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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 -
Oncology Letters Jun 2020Pulmonary sarcomatoid carcinoma (PSC) is a group of five rare non-small cell lung cancer subtypes. In the present study, the clinical characteristics and outcomes of...
Pulmonary sarcomatoid carcinoma (PSC) is a group of five rare non-small cell lung cancer subtypes. In the present study, the clinical characteristics and outcomes of patients with PSC registered in the Surveillance, Epidemiology and End Results (SEER) database were investigated. For this purpose, data for patients with PSC (n=1,723) who received their initial diagnosis between 1988 and 2016 were collected from the SEER database. Survival analysis was performed using the Kaplan-Meier curves and the log-rank test. Subsequently, multivariate analyses with the Cox proportional hazards model were used to identify significant independent predictors. A nomogram model was established to predict survival performance using the concordance index (C-index). From the total cohort, patients with pulmonary blastoma demonstrated improved 1-year overall survival (OS) rate compared with other pathological types (P<0.001). The 2-year overall survival rates of the 'only radiotherapy' cohort and the 'no specific treatment' cohort were 9.1 and 5.4% (P<0.001), respectively. Radiotherapy significantly improved the OS rate in stage I-III patients with PSC (P<0.001) when stratified by stage. After matching the propensity scores, the 'surgery combined with radiotherapy' group comprised 156 patients and the 'surgery-only' group had 247 patients (1:1.6). However, no significant differences in prognosis were found between the 2 subgroups (P=0.052). The multivariate Cox analysis demonstrated that older age (≥76 years old), male, unmarried, pathological type, larger tumor size (≥56 mm), later tumor node metastasis stages and treatment modalities were independent prognostic factors. A nomogram model was established to predict the survival of patients with PSC. This model incorporated the seven aforementioned independent prognostic factors (C-index for survival, 0.75; 95% confidence interval, 0.74-0.76). Radiotherapy needs to considered for stage I-III patients with PSC who undergo radiation therapy without surgical resection.
PubMed: 32382345
DOI: 10.3892/ol.2020.11472 -
Journal of Pediatric Surgery Jan 2016The management of congenital cystic lung lesions is controversial. Arguments for routine resection during infancy include the possibility of the lesion being Type I...
BACKGROUND
The management of congenital cystic lung lesions is controversial. Arguments for routine resection during infancy include the possibility of the lesion being Type I pleuropulmonary blastoma (PPB) rather than a cystic congenital pulmonary airway malformation (CPAM). We aimed to identify clinical and radiological features that might distinguish between CPAM and PPB and to develop a diagnostic algorithm based on these features.
METHODS
All recorded cases of Type I PPB were retrieved from the International PPB Registry and compared with an institutional cohort of children undergoing resection of CPAM (2002-2013) that was noted at some stage to be at least partially cystic. Regression models were created to identify variables that might differentiate CPAM from PPB. Odds ratio (OR) and positive predictive value (PPV) were calculated for each variable and a decision algorithm developed.
RESULTS
In 112 cases of Type I PPB and 103 of CPAM, factors favoring a diagnosis of CPAM included prenatal detection (OR 89.4), systemic feeding vessel (OR 61.7), asymptomatic (OR 8.0), and hyperinflated lung (OR 6.6). Factors favoring a diagnosis of PPB included bilateral or multisegment involvement (OR 2.4). A decision algorithm that helps to identify lesions requiring resection and those which can be safely observed is presented.
CONCLUSION
Clinical and radiological features can help to differentiate between CPAM and PPB. Our algorithm allows identification of children at higher risk of PPB in whom we would recommend resection and those at low risk in whom continued close observation is safe.
Topics: Algorithms; Child; Child, Preschool; Cystic Adenomatoid Malformation of Lung, Congenital; Decision Support Techniques; Diagnosis, Differential; Female; Humans; Infant; Infant, Newborn; Lung Neoplasms; Male; Odds Ratio; Predictive Value of Tests; Pulmonary Blastoma; Registries; Retrospective Studies
PubMed: 26561249
DOI: 10.1016/j.jpedsurg.2015.10.019 -
The Pan African Medical Journal 2022Pleuropulmonary blastoma is a rare intrathoracic tumor in children. It is associated with poor prognosis and diagnosis is based on histological examination. We conducted...
Pleuropulmonary blastoma is a rare intrathoracic tumor in children. It is associated with poor prognosis and diagnosis is based on histological examination. We conducted a didactic study involving a 3-year-old child with severe acute respiratory distress associated with hemothorax; radiological and thoracoscopic examination suggested malignant pleuropulmonary process. Anatomopathological examination with radio-clinical comparison allowed for the diagnosis of solid-cystic pleuropulmonary blastoma type II. Unfortunately, given the severity of the clinical features, the child died within a few weeks due to multiple organ failure. Pathologist experience is very important to recognize the disease and to start adequate treatment as soon as possible. This allows for a tumor regression rate up to 90% after neoadjuvant treatment and a 5-year survival rate of at least 53% for aggressive forms: solid and solido-cystic tumors.
Topics: Humans; Child, Preschool; Lung Neoplasms; Pulmonary Blastoma; Neoadjuvant Therapy; Radiography
PubMed: 36284883
DOI: 10.11604/pamj.2022.43.8.33823 -
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 -
Journal of Diabetes and Metabolic... 2015Tumor induced hypoglycemia (TIH) is a rare clinical entity that can be caused by different mechanisms such as secretion of various substances, autoimmune disorders,...
BACKGROUND
Tumor induced hypoglycemia (TIH) is a rare clinical entity that can be caused by different mechanisms such as secretion of various substances, autoimmune disorders, massive tumoral infiltration of liver, and pituitary or adrenal glands destruction by tumors. Furthermore, any type of neoplasms can cause TIH.
CASE PRESENTATION
The patient presented with a case of classic biphasic pulmonary blastoma (CBPB) with hypoglycemia. Chest CT scan showed 2 huge masses in the right hemi-thorax and multiple smaller masses located in the left hemi-thorax. The patient underwent surgery, and was referred to an oncologist for adjuvant therapy.
CONCLUSION
CBPB is a rare primary lung tumor with poor prognosis. They are classically large, symptomatic tumors with lymph node metastasis. Surgical resection at early stages has been more effective than other treatments; however, there is no standard treatment in unresectable cases. Adjuvant treatments have been temporarily effective.
PubMed: 27532029
DOI: 10.1186/s40200-016-0255-5 -
Cancer Jan 2015Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway ranging from type I (cystic) to type II (cystic/solid) and type III (completely solid). A...
BACKGROUND
Pleuropulmonary blastoma (PPB) has 3 subtypes on a tumor progression pathway ranging from type I (cystic) to type II (cystic/solid) and type III (completely solid). A germline mutation in DICER1 is the genetic cause in the majority of PPB cases.
METHODS
Patients confirmed to have PPB by central pathology review were included, and their clinical characteristics and outcomes were reported. Germline DICER1 mutations were sought with Sanger sequencing.
RESULTS
There were 435 cases, and a central review confirmed 350 cases to be PPB; 85 cases (20%) were another entity. Thirty-three percent of the 350 PPB cases were type I or type I regressed (type Ir), 35% were type II, and 32% were type III or type II/III. The median ages at diagnosis for type I, type II, and type III patients were 8, 35, and 41 months, respectively. The 5-year overall survival (OS) rate for type I/Ir patients was 91%; all deaths in this group were due to progression to type II or III. OS was significantly better for type II versus type III (P = .0061); the 5-year OS rates were 71% and 53%, respectively. Disease-free survival (DFS) was also significantly better for type II versus type III (P = .0002); the 5-year DFS rates were 59% and 37%, respectively. The PPB type was the strongest predictor of outcome. Metastatic disease at the diagnosis of types II and III was also an independent unfavorable prognostic factor. Sixty-six percent of the 97 patients tested had a heterozygous germline DICER1 mutation. In this subset, the DICER1 germline mutation status was not related to the outcome.
CONCLUSIONS
Cystic type I/Ir PPB has a better prognosis than type II, and type II has a better outcome than type III. Surveillance of DICER1 carriers may allow the earlier detection of cystic PPB before its progression to type II or III PPB and thereby improve outcomes.
Topics: Adolescent; Child; Child, Preschool; DEAD-box RNA Helicases; Disease Progression; Disease-Free Survival; Female; Germ-Line Mutation; Humans; Infant; International Cooperation; Kaplan-Meier Estimate; Lung Neoplasms; Male; Pleural Neoplasms; Proportional Hazards Models; Pulmonary Blastoma; Registries; Ribonuclease III; United States; Young Adult
PubMed: 25209242
DOI: 10.1002/cncr.29032 -
Surgical Case Reports Nov 2023Pleuropulmonary blastoma (PPB) is an extremely rare and malignant pediatric lung tumor. Purely cystic PPB has a more favorable prognosis than solid PPB, but may be...
BACKGROUND
Pleuropulmonary blastoma (PPB) is an extremely rare and malignant pediatric lung tumor. Purely cystic PPB has a more favorable prognosis than solid PPB, but may be difficult to distinguish from a certain type of "benign" congenital pulmonary airway malformation before and during surgery. The influence of tumor rupture on long life prognosis has not been clarified in detail.
CASE PRESENTATION
A 5-month-old boy underwent emergency transfer from another hospital due to a left thoracic cystic lesion and left pneumothorax detected on chest radiography performed for persistent wheeze and cough. Contrast-enhanced computed tomography of the chest revealed marked deviation of the mediastinum to the right due to a giant cystic lesion and pneumothorax. Thoracotomy was performed on hospital day 2. A cystic lesion had developed from the distal alveolar region of lower lobe of the left lung and the tumor showed a tiny adhesion to the left diaphragm and a tiny rupture near the adhesion. Partial lung excision including the cyst and scraping of the adhesion were performed. Histopathological investigations revealed immature blast cell-like mesenchymal cells and differentiated striated muscle cells in a dense cambium layer were found under the epithelium of the cystic lesion. Type I PPB was diagnosed.
CONCLUSIONS
Surgery should be performed with the possibility of type I PPB in mind when an extrapulmonary cystic lung lesion is found. Since issues such as the pathogenesis and long-term prognosis of ruptured cases remain unclear, continued careful follow-up of this case will be required.
PubMed: 37930461
DOI: 10.1186/s40792-023-01777-7 -
Turk Patoloji Dergisi 2024Pulmonary blastoma (PB) is an exceedingly rare and aggressive malignant lung neoplasm that has distinct biphasic morphology. In this report, we document rare...
Pulmonary blastoma (PB) is an exceedingly rare and aggressive malignant lung neoplasm that has distinct biphasic morphology. In this report, we document rare manifestations and molecular alterations in PB. A 59-year-old non-smoker female, presented with cough and hemoptysis for 4 months. The high-resolution computed tomography chest scan showed a 3.5x2.7 cm mass in the basal segment of the left lung. Positron emission tomography and computed tomography revealed a fluorodeoxyglucose avid lobulated mass in the superior segment of the lower lobe of the left lung. On core biopsy, the diagnosis of pleomorphic carcinoma in a background of adenocarcinoma was made. A definite diagnosis of pulmonary blastoma was established on the left lung lobectomy specimen based on morphological and immunohistochemical findings. Post-surgical biopsy from the scalp swelling showed metastatic deposits. On Next Generation Sequencing (NGS), in addition to conventional CTNNB1 gene mutation, new pathogenic MYCN and ATM gene mutations were detected. Post-chemotherapy, the patient was doing well after 10 months of close follow-up. PB exhibited rare associations in the form of non-smoker status, scalp metastasis, and MYCN and ATM gene mutations on NGS in addition to conventional CTNNB1 gene mutation. Large cohort studies are required to discover the incidence, significance and therapeutic implications of these co-existing pathogenic molecular alterations in PB.
Topics: Female; Humans; Middle Aged; Hemoptysis; Lung; Lung Neoplasms; N-Myc Proto-Oncogene Protein; Pulmonary Blastoma
PubMed: 38235566
DOI: 10.5146/tjpath.2023.01597 -
Nuclear Medicine and Molecular Imaging Oct 2020Pulmonary blastoma (PB) is a rare thoracic malignancy and preoperative diagnosis is challenging. A young man presented with dyspnea and chest pain for 3-4 months and...
Pulmonary blastoma (PB) is a rare thoracic malignancy and preoperative diagnosis is challenging. A young man presented with dyspnea and chest pain for 3-4 months and chest-computed tomography (CT) revealed large mass in the left lung upper lobe and pleural effusion. Repeated CT-guided fine-needle aspiration cytology from the lesion and pleural fluid aspiration was negative for malignancy. F-18-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) revealed heterogeneous tracer avidity in left lung mass with areas of necrosis. Real-time PET-CT-guided biopsy from metabolically active component of the lesion revealed biphasic PB on histopathology.
PubMed: 33088357
DOI: 10.1007/s13139-020-00655-6