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