Y HQC VigT NAM THANG 8 - SO 2/2011
CAC Chi TO UNG THI/ GAN
Hoang Van Son*
TOM TAT
Trong nhffng nam gan day, cac nha nghien cuXi tren the gidi da cong bo nhieu chi to ung thiT gan mdi, nham phat hien s6m, sang loc, chan doan chinh xac va theo doi dieu trj ung thu" te bao gan. Da so cac chi to mdi hien dang duWc nghien cuTu tren lam sang. Chi to AFP huyet thanh van c6 gia trj nhat, neu l<et hdp djnh lu'dng AFP vdi sieu am gan thi c6 the chan doan sdm ung thu* gan 6 nhffng nhom c6 nguy cd. Ben canh do, cac chi to AFP-L3, DCP, GPC-3 c6 nhieu huTa hen de nang cao hieu qua trong chan doan ung thu* gan.
SUMMARY
TUMOR MARKERS OF LIVER CANCER In recent years, many authors in the world have published new tumor markers of hepatocellular carcinoma, in the effort of early detection, screening, effective diagnosis and monitoring of liver cancel^ost of new markers have been currently studied in clinical oncology.
The AFP in serum proved to be the most valuable, the combination of determination of AFP and abdominal ultrasound might early detect hepatoma in high risk groups. Besides, AFP-L3, DCP and GPC-3 offer promise in the improvement of diagnosis of liver cancer.
Ung thu tS bao gan, ho^c ung thu gan, la mpt trong cac lo?ii ung thu pho bien tren the gioi va a Vi?t Nam, ty le mSc benh c6 xu hudmg t3ng len. Th6ng ke cua Hpi Ung thu lam sang Au chau (ESMO) nam 2009 cho thSy: tren th6 gioi, img thu t6 bao gan dung
hang thu 5 a nam, thii 8 a nu trong cac loai ung thu. Nhiing nhom nguai c6 nguy ca cao bi ung thu gan la: xa gan (nhSt la xa gan do rugru), viem gan B, viem gan C. Trong khi do, theo To chiic Y tl thg gioi, c6 tai 380 trieu nguoi bi viem gan B, 170 trieu bi viem gan C tren toan cau va c6 xu huong tang len.
Dai da so nguai bi ung thu gan duac chan doan muon. Rieng a Nhat, c6 nhung bao cao ve chdn doan som ung thu gan.Hien nay, nguai ta dang c6 gang tim ra cac bien phap, cac xet nghiem de chan doan som ung thu gan, sang loc ung thu gan a nhung nhom CO nguy ca, de tang cuong gia tri chan doan xac dinh, theo doi di8u tri, phat hien tai phat ung thu. Cac chi to ung thu gan c6 vai tro quan trong trong nhimg nghien cuu nay.
I. CHAN DOAN SOM VA SANG LOC UNGTHlTGAN
Cho tai nay,chi to ung thu gan dugc cong nhan rong rai nhat tren th6 gioi la AFP (Alpha Feto Protein) trong s6 tren 50 chi t6 dugc nghien cuix. AFP c6 chan doan som dugc ung thu gan khong? Da s6 cac tac gia deu cho rang c6 the chan doan som ung thu gan n6u kSt hop dinh lugng AFP trong mau voi xet nghiem sieu am gan. N8u AFP cao hon binh thuong va sieu am phat hien c6 nhan ca tvr 1cm (c6 thI nho han) thi do la nhtog diu hieu dhu tien de theo doi ung thu gan, thong qua viec xet nghiem lai nhSm chan doan som, truac khi xuat hien cac trieu chung. Thai gian xet nghiem lai: tu 3 6 thang(bang 1).
* Hdi Hda sinh Y hoc Viet Nam
HOI NGH! KHOA HOC CCiA HOI HOA SINH Y DUOC HA NOI VA CAC TJNH PHIA BAC LAH THCTXVII
Bang 1: Chin doan som va sang loc ung thu gan
Xet nghiem
AFP huyet thanh + sieu am gan (3 6 thang mot Ian)
Cac nhom nghien cihi BRSGE
2003 Oongy
EBCIGI 2008 Dong y (AFP va AFP - L3,
DCP)
ESMO 2009 Dong y
AOS 2009 Dong y
NCCN 2010 Dong y
NACB 2010 Dongy
Chii y: BRSGE: Hoi Tieu hoa Anh (British Society of Gastroenterology)
EBCIGI: Huong dan chung cu lam sang Nhat Ban (Japanese Evidence-Based Clinical Guidelines)
- ESMO: Hoi Ung thu Au Chau (European Society for Medical Oncology) - AOS: Thugng dinh ung thu A Chau (Asian Oncology Summit)
NCCN: Mang luai ung thu quoc gia Hoa Ky {National Comprehensive Cancer Nettvoric)
NACB: Vien Han lam Hoa sinh lam sang qu6c gia Hoa Ky (National Academy of Clinical Biochemistry)
Nam 2003, Hoi Tieu hoa Anh da dua ra Huang dSn sang loc ung thu gan a nhiing nhom nguai c6 nguy ca cao bSng each dinh lugng AFP trong huyet thanh va sieu am bung 6 thang mot ISn. Do la nhung nhom:
nam gioi xa gan do rugu va xa gan do mat, nam va nii bi xa gan do viem gan B hoac C, nam va nu nhilm thiSt huygt t6.
CJ Nhat, Hoi Gan mat Nhat da dua ra cac Huang dan chan doan chung cii lam sang \k ung thu gan dua tren cac cong trinh nghien cuu cua Kudo va Okanoue (2007), Makuuchi va cong sir (2008). Theo cac huong dan nay, de chan doan som ung thu gan a nhiing nguai CO nguy ca cao (xo gan do viem gan B,C, xo gan khong do viem gan B, C), cSn phai lam sieu am 6 bung va dinh lugng ca ba chi t6 :AFP, AFP-L3 (AFP - iectin-affmity 3, AFP CO ai lire lectin nhom 3),va DCP (Des- y-carboxy- prothrombin), tur 3 6 thang mot ISn. Khi cSn thi6t se chup cSt lop vi tinh (CT) hoSc cong hucmg tir hat nhan (MRI).
Nam 2009, Thugng dinh Ung thu A Chau da dua ra ddng thuan ve viec su dung sieu am gan va dinh lugng AFP trong mau 3 - 6 thang mot Ian cho tSt ca cac benh nhan xo gan, nhat la xo gan do viem gan B, nhlm chin doan som ung thu gan.
Nam 2010, cac huong dan do mang ludi ung thu quoc gia Hoa Ky (NCCN) va Vi?n Han lam Hoa sinh lam sang quoc gia Hoa ky (NACB) deu khuySn cao: c&i dinh lugng AFP va sieu am gan cho nhiing nhom c6 nguy CO cao ung thu gan: xo gan do viem gan B,C, do rugu, b?nh nhiem thiSt huyet to, xo gan do mat, viem gan tu miln.Thoi gian xet nghiem: 6 thang mot Ian. Nhu vay, c6 the phat hien som ung thu gan.
Ngoai AFP, mot s6 chi t6 dugc cac tac gia dua ra, cho rang c6 the chan doan som ung thu te bao gan. Cac chi t6 nay van dang dugc ti6p tuc nghien cuu, chua ap dvmg trong lam sang. Co the kl ra: xet nghi?m
Y HQC VlgT NAM THANG 8 - SO 2/2011
proteomic, chi t6 pl6 methyl hoa, AFP monosialyl, glutamate carboxy-peptidase.
1. Chi t6 pi6 methyl hoa. N&n 1999, Wong va cong sir phat hien dugc pi6 methyl hoa trong mau va cho ring chi t6 nay chin doan dugc som ung thu gan.
2. AFP monosialyl. Nhom nghien cuu cua Poon (2002) diing ky thuat dien di didm ding di?n, phat hien dugc giai AFP dac hieu vai ung thu gan, do la AFP monosialyl, xult hien tru6c khi c6 trieu chumg ung thu.
3. Glutamate carboxy-peptidase va phospholipase A2G13 ,G7. do Smith va cong su cong b6 nam 2003, neu len c6 thi chin doan sdm ung thu gan o nhiing nguoi nhiem virus viem gan C.
4. Doan NH2 cua GPC-3, do Hippo va cgng su bao cao nam 2004. Do la 1 heparan sulfate proteoglycan c6 thd phat hien som ung thu gan tu nguoi bi xo gan, nhay hon AFP.
5. Gan day, nhiSu tac gia, trong do c6 Zinkin va cgng sir, sir dimg cong nghe proteomic, da phdt hien ra nhiing chi t6 ung thu moi, CO the chan doan som ung thu gan 6 nhiing b?nh nhan viem gan man tinh (2008).
Con dang tilp tuc nghien cuu gia tri cua chung, truoc khi dua vao umg dimg trong lam sang.
Vi?c sang loc va chin doan sdm ung thu gan chii ySu tap trung vao nhiing nhom c6 nguy CO, va da c6 nhiing hieu qua c\i the. Mc Mahon va cgng s\r da bao cao gia trj cua viec s^g loc ung thu gan a nhiing nguoi ban xii Alaska bi viem gan B voi 2230 truong hgp (2000). Yuen va cgng su a H6ng Kong ciing
chin doan (2004). Zhang va cgng su a Hong Kong (2004), Lin va cgng su (2004), Thompson va cgng sir (2007) a My deu danh gia cao vai tro ciia sang loc ung thu gan a nhiing nguoi c6 nguy co.
I I . CHAN DOAN UNG THl/GAN
Cho toi nay, ngoai AFP da dugc xac dinh gia tri, c6 rit nhieu chi t6 khac dugc nghien cuu dk chin doan ung thu gan.
2.1 Chi to mo
2.I.1.GPC3: Glypican -3 do Capurro va cgng su dua ra nam 2003. Do la mot xet nghiem hoa mo hgc de chan doan ung thu te bao gan. Cong trinh nghien cuu con dang tiep tuc danh gia, chua khang dinh.
2.1.2. GPC3, HSP70, GS.
Ba chi t6 nay do nhom Di Tommaso dua ra nam 2009, xet nghiem trong cac mlu sinh thiet gan de chan doan ung thu gan. HSP 70 la heat shock protein 70, GS la glutamine synthetase.
2.2. Chi to trong huyet thanh
Rit nhi6u chi t6, nhung AFP vin dugc sir dimg nhieu nhit, c6 gia tri cao trong lam sang. Cac chi to khac ciing da dugc nghien cihi lam sang nhung chua dugc ap dung trong thuc tien, trii cac chi to enzym.
2.2.1 Chi to enzym
LDHs: Isoenzym 5 ciia lactat dehydrogenase (LDH) tang trong ung thu gan, dac biet la ty le LDH5/ LDHi tang. Do la mot chi thi c6 gia tri, nhat la khi AFP khong tang.
Isoenzjon ciia GGT. Isoenzym cua gamma - glutamyl - transpeptidase (GGT) neu ro gia tri ciia sang Igc ung thu gan: tilt ciing la mot dIu In gia tri trong chan doan ki|m chi phi, tang thoi gian s6ng len 35% ung thu gan, do Kew va cgng su dua ra tir (2000, 2003). Sangiovaimi va cgng su o Y nam 1984.
ciing thiy ro thai gian song tang len 6 nhiing Isoenzym V cua 5 -nucleotidase do ngudi bi ung thu gan dS dugc sang loc dk Fujiyama va cgng su bao cao nam 1990, la
HOI NGH! KHOA H(5c COA HOI HOA SINH Y Dl/OC HA NOI VA CAC TINH PHIA BAC \JM THifXVII
dIu In gia tri dk chin doan ung thu gan, khi AFP khong cao.
2.2.2. Chi tS lien quan den AFP
-AFP gin LCA (AFP-LCA) do Aoyagi va cgng su dua ra nam 1991. Khi dinh lugng AFP trong huyet thanh, nguoi ta xet nghiem d6ng thai cac chi so glucosaminyl va flicosyl, dk phan biet cac truong hgp tang AFP do ung thu gan voi cac benh gan khac.
-AFP gin concanavalin A do Mora va cgng su dua ra nam 1995, dk phan biet AFP tang do benh te bao mim voi ung thu gan.
-AFP-L3. Do la AFP gin lectin. Nam 1993, Taketa va cgng su bao cao cong trinh nghien cuu sir dung ky thuat dien di ai luc lectin dk phat hien AFP ai luc vai lectin, nham chan doan ung thu te bao gan. Tiep sau do, nhieu tac gia khac da nghien cuu AFP gan lectin va thay nhom AFP-L3 c6 vai tro quan trgng hon ca. Shiraki va cgng su (1995), Yamashita va cgng sir (1996) con cho rang AFP-L3 c6 the chan doan som ung thu gan. Xet nghiem nay dugc dung nhieu a
Nhat va da c6 nhiing bg thu6c thur ban tren thi truong.
2.2.3. Cdc chi tS ung thu gan khac
2.13 A. DCP (Des-gamma-carboxy^
prothrombin) do Liebman va cgng su bao cao nam 1984.Chi t6 nay c6 nhidu hiia hen trong chan doan ung thu gan, nhIt la khi phoi hgp voi AFP. Da c6 cac bg thuoc thvr ban tren thi truong, sii dung rdiilu 6 Nhat va My.
2.2.3.2. GPC-3 (Glypican-3). Chi t6 huyet thanh nay c6 do nhay cao hon AFP, va do dac hieu rat cao trong chan doan ung thu gan, dugc Hsu va cgng sir dua ra nam 1997.
2.2.3.3. Transforming growth factor pi do Song va cgng su mo ta nam 2002, c6 gia tri chan doan ung thu gan kich thuoc nho.
2.2.3.4. Insulin-like growth factor II dugc Tsai va cgng su neu len nam 2003: khi kit hgp voi AFP se nang cao tinh dac hieu va nhay trong chan doan ung thu gan.
Cac chi t6 huylt thanh moi dugc nghien cuu trong chin doan ung thu gan con dang dugc tilp tuc danh gia. Co nhidu hua hen la cac chi to DCP va GPC-3 trong huyet thanh.
Thufti/
1 2 3 4 5 6 7 8 g 10 11 12 13
Bang 2. Cac chi to ung thu gan m6i cong b6 (20 nam gdr Ten chi to
AFP -LCA AFP - L3
AFP - concanavalin Glypican - 3 p16methylation Telomerase
Transforming Growth Factor pi AFP monosialyl
Insulin - like growth Factor II Glutamate Carboxypeptidase NHj Fragment GPC-3
Telomerase reverse transcriptase mRNA Proteomic biomarkers
Tic gia Aoyagi vd c6ng sir Taketa v^ c6ng sir Mora va cdng sir Hsu va c6ng su Wong va cOng sir Tatsuma va c6ng sir Song vd c6ng si;
Poon va c6ng six Tsai vS cOng six Smith va cOng six Hippo v^ cOng sir Miura va c6ng sir Zinkin vScOng sir
iday)
Thdi gian cong bd' iggi ig93 1995 1997 1999 2000 2002 2002 2003 2003 2004 2007 2008
YHQC VI$T NAM THANG 8 - SO 2/2011
14 15 16 17 18
GPC-3
Heat shock protein 70 Glutamin synthetase interleukin - 6 Proteasome
Di Tommaso va c6ng sir Di Tommaso va c6ng sir Di Tommaso va c6ng sir Wong va c6ng sir Henry va cfing sir
2009 2009 2009 2009 2009
Cho toi nay, AFP huyet thanh van dugc thdng nhIt la c6 gia tri nhIt trong chin doan ung thu gan. Tuy nhien, cin chii y la: AFP huySt thanh ciing tang trong mot s6 truong hgp khac: thai nghen binh thuong, viem gan o giai doan h6i phuc, mot s6 truong hgp viem gan man tinh; ung thu tk bao mIm nhu
ung thu tinh hoan, mot s6 truong hgp ung thu da day, ung thu duong mat. Tuy vay, AFP huyet thanh tang khong cao trong cac truong hgp nay. Ngu AFP vugt qua 200 ng/ml va sieu am gan thIy c6 hinh anh mot nhan tren 2 cm, thi CO the chin doan la ung thu te bao gan, khong cIn phai sinh thilt gan.
Bang 3. AFP tang trong mau
Tru'O'ng hap tang Ung thu gan ti§n phat (hepatom)
UngthLTt^bdomam
(Seminom, teratocarcinom tinh ho^n) Dicanungthirvaogan
Phu nff CO thai PhunOcothaidjtat
(khuyfit tat 6ng than kinh, v6 nao, spina bifida) Ung thu da ddy, tuy, dudng mat - Vi6m gan B thdi ky h6i phuc tai tao t^ b^o gan
- Xo gan do ruou
Mu'c do tang Rat cao
Cao Nhe Nhe hoac vUa (tuy theo tudi thai)
Nhe hoac vUa Nhe hoac khdng tang
Nhe vS nhat thdi
Bang 4. Nong do AFP trong mau phu nii c6 thai Tudi thai (tuan il sau kjr kinh cuoi ciing)
14 15 16 17 18 19 20 21
AFP (ng/ml) 7-54.5 12-117 18-85 26-110 28-123 20-155.7 17.5-136 30.5-183.5
HQI NGH! KHOA HOC COA HOI HOA SINH Y Dl/OC HA NQI VA CAC TINH PHfA BAC LAN THlf XVII
I I I . TIEN Ll/QNG VA THEO DOI DIEU TRI UNG THU* GAN
Tien lugng chu ylu dua tren cac giai doan theo he TNM. Dua tren giai doan phat triSn cua khoi u, kich thuoc kh6i u, hien tugng di can, chiic nang gan, cac xet nghiem dinh lugng AFP, bilirubin, huylt thanh, w . . . the trang benh nhan ma danh gia tien lugng.
Cac cong trinh cua nhieu tac gia trong do c6 Marrero va cgng su (2005), Bruix va cgng su (2005) da neu ro van de nay. AFP la mot chi tieu quan trgng de tien lugng, cang cao thi tien lugng cang kem. Cac bao cao ciia Tangkijvanich va cgng su (2000), Farinati va cgng su (2006) nghien cijru 309 benh nhan va 1158 benh nhan ung thu gan xep ra 3 nhom CO AFP huylt thanh truac khi di6u tri lln lugt la: < 20 ng/ml, 20 - 399 ng/ml, > 400 ng/ml, dSu cho thay AFP c6 gia tri tien lugng cao. Matsumoto va cgng sir bao cao : khi AFP > 10.000 ng/ml, thoi gian song sot trung binh chi c6 7,6 thang, khac han thoi gian s6ng trung binh 33,9 thang ngu AFP< 200 ng/ml.
AFP dong vai tro rat quan trgng dk theo doi dieu tri ung thu gan. Sau khi m6 lly kh6i u, AFP huyk thanh giam ro ret. Khi phau thuat CO hieu qua, AFP tro v6 binh thuong.
Tuy nhien, ciing c6 nhftng truong hgp AFP da binh thuong ma c6 thi tai phat ung thu sau ghep gan (Andomo va cgng sur, 1989;
Urabe va cgng su, 1990).
Khi dilu tri blng hoa lieu phap, su giam di ciia AFP cung danh gia dugc thanh cong.
NhiSu tac gia da bao cao vIn dk nay:
Mclntire va cgng su, Matsumoto va cgng sir, Leung va cgng su. Cac nha nghien curu 6 Trung tam ung thu cua benh vien Massachusetts va 6 trucmg Dai hgc y khoa Harvard (2009) deu danh gia cao vai tro
cua AFP huylt thanh trong theo doi dieu tri ung thu gan.
Mang ludi ung thu qu6c gia Hoa ky (NCCN) nam 2010 neu: dk theo doi d i k tri, can dinh lugng AFP moi 3 thang trong 2 nam dau tir khi dieu tri, sau do cu 6 thang mot lln, cimg vai chin doan hinh anh m6i 3-6 thang trong 2 nam va hang nam sau .
Nam 2009, Hoi Ung thu Au chau (ESMO) ciing khuyen cao: ke tir khi dieu tri, nen dinh lugng AFP va chin doan hinh anh moi 3 - 6 thang trong 2 nam dIu va hang nam sau do.
Vien Han lam Hoa sinh lam sang qu6c gia Hoa Ky (NACB) ciing khuydn cao nhu vay nam 2010.
Tom lai, hien dang c6 nhieu cong trinh nghien curu dua ra nhieu chi to moi nhlm chan doan som va chan doan xac dinh ung thu tk bao gan. Dai da so cac chi t6 moi con dang dugc nghien curu tren lam sang. Chi t6 AFP huyet thanh vIn dugc coi la c6 gia tri nhIt, ben canh do cac chi t6 AFP-L3, DCP, GPC-3 CO nhidu hua hen.
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