Transcript lymphoma 2011

Lymphoma
Farjah Hassan AlGahtani
Assistant Professor, Consultant
Hematology
Director 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
ALL
CLL
Lymphomas
MM
naïve
B-lymphocytes
Lymphoid
progenitor
AML
Hematopoietic
stem cell
Myeloid
progenitor
Plasma
cells
T-lymphocytes
Myeloproliferative disorders
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
B-cell development
CLL
stem
cell
mature
naive
B-cell
germinal
center
B-cell
memory
B-cell
lymphoid
progenitor
MM
progenitor-B
ALL
pre-B
immature
B-cell
DLBCL,
FL, HL
plasma cell
Classification
Biologically rational
classification
Clinically useful
classification
Diseases that have distinct
• morphology
• immunophenotype
• genetic features
• clinical features
Diseases that have distinct
• clinical features
• natural history
• prognosis
• treatment
Lymphoma classification
(2001 WHO)
• B-cell neoplasms
– precursor
– mature
• T-cell & NK-cell neoplasms
– precursor
– mature
• Hodgkin lymphoma
NonHodgkin
Lymphomas
A practical way to think of
lymphoma
Category
NonHodgkin
lymphoma
Hodgkin
lymphoma
Survival of
untreated
patients
Curability
To treat or
not to treat
Indolent
Years
Generally
not curable
Generally
defer Rx if
asymptomatic
Aggressive
Months
Curable in
some
Treat
Very
aggressive
Weeks
Curable in
some
Treat
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
age adjusted incidence/100,000/yr
Incidence of lymphomas in
comparison with other cancers in
Canada
70
60
lung
colorectal
breast
50
40
30
20
NHL
10
Hodgkin
lymphoma
0
1985
1990
1995
Year
2000
0-1
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
Incidence/100,000/annum
Age distribution of new NHL
cases in Canada
100
80
60
40
20
0
Age (years)
0-1
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
incidence/100,000/annum
Age distribution of new Hodgkin
lymphoma cases in Canada
6
5
4
3
2
1
0
Age (years)
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
Staging of lymphoma
Stage I
Stage II
Stage III
Stage IV
A: absence of B symptoms
B: fever, night sweats, weight loss
Three common lymphomas
• Follicular lymphoma
• Diffuse large B-cell lymphoma
• Hodgkin lymphoma
Relative frequencies of
different lymphomas
Non-Hodgkin
Lymphomas
Hodgkin
lymphom
a
NHL
Diffuse large
B-cell
Follicular
Other NHL
~85% of NHL are Blineage
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 –
Lymphocytic and Histiocytic
Cell
• “popcorn cell”
•Polylobated nucleus
•Lack of prominent eosinophilic
nucleoli
•Lack of halo
RS cell and variants
classic RS cell
lacunar cell
popcorn cell
(mixed cellularity)
(nodular sclerosis)
(lymphocyte
predominance)
A possible model of
pathogenesis
transforming
event(s)
EBV?
loss of apoptosis
cytokines
germinal
centre
B cell
RS cell
inflammatory
response
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
Brief ABVD Chemotherapy followed by irradiation for limited stage HL
Milan
Vancouver
GHSG
# of patients
114
170
204
Median follow
up (months)
38
42
22
Months of
ABVD
4
2
2
RT field
IF or EF
IF or EF
EF
DFS %
94
96
96
OS %
100
97
98
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 multiagent 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
MOPP
MOPP/ABVD
ABVD
CR
67%
83%
82%
*significant difference
between MOPP alone
and ABVD containing
regimens
DFS
50%
65%
61%
*significant difference
between MOPP alone
and ABVD containing
regimens
OS
66%
75%
73%
No significant
difference
Canellos 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
I,II
ABVD x 4
& radiation
III,IV
ABVD x 6
Failurefree
survival
70-80%
Overall 5
year
survival
80-90%
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