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V�"�"�"�"�"�"�"�"�"<>z:	Cox2 and CD163 expression were associated with microvessel density and can predict relapse in classical Hodgkin lymphoma
Abstract                  
Background and Purpose: Tumour microenvironment especially tumour associated macrophages plays an important role in tumour initiation and progression. CD163 has been recognized as a valuable specific macrophage marker. Cyclo-oxygenase 2 (Cox 2) plays a role in tumor progression. CD31 is reliable for estimation of microvesseles density (MVD) that has prognostic importance in many malignant tumors.
We aimed to examine the association of CD 163, Cox-2 and CD31 expression and to assess their prognostic significance and potential correlation with clinicopathological variables in classical HL. 
Methodology: CD163, Cox-2 and CD31 expressions were examined in patients of HL by immunohistochemistry. 
Results: 83 patients were included in this study. High CD163 was found in 71.08 % of patients.  Cox2 was positive in 62.65% of patients. CD 31 with high MVD (e"10%) was found in (44.5%) of patients.
There were significant correlations between expression of CD163 with both Cox2 and CD 31(p= 0.01 and 0.042) respectively. And also between Cox2 and CD31 (p=0.017). Significant correlations were detected between CD163 and Cox2 with tumor stage (p=0.001, and 0.01) respectively, but not with CD31 (p=0.5). Only CD31 showed significant correlation with histological subtype (p=0.04). Significant relationship was found between Cox-2 and CD163 expression with relapse rate (p= 0.027, 0.008) respectively, and only Cox-2 showed significant association with disease free survival (p= 0.0379). 
 Conclusions: These findings support that Cox-2 and CD163 expression can be used as predicator for early relapse and can be used as new therapeutic targets in cHL.

Key words:
Hodgkin lymphoma; Tumour microenvironment; CD163; Cox2 and CD31









Introduction
	Tumor microenvironment is an emerging player in many solid tumors including (classical Hodgkin Lymphoma) cHL [1]. Tumor associated macrophages (TAM) are group of macrophages that recruited to the area of the tumor tissue. Macrophages have plasticity and can change their profiles in response to environmental stimuli. When macrophages exposed to IFN-� they are polarized to proinflammatory M1macrophages which have strong microbicidal and tumoricidal effect. When exposed to Th2 cytokines as IL-13 & IL-4, they are polarized to immunosuppressive M2 macrophages [2, 3]. In tumours TAMs display an M-2 like phenotype which express specific surface marker as CD163. In the tumour microenvironment, TAMs affect tumour progression in several aspects; they accelerate tumour growth and dissemination, contribute to matrix degradation and suppress the adaptive immune response against tumour through releasing various factors including chemokines, inflammatory and growth factors. Also TAMs are important inducers of the "angiogenic switch" that support tumour growth by expression of HIF 1� that induce transcription of many genes responsible for angiogenesis [4]. 
On the other hand, detection of CD31 positive vessels by immunohistochemistry is reliable for estimation of microvesseles density (MVD) and also has a prognostic importance in many malignant tumors including high grade non Hodgkin lymphoma, multiple myeloma and acute and chronic leukeamia [5, 6]. MVD has been correlated with biological behavior of cHL [7-9]. 
 Based on the above mentioned function of TAMs, it is not surprising that increased TAMs infiltration will correlate with reduced patient survival as observed in some tumours e.g. follicular lymphoma, breast and ovarian carcinoma, however the mechanism of which remains elusive [10].
	 
Cyclooxygenase-2 (COX2) was proved by some studies to play a major role in affection of prognosis of cHL. Cox2 was described as an inflammation-associated enzyme and many studies described a link between inflammation and cancer with special interest in Cox2 [11, 12]. Nonsteroidal anti-inflammatory drugs that inhibit Cox2 decreased the number of adenocarcinomas in a mouse model of adenomatous polyposis [13].  Also many previous investigations found that overexpression of Cox2 were correlated with progressive disease and a poor prognosis in several tumors as colon, cervix and breast, suggesting that Cox2 plays a role in cancer progression [14-16]. However, little number of studies was performed regarding association of Cox2 with Hodgkin lymphoma as its expression by HRS cells could affect the inflammatory microenvironment of cHL.  

The aim of this study is to evaluate the expression of CD163, CD31 and Cox2 in cHL by immunohistochemistry and to determine their correlation with each other and with various pathological and prognostic parameters.

Patients and methods
This prospective study included 83 patients with cHL who presented to outpatient clinic in south Egypt cancer Institute during the period from Jan 2012 to June 2016.  H&E stained slides were reevaluated to determine the histological type. Tumor stage and IPS (International prognostic score) were also determined. Follow up period ranged from (12-48) months.

Immunohistochemistry (IHC): 	Immunohistochemistry staining for CD163, CD31 and cox2 was done according to manufacturer's protocol. 4-5 micron thickness slides were cut from the paraffin blocks, rehydrated and subjected to hydrogen peroxide blocking. Antigen retrieval was done using microwave in citrate buffer for 15 min. Primary antibodies incubation were done using  CD163 Ab-1 (Clone 10D6), Cat. #MS-1103-S0, Cox2 cat No. 35-8200 (thermo fisher scientific, Fremont Blvd. Fremont, CA 94538, USA) at a concentration of 1/100 for 16 hours (overnight),  and CD31 (PECAM-1) clone GM006 (Genemed Biotechnologies, Inc, South San Francisco, CA 94080, USA),  at a concentration of 1/50 for 1 hour. 

The slides were incubated for 10 min at room temperature with the biotinylated goat antipolyvalent and then incubated for 10 min with steptavidin peroxidase at room temperature. Diaminibenzidine was applied to slides for 5 min at room temperature. Finally, the slides counterstained with Mayer�s hematoxylin, dehydrated, and mounted. 

Negative control slides were done by omitting primary antibody. Sections from placenta were used as appositive control for CD163. Slides from a case of angiosarcoma were used for CD31 and breast carcinoma for Cox2.  

Evaluation of immunohistochemistry 
The stained slides were examined and positivity were evaluated as follow CD163  expression was cytoplasmic and the evaluation was done by determining the percentage of positive cells for CD163 to overall cellularity. All cases were divided as low expression (<25% of positive cells) and high expression (> 25% of positive cells as previously described [17]. 
For CD31 (microvessels density counting), evaluation was done in areas of highest blood vessels density. Counting was done in three hot spots each of which 5 high power fields were counted and the average were calculated. Microvessels defined with clear cut lumen and well defined shapes were considered for counting 9. For purpose of statistical analysis the MVC were divided to high (e"10) and low count (<10).
Cox2 expression was determined in HRS cells. Cytoplasmic and/or membranous staining was considered as positive expression in these cells [18]. 

Statistical analysis
Statistical analysis was done using SPSS version 16. Chi square test was used for classified data. Spearman correlation coefficient was used to determine correlations. Survival analysis was done using Kaplan-Meier method with comparison analyzed by Log-Rank testing. Over all survival (OS) was measured from the date of diagnosis to the date of death due to any cause. Disease free survival (DFS) was measured as the interval from the date of diagnosis to the date of disease progression, relapse or death due to any cause.  Results were evaluated and P<0.05 was considered as level of significance.  


Results
Between 2012 and 2016, 83 patients were included in this study. The clinico-pathologic characteristics of the patients were summarized in (Table 1).
CD163, CD31 and Cox2 expression in cHL tissue: 
Immunohistochemical expression of CD163, CD31 and Cox2 were   shown in (Table 2 and Fig 1).
Correlation of expression of CD163, CD31 and Cox2 with each other
There were significant correlations between expression of CD163 and Cox2 (p=0.01, r=0.29), Cox2 and CD31 (p=0.017, r=0.31) and between CD31 and CD163 (p=0.042, r=0.35) (Table 3).
Correlation of expression of CD163, CD31 and Cox2 with clinicopathological variables:
Significant correlations were detected between CD163, Cox2, and tumor stage (p=0.001 & 0.01) respectively, but not with CD31 (p=0.5). 
CD31 showed significant correlation with histological subtype (p=0.04) as mixed cellularity subtype showed higher MVD count than other types. However, no significant difference regarding CD163 and Cox2 expression with histological subtype was found (p=0.097 and 0.1 respectively) (Table 4). 
No significant difference was found regarding the expression of the three markers with age and gender.
Prognostic significance of CD163, CD31 and Cox2:
	33 patients out of 83 relapsed over the period of follow up ranged from 12-48 months. Higher CD163 expression was found in relapsed cases than non relapsed and the difference was statistically significant as cases with relapse showed higher mean expression of CD163 than non relapsed cases (p=0.008) (Table 4). On the other hand we didn't found any significant relationship of CD 163 with DFS or OS. Regarding Cox2, a significant relationship was found between Cox-2 expression with relapse rate and disease free survival (DFS) (p= 0.027, 0.0379) respectively (Table 4 & Fig 2).
No significant association was found between CD31 expression and relapse rate, DFS. No significant correlation was found between expression of the three markers and OS (Fig 2). 
Discussion
The unique nature of cHL regarding paucity of tumor cells and abundant inflammatory background raises the interest that microenvironment plays a key role in progression and sustainability of this tumor [19]. M2-macrophages differentiation from monocytes occur in response to specific growth factors released by both malignant and stromal tumor compartments, including CCL2, M-CSF, vascular endothelial growth factor (VEGF) and CXCL12. M2-macrophages exhibit high expression of IL-10, VEGF, cyclooxygenase-2 (COX2), epidermal growth factor receptor (EGFR), and metalloproteinases (MMPs) [20-22].
This study demonstrates high expression of CD163 TAM in about 70% of cases and we found significant difference in expression between relapsed and non-relapsed cases with higher CD136 expression in relapsed patients. This finding is consistent with previous studies which confirm expression of TAM marker CD163 in cHL [23-25]. An earlier report using a gene-expression profile, Stedil and colleagues [26] observed that overexpression of a TAM-associated gene signature in cHL significantly correlated with worse outcomes in cHL patients who do not respond to therapy. Immunohistochemical analysis showed that less than 5% TAM correlated with longer progression-free survival (PFS) after primary treatment and lower relapse rates after autologous transplantation. The authors also showed that a very low percentage of TAM could identify a subset of patients with low stage disease who had a survival rate of 100%. Their results suggest that semi-quantitative assessment of TAMs can be used to identify patients at high risk of disease relapse or progression, as well as patients with early-stage disease with low risk for relapse who are currently over-treated. 
 
Also we detected a significant association of CD163 expression and tumour stage but not with other clinicopathological variables. This was consistent with previous studies [17, 27]. We could not establish association between CD163and DFS and OS similar to several previous studies [25, 27-29]. However other studies confirmed a significant correlation of CD163 with inferior clinical outcome. CD163 in their studies was significant predictor of DFS and OS [30-32]. The reasons for these discrepancies may be due to different inclusion criteria for patient selection regarding age and stage and EVB status which is described in many reports as bad prognostic factor. Also, different criteria for patient enrolling in the study either consecutive or selected with more patients suffering from relapse or treatment failure. Diverse methodology approach used also affect the results as different biomarkers selection and lack of technical standardization may add to these factors [23, 25]. 

In the current study significant association was seen between CD163 and MVD. This is not surprising as inflammatory cells as TAM release many growth factors, inflammatory mediators and cytokines including VEGF family and other angiogenic peptides that act on endothelial cells. Moreover, TAM serve as bridge cells or cellular chaperones that guide the fusion of endothelial cells tips to perform anastomosis and facilitate vascular sprouting [33, 34]. Macrophages interact with cancer cells and secrete angiogenic factors which affect other surrounding cells   and blood vessels [30, 35].
Several studies have emphasized the role of angiogenesis in solid malignancies. Microvessels density (MVD) may determine the risk of progression in other tumors. However, this may not be the case for cHL. Although a significant association between CD31 expression and histological subtypes was found in this study, it failed to confirm a correlation with patient survival or diseases stage. Some studies [30, 36] have observed lack of correlation of CD31 with patient outcome. However other studies described correlation of MVD with disease progression. In their study they compared CD31 expression in patients with cHL with relapse and they reported role of CD31 in tumor progression [9]. Another larger study by Korkolopoulos and coworkers [8] found increased MVD in early stages of cHL but not in advanced stages of the disease. Moreover, Passam and his colleagues [37] compare the expression of CD31 in cHL and in control lymph node (non infiltrated lymph nodes from breast cancer patients) and they did not found any difference in MVD between HL cases and control lymph nodes. They said that the results of CD31 could not be easily interpreted in HL. They concluded that the role of MVD in HL may be limited. Also they did not found any correlation of MVD and angiogenic factors like VEGF and HIF1 [30, 36]. In view of these data, our results may be explained by contribution of TAM to tumor progression by mechanisms other than angiogenesis. 
 
In our study, Cox2 was expressed in Reed Sternberg cells in 62.6% of cases in this study, and showed significant correlation with relapse rate and DFS. This finding is in concordance with previous studies 38-41. Cox2 pathway is of importance in cHL which is characterized by small number of tumor cells population in a milieu of proinflammatory cytokines and several other non neoplastic cell types [42]. Cox2 exerts its tumerogrnic effect through different mechanisms. Cox2 expression was associated with angiogenesis and chemoresistance in cHL through stimulation of antiapoptotic mechanisms as upregulation of bcl2 or resistance to Fas or through promotion of metastasis via matrix metalloproteinases activation [43]. 
Cox2 expression in our study showed significant correlation with MVD similar to previous works [12, 41]. And this was expected as Cox2 affect angiogenesis through induction of production of many angiogenic factors as VEGF, basic fibroblastic growth factor and platelet derived growth factors which stimulate microvesels production [41]. Also, Fhu and coworkers reported that lymphotoxin alpha which is a cytokine derived from HRS cells can also stimulate endothelial cell activation through different mechanisms including activation of Cox2 [44]. 

Accumulating evidence suggested that Cox2 is an essential factor for induction and maintenance of M2 polarity in many tumours as breast carcinoma [4, 45]. Another study reported that Cox2 inhibition, alters the phenotype of tumor-associated macrophages from M2 to M1 in animal models [46]. In breast cancer model. Cox2 inhibition potentiates macrophage�s inflammatory cytokine responses but reduced IL-10 secretion thus might skew overall tumor microenvironment. Reducing M2 macrophage characteristics systemically may provide advantages to cancer patients because they express much lower levels of TGFb, VEGFA, VEGFC, MMP-9, and MMP-1. All of these molecules enhance tumor cell metastasis directly or indirectly [45]. All these data raised our interest to investigate the correlation between M2 macrophages and Cox2 in cHL as to best of our knowledge, no previous studies investigate the correlation between CD 163 and Cox2 in cHL. Interestingly, we found statistically significant correlation between them, also Cox2 & CD163 were significantly associated with tumour stage and occurrence of relapse. Moreover, we found that Cox2 can help to predict relapse. Taken together we can suggest that detection of CD163 and Cox2 expression may be powerful indicator to predict relapse in CHL patients.  Also, future targeting COX-2 and macrophage polarization may help reduce relapse rate in cancer patients. 

Limitation of this study include retrospective design, short follow period and small sample size. The relatively small size of the present cohort may preclude the power needed to fully demonstrate the role of studied markers, thereby limiting the interpretation of the present results and require further validation.

Conclusion
In conclusion, tumour microenvironment has an impact on tumour progression in Hodgkin lymphoma as expression of CD163 and Cox-2 might be helpful to predict relapse in patients with Hodgkin lymphoma.  Cox2 expression can be used to identify a subgroup of cHL patients at high risk of recurrence and candidate for more aggressive treatment.

Conflict of interest statement:
The authors declare that they have no conflict of interest

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Figure legends:

Figure (1): Immunohistochemical expression of CD163, CD31 and Cox2 in classicalal Hodgkin lymphoma. A: High CD163 expression. B: Low CD163 expression. C: Positive Cox2 in HRS cells. D: Negative Cox2 in HRS cells. E: High MVC by CD31. F: Low MVC by CD31. (A, B, C, D x1000, E and F x200). 
HRS: Hodgkin Reed Sternberg cells, MVC: Micro-vessels count. 

Figure (2): Comparison of survival rates according to CD163, Cox-2 and CD31 expression. CD163 expression was not significantly associated with DFS (A) or OS (B). C: The DFS was significantly worse in the Cox-2 negative group. D: The difference in OS between Cox-2 positive versus Cox-2 negative groups was not statistically significant. CD31 expression was not significantly associated with DFS (E) or OS (F).










PAGE  


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