Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Histopathology. 2018 Jan;72(2):239-247. doi: 10.1111/his.13337. Epub 2017 Oct 19.
Multiple genetic alterations, including alternative lengthening of telomeres (ALT) and NOTCH mutations, have been described in angiosarcoma. Loss of α-thalassaemia/mental retardation syndrome X-linked (ATRX) and death domain-associated protein 6 (DAXX) expression is frequently associated with the ALT phenotype. Additionally, inhibition of NOTCH signalling induces the development of malignant vascular tumours in mice, indicating a tumour 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 clinicopathological and prognostic significance.
One hundred and forty cases of angiosarcoma were stained for ATRX, DAXX, NOTCH1 and NOTCH2. ATRX loss (<10% labelling) was seen in seven of 118 (6%) cases, and was more frequent in deep soft tissue tumours than in other body sites (P = 0.004). Angiosarcomas with ATRX loss were associated with worse event-free survival than angiosarcomas with retained ATRX expression (P = 0.003). DAXX was retained in all specimens examined. Decreased NOTCH1 expression (≤1+ intensity) was seen in 29 of 123 (24%) cases, and was associated with a cutaneous site of origin (P = 0.013) and advanced disease (P = 0.026). NOTCH2 expression was decreased in 16 of 103 (16%) cases, was associated with visceral tumours (P = 0.001), and correlated with worse disease-specific survival (P = 0.033).
ATRX, NOTCH1 and NOTCH2 expression varies in angiosarcomas and shows significant correlations with site of origin and poor clinical outcome, thus highlighting the biological heterogeneity within this tumour type.
多种遗传改变，包括端粒的非经典延长（ALT）和 NOTCH 突变，已在血管肉瘤中被描述。α-地中海贫血/智力迟钝综合征 X 连锁（ATRX）和死亡域相关蛋白 6（DAXX）表达的缺失常与 ALT 表型相关。此外，NOTCH 信号的抑制会在小鼠中诱导恶性血管肿瘤的发展，表明 NOTCH 通路在血管肉瘤发病机制中具有肿瘤抑制作用。本研究的目的是评估 ATRX、DAXX 和 NOTCH 受体（NOTCH1 和 NOTCH2）在一大群血管肉瘤中的免疫组织化学表达，并研究其临床病理和预后意义。
对 140 例血管肉瘤进行了 ATRX、DAXX、NOTCH1 和 NOTCH2 的染色。在 118 例中有 7 例（6%）出现 ATRX 缺失（<10%的标记），在深部软组织肿瘤中比其他部位更常见（P = 0.004）。与保留 ATRX 表达的血管肉瘤相比，ATRX 缺失的血管肉瘤的无事件生存时间更差（P = 0.003）。所有检查的标本均保留了 DAXX。在 123 例中有 29 例（24%）出现 NOTCH1 表达减少（≤1+强度），与皮肤起源部位（P = 0.013）和晚期疾病（P = 0.026）相关。在 103 例中有 16 例（16%）出现 NOTCH2 表达减少，与内脏肿瘤相关（P = 0.001），并与较差的疾病特异性生存相关（P = 0.033）。
血管肉瘤中 ATRX、NOTCH1 和 NOTCH2 的表达不同，与起源部位和不良临床结果有显著相关性，因此突出了该肿瘤类型的生物学异质性。
