1
Q
CML
A
Things Must Know
- Neutrophilic leukocytosis
- Basophilia
- Philadelphia chromosome
- Three phases (chronic, accelerated, blast crisis)
Signs
Huge spleen,
Big liver,
Maybe some lymphadenopathy
Symptoms Slow onset, Fever, Fatigue, Night sweats, Abdominal fullness
Labs - ↑↑↑ WBC - Neutrophilia with left shift - Basophilia - ↓ hemoglobin - ↑ platelet count (at first) - ↓ LAP (leukocyte alkaline phosphatase) - Cytogenetics: t(9,22) → BCR-ABL (tyrosine K & IgL)
Treatment
- Imatinib (Gleevac)
Remission:
- Hematologic: WBC <10K, normal morphology, Hgb, Plt
- Cytogenetic: no M phase, t(9;22)
- Molecular: no BCR-ABL
Leukemic transformation can occur
2
Q
Polycythemia
Vera (PV), aka primary
A
Things Must Know
- High RBC (makes blood sludgy)
- Different from secondary polycythemia
- Thrombosis and hemorrhage
- Jak-2 mutation
Signs
- Headache
- Pruritis
- Dizziness
- Thrombosis (due to sludgy-ness of blood)
- Infarction
Symptoms
Big spleen, liver
Plethora (red face)
Labs ↑ red cell mass Normal O2 saturation Thrombocytosis ↑ WBC without infection ↑ LAP – not sure why… ↑ B12 – abnormal B12 metabolism
Treatment
- Phlebotomy
- Maybe myelosuppressive drugs
- Roluxinib (sp?)
Median survival: 9-14 years
Death from thrombosis or hemorrhage; can undergo leukemic transformation in some
3
Q
Essential Thrombo-cythemia
A
Things Must Know
- Very high platelet count in blood
- Can occur in young women (~30s)
- Diagnosis of exclusion
- Thrombosis and hemorrhage
Signs
Purpura, bruising, Pallor, tachycardia, Biggish spleen
Symptoms
Bleeding, Thrombosis
Labs
- Platelet count >600,000
- Hgb <13 or RBC mass normal
- No Philadelphia chromosome
- No marrow fibrosis
- No other reason for thrombocytosis
Treatment
- Platelet pheresis
- Maybe myelosuppressive drugs
- Aspirin
Median survival: 5-8 years
Death from thrombosis or hemorrhage; can transform into acute leukemia
4
Q
Chronic Myelofibrosis
A
Things Must Know
- Panmyelosis…
- …then marrow fibrosis
- Extramedullary hematopoiesis
- Teardrop red cells
Signs
Huge spleen, Pallor, tachycardia
Symptoms
Left upper quadrant fullness, Weakness, fatigue, palpitations
Labs
Treatment
Left upper quadrant fullness, Weakness, fatigue, palpitations
5
Q
CLL/SLL
A
Things Must Know
- Small, mature lymphocytes
- = small lymphocytic lymphoma (SLL)
- B-cell, but CD5+ (Pan-T cell marker; weird!)
- Long but inexorable course
Clinical Findings
- Older (>40)
- Asymptomatic at first
- Later, organ infiltration
- Infection may occur due to hypogammaglobulinemia
Immunophenotype
- Positive for: B-cell antigens (CD20), A T-cell antigen (CD5)!
- Negative for: TdT
Treatment
- Conservative (tx can be worse than leaving it alone)
- Reduce organomegaly, infections
Mean survival: 9 yrs
Death from infection
6
Q
Hairy Cell Leukemia
A
Things Must Know
- Hairy cells
- Splenomegaly without lymphadenopathy
- Pancytopenia
- TRAP +
- B cell neoplasm
Clinical Findings
- Older (>40)
- M:F = 5:1
- Big spleen but no lymphadenopathy!
- Pancytopenia (usually) and monocytopenia (always)
Immunophenotype
Cytochemistry: TRAP+ (red)
- Positive for B-cell antigens
- Negative for CD5
Treatment
Chemotherapy (Rituximab, IFNα?)
Good! Usually 10+ years
7
Q
Prolymphocytic Leukemia
A
Things Must Know
- Prolymphocytes
- Splenomegaly without lymphadenopathy
- Rare
- Aggressive (< survival)
Clinical Findings
- Splenomegaly without lymphadenopathy
- Aggressive
Immunophenotype
- ↑↑ WBC (~50K)
- ↓ Hgb
- ↓ platelet count
Treatment
Condensed chromatin with nucleoli (weird!)
8
Q
Large Granulated Lymphocyte Leukemia
A
Things Must Know
- Large granulated lymphocytes
- T-cell (+ granules)
- Neutropenia → recurrent infections
- Long survival
Clinical Findings
Infections (from neutropenia)
Immunophenotype
Modest leukocytosis
Neutropenic
Treatment
Long survival
9
Q
Hereditary Bleeding Disorder:
von Willebrand Disease (vWD)
A
Things Must Know
- Most common hereditary bleeding disorder
- Autosomal dominant
- vW factor decreased (or abnormal); carries VIII (intrinsic pathway)
- Variable severity
- Three types (1, 2, 3)
Symptoms
- Mucosal bleeding in most patients
- Deep joint bleeding in severe cases
Lab Tests
- Bleeding time: prolonged
- PTT: prolonged (“corrects” with mixing study)
- INR: normal
- vWF level decreased (normal in type 2)
- Platelet aggregation studies abnormal
- Ristocetin assay
Treatment
- DDAVP (raises VIII and vWF levels)
- Cryoprecipitate (contains vWF and VIII)
- Factor VIII (don’t give all the time, since body will make Ab against it)
10
Q
Hereditary Bleeding Disorder:
Hemophilia A
A
Things Must Know - Most common factor deficiency - X-linked recessive in most cases *(30% are random mutations) - Factor VIII level decreased (intrinsic pathway) Variable amount of “factor” bleeding
Symptoms
- Severity depends on amount of VIII
- Typical “factor” bleeding
- deep joint bleeding
- prolonged bleeding after dental work
- Rarely, mucosal hemorrhage
Lab Tests
- INR, TT, platelet count, bleeding time: normal
- PTT: prolonged (“corrects” with mixing study)
- Factor VIII assays: abnormal
- DNA studies: abnormal
Treatment
- DDAVP
- Factor VIII
11
Q
Hereditary Bleeding Disorder:
Hemophilia B
A
Things Must Know
- Factor IX level decreased (intrinsic pathway)
- Much less common than hemophilia A
- X-linked recessive in most
- Same clinical and laboratory findings
Symptoms
- Severity depends on amount of VIII
- Typical “factor” bleeding
- deep joint bleeding
- prolonged bleeding after dental work
- Rarely, mucosal hemorrhage
Lab Tests
- INR, TT, platelet count, bleeding time: normal
- PTT: prolonged (“corrects” with mixing study)
- Factor VIII assays: abnormal
- DNA studies: abnormal
Treatment
- DDAVP
- Factor VIII
12
Q
Hereditary Platelet Disorder:
Bernard-Soulier Syndrome
A
Things Must Know
- Abnormal Ib
- Abnormal adhesion
- Big platelets
- Severe bleeding
Treatment
Platelets as big as RBCs!
13
Q
Hereditary Platelet Disorder:
Glanzmann Thrombasthenia
A
Things Must Know
- No IIb-IIIa
- No aggregation
- Severe bleeding
14
Q
Hereditary Platelet Disorder:
Gray Platelet Syndrome
A
Things Must Know
- No α granules (vWF, fibrinogen, etc.)
- Big, empty platelets
- Mild bleeding
15
Q
Hereditary Platelet Disorder:
Granule Deficiency
A
Things Must Know
- No δ granules (Ca2+, ADP, ATP, 5HT)
- Can be part of syndrome (e.g., Chediak-Higashi)
16
Q
Acquired Bleeding Disorders:
DIC
A
Most Common Causes
- Malignancy (APL)
- OB complications
- Sepsis
- Trauma
Things Must Know
- Lots of underlying disorders
- Something triggers coagulation, causing thrombosis
- Platelets and factors get used up, causing bleeding
- Microangiopathic hemolytic anemia (MAHA)
Symptoms
- Insidious or fulminant
- Multi-system disease
- Thrombosis and/or bleeding
Lab Tests
- INR, PTT, TT prolonged
- FDPs: increased
- Fibrinogen: decreased
Treatment
- Treat underlying disorder
- Support with blood products
17
Q
Acquired Bleeding Disorders:
ITP (Idiopathic Thrombocytopenia Purpura)
A
Things Must Know
- Antiplatelet antibodies
- Acute vs. chronic
- Diagnosis of exclusion
- Steroids or splenectomy
Pathogenesis:
- Autoantibodies to GpIIb-GpIIIa or Ib
- Binds to platelets
- Splenic macrophages eat platelets
Symptoms
- Chronic
- Adult women
- Primary or secondary
- Insidious: easy bruising, nosebleeds
- Danger: bleeding into brain
- Acute
- Children
- Abrupt; follows viral illness
- Usually self-limiting
- May become chronic
Lab Tests
- Signs of platelet destruction:
- thrombocytopenia
- normal/increased megakaryocytes
- big platelets
- INR/PTT normal
- No specific diagnostic test for ITP
Treatment
- Glucocorticoids
- Splenectomy
- Intravenous immunoglobulin (IVIG)
18
Q
Acquired Bleeding Disorders:
TTP
Thrombotic Thrombocytopenic
Purpura
A
Things Must Know
- Pentad: MAHA, thrombocytopenia, fever, neurologic defects, renal failure
- Deficiency of ADAMTS13
- Big vWF multimers trap platelets
- Plasmapheresis or plasma infusions
Symptoms
- Hematuria, jaundice (MAHA)
- Bleeding, bruising (thrombocytopenia)
- Fever
- Bizarre behavior (neurologic deficits)
- Decreased urine output (renal failure
Lab Tests
Pathogenesis of TTP:
- Just-released vWF is unusually large (UL)
- UL vWF casues platelet aggregation
- ADAMTS13 cleaves UL vWF into less active bits
- TTP is due to ADAMTS13 deficiency
Treatment
- Acquired TTP: plasmapheresis
- Hereditary TTP: plasma infusions
19
Q
Acquired Bleeding Disorders:
HUS
Hemolytic Uremic Syndrome
A
Things Must Know
- MAHA and thrombocytopenia
- Epidemic (E. coli) vs. non-epidemic
- Toxin (or ?) damages endothelium
- Treat supportively
Symptoms Epidemic: - Children, elderly - Bloody diarrhea, then renal failure - Fatal in 5% of cases Non-epidemic: - Renal failure - Relapsing-remitting course - Fatal in 50% of cases
Lab Tests Pathogenesis Epidemic: - E.coli O157:H7 (raw hamburger) - Makes nasty toxin - Injures endothelial cells Non-epidemic: - Defect in complement factor H - Inherited or acquired
Treatment
- Supportive care
- Dialysis
- NOT antibiotics (may increase toxin release!)
20
Q
AML-M0
Old Classification System
A
Important Characteristics
- ↑↑↑ myeloblasts (»20% → ~90%)
- Bland – minimal differentiation
- MPO (myeloperoxidase stain) negative
- Need markers → flow cytometry
21
Q
AML-M1
Old Classification System
A
Important Characteristics
- ↑↑↑ myeloblasts
- No maturation
- Auer rods
- MPO positive
22
Q
AML-M2
Old Classification System
A
Important Characteristics
- ↑ myeloblasts
- Maturing neutrophils + blasts + (auer rods)
- t(8;21) in some cases – better prognosis!
23
Q
AML-M3
Old Classification System
A
Important Characteristics
- ↑↑↑ promyelocytes
- Faggot cells – tons of auer rods
- DIC; if bust open these cells with chemo → patient will develop DIC and will clot everywhere (tx w/ ATRA)
- t(15;17) in all cases!!!!
24
Q
AML-M4
Old Classification System
A
Important Characteristics
- ↑↑ myeloblasts
- ↑↑ monocytic cells
- Extramedullary tumor masses (CNS, skin, gums, testes)
- inv(16) in some cases → better prognosis
25
AML-M5
| Old Classification System
Important Characteristics
- ↑↑ monocytic cells
- NSE positive (red blasts)
- Confirm with flow
- M5A and M5B (folded tissue paper)
- Extramedullary tumor masses
26
AML-M6
| Old Classification System
Important Characteristics
- ↑↑ erythroblasts
- ↑↑ myeloblasts
- Dyserythropoiesis
27
AML-M7
| Old Classification System
Important Characteristics
- ↑↑ megakaryoblasts
- Bland blasts
- MPO negative
- Need markers – flow needed
28
AML with genetic abnormalities
| New Classification System
Important Characteristics
- t(8;21) → (AML-M2); cells become huge
- t(15;17) → (AML-M3); ALL cases have this translocation
- inv(16) → (AML-M4, Eo); gigantic eosinophils
* Three above have a good prognosis
- 11q23 → doesn’t indicate what problem is occurring; confers a bad prognosis
* 11 q two three → two = band, three sub-band
* Usually seen in AML with a monocytic series
29
AML with FLT-3 mutation
| New Classification System
Important Characteristics
- Mutation of FLT-3 (a tyrosine kinase)
- Present in 1/3 of cases of AML!
- Monocytic cells
- Poor prognosis
30
AML with multilineage dysplasia
| New Classification System
Important Characteristics
- ≥ 20% blasts + dysplasia in ≥ 2 cell lines (dysgranulopoiesis, dyserythropoiesis, etc.)
- Elderly
- Severe pancytopenia (decreased RBC, WBC, platelets)
- Chromosome abnormalities (5, 7)
- Poor prognosis
- Not a common condition within the AML series
31
AML, therapy-related
| New Classification System
Important Characteristics
- Previous chemotherapy which typically include: alkylating agents (Busulfan) or topoisomerase II inhibitors (Etoposide)
- 2-5 years to onset
- Chromosomal abnormalities sometimes (5, 7, 11q23)
- Very hard to treat
32
AML, not otherwise specified
| New Classification System
Important Characteristics
| ???
33
Benign Follicular Hyperplasia
Large, irregular follicles
- Mixture of cells in germinal centers
- Tingible body macrophages
- B-cell response to some immune stimulus
34
Benign Interfollicular Hyperplasia
- Expanded area between follicles
- Mixture of cells
- Partial effacement (lymph node is not completely replaced by cells)
- T-cell response to some immune stimulus
35
low grade non-hodgkins
- Older patients
- Indolent (incurable!)
- Small, mature cells
- Non-destructive
High-grade:
- Children, sometimes
- Aggressive (curable?)
- Big, ugly cells
- Destructive
- Malignant proliferation of lymphoid cells (blasts or mature cells) in lymph nodes
- Skips around in body (not predictable)
- Many subtypes
- Most are B cell
Symptoms:
- Painless, firm lymphadenopathy
- Extranodal manifestations (possible CNS, liver, or spleen involvement)
- “B” symptoms, aka constitutional symptoms: weight loss (20-30lbs), night sweats, fever
* If these symptoms are absent, then the person has a better prognosis
36
Small Lymphocytic Lymphoma (aka CLL)
- Small mature lymphocytes
- Same thing as CLL
- B-cell lesion, but CD5+ (weird!)
- Long course; death from infection
- Richter transformation → changes low-grade to high-grade
37
Marginal Zone Lymphoma
Malt Lymphoma
- Actually a bunch of lymphomas
- Marginal zone pattern
- Malt lymphoma is a common type
- Helicobacter pylori
- Tx: antibiotics for H. pylori
38
Follicular Lymphoma
- Follicular pattern (later diffuse)
- Small cleaved cell, mixed or large cell
- Grade 1, 2, or 3 → differences in prognosis
- t(14;18) - IgH and bcl-2
* Cell becomes immortal
- Butt Cells!
39
Mycosis Fungoides / Sézary Syndrome
- Skin lesions → Leonine facies
- Blood involvement
- Cerebriform (looks like brain) lymphocytes
- T-cell immunophenotype
Present with rash that is not cured with cortisone, becomes a “mushroom”
40
Mantle Cell Lymphoma
- Mantle zone pattern
- Small angulated lymphocytes
- t(11;14) – cyclin D1 (passes G1 – S checkpoint) and IgH (heavy chain Ig)
- More aggressive
41
Diffuse Large Cell Lymphoma
- Large B cells
- Extranodal involvement
- Grows rapidly
- Bad prognosis
42
Lymphoblastic Lymphoma
- Two types: B and T
- Lymphoblasts in diffuse pattern (fine chromatin)
- Same as ALL
- T-lymphoblastic lymphoma (aka T cell ALL) often in teenage male with mediastinal mass
43
Adult T Cell Leukemia / Lymphoma
- Japan/Caribbean basin
- HTLV-1 infection
- Skin lesions, hypercalcemia
- Very aggressive
- Flowery cells
44
Burkitt Lymphoma
- Two Types: Endemic (African) and Non-endemic
- Child with fast-growing, extranodal mass
- Starry-sky pattern
- t(8,14) = c-myc and IgH
- Occasionally involves blood
45
hodgkins
- Younger patients, good prognosis
- Contiguous spread
- Five subtypes; stages are more important
- Reed-Sternberg cell (CD 15,
CD 30)
EBER+
Inf. w/
EBV
46
Nodular Lymphocyte-Predominant
(background cells) Hodgkin Lymphoma
- Asymptomatic young male with cervical lymphadenopathy
- Good prognosis (early stage)
- B-cell origin
- Popcorn cells
47
Nodular Sclerosing Hodgkin Lymphoma
- Most common subtype
- Good prognosis (early stage)
- Lacunar cells (variant of Reed Sternberg cell)
48
Mixed Cellularity Hodgkin Lymphoma
- Worse prognosis
- Usually disseminated at presentation
- Classic Reed-Sternberg cells
- Mixture of background cells (eosinophils, histiocytes)
49
Lymphocyte-Rich Hodgkin Lymphoma
- Uncommon
- Usually localized at presentation
- Popcorn cells
50
Lymphocyte Depletion Hodgkin Lymphoma
- Rare
- Often disseminated at presentation
- Classic Reed-Sternberg cell
- Collagen or reticulin backgr
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