Continuing Education Activity

Pleuropulmonary blastomas are rare, malignant mesenchymal tumors that typically present with non-specific symptoms. Radiologic features may increase the clinical suspicion for this condition, however, the diagnosis of a pleuropulmonary blastoma is based on microscopic features. This activity reviews the presentation, evaluation, and management of pulmonary blastomas and highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Identify the etiology of pulmonary blastoma.
• Describe the presentation of a patient with pulmonary blastomas.
• Review the treatment and management options available for pulmonary blastomas.
• Explain interprofessional team strategies for improving care coordination and communication to advance the diagnosis and management of pulmonary blastoma and improve patient outcomes.

Introduction

Childhood tumors of the lung are rare malignant tumors accounting for 0.5% to 1% of all primary malignant lung tumors. These tumors are subdivided into 3 subtypes: pulmonary blastoma, fetal adenocarcinoma, and pleuropulmonary blastoma (PPB). An epithelial malignant and immature component characterizes fetal adenocarcinoma. A malignant immature mesenchymal proliferation characterizes the pleuropulmonary blastoma. Biphasic components define the blastoma; a mesenchymal and an epithelial malignant and immature component, that look like a 10- to 16-week gestational lung. In the 2015 World Health Organization Classification, fetal adenocarcinoma belongs to the group of adenocarcinomas, pulmonary blastoma belongs to the group of sarcomatoid carcinoma, and pleuropulmonary blastoma belongs to the group of mesenchymal tumors. Pleuropulmonary blastomas are rare tumors which present non-specific symptoms. Although the importance of the radiologic features to suspect the diagnosis, the positive diagnosis remains based on the microscopic features.[1][2] Many synonyms of pleuropulmonary tumors exist in the literature including:

• Cystic mesenchymal hamartoma
• Mesenchymal cystic hamartoma
• Pediatric pulmonary blastoma
• Pneumoblastoma
• Pulmonary rhabdomyosarcoma
• Rhabdomyosarcoma in lung cyst

Etiology

Genetic forms have been identified in 40% of the cases. They are called the pleuropulmonary blastoma family tumor and dysplasia syndrome or DICER1 syndrome. Patients suffer from neoplastic and dysplastic disease in the first 5 to 6 years of life with rare cases in adolescence. Germline loss-of-function mutations in DICER 1 have been identified in some families with loss of DICER 1 staining in epithelial cells. Most mutation carriers are unaffected.[3] Genetic forms can be suspected when dealing with patients presenting varying symptoms in association with respiratory symptoms such as irregular menstrual cycles or other symptoms related to sex hormone secretion.

Epidemiology

Pleuropulmonary blastomas are mainly diagnosed before 4 years of age. They are divided into:

• Type I pleuropulmonary tumors: Purely cystic tumors occurring in children younger than 2 years of age with a median age of 10 months
• Type II pleuropulmonary tumors: Cystic and solid tumors occurring at a median age of 35 months
• Type III pleuropulmonary tumors: Solid tumors occurring at a median age of 41 months[4][5]

Pathophysiology

One of the case series by Vargas et al. found that on cytogenetic analysis, polysomy of chromosome 8 is a constant feature of pleuropulmonary blastoma. In addition, the clonal proliferation in pleuropulmonary blastoma is mainly due to the multiplication of malignant mesenchymal elements, while epithelial components are mostly non-neoplastic.

PPB occurs not only in the lung, but it can also arise from mediastinum, diaphragm and/or pleura. This has led to the possibility that PPB may arise from the splanchnopleural or somatopleural mesoderm. Common metastatic sites include the brain, liver, bone, lymph nodes, kidney, pancreas and adrenal glands.

Histopathology

Gross findings vary according to the types of pleuropulmonary blastomas[6]:

• Type I  pleuropulmonary tumors consist of thin-walled structures.
• Type II pleuropulmonary tumors contain a mixture of solid and cystic lesions.
• Type III pleuropulmonary tumors present as a mass with a variegated cut surface that may be hemorrhagic and or necrotic.

Microscopic findings vary according to the different subtypes:

• Type I pleuropulmonary tumor is characterized by multicystic lesions lined by respiratory-type epithelium with the presence in the cystic wall of a population of small malignant cells that can lie as a continuous or discontinuous cambium layer zone. Areas of rhabdomyoblastic differentiation may be present such as immature cartilage.
• Type II pleuropulmonary tumor is characterized by a complete overgrowth of the septal stroma by sheets of primitive small cells without apparent differentiation, areas of embryonal rhabdomyosarcoma or fascicles of a spindle cell sarcoma.
• Type III pleuropulmonary blastoma is characterized by mixed sheets of blastematous and sarcomatous areas like chondrosarcoma-like, fibrosarcoma-like, rhabdomyosarcoma-like or anaplastic areas.

Morphologic features are mandatory to make the diagnosis, but the immunohistochemical study may be helpful in highlighting the diagnosis. Immunohistochemical studies show the reactivity of the tumor cells to vimentin and the reactivity of rhabdomyoblastic cells with the desmin antibody. Morphologically, Type II is similar to Wilms tumor and therefore, it is sometimes called as “extra-renal Wilms tumor”.

History and Physical

Signs and symptoms vary according to the different subtypes:

• Type I tumors are revealed by respiratory distress due to air-filled cysts compressing on airways with or without pneumothorax.
• Types II and III tumors are revealed by dyspnea and chest pain. These children may present with signs of pneumonia or other generalized symptoms such as cough, fever, difficulty breathing, fatigue, loss of energy and decreased appetite. 

Asymptomatic lesions revealed by a chest wall deformity or a tension pneumothorax have also been reported.[7]

Evaluation

Typically, pleuropulmonary blastomas involve the lung and the pleura. The CT-scan shoes either a mass or a consolidation. There may also be multiloculated cystic or solid changes. Fifty percent to 60% of type I lesions are limited to the lungs. Spread beyond the lung is more common in type II and III lesions.[8]

PPB appears to have a constitutional and heritable predisposition to other dysplastic or neoplastic diseases in approximately 25% of the patients. Associated conditions include medulloblastoma, thyroid neoplasia, malignant germ cell tumor and others. Thus, all patients with pleuropulmonary blastomas and their families should be evaluated carefully.

Treatment / Management

Patients with type I tumors are treated with surgical resection to diagnose the lesion and to treat it. Some authors advocate adjuvant chemotherapy, but there is no consensus. Radiation therapy is not used for type I PPB. If type I pleuropulmonary blastoma recurs in a child as type II or type III PPB, then the treatment options for types II and III disease are used.

Type II and III PPB are both aggressive tumors. For patients with types II and III lesions, surgical resection is recommended if feasible, followed by chemotherapy and/or radiation therapy. Intracavitary chemotherapy has been reported in the literature. There is a benefit of doxorubicin-based regimes. Recurrence is often local.

Radiation therapy can be used on individual basis in PPB patients. In general, if there is a small part of tumor that cannot be removed surgically and is resistant to chemotherapy, then radiation can be considered. Pleuropulmonary blastomas can widely metastasize. When PPB spreads to the brain, surgery followed by radiation therapy is often advised.  For recurrent tumors, we recommend high-dose consolidation therapy with autologous stem cell rescue.[9]

Differential Diagnosis

The major differential diagnoses are represented by synovial sarcoma, congenital cystic adenomatoid malformations, and fetal lung interstitial tumor.

• Synovial sarcoma is characterized by the presence of spindle cells that can be associated with ovoid cells that are reactive for epithelial membrane antigen, cytokeratin, and CD99. This reactivity is not noticed in pleuropulmonary blastoma. Molecular analyses are helpful when assessing DI-CER1 mutation and X;18 translocations [10][11] as they are mimickers of type I pleuropulmonary blastomas. The presence of blastematous areas is a diagnostic feature of pleuropulmonary blastoma.
• Fetal lung interstitial tumor is characterized by features resembling the lung at 20 to 24 weeks gestation.

Staging

There is no consensual staging system for pleuropulmonary blastomas. Recommendations are to perform chest and abdominal CT-scan in type I tumors and chest and abdominal CT-scan with head MRI and bone scan in type II and III tumors.[12]

Prognosis

Patients with type I tumors have 80% to 90% 5-year, disease-free survival. Patients with types II and III tumors present a 5-year, disease-free survival inferior to 50%.[6]

Pearls and Other Issues

Many authors reported gains in chromosome 8, especially trisomy with losses in chromosomes 9 and 11. The DICER1 gene is located on chromosome 14q. Patients with pleuropulmonary blastomas should undergo surveillance in relation to the possibility of the appearance of other tumors. Surveillance of siblings or family members is more controversial due to the need to balance the modest risk of tumor development against the possibility of caused anxiety.

In addition to pleuropulmonary blastoma, DICER1 syndrome can be associated with other tumors such as ovarian tumors including Sertoli-Leydig cell tumors, multinodular goiter, or thyroid carcinomas. The association to these tumors can make the symptoms and signs more challenging and unspecific. Thinking about such a syndrome is mandatory when dealing with a patient presenting respiratory symptoms and other hormonal or extrapulmonary symptoms.

Enhancing Healthcare Team Outcomes

Pleuropulmonary blastomas are very rare tumors in young children. They have a diverse presentation and are best managed by an interprofessional team including oncology nurses. Surgery is the treatment of choice but recent reports suggest chemotherapy. Without any guidelines, each case is managed according to personal experience and available facilities

For patients with types II and III lesions, surgical resection is recommended if feasible, followed by chemotherapy and/or radiation therapy. Intracavitary chemotherapy has been reported in the literature. There is a benefit of doxorubicin-based regimes. Recurrence is often local. Pleuropulmonary blastomas can widely metastasize. For recurrent tumors, we recommend high-dose consolidation therapy with autologous stem cell rescue.