NON HODGKIN’S LYMPHOMA

Palit daw kami ni riccel

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

• 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

• 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

Infectious Agents Associated with the Development of Lymphoid Malignancies

Infectious Agent Lymphoid Malignancy

Epstein-Barr virus Burkitt's lymphoma

Post–organ transplant lymphoma

Primary CNS diffuse large B cell lymphoma

Hodgkin's disease

Extranodal NK/T cell lymphoma, nasal type

HTLV-I Adult T cell leukemia/lymphoma

HIV Diffuse large B cell lymphoma

Burkitt's lymphoma

Hepatitis C virus Lymphoplasmacytic lymphoma

Helicobacter pylori Gastric MALT lymphoma

HHV 8 Primary effusion lymphoma

Multicentric Castleman's disease

• 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

• 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.

• 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.

• 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 Chlamydophila psittaci, and those of the small intestine to Campylobacter jejuni.

• CHRONIC HEP C – Associated with the development of

lymphoplasmacytic lymphoma

• HUMAN HERPESVIRUS 8– Associated with primary effusion lymphoma in HIV-

infected persons and multicentric Castleman's disease,

– A diffuse lymphadenopathy associated with systemic symptoms of fever, malaise, and weight loss

Diseases or Exposures Associated with Increased Risk of Development of Malignant Lymphoma

Inherited immunodeficiency disease

Autoimmune disease

Klinefelter's syndrome Sjögren's syndrome

Chédiak-Higashi syndrome Celiac sprue

Ataxia telangiectasia syndrome Rheumatoid arthritis and systemic lupus erythematosus

Wiscott-Aldrich syndrome Chemical or drug exposures

Common variable immunodeficiency disease

Phenytoin

Acquired immunodeficiency diseases

Dioxin, phenoxyherbicides

Iatrogenic immunosuppression Radiation

HIV-1 infection Prior chemotherapy and radiation therapy

Acquired hypogammaglobulinemia

IMMUNOLOGY

• 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.

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.

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.

• 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

• 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

• 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 antiapoptotic bcl-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

• 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

• 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

• 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.

• 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 agents

• 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.

• 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.

Cytogenetic Translocation and Associated Oncogenes Often Seen in

Lymphoid Malignancies Disease Cytogenetic

Abnormality Oncogene

CLL/small lymphocytic lymphoma

t(14;15)(q32;q13) —

MALT lymphoma t(11;18)(q21;q21) API2/MALT, BCL-10

Precursor B cell acute lymphoid leukemia

t(9;22)(q34;q11) or variant

t(4;11)(q21;q23)

BCR/ABL

AF4, ALLI

Precursor acute lymphoid leukemia

t(9;22)

t(1;19)

t(17;19)

t(5;14)

BCR, ABL

E2A, PBX

HLF, E2A

HOX11L2,CTIP2

Mantle cell lymphoma t(11;14)(q13;q32) BCL-1, IgH

Cytogenetic Translocation and Associated Oncogenes Often Seen in

Lymphoid Malignancies Disease Cytogenetic

Abnormality Oncogene

Follicular lymphoma t(14;18)(q32;q21) BCL-2, IgH

Diffuse large cell lymphoma

t(3;-)(q27;-)a

t(17;-)(p13;-)

BCL-6

p53

Burkitt's lymphoma, Burkitt's leukemia

t(8;-)(q24;-)a C-MYC

CD30+ Anaplastic large cell lymphoma

t(2;5)(p23;q35) ALK

Lymphoplasmacytoid lymphoma

t(9;14)(p13;q32) PAX5, IgH

• 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.

• 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

• 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.

SALIENT FEATURES

• 70 year old male• (+) Masses in both sides of the neck

– Progressively incresed in size since 1 year prior to consultation)

• Gradual weight loss• Low grade fever• Anorexia• Body weakness• (-) cough, shortness of breath, abdominal pain

and leg swelling

PHYSICAL EXAM FINDINGS

• BP: 120/80; PR: 87/min; RR: 20/min; T:38C• No pallor, no jaundice• Buccal mucosa intact• (+) bilateral cervical lymph nodes, largest measuring

3x2cm, discrete, non tender and movable• (+) mass in the axilla of the same character• (-) inguinal lymph nodes• Heart and lungs are normal• Spleen is palpable 3cm below the left subcostal margin

at the midclavicular line• (-) pedal edema

Staging Evaluation for Non-Hodgkin's Lymphoma

Physical examination

Documentation of B symptoms

Laboratory evaluation:

Complete blood counts

Liver function tests

Uric acid

Calcium

Serum protein electrophoresis

Serum 2-microglobulin

Chest radiograph

CT scan of abdomen, pelvis, and usually chest

Bone marrow biopsy

Lumbar puncture in lymphoblastic, Burkitt's, and diffuse large B cell lymphoma with positive marrow biopsy

Gallium scan (SPECT) or PET scan in large cell lymphoma

International Prognostic Index for NHL

Five clinical risk factors:

Age 60 years

Serum lactate dehydrogenase levels elevated

Performance status 2 (ECOG) or 70 (Karnofsky)

Ann Arbor stage III or IV

>1 site of extranodal involvement

Patients are assigned a number for each risk factor they have

Patients are grouped differently based upon the type of lymphoma

For diffuse large B cell lymphoma:

0, 1 factor = low risk: 35% of cases; 5-year survival, 73%

2 factors = low-intermediate risk: 27% of cases; 5-year survival, 51%

3 factors = high-intermediate risk: 22% of cases; 5-year survival, 43%

4, 5 factors = high risk: 16% of cases; 5-year survival, 26%

For diffuse large B cell lymphoma treated with R-CHOP:

0 factor = very good: 10% of cases; 5-year survival, 94%

1, 2 factors = good: 45% of cases; 5-year survival, 79%

3, 4, 5 factors = poor: 45% of cases; 5-year survival, 55%

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.

REFERENCES

• Harrison’s Principles of Internal Medicine, 17th Edition