NGHIÊN CỨU PHÂN LOẠI MÔ BỆNH HỌC UNG THƯ BIỂU MÔ PHỔI THEO WHO 2004 VÀ IASLC ATS ERS 2011 CÓ SỬ DỤNG DẤU ẤN HÓA MÔ MIỄN DỊCH

Header Page of 161 T VN Ung th phi l bnh lý ỏc tớnh thng gp nht v l nguyờn nhõn gõy t vong hng u ung th trờn th gii, vi khong 1,3 triu ca mi mc nm 2003 Vit Nam, theo Nguyn Bỏ c v cng s, nm 2006, ung th ph qun - phi chim 20% tng s cỏc ung th, l ung th ph bin nht nam gii v ng hng th ba s cỏc ung th n gii sau ung th vỳ v ung th d dy [1] Tn sut chung ca bnh trờn th gii ngy cng tng Ti thi im phỏt hin c bnh, ch cú 20% bnh nhõn b ung th ph qun - phi cú biu hin ti ch, 25% bnh nhõn ó cú biu hin lan rng n cỏc hch bch huyt khu vc, v 55% bnh nhõn ó cú nhng biu hin di cn xa Hin nay, t l sng sút ca ung th ph qun - phi sau nm k t chn oỏn l 14% [2] Nh vy, ung th ph qun - phi nguyờn phỏt l mt ln y t v tiờn lng bnh thng rt dố dt Chn oỏn ban u ca ung th ph qun - phi hay nhm vi cỏc bnh phi ph qun khỏc Bnh thng c phỏt hin giai on mun, nh hng nhiu n kh nng iu tr v cht lng sng ca bnh nhõn Chn oỏn ung th phi da trờn cỏc triu chng lõm sng, X quang phi ch cú vai trũ nh hng cho chn oỏn Chn oỏn mụ bnh hc giỳp chn oỏn xỏc nh, phõn loi c mt s typ mụ bnh hc ca ung th ph qun - phi, nhiờn mt s trng hp cha phõn bit c typ v di typ mụ hc, cha ỏnh giỏ c s tin trin v tiờn lng ca bnh Mc khỏc, hỡnh nh vi th ung th phi rt a dng, nờn cn thit cú s nghiờn cu sõu hn v hỡnh thỏi hc t bo ung th v cỏc tớnh cht ca chỳng trờn s h tr ca cỏc k thut hin i cng nh hiu bit ca chỳng ta cú th a cỏc chn oỏn chớnh xỏc hn v bnh hc ung th núi chung v ung th phi núi riờng, cng nh phn ỏnh c tiờn lng bnh Song song vi vic chn oỏn bnh hc mc t bo, vic iu tr Footer Page of 161 Header Page of 161 cỏc bnh ung th núi chung v bnh ung th phi núi riờng hin ang cú xu hng iu tr tn gc hay iu tr ớch Vic iu tr ny cn thit phi da vo cỏc chn oỏn bnh hc xỏc nh hỡnh thỏi v tớnh cht cng nh ngun gc ca t bo Ti Vit nam, ó cú nhiu cụng trỡnh nghiờn cu v ung th phi, nhng trung ch yu v khớa cnh dch t hc, chn oỏn mụ bnh hc v phng phỏp iu tr Nghiờn cu s bc l cỏc du n hoỏ mụ dch xỏc nh c tớnh ca mụ v ngun gc t bo ung th phi v mi liờn quan ca chỳng vi mt s triu chng lõm sng, mụ bnh hc cng nh yu t tiờn lng ung th phi hin cha c nghiờn cu nhiu Xut phỏt t thc t ú, trờn c s v nhng hiu bit bc u dch hc ung th, v s h tr ca k thut hoỏ mụ dch, tụi tin hnh nghiờn cu ti: Nghiờn cu phõn loi mụ bnh hc ung th biu mụ phi theo WHO 2004 v IASLC/ATS/ERS 2011 cú s dng du n húa mụ dch, vi cỏc mc tiờu sau: Mc tiờu 1: Xỏc nh cỏc typ mụ bnh hc ung th biu mụ phi theo phõn loi WHO 2004 v IASLC/ATS/ERS 2011 vi s h tr ca húa mụ dch Mc tiờu 2: ỏnh giỏ tn sut bc l cỏc du n húa mụ dch v liờn quan vi typ mụ bnh hc ca ung th biu mụ phi Footer Page of 161 Header Page of 161 CHNG TNG QUAN TI LIU 1.1 Dch t hc ung th phi 1.1.1 Trờn th gii Vo cui th k XX, ung th ph qun - phi ó l mt nhng nguyờn nhõn gõy t vong hng u trờn th gii ú l mt bnh him vo u th k, nhng s phi nhim vi cỏc tỏc nhõn gõy bnh mi cựng vi s tng tui th ó lm cho ung th ph qun - phi tr thnh mt tai ca th k [3],[4] Ung th ph qun - phi l nguyờn nhõn gõy t vong cao nht cỏc bnh ung th nam gii cỏc nc cụng nghip hoỏ Do tiờn lng xu ca nú, t l mc mi v t l cht gn bng S trng hp mi mc hng nm trờn th gii tng lờn u n, 660.000 trng hp vo nm 1980, gn 900.000 trng hp vo nm 1985 T l mc cao cỏc nc cụng nghip hoỏ, thp chõu Phi v trung gian chõu v Nam M T nm 1985, t l mc gim xung cỏc nc gim tiờu th thuc lỏ (M, Anh) Phỏp, t l mc mi hin gn 25.000 trng hp/nm, n nh nam gii v tip tc tng n gii, nhng nam tri hn n vi t l 9/1, l 2/1 M, ni m mt s bang, ung th ph qun - phi n cũn hay gp hn c ung th vỳ Nm 1990, t vong ung th ph qun - phi Phỏp l 77,9/100.000 dõn nam gii v 6/100.000 dõn n gii Anh nm 1991, ung th ph qun - phi l nguyờn nhõn t vong ca 22.000 nam v 10.000 n [5] Nm 2000, ti Thng Hi (Trung Quc), t vong ung th ph qun phi tng lờn t 25,2-40/100.000 dõn vi mc tng hng nm l 1,79%, t l mc nam l 72,8/100.000, n l 30/100.000 dõn M cú 1,3 triu ngi cht ung th ph qun - phi vo nm 2000, ú cú gn triu nam v hn 300.000 n; hn th na, ung th ph qun- phi cũn l bnh ung th Footer Page of 161 Header Page of 161 gõy t vong nhiu nht n gii, cao hn hn ung th vỳ mc dự t l n mc ung th vỳ cao gp 2,5 ln n ung th phi M Trong vi thp niờn gn õy, t l t vong ung th ph qun - phi trờn ton th gii tng Ung th ph qun - phi hay gp tui t 50 n 75 tui, nh cao l 65 tui [6] 1.1.2 Vit Nam Theo thng kờ ca B Y t, ung th phi ng hng th v t l t vong ca cỏc loi ung th hng nm vi c hai gii nam v n Mi nm c nc cú hn 20.000 bnh nhõn ung th phi mi c phỏt hin v cú ti 17.000 trng hp t vong Riờng ti Bnh vin Phi Trung ng, tớnh n nm 2012, s ngi mc bnh ny n khỏm v iu tr lờn ti 16.677 ngi Theo s liu ca ghi nhn ung th H Ni giai on 2001-2004, c tớnh hng nm cú 17.073 trng hp mi mc ung th ph qun - phi, ú 12.958 nam v 4.115 n v l ung th ng hng u nam gii T l mc chun theo tui l 40,2/100.000 dõn nam v 10,6/100.000 dõn n [7] 1.2 Mụ bnh hc ung th biu mụ phi T nhng nm 80 ca th k 20 bt u xut hin quan nim chia ung th biu mụ phi thnh nhúm ln l ung th biu mụ t bo nh v ung th biu mụ khụng t bo nh Nhúm th nht ch bao gm typ ung th biu mụ t bo nh, nhúm bao gm tt c cỏc t typ mụ bnh hc cũn li S phõn chia n gin ny bt ngun t thc t lõm sng l tt c cỏc ung th biu mụ t bo khụng nh thớch hp vi iu tr bng phu thut, cũn cỏc ung th biu mụ t bo khụng nh thỡ phn ln thớch hp vi x tr hay húa tr S xut hin ca nhiu phõn loi cho thy tớnh phong phỳ v to mụ hc ca UTP v õy l c rt nhiu ngi quan tõm, song nú li to s khụng thng nht v danh phỏp, nh ngha, cỏch ỏp dng thc hnh v vy, hn ch kh nng hp tỏc quc t Trc thc trng ny, phõn loi mụ hc cỏc u phi ca WHO ó c xut bn nm 1967 v phõn loi mụ hc cỏc u phi ln th ó c cụng b nm 1981 Vic nh typ cú th gp khú khn Footer Page of 161 Header Page of 161 nhng phn khỏc ca cựng mt loi u li cú mc bit húa khỏc nhau, thm cú nhiu loi bit húa Theo cỏch phõn loi thng dựng cho cỏc u ca cỏc c quan khỏc thỡ cú th xỏc nh typ mụ hc da trờn cỏc mụ bit húa cao nht c nh tớnh bng nhng tớnh t c trng cho mc bit húa ca nhng phn kộm bit húa nht; núi cỏch khỏc y l mt chia mụ hc Mc dự phõn loi ny ó ỏp ng c nhng ũi hi ca vic nh typ mụ bnh hc ung th phi ú, song khụng phi khụng cú nhng nghiờn cu phõn loi mi, vớ d cỏc u nhy, ung th t bo nhn, ung th a hỡnh, cỏc u typ tuyn nc bt Nhng typ mụ bnh hc mi ny ó c cỏc nh bnh hc tỏi hin li, b sung, hon chnh thờm v l c s cho phõn loi mi ca WHO ln th (1999) Phõn loi mi ny cú cỏc mó hỡnh thỏi hc ca phõn loi quc t cỏc bnh u (ICD-O) v danh phỏp h thng húa v y hc (S,NOMED) Nu so sỏnh phõn loi ln th nht (1967) v ln th hai (1981), ngi ta d dng nhn thy v c bn hai phõn loi ny khụng khỏc nhiu, song phõn loi ln th cú nhiu thay i so vi hai phõn loi trc ú, nhiu typ/th typ mi c tha nhn v cha tng cú cỏc phõn loi trc ú Dự cú nhiu phõn loi mụ hc UTP ca cỏc tỏc gi hoc nhúm tỏc gi ó cụng b v c ỏp dng thc hnh lõm sng ni ny, ni khỏc, song k t cú phõn loi mụ hc ung th phi ca WHO ln u tiờn (1967), phõn loi ny lp tc ó c ún nhn khỏ rng rói Ngi ta hoan nghờnh v ún nhn cỏc phõn loi ca WHO vỡ nhng lý chớnh sau: (1) xõy dng v hon thin cỏc phõn loi ny, WHO ó hp c trớ tu cỏc nh bnh hc phi hng u th gii, mt Ban son tho cú uy tớn (h l nhng ngi cú nhiu nghiờn u v phõn lai mụ hc UTP ó cụng b) m trỏch, c nhiu Trung tõm bnh hc hng u th gii kim nh, tỏi hin li v ú nú mang tớnh hon thin v tớnh tng hp v mt tri thc (2) Vic s dng loi ca WHO s mang li hiu qu vic tỡm ting núi chung Footer Page of 161 Header Page of 161 trờn ton cu, d so sỏnh i chiu cỏc nghiờn cu gia cỏc quc gia, khu vc v vy d dng cho vic hp tỏc nghiờn cu, phũng bnh, phỏt hin v iu tr ung th phi (3) Cỏc phũng xột nghim gii phu bnh trờn ton th gii u cú th ỏp dng c vỡ nú khụng ũi hi cỏc k thut nhum c bit Trong phõn loi mụ hc ung th phi v mng phi ca WHO, phõn loi cp nht ln th (1999) cú nhiu u im ni bt so vi cỏc phõn loi trc ú Nhng im khỏc bit l bng phõn loi khụng quỏ phc tp, khụng quỏ chi tit nờn d ỏp dng (gm typ), song th hin c cỏc c im v mụ bnh hc, phn ỏnh c tiờn lng bnh tt hn, c tớnh sinh hc ca tt c cỏc typ u Nm 2004, WHO ó a mt phõn loi mi cú sa i v phõn loi cỏc bnh ca phi v u mng phi H thng phõn loi u rt quan trng vic chn oỏn, lp k hoch iu tr bnh nhõn v cung cp c s cỏc nghiờn cu dch t hc v hỡnh thỏi mụ bnh hc Theo bng phõn loi mụ bnh hc ung th phi - ph qun nm 2004 ca T chc Y t Th gii (WHO), ung th biu mụ phi c chia thnh nhiu loi v c mó húa Mi õy, bng phõn loi mụ bnh hc ung th phi - ph qun nm 1999 v 2004 ca T chc Y t Th gii tr nờn ớt hu ớch hn vỡ mt quan im lõm sng mi, hu ht cỏc loi ung th biu mụ tuyn typ hn hp v ung th biu mụ tuyn typ tiu ph qun ph nang gõy nhiu nhm ln gia cỏc bỏc s lõm sng Do ú, bng phõn loi ung th tuyn mi ó c gii thiu vo nm 2011 bi mt nhúm chuyờn gia thuc Hip hi Quc t v Nghiờn cu Ung th phi (IASLC), Hip hi Lng ngc Hoa k (ATS) v Hip hi Hụ hp chõu u (ERS) Cỏc chuyờn gia ny i din cho cỏc chuyờn gia quc t v chuyờn ngnh bnh hc, sinh hc phõn t, X-quang, bỏc s phu thut lng ngc Theo ú, bng phõn loi mi hin phõn bit gia tn thng tin xõm ln, tn thng xõm ln ti thiu v xõm ln Do thut ng ung th Footer Page of 161 Header Page of 161 biu mụ tiu ph qun ph nang d nhm ln nờn khụng c s dng na v typ mi bao gm ung th biu mụ tuyn ti ch v ung th biu mụ tuyn xõm ln ti thiu Vic phõn loi mi ny nhn mnh typ mụ bnh hc vi tng quan ca cỏc k thut hỡnh nh v tỏc ng ca nú v chn oỏn, iu tr v tiờn lng bnh Phõn loi mi ny cng s cú nh hng n vic phõn loi TNM Bỏc s phu thut lng ngc s tip tc úng mt vai trũ quan trng vic ỏp dng, ỏnh giỏ v nõng cao hn na phõn loi ung th biu mụ tuyn mi ny [8], [9], [10], [11], [12] Mc ớch phõn loi mụ bnh hc ung th biu mụ phi l em li s thng nht chn oỏn bnh hc, thun tin cho vic ghi nhn ung th v nghiờn cu khoa hc cng nh phc v cỏc bỏc s lõm sng vic lp k hoch iu tr 1.3 Húa mụ dch 1.3.1 K thut húa mụ dch Húa mụ dch (HMMD) l s kt hp gia mụ hc v dch hc nhm xỏc nh s biu hin ca mt khỏng nguyờn riờng bit ca mt mụ v tỡnh trng khỏng nguyờn khỏc ca cỏc t bo cựng mt mụ, da vo tớnh cht c hiu cao ca cỏc khỏng th xỏc nh cỏc khỏng nguyờn riờng bit T ú nhn dng c hiu dũng cỏc qun th t bo, xỏc nh c cỏc c tớnh sinh hc v chc nng cỏc t bo cựng mt dũng Trong lnh vc gii phu bnh ngoi khoa, HMMD gúp phn quan trng nõng cao cht lng chn oỏn K thut HMMD cú th ỏp dng trờn cỏc tiờu bn ct t bnh phm ỳc paraffin, tiờu bn t bo hc v tiờu bn ct lnh t cỏc bnh phm mụ v dch c th Cú th núi vic thc hin thnh cụng k thut nhum húa mụ dch trờn cỏc mnh vựi paraffin l mt cuc cỏch mng bnh hc phõn t Cú nhiu khỏng nguyờn rt bn vng, nhng cng cú nhng khỏng nguyờn rt nhanh b phõn hy, mt s khỏng nguyờn ch tn ti trờn tiờu bn Footer Page of 161 Header Page of 161 ct lnh nhng li b mt tớnh khỏng nguyờn quỏ trỡnh chuyn ỳc Do vy cụng tỏc k thut sau ly bnh phm l ht sc quan trng HMMD ang c ng dng rt rng rói lnh vc chn oỏn cỏc bnh ung th, ú cú bnh ung th phi, mt 10 loi ung th ph bin nht hin Ti Vit Nam, vic nghiờn cu bc l cỏc sn phm gen v cỏc du n dch bng nhum HMMD ung th biu mụ phi cũn cha c nghiờn cu nhiu Tỡm hiu nguyờn lý ca phng phỏp HMMD v cỏc du n dch l c s cho cỏc nh gii phu bnh vic gúp phn chn oỏn chớnh xỏc bnh ung th phi 1.3.2 Cỏc nguyờn lý ca phng phỏp húa mụ dch HMMD l mt k thut nhum c bit, s dng khỏng th (KT) c hiu xỏc nh s hin din ca cỏc khỏng nguyờn (KN) tng ng trờn cỏc lỏt ct mụ hc hoc trờn cỏc loi t bo cú mụ Nguyờn tc l cho KT c hiu lờn mụ, nu mụ cú KN s cú phn ng kt hp KN - KT Cú cỏch quan sỏt phc hp ny: + Min dch hunh quang: KT c gn vi mt cht phỏt hunh quang (quan sỏt kt qu di kớnh hin vi hunh quang) + Min dch enzym: KT c gn vi mt loi enzym, enzym ny xỳc tỏc cho mt phn ng húa hc chuyn mt cht khụng mu thnh mt cht cú mu (quan sỏt c di kớnh hin vi quang hc) - Khỏng nguyờn: cỏc KN thng l cỏc protein, mt s khỏc l carbohydrat, cú th t ngoi c th vo (vi khun, c t, virus,) hoc t c th (cỏc t trung gian, cỏc th th hormon, cỏc protein l sn phm ca t bin gen, cú th hin din bo tng, mng t bo hoc nhõn) Quyt nh KN (epitop) l mt phn nh ca KN, ni tip xỳc vi KT Mt KN cú th cú vi epitop, mi epitop c nhn bit bi mt KT riờng bit Trong qui trỡnh nhum HMMD, cn bc l epitop trc cho tip xỳc Footer Page of 161 Header Page of 161 vi KT - Khỏng th: l cỏc protein nhn bit v kt ni vi KN c hiu, mi KT cú ớt nht hai v trớ kt ni KN KT ch yu l IgG, tip n l IgM KT kt hp trc tip vi KN gi l KT th nht Tu theo cỏch sn xut, cú loi KT: + KT a dũng: c sn xut bng cỏch gõy dch ng vt vi KN c hiu ng vt ỏp ng dch v to khỏng huyt bao gm nhiu loi KT c hiu v khụng c hiu Sau ú KT c lm tinh khit (loi b cỏc KT khụng cn thit) KT a dũng cú th kt hp vi nhiu v trớ ca mt KN nờn nhy cao, tng kh nng phỏt hin Tuy nhiờn, KT a dũng cú th cha cỏc KT phn ng khụng c hiu vi cỏc KN nờn cú khuynh hng nhum nn cao + KT n dũng: c sn xut bng k thut u lai, phi hp kh nng to KT c hiu t tng bo vi lympho bo B lỏch ng vt c gõy dch, hỡnh thnh nhiu dũng t bo u lai sn xut KT c hiu Cỏc t bo ny c la chn v nhõn ging mụi trng nuụi cy t bo KT n dũng c sn xut t mt dũng ca t bo u lai nờn rt tinh khit, ch phn ng vi mt loi quyt nh KN Tuy nhiờn, vỡ KT n dũng ch phn ng vi mt v trớ c hiu ch khụng phi ton b KN nờn ớt nhy hn so vi KT a dũng Hn na, mt s KT n dũng ch phn ng c trờn tiờu bn ct lnh Cu trỳc ca KT cú hỡnh ch Y vi chui protein, gm chui nh v chui nng KT cú hai vựng: + Vựng thay i (Fab): hai phn u ca nhỏnh ch Y cha v trớ kt ni KN + Vựng n nh (Fc): phn gc ca ch Y, õy l vựng rt quan trng vỡ cú th kt ni vi b th hay cỏc t bo - H thng nhn bit: vỡ cỏc phc hp KN - KT khụng quan sỏt thy c di kớnh hin vi quang hc nờn cn mt h thng hin th v trớ cú phn ng KN-KT H thng ny gm phn: KT th (KT bc cu) v h Footer Page of 161 Header Page 10 of 161 10 thng phúng i du hiu nhn bit (gm enzym, cỏc phõn t phỏt hin, cht kt ni v cht mu) + Khỏng th th hai (KT bc cu, KT kt ni): l KT phn ng c hiu vi KT th nht sau KT ny ó gn vi KN Nú phn ng vi phõn t globulin dch huyt ca ng vt ó sn xut KT th nht KT th hai thng c gn biotin v c coi nh kớt phỏt hin chung + Cỏc enzym: enzym l mt protein gõy s thay i hoỏ hc ca cỏc cht khỏc nhng bn thõn nú khụng thay i, enzym úng vai trũ nh cht ch im Trong k thut HMMD, enzym cn phi m bo c cỏc iu kin sau: - Phi to mt sn phm phn ng m khụng th ho tan, mu rừ rng, kt ta trc tip ti sn phm ú - Phi c bn vng nhit phũng, cú th sn xut c nhiu v cú th trỡ hu ht cỏc hot ng ca nú sau ó kt ni Ch cú mt vi loi enzym ỏp ng c nhng nhu cu trờn, hai loi enzym c s dng rng rói sn xut d v giỏ thnh thp l peroxydase, c chit xut t r cõy ci nga v phosphatase kim (Alkaline phosphatase), chit xut t E.Coli hoc t i trng + Cỏc phõn t phỏt hin: protein A, biotin v avidin l nhng phõn t phỏt hin Cỏc IgG hoc nhng on ca nú phi dng ó c tinh ch S kt ni tt ch cú th t c on phõn t IgG ly t huyt c s dng nh mt cht ng Cn lu ý, cỏc KT khụng c ln vi cỏc protein, cỏc peptid hoc nhng cht khỏc cú cha nhúm amino Cht kt ni: nhng cht ny phi cú hai chc nng: - Cú th phn ng vi enzym - Phn ng ng thi hoc tip theo vi phõn t phỏt hin hỡnh thnh cu ni gia cỏc khỏng th Footer Page 10 of 161 Header Page 128 of 161 80 Wick MR, Ritter JH, Humphrey PA (1997) Sarcomatoid carcinomas of the lung: a clinicopathologic review Am J Clin Pathol, 108, 40-53 81 Fishback NF, Travis WD, Moran CA et al (1994) Pleomorphic (spindle/giant cell) carcinoma of the lung A clinicopathologic correlation of 78 cases Cancer, 73, 2925-2936 82 Franks TJ, Galvin JR (2010) Sarcomatoid carcinoma of the lung: histologic criteria and common lesions in the differential diagnosis Arch Pathol Lab Med, 134, 49-54 83 Matsui K, Kitagawa M (1991) Spindle cell carcinoma of the lung: a clinicopathologic study of three cases Cancer, 67, 2361-2367 84 Matsui K, Kitagawa M, Miwa A (1992) Lung carcinoma with spindle cell components Sixteen cases examined by immunohistochemistry Hum Pathol, 23, 1289-1297 85 Leschke H (1956) ĩber nur regionọr bửsartige und ỹber krebsig entartete Bronchusadenome bzw Carcinoide Virch Arch, 328, 635-657 86 Arrigoni MG, Woolner LB, Berantz PE (1972) Atypical carcinoid tumors of the lung J Thorac Cardiovasc Surg 64, 413-421 87 Mark EJ, Ramirerz JF (1985) Peripheral small-cell carcinoma of the lung resembling carcinoid tumor: a clinical and pathologic study of 14 cases Arch Pathol Lab Med, 109, 263-269 88 Travis WD, Colby TV, Corrin B, et al (1999) Histological Typing of Lung and Pleural Tumors Springer-Verlag New York 89 Slodkowska J, Langfort R, Rudzinski 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the lung with proposed criteria for large cell neuroendocrine carcinoma: an ultrastructural, immunohistochemical and flow cytometric study of 35 cases Am J Surg Pathol, 15, 529-533 96 Hammar S, Bockus D, Remington F, et al (1989) The unusual spectrum of neuroendocrine lung neoplasms Ultra Pathol, 13, 515-560 97 Jiang SX, Kameya T, Shoji M, et al (1998) Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases Am J Surg Pathol, 22, 526-537 98 Sturm N, Lantuejoul S, Laverriere MH, et al (2001) Thyroid transcription factor-1 and cytokeratins 1, 5, 10, 14 (34E12) expression in basaloid and large cell neuroendocrine carcinomas of the lung Hum Pathol, 32, 918-925 99 Mazieres J, Daste G, Molinier L, et al (2002) Large cell neuroendocrine carcinoma of the lung: pathological study and clinical outcome of 18 resected cases Lung Cancer, 37, 287-292 100 Paci M, Cavazza A, Annessi V, et al (2004) Large cell neuroendocrine carcinoma of the lung: a 10 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Montezuma D, Azevedo R, Lopes P, Vieira R, Cunha AL, Henrique R (2013) A panel of four immunohistochemical markers (CK7, CK20, TTF-1, and p63) allows accurate diagnosis of primary and metastatic lung carcinoma on biopsy specimens Virchows Arch 463(6), 749-54 107 Ngụ Vn Trung (2001) Nghiờn cu mụ bnh hc cỏc v trớ khỏc ca bnh phm ung th phi sau phu thut Lun Thc s Y hc H Ni 108 Sakurai H, Asamura H, Miyaoka E et al (2013) Differences in the prognosis of resected lung adenocarcinoma according to the histological subtype: a retrospective analysis of Japanese lung cancer registry data Eur J Cardiothorac Surg 31 Footer Page 130 of 161 Header Page 131 of 161 109 Urer HN, Kocaturk CI, Gunluoglu MZ, Arda N, Bedirhan MA, Fener N (2013) Dincer SI Relationship between Lung Adenocarcinoma Histological Subtype and Patient Prognosis Ann Thorac Cardiovasc Surg, 31 110 Mcue PA, Finkel GC (1993) Small-cell lung carcinoma An evolving histopathological spectrum Semin Oncol, 20, 153-162 111 Colby TV, Koss 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Detection of large cell component in small cell lung carcinoma by combined cytologic and histologic examinations and its clinical implication Cancer, 70, 599-605 117 Klein-Szanto AJP, Barr RJ, Reiners JJ, et al (1984) Filaggrin distribution in keratoacanthomas and squamous cell carcinomas Arch Pathol Lab Med 108, 888-890 Footer Page 131 of 161 Header Page 132 of 161 118 Satoshi I, Masahiko F, Satoshi S, Masazumi O, et al (2006) Combined in immunohistochemistry of -catenin, cytokeratin 7, and cytokeratin 20 is useful in discriminating primary lung adenocarcinomas from metastatic colorectal cancer BMC Cancer, 6, 31 119 Kargi A1, Gurel D, Tuna B (2007) The diagnostic value of TTF-1, CK 5/6, and p63 immunostaining in classification of lung carcinomas Appl Immunohistochem Mol Morphol Dec, 15(4), 415-20 120 Kim MJ, Shin HC, Shin KC, Ro JY (2013) Best immunohistochemical panel in distinguishing adenocarcinoma from squamous cell carcinoma of lung: tissue microarray assay in resected lung 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Carcinomas Am J Surg Pathol 16 131 Whithaus K 1, Fukuoka J, Prihoda TJ, Jagirdar J (2012) Evaluation of napsin A, cytokeratin 5/6, p63, and thyroid transcription factor in adenocarcinoma versus squamous cell carcinoma of the lung Arch Pathol Lab Med, 136(2), 155-62 132 MuKhopadhyay S, Katzenstein AL (2011) Subclassification of non small cell lung carcinomas lacking morphologic differentiation on biopsy scpecimens: Utility of an immunohistochemical panel containing TTF-1, Napsin A, p63, and CK5/5 Am J Surg pathol, 35(1), 15 25 133 Brunnstrửm H, Johansson L, Jirstrửm K, Jửnsson M, Jửnsson P, Planck M (2013) Immunohistochemistry in the differential diagnostics of primary lung cancer: an investigation within the Southern Swedish Lung Cancer Study Am J Clin Pathol, 140(1), 37-46 Footer Page 133 of 161 Header Page 134 of 161 134 Morita K, Sasaki H, Furuse M, et al (1999) Endothelial claudin: claudin5/TMVCF constitutes tight junction strands in endothelial cells J Cell Biol 147, 185-194 135 Mukarami I, Hiyama K, Ishioka S, et al (2000) P53 gene mutations are associated with shortened survival in patients with advanced non-small cell lung cancer: an analysis of medically managed patients Clin Cancer Res 6, 526-530 136 Nguyn Minh Hi, Trnh Tun Dng, ng Khc Hng (2011) Biu l p53 v ý ngha tiờn lng ung th phi khụng t bo nh Tp dc lõm sng 108 Tp s c bit thỏng 3/2011 137 Haninger DM, Kloecker GH, Bousamra Ii M, Nowacki MR, Slone SP (2013) Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature Mod Pathol, 13 Footer Page 134 of 161 Header Page 135 of 161 Bộ giáo dục đào tạo y tế Trường Đại học Y Hà Nội PHM NGUYấN CNG NGHIÊN CứU PHÂN LOạI MÔ BệNH HọC UNG THƯ BIểU MÔ PHổI THEO WHO 2004 Và IASLC/ATS/ERS 2011 Có Sử DụNG DấU ấN HóA MÔ MIễN DịCH Luận án Tiến sĩ y học Hà Nội - 2014 Footer Page 135 of 161 Header Page 136 of 161 Bộ giáo dục đào tạo y tế Trường Đại học Y Hà Nội PHM NGUYấN CNG NGHIấN CU PHN LOI Mễ BNH HC UNG TH BIU Mễ PHI THEO WHO 2004 V IASLC/ATS/ERS 2011 Cể S DNG DU N HểA Mễ MIN DCH Chuyên ngành: Gii phu bnh v phỏp y Mã số : 62720105 luận án tiến sĩ y học Người hướng dẫn khoa học: PGS.TS Lờ ỡnh Roanh PGS.TS Nguyễn Văn Hng hà Nội - 2014 Footer Page 136 of 161 Header Page 137 of 161 MC LC T VN CHNG 1: TNG QUAN TI LIU 1.1 Dch t hc ung th phi 1.1.1 Trờn th gii 1.1.2 Vit Nam 1.2 Mụ bnh hc ung th biu mụ phi 1.3 Húa mụ dch 1.3.1 K thut húa mụ dch 1.3.2 Cỏc nguyờn lý ca phng phỏp húa mụ dch 1.3.3 Yờu cu k thut 12 1.3.4 Phng phỏp 12 1.3.5 í ngha 16 1.4 Mt s du n húa mụ dch ung th biu mụ phi 17 1.4.1 p53 17 1.4.2 p63 18 1.4.3 Nhúm Cytokeratin 19 1.4.4 TTF-1 20 1.4.5 Ki-67 20 1.4.6 NSE 21 1.4.7 Napsin A 21 1.4.8 Claudin 21 1.5 Cỏc nghiờn cu v ngoi nc v vai trũ ca cỏc du n dch ung th phi 23 1.5.1 Trờn th gii 23 1.5.2 Trong nc 32 CHNG 2: I TNG V PHNG PHP NGHIấN CU 32 2.1 i tng nghiờn cu 32 2.2 Phng phỏp nghiờn cu 32 Footer Page 137 of 161 Header Page 138 of 161 2.2.1 Phng phỏp nghiờn cu 32 2.2.2 Cỏch tin hnh 32 2.2.3 X lý s liu 43 2.3 o c nghiờn cu 44 CHNG 3: KT QU NGHIấN CU 45 3.1 Tui v gii 45 3.1.1 Ung th phi khụng t bo nh 45 3.1.2 Ung th phi t bo nh 46 3.2 Mễ HC 47 3.2.1 Ung th biu mụ phi khụng t bo nh 48 3.2.2 Ung th biu mụ phi t bo nh 52 3.3 HO Mễ MIN DCH 53 3.3.1 Hoỏ mụ dch ung th phi khụng t bo nh 53 3.3.2 Hoỏ mụ dch ung th phi t bo nh 78 CHNG 4: BN LUN 80 4.1 Tui v gii 80 4.1.1 Ung th biu mụ khụng t bo nh 80 4.1.2 Ung th biu mụ t bo nh 81 4.2 Phõn loi mụ hc 81 4.2.1 Ung th biu mụ phi khụng t bo nh 81 4.2.2 Ung th biu mụ phi t bo nh 91 4.3 Hoỏ mụ dch ung th biu mụ t bo khụng nh 95 4.4 Hoỏ mụ dch ung th biu mụ t bo nh 111 4.5 Hoỏ mụ dch cỏc typ ung th biu mụ hiờm gp 112 KT LUN 114 DANH MC CC CễNG TRèNH CễNG B Cể LIấN QUAN N LUN N TI LIU THAM KHO PH LC Footer Page 138 of 161 Header Page 139 of 161 DANH MC BNG Bng 3.1 Phõn b theo nhúm tui 45 Bng 3.2 Phõn b bnh nhõn theo gii 46 Bng 3.3 Phõn b bnh nhõn theo nhúm tui 46 Bng 3.4 Phõn b bnh nhõn theo gii 47 Bng 3.5 Phõn typ mụ hc theo WHO 2004 48 Bng 3.6 Phõn typ mụ hc UTBM tuyn theo WHO 2004 49 Bng 3.7 Phõn typ mụ hc UTBM tuyn theo IASLC/ATS/ERS 2011 50 Bng 3.8 Phõn typ mụ hc ca cỏc nhúm ln ca UTBM theo WHO 2004 51 Bng 3.9 Bc l CK7 cỏc typ mụ hc theo WHO 2004 53 Bng 3.10 Bc l CK7 cỏc typ mụ hc UTBM tuyn theo WHO 2004 54 Bng 3.11 Bc l CK7 ca cỏc typ UTBM tuyn theo IASLC/ATS/ERS 2011 55 Bng 3.12 Bc l CK7 cỏc typ UTBM tuyn v UTBM vy theo WHO 200455 Bng 3.13 Bc l CK5/6 ca cỏc typ mụ hc theo WHO 2004 56 Bng 3.14 Bc l CK5/6 ca UTBM tuyn v UTBM vy (WHO 2004) 56 Bng 3.15 Bc l p63 cỏc typ mụ hc theo WHO 2004 57 Bng 3.16 Bc l p63 ca cỏc typ mụ hc UTBM tuyn theo WHO 2004 57 Bng 3.17 Bc l p63 ca cỏc typ UTBM tuyn theo IASLC/ATS/ERS 2011 58 Bng 3.18 Bc l p63 ca UTBM vy v UTBM tuyn theo WHO 2004 59 Bng 3.19 Bc l TTF-1 ca cỏc typ mụ hc theo WHO 2004 59 Bng 3.20 Bc l TTF-1 ca cỏc typ mụ hc UTBM tuyn theo WHO 2004 61 Bng 3.21 Bc l TTF-1 ca cỏc typ UTBM tuyn theo IASLC/ATS/ERS 2011 62 Bng 3.22 Bc l TTF-1 ca UTBM vy v UTBM tuyn theo WHO 2004 62 Bng 3.23 Bc l Napsin A ca cỏc typ mụ hc theo WHO 2004 63 Bng 3.24 Bc l Napsin A ca cỏc typ mụ hc UTBM tuyn theo WHO 2004 64 Bng 3.25 Bc l Napsin A ca cỏc typ UTBM tuyn theo IASLC/ATS/ERS 2011 65 Footer Page 139 of 161 Header Page 140 of 161 Bng 3.26 Bc l Napsin A ca UTBM tuyn v UTBM vy theo WHO 2004 66 Bng 3.27 Bc l Claudin-1 ca cỏc typ mụ hc theo WHO 2004 66 Bng 3.28 Bc l Claudin-1 ca cỏc typ UTBM tuyn theo WHO 2004 67 Bng 3.29 Bc l Claudin-1 ca cỏc typ UTBM tuyn theo IASLC/ATS/ERS2011 68 Bng 3.30 Bc l Claudin-1 ca UTBM tuyn v UTBM vy theo WHO 2004 69 Bng 3.31 Bc l Claudin-5 ca cỏc typ mụ hc theo WHO 2004 69 Bng 3.32 Bc l Claudin-5 ca cỏc typ mụ hc UTBM tuyn theo WHO 2004 70 Bng 3.33 Bc l Claudin-5 ca cỏc typ UTBM tuyn theo IASLC/ATS/ERS2011 71 Bng 3.34 Bc l Claudin-5 ca UTBM tuyn v UTBM vy theo WHO 2004 71 Bng 3.35 Bc l Ki67 ca cỏc typ mụ hc theo WHO 2004 72 Bng 3.36 Bc l Ki67 ca cỏc typ UTBM tuyn theo WHO 2004 72 Bng 3.37 Bc l Ki67 ca cỏc typ UTBM tuyn theo IASLC/ATS/ERS 2011 74 Bng 3.38 Bc l Ki-67 ca UTBM tuyn v UTBM vy theo WHO 2004 74 Bng 3.39 Bc l p53 ca cỏc typ mụ hc theo WHO 2004 75 Bng 3.40 Bc l p53 ca cỏc typ UTBM tuyn theo WHO 2004 76 Bng 3.41 Bc l p53 ca cỏc typ UTBM tuyn theo IASLC/ATS/ERS 2011 76 Bng 3.42 Bc l p53 ca UTBM tuyn v UTBM vy theo WHO 2004 77 Bng 3.43 T l bc l HMMH ca ung th phi t bo nh 78 Bng 4.1 T l bc l TTF-1 ca UTBM tuyn phi theo tỏc gi 99 Bng 4.2 T l bc l Napsin A ca UTBM tuyn phi theo cỏc tỏc gi 103 Footer Page 140 of 161 Header Page 141 of 161 DANH MC BIU Biu 3.1 Phõn b theo nhúm tui ca UTBM phi t bo nh 47 Footer Page 141 of 161 Header Page 142 of 161 DANH MC HèNH Hỡnh 1.1: Phng phỏp HMMD 14 DANH MC NH nh 3.1: ng Ngc ., 1958, s tiờu bn: 3740: UTBM vy 49 nh 3.2: Nguyn Vn Ph., 51 tui, s tiờu bn: 4417: UTBM tuyn hn hp 50 nh 3.3: Bựi Hu T., 61 tui, S tiờu bn: 307: UTBM t bo sỏng 51 nh 3.4: Vn S., 65 tui, S tiờu bn: 81871: UTBM t bo nh 52 nh 3.5: H Th C., 59 tui, S tiờu bn: 3985: UTBM dng sarcom 54 nh 3.6: Nguyn Vn Ph., 1963, S tiờu bn: 4417: UTBM tuyn hn hp 55 nh 3.7: ng Ngc ., 56 tui, S tiờu bn: 3740: UTBM vy 58 nh 3.8: Nguyn Vn Ph., 1963, S tiờu bn: 4417: UTBM tuyn hn hp 65 nh 3.9: Nguyn Vn Ph., 1963, S tiờu bn: 4417: UTBM tuyn hn hp 71 nh 3.10: ng Ngc ., 1958, S tiờu bn: 3740: Carcinoma vy 76 nh 3.11: Nguyn Ngc Th., 70 tui, S tiờu bn: 82186: UTBM t bo nh 79 nh 3.12: Vn S., 65 tui, S tiờu bn: 81871: UTBM t bo nh 79 Footer Page 142 of 161 ... biu mụ phi theo WHO 2004 v IASLC/ ATS/ ERS 2011 cú s dng du n húa mụ dch, vi cỏc mc tiờu sau: Mc tiờu 1: Xỏc nh cỏc typ mụ bnh hc ung th biu mụ phi theo phõn loi WHO 2004 v IASLC/ ATS/ ERS 2011 vi... mu ung th phi biu mụ tuyn, 48 mu ung th phi biu mụ vy, ung th phi ni mụ thn kinh, ung th biu mụ tuyn i trng, 31 ung th biu mụ tuyn ca tuyn ty, 17 ung th biu mụ tuyn ca tuyn vỳ, 38 ung th trung... ú, bng phõn loi ung th tuyn mi ó c gii thiu vo nm 2011 bi mt nhúm chuyờn gia thuc Hip hi Quc t v Nghiờn cu Ung th phi (IASLC) , Hip hi Lng ngc Hoa k (ATS) v Hip hi Hụ hp chõu u (ERS) Cỏc chuyờn