Clinicopathological analysis of ATRX, DAXX and NOTCH Receptor Expression in Angiosarcomas

Abstract

Aims

Multiple genetic alterations including alternative lengthening of telomeres (ALT) and NOTCH mutations have been described in angiosarcoma. Loss of ATRX (α-thalessemia/mental retardation syndrome X-linked) and DAXX (death domain-associated 6) expression is frequently associated with the ALT phenotype. Additionally, inhibition of NOTCH signaling induces malignant vascular tumors in mice, indicating a tumor suppressive role of the NOTCH pathway in the pathogenesis of angiosarcoma. The aim of this study was to evaluate the immunohistochemical expression of ATRX, DAXX and NOTCH receptors (NOTCH1 and NOTCH2) in a large cohort of angiosarcomas and study their clinicopathologic and prognostic significance.

Methods and results

140 cases of angiosarcoma were stained for ATRX, DAXX, NOTCH1 and NOTCH2. ATRX loss (<10% labelling) was seen in 7/118 (6%) cases and was more frequent in deep soft tissue tumors as compared to other body sites (p=0.004). ATRX loss was associated with worse event free survival (EFS) as compared to angiosarcomas with retained ATRX expression (p=0.003). DAXX was retained in all specimens examined. Decreased NOTCH1 expression (≤1+ intensity) was seen in 29/123 (24%) cases and was associated with cutaneous site of origin (p=0.013) and advanced disease (p=0.026). NOTCH2 expression was decreased in 16/103 (16%) cases, was associated with visceral tumors (p=0.001) and correlated with worse disease specific survival (DSS) (p=0.033).

Conclusions

ATRX, NOTCH1 and NOTCH2 expression varies in angiosarcomas, showing significant correlation with site of origin and poor clinical outcome and highlighting the biological heterogeneity within this tumor type.

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