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Background
This virus is a member of the Herpes virus family. The virus infects human B lymphocytes and is present in nearly every adult in the world. There are many diseases caused by this virus.
Infectious mononucleosis
EBV lymphoproliferative disorder
EBV post-transplantation syndrome
EBV post-transplant smooth muscle neoplasmsOUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION ATAXIA TELANGIECTASIA Epstein-Barr virus–associated smooth muscle tumors in ataxia-telangiectasia: A case report and review
Christine Reyes, MD
Omar Abuzaitoun, MD
Andrew de Jong, MD
Celine Hanson, MD
Claire Langston, MDHum Pathol 2002;33:133-136. Abstract quote
Chromosomal breakage syndromes, including ataxia-telangiectasia (AT), are autosomal recessive disorders in which DNA repair mechanisms are defective resulting in chromosomal instability. Affected individuals are at high risk for developing malignancy because of the widespread resulting cellular effects. One such effect, severe immunosuppression, can permit virally mediated neoplasms to manifest, similar to those seen in acquired immunodeficiency syndrome (AIDS), congenital immune deficiency syndromes, and posttransplant populations. Epstein-Barr virus (EBV) is a common viral agent known to be associated with lymphoid, epithelial, and smooth muscle malignancies in such patients. Although smooth muscle tumors have been reported in patients with AT, their association with EBV has not been evaluated.
We present a case of EBV-associated laryngeal leiomyosarcoma and jejunal cellular leiomyoma in a child with AT. This case suggests that the development of neoplasia in patients with chromosomal breakage syndromes may be related to the immunosuppressive consequences of these diseases, and searching for infectious causes (such as EBV) is important.
HYDROA VACCINIFORME The association of latent Epstein-Barr virus infection with hydroa vacciniforme.
Iwatsuki K, Xu Z, Takata M, Iguchi M, Ohtsuka M, Akiba H, Mitsuhashi Y, Takenoshita H, Sugiuchi R, Tagami H, Kaneko F.
Fukushima Medical University School of Medicine, 1-Hikarigaoka, Fukushima 960-1295, USA.
Br J Dermatol 1999 Apr;140(4):715-21 Abstract quote
Patients with hydroa vacciniforme (HV)-like eruptions and malignant potential have been reported from Asia and Mexico, and those patients frequently had an associated latent Epstein-Barr virus (EBV) infection.
In order to elucidate the association of latent EBV infection with HV, we studied six children with typical manifestations of HV by detection of EBV genes and EBV-related RNAs in biopsy specimens from cutaneous lesions.
Cutaneous lesions of all six children with typical HV contained EBV-encoded small nuclear RNA (EBER)+ cells in 3-10% of the dermal infiltrates, whereas no Bam HI-H, l-fragment (BHLF) mRNA, or transcripts encoding EA-D antigen, were detected. No EBER + cells were detected in other inflammatory or benign lymphoproliferative skin disorders tested. Polymerase chain reaction amplification confirmed the presence of EBV DNA sequences in five of six biopsy specimens from the patients.
Latent EBV infection is associated with the development of cutaneous lesions of HV.
IMMUNODEFICIENCY
Epstein-Barr virus-positive B-cell lymphoproliferative disorders arising in immunodeficient patients previously treated with fludarabine for low-grade B-cell neoplasms.Abruzzo LV, Rosales CM, Medeiros LJ, Vega F, Luthra R, Manning JT, Keating MJ, Jones D.
Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Am J Surg Pathol 2002 May;26(5):630-6 Abstract quote We describe five patients with treated low-grade B-cell neoplasms who subsequently developed Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorders (BLPDs).
The low-grade B-cell neoplasms were B-cell chronic lymphocytic leukemia in four patients and splenic marginal zone lymphoma in one patient. All patients had received treatment with fludarabine for the low-grade B-cell neoplasm, and three had also received Campath-1H. The EBV-BLPDs arose 2-12 months after completion of fludarabine therapy and morphologically resembled the EBV-BLPDs that occur in the setting of iatrogenic immunodeficiency. Molecular genetic studies showed that these lesions were clonally distinct from the low-grade B-cell neoplasm in three of four cases assessed. Two patients did not receive therapy for the EBV-BLPD. The lesions regressed spontaneously in both patients but recurred in one. One patient underwent surgical excision and remains without evidence of the EBV-BLPD. One patient received aggressive multiagent chemotherapy with a complete response initially, but the EBV-BLPD recurred after 12 months. One patient received antiviral therapy and responded completely but died 2 months later of an opportunistic infection.
We conclude that patients with low-grade B-cell neoplasms treated with fludarabine, possibly in combination with other immune suppressive agents, may subsequently develop EBV-BLPDs that morphologically resemble other iatrogenic immunodeficiency-associated BLPDs. Most are clonally distinct from the underlying low-grade B-cell neoplasm. A subset of these lesions may regress without systemic therapy.
INFECTIOUS MONONUCLEOSIS Cytotoxic T-cell lymphoma diffusely involving the entire gastrointestinal tract associated with Epstein-Barr virus and tubercle bacilli infection.
Abe Y, Muta K, Ohshima K, Hirase N, Matsushima T, Yufu Y, Nishimura J, Nawata H.
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Int J Hematol 2000 Jun;71(4):379-84 Abstract quote
We describe a rare case of cytotoxic gastrointestinal T-cell lymphoma with protein-losing enteropathy. Initial examination revealed the coexistence of T-cell lymphoma and tuberculosis in the mesenteric lymph node and liver.
Despite anti-tuberculosis and anti-cancer treatment, the patient experienced chronic diarrhea and malabsorption and died approximately 3 years after onset. Autopsy specimens revealed medium-sized lymphoma cells, with a phenotype of CD3+, CD4-, CD7+, CD8+, CD30-, CD56-, CD103 (HML-1)-, TIA-1+, and granzyme B+, proliferating primarily and consistently in the mucosa of the entire bowel tract from esophagus to rectum. Interestingly, Epstein-Barr virus (EBV)-encoded small nuclear RNAs were detected in the tumors by in situ hybridization. Southern blot analysis revealed monoclonal proliferation in the EBV-infected T cells.
Although the present case can possibly be categorized as an intestinal T-cell lymphoma according to the Revised European-American Lymphoma Classification, the case showed a unique clinical course and distribution of lymphoma cells. We present here an interesting case of gastrointestinal cytotoxic T-cell lymphoma and examine the possible association with infectious agents.
The molecular characterization of fatal infectious mononucleosis.Wick MJ, Woronzoff-Dashkoff KP, McGlennen RC.
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis 55455, USA.
Am J Clin Pathol 2002 Apr;117(4):582-8 Abstract quote We describe a retrospective study of 4 cases of sporadic fatal infectious mononucleosis (IM), 1 case of fatal IM, and 1 case of sporadic severe IM.
Patients were 26 months to 17 years old; 3 were male. Five died of complications of IM. All 5 of these patients had the Epstein-Barr virus (EBV) present in examined tissue specimens; EBV was monoclonal in 3 patients and biclonal in 1. EBV clonality studies were not performed in the remaining patient. All 5 patients also had monoclonal gene rearrangements. The sixth patient survived despite a life-threatening clinical course; EBV was oligoclonal, and gene rearrangements were not detected. EBV clonality and gene rearrangement studies may be usefulfor predicting which patients with clinically aggressive IM are at highest risk for fatal outcome. Patients in whom IM has a fatal outcome are more likely to have monoclonal or biclonal EBV and immunoglobulin heavy chain or T-cell receptor gene rearrangements.
In contrast, patients with nonfatal IM may lack monoclonal EBV and monoclonal rearrangements of the aforementioned genes. The reasons EBV induces a monoclonal proliferation only in some patients remain to be elucidated.
LYMPHOMAS NK/T cell lymphoma
Burkitt lymphoma
Some cases of Hodgkin's lymphoma
Post-transplant lymphoproliferative disorder
Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA.
Epstein-Barr virus (EBV) is a member of the human herpesvirus family that was initially isolated from a cultured Burkitt lymphoma cell line by Epstein et al in 1964. Subsequent studies have proven that it is the causative agent in most cases of infectious mononucleosis.
Primary infection is usually asymptomatic in childhood; but in adulthood, it is associated with a self-limiting infectious mononucleosis syndrome in approximately one third of the cases. EBV has been linked to many human neoplasms including hematopoietic, epithelial, and mesenchymal tumors.
In this review, we will only discuss the EBV-associated lymphoproliferative disorders, dividing them into B-cell, T/NK-cell, and HIV-related lymphoproliferative disorders.
- Plasmablastic Lymphoma in HIV-Positive Patients: An Aggressive Epstein-Barr Virus-Associated Extramedullary Plasmacytic Neoplasm.
Dong HY, Scadden DT, de Leval L, Tang Z, Isaacson PG, Harris NL.
From the *Department of Pathology and daggerAIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and double daggerDepartment of Pathology, University College of London, London, UK.
Am J Surg Pathol. 2005 Dec;29(12):1633-1641. Abstract quote
AIDS-associated aggressive B-cell lymphomas often have plasmacytoid features. Plasma cell neoplasms in HIV patients were commonly described to have atypical morphology and an aggressive clinical course in the literature.
We reviewed 14 cases of neoplasms with marked plasmacytic differentiation in HIV-positive patients to determine their clinicopathologic features. Of these, 13 of 14 had homogeneous morphology and were generally CD45+, CD20-, PAX-5-, and CD138+. All were positive for Epstein-Barr virus-encoded RNA (EBER) but lacked EBV late membrane proteins (LMP). Human herpes virus 8 (HHV8) DNA was detected in 6 of 10 cases by nested PCR, but HHV8 latent nuclear antigen (LNA) was absent. The 13 patients ranged in age from 28 to 44 years (median, 41 years) (11 male patients; 2 female patients). All patients had extramedullary and 11 of 13 had extranodal tumor at the initial presentation; 2 had distant marrow involvement. The most commonly involved location was the oral cavity (6 of 13 cases), followed by bone and soft tissue (4 of 13), and the gastrointestinal tract (3 of 13). All 11 patients with follow-up died within 34 months (median, 7 months). The 14th patient who had a nodal disease with more undifferentiated morphology and expression of the HHV8 LNA protein was alive without disease at last follow-up (>72 months), probably representing a novel HHV8+ lymphoma.
We conclude that most plasmacytic tumors in HIV-positive individuals are extramedullary, clinically aggressive EBV+ tumors identical to plasmablastic lymphoma that does not have the clinical features of plasma cell myeloma.
Assessment of Epstein-Barr virus association with pediatric non-hodgkin lymphoma in immunocompetent and in immunocompromised patients in Argentina.Chabay PA, De Matteo EN, Aversa L, Maglio S, Grinstein S, Preciado MV.
Virology Laboratory, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina.
Arch Pathol Lab Med 2002 Mar;126(3):331-5 Abstract quote CONTEXT: Epstein-Barr virus (EBV) has been classically associated with 3 malignancies, Burkitt lymphoma, B-cell lymphoproliferative syndromes, and nasopharyngeal carcinoma, and more recently with Hodgkin disease, T-cell lymphomas, and gastric and breast carcinomas, as well as with leiomyosarcoma and leiomyoma associated with immunosuppression.
OBJECTIVE: To compare EBV expression in Argentine tumor samples with those reported elsewhere, we analyzed EBV expression in an Argentine pediatric population with non-Hodgkin lymphoma and correlated these results with clinical course and outcome.
METHODS: We studied EBV presence by latent membrane protein-1 protein labeling by immunohistochemistry, by in situ hybridization, and by polymerase chain reaction for Epstein-Barr-encoded RNAs (EBERs) in formalin-fixed and paraffin-embedded non-Hodgkin lymphoma tissue samples (collected retrospectively) from 32 pediatric patients at Ricardo Gutierrez Children's Hospital from 1993 to 2000.
RESULTS: Eight out of the 32 (25%) non-Hodgkin lymphoma cases showed latent membrane protein-1 and EBERs by in situ hybridization positive staining in tumor cells. Among EBERs and latent membrane protein-1-positive cases, there were 5 immunocompromised patients, with either human immunodeficiency virus infection or primary immunodeficiency. The EBERs in situ hybridization results were confirmed by EBERs polymerase chain reaction in good-quality DNA from 11 samples, with 3 proving positive and 8 negative.
CONCLUSIONS: The association of EBV with non-Hodgkin lymphoma in the Argentine pediatric population was low (25%), and this figure rose to 100% when only the immunocompromised patients subgroup was considered, confirming that the virus is probably a cofactor in the lymphomagenesis of some but not all pediatric non-Hodgkin lymphoma. So far, no differences in clinical outcome are discernible between EBV-positive and EBV-negative non-Hodgkin lymphoma patients.
Senile EBV+ B-Cell Lymphoproliferative Disorders: A Clinicopathologic Study of 22 Patients.Oyama T, Ichimura K, Suzuki R, Suzumiya J, Ohshima K, Yatabe Y, Yokoi T, Kojima M, Kamiya Y, Taji H, Kagami Y, Ogura M, Saito H, Morishima Y, Nakamura S.
Am J Surg Pathol 2003 Jan;27(1):16-26 Abstract quote Twenty-two Epstein-Barr virus-associated B-cell lymphoproliferative disorders (LPDs) without predisposing immunodeficiencies were evaluated clinically and pathologically.
All patients were Japanese and negative for anti-human immunodeficiency virus antibody. They were all more than 60 years old with a median age of 75.5 years. Eighteen (82%) patients showed extranodal involvement. Biopsied specimens contained variable numbers of centroblasts, immunoblasts, and Reed-Sternberg-like giant cells often with necrosis and an angiocentric pattern. The 13 cases showing polymorphous composition and inflammatory background were categorized as polymorphic LPD subtype. The other nine cases contained diffuse proliferative lesions of large lymphoid cells and were categorized as large cell lymphoma subtype.
Tumor cells expressed CD20 and/or CD79a, and in situ hybridization showed them to be associated with Epstein-Barr virus. LMP1 was detected in all cases and EBNA2 in seven. Eighteen patients initially received combination chemotherapy, and 12 achieved complete remission. However, six patients were refractory to chemotherapy and four patients with complete remission later relapsed. Eight of the 18 patients who received chemotherapy showed an aggressive disease course within a year after the diagnosis. There was a significant difference in prognosis between the group with polymorphic LPDs and the one with large cell lymphomas (p = 0.003). Although the disease profile of the 22 cases was analogous to that of immunodeficiency-associated B-cell LPDs, none of the patients showed evidence of underlying immunodeficiency-related diseases.
These findings suggest that Epstein-Barr virus-associated LPD without immunodeficiency mainly occurs in elderly patients. Further investigations are needed to clarify the pathogenesis of this disease and to determine the optimal treatment strategy.
T CELL PROLIFERATION
- Vascular lesion in a patient of chronic active Epstein-Barr virus infection with hypersensitivity to mosquito bites: Vasculitis induced by mosquito bite with the infiltration of nonneoplastic Epstein-Barr virus-positive cells and subsequent development of natural killer/T-cell lymphoma with angiodestruction.
Kanno H, Onodera H, Endo M, Maeda F, Chida S, Akasaka T, Sawai T.
Hum Pathol. 2005 Feb;36(2):212-8. Abstract quote
Summary This report describes a vasculitis and subsequently developing angiodestructive lymphoma in an 11-year-old Japanese-Filipino girl exhibiting mosquito allergy with the background of chronic active Epstein-Barr virus (EBV) infection.
She developed necrotic skin ulcer at the site of mosquito bite, and histopathological examination revealed EBV-positive mononuclear cell infiltration throughout the wall of small-sized muscular artery. These EBV-positive lymphoid cells were oligoclonal in Southern blot analysis for EBV terminal repeats. Effectiveness of steroid therapy also supports the nonneoplastic nature. Approximately 1 year later, she developed progressive large skin ulcer without mosquito bites.
Microscopically, the angiocentric or angiodestructive pattern of EBV-positive atypical cells supported the diagnosis of extranodal natural killer/T-cell lymphoma. Southern blot analysis revealed the monoclonal neoplastic nature of EBV-positive cells.
In contrast to the primary mosquito bite lesion, natural killer/T-cell lymphoma cells exhibited the higher expression of EBV latent membrane protein 1 mRNA and the apparent protein expression detected by immunohistochemistry.Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome.
Quintanilla-Martinez L, Kumar S, Fend F, Reyes E, Teruya-Feldstein J, Kingma DW, Sorbara L, Raffeld M, Straus SE, Jaffe ES.
Hematopathology Section, Laboratory of Pathology, National Cancer Institute, and Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Blood 2000 Jul 15;96(2):443-51 Abstract quote
This study describes the clinicopathologic features of 5 patients who developed a fulminant Epstein-Barr virus (EBV)-positive clonal T-cell lymphoproliferative disorder (LPD) after acute EBV infection.
One additional patient developed a similar disorder in the setting of long-standing chronic active EBV infection. Detailed immunophenotyping, in situ hybridization for EBV early RNA-1 (EBER1) and polymerase chain reaction (PCR) analyses for immunoglobulin (Ig) heavy chain and T-cell receptor (TCR)-gamma gene rearrangements were performed on paraffin-embedded tissue from all patients. In addition, EBV strain typing and detection of the characteristic 30-bp deletion of the latent membrane protein-1 (LMP-1) gene were performed by PCR. Controls included 8 cases of uncomplicated infectious mononucleosis (IM). Patients included 4 males and 2 females with a median age of 18 years (2-37 years). Three patients were Mexican, 2 were white, and 1 was of Asian descent. All presented with fever, hepatosplenomegaly, and pancytopenia; 5 were previously healthy, but had a clinical history of a recent viral-like upper respiratory illness (1 week to 2 months), and 1 patient had documented chronic active EBV infection for 7 years. Serologic data for EBV were incomplete but titers were either negative or only modestly elevated in 3 cases. In 1 case serology was consistent with severe chronic active EBV infection. In the remaining 2 cases serologic studies were not performed. All patients died within 7 days to 8 months of presentation with T-cell LPD. On histologic examination, the liver and spleen showed prominent sinusoidal and portal lymphoid infiltrates of CD3(+), beta F1(+), EBER1(+) T cells lacking significant cytologic atypia. Two cases were CD4(+), 2 cases were CD8(+), and 2 cases had admixed CD4(+) and CD8(+) cells without clear subset predominance. All were TIA-1(+), CD56(-). Only rare B cells were noted. Marked erythrophagocytosis was present. Molecular analysis revealed identical T-cell clones in 2 or more sites (liver, spleen, lymph node) in 5 cases. All patients carried type A EBV; 4 cases had wild-type EBV-LMP, and 2 showed the 30-bp deletion.
This fulminant T-cell LPD after acute/chronic EBV infection is characterized by hepatosplenomegaly, often without significant lymphadenopathy, fever, liver failure, pancytopenia, and erythrophagocytosis indicative of a hemophagocytic syndrome. EBV serology may be misleading, with lack of elevated titers. The presence of an EBER1(+) T-cell infiltrate with scant B cells should alert one to this diagnosis. Although cytologic atypia is minimal, studies for T-cell clonality confirm the diagnosis.
Fatal atypical T-cell proliferation associated with Epstein-Barr virus infection.
Hauptmann S, Meru N, Schewe C, Jung A, Hiepe F, Burmester G, Niedobitek G, Buttgereit F.
Institute of Pathology and Department of Rheumatology, Charite Hospital Berlin, and Institute of Pathology, University Erlangen, Erlangen, Germany.
Br J Haematol 2001 Feb;112(2):377-80 Abstract quote
We report the case of a young Caucasian man who presented with polyneuropathy and severe, ultimately fatal, congestive heart failure in the context of a chronic active Epstein-Barr virus (EBV) infection. Post-mortem examination revealed both monoclonal and polyclonal proliferation of EBV-positive atypical T lymphocytes within different organs. Predominant infiltration of the nervous system and heart with extensive myocardial scarring accounted for the clinical symptoms.
The remarkable features of this case are (i) the occurrence in a Caucasian patient, (ii) the absence of detectable immunodeficiency, and (iii) the myocardial destruction by EBV-infected monoclonal T cells.
Fatal Cytotoxic T-Cell Proliferation in Chronic Active Epstein-Barr Virus Infection in Childhood
Atsuko Nakagawa, MD, PhD
Masafumi Ito, MD, PhD
and Shinsuke Saga, MD, PhDAm J Clin Pathol 2002;117:283-290 Abstract quote
Histopathologic features of 5 cases (4 boys and 1 girl; 4-9 years old) with severe chronic active Epstein-Barr virus (EBV) infection are discussed.
All patients died within 3 years after disease onset without developing hematolymphoid malignant neoplasms. The pathology specimens (autopsy, 2 cases; multiple organs and tissues obtained by surgery or biopsy, 3 cases) showed polymorphic lymphocytic proliferation in the lymph nodes (4/5) and spleen (3/3), and systemic lymphocytic infiltration of the liver (4/4), lung (2/2), bone marrow (3/4), and kidney (2/2). Skin lesions were noted clinically in 3 of 5 cases. Two cases had coronary artery aneurysm due to lymphocytic vasculitis.
The lymphocytes had a characteristic phenotype of cytotoxic T cells expressing CD3, CD8, and cytotoxic molecules, and were negative for CD4. EBV-encoded small nonpolyadenylated RNAs were detected in the nuclei of the lymphocytes, but latent membrane protein 1 and EBNA2 were not seen. In 4 of 4 cases, an oligoclonal growth pattern of EBV was determined after detecting terminal repetitive sequences by Southern blot. In 3 of 3 cases, the lymphocytes did not have T-cell receptor beta or JH gene rearrangement.
VIRUS ASSOCIATED HEMOPHAGOCYTIC SYNDROME Chronic active Epstein-Barr virus infection and virus-associated hemophagocytic syndrome.
Ross CW, Schnitzer B, Weston BW, Hanson CA.
Department of Pathology, University of Michigan, Ann Arbor.
Arch Pathol Lab Med 1991 May;115(5):470-4 Abstract quote
We describe two unusual cases of Epstein-Barr virus infection that were complicated by the virus-associated hemophagocytic syndrome, predominantly involving the spleen. Both patients were young adult men who presented with fever, pancytopenia, and hepatosplenomegaly.
Both had prompt symptomatic and hematologic improvement following splenectomy. Severe constitutional symptoms recurred in one patient 1 month after splenectomy, and he died of septicemia 2 months later. In both cases, there was prominent hemophagocytosis in the splenic red pulp. Some hemophagocytosis was also noted in the liver from the fatal case. Unexpectedly, no hemophagocytosis was detected in the bone marrow biopsy specimens or marrow aspirates obtained from these patients. The DNA hybridization studies detected Epstein-Barr virus genomes in spleen samples from both patients, and both patients had atypical patterns of serologic response to the virus, suggesting that a defective immune response may lead to an unrestrained viral proliferation.
We conclude that there is an association between chronic active Epstein-Barr virus infection and the hemophagocytic syndrome, but that the tissue distribution of the hemophagocytosis may be variable.
LABORATORY/
RADIOLOGICCHARACTERIZATION TESTING FOR EPSTEIN-BARR VIRUS Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001. Immunostaining May be used for EBV-LMP1 in place of in-situ hybridization for EBER (EBV encoded early RNA) in following situations:
Hodgkin's lymphoma
Post-transplant lymphoproliferative disorder
Infectious mononucleosisFor other types of EBV associated lymphomas (in particular Burkitt lymphoma), immunostaining for EBV-LMP1 cannot replace in-situ hybridization for EBV
Except for Hodgkin lymphoma, the number of positive cells is generally much higher with ISH for EBER compared with immunostaining for EBV-LMP1
There are three patterns of EBV latency:
LMP1 negative LMP1 positive-For NK/T cell lymphoma, however, LMP1 expression is very weak or even absent at the immunohistochemical level, and thus immunostaining for EBV is not reliable for this lymphoma type LMP1 positive Southern blot May demonstrate EBV clonality but time consuming and requires fresh/frozen tissue PCR Not helpful
Positive results can be obtained even if there are only a few bystander lymphocytes harboring EBVIn situ hybridization for EBV DNA Allows morphologic correlation but difficult to perform In situ hybridization for EBER Allows morphologic correclation
Sensitive test
Easy to perform
- Rapid determination of Epstein-Barr virus latent or lytic infection in single human cells using in situ hybridization.
Leenman EE, Panzer-Grumayer RE, Fischer S, Leitch HA, Horsman DE, Lion T, Gadner H, Ambros PF, Lestou VS.
[1] 1Research Institute of Radiology and Roentgenology, St Petersburg, Russia [2] 2CCRI, Children's Cancer Research Institute, St Anna Kinderspital, Vienna, Austria.
Mod Pathol. 2004 Dec;17(12):1564-72. Abstract quote
Epstein-Barr (EBV) virus is associated with malignancies such as lymphoma and carcinoma. Infection of cells with EBV may result in either lytic infection with production of viral particles, characterized by the presence of linear DNA forms, or latent infection, characterized by either episomal or integrated DNA forms.
To examine whether the different lytic and latent EBV DNA forms can reliably be distinguished in single human cells, in situ hybridization was performed in EBV-positive cell lines. Immunocytochemistry and Southern blot analysis were performed supplementary to in situ hybridization. In latent infection, three in situ hybridization patterns were observed: large-disperse (episomal), small-punctate (integrated) and combined (both), signal types 1, 2 and 3 respectively. These were associated with expression of latent membrane protein 1, but not with Z fragment of Epstein-Barr replication activator or viral capsid antigen.
In lytic infection, three additional in situ hybridization patterns were observed: nuclear membrane associated, bubble (filling up the nucleus) and spillover (covering the lysed cells) signals types 4, 5 and 6 respectively. Signal types 4 and 5 were associated with expression of latent membrane protein 1 and Z fragment of Epstein-Barr replication activator but not viral capsid antigen, whereas type 6 was associated with expression of viral capsid antigen only. Southern blot analysis confirmed these results; however, low copy numbers of integrated virus were often missed by Southern blot, confirming that in situ hybridization is more sensitive in determining the presence of all types of EBV DNA.
In situ hybridization may prove useful in rapidly screening large series of tissue microarrays and other clinical specimens for the presence of lytic or latent EBV.ADDITIONAL ASSAYS SEROLOGY A Systematic Study of Epstein-Barr Virus Serologic Assays Following Acute Infection
Thomas D. Rea, MD
Rhoda L. Ashley, PhD
Joan E. Russo, PhD
and Dedra S. Buchwald, MDAm J Clin Pathol 2002;117:156-161 Abstract quote
We determined the presence of IgG and IgM antibody to viral capsid antigen (VCA-IgG, VCA-IgM) and IgG antibody to the Epstein-Barr virus nuclear antigen (EBNA) by indirect immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA) during the acute illness and at 1, 2, 6, and 48 months in a prospective population-based case series of 95 persons with an acute illness serologically confirmed as Epstein-Barr virus infection.
The acute illness was characterized by the presence of VCA-IgG and VCA-IgM (by ELISA) and by the absence of EBNA in most, but not all, patients. During follow-up, VCA-IgG antibodies remained detectable in all patients, while the proportion with VCA-IgM declined and the number with detectable EBNA antibodies steadily increased.
The primary differences between the 2 serologic test methods were the increased persistence of VCA-IgM during follow-up by ELISA and the earlier detection of EBNA by IFA.
Clinicians should consider the illness stage and the laboratory technique to appropriately interpret serologic test results in suspected cases of mononucleosis caused by the Epstein-Barr virus.
GROSS OR CLINICAL VARIANTS CHARACTERIZATION CHRONIC ACTIVE EBV INFECTION Clinical and virologic characteristics of chronic active Epstein-Barr virus infection.
Kimura H, Hoshino Y, Kanegane H, Tsuge I, Okamura T, Kawa K, Morishima T.
Department of Pediatrics, Nagoya University Graduate School of Medicine, Japan.
Blood 2001 Jul 15;98(2):280-6 Abstract quote
Thirty patients with chronic active Epstein-Barr virus (CAEBV) infection were analyzed.
The study group included 18 male and 12 female patients, ranging in age from 5 to 31 years with a mean age of 14.2 years. Not all patients had high titers of EBV-specific antibodies, but all patients had high viral loads in their peripheral blood (more than 10(2.5) copies/microg DNA). Fifty percent of the patients displayed chromosomal aberrations, and 79% had monoclonality of EBV. Patients were divided into 2 clinically distinct groups, based on whether the predominantly infected cells in their peripheral blood were T cells or natural killer (NK) cells.
Over a 68-month period of observation, 10 patients died from hepatic failure, malignant lymphoma, or other causes. Patients with T-cell CAEBV had a shorter survival time than those with NK-cell type of disease.
Heterogeneous, restricted patterns of Epstein-Barr virus (EBV) latent gene expression in patients with chronic active EBV infection.
Yoshioka M, Ishiguro N, Ishiko H, Ma X, Kikuta H, Kobayashi K.
Department of Pediatrics, Hokkaido University School of Medicine, N-15, W-7, Kita-ku, Sapporo 060-8638, Japan.
J Gen Virol 2001 Oct;82(Pt 10):2385-92 Abstract quote
Epstein-Barr virus (EBV) has been shown to infect T lymphocytes and to be associated with a chronic active infection (CAEBV), which has been recognized as a mainly non-neoplastic T-cell lymphoproliferative disorder (T-cell LPD).
The systemic distribution of EBV genomes was studied, by real-time PCR, in multiple tissues from six patients with CAEBV, including three patients with T-cell LPD, one patient with B-cell LPD and two patients with undetermined cell-type LPD. There were extremely high loads of EBV genomes in all tissues from the patients. This reflects an abundance of circulating and infiltrating EBV-infected cells and a wide variety of clinical symptoms in the affected tissues.
We chose one sample from each patient that was shown by real-time PCR to contain a high load of EBV genomes and examined the expression of EBV latent genes by RT-PCR. EBER1 and EBNA1 transcripts were detected in all samples. Only one sample also expressed EBNA2, LMP1 and LMP2A transcripts in addition to EBER1 and EBNA1 transcripts. Two of the remaining five samples expressed LMP1 and LMP2A transcripts. One sample expressed LMP2A but not LMP1 and EBNA2 transcripts. Another sample expressed EBNA2 but not LMP1 and LMP2A transcripts. The other sample did not express transcripts of any of the other EBNAs or LMPs. None of the samples expressed the viral immediate-early gene BZLF1.
These results showed that EBV latent gene expression in CAEBV is heterogeneous and that restricted forms of EBV latency might play a pathogenic role in the development of CAEBV.
INFLAMMATORY PSEUDOTUMOR OF THE SPLEEN Inflammatory Pseudotumor of the Spleen Associated With a Clonal Epstein-Barr Virus Genome
Case Report and Review of the Literature
Jason T. Lewis, MD,1 Robyn L. Gaffney, MD,1* Mary B. Casey, MD,1 Michael A. Farrell, MD,2 William G. Morice, MD, PhD,1 and William R. Macon, MDAm J Clin Pathol 2003;120:56-61 Abstract quote
We report a case of an inflammatory pseudotumor (IPT) of the spleen occurring in an 81-year-old woman with a history of a monoclonal gammopathy of undetermined significance.
Eighteen-month follow-up after splenectomy demonstrated no tumor recurrence or progression of underlying plasma cell disease. Histologic examination of the tumor demonstrated a polymorphic population of inflammatory and epithelioid and spindle cells. Immunophenotyping showed large numbers of T cells, B cells, and polyclonal plasma cells. The epithelioid and spindle cells were positive for vimentin and CD68 but lacked expression of follicular dendritic cell markers and actin. Epstein-Barr virus (EBV) genome was identified in the epithelioid and spindle cell population by in situ hybridization using probes specific for EBV-encoded RNAs (EBER1 and EBER2). Southern blot analysis of digested DNA extracted from the tumor using an EBV-specific probe (XhoI) demonstrated the presence of a single high-intensity band, indicative of EBV monoclonality.
While there have been 2 previous reports of hepatic IPTs containing a monoclonal population of EBV-infected tumor cells, this is the first report of such an association occurring in the spleen. The presence of clonal EBV DNA suggests some splenic IPTs may be true neoplasms.NECROTIC PAPULOVESICLES Epstein-Barr virus-associated recurrent necrotic papulovesicles with repeated bacterial infections ending in sepsis and death: consideration of the relationship between Epstein-Barr virus infection and immune defect.
Yoon TY, Yang TH, Hahn YS, Huh JR, Soo Y.
Department of Dermatology, College of Medicine & Medical Research Institute, Chungbuk National University, Cheongju, Korea.
J Dermatol 2001 Aug;28(8):442-7 Abstract quote
The disease of Epstein-Barr virus (EBV) -associated recurrent necrotic papulovesicles is a distinct clinicopathologic entity different from classic hydroa vacciniforme (HV). A few patients have been reported as atypical HV with systemic involvement, development of lymphoma, and poor prognosis.
We describe a patient with recurrent necrotic papulovesicles and multiple varioliform scars in both sun-exposed and covered areas. In contrast to cases of previously reported atypical HV, our patient suffered from repeated bacterial infections on various sites ending in sepsis and death, but without malignant transformation. EBV was detected in the lymphoid cells from the skin lesions by anti-latent membrane protein (LMP) antibody and in situ hybridization.
We suggest that the repeated bacterial infections in this case raise the possibility of an association of EBV infection with increased susceptibility to bacterial infections.
HISTOPATHOLOGICAL VARIANTS CHARACTERIZATION EARLY INFECTION
- Epstein-Barr Virus Infection of Monocytoid B-Cell Proliferates: An Early Feature of Primary Viral Infection?
Anagnostopoulos I, Hummel M, Falini B, Joehrens K, Stein H.
From the *Consultation and Reference Center for Hematopathology at the Institute of Pathology, Charite, Campus Benjamin Franklin, Medical University, Berlin, Germany; and the daggerInstitute of Hematology, University of Perugia, Perugia, Italy.
Am J Surg Pathol. 2005 May;29(5):595-601. Abstract quote
Monocytoid cells are a subset of B lymphocytes with characteristic morphology and immunophenotype, which proliferate in a broad variety of reactive lymph node conditions. Up to now, no direct infection of these cells by a pathogenic organism has been identified.
We found in a series of lymph node specimens from 13 patients having in common a prominent monocytoid B (MCB)-cell reaction in the absence of epithelioid cells or necrosis evidence that Epstein-Barr virus (EBV) can infect MCB cells. Clinical and serologic findings indicative for an acute EBV infection were reported only in 2 cases. By in situ hybridization and immunohistology, a number of MCB cells in all cases was found to contain EBV-encoded small nuclear RNAs and to express the EBV-encoded nuclear antigen (EBNA)-2 and, in lesser extent, the latent membrane protein-1. EBV-transcripts and proteins were also detectable in a number of extrafollicular B blasts and germinal center B cells in 10 of 13 cases.
Our findings imply that an EBV infection of MCB cells associated with predominant EBNA-2 expression represents an early sign of primary infection and that it should be included in the differential diagnosis of activated lymph nodes with prominent MCB-cell reaction in the absence of epithelioid cells.FULMINANT T-CELL LYMPHOPROLIFERATIVE DISORDER Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome.
Quintanilla-Martinez L, Kumar S, Fend F, Reyes E, Teruya-Feldstein J, Kingma DW, Sorbara L, Raffeld M, Straus SE, Jaffe ES.
Hematopathology Section, Laboratory of Pathology, National Cancer Institute, and Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Blood 2000 Jul 15;96(2):443-51 Abstract quote
This study describes the clinicopathologic features of 5 patients who developed a fulminant Epstein-Barr virus (EBV)-positive clonal T-cell lymphoproliferative disorder (LPD) after acute EBV infection.
One additional patient developed a similar disorder in the setting of long-standing chronic active EBV infection. Detailed immunophenotyping, in situ hybridization for EBV early RNA-1 (EBER1) and polymerase chain reaction (PCR) analyses for immunoglobulin (Ig) heavy chain and T-cell receptor (TCR)-gamma gene rearrangements were performed on paraffin-embedded tissue from all patients.
In addition, EBV strain typing and detection of the characteristic 30-bp deletion of the latent membrane protein-1 (LMP-1) gene were performed by PCR. Controls included 8 cases of uncomplicated infectious mononucleosis (IM). Patients included 4 males and 2 females with a median age of 18 years (2-37 years). Three patients were Mexican, 2 were white, and 1 was of Asian descent. All presented with fever, hepatosplenomegaly, and pancytopenia; 5 were previously healthy, but had a clinical history of a recent viral-like upper respiratory illness (1 week to 2 months), and 1 patient had documented chronic active EBV infection for 7 years.
Serologic data for EBV were incomplete but titers were either negative or only modestly elevated in 3 cases. In 1 case serology was consistent with severe chronic active EBV infection. In the remaining 2 cases serologic studies were not performed. All patients died within 7 days to 8 months of presentation with T-cell LPD. On histologic examination, the liver and spleen showed prominent sinusoidal and portal lymphoid infiltrates of CD3(+), beta F1(+), EBER1(+) T cells lacking significant cytologic atypia. Two cases were CD4(+), 2 cases were CD8(+), and 2 cases had admixed CD4(+) and CD8(+) cells without clear subset predominance. All were TIA-1(+), CD56(-). Only rare B cells were noted. Marked erythrophagocytosis was present. Molecular analysis revealed identical T-cell clones in 2 or more sites (liver, spleen, lymph node) in 5 cases. All patients carried type A EBV; 4 cases had wild-type EBV-LMP, and 2 showed the 30-bp deletion.
This fulminant T-cell LPD after acute/chronic EBV infection is characterized by hepatosplenomegaly, often without significant lymphadenopathy, fever, liver failure, pancytopenia, and erythrophagocytosis indicative of a hemophagocytic syndrome. EBV serology may be misleading, with lack of elevated titers. The presence of an EBER1(+) T-cell infiltrate with scant B cells should alert one to this diagnosis. Although cytologic atypia is minimal, studies for T-cell clonality confirm the diagnosis.
GASTRITIS
Departments of *Pathology and Immunology †Medicine/
Gastroenterology, Washington University School of Medicine, St Louis, MO.
We describe an exceedingly rare case of severe gastritis that was temporally associated with primary Epstein-Barr virus (EBV) infection.
The patient was a 59-year-old immunocompetent man who presented with intermittent fever of unknown origin and epigastric pain for 18 days. A computed tomographic scan of the abdomen showed diffuse thickening of the gastric wall and esophagogastroduodenoscopy revealed numerous ulcers in the stomach.
Histologic examination of gastric biopsies showed a dense and diffuse atypical lymphoid infiltrate in the lamina propria with erosions and focal lymphoepithelial lesions. No lymphoid follicles or Helicobacter microorganisms were identified. Immunohistochemical studies demonstrated the lymphoid infiltrate to consist of mixed T and B cells. Immunoglobulin heavy chain gene arrangement analysis showed a polyclonal pattern. The plasma cells present in the biopsies exhibited no light chain restriction as determined by in situ hybridization. Concurrent clinical work-up revealed peripheral lymphocytosis with atypical lymphocytes and positive serum IgM antibody to EBV capsid antigen in the absence of IgG antibody.
These findings indicated that the gastric abnormalities were related to primary EBV infection as the predominant manifestation of infectious mononucleosis. This was further confirmed by subsequent in situ hybridization showing numerous EBV-positive lymphocytes in the gastric mucosa. The patient's symptoms were spontaneously resolved with only supportive treatment. A follow-up endoscopy 2 months later showed completely normal gastric mucosa and he remained well with no gastrointestinal complaints for 2 and a half years.
This case illustrates the importance of a high index of suspicion to avoid misdiagnosis of gastric lymphoma that requires more aggressive therapies.HEPATITIS
*Department of Pathology and Immunology, Washington University School of Medicine ‡Department of Pathology, Saint Louis University School of Medicine, St Louis, MO †Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
Epstein-Barr virus (EBV) hepatitis is an uncommon, almost always self-limited disease in immunocompetent patients. Accurate diagnosis is imperative for appropriate clinical management.
The aim of this study was to compare 3 available methods for EBV detection on routinely processed liver biopsies to determine their effectiveness in aiding the diagnosis. In 6 of the 8 cases of EBV hepatitis, EBV was detected by both polymerase chain reaction (PCR) for EBV DNA and in situ hybridization (ISH) for EBV early RNA (EBER). EBV was detected by PCR only in 1 case, and by ISH only in another. EBER-positive cells detected by ISH were typically few and individually distributed in the portal tracts and sinusoids. Immunohistochemical staining for EBV latent membrane proteins was negative in all 8 cases. Five cases of chronic hepatitis C used as negative controls were negative by all 3 detection methods for EBV. These data indicate that PCR and ISH are equally sensitive in detecting EBV in routinely processed liver biopsies.
The ready implementation of ISH in pathology laboratories makes it a useful ancillary tool in confirming the diagnosis of EBV hepatitis in equivocal cases. However, EBER-positive cells can be sparse and easily overlooked. Immunohistochemistry for EBV latent membrane proteins apparently has no utility in the diagnosis of EBV hepatitis.SMOOTH MUSCLE TUMORS
- Epstein-Barr Virus-Associated Smooth Muscle Tumors Are Distinctive Mesenchymal Tumors Reflecting Multiple Infection Events: A Clinicopathologic and Molecular Analysis of 29 Tumors From 19 Patients.
Deyrup AT, Lee VK, Hill CE, Cheuk W, Toh HC, Kesavan S, Chan EW, Weiss SW.
From the *Department of Pathology and Laboratory Medicine, Emory University, Atlanta GA; daggerDepartment of Pathology, Singapore General Hospital, Singapore; double daggerDepartment of Pathology, Queen Elizabeth Hospital, Hong Kong, China; section signDepartment of Medical Oncology, National Cancer Centre, Singapore; parallelDepartment of Histopathology, Tan Tock Seng Hospital, Singapore; and
paragraph signNational University of Singapore, Singapore.
Am J Surg Pathol. 2006 Jan;30(1):75-82. Abstract quote
Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) are rare lesions that occur in immunocompromised patients. Because they have not been fully characterized pathologically or at the molecular level, we have studied 29 tumors from 19 patients, the largest series to date.
Cases coded as EBV-SMT were identified in 19 patients from consultation files and from the renal transplant database at Singapore General Hospital. EBV-SMT occurred in adults (mean age 39 years; range, 21-57 years) and predominantly affected males (12 male, 7 female). Causes of immunocompromise were renal transplantation (10), AIDS (8), and steroid therapy (1). Tumors were located in soft tissue (5), lung (5), liver (4), and miscellaneous sites (15). In 13 patients (68%), the tumors were multiple. Infection with EBV was confirmed in all cases by in situ hybridization for EBV early RNAs (EBER). EBV-SMT were typically well-differentiated smooth muscle tumors with little atypia and usually a low level of mitotic activity. Unlike classic leiomyosarcomas, they lacked significant pleomorphism but frequently displayed primitive round cell areas and prominent intratumoral T lymphocytes.
No consistent relationship between histologic features and clinical outcome was noted. All expressed actin (29 of 29) and less frequently desmin (14 of 26). Multiple tumors in a given patient were clonally distinct as assessed by the long terminal repeat region of the virus, supporting the view that multifocal tumors arise from multiple infection events rather than from metastasis. Strain typing by analysis of the EBNA-3C gene confirmed the presence of EBV type 2. Two of four tumors assessed were positive for a 30-bp deletion in the LMP1 gene. EBV copy number per cell ranged greatly between patients and between tumors from the same patient. Follow-up information was available in 18 of 19 patients (mean, 25 months; range, 1-105 months). Fifteen patients were alive: 11 with disease and 4 without. Three patients died, 1 due to disease.
We conclude that EBV-SMT are histologically distinct from classic soft tissue smooth muscle tumors, are not readily evaluated by means of conventional histologic criteria, and in the case of multifocal tumors are the result of multiple infection events rather than metastasis. EBV-2 can transform smooth muscle cells, independent of the presence of the LMP1 deletion associated with greater virulence.
STOMACH
Severe gastritis secondary to Epstein-Barr viral infection. Unusual presentation of infectious mononucleosis and associated diffuse lymphoid hyperplasia in gastric mucosa.Zhang Y, Molot R.
Department of Pathology and Laboratory Medicine, University of Wisconsin Hospital and Clinics, Madison, Wis, USA.
Arch Pathol Lab Med 2003 Apr;127(4):478-80 Abstract quote Infectious mononucleosis is usually a self-limited clinical syndrome caused by primary Epstein-Barr virus infection. It is occasionally compounded by severe complications involving many different organ systems. Predominant gastrointestinal involvement is rarely documented.
We present an unusual case of acute Epstein-Barr virus infection-associated gastritis with diffuse atypical lymphoid hyperplasia in gastric mucosa.
The clinical, radiographic, histopathologic, immunohistochemical, and in situ hybridization features needed for accurate diagnosis and differentiation from gastric malignancies are discussed.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES NOTE: Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001.
It has been stated that, "The most serious complication of infectious mononucleosis is having a biopsy" because the pathologist is going to misinterpret the lesion as a malignancy.Diffuse large cell lymphoma These features favor infectious mononucleosis:
Young age
Presence of some residual normal lymphoid architecture in at least some areas, eg. preserved sinuses, residual lymphoid follicles
Necrosis of germinal centers
Lack ot atypia of the large transformed cells (such as marked irregular foldings of the nuclear membrane, coarse granular chromatin pattern)
Polymorphous appearance with immunoblasts showing a range of sizes and cytoplasmic basophilia, as well as transition to plasmablasts and plasma cells
Immunoblastic proliferation merging imperceptibly with adjacent reactive follicles and paracortical zones
PROGNOSIS AND TREATMENT CHARACTERIZATION TREATMENT STEM CELL TRANSPLANTATION Allogeneic peripheral blood stem cell transplantation for the treatment of chronic active Epstein-Barr virus infection.
Fujii N, Takenaka K, Hiraki A, Maeda Y, Ikeda K, Shinagawa K, Ashiba A, Munemasa M, Sunami K, Hiramatsu Y, Ishimaru F, Niiya K, Yoshino T, Harada M.
Department of Internal Medicine II, Okayama University Medical School, Okayama, Japan.
Bone Marrow Transplant 2000 Oct;26(7):805-8 Abstract quote
The prognosis of chronic active Epstein-Barr virus infection (CAEBV) is very poor.
We describe a 24-year-old male with severe CAEBV who was treated with allogeneic peripheral blood stem cell transplantation (allo-PBSCT). On admission, EBER-1 in lymphocytes infiltrating the liver, EBV-DNA in peripheral blood mononuclear cells (PBMC) and monoclonal NK cell proliferation were confirmed. After unsuccessful chemotherapy, he received an allo-PBSCT from his HLA-identical sister. Although he died of pulmonary hemorrhage on day +19, EBV-DNA was undetectable by PCR in PBMC, and the post-mortem liver showed no EBER-1-positive lymphocytes.
This experience suggests that EBV-positive lymphocytes in CAEBV may be eradicated by allo-PBSCT, thereby raising the possibility of a new treatment modality.
VIDARABINE Vidarabine Therapy for Severe Chronic Active Epstein-Barr Virus Infection.
Kimura H, Morita M, Tsuge I, Hoshino Y, Tanaka N, Ito Y, Morishima T.
Department of Pediatrics (H.K., M.M., I.T., Y.H., N.T., Y.I.) and Health Science (T.M.), Nagoya University School of Medicine, Nagoya, Japan.
Am J Pediatr Hematol Oncol 2001 Jun;23(5):294-299 Abstract quote
PURPOSE: Severe chronic active Epstein-Barr virus infection (SCAEBV) is an intractable disease with a poor prognosis, and a definitive treatment has not been established. We administered vidarabine to patients with natural killer (NK) cell-type SCAEBV and evaluated clinical and virologic effects.
PATIENTS AND METHODS: Four patients with SCAEBV were enrolled in this study. These patients had various symptoms, including fever, chronic hepatitis, hepatosplenomegaly, and hypersensitivity to mosquito bites. All patients had increased numbers of NK cells in their peripheral blood, and most of these were infected with EBV. Viral load was measured by in situ hybridization and quantitative polymerase chain reaction (PCR).
RESULTS: The patients all responded to the therapy, and their symptoms improved. After the therapy, the number of NK cells in their peripheral blood decreased. In two patients who were closely monitored, the viral load measured by in situ hybridization and quantitative PCR decreased in parallel with the symptomatic improvement. After discontinuing this drug, the patient's symptoms returned and the Epstein-Barr virus load increased again.
CONCLUSION: These results indicate that vidarabine therapy is a therapeutic choice to control SCAEBV, although its effect may be transient.
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001.
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