Annals of Oncology Advance Access originally published online on March 8, 2006
Annals of Oncology 2006 17(5):769-772; doi:10.1093/annonc/mdl027
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© 2006 European Society for Medical Oncology
Clinical implications of hepatitis C virus infection in MALT-type lymphoma of the ocular adnexa
1 Medical Oncology, 2 Gastroenterology, 4 Ophthalmology, 6 Neuroradiology, and 7 Pathology Units, San Raffaele H Scientific Institute, Milan, Italy; 3 Immunovirology and Biotherapy Unit, Department of Pre-Clinical and Epidemiological Research, Centro di Riferimento Oncologico, IRCCS National Cancer Institute, Aviano, Italy; 5 Ophthalmology Unit, Ospedale San Giuseppe, Milan, Italy
* Correspondence to: Dr A. J. M. Ferreri, Medical Oncology Unit, Dept. of Oncology, San Raffaele H Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Tel: +39-02-26437649; Fax: +39-02-26437603; E-mail: andres.ferreri{at}hsr.it
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Abstract |
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Background: A pathogenic link between hepatitis C virus (HCV) and MALT-type lymphomas has been suggested. However, studies assessing the role of HCV infection separately in different forms of MALT lymphomas are not available.
Patients and methods: The prevalence and clinical implications of HCV seropositivity were analyzed in 55 patients with ocular adnexa lymphoma (OAL) of MALT-type.
Results: HCV seropositivity was detected in seven (13%) patients. At presentation, HCV infection was significantly associated with concomitant extra-orbital disease, lymph node dissemination and involvement of additional extranodal organs. HCV seropositivity was associated also with a higher relapse rate and worse progression-free survival. In fact, 16 patients experienced relapse after first-line treatment: five (71%) were HCV-seropositive and 11 (23%) were HCV-seronegative, with a median TTP of 31 and 50+ months (P = 0.01), and a 5-year progression-free survival of 43 ± 18% and 77 ± 7% (P = 0.005), respectively. HCV-seropositive patients experienced frequent relapses despite further lines of therapy; relapses were systemic in all cases but one; multiple subcutaneous nodules were common at relapse.
Conclusions: HCV seropositivity is present in 13% of OAL of MALT-type. Concomitant HCV infection is associated with more disseminated disease and aggressive behavior in OAL, with a consequent potential negative impact in patients managed with radiotherapy alone.
Key words: MALT lymphoma, ocular adnexal lymphoma, hepatitis C virus, infectious agents
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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A pathogenic link between some infectious agents and non-Hodgkin's lymphomas (NHL), mostly marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)-type, has been reported [1
–3]. It has been suggested that the chronic antigenic stimulation provided by these agents may elicit host immune responses able to promote and sustain clonal B cell expansion [4]. Moreover, infection by specific agents could affect the natural history and the clinical features of the disease, and provide the rationale for new therapeutic modalities. Hepatitis C virus (HCV) may be implicated in these processes. HCV infection is present in 12% of extranodal MALT lymphomas [5], rising up to 17.5% in Italian series [6]. However, studies assessing the role of HCV infection separately in different forms of MALT lymphomas are not available.
Ocular adnexal lymphomas (OAL) (i.e. conjunctiva, lachrymal gland and orbital soft tissues) are one of the commonest forms of extranodal lymphomas. A strong correlation between OAL and chronic Infection by Chlamydia psittaci has been reported [3, 7]. However, the potential association between these malignancies and other infectious agents, including HCV, remains to be elucidated.
Herein, we report the first study focusing on the prevalence of HCV infection in OAL of MALT-type. The impact of HCV infection on clinical presentation, behavior and therapeutic decision is discussed.
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patients and methods |
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study group
Fifty-five HIV-negative adults with low-grade marginal zone lymphoma of MALT-type of the ocular adnexa, diagnosed between 1990 and 2004, were reviewed. In these patients, the lymphomatous lesion in the ocular adnexa was the sole evident site of disease at presentation, while other nodal or extranodal lesions were detected during staging. Histopathological specimens were reviewed by two pathologists (M.P. and C.D.) and categorized according to the WHO classification [8
]. Staging work-up consisted of physical examination, biochemical blood profile, ultrasonography of the neck, total-body CT scan, gastroscopy, and bone marrow biopsy. Stage of disease was defined according to the Ann Arbor staging system [9]. First-line treatment consisted of 45 Gy orbit irradiation (n = 22), alkylating-based chemotherapy (n = 16) and doxycycline (n = 8); nine patients with stage I-disease did not receive any treatment after complete surgical resection of the lesion. Serum viral hepatitis markers were assessed in all cases by using an enzyme immunoassay (EIA-3, Ortho HCV 3rd generation; Ortho Diagnostic System, Raritan, NJ); HCV RNA levels were determined in cases with positive antibodies titers.
statistical considerations
Clinical characteristics and response rate among different subgroups were compared using the Fisher exact test for categorical variables. Survival curves were generated using the Kaplan-Meier method and compared by log-rank test. Overall survival (OS) was calculated from the date of pathologic diagnosis to death or to the last date of follow-up, while time to progression (TTP) and progression-free survival (PFS) were calculated from the first day of treatment to relapse, progression or death, or to the last date of follow-up. Multivariate analysis of survival-determining factors was not performed due to the small number of events. All the probability values were two-sided. All analyses were carried out using the Statistica 4.0 statistical package for Windows (Statsoft Inc, 1993, Tulsa, OK 74104, USA).
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results |
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patients' characteristics
The clinical characteristics of the 55 patients included in this study are summarized in Table 1. The median age of the patients was 62 years (range 32–89), with a male:female ratio of 0.41. Eight patients had a history of previous cancer, one had Sjögren's syndrome, two had essential mixed cryoglobulinemia, and two had been referred to hepatic transplantation due to post-viral cirrhosis 12 and 15 years before lymphoma diagnosis. The interval period between clinical onset of OAL and histopathological diagnosis ranged between 1 and 144 months (median 7).
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Antibody titers against HCV were detected in seven patients (13%). A positive determination of HCV RNA was confirmed in all the seven HCV-positive patients. As reported in Table 1, HCV chronic infection was significantly associated with advanced extra-orbital disease (57% versus 6%; P = 0.003), lymph node dissemination (43% versus 10%, P = 0.05) and involvement of other extranodal organs (43% versus 6%, P = 0.02).
therapeutic results
Fifty-one patients (93%) achieved an objective response after first-line treatment. Sixteen patients experienced failure (Table 2); five (71%) patients were HCV-seropositive and 11 (23%) were HCV-seronegative (P = 0.01), with a median TTP of 31 and 50+ months (P = 0.01), and a 5-year PFS of 43 ± 18% and 77 ± 7% (P = 0.005), respectively (Figure 1).
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As reported in Table 3, HCV-seropositive patients experienced frequent relapses despite further lines of therapy. In fact, after a median follow-up of more than 5 years for both subgroups, four (57%) of the seven HCV-seropositive patients experienced two failures or more, which was observed in five (10%) of the 48 HCV-seronegative patients (P = 0.01). Relapses in HCV-seropositive patient were systemic in all cases but one (local relapse in a patient with conjunctival lymphoma). The presence of multiple subcutaneous nodules at relapse was observed in both subgroups, with a higher, but not significant, prevalence among HCV-positive patients (Table 2).
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Fifty-three patients are alive at a median follow-up of 63 months, with a 10-year OS of 88 ± 12%. Deaths were caused by chronic renal failure while lymphoma-free and HCV-related cirrhosis with evidence of systemic lymphoma after a follow-up of 45 and 81 months, respectively.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The present study, which includes one of the largest reported series of OAL of MALT-type, is the first one focusing on the prevalence and role of HCV infection in these malignancies. OAL of MALT-type usually displays limited stage of disease, indolent behavior and tendency to remain localized for several years [10
]. Our observations, albeit retrospective, suggest that concomitant HCV infection is associated with more disseminated disease and aggressive behavior in OAL. These findings may be helpful at the time to design future therapeutic strategies against OAL, which is a relevant issue considering that prospective trials on these uncommon malignancies are lacking.
The possible contribution of HCV in lymphomagenesis is still a matter of debate. A significantly increased risk of NHL in patients with more than 15 years of HCV infection has been reported [11]. The prevalence of HCV seropositivity in patients with B-cell lymphoma is near to 15% [5], with a relevant geographic variation, rising up to 17.5% in Italy [6]. Among indolent lymphomas, HCV is present in near 30% of lymphoplasmacytic lymphoma, 27% of nodal and splenic marginal zone lymphomas and 12% of extranodal MALT lymphomas [6]. Accordingly to our observations, the prevalence of HCV seropositivity in OAL (13%) is similar to the average prevalence reported for unselected MALT lymphomas. At a variance with other HCV-related lymphomas, where 60% of patients are elderly males [6, 12], all our HCV-seropositive patients were females, and they were not older than HCV-seronegative cases (Table 1).
In our series, HCV infection was strongly associated with peculiar features. In fact, HCV-seropositive patients had more commonly advanced disease, lymph node infiltration and multiple extranodal involvement at diagnosis, and suffered from frequent systemic relapses despite the use of further active salvage therapies. Our data also confirm a previous study reporting the presence of multiple subcutaneous nodules in one third of relapses in OAL [13], being more commonly, but not exclusively, associated with HCV infection. Accordingly, patients with OAL of MALT-type should be assessed for HCV seroreactivity, with therapeutic and prognostic purposes. The risk of systemic dissemination associated with HCV infection may be important in patients eligible for radiation therapy as exclusive treatment, the standard approach against limited-stage OAL [14]. As a proof of principle, our single HCV-positive patient with stage-I disease treated with radiotherapy alone experienced systemic relapse after 8 months (Table 3). The actual impact on survival of this new knowledge remains however to be defined considering that, as previously reported [15, 16], no patient with OAL died of lymphoma.
Importantly, the encouraging results obtained with antiviral therapy (interferon plus ribavirin) in small series of HCV-related indolent lymphomas [17] deserve to be assessed in HCV-positive patients with OAL. Even if molecular remission of clonal IgH rearrangement and bcl-2 translocation is rarely achieved [18], more than 70% of patients with HCV-related lymphomas display virology response and lymphoma regression, which seems to be unrelated to HCV genotype [18]. In the forthcoming years, a better knowledge on the association between infectious agents and MALT lymphomas may be relevant for the development of new, active anti-microbial strategies exploiting mechanisms different from those of conventional chemotherapy and radiotherapy, enlarging thus the therapeutic armamentarium against lymphomas.
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Acknowledgements |
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Preliminary results have been published in part in abstract form as: A. J. M. Ferreri, M. Ponzoni, M. Ghidoni, A. Giordano Resti, C. De Conciliis, M. Guidoboni, R. Stefano, R. Dolcetti, C. Doglioni. Associations between infectious agents and MALT lymphoma of the ocular adnexa (OAL): behavioral and therapeutic implications. Ann Oncol 16: v221-v225, 2005, and presented at the 9th International Conference on Malignant Lymphoma. Lugano, Switzerland, 2005.
Received for publication November 30, 2005. Revision received December 16, 2005. Accepted for publication January 20, 2006.
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