Epithelioid hemangioma of bone harboring FOS and FOSB gene rearrangements: A clinicopathologic and molecular study

Abstract

The diagnosis of epithelioid hemangioma (EH) remains challenging due to its rarity, worrisome histologic features, and locally aggressive clinical and radiographic presentation. Especially in the bone, EH can be misdiagnosed as a malignant vascular neoplasm due its lytic, often destructive or multifocal growth, as well as atypical morphology. The discovery of recurrent FOS and FOSB gene fusions in the pathogenesis of most EH has strengthened its stand-alone classification, distinct from other malignant epithelioid vascular lesions, such as epithelioid hemangioendothelioma or angiosarcoma. In this study we investigate a group of molecularly confirmed skeletal EH by the presence of FOS or FOSB gene rearrangements to better define its clinical and pathologic characteristics within a homogenous molecular subset. The cohort included 38 patients (25 males, 13 females), with a mean age at diagnosis of 38 years (range, 4-75). Regional, multifocal presentation was noted in 10 cases. Only six cases were correctly recognized as EH by the referring institutions, while most were misdiagnosed as other vascular tumors. Of the 17 patients with follow-up data available, five patients (29%) developed local recurrence after marginal en bloc excision (n = 3) or curettage (n = 2). Local recurrence-free survival rates were 84% at 3 years and 38% at 5 years. No metastasis or disease-related death was identified. Imaging studies exhibited no specific features, showing cortical bone destruction and soft-tissue extension in 14 (38%) cases. FOS gene rearrangements were detected in 28 (74%) of cases, while FOSB rearrangements in 10 (26%) cases. Our results highlight the significant challenges encountered in establishing a correct diagnosis exclusive of the molecular testing, mainly due to its overlap to other malignant epithelioid vascular tumors. Skeletal EH emerges as a genetically defined locally aggressive vascular neoplasm, with a high rate of local recurrence, but lacking the propensity for distant spread.

Immunohistochemistry for FOSB and FOS is a Useful Ancillary Tool in the Diagnosis of Epithelioid Hemangioma but There are Pitfalls in Interpretation Including Expression in Other Vascular Lesions

“…In intraosseous epithelioid hemangiomas, 6 only FISH was employed with cases being mutually exclusive for FOSB and FOS rearrangements. 6 The performance of the antibodies was not assessed in that study. In intravascular cases , 8 no co-staining was identified in a very limited number of cases (n = 6).…”

“…Recurrent FOS and FOSB gene rearrangements are characteristic in subsets of epithelioid hemangiomas, mostly restricted to skeletal, soft tissue and penile locations. 4,6,12,16 FOS gene fusions, with gene partners including LMNA, MBNL1, VIM and lincRNA, 11 are documented in 29% of epithelioid hemangiomas with a higher incidence in skeletal cases (59%-74%) followed by soft tissue (19%) and those in a penile location . 4,6,16,17 FOS gene fusions, however, appear absent in conventional-type cutaneous epithelioid hemangioma and in the ALHE variant.…”

“…4,6,12,16 FOS gene fusions, with gene partners including LMNA, MBNL1, VIM and lincRNA, 11 are documented in 29% of epithelioid hemangiomas with a higher incidence in skeletal cases (59%-74%) followed by soft tissue (19%) and those in a penile location . 4,6,16,17 FOS gene fusions, however, appear absent in conventional-type cutaneous epithelioid hemangioma and in the ALHE variant. 4 On the other hand, FOSB fusions, with translocation partners including ZFP36, WWTR1 and SETD1B, 12,16 are slightly less frequent, presenting in up to 20% of all cases of epithelioid hemangiomas .…”

“…4 Furthermore, epithelioid hemangioma can display atypical histologic features including necrosis and a degree of cytologic atypia but without endothelial multilayering or significant cytologic atypia. 4,5 Anatomical/clinical variants of epithelioid hemangioma include intraosseous, 5,6 an eruptive multifocal presentation 7 and intravascular variants involving large arteries. 8 Over half of all combined variants are associated with immunohistochemical expression of FOSB, being reported in 100% of ALHE and in the eruptive multifocal form and in 75%, 17% and 10% of conventional, intravascular and cellular variants, respectively .…”

“…11 Recurrent FOS or FOSB gene rearrangements are present in one-third of EH cases, with FOS fusions twice as common as FOSB . 4,6,11,12 FOS and FOSB are part of the FOS family of genes together with FOSL1 , FOSL2 and FOSB splice variants ( FOSB2 and delta FOSB 2). The FOS genes encode leucine zipper proteins that can dimerize with members of the Jun family (c-JUN, JUNB, and JUND), constituting the major components of the activating protein-1 (AP-1) complex.…”