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EBV-positive diffuse large B-cell lymphoma in a human T-lymphotropic virus type 1 carrier

EBV-positive diffuse large B-cell lymphoma in a human T-lymphotropic virus type 1 carrier The development of B-cell lymphomas has been seldom described in HTLV-1 carriers. We present the case of an elderly Peruvian HTLV-1 carrier who was diagnosed with EBV-positive diffuse large B-cell lymphoma. Despite an initial good response to therapy, patient died during treatment due to fatal Pneumocystis jirovecci pneumonia. EBV infection is characterized by B-cell lymphotropism and selective immunodeficiency. HTLV-1, on the other hand, induces T-cell dysfunction and B-cell proliferation. Finally, immunosenescence is characterized by T-cell dysregulation, decreased apoptosis and cytokine upregulation. In this elderly patient, the combination of EBV and HTLV-1 coinfection and immunosenescence may have played a role in the development of this aggressive diffuse large B-cell lymphoma. Furthermore, the immunodeficiency caused by the viral infections and chemotherapy may have played a role in developing life-threatening infectious complications. Findings and, akin to Asian countries, there is high incidence of T- The Epstein Barr virus (EBV) was the first described onco- cell lymphomas and low incidence of follicular lympho- virus, which has been associated with the development of mas [8]. On the other hand, the human T-lymphotropic a variety of lymphoproliferative disorders, such as Burkitt virus type 1 (HTLV-1) is a retrovirus and is the pathogenic [1], primary CNS [2], NK/T-cell [3], plasmablastic [4] and agent of adult T-cell lymphoma/leukemia (ATLL) and Hodgkin lymphoma [5]. EBV infection occurs early in other diseases [9]. HTLV-1 is endemic in Japan, the Mela- childhood, and approximately 90 to 95% of adults world- nesian Islands, the Caribbean, South America, the Middle wide are EBV-seropositive. EBV expression has also been East and parts of Africa. The prevalence of HTLV-1 in reported in patients with diffuse large B-cell lymphoma Europe and the US is lower than 1%. In Peru, it is esti- (DLBCL) [6]. DLBCL is the most common variant of non- mated that up to 3% of the healthy adult population carry Hodgkin lymphoma in the United States (US) and HTLV-1 [10]. The interaction of these two oncoviruses, accounts for approximately 25–30% of the cases [7]. In EBV and HTLV-1, has seldom been reported in the medi- Peru, DLBCL accounts for up to 45% of all lymphomas cal literature. Page 1 of 4 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:10 http://www.infectagentscancer.com/content/4/1/10 The case is an 85-year-old Peruvian man with a past med- CD10 (Novocastra; Newcastle upon Tyne, UK; dilution ical history of hypertension, who presented with a seven- 1:10), BCL-6 (Dako; dilution 1:10), CD30 (Novocastra; week history of bilateral cervical node enlargement. The dilution 1:100) and LMP-1 (Dako; dilution 1:100). Auto- patient denied weight loss, drenching night sweats or mated chromogenic in situ hybridization (CISH) for fever. Physical examination showed an elderly individual EBER was performed according to the manufacturer's pro- with good performance status (ECOG 1) and non-tender tocol (Dako), and showed positive nuclear expression in bilateral cervical lymphadenopathy. No hepatosplenome- tumoral cells (Figure 3). galy was found. CT scans of the neck, chest, abdomen and pelvis did not reveal other sites of disease. Complete Before treatment, written consent was obtained from the blood count revealed 6,900 leucocytes per mm , with patient, who was then defined as stage IIA DLBCL with a 52% neutrophils and 28% lymphocytes; the white blood low-risk International Prognostic Index (IPI) score of 1 cell morphology was unremarkable. Hemoglobin was out of 5 (i.e. age older than 60 years). Treatment was 13.6 g/dl and platelets 245,000 per mm . Serum lactate started with cyclophosphamide, doxorubicin, vincristine dehydrogenase (LDH) levels were within normal limits. and prednisone (CHOP) every 21 days with 25% dose- Renal and hepatic function tests and immunoglobulin A, reduction of cyclophosphamide and doxorubicin with G, M and E quantification were within normal ranges. The granulocyte-colony stimulating factor (G-CSF) support patient was seropositive to HTLV-1 using Western Blot given patient's age. Four cycles of dose-reduced CHOP testing and was seronegative for the Human Immunodefi- were administered. The patient achieved a complete ciency Virus (HIV). Hepatitis B and C and Cytomegalovi- response by radiologic criteria after the fourth cycle of rus viral capside antigen (CMV VCA) IgM antibodies were treatment. Before the fifth cycle, the patient developed an not detected. EBV nuclear antigen IgG was positive, this interstitial pneumonia with increased serum LDH levels. pattern is characteristic of past EBV infection. An exci- Pneumocystis jirovecci pneumonia (PJP) was confirmed sional biopsy from a left cervical lymph node showed a by immunofluorescent staining. Serology for Legionella, diffuse, large-cell B-cell morphology. Bone marrow aspi- Chlamydia and Mycoplasma were negative. The patient ration and biopsy revealed a normocellular marrow show- died in the Intensive Care Unit 25 days after onset of PJP, ing trilineage hematopoiesis, without evidence of 5 months after his lymphoma diagnosis. lymphoma or other morphological abnormalities. EBV is a herpesvirus with demonstrated B-cell lymphotro- Automated immunohistochemistry studies were per- pism. EBV infection starts by attachment of the virus to formed on paraffin-embedded tissue sections. The tumor the CD21 antigen; this initial step prepares the B-lym- cells were positive for CD20 (Dako, Carpinteria, CA; dilu- phocyte for EBV infection and is characterized by tion 1:100; Figure 1), PAX5 (Santa Cruz Biotechnology, increased production of IL-6 and mRNA along with blas- Santa Cruz, CA; dilution 1:100) and MUM1 (Santa Cruz tic transformation and mobilization of calcium. EBV is Biotechnology; dilution 1:200; Figure 2) and negative for Imm Figure 2 unohistochemical expression of MUM1 Immunohistochemica Figure 1 l expression of CD20 Immunohistochemical expression of MUM1. MUM1 is Immunohistochemical expression of CD20. CD20 is a a plasma cell marker and, in DLBCL, is consistent with a non- pan-B-cell marker, demonstrating the B-cell lineage of this germinal center subtype. DLBCL with a non-germinal center lymphoma (100×) profile have been associated with worse survival (100×) Page 2 of 4 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:10 http://www.infectagentscancer.com/content/4/1/10 importance of this allele in cytotoxic T-lymphocyte responses [16]. HTLV-1 is a deltaretrovirus that infects a wide variety of cells, such as lymphocytes, monocytes and fibroblasts by virtue of its receptor, a commonly expressed transporter of glucose [17]. HTLV-1 induces a higher rate of production of infected cells rather than replicating itself, unlike HIV. A first step is to produce viral-associated proteins such as Tax, which is encoded in the pX region of the viral genome. Tax increases proliferation of virus-infected cells by accelerating all the phases of the cell cycle and renders the affected cells tolerant to a series of genetic and epigenetic changes [18]. The expres- sion of Tax wears out as cells acquire the ability to proliferate independently. Due to its prolonged latency period of 40 to 60 years, HTLV-1 infected cells are more susceptible to acquire malignant phenotypes in a multistep process. Previ- Immunohistochemica (EB Figure 3 ER) l detection of EBV-encoded RNA ous studies have indicated that the frequency of primary Immunohistochemical detection of EBV-encoded RNA (EBER). Nuclear expression is demonstrated through malignant neoplasms in HTLV-1 carriers is higher than in automated chromogenic in situ hybridization (75×) HTLV-1 seronegative non-Hodgkin lymphoma cases [19]. HTLV-1 infection is strongly associated to the development of ATLL and several Peruvian studies on clinical characteris- then inserted into the nucleus where it, episomally, tics and outcomes of patients with ATLL have been reported acquires a circle-shaped configuration. EBV nuclear anti- [20]. Although HTLV-1 has not been associated with the gens (EBNA-LP, -1, -2 and -3) are the first to be produced development of B-cell lymphomas, HTLV-1 carriers with B- after infection; these products are essential for immortali- cell lymphoma tend to have a worse prognosis [21]. Theoret- zation of the cell and upregulation of the expression of ically, chronic HTLV-1 infection can cause T-cell dysfunction other molecules and genes such as the latent membrane and B-cell proliferation inducing a particular state of immu- proteins (LMP-1 and -2). EBNAs also upregulate c-myc, nosuppression favoring lymphomagenesis. which is a well-known human oncogene associated with cell proliferation. LMPs increase expression of BCL-2 and As people ages, their immune systems do not respond drive the cell into a latent state, which is maintained by adequately to external pathogens or new antigens, such as the production of EBV-encoded RNA (EBER-1 and -2). In immunizations or cancer. T-lymphocytes are greatly this way, EBV-infected B-cells enter the resting phase affected by this immune dysregulation state called immu- avoiding immunosurveillance but, due to their activated nosenescence since the number of naïve T-cells decrease phenotype, more prone to develop secondary oncogenic in peripheral blood and lymph nodes [22], the distribu- changes [11]. In the present case, the serologic studies are tion of T-cell population is altered [23] and the T-cell consistent with a prior EBV infection and the immunohis- receptor repertoire becomes more limited [24]. The pres- tochemical studies showed expression of EBER. The pres- ence of persistent infections, such as EBV or HTLV-1 or ence of EBNA-2 was observed in 28% of the cases of age- other persistent antigens, such as cancer will also induce a related EBV-associated lymphoproliferative disorder phenomenon called immune exhaustion [25]. Other reported by Oyama and colleagues [12], which is indica- immunological changes associated with age include tive of a type III EBV latency, similar to the one observed decrease in apoptosis [26] and elevation of levels of proin- in some cases of HIV-associated [13] and post-transplant flammatory molecules [27]. This could potentially lymphoproliferative disorders [14]. Genetic factors could explain the increased incidence of cancers in the elderly. also play a role in the development of EBV-associated Furthermore, the detection of a type III EBV latency pat- lymphoma; it has been suggested that a genetically deter- tern speaks of a severe immunosuppression that could be mined susceptibility, possibly based on certain HLA types, partially explained by chronic HTLV-1 infection and/or results in an abnormal response to primary EBV infection immunosencescence. This theoretical relationship is cur- in certain parts of Asia [15]. These variations in HLA phe- rently unclear but plausible. To date, there are very few notype may provide a basis for the higher frequency of cases reporting the emergence of lymphoma in patients EBV-positive tumors among Asians. In addition, a recent with coinfection by EBV and HTLV-1 [28-30]. study from Japan has shown that patients with EBV-asso- ciated NK/T-cell lymphomas, nasal type, have a low fre- Likely, HTLV-1 infection will cause chronic immunosup- quency of the HLA-A*0201 allele, suggesting the presion and activate B-cell proliferation, favoring the development of EBV infection, which in turn will prepare Page 3 of 4 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:10 http://www.infectagentscancer.com/content/4/1/10 related to the pathological features of post-transplant lym- the host for the development of B-cell lymphoma por- phoproliferative disorders. Am J Pathol 1995, 146:1113-1120. tending a worse prognosis. It seems intuitive that a patient 15. de Campos-Lima PO, Levitsky V, Brooks J, Lee SP, Hu LF, Rickinson with a combination of severe immunological impairment AB, Masucci MG: T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus iso- due to EBV and HTLV-1 infections, immunosenescence lates from highly A11-positive populations by selective and chemotherapy would develop life-threatening oppor- mutation of anchor residues. J Exp Med 1994, 179:1297-1305. 16. Kanno H, Kojya S, Li T, Ohsawa M, Nakatsuka S, Miyaguchi M, tunistic infections, although the occurrence of PJP in Harabuchi Y, Aozasa K: Low frequency of HLA-A*0201 allele in HTLV-1 carriers has seldom been reported in the medical patients with Epstein-Barr virus-positive nasal lymphomas literature [31,32]. Further research is needed to better with polymorphic reticulosis morphology. Int J Cancer 2000, 87:195-199. understand the interaction between EBV and HTLV-1 in 17. Manel N, Battini JL, Sitbon M: Human T cell leukemia virus enve- lymphomagenesis. lope binding and virus entry are mediated by distinct domains of the glucose transporter GLUT1. J Biol Chem 2005, 280:29025-29029. Competing interests 18. Yoshida M: Multiple viral strategies of HTLV-1 for dysregula- The authors declare that they have no competing interests. tion of cell growth control. Annu Rev Immunol 2001, 19:475-496. 19. Kozuru M, Uike N, Muta K, Goto T, Suehiro Y, Nagano M: High occurrence of primary malignant neoplasms in patients with Authors' contributions adult T-cell leukemia/lymphoma, their siblings, and their BB, RS, FH, EC and LR provided clinical care to patient. mothers. Cancer 1996, 78:1119-1124. 20. Beltran-Garate BE, Carrasco-Yalan AA, Lopez-Odria OM, Riva- PQ and DM carried out pathological studies. BB and JC Gonzales L, Rios H, Chumpitaz-Anchiraico G, Falcon-Lisarazo S, Nav- prepared the manuscript. All the authors read and arro-M J, de Mendoza FH, Castillo-Aguirre J: Clinical Outcomes in Adult T Leukemia/Lymphoma: Report of 55 Cases from approved the final manuscript. Peru. ASH Annual Meeting Abstracts 2005, 106:4797. 21. Pimentel P, Beltran B, Flores D, Ferrel G, Falcon S, Vera L, Figueroa References A, Portugal K, Bermudez V: Clinical characteristics of lymphom- atous form of Adult T cell lymphoma-leukemia in Peru. 1. Brady G, MacArthur GJ, Farrell PJ: Epstein-Barr virus and Burkitt lymphoma. J Clin Pathol 2007, 60:1397-1402. ASCO Meeting Abstracts 2005, 23:6728. 22. Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lava- 2. Yu GH, Montone KT, Frias-Hidvegi D, Cajulis RS, Brody BA, Levy RM: Cytomorphology of primary CNS lymphoma: review of 23 getto G, Casti A, Franceschi C, Passeri M, Sansoni P: Shortage of circulating naive CD8(+) T cells provides new insights on cases and evidence for the role of EBV. Diagn Cytopathol 1996, 14:114-120. immunodeficiency in aging. Blood 2000, 95:2860-2868. 23. Koch S, Larbi A, Derhovanessian E, Ozcelik D, Naumova E, Pawelec 3. Siu LL, Chan JK, Kwong YL: Natural killer cell malignancies: clin- icopathologic and molecular features. Histol Histopathol 2002, G: Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing 2008, 5:6. 17:539-554. 4. Castillo J, Pantanowitz L, Dezube BJ: HIV-associated plasmablas- 24. Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ: The influence of age on T tic lymphoma: lessons learned from 112 published cases. Am J Hematol 2008, 83:804-809. cell generation and TCR diversity. J Immunol 2005, 174:7446-7452. 5. Pallesen G, Hamilton-Dutoit SJ, Rowe M, Young LS: Expression of Epstein-Barr virus latent gene products in tumour cells of 25. Zinkernagel RM, Moskophidis D, Kundig T, Oehen S, Pircher H, Hen- gartner H: Effector T-cell induction and T-cell memory versus Hodgkin's disease. Lancet 1991, 337:320-322. 6. Park S, Lee J, Ko YH, Han A, Jun HJ, Lee SC, Hwang IG, Park YH, Ahn peripheral deletion of T cells. Immunol Rev 1993, 133:199-223. 26. Spaulding C, Guo W, Effros RB: Resistance to apoptosis in JS, Jung CW, et al.: The impact of Epstein-Barr virus status on clinical outcome in diffuse large B-cell lymphoma. Blood 2007, human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 110:972-978. 7. Swerdlow S, Campo E, Harris N, Jaffe E: WHO Classification of Tumours 1999, 34:633-644. 27. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panour- of Haematopoietic and Lymphoid Tissues 4th edition. Lyon, France: International Agency for Research on Cancer; 2008. gia MP, Invidia L, Celani L, Scurti M, et al.: Inflammaging and anti- inflammaging: a systemic perspective on aging and longevity 8. Beltran B, Morales D, Quinones P, Salas A, Riva L, Carrasco A: Dis- tribution and Pathology Characteristics of Non Hodgkin emerged from studies in humans. Mech Ageing Dev 2007, 128:92-105. Lymphoma in Peru: A Study of 1014 Cases Using WHO Classification of Lymphoid Neoplasm. ASH Annual Meeting 28. Murata T, Nakamura S, Kato H, Yatabe Y, Shiraishi T, Kuroda M, Yat- ani R, Suchi T: Epstein-Barr virus-related Hodgkin's disease Abstracts 2007, 110:4419. 9. Ohshima K, Kikuchi M, Masuda Y, Sumiyoshi Y, Eguchi F, Mohtai H, showing B cell lineage in an immunosuppressive patient seropositive for HTLV-I. Pathol Int 1997, 47:801-805. Takeshita M, Kimura N: Human T-cell leukemia virus type I associated lymphadenitis. Cancer 1992, 69:239-248. 29. Sadahira Y, Nishihara H, Shimizu M, Hirokawa M, Wada H, Yamada O, Yawata Y, Manabe T: Epstein-Barr virus-associated Hodg- 10. Alarcon JO, Friedman HB, Montano SM, Zunt JR, Holmes KK, Quin- nan GV Jr: High endemicity of human T-cell lymphotropic kin's disease in HTLV-I seropositive patients: a report of two cases. Pathol Int 1998, 48:67-73. virus type 1 among pregnant women in peru. J Acquir Immune Defic Syndr 2006, 42:604-609. 30. Tobinai K, Ohtsu T, Hayashi M, Kinoshita T, Matsuno Y, Mukai K, Shi- moyama M: Epstein-Barr virus (EBV) genome carrying mono- 11. Thompson MP, Kurzrock R: Epstein-Barr virus and cancer. Clin Cancer Res 2004, 10:803-821. clonal B-cell lymphoma in a patient with adult T-cell leukemia-lymphoma. Leuk Res 1991, 15:837-846. 12. Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y, Morishima Y, Takeuchi K, Izumo T, Mori S, et al.: Age-related EBV- 31. Roudier M, Lamaury I, Strobel M: Human T cell leukemia/lym- phoma virus type I (HTLV-I) and Pneumocystis carinii asso- associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin ciated with T cell proliferation and haemophagocytic syndrome. Leukemia 1997, 11:453-454. Cancer Res 2007, 13:5124-5132. 13. Buisson M, Morand P, Genoulaz O, Bourgeat MJ, Micoud M, Sei- 32. Shahnaz S, Reich D, Arevalo-Valencia D, Kucinska S, Tulczynska J, Fleischman J: HTLV-1-associated adult T cell leukemia lym- gneurin JM: Changes in the dominant Epstein-Barr virus type during human immunodeficiency virus infection. J Gen Virol phoma presenting as granulomatous pneumocystis jiroveci pneumonia (PJP) and hypercalcemia. J Gen Intern Med 2007, 1994, 75(Pt 2):431-437. 14. Delecluse HJ, Kremmer E, Rouault JP, Cour C, Bornkamm G, Berger 22:420-423. F: The expression of Epstein-Barr virus latent proteins is Page 4 of 4 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

EBV-positive diffuse large B-cell lymphoma in a human T-lymphotropic virus type 1 carrier

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Springer Journals
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Copyright © 2009 by Beltran et al; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Infectious Diseases; Oncology
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1750-9378
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10.1186/1750-9378-4-10
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19580668
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Abstract

The development of B-cell lymphomas has been seldom described in HTLV-1 carriers. We present the case of an elderly Peruvian HTLV-1 carrier who was diagnosed with EBV-positive diffuse large B-cell lymphoma. Despite an initial good response to therapy, patient died during treatment due to fatal Pneumocystis jirovecci pneumonia. EBV infection is characterized by B-cell lymphotropism and selective immunodeficiency. HTLV-1, on the other hand, induces T-cell dysfunction and B-cell proliferation. Finally, immunosenescence is characterized by T-cell dysregulation, decreased apoptosis and cytokine upregulation. In this elderly patient, the combination of EBV and HTLV-1 coinfection and immunosenescence may have played a role in the development of this aggressive diffuse large B-cell lymphoma. Furthermore, the immunodeficiency caused by the viral infections and chemotherapy may have played a role in developing life-threatening infectious complications. Findings and, akin to Asian countries, there is high incidence of T- The Epstein Barr virus (EBV) was the first described onco- cell lymphomas and low incidence of follicular lympho- virus, which has been associated with the development of mas [8]. On the other hand, the human T-lymphotropic a variety of lymphoproliferative disorders, such as Burkitt virus type 1 (HTLV-1) is a retrovirus and is the pathogenic [1], primary CNS [2], NK/T-cell [3], plasmablastic [4] and agent of adult T-cell lymphoma/leukemia (ATLL) and Hodgkin lymphoma [5]. EBV infection occurs early in other diseases [9]. HTLV-1 is endemic in Japan, the Mela- childhood, and approximately 90 to 95% of adults world- nesian Islands, the Caribbean, South America, the Middle wide are EBV-seropositive. EBV expression has also been East and parts of Africa. The prevalence of HTLV-1 in reported in patients with diffuse large B-cell lymphoma Europe and the US is lower than 1%. In Peru, it is esti- (DLBCL) [6]. DLBCL is the most common variant of non- mated that up to 3% of the healthy adult population carry Hodgkin lymphoma in the United States (US) and HTLV-1 [10]. The interaction of these two oncoviruses, accounts for approximately 25–30% of the cases [7]. In EBV and HTLV-1, has seldom been reported in the medi- Peru, DLBCL accounts for up to 45% of all lymphomas cal literature. Page 1 of 4 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:10 http://www.infectagentscancer.com/content/4/1/10 The case is an 85-year-old Peruvian man with a past med- CD10 (Novocastra; Newcastle upon Tyne, UK; dilution ical history of hypertension, who presented with a seven- 1:10), BCL-6 (Dako; dilution 1:10), CD30 (Novocastra; week history of bilateral cervical node enlargement. The dilution 1:100) and LMP-1 (Dako; dilution 1:100). Auto- patient denied weight loss, drenching night sweats or mated chromogenic in situ hybridization (CISH) for fever. Physical examination showed an elderly individual EBER was performed according to the manufacturer's pro- with good performance status (ECOG 1) and non-tender tocol (Dako), and showed positive nuclear expression in bilateral cervical lymphadenopathy. No hepatosplenome- tumoral cells (Figure 3). galy was found. CT scans of the neck, chest, abdomen and pelvis did not reveal other sites of disease. Complete Before treatment, written consent was obtained from the blood count revealed 6,900 leucocytes per mm , with patient, who was then defined as stage IIA DLBCL with a 52% neutrophils and 28% lymphocytes; the white blood low-risk International Prognostic Index (IPI) score of 1 cell morphology was unremarkable. Hemoglobin was out of 5 (i.e. age older than 60 years). Treatment was 13.6 g/dl and platelets 245,000 per mm . Serum lactate started with cyclophosphamide, doxorubicin, vincristine dehydrogenase (LDH) levels were within normal limits. and prednisone (CHOP) every 21 days with 25% dose- Renal and hepatic function tests and immunoglobulin A, reduction of cyclophosphamide and doxorubicin with G, M and E quantification were within normal ranges. The granulocyte-colony stimulating factor (G-CSF) support patient was seropositive to HTLV-1 using Western Blot given patient's age. Four cycles of dose-reduced CHOP testing and was seronegative for the Human Immunodefi- were administered. The patient achieved a complete ciency Virus (HIV). Hepatitis B and C and Cytomegalovi- response by radiologic criteria after the fourth cycle of rus viral capside antigen (CMV VCA) IgM antibodies were treatment. Before the fifth cycle, the patient developed an not detected. EBV nuclear antigen IgG was positive, this interstitial pneumonia with increased serum LDH levels. pattern is characteristic of past EBV infection. An exci- Pneumocystis jirovecci pneumonia (PJP) was confirmed sional biopsy from a left cervical lymph node showed a by immunofluorescent staining. Serology for Legionella, diffuse, large-cell B-cell morphology. Bone marrow aspi- Chlamydia and Mycoplasma were negative. The patient ration and biopsy revealed a normocellular marrow show- died in the Intensive Care Unit 25 days after onset of PJP, ing trilineage hematopoiesis, without evidence of 5 months after his lymphoma diagnosis. lymphoma or other morphological abnormalities. EBV is a herpesvirus with demonstrated B-cell lymphotro- Automated immunohistochemistry studies were per- pism. EBV infection starts by attachment of the virus to formed on paraffin-embedded tissue sections. The tumor the CD21 antigen; this initial step prepares the B-lym- cells were positive for CD20 (Dako, Carpinteria, CA; dilu- phocyte for EBV infection and is characterized by tion 1:100; Figure 1), PAX5 (Santa Cruz Biotechnology, increased production of IL-6 and mRNA along with blas- Santa Cruz, CA; dilution 1:100) and MUM1 (Santa Cruz tic transformation and mobilization of calcium. EBV is Biotechnology; dilution 1:200; Figure 2) and negative for Imm Figure 2 unohistochemical expression of MUM1 Immunohistochemica Figure 1 l expression of CD20 Immunohistochemical expression of MUM1. MUM1 is Immunohistochemical expression of CD20. CD20 is a a plasma cell marker and, in DLBCL, is consistent with a non- pan-B-cell marker, demonstrating the B-cell lineage of this germinal center subtype. DLBCL with a non-germinal center lymphoma (100×) profile have been associated with worse survival (100×) Page 2 of 4 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:10 http://www.infectagentscancer.com/content/4/1/10 importance of this allele in cytotoxic T-lymphocyte responses [16]. HTLV-1 is a deltaretrovirus that infects a wide variety of cells, such as lymphocytes, monocytes and fibroblasts by virtue of its receptor, a commonly expressed transporter of glucose [17]. HTLV-1 induces a higher rate of production of infected cells rather than replicating itself, unlike HIV. A first step is to produce viral-associated proteins such as Tax, which is encoded in the pX region of the viral genome. Tax increases proliferation of virus-infected cells by accelerating all the phases of the cell cycle and renders the affected cells tolerant to a series of genetic and epigenetic changes [18]. The expres- sion of Tax wears out as cells acquire the ability to proliferate independently. Due to its prolonged latency period of 40 to 60 years, HTLV-1 infected cells are more susceptible to acquire malignant phenotypes in a multistep process. Previ- Immunohistochemica (EB Figure 3 ER) l detection of EBV-encoded RNA ous studies have indicated that the frequency of primary Immunohistochemical detection of EBV-encoded RNA (EBER). Nuclear expression is demonstrated through malignant neoplasms in HTLV-1 carriers is higher than in automated chromogenic in situ hybridization (75×) HTLV-1 seronegative non-Hodgkin lymphoma cases [19]. HTLV-1 infection is strongly associated to the development of ATLL and several Peruvian studies on clinical characteris- then inserted into the nucleus where it, episomally, tics and outcomes of patients with ATLL have been reported acquires a circle-shaped configuration. EBV nuclear anti- [20]. Although HTLV-1 has not been associated with the gens (EBNA-LP, -1, -2 and -3) are the first to be produced development of B-cell lymphomas, HTLV-1 carriers with B- after infection; these products are essential for immortali- cell lymphoma tend to have a worse prognosis [21]. Theoret- zation of the cell and upregulation of the expression of ically, chronic HTLV-1 infection can cause T-cell dysfunction other molecules and genes such as the latent membrane and B-cell proliferation inducing a particular state of immu- proteins (LMP-1 and -2). EBNAs also upregulate c-myc, nosuppression favoring lymphomagenesis. which is a well-known human oncogene associated with cell proliferation. LMPs increase expression of BCL-2 and As people ages, their immune systems do not respond drive the cell into a latent state, which is maintained by adequately to external pathogens or new antigens, such as the production of EBV-encoded RNA (EBER-1 and -2). In immunizations or cancer. T-lymphocytes are greatly this way, EBV-infected B-cells enter the resting phase affected by this immune dysregulation state called immu- avoiding immunosurveillance but, due to their activated nosenescence since the number of naïve T-cells decrease phenotype, more prone to develop secondary oncogenic in peripheral blood and lymph nodes [22], the distribu- changes [11]. In the present case, the serologic studies are tion of T-cell population is altered [23] and the T-cell consistent with a prior EBV infection and the immunohis- receptor repertoire becomes more limited [24]. The pres- tochemical studies showed expression of EBER. The pres- ence of persistent infections, such as EBV or HTLV-1 or ence of EBNA-2 was observed in 28% of the cases of age- other persistent antigens, such as cancer will also induce a related EBV-associated lymphoproliferative disorder phenomenon called immune exhaustion [25]. Other reported by Oyama and colleagues [12], which is indica- immunological changes associated with age include tive of a type III EBV latency, similar to the one observed decrease in apoptosis [26] and elevation of levels of proin- in some cases of HIV-associated [13] and post-transplant flammatory molecules [27]. This could potentially lymphoproliferative disorders [14]. Genetic factors could explain the increased incidence of cancers in the elderly. also play a role in the development of EBV-associated Furthermore, the detection of a type III EBV latency pat- lymphoma; it has been suggested that a genetically deter- tern speaks of a severe immunosuppression that could be mined susceptibility, possibly based on certain HLA types, partially explained by chronic HTLV-1 infection and/or results in an abnormal response to primary EBV infection immunosencescence. This theoretical relationship is cur- in certain parts of Asia [15]. These variations in HLA phe- rently unclear but plausible. To date, there are very few notype may provide a basis for the higher frequency of cases reporting the emergence of lymphoma in patients EBV-positive tumors among Asians. In addition, a recent with coinfection by EBV and HTLV-1 [28-30]. study from Japan has shown that patients with EBV-asso- ciated NK/T-cell lymphomas, nasal type, have a low fre- Likely, HTLV-1 infection will cause chronic immunosup- quency of the HLA-A*0201 allele, suggesting the presion and activate B-cell proliferation, favoring the development of EBV infection, which in turn will prepare Page 3 of 4 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4:10 http://www.infectagentscancer.com/content/4/1/10 related to the pathological features of post-transplant lym- the host for the development of B-cell lymphoma por- phoproliferative disorders. Am J Pathol 1995, 146:1113-1120. tending a worse prognosis. It seems intuitive that a patient 15. de Campos-Lima PO, Levitsky V, Brooks J, Lee SP, Hu LF, Rickinson with a combination of severe immunological impairment AB, Masucci MG: T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus iso- due to EBV and HTLV-1 infections, immunosenescence lates from highly A11-positive populations by selective and chemotherapy would develop life-threatening oppor- mutation of anchor residues. J Exp Med 1994, 179:1297-1305. 16. Kanno H, Kojya S, Li T, Ohsawa M, Nakatsuka S, Miyaguchi M, tunistic infections, although the occurrence of PJP in Harabuchi Y, Aozasa K: Low frequency of HLA-A*0201 allele in HTLV-1 carriers has seldom been reported in the medical patients with Epstein-Barr virus-positive nasal lymphomas literature [31,32]. Further research is needed to better with polymorphic reticulosis morphology. Int J Cancer 2000, 87:195-199. understand the interaction between EBV and HTLV-1 in 17. Manel N, Battini JL, Sitbon M: Human T cell leukemia virus enve- lymphomagenesis. lope binding and virus entry are mediated by distinct domains of the glucose transporter GLUT1. J Biol Chem 2005, 280:29025-29029. Competing interests 18. Yoshida M: Multiple viral strategies of HTLV-1 for dysregula- The authors declare that they have no competing interests. tion of cell growth control. Annu Rev Immunol 2001, 19:475-496. 19. Kozuru M, Uike N, Muta K, Goto T, Suehiro Y, Nagano M: High occurrence of primary malignant neoplasms in patients with Authors' contributions adult T-cell leukemia/lymphoma, their siblings, and their BB, RS, FH, EC and LR provided clinical care to patient. mothers. Cancer 1996, 78:1119-1124. 20. Beltran-Garate BE, Carrasco-Yalan AA, Lopez-Odria OM, Riva- PQ and DM carried out pathological studies. BB and JC Gonzales L, Rios H, Chumpitaz-Anchiraico G, Falcon-Lisarazo S, Nav- prepared the manuscript. All the authors read and arro-M J, de Mendoza FH, Castillo-Aguirre J: Clinical Outcomes in Adult T Leukemia/Lymphoma: Report of 55 Cases from approved the final manuscript. Peru. ASH Annual Meeting Abstracts 2005, 106:4797. 21. Pimentel P, Beltran B, Flores D, Ferrel G, Falcon S, Vera L, Figueroa References A, Portugal K, Bermudez V: Clinical characteristics of lymphom- atous form of Adult T cell lymphoma-leukemia in Peru. 1. Brady G, MacArthur GJ, Farrell PJ: Epstein-Barr virus and Burkitt lymphoma. J Clin Pathol 2007, 60:1397-1402. ASCO Meeting Abstracts 2005, 23:6728. 22. Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lava- 2. Yu GH, Montone KT, Frias-Hidvegi D, Cajulis RS, Brody BA, Levy RM: Cytomorphology of primary CNS lymphoma: review of 23 getto G, Casti A, Franceschi C, Passeri M, Sansoni P: Shortage of circulating naive CD8(+) T cells provides new insights on cases and evidence for the role of EBV. Diagn Cytopathol 1996, 14:114-120. immunodeficiency in aging. Blood 2000, 95:2860-2868. 23. Koch S, Larbi A, Derhovanessian E, Ozcelik D, Naumova E, Pawelec 3. Siu LL, Chan JK, Kwong YL: Natural killer cell malignancies: clin- icopathologic and molecular features. Histol Histopathol 2002, G: Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing 2008, 5:6. 17:539-554. 4. Castillo J, Pantanowitz L, Dezube BJ: HIV-associated plasmablas- 24. Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ: The influence of age on T tic lymphoma: lessons learned from 112 published cases. Am J Hematol 2008, 83:804-809. cell generation and TCR diversity. J Immunol 2005, 174:7446-7452. 5. Pallesen G, Hamilton-Dutoit SJ, Rowe M, Young LS: Expression of Epstein-Barr virus latent gene products in tumour cells of 25. Zinkernagel RM, Moskophidis D, Kundig T, Oehen S, Pircher H, Hen- gartner H: Effector T-cell induction and T-cell memory versus Hodgkin's disease. Lancet 1991, 337:320-322. 6. Park S, Lee J, Ko YH, Han A, Jun HJ, Lee SC, Hwang IG, Park YH, Ahn peripheral deletion of T cells. Immunol Rev 1993, 133:199-223. 26. Spaulding C, Guo W, Effros RB: Resistance to apoptosis in JS, Jung CW, et al.: The impact of Epstein-Barr virus status on clinical outcome in diffuse large B-cell lymphoma. Blood 2007, human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 110:972-978. 7. Swerdlow S, Campo E, Harris N, Jaffe E: WHO Classification of Tumours 1999, 34:633-644. 27. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panour- of Haematopoietic and Lymphoid Tissues 4th edition. Lyon, France: International Agency for Research on Cancer; 2008. gia MP, Invidia L, Celani L, Scurti M, et al.: Inflammaging and anti- inflammaging: a systemic perspective on aging and longevity 8. Beltran B, Morales D, Quinones P, Salas A, Riva L, Carrasco A: Dis- tribution and Pathology Characteristics of Non Hodgkin emerged from studies in humans. Mech Ageing Dev 2007, 128:92-105. Lymphoma in Peru: A Study of 1014 Cases Using WHO Classification of Lymphoid Neoplasm. ASH Annual Meeting 28. Murata T, Nakamura S, Kato H, Yatabe Y, Shiraishi T, Kuroda M, Yat- ani R, Suchi T: Epstein-Barr virus-related Hodgkin's disease Abstracts 2007, 110:4419. 9. Ohshima K, Kikuchi M, Masuda Y, Sumiyoshi Y, Eguchi F, Mohtai H, showing B cell lineage in an immunosuppressive patient seropositive for HTLV-I. Pathol Int 1997, 47:801-805. Takeshita M, Kimura N: Human T-cell leukemia virus type I associated lymphadenitis. Cancer 1992, 69:239-248. 29. Sadahira Y, Nishihara H, Shimizu M, Hirokawa M, Wada H, Yamada O, Yawata Y, Manabe T: Epstein-Barr virus-associated Hodg- 10. Alarcon JO, Friedman HB, Montano SM, Zunt JR, Holmes KK, Quin- nan GV Jr: High endemicity of human T-cell lymphotropic kin's disease in HTLV-I seropositive patients: a report of two cases. Pathol Int 1998, 48:67-73. virus type 1 among pregnant women in peru. J Acquir Immune Defic Syndr 2006, 42:604-609. 30. Tobinai K, Ohtsu T, Hayashi M, Kinoshita T, Matsuno Y, Mukai K, Shi- moyama M: Epstein-Barr virus (EBV) genome carrying mono- 11. Thompson MP, Kurzrock R: Epstein-Barr virus and cancer. Clin Cancer Res 2004, 10:803-821. clonal B-cell lymphoma in a patient with adult T-cell leukemia-lymphoma. Leuk Res 1991, 15:837-846. 12. Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y, Morishima Y, Takeuchi K, Izumo T, Mori S, et al.: Age-related EBV- 31. Roudier M, Lamaury I, Strobel M: Human T cell leukemia/lym- phoma virus type I (HTLV-I) and Pneumocystis carinii asso- associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin ciated with T cell proliferation and haemophagocytic syndrome. Leukemia 1997, 11:453-454. Cancer Res 2007, 13:5124-5132. 13. Buisson M, Morand P, Genoulaz O, Bourgeat MJ, Micoud M, Sei- 32. Shahnaz S, Reich D, Arevalo-Valencia D, Kucinska S, Tulczynska J, Fleischman J: HTLV-1-associated adult T cell leukemia lym- gneurin JM: Changes in the dominant Epstein-Barr virus type during human immunodeficiency virus infection. J Gen Virol phoma presenting as granulomatous pneumocystis jiroveci pneumonia (PJP) and hypercalcemia. J Gen Intern Med 2007, 1994, 75(Pt 2):431-437. 14. Delecluse HJ, Kremmer E, Rouault JP, Cour C, Bornkamm G, Berger 22:420-423. 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