High prevalence of occult hepatitis B virus infection in patients with B cell non-Hodgkin’s lymphoma
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- Chen, M., Hsiao, L., Chiou, T. et al. Ann Hematol (2008) 87: 475. doi:10.1007/s00277-008-0469-9
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Several reports recently found that patients with B cell non-Hodgkin’s lymphoma (NHL) had a higher carrier rate of hepatitis B surface antigen (HBsAg). The current study aimed to examine the hepatitis B virus (HBV) infection status of NHL patients in Taiwan, an HBV-endemic area. Serum HBV and serum hepatitis C virus were measured in 471 NHL patients and 1,013 non-lymphoma cancer patients enrolled between February 2000 and March 2007. Furthermore, nested polymerase chain reaction of HBV-DNA was used to examine the sera from selected patients in these two populations and healthy volunteers for the presence of occult HBV infection. The infection rates (as indicated by the rates of HBsAg and occult HBV) were compared between different groups. There was a higher incidence of HBV infection in B cell NHL patients (23.5%), especially patients with diffuse large B lymphoma, than solid tumor patients (15.6%, P = 0.001). Among HbsAg-negative patients, those with B cell NHL had a higher prevalence of occult HBV infection (6%) than those with non-lymphoma solid tumors and healthy volunteers, 0% and 0.9%, respectively (P = 0.005). B cell NHL patients, even HBsAg-negative B cell NHL patients, but not T cell NHL patients, have a higher incidence of HBV infection than patients with solid tumors. Our findings support the etiologic role of HBV infection in B cell NHL.
KeywordsHepatitis B virusNon-Hodgkin’s lymphomaOccult hepatitis B
Patients with chronic hepatitis B and C virus (HBV and HCV) infections have an increased risk of developing hepatocellular carcinoma [1–3]. Evidence indicates that both viruses are lymphotropic [4, 5]. Several studies conducted in different parts of the world have shown that patients with non-Hodgkin’s lymphoma have a higher prevalence of HCV infection [6, 7].
Similarly, several recent reports from different countries also found that patients with B cell non-Hodgkin’s lymphoma (NHL) had a higher carrier rate of hepatitis B, i.e., were positive for hepatitis B surface antigen (HBsAg) [8–12].
With the advance of polymerase chain reaction (PCR) technology, occult hepatitis B virus infection has been redefined in terms of persistence of hepatitis B virus genomes in the liver or serum of HbsAg-negative individuals [13–18]. Several studies showed that rate of occult HBV infection was increased in patients infected with human immunodeficiency virus (HIV) [19–21] and HCV [16, 18, 22] and in individuals at high risk of parenterally transmitted infection including intravenous drug addicts , hemophilia patients , and hemodialysis patients [25, 26]. Moreover, a higher rate of occult HBV infection has been observed in most HBsAg-negative populations in HBV-endemic areas (as defined by the carrier rate of HBsAg) .
As Taiwan is an HBV-endemic area, analyzing the status of HBV infection in Taiwanese patients with non-Hodgkin’s lymphoma would be informative. The current study examined and compared the HBV infection status (i.e., the HBsAg carrier rate and occult HBV infection rate) of NHL patients with that of different control populations. We provide additional evidence supporting the possible role of HBV infection in the etiology of NHL.
Materials and methods
Totally, 471 patients with the diagnosis of NHL at Taipei Veterans General Hospital were enrolled between February 2000 and March 2007. The type of lymphoma was diagnosed according to the World Health Organization (WHO) classification criteria . Blood samples were routinely drawn from all patients, and serological tests for HBsAg, HCV, and HIV were routinely performed at diagnosis. The available sera (stored at diagnosis) from HBsAg-negative patients were screened for occult HBV infection (i.e., HBV-DNA by nested PCR). The study used three different control groups: (1) patients with non-lymphoma cancers (except hepatocellular carcinoma) enrolled by our department during the period of NHL patient enrollment (n = 1013) and used to determine the prevalence of HBsAg carrier status; (2) HBsAg-negative patients in control group 1 with sera stored at diagnosis (n = 124) and chosen at random to determine occult HBV infection status; and (3) HBsAg-negative healthy volunteers (n = 108) enrolled at the time of the study also to determine occult status. All participants provided written informed consent. The evaluations were based on the data available on March 31, 2007.
Serological tests for viral infection
HBsAg was detected by the microparticle enzyme immunoassay (IMx-Abbott Laboratories, Abbott Park, IL, USA), and the reactivity of HBsAg was calculated from the ratio of the sample rate to the MODE 1 calibrator rate. Antibodies to hepatitis C virus were also detected using a microparticle enzyme immunoassay (MEIA, Abbott IMx HCV version 3.0, USA).
Nested PCR for occult HBV infection
PCR primers for detecting HBV genome
Primer set designation
PCR reaction product size (bp)
5′-CAT CAG GAC TCC TAG GAC CC-3
5′-TGC TCG TGT TAC AGG CG-3′
5′-GAG GAC AAA CGG GCA ACA-3′
5′-GAG GCA TAG CAG CAG GAT G-3′
5′-CCA TAC TGC GGA ACT CCT AGC-3′
5′-GCT AGG CTG TGC TGC CAA CT-3¢
5′-CGT TCA CGG TGG TCT CCA T-3′
5′-CGT AAA GAG AGG TGC GCC CCG-3′
5′-TCG CAT GGA GAC CAC CGT GA-3′
5′-CAT AAG AGG ACT CTT GGA CT-3′
5′-ATA GCT TGC CTG AGT GC-3′
5′-GGA AAG AAG TCA GAA GGC-3′
The values are expressed as number (%) for categorical variables and median (range) for continuous variables. Patient demographics and baseline characteristics were compared using an independent-sample t test for continuous variables and chi-square test or Fisher’s exact test for categorical variables. All analyses were performed using the SPSS 13.0 statistical package (SPSS Inc, Chicago IL, USA) and P values of <0.05 were considered statistically significant.
Carrier rates of HBsAg in patients with non-Hodgkin’s lymphoma and other solid tumors
Serological status of hepatitis B surface antigen in patients with B cell and T cell NHL and non-lymphoma cancer patients
Non-lymphoma cancer (%)
No. of patients
No. of patients
Carrier rates of HBsAg in NHL patients of different types
Hepatitis B surface antigen status in patients classified according to WHO criteria for B cell and T cell NHL
B cell lymphoma
Precursor B lymphoblastic leukemia/lymphoma
Chronic lymphoblastic leukemia
Marginal zone B cell lymphoma
Mantle cell lymphoma
T cell lymphoma
Precursor T lymphoblastic leukemia
NK/T cell lymphoma
Subcutaneous panniculitis-like T cell lymphoma
Primary cutaneous anaplastic large cell lymphoma
Peripheral T cell lymphoma-unclassified
Angioimmunoblastic T cell lymphoma
Anaplastic large cell lymphoma
Hepatitis B surface antigen status in patients with non-lymphoma cancers
Head and neck cancer
RCC/bladder cancer/ureteral cancer
Germ cell tumor
Soft tissue tumor
Gastrointestinal stromal tumor
Adrenal gland tumor
Unknown primary cancer
Occult HBV infection in HBsAg-negative NHL patients and non-lymphoma cancer patients
Characteristics of HBsAg-negative B cell NHL patients and different control populations
B cell NHL
No. of patients
The rates of both serum HBsAg and occult HBV infection in our present study showed that HBV infection was more prevalent in NHL patients than in patients in different control populations. This finding provides additional support for the relationship between HBV infection and B cell NHL. In current study, the infection rate (i.e., HBsAg seropositivity) in patients with solid tumors (15.6%) was similar to the previously reported rates in Taiwanese adults (12.8–15.7%) [30, 31]. The rate of occult hepatitis B infection was relatively lower in the HBsAg-negative population including patients with B cell NHL (6%), those with solid tumors (0%), and healthy volunteers (0.9%) than in those reported from other HBV-endemic areas (0–18% of subjects without liver disease) [32, 33]. In addition to differences in geographic distribution and in population, there were differences in samples (e.g., sera or liver tissues), PCR methods (simple vs. nested), and definition of occult HBV infection between the current and previous studies [14–16, 18].
Furthermore, the finding that the higher HBV infection rate was mainly in patients with diffuse large B cell lymphoma (Table 3) has not been previously reported [8–12]. Although possibly biased by differences in B cell lymphoma subtype frequency between our study populations and those of past studies, our finding may provide information that could help decide the population makeup needed to study the relationship between NHL and HBV infection.
Although HBV infection occurred at a higher rate in NHL patients’ sera, we failed to provide direct evidence linking HBV infection to lymphoma, i.e., to detect the viral genome in lymphoma tissues. This pattern of evidence was similar to that for HCV infection in NHL patients in that detection of HCV infection (HCV antibodies and RNA) was also almost entirely restricted to patients’ sera [4, 7, 34]. Possibly, HBV infection does not directly cause lymphoma but rather acts indirectly on B lymphocytes in hosts with persistent HBV infection to transform them after an incubation period .
Although our findings did not provide direct evidence supporting the etiologic role of HBV in the development of lymphoma, the impact of a higher HBV infection rate in patients with B cell NHL (especially those with occult HBV infection) cannot be overlooked. During chemotherapy, occult hepatitis B in NHL patients may reactivate and lead to a typical course of chronic HBV infection [35, 36]. Early detection of occult hepatitis B infection and preemptive use of anti-HBV drugs (e.g., lamivudine) may be effective in decreasing these HBV-related events .
In conclusion, the current study demonstrated a higher prevalence rate of HBV infection in patients with B cell NHL, including those negative for surface antigen. In addition to its etiologic role in lymphoma, occult HBV infection affects the therapy of lymphoma.
We thank Ms. Shu-Chou Chaou and Ms. Chia-Min Shih for performing the laboratory analyses of HBV and HCV markers and Ms. Pui-Ching Lee for statistical analysis. The study was supported by the grants from Taiwan Cancer Clinic Foundation, Taipei Veterans General Hospital (VGH93-192 and 94-236 for PMC, and 96B2-012 for LTH) and National Science Council (NSC), Taiwan (NSC94-2314-B075-049 for PMC, and NSC95-2745-B-075-008 & 96-2321-B-075-008 for LTH).