Lymphoma Farjah Hassan AlGahtani Assistant Professor, Consultant Hematology Director of Transfusion...

Lymphoma

Farjah Hassan AlGahtaniAssistant Professor, Consultant

HematologyDirector of Transfusion Medicine and

Blood Bank

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

ALLALL MM MM CLLCLL LymphomasLymphomas

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Myeloproliferative disordersMyeloproliferative disordersAMLAML

Lymphoidprogenitor T-lymphocytes

Plasmacells

B-lymphocytes

nanaïïveve

B-cell development

stemcell

lymphoidprogenitor

progenitor-B

pre-B

immatureB-cell

memoryB-cell

plasma cellplasma cell

DLBCL,FL, HL

ALL

CLL

MM

germinalgerminalcentercenterB-cellB-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)

Epidemiology

• ~ 20 000 new cases in North America and Europe every year– Annual incidence 2.7/100 000 per year– Annual mortality only 0.5/100 000 per year– North American lifetime risk – 1/250 to 1/300

• Young adults– 90% in adults 16-65– Median Age 35

• Slight male predominance• Much less frequent in eastern Asian

populations

Associated (etiological?) factors

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

herbicides?

• The EBV Association– 3x increased risk Hodgkins with serologically

confirmed infectious mononucleosis– EBV genomes detected in ~ 1/3 of Hodgkin

lymphoma tissues (developed countries)• Highest proportion mixed cellularity

– Population study showed high pre-diagnostic titres of EBV in patients later diagnosed with Hodgkin’s

– ?causative – especially in younger patients

Pathology

• B cell neoplasm– Unique due to the relative paucity of clonal

malignant cells in a background of reactive inflammatory cells

• 2 distinct entities– Nodular Lymphocyte predominant HL

• L&H cell “popcorn cell”

– Classical HL• Reed Sternberg cell• 4 subtypes

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

Reed Sternberg Cell

•“owl’s eye”

•2 nuclear lobes with large inclusion like nucleoli (eosinophilic)

•Clear halo around nucleolus (chromatin condensed to nuclear membrane)

•Abundant cytoplasm – usually eosinophilic

Lymphocytic and Histiocytic Cell

• “popcorn cell”

•Polylobated nucleus

•Lack of prominent eosinophilic nucleoli

•Lack of halo

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

Nodular Lymphocyte Predominant Hodgkin’s

Lymphoma• 5-10% of patients• “popcorn cell”

– Positive for CD 45– express B-cell associated antigens CD19, CD20, CD22,

CD79a, EMA– lack CD15 and CD30

• Background of primarily B lymphocytes +/- histiocytes

• Commonly presents early stage (~80%)• 4:1 M:F • slightly higher risk of development of NHL (2% to

5%)– Usually DLBCL

• Some treatment differences compared with classical Hodgkin’s

Classical Hodgkin’s Lymphoma

• Nodular Sclerosis• Mixed Cellularity• Lymphocyte-depleted• Lymphocyte-rich

• CD 15 and CD 30 positive +/- CD 20

Nodular Sclerosis

• partially nodular pattern with fibrous bands separating the nodules – lacunar type RS cells - multilobated nuclei

and small nucleoli with abundant pale cytoplasm that retracts in formalin-fixed sections producing an empty space

• 40%-70% of patients• Commonly present early stage (~70%)

– Often confined above the diaphragm• Slight female predominance• Commonly adolescents and young adults

Mixed Cellularity

• Classic RS cells common– Background of lymphocytes, eosinophils,

plasma cells and histiocytes

• 30%-50% of patients• More commonly presents with

advanced stage disease, B symptoms• Pediatric and older patients

• Lymphocyte-depleted– Classic RS cells with hypocellular fibrotic

or reticular background– Presents more commonly in older patients– Commonly advanced stage

• Less common involvement of peripheral nodes and mediastinum

• Lymphocye-rich– Similar to NLPHL but has classical

immunophenotype

Clinical Presentation

• Painless lymphadenopathy– Contiguous spread between lymphoid regions– Usually begins supra diaphragmatically

• Regional sub diaphragmatic disease < 10%

• Symptoms associated with compressive effect– *mediastinal mass– Abdominal/inguinal

• “B symptoms”– Wt loss > 10% over 6 months– Persistent fever >38.2– Drenching night sweats

• Puritis

• Weird and wonderful…– Alcohol induced pain– Nephrotic syndrome

• paraneoplastic secondary to lymphokines

– Dermatologic• ichthyosis, acrokeratosis (Bazex syndrome),

urticaria, erythema multiforme, erythema nodosum, necrotizing lesions, hyperpigmentation, and skin infiltration

• Neurologic– cerebellar degeneration, chorea,

neuromyotonia, limbic encephalitis, subacute sensory neuronopathy, subacute lower motor neuronopathy, and the stiff man syndrome

• Cholestatic liver disease• Hypercalcemia

Modified Ann Arbour Staging System

• I – Single lymph node region (I)

– or one extralymphatic site (IE)

• II – Two or more lymph node regions, same

side of the diaphragm (II)– or local extralymphatic extension plus

one or more lymph node regions same side of the diaphragm (IIE)

• III– Lymph node regions on both sides

of the diaphragm (III)– Which may be accompanied by

local extralymphatic extension (IIIE)

• IV– Diffuse involvement of one or more

extralymphatic organs or sites

• A = no B symptoms• B = atleast one of

– Unexplained weight loss > 10% during preceding 6 months

– Recurrent unexplained fever > 38– Recurrent night sweats

• Bulky disease– Single mass > 10 cm largest diameter

Staging Evaluation

• Pathology Review• History looking for B symptoms or other

symptoms suggesting systemic disease• Physical for lymphadenopathy and

organomegaly• CBC and ESR• Cr, ALP, LDH, bili, Ca, AST, albumin, SPEP• CXR – PA and lat• CT neck, thorax, abdomen and pelvis

• Bone marrow aspirate and biopsy if – B symptoms– WBC < 4– Hgb <120 (women) 130 (men)– Platelets < 125

• ENT examination if– Stage IA or IIA disease with upper

cervical lymph node involvement (supra-hyoid)

• Limited Stage Disease– Stage IA or IIA with no bulky disease

• Advanced Stage– Any stage with B symptoms or bulky

disease– Stage III and IV

Treatment

• Goal is to maximize cure rates with minimum long term treatment toxicity

Limited Stage Disease

• 30% of presenting cases• Expected long term disease control >

90%• Traditionally treated with radiotherapy

– Second malignancies– Premature cardiovascular disease

• Late 1990’s 3 studies of combined abbreviated ABVD and radiotherapy

MilanMilan VancouverVancouver GHSGGHSG

# of patients# of patients 114114 170170 204204

Median Median follow up follow up (months)(months)

3838 4242 2222

Months of Months of ABVDABVD

44 22 22

RT fieldRT field IF or EFIF or EF IF or EFIF or EF EFEF

DFS %DFS % 9494 9696 9696

OS %OS % 100100 9797 9898

Brief ABVD Chemotherapy followed by irradiation for limited stage HL

Bonfante et al. Proc Amer Soc Clin Oncol. 2001;20:281a (abstract 1120).Klasa et al. Annal Oncol. 1996;7(Suppl 3):21 (abstract 67).

Tesch et al Blood. 1998:485a.

• Randomized Comparison of ABVD Chemotherapy With a Strategy That Includes Radiation Therapy in Patients With Limited-Stage Hodgkin’s Lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative

Oncology Group – Meyer et al. Journal of Clinical Oncology, Vol 23, No

21 (July 20), 2005: pp. 4634-4642

• 399 patients• Median follow up 4.2 years

– Interim analysis – planned 12 yr follow up

• Age > 16 yrs• Previously untreated• Primary end point overall survival• ~85%-90% patients received

assigned protocol

• Limited Stage– ABVD X 4 cycles alone if CR after 2

cycles– ABVD X 2 + IFRT if < CR after 2

cycles

Advanced Stage Disease

• High cure rates observed with multi-agent chemotherapy for 30 years– Initially MOPP – disease free survival

50%• Sterility• Premature menopause• Leukomogenic

• 1992 - CALGB– RCT MOPP vs ABVD/MOPP alternating vs ABVD– 361 Stage III and IV patients– stratified according to age, stage, previous

radiation, histologic features, and performance status

– Examined response rates, disease free survival and overall survival

Canellos et al, NEJM; Volume 327:1478-1484

MOPPMOPP MOPP/MOPP/ABVDABVD

ABVDABVD

CRCR 67%67% 83%83% 82%82% *significant *significant difference between difference between MOPP alone and MOPP alone and ABVD containing ABVD containing regimensregimens

DFSDFS 50%50% 65%65% 61%61% *significant *significant difference between difference between MOPP alone and MOPP alone and ABVD containing ABVD containing regimensregimens

OSOS 66%66% 75%75% 73%73% No significant No significant differencedifference

Canellos et al, NEJM; Volume 327:1478-1484Canellos et al, NEJM; Volume 327:1478-1484

Newer Regimens

• Stanford V– Weekly chemotherapy for 12 weeks

with post radiation for bulk (> 5 cm) – 6.9 yr follow up

• Freedom form progression – 91%• Overall survival – 95%

– RCT Stanford V vs ABVD ongoing

• BEACOPP– Bleomycin, etoposide, doxyrubicin,

cyclophosphamide, vincristine, prednisone and procarbazine

– ***infertility, premature meonopause, higher rate of hematologic toxicity, increased rate second malignancy

• German Hodgkin Study Group HD9 trial– RCT – 1195 patients– COPP/ABVD+RT– BEACOPP (dose esc) +RT– BEACOPP + RT

Relapsed Disease

• Auto BMT– 2 RCT’s– Linch et al Lancet 1993 341: 1051-

1054– Schmitz et al Lancet 2002 359: 2065-

2071

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

Thanks