Hepatitis C virus infection and primary hepatic large B-cell lymphoma: a non-fortuitous association. Case report and review of literature

We report a case of hepatitis C virus infection in association with primary hepatic large B-cell non-Hodgkin's lymphoma. Primary hepatic non-Hodgkin's lymphoma is a rare disease. Association of hepatitis C virus infection with primary hepatic B-cell non-hodgkin's lymphoma is probably not fortuitous. Indeed, in case of primary hepatic non-hodgkin's lymphoma' patients are often hepatitis C virus positive. Moreover, several studies have reported a high prevalence of chronic hepatitis C virus infection among patients with B-cell non-Hodgkin's lymphoma whatever the localization of the lymphoma. A recent study found a high rate of remission of a splenic form of lymphoma after treatment of hepatitis C virus infection. Our case report confirms the hypothesis of a key role of hepatitis C virus in the pathogenesis of various forms of B-cell lymphoproliferative disorders and in particular in primary hepatic lymphoma.     

The relationship between splenic marginal zone B-cell lymphoma and chronic liver disease associated with hepatitis C virus infection

An etiologically important role has been suggested for hepatitis C virus infection in the development of low-grade B-cell non-Hodgkin's lymphoma, such as splenic marginal zone B-cell lymphoma. We present a study of 3 patients with splenic marginal zone B-cell lymphoma and chronic hepatitis C, and describe clinical, histologic, and immunohistochemical features and the response to therapy in these cases. All 3 patients underwent splenectomy, polychemotherapy and alpha-interferon therapy. The first patient achieved complete remission; the second died of hepatic failure and anasarca 3 months after admission; as this writing, the third remains in complete remission 4.5 years after diagnosis. In the second patient, a long latency period of chronic hepatitis C virus infection was observed. Our data indicate that when early detection of the disease is possible, splenic marginal zone B-cell lymphoma has a relatively favorable prognosis. Our results could furthermore suggest an etiologic role for hepatitis C virus infection in the development of splenic B-cell lymphoma through multistep cooperating events. A fuller understanding of the virus-related mechanisms of lymphoproliferation could contribute significantly to the development of new therapeutic strategies.     

Hepatitis C virus and non-Hodgkin's lymphoma 10 years later

Hepatitis C virus is associated with chronic liver disease as well as with lymphoproliferative disorders such as mixed cryoglobulinemia and, likely, non-Hodgkin's lymphomas. The association between hepatitis C virus infection and B-cell lymphoma is controversial since it shows a strong regional variation. In fact, the prevalence of hepatitis C virus infection in non-Hodgkin's lymphoma shows a prevalence ranging between 7.4 and 37.0%. However, the intimate pathogenetic mechanism involved in hepatitis C virus-associated lymphomas remains considerably unknown. Hepatitis C virus may exert its oncogenic potential via an indirect mechanism or utilise other pathways directly. It is reasonable to assume that several different pathogenetic mechanisms operate in the wide spectrum of hepatitis C virus-related lymphoproliferative disorders, which include the intermediate to high-grade lymphoma, and the more common indolent, low-grade lymphoma, preceded by long standing symptomatic mixed cryoglobulinemia Type II. In this review, the etiopathogenetic role of hepatitis C virus in non-Hodgkin's lymphoma is discussed on the basis of molecular, clinical and epidemiological considerations.The management of hepatitis C virus-associated non-Hodgkin's lymphoma is similar to that of conventional lymphoma, although viral reactivation or the underlying chronic liver disease can complicate chemotherapy. Whether to treat low-grade hepatitis C virus-related lymphomas with anti-viral therapy is still debatable, but encouraging data emerge from some recent studies.     

Splenic marginal zone lymphoma in a HIV-1 infected patient: evidence favouring a pathogenetic role of HIV-1 itself in the lymphomagenesis

A rare case of splenic marginal zone lymphoma (SMZL) in a human immunodeficiency virus (HIV)-1 infected patient is described. As an association between SMZL and viral infections has been reported, the presence of the hepatitis C virus and HIV-1 genomes was evaluated. Only HIV-1 DNA levels were detected in enriched splenic B lymphocytes, suggesting a HIV-1 involvement in lymphomagenesis.     

Accelerated hepatitis C virus replication with rituximab treatment in a non‐Hodgkin's lymphoma patient

The treatment of patients with non‐Hodgkin's lymphoma (NHL) may be complicated by concomitant chronic hepatitis C virus (HCV) infection. Recent data suggest that HCV may also be a contributing factor to the development of this disease. Although antiviral treatment has occasionally been reported to result in the regression of lymphoma in patients with HCV infection, the importance of the control of this infection on the prognosis of lymphoma needs to be defined. Here we report a patient with diffuse large B‐cell lymphoma who presented with a mass in her left breast. She had had HCV‐related liver cirrhosis for 6 years. She was given rituximab monotherapy for three consecutive weeks, but treatment had to be discontinued as a result of hematological toxicity. HCV viral load also increased, but then decreased gradually after rituximab was stopped. She could be given no further therapy. Six months later she presented with spinal involvement with infiltration of the cauda equina. Though cranial–spinal radiotherapy and steroids were started, she died shortly thereafter. Though rituximab is an invaluable drug in the treatment of B‐cell lymphomas, we believe that the use of such agents with potentially long‐lasting effects on B lymphocytes requires extended vigilance for accelerated replication of hepatitis B and C viruses.     

Hepatitis B virus reactivation after a resolutive acute hepatitis leading to a diagnosis of T cell lymphoma

A case of hepatitis B virus reactivation leading to the diagnosis of a T cell lymphoma is reported. A 66-year-old woman with a past history (10 years before) of spontaneously recovered acute hepatitis B (with disappearance of serum hepatitis B surface antigen and appearance of anti-HBs), has been referred for hepatologic consultation for acute hepatitis. The patient was found positive again for hepatitis B surface antigen as well HBeAg and hepatitis B virus DNA. No other cause of liver disease was identified and a diagnosis of spontaneous hepatitis B virus reactivation was made. Five months later a peripheral T cell lymphoma was diagnosed. This unusual case confirms that natural immunity is not protective against hepatitis B virus reactivation and shows that such hepatitis B virus reactivation may precede the usual clinical manifestations of a peripheral T cell lymphoma.     

Lymphomas complicating Sjögren's syndrome and hepatitis C virus infection may share a common pathogenesis: chronic stimulation of rheumatoid factor B cells

BACKGROUND: The occurrence of B cell non-Hodgkin's lymphoma is a complication of Sj?gren's syndrome (SS) and, at least in some countries, of chronic hepatitis C virus (HCV) infection. Lymphomas occurring in both diseases share a number of characteristics: predominance of low grade, marginal zone histological type, frequency of mucosal localisation, possible transformation into a large B cell lymphoma, association with asymptomatic low level cryoglobulinaemia, absence of virus within lymphoma cells, but localisation of lymphomas in organs where the chronic viral infection is active in patients with HCV and where the autoimmune disease is active in patients with SS. HYPOTHESIS: It is proposed that in both diseases the first event of lymphomagenesis is the chronic stimulation at the site of the disease of polyclonal B cells secreting rheumatoid factor (RF). Then, that these RF B cells may become monoclonal and disseminate in other organs. The monoclonal secreted RF complexed with polyclonal IgG may cryoprecipitate. The following step would be a chromosomal abnormality (for example, trisomy 3 or bcl-2 translocation) which would confer to these cells a low grade B cell lymphoma comportment. A last event (for example, a mutation of p53) might transform this low grade B cell lymphoma into a high grade, large B cell lymphoma. The non-random utilisation of VH and VL by SS associated lymphoma B cells and the recent demonstration that these lymphoma B cells may display RF activity support the hypothesis that these lymphomas grow through an autoantigen driven process. CONCLUSION: The best preventive treatment of lymphoproliferations occurring in SS probably consists in decreasing the hyperactivation of autoreactive B cells when it is present, allowing the use of immunosuppressive drugs such as methotrexate or even tumour necrosis factor alpha antagonists, which in theory could favour other types of lymphoproliferation.     

Hepatitis C virus infection and non-Hodgkin's lymphoma: a review and case report of nine patient

The role of hepatitis C virus (HCV) is well established in the development of chronic hepatitis, cirrhosis and hepatic carcinoma, as well as in mixed type II cryoglobulinemia, membranoproliferative glomerulonephritis(MPGN) and porphyria cutanea tarda (PCT). Increasing evidence has been reported of a close association of HCV infection with autoimmune and hematological processes, mainly cytopenias and lymphoproliferative disorders such as B cell non-Hodgkin's lymphoma. We describe the demographic, clinical and histopathological findings of nine patients from the Mexican population with non-Hodgkin's lymphoma and HCV infection.     

A case of primary hepatic lymphoma with hepatitis C liver cirrhosis

Primary hepatic lymphoma is rare. The usual type is a large-cell, high-grade malignant B-cell lymphoma, although T-cell types have been described. Several cases of primary hepatic lymphoma of B-cell origin developing in patients with chronic hepatitis C virus infection have been reported. Recently, new findings have raised the question of the induction of lymphoma by hepatitis C virus. However, the causal relationship between hepatitis C viral infection and primary hepatic lymphoma remains obscure. This article reports a case of histologically proven primary hepatic lymphoma of T-cell origin, which was confined to the liver, in the setting of hepatitis C liver cirrhosis. This association has not previously been reported.     

Prevalence of hepatitis B and C viruses in patients with lymphoproliferative disorders

The etiology of most lymphoproliferative disorders remains unclear, though several hypotheses have been proposed. One of the conjectured mechanisms is infection of a tumor clone by an oncologic virus. Recently, evidence has arisen implicating both hepatitis B and, even more so, hepatitis C viruses in the pathogenesis of lymphoproliferative disease. Based on this information, we surveyed the prevalence of hepatitis B and C virus in patients with lymphoproliferative disease. A total of 334 newly-diagnosed lymphoproliferative disease patients (200 males, 134 females) and 1,014 (133 females, 881 males) healthy controls were randomly recruited from the university blood bank. Serologic evaluation for hepatitis B and C viruses was conducted and confirmed using PCR analyses. Those with hepatitis B and/or C, controls, and subgroups of patients with lymphoproliferative disease were compared using Pearson Chi-square analysis. Among patients with lymphoid tumors, the seropositivity of HbsAg and/or anti-HCV was 8.7% (29/334), and among the controls 6.1% (49/802), however this difference did not achieve statistical significance (P = 0.23, OR: 1.36, 95% CI: 0.82–2.26). We found no significant gender- or age-related differences for either hepatitis B or C seropositivity. There were no significant differences between the seropositivity rates of hepatitis B, C, or both in either NHL or Hodgkin’s lymphoma. However, in the diffuse large cell lymphoma and follicular lymphoma subgroups, the HbsAg seropositivity rate was significantly higher than that in the controls (P = 0.017, P = 0.048, respectively), as was the seropositivity rate for hepatitis C in those with diffuse B cell lymphoma versus controls (P = 0.008). We did not identify any significant difference in the combined prevalence of hepatitis B or C seropositivity between patients with lymphoproliferative disorders and controls. However, significant differences were revealed among certain patient subgroups versus the controls. These two viruses could play a role in the development of certain specific lymphoproliferative disorders. Nevertheless, larger epidemiological studies are necessary and should focus, particulary on specific patient subgroups.     

Update in Hepatitis C virus associated extrahepatic manifestations

INTRODUCTION: Since the discovery of the hepatitis C virus, many manifestations, so called extra-hepatic manifestations (EHM), are largely reported with more or less relationship proofs. ACTUALITIES AND MAIN POINTS: This article proposes a review of the main extra-hepatic manifestations associated with the Hepatis C Virus infection and which remain a topical subject, more than fifteen years after the discovery of this virus. Mixed cryoglobulin and its vasculitic manifestations are still one of the more frequent Hepatis C Virus associated-extra-hepatic manifestations. Its management may be critically changed due to the increasing use of anti-CD20 therapy. Among other HCV-EHM, the following extra-hepatic manifestations are still of interest: the chronic fatigue syndrome, the sicca syndrome, the non-insulin-dependent diabetes mellitus, malignant B cell proliferations, mainly the Hepatis C Virus-related splenic lymphoma with villous lymphocytes and the production of auto-antibodies. PERSPECTIVES AND PROJECTS: The mechanisms underlying these HCV-associated EHM are ill-elucidated and still remain of great interest as proved by current studies. The use of anti-CD20 antibodies in the treatment of cryoglobulinemic vasculitis is also under investigation.     

Fatal Hepatitis B Reactivation Treated With Entecavir in an Isolated Anti-HBs Positive Lymphoma Patient: A Case Report and Literature Review

Hepatitis B virus (HBV) reactivation is a well-recognized complication that occurs in lymphoma patients who undergo chemotherapy. Only very few cases of HBV reactivation in patients with isolated antibody against hepatitis B surface antigen (anti-HBs) have been reported. We present a case of a 78-year-old woman diagnosed with diffuse large B cell non-Hodgkin''s lymphoma who only displayed a positive anti-HBs, as the single possible marker of occult HBV infection, before starting therapy. She was treated with several chemotherapeutic regimens (including rituximab) for disease relapses during 3 years. Forty days after the last cycle of chemotherapy, she presented with jaundice, markedly elevated serum aminotransferase levels, and coagulopathy. HBV serology showed positivity for HBsAg, anti-HBc and anti-HBs. HBV DNA was positive. Antiviral treatment with entecavir was promptly initiated, but the patient died from liver failure. A review of the literature of HBV reactivation in patients with detectable anti-HBs levels is discussed.     

Lymphomas complicating Sjögren's syndrome and hepatitis C virus infection may share a common pathogenesis: chronic stimulation of rheumatoid factor B cells

BACKGROUND—The occurrence of B cell non-Hodgkin's lymphoma is a complication of Sjögren's syndrome (SS) and, at least in some countries, of chronic hepatitis C virus (HCV) infection. Lymphomas occurring in both diseases share a number of characteristics: predominance of low grade, marginal zone histological type, frequency of mucosal localisation, possible transformation into a large B cell lymphoma, association with asymptomatic low level cryoglobulinaemia, absence of virus within lymphoma cells, but localisation of lymphomas in organs where the chronic viral infection is active in patients with HCV and where the autoimmune disease is active in patients with SS.
HYPOTHESIS—It is proposed that in both diseases the first event of lymphomagenesis is the chronic stimulation at the site of the disease of polyclonal B cells secreting rheumatoid factor (RF). Then, that these RF B cells may become monoclonal and disseminate in other organs. The monoclonal secreted RF complexed with polyclonal IgG may cryoprecipitate. The following step would be a chromosomal abnormality (for example, trisomy 3 or bcl-2 translocation) which would confer to these cells a low grade B cell lymphoma comportment. A last event (for example, a mutation of p53) might transform this low grade B cell lymphoma into a high grade, large B cell lymphoma. The non-random utilisation of VH and VL by SS associated lymphoma B cells and the recent demonstration that these lymphoma B cells may display RF activity support the hypothesis that these lymphomas grow through an autoantigen driven process.
CONCLUSION—The best preventive treatment of lymphoproliferations occurring in SS probably consists in decreasing the hyperactivation of autoreactive B cells when it is present, allowing the use of immunosuppressive drugs such as methotrexate or even tumour necrosis factor α antagonists, which in theory could favour other types of lymphoproliferation.

     

Complete remission of splenic marginal zone lymphoma after an acute flare-up of hepatitis B in a hepatitis B virus carrier

A 44-year-old female presented with asymptomatic leukocytosis and moderate splenomegaly. The diagnosis of splenic marginal zone lymphoma (SMZL) was made by a splenectomy. A virological examination revealed the patient to be a hepatitis B virus (HBV) carrier. The lymphocyte count in her peripheral blood decreased after splenectomy, but remained high for 2 years and bone marrow infiltration was obvious. Two years after the splenectomy, she was admitted for an acute flare-up of hepatitis B. The liver dysfunction improved without any medication and thereafter returned to the normal range within a few weeks. At the same time, the lymphocyte count in her peripheral blood rapidly decreased to normal levels. Atypical lymphocytes disappeared from the peripheral blood and bone marrow aspirates and biopsy specimen revealed complete remission of SMZL, including the disappearance of the clonal rearrangement of IgH-JH. There has been no recurrence of acute hepatitis and she has been in complete remission for SMZL for more than 6 years. The clinical course of this patient suggests that an immune response against HBV also affects the clearance of lymphoma cells. This is the first report that a complete remission was achieved in a patient with SMZL after a hepatitis B flare-up.     

Simultaneous occurrence of a hepatocellular carcinoma and a hepatic non-Hodgkin's lymphoma infiltration

To investigate the simultaneous occurrence of hepatocellular carcinoma and non-Hodgkin's lymphoma, we report the case of a 70 year old patient with a primary diagnosis of non-Hodgkin's lymphoma in 2002. In a routine follow up investigation of his chronic lymphocytic leukemia a newly detected mass in the Couinaud's segments 2 and 3 was found. No hepatitis C virus or hepatitis B virus infection or cirrhosis was evident. After laparoscopic segmentectomy the histological examination revealed a hepatocellular carcinoma. While the relation between liver parenchyma damages and hepatocellular carcinoma or non-Hodgkin's lymphoma is well known, only a few publications have focused on the coexistence of hepatocellular carcinoma and non-Hodgkin's lymphoma. With this case we demonstrate the coexistence of these diseases without having a predamaged liver parenchyma.     

Hepatitis C virus risk: a hepatitis C virus related syndrome

BACKGROUND: The association between mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) infection has been recently described in many reports. OBJECTIVE: The aim of this study was to evaluate the long-term prognosis of hepatitis C virus-positive patients affected by mixed cryoglobulinemia with or without kidney involvement. PATIENTS: At total of 119 hepatitis C virus-positive patients affected by mixed cryoglobulinemia were divided in two groups. Group A: mixed cryoglobulinemia without kidney involvement (103 cases); group B: mixed cryoglobulinemia with glomerulonephritis (GN) (16 cases). A further 37 patients affected by mesangio-proliferative glomerulonephritis (MPGN) were evaluated as controls (group C). METHODS: Anti-hepatitis C virus antibodies were determined by commercial kits and hepatitis C virus-RNA was detected by polymerase chain reaction (PCR) amplification of the 5' untranslated region (5'UTR) of the virus. The hepatitis C virus genotype was determined according to Okamoto. Liver biopsy was performed in 62 patients, bone marrow biopsy in 65 patients, and kidney biopsy in all patients with proteinuria. RESULTS: In group A, 46 patients (45%) were affected by chronic liver disease (CLD), 21 (20%) by low-grade non-Hodgkin's lymphoma (NHL) and 16 (15%) by both diseases. All patients of group B were affected by type I membrano-proliferative glomerulonephritis, 3 (19%) by chronic liver disease, 6 (37%) by low-grade non-Hodgkin's lymphoma, and 7 (44%) by both diseases. Several genotypes of hepatitis C virus were found, but Type 1b was prevalent. In group C, no patient showed chronic liver disease or non-Hodgkin's lymphoma. Younger age, higher mean blood pressure, lower C4 serum level, and poorer survival significantly distinguished group B from group A. Survival rates at 5 years were: 87.4% for group A, 89.5% for group C, and 50.0% for group B. None of the patients of group B developed kidney failure requiring dialysis, whilst infections were the leading cause of death. CONCLUSIONS: In hepatitis C virus-positive patients, the presence of mixed cryoglobulinemia associated with kidney involvement seems to indicate a new syndrome characterized by immune system impairment, lack of progression to kidney failure, and poor survival (hepatitis C virus-Risk syndrome).     

Chronic hepatitis C virus infection associated with primary warm-type autoimmune hemolytic anemia

Autoimmune hematologic abnormalities are not well recognized in chronic hepatitis C virus infection. We demonstrate an unusual association between primary autoimmune hemolytic anemia and chronic hepatitis C virus infection. A 69-year-old woman who had a history of hepatitis C virus-related liver cirrhosis was found to have deteriorating anemia with reticulocytosis when admitted to the hospital. Laboratory work revealed both positive direct and indirect Coombs' tests, and warm-type immunoglobulin G against surface antigens of red blood cells. After prednisolone therapy, her anemia improved dramatically. To our knowledge, this is the first reported case of chronic hepatitis C virus infection linked with autoimmune hemolytic anemia in its natural course, not related to prior interferon treatment. Our report suggests that isolated autoimmune hemolytic anemia may be one of the unusual hematologic manifestations of chronic hepatitis C virus infection.     

Hepatitis viruses (other than hepatitis B and C viruses) as causes of hepatocellular carcinoma: an update

Chronic hepatitis B and C virus infections are universally accepted as causes of hepatocellular carcinoma in humans. Hepatitis A and E viruses cause only acute self‐limiting infections of the liver. Of the remaining hepatitis viruses ‐ Delta hepatitis, hepatitis G (GB‐C), TT and SEN ‐ all have at some time been incriminated as causes of hepatocellular carcinoma. Delta hepatitis virus requires helper functions from hepatitis B virus to become invasive. Chronic Delta/hepatitis B viral co‐infection runs a more severe course than that resulting from chronic hepatitis B virus infection alone, with progression to cirrhosis being more likely and more rapid. A substantial majority of the early studies did not find an increased incidence of hepatocellular carcinoma in co‐infected individuals. But more recently, an increased incidence of the tumour has been recorded more often than no increase. Further studies are needed to draw a firm conclusion with regard to the hepatocarcinogenic effect of dual Delta/hepatitis B virus co‐infection. With one exception, no published study (of 13) has incriminated chronic infection with hepatitis G virus as a cause of hepatocellular carcinoma. The dissenting study, published in 1999, was the only one performed in the United States. Fewer studies of the hepatocarcinogenic effect of TT virus have been performed. Apart from one study, published in 1999, no convincing evidence is available that supports a causal role for TT virus in hepatocarcinogenesis. The exception was in Japanese patients with high hepatitis C viral loads but independent of chronic hepatitis C virus infection. No evidence has been produced to indicate that SEN virus causes hepatocellular carcinoma.     

Proliferating cell nuclear antigen assessed by a computer-assisted image analysis system in patients with chronic viral hepatitis and cirrhosis

BACKGROUND: Assessment of liver cell proliferation by immunodetection of proliferating cell nuclear antigen may predict regenerative potential and survival of liver and hepatocellular carcinoma risk in patients with chronic viral hepatitis. AIM: To evaluate proliferating cell nuclear antigen status and its clinical significance in a large cohort of patients with chronic viral hepatitis and different degree of liver damage by a computer assisted imaging analysis system. MATERIALS: Liver biopsies from 358 patients with chronic hepatitis (259 males, 49 years, 63% with hepatitis C infection, 27% with hepatitis B virus, 10% with multiple infections) were studied. METHODS: Proliferating cell nuclear antigen was localised by immunoperoxidase on microwave oven pre-treated formalin-fixed, paraffin embedded sections using PC10 monoclonal antibody. Proliferating cell nuclear antigen labelling index was calculated by an automated imaging system (Immagini e Computers, Milan, Italy). RESULTS: Mean proliferating cell nuclear antigen labelling index ranged from 0.1% for patients with minimal changes to 3.6% for those with cirrhosis and hepatocellular carcinoma. Overall, proliferating cell nuclear antigen labelling index was higher in males, in older patients, in multiple infections and in hepatitis C virus compared to hepatitis B virus related cases. By linear regression analysis, proliferating cell nuclear antigen labelling index correlated with older age, male gender; higher transaminase levels, hepatitis C virus, higher histological gradIng and staging: by multivariate analysis male gender, hepatitis C virus, higher grading and staging resulted as independent variables. Both hepatitis C virus or hepatitis B virus cirrhotics had similar liver cell proliferation rate but those with hepatitis B virus had higher prevalence of liver cell dysplasia with respect to those with hepatitis C virus. CONCLUSIONS: Proliferating cell nuclear antigen labelling index was a reliable assay for assessing liver cell proliferation rate in patients with chronic viral hepatitis and correlated with liver disease severity     

Primary effusion lymphoma of the left scrotum

A 51-year-old man without human immunodeficiency virus, hepatitis B virus or hepatitis C virus was admitted with left scrotum swelling and hydrocele. The cytological finding of fluid in the left scrotum revealed malignant lymphoma, and the immunophenotypic analysis and monoclonal rearrangement of immunoglobulin heavy chain demonstrated B-cell lymphoma. However, no solid tumor of lymphoma was identified in the specimen following a left orchiectomy, or in any other body site and genomic human herpes virus-8 and Epstein-Barr virus were not detected in the lymphoma cells. So we interpreted this as a primary effusion lymphoma without any ethological viral infection. Subsequently, he underwent chemo-radiation therapy and has remained in remission.