Abstract
The prognostic value of proliferation index (PI) and apoptotic index (AI), caspase-8, -9 and -10 expression have been investigated in primary Ewing's sarcoma family of tumours (ESFT). Proliferating cells, detected by immunohistochemistry for Ki-67, were identified in 91% (91/100) of tumours with a median PI of 14 (range 0–87). Apoptotic cells, identified using the TUNEL assay, were detected in 96% (76/79) of ESFT; the median AI was 3 (range 0–33). Caspase-8 protein expression was negative (0) in 14% (11/79), low (1) in 33% (26/79), medium (2) in 38% (30/79) and high (3) in 15% (12/79) of tumours, caspase-9 expression was low (1) in 66% (39/59) and high (3) in 34% (20/59), and caspase-10 protein was low (1) in 37% (23/62) and negative (0) in 63% (39/62) of primary ESFT. There was no apparent relationship between caspase-8, -9 and -10 expression, PI and AI.PI was predictive of relapse-free survival (RFS; p = 0.011) and overall survival (OS; p = <0.001) in a continuous model, whereas AI did not predict outcome. Patients with tumours expressing low levels of caspase-9 protein had a trend towards a worse RFS than patients with tumours expressing higher levels of caspase-9 protein (p = 0.054, log rank test), although expression of caspases-8, -9 and/or -10 did not significantly predict RFS or OS. In a multivariate analysis model that included tumour site, tumour volume, the presence of metastatic disease at diagnosis, PI and AI, PI independently predicts OS (p = 0.003). Consistent with previous publications, patients with pelvic tumours had a significantly worse OS than patients with tumours at other sites (p = 0.028); patients with a pelvic tumour and a PI≥20 had a 6 fold-increased risk of death. These studies advocate the evaluation of PI in a risk model of outcome for patients with ESFT.
Highlights
Ewing’s sarcoma family of tumours (ESFT) can arise in bone or soft tissue sites at any age, but most frequently are diagnosed in bony sites in children and young adults [1]
In this study we demonstrate for the first time that high numbers of proliferating cells in primary ESFT are predictive of a worse relapse-free survival (RFS) and overall survival (OS) in a continuous model
High proliferation index (PI) was predictive of poor OS independent of tumour site, tumour volume, metastasis at diagnosis or apoptotic index (AI)
Summary
Ewing’s sarcoma family of tumours (ESFT) can arise in bone or soft tissue sites at any age, but most frequently are diagnosed in bony sites in children and young adults [1]. Since improved patient outcome is anticipated by adapting therapy based on risk, a number of prognostic clinical factors have been described including the presence of metastatic disease at the time of diagnosis [2], tumour volume (greater than 200 ml) [3] and pelvic primary tumours [4,5] at diagnosis in patients with localised disease Despite these observations there is currently no universally accepted informative staging system in ESFT. High AI is predictive of increased survival in patients with osteosarcoma [17] and gastric cancer [18], and low AI has been associated with high grade tumours of the ovary [19], kidney [20] and colon [6]. Low AI has been associated with a higher mean survival in childhood acute lymphoblastic leukaemia (ALL) [21] and patients with colorectal carcinoma [22]
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