December 2023 – Gynecological Pathology

Malignant epithelioid neoplasm with EWSR1:CREB1 fusion.

This is an example of the recently described entity “malignant epithelioid neoplasm with EWSR1/FUS-CREB fusion” that tends to arise in mesothelial-lined cavities, specifically peritoneal cavity, of young patients with a mean age of 36 years.¹ Morphologic clues to this tumor include a fairly well-circumscribed tumor surrounded by a fibrous capsule, with prominent pericapsular lymphoid aggregates. The tumor is comprised predominantly of epithelioid cells. In some instances, the tumor may have mixed epithelioid and spindle morphology. Occasionally, cysts or microcysts can be identified within the tumor. Immunohistochemically, the tumor cells show evidence of epithelial differentiation, with positivity for cytokeratins and/or EMA. A subset of cases shows expression of WT1; however, other mesothelial markers (calretinin) were negative. From a molecular standpoint, this tumor harbors CREM-related (EWSR1-CREM and FUS-CREM) and EWSR1-ATF1 fusions.¹ Little is known about the clinical behavior of this tumor; however, the available information demonstrates its malignant potential and propensity for both lymph node and distant spread.

The differential diagnosis for this tumor includes angiomatoid fibrous histiocytoma (AFH), epithelioid mesothelioma (EM), and intrahepatic cholangiocarcinoma, solid-tubulocystic variant.

AFH usually shows a combination of cystic changes, associated with hemorrhage and hemosiderin deposition, and brisk lymphocytic cuffing. However, the tumor cells are predominantly spindle. AFH usually harbors EWSR1-CREB1 fusions and follows an indolent clinical course with local recurrences if incompletely excised.² 

EM demonstrates overlapping features with the aforementioned entity due to its predilection for peritoneal or pleural surfaces and immunoreactivity for cytokeratin, with coexpression of WT1 in a subset of cases. However, EM usually shows focal papillary architecture, lacks lymphoid cuffing, demonstrates expression of more mesothelial markers (calretinin), and shows loss of expression of BAP1 [1].

Intrahepatic cholangiocarcinoma, solid-tubulocystic variant is a recently described entity that tends to affect young females. Morphologically the tumor is comprised of sheets and large nests of tumor cells alternating with tubular and cystic areas recapitulating sex cord-like morphology. Immunohistochemically, the tumor cells are positive for cytokeratin, CK7, and inhibin. From a molecular standpoint, these tumors show focal and large-scale copy number changes, and no recurrent pathogenic mutations.³

References

1. Argani P, Harvey I, Nielsen GP, Takano A, Suurmeijer AJH, Voltaggio L, Zhang L, Sung YS, Stenzinger A, Mechtersheimer G, Dickson BC, Antonescu CR. EWSR1/FUS-CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities. Mod Pathol. 2020 Nov;33(11):2233-2243. doi:10.1038/s41379-020-0646-5. Epub 2020 Aug 7. PMID: 32770123; PMCID: PMC7584759.
2. Antonescu CR, Dal Cin P, Nafa K, et al. EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer. 2007;46(12):1051-1060. doi:10.1002/gcc.20491. PMID: 17724745.
3. Wen KW, Joseph NM, Srivastava A, Saunders TA, Jain D, Rank J, Feely M, Zarrinpar A, Al Diffalha S, Shyn PB, Graham RP, Drage MG, Kakar S. Inhibin-positive hepatic carcinoma: proposal for a solid-tubulocystic variant of intrahepatic cholangiocarcinoma. Hum Pathol. 2021 Oct;116:82-93. doi:10.1016/j.humpath.2021.07.004. Epub 2021 Jul 20. PMID: 34298064.