Abstract
The interaction between multiple myeloma (MM) cells and the bone marrow stroma constitutes the basis of myeloma pathogenesis and has led the way for the corresponding therapeutic strategies. The aim of this study is to evaluate tumor-associated macrophages (TAMs) which is an important element of bone marrow stroma and its prognostic relevance in newly diagnosed MM patients. We also wanted to determine the association between TAMs and microvessel density (MVD). Sixty-eight patients, who were diagnosed with MM at the Department of Hematology, Gazi University Hospital, between January 2000 and January 2011, were reviewed retrospectively. Tumor-associated macrophages were evaluated by staining with anti-CD68 and anti-CD163 monoclonal antibodies, and MVD was evaluated by factor VIII staining. Median age was 60 (range, 40–84) years with 36 males and 32 females. The number of both CD 68+ and CD 163+ cells had a negative impact on OS at 6 years (p = 0.013 vs. 0.036; p = 0.015 vs. 0.039) in univariate and multivariate analysis in which age, sex, ISS, the induction treatment, and response to induction treatment are included as variables. High-grade MVD was found to be associated with increased CD163+ cell count. In conclusion, TAMs seems to be a promising prognostic histopathological marker in newly diagnosed MM patients.
Similar content being viewed by others
References
Podar K, Chauhan D, Anderson KC (2009) Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 23:10–24
Mitsiades CS, Mitsiades NS, Munshi NC et al (2006) The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions. Eur J Cancer 42:1564–1573
Mitsiades CS, Mitsiades NS, Richardson PG et al (2007) Multiple myeloma: a prototypic disease model for the characterization and therapeutic targeting of interactions between tumor cells and their local microenvironment. J Cell Biochem 101:950–968
Jakob C, Sterz J, Zavrski I et al (2006) Angiogenesis in multiple myeloma. Eur J Cancer 42:1581–1590
Vacca A, Ribatti D (2006) Bone marrow angiogenesis in multiple myeloma. Leukemia 20:193–199
Rajkumar SV, Leong T, Roche PC et al (2000) Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 6:3111–3116
Anderson KC (2007) Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions. Exp Hematol 35(4 Suppl 1):155–162
Anderson KC (2011) New insights into therapeutic targets in myeloma. Hematology Am Soc Hematol Educ Program 2011:184–190
Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22:231–237
Mantovani A (2011) B cells and macrophages in cancer: yin and yang. Nat Med 17:285–286
Allavena P, Sica A, Solinas G et al (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66:1–9
Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896
Zheng Y, Cai Z, Wang S et al (2009) Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood 114:3625–3628
Bartl R, Frisch B, Fateh-Moghadam A et al (1987) Histologic classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases. Am J Clin Pathol 87:342–355
Andjelic B, Mihaljevic B, Todorovic M et al (2012) The number of lymphoma-associated macrophages in tumor tissue is an independent prognostic factor in patients with follicular lymphoma. Appl Immunohistochem Mol Morphol 20:41–46
Ruffell B, Affara NI, Coussens LM (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33:119–126
Sica A, Larghi P, Mancino A et al (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18:349–355
Ch’ng ES, Jaafar H, Tuan Sharif SE (2011) Breast tumor angiogenesis and tumor-associated macrophages: histopathologist’s perspective. Patholog Res Int 2011:572706
Leek RD, Lewis CE, Whitehouse R et al (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629
Mahmoud SM, Lee AH, Paish EC et al (2012) Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol 65:159–163
Zhang B, Yao G, Zhang Y et al (2011) M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma. Clinics (Sao Paulo) 66:1879–1886
Nonomura N, Takayama H, Nakayama M et al (2011) Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer. BJU Int 107:1918–1922
Shimura S, Yang G, Ebara S et al (2000) Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res 60:5857–5861
Shirabe K, Mano Y, Muto J et al (2012) Role of tumor-associated macrophages in the progression of hepatocellular carcinoma. Surg Today 42:1–7
Ding T, Xu J, Wang F et al (2009) High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum Pathol 40:381–389
Hanada T, Nakagawa M, Emoto A et al (2000) Prognostic value of tumor-associated macrophage count in human bladder cancer. Int J Urol 7:263–269
Forssell J, Oberg A, Henriksson ML et al (2007) High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 13:1472–1479
Kurahara H, Shinchi H, Mataki Y et al (2011) Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 167:211–219
Bronkhorst IH, Ly LV, Jordanova ES et al (2011) Detection of M2-macrophages in uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci 52:643–650
Herwig MC, Grossniklaus HE (2011) Role of macrophages in uveal melanoma. Expert Rev Ophthalmol 6:405–407
Steidl C, Lee T, Shah SP et al (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362:875–885
Zaki MA, Wada N, Ikeda J et al (2011) Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma. Virchows Arch 459:361–366
Tzankov A, Matter MS, Dirnhofer S (2010) Refined prognostic role of CD68-positive tumor macrophages in the context of the cellular micromilieu of classical Hodgkin lymphoma. Pathobiology 77:301–308
Sanchez-Espiridion B, Martin-Moreno AM, Montalban C et al (2012) Immunohistochemical markers for tumor associated macrophages andsurvival in advanced classical Hodgkin lymphoma. Haematologica 97(7):1080–1084
Azambuja D, Natkunam Y, Biasoli I et al (2012) Lack of association of tumor-associated macrophages with clinical outcome in patients with classical Hodgkin’s lymphoma. Ann Oncol 23:736–742
Kamper P, Bendix K, Hamilton-Dutoit S et al (2011) Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica 96:269–276
Canioni D, Salles G, Mounier N et al (2008) High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial. J Clin Oncol 26:440–446
Wada N, Zaki MA, Hori Y, Osaka Lymphoma Study Group et al (2012) Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group. Histopathology 60:313–319
Hasselblom S, Hansson U, Sigurdardottir M et al (2008) Expression of CD68+ tumor-associated macrophages in patients with diffuse large B-cell lymphoma and its relation to prognosis. Pathol Int 58:529–532
Falini B, Flenghi L, Pileri S et al (1993) PG-M1: a new monoclonal antibody directed against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule. Am J Pathol 142:1359–1372
Pulford KA, Rigney EM, Micklem KJ et al (1989) KP1: a new monoclonal antibody that detects a monocyte/macrophage associated antigen in routinely processed tissue sections. J Clin Pathol 42:414–421
Lau SK, Chu PG, Weiss LM (2004) CD163: a specific marker of macrophages in paraffin-embedded tissue samples. Am J Clin Pathol 122:794–801
Buechler C, Ritter M, Orsó E et al (2000) Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 67:97–103
Harris JA, Jain S, Ren Q et al (2012) CD163 versus CD68 in tumor associated macrophages of classical Hodgkin lymphoma. Diagn Pathol 7:12
Pappa C, Miyakis S, Tsirakis G et al (2007) Serum levels of interleukin-15 and interleukin-10 and their correlation with proliferating cell nuclear antigen in multiple myeloma. Cytokine 37:171–175
Urbańska-Ryś H, Wiersbowska A, Stepień H, Robak T (2000) Relationship between circulating interleukin-10 (IL-10) with interleukin-6 (IL-6) type cytokines (IL-6, interleukin-11 (IL-11), oncostatin M (OSM)) and soluble interleukin-6 (IL-6) receptor (sIL-6R) in patients with multiple myeloma. Eur Cytokine Netw 11:443–451
Clear AJ, Lee AM, Calaminici M et al (2010) Increased angiogenic sprouting in poor prognosis FL is associated with elevated numbers of CD163+ macrophages within the immediate sprouting microenvironment. Blood 115:5053–5056
Acknowledgments
This study contains essential data from the dissertain study of Elif Suyanı and was supported by “Hematoloji Dayanışma Derneği” Foundation.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Suyanı, E., Sucak, G.T., Akyürek, N. et al. Tumor-associated macrophages as a prognostic parameter in multiple myeloma. Ann Hematol 92, 669–677 (2013). https://doi.org/10.1007/s00277-012-1652-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-012-1652-6