Document Type : Original Article


1 Department of Pathology, Assiut University, Assiut, Egypt

2 Department of Radiotherapy and Nuclear Medicine, South Egypt Cancer Institute, Assiut University, Assiut, Egypt

3 Department of Medical Oncology and Hematological Malignancy, South Egypt Cancer Institute, Assiut University, Assiut, Egypt


Background: Tumor microenvironment, specifically tumor-associated macrophages, plays an important role in tumor initiation and progression. CD163 has been recognized as a valuable specific macrophage marker. Cyclooxygenase-2 (Cox2) plays a role in tumor progression. CD31 is reliable for estimation of the density of microvesseles (MVD), which has prognostic importance in several malignant tumors. Thus, the current study was conducted to test the association between CD163, Cox2, and CD31 expression with the prognosis of classical Hodgkin lymphoma (cHL) patients and their potential correlation with clinicopathological variables.
Method: CD163, Cox2, and CD31 expressions were examined in newly diagnosed patients with cHL through immunohistochemistry on tissue biopsy and the results were correlated with the patients’ outcome after the median follow-up, which was about 35 months.
Results: 104 patients were included in this study. High CD163 was found in 32.7% of the patients. Cox2 was positive in 42.3% of them. CD 31 with high MVD (≥10%) was found in 51% of the subjects. A significant association was detected between CD163 and Cox2 with tumor stage (P = 0.001, and P = 0.001) and IPS score. Regarding CD31, we could not find any significant associations with disease parameters, except with histological subtype (P = 0.001). A significant relationship was observed between Cox2 and CD163 expression and the relapse rate (P = 0.001, P = 0.01, respectively). Regarding survival, only Cox2 showed a significant association with disease-free survival (P = 0.0379).
Conclusion: These findings suggested that Cox2 and CD163 expression can be used as predicator for early relapse and as new therapeutic targets in cHL.


How to cite this article:

Makboul R, Refaiy A, Mohamed R, Attia A, Osama D, El Emary AN, et al. Impact of Cox2, CD163, and microvessel density expression on the prediction of relapse and patients’ outcome in classical Hodgkin lymphoma. Middle East J Cancer. 2022;13(2):255- 65. doi: 10.30476/mejc.2021. 87421.1418.

1. Canioni D, Deau-Fischer B, Taupin P, Ribrag I, Delarue
R, Bosq J, et al. Prognostic significance of new
immunohistochemical markers in refractory classical
Hodgkin lymphoma: a study of 59 cases. PLoS One.
2009; 4 (7): 6341-8. doi: 10.1371/journal.pone.
2. Gordon S, Taylor PR. Monocyte and macrophage
heterogeneity. Nat Rev Immunol. 2005;5(12):953-64.
3. Mantovani A, Sica A, Locati M. Macrophage polarization
comes of age. Immunity. 2005;23(4):344-50.
4. Pham LV, Pogue E, Ford RJ. The role of
macrophage/B-Cell interactions in the Pathophysiology
of B-Cell lymphomas. Front Oncol. 2018;8:147. doi:
5. Sica A, Erreni M, Allavena P. Macrophage polarization
in pathology. Cell Mol Life Sci. 2015;72(21):4111-
26. doi: 10.1007/s00018-015-1995-y.
6. Gandhi J, Khera L, Gaur N, Paul C, Kaul R. Role of
modulator of inflammation cyclooxygenase-2 in
gammaherpesvirus mediated tumorigenesis. Front
Microbiol. 2017; 8:538-12. doi:
7. Korkolopoulou P, Thymara I, Kavantzas N , Vassilakopoulos
TP, Angelopoulou MK, Kokoris SI, et al.
Angiogenesis in Hodgkin's lymphoma: a morphometric
approach in 286 patients with prognostic implications.
Leukemia. 2005; 19:894-900. 10.1038/sj.leu.2403690.
8. Tilley S, Coffman T, Koller B. Mixed messages:
modulation of inflammation and immune responses
by prostaglandins and thromboxanes. J Clin Invest.
2001; 108(1):15-23. doi: 10.1172/JCI13416.
9. Ohsawa M, Fukushima H, Ikura Y, Inoue T, Shirai N,
Sugama Y, et al. Expression of cyclooxygenase-2 in
Hodgkin's lymphoma: its role in cell proliferation and
angiogenesis. Leuk Lymphoma. 2006;47(9):1863-71.
doi: 10.1080/10428190600685442.
10. Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA.
The cyclooxygenase-2 inhibitor celecoxib is a potent
preventive and therapeutic agent in the min mouse
model of adenomatous polyposis. Cancer Res.
11. Half E, Tang XM, Gwyn K, Sahin A, Wathen K,
Sinicrope FA. Cyclooxygenase-2 expression in human
breast cancers and adjacent ductal carcinoma in situ.
Cancer Res. 2002 ;62(6):1676-81.
12. Lee JS, Choi YD, Lee JH, Nam JH, Choi CH, Lee
M, et al. Expression of cyclooxygenase-2 in adenocarcinomas
of the uterine cervix and its relation to
angiogenesis and tumor growth. Gynecol Oncol.
2004;95(3):523-9. 10.1016/j.ygyno.2004.08.036.
13. Yao M, Zhou W, Sangha S, Albert A, Chang AJ, Liu
TC, et al. Effects of nonselective cyclooxygenase
inhibition with low-dose ibuprofen on tumor growth,
angiogenesis, metastasis, and survival in a mouse
model of colorectal cancer. Clin Cancer Res.
2005;11(4):1618-28. doi:10.1158/1078-0432.CCR-
14. Montanari F, Diefenbach C. Hodgkin lymphoma:
targeting the tumor microenvironment as a therapeutic
strategy. Clin Adv Hematol Oncol. 2015;13(8):518-24.
15. Kamper P, Bendix K, Hamilton-Dutoit S, Honoré B,
Nyengaard JR, d'Amore F. Tumor-infiltrating
macrophages correlate with adverse prognosis and
Epstein-Barr virus status in classical Hodgkin's
lymphoma. Haematologica. 2011; 96(2):269-76. doi:
16. Barisik ON, Suheyla Bozkurt S, Gumus M , Kaygusuz
I, Nimet Karadayi N, Bas E, et al. Expression and
prognostic significance of Cox-2 and p-53 in Hodgkin
lymphomas: a retrospective study. Diagn Pathol.
2010;5:19. doi: 10.1186/1746-1596-5-19.
17. Kaplan E, Meier P. Nonparametric estimation from
incomplete observations. J Am Stat
18. von Tresckow B, Engert A. Refractory Hodgkin
lymphoma. Curr Opin Oncol. 2013;25(5):463-9. doi:
19. Raemaekers JM, André MP, Federico M, Girinsky T,
Oumedaly R, Ercole Brusamolino E, et al. Omitting
radiotherapy in early positron emission tomographynegative
stage I/II Hodgkin lymphoma is associated
with an increased risk of early relapse: Clinical results
of the preplanned interim analysis of the randomized
EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;
32(12):1188-94. doi: 10.1200/JCO.2013.51.9298.
20. Engert A, Schiller P, Josting A, Herrmann R, Koch P,
Sieber M, et al. Involved-field radiotherapy is equally
effective and less toxic compared with extended-field
radiotherapy after four cycles of chemotherapy in
patients with early-stage unfavorable Hodgkin's
lymphoma: results of the HD8 trial of the German
Hodgkin's Lymphoma Study Group. J Clin Oncol.
21. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher
RI, Connors JM, et al. Report of an international
workshop to standardize response criteria for non-
Hodgkin's lymphomas. NCI Sponsored International
Working Group. J Clin Oncol. 1999;17(4):1244. doi:
22. Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q,
Prykhozhij S, et al. Tissue macrophages act as cellular
chaperones for vascular anastomosis downstream of
VEGF-mediated endothelial tip cell induction. Blood.
2010;116(5):829-40. doi: 10.1182/blood-2009-12-
257832 .
23. Schmidt T, Carmeliet P. Blood-vessel formation:
Bridges that guide and unite. Nature. 2010;
465(7299):697-9. doi: 10.1038/465697a.
24. Esbona K, Yi Y, Saha S, Yu M, Van Doorn RR, Conklin
MW, et al. The presence of cyclooxygenase 2, tumorassociated
macrophages, and collagen alignment as
prognostic markers for invasive breast carcinoma
patients. Am J Pathol. 2018;188(3):559-73. doi:
25. Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S,
Zammataro L, et al. Tumor-conditioned macrophages
secrete migration-stimulating factor: a new marker
for M2-polarization, influencing tumor cell motility.
J Immunol. 2010; 185(1):642-52. doi: 10.4049
26. Al-Salam S, Awwad A, Sudhadevi M, Daoud S,
Nagelkerke NJ, Castella A, et al. Epstein-Barr virus
infection correlates with the expression of COX-2,
p16(INK4A) and p53 in classic Hodgkin lymphoma.
Int J Clin Exp Pathol. 2013; 1;6(12):2765-77.
27. Ahmed H, Raslan W, Deifalla A, Fathallah M. CD163
is a predictive biomarker for prognosis of classical
Hodgkin's lymphoma in Saudi patients. Mol Clin
Oncol. 2019;11(1):67-76. doi: 10.3892/mco.2019.1850.
28. Xu X, Li Z, Liu J, Zhu F, Wang Z, Wang J, et al. The
prognostic value of tumor-associated macrophages in
Non-Hodgkin's Lymphoma: A systematic review and
meta-analysis. Scand J Immunol. 2020;91(1):e12814.
doi: 10.1111/sji.12814.
29. Kayal S, Mathur S, Karak AK, Kumar L, Sharma A,
Bakhshi S, et al. CD68 tumor-associated macrophage
marker is not prognostic of clinical outcome in classical
Hodgkin lymphoma. Leuk Lymphoma.
2014;55(5):1031-7. doi: 10.3109/10428194.2013.
30. Azambuja D, Natkunam Y, Biasoli I, Lossos IS,
Anderson MW, Morais JC, et al. Lack of association
of tumor-associated macrophages with clinical outcome
in patients with classical Hodgkin's lymphoma. Ann
Oncol. 2012;23(3):736-42. doi: 10.1093/annonc/
31. Koh YW, Park CS, Yoon DH, Suh C, Huh J. CD163
expression was associated with angiogenesis and
shortened survival in patients with uniformly treated
classical Hodgkin lymphoma. PLoS One. 2014;9(1):
e87066. doi: 10.1371/journal.pone.0087066.
32. Kimura YN, Watari K, Fotovati A, Hosoi F, Yasumoto
K, Izumi H, et al. Inflammatory stimuli from
macrophages and cancer cells synergistically promote
tumor growth and angiogenesis. Cancer Sci. 2007;
33. Panico L, Ronconi F, Lepore M, Tenneriello V, Cantore
N, Dell'Angelo AC, et al. Prognostic role of tumorassociated
macrophages and angiogenesis in classical
Hodgkin lymphoma. Leuk Lymphoma.
2013;54(11):2418-25. doi: 10.3109/10428194.2013.
34. Koh YW, Park C, Yoon D, Suh C, Huh J. Prognostic
significance of COX-2 expression and correlation with
Bcl-2 and VEGF expression, microvessel density, and
clinical variables in classical Hodgkin lymphoma. Am
J Surg Pathol. 2013; 37(8):1242-51. doi:
35. Na YR, Yoon YN, Son DI, Seok SH. Cyclooxygenase-
2 inhibition blocks M2 macrophage differentiation
and suppresses metastasis in murine breast cancer
model. PLoS One. 2013;8 (5): 63451-11. doi:
36. Nakanishi Y, Nakatsuji M, Seno H, Ishizu S, Akitake-
Kawano R, Kanda K, et al. COX-2 inhibition alters
the phenotype of tumor-associated macrophages from
M2 to M1 in ApcMin/+ mouse polyps. Carcinogenesis.
2011;32(9):1333-9. doi: 10.1093/carcin/bgr128.
37. Ohsawa M, Fukushima H, Ikura Y, Inoue T, Shirai N,
Sugama Y, et al. Expression of cyclooxygenase-2 in
Hodgkin's lymphoma: its role in cell proliferation and
angiogenesis. Leuk Lymphoma. 2006;47(9):1863-71.
38. Mestre F, Gutierrez A, Ramos R, Martinez-Serra J,
Sánchez L, Matheu G, et al. Expression of COX-2 on
Reed-Sternberg cells is an independent unfavorable
prognostic factor in Hodgkin lymphoma treated with
ABVD. Blood. 2012;119(25):6072-9. doi: 10.1182
39. Shi Y, Gao Z, Liu C, Huang X, Song Y, Ping L, et al.
Expression and prognostic value of COX- 2,
p16(INK4A) and p53 in patients with classical Hodgkin
lymphoma. [Article in Chinese] Zhonghua Xue Ye
Xue Za Zhi. 2015;36(11):926-32. doi: