NON HODGKIN’S LYMPHOMA
Sec C Group D
• NHL is a heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment.
• It usually originates in the lymphoid tissues and can spread to other organs.
• Separated from Hodgkin’s disease by the recognition of the Reed-Sternberg cells.
• However, unlike Hodgkin disease, NHL is much less predictable and has a far greater predilection to disseminate to extranodal sites.
Non-Hodgkin’s Lymphoma
Non-Hodgkin ‘s Lymphoma• It can occur at any age and are often marked by lymph nodes
that are larger than normal, fever, and weight loss.
• There are many different types of non-Hodgkin lymphoma.
• These types can be divided into:– Aggressive (fast-growing) types– Indolent (slow-growing) types
• They can be formed from either B-cells or T-cells. • Most NHLs are of B-cell origin.• The prognosis depends on the histologic type, stage, and
treatment.
Indolent lymphomas
• Relatively good prognosis, with median survival time as long as 10 years, but they are not usually curable in advanced stages.
• Early-stage (I and II) indolent NHL can be treated effectively with radiation therapy alone.
• Most of the indolent types are nodular (or follicular) in morphology.
Aggressive Lymphomas
• It has a shorter natural history, but a significant number of these patients can be cured with combination chemotherapy regimens.
B-cell non-Hodgkin lymphomas
• Burkitt lymphoma • Chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL)
• Diffuse large B-cell lymphoma
• Follicular lymphoma • Immunoblastic large cell
lymphoma• Precursor B-lymphoblastic
lymphoma • Mantle cell lymphoma
T-cell non-Hodgkin lymphomas
• Mycosis fungoides • Anaplastic large cell
lymphoma • Precursor T-lymphoblastic
lymphoma
General Aspects of Lymphoid Malignancies
Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma
Epidemiology Bimodal age distribution (20’s & 80s); males>females; whites>blacks
Elderly; men>women
Etiology/ Predisposition
HIVEBV
Primary & secondary immunodeficiency states; HIV; Organ transplant patients; inherited immune deficiency; Sicca syndrome; Rheumatoid arthritis
Fauci, et al., 2008. Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 687
Non-Hodgkin’s Lymphoma
• Incidence and patterns of expression of subtypes differ geographically– Asia – T cell lymphoma– Western countries – B cell (follicular) lymphoma– Southern Asia & Latin America – Angiocentric
nasal T/NK lymphoma– Southern Japan & Carribean – Adult T cell
Lymphoma (HTLV – 1)
Fauci, et al., 2008. Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688
Non-Hodgkin’s Lymphoma
• Environmental Factors:– Infectious agents– Chemical exposures– Medical treatments
Fauci, et al., 2008. Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688
Non-Hodgkin’s Lymphoma
• Infectious agents associated with the development of Lymphoid Malignancies
Infectious agent Lymphoid malignancy
Epstein-Barr virus Burkitt’s lymphomaPrimary CNS diffuse large B cell lymphomaExtranodal T cell/NK lymphoma
HTLV-1 Adult T cell leukemia/lymphoma
HIV Diffuse large B cell lymphomaBurkitt’s lymphoma
Hepatitis C virus Lymphoplasmacytic lymphoma
Helicobacter pylori Gastric MALT lymphoma
Human herpesvirus 8 Primary effusion lymphomaMulticentric Castleman’s disease
Fauci, et al., 2008. Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688
Non-Hodgkin’s Lymphoma
• Diseases or exposures associated with increased risk of development of malignant lymphomaInherited immunodeficiency states
Klinefelter’s syndromeChediak-Higashi syndromeAtaxia telangiectasia syndromeWiscott-Aldrich syndromeCommon variable immunodeficiency states
Acquired immunodeficiency states
Iatrogenic immunosuppressionHIV-1 infectionAcquired hypogammaglobulinemia
Autoimmune disease Sjogren’s syndromeCeliac sprueRheumatoid arthritis and SLE
Chemical and drug exposures PhenytoinDioxin, phenoxyherbicidesRadiationPrior chemotherapy and radiation therapy
Fauci, et al., 2008. Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688
Immunology
• All lymphoid cells are derived from a common hematopoietic progenitor
• Sequential activation of a series of TF’s, cells becomes committed to the lymphoid lineage T and B cells
B cells development
• A cell becomes committed to the B cell development arrangement of immunoglobulin genes
T cell development
• A cell becomes committed to T cell differentiation – upon migration to the thymus– Reaarangement of T cell antigen genes
Malignancies
• Associated with recurring genetic abnormalities
• At a variety of chromosomal changes – Gross (translocations, additions or deletions)– Rearrangement of specific genes– Underexpression– Mutation of specific oncogenes
Chromosomal translocations
• Antigen receptor genes• Immunoglobulin genes on Chr. 2, 14, and 22
on B cells• T cell antigen genes on chr. 7 and 14 in T cells.• Rearrangement to generate mature antigen
receptors create a site vulnerability to abnormal recombination
Non-Hodgkins Lymphoma
Clinical features
Non-Hodgkins Lymphoma
-heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment
-originates in the lymphoid tissues and can spread to other organs
-More common in elderly and males
http://emedicine.medscape.com/article/202677-overviewHarrison’s Principle of Internal Medicine 17th edition
Lymphadenopathy
• the most common manifestation of lymphoma• Waldeyer ring &mesenteric Lymph nodes are
commonly involved• Spreads in noncontiguous fashion
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 686
Lymphadenopathy
• 2/3 of NHL (and virtually all cases of HL) present with NONTEDER nodal enlargement often >2cm size that can be localized or generalized
• The remaining 1/3 of NHL’s arise at extranodal sites ( e.g. skin, stomach and brain)
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 668
Other Signs And Symptoms
• fevers, night sweats, weight loss, and fatigue• pruritus • shortness of breath, chest pain, cough,
abdominal pain and distension, or bone pain• pallor (suggesting anemia) • purpura, petechiae, or ecchymoses
(suggesting thrombocytopenia)
http://emedicine.medscape.com/article/202677-overviewHarrison’s Principle of Internal Medicine 17th edition
TYPE SALIENT CLINICAL FEATURESPrecursor B-cell acute lymphoblastic/leukemia/lymphoma
Predominantly children with Sx relating to pancytopenia secondary to marrow involvement; aggressive
Precursor T-cell acute lymphoblastic/leukemia/lymphoma
Predominantly adolescent males w/ thymic masses, variable splenic, hepatic and bone marrow involvement; aggressive
Burkitt lymphoma Adolescents/young adults w/ jaw or extranodal abdominal masses, uncommonly presents as “leukemia”; aggressive
Diffuse large B-cell lymphoma All ages but most common in adults; often appear as a single rapidly growing mass;30% extranodal; aggressive
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 671
TYPE SALIENT CLINICAL FEATURES
Extranodal marginal zone lymphoma In adults w/ chronic inflammatory diseases; may remain localized; indolent
Follicular Lymphoma Older adults w/ generalized lymphadenopathy and marrow involvement; indolent
Mantle cell lymphoma Older males with disseminated disease; moderately aggressive
Small lymphocytic lymphoma/ chronic lymphocytic leukemia
Older adults with bone marrow, lynph nodes, spleen and liver disease; most have peripheral blood involvement; autoimmune involvement and thrombocytopenia in a minority; indolent
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 671
TYPE SALIENT CLINICAL FEATURES
Anaplastic large cell lymphoma children and young adults, usually with lymph node and soft tissue disease; aggressive
Hairy cell leukemia Older males with pancytopenia and splenomegaly; indolent
Mycosis fungioides/ sezary syndrome Adult patients with cutaneous patches, plaques, nodules or generalized erythema; indolent
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 671
Lymphoid neoplasia can be suspected from all the clinical features but histological examination of lymph nodes or other involved tissues is required for the diagnosis
Robbins & Cotran Pathologic Basis of Diseases, 7th edition p. 668
Staging evaluation for NHL
Ann Arbor Staging system is applicable to both Hodgkin’s disease
and NHL
Ann Arbor Staging SystemStage Definition
I Involvement of a single LN region or lymphoid structure (eg. Spleen, thymus, Waldeyer’s ring)
II Involvement of ≥2 LN regions on the same side of the diaphragm (the mediastinum is a single site; hilar LN should be considered as “lateralized” and, when involved on both sides, constitute stage II disease)
III Involvement of LN regions or lymphoid structures on both sides of the diaphragm
III1 Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes
III2 Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III1
IV Involvement of extranodal site(s) beyond that designated as “E”>1 extranodal deposit at any locationAny involvement of liver or bone marrow
Source: p. 691
Ann Arbor Staging SystemStage Definition
A No symptoms
B - Unexplained weight loss of >10% of the body weight during the 6 months before staging investigation- Unexplained, persistent, or recurrent fever with temperatures >38°C during previous month- Recurrent drenching night sweats during the previous month
E Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow
Source: p. 691
Staging for our patient: Stage III1B
Ancillary procedures for Primary staging
• CBC• ESR• LDH• ß2- microglobulin• Serum protein electrophoresis• Chemistry studies reflecting major organ function• CT scans (chest, abdomen, pelvis)• Bone marrow biopsy
Source: p. 692
International Prognostic Index (IPI)for NHL
• A powerful predictor of outcome in all subtypes of NHL
• Scoring: based on presence or absence of – 5 adverse prognostic factors– may have none or all 5 of these
Source: p. 692
ECOG PERFORMANCE STATUS*
Grade ECOG
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours
3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5 Dead
http://ecog.dfci.harvard.edu/general/perf_stat.html
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA
Able to carry on normal activity and to work; no special care needed.
100 Normal no complaints; no evidence of disease.
90 Able to carry on normal activity; minor signs or symptoms of disease.
80 Normal activity with effort; some signs or symptoms of disease.
Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed.
70 Cares for self; unable to carry on normal activity or to do active work.
60 Requires occasional assistance, but is able to care for most of his personal needs.
50 Requires considerable assistance and frequent medical care.
Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly.
40 Disabled; requires special care and assistance.
30 Severely disabled; hospital admission is indicated although death not imminent.
20 Very sick; hospital admission necessary; active supportive treatment necessary.
10 Moribund; fatal processes progressing rapidly.
0 Dead
http://www.hospicepatients.org/karnofsky.html
International Prognostic Index (IPI)for NHL
Five clinical Risk Factors Age ≥ 60 years Serum lactate DH 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 havePatients are grouped differently based upon the type of lymphomaFor diffuse large B cell lymphoma 0, 1 factor 2 factors 3 factors 4, 5 factors
Low riskLow-intermediate riskHigh-intermediate riskHigh risk
35% of cases; 5-yr survival 73%27% 51%22% 43%16% 26%
For diffuse large B cell lymphoma treated with R-CHOP 0 factor 1, 2 factors 3, 4, 5 factors
Very goodGoodPoor
10% of cases; 5-yr survival 94%45% 79%45% 55%
Source: p. 692
IPI for Patient (Pre treatment)Age ≥ 60 yearsStage III1B
Age ≥ 60 yearsStage III1BSerum LDH levels elevated
2 factorsLow-intermediate risk27% of cases; 5-yr survival 51%
3 factorsHigh-intermediate risk22% of cases; 5-yr survival 43%
Treatment of Non- Hodgkin’s Lymphoma
Precursor B cell Lymphoblastic Leukemia
• Remission induction with combination therapy• Consolidation phase: – High dose systemic therapy– Treatment to eliminate CNS disease
• Continuing therapy: prevent relapse and effect cure
Precursor B cell Lymphoblastic Leukemia
• Combination therapy used:– Rituximab- fludarabine- cyclophosphamide• Associated with grade III or IV neutropenia
– Cyclophophamide- vincristine- prednisone– Cyclophosphamide- doxorubicin- vincristine-
prednisone
B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia
• Most common:– Chlorambucil: orally; few immediate side effects
• Chosen in elderly patients who require therapy
– Fludarabine: IV; with significant immune suppression• more active agent; with significant incidence of complete
remission• Regimens inclusive of this drug is chosen for young patients
presenting with leukemiarequiring therapy• Second line agent for patients with tumors unresponsive to
chlorambucin
B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia
• Rai stage O and Binet stage A ( no manifestations of disease other than BM involvement and lymphocytosis– Followed without a specific therapy
• With adequate number of circulating normal blood cells, asymptomatic– Require treatment for the first few years of follow
up
B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia
• Rai stage III or IV or Binet stage C (Bone Marrow failure)– Require initial therapy– Immune manifestations should be managed
independently of antileukemic therapy
MALT Lymphoma
• Radiation and Surgery– Because it is often localized
• Eradication of H. pylori infection• With more extensive diseases: Chlorambucil
Mantle Cell Lymphoma
• With disseminated disease: aggressive combination chemotherapy regimens+ autologous/ allogeneic BM transplantation
• Localized diseases: combination chemotherapy + radiotherapy
• Asymptomatic, elderly patient: observation + single- agent chemotherapy
Follicular Lymphoma
• Asymptomatic patient, older patient: watchful waiting
• For those who require treatment: single- agent chlorambucil or cyclophosphamide or combination therapy with CVP or CHOP
• For patients with localized follicular lymphoma: radiotherapy
Follicular Lymphoma
• Most responsive to chemotherapy and radiotherapy
• Active therapies:– Fludarabine– Interferon α: prolong survival in patients on
doxorubicin- containing combination therapies– Monoclonal antibodies with or without
radionuclides– Lymphoma vaccines
Diffuse Large B Cell Lymphoma
• Initial Treatmant: combination chemotherapy regimen= CHOP + Rituximab– Stage I or non bulky stage II: 3-4 cycles + field
radiotherapy– Bulky stage II, stage III, stage IV: 6-8 cycles or 4
cycles then reevaluate -> complete remission -> 2 more cycles, then therapy discontinued
Diffuse Large B Cell Lymphoma
• IPI : predict favorable responses– Score 0-1: 5 year survival >70 %– Score 4-5: 5 year survival ~20%
• For refractory cases or relapse– Salvage therapy– Alternative combination therapy– Autologous bone marrow transplantation
Burkitt’s Lymphoma
• Treatment should begin 48 hrs after diagnosis• High doses of cyclophosphamide• Prophylactic therapy to CNS mandatory
• Hairy cell leukemia: Cladribine• Splenic marginal zone lymphoma:
splenectomy, chlorambucil• Lymphoplasmacytic lymphoma: Chlorambucil,
fludarabine and cladribine• Nodal marginal zone lymphoma: treatment
same as follicular lymphoma
Precursor T Cell Lymphoblastic Leukemia
• Very intensive remission induction and consolidation regimens
• Leukemia- like regimens: for older children and young adults
• With high levels of LDH or BM, CNS involvement: BM transplantation
Anaplastic Large T/ Null Cell Lymphoma
• Treatment regimens same as for other aggressive lymphomas (diffuse large B cell lymphoma)
• Rituximab is omitted
• Mycoises Fungoides – Localized early stage: radiotherapy- total skin
electron beam irradiation– More advanced disease: topical glucocorticoids,
topical nitrogen mustard, phototherapy, psoralen with PUVA, electron beam radiation, IFN, Antibodies, fusion toxins and systemic cytotoxic therapy
• Adult T Cell Lymphoma/ Leukemia– Combination chemotherapy regimens