Absolute monocyte count predicts overall survival in mantle cell lymphomas: correlation with tumourassociated

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1 Hematological Oncology Hematol Oncol 2014; 32: Published online 29 October 2013 in Wiley Online Library (wileyonlinelibrary.com).2106 Original Research Article Absolute monocyte count predicts overall survival in mantle cell lymphomas: correlation with tumourassociated macrophages Young Wha Koh 1, Su-Jin Shin 2, Chansik Park 2, Dok Hyun Yoon 3, Cheolwon Suh 3 and Jooryung Huh 2 * 1 Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea 2 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea 3 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea *Correspondence to: Jooryung Huh, Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Seoul , Korea. jrhuh@amc.seoul.kr YW Koh and S-J Shin contributed equally to this work. Received: 2 May 2013 Revised: 16 September 2013 Accepted: 17 September 2013 Abstract Mantle cell lymphoma (MCL) is characterized by a variable clinical course in which patients can experience indolent disease or frequent relapses despite a good initial response to conventional therapy. Risk stratification of MCL is most frequently performed using the MCL International Prognostic Index (MIPI). Recent studies indicate that the peripheral blood absolute monocyte count (AMC) and tumour-associated macrophages may reflect the state of the tumour microenvironment in lymphomas. The significance of AMC and tumour-associated macrophages in the clinical course of MCL is unknown. The prognostic impact of the AMC, of CD68 expression and of CD163 expression was retrospectively examined in 103 MCL samples using the receiver operating characteristic curved. Patients with an AMC 375 cells/μl at diagnosis were more likely to present with advanced-stage disease (p = 0.026), leukocytosis (p < 0.001), lymphocytosis (p = 0.01) and granulocytosis (p = 0.003). On univariate analysis, a high AMC ( 375 cells/μl) correlated with poorer overall survival (OS) (p = 0.01). Neither CD68 nor CD163 expression was significantly associated with either OS or event-free survival. Multivariate analysis showed that a high AMC was a prognostic factor for OS, independent of the MIPI [hazards ratio (HR), 1.811; 95% confidence interval, ; p = 0.043]. This study demonstrates that the AMC at the time of diagnosis is an independent prognostic factor for OS in MCL, which suggests the possibility that AMC may be used in addition to the MIPI to predict outcome in patients with MCL. Copyright 2013 John Wiley & Sons, Ltd. Keywords: Mantle cell lymphoma; Monocyte; macrophage; Mantle Cell Lymphoma International Prognostic Index (MIPI); prognosis Introduction Mantle cell lymphoma (MCL) accounts for approximately 7% of all lymphoma subtypes [1,2]. MCL exhibits a shorter median survival than many other lymphomas because patients frequently relapse despite a good initial response to conventional therapy [3,4]. Although most cases of MCL have a dismal prognosis, some MCL cases have an indolent clinical course, and patients may not require therapy for several years after diagnosis [5]. The MCL International Prognostic Index (MIPI) is the most widely used stratification system for survival in patients with MCL [6]. However, previous validation studies have yielded conflicting results [7,8]. Therefore, the predictive impact of the MIPI still needs improvement. Several biologic factors have been proposed as predictors of clinical outcome in MCL patients. However, their prognostic value in patients with MCL has not been conclusively determined. In recent years, the complexity of the interactions between neoplastic tumour cells and their microenvironment has become increasingly recognized. The development and progression of lymphoid neoplasms depend not only on genetic abnormalities in the tumour cells but also on a variety of components in the surrounding tumour microenvironment [9,10]. Several groups have demonstrated that tumour-infiltrating lymphocytes and tumour-associated macrophages (TAMs) are prognostic factors for survival in patients with classical Hodgkin lymphoma [11], diffuse large B-cell lymphoma [12] and follicular lymphoma [13]. Because tissue inflammatory cells originate from the blood and are controlled by common cytokines, the peripheral blood count of these cells may reflect the cytokine and immunological profile of patients with lymphoid neoplasms. Copyright 2013 John Wiley & Sons, Ltd.

2 Absolute monocyte count and survival in mantle cell lymphoma 179 The absolute monocyte count (AMC) has been shown to be a reliable prognostic marker in diffuse large B-cell lymphoma [14], follicular lymphoma [15] and Hodgkin lymphoma [16,17]. However, the prognostic significance of the AMC and TAMs in patients with MCL has not yet been studied. Thus, we investigated whether the AMC and the presence of TAMs at diagnosis is a predictor of survival independent of MIPI in MCL patients. Materials and methods Patients Between 1996 and 2012, 103 patients were diagnosed with MCL at the Asan Medical Center, Seoul, Korea. All patients met the following criteria: pathologically confirmed MCL; no previous treatment; no previous history of malignancy, transplantation or immunosuppression; HIV negativity; prior treatment with combination chemotherapy with or without radiation treatment; and the availability of laboratory data and follow-up information. The AMCs were determined from routine complete blood counts with four-part differential counts (lymphocytes, monocytes, eosinophils and neutrophils) obtained at the time of the diagnosis of MCL using Sysmex automated hematology analyzers (Sysmex Corporation, Kobe, Japan). Models included the Sysmex E-4000, Sysmex SE-9000 and Sysmex XE Response criteria were based on standard guidelines. Routine follow-up imaging analyses were performed every 3 months for the first 2 years, every 6 months for the next 3 years and then annually or whenever clinically indicated thereafter. The study was performed in accordance with the ethical standards of the Declaration of Helsinki and was approved by a suitably constituted Ethics Committee of the Institution Histopathological analysis and immunohistochemistry Histological data from all patients were reviewed independently by three pathologists (J Huh, YW Koh and S-J Shin). A tissue microarray (TMA) was constructed with three tumour cores per patient (each 1 mm in diameter) from selected areas of formalin-fixed, paraffin-embedded tumour samples. The TMA was stained using an automatic immunohistochemistry staining device (Benchmark XT, Ventana Medical System, Tucson, AZ, USA). Briefly, 5 μm sections were transferred onto poly-l-lysine-coated adhesive slides and dried at 62 C for 30 min. After standard heat epitope retrieval for 30 min in ethylenediaminetetraacetic acid (ph 8.0), the samples were incubated with antibodies against cleaved CD68 (1:2000 dilution; DAKO, Glostrup, Denmark), CD163 (1:400 dilution; NOVO, Newcastle, UK) and Sox11 (1:100 dilution; Cell Marque, CA, USA). The sections were then incubated with biotinylated anti-mouse immunoglobulins, peroxidase-conjugated streptavidin (LSAB kit, DAKO, Glostrup, Denmark) and 3,3 -diaminobenzidine. Slides were counterstained with Harris hematoxylin. The Panoramic Viewer v and NuclearQuant application (3DHISTECH, Budapest, Hungary) were used to quantify the immunostained TMAs, as previously described [18]. The core that exhibited the most evenly distributed macrophages was selected from among the three cores for evaluation. The mean cell count per 1 mm 2 core and the mean percent area for CD68 or CD163 staining were then calculated. The average staining intensity of CD68 or CD163 positive cells was scored as 0 (none), 1 (weak), 2 (moderate) or 3 (strong) using the NuclearQuant application. The result was considered positive when the intensity of CD68 or CD163 staining was 2.Various cutoff points for CD68 and CD163 expressions were examined (from the fifth to the 30th percentile, in 5% increments; i.e. 5%, 10%, 15%, 20%, 25% and 30%) (Supplementary Table 1). The most significant difference in overall survival (OS) was observed at a cutoff of 25% for CD68 and 5% for CD163, employing the log-rank test. A sample was considered CD68-positive if 25% of overall cells showed immunohistochemical reactivity with the CD68 antibody (Supplementary Figure 1A). A sample was considered CD163-positive if 5% of overall cells showed immunohistochemical reactivity with the CD163 antibody (Supplementary Figure 1B). Statistical analysis Overall survival was defined as the time between the date of diagnosis and the date of death from any cause. For still-living patients, the OS was considered the time between the diagnosis and the latest follow-up date. Event-free survival (EFS) was defined as the interval between the date of diagnosis and the date of disease progression, relapse or death from any cause. For patients who did not experience disease progression or relapse, the time between the diagnosis and the latest follow-up date was used as the EFS. The OS and EFS were analysed with Kaplan-Meier curves, which were compared by logrank testing. The median follow-up with its 95% confidence interval was calculated using the reverse Kaplan- Meier method [19]. Multivariate prognostic analyses were performed on OS and EFS data with the Cox proportional hazards regression model. Receiver operating characteristic curve analysis was used to determine the optimal cutoff values of AMC corresponded with the maximum joint sensitivity and specificity. The binary clinical outcome (death/survival) was determined at 5 years after diagnosis. Patients were categorized as alive/censored when followup time was longer than 5 years and death for patients recognized to have died before this time point. The area

3 180 Y W Koh et al. under the curve was recorded as (95% confidence interval, ) for the AMC (Supplementary Figure 2). The AMC value of 375 corresponded to the maximum joint sensitivity and specificity on the receiver operating characteristic curve (78% sensitivity and 57% specificity). Continuous variables were compared using the Mann Whitney U-test, and Spearman correlation coefficients were used to evaluate associations for continuous variables. All statistical analyses were performed using the SPSS statistical software programme (Version 18.0; SPSS, Chicago, IL) or R Results were considered statistically significant when the p-value was less than Results Patient characteristics The clinical characteristics of the 103 patients in the present study are summarized in Table 1. The median follow-up after diagnosis was 84 months (range, months]. Eighty-two patients experienced disease progression, relapse or death. The median time to disease progression, relapse or death was 20 months (range, months). The estimated 5 year Table 1. Patient demographics and clinical characteristics Parameter Quantity n Age 60, no. (%) 63 (61.2) 103 Sex, no. male (%) 81 (78.6) 103 ECOG 2, no. (%) 16 (15.5) 103 Stage IV, no. (%) 66 (64.1) 103 B symptoms present, no. (%) 35 (34) 103 Bone marrow involvement 48 (46.6) 103 present, no. (%) Spleen involvement present, 36 (35.3) 102 no. (%) Extranodal sites > 1, no. (%) 49 (47.6) 103 No. involved nodal 60 (58.3) 103 areas > 4, (%) Median WBC count, 6.9 ( ) /L (range) Median lymphocyte count, 2.07 ( ) /L (range) Median granulocyte count, 3.54 ( ) /L (range) Median monocyte count, 0.5 ( ) /L (range) Median platelet count, 204 (33 417) /L (range) LDH, U/L 250 (%) 55 (53.9) 102 Haemoglobin, g/dl 12 (%) 59 (57.3) 103 Albumin, g/dl 4 (%) 39 (37.9) 103 β2-microglobulin, g/dl 2.4 (%) 33 (68.8) 48 R-CHOP chemotherapy, no. (%) 41 (39.8) 103 Radiation therapy, no. (%) 13 (12.6) 103 ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; R-CHOP, rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone. EFS and OS were 17.2% and 39.8%, respectively. At diagnosis, the median AMC was 450 cells/μl (range, ). Correlations among CD68 expression, CD163 expression, the AMC and clinicopathological variables To evaluate the relevance of the AMC at diagnosis in MCL patients, the patients were divided into two groups according to the AMC at diagnosis an AMC < 375 cells/μl (41 patients; 39.8%), or an AMC 375 cells/μl (62 patients; 60.2%) (Supplementary Table 2). Patients with an AMC 375 cells/μl at diagnosis were more likely to present with advanced-stage disease (p = 0.026), leukocytosis (p < 0.001), lymphocytosis (p = 0.01) and granulocytosis (p = 0.003). Patients with the highest CD68 expression ( 25% CD68 + cells; n = 16) had a greater area of nodal involvement (p = 0.041), a lower level of haemoglobin (p = 0.04) and were more likely to have received R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulphate and prednisone) (p = 0.022), than patients with low CD68 expression (<25% CD68 + cells; n =61) (Supplementary Table 2). Patients with higher CD163 expression ( 5% CD163 + cells; n = 11) were more likely to have bone marrow involvement (p = 0.021) than patients with low CD163 expression (<5% CD163 + cells; n = 62) (Supplementary Table 2). A correlation study was performed examining the relationship between CD68 expression, CD163 expression and the AMC. There was a weak positive correlation between the AMC and the CD163 index in MCL tissues by Spearman correlation regression analysis (rho = 0.233, p = 0.047, Figure 1A). No correlation between the AMC and the CD68 index was identified by Spearman correlation regression analysis (p = 0.322, Figure 1B). Prognostic significance of CD68 expression, CD163 expression and the AMC Patients with an AMC 375 cells/μl had a lower OS than those with an AMC < 375 cells/μl (5 year OS of 25% versus 63.9%; p = 0.01, Figure 2A), but did not differ significantly in terms of EFS (p = 0.216, Figure 2B). When AMC was evaluated as a continuous variable by univariate Cox analysis, it correlated with OS (p = 0.043) but not EFS (p = 0.208). CD68 expression was not significantly associated with either OS or EFS (p = 0.312, Figure 2C and p = 0.339, Figure 2D, respectively). CD163 expression was also not significantly associated with either OS or EFS (p = 0.368, Figure 2E and p = 0.898, Figure 2 F, respectively).

4 Absolute monocyte count and survival in mantle cell lymphoma 181 the MIPI showed that an AMC 375 cells/μl was an independent prognostic marker (p = 0.043) (Table 2). Patients with a high-risk MIPI ( 6.2) had a lower 5 year OS rate (p < 0.001, Figure 3A) and a lower 5 year EFS rate (p = 0.006, Figure 3B) than patients with intermediate or low-risk MIPIs. Because AMC and MIPI were confirmed as independent prognostic markers, we next determined whether they yielded additional prognostic value when combined. To evaluate the prognostic impact of the MIPI, the patients were divided into two groups: low-risk or intermediate-risk patients, with a MIPI < 6.2; and high-risk patients, with a MIPI 6.2. For low-risk or intermediaterisk MIPI cases, patients with an AMC 375 cells/μl tended to have worse OS than those with an AMC < 375 cells/μl, although statistical significance was not reached (p = 0.053, Figure 3C). For high-risk MIPI patients, those with an AMC 375 cells/μl had a worse OS than those with an AMC < 375 cells/μl (p = 0.005, Figure 3D). When the analysis was conducted for patients who received R-CHOP, those with an AMC 375 cells/μl had worse OS than patients with an AMC < 375 cells/μl (p = 0.012, Figure 4A). In patients who received CHOP alone, those with an AMC 375 cells/μl also had worse OS than patients with an AMC < 375 cells/μl (p = 0.045, Figure 4B). Discussion Figure 1. Spearman correlations among the CD68 expression, CD163 expression and absolute monocyte count (AMC). (A) A positive correlation was found between the CD163 staining index and the AMC (rho = 0.233, p = 0.047). (B) No correlation was found between the CD68 staining index and the AMC Additionally, we performed survival analyses for CD68 and CD163 expressions according to three subgroups: <5% + cells, score 1; 5 25% + cells, score 2; >25% + cells, score 3. However, there was no statistical significance among scores1 3 (data not shown) Univariate analysis revealed that OS was significantly associated with hypoalbuminemia, anaemia, a high stage, a high Eastern Cooperative Oncology Group (ECOG) grade, a large number of involved nodal sites, a large number of extranodal sites and a high MIPI (Table 2). Multivariate analysis adjusting for all of these factors and This study has several novel and important aspects. Firstly, it is the first study to demonstrate the prognostic value of AMC in patients with MCL, independently of MIPI. Secondly, it suggests the possibility that the AMC may provide additional prognostic information when used in conjunction with the MIPI, although statistical significance was not reached. Thirdly, it shows that AMC could predict survival in patients who receive R-CHOP or CHOP. Obtaining the AMC from a complete blood count at diagnosis is simple, widely available and can be used in clinical practice, especially in resource-poor areas. The limitations of this study include the retrospective nature of the study design, the short follow-up period and the relatively small sample size of the test participants. Myeloid-lineage cells may promote tumourigenesis through immunosuppression and enhancement of tumour angiogenesis, which is required for tumour growth and progression [20]. Previous studies have shown that both peripheral blood monocytes and their progeny within the tumour microenvironment inducibly express the T-cell co-inhibitory ligand B7-H1 (PD-L1) [21]. B7-H1 expression directly inhibits the expansion and effector functions of tumour-specific T-cells, and, when expressed by myeloidlineage cells within the tumour microenvironment, induces the expansion of suppressive regulatory T-cells [21]. It is well known that TAMs are a source of vascular endothelial growth

5 182 Y W Koh et al. Figure 2. Comparison of survival rates according to the absolute monocyte count (AMC). Overall survival (OS) (A) was significantly worse in patients with an AMC of 375 cells/μl than in those with an AMC of < 375 cells/μl. The difference in event-free survival (EFS) (B) between patients with an AMC of 375 cells/μl and those with an AMC of 375 cells/μl was not statistically significant. The CD68 staining index was not significantly associated with either OS (C) or EFS (D). The CD163 index was not significantly associated with either OS (E) or EFS (F) factor-a, which promotes tumour angiogenesis [20]. A subset of monocytes expresses the angiopoietin-2 receptor Tie2, which is required for vascularization [22]. The CD163 staining index weakly correlated with the AMC, but the CD68 staining index did not. CD163 may be a superior marker for TAMs because it is more specific for the monocyte macrophage lineage than CD68 [23]. In our study, AMC correlated with OS, but CD68 and CD163 expressions were not associated with EFS or OS. The reason for this discrepancy is not clear, but several

6 Absolute monocyte count and survival in mantle cell lymphoma 183 Table 2. Univariate and multivariate analyses for EFS and OS Univariate analysis covariate EFS OS HR 95% CI p-value HR 95% CI p-value AMC (continuous variable) AMC <375 cells/μl versus 375 cells/μl CD68 expression Low versus high CD163 expression Low versus high Sox11 expression ( ) versus (+) B symptoms ( ) versus (+) LDH <250 versus Albumin 4 g/dl versus <4 g/dl b2-microglobulin 2.4 g/dl versus >2.4 g/dl Haemoglobin 12 g/dl versus <12 g/dl < Sex female versus male Stage 1 3 versus ECOG <2 versus Bone marrow involvement ( ) versus (+) Spleen involvement ( ) versus (+) Extranodalsites involvement <2 versus No. of involved nodal areas <5 versus Treatment plan Chemotherapy only versus chemoradiotherapy Chemotherapic regimen non-r-chop versus R-CHOP MIPI low-risk (reference) 1 1 intermediate-risk high-risk < Multivariate analysis covariate EFS OS HR 95% CI p-value HR 95% CI p-value AMC <375 cells/μl versus 375 cells/μl Albumin 4 g/dl versus <4 g/dl Haemoglobin 12 g/dl versus <12 g/dl Stage 1 3 versus Extranodal sites <2 versus No. of involved nodal areas <5 versus MIPI low-risk (reference) 1 1 intermediate-risk high-risk Cox univariate analysis. AMC, absolute monocyte count; ALC, absolute lymphocyte count; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; LDH, lactate dehydrogenase; MIPI, Mantle Cell Lymphoma International Prognostic Index; R-CHOP, rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone.

7 184 Y W Koh et al. Figure 3. Comparison of survival rates according to the Mantle Cell Lymphoma International Prognostic Index (MIPI). Overall survival (OS) (A) and event-free survival (B) were significantly worse in the high-risk MIPI ( 6.2) group. Comparison of survival rates according to the AMC in low-risk to intermediate-risk or high-risk MIPI groups. For cases classified as low or intermediate risk by the MIPI, patients with an AMC of 375 cells/μl tended to have worse OS (C) than those with an AMC of < 375 cells/μl, although statistical significance was not reached. For patients classified as high risk by the MIPI, patients with an AMC of 375 cells/μl had a worse OS (D) than those with an AMC of < 375 cells/μl Figure 4. Comparison of survival rates according to the absolute monocyte count (AMC) in patients who received rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone (R-CHOP) or CHOP. In the R-CHOP group, overall survival (A) was significantly worse in patients with an AMC of 375 cells/μl. In the CHOP group, overall survival (B) was also significantly worse in patients with an AMC of 375 cells/μl

8 Absolute monocyte count and survival in mantle cell lymphoma 185 explanations are possible. Firstly, the heterogeneity of TAMs expression, with regional variations in histological sections, may be responsible for this difference [24]. Moreover, the TMA design of the study cannot reflect the distribution of TAM throughout the entire tissue sample. Secondly, monocytes can be an important source of soluble mediators such as B lymphocyte stimulator, which support the growth and survival of both normal and malignant B cells independently of differentiation toward macrophages. A previous study also reported that the monocyte-derived survival factor CD14 may support the survival of B-cell non-hodgkin lymphoma [25]. In the present study, an AMC 375 cells/μl was not significantly associated with shortened EFS. The reason for this is unknown. A possible explanation could be that patients with an AMC 375 cells/μl are more difficult to salvage after treatment failure or relapse; only 21 of 30 patients with an AMC < 375 cells/μl (70%) died after treatment failure or relapse, compared with 45 of 52 patients (86.5%) with an AMC 375 cells/μl. This indicates that cases with an AMC 375 cells/μl may be more resistant to salvage treatment. Previous studies also have found that monocytes may confer resistance to chemotherapeutic agents in non-hodgkin lymphoma [26]. Probably, the most common chemotherapy regimens in the past had been anthracycline-based therapies such as CHOP[27]. Recently, rituximab has been added to CHOP. The first reported study of R-CHOP in MCL reported that 36% of the patients achieved a molecular complete response; however, there was no significant difference in the median progression-free survival between the patients who achieved a molecular complete response (16.5 months) and those who did not (18.8 months)[28]. In a randomized clinical trial, frontline R-CHOP treatment improved overall response and complete response rate; however, there was no significant improvement in progression-free survival or OS [29]. In the present cohort, there was no significant difference in survival between R-CHOP-treated group and CHOP alone group. Patients with high AMC showed a worse OS in both R-CHOP and CHOP alone groups. In this study, patients with a high AMC tended to have worse OS than those with a low AMC when the AMC was used in conjunction with the MIPI, although this did not reach statistical significance because of the small sample size. Therefore, it is necessary to validate this result in a larger cohort of uniformly treated patients and to test the validity of this finding in a prospective study. In conclusion, the present results suggest that the AMC can be used to determine prognosis in MCL. This supports the possibility that the tumour microenvironment is of prognostic relevance with regard to clinical outcome in MCL. Moreover, the AMC may provide additional prognostic information independently of the MIPI. Conflict of interest The authors indicated no potential conflicts of interest. Acknowledgement This study was supported by a grant ( ) from the Asan Institute for Life Sciences, Seoul, Korea. References 1. Sant M, Allemani C, De Angelis R, et al. Influence of morphology on survival for non-hodgkin lymphoma in Europe and the United States. Eur J Cancer 2008; 44(4): Devesa SS, Fears T. Non-Hodgkin s lymphoma time trends: United States and international data. Cancer Res 1992; 52(19 Suppl): 5432s 5440s. 3. Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 2009; 27(4): Hiddemann W, Unterhalt M, Herrmann R, et al. Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol 1998; 16(5): Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 2009; 27(8): Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 2008; 111(2): Geisler CH, Kolstad A, Laurell A, et al. The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT). Blood 2010; 115(8): Shah JJ, Fayad L, Romaguera J. Mantle cell International Prognostic Index (MIPI) not prognostic after R-hyper-CVAD. Blood 2008; 112(6): 2583; author reply Mantovani A, Schioppa T, Porta C, et al. Sica A. Role of tumorassociated macrophages in tumor progression and invasion. Cancer Metastasis Rev 2006; 25(3): Murdoch C, Muthana M, Coffelt SB, et al. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008; 8(8): Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin s lymphoma. N Engl J Med 2010; 362(10): Wada N, Zaki MA, Hori Y, et al. Tumour-associated macrophages in diffuse large B-cell lymphoma a study of the Osaka Lymphoma Study Group. Histopathology 2012; 60(2): Farinha P, Masoudi H, Skinnider BF, et al. Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 2005; 106(6): Wilcox RA, Ristow K, Habermann TM, et al. The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high-risk patients in diffuse large-b-cell lymphoma. Leukemia 2011; 25(9): Wilcox RA, Ristow K, Habermann TM, et al. The absolute monocyte count is associated with overall survival in patients newly diagnosed with follicular lymphoma. Leuk Lymphoma 2012; 53(4):

9 186 Y W Koh et al. 16. Porrata LF, Ristow K, Colgan JP, et al. Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in classical Hodgkin s lymphoma. Haematologica 2012; 97(2): Koh YW, Kang HJ, Park C, et al. The ratio of the absolute lymphocyte count to the absolute monocyte count is associated with prognosis in Hodgkin s lymphoma: correlation with tumorassociated macrophages. Oncologist 2012; 17(6): Krecsak L, Micsik T, Kiszler G, et al. Technical note on the validation of a semi-automated image analysis software application for estrogen and progesterone receptor detection in breast cancer. Diagn Pathol 2011; 6: Clark TG, Bradburn MJ, Love SB, Altman DG. Survival analysis part I: basic concepts and first analyses. Br J Cancer 2003; 89(2): Tsutsumi C, Sonoda KH, Egashira K, et al. The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization. J Leukoc Biol 2003; 74(1): Wilcox RA, Feldman AL, Wada DA, et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood 2009a; 114(10): Venneri MA, De Palma M, Ponzoni M, et al. Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 2007; 109(12): Lau SK, Chu PG, Weiss LM. CD163 a specific marker of macrophages in paraffin-embedded tissue samples. Am J Clin Pathol 2004; 122(5): Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5(12): Seiffert M, Schulz A, Ohl S, et al. Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells in vitro and present at abnormally high levels in vivo. Blood 2010; 116(20): Wilcox RA, Wada DA, Ziesmer SC, et al. Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells. Blood 2009b; 114(14): Weisenburger DD, Vose JM, Greiner TC, et al. Mantle cell lymphoma. A clinicopathologic study of 68 cases from the Nebraska Lymphoma Study Group. Am J Hematol 2000; 64(3): Howard OM, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol 2002; 20(5): Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005; 23(9): Supporting information Additional supporting information may be found in the online version of this article at the publisher s website. Supplementary Figure 1. CD68 and CD163 expression in mantle cell lymphoma tissues. (A) CD68 expression on background-reactive cells. (B) CD163 expression on background-reactive cells. Supplementary Figure 2. Receiver operating characteristic (ROC) and area under the curve (AUC) for absolute monocyte count at diagnosis(amc)

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