CHẨN đoán GIẢI PHẪU BỆNH UNG THƯ vòm mũi HỌNG

B GIO DC O TO B Y T TRNG I HC Y H NI PHM TIN CHUNG CHẩN ĐOáN GIảI PHẫU BệNH UNG THƯ VòM MũI HọNG CHUYấN TIN S H NI - 2015 B GIO DC O TO B Y T TRNG I HC Y H NI ======= PHM TIN CHUNG CHẩN ĐOáN GIảI PHẫU BệNH UNG THƯ VòM MũI HọNG Ngi hng dn khoa hc: PGS.TS T VN T Thuc ti: Nghiờn cu phỏc húa x tr ng thi cú húa tr trc cho ung th vũm mi hng giai on di cn hch N2,3M0 ti Bnh vin K Chuyờn ngnh : Ung th hc Mó s : 62720149 CHUYấN TIN S H NI - 2015 CC T VIT TT BM Biu mụ CS Cng s DNA Desoxy ribonucleic acid EA Khỏng nguyờn sm EBER RNA ca EBV iu chnh protein mng gõy nhim trựng tim tng (EB encoded latent infection membran protein regulator RNA) EBNA Khỏng nguyờn nhõn EBV Epstein Barr Virus EGFR Th th yu t phỏt trin biu bỡ GPB Gii phu bnh HE Hematoxylin Eosin HLA Khỏng nguyờn bch cu ngi (Human Leucocyte Antigen) HMMD Húa mụ dch MBH Mụ bnh hc RNA Ribonucleic acid UTVMH Ung th vũm mi hng VCA Khỏng nguyờn v virus (Viral Capsid Antigen) WHO T chc y t th gii MC LC T VN 1 MT S K THUT THNG QUY TRONG CHN ON MBH 1.1 Nhum Hematoxylin & Eosin (H&E) 1.2 Nhum húa mụ dch CC TIấU CHUN CHN ON CA UNG TH BIU Mễ LYMPHO-BIU Mễ TYP VềM HNG 2.1 Mụ hc 2.2 V trớ .7 2.3 Tỡnh trng virus EB Mễ HC 3.1 Ung th biu mụ t bo vy 3.2 Ung th biu mụ khụng sng hoỏ 3.3 Ung th BM khụng bit húa 11 MT S K THUT TRONG CHN ON Mễ BNH HC UTVMH 13 4.1 Húa mụ dch 13 4.2 Phỏt hin EB 15 4.3 Cỏc du n ca lympho bo 16 4.4 Th th ca yu t phỏt trin biu bỡ (EGFR) 17 NHNG KHể KHN TRONG CHN ON .17 5.1 m tớnh gi 17 5.2 Dng tớnh gi 18 5.3 Chn oỏn phõn bit .18 5.4 Di cn 20 5.5 Sau iu tr tia x 21 KT LUN 22 TI LIU THAM KHO DANH MC HèNH Hỡnh 1: Ung th BM khụng bit húa ca vũm (typ Schmincke) [1] Hỡnh 2: Ung th BM khụng bit húa ti vũm (typ Schmincke) [1] .4 Hỡnh 3: Hỡnh nh nhum húa mụ dch typ Schmincke Cỏc t bo u mu nõu cho thy s hin din ca cytokeratin t bo [1] .5 Hỡnh 4: Ung th BM khụng bit húa (lympho biu mụ) ca vũm .5 (typ Regaud) [1] Hỡnh 5: Ung th BM khụng bit húa (lympho biu mụ) ca vũm (typ Regaud) cỏc bố t bo u gm cỏc t bo cú mng nhõn rừ [1] Hỡnh 6: Ung th BM khụng bit húa (lympho biu mụ) ca vũm (typ Regaud): Cỏc t bo cú ht nhõn rừ v thiu cỏc cu ni gian bo [1] Hỡnh 7: Ung th biu mụ t bo vy sng húa (Nhum HE vi phúng i 200 ln) [4] .9 Hỡnh 8: Ung th biu mụ khụng sng húa vi tng ỏm t bo dớnh lin cú gii hn rừ (nhum HE vi phúng i 400 ln) [4] .10 Hỡnh 9: Ung th biu mụ khụng sng húa tớp nhỳ (nhum HE vi phúng i 200 ln) [4] .10 Hỡnh 10: Ung th biu mụ khụng bit húa vi c im cỏc t bo u trung thnh di xen k vi cỏc t bo lympho .12 ( Nhum HE vi phúng i 200) [4] 12 Hỡnh 11: Ung th biu mụ khụng bit húa vi c im cỏc t bo u ri rỏc gn bú lng lo, xen k l rt nhiu t bo lympho 12 (Nhum HE vi phúng i 600) [4] 12 Hỡnh 12: Ung th biu mụ khụng bit húa khụng in hỡnh vi c im cỏc t bo u hỡnh thoi ( Nhum HE vi phúng i 400) [4] 13 Hỡnh 13: Hỡnh nh húa mụ dch ung th biu mụ khụng bit húa dng tớnh vi cytokeratin vi phúng i 200 ln [4] 14 Hỡnh 14: Hỡnh nh ung th biu mụ khụng bit húa vi EBER dng tớnh bi k thut lai ti ch [4] 16 T VN Ung th vũm mi hng (UTVMH) theo ngha rng bao gm nhiu u khỏc ca vũm hng, t ung th biu mụ ca tuyn nc bt ph n u hc t ỏc tớnh nguyờn phỏt, u lympho ỏc tớnh v c cỏc loi sacụm khỏc Tuy nhiờn ụng nam ỏ, ung th biu mụ vũm hng thng cú ngha l loi u ph bin c bit l loi ung th biu mụ lymho-biu mụ ca vũm hng hoc ung th biu mụ vũm hng khụng bit hoỏ Trong cỏc phng phỏp chn oỏn UTVMH, chn oỏn MBH l chn oỏn quyt nh, l tiờu chun vng cú nhy v c hiu cao nht tỡm hiu sõu hn v chn oỏn mụ bnh hc UTVMH chỳng tụi thc hin chuyờn nhm phc v cho lun ỏn: Nghiờn cu phỏc húa x tr ng thi cú húa tr trc cho ung th vũm mi hng giai on di cn hch N2,3M0 ti Bnh vin K MT S K THUT THNG QUY TRONG CHN ON MBH 1.1 Nhum Hematoxylin & Eosin (H&E) Nhum H&E l phng phỏp ph bin nht chn oỏn mụ hc Phng phỏp ny s dng cht nhum c bn l: - Hematoxylin hin hỡnh cỏc cu trỳc a ba-z thnh mu xanh tớm than Cỏc cu trỳc ny thng cú cha acid nucleic nh cỏc ribosome, nhõn t bo cha nhiu cht nhim sc v cỏc vựng ca bo tng cha nhiu RNA - Eosin Y hin hỡnh cỏc cu trỳc a acid thnh mu hng sỏng Cỏc cu trỳc ny thng cha cỏc protein ni bo hoc ngoi bo Hu ht bo tng u bt mu eosin 1.2 Nhum húa mụ dch õy l phng phỏp lm bc l khỏng nguyờn ca mụ bng khỏng th c hiu Sau cú c s kt hp khỏng nguyờn khỏng th, phc hp ny s c nhn din thụng qua phn ng húa mụ to mu cú th nhỡn c di kớnh hin vi quang hc p dng chn oỏn UTVMH, nguyờn lý ca phng phỏp ny nh sau: cytokeratins l cỏc protein cú bo tng ca cỏc t bo biu mụ, cỏc t bo ung th biu mụ vũm hng cú th phỏt hin c bng nhum húa mụ dch vi khỏng th khỏng cytokeratin T nm 2006 mt h thng danh phỏp mi i, khuyn cỏo s dng keratin thay cho cytokeratin nh trc CC TIấU CHUN CHN ON CA UNG TH BIU Mễ LYMPHO-BIU Mễ TYP VềM HNG Mụ hc ca u c xỏc nh nm 1921 bi Schminke trờn y c v bi Rigaud v Riverchon Phỏp Sau nhng cụng b u tiờn ny, hai loi mụ hc ca ung th biu mụ vũm hng lympho-biu mụ c nhn bit Loi ph bin hn Schminke bao gm cỏc di lan to ca cỏc t bo u khụng bit hoỏ vi gii hn t bo khụng rừ Cỏc di t bo u ny b xõm nhp bi nhiu lympho bo ó dn n tờn gi ung th biu mụ lympho-biu mụ Loi th hai ớt ph bin hn Regaud cú c im l cỏc bố, cỏc ct v cỏc t bo khụng bit hoỏ vi gii hn t bo rừ rng, c nõng bi mt mụ m x lng lo cú xõm nhp bi cỏc lympho bo Xõm nhp lympho gii hn mụ m nõng võy quanh cỏc bố t bo u Da trờn vic xem xột li cỏc tiờu bn lu tr ca trờn 600 cỏc u vũm hng, hu ht cỏc trng hp ny l cỏc ung th biu mụ lympho-biu mụ vũm hng v kinh nghim bn thõn cỏc bui hi tho hng tun v cỏc ung th u v c bnh vin Prince of Wales, Hng Kụng Ellen cho rng v trớ ca u, tỡnh trng chun huyt ca virus EB v s cú mt ca RNAs mó hoỏ Virus EB trờn cỏc lỏt ct mụ u phi c b sung vo cỏc tiờu chun chn oỏn ung th biu mụ lympho-biu mụ vũm hng typ vũm hng Tỏc gi ngh ba tiờu chun chn oỏn nh sau: 2.1 Mụ hc U nguyờn phỏt cha c iu tr phi l ung th biu mụ kộm bit hoỏ khụng cú cỏc cu sng, cỏc cu ni gian bo hoc sng hoỏ ca cỏc t bo riờng l, phi biu hin typ Schminke (hp bo) (nh 1,2,3) hoc typ Regaud (bố) ( nh 4,5,6) v phi dng tớnh vi cytokeratin trờn nhum hoỏ mụ dch (nh 3) Cỏc cu sng, cu ni gian bo v sng hoỏ ca cỏc t bo riờng l phi c xỏc nh chc chn v rừ rng trc mt u b loi ung th biu mụ lympho biu mụ v c xp loi nh mt ung th biu mụ vy Hỡnh nh dng vy l c trng ca typ Regaud ca ung th biu mụ lympho-biu mụ, s dng tớnh ca keratin rừ rt trờn nhum hoỏ mụ dch v cỏc th liờn kt (desmosome) v cỏc t lc quan sỏt thy trờn hin vi in t l chc chn ca hỡnh nh biu mụ vy nhng khụng nờn s dng cỏc tiờu chun ny chng minh cho loi bit hoỏ vy, cỏc c im dch t hc v c tớnh lõm sng ca ung th biu mụ t bo vy khụng ph bin ca vũm hng, ú l mt u khỏc v sinh hc vi ung th biu mụ lympho-biu mụ [1] Thờm vo cỏc c im biu hin rừ trờn cỏc tiờu bn nhum H&E ny, ớt nht mt hai tiờu chun sau õy phi cú trc mt chn oỏn ung th biu mụ lympho biu mụ typ vũm hng c chp nhn Hỡnh 1: Ung th BM khụng bit húa ca vũm (typ Schmincke) [1] Hỡnh 2: Ung th BM khụng bit húa ti vũm (typ Schmincke) [1] (Cỏc t bo u gii hn khụng rừ rng, cỏc di t bo u b xõm nhp bi cỏc t bo lympho) Hỡnh 3: Hỡnh nh nhum húa mụ dch typ Schmincke Cỏc t bo u mu nõu cho thy s hin din ca cytokeratin t bo [1] Hỡnh 4: Ung th BM khụng bit húa (lympho biu mụ) ca vũm (typ Regaud) [1] 16 ó c xỏc nh hn 20 nm trc Tuy nhiờn vai trũ chớnh xỏc ca nú chuyn dng u cha c bit rừ Vỡ cỏc t bo lnh tớnh, khụng phi u cng cú th cú cỏc sn phm ca virus EB, cỏc kt qu dng tớnh ca cỏc xột nghim ny khụng cú ý ngha chn oỏn tn thng ỏc tớnh, nh ụi ó c t (Nicholls v CS, 1996)[17] Hỡnh 14: Hỡnh nh ung th biu mụ khụng bit húa vi EBER dng tớnh bi k thut lai ti ch [4] 4.3 Cỏc du n ca lympho bo Lai v CS (1990) [18] ó nghiờn cu cỏc c im hoỏ mụ dch ca cỏc t bo lympho xõm nhp v s bc l cỏc khỏng nguyờn lp HLA I v II 50 trng hp ung th biu mụ vũm hng trc iu tr Hu ht cỏc t bo lympho l nhng lympho bo hot hoỏ bc l du n OKT10 ca c bo Cỏc t bo T h tr/cm ng CD4+ cú s lng cao hn rừ rt so vi cỏc t bo CD8+ (T-c ch/c t bo) Cỏc t bo lympho bo pan-B CD22+ nghốo 17 nn cỏc vựng quanh u v õm tớnh 29 s 50 sinh thit Mt s lng va phi cỏc t bo bc l CD15 (bch cu n nhõn/i thc bo) cng ó c phỏt hin Cỏc t bo CD16+ (t bo git t nhiờn) cng c tỡm thy ri rỏc hoc khụng cú 4.4 Th th ca yu t phỏt trin biu bỡ (EGFR) Nghiờn cu ca Ma v CS (2003) [19] ó ch rừ s bc l ca EGFR ung th biu mụ vũm hng khụng bit hoỏ kt hp vi kt thỳc lõm sng xu v t l nhum dng tớnh tng i cao cn ung th biu mụ vũm hng vi EGFR ng h vic s dng ớch phõn t iu tr bnh ny Nghiờn cu ca Chua v CS (2004) [20] cng ó gi ý rng tỡnh trng bc lụ EGFR cú th giỳp xỏc nh nhúm bnh nhõn giai on mun ca ung th biu mụ vũm hng cú tiờn lng xu sau hoỏ tr cm ng v x tr Tuy nhiờn cn nghiờn cu tip xỏc nh liu nhúm bnh nhõn ny cú c hng li ớch t mt chin lc iu tr xen k hoc iu tr ớch khỏng EGFR hay khụng NHNG KHể KHN TRONG CHN ON 5.1 m tớnh gi Nguyờn nhõn ph bin nht ca õm tớnh gi l sinh thit khụng ỳng tn thng Vỡ ung th biu mụ lympho-biu mụ ch yu l mt bnh di niờm mc, nhng sinh thit nụng nh thng õm tớnh, c giai on mun Phu thut viờn cn ly c cỏc sinh thit sõu Mt nguyờn nhõn quan trng khỏc l khụng nhn bit c cỏc t bo ỏc tớnh riờng l hoc mt ỏm nh khụng rừ rng ca u, nú cú th b b qua trờn cỏc tiờu bn nhum H&E hoc ct ngha nhm nh trung tõm mm ca cỏc nang lympho Nu nghi ng nhiu trờn lõm sng l ung th biu mụ vũm hng v nhiu sinh thit c ct ngha l õm tớnh, vic xem xột k li cỏc tiờu bn nhum H&E v nhum cytokeratin cỏc tiờu bn b sung ụi cú 18 th lm hin rừ cỏc t bo u lỳc u b b qua trờn cỏc tiờu bn nhum H&E Nu cú hỡnh nh gi to bnh phm b tn hi nng, cỏc t bo u cú th b bin dng nng lm khụng th phõn bit c vi cỏc lympho bo, nhum cytokeratin giỳp phõn bit hai loi t bo ny 5.2 Dng tớnh gi Cỏc kt qu dng tớnh gi l ct ngha nhm trung tõm mm lnh tớnh ca nang lympho nh u v nhm ln cỏc t bo ni mụ tng sinh xng to hoc cỏc tng bo, c bit sau x tr, chn oỏn nhm cỏc t bo biu mụ vy b mt lnh tớnh khụng in hiỡnh gõy nờn tia x hoc tht bi vic nhn bit cỏc t bo lympho hay biu mụ lnh tớnh b bin dng b kp nỏt 5.3 Chn oỏn phõn bit Cỏc trung tõm mm phn ng v cỏc t bo ni mụ u cú th d dng phõn bit vi ung th biu mụ bng nhum c bit Tuy nhiờn cỏc khe biu mụ di niờm mc thng gp cỏc sinh thit vũm thng dng tớnh mnh vi cytokeratin ỏng tic khụng cú phng phỏp nhum no giỳp phõn bit cỏc t bo biu mụ lnh tớnh vi cỏc t bo ỏc tớnh Vic quyt nh tỡnh trng ny phi da trờn hỡnh thỏi hc ca nhõn trờn cỏc tiờu bn nhum H&E Trờn cỏc bnh phm bnh nhõn mi x tr, cỏc t bo biu mụ vy ca niờm mc cú th tr nờn cc k khụng in hỡnh v ụi b chn oỏn nhm l ung th biu mụ vy Bit hoỏ vy ớch thc khụng thy cỏc ung th biu mụ lympho-biu mụ cha c iu tr Hn na, cỏc t bo biu mụ vy khụng in hỡnh, nhiu tng bo quan sỏt thy trờn cỏc sinh thit vũm hng ly sau iu tr cú th tng sc v nhiu nhõn v rt him 19 b chn oỏn nhm l cỏc t bo ỏc tớnh Cỏc t bo ny õm tớnh vi cytokeratin Cỏc hỡnh gi to nng ca cỏc khe biu mụ lnh tớnh cú th nhm vi tn thng ỏc tớnh Vic quyt nh phi da trờn cỏc tiờu bn nhum H&E Chn oỏn cỏc tớnh khụng th thc hin tr mt s t bo u cũn gi c hỡnh thỏi rừ v cú th c nhn bit l ung th biu mụ, khụng cú kh nng nhm ln no dự l nh nht Ung th khụng th c chn oỏn nu cỏc t bo khụng in hỡnh cũn c t cõu hi l cú phi lnh tớnh khụng U lympho ỏc tớnh cú th cc k khú khn chn oỏn phõn bit vi ung th biu mụ lympho-biu mụ da trờn cỏc tiờu bn nhum H&E ca cỏc sinh thit nh Ch cú mt du hiu tinh t l khụng cú bt k tớnh a toan no ca bo tng hu ht cỏc u lympho Tớnh a toan nh ca bo tng cỏc ung th biu mụ lympho-biu mụ cú l l cỏc t trung gian keratin bo tng, nú cú th hin rừ trờn hin vi in t v nhum hoỏ mụ dch Nhum cytokeratin giỳp phõn bit v ỏng tin cy cỏc u lympho vi ung th biu mụ Cỏc u lympho õm tớnh vi keratin v dng tớnh vi cỏc du n ca lympho bo, c bit khỏng nguyờn chung bch cu ung th biu mụ lympho-biu mụ dng tớnh vi keratin trng lng phõn t thp nhng õm tớnh vi khỏng nguyờn chung bch cu Cỏc ung th biu mụ vy kộm bit hoỏ cú th ging ung th biu mụ lympho-biu mụ, c bit cỏc sinh thit nh nhng nu ly mu y thng thy cỏc cu sng rừ rng, cỏc cu ni gian bo chc chn hoc sng hoỏ ca t bo riờng l Thờm vo ú, huyt hc virus Epstein Barr v u thng phỏt sinh ngoi v trớ thụng thng ca ung th biu mụ lymphobiu mụ 20 U hc t ỏc tớnh him xõm nhp vo h Rossenmuller Loi u him gp ny thng phỏt sinh mi v ming v cỏc t bo u gn nh luụn luụn dng tớnh vi S-100, trỏi li cỏc t bo u ca ung th biu mụ lympho-biu mụ õm tớnh vi du n ny Vựng mi xoang, trỏi vi vũm hng, cú th l v trớ ca nhiu u bit hoỏ kộm t ung th biu mụ (thn kinh ni tit) t bo nh ti u nguyờn bo thn kinh khu giỏc v sacụm c võn Cỏc u ny thng khụng phỏt sinh h Rossenmuller Cỏc u ca tuyn yờn, gm u tuyn v u s yt (craniopharyngioma) cng nh cỏc u dõy sng cú th xõm nhp niờm mc ng gia ca núc vũm nhng chỳng thng bit hoỏ hn ung th biu mụ lympho-biu mụ v hỡnh nh X quang ca cỏc u ny thng khỏc 5.4 Di cn Cỏc hch c sõu l v trớ di cn u tiờn ca ung th biu mụ vũm hng v hch c to l mt nhng triu chng ph bin nht Trong mt cụng trỡnh nghiờn cu mi nht ca Huang v CS (1996) [21], cỏc di cn xa t cỏc hch bch huyt ca c sau x tr ung th biu mụ nguyờn phỏt vũm hng xy 125 s 629 bnh nhõn (20%) Cỏc di cn khu trỳ xng (75%), phi (46%), gan (38%), v cỏc hch bch huuyt sau phỳc mc (10%) Di cn nhiu c quan xy 57% Chớn mi lm phn trm cỏc di cn xa xut hin nm sau hon thnh x tr ban u, 52% nm th nht, 23% nm th hai v 20% nm th ba Thi gian sng thờm trung bỡnh k t phỏt hin di cn xa l 11,2 thỏng vi di cn xng, 16,3 thỏng vi di cn phi, v 3,2 thỏng cho cỏc di cn gan Hỡnh nh mụ hc ca cỏc u thu c qua cỏc sinh thit m ca cỏc hch c thng ging vi u nguyờn phỏt ụi u gõy phn ng u ht vi cỏc t bo bỏn liờn v khng l 21 (Workel v Wernet, 1986) [22], cú th chn oỏn nhm l lao hch Vỡ vi khun lao thng khụng c phỏt hin nhng trng hp lao rừ rt, nhum Ziehl Nielson ch cú ý ngha nú dng tớnh Nu khụng cú s h tr lõm sng cho mt chn oỏn bnh lao v nu nhum khỏng acid õm tớnh, tt nht l khụng iu tr chng lao v coi mt u ht nh vy l mt phn ng ca tỳc ch vi u cho n cú bng chng rừ hn ca mt bnh lao 5.5 Sau iu tr tia x X tr l phng phỏp iu tr chớnh i vi UTV Nhỡn chung u cũn ỏp ng vi x tr 10-12 tun sau iu tr Cỏc t bo ung th cũn sút li sau x tr cú nhõn quỏi v bo tng cú nhiu hc nh Cỏc t bo ny nhum HMMD dng tớnh vi EBER ISH Cỏc t bo mụ m bin i khụng in hỡnh vi nhõn ln, ht nhõn rừ v õm tớnh vi cytokeratin Do hu qu ca s gii hn hp v gii phu ca vũm mi hng v xu hng cỏc u ny biu hin giai on mun, x tr in th cao phi c coi l bin phỏp iu tr chn lc Tớnh ỏp ng vi x tr thay i theo loi mụ hc Loi sng hoỏ khụng nhy cm vi x tr Loi ny ca ung th biu mụ vũm mi hng cú xu hng cũn khu trỳ, khụng cú di cn hch, nhng khỏng vi x tr, t l sng thờm nm nm gii hn t 20 n 40% Loi khụng sng hoỏ cú tớnh nhy cm tia thay i Loi ny ca ung th biu mụ vũm mi hng cú xu hng di cn ti hch bch huyt vựng Loi khụng bit hoỏ nhy cm tia Loi ny ca ung th biu mụ vũm mi hng cú xu hng di cn sm ti cỏc hch bch huyt vựng Mc dự cú xu hng lan trn mnh, t l sng thờm nm vi cỏc ung th biu mụ khụng sng hoỏ (WHO2 v 3) vo khong 65% 22 KT LUN Ung th biu mụ mi hng (Nasopharyngeal carcinoma - NPC) l ung th biu mụ phỏt sinh t biu mụ b mt v c xp loi theo T chc y t th gii (WHO) thnh hai loi mụ hc, sng hoỏ (WHO1) v khụng sng hoỏ Loi khụng sng hoỏ c chia tip thnh bit hoỏ khụng sng hoỏ (WHO2) v khụng bit hoỏ khụng sng hoỏ (WHO3) Phõn loi mụ bnh hc c xỏc nh da trờn hỡnh nh 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H NI ======= PHM TIN CHUNG CHẩN ĐOáN GIảI PHẫU BệNH UNG THƯ VòM MũI HọNG Ngi hng dn khoa hc: PGS.TS T VN T Thuc ti: Nghiờn cu phỏc húa x tr ng thi cú húa tr trc cho ung th vũm mi hng giai on... khỏng nguyờn chung bch cu ung th biu mụ lympho-biu mụ dng tớnh vi keratin trng lng phõn t thp nhng õm tớnh vi khỏng nguyờn chung bch cu Cỏc ung th biu mụ vy kộm bit hoỏ cú th ging ung th biu mụ... Hỡnh 7: Ung th biu mụ t bo vy sng húa (Nhum HE vi phúng i 200 ln) [4] 3.2 Ung th biu mụ khụng sng hoỏ Ung th biu mụ khụng sng hoỏ cú ớt hoc khụng sng hoỏ v cú hỡnh thỏi phỏt trin ging ung th