She presented with cough and fever which was treated as pneumonia. When her symptoms did not improve, a chest X-ray showed a right lower lobe infiltrate with pleural effusion and a cystic lesion superiorly. She was further treated with antibiotics and improved clinically, but follow-up with chest CT showed a persistent cystic area in the right lower lobe and pneumothorax. She thus underwent pleural drainage and thoracoscopic biopsy, revealing a diagnosis of "cystic pleuropulmonary blastoma". She has been clinically well and staging workup were negative for evidence of distant metastasis. The initial plan is to proceed with chemotherapy using 3 cycles of VAIA followed by restaging and aggressive surgical resection.
1) Do you agree with the treatment chosen?
3) Possible options to the surgical operation?
2 years old , female, Italy
Diagnosis: Cystic Pleuro-Pulmonary Blastoma
Diagnosis of pneumonia for the appearance of hyperpyrexia and cough treated with antibiotic by oral way. In the absence of clinical response after over 48 hours’ treatment, the patient has been taken to the Emergency Room where a chest radiography was carried out with finding of a right basal opacity with associated effusion and a bullous area located cranially to the lesion, of difficult interpretation.
In May, 2009 Following a parenteral antibiotic therapy at the beginning, and afterwards by oral way, the young patient felt well and 3 weeks later she underwent a clinical and radiological follow-up. The chest CT scan performed on that occasion still showed a non-specific pulmonary cystic area cranially to the area of the flogistic infiltrate put down to pneumonia. As there was a persisting diagnostic doubt, it was decided that the young patient had to undergo repeated radiological follow-ups until definition or resolution of the clinical picture.
During June examination a picture of hypertensive pneumothorax with the mediastinum mobility was found, with the patient always being asymptomatic. The patient underwent pleural drainage and afterwards to exeresis operation of the pulmonary lesion via thoracoscopy. The tissue taken has been, therefore, subject to hystopathologic analysis that is indicative of cystic pleuro-pulmonary blastoma.
During hospitalization in DH dated 8/2009 at admission to ward, the young patient showed good general conditions, she was lively and reactive; at the thorax level a slight reduction in the inspiratory airflow at the right lung base was appreciated. Clear thoracoscopy scars. Remaining examinations within normal limits. The hematochemical examinations performed showed: WBC: 9 750/mrnc; N: 3i00/mmc. Platelets: 864 000, Hb: 10.5 g/dI; °ERS: 58 mm/h; APC: 0.26 mg/dl; ° Ferritin: 71.36 ng/ml; ° Haepatic and renal function, electrolytes within normal limits; ° LDH:336U/L; ° IgG: 946 rng/dl; IgA: 110 mgldl; IgM: 172 mg/dl; ° CA 125: 39.14 U.LmL ° CA 19-9: 4.25 U.L1’ml; ° CEA: 1,19 ng/ml;
Staging of neoplasia has been carried out by means of:
- Bone scintigraphy: Negative;
- Cranial, neck, chest and abdomen CT scan: Some small lymph nodes of around a centimeter size are observed in the laterocervical area, posterior to the carotid space bilaterally and in left inguinal fossa. At the right chest level various ovalar air bubbles are observed. Showing a maximum diameter of 2.5 cm, they are next to each other and located both in pleural and parenchymal area, of triangle morphology as a whole, encircled by hypodense material that extendes, thickening it, to the pleura in lateral and posterior costal margin area, in intratissular and mediastinal area, at the level of the right hilus and between the right cardiac margin and paravertebral region. Focal pleural thickening hypodense at the inferior middle third level in the rear and in right area over the diaphragm. Transverse mega-apophysis on the right side at L5. Therefore, the disease seems to be located at the pleural/pulmonary level without any sign of long-term metastasis.
The attending doctors talked about the case with their surgery colleagues and with the person in charge of the TREP protocol (Rare Paediatric Tumors) and, in accordance with the parents, it was decided to start with 3 cycles of chemotherapy as per the protocol (VAIA) and afterwards to carry out a CT scan reassessment and surgical operation with radical attempt.
The first cycle envisages the infusion of Ifosfamide, Vincristine and Actinomycin D on the first day, in hospitalization; afterwards Vincristine in Day Hospital once a week for 2 weeks.
1) Do you agree with the treatment chosen?
Yes, the treatment plan proposed by Dr. Z and his colleagues is a very reasonable one. However, it would be helpful to have some additional details. First, I wonder whether the histologic diagnosis of PPB has been further subclassified. It has been described as a cystic PPB. There are classically 3 subtypes described for PPB: type I: purely cystic; type II: purely solid; and type III: mixed cystic and solid. I suspect from the radiographic description and the child's age that this is a type III (mixed) as the type I, purely cystic lesions tend to occur in younger infants and would often be less extensive. There is some suggestion in the literature that type I lesions are favorable in their prognosis and also that chemotherapy and/or radiation therapy may not be necessary if the tumor can be removed in entirety through surgical resection. One consideration if there is any uncertainty about the histologic subtype would be to send the pathologic materials for outside review. This could be done at our institution (in particular, would recommend Dr. Andrew Rosenberg here at MGH) or by Dr. Louis Dehner, a pathologist at the University of Minnesota who is recognized as an expert in this rare tumor type. I would be happy to help arrange for this to be done if you are interested. Having said this, I do feel that the likelihood clinically is that this is a mixed, type III lesion.
My other question is whether the surgical consultants felt there was any feasibility to resecting the tumor at the time of initial diagnosis. Again, I would speculate given the description of the tumor location and its behavior was that this was not felt to be readily amenable to surgical resection and this is the rationale for starting with chemotherapy and deferring surgery. Generally, the approach has been to remove tumor at the time of diagnosis if possible but there are patients in whom this is not feasible and treatment has been successful with a delayed surgery after some upfront treatment with chemotherapy. In one of the larger published series of PPB patients, Indolfi and colleagues outlined the management and outcome of 11 children, and 3 of these 11 had delayed surgery, 2 of 3 with a good treatment outcome (Indolfi P, Cancer 2000; 89:1396-1401).
As to the question of optimal chemotherapy if this is not a type I, purely cystic tumor that would be amenable to up-front surgical resection, the choice you have proposed is a standard regimen that has been used with some frequency in this disease. Given the relative rarity of PPB, there has not been one gold standard chemotherapy regimen that has been used universally. The regimens generally chosen (VAIA, VAC, and CEVAIE) are typical regimens used for sarcomas of childhood and in particular for rhabdomyosarcoma with which this tumor shares some similarities. VAC has been the U.S. standard regimen for rhabdomyosarcoma and is probably used more often here than VAIA, while VAIA has been a very comparable European standard regimen. Studies in rhabdomyosarcoma comparing these regimens show very similar effectiveness and I think it makes the most sense to choose a good sarcoma regimen as you have done that your group and team are comfortable with.
One additional consideration is whether this child should receive radiation therapy as part of her treatment. This will depend to some extent on whether the tumor can be completely removed with clear surgical margins, in which case radiation may be able to be avoided. There is a suggestion in the literature that there may be a benefit to including local radiotherapy in the overall treatment plan (see Indolfi reference), and I think this should be strongly considered post-operatively, particularly if there is known to be residual tumor left in place. Certainly, radiating the chest of such a young child has significant attendant morbidities, particularly long-term toxicities such as impaired growth of musculoskeletal tissues and adverse effects on cardiac and pulmonary function. The magnitude of these late toxicities depends on the dose used, the size of the field, and also the form of radiation delivered. There may be benefit in terms of the reduction of late toxicities to using proton beam irradiation if this is available. We would certainly consider this form of radiation here but it is available at just a few centers internationally (including our own).
Prognosis depends on histologic subtype and also on extent of disease. Patients with types 2 and 3 PPB as well as those with pleural and/or mediastinal involvement appear to have a worse outcome in the published series (Indolfi reference and Priest JR, Cancer, 1997;80:147-1961). If this is indeed a type 3 with pleural and mediastinal involvement as the description of the imaging studies suggests, the literature suggests that there is about a 40-45% chance of event-free survival and possibly a small number of patients who are successfully retreated after salvage therapy. Certainly, there are long-term survivors of this disease and my recommendation would be to treat this aggressively with a curative intent to include at least chemotherapy and surgery as you have outlined, and possibly also radiation therapy if there is residual disease remaining after surgery.
3) Possible options to the surgical operation?
I would defer this question to my pediatric surgery colleagues. This is difficult to answer without direct review of the imaging studies but my general recommendation would be to undertake whatever aggressive surgery is required to remove as much disease as possible. It would be helpful to know whether the effusion was malignant (positive tumor cells by cytology) or reactive/inflammatory and whether the tumor is felt to be adherent to pleura and mediastinum or nearly abutting these structures. If there were tumor cells in pleural fluid and/or tumor is densely adherent to pleura, consideration may need to be given to pneumonectomy. The decision as to how to approach this surgically will be easier to address once the response to neoadjuvant chemotherapy has been assessed. I would be very happy to review the actual images and also discuss/review the case in a multidisciplinary manner with my radiation oncology and pediatric surgery colleagues for a more detailed opinion on multimodality therapy, including the role of radiotherapy (and possibly protons) and recommendations for surgery.