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 Table of Contents  
Year : 2013  |  Volume : 38  |  Issue : 3  |  Page : 102-107

CD163 and c-Met expression and serum free light chain in advanced classical Hodgkin’s lymphoma ( correlation with different clinicopathological parameters)

1 Hematology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
2 Department of Pathology, Medical Military Academy, Cairo, Egypt

Date of Submission20-Feb-2013
Date of Acceptance28-Feb-2013
Date of Web Publication19-Jun-2014

Correspondence Address:
Ahmed M.L. Bedewy
Hematology Department, Medical Research Institute, Alexandria University, Alexandria
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Source of Support: None, Conflict of Interest: None

DOI: 10.7123/01.EJH.0000430747.18411.4a

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Advances in the understanding of classical Hodgkin’s lymphoma (cHL) biology and immunology show that infiltrating immune cells and cytokines play different roles in relation to clinical outcomes. High levels of expression of the monocyte/macrophage lineage antigen CD163 were suggested to exert protumor effects. Lymphoid malignancies were found to express c-Met with a possible role in the pathogenesis of these diseases. Lymphoid malignancies often have a polyclonal B-cell infiltrate that can secrete immunoglobulins. This study aimed to evaluate the expressions of CD163 and c-Met and serum free light chain (sFLC) in relation to the clinicopathological features in patients with advanced cHL.

Materials and methods

Thirty-four patients with cHL were enrolled. CD163 and c-Met expressions were assessed immunohistochemically on lymph node biopsy sections together with a pretreatment estimation of sFLC using Enzyme Linked Immunosorbent Assay (ELISA).


The median age of the patients was 30 years, with a 1 : 1 male to female ratio. High CD163 expression correlated with increased age, B symptoms, International Prognostic Score of at least 3, mixed cellularity subtype, and low response to treatment. Also, high c-Met expression was correlated with increased age at diagnosis, leukocytosis, B symptoms, and lower complete remission rates. Elevated sFLC correlated with increased age at diagnosis, lymphopenia, International Prognostic Score of at least 3, B symptoms, and lower complete remission rates.


In cHL, high expression of CD163 and c-Met and elevated sFLC correlates with adverse outcome.

Keywords: CD163, c-Met, free light chain, Hodgkin′s lymphoma

How to cite this article:
Bedewy AM, EL-Maghraby SM, Bedewy MM. CD163 and c-Met expression and serum free light chain in advanced classical Hodgkin’s lymphoma ( correlation with different clinicopathological parameters). Egypt J Haematol 2013;38:102-7

How to cite this URL:
Bedewy AM, EL-Maghraby SM, Bedewy MM. CD163 and c-Met expression and serum free light chain in advanced classical Hodgkin’s lymphoma ( correlation with different clinicopathological parameters). Egypt J Haematol [serial online] 2013 [cited 2019 Dec 14];38:102-7. Available from: http://www.ehj.eg.net/text.asp?2013/38/3/102/134786

  Introduction Top

Although Hodgkin’s lymphoma (HL) can be considered a successful paradigm of modern treatment strategies, about 20% of patients with advanced-stage HL still die following relapse or progressive disease and a similar proportion of patients are overtreated, leading to treatment-related late sequelae including solid tumors and end-organ dysfunction 1,2.

It has been suggested that lymphoma-associated macrophages may play a prognostic role in several different lymphoproliferative entities, including classical Hodgkin’s lymphoma (cHL). Gene expression profiling data showed a correlation between upregulation of genes related to intratumor macrophage infiltration and poor response to treatment, suggesting an underlying tumor-promoting role for these cells 3.

CD68, the most commonly used macrophage marker, is widely synthesized by a variety of normal and neoplastic cells and is thus nonspecific for the monocyte/macrophage lineage 4. CD163 appears to be involved in anti-inflammatory functions predominantly associated with macrophages that promote tumor cell growth and metastasis (M2 macrophages), in contrast to M1 macrophages that kill tumor cells 5. Unlike CD68, the CD163 staining pattern is reported to show a more clean background with less nonspecific staining of Hodgkin’s Reed–Sternberg (RS) cells and other inflammatory elements 6.

CD163 is a glycoprotein belonging to the scavenger receptor cysteine-rich superfamily 7. It is controlled by various inflammatory mediators such as interferon-γ, interleukins-6, interleukin-10, and glucocorticoids 8.

The MET proto-oncogene, located on the 7q31 locus, encodes the receptor tyrosine kinase MET, also known as the MET or hepatocyte growth factor (HGF) receptor 9. The binding of HGF to its receptor, MET, results in C-terminus receptor tyrosine phosphorylation and receptor activation, triggering downstream signal transduction 10. This signaling pathway is involved in cellular proliferation, survival, and migration 11. Furthermore, c-Met has been shown to have prognostic significance in numerous malignancies including non-Hodgkin’s lymphoma 12.

The serum free light chains (sFLC) are κ and &lgr; light chains 13, which are produced by monoclonal and/or polyclonal B-cell populations. The diagnostic and prognostic values of elevated sFLC levels are established in monoclonal gammopathy of undetermined significance, multiple myeloma, solitary plasmacytoma, and AL-amyloidosis 14.

FLC abnormalities can occur in different ways: monoclonal elevated FLC (elevated κ and/or &lgr; with an abnormal FLC ratio), polyclonal elevated FLC (elevated κ and/or &lgr; with a normal FLC ratio), and ratio-only FLC abnormality (normal range κ and &lgr; with an abnormal FLC ratio). The polyclonal increases in sFLCs are not associated with an abnormal FLC ratio and may be indicative of renal dysfunction 15, older age 16, autoimmune disease 17, and chronic inflammation 18.

In the current study, we carried out an immunohistochemical assay of CD163 and c-Met expression on lymph node biopsy sections from newly diagnosed cases of advanced cHL together with estimation of pretreatment sFLC and correlated them with the clinicopathological features and the response to treatment.

  Patients and methods Top

The present work studied 34 newly diagnosed patients with advanced cHL (stages from IIB to IV on the Ann Arbor scale) who presented to the Hematology Department, Medical Research Institute, Alexandria University, and Mostafa Kamel Military Hospital (Alexandria). Patients were diagnosed and classified according to the morphological and immunohistochemical examination of lymph node biopsy materials on the basis of the WHO criteria 19.

Patients were staged according to the Ann Arbor staging system 20. Staging evaluation for each patient involved a physical examination; CT scans of the thorax, abdomen, and pelvis, bone marrow aspiration, and bilateral trephine biopsy. Laboratory evaluation included complete blood cell count, erythrocyte sedimentation rate, and liver and kidney function tests. The presence or absence of B symptoms and bulky disease was reported. The International Prognostic Score (IPS), which is based on age, sex, stage, presence of hypoalbuminemia, lymphopenia, and leukocytosis, was adopted 21.

Patients were treated with six cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), complemented by radiation therapy in patients with bulky disease or localized residual masses. Treatment response was assessed using standardized guidelines 22.

Complete remission (CR) was defined as the disappearance of all clinical evidence of disease and normalization of all laboratory values and radiographic results lasting for at least 4 weeks. Partial response was defined as a reduction of 50% or more in the sum of the products of the cross-sectional diameters of all known lesions lasting for at least 4 weeks 23.

Immunohistochemistry for CD163 and c-Met

Paraffin sections of lymph nodes were immune-stained according to the manufacturer’s instructions using monoclonal antibodies against CD163 (Thermo Fisher Scientific, Kalamazoo, Michigan, USA) and c-Met (Santa Cruz Biotechnology, Santa Cruz, California, USA). Staining was performed using the EconoTek HRP Anti-Polyvalent (DAB) Kit (Scytek Laboratories, Logan, Utah, USA). The slides were counterstained with hematoxylin and cover slipped. Cut-offs of 20 and 30% of relative expression in relation to overall cellularity were adopted for CD163 and c-Met, respectively. These cut-off points were adopted by Yoon et al. 24 and Xu et al. 11, respectively.

The slides were evaluated by two hematologists. CD163 was characterized by a membranous pattern whereas c-Met immunoreactivity was characterized by membranous and cytoplasmic staining.

Serum free light chain assay

Pretreatment serum samples with normal renal function were assayed to detect κ and &lgr; light chains using human immunoglobulin FLC κ and &lgr; by the ELISA-based method (Biovendor Research and Diagnostic Products, Candler, North Carolina, USA).

The assay separately measures κ FLCs (the normal range is from 0.225 to 3.45 mg/dl) and &lgr; FLCs (the normal range is from 0.45 to 5.42 mg/dl). Elevated sFLC was defined as a κ or a &lgr; above the normal range. In addition, the assay provides sFLC ratio (the normal range is from 0.23 to 1.85).

Statistical analysis

Data were fed to the computer using the IBM SPSS software package version 20.0 (IBM Corporation, Armonk, New York, USA). Qualitative data were described as number and percent. Comparison between different groups of categorical variables was carried out using the χ2-test. When more than 20% of the cells had an expected count less than 5, correction for χ2 was performed using Fisher’s exact test or Monte Carlo correction. The distributions of quantitative variables were tested for normality using the Shapiro–Wilk test and D’Agostino test; also, histogram and QQ plot were used for vision test. If it showed a normal data distribution, parametric tests were used. If the data were abnormally distributed, nonparametric tests were used. Quantitative data were described as mean and SD for normally distributed data whereas abnormally distributed data were expressed using median, minimum, and maximum. For abnormally distributed data, the Mann–Whitney test (for data distribution that was significantly deviated from normal) was used to analyze two independent populations. Significance test results are quoted as two-tailed probabilities. Significance of the obtained results was considered at the 5% level. Informed consents were signed by all participants.

  Results Top

Clinicopathological features of the studied patients

The main clinical and laboratory features at presentation of the study cohort are summarized in [Table 1].
Table 1: The clinical and laboratory characteristics of the studied patients

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CD163 expression and patients’ clinicopathological features

CD163 expression varied widely from 5 to 85%, with a median of 15%. The expression of CD163 was categorized into two groups on the basis of 20% cutoff. Fifteen patients (44%) had CD163 expression of at least 20% and 19 patients (56%) had CD163 expression of less than 20. The pattern of macrophage infiltration was membranous [Figure 1]. The expression of CD163 was higher in mixed cellularity cases than in nodular sclerosis cases (P=0.006)
Figure 1: CD163 expression by immunohistochemistry in classical Hodgkin’s lymphoma tissue (×1000 magnification).

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Correlations between the CD163 expression and the clinicopathological features are listed in [Table 2]. High CD163 expression was associated with increased age (P=0.008), presence of B symptoms (P<0.001), an IPS of at least 3 (P=0.033) and lower CR rates (P=0.005).
Table 2: CD163 expression, c-Met expression, and serum free light chain levels in relation to the clinical and laboratory parameters

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c-Met expression and patients’ clinicopathological features

c-Met expression ranged from 15 to 90%, with a median of 35% [Figure 2]. c-Met was expressed in more than 30% of the tumor cells in 19 of 34 patients (56%). High expression of c-Met was associated with increased age (P=0.015), leukocytosis (P=0.046), presence of B symptoms (P=0.015), and lower CR rates (P=0.012) but was not associated with sex, histological subtype, and other known clinical prognostic factors (bulky disease and IPS≥3) [Table 2].
Figure 2: c-Met expression in classical Hodgkin’s lymphoma tissue (×1000 magnification).

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Serum free light chain results and the clinicopathological features

The median κ and &lgr; FLC levels were 3 mg/dl (range, 1–9 mg/dl) and 2.2 mg/dl (range, 0.6–9 mg/dl), respectively. In 14 patients (41%), serum κ and &lgr; FLC were elevated with normal sFLC ratio. This was associated with increased age (P<0.001), lymphopenia (P=0.023), and IPS of at least 3 (P=0.03), presence of B symptoms (P=0.015), and lower CR rates (P=0.034), but not with other risk factors such as sex, leukocytosis, stage, bulky disease, subtype, and albumin [Table 2].

  Discussion Top

The tumor microenvironment is an important factor in the development and progression of cancer. Recent evidence suggests that the cellular composition of the tumor microenvironment can significantly modify the clinical outcome in hematologic malignancies, particularly follicular lymphoma and cHL 25.

It is now accepted that tumor-associated macrophages (TAM) are major players in the connection between inflammation and cancer through a number of functions (e.g. promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity) that ultimately have a major impact on disease progression 26.

In the present study, TAM comprised 20% or more of Hodgkin’s tissue, as per CD163 positivity, in 44% of our patients, and this was associated with older age at presentation, IPS of at least 3, presence of B symptoms, mixed cellularity subtype, and lower complete response rates. However, the recent study of Azambuja et al. 27 found no associations between clinical characteristics and the expression of CD163. However, in agreement with our work, several published researchers noted the inferior prognosis related to patients with increased TAM.

Steidl et al. 28 reported that the increased number of TAM, as per immunohistochemical positivity for CD68, was correlated with an inferior outcome in cHL patients. Two recent studies reported similar results. Tan et al. 29, in a multicenter study, reported that increased CD163 expression was significantly associated with increased age, mixed cellularity subtype, inferior failure-free survival, and overall survival in locally extensive and advanced-stage cHL. Yoon et al. 24 reported the association between high CD163 indices (≥20%) on one hand and older age, male sex, presence of B symptoms, higher IPS (≥4), lower CR rates, and shorter duration of CR on the other in cHL patients of any stage . Kamper et al. 30 found that, in cHL, a high number of intratumoral CD163+ monocytes/macrophages correlate with an adverse outcome and with clinical parameters reflecting underlying aggressive disease biology.

Lymphoid malignancies, such as multiple myeloma and several B-cell lymphomas, were found to express c-Met, suggesting that c-Met is involved in the pathogenesis of these diseases 31. We found high c-Met expression (positivity in ≥30% of cells in Hodgkin’s tissue) in 56% of our patients and was associated with older age at diagnosis, leukocytosis (≥15 000/µl), presence of B symptoms, and a low chance of achieving CR. The study of Teofili et al. 32 found a similar association and they hypothesized that the HGF/c-Met interaction stimulates cytokine release by c-MET-positive RS cells, leading to some of the disease characteristics, namely the B symptoms. Moreover, c-Met could also play an antiapoptotic role because of its association with the antiapoptotic protein BAG-1and its functional partner of Bcl-2 33.

However, Xu et al. 11 reported that the expression of c-Met in tumor cells from patients with cHL was strongly correlated with higher progression-free survival, whereas the lack of c-Met expression was correlated with a lower progression-free survival in the combined cohort . It is noteworthy that the immunohistochemical reporting of c-Met positivity was limited to RS cells in the study of Xu et al. 11 whereas in our study, it refers to the Hodgkin’s tissue as a whole. We chose this method of evaluation because it is impractical to limit the immunohistochemical evaluation to RS cells, which are infrequent. Moreover, atypical forms of these malignant cells are present in certain subtypes of HL. Furthermore, in the study of Xu et al. 11 the reactive cells in Hodgkin tissue also reacted to c-Met as reported in their photo. Finally, it is known that there is bidirectional cross-talk between the malignant cells and the reactive cells in the Hodgkin tissue; thus, it is not justified to ignore the role of the reactive cells in the tumor behavior. Consequently, it can be hypothesized that this difference in the reporting may explain the discordant results.

Nevertheless, the work of recent studies carried out by Scott et al. 34 and Steidl et al. 35 defies this claim. These two groups of researchers recently published their work on the correlation between gene expression profiling and prognosis in cHL. Scott et al. 34 carried out their research using formalin-fixed paraffin-embedded biopsies, containing the Hodgkin’s tissue, whereas Steidl et al. 35 used microdissected Hodgkin RS cells restricting the sample only to malignant cells. The observed impact of the profiling signature retained its significance in both studies despite the difference in the samples studied.

Moreover, contradicting results on the prognostic impact of c-Met have been reported by many researchers in multiple studies of different tumors. Namely, a favorable prognostic impact of c-Met expression has been shown in the small-scale study on breast cancer by Nakopoulou et al. 36 and in diffuse large B-cell lymphoma by Uddin et al. 37. However, studies of Kawano et al. 12 and Lengyel et al. 38showed opposite effects for both types of tumors.

Lymphoid malignancies often have a polyclonal B-cell infiltrate that can secrete immunoglobulin 39. In the present study, 14 patients (41%) had an elevated sFLC and the elevation was polyclonal. Elevated sFLC levels may reflect an increased polyclonal B-cell activity in the cHL microenvironment. Elevated sFLC levels were correlated with increased age at diagnosis, lymphopenia (<0.6×103/µl), unfavorable IPS (≥3), presence of B symptoms, and lower CR rates but not with other risk factors such as sex, leukocytosis, stage, bulky disease, subtype, and serum albumin level.

In agreement with our results, Thompson et al. 39 have reported elevated sFLC in 30% of their cohort of cHL patients. sFLC elevation was significantly associated with age more than 45 at diagnosis, advanced stage, presence of B symptoms, elevated erythrocyte sedimentation rate, and unfavorable IPS. There was no association of FLC elevation with lymphopenia or bulky disease 39.

However, Rosaria et al. 40 reported that high sFLC levels were correlated with lymphopenia, leukocytosis (WBC>15×103/µl), elevated erythrocytes sedimentation rate (>50 mm/h), and unfavorable IPS (≥3), but not with stage, presence of B symptoms, bulky and extra nodal disease, serum LDH level, serum albumin level, and response rate.

Moreover, Rosaria et al. 41 reported that combining sFLC and interim 2-[18F]fluoro-2-deoxy-D-glucose PET2 can differentiate poor-risk HL patient subsets, who may benefit from upfront treatment escalation or early salvage.

In agreement with our results on response to treatment, Ogura et al. 42 reported that the CR rate after ABVD therapy was 58.2% for III or IV but after radiation therapy, the CR rate increased to78.5%.

To sum up, in advanced cHL, increased TAM correlated with adverse prognostic parameters and inferior response to treatment, reflecting underlying aggressive disease; thus, it might be a reliable marker to assess prognosis. Although c-Met expression correlated with some poor prognostic parameters and affected the response to treatment, published reports have shown contradicting results on c-Met expression. Thus, researchers should carry out further work in order to validate the value of c-Met expression in cHL. Pretreatment elevated sFLC correlated with poor risk factors and can be used as a candidate prognostic marker. A comprehensive approach to define prognostic markers reflecting diverse pathophysiologic concerns might represent a step toward a tailored therapeutic approach best suitable to the individual patient’s needs.[42]

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  [Table 1], [Table 2]


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