The Stromal Cell Marker SPARC Predicts for Survival in Patients With Diffuse Large B-Cell Lymphoma Treated With Rituximab

Abstract

The cellular composition of the tumor microenvironment may affect survival in diffuse large B-cell lymphoma (DLBCL). We performed immunostains for 2 stromal cell markers, CD68 and SPARC (secreted protein, acidic and rich in cysteine), in 262 patients with DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapies. Patients with any SPARC+ cells in the microenvironment had a significantly longer overall survival, and patients with high SPARC positivity in the microenvironment also had a significantly longer event-free survival. Survival differences were mainly due to the prognostic effect of SPARC+ cells in activated B-cell (ABC)-type DLBCL, with no effect found in the germinal center B-cell-type DLBCL. Of clinical features examined, only the number of extranodal sites was significantly associated with SPARC expression. Multivariate analysis revealed that SPARC expression predicted patient survival independent of the International Prognostic Index or tumor cell of origin. SPARC expression in the microenvironment of DLBCL can be used for prognostic purposes, determining a subgroup of patients with ABC DLBCL who have significantly longer survival. More aggressive chemotherapy protocols should be considered for patients with ABC DLBCL without SPARC+ stromal cells. CD68 expression by cells in the microenvironment did not predict survival.

Tumor-associated macrophages in diffuse large B-cell lymphoma

“…Whereas Nam et al 8 reported similar findings, as mentioned above, and the study by Cai et al 15 also showed that CD68 is a marker of poor outcome in CHOP-treated DLBCL patients, the studies by Hasselblom et al, 16 Meyer et al 17 and Coutinho et al 18 did not reveal significant associations between CD68 protein expression and survival. Furthermore, Wada et al 19 and Marchesi et al 20 reported that an M2 macrophage phenotype, as defined by double staining for CD68 and CD163, is associated with adverse outcome in R-CHOP-treated patients, whereas an M1 phenotype is not.…”

MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program

“…27 Both stroma-poor and proliferation signatures are associated with poor prognosis in DLBCL. 27,28,34,35 A cell-adhesion signature has not been described in lymphoma to date although its role in the invasion of solid tumors is wellestablished. 36 Presumably, the lack of cell-cell and cell-matrix adhesions might play a role in the high frequency of advanced stage of disease and involvement of multiple extranodal sites in DLBCL with MYC/BCL2 coexpression.…”

A new biologic prognostic model based on immunohistochemistry predicts survival in patients with diffuse large B-cell lymphoma

“…The validation set consisted of 74 patients from the Nebraska Lymphoma Study Group who were also treated with rituximab (R) and CHOP or CHOP-like therapies. The total of 199 patients from the training and validation sets was treated as follows: R-CHOP (166 patients, 83%); R-CNOP (cyclophosphamide, mitoxantrone, vincristine and prednisone; 31 patients, 16%); and R-ESHAP (etoposide, methylpredisolone, cytarabine, and cisplatin; 2 patients, 1% The data used in this study originated from 3 previously published studies 15,17,18 that examined the same cohort of patients. The classification of DLBCL into GCB and non-GCB subtypes was done by Meyer et al, 15 and expression of SPARC in the tumor microenvironment was evaluated in a separate article by Meyer et al 17 Cardesa-Salzmann et al evaluated the MVD in the same group of patients.…”

“…Meyer et al recently attempted to reproduce the stromal-1 signature using an antibody against SPARC (secreted protein, acidic, and rich in cysteine) to evaluate expression in stromal cells and histiocytes in the tumor microenvironment. 17 They showed that patients with SPARC positivity in the tumor stroma had a significantly longer survival than those without significant SPARC expression. The stromal-2 signature largely reflects angiogenesis and blood vessel density in the tumor stroma, and portends a poor prognosis.…”