case 39-2008 - myeloproliferative disorders

7/28/2019 Case 39-2008 - Myeloproliferative Disorders

1/83

Clinicopathological Conference

Case 39-2008

Jeremy S. Abramson, M.D.

Hematology-Oncology

Manjil Chatterji, M.D.

RadiologyAliyah Rahemtullah, M.D.

Pathology


2/83

A 51-year-old woman withsplenomegaly and anemia

Presentation of Case

Jeffrey Barnes, M.D.,Ph.D.

Hematology-Oncology


3/83

Presentation

51-year-old woman admitted to MGH because ofanemia and splenomegaly.

2 months before admission pain in her feet, nightsweats and fatigue developed .

Left upper quadrant fullness, early satiety, edema ofthe legs, and dyspnea on exertion;

Furosemide was prescribed, but symptoms persisted.

First admission to another hospital

On examination, the spleen extended to the pelvic brimand the legs were edematous.


4/83

Labs at the Other Hospital

WBC 4.7 with nl diff

Hgb/HCT 6.1/21.1

MCV 77

PLTs 209K

Iron 18TIBC 222

Ferritin 167

IgG 284

IgA 72

IgM 329

SPEP Faint IgM kappa band

PT 14.5INR1.5

PTT 64.6


5/83

Other Hospital, First Admission

Direct Coombs (DAT-IgG and DAT-Complement):negative.

Two units of red blood cells were transfused

CT of the chest, abdomen and pelvis: splenomegaly, ascites, lymphadenopathy (neck, splenic hilum,

paraaortic)

PTT prolongation Did not correct with mixing with normal plasma in a 1:1 ratio

Remained prolonged after 2 hours. Three units of fresh frozen plasma and two additional units

of red cells were given.

Bone marrow biopsy performed and she was discharged onday 5


6/83

Bone Marrow Biopsy

Lymphoid aggregates comprising approximately 10% of

the marrow cellularity, and increased interstitial lymphoid

cells.

Flow cytometry: CD19+ kappa+ B cells, lacking CD5,

CD23, CD10, and CD103.


7/83

Hematology Visit

3 weeks before admission she saw a local

hematologist

HCT stable at 29.

LDH elevated at 530.

Anticardiolipin IgM elevated at >100 units/ml

Referral to MGH Cancer Center


8/83

Readmission

One day before MGH admission, she was

readmitted to the other hospital

Increasing malaise, lower extremity edema, feverto 101.5F, and night sweats.

On examination, the temperature was 98.8F; the

splenomegaly was unchanged. There was 2+

edema of the legs.


9/83

Readmission labs

WBC 4.5 with 8% bands

Hgb/HCT 5.7/20.3

PLTs 174K

LDH 1030

PT 15.5

INR1.6

PTT 63


10/83

Readmission to Other Hospital

2 units of packed, leukocyte-reduced,red

cells were transfused.

CT of the abdomen: splenomegaly andlymphadenopathy unchanged

She was transferred to MGH.


11/83

Other History

Medical

Follicular carcinoma of the thyroid (remote):thyroidectomy andradioactive iodine.

Migraine headaches, tremors, depression, anxiety.

Social Homemaker, lived with husbandand stepchild.

Past tobacco, ETOH; no illicit drugs.

Family

Mother: systemic lupus erythematosus, coronary artery disease,stroke; died aged 55 years

Fatheralive, 80s: tremors, stroke, myocardial infarction, cerebralaneurysm

3siblings healthy.

Medications listed in handout; NKDA


12/83

Physical Examination

T101.0F, BP110/68, HR 105, RR 18, 96 %RA

Mild scleral icterus Abdomen soft, no tenderness or distension.

Spleen firm and nontender, extended below thepelvic brim.

No peripheral lymphadenopathy

Remainder of exam normal


13/83

Initial Hospital Course

Serum protein electrophoresis:

Small monoclonal IgM kappa band

Marked decrease in normal immunoglobulin. CT of the chest, abdomen and pelvis confirmed

findings from outside hospital

Two units of filtered red cells transfused.

Folic acid (5 mg daily) begun.

Vitamin K (total 25 mg) given subcutaneously.


14/83

Hospital Course cont.

3 additional units of red cells and 4 units of fresh frozenplasma were transfused; no correction of the PTT occurred

Coagulation testing:

Mixing study: PTT did not correct with addition of normal plasma. Coagulation factors II, V, VII, X levels normal

Factors VIII, IX, XI and XII decreased

Hepatitis A IgM antibody reactive; total antibody toHepatitis A non-reactive.

Peripheral blood flow cytometry: CD19+, CD20+ kappa+B-cell population dimly co-expressing CD23 and negativefor CD5 and CD10.

A diagnostic procedure was performed


15/83

Differential Diagnosis

Jeremy S. Abramson, M.D.

Hematology-Oncology


16/83

Salient features to Differential

Diagnosis Splenomegaly

Anemia

Paraproteinemia

Coagulopathy


17/83

Radiology Studies

Manjil Chatterji, M.D.

Radiology


18/83

30 cm


19/83

Coronal (Panel A) and axial (Panel B)images show splenomegaly (30 cm in

greatest length, Panel A) and scattered,

slightly enlarged lymph nodes in the

paraaortic and splenic hilar regions (arrows,

Panel B).

30 cm

10 cm

A B


20/83

Splenomegaly

Hematologic

Membrane defects

Hemoglobinopathies

Autoimmune cytopenias

Rheumatologic Diseases Rheumatoid arthritis

Lupus

Sarcoidosis

Infections

Congestion

Cirrhosis

Venous thromboses

Congestive heart failure

Infiltrative diseases Hematologic neoplasms

Myeloproliferative

diseases

Amyloidosis Glycogen storage

diseases


21/83

Massive Splenomegaly

Thallasemia Major

Infections

Visceral leishmaniasis

Hyperreactive malarialsplenomegaly syndrome

Mycobacterium avium

complex

Infiltrative diseases Lymphoproliferative

diseases

Myeloproliferative

diseases

Gauchers disease


22/83

Massive Splenomegaly

Thallasemia Major

Infections

Visceral leishmaniasis

Hyperreactive malarialsplenomegaly syndrome

Mycobacterium avium

complex

Infiltrative diseases Lymphoproliferative

diseases

Myeloproliferative

diseases

Gauchers disease


23/83

Gauchers Disease

Mutation of Glucocerebrosidase gene More common in Ashkenazi Jewish population

Autosomal recessive

Variability in clinical presentation and severity

Half of cases diagnosed before 10 years, but 20% over 30.

Some cases diagnosed late into adulthood

Presents with symptoms related to splenomegaly, hepatomegaly,

anemia, thrombocytopenia, and osteopenia

Monoclonal gammopathy may be present

Diagnosis: Biopsy of organ or marrow

Charrow J, et al. Arch Int Med 2000.Beutler E. in Williams Hematology.


24/83

Myeloproliferative diseases

Clonal stem cell disorders resulting inproliferation of one or more cell line

Chronic Myelogenous Leukemia

Polycythemia Vera

Essential thrombocytosis

Chronic Idiopathic myelofibrosis

Antecedent increase in one or more cell lines

Late pancytopenia

Peripheral evidence of extramedullaryhematopoiesis and myelophthisis


25/83

Lymphoproliferative diseases

with splenomegaly

Primary vs. Secondary

Indolent vs. Aggressive

108 splenectomies for lymphoproliferative disease

B-cell diseases 96% DLBCL 33.3%

CLL/SLL 19.4%

Follicular lymphoma 13%

Lymphoplasmacytic lymphoma 9.3%

Splenic marginal zone lymphoma 8.3%

Mantle Cell lymphoma 6.5%

Hairy Cell leukemia 6.5%

T-cell diseases 4%

Arber, et al. Modern Path 1997.


26/83

Large Granular Lymphocyte

Leukemia (LGL)

Clonal disease of cytotoxic T-cells or NK-cells

Presents with prominent cytopenias (neutropenia most

common) +/- splenomegaly

Indolent natural history

Median age 60

Associated with autoimmune diseases (esp. RA)

Monoclonal gammopathy may be present Diagnosis: Examination and flow cytometry of the

peripheral blood and bone marrow


27/83

Hepatosplenic T-celllymphoma

Aggressive clonal proliferation of T-cells in liver,

spleen and bone marrow

Prominent hepatosplenomegaly, B symptoms andcytopenias

Presents in young men, median age 34

Risk factor is immunosuppression, transplant

Diagnosis: Examination of bone marrow, liver,

spleen


28/83

Systemic B-cell Lymphomas

Diffuse Large B-cell lymphoma

Follicular Lymphoma

Mantle Cell Lymphoma Small lymphocytic lymphoma/Chronic

lymphocytic leukemia

Lymphoplasmacytic lymphoma Marginal zone lymphoma

Hairy cell leukemia


29/83

CLL/SLL

Indolent mature B-cell leukemia/lymphoma

Median age 65

Male:Female 2:1

May present with lymphocytosis, adenopathy,

splenomegaly, cytopenias

Monoclonal gammopathy may be present

Diagnosis: Examination and flow cytometry of blood,marrow or nodal disease


30/83

Lymphoplasmacytic Lymphoma/

Waldenstrms Macroblobulinemia

Lymphoplasmacytic infiltration of bone marrow, lymph nodes,

spleen and liver

IgM paraprotein production

Symptoms due to tumor itself and IgM

Anemia is common

Median age 63

Very slight male predominance

Diagnosis: Marrow examination and flow cytometry and IgM


31/83

Hairy Cell Leukemia

Indolent B-cell neoplasm infiltrating bone marrow, peripheral

blood, and spleen

Presents with pancytopenia and marked splenomegaly

Monocytopenia common

Median age 55

Male: Female 4:1

Diagnosis: examination and flow cytometry of peripheral bloodand bone marrow


32/83

Splenic Marginal Zone Lymphoma

+/- Villous Lymphocytes

Mature B-cell lymphoma with involvement of the

spleen, splenic hilar lymph nodes, bone marrow and

peripheral blood

Distinct from other marginal zone lymphomas(extranodal MALT and nodal)

May be HCV associated

Small paraprotein is common, IgM > IgG Has been associated with autoimmune phenomena

S i i


33/83


+/- Villous Lymphocytes

Median age is 68, no gender predominance

Presents with symptoms of splenomegaly and anemia

Anemia may be due to splenic sequestration,

autoimmune destruction, or marrow infiltration

Other cytopenias generally mild

Minimal systemic lymphadenopathy

Diagnosis: Examination and flow cytometry of blood,bone marrow, spleen in context of clinical presentation


34/83

Clinical Diagnosis

Massive splenomegaly with minimal systemic

adenopathy

Mature clonal B-cell population in blood andmarrow CD20+CD10-CD5-CD23-

Anemia and IgM paraproteinemia

SPLENIC MARGINAL ZONE LYMPHOMA


35/83

Etiology of the Anemia


36/83

General Approach to Cytopenias

Cell Production Cell Destruction


37/83

Increased Cell Destruction or Loss

Bleeding

Dilution

Autoimmune destruction

Mechanical destruction

Splenic sequestration

Retic


38/83

Hemolytic Anemia

Increased reticulocyte count

Increased lactate dehydrogenase (LDH)

Undetectable haptoglobin

Increased total and indirect bilirubin


39/83

Hemolytic Anemia

Intrinsic red cell defects

Membrane

Hemoglobinopathy

Enzyme deficiency

PNH

Extrinsic Immune-mediated

Autoimmune

Warm Cold

Seronegative

Alloimmune

Extrinsic non-immune



Microangiopathic

Macroangiopathic

March hemoglobinuria

Foreign body

Oxidant drugs

Toxins

Osmotic lysis

Infection

Malaria/Babesia

Clostridial sepsis


40/83

Hemolytic Anemia


Membrane

Hemoglobinopathy

Enzyme deficiency

PNH


Autoimmune

Warm Cold

Seronegative

Alloimmune




Microangiopathic

Macroangiopathic


Foreign body

Oxidant drugs

Toxins

Osmotic lysis

Infection

Malaria/Babesia

Clostridial sepsis


41/83

Hemolytic Anemia


Membrane

Hemoglobinopathy

Enzyme deficiency

PNH


Autoimmune

Warm Cold

Seronegative

Alloimmune




Microangiopathic

Macroangiopathic


Foreign body

Oxidant drugs

Toxins

Osmotic lysis

Infection

Malaria/Babesia

Clostridial sepsis


42/83

Seronegative AIHA

3-7% of autoimmune hemolytic anemia

Etiology

Low level of IgG bound to red cells below

limits of detection by DAT

Low affinity IgG autoantibodies

IgA or IgM autoantibodies

Garrity G. Sem Heme 2005.


43/83

Autoimmune phenomena in this patient

Mildly increased IgM with monoclonal band

False positive anti-Hepatitis A IgM

High titer anticardiolipin IgM

High titer lupus anticoagulant

? Coombs negative AIHA


44/83

Etiology of the Coagulopathy

C l h (i d PT d PTT)


45/83

Coagulopathy (increased PT and aPTT):

Differential Diagnosis

Vitamin K deficiency due to anorexia

Disseminated intravascular coagulation

Hypo- or dysfibrinogenemia

Acquired coagulopathy in lymphoproliferative disease Acquired factor deficiency due to adsorption

Acquired factor inhibitor

Acquired Von Willebrand disease

Lupus anticoagulant

C l h (i d PT d PTT)


46/83

Coagulopathy (increased PT and aPTT):

Workup

PT corrected with Vitamin K, aPTT still prolonged

Mixing study showed no correction with factor

replacement

Increased D-dimer Thrombin time normal.

No factor inhibitor identified

High titer lupus anticoagulant present


47/83

Clinical Diagnosis

Splenic Marginal zone lymphoma with an IgM

paraprotein and lupus anticoagulant

Hemolytic anemia due to splenic sequestration

+/- Coombs negative AIHA

Diagnostic/therapeutic procedure: Splenectomy


48/83

Pathology

Aliyah Rahemtullah, M.D.

Hematopathology


49/83

The bone marrow biopsy specimen contains multiple ill-circumscribed and nonparatrabecular lymphoid

aggregates (arrow) and increased interstitial lymphocytes; lymphocytes make up approximately 10% of the marrow

cellularity.


50/83

See notes

CD20H&E


51/83

CD20CD3

See notes


52/83

The lymphoid aggregates and interstitial lymphocytes are mainly CD20+ B cells (CD20

stain) reveals a linear distribution of some of the B cells (arrow), suggesting localization

within bone marrow sinusoids

CBC & P i h l S


53/83

CBC & Peripheral Smear

CBC

WBC: 3,800/mm3

Hematocrit: 20.3%

Platelets: 154,000/ mm3

Differential (reference range)

63% neutrophils (40-70)

28% lymphocytes (22-44)

7% monocytes (4-11)

2% eosinophils (0-8)

Absolute neutrophil, lymphocyte and monocyte

counts all within normal limits


54/83

A peripheral-blood smear shows occasional mildly enlarged lymphocytes with

slightly open chromatin, small nucleoli, and moderately abundant pale basophilic cytoplasm with noncircumferential

villous cytoplasmic projections (arrow).

P i h l Bl d Fl C t t


55/83

Peripheral Blood Flow Cytometry

Light scatter analysis

21% lymphocytes

11% monocytes

62% granulocytes

Lymphocyte gate

33% CD19+CD43- B cells

62% CD19-CD43+ T cells

See notes



56/83


See notes



57/83


Kappa-light chain

restricted B-cell

population dimly

co-expressing

CD23, negative for

CD5 and CD10

Findings consistent

with peripheral

blood involvement

by B-cell

lymphoma

See notes

B C ll L h


58/83

B-Cell Lymphomas

That Lack CD5, CD10 and CD23

Splenic marginal zone lymphoma

Lymphoplasmacytic lymphoma (Waldenstrms

macroglobulinemia)

Hairy cell leukemia

B-cell lymphoma with leukemic dissemination lacking an

antigen that is usually expressed

CD10- follicular lymphoma

CD5- mantle cell lymphoma

Th di ti d


59/83

The diagnostic procedure

3 cm

On gross examination of the cut surface of the spleen , there is a relative prominence of the white pulp, with nodules that

range in size from 0.1 to 0.3 cm in diameter.

CD20 spleen


60/83

See notes


61/83

white

pulp

On microscopical examination, the white-pulp nodules are expanded and replaced by an infiltrate of monomorphous,

small lymphocytes with irregular nuclei and scant-to-moderately-abundant cytoplasm

red

l


62/83

pulp

See notes

CD20H&E


63/83

Ki67CD21

See notes


64/83

Clusters of similar cells were also present in the red pulp. Immunohistochemical stains show that

the atypical cells are CD20+ B cells . They strongly coexpressed IgM heavy chain, but not IgD,

with immunoglobulin kappa light chain restriction by in situ hybridization (not shown).

lambdakappa


65/83

IgDIgM

See notes

hilarLN


66/83

LN

See notes


67/83

Summary of Pathology

Bone marrow Involvement by small B-cell lymphoma (non-paratrabecular

lymphoid aggregates; interstitial and intrasinusoidal infiltration)

Peripheral blood

Small population of circulating villous lymphocytes

Spleen (2.4 kg)

Small IgMk+, IgD-/+ B-lymphocytes with moderately abundant

cytoplasm replacing reactive follicles of white pulp, within

sinusoids of red pulp; involvement of hilar lymph node

Cytogenetics: 46,XX[8]; no 7q31 loss seen by FISH (100 nuclei) Flow cytometry (blood, bone marrow, spleen)

CD5-, CD10-, CD23-/+ clonal B-cell population



68/83


Postulated cell of origin: post-germinal center B-cell of the

splenic marginal zone Recent studies suggest greater heterogeneity in terms of

histology, immunophenotype, genetics and cell of origin

Unmutated IGHV regions

Associated with loss of 7q22-32

More aggressive clinical course

No association with CD38 positivity

Mutated IGHV regions

Absence of 7q loss

IgD negative

Selective use of IGHV regions in V-D-J gene rearrangement

Common antigen (? autoantigen) responsible for preferential

VH gene usage, leading to clonal expansion and transformation

Algara P et al. Blood 2002

Stamatopoulos K et al. Mol Med 2004Papadaki et al. Am J Surg Pathol 2007

C l ti Ab liti


69/83

Coagulation Abnormalities

PTT: 63.9 seconds (normal 22.1-34.0) Presence of lupus anticoagulant suspected on screening

assay (PTT-LA), confirmed by second assay

(hexagonal phase)

PTT-related factors Factor VIII: >42%

Factor XII: >14%

Factor IX: 42%

Factor XI: 38%

Not accurately quantified due to lupus

anticoagulant interference

Presumably false underestimates due to lupus


C l ti Ab liti


70/83

Coagulation Abnormalities

PTT: 63.9 seconds (normal 22.1-34.0) Presence of lupus anticoagulant suspected on screening

assay (PTT-LA), confirmed by second assay

(hexagonal phase)

PTT-related factors Factor VIII: >42%

Factor XII: >14%

Factor IX: 42%

Factor XI: 38%

Anticardiolipin antibodies

IgM: >150 MPL (normal 0-15)

IgG: 5.2 GPL (normal 0-15)

Not accurately quantified due to lupus


Presumably false underestimates due to lupus


Work-Up of Prolonged PTT


71/83

Work Up of Prolonged PTT

1:1 mix with normal plasma

Re-measure PTT at 0

hours and after

incubation

PTT remains

prolonged

PTT corrects into

normal range

PTT corrects initially

then prolongs after

incubation

Factor DeficiencyLupus

Anticoagulant

Factor Inhibitor

Rule-out Heparin (e.g. with heparinase)

Van Cott and Laposata. In Henry JB (20th ed.), 2001

Coagulation Work Up


72/83

Coagulation Work-Up

PTT mixing study

Initial PTT: 63.9 seconds (normal 22.1-34.0); no changeafter heparinase

1:1 mix with normal plasma: 49.0 seconds

After 2 hour incubation: 58.1 seconds

Consistent with a lupus anticoagulant

Factor VIII mixing study (a mini-Bethesda assay)

Factor VIII activity measured after 1:1 mix of patient

and normal plasma at time zero and after 2 hour

incubation

No apparent decrease in factor VIII activity at 2 hours

Factor VIII inhibitor excluded

Pathogenesis of SMZL


73/83

Pathogenesis of SMZL

Associated Antibodies

Direct

IgM paraprotein itself has autoimmune activity

Cases of SMZL frequently use V genes that encode

autoantibodies Also a feature of normal marginal zone B cells of spleen

Indirect

T-independent antigens promote clonal expansion of B

cells through repeated activation signals

Auto-reactive T-cell clones induce B-cell oligoclonal

responses

Sawamura et al. Ann Hematol 1994

Papadaki et al. Am J Surg Pathol 2007Ziakas PD. Leuk Lympoma 2006


74/83

Discussion of Management

J eremy S. Abramson, M.D.



75/83


Clinical features

Median age 60s HCV+ in as many as 17%

Autoimmune phenomena 10-20%

B symptoms 20-25%

Site

Spleen 100%

Peripheral blood 57-65% Bone marrow >90% (perhaps 100%)

Liver 15-30%

Systemic adenopathy 15-35% (Abdominal > Peripheral> Mediastinal)

Labs

Anemia 30-65%

Thrombocytopenia 15-25% Neutropenia 5%

Absolute lymphocytosis 58%

LDH 28-43%

Monoclonal gammopathy 10-46%Troussard, et al. BJH 1996.Berger, et al. Blood 2000.Chacon, et al. Blood 2002.Thieblemont, et al. Clin Lymph 2002.Parry-Jones, et al. BJH 2003.

Iannitto, et al. Cancer 2004.Arcaini, et al. Blood 2006.


76/83

Immunologic Abnormalities in SMZL

Autoimmune hemolytic anemia- warm (IgG) and cold (IgM)

Immune thrombocytopenic purpura (ITP): IgG mediated

Evans syndrome

IgM anticardiolipin antibody and/or lupus anticoagulant Antibodies to parietal cells, intrinsic factor, thyroid peroxidase,

thyroglobulin, and adrenal cortex

Gradual resolution of autoantibodies post-treatment is common.

May not be complete.

Ciaudo, et al. Am J Hem 1991.Murakami, et al. Am J Hem 1997.Chacon, et al. Blood 2002.

Martin, et al. Leuk Lymph 2006.Ziakas, et al. Leuk Lymph 2006.



77/83


Outcome

Median overall survival 9 - 13 years 5 year overall survival 65-72%

Lifetime transformation risk 10%

Adverse risk factors

Anemia, Increased LDH, hypoalbuminemia, lymphocytosis, andinvolvement of non-hematopoietic sites

Indications for Treatment

Symptomatic splenomegaly Cytopenias

Autoimmune complications

B symptoms

Troussard, et al. BJH 1996.Camacho, et al. AJSP 2001.

Chacon, et al. Blood 2002.Arcaini, et al. Blood 2006.

Treatment Options


78/83

Treatment Options

Observation

Splenectomy

Radiotherapy Chemotherapy

Rituximab

HCV therapy*

T t t O ti


79/83

Treatment Options

Splenectomy Resolution of cytopenias, paraproteinemia, and symptoms

Reduction or resolution of autoantibodies

Median TTP of 3-7 years

Regression of marrow disease does not occur

Chemotherapy Alkylating agents

Nucleoside analogues

Combination chemotherapy

Rituximab

ORR 88-100%, 43-88% CR/CRu

Median time to response: 3 weeks

Median FFS 2-3 yearsMulligan, et al. BJH 1991Chacon, et al. Blood 2002.Thieblemont, et al. Clin Lymph 2002.Tsimberidou, et al. Cancer 2006.Franco, et al. Cancer 2001.Murakami, et al. Am J Hem 1997.

Kalpadakis, et al. Hem Oncol 2007.Bennett, et al. Haematologica 2005.


80/83

Follow-up

Dr. Abramson

Labs Post Splenectomy


81/83


Time Pre-op 20 days post-op 53 days post-op

HCT (%) 19.5 33.6 37.5

PLT 130 667 569

WBC 3.2 7.0 12.1

Retic (%) 9.2 4.4 Not performed

T. Bili 3.6 0.4 0.3

LDH 1574 463 302

Haptoglobin


82/83


Time Pre-op 20 days post-op 53 days post-op

IgM (g/dL) 270 64 Not performed

IgMkappa M-

Component (g/dL)

0.12 0.04 Not performed

PTT (seconds) 63.9 35.3 30.7

Lupus

Anticoagulant Positive Positive Positive

IgM Anticardiolipin

Antibody (MPL) >150.0 >150.0 114.9

Hepatitis A IgM Reactive Non-reactive Non-reactive


83/83

case 39-2008 - myeloproliferative disorders

Documents