High Prevalence of Hepatitis C Virus among B-Cell Lymphoma Patients in Mansoura Region (Egypt), ANRS 12263 Study
Layla M. Saleh1,2,
Danielle Canioni5, Sameh Shamaa3,4, Maha
El-Zaafarany3,4, Ziad Emarah3,4, Sherin Abdel-Aziz1,2,
Entsar Eladle9, Alsaeed Abdelaziz10, Olivier
Hermine6,7, Caroline Besson8 and Hasan
Laboratory, Oncology Center, Mansoura University, Egypt.
2 Hematology section, Clinical Pathology Department, Faculty of Medicine, Mansoura University, Egypt.
3 Medical Oncology Department, Oncology Center, Mansoura University, Egypt.
4 Internal Medicine Department, Faculty of Medicine, Mansoura University, Egypt.
5 Department of Pathology, Hôpital Necker Enfants Malades, Paris 5 Descartes University, Paris, France.
6 Department of Adult Hematology, Paris 5 Descartes University, Paris, France.
7 Imagine Institute, Université Sorbonne Paris Cité, Paris, France.
8 Service d’Hématologie-Oncologie, Centre Hospitalier de Versailles, Le Chesnay, France; Université Versailles Saint Quentin en Yvelines, Université Paris-Saclay.
9 Pathology Department, Faculty of Medicine, Mansoura University, Egypt.
10 Internal fellowship, Mansoura University Hospital, Mansoura University, Egypt.
Received: June 2, 2018
Accepted: November 25, 2018
Mediterr J Hematol Infect Dis 2019, 11(1): e2019011 DOI 10.4084/MJHID.2019.011
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The prevalence of Hepatitis C virus in Egypt reaches 15%, which is
considered the highest in the world. Genotype 4 represents 93% of
Egyptian HCV infections. Non- Hodgkin lymphoma (NHL) is the 5th most
common cancer in Egypt. The association between HCV infection and
occurrence of B-cell NHL is well known while data are scarce in Eastern
Patients and Methods
Laboratory methods. Enzyme-linked immunosorbent assays (ELISA): ELISA assays were used to determine anti-HCV antibodies, Hepatitis B virus (HBV) antibodies and HBsAg and HIV antibodies (BIOTEC, UK) from serum samples of all patients. RNA isolation and Quantitative real-time polymerase chain reaction: RNA was extracted from serum samples according to the manufacturer's instructions then RNA was reverse-transcribed and amplified by One Step RT- PCR QIAGEN Kit on a GeneAmp PCR system 9700. Real-time PCR was performed on the StepOne (Life Technologies). Routine laboratory testing: Transaminases (ALT & AST) serum levels were determined and expressed as IU/L, and Rheumatoid factor (RF) were determined for HCV-positive samples by turbid metric methods with cut off value > 25 international unit /ml.
Immunohistochemical testing. For all patients, cyto- histological data regarding B-NHL diagnosis were recorded and categorized according to the WHO 2008 classification. Pathological materials of 22 cases of HCV+ lymphoma samples; were reviewed by hematopathologist (DC) who coordinated the review of the ANRS-HC13 Lympho C study. Immunohistochemistry was performed in tumor samples following a three-step immunoperoxidase method. The antibody panel included CD20, CD3, CD5, CD10, Bcl6, Bcl2, MUM1 and Ki67.
Statistical analysis. All statistical computations were performed using SPSS Software version 20 (IBM Corp., Armonk, New York, 2011). Continuous data were represented as the mean ± standard deviation or the median (minimum–maximum), while categorical variables were represented by frequency. Student’s t- test, or Mann–Whitney test were used for comparison of continuous variables between groups while categorical data were compared between groups by using chi-square test with Yates correction. A p value of < 0.05 was considered statistically signiﬁcant. Follow-up was defined from the start of B-NHL diagnosis to the last follow-up visit. Overall survival (OS) was measured from the lymphoma diagnosis to the last follow-up or the death from any cause. The probability of OS was defined with Kaplan-Meier's method, and differences were compared with the log-rank test.
|Table 1. Characteristics of HCV positive and HCV negative patients with B-cell Non-Hodgkin Lymphoma (n=110).|
|Table 2. Comparison of B-NHL histological subtype distributions in HCV positive and HCV negative patients (N=110).|
Ann Arbor stage was III–IV in 78% in HCV positive studied patients. ECOG status was 0-1 in 57% of HCV positive patients. ALT and AST serum levels were higher in HCV positive NHL patients in comparison to HCV negative patients (66%versus 49%). LDH was found to be elevated in 82% of HCV positive NHL. Overall, IPI score was high/high intermediate in 78% of HCV positive patients. Table 3 presents a comparison between HCV positive and HCV negative DLBCL patients. In this subgroup also, HCV-positive patients were younger and had more frequently elevated transaminases than HCV-negative patients.
|Table 3. The characteristics of HCV positive and HCV negative patients with DLBCL (n=79).|
All patients except eight with DLBCL and four with marginal zone lymphoma were treated with front-line treatment for lymphoma. Lymphoma management was classified according to anthracycline use into “Anthracycline containing regimen” 45 patients (67%), “Non-anthracycline containing regimen” 14 patients (24%). Forty-five patients received CHOP, 13 patients received Alkylators ± corticosteroids. Four patients received rituximab in each case associated with CHOP. One MZL patient was treated with interferon alone.
With the exception of interferon, no antiviral treatment was given to these patients.
To our knowledge, 24 patients died out of the 67 HCV positive patients (36%). The median OS within the HCV positive group was 13 months (mean 21 ± 2 months) while it was 26 months (mean 25 ± 2.4 months) within the HCV negative patients (p=0.22) (Figure 1). The median OS of the HCV positive DLBCL patients was 12.7 months ( mean 18.7 ± 15.8 months) and 23.7 months ( mean 23.4 ± 15.7 months) within the HCV negative patients (p=0.37) (Figure 2).
Overall survival of B-cell NHL lymphoma patients according to HCV
status. HCV-positive patients (n= 67) HCV-negative patients (n= 43).
|Figure 2. Overall survival of DLBCL patients according to HCV status. HCV-positive DLBCL patients (n= 48) HCV-negative DLBCL patients (n= 31).|
In the present study, most of the patients had DLBCL (72%). MZL was rare (7.5%). The distribution of NHL we report here is similar to previous findings in Egypt[19,20,21] with DLBCL proportions of 55% to 76% among HCV associated NHL, being MZL proportion lower than 10%. Overall, our results are in agreement with many studies that reported HCV association with DLBCL, and MZL.[6,10,24,25] However, in Western/Northern countries most cases of HCV associated NHLs are MZL and DLBCL, and are frequently transformed from low-grade lymphomas. In our series, however, we did not identify such cases out of 22 cases reviewed by an expert hematopathologist (DC). The different distribution might be different due to the unique environmental background or to differences in access to care. It would be interesting to confirm this finding in a larger number of pathological samples from patients with HCV-associated lymphomas in Southern countries. The low frequency of low-grade lymphoma in the study is consistent with other studies in Egypt although it strongly contrasts with the distribution of HCV associated lymphomas in Northern countries. We cannot exclude that patients with low- grade lymphomas are underdiagnosed in Southern countries.
We did not find unique clinical or biological characteristics associated with HCV infection in lymphoma patients. This was previously reported in an Egyptian study performed on 132 DLBCL patients among whom 26.5% had HCV. There was indistinguishable demography for this group compared to HCV-negative patients. Additionally, another Egyptian study comparing HCV infected and HCV uninfected patients with NHL showed no statistically significant difference in age, sex, clinical presentation, stage, IPI score, LDH level, pathological type, and chemotherapy regimen. Of note in our population, HCV infected patients were younger and had more frequent elevated transaminases. Rheumatoid factor activity was positive in two-thirds of our population of HCV associated NHL, supporting a role of chronic antigenic stimulation on lymphomagenesis. These observations are similar to those reported in the Lympho C Study. Overall, there was a trend for a pejorative impact of HCV infection on OS.
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