RESUMO
Tumor-agnostic testing for NTRK1-3 gene rearrangements is required to identify patients who may benefit from TRK inhibitor therapies. The overarching objective of this study was to establish a high-quality pan-TRK immunohistochemistry (IHC) screening assay among 18 large regional pathology laboratories across Canada using pan-TRK monoclonal antibody clone EPR17341 in a ring study design. TRK-fusion positive and negative tumor samples were collected from participating sites, with fusion status confirmed by panel next-generation sequencing assays. Each laboratory received: (1) unstained sections from 30 cases of TRK-fusion-positive or -negative tumors, (2) 2 types of reference standards: TRK calibrator slides and IHC critical assay performance controls (iCAPCs), (3) EPR17341 antibody, and (4) suggestions for developing IHC protocols. Participants were asked to optimize the IHC protocol for their instruments and detection systems by using iCAPCs, to stain the 30 study cases, and to report the percentage scores for membranous, cytoplasmic, and nuclear staining. TRK calibrators were used to assess the analytical sensitivity of IHC protocols developed by using the 2 reference standards. Fifteen of 18 laboratories achieved diagnostic sensitivity of 100% against next-generation sequencing. The diagnostic specificity ranged from 40% to 90%. The results did not differ significantly between positive scores based on the presence of any type of staining vs the presence of overall staining in ≥1% of cells. The median limit of detection measured by TRK calibrators was 76,000 molecules/cell (range 38,000 to >200,000 molecules/cell). Three different patterns of staining were observed in 19 TRK-positive cases, cytoplasmic-only in 7 samples, nuclear and cytoplasmic in 9 samples, and cytoplasmic and membranous in 3 samples. The Canadian multicentric pan-TRK study illustrates a successful strategy to accelerate the multicenter harmonization and implementation of pan-TRK immunohistochemical screening that achieves high diagnostic sensitivity by using laboratory-developed tests where laboratories used centrally developed reference materials. The measurement of analytical sensitivity by using TRK calibrators provided additional insights into IHC protocol performance.
Assuntos
Neoplasias , Humanos , Imuno-Histoquímica , Canadá , Anticorpos Monoclonais , Receptor trkA/genética , Proteínas de Fusão Oncogênica/genética , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Small air-filled peripheral subpleural cysts are a well-described feature of pulmonary anatomy at computerized tomographic (CT) scan in children with Trisomy 21, yet only anecdotally described in association with other pathologies. The significance of these cysts is unknown. OBJECTIVE: To investigate and explore the pathogenesis of these subpleural cysts in children. MATERIALS AND METHODS: A retrospective review of 16 cases with subpleural cysts diagnosed on CT chest was performed. The distribution, location, and ancillary CT findings were recorded. Hospital charts were reviewed for clinical details, especially cardiac abnormalities, pulmonary artery hypertension (PAH) and genetic associations. Histopathological and clinical correlative data were recorded. RESULTS: Eleven of the 16 children (69%) were found to have an underlying chromosomal or genetic abnormality, six of whom had Trisomy 21. The remaining 5 of the 16 cases (21%) had miscellaneous disorders without an identifiable genetic basis. The most common co-morbidities were cardiac abnormalities (81%) and PAH (62.5%). Regardless of their underlying etiologies, the cysts were present bilaterally in most cases (14/16, 88%). We observed both the postnatal development and the progression of cysts in our cohort. On long-term follow-up, there were five deaths (31%) and six cases (38%) requiring maintenance oxygen therapy due to chronic hypoxia. Two cases (12.5%) became completely asymptomatic after correction of their underlying abnormalities. CONCLUSION: Subpleural cysts are not exclusive to Trisomy 21 and may be seen in other inherited or acquired causes, likely due to altered alveolar growth. We suspect these cysts are a sign of an underlying developmental disorder with variable clinical effect, especially in children with congenital cardiac disease.
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Cistos , Síndrome de Down , Cardiopatias Congênitas , Pneumopatias , Humanos , Criança , Síndrome de Down/complicações , Pneumopatias/diagnóstico por imagem , Pneumopatias/genética , Pneumopatias/complicações , Pulmão/patologia , Cistos/diagnóstico por imagem , Cistos/genética , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/genéticaAssuntos
Linfoma Cutâneo de Células T , Linfoma de Células T , Paniculite , Neoplasias Cutâneas , Humanos , Feminino , Adolescente , Paniculite/etiologia , Paniculite/patologia , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Neoplasias Cutâneas/patologia , Linfoma Cutâneo de Células T/complicaçõesRESUMO
BACKGROUND & AIMS: Non-invasive monitoring of intestinal failure (IF) associated liver disease is an ongoing challenge in children with IF. Our objective was to develop a combined algorithm of clinical, transient elastography (TE) and biochemical parameters to identify liver fibrosis in this population. METHODS: A retrospective cohort study of IF patients followed by our intestinal rehabilitation program between November 2015 to October 2019. Patients with a liver biopsy and TE were included. Demographic and liver function tests were collected. Fibrosis on liver biopsies was graded using the modified Scheuer score. Decision tree based algorithms classified low (F0-F1) versus high (F2-F4) fibrosis scores based on a combination of TE, biochemical and demographic parameters, using 6-fold classification error, sensitivity and specificity cross-validation (CV) scores. RESULTS: 42 patients (74% male, median age 7.6 (4.6; 42.7) months) were evaluated. Median length of PN therapy was 182 (121; 556) days. High fibrosis was present in 40.5% with a median TE of 12.1 (6.7; 12.9) kPa in high fibrosis children. An algorithm, based on cut-off values for TE of 11.3 kPa and AST of 40 U/L, and grouping of the underlying etiology resulted in a correct classification of 88.1% of the pathology scores; with sensitivity 0.82 (95% CI 0.57; 0.96), specificity 0.92 (95% CI 0.74; 0.99), positive predictive value 0.88 (95% CI 0.64; 0.96) and negative predictive value 0.88 (95% CI 0.73; 0.96). The CV classification error was 28.6%, CV sensitivity 72.2% and CV specificity 75.5%. CONCLUSIONS: This algorithm shows promising results that could simplify non-invasive monitoring of liver fibrosis in children with IF. Validation in additional IF cohorts is needed.
Assuntos
Técnicas de Imagem por Elasticidade , Insuficiência Intestinal , Humanos , Criança , Técnicas de Imagem por Elasticidade/métodos , Estudos Retrospectivos , Cirrose Hepática/diagnóstico , Cirrose Hepática/diagnóstico por imagem , Fígado/diagnóstico por imagem , Fígado/patologiaRESUMO
BACKGROUND AND AIMS: Wilson disease (WD) has diverse presentations that frequently mimic other liver diseases. Distinguishing WD from non-alcoholic fatty liver disease (NAFLD) and autoimmune hepatitis (AIH), can be difficult and has critical implications for medical management. This study aimed to examine the utility of histological features of WD in children compared to those with NAFLD and AIH. METHODS: A review of liver biopsy slides was performed in children with a clinical and/or genetic diagnosis of WD, seen at the Hospital for Sick Children between 1981 and 2019 and compared to controls with NAFLD and AIH. 37 children with WD and 37 disease controls (20 NAFLD; 17 AIH) were included. Three pathologists, blind to clinical details and diagnosis, reviewed all liver biopsies to reach consensus. Clinical and histopathologic features were compared between groups. RESULTS: Most WD cases displayed steatosis or steatohepatitis on histology (34/37), active AIH-pattern in 1 and inactive cirrhosis in 2 cases. Electron microscopy (EM) findings of mitochondrial abnormalities including dilated tips of cristae, pleomorphism, membrane duplication and dense matrix were more frequent in the WD group as compared to disease controls (p < 0.0001). In WD, dilated tips of mitochondrial cristae had a sensitivity of 91% and specificity of 86%, best among EM features. CONCLUSIONS: Light microscopic findings display considerable overlap among children with WD, NAFLD and AIH. Ultrastructural findings of mitochondrial abnormalities are important to distinguish WD from NAFLD and AIH. EM examination should be considered essential in the diagnostic work-up of paediatric liver biopsies.
Assuntos
Hepatite Autoimune , Degeneração Hepatolenticular , Hepatopatia Gordurosa não Alcoólica , Criança , Hepatite Autoimune/complicações , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/patologia , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/diagnóstico , Humanos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
DICER1 syndrome is an autosomal dominant tumour predisposition syndrome usually affecting persons under 30 years of age. Many of the associated benign and malignant lesions occur almost exclusively in DICER1 syndrome. One such tumour, pituitary blastoma (pitB), overexpresses PRAME 500x above control levels. PRAME (PReferentially expressed Antigen in MElanoma) is expressed in malignancies that are not DICER1-related (e.g. melanoma). To address whether PRAME expression is part of the DICER1 phenotype, or simply a feature of pitB, a series of 75 DICER1-mutated specimens and 33 non-mutated specimens was surveyed using immunohistochemistry for PRAME, together with EZH2, which complexes with PRAME. In DICER1-mutated specimens, positive staining for PRAME was only seen in malignant tumours; 7 of 11 histological types and 34/62 individual tumours were positive, while non-tumourous lesions were always negative. Pleuropulmonary blastoma (PPB) showed a continuum in staining, with type I lesions being PRAME negative (n = 7) but all type II and type III lesions PRAME positive (n = 7). Similarly, cystic nephroma (CN) was negative (n = 8), with anaplastic sarcoma of the kidney being positive (n = 2). However, one atypical CN with mesenchymal cell proliferation was PRAME-positive. Embryonal rhabdomyosarcoma (RMS) with DICER1 pathogenic variants (PVs) was positive for PRAME (5/6), but the same tumour type without DICER1 PVs was also positive (9/15). Staining for EZH2 corresponded to that seen with PRAME, validating the latter. This study leads us to conclude that (1) PRAME expression occurs in two-thirds of DICER1-related malignancies; (2) PRAME may be a marker for the progression that certain DICER1-related lesions are thought to undergo, such as PPB and CN; and (3) PRAME expression in some tumours, such as RMS, appears to be an intrinsic feature of the tumour, rather than specifically related to DICER1 PVs. Therapy directed against PRAME may offer novel treatment options in patients with the DICER1 syndrome.
Assuntos
Neoplasias Renais , Síndromes Neoplásicas Hereditárias , Blastoma Pulmonar , Sarcoma , Antígenos de Neoplasias , RNA Helicases DEAD-box/genética , Humanos , Síndromes Neoplásicas Hereditárias/genética , Fenótipo , Blastoma Pulmonar/genética , Blastoma Pulmonar/metabolismo , Ribonuclease III/genéticaRESUMO
Pediatric papillary thyroid carcinoma (PPTC) is clinically distinct from adult-onset disease. Although there are higher rates of metastasis and recurrence in PPTC, prognosis remains highly favorable. Molecular characterization of PPTC has been lacking. Historically, only 40% to 50% of childhood papillary thyroid carcinoma (PTC) were known to be driven by genomic variants common to adult PTC; oncogenic drivers in the remainder were unknown. This contrasts with approximately 90% of adult PTC driven by a discrete number of variants. In this study, 52 PPTCs underwent candidate gene testing, followed in a subset by whole-exome and transcriptome sequencing. Within these samples, candidate gene testing identified variants in 31 (60%) tumors, while exome and transcriptome sequencing identified oncogenic variants in 19 of 21 (90%) remaining tumors. The latter were enriched for oncogenic fusions, with 11 nonrecurrent fusion transcripts, including two previously undescribed fusions, STRN-RET and TG-PBF. Most fusions were associated with 3' receptor tyrosine kinase (RTK) moieties: RET, MET, ALK, and NTRK3. For advanced (distally metastatic) tumors, a driver variant was described in 91%. Gene expression analysis defined three clusters that demonstrated distinct expression of genes involved in thyroid differentiation and MAPK signaling. Among RET-CCDC6-driven tumors, gene expression in pediatric tumors was distinguishable from that in adults. Collectively, these results show that the genomic landscape of pediatric PTC is different from adult PTC. Moreover, they identify genomic drivers in 98% of PPTCs, predominantly oncogenic fusion transcripts involving RTKs, with a pronounced impact on gene expression. Notably, most advanced tumors were driven by a variant for which targeted systemic therapy exists. SIGNIFICANCE: This study highlights important distinctions between the genomes and transcriptomes of pediatric and adult papillary thyroid carcinoma, with implications for understanding the biology, diagnosis, and treatment of advanced disease in children.
Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Fusão Oncogênica , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Transcriptoma , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genéticaRESUMO
Salivary gland tumors represent a diverse group of neoplasms that occasionally pose a diagnostic challenge for pathologists, particularly with limited sampling. Gene fusions, which may reflect genetic drivers, are increasingly recognized in a subset of these neoplasms, and can be leveraged for diagnostic purposes. We performed a retrospective analysis on a cohort of 80 benign and malignant salivary gland tumors, enriched for subtypes known to harbor recurrent fusion events, to validate the diagnostic use of a targeted RNA sequencing assay to detect fusion transcripts. Testing identified fusion genes in 71% (24/34) of pleomorphic adenoma and carcinoma-ex-pleomorphic adenoma, with 56% of cases showing rearrangement of PLAG1 and 15% HMGA2. In addition to confirming known partners for these genes, novel PLAG1 fusion partners were identified, including DSTN, NTF3, and MEG3; CNOT2 was identified as a novel fusion partner for HMGA2. In adenoid cystic carcinoma, 95% of cases (19/20) were positive for a fusion event. MYB was rearranged in 60% (12/20), MYBL1 in 30% (6/20), and NFIB in 5% (1/20); two tumors exhibited novel fusion products, including NFIB-TBPL1 and MYBL1-VCPIP1. Fusion genes were identified in 64% (9/14) of cases of mucoepidermoid carcinoma; MAML2 was confirmed to partner with either CRTC1 (43%) or CRTC3 (21%). One salivary duct carcinoma was found to harbor a novel RAPGEF6-ACSL6 fusion gene. Finally, as anticipated, gene fusions were not detected in any of the five acinic cell carcinomas included in the cohort. In summary, targeted RNA sequencing represents a diagnostically useful ancillary technique for identifying a variety of existing, and novel, fusion transcripts in the classification of salivary gland neoplasms.
Assuntos
Adenoma Pleomorfo/patologia , Biomarcadores Tumorais/genética , Carcinoma Adenoide Cístico/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Neoplasias das Glândulas Salivares/patologia , Análise de Sequência de RNA/métodos , Adenoma Pleomorfo/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/genética , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/genética , Adulto JovemRESUMO
OBJECTIVE: Disease spectrum in pediatric sarcoma differs substantially from adults. We report a cohort of very young children with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) detailing their molecular features, treatment, and outcome. METHODS: We report features of consecutive children (age <2 years) with NRSTS (2000-2017). Archival pathological material was re-reviewed, with additional molecular techniques applied where indicated. RESULTS: Twenty-nine patients (16 females, 55%) were identified (median age 6 months; range 0-23). Most common diagnoses included infantile fibrosarcoma (IFS, n = 14, 48%), malignant rhabdoid tumor (MRT, n = 4, 14%), and undifferentiated sarcoma (n = 4, 14%). Twenty-seven of 29 (93%) had tumor molecular characterization to confirm diagnosis. Clinical presentation included a swelling/mass (n = 23, 79%). Disease extent was localized (n = 20, 69%), locoregional (n = 6, 21%), or metastatic (n = 3, 10%). Seventeen of 29 (59%) who underwent surgery achieved complete resection (R0). Other treatments included conventional chemotherapy (n = 26, 90%), molecularly targeted therapies (n = 3, 10%), and radiation (n = 5, 17%). At last follow-up (median 3 years; range 0.3-16.4), 23 (79%) were alive, disease-free and six (21%) had died of disease. All patients with IFS were alive and all those with MRT died. A cancer predisposition syndrome (CPS) was confirmed in three of 10 (30%) genetically tested patients. CONCLUSION: We recommend tumor molecular characterization in all young patients including evaluation for CPS to optimize treatment options and prognostication.
Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Intervalo Livre de Doença , Feminino , Fibrossarcoma/diagnóstico , Fibrossarcoma/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/terapia , Sarcoma/diagnóstico , Sarcoma/terapia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/terapiaRESUMO
Neurotrophic tyrosine receptor kinase gene fusions (NTRK) are oncogenic drivers present at a low frequency in most tumour types (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., infantile fibrosarcoma [IFS]) and considered mutually exclusive with other common oncogenic drivers. Health Canada recently approved two tyrosine receptor kinase (TRK) inhibitors, larotrectinib (for adults and children) and entrectinib (for adults), for the treatment of solid tumours harbouring NTRK gene fusions. In Phase I/II trials, these TRK inhibitors have demonstrated promising overall response rates and tolerability in patients with TRK fusion cancer who have exhausted other treatment options. In these studies, children appear to have similar responses and tolerability to adults. In this report, we provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor for pediatric patients with solid tumours. We focus on three pediatric tumour types: non-rhabdomyosarcoma soft tissue sarcoma/unspecified spindle cell tumours including IFS, differentiated thyroid carcinoma, and glioma. We also propose a tumour-agnostic consensus based on the probability of the tumour harbouring an NTRK gene fusion. For children with locally advanced or metastatic TRK fusion cancer who have either failed upfront therapy or lack satisfactory treatment options, TRK inhibitor therapy should be considered.
Assuntos
Neoplasias , Receptor trkA , Biomarcadores , Canadá , Criança , Consenso , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genéticaRESUMO
INTRODUCTION: Pediatric Leydig cell tumors (LCTs) represent approximately 4% of pre-pubertal testicular tumors and are known to cause precocious puberty secondary to testosterone production. While gonadotropins and testosterone are known to initiate spermatogenesis beginning in puberty, it is yet to be determined if a similar phenomenon is triggered by isolated testosterone production in prepubescent boys. OBJECTIVE: To determine if testicular pathology in pre-pubertal pediatric patients with LCTs exhibit spermatogenesis secondary to paracrine testosterone stimulation. STUDY DESIGN: We reviewed patients who underwent orchiectomy for a testicular tumor from 2003-17. We included patients with LCTs and compared them to children with non-LCT pathology (teratomas and epidermoid cysts). We excluded other pathologies and tumors in pubertal patients. Data were collected on the presence of spermatogenesis on pathology, tumor markers and serum hormone results. RESULTS: Orchiectomy for testicular tumors were completed in 66 patients, of which 20 were included in the non-LCT group and 9 in the LCT group. Two of the 9 LCT patients had bilateral pathology. Age at presentation was 6.3 ± 5.8 years for the non-LCT group vs. 8.4 ± 1.6 years for LCTs (p = 0.261). Spermatogenesis was detected in 7 (64%) LCT specimens vs 2 (10%) non-LCT specimens (p = 0.002). Age of the spermatogenesis patients in the non-LCT group (11.08 ± 2.5 years) was older than LCT ones (8.3 ± 2.0 years), suggesting that spermatogenesis in the non-LCT group may be due to early pubertal development. The summary figure demonstrates spermatogenesis identified in a pre-pubertal LCT patient. DISCUSSION: In this study, pre-pubertal males with LCTs were identified to have pathology evidence of spermatogenesis compared to controls with non-LCT pathology. This represents the first study assessing paracrine testosterone effects on spermatogenesis in pre-pubertal patients with LCTs. In contrast, adult literature on LCTs primarily report on resulting concerns for fertility, gynecomastia and testicular atrophy. CONCLUSION: LCTs can induce spermatogenesis in prepubertal patients. This reinforces the hypothesis that paracrine testosterone signaling plays a role in spermatogenesis. Our findings could help explore novel fertility preservation opportunities in children.
Assuntos
Tumor de Células de Leydig , Neoplasias Testiculares , Adolescente , Adulto , Criança , Humanos , Tumor de Células de Leydig/cirurgia , Células Intersticiais do Testículo , Masculino , Orquiectomia , Espermatogênese , Neoplasias Testiculares/cirurgia , TestosteronaRESUMO
The classification of undifferentiated soft tissue tumors continues to evolve with the expanded application of molecular analysis in clinical practice. We report three cases of a unique soft tissue tumor in young children (5 months to 2 years old) displaying a purely fibromyxoid histology, with positive staining for desmin and CD34. In two cases, RNA sequencing detected a YWHAZ-PLAG1 gene fusion, while in the third case, a previously unreported EEF1A1-PLAG1 fusion was identified. PLAG1 fusions have been reported in several pathologic entities including pleomorphic adenoma, myoepithelial tumors of skin and soft tissue, and lipoblastoma, the latter occurring preferentially in young children. In these tumors, expression of a full length PLAG1 protein comes under the control of the constitutively active promoter of the partner gene in the fusion, and the current cases conform to that model. Overexpression of PLAG1 was confirmed by diffusely positive immunostaining for PLAG1 in all three cases. Our findings raise the possibility of a novel fibromyxoid neoplasm in childhood associated with these rare PLAG1 fusion variants. The only other report of a PLAG1-YWHAZ fusion occurred in a pediatric tumor diagnosed as a "fibroblastic lipoblastoma." This finding raises the possibility of a relationship with our three cases, even though our cases lacked any fat component. Further studies with regard to a shared pathogenesis are required.
Assuntos
Proteínas de Ligação a DNA/genética , Fibroma/genética , Neoplasias de Cabeça e Pescoço/genética , Fusão Oncogênica , Neoplasias Cutâneas/genética , Proteínas 14-3-3/genética , Pré-Escolar , Feminino , Fibroma/patologia , Doenças do Pé/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Lactente , Masculino , Fator 1 de Elongação de Peptídeos/genética , RNA-Seq , Couro Cabeludo , Neoplasias Cutâneas/patologiaRESUMO
An earlier incorrect version of this article appeared online. This article was corrected on December 17, 2019.
Assuntos
Transtornos Linfoproliferativos/diagnóstico por imagem , Transtornos Linfoproliferativos/imunologia , Transplante de Órgãos , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/imunologia , Criança , Diagnóstico Diferencial , Humanos , Hospedeiro Imunocomprometido , Transtornos Linfoproliferativos/terapia , Complicações Pós-Operatórias/terapia , Fatores de RiscoRESUMO
Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that may be associated with Kasabach-Merritt Phenomenon (KMP), which is a consumptive coagulopathy with potentially life-threatening thrombocytopenia. Management of KHE and KMP is challenging, and currently, there are no standardized validated treatment protocols. Mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of KHE. We describe a term male who presented as a diagnostic dilemma with life-threatening pleural and pericardial effusions and severe thrombocytopenia. After extensive work-up the etiology for his condition was determined to be KHE with KMP. The patient was commenced on sirolimus and responded well to therapy with resolution of KMP.
Assuntos
Hemangioendotelioma/tratamento farmacológico , Síndrome de Kasabach-Merritt/tratamento farmacológico , Derrame Pericárdico/tratamento farmacológico , Derrame Pleural Maligno/tratamento farmacológico , Sarcoma de Kaposi/tratamento farmacológico , Sirolimo/administração & dosagem , Hemangioendotelioma/diagnóstico , Humanos , Recém-Nascido , Síndrome de Kasabach-Merritt/diagnóstico , Masculino , Derrame Pericárdico/diagnóstico , Derrame Pleural Maligno/diagnóstico , Sarcoma de Kaposi/diagnósticoAssuntos
Injúria Renal Aguda/diagnóstico , Linfadenopatia/diagnóstico , Neutropenia/diagnóstico , Esplenomegalia/diagnóstico , Injúria Renal Aguda/sangue , Injúria Renal Aguda/urina , Biópsia , Pré-Escolar , Creatinina/sangue , Diagnóstico Diferencial , Feminino , Ferritinas/sangue , Humanos , Rim/patologia , Linfadenopatia/sangue , Linfadenopatia/urina , Neutropenia/sangue , Neutropenia/urina , Esplenomegalia/sangue , Esplenomegalia/urina , Ureia/sangueAssuntos
Injúria Renal Aguda/imunologia , Glomerulonefrite/diagnóstico , Linfadenopatia/imunologia , Neutropenia/imunologia , Esplenomegalia/imunologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Complexo Antígeno-Anticorpo/imunologia , Biópsia , Medula Óssea/patologia , Pré-Escolar , Diagnóstico Diferencial , Feminino , Glomerulonefrite/complicações , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Humanos , Vasculite por IgA/diagnóstico , Imunossupressores/uso terapêutico , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Linfadenopatia/tratamento farmacológico , Microscopia Eletrônica , Neoplasias/diagnóstico , Neutropenia/tratamento farmacológico , Esplenomegalia/tratamento farmacológicoRESUMO
Microcystic congenital cystic adenomatoid malformations (CCAM), when associated with hydrops, carry a dismal prognosis. Options for treatment are limited and experimental, including antenatal corticosteroids, open fetal surgery, laser ablation and, more recently, sclerotherapy. We describe a case of a large, predominantly microcystic CCAM in a hydropic fetus treated successfully with direct interstitial injection of a sclerosant agent (3% sodium tetradecyl sulfate) at 23+3 weeks gestation, after multiple failed courses of steroids. Elective thoracoscopic right lower lobectomy was performed at 1 year of life and there have been no respiratory or other medical morbidities since. A literature review of fetal lung masses treated with sclerosants antenatally reveals that sclerotherapy may represent a novel treatment option for large hydropic microcystic CCAMs, which are unresponsive to corticosteroids. Further studies are required to evaluate the utility and safety of fetal sclerotherapy, as this may represent an alternative minimally invasive treatment option to fetal lobectomy.
Assuntos
Malformação Adenomatoide Cística Congênita do Pulmão/terapia , Terapias Fetais , Hidropisia Fetal/terapia , Escleroterapia , Adulto , Malformação Adenomatoide Cística Congênita do Pulmão/complicações , Malformação Adenomatoide Cística Congênita do Pulmão/diagnóstico por imagem , Feminino , Humanos , Hidropisia Fetal/diagnóstico por imagem , Hidropisia Fetal/etiologia , Gravidez , Ultrassonografia Pré-NatalRESUMO
Neuroblastoma is the most common extracranial solid tumor of childhood with a median age of presentation of 17 months. A common theme in high-risk neuroblastoma is maintenance of telomeres, one mechanism for which involves alternate lengthening of telomeres (ALT) associated with ATRX gene mutations. Mutations are believed to result in loss of ATRX protein, and therefore immunohistochemistry is used to detect mutations. We screened 133 cases of neuroblastoma by ATRX immunohistochemistry, and found 9 cases with partial to total absence of ATRX. Sequencing for ATRX mutations detected a mutation in 1 of 9 cases, suggesting immunostaining was not reliable for detecting mutations. To correlate immunostaining with ALT, fluorescence in situ hybridization (FISH) for ALT was performed in 6 of these cases and 5 (from 4 patients) showed ALT, implying impaired ATRX protein function, despite the failure to identify a mutation. Two other cases with large deletions in the ATRX gene showed diffusely positive staining for ATRX protein but showed ALT by FISH. Four of the 6 patients with ALT-positive tumors were over 5 years old. Therefore, 29 additional patients 5 years old and above with ATRX-positive tumors were screened for ALT by FISH and 6 additional cases with ALT were detected, bringing the total to 29% (10/34) of children 5 years old and above, 70% of which showed positive ATRX immunohistochemistry. Patients with ATRX mutations in neuroblastoma tend to have a more chronic and progressive course of disease. Screening neuroblastoma tumors at diagnosis for ATRX mutations may help identify patients who might benefit from personalized therapy directed against ALT. However, relaying on negative immunohistochemistry for ATRX protein to identify ALT in neuroblastoma may miss a significant proportion of patients. The addition of FISH for ALT as part of the diagnostic workup, especially for older children (5 y old and above), would help ensure that patients are correctly identified for anti-ALT therapy.
Assuntos
Imuno-Histoquímica/métodos , Neuroblastoma/genética , Proteína Nuclear Ligada ao X/análise , Adolescente , Criança , Pré-Escolar , Reações Falso-Negativas , Feminino , Humanos , Lactente , Masculino , Mutação , Reprodutibilidade dos Testes , Proteína Nuclear Ligada ao X/genética , Adulto JovemRESUMO
Context: Papillary thyroid carcinoma (PTC) is a common malignancy in adolescence and is molecularly and clinically distinct from adult PTC. Mutations in the DICER1 gene are associated with thyroid abnormalities, including multinodular goiter and differentiated thyroid carcinoma. Objective: In this study, we sought to characterize the prevalence of DICER1 variants in pediatric PTC, specifically in tumors without conventional PTC oncogenic alterations. Patients: Patients (N = 40) who underwent partial or total thyroidectomy and who were <18 years of age at the time of surgery were selected. Design: The 40 consecutive thyroidectomy specimens (30 malignant, 10 benign) underwent genotyping for 17 PTC-associated variants, as well as full sequencing of the exons and exon-intron boundaries of DICER1. Results: Conventional alterations were found in 12 of 30 (40%) PTCs (five BRAFV600E, three RET/PTC1, four RET/PTC3). Pathogenic DICER1 variants were identified in 3 of 30 (10%) PTCs and in 2 of 10 (20%) benign nodules, all of which lacked conventional alterations and did not recur during follow-up. DICER1 alterations thus constituted 3 of 18 (16.7%) PTCs without conventional alterations. The three DICER1-mutated carcinomas each had two somatic DICER1 alterations, whereas two follicular-nodular lesions arose in those with germline DICER1 mutations and harbored characteristic second somatic RNase IIIb "hotspot" mutations. Conclusions: DICER1 is a driver of pediatric thyroid nodules, and DICER1-mutated PTC may represent a distinct class of low-risk malignancies. Given the prevalence of variants in children, we advocate for inclusion of DICER1 sequencing and gene dosage determination in molecular analysis of pediatric thyroid specimens.