Topic 3 Autoimmunity
Part 8 Immunoproliferative Diseases
Terry Kotrla, MS, MT(ASCP)BB
Immunoproliferative Diseases
 Focus 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 nodes
 Tonsils
 Spleen
 Classified according to site malignancy first arose.
Immunoproliferative Diseases
 Plasma 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 Transformation
 Malignancy 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 Transformation
 Malignant 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 antigens
 Secretion of antibody
 Used to classify
Malignant Transformation - Lymphoma
 Arise 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 Transformation
 Immune 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 Diseases
 B-cell immunoproliferative disorders most commonly
evaluated.
 B-cell lineage develop into plasma cells
 Urine antibodies used to diagnose and evaluate certain B-cell
proliferations
 B-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.
Lymphomas
 Lymphomas
 Hodgkin’s lymphoma
 Non-Hodgkin’s lymphoma
 Historically difficult to classify, no one gold standard.
 Revised European-American Lymphoma (REAL)
classification adopted by WHO.





Cell origins
Morphology
Immunophenotype
Genetic features
Clinical features
Hodgkin’s Lymphoma
 Highly 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
 Fever
 Night sweats
 Weight loss
 Enlarged lymph nodes
 Hepatomegaly, splenomegaly or hepatosplenomegaly
Hodgkin’s Lymphoma
 Characterized by presence of Reed-Sternberg cells.
 Abnormal lymphocyte which contains more than one nucleus
 Found in affected lymph nodes and lymphoid organs
 B-cell lineage
Hodgkin’s Lymphoma – Diagnosis and
Treatment
 In some cases there appears to be a correlation between HL
and infection with Epstein-Barr virus (EBV) infection
 Determine EBV antibody level
 Test for EBV virus
 Histological examination of lymph node biopsy
 Four types of HL differentiation based on cell determinants
(CD) found on the affected cells.
 Treatment
 Radiation therapy
 Chemotherapy
 Stem cell transplant
Non-Hodgkin’s Lymphoma - NHL
 Wide range of neoplasms that can include any type of
lymphoma EXCEPT Hodgkin’s
 B-cell lymphomas – most prevalent type 85%
 T- cell lymphomas
 Prognosis varies significantly in severity.
 Slow progression – long term survival good
 Highly aggressive – fatal
Non-Hodgkin’s Lymphoma - NHL
 As lymphoma progresses and cancerous lymphs spread
beyond lymphatics body loses ability to fight infection.
 Symptoms depend on type of NHL
 Lymphadenopathy
 Fever
 Night sweats
 Weight loss
 Loss of apetite
 Red patches on the skin
 Severely itchy skin, often affecting legs/feet
Non-Hodgkin’s Lymphoma - N
 Diagnosis
 Tissue biopsy
 Flow cytometry
 Imaging tests to determine where tumors are located.
 Treatment
 Watch and wait
 Radiation therapy
 Chemotherapy
 Targeted therapy – use monoclonal antibodies to target specific
marker on cells where cancer starts.
Lymphoblastic Leukemias
 Covered 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 Dyscrasias
 Characteristic 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 Dyscrasias
 Include several related syndromes:
 Multiple myeloma
 Waldenstrom’s macroglobulinemia
 Light-chain disease
 Heavy-chain disease
 Monoclonal gammopathy of undetermined significance.
Multiple Myeloma
 Malignancy 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 Myeloma
 Immunoglobulin 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 - Symptoms
 The presence of unexplained
 Anemia
 Kidney dysfunction
 Elevated ESR
 Broken 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:
 Anemia
 Thrombocytopenia
 Neutropenia
Multiple Myeloma
 Bone Marrow – Malignant
plasma cells
 Peripheral smear –
pathologic rouleaux
Waldenstrom’s Macroglobulinemia
 Malignant proliferation of IgM producing lymphocytes
 Malignant 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 Macroglobulinemia
 Patients with stable production of monoclonal IgM without
infiltration of marrow or lymphoid tissue are considered to
have cold agglutinin syndrome.
Waldenstrom’s Macroglobulinemia
 Symptoms





Anemia
Hyperviscosity
Fatigue
Mucosal or GI bleeding
Nausea
 Treatment




Plasmapheresis
Chemotherapy
Stem cell transplant
Median 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 Diagnosis
 Measurement of immunoglobulin levels in serum.
 Serum protein electrophoresis to separate and detect
abnormal levels, myelomas which produce only light chains
may be missed.
Laboratory Diagnosis
 Immunoelectrophoresis 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 Role
 Perform specialized tests such as
 Immunophenotyping by flow cytometry
 Evaluation of immunoglobulins
 Serum protein electrophoresis
 Immunofixation electrophoresis
 Evaluation of genetic and chromosomal abnormalities.
 May require additional education to be qualified to perform.
References
 http://www.ucl.ac.uk/~regfjxe/Arthritis.htm
 http://www.haps.nsw.gov.au/edrsrch/edinfo/lupus.html
 http://pathmicro.med.sc.edu/ghaffar/tolerance2000.htm
 http://repro-med.net/info/cat4.php
 http://stemcells.nih.gov/info/scireport/chapter6.asp
 http://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
The End