NON HODGKIN’S LYMPHOMA

1. NON HODGKIN’S LYMPHOMA

2. ETIOLOGY • Non-Hodgkin's lymphomas • Are more frequent in the elderly and more frequent in men • Patients with both primary and secondary immunodeficiency states are predisposed to developing non-Hodgkin's lymphomas. • Patients with HIV infection • Patients who have undergone organ transplantation • Patients with inherited immune deficiencies, the sicca syndrome, and rheumatoid arthritis

3. Incidence and the patterns of expression of non-Hodgkin's lymphomas • Various subtypes differ geographically. • T cell lymphomas • Common in Asia than in Western countries • Subtypes of B cell lymphomas such as Follicular lymphoma • Common in Western countries. • A specific subtype of non-Hodgkin's lymphoma known as the Angiocentric nasal T/natural killer (NK) cell lymphoma • Striking geographic occurrence • Most frequent in Southern Asia and parts of Latin America. • Another subtype of non-Hodgkin's lymphoma associated with infection by human T cell lymphotropic virus (HTLV) I • Southern Japan and the Caribbean

4. Environmental factors • Infectious agents, chemical exposures, and medical treatments • Agricultural chemicals • Increased incidence in non-Hodgkin's lymphoma. • Patients treated for Hodgkin's disease can develop non-Hodgkin's lymphoma • It is unclear whether this is a consequence of the Hodgkin's disease or its treatment

6. HTLV-I • Infects T cells and leads directly to the development of Adult T cell lymphoma (ATL) in a small percentage of infected patients. • The cumulative lifetime risk of developing lymphoma in an infected patient is 2.5%. • The virus is transmitted by infected lymphocytes ingested by nursing babies of infected mothers, blood-borne transmission, or sexually. • The median age of patients with ATL is ~56 years, emphasizing the long latency. • HTLV-I is also the cause of tropical spastic paraparesis • A neurologic disorder that occurs somewhat more frequently than lymphoma and with shorter latency and usually from transfusion-transmitted virus

7. EBV • Associated with the majority of primary central nervous system (CNS) lymphomas • It is strongly associated with the occurrence of extranodal nasal T/NK cell lymphomas in Asia and South America. • Associated with the development of Burkitt's lymphoma in Central Africa • Associated with the occurrence of aggressive non-Hodgkin's lymphomas in immunosuppressed patients in western countries.

8. HIV • Infection with HIV predisposes to the development of aggressive, B cell non-Hodgkin's lymphoma. • This may be through over expression of interleukin 6 by infected macrophages.

9. HELICOBACTER PYLORI • Induces the development of gastric MALT (mucosa-associated lymphoid tissue) lymphomas. • Patients treated with antibiotics to eradicate H. pylori have regression of their MALT lymphoma. • The bacterium does not transform lymphocytes to produce the lymphoma; instead, a vigorous immune response is made to the bacterium, and the chronic antigenic stimulation leads to the neoplasia. • MALT lymphomas of the skin may be related to Borrelia sp. infections, those of the eyes to Chlamydophilapsittaci, and those of the small intestine to Campylobacter jejuni.

10. CHRONIC HEPATITIS C • Associated with the development of lymphoplasmacytic lymphoma • HUMAN HERPESVIRUS 8 • Associated with primary effusion lymphoma in HIV-infected persons and multicentricCastleman's disease, • A diffuse lymphadenopathy associated with systemic symptoms of fever, malaise, and weight loss

12. IMMUNOLOGY

13. All lymphoid cells are derived from a common hematopoietic progenitor that gives rise to lymphoid, myeloid, erythroid, monocyte, and megakaryocyte lineages. • Through the ordered and sequential activation of a series of transcription factors, the cell first becomes committed to the lymphoid lineage and then gives rise to B and T cells. • About 75% of all lymphoid leukemias and 90% of all lymphomas are of B cell origin. • A cell becomes committed to B cell development • Begins to rearrange its immunoglobulin genes. • A cell becomes committed to T cell differentiation • Upon migration to the thymus and rearrangement of T cell antigen receptor genes.

14. Pathway of normal B cell differentiation and relationship to B cell lymphomas. HLA-DR, CD10, CD19, CD20, CD21, CD22, CD5, and CD38 are cell markers used to distinguish stages of development. Terminal transferase (TdT) is a cellular enzyme. Immunoglobulin heavy chain gene rearrangement (HCR) and light chain gene rearrangement or deletion ( R or D, R or D) occur early in B cell development. The approximate normal stage of differentiation associated with particular lymphomas is shown. ALL, acute lymphoid leukemia; CLL, chronic lymphoid leukemia; SL, small lymphocytic lymphoma.

15. Pathway of normal T cell differentiation and relationship to T cell lymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and CD71 are cell markers used to distinguish stages of development. T cell antigen receptors (TCR) rearrange in the thymus, and mature T cells emigrate to nodes and peripheral blood. ALL, acute lymphoid leukemia; T-ALL, T cell ALL; T-LL, T cell lymphoblastic lymphoma; T-CLL, T cell chronic lymphoid leukemia; CTCL, cutaneous T cell lymphoma; NHL, non-Hodgkin's lymphoma.

16. Although lymphoid malignancies often retain the cell-surface phenotype of lymphoid cells at particular stages of differentiation, this information is of little consequence. • The so-called stage of differentiation of a malignant lymphoma does not predict its natural history

17. Burkitt's leukemia • Clinically most aggressive lymphoid leukemia • It has the phenotype of a mature follicle center IgM-bearing B cell • Leukemias bearing the immunologic cell-surface phenotype of more primitive cells (e.g., pre-B ALL, CD10+) are less aggressive and more amenable to curative therapy than the "more mature" appearing Burkitt's leukemia cells

18. The apparent stage of differentiation of the malignant cell does not reflect the stage at which the genetic lesions that gave rise to the malignancy developed • Follicular lymphoma • Has the cell-surface phenotype of a follicle center cell • Its characteristic chromosomal translocation, the t(14;18), which involves juxtaposition of the antiapoptoticbcl-2 gene next to the immunoglobulin heavy chain gene, had to develop early in ontogeny as an error in the process of immunoglobulin gene rearrangement

19. The major value of cell-surface phenotyping is to aid in the differential diagnosis of lymphoid tumors that appear similar by light microscopy • Benign Follicular Hyperplasia may resemble Follicular Lymphoma • The demonstration that all the cells bear the same immunoglobulin light chain isotype strongly suggests the mass is a clonal proliferation rather than a polyclonal response to an exogenous stimulus

20. Genetic abnormalities • Malignancies of lymphoid cells are associated with recurring genetic abnormalities • Specific genetic abnormalities have not been identified for all subtypes of lymphoid malignancies, it is presumed that they exist • It can be identified at a variety of levels including gross chromosomal changes (i.e., translocations, additions, or deletions); rearrangement of specific genes that may or may not be apparent from cytogenetic studies; and overexpression, underexpression, or mutation of specific oncogenes

21. Altered expression or mutation of specific proteins • Many lymphomas contain balanced chromosomal translocations involving the antigen receptor genes • Immunoglobulin genes on chromosomes 2, 14, and 22 in B cells • T cell antigen receptor genes on chromosomes 7 and 14 in T cells • The rearrangement of chromosome segments to generate mature antigen receptors must create a site of vulnerability to aberrant recombination. • B cells are even more susceptible to acquiring mutations during their maturation in germinal centers • The generation of antibody of higher affinity requires the introduction of mutations into the variable region genes in the germinal centers. • Other nonimmunoglobulin genes, e.g., bcl-6, may acquire mutations as well.

22. Diffuse large B cell lymphoma • The translocation t(14;18) occurs in ~30% of patients and leads to overexpression of the bcl-2 gene found on chromosome 18. • Some other patients without the translocation also over express the BCL-2 protein. • This protein is involved in suppressing apoptosis—i.e., the mechanism of cell death most often induced by cytotoxic chemotherapeutic agent • A higher relapse rate has been observed in patients whose tumors overexpress the BCL-2 protein, but not in those patients whose lymphoma cells show only the translocation. Thus, particular genetic mechanisms have clinical ramifications.

23. Translocations and associated oncogenes • The great majority of tumors in patients with these diagnoses display these abnormalities. • t(14;18) in Follicular lymphoma • t(2;5) in Anaplastic large T/null cell lymphoma • t(8;14) in Burkitt's lymphoma • t(11;14) in Mantle cell lymphoma • In other types of lymphoma where a minority of the patients have tumors expressing specific genetic abnormalities, the defects may have prognostic significance. • Hodgkin's disease • No specific genetic abnormalities have been identified in other than aneuploidy.

26. In typical B cell CLL, trisomy 12 conveys a poorer prognosis. • In ALL in both adults and children, • Genetic abnormalities have important prognostic significance • t(9;22) • Have a much poorer outlook than patients who do not have this translocation • Other genetic abnormalities that occur frequently in adults with ALL include the t(4;11) and the t(8;14). • t(4;11) • Associated with younger age, female predominance, high white cell counts, and L1 morphology • t(8;14) • Associated with older age, male predominance, frequent CNS involvement, and L3 morphology. • Both are associated with a poor prognosis. • In childhood ALL, hyperdiploidy has been shown to have a favorable prognosis.

27. Gene profiling • Uses array of technology which allows the simultaneous assessment of the expression of thousands of genes • Provides the possibility to identify new genes with pathologic importance in lymphomas, the identification of patterns of gene expression with diagnostic and/or prognostic significance, and the identification of new therapeutic targets

28. Recognition of patterns of gene expression is complicated and requires sophisticated mathematical techniques. • Early successes using this technology in lymphoma include the identification of previously unrecognized subtypes of diffuse large B cell lymphoma whose gene expression patterns resemble either those of follicular center B cells or activated peripheral blood B cells. • Patients whose lymphomas have a germinal center B cell pattern of gene expression have a considerably better prognosis than those whose lymphomas have a pattern resembling activated peripheral blood B cells. • This improved prognosis is independent of other known prognostic factors. • Similar information is being generated in follicular lymphoma and mantle cell lymphoma. • The challenge remains to provide information from such techniques in a clinically useful time frame.

31. Relationship of International Prognostic Index (IPI) to survival. Kaplan-Meier survival curves for 1300 patients with various kinds of lymphoma stratified according to the IPI.

32. Specific Lymphoid Malignancies

33. Precursor B-Cell Neoplasms

34. 1. Precursor B Cell Lymphoblastic Leukemia/Lymphoma

36. Mature (Peripheral) B-cell neoplasms

37. 1. B Cell chronic lymphoid leukemia/small lymphocytic lymphoma

39. 2. Extranodal Marginal Zone B cell Lymphoma of MALT type

41. 3. Mantle Cell Lymphoma

43. 4. Follicular lymphoma

45. 5. Diffuse large b cell lymphoma

47. 6. Burkitt’s lymphoma

49. 7. Other b cell Lymphoid malignancies

50. A. B Cell Prolymphocytic Leukemia • Involves blood and marrow filtration by large lymphocytes with prominent nucleoli • High white cell count in patients • Splenomegaly and minimal lymphadenopathy • Complete response to therapy is poor