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Leiomyoma is the most prevalent benign tumor of the female reproductive system. Benign metastasizing leiomyoma (BML) is a rare phenomenon that presents at distant sites, typically the lungs, exhibiting histopathological features similar to the primary uterine tumor in the absence of malignancy features in both. Fumarate hydratase-deficient uterine leiomyoma (FH-d UL) is an uncommon subtype among uterine smooth muscle tumors (0.5-2%), showing distinctive histomorphology and FH inactivation. The majority of FH-d ULs are sporadic, caused by somatic FH inactivation, while a minority of cases occur in the context of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome caused by germline FH inactivation. Metastasizing FH-d UL has not been well documented and might be under-reported. Here, we present two cases (21- and 34-year-old females) who presented with metastasizing FH-d UL after myomectomy/hysterectomy with histologically proven multiple lung metastases in both, in addition to multi-organ involvement in one case (cervical-thoracic lymph nodes, left kidney, perihepatic region, left zygomatic bone, and soft tissues). Pathological examination confirmed FH-d leiomyomas in the primary/recurrent uterine tumors, multiple lung lesions, and a renal mass. The minimal criteria for diagnosis of leiomyosarcoma were not fulfilled. Genetic testing revealed germline pathogenic FH variants in both cases (c.1256C > T; p.Ser419Leu in Case 1 and c.425A > G; p.Gln142Arg in Case 2). These novel cases highlight a rare but possibly under-recognized presentation of FH-d BML. Our study suggests that FH-d BML cases might be enriched for the HLRCC syndrome.
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PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. EXPERIMENTAL DESIGN: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. RESULTS: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. CONCLUSIONS: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell-derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.
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Carcinoma de Células Renales , Fumarato Hidratasa , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/terapia , Fumarato Hidratasa/deficiencia , Fumarato Hidratasa/genética , Masculino , Femenino , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/inmunología , Neoplasias Renales/mortalidad , Neoplasias Renales/terapia , Persona de Mediana Edad , Anciano , Adulto , Activación de Linfocitos/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Memoria Inmunológica , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inmunoterapia/métodos , Células T de Memoria/inmunología , Linfocitos T/inmunologíaRESUMEN
Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis-associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1-4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. SIGNIFICANCE: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.
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Adenocarcinoma , Carcinoma Intraductal no Infiltrante , Neoplasias de la Próstata , Masculino , Humanos , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Próstata/patología , Adenocarcinoma/genética , Adenocarcinoma/patología , Neoplasias de la Próstata/patología , Genómica , Clasificación del TumorRESUMEN
Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and aggressive tumor characterized by pathogenic alterations in the fumarate hydratase (FH) gene. Clear cell renal cell carcinoma (clear cell RCC) is a common renal cell carcinoma (RCC) associated with von Hippel-Lindau (VHL) gene variations. Here, we reported a case of bilateral RCCs. A 60-year-old man was admitted to hospital with a 3.6 cm × 3.3 cm mass in the right kidney and a 2.8 cm × 2.3 cm nodule in the left kidney. Pathologically, the right tumor showed a nested growth pattern of cells with clear cytoplasm and was FH positive and 2-succinylcysteine (2SC) negative. The left tumor demonstrated a high-grade papillary pattern and was FH negative and 2SC positive. Whole-exome sequencing and Sanger sequencing identified a germline FH c.563A > T mutation in both the tumors and an additional somatic VHL c.479_480insA mutation in the right tumor, confirming the diagnosis of clear cell RCC and FH-deficient RCC in the right and left kidneys, respectively. We reported a rare case of synchronous bilateral clear cell RCC (right) and FH-deficient RCC (left) likely driven by somatic VHL mutation and germline FH mutation, respectively.
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Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and distinct subtype of renal cancer caused by FH gene mutations. FH negativity and s-2-succinocysteine (2SC) positivity on immunohistochemistry can be used to screen for FH-deficient RCC, but their sensitivity and specificity are not perfect. The expression of AKR1B10, an aldo-keto reductase that catalyzes cofactor-dependent oxidation-reduction reactions, in RCC is unclear. We compared AKR1B10, 2SC, and FH as diagnostic biomarkers for FH-deficient RCC. We included genetically confirmed FH-deficient RCCs (n = 58), genetically confirmed TFE3 translocation RCCs (TFE3-tRCC) (n = 83), clear cell RCCs (n = 188), chromophobe RCCs (n = 128), and papillary RCCs (pRCC) (n = 97). AKR1B10, 2SC, and FH were informative diagnostic markers. AKR1B10 had 100% sensitivity and 91.4% specificity for FH-deficient RCC. The nonspecificity of AKR1B10 was shown in 26.5% of TFE3-tRCCs and 21.6% of pRCCs. 2SC showed 100% sensitivity and 88.9% specificity. However, nonspecificity for 2SC was evident in multiple RCCs, including pRCC, TFE3-tRCC, clear cell RCCs, and chromophobe RCCs. FH was 100% specific but 84.5% sensitive. AKR1B10 served as a highly sensitive and specific diagnostic biomarker. Our findings suggest the value of combining AKR1B10 and 2SC to screen for FH-deficient RCC. AKR1B10+/2SC+/FH- cases can be diagnosed as FH-deficient RCC. Patients with AKR1B10+/2SC+/FH+ are highly suspicious of FH-deficient RCC and should be referred for FH genetic tests.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Fumarato Hidratasa/genética , Fumarato Hidratasa/metabolismo , Neoplasias Renales/patología , Factores de Transcripción , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Aldo-Ceto ReductasasRESUMEN
BACKGROUND: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare highly aggressive subtype of kidney cancer for which the distinct genomic, transcriptomic, and evolutionary relationships between metastatic and primary lesions are still unclear. METHODS: In this study, whole-exome, RNA-seq, and DNA methylation sequencing were performed on primary-metastatic paired specimens from 19 FH-RCC cases, including 23 primary and 35 matched metastatic lesions. Phylogenetic and clonal evolutionary analyses were used to investigate the evolutionary characteristics of FH-RCC. Transcriptomic analyses, immunohistochemistry, and multiple immunofluorescence experiments were performed to identify the tumor microenvironmental features of metastatic lesions. RESULTS: Paired primary and metastatic lesions generally showed similar characteristics of tumor mutation burden, tumor neoantigen burden, microsatellite instability score, CNV burden, and genome instability index. Notably, we identified an FH-mutated founding MRCA (the most recent common ancestor) clone that dominated the early evolutionary trajectories in FH-RCC. Although both primary and metastatic lesions manifested high immunogenicity, metastatic lesions exhibited higher enrichment of T effector cells and immune-related chemokines, together with upregulation of PD-L1, TIGIT, and BTLA. In addition, we found that concurrent NF2 mutation may be associated with bone metastasis and upregulation of cell cycle signature in metastatic lesions. Furthermore, although in FH-RCC metastatic lesions in general shared similar CpG island methylator phenotype with primary lesions, we found metastatic lesions displaying hypomethylated chemokine and immune checkpoints related genomic loci. CONCLUSIONS: Overall, our study demonstrated the genomic, epigenomic, and transcriptomic features of metastatic lesions in FH-RCC and revealed their early evolutionary trajectory. These results provided multi-omics evidence portraying the progression of FH-RCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Fumarato Hidratasa/genética , Fumarato Hidratasa/metabolismo , Transcriptoma , Filogenia , Neoplasias Renales/genética , Neoplasias Renales/patología , GenómicaRESUMEN
OBJECTIVE: To explore the predictive value of quantitative features extracted from conventional magnetic resonance imaging (MRI) in distinguishing Zinc Finger Translocation Associated (ZFTA)-RELA fusion-positive and wild-type ependymomas. METHODS: Twenty-seven patients with pathologically confirmed ependymomas (17 patients with ZFTA-RELA fusions and 10 ZFTA-RELA fusion-negative patients) who underwent conventional MRI were enrolled in this retrospective study. Two experienced neuroradiologists who were blinded to the histopathological subtypes independently extracted imaging features using Visually Accessible Rembrandt Images annotations. The consistency between the readers was evaluated with the Kappa test. The imaging features with significant differences between the 2 groups were obtained using the least absolute shrinkage and selection operator regression model. Logistic regression analysis and receiver operating characteristic analysis were performed to analyze the diagnostic performance of the imaging features in predicting the ZFTA-RELA fusion status in ependymoma. RESULTS: There was a good interevaluator agreement on the imaging features (kappa value range 0.601-1.000). Enhancement quality, thickness of the enhancing margin, and edema crossing the midline have high predictive performance in identifying ZFTA-RELA fusion-positive and ZFTA-RELA fusion-negative ependymomas (C-index = 0.862 and area under the curve= 0.8618). CONCLUSIONS: Quantitative features extracted from preoperative conventional MRI by Visually Accessible Rembrandt Images provide high discriminatory accuracy in predicting the ZFTA-RELA fusion status of ependymoma.
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Ependimoma , Neoplasias Supratentoriales , Humanos , Ependimoma/diagnóstico por imagen , Ependimoma/genética , Ependimoma/cirugía , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Neoplasias Supratentoriales/cirugía , Factor de Transcripción ReIARESUMEN
PURPOSE: We aim to explore the predictive value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel as first-line therapy. METHODS: We retrospectively analyzed data of 262 mCRPC patients receiving abiraterone or docetaxel as first-line mCRPC treatment. NED was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan-Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). RESULTS: NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED < 10% and NED ≥ 10%, respectively. 203/262 (77.5%) and 59/262 (22.5%) patients received abiraterone and docetaxel, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5 vs. 10.3-Mo, P < 0.001), median rPFS (mrPFS, 15.9 vs. 19.5-Mo, P = 0.010), and median OS (mOS, 23.2 vs. 34.3-Mo, P = 0.014)). Likewise, for mCRPC patients receiving docetaxel, the positive detection of NED also predicted shorter mPSA-PFS (3.8 vs. 5.9-Mo, P = 0.052), mrPFS (8.4 vs. 20.4-Mo, P = 0.016) and mOS (13.6 vs. 29.0-Mo, P = 0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients' survival outcomes deteriorated as the NED proportion grew in both therapies. After propensity score matching, NED-positive patients showed comparable prognosis in abiraterone and docetaxel therapy. CONCLUSION: For mCRPC patients receiving abiraterone or docetaxel, NED and its proportion were critical predictive factors. NED detection at mCRPC might aid in predicting patients' outcomes and optimizing treatment decisions.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Femenino , Docetaxel , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Antígeno Prostático Específico , Estudios Retrospectivos , Resultado del Tratamiento , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal complication of visceral leishmaniasis (VL). To provide a basis for early and correct diagnosis and to improve prognosis in the future, we describe a case series of VL-associated HLH in adults in our center in the past decade after review of all reported cases of adult VL-associated HLH in English through May 2022. In our case series, a total of 111 patients were diagnosed with VL. Among these patients, only six cases were diagnosed with VL-associated HLH. All patients tested positive for serology. Leishmania was detected for the first time by bone marrow aspiration (BMA) in three of the six patients and in the other three patients after three or four BMAs. It took more than 1 month from onset to diagnosis of VL for all the six cases, and the longest time was 6 months. Five of the six patients recovered after receiving sodium stibogluconate. VL-associated HLH is rare but potentially life-threatening in adults and predisposes to early delays in diagnosis. However, diagnostic techniques are not complicated or difficult, so it is more important to consider that it is not recognized by physicians. Although guidelines recommend liposomal amphotericin B as the most effective therapy, our experience suggests that sodium stibogluconate can be an alternative option when liposomal amphotericin B is unavailable or unaffordable.
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Antiprotozoarios , Leishmaniasis Visceral , Linfohistiocitosis Hemofagocítica , Adulto , Humanos , Leishmaniasis Visceral/complicaciones , Leishmaniasis Visceral/diagnóstico , Leishmaniasis Visceral/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Antiprotozoarios/uso terapéutico , Gluconato de Sodio Antimonio/uso terapéuticoRESUMEN
Background: Metanephric adenomas (MAs) are rare, benign renal tumors. Wilms' tumors (WTs) are malignant embryonic tumors that originated from nephrogenic blastemal cells. However, some tumors have similar morphology to both MA and epithelial-predominant WT, which makes differential diagnosis difficult. We aimed to analyze the morphological, immunophenotypic and molecular changes in overlapping cases to explore their attribution. Methods and results: Twenty MAs, ten WTs, and nine cases with MA/WT overlapping histological features were studied. Twenty tumors demonstrated the typical morphological spectrum of MA with high cellularity and were composed of tightly packed small, uniform, round acini with a lower Ki67 index. Almost all MAs (94.7%, 18/19) were detected with BRAF V600E mutation. The ten WTs were epithelial-predominant WTs with glands, rosettes and glomerular structures, which also showed a higher Ki-67 index (up to 60%), invasive growth patterns, and a lack of BRAF mutation. However, the other nine overlapping cases showed two components: typical MA-like areas and epithelial WT-like areas. The cells of the WT-like areas were tubular, columnar and showed marked cytological atypia, with a Ki-67 proliferative index of up to 30%. The immunophenotype of these overlapping lesions was not significantly different from that of typical MA and they positively expressed WT1 and CD57. The BRAF V600E mutation was detected in both WT-like and MA-like areas in nine overlapping tumors. The follow-up data of 31 patients were analyzed, with a median follow-up time of 66 months (range, 8-45 months). Even though most patients with WT underwent radiotherapy or chemotherapy after surgery, two died, and one had liver metastasis. No MA or overlapping cases showed any evidence of recurrence or metastasis after surgery. Conclusions: The molecular changes in tumors with overlapping morphological features were the same as those of typical MA; thus, we think that these tumors should be classified as MA and further called atypical MA. It is important to note that atypical MA is not a neglected subtype of MA. It possesses different histological morphology and a higher Ki-67 index but has the common imaging characteristics, immunophenotype and gene expression as typical MA, and patients usually have a good prognosis.
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CDK12 (Cyclin-Dependent Kinase 12)-mutated prostate cancer patients often respond badly to current therapies. Immunotherapy and platinum-based chemotherapy are recommended based on the molecular features of CDK12-mutated tumors, but the reported patient outcomes are still unsatisfying. Here we report a prostate cancer patient with CDK12 somatic mutation who received multiple therapy options, including platinum-based chemotherapy and immunotherapy. His sequential circulating tumor DNA (ctDNA) -based liquid biopsy tests showed that his original CDK12 mutation fell undetectable twice. This phenomenon was observed only when he was responding well to platinum-based chemotherapy. His responses to immunotherapy were not satisfying. This case indicates that platinum-based chemotherapy can be a good option for treating patients with CDK12 mutation. More importantly, dynamic ctDNA-based liquid biopsies to monitor patients' CDK12 mutation status are critical in evaluating patients' response and tolerance during platinum-based chemotherapy, therefore may lead to a better overall prognosis. In conclusion, CDK12-mutated prostate cancer patients are likely to benefit from platinum-based chemotherapy, especially with the help of dynamic ctDNA-based liquid biopsies to monitor their CDK12 mutation status.
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SPINK1-positive prostate cancer (PCa) has been identified as an aggressive PCa subtype. However, there is a lack of definite studies to elucidate the underlying mechanism of the loss of SPINK1 expression in most PCa cells except 22Rv1 cells, which are derived from a human prostatic carcinoma xenograft, CWR22R. The aim of this study was to investigate the mechanisms of SPINK1 protein positive/negative expression and its biological roles in PCa cell lines. SPINK1 mRNA was highly expressed in 22Rv1 cells compared with LNCaP, C4-2B, DU145, and PC-3 cells, and the protein was only detected in 22Rv1 cells. Among these cell lines, the wild-type SPINK1 coding sequence was only found in 22Rv1 cells, and two mutation sites, the c.194G>A missense mutation and the c.210T>C synonymous mutation, were found in other cell lines. Our further research showed that the mutations were associated with a reduction in SPINK1 mRNA and protein levels. Functional experiments indicated that SPINK1 promoted PC-3 cell proliferation, migration, and invasion, while knockdown of SPINK1 attenuated 22Rv1 cell proliferation, migration, and invasion. The wild-type SPINK1 gene can promote the malignant behaviors of cells more than the mutated ones. Cell cycle analysis by flow cytometry showed that SPINK1 decreased the percentage of cells in the G0/G1 phase and increased the percentage of S phase cells. We demonstrated that the c.194G>A and c.210T>C mutations in the SPINK1 gene decreased the mRNA and protein levels. The wild-type SPINK1 gene is related to aggressive biological behaviors of PCa cells and may be a potential therapeutic target for PCa.
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Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/genética , ARN Mensajero/genética , Inhibidor de Tripsina Pancreática de Kazal/genéticaRESUMEN
Diffuse midline glioma, H3 K27M-mutant (H3 K27M-mt DMG), is a rare and highly aggressive tumor that is more common in children than in adults. Few studies have compared the differences between pediatric and adult patients with this rare tumor. We here report our retrospective study of 94 adult and 70 pediatric cases of diffuse midline glioma. Surgical tumor samples were analyzed by routine histopathology and immunohistochemistry for H3 K27M, IDH1 R132H, ATRX, p53, OLIG2, glial fibrillary acidic protein, and Ki-67; Sanger sequencing for hot mutation spots in genes including H3F3A, HIST1H3B, IDH1, IDH2, TERT, and BRAF; and methylation-specific polymerase chain reaction for O6-methylguanine DNA methyltransferase promoter methylation. The most frequent anatomic locations in adult and pediatric patients were the thalamus and brainstem, respectively. Molecular profiling revealed higher frequencies of ATRX loss and H3.3 mutation in adult than in pediatric H3 K27M-mt DMGs. TERT promoter mutations and O6-methylguanine DNA methyltransferase promoter methylation were not detected in pediatric patients but were present in a few adult patients. During the follow-up period, 93/122 patients (70.1%) died from the disease, with a median survival time of 10.5 months (range: 1 to 104 mo). Kaplan-Meier analyses demonstrated that the prognosis was better for adult patients than the pediatric cohort (P=0.0003). Multivariate analyses indicated that patient age, primary tumor size, status of ATRX expression, and Ki-67 index were independent prognosticators. The present study showed that there were differences between adult and pediatric H3 K27M-mt DMGs in terms of the anatomic location of tumor, molecular changes, and prognosis.
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Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/patología , Niño , ADN , Glioma/genética , Glioma/patología , Histonas/genética , Humanos , Antígeno Ki-67/metabolismo , Mutación , Estudios RetrospectivosRESUMEN
We report a case of primary rectal neoplasm with a novel DDX5-TFEB fusion in a 14-year-old boy. Histologically, the neoplasm was composed of epithelioid tumor cells with abundant clear to eosinophilic cytoplasm, arranged in nests with rich stromal capillary vasculature. Immunohistochemically, the tumor cells were positive for transcription factor EB (TFEB) and negative for PAX8, TFE3, HMB45, and PCK. TFEB gene rearrangement and low-level amplification were identified using break-apart fluorescence in situ hybridization. Next-generation sequencing identified a heretofore unreported DDX5-TFEB gene fusion, which was confirmed by using reverse transcription-polymerase chain reaction and Sanger sequencing. The major morphological differential diagnoses include perivascular epithelioid cell tumor, microphthalmia-associated transcriptional factor family translocation renal cell carcinoma, and alveolar soft part sarcoma. The morphological, immumophenotypical, and genetic characteristics of this tumor did not fit well with current classification, but it may represent an unusual PEComa-like tumor with a novel DDX5-TFEB fusion.
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Carcinoma de Células Renales , Neoplasias Renales , Neoplasias de Células Epitelioides Perivasculares , Neoplasias del Recto , Adolescente , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/análisis , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , ARN Helicasas DEAD-box/genética , Fusión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Renales/patología , Masculino , Neoplasias de Células Epitelioides Perivasculares/patología , Neoplasias del Recto/genética , Translocación GenéticaRESUMEN
TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion and several somatic copy number alterations, including the loss of 22q, are associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibit low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis reveals five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which show association with fusion patterns and prognosis. In line with the aggressive nature, the high angiogenesis/stroma/proliferation cluster exclusively consists of tumors with ASPSCR1-TFE3 fusion. Here, we describe the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Adolescente , Adulto , Anciano , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Niño , Preescolar , Femenino , Regulación Neoplásica de la Expresión Génica , Fusión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Renales/patología , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Análisis de Secuencia de ARN , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Secuenciación del Exoma , Adulto JovenRESUMEN
The 2016 World Health Organization classification of central nervous system tumor firstly introduces molecular diagnosis to glioma, while the molecular features of adult thalamic gliomas (ATGs) in a relatively large sample have not been reported. We aimed at exploring molecular characteristics in ATGs. The data of 97 and 575 newly diagnosed ATGs and superficial gliomas (SGs) patients were collected, and we performed a comparative analysis of molecular characteristics between them. We analyzed expressions of molecules as follow: H3 K27M, isocitrate dehydrogenase1 (IDH1), Ki-67, O6-Methylguanine-DNA methyltransferase (MGMT) promoter, EGFR, p53, ATRX, GFAP, Oligo2, PTEN, MGMT, and MMP9 by immunohistochemistry. Direct gene sequencing was performed to test the H3 K27M, IDH1, and TERT promoter mutation. The median age at diagnosis of ATGs was 36.0 years, and majority of them were high-grade glioma. We found a significant difference in H3 K27M mutation (P = 0.003), IDH1 mutation (P < 0.001), MGMT promoter methylation (P = 0.005), and Ki67 > 0.1 (P < 0.001) between ATGs and SGs. The statuses of IDH1 (P < 0.001), MGMT promoter (P < 0.001), and Ki67 (P < 0.001) were significantly different between these two groups in lower-grade gliomas. And statuses of IDH1 (P < 0.001), Ki67 (P < 0.001), and EGFR (P = 0.032) were different between these two groups in high-grade gliomas. Only Ki67 > 0.1 was differentially expressed between lower- and high-grade gliomas in ATGs (P = 0.014). The high occurrence of H3 K27M mutation and Ki67 > 0.1, rare occurrence of IDH1 mutation, and MGMT promoter methylation in ATGs suggested that ATGs may be a distinct type of glioma entity.
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Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Tálamo/metabolismo , Adulto , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Metilación de ADN , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Glioma/genética , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismoRESUMEN
PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC. EXPERIMENTAL DESIGN: Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded. RESULTS: We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade-based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03). CONCLUSIONS: These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/patología , Epigénesis Genética , Fumarato Hidratasa/deficiencia , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/patología , Mutación , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Metilación de ADN , Femenino , Estudios de Seguimiento , Fumarato Hidratasa/genética , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
AIMS: Xp11 translocation renal cell carcinoma (RCC) is a distinctive subtype of RCC with TFE3 (Transcription Factor Binding to IGHM Enhancer 3) gene rearrangement. The gross features in most Xp11 translocation RCCs closely resemble clear cell RCCs. In this study, we report six cases of Xp11 translocation RCCs with a unique multicystic architecture, reminiscent of multilocular cystic renal cell neoplasm of low malignant potential (MCRN-LMP). METHODS AND RESULTS: Microscopically, the renal mass was well circumscribed with multilocular cystic architecture. The cyst walls and septa were mostly lined by a single layer of cells with clear cytoplasm and low-grade nuclei, reminiscent of MCRN-LMP. Psammoma bodies were detected in four cases. One particular patient was misdiagnosed with benign cysts in local hospitals and led to second operation. Tumour cells were settled according to the track of the first surgical procedure. TFE3 fluorescence in situ hybridization (FISH) assay confirmed the diagnosis of Xp11 translocation RCCs. FISH and RNA sequencing analyses confirmed MED15-TFE3 gene fusion in all six cases. Respective patients were alive, without any recent evidence of disease recurrence and/or metastasis. CONCLUSIONS: Here, we introduce a relatively inertia-variant of Xp11 translocation RCC which mimics MCRN-LMP. The distinctive morphological condition is linked to MED15-TFE3 gene fusion. In fact, renal neoplasms with morphological features of MCRN-LMP, especially those containing psammoma bodies, should be routinely evaluated for evidence of TFE3 gene rearrangements.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carcinoma de Células Renales/diagnóstico por imagen , Cromosomas Humanos X/genética , Fusión Génica , Neoplasias Renales/diagnóstico por imagen , Complejo Mediador/genética , Translocación Genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Femenino , Reordenamiento Génico , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Masculino , Complejo Mediador/metabolismoRESUMEN
A 20-year-old female presented with fine motor deficits and visual field defect was admitted to our hospital. CSF tests for autoimmune encephalitis antibodies and onconeuronal antibodies were unremarkable. MRI showed unilateral lesion involving left basal ganglia, external capsule, insula, hippocampus, and amygdala, which was considered to be demyelinating pseudotumor after surgical intervention. The patient's symptoms relieved so she didn't consent to immunotherapy. Two years and a half later our patient reported sudden anosmia. Reexamination by MRI demonstrated a new lesion. We then detected anti-CASPR2 antibodies in the patient's serum and gave her immunotherapy.