LYMPHOMA
BY : KODAM HARSHITHA, MBBS 5TH YEAR
VOLGOGRAD STATE MEDICAL UNIVERSITY
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
Plasma
Lymphoid cells
progenitor T-lymphocytes
AML Myeloproliferative disorders
Hematopoietic Myeloid Neutrophils
stem cell progenitor
Eosinophils
Basophils
Monocytes
Platelets
Red cells
B-CELL DEVELOPMENT
memory
B-cell
stem CLL mature
germinal
center
cell
naive B-cell
B-cell
lymphoid
progenitor
progenitor-B
MM
ALL
pre-B DLBCL,
immature FL, HL
B-cell plasma cell
CLASSIFICATION
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
LYMPHOMA CLASSIFICATION
(2001 WHO)
• B-cell neoplasms
• precursor
• mature
Non-
• T-cell & NK-cell neoplasms Hodgkin
• precursor Lymphomas
• mature
• Hodgkin lymphoma
A PRACTICAL WAY TO THINK OF
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
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
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
20
40
60
80
0
100
0-1
1-4
5-9
10-14
15-19
20-24
25-29
30-34
35-39
CASES IN CANADA
40-44
45-49
Age (years)
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85+
AGE DISTRIBUTION OF NEW NHL
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
LYMPHOMA CASES IN CANADA
75-79
80-84
85+
AGE DISTRIBUTION OF NEW HODGKIN
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
Diffuse large
Hodgkin B-cell
NHL
lymphom Follicular
a Other NHL
~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 Lymphocytic and Histiocytic
• “owl’s eye” Cell
• 2 nuclear lobes with large • “popcorn cell”
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 –
usually eosinophilic
RS CELL AND VARIANTS
classic RS cell lacunar cell popcorn cell
(mixed cellularity) (nodular sclerosis) (lymphocyte
predominance)
A POSSIBLE MODEL OF PATHOGENESIS
transforming loss of apoptosis
event(s)
EBV?
cytokines
germinal
centre RS cell
inflammatory
B cell
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
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 38 42 22
follow 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
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
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 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%
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
