Invasive Breast Carcinoma with Abundant Collagenous Stroma Shows Lower Level of CD68-Positive Tumor Associated Macrophages than Those of Invasive Carcinoma without Abundant Collagenous Stroma
Keywords:
Breast cancer, pseudoangiomatous stromal hyperplasia, tumor microenvironment, tumor-associated macrophages, CD68Abstract
Background and aim of the work: The significance of association between cancer and its stromal microenvironment has been recognized. We aimed to investigate the immunohistochemical staining features of D2-40 (podoplanin), SMA (smooth muscle actin) and CD68 (pan-macrophage marker) in patients with early stage invasive breast cancer with/out peritumoral PASH-like stroma.
Methods: The H&E sections of core needle biopsy specimens of invasive breast carcinomas diagnosed during one-year time period were reviewed in terms of the presence of accompanying PASH-like stroma retrospectively. Cases with similar pattern of growth in their surgical excision materials were included. Eight cases were grouped as ‘Invasive tumor with PASH-like stroma’ and 21 cases as ‘Invasive tumor without PASH-like stroma’, consecutively. The results of immunohistochemical staining for D2-40, SMA and CD68 were noted semiquantitatively as ‘negative’,’weak’, moderate’ or ‘strong’.
Results: CD68 was found significantly lower in invasive tumor with peritumoral PASH-like stroma than those of tumor without PASH-like stroma. No significant differences were found for SMA and D2-40 between two groups.
Conclusions: Tumor-associated macrophages (CD68 positive) in tumor stroma have been demonstrated in association with tumor behavior in several studies. The presence of peritumoral PASH-like stroma, which is poorly staining for CD68, might be a morphological clue for the behavior of tumor.
References
1. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27(45):5904-12.
2. Mittal S, Brown NJ, Holen I. The breast tumor microenvironment: role in cancer development, progression and response to therapy. Expert Rev Mol Diagn. 2018;18(3):227-43.
3. Yang J, Li X, Liu X, Liu Y. The role of tumor-associated macrophages in breast carcinoma invasion and metastasis. Int J Clin Exp Pathol. 2015;8(6):6656-64.
4. Place AE, Jin Huh S, Polyak K. The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res. 2011;13(6):227.
5. Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009;9(4):259-70.
6. Soysal SD, Tzankov A, Muenst SE. Role of the Tumor Microenvironment in Breast Cancer. Pathobiology. 2015;82(3-4):142-52.
7. Lee CH, Liu SY, Chou KC, Yeh CT, Shiah SG, Huang RY, et al. Tumor-associated macrophages promote oral cancer progression through activation of the Axl signaling pathway. Ann Surg Oncol. 2014;21(3):1031-7.
8. Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008;6:11.
9. Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol. 2011;178(3):1221-32.
10. Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010;70(12):4840-9.
11. Wu P, Wu D, Zhao L, Huang L, Chen G, Shen G, et al. Inverse role of distinct subsets and distribution of macrophage in lung cancer prognosis: a meta-analysis. Oncotarget. 2016;7(26):40451-60.
12. Chen XJ, Han LF, Wu XG, Wei WF, Wu LF, Yi HY, et al. Clinical Significance of CD163+ and CD68+ Tumor-associated Macrophages in High-risk HPV-related Cervical Cancer. J Cancer. 2017;8(18):3868-75.
13. Medrek C, Ponten F, Jirstrom K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012;12:306.
14. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 2010;362(10):875-85.
15. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27(4):462-72.
16. Charpin C, Bergeret D, Garcia S, Andrac L, Martini F, Horschowski N, et al. ELAM selectin expression in breast carcinomas detected by automated and quantitative immunohistochemical assays. Int J Oncol. 1998;12(5):1041-8.
17. Nguyen M, Corless CL, Kraling BM, Tran C, Atha T, Bischoff J, et al. Vascular expression of E-selectin is increased in estrogen-receptor-negative breast cancer: a role for tumor-cell-secreted interleukin-1 alpha. Am J Pathol. 1997;150(4):1307-14.
18. Muller AM, Weichert A, Muller KM. E-cadherin, E-selectin and vascular cell adhesion molecule: immunohistochemical markers for differentiation between mesothelioma and metastatic pulmonary adenocarcinoma? Virchows Arch. 2002;441(1):41-6.
19. Staal-van den Brekel AJ, Thunnissen FB, Buurman WA, Wouters EF. Expression of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in non-small-cell lung carcinoma. Virchows Arch. 1996;428(1):21-7.
20. Bhaskar V, Law DA, Ibsen E, Breinberg D, Cass KM, DuBridge RB, et al. E-selectin up-regulation allows for targeted drug delivery in prostate cancer. Cancer Res. 2003;63(19):6387-94.
21. Brabrand A, Kariuki, II, Engstrom MJ, Haugen OA, Dyrnes LA, Asvold BO, et al. Alterations in collagen fibre patterns in breast cancer. A premise for tumour invasiveness? APMIS. 2015;123(1):1-8.
22. Kelten Talu C, Boyaci C, Leblebici C, Hacihasanoglu E, Bozkurt ER. Pseudoangiomatous Stromal Hyperplasia in Core Needle Biopsies of Breast Specimens. Int J Surg Pathol. 2017;25(1):26-30.
23. Vuitch MF, Rosen PP, Erlandson RA. Pseudoangiomatous hyperplasia of mammary stroma. Hum Pathol. 1986;17(2):185-91.
24. Powell CM, Cranor ML, Rosen PP. Pseudoangiomatous stromal hyperplasia (PASH). A mammary stromal tumor with myofibroblastic differentiation. Am J Surg Pathol. 1995;19(3):270-7.
25. Degnim AC, Frost MH, Radisky DC, Anderson SS, Vierkant RA, Boughey JC, et al. Pseudoangiomatous stromal hyperplasia and breast cancer risk. Ann Surg Oncol. 2010;17(12):3269-77.
26. Ibrahim RE, Sciotto CG, Weidner N. Pseudoangiomatous hyperplasia of mammary stroma. Some observations regarding its clinicopathologic spectrum. Cancer. 1989;63(6):1154-60.
27. Milanezi MF, Saggioro FP, Zanati SG, Bazan R, Schmitt FC. Pseudoangiomatous hyperplasia of mammary stroma associated with gynaecomastia. J Clin Pathol. 1998;51(3):204-6.
28. Damiani S, Eusebi V, Peterse JL. Malignant neoplasms infiltrating pseudoangiomatous' stromal hyperplasia of the breast: an unrecognized pathway of tumour spread. Histopathology. 2002;41(3):208-15.
29. Drinka EK, Bargaje A, Ersahin CH, Patel P, Salhadar A, Sinacore J, et al. Pseudoangiomatous stromal hyperplasia (PASH) of the breast: a clinicopathological study of 79 cases. Int J Surg Pathol. 2012;20(1):54-8.
30. Zubor P, Kajo K, Dussan CA, Szunyogh N, Danko J. Rapidly growing nodular pseudoangiomatous stromal hyperplasia of the breast in an 18-year-old girl. APMIS. 2006;114(5):389-92.
31. 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.
32. 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;7:1475-80.
33. Zhang Y, Cheng S, Zhang M, Zhen L, Pang D, Zhang Q, et al. High-infiltration of tumor-associated macrophages predicts unfavorable clinical outcome for node-negative breast cancer. PLoS One. 2013;8(9):e76147.
34. Jensen TO, Schmidt H, Moller HJ, Hoyer M, Maniecki MB, Sjoegren P, et al. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J Clin Oncol. 2009;27(20):3330-7.
35. Komohara Y, Hasita H, Ohnishi K, Fujiwara Y, Suzu S, Eto M, et al. Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci. 2011;102(7):1424-31.
36. Lima L, Oliveira D, Tavares A, Amaro T, Cruz R, Oliveira MJ, et al. The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure. Urol Oncol. 2014;32(4):449-57.
37. Zhao X, Qu J, Sun Y, Wang J, Liu X, Wang F, et al. Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature. Oncotarget. 2017;8(18):30576-86.
38. Mundim FG, Pasini FS, Nonogaki S, Rocha RM, Soares FA, Brentani MM, et al. Breast Carcinoma-associated Fibroblasts Share Similar Biomarker Profiles in Matched Lymph Node Metastasis. Appl Immunohistochem Mol Morphol. 2016;24(10):712-20.
39. Rozenchan PB, Pasini FS, Roela RA, Katayama ML, Mundim FG, Brentani H, et al. Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer. Tumour Biol. 2015;36(12):9589-97.
40. Zou A, Lambert D, Yeh H, Yasukawa K, Behbod F, Fan F, et al. Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-beta signaling proteins. BMC Cancer. 2014;14:781.
41. Cai D, Wu X, Hong T, Mao Y, Ge X, Hua D. CD61+ and CAF+ were found to be good prognosis factors for invasive breast cancer patients. Pathol Res Pract. 2017;213(10):1296-301.
42. Kim HM, Jung WH, Koo JS. Expression of cancer-associated fibroblast related proteins in metastatic breast cancer: an immunohistochemical analysis. J Transl Med. 2015;13:222.
2. Mittal S, Brown NJ, Holen I. The breast tumor microenvironment: role in cancer development, progression and response to therapy. Expert Rev Mol Diagn. 2018;18(3):227-43.
3. Yang J, Li X, Liu X, Liu Y. The role of tumor-associated macrophages in breast carcinoma invasion and metastasis. Int J Clin Exp Pathol. 2015;8(6):6656-64.
4. Place AE, Jin Huh S, Polyak K. The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res. 2011;13(6):227.
5. Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009;9(4):259-70.
6. Soysal SD, Tzankov A, Muenst SE. Role of the Tumor Microenvironment in Breast Cancer. Pathobiology. 2015;82(3-4):142-52.
7. Lee CH, Liu SY, Chou KC, Yeh CT, Shiah SG, Huang RY, et al. Tumor-associated macrophages promote oral cancer progression through activation of the Axl signaling pathway. Ann Surg Oncol. 2014;21(3):1031-7.
8. Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008;6:11.
9. Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol. 2011;178(3):1221-32.
10. Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010;70(12):4840-9.
11. Wu P, Wu D, Zhao L, Huang L, Chen G, Shen G, et al. Inverse role of distinct subsets and distribution of macrophage in lung cancer prognosis: a meta-analysis. Oncotarget. 2016;7(26):40451-60.
12. Chen XJ, Han LF, Wu XG, Wei WF, Wu LF, Yi HY, et al. Clinical Significance of CD163+ and CD68+ Tumor-associated Macrophages in High-risk HPV-related Cervical Cancer. J Cancer. 2017;8(18):3868-75.
13. Medrek C, Ponten F, Jirstrom K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012;12:306.
14. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 2010;362(10):875-85.
15. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27(4):462-72.
16. Charpin C, Bergeret D, Garcia S, Andrac L, Martini F, Horschowski N, et al. ELAM selectin expression in breast carcinomas detected by automated and quantitative immunohistochemical assays. Int J Oncol. 1998;12(5):1041-8.
17. Nguyen M, Corless CL, Kraling BM, Tran C, Atha T, Bischoff J, et al. Vascular expression of E-selectin is increased in estrogen-receptor-negative breast cancer: a role for tumor-cell-secreted interleukin-1 alpha. Am J Pathol. 1997;150(4):1307-14.
18. Muller AM, Weichert A, Muller KM. E-cadherin, E-selectin and vascular cell adhesion molecule: immunohistochemical markers for differentiation between mesothelioma and metastatic pulmonary adenocarcinoma? Virchows Arch. 2002;441(1):41-6.
19. Staal-van den Brekel AJ, Thunnissen FB, Buurman WA, Wouters EF. Expression of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in non-small-cell lung carcinoma. Virchows Arch. 1996;428(1):21-7.
20. Bhaskar V, Law DA, Ibsen E, Breinberg D, Cass KM, DuBridge RB, et al. E-selectin up-regulation allows for targeted drug delivery in prostate cancer. Cancer Res. 2003;63(19):6387-94.
21. Brabrand A, Kariuki, II, Engstrom MJ, Haugen OA, Dyrnes LA, Asvold BO, et al. Alterations in collagen fibre patterns in breast cancer. A premise for tumour invasiveness? APMIS. 2015;123(1):1-8.
22. Kelten Talu C, Boyaci C, Leblebici C, Hacihasanoglu E, Bozkurt ER. Pseudoangiomatous Stromal Hyperplasia in Core Needle Biopsies of Breast Specimens. Int J Surg Pathol. 2017;25(1):26-30.
23. Vuitch MF, Rosen PP, Erlandson RA. Pseudoangiomatous hyperplasia of mammary stroma. Hum Pathol. 1986;17(2):185-91.
24. Powell CM, Cranor ML, Rosen PP. Pseudoangiomatous stromal hyperplasia (PASH). A mammary stromal tumor with myofibroblastic differentiation. Am J Surg Pathol. 1995;19(3):270-7.
25. Degnim AC, Frost MH, Radisky DC, Anderson SS, Vierkant RA, Boughey JC, et al. Pseudoangiomatous stromal hyperplasia and breast cancer risk. Ann Surg Oncol. 2010;17(12):3269-77.
26. Ibrahim RE, Sciotto CG, Weidner N. Pseudoangiomatous hyperplasia of mammary stroma. Some observations regarding its clinicopathologic spectrum. Cancer. 1989;63(6):1154-60.
27. Milanezi MF, Saggioro FP, Zanati SG, Bazan R, Schmitt FC. Pseudoangiomatous hyperplasia of mammary stroma associated with gynaecomastia. J Clin Pathol. 1998;51(3):204-6.
28. Damiani S, Eusebi V, Peterse JL. Malignant neoplasms infiltrating pseudoangiomatous' stromal hyperplasia of the breast: an unrecognized pathway of tumour spread. Histopathology. 2002;41(3):208-15.
29. Drinka EK, Bargaje A, Ersahin CH, Patel P, Salhadar A, Sinacore J, et al. Pseudoangiomatous stromal hyperplasia (PASH) of the breast: a clinicopathological study of 79 cases. Int J Surg Pathol. 2012;20(1):54-8.
30. Zubor P, Kajo K, Dussan CA, Szunyogh N, Danko J. Rapidly growing nodular pseudoangiomatous stromal hyperplasia of the breast in an 18-year-old girl. APMIS. 2006;114(5):389-92.
31. 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.
32. 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;7:1475-80.
33. Zhang Y, Cheng S, Zhang M, Zhen L, Pang D, Zhang Q, et al. High-infiltration of tumor-associated macrophages predicts unfavorable clinical outcome for node-negative breast cancer. PLoS One. 2013;8(9):e76147.
34. Jensen TO, Schmidt H, Moller HJ, Hoyer M, Maniecki MB, Sjoegren P, et al. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J Clin Oncol. 2009;27(20):3330-7.
35. Komohara Y, Hasita H, Ohnishi K, Fujiwara Y, Suzu S, Eto M, et al. Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci. 2011;102(7):1424-31.
36. Lima L, Oliveira D, Tavares A, Amaro T, Cruz R, Oliveira MJ, et al. The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure. Urol Oncol. 2014;32(4):449-57.
37. Zhao X, Qu J, Sun Y, Wang J, Liu X, Wang F, et al. Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature. Oncotarget. 2017;8(18):30576-86.
38. Mundim FG, Pasini FS, Nonogaki S, Rocha RM, Soares FA, Brentani MM, et al. Breast Carcinoma-associated Fibroblasts Share Similar Biomarker Profiles in Matched Lymph Node Metastasis. Appl Immunohistochem Mol Morphol. 2016;24(10):712-20.
39. Rozenchan PB, Pasini FS, Roela RA, Katayama ML, Mundim FG, Brentani H, et al. Specific upregulation of RHOA and RAC1 in cancer-associated fibroblasts found at primary tumor and lymph node metastatic sites in breast cancer. Tumour Biol. 2015;36(12):9589-97.
40. Zou A, Lambert D, Yeh H, Yasukawa K, Behbod F, Fan F, et al. Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-beta signaling proteins. BMC Cancer. 2014;14:781.
41. Cai D, Wu X, Hong T, Mao Y, Ge X, Hua D. CD61+ and CAF+ were found to be good prognosis factors for invasive breast cancer patients. Pathol Res Pract. 2017;213(10):1296-301.
42. Kim HM, Jung WH, Koo JS. Expression of cancer-associated fibroblast related proteins in metastatic breast cancer: an immunohistochemical analysis. J Transl Med. 2015;13:222.
Downloads
Published
03-11-2021
Issue
Section
ORIGINAL ARTICLES
License
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers.
Authors retain the copyright for their published work. No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.
How to Cite
1.
Kelten Talu C, Hacihasanoglu E, Leblebici C, Nazli MA, Arslan E, Can Trabulus D. Invasive Breast Carcinoma with Abundant Collagenous Stroma Shows Lower Level of CD68-Positive Tumor Associated Macrophages than Those of Invasive Carcinoma without Abundant Collagenous Stroma . Acta Biomed. 2021;92(5):e2021254. doi:10.23750/abm.v92i5.10954
