Leiomyosarcoma with alternative lengthening of telomeres is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome
Journal
American Journal of Surgical Pathology
Journal Volume
39
Journal Issue
2
Pages
236-244
Date Issued
2015
Author(s)
Abstract
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. ? 2014 Wolters kluwer Health, Inc. All rights reserved.
Other Subjects
ATRX protein, human; DNA helicase; nuclear protein; telomerase; TERT protein, human; adult; aged; biosynthesis; female; fluorescence in situ hybridization; genetics; human; immunohistochemistry; Kaplan Meier method; leiomyosarcoma; male; middle aged; mortality; nucleotide sequence; pathology; physiology; retrospective study; telomere; telomere homeostasis; very elderly; Adult; Aged; Aged, 80 and over; DNA Helicases; DNA Mutational Analysis; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Leiomyosarcoma; Male; Middle Aged; Nuclear Proteins; Retrospective Studies; Telomerase; Telomere; Telomere Homeostasis
Publisher
Lippincott Williams and Wilkins
Type
journal article