RESUMEN
AIMS: NTRK-rearranged sarcomas of the female genital tract mainly occur in the uterus (more commonly cervix than corpus) and are characterized by a "fibrosarcoma-like" morphology and NTRK gene rearrangements. These neoplasms may exhibit histological overlap with other entities and can present diagnostic difficulties without molecular confirmation. Pan-TRK immunohistochemistry was developed to identify tumours harbouring NTRK rearrangements. The aim of this study was to characterize pan-TRK immunohistochemical expression in a large cohort of gynaecological mesenchymal neoplasms and investigate the utility of pan-TRK immunohistochemistry to distinguish NTRK-rearranged sarcoma from its mimics. METHODS AND RESULTS: A total of 473 gynaecological mesenchymal tumours (461 without known NTRK fusions and 12 NTRK-rearranged sarcomas) were selected. Pan-TRK immunohistochemistry (EPR17341, Abcam) was performed on whole tissue sections and tissue microarrays. Molecular interrogation of pan-TRK positive tumours was performed by RNA sequencing or fluorescence in situ hybridization (FISH). Of the 12 NTRK-rearranged sarcomas, 11 (92%) exhibited diffuse (≥70%) cytoplasmic pan-TRK staining with moderate/marked intensity, while the other was negative. Eleven (2.4%) additional tumours also exhibited pan-TRK immunohistochemical expression: three low-grade endometrial stromal sarcomas, seven high-grade endometrial stromal sarcomas, and an undifferentiated uterine sarcoma. Molecular confirmation of the absence of NTRK rearrangements was possible in nine of these tumours. Of these nine neoplasms, seven exhibited focal/multifocal (<70%) pan-TRK cytoplasmic staining with weak/moderate intensity. CONCLUSION: Even though pan-TRK immunohistochemical expression is not entirely sensitive or specific for NTRK-rearranged sarcomas, these neoplasms tend to exhibit diffuse staining of moderate/strong intensity, unlike its mimics. Pan-TRK should be performed in monomorphic uterine (corpus and cervix) spindle cell neoplasms that are negative for smooth muscle markers and hormone receptors and positive for CD34 and/ or S100. Ultimately, the diagnosis requires molecular confirmation.
Asunto(s)
Neoplasias Endometriales , Neoplasias de los Tejidos Conjuntivo y Blando , Sarcoma Estromático Endometrial , Sarcoma , Neoplasias de los Tejidos Blandos , Femenino , Humanos , Biomarcadores de Tumor/genética , Inmunohistoquímica , Hibridación Fluorescente in Situ , Proteínas de Fusión Oncogénica/genética , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patología , Receptor trkARESUMEN
Although well known as a fusion partner in hematological malignancies, fusion genes involving the ABL proto-oncogene 1 (ABL1), mapping to chromosomal region 9q34.12, have only been anecdotally reported in five soft tissue tumors. These neoplasms have been variously reported as perineurioma, angiofibroma, and solitary fibrous tumor, and all have harbored a GAB1::ABL1 gene fusion; however, the nosology and clinicopathological characteristics of soft tissue tumors carrying this rare fusion have not been delineated. We herein describe eight tumors containing the GAB1::ABL1 fusion and review previously reported cases in a series to define their morphological spectrum, address immunohistochemical evidence for a line of differentiation, with special reference to the presence or absence of a perineurial immunophenotype, and gather insight into their behavior. The patients included four females and four males, aged 13-37 years (median, 24 years). Two cases each originated in the shoulder area, trunk, hands, and lower extremities, with a size range of 1.5-8 cm (median, 3.4 cm). Four tumors were deep and four superficial. All tumors were morphologically similar, being composed of bland fibroblast-like spindle to ovoid cells diffusely arranged in a paucivascular fibrous to fibromyxoid stroma with variable resemblance to soft tissue perineurioma. Mitotic activity was generally low (0-8 mitoses in 10 high-power fields [HPFs]; median, 1). All lesions had at least focally infiltrative margins, but they otherwise lacked pleomorphism and necrosis. Immunohistochemistry showed focal reactivity for CD34 (5/7), epithelial membrane antigen (EMA) (3/8), claudin1 (2/3), GLUT1 (4/6), and S100 (2/7); other markers, including MUC4 (0/7), desmin (0/9), and smooth muscle actin (SMA) (0/4), were negative. RNA sequencing revealed a GAB1::ABL1 fusion in all cases with exon 6 of GAB1 fused to exon 2 of ABL1. Treatments included various forms of surgical intervention in seven cases; one tumor was biopsied only. Limited follow-up was available for five patients. One tumor regrew rapidly within 1 month to 1.5 cm after an initial marginal excision and was re-excised with close margins. Four patients were disease-free at 1, 3, 14, and 25 months of follow-up. Metastases have not, to date, been observed. This series characterizes "GAB1::ABL1 fusion-positive spindle cell neoplasm" as a distinct entity, with overlapping features with soft tissue perineurioma and predilection for children and young adults.
Asunto(s)
Neoplasias de la Vaina del Nervio , Neoplasias de los Tejidos Blandos , Femenino , Humanos , Masculino , Adulto Joven , Proteínas Adaptadoras Transductoras de Señales , Biomarcadores de Tumor , Diferenciación Celular , Fibroblastos/patología , Neoplasias de la Vaina del Nervio/genética , Neoplasias de los Tejidos Blandos/patología , Adolescente , AdultoRESUMEN
DICER1-mutated rhabdomyosarcoma is a rare, emerging entity with a predilection for the gynecologic and genitourinary tracts. We report here a case of DICER1-mutated rhabdomyosarcoma of the ovary in a 14 years old girl which displayed interspersed mature teratoid glands, neuroectodermal rosettes and immature blastematous-like tubes. Morphologically the sarcomatous component predominated, corresponding to a high grade spindle cell rhabdomyosarcoma with botryoid features. Islets of cartilage were present. The sarcomatous proliferation encased the teratoid glands, forming cambium layer-like arrangements. The sarcoma cells were Myogenin and MYOD1 positive, the neuroectodermal rosettes expressed SALL4 along with cytokeratins and EMA and were negative for Inhibin; immature blastematous-like tubes were negative for SALL4 and Inhibin. Whole RNA- and targeted DNA-sequencing revealed two DICER1 mutations in exon 26: c.5113G>A: p.(Glu1705Lys) and exon 12: c.1642C>T: p.(Gln548X). The sarcomatous component harbored a complex genetic profile while the teratoid component was diploid, none of the above displayed abnormality of 12p. DICER1-mutated sarcomas display pathological features similar to embryonal rhabdomyosarcomas, botryoid type. They also display heterogeneous features combining cartilage foci, teratoid mature glands, immature blastematous-like tubes and/or neuroectodermal components. Molecular testing remains necessary to confirm the diagnosis. Further studies need to clarify the nosology of DICER1-mutated sarcomas and devise specific therapeutic strategies.
Asunto(s)
Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Adolescente , Adulto , Niño , Femenino , Humanos , ARN Helicasas DEAD-box/genética , Inhibinas/genética , Mutación , Ovario/metabolismo , Ovario/patología , Rabdomiosarcoma/genética , Rabdomiosarcoma Embrionario/patología , Ribonucleasa III/genética , Ribonucleasa III/metabolismoRESUMEN
Neoplasms harboring a KAT6B/A::KANSL1 fusion were initially reported as benign (leiomyomas) and malignant (leiomyosarcomas, low-grade endometrial stromal sarcomas [LG-ESSs]) uterine neoplasms. However, they may represent an emerging entity characterized by clinical aggressiveness contrasting with a rather reassuring microscopic appearance. Here, we aimed to confirm that this neoplasm is a distinct clinicopathologic and molecular sarcoma and identify criteria that should alert pathologists and lead to KAT6B/A::KANSL1 fusion testing in routine practice. Therefore, we conducted a comprehensive clinical, histopathologic, immunohistochemical, and molecular study, including array comparative genomic hybridization, whole RNA-sequencing, unsupervised clustering, and cDNA mutational profile analyses of 16 tumors with KAT6B::KANSL1 fusion from 12 patients. At presentation, patients were peri-menopausal (median, 47.5 years), and the primary tumors were located in the uterine corpus (12/12, 100%), with an additional prevesical location in 1 (8.3%) of 12 cases. The relapse rate was 33.3% (3/9). All tumors (16/16, 100%) showed morphologic and immunohistochemical features overlapping between leiomyoma and endometrial stromal tumors. A whirling recurrent architecture (resembling fibromyxoid-ESS/fibrosarcoma) was found in 13 (81.3%) of 16 tumors. All tumors (16/16, 100%) exhibited numerous arterioliform vessels, and 13 (81.3%) of 18 had large hyalinized central vessels and collagen deposits. Estrogen and progesterone receptors were expressed in 16 (100%) of 16 and 14 (87.5%) of 16 tumors, respectively. Array comparative genomic hybridization performed on 10 tumors classified these neoplasms as simple genomic sarcomas. Whole RNA-sequencing on 16 samples and clustering analysis on primary tumors found that the KAT6B::KANSL1 fusion always occurred between exons 3 of KAT6B and 11 of KANSL1; no pathogenic variant was identified on cDNA, all neoplasms clustered together, close to LG-ESS, and pathway enrichment analysis showed cell proliferation and immune infiltrate recruitment pathway involvement. These results confirm that the sarcomas harboring a KAT6B/A::KANSL1 fusion represent a distinct clinicopathologic entity, close to LG-ESS but different, with clinical aggressiveness despite a reassuring morphology, for which the KAT6B/A::KANSL1 fusion is the molecular driver alteration.
RESUMEN
AIMS: NTRK gene fusions have been described in a wide variety of central nervous system (CNS) and soft tissue tumours, including the provisional tumour type 'spindle cell neoplasm, NTRK-rearranged' (SCN-NTRK), added to the 2020 World Health Organisation Classification of Soft Tissue Tumours. Because of histopathological and molecular overlaps with other soft tissue entities, controversy remains concerning the lineage and terminology of SCN-NTRK. METHODS AND RESULTS: This study included 16 mesenchymal tumours displaying kinase gene fusions (NTRK fusions and one MET fusion) initially diagnosed as infantile fibrosarcomas (IFS), SCN-NTRK and adult-type fibrosarcomas from the soft tissue, viscera and CNS. We used immunohistochemistry, DNA methylation profiling, whole RNA-sequencing and ultrastructural analysis to characterise them. Unsupervised t-distributed stochastic neighbour embedding analysis showed that 11 cases (two CNS tumours and nine extra-CNS) formed a unique and new methylation cluster, while all tumours but one, initially diagnosed as IFS, clustered in a distinct methylation class. All the tumours except one formed a single cluster within the hierarchical clustering of whole RNA-sequencing data. Tumours from the novel methylation class co-expressed CD34 and S100, had variable histopathological grades and frequently displayed a CDKN2A deletion. Ultrastructural analyses evidenced a myofibroblastic differentiation. CONCLUSIONS: Our findings confirm that SCN-NTRK share similar features in adults and children and in all locations combine an infiltrative pattern, distinct epigenetic and transcriptomic profiles, and ultrastructural evidence of a myofibroblastic lineage. Further studies may support the use of new terminology to better describe their myofibroblastic nature.
Asunto(s)
Fibrosarcoma , Neoplasias , Neoplasias de los Tejidos Blandos , Niño , Adulto , Humanos , Receptor trkA/genética , Metilación , Neoplasias/patología , Neoplasias de los Tejidos Blandos/genética , Fibrosarcoma/genética , ARN , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare soft tissue tumor with a predilection for the distal extremities and a tendency for local recurrence. Morphologically, MIFS consists of spindle and bizarre epithelioid cells resembling virocytes embedded in a fibrous to myxoid stroma with an abundant inflammatory infiltrate. Importantly, the molecular landscape of MIFS is wide and includes: VGLL3 amplification, BRAF fusion/amplification and OGA/TGFBR3 rearrangements. In this study, we describe a variant of MIFS showing a frequent nodular configuration associated with necrosis and recurrent YAP1::MAML2 fusions. The cohort consisted of 7 patients (4 females and 3 males) ranging in age from 21 to 71 years (median: 47 years). Two tumors (28%) occurred in acral locations while the remaining cases were more widely distributed (thigh, n = 2; arm, n = 1; neck; n = 1; chest-wall, n = 1). Tumor size ranged from 10 to 38 mm (median: 20 mm). Histologically, lesions frequently presented as nodules with central areas of necrosis, and were predominantly composed of sheets of epithelioid cells with large vesicular nuclei and prominent nucleoli (Reed-Sternberg-like cells or virocytes). The stroma was mostly fibrous and showed a polymorphous inflammatory infiltrate. Myxoid stromal changes were focally seen in one case, and pseudolipoblasts were absent. The immunophenotype was nonspecific, with only pan-keratin (AE1-AE3) and cyclin D1 expression in a subset of cases. RNA-Sequencing detected YAP1::MAML2 fusions in 3/7 cases; aCGH showed no significant gene copy number variations in 4 tested cases, and FISH analysis showed no VGLL3 amplification in 1 tested case. Follow-up was available for 6 cases, ranging from 7 to 63 months (median: 42 months). Local recurrence and metastasis were not seen and one tumor showed spontaneous regression following initial biopsy. In conclusion, we describe a novel variant of MIFS with distinctive clinicopathological and molecular features for which we propose the term "nodular necrotizing" MIFS.
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Fibrosarcoma , Neoplasias Cutáneas , Neoplasias de los Tejidos Blandos , Ciclina D1/genética , Variaciones en el Número de Copia de ADN , Femenino , Fibrosarcoma/genética , Humanos , Queratinas , Masculino , Necrosis , Proteínas Proto-Oncogénicas B-raf/genética , ARN , Neoplasias de los Tejidos Blandos/patología , Transactivadores/genética , Factores de Transcripción/genética , Proteínas Señalizadoras YAPRESUMEN
Round cell sarcomas represent a diagnostic challenge for pathologists, owing to the poorly differentiated features of these high-grade tumours. The diagnosis of round cell sarcoma requires large immunohistochemical panels and molecular testing in many cases. This spectrum of malignancies is largely dominated by Ewing sarcomas (ESs), which represent the most common family of these tumours. Nonetheless, new families have been delineated in the past few years, with the addition of two additional families in the 2020 World Health Organization classification of bone and soft tissue tumours, namely sarcomas with CIC rearrangements and sarcomas with BCOR alterations. EWSR1, one of the genes involved in the driver fusion of ESs, is also implicated in the translocation of many other tumours with heterogeneous lineages and variable levels of aggressiveness. Round cell sarcomas associated with fusions inwhichEWSR1is partnered with genes encoding transcription factors distinct from those of the 'Ewing family' represent a heterogeneous group of rare tumours that require further study to determine whether their fusions may or not define a specific subgroup. They include mainly sarcomas with NFATc2 rearrangements and sarcomas with PATZ1 rearrangements. At this point, PATZ1 fusions seem to be associated with tumours of high clinical and morphological heterogeneity. Molecular studies have also helped in the identification of more consistent biomarkers that give tremendous help to pathologists in triaging, if not diagnosing, these tumours in practice. This review compiles the latest accumulated evidence regarding round cell sarcomas, and discusses the areas that are still under investigation.
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Neoplasias Óseas/diagnóstico , Fusión Génica , Liposarcoma Mixoide/diagnóstico , Neoplasias de los Tejidos Blandos/diagnóstico , Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Reordenamiento Génico , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/patología , Factores de Transcripción NFATC/genética , Proteínas Represoras/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Translocación GenéticaAsunto(s)
Fibroma Osificante , Reordenamiento Génico , Proteínas de Unión a la Región de Fijación a la Matriz , Factores de Transcripción , Humanos , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Fibroma Osificante/genética , Fibroma Osificante/patología , Factores de Transcripción/genética , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Masculino , Femenino , NiñoRESUMEN
Recently, FN1 fusions to receptor tyrosine kinase genes have been identified in soft tissue tumors with calcified chondroid matrix named calcifying chondroid mesenchymal neoplasms (CCMNs). We collected 33 cases of CCMN from the French network for soft tissue and bone tumors. We performed whole-exome RNA sequencing, expression analysis, and genome-wide DNA methylation profiling in 33, 30, and 20 cases of CCMN compared with a control group of tumors, including noncalcified tenosynovial giant cell tumor (TGCT). Among them, 15 cases showed morphologic overlap with soft tissue chondroma, 8 cases with tophaceous pseudogout, and 10 cases with chondroid TGCT. RNA-sequencing revealed a fusion of FN1 in 76% of cases (25/33) with different 5' partners, including most frequently FGFR2 (14 cases), TEK or FGFR1. Among CCMN associated with FGFR1 fusions, 2 cases had overexpression of FGF23 without tumor-induced osteomalacia. Four CCMN had PDGFRA::USP8 fusions; 3 of which had histologic features of TGCT and were located in the hip, foot, and temporomandibular joint (TMJ). All cases with FN1::TEK fusion were located at TMJ and had histologic features of TGCT with or without chondroid matrix. They formed a distinct cluster on unsupervised clustering analyses based on whole transcriptome and genome-wide methylome data. Our study confirms the high prevalence of FN1 fusions in CCMN. In addition, through transcriptome and methylome analyses, we have identified a novel subgroup of tumors located at the TMJ, exhibiting TGCT-like features and FN1::TEK fusions.
Asunto(s)
Biomarcadores de Tumor , Calcinosis , Factor-23 de Crecimiento de Fibroblastos , Humanos , Femenino , Masculino , Persona de Mediana Edad , Calcinosis/genética , Calcinosis/patología , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Adulto Joven , Metilación de ADN , Adolescente , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Fibronectinas/genética , Secuenciación del Exoma , Niño , Anciano de 80 o más Años , Francia , FenotipoRESUMEN
Giant cell tumors (GCTs) with high mobility group AT-Hook 2 ( HMGA2 )::nuclear receptor corepressor 2 ( NCOR2 ) fusion are rare mesenchymal tumors of controversial nosology, which have been anecdotally reported to respond to CSFR1 inhibitors. Here, we performed a comprehensive study of 6 GCTs with HMGA2::NCOR2 fusion and explored their relationship with other giant cell-rich neoplasms. Tumors occurred in 4 females and 2 males ranging in age from 17 to 32 years old (median 24). Three lesions originated in subcutaneous soft tissue and 3 in bone. Tumor size ranged from 20 to 33 mm (median 27 mm). The lesions had a nodular/multinodular architecture and were composed of sheets of mononuclear "histiocytoid" cells with uniform nuclei intermingled with multinucleated giant cells. Mitotic activity was low and nuclear atypia and metaplastic bone were absent. Variable findings included necrosis, cystic degeneration, lymphocytic infiltrate (sometimes forming nodules), and xanthogranulomatous inflammation. On immunohistochemistry, all cases focally expressed pan-keratin and were negative with SATB2 and H3.3G34W. Whole RNA-sequencing was performed in all cases of GCT with HMGA2::NCOR2 fusion and a subset of giant cell-rich tumors (tenosynovial-GCT, n = 19 and "wild-type" GCT of soft tissue, n = 9). Hierarchical clustering of RNA-sequencing data showed that GCT with HMGA2::NCOR2 fusion formed a single cluster, independent of the other 2 entities. Methylome profiling showed similar results, but the distinction from "wild-type" GCT of soft tissue was less flagrant. Gene expression analysis showed similar levels of expression of the CSF1/CSFR1 axis between GCT with HMGA2::NCOR2 fusion and tenosynovial-GCT, supporting their potential sensitivity to CSFR1 inhibitors. Clinical follow-up was available for 5 patients (range: 10 to 64 mo; median 32 mo). Three patients (60%) experienced local recurrences, whereas none had distant metastases or died of disease. Overall, our study confirms and expands previous knowledge on GCT with HMGA2::NCOR2 fusion and supports its inclusion as an independent entity.
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Biomarcadores de Tumor , Tumores de Células Gigantes , Masculino , Femenino , Humanos , Adolescente , Adulto Joven , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Tumores de Células Gigantes/patología , Inmunohistoquímica , Huesos/patología , Epigénesis Genética , Co-Represor 2 de Receptor Nuclear/genéticaRESUMEN
A subset of benign peripheral nerve sheath tumors are "hybrid" combining several lines of differentiation, most often schwannian and perineurial features. The pathogenesis of these tumors was poorly described until the recent discovery of recurrent VGLL3 rearrangements in hybrid schwannoma/perineuriomas, supporting the hypothesis that this entity represents a distinct subgroup of tumors and not only a morphologic variation of other peripheral nerve sheath tumors. Following this finding, we investigated 10 cases of hybrid peripheral nerve sheath tumors with immunohistochemistry, RNA sequencing, and array comparative genomic hybridization. By light microscopy, 7 tumors were hybrid schwannoma/perineurioma tumors, and 3 were hybrid schwannoma/neurofibroma. Most cases of hybrid schwannoma/perineuriomas displayed VGLL3 rearrangements fused in 5' either to CHD7 or CHD9 (n=6/7) and had simple diploid genetic profiles with few copy number alterations. Compared with a control group composed of 28 tumors associated with varied neural phenotypes, all VGLL3-fused tumors clustered together by transcriptomic analysis. In contrast, 1 case of hybrid schwannoma/perineurioma tumor harbored a CDH9-ZFHX3 fusion, a prominent perineurial component identified by immunohistochemistry and clustered with perineuriomas. No recurrent genetic alteration was seen in the 3 hybrid schwannoma/neurofibromas. To summarize, this study confirms and expands the recent findings on hybrid schwannoma/perineurioma, highlighting the predominance of VGLL3 fusions in these tumors.
Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Vaina del Nervio , Neurilemoma , Neurofibroma , Neoplasias del Sistema Nervioso Periférico , Biomarcadores de Tumor/genética , Hibridación Genómica Comparativa , Humanos , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/patología , Neurilemoma/genética , Neurilemoma/patología , Neurofibroma/patología , Factores de Transcripción/genéticaRESUMEN
A novel DNA methylation class of tumor within the central nervous system, the "neuroepithelial tumor (NET), PATZ1 fusion-positive" has recently been identified in the literature, characterized by EWSR1- and MN1-PATZ1 fusions. The cellular origin of this tumor type remains unknown, wavering between glioneuronal or mesenchymal (as round cell sarcomas with EWSR1-PATZ1 of the soft tissue). Because of the low number of reported cases, this tumor type will not be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS). Herein, we report one case of a CNS tumor classified by DNA methylation analysis as NET-PATZ1 but harboring a novel LARGE1-AFF2 fusion which has until now never been described in soft tissue or the CNS. We compare its clinical, histopathological, immunophenotypical, and genetic features with those previously described in NET-PATZ1. Interestingly, the current case presented histopathological (astroblastoma-like features, glioneuronal phenotype), clinical (with a favorable course), genetic (1p loss), and epigenetic (DNA-methylation profiling) similarities to previously reported cases of NET-PATZ1. Our results added data suggesting that different histomolecular tumor subtypes seem to be included within the methylation class "NET, PATZ1 fusion-positive", including non PATZ1 fusions, and that further cases are needed to better characterize them.