Plasma Cell Dyscrasias

Plasma Cell Dyscrasia+Multiple Choice QuestionsBy Mojgan Talebian

Plasma Cell DyscrasiasFrom a single cell of B cell lineageProliferation of monoclonal population of plasma cellsProduction of a single type of immunoglobulin/immunoglobulin fragmentHomogenous M protein in serum protein electrophoresis

2

Malignant Disordersof Plasma CellMultiple Myeloma

Macroglobulinemia

Heavy chain disease

Multiple Myeloma (MM)A Trial of: An abnormal proliferation of plasma cells in the bone marrowOverproduction of monoclonal immunoglobulinRelated tissue/organ impairment; lytic bone disease, increased calcium ,renal insufficiency, anemia,Classification is according to the type of Ig Mostly produce IgG or IgA, a few IgD and IgEIgM production is rare, usually in Waldenstrm's macroglobulinemiaMM variants:IgM myeloma; with the presence of osteolytic lesionsBence-Jones myeloma; production of excess light chains, dimers form of either or , in serum and urine

MM pathogenesisChronic progressive disorder, fatalthe median age at the time of diagnosis 65; prevalence increase with aging processMore in mengenetics; more common in primary relatives of the patientOther potential risk factors:Exposure to large doses of radiation, chemicalsChronic antigenic exposuresArthritisOsteomyelitis

MM PathogenesisProduction of multiple tumors in the boneSecretion of osteoclast activating factor by solid tumors in the bone results in osteoporosis:Bone fractures, lytic bone lesions: hypercalcemia Reduction in normal hemopoiesis; anemia, neutropenia, and thrombocytopenia

Production of paraproteins; hyperviscosity, dilutional anemia, hyponatremia, high ESR, and rouleaux formation

Reduction of normal Ig level; rise of the total serum globulin and reduction of serum albumin

Easy bruising and bleeding due to interference with platelet function

Amyloidosis; deposition of glycoprotein, amyloid in tissues and organs

Proteinuria, renal tubular dysfunction, renal failure due to excess light chain and paraprotein precipitationLight chains filtered and reabsorbed by the renal tubules; damaging the tubulesIncrease loss of amino acids, glucose and electrolytesGranular or waxy casts

Plasma cell leukemia: if plasma cells presence in large number in the peripheral blood

Chromosome abnormalitiesSeen in 30% to 40% of patientsTranslocations; t(11;14) and t(4;14), t(14;16), (q13;q32)Trisomy 3, 5, 7, 9 and 11 The worst prognosis: monosomy 13, 13q14 deletion, and hypodiploidy The most frequent abnormality: translocations involving 14q32 (the site of heavy chain locus)Hyperdiploidy and aneuploidy; plasma cells are bi- and multi-nucleated

Clinical symptomsBone pain, bone fractures, skeletal deformityCNS involvementAmyloidosisHypercalcemia: anorexia, nausea, vomiting, constipation and dehydrationRenal dysfunction, edemaHyperviscosity syndrome; purpura, bruises, nose bleeding, headaches, and blurred vision

Laboratory FindingsMild to moderate reduction in HemoglobinNormochromic normocytic anemiaRouleaux formation, blue background stainHigh ESR over 100 mm/hr, (in light chain disease it is normal or moderately increased)Decreased leukocyte number, neutropeniaMild decrease in platelets numberFew number of plasma cell in peripheral bloodHypercalcemia

Bone Marrow BM examinations: aspirate and biopsyDiffuse or localized marrow infiltration, hypercellularityBM plasma cell labeling index (% of dividing plasma cells), differentiate between benign and malignant plasma cell, a major prognosis factorPlasmacytosis; ranging from 10% to 100%Malignant plasma cells: small and mature to large and immature and atypicalFlaming plasma cells, red areas in the cytoplasm, associated with IgA myeloma

Grey gelatinous bone marrow in advanced form of the disease

Myeloma Plasma cellsTwo variants:Mature:Eccentric nucleus with coarse chromatin pattern, typical cartwheel appearance is not apparentVery blue cytoplasm with perinuclear haloImmature:Finer nucleus with prominent nucleoliMultinucleated cells; in the advanced form of the disease and presence of hyperdiploidy and aneuploidyMore cytoplasm but lighter with perinuclear halo, vacuoles and Russell bodies (Mott cell)

MMBlood Chemistry and ElectrophoresisIncrease of plasma volume and serum viscositySerum calcium, indicator of hypercalcemiaSerum creatinine, indicator of renal functionIncreased total proteinDecreased albuminSerum protein electrophoresisSingle homogeneous M-band, mostly in gamma or occasionally in beta regionNo noticeable M-band in patients with light chain myeloma, presence of light chain in Ig electrophoresisIn rare cases of non-secretory myeloma: no M-band and no light chains fragments in Pr or Ig electrophoresisDecreased gamma globulin

MM Bone Marrow

http://www.thrombocyte.com/causes-of-multiple-myeloma-cancer

13

MM Blood Chemistry and ElectrophoresisImmunoelectrophoresisThe type of monoclonal IgThe class of heavy chainThe monoclonality confirmation, single light chainOn concentrated urine sample to identify Bence-Jones ProteinuriaThe heat precipitation of B-J protein: solubility of B-J protein by slowly heating urine to 50 to 60 C, and reappearance of the Protein when the urine temperature cools to below 60CThe test of choice is immunoelectrophoresisSerum immunofixation test, to clarify if the monoclonal pattern is masked by normal proteins

Serum Protein Electrophoresis

http://pleiad.umdnj.edu/~dweiss/pc/pcSerum_img.html

MM Staging

New International Staging SystemStage I: Serum 2 microglobulin 3.5 g/dlStage II: not stage I or IIISerum 2 microglobulin 5.5 mg/L

Grippe PR et all : international staging system for multiple myeloma J Clin Oncol 23: 3412, 2005HemoglobinCorrected serum CalciumLytic bone lesionsM-SpikeMedial survivalStage I>100 g/L70 g/LIgA >50 g/LUrine light chain > 12 g / 24 hrs23 monthsType A. Serum creatinine < 2.0 mg/dL (0.18 mmol/L)Type B. Serum creatinine > 2.0 mg/dL (0.18 mmol/L)

MM Clinical PresentationSign and SymptomsLaboratory findingsRadiographic FeaturesBone MarrowBone painFatigueWeight lossRecurrent infectionRenal failureSpinal cord compression Back painParesthesiaElevated paraproteins-M peakLow hemoglobinHypercalcemiaLow albuminHigh 2 microglobulinHigh serum creatinineHigh c-reactive proteinLytic lesionsOsteoporosisfracturesHigh in plasma cells

Treatment An Incurable hematological malignancyChemotherapy; Dexamethasone, thalidomide and/or lemalidomiteRadiotherapy, reducing bone painPlasmapheresis, reducing hyperviscosityBlood transfusionIV fluids and diuretics, increasing urinary excretion of calciumBisphophonates, preventing of bone loss and repairing of bone lesions and control of hypercalcemia

Waldenstrm's MacroglobulinemiaWMInvolve small lymphocytes with the exhibition of plasma cell differentiation; plasmacytoid lymphocytesCells exhibit Pan-B lymphocyte surface antigens: CD19, CD20, CD24, with light chain restriction mostly

IgM-secreting lymphoplasmacytoid cells express both cytoplasmic and surface IgM Accumulation of monoclonal IgM paraproteins (macroglobulin) in the bloodThe IgM acts like cryoglobulin with anti-i specificity; cold autoimmune hemolytic anemia

Diseases associated with IgM monoclonal proteinsIgM monoclonal gammapathy of undetermined significance (MGUS), the most common Waldenstrm's macroglobulinemia, the next most commonmalignant lymphoma IgM MMchronic lymphocytic leukemia (CLL), primary systemic Amyloidosis, the least common

WM Bone Marrow Aspirate

http://imagebank.hematology.org/AssetDetail.aspx?AssetID=1178&AssetType=Asset

Differential Diagnosis WM vs IgM MMWMBone marrow infiltration by small lymphocytesSurface Ig+, CD5-, CD10-, CD19+, CD20+, CD22+, CD23- IgM MM Is extremely rare, account for