This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood pleuropulmonary blastoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Types of Pleuropulmonary Blastoma and Other DICER1-Associated Neoplasms

Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy that can present as a pulmonary or pleural mass. In most cases, pleuropulmonary blastoma is associated with germline mutations of the DICER1 gene. The International Pleuropulmonary Blastoma Registry is a valuable resource for information on this rare malignancy.[1,2]

The following three subtypes of pleuropulmonary blastoma have been identified:

• Type I: A purely lung cystic neoplasm with subtle malignant changes that typically occurs in the first 2 years of life and has a good prognosis. The median age at diagnosis for Type I tumors is 8 months, and there is a slight male predominance. Transition from Type I to Type III occurs; however, a significant proportion of Type I lesions may not progress to Type II and Type III tumors.[2,3]
  Histologically, these tumors appear as a multilocular cyst with variable numbers of primitive mesenchymal cells beneath a benign epithelial surface, with skeletal differentiation in one-half of the cases.[3] This form of disease can be clinically and pathologically deceptive because of its resemblance to some developmental lung cysts.
• Type Ir: A purely cystic tumor that lacks a primitive cell component. The r designation signifies regression or nonprogression. Type Ir was originally recognized in older siblings of pleuropulmonary blastoma patients but can be seen in very young children. A lung cyst in an older individual with a DICER1 mutation or in a relative of a pleuropulmonary blastoma patient is most likely to be Type Ir.[2]
  In the Pleuropulmonary Blastoma Registry experience, most Type I and Ir cysts are unilateral (74%), half are unifocal, and 55% are larger than 5 cm. Pneumothorax may be present at diagnosis in up to 30% of Type I and Ir pleuropulmonary blastoma cases.[2]
• Type II: Type II exhibits both cystic and solid components. The solid areas have mixed blastomatous and sarcomatous features. Most of the cases exhibit rhabdomyoblasts, and nodules with cartilaginous differentiation are common.[4]
  Anaplasia is present in up to 60% of the cases.[5] In the Pleuropulmonary Blastoma Registry, the median age at diagnosis was 35 months, and distant metastases were present at the time of diagnosis in 7% of patients.[2]
• Type III: A purely solid neoplasm, with the blastomatous and sarcomatous elements described above, and the presence of anaplasia in 70% of patients.[5-7]
  Median age at diagnosis in the Pleuropulmonary Blastoma Registry was 41 months, and distant metastases were present at the time of diagnosis in 10% of patients.[2]

The Pleuropulmonary Blastoma Registry reported on 350 centrally reviewed and confirmed cases of pleuropulmonary blastoma over a 50-year period (see Table 1).[2]

Molecular Features

In one report, 15 of 16 pleuropulmonary blastoma tumors were positive for IGF1R expression by immunohistochemistry.[1] Genomic profiling showed amplification of the IGF1R gene in 4 of 16 pleuropulmonary blastoma tumors. All of these gene-amplified tumors were Type III.

Prognostic Factors

In a comprehensive analysis of 350 patients reported by the Pleuropulmonary Blastoma Registry, only two prognostic factors were identified: the type of pleuropulmonary blastoma and the presence of metastatic disease at diagnosis.[1] For more information, see Table 1. In three additional small cohort series, the ability to perform a complete surgical resection was also identified as a prognostic factor.[2-4]

The presence of a germline DICER1 mutation is not a prognostic factor.[1]

A retrospective study analyzed TP53 expression by immunohistochemistry (IHC) in patients with pleuropulmonary blastoma.[5] A total of 143 cases were included in the study, with the following distribution of pleuropulmonary blastoma Types: Type I, 23%; Type Ir, 14%; Type II, 32%; and Type III, 31%. Four groups of TP53 expression by IHC were recorded, which included 0%, 1% to 25%, 26% to 75%, and 76% to 100%. All Type I pleuropulmonary blastomas showed TP53 expressions of 0% to 25%, compared with Type III pleuropulmonary blastomas, which had higher TP53 expressions (>25%) (P < .0001). High TP53 expression (staining observed in >25% of the tumor cells) was significantly associated with age older than 1 year (P = .0033), neoadjuvant therapy (P = .0009), positive resection margin (P = .0008), and anaplasia (P < .0001). TP53 expression was significantly associated with recurrence-free survival (P < .0001) and overall survival (P = .0350). Higher TP53 expression was associated with a worse prognosis.

Risk Factors

Close to two-thirds of patients with pleuropulmonary blastoma have a germline DICER1 mutation. Approximately one-third of families of children with pleuropulmonary blastoma manifest a number of dysplastic and/or neoplastic conditions comprising the DICER1 syndrome.[1-3]

Germline DICER1 mutations have been associated with the following:[1-5]

• Cystic nephroma and Wilms tumor. Up to 10% of patients with pleuropulmonary blastoma have been reported to develop cystic nephroma or Wilms tumor, which are the most relevant associated malignancies. These tumors are also more prevalent among family members.[6]
• Ovarian sex cord–stromal tumors (especially Sertoli-Leydig cell tumor).
• Multinodular goiter and thyroid carcinoma.[7]
• Uterine cervix embryonal rhabdomyosarcoma.
• Nasal chondromesenchymal hamartoma.
• Renal sarcoma.
• Pulmonary sequestration.
• Juvenile intestinal polyps.
• Ciliary body medulloepithelioma.
• Medulloblastoma.
• Pineoblastoma.
• Pituitary blastoma.
• Seminoma.

The penetrance of DICER1 germline mutations associated with each pathologic condition is not well understood, but lung cysts, pleuropulmonary blastoma, and thyroid nodules are the most commonly reported manifestations in individuals who have loss-of-function mutations.[5] Most associated conditions occur in children younger than 10 years, although ovarian tumors and multinodular goiters are described in children and adults aged up to 30 years.[3,5] A study of 102 individuals with DICER1 germline mutations revealed a neoplasm risk of 5% by the age of 10 years and 19% by the age of 50 years.[8] Surveillance and screening recommendations have been proposed.[5]

Surveillance

As with other cancer predisposition conditions, before individuals with DICER1 mutations are screened, factors that must be considered include typical age of onset of each disease, potential benefits of early detection, and risks and availability of screening modalities. A consensus panel convened by the International Pleuropulmonary Blastoma Registry has proposed guidelines for surveillance. In addition to imaging-based surveillance, individuals and families can be counseled at each visit regarding potential signs and symptoms of DICER1-associated conditions and undergo appropriate age- and gender-specific preventive screening studies (see Table 2).[1]

Clinical Presentation

Presenting symptoms are not specific. They commonly include the following:

• Respiratory distress.
• Fever.
• Chest pain.

The tumor is usually located in the lung periphery, but it may be extrapulmonary with involvement of the heart/great vessels, mediastinum, diaphragm, and/or pleura.[1,2] Tumor embolism is a known risk, and radiographic evaluation of the central circulation is performed to identify potentially fatal embolic complications.[3]

Treatment of Childhood Pleuropulmonary Blastoma

There are no standard treatment options for childhood pleuropulmonary blastoma. Current treatment regimens for these rare tumors have been informed by consensus opinion. The European Cooperative Study Group for Pediatric Rare Tumors within the PARTNER project (Paediatric Rare Tumours Network–European Registry) published comprehensive recommendations for the diagnosis and treatment of pleuropulmonary blastoma in children and adolescents.[1]

Treatment options for childhood pleuropulmonary blastoma include the following:

1. Surgery.
2. Adjuvant chemotherapy.

A complete surgical resection is required for cure.[2]

Data from the International Pleuropulmonary Blastoma Registry and the European Cooperative Study Group for Pediatric Rare Tumors suggest that adjuvant chemotherapy may reduce the risk of recurrence.[3]; [4][Level of evidence C1] Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma.[3-5]

Some general treatment considerations from the International Pleuropulmonary Blastoma Registry include the following:[3,6]

1. Type I and Type Ir: Surgery is the treatment of choice. In the Pleuropulmonary Blastoma Registry series, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 82% and 91%, respectively. Approximately 10% of cases may progress to Type II or Type III after surgery, but adjuvant chemotherapy does not appear to impact the rate of progression and survival.[3,4]
2. Type II and Type III: A multimodal sarcoma treatment approach is recommended, usually including rhabdomyosarcoma regimens and either upfront or delayed surgery.[3,4,7] Anthracycline-containing regimens appear to be superior.[4] The respective 5-year DFS and OS rates were 59% and 71% for Type II, and 37% and 53% for Type III.[3] The role of radiation therapy is not well defined. While the use of radiation did not impact survival in the International Pleuropulmonary Blastoma Registry series, only 20% of patients with Type II and Type III received it.[3] Approximately 50% of relapses occur in the brain.[3] The International Pleuropulmonary Blastoma/DICER1 Registry reported outcomes for children with Type II and Type III pleuropulmonary blastoma whose first treatment was ifosfamide, vincristine, dactinomycin, and doxorubicin (IVADo).[8] From 1987 to 2021, 314 children with centrally confirmed Type II and Type III pleuropulmonary blastoma who received up-front chemotherapy were enrolled, 132 of whom (75 with Type II and 57 with Type III) received IVADo chemotherapy. Adjusted analyses suggested improved OS for children treated with IVADo compared with historical controls, with an estimated hazard ratio (HR) of 0.65 (95% confidence interval [CI], 0.39–1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse pleuropulmonary blastoma event-free survival and OS, with HRs of 4.23 (95% CI, 2.42–7.38) and 4.69 (95% CI, 2.50–8.80), respectively.

Treatment of Progressive or Recurrent Pleuropulmonary Blastoma

A retrospective review included children with a diagnosis of pleuropulmonary blastoma Type II and Type III and progressive or recurrent disease who were registered in national and European databases and trials (2000–2018).[1] Patients had a median age of 3.9 years (range, 0.5–17.8 years). The median time to progression was 0.58 years (range, 0.02–1.27 years) from diagnosis despite surgery, chemotherapy (n = 9), and radiation therapy (n = 1). All of these patients died. Patients were diagnosed with recurrent disease at a median age of 4.3 years (range, 1.7–15.1 years) and had a median delay to relapse of 1.03 years (range, 0.03–2.95 years). Recurrent disease occurred locally (n = 12), in combined sites (locally and metastatic) (n = 1), and in metastatic sites (n = 13), including the central nervous system (n = 11) and unspecified sites (n = 2). The 5-year event-free survival rate and overall survival (OS) rate for patients with recurrent disease were both 37% (± 19%; 95% confidence interval). Local therapy (surgery and radiation therapy) had a favorable impact on OS (P = .03 and .02, respectively).

Treatment Options Under Clinical Evaluation for Childhood Pleuropulmonary Blastoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.
  Patients with tumors that have molecular variants addressed by open treatment arms in the trial may be enrolled in treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.
• Child-life professionals.
• Psychologists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3-5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than 2 cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than 2 cases per 1 million people were also included in the very rare group because there is a lack of knowledge and expertise in the management of these tumors.[9]
• The Children's Oncology Group (COG) defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers, colorectal cancers, etc.).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]
  Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers in children aged 0 to 14 years and 9.3% of the cancers in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer.

Changes to This Summary (12/08/2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Childhood Pleuropulmonary Blastoma

Added text to state that the European Cooperative Study Group for Pediatric Rare Tumors within the PARTNER project published comprehensive recommendations for the diagnosis and treatment of pleuropulmonary blastoma in children and adolescents (cited Bisogno et al. as reference 1).

Added text about the results of an International Pleuropulmonary Blastoma/DICER1 Registry study that reported outcomes for children with Type II and Type III pleuropulmonary blastoma whose first treatment was ifosfamide, vincristine, dactinomycin, and doxorubicin (cited Schultz et al. as reference 8).

Special Considerations for the Treatment of Children With Cancer

Revised text to state that between 1975 and 2020, childhood cancer mortality decreased by more than 50% (cited National Cancer Institute as reference 4 and Surveillance Research Program, National Cancer Institute as reference 5).

Revised text to state that rare pediatric cancers account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years. Also revised text to state that most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers in children aged 0 to 14 years and 9.3% of cancers in adolescents aged 15 to 19 years.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary