Table 5.

Suggested integrated phenotypic-genotypic diagnostic approach to high-grade uterine mesenchymal tumors with ambiguous histologic appearances

		1. Histopathologic evaluation
One or more morphologic features seen in part or all of tumor	Spindle cells with round-ended nuclei, diffuse, moderate-to-severe nuclear atypia and coagulative tumor necrosis	Epithelioid and/or spindled cells with variably clear cytoplasm, variable nuclear pleomorphism, nested or corded architecture, stromal hyalinization	Tongue-like growth, small round to oval cells with scant cytoplasm	No specific morphologic features, or a combination of features typical of more than one entity
Favored diagnosis	Leiomyosarcoma	PEComa	ESS	Sarcoma, NOS
		Confirm morphologic impression with:
		2. Immunohistochemistry
Myogenic markers Melanocytic markers ESS markers	+ − (may be focal) −	+ + (2 or more) −	+/− − +	Other combinations
Favored diagnosis	Suggestive of leiomyosarcoma	Suggestive of PEComa	Suggestive of ESS	Consider hybrid tumor or sarcoma NOS with a descriptive diagnosis
		If immunophenotype is inconsistent with morphologic impression or the diagnosis remains in question, proceed to:
		3. Molecular profiling
Mutations/rearrangements identified	TP53, MED12, FH, ATRX, DAXX, RB1	TSC2, TFE3, RAD51B	JAZF1-JJAZ1, JAZF1-SUZ12, JAZF1-PHF1, YWHAE-FAM22, ZC3H7-BCOR	Various combinations
Favored diagnosis	Leiomyosarcoma	PEComa	ESS	Consider hybrid tumor or sarcoma NOS with a descriptive diagnosis

Note: Clearly the spectrum of tumors in the differential diagnosis, the number of immunohistochemical markers that are used to aid diagnosis of uterine mesenchymal tumors and the number of genetic alterations that may be found is much larger in reality, but this highly simplified approach is presented to illustrate one possible scheme for integrated phenotypic-genotypic classification. ESS – endometrial stromal sarcoma