Eugene Heme Oncology Flashcards
Cell Cycle Cancer examples
Hereditary Melanoma, Retinoblastoma, Li-Fraumeni Syndrome Catergory
point mutation in cyclin-dependent kinase (cdk4) inhibitor on Chr9; insensitive to p16 inhibition
Hereditary Melanoma: Pathophysiology
Loss of RB (cell cycle control protein)
Retinoblastoma: Pathophysiology/Diagnosis
tumor suppresor: when NOT phosphorylated, binds E2F to block transcription and cell division (inactive in most human cancers)
Rb pathway: Rb
onco, TFs required for cell cycle progression, blocked by Rb binding
Rb pathway: E2F
onco, phosphorylate (inactivate) Rb
Rb pathway: Cdk4/Cyclin D
tumor suppressor, downregulate Cdk4/Cyclin D activity
Rb pathway: p16
Lots of cancers (breast, colon, etc.)
Li-Fraumeni Syndrome: Signs/Symptoms
Inherited p53 mutation
Li-Fraumeni Syndrome: Pathophysiology/Diagnosis
tumor suppressor, activates p53
p53 pathway: ATM (Li-Fraumeni)
oncoprotein, inhibits p53
p53 pathway: Mdm2 (Li-Fraumeni)
tumor suppressor, G1 cycle arrest allows for DNA repair in fibroblasts, some epithelial cells, apoptosis in thymocytes
p53 pathway: p53 (Li-Fraumeni)
tumor suppressor, downstream of p53
p53 pathway: p21 (Li-Fraumeni)
trisomy 21, Fanconi’s anemia, Li-Fraumeni
Acute Myloid Leukemia (AML): Inherited
Downs also ALL
Age (>60 yo = poor outcomes), rad exposure, MDS, myeloproliferative neoplasms (CML, PV, ET), prior chemo (alkylating agents for lymphoma, breast cancer; topoisomerase inhibitors for testicular cancer via 11q23 MLL gene deletion)
Acute Myeloid Leukemia (AML): Epi/Risk Factors
large, very granular cells with bilobed nuclei
Acute Myloid Leukemia: APL subtype
blasts w/lots of cytoplasm, prominent nucleoli, granules and some maturing cells
Acute Myloid Leukemia: M2 subtype Histology
Sx: Anemia, infections, bleeding. Hemorrhage, skin or gum infiltration, no mediastinal masses, LAD and hepatosplenomegaly less likely
Acute Myeloid Leukemia (AML): Signs/Symptoms
Generally poor (<60% @ 5yr); t(8;21)(15;17), inv(16) good, 5q, chemo or complex karyotype bad
Acute Myeloid Leukemia (AML): Prognosis
If good prognosis: 7+3: cytarabine x7d, doxorubicin x3d
Acute Myeloid Leukemia (AML): Treatment/Notes
AML by day 14 of cyta/doxo 7+3
hopefully shows aplastic marrow
if not salvage/clinical trial/palliation
Sx: Anemia, infections, high risk for hemorrhage; differentiation syndrome: fever, dyspnea, weight gain, pulmonary infiltrates, pleural and pericardial infusions
Acute Promyelocytic Leukemia (APL)(AML M3 Subtype)
Myeloblast/lymphoblast progenitor cell overgrowth; t(15;17) PML/RAR-alpha fusion transcript
Acute Promyelocytic Leukemia (APL)(AML M3 Subtype): Pathophysiology/Diagnosis
Acute Promyelocytic Leukemia (APL)(AML M3 Subtype): Prognosis
80-90% at five years
Sensitive to ATRA, may cause differentiation syndrome. Tx: dexamethasone, arsenic trioxide (ATO)
Acute Promyelocytic Leukemia (APL)(AML M3 Subtype): Treatment/Notes
myeloblast/lymphoblast progenitor cell overgrowth
Acute Leukemias (AML, APL, ALL): pathophysiology
iliac crest bone biopsy, blood tests
Acute Leukemias (AML, APL, ALL): diagnosis
leukostasis (AML>ALL, tx: leukaphoresis, hydroxyurea), DIC, tumor lysis syndrome
Acute Leukemias (AML, APL, ALL): complications
Rare. Extremes of age, radiation, downs
Acute Lymphoblastic Leukemia (ALL): Epi/Risk Factors
Sx: Anemia, infections, bleeding, ant. mediastinal mass, DIC, bone pain; rarely lymphadenopathy and hepatosplenomegaly
Acute Lymphoblastic Leukemia (ALL): Signs/Symptoms/Findings
Mediastinal mass, especially
T-ALL common presentation
way high lymphocytes, large cells, high N:C ratio, prominent nucleoli, no granules, open chromatin, lack of PMNs and platelets
Acute Lymphoblastic Leukemia histology
TdT+, Ig+, CD10+
B-cell ALL surface markers
TdT+, CD2+, CD3+
T-cell ALL surface markers
peds: 10; adults >60
ALL adverse prognostic factors: age
> 30k (B), or >100k (T)
ALL adverse prognostic factors: WBC
philedelphia: t(9;22), found in adults >60; t(4;11), found in peds <1
ALL adverse prognostic factors: cytogenetics
Acute Lymphoblastic Leukemia (ALL): Prognosis
> 90% five year survival. Philadelphia chromosome bad
Induction w/ CHOP; CNS prophylaxis, stem cell xplant, maintenance (prednisone, mercaptopurine, MTX)
Acute Lymphoblastic Leukemia (ALL): Treatment/Notes
myelodysplasia 5 ways
Mylodystplastic syndrome, 5q, Polycythemia Vera, Essential thrombocythemia, primary myelofibrosis
Risk of transformation to AML
Myelodysplastic Syndrome (MDS)
High blasts, proliferation, apoptosis; low WBC, RBC, plts. anemia
Myelodysplastic Syndrome (MDS): Signs/Symptoms/Findings
Stem cell disorder: bad hematopoesis leads to defects in all non lymphoid lined, cytopenia due to TNF-mediated apoptosis. De novo or exposure: chemo, radiation, benzenes
Myelodysplastic Syndrome MDS
Low risk: Lenalidomide if 5q del, growth factor therapy if not
High risk or EPOdecitabine if no Sx
stem cell transplant curative
Myelodysplastic Syndrome (MDS): Treatment/Notes
Deletion leads to Anemia with increased PLT (megakaryocytes slow-growing)
5q Syndrome, MDS subtype
Del(5q31) leads to del(RPS14) leads to death of rapidly dividing cells (erythroid). Low AML conversion
5q Syndrome
MPN: expansion of RBC lineage
Polycythemia Vera: Findings
itching, ruddy complexion, splenomegaly, early saiety, DVT or PE
Polycythemia Vera: Symptoms
JAK2V617F in 92% of cases leads to increase in all cell types (mainly RBC lineage)
Polycythemia Vera: Pathophysiology/Diagnosis
MPN w/Good prognosis. 3% yearly mortality
Polycythemia Vera: Prognosis
Platelet lineage expansion. increased PLT, normal Hgb
Essential Thrombocytosis (Primary Thrombocythemia): Findings
megokaryocytes in bone marrow, exclusion, JAK2 mut in 42%
Essential Thrombocytosis (Primary Thrombocythemia): Pathophysiology/Diagnosis
low risk: low dose aspirin; high risk (>60, past thrombosis, CV risk): low dose aspirin, hydroxyurea
Essential Thrombocytosis (Primary Thrombocythemia): Treatment/Notes
teardrop RBCs (dacrocytes), increased LDH
Primary Myelofibrosis (Idiopathic Myelofibrosis): Findings
bleeding, anemia, infxn, cachexia, fullness, splenomagaly
Primary Myelofibrosis (Idiopathic Myelofibrosis): Signs/Symptoms
Marrow fibrosis, extra-medullary hematopoiesis
Primary Myelofibrosis (Idiopathic Myelofibrosis): Pathophysiology/Diagnosis
5 year survival, CALR better than JAK2
Primary Myelofibrosis: Prognosis
epo/transfusion, hydroxyurea, thalidomide/steroids, SC transplant (cure!), JAK inhibitors
Primary Myelofibrosis (Idiopathic Myelofibrosis): Treatment/Notes
increased mature and immature myeloid cells, basophilia, decreased hgb/hct, increased platelets (thrombocytosis)
Chronic Myelogenous Leukemia (CML): Findings
fatigue, fullness, hepatosplenomagaly, weight loss, ecchymoses, anemia
Chronic Myelogenous Leukemia (CML): Signs/Symptoms
abl is oncogene, MR3 (major) = >3log bcr-abl reduction, MR4.5 (complete) = 4.5 log reduction
chronic myelogenous leukemia (CML): genetics
t(9;22) leads to Bcr/Abl fusion gene on Philadelphia chromosome (22q-) leads to increased tyrosine kinase activity
Chronic Myelogenous Leukemia (CML): Pathophysiology/Diagnosis
slow-growing Ca harder to kill. Chronic phase of high blood counts (4-6 years) leads to accelerated phase (`1y) leads to blast crisis, AML (3-6 mos to death)
Chronic Myelogenous Leukemia (CML): Prognosis
Tx: Imatinib (Gleevec) ± xplant
Progresses from chronic (splenomegaly or asymptomatic) leads to accelerated (anemia, decreased PLT) leads to blast crisis (~AML)
Chronic Myelogenous Leukemia (CML): Treatment
most common leukemia, >60 yo, not radiation!
Chronic Lymphocytic Leukemia (CLL): Epi/Risk Factors
Sx: Asymptomatic increased WBC, lymphadenopathy, splenomegaly, sino-pulmonary infxns, gradual onset fatigue, dyspnea, dizziness, weight loss
Chronic Lymphocytic Leukemia (CLL): Signs/Symptoms