Fli-1, Friend Leukaemia Virus Integration 1 gene

Fli-1 protein is a member of the ETS family of DNA-binding transcription factors. Approximately 90% of Ewing's sarcoma/PNETs have a specific translocation, t(11;22)(q24;q12). This results in the fusion of EWS to Fli-1 and production of a fusion protein which is a more potent transcription factor than normal Fli-1. The EWS/Fli-1 fusion transcript is not specific to Ewing's sarcoma/PNET, having also been described in childhood soft tissue sarcomas with neural and myogenic differentiation3,4 and classic neuroblastoma5.

Both polyclonal (Fli-1p) and monoclonal (Fli-1m) antibodies are available.

Immunohistochemical expression

Immunoreactivity is nuclear.

Among small round cell tumours, it is specific to Ewing sarcoma/PNET and lymphoblastic lymphoma:

The sensitivity and specificity of polyclonal (Fli-1p) and monoclonal (Fli-1m) anti-Fli-1, CD99 and FISH with the EWSR1 (22q12) dual-colour break-apart probe have been compared6. In normal tissues, Fli-1p expression was restricted to haemopoietic and endothelial cells. However, Fli-1m was also expressed by the prostate, breast , colon and squamous epithelium.

In conclusion, Fli-1m is sensitive but lacks specificity for EWS/PNET. The combination of CD99 and Fli-1p is optimal.

• endothelial cells and vascular tumours2:

  	Angiosarcoma	20/22 Angiosarcoma, epithelioid: 11/13 Angiosarcoma, conventional: 9/9 2
  	Haemangioendothelioma	11/12 haemangioendothelioma, epithelioid: 8/9 haemangioendothelioma, retiform: 2/2 Dabska tumour: 1/1 2
  	Haemangioma, capillary	7/7 Haemangioma, capillary: 3/3 Haemangioma, spindle cell: 2/2 Haemangioma, epithelioid: 2/2 2
  	Kaposi's sarcoma	12/122
  	Melanoma	0/72
  	Non-vascular sarcomas	0/16 Epithelioid sarcoma: 0/6 MFH: 0/1 MPNST: 0/1 Synovial sarcoma: 0/5 Fibrosarcoma: 0/1 Rhabdomyosarcoma: 0/2 2
  	Carcinomas	0/452 0/45 (Cutaneous squamous: 0/3, Breast infiltrating ductal: 0/12, Pancreatic adenocarcinoma: 0/4, Pulmonary adenocarcinoma: 0/5, Ovarian papillary serous: 0/5, Uterine endometrioid: 0/6, Colonic adenocarcinoma: 0/1, Renal cell: 0/3, Salivary mucoepidermoid: 0/3, Pulmonary carcinoid: 0/2)

• small lymphocytes

• non-specific background cytoplasmic staining has been noted in breast epithelium and cutaneous eccrine glands.

Diagnostic utility

• The identification of Ewing's sarcoma/PNET and its differentiation from other small round cell tumours, noting that lymphoblastic lymphoma is also positive for Fli-1.

• The initial evidence is that Fli-1 may be superior in sensitivity 93% of vascular tumours tested (38 of 41) and specificity (100% to date for those tumours which are likely to form a differential diagnosis with vascular tumours) to CD31, CD34 and factor VIIIRA as a marker of vascular tumours. In particular, it looks promising for the differentiation of epithelioid angiosarcoma from carcinoma and epithelioid sarcoma.

References

1 Folpe, A. L., Hill, C. E., Parham, D. M., O'Shea, P. A., Weiss, S. W. Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor Am J Surg Pathol 2000;24:1657-1662.

2 Folpe, A. L., Chand, E. M., Goldblum, J. R., Weiss, S. W. Expression of Fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. Am J Surg Pathol 2001;25:1061-1066.

3 Sorensen, P. H., Shimada, H.,m Liu, X. F., Lim, J. F., Thomas, G., Triche, T. J. Biphenotypic sarcomas with myogenic and neural differentiation express the Ewing's sarcoma EWS/FLI1 fusion gene. Cancer Res 1995;55:1385-92.

4 Thorner, P., Squire, J., Chilton-MacNeil, S., Marrano, P., Bayani, J., Malkin, D., Greenberg, M., Lorenzana, A., Zielenska, M. Is the EWS/FLI-1 fusion transcript specific for Ewing sarcoma and peripheral primitive neuroectodermal tumor? A report of four cases showing this transcript in a wider range of tumor types. Am J Pathol 1996;148:1125-38.

5 Burchill, S. A., Wheeldon, J., Cullinane, C., Lewis, I. J. EWS-FLI1 fusion transcripts identified in patients with typical neuroblastoma. Eur J Cancer 1997;33239-43.

6 Mhawech-Fauceglia P, Herrmann F, Penetrante R, et al. Diagnostic utility of FLI-1 monoclonal antibody and dual-colour, break-apart probe fluorescence in situ (FISH) analysis in Ewing's sarcoma/primitive neuroectodermal tumour (EWS/PNET). A comparative study with CD99 and FLI-1 polyclonal antibodies. Histopathology 2006; 49:569-75

This page last revised 20.1.2007.

©SMUHT/PW Bishop