Robbins Essential Pathology PDF, Hematopoietic and Lymphoid Systems

CHAPTER 9 Hematopoietic and Lymphoid Systems 153 B-ce recepor sgnang,...

CHAPTER 9 Hematopoietic and Lymphoid Systems 153 B-ce recepor sgnang, and BCL2 anagonss. he presence o TP53 Morphology. Lymp nodes are usuay efaced by a dsncy muaons porends a worse prognoss. Cure may ony be aceved w noduar proferaton (Fg. 9.17A). Mos commony, e predomnan emaopoec sem ce ranspanaon, wc s reser ved or younger neopasc ces are so-caed centrocytes, ces sgy arger an paens wo a convenona erapes. A sma racon o CLL/SLL resng ympocyes a ave anguar “ceaved” nuce w cases ransorm o aggressve umors resembng dfuse arge B-ce ndenaons and near nodngs, coarse condensed croman, and ympoma (Rcer ransormaon); once ransormaon occurs, e ndsnc nuceo (Fg. 9.17B). Cenrocyes are mxed w varabe medan sur vva me s ess an 1 year. numbers o centrobasts, arger ces w vescuar croman, severa nuceo, and modes amouns o cyopasm. Uncommony, cenrobass predomnae, a eaure a correaes w more Follicular Lymphoma aggressve cnca beavor. he umor ces express e B-ce marker Follicular lymphoma is strongly associated with a (14;18) translo- CD20, germna cener B-ce markers, surace mmunogobun, cation that increases the expression of the antiapoptotic BCL2 gene. and g eves o BCL2. Because BCL2 s no expressed n norma Focuar ympoma consues approxmaey 25% o cases o adu germna cener B ces, sans or BCL2 ep dsngus ocuar non-Hodgkn ympoma n e Uned Saes, makng  e mos com- ympoma rom ocuar yperpasa. mon “ndoen” non-Hodgkn ympoma. Lke CLL/SLL,  occurs ess re- queny n Asan popuaons. he ce o orgn s a germna cener B ce. Clncal Features. Focuar ympoma afecs adus oder an 50 and Pathogeness. More an 85% o ocuar ympomas ave a carac- usuay maness as paness generazed ympadenopay. he mar- ersc (14;18) ransocaon a uses e BCL2 gene on cromosome row s nvoved a dagnoss n approxmaey 80% o cases. Aoug e 18 o e IGH (mmunogobun eavy can) ocus on cromosome naura sor y s proonged (overa medan sur vva s approxmaey 14, resung n “overexpresson” o BCL2 proen, an nbor o apop- 10 years), e dsease s no curabe; erapy s reser ved or paens w oss (see Caper 1). In abou a rd o cases, addona muaons n buky, sympomac dsease. Treamen ncudes “gene” cemoerapy, genes encodng sone-modyng proens are seen. anbodes agans CD20, and BCR sgnang nbors. In 30% o 40% o paens, ocuar ympoma progresses o dfuse arge B-ce ym- poma (DLBCL). DLBCL arsng rom ocuar ympoma as a worse prognoss an de novo dfuse DLBCL, descrbed aer. Mantle Cell Lymphoma Mantle cell lymphoma is strongly associated with an (11;14) trans- location that increases expression of the cyclin D1 gene. Mane ce ympoma s derved rom ces resembng e naïve B ces a are ound n e mane zones o norma ympod oces. I consues approxmaey 6% o a non-Hodgkn ympomas and occurs many n men oder an 50 years. Pathogenes s. Cycn D1 smuaes grow by ormng a compex w cycn-dependen knases and nacvang RB, promong progresson o ces rom e G pase o e S pase o e ce cyce (see Cap- 1 er 5). Overexpresson o cycn D1 over wems e brakng efec o A RB, drvng ympoma ce grow. Addona drver muaons ave aso been dened n genes encodng a varey o sgnang moecues, ranscrpon acors, and epgenec reguaors. Morphology. Lymp nodes are efaced by umor ces growng n dfuse or vaguey noduar paerns. he umor ces usuay are sgy arger an norma ympocyes and ave an rreguar nuceus, nconspcuous nuceo, and scan cyopasm. he bone marrow s nvoved n mos cases and e perpera bood n abou 20% o cases. he umor ces express surace IgM and IgD, e B-ce angen CD20, and CD5, and ave g eves o cycn D1 proen, a ndng a s dagnoscay epu. Clncal Features. Mos paens presen w ague and ympadenop- ay and are ound o ave generazed dsease nvovng e bone mar- row, speen, ver, and (oten) e gasronesna rac. hese umors are B moderaey aggressve and ncurabe. Treamen nvoves e use o ow- Fig. 9.16 Chronic lymphocytic leukemia/small lymphocytic lymphoma: dose cemoerapy, anbodes agans CD20, and drugs a nb B-ce lymph node. (A) Low-power view shows diffuse effacement of nodal recepor sgnang. he medan survva s 4 o 6 years. architecture. (B) At high power, a majority of the tumor cells have the appearance of small, round lymphocytes. A “prolymphocyte,” a larger Extranodal Marginal Zone Lymphoma cell with a centrally placed nucleolus, also is present in this field (arrow). Extranodal marginal zone lymphoma is an example of a cancer (A, Courtesy of Dr. José Hernandez, Department of Pathology, Univer- sity of Texas Southwestern Medical School, Dallas.) that arises within and is sustained by chronic inammation. 154 CHAPTER 9 Hematopoietic and Lymphoid Systems A B Fig. 9.17 Follicular lymphoma: lymph node. (A) Nodular aggregates of lymphoma cells are present through- out. (B) At high magnification, small lymphoid cells with condensed chromatin and irregular or cleaved nuclear outlines (centrocytes) are mixed with a population of larger cells with nucleoli (centroblasts). (A, Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas.) Exranoda margna zone ympoma s an ndoen umor derved rom    B CL6. Abou one rd o DLBCLs ave rearrangemens o BCL6, angen-smuaed B ces. I occurs mos commony n organs w epe- ocaed on cromosome 3q27, and an even ger racon ave a nngs, suc as e gasronesna rac (so-caed MALTomas [muco- pon muaons n e BCL6 promoer. Bo aberraons resu n sa-assocaed ympod umors]), savary gands, ungs, orb, and breas. ncreased eves o BCL6 proen, an mporan ranscrpona reg- uaor o gene expresson n germna cener B ces. Pathogeness. hs ympoma arses mos oten n ssues a are    BCL2. Approxmaey 30% o umors ave a (14;18) ransocaon nlamed due o auommune dsorders (e.g., Sjögren syndrome, nvovng e BCL2 gene a resus n overexpresson o e anapo- Hasmoo yrods) or cronc necon (e.g., Hecobacter pyor oc B CL2 proen. Some o ese umors may represen “ransormed” gasrs). Eradcaon o H. pyor w anboc erapy oten eads o ocuar ympomas, wc vruay aways ave e (14;18). regresson o e umor ces, wc depend on nlammaory cyoknes    MYC. Approxmaey 5% o 10% o DLBCLs ave rearrangemens secreed by H. pyor–specc T ces or er grow and survva. I s nvovng MYC, a gene encodng a ranscrpon acor a reguaes oug a e dsease begns as a poycona mmune reacon, and many aspecs o grow-promong meabosm, suc as e Warburg ater subsequen, s-unknown drver muaons, a neopasc cone efec. emerges a remans dependen on angen-smuaed T-eper ces or In addon o ese ransocaons, numerous oer drver mua- sgnas o drve grow and survva. Hence, wdrawa o e respons- ons ave been dened a afec varous epgenec reguaors, be angen, suc as H. pyor proens, causes umor nvouon. sgnang moecues, and ranscrpon acors a ave mporan uncons n B ces. Morphology. he cona B ces nrae e epeum o nvoved ssues and coec n sma aggregaes (ymphoepthea esons). Morphology. he neopasc B ces are arge, a eas ree o our he cyopasm may be abundan and pae or exb pasma ce mes e sze o resng ympocyes; owever, ere s consderabe dferenaon. he umor ces express e B-ce angen CD20 and soogc varaon. Ces w ova nucear conours, dspersed surace mmunogobun, usuay IgM. croman, severa dsnc nuceo, and modes amouns o pae cyopasm may predomnae (Fg. 9.18), or e ces may ave a round or muobae vescuar nuceus, one or wo promnen Clncal Features. Exranoda margna zone ympomas ypcay pres- cenray paced nuceo, and abundan pae or basopc cyopasm. en as swengs o e savary gand, yrod, or orb, or are dscovered Occasonay, e umor ces are anapasc and ncude umor gan ncdenay n e seng o H. pyor–nduced gasrs. Unke oer ces resembng Reed-Sernberg ces, e magnan ces o Hodgkn non-Hodgkn ympomas, wen ocazed ey are oten cured by smpe ympoma (descrbed aer). he umors express e B-ce angen excson oowed by radoerapy, or (n e case o H. pyor-assocaed CD20, and many express surace IgM and/or IgG. Oer proen dsease) may aso compeey regress n response o anboc erapy. markers suc as BCL2, BCL6, and MYC are varaby expressed. Diffuse Large B Cell Lymphoma Diffuse large B-cel l l y mp h oma is th e mo s t common t y pe of ly m- Severa dsncve cncopaoogc subypes are ncuded n e phoma, accountin g fo r a p p ro x i ma te ly 35% of n o n - H o d g k in caegor y o DLBCLs. lymphoma s in the Un i ted S ta tes.    EBV-assocated DLBCLs arse n e seng o AIDS, arogenc Dfuse arge B-ce ympoma (DLB CL) occurs a a ages bu s mmunosuppresson (e.g., n ranspan recpens), and n edery mos common n adus oder an 50 years. I s derved rom angen- persons. In e posranspanaon seng, ese umors oten smuaed B ces and encompasses a eerogeneous group o neopasms begn as EBV-drven poycona B-ce proeraons a may a demonsrae subsana morpoogc, mmunopenoypc, and regress  mmune uncon s resored. genoypc varaon.    Human er pesv rus ty pe 8 (HHV8, aso caed Kapos sarcoma erpesvrus [KSHV]) s assocated w t rare prmar y euson Pathogeness. Among e mos common drver muaons n DLBCL y mphomas, wc may arse wn e peura cavy, percar- are cromosoma ransocaons a ead o e overexpresson o sev- dum, or peroneum. hese umors are aeny neced w era dferen oncogenes, ncudng e oowng: HHV8, wc encodes proens omoogous o severa known  CHAPTER 9 Hematopoietic and Lymphoid Systems 155 Fig. 9.18 Diffuse large B cell lymphoma: lymph node. The tumor cells Fig. 9.19 Burkitt lymphoma: lymph node. The tumor cells and their have large nuclei with open chromatin and prominent nucleoli. (Cour- nuclei are fairly uniform, giving a monotonous appearance. Note the tesy of Dr. Robert W. McKenna, Department of Pathology, University of high level of mitotic activity (arrowheads) and prominent nucleoli. The Texas Southwestern Medical School, Dallas.) “starry sky” pattern produced by interspersed, lightly staining, normal macrophages is better appreciated at a lower magnification. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of oncoproens, ncudng c ycn D1. Mos afeced paens are Texas Southwestern Medical School, Dallas.) mmunosuppressed.    Medastna arge B-ce ympoma occurs mos oten n young e IGH gene on cromosome 14, wc s ranscrponay acve n B women and appears o orgnae rom an unusua popuaon o ces; varan ransocaons nvovng e Ig κ and λ g-can oc on ymc B ces. hs umor requeny as cromosoma amp- cromosomes 2 and 22, respecvey, aso are obser ved. he ne resu caons a ead o e overexpresson o e mmune ceckpon o eac s e same: e dysreguaon and overexpresson o e MYC proens PD-L1 and PD-L2, suggesng a mmune evason pays proen. In mos endemc cases and abou 20% o sporadc cases, e an mporan roe n s paogeness. umor ces are aeny neced w EBV, bu e precse roe a EBV    D oube-t ympoma reers o unusua umors a ave dua rans- pays n e paogeness s unceran. ocaons nvovng MYC and anoer oncogene, mos commony BCL2. he combnaon o a poen progrow oncogene (MYC) Morphology. he umor ces are nermedae n sze and ave and a srong prosur vva oncogene (BCL2) yeds umors a round or ova nuce and wo o ve dsnc nuceo (Fg. 9.19). exb ver y aggressve beavor w subsanay worse oucomes here s a moderae amoun o basopc or ampopc cyopasm an convenona DLBCL. a oten conans sma, pd-ed vacuoes. Ver y g raes o proeraon and apoposs are caracersc, e aer assocaed Clncal Features. Aoug mos common n oder adus, DLB CL can w numerous ssue macropages conanng ngesed nucear occur a any age;  consues abou 15% o cdood ympomas. debrs a creae a “starry sky” pattern. Tumor ces express surace Paens ypcay presen w a rapdy enargng, oten sympomac IgM, e B-ce marker CD20, and germna cener B-ce markers. mass a one or severa ses. Exranoda presenaons are common; e gasronesna rac s e mos common exranoda se, bu DLB CL Clncal Features. Bo e endemc and nonendemc orms afec many can arse n vruay any organ or ssue. Unke e more ndoen ym- cdren and young adus: Burk ympoma accouns or approxmaey pomas (e.g., ocuar ympoma), nvovemen o e ver, speen, 30% o cdood non-Hodgkn ympomas n e Uned Saes. he and bone marrow s uncommon a dagnoss. dsease usuay arses a exranoda ses. Endemc umors oten manes Wou reamen, DLBCL s aggressve and rapdy aa. W as maxary or mandbuar masses, wereas n Nor Amerca, umors nensve combnaon cemoerapy and an-CD20 mmunoerapy, nvovng e bowe, reroperoneum, and ovares are more common. compee remssons are aceved n 60% o 80% o paens; o ese, Burk ympoma s gy aggressve; owever, w very nensve ce- approxmaey 50% reman ree o dsease and appear o be cured. For moerapy regmens, a majory o paens can be cured. oers, oer aggressve reamens (e.g., emaopoec sem ce rans- panaon) ofer ope. Other Neoplasms of Mature Lymphoid Cells Among e many oer orms o ympod neopasa n e Word Burkitt Lymphoma Hea Organzaon casscaon, severa w dsncve or cncay Burkitt lymphoma is associated with translocations involving the mporan eaures are wory o a bre dscusson. MYC gene that result in overexpression of the MYC transcription    Hary ce eukema s an uncommon, ndoen B-ce neopasm w a factor. dsncve morpoogy caracerzed by e presence o ne, arke Burk ympoma s endemc n pars o Arca and occurs sporad- cyopasmc projecons. Vruay a cases are assocaed w drver cay n oer geograpc areas, ncudng e Uned Saes. Hsoogcay, muaons n e serne/reonne knase BRAF, wc acs down- e Arcan and nonendemc dseases are denca, aoug ere are cn- sream o RAS. I occurs many n oder maes, and s manesa- ca and vroogc dferences. he ce o orgn s a germna cener B ce. ons resu rom nraon o e bone marrow and speen, wc s usuay enarged. Pancyopena s seen n more an a o cases. Pathogeness. MYC s a maser reguaor o Warburg meabosm (aer- Scaered “ary ces” can be dened n e perpera bood smear obc gycoyss), a cancer amark assocaed w rapd ce grow n mos cases. he dsease s progressve  unreaed bu s exremey (see Caper 5). Burk ympoma may be e ases-growng uman sensve o ceran cemoerapeuc agens and responds we o umor. Mos ransocaons use e MYC gene on cromosome 8 w BRAF nbors. he overa prognoss s exceen. 156 CHAPTER 9 Hematopoietic and Lymphoid Systems    Mycoss fungodes and Sézary syndrome are umors o neopasc CD4+ T ces a are ound n e skn, and are ence grouped under cua- neous T-ce ympoma. Mycoss ungodes usuay maness as a ras a progresses over me o paques and cuaneous umors, oowed by sysemc dssemnaon. he neopasc T ces ave a cerebrorm appearance produced by marked nodng o e nucear membranes, and ey nrae e upper derms and epderms. Sézary syndrome s caracerzed by a generazed exoave eryroderma and e presence o umor ces (Sézary ces) n e perpera bood. Paens dagnosed w eary-pase mycoss ungodes oten survve or many years, wereas paens w umor-pase dsease, dssemnaed ds- ease, or Sézary syndrome survve on average or 1 o 3 years.   Adut T-ce eukema/ympoma (ATL) s a neopasm o CD4+ T ces caused by a rerovrus, uman T-ce eukema vrus ype 1 (HTLV-1). HTLV-1 necon s endemc n souern Japan, e Carbbean basn, Fig. 9.20 Hodgkin lymphoma: lymph node. A binucleate Reed-Stern- and Wes Arca, and occurs sporadcay esewere, ncudng n e berg cell with large, inclusion-like nucleoli and abundant cytoplasm is soueasern Uned Saes. he roe o e vrus n ympogeness s surrounded by lymphocytes, macrophages, and an eosinophil. (Cour- uncear bu key nvoves ceran vra proens and susaned proer- tesy of Dr. Robert W. McKenna, Department of Pathology, University of aon o neced T ces. Adu T-ce eukema/ympoma s assocaed Texas Southwestern Medical School, Dallas.) w skn esons, ympadenopay, epaospenomegay, ypercace- ma, and varabe ympocyoss. Mos cases are very aggressve and respond poory o reamen. he medan survva me s ony 8 mons.    Perpera T-ce ympoma encompasses a eerogeneous group o umors a make up abou 10% o non-Hodgkn ympomas. In genera, ese are aggressve umors a respond poory o erapy. Moreover, because ese are umors o uncona T ces, paens oten sufer rom sympoms reaed o umor-derved nlammaor y producs, even wen e umor burden s reavey ow. Hodgkin Lymphoma Hodgkin lymphomas are characterized by the presence of distinc- tive tumor giant cells known as Reed-Sternberg cells and variants. Hsorcay, Hodgkn ympoma was consdered apar rom non- Hodgkn ympomas because e dagnosc Reed-Sernberg ces ave a dsncve appearance and comprse ony a sma racon o e ces n e umor. Aoug e Hodgkn ympomas are now undersood o be Fig. 9.21 Hodgkin lymphoma, nodular sclerosis type: lymph node. A umors o B-ce  or  g  n ,  e y con  nu e o be ds  nguse d b e c aus e low-power view shows well-defined bands of pink, acellular collagen o  er unque bo og y and resp ons e o  er apy. that have subdivided the tumor cells into nodules. (Courtesy of Dr. Rob- Fve subypes o Hodgkn ympoma are recognzed: (1) noduar ert W. McKenna, Department of Pathology, University of Texas South- sceross, (2) mxed ceuary, (3) ympocye rc, (4) ympocye western Medical School, Dallas.) depeon, and (5) ympocye predomnan. In e rs our subypes, e Reed-Sernberg ces sare ceran morpoogc and mmunope- noypc eaures (descrbed aer), and as a resu ese are umped Reed-Sernberg varans and e ssue response o ese ces denes ogeer under e rubrc cassc Hodgkn ympoma. e mos common subypes o cassca Hodgkn ympoma:    Noduar sceross Hodgkn ympoma oten nvoves e medas- Pathogeness. A subypes o Hodgkn ympoma are caused by drver num o adoescens or young adus. I s dened by e presence muaons n cancer genes; ese are bes caracerzed n cassc Hodgkn o acunar ces, Reed-Sernberg varans w a snge muo- ympoma. NF-κB, a ranscrpon acor a suppors B-ce survva, s bae nuceus, mupe sma nuceo and abundan, pae-sanng commony upreguaed by varous muaons, and genes encodng PD-L1 cyopasm, and coagen bands, wc dvde nvoved ssues no and PD-L2, wo mmune ceckpon acvaors, are oten amped, wc crcumscrbed nodues (Fg. 9.21). Aso presen are varyng pro- eads o er overexpresson and eps Reed-Sernberg ces evade e os porons o reacve ympocyes, eosnops, and macropages, mmune response. EBV s ound n e Reed-Sernberg ces n as many wc are drawn n by cyoknes produced by Reed-Sernberg as 70% o cases o e mxed-ceuary subype and a smaer racon o ces and sroma ces n nvoved ssues. oer “cassc” orms o Hodgkn ympoma.    Mxed-ceuarty Hodgkn ympoma s mos common n paens oder an 50 years and comprses abou 25% o cases overa. Cassc Reed-Sernberg ces are penu wn a e- Morphology. he sne qua non o cassc Hodgkn ympoma s e erogeneous nlammaor y nrae conanng sma ympo- Reed-Sernberg ce (Fg. 9.20), a very arge ce w an enormous cyes, eosnops, pasma ces, and macropages. muobae nuceus, exceponay promnen ncuson-ke nuceo,    he ympocyte-rc and ympocyte-depeted subypes o cas- and abundan cyopasm. Reed-Sernberg ces and er varans sc Hodgkn ympoma are bo rare. As e names mpy, ey ave a caracersc mmunopenoype: hey express CD15 and are caracerzed by e presence o unusuay promnen or CD30 and do no express CD45 (eukocye common angen), B-ce sparse nraes o reacve sma ympocyes, respecvey. he angens, or T-ce angens. Dferences n e appearance o e  CHAPTER 9 Hematopoietic and Lymphoid Systems 157 he proerang pasma ces ave deeerous efecs on e skeeon, Reed-Sernberg ces and varans resembe ose seen n e e mmune sysem, and e kdney, a o wc conrbue o morbd- mxed ceuary subype. y and moray :    Se apar rom cassca Hodgkn ympoma s e ympo-    S evera acors produced by myeoma ces cause bone resorpon cyte-predomnant subtype, wc accouns or abou 5% o cases. and ead o ypercacema and paoogc racures, mos re- I s dened by e presence o ymposocyc (L&H) varan queny n e spne and emur. Reed-Sernberg ces w a decae muobed, pufy nuceus    Myeoma causes deecs n umora mmuny, ncreasng e rsk resembng popped corn (popcorn ce). L&H varans are ound or bacera necons. wn arge nodues conanng many sma B ces admxed w    Myeoma eads o rena aure owng o (1) obsrucve proen- varabe numbers o macropages. Unke e Reed-Sernberg var- aceous cass comprsed o precpaed Bence-Jones proens; ans n cassc Hodgkn ympoma, L&H varans express B-ce (2) g-can deposon n e gomeru or e nersum, markers (e.g., CD20) and do no express CD15 and CD30. eer as amyod or near deposs; (3) ypercacema, wc eads Regardess o subype, e dagnoss s based on e dencaon o deydraon and rena sones; and (4) requen bous o bacera o Reed-Sernberg ces or varans n e approprae background o pyeoneprs due o deecve umora mmuny. reacve ces. Ces resembng Reed-Sernberg ces may be seen n oer cancers and some reacve condons; us, mmunopenoypng Morphology. Mupe myeoma usuay maness w muoca s oten requred or dagnoss. desrucve skeea esons a mos commony nvove e verebra coumn, rbs, sku, pevs, emur, cavce, and scapua Radoogcay, Clncal Features. Hodgkn ympoma usuay maness as paness e bone esons appear as punced-ou deecs 1 o 4 cm n dameer ympadenopay or, w e noduar sceross subype, sympoms (Fg. 9.22A). he marrow conans ncreased numbers o pasma reaed o e presence o a medasna mass. he sysemc efecs o cyo- ces, ypcay more an 30% o e ceuary (see Fg. 9.22B). Rena knes cause anema o cronc nlammaon, eukocyoss, and so-caed nvovemen (myeoma nepross) s assocaed w proenaceous cass B sympoms (ever, weg oss, ng sweas). Sagng gudes erapy and a obsruc e dsa convoued ubues and e coecng ducs. deermnes e prognoss. Younger paens w more avorabe subypes Oten, epea ces adjacen o e cass become necroc or aropc end o presen w ow-sage dsease and are ree o so-caed B symp- because Bence-Jones proens are oxc. Oer common paoogc oms, wereas paens w more exensve dsease are more key o ave processes nvovng e kdney ncude measac caccaon, g- B sympoms and anema. Ina reamen s w cemoerapy, some- can (AL) amyodoss, and bacera pyeoneprs. mes w nvoved ed radoerapy or arge umor masses. he overa ouook s exceen. he 5-year survva rae or paens w ow-sage dsease s over 90%. Even w wdespread dsease, e overa Clncal Features he dagnoss rees on e deecon o a serum 5-year dsease-ree survva rae s around 50%. Immune ceckpon nb- monocona mmunogobun (a so-caed M proen, or myeoma) ors ave produced exceen responses n paens w reapsed, reracory and/or g eves o ree mmunogobun g cans n e serum dsease and may soon be added o ronne erapeuc regmens. or e urne; e dencaon o a arge number o pasma ces n e marrow ; and e caracersc radoogc ndngs. Hypercacema and Plasma Cell Neoplasms and Related Entities rena aure aso are common a e me o presenaon. he progno- These B-cell proliferations are composed entirely or in part of ss s varabe. Paens w mupe bony esons,  unreaed, rarey plasma cells and virtually always secrete a monoclonal immuno- sur vve or more an 6 o 12 mons, wereas paens w “smoder- globulin or immunoglobulin fragments. ng myeoma” may be asympomac or many years. Coecvey, pasma ce neopasms and reaed dsorders accoun Aoug cures ave ye o be aceved, severa receny deve- or abou 15% o e deas caused by ympod neopasms. he mos oped erapes ave mproved oucomes. Msoded mmunogobun mporan o ese neopasms, mupe myeoma, s dscussed nex. cans accumuae n myeoma ces and cause ce sress by acva- ng e unoded proen response (see Caper 1). Inbors o e Multiple Myeloma proeasome, a ceuar organee a dsposes o msoded proens, Mupe myeoma s one o e mos common emaoogc magnances: nduce apoposs o myeoma ces and are efecve erapes. he Approxmaey 20,000 new cases are dagnosed n e Uned Saes eac adomde-ke compound enadomde aso as acvy agans year. he medan age a dagnoss s 70 years. I s more common n maes myeoma because o s aby o acvae ceran ubqun gases, and n peope o Arcan orgn. I prncpay nvoves e marrow and wc ag proens w ubqun, ereby markng em or pro- usuay s assocaed w yc esons rougou e skeea sysem. easoma degradaon. Bsposponaes, dr ugs a nb bone he mos requen mmunogobun produced by myeoma ces s resorpon, reduce paoogc  racures and m ypercacema. IgG (60%), oowed by IgA (20% o 25%); n e remanng 15% o 20% Hemaopoec sem ce ranspanaon proongs e bu as no ye o cases, e pasma ces produce ony κ or λ mmunogobun g proven o be curave. Tras o CAR-T ces a recognze pasma ce cans. Ony rarey are IgM, IgD, or IgE produced. Even n myeomas angens are ongong. a produce compee mmunogobuns, mmunogobun g cans are oten syneszed n excess o mmunogobun eavy cans, resu- Other Plasma Cell Neoplasms and Related Entities ng n ree, unpared g cans. Once secreed, e sma ree g A ese umors are assocaed w e producon o monocona cans are excreed n e urne as Bence-Jones protens. As descrbed n mmunogobuns, markng em as cona proeraons o anbody- e oowng, ree g cans ave mporan paoogc efecs. producng B ympocyes or pasma ces. hree umors n s group mer dscusson.    Monocona gammopaty of undetermned sgnicance (MGUS) s seen Morphology. Myeoma oten as cromosoma ransocaons a n paens wou sgns or sympoms wo ave monocona mmu- use e IGH ocus on cromosome 14 o proo-oncogenes suc as nogobuns n er bood. MGUS s very common n oder adus, and e cycn D1 gene. A wde varey o oer drver muaons ave abou 1% o cases ransorm no a sympomac neopasm, mos oten been descrbed. Proeraon o myeoma ces s suppored by e mupe myeoma, eac year. cyokne nereukn 6 (IL-6). 158 CHAPTER 9 Hematopoietic and Lymphoid Systems as ver y rare socyc sarcomas, are gy magnan neopasms, wereas oers are bengn reacve yperpasas. Beween ese wo exremes e a group o umors comprsed o Langerans ces, e Langerans ce stocytoses, wc mer a bre descrpon. Pathogeness. A orms o Langerans ce socyoss are assocaed w drver muaons a acvae e serne/reonne knase BRAF. BRAF s a componen o e RAS sgnang paway a suppors ceuar proera- on and survva. Tumors wou BRAF muaons oten ave muaons n a dferen serne/reonne knase caed MAP2K1 a acs down- sream o BRAF, urer mpcang s paway n e paogeness. Morphology. Proerang Langerans ces ave abundan cyopasm and vescuar nuce, smar o a o ssue macropages (aso known as socyes); ence, e erm stocytoss. Numerous reacve eosnops are oten admxed. Langerans ces express a unque proen caed angern and can be dened by sanng or angern and CD1a. Clncal Features. Langerans ce socyoss can be grouped no severa cncopaoogc enes.   he mos common subype s unfoca unsystem dsease, n wc e A proeraon s conned o a snge se n a snge organ sysem, mos commony bone bu aso sot ssues suc as e ung, skn, or gu. I may be asympomac or cause pan, enderness, and paoogc racures. I s ndoen and s cured by oca excson or rradaon.    Mutfoca unsystem dsease usuay afecs cdren and ypcay maness w mupe erosve bony masses. In abou 50% o cases, nvovemen o e poseror puar y sak o e ypoaamus eads o dabees nspdus. he combnaon o cavara bone deecs, dabees nspdus, and exopamos s reerred o as e Hand-Scüer-Crstan trad. Some paens experence spona- neous regressons; oers are reaed efecvey w cemoerapy.   Mutsystem dsease (Letterer-Swe dsease) s an aggressve dsorder a usuay occurs n cdren younger an 2 years o age. I oten maness w cuaneous esons a mmc seborrec skn erup- ons and requeny eads o epaospenomegay, ympadenopay, B pumonary