Chapter 13Chapter 13Diseases of White Diseases of White Blood Cells, Lymph Blood Cells, Lymph Nodes, Spleen, and Nodes, Spleen, and ThymusThymus

Components of the Components of the Hematopoietic SystemHematopoietic System

Myeloid TissuesMyeloid Tissues

Bone marrow and cells derived from itBone marrow and cells derived from it

Lymphoid TissuesLymphoid Tissues

Thymus, Lymph nodes, SpleenThymus, Lymph nodes, Spleen

Development and Development and Maintenance of the Maintenance of the Hemapoietic TissuesHemapoietic Tissues

Hemapoietic Stem Cells Hemapoietic Stem Cells MesodermMesodermMigrate to the liver – Chief site of blood Migrate to the liver – Chief site of blood cell cell formation until shortly before birthformation until shortly before birthAt birth bone marrow throughout the skeleton At birth bone marrow throughout the skeleton is active and then liver shuts downis active and then liver shuts downAt puberty activity restricted to the axial At puberty activity restricted to the axial skeletonskeleton

Figure 13-1 Figure 13-1 Differentiation of Blood Differentiation of Blood CellsCells

The formed elements of blood have a common origin from HSCsThe formed elements of blood have a common origin from HSCsHSCs – Essential propertiesHSCs – Essential properties

PluripotencyPluripotencyCapacity for self-renewalCapacity for self-renewalCan appear in peripheral blood during times of stress ( e.g. severe anemia)Can appear in peripheral blood during times of stress ( e.g. severe anemia)Niches in other tissues “unveiled” – extramedullary hematopoiesisNiches in other tissues “unveiled” – extramedullary hematopoiesis

The marrow response to short-term physiologic needs regulated by The marrow response to short-term physiologic needs regulated by hematopoietic growth factors through effects on committed progenitorshematopoietic growth factors through effects on committed progenitors

Many diseases alter the production of blood cellsMany diseases alter the production of blood cellsTumors of hematopoietic origin are often associated with mutations that block Tumors of hematopoietic origin are often associated with mutations that block

progenitor cell maturation or abrogate their growth factor dependenceprogenitor cell maturation or abrogate their growth factor dependenceLeukoerythroblastosis – abnormal release of immature precursors into the Leukoerythroblastosis – abnormal release of immature precursors into the

peripheral bloodperipheral bloodTable 13-1 Adult reference ranges for blood cellsTable 13-1 Adult reference ranges for blood cellsNurse cells = macrophages that supply iron to RBCs in BMNurse cells = macrophages that supply iron to RBCs in BMNormal fat to hempatopoeitic elements ratio = 1:1Normal fat to hempatopoeitic elements ratio = 1:1

LeukopeniaLeukopenia

Neutropenia (granulocytopenia)Neutropenia (granulocytopenia)more commonmore commonagranulocytosis – clinically significant reduction, severe infecitons when neutrophil count <500/mmagranulocytosis – clinically significant reduction, severe infecitons when neutrophil count <500/mm 33

Inadequate or ineffective granulopoiesisInadequate or ineffective granulopoiesisSuppression of HSCsSuppression of HSCsSuppression of committed granulocytic precursors by drugs – most common causeSuppression of committed granulocytic precursors by drugs – most common causeDisease states with ineffective hematopoiesisDisease states with ineffective hematopoiesisRare congenital conditions – impairment of granulocytic Rare congenital conditions – impairment of granulocytic

differentiation differentiation (Kostmann Syndrome)(Kostmann Syndrome)Accelerated removal or destruction of neutrophilsAccelerated removal or destruction of neutrophils

Immunologically mediated injuryImmunologically mediated injurySplenomegalySplenomegalyIncreased peripheral utilizationIncreased peripheral utilization

Clinical features – infection, malaise, chills, fever, weakness, fatigueClinical features – infection, malaise, chills, fever, weakness, fatigueLymphopeniaLymphopenia

immunodeficiency diseasesimmunodeficiency diseasesTreatment with steroids, cytotoxic drugsTreatment with steroids, cytotoxic drugsautoimmune disordersautoimmune disordersAcute viral infectionsAcute viral infections

LeukocytosisLeukocytosis

Mechanisms of leukocytosis -Table 13-2Mechanisms of leukocytosis -Table 13-2Increased productionIncreased productionIncreased release from marrow storesIncreased release from marrow storesDecreased marginationDecreased marginationDecreased extravasation into tissuesDecreased extravasation into tissues

Types of leukocytosis – Table 13-3Types of leukocytosis – Table 13-3Neutrophils – acute bacterial infections, tissue necrosisNeutrophils – acute bacterial infections, tissue necrosisEosinophils – allergic, parasitic, drugs, certain malignancies, collagen vascularEosinophils – allergic, parasitic, drugs, certain malignancies, collagen vascularBasophils – myeloproliferativeBasophils – myeloproliferativeMonocytosis – chronic infections, IBDMonocytosis – chronic infections, IBDLymphocytosis – chronic infections, viral infections, pertussis Lymphocytosis – chronic infections, viral infections, pertussis

Reactive changes – Reactive changes – in sepsis or severe inflammatory disordersin sepsis or severe inflammatory disordersDohle bodiesDohle bodiesToxic granulesToxic granulescytoplamic vacuolescytoplamic vacuoles

Leukomoid reactionLeukomoid reaction

LymphadenitisLymphadenitisThe activation of resident immune cells leads to The activation of resident immune cells leads to

morphologic changes in lymph nodesmorphologic changes in lymph nodesAcute Nonspecific lymphadenitis – painful, red, Acute Nonspecific lymphadenitis – painful, red,

absecessesabsecessesChronic Nonspecific lymphadenitis-nontenderChronic Nonspecific lymphadenitis-nontender

Follicular hyperplasia Follicular hyperplasia (tingible-body macrophages; B-(tingible-body macrophages; B-cells, centroblasts/cytes)cells, centroblasts/cytes)Paracortical hyperplasia Paracortical hyperplasia (T-cells)(T-cells)Reticular hyperplasia ( sinus histiocytosisReticular hyperplasia ( sinus histiocytosis; ; macrophage and dendritic cellsmacrophage and dendritic cells))Organized collections in non-immune tissuesOrganized collections in non-immune tissues

Neoplastic Proliferation Neoplastic Proliferation of WBCsof WBCs

Lymphoid neoplasms- B-cells, T-cells, NK Lymphoid neoplasms- B-cells, T-cells, NK cells origincells origin

Myeloid neoplasms – Acute myeloid Myeloid neoplasms – Acute myeloid leukemias, myelodysplastic, leukemias, myelodysplastic, myeloproliferativemyeloproliferative

Histiocytosis – macrophages, dendritic Histiocytosis – macrophages, dendritic cells, Langerhans cellscells, Langerhans cells

Overview of Etiologic and Overview of Etiologic and Pathogenetic FactorsPathogenetic Factors

Chromosome translocations and other acquired mutationsChromosome translocations and other acquired mutationsNonrandom chromosomal abnormalities, most commonly Nonrandom chromosomal abnormalities, most commonly translocationstranslocations, occur in the majority , occur in the majority of white cell neoplasmsof white cell neoplasms

Mutated or altered genes often play critical roles in the development, growth, or survival of the Mutated or altered genes often play critical roles in the development, growth, or survival of the normal counterparts of the malignant cells ( e.g. MALTomas normal counterparts of the malignant cells ( e.g. MALTomas = B-cell lymphoma of = B-cell lymphoma of MALT1/BCL10 constitutively activating NF-kBMALT1/BCL10 constitutively activating NF-kB))

Oncoproteins created by genomic aberrations often block normal maturation Oncoproteins created by genomic aberrations often block normal maturation (BCL6 need for (BCL6 need for germinal centers but turn off for maturation)germinal centers but turn off for maturation)

Proto-oncogenes are often activated in lymphoid cells by errors that occur during antigen Proto-oncogenes are often activated in lymphoid cells by errors that occur during antigen receptor gene rearrangement and diverification ( e.g. in germinal center B cells during receptor gene rearrangement and diverification ( e.g. in germinal center B cells during antobody diversificaiton antobody diversificaiton AID inducing translocations and lesions in DNA AID inducing translocations and lesions in DNA))

Inherited genetic factorsInherited genetic factorsBloom, Fanconi, Down, Bloom, Fanconi, Down, ataxia teleangectasia and type I NFataxia teleangectasia and type I NF

VirusesVirusesHTLV-1, EBV, HHV-8HTLV-1, EBV, HHV-8

Chronic Immune stimulation (Chronic Immune stimulation (H. pylori, celiacs, HIV) H. pylori, celiacs, HIV) Iatrogenic factors (radiation therapy)Iatrogenic factors (radiation therapy)Smoking Smoking (AML)(AML)

Lymphoid NeoplasmsLymphoid Neoplasms

Lymphocytic leukemia vs lymphomaLymphocytic leukemia vs lymphomaWidespread involvement of the bone marrow Widespread involvement of the bone marrow and peripheral blood vsand peripheral blood vsDiscrete tissue massesDiscrete tissue masses

Clinical presentationsClinical presentationsEnlarged lymph nodesEnlarged lymph nodesInvolvement of extranodal sitesInvolvement of extranodal sitesSuppression of normal hematopoiesis Suppression of normal hematopoiesis Secretion of circulating factorsSecretion of circulating factorsPain due to bone destructionPain due to bone destruction

Lymphoid NeoplasmsLymphoid Neoplasms

Precursor B cell (immature B cells)Precursor B cell (immature B cells)

Peripheral B cell (mature B cells)Peripheral B cell (mature B cells)

Precursor T cell (immature T cells)Precursor T cell (immature T cells)

Peripheral T cell amd NK cell ( mature Peripheral T cell amd NK cell ( mature cells)cells)

Hodgkin lymphoma ( Reed-Sternberg cells)Hodgkin lymphoma ( Reed-Sternberg cells)

Lymphoid NeoplasmsLymphoid Neoplasms

Histologic examination is required for diagnosisHistologic examination is required for diagnosisMost of the time, antigen receptor gene Most of the time, antigen receptor gene

rearrangement preceded transformation: hence rearrangement preceded transformation: hence all of daughter cells share the same antigen all of daughter cells share the same antigen receptor gene configurationreceptor gene configuration

Vast majority are of B cell origin ( 85-90%)Vast majority are of B cell origin ( 85-90%)Often associated with immune abnormalitiesOften associated with immune abnormalitiesNeoplastic B and T cells tend to behave like their Neoplastic B and T cells tend to behave like their

normal counterparts normal counterparts (T-cells to skin and B-cells (T-cells to skin and B-cells to germinal centers)to germinal centers)

Hodgkin lymphoma spreads in an orderly fashionHodgkin lymphoma spreads in an orderly fashion

ALLALL85% 0f B-ALLs 85% 0f B-ALLs childhoodchildhood acute leukemias acute leukemias

T-Alls less common, present as thymic T-Alls less common, present as thymic lymphomas in lymphomas in adolescentadolescent males males (lymphadenopathy and splenomegaly)(lymphadenopathy and splenomegaly)

ALL is the most common cancer of childhoodALL is the most common cancer of childhood

Must be distinguished from AML because of Must be distinguished from AML because of differing responses to chemotherapy differing responses to chemotherapy (ALL (ALL myeloperoxidase negative)myeloperoxidase negative)

TdT +, starry sky, hypercellularTdT +, starry sky, hypercellular

ALL – Molecular ALL – Molecular PathogenesisPathogenesis

90% have numerical or structural chromosomal 90% have numerical or structural chromosomal changes changes (hyperploidy)(hyperploidy)

Many of the chromosomal aberrations seen in Many of the chromosomal aberrations seen in ALL dysregulate the expression and function of ALL dysregulate the expression and function of transcription factors that are required for normal transcription factors that are required for normal b and t cells development. b and t cells development.

- - T-cell GOF in NOTCH1, B-cell LOF in PAX5, T-cell GOF in NOTCH1, B-cell LOF in PAX5, EBF, E2AEBF, E2A

Single mutations are not sufficient to produce ALLSingle mutations are not sufficient to produce ALL

ALL – Clinical FeaturesALL – Clinical Features

Abrupt stormy onsetAbrupt stormy onset

Symptoms related to bone marrow Symptoms related to bone marrow suppressionsuppression

Mass effect caused by neoplastic Mass effect caused by neoplastic infiltration infiltration (testicular enlargement)(testicular enlargement)

CNS manifestationsCNS manifestations

ALL – Prognostic FactorsALL – Prognostic Factors

Worse prognosisWorse prognosisAge under 2 (MLL gene translocations)Age under 2 (MLL gene translocations)Presentation in adolescence or adulthoodPresentation in adolescence or adulthoodPeripheral blast counts >100,000Peripheral blast counts >100,000Presence of particular cytogenic aberrations (Ph chromosome)Presence of particular cytogenic aberrations (Ph chromosome)

““2 Adolescents in Philadelphia stole > $100,000”2 Adolescents in Philadelphia stole > $100,000”Favorable prognosisFavorable prognosis

2-10 years of age2-10 years of agelow WBC countlow WBC counthyperploidyhyperploidyTrisomy of 4,7,10Trisomy of 4,7,10Presence of t (12:21)Presence of t (12:21)

CLL/SLLCLL/SLL

Most common leukemia of adults in the Most common leukemia of adults in the Western worldWestern world

Proliferation centers are pathognomicProliferation centers are pathognomic

Smudge cellsSmudge cells

Distinctive immunophenotype (Distinctive immunophenotype (CD19/20 CD19/20 and low IgM/D; translocations rare, and low IgM/D; translocations rare, deletions common)deletions common)

CLL/SLL – Clinical CLL/SLL – Clinical featuresfeatures

Often asymptomatic at diagnosisOften asymptomatic at diagnosisNonspecific –fatigue, weight loss, anorexiaNonspecific –fatigue, weight loss, anorexiaGeneralized lymphadenopathyGeneralized lymphadenopathyHepatosplenomegalyHepatosplenomegalyDisrupts normal immune function through uncertain Disrupts normal immune function through uncertain

mechanisms (mechanisms (hypogammaglobinemia, hypogammaglobinemia, autoantibodes -> anemia, thrombocytopenia)autoantibodes -> anemia, thrombocytopenia)

Variable course and prognosisVariable course and prognosisTendency to transform to more aggressive tumors – Tendency to transform to more aggressive tumors –

Prolymphocytic and large-cell transformations Prolymphocytic and large-cell transformations (latter = Richter syndrome) (latter = Richter syndrome) – poor prognosis– poor prognosis

Follicular lymphomaFollicular lymphoma

Most common form of indolent NHLMost common form of indolent NHLArises from germinal center B cellsArises from germinal center B cellsStrongly associated with chromosomal Strongly associated with chromosomal

translocations involving BCL2translocations involving BCL2Centrocytes (Centrocytes (small cleaved cells) small cleaved cells) and Centroblastsand Centroblastst(14;18) overexpression of BCL2 (t(14;18) overexpression of BCL2 (no apoptosis)no apoptosis)Clinical presentationClinical presentation

Painless, generalized lymphadenopathyPainless, generalized lymphadenopathyHistologic transformation to diffuse large B-cell Histologic transformation to diffuse large B-cell

lymphomalymphoma

Diffuse large B-cell Diffuse large B-cell lymphomalymphoma

Most common form of NHLMost common form of NHLLarge cell size and diffuse pattern of growthLarge cell size and diffuse pattern of growthDysregulation of BCL6Dysregulation of BCL6t(14:18)t(14:18)Immunodeficiency-associated large b-cell lymphoma in Immunodeficiency-associated large b-cell lymphoma in

setting of T-cell immundeficiency – EBVsetting of T-cell immundeficiency – EBVPrimary effusion lymphoma – KSHV/HHV-8Primary effusion lymphoma – KSHV/HHV-8Clinical featuresClinical features

Typically presents as a rapidly enlarging mass at a Typically presents as a rapidly enlarging mass at a nodal or extranodal site nodal or extranodal site (waldeyer ring commonly (waldeyer ring commonly affected)affected)AggressiveAggressive

Burkitt LymphomaBurkitt Lymphoma

African (endemic) African (endemic) Sporadic (nonendemic)Sporadic (nonendemic)Aggressive subset in HIVAggressive subset in HIVStarry sky pattern Starry sky pattern – high mitotic index and numerous – high mitotic index and numerous

apoptotic cellsapoptotic cellsTranslocations of the c-MYC gene on Chromosome 8 Translocations of the c-MYC gene on Chromosome 8 t(8,14)t(8,14)Essentially all endemic tumors are infected with EBVEssentially all endemic tumors are infected with EBVClinical featuresClinical features

most present as tumor at extranodal sitemost present as tumor at extranodal site- Endemic = mandible, ab viscera- Endemic = mandible, ab viscera- Sporadic = ileocecum, peritoneum- Sporadic = ileocecum, peritoneum

Plasma cell neoplasms Plasma cell neoplasms and related disordersand related disorders

Secrete a monoclonal Ig or Ig fragmentSecrete a monoclonal Ig or Ig fragment

Most common and deadly is multiple Most common and deadly is multiple myelomamyeloma

Often synthesize excess light or heavy Often synthesize excess light or heavy chains along with complete Igs chains along with complete Igs (M (M component)component)

Bence-Jones proteinsBence-Jones proteins

Monoclonal Monoclonal gammaopathiesgammaopathies

Multiple myelomaMultiple myeloma

Waldenstrom macroglobulinemia Waldenstrom macroglobulinemia (high Igm, (high Igm, hyperviscosity)hyperviscosity)

Heavy-chain diseaseHeavy-chain disease

Primary or immunocyte-associated amyloidosisPrimary or immunocyte-associated amyloidosis

Monoclonal gamopathy of undetermined Monoclonal gamopathy of undetermined significance (significance (most common pasma cell most common pasma cell dyscrasia; asymptomatic, M protein < 3)dyscrasia; asymptomatic, M protein < 3)

Multiple myelomaMultiple myeloma

Multifocal involvement of the skeletonMultifocal involvement of the skeletonThe Ig genes in myeloma cells show evidence of hypermutationThe Ig genes in myeloma cells show evidence of hypermutationThe proliferation and survival of myeloma cells are dependent are several cytokines, The proliferation and survival of myeloma cells are dependent are several cytokines,

particularly particularly IL-6IL-6Factors produced by the neoplasti plasma cells mediate boney destructionFactors produced by the neoplasti plasma cells mediate boney destructionRearrangements involving the Ig heavy chain gene of Chromosome 14q32Rearrangements involving the Ig heavy chain gene of Chromosome 14q32Axial skeletonAxial skeletonPunched-out defects 1-4 cm in diameterPunched-out defects 1-4 cm in diameterPlasmablasts, Flame cells, Mott cells, Russell bodies Plasmablasts, Flame cells, Mott cells, Russell bodies (cytoplasmic)(cytoplasmic), Dutcher bodies , Dutcher bodies

(nuclear)(nuclear)Rouleaux formation, Myeloma kidneyRouleaux formation, Myeloma kidneyClinical featuresClinical features

BBone resorption leading to pathologic fractures and hroni painone resorption leading to pathologic fractures and hroni painHyperHyperccalcemiaalcemiaRecurrent bacterial infectionsRecurrent bacterial infectionsRRenal insufficiencyenal insufficiencySPE M proteinSPE M proteinAAnemia (nemia (CRAB)CRAB)

Solitary Myeloma (Plasmacytoma); Smoldering Myeloma (Solitary Myeloma (Plasmacytoma); Smoldering Myeloma (asymptomatic, M protein > 3)asymptomatic, M protein > 3)

Lympoplasmacytic Lympoplasmacytic LymphomaLymphoma

Plasma cell component secretes monoclonal Plasma cell component secretes monoclonal IgMIgM leading to leading to hyperviscosity syndrome _ Waldenstrom macroglobulinemiahyperviscosity syndrome _ Waldenstrom macroglobulinemia

Clinical featuresClinical featuresweakness, fatigue, weight lossweakness, fatigue, weight losslymphadenopathy, hepatosplenomegalylymphadenopathy, hepatosplenomegalyAnemia, auto-immune hemolysis Anemia, auto-immune hemolysis caused by cold agglutininscaused by cold agglutininshyperviscosity syndromehyperviscosity syndrome

Visual impairmentVisual impairmentneurologic problemsneurologic problemsBleedingBleedingCryoglobulinemiaCryoglobulinemia

Incurable, plasmapheresisIncurable, plasmapheresis

Mantle Cell LymphomaMantle Cell Lymphoma

Tumor cells closely resemble the normal Tumor cells closely resemble the normal mantle zone B cells that surround mantle zone B cells that surround germinal centersgerminal centers

Express high levels of Express high levels of cyclin D1cyclin D1

t(11:14)t(11:14)

Small lmphocytes with cleaved contoursSmall lmphocytes with cleaved contours

Painless adenopathyPainless adenopathy

Marginal Zone Marginal Zone LymphomasLymphomas

MaltomasMaltomas

Often arise in areas of chronic inflammation Often arise in areas of chronic inflammation (h. pylori)(h. pylori)

Remain localized for prolonged periodsRemain localized for prolonged periods

May regress if inciting agent is eradicatedMay regress if inciting agent is eradicated

Continuum between reactive lymphoid Continuum between reactive lymphoid hyperplasia and full-blown lymphomahyperplasia and full-blown lymphoma

Up regulations of BCL10/MALT1Up regulations of BCL10/MALT1

Hairy Cell LeukemiaHairy Cell Leukemia

Dry tapDry tap

Spenomegaly, pancytopenia, infectionsSpenomegaly, pancytopenia, infections

Indolent course, excellent prognosisIndolent course, excellent prognosis

Pale blue cytoplasmPale blue cytoplasm

Peripheral T-cells and Peripheral T-cells and NK-Cell NeoplasmsNK-Cell Neoplasms

Peripheral T-cell lymphoma, unspecified Peripheral T-cell lymphoma, unspecified (malignant T cells; infiltrate of (malignant T cells; infiltrate of reactive cells)reactive cells)

Anaplastic Large-cell lymphoma – ALK gene, Anaplastic Large-cell lymphoma – ALK gene, hallmark cell (horse-shoe hallmark cell (horse-shoe shaped nuclei; involve soft tissues, good prognosis)shaped nuclei; involve soft tissues, good prognosis)

Adult T-cell leukemia/lymphoma- CD4+cells, HTLV-1 Adult T-cell leukemia/lymphoma- CD4+cells, HTLV-1 (cloverlef, flow cells)(cloverlef, flow cells)Mycosis fungoides/Sezary SyndromeMycosis fungoides/Sezary Syndrome

CD4+helper Tell tumor, homes to the skin CD4+helper Tell tumor, homes to the skin (CLA and CCR4/10)(CLA and CCR4/10)Sezary syndrome = generalized exfolaitive erythroderma Sezary syndrome = generalized exfolaitive erythroderma

Large granular lymphocytic leukemiaLarge granular lymphocytic leukemianeutropenia and anemia, Increased rheumatologic disorders; neutropenia and anemia, Increased rheumatologic disorders; large large lymphocytes with abundant blue cytoplasmlymphocytes with abundant blue cytoplasmFelty syndrome = rheumatoid arthritis, neutropenia, splenomegalyFelty syndrome = rheumatoid arthritis, neutropenia, splenomegaly

Extranodal NK/Tcell LymphomaExtranodal NK/Tcell LymphomaDestructive nasopharyngeal mass, surrounds and invades blood Destructive nasopharyngeal mass, surrounds and invades blood vessels leading to ischemic necroisvessels leading to ischemic necroisassociated with EBVassociated with EBV

Hodgkin LymphomaHodgkin Lymphoma

HL arises in a single node or chain of nodes and spreads HL arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissuesfirst to anatomically contiguous lymphoid tissues

Staging is very important in guiding therapyStaging is very important in guiding therapyReed-Sternberg cellsReed-Sternberg cellsWHO classificationWHO classification

Nodular sclerosis-Nodular sclerosis-Mixed cellularity-Mixed cellularity- -Classical forms -Classical forms RS RS CD30/15+CD30/15+Lymphocyte-rich-Lymphocyte-rich-Lymphocyte depletion-Lymphocyte depletion-Lymphocyte predominanceLymphocyte predominance

Hodgkin LymphomaHodgkin Lymphoma

Nodular SclerosisNodular SclerosisLacunar variant RS cellsLacunar variant RS cellsCollagen bands that divide lymph nodes into circumscribed Collagen bands that divide lymph nodes into circumscribed nodulesnodules

Mixed-cellularityMixed-cellularityT cells, eosinophils, plasma cells, macrophages, RS cells, T cells, eosinophils, plasma cells, macrophages, RS cells, EBVEBV

Lymphocyte-richLymphocyte-richReactive lymphocytes most of cellular infiltrate, Reactive lymphocytes most of cellular infiltrate, EBVEBV

Lymphocyte depletionLymphocyte depletionPaucity of lymphocytes, Paucity of lymphocytes, EBVEBV

Lymphocyte predominanceLymphocyte predominanceNon-classical RS cells- L&H variants Non-classical RS cells- L&H variants (popcorn cell)(popcorn cell)

Hodgkin LymphomaHodgkin Lymphoma

Clinical featuresClinical features

Painless lymphadenopathyPainless lymphadenopathy

Constitutional symptoms – fever, night Constitutional symptoms – fever, night sweats, weight losssweats, weight loss

Cutaneous anergyCutaneous anergy

Staging – Table 13-9Staging – Table 13-9

Secondary CancersSecondary Cancers

Myeloid NeoplasmsMyeloid Neoplasms

The common feature of this group is origin from The common feature of this group is origin from hematopoietic progenitor cellshematopoietic progenitor cells

Primarily involve the bone marrowPrimarily involve the bone marrowUsually present with altered hematopoiesisUsually present with altered hematopoiesisAcute myeloid leukemiaAcute myeloid leukemiaMyelodysplastic syndromesMyelodysplastic syndromesMyeloproliferative disordersMyeloproliferative disordersManifestations due toManifestations due to

The position of the transformed cell within the hierarchy The position of the transformed cell within the hierarchy of progenitorsof progenitorsThe effect of the transporting events on differentiationThe effect of the transporting events on differentiation

Acute Myeloid LeukemiaAcute Myeloid Leukemia

Tumor of hematopoietic progenitorsTumor of hematopoietic progenitorsCaused by acquired oncogenic mutations Caused by acquired oncogenic mutations

that impede differentiationthat impede differentiationLeading to accumulation of immature Leading to accumulation of immature

myeloid blasts in the marrowmyeloid blasts in the marrowLeading to marrow failureLeading to marrow failure

Neutropenia,anemia, thrombocytopeniaNeutropenia,anemia, thrombocytopeniaIncidence peaks after 60 yearsIncidence peaks after 60 years

AMLAML

DiagnosisDiagnosis> > 20% myeloid blasts in bone marrow20% myeloid blasts in bone marrowAuer rodsAuer rodsImmunophenotype helps distinguish myeloblasts from lymphoblasts Immunophenotype helps distinguish myeloblasts from lymphoblasts *myeloperoxidase positive*myeloperoxidase positiveCytogenetics – central role in classificationCytogenetics – central role in classificationMany recurrent genetic aberrations seen in AML disrupt genes encoding Many recurrent genetic aberrations seen in AML disrupt genes encoding transcription factors that are required for normal differentiationtranscription factors that are required for normal differentiation

Evidence that mutated tyrosine kinases collaborate with transcription Evidence that mutated tyrosine kinases collaborate with transcription factors to produce AMLfactors to produce AML

t(15;17) respond to all-t(15;17) respond to all-transtrans retinoic acid) retinoic acid)

Most patients present with anemia, neutropenia, thrombocytopeniaMost patients present with anemia, neutropenia, thrombocytopenia

Fever, fatigue, mucosal and cutaneous bleedingFever, fatigue, mucosal and cutaneous bleeding

Myelodysplastic Myelodysplastic SyndromesSyndromes

Group of clonal stem cell disorders characterized by Group of clonal stem cell disorders characterized by maturation defectsmaturation defectsineffective hematopoiesisineffective hematopoiesishigh risk of transformation to AMLhigh risk of transformation to AML

Disordered differentiationDisordered differentiationringed sideroblasts ringed sideroblasts RBCsRBCs, megaloblastic , megaloblastic

maturation maturation plateletsplatelets, nuclear budding , nuclear budding abnormalities, abnormalities, Pseudo-Pelger-Huet cells Pseudo-Pelger-Huet cells neutrophilsneutrophils, pawn ball , pawn ball megakarocytes, myeloid megakarocytes, myeloid blasts usually less than blasts usually less than 10%10%

Myeloproliferative Myeloproliferative DisordersDisorders

Common featuresCommon features

mutated tyrosine kinasemutated tyrosine kinase

increased proliferative drive in the bmincreased proliferative drive in the bm

Extra medullary hematopoiesisExtra medullary hematopoiesis

Variable transformation to spent phaseVariable transformation to spent phase

Variable transformation to acute Variable transformation to acute leukemialeukemia

Myeloproliferative Myeloproliferative DisordersDisorders

CMLCML

Polycythemia veraPolycythemia vera

Essential thrombocythemiaEssential thrombocythemia

Primary myelofibrosisPrimary myelofibrosis

Systemic mastocytosisSystemic mastocytosis

Chronic eosinophilic leukemiaChronic eosinophilic leukemia

Stem cell leukemiaStem cell leukemia

CMLCML

Chimeric BCR-ABL geneChimeric BCR-ABL gene

Ph chromosome – t (9;22) (q34;q11)Ph chromosome – t (9;22) (q34;q11)

Adults, 4500 new cases per yearAdults, 4500 new cases per year

Hypercellular marrowHypercellular marrow

WBC >100,000WBC >100,000

Splenomegaly Splenomegaly (extramedullary hematopoeisis)(extramedullary hematopoeisis)

Insidious onset, slow progressionInsidious onset, slow progression

Blast crisisBlast crisis

Mutations in IkarosMutations in Ikaros

Polycythemia VeraPolycythemia Vera

Increased RBCs cause the most Increased RBCs cause the most symptomssymptoms

Low erthropoietinLow erthropoietin

Increased blood viscosityIncreased blood viscosity

Bleeding and thrombosisBleeding and thrombosis

Point mutations in JAK2 Point mutations in JAK2

Essential thrombocytosisEssential thrombocytosis

Abnormally large platelets in peripheral Abnormally large platelets in peripheral smearsmear

Dysfunctional platelets (Dysfunctional platelets (thrombosis and thrombosis and hemorrhage)hemorrhage)

Erthromelalgia Erthromelalgia (throbbing and burning of (throbbing and burning of hands and feet)hands and feet)

Mutations in JAK2 or MPLMutations in JAK2 or MPL

Primary myelofibrosisPrimary myelofibrosis

Development of obliterative marrow fibrosisDevelopment of obliterative marrow fibrosis

Extramedullary hematopoiesisExtramedullary hematopoiesis

LeukoerthroblastosisLeukoerthroblastosis

Teardrop-shaped red cells Teardrop-shaped red cells

Increased uric acid Increased uric acid gout gout

Nonspecific symptoms due to increased Nonspecific symptoms due to increased metabolismmetabolism

Jak2 and MPL mutations; must have bone marrow Jak2 and MPL mutations; must have bone marrow biopsybiopsy

Langerhans cell Langerhans cell histiocytosishistiocytosis

Birbeck granules in the cytoplasmBirbeck granules in the cytoplasmLetterer-Siwe Disease (Letterer-Siwe Disease (multifocal)multifocal)

seborrheic like skin eruptionseborrheic like skin eruptionEosinophilic granulomaEosinophilic granuloma

Unifocal – boneUnifocal – boneMultifocalMultifocal

Hand-Schuller-Christian TriadHand-Schuller-Christian TriadDI, exophthalmos, calvarial boney defectsDI, exophthalmos, calvarial boney defects

Pulmonary Langerhans cell histiocytosisPulmonary Langerhans cell histiocytosisAdult smokersAdult smokersRegresses when smoking is stoppedRegresses when smoking is stopped

SpleenSpleen

Filter for the bloodFilter for the bloodSite of immune responses to blood –borneSite of immune responses to blood –borne

pathogenspathogensFunctionsFunctions

Phagocytosis of blood cells and particulate matterPhagocytosis of blood cells and particulate matterAntibody productionAntibody productionHematopoiesisHematopoiesisSequestration of formed blood elementsSequestration of formed blood elements

No spleenNo spleenHib, pneumococcus, meningococcusHib, pneumococcus, meningococcus

SpenomegalySpenomegalyInfectionsInfectionsCongestive states (Congestive states (cirrhosis is the main cause, also portal vein thrombosiscirrhosis is the main cause, also portal vein thrombosisLymphohematogeneous disordersLymphohematogeneous disordersImmunologicalImmunologicalStorage diseasesStorage diseasesMiscMisc

Infarcts- bland or septic (Infarcts- bland or septic (bland are subcapsular, wedge-shaped; septic infarcts have suppurative necrosiis)bland are subcapsular, wedge-shaped; septic infarcts have suppurative necrosiis)Accessory spleensAccessory spleensRupture (Rupture (trauma, malaria, mono, typhoid fever, lymphoid neoplasms)trauma, malaria, mono, typhoid fever, lymphoid neoplasms)

ThymusThymusThird, sometimes fourth pharyngeal pouchThird, sometimes fourth pharyngeal pouch

Hassall corpusclesHassall corpuscles

TcellsTcells

Thymic hypopasia (DiGeorge syndrome 22q11, cysts)Thymic hypopasia (DiGeorge syndrome 22q11, cysts)

Thymic hyperplasia Thymic hyperplasia (myasthenia gravis -> myoid (myasthenia gravis -> myoid cells)cells)

Thymomas- MG, other autoimmuneThymomas- MG, other autoimmune

40% present because of impingement on other 40% present because of impingement on other mediastinal structuresmediastinal structures