title: Proliferation index: a continuous model to predict prognosis in patients with tumours of the Ewing's sarcoma family.
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.
authors.affiliation: Children's Cancer Research Group, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Samantha
authors.initials: S
authors.lastname: Brownhill
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Dena
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Children's Cancer Research Group, Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Sue
authors.initials: S
authors.lastname: Burchill
mesh_terms: D017209:Apoptosis; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D053455:Caspase 10 / Q000032:analysis; D053181:Caspase 8 / Q000032:analysis; D053453:Caspase 9 / Q000032:analysis; D049109:Cell Proliferation; D006801:Humans; D008954:Models, Biological; D015233:Models, Statistical; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000473:pathology; D011379:Prognosis; D012512:Sarcoma, Ewing / Q000175:diagnosis* / Q000473:pathology; D016019:Survival Analysis
chemical_list: D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9