Malignant Monoclonal Gammopathies Research Articles

Báo cáo một trường hợp hiếm bệnh tăng globulin đại phân tử Waldenstrom có tổn thương xương và Cd20 âm tính

Background: Waldenström’s macroglobulinemia is a rare malignant monoclonal gammopathy characterized by the production of excess IgM monoclonal protein. It presents with symptoms related to the infiltration of the hematopoietic tissues or the effects of monoclonal IgM in the blood. We present a case report to have much more experience of diagnosis of rare entity of maglinant lymphoid proliferation. Case report: A 70-year-old male hospitalized with weakness, bruising, splenomegaly, no hepatomegaly, no lymphadenopathy. Red blood count: 1.1 x1012/l, Hb 45g/l, white blood count: 9.9 x109/l (74% lymphocytes, 11% plasmacytoid lymphocytes, 1% plasmocyte, 11% neutrophils (1.08 x109/l), 3% monocytes), and platelet count: 15 x109/l. LDH, liver and renal function tests were normal. Serology for HIV, hepatitis B and hepatitis C were normal. Karyotype had no metaphase cells. MYD88 L265P mutation was negative. The bone marrow aspiration and biopsy showed a massive proliferation of small lymphocytes (61% lymphocytes mixed with plasmacytoid lymphocytes (17%) and plasma cells (3%). Immunophenotype: Positive for CD19, CD22, CD79a. Negative for CD20, CD34, CD10, CD5. Elevated erythrocyte sedimentation rate: 49mm/1st. Rouleaux formation. Protein 90g/l; Albumin 27.5g/l; A/G: 0.44; Monoclonal Gamma: 51.1g/l; IgM: 5.47g/dl. The bone SPECT image showed an abnormal concentration of radiation at the front arc of the rib 5 and the left side of the ribs 6 and 7. High-risk prognosis with 4 prognosis points according to the International Prognostic Scoring System. Conclusion: Diagnosis: A Waldenstrom’s Macroglobulinemia Case with Bone Lesions and CD20 negative.

Optimization of workflow and screening panels for the detection of malignant monoclonal gammopathies.

Multiple myeloma (MM) is one of the hematologic malignancies with a greater delay in diagnosis. Laboratories receive numerous MM screening test requests without a specific suspicion, which entails a substantial workload and reduces the efficiency of laboratories. Objective: to increase the efficacy of MM screening protocols. The results of serum protein electrophoresis (SPEP), serum protein immunofixation electrophoresis (SIFE), urine protein immunofixation electrophoresis, and serum free light chain assays of 75 patients with MM, three with amyloidosis, and a patient with solitary plasmocytoma were collected. The frequency of a set of biochemical alterations in these patients was compared with that in controls (n=120). A validation of the screening algorithm was carried out in 261 consecutive patients with a clinical or analytical suspicion of MM. SPEP+SFLC or SIFE+SFLC (98% sensitivity) were the screening algorithms with the highest sensitivity. Prospectively, the SPEP+SFLC detected 27 of the 28 confirmed cases of MG and saved 15h of work. Alterations in five of the six parameters studied were more frequent in the study group, with a cumulative value of≥3 parameters altered (61.1 vs. 1.7%) (positive predictive value: 85%; negative predictive value: 94%). The SPEP+SFLC screening protocol demonstrated the highest sensitivity and was the least time-consuming protocol. In addition, this protocol improves diagnostic sensitivity and laboratory performance.

Pro-kidney transplantation should be considered in patients with multiple myeloma

Multiple myeloma is the most frequent malignant monoclonal gammopathy and the second most common hematological malignancy after non-Hodgkin lymphoma. There continues to be evolving therapies in the treatment which has significantly changed progression-free and overall survival of the patients. Increasingly, evidence shows that multiple myeloma no longer portends poor and lethal prognosis. With the advances in treatment of multiple myeloma and improved survival as seen in several studies, perhaps more attention should focus on kidney transplantation in these individuals given their suboptimal outcomes on dialysis. We would like to propose that a diagnosis of multiple myeloma not be considered as an absolute contraindication for kidney transplantation. Rather, a careful consideration of kidney transplantation is appropriate for a subset of patients with multiple myeloma and end-stage kidney disease. The candidacy of these patients should be reviewed by a multidisciplinary team comprising experts in hematology, kidney transplantation, and key stakeholders (including laboratory medicine, renal pathologists, and pharmacists) to allow appropriate risk stratification, prognostication for a successful and safe kidney transplantation.

Diagnosis of haematological diseases with monoclonal gammopathy

AbstractDespite the complexity of lymphoproliferative disorders, the presence of monoclonal immunoglobulins has been providing diagnostic guidance to the haematologist for more than a century. Clinicians may be alerted for the possible presence of serum monoclonal immunoglobulins produced in excess by increased erythrocyte sedimentation rate. Thereafter the diagnosis of monoclonal gammopathy could be proven by serum protein electrophoresis followed by immunofixation to properly identify the M‐protein. In a quarter of the cases, no intact monoclonal immunoglobulin could be detected in the sera, however, free light chains produced in excess may be identified using specialized immunoassays, so called free light chain analysis.Idiopathic monoclonal gammopathy of unknown significance (MGUS) may be present in 1% of the population above age 50 and up to 10% for individuals over 80 years of age. Due to the high frequency of MGUS, between 50‐65% of all monoclonal proteins detected fall into this category and most asymptomatic patients remain undetected for many years. MGUS patients have a 1% per year chance for transformation into malignant monoclonal gammopathies. Presently, it is accepted that most multiple myeloma and amyloidosis patients have their disease developed by transformation from preexisting MGUS. Additionally, some nonmalignant hematological disease also frequently exhibit monoclonal immunoglobulin synthesis, most notably Gaucher’s disease.From the field of neoplastic hematological diseases, smouldering and symptomatic multiple myeloma as well as Waldenström’s macroglobulinaemia almost always exhibit significant amounts of serum M‐protein and/or monoclonal free light chain excess. In case of solitary plasmocytoma, primary AL amyloidosis, cryoglobulinaemia and plasma cell leukemia, the correlation with gammopathy is less strict. Monoclonal gammopathy is less common in different types of non‐Hodgkin lymphoma. Within lymphomas lymphoplasmocytic lymphoma and marginal zone lymphoma more commonly secrete monoclonal immunoglobulins, while other B‐cell lymphomas have 14% cumulative chance for specific gammopathy. In the case of B‐cell chronic lymphocytic leukemia (the most common leukemia), intact monoclonal gammopathy has a 2% appearance, while abnormal free light chains may be detected in a third of the cases. Sporadically monoclonal gammopathy may be detected in chronic myelomonocytic leukemia, refractory anaemia, large granular cell leukemia and angioimmunoblastic lymphoma. Notably, in many of these diseases, the amount of secreted monoclonal immunoglobulin and/or free light chains correlate with the tumor burden and could be used for disease monitoring, especially in indolent hematological neoplasias.

An unusual presentation of a rare neoplasm - Waldenstrom’s macroglobulinemia

Waldenstrom’s macroglobulinemia (WM) is a rare malignant lymphoproliferative disorder with an overall incidence of 2.5cases/ million/year. This is a case report of a 48-year-old woman who presented with an unusual, yet significant gastrointestinal involvement. Biopsy of the duodenum clinched the diagnosis of WM. Further bone marrow and serum electrophoresis confirmed the diagnosis. WM is an uncommon slow growing malignant monoclonal gammopathy which is chronic, indolent and predominantly involving the bone marrow and characterized by secretion of high levels of monoclonal immunoglobulin (IgM–hence called macroglobulinaemia), elevated serum viscosity and presence of lymphoplasmacytic infiltration of the bone marrow. This causes the most common non specific symptom of weakness and easy fatiguability. In some individuals, the IgM proteins clump together in the hands and feet, where the body temperature is cooler than at the centre of the body, hence being referred to as cryoglogubulins, their clumping causing a condition called cryoglobulinemia. Extramedullary involvement is rare and may affect central nervous system, articular and periarticular structures, lungs, kidneys, eyes, and gastrointestinal system.

Understanding the Cellular Origin and Pathogenic Transcriptional Programs in Multiple Myeloma (MM) and Light-Chain Amyloidosis (AL) through the Dissection of the Normal Plasma Cell (PC) Development

Understanding the Cellular Origin and Pathogenic Transcriptional Programs in Multiple Myeloma (MM) and Light-Chain Amyloidosis (AL) through the Dissection of the Normal Plasma Cell (PC) Development

Clinical and electrophysiological aspects in amyotrophic lateral sclerosis syndromes associated to gammopathies

The sensory or sensitivo-motor neuropathies were the most described Peripheral neurological complications of benign or malignant monoclonal gammopathy (MG). Cases of pure motor impairment simulating amyotrophic lateral sclerosis (ALS) have more rarely been described. Herein we describe the clinical and electrophysiological aspects of three patients presenting an ALS like clinical syndrome associated to a MG and we stand out the particular features. There were two men and one woman with an average age of 61.3 years. All patients had a progressive weakness of 4 members and two of them presented a deglutition disorder. All patients became bedridden after few months of the onset. All patients had a very evocative clinical signs of ALS without subjective neither objective sensory troubles. An ALS clinical syndrome in its polyneuritic form was encountered in one patient. In all cases, the electromyographic data were compatible with an attack of the neurons of the anterior horn: many potentials of fibrillation, potential of fasciculation at rest and reducing of the number of potential motor unit during the voluntary contraction with increase in their amplitude and duration. Low amplitudes in motor nerve compound muscle action potentials were noted at the level of at least one nervous trunk in all patients. Low amplitudes of sensory nerve action potential were shown in one patient. MG type was demonstrated during the hospitalization in all patients. Two patients had non Ig M MG of undetermined significance and one patient had Ig M MG associated to a myeloma. Sensory potentials impairment in ALS syndrome has to prompt us to search for an underlying aetiology and especially for GM.

Hemodialysis Using High Cut Off Filters in Light Chain Cast Nephropathy

Background/Aim: Hemodialysis using high cutoff (HCO) filters possibly improves renal function in diseases with light chain (LC) overproduction and acute kidney injury. We established the effect of HCO dialysis on renal outcome in consecutive patients with malignant monoclonal gammopathies and LC cast nephropathy. Methods: LC concentration was measured before and after each dialysis session in 10 patients receiving HCO dialysis and bortezomib-based chemotherapy, and their renal function was monitored by plasma creatinine. Results: The number of HCO sessions ranged from 4 to 34 (mean 13). Six patients recovered kidney function, 3 regained partial function while 1 patient continued chronic dialysis. Patients with the largest reductions in LC during HCO treatments had the lowest creatinine at 6 and 9 months of follow-up. For comparison, only 2 out of 10 patients in a historic control group recovered kidney function. Conclusion: HCO dialysis combined with bortezomib results in good renal recovery with kidney function being dependent on the degree of LC lowering.

Plasma cell leukemia: from biology to treatment.

Plasma cell leukemia (PCL) is a very aggressive and rare form of malignant monoclonal gammopathy characterized by the presence of plasmocytes in peripheral blood. It is classified as primary PCL occuring 'de novo', or as secondary PCL in patients with relapsed/refractory multiple myeloma. Primary PCL is a distinct clinicopathological entity from myeloma with different cytogenetic abnormalities and molecular findings, which are usually found only in advanced multiple myeloma. The clinical course is aggressive with short remissions and reduced overall survival. The diagnostic criteria are based on the percentage (>20%) and absolute number (2×10(9) /L) of plasma cells in peripheral blood. After establishing diagnosis, induction therapy should begin promptly which is aimed to rapid disease control and to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens, followed by high-dose therapy with autologous stem cell transplantation, are recommended. Allogeneic transplantation can be considered in younger patients. This article reviews recent knowledge of this hematological malignancy that is associated with a very poor prognosis.

Data quality of the monoclonal gammopathy of undetermined significance diagnosis in a hospital registry

ObjectiveTo estimate the positive predictive value (PPV) and completeness of the monoclonal gammopathy of undetermined significance (MGUS) diagnosis coding in a hospital registry within a population-based health-care setting.Patients and methodsThrough the Danish National Patient Registry (DNPR), we identified 627 patients registered with MGUS in two Danish regions during the period January 2001–February 2011. We reviewed the medical records of all patients registered with MGUS at the Department of Hematology, Aalborg University Hospital, and a sample of patients registered at the other three hematological departments in the two regions. We estimated the PPV of the MGUS diagnosis based on this sample of 327 medical records. We also estimated the completeness of the DNPR by linking data from the DNPR and data from a previously validated MGUS cohort of 791 patients identified through the laboratory system covering North Jutland Region.ResultsThe diagnosis of MGUS was confirmed in 231 patients and assessed as probable in an additional 38 patients, corresponding to a PPV of 82.3% (95% confidence interval [CI] 78.1%–86.4%). By contrast, 58 (17.7%) of the patients did not definitively meet the diagnostic criteria for MGUS. When we excluded patients registered with malignant monoclonal gammopathy recorded prior to or within the first year after registration of MGUS in the DNPR, the PPV increased to 88.3% (95% CI 84.5%–92.1%). The DNPR only registered a diagnosis of MGUS in 133 of the 791 MGUS patients identified through the laboratory system, corresponding to a completeness of 16.8% (95% CI 14.1%–19.6%).ConclusionThe PPV of the diagnosis coding for MGUS in the DNPR is high and can be further improved by simple data restriction. However, the low completeness raises concern that MGUS patients registered in the hospital system may be highly selected.

Efficient use of basic biochemical methods to prove the presence of monoclonal protein in the clinical diagnosis of malignant monoclonal gammopathy

Background: This retrospective study evaluates the diagnostic sensitivity of biochemistry methods for the clinical diagnosis of malignant monoclonal gammopathy. In patients with renal insufficiency, renal reference interval as well as standard reference interval is used for evaluating the ratio of free light chains. Methods: We examined samples in 281 patients who were diagnosed with malignant monoclonal gammopathy. The samples were taken at baseline, prior to treatment. Serum and urine protein electrophoresis, serum and urine immunofixation electrophoresis (SIFE+UIFE) and levels of free light chains in serum (FLC) were investigated. Results: Combination of methods with the highest diagnostic sensitivity is the use of maximal number of tests (SIFE+ UIFE + FLC), which identified 98.6% of patients. The achieved results do not statistically significantly differ from the procedure recommended by the International Myeloma Working Group (IMWG) which omitts the urine testing (SIFE + FLC) and identifies 97.9 % of patients (p = 0.523). By using the renal reference ratio of free light chains in patients with renal insufficiency the number of patients identified decreased to the border of significance (p = 0.06) but the number of patients identified by the combination with serum immunofixation (SIFE + FLC) remained the same. Conclusions: The testing algorithm recommended by IMWG for screening patients with the diagnosis of monoclonal gammopathy is effective, diagnostic sensitivity is not significantly lower than the maximal available. Using the renal reference ratio of FLC for evaluation in combination with immunofixation in the serum does not reduce the diagnostic sensitivity of the test and has been reported to increase specificity.

Abnormal radiological features in a multiple myeloma patient: a case report and radiological review of myelomas

Multiple myeloma is the prototype of malignant monoclonal gammopathies. The most common skeletal sites are pelvis, skull, spine, ribs and femoral and humeral shafts. The classic radiographic presentation of multiple myeloma is lytic skeletal lesions. Other types of presentation include sclerotic and porotic changes. Primary sclerotic manifestations are rare and occur in only 3% of cases. Although exceptional, multiple myeloma must be borne in mind in the presence of bone sclerosis. This report presents a patient with multiple myeloma with a sunburst/hair-on-end pattern on the radiograph and sclerotic skeletal lesions.

High Frequency of Monoclonal Immunoglobulins Exhibiting Natural Autoantibody-Like Activity in Patients with Multiple Myeloma and Waldenström Macroglobulinemia

Abstract 2893Serum monoclonal immunoglobulins (M-Igs) of patients with monoclonal gammopathies are known to possess antibody activity against autoantigens, bacterial antigens and haptens, but their incidence is controversial. So far, high incidence of autoantibodies (autoAb) have been demonstrated against actin, Ro/SS-A and La/SS-B for M-Igs of all three classes (IgG, IgA, IgM) and against Fc fragment of IgG and the Ii group exclusively for IgM M-Ig. Other less frequent antiboby specificities of M-Igs include anti-myosin, anti-tubulin, anti-thyroglobulin and anti-DNA. M-Igs with anti-actin activity were found to express polyreactivity, which is a property of natural autoAbs (NAbs). NAbs are germ-line encoded, occur in all species, circulate in low concentrations and belong to all Ig classes. NAbs play important immunoregulatory role and anti-F(ab')2 reactivity is crucial for the establishment of the idiotypic network.The aim of this study was to investigate the frequency of human M-Igs that exhibit NAb-like activity in patients with monoclonal gammopathies and to explore possible correlations with their clinical features. Thus, 151 M-Igs (124 of IgG class: 71IgG-kappa/53 IgG-lambda and 27 of IgA class: 16 IgA-kappa/11 IgA-lambda) from patients with symptomatic multiple myeloma (MM; n=136), asymptomatic MM (n=8) or MGUS (n=7) and 50 M-Igs from patients with Waldenström Macroglobulinemia (WM) or IgM-MGUS (43 IgM-kappa and 7 IgM-lambda), without any autoimmune diseases, were studied by an in-house ELISA for polyreactivity against six autoantigens (native DNA, actin, tubulin, myosin, carbonic anhydrase, thyroglobulin) and the non-self hapten TriNitroPhenyl (TNP). Sera were also tested for antibody activity against F(ab’)2 fragment of human polyclonal IgGs. Most of these antigens are known targets of NAbs. Sera were first screened with enzyme-coupled human heavy chain antibodies (anti-G, anti-M and anti-A), and reactivity–with the exception of anti-F(ab’)2–was further attributed to the M-Ig using enzyme-coupled light chain antibodies (anti-kappa and anti-lambda).A significant proportion (18.2%: 35/192 evaluated patients) of pathological sera exhibited anti-F(ab')2 activity (27 from IgG-MM, 3 from IgA-MM and 5 from WM patients). Among the total M-Igs tested, 9.5% (18/189) recognised actin, 8.7% (17/194) carbonic anhydrase, 4.6% (9/194) thyroglobulin, 3.7% (7/186) TNP, 3.5% (7/196) tubulin, 2.5% (5/193) myosin and 1.5% (3/188) DNA. M-Igs reacting with actin, carbonic anhydrase, tubulin, myosin and TNP were found to belong to all three Ig classes (IgG, IgA, and IgM). Among the IgG M-Igs tested, the most frequent reactivity was that for thyroglobulin (7.6%), while among the IgA and IgM M-Igs the highest incidence observed was for actin and carbonic anhydrase (23%, 23% and 16.6%, 15.2%, respectively). Positive IgM and IgG M-Ig had either kappa or lambda light chain in a similar proportion, while positive IgA were mostly IgA-lambda (16/18). A high percentage of positive M-Igs from MM and WM patients were polyreactive (46%), i.e., reacted with at least two panel antigens. Polyreactivity was a prominent characteristic of IgA (6/6) and IgM (9/13) but not of IgG (6/36) M-Ig. Most frequent polyreactivity profile was that for actin, carbonic anhydrase and TNP.There was no significant correlation of immune-related features of symptomatic WM (immune cytopenias, cold agglutinin disease, cryoglobulinemia) or of MM characteristics (ISS, CRAB, LDH, plasma cell infiltration) with any of the detected M-Ig specificities or their NAb-like profile.In conclusion, we report for the first time anti-carbonic anhydrase and anti-TNP activity of the M-Igs from patients with monoclonal gammopathies. We also report high incidence of anti- F(ab')2 activity in the sera of these patients as well as of polyreactive M-Igs. Our findings suggest that the M-Igs with NAb activity might reflect the expansion of a clone normally producing a NAb. To-date, it has been assumed that a naive B-cell is first driven to clonal expansion by antigenic stimulation and that subsequently, an oncogenic stimulus results in malignant transformation. Assuming that certain malignant monoclonal gammopathies arise from the proliferation of a clone normally producing a NAb which recognise F(ab')2 and hence is probably involved in the regulation of the NAbs network, it may also be postulated that this may result in deregulation of this network. Disclosures:No relevant conflicts of interest to declare.

Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma: Implications for tumor evasion of T and NK cells

The molecular basis of monoclonal gammopathy of undetermined significance (MGUS) progression to a malignant monoclonal gammopathy remains poorly understood. It was recently suggested that this process involves the suppression of innate and adaptive immunity. In this study, we examined immunogenic differences in bone marrow plasma cells among individuals without gammopathy (controls) and patients with MGUS, multiple myeloma (MM), and plasma cell leukemia. We detected differences in major histocompatibility complex (MHC) class I expression, MHC class I chain-related molecule A, and CD95 that were more evident between MGUS and MM samples; there appeared to be a critical imbalance between natural killer (NK)-cell activating and inhibitory signals during the transition from MGUS to MM. Our results indicate that the human leukocyte antigen (HLA) class I bright, MICA dim/-, and CD95 dim/- immunophenotype reported in myeloma cells may result from an extensive interaction of malignant cells with cytotoxic T and NK cells and appears to be immunoedited for the evasion of immunosurveillance.

Polymorphism of alpha-1-antitrypsin in hematological malignancies

Alpha-1-antitrypsin (AAT) or serine protease inhibitor A1 (SERPINA1) is an important serine protease inhibitor in humans. The main physiological role of AAT is to inhibit neutrophil elastase (NE) released from triggered neutrophils, with an additional lesser role in the defense against damage inflicted by other serine proteases, such as cathepsin G and proteinase 3. Although there is a reported association between AAT polymorphism and different types of cancer, this association with hematological malignancies (HM) is, as yet, unknown. We identified AAT phenotypes by isoelectric focusing (in the pH 4.2-4.9 range) in 151 serum samples from patients with HM (Hodgkins lymphomas, non-Hodgkins lymphomas and malignant monoclonal gammopathies). Healthy blood-donors constituted the control group (n = 272). The evaluated population of patients as well as the control group, were at Hardy-Weinberg equilibrium for the AAT gene (χ2 = 4.42, d.f.11, p = 0.96 and χ2 = 4.71, d.f.11, p = 0.97, respectively). There was no difference in the frequency of deficient AAT alleles (Pi Z and Pi S) between patients and control. However, we found a significantly higher frequency of PiM1M1 homozygote and PiM1 allele in HM patients than in control (for phenotype: f = 0.5166 and 0.4118 respectively, p = 0.037; for allele: f = 0.7020 and 0.6360 respectively, p = 0.05). In addition, PiM homozygotes in HM-patients were more numerous than in controls (59% and 48%, respectively, p = 0.044). PiM1 alleles and PiM1 homozygotes are both associated with hematological malignancies, although this is considered a functionally normal AAT variant.

Pathogenesis and progression of monoclonal gammopathy of undetermined significance

In Caucasians, monoclonal gammopathy of undetermined significance (MGUS) is an age-related condition with prevalence as high as 3% in persons older than 50 years. Compared with whites, blacks have around two- and threefold higher prevalence rates of MGUS and multiple myeloma (MM), respectively. Risk of progression from MGUS to MM has been found to be very similar in whites and blacks. On average, the transformation rate to a malignant monoclonal gammopathy is 1% per year, with the mechanisms of progression likely related to bone marrow microenvironment and/or the cytokine network. Overall, the actuarial probability of progression at 25 years of follow-up is about 30%. However, when the competing causes of death are taken into account, the actual rate of progression is only 11%. The predictors of malignant transformation are the plasma cell mass (M-protein size and/or proportion of plasma cell in the bone marrow), IgA isotype, serum free light-chain ratio and 'evolving' type and ratio between phenotypically aberrant and normal bone marrow plasma cells. It is recommended to follow these patients, particularly those with high risk of progression, annually to detect MM before complications, such as renal failure or extensive skeletal, involvement occur.

Paraneoplastic Disorders of the Nervous System

Paraneoplastic neurologic disorders (PND) refer to an extensive group of syndromes that can affect any part of the nervous system by mechanisms that are mostly immune mediated (Table 1). PND are more frequent than previously considered, with an incidence that varies with tumor type. The tumors more frequently involved are small-cell lung cancer (SCLC, ~3% of patients develop PND), thymoma (15%), and the plasma cell dyscrasias associated with malignant monoclonal gammopathies (~5-15%). For solid tumors other than SCLC the incidence of PND is less than 1%. In 60% of patients, symptoms of PND precede the tumor diagnosis. The majority of these patients are first seen by neurologists who should be aware that prompt diagnosis and treatment of the tumor along with immunotherapy may stabilize or improve the PND.

Paraneoplastic disorders of the nervous system

Paraneoplastic neurologic disorders (PND) refer to an extensive group of syndromes that can affect any part of the nervous system by mechanisms that are mostly immune mediated (Table 1). PND are more frequent than previously considered, with an incidence that varies with tumor type. The tumors more frequently involved are small-cell lung cancer (SCLC, ~3% of patients develop PND), thymoma (15%), and the plasma cell dyscrasias associated with malignant monoclonal gammopathies (~5-15%). For solid tumors other than SCLC the incidence of PND is less than 1%. In 60% of patients, symptoms of PND precede the tumor diagnosis. The majority of these patients are first seen by neurologists who should be aware that prompt diagnosis and treatment of the tumor along with immunotherapy may stabilize or improve the PND.

Retrospective study of monoclonal gammopathies detected in the clinical laboratory of a Spanish healthcare district: 14-year series

We studied the incidence, classification and isotype distribution of monoclonal gammopathies and M-protein detected between 1992 and 2005 inclusive in the clinical laboratory of a healthcare district in Madrid (Spain) with an average population of 280,574 inhabitants. Serum electrophoresis was carried out on a cellulose acetate support up until 1997, and then using capillary zone electrophoresis systems, with M-protein identification carried out by agarose gel immunofixation. The age-adjusted incidences were standardized with respect to the WHO World Standard Population Distribution, based on the world average population between 2000 and 2025. The clinical diagnosis was recorded from the patient case history. M-protein was detected in a total of 537 patients; of these, 42 had been diagnosed before 1992, representing a 0.19% prevalence in our population. The mean age-adjusted incidence of monoclonal gammopathy was 10.72 per 100,000 inhabitants/year (SE 1.31), ranging from 4.85/100,000 in 1992 to 14.28/100,000 in 2003 and 2004. The median patient age at diagnosis was 73 years (range 25-96 years), with males accounting for 46.8% of all cases of monoclonal gammopathy, and 57.8% of all malignant monoclonal gammopathies. A total of 54.1% of the patients were clinically defined as presenting monoclonal gammopathy of undetermined significance, 31.3% presented multiple myeloma, and the remaining 14.6% presented malignant gammopathies. The most frequent M-protein isotype was IgG (55.8%), followed by IgA (20.8%) and IgM (13.6%). A total of 88% of the light chain M-proteins, 54% of isotype IgM, 51% of isotype IgA and 36% of isotype IgG were associated with B lymphoproliferative diseases. We conclude that the clinical laboratory should play an important role in the study of monoclonal gammopathies, since it is the only location where all M-protein patients are observed. On the other hand, studies of this type should be carried out over long-term periods, owing to the variations we have noted in the detection of M-proteins.

Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment

The immunological bone marrow (BM) microenvironment plays a major role in controlling growth and survival of clonal plasma cells (PC); this might translate into different patterns of expression of molecules involved in immune responses on PC from different types of monoclonal gammopathies (MG). We have studied the expression of a group of nine such molecules on both BMPC and the plasma of 61 newly diagnosed MG patients (30 MG of undetermined significance (MGUS), 27 multiple myeloma (MM) and four plasma cell leukemia (PCL)) and five normal individuals. Clonal PC from all MG displayed significantly increased levels of CD56, CD86 and CD126, and decreased amounts of CD38 (P<0.001). Additionally, HLA-I and beta2-microglobulin were abnormally highly expressed in MGUS, while CD40 expression was decreased in MM and PCL (P<0.05). Interestingly, a progressive increase in the soluble levels of beta2-microglobulin was found from MGUS to MM and PCL patients (P=0.03). In contrast, all groups showed similar surface and soluble amounts of CD126, CD130 and CD95, except for increased soluble levels of CD95 observed in PCL. Overall, those phenotypic differences are consistent with increased antigen presentation and costimulatory capacities in MGUS, which progressively deteriorate in malignant MG (MM and PCL).