Pleuropulmonary Blastoma

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](B2)

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]