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Clinical Practice Points • The Bing-Neel syndrome is a rare clinicopathological entity which refers to central nervous system localization by lymphoplasmacytic lymphoma. • The treatment of Bing-Neel syndrome remains non‐standardized and further data about patient long‐term outcome is needed. • This case-report supports the evidence of effectiveness and safety of MaTrix regimen as induction therapy in Bing-Neel syndrome patients.

Pulmonary amyloidosis, whether isolated or seen as part of systemic amyloidosis, has a variety of radiographic manifestations. Known parenchymal lung findings include reticulonodular opacities, diffuse interstitial infiltrates, or cystic lesions. Here, we present a case of systemic amyloid light-chain (AL) amyloidosis presenting with severe exertional dyspnea and emphysematous lung lesions on chest CT, a finding described only once before. Although factors that influence the pattern of pulmonary amyloid deposition remain unclear, CT image findings typically reflect the histopathologic patterns of deposition. In this case, we hypothesize that the emphysematous changes in the lower lung zones are likely a manifestation of severe alveolar-septal involvement. This case suggests that radiographic findings of pulmonary amyloidosis are not limited to the more common findings of reticular opacities or interstitial infiltrates. Emphysematous changes are possible, and clinicians should maintain a broad differential when seen in the setting of dyspnea.

Purpose To describe clinical findings, laboratory values, and treatment response of patients with monoclonal gammopathy of undetermined significance (MGUS) demonstrating neurosensory macular detachment. Design Retrospective case series. Participants Seven eyes of 4 patients (3 men and 1 woman; age range, 60–81 years) with neurosensory macular detachment, treatment-resistant submacular fluid, and vitelliform material. Methods We retrospectively reviewed the medical and ocular histories, ocular examination findings, retinal imaging, ocular disease course, and laboratory findings in 4 patients with submacular fluid associated with MGUS. Main Outcome Measures Description of the macular findings and treatment courses of 4 patients diagnosed with MGUS maculopathy. Results Seven eyes of 4 patients demonstrated neurosensory macular detachment with treatment-resistant submacular fluid and vitelliform material. No eyes demonstrated signs of significant hyperviscosity retinopathy. Fluorescein angiography showed no definite leakage in any involved eye. Laboratory evaluation revealed immunoglobulin G MGUS in all 4 patients. All 4 patients were resistant to treatments aimed at resolving the subretinal fluid, including some combination of anti–vascular endothelial growth factor injections, photodynamic therapy, topical dorzolamide, oral dosing of eplerenone or acetazolamide, or some combination thereof. In 3 patients, MGUS underwent malignant transformation 24 to 144 months after diagnosis, in 1 patient to lymphoplasmacytic lymphoma and in 2 patients to multiple myeloma. The fourth patient showed no evidence of malignancy 8 years after diagnosis. Conclusions Submacular fluid without fluorescein leakage and unresponsive to conventional treatment may suggest an underlying immunoproliferative disorder that we have termed monoclonal gammopathy of macular significance. Given the propensity for monoclonal gammopathy of macular significance to transform into malignant disease in our series, serum protein analysis should be considered in patients with neurosensory macular detachment not attributable to known causes.

Bing-Neel syndrome (BNS) is characterised by infiltration of the central nervous system by lymphoplasmacytic lymphoma (LPL) cells and is traditionally regarded as a complication of pre-existing systemic Waldenstrom’s macroglobulinaemia (WM). We describe the case of a 49 year old woman with leptomeningeal LPL who did not fulfil diagnostic criteria for concomitant systemic WM at presentation, and who failed to respond to conventional chemotherapy treatment (including high dose methotrexate) but did respond to the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib. This highlights an important variation in the typical natural history of this rare disease and also further supplements emerging evidence regarding efficacy of ibrutinib in its treatment.

Schnitzler syndrome (SS) is a rare autoinflammatory disease with unclear etiopathogenesis. The disease is associated with cytokine dysregulation involving interleukin (IL)-1β and the inflammasome pathway and manifests with major clinical criteria, namely IgM paraprotein and urticarial rash, and minor criteria, including fever, lymphadenopathy, musculoskeletal pain, and thrombosis.1 Anakinra is a recombinant version of human IL-1 receptor (IL-1R) antagonist and binds to IL-1R, inhibiting IL-1α and IL-1β signaling. SS typically responds dramatically to IL-1R blockade.2 No recurrent genetic alterations have been identified in SS to date. Interestingly, a case series examining 21 SS patients sequenced 32 autoinflammatory genes without identifying a single genetic alteration in the cohorts.3 SS carries a 15% to 20% risk of an associated lymphoproliferative disorder, similar to that of other conditions with IgM paraproteinemia, including lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), and systemic amyloidosis. The precise relationship amongst hematologic disorders is unknown. WM is an IgM-secreting LPL with clinical features including cytopenias and lymphadenopathy and paraprotein-related manifestations. MYD88 is a gene involved in nuclear factor κ light chain enhancer of activated B cells (NF-κB) signaling. Mutations in MYD88 (eg, L265P) are the molecular hallmark of WM and have been identified in more than 90% of WM cases.4 This mutation was not included in previous molecular panels investigating SS.3 Here we present the first case, to our knowledge, of SS with MYD88 L265P mutation and explore the proposed role of this alteration in the pathogenesis of SS. Consent was obtained in accordance with University of California San Diego Institutional Review Board guidelines.

Ureteral amyloidosis is a rare entity and of interest to urologists, hematologists, radiologists, and pathologists because it mimics urothelial cell carcinoma clinically, endoscopically and radiologically. A pre-operative ureteroscopy or surgical biopsy is required, and it is essential to exclude systemic amyloidosis. We report a male who was diagnosed with IIIA stage lymphoplasmacytic lymphoma associating systemic amyloidosis with concomitant hematuria. Urine cytology was negative and computerized tomography urography (CTU) scan evidenced bilateral, proximal and medium, ureteral stenosis and wall thickening. Diagnosis of suspected amyloidosis was confirmed with laparoscopic biopsy due to ureteral stenosis, being positive for Congo red stain. Patient underwent systemic chemotherapy.

Glutamine (Gln) is important not only for cell proliferation but also for differentiation. Although Gln is essential for plasmacytic differentiation of lymphocytes, no study has been done on the effect of Gln on differentiation of tumor cells, such as lymphoma. Here we examined the effect of Gln on plasmacytic differentiation of lymphoplasmacytic lymphoma (LPL) with its cell lines, MWCL-1 and RPCI-WM1. Gln promoted plasmacytic differentiation of LPL, and p38 MAPK signaling pathway mediated such differentiation. We previously reported that the subpopulation with plasmacytic differentiation was vulnerable to apoptosis in LPL. Although it is difficult to lead these findings to the radical therapy, they might help the treatment of LPL, in which stimulation of p38 MAPK by Gln induced differentiation of LPL into vulnerable subpopulation.

Objective To determine the incidence of Waldenstrom macroglobulinemia (WM) in a strictly defined geographic area over a 50-year period. Patients and Methods All residents of Olmsted County with a diagnosis of WM, consisting of a monoclonal IgM protein of any size and/or 10% or more lymphoplasmacytic infiltration of the bone marrow along with anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly requiring therapy, were identified from January 1, 1961, to December 31, 2010. Patients with smoldering WM, lymphoplasmacytic lymphoma with an IgG or IgA monoclonal protein, and those with an IgM monoclonal gammopathy of undetermined significance were excluded. The peripheral blood smears, bone marrow aspirates, and biopsy specimens were reviewed by an experienced hematopathologist. Results Twenty-two patients were identified as having WM. The age-adjusted incidence rate for males was 0.92 per 100,000 person-years (95% CI, 0.44-1.39 per 100,000 person-years) and for females was 0.30 per 100,000 person-years (95% CI, 0.08-0.53 per 100,000 person-years) with an age- and sex-adjusted incidence of 0.57 per 100,000 person-years (95% CI, 0.33-0.81 per 100,000 person-years). When evaluated using a smoothing spline, there was no convincing evidence for a change in the incidence of WM over the past 50 years. Patients diagnosed with WM after 2000 had an approximately 2-fold excess mortality compared with the expected population mortality (standardized mortality ratio, 2.4; 95% CI, 0.64-6.0). Conclusion Waldenstrom macroglobulinemia is a rare malignancy, and the incidence in Olmsted County, Minnesota, has shown virtually no change over the past 50 years.

Background Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is a heterogeneous disease whose role of immunoglobulin heavy chain variable gene (IGHV) usage remains unknown. Methods To determine the clinical relevance of IGHV repertoire in WM/LPL treated with standard immunochemotherapy, we performed the immunoglobulin gene rearrangements and complementarity determining region 3 (CDR3) analysis on 136 patients with WM/LPL. Results The IGHV gene repertoire was remarkably biased in WM/LPL. IGHV3-23, IGHV4-34, IGHV3-30, IGHV3-7 and IGHV3-74 accounted for half of the whole cohort. Most of the cases were mutated (97.0%) using a 98% IGHV germline homology cutoff. IGHV3-30 was associated with long heavy chain CDR3, indicating the specific antigen selection in WM/LPL. Patients with IGHV3-7 were significantly more likely to harbor 6q deletion (p Conclusion WM/LPL appears to be composed of different subgroups based on the IGHV repertoire. The mutational status and the IGHV CDR3 length indicated the role for antigen selection in WM/LPL development. The presence of IGHV4 genes proved to be a potential risk factor associated with outcome which deserved further study.

In about 4% of cases, amyloid light chain (AL) amyloidosis is due to an underlying lymphoplasmacytic lymphoma (LPL) or other monoclonal protein (M-protein) forming low-grade B-cell lymphoma, instead of a plasma cell neoplasm. We report an unusual case of a 55 year old male with co-localization of an IgG positive LPL and AL amyloidosis in his endomyocardial biopsy (EMB). The patient was diagnosed 4 years earlier with a low grade B-cell non Hodgkin lymphoma stage IV, at the time classified as marginal zone lymphoma. He received several lines of treatment for his lymphoma, which had shown progressive disease. Four years after initial diagnosis, he developed increasing dyspnea on exertion. Echocardiography demonstrated left and right ventricular hypertrophy with classical apical sparing, suspicious for cardiac amyloidosis. Bone marrow biopsy revealed massive infiltration by his low grade B-cell lymphoma, which was now reclassified as LPL based on the demonstration of a MYD88 L265P mutation. An EMB confirmed the presence of amyloid, which was typed as AL amyloidosis by the use of immunoelectron microscopy. In addition, mild B-cell infiltrates were present in the EMB, which were shown to be part of his LPL by the demonstration of the MYD88 L265P mutation using the highly sensitive droplet digital PCR (ddPCR) technique. This is a rare case of cardiac AL amyloidosis based on an IgG kappa positive LPL, in which not only the amyloid but also the lymphoma itself were present in the EMB. In addition, this case nicely illustrates the use of two highly sensitive techniques (immunoelectron microscopy and ddPCR), which both can be performed on small, formalin-fixed paraffin-embedded biopsies.

Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma defined by a monoclonal proliferation of bone marrow infiltrating immunoglobulin M producing B lymphocytes. Neurological simptoms of Waldenstrom macroglobulinemia are mainly dominated by signs of hyperviscosity and autoimmune neuropathies mediated by immunoglobulin M. Neurological involvement secondary to the infiltration of IgM producing B lymphocytes, is defined as a Bing-Neel syndrome. This syndrome has a low prevalence and the clinical manifestations are variable. The case described is about a 76 year-old female with a history of Waldenstrom macroglobulinemia, who presents sudden neurological signs such as alteration of spoken language and clumsiness of the right hand. The clinical laboratory has a primary role in the diagnosis of Bing-Neel syndrome and monitoring of the treatment.

Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and immunoglobulin M production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients that received adult alloHCT for WM/LPL. Data was obtained from the Center for International Blood and Marrow Transplant Research database (2001-2013). Patients received myeloablative (n=67) or reduced intensity conditioning (RIC; n=67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n=18) failed prior autologous hematopoietic cell transplantation. About half (n=82, 57%) had chemo-sensitive disease at the time of transplantation, while 22% had progressive disease. Progression free survival, overall survival, rate of relapse, and non-relapse mortality at 5-years were 46%, 52%, 24%, and 30% respectively. Patients with chemo-sensitive disease and better pre-transplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative 50% vs. RIC 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.

MYD88 L265P, a diagnostic marker for lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) can also be detected in other hematopoietic malignancies. We demonstrate a novel approach to increase the specificity of this marker for WM/LPL diagnosis by combining flow cytometric cell sorting with molecular analysis. Clonal B-lymphocyte and co-occurring clonal plasma cell populations of low-grade B-cell lymphomas were sorted by flow cytometry and analyzed for immunoglobulin gene rearrangements (PCR), and for MYD88 and CXCR4 mutations. Identical clonal origin was confirmed by PCR for 21 LPL/WM cases and MYD88 L265P was detected in both B-cell and plasma cell fractions. 9/20 other B-cell lymphomas with identical light chain restriction on B-cells and plasma cells were genotypically identical by PCR and MYD88 L265P was detected in both cell fractions in 7/9 whereas in 11/20 specimens with different clonal origin, MYD88 L265P was absent (5/11), or only found in B-lymphocytes (4/11), or plasma cells (2/11). CXCR4 mutations were detected in 17/39 cases, but missed in 63% of these without cell sorting. Confirming MYD88L265P in both B-cells and plasma cell fractions can provide a novel and powerful discriminator to distinguish LPL/WM from phenotypically similar disorders. Furthermore, this approach significantly increases CXCR4 detection sensitivity.

Purpose: We present the first reported case of Waldenstrom macroglobulinemia in the right superior rectus causing diplopia. Observations: A 72-year-old man with a 6-month history of untreated asymptomatic Waldenstrom macroglobulinemia presented with 2 years of diagonal binocular diplopia that was previously thought to be due to ocular myasthenia gravis. Examination showed mild right proptosis and right hypotropia, and MRI revealed a focal lesion of the right superior rectus muscle. Orbital biopsy was performed, and histopathology showed lymphoplasmacytic infiltration among the skeletal muscle fibers of the rectus muscle. Immunostaining confirmed a B-cell preponderance, along with more extensive staining for IgM than IgG, and in situ hybridization confirmed lambda restriction. These findings corresponded with those of his previous bone marrow biopsy, confirming Waldenstrom macroglobulinemia as the etiology for the extraocular muscle mass. Conclusions and Importance: Lymphoma of an extraocular muscle is a rare manifestation of orbital lymphoma, and the tumors are usually mucosa-associated lymphoid tissue (MALT) lymphomas (i.e. extranodal marginal zone lymphomas). There are 4 previous reports of lymphoplasmacytic lymphoma of an extraocular muscle; however this is the first reported case of such a lesion in a patient with concurrent Waldenstrom macroglobulinemia at the time of diagnosis. Keywords: Waldenstrom's macroglobulinemia, Lymphoma, Superior rectus, Diplopia

Waldenstrӧm Macroglobulinemia (WM) is a rare B-cell malignancy characterized by lymphoplasmacytic lymphoma (LPL) involvement of the bone marrow with an IgM monoclonal gammopathy. We present a case of Parkinson-like symptoms, in which diagnostic workup including imaging, biopsy, and lumbar puncture revealed both an LPL manifesting as a cervical spine mass and central nervous system involvement of LPL (termed Bing Neel syndrome) as the etiologies of the patient's presenting symptoms. Ibrutinib was administered, at a lower dose of 280 mg, due to the patient's history of arrhythmias, in combination with radiation to the cervical spine mass and steroids. Four weeks later, the patient's symptoms had completely resolved. This case highlights a rare presentation of LPL as well as the efficacy of ibrutinib.

Epigenomics refers to study of the epigenome, which represents changes in gene expression that are not induced by DNA sequence aberrations. For instance, DNA methylation, histone acetylation and microRNAs may modulate gene expression without altering the gene sequence. Waldenström's macroglobulinaemia (WM) is a low-grade B-cell lymphoma, classified as lymphoplasmacytic lymphoma, characterized by the presence of clonal lymphoplasmacytic cells in the bone marrow and serum monoclonal immunoglobulin-M in the circulation. It is a rare disease and, although indolent, it remains incurable with a median overall survival of 5-6 years. Most patients succumb to disease progression. WM cells present with aberrant histone hypoacetylation that may be explained, at least in part, via deregulated microRNAs, thus suggesting the use of histone deacetylase inhibitors or microRNA-based therapies in this disease.

Waldenstrom's macroglobulinaemia (WM) is an MYD88 L265P -mutated lymphoplasmacytic lymphoma that invades bone marrow and secretes monoclonal immunoglobulin M (IgM). WM cells are usually unable to undergo class switch recombination, and have mutated IGHV, with a typical immunophenotype CD19 + /CD22 low+ /CD23 – /CD25 + /CD27 + /CD45 + /CD38 low+ /SmIgM + (negative for CD5, CD10, CD11c, CD103). This immunophenotype matches memory B cells (smIgM –/+ /CD10 – /CD19 + /CD20 + /CD27 + /CD38 low+ /CD45 + ), representing 30% of B cells in the blood. Fifty percent of them have not undergone class switch recombination and are IgM + . These cells have suffered somatic hypermutation as WM cells. Genetic abnormalities do not abrogate the capacity to progress to plasma cells that usually belong to the clonal WM compartment, with a normal immunophenotype and functional characteristics. However, some WM cells are CD27 − , MYD88 WT , without somatic hypermutation, or with class switch recombination capable of reactivation. Thus, most data support a B-memory-cell origin for WM, but a small fraction of cases may have a different origin.

B-cell non-Hodgkin lymphomas with plasmacytic differentiation are a diverse group of entities with extremely variable morphologic features. Diagnostic challenges can arise in differentiating lymphoplasmacytic lymphoma from marginal zone lymphoma and other low-grade B-cell lymphomas. In addition, plasmablastic lymphomas can be difficult to distinguish from diffuse large B-cell lymphoma or other high-grade lymphomas. Judicious use of immunohistochemical studies and molecular testing can assist in appropriate classification.

Amyloidoma is a rare cause for intracranial space-occupying lesions diagnosed on brain imaging. Histology of excised tissue usually reveals the presence of a discrete, λ-light chain secreting plasmacytoma adjacent to an amyloid mass comprising aggregated monoclonal immunoglobulin light chains. We described a patient with intracerebral amyloidoma associated with a localised lymphoplasmacytic lymphoma and no systemic paraproteinaemia, tumour or amyloid deposits.

Purpose: To describe a case of Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma with infiltration of both lacrimal glands. Observations: A 63-year-old male with Waldenström's macroglobulinemia was referred to the ophthalmological clinic due to intermittent bilateral painless swollen eyelids. The patient had slight bilateral chemosis along with swelling of both eyelids. A mechanical ptosis was present on both sides. Funduscopic examination and tonometry were normal. Computed tomography and positron emission tomography showed an enlargement of both lacrimal glands with positive PET signal, and hence a biopsy was performed for histological and cytogenetic examination. Histopathological examination revealed an infiltrate of lymphoplasmacytic cells and small lymphocytes within the lacrimal gland. The tumor cells stained positive for IgM and CD20, CD79, BCL-2, and kappa light chain. A cytogenetic examination revealed a mutation in MYD88 confirming Morbus Waldenström/lymphoplasmacytic lymphoma. Conclusions and importance: Intermittent swollen lacrimal glands are a rather common symptom, and Morbus Waldenström/lymphoplasmacytic lymphoma should be considered as a differential diagnosis. This symptom should be carefully evaluated in Waldenström patients, as it can be a sign of disease progression in case of lacrimal gland involvement. Keywords: Lymphoplasmacytic lymphoma, Lymphoma, Waldenström macroglobulinaemia, Bilateral, Lacrimal gland

A 60-year-old man was admitted for ground glass opacity in the lower lung field and mediastinal lymphadenopathy. Blood tests revealed elevated serum IgM levels, and the urine test detected Bence-Jones protein. Surgical biopsy from the mediastinal lymph node and lung showed small lymphocytes and plasma cells between follicles, and AL kappa amyloid deposition. Genetic examination detected MYD88 L265P mutation. Our diagnosis was lymphoplasmacytic lymphoma (LPL), involving the mediastinum and the lung, followed by amyloidosis. Mutation analysis, in addition to conventional histological evaluation, was useful for a precise diagnosis.

Background Lymphoplasmacytic lymphoma (LPL) is associated with production of monoclonal paraproteins. Rarely, these paraproteins misfold, aggregate and form amyloid fibrils which deposit in organs and disrupt their structure and function. Several reports have described this association; however, transplant outcomes in patients with LPL and co-existing systemic amyloidosis are not well described. Methods We identified fifty patients with co-existing LPL and systemic amyloidosis diagnosed between 1997 and 2018 who were treated at the Memorial Sloan Kettering Cancer Center. Of these, eight patients underwent high dose therapy (HDT) followed by autologous hematopoietic cell transplant (AHCT) and are subjects of the current study. Results Among the eight patients, the median age was 60 years (range 55-70 years) with 37.5% females. Lymph nodes were the most commonly involved organ (N=6), followed by the heart (N=5), Kidneys (N=4), lungs (N=4) and peripheral nervous system (N=4). Median number of organs involved per patient was 4 (range 1-6). The monoclonal protein was IgM (N=5), IgG (N=2) and free lambda light chain (N=1); lambda light chain was involved in seven of eight patients. Median M spike was 0.43 gm/dL (range 0.2-1.3 gm/dL) and dFLC was 7.93 mg/dL (range 1.89-22.87 mg/dL). All patients had less than 10% plasma cell involvement of bone marrow. Induction regimens varied. Five patients received HDT/AHCT as part of initial therapy and three patients were transplanted at relapse (range 3-6 lines of prior therapy). CD34+ cells were mobilized using GCSF with Plerixafor (N=5), Rituximab, cyclophosphamide and GCSF (N=2) and cyclophosphamide alone (N=1). Median CD34+ cell yield was 8.74 × 106 cells/kg (range 4.5-12.2 × 106 cells/kg). High dose therapy was BCNU, etoposide, Ara-C and melphalan (BEAM) (N=2) and melphalan alone (N=6). Among patients conditioned with melphalan, 3 each received 140 mg/m2 and 200 mg/m2 based on risk adapted dosing. Median number of CD34+ cells infused was 5.325 × 106 cells/kg (range 3.2-5.9 × 106 cells/kg). Hematologic response following HDT/AHCT was very good partial response (VGPR) or better in five of the six patients with long term follow up. At median follow up of 64.5 months (range 3-116 months), all patients were alive at last contact. Only one patient relapsed more than 4 years post-transplant and has responded to salvage Daratumumab. Conclusion Amyloidosis can complicate lymphoplasmacytic lymphoma and pose a diagnostic and therapeutic challenge. Lymph node and lung involvement are common and may serve as distinguishing features. With over 5 years of follow up, all patients are alive with only a single patient who progressed. While numbers are small and patients were selected, these data indicate excellent long-term outcomes in patients with LPL-associated amyloidosis treated with risk adapted melphalan and suggest BEAM conditioning may not be essential.

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the proliferation of small B-lymphocytes in the bone marrow that produce monoclonal immunoglobulin M (IgM). We describe two patients with WM who presented with neurological symptoms due to infiltration of lymphoplasmacytoid tumor cells in the central nervous system, a condition known as Bing-Neel syndrome. A literature review revealed that this syndrome is rare and commonly missed in clinical practice due to its variable presentation and a lack of awareness or knowledge. Brain and spinal magnetic resonance imaging may show a focal mass or diffuse infiltration. The diagnosis of Bing-Neel syndrome requires proof of IgM or lymphoplasmacytoid cells in cerebrospinal fluid or in a brain biopsy. Treatment with intravenous and/or intrathecal chemotherapy and cranial radiotherapy is described in literature with generally poor outcome, although a combination of these therapies seems to improve outcome. Nevertheless, insufficient data are currently available to make general treatment recommendations.

The diagnosis of lymphoplasmacytic lymphoma is often challenging, especially in extramedullary tissues where the differential diagnosis includes nodal marginal zone lymphoma, splenic marginal zone lymphoma, or other small B-cell neoplasms with plasmacytic differentiation. The MYD88 L265P mutation has been recently identified in >90% of bone-marrow-based lymphoplasmacytic lymphoma, but the incidence of this abnormality and corresponding morphologic correlates in nodal lymphoplasmacytic lymphoma have not been established. We analyzed 87 cases of extramedullary lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, unclassifiable splenic B-cell lymphomas, nodal marginal zone lymphoma with plasmacytic differentiation, and chronic lymphocytic leukemia/small lymphocytic lymphoma with plasmacytic differentiation for MYD88 L265P. Eighteen cases (21%) were positive, including 9/9 (100%) lymphoplasmacytic lymphomas with classic histologic features, 5/12 (42%) cases that met 2008 WHO criteria for lymphoplasmacytic lymphoma but with atypical morphologic features, 3/15 (20%) cases initially considered nodal marginal zone lymphoma with plasmacytic differentiation, and 1/6 (17%) unclassifiable splenic B-cell lymphomas. The presence of MYD88 L265P was associated with IgM paraprotein (P

The diagnosis of bone marrow (BM) infiltration by Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) poses a diagnostic challenge in hematopathology. No definitive morphology or immunophenotype is able to distinguish between infiltration of paraffin-embedded BM sections by WM/LPL and other indolent lymphomas, in particular those of the splenic marginal zone (SMZL) which may also show plasmacytic maturation. An oncogenic gain-of-function mutation (L265P) in the human MYD88 gene has been found to be present in most cases of WM/LPL, yet is absent in most other cases of B-cell chronic lymphoproliferative disorders (LPD), including SMZL. Here, we compare two newly developed diagnostic protocols for detection of this mutation in paraffin-embedded archival tissues which are particularly applicable to decalcified BM biopsies. Sanger sequencing can easily detect levels of BM infiltration above 15% by WM lymphoplasmacytic cells, while the allele-specific PCR can detect the L265P mutation in BM infiltrations below 1% of lymphoma cells. We show that these methods are easily applicable to archival BM specimens and markedly improve diagnostic accuracy of BM infiltrations by indolent B-cell lymphomas.

The diagnosis of marginal zone lymphomas (MZL) is challenged by the lack of specific markers that distinguish them from other low-grade non-Hodgkin B-cell lymphomas. Myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein that labels myelomonocytic cells as well as B lymphocytes that localize to the marginal zone areas of splenic white pulp. We evaluated MNDA expression in a large series of B-cell lymphomas to assess the sensitivity and specificity of this antigen for the characterization of MZL. A total of 440 tissue sections containing extramedullary B-cell lymphomas and 216 bone marrow biopsies containing atypical or neoplastic lymphoid infiltrates were stained for MNDA by immunohistochemistry. Among the extramedullary lymphoma cases, approximately 67% of nodal MZL, 61% of extranodal MZL, and 24% of splenic MZL expressed MNDA. MNDA was also infrequently expressed in other B-cell neoplasms including mantle cell lymphoma (6%), chronic lymphocytic leukemia/small lymphocytic lymphoma (13%), follicular lymphoma (FL) (4%), lymphoplasmacytic lymphoma (25%), and diffuse large B-cell lymphoma (3%). In contrast, MNDA was only expressed in 2.3% of all bone marrow biopsies involved by lymphoid infiltrates, including 2 cases of FL and one case of MZL. Collectively, these data support the inclusion of MNDA in the diagnostic evaluation of extramedullary B-cell lymphomas, particularly those in which the differential diagnosis is between low-grade FL and MZL.

Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma.

Waldenström’s macroglobulinemia first described by Jan Waldenström in 1944 is a lymphoplasmacytic lymphoma characterized by the presence of an immunoglobulin M (IgM) monoclonal gammopathy in the blood and monoclonal small lymphocytes and lymphoplasmacytoid cells in the bone marrow. WM is a rare and indolent disease but remains incurable. In this review we discuss the pathogenesis of Waldenström macroglobulinemia and focus on novel treatment options that target pathways deregulated in this disease. Recent studies have helped us identify specific genetic mutations that are commonly seen in WM and may prove to be important therapeutic targets in the future. We discuss the role of epigenetics and the changes in the bone marrow microenvironment that are important in the pathogenesis of WM. The commonly used drugs are discussed with a focus on novel agents that are currently being used as single agents or in combinations to treat WM. We finally focus on some agents that have shown preclinical efficacy and may be available in the near future.

Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by widespread involvement of the bone marrow (BM). The BM microenvironment serves as not only a site for disease involvement, but it also appears that the interaction of WM cells with the BM is essential for the pathogenesis of WM. The BM microenvironment consists of the cellular and noncellular compartments. The BM has been shown to regulate cell proliferation, cell cycle, and drug resistance as well as cell dissemination and cell trafficking of WM cells. A better understanding of the role of the BM microenvironment in the pathogenesis of WM can help guide better therapeutic strategies that can target the tumor clone and also regulate the BM microenvironment.

Waldenstrom macroglobulinemia and plasma cell myeloma are both mature B-cell neoplasms primarily involving bone marrow and frequently demonstrating paraproteinemia. Plasma cell myeloma has been described in association with other indolent B-cell lymphomas, particularly chronic lymphocytic leukemia, but concomitant Waldenstrom macroglobulinemia and plasma cell myeloma has not been previously described. We report the first case of sequential development of Waldenstrom macroglobulinemia and plasma cell myeloma over a 10-year period in a 73-year-old man with untreated IgM paraproteinemia. The bone marrow biopsy demonstrated dual populations of lymphoid cells: small mature lymphocytes and immature plasma cells. Although both Waldenstrom macroglobulinemia and plasma cell myeloma were restricted to κ light chain, plasma cell myeloma expressed IgA, whereas the plasmacytic component in Waldenstrom macroglobulinemia produced IgM. The biclonal nature of these 2 B-cell neoplasms was further supported by immunofixation electrophoresis and cytogenetic studies. Although the clinical outcome of plasma cell myeloma when concomitant with other indolent B-cell neoplasms is unfavorable, our patient seemed to respond to high-dose bortezomib plus lenalidomide.

Many of the efforts toward developing vaccines against human malignancies have been frustrated by the lack of identification of a tumor-specific antigen that would allow tumor cells to be distinguished from normal cells. Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given patient's B-cell lymphoma are unique to that tumor, and can thus serve as a tumor-specific marker. When conjugated to the immune carrier keyhole limpet hemocyanin (KLH), vaccination with an idiotype protein vaccine has been able to improve length of freedom from disease relapse in patients with follicular lymphoma (FL) in a minimal residual disease (MRD) state after induction therapy, as demonstrated in a recent randomized, controlled phase III trial. In addition to predictive biomarker discovery, using residual autologous tumor and blood samples from patients vaccinated on the phase III trial, we have now developed a next generation idiotype DNA vaccine with the goal of reducing vaccine production time while maintaining efficacy. A first-in-human study is planned to evaluate its use in patients with asymptomatic phase lymphoplasmacytic lymphoma.

CD5 positivity in B-cell lymphoproliferative disorders (LPD) is usually considered characteristic of either chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL). However, other neoplastic B-LPDs may express CD5, albeit infrequently. In this study we have reviewed the tissue pathology of CD5+ B-LPDs that do not fulfill diagnostic criteria for CLL or MCL on flow cytometric studies of peripheral blood or bone marrow. Our results indicate that although CD5 positivity is most commonly associated with CLL and MCL, a significant minority of cases do not fall into these two categories. Phenotypically unusual CLL, marginal zone lymphoma and lymphoplasmacytic lymphoma were the most common diagnoses in this group of patients. Applying strict flow cytometry criteria, using genetic studies, and deferring to a lymph node/tissue diagnosis in non-classical cases are critical for accurate diagnosis and classification of CD5+ B-cell LPD.

Waldenström's macroglobulinemia is classified by the World Health Organization (WHO) as one of the mature B cell lymphomas. It is a rare clinical entity characterized by a serum monoclonal IgM with morphological evidence of lymphoplasmacytic lymphoma and a specific immunophenotype. Due to the scarcity of the disease, the most optimal therapeutic strategy has not yet been identified. There are, however, a number of active agents used in the treatment of this disease. In this paper we will examine the prognostication of the disease, with emphasis on the International Prognostic Scoring System for Waldenström's macroglobulinemia (IPSSWM), and outline current therapeutic options.

Fungal osteomyelitis of the hand is rare with limited evidence-based literature to guide diagnosis and management. We report a case of disseminated cryptococcal osteomyelitis in the middle phalanx from a pulmonary fungal infection in a patient with a history of lymphoplasmacytic lymphoma. Although rare, cryptococcosis should be considered in the differential diagnosis of aggressive lytic lesions with bone pain and associated large soft tissue masses, especially in the immunosuppressed host.

The 5th International Workshop on Waldenstrom’s Macroglobulinemia (IWWM5) was held on October 15-19, 2008, in Stockholm, Sweden. The meeting was co-organized by Drs. Eva Kimby (Sweden) and Steven Treon (United States), who served as Co-Chairs, and Christopher Patterson (United States) who served as Organizing Secretariat. During the four-day meeting, over 80 invited speakers and young investigator award recipients presented their latest findings on the genetic basis, pathogenesis, and treatment of Waldenstrom’s macroglobulinemia (WM). A summary of those efforts appears in this edition of Clinical Lymphoma & Myeloma, for which Dr. Marvin Stone (United States) served as Senior Guest Editor. At the opening ceremonies of IWWM5, Dr. Robert A. Kyle presented the Robert A. Kyle Award, in recognition of outstanding contributions to WM, to Dr. Veronique LeBlond (France). Some new important insights into the genetic basis of WM were made at IWWM5. Kyle et al1 and McMaster et al2 reported that monoclonal gammopathy of unknown significance (MGUS) of the IgM type is an important predisposition to symptomatic WM, with an estimated annual progression rate of 10.5% in the series presented by Kyle et al.1 While the familial nature of WM has been previously reported, with up to 20% of patients with WM having a first degree relative with WM or a closely related B-cell disorder,3 Kristinsson et al4 reported that, among first degree relatives of patients with lymphoplasmacytic lymphoma (LPL)/WM, there was a 20, 3, 3.4- and 5-fold increased risk of developing LPL/WM, nonHodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and MGUS, respectively. Hunter et al5 reported the interim findings

Waldenström macroglobulinemia (WM) is a lymphoma characterized by lymphoplasmacytic bone marrow infiltration and elevated immunoglobulin M levels. Effective treatment modalities exist for this disease but no cure. We review available treatment modalities, the findings of relevant and comparative recent clinical trials, and the latest therapeutic advances in the management of patients with WM. Alkylating agents, nucleoside analogues, monoclonal antibodies, and proteasome inhibitors have been studied as single therapeutic agents and as combination therapies. The encouraging results of combination regimens have resulted in their use as first-line and salvage treatments. Further clinical trials are required before a specific regimen can be recommended.

Background & Aims: Increasing evidence points towards a role of hepatitis C virus (HCV) infection in causing malignant lymphomas. We pooled case-control study data to provide robust estimates of the risk of non-Hodgkin's lymphoma (NHL) subtypes after HCV infection. Methods: The analysis included 7 member studies from the International Lymphoma Epidemiology Consortium (InterLymph) based in Europe, North America, and Australia. Adult cases of NHL (n = 4784) were diagnosed between 1988 and 2004 and controls (n = 6269) were matched by age, sex, and study center. All studies used third-generation enzyme-linked immunosorbent assays to test for antibodies against HCV in serum samples. Participants who were human immunodeficiency virus positive or were organ-transplant recipients were excluded. Results: HCV infection was detected in 172 NHL cases (3.60%) and in 169 (2.70%) controls (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40-2.25). In subtype-specific analyses, HCV prevalence was associated with marginal zone lymphoma (OR, 2.47; 95% CI, 1.44-4.23), diffuse large B-cell lymphoma (OR, 2.24; 95% CI, 1.68-2.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14-5.79). Notably, risk estimates were not increased for follicular lymphoma (OR, 1.02; 95% CI, 0.65-1.60). Conclusions: These results confirm the association between HCV infection and NHL and specific B-NHL subtypes (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma). © 2008 AGA Institute.

Inversion of chromosome 16, inv(16)(p13q22), juxtaposes the core binding factor beta (CBFB) and myosin heavy chain 11 (MYH11) genes, resulting in a myeloid leukemic disease phenotype characterized by increased bone marrow and peripheral blood blasts with myelomonocytic antigen expression and an accompanying eosinophilia. This cytogenetic abnormality has been reported in a variety of other neoplasms, in which it generally occurs as part of a complex karyotype, including rare B-lineage non-Hodgkin lymphomas. We report a case of clinically, morphologically, and immunologically typical lymphoplasmacytic lymphoma/Waldenström macroglobulinemia in which a majority of the malignant cells had an inv(16)(p13q22) as a sole abnormality. We review the literature and discuss the possible role of this genetic lesion in B-cell neoplasia.

To date, the presence of amyloidosis associated with immunoglobulin heavy chain (AH amyloidosis) was reported in only 7 cases. Although AH amyloidosis is caused mainly by plasma cell dyscrasia, as in AL amyloidosis, we report a 61-year-old patient who presented with nephrotic syndrome caused by AH amyloidosis associated with lymphoplasmacytic lymphoma. Biochemical and molecular analyses of the deposited amyloid fibrils and heavy-chain genes of lymphocytes showed that proliferative lymphoma cells produced a gamma heavy chain, not a mu heavy chain, which carried an unusual truncated diversity (D) segment of the variable region. Our results indicate that production of the abnormal heavy chain caused by the partially deleted D segment gene is responsible for gamma heavy-chain-related amyloid fibril formation in this patient.