Histological Characteristics Of Hepatitis C-Associated B-Cell Non-Hodgkin Lymphomas. Results Of The French Lympho-C ANRS HC-13 Multicentric Study Of 133 Patients
Authors: Canioni Danielle , Michot Jean Marie , Settegrana Catherine , Driss Henda , Rabiega Pascaline , Barthe Yves , Alric Laurent , Suarez Felipe , Cacoub Patrice , Sibon David , Thieblemont Catherine , Tilly Herve , Haioun Corinne , Felim Anne , NGuyen Khac Florence , Merle-Beral Helene , Taoufik Yacine , Carrat Fabrice , Davi Frederic , Hermine Olivier , Besson Caroline 
Published: October 2019

Abstract

Introduction
HCV infection is associated with the development of B-cell non Hodgkin lymphomas (NHL), preferentially of marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL) subtypes. Other subtypes of B-cell NHL are rare. HCV-related lymphomagenesis may constitute in some cases a model of lymphoma induced by chronic antigenic stimulation. Moreover, a direct role of an infection of B cells by HCV is also an alternative hypothesis. We performed a multicentric observational study of HCV-related B-cell NHL in France in order to study the real distribution of their histological subtypes and their correlation with in situ expression of HCV virus.

Patients & Methods
Adult patients with B-NHL and active HCV infection were included in an observational multicentric study with the exclusion of those who were co-infected with HIV. Data were collected from patients with either ongoing or past history of HCV infection. Cytological and histological samples were collected for centralized review and molecular analyses. A large panel of antibodies was performed on each sample for subtyping the B-cell NHL and HCV-NS3 antibody immunostaining was made each time we had enough material.

Results
Between 2006 and 2012, 133 consecutive patients were enrolled in 26 French hospitals, among them 17 patients were excluded from analysis. At lymphoma diagnosis the median age was 61 years and the gender M/F ratio was 1. Histological samples of 81/116 patients were reviewed by a panel of expert hematopathologists. The most frequent B-cell NHL subtype was DLBCL in 30/81 patients (37.5%) among them 14/30 (46.6%) were transformed from underlying low grade B-cell NHL. For 26/30 DLBCL we had enough material for performing Hans score: 18 (69%) were of non germinal center (GC) origin and 8 (31%) of GC origin. Interestingly, most de novo DLBCL were of non GC subtype (92%) whereas in transformed DLBCL 50% were of non GC subtype. MZL represent 22/81 cases (27%), 8/81 (9.9%) were follicular lymphomas and other small B-NHL subtypes represent the other cases. Patients with DLBCL displayed frequent extra-nodal involvement (digestive tract, liver) (60%) and those with MZL had the highest proportion (73%) of extranodal localisations (spleen, bone marrow, blood, eye) whereas follicular lymphomas were mainly developed in lymph nodes. Twenty-nine cases could be tested for HCV NS3 antibody, 26 exhibited evaluable staining: 12 B-NHL had in situ positive staining (most of them were DLBCL (67%) with a slight predominance of transformed DLBCL compared to de novo (62%) and 14 had negative staining (most of them were MZL or other small B-cell NHL (92%).

Conclusion
This study underlines the heterogeneity of HCV-related B-cell NHL with a majority of extra-nodal localizations of these lymphomas, a predominance of DLBCL and MZL and a high proportion of DLBCL developed on low grade B-NHL comparing to de novo DLBCL. We found a different GC/non GC repartition between de novo versus transformed DLBCL with a higher proportion of GC versus non GC in transformed DLBCL than in de novo DLBCL. In situ HCV virus expression was more frequently observed in DLBCL than in other subtypes of B-NHL which could indicate that the growth and development of lymphoma cells may be associated with the presence of HCV infection of B cells. Therefore, we postulate that the B cell transformation is linked with chronic antigenic stimulation in MZL and to direct infection in DLBCL. It might also explain that virological success seems to improve prognosis preferentially in MZL subtype in our series.

Disclosures:
Haioun: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.