Georgette A Dent MD University of North Carolina School of Medicine Objectives To review normal peripheral blood bone marrow and lymph node pathology To briefly review the categories of treatment used to treat these malignancies ID: 1041134
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1. Hematologic MalignanciesGeorgette A. Dent, MDUniversity of North Carolina School of Medicine
2. ObjectivesTo review normal peripheral blood, bone marrow, and lymph node pathologyTo briefly review the categories of treatment used to treat these malignanciesTo review the epidemiology, pathology, and clinical findings associate with the following three types of hematologic malignancies:LeukemiaLymphomaMultiple Myeloma
3. Hematologic Malignancies: Incidencehttps://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21654
4. TreatmentWe will not get into the details of treatment, but…In general these disorders are treated with one or more of the following:ChemotherapyRadiation therapyBone marrow transplantationTargeted therapyCAR-T Chimeric antigen receptor T-cell therapyVaccines (experimental!)
5. LeukemiaMyeloid:AcuteChronicLymphoid:AcuteChronic
6. The Leukemias: An OverviewLeukemia is a neoplastic disease composed of malignant blood cellsThey originate in the bone marrow and can involve the patient’s peripheral blood.They can manifest clinically over weeks to months: acute leukemiaThey can manifest clinically over months to years: chronic leukemia
7. Normal Hematopoiesis
8. NormalPeripheral BloodBone Marrow BiopsyBone Marrow Aspirate
9. Leukemia: Epidemiologyhttps://www.sciencedirect.com/science/article/pii/S0268960X18301395?via%3Dihub
10. Acute Myeloid Leukemia
11. AML is a Disease Primarily of Adults
12. Origins of AMLAML is a malignancy of a committed myeloid progenitor cell.In AML, the malignant cells largely lose the ability to differentiate.Morphologically homogeneous population of myeloblasts.
13. Acute Myeloid LeukemiaClonal expansion of myeloid blastsCan arise de novo or as a consequence of underlying disorder (such as: a bone marrow failure syndrome, myelodyplastic syndrome, myeloproliferative disorder)
14. Bone Marrow BiopsyNORMALTrilineage hematopoiesisABNORMALMonotonous population of mononuclear cells
15. Clinical ManifestationsAnemia -- severeFatigue, dyspneaNeutropenia -- severeInfectionsThrombocytopenia – severe (decreased platelets)brusing, petechiae, mucocutaneous bleedingHyperleukocytosisIncreased white blood cellsMental status changes (somnolence).Dyspnea with bilateral infiltrates on CXR.Due to stasis of blood flow.More likely in AML.Acute Disseminated intravascular coagulation (DIC)Hyperleukocytosis in a patient with AML
16. Bone Marrow Biopsy: AML vs. CMLABNORMAL:AMLMonotonous populationABNORMAL:CMLMaturing granulocytes
17. Chronic Myelogenous Leukemia
18. Origins of CMLNeoplastic transformation of a hematopoietic progenitor cell (HPC).The malignant cells maintain the ability to differentiate.
19. CML: EpidemiologyIncidence: 1 to 2 / 100,0004830 new cases in US in 2008.450 deaths.Median age at diagnosis: 66 yrs.Male/Female ratio: 1.4 / 1Risk FactorsIonizing radiation exposureJemal A, et al. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96.
20. Clinical Presentation of CMLCommon SymptomsFatigue, sweats, fevers Weight loss/anorexiaAbdominal fullness, early satietyPhysical Exam FindingsSplenomegalyHepatomegalyCommon Laboratory FindingsLeukocytosis (high WBC count)NeutrophiliaBasophiliaEosinophiliaAnemiaThrombocytosis*20-40% of patients are asymptomatic
21. Chronic Myelogenous LeukemiaPeripheral bloodBone marrow aspirate-Numerous immature granulocytes-Increased basophils*-Hypercellular-Increased M:E
22. Bone Marrow Biopsy: Normal vs. CMLNORMALTrilineage hematopoiesisABNORMAL: CMLMaturing granulocytes
23. Bone Marrow Biopsy: AML vs. CMLABNORMAL:AMLMonotonous populationABNORMAL:CMLMaturing granulocytes
24. Pathogenesis: The Philadelphia ChromosomeFUSION PROTEINWITH CONSTITUTIVE TYROSINEKINASE ACTIVITY
25. Acute Lymphoblastic Leukemia
26. Origins of ALLALL is a malignancy of a committed lymphoid progenitor cell (pre-T or –B cell).In ALL, the malignant cells largely lose the ability to differentiate and from a morphologically homogeneous population of lymphoblasts.
27. ALL: EpidemiologyMost common cancer in children.Peak incidence between ages 2 to 5.Median age at diagnosis: 11.Risk factorsPrior radiationPrior chemotherapyFamilial syndromes (e.g. Down syndrome)
28. Clinical ManifestationsAnemia -- severeFatigue, dyspneaNeutropenia -- severeOpportunistic infections (staph, gram negatives, fungal)Thrombocytopenia – severe (decreased platelets)bruising, petechiae, mucocutaneous bleedingHepatosplenomegalyAbdominal pain, early satiety
29. Summary ALL TreatmentThe great success story for cancer chemotherapy in the 21st centuryChildhood ALL was a death sentence until the late 1960sThis story is beautifully told in The Emperor of All Maladies.The majority of childhood ALL patients are cured but disparities exist impacting patients of color
30. Chronic Lymphocytic Leukemia
31. Origins of CLLCLL is a malignancy of mature B-cells.In CLL, the malignant cells are a morphologically homogeneous population of mature lymphocytes.
32. CLL: EpidemiologyThe most common adult leukemia 15,110 new US cases in 20084,390 deaths from CLLMedian age at diagnosis: 72Risk FactorsFamilialEnvironmental Agent Orange“Smudge” cellJemal A, et al. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96.
33. Clinical Presentation of CLL*Common SymptomsFatigue, sweats, fevers Weight loss/anorexiaAbdominal fullness, early satiety– Frequent infectionsRespiratory infectionsEncapsulated organisms– Incidental lab finding in ~20%Common Physical Exam FindingsLymphadenopathySplenomegalyHepatomegalyCommon Laboratory FindingsLeukocytosis (high WBC count)LymphocytosisAnemiaThrombocytopeniaHypogammaglobulinemia* CLL characterized by accumulation of mature, homogeneous, mature lymphocytes.
34. MorphologyBone Marrow Aspirate: CLL-variable involvement-loss of heterogeneityPeripheral blood: CLL-usually diagnostic-lymphocytosisNormal blood:-mostly neutrophils-scattered lymphs
35. LymphomaTo review the epidemiology, pathology, and clinical findings associate with the following three types of hematologic lymphomas:Low gradeIntermediate gradeHigh grade
36. Causes of lymphadenopathy include:Reactive (benign such as seen with Strep throat, mononucleosis, etc) LymphomaHodgkin diseaseNon-Hodgkin lymphomaMetastatic diseaseDifferential Diagnosis of an Enlarged Lymph Node
37. The Lymph Node
38. Lymph Node GroupsBuzzle.com
39. LymphomaNodalExtra Nodal, Colon
40. Lymphoma EpidemiologyLymphoma definition: malignant neoplasm of lymphocytes associated with a solid mass or infiltrate6th most common cancer in AmericaApproximately 77,000 new lymphoma cases diagnosed a year in US42,000 males35,00 females65,000 Non-Hodgkin9,000 HodgkinApproximately 20,000 deaths a year in US due to lymphoma (11,000 males, 9,000 females)Approximately 1,000 people worldwide are diagnosed with lymphoma every day.
41. Incidence of Non-Hodgkin Lymphoma Varies Worldwide
42. Non-Hodgkin Lymphoma: Risk FactorsInfectionsHIVEpstein-Barr virus (EBV), virus associated with mononucleosisHelicobacter pyloriHepatitis BHepatitis CHuman T-cell leukemia virus type 1 (HTLV-1)HHV-8Medical conditions that compromise the immune systemHIVAutoimmune disease (e.g. Hashimoto thyroiditis, Sjögren syndrome)Use of immune suppressive therapy (e.g. associated with organ transplant)Inherited immunodeficiency diseases (e.g. severe combined immunodeficiency, ataxia telangiectasia, IgA deficiency, many others)Toxic chemicalsPesticides, herbicides, or benzeneHair dye use in patients who started to use the dyes before 1980AgeWhile risk factors are important, most patients have no identifiable risk factor
43. Lymphoma Types:WHO ClassificationNon-HodgkinB-cell (85% of North-American lymphomas)T-cell (15% of North-American lymphomas)Hodgkin Disease
44. Maturation of Lymphocytes
45. Lymphoma Types:WHO ClassificationNon-HodgkinB-cell Precursor B-cell neoplasmsMature B-cell neoplasmsT-cell Precursor T-cell neoplasmsMature T-cell neoplasms
46. B-cell Malignancies Cells of Origin
47. World Health Organization 2016B-cell NeoplasmsPrecursor B-cell neoplasmPrecursor B-cell acute lymphoblastic leukemia or lymphomaMature B-cell neoplasmsChronic lymphocytic leukemia/small lymphocytic lymphomaMonoclonal B-cell lymphocytosisB-cell prolymphocytic leukemiaSplenic marginal zone lymphomaHairy-cell leukemiaLymphoplasmacytic lymphoma/Waldenström macroglobulinemiaMonoclonal gammopathy of undetermined significance (IgM, IgG, IgA)Heavy chain diseases (Mu, Gamma, Alph)Plasma-cell myelomaSolitary plasmacytoma of boneExtraosseous plasmacytomaMonoclonal immunoglobulin deposition diseasesExtranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)Nodal marginal-zone B-cell lymphomaFollicular lymphomaPediatric-type follicular lymphomaPrimary cutaneous follicle center lymphomaMantle-cell lymphomaDiffuse Large B-cell lymphoma (DLBCL)Primary mediastinal large B-cell lymphoma (DLBCL)T cell/histiocyte-rich large B-cell lymphomaPrimary DLBCL of the CNSPrimary cutaneous DLBCL, let typeEBV positive DLBCL, NOSDLBCL associated with chronic inflammationLymphomatoid granulomatosisPrimary medicastinal (thynic) large B-cell lymphomaIntravascular large B-cell lymphomaALK positive large B-cell lymphomaPlasmablastic lymphomaPrimary effusion lymphomaBurkitt's lymphomaB-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphomaHigh grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangementsHigh grade B-cell lymphoma, NOSB-cell lymphoma, unclassifiable with features intermediate between DLBCL and Hodgkin lymphoma
48. T-cell Malignancies Cells of Origin
49. World Health Organization 2016T-cell NeoplasmsPrecursor T-cell neoplasmPrecursor T-cell acute lymphoblastic leukemia or lymphomaMature (peripheral) T-cell neoplasmsT-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaAggressive natural-killer cell leukemiaSystemic EBV+ T-cell lymphoma of childhoodHyroa vacciniforme-like lymphoproliferative disorderAdult T-cell leukemia/lymphomaExtranodal natural-killer/T-cell lymphoma, nasal typeEnteropathy-type T-cell lymphomaMonomorphic epitheliotropic intestinal T-cell lymphomaHepatosplenic T-cell lymphomaSubcutaneous panniculitis-like T-cell lymphomaMycosis fungoides Sezary syndromePrimary cutaneous CD30 positive T-cell lymphoproliferative disourdersPrimary cutaneous gamma-delta T-cell lymphomaPeripheral T-cell lymphoma, not otherwise characterizedAngioimmunoblastic T-cell lymphomaAnaplastic large-cell lymphoma, ALK positiveAnaplastic large-cell lymphoma, ALK negative
50. The Lymph Node
51. SmallLargeIntermediateHistologic Classification:Cell Size
52. Lymphoma Grades Low Grade (indolent, slow growing)Small lymphocytic lymphomaFollicular small cleaved lymphomaIntermediate Grade (in between, prognosis depends on stage)Diffuse large cell lymphomaHigh Grade (aggressive, fast growing)Burkitt lymphomaLymphoblastic lymphoma
53. Natural HistoryCure RateLow Grade(Follicular, Small lymphocytic)Many yearsIncurableIntermediate Grade(Diffuse Large B-Cell)A few yearsCurable(20 to 80%)High Grade(Burkitt, Lymphoblastic)MonthsCurable(> 80%)Hodgkin’s Disease is similar to intermediate grades with 60 to 95% cureThe Working Formulation
54. Small LymphocyticFollicularMantle CellLow/Intermediate GradeDiffuse Large B-CellIntermediate GradeHodgkin’s DiseaseBurkitt’s,LymphoblasticHigh GradeB SymptomsMassesLow GradePresents like an intermediate gradeAsymptomatic
55. Reed-Sternberg CellHodgkin LymphomaTumor is primarily composed of benign reactive cells with rare malignant Reed-Sternberg Cell
56. Multiple MyelomaTo review normal peripheral blood, bone marrow, and lymph node pathology of multiple myeloma
57. Multiple Myeloma is a Malignancy of Plasma cells
58. Cells of origin of B-cell malignancies
59. Approximately 1% of all malignanciesApproximately 10% of hematological malignanciesApproximately 20,000 cases a yearPrimarily incurable, but survival has increased in the past decadeMultiple Myeloma: Epidemiology
60. Risk factors include:Age (peak incidence between 65 and 70)Gender (males>females)Genetic ancestry (Blacks>Whites>Hispanic>Asian)Family historyRadiation exposureChronic antigenic stimulationMultiple Myeloma: Risk factors
61. Demographics**Substitute genetic ancestry for race
62. The clinical and pathologic findings associated with multiple myeloma are in large part a consequence of:Tumor mass effect of the malignant plasma cells proliferating in the bone marrow or from:Abnormal secretory products from the malignant plasma cells including monoclonal immunoglobulins and cytokinesMultiple Myeloma
63. Bone Marrow Clonal Plasmacytosis
64. Lytic Skull LesionLytic lesions see on skeletal survey, but not bone scans
65. Lytic Skull LesionLytic lesions see on skeletal survey, but not bone scans
66. Multiple Myeloma – Lytic lesions in skull
67. Complete blood count (CBC)Chemistries, especially calcium and creatinineSerum and urine protein electrophoresis and immunofixationBone marrow for morphology, immunophenotyping and cytogeneticsBone imaging studies (skeletal radiography, CT, or PET-CT)Multiple MyelomaLaboratory Studies
68. Colin Powell & Multiple Myelomahttps://www.cbsnews.com/news/colin-powell-covid-vaccine-multiple-myeloma-cancer-risk/Multiple myeloma is associated with suppression of normal immunoglobulinsThis causes patients to be more vulnerable to infectionsThey do not make normal immunoglobulins like people with normal immune systemsThey might not make antibodies in response to a vaccine
69. Serum protein electrophoresis and immunofixation – IgG Lambda SPEP P N ImmunofixationAlbuminBand indicating monoclonal immunoglobulin in gamma globulin regionP=PatientN=Normal
70. Evidence of end organ damage (CRAB)HypercalcemiaRenal diseaseAnemiaBone diseaseBiomarkersExtreme bone marrow clonal plasmacytosis Elevated free serum light chain level (FLC)More than one focal lesion on MRIMyeloma Defining Events (MDE)
71. Bone marrow plasmacytosis
72. SummaryHematologic neoplasms include leukemia, lymphoma, and multiple myelomaThese diseases occur throughout lifeDisparities exist based on socioeconomics and genetic ancestryThere have been many advances in therapy in the last decades but more work needs to be done