ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma

Abstract

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.

Fig. 1.

A. Nuclear ERG-expression in primitive subepidermal mesenchyme and vascular endothelial cells in early first trimester human embryo. B. Developing cartilage, especially peripherally at the joints and foci of perichondrial mesenchyme and capillary endothelia show nuclear ERG-positivity in late first trimester fetus.

Fig. 2.

Nuclear ERG-expression in benign vascular tumors. A. Juvenile capillary hemangioma involving lacrimal gland contains both ERG-positive endothelial cells and ERG-negative pericytes. B. Cavernous hemangioma vascular lumens are lined by ERG-positive endothelial cells. C. Lymphangioma endothelia are ERG-positive. D. In spindle cell hemangioma, ERG is restricted to the endothelial component, and the interstitial spindle cells are negative.

Fig. 3.

ERG-expression in hemangioendotheliomas. A. Retiform hemangioendo-thelioma with ERG-positive endothelial nuclei. B. Epithelioid hemangioendothelioma cords show both nuclear and cytoplasmic ERG-expression. C. Kaposiform hemangioendothelioma contains an ERG-positive endothelial component and an ERG-negative pericytic element.

Fig. 4.

Nuclear ERG expression in angiosarcoma in comparison with cytoplasmic and membranous CD31 staining. Each vertical group represents one case and horizontal line one marker. A. Vasoformative pericardial angiosarcoma in a man with a history of mediastinal radiation. B. Solid, poorly differentiated angiosarcoma involving skeletal muscle. C. Pleomorphic splenic angiosarcoma; mitotic cells lack distinct nuclear ERG-staining. Note that all tumors are positive for both markers.

Fig 5.

Nuclear ERG-expression in non-vascular tumors. A. Intestinal relapse of acute myeloid leukemia (blastic extramedullary myeloid tumor). B. Ewing sarcoma. C. ERG-positive prostatic adenocarcinoma with a negative normal duct. D. Large cell anaplastic pulmonary carcinoma with focal nuclear ERG-expression.

Fig 6.

A hemorrhagic poorly differentiated carcinoma simulating an angiosarcoma is negative for both ERG and CD31, but is positive for keratin 8.