Epithelioid Sarcoma and Unclassified Sarcoma with Epithelioid Features: Clinicopathological Variables, Molecular Markers, and a New Experimental Model

Sakharpe, Aniket; Lahat, Guy; Gulamhusein, Taher; Liu, Ping; Bolshakov, Svetlana; Nguyen, Theresa; Zhang, Pingyu; Belousov, Roman; Young, Eric D.; Xie, Xianbiao; Rao, Priya; Hornick, Jason L.; Lazar, Alexander J.; Pollock, Raphael E.; Lev, Dina

doi:10.1634/theoncologist.2010-0174

Cited by 52 publications

(50 citation statements)

References 37 publications

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“…Some histologic types of soft tissue sarcoma have a predilection for certain anatomic sites. As an example, while only 14 percent of all soft tissue sarcomas present in the upper extremity, 40-50 percent of all epithelioid sarcomas arise on the forearm and finger (Baratti et al, 2007;Sakharpe et al, 2011). Common localizations were extremities and uterine in our study.…”

Section: Discussionmentioning

confidence: 48%

Retrospective Analysis of 498 Primary Soft Tissue Sarcomas in a Single Turkish Centre

Duman¹,

Günaldı²,

Erçolak³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: Soft tissue sarcomas (STS) must be managed with a team involving pathologists, radiologists, surgeons, radiation therapists and medical oncologists. Treatment modalities and demographic charasteristics of Turkish STS were analysed in the current study. Material-Methods: Primary adult STS followed between 1999-2010 in Cukurova University Medical Faculty Department of Medical Oncology were analzied retrospectively Results: Of the total of 498 patients, 238 were male and 260 female. The most seen adult sarcomas were leomyosarcoma (23%). Localization of disease was upper extremity (8.8%), lower extremity (24.7%), head-neck 8.2%, thoracic 8%, retroperitoneal 5.6%, uterine 12.4%, abdominal 10%, pelvic region 3.6 and other regions 10%. Some 13.1% were early stage, 10.2% locally advanced, 8.2% metastatic and 12.2% recurrent disease. Patients were treated with neoadjuvant/adjuvant (12%) or palliative chemotherapy (7.2%) and 11.4% patients did not receive chemotherapy. Surgery was performed as radical or conservative. The most preferred regimen was MAID combination chemotherapy in the rate of 17.6%. The most common metastatic site was lung (18.1%). The overall survival was 45 months (95%CI 30-59), 36 months in men and 55 months in women, with no statistically significant difference (p=0.5). The survival rates were not different between the group of adjuvant and palliative chemotherapy (respectively 28 versus 18 months) (p=0.06), but radical surgery at 37 months was better than 22 months for conservative surgery (p=0.0001). No differences were evident for localization (p=0.152). Locally advanced group had higher overall survival rates (72 months) than other stages (p=0.0001). Conclusion: STS can be treated successfully with surgery, chemotherapy and radiotherapy. The survival rates of Turkish people were higher in locally advanced group; these results show the importance of multimodality treatment approach and radical surgery.

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Section: Discussionmentioning

confidence: 48%

Retrospective Analysis of 498 Primary Soft Tissue Sarcomas in a Single Turkish Centre

Duman¹,

Günaldı²,

Erçolak³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…In contrast, epithelioid sarcoma (11,34) and VAESBJ epithelioid sarcoma model system (ref. 35; see also http://www.sanger.ac. uk/cgi-bin/genetics/CGP/cghviewer/CghHome.cgi), despite the shared feature of recurrent SMARCB1 inactivation, show a much more unstable genome, thus suggesting that in the adult setting, the cancer-initiating cell of epithelioid sarcoma requires the overriding of multiple pathways, including the one involved in the control of genome integrity.…”

Section: Discussionmentioning

confidence: 99%

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

Brenca

Rossi

Lorenzetto

et al. 2013

Molecular Cancer Therapeutics

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Epithelioid sarcoma is a rare soft tissue neoplasm that usually arises in the distal extremities of young adults. Epithelioid sarcoma presents a high rate of recurrences and metastases and frequently poses diagnostic dilemmas. We previously reported loss of tumor suppressor SMARCB1 protein expression and SMARCB1 gene deletion in the majority of epithelioid sarcoma cases. Unfortunately, no appropriate preclinical models of such genetic alteration in epithelioid sarcoma are available. In the present report, we identified lack of SMARCB1 protein due to a homozygous deletion of exon 1 and upstream regulatory region in epithelioid sarcoma cell line VAESBJ. Restoration of SMARCB1 expression significantly affected VAESBJ cell proliferation, anchorage-independent growth, and cell migration properties, thus supporting the causative role of SMARCB1 loss in epithelioid sarcoma pathogenesis. We investigated the translational relevance of this genetic background in epithelioid sarcoma and showed that SMARCB1 ectopic expression significantly augmented VAESBJ sensitivity to gamma irradiation and acted synergistically with flavopiridol treatment. In VAESBJ, both activated ERBB1/EGFR and HGFR/MET impinged on AKT and ERK phosphorylation. We showed a synergistic effect of combined inhibition of these 2 receptor tyrosine kinases using selective small-molecule inhibitors on cell proliferation. These observations provide definitive support to the role of SMARCB1 inactivation in the pathogenesis of epithelioid sarcoma and disclose novel clues to therapeutic approaches tailored to SMARCB1-negative epithelioid sarcoma.

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“…Archived paraffin blocks from 37 localized epithelioid sarcomas and 8 primary breast cancer surgical samples (controls for epithelial-related markers) were assembled in a tissue microarray and processed as previously published. 5 Immunohistochemical study was performed following pressure cooker antigen retrieval using a mouse anti-ERG monoclonal antibody to the N-terminus (1:2000; 9FY; BioCare Medical, Concord, CA, USA), a rabbit anti-ERG monoclonal antibody to the C-terminus (1:2000; EPR3864(2); Epitomics, Burlingame, CA, USA), and a mouse anti-FLI1 monoclonal antibody (1:100; G146-222; BD Biosciences, San Jose, CA, USA). Comparison was made to mouse anti-CD34 monoclonal antibody (1:40; my10, BD Biosciences), mouse anti-CD31 monoclonal antibody (1:30, 1A10, NovoCastra Vision Biosystems, Newcastle upon Tyne, UK), and mouse anti-D2-40 monoclonal antibody (1:50; Covance, Princeton, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

ERG and FLI1 protein expression in epithelioid sarcoma

et al. 2014

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Epithelioid sarcoma is a rare, aggressive keratin-positive sarcoma that co-expresses CD34 in 50% of cases and may mimic an angiosarcoma. Recently, we have observed one case of epithelioid sarcoma that labeled for ERG, an ETS family regulatory transcription factor, which is considered to be a reliable marker for vascular differentiation. We investigated the prevalence of nuclear expression of ERG and FLI1, a homologous transcription factor, in these tumors. A formalin-fixed paraffin-embedded tissue microarray of 37 epithelioid sarcomas was examined. Immunohistochemistry was performed using anti-ERG monoclonal antibody to the N-terminus, anti-ERG monoclonal antibody to the C-terminus and anti-FLI1 monoclonal antibody. Comparison was made with CD34, CD31, and D2-40 labeling. The extent of immunoreactivity was graded according to the percentage of positive tumor cell nuclei (0: no staining; 1 þ : o5%; 2 þ : 5-25%; 3 þ : 26-50%; 4 þ : 51-75%; and 5 þ : 76-100%), and the intensity of staining was graded as weak, moderate, or strong. Nuclear staining for the N-terminus of ERG was seen in 19 out of 28 cases: 10 with diffuse(4 to 5 þ ) strong/moderate labeling; 1 with 2 þ moderate labeling and 8 with weak labeling (1 to 4 þ , 2 each). Focal staining for the C-terminus of ERG was seen in only 1 out of 29 cases (2 þ moderate). FLI1 labeling was seen in nearly all (28 out of 30) cases: 16 with diffuse (5 þ ) predominantly moderate labeling, and 8 cases with diffuse(5 þ ) weak labeling. The remainder had variable moderate (1 to 3 þ ) or weak (1 to 4 þ ) FLI1 staining. CD34 was positive in 22 out of 30 cases and D2-40 was found to be positive in 22 out of 31 cases. All cases were negative for CD31 (0 out of 30). Epithelioid sarcoma can label with antibodies to the N-terminus of ERG, FLI1, and D2-40, which may cause diagnostic confusion for a vascular tumor. A panel of other antibodies including SMARCB1 and CD31 should be used in evaluating these tumors. ERG antibody selection is also critical, as those directed against the C-terminus are less likely to label epithelioid sarcoma. Modern Pathology (2014) 27, 496-501; doi:10.1038/modpathol.2013.161; published online 27 September 2013 Keywords: epithelioid sarcoma; ERG; FLI1 ERG and FLI1, members of the ETS family of transcription factors, are markers of endothelial differentiation. The utility of ERG and FLI1 in distinguishing cutaneous and non-cutaneous angiosarcomas from other histologic mimics has been previously described. [1][2][3][4] Recently, a recurrent epithelioid sarcoma at our institution showed histologic features suggestive of vascular differentiation: hemorrhagic at low power, discohesive sheets of large atypical epithelioid cells, and areas of hobnailed-appearing cells in blood-filled cystic spaces mimicking epithelioid angiosarcoma. (Figure 1) Immunohistochemical studies showed the tumor to be reactive for keratin, CD34, and ERG but negative for CD31; SMARCB1 expression was lost. Initial biopsies showed central geographic necrosis with palisading tumor cells, cha...

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Epithelioid Sarcoma and Unclassified Sarcoma with Epithelioid Features: Clinicopathological Variables, Molecular Markers, and a New Experimental Model

Cited by 52 publications

References 37 publications

Retrospective Analysis of 498 Primary Soft Tissue Sarcomas in a Single Turkish Centre

Retrospective Analysis of 498 Primary Soft Tissue Sarcomas in a Single Turkish Centre

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

ERG and FLI1 protein expression in epithelioid sarcoma

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