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Heme/Onc ABIM review
Overview of anemia - Big pictures: hypoproliferative vs. hemolytic vs. blood loss vs. sequestration Hypoproliferative: 1. Production defects (ACD, acute inflammation, impaired renal fxn, hypometabolism-Thyroid, hypogonadism, adrenal insuff; BM damage; all with little polychromasia, few retics; 2. Maturation defects: a. Cytoplasmic- Hgb synthesis-Fe def, sideroblastic, globin synthesis (thallasemia); b. Nuclear- DNA synthesis defect (B12, folate) Hemolytic: 1. Intrinsic (inherited)- membrane cytoskeletal defect (spherocytosis, elliptocytosis), metabolic enzymes (G6PD deficiency, pyruvate kinase deficiency), hemoglobinopathy (SS, thal);
- Extrinsic (acquired)- autoimmune hemolysis, malaria, DIC, TTP, HUS, HELLP Sideroblastic anemia - Defect in ability to incorporate iron into Hgb see with protoporphyrin deficiency, myelodysplastic syndrome, drugs, toxins Iron studies - Transferin- binds iron for transport to tissues Soluble transferrin receptor concentration- new test, elevated with FeDef, nl with ACD Serum Fe- total bound to transferrin TIBC- indirect measure of transferrin; measures the total amt of Fe the blood can bind Transferrin saturation: Fe/TIBC Ferritin - binds iron in cells; good marker for total body stores IF no inflammation (check CRP) Pertinent peripheral smear findings -
- RBC fragments (schistocytes)- microangiopathic hemolytic anemia- TTP, HUS, DIC, HELLP, vasculitis, severe burns, vavle hemolysis
- Spherocytes- autoimmune hemolytic anemia, hereditary spherocytosis
- Target cells- liver dz, thalassemia, hemoglobinopathies
- Teardrop cells- myelofibrosis, infiltrating BM processes, occ. with thalassemia
- Burr cells- uremia
- Spur cells- liver dz
- Howell-Jolly bodies- splenectomy or functinal asplenia: nuclear fragments in cytoplasm, usually cleared by spleen
- Hypersegmented PMN's- megaloblastic anemia (B12, folate, pernicious) Anemia of Chronic Dz - Impaired iron utilization, although stores are nl; lower epo Causes- chronic rheum, ID, neoplastic dz Lab: low FE, TIBC, transferrin sat; high/high-nl ferritin; nl soluble transferrin receptor Anemia from bone marrow damage -
- Aplastic anemia: primary stem cell, autoimmune, or drug etiology; pancytopenia
- Pure red cell aplasia: decrease RBC precursors; congenital from abnormal stem cells or acquired from virus, infection, thymoma, autoimmune, drugs; suspect Parvo B19 if h/o HIV, Sickle cell
- Marrow infiltration: fibrosis, granulomas, tumors; teardrop cells, immature RBC/WBC's
Iron deficiency anemia - Microcytic, hypochromic, low retic count, low Fe, ferritin, high TIBC, low transferrin sat, soluble transferrin receptor low Must pursue etiology if found: blood loss (GI, GU), pregnancy (increased requirement), diet, malabsorption (celiac, gastric bypass), chronic intravascular hemolysis (PNH) Thalassemia basics - Hgb from a tetramer, 2 alpha, 2 beta; 4 alpha genes, 2 beta genes Get decreased production of nl tetrameres->fewer RBCs; abnormal tetrameres precipitate in cytoplasm->hemolyzed, ineffective erythropoesis Often misdiagnosed as feDef Microcytosis+ no Fe def= thal; confirm with Hgb electrophoresis Alpha-thalassemia - Asians/Africans/ Mediterraneans Defect: alpha-globin gene mutation leading to decreased alpha-globin synthesis. Deletion of 1 gene- alpha-thal trait- no heme abnormality Deletion of 2 genes- alpha-thal minor- asx, MCV low, little/no anemia Deletion of 3 genes leads to HbH disease- B-chains for tetramers (HgH), make inclusions in periph cells, not in marrow. Mod/severe hemolytic anemia Deletion of 4 genes leads to Hb Barts (gamma-4), causing hydrops fetalis. Beta-thalassemia - Mediterranean/asian/ middle eastern descent
- B-thal minor- heterozygous; mild/no anemia, low MCV; elevated Hgb A2 (a2delta2) and HgF(a2Gamma2)
- B-Thal major- no B-Hg, insoluble a-tetramers, inclusion bodies are toxic to erythrocytes, die in marrow; surviving cells have inclusion bodies removed by spleen; severe anemia; increased Epo, can get extramedullary erythropoesis- liver spleen, bones (skull and facial bones- chipmunk face); tansfusion dependant, get Fe overload; Bilirubin stones
- B-thal intermedia- minor defects, still homozygous; coinheretance of a-thal causing less toxic tetramers; increased HgF B12 deficiency - Defect in DNA synthesis Causes-pernicious anemia (parietal cell autoimmune destruction), vegan diet, alcohol abuse, inability to release from food stores (in elderly), malabsorption in terminal ileum (IBD, bacterial overgrowth, pancreatic insuff) Megaloblastic- RBC destroyed in marrow, surviving are large, get hypersegmented PMNs, low plts as well GI effects: smooth sore tongue, diarrhea Neuro effects: paresthesias, psychosis Dx- B12<200; if borderline, check MMA, Homocysteine- both elevated (HC only in Folate) Look for etiology if found: pernicious anemia test anti-parietal cell and -intrinsic factor Abs Tx- weekly B12 injections
Dx: osmotic fragility test; confirm with molecular membrane studies Paroxysmal nocturnal hemoglobinuria (PNH) - Stem cell d/o of PIG-A gene; lose ability to anchor membrane-> complement mediated hemolysis Present with intravascular hemolysis, iron deficiency; can see arterial and venous thrombosis ****can transform to aplastic anemia, leukemia, myelofibrosis! Dx- flow cytometry for CD55, CD59- both missing Rx- steroids, anticoagulant for thrombotic events; new drug: eculizumab Autoimmune hemolytic anemia - IgG/IgM Abs, stimulate macrophages or spleen to remove cells-> snips off portions of membrane (spherocytosis) or complement mediated lysis IgG- Warm Abs (react best at body temp)-idiopathic or due to neoplasm/ connective tissue dz; positive direct coombs; rx- steroids, splenectomy if refractory IgM- complement or polysaccharide abs, Cold antibodies- react best at room temp; IgM not detected on cell= neg Coombs; positive test with C3 antibodies; see RBC clumping; Cause- neoplasm, infection (mycoplasma, EBV); rx= stay in warm environment; steroids ineffective! AIHA is assc with CLL, lymphoma, SLE, EBV!!!! Drug induced hemolysis - PCN- can cause Ab response Quinine, methyldopa, some cephalosporins also cause response Effects of liver dz on anemia - Cirrhosis-> spur cell anemia from abnormal cholesterol production Portal HTN-> splenic sequestration EtOH abuse-> megaloblastic anemia, esp folate def; inhibits Epo production Viral hep-> inhibits bone marrow, AIHA Varices- GI blood loss Cancer effects on anemia - BM infiltration Chemo induced Infection from BM suppression Medication induced AIHA (CLL, lymphoma) Sequestration ACD Blood loss from bleeding tumors Malnutrition Methemoglobinemia - Fe oxidized from Fe2 to Fe3, doesn't hold oxygen well= dark colored=cyanotic appearance with nl paO
sx- like hypoxia (HA, dizzy, tachypnea, tachycardia, obtundation); can see severe tissue hypoxia, death Causes: hereditary, industrial chemicals, drugs (nitrates-NTG, nitroprusside, amyl nitrate; tylenol, phenacetin, dapsone, sulfonamide, anesthetics) Rx- methylene blue Hemochromatosis - HFE gene-body insensitive to fe level, keeps absorbing; autosomal recessive triad of cirrhosis, bronze skin, DM; also see fatigue, arthritis, myalgias, abd pain Test: tranferrin sat >45% women, 50% men, check Fe studies, genetic tests; also test 1st deg. relatives Liver bx is gold standard, used for prognosis Rx: phlebotomy- do weekly at start, goal ferritin 25-50, sat <30%; after to this level, usual 2-4x/yr, goal ferritin 50-100, sat < What are the two branches of hemostasis - Primary hemostasis= platelet plug formation, vascular spasm, endothelial capillary adhesion; lasts 12-24 hrs only if not fibrosed by secondary Secondary hemostasis= clotting cascade for fibrin clot formation Mechanism of primary hemostasis - 3 parts: platelet attachment->activation->aggregation Plts attach to newly exposed subendothelial collagen+endthelium releases vWF->reacts with platelet glycoprotein Ib/IX->increased stickiness Activation-release cytokines ADP+arachadonic acid->cause aggregation Arachadonic acid->cyclooxygenase->Thromboxane A2->recruits more platelets and exposes platelet glycoprotein IIb/IIIa+vasoconstriction->fibrin crosslinks at IIb/IIIa to make platelet plug Drug effects on primary hemostasis - IIb/IIIa receptor inhibitors- block fibrin crosslinks, used in unstable angina, angioplasty Aspirin- actylates COO->no thromboxane; 40mg/d blocks 95% of activity irreversably NSAIDs- also work on COO, but reversable, can block the receptor for ASA Clopidogrel- irreversably binds ADP- decreased platelet aggregation Secondary hemostasis cascade - Tissue factor from injury site->interacts with VII->activates rest of cascade (extrinsic path) Intrinsic pathway (VIII, IX, XI, XII) amplify the initial TF+VII process Prothrombin->thrombin->1. converts fibrinogen to fibrin; 2. Activates XII-fibrin cross links; 3. Activate XII, VIII->increase intrinsic path, upregulates clotting Lysis of clot: tPA from endothelium->plasminogen to plasmin->breaks down fibrin and fibrinogen Protein C, S block inhibition of tPA= blocks clot breakdown Primary vs. secondary problems - Primary: 90% due to platelet dysfunction or low plts; multiple small superficial hemorrhages- petechiae, purpura, ecchymosis, mucocutaneous bleeding
Treatment for ITP - treat if symptomatic or very low Steroids first IVIG: overwhelms macrophages->increased plts; use if need rapid improvement; only lasts several weeks Anti-D IG (rhogam): if Rh-positive and functioning spleen; binds to RBCs, taken up by spleen so it's busy with these, not plts; get mild hemolysis Splenectomy: works in 2/3, may see relapses; use if no response to steroids, frequent relapses, unable to taper off steroids in 3-6 months Thrombotic thrombocytopenic purpura - High mortality; from deficiency in the ability to inactivate vWF->plt activation->vessel thrombosis Young adults; often idiopathic, see with metastatic CA, pregnancy, SLE, mitomycin C, ticlodipine Pentad for TTP (FARTS)- Fever, Anemia (microangiopathic, schistocytes), Renal failure, Thrombocytopenia, Seizure (and other neuro abnormalities); usually don't have all PT/PTT are nl, LDH elevated, indirect bili elevated Rx: plasma exchange with FFP/cryosupernatant (plasma w/o cryoprecipitant- no VWF); can transfuse with FFP, steroids while making arrangements NO PLT transfusions! can make thrombosis worse! Hemolytic uremic syndrome - Like TTP, more renal, less neuro issues In kids, assc with E. coli O157:H7; due to endothelial damage from shiga-like toxin If due to E. coli, do NOT use antibiotics- can make it worse HELLP syndrome - Hemolysis, Elevated LFTs, Low Platelets 20% of preeclampsia, 10% of eclampsia Microangiopathic anemia, can see liver rupture Rx- deliver fetus Heparin Induced Thrombocytopenia (HIT) - forms heparin-plt complexes->clumping and thrombocytopenia; usually w/in 5-10 days of start of heparin See venous and arterial thrombosis It is a clinical dx, don't need assays Tx: stop heparin (not immediate effect, still has abs), start direct thrombin inhibitors (lepirudin, argatroban), then Coumadin when plts normalize, do x 3 months Caution with lepirudinin renal insuff- reduce dose With Argatroban, INR is artificially elevated, shoot for > Post-transfusion purpura - Rare; women presensitized by pregnancy
1 wk post transfusion, lasts days/weeks Plts low, get petechia, purpura HPA-1 abs react against HPA-1 neg pts No evidence of hemolysis, CNS, renal changes Tx: IVIG; steroids & plasma exchange are slower Medicines causing thrombocytopenia - Quinine, quinidine, sulfas, rifampin, digoxin, vancomycon, acetaminophen von Willebrand disease - Autosomal dominant, variable expression; most common inherited bleeding disorder (1%) Sx- mucocutaneous bleeding, menorrhagia, epistaxis, surgical bleeding, excess bruising Carries factor VIII, so see both in vWD Lower vWF in type O blood, higher in pregnancy, estrogen Labs: prolonged PTT (factor VIII) & bleeding time Types of vWD - Type 1- most common (70%), quantitative defect Type 2 - qualitative; 4 subtypes 2A- 2nd most common, too little large vWF multimer 2B- increased plt affinity->binding in large complexes that get cleared; mild thrombocytopenia; do NOT use DDAVP-> worsens thrombocytopenia! 2M- decreased plt affinity 2N- doesn't bind to factor VIII-> decreased->long PTT Type 3- rare, sever, autosomal recessive; undetectable low levels, spontaneous bleeding Diagnosis of vWD - Abnl plt function tests decreased vWF antigen proportionate decrease in factor VIII Proportionate decrease in activity via ristocetin cofactor assay Treatment of vWD - Mild-mod= desmopressin (DDAVP)- causes release of vWF and VIII from endothelium Bleeding = factor VIII concentrates Bernard-Soulier syndrome - giant platelets severely decreased platelet adhesion- no gp1b Modestly low plt count due to clearance Autosomal recessive Glanzmann thrombasthenia - deficient gp IIb/IIIa- no fibrinogen crosslinking nl plt count autosomal recessive
Treatment for DIC - treat the underlying disorder!!!! can give FFP, plts if severe bleeding heparin usually ineffective Vitamin K deficiency - Decreased production of II, VII, IX, X, protein C, S Causes- decreased dietary intake, malabsorption, antibiotics, liver disease: TPN usually doesn't have vit K Thrombin time, D-dimer nl (vs. DIC) Rx- FFP if bleeding, oral vit K (more predictably absorbed); risk of anaphylaxis with IV Vit K Primary fibrinolysis - assc with prostate cancer and/or surgery plasmin released into circulation in response to endothelial agents like tPA See abnl PT, PTT, fibrinogen, FDP, D-Dimer, BUT nl plt count (unlike DIC) Factor VIII deficiency - assc with lymphoproliferatve disorders, infections, postpartum Most idiopathic, in elderly Severe bleeding Mixing study corrects initially (like lupus anticoagulant), but uncorrects after 2 hr incubation Virchow's triad for thrombosis - Stasis, vascular damage, hypercoagulable state Acquired causes of thrombosis - Malignancy, pregnancy, smoking, estrogen use, immobilization, major surgery, HIT, myeloproliferative disorders (esp polycythemia vera, essential thrombocytosis), antiphospholipid antibody syndrome, PNH, multiple myeloma Antiphospholipid antibody syndrome - Anitbodies=lupus anticoagulant, anticardiolipin, anti-B2-glycoprotein I-Ab; they are acquired, assc with drugs, autoimmune dz (SLE), malignancy Found by coagulation assay; PTT prolonged, doesn't correct Rx= indefinite warfarin therapy, goal 2-3; 50% recurrence of clot in 2 yrs if no treated Dx of antiphospholipid antibody syndrome - at least one clinical and one lab abnormality Clinical=1. H/O arterial, venous, or small vessel clot;2. loss of nl fetus at 10+ wks; 3. birth of nl fetus before 34 wks from eclapsia, pre-eclampsia, or placenta insufficiency; 4. 3+ spontaneous abortions <10 wks gestation Lab=antiphospholipid antibody on 2+ occasions at least 12 wk apart: anticardiolipin IgG or IgM, lupus anticoagulant, or Ab to B2-glycoprotein-1 IgG or IgM can use as minor criteria: livido reticularis, sterile valvular vegetations
Inherited thrombotic disorders - Factor V Leiden deficiency=causes resistance to normal inhibitory effect of protein C-> unrestricted thrombosis w/o breakdown Prothrombin gene mutations= elevated prothrombin Antithrombin deficiency=normally inactivates thrombin, esp with heparin; quantitative (type 1) or qualitative (type 2) defect; clots at young age; Dx type 1 with immunoassay, type 2 with functional study (AT-heparin cofactor assay) Protein C/S deficiency=loss of nl cleaving factors for V, VIII, autosomal dominant Testing for thrombophilia - Strongly thrombophilic=1st clot<50 y/o, recurrent, 1st degree family member with clot<50; test Factor V Leiden, Prothrombin gene mutation, protein C/S, antithrombin, APS Weakly thrombophilic=first clot at 50+yrs; likely acquired hypercoagulable state, esp cancer; screen for APS, malignancy (solid tumors, lymphoma, lymphoproliferative d/o); drugs (hydralazine, procainamide, HCTZ, propranolol, phenytoin, phenothiazines) Heparin decreases AT levels; coumadin decreases C, S levels, can give false positive APS; wait 2 wks after completion of therapy to test Management of thrombosis - Provoked clot with transient risk factors- rx for 3 mo Unprovoked clot- rx for 6 mo Recurrent, one unprovoked life threatening clot, one spontaneous clot with APS- consider indefinite anticoagulation Clot with active malignancy- use LMWH- more effective Pregnancy- use LMWH, even with mechanical valves IVC filter: anticoagulation if contraindicated, failure of anticoagulation, severe cardiopulmonary comorbidity that would make a new PE life threatening Acute hemolytic transfusion reaction - rapid intravascular hemolysis, usually ABO incompatability Stop transfusion, give supportive care Lab: Coombs test, serum free hemoglobin, hemolysis labs, urine hgb testing, repeat T&C on transfused RBCs Delayed hemolytic transfusion reaction - extravascular hemolysis, due to Rh or minor antigen mismatch Anemia, mild fever, mild increase bili 7 days after transfusion No treatment needed Febrile transfusion reactions - commonly from non-hemolytic reaction to leukocytes in blood Stop transfusion and assess for hemolysis; if Coombs negative, likely is this Give antipyretics, meperidine Consider leukoreduction in future
Aplastic anemia, B12/ folate deficiency, primary hematologic malignancy, myelodysplastic syndrome, myelofibrosis, BM infiltration Acute leukemia basics - early myeloid (AML) or lymphoid (ALL) cell lines lose ability to differentiate but retain ability to multiply->crowd out nl bone marrow growth; see maturation arrest of cells with blasts in blood stream Chronic leukemia- overproduction of a cell line, but NO blasts Dx relies on morphology, cytogenetics (karyotyping), cytochemical analysis (PAS, peroxidase, esterase, Sudan black), cell surface markers (flow cytometry, immunophenotyping) Tx: induction phase=suppress all hematopoesis with high dose chemo; Consolidation phase=used to prolong remission and survival Myeloid growth factors in induction decrease hospitalization and infection, but NOT survival Acute myelogenous leukemia - Causes- benzene, chemotherapy, myeloprolif d/o, myelodysplasia, PNH (secondary causes=worse px) Dx=BM bx with 20+% blasts; need cytogenetics to tell AML vs. ALL; Auer rods=AML!!! (azurophilic needle shaped crystals in AML blast cytoplasm) Leukostasis - blasts >100K in blood->increased viscosity=end organ dz (brain ischemia+hemorrhage, sludging lin lungs=resp distress) Medical emergency! Rx= leukopheresis +/- hydroxyurea Prognostic factors in AML - Karyotype: favorable=t(8:21), t(15:17), inv (16); intermediate= nl or t(19:11); unfavorable= inv(3), -5/del(5q), -7, or complex aberrations Unfavorable px=age 60+, poor performance status, WBC 100K+, prior BM dz (MPD, myelodysplasia), FLT3 mutation Good px= nuclophosmin (NPM1) gene Rx for AML - Induction=7d of cytosine arabinosie (ara-c)+3d daunorubicin (7+3 regimen) Consolidation with same drugs, lower doses Age 60+: 40-50% remission, <10% long term event free Age <60: 20-30% long term survival Stem cell transplant: use in relapsed pts, preferably in second remission; failure to achieve remission with initial induction; poor risk cytogenetics Acute promyelocytic leukemia (aPML, M3 AML type) - Translocation if 15:17- retinoic acid gene Treat will all-trans-retinoic acid+ daunorubicin= 80+% remission, 70+% cure Lots of Auer rods, get DIC from release into bloodstream
ATRA syndrome- fever, volume overload, pleural/ pericardial effusions, resp distress, HoTN from all-trans retinoic acid therapy; can be life threatening; Tx with steroids, may need to stop therapy FAB classification of AML - M0=acute myeloblastic, poorly differentiated (5-10%) M1=myeloblastic, w/o maturation (5-10%) M2=myeloblastic with maturation; assc with t(8:21), good px (25-30% M3=acute promyelocytic leukemia; assc with t(15:17), DIC; good px; 3-15% M4=myelomonocytic; assc with inv16, good px; 15-30% M5=monocytic (10-20%) M6=erythroleukemia; poor px (3-7%) M7=megakaryocytic; assc with marrow fibrosis; poor px; 3-6% Acute lymphoblastic leukemia - Usually in kids, 20% of adult leukemias WHO class=precursor B-cell (70%), precursor T-cell(20-25%), mature B-cell (5%, Burkitt) Present with pancytopenia+ extramedullary blast deposits (CNS, testes, spleen, lymph nodes, retina) Poor prognosis=age>30, WBC>30K, mature B or early T type, persistent residual dz after remission, t(9:22) translocation (Philadelphia chromosome) Rx=multiple agents (Prednisone, vincristine, daunorubicin + cyclophosphamide, L-asparginie) 80% response, 60% long term if poor px rx complications= hyperuricemia, hyperphosphatemia, hypocalcemia Myelodysplastic syndrome (MDS) - clonal stem cell disorder-ineffective cell production, variable progression to leukemia Unfavorable px: high percentage of marrow blasts, number of cytopenias, cytogenetic abnl (esp chr 7), older Favorable px: deletion of 5q or 20q MDS with >20% blasts= transformed to acute leukemia % of blasts is most important prognostic item Survival 5mo-5.7 yrs Tx depends on age, agressiveness of dz, comorbidities; can do BM txpt in younger 5q- syndrome - type of MDS Frequently females See thrombocytopenia, refractory anemia respond to lenalidomide therapy prolonged survival, less transformation to leukemia Chronic myelomonocytic leukemia (CMML) - overlap syndrome with MDS Older, poorer prognosis blood smear= monocytosis with myeloid/erythroid precursors
Sx- weak, dizzy from hyperviscosity, pruritis after hot shower, gout, splenomegaly; see elevated LAP score Mortality from thrombosis, conversion to AML, myelofibrosis Rx=phlebotomy to hct<45%, low dose ASA; hydroxyurea lowers risk, but increases leukemic transformation Agnogenic Myeloid Metaplasia (AMM) - Hyperplasia of atypical megakaryocytes->stimulates fibroblasts->marrow fibrosis Can get from transformation of ET or PV Peripheral blood: teardrop cells Sx: constitutional sxs, extramedullary hematopoesis, hepatosplenomegaly, spinal compression, ascites Rx: BM txpt is only chance for cure, usually done in younger pts only Non-Hodgkin lymphoma - Clonal proliferation of lymphocytes-B, T, natural killer; lymphoma-cells in a solid mass, leukemia-cells in blood; can see overlap of leukemia and lymphoma NHL presentation - Palpable adenopathy, compression from nodes (mediastinum-airway obstruction, SVC syndrome; mesentery or retroperitineum-GI or GU obstruction), splenomegaly Some produce monoclonal gammopathy- hyper viscosity (waldenstoms) or autoimmune cytopenia Can get agammaglobulinemia (CLL/SLL), cytopenia from BM infiltration, splenomegaly dx of NHL - Excisional bx of a node Do staging afterwards: CT chest, neck, abdomen, pelvis PET scan after treatment to look for recurrence BM bx if need further confirmation of cytopeNias Indolent vs. Aggressive NHL - Indolent- CLL/SLL, follicular lymphoma, marginal zone (MALT, nodal, splenic)' mycosis fungoides- long clinical course, seldom cured, usually watch and wait treatment Aggressive- diffuse large B cell, Burkitt, precursor T-lymphoblastic, B-lymphoblastic, mantle cell- quick growth, death in months if not treated; good sense to chemotherapy Prognostic factors in NHL - Age, serum LDH, Ann Arbor stage, performance status, number of extra nodal sites Monoclonal antibodies in NHL treatment - Rituximab- ab against CD20 on many B cell lymphomas, complement mediated lysis, well tolerated, can use with other chemotherapies Alemtuzumab- anti-CD520 on many CLL, but also on nl B and T cells Follicular NHL -
Most common indolent, elderly, usually present at late stage; over expression of BCL-2 from t(14:18) No treatment if asx, younger can use combo chemotherapy, older with single agent, rituximab Progress to cytopenias, get infections or anemia sx. 10% transform to aggressive diffuse large cell lymphoma, resistant to chemotherapy, usually rapidly fatal Marginal zone lymphoma - From chronic immune stimulation, usually from H. pylori; can be MALT (extranodal), nodal, splenic marginal zone Most common location is GI/ intestinal mucosa, can see in bronchial mucosa, salavary glands Early stage gastric MALT can rx with abx for H. pylori alone, radiation if fails Splenic MZL can be from HCV Always look for an infectious cause Presents early, early tx results in prolonged dz free survival Chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) - Indolent, proliferation of mature, poorly functionig B-lymphocytes Initial leukemic phase (CLL) progresses to lymphoma stage (SLL) Rai and Binet systems for staging Usually asx, can get cytopenia from marrow infiltration, splenomegaly, Ab mediated destruction See disorders of immune system: autoantibodies against RBCs, plts, can also see hypogammaglobulinemia with recurrent infection (treat with IVIG) 10% transform to diffuse large cell lymphoma (fever, rapidly worsening nodal dz, rising LDH See high lymphocyte count with smudge cells CLL/SLL prognosis and treatment - Good prognosis: mutated Ig heavy chain variable resion, 13q deletion, low ZAP-70, CD levels Poor prognosis: 17p or 11q deletion Rx: watch and wait until sx or rapid dz progression Young- multiple agents (fludarabine, rituximab), goal of prolonged remission Elderly pts- chlorambucil, goal of palliation Hairy Cell Leukemia - Part lymphoma, part leukemia Splenomegaly, cytopenia complications smear with lyphocytes having hairy projections from cytoplasm Responds well to chemo, get prolonged remission Waldenstrom macroglobulinemia - B-cell expansion of lymphocytes producing monoclonal IgM Sx- lymphadenopathy, splenomegaly, BM infiltration, hyperviscosity (HA, dizzy, vision changes) from high IgM Rx viscosity syndrome with plasmapheresis Treat if sxs occur only
Ann Arbor Hodgkin disease staging - I= one node, lymphoid structure (spleen, thymus), or extranodal site II= 2 or more lymph node regions, same side of diaphragm III= both sides of diaphragm; IIIe= adds extranodal site, IIIs= adds spleen IV= disseminated Also add: A=asymptomatic B= sxs- fever, night sweats, 10% wt loss in 6 months X= bulky dz- nodal mass dimension >10 cm Lymphoma and HIV - Usually aggressive NHL (DLCL, Burkitts), increased risk for Hodgkins Primary CNS lymphoma- assc with EBV in HIV pts Primary effusion lymphoma- presents as ascites or pleural effusions, assc with HHV-8+HIV Use nl treatments, EXCEPT rituximab may not work in DLCL if CD4< Transplant and lymphoma - Occurs in 5% of solid organ transplants, highest in 1st yr. Usually nonclonal B cells, 90% assc with EBV Rx - lower degree of immunosuppression; if not tolerated, use chemo Diseases associated with lymphoma risk - Chronic autoimmune thyroiditis (hashimotos) Sjogren syndrome Celiac disease Chronic H. pylori HIV/AIDS Multiple Myeloma - Neoplasm of B-plasma cells, produce a M (monoclonal) component; can be any Ig class, complete or fragments; Waldenstoms also makes IgM, but presents differently Sx- bone pain (tumor invades bone-osteoclast activation->lytic lesions (punched out), don't see on bone scan); infection (decreased nl Ig production and increased clearance); renal failure (hypercalcemia, amyloid deposits, tubular obstruction, toxic paraproteins); plasmacytomas with local mass effect symptoms Think of MM with bone pain, hyperviscosity and recurrent infections Labs for MM - Rouleaux on peripheral smear, hypercalcemia, ARF +/- RTA, normochromic/normocytic anemia, elevated total protein with low ablumin, decreased anion gap Dx with SPEP, UPEP Plasmacytoma variant may not have abnormal electrophoresis, need direct viscosity of the M- component Check bone survey for lytic lesions Check B2-microglobulin- increased=more lymphocytes=bad
ISS staging for MM - Stage I= B2-MG<3.5, albumin>3.5; survival 62 mo Stage II=between I and III; survival 44 mo Stage III= B2-MG >5.5; survival 29 mo Rx for MM - Thalidomide+dexamethasone to induce remission; can use thalidomide like agent (lenalidomide), proteosome inhibitor (bortezomib) Stem cell txpt to prolong remission Older pts= use melphalan or cyclophosphamide Plasmacytoma= use local radiation Monoclonal gammopathy of uncertain significance (MGUS) - Assc with toxins, pestacides Increase with age Marrow plasmacytosis<10%, no bony lesions, M-component <3g/dl, no urinary light chains, no risk of infection renal dz, anemia Do repeat SPEP q6 mo x 13y, then annual Smoldering myeloma vs. MM vs. MGUS - MGUS= serum monoclonal protein <3g; BM plasma cells <10%, no end-organ damage Smoldering myeloma= monoclonal protein>3g OR BM plasma cells>10% and no end-organ damage MM= BM plasma cells>10% or bx proven plasmacytoma and end-organ damage (lytic lesions, anemia, hypercalcemia, ARF) Hypercalcemia in malignancy - most common paraneoplastic syndrome Most common with SCC of lung or neck, MM, Breast CA, T-cell lymphoma, Renal cell CA Sx- fatigue, constipation, anorexia, polyuria, obtundation, hypovolemia; sxs worsen as rate of change increases Causes: increased osteoclast activity from local met, ectopic PTHrP (SCC lung), overproduction of 1,25-OH-vitamin D Rx: hydration, furosemide if needed, bisphosphonate=zoledronic acid IV preferred- more potent, quicker; can see osteonecrosis of the jaw, so do dental work prior to infusion if able SVC syndrome - Seen with lung CA (esp Small cell), lymphoma (any), mediastinal germ cell tumors Sx: swelling of face, neck, arms; cough, dyspnea, hoarseness from laryngeal edema, HA from high ICP Exam: periorbital, arm edema, facial plethora, elevated JVP, increased collateral veins on chest wall Dx- CT chest - large mediastinal or R hilar mass Get tissue dx before rx if possible Radiation therapy to start, chemo specific for the tumor next
