Clinico-Pathological Characteristics of B-Cell Non Hodgkins Lymphomas Associated with Hepatitis C Virus ANRS HC13 LYMPHO-C Observational Study.

Hepatitis C virus (HCV) associated B-cell non-Hodgkin's lymphoma (B-NHL) is a rare entity that constitutes a model to study chronic immune stimulation related lymphomas. They are known to be preferentially Marginal Zone Lymphomas (MZL) and Diffuse Large B Cell Lymphoma (DLBCL) subtypes. Conflicting results are reported on the association between Follicular Lymphoma (FL) and HCV. In order to study the physiopathology of HCV-related B-NHL, we pursue a multicentric observational study in France. We present here the clinicopathological characteristics of the patients included.

Adult patients with a history of HCV associated B-NHL are included in the study. HCV infection is defined by a positive viral load at diagnosis of NHL. Patients with HIV infection are excluded from the study. Each patient is followed every 6 months during 5 years. At each follow-up, a blood sample is withdrawn allowing ancillary studies. Data collection concerns clinical presentation, treatment and evolution of NHL and HCV infection. Pathological and cytological materials are centralized in order to allow their review and a concerted analysis by a group of expert hematopathologists, haematologists and immunologists.

The data of the 54 consecutive patients included between november 2006 and april 2009 in 20 french centers are presented. Median age is 63 years (ranging from 39 to 87 years). There is a predominance of men: sex ratio (m/f) is 1.45 (32/22). Included women are older than men (p<0.01), median age being 71 among women and 60 years among men. HCV genotypic distribution does not differ from expected in a HCV infected population in France: 1: 51% (25/49), 2: 29% (14/49), 3: 8% (4/49), 4: 12% (6/49), 5 missing data. Transmission risk groups, known in 50% (27/54) of cases, are transfusion (18), drug abuse (5), endemic origin (2), and tattoo/acupuncture (2). Two patients are co-infected with HBV. Twenty-four patients out of 42 tested (57%) had positive cryoglobulinemia at diagnosis of NHL. This proportion did not differ with gender nor with genotype.

Fifteen cases were included at diagnosis of B-NHL. The 39 other cases were included during follow-up of NHL. The median interval between NHL diagnosis and last follow-up is 15 months (range 0-13y). The histological subtype distribution is DLBCL 39% (21), MZL 35% (19), FL 13% (7), CLL 6% (3). Remarkably, there is a continuum between MZL and DLBCL, 6 cases with ongoing transformation. Four cases could not be classified due to small disease infiltration or lack of material. We confirm the link between cryoglobulinemia and MZL, 12+ out of 17 tested, 6+/12 in DLBCL versus 2+/5 in FL and 1+/2 in CLL. Nodal involvement is infrequent (5 out of 21 cases of DLBCL, 2/19 MZL, 4/7 FL). Extranodal involvements predominated in spleen (15 including 8 MZL), lung (6), digestive tract (4), liver (3), heart (1), skin (6) and bone marrow (4). The efficiency of antiviral treatment is confirmed in 5 cases with MZL, and remarkably, was followed by a good response in one case with FL. However, most patients in this observational study received treatment with Rituximab (R) either alone (5 cases with MZL), or combined with chemotherapy (including 15 cases with DLBCL and 4 with FL) or with antiviral treatment. This was associated with good clinical responses in most cases and low toxicity. Indeed, only 5 patients died during follow-up – two from disease progression - a 85 y man and a 40 y woman with liver DLBCL who was resistant to 3 lines of R-chemotherapy. The other patients died of sepsis (2), and cardiac ischemia (1).

This study strengthens the heterogeneity of HCV-related lymphomas. The observation of cases with MZL and, remarkably, of one case with FL responding to antiviral treatment suggests that they are both linked to chronic immune stimulation. Therefore, the concept of antigen-driven lymphomagenesis seems more heterogeneous than initially anticipated: it could involve a T independent response in MZL, and a T dependent response in FL. The ongoing pathophysiological study will improve further understanding of the mechanisms by which antigen-driven lymphoproliferation arise.

No relevant conflicts of interest to declare.