Bacterial Infection and Non-Hodgkin B-Cell Lymphoma: Interactions between Pathogen, Host and the Tumor Environment.

Non-Hodgkin B-cell lymphomas (NHL) are a heterogeneous group of lymphoid neoplasms with complex etiopathology, rich symptomatology, and a variety of clinical courses, therefore requiring different therapeutic approaches. The hypothesis that an infectious agent may initiate chronic inflammation and facilitate B lymphocyte transformation and lymphogenesis has been raised in recent years. Viruses, like EBV, HTLV-1, HIV, HCV and parasites, like Plasmodium falciparum, have been linked to the development of lymphomas. The association of chronic Helicobacter pylori (H. pylori) infection with mucosa-associated lymphoid tissue (MALT) lymphoma, Borrelia burgdorferi with cutaneous MALT lymphoma and Chlamydophila psittaci with ocular adnexal MALT lymphoma is well documented. Recent studies have indicated that other infectious agents may also be relevant in B-cell lymphogenesis such as Coxiella burnettii, Campylobacter jejuni, Achromobacter xylosoxidans, and Escherichia coli. The aim of the present review is to provide a summary of the current literature on infectious bacterial agents associated with B-cell NHL and to discuss its role in lymphogenesis, taking into account the interaction between infectious agents, host factors, and the tumor environment.

Endoscopic ultrasound-guided diagnosis of Helicobacter pylori-associated gastric Burkitt's lymphoma in an adolescent patient: a rare case.

Primary gastric Burkitt's lymphoma (BL) is rare in the pediatric population. Furthermore, the association of Burkitt's lymphoma with Helicobacter pylori is not well defined. We report a case of primary gastric Burkitt's lymphoma associated with Helicobacter pylori diagnosed in a pediatric patient. This diagnosis was made with the aid of endoscopic ultrasound (EUS)-guided fine-needle biopsy (FNB). This is one of the first pediatric cases of EUS-guided FNB for the diagnosis of H. pylori-associated gastric BL.

Complete remission of gastric Burkitt's lymphoma after eradication of Helicobacter pylori.

Burkitt's lymphoma is a highly aggressive non-Hodgkin lymphoma, often presenting in extra-nodal sites. It generally has a poor spontaneous outcome and needs aggressive treatment with systemic and intrathecal chemotherapy. Occurrence at the gastric site is rare. We report the case of a 39-year old woman who presented with a prominent ulcerated lesion of the antrum corresponding histologically to a Burkitt's lymphoma associated with Helicobacter pylori (H pylori) infection. Interphase fluorescence in situ hybridization (FISH) demonstrated c-MYC gene rearrangement in tumour cells without BCL2 or BCL6 gene translocations. Ulcer healing and tumour regression with a complete histological response were obtained 8 wk after H pylori eradication. In spite of this complete remission, taking into account the high risk of recurrence, the patient received systemic and intrathecal chemotherapy. Two years later, the patient remained in complete remission. This is the first report of a gastric Burkitt's lymphoma responding to H pylori eradication. These findings raise the question of the potential role of H pylori in the pathogenesis of some gastric Burkitt's lymphomas, and show the importance of searching for and eradicating the bacteria in combination with conventional chemotherapy regimens.

Lethal double infection with Acremonium strictum and Aspergillus fumigatus during induction chemotherapy in a child with ALL.

Fungal infections are a major cause of morbidity and mortality in patients during chemotherapeutic treatments and malignant hematologic disease. We present a case of a double fungal infection with disseminated Acremonium strictum (A. strictum) and pulmonary Aspergillus fumigatus (A. fumigatus) and its rapid clinical course. A 17-year-old boy with prolonged neutropenia developed a disseminated fungal infection during induction chemotherapy of his acute lymphoblastic leukemia. The infection was rapidly lethal despite neutrophil recovery and early antifungal combination therapy with amphotericin B and caspofungin. Since there are only a few reports about invasive Acremonium infections, we present this case with regard to differences in the clinic pathologic features of Aspergillosis and other opportunistic fungal infections due to Fusarium or Acremonium species.

Infection of human B lymphoma cells by Mycoplasma fermentans induces interaction of its elongation factor with the intracytoplasmic domain of Epstein-Barr virus receptor (gp140, EBV/C3dR, CR2, CD21).

Human cell lines are often infected by mycoplama strains. We have demonstrated that when infected by Mycoplasma fermentans, human B lymphoma cell proliferation increased strongly. These infected B cells expressed a p45 kDa protein which interacted with the intracellular domain of CD21, the EBV/C3d receptor. p45 analysis demonstrated that this is a new gene which encodes an elongation factor originating from Mycoplasma fermentans. p45 interaction with CD21 was specific, there being no interaction with CD19. This is the first demonstration that Mycoplasma fermentans, in infecting human B cells, generates a p45 Mycoplasma component that interacts with CD21, which is involved in B cell proliferation.

[Sporadic Burkitt's lymphoma (BL) with stomach involvement associated with Helicobacter pylori infection--case report and literature review]. / Sporadyczny chloniak Burkitta z zajeciem zoladka i towarzyszaca infekcja Helicobacter pylori--opis przypadku i przeglad literatury.

UNLABELLED: Extranodal lymphomas represent up to 40% of all lymphomas and their prevalence is still increasing. Sporadic BL is rare. It occurs mainly in young men and is associated with viral infection in only about 30% of cases. Most frequently it affects the digestive tract. CASE REPORT: 46-year-old patient was admitted to hospital due to painless tuberous changes of right occipital region and cheek, weakness and non-specific abdominal pain. Clinical examination revealed hepatomegaly. Leucocytosis, raised level of transaminases and LDH were found. Imaging investigations disclosed the enlargement of epigastric lymph nodes and thickening of stomach wall. FNAB of the cheek's tumor allowed to suspect a lymphoma. Biopsy specimens taken from the stomach, cheek and bone marrow confirmed the diagnosis of BL. Microscopic examination revealed cellular infiltration consisting of monomorphic, lymphoid cells with round or oval nuclei containing a few nucleoli with scanty cytoplasm. Mitoses, also atypic, were very numerous. Immunohistochemistry staining was very characteristic for this type of lymphoma: CD20, CD79a, CD10, C-myc, IgM positive, MIB positive in 100% of neoplasmatic cells. There was no evidence of EBV infection. In gastric specimens Helicobacter pylori infection was found. CONCLUSION: Clinical features of sporadic BL are often very non-typical. It is important to diagnose BL in its early stage, because it responds well to treatment and there is a chance of full recovery. Relation between H. pylori infection and BL is probable but demands further investigations.

Does amphotericin B lipid complex (Abelcet) affect haematological parameters erroneously?

Abelcet is composed of large particles which could be misinterpreted as blood cells on measurements with blood cell counters. The direct measurement of drug suspensions on blood cell counters has been performed in an in vitro study. In an ex vivo study, the haematological parameters were compared before and during Abelcet infusions. A significant interference effect was observed in platelet counts, together with minimal differences in the WBC, RBC, and Hb parameters in the in vitro study. In the ex vivo study, there were statistically significant deviations only in RBC counts and in haemoglobin (Hb) level, while there was no difference in the other parameters. It is been reported that the drug accumulates very rapidly in the reticuloendothelial system and circulates minimally in the plasma. That is why there is a significant deviation in the direct counting of platelets, while the platelet counts taken from the patients do not differ statistically.

Primary intestinal non-Hodgkin's lymphoma and Epstein-Barr virus: high frequency of EBV-infection in T-cell lymphomas of Mexican origin.

Epstein-Barr virus is universally associated with endemic Burkitt's lymphoma (BL) and undifferentiated nasopharyngeal carcinoma and can be detected in a significant proportion of cases of Hodgkin's disease (HD) and peripheral T-cell lymphoma, but only rarely in sporadic B-NHL. The frequency of EBV-positivity in certain neoplasms shows important geographic variations. Both HD and sporadic BL from Latin America have shown higher rates of EBV-association than cases from Western countries. In T-NHL, the frequency of EBV-positivity is influenced by the site of the primary tumor and the phenotype of the neoplastic cells. Nasal and nasal-type T-NHL, which show a T/NK-cell phenotype with expression of CD56 are virtually always EBV-associated, whereas only a proportion of nodal, gastrointestinal and pulmonary T-NHL are EBV-infected. A recent investigation of primary intestinal lymphomas of Mexican origin demonstrated EBV-positivity in all examined cases of T-NHL and BL and a proportion of other B-NHLs. The presence of EBV was independent of the presence or absence of enteropathy. Two of 6 cases studied showed CD56 expression. The high rate of EBV-positivity independent of histologic subtype is in contrast to the low to intermediate rates of EBV-positivity found in cases of intestinal T-NHL from Western countries and indicates that geographic differences in the frequency of EBV-association of lymphoid neoplasms might also extend to a fraction of peripheral T-cell lymphomas.

EBV-B cell interactions: immortalization, rescue from apoptosis, tumorigenicity (a short review).

Translocation of the c-myc gene to an immunoglobulin locus is a rate-limiting step in the genesis of three B-cell derived tumors: Burkitt lymphoma (BL) in humans, mouse plasmacytoma (MPC) and rat immunocytoma. Its consequences have been best analyzed in BL. They involve a non-immunological and an immunological component. The former acts by preventing the B cell from leaving the cycling compartment and entering the resting stage when programmed to do so. The latter acts by the down regulation of certain HLA class I polymorphic specificities, adhesion molecules and EBV encoded proteins. According to our interpretation, the translocation fixes the BL cell in a phenotypic window that can be referred to as "a resting cell that is not resting". The linking of c-myc to immunoglobulin sequences in a B cell leads to constitutive myc expression. In spite of its switch to a "resting phenotype", the cell is therefore unable to leave the cycling compartment. Normally, EBV-carrying B-blasts face immune controls. They can only proliferate in immunodefectives, as in XLP or transplant lymphoma. Due to its "resting" rather than B-blast phenotype and the correlated defective expression of certain EBV, HLA and adhesion molecules, the BL cell is not rejected by the EBV-specific immune response, however. The down-regulation of EBNA 2-6 in the BL cell may be also considered in relation to viral latency. The exclusive expression of EBNA 1 in the BL cell reflects the adaptation of the virus to prolonged persistence in long lived resting B cells, an important if not exclusive reservoir of the latent virus. Normal B cells that fail to be activated by appropriate mitogens or antigens within a limited period of time undergo apoptosis, as a rule. EBV may protect resting B cells. The role of the only virally encoded protein they are known to express, EBNA 1, remains to be explored in this respect. EBV infected immunoblasts are protected from apoptosis by the LMP 1 induced elevation of bcl-2 expression. During the lytic cycle when cellular protein synthesis is switched off by the early viral proteins, a member of the early protein group, a bcl-2 homologous protein encoded by the BHRF1 gene, takes over the function to protect against untimely apoptosis.

Selective loss of integrated Epstein-Barr virus genomes after long-term cultivation of Burkitt's lymphoma x B-lymphoblastoid cell hybrids due to chromatin instability at the integration site.

Independently established somatic cell hybrid clones between the Burkitt's lymphoma (BL) cell line BL 60 and the autologous Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell line (LCL) IARC 277 were analyzed with regard to physical state of EBV and karyotype changes in long-term culture. Early after fusion these hybrids carry EBV genomes of the parental BL cell line integrated near the breakpoint of a translocation chromosome der(19) t(11;19) as well as episomal viral DNA molecules of the parental LCL. During long-term culture, however, all hybrid cell lines lost the integrated EBV sequences and retained exclusively episomal EBV, whereas in parental BL cells the EBV genomes remained stably integrated. Loss of integrated EBV in all cases resulted from a break proximal to the EBV integration site. Fluorescence in situ hybridization revealed that this integration site had become a gap-like chromatin area. We thus conclude that the integration of the EBV genomes constitutes a chromosomal region prone to break events akin to the phenomenon of fragile sites. This instability might have led directly to the loss of the EBV DNA itself and of the chromosome 11 region distal to it.

Parallel existence of Epstein-Barr virus (EBV) positive and negative cells in a sporadic case of Burkitt lymphoma.

In the Burkitt lymphoma line Oma-BL1, EBV positive and negative cells coexist. We demonstrate that EBV positive and negative subclones are identical with respect to chromosome markers and HLA type and that the same c-myc rearrangement occurs in all the subclones. This shows that the tumor cells are derived from the same patient and are of monoclonal origin. In the positive subclones, the EBV genome was stably maintained in the episomal form. The EBV negative subclones could be derived from previously uncloned tumor cells in early passage, but not from the EBV positive subclones.

High expression of latent membrane protein 1 of Epstein-Barr virus and BCL-2 oncoprotein in acquired immunodeficiency syndrome-related primary brain lymphomas.

Nearly all primary brain lymphomas in acquired immunodeficiency syndrome (AIDS) patients are associated withEpstein-Barr virus (EBV). The role of EBV in lymphomagenesis is not totally elucidated. One possible mechanism is the overexpression of the BCL-2 oncoprotein, because the latent membrane protein 1 (LMP1) has been reported to transactivate the bcl-2 gene in vitro. To study the interrelationship beetween LMP1 and BCL-2 in vivo, we have analyzed and compared their expression in 11 AIDS-related primary brain lymphomas and 57 AIDS-related systemic lymphomas by immunoperoxidase technique on frozen sections. In AIDS-related primary brain lymphoma, LMP1 and BCL-2 were expressed in all cases but 1. All positive cases exhibited morphologic immunoblastic features. In contrast, the only negative case was histologically close to Burkitt's lymphoma. In systemic lymphomas, LMP1 was expressed in 21 cases, whereas BCL-2 was positive in only 3 cases, all of which were extranodal. These results indicate that, in addition to the histologic type, the role of EBV genes and BCL-2 expression in lymphomatous cells differ as a function of their localization. In AIDS-related primary brain lymphomas, this correlation between LMP1 and BCL-2 overexpression may have a major implication in lymphomagenesis.

Latent Epstein-Barr virus infection in cottontop tamarins. A possible model for Epstein-Barr virus infection in humans.

The association of Epstein-Barr virus (EBV) with a growing number of human malignancies underlines the importance of efforts aimed at preventing the infection with this potential carcinogen and of establishing animal models for human virus-associated tumors. Cottontop tamarins have been used in EBV vaccine studies because virus infection regularly induces lymphomas similar to those seen in human immunocompromised individuals. In recent years, several vaccines based on the gp340/220 envelope protein of EBV have been developed and shown to prevent the development of EBV-associated lymphomas in this model. Using in situ hybridization and immunohistology, we have characterized EBV infection in one nonimmunized and three immunized animals after challenge with a standard tumorigenic dose of EBV. In the nonimmunized animal, EBV-infected lymphoid cells were detected in numerous tissues showing no obvious lymphoma infiltration. Surprisingly, variable numbers of virus-carrying cells were also found in all three immunized animals that were protected against the development of virus-associated lymphoma. This observation demonstrates that vaccination does not induce sterilizing immunity against EBV infection in this model. Double labeling suggested a B cell phenotype of the majority of these cells. EBV infection of nonlymphoid cells was not observed. Analysis of viral gene expression in immunized animals suggested a restricted form of virus latency different from that seen in EBV-driven lymphomas in nonimmunized cottontop tamarins. These results raise the possibility that immunized cottontop tamarins protected against the development of EBV-driven lymphoma or animals exposed to a sublymphomagenic dose of virus may serve as a model for EBV infection in humans.

Isolation of Epstein-Barr virus (EBV)-negative cell clones from the EBV-positive Burkitt's lymphoma (BL) line Akata: malignant phenotypes of BL cells are dependent on EBV.

During cultivation of the Epstein-Barr virus (EBV)-positive Burkitt's lymphoma (BL) line Akata, it was noted that EBV DNA is lost from some of the cells. Isolation of EBV-positive and EBV-negative clones with the same origin made it possible to examine the effects of EBV in BL cells. The results indicate that malignant phenotypes of BL, such as growth in low serum, anchorage-independent growth in soft agar, and tumorigenicity in nude mice, are dependent on the presence of EBV genomes and underline the oncogenic function of EBV in human cancer.