Case 1: Acute Promyelocytic Leukemia (APL)

pathophys of ALL

-Many chromosomal aberrations-> dysregulation of expression/function of transcription factors needed for B and T cell development -90% have numerical or structural chromosomal changes 1. 25% of ALL have hyperdiploidy (>50 chromosomes) 2. 25% have t(12;21)->TEL-AML1 (ETV6-RUNX1) 3. T-ALL: 70% have gain of function mutation in NOTCH1 4. B-ALL: loss of function mutation in PAX5, E2A, EBF or balanced t(12;21)

APL

-biologically distinct variant of AML due to t(15;17) =medical emergency with high rate of early mortality often due to hemorrhage from characteristic coagulopathy

DIC and ag-ab complexes

-complexes can activate the classical complement cascade-> activation of platelets and granulocytes

DIC and microorganisms

-endotoxins (eg. s. pyogenes) can inhibit thrombomodulin expression directly and indirectly (thru TNF) and activate factor XII

DIC and trauma

-trauma and burns-> major release of TF-> activation of coagulation cascade

Follicular lymphoma

1. 2nd most common NHL (20%) -most common indolent lymphoma (70%) 2. patho: t(14;18)-> BCL2 on 18 put next to Ig H-chain gene on 14->overexpression of BCL2->inhibits apoptosis->hyperplasia of germinal center B cells 3. can progress to DLBCL 4. Presentation -late adulthood (60s) -painless lymphadenopathy -F>M 5. Cell markers: CD19, CD20, CD10, surface Ig, BCL2, BCL6 6. Tx: rituximab or low dose chemo 7. Histo: capsule of LN invaded, lymphoma cells extend into surrounding adipose tissue, numerous follicles that are irregularly shaped->nodular appearance

APL epidemiology

1. 5-20% of AML -600-800 new cases/yr in US 2. increases in incidence in 2nd decade of life, reaches plateau during early adulthood, then consistent until it decreases after age 60

Bad prognostic features in HL

1. >3 nodal site involved 2. Bulk -10 cm mass or mediastinal mass >1/3 thorax diameter 3. ESR>50 4. "B" symptoms 5. invasion to critical organs 6. Male 7. age>40 8. Mixed cellularity or lymphocyte depleted subtypes 9. Low WBC (Cytopenias) and low Hgb

Biomarker-driven meyloma features

1. >60% clonal plasma cells by BM 2. serum free light chain ratio involved: uninvolved >100% 3. >1 focal lesion detected by MRI

Tx of HL

1. ABVD day 1 and day 15 is mainly used -Adriamycin (Doxorubicin) -Bleomycin -Vinblastine -Dacarbazine 2.Following 2 cycles (2 mos)->PET scan to restage 3. Stem cell transplant is useful in patients who are non-responsive to chemo

Waldenstrom Macroblobulinemia (aka lymphoplasmacytic lymphoma)

1. B cell lymphoma with monoclonal IgM production 2. more commonly seen in older men (>50 yrs) 3. main risk factor: history of MGUS 4. Presentation: -generalized lymphadenopathy, splenomegaly, cutaneous lesion (due to visceral organ infiltration) -increased serum protein with M spike -Visual and neuro deficits (eg retinal hemorrhage, stroke)-due to hyperviscosity caused by excessive IgM (large pentamer) -bleeding due to hyperviscosity of blood->defective plt aggregation -anemia, thrombocytopenia, neutropenia due to BM infiltration 5. Tx: plasmapheresis which removes IgM from serum, chemo is also used

Multiple Myeloma evaluation/workup

1. CMP -kidney function, protein/albumin 2. CBC -hgb, hct, plt 3. ESR 4. UA -proteinuria, kidney function 5. SPEP 6. light chain -quantitative and ratio to confirm monoclonality 7. Beta-2 microglobulin 8. BM biopsy

Moderate hypothermia (HT II)

1. presentation: altered mental status w.out shivering -proportionate reductions in HR and CO -hypoventilation -CNS depression, hyporeflexia -decreased RBF -paradoxical undressing can be observed -A. fib, unctional bradycardia, other arrhythmias 2. Core temp: 28-32C 3. Tx: active external and internal rewarming -warmed humidified O2 and heated blankets -rewarm trunk first to minimize risk of core temp afterdrop (due to return of cold blood to core from extremities)

Severe hypothermia (HT IV)

1. presentation: apparent death 2. Core temp: 13.7-24C 3. Tx: resuscitation may be possible

Chronic Lymphocytic leukemia (CLL)/Small lmyphocytic lymphoma

1. proliferation of naive B cells that are CD5+ and CD20+ 2. most common leukemia overall in adults -presents after age 60 3. Presentation: generalized lymphadenopathy (small lymphocytic lymphoma), Smudge cells on peripheral smear 4. Complications: -hypogammaglobulinemia (infection is most common cause of death since naive B cells can't become plasma cells) -autoimmune hemolytic anemia (if the B cells can produce Ig, they produce autoantibodies vs. RBCs) -Richter Transformation (transformation to DLBCL->enlarging LN or spleen)

ALL tx and prognosis

1. responds well to chemo 2. requires prophylactic tx to scrotum and CSF 3. prognosis based on cytogenetics: -t(12;21), hyperdiploid (>50)->good -hyperdiploid (47-50), normal diploidy->intermediate -t(9;22), hypoploidy (near haploid)->poor

Side effects of induction therapy in APL

1. severe pancytopenia in all patients -requires transfusion support and abx as needed 2. daily lab tests: CBC, CMP, coagulation studies 3. stomatitis 4. alopecia 5. daunorubicin: cardiac arrythmia, HF

Aggressive NHL

1. short natural history with rapid accumulation of cells that responds to chemotherapy 2. aggressive NHL=curable -makes sense bc chemo targets rapidly dividing cells 3. examples -Grade III follicular lymphoma -diffuse large cell lymphoma -primary effusion lymphoma -Burkitt -precursor B/T lymphoplastic lymphoma -peripheral T cell lymphoma

APL dx

1. suspected by cellular morphology, immunophenotypes and presence of severe caogulopathy 2. confirm dx by ID PML-RARA fusion gene or associated chromosomal translocation t(15;17) via FISH or RT-PCR *start tx with ATRA in suspected cases before confirmation of fusion protein

Presentation of PV

1. sxms are related to increased RBC mass and hyperviscosity-> -blurry vision -headache -increased risk for thrombosis (eg. hepatic vein-> Budd-Chiari syndrome) -stoke -MI -flushed face due to congestion (plethora) -itching after bathing (histamine release from increased mast cell) 2. Progression: -Pre-PV phase with JAK2 mutation and decreased EPO -overt PV: increased red cell mass, panmyelosis -post-PV phase: after 10-15 yrs, presents with myelofibrosis and blast formation

Management of DIC

1. treat underlying cause to eliminate stimulus for ongoing coagulation and fibrinolysis 2. supportive care - hemodynamic/ventilator support -aggressive hydration -transfusion for severe bleeding

Mantle cell lymhoma

1. uncommon NHL (2.5%) 2. patho: t(11;14)->cyclin D1 (ch.11)->next to Ig H chain gene-> overexpression of cyclin D1 and BCl-1->promotes G1/S transition in cell cycle 3. Cell type: Naive B cell (no somatic hypermutation) -markers: Cyclin D1, CD19, CD20, Surface Ig, CD5 4. Presentation -late adulthood -M>F -painless lymphadenopathy -can also involve spleen and GI tract 5. histo: neoplastic lymphoid cells surround a small, atrophic germinal center, producing a mantle zone pattern of growth

Multiple Myeloma diagnosis

1. underlying plasma cell proliferative disorder AND 2. 1 or more myeloma defining events including: -either >1 CRAB features OR >1 biomarker driven feature

APL morphology

=abnormal promyelocytes in BM and peripheral blood 1. large (>20 microns) 2. high N:C ratio 3. fine chromatin 4. prominent nucleoli 5. violet cytoplasmic granules with dense or coarse pattern 6. Bilobed, folded, kidney-shaped or dumb-bell nuclei 7. hypergranular form (most common) contain Auer rods or bundles of auer rods 8. immunohistochemistry: MPO+ CD13+ CD33+ 9. Tx: Chemo-> induction, consolidation, maintenance

Diffuse intravascular Coagulopathy (DIC)

=acute, subacute, chronic thrombohemorrhagic disorder 1. Characterized by excessive activation and formation of thrombi in microvasculature of the body 2. -> consumption of platelets, fibrin, coag factors as well as activation of fibrinolysis 3. NOT a primary disease (secondary to something else)

Daunorubicin

=anthracycline 1. MOA -intercalates btwn DNA base pairs-> steric obstruction/strand breaks-> inhibits DNA and RNA synthesis -inhibits topoisomerase II->strand breaks->inhibits DNA/RNA synthesis -chelator->generation of free radicals 2. toxicity: -cardio-toxicity (dose-releated, may be delayed 7-8 yrs -red urine -meylosuppression

Hypothermia

=core temp below 35 (95F) 1. stages are defined by core temp. and determine tx -mild: 32-35 -moderate: 28-32 -severe: <28

myelodysplastic syndromes

=group of diverse bone marrow disorders in which bone marrow does NOT produce sufficient functional, mature blood cells -stem cell disordr involving ineffective hematopoiesis-> defecsts in cell maturation of all nonlymphoid lineages 1. major clinical findings: cytopenias and dysplasias-> blood cell dysfunction 2. cause is unknown, but can occur after chemo/radiation or can result from chromosomal abnormalities 3. Pts. often present with anemia, neutropenia (infection), thrombocytopenia (bleeding) 4. 30% of cases it can progress to acute myeloid leukemia 5. Examples: -Multiple Myeloma -MGUS -lymohoplasmacytic lymphoma (Waldenstrom Macroglobulinemia)

MGUS

=monoclonal gammopathy of undetermined significance 1. increased serum prot with M spike on SPEP, but other features of MM absent -no lytic lesions, hypercalcemia, AL amyloid, Bence Jones proteinuria 2. commonly seen in elderly -5% of those >70 yrs 3. about 1% of MGUS pts develop MM each year 4. proliferation is triggered by translocations involving IgH on chromosome 14q32 in >50% of MGUS 5. transformation from MGUS to MM is not understood 6. secondary genetic abnormalities can also occur -mutations in Ras, p53, secondary translocations

Myeloproliferative disorders

=neoplastic proliferation of mature cells of myeloid lineage 1. usually presents in late adulthood (50-70yrs) 2. presents with: -leukocytosis with hypercellular BM -all myeloid cells are increased but classification is based upon DOMINANT myeloid cell produced 3. Complications: -hyperuricemia and gout (tumor lysis syndrome due to high cell turnover) -marrow fibrosis -progression to acute leukemia 4. most commonly results from constitutively active tyrosine kinases or other factors of growth independence 5. Examples: CML, Polycythemia vera, essential thrombocytopenia, myelofibrosis

Chronic leukemia

=neoplastic proliferation of mature circulating lymphocytes with leukocytosis -usually insidious and seen in older adults

DIC patho

=pathological activation of coagulation and/or impairment of clot-inhibiting mechanisms 2 major triggers 1. Release of TF (and other procoagulants) into circulation 2. Widespread injury to endothelial cells -TNF induces endothelial cells to express TF and decreases expression of thrombomodulin-> promotes coagulation -TNF also upregulates expression of endothelial adhesion mols-> promotes adhesion of leukocytes->further damage thru ROS and protease release -can also be from deposition of ag-ab complexes (eg. SLE), temp extremes (eg. burns, heat stroke), microorganisms -hypoxia, acidosis, shock seen in ill pts can-> widespread endothelial injury

Multiple Myeloma presentation

1. bone pain (lytic lesions-"punched out") with hypercalcemia and pathological fractures -due to plasma cell proliferation in bone marrow -increased osteoclast activity due to increased macrophage inflamm. protein (MIP-1 alpha), increased activation of RANKL receptor, decreased OPC (decoy receptor for RANKL) 2. fatigue 3. Neuro sxms -can result due to hypercalcemia (weakness, confusion) and hyperviscosity of blood (headaches, vision changes) 4. Infection -due to monoclonality of Ab produced->decreased host defense -most common cause of death in MM 5. Anemia (normocytic), thrombocytopenia (plasma cells crowd out BM) 6. high ESR, LDH 7. Elevated serum protein-low albumin with increased immunoglobulin (IgG or IgA) -detected w. SPEP->M peak -creates rouleaux formation of RBCs on smear as neg. charges of serum prot interacts with RBCs -can lead to primary AL amyloidosis due to free light chain depositing in tissues 8. Proteinuria (Bence Jones proteins) and renal failure -excretion of free light cahins -Bence Jones prot can deposit in kidney-> renal failure (myeloma kidney) 9. high serum IL6 -IL-6 stimulates plasma cell growth and Ig production

pathophys of WBC malignancies

1. chromosomal abnormalities (most common) 2. genetics -inherited and possess potential to promote genomic instability (eg. Down Syndrome) 3. Viruses (HTLV-1, EBV, HHV-8) 4. Chronic inflammation (H. pylori, gastric B cell lymphoma) 5. Iatrogenic factors (radiation, chemo) 6. Smoking

Clinical presentation of acute (uncompensated) DIC

1. bleeding -petechiae, ecchymoses, blood oozing (wound sites, IV lines, catheters, mucosal surfaces) 2. renal dysfxn -acute renal failure 3. hepatic dyfxn -jaundice, preexisting liver failure can exacerbate DIC by impairing production/clearance of coag factors 4. Respiratory dysfxn -pulmonary hemorrhage w. hemoptysis and dyspnea, ARDS 5. shock 6. thromboembolism 7. CNS involvement -coma, delirium, transient focal deficits 8. Adrenal failure -Waterhouse-Friderichsen syndrome 9. Purpura fulminans -extensive tissue thrombosis and hemorrhagic skin necrosis

Complications/management in APL

1. coagulopathy -frequent/severe hemorrhage that->DIC and/or primary fibrinolysis -monitor coagulation parameters, transfuse plts, cryoprecipitate or FFP to maintain plts >30,000 and fibrinogen >150 2. Differentiation syndrome -"cytokine storm" as ATRA induces differentiation of PMNs-> massive release of cytokines -25% of APL Pts 2-21 days after initiation of tx, esp. those with high WBC at dx -fever, edema, pulmonary infiltrates, hypoxemia, resp. distress, hypotension, renal/hepatic dysfxn, serositis->pleural and pericardial effusions -tx: dexamethasone 3. Hyperleukocytosis =abnromal intravascular leukocyte aggregation/clumping-> decreased tissue perfusion -due to rapid maturation of large mass of leukemic cells -50% of pts treated with ATRA alone at induction -presents w. resp/neuro distress as lungs and brain are most commonly affected -tx: induction of chemo + prophylaxis for tumor lysis syndrome

Lymphocyte depletion HL

1. frequent diagnostic RS cells and variants 2. paucity of background reactive cells 3. cell markers: CD15/30+, most EBV+, PAX5+, CD45- 4. uncommon 5. most aggressive HL subtype 6. affects elderly and HIV-infected

Mixed Cellularity HL

1. frequent mononculear and diagnostic RS cells -mononuclear contain single nucleus with a large inclusion-like nucleolus 2. infiltration of T cells, eosinophils, macrophages, plasma cells -often associated with abundant eosinophils due to IL-5 production 3. Cell markers: CD15+, CD30+, 70% are EBV+, PAX5+, CD45- 4. uncommon

Lymphocyte rich HL

1. frequent mononuclear cells and diagnostic RS cells 2. infiltrate is rich in T cells 3. Best prognosis 4. Cell markers: CD15/30+, 40% EBV+, PAX5+, CD45-

Clinical presentation of chronic (compensated) DIC

1. history of malignancy, esp. pancreatic, gastric, ovarian or brain tumors 2. venous or arterial thromboembolism *many pts are asymptomatic w. lab evidence only -low-grade coagulation and fibrinolysis

Marginal zone lymphoma

1. indolent NHL 2. patho: chronic inflammatory states (eg. Hashimoto thyroiditis, H. pylori gastritis)-> polyclonal reaction (reactive hyperplasia)-> B cell monoclonality after acquired mutation (BCL10, MALT-1)-> activation of NFkB 3. Presentation -tumors arise in LN, spleen and extranodal tissues (MALTomas) 4. Cell type: memory B cell (somatic hypermutation) 5. Cell markers: BCL10, MALT-1, CD19, CD20, surface Ig 6. HIsto: MALToma lesion of gastric mucosa

Indolent NHL

1. indolent NHL have long natural history w. slow cellular accumulation -patients can live for yrs w.out treatment 2. Chemotherapy does NOT cure -slows the accumulation of cells -patients suffer the side effects 3. Indolent=incurable 4. examples: -CLL/SLL -marginal lymphoma -MALT-oma -lymphoplasmacytic lymphoma -follicular lymphoma -hairy cell leukemia -mycosis fungoides 5. Treatment is guided by GELF criteria -worse prognossitic conditions/sxms (eg. bulk, b sxms, cytopenias, transformations)->treat

management of hypothermia

1. initiation of rewarming (based on severity) 2. manage/support airway, breathing, circulation 3. prevent further heat loss 4. tx of hypotension, arrhythmia, complications (hypoglycemia)

Hodgkin Lymphoma general

1. localized -single group of nodes with contiguous spread to adjacent LN/node groups before developing hematogenous spread 2. RS cell -CD15+, CD30+ with bilobed nuclei ("Owl eye") -B cell origin 3. Bimodal age distribution -young adulthood and >55 yrs 4. M>F EXCEPT nodular sclerosing type 5. White>AA>asian 6. no clear risk factors -implicated with EBV, HIV, woodworking, rare familial aggregations 7. Constitutional "B symptoms" -low grade fever, night sweats, weight loss 8. elevated ESR 9. biopsy required for Dx 10. Mass=composed of malignant cells

WBC malignancies

1. lymphoid neoplasms -tumors of B cells, T cells and NK-cell origins 2. Myeloid neoplasms 3. Histiocytoses -uncommon -proliferative lesions of macrophages and dendritic cells

Multiple Myeloma general

1. malignant proliferation of plasma cells in bone marrow 2. most common primary malignancy of the bone -metastatic cancer to the bone is more common than primary bone malignancy 3. with tx, it's relapsing-remitting course -incurable 4. Cell markers: CD138+, CD20- with monoclonality of light chains (kappa or lambda)

Multiple Myeloma epidemiology

1. median age=60s 2. M>F 3. AA are 2x more likely to develop it 4. association with rare familial clustering and exposure to radiation, pesticides, benzene

Normal PMN maturation pathway

1. meyloblast 2. Promyelocyte 3. Myelocyte 4. Metamyelocyte 5. Band neutrophil 6. PMN

DLBCL

1. most common NHL, clinically aggressive 2. Patho: molecularly heterogenous -frequently there's a dysregulation of BCL6 on chromosome 3 (30%), BCL2 (10%), MYC (5%) 3. Presentation -late adulthood (70s) -M>F 4. Cell markers: CD19, CD20, surface Ig -possible CD10, BCL6 5. Tx: R-CHOP/EPOCH-R + radiotherapy depending on stage 6. Histo: tumor cells have large nuclei, open chromatin, prominent nucleoli

Nodular Sclerosis HL

1. most common subtype of HL (65-70%) 2. Cell markers: CD15+, CD30+, PAX5+, CD45- 3. Presentation -presents stage I or II of disease -young adults -frequent mediastinal involvement -"Classic presentation" =enlarging cervical/mediastinal LN in young adult, usually female 4. Histo: -frequent lacunar cells (RS cells w. abundant pale cytoplasm)->nucleus in hole -LN divided by bands of sclerosis (fibrosis) -infiltration of T cells, eosinophils, macrophages, plasma cells

Non-Hodgkin lymphoma general characteristics

1. multiple LNs involved along with non-contiguous spread -commonly has extranodal involvement including skin, stomach, brain, spleen, etc. 2. Majority involve B cells (85%) -15% T cell 3. 90% are CD20+->good for therapy 4. may be associated with HIV and autoimmune ds 5. May present with constitutional sxms 6. May present with cytopenias due to BM infiltration 7. biopsy required for Dx 8. one of the most common cancers in young adults and adolescents, curable in most cases

HL

1. neoplastic proliferation of RS cells -large B cells -multilobed nuclei w. prominent nucleoli (owl eye) -CD15/CD30+ 2. Mass: few malignant RS cells that recruit inflamm cells which-> mass formation 3. Patho: -RS cells secrete cytokines (IL5, 10, M-CSF, chemokines, etc.) which-> -B symptoms (fever, chills, wt loss, night sweats, associated with poorer prognosis) -attract/support growth/survival of reactive cells 4. biopsy: reactive lymphocytes, plasma cells, macrophages, eosinophils (many cell types present) 5. Can-> bone marrow fibrosis 6. Spread: LNs->splenic/hepatic disease->marrow involvement and other tissue

Acute leukemias

1. neoplastic proliferation of blasts -accumulation of >20% blasts in BM 2. blasts "crowd out" normal hematopoiesis-> acute presentation of: -anemia (fatigue) -thrombocytopenia (bleeding) -neutropenia (infection) 3. blasts enter bloodstream->leukocytosis

Lymphocyte predominance HL

1. nonclassical HL -frequent L&H or lymphohistiocytic (popcorn cell) variants with infiltration of dendritic cells and reactive B cells 2. involved nodes have nodular infiltrate 3. cell markers: BCL6+, CD20+, CD15-, CD30-, EBV- 4. uncommon -affects young males -presents with cervical or axillary lymphadenopathy

APL clinical features

1. normal AML sxms -complications of pancytopenia (anemia, thrombocytopenia, neutropenia) 2. Bleeding secondary to DIC (unique to APL)

Mild hypothermia (HT I)

1. presentation: -normal mental status with shivering -can also demonstrate tachypnea, tachycardia, hyperventilation, ataxia, dysarthia, impaired judgement, cold diruesis 2. Core temp: 32-35C 3. Tx: passive external rewarming -remove wet clothes -cover w. blankets which utilizes pts own ability to generate heat

Severe hypothermia (HT III)

1. presentation: Unconscious -can-> pulmonary edema, oliguria, areflexia, coma, hypotension, bradycardia, ventricular arrhythmias (v. fib), asystole 2. Core temp: 24-28C 3. Tx: active internal rewarming and active external rewarming -warm humidified O2 -warm IV fluids -pleural and peritoneal irrigation with warm saline -extracorporeal options like vnovenous rewarming, hemodialysis, continuous AV rewarming, cardiopulmonary bypass

Essential Thrombocytopenia (ET)

Myeloproliferative disorder 1. neoplastic proliferation of mature myeloid cells, esp. platelets but RBCs and granulocytes are increased 2. Major criteria: -plts > 450 -BM is hypercellular with megakaryocyte predominance -dont meed criteria for BCR-ABL, CML, PV, PML, meylodysplastic syndromes or other myeloid neoplasms -presence of JAK2, CALR, or MPL mutation 3. Minor criteria: -presence of clonal marker or absence of evidence for reactive thrombocytosis 4. Dx requires all 4 major criteria or first 3 + minor criterion 5. Clinical: symptoms related to increased risk of bleeding/thrombosis -excessive plts and/or abnormal platelets on smear

Polycythemia vera (PV)

Myeloproliferative disorder 1. neoplastic proliferation of mature myeloid cells, particularly RBCs (but granulocytes and plts can also be increased) 2. DX major criteria: -hemoglobin >16.5 in men, >16 in women, hematocrit >49% in men, >48% in women, increased RBC mass -BM biopsy shows hypercellularity -JAK2 kinase mutation 3. DX minor criteria: -subnormal serum EPO levels 4. Dx=meetin all 3 major criteria or first 2 major + minor criterion 5. Tx: phlebotomy (keep hct below 45%), hydroxyurea (2nd line), low dose aspirin

NHL proliferation

Rate of proliferation is based on mutation 1. mutation affecting maturation/proliferation (eg. Myc proto-oncogene)->rapidly growing and fatal 2. Mutation affecting B cell death (eg. BCL2)->slow growing and may not be fatal for years

DIC etiology

Sepsis malignancy (acute PML, mucinous adenocarcinomas) truama obstetric complications (preeclampsia) intravascular hemolysis (ABO incompatibility) etc.

CML presentation

insidious onset with: 1. hepatosplenomegaly -due to extramedullary hematopoiesis -enlarging spleen suggests progression to accelerated phase of disease 2. WBC count demonstrates granulocytosis with few blasts, basophilia, eosinophilia 3. Elevated platelets 4. mild anemia 5. increase in circulating blasts, worsening anemia and thrombocytopenia during accelerated phase along with fibrosis of bone marrow (teardrop cells) 6. Tx: responds to Gleevac (imantinib) which inhibits BCR-ABL TK

Myelodysplastic syndromes

presents with cytopenias, hypercellular BM, abnormal maturation of cells, increased blasts (<20%) -most patients die from infection or bleeding, though some progress to acute leukemia

ALL clinical features

abrupt onset of: 1. sxms related to depressed BM function -anemia, infection, bleeding 2. mass effect sxms -bone pain due to marrow expansion, lymphadenopathy, hepatosplenomegaly -T-ALL may present with SVC syndrome or breathing probs due to mediastinal involvement 3. CNS sxms -due to menigeal spread

Myeloid Neoplasms

arise from early hematopoietic progenitors divided into: 1. acute myeloid leukemias -immature progenitors accumulate in BM 2. myelodysplastic syndromes -ineffective hematopoiesis with resultant cytopenias 3. chronic myeloproliferative disorders -increased production of one or more differentiated myeloid elements->cytosis

APL pathophys

t(15;17) -Retinoic acid receptor alpha (17)->chromosome 15 1. Retinoic acid receptor alpha: involved in differentiation pathway of multiple tissues, alpha is form expressed in hematopoietic cells -retinoid-binding transcription factor (including RXR) that regulates gene expression 2. RARA heterodimerizes with reinoid X receptor (RXR) and binds to retinoic response elements (RARE) to regulate transcription of target genes in response to retinoic acid (vit. A) 3. absence of retinoic acid->RARA/RXR heterodimers interact with N-CoR (nuclear corepressor) which mediates transcription repression 4. Retinoic acid dissociates N-CoR from RARA/RXR->relief of transcriptional repression->activating genes that lead to terminal differentiation of promyelocytes 5. Translocation->fusion protein PML-RARA -altered binding to N-CoR and altered transcriptional regulation->blockade of myeloid differentiation (stuck in promyelocyte phase)

Lab findings in chronic (compensated) DIC

variable platelets normal PT/PTT normal/slightly prolonged thrombin time normal-elevated fibrinogen normal coag factors (V, VIII) elevated fibrin degradation products and D-dimer

Hypothermia EKG changes

hypothermia can-> 1. decreased depolarization of cardiac pacemaker cells-> bradycardia EKG can show: 1. J or Osborne waves -can result also from sepsis, MI or can be normal variant 2. prolonged intervals 3. arrythmias

Pathophys of PV

1. associated with JAK2 kinase mutation -downstream of multiple hematopoietic GF receptors including EPO

APL induction

1. Goal: reduce total leukemia cell population to below detectable levels -recovery of normal hematopoiesis followed by molecular remission (MR may not occur until after consolidation) 2. Agents: -ATRA (retinoic acid analog, aka tetinoin)->promotes terminal differentiation of malignant promyelocytes to PMNs -combine ATRA with other agents to reduce remission since ATRA-induced remission only lasts about 3.5 mos -combine with Chemo (anthracycline like daunorubicin and cytarabine or idarubicin) -combine with arsenic trioxide (ATO) 3. choice of induction therapy depends on WBC at presentation -low/intermediate risk (WBC <10,000)-ATRA + ATO (less myelosuppression, cardiotoxicity, reduced risk of secondary leukemia vs. chemo) but if ATO is not available use ATRA+ chemo -high risk (WBC >10,000)-ATRA + chemo 4. continue until Clinical remission is obtained 5. schedule: administer ATRA daily day 0, followed by 7 days of cytarabine continuous infusion and 4 days of daunorubicin, both starting day 3

Multiple Myeloma treatment

1. High dose chemo -prevent pathological fractures -add bisposponates as well 2. Autologous stem cell transplant (ASCL) 3. Bortezumib -inhibitor of 26S proteosome (ubiquination pathway)-> accumulation of proteins, esp in malignant cells-> apoptosis

APL coagulopathy MOA

1. Increased coagulation: RARA activates TF promoter-> increased expression of TF in leukemic cells-> procoagulant states -TF forms complex with factor VII (extrinsic pathway)->activation of X and IX -TF expression can be upregulated on cells undergoing apoptosis 2. Increased fibrinolysis -Annexin II expression is increased in leukemic promyelocytes-> binds plasmnogen and its activator (tpa)-> increasing plasmin formation (60x) * induction of tumor cell differentiation via ATRA (tretinoin) can lead to rapid improvement in coagulopathy primarily by reducing hypercoaguable state but with little effect on hyperfibrinolytic pathway

Smoldering myeloma diagnosis

1. M-Protein >3 g/dL or >500 mg/24 hrs in urine 2. clonal plasma cells in BM >10-60% 3. No myeloma defining events

MGUS diagnosis

1. M-protein <3 g/dL 2. clonal plasma cells in BM <10% 3. no myeloma defining events

ATRA (tretinoin)

1. MOA: binds to nuclear receptors and decreases proliferation and induces differention of APL cells -initially produces maturation of primitive promyelocytes and repopulates BM and peripheral blood with normal hematopoietic cells to achieve CR 2. Side effects: -headache, fever, weakness, fatigue-most common -differentiation syndrome

ATO (arsenic trioxide)

1. MOA: induces apoptosis in APL cells via morphological changes and DNA fragmentation -also damages/degrades fusion protein (PML-RARA) 2. toxicity: -myelosuppression -nephrotoxicity -neurotoxicity

Cutaneous T cell lymphoma (CTCL)

1. NHL 2. lymphoporliferative disorder of mature CD4+ T cells that infiltrate the skin->skin rash, plaques and nodules 3. aggregates in epidermis=Pautrier microabscesses 4. Mycosis Fungoides: cutaneous involvement only 5 Sezary syndrome: CTCL (sezary) cells circulating in the blood -sezary cells have cerebriform nuclei (lobular on smear)

Primary CNS lymphoma

1. NHL 2. never spreads systemically so typically presents as CNS deficits -CN neuropathy, cord syndromes, ocular involvement, letomeningeal lymphomatosis 3. almost always associated with EBV and is considered an AIDS-defining illness 4. Tx: high dose intrathecal methotrexate + rescue with leucovorin

Adult T cell lymphoma/leukemia

1. NHL 2. proliferation of mature CD4+ T cells 3. patho: adults infected by HTLV-1 which encodes a Tax protein-> activates NFkB 4. findings: -skin lesions -generalized lymphadenopathy -hepatosplenomegaly -lymphocytosis -hypercalcemia (lytic bone lesions) -tumors hav multilobed nuclei

PV vs. reactive polycythemia

1. PV: EPO is decreased due to negative feedback, nromal O2 saturation 2. high altitude/lung disease: O2 sat is low, EPO is increaesd 3. Ectopic EPO (renal cell carcinoma): EPO is high, O2 sat is normal

Maintenance therapy in APL

1. Regimen depends on induction/consolidation therapy used 2. studies show that those who receive ATO during induction/consolidation do NOT need maintenance after complete molecular remission 3. those w.out ATOP should receive maintenance with ATRA + anthracycline 4. during tx pts are monitored via RT-PCR for fusion protein to monitor for relapse

Clotting cascade

1. TF combines with factor VII 2. -->activation of X and IX 3. X-> thrombin generation 4. thrombin converts fibrinogen to fibrin at sites of endothelial dysfunction 5. Feedback to activate factors->formation of a stable clot Fibrinolysis 1. Thrombomodulin-> activation of protein C 2. C combines with S-> inhibits factors V and VIII also: 1. tPA is released and initiates fibrinolysis by converting plasminogen to plasmin

Consolidation therapy in APL

1. about 90% of patients will achieve complete remission with induction chemo 2. goal: prevent relapse -90% of pts will relapse w.out consolidation 3. directed at leukemic cells that survived induction and are not detectable by serological testing 4. Regimen: 2 cycles of ATO then 2 cycles of anthracycline +ATRA

Acute Myelogenous leukemia (AML)

1. accumulation of immature myeloid cells (>20%) in BM 2. myeloblasts will test + for MPO (myeloperoxidase) and esterases which may crystalize to form Auer rods 3. most commonly arises in older adults (50-70 yrs) 4. Risk factors: -prior alkylating agents or radiation -meyloproliferative disorder -Down syndrome 5. Can develo from pre-existing dysplasia (meylodysplastic syndromes) due to risk factors 6. classification Based on cytogenetics, lineage of myeloid cells, surface markers

Acute lymphoblastic leukemia (ALL)

1. accumulation of lymphoblasts (>25%) in BM 2. lymphoblasts are TdT+ -DNA polymerase 3. most common cancer in childhood 4. associated with Down Syndrome after age 5 5. 85% are B-ALL, 15% are T-ALL -B markers: TDT, CD79a, PAX5, CD19, CD20, CD22 -T markers: TDT, CD1-CD8

Burkitt lymphoma

1. aggressive NHL 2. Types: -African (endemic) -Sporadic -HIV-associated 3. Patho: t(8;14)-> translocation of c-MYC->overexpression of c-MYC -other translocations: t(2;8), t(8;22) -associated with latently infective EBV 4. Presentation -fastest growing human tumor->AGGRESSIVE -rapidly fatal unless treated with high dose chemo -endemic (African)->mandible mass -sporadic->abdominal mass 5. cell markers: surface IgM, CD19, CD20, CD10, BCL6 6. Histo: "starry sky" as macrophages consume apoptotic lymphocytes amongst diffuse B lymphocyte proliferation

Chronic myeloloid leukemia (CML)

Myeloproliferative disorder 1. neoplastic proliferation of mature myeloid cells, esp. granulocytes and their precursors -basophils are characteristically increased 2. Patho: t(9;22)->BCR-ABL fusion protein-> constitutively active tyrosine kinase (ABL)->increased cell proliferation and decreased apoptosis 3. Clinical course=triphasic

Acute Megakaryoblastic leukemia

AML subtype -proliferation of megakaryocytes -associated with Down Syndrome before age 5

Acute Monocytic leukemia

AML subtype -proliferation of monoblasts that usually lack MPO -presents as infiltration of gums

Acute Promyelocytic Leukemia

AML subtype MOA: t(15;17)->Retinoic acid receptor (17)->ch. 15->PML-RARA fusion protein which blocks maturation of mature promyelocytes 1. contain primary granules of procoagulants and fibrinolytic factors that increase risk for DIC (often at presentation) 2. Tx: ATRA (tretinoin) which binds to altered receptor to cause blasts to mature and then die

Myeloma-defining events

CRAB C: calcium elevation (>11 mg/dl or >1mg higher than ULN) R: renal insufficiency (Creatinine clearance <40 or serum creatinine >2 mg/dL) A: anemia (Hgb <10, or 2 g/dl below normal) B: bone disease (>1 lytic lesion on skeletal radiography, CT, PET-CT)

CML clinical course

Clinical course=triphasic 1. chronic: -presents at time of dx in 85% of patients -3-5 yrs 2. accelerated: -lasts 3-6 mos -PMN differentiation becomes progressively impaired and leukocyte counts are difficult to control with myelosuppressive meds 3. blast crisis: -resembles acute leukemia with myeloid and/or lymphoid blasts that fail to differentiate -becoming B-ALL 1/4 of pts or AML in 3/4 of pts

Myelofibrosis

Myeloproliferative disorder 1. neoplastic proliferation of mature myeloid cells, esp. megakaryocytes 2. patho: JAK2 mutation (50%)->excessive megakaryocyte production-> excessive PDGF production-> marrow fibrosis due to increased fibroblast activity 3. Clinical: -splenomegaly (extramedullary hematopoiesis) -leukoerythroblastic smear (teardrop RBCs, nucleated RBCs, immature granulocytes-> megakaryocyte and fibrosis crowding out cells in BM) -increased risk for infection, bleeding, thrombosis 4. Tx: JAK inhibitor, splenectomy (if complications arise), hydroxyurea, IFN-alpha

Dx of DIC

DIC=clinical and lab dx based on findings of coagulopathy and/or fibrinolysis in appropriate clinical setting (eg. sepsis, malignancy, etc.)

Staging of HL/NHL

I: involvement of single LN region (I) or single extralymphatic organ/site (IE) II: involvement of 2 or more LN regions on same side of diaphragm (II) or localized involvment of extralymphatic organ/site (IIE) III: involvement of LN regions on both sides of diaphragm without (III) or with (IIIE) localized involvement of extralymphatic organ/site IV: diffuse invovlement of 1 or more extralymphatic organs or sites with or witout lymphatic involvement *S=splenic involvement, E=extranodal involvement *all stages further divided bases on Absence (A) or presence (B) of sxms: fever, night sweats, weight loss of >10% body weight

Chromosomal abnormalities in WBC malignancies

Involved in majority of WBC malignancies 1. most common=translocations 2. mutated/altered genes play crucial role in development, growth, or survival of normal counterpart of malignant cell 3. onco-proteins may block normal maturation, turn on pro-growth pathways or protect from apoptosis 4. proto-oncogenes become activated by errors in antigen receptor gene rearrangement and diversification in lymphoid precursors

Outcomes of DIC

Widespread deposition of fibrin in microcirculation-> 1. ischemia of multiple organs 2. microangiopathic anemis (schistocytes) 3. consumption of platelets and coag factors + activation of plasminogen-> hemorrhagic diathesis (bleeding)

Death (HT V)

death due to irreversible hypothermia -estimated core temp <9-13.7C -resuscitation is NOT possible

Lab findings in acute (uncompensated) DIC

decreased platelets prolonged PT/PTT/thrombin time decreased fibrinogen decreased coag factors (V, VIII) elevated fibrin degradation products elevated D-dimer

Hairy cell leukemia

chronic leukemia 1. proliferation of mature B cells that have hairy cytoplasmic processes 2. cells are TRAP+ (tartrate-resistant acid phosphatase) 3. most commonly presents in adult males 4. Presentation: -splenomegaly (accum of hairy cells in RED pulp) -"dry tap" (BM aspiration is dry due to fibrosis) -lymphadenopathy is absent 5. Tx: responds to 2-CDA (Cladribine) and pentostatin -cladribine=adenosine deaminase inhibitor (adenosine is found at toxic levels in neoplastic B cells), pruing degradation pathway