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Serum levels of interleukins 6, 10, and 13 before and after treatment of classic Hodgkin lymphoma.

Multiagent chemotherapy is the standard treatment for Hodgkin lymphoma (HL), and it usually provides high cure rates. However, in some cases, especially in patients with an advanced disease, the disease progresses during treatment or the patient relapses after complete remission. (1-6) The identification of patients who would benefit from more- or less-aggressive therapeutic approaches is important, and several investigators have attempted to identify clinical and laboratory markers that predict unfavorable outcomes from HL.

In this setting, 3 large, cooperative groups have independently developed prognostic scoring systems for early Ann Arbor stages of HL using clinical and biologic parameters. (7-9) The German Hodgkin Study Group has developed an international prognostic score for advanced stages of the disease, based on 7 adverse laboratorial and clinical parameters. (10) Although these prognostic models are useful for identifying better responses to standard therapy, they are of limited use in recognizing patients with a high risk of treatment failure. Indeed, none of the models provide enough information to support changes in the standard treatment that would improve the outcome of HL, even in the early stage of the disease. (11,12) In addition, most of the proposed models do not account for important biologic features of HL, notably changes in the immune system during the course of the disease.

It is well established that patients with HL have a defect in the cell-mediated immune response, and that defect may be attributable to cytokines produced by Hodgkin and Reed-Sternberg (H-RS) cells and by reactive inflammatory cells. (13-15) Indeed, cytokines are important in the pathogenesis of classic HL (cHL). (16-20) Most cHL cases are characterized by an unbalanced production of [T.sub.H2] cytokines. (15,21-29)

Interleukins (ILs) 6, 10, and 13 are among the cytokines commonly detected in patients with HL. In addition, these cytokines and their respective receptors have been reported to be expressed in H-RS cells. (13,26,30-32) Interleukin 6 is an important immunomodulatory cytokine that can induce growth and maturation of B and T cells (33,34 ) and acts as a growth factor for B cells, including those transformed by the Epstein-Barr virus (EBV). (35) Elevated IL-6 levels in the serum of patients with HL have been associated with poor prognosis because of lower rates of complete remission. (23,27) Interleukin 10 is a cytokine with strong anti-inflammatory properties. (13) It supports the growth and differentiation of B cells and inhibits apoptosis of B and T cells induced by glucocorticoids and chemotherapy. (36) Elevated serum levels of IL-10 have been associated with poor outcomes in HL. (23,37-39) Interleukin 13 regulates the humoral response by driving the proliferation and survival of B cells and triggering immunoglobulin class switching. It has been suggested that IL-13 acts as an autocrine growth factor for the neoplastic cells in HL. (24,40-42)

Although the literature suggests that IL-6, IL-10, and IL-13 are important in the pathogenesis of cHL, few studies have analyzed these cytokines for the clinical and prognostic information they may provide about the disease. (24-28,39,43) In addition, insufficient data are available on the levels of these cytokines before and after antineoplastic treatment. (26) Therefore, the present study aimed to evaluate IL-6, IL-10, and IL-13 serum levels before and after cHL treatment and to investigate the possible associations with clinicopathologic parameters and response to treatment.

MATERIALS AND METHODS

Patients

Twenty-seven patients were selected for this study. They were all negative for human immunodeficiency virus, and their diagnosis of cHL was confirmed by histopathology and immunophenotyping. None of them had previously undergone cytotoxic or radiation treatments. Patients were treated between 2005 and 2008 at Botucatu Medical School, Sao Paulo State University, and Amaral Carvalho Hospital, both in Sao Paulo State, Brazil. Serum samples were collected at the initial medical visit on diagnosis of HL and again 1 month after the end of chemotherapy. In addition, serum samples from 26 healthy, blood donor volunteers were collected and evaluated as a non-HL control group. All samples were stored at -80[degrees]C until evaluation. The study was approved by the Research Ethics Committee of both institutions from which subjects originated, and informed consent was obtained from all participants, in agreement with institutional guidelines. All study procedures were in accordance with the Helsinki Declaration of 1975.

Disease Staging and Laboratory Evaluation

All patients had their disease stage determined clinically according to the Ann Arbor system. (44) Each patient underwent a complete medical history interview and physical examination and had blood cell counts; biochemical profiles; computed tomographies of the chest, abdomen, and pelvis; bone marrow biopsy and aspiration. The presence of B symptoms was characterized by one or more of the following symptoms: unexplained fever of 38[degrees]C or higher, drenching night sweats, or unexplained loss of more than 10% of body weight in the preceding 6 months. Bulky disease was defined as the presence of a nodal mass greater than 10 cm in diameter. Hemoglobin, white blood cell counts, serum albumin, erythrocyte sedimentation rate, and serum lactate dehydrogenase were measured by standard assays. Anemia was defined as a hemoglobin level of less than 12 g/dL. In both institutions, the lower reference range cutoff for albumin was 3.5 g/dL. Serum [beta]2 microglobulin was measured by radioimmunoassay, and its upper reference range cutoff was 3.5 mg/dL. All patients with advanced HL were categorized according to their international prognostic score. (10)

Immunohistochemistry and EBV Status

Immunohistochemical staining was performed on histologic sections of paraffin-embedded tumor biopsies. The sections were stained with the monoclonal antibodies anti-CD43 (DF-T1 clone, 1:150), anti-CD45 (2B11 + PD7/26 clone, 1:200), anti-CD20 (L26 clone, 1:200), anti-CD30 (Ber-H2 clone, 1:40), anti-CD15 (C3D-1 clone, 1:150), and the polyclonal anti-CD3 (1:150) antibody, all from DakoCytomation (Carpinteria, California). All cases were reviewed by an experienced hematopathologist. Epstein-Barr virus infection was assessed by in situ hybridization with a biotinylated probe against EBV-encoded RNA 1, as previously described. (45) Validated EBV-positive Burkitt lymphoma biopsies were used as positive controls for EBV assessment, using EBV-encoded RNA 1 in situ hybridization.

Determination of IL Serum Levels

The levels of IL-6, IL-10, and IL-13 were determined in serum of patients and controls. Samples were stored frozen in small aliquots (500 [micro].L) and thawed only once. Quantification of cytokines was performed using the following commercially available, sandwich enzyme-linked immunosorbent assays (ELISA), according to manufacturer instructions: human IL-13 Quantikine (R&D Systems, Inc, Minneapolis, Minnesota) and human IL-6 ELISA MAX and human IL-10 ELISA MAX (BioLegend, Inc, San Diego, California). Each serum sample was assayed twice, and cytokine levels were determined with the Bio-Rad microplate reader model 680 (Bio-Rad Laboratories Inc, Hercules, California) set at a wavelength of 450 nm, with (IL-13) or without (IL-6 and IL-10) corrections at 570 nm. According to the information provided by the manufacturer of the ELISA kits, the lower detection limits for IL-6, IL-10, and IL-13 were 4 pg/ mL, 2 pg/mL, and 32 pg/mL, respectively.

HL Treatment

Treatment of patients with HL was based on adriamycin, bleomycin, vinblastine, and dacarbazine or on bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone regimens. Involved-field radiation therapy was considered consolidation treatment for patients in early and intermediate stages or for those presenting with bulky disease. Complete remission was defined as absence of the disease for at least 1 month, as assessed by physical examination and appropriate laboratory and imaging studies. Partial remission was defined as more than 50% reduction of tumor mass measurable in 2 dimensions. Progressive disease was defined as enlargement (>25%) of a tumor at preexisting disease site or development of disease at a previously uninvolved site. Primary treatment failure was defined as progressive disease during initial treatment, failure to achieve complete remission or partial remission after initial therapy, or progressive disease within 5 months after complete remission.

Statistical Analysis

Data were grouped as medians and lower and upper quartiles. Categorical variables were compared by the [chi square] test and continuous variables by the Mann-Whitney U test or a 1-way analysis of variance. The Wilcoxon test was used to compare serum levels of both IL-6 and IL-10 before and after treatment. The Spearman rank correlation test was conducted to assess correlations between serum levels of the studied ILs and the storage time of the serum samples to investigate any detrimental effect of this parameter on the cytokines levels detected by the ELISA.

Clinical and laboratory data were used in 2 models of multiple linear regression to predict serum levels of IL-6 and IL-10. Before performing the statistical tests, values for cytokine levels were transformed to their Naperian logarithms to normalize their distribution. Collinearity among variables was tested using the [chi square] test. The models were checked for linearity, independence, and normality. All statistical calculations were performed with the SigmaStat 3.5 Software (Systat Software Inc, San Jose, California), and P values were considered significant if lower than .05.

RESULTS

Serum IL-6 levels in the blood donor (control) group ranged from less than 4 pg/mL to 20.2 pg/mL (median, <4 pg/mL), and serum IL-10 levels from less than 2 pg/ mL to 50.1 pg/mL (median, <2 pg/mL). Serum IL-13 levels were always less than the detection limit of the assay (<32 pg/mL). Eighteen out of 26 controls (69%) had serum IL-6 levels less than the assay detection limit (<4 pg/mL), whereas the levels of 19 controls (73%) were less than the detection limit for IL-10 (<2 pg/mL).

[FIGURE 1 OMITTED]

Age and sex distributions were similar between patients with HL and control volunteers. During the follow-up (median, 29 months), 25 of the 27 patients (93%) survived. Five patients (19%) failed to respond to treatment: 4 of the 5 patients (80%) responded only partially to chemotherapy, and 1 of the 5 patients (20%) presented with disease progression 4 months after complete remission. Among the 5 patients, 2 patients (40%) had advanced-stage disease. Deaths were due to disease progression in 2 of the 5 patients (40%) in the treatment-failure group.

The median value for the IL-6 serum levels at diagnosis was 20.7 pg/mL (range, <4-434.2 pg/mL). Only 5 patients (19%) had serum IL-6 levels less than the detection limit of the assay. In the case of IL-10, the median value of the pretreatment serum levels was 14.6 pg/mL (range, <2-250 pg/mL), and only 4 patients (15%) had serum levels less than the assay detection limit. For both IL-6 and IL-10, the serum levels of the cytokines were significantly higher in patients with HL before treatment compared with volunteers in the control group (P < .001). After treatment, the median serum IL-6 level was less than 4 pg/mL in patients with HL--significantly less than their pretreatment median (P < .001). The same was observed for IL-10 (median, 4.6 pg/mL after treatment; P < .001). Before and after treatment, all patients with HL had serum IL-13 levels less than the assay detection limit.

The median time samples that were stored before ELISA experiments were conducted was 18.6 months for IL-6 (range, 4.4-40.7 months), 18.8 months for IL-10 (range, 13.3-30.5 months), and 18.6 months for IL-13 (range, 13.2-30.3 months). The storage duration had no influence on the levels of cytokines detected (IL-6, R = -0.15, P = .44; IL-10, R = -0.15, P = .46).

Association of Serum ILs and Disease Features

When analyzed as continuous variables, serum IL-6 levels before treatment were higher in patients with abdominal HL involvement, hepatomegaly, B symptoms, and anemia (Figure 1). Serum IL-6 was also compared with age and gender, Ann Arbor stage, mediastinal involvement, splenomegaly, extranodal disease, bone marrow involvement, bulky disease, leukocytosis, lymphocytopenia, albumin serum levels, lactate dehydrogenase, serum [beta]2 microglobulin, EBV-encoded RNA 1, HL histologic subtype, CD15 and CD20 positivity and response to treatment, but no association was found (Table 1). Higher pretreatment levels of IL-6 were observed in patients with treatment failure (P = .03), independent of the initial response. Otherwise no association was observed between the posttreatment levels of IL-6 and treatment response or treatment failure. The 2 patients who died from disease progression presented with significantly higher posttreatment levels of IL-6 (P = .02).

Serum IL-10 levels were higher in patients with low serum albumin. In addition, patients with advanced Ann Arbor stage, abdominal involvement, hepatomegaly, B symptoms, and anemia also tended to present with higher IL-10 levels (Figure 2). There was no association between IL-10 levels and the remaining aforementioned variables. In advanced HL, no association was found between serum IL-6 or IL-10 and the prognostic categories defined by international prognostic score.

Multiple linear regression was performed for Ann Arbor stage, mediastinal involvement, bulky disease, hepatomegaly, bone marrow infiltration, B symptoms, leukocytosis, and lymphocytopenia, all well-known clinical parameters in cHL. Gender and age were included, independent of association with IL-6 or IL-10 levels, because they are also relevant prognostic parameters for HL. Abdominal involvement, splenomegaly, extranodal disease, and anemia were excluded from the model because of collinearity. Serum [beta]2 microglobulin, lactate dehydrogenase, serum albumin, and EBV-encoded RNA 1 were not included because data on these parameters were not available for some patients. B symptoms and lymphocytopenia were identified as potent predictors of serum IL-6 levels before treatment, as shown in Table 2. Although hepatomegaly was found to be associated with high IL-10 levels (P = .01), none of the variables evaluated could predict the serum levels of this cytokine.

COMMENT

Classic HL is characterized by well-defined histologic features, notably H-RS cells surrounded by heterogeneous and abundant inflammatory infiltrates, which provide a favorable microenvironment for H-RS cell proliferation and survival. A complex signaling network, shaped by cytokines, chemokines, and cell-cell interactions, seems to be crucial for the development and progression of HL tumors. (16,46) Several aspects of the cytokines that contribute to HL pathogenesis provide a better understanding of immune dysfunction and the symptomatology associated with this disease. (13,14,16,17) Nevertheless, the exact role of cytokines in the cause-effect relationship between H-RS cells and the microenvironment remains to be properly elucidated.

In the present study, serum levels of IL-6 and IL-10 were frequently elevated in patients with cHL at diagnosis, when compared with the levels in healthy, volunteer blood donors, and after treatment, those levels decreased substantially. Interleukin 13, however, was always undetectable in serum. Serum IL-6 and IL-10 were associated with some clinical and laboratory features of HL. Remarkably, in the patients with HL evaluated in this study, the level of serum IL-6 could be predicted by the presence of B symptoms (high levels) and lymphocytopenia (low levels).

[FIGURE 2 OMITTED]

Besides its activity as an activator of acute phase response and as a stimulatory factor for growth and proliferation of lymphocytes, IL-6 has important roles documented in both innate immunity and in the development of acquired immune response. (47,48) In inflammation, IL-6 acts as a regulator of the transition between humoral and cellular responses, which may explain some features of HL pathobiology and its clinical manifestations.

Clinical and laboratory correlates of IL-6 levels in HL have been previously studied in both untreated and relapsed patients, with some controversial results. (19,22,25,49) In agreement with previously reported data, the present study verified an association between higher IL-6 serum levels before treatment and the presence of B symptoms. (25,26) Additionally, patients with higher IL-6 levels more often presented with hepatomegaly, abdominal disease, and anemia. On the other hand, we found no association with gender, Ann Arbor stage, or bulky disease.

Interleukin 6 is known to be important in the pathophysiology of cancer-induced cachexia because of its catabolic properties. (34,50,51) Other systemic changes that might be associated with elevated IL-6 levels include the fever, night sweats, and weight loss observed in patients with HL, which are relevant for HL diagnosis and treatment design. To date, the predominant source of IL-6 in patients with HL and its activity in the tumoral microenvironment remain elusive. Of note, it has been reported that reactive inflammatory cells, especially T lymphocytes, adjacent to H-RS cells may stimulate the growth of H-RS cells both by direct production of IL-6 and by stimulation from secreted IL-6 producing other stimulatory cytokines. (30)

Interestingly, lower serum IL-6 levels in the present study were predicted by lymphocytopenia, which has previously been reported, likewise B symptoms, as an adverse prognostic factor associated with advanced. (18) One possible explanation for this phenomenon is that the low lymphocyte count might reflect a histologic change in HL toward a pattern with more proliferation of H-RS cells, rather than a pattern of reactive inflammatory cell stimulation. Taken together, these data suggest that a subset of HL may exhibit a less-prominent inflammatory component, along with a higher number of H-RS cells, and consequentially, a worsening evolution of the disease.

As a prognostic biomarker, IL-6 has been associated with lower survival rates in pretreated and refractory patients,25 and IL-6 immunoexpression in HL biopsies has beencorrelated with decreased complete response. (22) In the present study, an association between higher pretreatment serum levels of IL-6 in newly diagnosed patients with HL was observed, as well as an increased likelihood of treatment failure. These data strengthen the idea that IL-6 may have a relevant role as a biomarker of treatment response and outcome in HL.

Higher IL-10 serum levels before treatment of HL, however, were associated with low serum albumin and hepatomegaly and were also associated with advanced Ann Arbor stages, abdominal involvement, B symptoms, and anemia, which is in agreement with what has been found in previous studies. (23,27) However, the previously reported association between high IL-10 levels and EBV infection status was not observed in this study. Herling et al (2003) reported that higher serum IL-10 levels before treatment were associated with EBV LMP-1 immunostaining, mainly in the mixed-cellularity cHL subtype. (28) One limitation of the present study is that the EBV status could not be assessed for all patients, and the lack of association between IL-10 levels and EBV infection might be due to the limited number of patients with EBV-positive HL, or even the low number of HL cases evaluated.

For all subjects evaluated, serum IL-13 levels were systematically undetectable. Similarly, a low frequency of detectable levels of this cytokine and no association with clinical features of HL were previously described. (52) Interestingly, several studies have suggested a key role of IL-13 as an autocrine growth factor in HL, (13,24,40,41) and IL-13 mRNA is frequently expressed in the tumors, almost exclusively by H-RS cells. (40) The IL-13 receptor transcripts are expressed not only by H-RS cells but also by a large proportion of other cells within the reactive infiltrate, including fibroblasts. (41) These data suggest that IL-13 may also support the maintenance of the reactive infiltrate in HL. In addition, treatment of an HL-derived cell line with an antibody that neutralizes IL-13 resulted in a dose-dependent inhibition of H-RS proliferation. (40-42) The accumulating evidence indicates that coexpression of IL-13 and its receptor is a common feature of H-RS cells that boost IL-13 activity as an autocrine growth factor in HL. Although the lack of detectable serum IL-13 does not refute this hypothesis, it suggests that IL-13 might act predominantly at the tumor microenvironment level, possibly at very low concentrations and with a short range of action.

To the best of our knowledge, serum IL-6 levels after HL treatment had been evaluated previously in only one study, (26) and there is no report on the IL-10 levels after treatment. Seymor and coworkers (1997) reported that only 10 of 65 patients (15%) evaluated had detectable levels of serum IL-6 after treatment, and they were significantly lower than the levels measured before chemotherapy. (26) In the present study, a significant decrease of IL-6 and IL-10 was observed in serum after the antineoplastic treatment, which demonstrates that the chemotherapy disrupts the microenvironment network of cytokine signaling. In addition, it was also observed that patients who died because of disease progression had higher IL-6 levels in their serum posttreatment, suggesting that IL-6 may be involved in mechanisms of tumor resistance. A longer follow-up with a more significant number of patients with HL would be valuable to conclusively define whether the reduction of IL-6 with treatment is a clear-cut predictor of good response to treatment.

In summary, it was observed that pretreatment serum levels of IL-6 and IL-10 were associated with relevant clinical and laboratory findings in patients with cHL and that these cytokines decreased significantly after standard treatment for the disease. Higher IL-6 serum levels before chemotherapy seem to be associated with treatment failure, although this finding requires further validation with a larger series of cHL cases.

We thank Ms Celene Maria Gandin, Mr Marcos Roberto Franchi, and Mr Luis Fernando Franchi for their technical assistance in histologic and immunohistochemical techniques; Carlos Eduardo Bacchi, MD, PhD, and Francisco Carlos Quevedo, MD, for providing us access to HL biopsies for analysis; Sergio Alberto Rupp de Paiva, MD, PhD, Marcos Ferreira Minicucci, MD, PhD, and Suzana Erico Tani Minamoto, MD, PhD, for their support with the statistical analysis; and Alice de Oliveira Goncalves, BSc, and the staff of the Molecular Pathology Laboratory at Botucatu School of Medicine for help with samples and experiments. This study was funded by the Fundacaode Amparo a Pesquisa do Estado de Sao Paulo, grant AP 2006/00591-5 (Dr Oliveira).

References

(1.) Straus DJ. Treatment of early-stage nonbulky Hodgkin lymphoma. Curr Opin Oncol. 2006;18(5):432-436.

(2.) Diehl V. Chemotherapy or combined modality treatment: the optimal treatment for Hodgkin's disease. J Clin Oncol. 2004;22(1):15-18.

(3.) Laskar S, Gupta T, Vimal S, et al. Consolidation radiation after complete remission in Hodgkin's disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: is there a need? J Clin Oncol. 2004; 22(1):62-68.

(4.) Lazarus HM, Rowlings PA, Zhang MJ, et al. Autotransplants for Hodgkin's disease in patients never achieving remission: are port from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol. 1999;17(2):534-545.

(5.) Bartlett NL. Therapies for relapsed Hodgkin lymphoma: transplant and non-transplant approaches including immunotherapy. Hematology Am Soc Hematol Educ Program. 2005;245-251.

(6.) Brice P. Managing relapsed and refractory Hodgkin lymphoma. Br J Haematol. 2008;141(1):3-13.

(7.) Carde P, Hagenbeek A, Hayat M, et al. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol. 1993;11(11):2258-2272.

(8.) Duhmke E, Diehl V, Loeffler M, et al. Randomized trial with early-stage Hodgkin's disease testing 30 Gy vs. 40 Gy extended field radiotherapy alone. Int J Radiat Oncol Biol Phys. 1996;36(2):305-310.

(9.) Gospodarowicz MK, Sutcliffe SB, Bergsagel DE, Chua T; Princess Margaret Hospital Lymphoma Group. Radiation therapy in clinical stage I and II Hodgkin's disease. Eur J Cancer. 1992; 28A(11):1841-1846.

(10.) Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. N Engl J Med. 1998; 339(21):1506-1514.

(11.) Diehl V, Stein H, Hummel M, Zollinger R, Connors JM. Hodgkin's lymphoma: biology and treatment strategies for primary, refractory and relapsed disease. Hematology Am Soc Hematol Educ Program. 2003;225-247.

(12.) Klimm B, Diehl V, Pfistner B, Engert A. Current treatment strategies of the German Hodgkin Study Group (GHSG). Eur J Haematol Suppl. 2005;(66):125-134.

(13.) Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood. 2002;99(12):4283-4297.

(14.) Khan G. Epstein-Barrvirus, cytokines, and inflammation: a cocktail for the pathogenesis of Hodgkin's lymphoma. Experimental Hematology. 2006;34(4): 399-406.

(15.) Poppema S. Immunobiology and pathophysiology of Hodgkin lymphomas. Hematology Am Soc Hematol Educ Program. 2005;231-238.

(16.) Gruss HJ, Pinto A, Duyster J, Poppema S, Herrmann F. Hodgkin's disease: a tumor with disturbed immunological pathways. Immunol Today. 1997;18(4): 156-163.

(17.) SchmitzR,StanelleJ,HansmannML,KuppersR.Pathogenesisofclassicaland lymphocyte-predominant Hodgkin lymphoma. Annu Rev Pathol. 2009;4:151-174.

(18.) Re D, Thomas RK, Behringer K, Diehl V. From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential. Blood. 2005; 105(12):4553-4560.

(19.) Teruya-Feldstein J, Tosato G, Jaffe ES. The role of chemokines in Hodgkin's disease. Leuk Lymphoma. 2000;38(3-4):363-371.

(20.) Maggio E, van den Berg A, Diepstra A, Kluiver J, Visser L, Poppema S. Chemokines, cytokines and their receptors in Hodgkin's lymphoma cell lines and tissue. Ann Oncol. 2002;13(suppl 1):52-56.

(21.) Cozen W, Gill PS, Ingles SA, et al. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood. 2004;103(8):3216-3221.

(22.) Reynolds GM, Billingham LJ, Gray LJ, et al. Interleukin 6 expression by Hodgkin/Reed-Sternberg cells is associated with the presence of 'B' symptoms and failure to achieve complete remission in patients with advanced Hodgkin's disease. Br J Haematol. 2002;118(1):195-201.

(23.) Vassilakopoulos TP, Nadali G, Angelopoulou MK, et al. Serum interleuk in-10 levels are an independent prognostic factor for patients with Hodgkin's lymphoma. Haematologica. 2001;86(3):274-281.

(24.) Skinnider BF, Kapp U, Mak TW. The role of interleukin 13 in classical Hodgkin lymphoma. Leuk Lymphoma. 2002;43(6):1203-1210.

(25.) Kurzrock R, Redman J, Cabanillas F, Jones D, Rothberg J, Talpaz M. Serum interleukin 6 levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin's disease and with B symptoms. Cancer Res. 1993;53(9): 2118-2122.

(26.) Seymor JF, Talpaz M, Hagemeister FB, Cabanillas F, Kurzrock R. Clinical correlates of elevated levels of interleukin-6 in patients with untreated Hodgkin's disease. Am J Med. 1997;102(1):21-28.

(27.) Sarris AH, Kliche KO, Pethambaram P, et al. Interleukin-10 levels are often elevated in serum of adults with Hodgkin's disease and are associated with inferior failure-free survival. Ann Oncol. 1999;10(4):433-440.

(28.) Herling M, Rassidakis GZ, Medeiros JL, et al. Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome. Clin Cancer Res. 2003;9(60):2114-2120.

(29.) Herbst H, Foss HD, Samol J, et al. Frequent expression of interleukin-10 by Epstein-Barr Virus-harboring tumor cells ofHodgkin's disease. Blood. 1996;87(7): 2918-2929.

(30.) Jucker M, Abts H, Li W, et al. Expression of interleukin-6 and interleukin-6 receptor in Hodgkin's disease. Blood. 1991;77(11):2413-2418.

(31.) Foss HD, Herbst H, Oelman E, et al. Lymhpotoxin, tumor necrosis factor and interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin's disease cases. Br J Haematol. 1993;84(4):627-635.

(32.) Duckers DF, Jaspars LH, Voss W, et al. Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr virus-positive and negative cases of Hodgkin's disease. J Pathol. 2000;190(2):143-149.

(33.) Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1-78.

(34.) Barton BE. The biological effects of interleukin 6. Med Res Rev. 1996; 16(1):87-109.

(35.) Herbst H, Samol J, Foss HD, Raff T, Niedobitek G. Modulation of interleukin-6 expression in Hodgkin and Reed-Sternberg cells by Epstein-Barr virus. J Pathol. 1997;182(3):299-306.

(36.) Levy Y, Brouet JC. Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Investig. 1994;93(1):424-428.

(37.) Bohlen H, Kessler M, Sextro M, Diehl V, Tesch H. Poor clinical outcome of patients with Hodgkin's disease and elevated interleukin-10 serum levels: clinical significance of interleukin-10 serum levels for Hodgkin's disease. Ann Hematol. 2000;79(3):110-113.

(38.) Viviani S, Notti P, Bonfante V, Verderio P, Valagussa P, Bonddonna G. Elevated pretreatment serum of IL-10 are associated with poor prognosis in Hodgkin's disease, the Milan Cancer Institute experience. Med Oncol. 2000; 17(1):59-63.

(39.) Rautert R, Schinkothe T, Franklin J, et al. Elevated pretreatment interleukin-10 serum level is an International Prognostic Score (IPS)-independent risk factor for early treatment failure in advanced stage Hodgkin lymphoma. Leuk Lymphoma. 2008;49(11):2091-2098.

(40.) Kapp U, Yeh WC, Patterson B, et al. Interleukin 13 is secreted by and stimulates the growth of Reed-Sternberg cells. J Exp Med. 1999;189(12):1939-1946.

(41.) Ohshima K, Akaiwa M, Umeshita R, Suzumiya J, Izuhara K, Kikuchi M. Interleukin-13 and interleukin-13 receptor in Hodgkin's disease: possible autocrine mechanism and involvement in fibrosis. Histopathology. 2001;38(4): 368-375.

(42.) Skinnider BF, Elia AJ, Gascoyne RD, et al. Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2001;97(1):250-255.

(43.) Casasnovas RO, Mounier N, Brice P, et al. Plasma Cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin's lymphoma: a study from the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2007;25(13):1732-1740.

(44.) Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol. 1989;7(11):1630-1636.

(45.) de Oliveira DE, Bacchi MM, Macarenco RS, Tagliarini JV, Cordeiro RC, Bacchi CE. Human papillomavirus and Epstein-Barr virus infection, p53 expression, and cellular proliferation in laryngeal carcinoma. Am J Clin Pathol. 2006;126(2):284-293.

(46.) Enblad G, Molin D, Glimelius I, Fisher M, Nilsson G. The potential role of innate immunity in the pathogenesis of Hodgkin's lymphoma. Hematol Oncol Clin North Am. 2007;21(5):805-823.

(47.) Jones AS. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol. 2005;175(6):3463-3468.

(48.) Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80(2):227-236.

(49.) Gause A, Scholz R, Klein S, et al. Increased levels of circulating interleukin-6 in patients with Hodgkin's disease. Hematol Oncol. 1991;9(6): 307-313.

(50.) Barton BE, Murphy TF. Cancer cachexia is mediated in part by the induction of IL-6-like cytokines from the spleen. Cytokine. 2001;16(6):251-257.

(51.) Barton BE. IL-6: insights into novel biological activities. Clin Immunol Immunopathol. 1997;85(1):16-20.

(52.) Fiumara P, Cabanillas F, Younes A. Interleukin-13 levels in serum from patients with Hodgkin disease and healthy volunteers. Blood. 2001;98(9):2877-2878.

Rafael D. Gaiolla, MD; Maria A. C. Domingues, MD, PhD; Ligia Niero-Melo, MD, PhD; Deilson Elgui de Oliveira, PhD

Accepted for publication May 24, 2010.

From the Departments of Internal Medicine (Drs Gaiolla and Niero-Melo) and Pathology (Drs Domingues and Elgui de Oliveira), Botucatu Medical School, Sao Paulo State University, Botucatu, Brazil.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Rafael D. Gaiolla, MD, Department of Internal Medicine, Botucatu Medical School, Sao Paulo State University, Distrito de Rubiao Junior s/n, Botucatu, SP 18603-970, Brazil (e-mail: rgaiolla@fmb.unesp.br).
Table 1. Associations Among Clinical and Laboratory Data and
Pretreatment Serum Levels of Interleukin (IL) 6 and IL-10 in 27
Patients With Hodgkin Lymphoma

 Patients, No. (%), Serum IL-6, pg/mL,
Category Findings N = 27 Median (Range) (a)

Age y
 19-39 18 (66) 24.94 (12.04-41.03)
 [greater than or 9 (34) 19 (11.2-59.37)
 equal to] 40

Sex
 M 18 (66) 19.72 (14.49-51.76)
 F 9 (34) 24.22 (9.03-33.75)

Stage, Ann Arbor
 Early, I/II 16 (59) 19.58 (5.15-39.65)
 Advanced, III/IV 11 (41) 24.22 (17.65-85.06)

Mediastinal involvement
 Present 16 (59) 24.94 (18.85-39.29)
 Absent 11 (41) 17.11 (2.57-72.34)

Abdominal involvement
 Present 13 (48) 39.29 (19.29-99.74)
 Absent 14 (52) 18.71 (0-26.93)

Hepatomegaly
 Present 3 (11) 99.74 (55.7-217.08)
 Absent 24 (89) 19.72 (11.17-37.04)

Splenomegaly
 Present 6 (22) 41.9 (24.22-99.74)
 Absent 21 (78) 19.29 (11.6-36.79)

Extranodal disease
 Present 7 (26) 37.55 (4.28-203.02)
 Absent 20 (74) 20.45 (23.49-38.78)

B symptoms
 Present 14 (52) 40.16 (19.29-99.74)
 Absent 13 (48) 18.71 (7.72-25.85)

Bulky disease
 >10 cm 5 (19) 12.04 (0-24.25)
 <10 cm 22 (81) 24.94 (17.11-51.76)

Bone marrow
 Infiltrated 3 (11) 37.55 (9.38-201.53)
 Not infiltrated 24 (89) 20.45 (13.49-41.9)

Anemia
 Present 8 (30) 75.75 (28.85-203.85)
 Absent 19 (70) 19.29 (10.73-29.47)

WBC, cells/[mm.sup.3]
 >15 000 4 (15) 28.64 (17.84-44.15)
 <15 000 23 (85) 20.16 (10.73-42.33)

Lymphocytopenia
 Present 2 (8) 7.47 (0-14.94)
 Absent 25 (92) 24.22 (15.84-45.02)

Treatment failure
 Yes 5 (19) 42.8 (33.46-227.17)
 No 22 (81) 19.14 (10.3-37.5)

Response to treatment
 Complete 23 (85) 94.02 (30.38-292.85)
 Partial 4 (15) 19.29 (10.73-40.16)

EBV infection, N = 23
 Absent 18 (78) 22.48 (12.04-41.03)
 Present 5 (22) 36.54 (14.47-177.68)

Serum albumin, N = 22
 Normal 10 (45) 20.45 (17.11-30.74)
 Low 12 (55) 44.65 (16.82-125.62)

[beta]2 microglobulin,
N = 17
 Normal 15 (88) 25.66 (17.51-48.21)
 High 2 (11) 10.37 (0-20.74)

LDH, N = 25
 Normal 14 (56) 19.43 (10.3-82.2)
 High 11 (44) 36.54 (20.74-39.91)

Histologic subtype
 NS 23 (85) 20.74 (13.31-41.46)
 MC 3 (11) 14.94 (3.73-34.51)
 LD 1 (4) 99.74 (99.74-99.74)

CD20
 Positive 19 (70) 19.29 (11.46-72.34)
 Negative 8 (30) 28.2 (16.1-38.78)

CD15
 Positive 23 (85) 20.16 (12.76-40.16)
 Negative 4 (15) 53.93 (12.83-169.2)

 Serum IL-10, pg/mL,
Category Findings P Median (Range) (a) P

Age y
 19-39 .70 11.02 (6.45-25.88) .35
 [greater than or 22.83 (12.25-34.76)
 equal to] 40

Sex
 M .78 14.42 (8.7-23.05) .92
 F 25.88 (0-54.76)

Stage, Ann Arbor
 Early, I/II .26 8.19 (1.99-24.82) .06
 Advanced, III/IV 22.83 (12.72-39.83)

Mediastinal involvement
 Present .54 11.02 (6.13-24.46) .44
 Absent 22.83 (10.1-39.86)

Abdominal involvement
 Present .02 20.58 (12.11-30.52) .09
 Absent 7.11 (2.99-29.16)

Hepatomegaly
 Present .03 109.5 (36.46-214.87 .08
 Absent 14.42 (6.13-26.24)

Splenomegaly
 Present .15 18.99 (8.7-109.5) .52
 Absent 14.57 (6.29-27.58)

Extranodal disease
 Present .45 23.05 (13.16-38.88) .16
 Absent 13.19 (4.9-28.2)

B symptoms
 Present .02 20.69 (9.93-42.98) .06
 Absent 9.28 (2.99-23.59)

Bulky disease
 >10 cm .11 9.28 (7.97-36.44) .88
 <10 cm 14.79 (6.45-30.52)

Bone marrow
 Infiltrated .67 9.93 (9.0-189.98) .73
 Not infiltrated 14.79 (6.13-28.56)

Anemia
 Present .02 34.79 (11.85-96.03) .07
 Absent 12.11 (5.96-22.99)

WBC, cells/[mm.sup.3]
 >15 000 .70 22.76 (12.14-56.54) .32
 <15 000 14.28 (5.96-26.42)

Lymphocytopenia
 Present .12 11.85 (8.7-15.01) .75
 Absent 14.57 (6.29-33.63)

Treatment failure
 Yes .03 25.88 (6.96-30.69) .85
 No 14.42 (6.45-30.52)

Response to treatment
 Complete .05 14.28 (5.96-28.65) .32
 Partial 26.24 (17.58-28.65)

EBV infection, N = 23
 Absent .45 13.19 (6.45-30.52) .19
 Present 26.6 (13.25-98.11)

Serum albumin, N = 22
 Normal .15 8.19 (3.99-22.83) .04
 Low 24.46 (12.47-62.77)

[beta]2 microglobulin,
N = 17
 Normal .23 15.01 (6.62-38.7) .94
 High 19.61 (8.7-30.52)

LDH, N = 25
 Normal .85 16.31 (5.8-42.98) .49
 High 15.01 (9.99-29.36)

Histologic subtype
 NS .32 14.57 (6.62-29.54)
 MC 12.11 (3.03-14.28) .21
 LD 109.5 (109.5-109.5)

CD20
 Positive .85 18.34 (7.32-29.54) .42
 Negative 8.99 (6.45-44.36)

CD15
 Positive .43 14.28 (5.96-29.54) .39
 Negative 20.69 (12.72-136.52)

Abbreviations: EBV, Epstein-Barr virus; LD, lymphocyte depletion; LDH,
lactate dehydrogenase; MC, mixed cellularity; NS, nodular
sclerosis; WBC, white blood cell count.

(a) Range refers to lower and upper quartiles.

Table 2. Multiple Linear Regression Analysis of
Predictors for Interleukin (IL) 6 Serum Levels in 27
Patients With Hodgkin Lymphoma

Dependent
Variable Predictors Coefficient SE P

IL-6, pg/mL Sex -0.619 0.449 .31
 Age -0.544 0.586 .75
 B symptoms 0.972 0.697 .01
 Lymphocytopenia - 1.793 0.852 .02
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Article Details
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Author:Gaiolla, Rafael D.; Domingues, Maria A.C.; Niero-Melo, Ligia; de Oliveira, Deilson Elgui
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Disease/Disorder overview
Date:Apr 1, 2011
Words:6101
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