lymphoma farjah hassan algahtani assistant professor, consultant hematology director of transfusion...
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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