Transcript Lymphoma

Lymphoma
Uglyar T.Y.
Adapted from Joe Waller, MD 2013 Drs. Wang and Young
and By David Lee MD, FRCPC
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
Risk Factors
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• Mostly unknown, although both genetic and infectious
processes are suspected
• Living in Western countries, being of higher social class,
more educated.
• Genetic pre-disposition, clusters noted in siblings with
similar HLA genotypes.
– Mack et al: 99x risk in monozygotic vs dizygotic twins
• EBV (MC subtype)
• HIV+ pts have different patterns of spread, more
systemic sx, poor tolerance to chemo
• Children do better than adults
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
Staging
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Stage I: a single LN region (on either side of the diaphragm)
Stage II: two or more LN regions of the same side of the diaphragm
Stage III: both sides of the diaphragm
Stage III-1: upper abd: splenic, celiac, portal LN only, <4 splenic
nodules
Stage III-2: lower abd: Paraaortic, mesenteric, pelvic
Stage III(S)+ Minimal: <4 splenic nodules
Stage III(S)+ Extensive: 5 or more splenic nodules
Stage IV: diffuse involvement of extralymphatic tissues, with or
without simultaneous LN involvement.
E subtypes: extranodal disease
S subtype: spleen involvement
“A” and “B”: absent or present “B” symptoms.
X subtype: bulky disease of > 1/3 thoracic diameter or > 10 cm
Lymph Node Regions
International Prognostic Score
• In patients with Stage III-IV disease, each of the following
factors
• reduces survival by 7%:
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Age >45
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Male sex
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Stage IV disease
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Albumin < 4g/dL
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Hb<10.5
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WBC>15,000
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Lymphoctes count <8% or ALC<600
• Used for individualized treatment management
Mediastinal LAN
Other Manifestations
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SVC syndrome
• Spinal Cord
Compression
• Bone involvement
• Hepatic involvement
• Renal involvement
• Infections
• Immunologic
Abnormalities
• Rarely:
– Waldeyer's Ring,
Peyer's patches, CNS,
skin
Epidemiology of lymphomas
• 5th most frequently diagnosed cancer in both sexes
• males > females
• incidence
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NHL increasing
Hodgkin lymphoma stable
Epidemiology
• ~8000 new cases of Hodgkin’s Disease in
the U.S. in 2008, causing ~1500 deaths
• M:F ratio is 1.3:1; more pronounced in
children
• Bimodal age distribution: 2-3rd decade,
and 6-7th decade.
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
complications of lymphoma
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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
Work
Up
Diagnosis should be biopsy-proven before treatment is initiated
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• Need enough tissue to assess cells and architecture
– open bx vs core needle bx vs FNA
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Excisional biopsy
– Most commonly of cervical nodes
– Presence of RS cells is necessary but not sufficient
• Laparotomy
– 1960’s
– Determine extent of disease below diaphragm
– Largely eliminated by more effective chemo regimens
– EORTC study did not show survival benefit for
pathologic staging over clinical staging (Carde et al.
JCO 1993)
Adverse Prognostic Factors
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• B symptoms esp. weight loss and night sweats.
• Pruritis
• Higher stage, esp.with bone marrow or organ
involvement.
• Bulky disease with large tumor burden. This includes
large mediastinal lymphadenopathy, which is >1/3 of
maximal thoracic diameter (T5-T6).
• Worrisome labs include ESR>70 and high serum copper.
• Older age
• LD type
• male
CHOP Chemotherapy
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Cyclophosphamide (Cytoxan)
Hydroxydaunorubicin (Adriamycin)
Oncovin (vincristine)
Prednisone
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%
Treatment Options:
Aggressive Lymphomas
Aggressive
• Diffuse large cell lymphoma, large cell
anaplastic lymphoma, peripheral T cell
lymphoma.
Very Aggressive
• Burkitt’s lymphoma and lymphoblastic
lymphoma.
Treatment Options for Advanced
Stage Aggressive Lymphomas
• Systemic chemotherapy
– CHOP (± Rituxan for over 70 age group)
• ± Intrathecal chemotherapy
– AIDS patients and CNS involvement
• ± Radiotherapy
– Spinal cord compression, bulky disease
Burkitt’s Lymphoma
• African variety: jaw tumor, strongly
linked to Epstein-Barr Virus infection.
• In U.S., about 50% EBV infection.
• May present as abdominal mass.
• Most rapidly growing human tumor.
• Typical chromosome abnormality: cmyc oncogene linked to one of the
immunoglobulin genes.
Burkitt’s Lymphoma
• Treated with multidrug regimen similar
to pediatric leukemia/lymphoma
regimens.
• Treated with multidrug regimen similar
to pediatric leukemia/lymphoma
regimens.
MALT Lymphoma
• Mucosa-Associated Lymphoid Tissue
• Chronic infection of the stomach by
Helicobacter pylori.
• Localized to the stomach, indolent
course.
• Can be cured in many cases by
antibiotics against H. pylori.
Treatment Options for Early
Stage Aggressive Lymphomas
• Often in Stage I or II
– potentially curable
– disseminates through bloodstream early
– must use systemic chemotherapy
• CHOP x 6 cycles
• CHOP x 3 cycles followed by radiotherapy
Hodgkin lymphoma
Thomas Hodgkin
(1798-1866)
Classical Hodgkin Lymphoma
Hodgkin’s Disease
Hodgkin’s Disease
• One-seventh as common a snonHodgkin’s lymphoma.
• Highly treatable and curable, even when
disseminated.
• Presence of Reed-Sternberg cell is
necessary to make diagnosis.
Subtypes of Hodgkin’s Disease
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Lymphocyte predominant
Nodular sclerosis
Mixed cellularity
Lymphocyte depleted
• Unlike non-Hodgkin’s lymphoma, in Hodgkin’s
Disease
• the histologic subtype does not determine how the
• disease is treated.
CHL Pathologic Variants
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Nodular Sclerosis (NS) (70%)
• Large RS cells
• Cervical nodes
• Anterior mediastinum
• Adolescent patients
• Lymphocyte Rich (5%)
• Rare RS cells. Many lymphocytes. Age <35 y/o with localized disease. Good
prognosis. M>F (4:1).
• Lymphocyte Depleted (rare)
• Many RS cells, few lymphocytes
• Age > 50.
• Diffuse abdominal disease, marrow, and liver involvement. Most patients p/w
advanced disease
• Poorest prognosis
• Mixed cellularity (25%)
• Moderate RS cells, mixed infiltrate of neutrophils, eosinophils, and plasma cells.
• Age 30-50, EBV associated, developing countries
• Retro-peritoneal presentation
• Intermediate prognosis
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
Histology
• Reed-Stenberg Cell: “owl eyes”
• – Large, with abundant cytoplasm, 2-3 nuclei with
• prominent nucleolus “owl eyes” appearance
• – NOT pathognomonic, can be reactive, infectious or
• malignant
• – RS cells stain for CD30/15+, but are CD45/20• *Contrast w/ NLPHL which are CD30/15-,
• CD45/20+
Reed-Sternberg cell
RS cell and variants
classic RS cell
lacunar cell
popcorn cell
(mixed cellularity)
(nodular sclerosis)
(lymphocyte
predominance)
Molecular Biology
• The Reed Sternberg (RS) cell likely arises
from
• either lymphocyte or antigen-presenting cells
of
• the monocyte-macrophage line. Regarding
• lymphocyte origin, 60% of RS cells have T or
B
• cell specific antigens, and B cells are the
usual
• target for EBV
Molecular Biology
• RS-like cells are found in several infectious, inflammatory, and
• neoplastic conditions including infectious mononucleosis, reactive
• lymphoid hyperplasia, and immunoblastic lymphoma.
• • Thus, diagnosing Hodgkin’s depends on finding RS cells in the
• appropriate clinical setting. The lymphocytes are predominantly CD• 4 positive T-cells.
• • The BCL2 Oncogene is found in 1/3 of Hodgkins patients.
• • The p53 suppressor gene is found in almost all Hodgkin’s patients
• except those with lymphocyte predominant disease.
• • The common t(14:18) translocation of B cell lymphoma are RARE in
• RS cells.
A possible model of
pathogenesis
transforming
event(s)
EBV?
loss of apoptosis
cytokines
germinal
centre
B cell
RS cell
inflammatory
response
Etiology of
Hodgkin’s Disease
• Reed-Sternberg cells are the malignant cells.
• Minor population in the malignant tissues
– many normal lymphocytes, eosinophils, other cells
• Cell of origin is unknown: T, B, both, neither.
• Some R-S cells contain EBV genomes.
Epidemiology
• less frequent than non-Hodgkin
lymphoma
• overall M>F
• peak incidence in 3rd decade
Clinical Features
• T cell mediated immune deficiency,
even in early stage disease. Prone to
infections:
– Herpes zoster (“shingles”) in one fourth of
patients
– Fungal or mycobacterial infections
• Immune defect may persist even after
lymphoma is cured.
Clinical manifestations:
• lymphadenopathy
• contiguous spread
• extranodal sites relatively uncommon
except in advanced disease
• “B” symptoms
Clinical Features
• Predictable contiguous spread of
disease:
– cervical nodes to mediastinum or axilla
– mediastinum to periaortic nodes or spleen,
etc.
• Basis for staging and treatment
decisions.
Diagnosis
• Excisional biopsy of a lymph node.
Fine needle aspirate is not sufficient to
make the diagnosis of Hodgkin’s
disease.
Staging of Hodgkin’s
Disease
Same as for non-Hodgkin’s:
• H + P, labs, CT scans, bone
marrow biopsy
PLUS:
• Gallium scan
• Lymphangiogram or staging
laparotomy ONLY if results would
affect treatment decisions
Treatment by Stage
Stage
Therapy
% Cure
IA
XRT
95
IIA
XRT
85
IB, IIB
XRT (Total Nodal)
70
IIIA
XRT
70
IIIB, IV Combination Chemo
50
Chemotherapy Regimens
• MOPP
– Mechlorethamine, Oncovin,
Procarbazine, Prednisone
• ABVD
– Adriamycin, Bleomycin, Vinblastine,
Dacarbazine
• BEACOPP
Treatment Options
• Often, patients who relapse after
radiotherapy can be cured by salvage
chemotherapy.
• Combined chemotherapy and
radiotherapy is given for bulky
mediastinal masses.
• Chemotherapy now being tested for
earlier stages of the disease.
Late Complications of
Hodgkin’s Disease
• High incidence of second malignancies
– leukemia first 10 years, solid tumors over
time.
• Leukemia in patients receiving
alkylating agents or combined
chemo/XRT.
• Lung cancer and breast cancer in
patients receiving XRT to chest. Lung
cancer especially high in smokers.
Late Complications of
Hodgkin’s Disease
• Hypothyroidism after irradiation of
the neck.
• Constrictive pericarditis after
radiotherapy to the mediastinum.
• Infertility after use of alkylating
agents.
• Heart failure after Adriamycin
treatment.
Treatment
• Overall survival exceeds 80%, therefore therapy is evolving to
• minimize toxicity while maintaining excellent disease control
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The German Hodgkin's Study Group (GHSG) has performed a
• number of trials with various iterations of treatment regimens
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Major chemotherapy options:
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ABVD
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Doxorubicin, bleomycin, vinblastine, dacarbazine
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Most commonly prescribed regimen
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Stanford V
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Doxorubicin, vinblastine, mechlorethamine, etoposide,
vincristine,
• bleomycin, and prednisone
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Overall lower doses bleo/doxo than ABVD
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BEACOPP
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Bleomycin, etoposide, doxorubicine, cyclophosphamide,
vincristine,
• procarbazine, and prednisone
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Dose dense
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Being studied for advanced disease