Pseudomyogenic Haemangioendothelioma

Not clinically relevant

Pseudomyogenic haemangioendothelioma was initially described as being caused by a balanced translocation t(7;19)(q22;q13), resulting in the fusion of SERPINE1 to FOSB. Recently, an alternative ACTB-FOSB gene fusion was identified in half of the cases. These fusions lead to upregulation of FOSB, probably by a promoter-swapping mechanism, because most of the FOSB gene is retained in the fusion (fused at exon 2). SERPINE1 (fusion occurs in non-coding exon 1) is normally highly expressed in vascular cells, and ACTB (fused at exon 3) is a ubiquitously expressed gene. FOSB is a member of the FOS family of transcription factors, which encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1, regulating cell proliferation, differentiation, angiogenesis, and survival. Upregulation of FOSB causes activation of the AP-1 complex. Overexpression of the retained part of FOSB in endothelial cells affects angiogenesis in vitro, with the retained part acting as an active transcription factor capable of regulating its own transcription. The clinicopathological features and behavior do not differ between pseudomyogenic haemangioendotheliomas with SERPINE1-FOSB and ACTB-FOSB fusions, although tumors with the ACTB variant more often present as solitary lesions.

Grossly, margins are ill defined and the cut surface is firm and grey or white. Most tumor nodules are 1–2.5 cm in greatest dimension; only 10% of tumors are > 3 cm in size.

The tumor is composed of sheets and loose fascicles of plump spindle cells with abundant, brightly eosinophilic cytoplasm, sometimes mimicking rhabdomyoblasts. A minor component of cells with epithelioid cytomorphology is often present; but sometimes epithelioid cells predominate. Intraosseous lesions are often dominated by epithelioid cells with marked cytoplasmic eosinophilia, associated with reactive woven bone, hemorrhage, and osteoclast-like giant cells. The tumor cells contain vesicular nuclei with generally small nucleoli. The degree of nuclear atypia is usually mild, and mitotic activity is scarce. About 10% of tumors show notable pleomorphism or large nucleoli. Occasional tumors contain focally myxoid stroma. About 50% of cases contain prominent stromal neutrophils. The tumors show infiltrative margins.

By immunohistochemistry, these tumors show diffuse expression of keratins (with AE1/AE3 but not MNF116) and the endothelial transcription factors FLI1 and ERG. About 50% of cases are positive for CD31. Focal expression of SMA is observed in one third of tumors. Nuclear staining for FOSB is a consistent finding.

Not clinically relevant

Approximately 60% of patients with this tumor type experience local recurrences (often multiple) or develop additional nodules in the same anatomical region. The interval between excision of the primary tumor and recurrence is usually short, within 1–2 years. The relationship between margin status and recurrence has not been established. Regional lymph node and distant metastases are uncommon (< 5%), most often occurring years or decades after presentation, rarely within a short interval. Metastatic sites may include lungs, bones, and soft tissues. Histological features do not predict metastasis.

Detection of FOSB rearrangement can be helpful for diagnosis.

Essential: plump spindle or more rarely epithelioid cell morphology with vesicular chromatin and eosinophilic cytoplasm; fascicular or sheet-like growth pattern; expression of ERG, FOSB, and keratins (AE1/AE3).

Desirable: demonstration of FOSB gene rearrangement (in selected cases).