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1.
Mod Pathol ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599283

RESUMO

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.

2.
Pediatr Blood Cancer ; 68(11): e29284, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34398502

RESUMO

A 2-year-old boy presented with a large cystic and solid chest mass arising from the lung, radiographically consistent with pleuropulmonary blastoma (PPB). He underwent right lower lobectomy with resection of a well-circumscribed, mixed solid and cystic mass. The solid areas were composed of cords and nests of tumor cells in the myxoid stroma and retiform foci whose pathologic and immunophenotypic findings were consistent with a sex cord-stromal tumor with features of a Sertoli-Leydig cell tumor. Tumor testing showed a pathogenic variant in the DICER1 RNase IIIb hotspot domain. Family history was suggestive of DICER1 germline pathogenic DICER1 variation in absence of a detectable germline variant. He received 12 cycles of chemotherapy with ifosfamide, vincristine, dactinomycin and doxorubicin (IVADo) and surgery with complete response. One year after completion of chemotherapy, imaging studies showed concern for recurrence confirmed by thorascopic biopsy of a pleural-based mass. He is currently receiving cisplatin-based chemotherapy with reduction in tumor size. Review of the literature showed no similar cases; however, review of our pathology files revealed a single similar case of anterior mediastinal Sertoli cell tumor in a 3-year-old girl.

3.
J Allergy Clin Immunol Pract ; 9(9): 3331-3338.e2, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34273581

RESUMO

BACKGROUND: The complex relationship between clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and individual immune responses is not fully elucidated. OBJECTIVE: To examine phenotypes of symptomatology and their relationship with positive anti-SARS-CoV-2 IgG antibody responses. METHODS: An observational study was performed of adults (≥18 years) from 5 US states. Participants completed an electronic survey and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody between May and July 2020. Latent class analysis was used to identify characteristic symptom clusters. RESULTS: Overall, 9507 adults (mean age, 39.6 ± 15.0 years) completed the survey; 6665 (70.1%) underwent antibody testing for anti-SARS-CoV-2 IgG. Positive SARS-CoV-2 antibodies were associated with self-reported positive SARS-CoV-2 nasal swab result (bivariable logistic regression; odds ratio [95% CI], 5.98 [4.83-7.41]), household with 6 or more members (1.27 [1.14-1.41]) and sick contact (3.65 [3.19-4.17]), and older age (50-69 years: 1.55 [1.37-1.76]; ≥70 years: 1.52 [1.16-1.99]), but inversely associated with female sex (0.61 [0.55-0.68]). Latent class analysis revealed 8 latent classes of symptoms. Latent classes 1 (all symptoms) and 4 (fever, cough, muscle ache, anosmia, dysgeusia, and headache) were associated with the highest proportion (62.0% and 57.4%) of positive antibodies, whereas classes 6 (fever, cough, muscle ache, headache) and 8 (anosmia, dysgeusia) had intermediate proportions (48.2% and 40.5%), and classes 3 (headache, diarrhea, stomach pain) and 7 (no symptoms) had the lowest proportion (7.8% and 8.5%) of positive antibodies. CONCLUSIONS: SARS-CoV-2 infections manifest with substantial diversity of symptoms, which are associated with variable anti-SARS-CoV-2 IgG antibody responses. Prolonged fever, anosmia, and receiving supplemental oxygen therapy had strongest associations with positive SARS-CoV-2 IgG.


Assuntos
COVID-19 , Adulto , Idoso , Anticorpos Antivirais , Estudos Transversais , Feminino , Humanos , Imunoglobulina G , Pessoa de Meia-Idade , SARS-CoV-2
4.
Pediatr Dev Pathol ; : 10935266211027417, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266329

RESUMO

INTRODUCTION: Pleuropulmonary blastoma (PPB), a rare childhood neoplasm of the lung, is linked to pathogenic DICER1 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/DICER1 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 (P < .05). The density of PD1 and CD8 in the interface area was higher than within tumor (P < .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.

5.
Am Fam Physician ; 103(10): 597-604, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33983001

RESUMO

Dyspareunia is recurrent or persistent pain with sexual intercourse that causes distress. It affects approximately 10% to 20% of U.S. women. Dyspareunia may be superficial, causing pain with attempted vaginal insertion, or deep. Women with sexual pain are at increased risk of sexual dysfunction, relationship distress, diminished quality of life, anxiety, and depression. Because discussing sexual issues may be uncomfortable, clinicians should create a safe and welcoming environment when taking a sexual history, where patients describe the characteristics of the pain (e.g., location, intensity, duration). Physical examination of the external genitalia includes visual inspection and sequential pressure with a cotton swab, assessing for focal erythema or pain. A single-digit vaginal examination may identify tender pelvic floor muscles, and a bimanual examination can assess for uterine retroversion and pelvic masses. Common diagnoses include vulvodynia, inadequate lubrication, vaginal atrophy, postpartum causes, pelvic floor dysfunction, endometriosis, and vaginismus. Treatment is focused on the cause and may include lubricants, pelvic floor physical therapy, topical analgesics, vaginal estrogen, cognitive behavior therapy, vaginal dilators, modified vestibulectomy, or onabotulinumtoxinA injections.


Assuntos
Dispareunia , Exame Ginecológico/métodos , Administração dos Cuidados ao Paciente/métodos , Qualidade de Vida , Estresse Psicológico , Adulto , Dispareunia/diagnóstico , Dispareunia/etiologia , Dispareunia/psicologia , Dispareunia/terapia , Feminino , Doenças dos Genitais Femininos/complicações , Exame Ginecológico/psicologia , Humanos , Anamnese/métodos , Anamnese/normas , Medição da Dor , Medição de Risco , Fatores de Risco , Estresse Psicológico/fisiopatologia , Estresse Psicológico/prevenção & controle
7.
JAMA Netw Open ; 4(3): e212816, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33688968

RESUMO

Importance: Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in the United States are still emerging. Objective: To elucidate SARS-CoV-2 seroprevalence and symptom onset in a culturally linked community across 5 states in the United States. Design, Setting, and Participants: This cross-sectional study included adults (aged ≥18 years) recruited from the orthodox Jewish community across 5 states (California, Connecticut, Michigan, New Jersey, and New York) in 3 geographically distinct areas of the United States between May 13 and July 6, 2020. Participants completed an online survey and underwent SARS-CoV-2 antibody testing. Main Outcomes and Measures: Seroprevalence and date of symptom onset of SARS-CoV-2. Results: Overall, 9507 adults (mean [SD] age, 39.6 [15.0] years; 3777 [39.7%] women) completed the SARS-CoV-2 survey, of whom 6665 (70.1%) had immunoglobin G anti-SARS-CoV-2 antibody levels assessed. A high seroprevalence of SARS-CoV-2 antibodies was observed across all communities, with the highest proportion of positive testing observed in New Jersey (1080 of 3323 [32.5%]) and New York (671 of 2196 [30.6%]). Most individuals with a positive SARS-CoV-2 immunoglobin G antibody test reported a date of symptom-onset between March 9 and March 31, 2020 (California: 135 of 154 [87.7%]; Connecticut: 32 of 34 [94.1%]; Michigan: 44 of 50 [88.0%]; New Jersey: 964 of 1168 [82.5%]; New York: 571 of 677 [84.3%]). This start date was coincident with the Jewish festival of Purim, celebrated March 9 to 10, 2020, with extensive intracommunity spread in the weeks following (mean and mode of peak symptom onset, March 20, 2020), occurring in the absence of strong general and culture-specific public health directives. Conclusions and Relevance: This cross-sectional study of orthodox Jewish adults across the US found that socioculturally bound communities experienced early parallel outbreaks in discrete locations, notably prior to substantive medical and governmental directives. Further research should clarify optimal national, local, community-based, and government policies to prevent outbreaks in social and cultural communities that traditionally gather for holidays, assemblies, and festivals.


Assuntos
COVID-19/epidemiologia , Assistência à Saúde Culturalmente Competente , Transmissão de Doença Infecciosa , Férias e Feriados , Judeus/estatística & dados numéricos , Grupos Minoritários , Saúde Pública , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/transmissão , Teste Sorológico para COVID-19 , California/epidemiologia , Connecticut/epidemiologia , Estudos Transversais , Surtos de Doenças , Feminino , Humanos , Judaísmo , Masculino , Michigan/epidemiologia , Pessoa de Meia-Idade , New Jersey/epidemiologia , New York/epidemiologia , Características de Residência , SARS-CoV-2 , Estudos Soroepidemiológicos , Estados Unidos/epidemiologia , Adulto Jovem
8.
JAMA Netw Open ; 4(2): e210112, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33630087

RESUMO

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.


Assuntos
RNA Helicases DEAD-box/genética , Penetrância , Fenótipo , Ribonuclease III/genética , Doenças da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Genoma , Mutação em Linhagem Germinativa , Bócio Nodular/epidemiologia , Bócio Nodular/genética , Doença de Graves/epidemiologia , Doença de Graves/genética , Heterozigoto , Humanos , Hipotireoidismo/epidemiologia , Hipotireoidismo/genética , Neoplasias Renais/epidemiologia , Neoplasias Renais/genética , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Prevalência , Blastoma Pulmonar/epidemiologia , Blastoma Pulmonar/genética , Sarcoma/epidemiologia , Sarcoma/genética , Tumor de Células de Sertoli-Leydig/epidemiologia , Tumor de Células de Sertoli-Leydig/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/epidemiologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Neoplasias Testiculares/epidemiologia , Neoplasias Testiculares/genética , Doenças da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/epidemiologia , Nódulo da Glândula Tireoide/epidemiologia , Nódulo da Glândula Tireoide/genética , Tireoidectomia/estatística & dados numéricos , Tireotoxicose/epidemiologia , Tireotoxicose/genética , Tumor de Wilms/epidemiologia , Tumor de Wilms/genética , Adulto Jovem
9.
Mod Pathol ; 34(6): 1104-1115, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33637876

RESUMO

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.

10.
J Pediatr Adolesc Gynecol ; 34(4): 449-453, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33484847

RESUMO

STUDY OBJECTIVE: Rhabdomyosarcomas (RMSs) of the female genital tract (FGT) have been recently shown to be associated with germline pathogenic variation in DICER1, which can underlie a tumor predisposition disorder. We sought to determine the incidence of a pathogenic variation in DICER1 in a cohort of RMSs of the FGT, as well as to evaluate the clinicopathological features and outcomes of the patients. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We retrospectively reviewed medical records of the patients diagnosed with RMS of the FGT between 1990 and 2019. Molecular genetic sequencing of the tumor to detect an RNase IIIb domain hot spot mutation in DICER1 samples was performed in 7 patients. Individuals with a missense mutation in the tumor were also screened for a loss of function germline mutation in DICER1. RESULTS: Of 210 cases of pediatric RMS, 11 arose from the FGT. Molecular genetic sequencing of the tumor samples revealed a somatic missense mutation in the RNase IIIb domain of DICER1 in a total of 3 patients, 2 patients with embryonal RMS of the cervix/uterus, and 1 patient with ovarian embryonal RMS. As a result of genetic testing for the loss of function germline mutation in DICER1, a heterozygous pathogenic variant was also found in 2 of these patients. CONCLUSION: Despite the limited number of patients, our findings suggest that it is important to be aware of the possible association between RMS of FGT and pathogenic germline DICER1 variants because the detection of this mutation in a patient or relatives can provide the opportunity for surveillance of related conditions that might improve long-term outcomes and survival.


Assuntos
RNA Helicases DEAD-box/genética , Neoplasias dos Genitais Femininos/genética , Rabdomiossarcoma/genética , Ribonuclease III/genética , Adolescente , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Humanos , Lactente , Estudos Retrospectivos
11.
Am Fam Physician ; 102(2): 84-90, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32667171

RESUMO

Shoulder dystocia is an obstetric emergency in which normal traction on the fetal head does not lead to delivery of the shoulders. This can cause neonatal brachial plexus injuries, hypoxia, and maternal trauma, including damage to the bladder, anal sphincter, and rectum, and postpartum hemorrhage. Although fetal macrosomia, prior shoulder dystocia, and preexisting or gestational diabetes mellitus increases the risk of shoulder dystocia, most cases occur without warning. Labor and delivery teams should always be prepared to recognize and treat this emergency. Training and simulation exercises improve physician and team performance when shoulder dystocia occurs. Unequivocally announcing that dystocia is happening, summoning extra assistance, keeping track of the time from delivery of the head to full delivery of the neonate, and communicating with the patient and health care team are helpful. Calm and thoughtful use of release maneuvers such as knee to chest (McRoberts maneuver), suprapubic pressure, posterior arm or shoulder delivery, and internal rotational maneuvers will almost always result in successful delivery. When these are unsuccessful, additional maneuvers, including intentional clavicular fracture or cephalic replacement, may lead to delivery. Each institution should consider the length of time it will take to prepare the operating room for general inhalational anesthesia and abdominal rescue and practice this during simulation exercises.


Assuntos
Parto Obstétrico/normas , Serviços Médicos de Emergência/normas , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/terapia , Guias de Prática Clínica como Assunto , Distocia do Ombro/diagnóstico , Distocia do Ombro/terapia , Adulto , Currículo , Educação Médica Continuada , Feminino , Pessoal de Saúde/educação , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Gravidez
12.
Gynecol Oncol ; 156(3): 647-653, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31952842

RESUMO

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.


Assuntos
RNA Helicases DEAD-box/genética , Doenças dos Genitais Femininos/genética , Ribonuclease III/genética , Adolescente , Adulto , Idoso , Amenorreia/genética , Criança , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Gravidez , Blastoma Pulmonar/genética , Saúde Reprodutiva , Rabdomiossarcoma Embrionário/genética , Neoplasias do Colo do Útero/genética , Adulto Jovem
13.
Mod Pathol ; 33(7): 1264-1274, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31937902

RESUMO

Poorly differentiated thyroid carcinomas (PDTC) in young individuals are rare and their clinical and histopathologic features, genetic mechanisms, and outcomes remain largely unknown. Here, we report a detailed characterization of a series of six PDTC in patients ≤21 years old defined by Turin diagnostic criteria studied for mutations and gene fusions characteristic of thyroid cancer using targeted next-generation sequencing (NGS) and whole-exome sequencing (WES). All tumors had solid, insular, or trabecular growth pattern and high mitotic rate, and five out of six tumors showed tumor necrosis. Targeted NGS assay identified somatic mutations in the DICER1 gene in five of six (83%) tumors, all of which were "hotspot" mutations encoding the metal-ion binding sites of the RNase IIIb domain of DICER1. WES was performed in five cases which confirmed all hotspot mutations and detected two tumors with additional inactivating DICER1 alterations. Of these two, one was a germline pathogenic DICER1 variant and the other had loss of heterozygosity for DICER1. No other mutations or gene fusions characteristic of adult well-differentiated thyroid cancer and PDTC (BRAF, RAS, TERT, RET/PTC, and other) were detected. On follow-up, available for five patients, three patients died of disease 8-24 months after diagnosis, whereas two were alive with no disease. The results of our study demonstrate that childhood- and adolescent-onset PDTC are genetically distinct from adult-onset PDTC in that they are strongly associated with DICER1 mutations and may herald DICER1 syndrome in a minority. As such, all young persons with PDTC may benefit from genetic counseling. Furthermore, their clinically aggressive behavior contrasts sharply with the indolent nature of the great majority of thyroid tumors with DICER1 mutations reported to date.

14.
Acta Neuropathol ; 139(2): 223-241, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31820118

RESUMO

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glândula Pineal , Pinealoma/genética , Pinealoma/patologia , Adolescente , Adulto , Fatores Etários , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , MicroRNAs/metabolismo , Mutação/genética , Pinealoma/mortalidade , Sistema de Registros , Taxa de Sobrevida , Adulto Jovem
15.
J Pediatr Adolesc Gynecol ; 33(2): 173-176, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31838154

RESUMO

BACKGROUND: Germline DICER1 mutations increase the risk of developing a wide variety of generally uncommon tumors. We describe a case of DICER1-related embryonal rhabdomyosarcoma (ERMS) of the uterine corpus in a prepubertal girl. CASE: A 10-year-old- girl with a history of cystic nephroma presented with a 3-week history of vaginal bleeding. A 3-cm mass filling the uterine cavity was detected, and histopathologic examination of hysteroscopy-guided biopsy samples revealed ERMS. Molecular genetic sequencing of the tumor sample revealed a DICER1 mutation. SUMMARY AND CONCLUSION: This report highlights the importance of screening for DICER1 mutations in the presence of the early-onset features of this syndrome, and extends the spectrum of DICER1-related tumors by showing the mutation in a case of ERMS of the uterine corpus.


Assuntos
Rabdomiossarcoma Embrionário/genética , Neoplasias Uterinas/genética , Quimioterapia Adjuvante/métodos , Criança , RNA Helicases DEAD-box , Feminino , Mutação em Linhagem Germinativa , Humanos , Histerectomia , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma Embrionário/terapia , Ribonuclease III , Hemorragia Uterina/etiologia , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia
16.
Mo Med ; 116(3): 206-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31527943

RESUMO

Pleuropulmonary blastoma (PPB), the most common primary malignant neoplasm of the lung in childhood, occurs in the same early age group (0-6 years) as the other more common solid tumors such as neuroblastoma and Wilms tumor. The tumor begins as a cystic lung lesion with the potential over a period of 3-5 years to progress to a high grade multipatterned primitive sarcoma in the absence of a malignant epithelial component. Several years after its initial description as a unique clinicopathologic entity, this and other tumors appeared to have a familial predilection which was later confirmed with the discovery of a heterozygous germline mutation in DICER1 whose protein is a member of ribonuclease III family of enzymes. It is estimated that 75%-80% of children with a PPB have the germline mutation. The other notable finding from our studies is the identification of a family of extrapulmonary neoplasms, including cystic nephroma and Sertoli-Leydig cell tumor of the ovary as two examples, also with DICER1 mutations.


Assuntos
RNA Helicases DEAD-box/genética , Mutação em Linhagem Germinativa , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Blastoma Pulmonar/genética , Blastoma Pulmonar/patologia , Ribonuclease III/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Neoplasias Pulmonares/diagnóstico , Masculino , Blastoma Pulmonar/diagnóstico
17.
Mod Pathol ; 32(12): 1744-1750, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31296931

RESUMO

We report two malignant sacrococcygeal tumors in infants that were associated with pathogenic DICER1 variation. These tumors were composed of primitive neuroepithelium, embryonal rhabdomyosarcoma, and cartilage and initially diagnosed as immature teratomas. One child developed intracranial metastasis and died. The second child underwent surgery and chemotherapy and achieved complete remission. This child subsequently developed five additional DICER1-associated neoplasms by age nine. Genetic analysis revealed that both tumors harbored biallelic pathogenic DICER1 variation. We believe these cases represent another novel subtype of DICER1-associated tumor. This new entity, which we propose to call DICER1-associated presacral malignant teratoid neoplasm, may be difficult initially to distinguish from immature teratoma, but recognizing it as an entity can prompt appropriate classification as an aggressive malignancy and facilitate appropriate genetic counseling, DICER1 germline variant testing, screening, and education.


Assuntos
RNA Helicases DEAD-box/genética , Ribonuclease III/genética , Teratoma/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Recém-Nascido , Masculino , Região Sacrococcígea , Teratoma/patologia
19.
J Clin Oncol ; 37(8): 668-676, 2019 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-30715996

RESUMO

PURPOSE: DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard rates, and the probability of neoplasm incidence accounting for competing risks ("cumulative incidence") of neoplasms (benign and malignant) and standardized incidence ratios for malignant tumors in individuals with DICER1 pathogenic variation. PATIENTS AND METHODS: We combined data from three large cohorts of patients who carry germline pathogenic variation in DICER1. To reduce ascertainment bias, we distinguished probands from nonprobands. Neoplasm diagnoses were confirmed by review of pathology reports and/or central review of surgical pathology materials. Standardized cancer incidence ratios were determined relative to the SEER program, which does not capture all DICER1-associated neoplasms. For all malignancies and benign tumors ("neoplasms," excluding type Ir pleuropulmonary blastoma and thyroid nodules), we used the Kaplan-Meier method and nonparametric cumulative incidence curves to estimate neoplasm-free survival. RESULTS: We calculated the age at first neoplasm diagnosis (systematically ascertained cancers plus DICER1-associated neoplasms pleuropulmonary blastoma, cystic nephroma, and nasal chondromesenchymal hamartoma) in 102 female and male nonproband DICER1 carriers. By age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of nonproband DICER1 carriers had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had developed a neoplasm (females, 26.5%; males, 10.2%). After age 10 years, female risk was elevated compared with male risk. Standardized cancer incidence ratio analysis of 102 nonproband DICER1 carriers, which represented 3,344 person-years of observation, showed significant cancer excesses overall, particularly of gynecologic and thyroid cancers. CONCLUSION: This work provides the first quantitative analysis of site-specific neoplasm risk and excess malignancy risk in 102 systematically characterized nonproband DICER1 carriers. Our findings inform DICER1 syndrome phenotype, natural history, and genetic counseling.


Assuntos
RNA Helicases DEAD-box/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Neoplasias Pulmonares/genética , Blastoma Pulmonar/genética , Ribonuclease III/genética , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Adulto Jovem
20.
Pediatr Blood Cancer ; 66(5): e27628, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30677214

RESUMO

Pleuropulmonary blastoma (PPB) is a rare pediatric tumor. The central nervous system (CNS) is the most common site of extrathoracic metastasis. The prognosis of PPB patients with CNS metastases is dismal: most patients die within one year after recurrence. Here, we describe two patients diagnosed with PPB who developed intracranial recurrences shortly after the end of their initial treatment and were successfully treated by gross total resection, radiotherapy, and chemotherapy. Both patients are in complete remission four and three years after recurrence. Although an optimal regimen remains to be determined, these cases demonstrate that PPB with CNS metastases is potentially curable.


Assuntos
Neoplasias Encefálicas/terapia , Recidiva Local de Neoplasia/terapia , Blastoma Pulmonar/terapia , Neoplasias Encefálicas/secundário , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Prognóstico , Blastoma Pulmonar/patologia
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