Characterization of Overt B-Cell Lymphomas in Patients With Hepatitis C Virus Infection

Abstract A pathogenetic role of the hepatitis C virus (HCV) has been hypothesized for a subset of B-cell non-Hodgkin's lymphomas (NHLs). However, the preliminary characterization of B-cell NHLs in HCV-infected individuals has been poorly addressed. In the present study, we report detailed information on 35 consecutive patients with overt B-cell NHL of recent onset and HCV infection; all patients referred to a single oncological center in Northeast Italy. Histopathologic evaluation was performed by a single reference hemopathologist, and the link with the two relevant autoimmune diseases predisposing to B-cell NHL and in which HCV has been implied, ie, “essential” mixed cryoglobulinemia (EMC) and Sjögren's syndrome, was investigated. Control groups included 122 consecutive HCV-negative patients with B-cell NHL and 464 consecutive histopathologic cases of B-cell NHL referred to the same center, as well as 127 consecutive patients with HCV infection and without lymphoma referred to a different center in the same geographical area. B-cell NHLs in HCV-infected patients frequently presented at onset (1) an extranodal localization with peculiar target organs of HCV infection (ie, the liver and major salivary glands) being significantly overrepresented; (2) a diffuse large cell histotype without any prior history of low-grade B-cell malignancy or bone marrow involvement; and (3) a weak association with a full-blown predisposing autoimmune disease, although serum autoimmune features were common and cryoglobulins were always present. Therefore, the HCV-related B-cell NHLs in this oncological series presented distinctive features compared with B-cell NHLs in HCV-negative patients, and they differed from bone marrow low-grade NHLs frequently diagnosed in HCV-positive patients with EMC. Such novel information may be relevant for future research aimed at clarifying the possible link between HCV infection, autoimmunity, nonmalignant B-cell lymphoproliferation, and overt B-cell malignancy.

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Characterization of Overt B-Cell Lymphomas in Patients With Hepatitis C Virus Infection

Blood ◽

10.1182/blood.v90.2.776.776_776_782 ◽

1997 ◽

Vol 90 (2) ◽

pp. 776-782 ◽

Cited By ~ 2

Author(s):

Salvatore De Vita ◽

Cosimo Sacco ◽

Domenico Sansonno ◽

Annunziata Gloghini ◽

Franco Dammacco ◽

...

Keyword(s):

Bone Marrow ◽

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Hcv Infection ◽

Low Grade ◽

B Cell Malignancy ◽

Hodgkin's Lymphomas ◽

Cell Malignancy

A pathogenetic role of the hepatitis C virus (HCV) has been hypothesized for a subset of B-cell non-Hodgkin's lymphomas (NHLs). However, the preliminary characterization of B-cell NHLs in HCV-infected individuals has been poorly addressed. In the present study, we report detailed information on 35 consecutive patients with overt B-cell NHL of recent onset and HCV infection; all patients referred to a single oncological center in Northeast Italy. Histopathologic evaluation was performed by a single reference hemopathologist, and the link with the two relevant autoimmune diseases predisposing to B-cell NHL and in which HCV has been implied, ie, “essential” mixed cryoglobulinemia (EMC) and Sjögren's syndrome, was investigated. Control groups included 122 consecutive HCV-negative patients with B-cell NHL and 464 consecutive histopathologic cases of B-cell NHL referred to the same center, as well as 127 consecutive patients with HCV infection and without lymphoma referred to a different center in the same geographical area. B-cell NHLs in HCV-infected patients frequently presented at onset (1) an extranodal localization with peculiar target organs of HCV infection (ie, the liver and major salivary glands) being significantly overrepresented; (2) a diffuse large cell histotype without any prior history of low-grade B-cell malignancy or bone marrow involvement; and (3) a weak association with a full-blown predisposing autoimmune disease, although serum autoimmune features were common and cryoglobulins were always present. Therefore, the HCV-related B-cell NHLs in this oncological series presented distinctive features compared with B-cell NHLs in HCV-negative patients, and they differed from bone marrow low-grade NHLs frequently diagnosed in HCV-positive patients with EMC. Such novel information may be relevant for future research aimed at clarifying the possible link between HCV infection, autoimmunity, nonmalignant B-cell lymphoproliferation, and overt B-cell malignancy.

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Clinico-pathological characterization of hepatitis C virus-related B-cell non-Hodgkin’s lymphomas without symptomatic cryoglobulinemia

Annals of Oncology ◽

10.1023/a:1008255830453 ◽

1998 ◽

Vol 9 (5) ◽

pp. 495-498 ◽

Cited By ~ 74

Author(s):

M. Luppi ◽

G. Longo ◽

M.G. Ferrari ◽

P. Barozzi ◽

R. Marasca ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Hodgkin's Lymphomas

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Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders

Blood ◽

10.1182/blood.v87.10.4296.bloodjournal87104296 ◽

1996 ◽

Vol 87 (10) ◽

pp. 4296-4301 ◽

Cited By ~ 237

Author(s):

F Silvestri ◽

C Pipan ◽

G Barillari ◽

F Zaja ◽

R Fanin ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Close Association ◽

Mixed Cryoglobulinemia ◽

Lymphoproliferative Disorders ◽

Hcv Infection ◽

Hcv Rna ◽

Hodgkin's Lymphomas ◽

Hcv Genotyping

It has been recently hypothesized that the hepatitis C virus (HCV) might be involved in the pathogenesis of malignant B-cell non-Hodgkin's lymphomas (NHL). On the basis of this observation we sought to determine the prevalence of HCV infection in the patients affected by B- cell NHL and extended our analysis to all the patients affected by lymphoproliferation disorders seen at our institution in the last 30 months. Five hundred and thirty-seven unselected, consecutive patients were studied. HCV infection was investigated through detection of anti- HCV antibodies and HCV-RNA. HCV genotyping was performed on HCV-RNA positive specimens. The risk of being infected by HCV was compared with that of the general population of our area. Among all lymphoproliferative disorders, the prevalence and the relative risk (RR) of being infected by HCV were increased only among B-cell NHL (9%; RR 3.24; p < .0001). Among these, a strong prevalence of HCV was found only in the subgroup of immunocytomas (30%; RR 10.27; P < .0001), while other histotypes were associated with it only occasionally. Because HCV- positive lymphomas clinically behave as essential mixed cryoglobulinemia (EMC), the close association between HCV infection and EMC is confirmed, and evidence is provided that the pathological substrate of EMC corresponds to the immunocytoma. HCV genomic sequences were found in 84% of patients analyzed. Viral genotypes were those more frequent in our area.

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Clinical Features and Outcome of 147 Patients with Diffuse Large B-Cell Lymphoma and Hepatitis C Virus Infection.

Blood ◽

10.1182/blood.v106.11.1921.1921 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1921-1921

Author(s):

Carlo Visco ◽

Luca Arcaini ◽

Michele Merli ◽

Annalisa Andreoli ◽

Sara Burcheri ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

Hcv Infection ◽

Low Grade ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Hepatitis C virus (HCV) has been implicated in the pathogenesis of a subset of low-grade non-Hodgkin lymphomas. Furthermore, diffuse large B-cell lymphoma (DLBCL) has been correlated to HCV infection in several series from our geographical area (north-east of Italy), but little is known about the characteristics of such high-grade tumors. We analyzed presentation features of 147 previously untreated HCV-positive patients with DLBCL who presented to the three participating centers between 1993 and 2004. All patients were provided with complete clinical information, were HIV negative, and had been tested at tumor onset for HCV antibodies by ELISA and RIBA. Median age at presentation was 64 years old (range 29–88), 47% were males, ECOG performance status was >1 in 20%, Ann Arbor stage was I in 20%, II in 27%, III in 26%, IV in 27%, and B-symptoms were present in 37% of patients. The International Prognostic Index (IPI) value at diagnosis was low in 18%, int/low in 23%, int/high in 32%, and high in 27% of patients. Surprisingly, DLBCL transformed from a low-grade histology represented only 7% of the whole population, while primary mediastinal DLBCL were extremely rare (1/147, <1%). Patients frequently presented as primary extranodal DLBCL (65/147, 44%). Most involved extranodal sites were skin, liver, stomach, and spleen, with the latter being the most represented syte (33% of patients). Remarkably, spleen was the only extranodal involved organ in 20% of patients. Treatment was delivered with cure-intent, and consisted of CHOP-like regimens +/− Rituximab for the large majority of patients, except for 16 (11%) patients with cirrhosis or severe hepatic dysfunction, who received mono-chemotherapy or radiotherapy. Only three (2%) HCV-positive patients had to discontinue chemotherapy due to liver function impairment. The addition of Rituximab to chemotherapy did not seem to affect patients’ tolerance to treatment. With a median follow-up of 48 months for survivors, 5-year overall survival (OS) was 75%, while 5-year failure-free survival (FFS) was 51%. In particular, the 65 patients with primary extranodal DLBCL shared a better 5-year OS (83% vs 71%, p=0.01) and FFS (75% vs 39%, p=0.009) than their nodal counterpart. Nodal origin of the tumor resulted the strongest independent adverse factor both in terms of OS and FFS in multivariate analysis. The peculiar clinical behavior shared by HCV-positive DLBCL may disclose relevant biological features of these tumors, and may be relevant for future studies aiming to clarify the link between HCV infection and aggressive lymphoproliferative disorders.

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Role of Anti-Hepatitis C Virus (HCV) Treatment in HCV-Related, Low-Grade, B-Cell, Non-Hodgkin's Lymphoma: A Multicenter Italian Experience

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.008 ◽

2005 ◽

Vol 23 (3) ◽

pp. 468-473 ◽

Cited By ~ 174

Author(s):

Daniele Vallisa ◽

Patrizia Bernuzzi ◽

Luca Arcaini ◽

Stefano Sacchi ◽

Vittorio Callea ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Antiviral Treatment ◽

Complete Response ◽

Hcv Infection ◽

Low Grade ◽

Hcv Treatment ◽

Hematologic Response

Purpose Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. Patients and Methods Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. Results Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 ± 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. Conclusion This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

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Detection and distribution of hepatitis C virus-related proteins in lymph nodes of patients with type II mixed cryoglobulinemia and neoplastic or non-neoplastic lymphoproliferation

Blood ◽

10.1182/blood.v88.12.4638.bloodjournal88124638 ◽

1996 ◽

Vol 88 (12) ◽

pp. 4638-4645 ◽

Cited By ~ 82

Author(s):

D Sansonno ◽

S De Vita ◽

V Cornacchiulo ◽

A Carbone ◽

M Boiocchi ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Mixed Cryoglobulinemia ◽

Hcv Infection ◽

Lymphoid Cells ◽

Small Cells ◽

Low Grade ◽

Type Ii ◽

Related Proteins

The role of hepatitis C virus (HCV) in the pathogenesis of type II mixed cryoglobulinemia (MC) has been strongly emphasized in the last few years. Although MC is a benign lymphoproliferative disorder, the risk of overt B-cell malignancy greatly increases during its course. The occurrence of HCV infection in 10% to 30% of patients with non-Hodgkin's lymphoma (NHL) suggests that this virus may have a role in the development of MC-associated B-cell malignancies. We identified 2 patients with hyperplastic reactive lymphadenopathy (HRL) and 12 with NHL in two series of MC patients chronically infected with HCV collected over a 5-year period. Structural and nonstructural HCV-related proteins were investigated in lymph node sections by immunohistochemistry and their location and distribution were correlated with clinical and histologic findings, viremic state, and HCV genotypes. In HRL, HCV proteins were found in the cytoplasm of lymphoid cells, mainly in interfollicular areas. However, occasional positive cells were found in the mantle zone and in the germinal centers of follicles. In addition, strong reactivity was found in the circulating mononuclear cells of capsular blood vessels. HCV immunodeposits were found in 3 of 12 (25%) NHL cases. Positive cells were frequently restricted to the cortex; if not, they were randomly diffused in the neoplastic tissue. Positivity was related to the low-grade type of NHL; in the 2 composite cases, HCV immunodetection was found in the small cells, whereas large anaplastic cells were regularly negative. Other viruses previously involved in lymphoproliferation, ie, human herpes virus-6 and Epstein-Barr virus, were absent in all tissues. These data emphasize that lymphoid organs may be a site of HCV infection. The demonstration of HCV-related proteins in a nonmalignant condition, namely HRL, indicates that HCV infection precedes the neoplastic transformation and possibly plays a major role in lymphomagenesis in MC.

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B cell malignancy and hepatitis C virus infection

Leukemia Research ◽

10.1016/0145-2126(95)00091-7 ◽

1996 ◽

Vol 20 (5) ◽

pp. 445 ◽

Cited By ~ 22

Author(s):

Tohru Izumi ◽

Ryuhei Sasaki ◽

Yasusada Miura ◽

Hiroaki Okamoto

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Virus Infection ◽

B Cell ◽

Hepatitis C Virus Infection ◽

B Cell Malignancy ◽

Cell Malignancy

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Pathogenetic Mechanisms of Hepatitis C Virus-Induced B-Cell Lymphomagenesis

Clinical and Developmental Immunology ◽

10.1155/2012/807351 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 16

Author(s):

Fabio Forghieri ◽

Mario Luppi ◽

Patrizia Barozzi ◽

Rossana Maffei ◽

Leonardo Potenza ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cell ◽

Epidemiological Studies ◽

Hcv Infection ◽

Chronic Hcv Infection ◽

Chronic Hcv ◽

Hodgkin's Lymphomas ◽

Affinity Interaction ◽

Global Population

Hepatitis C virus (HCV) infection is probably the most common chronic viral infection and affects an estimated 180 million people worldwide, accounting for 3% of the global population. Although the liver is considered to be the primary target, extrahepatic manifestations are well recognized among patients with chronic HCV infection. Epidemiological studies have clearly demonstrated a correlation between chronic HCV infection and occurrence of B-cell non-Hodgkin's lymphomas (B-NHL). The clinical evidence that antiviral therapy has a significant role in the treatment at least of some HCV-associated lymphoproliferative disorders, especially indolent B-NHL, further supports the existence of an etiopathogenetic link. However, the mechanisms exploited by HCV to induce B-cell lymphoproliferation have so far not completely clarified. It is conceivable that different biological mechanisms, namely, chronic antigen stimulation, high-affinity interaction between HCV-E2 protein and its cellular receptors, direct HCV infection of B-cells, and “hit and run” transforming events, may be combined themselves and cooperate in a multifactorial model of HCV-associated lymphomagenesis.

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Non-Hodgkin's Lymphomas Associated With Positive Hepatitis-C Virus Infection: A Prospective Multicentric Observational Study On Behalf Of The “Rete Ematologica Lombarda/Hematology Network Of Lombardia Region”

Blood ◽

10.1182/blood.v122.21.3003.3003 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3003-3003

Author(s):

Sara Rattotti ◽

Luca Arcaini ◽

Virginia Valeria Ferretti ◽

Andrea Rossi ◽

Stefano Fogazzi ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Observational Study ◽

B Cell ◽

Virological Response ◽

Liver Toxicity ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Low Grade ◽

Hodgkin's Lymphomas

Abstract Introduction The association between hepatitis-C virus (HCV) infection and non-Hodgkin’s lymphomas (NHL) has been demonstrated in epidemiological studies. In Lombardia, a densely populated region of northern Italy with around 10 millions of inhabitants, the prevalence of infected people is around 5%. In 2008, the “Rete Ematologica Lombarda” (Hematology Network of Lombardia region) started a prospective multicentric observational study, with the aim to collect data on virological and hematological features, on treatment and outcome of HCV-related NHL. Herein, we present the final results of this study. Methods Between January 2008 and December 2012, 241 consecutive adult patients (pts) with first diagnosis of NHL associated with HCV-positivity were enrolled in this prospective observational study (“Registro Lombardo dei Linfomi HCV-positivi”), approved by the Regional Administration and by IRBs of 10 Hematology Centres of Lombardia region. All pts signed a written informed consent. HIV-positive pts were excluded. Results Median age at lymphoma diagnosis was 69 years (yrs) (range 32-90); females were 60%. Histotypes were classified as follows: diffuse large B-cell lymphoma (DLBCL) (44%), marginal zone lymphoma (MZL) (28%), follicular lymphoma (10%), low-grade B-cell lymphoma NOS (10%), small lymphocytic lymphoma (SLL) (3%), lymphoplasmacytic lymphoma (3%), mantle cell lymphoma (1%), peripheral T-cell lymphoma NOS (1%). Ann Arbor stage was III-IV in 79% of pts, with bone marrow involvement in 47%. ECOG score was ≥ 2 in 16% of pts; 63% of pts showed at least one extranodal localization (spleen in 22%, skin in 11%, liver in 10%, Waldeyer’s ring in 5%, ocular adnexa in 3%). Virological features and treatment details are summarized in Table 1. HCV-positivity was detected before the diagnosis of NHL in 166 pts (69%) and median time between HCV detection and NHL diagnosis was 11 yrs. Serum monoclonal component (p=0.003), autoimmunity manifestations (p<0.001) and cryoglobulinemia (p=0.002) resulted more frequent in indolent NHL respect to aggressive subtypes. A shorter overall survival (OS) was observed in pts with ECOG ≥ 2 (p<0.001), hemoglobin < 12 g/dl (p=0.008), albumin < 3.5 g/dl (p=0.005), platelets < 100 x 109/L (p<0.001) and lactate dehydrogenase ≥ UNL (p=0.031). Data on first line treatment for NHL were available in 231 pts: 178 pts (77%) received chemotherapy (CHT) [plus Rituximab (R) in 122]; anthracycline contain-regimens (+/- R) were used in 121 pts (52%). Forty pts (17%) developed liver toxicity of any grade (grade III-IV in 19 pts) and 22 pts (10%) interrupted early the treatment. Fifty-three pts were treated with antiviral therapy (AT) for active HCV infection and among them 12 pts (8 MZL, 3 low-grade B-cell lymphoma NOS, 1 SLL) were treated with AT as first anti-lymphoma therapy; 8 pts obtained a virological response and a complete lymphoma response, 2 pts had a partial response (HCV-RNA negative in 1), 1 pt had neither hematological nor virological response and 1 pt is still on therapy. After a median follow-up of 32 months, 47 pts (20%) died (24 with aggressive NHL, 23 with indolent NHL): 23 due to lymphoma, 10 due to cirrhosis/hepatocarcinoma, 7 due to other solid neoplasms, 7 due to other causes. Conclusions In this prospective study conducted in Lombardia, a northern region of Italy, the most common histologies of HCV-associated NHL are DLBCL and MZL. In nearly 70% of pts, first detection of HCV positivity preceded the lymphoma diagnosis. A proportion of pts developed meaningful liver toxicity and/or were not able to complete the therapeutic program. In the indolent lymphomas treated with AT as first anti-lymphoma approach, virological and hematological responses are achieved in about two thirds of pts. Disclosures: No relevant conflicts of interest to declare.

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