Diagnostic utility of FOSB immunohistochemistry in pseudomyogenic hemangioendothelioma and its histological mimics

Abstract

BackgroundPseudomyogenic hemangioendothelioma (PHE) is an unusual vascular tumor of intermediate malignancy that rarely metastasizes and tends to arise in the lower limbs of young adults and children. Histologically, PHE shows fascicular proliferation of eosinophilic spindle cells and/or epithelioid cells showing “pseudomyogenic” morphology. Immunohistochemically, PHE is usually positive for vimentin, cytokeratin, CD31 and ERG.MethodWe examined FOSB immunohistochemistry (IHC) in 27 cases consisting of 4 PHE and its histologic mimics including 6 epithelioid hemangioendotheliomas (EHE), 8 angiosarcomas (AS), 4 Kaposi sarcomas (KS) and 5 epithelioid sarcomas (ES). In addition, we performed IHC of CAMTA1 which has recently been established as a useful marker of EHE. We elucidated the diagnostic utility of FOSB IHC in the differential diagnosis of PHE and its histological mimics and also examined the usefulness of FOSB and CAMTA1 IHC combination in the differential diagnosis of the tumors.ResultsIHC revealed diffuse and strong FOSB expression in all PHE cases, while the other tumor types demonstrated limited, weak or no FOSB expression. All EHE cases exhibited diffuse and moderate to strong expression of CAMTA1. All tumor types except for EHE showed limited, weak or no CAMTA1 reactivity.ConclusionsDiffuse and strong FOSB expression was specific for PHE in the current series and FOSB IHC is an effective tool for differentiating between PHE and its histological mimics. Moreover, the combination of FOSB and CAMTA1 IHC is useful for distinguishing PHE from EHE.

Fusion of the Genes WWTR1 and FOSB in Pseudomyogenic Hemangioendothelioma

“…The SERPINE1-FOSB, ACTB-FOSB, and WWTR1-FOSB fusion genes and the taking over of FOSB expression control by SERPINE1, ACTB, and WWTR1 strong promoters makes FOSB a useful immunohistochemical diagnostic marker for pseudomyogenic hemangioendotheliomas as it was the case here (5,13,14). However, genomic analyses are needed to clarify which gene recombinations occur at which frequencies in these tumors, and also whether as yet unknown variants of the FOSB-activation theme exist.…”

FOSB immunoreactivity in endothelia of epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia)

“…It must be pointed out that FOSB immunoreactivity is not specific for EH. As stated above, PHE is defined by a recurrent Positive for either CAMTA1 27,42 or TFE3 35,42,43 ; negative for FOSB 29 Often positive for D2-40/podoplanin 43 ; MYC-negative; INI1 preserved 43,44 Angiosarcoma (AS) Negative for FOSB 29 , CAMTA1 27,42 Often co-expressing D2-40/podoplanin and c-MYC 38,39 Epithelioid angiosarcoma (EAS) Negative for FOSB, 27,29 CAMTA1 27,42 Often (focal) co-expression of cytokeratin and EMA 45,46 ; ERG-positive 47 Pseudomyogenic/epithelioid sarcoma-like hemangioendothelioma (PHE) 36 Co-expression of FOSB 27,29 and AE1/AE3 27,48 Negative for pan-cytokeratin MNF116 49 ; INI1 preserved 48,49 Epithelioid sarcoma (ES) INI1 (SMARCB3)-negative 44,50 Mostly ERG-negative 47 (ERG-expression extremely rare); negative for CAMTA1 27,42 , FOSB 27,29 Cutaneous epithelioid angiomatous nodule Negative for FOSB 29 This study adds to previous evidence of the oncogenic role of FOSB in the pathogenesis of endothelial neoplasms, such as EH and PHE.…”

“…, CAMTA1 42 SERPINE1-FOSB fusion gene, which is associated with significantly higher FOSB mRNA expression in tumor cells 26. Not surprisingly, PHE displays a diffuse and strong FOSB immunoreactivity and this staining pattern is remarkably different from its histological mimics, making FOSB immunohistochemistry a useful diagnostic tool 27. Histologically, PHE consists of fascicular or sheet-like proliferations of spindle-shaped and/or epithelioid cells with oval nuclei and abundant eosinophilic cytoplasm, exhibiting "pseudomyogenic" morphology.…”

Pseudomyogenic Hemangioendothelioma

“…Most of these tumors stain positively for keratin AE1/AE3, ERG, FLI1, and FOSB. 3,14,15 CD31 was positive in 22 of 47 cases (47%) examined by Hornick and Fletcher. 3 Keratin MNF, desmin, CD34, podoplanin (D2-40), S100, H-caldesmon, myogenin, MyoD1, CD68, p63, human herpes virus 8, and factor XIII are typically negative ( Figures 3 through 6).…”

“…Conversely, FOSB is strongly expressed in PH whereas it is negative or focal and weak in EHE. [14][15][16][17] Focal nuclear atypia and increased mitotic activity in some cases of PH may lead to consideration of an epithelioid angiosarcoma diagnosis. Unlike PH, most cases of epithelioid angiosarcoma contain vascular channels or cystically dilated spaces lined by malignant endothelial cells.…”