Epithelioid Haemangioendothelioma of Bone

Staging is according to bone sarcoma protocols (see TNM staging of tumors of bone). See also the information on staging in section Bone tumors: Introduction.

The overwhelming majority of epithelioid haemangioendotheliomas harbor a t(1;3)(p36;q25), resulting in a fusion of WWTR1 at 3q25.1 with CAMTA1 at 1p36.31-p36.23. The WWTR1 (TAZ) protein is a transcriptional coactivator and effector of the Hippo pathway. The Hippo pathway phosphorylates WWTR1 (TAZ), which leads to its cytoplasmic localization and ubiquitin-dependent degradation. Fusion of WWTR1 (TAZ) to CAMTA1 results in dysregulation of the Hippo pathway, such that WWTR1-CAMTA1 constitutively localizes in the nucleus, where it acts as a neomorphic transcription factor to activate a WWTR1 (TAZ)-like transcriptional program. The monoclonal origin of multifocal epithelioid haemangioendothelioma has also been established using WWTR1-CAMTA1 breakpoint analysis. This indicates that multiple lesions arise from locoregional or distant metastatic spread from a single primary as opposed to multiple independent primaries. A small subset of tumors (< 5%) have a YAP1-TFE3 fusion resulting in oncogenic activation of TFE3.

The tumors are ovoid, rubbery, tan or less frequently hemorrhagic masses that are < 1 cm to 10 cm in size.

Epithelioid haemangioendothelioma is a solid mass that lacks a lobular architecture and is composed of large epithelioid and spindle cells with round or elongated vesicular nuclei, prominent nucleoli, and abundant densely eosinophilic cytoplasm. Intracytoplasmic lumina appear as clear vacuoles that may contain intact or fragmented red blood cells (so-called blister cells or signet-ring cells). Well-formed blood vessels are not present in the classic epithelioid haemangioendothelioma; instead, the tumor cells are arranged in cords and nests, which are embedded within a myxohyaline stroma that may resemble cartilaginous matrix. Cytological atypia and mitotic activity are often limited. A small subset of epithelioid haemangioendotheliomas have atypical histological features, including nuclear pleomorphism, increased mitotic activity, solid sheet-like growth, and necrosis. Epithelioid haemangioendothelioma with YAP1-TFE3 fusion is associated with distinct morphology. The tumor cells are large, with abundant voluminous cytoplasm that is sometimes feathery in appearance. The nuclei can exhibit mild to moderate atypia. The epithelioid cells may delineate well-formed vascular lumina or grow in solid sheets; a myxohyaline stroma is usually absent or inconspicuous.

Not clinically relevant

Wide resection is the treatment of choice. The clinical course can be highly variable. The overall survival rate of patients with epithelioid haemangioendothelioma of bone is 92% at 10 years. Involvement of two or more bones is associated with a worse prognosis (74% 10-year overall survival rate), regardless of the number of organs involved. The mortality rate is about 20%. One study found no correlation between histological parameters and prognosis. Histological risk stratification systems, which were proposed for soft tissue or thoracic examples, have not been tested for bone tumors.

The WWTR1-CAMTA1 fusion can be detected in 89–100% of all epithelioid haemangioendotheliomas with classic histological features, and it is not found in epithelioid haemangioendothelioma’s mimics. YAP1-TFE3 fusions are found in a small subset of cases.

Essential: classic epithelioid haemangioendothelioma is composed of cords or nests of epithelioid endothelial cells within a myxohyaline stroma; epithelioid haemangioendothelioma with YAP1-TFE3 fusion shows either solid growth or well-formed vascular channels lined by epithelioid endothelial cells with nuclear atypia and abundant pale cytoplasm.

Desirable (in selected cases): CAMTA1 expression by immunohistochemistry and/or WWTR1-CAMTA1 fusion; TFE3 overexpression by immunohistochemistry and/or TFE3 gene rearrangement.