Search

A 67-year-old woman presented with a 3-month history of patchy alopecia areata (AA)-like hair loss and multiple painful enlarged lymph nodes at cervical, nuchal, and left axillary site. The patient was on follow-up for IgM monoclonal gammopathy of undetermined significance, stable for many years. A punch biopsy from a patch of the temporal scalp revealed the presence of B-cell lymphoid infiltrates consistent with marginal zone B-cell lymphoma (MZL). Other staging examinations were conducted to make a definitive diagnosis of nodal MZL with secondary cutaneous involvement. The patient showed a complete remission of the alopecia, without evidence of scarring, after immunochemotherapy for lymphoma.

Background Waldenström macroglobulinemia (WM) is a subset of lymphoplasmacytic lymphoma (LPL) with bone marrow (BM) involvement and an IgM monoclonal gammopathy of any level. We aimed to identify the clinical, laboratory, and BM findings of patients with WM and to evaluate the usefulness of CD154 for the diagnosis and prognosis of WM. Methods We reviewed the medical records and BM studies and/or flow cytometric immunotyping of 31 patients with untreated WM. Semiquantitative immunohistochemistry (CD20, CD138, tryptase, and CD154) of BM was performed. Results Only six patients presented with symptoms of hyperviscosity syndrome. Eleven patients had solid cancer and/or another hematologic malignancy. Mast cells (MC) increased in all samples, with some in close contact with tumor cells. Tryptase-positive MC (17.1/ high-power fields [HPF], 1.2–72.0/HPF) and CD154-positive MC (8.6/HPF, 0.1–31.1/HPF) were observed. The high CD154-positive MC (≥8.6/HPF) group showed a lower overall five-year survival rate than the low CD154-positive MC (

The presence of lymphoid nodule in the bone marrow biopsy needs to be differentiated as to whether it is benign or malignant in nature. Several morphological criteria have been suggested to differentiate benign from neoplastic nodules. However, the distinction may not always be clear. Recently, it has been shown that when morphology is taken together with immunohistochemistry, differentiation of benign from neoplastic nodule can be suggested. Although, in present times, ancillary techniques of flow cytometry and molecular diagnostics are available, the importance of morphologic analysis along with immunohistochemistry cannot be undermined. We report a case of IgM monoclonal gammopathy of undetermined significance with reactive lymphoid nodules, differentiated using morphology and immunohistochemistry.

We report a case of membranous nephropathy with monoclonal immunoglobulin (Ig)M lambda deposits in a patient with IgM monoclonal gammopathy, in whom histological changes were observed on repeat renal biopsy. A 72-year-old Japanese woman was referred to our hospital because of massive proteinuria. A prominent increase in monoclonal IgM lambda level was identified, and she was diagnosed as having IgM monoclonal gammopathy of undetermined significance. Renal biopsy showed glomerular subepithelial electron-dense deposits that were found to be granular deposits of IgM lambda but not kappa or IgG by immunofluorescence staining, resulting in a diagnosis of membranous nephropathy with monoclonal IgM deposits. The second biopsy, which was performed 2 years later because of exacerbation of her nephrotic syndrome, demonstrated less immunofluorescence staining of IgM, and dominant IgG2 deposition without light chain restriction. Interestingly, immunostaining for thrombospondin-type-1-domain-containing-7A was positive in both renal biopsy tissues, although the second biopsy showed clearly stronger immunoreactivity. The effect of steroid therapy was limited; however, rituximab treatment improved both the hematological and renal abnormalities. Solitary deposition of IgM in membranous nephropathy is a quite rare condition. To our knowledge, this is the first case of monoclonal gammopathy of renal significance presenting as membranous nephropathy with monoclonal IgM deposits, in which chronological immunohistochemical changes were observed and rituximab therapy was effective.

Background and Aims Renal manifestations of IgM gammopathy are less common than those seen in patients with multiple myeloma. However, a wide spectrum of kidney diseases has been described in previous publications. We aim to characterize kidney involvement in patients with Waldenström Macroglobulinemia and IgM-secreting B cell lymphoproliferative disorders. Method We retrospectively studied 7 patients with a circulating monoclonal IgM and renal histology showing evidence of monoclonal immunoglobulin deposits or lymphomatous infiltration. Demographic, clinical and laboratory data were collected. Results Of the 7 patients studied, four (57%) were male and the median age was 68 years old (range 41-79). Among the 7 patients, 5 met criteria for Waldenström Macroglobulinemia after bone marrow biopsy; none of them had hyperviscosity syndrome. Four patients presented with nephrotic syndrome and all had impaired renal function and hypertension. Four patients had microscopic hematuria and only one patient showed no proteinuria. Mean serum creatinine levels were 2.9mg/dL. Renal biopsy showed different patterns of renal injury, including typical intracapillary monoclonal deposits disease (5 patients), membranoproliferative glomerulonephritis with cryoglobulinemia (1 patient), AL-amyloidosis (1 patient) and interstitial lymphoplasmacytic infiltration with CD20+ lymphocytes associated with minimal change disease. Follow-up data were obtained in 4 patients: 3 underwent chemotherapy but only one achieved complete remission and 2 progressed to end-stage renal disease. Conclusion Although rare, Waldenström Macroglobulinemia and IgM gammopathy are responsible for diverse manifestations of renal disease. A prompt diagnosis is of utmost importance in order to ensure early start of therapy, which should be directed at the underlying hematologic disorder, to improve renal survival.

To clarify the pathogenesis of anti-myelin-associated glycoprotein (MAG) antibody neuropathy associated with IgM monoclonal gammopathy (anti-MAG neuropathy), sural nerve biopsy specimens from 15 patients were investigated. Sodium channels, potassium channels, contactin-associated protein 1 (Caspr1), contactin 1, and neurofascin were evaluated by immunofluorescence in teased-fiber preparations. Immunoreactivity to the pan-sodium channel in both anti-MAG neuropathy patients and in normal controls was concentrated at the node of Ranvier unless there was demyelination, which was defined as the widening of the node of Ranvier. However, this immunoreactivity became weak or disappeared as demyelination progressed. In contrast, KCNQ2 immunostaining was nearly absent even in the absence of demyelination. The lengths of Caspr1, contactin 1, and pan-neurofascin immunostaining sites at the paranode were significantly increased compared with those of normal controls despite the absence of demyelination. The length of paranodal neurofascin staining correlated with the anti-MAG antibody titer, nerve conduction indices, the frequency of de/remyelination in teased-fiber preparations, and the frequency of widely spaced myelin (p < 0.05, p < 0.05, p < 0.01, and

Background: Fibrillary glomerulonephritis (FGN) is distinguished from amyloidosis by thicker fibrils and the lack of staining with histochemical dyes typically reactive with amyloid. However, congophilic FGN has been proposed recently and adding laser microdissection followed by mass spectrometry (LMD/MS) to conventional pathological methods would be helpful to diagnose FGN. Here, we report a patient initially diagnosed with FGN whose final pathological diagnosis was changed to immunoglobulin heavy-and-light-chain amyloidosis (AHL) after LMD/MS. Case presentation: A 75-year-old male developed nephrotic syndrome. Protein electrophoresis showed IgM κ type M proteinemia and he was diagnosed with IgM monoclonal gammopathy. A renal biopsy was performed and pathological examination showed marked periodic acid-Schiff-positive enlargement of the mesangial region and silver stain positivity, but weak direct fast scarlet staining. Immunofluorescence analysis showed monoclonal deposition of IgM-κ chain in the glomerulus. Under electron microscopy, the fibrils were about 20 nm in diameter, which was thicker than typical amyloid fibrils. Based on these findings, the patient was diagnosed with FGN. Although cyclophosphamide and prednisolone were administered, his renal function deteriorated and progressed to end stage renal disease requiring maintenance hemodialysis. As congophilic FGN has been recognized since 2018, Congo red staining and LMD/MS were performed. The Congo red staining was positive and LMD/MS results indicated that this was a case of AHL. Conclusions: We reported a case of μ and κ chain AHL resembling FGN requiring LMD/MS for definitive diagnosis. Since FGN and amyloidosis exhibit pathological findings, even if Congo red staining is positive, LMD/MS needs to be considered in cases atypical pathological findings, such as silver stain positivity or thicker fibrils., BMC Nephrology, 21(1), art.no.195; 2020

Purpose Multiple myeloma (MM) is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated postgerminal B cells. It is a heterogeneous disease both at the genetic level and in terms of clinical outcome. Immunoglobulin M (IgM) MM is a rare subtype of myeloma. Similar to Waldenström macroglobulinemia (WM), patients with MM experience IgM monoclonal gammopathy; however, both diseases are distinct in terms of treatment and clinical behavior. Materials and Methods To shed light on the presentation of IgM MM, its prognosis, and its gene expression profiling, we identified and characterized 21 patients with IgM MM from our database. Results One of these patients presented with a rare IgM monoclonal gammopathy of undetermined significance that progressed to smoldering myeloma. The median survival of the 21 patients was 4.9 years, which was comparable to a matched group of patients with non-IgM MM with similar myeloma prognostic factors (age, gender, albumin, creatinine, anemia, lactate dehydrogenase, β2-microglobulin, cytogenetics abnormalities), but much less than the median survival reported for patients with WM (9 years). We identified a cluster of genes that differ in their expression profile between MM and WM and found that the patients with IgM MM displayed a gene expression profile most similar to patients with non-IgM MM, confirming that IgM MM is a subtype of MM that should be differentiated from WM. Conclusion Because the prognosis of IgM MM and WM differ significantly, an accurate diagnosis is essential. Our gene expression model can assist with the differential diagnosis in controversial cases.

IgM secreting myelomas or lymphomas, including Waldenström macroglobulinemia, are associated with a varied spectrum of renal pathology, including intracapillary hyaline deposits, cryoglobulin, membranoproliferative glomerulonephritis, amyloid, monoclonal immunoglobulin deposition disease, cast nephropathy, and lymphoma infiltration. We report our single institution experience, and describe five cases with distinctive glomerular pathology: intracapillary IgM pseudothrombi and thrombotic microangiopathic change, with glomerular intracellular crystals in two biopsies. Two patients were hypocomplementemic at presentation. This series adds to the recent literature on paraprotein associated thrombotic microangiopathy.

Bilateral and simultaneous facial nerve palsy (FNP) is a rare clinical condition occurring in 0.3-2.0% of facial palsy cases and is typically a manifestation of an underlying systemic disease. We here describe a case of a 67-year-old Hispanic man with a known history of Waldenstrom's Macroglobulinemia (WM) who presented to the clinic with a sub-acute onset of bilateral facial weakness. No alternate etiology for the facial weakness was identified after a thorough diagnostic approach. WM is a rare hematological condition due to low-grade B cell lymphoma, where lymphoplasmacytoid cells infiltrate different tissues and secrete monoclonal IgM. Peripheral neuropathy develops in 15-30% of the cases, being usually a chronic, progressive, symmetric, predominantly distal polyneuropathy. Facial nerve impairment is unusual; however, it could be caused by anoxic damage as a result of an increased blood viscosity from IgM monoclonal gammopathy, direct nerve infiltration of tumorous cells and an antibody (anti-MAG) mediated demyelinating process. Treatment is directed to the established mechanism for neural injury. This report highlights a rare condition (WM) with a rare complication (bilateral facial nerve palsy) and illustrates the broad differential comprised by this presenting complaint.

Although both are characterized by the presence of an IgM monoclonal gammopathy, IgM multiple myeloma and Waldenstrom’s macroglobulinemia are two distinct hematologic entities. Differentiation of each however, may be challenging, but obviously critical to ensuring appropriate therapeutic decision-making and patient prognostication. Herein we report a case of a patient with Waldenstrom’s macroglobulinemia presenting with bone marrow morphology mimicking plasma cell myeloma, highlighting the importance of clinical correlation and ancillary studies to reach an appropriate diagnosis.

e20040 Background: Monoclonal gammopathy of undetermined significance (MGUS) can be associated with significant neurologic morbidity. Of non-IgM MGUS, types IgG and IgA are most commonly associated with peripheral neuropathy (PN). Methods: With IRB approval, we conducted a retrospective cohort study of consecutive patients with non-IgM type MGUS treated at our institution from 2014-2021. Other conditions potentially causing PN were excluded. Statistical analysis: Descriptive statistics were calculated to characterize the study population, and Relative Risk (RR) of PN was evaluated for selected patient, and disease, related factors. P < 0.05 was defined as statistically significant. Results: During the study period, 94 patients with non-IgM type MGUS were seen and comprised the study population. Twenty-two (23.4%) had evidence of PN. Median age was 74; 82% (18/22 ) were Caucasian; 73% (16/22) were women. 82% (18/22) patients had MGUS type IgG kappa or IgA kappa. We identified only 2 patients with each MGUS kappa light chain (LC) and MGUS IgG lambda. Median M-protein size was 0.11 g/dL, and median free LC value was 6.84 mg/L. Incidence/severity of kidney disease was similar in non-IgM MGUS patients with and without PN (p > 0.05). RR of PN was not found to be significantly different based on race or gender, although there appeared to be a tendency for women to be at higher risk compared to men (RR = 1.98, 95% CI = 0.85 to 4.60, p = 0.114.) Kappa LC restriction was strongly associated with PN (RR = 4.31, 95% CI = 1.58 to 11.78; p = 0.004). Electromyographic (EMG) studies identified 14 patients (64%) with distal symmetric axonal neuropathy (DSAN) and 8 patients (36%) with chronic inflammatory demyelinating polyneuropathy (CIDP). Clinically severe PN was identified in 11 (50%) patients; all were subsequently treated with IVIg therapy. Only 5/11 (45%) patients responded to IVIg, and the responses were only partial and transient. Conclusions: This is the first report, to our knowledge, of a significant association of kappa (as opposed to lambda) LC restriction with PN among patients with non-IgM type MGUS. Further investigation is warranted to explain this finding, elucidate pathophysiology and aid in developing more effective therapeutic options. Pending mechanistic characterization of this association, trials of contemporary agents used to treat other plasma cell disorders may be in order. Final statistical analysis, comparison to published series and significance will be presented.

We analyzed MYD88 and CXCR4 mutation status of 260 patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance using allele-specific real time quantitative polymerase chain reaction and Sanger sequencing, respectively. A subgroup of 119 patients was further studied with next-generation sequencing of 11 target genes (MYD88, CXCR4, ARID1A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, and TNFAIP3). MYD88 (L265P) was found at diagnosis in 91% of patients with Waldenström macroglobulinemia and in 60% of patients with IgM monoclonal gammopathy of undetermined significance using allele-specific polymerase chain reaction analysis. MYD88 mutations other than the classical L265P (V217F, S219C and M232T) were found in four cases by next-generation sequencing. Waldenström macroglobulinemia patients with wild-type MYD88 had a distinct clinical phenotype characterized by less bone marrow infiltration (P=0.01) and more frequent extramedullary involvement (P=0.001) compared to patients with mutated MYD88. Patients with wild-type MYD88 did not show additional mutations in the other target genes. CXCR4 mutations were found by Sanger sequencing in 22% of patients with Waldenström macroglobulinemia. With next-generation sequencing, a CXCR4 mutation was detected in 23% of patients with Waldenström macroglobulinemia and 9% of those with IgM monoclonal gammopathy of undetermined significance. Asymptomatic Waldenström macroglobulinemia patients harboring a CXCR4 mutation had a shorter treatment-free survival (51 months) than that of patients with wild-type CXCR4 (median not reached) (P=0.007). Analysis of variant allele frequencies indicated that CXCR4 mutations were present in the dominant clone in the majority of cases. Recurrent somatic mutations of KMT2D were found in 24% of patients with Waldenström macroglobulinemia and 5% of patients with IgM monoclonal gammopathy of undetermined significance and were primarily subclonal.

Objectives We retrospectively evaluated the clinical features, serum levels of IgM, and prevalence of IgM related diseases in patients with serum immunofixation electrophoresis (sIFE) confirmed IgM monoclonal gammopathy at our center. Methods We included patients with sIFE confirmed IgM monoclonal gammopathy between January 2008 and December 2014 in this retrospective study. We evaluated clinical data, sIFE, serum IgM levels, and diagnosis. Results In total, 7107 patients had sIFE confirmed monoclonal gammopathy, with 377 (5.3%) patients having the IgM type. The median age was 62 years (range, 19–105 years). The median level of serum IgM is 8.3 g/L (range, 0.24–150 g/L). The diagnosis included monoclonal gammopathy of undetermined significance (MGUS, 157 patients, 41.6%), Waldenstrom macroglobulinemia (WM, 105 patients, 27.9%), B cell non-Hodgkin’s lymphoma (69 patients, 18.3%), primary cold agglutinin disease (pCAD, 16 patients, 4.2%), primary amyloidosis (14 patients, 3.7%), cryoglobulinaemia (six patients, 1.6%), IgM MGUS associated neuropathy (five patients, 1.3%), multiple myeloma (three patients, 0.8%), and POEMS syndrome (two patients, 0.5%). Levels of serum IgM > 15.5 g/L were 80.6% sensitive and 89.2% specific for the diagnosis of WM. Kappa type light chain indicated the diagnosis of WM, pCAD, IgM MGUS associated neuropathy and cryoglobulinaemia, while lambda type light chain indicated POEMS and amyloidosis. There were 41/157 (26.1%) MGUS patients diagnosed with complications due to IgM-unrelated autoimmune diseases. Conclusion IgM monoclonal gammopathy contains a broad spectrum of diseases. Levels of serum IgM and the type of light chain can be used to help with differential diagnosis. The association between MGUS and some autoimmune diseases requires further investigation.

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.

Antibodies against myelin-associated glycoprotein (MAG) almost invariably appear in the context of an IgM monoclonal gammopathy associated neuropathy. Very few cases of anti-MAG neuropathy lacking IgM-monoclonal gammopathy have been reported. We investigated the presence of anti-MAG antibodies in 69 patients fulfilling diagnostic criteria for CIDP. Anti-MAG antibodies were tested by ELISA and confirmed by immunohistochemistry. We identified four (5.8%) anti-MAG positive patients without detectable IgM-monoclonal gammopathy. In two of them, IgM-monoclonal gammopathy was detected at 3 and 4-year follow-up coinciding with an increase in anti-MAG antibodies titers. In conclusion, anti-MAG antibody testing should be considered in chronic demyelinating neuropathies, even if IgM-monoclonal gammopathy is not detectable.

Background: Light-chain (AL) amyloidosis is a condition in which extracellular tissue deposition of protein derived from light chain immunoglobulin fragments can affect any organ in the body, and therefore has a variety of clinical manifestations, mimics variety of diseases and can easily be misdiagnosed. Case Presentation: This is a case of 79-year-old man with 9-year history of IgM monoclonal gammopathy of undetermined significance. Patient presented with right-sided effusion with pulmonary infiltrate. After antibiotic treatment the infiltrate resolved, but effusion progressed and appeared also on the left side. Extensive workup revealed generalized lymphadenopathy and no signs of any organ failure. Lymph node biopsy was analyzed applying Congo red, immunohistochemistry, immunofluorescence and electron microscope, and diagnosis of AL amyloidosis with monoclonal kappa chains was established. Conclusions: Since prognosis and natural history of the disease is dependent on time of discovery, it is important to raise suspicion for AL amyloidosis and use all available diagnostic tools and collaborate with appropriate institutions.

The finding of an IgM monoclonal gammopathy often represents a diagnostic challenge. In fact, there are many pathological disorders associated with this condition, each of which has distinctive characteristics and requires specific clinical, instrumental, and laboratory assessments to set the appropriate treatment. This review has two aims. Firstly, to provide a framework of the broad spectrum of IgM-associated disorders: (1) monoclonal gammopathy of undetermined significance (MGUS); (2) Waldenstrom macroglobulinemia (WM); (3) IgM-related disorders (among which hyperviscosity syndrome, light chain amyloidosis, cold agglutinin disease, cryoglobulinaemia, IgM neuropathy, Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome, Castleman disease); (4) IgM-secreting multiple myeloma (IgM-MM); and (5) other lymphoproliferative disorders which may be associated with IgM (such as chronic lymphocytic leukemia, small lymphocytic lymphoma, and B-cell non Hodgkin lymphoma). Secondly, to give a detailed insight regarding diagnosis and treatment of WM.

Polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin associated glycoprotein (MAG) antibodies is an immune-mediated demyelinating neuropathy. The pathophysiology of this condition is likely to involve anti-MAG antibody deposition on myelin sheaths of the peripheral nerves and it is supposed to be distinct from chronic inflammatory demyelinating neuropathy (CIDP), another immune-mediated demyelinating peripheral neuropathy. In this series, we have retrospectively reviewed clinical and laboratory findings from 60 patients with polyneuropathy, IgM gammopathy, and anti-MAG antibodies. We found that the clinical picture in these patients is highly variable suggesting a direct link between the monoclonal gammopathy and the neuropathy. Conversely, one-third of patients had a CIDP-like phenotype on electrodiagnostic testing and this was correlated with a low titer of anti-MAG antibodies and the absence of widening of myelin lamellae. Our data suggest that polyneuropathy associated with anti-MAG antibodies is less homogeneous than previously said and that the pathophysiology of the condition is likely to be heterogeneous as well with the self-antigen being MAG in most of the patients but possibly being another component of myelin in the others.

Distal acquired demyelinating symmetric (DADS) neuropathy patients present with distal symmetrical sensory ataxic neuropathy similar to the idiopathic peripheral polyneuropathy. Electrophysiology differentiates it by having predominantly motor demyelination. Two thirds of cases are associated with IgM paraprotein or anti-MAG antibody. The condition is usually treatment refractory.

BACKGROUND: Myelin-associated glycoprotein (MAG) is a glycoprotein specific to Schwann cells. Schwann cells produce myelin for nerve cells in the peripheral nervous system. MAG also plays a role in the central nervous system (CNS) by maintaining myelin integrity and inhibiting axonal regeneration from cerebellar neurons. There is a well-established link between distal demyelinating neuropathy and anti-MAG antibodies in patients with monoclonal gammopathy of unknown significance. We describe a series of five patients with anti-MAG antibodies with evidence of cerebellar rather than just sensory ataxia and our experience of treatment with rituximab. METHODS: Cerebellar ataxia was clinically suspected and confirmed using magnetic resonance spectroscopy (MRS) of the cerebellum. All patients underwent detailed nerve conduction studies. RESULTS: Four patients were males. The ages ranged from 64 to 82 years. All patients were anti-MAG positive and also had IgM monoclonal gammopathy. Four patients had neuropathy, whilst one had no evidence of neuropathy. All patients were treated with rituximab and showed improvement in the MRS parameters of the cerebellum. CONCLUSION: Anti-MAG antibodies might be involved in the pathogenesis of idiopathic sporadic ataxias, even in the absence of peripheral neuropathy. Rituximab seems to be a promising therapeutic intervention for those cases. 265 1 115 118

Lymphadenopathy as a manifestation of amyloidosis is rare. Of 3008 new patients with amyloidosis evaluated from 1994 to 2013 at a single center, 47 (1.6%) presented with lymph node enlargement leading to a biopsy and the diagnosis. We conducted a retrospective review of the initial presentation, time to progression, and treatment outcomes for these patients. Upon initial evaluation, 14 (30%) had isolated lymphadenopathy while 33 (70%) had evidence of vital organ involvement. Thirty-nine patients (83%) had systemic AL amyloidosis at initial evaluation or developed it on follow up; there was a single case each of AA, wtTTR and V122ITTR and one untyped amyloidosis. Eleven patients (23%) had IgM monoclonal gammopathy and 3 (6%) had histology consistent with lymphoplasmacytic lymphoma. Of the 14 patients with isolated lymphadenopathy, 10 (71%) eventually progressed to other organ disease requiring treatment at a median time of 10 months (range 4-71). This series demonstrates that patients presenting with amyloid lymphadenopathy usually have AL amyloidosis, and should have a thorough evaluation for other organ involvement at diagnosis. If present, treatment should be similar to that of other patients with systemic AL amyloidosis, but if not, patients should be monitored regularly for development of other organ disease over time.

Waldenstrom macroglobulinemia (WM) is an uncommon B-cell malignancy arising from B cells that are arrested after somatic hypermutation in the germinal center and before terminal differentiation to plasma cells [1]. It is characterized by IgM monoclonal gammopathy and bone marrow involvement by a lymphoplasmacytic lymphoma clone. WM accounts for approximately 5% of non-Hodgkin’s lymphomas, although recent data suggest its incidence is declining [2,3]. WM, considered an incurable disease in most cases, is an indolent lymphoma with a median age at diagnosis of 65 years and median survival of 5–10 years [4]. While once thought to closely resemble multiple myeloma, genomic studies of WM have found that this condition genetically clusters with other indolent lymphomas [5]. Morphologically, bone marrow in WM reveals plasmacytoid lymphocytes, small lymphocytes and plasma cells [6]. Characteristic features include the presence of Dutcher bodies (intranuclear pseudo-inclusions of IgM) and Russell bodies (prominent cytoplasmic globules). Cells stain positive for pan-B-cell markers, including CD19, CD20, CD25 and, in most cases, CD79a. Unlike chronic lymphocytic leukemia and follicular lymphoma, cells are usually negative for CD5, CD10 and CD23. One of the unique features of WM is its genetics. Recent studies revealed that deletion of 6q21 occurs in 42–63% of WM cases and over 70% demonstrate MYD88 mutations, which may convey a more aggressive phenotype [7]. In addition, the mutation of CXCR4 is present in 29% of cases and appears to play a critical role in WM biology [8]. WM is associated with a spectrum of disease severity. The presence of IgM monoclonal gammopathy of unknown significance (serum M spike

MYD88 L265P is highly prevalent in Waldenstrom's Macroglobulinemia (WM) and IgM monoclonal gammopathy of unknown significance (MGUS). We investigated whether MYD88 L265P could be identified by peripheral blood (PB) allele-specific PCR. MYD88 L265P was detected in untreated WM (114/118; 96.6%); previously treated WM (63/102; 61.8%); and IgM MGUS (5/12; 41.7%) but in none of 3 hyper-IgM or 40 healthy individuals. Median PB MYD88 L265P ΔCt was 3.77, 7.24, 10.89, 12.33 and 14.07 for untreated WM, previously treated WM, IgM MGUS, hyper-IgM and healthy individuals, respectively (P0.0001). For the 232 IgM MGUS and WM patients, PB MYD88 L265P ΔCt moderately correlated to bone marrow (BM) disease (r=-0.3553; P0.0001), serum IgM (r=-0.3262; P0.0001) and hemoglobin (r=0.3005; P0.0001) levels. PB MYD88 L265P ΔCt and serum IgM correlated similarly with BM disease burden. For positive patients, PB MYD88 L265P ΔCt was6.5 in 100/114 (88%) untreated WM, and6.5 in 4/5 (80%) IgM MGUS patients (P=0.0034). Attainment of a negative PB MYD88 L265P mutation status was associated with lower BM disease (P=0.001), serum IgM (P=0.019) and higher hemoglobin (P=0.004) levels in treated patients. These studies show the feasibility for detecting MYD88 L265P by PB examination, and the potential for PB MYD88 L265P ΔCt use in the diagnosis and management of WM patients.

The objective of this study was to investigate if the clinical and electrophysiological phenotype of patients with polyneuropathy associated with IgM monoclonal gammopathy (IgM-PNP) is related to the presence of antibodies against gangliosides or myelin-associated glycoprotein (MAG). We compared clinical and nerve conduction study (NCS) characteristics of 11 IgM-PNP patients with antibodies against asialo-GM1 or gangliosides (GM1, GD1a, GD1b, GM2 or GQ1b) to 11 consecutive IgM-PNP patients with anti-MAG neuropathy and to 9 IgM-PNP patients without antibodies against either MAG or gangliosides. Patients with anti-ganglioside antibodies could not be differentiated from those with anti-MAG antibodies based on clinical characteristics. However, within the group of anti-ganglioside antibody positive patients, antibodies against GD1b and GQ1b were associated with a purely sensory neuropathy (p = 0.002), while asymmetric weakness with symmetric sensory loss was associated with anti-asialo-GM1 antibodies. In conclusion, polyneuropathy associated with IgM monoclonal gammopathy and anti-ganglioside antibodies clinically resembles anti-MAG neuropathy. Pure sensory neuropathy and marked asymmetry may suggest the presence of anti-ganglioside rather than anti-MAG antibodies.

A broad spectrum of diseases are associated with IgM monoclonal gammopathy, including Waldenstrom macroglobulinemia (WM), various types of B cell non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), primary amyloidosis (AL), and monoclonal gammopathy of undetermined significance (MGUS); these are called IgM monoclonal gammopathy related diseases (IgM-RD). We investigated MYD88 L265P and WHIM-like CXCR4 mutations in various IgM-RD. Patients with serum immunofixation electrophoresis confirmed IgM monoclonal gammopathy who had enough material for DNA extraction and presented between January 2008 and October 2016 at Peking Union Medical College Hospital were enrolled in this cohort. We performed real-time allele-specific-polymerase chain reaction and Sanger sequencing to explore the presence of MYD88 L265P and WHIM-like CXCR4 mutations. One hundred and twelve patients (64 male and 48 female patients) were included in this retrospective study. The median age at diagnosis was 62 years (range, 30–84 years). In total, 64 patients (57.1%) carried the MYD88 L265P mutation and 14 patients (12.5%) carried the CXCR4 WHIM-like mutation. We identified the MYD88 L265P somatic variant in cases with WM (39/42), MGUS (8/18), NHL (14/41, including 4/13 diffuse large B cell lymphoma (DLBCL), 1/8 mucosa-associated lymphoid tissue, 3/6 splenic marginal zone lymphoma (SMZL), 1/4 chronic lymphocytic leukemia, 2/3 nodal marginal zone lymphoma (NMZL), 1/2 mantle cell lymphoma, 1 Burkitt lymphoma, and 1 B cell NHL that could not be classified), primary AL (2/2), and IgM-PN (1/1). The mutation was absent in five patients with Cryoglobulinemia, two with primary cold agglutinin disease and one with MM. The CXCR4 WHIM-like mutation was present in 10/42 patients with WM, 3/41 with NHL (1 DLBCL, 1 SMZL, and 1 NMZL), and 1/18 patients with IgM MGUS. Among the patients with NHL, those with the mutated MYD88 L265P genotype were younger and had lower level of IgG and IgA than the patients with the wild-type genotype. Patients with the mutated MYD88 L265P genotype with WM and MZL were compared. More male patients, higher levels of IgM and lower levels of LDH were found in the WM group. There was no significant difference in overall survival between the two groups. We present a study of the prevalence of the MYD88 L265P mutation and CXCR4 WHIM-like mutation in IgM RD. The MYD88 L265P mutation may play a key role in the pathogenesis of IgM monoclonal gammopathies. It would be interesting in the future to use MYD88 mutation status to differentiate among diseases.

An 80-year-old male with a 3-year history of IgM kappa paraproteinemia and a presumed diagnosis of Waldenstrom's macroglobulinemia (WM) presented as a new patient to establish care. He had initially presented 3y ears ago with 6 months of intermittent fevers and chills occurring approximately twice monthly. Diagnostic work-up at that point had included positron emission tomography-computed tomography (PET-CT) and MRI, both of which were negative. No esophagogastroduodenoscopy (EGD) was performed as part of the work-up. Blood work revealed an IgM paraproteinemia of 492 mg/dl. He was further evaluated by hematology and rheumatologyphysicians who gavea diagnosis of WM for his paraproteinemia and familial Mediterranean fever (FMF) for his intermittent fevers and chills. The FMF was clinically diagnosed after demonstrating symptom resolutionwith a trial of colchicine. Gene testing was not performed. With the resolution of the fever and chills, management consisted of interval trending of the IgM paraproteinemia. Over a 3-year

Thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP) is a rare but potentially lethal condition requiring rapid recognition, diagnosis, and initiation of therapy. We experienced a case of a 61-year-old woman with primary Sjögren's syndrome (pSS) complicated with severe renal TMA/TTP following IgM monoclonal gammopathy of undetermined significance (MGUS). She was admitted to our hospital for further evaluation of hypergammaglobulinema, acute renal failure, and severe thrombocytopenia. She had been diagnosed with pSS 13 years prior to admission. Histological examination of her kidney revealed fibrin thrombi in the glomeruli and arterioles, a finding that is consistent with TMA/TTP. The patient was subsequently treated with plasma exchange, which resulted in a successful outcome without any complications. This rare case suggests that it is important to make a therapeutic decision based on appropriate and prompt pathological diagnosis., The original publication is available at www.springerlink.com, Rheumatology international, 33(1), pp.227-230; 2013

Waldenstrom macroglobulinaemia (WM) is a B-cell lymphoproliferative disorder characterised by IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic lymphoma (LPL). Historically LPL has been considered a poorly reproducible diagnostic category and largely a diagnosis of exclusion as a consequence of a lack of disease defining immunophenotypic and genotypic features. Considerable advances have been made recently with the demonstration of a WM-specific (CD22weak CD25+) immunophenotype and the MYD88 L265P mutation in the vast majority of patients. These developments have resulted in advances in diagnosis, prognostic assessment and post-treatment response evaluation. Similarly the demonstration of the MYD88 L265P mutation and its biologic effect has resulted in major therapeutic advances and improved survival outcomes for patients.

Monoclonal gammopathy of unknown significance (MGUS) is a clinically asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. Smoldering multiple myeloma, also called asymptomatic multiple myeloma, is an intermediate stage between MGUS and symptomatic multiple myeloma. As the name implies, extraosseous or extramedullary myeloma refers to the presence of myeloma deposits outside the skeletal system. Waldenstrom macroglobulinemia is a distinct subtype of plasma cell dyscrasia characterized by lymphoplasmacytic lymphoma in the bone marrow with an associated IgM monoclonal gammopathy. Amyloidosis is a condition characterized by extracellular deposition of fibrils composed of a variety of normal serum proteins.

Small case series suggest tremor occurs frequently in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) neuropathy. Epidemiologic study to confirm this association is lacking. Whether the neuropathy or another remote IgM-effect is causal remains unsettled.An IgM-MGUS neuropathy case cohort (n = 207) was compared to age, gender, and neuropathy impairment score (NIS) matched, other-cause neuropathy controls (n = 414). Tremor details were extracted from structured neurologic evaluation. All patients underwent nerve conductions.Tremor occurrence was significantly higher in IgM-MGUS case cohort (29%) than in control cohort (9.2%) (p = 0.001). In IgM-MGUS cases, tremor was associated with worse NIS (p = 0.025) and demyelinating nerve conductions (p = 0.020), but 11 of 60 (18%) IgM-MGUS cases with tremor had axonal neuropathy. In other-cause neuropathy controls, tremor was associated with axonal nerve conductions (p = 0.03) but not with NIS severity (p = 0.57). Tremor occurrence associated with older age in controls, (p = 0.004) but not in IgM-MGUS cases (p = 0.272). Most IgM-MGUS tremor cases (49/60) had a postural-kinetic tremor, 8 had rest tremor, 3 had mixed rest-action. Alternative causes of tremor was identified in 42% of IgM-MGUS cases, the most common type is inherited essential tremor 6/60 (p = 0.04).This first epidemiologic case-control study validates association between IgM-MGUS neuropathy and tremor. Among IgM-MGUS neuropathy cases, severity as well as type of neuropathy (demyelinating over axonal) correlated with tremor occurrence. IgM-MGUS paraproteinemia may increase tremor expression in persons recognized with common other risk factors for tremor.

Background and purpose: Some patients within the spectrum of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) have distal acquired demyelinating symmetric (DADS) neuropathy, usually associated with anti-myelin-associated-glycoprotein (MAG) IgM monoclonal gammopathy. The aim of this retrospective study was to investigate patients with DADS neuropathy without anti-MAG antibodies, and study their response to immunotherapy. Methods: Patients were selected on the basis of (i) ‘Definite CIDP’ according to the EFNS/PNS Guideline criteria, (ii) The presence of disproportionately prolonged motor latencies resulting in a terminal latency index (TLI) ≤0.25 in at least two motor nerves and (iii) The absence of anti-MAG antibodies on ELISA. Response to immunotherapy was defined as persistent improvement by at least one point on the INCAT disability score. Results: Data from 146 CIDP patients were analysed, and 10 patients were included. Six had clinically pure sensory neuropathy, and four had sensorimotor neuropathy. Ataxia was present in nine patients, generalized areflexia in seven and postural tremor in two. Five of the 10 patients had abnormal sensory potentials only in the upper limbs. An associated condition was found in nine patients: two chronic lymphocytic leukaemias, four IgG monoclonal gammopathies (one associated with non-Hodgkin’s lymphoma) and two IgM monoclonal gammopathies of unknown significance. Patients were mostly improved with intravenous immunoglobulin (IVIg), corticosteroids, plasma exchanges, or a combination thereof. Conclusion: DADS neuropathy without anti-MAG antibodies is more likely to be considered a variant of CIDP. In addition, such patients should be systematically investigated for an associated haematological or immunological condition.

To characterize the morphological progression of neuropathy associated with immunoglobulin M-monoclonal gammopathy of undetermined significance with anti-myelin-associated glycoprotein antibody, we assessed histopathologic features of sural nerve specimens from 15 patients, emphasizing widely spaced myelin (WSM), demyelination, and tomaculous changes. The frequency of WSM correlated with that of demyelination and tomaculous appearance in teased-fiber preparations. In longitudinal sections at nodes of Ranvier and paranodal regions, the spaces between terminal myelin loops, particularly those adjacent to the node of Ranvier, were widened, indicating an early change before demyelination, and there was concomitant swelling of terminal myelin loops. Some conspicuously swollen terminal myelin loops were detached from the paranodal axolemma, thereby widening the nodes of Ranvier. Tomacula coexisted frequently with redundant myelin loops and WSM, particularly in the outermost layer of myelin sheaths, suggesting that loosening of the outer layers contributes to their formation. By immunofluorescence microscopy, immunoglobulin M and myelin-associated glycoprotein were colocalized in paranodal regions and Schmidt-Lanterman incisures. Confocal analysis revealed colocalization of immunoglobulin M and complement product C3d corresponding to the area of WSM. Thus, morphological changes in terminal myelin loops, formation of WSM at paranodes, and subsequent dissociation from paranodal axolemma (which may be associated with activation of the complement pathway) likely contribute to demyelination in this condition. Loosening of compact myelin seems to contribute to tomacula formation.

Objective - The neuropathy associated with IgM monoclonal gammopathy (IgM-MG) is regarded as a sensorimotor, mainly demyelinating neuropathy. It is not fully known whether the neuropathy in IgG-MG is caused by the same mechanisms and shows the same electrophysiological characteristics. We aimed at making a comparison between clinical and neurophysiological findings in these two conditions. Patients and methods - Twenty-seven patients with IgM-associated neuropathy [18 with anti-myelin-associated glycoprotein (anti-MAG) antibodies] were compared with 15 age-matched patients with IgG-associated neuropathy. Results - Patients with IgM-associated neuropathy (especially those with anti-MAG antibodies) had significantly clinically more severe disabilities with involvement of both motor and sensory functions compared with patients with IgG-associated neuropathy in whom clinical sensory disturbances were more prominent than motor dysfunction. Motor and sensory conduction velocities were significantly lower and distal latencies significantly longer in the IgM group than in the IgG group concerning the median, ulnar and peroneal nerves. Fifty-four per cent of the patients in the IgM group did not present a sensory response of the median nerve vs 13% in the IgG group. There was also a significant difference concerning absent responses from the peroneal and sural nerves in the IgM vs IgG group (peroneal: 48% vs 13%, sural: 88% vs 27%). Conclusion - Polyneuropathy associated with IgM-MG, especially when associated with anti-MAG antibodies, appears to have more of a demyelinating involvement that meets the criteria for demyelination. This was not as clear in those associated with IgG. The IgG neuropathy showed less and milder deficit in the electrophysiological studies.

Purpose of review The management of peripheral neuropathy associated with monoclonal gammopathies has been advanced by recent clinical studies. We review the causal association between monoclonal gammopathy and neuropathy, and critically review the recent evidence on treatment. Recent findings IgM monoclonal gammopathy of undetermined significance (MGUS) is the most commonly found monoclonal gammopathy associated with neuropathy. Neuropathies associated with specific lymphoproliferative disorders may not respond to treatments aimed at that disorder. Standard immunomodulatory agents including steroids, intravenous immunoglobulin, and plasmapheresis have shown limited efficacy in IgM monoclonal gammopathy of undetermined significance. Newer studies have shown promising results with rituximab, a monoclonal antibody which targets the B cell surface antigen CD20 and results in a rapid and sustained depletion of B cells. Summary There is a clear association between peripheral neuropathy and IgM MGUS with characteristic clinical, electrophysiology and pathologic features that make the disorder distinct from chronic inflammatory demyelinating polyneuropathy. The IgG and IgA monoclonal gammopathies are rarely associated with specific neuropathies. Long-term studies looking at the association between specific immunologic markers and disease recurrence are needed to ultimately develop targeted therapies.

Background: Detection of serum antibodies to myelin-associated glycoprotein (MAG) by Western blot (WB) is a valuable assay to diagnose a distinct type of demyelinating polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy. In this study, the diagnostic accuracy of a new and more practical ELISA to detect these antibodies was validated. Methods: Routine WBs from 2 independent laboratories and ELISA were used to detect anti-MAG IgM in serum from 207 patients with neuropathy and controls. The sensitivity and specificity of these assays were compared and related to the patient clinical and electrophysiologic characteristics. Results: In ELISA, anti-MAG antibodies were found in serum from 49 (72%) of 68 patients with demyelinating polyneuropathy and IgM monoclonal gammopathy. However, in this subgroup of patients, only 30 (44%) and 37 (54%) were positive in the 2 WBs. All of the patients positive in the 2 WBs were also positive in ELISA. A high correlation was found for IgM activity in ELISA to MAG and sulfate-3-glucuronyl paragloboside (SGPG) (Spearman rho = 0.72, p < 0.0001), supporting the notion that the shared sulfated glucuronic acid moiety of MAG and SGPG is preserved. Most patients positive in anti-MAG ELISA had a slowly progressive sensory-motor demyelinating polyneuropathy, even if the WB was negative. In control groups, however, 4 WB-negative patients with a nondemyelinating monoclonal gammopathy-related polyneuropathy were positive in anti-MAG ELISA. The remaining samples were negative in ELISA. Conclusion: ELISA is more sensitive than Western blot to diagnose anti-myelin-associated glycoprotein related polyneuropathy, although a positive serology may be found in other forms of polyneuropathy as well. Neurology (R) 2009; 73: 688-695

Waldenstrom’s Macroglobulinemia (WM) is a rare disease, accounting for approximately 6% of all B cell lymphoproliferative disorders, with clinical features that are due to either infiltration of neoplastic cells or properties of the circulating IgM. This case report documents a Filipino-Chinese woman who had constellation of anemia, thrombocytopenia, cranial and spinal involvement, and sensory-motor polyneuropathy. Further evaluation showed clear pattern of WM demonstrated by IgM monoclonal gammopathy, presence of plasmacytoid cells on bone marrow aspirate and biopsy, and presence of B-cell markers on flow cytometry. Regimen of dexamethasone, rituximab and cyclophosphamide was given every 21 days for six courses. Follow-up studies showed negative results in serum protein and IgG electrophoresis. Repeat electrodiagnostic studies showed improved demyelinating neuropathies of the affected nerves and repeat neuroimaging showed reduction in size of the previously noted intracranial nodules and clearing of the spinal cord lesions. Appropriate treatment and follow up is very important in treating patients with WM. This report documents a serially monitored patient who remained in remission for nine years after prompt initiation of treatment. A review focusing on the neurologic sequel of WM was then performed.

Objective: To describe myelodysplastic syndrome (MDS)/ myeloproliferative neoplasm (MPN) combined with monoclonal gammopathy of undetermined significance (MGUS) in order to investigate the potential association between these 2 diseases. Methods: Two cases of confirmed chronic myelomonocytic leukemia (CMML) combined with MGUS were reported here. In addition, reports related to cases with combined MDS or MPN with MGUS were reviewed. Results: The first case was a 77-year-old man whose routine blood tests showed abnormal hemogram results. The diagnosis was CMML combined with IgM monoclonal gammopathy, and the disease course was 4 years. The CMML gradually progressed, and the patient presented with anemia, thrombocytopenia, autoimmune hemolysis, and an increase in the number of immature cells in the bone marrow. Although the MGUS caused fluctuations in the concentrations of IgM, no IgM-associated organ damage was observed. Eventually, this patient died of lung infection. The second case was a 78-year-old man who sought treatment because of fever and a cough. An increase in the number of monocytes was discovered in the peripheral blood. Bone marrow smear results suggested obvious active granulocytes and an increase in the percentages of promyelocytes, myelocytes, and metamyelocytes. Unhealthy granulocytes and immature monocytes could also be observed, and the percentage of monocytes was increased. In addition, serum IgG levels were increased, and immunofixation electrophoresis results showed IgG-κ type M proteins. The diagnosis was CMML combined with IgG monoclonal gammopathy. These diseases were stable, and follow-up was conducted for 1 year after diagnosis. Conclusion: The cases in this study combined with those that were reviewed from the relevant literature indicated that the presence of the above 2 tumors in 1 patient might not be a coincidence. The development of the 2 diseases in case 1 was different, and it was speculated that they might have had different clonal origins. Whether CMML may serve as a risk factor for MGUS as well as the function of clonal plasma cells in the occurrence and development of MDS or MDS/MPN still requires further studies on a large number of clinical cases.

The occurrence and nature of cytogenetic aberrations in polyneuropathy associated with IgM monoclonal gammopathy was determined. Therefore, interphase fluorescence in situ hybridization (FISH) was applied in 22 patients with polyneuropathy associated with IgM monoclonal gammopathy, multiplex ligation-dependent probe amplification (MLPA) assay in 18 of these patients and genome-wide-array-based comparative genomic hybridization (CGH) in eight of these 18 patients. Four patients had 10-20% and one patient had 30% B cells with IgH rearrangements; one patient had additional loss of 14qter; one patient had amplification of 6p and loss of 6q. Cytogenetic aberrations may be found in one third of the patients with neuropathy associated with IgM monoclonal gammopathy and are mainly associated with indolent Waldenstrom's Macroglobulinemia.

An unusual case having IgM monoclonal gammopathy with clinical and pathologic features of multiple myeloma (MM) in association with neutrophilia and nephrotic syndrome is reported. The patient showed lytic bone lesions, decreased IgG and IgA levels, Bence-Jones proteinuria, nephrotic proteinuria with edema, and histological plasma cell infiltration typical of MM. Moreover, mature neutrophilic leukocytosis, hepatomegaly, high leukocyte alkaline phosphatase score (LAP), absence of Philadelphia (Ph) chromosome and bcr gene rearrangement were also evidenced, all these features representing findings typical of the recently described plasma cell dyscrasia-associated neutrophilia. After the diagnosis, the patient was treated with melphalan and prednisone, with an excellent response to the treatment. Different from the 30 cases so far reported, this is the first case of plasma-cell dyscrasia with associated neutrophilia due to IgM-producing monoclonal gammopathy. At the same time, this is the first reported case of nephrotic syndrome secondary to IgM myeloma.

International audience; BACKGROUND:Kidney diseases associated with immunoglobulin M (IgM) monoclonal gammopathy are poorly described, with few data for patient outcomes and renal response.STUDY DESIGN:Case series.SETTING & PARTICIPANTS:35 patients from 8 French departments of nephrology were retrospectively studied. Inclusion criteria were: (1) detectable serum monoclonal IgM, (2) estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2 and/or proteinuria with protein excretion > 0.5g/d and/or microscopic hematuria, and (3) kidney biopsy showing monoclonal immunoglobulin deposits and/or lymphomatous B-cell renal infiltration. All patients received chemotherapy, including rituximab-based regimens in 8 cases.PREDICTORS:Patients were classified into 3 groups according to renal pathology: glomerular AL amyloidosis (group 1; n=11), nonamyloid glomerulopathies (group 2; n=15, including 9 patients with membranoproliferative glomerulonephritis), and tubulointerstitial nephropathies (group 3; n=9, including cast nephropathy in 5, light-chain Fanconi syndrome in 3, and isolated tumor infiltration in 1).OUTCOMES:Posttreatment hematologic response (≥50% reduction in serum monoclonal IgM and/or free light chain level) and renal response (≥50% reduction in 24-hour proteinuria or eGFR≥30mL/min/1.73m2 in patients with glomerular and tubulointerstitial disorders, respectively).RESULTS:Nephrotic syndrome was observed in 11 and 6 patients in groups 1 and 2, respectively. Patients in group 3 presented with acute kidney injury (n=7) and/or proximal tubular dysfunction (n=3). Waldenström macroglobulinemia was present in 26 patients (8, 12, and 6 in groups 1, 2, and 3, respectively). Significant lymphomatous interstitial infiltration was observed in 18 patients (4, 9, and 5 patients, respectively). Only 9 of 29 evaluable patients had systemic signs of symptomatic hematologic disease (2, 5, and 2, respectively). In groups 1, 2, and 3, respectively, hematologic response was achieved after first-line treatment in 3 of 9, 9 of 10, and 5 of 6 evaluable patients, while renal response occurred in 5 of 10, 9 of 15, and 5 of 8 evaluable patients.LIMITATIONS:Retrospective study; insufficient population to establish the impact of chemotherapy.CONCLUSIONS:IgM monoclonal gammopathy is associated with a wide spectrum of renal manifestations, with an under-recognized frequency of tubulointerstitial disorders.

Waldenstrom's macroglobulinemia (WM) is considered in the World Health Organization classification as a clinical syndrome associated with monoclonal immunoglobulin (Ig) M secretion, mainly observed in patients with lymphoplasmacytic lymphoma (LPL) and occasionally with other small B-cell lymphomas. Some authors consider it a rare distinct lymphoproliferative disorder with primary bone marrow infiltration and IgM monoclonal gammopathy. As LPL shares important morphologic and immunophenotypic overlaps with marginal zone B-cell lymphomas (MZLs) in cases showing plasmacytic maturation, it remains unclear if they constitute unique or distinct entities. Both diseases are composed of lymphocytes, lymphoplasmacytoid cells, and tumoral plasma cells with a surface (s) IgM-positive sIgD+/ cytoplasmic IgMpositive CD19+ CD20+ CD27+/ CD5 CD10 CD23 phenotype, without a specific marker. Extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, nodal MZL (NMZL), and splenic MZL (SMZL) are distinct entities displaying common morphologic, immunophenotypic, and genetic characteristics. MALT lymphoma is clearly distinct from LPL, although bone marrow infiltration and IgM paraprotein are not rare. Splenic MZL and NMZL are incompletely characterized, but a plasmacytoid/plasmacytic differentiation, autoimmune manifestations, and monoclonal component are frequent in both diseases. Bone marrow involvement is constant in SMZL and present in 60% of NMZLs. Molecular IgVH gene analysis has confirmed this heterogeneity, particularly within SMZL, with mutated and unmutated cases. Further studies are needed to clarify the pathogenesis of these MZLs and their relationship with LPL.

albayrak, murat/0000-0003-4025-741X; Onec, Birgul/0000-0003-2824-1044 WOS: 000385138900009 …

Neuropathic tremor is defined as tremor that occurs in association with peripheral neuropathy in the absence of any other neurological disorder. Certain peripheral neuropathies, especially demyelinating polyneuropathies, are more prone to development of tremor than others [1]. We report on a patient with sensorimotor demyelinating polyneuropathy associated with prostate adenocarcinoma and IgM monoclonal gammopathy of undetermined significance (IgM-MGUS) with high titres of anti-myelin-associated glycoprotein (MAG), presenting with upper limbs tremor and mild gait instability, who had a good response to treatment of underlying malignancy.

The natural history of asymptomatic IgM monoclonal gammopathies (MG) and variables predicting evolution to symptomatic lymphoproliferative disorders were investigated in 452 patients diagnosed from 1975 to 2001. Univariate and multivariate Cox models were used to identify possible predictors of disease progression. At a median follow-up of 49 months (range, 12 to 233), 41 cases (9.1%) evolved to symptomatic Waldenstrom's macroglobulinemia (n = 36), non-Hodgkin's lymphoma (n = 2), B-cell chronic lymphocytic leukemia (n = 1), IgM multiple myeloma (n = 1), and primary amyloidosis (n = 1); the median interval from diagnosis was 53 months (range, 12 to 154). The cumulative probabilities of transformation into a symptomatic lymphoproliferative disease at 5 and 10 years were 8% (95% confidence interval [CI], 6% to 12%) and 21% (95% CI, 16% to 29%), respectively. At univariate analysis, monoclonal component size and hemoglobin level as continuous parameters, lymphocytosis (>4 × 109/L), bone marrow lymphoplasmacytoid infiltration (>10%), erythrocyte sedimentation rate (>40 mm/h), and detectable Bence Jones proteinuria were significantly related with evolution probability. At multivariate analysis, paraprotein level (P < .0001), hemoglobin level (P < .05), and lymphocytosis (P < .0001) independently predicted malignant evolution (P < .0001). In conclusion, patients with asymptomatic IgM-MG showing hematological features predictive of progression should be carefully monitored in view of an early treatment of the disease. Semin Oncol 30:172-177. © 2003 Elsevier Inc. All rights reserved.

This presentation represents consensus recommendations for the clinicopathological definition of Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the Second International Workshop held in Athens, Greece during September 2002. WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy. It should be considered a distinct clinicopathological entity rather than a clinical syndrome secondary to IgM secretion. The underlying pathological diagnosis in WM is lymphoplasmacytic lymphoma as defined by the World Health Organization (WHO) and Revised European-American Lymphoma (REAL) classification criteria. The concentration of monoclonal IgM can vary widely in WM and it is not possible to define a concentration that reliably distinguishes WM from monoclonal gammopathy of undetermined significance (MGUS) and other lymphoproliferative disorders. A diagnosis of WM can therefore be made irrespective of IgM concentration if there is evidence on a bone marrow trephine biopsy of bone marrow infiltration by lymphoplasmacytic lymphoma with predominantly an intertrabecular pattern, supported by appropriate immunophenotypic studies. Simple criteria to distinguish patients with symptomatic WM who require therapy from those with asymptomatic WM and MGUS were also proposed. Patients with clinical features attributable to IgM monoclonal gammopathy but no overt evidence of lymphoma are considered to constitute a distinct clinical group and the term "IgM-related disorders" is proposed.

Immunophenotyping has become an essential tool for diagnosis of hematological malignancies. By contrast, for diagnosis of Waldenstrom's macroglobulinemia (WM) immunophenotyping is used only occasionally. From 150 patients with a IgM monoclonal gammopathy we have selected 60 cases with (1) morphological lymphoplasmocytoid bone marrow (BM) infiltration (>20%); (2) IgM paraprotein (>10g/L); and (3) absence of features of other lymphoma types. Immunophenotypic analysis was based on the use of the triple or quadruple monoclonal antibody (MoAb) combinations. To increase the sensitivity of the analysis of antigen expression, selected CD19(+)CD20(+) B cells were targeted. We have also explored the antigenic characteristics of both the plasma cell (PC) and mast cell (MC) compartments present in the BM from 15 WM patients. Clonal WM lymphocytes were characterized by the constant expression of pan-B markers (CD19, CD20, CD22, CD24) together with sIg, predominantly kappa (5:1, kappa:lambda ratio). A high proportion of cases (75%) were positive for FMC7 and CD25, but in contrast to hairy cell leukemia (HCL), these lymphocytes were always negative for CD103 and CD11c. CD10 antigen was also absent in all WM patients and less than one fifth of patients were positive for CD5 and CD23, while CD27, CD45RA, and BCL-2 were present in most malignant cells. In two cases, the coexistence of two different clones of B lymphocytes was identified, and in eight additional cases, intraclonal phenotypic heterogeneity was observed. As far as PCs are concerned, in most patients (85%) the number of PCs was within the normal range (median, 0.36%). The antigenic profile of these PCs differed from that observed in normal and myelomatous PC (CD38(++)CD19(++/-)CD56(-)CD45(++)CD20(+)). In three cases, PCs showed aberrant expression for CD5, CD22, or FMC7. Finally, the number of mast cells was significantly higher (0.058 +/- 0.13) as compared to normal BM (0.019 +/- 0.02) (P