title: Identification of MUM1 as a prognostic immunohistochemical marker in follicular lymphoma using computerized image analysis.
abstract: Detection of MUM1+ cells in follicular lymphoma (FL) tissues was previously found to be associated with poor prognosis in a single report, whereas the usefulness of Ki-67 immunostaining remains debated. Our goal was to establish whether these markers have predictive value for patients with FL. We analyzed MUM1 and Ki-67 expression using immunohistochemistry in biopsy samples from 434 patients from the PRIMA randomized trial. The MUM1 prognostic value was then validated in a cohort of 138 patients from the FL2000 randomized trial, using the optimal cutoff value obtained from the PRIMA cohort. The surface of positive staining was quantified using computerized image analysis. In the PRIMA cohort, both high levels of MUM1 positivity (cutoff value of 0.80%) and high levels of Ki-67 positivity (cutoff value of 10.25%) were significantly associated with a shorter progression-free survival (PFS) (P = .004 and P = .007 for MUM1 and Ki-67, respectively). In a multivariate Cox proportional hazards regression model, only MUM1 retained a statistical significance (hazards ratio 1.56; 95% confidence interval, 1.02-2.37; P = .038) after adjustment for the maintenance arm of treatment and the follicular lymphoma international prognostic index score. In the FL2000 cohort, high levels of MUM1 positivity were significantly associated to a shorter PFS (P = .004) and to a trend toward a shorter overall survival (P = .043). This remained significant using a multivariate Cox regression model after adjustment for the follicular lymphoma international prognostic index and the treatment arm for PFS (P = .016). These results show that MUM1 is a strong and robust predictive immunohistochemical marker in patients with FL.
authors.affiliation: Departments of Bio-Pathology, Molecular Oncology, Hematology, and Tumor Immunology, Institut Paoli-Calmettes and Aix-Marseille Université, 13009 Marseille, France. Electronic address: xerril@ipc.unicancer.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Xerri
authors.affiliation: Hospices Civils de Lyon; CHU Lyon-sud, Department of Hematology, 69310 Pierre-Bénite, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bachy
authors.affiliation: Department of Pathology, Centre Hospitalier Saint Antoine, 75012 Paris, France.
authors.forename: Bettina
authors.initials: B
authors.lastname: Fabiani
authors.affiliation: Department of Pathology, Centre Hospitalier Necker, 75015 Paris, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Canioni
authors.affiliation: Department of Pathology, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chassagne-Clément
authors.affiliation: Department of Pathology, Institut Gustave Roussy, 94805 France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Dartigues-Cuilléres
authors.affiliation: Department of Pathology, Centre Hospitalier Pitié-Salpêtriére, 75013 Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charlotte
authors.affiliation: Department of Pathology, Centre Hospitalier Necker, 75015 Paris, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.affiliation: Department of Pathology, Centre Hospitalier, 49100 Angers, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Rousselet
authors.affiliation: Department of Pathology, Centre Hospitalier, 49100 Angers, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Foussard
authors.affiliation: Department of Hematology, Centre Hospitalier Saint Louis, 75010 Paris, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Brice
authors.affiliation: Department of Hematology, Centre Hospitalier, 54035 Nancy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Feugier
authors.affiliation: Department of Hematology and EA 4481 GRIIOT, CHU, 59000 Lille, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Department of Hematology, Centre Hospitalier de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Sonet
authors.affiliation: Departments of Bio-Pathology, Molecular Oncology, Hematology, and Tumor Immunology, Institut Paoli-Calmettes and Aix-Marseille Université, 13009 Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.affiliation: Hospices Civils de Lyon; CHU Lyon-sud, Department of Hematology, 69310 Pierre-Bénite, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D050835:Interferon Regulatory Factors / Q000032:analysis / Q000096:biosynthesis*; D019394:Ki-67 Antigen / Q000032:analysis / Q000096:biosynthesis; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D055815:Young Adult; D000099218:Interferon Regulatory Factor-4
chemical_list: D014408:Biomarkers, Tumor; D050835:Interferon Regulatory Factors; D019394:Ki-67 Antigen; D000099218:Interferon Regulatory Factor-4
keywords: Follicular lymphoma; Image analysis; Immunohistochemistry; Ki-67; MUM1; Prognosis