DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma.

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.

Pleuropulmonary blastoma type I might arise in congenital pulmonary airway malformation type 4 by acquiring a Dicer 1 mutation.

Congenital pulmonary airway malformation (CPAM) occurs most commonly in infants. It is divided into 5 types. The most common types 1 and 2 are cystic, type 0 presents as bronchial buds without alveolar tissue, most likely corresponding to alveolar dysgenesis, while type 3 is composed of branching bronchioles and appears as a solid lesion. A defect in the epithelial-mesenchymal crosstalk might be the underlying mechanism for all. Type 4 is a peripheral cystic lesion with a thin cyst wall covered by pneumocytes. CPAM 4 has been mixed up with pleuropulmonary blastoma (PPB) type I and some authors question its existence. We investigated five cases of CPAM type 4 for the presence or absence of rhabdomyoblasts, and for markers associated with CPAM development. In addition, all cases were evaluated for mutations within the Dicer gene and for mutations of the RAS family of oncogenes. All five cases showed smooth muscle actin and desmin-positive cells; however, only one case showed a few cells positive for MyoD. The same case showed a mutation of Dicer 1. All cases were negative for mutations of the RAS family of genes. Fibroblast growth factor 10 was similarly expressed in all cases, and thus cannot be used to differentiate CPAM4 from PPB-I. Low expression of the proliferation marker Ki67 was seen in our CPAM 4 cases and the probable PPB-I case. YingYang-1 protein seems to play an active role in the development of PPB-I. CPAM 4 can be separated from PPB-I based on the presence of rhabdomyoblasts and mutations in Dicer 1 gene. These cells might not be numerous; therefore, all available tissue has to be evaluated. As CPAM 4 morphologically looks very similar to PPB-I, it might be speculated, that there exists a potential for progression from CPAM 4 to PPB-I, by acquiring somatic mutations in Dicer 1.

Congenital pulmonary airway malformations: state-of-the-art review for pediatrician's use.

Congenital pulmonary airway malformations or CPAM are rare developmental lung malformations, leading to cystic and/or adenomatous pulmonary areas. Nowadays, CPAM are diagnosed prenatally, improving the prenatal and immediate postnatal care and ultimately the knowledge on CPAM pathophysiology. CPAM natural evolution can lead to infections or malignancies, whose exact prevalence is still difficult to assess. The aim of this "state-of-the-art" review is to cover the recently published literature on CPAM management whether the pulmonary lesion was detected during pregnancy or after birth, the current indications of surgery or surveillance and finally its potential evolution to pleuro-pulmonary blastoma. CONCLUSION: Surgery remains the cornerstone treatment of symptomatic lesions but the postnatal management of asymptomatic CPAM remains controversial. There are pros and cons of surgical resection, as increasing rate of infections over time renders the surgery more difficult after months or years of evolution, as well as risk of malignancy, though exact incidence is still unknown. What is known: • Congenital pulmonary airway malformations (CPAM) are rare developmental lung malformations mainly antenatally diagnosed. • While the neonatal management of symptomatic CPAM is clear and includes prompt surgery, controversies remain for asymptomatic CPAM due to risk of infections and malignancies. What is new: • Increased rate of infection over time renders the surgery more difficult after months or years of evolution and pushes for recommendation of early elective surgery. • New molecular or pathological pathways may help in the distinction of type 4 CPAM from type I pleuropulmonary blastoma.

Malformación adenomatoidea quística y riesgo de tumores malignos pulmonares / Adenomatoid lung malformation and malignant tumors

Cystic adenomatoid malformation is the most frequent congenital pulmonary malformation. The usual treatment is surgical resection. However there is controversy over management in asymptomatic patients. The possible malignization would justify surgery of cystic lesions. Relation with pleuropulmonary blastoma has been described, however it is not clear whether this is a primary tumor or cyst malignization. Cystic adenomatoid malformation also has association with adenocarcinoma and rhabdomyosarcoma. Currently available evidence suggests surgical resection, despite the natural course of congenital lung cystic lesions is uncertain

La malformación adenomatoidea quística (MAQ) es la anomalía del desarrollo pulmonar más frecuente. El tratamiento habitual es la resección quirúrgica, no obstante existe controversia sobre el manejo en pacientes asintomáticos. La posible malignización de las lesiones quísticas es uno de los argumentos que justifican la cirugía en estos pacientes. Se ha descrito relación con blastoma pleuropulmonar, sin embargo no está claro si se trataría de una lesión quística que se maligniza o es una entidad diferente. También hay asociación con adenocarcinoma y rabdomiosarcoma . Actualmente se sugiere la resección quirúrgica como el tratamiento más adecuado, sin embargo la evolución natural de las lesiones quísticas pulmonares congénitas es incierta

The Radiologic and Pathologic Diagnosis of Biphasic Pulmonary Blastoma.

Pulmonary blastomas are rare malignancies, representing 0.25% to 0.5% of all primary lung neoplasms with often aggressive progression and poor prognosis. Clinical management of pulmonary blastomas depends on histologic subtype, staging, and presentation, and may consist of surgery, chemotherapy, and radiation. Biphasic pulmonary blastoma is a subtype of pulmonary blastoma that exhibits biphasic histology, with both epithelial and mesenchymal malignant elements. We report a case of biphasic pulmonary blastoma in a 33-year-old female with 1 pack per day history of smoking for approximately 16 years, who presented with left-sided pleuritic chest pain on deep inspiration without otherwise significant pat medical history. Imaging evaluation using chest radiography, computed tomography, and magnetic resonance imaging identified a heterogenous, well-circumscribed, left lower lobe mass with extensive necrosis and hemorrhage. No lymphadenopathy or distant metastasis was detected through imaging evaluation. Surgical resection of the tumor followed by histopathological analysis confirmed a biphasic pulmonary blastoma.

[Newborn with lung mass of uncommon etiology]. / Recién nacido con masa pulmonar de etiología infrecuente.

Thoracic masses in neonates usually respond to congenital anomalies of the respiratory system. They comprise a large number of diseases that can compromise the development of larynx, trachea, bronchi, pulmonary parenchyma and diaphragm or chest wall. Diagnosis is carried out during prenatal period by ultrasound in most cases. In others, respiratory distress is diagnosed during post-birth examination or later as a radiological finding. We present the case of a full term newborn with prenatal diagnosis of cystic "lung mass". Physical examination was unremarkable except for decreased breath sounds on the right lung. Different image studies were carried out to characterize the lesion. The patient underwent surgery and chemotherapy at fifth month of life. Pleuropulmonary blastoma diagnosis was confirmed by pathological study of the surgical specimen. This is a rare intrathoracic malignant tumor, appearing almost exclusively in children less than 7-years-old.

Recién nacido con masa pulmonar de etiología infrecuente / Newborn whit lung mass of uncommon etiology

En neonatología, las masas torácicas generalmente responden a anomalías congénitas del aparato respiratorio. Comprenden un extenso número de patologías que pueden comprometer el desarrollo de laringe, tráquea, bronquios, parénquima pulmonar, diafragma o pared torácica. El diagnóstico, en la mayoría de los casos, se efectúa en el período prenatal mediante ecografía. El resto se diagnostica por la clínica, difcultad respiratoria en el recién nacido, o es un hallazgo radiológico en el transcurso de la vida. Presentamos el caso de un recién nacido de término con diagnóstico prenatal de "masa pulmonar" con imágenes quísticas en su interior. Al examen físico solo presentó disminución de la entrada de aire en base derecha. Se realizaron diferentes estudios por imágenes para caracterizar mejor la lesión y estudiar su extensión. Al quinto mes de vida, el paciente fue sometido a tratamiento quirúrgico y quimioterápico. El estudio anatomopatológico de la pieza quirúrgica arrojó como diagnóstico "blastoma pleuropulmonar" (BPP), tumor intratorácico maligno, muy poco frecuente, que aparece casi exclusivamente en niños menores de 7 años.

Thoracic masses in neonates usually respond to congenital anomalies of the respiratory system. They comprise a large number of diseases that can compromise the development of larynx, trachea, bronchi, pulmonary parenchyma and diaphragm or chest wall. Diagnosis is carried out during prenatal period by ultrasound in most cases. In others, respiratory distress is diagnosed during post-birth examination or later as a radiological fnding. We present the case of a full term newborn with prenatal diagnosis of cystic "lung mass". Physical examination was unremarkable except for decreased breath sounds on the right lung. Different image studies were carried out to characterize the lesion. The patient underwent surgery and chemotherapy at ffth month of life. Pleuropulmonary blastoma diagnosis was confrmed by pathological study of the surgical specimen. This is a rare intrathoracic malignant tumor, appearing almost exclusively in children less than 7-years-old.

Clonality and heterogeneity of pulmonary blastoma from the viewpoint of genetic alterations: a case report.

Biphasic pulmonary blastoma is a rare lung tumor with epithelial and mesenchymal components. Genetic alterations in this tumor are largely unknown, except for the presence of beta-catenin and p53 mutations and the absence of KRAS mutation. To understand the molecular process of histogenesis of this tumor, a whole genome allelic imbalance (AI) scanning using a high-resolution single nucleotide polymorphism array as well as mutational analysis of the p53, EGFR, KRAS and beta-catenin genes were performed against the epithelial and mesenchymal components in the primary tumor and a metastatic tumor in a case of pulmonary blastoma. AI at chromosome regions 14q24-q32 and 17p11-p13 and beta-catenin mutation were commonly detected in all tumors. On the other hand, AI at chromosome regions 3p11-p14 and 9p21-p24 and p53 mutation were detected only in the mesenchymal component in the primary tumor but not in the epithelial component in the primary tumor and the brain metastasis. Likewise, AI at chromosome regions 6p24-p25 and 6q14-q27 was detected in the epithelial component in the primary tumor and the brain metastasis but not in the mesenchymal component in the primary tumor. Furthermore, the genetic alterations detected in the metastatic tumor were completely the same as those in the epithelial component in the primary tumor, indicating that a tumor cell(s) in the epithelial component in the primary tumor selectively metastasized to the brain. These results indicate that this biphasic tumor is of monoclonal origin and the phenotypic heterogeneity of the tumor is due to the differences in the accumulated genetic alterations in each component of the tumor.

Cytogenetic and p53 profiles in congenital cystic adenomatoid malformation: insights into its relationship with pleuropulmonary blastoma.

Congenital cystic adenomatoid malformation (CCAM), a developmental anomaly of lung, shares many features with the pediatric tumor pleuropulmonary blastoma (PPB). Both may show benign epithelium-lined cysts and mesenchymal proliferation, often with skeletal muscle differentiation. Before its recognition as a distinct entity, PPB was described in several reports as "rhabdomyosarcoma arising in CCAM." Abnormal karyotypes in PPB often show excess material from chromosome 8. It has also been suggested that PPB may harbor p53 mutations. We examined the karyotype and searched for p53 mutations (via immunostaining and single-strand conformation polymorphism analysis) in 11 CCAM and in 2 PPB. Karyotypes were normal in all CCAM and showed clonal abnormalities in both PPB. There was marked and diffuse immunopositivity for nuclear p53 in the epithelial cells of CCAM and PPB. Strong staining was also observed in approximately 50% of the stromal cells in all PPB, but was seen in the stroma of only 2 of 10 CCAM, where it was faint and focal. TP53 mutations were not identified in CCAM or PPB. We conclude that CCAM does not contain the clonal chromosomal aberrations reported in PPB and shows less stromal p53 immunostaining than PPB. Since p53 mutations were not identified in either entity, the observed p53 immunoreactivity may be caused by another mechanism; its role in PPB and CCAM pathogenesis remains to be determined. Overall, these findings provide evidence that CCAM is nonneoplastic. Although some may view CCAM as a PPB precursor, it remains biologically distinct in terms of karyotype and p53 status.

Pulmonary blastoma after liver transplant: a case report.

There is an increased risk of cancer after organ transplantation mainly due to the immunosuppressive therapy required in these patients. We report a case of biphasic pulmonary blastoma in an adult male who underwent liver transplant for hepatocellular carcinoma in March 1999, followed by immunosuppressive treatment and adjuvant chemotherapy with epirubicin. Disease-free survival lasted 18 months, then a diagnosis of biphasic pulmonary blastoma was made and the patient underwent a lung lobectomy. Five months after surgical resection a recurrence of this rare tumor was recorded and two cycles of cisplatin + etoposide and ifosfamide + etoposide and one cycle of second-line chemotherapy with vinorelbine were administered. The tolerability and the efficacy of this treatment were poor. The patient died less than one year after diagnosis. To our knowledge this is the first reported case of pulmonary blastoma in a transplant patient. Our findings confirm that organ transplant recipients deserve long-term medical surveillance also in the absence of graft complications, and that pulmonary blastoma is an aggressive tumor with a poor prognosis.

P53 gene mutations in pleuropulmonary blastomas.

Pleuropulmonary blastoma (PPB) is rare childhood tumor oniginating from either lung or pleura. Although several cytogenetic changes, such as tisomy 2, trisomy 8, and loss of 17p material, have been reported, evidence of gene mutations is still lacking. Pathologically, PPB shares similarities with rhabdomyosarcoma in which p53 mutations arefrequently detected. Possible implication of p53 mutations in PPB was investigated. PPBs of 3 patients were analyzed for occurrence of p53 mutations by using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method, and the nature of mutations was confirmed by direct sequencing. Two PPBs were confirmed to harbor p53 mutations. One was a Val to Leu substitution at codon 173, and another was a ArgArg to TrpCys substitution at codons 282 and 283. In each tumor, only the mutated allele was detected, suggesting inactivation of p53. Both patients with mutations had fatal outcome, while the remaining patient in whom no mutation was detected is disease free for 3 years after completion of treatment. The results raise the possibility that p53 inactivation can occur as a nonrandom genetic change involving the pathogenesis and outcome of PPB. Further studies in a larger series are necessary to clarify these matters.