Annals of Oncology Advance Access originally published online on June 9, 2006
Annals of Oncology 2006 17(9):1434-1440; doi:10.1093/annonc/mdl131
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© 2006 European Society for Medical Oncology
hematologic malignancies |
Distinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy
1 Department of Hematology, Ospedale S. Bortolo, Vicenza, Italy
2 Department of Pathology, Ospedale S. Bortolo, Vicenza, Italy
3 Department of Cinical and Experimental Medicine, Section of Hematology, University of Verona, Italy
4 Department of Pathology, University of Verona, Italy
5 Division of Hematology, University of Pavia, Italy
6 Department of Human Pathology, IRCCS Policlinico San Matteo, University of Pavia, Italy
*Correspondence to: Dr C. Visco, Divisione di Ematologia, Ospedale S. Bortolo, Via Rodolfi 37, 36100 Vicenza, Italy. Tel: +39-0444-753626; Fax: +39-0444-753922; E-mail: carlovisco{at}hotmail.com
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Abstract |
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Background: Diffuse large B-cell lymphoma (DLBCL) has been correlated to hepatitis C virus (HCV) infection in few series, but characteristics and outcome of these patients remain undefined.
Patients and methods: We analyzed 156 previously untreated consecutive HCV-positive patients with DLBCL observed between 1994 and 2004 in three major institutions from northern Italy.
Results: Median age at presentation was 63 years and 8% of patients had DLBCL transformed from low-grade lymphomas. Spleen was the most frequently involved extranodal site, followed by liver and stomach. Treatment was delivered with cure-intent in 132 patients, while the remaining 24 patients received monochemotherapy or radiotherapy alone due to old age or seriously impaired hepatic function. Only five patients (4%) had to discontinue chemotherapy due to severe liver function impairment. The addition of rituximab did not seem to affect patients' tolerance to treatment. Five-year overall survival of the entire cohort was 72%, while 5-year progression-free survival (PFS) of the 132 patients treated with cure-intent was 51%. Hepatitis B virus co-infection, advanced Ann Arbor stage and nodal origin of the tumor resulted the strongest adverse prognostic factors.
Conclusions: Patients with HCV-positive DLBCL share distinctive clinical features. Future studies should prospectively evaluate the association between HCV and aggressive lymphomas.
Key words: diffuse large B-cell lymphoma, hepatitis, HCV, HBV, spleen
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Hepatitis C virus (HCV) infection has been associated with increased risk of developing B-cell lymphoproliferative disorders [1, 2]. Several reports from countries with relatively high prevalence of HCV infection have documented a significant association between HCV and overt B-cell non Hodgkin's lymphoma [3–6]. However, observations from geographical areas with low incidence of HCV infection have not confirmed this association [7–9].
Maintainance of the expanded B-cell clone requires the persistence of the viral infection, nevertheless, the exact mechanism inducing HCV mediated lymphomagenesis has yet to be fully elucidated [10, 11]. Bcl-2 rearrangements, as well as t(14;18), both implicated in the pathogenesis of lymphomas with germinal center origin, are more prevalent in peripheral blood mononuclear cells of HCV-infected patients [12]. Furthermore, several reports have demonstrated a prominent effect of antiviral therapy both on clonal HCV-related B-cell proliferations such as type II mixed cryoglobulinemia (MC), and on low-grade overt B-cell lymphomas [13–16]. Such effect of antiviral therapy implies a direct role of viral load in maintaining B-cell proliferation. As a matter of fact, Hermine et al. [15] observed no hematologic response to interferon in HCV-negative low-grade lymphomas, while Giannelli et al. [17] described a striking association between virologic response to treatment and regression of peripheral blood B-cell clones harboring the t(14;18).
Low-grade marginal zone lymphoma (MZL) has been the lymphoma subtype most commonly associated with HCV-infection, while less data are available regarding HCV-positive patients with diffuse large B-cell lymphoma (DLBCL) [2, 3, 5]. Clinicopathological characteristics at presentation, tolerance to chemotherapy, natural history and final outcome of patients with HCV-positive DLBCL are still undefined, due to the lack of data based on large series of unselected patients. Limited data indicate that these patients may exhibit characteristic clinical presentation, and a poor tolerance to intensive chemotherapy [18].
We describe the first large series of unselected patients with HCV-positive DLBCL from three major institutions from northern Italy, where HCV prevalence is relatively high, attesting at 3.2% [19]. Our analysis indicates that these patients present with distinctive clinical features, show good tolerance to standard chemoimmunotherapy and have a favorable survival.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patients selection
All unselected consecutive patients with DLBCL and a positive test for HCV antibodies diagnosed in three major hematology institutions from northern Italy were included in this analysis. The diagnosis was performed between January 1994 and December 2004. All patients were of Italian origin and proved negative for human immunodeficiency virus (HIV). They had no history of intravenous drug abuse or homosexual intercourses and no evidence of hepatocellular carcinoma before and during the observation period.
A total of 156 HCV-positive patients with DLBCL satisfying the above mentioned criteria were identified and included in the study. The average prevalence of HCV-positivity among DLBCL in these three centers was 16%.
virologic studies
Patients were tested for the presence of serum antibodies against HCV by enzyme-linked immunosorbent assay (ELISA; HCV 3.0; Ortho Diagnostic System, Raritan, NJ). Confirmatory test included recombinant-based immunoblot assay (Chiron RIBA; Ortho Diagnostic System).
A total of 103 patients (66%) were also tested for RNA sequences of HCV by reverse transcriptase polymerase chain reaction using primers for the 5' non-coding region and 98 resulted positive (95%).
Serum hepatitis B virus (HBV) antigen HBsAg, as well as HIV antibodies, were also tested on all patients by commercial enzyme immunoassays at the time of lymphoma diagnosis.
Liver function tests were monitored carefully before and during treatment, as well as during the follow-up period. Thirty-two patients had also been tested for the presence of cryoglobulins (positivity for cryocrit levels > 0.1%) and 15 of them resulted positive (47%).
Definition of hepatic toxicity relied on the standard National Cancer Institutes common toxicity criteria grading scale. Hepatitis was defined as the presence of alterations of transaminase levels (AST and ALT, grade 2–4) or of impaired hepatic synthesis (hypoalbuminemia, grade 2–4) at least in two consecutive measurements at diagnosis or at any time after the start of therapy. The definition of cirrhosis required the presence of at least one of the following findings: a diagnostic liver biopsy, the detection of oesophagus varices at esophagogastroduodenoscopy, an ultrasonography or computerized axial tomography (CT) describing typical liver morphology.
staging
All records were reviewed to verify presentation, staging, treatment and outcome. Staging evaluation included physical examination, routine laboratory, bone marrow aspirate and biopsy, chest radiographs, and CT of chest, abdomen and pelvis. CT of the neck, abdomen ultrasonographic study, esophagogastroduodenoscopy and liver biopsy were performed when clinically indicated. All patients were classified according to Ann Arbor staging system (AAS) [20]. B-symptoms were defined as the presence of unexplained fever (temperature >38°C), sweating, or weight loss >10% of patient's usual value.
Mediastinal mass was considered ‘bulky’ when the ratio of mediastinal mass to thoracic diameter, measured at the T4–T5 interspace, exceeded 0.33. Any other mass was considered bulky if any of its diameters were larger than 7.5 cm. Liver and spleen were considered to be involved by the tumor when definite nodular lesions could be detected by CT, or when marked organomegaly significantly regressed after treatment.
The definition of extranodal tumor was limited to those cases without nodal involvement. Ambiguous cases (AAS III-IV), with tumor involving both nodal and extranodal tissues, were considered extranodal when the main bulk of disease was an extranodal site, necessitating direction of treatment to that site, as defined by Isaacson [21]. Bone marrow was not considered as extranodal site.
pathology
All pathological specimens were classified according to WHO classification by expert hemopathologists in each center. All bone marrow biopsy specimens were also investigated at the time of diagnosis in order to detect any clonal proliferation of small lymphocytes. Such cases, as well as those characterized by nodal or extranodal concomitant presence of low-grade lymphoma and DLBCL, were classified as transformed-DLBCL (t-DLBCL).
Immunohistochemical (IHC) evaluation was performed in all cases on formalin-fixed paraffin embedded tissues, in order to guarantee a correct lineage assignment and diagnosis. A total of 46 unselected patients presenting to the three institutions after 2002 were also analyzed with an antibody panel including CD10, BCL-6, MUM-1/IRF4 and CD138. Such patients were subdivided into germinal center (GC) or non-GC subgroups following the indications given by Hans et al. [22] whose report gives confirmation by IHC of the predictive value of cDNA microarray results.
treatment
Anti-tumor treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or third generation regimens like VACOP-B (vincristin, doxorubicin, cyclophosphamide, bleomycin, prednisone and etoposide) for 79 out of 83 patients younger than 65 years. Similarly, 53 out of 73 patients older than 65 with no significant co-morbidities were treated with age-tailored reduced intensity antracyclin containing regimens (i.e. mini-CEOP, cyclophosphamide, epirubicin, vincristine and prednisone, or VEMP, etoposide, mitoxantrone, vincristine, prednisone; median five cycles). These patients did not suffer severe hepatic function impairment or significant co-morbidities that clinically discouraged a curative approach. The remaining 24 patients who were too old and/or affected by relevant co-morbidities, were treated with mono-chemotherapy (16), or radiotherapy (RT) alone (five) with palliative intent, while three patients received no treatment at all. Rituximab was added routinely to any of the regimens after 2002, for a total of 35 patients. Radiotherapy (RT) followed chemotherapy in 47 patients who presented with a bulky mass or with a detectable residual mass after chemotherapy. Median dose was 38 Gy (range 20–50 Gy).
Altogether, 132 of our 156 patients (85%) could be considered treated initially with cure-intent, and represented our study group for statistical considerations about progression-free survival (PFS).
None of the patients were treated with anti-viral therapy during the observation period or during the year preceding lymphoma diagnosis.
response definitions, outcome end points, statistical analysis
Complete remission (CR) was defined as the absence of disease for at least 1 month after the end of therapy. Partial response (PR) was defined as more than 50% reduction of tumor area measurable in two dimensions. Progressive disease (PD) was defined as enlargement of an existing site of disease, or the development of disease in a previously uninvolved site during front-line chemotherapy. Primary treatment failure was defined as failure to achieve either CR or PR during initial therapy. Relapse was defined as disease progression at least 1 month after CR or PR. PFS was measured from the beginning of treatment to the time of PD, primary treatment failure, or relapse. All other events were censored, including deaths for causes unrelated to lymphoma. Overall survival (OS) was measured from start of treatment to last follow-up or to death from any cause. The actuarial probability of PFS and OS was determined with Kaplan–Meier's method, and differences were compared with the log-rank test. Proportional Cox's hazard model was used for multivariate analysis.
At univariate analysis AAS, LDH, performance status and number of extranodal sites were analyzed with the cut-offs defined by Shipp et al. [23]. All variables with a P value <0.05 were considered to be statistically significant.
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clinical features
Of our 156 patients, 74 were males (47%) and the mean age at onset of the tumor was 63 years. Clinicopathological features at presentation are listed in Table 1.
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Liver function tests at diagnosis revealed that 116 patients (75%) had mild or no signs or symptoms (grade 0–1) of HCV infection except for a positive serological test, 27 (17%) had hepatitis, while 13 (8%) had cirrhosis. Nine patients (6%) were co-infected by HBV (HbsAg-positive) and all of them had hepatitis, except one who was affected by cirrhosis.
Patients frequently presented with an elevated LDH (62%), and with a PE-DLBCL (43%). At least one extranodal organ was involved by the tumor in 105 of 156 (67%) of patients. Spleen was the more frequently involved extranodal organ (53 of 156, 34%), followed by liver (18 of 156, 11%) and stomach (16 of 156, 10%). Spleen was the unique extranodal involved organ in 19% patients, while involvement of both liver and spleen was present in 8% of patients. Among other extranodal sites, skin was involved in nine of 156 (6%), mouth (including tongue, palatum, gingiva and salivary glands) in seven of 156 (4%), tonsils in seven of 156 (4%) and bone in five of 156 (3%). Six patients could be classified as primary cutaneous DLBCL of AAS I.
Hepatic involvement by the tumor was significantly more common among patients with hepatitis or cirrhosis at diagnosis: 26% of patients with hepatitis or cirrhosis had liver involvement by the tumor versus 9% for patients with no signs of liver function impairment (0.04).
histology and immunohistochemistry
A total of 14 patients (8%) were classified as t-DLBCL. Of them, five had a marginal zone component, four had lymphoplasmacytic features, four had a follicular pattern, and one had bone marrow infiltration of CD5+ small lymphocytes. Of note, primary mediastinal DLBCL was extremely rare (one of 156).
Of the 46 patients who were analyzed by IHC in order to establish lymphoma subtype, 20 (43%) had a GC phenotype, while 26 (57%) shared a non-GC phenotype. Only one patient expressed CD138. Specifically, BCL-6 was expressed in 46%, CD10 in 31% and MUM-1/IRF4 in 69% of patients.
survival analysis
With a median follow-up of 42 months, 30 patients died. Twenty of the deaths (66%) were due to lymphoma progression and seven (23%) to causes related to liver infection. Five-year OS was 72% (Figure 1).
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Treatment was delivered with cure-intent in 132 of 156 patients and consisted of antracyclin containing regimens ± rituximab ± RT. The remaining 24 patients were too old or had significant co-morbidities that clinically contro-indicated a curative approach. Overall, 88 of these 132 patients achieved CR (67%), 32 had a PR (24%) and 12 had PD (9%).
Patients with no hepatic dysfunction at diagnosis shared a better 5-year OS compared to patients with hepatitis or cirrhosis (80% versus 70% versus 50%, respectively), but these differences did not reach statistical significance (0.33). Survival was instead significantly conditioned by the presence of HBV co-infection, with five of nine HBV-positive patients who died within 2 years from diagnosis (2-year OS of 42% versus 87% for HBV-negative, 0.004). Also low and low-intermediate IPI value and PE-DLBCL were associated with a significantly better 5-year OS (87% and 86%, respectively) when compared to patients with nodal DLBCL (70%, 0.04), or intermediate-high and high IPI (56%, 0.008).
No difference in OS emerged when patients were divided according to the department where they were treated and followed-up, or according to the year of diagnosis.
tolerance to chemotherapy and rituximab
Treatment was well tolerated on average, with 112 patients (85%) completing their therapeutic program without any interruption or dosage reduction. Five patients (4%) had to discontinue chemotherapy due to severe hepatic function impairment (toxicity grade 3–4). The remaining 15 patients required prolongation of intervals between chemotherapy cycles, or reduction of scheduled dosage, mainly because of elevated liver enzymes (toxicity grade 2–3). One patient co-infected with HBV suffered from grade 4 hepatic toxicity after discontinuation of chemotherapy and died.
There was no association between the initial severity of hepatic disease and subsequent liver drug toxicity, regardless of the regimen that was administered.
The addition of rituximab to chemotherapy regimens did not influence patients' tolerance to therapy, with only five of the 35 patients treated with rituximab experiencing a mild increase of liver enzymes levels (grade 1), not requiring discontinuation of treatment. None of the patients treated with rituximab was co-infected by HBV.
prognostic factors
Median follow-up for the 132 patients treated with cure intent was 46 months and 47 patients relapsed or had PD. Five-year PFS was 51% and 5-year OS was 75% (Figure 2). There were two very late relapses at 152 and 154 months from the start of therapy. Both patients were re-biopsed: the first confirmed a high-grade histology, while the second showed a marginal zone low-grade pattern.
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We performed a univariate analysis for prognostic factors and the results are shown in Table 2. Of note, PE-DLBCL maintained their statistically significant superior PFS in respect to their nodal counterpart, even when the six patients with primary cutaneous DLBCL, which are well-known for their favorable prognosis [24], were excluded from the analysis.
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Multivariate analysis in terms of OS and PFS was performed including all variables that were significant at univariate analysis. In terms of OS, HBV co-infection, high IPI value and nodal DLBCL shared an independent negative impact on our patients (0.02, 0.005 and 0.02, respectively). The contemporary presence of two or three such adverse factors could identify 30% of patients with a 5-year OS of 41%.
As shown in Table 3, advanced AAS (0.003), nodal DLBCL (0.006) and the presence of HBV co-infection (0.007) were associated with inferior PFS. On the basis of Cox's model results we developed a prognostic model encompassing such three variables (Figure 3), which could discriminate 31 patients (23%) with no risk factors sharing an extremely favorable 5-year PFS of 92%. By contrast, the 47 patients (36%) with two adverse factors had a 5-year PFS of 21%. The remaining intermediate group of 54 patients (41%) with only one risk factor had a 5-year PFS of 54%. None of the patients shared three risk factors.
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discussion |
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We report here the clinical characteristics and the outcome analysis of a large series of HCV-positive DLBCL patients consecutively diagnosed in three major hematology institutions of northern Italy. To the best of our knowledge this is the largest cohort of HCV-positive DLBCL patients with detailed description of clinicopathological presentation, treatment and outcome available in the literature.
In comparison to data from the largest series including HCV-negative DLBCL [23], our HCV-positive patients often presented with extranodal abdominal disease, had a more frequently elevated LDH and were older at diagnosis. Tolerance to standard chemoimmunotherapy was generally good and a rather favorable outcome was observed.
In spite of our strict criteria for definition of PE-DLBCL, 43% of patients presented with such distinctive features, and this presentation had a favorable independent impact on outcome (Tables 2 and 3). Spleen involvement characterized 34% of our patients, and was the most frequently involved extranodal site, considerably exceeding that reported in the literature for HCV-negative DLBCL (13%) [23]. Portal hypertension due to impaired liver circulation in HCV infected patients may have caused spleen enlargement, thus accounting for some cases of splenomegaly. However, our criteria for the definition of spleen involvement by the tumor, requiring the presence of nodular lesions or of significant volume reduction after antitumor therapy, are specific for spleen enlargements due to lymphoma infiltration. Nevertheless, the high prevalence of spleen involvement could also suggest that some DLBCL would represent transformed low-grade lymphomas, probably of marginal-zone derivation.
Liver involvement was significantly more common among patients with clinical evidence of active infection and was detected in one fourth of the patients with hepatitis or cirrhosis at diagnosis. This suggests that active viral replication could be related to lymphomagenesis in the liver.
Furthermore, HCV-positive DLBCL also involved atypical extranodal sites. We observed a lymphoma of the pancreas and one of the thorax soft-tissue wall, corroborating two case reports that described primary DLBCL at very unusual sites such as hand and oesophagus in two HCV-positive patients [25, 26].
Our study confirms the already reported assumption [27, 28] of good tolerance to standard chemotherapy for HCV infected patients with lymphoma. Of our patients only five (4%) had to discontinue therapy due to severe hepatic function impairment and 15 (11%) required a delay or reduction of the chemotherapy scheduled doses. Furthermore, we show for the first time that rituximab, which has been reported as a safe and effective therapeutic approach in patients with HCV-related type II MC or autoimmune disorders [29], might be administered in combination with chemotherapy to HCV-positive patients with lymphoma. However, since a higher incidence of toxic deaths among HCV-positive DLBCL than among HCV-negative patients treated with aggressive chemotherapy has recently been reported [18], and since treatment with rituximab has been associated with HBV reactivations, we still recommend careful monitoring of liver function and viremia in HCV-positive patients. Moreover, the occurrence of late complications for rituximab-treated patients may not be ruled out, since median follow-up of these patients was 12 months.
Both OS, PFS and response to chemotherapy of our HCV-positive patients compared favorably with data reported in the literature for age-matched cohorts of HCV-negative DLBCL patients [23]. Despite a 5-year PFS of 51%, with median time to tumor progression of 18 months, OS of our patients was unexpectedly good. While a small series from Japan reported a similar outcome for aggressive NHL with or without HCV infection [30], a recently published series reported a negative effect of HCV infection on OS, but no significant impact on event-free survival [18]. However, the shorter OS of HCV-positive patients described by the GELA group was based on a very limited number of patients and was correlated mainly to the high incidence of toxic deaths for hepatotoxicity [18].
Such an indolent clinical course may reveal an influence of the virus in sustaining lymphoid proliferation, as already shown in low-grade lymphomas attaining complete remissions after anti-viral therapy [15, 16]. Thus, although the mechanism underlying the biologic interactions between transformed lymphocyte and viral replication remains undefined both in low and high-grade lymphomas, a possible role for anti-viral therapy in aggressive lymphomas should also be considered. In the light of these considerations, a case-report of an HCV-positive patient with DLBCL achieving long-lasting remission with anti-viral therapy [31], gives rise to exciting expectations on the possible role of the antiviral treatment associated to immunochemotherapy also in HCV-positive high-grade lymphomas.
Results of our IHC analysis indicate that the distribution of GC and non-GC-DLBCL was similar to that reported for HCV-negative DLBCL [22]. Therefore, this feature does not represent a suitable explanation for the more favorable clinical behavior of our patients.
In our statistical analysis for prognostic factors, surprisingly both LDH serum level, and IPI values were not significantly associated with variations of PFS (Table 2). The intrinsic prognostic power of LDH, which also affects IPI score, could be hampered in these patients by hepatic LDH isoforms, which are normally released by the infected liver, creating a confounding effect. Corroborating this assumption, all of our nine patients co-infected by HBV, all of whom had at least hepatitis, shared an elevated LDH at diagnosis. Moreover, two previous series [18, 30] reported similar findings in HCV-positive DLBCL patients, with 76% and 77% of patients sharing an elevated LDH at presentation, respectively. Therefore, the prognostic role of LDH, and consequently of IPI in these patients, does not seem to be sufficiently useful to make treatment decisions, or for risk assessment, substantiating the relevance of our predictive model (Figure 3).
Although HBV co-infection characterized only nine of our patients, it represented a strong adverse factor both in terms of OS and PFS. While hepatitis due to reactivation of HBV is a well recognized complication in patients with chronic HBV infection undergoing cytotoxic or immunosuppressive therapy, the impact of HBV on clinical presentation and final outcome of HBV-positive patients with DLBCL remains unknown, and our data suggest that at least in HCV co-infected patients HBV often correlates with impaired outcome.
In conclusion, a significant proportion of patients with DLBCL in northern Italy have a coincidental infection with HCV. In comparison with patients from large series of DLBCL these subjects seem to present a distinctive presentation and natural history. Furthermore, in comparison with patients of similar age they seem able to sustain treatment with acceptable major toxicity and should not be deprived of a standard chemotherapy approach. Future studies should perhaps consider these patients as a distinct population, which could benefit from combined anti-viral and antitumor treatment.
Received for publication March 21, 2006. Revision received May 2, 2006. Accepted for publication May 3, 2006.
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