Ewing family tumour

Definition

There was initially a sharp distinction between Ewing sarcoma of bone and extraskeletal primitive neuroectodermal tumour (PNET). However, both are now recognised to be members of the Ewing family of tumours, small round blue cell tumours characterised by positivity for CD99 and Fli1, with a translocation t(11;22)(q24;q12). There is a spectrum from undifferentiated Ewing sarcoma to PNET with neuroendocrine differentiation. This family includes malignant small cell tumour of the thoracopulmonary region (Askin tumour) and peripheral neuroepithelioma.

Epidemiology

Tumours of the Ewing family occur predominantly in children and young adults.

Histopathology

The cells of Ewing tumour contain glycogen.

Variants:

• Typical Ewing sarcoma: may occur in bone or soft tissue. Cells are uniform and round with little clear to pale cytoplasm, forming sheets or vague lobules. The nuclear chromatin is finely dispersed and nucleoli are inconspicuous. There are frequent individual degenerating dark cells and geographical areas of necrosis.

• Typical PNET: these tumours show spindling and poorly formed rosettes.

• Spindle cell sarcoma-like: there is marked spindling of cells.

• Sclerosing: abundant hyalinised eosinophilic matrix. The cells resemble those of typical Ewing tumour.

• Large-cell atypical Ewing tumour: in addition to areas of typical Ewing tumour, there are variable numbers of enlarged epithelioid cells with variably clear cytoplasm and moderately large nuclei are with an irregular outlines and prominent nucleoli.

• Adamantinoma-like: There are nests of moderately pleomorphic hyperchromatic cells forming peripheral palisades, surrounded by a marked desmoplastic response. There are often large polygonal cells with a moderate amount of cytoplasm, hyperchromatic nuclei and prominent nucleoli. Rarely, there may be squamous pearl formation. This variant shows immunohistochemical evidence of epithelial differentiation with positivity for high molecular weight cytokeratins.

• Cytokeratin-positive

• Desmin-positive

• Malignant small cell tumour of the thoracopulmonary region (Askin tumour)

Immunohistochemistry

		Usual Ewing tumour	Usual PNET	Spindle-cell sarcoma-like Ewing tumour	Spindle-cell sarcoma-like Ewing tumour	Atypical Ewing sarcoma	Adamantinoma-like	Overall
	CD99	35/351	8/81	3/31	2/21	3/31	3/31	52/521
	Fli1	29/321	5/51	3/31	2/21	3/31	3/31	44/471
	AE1/AE3	7/371	4/81	2/31	1/21	1/31	3/31, 1/12	18/561
	Pancytokeratin MAK-6						2/32
	Cam5.2						1/12
	Cam5.2 or AE1/AE3							10/50 (five diffuse and five focal)4
	34bE12	0/371	0/91	0/31	0/21	0/31	3/31	3/551
	Cytokeratin, NOS							13/41 (diffuse cytoplasmic in four cases, cytoplasmic dot-like in three cases, membrane in three cases, mixed in three cases)3
	Desmin	1/371	0/91	0/31	0/21	0/31	0/31	1/561
	CD99+/Fli1+/CK-/desmin-	24/321
	CD117	9/381	2/81	1/31	0/21	0/31	1/21	13/541
	NSE							35/413, 13/503
	Synaptophysin							14/403
	CD56							9/403
	Mic-2						1/32

Cytogenetics

The cytogenetic abnormalities are highly specific to Ewing tumours:

	translocation	gene fusion product	frequency in Ewing tumours
	t(11;22)(q24;q12)	EWS-Fli1	>90%
	t(21;22)(q22;q12)	EWS-ERG	5%
	t(17;22)(q12;q12)	EWS-E1AF	<1%
	t(2;22)(q33;q12)	EWS-FEV	<1%
	t(7;22)(p22;q12)	EWS-ETV1	1%
		EWS-ZSG	rare3

Typical Ewing tumour can be diagnosed on morphology and immunohistochemistry, but the variants need cytogenetic or molecular confirmation of the diagnosis. The EWS-Fli1 transcript has been reported in two polyphenotypic tumours and two rhabdomyosarcomas⁵

Ultrastructure

The cells appear undifferentiated. The adamantinoma-like variant shows epithelial differentiation in the form of tonofilaments and numerous desmosomes^1,2.

Differential diagnosis

• Sclerosing Ewing tumour:

  • sclerosing epithelioid fibrosarcoma

  • sclerosing rhabdomyosarcoma: positive for desmin, myogenin and MyoD1.

• Adamantinoma-like:

  • adamantinoma: a tumour of long bones, particularly the tibia. It shows trisomies of chromosomes 7, 8 and 12, but not the t(11;22)(q24;q12) translocation.

  • desmoplastic round cell tumour: negative for CD99 and Fli1, but almost always positive for desmin and WT1. The characteristic cytogenetic abnormality in DRCT is t(11;22)(p13;q12)(EWS-WT1).

• Spindle-cell sarcoma-like:

  • synovial sarcoma

• Translocations producing EWS-Fli1 or EWS-ERG fusion genes have rarely been reported in polyphenotypic round cell tumour, rhabdomyosarcoma or desmoplastic round cell tumour.

Management

Chemotherapy

Prognosis

Reportedly, type I fusion transcripts (junction between exon 7 of EWS and exon 6 of FLI-1) appear to have a survival advantage when compared with type II fusion transcripts (junction between exon 7 of EWS and exon 5 of FLI-1) independent of tumor site and stage². The adamantinoma-like variant may be more aggressive².

References

¹ Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol 2005; 29:1025-33

² Bridge JA, Fidler ME, Neff JR, et al. Adamantinoma-like Ewing's sarcoma: genomic confirmation, phenotypic drift. Am J Surg Pathol 1999; 23:159-65

³ Collini P, Sampietro G, Bertulli R, et al. Cytokeratin immunoreactivity in 41 cases of ES/PNET confirmed by molecular diagnostic studies. Am J Surg Pathol 2001; 25:273-4

⁴ Gu M, Antonescu CR, Guiter G, et al. Cytokeratin immunoreactivity in Ewing's sarcoma: prevalence in 50 cases confirmed by molecular diagnostic studies. Am J Surg Pathol 2000; 24:410-6

⁵ Thorner P, Squire J, Chilton-MacNeil S, et al. 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

This page last revised 19.11.2005.

©SMUHT/PW Bishop