RESUMO
Soft tissue tumors are a very heterogeneous group of tumors. Their classification is regularly updated by the World Health Organization (WHO), most recently in 2020. The current classification of soft tissue tumors emphasizes molecular biological tumor characteristics, which enable tumor-specific treatment. In addition to Ewing's sarcoma, which occurs as bone as well as extra-skeletal soft tissue tumors as a small round cell sarcoma, three other subtypes of undifferentiated, small and round cell sarcomas have been introduced. Some names of the new sarcomas can be derived from the gene mutations. The groups of adipocytic and (myo)fibroblastic tumors have been extended by three further entities. There were further additions to vascular soft tissue tumors, smooth muscle cell tumors, peripheral nerve sheath tumors and tumors of uncertain differentiation. A distinction is made between benign, intermediate locally aggressive, intermediate rarely metastatic and malignant soft tissue tumors.
Assuntos
Neoplasias de Tecidos Moles , Humanos , Neoplasias de Tecidos Moles/classificação , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/genética , Sarcoma/classificação , Sarcoma/patologia , Sarcoma/genética , Organização Mundial da SaúdeRESUMO
The most common and aggressive tumor is brain malignancy, which has a short life span in the fourth grade of the disease. As a result, the medical plan may be a crucial step toward improving the well-being of a patient. Both diagnosis and therapy are part of the medical plan. Brain tumors are commonly imaged with magnetic resonance imaging (MRI), positron emission tomography (PET), and computed tomography (CT). In this paper, multimodal fused imaging with classification and segmentation for brain tumors was proposed using the deep learning method. The MRI and CT brain tumor images of the same slices (308 slices of meningioma and sarcoma) are combined using three different types of pixel-level fusion methods. The presence/absence of a tumor is classified using the proposed Tumnet technique, and the tumor area is found accordingly. In the other case, Tumnet is also applied for single-modal MRI/CT (561 image slices) for classification. The proposed Tumnet was modeled with 5 convolutional layers, 3 pooling layers with ReLU activation function, and 3 fully connected layers. The first-order statistical fusion metrics for an average method of MRI-CT images are obtained as SSIM tissue at 83%, SSIM bone at 84%, accuracy at 90%, sensitivity at 96%, and specificity at 95%, and the second-order statistical fusion metrics are obtained as the standard deviation of fused images at 79% and entropy at 0.99. The entropy value confirms the presence of additional features in the fused image. The proposed Tumnet yields a sensitivity of 96%, an accuracy of 98%, a specificity of 99%, normalized values of the mean of 0.75, a standard deviation of 0.4, a variance of 0.16, and an entropy of 0.90.
Assuntos
Neoplasias Encefálicas , Aprendizado Profundo , Imageamento por Ressonância Magnética , Meningioma , Imagem Multimodal , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/classificação , Imageamento por Ressonância Magnética/métodos , Meningioma/diagnóstico por imagem , Meningioma/patologia , Meningioma/classificação , Imagem Multimodal/métodos , Tomografia Computadorizada por Raios X/métodos , Sarcoma/diagnóstico por imagem , Sarcoma/patologia , Sarcoma/classificação , Processamento de Imagem Assistida por Computador/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Redes Neurais de Computação , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/classificaçãoRESUMO
BACKGROUND: Definition of histologic subtype of malignant pleural mesothelioma (MPM) is important for management of patients, because surgical treatment improves prognosis for patients with epithelioid but not biphasic or sarcomatoid MPM. In a series of necropsies performed in a hospital specialized for MPM diagnosis, we retrospectively investigated the accuracy of histologic diagnosis performed on pathologic specimens collected through pleural biopsies obtained at video-assisted thoracoscopic surgery (VATS) or surgery. METHODS: We reviewed histologic records of an unselected series of autopsies performed in patients with MPM employed in the Monfalcone shipyards (Northeast Italy) or living with shipyard workers from 1999 through 2017. Using necropsy results as a gold standard, we calculated sensitivity, specificity, and positive and negative predictive values of histology from VATS or surgery after combining nonepithelioid subtypes. RESULTS: We retrieved necropsy records for 134 patients: 62 (46.3%) with epithelioid, 51 (38.1%) with biphasic, and 21 (15.7%) with sarcomatoid MPM. We observed good sensitivity of VATS (0.94) and surgery (0.89) in diagnosing epithelioid MPM. Conversely, specificity was low (VATS: 0.46; surgery: 0.32). Therefore, positive predictive values were also low (VATS: 0.58; surgery: 0.60). Misclassification was particularly high for biphasic MPM (three-fourths of biphasic MPM at necropsy had been classified as epithelioid at VATS or surgery). CONCLUSIONS: We observed a substantial degree of misclassification between epithelioid and biphasic MPM for pleural biopsies performed during VATS. Our results suggest caution should be taken in using histologic subtype obtained from VATS in selecting patients with MPM for surgical treatment. We also observed substantial misclassification of biospecimens collected during MPM surgery.
Assuntos
Mesotelioma Maligno/diagnóstico , Neoplasias Pleurais/diagnóstico , Sarcoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Biópsia , Feminino , Humanos , Itália/epidemiologia , Masculino , Mesotelioma Maligno/classificação , Mesotelioma Maligno/patologia , Mesotelioma Maligno/cirurgia , Pessoa de Meia-Idade , Pleura/diagnóstico por imagem , Pleura/patologia , Neoplasias Pleurais/classificação , Neoplasias Pleurais/patologia , Neoplasias Pleurais/cirurgia , Prognóstico , Estudos Retrospectivos , Sarcoma/classificação , Sarcoma/patologia , Sarcoma/cirurgia , Cirurgia Torácica VídeoassistidaRESUMO
Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a rare subtype of rhabdomyosarcoma (RMS) that has fascicular spindle cell and/or sclerosing morphology. SsRMS has a diverse molecular background and is categorized into three groups: congenital/infantile ssRMS with a gene fusion involving the NCOA2 and VGLL2, ssRMS with the MYOD1 mutation, and ssRMS with no recurrent identifiable genetic alterations. Because ssRMS is a newly defined disease concept of RMS, the optimal treatment methods have not been determined. This results in unfavorable prognosis and consequently signals the urgent need for continuous research. Patient-derived cell lines are essential tools in basic and translational research. However, only two ssRMS cell lines with the MYOD1 mutation have been reported to date. Thus, we established a novel ssRMS cell line named NCC-ssRMS2-C1 using a surgically resected tumor tissue from an adult ssRMS patient. NCC-ssRMS2-C1 cells retained the copy number alterations corresponding to the original tumor and are categorized into the group with no recurrent identifiable genetic alterations. NCC-ssRMS2-C1 cells demonstrated constant proliferation, spheroid formation, and capability for invasion in vitro, reflecting the malignant features of the original tumor tissue. In a drug screening test, ssRMS demonstrated remarkable sensitivity to romidepsin, trabectedin, actinomycin D, and bortezomib. Hence, we conclude that the NCC-ssRMS2-C1 cell line is the first ssRMS cell line which belongs to the group with no recurrent identifiable genetic alterations, and it will be a useful resource in both basic and translational studies for ssRMS.
Assuntos
Neoplasias de Cabeça e Pescoço , Rabdomiossarcoma , Sarcoma , Adulto , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Linhagem Celular Tumoral , Dactinomicina/farmacologia , Depsipeptídeos/farmacologia , Fusão Gênica , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Proteínas Musculares/genética , Mutação , Proteína MyoD/genética , Coativador 2 de Receptor Nuclear/genética , Rabdomiossarcoma/classificação , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Sarcoma/classificação , Sarcoma/genética , Sarcoma/patologia , Trabectedina/farmacologia , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Primary sarcomas originating from the mobile spine portends a particularly sinister outcome. Rarity of the disease process has resulted in inconsistent data due to small sample size and heterogeneity in patient selection and analytics. METHODS: Surveillance, Epidemiology and End Result (SEER) database from 1975 to 2017 was queried to report incidence and survival data in 712 patients in the United States. Kaplan-Meier and Cox Regression were used to determine the prognostic factors affecting survival. RESULTS: Incidence of spinal sarcoma was 0.019 per 100,000 persons in 2017 and has not significantly changed since 2000 (p > 0.05). Disease-specific 5-year survival for the entire cohort was 57%. Osteosarcoma has the worst 5-year survival (39%) and chondrosarcoma has the best 5-year survival (69%). Independent predictors of survival for the entire cohort included age, grade, and stage. Stage was an independent predictor of survival for every histologic subtype. Additional predictors of survival for spinal osteosarcoma, Ewing sarcoma, and chondrosarcoma included age, size, and grade, respectively. CONCLUSIONS: The current study is an analysis of a population-based registry reporting incidence survival data for patients with sarcoma of mobile vertebral column. Survival and prognostic factors vary by histologic subtypes. There is lack of improvement in survival over the last three decades.
Assuntos
Programa de SEER/estatística & dados numéricos , Sarcoma/epidemiologia , Sarcoma/mortalidade , Coluna Vertebral/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prognóstico , Sarcoma/classificação , Sarcoma/patologia , Taxa de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Pediatric fibroblastic/myofibroblastic tumors (PFMTs) can be challenging to definitively classify. Large case series or diagnostic updates have not been recently published despite identification of molecular alterations that could improve diagnostic accuracy. Our review of the literature found that over two-thirds of the more than 30 types of PFMTs harbor recurrent molecular alterations. We performed an institutional review of PFMTs to highlight limitations of a predominantly morphological classification, and evaluated the utility of a next-generation sequencing assay to aid diagnosis. METHODS: PFMTs identified over a period of 12 years were reviewed, categorized per the new WHO classification, and tested using the Oncomine Childhood Cancer Research Assay. RESULTS: Eighty-seven specimens from 58 patients were reviewed; 50 were chosen for molecular analysis, 16 (32%) lacking definitive classification. We identified alterations, some novel, in 33% of assayed cases. Expected alterations were identified for most known diagnoses and mutations were identified in 6 of 16 tumors (38%) that were initially unclassified. CONCLUSION: We confirmed a significant subset of PFMTs remain difficult to classify using current criteria, and that a combined DNA/RNA assay can identify alterations in many of these cases, improving diagnostic certainty and suggesting a clinical utility for challenging cases.
Assuntos
Biomarcadores Tumorais/genética , Fibroma/genética , Granuloma de Células Plasmáticas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Miofibroma/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Adolescente , Criança , Pré-Escolar , Feminino , Fibroma/classificação , Fibroma/diagnóstico , Fibroma/patologia , Granuloma de Células Plasmáticas/classificação , Granuloma de Células Plasmáticas/diagnóstico , Granuloma de Células Plasmáticas/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Miofibroma/classificação , Miofibroma/diagnóstico , Miofibroma/patologia , Proteínas de Fusão Oncogênica/genética , Estudos Retrospectivos , Sarcoma/classificação , Sarcoma/diagnóstico , Sarcoma/patologia , Neoplasias de Tecidos Moles/classificação , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologia , Organização Mundial da SaúdeRESUMO
Diagnosing bone and soft tissue neoplasms remains challenging because of the large number of subtypes, many of which lack diagnostic biomarkers. DNA methylation profiles have proven to be a reliable basis for the classification of brain tumours and, following this success, a DNA methylation-based sarcoma classification tool from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg has been developed. In this study, we assessed the performance of their classifier on DNA methylation profiles of an independent data set of 986 bone and soft tissue tumours and controls. We found that the 'DKFZ Sarcoma Classifier' was able to produce a diagnostic prediction for 55% of the 986 samples, with 83% of these predictions concordant with the histological diagnosis. On limiting the validation to the 820 cases with histological diagnoses for which the DKFZ Classifier was trained, 61% of cases received a prediction, and the histological diagnosis was concordant with the predicted methylation class in 88% of these cases, findings comparable to those reported in the DKFZ Classifier paper. The classifier performed best when diagnosing mesenchymal chondrosarcomas (CHSs, 88% sensitivity), chordomas (85% sensitivity), and fibrous dysplasia (83% sensitivity). Amongst the subtypes least often classified correctly were clear cell CHSs (14% sensitivity), malignant peripheral nerve sheath tumours (27% sensitivity), and pleomorphic liposarcomas (29% sensitivity). The classifier predictions resulted in revision of the histological diagnosis in six of our cases. We observed that, although a higher tumour purity resulted in a greater likelihood of a prediction being made, it did not correlate with classifier accuracy. Our results show that the DKFZ Classifier represents a powerful research tool for exploring the pathogenesis of sarcoma; with refinement, it has the potential to be a valuable diagnostic tool.
Assuntos
Metilação de DNA/genética , Sarcoma/classificação , Biomarcadores Tumorais , Neoplasias Ósseas/classificação , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/patologia , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Classificação , Diagnóstico Diferencial , Perfilação da Expressão Gênica , Técnicas Genéticas , Humanos , Sarcoma/diagnóstico , Sarcoma/patologia , Neoplasias de Tecidos Moles/classificação , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/patologiaRESUMO
ABSTRACT: Soft tissue sarcomas (STSs) are heterogeneous at the clinical with a variable tendency of aggressive behavior. In this study, we constructed a specific DNA methylation-based classification to identify the distinct prognosis-subtypes of STSs based on the DNA methylation spectrum from the TCGA database. Eventually, samples were clustered into 4 subgroups, and their survival curves were distinct from each other. Meanwhile, the samples in each subgroup reflected differentially in several clinical features. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was also conducted on the genes of the corresponding promoter regions of the above-described specific methylation sites, revealing that these genes were mainly concentrated in certain cancer-associated biological functions and pathways. In addition, we calculated the differences among clustered methylation sites and performed the specific methylation sites with LASSO algorithm. The selection operator algorithm was employed to derive a risk signature model, and a prognostic signature based on these methylation sites performed well for risk stratification in STSs patients. At last, a nomogram consisted of clinical features and risk score was developed for the survival prediction. This study declares that DNA methylation-based STSs subtype classification is highly relevant for future development of personalized therapy as it identifies the prediction value of patient prognosis.
Assuntos
Metilação de DNA/genética , Nomogramas , Sarcoma/classificação , Neoplasias de Tecidos Moles/classificação , Algoritmos , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Humanos , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Sarcoma/genética , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/mortalidadeRESUMO
BACKGROUND: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. METHODS: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. RESULTS: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. CONCLUSIONS: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.
Assuntos
Sarcoma/epidemiologia , Sarcoma/patologia , Adolescente , Adulto , Idoso , Feminino , França/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Sarcoma/classificação , Sarcoma/diagnóstico , Organização Mundial da Saúde , Adulto JovemRESUMO
Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
Assuntos
Algoritmos , Neoplasias Ósseas/genética , Metilação de DNA , Aprendizado de Máquina , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Neoplasias Ósseas/classificação , Neoplasias Ósseas/diagnóstico , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Humanos , Internet , Reprodutibilidade dos Testes , Sarcoma/classificação , Sarcoma/diagnóstico , Sensibilidade e Especificidade , Neoplasias de Tecidos Moles/classificação , Neoplasias de Tecidos Moles/diagnósticoRESUMO
Soft tissue tumors are a relatively rare and diagnostically challenging group of neoplasms that can have varying lines of differentiation. Accurate diagnosis is important for appropriate treatment and prognostication. In the 8 years since the publication of the 4th Edition of World Health Organization (WHO) classification of soft tissue tumors, significant advances have been made in our understanding of soft tissue tumor molecular biology and diagnostic criteria. The 5th Edition of the 2020 WHO classification of tumors of soft tissue and bone incorporated these changes. Classification of tumors, in general, but particularly in soft tissue tumors, is increasingly based on the molecular characteristics of tumor types. Understanding tumor molecular genetics improves diagnostic accuracy for tumors that have been difficult to classify on the basis of morphology alone, or that have overlapping morphologic features. In many large hospitals in the United States and Europe, molecular tests on soft tissue tumors are a routine part of diagnosis. Therefore, surgical pathologists should be familiar with newly emerging molecular genetic techniques in clinical settings. In the near future, molecular tests, particularly in soft tissue tumor diagnosis, will become as routine during diagnosis as immunohistochemistry is currently. This new edition provides an updated classification scheme and essential diagnostic criteria for soft tissue tumors. Newly recognized entities and subtypes of existing tumor types, several reclassified tumors, and newly defined molecular and genetic data have been incorporated. Herein, we summarize the updates in the WHO 5th Edition, focusing on major changes in each category of soft tissue tumor, and the newly described tumor entities and subtypes.
Assuntos
Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Humanos , Imuno-Histoquímica , Sarcoma/classificação , Neoplasias de Tecidos Moles/classificação , Organização Mundial da SaúdeAssuntos
Sarcoma/genética , Adulto , Apolipoproteínas D , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Fusão Oncogênica , Sarcoma/classificação , Sarcoma/diagnóstico , Sarcoma/patologia , Neoplasias de Tecidos Moles , Coxa da Perna/patologia , Proteína GLI1 em Dedos de ZincoRESUMO
BACKGROUND: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) share clinical, pathological, immunohistochemical and molecular features, though PDS is associated with a more aggressive behavior. METHODS: We reviewed 71 tumors fulfilling criteria for AFX and PDS to further stratify their biological potential. RESULTS: Lesions were mainly located on the scalps of elderly men, and were often ulcerated. One case was necrotic, one showed vascular invasion, and one showed perineural invasion. Fifty-one tumors were limited to reticular dermis (71.8%), 20 invaded subcutaneous tissue, focally in 13 cases (18.3%), and diffusely in seven (9.9%). Subcutaneous invasion was present significantly more often in tumors showing predominantly spindle compared to pleomorphic/mixed cell morphology (P = 0.02). At a follow-up of 17-125 months, 4 cases recurred locally, 4, 6, 10 and 13 months after surgery; no metastases were observed. Three tumors were composed of spindle cells, and one of clear cells. Three cases had margins focally involved, while the fourth case had clear margins. CONCLUSION: Depth of invasion and state of margins are criteria predicting prognosis in AFX/PDS; in addition, spindle cell morphology seems to be related to a more infiltrative pattern of growth and to aggressiveness. Grouping these tumors on a morphologic base could help to clarify their different biological behavior.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias de Cabeça e Pescoço , Sarcoma , Neoplasias Cutâneas , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma/classificação , Sarcoma/diagnóstico , Sarcoma/metabolismo , Sarcoma/patologia , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Although diagnosis of high-grade uterine mesenchymal tumors (UMTs) exhibiting classic morphologic features is straightforward, diagnosis is more challenging in tumors in which prototypical features are poorly developed, focal, and/or coexist with features seen in other neoplasms. Here, we sought to define the repertoire of somatic genetic alterations in diagnostically challenging UMTs with myomelanocytic differentiation, including some reported as perivascular epithelioid cell tumors (PEComas). In 17 samples from 15 women, the tumors were histologically heterogenous. Immunohistochemical expression of at least 1 melanocytic marker (HMB45, Melan-A, or MiTF) was identified in all tumors, and of myogenic markers (desmin or smooth muscle actin) in most tumors. Targeted massively parallel sequencing revealed several genetic alterations, most commonly in TP53 (41% mutation, 12% deletion), TSC2 (29% mutation, 6% deletion), RB1 (18% deletion), ATRX (24% mutation), MED12 (12% mutation), BRCA2 (12% deletion), CDKN2A (6% deletion) as well as FGFR3, NTRK1, and ERBB3 amplification (each 6%). Gene rearrangements (JAZF1-SUZ12; DNAJB6-PLAG1; and SFPQ-TFE3) were identified in 3 tumors. Integrating histopathologic, immunohistochemical, and genetic findings, tumors from 4 patients were consistent with malignant PEComa (1 TFE3-rearranged); 6 were classified as leiomyosarcomas; 3 showed overlapping features of PEComa and other sarcoma types (leiomyosarcoma or low-grade endometrial stromal sarcoma); and 2 were classified as sarcoma, not otherwise specified. Our findings suggest that diagnostically challenging UMTs with myomelanocytic differentiation represent a heterogenous group of neoplasms which harbor a diverse repertoire of somatic genetic alterations; these genetic alterations can aid classification.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias de Células Epitelioides Perivasculares/diagnóstico , Sarcoma/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias de Células Epitelioides Perivasculares/classificação , Neoplasias de Células Epitelioides Perivasculares/genética , Sarcoma/classificação , Sarcoma/genética , Neoplasias Uterinas/classificação , Neoplasias Uterinas/genéticaRESUMO
OBJECTIVE: To identify which classification systems have been used for tumor margin reporting and to determine whether factors (publication year, tumor type, and specialty of the contributing authors) influenced trends in margin reporting within literature describing canine soft tissue sarcoma (STS) and cutaneous mast cell tumors (MCT). STUDY DESIGN: Systematic literature review. METHODS: Eligible articles were identified through electronic database searches performed for STS and MCT. Data abstracted from relevant studies included publication year, author list, specialty of contributing authors, criteria used to report the planned surgical margins, and the status of histologic margins. Categorization of papers was based on the classification systems used to report surgical and histologic tumor margins. RESULTS: Fifty-three articles were included, 11 on STS, 37 on MCT, and five that included both tumor types. Criteria for classifying the planned surgical margins were described in only 50.9% of studies. Articles that listed a veterinary surgeon as a contributing author (P = .01) and STS articles compared to MCT papers (P = .01) were more likely to report surgical margins. Most (56.6%) studies reported the status of histologic margins dichotomously as "complete" or "incomplete." Although a previously published consensus statement recommended that quantitative criteria be used to report histologic margins, only 7.5% of articles used quantitative methods. CONCLUSION: Classification systems used for reporting tumor margins were highly variable among studies. CLINICAL SIGNIFICANCE: The findings of this review provide evidence that a standardized classification system for reporting surgical and histologic tumor margins is required in veterinary medicine. A universal system may support more consistent reporting of neoplastic biopsy specimens and allow for more meaningful comparisons across research studies.
Assuntos
Doenças do Cão/cirurgia , Margens de Excisão , Sarcoma/veterinária , Neoplasias de Tecidos Moles/veterinária , Animais , Doenças do Cão/classificação , Cães , Sarcoma/classificação , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/classificação , Neoplasias de Tecidos Moles/cirurgiaAssuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Imunoterapia , Doenças Raras , Sarcoma/classificação , Neoplasias de Tecidos Moles/classificação , Resultado do TratamentoRESUMO
Sarcomas constitute a rare heterogeneous group of tumors, including a wide variety of histological subtypes. Despite advances in our understanding of the pathophysiology of the disease, first-line sarcoma treatment options are still limited and new treatment approaches are needed. Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development. In this study, we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein, an inducer of DNA damage through ROS increase, as prognostic biomarkers in sarcoma tumors. Next, we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers. We evaluate retrospectively the levels of pH2AX (Ser139) and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features. We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival. Next, we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma. We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro, inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation, as a result of DNA damage. The synergism was corroborated in patient-derived xenografts (PDX) where the combination was effective in tumors with high levels of pH2AX and MAP17, suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Histonas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Sarcoma , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Ftalazinas/farmacologia , Piperazinas/farmacologia , Prognóstico , Sarcoma/classificação , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológico , Sarcoma/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OPINION STATEMENT: The diagnosis of round cell sarcomas has changed rapidly over the last decade, causing much diagnostic confusion for pathologists and oncologists. The advances in diagnosis are largely due to the advent of next-generation sequencing techniques, which allowed the recognition of novel gene fusions in round cell sarcomas. The new 5th edition of the WHO Classification of Tumors of Soft Tissue and Bone recognizes four subgroups of undifferentiated round cell sarcomas: Ewing sarcoma, CIC-rearranged sarcomas, BCOR-altered sarcomas, and sarcomas with EWSR1-non-ETS fusions, in addition to desmoplastic small round cell tumor. This classification is based on a variety of publications showing that each of these molecular subtypes has unique clinical and prognostic characteristics distinct from Ewing sarcoma, therefore supporting the validity of recognizing these as discrete diagnostic entities. Despite our improved ability to diagnose these new round cell sarcomas, there remains confusion on how best to identify and treat these tumors. However, several key clinicopathologic features can point the physician toward the correct diagnosis. The goal of the following article is to emphasize the key clinical, pathologic, molecular, and prognostic differences between Ewing sarcoma and these non-Ewing round cell malignancies to improve recognition of these rare diseases.
Assuntos
Neoplasias Ósseas/diagnóstico , Tumor Desmoplásico de Pequenas Células Redondas/diagnóstico , Sarcoma de Ewing/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Tumor Desmoplásico de Pequenas Células Redondas/genética , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Tumor Desmoplásico de Pequenas Células Redondas/terapia , Rearranjo Gênico , Humanos , Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma/classificação , Sarcoma/genética , Sarcoma/patologia , Sarcoma/terapia , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Sarcoma de Ewing/terapia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapiaRESUMO
Canine liposarcoma is classified as well differentiated (WDL), dedifferentiated (DDL), myxoid (ML), and pleomorphic (PL). Overexpression of the protooncogene MDM2 has been reported in WDL and DDL, but little is known regarding the role of p53 in their tumorigenesis. The aim of this study was to assess p53 expression in canine liposarcoma and compare it with subtype, grade, mitotic count (MC), Ki67 labeling index (LI), and MDM2 expression. Forty-seven cases were included (13 WDL, 3 DDL, 7 ML, and 24 PL); 17 were MDM2-positive (13 WDL, 3DDL, and 1ML). Five were p53-positive (4 ML and 1 WDL) but DDL and PL were consistently negative. p53 expression correlated with higher Ki67-LI, higher MC, and myxoid histotype. No correlation was found with grade and MDM2 expression. Based on these results canine liposarcoma seems to embody a group of neoplasms whose subtypes, especially ML, may represent distinct diseases rather than morphological variants of the same entity.
Assuntos
Biomarcadores Tumorais/metabolismo , Doenças do Cão/classificação , Lipossarcoma/veterinária , Sarcoma/veterinária , Proteína Supressora de Tumor p53/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Transformação Celular Neoplásica , Doenças do Cão/patologia , Cães , Imuno-Histoquímica/veterinária , Antígeno Ki-67/metabolismo , Lipossarcoma/classificação , Lipossarcoma/patologia , Índice Mitótico , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Sarcoma/classificação , Sarcoma/patologiaRESUMO
Tumor classifiers based on molecular patterns promise to define and reliably classify tumor entities. The high tissue- and cell type-specificity of DNA methylation, as well as its high stability, makes DNA methylation an ideal choice for the development of tumor classifiers. Herein, we review existing tumor classifiers using DNA methylome analysis and will provide an overview on their emerging impact on cancer classification, the detection of novel cancer subentities and patient stratification with a focus on brain tumors, sarcomas and hematopoietic malignancies. Furthermore, we provide an outlook on the enormous potential of DNA methylome analysis to complement classical histopathological and genetic diagnostics, including the emerging field of epigenomic analysis in liquid biopsies.