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2.
Surg Pathol Clin ; 17(1): 1-12, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38278599

RESUMO

Superficial CD34-positive fibroblastic tumor is a mesenchymal neoplasm of "intermediate malignancy" recently included in the fifth edition of the World Health Organization classification of soft tissue and bone tumors. In this review, we summarize the current knowledge on this rare entity with a special focus on its clinicopathological features, morphologic spectrum, and differential diagnosis. We also provide data regarding recent discoveries on its molecular profile and discuss its prognosis and management.


Assuntos
Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias de Tecidos Moles , Humanos , Antígenos CD34 , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/diagnóstico , Diagnóstico Diferencial , Biomarcadores Tumorais
3.
Int J Gynecol Pathol ; 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38289183

RESUMO

Pathogenic variants (mutations) and other molecular events involving subunits of the SWItch/Sucrose Non-Fermentable chromatin remodelling complex are common in a wide variety of malignancies. Many of these neoplasms are characterized by undifferentiated morphology. They arise at a variety of sites in the female genital tract but have rarely been reported in the uterine cervix. We report 2 primary cervical neoplasms arising in young women (ages 28 and 29 yr) exhibiting loss of nuclear immunoreactivity with SMARCB1 (INI1). In one case, which had a mixture of epithelioid and spindle cells, molecular studies revealed no SMARCB1 pathogenic variant, but showed a SPECCL1::NTRK 3 fusion, in keeping with an NTRK fusion sarcoma. The second case exhibited rhabdoid morphology and molecular testing confirmed a SMARCB1 pathogenic variant (c.425 T>G:p.(Leu142Ter) which, interpreted in conjunction with the morphology and immunohistochemistry, resulted in classification as a proximal-type epithelioid sarcoma. To our knowledge, this is the first reported cervical neoplasm exhibiting a SMARCB1 pathogenic variant and the first NTRK fusion sarcoma showing SMARCB1 protein loss. We discuss the diagnostic challenges and complexities of the molecular findings.

4.
Histopathology ; 84(3): 451-462, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37988282

RESUMO

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.


Assuntos
Neoplasias do Endométrio , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Sarcoma do Estroma Endometrial , Sarcoma , Neoplasias de Tecidos Moles , Feminino , Humanos , Biomarcadores Tumorais/genética , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Proteínas de Fusão Oncogênica/genética , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patologia , Receptor trkA
5.
NPJ Precis Oncol ; 7(1): 71, 2023 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-37488222

RESUMO

Risk assessment of gastrointestinal stromal tumor (GIST) according to the AFIP/Miettinen classification and mutational profiling are major tools for patient management. However, the AFIP/Miettinen classification depends heavily on mitotic counts, which is laborious and sometimes inconsistent between pathologists. It has also been shown to be imperfect in stratifying patients. Molecular testing is costly and time-consuming, therefore, not systematically performed in all countries. New methods to improve risk and molecular predictions are hence crucial to improve the tailoring of adjuvant therapy. We have built deep learning (DL) models on digitized HES-stained whole slide images (WSI) to predict patients' outcome and mutations. Models were trained with a cohort of 1233 GIST and validated on an independent cohort of 286 GIST. DL models yielded comparable results to the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in cross-validation and 0.72 for independent testing). DL splitted Miettinen intermediate risk GIST into high/low-risk groups (p value = 0.002 in the training set and p value = 0.29 in the testing set). DL models achieved an area under the receiver operating characteristic curve (AUC) of 0.81, 0.91, and 0.71 for predicting mutations in KIT, PDGFRA and wild type, respectively, in cross-validation and 0.76, 0.90, and 0.55 in independent testing. Notably, PDGFRA exon18 D842V mutation, which is resistant to Imatinib, was predicted with an AUC of 0.87 and 0.90 in cross-validation and independent testing, respectively. Additionally, novel histological criteria predictive of patients' outcome and mutations were identified by reviewing the tiles selected by the models. As a proof of concept, our study showed the possibility of implementing DL with digitized WSI and may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.

6.
Virchows Arch ; 483(2): 207-214, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37338620

RESUMO

Since the publication of the 2020 World Health Organization classification of soft tissue and bone tumors, the classification of "fibroblastic" tumors has expanded to include a novel subset of tumors characterized by PRRX1::NCOA1/2 gene fusions. These tumors defy conventional classification and are morphologically distinct, characterized by a multi-nodular growth of bland spindle cells suspended in a myxo-collagenous stroma with mild cytologic atypia, "staghorn-like" vessels, and variable perivascular hyalinization. Mitotic activity is rare, and necrosis is not identified. Herein, we present six additional cases of PRRX1-rearranged mesenchymal tumors, including five cases with PRRX1::NCOA1 fusion and one case with PRRX1::KMT2D fusion. Three cases (3/6, 50%) demonstrated focal co-expression of S100 protein and SOX10, thereby expanding the immunohistochemical profile of this emerging entity. Like prior reported cases, there was no evidence of malignant behavior on short-term follow-up. The novel fusion, PRRX1::KMT2D, further expands the molecular spectrum of this entity and leads to a proposed revision of the provisional nomenclature to "PRRX1-rearranged mesenchymal tumor" to both accommodate non-NCOA1/2 fusion partners and allow for the possibility of partial neural or neuroectodermal differentiation.


Assuntos
Neoplasias Ósseas , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias de Tecidos Moles , Humanos , Fusão Gênica , Proteínas S100 , Biomarcadores Tumorais/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Proteínas de Homeodomínio/genética
7.
Mod Pathol ; 36(10): 100243, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37307879

RESUMO

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.

8.
Am J Surg Pathol ; 47(7): 801-811, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37170907

RESUMO

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.


Assuntos
Biomarcadores Tumorais , Tumores de Células Gigantes , Masculino , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Tumores de Células Gigantes/patologia , Imuno-Histoquímica , Osso e Ossos/patologia , Epigênese Genética , Correpressor 2 de Receptor Nuclear/genética
9.
Histopathology ; 82(4): 596-607, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36413100

RESUMO

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.


Assuntos
Fibrossarcoma , Neoplasias , Neoplasias de Tecidos Moles , Criança , Adulto , Humanos , Receptor trkA/genética , Metilação , Neoplasias/patologia , Neoplasias de Tecidos Moles/genética , Fibrossarcoma/genética , RNA , Proteínas de Fusão Oncogênica/genética
11.
Mod Pathol ; 35(5): 649-663, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35075283

RESUMO

Morphological, immunohistochemical, and molecular methods often need to be combined for accurate diagnosis and optimal clinical management of sarcomas. Here, we have developed, a new molecular diagnostic assay, for the detection of gene fusions in sarcomas. This targeted multiplexed next-generation sequencing (NGS)-based method utilizes ligation dependent reverse-transcriptase polymerase chain reaction (LD-RT-PCR-NGS) to detect oncogenic fusion transcripts involving 137 genes, leading to 139 gene fusions known to be recurrently rearranged in soft-tissue and bone tumors. 158 bone and soft-tissue tumors with previously identified fusion genes by fluorescent in situ hybridization (FISH) or RT-PCR were selected to test the specificity and the sensitivity of this assay. RNA were extracted from formalin-fixed paraffin-embedded (n = 143) or frozen (n = 15) material (specimen; n = 42 or core needle biopsies; n = 116). Tested tumors encompassed 23 major translocation-related sarcomas types, including Ewing and Ewing-like sarcomas, rhabdomyosarcomas, desmoplastic small round-cell tumors, clear-cell sarcomas, infantile fibrosarcomas, endometrial stromal sarcomas, epithelioid hemangioendotheliomas, alveolar soft-part sarcomas, biphenotypic sinonasal sarcomas, extraskeletal myxoid chondrosarcomas, myxoid/round-cell liposarcomas, dermatofibrosarcomas protuberans and solitary fibrous tumors. In-frame fusion transcripts were detected in 98.1% of cases (155/158). Gene fusion assay results correlated with conventional techniques (FISH and RT-PCR) in 155/158 tumors (98.1%). These data demonstrate that this assay is a rapid, robust, highly sensitive, and multiplexed targeted RNA sequencing assay for the detection of recurrent gene fusions on RNA extracted from routine clinical specimens of sarcomas (formalin-fixed paraffin-embedded or frozen). It facilitates the precise diagnosis and identification of tumors with potential targetable fusions. In addition, this assay can be easily customized to cover new fusions.


Assuntos
Neoplasias do Endométrio , Sarcoma , Neoplasias de Tecidos Moles , Neoplasias do Endométrio/genética , Feminino , Formaldeído , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Hibridização in Situ Fluorescente/métodos , Proteínas de Fusão Oncogênica/genética , RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma/genética , Sarcoma/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
12.
Int J Gynecol Pathol ; 41(4): 370-377, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34570014

RESUMO

We report a unique primary cervical neoplasm in a 44-yr-old woman which we believe, based on the morphology and immunophenotype, represents an extremely unusual small cell variant of paraganglioma. This represents the first report of a primary cervical paraganglioma. Following chemoradiation treatment, the tumor underwent malignant transformation into an S100 and SOX10 positive sarcoma, morphologically and immunohistochemically resembling a malignant peripheral nerve sheath tumor, which we believe represents a sarcoma derived from the sustentacular cells of the paraganglioma. Mutational analysis detected a nonsense mutation of NF1 gene in the sarcoma. This further supports the diagnosis as both somatic and germline NF1 mutations have been associated with paragangliomas and malignant peripheral nerve sheath tumors. Targeted RNA sequencing (ARCHER, expanded sarcoma panel) covering many known genes implicated in sarcoma development, did not reveal any other molecular alteration (fusion or internal tandem duplication).


Assuntos
Paraganglioma , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Feminino , Mutação em Linhagem Germinativa , Humanos , Paraganglioma/genética , Sarcoma/diagnóstico , Sarcoma/genética
13.
Genes Chromosomes Cancer ; 60(3): 147-159, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33099837

RESUMO

The landscape of uterine sarcomas has greatly expanded in recent years to include neoplasms with recurrent gene fusions, such as BCOR and YWHAE translocated high-grade endometrial stromal sarcomas. Sophisticated molecular techniques have also resulted in the description of "new" entities associated with recurrent kinase fusions involving NTRK and RET as well as COL1A1-PDGFB rearranged uterine sarcomas. These rare neoplasms will be discussed in this review, highlighting that some of the underlying molecular events are clinically actionable and potentially susceptible to targeted therapy. While relatively few of these neoplasms have been described to date, likely being previously lumped under the spectrum of undifferentiated uterine sarcoma, the number of cases will expand in the future given their recognition and the increasing availability of molecular testing. These neoplasms have overlapping morphology (often with a "fibrosarcoma-like" appearance) and immunohistochemical features, and are characterized by variable clinical outcomes. Although immunohistochemistry may assist in some cases, a definitive subclassification requires confirmatory molecular studies. As these molecular assays may not be routinely available in most laboratories, referral to reference centers may be needed. In order to assist the pathologist, we suggest a diagnostic algorithm for routine practice when dealing with a malignant or potentially malignant uterine spindle cell neoplasm.


Assuntos
Receptor trkA/metabolismo , Sarcoma/metabolismo , Neoplasias Uterinas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cadeia alfa 1 do Colágeno Tipo I/genética , Feminino , Fusão Gênica/genética , Rearranjo Gênico , Genes sis , Humanos , Imuno-Histoquímica , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Receptor trkA/genética , Sarcoma/enzimologia , Sarcoma/genética , Sarcoma do Estroma Endometrial/enzimologia , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/metabolismo , Neoplasias de Tecidos Moles/genética
14.
Am J Surg Pathol ; 43(6): 747-754, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30829729

RESUMO

Biphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor.


Assuntos
Biomarcadores Tumorais , Cavidade Nasal , Neoplasias dos Seios Paranasais , Seios Paranasais , Sarcoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Diferenciação Celular , Feminino , Fusão Gênica , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteína MyoD/análise , Cavidade Nasal/química , Cavidade Nasal/patologia , Coativador 2 de Receptor Nuclear/genética , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição PAX3/genética , Fatores de Transcrição Box Pareados/genética , Neoplasias dos Seios Paranasais/química , Neoplasias dos Seios Paranasais/genética , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/terapia , Seios Paranasais/química , Seios Paranasais/patologia , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Sarcoma/química , Sarcoma/genética , Sarcoma/patologia , Sarcoma/terapia , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
15.
Mod Pathol ; 32(7): 1008-1022, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30877273

RESUMO

Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:- an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.


Assuntos
Colágeno Tipo I/genética , Fibrossarcoma/diagnóstico , Proteínas Proto-Oncogênicas c-sis/genética , Neoplasias Uterinas/diagnóstico , Neoplasias Vaginais/diagnóstico , Adulto , Idoso de 80 Anos ou mais , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Fibrossarcoma/genética , Fibrossarcoma/patologia , Rearranjo Gênico , Humanos , Pessoa de Meia-Idade , Fusão Oncogênica , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Vaginais/genética , Neoplasias Vaginais/patologia , Adulto Jovem
16.
Thyroid ; 27(5): 682-692, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28351340

RESUMO

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations. METHODS AND MATERIALS: One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened. RESULTS: Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest. CONCLUSION: This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.


Assuntos
Receptores Proteína Tirosina Quinases/genética , Telomerase/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Patologia Molecular , Fosfatidilinositol 3-Quinases/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Transdução de Sinais/genética , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia
17.
J Hematol Oncol ; 10(1): 45, 2017 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-28179005

RESUMO

Previous precision medicine studies have investigated conventional molecular techniques and/or limited sets of gene alterations. The aim of this study was to describe the impact of the next-generation sequencing of the largest panel of genes used to date in tumour tissue and blood in the context of institutional molecular screening programmes. DNA analysis was performed by next-generation sequencing using a panel of 426 cancer-related genes and by comparative genomic hybridization from formalin-fixed and paraffin-embedded archived tumour samples when available or from fresh tumour samples. Five hundred sixty-eight patients were enrolled. The median number of prior lines of treatment was 2 (range 0-9). The most common primary tumour types were lung (16.9%), colorectal (14.4%), breast (10.6%), ovarian (10.2%) and sarcoma (10.2%). The median patient age was 63 years (range 19-88). A total of 292 patients (51.4%) presented with at least one actionable genetic alteration. The 20 genes most frequently altered were TP53, CDKN2A, KRAS, PTEN, PI3KCA, RB1, APC, ERBB2, MYC, EGFR, CDKN2B, ARID1A, SMAD4, FGFR1, MDM2, BRAF, ATM, CCNE1, FGFR3 and FRS2. One hundred fifty-nine patients (28%) were included in early phase trials. The treatment was matched with a tumour profile in 86 cases (15%). The two main reasons for non-inclusion were non-progressive disease (31.5%) and general status deterioration (25%). Twenty-eight percent of patients presented with a growth modulation index (time to progression under the early phase trial treatment/time to progression of the previous line of treatment) >1.3.Extensive molecular profiling using high-throughput techniques allows for the identification of actionable mutations in the majority of cases and is associated with substantial clinical benefit in up to one in four patients.


Assuntos
Hibridização Genômica Comparativa , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Dosagem de Genes , Fusão Gênica , Humanos , Pessoa de Meia-Idade , Mutação , Medicina de Precisão/métodos , Análise de Sequência de DNA , Adulto Jovem
18.
Int J Gynecol Pathol ; 35(4): 301-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26598979

RESUMO

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm which morphologically and immunohistochemically exhibits overlap with an ovarian sex cord tumor. Although many of these neoplasms are positive with markers of ovarian sex cord-stromal tumors, staining is often limited and the pathogenesis of UTROSCT is unknown. To further explore the sex cord lineage of UTROSCT, we studied 19 of these neoplasms and examined the expression of 2 recently described markers of ovarian sex cord-stromal tumors, FOXL2, and steroidogenic factor-1. We also undertook FOXL2 and DICER1 mutation analysis in these cases; a somatic missense mutation in codon C134W (402C→G) of FOXL2 gene has been demonstrated in the vast majority (>95%) of ovarian adult granulosa cell tumors and somatic DICER1 mutations are found in approximately 60% of ovarian Sertoli-Leydig cell tumors. Ten of 19 cases (53%) exhibited nuclear immunoreactivity with FOXL2 and 11 of 19 (58%) exhibited nuclear staining with steroidogenic factor-1. Neither FOXL2 nor DICER1 mutations were identified in any case where there was sufficient tumor tissue for analysis (18 and 9 cases, respectively). Despite exhibiting an immunophenotype characteristic of a sex cord-stromal tumor, mutations in FOXL2 and DICER1, the 2 most common mutations hitherto reported in ovarian sex cord-stromal tumors, are not a feature of UTROSCT.


Assuntos
RNA Helicases DEAD-box/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Tumor de Células da Granulosa/genética , Neoplasias Ovarianas/genética , Ribonuclease III/metabolismo , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Neoplasias Uterinas/genética , Adulto , RNA Helicases DEAD-box/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Proteína Forkhead Box L2 , Fatores de Transcrição Forkhead/genética , Tumor de Células da Granulosa/diagnóstico , Tumor de Células da Granulosa/metabolismo , Tumor de Células da Granulosa/patologia , Humanos , Imuno-Histoquímica , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ribonuclease III/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/metabolismo , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Útero/metabolismo , Útero/patologia
19.
Virchows Arch ; 468(3): 369-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26666421

RESUMO

Desmoid type fibromatosis (DT) is a rare lesion of unclear pathogenesis that most often presents a mutation of the (ß-catenin) gene. The natural history and clinical evolution are highly variable between patients and to date there is no consensus on optimal therapy. We report two cases of a patient with multiple DT lesions. Molecular investigations performed in both patients on multiple tumors at different anatomical sites revealed non-identical CTNNB1 mutations. The first patient was a 39-year-old man with a history of recurrent DT. In two of the DT lesions, three different mutations were found in codons 41 and 45, respectively. The lesions showed marked inflammatory features, characterized by IgG4 positive lymphoplasmacytic infiltrates and a foreign body reaction, which increased in intensity over time. The patient was eventually treated with a COX-2 inhibitor and the remaining mass was stabilized. In the two DT lesions of the second patient, CTNNB1 mutations S45P and T41A were found. The presence of different mutations in multiple focally recurrent sporadic DT lesions indicates that they do not have a clonal relationship. Our data suggest that a CTNNB1 mutation is a necessary event probably by providing a selective growth advantage. An IgG4 host antigen response is discussed as a potential predisposing factor for one of the patients.


Assuntos
Fibromatose Agressiva/genética , Heterogeneidade Genética , Predisposição Genética para Doença , Mutação/genética , beta Catenina/genética , Adulto , Idoso , Núcleo Celular/patologia , Códon/metabolismo , Feminino , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , beta Catenina/metabolismo
20.
PLoS One ; 10(10): e0137794, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26427052

RESUMO

Nutlin inhibits TP53-MDM2 interaction and is under investigation in soft-tissue sarcomas (STS) and other malignancies. Molecular mechanisms of secondary resistance to nutlin in STS are unknown. We performed whole-transcriptome sequencing (RNA-seq) on three pretreatment and secondary resistant STS cell lines selected based on their high primary sensitivity to nutlin. Our data identified a subset of cancer gene mutations and ploidy variations that were positively selected following treatment, including TP53 mutations in 2 out of 3 resistant cell lines. Further, secondary resistance to nutlin was associated with deregulation of apoptosis-related genes and marked productive autophagy, the inhibition of which resulted in significant restoration of nutlin-induced cell death. Collectively, our findings argue that secondary resistance to nutlin in STS involved heterogeneous mechanisms resulting from clonal evolution and several biological pathways. Alternative dosing regimens and combination with other targeted agents are needed to achieve successful development of nutlin in the clinical setting.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Imidazóis/farmacologia , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Clonais/efeitos dos fármacos , Células Clonais/patologia , Perfilação da Expressão Gênica , Humanos , Mutação , Ploidias , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirrolidinas/farmacologia , Sarcoma/genética , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , para-Aminobenzoatos/farmacologia
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