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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2851-2852 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.0676
Simultaneous Manifestation of Fulminant Infectious Mononucleosis With B-Cell Non-Hodgkin's LymphomaDepartment of Pediatrics, Division of Hematology/Oncology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
Department of Pathology, Nemazee Hospital, Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Department of Pediatrics, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran A 9-year-old boy was admitted with a sore throat, high-grade fever, and myalgia. The patient was well until about 8 days before admission, when he developed abdominal pain, headache, inability of solid food ingestion, and difficulty in respiration. The patient received a penicillin injection without improvement. In his past medical history, there was no significant history of recurrent infection. The patient received complete vaccination without an adverse effect. There was no history of immune deficiency in his male relatives. On admission, the patient was well developed and nourished, febrile (39°C axillary), with a pulse of 130 beats and respiratory rate of 40 breaths per minute. His blood pressure was within normal range. On physical examination of the head, icteric sclera and bilateral tonsilar enlargement with extensive whitish membrane were visible. A 3 x 3 cm nontender, hard, nonmobile submandibular mass was palpable. He also had severe bilateral neck, axillary and inguinal lymphadenopathy, and hepatosplemomegaly (liver 6 cm and spleen 4 cm below costal margins). Other examinations were normal. About 48 hours after admission, the patient's condition became worse. He developed tachypnea, tachycardia, and decreased O2 saturation from 95% to 70%, which progressed finally to respiratory arrest. The patient was intubated, but after a few hours, he developed pneumothorax and disseminated intravascular coagulation. A chest tube was inserted. One day later, he developed cardiopulmonary arrest without any response to cardiopulmonary resuscitation. Lab studies showed WBC count of 21.5 x 103/µL, with 44% neutrophil, 50% lymphocyte, 28% atypical lymphocyte, hemoglobin 10.1 gr/dL, and platelet count of 85 x 103/µL. Erythrocytes sedimentation rate and C-reactive protein were significantly elevated, and heterophil antibody (monospot test) and febrile agglutination test were both negative. Liver function tests were abnormal: total protein 8.4 gr/dL, albumin 3.5 gr/dL (3.8 to 5.0 gr/dL dye-binding method), globulin 4.4 gr/dL (2.3 to 3.5 gr/dL), AST 599 U/L (8 to 33 U/L), ALT 310 U/L (3 to 36 U/L), total bilirubin 8.3 mg/dL (0.1 to 1.2 mg/dL), direct bilirubin 3 mg/dL (< 0.3 mg/dL), alkaline phosphatase 1,665 U/L (20 to 130 U/L), and lactate dehydrogenase 2,040 U/L (90 to 310 U/L). The other lab data were normal, except the high serum potassium level. Epstein-Barr virus (EBV) caspid IgM (viral caspid antigen [VCA] IgM) was positive using the enzyme-linked immunosorbent assay method (Table 1). Chest x-ray showed mediastinal widening (Fig 1). Abdominopelvic sonography revealed enlarged liver and spleen with multiple lymphadenopathy in the hilum of the spleen and para-aortic area. Biopsy of the submandibular lymph node showed complete effacement of lymph node architecture, and severe infiltration of many intermediate size cells (Figs 2 and 3) were seen with some tingible body macrophages. Lymphoma cells were diffusely reactive for leukocyte common antigen (CD45) and CD20. The pathological diagnosis was B-cell non-Hodgkin's lymphoma.
The lymph node biopsy polymerase chain reaction (PCR) for EBV was positive. The bone marrow aspiration and biopsy showed normocellular marrow without evidence of malignant cell infiltration. EBV, discovered more than 40 years ago from a Burkitt's lymphoma biopsy, was the first virus to be directly associated with human cancer.1-3 EBV is one of the eight known herpes viruses, is a member of the  -herpes viruses, and causes more than 90% of infectious mononucleosis cases. The B lymphocytes and epithelium of oral nasopharynx are the natural cell targets of the virus. EBV initially infects B lymphocytes in lymphoid tissue of Waldeyer's ring.2,4,5 EBV has two distinct life cycles in the human host: a lytic form of infection that produces new infectious virions, and a latent form of infection that allows the virus to persist in a dormant state for the lifetime of the host.1 EBV infection may result in a spectrum of proliferative disorder ranging from a self-limited usually benign disease, such as infectious mononucleosis, to aggressive, nonmalignant proliferations, such as virus-associated hemophagocytic syndrome, to lymphoid and epithelial cell malignancies.6-8 In addition, EBV has been associated with autoimmune diseases. Changes in the viral burden or atypical behavior of the virus may be an indirect effect on a compromised immune system that results from the autoimmune diseases, rather than evidence that the virus has a role in the disease.9 Malignant EBV-associated proliferations include nasopharyngeal carcinoma, Burkitt's lymphoma, Hodgkin's disease, lymphoproliferative disorders, and leiomyosarcoma in immunodeficient states, including AIDS and X-linked lymphoproliferative disease.10 EBV infection has a major role in the pathogenesis of Burkitt's lymphoma. The EBV genome is present in tumor cells in 95% of endemic cases in equatorial Africa, compared with 15% in sporadic cases in the United States. Immunosuppression permits reactivation of latent EBV; 60% to 90% of EBV-infected immuosuppressed patients shed the virus. EBV-specific antibody testing is useful to confirm acute EBV infection. The acute phase of infectious mononucleosis is characterized by rapid IgM and IgG antibody responses to VCA in all cases and an IgG response to early antigen in most cases. The IgM response to VCA is transient, but can be detected for at least 4 weeks and, occasionally, up to 3 months.11 In individuals with EBV reactivation and Burkitt's lymphoma, the VCA IgM is negative, but they have unusually and characteristically high levels of antibody to VCA (IgG) and early antigen that correlate with the risk of developing a tumor. In addition, immunohistochemistry, RNA in situ hybridization, and PCR are used to determine the role of EBV in malignancies. Detection of EBV in the pathology samples is relevant, as its high prevalence in some cancers makes the virus a promising target of specific therapies. RNA in situ hybridization is the standard diagnostic procedure, whereas PCR-based methods are used for strain (EBV type 1 or 2).12 In our case, EBV-associated fulminant infectious mononucleosis and B-cell non-Hodgkin's lymphoma, Burkitt's type, occurred concomitantly, and they may be difficult to distinguish due to their similar histological pictures. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Pattle SB, Farrell PJ: The role of Epstein-Barr virus in cancer. Expert Opin Boil Ther 6:1193-1205, 2006[CrossRef] 2. Neri A, Barriga F, Inghirami G, et al: Epstein-Barr virus infection precedes clonal expansion in Burkitt's and acquired immunodeficiency syndrome-associated lymphoma. Blood 77:1092-1095, 1991 3. Cohen JI: Epstein-Barr virus infection. N Engl J Med 343:481-492, 2000 4. Jenson H: Acute complications of Epstein-Barr virus infectious monocucleosis. Curr Opin Pediatr 12:263-268, 2000[CrossRef][Medline] 5. Li QX, Young LS, Niedobitek G, et al: Epstein-Barr virus infection and replication in a human epithelial cell system. Nature 356:347-350, 1992[CrossRef][Medline] 6. Tinguely M, Brundler MA, Gogos S, et al: Epstein-Barr virus association in pediatric abdominal non-Hodgkin-lymphoma from Turkey. Arch Immunol Ther Exp (Warsz) 48:317-322, 2000[Medline] 7. Kelly G, Bell A, Rickinson A: Epstein-Barr virus-associated Burkitt lymphomagenesis selects for down regulation of the nuclear antigen EBNA2. Nat Med 8:1098-1104, 2002[CrossRef][Medline] 8. Hecht JL, Aster JC: Molecular biology of Burkitt's lymphoma. J Clin Oncol 18:3707-3721, 2000 9. Thorley-Lawson DA, Gross A: Persistence of the Epstein-Barr virus and the origins of associated lymphoma. New Eng J of Med 25:1328-1337, 2004 10. Hugle B, Astigarrage I, Henter JI, et al: Simultaneous manifestaiton of fulminant infectious mononucleosis with haemophagocytic syndrome and B-cell lymphoma in X-linked lymphoroliferative disease. Eur J Pediatr 166:589-593, 2006[CrossRef][Medline] 11. Rose NR, Hamilton RB, Detrick B (eds): Manual of Clinical Laboratory Immunology (ed 6). Washington, DC, American Society for Microbiology Press, 2002, pp 615-626 12. Hassan R, White LR, Stefanoff CG, et al: Epstein-Barr virus (EBV) detection and typing by PCR: A contribution to diagnostic screening of EBV-positive Burkitt's lymphoma. Diagn Pathol 1:17, 2006[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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