Terry Kotrla, MS, MT(ASCP)BB

Topic 3 AutoimmunityPart 8 Immunoproliferative

Diseases

Immunoproliferative DiseasesFocus on malignancies of the immune system,

lymphoid cell line.Broadly classified as lymphomas and leukemias.Leukemias malignant cells present in bone

marrow and peripheral blood.Lymphomas, malignant cells arise in lymphoid

tissues:Lymph nodesTonsilsSpleen

Classified according to site malignancy first arose.

Immunoproliferative DiseasesPlasma cell dyscrasias

Multiple myeloma (MM)Waldenstrom’s macroglobulinemia

Involve bone marrow, lymphoid organs and other non-lymphoid tissue.

Biologically distinct, NOT classified as either lymphoma or leukemia.

Plasma cells may be found in blood later in myeloma, then classified as plasma cell leukemia.

Malignant TransformationMalignancy characterized by excess accumulation

of cells.Rapidly proliferating cells.Normal proliferation but do not undergo apoptosis

(programmed cell death).Rapid cell proliferation normal process of the

immune system to respond to antigenic stimulus.Malignancy occurs when regulatory processes fail

or mutations occur.Malignant cells “stuck” at early stage of

differentiation.May require altered or abnormal genes.May be triggered by viral infection or other

stimulus.

Malignant TransformationMalignant and premalignant proliferation of

cells can occur at any stage of differentiation.

Malignant cells may retain some or all of morphological and functional characteristics.Cell surface antigensSecretion of antibodyUsed to classify

Malignant Transformation - LymphomaArise due to persistent immunostimulation

coincides with immune deficiency.Provokes continuous proliferation and

mutations in lymphoid precursors.Immune deficiencies play two roles:

Ineffective immune response causes persistent stimulation to clear infection.

Immune surveillance for malignancy fails, especially in response to viral infections.

Malignant TransformationImmune system has diverse response to antigenic

challenge, “polyclonal response”.Malignancy may arise from excessive proliferation of

SINGLE genetically identical cell line or CLONE of cells.Malignancy occurs with population of uniform cells.

Presence of a large amount of single immunoglobulin type.

Increase in total amount of immunoglobulin.Malignancy diagnosed when lymphocytic cells in

bloodstream, bone marrow or lymphoid tissues consist of a uniform population of cells.

Specific mutations not known for most malignancies but more are being identified every day, may lead to effective treatment.

Immunoproliferative DiseasesB-cell immunoproliferative disorders most

commonly evaluated.B-cell lineage develop into plasma cellsUrine antibodies used to diagnose and

evaluate certain B-cell proliferationsB-cells produce one antibody specificity

(monoclonal).Persistent presence of large amounts of a

single immunoglobulin suggests malignancy.Increase in total amount of one specific clone

characteristic of benign reactive immunoproliferative disease.

LymphomasLymphomas

Hodgkin’s lymphomaNon-Hodgkin’s lymphoma

Historically difficult to classify, no one gold standard.

Revised European-American Lymphoma (REAL) classification adopted by WHO.Cell originsMorphologyImmunophenotypeGenetic featuresClinical features

Hodgkin’s LymphomaHighly treatable and curable.Occurs in young adults (15-35) and elderly

(over 55).Characterized by orderly spread of disease from

one lymph node group to another.Symptoms

FeverNight sweatsWeight lossEnlarged lymph nodesHepatomegaly, splenomegaly or

hepatosplenomegaly

Hodgkin’s LymphomaCharacterized by presence of Reed-Sternberg

cells.Abnormal lymphocyte which contains more than one

nucleusFound in affected lymph nodes and lymphoid organsB-cell lineage

Hodgkin’s Lymphoma – Diagnosis and TreatmentIn some cases there appears to be a

correlation between HL and infection with Epstein-Barr virus (EBV) infectionDetermine EBV antibody levelTest for EBV virus

Histological examination of lymph node biopsyFour types of HL differentiation based on cell

determinants (CD) found on the affected cells.Treatment

Radiation therapyChemotherapyStem cell transplant

Non-Hodgkin’s Lymphoma - NHLWide range of neoplasms that can include

any type of lymphoma EXCEPT Hodgkin’sB-cell lymphomas – most prevalent type 85%T- cell lymphomas

Prognosis varies significantly in severity.Slow progression – long term survival goodHighly aggressive – fatal

Non-Hodgkin’s Lymphoma - NHLAs lymphoma progresses and cancerous

lymphs spread beyond lymphatics body loses ability to fight infection.

Symptoms depend on type of NHLLymphadenopathyFeverNight sweatsWeight lossLoss of apetiteRed patches on the skinSeverely itchy skin, often affecting legs/feet

Non-Hodgkin’s Lymphoma - NDiagnosis

Tissue biopsyFlow cytometryImaging tests to determine where tumors are

located.Treatment

Watch and waitRadiation therapyChemotherapyTargeted therapy – use monoclonal antibodies to

target specific marker on cells where cancer starts.

Lymphoblastic LeukemiasCovered in Hematology, will not be covered

in this course.No questions for exams.Expected to know the material for future

exams and exit exam.Use material in textbook to enhance review

of the material.

Plasma Cell DyscrasiasCharacteristic is over production of a single

immunoglobulin component.Paraprotein or myeloma protein.Diagnosis and monitoring dependent on detecting

and quantitating the paraprotein.Screening and confirmatory tests performed in

most clinical laboratories.

Plasma Cell DyscrasiasInclude several related syndromes:

Multiple myelomaWaldenstrom’s macroglobulinemiaLight-chain diseaseHeavy-chain diseaseMonoclonal gammopathy of undetermined

significance.

Multiple MyelomaMalignancy of mature plasma cells.

Most serious and common of plasma cell dyscrasias.

Age of diagnosis 40 to 70 years, found in blacks twice as frequently as whites, and men twice as likely as women.

Have excess of plasma cells in the bone marrow.

Level of normal immunoglobulin decreased in proportion to abnormal immunoglobulin.

Multiple MyelomaImmunoglobulin produced by malignant

clone, can be of any class, IgG most common.

Important diagnostic feature is presence of Bence Jones protein in the urine.Abnormal production of free immunoglobulin

light chains, kappa or lambda.Can be detected by immunoelectrophoresis

or heat precipitation.

Multiple Myeloma - SymptomsThe presence of unexplained

AnemiaKidney dysfunctionElevated ESRBroken bones -lytic lesions cause bone pain

and fractures.Hemorrhage can occur due to

thrombocytopenia and paraprotein interferes in normal hemostasis.

Deposition of antibody derived material leads to organ dysfunctions, with kidneys most commonly involved.

Laboratory 10% or higher plasma cells in bone marrow. High serum protein level

Bence-Jones proteins being present in 60-70% of the cases.

Hyperviscosity develops when protein levels are high, especially with IgM producing tumors.

High levels of immunoglobulins lead to rouleaux formation being noted on blood smear.

Failure of bone marrow to produce normal number of hematopoietic cells leads to: AnemiaThrombocytopeniaNeutropenia

Multiple MyelomaBone Marrow –

Malignant plasma cells

Peripheral smear – pathologic rouleaux

Waldenstrom’s MacroglobulinemiaMalignant proliferation of IgM producing

lymphocytesMalignant cells more immature than plasma cells,

with appearance being between small lymph and plasma cell.

Plasmacytoid lymphs infiltrate bone marrow, spleen and lymph nodes.

Some IgM paraproteins behave as cryoglobulins, precipitate at cold temperatures.Occlude small vessels in patient’s extremities in cold

weather.Leads to skin sores and necrosis of fingers and toes.

Waldenstrom’s MacroglobulinemiaPatients with stable production of

monoclonal IgM without infiltration of marrow or lymphoid tissue are considered to have cold agglutinin syndrome.

Waldenstrom’s MacroglobulinemiaSymptoms

AnemiaHyperviscosityFatigueMucosal or GI bleedingNausea

TreatmentPlasmapheresisChemotherapyStem cell transplantMedian survival 5 years versus multiple

myeloma, 3 years.

Waldenstrom’s Macroglobulinemia

Cryoglobulins detected in blood or plasma by placing the sample in a refrigerator in the clinical laboratory.Precipitate forms at low temperatures (4C).Dissolves upon rewarming.May be associated with a cold red cell autoantibody

directed against the I antigen on the patient’s own red blood cells, may result in hemolytic anemia.

Laboratory DiagnosisMeasurement of immunoglobulin levels in

serum.Serum protein electrophoresis to separate

and detect abnormal levels, myelomas which produce only light chains may be missed.

Laboratory DiagnosisImmunoelectrophoresis used to evaluate

monoclonal gammopathies detected by SPE.

Immunofixation electrophoresis also used to evaluate monoclonal gammopathies.

Serum viscosity measurements useful for Waldenstrom’s macroglobulinemia or high levels of IgG or IgA paraproteins.

Bone marrow biopsy to establish diagnosis of lymphoproliferative disorder and determine extent of bone marrow replacement by malignancy.

Laboratory RolePerform specialized tests such as

Immunophenotyping by flow cytometryEvaluation of immunoglobulinsSerum protein electrophoresisImmunofixation electrophoresisEvaluation of genetic and chromosomal

abnormalities.May require additional education to be

qualified to perform.

Referenceshttp://www.ucl.ac.uk/~regfjxe/Arthritis.htm http://www.haps.nsw.gov.au/edrsrch/edinfo/

lupus.html http://pathmicro.med.sc.edu/ghaffar/

tolerance2000.htmhttp://repro-med.net/info/cat4.phphttp://stemcells.nih.gov/info/scireport/

chapter6.asphttp://www-ermm.cbcu.cam.ac.uk/

04008427h.htm http://www.biotest.de/ww/en/pub/folder_pharma/fields_of_use/

autoimmune_disease.htm http://72.14.203.104/search?q=cache:H7KcpVQ4xkYJ:www.peppypaws.com/

Glossary.html+Forbidden+clone+theory&hl=en&client=firefox-a

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