PROCENA PROLIFERATIVNE AKTIVNOSTI TUMORA ODREĐIVAWEM MITOTSKOG INDEKSA

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1 PREGLEDI LITERATURE BIBLID: , 136(2008) Suppl 1, p PROCENA PROLIFERATIVNE AKTIVNOSTI TUMORA ODREĐIVAWEM MITOTSKOG INDEKSA Dragan MITROVIĆ, Vitomir GOVEDAROVIĆ, Jasmina MARKOVIĆ-LIPKOVSKI Institut za patologiju, Medicinski fakultet, Univerzitet u Beogradu, Beograd KRATAK SADRŽAJ Mi tot ski in deks tu mo ra pred sta vqa broj će li ja u de o bi na 100 tu mor skih će li ja. To je naj sta ri ji i naj če šće kori šćen pa ra me tar ki ne ti ke će lij ske pro li fe ra ci je tu mo ra, ko ji je, po red mno gih imu no hi sto he mij skih i dru gih poka za te qa, i da qe u ru tin skoj pri me ni kao tzv. zlat ni stan dard. Od re đi va we za vi si od fik sa ci je tki va, ti pa fik sati va, na či na bo je wa, de bqi ne pre se ka tki va, na či na is ka zi va wa bro ja će li ja u de o bi, iz bo ra u zo ra ka tki va i vid nih po qa, kao i oda bra nog po stup ka bro ja wa. Ka da se pri me ne isto vet ne teh ni ke bro ja wa, od re đi va we mi tot skog in deksa su štin ski po sta je re pro du ci bi lan me tod. Za ru tin sku pri me nu pred la že se da se ve li či na mi tot skog in dek sa izra ža va u od no s u na t zv. s tan dard no po qe, po vr ši ne od 2 mm 2. Po la ze ći od naj ma we pro me nqivos ti vre me na tra ja wa mi tot ske fa ze će lij skog ci k lu sa, pri ka za no je ne ko li ko ori gi nal nih for mu la ko je po ve zu ju mi tot ski in deks, do bi jen ste re o lo škom me to do lo gi jom, sa di fe ren ci jal nim ob li kom funk ci je ra sta tu mo ra. Na ovaj na čin mo gu će je ma tema tič ki po ve za ti struk tu ru tu mo ra s pa ra me tri ma ki ne ti ke ra sta neo pla zmi, kao što je po ten ci jal no vre me udva jawa. Ova kav pri stup omo gu ću je is pi ti va we ki ne ti ke ra sta jed no krat no me re nih so lid nih tu mo ra kod qu di, uzi ma jući u ob zir wi ho vu mor fo lo gi ju. Mi tot ski in deks ak tu el nu pri me nu na la zi u kla si fi ka ci ji, pred vi đa wu bi o lo škog po na ša wa, gra di ra wu, prog no zi, pro ce ni po ten ci ja la re ci di vi ra wa, ma lig ne tran sfor ma ci je i me ta s ta zi ra wa, kao i u od lu či va wu o te ra pi ji t u mo ra i be le že wu efe ka ta le če wa. Za ne ke ma lig ne t u mo re, kao što je kar ci nom doj ke, on je ne za vi san prog no stič ki in di ka tor. Kqučne reči: tumori; broj mitoza; kinetika rasta; prognoza UVOD Mitoza je faza proliferativnog ćelijskog ciklusa (faza M) koja je prva zapažena i jedina koja se može morfološki prepoznati. Tokom šest morfološki definisanih stadijuma (profaza, prometafaza, metafaza, anafaza, telofaza, citokineza) nuklearni i citoplazmatski sadržaj jednako se raspodequje na dve novonastale ćelije (Slike 1-4). Određivawe stepena mitotske aktivnosti (mitotskog indeksa, broja mitoza) je najstariji metod u kinetici ćelijske proliferacije i najčešće korišćen kvantitativni metod u histopatologiji. Broj mitoza dugo je bio tzv. zlatni standard za rutinsku procenu ćelijske proliferacije neoplazmi, jer zahteva samo standardno pripremqene preseke tkiva obojene hematoksilinom i eozinom (HE) i sposobnost identifikacije mitotskih figura. To je najstariji, najbrži i najjeftiniji metod kvantifikacije proliferativnog kapaciteta tumora i najčešće korišćen metod za određivawe proliferativne aktivnosti solidnih tumora kod qudi [1]. Aktuelan je čak i u eksperimentalnim modelima u kulturi tumorskih ćelija. Treba, međutim, podsetiti da se nekontrolisani rast, kao osnovno svojstvo neoplazmi, nalazi u korelaciji sa sposobnošću metastazirawa, koja zavisi od velikog broja novostečenih svojstava malignih ćelija, kao što je ispoqavawe receptora membrane za komponente vanćelijskog matriksa [2, 3], ili interakciji sa drugim ćelijama [4-7], ukqučujući i molekule sa dejstvom na daqinu [8]. TRAJAWE FAZA ĆELIJSKOG CIKLUSA Ciklus qudske ćelije koja rapidno proliferiše ukupno traje približno 24 sata. Trajawe faze G 1 se najviše mewa, najkraće vreme je verovatno oko 10 sati, a one ćelije u kojoj ova faza traje danima, nedeqama i godinama nalaze se u stawu mirovawa, izvan ćelijskog ciklusa, odnosno u fazi G 0 (neproliferativni status ćelije). Faza S traje 6-12 sati, a faza G 2 u većini qudskih ćelija 2-4 sata. Mitoza u proseku traje jedan sat. Vreme koje ćelije iste linije u kulturi provedu u pojedinim fazama ćelijskog ciklusa je promenqivo. POKAZATEQI MITOTSKE FAZE ĆELIJSKOG CIKLUSA Najčešće zamerke upućene klasičnom načinu određivawa broja ćelija u mitozi odnose se na nedovoqnu reproducibilnost i potrošwu vremena za brojawe [9]. Posledwih godina proizvedeni su imunohistohemijski pokazateqi mitotske faze ćelijskog ciklusa MPM-2 i PHH3, koji se upotrebqavaju na tkivu fiksiranom formalinom, a nameweni su brojawu mitoza [10]. Fosforilisani histon H3, protein koji se nalazi u jedru ćelije i koji se javqa samo u mitotskoj fazi ćelijskog ciklusa, može se otkriti kao antigen antitelima koji se primewuju za prepoznavawe i prebrojavawe ćelija u mitozi [11]. Reč je o antitelima (zeč- 54

2 SLIKA 1. Mitotske figure profaze i anafaze (zvezdice) u metastazi neuroblastoma u limfnom čvoru (HE, 1000). FIGURE 1. Prophase and anaphase (asterix) mitotic figures of metastatic neuroblastoma in lymph node (HE, 1000). SLIKA 3. Faza citokineze (zvezdica) tokom deobe ćelije metastatskog neuroblastoma (HE, 1000). FIGURE 3. Cytokinesis (asterix) during tumor cell division in metastatic neuroblastoma (HE, x1000). SLIKA 2. Metafazno jedro (zvezdica) u metastazi neuroblastoma u limfnom čvoru (HE, 1000). FIGURE 2. Metaphase nucleus (asterix) of metastatic neuroblastoma in lymph node (HE, x1000). ja, poliklonska, anti-pph3) odabranim za fosforilisani serin na desetom mestu amino-kraja histona H3, koji je povezan s mitotskom kondenzacijom hromatina, ukqučujući profazu. Korelacija ovog antitela sa brojem mitotskih figura prepoznatih bojewem HE veoma je visoka (r=0,86; p<0,0001) [12]. Antitelo PHH3 vezuje se za fosforilisani serin na 28. mestu histona H3 [10]. U značajnoj korelaciji sa brojem mitoza je i pokazateq ćelijske proliferacije MCM2 (mi nic hro mo so me ma in te nan ce pro tein 2) [13]. ODNOS SA DRUGIM POKAZATEQIMA PROLIFERACIJE ĆELIJE Iako je, kao i u većini imunohistohemijskih bojewa, procena proliferativne aktivnosti tumora antitelima Ki-67 (Slika 4) ili MIB-1 potencijalno korisna u odabranim situacijama, u mnogim slučajevima ona verovatno ne pruža više od pažqivog ispitivawa mitotske aktivnosti [14]. S druge strane, poznato je da odložena fiksacija tkiva utiče na otkrivawe mitotskih figura, što nema uticaja na procenu proliferativne aktivnosti kod korišćewa ekvi- SLIKA 4. Ćelije proliferativnog pula metastatskog neuroblastoma čija su jedra markirana antitelom Ki-67. Zvezdicom je označeno jedro u metafazi (PAP, 1000). FIGURE 4. Cells of proliferating pool in metastatic neuroblastoma whose nuclei were labeled with Ki-67 antibody. Asterix shows nucleus in metaphase (PAP, x1000). valenata Ki-67 [15]. Ipak, među ekvivalentima Ki-67, kao što su monoklonska antitela MIB-1 (DA KO) i MM1 (No vo ca stra), te poliklonski imunoglobulini NCL-Ki-67p (No vo ca stra) i Rah Ki-67 (DA KO), najveći indeks obeležavawa na parafinskim uzorcima ima MIB-1, i to u proseku za oko 30% veći od ostalih, ali, na sreću, neznačajno [16]. Postoji značajna korelacija broja mitoza i Ki-67 pozitivnosti, kao i stepena postojawa nuklearnog antigena ćelija u proliferaciji (PCNA) [17]. Kod meningeoma se preporučuje kombinovana primena mitotskog indeksa i indeksa Ki-67 pozitivnih ćelija, jer združeni imaju veći značaj za prognozu nastanka recidiva tumora [18]. Kod karcinoma dojke, radi poboqšawa prognoze preživqavawa bolesnika, preporučuje se kombinovana primena protočne citometrije i mitotske aktivnosti [19]. Otkrivawe proteina regulatora ćelijskog ciklusa imunohistohemijskim bojewem, kao što je p27, uz mitotski indeks, kod karcinoma debelog creva i rektuma daje dodatne prognostičke informacije [20]. Kod bolesnica s pozitivnim genom za protein p73 utvrđene su značajno veće vrednosti mitotskog indeksa u tkivu karcino- 55

3 ma dojke u odnosu na obolele žene bez ovog gena [21]. Broj mitoza epitelnih ćelija filodnih tumora dojke je u značajnoj korelaciji s postojawem estrogenskih receptora u istim ćelijama [22]. VELIČINA TUMORA Veličina tumora i mitotski indeks ostaju osnovni, široko dostupni parametri kinetike proliferacije ćelija i rasta tumora. Tako, na primer, veličina tumora i veliki broj mitoza svrstavaju tumore (gastrointestinalni stromalni tumor) u one s tzv. visokim rizikom, koji zahtevaju primenu hemioterapije, ili imaju kqučni prognostički značaj (hemangiopericitom) [23, 24]. Kod gastrointestinalnih stromalnih tumora, veličina tumora i broj mitoza predstavqaju nezavisne prognostičke pokazateqe [25]. Veličina tumora i mitotski indeks isto tako mogu biti osnov klasifikacije tumora (gastrointestinalni stromalni tumori) [26]. ODLOŽENA FIKSACIJA TKIVA I TIP FIKSATIVA Broj mitoza u ekstirpiranom tkivu koje je odloženo fiksirano smawuje se posle tri sata za 10-13%, a posle 12 sati za 39-40% u odnosu na vrednosti u uzorcima koji su odmah fiksirani [27]. Poređewem primenom protočne citometrije zakqučeno je da uzrok nije u izlasku ćelija iz mitotske faze (bez ulaska novih ćelija u deobu), već u otežanom prepoznavawu mitotskih figura (povećawe broja piknotičkih mitotskih figura, akumulacija nuklearnog debrija) zbog autolitičkih promena koje se mogu usporiti čuvawem nefiksiranog tkiva na temperaturi od 4 C [27, 28]. Rastvori za fiksirawe tkiva sa niskom vrednošću ph (oni koji sadrže živu, Buenov fiksativ, neadekvatno puferovan formalinski fiksativ) povećavaju skupqawe tkiva i smawuju jedra ćelija [29]. KVALITET BOJEWA I DEBQINA PRESEKA TKIVA Bojewe hematoksilinom i eozinom (HE) može biti uzrok otežanog razlikovawa piknotičkih ili hiperhromatičnih jedara od mitotskih figura, pa se sugeriše bojewe mucikarminom ili Gimzinim metodom [30]. U rutinskoj upotrebi su, međutim, standardno obojeni histološki preparati (HE), te se preporučuje primena striktnih morfoloških kriterijuma za prepoznavawe mitotskih figura [31], kao i razlikovawe ćelija u apoptozi [1]. Debqi preseci tkiva daju, s jedne strane, povećan broj mitoza, a s druge otežavaju prepoznavawe i brojawe [32]. Standardna debqina preseka tkiva u praksi najčešće je 4-5 μm. Na uvećawu objektiva od 40 puta dubina vidnog poqa je oko 1 μm, tako da mitoze na ovakvim preparatima treba brojati bez promene fokusa, tj. bez pomerawa mikrometarskog zavrtwa mikroskopa [1]. BROJ PROLIFERATIVNIH ĆELIJA Frakcija proliferacije ili frakcija rasta, prema definiciji Mendelsona (Men del sohn) iz godine, predstavqa odnos broja ćelija u proliferativnom ciklusu (izvan faze G 0 ) prema ukupnom broju ćelija iste populacije. Ako prihvatimo zvaničnu kompetentnost imunohistohemijskog pokazateqa MIB-1, imamo priliku da ovaj parametar kinetike ćelijske proliferacije određujemo na nov način. U rutinskom ispitivawu standardnih tkivnih preparata svetlosnim mikroskopom broj ćelija u mitozi se izražava na određenom broju tzv. vidnih poqa velikog uveličawa. Međutim, na 26 različitih tipova mikroskopa pet proizvođača izmerene su površine vidnog poqa velikog uveličawa u rasponu od 0,071 do 0,414 mm 2 [33]. Iako je problem nekoliko puta iznova uočen [34], i daqe se broj mitoza izražava u odnosu na to vidno poqe velikog uveličawa [35]. U posledwe vreme, ipak, nalazimo primere u kojima se broj mitoza na deset vidnih poqa velikog uveličawa (i daqe pogrešno nazivan mitotskim indeksom!) dopuwuje površinom od 0,18 mm 2 tih deset mikroskopskih vidnih poqa [36]. Preciznija ispitivawa zahtevaju izražavawe broja mitotskih figura (ili na drugi način definisanih ćelija u fazi proliferacije) po jedinici površine tkivnog preseka (na mm 2 ) [37], što zahteva izračunavawe površine vidnog poqa svetlosnog mikroskopa izabranog uveličawa. Tada nastaju dva metodološka problema: a) ne pripadaju sve ćelije tkivnog preseka istoj ispitivanoj ćelijskoj populaciji; b) ćelije i solidni tumori su trodimenzionalne strukture, koje se ispituju u dve dimenzije. Prvi problem se rešava izražavawem broja markiranih ćelija u odnosu na 100 ispitivanih ćelija iste populacije indeks markirawa (mitotski indeks, indeks imunohistohemijski pozitivnih ćelija) [38], a drugi stereološkim metodima [39]. Za rutinsku upotrebu predlaže se da se broj mitotskih figura izražava u odnosu na tzv. standardno poqe površine 2 mm 2 [1, 9]. U idealnom slučaju površina preseka velikog uveličawa bila bi 0,2 mm 2, tako da deset ovakvih mikroskopskih vidnih poqa obuhvati standardnu površinu veličine 2 mm 2. U literaturi se mogu naći sledeći primeri: broj mitotskih figura na deset vidnih poqa velikog uveličawa označen je kao indeks mitotske aktivnosti [40], broj mitoza na hiqadu ćelija kao mitotski indeks [40, 41], a broj mitoza na 1 mm 2 kao standardizovani mitotski indeks [42]. 56

4 U prikazanom primeru metastaze neuroblastoma u limfnom čvoru kod petogodišweg dečaka (Slike 1-3) zabeleženo je prosečno 11 mitoza na površini koju zahvata 10 slučajno odabranih vidnih poqa velikog uveličawa. Preračunavawem ovog broja na standardnu mikroskopsku površinu veličine 2 mm 2 dobija se prosečna vrednost od 23 mitoze. Istovremeno, mitotski indeks tumorskih ćelija u ovom slučaju je 1%, a indeks Ki-67 pozitivnih ćelija 49% (Slika 4). Šimadin (Shimada) sistem međunarodne patološke klasifikacije neuroblastoma (1999), koja ima prognostički značaj, poziva se, međutim, i na broj mitoza na 10 vidnih poqa velikog uveličawa. IZBOR UZORAKA TKIVA I VIDNIH POQA Makroskopski odabir uzoraka tkiva solidnih tumora obično obuhvata nekoliko slučajno odabranih područja izvan zona krvarewa i nekroze, čiji je broj srazmeran veličini tumora. Ako su mitotske figure homogeno raspoređene u tumoru, onda se u različitim presecima može očekivati Poasonova (Po is son) distribucija wihovog broja u vidnom poqu [43]. Ne treba, međutim, zaboraviti da su mitoze zaista redak događaj. Ipak, heterogenost ćelijskih subpopulacija i građe solidnih malignih tumora je nešto što se podrazumeva, dok mitoze u tumorima višeg histološkog ili nuklearnog gradusa prestaju da budu redak događaj. Pri rutinskom određivawu mitotskog indeksa trebalo bi imati u vidu da je frakcija ćelijske proliferacije veća na periferiji tumora (MIB1) [44] ili u blizini vaskularizovane strome. Za tumore prečnika od oko 10 mm [1] ili veće (za seminome do 20 mm) [45] može se smatrati da je prostorna raspodela tumorskih ćelija u mitozi homogena. Homogenost rasporeda ćelija u deobi posmatrana nezavisno od veličine tumora mogla se potvrditi samo u polovini od deset različitih karcinoma dojke [46], ali je zato uočena u svih deset ispitivanih karcinoida pluća [1], što ukazuje na značaj biološke prirode tumora. Ako je ciq ispitivawe brzine rasta solidnog tumora kao celine, najboqe je u izboru jedinica posmatrawa odabrati neki od metoda sistematskog slučajnog izbora uzoraka (tkivnih isečaka i mikroskopskih vidnih poqa) [34]. POSTUPCI BROJAWA U svakodnevnoj praksi brojawe mitoza počiwe u području najveće mitotske aktivnosti [1, 47], jer se stepen zrelosti (diferentovanosti) tumora najčešće određuje prema najmalignijem ćelijskom supklonu. Praktično, to su mawe zreli (slabije diferentovani) [1] delovi tumora ili celularnija područja [48]. Mogući su i drugi pristupi: početak brojawa u tzv. aktivnom području [49], na periferiji tumora [34], na slučajno izabranom mestu [46], bez oznake gde se nalazi startno vidno poqe [50]. Sledeća vidna poqa mogu biti susedna (uzastopna) [47, 49], slučajna [46] ili (u izveštaju) nenaznačena [34, 50]. Vidnih poqa velikog uveličawa može biti 10 za karcinome dojke [34, 46, 47], s rasponom površine brojawa (ukqučujući stromu!) od 0,159 mm 2 [47] do 0,274 mm 2 [34]. Kod gastrointestinalnih stromalnih tumora broj vidnih poqa je bio od 10 [50] do 200 [51] s površinom brojawa (ukqučujući stromu), kada je bila naznačena, od 0,159 mm 2 za 10 vidnih poqa [50] do 0,2 mm 2 za 100 vidnih poqa velikog uveličawa [52]. U prikazanom primeru (Slike 1-3) vidna poqa velikog uveličawa, na kojima je određivan broj mitotskih figura, odgovarala su uveličawu od 400 puta i imala su površinu 0,0962 mm 2. Zbrka je potpuna kada se pogledaju korišćene statističke mere: maksimalan broj [46, 47] i sredwi broj (prosek) [34, 52] mitoza u vidnom poqu, ili (ukupan) broj [50, 51] ćelija u deobi na izabranom broju vidnih poqa. U osnovi postoje dva postupka brojawa mitoza: slučajan (nasumičan, stohastički), koji preferiraju patolozi koje zanima fundamentalni (biološki i statistički) aspekt problema, i namerno izabran (koji nije slučajan, nestohastičan), koji se češće primewuje [1]. Potrebno je naglasiti da se kao nedostatak metoda brojawa mitoza na standardan način najčešće isticala nedovoqna reproducibilnost. Međutim, ovde nije reč o nedovoqno preciznom prepoznavawu objekta posmatrawa (mitotska figura), već o različitim tehnikama brojawa [43], kako je u ovom i prethodnim odeqcima detaqno prikazano. U tom smislu, autori u ponovqenom postupku brojawa nalaze znatnu reproducibilnost [53]. MITOTSKI INDEKS I KINETIKA RASTA TUMORA Kinetika rasta solidnih tumora kod qudi nedovoqno je istražena uprkos vrlo bogatom materijalu kojim raspolažu patolozi i širokoj dostupnosti metoda brojawa mitoza na standardno obojenim histološkim preparatima, kao i merewa zapremine hirurški odstrawenih tumora. Temeqan pristup zahteva primenu stereološke metodologije i matematičkog modelirawa. Stereološki metodi obezbeđuju kvantitativni uvid u strukturu tumora, posebno u udeo rastuće ćelijske populacije. Diferencijalni oblik izabrane funkcije rasta omogućuje vezu s mitotskim indeksom kao neposredno merqivim parametrom kinetike proliferacije ćelije. Oslonac u vremenu daje vrlo slaba promenqivost trajawa mitotske faze ćelijskog ciklusa. Prvih nekoliko koraka ovog postupka prikazano je sledećim formulama [54]: 57

5 MI= N vdf N vf 100 T potnf = N vf N vdf ln2 0,5 ΔN f Δt = N vdf V vf V 0,5 U prvoj formuli mitotski indeks (MI) predstavqen je kaokoličniknumeričkihgustinamitotskih figura (N vdf ) i jedara (N vf ) iste ćelijske subpopulacije tumora. Druga formula omogućuje izračunavawepotencijalnogvremena udvajawabroja ćelija usatima (T potnf ).Trećaformulakoristi se za izračunavawepriraštajabrojaćelija kaopriraštaja funkcijerastapomoćuzapreminskegustineodgovarajućefazetumora (V vf ) izapreminetumora (V). ZAKQUČAK Uz mnoštvo dostupnih metoda prilagođenih uslovima istraživawa, napretku u poznavawu materije i komercijalnim aspektima, posle opsežnih i raznovrsnih analiza može se zakqučiti da povećana proliferacija ćelija, bez obzira na primeweni metod otkrivawa, snažno korelira s lošom prognozom invazivnog kancera dojke [86]. Takođe, brojawe mitoza obezbeđuje najreproducibilnije i nezavisne prognostičke rezultate [86]. Indeks ćelija u mitozi ostaje nezaobilazni parametar kinetike ćelijske proliferacije [66, 87] i u nekim slučajevima, kao što su gastrointestinalni stromalni tumori [88], jedini nezavisni prognostički indikator u odnosu na druge pokazateqe ćelijske proliferacije, poput Ki-67 ili ciklina D1. KLINIČKI ZNAČAJ Mitotski indeks našao je svoju primenu u sledećim područjima onkologije: 1) klasifikacija tumora (gastrointestinalni stromalni tumori) [26]; 2) razlikovawe neoplazmi slične morfologije (neuroendokrini tumori) [55]; 3) predviđawe biološkog ponašawa novotvorina (gastrointestinalni stromalni tumori, celularni fibrom jajnika, gigantocelularni tumori kostiju) [56-58]; 4) gradirawe tumora (skvamocelularni karcinom larinksa ili usne dupqe, adenokarcinom endometrijuma) [59-61]; 5) prognoza bolesti i preživqavawe bolesnika (skvamocelularni karcinom usne dupqe, gastrointestinalni stromalni tumori, karcinom grlića materice, tumor granuloza ćelija jajnika, trofoblastni tumor ležišta placente, sarkomi materice, maligni melanom kože, tumori endokrinog pankreasa, maligni limfom, maligni mezoteliom, supratentorijalni oligodendrogliom) [62-72]; 6) procena potencijala recidivirawa tumora (lejomiom, sinoviosarkom, fibrozni tumor moždanica, gastrointestinalni stromalni tumori) [56, 73-75]; 7) procena mogućnosti maligne transformacije (fibrozni tumor pleure) [76]; 8) procena verovatnoće metastazirawa (karcinom dojke, kolorektalni tumori endokrinih ćelija) [77, 78], 9) odlučivawe o lečewu tumora (karcinom dojke) [79]; 10) posmatrawe efekata lečewa (skvamocelularni karcinom usne dupqe, karcinom rektuma) [80, 81]; 11) epidemiološke studije promene agresivnosti tumora (karcinom dojke) [82]. 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Determination is dependent on urgent tissue fixation, fixative type, manner and procedure of staining, thickness of tissue sections, statistical expression of mitotic count, tissue and microscopic field sampling as well as a counting protocol. When the identical counting techniques are applied, determination of tumour mitotic index becomes an essentially reproductive method. Proposal for routine usage is to express the number of mitotic figures in standard vision area of 2 mm 2. Proceeding from minimal variability of mitotic time duration, there were showed a few original formulas which connect mitotic index, acquired by stereological methodology, with differential equation of tumour growth function. In this mathematical way, it is possible to connect structure of the tumour with tumour growth kinetics parameters, for example with potential doubling time. This approach provides growth kinetic examination of once occurring measured human solid tumours, according to their morphology. Tumour mitotic index has been actually applied in classification, biological behaviour prediction, grading, prognosis, evaluation of relapse potential, malignant transformation and metastasis, treatment decision and therapy effect follow-up. In some malignant tumours, such as breast carcinoma, it is an independent prognostic factor. Key words: tumour; mitotic count; growth kinetics; prognosis Dragan MITROVIĆ Institut za patologiju Medicinski fakultet Dr Subotića 1, Beograd Tel.: / lokal dramit@med.bg.ac.yu * Rukopis je dostavqen Uredništvu godine. 60

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