ERG and FLI1 protein expression in epithelioid sarcoma

Abstract

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...

Novel uses of immunohistochemistry in the diagnosis and classification of soft tissue tumors

“…9,10 Of note, some anti-ERG antibodies show cross-reactivity with FLI1, reducing the specificity of such reagents. Immunoreactivity for ERG may also be observed in epithelioid sarcomas, particularly using antibodies that recognize the N-terminus of ERG; 11,12 an antibody directed against the C-terminus of ERG is rarely positive in epithelioid sarcoma. 12 ERG is also positive in a selected group of tumors that harbor translocations involving ERG: B50% of prostatic adenocarcinomas, 5-10% of Ewing sarcomas, and a small subset of acute myeloid leukemias.…”

Diagnostically Challenging Epithelioid Vascular Tumors

“…50 Absence or weak immunoreactivity for ERG in epithelioid sarcoma also can be helpful if antibody to C-terminus is used; epithelioid sarcomas are frequently ERG positive with antibodies against the N-terminus. 42,43 In predominantly spindled cases, leiomyosarcoma may be considered. Epithelioid sarcomalike hemangioendothelioma lacks the intersecting fascicular pattern of a true smooth muscle tumor and is negative for smooth muscle markers by immunohistochemistry.…”

“…42 Epithelioid sarcoma is negative for CD31 and shows loss of SMARCB1 (INI-1). 43 Epithelioid sarcomalike hemangioendothelioma has a more solid growth pattern, and is composed of myoid-appearing spindled cells in loose fascicles. It is consistently negative for CD34.…”

Immunohistochemistry in Dermatopathology

“…However, it is also expressed in subsets of lymphomas, MCCs, and melanomas. 203,[205][206][207][208] Pankeratin reactivity is usually absent in EWS/PNET, and CK20 expression has not been reported, unlike MCCs. The surest way to distinguish EWS/PNET from MCC is cytogenetic analysis revealing t(11;22), usually involving EWS and FLI1 genes, in EWS/PNET.…”