Topic 3 Autoimmunity Part 8 Immunoproliferative Diseases

1. Topic 3 AutoimmunityPart 8 Immunoproliferative Diseases Terry Kotrla, MS, MT(ASCP)BB

2. 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.

3. 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.

4. 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.

5. 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

6. 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.

7. 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.

8. 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.

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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.

16. 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.

17. 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.

18. Plasma Cell Dyscrasias • Include several related syndromes: • Multiple myeloma • Waldenstrom’s macroglobulinemia • Light-chain disease • Heavy-chain disease • Monoclonal gammopathy of undetermined significance.

19. 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.

20. 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.

21. 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.

22. 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

23. Multiple Myeloma • Bone Marrow – Malignant plasma cells • Peripheral smear – pathologic rouleaux

24. 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.

25. Waldenstrom’s Macroglobulinemia • Patients with stable production of monoclonal IgM without infiltration of marrow or lymphoid tissue are considered to have cold agglutinin syndrome.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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

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