Epstein-Barr virus (EBV)-associated smooth-muscle tumor arising in a post-transplant patient treated successfully for two PT-EBV-associated large-cell lymphomas. Case report.

The association of Epstein-Barr virus (EBV) with smooth-muscle tumors was recently reported in the setting of acquired immunodeficiency syndrome (AIDS) and post-transplantation. We report a case of an EBV-associated smooth-muscle tumor arising in a post-transplant (PT) patient who previously was treated successfully for two EBV-associated PT large-cell lymphomas. A 4-year-old girl required cardiac transplantation for dilated cardiomyopathy when she was aged 23 months. Her PT regimen included cyclosporine, azothiaprine, and diltiazem. At 16 months PT, she presented with anemia, guaiac-positive stools, and an abdominal mass diagnosed as diffuse large-cell lymphoma of B-cell phenotype. Immunosuppressive therapy was reduced, and interferon and i.v. immunoglobulin were initiated. She rapidly developed signs of rejection, and a cardiac biopsy was performed, revealing grade IIIB rejection. Subsequently, immunosuppressive therapy increased. At 23 months PT, a biopsy was done of a large pelvic mass that was diagnosed as immunoblastic large-cell lymphoma. After treatment with chemotherapy and retinoic acid, the size of the mass markedly decreased. Follow-up computed tomography scan revealed multiple liver nodules. A needle biopsy of the liver showed a smooth-muscle tumor of indeterminate grade. Both the lymphomas and the smooth-muscle tumor contained EBV within > 95% of tumor cells by Epstein-Barr (EBER1) in situ hybridization, were of strain type A by Epstein-Barr nuclear antigen-2 (EBNA-2) polymerase chain reaction (PCR) and contained an identical 30 base-pair deletion (amino acids 346-355) of the latent membrane protein (LMP)-1 oncogene by PCR analysis. Notably, the initial large-cell lymphoma and the subsequent immunoblastic lymphoma each contained a unique p53 mutation, suggesting that they were distinct. These data suggest that the same virus contributed to the pathogenesis of both the malignant lymphomas and the smooth-muscle tumor.

Prevalence of Epstein-Barr viral sequences and EBV LMP1 oncogene deletions in Burkitt's lymphoma from Pakistan: epidemiological correlations.

To investigate the potential relationship of socioeconomic status with the prevalence of Epstein-Barr virus (EBV) and to understand the significance of del-LMP-1 within EBV+ cases of Burkitt's lymphoma (BL), we studied 10 cases of BL, 30 cases of diffuse large cell lymphoma (DLCL) arising in nonimmunocompromised patients, and 30 reactive tonsillar biopsy specimens from Pakistan. Each lymphoma was analyzed for EBV by EBER1 RNA in situ hybridization (EBV-RISH). Cases showing hybridization signal within neoplastic cells and all reactive tonsillar tissues were analyzed for EBV strain type by EBNA-2 polymerase chain reaction (PCR) and for the presence of a del-LMP-1 by PCR. Eight of 10 (80%) of BL were EBV+, each containing EBV strain A and a wild-type LMP-1 gene. In contrast, only 4 of 30 DLCL (13%) cases were EBV positive (three strain A, one strain B), each containing a wild-type LMP-1 gene. Fifteen of 30 tonsillar biopsy specimens contained EBV, all of which were strain A and wild-type for LMP1. The prevalence of EBV in BL from Pakistan is slightly lower than in BL in endemic regions, but significantly higher than in BL in North America. EBV positivity probably reflects the socioeconomic status of the patient population and age at seroconversion. The absence of del-LMP-1 within all EBV+ BL cases is consistent with the view that del-LMP-1 is not involved in the pathogenesis of BL, and the presence of del-LMP-1 in EBV+ cases of BL reported in other studies may likely reflect the prevalence of a viral strain containing the 30-bp deletion within the respective population studied.

Low-grade monoclonal Epstein-Barr virus-associated lymphoproliferative disorder of the brain presenting as human immunodeficiency virus-associated encephalopathy in a child with acquired immunodeficiency syndrome.

The association of the Epstein-Barr virus with human immunodeficiency virus-associated primary central nervous system lymphomas is well known. We describe a pediatric patient infected with human immunodeficiency virus who developed a lesion in the central nervous system that appeared to be histologically reactive and that proved to be an Epstein-Barr virus-associated monoclonal B-cell lymphoproliferative disorder by molecular analysis. An 8-year-old girl was diagnosed with vertically transmitted human immunodeficiency virus infection at age 5, for which she was treated empirically with a combination of zidovudine and didanosine. At the age of 7 years, during evaluation for entry into an antiretroviral protocol, a single hypodense frontal lobe lesion was identified by computed tomography. After unsuccessful treatment for presumed toxoplasmosis and progressive neurologic deterioration, a stereotactic brain biopsy was performed. Although the biopsy contained a polymorphic lymphoid infiltrate that appeared to be cytologically reactive, polymerase chain reaction and in situ hybridization studies revealed a monoclonal Epstein-Barr virus-associated B-cell lymphoproliferative disorder, which was reminiscent of polymorphic B-cell hyperplasia observed in the setting of immunosuppression following organ transplantation. Postoperative therapy included steroids and antiretroviral therapy. The lesion decreased slightly in size, and the child's neurologic status was relatively unremarkable for 5 months. Subsequently, she developed cytomegalovirus retinitis, progressive encephalopathy, and died with pancytopenia. This case represents a newly described manifestation of Epstein-Barr virus-associated lymphoproliferative disorder, a diagnosis that should be considered in patients with neurologic symptoms and immunodeficiency. In addition, this case exhibited histologic features reminiscent of posttransplant lymphoproliferative disease, a histologic pattern that to our knowledge has not previously been reported in the setting of acquired immunodeficiency syndrome.

Epstein-Barr virus latent membrane protein-1 oncogene deletions: correlations with malignancy in Epstein-Barr virus--associated lymphoproliferative disorders and malignant lymphomas.

LMP-1, an Epstein-Barr viral (EBV) latency protein, is considered a viral oncogene because of its ability to transform rodent fibroblasts in vivo and render them tumorigenic in nude mice. In human B cells, EBV LMP-1 induces DNA synthesis and abrogates apoptosis. LMP-1 is expressed in EBV-transformed lymphoblastoid cell lines, nasopharyngeal carcinoma (NPC), a subset of Hodgkin's disease (HD), and in EBV-associated lymphoproliferative disorders (EBV-LPDs). Recently, focused deletions near the 3' end of the LMP-1 gene (del-LMP-1, amino acids 346-355), in a region functionally related to the half-life to the LMP-1 protein, have been reported frequently in human immunodeficiency virus (HIV)-associated HD (100%) and EBV+ Malaysian and Danish peripheral T-cell lymphomas (100%, 61% respectively), but less frequently in cases of HD not associated with HIV (28%, 33%) and infectious mononucleosis (33%). To further investigate the potential relationship of del-LMP-1 to EBV-LPDs associated with immunosuppression or immunodeficiency, we studied 39 EBV-associated lymphoproliferations (10 benign, 29 malignant) from four distinct clinical settings: posttransplant (4 malignant, 1 reactive); HIV+ (18 malignant, 2 reactive); nonimmunodeficiency malignant lymphoma (ML) (7 cases); and sporadic EBV infection with lymphoid hyperplasia (7 cases). The presence of EBV within lymphoid cells was confirmed by EBV EBER1 RNA in situ hybridization or by polymerase chain reaction (PCR) analysis. EBV strain type and LMP-1 deletion status were determined by PCR. EBV strain types segregated into two distinct distributions: HIV+ (9 A; 11 B) and non-HIV (19 A, 0 B), consistent with previous reports. Overall, del-LMP-1 were found in 1 of 5 (20%) Burkitt lymphomas (BL); 17 of 24 (71%) aggressive non-Hodgkin's lymphoma (agg-NHL), and 2 of 10 (20%) reactive lymphoid proliferations. Of the agg-NHLs, del-LMP-1 were present in 4 of 4 PT-ML (100%); 10 of 15 HIV+ ML (67%); and 3 of 5 nonimmunodeficiency malignant lymphoma (ML, 60%). A total of 2 of 7 (28%) sporadic EBV-associated lymphoid hyperplasias contained a del-LMP-1. All del-LMP-1 were identical by DNA sequence analysis. No correlation was identified between the presence of del-LMP-1 and the EBV strain type observed. The high incidence of del-LMP-1 observed in agg-NHLs (71%), in contrast to the relatively low incidence observed in reactive lymphoid proliferations (28%), suggests that the deleted form may be preferentially selected in lymphomatous processes. All posttransplant agg-NHLs contained a del-LMP-1, and a similar frequency of del-LMP-1 was observed in both HIV-associated ML (66%) and nonimmunodeficiency ML (60%), suggesting that impairment of immune function alone is not a requirement for the expansion of malignant cells infected by EBV stains containing the deleted LMP-1 gene.