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PURPOSE: There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ-CAMTA1 (TC) fusion gene. Here, we aimed to understand the regulation of TC using pharmacological tools and identify vulnerabilities that can potentially be exploited for the treatment of EHE. EXPERIMENTAL DESIGN: TC is a transcriptional co-regulator; we hypothesized that compounds that reduce TC nuclear levels, either through translocation of TC to the cytoplasm, or through degradation, would render TC less oncogenic. TC localization was monitored using immunofluorescence (IF) in an EHE tumor cell line. Two target-selective libraries were used to identify small molecules that reduce TC localization in the nucleus. The ability of the shortlisted hits to affect cell viability, apoptosis, and tumorigenesis was also evaluated. RESULTS: Basal TC remained 'immobile' in the nucleus; administration of cyclin-dependent kinase inhibitors (CDKi) such as CGP60474 and dinaciclib mobilized TC. 'Mobile' TC shuttled between the nucleus and cytoplasm; however, it was eventually degraded through proteasomes. This dramatically suppressed the levels of TC-regulated transcripts and cell viability, promoted apoptosis, and reduced the area of metastatic lesions in the allograft model of EHE. We specifically identified that the inhibition of CDK9, a transcriptional CDK, destabilizes TC. CONCLUSIONS: The CDK inhibitor dinaciclib exhibited anti-tumorigenic properties both in vitro and in vivo in EHE models. Dinaciclib has been rigorously tested in clinical trials and displayed an acceptable toxicity profile. Therefore, there is a potential therapeutic window for repurposing dinaciclib for the treatment of EHE.
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PURPOSE: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 operating as an oncogenic driver through activation of MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. PATIENTS AND METHODS: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management prior to enrollment. The primary endpoint was objective response rate (ORR) per RECIST1.1 in cases with TAZ-CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median PFS, 2-year OS rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. RESULTS: 44 patients enrolled and 42 started trametinib. TAZ-CAMTA1 was detected in 27 tumor samples. The ORR was 3.7% (95% CI: 0.094, 19.0), median PFS was 10.4 months (95% CI: 7.1, NA), and 2-year OS rate was 33.3% (95% CI: 19.1, 58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia and edema; one Grade 5 ARDS/pneumonitis was related to trametinib. CONCLUSIONS: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal.
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¼ Negative margin resection of musculoskeletal sarcomas is associated with reduced risk of local recurrence.¼ There is limited evidence to support an absolute margin width of soft tissue or bone that correlates with reduced risk of local recurrence.¼ Factors intrinsic to the tumor, including histologic subtype, grade, growth pattern and neurovascular involvement impact margin status and local recurrence, and should be considered when evaluating a patient's individual risk after positive margins.¼ Appropriate use of adjuvant therapy, critical analysis of preoperative advanced cross-sectional imaging, and the involvement of a multidisciplinary team are essential to obtain negative margins when resecting sarcomas.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Margens de Excisão , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/cirurgia , Proliferação de Células , Terapia CombinadaRESUMO
Epithelioid hemangioendothelioma (EHE) is a rare endothelial sarcoma associated with a high incidence of metastases and for which there are no standard treatment options. Based on disease-defining mutations, most EHEs are classified into two subtypes: WWTR1::CAMTA1-fused EHE or YAP1::TFE3-fused EHE. However, rare non-canonical fusions have been identified in clinical samples of EHE cases and are challenging to classify. In this study, we report the identification of a novel WWTR1::TFE3 fusion variant in an EHE patient using targeted RNA sequencing. Histologically, the tumor exhibited hybrid morphological characteristics between WWTR1::CAMTA1-fused EHE and YAP1::TFE3-fused EHE. In addition to the driver fusion, there were six additional secondary mutations identified, including a loss-of-function FANCA mutation. Furthermore, in vitro studies were conducted to investigate the tumorigenic function of the WWTR1::TFE3 fusion protein in NIH3T3 cells and demonstrated that WWTR1::TFE3 promotes colony formation in soft agar. Finally, as the wild-type WWTR1 protein relies on binding the TEAD family of transcription factors to affect gene transcription, mutation of the WWTR1 domain of the fusion protein to inhibit such binding abrogates the transformative effect of WWTR1::TFE3. Overall, we describe a novel gene fusion in EHE with a hybrid histological appearance between the two major genetic subtypes of EHE. Further cases of this very rare subtype of EHE will need to be identified to fully elucidate the clinical and pathological characteristics of this unusual subtype of EHE.
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Hemangioendotelioma Epitelioide , Transativadores , Humanos , Camundongos , Animais , Transativadores/genética , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Células NIH 3T3 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fusão Gênica , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
Spindle cell mesenchymal neoplasms are a diverse and often challenging diagnostic group. While morphological impression is sufficient for some diagnoses, increasingly immunohistochemical and even molecular data is required to render an accurate diagnosis, which can lead to the characterization of new entities. We describe five cases of novel mesenchymal neoplasms with rearrangements in the NCOA2 and NCOA3 genes partnered with either CTCF or CRTC1. Three tumors occurred in the head and neck (palate, auditory canal), while the other two were in visceral organs (lung, urinary bladder). All cases occurred in adults (range 33-86) with a median age of 42 and fairly even sex distribution = (male-to-female = 3:2). Morphologically, they had similar features consisting of monotonous, bland spindle to ovoid cells with fascicular and reticular arrangements in a myxohyaline to collagenous stroma. However, immunophenotypically they had essentially a null phenotype, with only two tumors staining partially for CD34 and smooth muscle actin. Targeted RNA sequencing detected in-frame CTCF::NCOA2 (one case), CRTC1::NCOA2 (two cases), and CTCF::NCOA3 (two cases) fusions. Treatment was surgical resection in all cases. Local recurrence and/or distant metastases were not observed in any case (median follow-up, 7.5 months; range, 2-19 months). Given their morphologic, immunohistochemical, and molecular similarities, we believe that these cases may represent an emerging family of low-grade NCOA2/3-rearranged fibroblastic spindle cell neoplasms.
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Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias de Tecidos Moles , Adulto , Humanos , Masculino , Feminino , Fibroblastos/patologia , Sequência de Bases , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Fenótipo , Biomarcadores Tumorais/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Coativador 2 de Receptor Nuclear/genéticaRESUMO
Cancer of unknown primary (CUP) presents a complex diagnostic challenge, characterized by metastatic tumors of unknown tissue origin and a dismal prognosis. This review delves into the emerging significance of artificial intelligence (AI) and machine learning (ML) in transforming the landscape of CUP diagnosis, classification, and treatment. ML approaches, trained on extensive molecular profiling data, have shown promise in accurately predicting tissue of origin. Genomic profiling, encompassing driver mutations and copy number variations, plays a pivotal role in CUP diagnosis by providing insights into tumor type-specific oncogenic alterations. Mutational signatures (MS), reflecting somatic mutation patterns, offer further insights into CUP diagnosis. Known MS with established etiology, such as ultraviolet (UV) light-induced DNA damage and tobacco exposure, have been identified in cases of dedifferentiated/transdifferentiated melanoma and carcinoma. Deep learning models that integrate gene expression data and DNA methylation patterns offer insights into tissue lineage and tumor classification. In digital pathology, machine learning algorithms analyze whole-slide images to aid in CUP classification. Finally, precision oncology, guided by molecular profiling, offers targeted therapies independent of primary tissue identification. Clinical trials assigning CUP patients to molecularly guided therapies, including targetable alterations and tumor mutation burden as an immunotherapy biomarker, have resulted in improved overall survival in a subset of patients. In conclusion, AI- and ML-driven approaches are revolutionizing CUP management by enhancing diagnostic accuracy. Precision oncology utilizing enhanced molecular profiling facilitates the identification of targeted therapies that transcend the need to identify the tissue of origin, ultimately improving patient outcomes.
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Neoplasias Primárias Desconhecidas , Humanos , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/terapia , Perfilação da Expressão Gênica/métodos , Inteligência Artificial , Variações do Número de Cópias de DNA , Medicina de PrecisãoRESUMO
TAZ::CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ::CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ::CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ::CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ::CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ::CAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.
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Hemangioendotelioma Epitelioide , Transativadores , Humanos , Transativadores/genética , Células Endoteliais/patologia , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Ligação ao Cálcio/genética , Fatores de Transcrição/genética , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Proteínas de Fusão Oncogênica/genética , Instabilidade GenômicaRESUMO
Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low levels in other rhabdomyosarcoma subtypes. Lower immune infiltrate was associated with complete loss of both TP53 and RB1. This comprehensive characterization of the genetic, epigenetic, and immune landscape of PRMS provides a roadmap for improved prognostications and therapeutic exploration.
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Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Criança , Rabdomiossarcoma/genética , Rabdomiossarcoma Embrionário/genética , Genômica , Processamento de Proteína Pós-Traducional , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases , Proteínas de Ligação a Retinoblastoma/genéticaRESUMO
Bone and soft tissue tumors are generally classified into complex karyotype sarcomas versus those with recurrent genetic alterations, often in the form of gene fusions. In this review, we provide an overview of important co-occurring genomic alterations, organized by biological mechanisms and covering a spectrum of genomic alteration types: mutations (single-nucleotide variations or indels) in oncogenes or tumor suppressor genes, copy number alterations, transcriptomic signatures, genomic complexity indices (e.g. CINSARC), and complex genomic structural variants. We discuss the biological and prognostic roles of these so-called secondary or co-occurring alterations, arguing that recognition and detection of these alterations may be significant for our understanding and management of mesenchymal tumors. On a related note, we also discuss major recurrent alterations in so-called complex karyotype sarcomas. These secondary alterations are essential to sarcomagenesis via a variety of mechanisms, such as inactivation of tumor suppressors, activation of proliferative signal transduction, telomere maintenance, and aberrant regulation of epigenomic/chromatin remodeling players. The use of comprehensive genomic profiling, including targeted next-generation sequencing panels or whole-exome sequencing, may be incorporated into clinical workflows to offer more comprehensive, potentially clinically actionable information. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Sarcoma , Neoplasias de Tecidos Moles , Humanos , Sarcoma/genética , Sarcoma/patologia , Mutação , Oncogenes/genética , Transcriptoma , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologiaRESUMO
SARS-CoV-2 mutation is minimized through a proofreading function encoded by NSP-14. Most estimates of the SARS-CoV-2 mutation rate are derived from population based sequence data. Our understanding of SARS-CoV-2 evolution might be enhanced through analysis of intra-host viral mutation rates in specific populations. Viral genome analysis was performed between paired samples and mutations quantified at allele frequencies (AF) ≥ 0.25, ≥ 0.5 and ≥ 0.75. Mutation rate was determined employing F81 and JC69 evolution models and compared between isolates with (ΔNSP-14) and without (wtNSP-14) non-synonymous mutations in NSP-14 and by patient comorbidity. Forty paired samples with median interval of 13 days [IQR 8.5-20] were analyzed. The estimated mutation rate by F81 modeling was 93.6 (95%CI 90.8-96.4], 40.7 (95%CI 38.9-42.6) and 34.7 (95%CI 33.0-36.4) substitutions/genome/year at AF ≥ 0.25, ≥ 0.5, ≥ 0.75 respectively. Mutation rate in ΔNSP-14 were significantly elevated at AF ≥ 0.25 vs wtNSP-14. Patients with immune comorbidities had higher mutation rate at all allele frequencies. Intra-host SARS-CoV-2 mutation rates are substantially higher than those reported through population analysis. Virus strains with altered NSP-14 have accelerated mutation rate at low AF. Immunosuppressed patients have elevated mutation rate at all AF. Understanding intra-host virus evolution will aid in current and future pandemic modeling.
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COVID-19 , Humanos , COVID-19/epidemiologia , Taxa de Mutação , SARS-CoV-2/genética , Pandemias , Mutação , Genoma Viral/genéticaRESUMO
BACKGROUND: Malignant hemangioendothelioma is an endothelial cancer with heterogeneous clinical behavior that can range from indolent to aggressive, of which the majority are epithelioid (EHE). Its incidence and demographics have not been previously well defined in a large cohort. METHODS: This retrospective analysis used the US Cancer Statistics National Program of Cancer Registries - Surveillance Epidemiology End Results (SEER) combined database to identify patients in the US newly diagnosed with hemangioendothelioma between the years of 2001 and 2017 (n = 1986). Survival analyses were performed on a subset of patients within the SEER-18 database with survival information available (n = 417). Outcomes included incidence, demographics of patients newly diagnosed with hemangioendothelioma, extent of disease at presentation, and overall survival. RESULTS: The incidence of hemangioendothelioma in the US is 0.4 cases per million person-years. Although cases rose to 122 newly diagnosed in the year 2017 (90 EHE, 32 other hemangioendothelioma), incidence rates were stable. Skin and connective tissues were the most common presenting sites (33.4%), followed by liver (24.5%), lung (17.6%), and bone (12.5%). Median age at diagnosis was 55 years; 27.2% of patients were pediatric, adolescent, or young adult (<40 years). At presentation, 36.4% of patients had localized disease; 21.6% presented with regional and 41.7% with distant metastases. Observed survival at 3 years was 79.7%, 70.7%, and 46.0% for patients presenting with local, regional, and distant disease and most deaths occurred within the first 2 years. CONCLUSIONS: Malignant hemangioendothelioma is ultra-rare but meaningfully impacts affected patients. These data may provide benchmarks for comparison of new approaches to hemangioendothelioma therapy and highlight poor survival outcomes.
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Hemangioendotelioma Epitelioide , Hemangioendotelioma , Hemangiossarcoma , Adolescente , Adulto Jovem , Humanos , Criança , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Incidência , Hemangioendotelioma Epitelioide/epidemiologia , Hemangioendotelioma Epitelioide/patologia , Estudos Retrospectivos , Hemangiossarcoma/patologia , Hemangioendotelioma/epidemiologia , Hemangioendotelioma/patologiaRESUMO
The Hippo signaling pathway is a highly conserved pathway that plays important roles in the regulation of cell proliferation and apoptosis. Transcription factors TEAD1-4 and transcriptional coregulators YAP/TAZ are the downstream effectors of the Hippo pathway and can modulate Hippo biology. Dysregulation of this pathway is implicated in tumorigenesis and acquired resistance to therapies. The emerging importance of YAP/TAZ-TEAD interaction in cancer development makes it a potential therapeutic target. In the past decade, disrupting YAP/TAZ-TEAD interaction as an effective approach for cancer treatment has achieved great progress. This approach followed a trajectory wherein peptidomimetic YAP-TEAD protein-protein interaction disruptors (PPIDs) were first designed, followed by the discovery of allosteric small molecule PPIDs, and currently, the development of direct small molecule PPIDs. YAP and TEAD form three interaction interfaces. Interfaces 2 and 3 are amenable for direct PPID design. One direct YAP-TEAD PPID (IAG933) that targets interface 3 has entered a clinical trial in 2021. However, in general, strategically designing effective small molecules PPIDs targeting TEAD interfaces 2 and 3 has been challenging compared with allosteric inhibitor development. This review focuses on the development of direct surface disruptors and discusses the challenges and opportunities for developing potent YAP/TAZ-TEAD inhibitors for the treatment of cancer.
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PURPOSE: Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma caused by the WWTR1(TAZ)-CAMTA1 (TC) gene fusion. This fusion gene has been observed in almost all reported EHE cases and functions as a constitutively activated TAZ. Sequencing of human tumors has, however, identified additional secondary mutations in approximately 50% of EHE, most commonly the loss of tumor suppressor CDKN2A. In this study, the effect of loss of CDKN2A in EHE tumorigenesis was evaluated. EXPERIMENTAL DESIGN: Mice bearing a conditional TC allele were paired with a conditional Cdkn2a knockout allele and an endothelial-specific Cre. Histologic characterization and single-cell RNA-seq of the resultant tumors were performed. EHE cell lines were established through ex vivo culture of tumor cells and evaluated for sensitivity to TEAD inhibition and trametinib. RESULTS: Loss of Cdkn2a within EHE was associated with more aggressive disease, as displayed by earlier tumor-related morbidity/mortality and enhanced tumor cell proliferation. As no previous EHE cell lines exist, we attempted, successfully, to expand EHE tumor cells ex vivo and produced the first EHE cell lines. These cell lines are "addicted" to the TC oncoprotein, replicate the EHE transcriptional profile, and generate EHE tumors when injected into immunodeficient mice. CONCLUSIONS: CDKN2A loss enhances the tumorigenicity of EHE in vivo and enabled the generation of the first cell lines of this disease. These cell lines replicate key facets of the human disease phenotype. Therefore, these cell lines and allograft tumors generated after implantation serve as robust model systems for therapeutic testing of compounds directed at either EHE or other TAZ-driven cancers.
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Hemangioendotelioma Epitelioide , Animais , Humanos , Camundongos , Proteínas de Ligação ao Cálcio/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Fusão Gênica , Hemangioendotelioma Epitelioide/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
The Hippo signaling pathway inhibits the activity of the oncogenic YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. The activity of this transcriptional complex can be effectively inhibited by targeting the TEAD family of transcription factors. The development of TEAD inhibitors has been driven by the discovery that TEAD has druggable hydrophobic pockets, and is currently at the clinical development stage. Three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials. In this review, we highlight the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TEAD inhibitors.
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Neoplasias , Fatores de Transcrição de Domínio TEA , Humanos , Fatores de Transcrição/metabolismo , Neoplasias/tratamento farmacológico , Via de Sinalização HippoRESUMO
Extraskeletal osteosarcoma (EOS) is a high grade soft tissue tumour characterised by the production of malignant osteoid, without attachment/involvement of underlying bone/periosteum. Rarely, EOS presents as a cutaneous tumour. The clinical behaviour of primary cutaneous EOS (PC-EOS) remains incompletely characterised. Herein we present the largest case series of PC-EOS reported to date. Sixteen PC-EOS cases from the archives/consultation files were retrieved (male:female 1:1; age 31-96 years, mean age 66 years). The tumours measured 1-10 cm (mean 3.2 cm) and were located on the lower extremity (7), head (6), upper extremity (2), and trunk (1). They consisted of pleomorphic, spindled-to-epithelioid cells, with fascicular, nodular, or sheet-like growth patterns and foci of malignant osteoid. Immunohistochemistry did not reveal specific lines of differentiation, and there was no evidence of other tumour types. A literature review was conducted to identify all well characterised cases of PC-EOS. A combined analysis of present and past cases was performed to determine overall trends in clinical characteristics and outcomes. The mean follow-up period was 23.9 months, during which 67.5% of patients experienced progression-free survival and 18% of patients died of disease. Rates of local recurrence and metastasis were 10% and 25%, respectively, approximately double past estimates. These data suggest that the prognosis of PC-EOS is less favourable than previously thought. The differential diagnosis includes benign entities (e.g., ossifying pyogenic granuloma) and malignant neoplasms with heterologous osteosarcomatous differentiation (e.g., carcinosarcoma, transdifferentiated melanoma). Wide excision remains the standard of care, and the role of chemotherapy and radiation remains inconclusive. Recognition of this rare entity can facilitate prompt diagnosis and appropriate treatment.
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Neoplasias Ósseas , Osteossarcoma , Neoplasias Cutâneas , Neoplasias de Tecidos Moles , Humanos , Masculino , Feminino , Idoso , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Neoplasias de Tecidos Moles/patologia , Neoplasias Cutâneas/patologia , Prognóstico , Osteossarcoma/diagnóstico , Osteossarcoma/patologiaRESUMO
Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein.
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Tumor de Células Gigantes de Bainha Tendinosa , Qualidade de Vida , Humanos , Consenso , Tumor de Células Gigantes de Bainha Tendinosa/tratamento farmacológico , Tumor de Células Gigantes de Bainha Tendinosa/patologiaAssuntos
Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mutação , Receptores Proteína Tirosina Quinases , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genéticaRESUMO
AIM: Post-radiation angiosarcoma is an iatrogenic event seen in the setting of breast cancer treatment. Histopathologically, there are morphologic variants of angiosarcoma that mimic benign entities, including the capillary lobule variant of post-radiation angiosarcoma. We present the largest case series to date of this histopathologic variant of post-radiation angiosarcoma. METHODS AND RESULTS: Cases of the capillary lobule variant of post-radiation angiosarcoma from institutional/consultation archives from 2008 to June 2022 were reviewed. For inclusion, tumors had to occur in irradiated skin and exhibit a multi-lobular proliferation of tightly packed capillary-like vessels, as previously described in this variant. Prior ancillary studies were also reviewed. Eight cases met the criteria. All occurred in women treated with radiation for breast cancer (median age 75 years). All cases had similar findings, including a multi-lobular proliferation of tightly packed vessels, infiltrative cords, and atypical single endothelial cells. A conventional angiosarcoma pattern was also seen in five cases. All cases tested were positive for vascular markers (CD31, CD34, and/or ERG) and MYC. MYC amplification was shown by FISH in all cases tested. Smooth muscle actin (SMA) was positive in pericytes in the capillary lobules in all five cases tested and areas of conventional angiosarcoma in two of three cases. CONCLUSIONS: The capillary lobule variant of angiosarcoma is a rare and therefore potentially under-recognized variant of post-radiation angiosarcoma. The lobular architecture and SMA positivity may mimic benign vascular proliferations. Careful attention to histopathologic features and ancillary tests may facilitate accurate diagnosis.
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Neoplasias da Mama , Hemangiossarcoma , Neoplasias Cutâneas , Doenças Vasculares , Feminino , Humanos , Hemangiossarcoma/etiologia , Hemangiossarcoma/patologia , Células Endoteliais/patologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/patologia , Pele/patologia , Doenças Vasculares/patologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologiaRESUMO
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are among the most frequent sarcomas. Accurate diagnosis, classification, and reporting are critical for prognostication and patient management, including selection of appropriate targeted therapy. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of GIST. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major international pathology and cancer organizations. An international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialized soft tissue tumour experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain its clinical relevance and the rationale for selection as a core or noncore element. Following international public consultation, the datasets, which include synoptic reporting guides, were finalized and ratified, and published on the ICCR website. These first international datasets for GIST are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will ultimately help to improve the management of patients with GIST. All the ICCR datasets, including these on GIST, are freely available worldwide on the ICCR website (www.iccr-cancer.org/datasets).