Lymphoma David Lee MD, FRCPC. Overview Concepts, classification, biology Epidemiology Clinical presentation Diagnosis Staging Three important types of.

Lymphoma

David Lee MD, FRCPC

Overview

• Concepts, classification, biology• Epidemiology• Clinical presentation• Diagnosis• Staging• Three important types of lymphoma

Conceptualizing lymphoma

• neoplasms of lymphoid origin, typically causing lymphadenopathy

• leukemia vs lymphoma• lymphomas as clonal expansions of

cells at certain developmental stages

ALL MM CLL Lymphomas

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Myeloproliferative disordersAML

Lymphoidprogenitor T-lymphocytes

Plasmacells

B-lymphocytes

naïve

B-cell development

stemcell

lymphoidprogenitor

progenitor-B

pre-B

immatureB-cell

memoryB-cell

plasma cell

DLBCL,FL, HL

ALL

CLL

MM

germinalcenterB-cell

maturenaiveB-cell

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

Classification

Lymphoma classification(2001 WHO)

• B-cell neoplasms– precursor– mature

• T-cell & NK-cell neoplasms– precursor– mature

• Hodgkin lymphoma

Non-HodgkinLymphomas

A practical way to think of lymphoma

Category 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 lymphomagenesis

• Genetic alterations• Infection• Antigen stimulation• Immunosuppression

Epidemiology of lymphomas

• 5th most frequently diagnosed cancer in both sexes

• males > females• incidence

– NHL increasing– Hodgkin lymphoma stable

Incidence of lymphomas in comparison with 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 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

20

40

60

80

100

Age distribution of new Hodgkin lymphoma 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 NHL

• immunosuppression or immunodeficiency• connective tissue disease• family history of lymphoma• infectious agents• ionizing radiation

Clinical manifestations• Variable

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

years

• Systemic manifestations• fever, night sweats, weight loss, anorexia, pruritis

• Local manifestations• lymphadenopathy, splenomegaly most common• any tissue potentially can be infiltrated

Other complications of lymphoma

• bone marrow failure (infiltration)• CNS infiltration• immune hemolysis or thrombocytopenia• compression of structures (eg spinal

cord, ureters)• pleural/pericardial effusions, ascites

Diagnosis requires an adequate biopsy

• Diagnosis should be biopsy-proven before treatment is initiated

• Need enough tissue to assess cells and architecture– open bx vs core needle bx vs FNA

Stage I Stage II Stage III Stage IV

Staging of lymphoma

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

Three common lymphomas

• Follicular lymphoma• Diffuse large B-cell lymphoma• Hodgkin lymphoma

Relative frequencies of different lymphomas

Hodgkinlymphoma

NHL

Diffuse large B-cell

Follicular

Other NHL

Non-Hodgkin Lymphomas

~85% of NHL are B-lineage

Follicular lymphoma

• most common type of “indolent” lymphoma

• usually widespread at presentation• often asymptomatic• not curable (some exceptions)• associated with BCL-2 gene

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

• defer treatment if asymptomatic (“watch-and-wait”)

• several chemotherapy options if symptomatic

• median survival: years• despite “indolent” label, morbidity and

mortality can be considerable• transformation to aggressive lymphoma

can occur

Diffuse large B-cell lymphoma

• most common type of “aggressive” lymphoma

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

Hodgkin lymphoma

Thomas Hodgkin(1798-1866)

Classical Hodgkin Lymphoma

Hodgkin lymphoma

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

the affected tissues• most cells in affected lymph node are

polyclonal reactive lymphoid cells, not neoplastic cells

Reed-Sternberg cell

RS cell and variants

popcorn celllacunar cellclassic RS cell

(mixed cellularity) (nodular sclerosis) (lymphocytepredominance)

A possible model of pathogenesis

germinalcentreB cell

transformingevent(s)

loss of apoptosis

RS cellinflammatory

response

EBV?

cytokines

Hodgkin lymphomaHistologic subtypes

• Classical Hodgkin lymphoma– nodular sclerosis (most common subtype)– mixed cellularity– lymphocyte-rich– lymphocyte depleted

Epidemiology

• less frequent than non-Hodgkin lymphoma

• overall M>F• peak incidence in 3rd decade

Associated (etiological?) factors

• EBV infection• smaller family size• higher socio-economic status• caucasian > non-caucasian• possible genetic predisposition• other: HIV? occupation? herbicides?

Clinical manifestations:

• lymphadenopathy• contiguous spread• extranodal sites relatively uncommon

except in advanced disease• “B” symptoms

Treatment and Prognosis

Stage Treatment Failure-free

survival

Overall 5 year

survival

I,II ABVD x 4 & radiation

70-80% 80-90%

III,IV ABVD x 6 60-70% 70-80%

Long term complications of treatment

• infertility– MOPP > ABVD; males > females– sperm banking should be discussed– premature menopause

• secondary malignancy– skin, AML, lung, MDS, NHL, thyroid,

breast...• cardiac disease

Overview

• Concepts, classification, biology• Epidemiology• Clinical presentation• Diagnosis• Staging• Three important types of lymphoma