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The Turkish Journal of Gastroenterology
2009, Volume 20, No 2, Page(s) 83-86
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Friend leukemia virus integration-1 (FLI-1) expression in gastrointestinal stromal tumors
Gülşah KAYGUSUZ, Işınsu KUZU
Department of Pathology, Ankara University, School of Medicine, Ankara
Keywords: Friend leukemia virus integration-1, Ewing’s sarcoma/primitive neuroectodermal tumor, gastrointestinal stromal tumor.
Summary
Background/aims: Friend leukemia virus integration-1 expression has been shown in a variety of tumors, including vascular tumors, desmoplastic small round cell tumor, Merkel cell carcinoma, and lymphoblastic lymphoma, in addition to Ewing’s sarcoma/ primitive neuroectodermal tumor. The aim of the current study was to examine Friend leukemia virus integration-1 protein expression in a series of gastrointestinal stromal tumors and also to assess if Friend leukemia virus integration-1 has any role in the disease process. It is the first study analyzing Friend leukemia virus integration-1 expression in gastrointestinal stromal tumors in the English literature. Methods: A tissue microarray block containing 52 cases of gastrointestinal stromal tumors was done. Immunohistochemical analysis was performed for Friend leukemia virus integration-1 polyclonal antibody. Results: Immunohistochemically, Friend leukemia virus integration-1 was negative in all cases. Conclusions: Friend leukemia virus integration-1 can be expressed in a variety of tumors, and is helpful in making the diagnosis of Ewing’s sarcoma/primitive neuroectodermal tumor. We think that this protein is not expressed in gastrointestinal stromal tumors and it is not a part of the pathogenesis of this disease.
  • Top
  • Summary
  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
    • Introduction
    Ewing’s sarcoma/primitive neuroectodermal tumor (EWS/PNET) is a member of the small, blue, round cell tumors that occur in bone and soft tissue. Approximately 80% of EWS/PNET cases have a characteristic balanced chromosomal translocation, t(11;22) (q24;q12), which includes the N-terminal transactivation domain of the EWS gene and the C-terminus DNA-binding domain of the Friend leukemia virus integration-1 (FLI-1) gene (1-3). The EWS/FLI-1 fusion proteins resulting from this type of translocation behave as aberrant transcriptional regulators and play an essential role in the development of EWS/PNET (4, 5). FLI-1 antibody, a polyclonal antibody directed against the C-terminus of the FLI-1 gene, has been proposed as a diagnostic immunohistochemical marker, combined with CD99, in differentiating EWS/PNET from the other small round cell tumors (6-8). FLI-1 is also expressed by hematopoietic cells and endothelial cells in normal tissues. FLI-1 expression has been shown in a variety of tumors, including vascular tumors, desmoplastic small round cell tumor, Merkel cell carcinoma, and lymphoblastic lymphoma, in addition to EWS/PNET (7-10).
    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract that may show spindle, epithelioid, or mixed type of cellular morphology, in contrast with EWS/PNET. The diagnosis of GISTs is dependent on clinical and morphological features, supported by KIT immunoreactivity and/or the presence of activating KIT mutations. A minority (4-15%) of GISTs fail to express detectable KIT protein, and may have a mutation of PDGFRA (11-13). The histopathological diagnosis in KIT-negative cases may be very difficult. For this reason, some other markers may be used for diagnostic purposes. With the development of specific targeted therapy (imatinib mesylate) for GISTs, it is crucially important to discriminate GISTs from the other lesions in their differential diagnosis (14).
    The aim of the current study was to examine FLI- 1 protein expression in a series of GISTs and also to assess whether or not FLI-1 has any role in the disease process. It is the first study analyzing FLI- 1 expression in GISTs.
  • Top
  • Summary
  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
    • Materials And Methods
    The cases, obtained from the archives of our department between 1996-2001, showing typical clinicopathological and immunohistochemical features of GISTs were included in this study. A tissue microarray (TMA) block containing 52 cases of GISTs was built. In the TMA block, each tumor was represented by two cores using a tissue arrayer (Beecher Instruments; Silver Spring, MD, USA). Cores (0.6 mm) were taken from paraffinembedded tumors. The following parameters were recorded for each case: age and gender, primary tumor location, morphological type, risk group, and immunohistochemical features.
    Immunohistochemistry
    Immunohistochemistry was performed for FLI-1 polyclonal (C-19) antibody (clone sc-356, 1:150; Santa Cruz, CA, USA) on tissue sections by using Ventana Automated Immunostainer. Positive and negative control tissues were put into the TMA block. Nuclear staining in the lymphocytes and endothelial cells was considered as positive internal control. The cases staining less than 5% of tumor cells were scored as negative.
  • Top
  • Summary
  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
    • Results
    Thirty-two of 52 cases were (61.5%) male. The mean age was 59.5 years (range: 26 to 90). The most frequent location of the lesion was the stomach (n=26, 51%), followed by small bowel (n=16, 31%), omentum (n=7, 14%), colon (n=1, 2%), and pelvis (n=1, 2%). In one case, the exact intra-abdominal site was not specified.
    Twenty-six cases (51%) were classified as high risk, 11 (21.5%) as intermediate risk, 11 (21.5%) as low risk and 3 (6%) as very low risk. One case could not be classified because of the inadequate clinical information regarding tumor size. The main morphological type of the tumor was spindle type (n=33, 63.5%), followed by epithelioid type (n=13, 25%) and mixed type (n=6, 11.5%) (Figure 1A-C).
    Immunohistochemically, FLI-1 was negative in all cases (Figure 1D,E). Only endothelial cells and lymphocytes were stained. To compare the FLI-1 staining profile, the previous immunohistochemical features of the cases at the time of diagnosis were recorded. CD117, CD34 and SMA positivity were seen in 45 cases (86.5%), 35 cases (67%) and 37 cases (71%), respectively. Very few cases were positive for desmin (n=3, 6%) and for S-100 (n=2, 4%).
  • Top
  • Summary
  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
    • Discussion
    Up to 80% of EWS/PNET are characterized by the chromosomal translocation, t(11;22) (q24;q12), which results in the EWS/FLI-1 fusion protein. This chimeric protein is located in the nucleus and induces malignant transformation in NIH3T3 cells (15-17). A polyclonal antiserum against the C-terminus of the FLI-1 protein has been shown to be a useful immunohistochemical marker in discriminating EWS/PNET from other round cell tumors (8). Histologically, EWS/PNET is composed of uniformly undifferentiated small round cells with vesicular nuclei and a small cytoplasm within a sparse intercellular stroma. The cellular origin of EWS/PNET is still debated. Endothelial and neuroectodermal origins have been postulated (19- 21). Riggi et al. (22) showed that the primary bone marrow-derived mesenchymal progenitor cells display permissiveness for EWS-FLI-1-mediated transformation and generate tumors that display hallmarks of EWS/PNET. They proposed that mesenchymal progenitor cells may constitute a candidate environment from which EWS/PNET originate.
    GISTs are specific mesenchymal tumors occurring in the GI tract but also in the omentum and mesentery. They originate from the interstitial cells of Cajal or their stem-cell-like precursors (11,23). These cells form a complex network providing the regulation of intestinal motility in the GI tract. Morphologically, most of the GISTs appear as spindle cell tumors, but epithelioid or mixed spindle-epithelioid cell appearance may occur. Epithelioid GISTs, similar to spindle cell lesions, tend to have uniform round-to-ovoid nuclei with vesicular chromatin. This histological feature may cause diagnostic confusion with epithelial, melanocytic or other neoplasms. More than 80% of GISTs display mutations in KIT or PDGFRA receptor tyrosine kinase proteins sporadically, but familial GISTs are also present. The end result of activating mutations of KIT and PDGFRA is increase in cellular proliferation and decrease in apoptosis, ultimately leading to neoplasia (11,24,25). The major diagnostic feature of GIST is positivity for the KIT (CD117) receptor tyrosine kinase, observed in more than 95% of GISTs. GISTs are also variably positive for CD34, smooth muscle markers and rarely desmin and S-100 protein. Protein kinase theta, a downstream effector in the KIT signaling pathway activated following KIT activation, and DOG1, a new gene encoding for a protein of unknown function, seem to be expressed in GISTs irrespective of mutation type (26,27). The diagnosis of GISTs is dependent on clinical and morphological features, supported by KIT immunoreactivity and/or the presence of activating KIT mutations.
    FLI-1 has been proposed as a diagnostic immunohistochemical marker, combined with CD99, in differentiating EWS/PNET from the other small round cell tumors (6-8). FLI-1 is also expressed by hematopoietic cells and endothelial cells in normal tissues (18). FLI-1 expression has been shown in a variety of tumors, including vascular tumors, desmoplastic small round cell tumor, Merkel cell carcinoma, and lymphoblastic lymphoma, in addition to EWS/PNET (7-10,28). Mhawech-Fauceglia et al. (29) analyzed the expression pattern of FLI-1 in a large series of benign and malignant solid tumors. They also tested this antibody on the spindle cell mesenchymal tumors that may enter the differential diagnosis of GIST. In their series, all cases of leiomyosarcoma, synovial sarcoma, fibrosarcoma, and malignant peripheral nerve sheath tumors were negative for FLI-1. In our study, we did not find FLI-1 expression in GIST cases. According to the clinical presentation, cellular morphology and immunohistochemical or molecular findings, the differentiation of GIST from EWS/PNET is generally not a diagnostic problem. But GISTs can display unusual morphological features, such as signet ring cell, rhabdoid, paraganglioma- like, or poorly differentiated morphology in the unusual sites (30-32), such that they may be confused with other sarcomas. We also know that EWS/PNET may be histologically indistinguishable, particularly when poorly differentiated or in the setting of a small biopsy (8).
    In conclusion, FLI-1 can be expressed in a variety of tumors and is helpful in making the diagnosis of EWS/PNET, but it seems that it is not expressed in GISTs or in the mesenchymal tumors that should be differentiated from GISTs. This finding could be helpful in differentiating these two entities in the setting of a limited amount of tissue biopsy from a tumor showing poorly differentiated morphology.
  • Top
  • Summary
  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
    • References
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  • Top
  • Summary
  • Introduction
  • Materials And Methods
  • Results
  • Discussion
  • References
    • [ Summary ] [ PDF ] [ Similar Articles ] [ Mail to Author ] [ Mail to Editor ]
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