Hepatitis C virus antibody in patients with B-cell non-Hodgkin lymphoma and with non-hematological solid tumors in Recife, Brazil
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Hepatitis C virus antibody in patients with B-cell non-Hodgkin lymphoma and with non-hematological solid tumors in Recife, Brazil(pdf)格式
1 Hospital das Clínicas (HC) da Universidade Federal de Pernambuco (UFPE), Av. Prof. Moraes Rego S/N, Cidade Universitária, 56670-420, PE, Brazil
2 Departamento de Medicina Clínica - Universidade Federal de Pernambuco, R. Irm Maria David, 154 / Apto. 3201, 52061-070, Recife, PE, Brazil
3 Centro de Pesquisa Aggeu Magalhes (FIOCRUZ), Av. Prof. Moraes Rego S/N, Cidade Universitária, 56670-420, PE, Brazil
4 Servio de Oncologia, Instituto Materno Infantil Prof. Fernando Figueira (IMIP), R. dos Coelhos, 300, Boa Vista, Recife, 50070-550, PE, Brazil
Corresponding to Edmundo Pessoa de Almeida Lopes, MD, PhD, Rua Irm Maria David, 154 / Apto. 3201, 52061-070, Recife, PE, Brazil
Tel: 55 (81) 3442-7596,Fax:55 (81) 3442-0400,E-mail: epalopes@terra.com.br
[Abstract] Hepatitis C virus (HCV) infection has been associated with the development of lymphoma proliferate disorders, such as essential cryoglobulinemia and non-Hodgkin lymphoma. The prevalence of HCV infection was investigated in patients attended in an outpatient oncology reference center in Recife, northeastern Brazil, between January, 2003 and December, 2004. HCV antibody (anti-HCV) detection was carried out using an ELISA-3 in 59 patients with B-cell non-Hodgkin lymphoma and in 119 cases of non-Hodgkin lymphoma solid tumor. The prevalence of HCV infection in patients with B-cell non-Hodgkin lymphoma was 6.7% and the risk attributed to the HCV was estimated as 2.52 (95% CI=1.54~4.11;P=0.043). The prevalence of anti-HCV in patients with solid tumors was 0.8% with a risk of 0.29 (95% CI=0.05~1.70;P=0.048). The prevalence of anti-HIV in patients with non-Hodgkin lymphoma was 1.6% and in patients with non-hematological solid tumor was 2.5%. In this study the prevalence of anti-HCV in patients with B-cell non-Hodgkin lymphoma was found to be eight times higher when compared with patients to non-hematological solid tumors.
[Key words] hepatitis C virus;lymphoma; B-cell non-Hodgkin lymphoma
INTRODUCTION
HCV infection is an important public health problem with an estimated 170 million persons infected worldwide and, consequently, at risk of chronic hepatitis, cirrhosis and hepatocellular carcinoma[1~3]. It has also been suggested that HCV is associated with systemic diseases, as its RNA has been found in blood cells and bone marrow of patients with lymphoproliferative diseases[4, 5].
A meta-analysis of 48 epidemiological studies showed a mean prevalence of 13% (95% CI=12%~14%) of HCV in 5 542 patients with B-cell non-Hodgkin lymphoma (NHL) from 14 different countries[6]. Fifteen of these studies were from Italy where the mean prevalence found was 20% (95% CI=18%~22%) for HCV infection in B-cell NHL. The second highest prevalence of HCV infection was found in Japan with mean value of 14% (95% CI=10%~18%)[6].
Another systematic review of 23 studies compared the results of HCV-antibody (anti-HCV) test in 4 049 patients with B-cell NHL and in 1 813 480 non-cancer subjects. The odds ratio of HCV infection in NHL patients was found to be 5.7 (95% CI=4.09~7.96;P<0.001)[7].
The mechanism for lymphoma genesis induced by HCV is not yet clear[8, 9]. However, the evidence that patients infected with HCV show translocation of chromosomes 14 and 18, similar to molecular damage found in NHL, suggests a possible direct effect of HCV on changing lymphocyte phenotype[10, 11]. Recently,it was suggested that the HCV indirectly increases the risk of lymphoid transformation by chronically stimulating the immune system to maintain a proliferative state[12]. In addition, further evidence was found in the fact that 7 of 9 patients infected by HCV and diagnosed with splenic NHL rich in villous lymphocytes showed a complete regression of the lymphoproliferative disorder when submitted to interferon therapy. The other 2 patients, who did not improve with interferon, one of them reduced partially and another showed a complete remission of the lymphoma activity, after associated ribavirin plus interferon[13]. Nowadays, a systematic review analyzing the efficacy of antiviral therapy for the association of HCV and lymphoma suggest that encouraging data emerge from recent studies showing that peginterferon plus ribavirin is an attractive option[14].
There is still a great deal of controversy regarding the role of HCV in lymphoma genesis, since the prevalence of the HCV in patients with NHL differs among individual countries and a strong molecular evidence that explains the phenomena of genetic damage does not yet exist[6, 7, 15]. In this report we present the prevalence of anti-HCV in patients evaluated at a University Hospital in Recife, northeastern Brazil.
MATERIALS AND METHODS
Population and Study Design
This is a prevalence study designed to determine the rate of HCV antibodies in patients with NHL and with non-hematological solid tumors attended in an outpatient adult oncology reference center in the Hospital of the Federal University of Pernambuco (HC-UFPE), in Recife, Brazil, between January, 2003 and December, 2004.
The sampling was not probabilistic and selection was realized by existing patient demand in the outpatient reference center. Of 612 patients attended, 102 had hematological and 510 non-hematological solid tumors (Figure 1). Considering the type of the tumor, the 10 most frequent or 85% of them were: 16.8% for lung, 16.0% for breast, 11.9% for colon, 10.9% for non-Hodgkin lymphoma, 8.8% for prostate, 7.2% for esophagus, 5.7% for stomach, 3.5% for ovary, 2.5% for bladder and 2% for cancer of the anal channel. Patients with hepatocellular carcinoma were excluded from this group due to its high correlation with HCV infection. As showed in Figure 1, 60 of 102 patients with hematological were diagnosed as having B-cell NHL, and 1 of them presented positive serology for anti-HIV and was excluded for analysis, due to the increased risk of developing lymphoma. Thus, a group of 59 patients with B-cell type NHL by histological analysis was compared with a second group formed by 119 patients chosen at random, drawn from 510 patients with non-hematological solid tumor.
Data Collection
Recruited subjects who agreed to participate in this study and signed the Ethical Consent Form in which HIV and HCV testing permission was included, and interviewed by the same physician using a standard questionnaire. The study was registered and approved by the HC-UFPE Ethical Committee. Those who were positive for HIV or HCV antibodies test were referred for evaluation in the Hepatology or AIDS specialized clinics at the HC-UFPE.
Figure 1 Selection of the patient population involved in this study, which were evaluated at the oncology reference center in the Hospital of the Federal University of Pernambuco, in Recife, Brazil, between 2003 and 2004
HCV Antibody and Viral Assays
All the recruited patients were asked to donate blood for serological investigation when they were undergoing blood collection for routine tests. HCV antibodies were detected using an enzyme immunoassay (EIA-3, Ortho HCV 3rd-generation; Ortho Diagnostic Systems, Raritan, NJ). Anti-HCV immunoreactivity was confirmed with a 3rd-generation recombinant immunoblot assay (RIBA-3; Chiron, Emeryville, CA; Ortho Diagnostic Systems). For the purposes of this analysis patients were considered HCV-positive when they presented antibodies for HCV by both EIA and RIBA. Anti-HIV antibodies were detected using the Abbott HIV1/2 g O EIA (Abbott Laboratories, Abbott Park, IL).
Data Analysis
Clinical, epidemiological and laboratorial informations were analyzed using the software Epi-Info version 6.0. Distributions of nominal and categorized variables were expressed by absolute values and percentage. The coefficient of prevalence and relative risk were calculated for the 59 patients with B-cell NHL and 119 patients with non-hematological solid tumors.
RESULTS
Characteristics of the Study Population
Some characteristics of the study population are shown in the Table 1. The median age was 33 years for group 1 (B-cell NHL) and 54 years for group 2 (non-hematological solid tumor). Males were slightly more prevalent in group 1 (57.6%) than in group 2 (52.9%). Both groups showed the same frequency distribution for income categorization and the patients came from the same macro region (Table 1).
Table 1 Characteristics of 59 Patients with Non-Hodgkin Lymphoma (Group 1) and of 119 Patients with Non-hematological Solid Tumors (Group 2) Evaluated at the Oncology Reference Center in the Hospital of the Federal University of Pernambuco, in Recife, Brazil n,%
Group 1 (non-Hodgkin lymphoma)
Adenomegaly was the main complaint of the patients (86.4%) during diagnosis. The classic symptoms were also referred to with high frequency: 71.2% described loss of weight, 57.6% cited fever and 47.4% nocturnal sudorese. Long lasting fever was mentioned by 27 patients (45.8%) and association between fever and splenomegaly was found in 11 cases (18.6%). Anemia was found in 35 (59%) and pancitopenia in 12 of the 59 patients with NHL (20%).
The most frequently compromised lymph nodes were: cervical (49%), mediastinal (39%), axilla (30.5%), supraclavicular (28.8%), retroperitoneal (22%) and inguinal (13%). The stomach was the most affected extra nodal site (16.9%). The distribution of NHL by histological subtype and staging is shown in the Table 2. The frequency of B-cell NHL patients diagnosed in an advanced stage of the disease was high, with the majority in stage ⅢB (25.5%) and ⅣB (23.7%).
Serology for anti-HCV detected by EIA-3 was positive in 4 of the 59 patients (6.7%) with B-cell NHL, which were confirmed by RIBA-2 (Table 2). The relative risk attributed to HCV in patients with B-cell NHL was of 2.52 (95% CI=1.54~4.11;P=0.043). Only 1 (1.6%) of the 60 patients with B-cell NHL presented anti-HIV positive.
Only 2 patients (3.4%) in this group reported having received a blood transfusion, 1 of them during their current illness and another had received blood products after a car accident 14 years prior to this study. These 2 patients were positive for anti-HCV.
Table 2 Prevalence of HCV Antibodies in 59 Patients with Non-Hodgkin Lymphoma Stratified by Histological Type and in 119 Patients with Non-hematological Solid Tumors Evaluated at the Oncology Reference Center in the Hospital of the Federal University of Pernambuco, in Recife, Brazil
Group 2 (non-hematological solid tumor)
Almost 60% of the 119 patients with non-hematological solid tumors were from lung, breast, colon and prostate tissue. The frequency of non-hematological solid tumors diagnosed in an advanced stage of the disease reached 74.5%, with the majority in stage III (40%) and IV (34.5%).
Of the 119 patients with non-hematological solid tumors, only 1 patient (0.8%) with colon cancer presented anti-HCV positive (relative risk of 0.29; 95% CI=0.05~1.70;P=0.048) and 3 patients (2.5%) showed positive serology for anti-HIV. HIV antibody was found in 1 case of breast cancer, 1 of anal channel cancer and another of osteosarcoma.
In this group, 14 patients (11.8%) mentioned having received a blood products and 12 of them (10.9%) had received during the phase of diagnosis or management of their current illnesses.
DISCUSSION
The present study showed an eight-fold greater prevalence of HCV antibodies in patients with B-cell NHL than in patients with non-hematological solid tumors evaluated at an outpatient adult oncology reference center in Recife, northeastern Brazil. We found a prevalence of anti-HCV in patients with B-cell NHL of 6.7% which is higher than that reported by a serological survey of a stratified, randomized and residence based population in So Paulo city, southeastern Brazil, which was around 1.7% [16]. Three out 4 patients (75%) observed here which presented positive anti-HCV have low-grade malignant lymphoma (Table 2), as also described by Pozzato et al[4]. The prevalence observed here in Recife, was only slightly lower than that reported for patients with lymphoma in Rio de Janeiro, southeastern Brazil, where HCV infection was found in 9% of 109 patients with non-Hodgkin lymphoma[20]. It was, however, lower than that observed in Italy (mean of 20%), Japan (mean of 15.5%) and Spain (mean of 14%) [6, 7, 18, 19, 20]. On the other hand, no association between HCV and B-cell NHL was detected in North America[21]. According to these results, we could consider the Brazil a country with intermediate prevalence of HCV in patients with B-cell NHL.
A systematic review reported in two meta-analyses estimated a mean prevalence between 10% and 13% of HCV in patients with lymphoma in the world, however an important variation between countries on the same continent was observed[6, 7]. In fact, in Europe evidence of HCV infection related to the development of lymphoma was found in Italy and Spain, but not in the United Kingdom[6, 7, 19, 20]. More recently, a study from Japan related a prevalence of anti-HCV in 400 patients with B-cell NHL of 11.3%, which was significantly higher than the blood donors, that was around 2.5%[22]. Geographic differences regarding the prevalence of HCV infection in patients with lymphoma suggest that the pathogenesis of lymphoma is multifactor, and that environmental and genetic factors should be also involved[6, 7, 15, 18, 23, 24]. Thus, high prevalence of HCV in patients with lymphoma could be a consequence of the prevalence of HCV infection for each country. This was observed in Italy, USA and Japan where the prevalence of HCV infection is high even among the healthy population[6, 7, 18, 22, 24].
HCV infection in patients with lymphoma could also be a consequence of the immunosuppression presented by these patients associated with an increased number of blood transfusions and invasive procedures, which they are subjected to during the course of the disease[18]. In fact, 2 of the 4 patients with lymphoma and HCV infection presented here reported the use of blood products, one of them during the medical management of the tumor. The frequency of blood transfusion in patients with B-cell NHL was 3.4% (2/59). Nevertheless, this seems not having a direct influence, as the group of non-hematological tumors presented a lower frequency of HCV infection (0.8%) despite showing a higher frequency of blood transfusion (11.8%). The prevalence of HCV infection in non-hematological tumors reported here was also lower than the frequencies (1% to 5%) published elsewhere[24, 25].
In conclusion, the study presented here correlates the results found by other authors demonstrating that the frequency of HCV is higher in patients with lymphoma than in patients with non-hematological tumors, other hematological disorders, blood donors or healthy individuals[4, 6, 7, 22]. Moreover, the prevalence of anti-HIV in patients with non-hematological tumors found in this study (2.5%) was higher than that observed in patients with B-cell NHL (6.7%), suggesting a correlation between HCV infection and lymphoma genesis.
Early diagnosis of the association between HCV and lymphoma should be encouraged, as some data suggest, and antiviral therapy could also be important to the outcome of lymphoma treatment[14, 18]. Thus, markers of HCV for patients with non-Hodgkin lymphoma would be a requirement, mainly for these with low-grade lymphoma[24]. Furthermore physicians treating patients with HCV infection or essential cryoglobulinemia should keep in mind that they might be carriers of an indolent lymphoma[14, 22].
The role of HCV infection on the development of non-Hodgkin lymphoma should be elucidated by further studies on tumor pathogenesis. In this context, molecular epidemiology studies on HCV infection in the general population with different genetic backgrounds and different geographical settings would contribute to our understanding of the differences in HCV infection frequency in lymphoma patients around the world.
Acknowledgements
The authors would like to thank the Oswaldo Cruz Foundation (FIOCRUZ) and the Oncology Service of the Clinics Hospital of Pernambuco for their support. The authors are also grateful to Ms Luciene Marques and Ms Maristela Costa for their assistance in attending the patients and performing blood collection.
REFERENCES
1. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis,2005, 5: 558-567.
2. Cacoub P, Renou C, Rosenthal E, et al. Extrahepatic manifestations associated with hepatitis C virus. Nephrologie,2001, 22: 295-296.
3. Capote Huelva FJ, Gil Garcia JL, Alvarez Rojas C, Calderon Sandubete E. Hepatitis C virus infection and genesis of lymphomas. Med Clin (Barc),2001, 117: 678-679.
4. Pozzato G, Mazzaro C, Crovatto M, et al. Low-grade malignant lymphoma, hepatitis C virus infection and mixed cryoglobulinemia. Blood,1994,84: 3047-3053.
5. Ferri C, Caracciolo F, Zignego AL, et al. Hepatitis C virus infection in patients with non-Hodgkin's lymphoma. Br J Haematol, 1994, 88: 392-394.
6. Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-Cell non-Hodgkin's lymphoma: systematic review and meta-analysis. Gastroenterology, 2003,125: 1723-1732.
7. Matsuo K, Kusano A, Sugumar A, Nakamura S, Tajima K, Mueller NE. Effect of hepatitis C virus infection on the risk of non-Hodgkin's lymphoma: a meta-analysis of epidemiological studies. Cancer Sci, 2004, 95: 745-752.
8. Polyak SJ. Hepatitis C virus cell interactions and their role in pathogenesis. Clin Liver Dis,2003, 7: 67-88.
9. Gasparotto D, De Re V, Boiocchi M. Hepatitis C virus, B-cell proliferation and lymphoma. Leuk Lymphoma, 2002, 43: 747-751.
10. Akasaka T, Ohno H, Mori T, Okuma M. Long distance polymerase chain reaction for detection of chromosome translocations in B-cell lymphoma/ leukemia. Leukemia,1997,11: 316-317.
11. Zuckerman E, Zuckerman T, Sahar D, et al. The effect of anti-viral therapy on t(14; 18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood,2001, 97: 1555-1559.
12. Suarez F, Lortholary O, Hermine O, Lecuit M. Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood,2006, 107:3034-3044.
13. Hermine O, Lefrere F, Bronowicki Jp, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med,2002, 347: 89-94.
14. Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther,2005,21:653-662.
15. McColl MD, Singer IO, Tait RC, McNeil IR, Cumming RL, Hogg RB. The role of hepatitis C virus in the aetiology of non-Hodgkin's lymphoma - a regional association? Leuk Lymphoma,1997, 26: 127-130.
16. Foccacia R, Conceio OJ, Sette H, et al. Estimated prevalence of viral hepatitis in the in the general population of the municipality of So Paulo, measured by a serologic survey of a stratified, randomized and residence-Based population. Braz J Infect Dis, 1998, 2: 269-284.
17. Chindamo MC, Spector N, Segadas JA, et al. Prevalence of hepatitis C infection in patients with non-Hodgkin's lymphomas. Oncol Rep,2002,9: 657-659.
18. Mele A, Pulsoni A, Bianco E, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian case-control study. Blood,2004, 102: 996-999.
19. Imai Y, Ohsawa M, Tanaka H, et al. High prevalence of HCV infection in patients with B-cell non-Hodgkin's lymphoma: comparison with birth cohort- and sex-matched blood donors in a Japanese population. Hepatology, 2002,35: 974-976.
20. Sanchez Ruiz AC, Yebra Bango M, Portero F, et al. Prevalence of hepatitis C virus infection in patients with non-Hodgkin's lymphoma. Med Clin (Barc), 2001, 116: 333-334.
21. Collier JD, Zanke B, Moore M, et al. No association between hepatitis C and B-cell lymphoma. Hepatology,1999, 29:1259-1261.
22. Takeshita M, Sakai H, Okamura S, et al. Prevalence of hepatitis C virus infection in cases of B-cell lymphoma in Japan. Histopathology,2006, 48: 189-198.
23. Mizorogi F, Hiramoto J, Nozato A, et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin's lymphoma. Intern Med,2000, 39: 112-117.
24. Zuckerman E, Zuckerman T, Levine AM. Hepatitis C virus in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med,1997, 127: 423-428.
25. Mazzaro C, Tirelli U, Pozzato G. Hepatitis C virus and non-Hodgkin's lymphoma 10 years later. Dig Liver Dis,2005,37:219-226.
(Editor Anne)(José Iran Costa Jr.1, Edm)
1 Hospital das Clínicas (HC) da Universidade Federal de Pernambuco (UFPE), Av. Prof. Moraes Rego S/N, Cidade Universitária, 56670-420, PE, Brazil
2 Departamento de Medicina Clínica - Universidade Federal de Pernambuco, R. Irm Maria David, 154 / Apto. 3201, 52061-070, Recife, PE, Brazil
3 Centro de Pesquisa Aggeu Magalhes (FIOCRUZ), Av. Prof. Moraes Rego S/N, Cidade Universitária, 56670-420, PE, Brazil
4 Servio de Oncologia, Instituto Materno Infantil Prof. Fernando Figueira (IMIP), R. dos Coelhos, 300, Boa Vista, Recife, 50070-550, PE, Brazil
Corresponding to Edmundo Pessoa de Almeida Lopes, MD, PhD, Rua Irm Maria David, 154 / Apto. 3201, 52061-070, Recife, PE, Brazil
Tel: 55 (81) 3442-7596,Fax:55 (81) 3442-0400,E-mail: epalopes@terra.com.br
[Abstract] Hepatitis C virus (HCV) infection has been associated with the development of lymphoma proliferate disorders, such as essential cryoglobulinemia and non-Hodgkin lymphoma. The prevalence of HCV infection was investigated in patients attended in an outpatient oncology reference center in Recife, northeastern Brazil, between January, 2003 and December, 2004. HCV antibody (anti-HCV) detection was carried out using an ELISA-3 in 59 patients with B-cell non-Hodgkin lymphoma and in 119 cases of non-Hodgkin lymphoma solid tumor. The prevalence of HCV infection in patients with B-cell non-Hodgkin lymphoma was 6.7% and the risk attributed to the HCV was estimated as 2.52 (95% CI=1.54~4.11;P=0.043). The prevalence of anti-HCV in patients with solid tumors was 0.8% with a risk of 0.29 (95% CI=0.05~1.70;P=0.048). The prevalence of anti-HIV in patients with non-Hodgkin lymphoma was 1.6% and in patients with non-hematological solid tumor was 2.5%. In this study the prevalence of anti-HCV in patients with B-cell non-Hodgkin lymphoma was found to be eight times higher when compared with patients to non-hematological solid tumors.
[Key words] hepatitis C virus;lymphoma; B-cell non-Hodgkin lymphoma
INTRODUCTION
HCV infection is an important public health problem with an estimated 170 million persons infected worldwide and, consequently, at risk of chronic hepatitis, cirrhosis and hepatocellular carcinoma[1~3]. It has also been suggested that HCV is associated with systemic diseases, as its RNA has been found in blood cells and bone marrow of patients with lymphoproliferative diseases[4, 5].
A meta-analysis of 48 epidemiological studies showed a mean prevalence of 13% (95% CI=12%~14%) of HCV in 5 542 patients with B-cell non-Hodgkin lymphoma (NHL) from 14 different countries[6]. Fifteen of these studies were from Italy where the mean prevalence found was 20% (95% CI=18%~22%) for HCV infection in B-cell NHL. The second highest prevalence of HCV infection was found in Japan with mean value of 14% (95% CI=10%~18%)[6].
Another systematic review of 23 studies compared the results of HCV-antibody (anti-HCV) test in 4 049 patients with B-cell NHL and in 1 813 480 non-cancer subjects. The odds ratio of HCV infection in NHL patients was found to be 5.7 (95% CI=4.09~7.96;P<0.001)[7].
The mechanism for lymphoma genesis induced by HCV is not yet clear[8, 9]. However, the evidence that patients infected with HCV show translocation of chromosomes 14 and 18, similar to molecular damage found in NHL, suggests a possible direct effect of HCV on changing lymphocyte phenotype[10, 11]. Recently,it was suggested that the HCV indirectly increases the risk of lymphoid transformation by chronically stimulating the immune system to maintain a proliferative state[12]. In addition, further evidence was found in the fact that 7 of 9 patients infected by HCV and diagnosed with splenic NHL rich in villous lymphocytes showed a complete regression of the lymphoproliferative disorder when submitted to interferon therapy. The other 2 patients, who did not improve with interferon, one of them reduced partially and another showed a complete remission of the lymphoma activity, after associated ribavirin plus interferon[13]. Nowadays, a systematic review analyzing the efficacy of antiviral therapy for the association of HCV and lymphoma suggest that encouraging data emerge from recent studies showing that peginterferon plus ribavirin is an attractive option[14].
There is still a great deal of controversy regarding the role of HCV in lymphoma genesis, since the prevalence of the HCV in patients with NHL differs among individual countries and a strong molecular evidence that explains the phenomena of genetic damage does not yet exist[6, 7, 15]. In this report we present the prevalence of anti-HCV in patients evaluated at a University Hospital in Recife, northeastern Brazil.
MATERIALS AND METHODS
Population and Study Design
This is a prevalence study designed to determine the rate of HCV antibodies in patients with NHL and with non-hematological solid tumors attended in an outpatient adult oncology reference center in the Hospital of the Federal University of Pernambuco (HC-UFPE), in Recife, Brazil, between January, 2003 and December, 2004.
The sampling was not probabilistic and selection was realized by existing patient demand in the outpatient reference center. Of 612 patients attended, 102 had hematological and 510 non-hematological solid tumors (Figure 1). Considering the type of the tumor, the 10 most frequent or 85% of them were: 16.8% for lung, 16.0% for breast, 11.9% for colon, 10.9% for non-Hodgkin lymphoma, 8.8% for prostate, 7.2% for esophagus, 5.7% for stomach, 3.5% for ovary, 2.5% for bladder and 2% for cancer of the anal channel. Patients with hepatocellular carcinoma were excluded from this group due to its high correlation with HCV infection. As showed in Figure 1, 60 of 102 patients with hematological were diagnosed as having B-cell NHL, and 1 of them presented positive serology for anti-HIV and was excluded for analysis, due to the increased risk of developing lymphoma. Thus, a group of 59 patients with B-cell type NHL by histological analysis was compared with a second group formed by 119 patients chosen at random, drawn from 510 patients with non-hematological solid tumor.
Data Collection
Recruited subjects who agreed to participate in this study and signed the Ethical Consent Form in which HIV and HCV testing permission was included, and interviewed by the same physician using a standard questionnaire. The study was registered and approved by the HC-UFPE Ethical Committee. Those who were positive for HIV or HCV antibodies test were referred for evaluation in the Hepatology or AIDS specialized clinics at the HC-UFPE.
Figure 1 Selection of the patient population involved in this study, which were evaluated at the oncology reference center in the Hospital of the Federal University of Pernambuco, in Recife, Brazil, between 2003 and 2004
HCV Antibody and Viral Assays
All the recruited patients were asked to donate blood for serological investigation when they were undergoing blood collection for routine tests. HCV antibodies were detected using an enzyme immunoassay (EIA-3, Ortho HCV 3rd-generation; Ortho Diagnostic Systems, Raritan, NJ). Anti-HCV immunoreactivity was confirmed with a 3rd-generation recombinant immunoblot assay (RIBA-3; Chiron, Emeryville, CA; Ortho Diagnostic Systems). For the purposes of this analysis patients were considered HCV-positive when they presented antibodies for HCV by both EIA and RIBA. Anti-HIV antibodies were detected using the Abbott HIV1/2 g O EIA (Abbott Laboratories, Abbott Park, IL).
Data Analysis
Clinical, epidemiological and laboratorial informations were analyzed using the software Epi-Info version 6.0. Distributions of nominal and categorized variables were expressed by absolute values and percentage. The coefficient of prevalence and relative risk were calculated for the 59 patients with B-cell NHL and 119 patients with non-hematological solid tumors.
RESULTS
Characteristics of the Study Population
Some characteristics of the study population are shown in the Table 1. The median age was 33 years for group 1 (B-cell NHL) and 54 years for group 2 (non-hematological solid tumor). Males were slightly more prevalent in group 1 (57.6%) than in group 2 (52.9%). Both groups showed the same frequency distribution for income categorization and the patients came from the same macro region (Table 1).
Table 1 Characteristics of 59 Patients with Non-Hodgkin Lymphoma (Group 1) and of 119 Patients with Non-hematological Solid Tumors (Group 2) Evaluated at the Oncology Reference Center in the Hospital of the Federal University of Pernambuco, in Recife, Brazil n,%
Group 1 (non-Hodgkin lymphoma)
Adenomegaly was the main complaint of the patients (86.4%) during diagnosis. The classic symptoms were also referred to with high frequency: 71.2% described loss of weight, 57.6% cited fever and 47.4% nocturnal sudorese. Long lasting fever was mentioned by 27 patients (45.8%) and association between fever and splenomegaly was found in 11 cases (18.6%). Anemia was found in 35 (59%) and pancitopenia in 12 of the 59 patients with NHL (20%).
The most frequently compromised lymph nodes were: cervical (49%), mediastinal (39%), axilla (30.5%), supraclavicular (28.8%), retroperitoneal (22%) and inguinal (13%). The stomach was the most affected extra nodal site (16.9%). The distribution of NHL by histological subtype and staging is shown in the Table 2. The frequency of B-cell NHL patients diagnosed in an advanced stage of the disease was high, with the majority in stage ⅢB (25.5%) and ⅣB (23.7%).
Serology for anti-HCV detected by EIA-3 was positive in 4 of the 59 patients (6.7%) with B-cell NHL, which were confirmed by RIBA-2 (Table 2). The relative risk attributed to HCV in patients with B-cell NHL was of 2.52 (95% CI=1.54~4.11;P=0.043). Only 1 (1.6%) of the 60 patients with B-cell NHL presented anti-HIV positive.
Only 2 patients (3.4%) in this group reported having received a blood transfusion, 1 of them during their current illness and another had received blood products after a car accident 14 years prior to this study. These 2 patients were positive for anti-HCV.
Table 2 Prevalence of HCV Antibodies in 59 Patients with Non-Hodgkin Lymphoma Stratified by Histological Type and in 119 Patients with Non-hematological Solid Tumors Evaluated at the Oncology Reference Center in the Hospital of the Federal University of Pernambuco, in Recife, Brazil
Group 2 (non-hematological solid tumor)
Almost 60% of the 119 patients with non-hematological solid tumors were from lung, breast, colon and prostate tissue. The frequency of non-hematological solid tumors diagnosed in an advanced stage of the disease reached 74.5%, with the majority in stage III (40%) and IV (34.5%).
Of the 119 patients with non-hematological solid tumors, only 1 patient (0.8%) with colon cancer presented anti-HCV positive (relative risk of 0.29; 95% CI=0.05~1.70;P=0.048) and 3 patients (2.5%) showed positive serology for anti-HIV. HIV antibody was found in 1 case of breast cancer, 1 of anal channel cancer and another of osteosarcoma.
In this group, 14 patients (11.8%) mentioned having received a blood products and 12 of them (10.9%) had received during the phase of diagnosis or management of their current illnesses.
DISCUSSION
The present study showed an eight-fold greater prevalence of HCV antibodies in patients with B-cell NHL than in patients with non-hematological solid tumors evaluated at an outpatient adult oncology reference center in Recife, northeastern Brazil. We found a prevalence of anti-HCV in patients with B-cell NHL of 6.7% which is higher than that reported by a serological survey of a stratified, randomized and residence based population in So Paulo city, southeastern Brazil, which was around 1.7% [16]. Three out 4 patients (75%) observed here which presented positive anti-HCV have low-grade malignant lymphoma (Table 2), as also described by Pozzato et al[4]. The prevalence observed here in Recife, was only slightly lower than that reported for patients with lymphoma in Rio de Janeiro, southeastern Brazil, where HCV infection was found in 9% of 109 patients with non-Hodgkin lymphoma[20]. It was, however, lower than that observed in Italy (mean of 20%), Japan (mean of 15.5%) and Spain (mean of 14%) [6, 7, 18, 19, 20]. On the other hand, no association between HCV and B-cell NHL was detected in North America[21]. According to these results, we could consider the Brazil a country with intermediate prevalence of HCV in patients with B-cell NHL.
A systematic review reported in two meta-analyses estimated a mean prevalence between 10% and 13% of HCV in patients with lymphoma in the world, however an important variation between countries on the same continent was observed[6, 7]. In fact, in Europe evidence of HCV infection related to the development of lymphoma was found in Italy and Spain, but not in the United Kingdom[6, 7, 19, 20]. More recently, a study from Japan related a prevalence of anti-HCV in 400 patients with B-cell NHL of 11.3%, which was significantly higher than the blood donors, that was around 2.5%[22]. Geographic differences regarding the prevalence of HCV infection in patients with lymphoma suggest that the pathogenesis of lymphoma is multifactor, and that environmental and genetic factors should be also involved[6, 7, 15, 18, 23, 24]. Thus, high prevalence of HCV in patients with lymphoma could be a consequence of the prevalence of HCV infection for each country. This was observed in Italy, USA and Japan where the prevalence of HCV infection is high even among the healthy population[6, 7, 18, 22, 24].
HCV infection in patients with lymphoma could also be a consequence of the immunosuppression presented by these patients associated with an increased number of blood transfusions and invasive procedures, which they are subjected to during the course of the disease[18]. In fact, 2 of the 4 patients with lymphoma and HCV infection presented here reported the use of blood products, one of them during the medical management of the tumor. The frequency of blood transfusion in patients with B-cell NHL was 3.4% (2/59). Nevertheless, this seems not having a direct influence, as the group of non-hematological tumors presented a lower frequency of HCV infection (0.8%) despite showing a higher frequency of blood transfusion (11.8%). The prevalence of HCV infection in non-hematological tumors reported here was also lower than the frequencies (1% to 5%) published elsewhere[24, 25].
In conclusion, the study presented here correlates the results found by other authors demonstrating that the frequency of HCV is higher in patients with lymphoma than in patients with non-hematological tumors, other hematological disorders, blood donors or healthy individuals[4, 6, 7, 22]. Moreover, the prevalence of anti-HIV in patients with non-hematological tumors found in this study (2.5%) was higher than that observed in patients with B-cell NHL (6.7%), suggesting a correlation between HCV infection and lymphoma genesis.
Early diagnosis of the association between HCV and lymphoma should be encouraged, as some data suggest, and antiviral therapy could also be important to the outcome of lymphoma treatment[14, 18]. Thus, markers of HCV for patients with non-Hodgkin lymphoma would be a requirement, mainly for these with low-grade lymphoma[24]. Furthermore physicians treating patients with HCV infection or essential cryoglobulinemia should keep in mind that they might be carriers of an indolent lymphoma[14, 22].
The role of HCV infection on the development of non-Hodgkin lymphoma should be elucidated by further studies on tumor pathogenesis. In this context, molecular epidemiology studies on HCV infection in the general population with different genetic backgrounds and different geographical settings would contribute to our understanding of the differences in HCV infection frequency in lymphoma patients around the world.
Acknowledgements
The authors would like to thank the Oswaldo Cruz Foundation (FIOCRUZ) and the Oncology Service of the Clinics Hospital of Pernambuco for their support. The authors are also grateful to Ms Luciene Marques and Ms Maristela Costa for their assistance in attending the patients and performing blood collection.
REFERENCES
1. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis,2005, 5: 558-567.
2. Cacoub P, Renou C, Rosenthal E, et al. Extrahepatic manifestations associated with hepatitis C virus. Nephrologie,2001, 22: 295-296.
3. Capote Huelva FJ, Gil Garcia JL, Alvarez Rojas C, Calderon Sandubete E. Hepatitis C virus infection and genesis of lymphomas. Med Clin (Barc),2001, 117: 678-679.
4. Pozzato G, Mazzaro C, Crovatto M, et al. Low-grade malignant lymphoma, hepatitis C virus infection and mixed cryoglobulinemia. Blood,1994,84: 3047-3053.
5. Ferri C, Caracciolo F, Zignego AL, et al. Hepatitis C virus infection in patients with non-Hodgkin's lymphoma. Br J Haematol, 1994, 88: 392-394.
6. Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-Cell non-Hodgkin's lymphoma: systematic review and meta-analysis. Gastroenterology, 2003,125: 1723-1732.
7. Matsuo K, Kusano A, Sugumar A, Nakamura S, Tajima K, Mueller NE. Effect of hepatitis C virus infection on the risk of non-Hodgkin's lymphoma: a meta-analysis of epidemiological studies. Cancer Sci, 2004, 95: 745-752.
8. Polyak SJ. Hepatitis C virus cell interactions and their role in pathogenesis. Clin Liver Dis,2003, 7: 67-88.
9. Gasparotto D, De Re V, Boiocchi M. Hepatitis C virus, B-cell proliferation and lymphoma. Leuk Lymphoma, 2002, 43: 747-751.
10. Akasaka T, Ohno H, Mori T, Okuma M. Long distance polymerase chain reaction for detection of chromosome translocations in B-cell lymphoma/ leukemia. Leukemia,1997,11: 316-317.
11. Zuckerman E, Zuckerman T, Sahar D, et al. The effect of anti-viral therapy on t(14; 18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood,2001, 97: 1555-1559.
12. Suarez F, Lortholary O, Hermine O, Lecuit M. Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood,2006, 107:3034-3044.
13. Hermine O, Lefrere F, Bronowicki Jp, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med,2002, 347: 89-94.
14. Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther,2005,21:653-662.
15. McColl MD, Singer IO, Tait RC, McNeil IR, Cumming RL, Hogg RB. The role of hepatitis C virus in the aetiology of non-Hodgkin's lymphoma - a regional association? Leuk Lymphoma,1997, 26: 127-130.
16. Foccacia R, Conceio OJ, Sette H, et al. Estimated prevalence of viral hepatitis in the in the general population of the municipality of So Paulo, measured by a serologic survey of a stratified, randomized and residence-Based population. Braz J Infect Dis, 1998, 2: 269-284.
17. Chindamo MC, Spector N, Segadas JA, et al. Prevalence of hepatitis C infection in patients with non-Hodgkin's lymphomas. Oncol Rep,2002,9: 657-659.
18. Mele A, Pulsoni A, Bianco E, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian case-control study. Blood,2004, 102: 996-999.
19. Imai Y, Ohsawa M, Tanaka H, et al. High prevalence of HCV infection in patients with B-cell non-Hodgkin's lymphoma: comparison with birth cohort- and sex-matched blood donors in a Japanese population. Hepatology, 2002,35: 974-976.
20. Sanchez Ruiz AC, Yebra Bango M, Portero F, et al. Prevalence of hepatitis C virus infection in patients with non-Hodgkin's lymphoma. Med Clin (Barc), 2001, 116: 333-334.
21. Collier JD, Zanke B, Moore M, et al. No association between hepatitis C and B-cell lymphoma. Hepatology,1999, 29:1259-1261.
22. Takeshita M, Sakai H, Okamura S, et al. Prevalence of hepatitis C virus infection in cases of B-cell lymphoma in Japan. Histopathology,2006, 48: 189-198.
23. Mizorogi F, Hiramoto J, Nozato A, et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin's lymphoma. Intern Med,2000, 39: 112-117.
24. Zuckerman E, Zuckerman T, Levine AM. Hepatitis C virus in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med,1997, 127: 423-428.
25. Mazzaro C, Tirelli U, Pozzato G. Hepatitis C virus and non-Hodgkin's lymphoma 10 years later. Dig Liver Dis,2005,37:219-226.
(Editor Anne)(José Iran Costa Jr.1, Edm)