Tumor-associated macrophages and survival in classic Hodgkin's lymphoma.
BACKGROUND
Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score.


METHODS
Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis.


RESULTS
Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies.


CONCLUSIONS
An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification.
Steidl
Christian
C
Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada.
Lee
Tang
T
Shah
Sohrab P
SP
Farinha
Pedro
P
Han
Guangming
G
Nayar
Tarun
T
Delaney
Allen
A
Jones
Steven J
SJ
Iqbal
Javeed
J
Weisenburger
Dennis D
DD
Bast
Martin A
MA
Rosenwald
Andreas
A
Muller-Hermelink
Hans-Konrad
HK
Rimsza
Lisa M
LM
Campo
Elias
E
Delabie
Jan
J
Braziel
Rita M
RM
Cook
James R
JR
Tubbs
Ray R
RR
Jaffe
Elaine S
ES
Lenz
Georg
G
Connors
Joseph M
JM
Staudt
Louis M
LM
Chan
Wing C
WC
Gascoyne
Randy D
RD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015703:Antigens, CD / Q000032:analysis*; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012334:RNA, Neoplasm / Q000032:analysis; D016539:Reed-Sternberg Cells / Q000473:pathology; D015996:Survival Rate; D017211:Treatment Failure; D055815:Young Adult; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D012334:RNA, Neoplasm; C067980:CD68 antigen, human; D000097382:CD68 Molecule