Lymphoma

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Lymphoma

• Farjah Hassan AlGahtani
• Assistant Professor, Consultant Hematology
• Director of Transfusion Medicine and Blood Bank

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Overview

• Concepts, classification, biology
• Epidemiology
• Clinical presentation
• Diagnosis
• Staging
• Three important types of lymphoma

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Conceptualizing lymphoma

• neoplasms of lymphoid origin, typically causing
  lymphadenopathy
• leukemia vs lymphoma
• lymphomas as clonal expansions of cells at
  certain developmental stages

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naïve
germinal center
B-lymphocytes
Plasma cells
Lymphoid progenitor
T-lymphocytes
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B-cell development
memory B-cell
germinal center B-cell
stem cell
mature naive B-cell
lymphoid progenitor
progenitor-B
pre-B
immature B-cell
plasma cell
Bone marrow
Lymphoid tissue
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Classification
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Lymphoma classification(2001 WHO)

• B-cell neoplasms
• precursor
• mature
• T-cell NK-cell neoplasms
• precursor
• mature
• Hodgkin lymphoma

Non- Hodgkin Lymphomas
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A practical way to think of lymphoma
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Mechanisms of lymphomagenesis

• Genetic alterations
• Infection
• Antigen stimulation
• Immunosuppression

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Epidemiology of lymphomas

• 5th most frequently diagnosed cancer in both
  sexes
• males gt females
• incidence
• NHL increasing
• Hodgkin lymphoma stable

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Incidence of lymphomas in comparison with other
cancers in Canada
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Age distribution of new NHL cases in Canada
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Age distribution of new Hodgkin lymphoma cases in
Canada
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Risk factors for NHL

• immunosuppression or immunodeficiency
• connective tissue disease
• family history of lymphoma
• infectious agents
• ionizing radiation

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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

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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

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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

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Staging of lymphoma
A absence of B symptoms B fever, night sweats,
weight loss
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Three common lymphomas

• Follicular lymphoma
• Diffuse large B-cell lymphoma
• Hodgkin lymphoma

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Relative frequencies of different lymphomas
Non-Hodgkin Lymphomas
Diffuse large B-cell
Hodgkin lymphoma
NHL
Follicular
Other NHL
85 of NHL are B-lineage
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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(1418)
• cell of origin germinal center B-cell

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• 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

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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

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Hodgkin lymphoma
Thomas Hodgkin (1798-1866)
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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

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Associated (etiological?) factors

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

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• 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
  Hodgkins
• ?causative especially in younger patients

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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
• LH cell popcorn cell
• Classical HL
• Reed Sternberg cell
• 4 subtypes

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Classical Hodgkin Lymphoma
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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

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Reed-Sternberg cell
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• Reed Sternberg Cell
• owls 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

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RS cell and variants
popcorn cell
lacunar cell
classic RS cell
(lymphocyte predominance)
(mixed cellularity)
(nodular sclerosis)
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A possible model of pathogenesis
loss of apoptosis
transforming event(s)
EBV?
cytokines
germinal centre B cell
RS cell
inflammatory response
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Nodular Lymphocyte Predominant Hodgkins 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)
• 41 MF
• slightly higher risk of development of NHL (2 to
  5)
• Usually DLBCL
• Some treatment differences compared with
  classical Hodgkins

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Classical Hodgkins Lymphoma

• Nodular Sclerosis
• Mixed Cellularity
• Lymphocyte-depleted
• Lymphocyte-rich
• CD 15 and CD 30 positive /- CD 20

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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

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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

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• 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

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Clinical Presentation

• Painless lymphadenopathy
• Contiguous spread between lymphoid regions
• Usually begins supra diaphragmatically
• Regional sub diaphragmatic disease lt 10
• Symptoms associated with compressive effect
• mediastinal mass
• Abdominal/inguinal
• B symptoms
• Wt loss gt 10 over 6 months
• Persistent fever gt38.2
• Drenching night sweats
• Puritis

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• 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

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• Neurologic
• cerebellar degeneration, chorea, neuromyotonia,
  limbic encephalitis, subacute sensory
  neuronopathy, subacute lower motor neuronopathy,
  and the stiff man syndrome
• Cholestatic liver disease
• Hypercalcemia

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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)

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• 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

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• A no B symptoms
• B atleast one of
• Unexplained weight loss gt 10 during preceding 6
  months
• Recurrent unexplained fever gt 38
• Recurrent night sweats
• Bulky disease
• Single mass gt 10 cm largest diameter

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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

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• Bone marrow aspirate and biopsy if
• B symptoms
• WBC lt 4
• Hgb lt120 (women) 130 (men)
• Platelets lt 125
• ENT examination if
• Stage IA or IIA disease with upper cervical lymph
  node involvement (supra-hyoid)

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• 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

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Treatment

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

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Limited Stage Disease

• 30 of presenting cases
• Expected long term disease control gt 90
• Traditionally treated with radiotherapy
• Second malignancies
• Premature cardiovascular disease
• Late 1990s 3 studies of combined abbreviated
  ABVD and radiotherapy

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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.
200120281a (abstract 1120). Klasa et al. Annal
Oncol. 19967(Suppl 3)21 (abstract 67). Tesch et
al Blood. 1998485a.
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• Randomized Comparison of ABVD Chemotherapy With a
  Strategy That Includes Radiation Therapy in
  Patients With Limited-Stage Hodgkins 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

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• 399 patients
• Median follow up 4.2 years
• Interim analysis planned 12 yr follow up
• Age gt 16 yrs
• Previously untreated
• Primary end point overall survival
• 85-90 patients received assigned protocol

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

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Advanced Stage Disease

• High cure rates observed with multi-agent
  chemotherapy for 30 years
• Initially MOPP disease free survival 50
• Sterility
• Premature menopause
• Leukomogenic

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• 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 3271478-1484

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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 3271478-1484

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Newer Regimens

• Stanford V
• Weekly chemotherapy for 12 weeks with post
  radiation for bulk (gt 5 cm)
• 6.9 yr follow up
• Freedom form progression 91
• Overall survival 95
• RCT Stanford V vs ABVD ongoing

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• 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/ABVDRT
• BEACOPP (dose esc) RT
• BEACOPP RT

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Relapsed Disease

• Auto BMT
• 2 RCTs
• Linch et al Lancet 1993 341 1051-1054
• Schmitz et al Lancet 2002 359 2065-2071

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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
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Long term complications of treatment

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

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• Thanks