sec c group d mamba - medenilla. heterogenous group of lymphoproliferative malignancies with...

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


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



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




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


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


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)


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

http://emedicine.medscape.com/article/202677-overview

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



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



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


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


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



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



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

THANK YOU!

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