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Advances in Anatomic Pathology Sep 2022DICER1 syndrome is a tumor predisposition syndrome in which patients are at an increased risk of developing a wide variety of benign and malignant neoplasms with a... (Review)
Review
DICER1 syndrome is a tumor predisposition syndrome in which patients are at an increased risk of developing a wide variety of benign and malignant neoplasms with a hallmark constellation of pediatric pleuropulmonary blastoma, cystic nephroma, and thyroid lesions. DICER1 encodes an RNA endoribonuclease that is crucial to the processing of microRNA and may play a role in the maturation of Müllerian tissue. Within the gynecologic tract, germline mutations in DICER1 are associated with an array of rare tumors, including Sertoli-Leydig cell tumor, embryonal rhabdomyosarcoma of the cervix, gynandroblastoma, and juvenile granulosa cell tumor, which typically present in childhood, adolescence, or early adulthood. In addition, somatic DICER1 mutations have been described in rare gynecologic tumors such as adenosarcoma, Sertoli cell tumor, ovarian fibrosarcoma, cervical primitive neuroectodermal tumor, carcinosarcoma, and germ cell tumors. In light of the significant association with multiple neoplasms, genetic counseling should be considered for patients who present with a personal or family history of these rare DICER1-associated gynecologic tumors. This review highlights the most current understanding of DICER1 genetic alterations and describes the clinical, histopathologic, and immunohistochemical features and differential diagnoses for gynecologic tumors associated with DICER1 mutation.
Topics: Adolescent; Adult; DEAD-box RNA Helicases; Diagnosis, Differential; Female; Fibrosarcoma; Genital Neoplasms, Female; Genitalia, Female; Germ-Line Mutation; Humans; Mutation; Ovarian Neoplasms; Ribonuclease III
PubMed: 35778792
DOI: 10.1097/PAP.0000000000000351 -
Diagnosis and treatment of pleuropulmonary blastoma in children: A single-center report of 41 cases.Journal of Pediatric Surgery Jul 2020This study was performed to investigate the age at onset, clinical manifestations, pathological types and features, treatment, and prognosis of pleuropulmonary blastoma...
OBJECTIVE
This study was performed to investigate the age at onset, clinical manifestations, pathological types and features, treatment, and prognosis of pleuropulmonary blastoma (PPB) in children in an attempt to reduce the misdiagnosis rate and achieve early detection and timely intervention.
METHODS
We retrospectively studied the clinical data of 41 pediatric patients with PPB who were treated in our center from March 2002 to November 2018. The data comprised the age at onset, clinical manifestations, characteristics of familial diseases, pathological types, surgical procedures, and prognosis.
RESULTS
Twenty male and 21 female patients were included, with a 0.95:1.00 male:female ratio. In total, 51.2% of the patients were misdiagnosed as having nonneoplastic lesions at the first presentation. The interval from symptom onset to surgery/chemotherapy ranged from 5 to 210 days. The pathological types were type I (cystic) PPB (n = 5, 11.9%), for which the median age at diagnosis was 21 months (range, 8-24 months); (solid/cystic) II PPB (n = 12, 28.6%), for which the median age at diagnosis was 37 months (range, 22-112 months); and type III (solid) PPB (n = 23, 54.8%), for which the median age at diagnosis was 39 months (range, 19-156 months). The pathologic type was undefined in one patient (2.4%). The patients were mainly treated by surgery and chemotherapy. The 5-year disease-free survival rate was 69.2%.
CONCLUSION
The clinical manifestations of PPB are nonspecific, its misdiagnosis rate is high, and it has a poor prognosis. Pediatricians should be aware of the seriousness of PPB. The possibility of PPB should be considered in children with pneumothorax, multiple pulmonary cystic lesions, a family history of pulmonary cysts, a family history of PPB, or space-occupying lesions associated with DICER1 syndromes. The lesion should be closely monitored and surgically removed if necessary. The nature of the lesion should be identified early to minimize the risk of progression of the PPB to worse types because of misdiagnosis and missed diagnosis. Multidisciplinary treatment including surgery, chemotherapy, and/or radiotherapy can be applied to patients with PPB.
TYPE OF STUDY
Treatment study.
LEVEL OF EVIDENCE
Level III.
Topics: Child; Child, Preschool; Diagnostic Errors; Female; Humans; Infant; Male; Pulmonary Blastoma; Retrospective Studies
PubMed: 31277979
DOI: 10.1016/j.jpedsurg.2019.06.009 -
Pediatric and Developmental Pathology :... 2021Pleuropulmonary blastoma (PPB), a rare childhood neoplasm of the lung, is linked to pathogenic variants. We investigated checkpoint inhibitor markers including...
INTRODUCTION
Pleuropulmonary blastoma (PPB), a rare childhood neoplasm of the lung, is linked to pathogenic variants. We investigated checkpoint inhibitor markers including Programmed Death Ligand 1 (PD-L1), PD1, CD8 and tumor mutational burden (TMB) in PPB.
MATERIAL AND METHODS
Cases were collected from departmental archives and the International PPB/ Registry. Immunohistochemistry (IHC) for PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) genes were performed. In addition, normal-tumor paired whole exome sequencing (WES) was performed in two cases.
RESULTS
Twenty-five PPB cases were studied, consisting of Type I (n = 8, including 2 Ir), Type II (n = 8) and Type III (n = 9). PD-L1 combined positive score (CPS) of 1, 4 and 80 was seen in three (3/25, 12.0%) cases of Type II PPB with negative staining in the remaining cases. PD-1 and CD8 stains demonstrated positive correlation ( < .05). The density of PD1 and CD8 in the interface area was higher than within tumor ( < .05). The MMR proteins were retained. TMB was 0.65 mutations/Mb in type II PPB with high expression of PD-L1, and 0.94 mutations/Mb in one negative PD-L1 case with metastatic tumor.
CONCLUSION
A small subpopulation of PPB patient might benefit from checkpoint immunotherapy due to positive PD-L1 staining.
Topics: B7-H1 Antigen; Biomarkers, Tumor; Child; DEAD-box RNA Helicases; Humans; Lung Neoplasms; Mutation; Pulmonary Blastoma; Ribonuclease III
PubMed: 34266329
DOI: 10.1177/10935266211027417 -
Pediatric Hematology and Oncology Feb 2021Pleuropulmonary blastoma (PPB) is a rare malignant tumor in childhood cancer. This type of tumor is difficult to identify and can easily be misdiagnosed. The...
Pleuropulmonary blastoma (PPB) is a rare malignant tumor in childhood cancer. This type of tumor is difficult to identify and can easily be misdiagnosed. The International PPB protocol is a complicated and aggressive protocol. It is not easily applicable to developing countries where hospitals do not have enough resources. Here we present a challanging case of a patient successfully treated in Vietnam, using limited medical resources. The patient (22 month old, male) was diagnosed with congenital cystic adenomatoid malformation in his 1 hospital admission. After 6 months of onset, the patient was diagnosed with PPB type II in the fourth hospitalization following analysis of a lung CT scan and a pathology report. After the aggressive chemotherapy regimen, the patient had two episodes of severe neutropenia and infection from which he recovered. The patient received chemotherapy and surgery treatment at our hospital, but received radiation under general anesthesia and rehabilitation therapy to improve respiration at another hospital over 600 km away. It has been 1.5 years after entering remission, and he is starting kindergarten. Lung CT scan and pathology should be analyzed to avoid missing diagnosis of PPB in patients with cystic or mixed cystic and solid lung lesions. Biopsies from cases of suspected PPB should be sent for expert pathology review. Two factors important to the successful application of the protocol are good supportive care and the multidisciplinary collaboration between medical facilities to provide proper resources during treatment. We hope to recreate more successful outcomes not only in Vietnam but also in all developing countries.
Topics: Humans; Infant; Male; Pulmonary Blastoma; Vietnam
PubMed: 32985315
DOI: 10.1080/08880018.2020.1818905 -
Acta Neuropathologica Apr 2020DICER1 syndrome is a rare tumor predisposition syndrome with manifestations that predominantly affect children and young adults. The syndrome is typically caused by... (Review)
Review
DICER1 syndrome is a rare tumor predisposition syndrome with manifestations that predominantly affect children and young adults. The syndrome is typically caused by heterozygous germline loss-of-function DICER1 alterations accompanied on the other allele by somatic missense mutations occurring at one of a few mutation hotspots within the sequence encoding the RNase IIIb domain. DICER1 encodes a member of the microRNA biogenesis machinery. The syndrome spectrum is highly pleiotropic and features a unique constellation of benign and malignant neoplastic and dysplastic lesions. Pleuropulmonary blastoma (PPB), the most common primary lung cancer in children, is the hallmark tumor of the syndrome. Other manifestations include ovarian Sertoli-Leydig cell tumor, cystic nephroma arising in childhood, multinodular goiter, thyroid carcinoma, anaplastic sarcoma of the kidney, embryonal rhabdomyosarcoma, and nasal chondromesenchymal hamartoma, in addition to other rare entities. Several central nervous system (CNS) manifestations have also been defined, including metastases of PPB to the cerebrum, pituitary blastoma, pineoblastoma, ciliary body medulloepithelioma, and most recently primary DICER1-associated CNS sarcomas and ETMR-like infantile cerebellar embryonal tumor. Macrocephaly is a recently reported non-neoplastic, haploinsufficient phenotype. In this manuscript, we review the CNS manifestations of DICER1 syndrome.
Topics: Brain Neoplasms; DEAD-box RNA Helicases; Genetic Predisposition to Disease; Humans; Megalencephaly; Mutation; Neoplastic Syndromes, Hereditary; Ribonuclease III
PubMed: 30953130
DOI: 10.1007/s00401-019-01997-y -
Journal of Clinical Oncology : Official... Feb 2023Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a...
PURPOSE
Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis.
METHODS
Patients with known or suspected PPB were enrolled in the International PPB/ Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort.
RESULTS
From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively.
CONCLUSION
The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.
Topics: Child; Humans; DEAD-box RNA Helicases; Doxorubicin; Lung Neoplasms; Pulmonary Blastoma; Registries; Ribonuclease III
PubMed: 36137255
DOI: 10.1200/JCO.21.02925 -
Annals of Diagnostic Pathology Oct 2022DICER1-related tumors occur hereditary or sporadically, with high-grade malignancies sharing clinicopathological and (epi)genetic features. We compared 4 pleuropulmonary... (Comparative Study)
Comparative Study
Pleuropulmonary blastoma (PPB) and other DICER1-associated high-grade malignancies are morphologically, genetically and epigenetically related - A comparative study of 4 PPBs and 6 sarcomas.
DICER1-related tumors occur hereditary or sporadically, with high-grade malignancies sharing clinicopathological and (epi)genetic features. We compared 4 pleuropulmonary blastomas (PPBs) and 6 sarcomas by mutation analysis, whole transcriptome sequencing and methylation profiling. 9/10 patients were female. PPB patients were 0-4 years. 3/4 were alive; 2 without disease. One patient died of metastatic disease (median follow-up, 16 months). Sarcoma patients were 16-56 years. Locations included: uterine cervix/corpus (3/1), soft tissue back/shoulder (1) and paravertebral (1). 5/6 patients were alive; 2 developed metastases: intracranial (1) and lung and kidney (1) (median follow-up, 17 months). The deceased patient previously had a PPB and a Sertoli-Leydig cell tumor. Histologically, tumors showed atypical primitive-looking cells with incomplete rhabdomyoblastic differentiation and cartilage (n = 5). Immunohistochemistry demonstrated desmin- (n = 9/10), myogenin- (n = 6/10) and keratin positivity (n = 1/1). Eight cases harbored biallelic DICER1 mutations with confirmed germline mutations in 4 cases. Two cases showed a monoallelic mutation. By RNA expression- and methylation profiling, distinct clustering of our cases was seen demonstrating a close relationship on (epi)genetic level and similarities to embryonal rhabdomyosarcoma. In conclusion, this study shows overlapping morphological, immunohistochemical and (epi)genetic features of PPBs and DICER1-associated high-grade sarcomas, arguing that these neoplasms form a spectrum with a broad clinicopathological range.
Topics: Female; Humans; Male; DEAD-box RNA Helicases; Desmin; Keratins; Mutation; Myogenin; Pulmonary Blastoma; Rhabdomyosarcoma, Embryonal; Ribonuclease III; RNA; Soft Tissue Neoplasms
PubMed: 35779311
DOI: 10.1016/j.anndiagpath.2022.152002