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Hematopathology tableEdit

HEMATOPATH

RISKS/EPI

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Acute Lymphoid Leukemia [ALL]

acute > 20% blasts

Downs syndrome

less than 15--peak 2-6 YOA

3500 a year in the USA

1/2000 before age 21

1/25K less than 1500

increased lymphoblasts

TDT + (marker of pre-t and pre-b)

marrow infiltration

t(12;21) = better prognosis

t(9;22) = poor prognosis → same as CML

85% B cell

15% T celll

anemia, pallor, tachycardia, systolic murmur

SOB with activity

mucosal bleeding, purpura, petechiae

leukopenia, neutropenia

infections/fever

bone pain

extramedullary spready (lymphadenopathy, spleen, liver)

CNS

very responsive to therapy

standard risk

high risk

very high risk

Based on age & WBC

Hyper-CVAD

OR

Danorubicin, Vincristine, Prednisone, L-asparaginase

LEUKEMIA CLASS

EPI/RISKS

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Chronic Lymphoid Leukemia [CLL]

Most common leukemia

10-15,000 new cases/year in U.S. with 5000 deaths.

Median age 72.

a disease of accumulation

post germinal cells

B cells more susceptible because they are already mutating as part of their job.

B >= 5K with small mature lymphocytes

clonality of circulating B using flow cytometry [CD19, CD20, CD23]

Prognosis based on stage, doubling time of WBC (<12) and the genes

Smudge cells are the CLL cells that are delicate/fragile that break upon plating. Indicative of chronic disease.

FAVORABLE

IgVh Genes: mutated

Ktype: Normal, 13q-

IgVh Genes: mutated

CD38: not expressed

ZAP70 not expressed

UNFAVORABLE

Ktype: 11q-, 17p- (P53)

IgVh Genes: unmutated → more prone to activate  → more immature

CD38+/ Zap70+

Mature B cells are mutated

Lymphadenopathy

Early satiety/LUQ fullness

Fatigue, weight loss

Fever, night Sweats

Recurrent infections,bleeding

Autoimmune

Big spleen/liver

Ecchymosis/petechiae

Staging 0-4 (Rai)

Complicated by infections (kill 60% of patients)

Cytopenias, anemia, thrombocytopenia

Autoimmune disease: AIHA; pure red cell aplasia, IIP

Secondary malignancies

(skin cancer, sarcoma, kidney, lung, prostate)

Richter’s Transformation: can go to NHL (10% of cases) bad prognosis.

can

Generally not curative (unless BMT).

Chemo→ alkylating agents (chlorambucil). Attempts to slow disease no impact on outcomes.

or

nucleoside analogs (fludarabine). Lengthens survival.

or

monoclonal antibodies (rituximab). only helps in addition to chemo.

or

allogeneic stem cell transplant (for young patients). only for folks who have relapsed.

patient may not need treatment: watch → wait.

indication for trx based on active disease; symptoms; labs; increased pace of disease; complications

LEUKEMIA CLASS

EPI/RISKS

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Hairy Cell

adults

hairy cells → filamentous hair like projections

TRAP stain

phosphatase +

dry tap on BMB

mature b cell tumor

causes marrow fibrosis

cladribine

Non-Hodgkin’s Lymphoma

GENERAL

most common

70K a year/19K deaths

elderly

Risks: infection (EBV, Hep C, HTLV-1 etc.)

Autoimmune, Exposure, Family (rare)

disease of proliferation

Grading:

1

 

2

3

and

indolent

aggresive

highly aggressive

CVP, R-CHOP

Non Hodgkins Lymphoma

Diffuse Large B cell

30% of NHL (most common)

median age 60

GCB: happening to your centroblasts (in the germinal center)

ABC: happening to the plasma blast outside of the GC.

activated B cell (ABC) →  NFKB; BCL2 amplification; CD79; CARD11; SPIB/E26 (19q)

germinal center (GCB): PTEN/PI3K; BCLT2 t(14;18), Rel, EZH2

primary mediastinal

Subtypes:

activated B cell (ABC)

germinal center (GCB)

primary mediastinal

B Symtpoms (30%)

BM (10-20%)

Extranodal sites

aggresive

primary: CHOP

relapsed/refractory: 2nd line chemo + autoBMT

Non Hodgkins Lymphoma

Cutaneous t-cell

HTLV-1

indolent

Non Hodgkins Lymphoma

Waldenstroms macroglobulinemia

serum IgM >3g/dl

plasmacytoid lymphocytes in marrow

between lymphoma and MM

fatigue

bleeding

hyperviscosity (confusion, headaches, lethargy)

anemia, infection, lymphadenopathy, splen/hepat, NO bone lytic lesions

indolent

plasmapheresis

CHOP

fludarabine

rituximab

Non Hodgkins Lymphoma

Marginal Zone

h. Pylori

chlamydia 

indolent

Non Hodgkins Lymphoma

Burkitts

2.5% of cases

endemic in Africa

sporadic (kiddos)

Immunodeficiency → AIDS

EBV/Malaria association

male

“starry sky”

monotonous proliferation of intermediate sized lymphoid cells

CD10, CD19, CD20 and kappa light chain

Ki67 close to 100%

happening to your centroblasts (in the germinal center)

t (8;14) CMYC

which is the regulator for lymph differentiation

BM is replaced by lymph

frequent extranodal involvement (GI, CNS, leukemia)

rapidly fatal if not treated

highly aggressive

intensive combination chemo → pretty good response

watch out for tumor lysis syndrome

cure?

Non Hodgkins Lymphoma

Mantle Cell

5% of cases

60 years

male

happening to the naive B cell outside of the GC.

t(11;14), Cyclin D1 overexpression

variability

extranodal disease common in AD

indolent

aggressive

not curable with standard therapies

some patients transplant

use drugs that target B cell signaling

Non Hodgkins Lymphoma

Follicular

 

second most common

Hep C

age 60

70% dx @ advanced stage

happening to the centrocyte within the germinal center.

t(14;18), BCL-2 (normally inhibits apoptosis) this mutation increases BCL-2 and decrease apoptosis

arise from germinal center→ b cells

adenopathy (wax/wane)

asymptomatic

3% chance of transformation per year

indolent

early treatment does not improve survival

advance stage not curable with standard therapies

R-CHOP and bendamustine

treatable but not curable

LEUKEMIA CLASS

EPI/RISKS

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Hodgkin’s Disease

uncommon 3/100K a year

males>females

age: 35

90% cases dx at age <65

prior infection with EBV; HIV; HTLV-1

RS cells large, binucleate, “owl eyes”

sometimes evidence of EBV in the cells

LAB EVAL→ CDC; ESR; Chems; HIV; HCG

IMAGING → CXR; CT chest; PET (sugar)

STAGING (include A or B symptoms; E-extranodal; X big mass)

?

transformation of B cells “Reed-Sternberg” and surrounding inflammatory cells

lymphadenopathy (70%)

pruritus

alcohol induced lymph pain

paraneoplastic (skin lesions; hypercalcemia; ITP/hemolytic anemia)

CLASSIC B SYMPTOMS (less than 20% of patients w/early stage)

fevers

drenching night sweats

weight loss

1) nodular sclerosis (70%) young females

mediastinum

sclerosis (owl eyes)

2) mixed cellularity (20%) adults, AD, spleen, liver, BM, worse prognosis, mix of cells

3) lymphocyte rich (5%) nodular/diffuse growth pattern

4) lymphocyte depleted (5%) common in HIV/elderlyl; abdomnal nodes, liver, spleen, BM, poor prognosis that #1

Stage ½ → 4 cycles chemo; or 2 cycles with low dose radiation.

Stage ¾: 6-8 months of chemo; radiation

ABVD-

LEUKEMIA CLASS

EPI/RISKS

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Multiple Myeloma

2/100K a year

65 YOA

male > female

black > white

age, gender, race, radiation, family history, obesity, MGUS

anaplastic cell

M protein in serum >3g/dL or urine

monoclonal BM plasma cells >10%

CRAB (1)

HyperCalcemia

Renal failure

Anemia

Lytic Bone Lesion

adverse prognostics: del 13; t (4;14), t(14;16), 17p del (p53 del)

monoclonal plasma cell disorder → malignant tumor characterized by accumulation of terminally differentiated B-lymphocytes

disruption of bone integrity (osteoblasts produce new bone; osteoclasts cause bone reabsorption; MM inhibits OB and MM inhibits OC.

bone pain

anemia

renal

hypercalcemia

liver/spleen (less common)

variable

complications:

bone disease, Ca2+, recurrent infections, renal failure, anemia, cardiac failure

international staging system

durie-salmon staging system

Rd or CYBOR-D

therapy not curative unless transplant

therapy for the bone lesions

autologous transplant

allogeneic transplantation (for younger patients; higher risk; graft vs. myeloma) 

Monoclonal gammopathies of undetermined significance (MGUS)

common in elderly (3% of elderly)

AA increase risk, male, pesticides

, family history

does not meet dx criteria for MM

IG <3g/dl

<10% BM plasma cells

risk of transformation @ 1% a year

Amyloidosis

congo-red → distinctive red-green birefringence when examined under cross-polarized light

amyloid fibrils self assemble and deposit with a B-sheet secondary structure.

linear non-branching fibrils 7-10nm in diameter

periorbital purpura

heart, GI tract, nervous system, kidneys

liver, kidney, spleen

heart, kidney, treated with liver transplant

1. Primary: plasma cell lymphoid neoplasms; precursor Ig light chains

2. Secondary; associated with chronic infections and autoimmune; serum amyloid A induced by IL-1, IL-6, TNF A

3. Hereditary: mutated transthyretin protein

LEUKEMIA CLASS

EPI/RISKS

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Myelodysplasia [MDS]

older patients

owns syndrome

fanconi anemia

aging

mutagen exposure-chemotherapy

AA

PNH

PC Vera

P-smear = macrocytes hypolobulated granulocytes and hypogranular granulocytes

Bone marrow = nuclear/cytoplasmic dysinchrony

multinuclear cells

loss of normal granulation

hypolobulated megakaryocytes

clonal disorder characterized by ineffective heamtopoiesis and predisposition to transform

uncoupling of proliferation and differentiation

caused by stromal/microenvironment abnormalities

hostile inflammatory environment.

anemia +/-

leukopenia

thrombocytopenia

risk to transform to AML

risk of infection and bleeding

lower risk: apoptosis prevails over proliferation.

high risk: MDS proliferation dominates.

BMT

supportive therapy

standard treatment

Lenalidomide

Acute Myeloid Leukemia [AML]

acute > 20% blasts

a disease of aging

65

ionizing radiation

benze + atomic bomb

Myeloid:          CD 33, 34, 117

B Cell: CD 10, 19, 20, 22

T Cell: 2, 3, 4, 7, 8

increase myeloblasts--accumulation of leukemic blasts of

myeloid origin

Auer rods

Perioxidase +

Cytoplasmic inclusions

underproduction of all other cells

FLT-3 ITD

clonal disorder (usually acquired mutation)  of

a single neoplastic

cell in the myeloid lineage

excess immature/useless progenitors compete for

scarce resources and inhibit normal

hematopoietic development

infiltration of blasts into bones (cause pain), spleen, CNS, sludge blood, skin lesions

DIC

thrombocytopenia, anemia, leukopenia, neutropenia

WBC unpredictable (can be high)

Tumor lysis syndrome

Untreated, death within weeks

1.  deal with immediate threats and avoid infection.

2. confirm dx

3.induction 3+7 chem--(anthracycline + cytosine arabinoside)

4.consolidation--HiDAC

5. allogeneic transplant

ATRA--start right away while you are waiting for your FISH/Cyto.

LEUKEMIA CLASS

EPI/RISKS

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Acute Proliferatory Leukemia [APML]

10% of AML

younger people

auer rods

bilobed nucleuses

t(15;17)

PML-RARalpha fusion

Leukopenia

Presents as DIC very dramatic and dangerous

Was most deadly now becoming most curable (>90%)

ATRA and arsenic

Chronic Myeloid Leukemia [CML]








    • is a classical MPN**

few deaths

5000 cases in the US a year

Nagasaki

Genetic predisposition?

Pregnancy

routine labs for dx

t(9;22) Philidelphia chromosome

BCR-ABL

You have to have this or this is NOT CML.

BCR-ABL becomes an unrestrained tyrosine kinase.

anemia

big spleen

increased WBC turnover

Phases:

1.stable→ massive expansion of myeloid cells; maturation/fxn normal; very treatable (4-6 years)

2.accelerated → advanced disease; malignant clone; new cytogenetic abnormalities (survival 6-18 months)

3.blast crisis → complete loss of differentiation  (survival less than 6 months) → AML (65%); ALL (30%); Tcell ALL (5%)

Imatinib (Gleevac) or FCR

TKIs

hydroxyurea

interferon

LEUKEMIA CLASS

EPI/RISKS

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Primary Myelofibrosis (PMF)








    • is a classical MPN**

1/100K a year

fibrosis, megakaryocytic hyperplasia/atypia/dyspoiesis

tear dropped shaped RBCs

nucleated erythrocytes/granulocyte precursors

usually have a dry tap with BMB

JAK 2 (50%)

Calreticulin (30%)

MPL (10%)

ineffective clinical megakaryocytopoiesis result in the liberation of excessive amount of GF that induce the growth of fibroblasts → transforming GF beta; fibroblast GF; plt GF

primary: dense fibrosis or infiltration w/tumor

secondary: other causes of BM fibrosis (infection; other cancer; lupus; post-ET or post-EV)

 

almost always a large spleen

anemic

large liver

portal hypertension (ascites; varices; liver failure)

Major: presence of MK prolif and atypia; JAK 2 mutation or other clonal marker.

Minor: leukoerythroblastosis, increase in serum LDH; anemia; big spleen

BEST outcomes: CALR mutation

WORST: triple negative (Jak2; CALR & MPL)

20% chance to transform to AML

anemia: transfusion, folate, iron, anabolic steroids, EPO, immunomodulatory agents

spleen/constitutional symptoms: hydroxyurea, cytotoxic chemo, splenic radiation, splenectomy, JAK2 inhibitors, steroids, immunomodulatory agents, etanercept

potential cure: allogeneic stem cell transplant

Essential Thrombocytosis








    • is a classical MPN**

megakaryocytic hyperplasia

elevated plt >450K

Ph-

normal iron stores

JAK 2 (50%)

Calreticulin (30%)

MPL (3-5%)

not to be confused with reactive/secondary (caused by trauma etc..)

sometimes spleen enlarged

anemic

painful swollen red digits

miscarriages

increased bleeding due to acquired VWF

risk of thrombosis increases with age >60, prior hx, cardiac, WBC >11K, and JAK2 V617F mutation.

prognosis:

normal life expectancy

low risk: <60 and WNC <150K

im risk: >=60 or WBC >= 15K

high risk: >=60 and WBC >= 15K

<5% chance to transform to AML or PMF.

aspirin

cytoreductive therapy for high risk patients <60 or prior thrombosis goal is plt <400K

hydroxyurea

anagrelide

Interferon alpha or pegylated alpha2b and alpha2a.

no cure--unless BMT--rare.

LEUKEMIA CLASS

EPI/RISKS

HISTO/DX

GENETICS

MOA

SYMPTOMS

SEVERITY

TRX

Polycythemia Vera (PV)








    • is a classical MPN**

71 years

2.2/100K per year

erythroid hyperplasia

JAK 2 (100%)

not to be confused with reactive/secondary (caused by hypoxia, illicit injection of EPO etc..)

bled-down or masked PV--due to GI bleeding etc..

spleen enlarged frequently

thrombocytosis/leukocytosis

thrombotic complications

erthymegalia

pruritus

transient visual disturbance

Major: >Hgb 18.5 in men or 16.5 in women + JAK2 mutation

Minor:BMB with hypercellularity, prominent erythroid, granulocytic, and megakaryocytic proliferation

or a serum EPO below normal

Prognosis based on age, WBC levels, history of venous thrombosis

10-25% chance to transform to AML

10-25% chance to transform to PMF

support care for pruritus

anagrelide

aspirin

ruxolitinib

Five gatekeepersEdit

5 GATEKEEPERS

1)    BCR-ABL: hematopoietic stem cells (CML only)

2)    APC: colonic epithelium

a)    mutations of the second APC found in 100% of FAP patients, 95% of sporadic adenomas, 95% of sporadic somatic cancer

3)    NF1: Schwann cells

4)    RB: retinal cells

5)    VHL: kidney cells

Hallmarks of cancerEdit

2/10 HALLMARKS

DRUGS

DETAILS/MOA

GENE MUTATIONS

Sustaining proliferative signaling

ONCOGENES

[gain of function]

EGFR inhibitors

results in neoplastic transformation

act dominant--1 activated allele is sufficient for phenotype

BCR-Abl

C-MYC: DNA binding protein that regulates lymphoblast cellular differentiation. Mutated state cancer replaces BM/lymph. Rapidly fatal.

RAS: codon 12, 13, or 61 results in loss of intrinsic GTPase activity and trapping of  the protein in the activated conformation. Constitutively active.

PML-RAR alpha: for differentiation in myeloid cells. Becomes fused.

FLT-3/ITD: Tyrosine kinase receptor and ITD leads to activation of kinase. Unfavorable risk marker.

NPM1/CEBPA: favorable markers.

Chromosomal Translocations:

BCR ABL→ Philadelphia Chromosome t(9;22), 95% CML

C MYC → Burkitt’s Lymphoma t(8;14)

PML-RARalpha → t(15;17), APL

ALK → lung cancer

Retinoic acid receptor

Amplification/point mutation:

HER2/Neu → breast, lung, gastric

Point mutation:

RAS

PIK3CA → breast, CC, endometrial

Point mutation/translocation:

BRAF → melanoma, CC, thyroid, lung, prostate.

Point mutation/in/dels:

EGFR → lung

KIT → GI stromal, AML, germ cell, melanoma, mast cell

FLT-3/ITD → AML

NPM1 → AML the cytogenetics look normal but 4 NT insertion and c-terminal mutations.

CEBPA → AML

Evading growth suppressors

TUMOR SUPPRESSOR GENES

Cyclin-dependent kinase inhibitors

loss of function results in tumors; serve as regulators for critical cell pathways.

both copies inactivate (lose both of the breaks)

Rb

familial: early age, autosomal dominant, variable penetrance, multiple tumors. 13q14 mutation in the germline.

sporadic : 2 mutations to get to 13q14.

p53: guardian of the genome, TF, regulator of apoptosis/cell cycle, DNA repair. Expression of p21. p21 blocks phosphorylation of RB. → lung, CC, ovarian, breast. Germline → Li-Fraumeni Syndrome


8/10 HALLMARKS

Avoiding immune destruction

immune activation anti-CTLA4 mAb

Enabling replicative immortality

Telomerase inhibitors

tumor-promoting inflammation

Selective anti-inflammatory

activation invasion and metastasis

inhibitors of HGF/c-Met

inducing angiogenesis

inhibitors of VEGF-signaling

genome instability and mutation

PARP inhibitors

resisting cell death

Proapoptotic BH3 mimetics

dysregulated cellular energetics

aerobic glycolysis inhibitors


Table 2Edit

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