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Gastrointestinal stromal tumors (GISTs) are sarcomas affecting the stomach and small intestine, with a rare subtype characterized by succinate dehydrogenase B (SDHB)-loss posing significant diagnostic and therapeutic challenges. A 62-year-old man with weight loss and abdominal pain was diagnosed with a gastric GIST showing SDHB-loss. Initial treatment with Imatinib reduced the tumor size, but surgery revealed no residual tumor. Despite adjuvant Imatinib, recurrence occurred, necessitating further surgical intervention. While GISTs typically benefit from surgery and tyrosine kinase inhibitors (TKIs), those with SDHB-loss are resistant to TKIs, requiring a different management approach. This case emphasizes the importance of surgical intervention for SDHB-deficient GISTs and the need for ongoing research into effective treatments for this subtype.
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BACKGROUND AND OBJECTIVES: The aim of this study is to explore the long-term prognostic risk factors associated with patients diagnosed with retroperitoneal paraganglioma (RPGL) and examine their clinical and pathological characteristics. METHODS: Expressions of biomarkers were identified using immunohistochemistry (IHC) and case databases were retrospectively searched. Survival analysis was performed using Kaplan-Meier and Cox risk regression to identify the factors that influence the postoperative progression-free survival of patients with RPGL. RESULTS: A total of 105 patients, most of whom had tumors situated in the paraaortic region, and whose average tumor size was 8.6 cm, were enrolled in this study. The average follow-up duration was 51 months, with a mortality rate of 19% and a recurrence and metastasis rate of 41.9%. Tumors were assessed using the modified Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP), and SDHB, S-100, and Ki-67 were stained using IHC in all cases. Out of the total cases examined, negative in SDHB expression were observed in 18.1% of cases, S-100 expression was negative in 36.2% of cases, and endovascular tumor enboluswas present in approximately 25.7% of cases. The results of the univariate analysis indicated that several factors significantly influenced the progression-free survival of patients with PGL as follow: maximum tumor diameter (>5.5 cm), tumor morphological features, tumor grading (modified GAPP score > 6), SDHB negative, S-100 negative, and expression of proliferation index Ki-67 (>3%) (X2 = 4.217-27.420, p < 0.05). The results of the multivariate analysis indicated that negative of S-100 (p = 0.021) and SDHB (p = 0.038), as well as intravascular tumor thrombus (p = 0.047) expression were independent risk factors for progression-free survival in patients. CONCLUSION: RPGL is characterized by diverse biological features and an elevated susceptibility to both recurrence and metastasis. Both SDHB and S-100 can be employed as traditional IHC indicators to predict the metastatic risk of PGL, whereas the tumor histomorphology-endovascular tumor enbolus assists in determining the metastasis risk of RPGL.
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Biomarcadores Tumorais , Paraganglioma , Neoplasias Retroperitoneais , Humanos , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/metabolismo , Neoplasias Retroperitoneais/cirurgia , Neoplasias Retroperitoneais/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Paraganglioma/patologia , Paraganglioma/metabolismo , Paraganglioma/cirurgia , Paraganglioma/mortalidade , Prognóstico , Adulto , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Idoso , Taxa de Sobrevida , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/metabolismo , Seguimentos , Adulto Jovem , Succinato DesidrogenaseRESUMO
OBJECTIVE: The existing prediction models for metastasis in pheochromocytomas/paragangliomas (PPGLs) showed high heterogeneity in different centers. Therefore, this study aimed to establish new prediction models integrating multiple variables based on different algorithms. DESIGN AND METHODS: Data of patients with PPGLs undergoing surgical resection at the Peking Union Medical College Hospital from 2007 to 2022 were collected retrospectively. Patients were randomly divided into the training and testing sets in a ratio of 7:3. Subsequently, decision trees, random forest, and logistic models were constructed for metastasis prediction with the training set and Cox models for metastasis-free survival (MFS) prediction with the total population. Additionally, Ki-67 index and tumor size were transformed into categorical variables for adjusting models. The testing set was used to assess the discrimination and calibration of models and the optimal models were visualized as nomograms. Clinical characteristics and MFS were compared between patients with and without risk factors. RESULTS: A total of 198 patients with 59 cases of metastasis were included and classified into the training set (n = 138) and testing set (n = 60). Among all models, the logistic regression model showed the best discrimination for metastasis prediction with an AUC of 0.891 (95% CI, 0.793-0.990), integrating SDHB germline mutations [OR: 96.72 (95% CI, 16.61-940.79)], S-100 (-) [OR: 11.22 (95% CI, 3.04-58.51)], ATRX (-) [OR: 8.42 (95% CI, 2.73-29.24)] and Ki-67 ≥ 3% [OR: 7.98 (95% CI, 2.27-32.24)] evaluated through immunohistochemistry (IHC), and tumor size ≥ 5 cm [OR: 4.59 (95% CI, 1.34-19.13)]. The multivariate Cox model including the above risk factors also showed a high C-index of 0.860 (95% CI, 0.810-0.911) in predicting MFS after surgery. Furthermore, patients with the above risk factors showed a significantly poorer MFS (P ≤ 0.001). CONCLUSIONS: Models established in this study provided alternative and reliable tools for clinicians to predict PPGLs patients' metastasis and MFS. More importantly, this study revealed for the first time that IHC of ATRX could act as an independent predictor of metastasis in PPGLs.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/patologia , Feminino , Masculino , Paraganglioma/patologia , Paraganglioma/cirurgia , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/secundário , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Prognóstico , Nomogramas , Metástase Neoplásica , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Seguimentos , Fatores de RiscoRESUMO
BACKGROUND: There are few studies on the efficacy of temozolomide (TMZ) in the treatment of Metastatic pheochromocytoma / paraganglioma (MPP) patients. And it remains unclear which MPP patients may benefit from TMZ treatment. METHODS: This was a prospective study. MPP patients were enrolled. Patients were treated with TMZ until disease progression or intolerable toxicities. The primary endpoints were disease control rate (DCR) and objective response rate (ORR). Secondary endpoints included biochemical response rate progression-free survival (PFS) and safety. We compared the difference between effective and ineffective groups, to explore which patients are more suitable for TMZ treatment. RESULTS: 62 patients with MPP were enrolled and tumor response were evaluated in 54 patients. The DCR was 83% (35/42), and the ORR was 24% (10/41) among the progressive patients. PFS was 25.2 ± 3.1 months. The most common adverse event was nausea (41/55). We found that 92.9% (13/14) of patients with MGMT methylation greater than 7% respond to treatment. For the patients with MGMT methylation less than 7%, Ki-67 index could be used to guide the use of TMZ in these patients. Among the patients with Ki-67 index less than 5%, 66% (8/12) patients showed respond to treatment, and only 33% (4/12) patients with Ki-67 index more than 5% showed respond to TMZ. CONCLUSIONS: This study indicated that TMZ is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. We recommended to MGMT methylation analysis test and Ki-67 index to guide TMZ application.
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Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours arising from chromaffin cells. Pathogenic variants in the gene succinate dehydrogenase subunit B (SDHB) are associated with malignancy and poor prognosis. When metastases arise, limited treatment options are available. The pathomechanism of SDHB-associated PPGL remains largely unknown, and the lack of suitable models hinders therapy development. Germline heterozygous SDHB pathogenic variants predispose to developing PPGLs with a life-long penetrance of around 50%. To mimic the human disease phenotype, we characterised adult heterozygous sdhb mutant zebrafish as a potential model to study SDHB-related PPGLs. Adult sdhb mutant zebrafish did not develop an obvious tumour phenotype and were anatomically and histologically like their wild-type siblings. However, sdhb mutants showed significantly increased succinate levels, a major hallmark of SDHB-related PPGLs. While basal activity was increased during day periods in mutants, mitochondrial complex activity and catecholamine metabolite levels were not significantly different. In conclusion, we characterised an adult in vivo zebrafish model, genetically resembling human carriers. Adult heterozygous sdhb mutants mimicked their human counterparts, showing systemic elevation of succinate levels despite the absence of a tumour phenotype. This model forms a promising basis for developing a full tumour phenotype and gaining knowledge of the pathomechanism behind SDHB-related PPGLs.
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Neoplasias das Glândulas Suprarrenais , Modelos Animais de Doenças , Paraganglioma , Feocromocitoma , Succinato Desidrogenase , Peixe-Zebra , Animais , Humanos , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Mutação , Paraganglioma/genética , Paraganglioma/patologia , Paraganglioma/metabolismo , Fenótipo , Feocromocitoma/genética , Feocromocitoma/patologia , Feocromocitoma/metabolismo , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Peixe-Zebra/genéticaRESUMO
Succinate dehydrogenase inhibitors (SDHIs) are keystone synthetic fungicides used to manage Botrytis cinerea in several hosts. In this study, we investigated the cross-resistance between five new SDHIs (pyraziflumid, isofetamid, benzovindiflupyr, fluxapyroxad, and pydiflumetofen) with commonly used SDHIs boscalid and fluopyram. Different mutations were detected in the sdhB gene in B. cinerea collected from Michigan grapes, and their frequency and EC50 value were determined. Among 216 B. cinerea boscalid-resistant isolates, five different mutations were detected, including H272R/Y, P225F/H, and N230I, at frequencies of 82.6, 4.3, 11.5, 0.4, and 5.3%, respectively. Five isolates of each genotype were used to screen the cross-resistance of the SDHIs. We classified the resistance profile of our mutants into five patterns. We report that all tested mutants were sensitive to benzovindiflupyr, indicating that it can be used as an effective fungicide against all B. cinerea mutants identified in this study. In addition, fluopyram, pydiflumetofen, and isofetamid can provide effective control according to which type of mutation is present in the field. We also developed and compared two molecular diagnostic tools, rhAMP and TaqMan assays, for rapid detection of SDHI resistance-associated mutants in B. cinerea. We report that the TaqMan assay was more successful than the rhAMP assay in detecting the B. cinerea mutant DNA at ≤10 pg and in a single assay was capable of monitoring two amino acid positions. Our results provide essential information about new SDHIs and provide molecular tools for monitoring SDHI resistance mutations, which will assist in gray mold disease control.
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Fungicidas Industriais , Succinato Desidrogenase , Succinato Desidrogenase/genética , Succinato Desidrogenase/farmacologia , Patologia Molecular , Doenças das Plantas , Fungicidas Industriais/farmacologia , Botrytis/genética , Niacinamida/farmacologia , Farmacorresistência Fúngica/genéticaRESUMO
Malignant middle ear paraganglioma (MEPGL) is an exceedingly rare tumor of the neuroendocrine system. In general, MEPGLs represent as slow growing and hypervascularized benign neoplasms. The genetic basis of MEPGL tumorigenesis has been poorly investigated. We report a case of malignant MEPGL accompanied by the comprehensive genetic analysis of the primary tumor and metastasis. Based on whole-exome sequencing data, the germline pathogenic mutation p.R230H in the SDHB gene, encoding for subunit B of mitochondrial complex II, was found in a patient. Analysis of somatic mutation spectra revealed five novel variants in different genes, including a potentially deleterious variant in UNC13C that was common for the tumor and metastasis. Identified somatic variants clustered into SBS1 and SBS5 mutational signatures. Of note, the primary tumor was characterized by Ki-67 4% and had an elevated mutational load (1.4/Mb); the metastasis' mutational load was about 4.5 times higher (6.4/Mb). In addition, we revealed somatic loss of the wild-type SDHB allele, as well as loss of heterozygosity (LOH) at the 11p locus. Thus, germline mutation in SDHB combined with somatic LOH seem to be drivers that lead to the tumor's initiation and progression. Other somatic changes identified can be additional disease-causing factors. Obtained results expand our understanding of molecular genetic mechanisms associated with the development of this rare tumor.
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Paraganglioma , Humanos , Paraganglioma/genética , Paraganglioma/patologia , Mutação , Mutação em Linhagem Germinativa , Perda de HeterozigosidadeRESUMO
PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ÉÉ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ÉÉ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.
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Neoplasias das Glândulas Suprarrenais , Succinato Desidrogenase , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Mutação em Linhagem Germinativa , Humanos , Fenótipo , Succinato Desidrogenase/genética , VirulênciaRESUMO
Succinate dehydrogenase inhibitors (SDHIs) are fungicides used in control of numerous fungal plant pathogens, including Erysiphe necator, the causal agent of grapevine powdery mildew (GPM). Here, the sdhb, sdhc, and sdhd genes of E. necator were screened for mutations that may be associated with SDHI resistance. GPM samples were collected from 2017 to 2020 from the U.S. states of California, Oregon, Washington, and Michigan, and the Canadian province of British Columbia. Forty-five polymorphisms were identified in the three sdh genes, 17 of which caused missense mutations. Of these, the SDHC-p.I244V substitution was shown in this study to reduce sensitivity of E. necator to boscalid and fluopyram, whereas the SDHC-p.G25R substitution did not affect SDHI sensitivity. Of the other 15 missense mutations, the SDHC-p.H242R substitution was shown in previous studies to reduce sensitivity of E. necator toward boscalid, whereas the equivalents of the SDHB-p.H242L, SDHC-p.A83V, and SDHD-p.I71F substitutions were shown to reduce sensitivity to SDHIs in other fungi. Generally, only a single amino acid substitution was present in the SDHB, SDHC, or SDHD subunit of E. necator isolates, but missense mutations putatively associated with SDHI resistance were widely distributed in the sampled areas and increased in frequency over time. Finally, isolates that had decreased sensitivity to boscalid or fluopyram were identified but with no or only the SDHC-p.G25R amino acid substitution present in SDHB, SDHC, and SDHD subunits. This suggests that target site mutations probably are not the only mechanism conferring resistance to SDHIs in E. necator.
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Inibidores Enzimáticos/farmacologia , Succinato Desidrogenase , Vitis , Colúmbia Britânica , Farmacorresistência Fúngica/genética , Erysiphe , Mutação , Doenças das Plantas/microbiologia , Succinato Desidrogenase/genéticaRESUMO
BACKGROUND: Enzymes of tricarboxylic acid (TCA) have recently been recognized as tumor suppressors. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) cause pheochromocytomas and paragangliomas (PCCs/PGLs) and predispose patients to malignant disease with poor prognosis. METHODS: Using the human pheochromocytoma cell line (hPheo1), we knocked down SDHB gene expression using CRISPR-cas9 technology. RESULTS: Microarray gene expression analysis showed that >500 differentially expressed gene targets, about 54%, were upregulated in response to SDHB knock down. Notably, genes involved in glycolysis, hypoxia, cell proliferation, and cell differentiation were up regulated, whereas genes involved in oxidative phosphorylation (OXPHOS) were downregulated. In vitro studies show that hPheo1 proliferation is not affected negatively and the cells that survive by shifting their metabolism to the use of glutamine as an alternative energy source and promote OXPHOS activity. Knock down of SDHB expression results in a significant increase in GLUD1 expression in hPheo1 cells cultured as monolayer or as 3D culture. Analysis of TCGA data confirms the enhancement of GLUD1 in SDHB mutated/low expressed PCCs/PGLs. CONCLUSIONS: Our data suggest that the downregulation of SDHB in PCCs/PGLs results in increased GLUD1 expression and may represent a potential biomarker and therapeutic target in SDHB mutated tumors and SDHB loss of activity-dependent diseases.
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Metabolismo Energético , Fosforilação Oxidativa , Succinato Desidrogenase/deficiência , Biomarcadores , Sistemas CRISPR-Cas , Adesão Celular , Linhagem Celular , Metabolismo Energético/genética , Dosagem de Genes , Edição de Genes , Expressão Gênica , Técnicas de Silenciamento de Genes , Glicólise , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , FenótipoRESUMO
Paragangliomas (PGLs) are rare neuroendocrine tumors that can develop from any paraganglion across the body. The carotid body is the most often location of PGLs in the head and neck region. Carotid PGLs (CPGLs) are characterized by predominantly non-aggressive behavior; however, all tumors have the potential to metastasize. To date, molecular mechanisms of paraganglioma progression remain elusive. We report a case of a 38-year-old woman with metastatic CPGL manifesting as a recurrent tumor with lymph node metastasis. The tumor was fast-growing and had a high Ki-67 proliferation index. Immunohistochemical (IHC) examination and whole-exome sequencing were performed for both recurrent tumor and metastasis. A germline pathogenic splice acceptor variant in the SDHB gene was found in the patient. Immunoreactivity of the SDHB subunit was weak diffuse in both samples, indicating deficiency of the succinate dehydrogenase. Moreover, the recurrent tumor exhibited loss of heterozygosity (LOH) at the SDHB locus, that is according to Knudson's "two-hit" hypothesis of cancer causation. We also identified a rare somatic promotor mutation in the TERT gene associated with the tumor progression. Obtained results confirmed the indicative role of the germline SDHB mutation for metastatic CPGLs, as well as the potential prognostic value of the TERT promoter mutation.
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Corpo Carotídeo/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Paraganglioma/diagnóstico , Paraganglioma/genética , Adulto , Biomarcadores Tumorais , Análise Mutacional de DNA , Progressão da Doença , Feminino , Testes Genéticos , Humanos , Imuno-Histoquímica , Mutação , Paraganglioma/terapia , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismoRESUMO
OBJECTIVE: To compare metastatic pheochromocytoma/paraganglioma (MPP) patients with germline SDHB mutations (SDHB MPP) and without SDHB mutations (non-SDHB MPP) in terms of baseline clinical manifestations, tumor characteristics, and outcomes. METHODS: Clinical data were retrospectively reviewed in 101 MPP patients, including 34 SDHB MPP patients and 61 non-SDHB MPP patients. RESULTS: SDHB MPP patients presented at a younger age at onset, diagnosis, or metastasis (25 ± 16 vs 36 ± 14, 28 ± 17 vs 38 ± 15, and 31 ± 17 vs 44 ± 14 years old, respectively, P < .01 for all) than non-SDHB patients. Compared with their non-SDHB counterparts, SDHB patients were more likely to have paragangliomas (83% vs 47%, P < .05), synchronous metastases (44% vs 23%, P < .05), bone metastases (80% vs 48%, P < .01), and a shorter progression-free survival (3 years vs 5 years, P < .01). The Ki-67 index was higher in SDHB tumors (P < .05). The 5- and 10-year survival rates were 79% and 74%, respectively, in all patients. Seventeen patients died from MPP, and the time from metastasis to death in patients who had received systemic therapy was significantly longer than in those who had not (3.1 ± 1.5 vs 1.4 ± 0.7 years, P < .01). CONCLUSION: Compared with MPP patients without SDHB mutations, MPP patients with SDHB mutations were younger at onset, diagnosis, or metastasis; had a higher incidence of synchronous metastases, higher ratio of paraganglioma, and higher Ki-67 index; had a shorter postoperative progression-free survival; and were more likely to develop bone metastasis or sole liver metastasis. Our results suggest that patients with SDHB mutations should be identified early and monitored regularly to achieve optimal clinical outcomes.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Criança , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Mutação , Paraganglioma/genética , Feocromocitoma/genética , Prognóstico , Estudos Retrospectivos , Succinato Desidrogenase/genética , Adulto JovemRESUMO
BACKGROUND: Pathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype. METHODS: Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes. RESULTS: Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of SDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (p<0.001). CONCLUSIONS: SDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.
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Proteínas de Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Adulto , Feminino , Mutação em Linhagem Germinativa/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Heterozigoto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Paraganglioma/patologia , Feocromocitoma/patologiaRESUMO
Metastatic paraganglioma (MPG) of the spine is a rare condition, with no established management. Herein, we report the longest survival case of a primary neck tumor that caused spinal MPG with a succinate dehydrogenase subunit B (SDHB) mutation (c.470delT, p.L157X) which could have promoted its malignancy. This male patient initially presented with a left neck PG which was diagnosed by a biopsy when he was 54 years-old. Simultaneously performed additional examinations revealed the spinal metastatic tumors on the T5-7 vertebrae and L3 vertebra-sacrum. These primary neck and metastatic spinal tumors' growths were once suppressed under the radiation therapy. Nineteen years later, he developed acute progressive paraparesis due to a mass located at the T2-3 level, tightly compressing the spinal cord, and protruding into the left thoracic cavity. We resected the maximum possible area of tumor in the spinal canal, confirmed MPG by histological examination, and then, we administered radiation therapy of 40 Gy in 20 fractions. Eventually, the patient was able to walk unaided with no evidential tumor recurrence for 3 years after treatment. Generally, clinical feature of MPG with SDHB mutation from abdominal lesion is thought to be poor prognosis. However, our case suggests the possibility of long-term control of spinal MPG with the adequate combination of radiation therapy and resection if metastatic lesions from primary-neck lesion with an SDHB mutation are remained to spine.
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Neoplasias de Cabeça e Pescoço , Paraganglioma , Neoplasias da Coluna Vertebral , Succinato Desidrogenase/genética , Idoso , Códon sem Sentido , Terapia Combinada , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/genética , Paraganglioma/radioterapia , Paraganglioma/secundário , Paraganglioma/cirurgia , Intervalo Livre de Progressão , Radioterapia Adjuvante , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/radioterapia , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/cirurgia , Resultado do TratamentoRESUMO
Loss of the morphological and immunophenotypic characteristics of a neoplasm is a well-known phenomenon in surgical pathology and occurs across different tumor types in almost all organs. This process may be either partial, characterized by transition from well differentiated to undifferentiated tumor component (=dedifferentiated carcinomas) or complete (=undifferentiated carcinomas). Diagnosis of undifferentiated carcinoma is significantly influenced by the extent of sampling. Although the concept of undifferentiated and dedifferentiated carcinoma has been well established for other organs (e.g. endometrium), it still has not been fully defined for urological carcinomas. Accordingly, undifferentiated/ dedifferentiated genitourinary carcinomas are typically lumped into the spectrum of poorly differentiated, sarcomatoid, or unclassified (NOS) carcinomas. In the kidney, dedifferentiation occurs across all subtypes of renal cell carcinoma (RCC), but certain genetically defined RCC types (SDH-, FH- and PBRM1- deficient RCC) seem to have inherent tendency to dedifferentiate. Histologically, the undifferentiated component displays variable combination of four patterns: spindle cells, pleomorphic giant cells, rhabdoid cells, and undifferentiated monomorphic cells with/without prominent osteoclastic giant cells. Any of these may occasionally be associated with heterologous mesenchymal component/s. Their immunophenotype is often simple with expression of vimentin and variably pankeratin or EMA. Precise subtyping of undifferentiated (urothelial versus RCC and the exact underlying RCC subtype) is best done by thorough sampling supplemented as necessary by immunohistochemistry (e.g. FH, SDHB, ALK) and/ or molecular studies. This review discusses the morphological and molecular genetic spectrum and the recent develoments on the topic of dedifferentiated and undifferentiated genitourinary carcinomas.
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Carcinoma de Células Renais , Carcinoma/classificação , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/classificação , Feminino , Humanos , Neoplasias Renais/classificaçãoRESUMO
Although pheochromocytomas and paragangliomas (PPGLs) are usual low-grade neoplasms, the metastatic forms of these lesions are associated with high morbidity and mortality. Recent studies have discovered multiple aberrantly expressed long non-coding RNAs (lncRNAs) in cancers that may have regulatory roles in tumor pathogenesis and metastasis; however, the roles of some lncRNAs in PPGLs are still unknown. The expression levels of lncRNAs including metastasis-associated lung adenocarcinoma transcript (MALAT1), prostate cancer antigen 3 (PCA3), and HOX transcript antisense intergenic RNA (HOTAIR) in PPGLs were analyzed by in situ hybridization, using two tissue microarrays (TMAs). The pheochromocytoma (PCC) TMA consisted of normal adrenal medulla (N = 25), non-metastatic PCCs (N = 76) and metastatic PCCs (N = 5) while the paraganglioma (PGL) TMA had 73 non-metastatic PGLs and 5 metastatic PGLs. Immunohistochemical staining was performed on all samples with an anti-SDHB antibody. The correlations between lncRNA expression, loss of SDHB expression and clinical characteristics including tumor progression and disease prognosis were investigated. The expression levels of MALAT1 and PCA3 were significantly elevated (2.5-3.9 folds) in both non-metastatic and metastatic PCCs compared to normal adrenal medulla, although there were no significant differences between the non-metastatic and metastatic neoplasms. In contrast to non-metastatic PGLs, metastatic PGLs had significantly upregulated expression of MALAT1, PCA3, and HOTAIR. SDHB loss was more frequently observed in PGLs (25 of 78), especially in metastatic PGLs (5 of 5), compared to PCCs (2 of 81) and in 0 of 5 metastatic PCCs. Patients with SDHB loss, in contrast to SDHB retained, were younger at diagnosis, had higher rates of tumor recurrence, metastatic disease, and mortality. In addition, PGLs with SDHB loss had significantly increased expression of PCA3 compared to tumors with intact SDHB expression. Our findings suggest that specific lncRNAs may be involved in the SDHx signaling pathways in the tumorigenesis and in the development of PPGL.
Assuntos
Paraganglioma , Feocromocitoma , RNA Longo não Codificante , Succinato Desidrogenase , Carcinogênese , Humanos , Mutação , Recidiva Local de Neoplasia , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Prognóstico , RNA Longo não Codificante/análise , RNA Longo não Codificante/genética , Transdução de Sinais , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismoRESUMO
BACKGROUND: The classification of renal cell carcinoma (RCC) has changed remarkably in recent years. OBJECTIVES: This is a short overview of the classification of RCC, focusing on new developments. MATERIALS AND METHODS: A literature search was performed resulting in an overview of the classification of RCC. Emerging entities were discussed in detail. RESULTS: Apart from the RCC subtypes in the WHO classification of 2016, several emerging entities came up over the last few years that are characterized by typical morphology, immunophenotype, and especially specific genetic alterations. CONCLUSION: Precise classification of RCC is the key to better prognostic assessment with potential tumor-specific therapy and plays an important role in the recognition of possible association with hereditary tumor syndromes.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Síndromes Neoplásicas Hereditárias , Carcinoma de Células Renais/genética , Humanos , Neoplasias Renais/genética , PrognósticoRESUMO
Trimethylamine N-oxide (TMAO) is produced from the phosphatidylcholine metabolism of gut flora and acts as a risk factor of cardiovascular disease. However, the underlying mechanisms for its proatherogenic action remain unclear. This study aimed to observe the effect of TMAO on endothelial cell pyroptosis and explore the underlying mechanisms. Our results showed that TMAO promoted the progression of atherosclerotic lesions in apolipoprotein E-deficient (apoE-/- ) mice fed a high-fat diet. Pyroptosis and succinate dehydrogenase complex subunit B (SDHB) upregulation were detected in the vascular endothelial cells of apoE-/- mice and in cultured human umbilical vein endothelial cells (HUVECs) treated with TMAO. Overexpression of SDHB in HUVECs enhanced pyroptosis and impaired mitochondria and high reactive oxygen species (ROS) level. Pyroptosis in the SDHB overexpression of endothelial cells was inhibited by the ROS scavenger NAC. In summary, TMAO promotes vascular endothelial cell pyroptosis via ROS induced through SDHB upregulation, thereby contributing to the progression of atherosclerotic lesions.
Assuntos
Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Metilaminas/farmacologia , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/metabolismo , Animais , Células Cultivadas , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Leigh syndrome is a clinically and radiologically heterogeneous condition with approximately 75 genes, nuclear and mitochondrial, known to be implicated in its pathogenesis. Leigh syndrome due to complex II deficiency constitutes 2% to 7% of these cases. Previously, nine individuals with Leigh syndrome have been reported with pathogenic variants in SDHB, which encodes for the iron-sulfur cluster subunit of mitochondrial respiratory chain complex II. The proband presented with Leigh syndrome. Exome sequencing revealed a homozygous missense variant p.(Ala102Thr) in SDHB. In silico protein modeling of the wild-type and mutant proteins showed potentially decreased protein stability. We hereby report another individual with Leigh syndrome due to SDHB-related mitochondrial complex II deficiency and review the phenotype and genotype associated with this condition.
Assuntos
Complexo II de Transporte de Elétrons/deficiência , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Succinato Desidrogenase/genética , Complexo II de Transporte de Elétrons/genética , Homozigoto , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Estrutura Secundária de Proteína , Sequenciamento do ExomaRESUMO
Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas-including the prognostically relevant SDH mutations-are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile.