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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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Choi JH, Ro JY. The Recent Advances in Molecular Diagnosis of Soft Tissue Tumors. Int J Mol Sci 2023; 24:ijms24065934. [PMID: 36983010 PMCID: PMC10051446 DOI: 10.3390/ijms24065934] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/17/2023] [Accepted: 03/19/2023] [Indexed: 03/30/2023] Open
Abstract
Soft tissue tumors are rare mesenchymal tumors with divergent differentiation. The diagnosis of soft tissue tumors is challenging for pathologists owing to the diversity of tumor types and histological overlap among the tumor entities. Present-day understanding of the molecular pathogenesis of soft tissue tumors has rapidly increased with the development of molecular genetic techniques (e.g., next-generation sequencing). Additionally, immunohistochemical markers that serve as surrogate markers for recurrent translocations in soft tissue tumors have been developed. This review aims to provide an update on recently described molecular findings and relevant novel immunohistochemical markers in selected soft tissue tumors.
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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
| | - Jae Y Ro
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College, Cornell University, Houston, TX 77030, USA
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Sirohi D, Ohe C, Smith SC, Amin MB. SWI/SNF-deficient neoplasms of the genitourinary tract. Semin Diagn Pathol 2021; 38:212-221. [PMID: 33840529 DOI: 10.1053/j.semdp.2021.03.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/13/2022]
Abstract
Since the discovery of association of SMARCB1 mutations with malignant rhabdoid tumors and renal medullary carcinoma, mutations in genes of the SWI/SNF chromatin remodeling complex have been increasingly identified across a diverse spectrum of neoplasms. As a group, SWI/SNF complex subunit mutations are now recognized to be the second most frequent type of mutations across tumors. SMARCB1 mutations were originally reported in malignant rhabdoid tumors of the kidney and thought to be pathognomonic for this tumor. However, more broadly, recognition of typical rhabdoid cytomorphology and SMARCB1 mutations beyond rhabdoid tumors has changed our understanding of the pathobiology of these tumors. While mutations of SWI/SNF complex are diagnostic of rhabdoid tumors and renal medullary carcinoma, their clinical relevance extends to potential prognostic and predictive utility in other tumors as well. Beyond SMARCB1, the PBRM1 and ARID1A genes are the most frequently altered members of the SWI/SNF complex in genitourinary neoplasms, especially in clear cell renal cell carcinoma and urothelial carcinoma. In this review, we provide an overview of alterations in the SWI/SNF complex encountered in genitourinary neoplasms and discuss their increasing clinical importance.
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Affiliation(s)
- Deepika Sirohi
- Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT, USA
| | - Chisato Ohe
- Department of Pathology, Kansai Medical University, Osaka, Japan
| | - Steven C Smith
- Departments of Pathology and Urology, Virginia Commonwealth University, School of Medicine, PO Box 980662, Richmond, VA 23298, USA.
| | - Mahul B Amin
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Sciences, Memphis, TN, USA; Department of Urology, USC Keck School of Medicine, Los Angeles, CA, USA
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4
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Kannan S, Lock I, Ozenberger BB, Jones KB. Genetic drivers and cells of origin in sarcomagenesis. J Pathol 2021; 254:474-493. [DOI: 10.1002/path.5617] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/01/2020] [Accepted: 01/06/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Sarmishta Kannan
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Ian Lock
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Benjamin B Ozenberger
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Kevin B Jones
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
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Jeong H, Hong YS, Kim YH, Kim CW, Song SY, Song JS, Cho KJ, Kim JE, Ahn JH. The Role and Clinical Effectiveness of Multiline Chemotherapy in Advanced Desmoplastic Small Round Cell Tumor. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2021; 15:1179554920987107. [PMID: 33642889 PMCID: PMC7894597 DOI: 10.1177/1179554920987107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 12/17/2020] [Indexed: 11/17/2022]
Abstract
Background: A multimodal approach is the standard treatment for desmoplastic small round cell tumor (DSRCT); however, many patients are diagnosed with inoperable disease, which leaves chemotherapy as the only treatment option. There are limited data on the effectiveness of palliative chemotherapy, especially when used after first-line treatment. Here, we evaluated the clinical outcomes of patients with DSRCT treated with multiple lines of chemotherapy. Methods: We reviewed medical records of 14 patients with pathologically confirmed DSRCT at Asan Medical Center between 2004 and 2018. Results: The median age at diagnosis was 25, with males comprising 92.9% of patients. All patients had inoperable disease at presentation and received chemotherapy as the initial treatment. Four patients (28.6%) were treated with surgery, and complete resection was achieved in 1 patient. Median overall survival (OS) was 23.9 months, and 1-, 2-, and 3-year survival rates were 92.9%, 48.6%, and 19.5%, respectively. In patients receiving first- (N = 14), second- (N = 10), and third-line (N = 8) chemotherapy, median time-to-progression was 9.9, 3.5, and 2.5 months, respectively, and the disease control rates were 100%, 88.9%, and 75.0%, respectively. Factors associated with longer OS in the univariable analysis were ⩽2 metastatic sites at presentation (27.0 vs 14.7 months; P = .024) and surgery with intended complete resection (43.5 vs 20.1 months; P = .027). Conclusions: Although advanced DSRCT may initially respond to chemotherapy after first-line treatment, the response becomes less durable as the disease progresses. Individualized treatment decisions focused on palliation should be made.
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Affiliation(s)
- Hyehyun Jeong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yong Sang Hong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Hoon Kim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chan Wook Kim
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Si Yeol Song
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joon Seon Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyung-Ja Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong Eun Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin-Hee Ahn
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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7
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Jahraus CD, Glisson SD, St Clair WH. Treatment of Desmoplastic Small round Cell Tumor with Image-Guided Intensity Modulated Radiation Therapy as a Component of Multimodality Treatment. TUMORI JOURNAL 2018; 91:253-5. [PMID: 16206650 DOI: 10.1177/030089160509100308] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and background The authors report the case of a 31-year-old black male diagnosed with a pelvic desmoplastic small round-cell tumor who was treated with a unique radiotherapy approach incorporating intensity-modulated radiotherapy and daily ultrasound localization to ensure accurate tumor targeting. Desmoplastic small round-cell tumor is a very rare tumor, most commonly presenting in the abdominopelvic regions of adolescents and young adults. It has generally been associated with a very poor prognosis. Methods The patient initially underwent biopsy of the mass and omentectomy for mesenteric implants followed by chemotherapy. Chemotherapy resulted in tumor shrinkage and was followed by a second-look laparotomy. Additional omental nodules were resected, but the primary tumor was adherent to the rectum and seminal vesicles. A radiation oncology consult was obtained, and a course of image-guided intensity-modulated radiotherapy ensued with daily ultrasound localization. This resulted in shrinkage of local disease, but a new lesion was identified. The patient was subsequently started on further chemotherapy, which has maintained the disease in a stable state for several months. Conclusions Image-guided intensity-modulated radiotherapy is a feasible option in the treatment of pelvic desmoplastic small round-cell tumor. Such therapy may permit escalation of conventional radiotherapy doses and could have a favorable impact on local control of disease. Confirmation of this belief will require additional data in the form of case reports like this. Pending such confirmation, we continue to be of the impression that desmoplastic small round-cell tumor has an overall unfavorable prognosis, regardless of treatment modalities employed.
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Affiliation(s)
- Christopher D Jahraus
- Department of Radiation Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
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8
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Llombart-Bosch A, Peydro-Olaya A, Carda C, Lopez-Gines C, Boix-Ferrero J, Pellin A. Primary Rhabdomyosarcoma Mimicking a Small Cell Sarcoma of Bone: A Nude Mice Xenograft, Cytogenetic, and Molecular Approach. Int J Surg Pathol 2016. [DOI: 10.1177/106689699800600202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Small cell sarcomas of bone are difficult to classify and diagnose. The present case deals with such a tumor in which the original biopsy and the resected specimen, studied by histology before chemotherapy, provided no final information about its real nature. Thus several techniques were applied to discern its histogenesis and biology. Myogenin proved positive in isolated cells of the primary neoplasm but was extensively expressed in nude mice xenografts. Electron microscopy confirmed the existence of myofilaments. The cytogenetic analysis revealed a large number of chromo somal abnormalities, but not those found in the Ewing's/PNET (peripheral neuroectodermal tumor) family of tumors. This was confirmed by polymerase chain reaction (RT-PCR) wherein no EWS/Fli 1 or PAX3/FKHR gene rearrangements were detected. Based upon these studies, a rhabdomyosarcoma of bone was diagnosed. Clinically the neoplasm showed a highly aggressive behavior, causing death of the patient within 2 years after diagnosis.
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Affiliation(s)
- A. Llombart-Bosch
- Department of Pathology, Medical School, University of Valencia, Avda. Blasco Ibafiez 17, E-46010-Valencia, Spain
| | | | | | | | | | - A. Pellin
- Department of Pathology, Medical School and Hospital Clinico Universitario, Valencia, Spain
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9
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Abstract
The first large series of desmoplastic small round cell tumor was reported twenty-five years ago. This article reviews the original characterization of this neoplasm, and the eventual expansion of its clinical and pathological spectrum. Relevant data on its molecular features are summarized, in order to understand the search for therapeutic targets. The challenge ahead is to better know and cure this disease through the finding and validation of actionable therapeutic targets.
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Affiliation(s)
- Enrique de Alava
- Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital, CSIC, University of Sevilla, Seville 41013, Spain; Department of Pathology, La Merced Hospital, AGS Osuna, Osuna, Spain.
| | - David Marcilla
- Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital, CSIC, University of Sevilla, Seville 41013, Spain; Department of Pathology, La Merced Hospital, AGS Osuna, Osuna, Spain
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Mora J, Modak S, Cheung NK, Meyers P, de Alava E, Kushner B, Magnan H, Tirado OM, Laquaglia M, Ladanyi M, Rosai J. Desmoplastic small round cell tumor 20 years after its discovery. Future Oncol 2016; 11:1071-81. [PMID: 25804122 DOI: 10.2217/fon.15.32] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Desmoplastic small round cell tumor (DSRCT) was proposed as a distinct disease entity by William L Gerald and Juan Rosai in 1991. Over 850 patients have been reported in the medical literature. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene. DSRCT is composed of nests of small round cells with polyphenotypic differentiation, typically a mixture of epithelial, mesenchymal and neural features, surrounded by a prominent desmoplastic stroma. DSRCT has a predilection for adolescent and young adult males, and primarily involves the abdominal cavity and pelvis. Survival is low despite their initial response to multimodal treatment. Most patients relapse with disseminated disease that is unresponsive to further therapy.
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Affiliation(s)
- Jaume Mora
- Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain
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11
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Chen J, Sheng J, Wang L, Wang ZM, Li L. Desmoplastic small-round-cell tumor of the abdomen: A report of two rare cases. Oncol Lett 2015; 10:705-708. [PMID: 26622557 DOI: 10.3892/ol.2015.3357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Accepted: 05/15/2015] [Indexed: 11/05/2022] Open
Abstract
Desmoplastic small-round-cell tumor (DSRCT) is an uncommon type of malignancy, which primarily occurs in adolescent males and develops in the abdominal cavity. The present study reports the case of two manifestations of DSRCT complicated with other diseases, which involved the invasion of the pelvis or abdominal vessels. The first case was of a 25-year-old man with repeated diarrhea and abdominal distension for 9 months; the second case was of a 68-year-old man who presented with persistent abdominal pain for 20 days. In each patient, a mass was identified in the abdomen and biopsies were performed in order to reach a diagnosis. Immunohistochemical staining of the biopsy material revealed a diagnosis of DSRCT in each case. In addition, the present study aimed to discuss the use of imaging techniques in providing evidence for the early diagnosis of DSRCT.
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Affiliation(s)
- Jiajia Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China ; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, P.R. China
| | - Jifang Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China ; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, P.R. China
| | - Lijun Wang
- Department of Pathology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Zhao-Ming Wang
- Department of Pathology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China ; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, P.R. China
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Cheah AL, Goldblum JR, Billings SD. Molecular diagnostics complementing morphology in superficial mesenchymal tumors. Semin Diagn Pathol 2013; 30:95-109. [PMID: 23327733 DOI: 10.1053/j.semdp.2012.01.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Molecular techniques are increasingly important in the practice of surgical pathology. In soft tissue tumors, there are a number of tumors with recurring cytogenetic abnormalities. Knowledge of these abnormalities has furthered our understanding of these tumors and has also allowed development of molecular techniques to aid in the diagnosis. This review will focus on mesenchymal tumors with specific cytogenetic abnormalities that may present as a superficial tumor of the dermis or subcutis.
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Affiliation(s)
- Alison L Cheah
- Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH 44195, USA
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13
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The Role of Molecular Testing in the Diagnosis of Cutaneous Soft Tissue Tumors. ACTA ACUST UNITED AC 2012; 31:221-33. [DOI: 10.1016/j.sder.2012.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 07/18/2012] [Indexed: 11/21/2022]
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Abstract
Significant progress has been made in understanding the molecular genetic alterations involved in sarcomagenesis. Cytogenetic and molecular studies have identified nonrandom genetic abnormalities, including tumor suppressor gene inactivation. Mutations, deletions, and other somatic alterations in the tumor suppressor gene INI1 (hSNF5; SMARCB1), which encodes a subunit of the SWI/SNF chromatin remodeling complex, were first described in the malignant rhabdoid tumor of infancy. Since then, INI1 has also been implicated in the pathogenesis of additional tumor types including renal medullary carcinomas and epithelioid sarcomas and a subset of epithelioid malignant peripheral nerve sheath tumors, myoepithelial carcinomas, and extraskeletal myxoid chondrosarcomas. As varied as this group appears, they all show loss of INI1 protein expression, a propensity for rhabdoid cytomorphology, and sometimes other overlapping immunohistochemical and histologic findings. We will review the clinicopathologic features of these tumor types and emphasize the clinical utility of INI1 immunohistochemistry in differential diagnosis.
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Koniari K, Mahera H, Nikolaou M, Chatzis O, Glezakou O, Magiasis V, Kiratzis G. Intraabdominal desmoplastic small round cell tumor: Report of a case and literature review. Int J Surg Case Rep 2011; 2:293-6. [PMID: 22096758 DOI: 10.1016/j.ijscr.2011.08.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2011] [Revised: 08/04/2011] [Accepted: 08/05/2011] [Indexed: 10/16/2022] Open
Abstract
INTRODUCTION Desmoplastic small round cell tumor is a rare malignancy with poor prognosis that predominantly affects young males. Its etiopathogenesis is still unknown and diagnosis can be achieved only by immunohistochemistry and cytogenetic studies. Due to our limited knowledge of the pathologic and clinical nature of this disease, there is no clear consensus regarding the optimal therapeutic procedures for treating this neoplasm. A high degree of care and improvements in diagnostic capabilities are required in order to identify this entity and avoid misdiagnosis. CASE PRESENTATION We report a new case of a 29-year-old male who proceeded to our Emergency Department complaining about non-specific abdominal pain. Physical examination revealed no abnormalities except for a palpable mass in the lower abdomen and a diffuse abdominal pain. Computed Tomography scan showed enlarged paraortic and mesenteric lymphadenopathy, thickness of the small bowel wall and dispersed masses intraperitoneally. He underwent an exploratory laparotomy and the resultant biopsy revealed desmoplastic small round cell tumor. DISCUSSION Diagnosis of desmoplastic small round cell tumor can easily be missed because it presents with few early warning symptoms and signs, while the routine blood tests are within normal limits. CONCLUSION A high degree of suspicion, a thorough physical examination, a full imaging check and an aggressive therapeutic approach are required in order to identify this disease and fight for a better quality of life for these patients. In addition we make a review of the literature in an effort to clarify the epidemiological, clinical and pathological aspects of this entity.
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Affiliation(s)
- Katerina Koniari
- Department of Internal Medicine, General Hospital KAT, Nikis 2, Kifisia, 14561, Athens, Greece
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Zumkeller W. The role of insulin-like growth factor system in soft tissue sarcomas: from physiopathology to targeted therapeutic approaches. Sarcoma 2011; 2:69-76. [PMID: 18521237 PMCID: PMC2395388 DOI: 10.1080/13577149878028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Purpose/Results. Although surgical, chemo- and radiotherapeutic treatment regimens in patients with soft tissue sarcomas have constantly been refined over the past two decades, the survival rate for these patients is rather low. Discussion. There is a great need to investigate the mechanisms for oncogenesis and to identify the factors involved in malignant transformation in sarcomas. Among these factors, IGFs are thought to play a pivotal role as progression factors in various types of sarcomas. The dysregulation of the IGF-II synthesis, e.g. by loss of imprinting which occurs in most
types of sarcomas, is a permissive effect through the suppression of cell death. In addition, cells that overexpress the type I IGF receptors are more susceptible to transformation by oncogenes. As TP53 suppresses the activity of IGF-II P3 and P4, as well as the type I IGF receptor promoter, mutations of TP53 in sarcomas may alternatively lead to the activation of these factors. Finally, the phenomenon of non-islet cell tumour hypoglycaemia that occurs in patients with sarcomas, and which is related to the secretion of IGF-II prohormones, is discussed. Future therapeutic strategies may be based upon the application of antibodies or antisense oligonucleotides directed against the type I IGF receptors, with the common goal of inducing apoptosis in sarcoma cells. Ultimately, these and other therapeutic approaches may lead to a better outcome in patients suffering from sarcoma.
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Affiliation(s)
- W Zumkeller
- Department of Hematology/Oncology Children's University Hospital Heidelberg Germany
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17
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Kuhnen C, Schäfer KL, Franke K, Poremba C. [Cystic desmoplastic small round cell tumor: tumor development from cystic-"mesothelioblastic" areas?]. DER PATHOLOGE 2010; 31:142-9. [PMID: 20066421 DOI: 10.1007/s00292-009-1258-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
A 7-cm cystic lesion in the upper left abdomen and additional smaller solid tumor nodules were diagnosed incidentally in a 15-year-old boy without tumor symptoms. The main tumorous cystic lesion showed a flattened single-cell tumor cell component in gradual transition to stratified, papillary and truly "invasive" typical desmoplastic areas of a desmoplastic small round-cell tumor (DSRCT). The Ki-67-proliferation index gradually increased within three histologic tumor patterns up to about 70% in the typical desmoplastic (infiltrating) component. Using microdissection techniques, EWS-WT1-gene fusion transcripts were detected in the cystic (single-cell-layered), the papillary and the solid tumor proliferations (exon 7 of EWS on chromosome 22 with exon 8 of WT1 on chromosome 11). The presented case illustrates a predominant cystic growth pattern of DSRCT, in which a stepwise development in the pathogenesis of DSRCT from cystic (-"mesothelioblastic") towards a more papillary proliferation and finally typical "infiltrative" desmoplastic tumor pattern might be discussed. The cystic pattern could represent an initial stage in the development of the neoplasia. The presence of specific EWS-WT1-gene fusion transcripts in all tumor growth patterns in this respect would indicate an early event in t(11;22)(p13;q12) translocation in the pathogenesis of DSRCT.
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MESH Headings
- Abdominal Neoplasms/genetics
- Abdominal Neoplasms/pathology
- Adolescent
- Biomarkers, Tumor/genetics
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Chromosomes, Human, Pair 11
- Chromosomes, Human, Pair 22
- Exons/genetics
- Gene Expression Regulation, Neoplastic/genetics
- Humans
- Ki-67 Antigen/genetics
- Male
- Neoplasms, Multiple Primary/genetics
- Neoplasms, Multiple Primary/pathology
- Oncogene Proteins, Fusion/genetics
- Sarcoma, Small Cell/genetics
- Sarcoma, Small Cell/pathology
- Translocation, Genetic/genetics
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Affiliation(s)
- C Kuhnen
- Institut für Pathologie am Clemenshospital, Medical Center, Düesbergweg 128, 48153 Münster.
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18
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The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-kappaB target genes by interaction with NFKBIZ. Oncogene 2008; 28:270-8. [PMID: 18850010 DOI: 10.1038/onc.2008.378] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
FUS (also called TLS), EWSR1 and TAF15 (also called TAF2N) are related genes involved in tumor type-specific fusion oncogenes in human malignancies. The FUS-DDIT3 fusion oncogene results from a t(12;16)(q13;p11) chromosome translocation and has a causative role in the initiation of myxoid/round cell liposarcomas (MLS/RCLS). The FUS-DDIT3 protein induces increased expression of the CAAT/enhancer-binding protein (C/EBP) and nuclear factor-kappaB (NF-kappaB)-controlled gene IL8, and the N-terminal FUS part is required for this activation. Chromatin immunoprecipitation analysis showed that FUS-DDIT3 binds the IL8 promoter. Expression studies of the IL8 promoter harboring a C/EBP-NF-kappaB composite site pinpointed the importance of NF-kappaB for IL8 expression in FUS-DDIT3-expressing cells. We therefore probed for possible interaction of FUS-DDIT3 with members of the NF-kappaB family. The nuclear factor NFKBIZ colocalizes with FUS-DDIT3 in nuclear structures, and immunoprecipitation experiments showed that FUS-DDIT3 binds the C-terminal of NFKBIZ. We also report that additional NF-kappaB-controlled genes are upregulated at the mRNA level in FUS-DDIT3-expressing cell lines and they can be induced by NFKBIZ. Taken together, the results indicate that FUS-DDIT3 deregulates some NF-kappaB-controlled genes through interactions with NFKBIZ. Similar mechanisms may be a part of the transformation process in other tumor types carrying FUS, EWSR1 and TAF15 containing fusion oncogenes.
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19
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Waugh MS, Dash RC, Turner KC, Dodd LG. Desmoplastic small round cell tumor: Using FISH as an ancillary technique to support cytologic diagnosis in an unusual case. Diagn Cytopathol 2007; 35:516-20. [PMID: 17636487 DOI: 10.1002/dc.20669] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Desmoplastic small round cell tumor is a rare and aggressive neoplasm that predominantly affects young males. In almost all cases, a reciprocal translocation is present resulting in the fusion of the Ewing sarcoma gene with the Wilms' tumor gene. Here we describe an unusual case occurring in a 59-year-old male, in which fluorescence in situ hybridization (FISH) was used in conjunction with immunohistochemical studies to confirm the diagnosis. To our knowledge, this is the first reported case of using FISH as an ancillary technique to confirm the cytologic diagnosis of this tumor.
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Affiliation(s)
- Michael S Waugh
- Division of Cytopathology, Department of Pathology, Duke University Health System, Durham, North Carolina 27710, USA.
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20
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Horvai AE, Kramer MJ, O'Donnell R. Beta-catenin nuclear expression correlates with cyclin D1 expression in primary and metastatic synovial sarcoma: a tissue microarray study. Arch Pathol Lab Med 2006; 130:792-8. [PMID: 16740029 DOI: 10.5858/2006-130-792-cnecwc] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT The association between aberrant (nuclear) beta-catenin expression and cyclin D1 accumulation has been demonstrated in diverse neoplasms. In synovial sarcoma (SS), aberrant beta-catenin expression has prognostic relevance, but the association with cyclin D1 has not been established. The SYT-SSX fusion protein, unique to SS, may independently increase cyclin D1. OBJECTIVE To determine whether nuclear beta-catenin is associated with cyclin D1 overexpression in SS and whether primary and metastatic SS differ in the expression of these markers. DESIGN We incorporated 82 tumors initially diagnosed as SS into a tissue array. Fluorescence in situ hybridization with custom probes was used to select t(X;18) positive tumors. Clinical data, tumor type and outcome were tabulated. The tumors were tested for the association between nuclear beta-catenin and cyclin D1 immunostaining. Primary and metastatic tumors were compared. RESULTS Fifty-one tumors (41 primary and 10 metastatic) from 43 patients demonstrated t(X;18). Cyclin D1 staining was identified in 21 (59%) primary and 8 (80%) metastatic tumors, respectively, and nuclear beta-catenin in 24 (41%) primary and 7 (70%) metastatic tumors, respectively. No significant difference was noted between primary and metastatic tumors with respect to the above markers. The presence of nuclear beta-catenin showed a significant association with cyclin D1 expression (P < .001). A small number of cyclin D1 cases were negative for nuclear beta-catenin but positive for phosphorylated Akt. CONCLUSIONS Increased cyclin D1 in SS may be driven by abnormally expressed beta-catenin, similar to other neoplasms. The pattern of expression of these markers is established early during tumorigenesis.
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MESH Headings
- Adolescent
- Adult
- Aged
- Biomarkers, Tumor/metabolism
- Cell Nucleus/chemistry
- Cell Nucleus/metabolism
- Cell Nucleus/pathology
- Chromosomes, Human, Pair 18/genetics
- Chromosomes, Human, X/genetics
- Cyclin D1/metabolism
- Extremities
- Female
- Humans
- Immunoenzyme Techniques
- In Situ Hybridization, Fluorescence
- Male
- Middle Aged
- Sarcoma, Synovial/genetics
- Sarcoma, Synovial/metabolism
- Sarcoma, Synovial/mortality
- Sarcoma, Synovial/secondary
- Soft Tissue Neoplasms/metabolism
- Soft Tissue Neoplasms/mortality
- Soft Tissue Neoplasms/pathology
- Survival Rate
- Tissue Array Analysis
- Translocation, Genetic
- beta Catenin/metabolism
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Affiliation(s)
- Andrew E Horvai
- Department of Pathology, University of California, San Francisco, CA 94114-1656, USA.
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21
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Chang CC, Hsu JT, Tseng JH, Hwang TL, Chen HM, Jan YY. Combined resection and multi-agent adjuvant chemotherapy for desmoplastic small round cell tumor arising in the abdominal cavity: report of a case. World J Gastroenterol 2006; 12:800-803. [PMID: 16521199 PMCID: PMC4066136 DOI: 10.3748/wjg.v12.i5.800] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2005] [Revised: 06/28/2005] [Accepted: 07/15/2005] [Indexed: 02/06/2023] Open
Abstract
Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive malignancy with distinctive histological features: a nesting pattern of cellular growth within dense desmoplastic stroma, occurring in young population with male predominance. The mean survival period is only about 1.5-2.5 years. The tumor has co-expressed epithelial, muscle, and neural markers in immunohistochemical studies. This work reports a 27-year-old man presenting with hematemesis and chronic constipation. Serial studies including endoscopy, upper gastrointestinal series, abdominal computed tomography and barium enema study showed disseminated involvement of visceral organs. The patient underwent aggressive surgery and received postoperative adjuvant chemotherapy consisting of 5-fluorouracil, cyclophosphamide, etoposide, doxorubicin, and cisplatin. He survived without any disease for 20 mo after the surgery. No standard treatment protocol has been established. Aggressive surgery combined with postoperative multi-agent adjuvant chemotherapy is justified not only to relieve symptoms but also to try to improve the outcome in this advanced DSRCT young patient.
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Affiliation(s)
- Chang-Cheng Chang
- Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan, China
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22
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Rijn MVD, Fletcher JA. GENETICS OF SOFT TISSUE TUMORS. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2006; 1:435-66. [DOI: 10.1146/annurev.pathol.1.110304.100052] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Matt van de Rijn
- Department of Pathology, Stanford University Medical Center, Stanford, California 94305;
| | - Jonathan A. Fletcher
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115;
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23
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Chouli M, Viala J, Dromain C, Fizazi K, Duvillard P, Vanel D. Intra-abdominal desmoplastic small round cell tumors: CT findings and clinicopathological correlations in 13 cases. Eur J Radiol 2005; 54:438-42. [PMID: 15899348 DOI: 10.1016/j.ejrad.2004.09.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2004] [Revised: 09/02/2004] [Accepted: 09/03/2004] [Indexed: 11/21/2022]
Abstract
PURPOSE We report computed tomography (CT) findings in 13 patients with a primary abdominal desmoplastic small round cell tumor. MATERIALS AND METHODS 13 cases (12 men, 1 woman, mean age=24.8 years) were found in our hospital database between 1991 and 2003. Clinical, CT and histopathological features were studied retrospectively. RESULTS Peritoneal involvement was the most common feature. In 10 cases, several lobulated peritoneal soft tissue masses (with a mean of four masses per patient) were seen. Two patients had diffused irregular peritoneal carcinomatosis without any distinct peritoneal masses. One patient had a solitary mass in the pelvic space. The main sites of peritoneal involvement were the pelvic space (n=7), omentum (n=5), retroperitoneal space (n=4), small bowel mesentery (n=3), paracolic gutter (n=2 on the right and n=1 on the left), transverse colon mesentery (n=1), peri-splenic space (n=1), peri-hepatic space (n=1). The soft tissue masses were often bulky (mean 6cm, range 1-28cm), lobulated and heterogeneous with hypodense areas (in 73% of cases). In six cases, moderate ascites was seen. In one case of pelvic involvement, unilateral hydronephrosis was seen. Adenopathies were present in seven cases at the time of the diagnosis (at intraperitoneal, retroperitoneal and pelvic sites in six patients and in the groin in one patient). Five patients had liver metastases (four lesions per case excepted one patient with 30 metastases). Associated thoracic metastases were seen in three patients. The diagnosis was confirmed with four CT-guided percutaneous biopsies. CONCLUSION Although CT features are nonspecific, the diagnosis of desmoplastic small round cell tumor may be suspected in young men with multiple bulky heterogeneous peritoneal soft tissue masses. Imaging is useful for staging and also to guide biopsies.
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Affiliation(s)
- Malik Chouli
- Department of Radiology, Institute Gustave Roussy, 39 Rue Camille Desmoulines, 94805 Villejuif Cedex, France
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24
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Tirado OM, Mateo-Lozano S, Notario V. Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity. Oncogene 2005; 24:3348-57. [PMID: 15782132 DOI: 10.1038/sj.onc.1208471] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Rapamycin, a complex macrolide and potent fungicide, immunosuppressant and anticancer agent, is a highly specific inhibitor of mammalian target of rapamycin (mTOR). Rapamycin has been shown to induce G1-phase cell cycle arrest in diverse tumor cell types, and its derivatives RAD001 and CCI-779 are currently in phase I and phase II clinical trials, respectively, as anticancer agents. In this study, we show that rapamycin induced the apoptotic death of JN-DSRCT-1 cells, the only available in vitro model for Desmoplastic Small Round Cell Tumors (DSRCT), while having only minor effects on their cell cycle. Rapamycin induced apoptosis by increasing the Bax : Bcl-xL ratio as a consequence of the concomitant downregulation of Bcl-xL and upregulation of Bax, both at the post-transcriptional level. Rapamycin also downregulated the levels of EWS/WT1, the fusion protein characteristic of DSRCT. Transient transfection studies using kinase-dead and rapamycin-resistant forms of mTOR demonstrated that only the downregulation of Bcl-xL was caused by the mTOR inhibitory action of rapamycin, which prevented cap-dependent translation initiation, whereas Bax upregulation was induced by rapamycin through a mechanism independent of its mTOR inhibitory activity. Moreover, rapamycin treatment downregulated the mRNA and protein levels of the 26S p44.5 proteasome subunit, suggesting the involvement of the proteasome complex in the mechanisms of rapamycin-induced apoptosis. Treatment of JN-DSRCT-1 cells with MG-132, a proteasome specific inhibitor, also resulted in the induction of apoptosis through a similar increase in the Bax : Bcl-xL ratio specifically caused by inhibiting Bax degradation and turnover. These results suggested that rapamycin induces apoptosis by preventing the degradation of the Bax protein by the proteasome, and that this process is independent of mTOR inhibition. Furthermore, these results strongly support the introduction of the use of rapamycin as a cytotoxic agent for the treatment of DSRCT.
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Affiliation(s)
- Oscar M Tirado
- Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, Georgetown University Medical Center, Washington, DC, USA
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25
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Fletcher JA. Molecular biology and cytogenetics of soft tissue sarcomas: relevance for targeted therapies. Cancer Treat Res 2004; 120:99-116. [PMID: 15217220 DOI: 10.1007/1-4020-7856-0_6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Affiliation(s)
- Jonathan A Fletcher
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
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26
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Chiu LL, Koay ESC, Chan NH, Salto-Tellez M. Sequence confirmation of theEWS-WT1 fusion gene transcript in the peritoneal effusion of a patient with desmoplastic small round cell tumor. Diagn Cytopathol 2003; 29:341-3. [PMID: 14648792 DOI: 10.1002/dc.10397] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Desmoplastic small round cell tumor (DSRCT) is a rare undifferentiated neoplasm. The prognosis is poor, even if therapy is instituted promptly, and thus it is important to differentiate it from other histologically and cytologically similar-looking malignancies of the young adult. We present a case of DSRCT in a 17-yr-old male with disseminated peritoneal disease and peritoneal effusion. The cytology sample showed a malignant small round cell tumor, the classical cytological features of DSRCT, and immunohistochemistry performed in the prepared cell block exhibited an antibody expression profile in keeping with DSRCT. Further material from the effusion was prepared for RNA extraction, following which a reverse-transcriptase polymerase chain reaction (RT-PCR) and sequencing of the t(11;22)(p13;q11 or q12) were carried out. The result showed the presence of the reciprocal translocation and thus confirmed the diagnosis of DSRCT. This case shows how molecular techniques (including sequencing) can be applied to cytology in clarifying and confirming certain difficult diagnosis of undifferentiated neoplasms, DSRCT in this particular case.
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MESH Headings
- Adolescent
- Ascites/diagnosis
- Ascites/genetics
- Ascites/metabolism
- Ascitic Fluid/diagnosis
- Ascitic Fluid/genetics
- Base Sequence
- Biomarkers, Tumor/analysis
- Carcinoma, Small Cell/chemistry
- Carcinoma, Small Cell/genetics
- Carcinoma, Small Cell/pathology
- Humans
- Male
- Molecular Sequence Data
- Oncogene Proteins, Fusion/genetics
- Proto-Oncogene Protein c-fli-1
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/analysis
- RNA-Binding Protein EWS
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Analysis, RNA
- Soft Tissue Neoplasms/chemistry
- Soft Tissue Neoplasms/genetics
- Soft Tissue Neoplasms/pathology
- Transcription Factors/genetics
- Translocation, Genetic
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Affiliation(s)
- L L Chiu
- Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital, Singapore
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27
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Nishio J, Iwasaki H, Ishiguro M, Fukuda T, Chuman H, Kaneko Y, Kikuchi M. Intra-abdominal small round cell tumour with EWS-WT1 fusion transcript in an elderly patient. Histopathology 2003; 42:410-2. [PMID: 12653957 DOI: 10.1046/j.1365-2559.2003.01552_5.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
MESH Headings
- Aged
- Biomarkers, Tumor/metabolism
- Chromosomes, Human, Pair 11
- Chromosomes, Human, Pair 22
- Fatal Outcome
- Humans
- Immunohistochemistry
- Karyotyping
- Male
- Neoplasm Proteins/metabolism
- Neoplasms, Fibroepithelial/genetics
- Neoplasms, Fibroepithelial/metabolism
- Neoplasms, Fibroepithelial/pathology
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Peritoneal Neoplasms/genetics
- Peritoneal Neoplasms/metabolism
- Peritoneal Neoplasms/pathology
- Reverse Transcriptase Polymerase Chain Reaction
- Translocation, Genetic
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28
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Abstract
This article retains the conventional approach to the classification of soft tissue sarcomas, dividing them into several major histogenetic categories based on their overall microscopic appearance, tissue differentiation pattern, and biologic potential. The author advocates a multimodal approach, in which four distinctive data sets--clinical, radiographic, microscopic, and, in some cases, molecular--are considered to establish the diagnosis and treatment plan. Such step-wise analysis is more likely to lead to consistency and accuracy as compared with an intuitive approach based on fragmentary data. The author describes individual lesions of soft tissue as clinicopathologic entities and believes that they can be more accurately diagnosed and appropriately treated with the help of data generated by a multidisciplinary team. In addition, this article emphasizes the need to use emerging molecular techniques that can provide important clues for both diagnosis and prognosis.
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Affiliation(s)
- Bogdan Czerniak
- Department of Pathology, University of Texas M.D. Anderson Cancer Center, Box 085, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
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29
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Zhang PJ, Goldblum JR, Pawel BR, Fisher C, Pasha TL, Barr FG. Immunophenotype of desmoplastic small round cell tumors as detected in cases with EWS-WT1 gene fusion product. Mod Pathol 2003; 16:229-35. [PMID: 12640103 DOI: 10.1097/01.mp.0000056630.76035.f3] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Desmoplastic small round cell tumor is a rare tumor typically involving peritoneum. Although the histogenesis of desmoplastic small round cell tumor has yet to be elucidated, immunophenotypical and morphological analysis shows a characteristic divergent phenotype overlapping with other round cell tumors such as Ewing's sarcoma/primitive neuroectodermal tumor, rhabdomyosarcoma, small cell mesothelioma, and carcinoma. Detection of the EWS-WT1 gene fusion is characteristic of desmoplastic small round cell tumor and has been used reliably in tumor diagnosis. In this study, we evaluated the immunophenotype of 23 desmoplastic small round cell tumor cases with the EWS-WT1 gene fusion product identified by reverse transcription-polymerase chain reaction. Paraffin sections were stained with antibodies against calretinin, WT1 (C19), desmin, myoglobin, MyoD, Myf5, myogenin, placental alkaline phosphatase, cytokeratins, MIC2, HER2/neu and c-kit using standard immunohistochemical methods. Immunoreactivity was evaluated semiquantitively by light microscopy. Desmoplastic small round cell tumors showed reactivity with calretinin in 4/21, desmin in 21/23, myoglobin in 5/17, placental alkaline phosphatase in 17/21, HER2/neu in 7/18 (3+ in 1 and 1+ in 6), c-kit in 2/14, MIC2 in 13/23, WT1 in 16/23, CAM5.2 in 21/23, and AE1/3 in 16/23 cases. The most sensitive myogenic and epithelial markers are desmin and CAM 5.2. Although nuclear reactivity of the early myogenic regulatory factors (MyoD, myogenin, Myf5) was not detected, myoglobin immunoreactivity was present in 29% of desmoplastic small round cell tumors. HER2/neu overexpression (3+) and c-kit expression are uncommon in desmoplastic small round cell tumors. A panel of myogenic and epithelial markers should be used to detect the divergent phenotype in desmoplastic small round cell tumors, a key feature in the differential diagnosis. Detection of EWS-WT1 fusion becomes critical for the diagnosis when the characteristic divergent phenotype cannot be detected immunohistochemically.
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MESH Headings
- Antigens, Neoplasm/analysis
- Biomarkers, Tumor/analysis
- Carcinoma, Small Cell/genetics
- Carcinoma, Small Cell/pathology
- Diagnosis, Differential
- Humans
- Immunohistochemistry
- Immunophenotyping
- Mesothelioma/genetics
- Mesothelioma/pathology
- Neuroectodermal Tumors, Primitive/genetics
- Neuroectodermal Tumors, Primitive/pathology
- Oncogene Proteins, Fusion/analysis
- Peritoneal Neoplasms/genetics
- Peritoneal Neoplasms/immunology
- Peritoneal Neoplasms/metabolism
- Peritoneal Neoplasms/pathology
- Proto-Oncogene Proteins c-kit/metabolism
- Receptor, ErbB-2/metabolism
- Retrospective Studies
- Reverse Transcriptase Polymerase Chain Reaction
- Rhabdomyosarcoma/genetics
- Rhabdomyosarcoma/pathology
- Sarcoma, Ewing/genetics
- Sarcoma, Ewing/pathology
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Affiliation(s)
- Paul J Zhang
- Anatomic Pathology, 6 Founders Pavilion, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19147, USA.
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30
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Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. desmoplastic small round-cell tumors. CANCER GENETICS AND CYTOGENETICS 2002; 138:1-10. [PMID: 12419577 DOI: 10.1016/s0165-4608(02)00680-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Avery A Sandberg
- Department of DNA Diagnostics, St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013, USA.
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31
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Goodman KA, Wolden SL, La Quaglia MP, Kushner BH. Whole abdominopelvic radiotherapy for desmoplastic small round-cell tumor. Int J Radiat Oncol Biol Phys 2002; 54:170-6. [PMID: 12182988 DOI: 10.1016/s0360-3016(02)02871-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Desmoplastic small round-cell tumor (DSRCT) is a rare, recently described intraperitoneal malignancy occurring predominantly in adolescent boys. Our objective was to evaluate the feasibility and outcome of whole abdominopelvic irradiation (WAPI) as part of a combined modality protocol for patients with DSRCT. METHODS AND MATERIALS The records of all 21 patients treated with WAPI for DSRCT at our institution from 1992 to 2001 were retrospectively reviewed. Patients were treated on an institutional protocol with 7 cycles of an alkylator-based chemotherapy. After maximal surgical debulking, patients were treated with external beam radiotherapy to the whole abdomen and pelvis to a dose of 30 Gy. RESULTS All 21 patients completed the prescribed treatment. The median follow-up was 28 months. The overall survival and relapse-free survival rate at 3 years was 48% and 19%, respectively. The median survival was 32 months, and the median time to relapse was 19 months. Most relapses were intraperitoneal and/or hepatic. Acute toxicities included Radiation Therapy Oncology Group Grade 2 upper and lower gastrointestinal toxicity in 81% and 71% of patients, respectively. All patients experienced acute hematologic toxicity, with Grade 4 thrombocytopenia, leukopenia, and anemia in 76%, 29%, and 33%, respectively. The major long-term toxicity was small bowel obstruction, which occurred in 7 patients (33%) after surgery and WAPI. CONCLUSION DSRCT is a rare and highly lethal disease, requiring aggressive multimodality therapy. WAPI is feasible in conjunction with intensive chemotherapy and surgery. Hematologic and gastrointestinal toxicities are expected but manageable with diligent supportive care. The long-term efficacy of this therapy remains disappointing, thus novel approaches are being investigated.
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Affiliation(s)
- Karyn A Goodman
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
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32
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Nishio J, Iwasaki H, Ishiguro M, Ohjimi Y, Fujita C, Yanai F, Nibu K, Mitsudome A, Kaneko Y, Kikuchi M. Establishment and characterization of a novel human desmoplastic small round cell tumor cell line, JN-DSRCT-1. J Transl Med 2002; 82:1175-82. [PMID: 12218078 DOI: 10.1097/01.lab.0000028059.92642.03] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
The exact nature of the desmoplastic small round cell tumor (DSRCT) remains controversial. More detailed analyses might be facilitated by the establishment of permanent DSRCT cell lines. To date, however, no human DSRCT cell line has been reported. In this study, we report the establishment of a new human cell line, JN-DSRCT-1, from the pleural effusion of a 7-year-old boy with pulmonary metastasis from a typical intra-abdominal DSRCT. JN-DSRCT-1 cells were small round or spindle shaped with oval nuclei and have been maintained continuously in vitro for over 190 passages during more than 40 months. Histologic features of the heterotransplanted tumors in severe combined immunodeficiency mouse were essentially the same as those of the original DSRCT, revealing nests or clusters of small round cells embedded in an abundant desmoplastic stroma. Both in vitro and in vivo, the cells exhibited immunopositive reactions for vimentin, desmin, cytokeratins (AE1/AE3 and CAM 5.2), epithelial membrane antigen, neuron-specific antigen, and CD57 (Leu-7). JN-DSRCT-1 cells exhibited a pathognomonic t(11;22)(p13;q12) translocation by cytogenetic analysis. In addition, RT-PCR and sequencing analysis revealed a chimeric transcriptional message of the Ewing's sarcoma gene exon 10 fused to the Wilms' tumor gene exon 8. To our knowledge, this is the first permanent human DSRCT cell line. The JN-DSRCT-1 cell line, which exhibits the unique morphologic and genetic characteristics of DSRCT, will be extremely useful for a variety of important studies such as the pathogenic mechanism, biologic behavior, and therapeutic model of human DSRCT.
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Affiliation(s)
- Jun Nishio
- Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan.
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33
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Lae ME, Roche PC, Jin L, Lloyd RV, Nascimento AG. Desmoplastic small round cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol 2002; 26:823-35. [PMID: 12131150 DOI: 10.1097/00000478-200207000-00001] [Citation(s) in RCA: 207] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Desmoplastic small round cell tumor is a rare, aggressive neoplasm that mainly affects young male patients and is characterized by a reciprocal translocation t(11;22)(p13;q12) associated with the EWS-WT1 gene fusion transcript. Clinical, histopathologic, immunohistochemical, and molecular genetics features were reviewed for 32 tumors. There were 29 male and three female patients, with ages from 6 to 54 years (mean, 25 years). The main clinical signs and symptoms included abdominal pain (eight patients), weight loss (five patients), and presence of umbilical hernia (four patients). Two tumors primarily involved the ethmoid sinus and the soft tissues of the scalp; the other tumors (mean size, 10 cm) involved the abdominal cavity (88%). One patient presented initially with an axillary lymph node metastasis. Generally, all tumors showed the typical histologic findings of variably sized clusters of small, round, or spindled cells lying in a desmoplastic stroma. The neoplastic cells in formalin-fixed, paraffin-embedded tissue sections were positive for desmin (dot pattern) (81% of the cases), WT1 (91%), keratin (87%), neuron-specific enolase (84%), CD99 (23%), and actin (3%). The EWS-WT1 gene fusion transcript was detected in 29 of 30 tumors. One tumor with typical clinicopathologic and immunohistochemical features did not show the gene fusion. Follow-up for 27 patients showed that 19 patients (70%) died of uncontrolled, local, or widespread metastatic disease 3-46 months (mean, 20 months) after diagnosis, and eight patients were alive with known evidence of disease. Occasionally, desmoplastic small round cell tumor lacks the classic clinical, histologic, and immunohistochemical features. This study emphasizes the utility of analysis of the EWS-WT1 gene fusion transcript, which was performed on paraffin-embedded tissues, to confirm the diagnosis.
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Affiliation(s)
- Marick E Lae
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA
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34
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Mihok NA, Cha I. Desmoplastic small round cell tumor presenting as a neck mass: a case report. Diagn Cytopathol 2001; 25:68-72. [PMID: 11466817 DOI: 10.1002/dc.2005] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
An unusual case study of a desmoplastic small round cell tumor presenting as a 3.5-cm, firm, supraclavicular neck mass and diagnosed by fine-needle aspirate biopsy in a 16-yr-old male is reported. Clinical, cytologic, and immunocytochemical findings are described. Histologic, immunohistochemical, and genetic features are discussed. Desmoplastic small round cell tumor should be considered in the differential diagnosis of small round cell tumors of any site; the importance of ancillary studies in arriving at the correct diagnosis is emphasized.
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Affiliation(s)
- N A Mihok
- Department of Surgical Pathology, University of California, San Francisco, California, 94143, USA
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35
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Rauscher FJ. Chromosome translocation-mediated conversion of a tumor suppressor gene into a dominant oncogene: fusion of EWS1 to WT1 in desmoplastic small round cell tumors. Curr Top Microbiol Immunol 2001; 220:151-62. [PMID: 9103681 DOI: 10.1007/978-3-642-60479-9_10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
MESH Headings
- Adolescent
- Cell Transformation, Neoplastic/genetics
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/physiology
- Female
- Gene Expression Regulation, Neoplastic
- Genes, Wilms Tumor
- Heterogeneous-Nuclear Ribonucleoproteins
- Humans
- Male
- Models, Genetic
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/physiology
- Oncogenes
- Ribonucleoproteins/genetics
- Ribonucleoproteins/physiology
- Sarcoma, Ewing/genetics
- Sarcoma, Ewing/pathology
- Sarcoma, Small Cell/genetics
- Sarcoma, Small Cell/pathology
- Transcription Factors/genetics
- Transcription Factors/physiology
- Translocation, Genetic
- WT1 Proteins
- Zinc Fingers/genetics
- Zinc Fingers/physiology
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36
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Rosoff PM, Hatcher S, West DC. Biphenotypic sarcoma with characteristics of both a Ewing sarcoma and a desmoplastic small round cell tumor. MEDICAL AND PEDIATRIC ONCOLOGY 2000; 34:407-12. [PMID: 10842247 DOI: 10.1002/(sici)1096-911x(200006)34:6<407::aid-mpo5>3.0.co;2-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The EWS gene, a transcription factor of unknown function, is involved in chromosomal translocations associated with a wide variety of tumors, particularly small round blue cell tumors such as Ewing sarcoma. It has previously been reported that desmoplastic small round blue cell tumor (DSRBCT) frequently has an associated t(11;22) abnormality resulting from fusion of the EWS and WT-1 genes. PROCEDURE We report a case of a small round blue cell tumor with characteristics of both Ewing sarcoma and DSRBCT with a t(11;22) translocation leading to fusion of the EWS and FLI1genes. RESULTS The translocation point and fusion products were confirmed by polymerase chain reaction amplification and restriction fragment mapping of the products. CONCLUSIONS The biphenotypic nature of this case and the apparent promiscuity of the EWS gene in tumor-associated translocations coupled with other reports of biphenotypic childhood sarcomas has potential implications for the relationship between small round blue cell tumors and the mechanism of EWS/FLI1 oncogenesis.
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MESH Headings
- Carcinoma, Small Cell/diagnostic imaging
- Carcinoma, Small Cell/genetics
- Carcinoma, Small Cell/pathology
- Chromosome Mapping
- Chromosomes, Human, Pair 11/genetics
- Chromosomes, Human, Pair 22/genetics
- Electrophoresis, Agar Gel
- Fibromatosis, Aggressive/genetics
- Fibromatosis, Aggressive/pathology
- Humans
- Phenotype
- Photomicrography
- Reverse Transcriptase Polymerase Chain Reaction
- Sarcoma/diagnostic imaging
- Sarcoma/genetics
- Sarcoma/pathology
- Sarcoma, Ewing/diagnostic imaging
- Sarcoma, Ewing/genetics
- Sarcoma, Ewing/pathology
- Tomography, X-Ray Computed
- Translocation, Genetic
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Affiliation(s)
- P M Rosoff
- Division of Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
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37
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Barnoud R, Sabourin JC, Pasquier D, Ranchère D, Bailly C, Terrier-Lacombe MJ, Pasquier B. Immunohistochemical expression of WT1 by desmoplastic small round cell tumor: a comparative study with other small round cell tumors. Am J Surg Pathol 2000; 24:830-6. [PMID: 10843285 DOI: 10.1097/00000478-200006000-00008] [Citation(s) in RCA: 109] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Desmoplastic small round cell tumors (DSRCTs) present a reciprocal chromosomal translocation, t(11;22)(p13;q12), that results in fusion of Ewing's sarcoma and Wilms' tumor (WT1) genes. The authors evaluated 15 DSRCTs and 71 other tumors often considered in the differential diagnosis for immunoreactivity using a polyclonal antibody directed against the WT1 part of the chimeric protein resulting from this translocation. WT1 immunostaining was performed on paraffin material using the WT(C-19) antibody after heat-antigen retrieval. All the DSRCTs (15 of 15, 100%) demonstrated strong WT1 nuclear immunoreactivity. Ten of 14 nephroblastomas (71%) disclosed WT1-positive nuclei in accordance with the staining reported by others, and rare and focal nuclear positivity was detected in two of 17 rhabdomyosarcomas. WT1 immunoreactivity was not observed in Ewing's sarcoma/primitive neuroectodermal tumors (zero of 21, 0%), neuroblastomas (zero of 17, 0%), or rhabdoid tumors of the kidney (zero of two, 0%). In nephroblastoma, differential diagnosis with DSRCT was not difficult: Clinical and morphologic data are not similar for these two entities. The current study validates WT1 immunoreactivity as a useful marker to separate DSRCT from other small round cell tumors.
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Affiliation(s)
- R Barnoud
- Service d'Anatomie-Pathologique, Centre Hospitalier Universitaire de Grenoble, France.
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38
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Kim J, Pelletier J. Molecular genetics of chromosome translocations involving EWS and related family members. Physiol Genomics 1999; 1:127-38. [PMID: 11015571 DOI: 10.1152/physiolgenomics.1999.1.3.127] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Many types of sarcomas are characterized by specific chromosomal translocations that appear to result in the production of novel, tumor-specific chimeric transcription factors. Many of these show striking similarities: the emerging picture is that the amino-terminal domain of the fusion product is donated by the Ewing's sarcoma gene (EWS) or a related member from the same gene family, whereas the carboxy-terminal domain often consists of a DNA-binding domain derived from one of a number of transcription factors. Given the observation that the different translocation partners of the EWS protooncogene are associated with distinct types of sarcomas, the functional consequence of fusing EWS (or a related family member) to a different DNA-binding domain can only be understood in the context of functional studies that define the specificity of action of the different fusion products. An understanding of the molecular structure and function of these translocations provides new methods for diagnosis and novel targets for therapeutics.
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Affiliation(s)
- J Kim
- Department of Biochemistry, Department of Oncology, McGill University, Montreal, Quebec, Canada H3G 1Y6
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39
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Wolf AN, Ladanyi M, Paull G, Blaugrund JE, Westra WH. The expanding clinical spectrum of desmoplastic small round-cell tumor: a report of two cases with molecular confirmation. Hum Pathol 1999; 30:430-5. [PMID: 10208465 DOI: 10.1016/s0046-8177(99)90119-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Desmoplastic small round cell tumor (DSRCT) is an aggressive neoplasm characterized by a consistent histological appearance, a unique immunohistochemical profile, and a specific chromosomal translocation. DSRCT is also hallmarked by distinctive clinical features. Most tumors arise in adolescent or young adult males, present as bulky abdominal masses, and diffusely spread along the peritoneal surface. We report two cases of DSRCT that do not fit this typical profile. One case involved the abdominal cavity of a 76-year-old woman. The other case arose in the parotid of a 22-year-old man. Histologically, the tumors showed the characteristic features of DSRCT. Immunohistochemically, the tumors showed positivity for cytokeratin, desmin, and neuron-specific enolase. Genetically, the tumors expressed the EWS-WT1 chimeric transcript. These two cases expand the differential diagnosis for poorly differentiated small-cell tumors that involve elderly patients or arise in the parotid. Moreover, they challenge the popular notion that DSRCT is a "blastomatous" tumor derived exclusively from the primitive mesothelium.
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Affiliation(s)
- A N Wolf
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
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40
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Chan AS, MacNeill S, Thorner P, Squire J, Zielenska M. Variant EWS-WT1 chimeric product in the desmoplastic small round cell tumor. Pediatr Dev Pathol 1999; 2:188-92. [PMID: 9949226 DOI: 10.1007/s100249900108] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chromosome translocations found in neoplasms often result in the creation of hybrid genes encoding chimeric proteins. Desmoplastic small round cell tumor (DSRCT) is a recently described aggressive malignancy associated with a unique chromosomal translocation t(11;22)(p13;q12). This translocation has recently been characterized, revealing the rearrangement and fusion of the WT1 gene on chromosome 11 to the EWS gene on chromosome 22. Fusion of these two genes results in the production of a putative oncogenic protein composed of the zinc finger DNA-binding domains of WT1 linked to the potential transcriptional regulatory domains of EWS. The typical chimeric transcript consists of the first 7 exons of EWS and the last 3 exons of WT1. We report here the first case of DSRCT with a variant EWS-WT1 chimeric product that includes 9 exons of EWS and 3 exons of WT1.
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Affiliation(s)
- A S Chan
- Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8
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41
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Perez RP, Zhang PJ. Detection of EWS-WT1 fusion mRNA in ascites of a patient with desmoplastic small round cell tumor by RT-PCR. Hum Pathol 1999; 30:239-42. [PMID: 10029456 DOI: 10.1016/s0046-8177(99)90283-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy characterized cytogenetically by a unique translocation of chromosomes 11 and 22 [t(11:22)(p13:ql2)], resulting in fusion of the EWS and WT1 genes. The presence of a unique fusion mRNA in DSRCT allows disease detection and diagnosis by reverse transcription polymerase chain reaction (RT-PCR), as previously described in fixed paraffin-embedded material. In this report, EWS WT1 fusion mRNA was detected in ascites from a patient with DSRCT by RT-PCR. RT-PCR results confirmed the diagnoses of DSRCT and of malignant ascites at the molecular level. RT-PCR assays for specific molecular markers, such as EWS-WT1 fusion mRNA, are potentially powerful methods that can complement routine histological, cytological, and/or immunohistologic assays.
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Affiliation(s)
- R P Perez
- Division of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
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42
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Thorner P, Squire J, Plavsic N, Jong R, Greenberg M, Zielenska M. Expression of WT1 in pediatric small cell tumors: report of two cases with a possible mesothelial origin. Pediatr Dev Pathol 1999; 2:33-41. [PMID: 9841704 DOI: 10.1007/s100249900087] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The WT1 gene is normally expressed in fetal kidney and mesothelium, and its expression has been suggested as a marker for Wilms tumor and mesothelioma. We examined WT1 expression levels by reverse-transcriptase polymerase chain reaction (RT-PCR) in 38 childhood small-cell tumors including Wilms tumor, embryonal and alveolar rhabdomyosarcoma, Ewing sarcoma, lymphoma, desmoplastic small round-cell tumor (DSRCT), synovial sarcoma, extrarenal rhabdoid tumor, and two tumors that were atypical for this group of tumors. WT1 expression was only detected in Wilms tumor, rhabdoid tumor, and in these two cases of uncertain histogenesis. Both arose in the peritoneal cavity and by immunohistochemistry were diffusely positive for vimentin, keratin, and desmin. Tonofilaments were identified by electron microscopy in one of the cases. RT-PCR failed to detect the t(11;22) translocation associated with DSRCT in either case. Our results suggest that WT1 expression is an unusual feature of childhood non-Wilms tumors and, in the right setting, it may indicate a mesothelial origin. The expression of WT1 may play a role in mesodermal cells acquiring epithelial characteristics, a concept supported by the mixed epithelial and mesenchymal phenotype of these two cases.
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MESH Headings
- Biomarkers, Tumor
- Carcinoma, Small Cell/genetics
- Carcinoma, Small Cell/metabolism
- Carcinoma, Small Cell/pathology
- Child, Preschool
- Chromosomes, Human, Pair 11
- DNA-Binding Proteins/biosynthesis
- DNA-Binding Proteins/genetics
- Epithelium/pathology
- Humans
- Infant
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Lymphoma/genetics
- Lymphoma/metabolism
- Lymphoma/pathology
- Male
- Mesothelioma/genetics
- Mesothelioma/metabolism
- Mesothelioma/pathology
- Polymerase Chain Reaction
- Rhabdomyosarcoma/genetics
- Rhabdomyosarcoma/metabolism
- Rhabdomyosarcoma/pathology
- Sarcoma, Ewing/genetics
- Sarcoma, Ewing/metabolism
- Sarcoma, Ewing/pathology
- Testicular Neoplasms/genetics
- Testicular Neoplasms/metabolism
- Testicular Neoplasms/pathology
- Transcription Factors/biosynthesis
- Transcription Factors/genetics
- WT1 Proteins
- Wilms Tumor/genetics
- Wilms Tumor/metabolism
- Wilms Tumor/pathology
- Zinc Fingers
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Affiliation(s)
- P Thorner
- Department of Pediatric Laboratory Medicine, Hospital for Sick Children Toronto, Ontario, Canada
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43
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Roberts P, Burchill SA, Beddow RA, Wheeldon J, Cullinane C, Lewis IJ. A combined cytogenetic and molecular approach to diagnosis in a case of desmoplastic small round cell tumor with a complex translocation (11;22;21). CANCER GENETICS AND CYTOGENETICS 1999; 108:19-25. [PMID: 9973919 DOI: 10.1016/s0165-4608(98)00103-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Desmoplastic small round cell tumor (DSRCT) has recently been described as a discrete tumor entity. It is distinguished from other small round cell tumors by its prominent desmoplastic quality, its preponderance in adolescent males, its almost exclusive intraabdominal location, a multi-immunophenotypic profile, and its aggressive nature. Diagnosis on histology alone is not always unequivocal. A recurrent t(11;22)(p13;q12) translocation has recently been described in this tumor, and a chimeric RNA fusion product formed from the WT1 and EWS genes is detectable by reverse transcriptase-polymerase chain reaction (RT-PCR). We describe the use of a multi-faceted approach using conventional G-banding, fluorescence in situ hybridization (FISH) and RT-PCR to assist the diagnosis of a case of DSRCT with a complex variant t(11;22;21)(p13;q12;q22.1) translocation and demonstrate the value of a combined approach to genetic investigation of solid tumors.
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MESH Headings
- Abdominal Neoplasms/diagnosis
- Abdominal Neoplasms/genetics
- Abdominal Neoplasms/pathology
- Abdominal Neoplasms/surgery
- Adolescent
- Base Sequence
- Bone Marrow/pathology
- Carcinoma, Small Cell/diagnosis
- Carcinoma, Small Cell/genetics
- Carcinoma, Small Cell/pathology
- Carcinoma, Small Cell/surgery
- Chromosome Mapping
- Chromosomes, Human, Pair 11
- Chromosomes, Human, Pair 21
- Chromosomes, Human, Pair 22
- DNA-Binding Proteins/genetics
- Diagnosis, Differential
- Exons
- Genes, Wilms Tumor
- Heterogeneous-Nuclear Ribonucleoproteins
- Humans
- In Situ Hybridization, Fluorescence/methods
- Male
- Molecular Sequence Data
- RNA-Binding Protein EWS
- Reverse Transcriptase Polymerase Chain Reaction
- Ribonucleoproteins/genetics
- Transcription Factors/genetics
- Translocation, Genetic
- WT1 Proteins
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Affiliation(s)
- P Roberts
- Regional Cytogenetics Unit, St. James's University Hospital, Leeds, UK
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44
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Barnoud R, Delattre O, Péoc'h M, Pasquier D, Plantaz D, Leroux D, Pasquier B. Desmoplastic small round cell tumor: RT-PCR analysis and immunohistochemical detection of the Wilm's tumor gene WT1. Pathol Res Pract 1998; 194:693-700. [PMID: 9820865 DOI: 10.1016/s0344-0338(98)80128-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Desmoplastic small round cell tumor is an aggressive neoplasm first described in 1991. Recently, a reciprocal translocation t(11;22)(p13;q12) has been characterized by conventional cytogenetic studies and molecular analysis. This translocation involves the Ewing's sarcoma gene on chromosome 22 and the Wilms' tumor gene WT1 on chromosome 11. The chimeric transcript corresponding to the fusion gene could be detected by the reverse transcriptase-polymerase chain reaction (RT-PCR). Using an anti-WT1 antibody, the WT1 part of the putative chimeric protein could be recognized by immunohistochemistry. We describe two well-characterized cases of intraabdominal desmoplastic small round cell tumor in two male patients aged 14 and 28 with both RT-PCR analysis and immunostaining for WT1. In this report, we insist on the necessity to increase the RT-PCR analysis in DSRCT in order to obtain a precise differential diagnosis. In addition, WT1 immunostaining may serve as a useful diagnostic marker for DSRCT.
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Affiliation(s)
- R Barnoud
- Département de Pathologie, Centre Hospitalier Universitaire, Grenoble, France
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45
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Ordóñez NG. Desmoplastic small round cell tumor: I: a histopathologic study of 39 cases with emphasis on unusual histological patterns. Am J Surg Pathol 1998; 22:1303-13. [PMID: 9808123 DOI: 10.1097/00000478-199811000-00001] [Citation(s) in RCA: 151] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The clinical and histological features of 39 cases of desmoplastic small round cell tumor (DSRCT) diagnosed at M.D. Anderson Cancer Center are presented. Thirty-two of the patients were men and seven were women ranging in age from 10 to 41 years (mean, 25 years). Twenty-five of the 35 patients for whom follow-up information was available died of widespread metastases 8 to 50 months (mean, 25.2 months) from the time of their diagnosis and the remaining 10 were alive with disease. With the exception of two cases that occurred in the liver and in the scrotum, respectively, all of the cases originated within the abdominal and/or pelvic peritoneum. Eight tumors also involved the retroperitoneum. Although the characteristic histologic pattern of "small, blue cells" embedded in a dense fibrous stroma was seen in most cases, about one third of the tumors exhibited a wide range of morphologic features. The recognition of these uncommon morphologic variants of DSRCT is of paramount importance to avoid a misdiagnosis because these tumors could potentially be confused with other neoplastic conditions.
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Affiliation(s)
- N G Ordóñez
- The University of Texas M.D. Anderson Cancer Center, Houston 77056, USA
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46
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Hui, Xue, Dai, Yu, Guo, Qian. Uterine involvement by intra-abdominal desmoplastic small round cell tumor in a 63-year-old female. Int J Gynecol Cancer 1998. [DOI: 10.1046/j.1525-1438.1998.09868.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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47
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Abstract
The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes; (2) loss of tumor suppressor genes; or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management.
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Affiliation(s)
- P S Thorner
- Department of Pediatric Laboratory Medicine, Division of Pathology, Hospital for Sick Children and the University of Toronto, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8
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48
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Ordi J, de Alava E, Torné A, Mellado B, Pardo-Mindan J, Iglesias X, Cardesa A. Intraabdominal desmoplastic small round cell tumor with EWS/ERG fusion transcript. Am J Surg Pathol 1998; 22:1026-32. [PMID: 9706984 DOI: 10.1097/00000478-199808000-00014] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
This report describes an intraabdominal small cell tumor in a 37-year-old woman, with clinical, topographic, and morphologic features highly suggestive of the desmoplastic small round cell tumor. Immunohistochemical analysis revealed a polyphenotypic profile consistent with this tumor--positivity for keratin, epithelial membrane antigen, neuron-specific enolase, vimentin, and desmin--but, in addition, a strong membranous immunoreactivity for CD99 (MIC2 protein). Reverse transcription polymerase chain reaction revealed a EWS/ERG fusion transcript characteristic of the Ewing's sarcoma/peripheral primitive neuroectodermal tumor group of tumors, rather than the EWS/WT1 chimeric transcript typical of the desmoplastic small round cell tumor. This is the third report of a hybrid tumor with features of the desmoplastic small round cell tumor and Ewing's sarcoma/peripheral primitive neuroectodermal tumor, and the first one with the EWS/ERG fusion gene. Our case shows the existence of some overlap between these two groups of tumors, which are considered to be histogenetically different, and the need for further studies of molecular characterization of small cell tumors, especially in those with atypical morphologic or immunohistochemical features.
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Affiliation(s)
- J Ordi
- Department of Pathology, IDIBAPS Hospital Clínic, Facultat de Medicina, Universitat de Barcelona, Spain
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49
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Schwarz RE, Gerald WL, Kushner BH, Coit DG, Brennan MF, La Quaglia MP. Desmoplastic small round cell tumors: prognostic indicators and results of surgical management. Ann Surg Oncol 1998; 5:416-22. [PMID: 9718171 DOI: 10.1007/bf02303860] [Citation(s) in RCA: 77] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Desmoplastic small round cell tumors (DSRCT or DSCT) are rare aggressive cancers of adolescence and early adulthood. There are few reported series to guide clinical therapy. This study correlates survival with treatment variables, including aggressive surgical debulking. METHODS Thirty-two patients with documented DSRCT received treatment at our institution. Demographic, clinical, and treatment variables were correlated with progression-free survival using log-rank statistics. RESULTS Thirty patients were male (96%), and two were female (4%), with a median age at diagnosis of 22 years. The primary site of disease in 97% of cases was the abdomen or pelvis. Twenty-nine patients (91%) had extensive disease involving peritoneal surfaces, lymph nodes, or discontinuous organs. All 32 patients received systemic chemotherapy. Fifteen (47%) underwent tumor debulking greater than 90% at diagnosis or during therapy. A complete or very good response to therapy occurred in 13 patients, and depended on surgical removal of bulk disease in all. Thirteen patients remained progression-free, but three of these patients died from treatment toxicity. Improved survival was correlated with a complete or very good partial response to multimodality therapy, surgical debulking of more than 90% either before or after chemotherapy, and use of the P6 protocol. CONCLUSIONS DSRCT is an aggressive cancer that occurs predominantly in young males. Improved survival is correlated with intense chemotherapy and aggressive resection.
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Affiliation(s)
- R E Schwarz
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
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50
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Katz RL, Quezado M, Senderowicz AM, Villalba L, Laskin WB, Tsokos M. An intra-abdominal small round cell neoplasm with features of primitive neuroectodermal and desmoplastic round cell tumor and a EWS/FLI-1 fusion transcript. Hum Pathol 1997; 28:502-9. [PMID: 9104953 DOI: 10.1016/s0046-8177(97)90042-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We report an intra-abdominal round cell tumor in a young man which exhibited the light and electron microscopic appearance of a peripheral primitive neuroectodermal tumor (PNET), in addition to the clinical and topographic characteristics, desmoplasia and a complex immunophenotypic profile of the intra-abdominal desmoplastic round cell tumor (DSRCT). Reverse transcription polymerase chain reaction revealed a EWS/FLI-1 fusion transcript as in PNET/Ewing's sarcoma, instead of the EWS/WT1 transcript of DSRCT. The tumor was also strongly positive for the mic2 protein. This is a unique case of a hybrid tumor arising in the peritoneal cavity of a young male. The existence of such a hybrid tumor in this location suggests that DSRCT and PNET may be related and possibly share a common histogenesis.
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Affiliation(s)
- R L Katz
- Department of Anatomic Pathology, National Naval Medical Center, Bethesda, MD, USA
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