RESUMO
Spindle cell mesenchymal neoplasms are a diverse and often challenging diagnostic group. While morphological impression is sufficient for some diagnoses, increasingly immunohistochemical and even molecular data is required to render an accurate diagnosis, which can lead to the characterization of new entities. We describe five cases of novel mesenchymal neoplasms with rearrangements in the NCOA2 and NCOA3 genes partnered with either CTCF or CRTC1. Three tumors occurred in the head and neck (palate, auditory canal), while the other two were in visceral organs (lung, urinary bladder). All cases occurred in adults (range 33-86) with a median age of 42 and fairly even sex distribution = (male-to-female = 3:2). Morphologically, they had similar features consisting of monotonous, bland spindle to ovoid cells with fascicular and reticular arrangements in a myxohyaline to collagenous stroma. However, immunophenotypically they had essentially a null phenotype, with only two tumors staining partially for CD34 and smooth muscle actin. Targeted RNA sequencing detected in-frame CTCF::NCOA2 (one case), CRTC1::NCOA2 (two cases), and CTCF::NCOA3 (two cases) fusions. Treatment was surgical resection in all cases. Local recurrence and/or distant metastases were not observed in any case (median follow-up, 7.5 months; range, 2-19 months). Given their morphologic, immunohistochemical, and molecular similarities, we believe that these cases may represent an emerging family of low-grade NCOA2/3-rearranged fibroblastic spindle cell neoplasms.
Assuntos
Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias de Tecidos Moles , Adulto , Humanos , Masculino , Feminino , Fibroblastos/patologia , Sequência de Bases , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Fenótipo , Biomarcadores Tumorais/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Coativador 2 de Receptor Nuclear/genéticaRESUMO
AIMS: Kinase fusion-positive soft tissue tumors represent an emerging, molecularly defined group of mesenchymal tumors with a wide morphologic spectrum and diverse activating kinases. Here, we present two cases of soft tissue tumors with novel LTK fusions. METHODS AND RESULTS: Both cases presented as acral skin nodules (big toe and middle finger) in pediatric patients (17-year-old girl and 2-year-old boy). The tumors measured 2 and 3 cm in greatest dimension. Histologically, both cases exhibited bland-looking spindle cells infiltrating adipose tissue and accompanied by collagenous stroma. One case additionally displayed perivascular hyalinization and band-like stromal collagen. Both cases exhibited focal S100 staining, and one case had patchy coexpression of CD34. Targeted RNA-seq revealed the presence of novel in-frame MYH9::LTK and MYH10::LTK fusions, resulting in upregulation of LTK expression. Of interest, DNA methylation-based unsupervised clustering analysis in one case showed that the tumor clustered with dermatofibrosarcoma protuberans (DFSP). One tumor was excised with amputation with no local recurrence or distant metastasis at 18-month follow-up. The other case was initially marginally excised with local recurrence after one year, followed by wide local excision, with no evidence of disease at 10 years of follow-up. CONCLUSIONS: This is the first reported case series of soft tissue tumors harboring LTK fusion, expanding the molecular landscape of soft tissue tumors driven by activating kinase fusions. Furthermore, studies involving a larger number of cases and integrated genomic analyses will be warranted to fully elucidate the pathogenesis and classification of these tumors.
Assuntos
Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Proteínas de Fusão Oncogênica , Neoplasias Cutâneas , Neoplasias de Tecidos Moles , Adolescente , Criança , Feminino , Humanos , Masculino , Antígenos CD34/metabolismo , Biomarcadores Tumorais/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Receptores Proteína Tirosina Quinases , Neoplasias Cutâneas/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Proteínas de Fusão Oncogênica/genética , Cadeias Pesadas de Miosina/genética , Miosina não Muscular Tipo IIB/genéticaRESUMO
Extraskeletal myxoid chondrosarcoma (EMC) is an uncommon mesenchymal neoplasm characteristically composed of uniform-appearing round to spindle-shaped cells with eosinophilic cytoplasm and abundant myxoid extracellular matrix. Although the majority of cases harbor a pathognomonic t(9;22) translocation that fuses EWSR1 with the orphan nuclear receptor NR4A3, there are less common variants that partner NR4A3 with TAF15, TCF12, or TFG. By immunohistochemistry, EMC has features of both cartilaginous and neuroendocrine differentiation, as evidenced by inconsistent expression of S100 protein and synaptophysin or INSM1, respectively, in a subset of cases. Given the limitations of available immunohistochemical stains for the diagnosis of EMC, we analyzed genome-wide gene expression microarray data to identify candidate biomarkers based on differential expression in EMC in comparison with other mesenchymal neoplasms. This analysis pointed to CHRNA6 as the gene with the highest relative expression in EMC (96-fold; P = 8.2 × 10-26) and the only gene with >50-fold increased expression in EMC compared with other tumors. Using RNA chromogenic in situ hybridization, we observed strong and diffuse expression of CHRNA6 in 25 cases of EMC, including both EWSR1-rearranged and TAF15-rearranged variants. All examined cases of histologic mimics were negative for CHRNA6 overexpression; however, limited CHRNA6 expression, not reaching a threshold of >5 puncta or 1 aggregate of chromogen in >25% of cells, was observed in 69 of 685 mimics (10.1%), spanning an array of mesenchymal tumors. Taken together, these findings suggest that, with careful interpretation and the use of appropriate thresholds, CHRNA6 RNA chromogenic in situ hybridization is a potentially useful ancillary histologic tool for the diagnosis of EMC.
Assuntos
Biomarcadores Tumorais , Condrossarcoma , Hibridização In Situ , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Condrossarcoma/genética , Condrossarcoma/patologia , Condrossarcoma/diagnóstico , Condrossarcoma/metabolismo , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Hibridização In Situ/métodos , Adulto , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Neoplasias de Tecido Conjuntivo/genética , Neoplasias de Tecido Conjuntivo/patologia , Neoplasias de Tecido Conjuntivo/diagnóstico , Idoso de 80 Anos ou mais , Imuno-HistoquímicaRESUMO
SMARCB1/INI1-deficient soft tissue tumors with epithelioid and myxoid features are diverse and mainly include soft tissue myoepithelial tumor, extraskeletal myxoid chondrosarcoma, and the recently described myoepithelioma-like tumor of the vulvar region and myxoepithelioid tumor with chordoid features. Because of their overlapping features, the accurate diagnosis and classification of these tumors are often challenging. Herein, we report two unique cases of SMARCB1/INI1-deficient soft tissue neoplasm with epithelioid and myxoid features occurring in male paratesticular region. The first case was a 52-year-old man presented with an intermittent painful left paratesticular mass for 1 year. The second case was a 41-year-old man presented with a painless paratesticular mass on the right side for 3 months. Both patients underwent an orchiectomy. After 6 and 26 months of follow-up, both were alive with no evidence of recurrence or metastasis. In both cases, the tumor was relatively well-demarcated and showed monomorphic round to epithelioid cells arranged in a nested, trabecular, reticular, and corded pattern, setting in a myxohyalinized and vascularized matrix. The tumor cells showed relatively uniform round nuclei with vesicular chromatin and variably prominent nucleoli. No rhabdoid cells were identified. Mitoses numbered 3 and 2 per 10 high-power fields. Tumor necrosis or lymphovascular invasion was absent. Immunohistochemically, both tumors expressed epithelial membrane antigen (focal), calponin (focal), and CD99. SMARCB1/INI1 expression was deficient in both cases. In addition, case 1 diffusely expressed pan-cytokeratin, and case 2 diffusely expressed CD34 and synaptophysin. Molecular genetically, case 1 showed SMARCB1 homozygous deletion as detected by fluorescence in-situ hybridization (FISH), and case 2 demonstrated SMARCB1 copy number deletions by next-generation sequencing and SMARCB1 monoallelic deletion by FISH. Both cases lacked EWSR1 rearrangements by FISH. The overall clinicopathologic profiles of the two cases made it difficult to classify them as one of the established categories of SMARCB1/INI1-deficient mesenchymal tumors. Our study further expands the clinicopathologic and molecular spectrum of SMARCB1/INI1-deficient epithelioid and myxoid neoplasms and highlights the challenges to diagnose these tumors.
Assuntos
Condrossarcoma , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias de Tecidos Moles , Humanos , Masculino , Pessoa de Meia-Idade , Adulto , Homozigoto , Deleção de Sequência , Proteína SMARCB1/genética , Condrossarcoma/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Biomarcadores TumoraisRESUMO
The majority of neurotrophic tyrosine receptor kinase (NTRK) rearranged neoplasms occur either in the superficial or deep soft tissues of extremities or trunk. Occasionally, it arises in visceral organs. However, its occurrence as a primary osseous tumor has not been documented thus far. Herein, we describe a unique case of an NTRK rearranged neoplasm that presented as a primary bony lesion. The tumor occurred in a 21-year-old woman who presented with an increasing pain in the right lower extremity. Radiologic examinations revealed a destructive lytic lesion located in the lower portion of the right femur. Histologically, the tumor was composed of haphazard fascicles of monomorphic spindle cells displaying mild nuclear atypia and rare mitotic activity. Immunohistochemically, the tumor cells showed focal staining of pan-TRK and S100 protein. Fluorescence in situ hybridization analysis was performed with the utilization of break-apart probes for NTRK1/NTRK2/NTRK3 genes. An NTRK3 rearrangement was identified. Subsequent next-generation sequencing (RNA-seq) revealed HMBOX1exon6::NTRK3exon 14 fusion. Our study illustrates, albeit extremely rare, that NTRK-rearranged neoplasms can arise as a primary bone lesion. In addition, we describe a novel HMBOX1::NTRK3 fusion that has not been documented before.
Assuntos
Neoplasias Ósseas , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Feminino , Humanos , Adulto Jovem , Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Fusão Gênica , Rearranjo Gênico , Proteínas de Homeodomínio/genética , Hibridização in Situ Fluorescente , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Proteínas de Fusão Oncogênica/genética , Receptores Proteína Tirosina Quinases/genética , Receptor trkA/genéticaRESUMO
NTRK-rearranged mesenchymal neoplasms mostly affect the soft tissues of pediatric patients. Given the responsiveness to selective NTRK inhibitors, it remains critical to identify those ultra-rare cases occurring in the viscera of adults. In five females and two males aged 18-53 years, we characterized visceral mesenchymal tumors harboring TPM3-NTRK1 [uterine cervix (N = 2), pleura, prostate], LMNA-NTRK1 (lung), SQSTM1-NTRK3 (heart), and NTRK3 rearrangement with unknown fusion partner (colon/mesocolon) with RNA sequencing, FISH, RT-PCR, and immunohistochemistry. The tumors exhibited spindled to ovoid/epithelioid or pleomorphic cells, often arranged in fascicles, and were low-to-intermediate-grade and high-grade in three and four cases, respectively. Keloid-like stromal collagen and perivascular hyalinization was noted in five. Adenosarcoma-like appearances were observed in two, manifesting frond-like protrusions in one cervical tumor and phyllodes-like architecture in the prostatic tumor. Abrupt high-grade transformation into pleomorphic liposarcoma was found in another cervical tumor, while the pleural tumor contained intermixed rhabdomyoblasts. Pan-TRK immunostaining was positive in all cases. All cases expressed CD34, while five were S100-positive. CDKN2A homozygous deletion with concomitant p16 loss occurred in 4/7. Whole-exome sequencing identified TP53 mutation (c.672+2T>C, involving a splice site, with concomitant protein loss) in a cervical sarcoma, limited to its heterologous liposarcomatous component. At least moderate pan-TRK immunoreactivity was present in varying proportions of potential pathologic mimics, with BCOR-positive sarcoma (56%, 5/9), undifferentiated uterine sarcoma (50%, 3/6), and spindle cell/sclerosing rhabdomyosarcoma (33%, 2/6) being among the most frequent. This underscored the unsatisfactory specificity of pan-TRK immunohistochemistry and warranted molecular confirmation in the diagnosis of adult NTRK-rearranged visceral mesenchymal neoplasms. The current report highlights the ever-expanding clinicopathologic and genetic spectrum of this entity by describing the unprecedented cardiac and pleural locations and heterologous differentiation, as well as the second NTRK-rearranged "prostatic stromal sarcoma," while substantiating CDKN2A deletion as a frequent occurrence.
Assuntos
Neoplasias do Endométrio , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Sarcoma , Neoplasias de Tecidos Moles , Neoplasias do Colo do Útero , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Criança , Neoplasias do Endométrio/genética , Feminino , Rearranjo Gênico , Homozigoto , Humanos , Masculino , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Proteínas de Fusão Oncogênica/genética , Receptor trkA/análise , Receptor trkA/genética , Sarcoma/genética , Deleção de Sequência , Neoplasias de Tecidos Moles/genética , Neoplasias do Colo do Útero/genética , Vísceras/química , Vísceras/patologiaRESUMO
Kinase alterations are increasingly recognised as oncogenic drivers in mesenchymal tumours. Infantile fibrosarcoma and the related renal tumour, congenital mesoblastic nephroma, were among the first solid tumours shown to harbour recurrent tyrosine kinase fusions, with the canonical ETV6::NTRK3 fusion identified more than 20 years ago. Although targeted testing has long been used in diagnosis, the advent of more robust sequencing techniques has driven the discovery of kinase alterations in an array of mesenchymal tumours. As our ability to identify these genetic alterations has improved, as has our recognition and understanding of the tumours that harbour these alterations. Specifically, this study will focus upon mesenchymal tumours harbouring NTRK or other kinase alterations, including tumours with an infantile fibrosarcoma-like appearance, spindle cell tumours resembling lipofibromatosis or peripheral nerve sheath tumours and those occurring in adults with a fibrosarcoma-like appearance. As publications describing the histology of these tumours increase so, too, do the variety kinase alterations reported, now including NTRK1/2/3, RET, MET, RAF1, BRAF, ALK, EGFR and ABL1 fusions or alterations. To date, these tumours appear locally aggressive and rarely metastatic, without a clear link between traditional features used in histological grading (e.g. mitotic activity, necrosis) and outcome. However, most of these tumours are amenable to new targeted therapies, making their recognition of both diagnostic and therapeutic import. The goal of this study is to review the clinicopathological features of tumours with NTRK and other tyrosine kinase alterations, discuss the most common differential diagnoses and provide recommendations for molecular confirmation with associated treatment implications.
Assuntos
Fibrossarcoma/genética , Rearranjo Gênico , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Nefroma Mesoblástico/genética , Receptor trkA/genética , Fibrossarcoma/patologia , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Nefroma Mesoblástico/patologiaRESUMO
Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain differentiation, characterized by recurrent chromosomal translocation involving NR4A3 (9q22.33) in more than 90% of cases. Five fusion partners for NR4A3 have been described including: EWSR1 (22q12.2), TAF15 (17q12), FUS (16p11.2), TCF12 (15q21), and TFG (3q12.2). This report describes a patient with an EMC at the dorsum of the right foot. The tumor showed a cord-like and reticular pattern in a background of myxoid matrix. The tumor cells demonstrated an epithelioid morphology with prominent nucleoli. The tumor cells were positive for synaptophysin, GFAP, with focal positivity for CD117, S100, Cam5.2, and NSE, and negative for AE1/3, desmin, and SMA. An RNA next-generation sequencing test showed a SMARCA2-NR4A3 gene fusion which has not been previously reported. The exon 3 of SMARCA2 was fused to exon 3 of NR4A3. This fusion was confirmed by NR4A3 break-apart FISH, although both SMARCA2 (9p24.3) and NR4A3 (9q22.33) are located on chromosome 9. The tumor cells showed retained expression of INI1 and SMARCA2 by immunohistochemistry.
Assuntos
Condrossarcoma/patologia , Proteínas de Ligação a DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Proteínas de Fusão Oncogênica/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Fatores de Transcrição/genética , Condrossarcoma/genética , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , PrognósticoRESUMO
PEComas of the female genital tract are rare mesenchymal neoplasms that are most common in the uterus, but also may occur in other gynecologic locations. As they morphologically and immunohistochemically resemble smooth muscle tumors, distinction between the two entities is often challenging, and may be aided by molecular analysis. Thus far, two distinct molecular groups-classic PEComas with TSC mutations and TFE3-translocation associated PEComas with TFE3 fusions have been described. Recognition of the first group is imperative as these patients may benefit from targeted therapy with mTOR inhibitors, if malignant. This review will focus on recognition of the morphologic and immunophenotypic features of PEComas, as well as the role of molecular testing in their diagnosis and treatment, analysis of the different algorithms to predict behavior, and differential diagnosis.
Assuntos
Neoplasias de Células Epitelioides Perivasculares , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores Tumorais , Diagnóstico Diferencial , Feminino , Fusão Gênica , Rearranjo Gênico , Humanos , Imunofenotipagem/métodos , Inibidores de MTOR/farmacologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/imunologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/metabolismo , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/imunologia , Neoplasias de Células Epitelioides Perivasculares/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismoRESUMO
Mesenchymal tumors driven by NTRK fusions are clinically and morphologically heterogeneous. With an increasing number of clinicopathological entities being associated with NTRK fusions, the diagnostic and predictive value of the identification of NTRK fusions is uncertain. Recently, mesenchymal tumors in the gastrointestinal tract with NTRK fusions were described as gastrointestinal stromal tumors (GIST), but the nosology of such neoplasms remains controversial. We report eight mesenchymal tumors involving the gastrointestinal tract with NTRK1 or NTRK3 rearrangements. The tumors occurred in six children and two adults, five males and three females (age range 2 months-55 years; median 3.5 years), and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1), and mesentery (n = 1). Clinical outcomes were variable, ranging from relatively indolent (n = 2) to aggressive diseases (n = 2). Morphologically, the tumors were heterogeneous and could be classified in the following three groups: (1) infantile fibrosarcoma involving the gastrointestinal tract (n = 4), enriched for NTRK3 fusions; (2) low-grade CD34-positive, S100 protein-positive spindle-cell tumors, associated with NTRK1 fusions (n = 2); and (3) unclassified high-grade spindle-cell sarcomas, with NTRK1 fusions (n = 2). By immunohistochemistry, the tumors demonstrated diffuse pan-TRK expression, of variable intensity, and lacked a specific line of differentiation. Four cases expressed CD34, which was coexpressed with S100 protein in three cases. Expression of SOX10, KIT, and DOG1 was consistently absent. Molecular genetic testing identified TPM3-NTRK1 (n = 3), TPR-NTRK1, LMNA-NTRK1, and ETV6-NTRK3 (n = 2), and SPECC1L-NTRK3 in-frame gene fusions. We conclude that the evaluation of mesenchymal spindle-cell neoplasms of the gastrointestinal tract without a definitive line of differentiation should include interrogation of NTRK alterations, particularly in pediatric patients. Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements are clinically and morphologically heterogeneous, and few, if any, seem related to GIST.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Adulto , Criança , Pré-Escolar , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Receptor trkA/genética , Estudos RetrospectivosRESUMO
AIMS: Clear cell (haemangioblastoma-like) stromal tumour of the lung is a newly described, rare pulmonary neoplasm. Recurrent YAP1-TFE3 gene fusions have recently been reported in three cases. We describe two additional cases and confirm the characteristic YAP1-TFE3 gene fusion. METHODS AND RESULTS: Two mesenchymal tumours of lung were identified from our soft tissue pathology consultation services and RNA sequencing was performed. Both cases were in male patients, aged 35 and 77 years. Both presented as solitary lung nodules measuring 3.9 and 7.5 cm in greatest dimension. Histopathologically, the tumours were composed of epithelioid to plump spindle cells arranged in packets and solid sheets. The cells showed fusiform to ovoid nuclei with open chromatin, variably prominent nucleoli and scant to moderate, clear to eosinophilic cytoplasm. Cytological atypia and significant mitotic activity were minimal. None of the tumours expressed lineage-specific immunophenotypical markers. Both cases were diffusely positive for nuclear TFE3. Unlike YAP1-TFE3-fused epithelioid haemangioendothelioma, for which the fusion breakpoint occurs in YAP1 exon 1 and TFE3 exons 4 or 6, the fusion breakpoints of these tumours were located in YAP1 exon 4 and TFE3 exon 7. Following complete surgical resection, neither of the tumours has recurred or metastasised (follow-up period 6-7 months). CONCLUSIONS: We validate the presence of YAP1-TFE3 gene fusion in a unique primary mesenchymal tumour of lung, adding additional support for clear cell stromal tumour of the lung as a distinct entity.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Neoplasias Pulmonares/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Sinalização YAP/genética , Adulto , Idoso , Humanos , Neoplasias Pulmonares/patologia , Masculino , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologiaRESUMO
Most primary thyroid tumours are of epithelial origin. Primary thyroid mesenchymal tumours are rare but are being increasingly detected. A vast majority of thyroid mesenchymal tumours occur between the fourth and seventh decades of life, presenting as progressively enlarging thyroid nodules that often yield non-diagnostic results or spindle cells on fine needle aspiration biopsy. Surgery is the preferred mode of treatment, with adjuvant chemoradiotherapy used for malignant thyroid mesenchymal tumours. Benign thyroid mesenchymal tumours have excellent prognosis, whereas the outcome of malignant thyroid mesenchymal tumours is variable. Each thyroid mesenchymal tumour is characterised by its unique histopathology and immunohistochemistry. Because of the rarity and aggressive nature of malignant thyroid mesenchymal tumours, a multidisciplinary team-based approach should ideally be used in the management of these tumours. Comprehensive guidelines on the management of thyroid mesenchymal tumours are currently lacking. In this Review, we provide a detailed description of thyroid mesenchymal tumours, their clinical characteristics and tumour behaviour, and provide recommendations for the optimal management of these tumours.
Assuntos
Biomarcadores Tumorais , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias da Glândula Tireoide , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Tomada de Decisão Clínica , Humanos , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/química , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/terapia , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Glândula Tireoide/química , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapiaRESUMO
Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma histotype with uncertain differentiation. EMC is hallmarked by the rearrangement of the NR4A3 gene, which in most cases fuses with EWSR1 or TAF15. TAF15-translocated EMC seem to feature a more aggressive course compared to EWSR1-positive EMCs, but whether the type of NR4A3 chimera impinges upon EMC biology is still largely undefined. To gain insights on this issue, a series of EMC samples (7 EWSR1-NR4A3 and 5 TAF15-NR4A3) were transcriptionally profiled. Our study unveiled that the two EMC variants display a distinct transcriptional profile and that the axon guidance pathway is a major discriminant. In particular, class 4-6 semaphorins and axonal guidance cues endowed with pro-tumorigenic activity were more expressed in TAF15-NR4A3 tumors; vice versa, class 3 semaphorins, considered to convey growth inhibitory signals, were more abundant in EWSR1-NR4A3 EMC. Intriguingly, the dichotomy in axon guidance signaling observed in the two tumor variants was recapitulated in in vitro cell models engineered to ectopically express EWSR1-NR4A3 or TAF15-NR4A3. Moreover, TAF15-NR4A3 cells displayed a more pronounced tumorigenic potential, as assessed by anchorage-independent growth. Overall, our results indicate that the type of NR4A3 chimera dictates an axon guidance switch and impacts on tumor cell biology. These findings may provide a framework for interpretation of the different clinical-pathological features of the two EMC variants and lay down the bases for the development of novel patient stratification criteria and therapeutic approaches. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Assuntos
Orientação de Axônios , Axônios/metabolismo , Biomarcadores Tumorais/metabolismo , Condrossarcoma/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Transativadores/metabolismo , Adulto , Idoso , Axônios/patologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Condrossarcoma/genética , Condrossarcoma/patologia , Proteínas de Ligação a DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Fusão Gênica , Predisposição Genética para Doença , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Proteínas de Fusão Oncogênica/genética , Fenótipo , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Semaforinas/genética , Semaforinas/metabolismo , Fatores Associados à Proteína de Ligação a TATA/genética , Transativadores/genética , Transcriptoma , Translocação GenéticaRESUMO
Nodular fasciitis (NF) is a self-limiting benign disease that is characterized by rapid proliferation of fibroblastic and myofibroblastic cells. The characteristic gene fusion containing the USP6 gene is a genetic hallmark of NF and MYH9-USP6 is the most frequent fusion, suggesting that NF is not a reactive condition but a neoplastic disease. Malignant transformation of NF has been reported rarely as a single case associated with the PPP6R3-USP6 fusion. Here we report a case of soft part tumor of which the histological feature was a typical NF but showed aggressive and non-regressing growth with local invasion. Targeted RNA sequencing and fluorescence in situ hybridization analysis identified PPP6R3-USP6 with gene amplification. These findings indicate that the present case is the second case of malignant NF, and we suggest potential malignant transformation in certain NF cases.
Assuntos
Fasciite/diagnóstico , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico , Fosfoproteínas Fosfatases/genética , Ubiquitina Tiolesterase/genética , Adulto , Transformação Celular Neoplásica , Fasciite/genética , Fasciite/patologia , Fusão Gênica , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Masculino , Miofibroblastos/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologiaRESUMO
Lipoblastoma-like tumor of the vulva was first described as a benign mesenchymal neoplasm of adipocytic differentiation having features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma. Prior studies of lipoblastoma-like tumor have evaluated PLAG1, HMGA2, and RB1 immunohistochemistry and DDIT3 rearrangement status, with results supporting its distinction from lipoblastoma and myxoid liposarcoma. However, absent RB1 expression was reported in a majority of tested cases, suggesting that lipoblastoma-like tumor may have underlying 13q alterations and be related to RB1-deleted soft tissue tumors. To further understand the molecular genetics of lipoblastoma-like tumor, we examined 7 cases by RB1 immunohistochemistry, DDIT3 and PLAG1 break apart FISH probes, RB1 enumeration FISH probe, and genomic copy number analysis by microarray. Patient age ranged from 21 to 56 years (median 35 years). Clinical follow up was available for 5 patients (71%) ranging 3-264 months (median 74 months). Microscopically, lipoblastoma-like tumor formed large lobules separated by thin and/or thick bands of fibrous tissue and had a prominent network of thin-walled vessels. Each tumor was predominantly composed of spindle cells and lipoblasts with variable quantities of mature adipocytes. RB1 immunohistochemistry exhibited a heterogeneous or "mosaic" pattern of weak and negative nuclear expression in all seven cases. DDIT3 and PLAG1 FISH were negative in each case. No evidence of RB1 regional gain or loss was identified by FISH. Genomic copy number analysis by chromosomal microarray showed a normal diploid profile in six tumors (86%). One tumor had copy number abnormalities consisting of an 11.9 megabase deletion from 1p13.3 to 1p11.2 and monosomy 14. Although lipoblastoma-like tumor has features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma, it is genetically different from these tumors. Furthermore, lipoblastoma-like tumor does not appear to have structural abnormalities of 13q resulting in deletion of RB1.
Assuntos
Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Neoplasias Vulvares/genética , Neoplasias Vulvares/patologia , Adulto , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Adulto JovemRESUMO
Extraskeletal myxoid chondrosarcoma is a rare subtype of sarcoma that affects the soft tissue and bones in middle-aged and elderly adults. Its diagnosis can be challenging, with the differential diagnoses including a wide variety of mesenchymal tumors. The line of differentiation of extraskeletal myxoid chondrosarcoma has been controversial, but recent evidence suggests a neuroendocrine phenotype. INSM1 is a zinc-finger transcription factor that plays a pivotal role in neuroendocrine differentiation, and has been proposed as a promising immunohistochemical marker of neuroendocrine carcinoma. The aim of this study was to determine the prevalence of INSM1 expression in extraskeletal myxoid chondrosarcoma and to understand its significance in sarcoma diagnosis. We immunostained the representative sections of 31 NR4A3-rearranged extraskeletal myxoid chondrosarcomas and 187 histological mimics. Nuclear staining of moderate or higher intensity in at least 5% of tumor cells was considered positive. Twenty-eight of the 31 extraskeletal myxoid chondrosarcomas (90%) were positive for INSM1, providing strong evidence for neuroendocrine differentiation. The staining was diffuse (>50%) in 17 cases, with most immunopositive tumors showing at least focal strong expression. The INSM1 staining extent was not correlated with cytomorphology, synaptophysin expression, or fusion types (EWSR1 vs non-EWSR1). In contrast, INSM1 expression was negative in 94% of the 187 other mesenchymal tumors. INSM1-positive mimics comprised a small subset of chordoma (1 of 10), soft tissue myoepithelioma (1 of 20), ossifying fibromyxoid tumor (3 of 10), and Ewing sarcoma (3 of 10), among other tumor types. The majority of these cases showed labeling in <25% of the tumor cells. Although not entirely sensitive or specific, INSM1 could be a potential marker for the diagnosis of extraskeletal myxoid chondrosarcoma when molecular genetic access is limited.
Assuntos
Condrossarcoma/diagnóstico , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Condrossarcoma/genética , Condrossarcoma/patologia , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Proteína EWS de Ligação a RNA/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Proteínas Repressoras/biossíntese , Sinaptofisina/biossíntese , Ativação TranscricionalRESUMO
Extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare soft tissue sarcoma, marked by a translocation involving the NR4A3 gene. EMC is usually indolent and moderately sensitive to anthracycline-based chemotherapy. Recently, we reported on the therapeutic activity of sunitinib in a series of EMC cases, however the molecular target of sunitinib in EMC is unknown. Moreover, there is still the need to identify alternative therapeutic strategies. To better characterize this disease, we performed whole transcriptome sequencing in five EMC cases. Peculiarly, in one sample, an in-frame deletion (c.1735_1737delGAT p.D579del) was identified in exon 11 of KIT. The deletion was somatic and heterozygous and was validated both at DNA and mRNA level. This sample showed a marked high expression of KIT at the mRNA level and a mild phosphorylation of the receptor. Sanger sequencing of KIT in additional 15 Formalin Fixed Paraffin Embedded (FFPE) EMC did not show any other mutated cases. In conclusion, exon 11 KIT mutation was detected only in one out of 20 EMC cases analyzed, indicating that KIT alteration is not a recurrent event in these tumors and cannot explain the EMC sensitivity to sunitinib, although it is an actionable mutation in the individual case in which it has been identified.
Assuntos
Sequência de Bases , Condrossarcoma/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Proteínas Proto-Oncogênicas c-kit/genética , Deleção de Sequência , Transcriptoma , Condrossarcoma/diagnóstico , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Biologia Computacional , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Éxons , Humanos , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/metabolismo , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Sequenciamento do ExomaRESUMO
Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma most often arising in the soft tissue. Rare EMC of the bone have been reported. EMC exhibits distinctive clinico-pathological and genetic features; however, despite the name, it lacks any feature of cartilaginous differentiation. EMC is characterized by the rearrangement of the NR4A3, which, in most cases (about 62-75%), is fused with EWSR1 and less frequently with other partners, including TAF15 (27%), TCF12 (4%), TFG, and FUS. We herein report the identification by whole-transcriptome sequencing of HSPA8 as a novel fusion partner of NR4A3 in a case of EMC. FISH analysis confirmed the presence of a genomic HSPA8-NR4A3 translocation in the vast majority of tumor cells. Our findings expand the spectrum of NR4A3 fusion partners involved in EMC pathobiology.
Assuntos
Condrossarcoma/genética , Proteínas de Ligação a DNA/genética , Proteínas de Choque Térmico HSC70/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Proteínas de Fusão Oncogênica/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Condrossarcoma/diagnóstico por imagem , Condrossarcoma/patologia , Feminino , Virilha/diagnóstico por imagem , Virilha/patologia , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Tomografia Computadorizada por Raios XRESUMO
AIMS: MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours. METHODS AND RESULTS: Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Müllerian adenosarcomas (including three tentatively diagnosed as 'variant adenosarcomas'), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three 'variant adenosarcomas' harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1-SUZ12 or JAZF1-PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated 'variant adenosarcomas' showed distinctive morphological features, including 'fibromyomatous' cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course. CONCLUSIONS: These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours.