LymphomasLymphomas

Dr. Sabir M. AminDr. Sabir M. Amin

DefinitionDefinition

collection of lymphoid malignancies in collection of lymphoid malignancies in which malignant lymphocytes which malignant lymphocytes accumulate in lymph nodes andaccumulate in lymph nodes and

lymphoid tissues, leading to lymphoid tissues, leading to lymphadenopathy, extranodal lymphadenopathy, extranodal disease, and constitutional disease, and constitutional symptomssymptoms

ClassificationClassification

Stage IStage I

.. ..involvement of a single lymph node region or involvement of a single lymph node region or extra lymphatic organ or siteextra lymphatic organ or site

• •Stage IIStage II .. ..involvement of two or more lymph node regions or involvement of two or more lymph node regions or

an extra lymphatic site and one or more lymph an extra lymphatic site and one or more lymph node regions on same side of diaphragmnode regions on same side of diaphragm

• •Stage IIIStage III .. ..involvement of lymph node regions on both sides involvement of lymph node regions on both sides

of the diaphragm; may or may not be of the diaphragm; may or may not be accompanied by single extra lymphatic site or accompanied by single extra lymphatic site or splenic involvementsplenic involvement

Classification…contClassification…cont

Stage IVStage IV • •diffuse involvement of one or more diffuse involvement of one or more

cxtralymphatic organs including BMcxtralymphatic organs including BM • •subtypessubtypes::

A = absence of B symptomsA = absence of B symptomsB = presence of B symptomsB = presence of B symptoms

• •unexplained fever >38°Cunexplained fever >38°C • •unexplained weight loss (>10% of body unexplained weight loss (>10% of body

weight in 6 months)weight in 6 months) • •night sweatsnight sweats

Hodgkin’s diseaseHodgkin’s disease

malignant proliferation of lymphoid cells malignant proliferation of lymphoid cells with with Reed-SternbergReed-Sternberg cells (thought cells (thought to arise from germinal center B-cells)to arise from germinal center B-cells)

Bimodal distribution with peaks at the Bimodal distribution with peaks at the age of 20 years and >50 yearsage of 20 years and >50 years

.. ..association with Epstein-Barr virus in association with Epstein-Barr virus in up to 50% of casesup to 50% of cases

Clinical featuresClinical features

asymptomatic lymphadenopathy (70%)asymptomatic lymphadenopathy (70%)

• •non-tender, rubbery consistencynon-tender, rubbery consistency

• •cervical/supraclavicular (60-80%), axillary cervical/supraclavicular (60-80%), axillary (10-20%), inguinal (6-12%) • (10-20%), inguinal (6-12%) • splenomegaly (50%) ± hepatomegalysplenomegaly (50%) ± hepatomegaly

• •mediastinal mass found on routine CXR, mediastinal mass found on routine CXR, may be symptomatic (cough) rarely may may be symptomatic (cough) rarely may present with SVC syndrome, pleural present with SVC syndrome, pleural effusioneffusion

Cl. Features…contCl. Features…cont

B symptoms (especially in widespread B symptoms (especially in widespread disease; fever in 30%), pruritusdisease; fever in 30%), pruritus

• •alcohol-induced pain in nodes. alcohol-induced pain in nodes. nephrotic syndromenephrotic syndrome

.. ..starts at a single site in lymphatic starts at a single site in lymphatic system (node), spreads first to system (node), spreads first to adjacent nodes disease progresses in adjacent nodes disease progresses in contiguity with lymphatic systemcontiguity with lymphatic system

InvestigationInvestigation

CBCCBC .. ..anemia (chronic disease, rarely hemolytic), anemia (chronic disease, rarely hemolytic),

eosinophilia, leukocytosis, platelets normal eosinophilia, leukocytosis, platelets normal or increased early, decreased in advanced or increased early, decreased in advanced diseasedisease

BiochemistryBiochemistryLFTs (liver involvement)LFTs (liver involvement)RFTs (prior to initiating chemotherapy)RFTs (prior to initiating chemotherapy)

.. ..ALP, Ca (bone involvement)ALP, Ca (bone involvement) • •ESR, LDH (monitor disease progression)ESR, LDH (monitor disease progression)

InvestigationInvestigation

iimagingmaging .. ..CXR, CT chest (lymph nodes, mediastinal mass), CXR, CT chest (lymph nodes, mediastinal mass),

CT abdomen/pelvis (liver or spleen involvement), CT abdomen/pelvis (liver or spleen involvement), gallium scan (assess treatment response)gallium scan (assess treatment response)cardiac function assessmentcardiac function assessment - ( Echo for EF) for - ( Echo for EF) for pts at high risk of pre-treatment cardiac disease pts at high risk of pre-treatment cardiac disease (age :>60, history of HT, CHF, CAD, MI, CVA)(age :>60, history of HT, CHF, CAD, MI, CVA)

.... PFTs PFTs - if history of lung disease (COPD. smoking. - if history of lung disease (COPD. smoking. previous radiation to lung)previous radiation to lung)

.. ..excisional lymph nodeexcisional lymph node biopsy biopsy confirms diagnosis confirms diagnosis .. ..bone marrow biopsy to assess marrow infiltration bone marrow biopsy to assess marrow infiltration

(only necessary if B symptoms, stage III or IV, (only necessary if B symptoms, stage III or IV, bulky disease or cytopenia)bulky disease or cytopenia)

DiagnosisDiagnosis

Diagnosis can be made with lymph node Diagnosis can be made with lymph node biopsy. There are four mainbiopsy. There are four main histologic histologic subtypes subtypes based on the No. of based on the No. of lymphocytes, Reedlymphocytes, Reed--Sternberg cells, and Sternberg cells, and the presence of fibrous tissuethe presence of fibrous tissue::

       11..Lymphocyte predominanceLymphocyte predominance          ( after age 50 )( after age 50 ) 2.Mixed cellularity2.Mixed cellularity      most common, young)most common, young)  )) 3.Nodular sclerosis3.Nodular sclerosis            4.Lymphocyte depletion4.Lymphocyte depletion

TreatmentTreatment

11 ) )stage I-IIstage I-II: chemotherapy (ABVD) followed : chemotherapy (ABVD) followed by involved field XRTby involved field XRT( Adriamycin, Bleomycin, ( Adriamycin, Bleomycin, Vinblastin, Dacarbazine)Vinblastin, Dacarbazine)

22 ) )stage III-IVstage III-IV: chemotherapy (ABVD, : chemotherapy (ABVD, BEACOPP), with XRT for bulky diseaseBEACOPP), with XRT for bulky disease

33 ) )Relapse, resistant to therapy: high dose Relapse, resistant to therapy: high dose chemotherapy, bone marrow transplantchemotherapy, bone marrow transplantBEACOPP( bleomycin, etoposide, adriamycin, BEACOPP( bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisolone)cyclophosphamide, vincristine, procarbazine, prednisolone)

Complications of treatmentComplications of treatment

cardiac diseasecardiac disease - 2° to XRT, adriamycin is cardiotoxic - 2° to XRT, adriamycin is cardiotoxicpulmonary diseasepulmonary disease - secondary to bleomycin( interstitial - secondary to bleomycin( interstitial pneumonitis)pneumonitis)

infertilityinfertility - recommend sperm banking - recommend sperm banking secondary malignancysecondary malignancy in irradiated field in irradiated field

< ..< ..2%2% risk of MDS, AML (2° to treatment, usually within 8 risk of MDS, AML (2° to treatment, usually within 8 years)years)

• •solid tumours of lung, breast, >10 years after treatmentsolid tumours of lung, breast, >10 years after treatment • •non-Hodgkin's lymphomanon-Hodgkin's lymphoma

hypothyroidismhypothyroidism - post XRT - post XRT infectioninfection - post splenectomy (give Pneumovax, HiB, and - post splenectomy (give Pneumovax, HiB, and

pneumococcal conjugate vaccines), during treatmentpneumococcal conjugate vaccines), during treatment

Adverse prognostic factorsAdverse prognostic factors

11 . .serum albumin <4 gm/dLserum albumin <4 gm/dL22 . .hemoglobin <10.5 gm/dLhemoglobin <10.5 gm/dL

33 . .malemale44 . .stage IV diseasestage IV disease

55 . .age:<45 yearsage:<45 years66 . .leukocytosis (WBC >15000)leukocytosis (WBC >15000)

77 . .lymphocytopenia (lymphocytes lymphocytopenia (lymphocytes <8% of WBC )<8% of WBC )

Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma

malignant proliferation of lymphoid malignant proliferation of lymphoid cells without Reed-Sternberg cellscells without Reed-Sternberg cells..Originates from both B- (85%) and T- Originates from both B- (85%) and T- or NK- (15%) cellsor NK- (15%) cells

• •B cell NHL - e.g. Burkitt"s lymphoma, B cell NHL - e.g. Burkitt"s lymphoma, mantle cell lymphoma. follicular mantle cell lymphoma. follicular lymphomalymphoma

• •T cell NHL - e.g. mycosis fungoides. T cell NHL - e.g. mycosis fungoides. anaplastic large cell lymphomaanaplastic large cell lymphoma

GradeGrade

WHO/REAL classification system - 3 WHO/REAL classification system - 3 categories of NHLs based on natural categories of NHLs based on natural historyhistory::

11 ) )Low-gradeLow-grade ( (indolentindolent) 35-40% - e.g. ) 35-40% - e.g. follicular lymphoma, small lymphocytic follicular lymphoma, small lymphocytic Iymphoma/CLL, mantle cell lymphomaIymphoma/CLL, mantle cell lymphoma

22))Intermediate-gradeIntermediate-grade ( (aggressiveaggressive) 50% - ) 50% - e.g. diffuse large B-cell lymphomae.g. diffuse large B-cell lymphoma

33))High-gradeHigh-grade ( (highly aggressivehighly aggressive) 5% - e.g. ) 5% - e.g. Burkitt's lymphomaBurkitt's lymphoma

Clinical featuresClinical features

painless superficial lymphadenopathy, painless superficial lymphadenopathy, usually >1 lymph regionusually >1 lymph region

• •usually presents as widespread usually presents as widespread diseasedisease

• •B symptoms (fever, weight loss, night B symptoms (fever, weight loss, night sweats) not as common as in sweats) not as common as in Hodgkin's diseaseHodgkin's disease

• •cytopenia: anemia ± neutropenia ± cytopenia: anemia ± neutropenia ± thrombocytopenia if BM failsthrombocytopenia if BM fails

Clinical featuresClinical features

• •hepatosplenomegalyhepatosplenomegaly

• •retroperitoneal and mesenteric retroperitoneal and mesenteric involvement (2nd most common site of involvement (2nd most common site of involvement)involvement)

• •oropharyngeal involvement in 5-10% with oropharyngeal involvement in 5-10% with sore throat and obstructive apneasore throat and obstructive apnea

• •extranodal involvement - most commonly extranodal involvement - most commonly Gl tract, also testes. bone. kidneyGl tract, also testes. bone. kidney

• •CNS involvement in 1% (often with HIV)CNS involvement in 1% (often with HIV)

InvestigationInvestigation

CBCCBCnormocytic normochromic anemianormocytic normochromic anemia

• •autoimmune hemolytic anemiaautoimmune hemolytic anemia • •advanced disease: thrombocytopenia, advanced disease: thrombocytopenia,

neutropenia, and leukoerythroblastic anemianeutropenia, and leukoerythroblastic anemiaperipheral blood film sometimes shows lymphoma peripheral blood film sometimes shows lymphoma cellscells

BiochemistryBiochemistryincrease in uric acidincrease in uric acid

• •abnormal LFTs in liver metastasesabnormal LFTs in liver metastases • •increased LDH (rapidly progressing disease. poor increased LDH (rapidly progressing disease. poor

prognostic factor)prognostic factor)

ImagingImaging

CXR and CT for thoracic involvementCXR and CT for thoracic involvement

• •CT for abdominal and pelvic involvementCT for abdominal and pelvic involvement

• •gallium scan is useful for monitoring gallium scan is useful for monitoring response to treatment and evaluation of response to treatment and evaluation of residual tumour following therapyresidual tumour following therapy

DiagnosedDiagnosed by lymph node biopsy by lymph node biopsy

• •fine needle aspiration occasionally fine needle aspiration occasionally sufficient. excisional biopsy preferredsufficient. excisional biopsy preferred

bone marrow biopsybone marrow biopsy

TreatmentTreatment

LocalizedLocalized disease (e.g. Gl. brain, disease (e.g. Gl. brain, bone, head and neck)bone, head and neck)

surgery (if applicable)surgery (if applicable)

• •radiotherapy to primary site and radiotherapy to primary site and adjacent nodal areasadjacent nodal areas

• •adjuvant chemotherapyadjuvant chemotherapy

Treatment..conTreatment..con

indolentindolent lymphoma - goal of lymphoma - goal of treatment is symptom managementtreatment is symptom management

watchful waitingwatchful waiting

radiation therapy for localized diseaseradiation therapy for localized disease

chemotherapy (single agent, chemotherapy (single agent, combination or rituximab/ Rituxan, combination or rituximab/ Rituxan, an anti-CD20 Ab)an anti-CD20 Ab)

Treatment..conTreatment..con

AggressiveAggressive lymphoma - goal of treatment lymphoma - goal of treatment is curativeis curative

--combination chemotherapy: CHOP is combination chemotherapy: CHOP is mainstay. plus rituximab if B-cell mainstay. plus rituximab if B-cell lymphomalymphoma

--radiation for localized /bulky diseaseradiation for localized /bulky disease--CNS prophylaxis with high-dose CNS prophylaxis with high-dose

methotrexate (intrathecal or systemic) if methotrexate (intrathecal or systemic) if certain sites involvedcertain sites involved

--relapse, resistant to therapy: high dose relapse, resistant to therapy: high dose chemotherapy, BMTchemotherapy, BMT

Treatment…conTreatment…con

Highly aggressive Highly aggressive lymphomalymphoma

--Burkitt"s Lymphoma - short bursts of Burkitt"s Lymphoma - short bursts of intensive chemotherapyintensive chemotherapy

'-'-CODOX-M"' chemotherapy regimen CODOX-M"' chemotherapy regimen also often used ± IVACalso often used ± IVAC

--CNS prophylaxis and tumour lysis CNS prophylaxis and tumour lysis syndrome prophylaxissyndrome prophylaxis

ComplicationComplication

11))HypersplenismHypersplenism

22 ) )infectioninfection

33 ) )autoimmune hemolytic anemia and autoimmune hemolytic anemia and thrombocytopeniathrombocytopenia

44))vascular obstruction (from enlarged vascular obstruction (from enlarged nodes)nodes)

55 ) )tumour lysis syndrome (particularly tumour lysis syndrome (particularly in very aggressive lymphoma)in very aggressive lymphoma)

PrognosisPrognosis

poor prognostic factorspoor prognostic factors> •> •6060 years oldyears old

• •poor response to therapypoor response to therapy • •multiple nodal regionsmultiple nodal regions

• •elevated LDHelevated LDHnodes >5 cmnodes >5 cm

• •previous history of low-grade disease previous history of low-grade disease or AIDSor AIDS

Chronic lymphocytic leukemiaChronic lymphocytic leukemia )CLL))CLL)

indolent disease characterized by indolent disease characterized by clonal malignancy of mature B-cellsclonal malignancy of mature B-cells

most common leukemia in Western most common leukemia in Western worldworld

• •mainly older patient; median age 65 mainly older patient; median age 65 yearsyears

• •M>FM>F

PathophysiologyPathophysiology

accumulation of neoplastic accumulation of neoplastic lymphocytes in blood, bone marrow, lymphocytes in blood, bone marrow, lymph nodes and spleenlymph nodes and spleen

Clinical featuresClinical features

25%25% asymptomatic (incidental finding)asymptomatic (incidental finding) • •5-10%5-10% present with B symptoms (≥1 of: present with B symptoms (≥1 of:

unintentional weight loss ≥10% of body weight unintentional weight loss ≥10% of body weight within previous 6 months, fevers >38°C or night within previous 6 months, fevers >38°C or night sweats for ≥2 weeks without evidence of sweats for ≥2 weeks without evidence of infection, extreme fatigue)infection, extreme fatigue)

• •lymphadenopathy (75%), splenomegaly (35%), lymphadenopathy (75%), splenomegaly (35%), hepatomegaly (20%)hepatomegaly (20%)

• •immune dysregulation - autoimmune hemolytic immune dysregulation - autoimmune hemolytic anemia (Coombs +), immune thrombocytopenia anemia (Coombs +), immune thrombocytopenia purpura (ITP), hypogammaglobulinemia ± purpura (ITP), hypogammaglobulinemia ± neutropenianeutropenia

• •BM failure - late, secondary to marrow BM failure - late, secondary to marrow involvement by CLL cellsinvolvement by CLL cells

InvestigationInvestigation

CBCCBC: absolute lymphocytosis >5000: absolute lymphocytosis >5000

• •peripheral blood filmperipheral blood film

• •lymphocytes are small and maturelymphocytes are small and mature

• •smudge cellssmudge cells

flow cytometryflow cytometry

cytogeneticscytogenetics - FISH - FISH

bone marrow aspiratebone marrow aspirate

lymphocytes >30% of all nucleated cellslymphocytes >30% of all nucleated cells

Natural history and treatmentNatural history and treatment

natural history - indolent but incurable, with slow natural history - indolent but incurable, with slow progression; thus select gentlest treatment that progression; thus select gentlest treatment that will control symptomswill control symptomsobservation if early, stable, asymptomaticobservation if early, stable, asymptomaticintermittent chlorambucil or fludarabineintermittent chlorambucil or fludarabine

corticosteroids, IVIG - especially for autoimmune corticosteroids, IVIG - especially for autoimmune phenomenaphenomena

• •radiotherapyradiotherapy • •chemotherapy - including Rituximab (anti-CD20 chemotherapy - including Rituximab (anti-CD20

mAb)mAb) • •small minority present with aggressive disease small minority present with aggressive disease

usually associated with chromosomal usually associated with chromosomal abnormalities (e.g. p53 deletion)abnormalities (e.g. p53 deletion)

• •99 year median survival, but varies greatlyyear median survival, but varies greatly

ComplicationsComplications

11 ) )5%5% undergo undergo Richter's Richter's Transformation - aggressive Transformation - aggressive transformation to Diffuse Large B-transformation to Diffuse Large B-Cell LymphomaCell Lymphoma

22 ) )hyperuricemia with treatmenthyperuricemia with treatment