NON HODGKIN’S LYMPHOMA Sec C Group D. NHL is a heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses

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


• 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)



• Environmental Factors:– Infectious agents– Chemical exposures– Medical treatments



• 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



• 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


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

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


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)


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


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


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


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

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


• 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

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

Documents

NON HODGKIN’S LYMPHOMA Sec C Group D. NHL is a heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses