-
Lung India : Official Organ of Indian... 2021Fetal lung interstitial tumor (FLIT) is a rare pediatric lung tumor with radiological features similar to developmental pulmonary malformations and other congenital lung...
Fetal lung interstitial tumor (FLIT) is a rare pediatric lung tumor with radiological features similar to developmental pulmonary malformations and other congenital lung neoplasms. There are about 17 cases of FLIT reported worldwide till date. We report the first case of FLIT in the Indian literature which was diagnosed in the early postnatal period (at the 21 day of life) by pathological examination. The tumor exhibited a novel focal micropapillary architecture, in addition to the previously described microscopic features. We discuss the pathogenesis and differential diagnoses of FLIT and review the literature.
PubMed: 33687015
DOI: 10.4103/lungindia.lungindia_646_20 -
Modern Pathology : An Official Journal... Jun 2021Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic),...
Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): a report from the International Pleuropulmonary Blastoma/DICER1 Registry.
Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic), type II (cystic and solid), and type III (solid). Prognosis varies by PPB type. Most cases are associated with a germline pathogenic mutation in DICER1; however, there is limited data on the factor(s) at a cellular level that drive progression from type I to type III. In this study, we evaluated the expression of p53 and its prognostic implications. A total of 143 PPB cases were included in the study with the following distribution in PPB types: Ir (14%), I (23%), II (32%), and III (31%). P53 expression by immunohistochemistry (IHC) was recorded as four groups: 0%, 1-25%, 26-75%, and 76-100%. All type I PPBs showed 0-25% p53 expression compared to the higher p53 expression (>25%) in type III PPB (p < 0.0001), to support the argument that p53 has a role in tumor progression. In addition, type Ir with the architectural hallmarks of type I PPB, but lacking the primitive cell population, has negligible p53 expression. High p53 expression (staining observed in >25% of the tumor cells) was significantly associated with age over 1 year (p = 0.0033), neoadjuvant therapy (p = 0.0009), positive resection margin (p = 0.0008) and anaplasia (p < 0.0001). P53 expression was significantly associated with recurrence-free survival (p < 0.0001) and overall survival (p = 0.0350), with higher p53 expression associated with worse prognosis. Comparisons of concordance statistics showed no significant difference in prognostication when using morphologic types compared to p53 expression groups (p = 0.647). TP53 sequence was performed in 16 cases; the most common variant identified was a missense variant (12 cases), and in one case a frameshift truncating variant was noted. Based on these findings, we recommend performing p53 IHC in all newly diagnosed cases of types II and III PPB to further aid in risk stratification.
Topics: Adolescent; Biomarkers, Tumor; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Prognosis; Pulmonary Blastoma; Registries; Survival Analysis; Tumor Suppressor Protein p53; Young Adult
PubMed: 33637876
DOI: 10.1038/s41379-021-00735-8 -
JAMA Network Open Feb 2021Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate...
IMPORTANCE
Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort.
OBJECTIVE
To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018.
MAIN OUTCOMES AND MEASURES
Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry.
RESULTS
A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype.
CONCLUSIONS AND RELEVANCE
This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; DEAD-box RNA Helicases; Female; Genome; Germ-Line Mutation; Goiter, Nodular; Graves Disease; Heterozygote; Humans; Hypothyroidism; Kidney Neoplasms; Loss of Function Mutation; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Penetrance; Phenotype; Prevalence; Pulmonary Blastoma; Ribonuclease III; Sarcoma; Sertoli-Leydig Cell Tumor; Sex Cord-Gonadal Stromal Tumors; Testicular Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Thyroid Nodule; Thyroidectomy; Thyrotoxicosis; Wilms Tumor; Young Adult
PubMed: 33630087
DOI: 10.1001/jamanetworkopen.2021.0112 -
Blood Advances Jan 2021Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder. Murine models with the loss of DICER1 in hematopoietic... (Review)
Review
Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder. Murine models with the loss of DICER1 in hematopoietic stem cell progenitors demonstrate hematologic aberrations that include reductions in red and white blood cell counts, hemoglobin volume, and impaired maturation resulting in dysplasia. We investigated whether hematologic abnormalities such as those observed in DICER1-deficient mice were observed in humans with a pathogenic germline variant in DICER1. A natural history study of individuals with germline pathogenic DICER1 variants and family controls conducted through the National Cancer Institute (NCI) evaluated enrollees at the National Institutes of Health Clinical Center during a comprehensive clinical outpatient visit that included collecting routine clinical laboratory studies. These were compared against normative laboratory values and compared between the DICER1 carriers and controls. There were no statistical differences in routine clinical hematology laboratory studies observed in DICER1 carriers and family controls. A review of the medical history of DICER1 carriers showed that none of the individuals in the NCI cohort developed myelodysplastic syndrome or leukemia. Query of the International Pleuropulmonary Blastoma/DICER1 Registry revealed 1 DICER1 carrier who developed a secondary leukemia after treatment of pleuropulmonary blastoma. We found limited evidence that the hematologic abnormalities observed in murine DICER1 models developed in our cohort of DICER1 carriers. In addition, no cases of myelodysplastic syndrome were observed in either the NCI cohort or the International Pleuropulmonary Blastoma/DICER1 Registry; 1 case of presumed secondary leukemia was reported. Abnormalities in hematologic indices should not be solely attributed to DICER1. This trial was registered at www.clinicaltrials.gov as #NCT01247597.
Topics: Animals; DEAD-box RNA Helicases; Germ Cells; Germ-Line Mutation; Hematology; Mice; Neoplasms; Pulmonary Blastoma; Ribonuclease III
PubMed: 33570641
DOI: 10.1182/bloodadvances.2020002651 -
Pathobiology : Journal of... 2021Pleuropulmonary blastoma (PPB) is a rare sarcomatous malignancy involving the lung and pleura which occurs in early childhood. Cystic PPB in the early stage can be...
INTRODUCTION
Pleuropulmonary blastoma (PPB) is a rare sarcomatous malignancy involving the lung and pleura which occurs in early childhood. Cystic PPB in the early stage can be misdiagnosed as other cystic diseases. Early detection of this entity is important for appropriate treatment and prevention of disease progression. Hotspot mutations in the ribonuclease IIIb (RNase IIIb) domain of DICER1 have been reported to have a crucial role as genetic factors of PPB and DICER1 familial syndrome. We reviewed the clinicopathologic findings of PPB and the status of DICER1 hotspot mutation and patients' clinical course.
METHODS
We retrospectively reviewed all patients with histologically confirmed PPB at Asan Medical Center between 2000 and 2017. Ten cases were identified in the database, and their clinicopathologic parameters were evaluated. PPB was classified into the following 3 pathologic subtypes: type I (purely cystic), type II (mixed cystic and solid), and type III (entirely solid). The status of DICER1 mutation in 2 hotspot regions of the RNase IIIb domain was evaluated by Sanger sequencing.
RESULTS
The most frequent PPB type was II (6 cases), followed by I and III (2 cases each). The age at diagnosis ranged from 16 months to 15 years. All patients underwent surgery, and all patients received adjuvant or neoadjuvant chemotherapy. Four of 7 patients had missense mutations in the RNase IIIb hotspot; the base and predicted corresponding amino acid changes were c.5113 G>A (p.E1705K), c.5407 G>A (p.E1803K), c.5425 G>A (p.G1809R), and c.5428 G>T (p.D1810Y). There was no particular association between the presence of the hotspot mutation and histologic type. Nine patients survived with no evidence of disease for a median interval of 93 (range, 13-199) months. Only 1 patient diagnosed with type III PPB at the age of 18 years had recurrence after 20.8 months and eventually died 66 months after the initial diagnosis.
CONCLUSIONS
Late detection of solid PPB is associated with poor prognosis. Considering the rarity of PPB disease and the importance of DICER1 hotspot mutation in pathogenesis, DICER1 hotspot mutation testing and identification in the early cystic stage can improve patient outcomes.
Topics: Adolescent; Child; Child, Preschool; DEAD-box RNA Helicases; Female; Germ-Line Mutation; Humans; Infant; Lung Neoplasms; Male; Pulmonary Blastoma; Retrospective Studies; Ribonuclease III
PubMed: 33567437
DOI: 10.1159/000512957 -
Frontiers in Oncology 2020DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the gene. The risk to present a neoplasm before the age of 10... (Review)
Review
DICER1 syndrome is a rare genetic condition predisposing to hereditary cancer and caused by variants in the gene. The risk to present a neoplasm before the age of 10 years is 5.3 and 31.5% before the age of 60. variants have been associated with a syndrome involving familial pleuropulmonary blastoma (PPB), a rare malignant tumor of the lung, which occurs primarily in children under the age of 6 years and represents the most common life-threatening manifestation of DICER1 syndrome. Type I, II, III, and Ir (type I regressed) PPB are reported with a 5-year overall survival ranging from 53 to 100% (for type Ir). gene should be screened in all patients with PPB and considered in other tumors mainly in thyroid neoplasms (multinodular goiter, thyroid cancer, adenomas), ovarian tumors (Sertoli-Leydig cell tumor, sarcoma, and gynandroblastoma), and cystic nephroma. A prompt identification of this syndrome is necessary to plan a correct follow-up and screening during lifetime.
PubMed: 33552988
DOI: 10.3389/fonc.2020.614541 -
Clinical Case Reports Dec 2020Pulmonary cysts and neoplasms, especially congenital or occurring at a young age, should be thoroughly investigated. Evaluation for mutations should be performed if...
Pulmonary cysts and neoplasms, especially congenital or occurring at a young age, should be thoroughly investigated. Evaluation for mutations should be performed if there is a family history of this syndrome, the lung cyst/neoplasm is a pleuropulmonary blastoma, or other clinical manifestations of this syndrome are present or develop.
PubMed: 33363744
DOI: 10.1002/ccr3.3098 -
Pediatric Blood & Cancer May 2021
Topics: Brain Neoplasms; Child, Preschool; Female; Humans; Lung Neoplasms; Male; Pulmonary Blastoma
PubMed: 33258270
DOI: 10.1002/pbc.28825 -
Translational Andrology and Urology Oct 2020Multiple genetic conditions predispose to the development of rhabdomyosarcoma. Much of the literature on rhabdomyosarcoma in genetic syndromes does not sub-divide the... (Review)
Review
Multiple genetic conditions predispose to the development of rhabdomyosarcoma. Much of the literature on rhabdomyosarcoma in genetic syndromes does not sub-divide the location or the pathology of the sarcomas. Therefore, there are limited data on genitourinary specific associations with certain genetic syndromes. We summarize, here, the primary differential considerations for rhabdomyosarcoma of the genitourinary system. Primary considerations include pathogenic variation, Li-Fraumeni syndrome, constitutional mismatch repair deficiency, mosaic variegated aneuploidy, neurofibromatosis type 1, Noonan syndrome, other RASopathies, Costello syndrome, and Beckwith-Wiedemann syndrome. Some conditions may present with specific pathological, clinical and/or family history features, but for others, the genitourinary tumor may be the only presenting sign at the time of diagnosis. Genetic evaluation with counseling and/or testing may help identify an underlying tumor predisposition. This manuscript serves as an introduction to germline considerations for children with genitourinary rhabdomyosarcoma.
PubMed: 33209717
DOI: 10.21037/tau-20-76 -
Disease Models & Mechanisms Nov 2020Pleuropulmonary blastoma (PPB) is a very rare pediatric lung disease. It can progress from abnormal epithelial cysts to an aggressive sarcoma with poor survival. PPB is...
Pleuropulmonary blastoma (PPB) is a very rare pediatric lung disease. It can progress from abnormal epithelial cysts to an aggressive sarcoma with poor survival. PPB is difficult to diagnose as it can be confounded with other cystic lung disorders, such as congenital pulmonary airway malformation (CPAM). PPB is associated with mutations in that perturb the microRNA (miRNA) profile in lung. How and miRNAs act during PPB pathogenesis remains unsolved. Lung epithelial deletion of the Yin Yang1 () gene in mice causes a phenotype mimicking the cystic form of PPB and affects the expression of key regulators of lung development. Similar changes in expression were observed in PPB but not in CPAM lung biopsies, revealing a distinctive PPB molecular signature. Deregulation of molecules promoting epithelial-mesenchymal transition (EMT) was detected in PPB specimens, suggesting that EMT might participate in tumor progression. Changes in miRNA expression also occurred in PPB lung biopsies. miR-125a-3p, a candidate to regulate expression and lung branching, was abnormally highly expressed in PPB samples. Together, these findings support the concept that reduced expression of YY1, due to the abnormal miRNA profile resulting from mutations, contributes to PPB development via its impact on the expression of key lung developmental genes.This article has an associated First Person interview with the joint first authors of the paper.
Topics: A549 Cells; Animals; Base Sequence; Biomarkers; Biopsy; Cadherins; Disease Progression; Epithelial Cells; Epithelial-Mesenchymal Transition; Epithelium; Fibroblast Growth Factor 9; Gene Deletion; Gene Expression Regulation; HEK293 Cells; Humans; Lung; Mice; MicroRNAs; Models, Biological; Protein Isoforms; Pulmonary Blastoma; Receptor, Fibroblast Growth Factor, Type 2; YY1 Transcription Factor; Zinc Finger E-box-Binding Homeobox 1
PubMed: 33158935
DOI: 10.1242/dmm.045989