Lymphoma:AnOverview

DrLouiseConnell
05/03/2103

Overview

Concepts,classification,biology
Epidemiology
Clinicalpresentation
Diagnosis/Staging
Treatment/Prognosis
Stemcelltransplantation

WhatisLymphoma?
Neoplasmsoflymphoid
origin,characterizedby
theabnormal
proliferationBorTcellsin
lymphoidtissue
typicallycausing
lymphadenopathy
Clonalexpansionsofcells
atcertaindevelopmental
stages

ALL

CLL

Lymphomas

MM

nave
B-lymphocytes

Lymphoid
progenitor

AML
Hematopoietic
stem cell

Myeloid
progenitor

Plasma
cells
T-lymphocytes

Myeloproliferative disorders
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells

Bcelldevelopment
CLL

stem
cell

mature
naive
B-cell

germinal
center
B-cell

memory
B-cell

lymphoid
progenitor

MM

progenitor-B

ALL
pre-B
immature
B-cell

DLBCL,
FL, HL

plasma cell

Mechanismsof
lymphomagenesis

Geneticalterations
Infection
Antigenstimulation
Immunosuppression

Epidemiology
5th mostfrequentlydiagnosedcancerin
bothsexes
Males>females
Incidence
NHLincreasing
HLdecreasing

Diagnosisrequiresanadequate
biopsy
Diagnosisshouldbebiopsyproven before
treatmentisinitiated
Needenoughtissuetoassesscellsand
architecture
openbxvscoreneedlebxvsFNA

Stagingoflymphoma
StageI

StageII

StageIII

StageIV

A:absenceofBsymptoms
B:fever,nightsweats,weightloss

Classificationoflymphoma

Relativefrequenciesofdifferent
lymphomas
NonHodgkinLymphomas
DiffuselargeBcell
Hodgkin
lymphoma

NHL

Follicular
OtherNHL
~85%ofNHLareBlineage

Threecommonlymphomas

Follicularlymphoma(NHL)
DiffuselargeBcelllymphoma(NHL)
Hodgkinlymphoma(HL)

NonHodgkinsLymphoma(NHL)

Mostcommonhematologicmalignancy
60,000newcasesannually
6thleadingcauseofcancerdeath
Incidencerising
overallincidenceupby73%since1973
epidemic
2ndmostrapidlyrisingmalignancy

NHL
LymphomawithoutofReedSternbergcell
BlymphocytemorethanTlymphocyte
IdentificationofCDs(clusterdeterminants)
CD5=Tcelltype
CD20=Bcelltype

Extranodalinvolvementiscommon,more
thanHL

RiskfactorsforNHL

Immunosuppressionorimmunodeficiency
Connectivetissuedisease
Familyhistoryoflymphoma
Infectiousagents
Ionizingradiation

Clinicalmanifestations
Variable
severity:asymptomatictoextremelyill
timecourse:evolutionoverweeks,months,oryears

Systemicmanifestations
fever,nightsweats,weightloss,anorexia,pruritis

Localmanifestations
lymphadenopathy,splenomegalymostcommon
anytissuepotentiallycanbeinfiltrated

Biology
Indolentvs.AggressiveNHL
keyprincipleinunderstandingbiology,&approachtothepatient
Indolent=incurable
Aggressive=curable

ChromosomalAbnormalitiesinNHL
frequentchromosomaltranslocationsintoIggeneloci
t(8;14),t(2;8),t(8;22)Burkitts
t(14;18)follicularNHL

 AggressiveNHL
shortnaturalhistory
diseaseofrapidcellularproliferation

IndolentNHL
longnaturalhistory
diseaseofslowcellularaccumulation

IndolentNHL

Smallcelllymphocytic
Follicular
Mantlecell
Splenicmarginalzonelymphoma
MALTlymphoma
LymphoplasmacyticNHL

AggressiveNHL

DiffuselargeBcell
Diffusemixedcelllymphoma
Burkitt'slymphoma
Anaplasticlargecelllymphoma
Diffusemixedcelllymphoma

NHL:Classification
KeyPoints
cellsize:smallcellvs.largecell
nodalarchitecture:follicularvs.diffuse
Principle
Moreaggressive: diffuse,largecell
Moreindolent: follicular,smallcell

NHL:ApproachtothePatient
Approachdictatedmainlybyhistology
reliablepathologycrucial

Approachalsoinfluencedby:
stage
prognosticfactors
comorbidities

Stagingevaluation
HistoryandPE
Routinebloodwork
CBC,diff,plts,electrolytes,LFTs,uricacid,LDH,B2M

Lymphnodeexcisionbiopsy,imageguidedneedlebiopsy
CTscanschest/abd/pelvis
Bonemarrowevaluation
Otherstudiesasindicated(lumbarpuncture,etc)

Prognosis
Poorprognosticsigns

Increasedage
Advancedstage
Concomitantdisease
RaisedLDH
Tcelllymphoma

5yearssurvivalfortreatedpatients
>50%lowgrade
30%highgrade

IndolentNHL:typicalscenario

patientpresentswithpainlessadenopathy
otherwiseasymptomatic
follicularsmallcellhistology
averageage59
usuallystageIIIIVatdiagnosis

FollicularLymphoma

Mostcommontypeofindolent lymphoma
Usuallywidespreadatpresentation
Oftenasymptomatic
Incurable(someexceptions)
AssociatedwithBCL2generearrangement[t(14;18)]
Celloforigin:germinalcenterBcell

 IndolentNHL:guidingtreatmentprinciple
earlytreatmentdoesnotprolongoverallsurvival

Whentotreat?
constitutionalsymptoms
compromiseofavitalorganbycompressionor
infiltration,particularlythebonemarrow
bulkyadenopathy
rapidprogression
evidenceoftransformation

IndolentNHL:typicalscenario

Watchfulwaiting:24years
Firstremissionlength:34years
Secondremission:23years
Thirdremission:12years
Eachsubsequentremissionshorterthanprior
Mediansurvival812yearsforFLSC

IndolentNHL:treatmentoptions
watchfulwaiting
radiationtoinvolvedfields
singleagentchemotherapy
chlorambucil+ prednisone,fludarabine

combinationchemotherapy
CVP,CF,FND,CHOP

chemotherapy+ interferon
chemotherapy+monoclonalantibodies
monoclonalantibodies
radiolabeledmonoclonalantibodies
stemcelltransplantation

AggressiveNHL:typicalscenario
Patients notes B symptoms of several weeks
duration
Work-up reveals pathologic adenopathy
Histology: diffuse large cell lymphoma
~ 50% patients stage I-II, 50% stage III-IV
Average age 64
IPI score

DiffuselargeBcelllymphoma

Mostcommontypeofaggressive lymphoma
Accountsfor~31%ofalllymphomas
Usuallysymptomatic
Extranodalinvolvementiscommon
Celloforigin:germinalcenterBcell
Treatmentshouldbeoffered
Curableifchemosensitiveupfront,notsoif
chemorefractoryorrelapseswithin6months

AggressiveNHL:treatment
approach
StageIII:combinedmodalitytherapy
CHOPchemotherapyx3+IFradiotherapy
cureratearound70%

StageIIIIV(alsobulkystageII)
(R)CHOPchemotherapyx68cycles
cureratearound40%

(R)CHOPisthestandard

Othercomplicationsof
lymphoma

Bonemarrowfailure(infiltration)
CNSinfiltration
Immunehaemolysisorthrombocytopenia
Compressionofstructures(egspinalcord,
ureters)
Pleural/pericardialeffusions,ascites

 InternationalPrognosticIndex
RiskFactors(05)
age>60
twoormoreextranodalsites
performancestatus> 2
elevatedLDH
stageIIIIV

AgeadjustedIPI(03)

CR and OS stratified by IPI

# RFs

CR

5 yr OS

0,1

87%

73%

67%

51%

55%

43%

4,5

44%

26%

RoleforAutologousStemCell
Transplantation
AggressiveNHL
clearbenefitwhenusedforaggressiveNHLin
firstrelapseinappropriatelyselectedpatients
1/3ofthesepatientscanbecuredbySCT

IndolentNHL
noindicationthatpatientsarecured
noindicationthatOSisprolonged

NHL:futuredirections
Indolent

monoclonalantibodies(Rituximab)
radiolabeledmonoclonalantibodies
chemotherapycombinedwithantibodies
antibodiescombinedwithimmunomodulators

Aggressive
riskstratification
CHOPvs.CHOPplusSCT
chemotherapyplusantibodies

ClinicalTrials

Treatment

Hodgkinlymphoma
Celloforigin:germinalcentreBcell
ReedSternbergcells(orRSvariants)inthe
affectedtissues
Mostcellsinaffectedlymphnodeare
polyclonalreactivelymphoidcells,not
neoplasticcells

ReedSternbergcell

binucleate Hodgkin
cell with owl eye
appearance

RScellandvariants

classicRScell

lacunarcell

popcorncell

(mixedcellularity)

(nodularsclerosis)

(lymphocyte
predominance)

Apossiblemodelofpathogenesis
transforming
event(s)
EBV?

lossofapoptosis

cytokines
germinal
centre
Bcell

RScell

inflammatory
response

Hodgkinlymphoma
Histologicsubtypes
ClassicalHodgkinlymphoma

nodularsclerosis(mostcommonsubtype)
mixedcellularity
lymphocyterich
lymphocytedepleted

Epidemiology
LessfrequentthannonHodgkinlymphoma
14% of malignant lymphomas

OverallM>F
Bimodalagedistribution
Firstpeakin20s/30s
Secondpeak>age50
Mixed cellularity (MC) Hodgkins Disease is
more common at younger ages

Associated(etiological?)factors
PathogenesisofHDisstilllargelyunknown

EBVinfection
Highersocioeconomicstatus
Caucasian>noncaucasian
Possiblegeneticpredisposition
Other:HIV?occupation?herbicides?

ClinicalPresentation
Nontenderlymphnodesenlargement(localized)
neckandsupraclaviculararea
mediastinaladenopathy
other(abdominal,extranodaldisease)
Contiguousspread
Extranodalsitesrelativelyuncommonexceptinadvanceddisease

Systemicsymptoms(Bsymptoms)
fever
nightsweats
unexplainedweightloss(10%per6months)

othersymptoms

fatigue,weakness,pruritus
cough,chestpain,shortnessofbreath,venacavasyndrome
abdominalpain,boweldisturbances,ascites
bonepain

HLClinicalPresentation
SIGNS & SYMPTOMS
% OF
PATIENTS
Lymphadenopathy
Mediastinal mass
B symptoms
Fever, weight loss, night sweats
Hepatosplenomegaly

90
60
30
25

Most commonly involved lymph nodes are the

cervical and supraclavicular in 75%
Bone marrow is involved in 5% of patients

InterestingFeatures
PelEbsteinfevers
Alcoholinducedpain

StagingEvaluation
H&P
CBC,diff,plts
ESR,LDH,albumin,LFTs,Cr
Lymphnodeexcisionbiopsy,imageguidedneedlebiopsy
CTscanschest/abd/pelvis
bonemarrowevaluation
**PETorgalliumscan**
**lymphangiogramorlaparotomy**

Modified Ann Arbor Staging

E designation for extranodal disease
B symptoms
recurrent drenching night sweats during previous month
unexplained, persistent, or recurrent fever with temps
above 38 C during the previous month
unexplained weight loss of more than 10% of the body
weight during the previous 6 months

Criteria for bulk

10 cm nodal mass
mediastinal mass > 1/3 thorax diameter

 AdverseprognosticfeaturesforstageI&II(EORTCdata)

morethan3nodalsites
bulkyadenopathy
ESR>50
Bsymptoms
invasionintocriticalorgans
male
age>40
MCorLDsubtype

shouldprobablynotreceiveXRTaloneifanyoftheabove
present(excessiverelapserate)

Independentadverseprognostic
factors

Advancedstage(IIIIV)
Malesex
Age> 45
Albumin<4gm/dl
HgB<10.5mg/dl
StageIVdisease
WBCcount>15,000/mm3
Lymphocytecount<600/mm3
(Hasencleveretal,NEJM339,15061514;1998)

Treatment
Withappropriatetreatmentabout85%ofpatientswith
Hodgkinsdiseasearecurable
Approachdependsuponstage,prognosticfactors,andco
morbidities
StageIII
considerXRT,chemotherapy,orcombinedtherapy

BulkystageIII
combinedmodalitytherapy

StageIIIIV
ABVDx68cyclesgoldstandard

TreatmentandPrognosis
Stage

Treatmen
t

I,II

ABVDx4
&
radiation
ABVDx6

III,IV

Failure
free
survival
7080%

Overall5
year
survival
8090%

6070%

7080%

HodgkinsDisease
ResultsofTreatment
stage
5yearoverallsurvival
I
90%
II
90%
III
80%
IV
65%

HodgkinLymphoma
LateComplications
dependsupontreatmentmodalityutilized
XRTvs.MOPPvs.ABVDvs.CMT
issuesdependsupontheageofpatient
relativeriskshigherinyoungerpatients
absoluteriskshigherinolderpatients

majorfocusofcurrentclinicaltrialstomaintainhigh
cureratewhileminimizinglatecomplication
shortercoursesofchemotherapywithlowerradiationdoses
insmallerfields
eliminationofradiotherapy

Longtermcomplicationsof
treatment
Infertility
MOPP>ABVD;males>females
spermbankingshouldbediscussed
prematuremenopause
Secondarymalignancy
skin,AML,lung,MDS,NHL,thyroid,breast...
Cardiacdisease

RoleforStemCell
Transplantation
Clinicaltrialsshowbenefitforpatientswho
receivehighdosechemotherapyfollowed
bySCTforpatientswho
Relapseafterinitialtherapy
Areprimaryrefractory

HODGKINSDISEASE/LYMPHOMA
SALVAGEREGIMENS
Regimen
DHAP

Patients CR/PR toASCT

102
87%

60%

(dexamethasone, ara-C, cisplatin)

Mini-BEAM

89

77%

82%

75%

75%

62%

88%

84%

86%

64%

--

(BCNU, etoposide, ara-C, melphalan; 2 series)

Dexa-BEAM

225

(above plus dexamethasone; 3 series)

GDP

34

(gemcitabine, dexamethasone, oxaloplatin)

ICE

65

(ifosfamide, carboplatin, etoposide)

GND

38

(gemcitabine, vinorelbine, liposomal doxorubicin)

Complicationsofstemcell
transplantation

Infection
Venoocclusivedisease
Mucositis
Graftversushostdisease(GVHD)

Generalprognosisofstemcell
transplantation

Widelydependentupondiseasetype,
stage,stemcellsource

Summary
NHLincidenceincreasing,HLdecreasing
HLcureratequitehigh
approachisdictatedmainlybydiseasestage

NHLcureratemediocre
approachisdictatedmainlybyhistologicsubtype
indolentvs.aggressive
indolent:watchfulwaitingperfectlyacceptableforasymptomatic
patients
aggressive:requireaggressivetreatmentASAPtoachievecure

ApproachtothePatient
HL
approachdictatedmainlybywherethe
diseaseislocatedrather(resultsof
staging)thantheexacthistologicsubtype
NHL
approachisdictatedmainlybythe
histologicsubtyperatherthantheresults
ofstaging
Thinkoflongtermcomplications