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The American Journal of Surgical... Jun 2024DICER1 tumor predisposition syndrome results from pathogenic variants in DICER1 and is associated with a variety of benign and malignant lesions, typically involving...
DICER1 tumor predisposition syndrome results from pathogenic variants in DICER1 and is associated with a variety of benign and malignant lesions, typically involving kidney, lung, and female reproductive system. Over 70% of sarcomas in DICER1 tumor predisposition syndrome occur in females. Notably, pediatric cystic nephroma (pCN), a classic DICER1 tumor predisposition syndrome lesion, shows estrogen receptor (ER) expression in stromal cells. There are also renal, hepatic, and pancreatic lesions unassociated with DICER1 tumor predisposition syndrome that have an adult female predominance and are characterized/defined by ER-positive stromal cells. Except for pCN, the expression of ER in DICER1-associated lesions remains uninvestigated. In the present study, ER expression was assessed by immunohistochemistry in 89 cases of DICER1-related lesions and 44 lesions lacking DICER1 pathogenic variants. Expression was seen in stromal cells in pCN and pleuropulmonary blastoma (PPB) types I and Ir, whereas anaplastic sarcoma of kidney and PPB types II and III were typically negative, as were other solid tumors of non-Müllerian origin. ER expression was unrelated to the sex or age of the patient. Expression of ER showed an inverse relationship to preferentially expressed antigen in melanoma (PRAME) expression; as lesions progressed from cystic to solid (pCN/anaplastic sarcoma of kidney, and PPB types I to III), ER expression was lost and (PRAME) expression increased. Thus, in DICER1 tumor predisposition syndrome, there is no evidence that non-Müllerian tumors are hormonally driven and antiestrogen therapy is not predicted to be beneficial. Lesions not associated with DICER1 pathogenic variants also showed ER-positive stromal cells, including cystic pulmonary airway malformations, cystic renal dysplasia, and simple renal cysts in adult kidneys. ER expression in stromal cells is not a feature of DICER1 perturbation but rather is related to the presence of cystic components.
Topics: Humans; Ribonuclease III; DEAD-box RNA Helicases; Female; Male; Receptors, Estrogen; Child; Adult; Biomarkers, Tumor; Immunohistochemistry; Adolescent; Middle Aged; Child, Preschool; Young Adult; Kidney Neoplasms; Pulmonary Blastoma; Genetic Predisposition to Disease; Infant; Aged
PubMed: 38539053
DOI: 10.1097/PAS.0000000000002209 -
MedRxiv : the Preprint Server For... Nov 2023Current clinical variant analysis pipelines focus on coding variants and intronic variants within 10-20 bases of an exon-intron boundary that may affect splicing. The...
BACKGROUND
Current clinical variant analysis pipelines focus on coding variants and intronic variants within 10-20 bases of an exon-intron boundary that may affect splicing. The impact of newer splicing prediction algorithms combined with splicing assays on rare variants currently considered Benign/Likely Benign (B/LB) is unknown.
METHODS
Exome sequencing data from 576 pediatric cancer patients enrolled in the Texas KidsCanSeq study were filtered for intronic or synonymous variants absent from population databases, predicted to alter splicing via SpliceAI (>0.20), and scored as potentially deleterious by CADD (>10.0). Total cellular RNA was extracted from monocytes and RT-PCR products analyzed. Subsequently, rare synonymous or intronic B/LB variants in a subset of genes submitted to ClinVar were similarly evaluated. Variants predicted to lead to a frameshifted splicing product were functionally assessed using an splicing reporter assay in HEK-293T cells.
RESULTS
KidsCanSeq exome data analysis revealed a rare, heterozygous, intronic variant (NM_177438.3():c.574-26A>G) predicted by SpliceAI to result in gain of a secondary splice acceptor site. The proband had a personal and family history of pleuropulmonary blastoma consistent with syndrome but negative clinical sequencing reports. Proband RNA analysis revealed alternative transcripts including the SpliceAI-predicted transcript.Similar bioinformatic analysis of synonymous or intronic B/LB variants (n=31,715) in ClinVar from 61 Mendelian disease genes yielded 18 variants, none of which could be scored by MaxEntScan. Eight of these variants were assessed ( n=4, n=2, n=2) using splice reporter assay and demonstrated abnormal splice products (mean 66%; range 6% to 100%). Available phenotypic information from submitting laboratories demonstrated phenotypes in 2 families (1 variant) and breast cancer phenotypes for in 3 families (2 variants).
CONCLUSIONS
Our results demonstrate the power of newer predictive splicing algorithms to highlight rare variants previously considered B/LB in patients with features of hereditary conditions. Incorporation of SpliceAI annotation of existing variant data combined with either direct RNA analysis or assays has the potential to identify disease-associated variants in patients without a molecular diagnosis.
PubMed: 37961416
DOI: 10.1101/2023.10.30.23297632 -
Zhonghua Bing Li Xue Za Zhi = Chinese... Nov 2023
Topics: Humans; Child; Pulmonary Blastoma; Lung Neoplasms
PubMed: 37899323
DOI: 10.3760/cma.j.cn112151-20230413-00256 -
Indian Journal of Pathology &... 2023Here we intend to document a rare case of PPB type III in a 2-year male presenting with an extensive tumor occupying the right hemithorax with immunohistochemical (IHC)...
Here we intend to document a rare case of PPB type III in a 2-year male presenting with an extensive tumor occupying the right hemithorax with immunohistochemical (IHC) study. Pleuropulmonary blastoma (PPB) is a rare variably aggressive, dysodontogenetic, childhood primary intrathoracic malignancy which in up to 25% of cases can be extrapulmonary with attachment to the parietal pleura. It is found in pediatric population under 5 years of age. It was initially proposed as a distinct entity by Manivel et al. in 1988. PPB is a proliferation of primitive mesenchymal cells that initially form air-filled cysts lined by benign-appearing epithelium (type I, cystic). Later on, the mesenchymal cells outgrow the cysts with formation of focal solid areas (type II, solid and cystic) and finally, mainly solid mass (type III, solid PPB).
Topics: Humans; Male; Child; Lung Neoplasms; Pleural Neoplasms; Pulmonary Blastoma; Cysts
PubMed: 37530358
DOI: 10.4103/ijpm.ijpm_781_21 -
The American Journal of Surgical... Feb 2024Germline and somatic pathogenic variants (PVs) in DICER1 , encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic...
Germline and somatic pathogenic variants (PVs) in DICER1 , encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic entities. The lung tumors pleuropulmonary blastoma, pulmonary blastoma (PB), and well-differentiated fetal lung adenocarcinoma (WDFLAC) are all known to harbor DICER1 biallelic variants (loss of function and/or somatic hotspot missense mutations), and all share pathologic features reminiscent of the immature lung. However, the role of DICER1 PVs in non-small cell lung cancer (NSCLC) is relatively unknown. Here, we aimed to establish the spectrum of lung pathologies associated with DICER1 hotspot PVs and to compare the mutational landscape of DICER1 -mutated NSCLC with and without hotspots. We queried DNA sequencing data from 12,146 NSCLCs featuring somatic DICER1 variants. 235 (1.9%) cases harboring ≥ 1 DICER1 PV were found and 9/235 (3.8%) were DICER1 hotspot-positive cases. Histologic review of DICER1 hotspot-positive cases showed that all but one tumor were classified as within the histologic spectrum of PB/WDFLAC, whereas all the DICER1 non-hotspot double variants were classified as lung adenocarcinomas, not otherwise specified. Comparison between the mutational landscape of DICER1 hotspot-positive and hotspot-negative cases revealed a higher frequency of CTNNB1 mutations in the hotspot-positive cases (5/9 vs. 2/225; P <0.00001). We conclude that DICER1 somatic hotspots are not implicated in the most common forms of NSCLC but rather select for morphologic features of lung tumor types such as PB and WDFLAC. As a corollary, cases showing this tumor morphology should undergo testing for DICER1 variants, and if positive, genetic counseling should be considered.
Topics: Humans; Infant, Newborn; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutation; MicroRNAs; Pulmonary Blastoma; Ribonuclease III; Germ-Line Mutation; DEAD-box RNA Helicases
PubMed: 38050371
DOI: 10.1097/PAS.0000000000002162 -
Journal of Pediatric Surgery Mar 2024Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have...
BACKGROUND
Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis.
METHODS
In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0-18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples.
RESULTS
Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28).
CONCLUSIONS
Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not.
LEVEL OF EVIDENCE
Level IV.
Topics: Child; Humans; Infant, Newborn; Infant; Child, Preschool; Adolescent; Cohort Studies; Retrospective Studies; Pulmonary Blastoma; Cystic Adenomatoid Malformation of Lung, Congenital; DNA; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37989646
DOI: 10.1016/j.jpedsurg.2023.10.031 -
A rare case of type III pleuropulmonary blastoma infiltrating the left heart in an 11-year-old girl.International Journal of Surgery Case... Feb 2024Pleuropulmonary blastoma (PPB) is a rare primary malignant tumor in the chest that mainly occurs in children <6 years of age. Vascular extensions are even rarer,...
INTRODUCTION AND IMPORTANCE
Pleuropulmonary blastoma (PPB) is a rare primary malignant tumor in the chest that mainly occurs in children <6 years of age. Vascular extensions are even rarer, approximately 3 % of types II and III PPB, and have fatal complications. The patients of reported cases who had tumor extension to the heart are younger than three years old, whereas in this case, we reported an 11-year-old girl who was of school age. This case report aims to describe a rare case of a type III Pleuropulmonary Blastoma infiltrating the left heart of a school-age girl.
CASE PRESENTATION
An 11-year-old girl presented at an emergency department with two months of progressive dyspnea with malnutrition. A fused mass was found in LA on an echocardiogram along with moderate MR, severe MS, and mild pericardial effusion. CT scan showed a massive pleural effusion with a solid mass in the left lung obstructing the left bronchial tree, accompanied by the expansion of the tumor mass into the left pulmonary vein and LA.
CLINICAL DISCUSSION
Total removal of the tumor was performed, aided by cardiopulmonary bypass. Type III PPB was confirmed histopathologically.
CONCLUSION
PPB is a rare, aggressive tumor that has three types. Various manifestations can occur in line with the presence of metastases. The treatment consists of aggressive surgery and chemotherapy. Because of its poor prognosis, prompt recognition of the involvement of the cardiac chamber and great vessels in type III PPB should be considered before surgery.
PubMed: 38232413
DOI: 10.1016/j.ijscr.2024.109237 -
Andes Pediatrica : Revista Chilena de... Dec 2023Pleuropulmonary blastoma (PPB) is the most common pediatric malignant primary lung tumor. It's associated with the DICER1 gene pathogenic germline variants. Antenatal...
UNLABELLED
Pleuropulmonary blastoma (PPB) is the most common pediatric malignant primary lung tumor. It's associated with the DICER1 gene pathogenic germline variants. Antenatal presentation is infrequent and poses a challenge in the differential diagnosis of congenital pulmonary airway malformation (CPAM).
OBJECTIVE
to report a case of unusual presentation of PPB associated with DICER1 syndrome and to describe the difficulty in differentiating it from CPAM.
CLINICAL CASE
Male patient with prenatal diagnosis of hypervascular left lung lesion, with mediastinal shift and progressive growth, initially interpreted as CPAM. He was born at 38 weeks, requiring transitory treatment with positive pressure due to ventilatory impairment. A CT scan with contrast showed a large multilocular cystic mass containing air causing mass effect, requiring open left upper lobectomy. Histology results were compatible with type I PPB, with negative margins, and positive genetic study for DICER1 syndrome. Seven weeks post-resection, an aerial image was detected in the upper left side of the chest, with progressive growth, requiring a new tumor resection and upper segmentectomy, with biopsy corresponding to recurrence of type I PPB with negative margins. He received adjuvant treatment with chemotherapy, with follow-up for 2 years, remaining asymptomatic, without recurrence, and with negative screening for other neoplasms associated with DICER1 syndrome. Among the family history, the mother had papillary thyroid cancer and tested positive for the mutation.
CONCLUSION
PPB is a rare cancer, difficult to distinguish from CPAM, especially in its antenatal presentation. Nowing its association with DICER1 syndrome and performing a genetic study are key to the early detection of BPP and the search for other tumors associated with the syndrome.
Topics: Female; Humans; Male; Pregnancy; DEAD-box RNA Helicases; Diagnosis, Differential; Lung; Lung Neoplasms; Pulmonary Blastoma; Ribonuclease III; Infant, Newborn
PubMed: 38329309
DOI: 10.32641/andespediatr.v94i6.4663 -
Cureus May 2024Primitive neuroectodermal tumors (PNETs) are unprecedented threatening neoplasms beginning from primitive neuroectodermal cells. PNETs are reported as the predominant...
Primitive neuroectodermal tumors (PNETs) are unprecedented threatening neoplasms beginning from primitive neuroectodermal cells. PNETs are reported as the predominant incidence observed in children and young adults with a high mortality rate. These neuroectodermal tumors are quite aggressive with a life expectancy of eight months on average. PNETs belong to the family of small round cell tumors majorly affecting bones and soft tissues in different body parts such as the brain, lungs, spine, and pelvic region. Computed tomography (CT) and magnetic resonance imaging (MRI) play a major role in giving the size, extent, and resectability of the tumors. A confirmed diagnosis is then made by histopathology and immunohistochemistry markers. This report depicts a case of PNET found within the right lung of a 13-year-old female, enumerating the clinical introduction, demonstrative handle, treatment modalities, and results. The case underscores the significance of precise conclusions and multidisciplinary approaches in pediatric PNET cases. Once the provisional diagnosis of pleuropulmonary blastoma or PNET was given on CT, a conformational histopathological examination was carried out. Histopathological analysis confirmed the final diagnosis of PNET, and the patient underwent neoadjuvant therapy as the tumor was non-resectable due to its massive size.
PubMed: 38910629
DOI: 10.7759/cureus.60820