title: Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial.
abstract: Increased tumor-associated macrophages (TAMs) are reported to be associated with poor prognosis in classic Hodgkin lymphoma (CHL). We investigated the prognostic significance of TAMs in the E2496 Intergroup trial, a multicenter phase 3 randomized controlled trial comparing ABVD and Stanford V chemotherapy in locally extensive and advanced stage CHL. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tumor tissue and included 287 patients. Patients were randomly assigned into training (n = 143) and validation (n = 144) cohorts. Immunohistochemistry for CD68 and CD163, and in situ hybridization for EBV-encoded RNA were performed. CD68 and CD163 IHC were analyzed by computer image analysis; optimum thresholds for overall survival (OS) were determined in the training cohort and tested in the independent validation cohort. Increased CD68 and CD163 expression was significantly associated with inferior failure-free survival and OS in the validation cohort. Increased CD68 and CD163 expression was associated with increased age, EBV-encoded RNA positivity, and mixed cellularity subtype of CHL. Multivariate analysis in the validation cohort showed increased CD68 or CD163 expression to be significant independent predictors of inferior failure-free survival and OS. We demonstrate the prognostic significance of TAMs in locally extensive and advanced-stage CHL in a multicenter phase 3 randomized controlled clinical trial.
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: King L
authors.initials: KL
authors.lastname: Tan
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.forename: Fangxin
authors.initials: F
authors.lastname: Hong
authors.forename: Brad S
authors.initials: BS
authors.lastname: Kahl
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Bartlett
authors.forename: Ranjana H
authors.initials: RH
authors.lastname: Advani
authors.forename: Rena
authors.initials: R
authors.lastname: Buckstein
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Leo I
authors.initials: LI
authors.lastname: Gordon
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Horning
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001761:Bleomycin / Q000627:therapeutic use; D015331:Cohort Studies; D003606:Dacarbazine / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease / Q000188:drug therapy / Q000276:immunology / Q000401:mortality*; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012367:RNA, Viral / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015996:Survival Rate; D046888:Tissue Array Analysis; D014747:Vinblastine / Q000627:therapeutic use; D000098902:CD163 Antigen; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D001761:Bleomycin; D003606:Dacarbazine; D004317:Doxorubicin; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D014747:Vinblastine; D000098902:CD163 Antigen; C067980:CD68 antigen, human; D000097382:CD68 Molecule