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Background

Lymphoproliferative disorders causing paraproteinemia can be associated with various kidney injuries including the deposition of monoclonal immunoglobulins (Ig). A known glomerular manifestation of Waldenström’s macroglobulinemia is characterized by prominent intracapillary hyaline thrombi and lack of conspicuous glomerular proliferation. The present case was special in 2 aspects: 1. the diagnosis of glomerulonephritis was unexpected before renal biopsy, 2. the prominent glomerular proliferation paired with large intracapillary hyaline thrombi is uncommon in Waldenström’s macroglobulinemia-associated glomerulonephritis.

Case presentation

A 73-year-old Caucasian woman with a long-standing history of rheumatoid arthritis and Waldenström’s macroglobulinemia was admitted for acute renal failure (ARF), which initially was presumed to be the consequence of extrarenal causes. Proteinuria and hematuria were only mild. In renal core biopsy, a membranoproliferative glomerulonephritis (MPGN) and prominent intracapillary hyaline monoclonal IgM thrombi were found in addition to acute tubular necrosis. Of note, the patient’s history was positive for purpuric skin changes, suspicious for cryoglobulinemia. However, serological tests for cryoglobulins were repeatedly negative. The ARF resolved before the start of immunomodulatory therapy for Waldenström’s macroglobulinemia.

Conclusion

The presence of MPGN with prominent hyaline thrombi in the context of Waldenström’s macroglobulinemia is uncommon and can be oligosymptomatic. We discuss this case in the context of previous literature and classifications suggested for monoclonal Ig-related renal pathologies.

The 4th edition of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues introduces many new items to the classification scheme of the so-called indolent B cell lymphomas. New proposed entities, such as splenic B cell lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, pediatric follicular lymphoma, and pediatric marginal zone lymphoma have been coined, and some definitions of established diseases, such as chronic lymphocytic leukemia or Waldenström’s macroglobulinemia have been revised. One aspect of major importance is the recent description of small clonal B cell populations, in part with a CLL phenotype, and their relationship to B-CLL. Some new subtypes or variants of follicular lymphoma with distinct clinicopathologic and/or molecular genetic characteristics have been described, including primary follicular lymphomas of the duodenum and pediatric follicular lymphomas. Furthermore, the impact of some probably early, or precursor lesions, such as follicular lymphoma in situ is discussed. Overall, we succinctly discuss the essential elements of the revisions made in the updated classification, and we identify potential opportunities for refinement of new or provisional categories in subsequent classifications.

The 4th edition of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues introduces many new items to the classification scheme of the so-called indolent B cell lymphomas. New proposed entities, such as splenic B cell lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, pediatric follicular lymphoma, and pediatric marginal zone lymphoma have been coined, and some definitions of established diseases, such as chronic lymphocytic leukemia or Waldenström’s macroglobulinemia have been revised. One aspect of major importance is the recent description of small clonal B cell populations, in part with a CLL phenotype, and their relationship to B-CLL. Some new subtypes or variants of follicular lymphoma with distinct clinicopathologic and/or molecular genetic characteristics have been described, including primary follicular lymphomas of the duodenum and pediatric follicular lymphomas. Furthermore, the impact of some probably early, or precursor lesions, such as follicular lymphoma in situ is discussed. Overall, we succinctly discuss the essential elements of the revisions made in the updated classification, and we identify potential opportunities for refinement of new or provisional categories in subsequent classifications.

Twelve cases of T gamma LPD (lymphoproliferative disorders of Fc gamma receptor-bearing T cells) involving an expansion of large granular lymphocyte/natural killer (LGL/NK) cells were investigated for the expression of LGL/NK-associated markers and for T beta gene rearrangement. All the cases selected were classified as T gamma LPD on the basis of morphology, function, and phenotype of the circulating cells. 10 to 12 cases displayed clonal rearrangements of the T beta locus and expression of the T3 antigen, whereas the 2 remaining cases displayed the germline configuration of the T beta gene and no expression of the T3 antigen. T8, Mol, B73.1, and N901 antigens were variably expressed among both T beta+T3+ and T beta-T3- T gamma LPD cases. We suggest that individual T gamma LPD cases represent the clonal expansion of cells frozen at different stages of differentiation/activation within an individual hematopoietic LGL/NK lineage.

Background: Recently novel Epstein–Barr virus (EBV) lymphoproliferative diseases (LPDs) have been identified in non-immunocompromised hosts, both in Asia and Western countries. These include aggressive T-cell and NK-cell LPDs often subsumed under the heading of chronic active Epstein–Barr virus (CAEBV) infection and EBV-driven B-cell LPDs mainly affecting the elderly.

Design: To better define the pathogenesis, classification, and treatment of these disorders, participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting.

Results: The term systemic EBV-positive T-cell LPD, as adopted by the WHO classification, is preferred as a pathological classification over CAEBV (the favored clinical term) for those cases that are clonal. The disease has an aggressive clinical course, but may arise in the background of CAEBV. Hydroa vacciniforme (HV) and HV-like lymphoma represent a spectrum of clonal EBV-positive T-cell LPDs, which have a more protracted clinical course; spontaneous regression may occur in adult life. Severe mosquito bite allergy is a related syndrome usually of NK cell origin. Immune senescence in the elderly is associated with both reactive and neoplastic EBV-driven LPDs, including EBV-positive diffuse large B-cell lymphomas.

Conclusion: The participants proposed an international consortium to facilitate further clinical and biological studies of novel EBV-driven LPDs.

Nasal NK/T-cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein–Barr virus (EBV). The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. To understand the pathogenesis of EBV-associated NK/T-cell lymphoproliferative disorders (LPD) and design new therapies, we employed a novel EBV DNA microarray to compare patterns of EBV expression in six cell lines established from EBV-associated NK/T-cell LPD. We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was expressed in SNK/T cells and the expression levels were preferentially high in cell lines from CAEBV infection. We also analyzsd the gene expression patterns of host cellular genes using a human oligonucleotide DNA microarray. We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression, which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD.

Opinion statement

Waldenström macroglobulinemia (WM) is a low-grade lymphoproliferative disorder characterized by the presence of an immunoglobulin M monoclonal protein in the blood and monoclonal small lymphocytes and lymphoplasmacytoid cells in the marrow. The disease is uncommon and there is a lack of clear diagnostic criteria. WM is treatable but not curable and long-term survival is possible. Therefore, the treating physician needs to carefully balance the risks and benefits of treatment. Treatments are aimed at relieving symptoms resulting from marrow infiltration and the hyperviscosity syndrome. Therapies available for initiation of treatment include alkylating agents, purine nucleoside analogs, and rituximab. Chlorambucil has been the mainstay of treatment for many years and remains useful, especially in older patients. Rituximab has become an important new therapy for this disease because of its positive treatment responses, acceptable toxicity, and lack of therapy-associated myelosuppression and myelodysplasia. Currently, rituximab is being combined with chemotherapy. Other options of treatment include interferon and corticosteroids. Emerging therapies include stem cell transplantation (autologous and allogeneic) for younger patients. Currently, there are few comparative data on which to state an absolute opinion concerning the best available treatment for patients with WM.

The most frequent ocular adnexal tumors and simulating lesions are lymphoproliferative disorders (LPDs), including malignant lymphomas and orbital inflammation with lymphoid hyperplasia or infiltration. IgG4-related orbital inflammation (IgG4-ROI) often involves lacrimal glands and other orbital tissues and is an important differential diagnosis. The present study evaluated clinical aspects of IgG4-ROI in a case series of orbital LPD. Sixty-two consecutive cases of orbital LPD, pathologically diagnosed from November, 2004, through March, 2011, were investigated. Histological types were 22 cases with MALT lymphoma, 11 cases with diffuse large B-cell lymphoma (DLBCL), 3 cases with other malignant lymphomas, 16 cases with IgG4-ROI, and 10 cases with non-IgG4-ROI. Ages of the IgG4-ROI group (56 ± 10 yrs) were significantly lower than the MALT lymphoma (71 ± 12 yrs) and DLBCL (75 ± 14 yrs) groups. Orbital lesions other than lacrimal glands were present in six cases including extraocular muscle swelling, mass lesions surrounding the optic nerve, and supraorbital and infraorbital nerves enlargements. Although none of the malignant lymphomas were related to IgG4, previous evidence suggested that malignant lymphomas can arise from IgG4-ROI. Based on this study (26%) and another report (33%), it is likely that nearly a quarter of orbital LPD are IgG4-ROI.

Chlamydia pneumoniae, Chlamydia trachomatis and Chlamydia psittaci were detected at low frequencies (<20%) among 69 pulmonary mucosa-associated lymphoid tissue (MALT) lymphomas, 30 other lymphoproliferative disorders (LPD) and 44 non-LPD. The incidence of individual Chlamydiae was generally higher in MALT lymphoma than non-LPD, although not reaching statistical significance. Mycoplasma pneumoniae DNA was not detected.

Patients with primary immunodeficiencies such as the Wiskott-Aldrich syndrome (WAS) are prone to develop Epstein-Barr virus (EBV) related lymphoproliferative disorders (LPDs). EBV LPD is most frequently seen in patients receiving immunosuppressive treatment after organ transplantation (post-transplant lymphoproliferative disorder), but can also arise in the primary immunodeficiencies. Typically, EBV LPD presents as a diffuse systemic disease with lymphadenopathy and organ involvement. A rare angiocentric and angiodestructive form of EBV associated B cell LPD, lymphomatoid granulomatosis (LyG), has also been reported in association with WAS. LyG most commonly involves the lung, but can also be seen in brain, kidney, liver, and skin. This report describes the case of a 16 year old boy with WAS who presented with an isolated non-healing ulcerating skin lesion. Biopsy revealed an EBV related LPD with the histological features of LyG. This cutaneous lesion responded dramatically to treatment with specific anti-CD20 immunotherapy and the patient remains clinically free of LPD at 18 months.

Fulminant Epstein-Barr virus (EBV)-driven clonal T-cell lymphoproliferative disorder (T-LPD) is rare and most patients are of Asian origin. The disease usually develops shortly after primary acute EBV infection and the mechanism remains poorly understood. Here we report such a rare case in a 28-year-old Caucasian female with systemic lupus erythematosus (SLE). Immunophenotypic and molecular studies revealed that the proliferating lymphoid cells displayed a CD8+ T-cell phenotype with clonal rearrangement of the T-cell receptor gamma gene. Epstein-Barr virus-encoded RNA was also observed in the clonal lymphoid cells by in situ hybridization. The patient subsequently developed fatal virus-associated hemophagocytic syndrome one month after the primary acute EBV infection. The case represents the first report of fulminant EBV-driven CD8+ T-LPD occurring in an immunocompromised Caucasian SLE patient. This study, along with studies of similar Asian cases reported in the literature, suggests that dysregulated immunity due to either acquired or genetically determined susceptibility may result in an abnormal response to primary EBV infection and contribute to the pathogenesis of EBV-mediated fatal T-LPD.

While B-Chronic Lymphocytic Leukemia (CLL) is known to be a heterogeneous disease, it is only recently that the familial component of CLL has been more thoroughly investigated. This entity is seen in approximately 5–10% of all CLL patients and can be associated with earlier age of diagnosis, more female prevalence, and increased incidence of other lymphoproliferative disorders (LPD), such as non-Hodgkin Lymphoma and the more recently described monoclonal B cell lymphocytosis CLL in family members. The prognostic parameters and clinical course of familial CLL is not clearly distinguishable from that of sporadic disease. In addition, it is not clear that the treatment responses for progressive disease has any discernible difference in familial vs. sporadic CLL. The genetic etiology of CLL is unknown and early work on familial CLL has not yet uncovered any obvious gene or group of genes that can be clearly related to the pathophysiology of CLL. However, the detailed genetic study of familial CLL is likely to be critical in uncovering relevant genes. At present it is best to indicate to concerned CLL patients that their relatives are at relatively low risk of developing CLL or other LPD.

Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies.

Waldenström’s macroglobulinemia (WM) is a distinct clinico-biological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow (BM) and immunoglobulin M paraprotein production. Cytogenetic analyses were historically limited by the difficulty in obtaining tumor metaphases and the genetic basis of the disease remains poorly defined. Here we performed a comprehensive analysis in 42 WM patients by using high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of patients have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%) and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in TRAF3 and TNFAIP3, two negative regulators of the NF-kB signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kB target genes. Mutational activation of the NF-kB pathway, which is normally activated by ligand-receptor interactions within the BM microenvironment, highlights its biologic importance, and suggests a therapeutic role for inhibitors of NF-kB pathway activation in the treatment of Waldenström’s macroglobulinemia.

Activator protein-1 (AP-1) is a dimeric transcription factor composed of the Jun, Fos and Atf families of proteins. Batf is expressed in the immune system and participates in AP-1 dimers that modulate gene expression in response to a variety of stimuli. Transgenic (Tg) mice overexpressing human BATF in T cells were generated using the human CD2 promoter (CD2-HA (hemagglutinin antigen) - BATF). By 1 year of age, over 90% of the mice developed a lymphoproliferative disorder (LPD). The enlarged lymph nodes characteristic of this LPD contain a polyclonal accumulation of T cells with a CD4+ bias, yet efforts to propagate these tumor cells in vitro demonstrate that they do not proliferate as well as wild-type CD4+ T cells. Instead, the accumulation of these cells is likely due to an apoptotic defect as CD2-HA-BATF Tg T cells challenged by trophic factor withdrawal in vitro resist apoptosis and display a pro-survival pattern of Bcl-2 family protein expression. As elevated levels of Batf expression are a feature of lymphoid tumors in both humans and mice, these observations support the use of CD2-HA-BATF mice as a model for investigating the molecular details of apoptotic dysregulation in LPD.

Coombs' negative autoimmune hemolytic anemia (AIHA) is a rare disease which shares similar clinical and hematological features with Coombs' positive AIHA, but its exact frequency remains unknown. There have been few reports of idiopathic thrombocytopenic purpura (ITP) and Coombs' negative AIHA associated with other lymphoproliferative disorders (LPDs). Since there is a well known association between LPDs and autoimmune phenomena, it is important to investigate the possibility of an underlying malignancy. We report a case of ITP and Coombs' negative AIHA associated with diffuse large B-cell lymphoma.

Aims: To describe and revise a flow cytometric assay for evaluating cyclin D1 overexpression in B cell lymphoproliferative disorders (B-LPDs).

Methods: Cyclin D1 expression was evaluated in 11 healthy controls and 51 patients with B-LPD by flow cytometry using the 5D4 monoclonal antibody. In 25 cases, experiments were repeated up to four times with mononuclear cells (MNC) fixed in ethanol for 1–120 days to evaluate the consistency of cyclin D1 expression. Flow cytometry results were compared with fluorescence in situ hybridisation (FISH) for the t(11;14) translocation in 19 patients and with immunohistochemistry (IHC) using the DCS-6 monoclonal antibody in nine patients.

Results: A mean fluorescence intensity ratio (MFIR) of 4.8 was defined as the cut off point for positivity based on cyclin D1 expression in healthy controls (mean + 3 SD). Ten patients overexpressed cyclin D1 by flow cytometry. These included five of eight patients with mantle cell lymphoma, four of 19 with chronic lymphocytic leukaemia, and one with follicular lymphoma. MFIR in the repeat experiments differed less than 25% in 20 of 25 patients and in no cases did it cross the cut off point. There was a good correlation between cyclin D1 expression by flow cytometry and FISH for t(11;14) in 15 of 19 patients and six of nine had concordant results with flow cytometry, FISH, and IHC.

Conclusion: Cyclin D1 expression remains fairly stable once MNC are fixed in ethanol and the flow cytometric assay can be used for the routine screening of B-LPD. Further comparisons between flow cytometry, IHC, and FISH may be needed to ascertain the diagnostic value of the flow cytometric assay.

The objective of the study was to evaluate the feasibility of a UK-based real-time service to improve the diagnosis and management of lymphoproliferative disorders (LPDs) in Ghana. Adult patients reporting to hospital with a suspected LPD, during a 1 year period, were prospectively enrolled. Bone marrow and/or lymph node biopsies were posted to the Haematology Malignancy Diagnostic Service (HMDS), Leeds, UK and underwent morphological analysis and immunophenotyping. Results were returned by e-mail. The initial diagnoses made in Ghana were compared with the final HMDS diagnoses to assess the contribution of the HMDS diagnosis to management decisions. The study was conducted at the two teaching hospitals in Ghana—Komfo Anokye, Kumasi and Korle Bu, Accra. Participants comprised 150 adult patients (≥12 years old), 79 women, median age 46 years. Bone marrow and lymph node biopsy samples from all adults presenting with features suggestive of a LPD, at the two teaching hospitals in Ghana, over 1 year were posted to a UK LPD diagnostic centre, where immunophenotyping was performed by immunohistochemistry. Molecular analysis was performed where indicated. Diagnostic classifications were made according to international criteria. Final diagnosis was compared to the initial Ghanaian diagnosis to evaluate discrepancies; implications for alterations in treatment decisions were evaluated. Median time between taking samples and receiving e-mail results in Ghana was 15 days. Concordance between initial and final diagnoses was 32% (48 of 150). The HMDS diagnosis would have changed management in 31% (46 of 150) of patients. It is feasible to provide a UK-based service for LPD diagnosis in Africa using postal services and e-mail. This study confirmed findings from wealthy countries that a specialised haematopathology service can improve LPD diagnosis. This model of Ghana–UK collaboration provides a platform on which to build local capacity to operate an international quality diagnostic service for LPDs.

The objective of the study was to evaluate the feasibility of a UK-based real-time service to improve the diagnosis and management of lymphoproliferative disorders (LPDs) in Ghana. Adult patients reporting to hospital with a suspected LPD, during a 1 year period, were prospectively enrolled. Bone marrow and/or lymph node biopsies were posted to the Haematology Malignancy Diagnostic Service (HMDS), Leeds, UK and underwent morphological analysis and immunophenotyping. Results were returned by e-mail. The initial diagnoses made in Ghana were compared with the final HMDS diagnoses to assess the contribution of the HMDS diagnosis to management decisions. The study was conducted at the two teaching hospitals in Ghana—Komfo Anokye, Kumasi and Korle Bu, Accra. Participants comprised 150 adult patients (≥12 years old), 79 women, median age 46 years. Bone marrow and lymph node biopsy samples from all adults presenting with features suggestive of a LPD, at the two teaching hospitals in Ghana, over 1 year were posted to a UK LPD diagnostic centre, where immunophenotyping was performed by immunohistochemistry. Molecular analysis was performed where indicated. Diagnostic classifications were made according to international criteria. Final diagnosis was compared to the initial Ghanaian diagnosis to evaluate discrepancies; implications for alterations in treatment decisions were evaluated. Median time between taking samples and receiving e-mail results in Ghana was 15 days. Concordance between initial and final diagnoses was 32% (48 of 150). The HMDS diagnosis would have changed management in 31% (46 of 150) of patients. It is feasible to provide a UK-based service for LPD diagnosis in Africa using postal services and e-mail. This study confirmed findings from wealthy countries that a specialised haematopathology service can improve LPD diagnosis. This model of Ghana–UK collaboration provides a platform on which to build local capacity to operate an international quality diagnostic service for LPDs.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (EBV-LPD) following bone marrow transplantation can be fatal. The major risk factors for the development of EBV-LPD are ex vivo T-cell depletion or in vivo T-cell depletion with either antithymocyte globulin (ATG) or monoclonal anti-T-cell antibodies. Between March 1999 and January 2001, a total of 23 transplants with ATG of equine source (20 transplants) and ATG of rabbit source (3 transplants) used as part of the preparatory regimen were performed at the Barbara Ann Karmanos Cancer Institute in Detroit, Mich. The three patients who received rabbit ATG developed EBV-LPD between 60 and 90 days following bone marrow transplantation. However, there were no cases of EBV-LPD in the equine group. Treatment given in these cases consisted of tapering immunosuppression, antiviral therapy, unprocessed donor lymphocyte infusion, mobilized peripheral blood progenitor cell rescue infusion (one patient), and chemotherapy (one patient). All three patients died of complications from EBV-LPD. The association of rabbit ATG with the development of EBV-LPD suggests that patients receiving rabbit ATG as part of their preparatory regimens require close monitoring of the EBV viral load and possible early intervention with antiviral therapy.

Patients affected by autoimmune diseases (rheumatoid arthritis, psoriasis, dermatomyositis) who are treated with methotrexate (MTX) sometimes develop lymphoproliferative disorders (LPDs). In approximately 40% of reported cases, the affected sites have been extranodal, and have included the gastrointestinal tract, skin, lung, kidney, and soft tissues. However, MTX-associated LPD (MTX-LPD) is extremely rare in the oral cavity. Here we report a 69-year-old Japanese woman with rheumatoid arthritis (RA) who developed MTX-LPD resembling Hodgkin’s disease—so-called “Hodgkin-like lesion”—in the left upper jaw. Histopathologically, large atypical lymphoid cells including Hodgkin or Reed-Sternberg-like cells were found to have infiltrated into granulation tissue in the ulcerative oral mucosa. Immunohistochemistry showed that the large atypical cells were positive for CD20, CD30 and Epstein-Barr virus (EBV)-latent infection membrane protein-1 (LMP-1) and negative for CD15. EBV was detected by in situ hybridization (ISH) with EBV-encoded small RNA (EBER), and polymerase chain reaction (PCR) for LMP-1 and EBNA-2 in material taken from the formalin-fixed, paraffin-embedded specimen. To our knowledge, this is the first reported case of MTX-related EBV-associated LPD (MTX-EBVLPD), “Hodgkin-like lesion”, of the oral cavity in a patient with RA.

We present a case of distal renal tubular acidosis and acute renal insufficiency in a patient with Waldenström’s macroglobulinemia. Distal renal tubular acidosis has been described in hypergammaglobulinemia, but not in patients with Waldenström’s macroglobulinemia. To our knowledge, this is the first report to describe a possible association between distal renal tubular acidosis and Waldenström’s macroglobulinemia. Our case also emphasizes the importance of prompt recognition of distal renal tubular acidosis in patients with Waldenström’s macroglobulinemia because of its metabolic disturbances and potentially life threatening complications.

Recently, we isolated from the blood of lymphoproliferative disease (LPD)-affected turkeys a type C retrovirus distinct from the avian leukosis-sarcoma virus complex and the reticuloendotheliosis virus group. We present molecular evidence for the implication of this virus in the LPD of turkeys. Using complementary DNA of LPD viral RNA, we found that the LPD viral genome is specifically and efficiently transcribed (2,500 copies per cell) in LPD tumor cells. Moreover, the LPD tumor cells contained newly inserted LPD viral information (5 to 10 copies per haploid genome), which was not present before the infection. From the absence of LPD virus-specific sequences in the normal cell genome of turkeys, it was concluded that the LPD virus is not an endogenous virus of turkeys. DNA-DNA annealing experiments revealed that the degree of sequence homology between LPD viral complementary DNA and cellular DNA of turkeys was not higher than that between LPD viral complementary DNA and cellular DNA of other species, thus indicating that the virus does not originate from turkeys.

Waldenström's macroglobulinemia (WM)/ lymphoplasmacytic lymphoma (LPL) is an indolent mature B-cell neoplasm. In rare cases of WM/LPL, diffuse large B-cell lymphoma (DLBCL) develops as a result of histologic transformation. In this report, we present a case of DLBCL developing in a patient with WM/LPL. Combination chemotherapy for DLBCL was effective and complete remission was eventually achieved. We attempted to determine the clonal relatedness between WM/LPL and DLBCL in the patient by analyzing complementarity-determining region 3 (CDR3) in the immunoglobulin heavy chain gene. A common CDR3 sequence was found in tumor cells of DLBCL and those of WM/LPL, indicating that tumor cells of DLBCL are clonally identical to those of WM/LPL. Therefore, in the present case, DLBCL is developed from WM/LPL cells by clonal evolution.

Lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) is a B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells. LPL/WM is a very rare disease, with an incidence rate of 3–4 cases per million people per year. Currently, the causes of LPL/WM are poorly understood; however, there are emerging data to support a role for immune-related factors in the pathogenesis of LPL/WM. In addition, data show that genetic factors are of importance in the etiology of LPL/WM. In this paper, we will review the current knowledge about familiality of LPL/WM and provide novel data on solid tumors and myeloid malignancies in first-degree relatives of LPL/WM patients.