RESUMO
GLI1(12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1, a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of MDM2 and CDK4. These included primary tumors (n = 60), local recurrences (n = 29), and metastases (n = 3). Primary tumors were most frequently retroperitoneal (47/60, 78%), mediastinal (4/60, 7%), and paratesticular (3/60, 5%). Average age was 63 years, with a male:female ratio of 3:2. The cohort was comprised of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-fifth (13/86, 17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86,30%) and high-grade myxofibrosarcoma-like (13/86,16%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was coamplified with all 3 of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1, and ESR1, were also amplified in a subset of cases. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.
Assuntos
Quinase 4 Dependente de Ciclina , Amplificação de Genes , Lipossarcoma , Proteína GLI1 em Dedos de Zinco , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Quinase 4 Dependente de Ciclina/genética , Lipossarcoma/genética , Lipossarcoma/patologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Estudos Retrospectivos , Proteína GLI1 em Dedos de Zinco/genéticaRESUMO
Osteosarcoma is the most common primary bone cancer, whose standard treatment includes pre-operative chemotherapy followed by resection. Chemotherapy response is used for prognosis and management of patients. Necrosis is routinely assessed after chemotherapy from histology slides on resection specimens, where necrosis ratio is defined as the ratio of necrotic tumor/overall tumor. Patients with necrosis ratio ≥90% are known to have a better outcome. Manual microscopic review of necrosis ratio from multiple glass slides is semiquantitative and can have intraobserver and interobserver variability. In this study, an objective and reproducible deep learning-based approach was proposed to estimate necrosis ratio with outcome prediction from scanned hematoxylin and eosin whole slide images (WSIs). To conduct the study, 103 osteosarcoma cases with 3134 WSIs were collected. Deep Multi-Magnification Network was trained to segment multiple tissue subtypes, including viable tumor and necrotic tumor at a pixel level and to calculate case-level necrosis ratio from multiple WSIs. Necrosis ratio estimated by the segmentation model highly correlates with necrosis ratio from pathology reports manually assessed by experts. Furthermore, patients were successfully stratified to predict overall survival with P = 2.4 × 10-6 and progression-free survival with P = 0.016. This study indicates that deep learning can support pathologists as an objective tool to analyze osteosarcoma from histology for assessing treatment response and predicting patient outcome.
Assuntos
Neoplasias Ósseas , Aprendizado Profundo , Osteossarcoma , Humanos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Prognóstico , Necrose/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologiaRESUMO
Digital pathology workflows can improve pathology operations by allowing reliable and fast retrieval of digital images, digitally reviewing pathology slides, enabling remote work and telepathology, use of computer-aided tools, and sharing of digital images for research and educational purposes. The need for quality systems is a prerequisite for successful clinical-grade digital pathology adoption and patient safety. In this article, we describe the development of a structured digital pathology laboratory quality management system (QMS) for clinical digital pathology operations at Memorial Sloan Kettering Cancer Center (MSK). This digital pathology-specific QMS development stemmed from the gaps that were identified when MSK integrated digital pathology into its clinical practice. The digital scan team in conjunction with the Department of Pathology and Laboratory Medicine quality team developed a QMS tailored to the scanning operation to support departmental and institutional needs. As a first step, systemic mapping of the digital pathology operations identified the prescan, scan, and postscan processes; instrumentation; and staffing involved in the digital pathology operation. Next, gaps identified in quality control and quality assurance measures led to the development of standard operating procedures and training material for the different roles and workflows in the process. All digital pathology-related documents were subject to regulatory review and approval by departmental leadership. The quality essentials were developed into an extensive Digital Pathology Quality Essentials framework to specifically address the needs of the growing clinical use of digital pathology technologies. Using the unique digital experience gained at MSK, we present our recommendations for QMS for large-scale digital pathology operations in clinical settings.
Assuntos
Neoplasias , Patologia Clínica , Telepatologia , Humanos , Laboratórios , Neoplasias/diagnóstico , Neoplasias/cirurgia , Patologia Clínica/métodos , Telepatologia/métodos , Gestão da Qualidade TotalRESUMO
The field of anatomic pathology has been evolving in the last few decades and the advancements have been largely fostered by innovative technology. Immunohistochemistry enabled a paradigm shift in discovery and diagnostic evaluation, followed by booming genomic advancements which allowed for submicroscopic pathologic characterization, and now the field of digital pathology coupled with machine learning and big data acquisition is paving the way to revolutionize the pathology medical domain. Whole slide imaging (WSI) is a disruptive technology where glass slides are digitized to produce on-screen whole slide images. Specifically, in the past decade, there have been significant advances in digital pathology systems that have allowed this technology to promote integration into clinical practice. Whole slide images (WSI), or digital slides, can be viewed and navigated comparable to glass slides on a microscope, as digital files. Whole slide imaging has increased in adoption among pathologists, pathology departments, and scientists for clinical, educational, and research initiatives. Integration of digital pathology systems requires a coordinated effort with numerous stakeholders, not only within the pathology department, but across the entire enterprise. Each pathology department has distinct needs, use cases and blueprints, however the framework components and variables for successful clinical integration can be generalized across any organization seeking to undergo a digital transformation at any scale. This article will review those components and considerations for integrating digital pathology systems into clinical practice.
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Microscopia , Patologia Clínica , Humanos , Microscopia/métodos , Patologistas , Patologia Clínica/métodosRESUMO
OBJECTIVE: To describe imaging and clinical features of primary mesenchymal chondrosarcoma (MCS) and evaluate for presence of a distinct biphasic pattern on imaging. MATERIAL AND METHODS: Patients with a pathologic diagnosis of MCS were identified along with imaging of their primary tumor. Size, location, appearance (lytic, sclerotic, or mixed), presence, extent and distribution of calcifications, cortical destruction, soft tissue extension, periosteal reaction, contrast enhancement, and radiotracer uptake were recorded. The presence of T2-hyperintense tumor lobules on MRI and a biphasic morphology (distinct calcified and non-calcified components) on CT were assessed. Presence and location of metastases were documented. RESULTS: Twenty-three patients (mean age 28.0 ± 13.8 years) were reviewed (13 skeletal, 10 extraskeletal). Overall mean tumor size was 10.2 ± 7.2 cm, 7.1 ± 7.3 cm in non-metastatic and 13.2 ± 5.9 cm (p = 0.004) in metastatic cases. Locations were extremities (n = 11), head/neck (n = 4), chest wall (n = 4), pelvis (n = 3), and retroperitoneum (n = 1). Skeletal MCS were aggressive mixed lytic and sclerotic (n = 8), purely lytic (n = 4), or juxtacortical (n = 1) lesions with cortical destruction and soft tissue extension. Chondroid calcifications were common (80%). On MRI, the presence of T2-hyperintense lobules was seen in 35%. A biphasic morphology on imaging was seen in 30%. Metastases were common (52%) with the most common site being the lungs (75%). All tumors were hypermetabolic with a mean SUVmax of 14.3 (5.6-34) on PET/CT. CONCLUSION: Skeletal MCS commonly present as aggressive lytic bone lesions with chondroid calcifications. A biphasic morphology was seen in one-third of cases. Metastases were common at initial presentation and more commonly seen with larger tumors.
Assuntos
Neoplasias Ósseas , Condrossarcoma Mesenquimal , Condrossarcoma , Adolescente , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Condrossarcoma Mesenquimal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos , Adulto JovemRESUMO
Background Dynamic contrast agent-enhanced (DCE) perfusion MRI may help differentiate between nonneoplastic and malignant lesions in the spine. Purpose To investigate the correlation between fractional plasma volume (Vp), a parameter derived from DCE perfusion MRI, and histopathologic diagnosis for spinal lesions. Materials and Methods In this retrospective study, patients who underwent DCE perfusion MRI and lesion biopsy between May 2015 and May 2018 were included. Inclusion criteria were short time interval (<30 days) between DCE perfusion MRI and biopsy, DCE perfusion MRI performed before biopsy, and DCE perfusion MRI performed at the same spine level as biopsy. Exclusion criteria were prior radiation treatment on vertebrae of interest, poor DCE perfusion MRI quality, nondiagnostic biopsy, and extensive spinal metastasis or prior kyphoplasty. One hundred thirty-four lesions were separated into a nonneoplastic group (n = 51) and a malignant group (n = 83) on the basis of histopathologic analysis. Two investigators manually defined regions of interest in the vertebrae. DCE perfusion MRI parameter Vp was calculated by using the Tofts pharmacokinetic two-compartment model. Vp was quantified, normalized to adjacent normal vertebrae, and compared between the two groups. A Mann-Whitney U test and receiver operating characteristic analysis was performed to verify the difference in Vp between the nonneoplastic and malignant groups. Reproducibility was assessed by calculating the Cohen κ coefficient. Results One hundred patients (mean age, 65 years ± 11 [standard deviation]; 52 men) were evaluated. Vp was lower in nonneoplastic lesions versus malignant lesions (1.6 ± 1.3 vs 4.2 ± 3.0, respectively; P < .001). The sensitivity of Vp was 93% (77 of 83; 95% confidence interval [CI]: 85%, 97%), specificity was 78% (40 of 51; 95% CI: 65%, 89%), and area under the receiver operating characteristic curve was 0.88 (95% CI: 0.82, 0.95). Cohen κ coefficient suggested substantial agreement in both intra- (κ = 0.72) and interreader (κ = 0.70) reproducibility. Conclusion This study indicated that dynamic contrast agent-enhanced perfusion MRI parameter, fractional plasma volume, was able to differentiate between nonneoplastic spinal lesions and malignant lesions. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Haller in this issue.
Assuntos
Imageamento por Ressonância Magnética/métodos , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Corpo Vertebral/diagnóstico por imagem , Idoso , Biópsia , Meios de Contraste , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias da Coluna Vertebral/patologia , Corpo Vertebral/patologiaRESUMO
Integration of morphological, immunohistochemical, and molecular methods is often necessary for the precise diagnosis and optimal clinical management of sarcomas. We have validated and implemented a clinical molecular diagnostic assay, MSK- Fusion Solid, for detection of gene fusions in solid tumors, including sarcomas. Starting with RNA extracted from formalin-fixed paraffin-embedded tumor material, this targeted RNA sequencing assay utilizes anchored multiplex PCR to detect oncogenic fusion transcripts involving 62 genes known to be recurrently rearranged in solid tumors including sarcomas without prior knowledge of fusion partners. From 1/2016 to 1/2018, 192 bone and soft tissue tumors were submitted for MSK- Fusion Solid analysis and 96% (184/192) successfully passed all the pre-sequencing quality control parameters and sequencing steps. These sarcomas encompass 24 major tumor types, including 175 soft tissue tumors and 9 osteosarcomas. Ewing and Ewing-like sarcomas, rhabdomyosarcoma, and sarcoma-not otherwise specified were the three most common tumor types. Diagnostic in-frame fusion transcripts were detected in 43% of cases, including 3% (6/184) with novel fusion partners, specifically TRPS1-PLAG1, VCP-TFE3, MYLK-BRAF, FUS-TFCP2, and ACTB-FOSB, the latter in two cases of pseudomyogenic hemangioendothelioma, representing a novel observation in this sarcoma. Our experience shows that this targeted RNA sequencing assay performs in a robust and sensitive fashion on RNA extracted from most routine clinical specimens of sarcomas thereby facilitating precise diagnosis and providing opportunities for novel fusion partner discovery.
Assuntos
Actinas/genética , Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Fusão Gênica , Hemangioendotelioma Epitelioide/genética , Proteínas Proto-Oncogênicas c-fos/genética , Sarcoma/genética , Análise de Sequência de RNA , Neoplasias de Tecidos Moles/genética , Adolescente , Adulto , Idoso , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Feminino , Predisposição Genética para Doença , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Sarcoma/patologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapiaRESUMO
Whole slide imaging is Food and Drug Administration-approved for primary diagnosis in the United States of America; however, relatively few pathology departments in the country have fully implemented an enterprise wide digital pathology system enabled for primary diagnosis. Digital pathology has significant potential to transform pathology practice with several published studies documenting some level of diagnostic equivalence between digital and conventional systems. However, whole slide imaging also has significant potential to disrupt pathology practice, due to the differences in efficiency of manipulating digital images vis-à-vis glass slides, and studies on the efficiency of actual digital pathology workload are lacking. Our randomized, equivalency and efficiency study aimed to replicate clinical workflow, comparing conventional microscopy to a complete digital pathology signout using whole slide images, evaluating the equivalency and efficiency of glass slide to whole slide image reporting, reflective of true pathology practice workloads in the clinical setting. All glass slides representing an entire day's routine clinical signout workload for six different anatomic pathology subspecialties at Memorial Sloan Kettering Cancer Center were scanned on Leica Aperio AT2 at ×40 (0.25 µm/pixel). Integration of whole slide images for each accessioned case is through an interface between the Leica eSlide manager database and the laboratory information system, Cerner CoPathPlus. Pathologists utilized a standard institution computer workstation and viewed whole slide images through an internally developed, vendor agnostic whole slide image viewer, named the "MSK Slide Viewer". Subspecialized pathologists first reported on glass slides from surgical pathology cases using routine clinical workflow. Glass slides were de-identified, scanned, and re-accessioned in the laboratory information system test environment. After a washout period of 13 weeks, pathologists reported the same clinical workload using whole slide image integrated within the laboratory information system. Intraobserver equivalency metrics included top-line diagnosis, margin status, lymphovascular and/or perineural invasion, pathology stage, and the need to order ancillary testing (i.e., recuts, immunohistochemistry). Turnaround time (efficiency) evaluation was defined by the start of each case when opened in the laboratory information system and when the case was completed for that day (i.e., case sent to signout queue or pending ancillary studies). Eight pathologists participated from the following subspecialties: bone and soft tissue, genitourinary, gastrointestinal, breast, gynecologic, and dermatopathology. Glass slides signouts comprised of 204 cases, encompassing 2091 glass slides; and digital signouts comprised of 199 cases, encompassing 2073 whole slide images. The median whole slide image file size was 1.54 GB; scan time/slide, 6 min 24 s; and scan area 32.1 × 18.52 mm. Overall diagnostic equivalency (e.g., top-line diagnosis) was 99.3% between digital and glass slide signout; however, signout using whole slide images showed a median overall 19% decrease in efficiency per case. No significant difference by reader, subspecialty, or specimen type was identified. Our experience is the most comprehensive study to date and shows high intraobserver whole slide image to glass slide equivalence in reporting of true clinical workflows and workloads. Efficiency needs to improve for digital pathology to gain more traction among pathologists.
Assuntos
Patologia Clínica/métodos , Patologia Cirúrgica/métodos , Telepatologia/métodos , Humanos , Processamento de Imagem Assistida por Computador , Microscopia/métodos , Reprodutibilidade dos TestesRESUMO
Erdheim-Chester disease is a rare, non-Langerhans cell histiocytosis histologically characterized by multi-systemic proliferation of mature histiocytes in a background of inflammatory stroma. The disease can involve virtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain are affected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range of morphological appearances have been described as part of case studies or small series. A comprehensive review of histopathological features in clinically and molecularly defined Erdheim-Chester disease has yet to be characterized. To address this issue and help guide clinical practice, we comprehensively analyzed the pathological spectrum of Erdheim-Chester disease in a clinically and molecularly defined cohort. We reviewed 73 biopsies from 42 patients showing involvement by histiocytosis from a variety of organ systems, including bone (16), retroperitoneum (11), skin (19), orbit (6), brain (5), lung (6), cardiac structures (2), epidural soft tissue (3), oral cavity (2), subcutaneous soft tissue (2), and testis (2). In eight patients, one or more bone marrow biopsies were performed due to clinical indication and an accompanying myeloid neoplasm was detected in six of them. Thirty-eight cases were investigated for genetic abnormalities. Somatic mutations involving BRAF (25/38), MAP2K1 (6/38), ARAF (2/38), MAP2K2 (1/38), KRAS (1/38), and NRAS (1/38) genes were detected. One of the cases with a MAP2K1 mutation also harbored a PIK3CA mutation. We have observed marked heterogeneity in histology and immunophenotype, identified site-specific features, overlap with other histiocytic and myeloid disorders and potential diagnostic pitfalls. We hope that broadening the spectrum of recognized pathologic manifestations of Erdheim-Chester disease will help practicing clinicians and pathologists to diagnose Erdheim-Chester disease early in the disease course and manage these patients effectively.
Assuntos
Doença de Erdheim-Chester/genética , Doença de Erdheim-Chester/patologia , Estudos de Coortes , HumanosRESUMO
BACKGROUND: Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. METHODS: We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. FINDINGS: 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 µg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 µg/mL (CV% 33.0) and from 123 µg/mL (CV% 31.2) to 156 µg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). INTERPRETATION: This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. FUNDING: Eli Lilly and Company.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Resultado do Tratamento , Estados UnidosRESUMO
A 57-year-old woman presented with a 3-year history of a progressive firm plaque on the right cheek. Skin biopsies revealed a bland, storiform, spindle-cell proliferation involving the deep dermis and subcutaneous fat. By immunohistochemistry, the tumor cells were diffusely positive for CD34 and caldesmon with multifocal reactivity for epithelial membrane antigen and focal, weak staining for smooth muscle actin. Retinoblastoma protein expression was not detectable in tumor cells by immunohistochemistry. An interphase fluorescence in situ hybridization analysis for platelet-derived growth factor B (PDGFB) gene rearrangement was negative. A single-nucleotide polymorphism array study detected 1) a gain of chromosome segment 17q21.33-q25.3 which overlapped the entire COL1A1 gene with a breakpoint at 17q21.33, approximately 250 Kb centromeric to the 3' end of COL1A1 gene, 2) several segmental gains on chromosome 11, and 3) an RB1 gene locus with normal copy number and allele frequency. Although the current case resembles dermatofibrosarcoma protuberans, it is unique in that it demonstrates a copy number gain of chromosome 17q in the absence of fusion of COL1A1 and PDGFB genes and an unusual immunohistochemical staining profile. The morphologic and molecular findings suggest a novel molecular variant of dermatofibrosarcoma protuberans not detectable with standard fluorescence in situ hybridization for PDGFB rearrangement. This variant appears to respond to imatinib after 9 months of follow-up.
Assuntos
Cromossomos Humanos Par 17 , Colágeno Tipo I/genética , Dermatofibrossarcoma/genética , Dosagem de Genes , Neoplasias Cutâneas/genética , Biomarcadores Tumorais/análise , Cadeia alfa 1 do Colágeno Tipo I , Dermatofibrossarcoma/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologiaRESUMO
We present a unique case of an aggressive scapular osteoblastoma that produced ß-hCG as a paraneoplastic manifestation in a 20-year-old woman. Serum ß-hCG was found to be elevated during presurgical workup and consequently delayed surgical resection of the increasingly painful tumor because of suspected pregnancy. The paraneoplastic production of ß-hCG was later proven by positive immunohistochemical stain of ß-hCG in a curettage specimen and normalization of ß-hCG levels after surgical resection of the aggressive osteoblastoma. Production of beta-human chorionic gonadotropin (ß-hCG) has been reported in several carcinomas and sarcomas but, to our knowledge, it has not been reported in osteoblastoma in the English-language literature.
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Gonadotropina Coriônica Humana Subunidade beta/sangue , Osteoblastoma/sangue , Osteoblastoma/diagnóstico por imagem , Escápula , Biomarcadores Tumorais/sangue , Meios de Contraste , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X , Imagem Corporal Total , Adulto JovemRESUMO
Malignant lipomatous tumors of the vulva are uncommon. We present 2 cases of liposarcoma arising in the vulva: a myxoid liposarcoma harboring DDIT3 and FUS rearrangements and a well differentiated liposarcoma/atypical lipomatous tumor harboring MDM2 amplification detected by fluorescence in situ hybridization. Both cases are the first liposarcomas of this site to be confirmed by molecular cytogenetic analysis. We also review the literature's cases of liposarcoma to further examine the clinicopathologic features of these tumors.
Assuntos
Lipoma/patologia , Lipossarcoma Mixoide/patologia , Vulva/patologia , Neoplasias Vulvares/patologia , Adulto , Idoso , Citogenética , Feminino , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Lipoma/genética , Lipossarcoma Mixoide/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína FUS de Ligação a RNA/genética , Fator de Transcrição CHOP/genética , Neoplasias Vulvares/genéticaRESUMO
BACKGROUND: Craniofacial osteosarcomas (CFOS) are uncommon malignant neoplasms of the head and neck with different clinical presentation, biological behavior and prognosis from conventional osteosarcomas of long bones. Very limited genetic data have been published on CFOS. METHODS: In the current study, we performed comprehensive genomic studies in 15 cases of high-grade CFOS by SNP array and targeted next generation sequencing. RESULT: Our study shows high-grade CFOS demonstrate highly complex and heterogenous genomic alterations and harbor frequently mutated tumor suppressor genes TP53, CDKN2A/B, and PTEN, similar to conventional osteosarcomas. Potentially actionable gene amplifications involving CCNE1, AKT2, MET, NTRK1, PDGFRA, KDR, KIT, MAP3K14, FGFR1, and AURKA were seen in 43% of cases. GNAS hotspot activating mutations were also identified in a subset of CFOS cases, with one case representing malignant transformation from fibrous dysplasia, suggesting a role for GNAS mutation in the development of CFOS. CONCLUSION: High-grade CFOS demonstrate highly complex and heterogenous genomic alterations, with amplification involving receptor tyrosine kinase genes, and frequent mutations involving tumor suppressor genes.
Assuntos
Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Osteossarcoma , Humanos , Feminino , Masculino , Adulto , Osteossarcoma/genética , Osteossarcoma/patologia , Pessoa de Meia-Idade , Adolescente , Mutação , Criança , Adulto Jovem , Idoso , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Cranianas/genética , Neoplasias Cranianas/patologia , Análise Mutacional de DNARESUMO
PURPOSE: This study sought to identify ß-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRß), affect these targets to alter natural history or treatment response in patients. EXPERIMENTAL DESIGN: In vitro experiments utilized primary desmoid cell lines to examine regulation of ß-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies. RESULTS: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a ß-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRß signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRß and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRß/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment. CONCLUSIONS: The ß-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.
Assuntos
Produtos Biológicos , Fibromatose Agressiva , Humanos , Fibromatose Agressiva/tratamento farmacológico , Fibromatose Agressiva/genética , beta Catenina/genética , beta Catenina/metabolismo , Sorafenibe/farmacologia , Transdução de SinaisRESUMO
CONTEXT.: Therapy targeted at human epidermal growth factor receptor 2 (HER2; also known as ERBB2) was used initially for breast and gastroesophageal carcinoma and has more recently been adopted for endometrial serous carcinoma (ESC) and colorectal carcinoma (CRC). There is evidence that predictive biomarker testing algorithms for HER2 must be tumor type specific and that an algorithm validated for one tumor type cannot be applied to another. OBJECTIVE.: To describe current laboratory practices for HER2 assessment in ESC and CRC. DESIGN.: We surveyed laboratories participating in the 2021 College of American Pathologists (CAP) HER2 immunohistochemistry proficiency testing program. RESULTS.: The survey was distributed to 1548 laboratories and returned by 1195, of which 83.5% (998) were in the United States. For ESC, 24.0% (287) of laboratories reported performing in-house testing for HER2 by immunohistochemical staining and/or in situ hybridization; of these, 44.3% (127) performed it reflexively on all cases of ESC. The most common criterion for evaluating HER2 was the American Society of Clinical Oncology/CAP 2018 guideline for breast carcinoma (69.0%; 194 of 281), whereas only 16.0% (45) of laboratories used guidelines specific to ESC. For CRC, 20.2% (239 of 1185) of laboratories performed in-house HER2 testing, and 82.0% of these (196) did the test only at the clinician's request. A plurality (49.4%; 115 of 233) used gastroesophageal cancer guidelines when scoring CRC, 30.0% (70) used the CRC scoring system from the HERACLES trial, and 16.3% (38) used the American Society of Clinical Oncology/CAP 2018 guideline for breast carcinoma. CONCLUSIONS.: Laboratories vary in their approach to HER2 testing in ESC and CRC. Most laboratories did not report using tumor type-specific recommendations for HER2 interpretation. The lack of standardization could present a challenge to evidence-based practice when considering targeted therapy for these diseases.
Assuntos
Neoplasias da Mama , Neoplasias Colorretais , Cistadenocarcinoma Seroso , Neoplasias do Endométrio , Neoplasias Esofágicas , Neoplasias Gástricas , Feminino , Humanos , Estados Unidos , Hibridização in Situ Fluorescente , Receptor ErbB-2/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Esofágicas/patologia , Neoplasias Colorretais/diagnóstico , Biomarcadores Tumorais/metabolismoRESUMO
CONTEXT.: Clinical testing for tumor cell-free DNA (cfDNA) has evolved rapidly, but no practice guidelines exist. OBJECTIVE.: To summarize cfDNA laboratory practices based on self-reporting and assess preanalytical, analytical, and postanalytical trends that may influence the quality, accuracy, and consistency of cfDNA testing. DESIGN.: Data were derived from the College of American Pathologists cfDNA proficiency testing program submitted by 101 participating laboratories from 2018 to 2019. RESULTS.: Most laboratories performing clinical circulating tumor DNA testing are commercial/nonhospital (71.2%; 72 of 101) and international (77.2%; 78 of 101) laboratories. Commercial laboratories had higher monthly test volumes than hospital-based laboratories (median, 36 versus 7-8) and tended to have larger gene panels (median, 50 versus 11 genes) when panel-based testing was offered. The main clinical indications include therapy selection and treatment/disease monitoring. Plasma is the most commonly accepted specimen, which is predominantly collected in cell-stabilizing tubes. Equal proportions of laboratories use next-generation sequencing (NGS) and non-NGS methods to assess key genes, including EGFR, BRAF, KRAS, NRAS, and IDH1. Most laboratories reported a lower limit of detection (LLOD) of 0.5%, variant allele frequency or less, which did not differ by method, NGS or non-NGS, except for EGFR. Sixty-five percent (17 of 26) of laboratories using the US Food and Drug Administration (FDA)-approved non-NGS EGFR assay report analytical sensitivities higher than 0.5%, as compared to 15% (16 of 104) of laboratories using an alternative NGS or non-NGS method. There is also a wider range in LLODs obtained for the FDA-approved EGFR assay than nonapproved assays. CONCLUSIONS.: These results highlight emerging practice trends and serve as a foundation to initiate future practice recommendations.