Understanding Lymphoma

dr. Agus Jati Sunggoro, Sp.PD.SubSp.HOM (K), FINASIM

Internist-Hematologist &Medical Oncologist

Sebelas Maret University- Surakarta
• Concepts, classification, biology
• Epidemiology
• Clinical presentation
• Diagnosis
• Staging
• Three important types of 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
inal center
naïve germ

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML Myeloproliferative disorders

Hematopoietic Myeloid Neutrophils
stem cell progenitor

Eosinophils

Basophils

Monocytes

Platelets

Red cells
 memory
B-cell
stem CLL germinal
cell mature center
naive B-cell
B-cell
lymphoid
progenitor

progenitor-B
MM
ALL
pre-B DLBCL,
immature FL, HL
B-cell plasma cell

Bone marrow Lymphoid tissue

Biologically rational Clinically useful
classification classification
Diseases that have distinct Diseases that have distinct
• morphology • clinical features
• immunophenotype • natural history
• genetic features • prognosis
• clinical features • treatment
• B-cell neoplasms
– precursor
– mature Non-
Hodgkin
• T-cell & NK-cell neoplasms Lymphomas

– precursor
– mature
• Hodgkin lymphoma
 Category Survival of Curability To treat or
untreated not to treat
patients

Non- Indolent Years Generally Generally

Hodgkin not curable defer Rx if
lymphoma asymptomatic
Aggressive Months Curable in Treat
some

Very Weeks Curable in Treat

aggressive some

Hodgkin All types Variable – Curable in Treat

lymphoma months to most
years
• Genetic alterations
• Infection
• Antigen stimulation
• Immunosuppression
• 5th most frequently diagnosed cancer in
both sexes
• males > females
• incidence
– NHL increasing
– Hodgkin lymphoma stable
age adjusted incidence/100,000/yr

70
60 lung
colorectal
50 breast

40

30
20 NHL
10 Hodgkin
lymphoma
0
1985 1990 1995 2000
Year
 Incidence/100,000/annum

0
20
40
60
80
100

0-1
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49

Age (years)
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
 incidence/100,000/annum

0
1
2
3
4
5
6

0-1
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54

Age (years)
55-59
60-64
65-69
70-74
75-79
80-84
85+
• immunosuppression or immunodeficiency
• connective tissue disease
• family history of lymphoma
• infectious agents
• ionizing radiation
• 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
• bone marrow failure (infiltration)
• CNS infiltration
• immune hemolysis or
thrombocytopenia
• compression of structures (eg spinal
cord, ureters)
• pleural/pericardial effusions, ascites
• 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

A: absence of B symptoms
B: fever, night sweats, weight loss
• Follicular lymphoma
• Diffuse large B-cell lymphoma
• Hodgkin lymphoma
 Non-Hodgkin
Lymphomas

Diffuse large
Hodgkin B-cell
NHL
lymphom Follicular
a Other NHL

~85% of NHL are B-

lineage
• 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
• 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%
Thomas Hodgkin
(1798-1866)
• ~ 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
• 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
• 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
• 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
 lhcell144x144

Reed Sternberg Cell Lymphocytic and Histiocytic

Cell
•“owl’s eye”
• “popcorn cell”
•2 nuclear lobes with large
inclusion like nucleoli •Polylobated nucleus
(eosinophilic)
•Lack of prominent eosinophilic
•Clear halo around nucleoli
nucleolus (chromatin
•Lack of halo
condensed to nuclear
membrane)
•Abundant cytoplasm –
classic RS cell lacunar cell popcorn cell
(mixed cellularity) (nodular sclerosis) (lymphocyte
predominance)
 transforming loss of apoptosis
event(s)
EBV?

cytokines
germinal
centre RS cell
inflammatory
B cell
response
• 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
• Nodular Sclerosis
• Mixed Cellularity
• Lymphocyte-depleted
• Lymphocyte-rich

• CD 15 and CD 30 positive +/- CD 20

• 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
• 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
• 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
•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
• 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
• Goal is to maximize cure rates with
minimum long term treatment toxicity
• 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 38 42 22
up (months)

Months of 4 2 2
ABVD
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
• 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

 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

• 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
• Auto BMT
– 2 RCT’s
– Linch et al Lancet 1993 341: 1051-1054
– Schmitz et al Lancet 2002 359: 2065-2071
Stage Treatment Failure- Overall 5
free year
survival survival
I,II ABVD x 4 70-80% 80-90%
& radiation

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

• infertility
– MOPP > ABVD; males > females
– sperm banking should be discussed
– premature menopause
• secondary malignancy
– skin, AML, lung, MDS, NHL, thyroid,
breast...
• cardiac disease
Thanks