Prognostic Significance of CD68 And CD163 Tumor-Associated Macrophages in Hormone Receptor-Positive Vs Triple-Negative Invasive Breast Carcinoma: A Retrospective IHC Study

Pratiksha Mishra; Pragyan Lisha Panda; Pragyna Paramita Das; Lity Mohanty; Bhuban Mohan Das

doi:10.55489/njmr.160320261276

Authors

Pratiksha Mishra Department of Pathology, SCB Medical College, Cuttack, India
Pragyan Lisha Panda Department of Pathology, SCB Medical College, Cuttack, India
Pragyna Paramita Das Department of Community Medicine, SCB Medical College, Cuttack, India
Lity Mohanty Department of Pathology, SRMMCH, Kalahandi, India
Bhuban Mohan Das Department of Surgery, SCB Medical College, Cuttack, India

DOI:

https://doi.org/10.55489/njmr.160320261276

Keywords:

Breast carcinoma, Densities, Invasive, Triple negative, Tumor Associated Macrophages

Abstract

Background: Tumor-associated macrophages (TAMs) influence tumor progression within the microenvironment. M1-like macrophages (CD68⁺) exhibit tumoricidal properties, whereas M2-like macrophages (CD68⁺/CD163⁺) promote tumor growth through hypoxia-driven angiogenesis. This study assessed the localization and density of CD68⁺ and CD163⁺ TAMs in hormone receptor-positive and triple-negative invasive breast carcinomas and evaluated their association with clinicopathological parameters.

Methods: A retrospective cross-sectional study was conducted on histopathologically confirmed invasive breast carcinoma cases. Formalin-fixed paraffin-embedded tissues underwent immunohistochemical staining for ER, PR, Her2/neu, CD68, and CD163. Descriptive statistics were calculated, and associations with clinicopathological variables were analyzed using the χ² test. Survival outcomes were assessed by Kaplan-Meier and log-rank tests, and prognostic significance was evaluated using univariate Cox regression analysis.

Results: The study showed association of CD68⁺ and CD163⁺ TAMs in ER, PR positive and Her2/neu negative cases in TS (tumor stroma) and TN (tumor nest) with higher histologic grades. High infiltration of both CD68⁺ and CD163⁺ TAMs were seen in triple negative invasive breast carcinomas (TNBC). There was significant correlation of increased CD163⁺ TAMs in TN and TS with relapse free survival and overall survival rates based on log rank tests.

Conclusion: Breast cancer remains the leading malignancy contributing to cancer-related mortality among women globally. Conventional treatment strategies have primarily focused on directly targeting tumor cells. However, increasing evidence highlights the importance of addressing the tumor microenvironment as a therapeutic approach to overcome treatment resistance and enhance clinical outcomes.

References

1. World Health Organization. Global cancer burden growing, amidst mounting need for services [Internet]. Geneva: WHO; 2024 Feb 1 [cited 2026 Jan 7]. Available from: https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services

2. Burugu S, Asleh-Aburaya K, Nielsen TO. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication. Breast Cancer. 2017;24(1):3-15. DOI: https://doi.org/10.1007/s12282-016-0698-z PMid:27138387

3. Choi J, Gyamfi J, Jang H, Koo JS. The role of tumor-associated macrophage in breast cancer biology. Histol Histopathol. 2018 Feb;33(2):133-145. DOI: https://doi.org/10.14670/HH-11-916 PMID: 28681373

4. Murray PJ, Wynn TA. Obstacles and opportunities for understanding macrophage polarization. J Leukoc Biol. 2011 Apr;89(4):557-563. DOI: https://doi.org/10.1189/jlb.0710409 PMid:21248152 PMCid:PMC3058818

5. Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86(5):1065-1073. DOI: https://doi.org/10.1189/jlb.0609385 PMid:19741157

6. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196(3):254-265. DOI: https://doi.org/10.1002/path.1027 PMid:11857487

7. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996 Oct 15;56(20):4625-4629. PMID: 8840975.

8. Medrek C, Pontén F, Jirström K, Leandersson K. The presence of tumor-associated macrophages in tumor stroma is associated with increased tumor cell proliferation and poor prognosis in breast cancer. BMC Cancer. 2012;12:306. DOI: https://doi.org/10.1186/1471-2407-12-306 PMid:22824040 PMCid:PMC3414782

9. Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol. 2012 Feb;65(2):159-163. DOI: https://doi.org/10.1136/jclinpath-2011-200355 PMid:22049225

10. Campbell MJ, Tonlaar NY, Garwood ER, Huo D, Moore DH, Khramtsov AI, et al. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat. 2011 Aug;128(3):703-711. DOI: https://doi.org/10.1007/s10549-010-1154-y PMid:20842526 PMCid:PMC4657137

11. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011 Jun;1(1):54-67. DOI: https://doi.org/10.1158/2159-8274.CD-10-0028 PMid:22039576 PMCid:PMC3203524

12. Mohammed ZM, Going JJ, Edwards J, Elsberger B, McMillan DC. The relationship between lymphocyte subsets and clinicopathological determinants of survival in patients with primary operable invasive ductal breast cancer. Br J Cancer. 2012;107(5):864-873. DOI: https://doi.org/10.1038/bjc.2012.346 PMid:22918394 PMCid:PMC3461152

13. Leek RD, Harris AL. Tumor-associated macrophages in breast cancer. J Mammary Gland Biol Neoplasia. 2002 Apr;7(2):177-189. DOI: https://doi.org/10.1023/a:1020304003704 PMID: 12463738

14. Movahedi K, Laoui D, Gysemans C, Baeten M, Stangé G, Van den Bossche J, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010 Jul 15;70(14):5728-5739. DOI: https://doi.org/10.1158/0008-5472.CAN-09-4672 PMid:20570887

15. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014 Jul 17;41(1):14-20. DOI: https://doi.org/10.1016/j.immuni.2014.06.008 PMid:25035950 PMCid:PMC4123412

16. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017 Jul;14(7):399-416. DOI: https://doi.org/10.1038/nrclinonc.2016.217 PMID: 28117416 PMCID: PMC5480600

17. Tang X. Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. Cancer Lett. 2013;332(1):3-10. DOI: https://doi.org/10.1016/j.canlet.2013.01.011 PMid:23376639 PMCid:PMC3675181

18. Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 2012;7(12):e50946. DOI: https://doi.org/10.1371/journal.pone.0050946 PMid:23284651 PMCid:PMC3532403

19. Boström MM, Irjala H, Mirtti T, Taimen P, Kauko T, Ålgars A, et al. Tumor-Associated Macrophages Provide Significant Prognostic Information in Urothelial Bladder Cancer. PLoS One. 2015 Jul 21;10(7):e0133552. DOI: https://doi.org/10.1371/journal.pone.0133552 PMid:26197470 PMCid:PMC4511010

20. Pelekanou V, Villarroel-Espindola F, Schalper KA, Pusztai L, Rimm DL. CD68, CD163, and matrix metalloproteinase 9 (MMP-9) co-localization in breast tumor microenvironment predicts survival differently in ER-positive and ER-negative cancers. Breast Cancer Res. 2018;20(1):154. DOI: https://doi.org/10.1186/s13058-018-1076-x PMid:30558648 PMCid:PMC6298021

21. Gwak JM, Jang MH, Kim DI, Seo AN, Park SY. Prognostic value of tumor associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS One. 2015;10(4):e0125728. DOI: https://doi.org/10.1371/journal.pone.0125728 PMid:25884955 PMCid:PMC4401667

22. Jeong H, Hwang I, Kang SH, Shin HC, Kwon SY. Tumor-associated macrophages as potential prognostic biomarkers of invasive breast cancer. J Breast Cancer. 2019;22(1):38-51. DOI: https://doi.org/10.4048/jbc.2019.22.e5 PMid:30941232 PMCid:PMC6438840

23. Ni C, Yang L, Xu Q, Yuan H, Wang W, Xia W, et al. CD68- and CD163-positive tumor infiltrating macrophages in non-metastatic breast cancer: a retrospective study and meta-analysis. J Cancer. 2019;10(19):4463-4472. DOI: https://doi.org/10.7150/jca.33914 PMid:31528210 PMCid:PMC6746141

24. Sousa S, Brion R, Lintunen M, Kronqvist P, Sandholm J, Mönkkönen J, et al. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res. 2015;17(1):101. DOI: https://doi.org/10.1186/s13058-015-0621-0 PMid:26243145 PMCid:PMC4531540

25. Yang M, Li Z, Ren M, Li S, Zhang L, Zhang X, et al. Stromal infiltration of tumor-associated macrophages conferring poor prognosis of patients with basal-like breast carcinoma. J Cancer. 2018;9(13):2308-2316. DOI: https://doi.org/10.7150/jca.25155 PMid:30026826 PMCid:PMC6036715

26. Ch'ng ES, Tuan Sharif SE, Jaafar H. In human invasive breast ductal carcinoma, tumor stromal macrophages and tumor nest macrophages have distinct relationships with clinicopathological parameters and tumor angiogenesis. Virchows Arch. 2013;462(3):257-267. DOI: https://doi.org/10.1007/s00428-012-1362-4 PMid:23283409

27. Yuan ZY, Luo RZ, Peng RJ, Wang SS, Xue C. High infiltration of tumor-associated macrophages in triple-negative breast cancer is associated with a higher risk of distant metastasis. Onco Targets Ther. 2014;7:1475-1480. DOI: https://doi.org/10.2147/OTT.S61838 PMid:25187727 PMCid:PMC4149399