lymphoma - acoi.orglymphoma that is cd 20 positive •low grade: rituxan, bendamustine, cvp, chop...
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LYMPHOMACheryl Kovalski, DO, FACOI
ACOI BOARD REVIEW, 2019
no disclosures
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• Solid neoplasm of the immune system characterized by uncontrolled proliferation of cells residing in the lymphoid tissues
• 2016 WHO revised classifications: 93 types
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• HODGKIN DISEASE
• ALL OTHER LYMPHOMAS
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• Low grade: Small lymphocytic and follicular small cleaved/follicular mixed. Usually affecting older people, presenting in advanced stage, indolent but incurable.
• Lymph nodes can wax and wane for years
• Survival of untreated disease-years
NONHODGKIN LYMPHOMA (NHL): WHO
CLASSIFICATION
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• Aggressive (formerly known as Intermediate grade): follicular large cell, diffuse small cleaved/diffuse mixed/diffuse large cell.
• Firm, enlarging mass, +/- B symptoms
• Survival of untreated disease-months
NHL: WHO CLASSIFICATION
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• High grade/Highly Aggressive: Immunoblastic, small non-cleaved, lymphoblastic, Burkitts. Wide age range, variable stage, 30-40% long-term remission with intensive treatment.
• Rapidly enlarging lymph node mass
• Survival of untreated disease-weeks
NHL: WHO CLASSIFICATION
CLASSIFICATION
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• Lymph node biopsy to evaluate architectural and cytologic features as well as adequate enough to do immunophenotyping.
• FINE NEEDLE ASPIRATE IS INADEQUATE!
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• Laboratory: CBC, diff, CMP, LDH, SPEP,
B2-microglobulin
• Radiography: CT chest/abdomen/pelvis
• PET
• Bone marrow biopsy
• LP with CSF analysis in pts with sinus, epidural, testis dz or those prone to have circulating tumor cells-Burkitts, lymphoblastic
NHL: DIAGNOSIS
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DEAUVILLE SCALE
• Internationally recommended 5 point scale for routine clinical reporting using FDG-PET/CT imaging for initial staging and follow-up to determine treatment response for lymphoma
• 1. No uptake or no residual uptake
• 2. Slight uptake but below blood pool (mediastinum)
• 3. Uptake above mediastinum but below or equal to uptake in liver
• 4. Uptake slightly to moderately higher than liver
• 5. Markedly increased uptake or any new lesion
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STAGING
I Involvement of 1 lymph node or 1
extralymphatic site (IE)
II Involvement of 2 or more lymph node regions or localized extralymphatic disease and involved lymph nodes on the same side of the diaphragm (IIE)
ANN ARBOR STAGING SYSTEM
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III Involvement of lymph node regions on both sides of the diaphragm, +/- localized extralymphatic disease (IIIE), spleen (IIIS), or both (IIIES)
IV Diffuse or disseminated involvement of 1 or more extralymphatic organs or tissues with or w/o LN involvement
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A Asymptomatic
B Fever, night sweats and/or unexplained
weight loss of 10% or more of body weight
in past 6 months
Only used for Hodgkin lymphoma
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Treatment
• Rituxan is added to treatment of B cell lymphoma that is CD 20 positive
• Low grade: Rituxan, bendamustine, CVP, CHOP
• Agressive grade: R-CHOP (cytoxan, adriamycin, oncovin, prednisone)
• Highly aggressive: Hyper CVAD, high dose methotrexate
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• 1% of all malignancies in US
• First malignancy to demonstrate curative potential of combination chemotherapy
• Most common in young adults; bimodal peak in 3rd and 7th decades
• Association with Epstein-Barr virus
• Arises from B lymphocytes
HODGKIN DISEASE
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• Differentiated from other lymphomas by the presence of large binucleate or multinucleate cell, Reed Sternberg cell
(Giant “owl eyes”)
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• Nodes are painless and rubbery, most commonly found in neck and mediastinum
• Most common etiology of mediastinal mass in young person
• Unusual symptoms of pruritus, alcohol-induced pain in involved lymph node sites, sweats, fevers; intermittent “Pel-Ebstein” fever rare
HODGKIN DISEASE
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• Lymphocyte Predominant
• Nodular Sclerosis
• Mixed Cellularity
• Lymphocyte Depleted
• Nodular lymphocyte predominant
HD: HISTOPATHOLOGIC SUBTYPES
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• Advanced Stage
• Large mediastinal mass (ratio>0.33)
• Systemic symptoms
• Extra nodal disease
• Advanced age
• Male sex
HD: POOR PROGNOSTIC FACTORS
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• Favorable Stage I and IIA: 2-4 cycles chemotherapy and involved field RT
• Limited HD with risk factors: Full chemotherapy & involved field RT
• Advanced HD: Full chemotherapy and RT only for patients with bulky mediastinal disease
• Bone marrow transplant usually considered after first relapse
• ABVD is standard regimen (adriamycin, bleomycin, vinblastine, dacarbazine)
HD: TREATMENT
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• Mantle RT: hypothyroid, heart disease
lung & breast cancer
• Para-aortic or splenic: gastric cancer
• MOPP chemotherapy: acute leukemia
sterility
HD: LATE EFFECTS OF TREATMENT
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• STAGE
• IA-IIA 80-90 %
• IB-IIB 80-85 %
• IIIA 75-80 %
• IIIB 60%
• IVA-B 60%
HODGKINS SURVIVAL
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LEUKEMIA
no disclosures
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ABNORMALITIES OF CELLULAR PROLIFERATION IN AL
Normal Leukemic
Stem Cells Normal Abnormal
Maturation
Synchronous with
proliferation;
terminates division
Asynchronous
Does not terminate
division
Feedback Controls production Absent or ineffective
Steady State Yes No
Release Orderly Random
End ProductMature cells-cannot
resume division
Immature cells-can
resume division
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LEUKEMIA CLASSIFICATION
ACUTE : LYMPHOCYTIC NONLYMPHOCYTIC
CHRONIC : LYMPHOCYTIC MYELOGENOUS
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ACUTE LEUKEMIA
A DIVERSE GROUP OF NEOPLASMS ARISING FROM TRANSFORMATION OF UNCOMMITTED OR PARTIALLY COMMITTED HEMATOPOIETIC STEM CELLS
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ACUTE LEUKEMIA PATHOGENESIS
Leukemic cell abnormalities: cytogenetic abnormality leading to
clonal proliferation of leukemic cell; maturation arrest of leukemic
cells
Leukemic cells inhibit normal cell lines from proliferation leading to :
anemia, bleeding, infection; electrolyte imbalance; leukostasis
Invasive & infiltrative effects
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ACUTE LEUKEMIA: PRESENTATION
Symptoms of only a few weeks duration
Symptoms reflect bone marrow failure +/- involvement of extramedullary sites
Fever, documented infections in up to half
Symptomatic anemia
May have bleeding, but hemorrhage rare
Bone pain, fatigue
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ACUTE LYMPHOCYTIC LEUKEMIA
Mainly occurs in children- peak ages: 2-8, >60
Worse prognosis with: increasing age
Philadelphia chromosome
WBC >30K
Sex: equal
Rare in blacks
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ALL-PREDISPOSING FACTORS
Irradiation early in life
Ataxia telangiectasia
Mongolism
Leukemia in family
Identical twin
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ALL FAB CLASSIFICATION
FAB Class Cell Size Nucleus Cytoplasm
L1Small
hoogeneous
Round, occasional cleft
or fold; homogeneous,
finely dispersed
chromatin; nucleoli small
or not visible
Usually scanty
slight to moderate
basophilia
L2 Large
heterogeneous
Fine to coarse
chromatin; clefts
1 or more nucleoli
Abundant, variable
basophilia
L3Large
homogeneous
Oval to round, dense
finely stippled
chromatin; 1 or more
prominent nucleoli
Moderately
abundant, intensely
basophilic ,
prominent vacuoles
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ACUTE LYMPHOCYTIC LEUKEMIA: PRESENTATION
Half have hepatomegaly, splenomegaly &/or lymphadenopathy
Mediastinal masses primarily in T cell lineage ALL
<10% with CNS involvement
Other sites of extramedullary involvement: testis, retina, skin, any
organ infiltrated
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ALL: ADDITIONAL CLINICAL FEATURES
C ALL: most common in children; lymphadenopathy common; gum,
skin, mediastinal infiltration uncommon; muramidase staining-low
or normal
T cell ALL: most common in 2nd & 3rd decades; blasts more
common in blood; frequent extra medullary disease-CNS,
mediastinum
B cell ALL: no distinct findings; responds poorly to conventional
therapy
Ph-positive ALL: shorter remissions than C ALL
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ALL: GOOD PROGNOSTIC FEATURES
Age less than 35 ( best 3-9)
WBC < 30,000
Blasts < 80%
Early complete remission after start of chemotherapy
Absence of translocations
Presence of hyperdiploid state
CALLA+ phenotype
Female
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DIAGNOSIS
Lymphoblasts seen on blood smear and bone marrow
May be difficult to distinguish from myeloblasts
Flow cytometry helpful in differentiating ALL from AML
Evaluate CSF for CNS involvement
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ALL: TREATMENT
Daunorubicin, Vincristine and Corticosteroids are key drugs in induction
Maintenance therapy at least 2 years
CNS Prophylaxis
Imatinib in Ph+ with chemotherapy
Radiation in bulky mediastinal disease
SCT if poor prognostic features or progressive disease
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ACUTE NONLYMPHOCYTIC LEUKEMIA
Group of marrow based malignancies, clinically similar, BUT
DISTINCT morphologically, immunophenotypically, and
cytogenetically
Must distinguish from ALL
More common in adults
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AML FAB CLASSIFICATION
FAB Class Predominant cell type
M1: undifferentiated myelocytic Myeloblasts
M2: myelocyticMyeloblasts, promyelocytes, myelocytes,
blasts
M3: promyelocytic Promyelocytes, blasts
M4: myelomonocyticPromyelocytes, myelocytes, proonocytes,
monocytes, blasts
M5: monocytic Monoblasts, myeloblasts
M6: erythroleukemia Erythroblasts, myeloblasts
M7: megakaryocytic leukemiaAbnormal appearing megakaryocytes
myeloblasts
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ANLL RISK FACTORS
Exposure to ionizing radiation
Exposure to chemicals: benzene, chloramphenicol, phenylbutazone
Exposure to drugs: alkylating agents and topoisomerase II inhibitors
Genetic factors: Mongolism, Bloom’s syndrome, Fanconi’s anemia
MDS, Myelofibrosis, Polycythemia, CGL
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ANLL PROGNOSTIC FACTORS
Worse if
Age>60
Poor performance status
AML secondary to prior chemotherapy or bone marrow dysfunction
WBC > 20K
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CLINICAL FEATURES
S & S secondary to anemia, thrombocytopenia, leukopenia or leukocytosis
Hyperleukocytosis (>100K blasts): most common in hypergranular APL causing obstruction,
vascular injury and hypoxia (due to pulmonary congestion) & ischemia increasing risk of stroke
Coagulation abnormalities: abnormal platelet function; consumption (DIC)-M3>M4 or M5
Typhilitis-mimics appendicitis
Metabolic abnormalities: tumor lysis syndrome; renal tubular dysfunction
Extramedullary : granulocytic sarcoma-M5, soft tissue involvement-skin, gingiva, lungs, lymph
nodes(splenomegaly uncommon), CNS: headache, mental status change, nerve palsy
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ANLL: LABORATORY FEATURES
Anemia universally present; reticulocyte count low
Thrombocytopenia nearly always present (decreased production &
survival)
Leukopenia in 20% with absolute neutropenia
Leukocytosis >50%; myeloblasts almost always present in blood
Auer rods <10%
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AUER RODS
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ANLL: BONE MARROW FINDINGS
Blasts
Decrease in normal blood cell progenitors
Cytogenetics performed to identify any genetic
abnormality diagnostic of a particular FAB class
Immunophenotyping
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ANLL: IMMUNOPHENOTYPE
May help establish diagnosis, more precise than morphology alone
Distinguishes ALL from ANLL, identifies subtypes, recognizes biphenotypic
Characteristic ANNL: CD 13 & 33+
Often CD 11& 14+
CD34 unfavorable
Lymphoid markers may be expressed
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ANLL: TREATMENT
Address concurrent medical problems
Supportive care:
-Blood product transfusion
-Broad spectrum antibiotics for fever and neutropenia
-Antifungal & antiviral therapy
-Nutrition
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ANLL: THERAPY
Remission induction: 7+3 regimen: ARA-C + daunorubicin= 60-80% CR
Postremission therapy:
-Consolidation with Ara-C
-Allogeneic SCT
APL: ATRA + chemotherapy
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CHRONIC LEUKEMIA
no disclosures
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Most common leukemia in Western worldMedian age at diagnosis: 65
Median survival: 9 yearsAdvanced disease has increased morbidity and mortality from infection: T cell dysfunction, lack
of ability to make Ig, results of treatment
CHRONIC LYMPHOCYTIC LEUKEMIA
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CLL: DIAGNOSIS
• Lymphocytosis (ALC> 5000) small, mature lymphocytes
• Bone marrow involvement >30% lymphs•< 55% atypical/immature lymphoid cells in
peripheral blood• Clonal expansion of abnormal B lymphs
-B-cell surface ags (CD 5, 19, 20, 23)
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CLL: CLINICAL COURSE
•Incidental finding of lymphocytosis
•Asymptomatic at time of diagnosis and for a prolonged period of time
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CLL CLINICAL COURSE
•Progressive bone marrow impairment•Progressive neutropenia and
hypogammaglobulinemia increasing risk of infection
•Autoimmune phenomena •Richter’s transformation
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CLL: AUTOIMMUNE COMPLICATIONS
•Coombs’ + hemolytic anemia in 15%•ITP•Pure red cell aplasia•Granulocytopenia
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CLL: RAI STAGING
Stage Risk Features Surv yr 0 Low Lymphocytosis > 12
I Intermediate Adenopathy 8 II Intermediate Splenomegaly +/- 6
HepatomegalyIII High Anemia 1.6IV High Thrombocytopenia 1.6
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CLL: POOR PROGNOSIS
•Advanced stage at diagnosis•Short lymphocyte doubling time (6 mos)•Diffuse pattern of marrow infiltration•Advanced age/male•17p or 11q deletion •High serum levels of B2 microglobulin and CD23•CLL-PLL•Richter’s syndrome
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CLL TREATMENT
•Incurable•Observation is appropriate for early stage or
asymptomatic CLL•No proven advantage to early chemotherapy if
asymptomatic
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CLL: INDICATIONS FOR TREATMENT
•B Symptoms secondary to CLL: weight loss >10%, night sweats, fever
•Progressive marrow failure•Massive splenomegaly•Massive lymphadenopathy
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CLL: INDICATIONS FOR TREATMENT
•Progressive lymphocytosis, >50% increase over 2 mos or lymphocyte doubling time <6 mos
•Richter’s syndrome-transformation from low to high grade lymphocytic malignancy
•Hemolytic anemia•ITP
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CLL: TREATMENT
•Alkylating agents: bendamustine, chlorambucil, cyclophosphamide
•Corticosteroids•Purine analogs: fludarabine, cladribine,
pentostatin•Monoclonal abs: Rituximab, Alemtuzumab •Kinase inhibitors: ibrutinib, idelalisib for deletion
11q or 17p
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HAIRY CELL LEUKEMIA
•Rare B-cell leukemia•Median age of onset: 55•Strong male predominance•Presents with pancytopenia and massive
splenomegaly•Characteristic “dry tap” bone marrow due to
hypercellularity
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HAIRY CELL LEUKEMIA
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HAIRY CELL LEUKEMIA
•TRAP +•Treatment with 2-CDA (cladribine) or
Pentostatin induces complete remission in most
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CHRONIC MYELOGENOUS LEUKEMIA
•Clonal myeloproliferative disorder of pluripotent stem cells affecting all cell lines
•Cytogenetic hallmark: Philadelphia chromosome (9;22)
•Molecular hallmark: BCR/ABL•7-15% adult leukemias•Median age: 45-55; 20-30% >60
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CML: PRESENTATION
•85% in chronic phase at diagnosis•5% Ph negative•Symptoms:• -Most asymptomatic, only leukocytosis • -LUQ discomfort and early satiety secondary
to splenomegaly• -Unusual infections
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PHILADELPHIA CHROMOSONE
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PHILADELPHIA CHROMOSONE
Translocation 9;22 = BCR-ABL rearrangementLeukemia phenotype IncidenceCML 95%ALL 25-30% adult
5% childrenAML 1-2%
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CML Phases
Chronic Accelerated Blastic
Past 3-5 years 12-18 months 3-9 months
Present 10+ years 4-5 years 6-12 months
Asympto-matic
Blasts >/= 15% Bl+Pros >29%
Basophils>19%Blasts >29%
Platelets <100KClonal evolution
extrmedullary disease with
localized immature blasts
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CML WORK-UP
Physical exam: performance status, splenomegalyCBC, diff, chem pro
Bone MarrowCytogenetics
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CML: CURRENT TREATMENT RECOMMENDATIONS
Frontline: Imatinib, Nilotinib, DasatinibImatinib failure: nilotinib, dasatinib, bosutinibAllogeneic SCT