LymphomaLymphoma
OverviewOverview
Concepts, classification, Concepts, classification, lymphomagenesislymphomagenesis
EpidemiologyEpidemiology Clinical presentationClinical presentation DiagnosisDiagnosis StagingStaging Three important types of lymphomaThree important types of lymphoma
Conceptualizing lymphomaConceptualizing lymphoma
neoplasms of lymphoid origin (lymph neoplasms of lymphoid origin (lymph nodes or extranodal lymphatic nodes or extranodal lymphatic tissues), typically causing tissues), typically causing lymphadenopathylymphadenopathy
leukemia vs lymphomaleukemia vs lymphoma lymphomas as clonal expansions of lymphomas as clonal expansions of
cells (B or T lymphocytes or NK cells) cells (B or T lymphocytes or NK cells) at certain developmental stagesat certain developmental stages
Conceptualizing lymphomaConceptualizing lymphoma
Hodgkin Lymphoma – relatively Hodgkin Lymphoma – relatively uniform in histology, clinical uniform in histology, clinical presentation and course of the presentation and course of the diseasedisease
Non Hodgkin Lymphoma – a large Non Hodgkin Lymphoma – a large and heterogeneous category with and heterogeneous category with various cell origin, histology, clinical various cell origin, histology, clinical course. Comprises most of course. Comprises most of lymphomaslymphomas
B-cell developmentB-cell development
stemcell
lymphoidprecursor
progenitor-B
pre-B
immatureB-cell
maturenaiveB-cell
germinalcenterB-cell
memoryB-cell
plasma cell
DLBCL,FL, BL, HL
LBL, ALL
CLLMCL
MM
MZLCLL
The challenge of lymphoma The challenge of lymphoma classificationclassification
Clinically useful classification
Diseases that have distinct• clinical features• natural history• prognosis• treatment
Biologically rational classification
Diseases that have distinct• morphology• immunophenotype• genetic features• clinical features
Lymphoma classificationLymphoma classification(based on 2001 WHO(based on 2001 WHO))
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)
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)
WHO classificationWHO classification
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Clinical classification of NHLClinical classification of NHL
A practical way to think of lymphomaA practical way to think of lymphomaCategory Survival of
untreated patients
Curability To treat or not to treat
Non-Hodgkin lymphoma
Indolent Years Generally not curable
Generally defer Rx if asymptomatic
Aggressive Months Curable in some
Treat
Very aggressive
Weeks Curable in some
Treat
Hodgkin lymphoma
All types Variable – months to years
Curable in most
Treat
Mechanisms of lymphomagenesisMechanisms of lymphomagenesis Genetic alterations - lack of apoptosis Genetic alterations - lack of apoptosis
(bcl-2), proliferation (c-myc)(bcl-2), proliferation (c-myc) Infection – viral (EBV, HCV, HTLV-1), Infection – viral (EBV, HCV, HTLV-1),
bacterial – H. Pyloribacterial – H. Pylori Environmental factors – chemicals, dietEnvironmental factors – chemicals, diet Immunosuppression – AIDS, post Immunosuppression – AIDS, post
transplant (solid organs, BMT)transplant (solid organs, BMT) Chronic antigen stimulation - Chronic antigen stimulation -
autoimmunityautoimmunity Family history – 3.3 times increase riskFamily history – 3.3 times increase risk
Epidemiology of lymphomasEpidemiology of lymphomas
55thth most frequently diagnosed most frequently diagnosed cancer, ±4% of all cancers and cancer, ±4% of all cancers and cancer deaths in USAcancer deaths in USA
males > femalesmales > females whites > other races whites > other races incidenceincidence
• NHL increasing over timeNHL increasing over time• Hodgkin lymphoma stableHodgkin lymphoma stable
Epidemiology of lymphomasEpidemiology of lymphomas
Geographic variability – B cell Geographic variability – B cell lymphoma common in Western world, T lymphoma common in Western world, T and NK cell lymphoma – most of and NK cell lymphoma – most of lymphomas in South East Asialymphomas in South East Asia
Incidence of lymphomas in comparison Incidence of lymphomas in comparison with other cancers in Canadawith other cancers in Canada
Year
1985 1990 1995 2000
age
adju
sted
inci
denc
e/10
0,00
0/yr
0
10
20
30
40
50
60
70
Hodgkinlymphoma
NHL
breastcolorectallung
Age distribution of new NHL cases in Age distribution of new NHL cases in CanadaCanada
Age (years)
0-1
1-4
5-9
10-1
415
-19
20-2
425
-29
30-3
435
-39
40-4
445
-49
50-5
455
-59
60-6
465
-69
70-7
475
-79
80-8
485
+
Inci
denc
e/10
0,00
0/an
num
0
20
40
60
80
100
Age distribution of new Hodgkin Age distribution of new Hodgkin lymphoma cases in Canadalymphoma cases in Canada
Age (years)
0-1
1-4
5-9
10-1
415
-19
20-2
425
-29
30-3
435
-39
40-4
445
-49
50-5
455
-59
60-6
465
-69
70-7
475
-79
80-8
485
+
inci
denc
e/10
0,00
0/an
num
0
1
2
3
4
5
6
Risk factors for NHLRisk factors for NHL
immunosuppression or immunodeficiencyimmunosuppression or immunodeficiency connective tissue diseaseconnective tissue disease family history of lymphomafamily history of lymphoma infectious agentsinfectious agents chemicalschemicals dietary dietary ionizing radiationionizing radiation
Clinical manifestationsClinical manifestations VariableVariable
severity: asymptomatic to extremely illseverity: asymptomatic to extremely ill time course: evolution over weeks, months, time course: evolution over weeks, months,
or yearsor years Systemic manifestationsSystemic manifestations
fever, night sweats, weight loss, anorexia, fever, night sweats, weight loss, anorexia, pruritispruritis
Local manifestationsLocal manifestations lymphadenopathy, splenomegaly most lymphadenopathy, splenomegaly most
commoncommon any tissue potentially can be infiltratedany tissue potentially can be infiltrated
Other complications of Other complications of lymphomalymphoma
bone marrow failure (infiltration)bone marrow failure (infiltration) CNS infiltrationCNS infiltration immune hemolysis or immune hemolysis or
thrombocytopeniathrombocytopenia compression of structures (eg spinal compression of structures (eg spinal
cord, ureters) by bulky diseasecord, ureters) 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 treatment is initiatedbefore treatment is initiated
Need enough tissue to assess cells Need enough tissue to assess cells and architecture, and architecture, immunopenotyping, cytogenetics immunopenotyping, cytogenetics and molecular studiesand molecular studies- open bx - open bx vsvs core needle bx core needle bx vsvs FNA FNA
Stage I Stage II Stage III Stage IV
Staging of lymphoma – Ann Staging of lymphoma – Ann Arbor systemArbor system
A: absence of B symptomsB: fever, night sweats, weight loss
Staging PoceduresStaging Pocedures
History and physical examinationHistory and physical examination Bone marrow aspiration and biopsyBone marrow aspiration and biopsy Imaging – anatomical: X-ray, CT scan Imaging – anatomical: X-ray, CT scan
– neck, chest, abdomen; functional – – neck, chest, abdomen; functional – radio isotope scanningradio isotope scanning - gallium - gallium6767, , PET-CTPET-CT
Prognostic factorsPrognostic factors
Histologic typeHistologic type AgeAge Performance statusPerformance status Ann Arbor stageAnn Arbor stage Size of tumor massSize of tumor mass Extranodal involvementExtranodal involvement LDH, LDH, ββ2-microglobulin2-microglobulin Molecular or cytogenetic abnormalitiesMolecular or cytogenetic abnormalities Response to treatment Response to treatment
Prognostic models - IPIPrognostic models - IPI
A – age > 60 ► 1 pt.A – age > 60 ► 1 pt. P – performance status > 2 ►1 pt.P – performance status > 2 ►1 pt. L – LDH ↑ ► 1 PT.L – LDH ↑ ► 1 PT. E – extranodal sites > 1 ► 1 pt.E – extranodal sites > 1 ► 1 pt. S – stage ≥ 3 ► 1 pt. S – stage ≥ 3 ► 1 pt.
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
Non-Hodgkin lymphomaNon-Hodgkin lymphomaIncidenceIncidence
Diffuse large B-cell lymphoma
Follicularlymphoma
Other NHL
Follicular lymphomaFollicular lymphoma
most common type of “indolent” most common type of “indolent” lymphoma in the Western worldlymphoma in the Western world
usually widespread at presentationusually widespread at presentation often asymptomaticoften asymptomatic not curable (some exceptions)not curable (some exceptions) associated with BCL-2 gene associated with BCL-2 gene
rearrangement [t(14;18)]rearrangement [t(14;18)] cell of origin: germinal center B-cellcell of origin: germinal center B-cell
defer treatment if asymptomatic defer treatment if asymptomatic (“watch-and-wait”)(“watch-and-wait”)
several chemotherapy options if several chemotherapy options if symptomaticsymptomatic
median survival: yearsmedian survival: years although considered “indolent”, although considered “indolent”,
morbidity and mortality can be morbidity and mortality can be considerableconsiderable
transformation to aggressive transformation to aggressive lymphoma can occurlymphoma can occur
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%
TreatmentTreatment
Chemotherapy – single agent ± Chemotherapy – single agent ± corticosteroids, combination – CVP, CHOP corticosteroids, combination – CVP, CHOP etc.etc.
Monoclonal Ab – anti-CD20, anti-CD22, Monoclonal Ab – anti-CD20, anti-CD22, anti-CD30, anti-CD25, anti-CD52anti-CD30, anti-CD25, anti-CD52
Combination of chemotherapy and Combination of chemotherapy and monoclonal antibodiesmonoclonal antibodies
Radiotherapy - involved field, extended, Radiotherapy - involved field, extended, adjuvant adjuvant
Hodgkin lymphomaHodgkin lymphoma
Thomas Hodgkin(1798-1866)
Thomas Hodgkin MD
Morbid anatomist & Social Activist
August 17th 1798–
April 4th 1866
“On Some Morbid Appearance of the Absorbent
Glands and Spleen”.
Transactions of the Medical and Chirurgical Society 1832
Phoebus Levin
Guy’s hospital medical school
Here rest the body of THOMAS HODGKIN MDOf Bedford square London.
A man distinguished alike for scientific attainment medical skill and self sacrificing PhilanthropyHe Died at Jaffa the 4th of April 1867 in the 68 year of his age
Here rest the body of THOMAS HODGKIN MD
Of Bedford square London.
A man distinguished alike for scientific attainment medical skill and self sacrificing Philanthropy
He Died at Jaffa the 4th of April 1867 in the 68 year of his age
Hodgkin lymphomaHodgkin lymphoma
cell of origin: germinal centre B-cell cell of origin: germinal centre B-cell Reed-Sternberg cells (or RS variants) Reed-Sternberg cells (or RS variants)
in the affected tissuesin the affected tissues most cells in affected lymph node are most cells in affected lymph node are
polyclonal reactive lymphoid cells, polyclonal reactive lymphoid cells, not neoplastic cellsnot neoplastic cells
Reed-Sternberg cellReed-Sternberg cell
RS cell and variantsRS cell and variants
popcorn celllacunar cellclassic RS cell
(mixed cellularity) (nodular sclerosis) (lymphocytepredominance)
The Scream, 1893 Edvard Munch
Reed-Sternberg cell
A possible model of A possible model of pathogenesispathogenesis
germinalcentreB cell
transformingevent(s)
loss of apoptosis
RS cellinflammatory
response
EBV?
cytokines
Hodgkin lymphomaHodgkin lymphomaHistologic subtypesHistologic subtypes
Nodular lymphocyte predominance Nodular lymphocyte predominance Hodgkin lymphomaHodgkin lymphoma
Classical Hodgkin lymphomaClassical Hodgkin lymphoma• nodular sclerosis (most common nodular sclerosis (most common
subtype)subtype)• mixed cellularitymixed cellularity• lymphocyte-richlymphocyte-rich• lymphocyte depletedlymphocyte depleted
EpidemiologyEpidemiology
less frequent than non-Hodgkin less frequent than non-Hodgkin lymphomalymphoma
overall M>Foverall M>F peak incidence in 3rd decadepeak incidence in 3rd decade
Associated (etiological?) factorsAssociated (etiological?) factors
EBV infectionEBV infection smaller family sizesmaller family size higher socio-economic statushigher socio-economic status caucasian > non-caucasiancaucasian > non-caucasian possible genetic predispositionpossible genetic predisposition other: HIV? occupation? herbicides?other: HIV? occupation? herbicides?
Clinical manifestationsClinical manifestations::
lymphadenopathy, mostly mediastinallymphadenopathy, mostly mediastinal contiguous spreadcontiguous spread extranodal sites relatively uncommon extranodal sites relatively uncommon
except in advanced diseaseexcept in advanced disease ““B” symptomsB” symptoms Very rare causes obstruction, like Very rare causes obstruction, like
superior vena cava syndrom superior vena cava syndrom
Treatment and PrognosisTreatment and Prognosis
StageStage TreatmeTreatmentnt
Failure-Failure-free free
survivalsurvival
Overall Overall 5 year 5 year
survivalsurvival
I,III,II ABVD x 4 ABVD x 4 & &
radiationradiation
70-80%70-80% 80-90%80-90%
III,IVIII,IV ABVD x 6 ABVD x 6 oror
BEACOPPBEACOPP
60-70%60-70% 70-80%70-80%
Long term complications of Long term complications of treatmenttreatment
infertilityinfertility• MOPP > ABVD; males > femalesMOPP > ABVD; males > females• sperm banking should be discussedsperm banking should be discussed• premature menopausepremature menopause
secondary malignancysecondary malignancy• skin, AML, lung, MDS, NHL, thyroid, skin, AML, lung, MDS, NHL, thyroid,
breast...breast... cardiac diseasecardiac disease
Case: W.PCase: W.P..
25 year old woman25 year old woman persistent dry coughpersistent dry cough fever, NS, weight loss x 3 monthsfever, NS, weight loss x 3 months left cervical lymphadenopathy (2 cm)left cervical lymphadenopathy (2 cm) left supraclavicular node (2 cm)left supraclavicular node (2 cm) no splenomegalyno splenomegaly
W.P. at presentation
W.P. at presentation
Case: W.P. differential Case: W.P. differential diagnosisdiagnosis
lymphomalymphoma• HodgkinHodgkin• non-Hodgkinnon-Hodgkin
lung cancerlung cancer other neoplasms: thyroid, germ cellother neoplasms: thyroid, germ cell non-neoplastic causes less likelynon-neoplastic causes less likely
• sarcoid, TB, ...sarcoid, TB, ...
What nextWhat next??
Needle aspirate of LN: a few necrotic Needle aspirate of LN: a few necrotic cellscells
Needle biopsy of LN: admixture of B- Needle biopsy of LN: admixture of B- and T-lymphocytes. A few atypical and T-lymphocytes. A few atypical cells.cells.
Case: W.P. lymph node Case: W.P. lymph node biopsybiopsy
Case: W.P. lymph node Case: W.P. lymph node biopsybiopsy
Case: W.P. lymph node Case: W.P. lymph node biopsybiopsy
Case: W.P. staging Case: W.P. staging investigationsinvestigations
CT neck/chest/abdomen/pelvisCT neck/chest/abdomen/pelvis bone marrowbone marrow gallium scangallium scan Blood work: normal CBC, ESR, LDH, Blood work: normal CBC, ESR, LDH,
albuminalbumin
W.P. at presentation
Staging investigationsStaging investigations
bone marrow normalbone marrow normal CT scan: Lt. supraclavicular CT scan: Lt. supraclavicular
adenopathy; large mediastinal mass; adenopathy; large mediastinal mass; Rt. hilum; no disease below Rt. hilum; no disease below diaphragmdiaphragm
gallium avidgallium avid
What is her diagnosis and What is her diagnosis and stagestage??
nodular sclerosis HDnodular sclerosis HD stage IIBstage IIB with bulky mediastinal masswith bulky mediastinal mass
Case: W.P. TreatmentCase: W.P. Treatment
discussion with patient discussion with patient treatment with ABVD x 6 cyclestreatment with ABVD x 6 cycles
• constitutional symptoms gone after 1constitutional symptoms gone after 1stst cyclecycle
bulky mediastinal mass is a special bulky mediastinal mass is a special situation that merits additional situation that merits additional radiation after chemotherapyradiation after chemotherapy
W.P. post-chemotherapy
Case: W.P. post-ABVDCase: W.P. post-ABVD
response to chemo, but residual response to chemo, but residual mediastinal/hilar massmediastinal/hilar mass
repeat gallium scan negative, repeat gallium scan negative, suggesting that residual mass may suggesting that residual mass may just be fibrotic tissuejust be fibrotic tissue
proceed with radiotherapy as proceed with radiotherapy as originally plannedoriginally planned
Case: W.P. post-radiotherapyCase: W.P. post-radiotherapy
serial CT scans did not show serial CT scans did not show progressionprogression
patient remains in remissionpatient remains in remission