Robbins Essential Pathology PDF - Hematopoietic and Lymphoid Systems

CHAPTER 9 Hematopoietic and Lymphoid Systems 147 Table 9.5 C...

CHAPTER 9 Hematopoietic and Lymphoid Systems 147 Table 9.5 Causes of Leukocytosis Neutrophilic Leukocytosis Acute bacterial infections (especially those caused by pyogenic organisms) Sterile inflammation caused by tissue damage (myocardial infarc- tion, burns) Eosinophilic Leukocytosis (Eosinophilia) Allergic disorders (asthma, hay fever, pemphigus, dermatitis her- petiformis) Parasitic infestations Drug reactions Neoplasms (e.g., Hodgkin lymphoma and some non-Hodgkin lymphomas) Collagen-vascular disorders, vasculitides Basophilic Leukocytosis (Basophilia) Fig. 9.10 Atypical lymphocytes in infectious mononucleosis. Rare, often indicative of a myeloproliferative neoplasm (e.g., chronic myeloid leukemia) laenly neced cells s released rom T-cell conrol and oten gves rse o Monocytosis EBV-posve B-ce ympoproerave dsease or even rank ympomas. Chronic infections (e.g., tuberculosis), bacterial endocarditis, rick- ettsiosis, and malaria Morphology. he major aeraons nvove e bood, ymp nodes, Collagen vascular diseases (e.g., systemic lupus erythematosus) Inflammatory bowel diseases (e.g., ulcerative colitis) and speen. here s perpera bood eukocyoss o arge atypca cytotoxc T ympocytes w abundan cyopasm conanng a ew Lymphocytosis azuropc granues (Fg. 9.10). Lympadenopay s common and s Accompanies monocytosis in many disorders associated with mos promnen n e poseror cervca, axary, and gron regons. chronic immunologic stimulation (tuberculosis, brucellosis) he enarged nodes conan an expanded popuaon o acvaed Viral infections (hepatitis A, cytomegalovirus, Epstein-Barr virus) T ces a may mmc ympoma. he speen s usuay enarged and Bordetella pertussis infection nraed by aypca ympocyes. enoug o mmc eukema (eukemod reactons). In parcuar, nec- ous mononuceoss, wc gves rse o a dsncve syndrome assoc- Clncal Features. Mononuceoss casscay maness w ever, sore aed w ympocyoss, can smuae neopasa. roa, and ympadens, bu aypca presenaons (e.g., ebre ras, epas) are no unusua. e dagnoss depends on e oowng ea- Infectious Mononucleosis. ures: (1) aypca ympocyoss; (2) a posve eerop anbody reac- Infectious mononucleosis is an acute, self-limited disease caused on (Monospo es); and (3) a rsng er o anbodes specc or EBV by Epstein-Barr virus infection. angens. he rapd ncrease n speen sze ncreases e rsk o spenc Epsen-Barr vrus (EBV), a member o e erpesvrus amy, s ubq- rupure, even w mnor rauma, wc can be aa. In mos paens, uous n uman popuaons. In ower-ncome counres, EBV necon n mononuceoss resoves wn 4 o 6 weeks, bu ague may as onger. eary cdood s neary unversa. Ineced cdren moun an mmune Reactive Lymphadenitis response, bu mos reman asympomac and more an a connue o sed vrus, usuay or e. In conras, n ger-ncome counres, nec- Inecons and nonmcroba nlammaor y smu (e.g., neoangens on ypcay s deayed un adoescence or young aduood and symp- rom cancer ces) oten acvae mmune ces n ymp nodes and omac necon s muc more common. For uncear reasons, n s can ead o ymp node enargemen (ympadenopay). Inecons seng ony abou 20% o ose wo are neced connue o sed e vrus. causng ympadens may be acue or cronc. Usuay, soogc canges n ymp nodes are nonspecc. he excepon s granuo- Pathogeness. Transmsson o EBV usuay nvoves ora conac w maous ympadens, wc can be seen n ubercuoss (marked by sava conanng vrus. EBV may rs nec oroparyngeal epelal cells, caseous necross), oer necous enes (ca-scrac dsease, unga bu  en spreads o underlyng onsls and adenods, were B cells are necons), and sarcodoss. neced. he necon o B ces akes one o wo orms: In a mnory o ces, e necon s yc, eadng o vra repcaon and reease o vr- NEOPLASTIC PROLIFERATIONS OF WHITE CELLS ons, wereas n mos B ces e necon s nonproducve and e vrus persss n aen orm. Severa EBV-encoded proens expressed n aeny he mos mporan dsorders o we ces are neopasms. A are neced ces smuae proeraon o e neced ces, wc dssem- magnan, bu ey ave a wde range o cnca beavors. Hemao- nae o ympod ssues and secree varous anbodes. Incuded among ogc magnances occur a a ages and as a group are que common; ese are eerop (cross-reacve w anoer speces) an–seep red n aggregae, ere are abou 150,000 new emaoogc magnances ce anbodes, wc are deeced n dagnosc ess or mononuceoss. dagnosed eac year n e Uned Saes. Hos CD8+ cyooxc T ces specc or vral angens conrol e Casscaon sysems or we ce neopasms rey on morpo- proleraon o EBV-neced B cells. However, a ew laenly neced ogc and moecuar crera, ncudng dencaon o neage-spe- EBV-posve B cells escape e mmune response by downregulang e cc proen markers and specc genec aberraons. he number expresson o vral proens and perss or e le o e paen. In paens o recognzed enes s numerous (>70 a as coun), relecng e w deecve T-cell mmuny (e.g., AIDS paens or ransplan recp- compexy o e norma emaopoec and mmune sysems  rom ens reaed w mmunosuppressve drugs), s perssen populaon o wc ese umors are derved. Here, we ocus on reavey common 148 CHAPTER 9 Hematopoietic and Lymphoid Systems Table 9.6 Acute Leukemias and Myeloid Neoplasms Entity Cell of Origin Salient Pathologic Features Commonly Mutated Genes B-cell acute lymphoblastic Immature B cell Marrow replacement by lymphoid Transcription factor genes, often by leukemia blasts, absence of Auer rods translocations; ABL tyrosine kinase, in the form of a BCR-ABL fusion gene (subset of cases) T-cell acute lymphoblastic Immature T cell Marrow replacement by lymphoid Transcription factor genes, often by leukemia blasts, absence of Auer rods, translocations; signaling frequent mediastinal involvement molecule genes Acute myeloid leukemia Hematopoietic stem cell or early Marrow replacement by myeloid Transcription factor genes, often by myeloid progenitor blasts, often with Auer rods translocations (e.g., RARA); signaling molecule genes Myelodysplastic syndrome Hematopoietic stem cell or early Dysplastic marrow progenitors and Genes encoding epigenetic regulators, myeloid progenitor peripheral blood elements RNA splicing factors, and transcrip- tion factors Chronic myeloid leukemia Hematopoietic stem cell Increased marrow granulocytic ABL tyrosine kinase, in the form of precursors and megakaryocytes, BCR-ABL fusion gene leukocytosis, basophilia, thrombocytosis, splenomegaly Polycythemia vera Early myeloid progenitor Increase in all marrow elements, Activating mutations in the JAK2 tyro- polycythemia, basophilia sine kinase gene Primary myelofibrosis Early myeloid progenitor Increased and atypical megakaryo- Activating mutations in the JAK2 or MPL cytes, marrow fibrosis, splenomeg- tyrosine kinase genes; mutations aly, leukoerythroblastosis in the CALR gene or cncopaoogcay dsncve enes. We w rs consder emaoogc magnances a orgnae n emaopoec sem ces or eary marrow progenors, e acue eukemas and myeod neo- pasms, caracerscs o wc are summarzed n Tabe 9.6 Acute Leukemias Acute leukemias are a diverse group of neoplastic proliferations of immature hematopoietic cells that often replace normal marrow elements, leading to symptoms related to marrow failure. Acue eukemas are subcassed by mmunopenoype no B-ce umors (B-ce acue ympobasc eukema, or B-ALL), T-ce umors (T-ce acue ympobasc eukema, or T-ALL), and myeod umors (acue myeod eukema, or AML). he mmaure neopasc ces are reerred o as bass. Typcay, n ALL ere s a compee mauraon arres a eary sages o B- or T- ce dferenaon and bass are e major umor ce popuaon n nvoved ssues. In conras, n AML e Fig. 9.11 Acute lymphoblastic leukemia (ALL). Lymphoblasts with bock n dferenaon s oten ncompee and dagnoss s based on condensed nuclear chromatin, small nucleoli, and scant agranular cyto- e presence o a eas 20% bass n e marrow or bood. Beyond er plasm are shown. TdT, terminal deoxynucleotidyl transferase. mmunopenoypc dferences, B-ce, T-ce, and myeod acue euke- mas aso ave somewa dsnc cncopaoogc eaures, as oows:    B-ALL s e mos common cdood eukema, w a peak nc- myeod neopasm (eer a myeoproerave neopasm or a dence beween e ages o 2 and 10 years. I amos aways arses myeodyspasc syndrome, descrbed aer), somemes ater a wn e marrow and repaces norma marrow eemens, resu- prodrome asng or years. Lke ALL, mos sympoms are reaed ng n sympoms reaed o anema (weakness, ague), rom- o marrow aure. Myeod bass end o be arger an ympod bocyopena (peecae [sma beeds no e skn and mucosa bass and ave ne croman, dsnc nuceo, and moderae membranes]), and neuropena (necon). he bass ave scan amouns o c yopasm w varabe numbers o granues (Fg. basopc cyopasm and nuce w decae, ney spped cro- 9.12A). In a subse o cases, ese granues ake e orm o Auer man and sma nuceo (Fg. 9.11A). rods, neede-ke ncusons a are paognomonc or myeod    T-ALL mos commony presens durng adoescence and oten bass (Fg. 9.13). In oer nsances, e bass o AML are so nvoves e ymus, as we as e bone marrow. In addon o mmaure a ey are dcu o dsngus  rom ympod marrow aure, more an a o T-ALLs presen w medas- bass morpoogcay and mmunopenoypng s necessar y or na masses due o ymc nvovemen. Bass are morpoog- dagnoss. cay denca o ose o B-ALL and can ony be dsngused by mmunopenoypng. Pathogeness. Among e mos common drver muaons n a ypes o    A ML occurs rougou e bu s mos common n ndvduas acue eukema are gene rearrangemens and base par subsuons a oder an 60. Unke ALL, AML oten arses  rom a preexsng nerere w e uncon o ranscrpon acors a reguae norma  CHAPTER 9 Hematopoietic and Lymphoid Systems 149 (>100,000 ces/μL) bu s somemes norma. Anema s amos aways presen, and e paee coun usuay s beow 100,000/μL. Neuropena s common.    Immunopenotypng. Denve dagnoss rees on sans per- ormed w anbodes o neage-specc angens, usuay by low cyomer y. For exampe, deecon o ermna deoxyrbose rans- erase (TdT) s useu or denyng earer B and T ce progenors. Hsocemca sans may aso be used, ncudng myeoperoxdase, seen n acue myeod eukema.    Cytogenetcs. Specc ransocaons are assocaed w parcuar subypes o acue eukema, ave prognosc mporance, and may deny erapeuc arges.    Moecuar Genetcs. Ceran orms o acue eukema are now dened by e presence o drver muaons n specc cancer genes. Mos acue eukemas are curreny evauaed by argeed DNA sequencng. Some o em are dscussed aer. Fig. 9.12 Acute myeloid leukemia (AML). Myeloblasts with delicate nuclear chromatin, prominent nucleoli, and fine azurophilic cytoplasmic Clncal Features. Acue eukema s an aggressve dsease. In addon granules are shown. o sympoms reaed o marrow repacemen and e aendan pancy- opena, ere may be    B one pan resung rom marrow expanson and nraon o e subperoseum    Lympadenopay, spenomegay, and epaomegay, more com- mon and more pronounced n ALL an AML    Tescuar enargemen due o eukemc nraon    Inraon o e skn and gums, mos caracersc o AML w monocyc dferenaon    In T-ALL w ymc nvovemen, compresson o arge vesses and ar ways n e medasnum    C enra ner vous sysem manesaons resung rom menngea spread, suc as eadace, vomng, and ner ve pases Treamen o acue eukema vares accordng o subype. Mos paens are reaed w combnaon cemoerapy usng regmens a dfer or ALL and AML. More an 80% o cdren w B-ALL and T-ALL are cured. Hgy efecve argeed erapes are avaabe Fig. 9.13 Acute promyelocytic leukemia, a variant of AML. The neo- or wo moecuar subypes o acue eukema: (1) BCR-ABL–postve plastic promyelocytes have abnormally coarse and numerous granules. B-ALL, dened by e presence o a BCR-ABL uson gene (descrbed A characteristic finding is a cell in the center of the field with multiple n dea under cronc myeod eukema) and (2) acute promyeocytc needle-like Auer rods (arrow). (Courtesy of Dr. Robert W. McKenna, eukema, a dsncve subype o AML caracerzed by e presence o Department of Pathology, University of Texas Southwestern Medical a (15;17) ransocaon a creaes a PML-RARA uson gene encodng School, Dallas.) an aberran orm o e renoc acd recepor a bocks ermna d- erenaon o promyeocyes. hs orm o acue eukema s now amos emaopoec ce dferenaon. hese muaons ypcay nvove ac- aways cured w argeed reamen conssng o a-trans renoc acd, ors a reguae e neage o wc e eukema beongs. For exam- a vamn A anaog a bnds e PML-RARA uson proen, combned pe, B-ALL oten conans muaons n ranscrpon acors requred or w arsenc sas, wc cause e degradaon o PML-RARA. hs eary sages o B-ce dferenaon. hese muaons cause mauraon reamen nduces e dferenaon o mmaure ces presumaby no arres and accumuaon o mmaure bass. Muaons n oer genes neurops, wc rapdy de, cearng e neopasc cone. A recen ead o grow acor–ndependen sgnang and proeraon. RAS and deveopmen s reamen o B-ALL w cyooxc T ces bearng c- genes encodng sgnang moecues a ac upsream and downsream merc angen recepors (CARs) engneered o speccay recognze and o RAS, ncudng severa grow acor recepors, are oten muaed. k ces expressng e B-ce angen CD19. hs erapy as produced dramac responses n reapsed/reracory B-ALL n cdren and adus, Pathology. he dagnoss and subypng o acue eukema requres bu a e cos o permanen oss o norma B ces and somemes severe a combnaon o compemenar y ess: or even aa oxcy caused by producon o cyoknes by e massvey    Mor poog y. Bass can be seen n e perpera bood and bone acvaed njeced T ces (cyokne sorm). marrow, aoug bopsy o a ssue mass may be requred or Caenges reman. Inane acue eukemas assocaed w rear- dagnoss, parcuary n T-ALL. he perpera bood ndngs rangemens o e KMT2A gene (prevousy known as MLL), wc are gy varabe. he we ce coun may be markedy eevaed encodes an epgenec reguaor, ave a poor prognoss. he prognoss 150 CHAPTER 9 Hematopoietic and Lymphoid Systems or adus w BCR-ABL–negave ALL s guarded, and e prognoss argeed erapy. We w dscuss CML and wo oer cncopaoog- or paens w AML subypes oer an acue promyeocyc eu- cay dsnc myeoproerave neopasms, poycyema vera and kema remans poor, parcuary n adus oder an age 60 years. A prmar y myeobross. parcuary caengng probem s e sma subse o acue eukemas Chronic Myeloid Leukemia w TP53 muaons, wc ave dsma oucomes even w emao- poec sem ce ranspanaon. Chronic myeloid leukemia is distinguished from other myelopro- liferative neoplasms by the presence of a BCR-ABL fusion gene Myelodysplastic Syndromes derived from portions of the BCR gene on chromosome 22 and the here s a arge group o myeod neopasms a ack e eaures a ABL gene on chromosome 9. dene AML (>20% bass and specc AML-denng drver mua- he posons o e DNA breakpons n cronc myeod eukema ons). hese neopasms a no wo broad, overappng groups, e (CML) and BCR-ABL–posve B-ALL (descrbed earer) dfer n sub- myeodyspasc syndrome (MDS) and e myeoproerave neo- e ways bu ave smar downsream consequences. pasms (MPNs; dscussed aer). MDS s neary as common as AML. I afecs abou 15,000 paens per year n e Uned Saes and s Pathogeness. he BCR ABL gene ound n CML encodes a cmerc ncreasng n requency as e popuaon ages. proen n wc e ABL yrosne knase becomes consuvey acve because o uson o par o e BCR proen and mmcs sgnas produced Pathogeness. MDS s caracerzed by mauraon deecs assocaed w by acvaed grow acor recepors. Because BCR-ABL does no nb nefecve emaopoess and a g rsk o ransormaon o AML. he dferenaon, e eary dsease course s marked by excessve producon marrow s pary or woy repaced by e cona progeny o a ransormed o reavey norma bood ces, parcuary granuocyes and paees. mupoen sem ce a demonsraes nefecve and dsordered mu- neage dferenaon. he marrow s yperceuar or normoceuar, bu e perpera bood sows one or more cyopenas. Morphology. he eukocye coun s eevaed, oten exceedng 100,000 In cdren and young adus, MDS s oten due o nerance o a ces/μL, due o e presence o ncreased numbers o neurops, muaed cancer gene or exposure o muagens (e.g., erapeuc akya- eosnops, and basops, as we as earer granuocyc orms suc ng agens or onzng radaon). In adus over e age o 60 years, MDS as meamyeocyes and myeocyes (Fg. 9.14). he paee coun s appears o be caused by sporadc muaons n cancer genes. Transorma- aso requeny eevaed. he marrow s yperceuar, and e speen on o AML s assocaed w addona muaons a drve ce grow, s markedy enarged by exrameduary emaopoess. I e bood suc as muaons n RAS and oer sgnang moecues. In addon, suppy canno keep up w e massve spenomegay, e resu may rougy 10% o MDS cases ave oss-o-uncon muaons n TP53; ese be spenc narcs. paens ave parcuary poor cnca oucomes. Clncal Features. he onse o CML s nsdous and na sympoms Morphology. he marrow s popuaed by emaopoec precursors are nonspecc. Spenomegay may be e eares sympom. he na- a exb dsordered dferenaon (dyspasa), ncudng ura sor y s varabe, bu unreaed CML s evenuay aa due o “megaobasod” eryrod precursors resembng ose seen n e ransormaon o acue eukema (so-caed bas crss). In 70% o megaobasc anemas, eryrod orms w ron deposs wn er cases, e bas crss resembes AML; n e remander,  resembes mocondra (rng sderobasts), granuocye precursors w abnorma B-ALL, wc s conssen w e dea a CML orgnaes rom granues or nucear mauraon, and sma megakaryocyes w snge mupoen emaopoec sem ces sma nuce or mupe separae nuce. Targeed erapy as dramacay aered e dsease course. Tyrosne knase nbors a arge e BCR-ABL uson proen nduce susaned remssons and preven bas crss, parcuary n paens w eary ds- Clncal Features. Mos paens are 50 o 70 years o age. As a resu o ease. he BCR-ABL–posve cone persss, and paens mus be reaed cyopenas, necons, anema, and beedng are common. he dagno- ss rees on e presence o cyopenas and caracersc morpoogc and genec ndngs. Cyogenec sudes oten revea cona abnorma- es; oss o a or a poron o cromosomes 5 and/or 7 s parcuary common. DNA sequencng sudes deny drver muaons n e majory o cases. MDS s dcu o rea;  does no respond we o convenona cemoerapy, and mos paens are oo od o undergo sem ce rans- panaon. Transormaon o AML occurs n 10% o 40% o cases. he medan survva me ranges rom 9 o 29 mons and s worse n cases assocaed w ncreased marrow bass, cyogenec abnormaes, or TP53 muaons. Myeloproliferative Neoplasms The common pathogenic feature of myeloproliferative neoplasms is the presence of mutated, constitutively activated tyrosine kinases or other acquired aberrations in signaling pathways that lead to Fig. 9.14 Chronic myeloid leukemia: peripheral blood smear. Granulo- growth factor independence. cytic forms at various stages of differentiation are present. (Courtesy of hese dverse myeod magnances are rare bu are noabe because Dr. Robert W. McKenna, Department of Pathology, University of Texas o e remarkabe response o cronc myeod eukema (CML) o Southwestern Medical School, Dallas.)  CHAPTER 9 Hematopoietic and Lymphoid Systems 151 or e. Reapses somemes occur, oten due o ougrow o cones w Morphology. he marrow appearance s denca o e spen muaons n BCR-ABL a preven nbors rom bndng. In some pase a s seen occasonay ae n e course o oer nsances, remssons can be obaned by swcng o dferen nbors myeoproerave neopasms suc as PCV. Inay, e marrow s a are acve agans parcuar muaed orms o BCR-ABL. For oers, yperceuar and mdy dsored by bross. Megakar yocyes are emaopoec sem ce ranspanaon ofers a cance o cure. arger an norma and presen n cusers. In advanced cases, e marrow s ypoceuar and dfusey broc, and compensaor y Polycythemia Vera exrameduar y emaopoess occurs. he perpera bood smear Polycythemia vera is a myeloproliferative disorder marked by s markedy abnorma (Fg. 9.15). Red ces exb bzarre sapes, increased production of all myeloid lineage cells and symptoms and nuceaed er yrod precursors are commony seen, aong related to increased red cell mass (polycythemia). w mmaure we ces (myeocyes and meamyeocyes), a combnaon o ndngs reerred o as eukoerytrobastoss. Pathogeness. Poycyema vera (PCV) s assocaed w acvang pon Abnormay arge paees are oten presen. Marked spenomegay muaons n e yrosne knase JAK2, a sgnang moecue n paways due o exensve exrameduar y emaopoess, oten assocaed downsream o e eryropoen recepor and oer grow acor recep- w subcapsuar nfarcts, s ypca. he speen may weg up o ors. he JAK2 muaons reduce e dependence o emaopoec ces on 4000 g, rougy 20 mes s norma weg. Moderae epatomegay, grow acors or grow and survva, eadng o excessve proeraon o aso due o exrameduar y emaopoess, s commonpace. eryrod, granuocyc, and megakaryocyc eemens. Clncal Features. Prmar y myeobross usuay occurs n ndvduas Mor pholog y. he marrow s yperceuar due o ncreased numbers oder an 60 years wo presen w sympoms reaed o anema and o er yrod, myeod, and megakar yoc yc orms. Marrow bross spenomegay. Fague, weg oss, and ng sweas are requen com- s seen n 10% o paens a dagnoss. hs can progress o a spent pans. Hyperurcema and gou due o a g rae o ce urnover are pase, were e marrow s repaced by brobass and coagen. oten seen. Laboraor y sudes sow a moderae o severe normocyc Increased bood voume and vscosy due o poyc yema cause anema accompaned by eukoer yrobasoss. he we ce coun congeson o many ssues. Paees are oten abnormay arge s usuay norma or mdy reduced bu can be eevaed eary n e and may be dysuncona, eadng o romboss and beedng. course. he paee coun s usuay norma or eevaed a dagnoss, Basops are oten ncreased n e perpera bood. bu rombocyopena oten super venes as e dsease progresses. Prmar y myeobross s more dcu o rea an PCV and CML. Clncal Features. PCV appears nsdousy, usuay n ae mdde age. he medan sur vva s 4 o 5 years. hreas o e ncude necon, Sympoms ncude cyanoss, eadace, dzzness, gasronesna symp- romboss and beedng, and ransormaon o AML, wc occurs oms, emaemess, and meena. hromboses may nvove vens or n 5% o 20% o cases. JAK2 nbors are efecve a decreasng e areres and can ead o sroke, myocarda narcon, and pumonary spenomegay and consuona sympoms. Hemaopoec sem ce embosm. Epsaxs s common, and e-reaenng emorrages occur ranspanaon may be curave. n 5% o 10% o paens. Because o e g ce urnover, gou s seen Non-Hodgkin Lymphomas and Chronic Lymphoid n 5% o 10% o paens. Leukemias Common aboraor y ndngs ncude a emaocr a s oten 60% or greaer, granuocyoss w basopa, and rombocyoss. Deec- hese common emaoogc magnances ncude a wde varey o on o JAK2 muaons conrms e dagnoss. neopasms a are derved rom maure ympod ces. Hodgkn ym- W ou  re a men, d e a   rom v as c u  ar comp c a  ons o c c urs pomas and pasma ce neopasms and reaed enes are aso derved w  n mon s; owe ver,  e me d  an sur v v a    me s  nc re as e d o rom maure ympocyes, bu ave unque cncopaoogc eaures ab ou 10 ye ars by ower ng o  e emao c r  o ne ar nor ma  by and are dscussed aer. rep e ae d p eb oomy. Pro onge d su r v v a  as re ve a e d a prop ens  y or PCV o e vove o a sp en pas e re s emb ng pr  mar y myeo  - bross (des cr b e d  aer) a e r an ave rage  ner v a  o 10 ye ars. JA K2 n bors are us e d o  re a  e sp e n pas e and ead o  mprove men n mos p a ens. Trans or ma  on o a b as cr s s  de n  c a  o  a o AML a s o o cc urs, bu muc e ss  re qu en y  an n CML. Primary Myelofibrosis The hallmark of primary myelobrosis is the development of oblit- erative marrow brosis, which reduces marrow hematopoiesis and leads to cytopenias and extensive extramedullary hematopoiesis. Pathogeness. Prmar y myeobross s caused by varous muaons a ncrease JAK/STAT sgnang, a paway downsream o grow acor recepors. he mos requen o ese are JAK2 muaons, wc are presen n 50% o 60% o cases. I s no known wy JAK2 muaons are assocaed w PCV n some paens and prmar y myeobross Fig. 9.15 Primary myelofibrosis: peripheral blood smear. Two nucleated n oers. Fbross s caused by pro-brogenc acors suc as pae- erythroid precursors and several teardrop-shaped red cells are evident. e-derved grow acor and TGF- a are eaboraed by neopas- Immature myeloid cells were present in other fields. An identical histo- c megakar yocyes. TGF- promoes angogeness as we as coagen logic picture can be seen in other diseases producing marrow distortion deposon, bo o wc are promnen n myeobroc marrows. and fibrosis. 152 CHAPTER 9 Hematopoietic and Lymphoid Systems Some genera aspecs o magnances o maure ympod ces bear 5000 ces/μL, e paen s dagnosed w CLL. Mos cases  e cr- empass: era or CLL, wc s e mos common eukema o adus n e    e erms eukema and ympoma refer o e usua paerns of s- Wesern word. For uncear reasons, CLL/SLL s ess common n Asa. sue nvovemen. Leukemas ypcay arse n bone marrow and are apparen n perpera bood, wereas ympomas presen as masses Pathogeness. CLL/SLL s an ndoen, sowy growng umor n wc n ymp nodes and oer ssues. However, ese dsncons are no ncreased umor ce sur vva s more mporan an umor ce pro- absoue: “ympomas” occasonay ave perpera bood nvove- eraon per se. CLL/SLL ces express g eves o B CL2, a proen a men and “eukemas” may presen as masses, wou perpera nbs apoposs. Aso o crca mporance are sgnas generaed by bood nvovemen. he dagnoss s based on e morpoogc and surace mmunogobun (e B-ce recepor, or B CR). B CR sgnas moecuar caracerscs o e umor ces, regardess o er oca- low roug an nermedar y caed Bruon yrosne knase (BTK) and on n e body. umaey urn on e ranscrpon acor NF-κB, wc conrbues    Maure ympod neopasms oten dsrup e funcon of e adap- o e expresson o genes a promoe e sur vva o CLL/SLL ces. ve mmune sysem; mmunodecency and auommuny coexs hroug uncear mecansms, e accumuaon o CLL/SLL ces n some nsances. suppresses norma B-ce uncon, oten resung n ypogammagob-    Paens w nered or acqured mmunodeicences are at ger unema Paradoxcay, approxmaey 15% o paens deveop auo- rsk for ympod neopasms, parcuary ose assocaed w EBV anbodes agans er own red ces or paees. Wen presen, e necon. auoanbodes are made by nonmagnan bysander B ces, ndcang    Atoug ympoma oten appears o be ocazed, neopasc ym- a CLL/SLL ces mpar mmune oerance. pocyes recrcuae ke norma ympocyes and umors are usuay Morphology. Invoved ymp nodes are dfusey efaced by sees wdespread a dagnoss. hereore, w ew excepons, ony sys- o sma ympocyes and scaered -dened areas conanng emc erapes are curave. arger, acvey dvdng ces (Fg. 9.16A). he sma ympocyes    B-ce umors are muc more common an T-ce umors, proba- ave dark, round nuce and scany cyopasm (see Fg. 9.16B). he by because ransocaons and muaons reaed o doube-srand oc o mocay acve ces are caed proferaon ceners, wc DNA breaks n mmunogobun genes (durng somac ypermua- are paognomonc or CLL/SLL. he marrow, speen, and ver on and cass-swcng) ncrease e rsk or oncogene acvaon. are aso nvoved n amos a cases. In paens w CLL, ere Many drver muaons n B-ce magnances conss o ransoca- s an absoue ympocyoss o sma, maure-ookng ympocyes. ons a use mmunogobun genes o proooncogenes. hese crcuang ces are rage and requeny dsruped on he casscaon o non-Hodgkn ympomas and cronc ym- soogc preparaons; ey are caed smudge ces. pod eukemas consders e morpoog y, ce o orgn (deer- mned by mmunopenoypng), cnca eaures, and genoype (e.g., kar yoype, presence o vra genomes) o eac eny. In e oowng Clncal Features. he dagnoss s based on ncreased ympocyes n secons, we w ocus on ose a are mos common and cncay e perpera bood and conrmed by low cyomer y, wc reveas mporan (summarzed n Tabe 9.7). We aso w ouc on a ew rare a popuaon o ces expressng B-ce markers suc as CD20, CD5 enes a nevereess deser ve bre menon because o unusua or (wc s aso expressed on norma T ces), and cona surace mmu- paogencay normave caracerscs. nogobun g can (eer kappa or ambda). In SLL, ssue bopsy o an enarged ymp node s requred or dagnoss. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma he prognoss s generay good because CLL usuay oows a ver y Cronc ympocyc eukema (CLL) and sma ympocyc ym- ndoen course. I dagnosed wen e paen s asympomac, e poma (SLL) are denca, dferng ony n e exen o perpera medan sur vva s greaer an 10 years, even wou reamen. Symp- bood nvovemen;  e perpera bood ympocye coun exceeds omac paens are reaed w anbodes agans CD20, nbors o Table 9.7 Characteristics of Non-Hodgkin Lymphomas and Chronic Lymphoid Leukemias Entity Cell of Origin Associated Characteristics Small lymphocytic lymphoma/ Mature B cell Occurs in older adults; usually involves lymph nodes, marrow, spleen; and chronic lymphocytic leukemia peripheral blood; indolent Follicular lymphoma Germinal center B cell Translocations involving BCL2; presents with generalized lymphadenopathy; indolent Mantle cell lymphoma Naïve mature B cell Translocations involving the cyclin D1 gene; presents with generalized lymphadenopathy; moderately aggressive Extranodal marginal zone lym- Mature B cell Arises at sites of chronic inflammation; very indolent phoma Diffuse large B-cell lymphoma Germinal center or post–ger- Heterogeneous, may arise at extranodal sites; variably associated with minal center B cell translocations involving BCL2, BCL6, and MYC; aggressive Burkitt lymphoma Germinal center B cell Usually arises at extranodal sites; translocations involving MYC in virtually all cases; subset of cases associated with EBV; aggressive Hairy cell leukemia Mature B cell Spleen and marrow involvement; most cases have BRAF mutations; indo- lent Adult T-cell leukemia/lymphoma CD4-positive T cell Usually presents with lymph node and blood involvement; uniformly asso- ciated with HTLV-1 infection; frequent hypercalcemia; aggressive Peripheral T-cell lymphoma Mature T cells Heterogeneous; often associated with systemic symptoms stemming from cytokine release; aggressive