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Annals of Hematology

, Volume 92, Issue 5, pp 669–677 | Cite as

Tumor-associated macrophages as a prognostic parameter in multiple myeloma

  • Elif Suyanı
  • Gülsan Türköz Sucak
  • Nalân Akyürek
  • Sevinç Şahin
  • Nuran Ahu Baysal
  • Münci Yağcı
  • Rauf Haznedar
Original Article

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.

Keywords

Multiple myeloma Tumor-associated macrophage Prognosis CD68 CD163 

Notes

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.

References

  1. 1.
    Podar K, Chauhan D, Anderson KC (2009) Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 23:10–24PubMedCrossRefGoogle Scholar
  2. 2.
    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 42:1564–1573PubMedCrossRefGoogle Scholar
  3. 3.
    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 101:950–968PubMedCrossRefGoogle Scholar
  4. 4.
    Jakob C, Sterz J, Zavrski I et al (2006) Angiogenesis in multiple myeloma. Eur J Cancer 42:1581–1590PubMedCrossRefGoogle Scholar
  5. 5.
    Vacca A, Ribatti D (2006) Bone marrow angiogenesis in multiple myeloma. Leukemia 20:193–199PubMedCrossRefGoogle Scholar
  6. 6.
    Rajkumar SV, Leong T, Roche PC et al (2000) Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 6:3111–3116PubMedGoogle Scholar
  7. 7.
    Anderson KC (2007) Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions. Exp Hematol 35(4 Suppl 1):155–162PubMedCrossRefGoogle Scholar
  8. 8.
    Anderson KC (2011) New insights into therapeutic targets in myeloma. Hematology Am Soc Hematol Educ Program 2011:184–190PubMedCrossRefGoogle Scholar
  9. 9.
    Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22:231–237PubMedCrossRefGoogle Scholar
  10. 10.
    Mantovani A (2011) B cells and macrophages in cancer: yin and yang. Nat Med 17:285–286PubMedCrossRefGoogle Scholar
  11. 11.
    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 66:1–9PubMedCrossRefGoogle Scholar
  12. 12.
    Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896PubMedCrossRefGoogle Scholar
  13. 13.
    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 114:3625–3628PubMedCrossRefGoogle Scholar
  14. 14.
    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 87:342–355PubMedGoogle Scholar
  15. 15.
    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 20:41–46PubMedCrossRefGoogle Scholar
  16. 16.
    Ruffell B, Affara NI, Coussens LM (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33:119–126PubMedCrossRefGoogle Scholar
  17. 17.
    Sica A, Larghi P, Mancino A et al (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18:349–355PubMedCrossRefGoogle Scholar
  18. 18.
    Ch’ng ES, Jaafar H, Tuan Sharif SE (2011) Breast tumor angiogenesis and tumor-associated macrophages: histopathologist’s perspective. Patholog Res Int 2011:572706PubMedGoogle Scholar
  19. 19.
    Leek RD, Lewis CE, Whitehouse R et al (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629PubMedGoogle Scholar
  20. 20.
    Mahmoud SM, Lee AH, Paish EC et al (2012) Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol 65:159–163PubMedCrossRefGoogle Scholar
  21. 21.
    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) 66:1879–1886CrossRefGoogle Scholar
  22. 22.
    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 107:1918–1922PubMedCrossRefGoogle Scholar
  23. 23.
    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 60:5857–5861PubMedGoogle Scholar
  24. 24.
    Shirabe K, Mano Y, Muto J et al (2012) Role of tumor-associated macrophages in the progression of hepatocellular carcinoma. Surg Today 42:1–7PubMedCrossRefGoogle Scholar
  25. 25.
    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 40:381–389PubMedCrossRefGoogle Scholar
  26. 26.
    Hanada T, Nakagawa M, Emoto A et al (2000) Prognostic value of tumor-associated macrophage count in human bladder cancer. Int J Urol 7:263–269PubMedCrossRefGoogle Scholar
  27. 27.
    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 13:1472–1479PubMedCrossRefGoogle Scholar
  28. 28.
    Kurahara H, Shinchi H, Mataki Y et al (2011) Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 167:211–219CrossRefGoogle Scholar
  29. 29.
    Bronkhorst IH, Ly LV, Jordanova ES et al (2011) Detection of M2-macrophages in uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci 52:643–650PubMedCrossRefGoogle Scholar
  30. 30.
    Herwig MC, Grossniklaus HE (2011) Role of macrophages in uveal melanoma. Expert Rev Ophthalmol 6:405–407PubMedCrossRefGoogle Scholar
  31. 31.
    Steidl C, Lee T, Shah SP et al (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362:875–885PubMedCrossRefGoogle Scholar
  32. 32.
    Zaki MA, Wada N, Ikeda J et al (2011) Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma. Virchows Arch 459:361–366PubMedCrossRefGoogle Scholar
  33. 33.
    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 77:301–308PubMedCrossRefGoogle Scholar
  34. 34.
    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):1080–1084PubMedCrossRefGoogle Scholar
  35. 35.
    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 23:736–742PubMedCrossRefGoogle Scholar
  36. 36.
    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 96:269–276PubMedCrossRefGoogle Scholar
  37. 37.
    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 26:440–446PubMedCrossRefGoogle Scholar
  38. 38.
    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 60:313–319PubMedCrossRefGoogle Scholar
  39. 39.
    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 58:529–532PubMedCrossRefGoogle Scholar
  40. 40.
    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 142:1359–1372PubMedGoogle Scholar
  41. 41.
    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 42:414–421PubMedCrossRefGoogle Scholar
  42. 42.
    Lau SK, Chu PG, Weiss LM (2004) CD163: a specific marker of macrophages in paraffin-embedded tissue samples. Am J Clin Pathol 122:794–801PubMedCrossRefGoogle Scholar
  43. 43.
    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 67:97–103PubMedGoogle Scholar
  44. 44.
    Harris JA, Jain S, Ren Q et al (2012) CD163 versus CD68 in tumor associated macrophages of classical Hodgkin lymphoma. Diagn Pathol 7:12PubMedCrossRefGoogle Scholar
  45. 45.
    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 37:171–175PubMedCrossRefGoogle Scholar
  46. 46.
    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 11:443–451PubMedGoogle Scholar
  47. 47.
    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 115:5053–5056PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elif Suyanı
    • 1
  • Gülsan Türköz Sucak
    • 1
  • Nalân Akyürek
    • 2
  • Sevinç Şahin
    • 2
  • Nuran Ahu Baysal
    • 1
  • Münci Yağcı
    • 1
  • Rauf Haznedar
    • 1
  1. 1.Department of HematologyGazi University Faculty of MedicineAnkaraTurkey
  2. 2.Department of PathologyGazi University Faculty of MedicineAnkaraTurkey

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