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Oncogenesis Sep 2019Pleuropulmonary blastoma (PPB) is a rare pediatric lung neoplasm that recapitulates developmental pathways of early embryonic lungs. As lung development proceeds with...
Pleuropulmonary blastoma (PPB) is a rare pediatric lung neoplasm that recapitulates developmental pathways of early embryonic lungs. As lung development proceeds with highly regulated mesenchymal-epithelial interactions, a DICER1 mutation in PPB generates a faulty lung differentiation program with resultant biphasic tumors composed of a primitive epithelial and mesenchymal stroma with early progenitor blastomatous cells. Deciphering of PPB progression has been hampered by the difficulty of culturing PPB cells, and specifically progenitor blastomatous cells. Here, we show that in contrast with in-vitro culture, establishment of PPB patient-derived xenograft (PDX) in NOD-SCID mice selects for highly proliferating progenitor blastoma overexpressing critical regulators of lung development and multiple imprinted genes. These stem-like tumors were sequentially interrogated by gene profiling to show a FGF module that is activated alongside Neural cell adhesion molecule 1 (NCAM1). Targeting the progenitor blastoma and these transitions with an anti-NCAM1 immunoconjugate (Lorvotuzumab mertansine) inhibited tumor growth and progression providing new paradigms for PPB therapeutics. Altogether, our novel in-vivo PPB xenograft model allowed us to enrich for highly proliferating stem-like cells and to identify FGFR and NCAM1 as two key players that can serve as therapeutic targets in this poorly understood and aggressive disease.
PubMed: 31477684
DOI: 10.1038/s41389-019-0156-9 -
Respiratory Medicine Case Reports 2023Pleuropulmonary blastoma (PPB) is a rare primitive malignant lung cancer that occurs in pediatric age. Its main differential diagnosis is congenital cystic pulmonary...
Pleuropulmonary blastoma (PPB) is a rare primitive malignant lung cancer that occurs in pediatric age. Its main differential diagnosis is congenital cystic pulmonary malformation (CPAM). A 30-day-old infant with respiratory failure obtained a chest x-ray and a computed tomography scan (CT) which revealed hypertensive pneumothorax with multifocal bilateral cysts. After thoracic drainage, the patient underwent multiple thoracoscopic pulmonary resections. The first histological diagnosis was of type 2 CPAM. During the radiological follow-up, an increase in the number and dimension of the lesions was detected. Thus, a histological revision was performed, leading to the diagnosis of type I PPB, at nine months. The patient subsequently underwent chemotherapy. At the five-year follow-up appointment, chest magnetic resonance (MR) and CT scans showed a dimensional increase in size of the lesions, with the risk of recurrent pneumothorax. An upper right lobectomy and wedge resection of the residual cysts were performed. Control MR scans showed normalization of the lung parenchyma and the patient showed substantial clinical improvement.
PubMed: 36579078
DOI: 10.1016/j.rmcr.2022.101793 -
Gynecologic Oncology Mar 2020Germline pathogenic variation in DICER1 underlies a tumor-predisposition disorder with increased risk for cervical embryonal rhabdomyosarcoma and ovarian sex-cord...
OBJECTIVE
Germline pathogenic variation in DICER1 underlies a tumor-predisposition disorder with increased risk for cervical embryonal rhabdomyosarcoma and ovarian sex-cord stromal tumors, particularly Sertoli-Leydig cell tumors. The gynecologic and reproductive health of these females has not yet been described.
METHODS
All female subjects recruited from November 2011 to July 2018 participating in an epidemiologic study of families with pathogenic DICER1 germline variation were included in this cross-sectional analysis. Participant evaluation included obstetric-gynecologic history, physical examination, hormone testing, pelvic ultrasound and record review.
RESULTS
Of 64 females aged 2-72 years, fifteen underwent treatment for pleuropulmonary blastoma as children and three were treated for cervical embryonal rhabdomyosarcoma. Of nine patients reporting a history of ovarian tumors, all presented with virilization or amenorrhea; eight occurred in adolescence. Post-pubertal females with no history of ovarian tumors experienced normal pubertal development, reported regular menstrual cycles, were fertile and underwent natural menopause at median age of 52 years. Thirty-two of 33 women who tried to conceive successfully delivered liveborn children. Of these 32, 10 experienced pregnancy-related thyroid enlargement resulting in thyroidectomy within one year of pregnancy; nine others had undergone pre-pregnancy thyroidectomy.
CONCLUSION
In these DICER1-carrier females, DICER1-related gynecological tumors occurred during childhood or adolescence in some after which women generally experienced healthy reproductive lives. Individual education and screening for these tumors is warranted. The high rate of DICER1-related multinodular goiter resulting in pre- and post-pregnancy thyroidectomy underscores the importance of thyroid monitoring during pregnancy to ensure maternal and fetal wellbeing.
Topics: Adolescent; Adult; Aged; Amenorrhea; Child; DEAD-box RNA Helicases; Female; Genital Diseases, Female; Germ-Line Mutation; Humans; Male; Middle Aged; Ovarian Neoplasms; Pregnancy; Pulmonary Blastoma; Reproductive Health; Rhabdomyosarcoma, Embryonal; Ribonuclease III; Uterine Cervical Neoplasms; Young Adult
PubMed: 31952842
DOI: 10.1016/j.ygyno.2019.12.037 -
Modern Pathology : An Official Journal... May 2022This report documents a unique multicystic neoplasm of the liver in an 8-month-old boy with a heterozygous germline pathogenic DICER1 variant. This neoplasm, initially...
This report documents a unique multicystic neoplasm of the liver in an 8-month-old boy with a heterozygous germline pathogenic DICER1 variant. This neoplasm, initially considered most likely a mesenchymal hamartoma based on imaging, demonstrated the characteristic histologic pattern of embryonal rhabdomyosarcoma residing in the subepithelial or cambium layer-like zone of the epithelial-lined cysts. Thus, although the differential diagnosis includes mesenchymal hamartoma, a young child with a multicystic mass lesion in the liver, lung, or kidney should both raise the possibility of a germline pathogenic DICER1 variant and also not be mistaken for one of the other hepatic neoplasms of childhood.
Topics: Child; DEAD-box RNA Helicases; Hamartoma; Humans; Infant; Liver Neoplasms; Lung Neoplasms; Male; Pulmonary Blastoma; Ribonuclease III
PubMed: 34907324
DOI: 10.1038/s41379-021-00947-y -
BJR Case Reports Jul 2021Pleuropulmonary blastoma (PPB) is a rare malignant intrathoracic mesenchymal tumour with a variable aggressiveness. It is the most common primary malignancy in the lung...
Pleuropulmonary blastoma (PPB) is a rare malignant intrathoracic mesenchymal tumour with a variable aggressiveness. It is the most common primary malignancy in the lung during childhood. In this study, we present a case of a 3-year-old male child who complained of persistent dry cough. Radiographs suggested the diagnosis of PPB, which was been confirmed by the histo-pathological examination of a biopsy taken from the tumour under CT guidance. This case was reported to emphasise the importance of radiology, whether diagnotic or interventional, in diagnosing rare cases such as PPB.
PubMed: 35047198
DOI: 10.1259/bjrcr.20200206 -
Nagoya Journal of Medical Science Dec 2016Pulmonary blastoma (PB) is a rare form of lung tumour and is accountable for 0.25-0.5% of primary pulmonary malignancies. Initially pulmonary blastoma was divided into...
Pulmonary blastoma (PB) is a rare form of lung tumour and is accountable for 0.25-0.5% of primary pulmonary malignancies. Initially pulmonary blastoma was divided into three subtypes: biphasic pulmonary blastoma (BPB) consisting of an epithelial and mesenchymal component, well differentiated fetal adenocarcinoma (WDFA) built of well differentiated epithelium and a mesenchymal component and malignant pleuropulmonary blastoma (PPB). Prognosis in this type of cancer is really poor. We present a current review of literature and a clinical case report. Treatment of PB is very difficult. Data and recommendations about the treatment of pulmonary blastoma are still available therefore we should use only observations and clinical case reports.
PubMed: 28008207
DOI: 10.18999/nagjms.78.4.507 -
Radiology Case Reports Sep 2021Pleuropulmonary blastoma (PPB) is a rare but aggressive pediatric tumor originates from either lung or pleura. It was recently linked to the DICER I mutation as a part...
Pleuropulmonary blastoma (PPB) is a rare but aggressive pediatric tumor originates from either lung or pleura. It was recently linked to the DICER I mutation as a part of predisposition syndrome for different type of tumor. It is characterized histologically by a primitive, variably mixed blastomatous and sarcomatous tissue. PPB is classified into four subtypes: cystic (type I and type Ir); cystic and solid (type II); solid (type III). PPB has no characteristic imaging findings. Integrated imaging can help to make a differential diagnosis and to recognize the subtypes in order to set up therapy. An early recognition and differentiation from congenital airway malformations and other benign cysts are very important. The treatment consists in a multimodal therapy including surgery and chemoterapy. We report a case of 3 years old female admitted at our hospital with fever, non productive cough and dyspnea, who was diagnosed with type II PPB.
PubMed: 34345335
DOI: 10.1016/j.radcr.2021.06.022 -
The Journal of International Medical... Oct 2020Pulmonary blastoma (PB) is a very rare malignant lung tumor consisting of classic biphasic PB, well-differentiated fetal adenocarcinoma, and pleuropulmonary blastoma. We... (Review)
Review
Pulmonary blastoma (PB) is a very rare malignant lung tumor consisting of classic biphasic PB, well-differentiated fetal adenocarcinoma, and pleuropulmonary blastoma. We herein present an unusual case involving a patient with classic biphasic PB who underwent right upper lobe resection and subsequent treatment. No standard treatment guidelines are available for PB because of its rarity. Our patient received nedaplatin plus paclitaxel as adjuvant chemotherapy. After disease recurrence, the patient received two cycles of etoposide-cisplatin and six cycles of pemetrexed, bevacizumab, and carboplatin. Because of severe adverse effects of the chemotherapy, the patient was finally administered anlotinib, a new oral multikinase inhibitor. Both the tumor size and the serum tumor marker concentration decreased. In conclusion, surgical excision is the treatment of choice for PB. Chemotherapy in the present case resulted in PB activity that was consistent with the literature. Targeted therapies including antiangiogenic agents should be considered as a new treatment option for this rare disease.
Topics: Biomarkers, Tumor; Humans; Lung; Lung Neoplasms; Neoplasm Recurrence, Local; Pulmonary Blastoma
PubMed: 33107372
DOI: 10.1177/0300060520962394 -
Modern Pathology : An Official Journal... Oct 2020Since the original description of pathogenic germline DICER1 variation underlying pleuropulmonary blastoma (PPB), the spectrum of extrapulmonary neoplasms known to be...
Since the original description of pathogenic germline DICER1 variation underlying pleuropulmonary blastoma (PPB), the spectrum of extrapulmonary neoplasms known to be associated with DICER1 has continued to expand and now includes tumors of the ovary, thyroid, kidney, eye, and brain among other sites. This report documents our experience with another manifestation: a primitive sarcoma that resembles PPB and DICER1-associated sarcoma of the kidney. These tumors are distinguished by their unusual location in the peritoneal cavity, associated with visceral and/or parietal mesothelium. A total of seven cases were identified through pathology review in children presenting at a median age of 13 years (range 3-14 years). Primary sites of origin included the fallopian tube (four cases), serosal surface of the colon (one case), and pelvic sidewall (two cases). One case had pathologic features of type I PPB, another type Ir (regressed) PPB, and the remaining five had features of type II or III PPB with a mixed primitive sarcomatous pattern with or without cystic elements. All had a pathogenic DICER1 variation identified in germline and/or tumor DNA. PPB-like peritoneal tumors represent a newly described manifestation of DICER1 pathogenic variation whose pathologic features are also recapitulated in DICER1-related renal sarcoma, cervical embryonal rhabdomyosarcoma, and some Sertoli-Leydig cell tumors with heterologous elements. Tumors arising from the fallopian tube or elsewhere in the abdomen/pelvis, especially those with heterogeneous rhabdomyosarcomatous and/or cartilaginous differentiation, should prompt consideration of germline and tumor DICER1 testing.
Topics: Adolescent; Child; Child, Preschool; DEAD-box RNA Helicases; Female; Humans; Male; Mutation; Peritoneal Neoplasms; Pulmonary Blastoma; Ribonuclease III; Sarcoma
PubMed: 32415267
DOI: 10.1038/s41379-020-0558-4 -
Pediatric Blood & Cancer Mar 2022Extrapulmonary DICER1-associated sarcomas (DS) can harbor morphological features overlapping with pleuropulmonary blastoma. We report three children with intracranial...
Phenotypic similarities within the morphologic spectrum of DICER1-associated sarcomas and pleuropulmonary blastoma: Histopathologic features guide diagnosis in the LMIC setting.
Extrapulmonary DICER1-associated sarcomas (DS) can harbor morphological features overlapping with pleuropulmonary blastoma. We report three children with intracranial and genital tract sarcomas, suspected to have DS based on a heterogeneous yet defining combination of spindle-cell sarcomatous and blastemal morphology, with rhabdomyomatous differentiation. Foci of immature cartilage at diagnosis (n = 2/3) and increased neuroepithelial differentiation at recurrence (n = 1) were noted. Morphological suspicion prompted somatic testing at reference centers, confirming likely biallelic, loss-of-function, and "hotspot" missense DICER1 variants in all three tumors. This can serve as a model for this diagnosis in resource-limited settings and has implications for germline testing, surveillance, and tumor management.
Topics: Child; DEAD-box RNA Helicases; Developing Countries; Germ-Line Mutation; Humans; Pulmonary Blastoma; Ribonuclease III; Sarcoma; Soft Tissue Neoplasms
PubMed: 34913555
DOI: 10.1002/pbc.29466