PubMed Health⌕ Search

Biomedical subjects

Francisco Vega

Publications and source records attributed to Francisco Vega.

At least 19 recordsLinked to original sources
PubMed2026

A Patient-Derived Xenograft Repository Capturing Clinical and Molecular Heterogeneity of Large B-cell Lymphoma.

UNLABELLED: Large B-cell lymphomas (LBCL) are a clinically and molecularly diverse group of malignancies with a rapidly evolving therapeutic landscape that has introduced new areas of clinical need, such as post-CD19 chimeric antigen receptor T (CART19) progression. Patient-derived xenograft (PDX) models are an important tool for mechanistic studies and preclinical evaluation of new therapies and can be generated from a variety of clinical contexts that capture tumor-intrinsic resistance mechanisms. We therefore undertook a comprehensive effort to generate PDX models that encompass the molecular landscape of LBCLs and include important clinical scenarios for new drug development. Here, we describe the first 48 models within this publicly available repository, capturing the transcriptional and genetic subsets of LBCL. These models also include 23 generated from post-CART19 progression patient biopsies, which reproduce patterns of progression driven by CD19 mutation or expression loss, as well as tumor cell-intrinsic CART19 resistance that we validated in vivo. SIGNIFICANCE: Here, we describe X-LYMPH (Xenografts of Lymphoma), a publicly available and molecularly annotated PDX repository that captures the heterogeneity of LBCL. X-LYMPH includes models of CAR T-cell resistance, providing a shared foundation for mechanistic research and therapeutic development for lymphomas. See related commentary by Evgin and Steidl, p. 655.

Humans↗
PubMed2006

Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in aberrant expression of chimeric nucleophosmin-ALK. Previously, nucleophosmin-ALK has been shown to activate phosphatidylinositol 3-kinase (PI3K) and its downstream effector, the serine/threonine kinase AKT. In this study, we hypothesized that the mammalian target of rapamycin (mTOR) pathway, which functions downstream of AKT, mediates the oncogenic effects of activated PI3K/AKT in ALK+ ALCL. Here, we provide evidence that mTOR signaling phosphoproteins, including mTOR, eukaryotic initiation factor 4E-binding protein-1, p70S6K, and ribosomal protein S6, are highly phosphorylated in ALK+ ALCL cell lines and tumors. We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors. Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation. In addition, pharmacologic inhibition of PI3K/AKT down-regulates the activation of the mTOR signaling pathway. We also show that inhibition of mTOR with rapamycin, as well as silencing mTOR gene product expression using mTOR-specific small interfering RNA, decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis in ALK+ ALCL cells. Cell cycle arrest was associated with modulation of G(1)-S-phase regulators, including the cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Apoptosis following inhibition of mTOR expression or function was associated with down-regulation of antiapoptotic proteins, including c-FLIP, MCL-1, and BCL-2. These findings suggest that the mTOR pathway contributes to nucleophosmin-ALK/PI3K/AKT-mediated tumorigenesis and that inhibition of mTOR represents a potential therapeutic strategy in ALK+ ALCL.

Anaplastic Lymphoma Kinase↗
PubMed2006

Atypical NK-cell proliferation of the gastrointestinal tract in a patient with antigliadin antibodies but not celiac disease.

We describe a unique case of atypical natural killer (NK)-cell proliferation likely related to gluten sensitivity, mimicking NK-cell lymphoma. The patient, a 32-year-old man, has had persistent multiple erythematous bull-eye lesions in the stomach, small bowel, and large bowel for 3 years. Histologically, the lesions were well circumscribed and relatively superficial, composed of atypical medium-sized to large-sized lymphocytes with slightly irregular nuclear contours, a dispersed chromatin pattern, and clear cytoplasm. Immunohistochemistry and flow cytometry showed that the cells were NK cells expressing CD56 (aberrantly bright), T-cell intracellular antigen (TIA)-1, cytoplasmic CD3, and CD94, but not surface CD3, with bright aberrant expression of CD7 and a lack of other NK cell-associated markers. Polymerase chain reaction for rearrangement of the T-cell receptor-gamma chain gene showed no evidence of a clonal T-cell population, and in situ hybridization for Epstein-Barr virus encoded RNA was negative. There was no evidence of the involvement of peripheral blood or bone marrow. Although a diagnosis of extranodal NK/T-cell lymphoma was considered because of the atypical morphology and immunophenotypic aberrancy, no chemotherapy was given because of the relatively superficial nature of the infiltrates, lack of significant symptoms, and negativity for Epstein-Barr virus. Two years after initial presentation, the patient was found to have high titers of antigliadin antibodies with no other evidence of celiac disease. After instituting a gluten-free diet, many of the lesions regressed, suggesting that this atypical NK-cell proliferation may be driven by an anomalous immune response. Awareness of this case may prevent pathologists from misdiagnosing similar lesions as NK/T-cell lymphomas. It is as yet unknown whether this process occurs more commonly in patients with gluten sensitivity, or in other settings, and the pathogenesis is as yet undetermined.

Adult↗
PubMed2006

Tissue-specific function of lymph node fibroblastic reticulum cells.

OBJECTIVE: We present the first characterization of the cytokine expression pattern of lymph node fibroblastic reticulum cells (FRC), which are the stromal cells responsible for maintaining the highly structured nodal reticular fiber framework. METHODS: Microarray expression profiles of cultured nodal FRC and dermal fibroblasts (DF) were compared as well as their response to TNF, IL-4, IL-6 and IL-13, cytokines responsible for intranodal stromal activation. RESULTS: Hierarchical clustering of FRC and DF short-term culture samples revealed genes that were differentially expressed in FRC and DF. Identified differently regulated genes were confirmed by RNase protection analysis, PCR or immunohistochemistry. At earlier culture time points, FRC showed higher levels of several chemokines, including CCL2/MCP-1, and cytokines, e.g. IL-6, whereas several genes related to the production of extracellular matrix and angiogenesis were preferentially expressed in early DF cultures. By 60 days in culture, FRC and DF showed similar expression patterns consistent with homogenization of specialized stromal subsets. FRC and DF showed nearly identical transcriptional responses to exogenous TNF stimulation. CONCLUSIONS: Cultured FRC showed an overall transcriptional profile similar to cultured DF, including parallel responsiveness to TNF, but with differences in the expression of chemotactic chemokines, which reflect their biological roles.

Cells, Cultured↗
PubMed2006

Primary cutaneous marginal zone B-cell lymphoma.

Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is included as one of the major types of primary cutaneous B-cell lymphoma in the revised World Health Organization-European Organization for Research and Treatment of Cancer classification. Clinically, PCMZL is an indolent disease and has an excellent prognosis. PCMZL is composed of a polymorphous infiltrate that includes centrocyte-like, monocytoid, and lymphoplasmacytoid lymphocytes and plasma cells. Numerous reactive T cells and lymphoid follicles are commonly associated with the neoplasm. The neoplastic cells express B-cell markers and usually bcl-2 and are negative for CD5, CD10, and bcl-6. Borrelia burgdorferi is a suspected etiologic agent identified in a subset of cases. Although all of these neoplasms presumably are monoclonal, monoclonal IgH rearrangement can only be detected in approximately 75% of cases. Most molecular studies to assess for clonality have used polymerase chain reaction-based methods, and thus this false-negative rate may be attributable to somatic mutation of the IgH variable region genes. Approximately 10% to 20% of PCMZLs have recurrent chromosomal translocations, including the t(14;18)(q32;q21)/IgH-malt1, t(11;18)(q21;q21), and t(3;14)(p14;q32). The t(14;18)(q32;q21) and t(11;18)(q21;q21) have been shown to activate the NF-kappaB pathway.

Adult↗
PubMed2006

Lymphomas involving the pleura: a clinicopathologic study of 34 cases diagnosed by pleural biopsy.

CONTEXT: Pleural involvement by lymphoma is relatively common. However, there are very few clinicopathologic studies reported in the literature of lymphomas involving the pleura. OBJECTIVE: To characterize the clinicopathologic features of lymphomas involving the pleura. DESIGN: We reviewed the clinicopathologic features of 34 patients with lymphoma involving the pleura proven by biopsy and classified these neoplasms using the World Health Organization classification. RESULTS: There were 22 men and 12 women, with an average age of 62 years (range, 22-82 years). Nine (26.5%) patients had pleural involvement as the only site of disease, 22 (64.7%) had other sites of involvement, and 3 (8.8%) had inadequate staging data. Eighteen (56.2%) of 32 patients with adequate clinical data had a history of lymphoma (including 3 patients with pleural involvement as the only disease site). In 29 (85.3%) cases, a specific diagnosis according to the World Health Organization classification could be made: 17 (58.6%) diffuse large B-cell lymphoma, 5 (17.2%) follicular lymphoma (including a case with areas of diffuse large B-cell lymphoma), 2 (6.9%) small lymphocytic lymphomas/chronic lymphocytic leukemia, 2 (6.9%) precursor T-cell lymphoblastic lymphoma/leukemia, 1 (3.4%) mantle cell lymphoma, 1 (3.4%) posttransplant lymphoproliferative disorder, and 1 (3.4%) classical Hodgkin lymphoma. The other 5 cases were B-cell lymphomas that could not be further classified. Cytologic examination of pleural fluid was performed in 15 cases and was positive for lymphoma in 8 (53.3%) cases. CONCLUSIONS: Most patients with lymphoma involving the pleura have simultaneous evidence of systemic involvement. The most frequent type is diffuse large B-cell lymphoma, followed by follicular lymphoma. Cytologic examination can have negative results in patients with pleural involvement by lymphoma.

Adult↗
PubMed2005

Extranodal lymphomas of the head and neck.

Malignant lymphomas represent approximately 5% of all malignant neoplasms of the head and neck and may involve nodal or extranodal sites. Nodal head and neck lymphomas are similar to other nodal sites and are not further reviewed here. The head and neck region is the second most frequent anatomical site of extranodal lymphomas (after the gastrointestinal tract). Most are non-Hodgkin's lymphomas of B-cell lineage, and overall diffuse large B-cell lymphoma is the most common type. Hodgkin's lymphoma rarely occurs in extranodal sites. Other hematologic neoplasms that commonly involve extranodal sites of the head and neck are also discussed. In this review, we begin by discussing lymphomas involving the head and neck according to anatomical site. Then we discuss specifically the pathological findings of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, plasmablastic lymphoma, extramedullary plasmacytoma, and extranodal natural killer/T-cell lymphoma of nasal type.

Head and Neck Neoplasms↗
PubMed2005

Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles.

Plasmablastic lymphoma is an aggressive neoplasm that shares many cytomorphologic and immunophenotypic features with plasmablastic plasma cell myeloma. However, plasmablastic lymphoma is listed in the World Health Organization (WHO) classification as a variant of diffuse large B-cell lymphoma. To characterize the relationship between plasmablastic lymphoma and plasmablastic plasma cell myeloma, we performed immunohistochemistry using a large panel of B-cell and plasma cell markers on nine cases of plasmablastic lymphoma and seven cases of plasmablastic plasma cell myeloma with and without HIV/AIDS. The expression profiles of the tumor suppressor genes p53, p16, and p27, and the presence of Epstein-Barr virus (EBV) and human herpes virus type 8 (HHV-8) were also analyzed. All cases of plasmablastic lymphoma and plasmablastic plasma cell myeloma were positive for MUM1/IRF4, CD138, and CD38, and negative for CD20, corresponding to a plasma cell immunophenotype. PAX-5 and BCL-6 were weakly positive in 2/9 and 1/5 plasmablastic lymphomas, and negative in all plasmablastic plasma cell myelomas. Three markers that are often aberrantly expressed in cases of plasma cell myelomas, CD56, CD4 and CD10, were positive in 5/9, 2/5, and 6/9 plasmablastic lymphomas, and in 3/7, 1/5, and 2/7 plasmablastic plasma cell myelomas. A high Ki-67 proliferation index, overexpression of p53, and loss of expression of p16 and p27 were present in both tumors. No evidence of HHV-8 infection was detected in either neoplasm. The only significant difference between plasmablastic lymphoma and plasma cell myeloma was the presence of EBV-encoded RNA, which was positive in all plasmablastic lymphoma cases tested and negative in all plasma cell myelomas. In conclusion, most cases of AIDS-related plasmablastic lymphoma have an immunophenotype and tumor suppressor gene expression profile virtually identical to plasmablastic plasma cell myeloma, and unlike diffuse large B-cell lymphoma. These results do not support the suggestion in the WHO classification that plasmablastic lymphoma is a variant of diffuse large B-cell lymphoma.

Adult↗
PubMed2003

Phenotypic modulation of the stromal reticular network in normal and neoplastic lymph nodes: tissue transglutaminase reveals coordinate regulation of multiple cell types.

The lymph node paracortex is composed of a network of fibroblastic reticular cells (FRC) and reticular fibers linking sinuses to blood vessels. Using immunostaining for the inducible enzyme/adhesion molecule tissue transglutaminase (TG), we demonstrate coordinate regulation of multiple stromal cell types of this reticular network including FRC, endothelial cells and sinus lining cells. Tissue transglutaminase is expressed at low levels in the paracortex around primary follicles but is markedly up-regulated in stromal cells around hyperplastic germinal centers and then down-regulated around regressing follicles. In cultured FRC, TG is induced 5- to 20-fold and becomes colocalized with matrix proteins by treatment with interleukin-4, but not by other cytokines that are commonly increased in lymph upon immune activation. Coordinate TG up-regulation is observed surrounding nodules of follicular lymphoma (14 of 15 cases) and in the FRC and endothelium of classical Hodgkin's disease, two tumor types that also showed an activated paracortical phenotype. Small lymphocytic lymphoma showed minimal TG staining, with other lymphoma types showing patterns suggesting differential TG regulation. Using TG as a stromal marker, we have identified differential modulation of the phenotype of the lymph node reticular network that parallels change in the B-cell compartment.

Animals↗
PubMed2003

Chromosomal translocations involved in non-Hodgkin lymphomas.

CONTEXT: The discovery that recurrent chromosomal translocations are involved in the pathogenesis of non-Hodgkin lymphomas has greatly improved our understanding of these diseases and revolutionized their diagnosis. OBJECTIVE: To review the mechanisms by which chromosomal translocations occur and contribute to the pathogenesis of various types of non-Hodgkin lymphomas and to review the utility of molecular genetic methods for the assessment of these translocations. DATA SOURCES AND STUDY SELECTION: Primary research studies and reviews published in the English language that focus on chromosomal translocation and non-Hodgkin lymphomas. DATA EXTRACTION AND SYNTHESIS: Chromosomal translocations, which usually result in oncogene activation, occur in many types of B- and T-cell lymphoma, and their detection is helpful for establishing an accurate diagnosis and monitoring disease following therapy. However, the precise mechanisms that explain how translocations occur remain unknown, although for some types of translocations a clear relationship has been established with immunoglobulin gene rearrangement mechanisms. In recent years, a number of genes deregulated by chromosomal translocations have been identified, and the detailed molecular mechanisms by which chromosomal translocations contribute to the pathogenesis of non-Hodgkin lymphoma are beginning to be elucidated. CONCLUSIONS: Molecular genetic analysis has played a major role in improving our understanding of B- and T-cell non-Hodgkin lymphomas and has allowed more precise definition of lymphoma types. Molecular genetic tests to detect these translocations are important ancillary tools for the diagnosis and classification of malignant lymphomas.

Chromosome Breakage↗
PubMed2002

Clonal heterogeneity in mycosis fungoides and its relationship to clinical course.

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma characterized by multifocal disease and protracted clinical course. The few studies that have assessed T-cell receptor (TCR) gene rearrangements (GRs) present at different anatomic sites in MF have generally reported a common clone. We used a previously validated 4-color polymerase chain reaction (PCR) assay to assess the size and V-family usage of TCR-gamma GRs in 102 concurrent and/or sequential morphologically involved biopsy specimens (91 skin and 11 lymph nodes) from 39 MF patients. This assay detected TCR-gamma clonal GRs in 89 samples (87%) from 36 patients (92%). In 24 patients (77%), an identical clonal GR was present in at least 2 skin samples. However, in one third of these patients, additional different clonal GRs were also noted. Four patients (13%) had clonal GRs that were distinct in different skin samples. In 3 patients (10%), no GR was detected in any sample. In a comparison of lymph node and skin samples, 8 patients had the identical clonal GRs at both sites, 2 patients had different clonal GRs, and 1 patient had no GR identified at either site. Independent of clinical stage, patients who had the same GR detected in multiple concurrent biopsy specimens at the time of diagnosis were more likely to have progressive disease than those who had different GRs (P =.04). Four-color TCR-gamma PCR analysis can uncover multiple distinct clonal GRs in different samples consistent with multiclonal or oligoclonal disease in a significant proportion of MF patients. Demonstration of identical clonal GRs in multiple biopsy specimens at the time of diagnosis may provide prognostic information related to disease progression.

Adolescent↗
PubMed2002

Quantification of bcl-2/JH fusion sequences and a control gene by multiplex real-time PCR coupled with automated amplicon sizing by capillary electrophoresis.

Follicular lymphoma is characterized by the presence of the t(14;18)(q32;q21) chromosomal translocation which juxtaposes the bcl-2 gene at 18q21 with the immunoglobulin heavy chain locus at 14q32. Quantification of t(14;18) carrying cells in FL patients can be achieved by real-time PCR, a highly sensitive technique for evaluating treatment efficacy and minimal residual disease. Despite the many advantages of real-time technology for this purpose, one disadvantage is that current real-time t(14;18) PCR assays amplify a control gene as a normalizer in a separate reaction. Since each PCR reaction has its own kinetics, separate PCR assays for target and control sequences can potentially result in inaccurate quantification of t(14;18)-positive cells. In addition, the real-time t(14;18) PCR assays do not determine the size of the amplified fusion sequence, which is helpful for excluding contamination and is commonly used to demonstrate clonal identity between pre- and post-treatment specimens from a patient. To address these limitations, we designed a multiplex real-time PCR protocol that allows amplification of control and target genes in the same reaction and precise size determination of bcl-2/JH fusion sequences by capillary electrophoresis. This multiplex PCR assay is equally sensitive to previous assays, allows more accurate quantification of bcl-2/JH fusion sequences, and is more convenient.

Chromosomes, Human, Pair 14↗
PubMed2002

Real-Time t(14;18)(q32;q21) PCR assay combined with high-resolution capillary electrophoresis: a novel and rapid approach that allows accurate quantitation and size determination of bcl-2/JH fusion sequences.

Follicular lymphoma is characterized by the presence of the t(14;18)(q32;q21) chromosomal translocation that juxtaposes the bcl-2 gene at 18q21 with the immunoglobulin heavy chain (IgH) locus at 14q32. We have previously shown that accurate quantitation of t(14;18)-carrying cells in follicular lymphoma patients can be achieved by non-gel-based real-time TaqMan polymerase chain reaction (PCR; Applied Biosystems, Foster City, CA). Since our report, several studies have demonstrated that real-time PCR is highly sensitive and a reliable tool for evaluating treatment effectiveness and for following minimal residual disease in follicular lymphoma patients. Unfortunately, currently available real-time PCR methods do not determine the size of the amplification product, which is useful for excluding contamination and is commonly used as presumptive evidence of clonal identity or disparity when multiple samples from the same patient are analyzed. We describe a modified real-time PCR assay that rapidly allows accurate quantitation and precise determination of the size of the t(14;18) fusion sequence without the need for gel electrophoresis. In this assay, a consensus immunoglobulin heavy chain-joining region gene (JH) primer labeled at its 5' end with the fluorescent dye NED (Applied Biosystems) is included in the real-time PCR assay and thus is incorporated into the bcl-2/JH fusion product. The JH-NED primer did not interfere with the TaqMan probe fluorescent signal or target detection and allowed subsequent amplicon size determination by semiautomated high-resolution capillary electrophoresis.

Chromosomes, Human, Pair 14↗
PubMed2002

The stromal composition of malignant lymphoid aggregates in bone marrow: variations in architecture and phenotype in different B-cell tumours.

We present evidence that different B-cell tumours, in bone marrow, have different relationships to stroma. Marrow core biopsies from 46 patients with B-cell tumours were immunostained with antibodies for distinct stromal cells. Cases included follicular lymphoma (FL), chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL), and nodal, extranodal and splenic marginal zone lymphoma (NMZL, MALT, SMZL). In normal marrow, low-affinity nerve growth factor receptor (LNGFR) highlighted a fine network of adventitial reticular cells (ARC). The nodular aggregates of CLL/SLL, NMZL, MALT and SMZL were characterized by distortion of the ARC network and downregulation of LNGFR. In contrast, the aggregates of FL, LPL and MCL were composed of linear arrays of ARC in tight association with individual tumour cells. LNFGR+ was upregulated in ARC associated with the aggregates in FL, LPL and focally in MCL. Upregulation of CD35, vascular cell adhesion molecule (VCAM-1) and CD40 on ARC was noted exclusively in FL. Marrow lymphoid aggregates in CLL/SLL, NMZL, MALT and SMZL probably grow by displacing the pre-existing marrow stroma, while FL and LPL maintain a close association with the ARC network. In FL, expression of follicular dendritic cell-associated markers is modulated in pre-existing marrow stromal cells.

Bone Marrow↗
PubMed2002

Chromosomal translocations and their role in the pathogenesis of non-Hodgkin's lymphomas.

The discovery that non-Hodgkin's lymphomas are monoclonal and that recurrent chromosomal translocations are involved in their pathogenesis has greatly revolutionised their diagnosis and improved our understanding of these diseases. In the last decades, many genes deregulated by such recurrent chromosomal translocations have been identified. However, we have also learned that these genetic alterations are apparently insufficient, in themselves, to cause neoplastic cell transformation and that more complex genetic events must be involved. This review examines the involved genes in chromosomal translocations and current evidence and postulated mechanisms for their role in the pathogenesis of non-Hodgkin's lymphomas.

Gene Expression↗
PubMed2002

CD4-CD8-"Double-negative" cutaneous T-cell lymphomas share common histologic features and an aggressive clinical course.

We report 15 patients with CD4-CD8-"double-negative" T-cell lymphoma arising in skin. There were seven women and eight men with a mean age at diagnosis of 53 years (range 19-77 years). All but two patients presented with solitary or multiple cutaneous nodule(s). Initial and recurrent biopsy specimens showed a dense infiltrate centered in the mid-dermis (extending into subcutis when sampled) of small to intermediate-sized lymphocytes with indistinct nucleoli and frequently irregular nuclear contours. Periadnexal infiltration and epidermal ulceration were present in five cases with the intraepidermal cells being primarily reactive CD4+ T cells. All cases were negative for CD30 and terminal deoxynucleotidyltransferase; one showed expression of CD56, and six of eight tested cases were positive for T-cell receptor-delta expression. Despite systemic chemotherapy, all 12 patients with clinical follow-up showed recurrent or progressive disease with widespread cutaneous dissemination in 10 of 12. Eventual dissemination to lymph nodes or bone marrow occurred in two patients each, with at least nine patients dead of disease or treatment complications. Only two patients achieved lasting clinical remission (with 2'-deoxycoformycin/pentostatin and nelarabine, respectively). CD4-CD8-"double-negative" CTCL has distinctive histologic features and cytomorphology with a marked propensity for rapid multifocal cutaneous dissemination.

Adult↗
PubMed2002

Epstein-Barr virus-positive B-cell lymphoproliferative disorders arising in immunodeficient patients previously treated with fludarabine for low-grade B-cell neoplasms.

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.

Antineoplastic Agents↗