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Granular cell tumors (GrCTs) are mesenchymal neoplasms of presumed schwannian differentiation that may present as solitary or multifocal lesions with excision usually being curative. A minority of cases, however, show histological features associated with an increased risk for metastasis and are highly aggressive leading to death in about a third of cases. While benign and malignant cases have been shown to harbor mutations in the H + ATPase genes, there is only limited data examining molecular aberrations associated with malignancy. The departmental archives were searched for cases of atypical/malignant GrCTs. Clinical and histopathological features were noted. Whole-exome sequencing was performed. Three cases of malignant GrCTs and one case of atypical GrCTs were included. All three malignant tumors metastasized to distant sites with a median disease-free survival of 16 months and an overall follow-up time of 35 months. Whole-exome sequencing showed mutations involving TGFß and MAPK pathways in all four tumors. Although the cohort size is small, our preliminary findings suggest that mutations involving the TGFß and MAPK pathways may be associated with tumor progression or malignant transformation in GrCT pathogenesis.
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Tumor de Células Granulares , Humanos , Tumor de Células Granulares/genética , Mutação , Fator de Crescimento Transformador beta/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismoRESUMO
The evolving classification of rhabdomyosarcoma (RMS) now includes spindle cell RMS (SRMS). Bone/soft tissue SRMS often harbor TFCP2, or less often MEIS1 rearrangements. We studied 25 fusion-driven SRMS involving bone (n = 19) and soft tissue (n = 6). Osseous SRMS occurred in 13 women and 6 men (median age: 41 years) and involved the pelvis (5), sacrum (2), spine (4), maxilla (4), mandible (1), skull (1), and femur (2). Follow-up (median: 5 months) demonstrated local recurrence in 2/16 and distant metastases in 8/17 patients (median time to metastasis: 1 month). Eight patients died of disease; 9 were alive with disease. Soft tissue SRMS occurred in 4 men and 2 women (median: 50 years). Follow-up (median: 10 months) revealed distant metastasis at diagnosis (1), alive with unresected tumor (1), and no evidence of disease (4). Next-generation sequencing demonstrated FUS::TFCP2 (12), EWSR1::TFCP2 (3) and MEIS1::NCOA2 (2); FISH identified EWSR1 (2) rearrangements. Most TFCP2-rearranged SRMS (13/17) showed spindled/epithelioid morphology, rarely with rhabdomyoblasts. The bone tumors were diffusely desmin and MyoD1 positive with limited myogenin; 10/13 were ALK -positive and 6/15 were keratin positive. Soft tissue SRMS harbored EWSR1::TFCP2, MEIS1::NCOA2, ZFP64::NCOA2, MEIS1::FOXO1, TCF12::VGLL3 and DCTN1::ALK, and displayed spindled/epithelioid, leiomyomatous, and myxofibrosarcoma-like morphologies. Immunohistochemistry (IHC) was positive for MyoD1 (6/6), focal desmin (5/6), myogenin (3/6), and keratin (1/6). We conclude that TFCP2-rearranged SRMS of bone and soft tissue show consistent morphologic and IHC features, likely representing a distinct subset of RMS. Non-TFCP2 fusion-positive SRMS could represent a single RMS subset, multiple subtypes of RMS, or "fusion-defined" sarcomas with rhabdomyoblastic differentiation.
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AIMS: Intraosseous hibernomas are rarely reported tumours with brown adipocytic differentiation of unknown aetiology, with only 38 cases documented in the literature. We sought to further characterise the clinicopathologic, imaging and molecular features of these tumours. METHODS AND RESULT: Eighteen cases were identified occurring in eight females and 10 males (median age = 65 years, range = 7-75). Imaging indication was cancer surveillance/staging in 11 patients and clinical concern for a metastasis was raised in 13 patients. The innominate bone (7), sacrum (5), mobile spine (4), humerus (1) and femur (1) were involved. Median tumour size was 1.5 cm (range = 0.8-3.8). Tumours were sclerotic (11), mixed sclerotic and lytic (4) or occult (1). Microscopically, tumours were composed of large polygonal cells with distinct cell membranes, finely vacuolated cytoplasm, central or paracentral small bland nuclei with prominent scalloping. Growth around trabecular bone was observed. Tumour cells were immunoreactive for S100 protein (15/15) and adipophilin (5/5), while negative for keratin AE1/AE3(/PCK26) (0/14) and brachyury (0/2). Chromosomal microarray analysis, performed on four cases, did not show clinically significant copy number variation across the genome or on 11q, the site of AIP and MEN1. CONCLUSION: Analysis of 18 cases of intraosseous hibernoma, to our knowledge, the largest series to date, revealed that these tumours are most often detected in the spine and pelvis of older adults. Tumours were generally small, sclerotic and frequently found incidentally and can raise concern for metastasis. Whether or not these tumours are related to soft tissue hibernomas is uncertain.
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Variações do Número de Cópias de DNA , Lipoma , Masculino , Feminino , Humanos , Idoso , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Lipoma/patologia , Proteínas S100/genética , Fêmur/patologiaRESUMO
Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone sarcoma characterized by low-intermediate grade cartilage component with abrupt transition to a high-grade non-chondrosarcomatous component. Generally, the dedifferentiated (DD) component is large. However, rare cases have minimal (<1 cm) or small (1-2 cm) areas of DD. We describe the clinicopathologic features of such tumors and evaluate the prognostic significance of this finding compared to cases with large DD (>2 cm). Available slides were re-reviewed for assessment of histologic features. The medical record was reviewed for imaging studies and clinical characteristics. Thirty-five cases were included. Six patients had minimal DD, four had small DD and 25 had large DD. None of the minimal DD showed definitive imaging evidence of DD. Two minimal DD (33%) locally recurred and 2 (33%) developed distant metastases. None of the small DD cases showed definitive imaging evidence of DD. None of the small DD locally recurred and at least 1 (25%) developed distant metastases. There was no significant difference in age, gender, pelvic site, tumor size >8 cm, tumor necrosis or undifferentiated pleomorphic sarcoma-like morphology between minimal or small DD compared to large DD, though osteosarcomatous differentiation was significantly more common in large DD. There was no significant difference in overall survival between minimal or small DD compared to large DD (p = 0.81 and p = 0.17, respectively), or in progression-free survival (p = 0.47 and 0.29, respectively), or metastasis-free survival (p = 0.06 and 0.62, respectively). DDCS with minimal or small DD show similar demographic distribution, anatomic localization and histologic features to large DD. DD in these cases is unlikely to be detected on imaging. Furthermore, at least a subset of these tumors is extremely aggressive despite the limited extent of DD. This highlights the need for thorough gross and histologic examination and sampling.
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Neoplasias Ósseas , Condrossarcoma , Osteossarcoma , Sarcoma , Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Humanos , Recidiva Local de NeoplasiaRESUMO
Xanthogranulomatous epithelial tumor (XGET) and keratin-positive giant cell-rich soft tissue tumor with HMGA2-NCOR2 fusion (KPGCT) are two recently described neoplasms with both distinct and overlapping clinical and histopathologic features. We hypothesized that XGET and KPGCT may be related and represent a histologic spectrum of a single entity. To test this, we sought to characterize the clinical, radiographic, immunohistochemical, ultrastructural and molecular features of additional tumors with features of XGET and/or KPGCT, which we refer to descriptively as keratin-positive xanthogranulomatous/giant cell-rich tumors (KPXG/GCT). The archives were searched for potential cases of KPXG/GCT. Clinical and imaging features were noted. Slides were assessed for histologic and immunohistochemical findings. Ultrastructural and next generation RNA sequencing-based analysis were also performed. Nine cases were identified arising in seven women and two men [median age of 33 years (range: 12-87)]. Median tumor size was 4 cm (range: 2.4-14.0 cm) and tumors presented in the thigh (2), buttock (1), forearm (2), groin (1), cranial fossa (1), ilium (1), and tibia (1). Morphologically, tumors were most frequently characterized by a fibrous capsule, with associated lymphoid reaction, enclosing a polymorphous proliferation of histiocytes, giant cells (Touton and osteoclast-types), mixed inflammatory infiltrate, hemorrhage and hemosiderin deposition, which imparted a variably xanthogranulomatous to giant cell tumor-like appearance. One case clearly showed mononuclear cells with eosinophilic cytoplasm characteristic of XGET. All cases expressed keratin and 7 of 9 were found to harbor HMGA2-NCOR2 fusions including cases with xanthogranulomatous appearance. One patient developed local recurrence and multifocal pulmonary lesions, which were radiographically suspicious for metastases. Shared clinical, histologic and immunohistochemical features, and the shared presence of HMGA2-NCOR2 fusions supports interpretation of KPXG/GCT as a single entity which includes XGET and KPGCT. Given limited clinical follow-up to date and rare cases with apparently aggressive findings, we provisionally regard these tumors as having uncertain biologic potential.
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Tumores de Células Gigantes , Neoplasias Epiteliais e Glandulares , Proteínas de Fusão Oncogênica , Neoplasias de Tecidos Moles , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Células Gigantes/patologia , Hemossiderina , Queratinas , Neoplasias Epiteliais e Glandulares/patologia , Correpressor 2 de Receptor Nuclear/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Proteínas de Fusão Oncogênica/genética , Proteína HMGA2/genéticaRESUMO
AIMS: Clear cell stromal tumour of the lung (CCST-L) is a rare, recently recognised neoplasm which has been found to express TFE3 and harbour YAP1::TFE3 fusions. Initial data suggested a benign process; however, a single reported case gave rise to distant metastases. We sought to describe the clinicopathological and molecular features of additional cases of CCST-L. METHODS AND RESULTS: Pathology and molecular archives were searched for cases of CCST-L or tumours with YAP1::TFE3 fusions. Clinical features were noted. Available slides, including immunohistochemical studies, were re-reviewed for diagnosis confirmation and assessment of pathological features. Results of molecular studies were also recorded. Four tumours were identified, all occurring in women (median age = 61 years, range = 24-69). Median tumour size was 4.4 cm (range = 1-9.5 cm); three tumours were unifocal and one was multifocal. Tumours were composed of epithelioid to spindled cells with eosinophilic to clear cytoplasm and grew in sheets, vague nests and short fascicles. Nuclear atypia was predominately mild; however, two cases showed scattered atypical cells. Mitotic activity was generally low, although one case showed a mitotic count of 6/2 mm2 . All tumours expressed TFE3 and harboured YAP1::TFE3 fusions. One case was unresectable and was treated with chemotherapy, and two underwent complete resection. One patient died of disease 7 months following diagnosis, while a second patient was alive with no evidence of disease after 43 months. Follow-up was not available for two cases. CONCLUSION: CCST-L expresses TFE3, harbours YAP1::TFE3 fusions and at least rare cases behave in an aggressive manner.
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Neoplasias Pulmonares , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Feminino , Fusão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Proteínas de Sinalização YAP , Adulto JovemRESUMO
Myofibroblastic stromal hyperplasia (MSH) is the proposed name for a benign spindle cell proliferation of the mammary stroma, which often raises clinical and radiographic concern for a mass or a malignant process. Ten cases were retrieved from the files of our institution. All presented as a mammographic abnormality. Patients ranged in age from 24 to 67 years. Seven were <50 years old. The salient histopathologic aspect was the proliferation of benign appearing spindle cell within the intralobular stroma. The most common pattern was a diffuse proliferation of compact spindle cells with areas of perilobular/periductal accentuation. Mitotic activity and atypia were not seen. Tumor cells were positive for CD34 and SMA and negative for estrogen receptor, Beta-catenin, and p63. Only one of the cases demonstrated an associated lesion that explained the mammographic abnormality. Follow-up was available for four cases and was uneventful. MSH has overlapping features with the fascicular pattern of PASH and is likely related to pseudoangiomatous stromal hyperplasia (PASH) but differs in that does not demonstrate pseudovascular structures and it predominantly involves perilobular stroma. Recognition of this pattern will avoid discordant radiologic pathologic findings and unnecessary surgery/repeat biopsies.
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Doenças Mamárias/patologia , Miofibroblastos/patologia , Adulto , Idoso , Proliferação de Células , Feminino , Humanos , Hiperplasia/patologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Well-differentiated liposarcomas (WDL) are often partly composed of sclerotic tissue, however, the amount varies widely between tumors, and its prognostic significance is unknown. We hypothesized that tumors with more sclerosis would behave more aggressively. METHODS: Primary retroperitoneal WDL from 29 patients resected at our institution with follow-up were histologically evaluated by soft tissue pathologists blinded to outcome. Tumors with ≥ 10% sclerosis were designated "sclerotic" while tumors with < 10% sclerosis were designated as "minimally sclerotic". Cellular and dedifferentiated tumors were excluded. Clinical parameters and radiologic assessments on computed tomography (CT) were recorded. RESULTS: Histological evaluation identified 13 minimally sclerotic WDL and 16 sclerotic WDL. Median follow-up was 9 years (range, 3-20). Median recurrence-free survival (RFS) and median overall survival (OS) were 6.16 and 13.9 years, respectively. Compared with patients with sclerotic WDL, those with minimally sclerotic WDL had superior RFS (HR = 0.17 [95% CI, 0.06-0.53], P = .002) and OS (log-rank test, P = .002). Sclerotic WDL exhibited higher Houndsfield Units than minimally sclerotic WDL (26 vs 1, P = .040). CONCLUSIONS: Minimally sclerotic WDL were associated with more favorable outcome compared with sclerotic tumors. Assessment of sclerosis in WDL is likely a useful prognostic marker.
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Lipossarcoma/patologia , Neoplasias Retroperitoneais/patologia , Esclerose/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular/fisiologia , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Doença , Feminino , Humanos , Lipossarcoma/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Retroperitoneais/cirurgia , Esclerose/cirurgia , Adulto JovemRESUMO
Nodular fasciitis is a self-limited myofibroblastic lesion that can be misdiagnosed as a sarcoma as a result of its rapid growth, cellularity, and sometimes prominent mitotic activity. A recurrent translocation t(17;22) has been identified in nodular fasciitis, fusing the coding region of USP6 to the promoter region of MYH9, and resulting in increased USP6 expression. A subset of cases show USP6 rearrangement without the typical fusion variants by RT-PCR, or any MYH9 rearrangement by FISH. We sought to further characterize such tumors using molecular diagnostic assays. A novel RT-PCR assay was designed to detect the two known MYH9-USP6 fusion types in formalin-fixed paraffin-embedded and frozen tissue, and a break-apart FISH assay was designed to detect USP6 rearrangement. Twenty-six cases of nodular fasciitis diagnosed between 2002 and 2013 were retrieved from the pathology files of our institutions and were confirmed to be positive by FISH and/or RT-PCR. Seven samples showed USP6 rearrangement by FISH but were negative for MYH9-USP6 fusion by RT-PCR; these cases were subjected to a next-generation sequencing assay utilizing anchored multiplex PCR technology. This assay targets a single partner gene associated with fusions in bone and soft tissue tumors for agnostic detection of gene fusion partners. Novel fusion partners were identified in all seven cases and confirmed by RT-PCR. Structurally, all fusions consisted of the juxtaposition of the entire coding region of USP6 with the promoter of the partner gene, driving increased USP6 expression. This study confirms the neoplastic nature of nodular fasciitis, defines additional pathogenic fusion partners, and adds to the growing body of literature on USP6-associated neoplasia. Given the diagnostic challenges of these tumors, molecular assays can be useful ancillary tools; however, the prevalence of promoter swapping must be recognized when interpreting results.
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Fasciite/genética , Miofibroma/genética , Proteínas Proto-Oncogênicas/biossíntese , Ubiquitina Tiolesterase/biossíntese , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética , Translocação Genética , Ubiquitina Tiolesterase/genética , Adulto JovemRESUMO
Cutaneous angiosarcoma can be challenging to diagnose particularly when poorly vasoformative and studied on biopsies. We report a case of a cutaneous angiosarcoma with strong positivity for tyrosinase, the first to our knowledge, initially misdiagnosed as melanoma. We subsequently evaluated the reactivity of panmelanocytic cocktail (tyrosinase, HMB-45 and Melan-A), SOX10, tyrosinase and MITF in a large tissue microarray (TMA) of angiosarcoma. The TMA included 142 cases of angiosarcomas (29 cutaneous, 22 primary breast, 41 post-radiation breast, 15 visceral, 26 deep soft tissue and bone, 5 chronic lymphedema-associated and 4 angiosarcomas arising in other sarcomas). Immunohistochemical studies were performed with anti-panmelanocytic cocktail, anti-SOX10, anti-MITF and anti-tyrosinase antibodies. TMA staining results were scored on intensity and percentage of tumoral labeling. Aside from the index case, no cases (0 of 133) showed positivity for tyrosinase including 28 cutaneous angiosarcomas. One breast angiosarcoma (1 of 131) was positive for MITF. All cases were negative for SOX10 and panmelanocytic cocktail (0 of 132). Angiosarcomas can rarely be positive for tyrosinase and MITF. Pathologists should be cognizant of these rare exceptions to prevent confusion with melanoma. Additional immunohistochemical markers for vascular and melanocytic differentiation, thorough histological examination for vasoformative and in situ areas as well as clinical impression are helpful in these exceptionally problematic cases.
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Biomarcadores Tumorais/metabolismo , Hemangiossarcoma , Melanócitos , Melanoma , Monofenol Mono-Oxigenase/metabolismo , Neoplasias Cutâneas , Idoso , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Feminino , Hemangiossarcoma/enzimologia , Hemangiossarcoma/patologia , Humanos , Masculino , Melanócitos/enzimologia , Melanócitos/patologia , Melanoma/enzimologia , Melanoma/patologia , Proteínas de Neoplasias , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologiaRESUMO
The WHO Classification of Soft Tissue and Bone Tumours currently recognizes four categories of undifferentiated small round cell sarcoma: Ewing sarcoma, round cell sarcoma with EWSR1-non-ETS fusions including NFATc2 and PATZ1, CIC-rearranged sarcoma, and sarcoma with BCOR genetic alterations. These neoplasms frequently pose significant diagnostic challenges due to rarity and overlapping morphologic and immunohistochemical findings. Further, molecular testing, with accompanying pitfalls, may be needed to establish a definitive diagnosis. This review summarizes the clinical, histologic, immunohistochemical, and molecular features of these neoplasms. In addition, differential diagnosis and areas of uncertainty and ongoing investigation are discussed.
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Biomarcadores Tumorais , Neoplasias Ósseas , Sarcoma de Ewing , Sarcoma de Células Pequenas , Organização Mundial da Saúde , Humanos , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Sarcoma de Ewing/classificação , Sarcoma de Ewing/química , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/classificação , Sarcoma de Células Pequenas/genética , Sarcoma de Células Pequenas/patologia , Sarcoma de Células Pequenas/classificação , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Imuno-Histoquímica , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/classificação , Proteína EWS de Ligação a RNA/genética , Proteínas Repressoras/genética , Rearranjo Gênico , Proteínas Proto-Oncogênicas/genética , Valor Preditivo dos Testes , Fenótipo , Predisposição Genética para Doença , Proteínas de Fusão Oncogênica/genéticaRESUMO
CASE: A healthy, 19-year-old woman was incidentally found to have a large, destructive tumor of T11 without neurologic symptoms. Biopsy demonstrated fibrocartilaginous mesenchymoma (FCM). The patient was treated with resection including subtotal corpectomy and T8-L1 fusion with use of cage and allograft strut construct. The patient remained without recurrence over 3 years of follow-up. CONCLUSION: FCM arising from the spine is a rare tumor, of which this is the sixth report. FCM affects primarily young adults and is benign but locally aggressive, requiring complete excision to prevent recurrence.
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Mesenquimoma , Neoplasias da Coluna Vertebral , Humanos , Feminino , Adulto Jovem , Mesenquimoma/cirurgia , Mesenquimoma/patologia , Mesenquimoma/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/patologia , Vértebras Torácicas/cirurgia , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/patologiaRESUMO
"Xanthogranulomatous epithelial tumor" (XGET) and "keratin-positive giant cell-rich soft tissue tumor" (KPGCT), two recently described mesenchymal neoplasms, likely represent different aspects of a single entity. Both tumors are composed of only a small minority of tumor cells surrounded by large numbers of non-neoplastic inflammatory cells and histiocytes, suggesting production of a paracrine factor with resulting "landscape effect," as seen in tenosynovial giant cell tumor. Recent evidence suggests that the paracrine factor in XGET/KPGCT may be CSF1, as in tenosynovial giant cell tumor. We hypothesized that CSF1 is overexpressed in XGET/KPGCT. To test our hypothesis, we performed quantitative real time PCR (qPCR) for CSF1 expression and CSF1 RNAscope chromogenic in situ hybridization (CISH) on 6 cases of XGET/KPGCT. All cases were positive with CSF1 CISH and showed increased expression of CSF1 by qPCR. Our findings provide additional evidence that the CSF1/CSF1R pathway is involved in the pathogenesis of XGET/KPGCT. These findings suggest a possible role for CSF1R inhibition in the treatment of unresectable or metastatic XGET/KPGCT.
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Carcinoma , Tumor de Células Gigantes de Bainha Tendinosa , Tumores de Células Gigantes , Neoplasias de Tecidos Moles , Humanos , Fator Estimulador de Colônias de Macrófagos/genética , Queratinas , Tumores de Células Gigantes/metabolismo , Tumores de Células Gigantes/patologia , Neoplasias de Tecidos Moles/patologia , Células Gigantes/patologiaRESUMO
The category of ALK-rearranged mesenchymal neoplasms has been evolving rapidly, with reports of morphologically diverse lesions of cutaneous, soft tissue, and visceral origin. While some of these represent morphologically defined entities harboring recurrent ALK fusions (inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma), others are unclassified by morphology with variable overlap with the tyrosine kinase family of neoplasia and their underlying ALK fusions cannot be suspected based on morphology. We herein report 3 cases that expand the anatomic, morphologic, and genotypic spectrum of ALK-rearranged unclassified neoplasms. Patients were all adults aged 46 to 69 (median: 63) who presented with a mass located in the gingiva, subcutis of the back, and submucosal posterior pharyngeal wall. The tumor size ranged from 1 to 2.7 cm (median: 1.6). Conservative surgery was the treatment in all patients. Follow-up was available for one patient who remained disease-free at 14 months. Histologically, all tumors displayed large polygonal cells with foamy to granular and lipogenic-like microvacuolated copious cytoplasm and medium-sized round nuclei with 1 or 2 prominent nucleoli. Mitoses and necrosis were not seen. The initial diagnostic impression was PEComa, inflammatory rhabdomyoblastic tumor and unclassified pseudolipogenic neoplasm. Strong cytoplasmic ALK was detected by immunohistochemistry in all cases. Other positive markers include Cathepsin K (2/2), desmin (1/3), focal MyoD1 (1/1), focal SMA (1/3), and focal EMA (1/2). Targeted RNA sequencing revealed ALK fusions with exon 20 (2 cases) and exon 19 (one case) of ALK fused to RND3 (exon 3), SQSTM1 (exon 6), and desmin (intron 6). Methylation profiling in the desmin-fused case (initially diagnosed as inflammatory rhabdomyoblastic tumor) revealed an inflammatory myofibroblastic tumor match with a low confidence score of 0.5 and a flat copy number variation (CNV) profile. No NF1 mutation was detected in this case, altogether excluding an inflammatory rhabdomyoblastic tumor. Our study highlights and expands the morphologic and anatomic diversity of ALK-fused neoplasms and documents novel fusion partners (RND3 and desmin).
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Tumors with pathogenic DICER1 mutation are rare and encompass sporadic or hereditary benign, intermediate and malignant tumors. DICER1-associated sarcomas are heterogeneous; however, the prototypical ones in the GYN-tract include embryonal rhabdomyosarcoma, adenosarcoma and moderately to poorly differentiated Sertoli-Leydig tumor. In this report, we present three unique uterine sarcomas with DICER1 mutation and remarkable diffuse round/spindle cell morphology. The tumors occurred in cervix (n = 1), and uterine corpus (n = 2). The patient ages were 30, 37 and 59 years with tumor size of 8.8, 10 and 8.6 cm, respectively. Morphologically all three tumors were characterized by distinct spindle/round cell morphology and various amounts of neuroectodermal differentiation (yolk sac-like tubules, blastomatous areas and rosette formation). Other morphologic features of DICER1-sarcoma reported in the literature including cambium layer, focal or diffuse anaplasia, solid and cystic architecture, and chondroid/osteoid areas were absent. All three sarcomas were positive for SALL4 and had variable neuroendocrine marker expression. Whole genome methylation analysis was performed on one of the uterine sarcomas, which clustered the tumor with embryonal tumor with multilayered rosettes. Follow up information was available on all three cases. Two patients were alive with no evidence of disease 13 and 14 months post operation, while one patient had imaging evidence of local recurrence 4 months post operation. In summary, we describe three unique DICER1-sarcomas and expand the phenotypic spectrum of this emerging entity, particularly with GYN-tract origin.
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PURPOSE: Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of PNST in cancer predisposition syndrome NF1. EXPERIMENTAL DESIGN: cfDNA was isolated from plasma samples of a novel cohort of 101 NF1 patients and 21 healthy controls and underwent whole genome sequencing. We investigated diagnosis-specific signatures of copy number alterations (CNA) with in silico size selection as well as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end-motifs, and fragment non-negative matrix factorization (NMF) signatures. RESULTS: The novel cohort of NF1 patients validated that our previous cfDNA CNA-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. CONCLUSIONS: Novel cfDNA fragmentomic signatures distinguish atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 and provides a blueprint for de-centralizing non-invasive cancer surveillance in hereditary cancer syndromes.
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Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.
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Granular cell tumors (GrCT) were recently found to be driven by inactivating mutations in vacuolar H + -ATPase (V-ATPase) genes, most frequently ATP6AP1 and ATP6AP2 . Multifocal presentation is present in ~10% of cases; however, the relationship between multifocal tumors in a given patient has not been elucidated. We hypothesized that benign-appearing multifocal GrCT are molecularly distinct whereas paired primary and metastatic malignant GrCT share identical mutations. To test this, we conducted targeted next-generation sequencing of the V-ATPase genes in multifocal GrCT and whole exome and Sanger sequencing in paired primary and metastatic malignant GrCT. Thirteen patients with≥2 GrCT were identified (total of 43 tumors). Forty-two tumors were successfully sequenced. Tumors showed somatic mutations in 3 of the 10 targeted genes in 32 of 42 samples (76%). Twenty tumors showed mutations in ATP6AP1 (48%), 10 tumors had mutations in ATP6AP2 (24%), and 2 tumors showed mutations in ATP6V0A4 (5%). Predicted loss-of-function mutations were found in ATP6AP1 in 17 tumors (40%), in ATP6AP2 in 10 tumors (24%), and in ATP6V0A4 in 1 tumor (2%). In 8 patients, mutually exclusive mutations were detected in at least 2 tumors per patient. Two patients were identified with malignant GrCT with material available from both primary and metastatic sites. Identical frameshift insertions were found in ATP6AP1 in 1 case and the second case showed identical nonsense mutations in ATP6AP1 . In conclusion, multifocal GrCT within an individual patient are molecularly distinct, while paired primary and metastatic GrCT share identical mutations.
Assuntos
Tumor de Células Granulares , ATPases Vacuolares Próton-Translocadoras , Humanos , Tumor de Células Granulares/genética , Mutação , Receptores de Superfície Celular , ATPases Vacuolares Próton-Translocadoras/genética , ATPases Vacuolares Próton-Translocadoras/metabolismo , Receptor de Pró-ReninaRESUMO
Biphenotypic sinonasal sarcoma (BSNS) is a rare low-grade malignancy occurring in the sinonasal tract that is characterized by dual neural and myogenic differentiation. Rearrangements involving the PAX3 gene, usually with MAML3, are a hallmark of this tumor type and their identification are useful for diagnosis. Rarely, a MAML3 rearrangement without associated PAX3 rearrangement has been described. Other gene fusions have not been previously reported. Herein, we report a 22 year-old woman with a BSNS harboring a novel gene fusion involving the PAX7 gene (specifically PAX7::PPARGC1A), which is a paralogue of PAX3. The histologic features of the tumor were typical with two exceptions: a lack of entrapment of surface respiratory mucosa and no hemangiopericytoma-like vasculature. Immunophenotypically, the tumor was notably negative for smooth muscle actin, which is usually positive in BSNS. However, the classic S100 protein-positive, SOX10-negative staining pattern was present. In addition, the tumor was positive for desmin and MyoD1 but negative for myogenin, a pattern that is common among BSNS with variant fusions. Awareness of the possibility of PAX7 gene fusions in BSNS is important as it may aid in the diagnosis of PAX3 fusion negative tumors.
Assuntos
Neoplasias dos Seios Paranasais , Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Adulto Jovem , Adulto , Fator de Transcrição PAX3/genética , Imuno-Histoquímica , Neoplasias dos Seios Paranasais/patologia , Sarcoma/patologia , Fusão Gênica , Fator de Transcrição PAX7/genéticaRESUMO
PURPOSE: Soft tissue sarcomas (STS) are rare mesenchymal neoplasms that frequently show complex chromosomal aberrations such as amplifications or deletions of DNA sequences or even whole chromosomes. We recently found that gain of chromosome (chr) 8 is associated with worse overall survival (OS) in STS as a group. We therefore aimed to investigate the overall copy number profile of rhabdomyosarcoma (RMS) to evaluate for prognostic signatures. METHODS: Fluorescence in situ hybridization (FISH) testing was performed on a cohort of STS to assess for chr8 gain. Copy number variation (CNV) data from the National Cancer Institute were analyzed to assess for prognostically significant CNV aberrations in FOXO1 fusion-negative (FN)- versus fusion-positive (FP)-RMS. FISH testing was performed on a cohort of FN-RMS to assess for chr3q loss and correlate with outcomes. RESULTS: Chr8 gain is a highly prevalent CNV in embryonal RMS and shows slightly improved prognosis. Meanwhile, loss of chr3q was associated with worse outcome in FN-RMS compared with FP-RMS. CONCLUSION: The pathogenesis of STS including FN-RMS remains poorly understood, emphasizing the need for new therapeutic advances and adequate risk stratification. Our data demonstrate that loss of chr3q is associated with poor OS in FN-RMS, supporting it as an important tool for risk stratification.