dr. Isbandiyah, SpPDdr. Isbandiyah, SpPD

LymphomaLymphoma

OverviewOverview

Concepts, classificationConcepts, classification EpidemiologyEpidemiology Clinical presentationClinical presentation DiagnosisDiagnosis StagingStaging Three important types of lymphomaThree important types of lymphoma

Conceptualizing lymphomaConceptualizing lymphoma

neoplasms of lymphoid origin, typically neoplasms of lymphoid origin, typically causing lymphadenopathycausing lymphadenopathy

lymphomas as clonal expansions of cells at lymphomas as clonal expansions of cells at certain developmental stagescertain developmental stages

EpidemiologyEpidemiology

55thth most frequently diagnosed cancer overall most frequently diagnosed cancer overall for both males and femalesfor both males and females

males > femalesmales > females incidenceincidence

– NHL increasing over timeNHL increasing over time– Hodgkin lymphoma stableHodgkin lymphoma stable

Lymphoma classificationLymphoma classification(based on 2001 WHO)(based on 2001 WHO)

B-cell neoplasmsB-cell neoplasms– PrecursorPrecursor B-cell neoplasms (2 types) B-cell neoplasms (2 types)– MatureMature B-cell neoplasms (19) B-cell neoplasms (19)– B-cell proliferations of uncertain malignant potential (2)B-cell proliferations of uncertain malignant potential (2)

T-cell & NK-cell neoplasmsT-cell & NK-cell neoplasms– PrecursorPrecursor T-cell neoplasms (3) T-cell neoplasms (3)– MatureMature T-cell and NK-cell neoplasms (14) T-cell and NK-cell neoplasms (14)– T-cell proliferation of uncertain malignant potential (1)T-cell proliferation of uncertain malignant potential (1)

Hodgkin lymphomaHodgkin lymphoma– Classical Hodgkin lymphomas (4)Classical Hodgkin lymphomas (4)– Nodular lymphocyte predominant Hodgkin lymphoma (1)Nodular lymphocyte predominant Hodgkin lymphoma (1)

Clinical manifestationsClinical manifestations VariableVariable

severity: asymptomatic to extremely illseverity: asymptomatic to extremely ill time course: evolution over weeks, months, or time course: evolution over weeks, months, or

yearsyears

Systemic manifestationsSystemic manifestations fever, night sweats, weight loss, anorexia, pruritisfever, night sweats, weight loss, anorexia, pruritis

Local manifestationsLocal manifestations lymphadenopathy, splenomegaly most commonlymphadenopathy, splenomegaly most common any tissue potentially can be infiltratedany tissue potentially can be infiltrated

Other complications of lymphomaOther complications of lymphoma

bone marrow failure (infiltration)bone marrow failure (infiltration) CNS infiltrationCNS infiltration immune hemolysis or thrombocytopeniaimmune hemolysis or thrombocytopenia compression of structures (eg spinal cord, compression of structures (eg spinal cord,

ureters) by bulky diseaseureters) by bulky disease pleural/pericardial effusions, ascitespleural/pericardial effusions, ascites

Diagnosis requires an adequate Diagnosis requires an adequate biopsybiopsy

Diagnosis should be Diagnosis should be biopsy-provenbiopsy-proven before before treatment is initiatedtreatment is initiated

Need enough tissue to assess cells and Need enough tissue to assess cells and architecturearchitecture– open bx open bx vsvs core needle bx core needle bx vsvs FNA FNA

Stage I Stage II Stage III Stage IV

Staging of lymphomaStaging of lymphoma

A: absence of B symptomsB: fever, night sweats, weight loss

Staging WorkupStaging Workup

CBC, chemistries, urinalysisCBC, chemistries, urinalysis USG or CT scans of chest, abdomen and USG or CT scans of chest, abdomen and

pelvispelvis Bone marrow biopsy and aspirateBone marrow biopsy and aspirate (Lumbar puncture)(Lumbar puncture)

– AIDS lymphomaAIDS lymphoma– T cell lymphoblastic lymphomaT cell lymphoblastic lymphoma– High grade lymphoma with positive marrowHigh grade lymphoma with positive marrow

Three types of lymphoma worth Three types of lymphoma worth knowing aboutknowing about

Follicular lymphomaFollicular lymphoma Diffuse large B-cell lymphomaDiffuse large B-cell lymphoma Hodgkin lymphomaHodgkin lymphoma

Follicular lymphomaFollicular lymphoma

most common type of “indolent” lymphomamost common type of “indolent” lymphoma usually widespread at presentationusually widespread at presentation often asymptomaticoften asymptomatic not curable (some exceptions)not curable (some exceptions) associated with BCL-2 gene rearrangement associated with BCL-2 gene rearrangement

[t(14;18)][t(14;18)] cell of origin: germinal center B-cellcell of origin: germinal center B-cell

Diffuse large B-cell lymphomaDiffuse large B-cell lymphoma

most common type of “aggressive” most common type of “aggressive” lymphomalymphoma

usually symptomaticusually symptomatic extranodal involvement is commonextranodal involvement is common cell of origin: germinal center B-cellcell of origin: germinal center B-cell treatment should be offeredtreatment should be offered curable in ~ 40%curable in ~ 40%

Hodgkin lymphomaHodgkin lymphoma

Thomas Hodgkin(1798-1866)

Hodgkin lymphomaHodgkin lymphoma

cell of origin: germinal centre B-cell cell of origin: germinal centre B-cell Reed-Sternberg cells (or RS variants) in the Reed-Sternberg cells (or RS variants) in the

affected tissuesaffected tissues most cells in affected lymph node are most cells in affected lymph node are

polyclonal reactive lymphoid cells, not polyclonal reactive lymphoid cells, not neoplastic cellsneoplastic cells

Reed-Sternberg cellReed-Sternberg cell

RS cell and variantsRS cell and variants

popcorn celllacunar cellclassic RS cell

(mixed cellularity) (nodular sclerosis) (lymphocytepredominance)

Hodgkin lymphomaHodgkin lymphomaHistologic subtypesHistologic subtypes

Classical Hodgkin lymphomaClassical Hodgkin lymphoma– nodular sclerosis (most common subtype)nodular sclerosis (most common subtype)– mixed cellularitymixed cellularity– lymphocyte-richlymphocyte-rich– lymphocyte depletedlymphocyte depleted

EpidemiologyEpidemiology

less frequent than non-Hodgkin lymphomaless frequent than non-Hodgkin lymphoma overall M>Foverall M>F peak incidence in 3rd decadepeak incidence in 3rd decade

Clinical manifestations:Clinical manifestations:

lymphadenopathylymphadenopathy contiguous spreadcontiguous spread extranodal sites relatively uncommon except extranodal sites relatively uncommon except

in advanced diseasein advanced disease ““B” symptomsB” symptoms

Treatment by StageTreatment by Stage

Stage Therapy % Cure

IA XRT 95

IIA XRT 85

IB, IIB XRT (Total Nodal) 70

IIIA XRT 70

IIIB, IV Combination Chemo 50

Chemotherapy RegimensChemotherapy Regimens

MOPPMOPP

– MMechlorethamine, echlorethamine, OOncovin, ncovin, PProcarbazine, rocarbazine, PPrednisonerednisone

ABVDABVD

– AAdriamycin, driamycin, BBleomycin, leomycin, VVinblastine, inblastine, DDacarbazineacarbazine

Long term complications of Long term complications of treatmenttreatment

infertilityinfertility– MOPP > ABVD; males > femalesMOPP > ABVD; males > females– premature menopausepremature menopause

secondary malignancysecondary malignancy– skin, AML, lung, MDS, NHL, thyroid, breast...skin, AML, lung, MDS, NHL, thyroid, breast...

cardiac disease cardiac disease after Adriamycin treatment.after Adriamycin treatment.

Non-Hodgkin’s LymphomaNon-Hodgkin’s Lymphoma

Types of LymphomaTypes of Lymphoma

Indolent (low grade)Indolent (low grade)– Life expectancy in years, untreatedLife expectancy in years, untreated– 85-90% present in Stage III or IV85-90% present in Stage III or IV– IncurableIncurable

IntermediateIntermediate Aggressive (high grade)Aggressive (high grade)

– Life expectancy in weeks, untreatedLife expectancy in weeks, untreated– Potentially curablePotentially curable

Commonly Used Commonly Used ClassificationsClassifications

WorkingWorking FormulationFormulation

Low GradeLow Grade

Small lymphocyticSmall lymphocytic

Follicular small cleavedFollicular small cleaved

Follicular mixedFollicular mixed

RappaportRappaport

Diffuse well-differentiated Diffuse well-differentiated lymphocytic lymphocytic (DWDL or WDLL)(DWDL or WDLL)

Nodular poorly Nodular poorly differentiated differentiated lymphocytic (NPDL)lymphocytic (NPDL)

Nodular mixed Nodular mixed lymphocytic-histiocytic lymphocytic-histiocytic (NM)(NM)

Commonly Used Commonly Used ClassificationsClassifications

WorkingWorking FormulationFormulation

Intermediate GradeIntermediate Grade

Follicular large cellFollicular large cell

Diffuse small cleaved cellDiffuse small cleaved cell

Diffuse mixedDiffuse mixed

Diffuse large cellDiffuse large cell

RappaportRappaport

Nodular histiocytic (NH)Nodular histiocytic (NH)

Diffuse poorly Diffuse poorly differentiated differentiated lymphocytic (DPDL)lymphocytic (DPDL)

Diffuse mixed Diffuse mixed lymphocytic-lymphocytic-histiocytic (DM)histiocytic (DM)

Diffuse histiocytic (DHL)Diffuse histiocytic (DHL)

Commonly Used Commonly Used ClassificationsClassifications

WorkingWorking FormulationFormulation

High GradeHigh Grade

Large cell immunoblasticLarge cell immunoblastic

Lymphoblastic lymphomaLymphoblastic lymphoma

Small noncleaved cellSmall noncleaved cell

• • Burkitt’sBurkitt’s

• • Non-Burkitt’sNon-Burkitt’s

RappaportRappaport

Diffuse histiocytic Diffuse histiocytic (DHL)(DHL)

Diffuse lymphoblasticDiffuse lymphoblastic

Diffuse Diffuse undifferentiated (DU)undifferentiated (DU)

Etiology of NHLEtiology of NHL

Immune suppressionImmune suppression– congenital (Wiskott-Aldrich)congenital (Wiskott-Aldrich)– organ transplant (cyclosporine)organ transplant (cyclosporine)– AIDSAIDS– increasing ageincreasing age

DNA repair defectsDNA repair defects– ataxia telangiectasiaataxia telangiectasia– xeroderma pigmentosumxeroderma pigmentosum

Etiology of NHLEtiology of NHL

Chronic inflammation and antigenic Chronic inflammation and antigenic stimulationstimulation– Helicobacter pylori Helicobacter pylori inflammation, stomachinflammation, stomach– Chlamydia psittaciChlamydia psittaci inflammation, ocular adnexal inflammation, ocular adnexal

tissuestissues– Sjögren’s syndromeSjögren’s syndrome

Viral causesViral causes– EBV and Burkitt’s lymphomaEBV and Burkitt’s lymphoma– HTLV-I and T cell leukemia-lymphomaHTLV-I and T cell leukemia-lymphoma– HTLV-V and cutaneous T cell lymphomaHTLV-V and cutaneous T cell lymphoma– Hepatitis CHepatitis C

Clinical FeaturesClinical Features

LymphadenopathyLymphadenopathy CytopeniasCytopenias Systemic symptomsSystemic symptoms HepatosplenomegalyHepatosplenomegaly FeverFever Night sweatsNight sweats

Treatment Options:Treatment Options:Indolent lymphomasIndolent lymphomas

WDLL, NPDLWDLL, NPDL 10-15% in Stage I or II10-15% in Stage I or II

– potentially curablepotentially curable– local radiotherapylocal radiotherapy

85-90% Stage III or IV85-90% Stage III or IV– incurableincurable– treatment does not prolong survivaltreatment does not prolong survival

Reasons to Treat in Reasons to Treat in Advanced Indolent LymphomasAdvanced Indolent Lymphomas

Constitutional symptomsConstitutional symptoms Anatomic obstructionAnatomic obstruction Organ dysfunctionOrgan dysfunction Cosmetic considerationsCosmetic considerations Painful lymph nodesPainful lymph nodes CytopeniasCytopenias

Treatment Options inTreatment Options inAdvanced Indolent LymphomasAdvanced Indolent Lymphomas

Observation only.Observation only. Radiotherapy to site of problem.Radiotherapy to site of problem. Systemic chemotherapySystemic chemotherapy

– oral agents: chlorambucil and prednisoneoral agents: chlorambucil and prednisone– IV agents: CHOP, COP, fludarabine, 2-CDA.IV agents: CHOP, COP, fludarabine, 2-CDA.

Antibody against CD20: Rituxan, Bexxar, Antibody against CD20: Rituxan, Bexxar, Zevalin.Zevalin.

Stem cell or bone marrow transplant.Stem cell or bone marrow transplant.

CHOP ChemotherapyCHOP Chemotherapy

CCyclophosphamide (Cytoxan)yclophosphamide (Cytoxan) HHydroxydaunorubicin ydroxydaunorubicin

(Adriamycin)(Adriamycin) OOncovin (vincristine)ncovin (vincristine) PPrednisonerednisone