Departments of *Pathology ‡Surgery, National Taiwan University Hospital †Graduate Institute of Pathology, National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan.
Am J Surg Pathol. 2015 Feb;39(2):236-44. doi: 10.1097/PAS.0000000000000324.
Leiomyosarcoma is an aggressive soft tissue sarcoma with poor patient survival. Recently, it was shown that 53% to 62% of leiomyosarcomas use the alternative lengthening of telomeres (ALT) as their telomere maintenance mechanism. The molecular basis of this mechanism has not been elucidated. Studies of pancreatic neuroendocrine tumor have suggested that the inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein is associated with the ALT phenotype. In this study, we sought to determine the clinicopathologic features of leiomyosarcoma with the ALT phenotype and the possible relationship between this phenotype and ATRX/DAXX expression. Telomerase reverse transcriptase gene (TERT) promoter mutation analysis was also performed. Ninety-two leiomyosarcomas derived from the uterus, retroperitoneum/intra-abdomen, and various other sites were analyzed. Telomere-specific fluorescence in situ hybridization revealed that 59% (51/86) of leiomyosarcomas had the ALT phenotype. Loss of ATRX expression was observed in 33% of the tumors (30/92), and all but 2 ATRX-deficient tumors were ALT positive. Both the ALT phenotype and loss of ATRX expression were associated with epithelioid/pleomorphic cell morphology, tumor necrosis, and poor differentiation. None of the 92 cases lost DAXX expression. No TERT promoter mutation was detected (n=39). For survival analysis, poor differentiation, high FNCLCC grade, tumor size, and ALT phenotype were correlated with poor overall survival in univariate analysis. Tumor size and ALT phenotype remained independent prognostic factors in multivariate analysis. We concluded that the ALT phenotype in the leiomyosarcoma is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome.
平滑肌肉瘤是一种侵袭性软组织肉瘤，患者生存预后较差。最近研究显示，有 53%-62%的平滑肌肉瘤采用端粒的非经典延长（ALT）作为其端粒维持机制。该机制的分子基础尚未阐明。对胰腺神经内分泌肿瘤的研究表明，α-地中海贫血/智力低下综合征 X 连锁（ATRX）或死亡结构域相关（DAXX）蛋白的失活与 ALT 表型有关。在这项研究中，我们试图确定具有 ALT 表型的平滑肌肉瘤的临床病理特征，以及这种表型与 ATRX/DAXX 表达之间的可能关系。还进行了端粒酶逆转录酶基因（TERT）启动子突变分析。分析了来自子宫、腹膜后/腹腔内和其他各种部位的 92 例平滑肌肉瘤。端粒特异性荧光原位杂交显示，有 59%（51/86）的平滑肌肉瘤具有 ALT 表型。在 92 例肿瘤中，有 33%（30/92）观察到 ATRX 表达缺失，并且除 2 例外所有 ATRX 缺失的肿瘤均为 ALT 阳性。ALT 表型和 ATRX 表达缺失均与上皮样/多形细胞形态、肿瘤坏死和分化不良相关。92 例中无一例丢失 DAXX 表达。未检测到 TERT 启动子突变（n=39）。在生存分析中，低分化、高 FNCLCC 分级、肿瘤大小和 ALT 表型与单因素分析中的总生存率差相关。肿瘤大小和 ALT 表型在多因素分析中仍然是独立的预后因素。我们得出结论，平滑肌肉瘤中的 ALT 表型与侵袭性组织学特征、ATRX 表达缺失和不良临床结局相关。
