Lymphomas and leukemias due to infectious organisms

Abstract

World-wide, approximately 25% of all human malignancies are caused by infectious organisms, including approximately 10% of cancers occurring in resource rich areas of the world. While some of these disorders are more likely to be seen in patients with underlying immunodeficiency, this is not a requisite for development of malignancy, and most patients, in fact, are not immune-suppressed at the time of diagnosis. In considering hematologic malignancies, several organisms have been implicated in disease etiology. These organisms include Human Herpesvirus 8 (HHV8/KSHV), which is linked to primary effusion lymphoma and to multicentric Castleman s disease, as well as to development of Kaposi’s sarcoma; Epstein Barr Virus (EBV) which has been associated with Burkitt lymphoma and nasal T cell lymphoma, among others; Human T lymphotrophic virus type I (HTLV 1), which is associated with Adult T cell leukemia/lymphoma (ATLL&rpar<?ENTCHAR semi?>; Hepatitis C virus, associated with splenic marginal and other lymphomas; and Helicobacter pylori, associated with gastric MALT lymphoma. The presentation will focus on the latter three disorders, describing pathogenesis of disease, clinical manifestations and therapeutic options.

Keywords:

• H. pylori
• Hepatitis C
• HTLV 1 (Human T-lymphotrophic virus, type I)
• MALT lymphoma
• ATLL (Adult T cell Leukemia/Lymphoma)
• Marginal zone lymphoma

Background

Globally, approximately 25% of all human malignancies are caused by infectious organisms, occurring in roughly 10% of cases from resource-rich areas of the world. These tumors characteristically have a long latent period between initial infection and subsequent malignancy, and most infected individuals never actually develop malignant disease. Multiple types of lymphoma and leukemia have been associated with preceding infection, including lymphoproliferative disorders caused by human herpesvirus 8 (HHV8/Kaposi sarcoma-associated herpesvirus); Epstein–Barr virus (EBV); human T-lymphotrophic virus (HTLV-1), hepatitis C virus (HCV), and Helicobacter pylori (H. pylori). Only the latter three disorders will be discussed herein.

Adult T-cell Leukemia/Lymphoma (ATLL)

ATLL was the first human malignancy known to be caused by an organism, HTLV-1.1 This retrovirus is transmitted via infected blood, sexual contact, or vertically from mother to infant via breastfeeding. While first described in small island communities in southwest Japan,2 the virus is present in 15–20 million people, worldwide. Nonetheless, only 2–5% will develop ATLL, at a latency of approximately 30–40 years. Patients present with lymphadenopathy (80%) and hepato-splenomegaly (50%), while up to 60% may also have manifestations on the skin, which may be indistinguishable from those seen in cutaneous T-cell lymphoma.3 Hypercalcemia is present in 30–40% at diagnosis, often with lytic bone lesions;4 parathormone levels are elevated, due to transactivation of parathyroid hormone-related protein promoter by the Tax gene of HTLV-1.5,6 The disease may be rather indolent and chronic, or quite aggressive. A carrier state is described, with infection in the absence of disease. Additionally, forms of ATLL include chronic, smoldering, acute, and lymphoma subtypes, with overall survival rates at 4 years of approximately 50% in the chronic and smoldering forms, and only 5–6% in the acute and lymphoma forms. Although various chemotherapeutic regimens have been studied, results are quite poor, and median survival has been in the range of 12 months.7 The combination of zidovudine and interferon alpha has been used with some success, although efficacy may not be related to the antiviral effects of the regimen.8,9 Autologous stem cell transplant is ineffective,10 although some success has been reported with allogeneic stem cell transplant, provided that the donor is not HTLV-1-infected.11 Newer approaches to therapy include the use of monoclonal antibodies, retinoids, arsenic trioxide with interferon-alpha, bortezomib, and others.7,12

HCV

While HCV has been associated with development of hepatocellular carcinoma, its role in the development of B-cell lymphoma has been more controversial. Retrospective serologic analyses of patients from Italy, France and the USA have confirmed a statistically significant association between prior infection by HCV and subsequent development of B-cell lymphoma, with a latent period of decades.13,14 These lymphomas may occur in the liver, or in other sites. While marginal zone lymphoma or plasmacytoma have been described most frequently, multiple diverse types of B-cell lymphoma have been noted in HCV-infected patients, with one case of mantle cell lymphoma (translocation 11;14 and cyclin D1-positive) treated successfully with pegylated interferon-alpha and ribavarin, associated with dramatic virologic as well as antitumor response.15 Prospective study of patients with marginal zone lymphoma associated with HCV has shown complete remission in the majority of patients, concomitant with antiviral response.16,17 Patients without anti-HCV response, or without HCV infection failed to respond to the regimen. Development of B-cell gene rearrangements have been described in HCV-infected patients, prior to the diagnosis of malignant lymphoma, and these rearrangements have resolved upon successful antiviral therapy.

H. pylori

H. pylori was designated as a human carcinogen by the International Agency for Research in Cancer in 1994, and is responsible for approximately 75% of non-cardia gastric cancers, and 5·5% of cancers, worldwide. It is a ubiquitous organism, acquired primarily through oral–fecal contact. Risk factors for infection include lower socioeconomic status, presence of infected family members, and host genetics, including polymorphisms of various cytokine genes, such as IL-1alpha, IL-1beta and tumor-necrosis factor-alpha. In the United States, the organism is found in approximately 62% of Mexican Americans, 53% of non-Hispanic Blacks, and 26% of non-Hispanic Whites.

In the area of lymphoproliferative malignancies, H. pylori has primarily been associated with marginal zone lymphomas, including the mucosa associated lymphoid tissue (MALT) lymphomas, as well as splenic marginal zone lymphoma. The most common presentation of H. pylori associated lymphoma is MALT lymphoma localized to the stomach.

The original recognition of the relationship between H. pylori and gastric MALT lymphoma was presented by Parsonnet and colleagues who studied 230 000 individuals from two large cohorts, including the Kasier health system in the USA and a cohort in Norway.18 Serum was collected on these individuals from 1964 through 1991, and the cohorts were followed for development of cancer. The odds ratio of developing gastric lymphoma in persons with prior serologic evidence of H. pylori was 6·3 (1–19·9), while that of lymphoma in general (not gastric) was 1·2 (0·5–3·0) when compared with matched controls who did not develop lymphoma. This seminal study proved that there was an increased risk of gastric lymphoma among persons who had been infected with H. pylori, and importantly, that the infection preceded the development of malignancy.

To determine if H. pylori continued to have a role in the ongoing pathogenesis of disease, once gastric MALT lymphoma had occurred, Isaacson and colleagues studied low-grade MALT lymphoma cells in vitro, and added H. pylori as well as non-neoplastic T cells.19 The lymphoma cells became activated, expressing the IL-2 receptor (CD25), with subsequent proliferation and synthesis of anti-H. pylori antibody; this work indicated that at a certain phase in the process, H. pylori remained an active participant in the progression and proliferation of the lymphoid malignancy.

To determine if treatment of H. pylori, per se, may be effective in the treatment of patients with H. pylori associated gastric MALT lymphoma, Wotherspoon was the first to show that complete remission could be achieved, using antibiotics alone, although the response could be rather slow.20 A recent study of 102 patients reported by Stathis and colleagues noted a 77% response rate (65% complete remission) in these individuals, with continuous remission in 78% of these, at a median follow-up of 7 years.21 The overall 5 and 10-year survivals were 92 and 83%. A study by Fischbach et al.22 in 108 patients confirmed that the responses may be quite slow, occurring beyond 12 months from the end of active antibiotic therapy.

In patients unresponsive to antibiotic therapy, or those with H. pylori negative gastric MALT lymphoma, multiple alternative treatments are available.23 Radiation therapy has been associated with complete remission rates approaching 100%, with long-term continuous remission seen in the majority.24 Surgery for localized disease is also effective in approximately 92%. Rituximab has been used effectively in patients unresponsive to H. pylori therapy, with response rates of approximately 77% reported in a series of 26 patients by Martinelli and colleagues.25

In time, H. pylori-associated gastric MALT lymphoma may evolve to H. pylori independence, at which time antibiotics will no longer be effective. This is associated with development of additional genetic alterations, including t(11;18), leading to the API2/MLT-1 fusion gene and protein; or t(1;14), leading to Bcl10 activation. In both circumstances, translocation of NF kappaB to the nucleus occurs, with ongoing signals for survival, activation and proliferation of the malignant cells. Transformation to large cell lymphoma, or progressive disease are associated with these cytogenetic and molecular changes.

Of interest, MALT lymphomas have been associated with other antigenic exposures, including development of gastric MALT lymphoma among patients with celiac disease;26 development of immunoproliferative small intestinal disease with Campylobacter jejuni; cutaneous MALT lymphoma with Borrelia burgdorferi; and development of ocular adnexal MALT lymphoma with infection by Chlamydia psittacci.