ERG Transcription Factor as an Immunohistochemical Marker for Vascular Endothelial Tumors and Prostatic Carcinoma

Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
The American journal of surgical pathology (Impact Factor: 5.15). 03/2011; 35(3):432-41. DOI: 10.1097/PAS.0b013e318206b67b
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ERG, an ETS family transcription factor, is known to be expressed in endothelial cells, and oncogenic ERG gene fusions occur in subsets of prostatic carcinoma, acute myeloid leukemia, and Ewing sarcoma. In this study, we immunohistochemically investigated nuclear ERG expression using a new monoclonal antibody, CPDR ERG-MAb, that is highly specific for detecting ERG protein and ERG-expressing prostate carcinomas. A broad range of vascular endothelial (n = 250), other mesenchymal (n = 973), and epithelial tumors (n = 657) was examined to determine the use of ERG immunohistochemistry in surgical pathology. Only immunostains with ERG-positive normal endothelia (internal control) were considered valid, and only nuclear staining was considered to be positive. In adult tissues, ERG was restricted to endothelial cells and to a subset of bone marrow precursors, but early fetal mesenchyme and subpopulations of fetal cartilage were also positive. In vascular tumors, ERG was expressed in endothelia of all hemangiomas and lymphangiomas, and typically extensively expressed in 96 of 100 angiosarcomas, 42 of 43 epithelioid hemangioendotheliomas, and all 26 Kaposi sarcomas. Among nonvascular mesenchymal tumors, only blastic extramedullary myeloid tumors (7 of 10) and rare Ewing sarcomas (2 of 29) were positive. Among epithelial tumors, 30 of 66 prostatic adenocarcinomas showed focal-to-extensive ERG positivity, with no immunoreactivity in the normal prostate. Other carcinomas and epithelial tumors (n = 643) were ERG negative, with the exception of 1 of 42 large cell undifferentiated pulmonary carcinomas and 1 of 27 mesotheliomas, each of which showed focal nuclear ERG positivity. On the basis of the above observations, ERG is a highly specific new marker for benign and malignant vascular tumors. Among epithelial tumors, ERG shows a great promise as a marker to identify prostatic carcinoma in both primary and metastatic settings.

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    • "Furthermore, a striking positional conservation of those genes was also found. Both the location and the direction of the genes are maintained within the genetic locus in Xenopus, including transcriptional regulator ERG and Beta-1,3-galactosyltrans- ferase 5, both known vascular and ovarian tumor markers, respectively (Miettinen, et al., 2011; Seko et al., 2009). These data indicate that DSCAM maintained synteny as well as sequence conservation throughout vertebrate evolution, likely reflecting a functionally conserved role of DSCAM in vertebrate development. "
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    ABSTRACT: The Down syndrome cell adhesion molecule (DSCAM) is an Ig containing cell adhesion molecule with remarkable structural conservation throughout metazoans. In insects, DSCAM has 38,000 potential isoforms that convey axon guidance, fasciculation and dendrite morphogenesis during neurodevelopment. In vertebrates, DSCAM is expressed throughout the nervous system and seems to also mediate proper axonal guidance and synaptogenesis without the isoform diversity found in insects. Differences in DSCAM function among several vertebrate species complicate the understanding of an evolutionarily conserved role during embryogenesis. We take advantage of the frog developmental model Xenopus tropicalis to study DSCAM function in early development by expression analysis and morpholino-mediated knockdown. Our results indicate that DSCAM is expressed early in development and restricted to the head and nervous system. Knockdown of protein expression results in early morphogenetic phenotypes characterized by failed gastrulation and improper posterior neural tube closure. Our results reveal a specific, fundamental role of DSCAM in early morphogenetic movements, presumably through its well-known role in homophilic cell adhesion. © 2014 Wiley Periodicals, Inc.
    genesis 10/2014; DOI:10.1002/dvg.22804 · 2.02 Impact Factor
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    • "However, some AS fail to show this feature, presenting instead as poorly differentiated epithelioid or spindled lesions that may mimic a wide variety of other mesenchymal and nonmesenchymal tumors, including carcinomas and various spindle cell sarcomas [1]. In these settings, immunohistochemistry (IHC) has proven to be extremely valuable in establishing the diagnosis of AS using endothelium-associated markers such as von Willebrand factor (factor 8–related antigen) [4]; CD31 [5]; CD34 [6]; and, more recently, FLI/ERG proteins [7] [8] and claudin-5 [9]. With increased reliance upon IHC for the diagnosis of AS, however, has come awareness of potential immunohistochemical pitfalls, including aberrant expression by AS of various antigens including cytokeratins [10], CD30 [11], and CD117 (c-kit) [12]. "
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    ABSTRACT: Angiosarcomas (AS) are uncommon endothelial malignancies, usually arising from sun-damaged skin in older adults. Although most AS are readily diagnosed by light microscopy alone, immunohistochemistry (IHC) for endothelial markers such as CD31, CD34, FLI1 and ERG plays a valuable adjunctive role. However, IHC studies of AS must be interpreted with caution, as aberrant expression of markers such as cytokeratins, CD30 and CD117 may be seen. We report 3 cases of AS showing aberrant expression of the neuroendocrine markers synaptophysin and/or chromogranin A, previously unreported phenomena. Cases presented as metastatic lesions in the lung of a 48-year-old woman and as primary tumors of the kidney and neck in 29-year-old and 51-year-old women, respectively. All cases expressed synaptophysin and/or chromogranin A, and various neuroendocrine/endocrine neoplasms were strongly considered as diagnoses by the initial evaluating pathologists. Additional morphological study and confirmatory IHC for CD31, FLI1 and ERG established the diagnosis of AS in all cases. Co-expression of synaptophysin and chromogranin A in one case suggests at least some AS show true neuroendocrine differentiation. Awareness of this potential diagnostic pitfall is important for correct diagnosis and treatment of this rare subset of AS.
    Human pathology 08/2014; 45(8). DOI:10.1016/j.humpath.2014.03.016 · 2.77 Impact Factor
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    • "In addition to CD31, these 2 markers are helpful in highlighting the vascular nature of EHE [10,20,21] and showed expression in all cases examined. These markers are of course expressed in all other vascular lesions [8,20,21], therefore, detection of the aforementioned fusion genes may be a valuable discriminatory tool in diagnosing EHE, especially in difficult cases. "
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    ABSTRACT: Epithelioid hemangioendothelioma is a malignant, often indolent vascular tumor which occurs at various anatomic sites. Based on a reciprocal translocation t (1;3)(p36;q25), a consistent WWTR1-CAMTA1 fusion gene has been found. An alternate YAP1-TFE3 fusion has been detected in a small and distinct subset of cases. Thirty-nine tumors, from 24 females and 15 males with an age range 9–85 years, were located in soft tissue (head and neck [8], trunk [5], upper extremities [3], lower extremities [2], mediastinal [1], and paratesticular [1]), lymph node (1), breast (1), skin (2), bone (6), lung (7), and liver (2). The cases were investigated using a panel of immunohistochemical markers. The aforementioned fusion-genes were examined using RT-PCR and/or FISH in order to validate their diagnostic value. Follow-up available for 17 patients ranged from 3 months to 7 years (median interval 1.5 years). Eleven patients were alive without disease, 2 patients were alive with disease after 1.5 and 2 years, respectively. Four patients died of disease after 4 months (n = 1), 5 months (n = 2), and 1.5 years (n = 1). The size, known for 30 lesions, was >3 cm in 9 of them. Histologically, all lesions had classical features, at least focally. Four tumors counted >3 mitoses/50 HPF. Immunohistochemically, all cases tested stained positive for ERG (21), FLI1 (5) and CD31 (39). CD34 and D2-40 positivity was seen in 81% and 71% of the examined cases, respectively. 11/35 cases expressed pan-keratin and 6/20 cases CK8.18. TFE3 showed a nuclear reaction in 21/24 cases, irrespective of TFE3 rearrangement. Molecular genetically, 35/35 cases revealed one of the fusion genes by FISH and/or RT-PCR with WWTR1-CAMTA1 in 33 cases and YAP1-TFE3 in 2 cases. These results demonstrate the high diagnostic value of FISH and RT-PCR in detecting the fusion genes of EHE. The immunohistochemical utility of TFE3 appears questionable in this study. Virtual Slides The virtual slide(s) for this article can be found here:
    Diagnostic Pathology 07/2014; 9(1):131. DOI:10.1186/1746-1596-9-131 · 2.60 Impact Factor
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