blood and bone marrow diagnosis: a challenge at any ... · •congenital dyserythropoietic anemia...
TRANSCRIPT
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Blood and Bone Marrow
Diagnosis: A Challenge at Any
Patient Age
Kathryn [email protected]
2019 Hawaii HemepathConference
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Objectives• Appreciate age-based normal
lymphocyte parameters
• Identify clues to unique blood and bone marrow disorders in children and adults
• Review pancytopenia causes and clues to diagnosis based on age
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Age-Related Variations in Blood Lymphocytes
• Lymphocytes predominate in blood by 2-3 weeks of age
• Sustained lymphocyte predominance in blood throughout childhood
• Neutrophils predominate by late childhood, early adolescence
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3 yr old—normal
Absolute Lymphocyte Count 9,000
65 yr old—CLL
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Absolute Lymphocyte Count by Age*
Lymphocytosis Lymphopenia
Newborn > 10,000 < 2,500
< 1year > 9,000 < 4,000
Child > 7,000 < 2,800
Adult > 4,000 < 1,500*Conventional units per µL 5
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Morphology: Non -Activated
Age, Clinical Features Key
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7Non-Activated Lymphs: CD4’s predominate
Age, Clinical Features KeyChild-PertussisAdult- Leuk/Lymphoma
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Lymphs: Child vs. Adult
Blood: 10-month-old male; “Kiddie Lymphs”
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Lymphs in Young Child: Distinct Vacuoles/Granules
Sialic Acid/Storage Disease
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Vacuolated Lymphocytes in Adult
10Mantle Cell Lymphoma
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Discrete vacuoles in lymphocytes as a subtle clue to mantle cell lymphoma
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Ref: Lynch DT, Foucar K. Blood 2016; 127: 3292
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Lymphocytosis: Key Tips• Dramatic age-related variations in normal • Assess lymphocytes: morphologic heterogeneity
(viral infection) vs. homogeneity (possible neoplasm); “kiddie” lymphs, pertussis
• Assess other lineages• Sustained lymphocytosis in adult often neoplastic• Isolated lymphocytosis in child more likely non-
neoplastic• Flow cytometric IP valuable on a limited basis
(Flow may be misleading)12
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Lymphocytes in Normal BM
Neonates, Infants, YoungChildren
Children (>4 years) Adults
% Lymphocytes May exceed 40%
~ 15-20% < 5-15%
Morphology of lymphocytes
Hematogonesmay be abundant
Variable proportion of hematogones
Usually mature
Distribution of lymphocytes
Diffuse, small clusters
Diffuse, small clusters
Diffuse, small clusters
IP of lymphocytes B’s predominate (HG’s)
Variable T’s predominate
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14Marked increase in lymphocytes > 50%
BMA in 2 year old with thrombocytopenia
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Morphology
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HG
Ly
Hematogones vs. Lymphs
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Hematogones• Benign B-cell precursors showing spectrum of
maturation• Key morphologic feature: homogeneous, dense
chromatin• Diffuse, small clusters on biopsy, clot section• Spectrum of maturation confirmed by flow
cytometry, IHC• Key clinical settings: young patient (variety of
pediatric conditions), BM recovery16
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Range inCD45
Range inCD10
Spectrum ofmaturation
CD10
CD20
19
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Hematogone-like ALL
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ALL, Precursor B
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Cytopenias•Single, bicytopenia, pancytopenia
•“Explained” vs “Unexplained”
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Age-Based Approach to Pancytopenia
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Neonate: Infection, germline disorder, maternal therapy/underlying illness
Infant: Infection, nutritional deficiency, neoplasm, germline disorder
Child: Infection, systemic illness, nutritional deficiency, neoplasm
Adult: Infection, systemic illness, medications, nutritional def., neoplasms, homeopathic remedies
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History:83 year old female with fatigue
and bruisingCBC:WBC 5.5 MCV 98
H/H 9.4/27 Plt 10
Case: Pancytopenia
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Blood
70% abnormal cells
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Blood: Pancytopenia• Absolute Neutrophil ct.: 0.1 x 109 /L
• Platelet Count: 10 x 109 /L
• Moderate N/N Anemia
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Hematopoietic Failure
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Flow Cytometry
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CD117
HLA
-DR
CD13CD34
CD
33
SSC
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Flow Cytometry Cytospin
26Dx: ?
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FISH for PML-RARA
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PML (red) RARA (green)
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Additional Studies• Quantitative PCR for PML-RARA
Positive – high copy number (typical at diagnosis)
• Final Diagnosis:Acute Promyelocytic Leukemia (confirmed molecularly)
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Acute Promyelocytic Leukemia• Rapid diagnosis essential• Morphologic features are highly characteristic;
rapid MPO cytochemical stain valuable• Flow cytometry features are highly characteristic• PML-RARA fusion gene may be cryptic by FISH
(6% of cases)• PCR can detect fusion gene in false negative
FISH cases29
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Case: Bicytopenia78-yr-old female with neutropenia, anemia and progressive functional decline.
CBC:WBC 1.5, Hgb 9.1, Hct 28%, MCV 98 Fl, RDW 16.7%, Plt 177
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Blood - Bicytopenia 31
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BM Aspirate 32
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BM Aspirate -Vacuoles 33
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BM Aspirate - Vacuoles 34
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BM biopsy - Normocellular 35
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Case: Diagnosis
Anemia and neutropenia secondary to zinc-induced copper deficiency
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Case: Disease Course• Searched EMR re dentures (found in Nurses
notes)• Alerted hematologist• Additional history: patient never removed
dentures even at night• Serum zinc 166 (H)• Serum copper < 10(L)• Complete resolution of CBC and functional
deficits after copper therapy37
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Features of Copper Deficiency• Neurologic syndrome mimics subacute
combined degeneration of cobalamin deficiency
• Patients may also have ataxic myelopathy
• Copper deficiency from zinc ingestion, prolonged parenteral nutrition, enteric feeding, following gastrectomy, liver disease (alcoholism) denture pastes (formerly)
• Cause of deficiency may not be apparent38
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Case: Pancytopenia42-yr-old male with 2 week history SOB, gum bleeding, tingling sensation upper and lower extremities, weight loss, malaise, weakness.
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Case
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CBC WBC 3.2 (↓ ANC)RBC 1.19Hgb 4.7Hct 15%MCV 122RDW 30.7%Plt 27Retic 5.9%4 NRBC/100WBC
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Blood-Pancytopenia 41
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NRBC at Feather 42
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Blood-Pancytopenia 43
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Case: DiagnosisClinical dx: TTP
Blood smear dx: ?
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Additional LabsAbsolute retic 0.07 NlHaptoglobin < 8 LDH 1600 Vitamin B12 93
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Case: Diagnosis
Megaloblastic anemia mimicking TTP
ReferenceHemolysis and schistocytes in ED: Consider microangiopathy related to Vitamin B12 deficiency. Noel, et. Q J Med 2013. 46
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Follow Up LabsADAMTS13: 71 NlMMA: 3.08 IF ab: positiveShiga toxin: negative
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Case: Key Tips• Megaloblastic anemia can manifest
with pancytopenia
• Oval macrocytes broken in spleen (frags, RDW)
• MCV 122 — not due to retics(Note MCV may be normal in Meg An)
• Retic % was elevated but not absolute retic count
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Case: Pancytopenia14-year-old African-American female with no past medical history; presents
with emesis x 3 days, excessive fatigue, decreased appetite
CBC: WBC 1.9, RBC 1.4, Hgb 4.7, Hct 13.6%, MCV 99, MCHC 34.8, RDW 34%, Plt 67
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86a13
Blood: 14-year-old girl 50
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86a12
Blood: 14-year-old girl 51
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86a16
Blood: 14-year-old girl 52
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86a17
Bone Marrow Biopsy 53
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Case: Differential Diagnosis
• Congenital dyserythropoietic anemia
• Other constitutional RBC disorder
• Myeloid neoplasm (pancytopenia, packed bone marrow)
• Megaloblastic anemia (?? normal MCV)
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Case: Additional Lab Data
• Low serum cobalamin
• Increased homocysteine
• Increased methylmalonic acid
• Positive intrinsic factor
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Case: Final Diagnosis
Megaloblastic anemia, pernicious anemia
Follow-up:Patient responded to cobalamin therapy
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Megaloblastic Anemia Caveats• Highly variable blood picture
(normal MCV, lack of “classic” features)
• Risk of vitamin B12 deficiency-associated neurologic impairment significant, especially in infants
• If cobalamin level is borderline but not below lower limit, still pursue other tests—MMA, IF ab, etc.
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Summary• Clinical information, CBC data, blood smear
and bone marrow morphology essential • Correlation with age-related normal parameters
essential• Appreciation of the full spectrum of findings in
megaloblastic anemia and copper deficiency is key to distinction from a neoplasm or other condition
• Pancytopenia may have non-neoplastic or neoplastic cause 58