Robbins Essential Pathology PDF - Neoplasia

68 CHAPTER 5 Neoplasia A B Fig. 5.9 Fibroadenoma of the breast. (A) The ta...

68 CHAPTER 5 Neoplasia A B Fig. 5.9 Fibroadenoma of the breast. (A) The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue. (B) Microscopic appearance. The fibrous capsule (right) sharply delimits the tumor from the surrounding tissue. (B, Courtesy Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas.) A B Fig. 5.10 Invasive ductal carcinoma of the breast. (A) The lesion infiltrates the surrounding breast substance, causing tissue retraction, and is stony-hard on palpation. (B) Microscopic view illustrates the invasion of breast stroma and fat by nests and cords of tumor cells. (B, Courtesy Dr. Trace Worrell, Department of Pathol- ogy, University of Texas Southwestern Medical School, Dallas.) Local Invasion Metastasis Next to the development of metastases, invasiveness is the feature Metastasis is dened by the spread of a tumor to sites that are that most reliably distinguishes cancers from benign tumors. physically discontinuous with the primary tumor and the ability As bengn umors sowy grow and expand, mos deveop a rm o to metastasize marks a tumor as malignant. brous ssue caed a capsue (Fg. 5.9). he capsue s ormed by depo- he nvasveness o cancer ces perms em o penerae no son o coagen by sroma ces, suc as brobass. Bengn encap- bood vesses, ympac cannes, and body caves, provdng oppor- suaed umors are dscree, movabe (nonxed), and usuay easy o unes or spread (Fg. 5.11). Approxmaey 30% o paens w excse. Invasve cancers can aso nduce a sroma response assocaed newy dagnosed magnan sod umors (excudng skn cancers oer w bross, and sowy growng magnan umors on gross nspec- an meanomas) ave cncay evden measases, and an addona on may appear o be encapsuaed. However, cancers, even ose a 20% ave occu (dden) measases a e me o dagnoss. In gen- appear o be crcumscrbed, ack rue capsues and progressvey nvade, era, arge, anapasc cancers are more key o measasze, bu even nrae, and desroy surroundng ssues (Fg. 5.10). hs nrave sma prmar y umors may be assocaed w measac dsease. Cer- grow necessaes remova o a wde margn o surroundng “norma” an cancers, suc as basa ce carcnoma o e skn and mos prmar y ssue wen surgca excson o a magnan umor s aemped. hese umors o e cenra ner vous sysem, are ocay aggressve bu meas- dsngusng eaures are no absoue: Some bengn umors (e.g., asze ony rarey. hus, e aby o nvade s no aways predcve o emangomas) ack capsues and are no dscreey dened. measac poena.  CHAPTER 5 Neoplasia 69 MOLECULAR BASIS OF NEOPLASIA Cancer Genes and “Driver” Mutations All forms of neoplasia stem from mutations that alter the function of genes that regulate the behavior of normal cells. hus, n essence, cancer s a genec dsease. Genes a are recur- reny muaed or dysreguaed n cancer ces can be reerred o as can- cer genes. hese number n e undreds and are no ony numerous bu oten ave unpronounceabe acronyms or names a are dicu o remember, even or e exper. One way o smpy s compexy s o consder a cancer genes a no our major uncona casses:    O ncogenes are genes a wen overexpressed or muaed pro- moe ncreased ce grow. her norma ceuar counerpars are caed protooncogenes. Mos oncogenes encode ranscrpon acors or sgnang moecues a parcpae n progrow pa- Fig. 5.11 A liver studded with metastatic cancer. ways. hey are consdered domnan genes because a muaon nvovng a snge aee s suicen o produce a prooncogenc efec. Magnances o e bood (eukemas and ympomas) are a spe-    Tumor suppressor genes are genes a normay preven uncon- ca crcumsance: hese umors are derved rom bood-ormng ces roed grow; e uncon o suc genes s os n neopasms due a crcuae roug e boodsream and mgrae o dsan ssues. o dsrupve muaons or epgenec sencng (gene represson). In hereore, w ony rare excepons, eukemas and ympomas are mos nsances, e uncon o bo aees o a umor suppressor dssemnaed dseases a dagnoss and are aways consdered o be gene mus be os o aow unreguaed ce grow. magnan.    G enes tat reg uate apoptos s pr mar  y ac  by en anc ng ce  Magnan neopasms spread by one o ree paways: sur v va , ra er  an by s  mu  a  ng pro era  on p er s e. G e ne s    S eedng wtn body cavtes. hs mode o dssemnaon s par-  a proe c  agans ap opo s s are o e n overex pre ss e d n c anc e r cuary caracersc o ovaran carcnomas, wc oten spread ce s, w ere as  os e  a promoe ap opo ss end o be und ere x- aong peronea suraces, and ceran neopasms o e cenra press e d. ner vous sysem (e.g., meduobasoma, ependymoma) a may    Genes tat reguate nteractons between tumor ces and ost ces ener e cerebra venrces, rave roug e cerebrospna lud, aso are recurreny muaed or unconay aered n ceran can- and mpan on menngea suraces adjacen o e bran or e cers. Parcuary mporan are genes a enance or nb e spna cord. recognon o umor ces by e os mmune sysem.    Ly mpatc spread. Aoug s s mos ypca o carcnomas, Muaons a promoe e deveopmen or progresson o cancers a orms o cancer may dssemnae roug ympac cannes. are reerred o as drver mutatons. Mos drver muaons afec genes he paern o ymp node nvovemen depends on e se o a encode proens, bu genes a encode reguaor y RNAs, suc as e prmar y neopasm and e naura paways o oca ympac mcroRNAs, aso can be afeced by drver muaons. Drver muaons dranage. A “sentne” y mp node s e rs regona ymp node are srucuray dverse and ncude: a receves ymp low  rom a prmar y umor. he resus o    Snge-nuceotde substtutons and sma nsertons and deetons. senne ymp node bopsy are used o gauge umor spread va Dependng on er precse ocaon and ype, ese may eer ac- ympacs, wc n urn gudes reamen. Lymp node enarge- vae an oncoproen or nacvae a umor suppressor proen. men near a prmar y umor may sem  rom e measac spread    Large deetons, wc requeny remove one or more genes w o cancer ces or rom mmunoogc reacons o umor angens. umor suppressor uncon. hus, e cause o ymp node enargemen can ony be deer-    Cromosome rearrangements (oten n e orm o cromosome mned w cerany by bopsy and sopaoogc examnaon ransocaons) produce gross canges n e cromosome sruc- o e afeced nodes. ure (Fg. 5.12). In some nsances nvovng oncogenes, e rear-    Hematogenous spread. Spread roug  bo o d vess es s e avored rangemen paces a srong reguaor y eemen (eer a promoer paway or sarcomas, bu carcnomas oow s cours e, as we. or an enancer) near an oncogene, eadng o overexpresson o a hn-waed vens are p eneraed more easy an ck-waed norma proen. In oer nsances, a cmerc gene s creaed a ar eres and are e usua avenue o spre ad. Bo o d-b orne umor encodes an oncogenc uson proen composed o porons o wo ces are oten arresed n e rs capar y b ed  e y encouner : dferen proens. hese ypes o rearrangemens are parcuary Gasronesna cancers  requeny spread roug  e p or  a common n bood cancers and sarcomas, bu may be ound n car- sysem o e ver, w ereas oer cancers oten me as asze rs cnomas, as we. o e ungs. C ancers arsng ne ar  e ver ebra coumn oten    Gene ampcatons produce exra copes o one or more oncogenes emb oze roug  e paraver ebra pexus; s pa way proba- and represen anoer way o ncrease e eve o a proen w by expans e g   requenc y o ver ebra me as as es n paens oncogenc acvy (Fg. 5.13). he amped genes may be carred w carcnomas o e yrod and pros ae. Howe ver, e ana- n exracromosoma DNA ragmens known as doube mnue omc o cazaon o a neopasm and s venous dranage can- cromosomes, or may be presen wn a cromosome and appear no w oy expan e sysemc dsrbuon o me as as es. For as an abnorma omogeneous-sanng regon, deeced by sanng exampe, ung carcnoma ends o spre ad o e adrena g ands a meapase cromosome w speca dyes. and e bran, and neurobasoma oten spreads o e ver and Anoer common genec ab erraon a s ound n cancer ces b ones. C onvers ey, skeea mus ces, aoug  r c n capar es, s aneupody, wc s dened as gans or osses o woe cromo- are rarey ses o umor meas as es. somes or arge p or ons ereo (s ee Caper 6). How s causes 70 CHAPTER 5 Neoplasia CHRONIC NORMAL MYELOID CHROMOSOMES LEUKEMIA 9 22 9 22 HSR BCR BCR NMYC locus ABL-BCR locus hybrid gene ABL oncogene Tyrosine Tyrosine kinase kinase inhibitor ABL Activation of oncogene growth factor signaling Double pathways minutes NORMAL BURKITT CHROMOSOMES LYMPHOMA 8 14 8 14 Fig. 5.13 Amplification of the NMYC gene in human neuroblastoma. The NMYC gene, present normally on chromosome 2p, becomes ampli- fied and is seen either as extrachromosomal double minutes or as a chromosomally integrated homogeneous-staining region, usually on a chromosome other than chromosome 2. NMYC is closely related in structure to MYC and also is an oncogenic transcription factor. (Modi- fied from Brodeur GM, Seeger RC, Sather H, et al: Clinical implications of oncogene activation in human neuroblastomas. Cancer 58:541, 1986. IG gene IG Increased Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley gene MYC & Sons, Inc.) protein MYC oncogene MYC oncogene Carcinogenesis: A Multistep Process Directed Increased expression of by Darwinian Evolution pro-growth genes Cancers are initiated and subsequently progress by the stepwise Fig. 5.12 Chromosomal translocations and associated oncogenes. In acquisition of multiple genetic aberrations that disrupt sets of can- chronic myeloid leukemia, a balanced translocation involving chromo- cer genes with complementary prooncogenic functions. somes 9 and 22 creates a chimeric gene containing pieces of the BCR Even oug umor ormaon s naed  rom a snge ound- and ABL genes that encode a chimeric BCR-ABL fusion protein with ng ce, cancers connue o evove genecay (Fg. 5.14), a process constitutively active tyrosine kinase activity. In Burkitt lymphoma, a bal- a conrbues o a penomenon reerred o as umor progresson. anced translocation involving chromosomes 8 and 14 places the coding sequence for the MYC gene adjacent to strong regulatory elements A e moecuar eve, umor progresson s beeved o resu rom in the immunoglobulin heavy-chain gene, leading to overexpression of addona muaons a accumuae ndependeny n dferen can- MYC, an oncogenic transcription factor. cer ces. S ome o ese muaons may aer e uncon o cancer genes, ereby makng e afeced ces more adep a grow, sur- vva, nvason, measass, or mmune evason, resung n progres- son akn o Dar wnan evouon (sur vva o e es). Due o s cancer s ncompeey underso o d, bu  s b eeved o nvove seecve advanage, subcones may come o domnae a umor, eer canges n e expresson o cancer genes a resde n afeced cro- a e prmar y se or a ses o measass. B ecause o connung mosoma regons. muaon and seecon, magnan umors a were monocona n Epigenetic Alterations in Cancer orgn are ypcay genecay eerogeneous a e me o cnca presenaon. Epigenetic changes are dened as heritable changes in the expres Genetic heterogeneity has implications not only for cancer pro- sion of a gene that occur without mutation of the gene. gression but also for the response to therapy. Gene expresson s reguaed by posransaona modcaons o Wen umors recur ater cemoerapy, e recurren umor s sones and by DNA meyaon, bo o wc are requeny aered amos aways ressan o e orgna drug regmen. hs acqured n cancer ces wen compared w er norma ceuar couner- ressance sems rom e ougrow o subcones a ave muaons pars. How ese aeraons n e epgenome conrbue o neopasa (or epgenec aeraons) a mpar drug ressance. hus, genec s poory undersood, bu are key n mos,  no a, nsances o sem evouon orged by dar wnan seecon can expan e wo mos rom e aered expresson o cancer genes.  CHAPTER 5 Neoplasia 71 Accumulation of driver and passenger mutations Carcinogen-induced Additional driver Additional mutations, mutation mutations Emergence of subclones Diagnosis Nor mal Initiated precursor with Founding cell stem cell-like proper ties cancer cell Genetically heterogeneous cancer Acquisition of Further genetic Initiating mutation cancer hallmarks evolution Fig. 5.14 Development of cancer through stepwise accumulation of complementary driver mutations. The order in which various driver mutations occur is usually unknown and may vary from tumor to tumor. perncous properes o cancers: e endency or cancers over me o o an umae carcnogen by endogenous meaboc paways. become more aggressve and ess responsve o erapy. Hence, poymorpsms o endogenous enzymes suc as cyocrome P-450 may nluence carcnogeness by aerng e converson o Origin of Carcinogenic Mutations ndrec-acng agens o acve carcnogens. Driver mutations that alter cancer gene function are most com-    Increased ceuar proferaton. Muaons are more key o occur monly acquired during life but may also be inherited. durng DNA repcaon and ceuar dvson, wc may be Facors a conrbue o e occurrence o oncogenc somac ncreased by severa acors. Cronc nlammaon s assocaed muaons a are acqured durng e ncude e oowng: w ncreased ceuar proeraon as par o e repar process.    Age. In genera, e requency o cancer ncreases w age, w hs may expan, a eas n par, e ncreased ncdence o carc- mos cancer deas occurrng beween ages 55 and 75. he rsng noma seen n e seng o many cronc nlammaor y dsorders ncdence w age s key expaned n arge par by e accumu- (Tabe 5.3). Increased exposure o mogenc ormones aso s asso- aon o somac muaons. Some muaons are expaned by ac- caed w an eevaed rsk o carcnoma n ormone-responsve ors descrbed beow, bu mos o e muaona burden assocaed ssues. For exampe, women exposed o g eves o esrogen (a w agng s e resu o sponaneous cemca reacons, suc as poen mogen or mammar y and endomera epeum) over e deamnaon o cyosne and mey-cyosne resdues o creae susaned perods o me ave an ncreased rsk o breas and endo- urac and ymne resdues, respecvey. mera carcnoma.    Exposure to mutagenc agents. Agens a damage DNA are assoc-    Reguated DNA rearrangement and mutageness. B and T ympo- aed w an ncreased rsk o a varey o cancers, ncudng obacco cyes use reguaed DNA breakage and rejonng o assembe a vas smokng, uravoe g (n gy pgmened ndvduas), cemo- array o angen-recepor genes (mmunogobun and T-ce recep- erapy drugs (many o wc damage DNA), radaon (oten gven ors) and (n e case o B ces) reguaed muageness o mprove as par o cancer erapy), and a varey o envronmena cemcas. e ainy o mmunogobuns or angens. Errors n ese pro- Some mporan carcnogenc agens are sed n Tabe 5.2. Cem- cesses can creae oncogenes and are mporan conrbuors o e ca carcnogens ave gy reacve eecrope groups a damage paogeness o B-ce and T-ce umors. DNA, causng muaons. hese a no wo casses: drec-acng Another important source of driver mutations is germline (inher- agens (e.g., akyang agens), wc do no requre meaboc con- ited) aberrations. verson o become carcnogenc, and ndrec-acng agens (e.g., ben- hese nered muaons are presen n ever y ce n e body, zo(a)pyrene, azo dyes, alaoxn), wc are no acve un convered pacng e afeced ndvdua a a g rsk or deveopng cancer. In Table 5.2 Major Carcinogens and Associated Cancers Agent Associated Human Cancers Mechanism Tobacco Lung, bladder, head and neck, pancreatic, and DNA damage caused by carcinogens and procarcinogens renal carcinomas in tobacco smoke (e.g., benzo[ a]pyrene) Ultraviolet light Skin cancer (melanoma, squamous cell carci- DNA damage noma, basal cell carcinoma) Asbestos Lung, esophageal, gastric, and colon carcinoma; Uncertain. Activates the inflammasome, leading to local mesothelioma inflammation. Alkylating chemotherapy agents Acute myeloid leukemia DNA damage Ionizing radiation Many cancers DNA damage Aflatoxin B Liver cancer DNA damage 1 Nitrosamine and nitrosamides Gastric cancer, esophageal cancer DNA damage 72 CHAPTER 5 Neoplasia Table 5.3 Chronic Inflammatory Disorders and Cancer Pathologic Condition Associated Neoplasm(s) Etiologic Agent Asbestosis, silicosis Mesothelioma, lung carcinoma Asbestos fibers, silica particles Inflammatory bowel disease Colorectal carcinoma Lichen sclerosis Vulvar squamous cell carcinoma Pancreatitis Pancreatic carcinoma Alcoholism, germline mutations Chronic cholecystitis Gallbladder cancer Gallbladder stones Barrett esophagus Esophageal carcinoma Gastric acid Sjögren syndrome, Hashimoto thyroiditis Extranodal marginal zone lymphoma Opisthorchis, cholangitis Cholangiocarcinoma, colon carcinoma Liver flukes Gastritis/ulcers Gastric adenocarcinoma, MALT lymphoma Helicobacter pylori Hepatitis Hepatocellular carcinoma Hepatitis B and/or C virus Osteomyelitis Carcinoma in draining sinuses Bacterial infection Chronic cystitis Bladder carcinoma Schistosomiasis Adapted from Tlsty TD, Coussens LM: Tumor stroma and regulation of cancer development. Ann Rev Pathol Mech Dis 1:119, 2006. ames w ese muaons, cancer rsk usuay acs ke an auoso- a arose n e germ ces o e parens or occurred n e eus ma domnan nered ra. he cause n mos nsances s a germne durng eary embr yogeness. muaon n a gene encodng a umor suppressor, a proen w one Role of Infectious Agents in Cancer or more acves a preven ceuar ransormaon. Tumor suppres- sor genes ypcay provde adequae uncon n e eerozygous sae; Infectious agents cause up to 25% of cancers worldwide; because us, afeced ndvduas are perecy norma un cancer arses (and, of this, some cancers can be prevented through vaccination against n some nsances, mupe cancers arse), oten eary n e. he rans- causative agents or by effective treatment of established infections. ormed ces ypcay conan a second, sporadc muaon n e norma Epdemoogc and mecansc sudes ave rmy mpcaed a aee a compeey emnaes e uncon o e umor suppressor. number o necous agens n e eoog y o varous cancers (Tabe he need or a second  (e two-t ypotess) o creae a “procancer” 5.5). Inecous agens appear o ncrease e rsk o cancer roug wo penoype was predced rom e auosoma domnan nerance o major mecansms: one suc cancer syndrome, ama renobasoma (descrbed aer),    By nducng cronc nlammaton and tssue repar, ereby ncreasng and as argey been borne ou by subsequen moecuar sudes. e rae o acquson o drver muaons, as descrbed earer. Exam- Imporan ama cancer syndromes and assocaed genes and pes ncude epas B vrus and epas C vrus, bo o wc cancers are summarzed n Tabe 5.4. Sequencng o genomes as aso nduce cronc ver damage and are srongy assocaed w epao- reveaed a a g racon o cancers occurrng n cdren are asso- ceuar carcnoma (ver cancer), and Hecobacter pyor, a bacerum caed w germne muaons n cancer genes, even n cdren w- a coonzes and damages e gasrc mucosa, wc as been nked ou any amy sor y. Presumaby, many o ese are new muaons o e deveopmen o gasrc carcnoma and gasrc ympoma. Table 5.4 Inherited Predisposition to Cancer Autosomal Dominant Cancer Syndromes Inherited Disorder Gene(s) Functional Defect Retinoblastoma RB Loss of cell cycle control Li-Fraumeni syndrome (various tumors) TP53 Increased genomic instability Melanoma p16-INK4A Loss of cell cycle control Familial adenomatous polyposis/colon cancer APC Increased signaling in the Wnt pathway Neurofibromatosis 1 and 2 NF1, NF2 Increased progrowth signaling Breast and ovarian tumors BRCA1, BRCA2 Increased genomic instability Hereditary nonpolyposis colon cancer MSH2, MLH1, MSH6 Increased genomic instability Nevoid basal cell carcinoma syndrome PTCH1 Increased signaling in the Hedgehog pathway Autosomal Recessive Syndromes of Defective DNA Repair Xeroderma pigmentosum Diverse genes involved in nucleotide excision Increased genomic instability repair Ataxia-telangiectasia ATM Increased genomic instability Bloom syndrome BLM Increased genomic instability Fanconi anemia Diverse genes involved in repair of DNA cross- Increased genomic instability links  CHAPTER 5 Neoplasia 73 Table 5.5 Infectious Agents Linked to Cancer Agent Cancers Mechanism DNA Viruses Human papillomavirus (HPV) Squamous cell carcinomas of the cervix, Virus encodes oncoproteins that inactivate p53 and RB tonsil, vulva, and penis Epstein-Barr virus (EBV) B cell lymphomas, nasopharyngeal Uncertain. Virus encodes proteins that activate oncogenic signaling carcinoma pathways Human herpesvirus 8 Kaposi sarcoma, B cell lymphomas Uncertain. Virus encodes proteins that activate oncogenic signaling (HHV8) pathways Hepatitis B virus Hepatocellular carcinoma Uncertain. Causes chronic liver inflammation and associated repair RNA Viruses Hepatitis C virus Hepatocellular carcinoma Uncertain. Causes chronic liver inflammation and associated repair Retroviruses Human T-cell lymphotrophic Adult T-cell leukemia Uncertain. Virus encodes proteins that causes expansion of infected virus 1 (HTLV1) T cells Bacteria Helicobacter pylori Gastric carcinoma, gastric B cell lymphoma Uncertain. Causes chronic gastritis and associated repair and stimu- lates a chronic immune response. Parasites Schistosoma haematobium Bladder carcinoma Uncertain. Causes chronic cystitis and associated repair Liver flukes Cholangiocarcinoma Uncertain. Causes chronic bile duct inflammation and associated repair    By aterng te functon of protens made by cancer genes or by stm- Avoiding immune Evading growth destruction suppressors uatng ceuar proferaton. he mos mporan and bes under- sood exampe o s mecansm s uman papomavrus (HPV), Sustaining Enabling wc s e eoogc agen n mos cases o cer vca carcnoma and proliferative replicative many cases o ead and neck squamous ce carcnoma. As w be signaling immor tality dscussed aer, HPV encodes wo proens, E6 and E7, a bnd and nacvae wo o e mos mporan umor suppressor pro- ens, p53 and RB, respecvey. Deregulating Tumor- cellular promoting Significance of Passenger Mutations energetics inflammation Passenger mutations create variants that do not alter growth prop- erties but inuence host response to the tumor. Activating hey greay ounumber drver muaons, parcuary n cancers Resisting invasion and cell death caused by exposure o muagens, suc as mos meanomas and smok- metastasis ng-reaed ung cancer. Despe er appareny nnocuous naure, passenger muaons are mporan n severa ways: Inducing Genomic instability    Passenger mutatons may create genetc varants tat confer ress- angiogenesis (mutator phenotype) tance to terapeutc agents. Under e seecve pressure o erapy, Fig. 5.15 Eight cancer hallmarks and two enabling factors (genomic instability and tumor-promoting inflammation). Most cancer cells rare ces arborng ressance muaons gan an advanage and acquire these properties during their development, typically owing to evenuay come o domnae e umor ce popuaon. mutations in critical genes. (From Hanahan D, Weinberg RA: Hallmarks    Passenger mutatons may create tumor neoantgens (proen of cancer: the next generation. Cell 144:646, 2011.) sequences a dfer rom ose o norma ces). Suc angens may be seen as “oregn” by ces o e mmune sysem, poenay ead- ng o a os anumor response. Neoangens and os mmuny w be dscussed aer.    S e-suicency n grow sgnas    Insensvy o grow-nbor y sgnas    Aered ceuar meabosm HALLMARKS OF CANCER    Evason o ce dea All cancers display fundamental changes in cell physiology, which    L mess repcave poena (mmoray) are considered the hallmarks of cancer.    Susaned angogeness As as aready been menoned, cancer genes numberng a eas n    Invason and measass e undreds can be consdered n e conex o e common peno-    Evason o mmune sur veance ypc properes o cancer ces. hese properes are usraed n Fg. In addon, e acquson o e genec and epgenec aeraons 5.15 and conss o e oowng: a coner ese properes may be acceeraed by cancer-promong