sec c group d mamba - medenilla. heterogenous group of lymphoproliferative malignancies with...
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NON HODGKIN’S LYMPHOMA
Sec C Group DMamba - Medenilla
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
Reed-Sternberg cells ◦ Separated from Hodgkin’s disease
Less predictable Greater predilection to disseminate to
extranodal sites
Non-Hodgkin’s Lymphoma
Can be divided into:◦ Aggressive (fast-growing) types◦ Indolent (slow-growing) types
Classification◦ B-cell◦ T-cell
Prognosis◦ Histologic type◦ Stage◦ Treatment
Non-Hodgkin’s Lymphoma
Indolent Lymphomas Aggressive Lymphomas
Relatively good prognosis
Median survival time:10 yrs
Not usually curable in advanced stages
Early-stage (I and II) indolent NHL ◦ treated effectively with
radiation therapy alone
Most of the indolent types are nodular (or follicular) in morphology
It has a shorter natural history
Significant number of patients◦ cured with combination
chemotherapy regimens
Precursor B cell Neoplasm◦ Precursor B-
lymphoblastic lymphoma Mature(Peripheral) B cell
neoplasm◦ B cell Chronic
Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
◦ B cell prolymphocytic leukemia
◦ Lymphoplasmacytic Lymphoma
◦ Splenic Marginal Zone B cell Lymphoma
B-cell Non-Hodgkin’s Lymphomas
o Plasma cell myeloma/ Plasmacytoma
o Extranodal Marginal Zone B cell Lymphoma of MALT Type
o Mantle Cell Lymphomao Follicular Lymphomao Nodal Marginal Zone B cell
Lymphomao Diffuse Large B-cell
Lymphomao Burkitt’s Lymphoma
Precursor T cell Neoplasm◦ Precursor T-
lymphoblastic lymphoma Mature(Peripheral) T cell
neoplasm◦ T cell prolymphocytic
leukemia◦ T cell granular lymphotic
leukemia◦ Aggressive NK cell Leukemia◦ Adult T cell Lymphoma◦ Extranodal NK/T cell
Lymphoma◦ Enteropathy-Type T cell
Lymphoma
T-cell Non-Hodgkin’s Lymphomas
◦ Hepatosplenic ɣδ T cell Lymphoma
◦ Subcutaneous Panniculitis-like T cell Lymphoma
◦ Mycosis Fungoides/Sezary Syndrome
◦ Anaplastic large cell lymphoma, primary cutaneous type
◦ Peripheral T cell Lymphoma, not otherwise specified
◦ Angioimmunoblastic T cell Lymphoma
◦ Anaplastic Large Cell Lymphoma, primary systemic type
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
General Aspects of Lymphoid Malignancies
Fauci, et al., 2008. Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 687
Non-Hodgkin’s Lymphoma
Fauci, et al., 2008. Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688
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 Lymhoma
Southern Japan & Carribean
Adult T cell Lymphoma
Environmental Factors:◦ Infectious agents◦ Chemical exposures◦ Medical treatments
Non-Hodgkin’s Lymphoma
Fauci, et al., 2008. Harrison’s Principles of Internal Medicine, 17th ed. US:Mcgraw Hill, p. 688
Non-Hodgkin’s Lymphoma
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 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
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
Immunology
A cell becomes committed to the B cell development arrangement of immunoglobulin genes
B cells development
A cell becomes committed to T cell differentiation ◦ upon migration to the thymus◦ Reaarangement of T cell antigen genes
T cell development
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
Malignancies
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
Chromosomal translocations
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
Clinical Features
2/3 of NHL (and virtually all cases of HL) present with NON TENDER 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
Lymphadenopathy
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
Other Signs And Symptoms
TYPE SALIENT CLINICAL FEATURES
Precursor 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/ Sézary 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
Stage 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
Ann Arbor Staging System
Source: p. 691
PATIENT: 70 y.o. Male•Gradual weight loss•Low grade fever•Anorexia•Body Weakness•Bilateral Cervical Lymph Nodes•Right Axillary Mass• Largest: 3x2cm• Discrete, nontender,
movable•Palpable spleen 3cm below L subcostal margin MCL
Stage
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
Ann Arbor Staging System
Source: p. 691
Staging for our patient:
Stage III1B
PATIENT: 70 y.o. Male•Gradual weight loss•Low grade fever•Anorexia•Body Weakness•Bilateral Cervical Lymph Nodes•Right Axillary Mass• Largest: 3x2cm• Discrete, nontender,
movable•Palpable spleen 3cm below L subcostal margin MCL
CBC ESR LDH ß2- microglobulin Serum protein electrophoresis Chemistry studies reflecting major organ
function CT scans (chest, abdomen, pelvis) Bone marrow biopsy
Ancillary procedures for Primary staging
Source: p. 692
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
International Prognostic Index (IPI)for NHL
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
PATIENT: 70 y.o. Male•Gradual weight loss•Low grade fever•Anorexia•Body Weakness•Bilateral Cervical Lymph Nodes•Right Axillary Mass• Largest: 3x2cm• Discrete, nontender, movable
•Palpable spleen 3cm below L subcostal margin MCL
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.
90Able to carry on normal activity; minor signs or symptoms of disease.
80Normal 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.
70Cares for self; unable to carry on normal activity or to do active work.
60Requires occasional assistance, but is able to care for most of his personal needs.
50Requires 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.
30Severely disabled; hospital admission is indicated although death not imminent.
20Very sick; hospital admission necessary; active supportive treatment necessary.
10 Moribund; fatal processes progressing rapidly.
0 Deadhttp://www.hospicepatients.org/karnofsky.html
PATIENT: 70 y.o. Male•Gradual weight loss•Low grade fever•Anorexia•Body Weakness•Bilateral Cervical Lymph Nodes•Right Axillary Mass• Largest: 3x2cm• Discrete, nontender, movable
•Palpable spleen 3cm below L subcostal margin MCL
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 have
Patients are grouped differently based upon the type of lymphoma
For 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%
International Prognostic Index (IPI)for NHL
Source: p. 692
PATIENT: 70 y.o. Male•Gradual weight loss•Low grade fever•Anorexia•Body Weakness•Bilateral Cervical Lymph Nodes•Right Axillary Mass• Largest: 3x2cm• Discrete, nontender,
movable•Palpable spleen 3cm below L subcostal margin MCL
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%
IPI for Patient (Pre treatment)
Treatment of Non- Hodgkin’s Lymphoma
Remission induction with combination therapy Consolidation phase:
◦ High dose systemic therapy◦ Treatment to eliminate CNS disease
Continuing therapy: prevent relapse and effect cure
Combination therapy used:◦ Rituximab- fludarabine- cyclophosphamide
Associated with grade III or IV neutropenia◦ Cyclophophamide- vincristine- prednisone◦ Cyclophosphamide- doxorubicin- vincristine- prednisone
Precursor B cell Lymphoblastic Leukemia
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 leukemia requiring therapy
◦ Second line agent for patients with tumors unresponsive to chlorambucil
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
Rai stage III or IV or Binet stage C (Bone Marrow failure)◦ Require initial therapy◦ Immune manifestations should be managed
independently of antileukemic therapy
B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia
Radiation and Surgery◦ Because it is often localized
Eradication of H. pylori infection With more extensive diseases: Chlorambucil
MALT Lymphoma
With disseminated disease: aggressive combination chemotherapy regimens+ autologous/ allogeneic BM transplantation
Localized diseases: combination chemotherapy + radiotherapy
Asymptomatic, elderly patient: observation + single- agent chemotherapy
Mantle Cell 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
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
Follicular 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
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
Diffuse Large B Cell Lymphoma
Treatment should begin 48 hrs after diagnosis
High doses of Cyclophosphamide Prophylactic therapy to CNS mandatory
Burkitt’s Lymphoma
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
Other B Cell Lymphoid Malignancies
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
Precursor T Cell Lymphoblastic Leukemia
Treatment regimens same as for other aggressive lymphomas (diffuse large B cell lymphoma)
Rituximab is omitted
Anaplastic Large T/ Null Cell Lymphoma
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
Mature/Peripheral T Cell Disorders
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