Childhood Pleuropulmonary Blastoma Treatment (PDQ®)

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 (refer to 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] (Refer to 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]

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 (refer to Figure 1).[1]

Figure 1. Suggested signs and symptoms and imaging surveillance by system for individuals with DICER1 pathogenic variants. Adapted from Clinical Cancer Research, Copyright 2018, Volume 20/Issue 10, Pages 2251–2261, Kris Ann P. Schultz, Gretchen M. Williams, Junne Kamihara, et al.: DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies, with permission from AACR.

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]

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.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

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 2010, childhood cancer mortality decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[4] 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.[5,6] 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.[7]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[8] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years.[9]
  Most cancers in subgroup XI are either melanomas or thyroid cancer, with other types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of 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.

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.

Treatment options for childhood pleuropulmonary blastoma include the following:

1. Surgery.
2. Adjuvant chemotherapy.

A complete surgical resection is required for cure.[1]

Data from the International Pleuropulmonary Blastoma Registry and the European Cooperative Study Group in Pediatric Rare Tumors suggest that adjuvant chemotherapy may reduce the risk of recurrence.[2]; [3][Level of evidence: 3iiiA] Responses to chemotherapy have been reported with agents similar to those used for the treatment of rhabdomyosarcoma.[2-4]

Some general treatment considerations from the International Pleuropulmonary Blastoma Registry include the following:[2,5]

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.[2,3]
2. Type II and Type III: A multimodal sarcoma treatment approach is recommended, usually including rhabdomyosarcoma regimens and either upfront or delayed surgery.[2,3,6] Anthracycline-containing regimens appear to be superior.[3] The respective 5-year DFS and OS rates were 59% and 71% for Type II, and 37% and 53% for Type III.[2] 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.[2] Approximately 50% of relapses occur in the brain.[2]

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 suffered from 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, refer to 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 using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Changes to This Summary (12/16/2021)

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.

This summary was comprehensively reviewed.

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® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary