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1
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Marcelis L, Folpe AL. "Putting the cart before the horse": an update on promiscuous gene fusions in soft tissue tumors. Virchows Arch 2025; 486:905-921. [PMID: 40205020 DOI: 10.1007/s00428-025-04099-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/31/2025] [Accepted: 04/02/2025] [Indexed: 04/11/2025]
Abstract
The ever-increasing availability and affordability of molecular genetic testing has revolutionized our understanding of the pathogenesis and proper classification of soft tissue tumors but has also brought new challenges. As is known, many soft tissue tumors harbor gene fusion events, and while it was initially thought that individual entities would be defined by single, specific fusions, it quickly became clear that some entities could be caused by several different fusion events (e.g., EWSR1::FLI1, EWSR1::ERG, EWSR1:FEV and others in Ewing sarcoma). More recently, it has become apparent that these fusion events themselves are "promiscuous", appearing in more than one discrete entity (e.g., EWSR1::CREB1 in clear cell sarcoma, angiomatoid fibrous histiocytoma and others). This review article will briefly discuss the best known examples of genetic promiscuity, the EWSR1/FUS::ATF1/CREB1 and ETV6::NTRK3 fusions, and more comprehensively cover recently discovered and less well-known examples of genetic promiscuity, including EWSR1::WT1, MALAT1::GLI1, YAP1::TFE3 and fusions involving members of the FET and ETS gene families.
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Affiliation(s)
- Lukas Marcelis
- Department of Pathology, University Hospitals Leuven, (UZ Leuven), 3000, Leuven, Belgium.
| | - Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55902, USA
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2
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Nie Y, Jing W, Zheng X, He X, Chen M, Zhang H. CAMTA1-immunonegative epithelioid hemangioendotheliomas of the liver: a clinicopathological and molecular analysis of seven cases. Front Oncol 2025; 15:1478036. [PMID: 40040722 PMCID: PMC11876046 DOI: 10.3389/fonc.2025.1478036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 01/27/2025] [Indexed: 03/06/2025] Open
Abstract
Background Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor. Most EHEs (>90%) cases harbor WWTR1::CAMTA1 fusion gene, and CAMTA1 immunohistochemistry (IHC) is a highly sensitive and specific tool for EHE diagnosis. However, there exist CAMTA1-immunonegative cases, the majority of which harbor YAP1::TFE3 fusion, with a few cases having more rare fusions. Liver is one of the most common sites of EHE, where the CAMTA1 subtype dominates, and the other variants are extremely rare. Hence, we focused on the hepatic CAMTA1-immunonegative EHEs to analyze the clinicopathological and molecular features of these peculiar cases. Methods The SNOMED search of the hospital pathology files between January 2016 to November 2023 identified 57 hepatic EHEs and 7 cases were CAMTA1-immunonegative. Fluorescence in situ hybridization (FISH), next generation sequencing (NGS) and Sanger sequencing were performed to identify the genetic change of the 7 cases. Results This series included 3 females and 4 males, aged from 33 to 64 years. All the 7 cases were negative for CAMTA1 IHC. Four cases were positive for TFE3 IHC and exhibited YAP1::TFE3 fusion. Another 3 cases were also negative for TFE3, while WWTR1::CAMTA1 fusion were detected by NGS in 1 case and demonstrated by FISH in all the 3 cases. Morphologically, among the 4 TFE3 rearrangement cases, 3 cases showed the TFE3-sutype morphologic appearance, while the histology of 1 case was similar to that of CAMTA1- subtype. In the 3 CAMTA1-rearranged lesions, 2 cases had classic EHE morphology, and 1 case exhibited atypical histology, with higher atypia and well-formed vessels. Surgical resection was performed on five cases and two cases were biopsied and received chemotherapy. Follow-up information was available in 6 patients (median 46 months), including 4 patients were alive without disease and 2 patients were alive with disease. Conclusion Our study reported 7 CAMTA1-immunonegative hepatic EHEs and most of them were TFE3-rearranged EHEs with morphology variation. Moreover, there does exist the CAMTA1-immunonegative but CAMTA1-rearranged EHE cases. Therefore, the diagnosis of EHE should be based on morphology, combined with CAMTA1 and TFE3 IHC, and if necessary, supplemented by genetic analysis including FISH and NGS, to establish correct diagnosis.
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Affiliation(s)
| | | | | | | | | | - Hongying Zhang
- Department of Pathology, West China Hospital, Sichuan University,
Chengdu, China
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3
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Choi JH, Thung SN. Mesenchymal Tumors of the Liver: An Update Review. Biomedicines 2025; 13:479. [PMID: 40002892 PMCID: PMC11852400 DOI: 10.3390/biomedicines13020479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Hepatic mesenchymal tumors (HMTs) are non-epithelial benign and malignant tumors with or without specific mesenchymal cell differentiation. They are relatively uncommon. Except for mesenchymal hamartoma, calcified nested stromal-epithelial tumor, and embryonal sarcoma, most mesenchymal lesions are not specific to the liver. Pathologists face challenges in diagnosing HMTs due to their diverse morphologies and phenotypic variations. Accurate diagnosis is critical for directing appropriate patient care and predicting outcomes. This review focuses on mesenchymal tumors with a relative predilection for the liver, including vascular and non-vascular mesenchymal neoplasms. It provides a thorough and up-to-date overview, concentrating on clinical and pathological features, differential diagnosis, and diagnostic approaches.
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Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Namgu, Daegu 42415, Republic of Korea
| | - Swan N. Thung
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA;
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Meng K, Yang X, Guo S, Tao J. Hepatic epithelioid hemangioendothelioma with TFE3 rearrangement: a case report and literature review. Front Oncol 2025; 15:1442233. [PMID: 39917171 PMCID: PMC11799294 DOI: 10.3389/fonc.2025.1442233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 01/03/2025] [Indexed: 02/09/2025] Open
Abstract
Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant tumor of vascular origin. It may be confusing as its manifestations of multifocal lesions on imaging and epithelial histomorphology in pathology. EHE is easy to be mistaken for a metastatic tumor by radiologists and clinicians. Correct diagnosis and therapy are important owing to the variable clinical course and special treatment. EHEs harbor major CAMTA1 rearrangement and <5% TFE3 rearrangement. Meanwhile, EHE with TFE3 rearrangement has distinctive morphology features. Currently, there are only two cases of hepatic EHE with TFE3 rearrangement reported, we present another case here that occurred in a 34-year-old female. Both the clinician and radiologist provisionally considered it as a metastatic tumor. The tumor cells have mild atypia but infiltrative growth patterns like benign vascular tumors. Our case is unique mainly in that the absence of its characteristic well-defined vessels, and the presence of unreported morphology of intraluminal papillary proliferation of tombstone or hobnail endothelial cells. The final diagnosis of EHE with TFE3 rearrangement was made by combining morphological, immunohistochemical, and molecular test results. The patient did not receive any treatment according to her condition and no change was detected in the mass's size and number on CT images during 3.5 years of follow-up.
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Affiliation(s)
| | | | | | - Juan Tao
- Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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5
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Wang B, Chen X, Li R, Ai B, Ye F, Zhao J, Zhang Y, Huang Z, Li Z, Bi X, Zhao H, Cao D, Cai J, Zhou J, Yan T. Comprehensive evaluation of clinical outcomes in hepatic epithelioid hemangioendothelioma subsets: insights from SEER Database and departmental cohort analysis. Front Immunol 2024; 15:1491922. [PMID: 39502705 PMCID: PMC11534872 DOI: 10.3389/fimmu.2024.1491922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 10/07/2024] [Indexed: 11/08/2024] Open
Abstract
Background Epithelioid hemangioendothelioma (EHE), is an uncommon, intermediate-grade malignant vascular tumor that can manifest in diverse organs, including the liver, lungs, and bones. Given its unique malignancy profile and rarity, there lacks a consensus on a standardized treatment protocol for EHE, particularly for hepatic epithelioid hemangioendothelioma (HEHE). This study aims to elucidate factors influencing the clinical prognosis of EHE by analyzing data from the SEER database, complemented with insights from a departmental cohort of 9 HEHE cases. Through this, we hope to shed light on potential clinical outcomes and therapeutic strategies for HEHE. Methods Using SEER data from 22 registries, we analyzed 313 liver cancer patients with ICD-O-3 9130 and 9133 histology. Twelve variables were examined using Cox regression and mlr3 machine learning. Significant variables were identified and compared. Clinical data, imaging characteristics, and treatment methods of nine patients from our cohort were also presented. Result In univariate and multivariate Cox regression analyses, Age, Sex, Year of diagnosis, Surgery of primary site, Chemotherapy, and Median household income were closely related to survival outcomes. Among the ten survival-related machine learning models, CoxPH, Flexible, Mboost, and Gamboost stood out based on Area Under the Curve(AUC), Decision Curve Analysis(DCA), and Calibration Curve Metrics. In the feature importance analysis of these four selected models, Age and Surgery of primary site were consistently identified as the most critical factors influencing prognosis. Additionally, the clinical data of nine patients from our cohort not only demonstrated unique imaging characteristics of HEHE but also underscored the importance of surgical intervention. Conclusion For patients with resectable HEHE, surgical treatment is currently a highly important therapeutic approach.
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Affiliation(s)
- Bingchen Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao Chen
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rongxuan Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bolun Ai
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Feng Ye
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yefan Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiyu Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dayong Cao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Yan
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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6
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Taheri N, Graham RP. How Molecular Discoveries Have Changed Liver Tumor Pathology: A Brief Review. Arch Pathol Lab Med 2024; 148:e96-e102. [PMID: 37639429 DOI: 10.5858/arpa.2023-0099-ra] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 08/31/2023]
Abstract
CONTEXT Recent molecular discoveries have led to improved understanding of tumor biology and the development of new diagnostic assays. OBJECTIVE To review primarily 3 examples of liver tumors and to briefly illustrate how recent molecular discoveries have altered clinical liver pathology practice. DATA SOURCES First, we will discuss fibrolamellar carcinoma, which will be the main focus of discussion, as an example for new diagnostic tests that have been developed as a result of molecular discoveries. Additional information on the role of molecular diagnostics in hepatocellular adenoma and hepatocellular carcinoma will be provided. Second, we will use the example of epithelioid hemangioendothelioma as an example of how new diagnostic tools, based on molecular discoveries, may support improved prognostication. Finally, we will use the example of intrahepatic cholangiocarcinoma as an example of a liver tumor where new molecular discoveries have identified tractable therapeutic targets and led to new effective therapies. This portion of the manuscript will also include a description of the anatomic and molecular differences between intrahepatic, hilar, and extrahepatic cholangiocarcinoma. CONCLUSIONS Fueled by molecular discoveries, new and better diagnostic tests and therapeutic targets have improved clinical care in patients affected by liver tumors.
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MESH Headings
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/diagnosis
- Cholangiocarcinoma/genetics
- Cholangiocarcinoma/pathology
- Cholangiocarcinoma/diagnosis
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/diagnosis
- Hemangioendothelioma, Epithelioid/genetics
- Hemangioendothelioma, Epithelioid/pathology
- Hemangioendothelioma, Epithelioid/diagnosis
- Adenoma, Liver Cell/pathology
- Adenoma, Liver Cell/genetics
- Adenoma, Liver Cell/diagnosis
- Bile Duct Neoplasms/genetics
- Bile Duct Neoplasms/pathology
- Bile Duct Neoplasms/diagnosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Molecular Diagnostic Techniques
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Affiliation(s)
- Negar Taheri
- From the Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering (Taheri)
- the Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota(Taheri)
| | - Rondell P Graham
- the Divisions of Anatomic Pathology, , Mayo Clinic, Rochester, Minnesota(Graham)
- Laboratory Genetics and Genomics, Mayo Clinic, Rochester, Minnesota(Graham)
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7
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Folpe AL. Vascular tumors of intermediate malignancy: An update. Hum Pathol 2024; 147:114-128. [PMID: 38360216 DOI: 10.1016/j.humpath.2024.01.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/17/2024]
Abstract
The term "hemangioendothelioma" is used for endothelial neoplasms of intermediate malignancy and describes a group of rare neoplasms having biologic behavior falling in between that of the benign hemangiomas and fully malignant angiosarcomas. The hemangioendotheliomas fall into several specific, clinicopathologically and genetically distinct entities, specifically epithelioid hemangioendothelioma, kaposiform hemangioendothelioma, papillary intralymphatic angioendothelioma and retiform hemangioendothelioma (hobnailed hemangioendothelioma), pseudomyogenic hemangioendothelioma, composite hemangioendothelioma, and YAP1::TFE3-fused hemangioendothelioma. The clinical, morphologic, immunohistochemical, and genetic features, and the differential diagnosis of each of these rare entities are discussed in this review.
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Affiliation(s)
- Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55902, United States.
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8
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Papke DJ. Mesenchymal Neoplasms of the Liver. Surg Pathol Clin 2023; 16:609-634. [PMID: 37536892 DOI: 10.1016/j.path.2023.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
Mesenchymal neoplasms of the liver can be diagnostically challenging, particularly on core needle biopsies. Here, I discuss recent updates in neoplasms that are specific to the liver (mesenchymal hamartoma, undifferentiated embryonal sarcoma, calcifying nested stromal-epithelial tumor), vascular tumors of the liver (anastomosing hemangioma, hepatic small vessel neoplasm, epithelioid hemangioendothelioma, angiosarcoma), and other tumor types that can occur primarily in the liver (PEComa/angiomyolipoma, inflammatory pseudotumor-like follicular dendritic cell sarcoma, EBV-associated smooth muscle tumor, inflammatory myofibroblastic tumor, malignant rhabdoid tumor). Lastly, I discuss metastatic sarcomas to the liver, as well as pitfalls presented by metastatic melanoma and sarcomatoid carcinoma.
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Affiliation(s)
- David J Papke
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
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9
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Jakša R, Stružinská I, Kendall Bártů M, Trča S, Matěj R, Dundr P. Clear cell stromal tumor of the lung with multinucleated giant cells: a report of a case with YAP1-TFE3 fusion. Diagn Pathol 2023; 18:9. [PMID: 36707859 PMCID: PMC9881279 DOI: 10.1186/s13000-023-01304-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 01/23/2023] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCSTL) is a rare pulmonary neoplasm. Recently, 9 cases of CCSTL harboring the YAP1-TFE3 gene fusion have been described, and it has been suggested that this aberration could be a characteristic feature of this tumor. CASE PRESENTATION We here report another case of CCSTL in a 57-year-old male, which presented as a solitary lung nodule 45 mm in the greatest dimension. Microscopically, the tumor consisted of epithelioid to spindled cells with mild-to-moderate nuclear atypia, finely granular or vesicular chromatin, and small nucleoli. Nuclear indentations were a common finding. There were up to 3 mitoses per 10 HPF. The cytoplasm was slightly eosinophilic or clear. Scattered non-tumor large multinucleated cells were present. Immunohistochemically, the tumor cells showed diffuse positivity for TFE3, CD10, vimentin, and IFITM1. Other markers examined were negative, and the expression of lineage-specific markers was not found. NGS analysis revealed a fusion transcript of the YAP1 and TFE3 genes, and a pathogenic variant of the MUTYH gene. CONCLUSION Our finding supports the recent data suggesting that CCSTL represents a distinct entity characterized by the recurrent YAP1-TFE3 fusion.
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Affiliation(s)
- Radek Jakša
- grid.411798.20000 0000 9100 9940Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, 128 00 Prague 2, Czech Republic
| | - Ivana Stružinská
- grid.411798.20000 0000 9100 9940Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, 128 00 Prague 2, Czech Republic
| | - Michaela Kendall Bártů
- grid.411798.20000 0000 9100 9940Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, 128 00 Prague 2, Czech Republic
| | - Stanislav Trča
- grid.411798.20000 0000 9100 9940Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 00 Prague 2, Czech Republic
| | - Radoslav Matěj
- grid.411798.20000 0000 9100 9940Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, 128 00 Prague 2, Czech Republic ,grid.4491.80000 0004 1937 116XDepartment of Pathology, Charles University, 3rd Faculty of Medicine, University Hospital Kralovske Vinohrady, Prague, Czech Republic ,grid.4491.80000 0004 1937 116XDepartment of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University, Thomayer Hospital, Prague, Czech Republic
| | - Pavel Dundr
- grid.411798.20000 0000 9100 9940Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Studničkova 2, 128 00 Prague 2, Czech Republic
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10
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Dermawan JK, Azzato EM, Billings SD, Fritchie KJ, Aubert S, Bahrami A, Barisella M, Baumhoer D, Blum V, Bode B, Aesif SW, Bovée JVMG, Dickson BC, van den Hout M, Lucas DR, Moch H, Oaxaca G, Righi A, Sciot R, Sumathi V, Yoshida A, Rubin BP. YAP1-TFE3-fused hemangioendothelioma: a multi-institutional clinicopathologic study of 24 genetically-confirmed cases. Mod Pathol 2021; 34:2211-2221. [PMID: 34381186 DOI: 10.1038/s41379-021-00879-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 11/09/2022]
Abstract
YAP1-TFE3-fused hemangioendothelioma is an extremely rare malignant vascular tumor. We present the largest multi-institutional clinicopathologic study of YAP1-TFE3-fused hemangioendothelioma to date. The 24 cases of YAP1-TFE3-fused hemangioendothelioma showed a female predominance (17 female, 7 male) across a wide age range (20-78 years old, median 44). Tumors were most commonly located in soft tissue (50%), followed by bone (29%), lung (13%), and liver (8%), ranging from 3 to 115 mm in size (median 40 mm). About two-thirds presented with multifocal disease, including 7 cases with distant organ metastasis. Histopathologically, we describe three dominant architectural patterns: solid sheets of coalescing nests, pseudoalveolar and (pseudo)vasoformative pattern, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. These patterns were present in variable proportions across different tumors and often coexisted within the same tumor. The dominant cytomorphology (88%) was large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli and well-demarcated cell borders. Multinucleated or binucleated cells, prominent admixed erythrocytic and lymphocytic infiltrates, and intratumoral fat were frequently present. Immunohistochemically, ERG, CD31, and TFE3 were consistently expressed, while expression of CD34 (83%) and cytokeratin AE1/AE3 (20%) was variable. CAMTA1 was negative in all but one case. All cases were confirmed by molecular testing to harbor YAP1-TFE3 gene fusions: majority with YAP1 exon 1 fused to TFE3 exon 4 (88%), or less commonly, TFE3 exon 6 (12%). Most patients (88%) were treated with primary surgical resection. Over a follow-up period of 4-360 months (median 36 months) in 17 cases, 35% of patients remained alive without disease, and 47% survived many years with stable, albeit multifocal and/or metastatic disease. Five-year progression-free survival probability was 88%. We propose categorizing YAP1-TFE3-fused hemangioendothelioma as a distinct disease entity given its unique clinical and histopathologic characteristics in comparison to conventional epithelioid hemangioendothelioma.
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Affiliation(s)
- Josephine K Dermawan
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Elizabeth M Azzato
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Steven D Billings
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Karen J Fritchie
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Sebastien Aubert
- Department of Pathology, Institut de Pathologie, University of Lille, Lille, France
| | - Armita Bahrami
- Department of Pathology, Emory University, Atlanta, GA, USA
| | - Marta Barisella
- Struttura Complessa Anatomia Patologica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Daniel Baumhoer
- Bone Tumor Reference Center at the Institute of Medical Genetics and Pathology, University Hospital and University of Basel, Basel, Switzerland
| | - Veronika Blum
- FMH Medical Oncology, Luzerner Kantonsspital, Luzern, Switzerland
| | - Beata Bode
- Pathology Institute Enge and University of Zurich, Zurich, Switzerland
| | - Scott W Aesif
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Judith V M G Bovée
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Brendan C Dickson
- Department of Pathology and Laboratory Medicine, Sinai Health System, Toronto, ON, Canada
| | - Mari van den Hout
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - David R Lucas
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Gabriel Oaxaca
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | | | - Raf Sciot
- Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Vaiyapuri Sumathi
- Department of Musculoskeletal Pathology, Robert Aitken Institute of Clinical Research, University of Birmingham, Birmingham, UK
| | - Akihiko Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Brian P Rubin
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
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11
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Bourgeau M, Martinez A, Deeb KK, Reid MD, Lewis M, Point du Jour KS, Lai J, Shi Q. Cytologic features of hepatic YAP1-TFE3 rearranged epithelioid hemangioendothelioma. Diagn Cytopathol 2021; 49:E447-E452. [PMID: 34411462 DOI: 10.1002/dc.24853] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 11/09/2022]
Abstract
Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor of intermediate malignancy, often with indolent behavior. Though most cases have a characteristic WWTR1-CAMTA1 gene fusion, a subtype of EHE with YAP1-TFE3 fusions and a distinct morphology has recently been described histologically, but no cases of YAP1-TFE3 EHE have been described in the cytology literature. We herein report on a case of YAP1-TFE3 fusion associated EHE diagnosed on fine-needle aspiration and core biopsy of a liver mass in an 18-year-old male patient who presented with synchronous lung and liver involvement. We also discuss the differential diagnosis of EHE on cytology specimens.
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Affiliation(s)
- Melanie Bourgeau
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Anthony Martinez
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Kristin K Deeb
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Michelle D Reid
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | - Melinda Lewis
- Department of Pathology, Emory University, Atlanta, Georgia, USA
| | | | - Jinping Lai
- Department of Pathology, Kaiser Permanente Sacramento Medical Center, Sacramento, California, USA
| | - Qiuying Shi
- Department of Pathology, Emory University, Atlanta, Georgia, USA
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12
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Dermawan JK, Azzato EM, McKenney JK, Liegl-Atzwanger B, Rubin BP. YAP1-TFE3 gene fusion variant in clear cell stromal tumour of lung: report of two cases in support of a distinct entity. Histopathology 2021; 79:940-946. [PMID: 34156713 DOI: 10.1111/his.14437] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/16/2021] [Accepted: 06/19/2021] [Indexed: 11/30/2022]
Abstract
AIMS Clear cell (haemangioblastoma-like) stromal tumour of the lung is a newly described, rare pulmonary neoplasm. Recurrent YAP1-TFE3 gene fusions have recently been reported in three cases. We describe two additional cases and confirm the characteristic YAP1-TFE3 gene fusion. METHODS AND RESULTS Two mesenchymal tumours of lung were identified from our soft tissue pathology consultation services and RNA sequencing was performed. Both cases were in male patients, aged 35 and 77 years. Both presented as solitary lung nodules measuring 3.9 and 7.5 cm in greatest dimension. Histopathologically, the tumours were composed of epithelioid to plump spindle cells arranged in packets and solid sheets. The cells showed fusiform to ovoid nuclei with open chromatin, variably prominent nucleoli and scant to moderate, clear to eosinophilic cytoplasm. Cytological atypia and significant mitotic activity were minimal. None of the tumours expressed lineage-specific immunophenotypical markers. Both cases were diffusely positive for nuclear TFE3. Unlike YAP1-TFE3-fused epithelioid haemangioendothelioma, for which the fusion breakpoint occurs in YAP1 exon 1 and TFE3 exons 4 or 6, the fusion breakpoints of these tumours were located in YAP1 exon 4 and TFE3 exon 7. Following complete surgical resection, neither of the tumours has recurred or metastasised (follow-up period 6-7 months). CONCLUSIONS We validate the presence of YAP1-TFE3 gene fusion in a unique primary mesenchymal tumour of lung, adding additional support for clear cell stromal tumour of the lung as a distinct entity.
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Affiliation(s)
- Josephine K Dermawan
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Elizabeth M Azzato
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jesse K McKenney
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Bernadette Liegl-Atzwanger
- Diagnostic and Research Institute of Pathology, Translational Sarcoma Pathology, Medical University of Graz, Graz, Austria
| | - Brian P Rubin
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
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13
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Kou K, Chen YG, Zhou JP, Sun XD, Sun DW, Li SX, Lv GY. Hepatic epithelioid hemangioendothelioma: Update on diagnosis and therapy. World J Clin Cases 2020; 8:3978-3987. [PMID: 33024754 PMCID: PMC7520791 DOI: 10.12998/wjcc.v8.i18.3978] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/12/2020] [Accepted: 08/21/2020] [Indexed: 02/05/2023] Open
Abstract
With an estimated incidence of only 1-2 cases in every 1 million people, hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular endothelial cell tumor occurring in the liver and consisting of epithelioid and histiocyte-like vascular endothelial cells in mucus or a fibrotic matrix. HEHE is characterized as a low-to-moderate grade malignant tumor and is classified into three types: solitary, multiple, and diffuse. Both the etiology and characteristic clinical manifestations of HEHE are unclear. However, HEHE has a characteristic appearance on imaging including ultrasound, magnetic resonance imaging, and positron emission tomography/computerized tomography. Still, its diagnosis depends mainly on pathological findings, with immunohistochemical detection of endothelial markers cluster of differentiation 31 (CD31), CD34, CD10, vimentin, and factor VIII antigen as the basis of diagnosis. Hepatectomy and/or liver transplantation are the first choice for treatment, but various chemotherapeutic drugs are reportedly effective, providing a promising treatment option. In this review, we summarize the literature related to the diagnosis and treatment of HEHE, which provides future perspectives for the clinical management of HEHE.
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Affiliation(s)
- Kai Kou
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yu-Guo Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jian-Peng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiao-Dong Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Da-Wei Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Shu-Xuan Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Guo-Yue Lv
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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14
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Current Approaches for Personalized Therapy of Soft Tissue Sarcomas. Sarcoma 2020; 2020:6716742. [PMID: 32317857 PMCID: PMC7152984 DOI: 10.1155/2020/6716742] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/27/2020] [Accepted: 03/09/2020] [Indexed: 02/07/2023] Open
Abstract
Soft tissue sarcomas (STS) are a highly heterogeneous group of cancers of mesenchymal origin with diverse morphologies and clinical behaviors. While surgical resection is the standard treatment for primary STS, advanced and metastatic STS patients are not eligible for surgery. Systemic treatments, including standard chemotherapy and newer chemical agents, still play the most relevant role in the management of the disease. Discovery of specific genetic alterations in distinct STS subtypes allowed better understanding of mechanisms driving their pathogenesis and treatment optimization. This review focuses on the available targeted drugs or drug combinations based on genetic aberration involved in STS development including chromosomal translocations, oncogenic mutations, gene amplifications, and their perspectives in STS treatment. Furthermore, in this review, we discuss the possible use of chemotherapy sensitivity and resistance assays (CSRA) for the adjustment of treatment for individual patients. In summary, current trends in personalized management of advanced and metastatic STS are based on combination of both genetic testing and CSRA.
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15
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Zhang HZ, Dong L, Wang SY, Yang XQ. TFE3 rearranged epithelioid hemangioendothelioma of bone: A clinicopathological, immunohistochemical and molecular study of two cases. Ann Diagn Pathol 2020; 46:151487. [PMID: 32151991 DOI: 10.1016/j.anndiagpath.2020.151487] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/12/2020] [Accepted: 02/25/2020] [Indexed: 01/22/2023]
Abstract
Epithelioid hemangioendothelioma (EHE) is a rare malignant angiocentric vascular neoplasm. Around 90% of classic EHE has a t(1;3)(p36;q25) that results in a WWTR1-CAMTA1 fusion gene, a histologically distinctive subset of EHE has been recently shown to have a t(10;14)(p13;q42)that results in a different fusion gene, YAP1-TFE3. Twenty-one cases of TFE3 Rearranged Epithelioid Hemangioendothelioma have been reported in the literature, and only two cases occurred in bone. In the report, we report additional two cases occurred in the femur and skull and review the related literature.
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Affiliation(s)
- Hui-Zhi Zhang
- Department of Pathology, Ningbo Diagnostic Pathology Center, Ningbo, Zhejiang 315000, China
| | - Lei Dong
- Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Su-Ying Wang
- Department of Pathology, Ningbo Diagnostic Pathology Center, Ningbo, Zhejiang 315000, China
| | - Xiao-Qun Yang
- Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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16
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Hepatic YAP1-TFE3 Rearranged Epithelioid Hemangioendothelioma. Case Rep Gastrointest Med 2019; 2019:7530845. [PMID: 31341686 PMCID: PMC6612390 DOI: 10.1155/2019/7530845] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 05/10/2019] [Accepted: 05/29/2019] [Indexed: 12/15/2022] Open
Abstract
Epithelioid hemangioendothelioma (EHE) is an uncommon low-grade malignant vascular tumor that may arise in soft tissue/bone or visceral sites such as the liver and lung. As this tumor exhibits epithelioid morphology, it frequently causes diagnostic confusion with other epithelioid vascular neoplasms as well as carcinoma. While 90% of classic EHE are driven by a WWTR1-CAMTA1 fusion gene, a histologically distinctive subset of EHE has been recently shown to harbor a different fusion gene, YAP1-TFE3. This variant is likely underrecognized given its rarity and only recent description. Notably, EHE frequently involves the liver but only one case of hepatic YAP1-TFE3 rearranged EHE has been reported to date. We present the second case of YAP1-TFE3 rearranged EHE affecting a 65-year-old woman and presenting as multiple liver masses, with characterization of the fusion gene at the transcriptomic and genomic levels. There are several educational points noted from this case. YAP1-TFE3 rearranged EHE shows distinctly vasoformative foci, unlike classic EHE and mimicking angiosarcoma or epithelioid hemangioma. The tumors cells show a histiocytoid appearance with voluminous cytoplasm, similar to other TFE3-rearranged tumors. Finally, in the liver, this tumor may in part mimic focal nodular hyperplasia of the liver which is an underrecognized diagnostic pitfall. This report highlights the key diagnostic and genetic features of this newly recognized variant of hepatic EHE to aid pathologists in appropriately classifying these tumors.
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