Morphologic Correlates of the Alternative Lengthening of Telomeres (ALT) Phenotype in High Grade Astrocytomas
Doreen N Nguyen, Christopher M Heaphy, Roeland F de Wilde, Brent Orr, Charles G Eberhart, Alan K Meeker, Fausto J Rodriguez. Johns Hopkins Medical Institutions, Baltimore, MD
Background: Recent studies have highlighted the occurrence of a telomerase-independent mechanism of telomere maintenance known as “alternative lengthening of telomeres” (ALT) in subsets of human cancers. An increased frequency of ALT has been described in infiltrating gliomas in particular, and associated with ATRX mutations. We retrospectively reviewed high grade astrocytomas to uncover correlations between ALT, ATRX expression, histology and molecular alterations typical of infiltrating astrocytomas.
Design: We studied 117 high grade astrocytomas with available ALT status (19 WHO grade III and 98 WHO grade IV tumors). Histologic review was performed, as well as immunohistochemistry for ATRX, DAXX, and mutant IDH1 protein. EGFR amplification was evaluated by Fluorescence in situ hybridization (FISH). Molecular and immunohistochemical studies were performed using tissue microarrays, while histologic evaluation was performed in whole H&E sections in a subset of cases with available slides (n=37). Oligodendroglial neoplasms were excluded from analysis.
Results: ALT was identified in 40 cases (34%), including 17 (89%) grade III astrocytomas, and 23 (24%) grade IV astrocytomas. When focusing on histologic subtypes, all small cell astrocytomas (n=6) and the single giant cell astrocytoma were ALT negative. The ALT phenotype was also correlated with the presence of round cells, fine chromatin, and microcysts, although these features were almost always present in grade III tumors. The ALT phenotype was positively correlated with the presence of IDH1 mutant protein (p<0.0001), ATRX protein loss (p<0.0001), and absence of EGFR amplification (p=0.004). There was no significant correlation with DAXX expression.
Conclusions: ALT represents a specific phenotype with distinctive pathologic and molecular features. Further studies are needed to clarify the clinical and biological significance of ALT in high grade astrocytomas.
Tuesday, March 20, 2012 1:30 PM
Platform Session: Section F, Tuesday Afternoon