Uterine smooth muscle tumours of uncertain malignant potential (STUMP) are diagnostically and clinically challenging. The alternative lengthening of telomeres (ALT) telomere maintenance mechanism is associated with poor survival in soft tissue leiomyosarcoma. Time to first recurrence and survival were known for 18 STUMP and 43 leiomyosarcomata (LMS). These were screened for ALT telomere maintenance by the presence of ALT‐associated PML bodies (APBs) and for changes associated with the ALT phenotype, namely aberrant p53 expression, isocitrate dehydrogenase 1 mutation (R132H substitution) expression, mutant ATRX (αthalassemia/mental retardation syndrome X‐linked) expression and mutant DAXX (death‐domain‐associated protein) expression by immunohistochemistry (IHC). Overexpression of p16INK4A was examined immunohistologically in a subset of cases. Many of the tumours associated with death or recurrence demonstrated APBs commensurate with ALT telomere maintenance. However, all uterine STUMP (4/4), and vaginal STUMP (2/2) patients, and almost all LMS patients (88.4%, 23/26, including 90% (9/10) of stage 1 LMS cases), who had died of disease or who had recurrent disease, displayed loss of ATRX or DAXX expression. Loss of ATRX or DAXX expression identified poor prognosis (95% CI 2.1 to 40.8, p < 0.003), in the LMS group. Thus, loss of ATRX or DAXX expression in uterine smooth muscle tumours identifies a clinically aggressive molecular subtype of early stage LMS and when histopathological features are problematic such as in STUMP. As ATRX and DAXX IHC is readily performed in diagnostic laboratories these are potentially useful for routine histopathological classification and management.

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In neoplasia, telomere maintenance mechanisms (TMMs) can be prognostic and may direct therapy in the future. Two types of TMM, telomerase and recombination-based alternative lengthening of telomeres (ALT), result in four prognostic tumor groups when they occur individually, in combination, or in mutual absence. Correct designation of the TMM therefore requires an assessment of telomerase activity and for ALT telomere length distribution and ALT associated promyelocytic leukaemia protein (PML) bodies (APBs). The four groups are associated with differing prognoses that are dependent on the tumor type. As TMM inhibitors are developed, oncologists will require that pathologists determine the TMM, and the treatments will differ accordingly. Furthermore, any anti-TMM therapy administered has the potential to selectively change the TMM used by a tumor, necessitating reassessment of the therapeutic strategy. Herein, we review the telomere maintenance mechanisms, the current diagnostic measures and their utility as prognostic markers in the clinical setting.