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.

Keywords: FOS; FOSB; epithelioid hemangioma; fusions.

Figure 1.

Kaplan-Meier curve showing local recurrence-free survival.

Figure 2.. Imaging studies of bone EH illustrating destructive appearance with emphasis on diagnostic pitfalls.

A. X-ray of a destructive thoracic spine lesion with left pedicle involvement; B. MRI showing spinal cord compression through soft-tissue extension of tumor. C. X-ray showing a lobulated, lytic lesion in the distal radius, with well-defined borders; D. X-ray showing a thoracic spine destructive lesion with ballooning and cortical bone thickening; E. CT showing a first metatarsal osteolytic lesion with ballooning and cortical bone destruction, which on F. MRI T1 and G. MRI T2 weighted image display a low to intermediate signal tumor; H, I. MRI image showing multifocal skull tumors.

Figure 3.. Morphologic spectrum of skeletal EH harboring FOS gene fusions.

A. whole mount view of a markedly destructive EH showing a predominant hemorrhagic appearance and very thin rim of residual bone noted at the periphery (19/F, T3–T4 lesion). B. High power of this lesion showed a mixture of spindle and epithelioid cells, forming ill-defined vascular spaces, obscured by abundant hemorrhage. C. Another example of bone EH associated with hemorrhagic stroma and predominantly spindle cells, showing only focal vasoformative areas lined by epithelioid cells (4/M, occipital lesion); D. Dilated vascular channels lined by plump epithelioid cells with densely eosinophilic cytoplasm and enlarged round nuclei with open chromatin and small nucleoli (64/M, humerus/coracoid, multifocal lesions). E. Rare FOS-positive EH showing abundant stromal eosinophilic infiltrate (61/M, tibia). F. EH associated with an exuberant reactive new bone formation showing foci of woven bone lined by prominent osteoblasts and scattered osteoclast-type giant cells (30/M, acetabulum).

Figure 4.. Histologic features of EH of bone showing FOSB gene rearrangements.

A,B. EH of bone showing a predominant solid growth pattern composed of packed epithelioid cells with densely eosinophilic cytoplasm and scattered small-sized vascular channels interspersed. B. Higher power depicts abrupt transition to areas of necrosis (34/M, scapula). C, D. High power view of a cellular EH with plump epithelioid and ovoid endothelial cells with pale eosinophilic cytoplasm and enlarged ovoid nuclei with fine chromatin and mild to moderate atypia. D. Large areas of necrosis were also noted (8/M, calcaneus, WWTR1-FOSB fusion).