Case of angioimmunoblastic T-cell lymphoma presenting as peripheral and bone marrow plasmacytosis: A diagnostic conundrum.

ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL), a subtype of peripheral T-cell lymphoma (PTCL), is associated with unique clinical, morphological, and immunohistochemical features. The peripheral circulation might show presence of an occasional reactive plasma cell but significant plasmacytosis masquerading as plasma cell leukemia is rare. We report a case of AITL in a 42-year-old male, who presented with two-month history of generalized lymphadenopathy. On investigations, he had hypergammaglobulinemia and plasmacytosis in the peripheral blood and bone marrow masquerading as plasma cell leukemia. Immunohistochemistry and serum protein electrophoresis revealed polyclonal nature of plasma cells. Diagnosis of AITL was made on cervical lymph node biopsy. This case highlights the diagnostic challenge faced due to heterogeneity in the clinical presentation and pathological findings and to alert the clinician so that timely accurate diagnosis can be made to initiate the treatment.

Polyclonal hypergammaglobulinaemia: towards definition of a threshold.

BACKGROUND: Polyclonal hypergammaglobulinaemia (PH) represents a classic diagnosis problem in internal medicine. However, there is no consensus threshold for PH. The aim of this study was to define a threshold for PH. METHODS: We conducted a retrospective multicentric study using laboratory biological databases between 1 January 2016 and 31 December 2016 in two university hospitals and one non-university hospital. All patients 18 years old or over and with at least one serum protein electrophoresis (SPE) available in 2016 were included. Exclusion criteria were monoclonal, biclonal, or oligoclonal spikes or, in case of hypogammaglobulinaemia, proven free light chain gammopathy. The main endpoint was to define the threshold values for PH in this population. Another objective was to define the 95th percentile of the distribution. RESULTS: 20 766 SPEs were included in this cohort. The PH threshold on 95th percentile was 18.9 g/L. The threshold varied according to geographical areas. CONCLUSIONS: This is the first study to scientifically define a PH threshold. The main limitation is that our threshold is only biological. The study was not designed to associate this threshold with a clinically active disease. In conclusion, while the 19 g/L cut-off seems the most relevant threshold, but it will need to be validated by prospective studies.

Significance of hypergammaglobulinemia in patients with chronic myelomonocytic leukemia.

Chronic inflammation is often indicated by a relative increase in the gamma globulin fraction in the serum electrophoresis. In a retrospective study, we analyzed the prevalence of relative hypergammaglobulinemia in 60 patients with chronic myelomonocytic leukemia (CMML), its potential prognostic impact, and potential correlations with laboratory and molecular features. Relative hypergammaglobulinemia (> 20%) was found in 25/60 (42%) patients. The median survival of patients with relative hypergammaglobulinemia was significantly shorter than in patients without hypergammaglobulinemia (10 vs. 24 months, p = 0.018). There was no difference between the groups regarding leukocyte count, hemoglobin value, and platelet count, but a higher prevalence of NRAS mutations and a lower prevalence of ZRSR2 mutations in patients with hypergammaglobulinemia. Our results show that hypergammaglobulinemia is present in a proportion of CMML patients and that this abnormality is associated with poor overall survival. The role of chronic inflammation in the pathophysiology of CMML needs to be further investigated.

Laboratory characteristics of IgG4-related disease: A retrospective study from a single tertiary medical center.

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition with unique histopathological features that can affect most organs, making diagnosis challenging. This study characterized detailed laboratory characteristics of IgG4-RD. Baseline clinical and laboratory features of 33 patients with IgG4-RD were reviewed, including serum IgG4 concentrations, serum free light chains (sFLCs), IgGĸ- and IgGλ-heavy/light chains (HLCs), capillary serum protein electrophoresis (SPE), and immunofixation electrophoresis (IFE) of IgG4 subclass. The cohort of 33 patients showed male predominance (94%), with 8 (24%) exhibiting multiple organ involvement. Most patients (88%) had an elevated IgG4 concentration, and 67% had elevated erythrocyte sedimentation rate and IgE levels. Median IgG4 concentration at baseline was significantly higher in patients with >2 organs involved than those with ≤2. Furthermore, erythrocyte sedimentation rate was significantly correlated with serum IgG4 concentrations at baseline. SPE results demonstrated polyclonal gammopathy in most patients. Half of the patients had an increased κ/λ sFLC ratio, 42% had an increased IgGκ/IgGλ HLC ratio. Most patients exhibited hypergammaglobulinemia in the anodal end of the ɤ region on SPE. This study describes detailed laboratory features of IgG4-RD. Although none of these tests are considered diagnostically sufficient by itself, the provided laboratory characteristics can increase awareness of this disorder and help distinguish it from other IgG4-RD mimics.

Inflammatory diseases in hematology: a review.

Hematopoietic cells are instrumental in generating and propagating protective inflammatory responses to infection or injury. However, excessive inflammation contributes to many diseases of the blood, bone marrow, and lymphatic system. We review three clinical categories of hematological inflammatory diseases in which recent clinical and translational advances have been made. The first category is monogenic inflammatory diseases. Genotype-driven research has revealed that previously mysterious diseases with protean manifestations are characterized by mutations that may be germline (e.g., deficiency of ADA2 or GATA2 deficiency) or somatic [e.g., vacuoles, enzyme E1, X-linked, autoinflammatory, somatic (VEXAS) syndrome]. The second category is the cytokine storm syndromes, including hemophagocytic lymphohistiocytosis, and Castleman disease. Cytokine storm syndromes are characterized by excessive production of inflammatory cytokines including interleukin-6 and interferon-γ, causing end-organ damage and high mortality. Finally, we review disorders associated with monoclonal and polyclonal hypergammaglobulinemia. The serum protein electrophoresis (SPEP) is typically ordered to screen for common diseases such as myeloma and humoral immunodeficiency. However, monoclonal and polyclonal hypergammaglobulinemia on SPEP can also provide important information in rare inflammatory diseases. For example, the autoinflammatory disease Schnitzler syndrome is notoriously difficult to diagnose. Although this orphan disease has eluded precise genetic or histological characterization, the presence of a monoclonal paraprotein, typically IgM, is an obligate diagnostic criterion. Likewise, polyclonal hypergammaglobulinemia may be an important early, noninvasive diagnostic clue for patients presenting with rare neoplastic diseases such as Rosai-Dorfman disease and angioimmunoblastic T-cell lymphoma. Applying these three categories to patients with unexplained inflammatory syndromes can facilitate the diagnosis of rare and underrecognized diseases.

Polyclonal hypergammaglobulinaemia: assessment, clinical interpretation, and management.

This Review outlines a practical approach to assessing and managing polyclonal hypergammaglobulinaemia in adults. Polyclonal hypergammaglobulinaemia is most commonly caused by liver disease, immune dysregulation, or inflammation, but can also provide an important diagnostic clue of rare diseases such as histiocyte disorders, autoimmune lymphoproliferative syndrome, Castleman disease, and IgG4-related disease. Causes of polyclonal hypergammaglobulinaemia can be divided into eight categories: liver disease, autoimmune disease and vasculitis, infection and inflammation, non-haematological malignancy, haematological disorders, IgG4-related disease, immunodeficiency syndromes, and iatrogenic (from immunoglobulin therapy). Measuring serum concentrations of C-reactive protein and IgG subclasses are helpful in diagnosis. IL-6-mediated inflammation, associated with persistently elevated C-reactive protein concentrations (≥30 mg/L), is an important driver of polyclonal hypergammaglobulinaemia in some cases. Although the presence of markedly elevated serum IgG4 concentrations (>5 g/L) is around 90% specific for diagnosing IgG4-related disease, mildly elevated serum IgG4 concentrations are seen in many conditions. In most cases, managing polyclonal hypergammaglobulinaemia simply involves treating the underlying condition. Rarely, however, polyclonal hypergammaglobulinaemia can lead to hyperviscosity, requiring plasmapheresis.

Calculated globulin as a screening tool for hypogammaglobulinaemia or paraproteins in hospitalized patients.

BACKGROUND: Calculated globulin fraction is derived from the liver function tests by subtracting albumin from the total protein. Since immunoglobulins comprise the largest component of the serum globulin concentration, increased or decreased calculated globulins and may identify patients with hypogammaglobulinaemia or hypergammaglobulinaemia, respectively. METHODS: A retrospective study of laboratory data over 2.5 years from inpatients at three tertiary hospitals was performed. Patients with paired calculated globulins and immunoglobulin results were identified and clinical details reviewed. The results of serum electrophoresis testing were also assessed where available. RESULTS: A total of 4035 patients had paired laboratory data available. A calculated globulin ≤20 g/L (<2nd percentile) had a low sensitivity (5.8%) but good positive predictive value (82.5%) for hypogammaglobulinaemia (IgG ≤5.7 g/L), with a positive predictive value of 37.5% for severe hypogammaglobulinaemia (IgG ≤3 g/L). Paraproteins were identified in 123/291 (42.3%) of patients with increased calculated globulins (≥42 g/L) who also had a serum electrophoresis performed. Significantly elevated calculated globulin ≥50 g/L (>4th percentile) were seen in patients with either liver disease (37%), haematological malignancy (36%), autoimmune disease (13%) or infections (9%). CONCLUSIONS: Calculated globulin is an inexpensive and easily available test that assists in the identification of hypogammaglobulinaemia or hypergammaglobulinaemia which may prompt further investigation and reduce diagnostic delays.

Síndrome de hiperviscosidade em paciente com mieloma múltiplo / Hyperviscosity syndrome in multiple myeloma patients

O mieloma múltiplo é uma neoplasia progressiva e incurável de células B, caracterizado pela proliferação desregulada e clonal de plasmócitos na medula óssea. A síndrome de hiperviscosidade é uma das complicações relacionadas às gamopatias monoclonais, sendo considerada emergência oncológica. O objetivo deste estudo foi descrever o quadro clínico de um paciente diagnosticado com mieloma múltiplo que apresentou síndrome de hiperviscosidade, avaliando a prevalência de sinais e sintomas, bem como características fisiopatológicas dessa entidade clínica. Foi revisado o prontuário de um paciente internado na enfermaria da Clínica Médica do Hospital Regional do Cariri (CE) no período de junho a julho de 2018. Além disso, foi realizada revisão de literatura em base de dados (PubMed®) direcionada ao tema proposto. O diagnóstico de mieloma múltiplo foi comprovado por mielograma, sendo prontamente iniciada a corticoterapia e avaliada a resposta clínica após essa terapêutica. Apesar de incomum e menos frequentemente relacionada ao mieloma múltiplo, a síndrome de hiperviscosidade está relacionada a uma grande taxa de mortalidade quando apresenta diagnóstico tardio. A terapia de primeira linha indicada para a síndrome de hiperviscosidade foi a plasmaferese, no entanto, as condições clínicas (instabilidade hemodinâmica) impossibilitaram sua realização. O desfecho deste caso foi o óbito do paciente. Concluiu-se que o diagnóstico precoce e a intervenção terapêutica estão diretamente relacionados à ocorrência de menor incidência de complicações relacionadas ao mieloma múltiplo e à síndrome de hiperviscosidade.

Multiple myeloma is a progressive and incurable B-cell neoplasm characterized by unregulated and clonal proliferation of plasmocytes in the bone marrow. Hyperviscosity syndrome is one of the complications related to monoclonal gammopathies and is considered an oncological emergency. The aim of this study was to describe the clinical condition of a patient diagnosed with multiple myeloma who presented hyperviscosity syndrome, evaluating the prevalence of symptoms and signs, as well as the pathophysiological characteristics of this clinical entity. The medical records of a patient admitted to the Internal Medicine ward of the Hospital Regional do Cariri (CE) from June to July of 2018 were reviewed. In addition, we conducted a literature review in a database (PubMed®) directed to the theme proposed. The diagnosis of multiple myeloma was confirmed by myelogram, and corticosteroid therapy was promptly initiated and the clinical response was evaluated after this therapy. Although uncommon and less frequently related to multiple myeoloma, hyperviscosity syndrome is related to a high mortality rate when diagnosed late. The first line therapy indicated to hyperviscosity syndrome was plasmapheresis; however, the clinical conditions (hemodynamic instability) precluded its performance. The outcome of this case was the patient's death. Thus, it was concluded that early diagnosis and therapeutic intervention are directly related to the occurrence of lower incidence of complications related to multiple myeloma and hyperviscosity syndrome.

Confirmed Cryoglobulinemia and Hyperviscosity Syndrome Secondary to Multiple Myeloma-IgA Kappa from Routine Blood Test: a Case Report.

BACKGROUND: Cryoglobulins and hyperviscosity syndrome (HS) sometimes occur in multiple myeloma (MM), which are considered clinical emergencies. In laboratory practice, aspiration failure in routine blood tests sometimes occurs when the sample is inadequate. Here, a case of cryoglobulinemia and HS associated with advanced multiple myeloma was reported, which unusually is initially confirmed by aspiration failure in a routine blood test with sufficient sample. METHODS: A case of a 48-year-old female whose diagnosis of cryoglobulinemia and hyperviscosity syndrome secondary to MM-IgA kappa was confirmed from routine blood test. RESULTS: The sufficient sample for routine blood test could not be analyzed in a hematology analyzer due to aspiration failure, which was found to be caused by high viscosity and poor liquidity. A peripheral blood smear showed numerous non-cellular clouds, erythrocyte rouleaux formation, and plasma cell infiltration. After a water bath, the non-cellular clouds evidently disappeared, and the routine blood test was successfully conducted. Centrifugation of the sample for biochemical test, which had previously failed, was also possible. The case was confirmed as complications of cryoglobulinemia and HS associated with advanced MM, and the non-cellular clouds were identified as cryoglobulins. CONCLUSIONS: This case report provides an effective way for clinicians to deal with this kind of abnormal sample and limited but important laboratory evidence to establish early diagnosis of cryoglobulinemia and HS secondary to MM.

Nodular pulmonary deposition disease in a patient with the acquired immunodeficiency syndrome: a case report.

BACKGROUND: Pulmonary nodules are a common cause for concern in patients with human immunodeficiency virus and acquired immunodeficiency syndrome. Most commonly, they are the result of an infection, given the patients' immunocompromised state; however, in some cases, pulmonary nodules in patients with human immunodeficiency virus and patients with acquired immunodeficiency syndrome can result from cellular or protein deposits. We report a rare case of nodular pulmonary light chain deposition disease in a patient with acquired immunodeficiency syndrome and monoclonal gammopathy of undetermined significance. CASE PRESENTATION: A 53-year-old African American woman with acquired immunodeficiency syndrome had pulmonary nodules detected incidentally by imaging of her lungs. Pulmonary tuberculosis was high on the differential diagnosis, but she had a negative test result for pulmonary tuberculosis. Imaging also revealed multiple lucent bone lesions, and earlier in the year, serum protein electrophoresis had shown an immunoglobulin G-kappa monoclonal protein (M spike). She was mildly anemic, so there was concern for progression to myeloma; however, the result of her bone marrow biopsy was unremarkable. Lung biopsy revealed finely granular eosinophilic material with negative Congo red staining, consistent with light chain deposition disease. CONCLUSIONS: The extent of this patient's light chain deposition disease was thought to be caused by a combination of acquired immunodeficiency syndrome and monoclonal gammopathy of undetermined significance, and the interval decrease in lung nodule size after restarting antiretroviral therapy confirms this hypothesis and also highlights a potentially unique contribution of the hypergammaglobulinemia to this disease process in patients with human immunodeficiency virus and patients with acquired immunodeficiency syndrome .

Lupus eritematoso sistémico en actividad y cociente albúmina/globulina invertido, ¿hallazgo propio de la enfermedad? / Systemic Erythematosus Lupus and Albumin-Globulin Index, a specific finding in lupus flares?

Introducción: El lupus eritematoso sistémico es el modelo clásico de enfermedad autoinmune. En el desarrollo de la enfermedad intervienen varios tipos de inmunoglobulinas, con predominio de la IgG, IgM e IgA. Objetivo: Describir la utilidad del cociente albúmina/globulina como un indicador de actividad en el lupus eritematoso sistémico. Desarrollo: Se estima que el 50 por ciento de los pacientes con lupus eritematoso sistémico muestran una hipoalbuminemia con una hipergammaglobulinemia. La hipoalbuminemia en mayor medida está relacionada con la presencia de nefritis lúpica. La mitad de los pacientes con nefritis lúpica presentan proteinuria en el orden del síndrome nefrótico. Esta proteinuria iguala o invierte parcialmente el valor del cociente albúmina/globulina. El cociente albúmina/globulina invertido por sí solo es insuficiente para afirmar la presencia de actividad en el lupus eritematoso sistémico. Se deben excluir otras entidades clínicas causantes de hipergammaglobulinemia policlonal. Los criterios de actividad del lupus eritematoso sistémico incrementan la sensibilidad del cociente albúmina/globulina invertido. Conclusiones: La interpretación del cociente albúmina/globulina debe ir aparejada a la estimación de actividad por los criterios clínicos de mayor uso (SLICC, SLEDAI, BILAG). No en todos los pacientes con lupus eritematoso sistémico puede interpretarse como criterio de actividad, por lo que es necesario excluir otras entidades clínicas(AU)

Introduction: Systemic lupus erythematosus is the model of autoimmune disease. Several types of immunoglobulins are involved in the development of the disease, mainly IgG, IgM and IgA. Objective: To describe the potential use of the albumin/globulin ratio as an indicator of activity in systemic lupus erythematosus. Development: fifty percent of patients with systemic lupus erythematosus exhibit hypoalbuminemia with hypergammaglobulinemia. Hypoalbuminemia is mainly related to the presence of lupus nephritis. The half of patients with lupus nephritis develops proteinuria with values of nephrotic syndrome. The proteinuria equals or partially reverses the albumin/globulin ratio. The inverted albumin/globulin ratio is insufficient to establish the presence of lupus activity. Other clinical entities producing polyclonal hypergammaglobulinaemia should be excluded. The systemic lupus erythematosus activity criteria increase the sensitivity of the inverted albumin/globulin ratio. Conclusions: The interpretation of the albumin/globulin ratio requires the activity estimation by different clinical criteria (SLICC, SLEDAI, BILAG). The inverted albumin/globulin ratio cannot be interpreted as a stand-alone indicator of disease activity in every systemic lupus erythematosus patients(AU)

An Extremely High IgA Value in a Young Child.

BACKGROUND: Hyper-IgA is not a rare finding in children although its causes are less reported than hypergamma-globulinemia in other classes of immunoglobulin. However, an isolated hyper-IgA might play a role as a diagnostic marker, in particular in children with an incomplete clinical picture at disease onset. RESULTS: We reported the case of a 3-year-old girl hospitalized for acute abdominal symptoms and suspicion of ruptured appendicitis. She presented severe inflammatory syndrome and her medical history related recurrent fever episodes. Serum immunoglobulin analysis was not in favor of an infection; indeed, IgA concentration alone increased and reached a surprising extremely high value in a young child (17-fold of the upper reference value). CONCLUSIONS: This case highlights the potential clinical significance of an isolated hyper-IgA that is known to be mostly found in serious diseases in children; it might contribute to reduce the delay in diagnosis and treatment of hyperimmunoglobulinemia D syndrome, an autoinflammatory disease.