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This chapter from Robbins Essential Pathology discusses neoplasia, focusing on the cellular and molecular mechanisms of tumor growth, angiogenesis, and evasion of apoptosis. It details the crucial role of growth factors, radiation, chemicals, DNA damage, and mutation of p53 in the development of neoplasia.
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80 CHAPTER 5 Neoplasia Lke norma ssues, umors requre dever y o oxygen and nurens...
80 CHAPTER 5 Neoplasia Lke norma ssues, umors requre dever y o oxygen and nurens Deficiency of ROS and remova o wase producs. Tumors are ony abe o grow o a sze growth factors Radiation and survival o 1 o 2 mm n e absence o angogeness, presumaby because s Chemicals signals sze represens e maxma dsance across wc oxygen, nurens, and wase can dfuse rom preexsng bood vesses. For neopasms o grow beyond s sze m, ey ave o smuae neoangogeness, n wc vesses sprou rom prevousy exsng capares. Neovascuar- zaon as a dua efec on umor grow: Peruson suppes needed DNA nurens and oxygen, and newy ormed endoea ces smuae e damage grow o adjacen umor ces by secreng grow acors. Aoug e resung umor vascuaure s efecve a deverng nurens and Mutation of p53 removng wases, s no norma: he vesses are eaky and daed w Overexpression p53 response of MDM2 a apazard paern o connecon. Invasve umor ces may ready penerae ese vesses, conrbung o measass. Activation of BAX/BAK various Tumor angogeness may be s muaed by proangogenc ac ors sensors a are pro duced by e umor ces, nlammaor y ces (e.g., mac- BCL-2 ropages), and o er resden s roma ces (e.g., umor-ass o caed BCL-XL brobass). Proe as es eab oraed by e umor ces or by s roma MCL-1 Mitochondria ces may as o ree as e p ep des w angogenc ac vy rom e exraceuar mar x. In u-bown cancers, e proangogenc s ae s ur er renorced by s e vera o er a era ons a ncre as e e ves Cytochrome c APAF-1 o vas c uar endo ea grow ac or (VEGF), a ke y proangogenc c yokne. Mos no aby, ssue yp oxa s abzes yp oxa-nduced ac or (HIF), an oxygen-s ens ve rans cr p on ac or a drec y IAP Caspase 9 upreguaes VEGF expresson. hs cre aes an angogenc g raden a smuaes e proera on o endo ea ces and gudes e Caspase 3 grow o ne w vess es oward e umor. Mu a ons nvovng umor suppress ors oten e baance o avor angogeness. For exampe, p53 repress es e expresson o VEGF and s muaes e expres- Apoptosis son o anangogenc moec ues. hus, oss o p53 n umor ces Fig. 5.21 Intrinsic pathway of apoptosis and mechanisms used by provdes a more p er mssve envronmen or angogeness. Grow tumor cells to evade cell death. Evasion mechanisms in tumor cells ac or–recepor sgnang and MYC as o s muae e expresson o are in red and include: (1) Loss of p53, leading to reduced function of VEGF. proapoptotic factors such as BAX. (2) Reduced egress of cytochrome Te dep endence o umors on ang ogeness c an be e x poe d c from mitochondria as a result of upregulation of antiapoptotic factors erap eu c a y. Te proo y p e an ang o genes s dr ug , b e vac zumab, such as BCL2, BCL-XL, and MCL-1. (3) Loss of apoptotic peptidase-acti- s an an b o dy a neu ra ze s VE GF and s approve d or e re a - vating factor 1 (APAF1). (4) Upregulation of inhibitors of apoptosis (IAP). men o mu pe c ancers. Howe ver, ang o ge nes s n bors ave no b e en as e e c ve as or g na y op e d; presumaby, sub cones o As dscussed prevousy n e conex o ceuar agng (see Caper umor ce s w g re aer nvasve c ap ac y and e ab y o mg rae 1), mos norma uman ces can doube 60 o 70 mes, ater wc e o exs ng bo o d vess es eme rge, ereby s d esepp ng e ne e d or ces ose e aby o dvde and ener senescence. hs penomenon s ne o ang ogeness. due o progressve sorenng o teomeres a e ends o cromosomes. he consequences o eomere sorenng, wen pronounced, Invasion and Metastasis are drasc. Sor eomeres are recognzed as doube-sranded DNA Invasion and metastasis result from complex interactions involv- breaks by e ce’s DNA damage “sensors, ” eadng o p53-medaed ing cancer cells, stromal cells, and the extracellular matrix. ce c yce arres and apoposs or senescence Even n ces w TP53 Mos sudes peran o carcnomas, wc are our ocus ere. For muaons, aemps o repar e damage roug oer DNA repar e purpose o dscusson, nvason and measass can be broken down paways eads o cromosome nsaby, wc evenuay eads o no a successve sequence o evens, dscussed nex. ce dea. I, owever, e ce reacvaes e enzyme eomerase (a specazed RNA-proen compex a uses s own RNA as a em- Invasion of the Extracellular Matrix pae or addng nuceodes o e ends o cromosomes), ce dea Tssues are organzed no comparmens separaed rom eac oer may be avered. by wo ypes o exraceuar marx (ECM), basemen membranes and Teomerase s acve n norma sem ces and s absen rom, or nersa connecve ssue, eac composed o coagens, gycopro- presen a ver y ow eves n, mos somac ces. In 85% o 95% o can- ens, and proeogycans (see Caper 2). Tumor ces nerac w e cers, eomere manenance s due o upreguaon o eomerase. he ECM a severa sages n e measac cascade (Fg. 5.22). A carc- remanng umors a o express eomerase and use anoer meca- noma ce mus rs breac e underyng basemen membrane, en nsm ermed aternatve engtenng of teomeres a depends on DNA raverse e nersa connecve ssue, and umaey gan access o recombnaon o manan eomeres. e crcuaon by penerang e vascuar basemen membrane. hs process s repeaed n reverse wen umor ces exravasae a dsan Sustained Angiogenesis ses. Invason o e ECM naes e measac cascade and s an In order to grow, solid tumors develop their own blood supply by acve process a can be resoved no severa sequena seps, as inducing angiogenesis. oows: CHAPTER 5 Neoplasia 81 metaoproteases (MMPs) produced by umor ces or sroma ces Transformed (e.g., brobass and nlammaor y ces) reacng o e umor. he cell PRIMARY Clonal expansion, eves o meaoproease nbors aso are reduced n carcnomas, TUMOR growth, diversification, urer ng e baance oward ssue degradaon. angiogenesis Locomoton, e na sep o nvason, propes umor ces roug e degraded basemen membranes and zones o marx proeo- yss. Suc movemen may be poenaed and dreced by umor Metastatic subclone ce–derved cemoknes. In addon, ceavage producs o marx Basement componens (e.g., coagen, amnn) and some grow acors ave membrane Adhesion to and cemoacc acvy or umor ces, and sroma ces aso produce invasion of basement paracrne efecors o ce moy. membrane Vascular Dissemination and Homing of Tumor Cells Passage through Tumor ces requeny escape er ses o orgn and ener e crcua- extracellular matrix on roug bood vesses or ympacs. Mons o umor ces are sed Intravasation day rom even sma cancers. Severa acors seem o m e mea- sac poena o crcuang umor ces: We n e crcuaon, umor ces are vunerabe o desrucon by os mmune ces, and e process o adeson o vascuar beds and nvason o norma ssues may be more dicu an e na nvason. Even oowng exravasaon, umor Interaction with host lymphoid cells ces a grow we n er prmary se may ack crca sroma suppor or be suppressed by resden mmune ces. Despe ese mng acors, Host negeced, vruay a magnan umors w evenuay produce mac- lymphocyte roscopc measases. The sites of metastases are related to two factors: the anatomic Platelets Tumor cell location and vascular or lymphatic drainage of the primary tumor, embolus and the tropism of particular tumors for specic tissues. Extracellular Mos measases arse n e rs capar y bed avaabe o e umor, matrix bu naura paways o dranage canno woy expan e dsrbu- Adhesion to on o measases. As menoned earer, or exampe, ung carcnoma basement membrane as a g procvy or spread o e adrena gands and e bran, and meanoma o e eye amos aways spreads o e ver. Suc organ ropsm may be reaed o e expresson o ssue-seecve adeson Extravasation moecues, e producon o specc cemoknes n dferen ssues or wc umor ces express recepors, and e presence o sroma Metastatic ces a suppor e grow o umors. A o ese acors make d- deposit eren ssues avorabe or unavorabe “so” or dferen umors. Metastasis Angiogenesis Tumors vary greay n er aby o measasze, n par because o METASTATIC neren dferences n beavor. In genera, arge umors are more key TUMOR o measasze an sma umors, presumaby because arge umors are Growth ypcay presen n e paen or onger perods o me, provdng add- ona cances or measass o occur. However, umor sze and ype can- no adequaey expan e beavor o ndvdua cancers, and s s open o queson weer measass s probabsc (a maer o cance muped by umor ce number and me) or deermnsc (relecng neren dferences n measac poena rom umor o umor). Fig. 5.22 The metastatic cascade: The sequential steps involved in the Evasion of Immune Surveillance hematogenous spread of a tumor. The host immune system is capable of destroying tumors, but can- cers evolve to evade or inhibit immune responses. L oos enng of nterceuar connec tons between tumor ce s. C ar- Tumor ces can be recognzed as “oregn” and emnaed by e cnoma ce s are nor ma y ed oge er by ad eson proens, mmune sysem; mmune surveance reers o e roe o e mmune suc as E-c ad er n. E-c ad er n unc on s o en os n me a - sysem n consany “scannng” e body or emergng magnan ces s a c c arcnomas due o e er deeer ous mu a ons n E-c ad- and desroyng em. Tumor-specc T ces and anbodes are ound er n or s encng o E-c ad er n expresson. L oss o E-c ad er n n many paens, and e exen and quay o mmune nraes n s ass o c ae d w canges n ce sap e, ncre as e d ce mo y, cancers s oten correaed w e cnca oucome (e.g., coon can- and upregu a on o genes a are more ypc a o mes ency ma cer). here s an ncreased ncdence o ceran cancers n mmuno- ce s (e.g., brob ass). Tes e canges are reer re d o as ep e- decency saes. Receny, erapeuc agens a ac by smuang a -mes ency ma rans on (EMT). aen os T-ce responses (descrbed aer) ave sown efecveness Loca degradaton of te basement membrane and nterstta n some advanced cancers. connectve tssue by proeoyc enzymes, parcuary matrx 82 CHAPTER 5 Neoplasia Because e mmune sysem s capabe o recognzng and em- angens. he presence o uncona CD8+ T ces s predcve o e nang nascen cancers, cancer sur vva requres a e umor ces be oucome o many cancers, and quancaon o e mmune ce n- nvsbe o e os mmune sysem or acvey suppress os mmu- rae (e mmunoscore) as some predcve vaue. he sgncance o ny. hs undersandng as ed o a modern revouon n cancer oer kng mecansms (e.g., macropages and NK ces) s uncear. mmunoerapy. Immune Escape Tumor Antigens Tumor cells evade the immune system either by being invisible to The major antigens of tumors that elicit immune responses are lymphoid cells or by hijacking inhibitory pathways designed for the products of mutated genes that produce neoantigens with regulation of immunity. MHC-binding mutated sequences. Severa mecansms o mmune evason ave been descrbed and Because ese angens are nove and are no presen normay, ey ave erapeuc vaue (Fg. 5.23): are seen as oregn by e os’s mmune sysem. Lke a cyosoc pro- Antgen oss varants. As umor subcones evove, ey end o eer ens, ese angens are processed and dspayed as cass I MHC-as- ose expresson o e angens a are arges o os mmuny or, socaed pepdes o CD8+ T ces. Some umor angens are no e more oten, ose expresson o cass I MHC moecues or compo- producs o muaed genes bu are expressed n cancer ces a muc nens o angen-processng paways, prevenng e presenaon ger eves an n norma ces (e.g., yrosnase n meanomas), o angens o T ces. and oers are normay expressed eary n deveopmen, repressed n Inbton of T ces usng ceckpont receptors. he wo bes-known maure ces, and derepressed n cancer ces (e.g., e so-caed cancer– recepors a mpose “ceckpons” n T-ce acvaon are PD-1 ess angens). Many oer angens ave been dened n umors and CTLA-4. Wen PD-1 and CTLA-4 expressed on CD8+ T ces because o er recognon by anbodes, bu mos o ese are aso engage er gands, e acvaon and uncon o ese ces are presen n norma ces and ey are neer nducers nor arges o nbed. hese ceckpons evoved o preven mmune responses anumor mmuny. agans se-angens and are “jacked” by umor ces o sence CD8+ T ces. PD-1 s engaged n umors because umor ces oten Immune Mechanisms of Tumor Destruction express e gands or ese recepors (PDL-1 and PDL-2) or nduce he mos mporan mecansm o umor emnaon s e kng o expresson o PDL-1 and PDL-2 on oer ces n e mmune n- umor ces by CD8+ cyooxc T ympocyes (CTLs) specc or umor rae. Bockng eer PD-1 or CTLA-4 w anbodes eads o Dendritic Dendritic cell cell Tumor peptide-MHC Tumor peptide-MHC Primed CTL capable CD28 of killing tumor cells TCR TCR CD28 B7 B7 CTLA-4 CTLA-4 CD8+ CD8+ CTL T cell T cell Anti- CTLA-4 A Lymph node NO COSTIMULATION COSTIMULATION Inhibited Activated CD8+ CD8+ Cytotoxic CTL CTL granules CTL CTL TCR TCR Peptide-MHC Peptide- PD-1 MHC PD-1 ligand Anti-PD-1 Killing of tumor cell Tumor Tumor cell cell Anti-PD-1 ligand B Tumor tissue Fig. 5.23 Activ ation of hos t a n titu m o r im m un i t y by c h e c k p oi n t in h i b i t or s. (A ) B l o c k a de of the C TL A - 4 surfac e m olecule with inh ib ito ry a nt i b od y a ll o w s cytolytic C D8 + T c el l s ( CT L s ) to en ga g e B7 f a mi l y co-re- ceptors, lea ding to T c ell a c t iv a tio n. (B ) B l o c k ad e of P D -1 re c e pt or or P D -1 ligand a br og a t e s i n h i b i t or y signals trans mitte d by PD- 1, again le a d i n g to activation of CTLs. ( Re p r i n t e d from A b ba s AK, Lichtman AH, Pilla i S: Cellular and mole c u la r im m u n o log y , ed 7, Phila delphia , 2012, Sa u n de r s.) CHAPTER 5 Neoplasia 83 e regresson o many umors, ncudng meanoma, non–sma nuceode excson repar sysem, wc s deecve n paens w s ce ung cancer, badder cancer, Hodgkn ympoma, and oers. dsease. he rae o somac muaon n sun-exposed skn s greay acce- hs approac, caed ceckpon bockade, s now an mporan eraed, resung n an exraordnary g ncdence o skn cancers suc componen o ancancer erapy. B ecause e ceckpons evoved as basa ce carcnoma and squamous ce carcnoma n ese paens. normay o preven auommuny, paens gven ese reamens Diseases with Defects in DNA Repair by Homologous oten deveop auommune nlammaon, ncudng cos, as we as nlammaon o e endocrne organs, ear, and oer ssues. Recombination Oter mecansms by wc umors nb mmune responses he auosoma recessve dsorders Boom sy ndrome, ataxa-teang- ncude nducon o reguaor y T ces and e oca producon o ectasa, and Fancon anema are caracerzed by ypersensvy o mmunosuppressve cyoknes suc as TGF- DNA-damagng agens, suc as onzng radaon (n Boom syn- drome and aaxa-eangecasa) or DNA cross-nkng agens suc Genomic Instability as an Enabler of Malignancy as nrogen musard (n Fancon anema). E ac s caused by deecs Defects in DNA repair pathways enable tumor growth by allowing n genes a are requred or DNA repar by omoogous recomb- accumulation of mutations in cancer genes. naon, n wc a “good” srand o DNA s used o repar a damaged he precedng secon dened e eg denng eaures o pece o DNA a as been broken or covaeny cross-nked. he magnancy, a o wc appear o be produced by genec aeraons penoypes o ese dseases are compex and ncude, n addon nvovng cancer genes. Aoug umans are awas n envronmen- o a predsposon o cancer, neura sympoms (n aaxa-eangec- a muagens, cancers are reavey rare oucomes o ese encouners asa), anema (n Fancon anema), and deveopmena deecs (n because norma ces are abe o sense and repar DNA damage. he Boom syndrome). mporance o DNA repar n mananng e negry o e genome Evdence o e oncogenc roe o deecve omoogous recomb- s gged by persons born w nered deecs n ree ypes o naon aso comes rom e sudy o eredar y breas cancer. Germne DNA repar sysems (msmac repar, nuceode excson repar, and muaons n wo genes a aso uncon n omoogous recombna- recombnaon repar), a o wc are assocaed w an ncreased rsk on, BRCA1 and BRCA2, are ound n 50% o ama breas cancers. or deveopng cancer. Aoug e dscusson beow ocuses on ese In addon o breas cancer, women w BRCA1 muaons ave a nered syndromes, sporadc cancers oten ncur muaons n DNA subsanay ger rsk o ovaran carcnoma and men ave a sgy repar genes, as we. Presumaby, as n ndvduas w nered DNA ger rsk o prosae cancer ; germne muaons n BRCA2 ncrease repar deecs, ese somac muaons speed e accumuaon o drver e rsk o breas cancer n bo men and women, as we as oer car- muaons n cancer genes and ereby e deveopmen o cancer. cnomas, meanoma, and ympomas. Smar o oer umor suppres- sor genes, bo copes o BRCA1 and BRCA2 mus be nacvaed or Hereditary Nonpolyposis Colon Cancer Syndrome cancer o deveop. he roe o DNA msmac repar genes n e predsposon o cancer Tumor-Promoting Inflammation as an Enabler s usraed by e eredtary nonpoyposs coon cancer (HNPCC) syn- drome, a dsorder caracerzed by ama carcnoma o e coon. Wen of Malignancy Inammatory cells can facilitate tumor cell growth and survival by a srand o DNA s beng repared, e proens encoded by ese genes producing soluble factors that inuence the hallmarks of cancer. ac as “spe ceckers. ” For exampe, ere s an erroneous parng o G Inrang cancers provoke a cronc nlammaor y reacon. In w T, raer an e norma A w T, e msmac repar proens paens w advanced cancers, s nlammaor y reacon can be so correc e deec. Wou ese “prooreaders, ” errors accumuae a an exensve as o cause sysemc sgns and sympoms, suc as anema ncreased rae. Muaons n a eas our msmac repar genes ave been (e anema o cronc nlammaon), ague, and cacexa. Anma ound n paens w HNPCC. One deecve copy o a DNA msmac modes sugges a nlammaor y ces aso mody e umor mcro- repar gene s nered, and a second “” n e oer aee o e same envronmen o enabe many o e amarks o cancer. hese efecs gene occurs n coonc epea ces. In s respec, ey resembe umor may sem rom drec neracons beween nlammaor y ces and suppressor genes. DNA repar genes afec ce grow ndrecy by aow- umor ces, or ndrec efecs o nlammaor y ces on oer resden ng muaons n oer genes durng e process o norma ce dvson. sroma ces, parcuary cancer-assocaed brobass and endoe- A caracersc ndng n e genome o paens w msmac repar a ces. Inlammaor y ces and resden sroma ces may promoe deecs s mcrosaee nsaby (MSI). Mcrosaees are andem cancer deveopmen by producng grow acors a ac on e neo- repeas o one o sx nuceodes ound rougou e genome. Usuay, pasc ces, promong angogeness, acvang ce sur vva paways e eng o ese mcrosaees remans consan. However, n paens n umors, producng enzymes a enance oca umor nvason and w HNPCC, ese saees are unsabe and ncrease or decrease n measass, and suppressng efecve anumor mmune responses. In eng. HNPCC syndrome accouns or ony 2% o 4% o a coonc can- s respec, ey resembe umor suppressor genes. cers, bu MSI can be deeced n abou 15% o sporadc cancers. MSI-asso- hese paopysoogc conceps ave provded a road map or caed umors end o be more responsve o mmune ceckpon nbor e deveopmen o new erapeuc agens or e reamen o can- erapes, presumaby because e deec n msmac repar eads o a cer (Fg. 5.24). As our undersandng o cancer paogeness expands, g burden o muaons producng umor neoangens. In ac, s ype ere s reason o ope a e nex ew years w see e deveopmen o mmunoerapy s now approved or a recurren umors w ms- o many more efecve argeed erapes. mac repar deecs regardess o e umor ype—e rs me a rea- men as been approved based ony on a muaona sgnaure. CLINICAL ASPECTS OF NEOPLASIA Xeroderma Pigmentosum Umaey, e mporance o cancer s s mpac on paens. he o- Paens w e auosoma recessve dsorder xeroderma pgmentosum owng dscusson consders e efecs o umors on er oss, e are a ncreased rsk or cancers arsng n sun-exposed skn. Uravoe gradng and cnca sagng o cancer, and e aboraor y dagnoss o (UV) rays n sung cause cross-nkng o pyrmdne resdues, pre- neopasms. venng norma DNA repcaon. Suc DNA damage s repared by e 84 CHAPTER 5 Neoplasia Checkpoint inhibitors Avoiding immune Evading growth Reactivation of p53 Anti-CTLA-4, anti-PD-1/PD-L1 destruction suppressors MDM2 inhibitors Sustaining Enabling EGFR proliferative replicative inhibitors signaling immortality Deregulating Tumor- cellular promoting energetics inflammation Activating Resisting BCL2 inhibitors invasion and cell death metastasis Inhibitors of Inducing Genome PARP inhibitors VEGF signaling angiogenesis instability and mutation Fig. 5.24 Therapeutic targeting of hallmarks of cancer. Therapies approved for use or in advanced clinical trials are listed. (From Hanahan D, Weiberg RA: The hallmarks of cancer: the next generation. Cell 144:646, 2011.) Clinical Effects of Tumors o e umor or by e eaboraon o ormones ndgenous o e ssue Benign and malignant tumors may cause local and systemic prob- o orgn o e umor hey appear n 10% o 15% o cancer paens, lems through a variety of direct and indirect effects. and er cnca recognon s mporan or severa reasons: Anaomc ocaon s a cruca deermnan o e oca, “space-- hey may be e eares manesaon o an occu neopasm ng” efecs o bo bengn and magnan umors. A sma (1-cm) hey may be severe and, n some nsances, may even be ea puar y adenoma can compress and desroy e surroundng norma hey may mmc measac dsease, ereby conoundng rea- gand, gvng rse o ypopuarsm, and a comparaby sma carc- men pannng noma wn e common be duc may nduce aa bar y rac Paraneopasc syndromes are dverse and are assocaed w many obsrucon. Oer mporan oca compcaons ncude spna cord dferen umors (Tabe 5.7). One umor may nduce severa syndromes compresson and paoogc racures due o srucura compromse o concurreny : Broncogenc carcnomas may eaborae producs den- bones by magnan umors. ca o or avng e efecs o ACTH, andurec ormone, paray- L o ca y nvasve cancers may u cerae roug a sur ace, w rod ormone, seroonn, uman coronc gonadoropn, and oer cons e quen be e dng or s e condar y ne c on Eroson no maj or ves- boacve subsances. he oowng are e mos common paraneo- s es or e e ar can e ad o ca as ropc be e dng, a or unaey rare pasc syndromes: e ven. More common y, s e condar y ne c on o non e a ng wounds Hypercacema n cancer paens s mos oten caused by e syn- may be due o ner erence o nor ma rep ar me cansms by ma g- ess o a parayrod ormone–reaed proen (PTHrP) by umor nan ce s. ces. Sgns and sympoms reaed o ormone producon are common Cusng syndrome, usuay reaed o producon o ACTH or w bengn and magnan neopasms arsng n endocrne gands. ACTH-ke ormones by cancer ces, s mos commony seen w Tumors arsng n e β ces o e pancreac ses o Langerans can sma ce carcnoma o e ung. produce ypernsunsm, and umors o e adrena corex may eabo- Hypercoaguabty, eadng o venous romboss and nonbace- rae a varey o serod ormones (e.g., adoserone, eadng o sodum ra romboc endocards, s prmary reaed o canges a reenon, yperenson, and ypokaema). enance e acvy o coaguaon acors (raer an paees). Many cancer p a ens sufer rom tumor cacexa, w c s Suspeced conrbuors ncude canges n endoea uncon marke d by prog ressve oss o b o dy a and skee a mus ce accomp a- reaed o e pronlammaor y efecs o cancer, and subsances ne d by proound we a kness and anorexa Tumor cacexa s caus e d reeased rom umor ces (suc as mucns) a drecy acvae e no by e nu r ona demands o e umor bu by an ncre as e n coaguaon cascade. crc u a ng ac ors a suppress e app e e and caus e canges n Grading and Staging of Cancer e me ab osm o ssues, suc as a and skee a mus ce. C a or e exp endure remans g and e b as a me ab oc rae s ncre as e d, Grading and staging are used to estimate the probable clinical despe re duce d o o d n a ke. hes e me ab oc abnor ma es are aggressiveness of a given neoplasm and to provide a standard p ar y a r bue d o e ac ons o e c yokne umor ne cross ac- that is used when comparing the outcomes of different treatment or (TNF), pro duce d by ac vae d macropages or by umor ce s protocols. ems eves, w c suppress es e app e e and n bs e ac on he sage o e cancer (ow exensve s n e paen) s assessed o p oproen p as e, pre ven ng e ree as e o re e ay acds rom many by cnca and radoogc sudes, wereas gradng s done by p oproens. paoogc examnaon usng eaures a are descrbed beow. In gen- Paraneopastc syndromes are sympom compexes a occur n era, aoug bo are useu, e umor sage s o greaer prognosc paens w cancer a canno be expaned by oca or dsan spread vaue an e umor grade. CHAPTER 5 Neoplasia 85 Table 5.7 Paraneoplastic Syndromes Clinical Syndrome Associated Neoplasms Causal Mechanism(s)/Agent(s) Endocrinopathies Cushing syndrome Small cell lung carcinoma ACTH or ACTH-like substance Pancreatic carcinoma Neural tumors Syndrome of inappropriate antidiuretic hor- Small cell lung carcinoma Antidiuretic hormone or atrial natriuretic mone secretion (SIADH) Intracranial neoplasms hormones Hypercalcemia Squamous cell lung carcinoma Parathyroid hormone–related protein, TGF- α, Breast carcinoma TNF, IL-1 Renal cell carcinoma Adult T-cell leukemia/lymphoma Hypoglycemia Fibrosarcoma Insulin or insulin-like substances Other mesenchymal sarcomas Ovarian carcinoma Nerve and Muscle Syndromes Myasthenia Lung carcinoma Immunologic Thymoma Disorders of the central and peripheral ner- Breast carcinoma Immunologic vous systems Teratoma Dermatologic Disorders Acanthosis nigricans Gastric carcinoma Immunologic; secretion of epidermal growth Lung carcinoma factor Uterine carcinoma Dermatomyositis Lung carcinoma Immunologic Breast carcinoma Osseous, Articular, and Soft Tissue Changes Hypertrophic osteoarthropathy and clubbing Lung carcinoma Unknown of the fingers Vascular and Hematologic Changes Venous thrombosis (Trousseau phenomenon) Pancreatic carcinoma Hypercoagulability due to secreted tumor Lung carcinoma products (e.g., mucins) that activate clotting Other cancers factors Red cell aplasia Thymoma Immunologic Polycythemia
