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AIMS: Superficial CD34-positive fibroblastic tumour (SCD34FT) is an uncommon but distinctive low-grade neoplasm of the skin and subcutis that shows frequent CADM3 expression by immunohistochemistry (IHC). In this study, prompted by an index case resembling 'atypical fibrous histiocytoma (FH)' that was positive for CADM3 IHC, we systematically examined a cohort of tumours previously diagnosed as 'atypical FH' by applying CADM3 and fluorescence in situ hybridization (FISH) for PRDM10 rearrangement, to investigate the overlap between these tumour types. METHODS AND RESULTS: Forty cases of atypical FH were retrieved, including CD34-positive tumours (n = 20) and CD34-negative tumours (n = 20). All tumours were stained for CADM3. All CADM3-positive tumours were evaluated by FISH to assess for PRDM10 rearrangement. Eleven CD34-positive tumours (11/20, 55%) coexpressed CADM3 and were reclassified as SCD34FT. None (0/20) of the CD34-negative atypical FH were CADM3-positive. Reclassified SCD34FT (10/11) arose on the lower extremity, with frequent involvement of the thigh (n = 8). Features suggestive of atypical FH were observed in many reclassified cases including variable cellularity, spindled morphology, infiltrative tumour margins, collagen entrapment, epidermal hyperpigmentation, and acanthosis. Variably prominent multinucleate giant cells, including Touton-like forms, were also present. An informative FISH result was obtained in 10/11 reclassified tumours, with 60% (6/10) demonstrating PRDM10 rearrangement. CONCLUSION: A significant subset of tumours that histologically resemble atypical FH, and are positive for CD34, coexpress CADM3 and harbour PRDM10 rearrangement, supporting their reclassification as SCD34FT. Awareness of this morphologic overlap and the application of CADM3 IHC can aid the distinction between SCD34FT and atypical FH.
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Superficial CD34 fibroblastic tumors (SCD34FT) and PRDM10-rearranged tumors (PRTs) are mesenchymal tumors that have recently received increased scientific attention due to their irrefutable similarities yet debatable relationship. A 74-year-old male presented to the dermatology clinic with a violaceous, well-defined nodule on the left medial knee of 2-year duration. Shave biopsy demonstrated spindle cells arranged in a vaguely storiform pattern forming fascicles. Immunohistochemical stains were positive for vimentin, CD68, CD10, and CD34 diffusely. ERG, S-100, HMB45, and SOX-10 were negative. Molecular studies identified a mediator complex subunit 12 (MED12)-PR/SET Domain 10 (PRDM10) gene fusion thus favoring confirming the diagnosis of a PRT. Our patient underwent wide local excision with negative margins and had no complications. This case aims to provide context for considering SCD34FT and PRT as intersecting entities and to discuss a diagnostic approach when encountering these tumors.
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Neoplasias de Tecido Fibroso , Neoplasias de Tecidos Moles , Masculino , Humanos , Idoso , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genética , Antígenos CD34 , Biópsia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Proteínas de Ligação a DNA/genéticaRESUMO
Ultraviolet (UV)-B radiation is a major environmental risk factor that is responsible for the development and progression of many skin disorders. Autophagy is the process of degradation and recycling of damaged cytoplasmic organelles, macromolecular aggregates, and long-lived proteins. Previously, we found that the autophagy inducer apigenin restored UVB-impaired autophagy and the cellular response by downregulating the expression of autophagy-related genes such as ATG5. To explore long noncoding RNAs (lncRNAs) involved in regulating these autophagy-related genes, in this study, we assessed the expression profiles of lncRNAs and mRNAs using a microarray in human epidermal keratinocytes (HEKs) treated with or without apigenin after UVB radiation. The expression levels of 80 selected autophagy-related genes and related lncRNAs were confirmed by quantitative real-time polymerase chain reaction (qRTâPCR). The lncRNA PRDM10-DT was proposed to regulate IRGM based on the ceRNA and coexpression pattern and was demonstrated to be involved in autophagy regulation, proliferation and migration of HEKs by qRTâPCR, Western blotting, colony formation and scratch wound assays, respectively. These findings suggest an autophagy-related lncRNA in response to UVB radiation that promotes the proliferation and migration of HEKs through inducing autophagy by competing microRNAs for IRGM.
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MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Apigenina/farmacologia , Queratinócitos/metabolismo , Epiderme/metabolismo , MicroRNAs/genética , Autofagia/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Superficial CD34-positive fibroblastic tumor is recognized as a distinct tumor of fibroblastic lineage in the recent World Health Organization (WHO) classification of tumors of soft tissues. There is an occasional report on cytomorphologic features of this rare tumor. CASE REPORT: A 28-year-old male presented with swelling in his left thigh of 3 years duration, that was diagnosed as a pleomorphic sarcoma, elsewhere. Radiological imaging showed a well-defined lesion measuring 2.8 cm along the anteromedial aspect of the left mid-thigh in the subcutaneous location. Review of FNAC smears revealed a hypercellular tumor composed of spindle and pleomorphic cells with fine to more vesicular chromatin, and moderate to abundant granular to characteristic "glassy" cytoplasm including cells showing intranuclear pseudo inclusions, devoid of mitotic figures. Interspersed was pink stroma and several inflammatory cells including lymphocytes. Immunohistochemically, tumor cells were diffusely positive for CD34 and focally for AE1/AE3. A diagnosis of superficial CD34-positive fibroblastic tumor was finally offered. CONCLUSIONS: This constitutes one of the first reports of cytomorphologic features of Superficial CD34-positive fibroblastic tumor. Its differential diagnoses, molecular updates and treatment-associated implications are discussed herewith.
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Sarcoma , Neoplasias de Tecidos Moles , Masculino , Humanos , Adulto , Biópsia por Agulha Fina , Biomarcadores Tumorais , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Sarcoma/patologia , Diagnóstico DiferencialRESUMO
Superficial CD34-positive fibroblastic tumor (SCPFT) is a fibroblastic/myofibroblastic soft tissue tumor of rarely metastasizing intermediate malignancy. Some recent studies have described a relationship between SCPFT and PRDM10-rearranged soft tissue tumor (PRT) based on SynCAM3 and PRDM10 expression on immunohistochemistry. We performed CD34, cytokeratin AE1/AE3, SynCAM3, and PRDM10 immunohistochemistry in SCPFT and its histological mimics, including myxoinflammatory fibroblastic sarcoma (MIFS), superficially localized myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma. We also examined cyclin D1 expression because it is expressed in MIFS and MFS. We conducted fluorescence in situ hybridization (FISH) of PRDM10 rearrangement in SCPFT cases. On immunohistochemistry, only SCPFT showed strong and diffuse SynCAM3 expression. SCPFT also exhibited strong nuclear and weak cytoplasmic cyclin D1 expression, which was similar to that observed in MIFS. Two of five SCPFT cases exhibited nuclear PRDM10 expression. FISH revealed PRDM10 split signals in 44% and 24% of tumor cells in two SCPFT cases showing nuclear PRDM10 expression on immunohistochemistry, respectively. A minority of non-SCPFT cases showed focal SynCAM3 expression, but a combination of SynCAM3 and cyclin D1 in addition to CD34 and cytokeratin AE1/AE3 may be useful for the differential diagnosis of SCPFT and its histological mimics.
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Fibrossarcoma , Neoplasias Cutâneas , Neoplasias de Tecidos Moles , Humanos , Imuno-Histoquímica , Ciclina D1 , Hibridização in Situ Fluorescente , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Fibrossarcoma/patologia , Queratinas , Biomarcadores TumoraisRESUMO
Positive regulatory domain member (PRDM) proteins play a critical role in the transmission of signals that control cell proliferation and differentiation, and neoplastic transformation. Positive regulatory domain member 10 (tristanin) is a poorly studied member of PRDM protein family. Gene fusion transcripts containing PRDM10 were recently identified in low-grade undifferentiated pleomorphic sarcomas (UPS), and associated with pleomorphic morphology and low mitotic index. The aim of this study was to investigate the immunohistochemical staining of PRDM10 in a larger sample of soft tissue sarcomas. Therefore, the study included 118 soft tissue sarcomas from different classes, and PRDM10 antibody was applied to all of them. Immuno-histochemically, staining was observed in 22 (19%) cases, while 96 (81%) showed no staining. When PRDM10 expression was compared with clinico-pathological features, there was a statistically significant correlation between PRDM10 expression and myxoid changes, multi-nucleated giant cells, and surgical margin (p = 0.017, p = 0.034, p = 0.032, respectively). No statistically significant association was found between PRDM10 expression and other parameters. Based on the obtained data, it can be said that PRDM10-positive-stained tumors (tumors with PDRM10 expression) are mostly myxoid, containing multi-nucleated giant cells, and can be removed with well-circumscribed margins.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Sarcoma/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias de Tecidos Moles/patologiaRESUMO
AIMS: Superficial CD34-positive fibroblastic tumor (SCD34FT) and PRDM10-rearranged soft tissue tumor (PRDM10-STT) are rare mesenchymal tumors. These lesions have clinicopathological similarities, but their relationship remains controversial. This study aimed to characterise a series of cases of SCD34FT and PRDM10-STT. METHODS AND RESULTS: Ten lesions each of SCD34FT and PRDM10-STT were studied using immunohistochemistry, array-comparative genomic hybridisation (aCGH), RNA sequencing and exome sequencing. Tumors mainly occurred in young adults, were generally small (< 5 cm) and arose predominantly in the superficial soft tissues of the lower extremities. Follow-up data were available in 15 cases (SCD34FT, n = 7, median 16 months; PRDM10-STT, n = 8, median 14 months), local recurrences occurred in four cases (SCD34FT, two of 10; PRDM10-STT, two of 10), while no distant spread was documented. Morphologically, tumors were relatively well-circumscribed and composed of sheets and fascicles of spindle and pleomorphic cells showing low mitotic activity (< 1/mm²) without necrosis. Other findings included: granular cell change, lipoblast-like cells, ectatic blood vessels with fibrinous material, myxoid stromal changes, metaplastic bone and increased mitotic activity (> 1/mm²). All tumors diffusely expressed CD34, while pan-keratin and desmin were commonly seen focally. SynCAM3 was diffusely expressed in 12 cases (SCD34FT, n = 5; PRDM10-STT, n = 7), independently of fusion status. aCGH profiles were 'flat' (PRDM10-STT, n = 4; SCD34FT, n = 2) and exome sequencing showed no recurrent pathogenic mutations (PRDM10-STT, n = 2; SCD34FT, n = 4). Overall, the only morphological features seen exclusively in PRDM10-STT were myxoid stromal changes (three of 10) and metaplastic bone (two of 10). CONCLUSION: We expand the current knowledge on PRDM10-STT and SCD34FT and provide additional evidence for considering them as overlapping entities.
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Antígenos CD34/metabolismo , Proteínas de Ligação a DNA , Fibroblastos/patologia , Neoplasias de Tecidos Moles , Fatores de Transcrição , Adolescente , Adulto , Biomarcadores Tumorais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adulto JovemRESUMO
Recent developments in tissue clearing methods have significantly advanced the three-dimensional analysis of biological structures in whole, intact tissue, providing a greater understanding of spatial relationships and biological circuits. Nonetheless, studies have reported issues with maintaining structural integrity and preventing tissue disintegration, limiting the wide application of these techniques to fragile tissues such as developing embryos. Here, we present an optimized passive tissue clearing technique (PACT)-based embryo clearing method, initial embedding PACT (IMPACT)-Basic, that improves tissue rigidity without compromising optical transparency. We also present IMPACT-Advance, which is specifically optimized for thin slices of mouse embryos past E13.5. We demonstrate proof-of-concept by investigating the expression of two relatively understudied PR domain (PRDM) proteins, PRDM10 and PRDM13, in intact cleared mouse embryos at various stages of development. We observed strong PRDM10 and PRDM13 expression in the developing nervous system and skeletal cartilage, suggesting a functional role for these proteins in these tissues throughout embryogenesis.
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Desenvolvimento Embrionário/genética , Histona-Lisina N-Metiltransferase/genética , Imageamento Tridimensional/métodos , Fatores de Transcrição/genética , Animais , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/genética , CamundongosRESUMO
Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive soft tissue tumor. A subset of UPS is characterized by a CITED2-PRDM10 or a MED12-PRDM10 gene fusion. Preliminary data suggest that these so-called PRDM10-rearranged tumors (PRT) are clinically more indolent than classical high-grade UPS, and hence important to recognize. Here, we assessed the spectrum of accompanying mutations and the gene expression profile in PRT using genomic arrays and sequencing of the genome (WGS) and transcriptome (RNA-seq). The fusion protein's function was further investigated by conditional expression of the CITED2-PRDM10 fusion in a fibroblast cell line, followed by RNA-seq and an assay for transposase-accessible chromatin (ATAC-seq). The CADM3 gene was found to be differentially up-regulated in PRT and cell lines and was also evaluated for expression at the protein level using immunohistochemistry (IHC). The genomic analyses identified few and nonrecurrent mutations in addition to the structural variants giving rise to the gene fusions, strongly indicating that the PRDM10-fusions represent the critical driver mutations. RNA-seq of tumors showed a distinct gene expression profile, separating PRT from high-grade UPS and other soft tissue tumors. CADM3 was among the genes that was consistently and highly expressed in both PRT and fibroblasts expressing CITED2-PRDM10, suggesting that it is a direct target of the PRDM10 transcription factor. This conclusion is in line with sequencing data from ATAC-seq, showing enrichment of PRDM10 binding sites, suggesting that the amino-terminal fusion partner contributes by making the DNA more accessible to PRDM10 binding. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Fusão Gênica , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição/genética , Transcriptoma , Biomarcadores Tumorais/metabolismo , Moléculas de Adesão Celular/genética , Diferenciação Celular , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Fibroblastos/enzimologia , Fibroblastos/patologia , Predisposição Genética para Doença , Humanos , Imunoglobulinas/genética , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Sarcoma/enzimologia , Sarcoma/patologia , Neoplasias de Tecidos Moles/enzimologia , Neoplasias de Tecidos Moles/patologia , Transativadores/genética , Fatores de Transcrição/metabolismoRESUMO
Superficial CD34-positive fibroblastic tumor is a mesenchymal neoplasm of "intermediate malignancy" recently included in the fifth edition of the World Health Organization classification of soft tissue and bone tumors. In this review, we summarize the current knowledge on this rare entity with a special focus on its clinicopathological features, morphologic spectrum, and differential diagnosis. We also provide data regarding recent discoveries on its molecular profile and discuss its prognosis and management.
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Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias de Tecidos Moles , Humanos , Antígenos CD34 , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico , Diagnóstico Diferencial , Biomarcadores TumoraisRESUMO
OBJECTIVES: Superficial CD34-positive fibroblastic tumor (SCD34FT) is a rare mesenchymal neoplasm. The genetic alterations of SCD34FT have yet to be determined. Recent studies suggest it overlaps with PRDM10-rearranged soft tissue tumor (PRDM10-STT). METHODS: This study aimed to characterize a series of 10 cases of SCD34FT using fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS). RESULTS: The study recruited 7 men and 3 women aged between 26 and 64 years. The tumors were located in the superficial soft tissues of the thigh (8 cases), foot, and back (1 case each), ranging in size from 1.5 to 7 cm. The tumors were composed of sheets and fascicles of plump spindled to polygonal cells, with glassy cytoplasm and pleomorphic nuclei. Mitotic activity was absent or low. Common and uncommon stromal findings included foamy histiocytic infiltrates, myxoid changes, peripheral lymphoid aggregates, large ectatic vessels, arborizing capillary vasculature, and hemosiderin deposition. All tumors expressed CD34, and 4 demonstrated focal cytokeratin immunoexpression. In 7 of 9 (77.8%) cases analyzed, FISH identified PRDM10 rearrangement. Targeted NGS revealed a MED12::PRDM10 fusion in 4 of 7 cases tested. Follow-up showed no recurrence or metastasis. CONCLUSIONS: We demonstrate recurrent PRDM10 rearrangements in SCD34FT and provide additional evidence of a close relationship to PRDM10-STT.
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Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias de Tecidos Moles , Humanos , Feminino , Hibridização in Situ Fluorescente , Fatores de Transcrição/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Núcleo Celular/patologia , Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genéticaRESUMO
Superficial CD34 positive fibroblastic tumor is a rare low-grade neoplasm of the skin and subcutis with indolent behavior. This entity has been included in the current World Health Organisation (WHO) classification of soft tissue tumors. Pathological diagnosis can be challenging due to significant morphological overlap with other entities and the large spectrum of CD34 positive tumors. We report a case in a twenty-five male which showed characteristic diagnostic features, but in addition showed myxoid stroma. The presence of myxoid stroma has not been previously emphasized in this entity and broadens the histologic differential diagnosis significantly to include myxoid soft tissue tumors. A subset of these tumors harbor PRDM10-rearrangements, but a defining molecular feature has not yet been described, highlighting the need for further molecular characterization of this potentially genetically heterogenous tumor. Awareness of this entity among surgeons and pathologists is important to prevent misclassification as an aggressive sarcoma and avoid over-treatment.
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Neoplasias de Tecido Fibroso , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Masculino , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecido Fibroso/diagnóstico , Neoplasias de Tecido Fibroso/cirurgia , Sarcoma/patologia , Rearranjo Gênico , Diagnóstico Diferencial , Biomarcadores TumoraisRESUMO
Superficial CD34-positive fibroblastic tumor (SCPFT) is a recently described entity that, despite significant pleomorphism, carries a good prognosis. We briefly describe this tumor and its principal differential diagnoses. Recognition of SCPFTs, including the clinical context in which they arise, is important to avoid confusion with other pleomorphic soft tissue tumors, particularly neoplasms in the group of pleomorphic sarcomas, which are typically aggressive tumors that could lead to unnecessary overtreatment.
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Antígenos CD34/análise , Biomarcadores Tumorais/análise , Derme/patologia , Neoplasias de Tecido Fibroso/diagnóstico , Neoplasias Cutâneas/diagnóstico , Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Biópsia , Derme/citologia , Diagnóstico Diferencial , Fibroblastos/patologia , Humanos , Masculino , Neoplasias de Tecido Fibroso/patologia , Sarcoma/diagnóstico , Neoplasias Cutâneas/patologia , Coxa da Perna , Adulto JovemRESUMO
Bcl-2 (B-cell lymphoma 2) protein is localized in the outer membrane of mitochondria, where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins. PRDM10 is a member of the PR/SET family of epigenetic regulators and may play a role in development and cell differentiation. Here we show that human PRDM10 contributes to the transcriptional regulation of human Bcl-2 gene. We found that PRDM10-depletion in human cells reduced the expression of Bcl-2 protein and over-expression of PRDM10 promoted Bcl-2 protein expression. Furthermore, luciferase reporter activity of Bcl-2 gene P1 promoter was significantly increased in cells co-transfected with PRDM10, and PRDM10 was able to bind to the Bcl-2 P1 promoter in vivo. Using The Cancer Genome Atlas (TCGA) data set, we found weak positive correlation between PRDM10 and Bcl-2 in several cancer types including cancers of the breast, colon, and lung tissues. These data identify a novel function for PRDM10 protein and provide insights on the transcriptional control of Bcl-2 expression.