Curr Oncol, Vol. 21, pp. e394-399; doi: http://dx.doi.org/10.3747/co.21.1768 CLINICAL MANIFESTATIONS IN AFP PRODUCING GASTRIC CANCER ORIGINAL ARTICLE Clinicl mnifesttions in ptients with lph-fetoprotein producing gstric cncer H.J. Lin md,* Y.H. Hsieh md, W.L. Fng md, # K.H. Hung md, # nd A.F.Y. Li md # ** ABSTRACT Bckground Ptients with lph-fetoprotein (fp) producing gstric cncer hve high incidence of liver metstsis nd poor prognosis. There is some controversy bout clinicl mnifesttions in these ptients. Methods Our study enrolled ptients who, before surgery, hd gstric cncer with serum fp exceeding 20 ng/ [fp>20 (n = 58)] nd with serum fp 20 ng/ or less [fp 20 (n = 1236)]. Clinicl mnifesttions were compred between the groups. Results Erly gstric cncer ws more frequent (30.1% vs. 4%) nd dvnced gstric cncer ws less frequent (69.9% vs. 96%) in the fp 20 group thn the fp>20 group (p < 0.001). Liver nd lymph node metstsis occurred less frequently in the fp 20 group (4.4% vs. 27.6%, p < 0.001, nd 60.7% vs. 91.4%, p < 0.001, respectively). The 1-, 3-, 5-, nd 10-yer survivl rtes of fp 20 ptients were 75.2%, 53.4%, 45.8%, nd 34.6% respectively. The 1-, 3-, 5-, nd 10-yer survivl rtes of ptients with fp greter thn 20 ng/, but 300 ng/ or less, were 46.7%, 28.9%, 17.8%, nd 13.3% respectively. The 1-, 3-, nd 5-yer survivl rtes of ptients with serum fp greter thn 300 ng/ were 15.4%, 7.7%, nd 0% respectively. The independent predictors for survivl time were fp concentrtion, ge, peritonel seeding, liver metstsis, lymph node metstsis, vsculr invsion, TNM stge, curtive surgery, serosl invsion, nd Luren clssifiction. Conclusions Ptients with high serum fp hd high frequency of liver nd lymph node metstsis nd very poor prognosis. More ggressive mngement with multimodl therpy (for exmple, chemotherpy, rdiotherpy) might be needed when treting such ptients. KEY WORDS Gstric cncer, lph-fetoprotein, erly gstric cncer, metstsis 1. INTRODUCTION Alph-fetoprotein (fp) is glycoprotein tht is normlly produced during gesttion by the fetl liver nd yolk sc 1. Elevtion of serum fp is considered to be bnorml in dults nd is often used s tumour mrker in heptocellulr crcinom nd tumours of gondl origin 2. However, vriety of other mlignncies lso produce fp, of which gstric cncer is the most common 3. Elevted serum fp cn occur in ptients without heptocellulr crcinom but with chronic liver disese such s virl heptitis or cirrhosis 4,5. The influence of serum fp on the prognosis of ptients with gstric cncer remins uncler. Alph-fetoprotein producing gstric cncer (fpgc) is rre, constituting only bout 1% 6% of ll gstric cncers 6. Poor prognosis is usully ssocited with fpgc becuse of liver nd lymph node metstsis 3,7. Few studies to dte hve ddressed the clinicopthologic fetures nd long-term survivl of ptients with fpgc. Controversy exists bout the clinicl mnifesttions in these ptients. Therefore, in this retrospective study, we reviewed clinicopthologic findings for 58 Chinese ptients with fpgc nd 1236 ptients with norml serum fp ttending single centre. We lso correlted survivl time with serum fp concentrtion. 2. METHODS We reviewed the medicl records of 3172 consecutive ptients with gstric denocrcinom who received surgicl intervention t the Veterns Generl e394
LIN et l. Hospitl Tipei between June 1988 nd December 2011. Preopertive serum fp ws ssessed by rdioimmunossy (norml vlue: <20 ng/) in 1331 ptients. The nlysis excluded 37 ptients with cute or chronic heptitis, cirrhosis, or heptocellulr crcinom. Surgicl nd pthologic findings for the remining 1294 ptients were recorded using the Jpnese clssifiction of gstric crcinom nd the Luren clssifiction 8,9. Nodl sttus nd disese stge were ssessed using the tumour node metstsis (TNM) system of the Union for Interntionl Cncer Control 10. Sex, ge, tumour size (mucosl size of the tumour), peritonel seeding, liver metstsis, lymph node metstsis, loction of the min tumour, lymphtic nd vsculr invsion, clinicl stging, curtive surgery, cuse of deth, morphologic ppernce nd depth of cncer involvement, cncer cell differentition, nd survivl time were recorded. Sttisticl nlysis ws performed using the SPSS softwre ppliction (SPSS for Windows, version 10.0: SPSS, Chicgo, IL, U.S.A.). The chi-squre test with Ytes correction for continuity ws used in comprisons of ctegoricl dt. The Fisher exct test ws used when the numbers were less thn 5. Survivl curves were estimted by the Kpln Meier method, nd differences were exmined using the log-rnk test. A multivrite nlysis of prognostic fctors ws evluted using the Cox proportionl hzrds model (forwrd stepwise method). Differences were considered significnt when the p vlue ws less thn 0.05. 3. RESULTS Of the 1294 eligible ptients, 58 (4.5%) were found to hve high serum fp (>20 ng/), with preopertive concentrtions rnging from 20.6 ng/ to 9999.9 ng/ (medin: 90.4 ng/). Medin followup ws 43.2 months. Tble i compres the clinicopthologic fetures of ptients with serum fp of 20 ng/ or less [fp 20 (n = 1236)] nd those with serum fp exceeding 20 ng/ [fp>20 (n = 58)]. Sex, ge, tumour size, peritonel seeding, nd tumour loction were similr in the two groups. Compred with the fp 20 group, the fp>20 group hd higher incidences of vsculr invsion (17.2% vs. 3.8%, p < 0.001), lymphtic invsion (70.7% vs. 59.7%, p < 0.001), liver metstsis (27.6% vs. 4.4%, p < 0.001), nd lymph node metstsis (91.4% vs. 60.7%, p < 0.001). Compred with ptients hving norml serum fp, those in the fp>20 group hd more stge iv disese nd less stge i or ii disese (p < 0.001). Fewer ptients in the fp>20 group received curtive surgery (10.3% vs. 37.9% in the fp 20 group, p < 0.001). More ptients in the fp>20 group died of their gstric cncer (58.6% vs. 27.1% in the fp 20 group, p < 0.001). Tble ii nlyzes the depth of cncer involvement in the gstric wll. The fp>20 group included fewer tble i Serum lph-fetoprotein (fp) nd clinicopthologic fetures in ptients with gstric cncer Vrible fp concentrtion p Vlue 20 ng/ >20 ng/ Ptients (n) 1236 58 Sex [n (%) men] 976 (78.2) 51 (87.9) 0.099 Men ge (yers) 66.2±11.7 68.0±9.5 0.257 Men tumour size (cm) 5.7±4.1 6.7±3.4 0.063 Peritonel seeding [n (%) yes] 179 (14.5) 8 (13.8) 1.000 Peritonel seeding present [n (%)] 0.728 b Proximl to trnsverse colon 83 (46.4) 3 (37.5) Distl to trnsverse colon 96 (53.6) 5 (62.5) Metstsis [n (%) yes] Liver 53 (4.4) 16 (27.6) <0.001 Lymph nodes 750 (60.7) 53 (91.4) <0.001 Loction of min tumour 0.932 Crdi 195 (15.8) 10 (17.2) Body 395 (32.0) 19 (32.8) Antrum 646 (52.3) 29 (50.0) Invsion [n (%) yes] Lymphtic 738 (59.7) 41 (70.7) <0.001 Vsculr 47 (3.8) 10 (17.2) <0.001 Stge <0.001 i 319 (25.2) 2 (3.3) ib 114 (9.0) 1 (1.6) ii 158 (12.5) 3 (4.9) iii 190 (15.0) 12 (19.7) iiib 153 (12.1) 11 (18.0) iv 333 (26.3) 32 (52.5) Curtive surgery [n (%)] 468 (37.9) 6 (10.3) <0.001 Cuse of deth [n (%) cncer] 330 (27.1) 34 (58.6) <0.001 By chi-squre test. b By Fisher exct test. cses of erly gstric cncer (egc: 4% vs. 30.1%; p < 0.001) nd more cses of dvnced gstric cncer (96% vs. 69.9%, p < 0.001). In the 2 egc ptients of the fp>20 group, cncer cells hd involved the intrmucosl nd musculris mucos lyers. In the fp 20 group, 349 ptients (30.1%) hd egc, with cncer cells confined to the intrmucos in 97 cses (27.8%), to the musculris mucos in 94 cses (26.9%), nd to the submucosl lyer in 158 cses (45.3%). Cncer cells penetrted to serosl lyer nd beyond in more ptients of the fp>20 group [40 ptients (80%) vs. 628 ptients (54.2%) in the fp 20 group, p < 0.001]. Tble iii summrizes the histologic clssifiction of cncer cells in the two groups. Poorly differentited cncers (por 1, por 2, signet-ring cell, mucinous denocrcinom) were not sttisticlly different between the groups (fp 20: n = 558, 48.7%; fp>20: n = 23, 50%; p = 0.87). The Luren clssifiction ws e395
CLINICAL MANIFESTATIONS IN AFP PRODUCING GASTRIC CANCER tble ii Serum lph-fetoprotein (fp) nd depth of cncer involvement of the gstric wll Vrible fp concentrtion [n (%)] p Vlue 20 ng/ >20 ng/ Ptients 1158 50 <0.001 b Gstric cncer Erly 349 (30.1) 2 (4.0) Advnced 809 (69.9) 48 (96.0) Depth of involvement <0.001 c Intrmucos 97 (8.4) 1 (2.0) Musculris mucos 94 (8.1) 1 (2.0) Submucos 158 (13.6) 0 (0) Musculris propri 133 (11.5) 2 (4.0) Subseros α 10 (0.9) 2 (4.0) Subseros β 18 (1.6) 3 (6.0) Subseros γ 20 (1.7) 1 (2.0) Serosl penetrtion 518 (44.7) 32 (62.7) Invsion of djcent structures 110 (9.5) 8 (16) Dt not vilble for 78 ptients in the 20 ng/ group, nd 7 in the >20 ng/ group. b By Fisher exct test. c By chi-squre test. tble iii Serum lph-fetoprotein (fp) nd cell differentition in gstric cncer Vrible fp concentrtion [n (%)] p Vlue 20 ng/ >20 ng/ not sttisticlly significntly different between the fp 20 nd fp>20 groups. Survivl time ws further nlyzed by vrious levels of high serum fp. In 45 ptients, serum fp ws greter thn 20 ng/ but less thn or equl to 300 ng/ (20<fp 300); in 13 ptients, serum fp exceeded 300 ng/ (fp>300). The 1-, 3-, 5-, nd 10-yer survivl rtes for ptients in the fp 20 group were 75.2%, 53.4%, 45.8%, nd 34.6% respectively. The 1-, 3-, 5-, nd 10-yer survivl rtes for 20<fp 300 ptients were 46.7%, 28.9%, 17.8%, nd 13.3% respectively. The 1-, 3-, nd 5-yer survivl rtes for ptients with fp>300 were 15.4%, 7.7%, nd 0% respectively. The ptients in the fp 20 group hd the best survivl time, nd the ptients in the 20<fp 300 group hd the poorest survivl (p < 0.001, Figure 1). In univrite nlysis, serum fp greter thn 20 ng/, mle sex, ge greter thn 60, tumour size greter thn 7 cm, peritonel seeding, liver metstsis, lymph node metstsis, lymphtic nd vsculr invsion, tumour stge iv, no curtive surgery, serosl invsion, nd poorly differentited nd diffuse cell types were ssocited with poor survivl time (Tble iv). In multivrite nlysis, the independent prognostic fctors for survivl were serum fp, ptient ge, peritonel seeding, liver metstsis, lymph node metstsis, vsculr invsion, TNM stge, curtive surgery, serosl invsion, nd Luren clssifiction (Tble v). 4. DISCUSSION In our study, 58 ptients with fpgc hd high percentge of lymph node nd liver metstsis nd poor prognosis. The prevlence of fpgc is reported to be Ptients 1145 46 0.002 b Ppillry denocrcinom 19 (1.7) 1 (2.2) Tubulr denocrcinom Well-differentited 113 (9.9) 1 (2.2) Modertely differentited 446 (39.0) 18 (39.1) Adenocrcinom, poorly differentited Solid type 43 (3.8) 4 (8.7) Non-solid type 387 (33.8) 16 (34.8) Signet-ring cell crcinom 89 (7.8) 3 (6.5) Mucinous denocrcinom 39 (3.4) 0 (0) Adenosqumous crcinom 1 (0.1) 1 (2.2) Undifferentited 3 (0.3) 1 (2.21) Miscellneous 5 (0.4) 1 (2.2) Luren clssifiction 0.802 b Intestinl 590 (51.5) 25 (54.3) Diffuse 350 (30.6) 16 (34.8) Mixed 205 (17.9) 5 (10.9) Dt not vilble for 91 ptients in the 20 ng/ group, nd 12 in the >20 ng/ group. b By chi-squre test. figure 1 Overll survivl by serum lph-fetoprotein (fp) concentrtion in nnogrms per milliliter. e396
LIN et l. tble iv Univrite nlysis of ll ptients by the Kpln Meier method Vrible Pts (n) 5-Yer survivl Log-rnk p vlue Alph-fetoprotein 20 ng/ 1236 0.458 <0.001 >20 ng/ 58 0.138 Sex Men 1018 0.423 <0.001 Women 276 0.519 Age <60 Yers 281 0.535 <0.001 60 Yers 1013 0.418 Tumour size <7 cm 862 0.577 <0.001 7 cm 431 0.176 Peritonel seeding Yes 187 0.032 <0.001 No 1107 0.513 Liver metstsis Yes 71 0.042 <0.001 No 1223 0.467 Lymph node metstsis Yes 803 0.228 <0.001 No 491 0.849 Loction of min tumour Crdi 205 0.402 0.056 Body 414 0.488 Antrum 675 0.429 Lymphtic invsion Yes 803 0.321 <0.001 No 491 0.795 Vsculr invsion Yes 57 0.140 < 0.001 No 1237 0.457 TNM stge i 314 0.843 <0.001 ii 280 0.687 iii 299 0.313 iv 400 0.055 Curtive surgery Yes 474 0.790 <0.001 No 820 0.243 Serosl invsion Yes 754 0.206 <0.001 No 540 0.775 Differentition Ppillry denocrcinom 20 0.450 <0.001 Tubulr denocrcinom 578 0.569 Poorly differentited 554 0.403 Mucinous 39 0.237 Luren clssifiction Intestinl 614 0.558 0.004 Diffuse 367 0.392 Mixed 208 0.403 Includes signet-ring cell crcinom. Pts = ptients. tble v Independent prognostic fctors by Cox modelling Vrible Coefficient hr 95% ci p Vlue fp group 0.575 1.777 1.297 <0.001 to 2.437 Sex 0.0.87 0.917 0.759 0.366 to 1.717 Age 0.028 1.029 1.021 <0.001 to 1.036 Tumour size 0.003 1.003 0.989 0.656 to 1.017 Peritonel seeding 0.628 1.874 1.490 <0.001 to 2.356 Liver metstsis 0.575 1.776 1.253 0.001 to 2.519 Lymph node metstsis 0.267 1.306 1.035 0.025 to 1.649 Lymphtic invsion 0.003 1.003 0.809 0.979 to 1.244 Vsculr invsion 0.313 0.731 0.550 0.032 to 0.974 TNM stge 0.417 1.518 1.310 <0.001 to 1.759 Curtive surgery 0.265 1.304 1.054 0.015 to 1.612 Serosl invsion 0.356 1.427 1.142 0.002 to 1.783 Differentition 0.070 1.073 0.928 0.343 to 1.240 Luren clssifiction 0.122 0.885 0.789 to 0.992 0.037 hr = hzrd rtio; ci = confidence intervl; fp = lph-fetoprotein. 0.17% 8.4% in ptients with gstric cncer 3,6,11 14. Clinicl mnifesttions in ptients with fpgc hve rrely been observed becuse of tht smll incidence 15. Furthermore, controversy exists bout those mnifesttions. We observed tht 4.5% of gstric cncer ptients (58 of 1294) hd n bnorml serum fp reding (>20 ng/), proportion tht is comprble with those in other reports. To void confounding fctors in ptients with fpgc, we excluded 37 ptients with liver disese (cirrhosis, heptom, cute heptitis) from the nlysis. Liver metstsis (14.3% 75.6%) is one of the min fetures of fpgc or heptoid denocrcinom of the stomch (hs) 12 14,16. In our series, 16 ptients (27.6%) in the fpgc group were found to hve liver metstsis during follow-up. Tht group more frequently hd liver metstsis thn did ptients with norml serum fp (n = 53, 4.4%, p < 0.001). However, the relted literture describes some different observtions. Nkjim et l. 17 reported tht there ws no correltion between preopertive fp vlues nd histopthology, lymph node metstsis, vessel invsion, nd liver metstsis. e397
CLINICAL MANIFESTATIONS IN AFP PRODUCING GASTRIC CANCER Lymph node involvement hs been reported to be present in 62.9% 100% ptients with fpgc 11 15. Lymph node metstsis ws found more often in our fpgc ptients thn in ptients with norml serum fp (91.4% vs. 60.7%, p < 0.001). Vsculr invsion is very common in fpgc, occurring in 63.5% 75.6% ptients with fpgc or hs 3,6,11,16. In our series, it occurred in 10 ptients (17.2%) with fpgc nd in 47 ptients (3.8%) with norml serum fp (p < 0.001). Lymphtic invsion hs been reported to occur in 71.4% 86.7% of ptients with fpgc or hs 11,12,16,18. In our series, it occurred in 41 ptients (70.7%) with fpgc nd in 738 (59.7%) ptients with norml serum fp (p < 0.001). The lower one third of the stomch is most common loction for fpgc or hs, in the rnge 40% 61.5% 3,6,11 13,16. Our observtion ws similr. In our series, the primry cncer ws bove the ntrum in 29 ptients with fpgc (50%) nd in 646 ptients (52.3%) with norml serum fp. With respect to clinicl stging, the literture reports number of different observtions. In one lrge series (270 ptients), Adchi et l. 15 showed tht most ptients with fpgc hd serosl invsion, lymph node metstsis, nd liver metstsis; three qurters hd stge iii or iv disese. Those uthors found tht the 5-yer survivl rte fter gstrectomy ws only 22%. The poor prognosis ws ttributble mostly to simultneous metstses or erly recurrence in the liver. However, Chun et l. 13 reported tht 74% (n = 26) of their fpgc ptients hd stge i or ii disese. In our study, ptients with norml serum fp were observed to hve more stge i disese (25.2% vs. 3.3% in ptients with fpgc) nd less stge iv disese (27.1% vs. 58.6% in ptients with fpgc, p < 0.001). In our study, more ptients died of gstric cncer in the fpgc group thn in the fp 20 group (58.6% vs. 27.1%, p < 0.001), n observtion tht might be explined by low rte of curtive surgery nd greter rtes of recurrent gstric cncer nd liver metstsis in the ptients with fpgc. In ptients with hs or fpgc, the rte of egc hs been reported to be 0% 42.9% 3,6,11 14,16,19, with most publictions reporting rtes of less thn 10% 6,12,14. However, different observtions hve lso been published. Chun et l. 13 found tht 42.9% of their ptients with fpgc (n = 15) hd erly-stge disese. In our series, egc ws found in 4% of ptients with fpgc (2 of 50), which is rte lower thn tht seen in the ptients with norml fp (349 of 1158, 30.1%, p < 0.001). Our finding is comptible with those in most other reports (0% 19.4%) 6,11,14, which found tht dvnced gstric cncer ws present in most ptients with hs or fpgc 3,6,12,14. In our study, ptients with fpgc more often hd dvnced gstric cncer thn did ptients with norml serum fp (96% vs. 69.9%, p < 0.001). Poorly differentited cncer cells hve been reported to predominte in ptients with fpgc or hs (48.6% 64.4%) 3,12,13,16 ; however, different findings hve lso been reported. In one lrge nlysis of pooled dt from Jpn, Adchi et l. 15 found tht well-differentited cncers ws predominted in ptients with fpgc (n = 218, 87.2%). In our study, the incidence of poorly differentited cncer cells (por 1, por 2, signet-ring cells, mucinous denocrcinom) ws similr in both ptient groups [50% in the fpgc group (n = 23) nd 48.7% in the norml serum fp group (n = 558), p = 0.87]. Surgery is the currently the min therpy for gstric cncer. However, rdicl surgery ws successful in only 6 ptients of our fpgc group (10.3%). In contrst, rdicl surgery ws much more successful in ptients with norml serum fp (n = 468, 37.9%, p < 0.001). Tht difference might explin why the fpgc group hd more liver metstsis nd worse prognosis thn did ptients with norml serum fp. The 5-yer survivl rte in ptients with fpgc hs been reported to be 9% 66% 6,12,13,16. However, there hs been some controversy bout the link between fp nd survivl durtion. Survivl durtion fter surgery hs been found not to be linked to preopertive serum fp 6. Inoue nd collegues observed tht 1 ptient with high serum fp (25,400 ng/) ws still living 12 yers fter dignosis of gstric cncer 6. The lrge Jpnese study using pooled dt lso showed similr results: Adchi et l. 15 found tht 5-yer survivl rtes were not different for ptients with gstric cncer nd serum fp less thn 1000 ng/ (42.7%) or greter thn 1000 ng/ (39.4%). Ngi et l. 20 lso reported tht the 5-yer survivl rte ws 40% in ptients with lower fp nd 38% in ptients with higher fp. Other uthors found tht ptients with fpgc hd shorter survivl durtion. In one lrge series, Liu et l. 3 found tht the 1-, 3-, nd 5-yer survivl rtes for ptients with fpgc were 53%, 35%, nd 28% respectively. Those uthors lso found tht ptients with fpgc or hs hd poorer prognosis thn did ptients who hd lower fp concentrtions (p < 0.01) or non-hs disese (p < 0.05) 3. Chun et l. 13 found tht the 5-yer survivl rte in ptients with fp-producing disese ws significntly poorer thn tht in non-fp-producing group (66% vs. 80%, p = 0.002); however, their reported 5-yer survivl rte ws extremely high compred with tht in other reports. In our study, we found tht 1-, 3-, 5-, nd 10-yer survivl rtes for 20<fp 300 ptients were 46.7%, 28.9%, 17.8%, nd 13.3% respectively. The 1-, 3-, nd 5-yer survivl rtes for fp>300 ptients were 15.4%, 7.7%, nd 0% respectively. Ptients in the fp 20 group hd the best survivl time, nd ptients in the 20<fp 300 group hd the poorest survivl time (p < 0.001, Figure 1). 5. CONCLUSIONS Ptients with fp-producing gstric cncer hd low rte of successful surgery, high rte of liver e398
LIN et l. nd lymph node metstsis, nd very poor prognosis. More ggressive mngement with multimodl therpy (for exmple, chemotherpy, rdiotherpy) might be needed when treting such ptients. 6. ACKNOWLEDGMENT This study ws supported by the Tomorrow Medicl Foundtion (grnt no. 101-2) nd ws presented s poster during Digestive Disese Week t Orlndo, Florid, U.S.A., in My 2013. The uthors express their grtitude to Miss Betty Tzu-En Lin, Mr. Austin Jen- Ling Lin, nd Mr. Alex Jen-Ho Lin for their ssistnce. 7. CONFLICT OF INTEREST DISCLOSURES The uthors declre tht they hve no finncil conflicts of interest. 8. REFERENCES 1. Bergstrnd CG, Czr B. Demonstrtion of new protein frction in serum from the humn fetus. Scnd J Clin Lb Invest 1956;8:174. 2. El-Bhrwy M. Alph-fetoprotein producing non-germ cell tumours of the femle genitl trct. Eur J Cncer 2010;46:1317 22. 3. Liu X, Cheng Y, Sheng W, et l. Clinicopthologic fetures nd prognostic fctors in lph-fetoprotein-producing gstric cncers: nlysis of 104 cses. J Surg Oncol 2010;102:249 55. 4. Sterling RK, Wright EC, Morgn TR, et l. Frequency of elevted heptocellulr crcinom (hcc) biomrkers in ptients with dvnced heptitis C. Am J Gstroenterol 2012;107:64 74. 5. Collier J, Shermn M. Screening for heptocellulr crcinom. Heptology 1998;27:273 8. 6. Inoue M, Sno T, Kuchib A, Tniguchi H, Fukgw T, Kti H. Long-term results of gstrectomy for lph-fetoproteinproducing gstric cncer. Br J Surg 2010;97:1056 61. 7. Chng YC, Ngsue N, Kohno H, et l. Clinicopthologic fetures nd long-term results of lph-fetoprotein-producing gstric cncer. Am J Gstroenterol 1990;85:1480 5. 8. Jpnese Gstric Cncer Assocition. Jpnese clssifiction of gstric crcinom: 3rd English edition. Gstric Cncer 2011;14:101 12. 9. Luren PA, Nevlinen TJ. Epidemiology of intestinl nd diffuse types of gstric crcinom. A time-trend study in Finlnd with comprison between studies from high- nd low-risk res. Cncer 1993;71:2926 33. 10. Sobin LH, Wittekind C, eds. TNM Clssifiction of Mlignnt Tumours. 6th ed. Hoboken, NJ: John Wiley nd Sons; 2002. 11. Bek SK, Hn SW, Oh DY, Im SA, Kim TY, Bng YJ. Clinicopthologic chrcteristics nd tretment outcomes of heptoid denocrcinom of the stomch, rre but unique subtype of gstric cncer. BMC Gstroenterol 2011;11:56. 12. Zhng JF, Shi SS, Sho YF, Zhng HZ. Clinicopthologicl nd prognostic fetures of heptoid denocrcinom of the stomch. Chin Med J (Engl) 2011;124:1470 6. 13. Chun H, Kwon SJ. Clinicopthologicl chrcteristics of lph-fetoprotein producing gstric cncer. J Gstric Cncer 2011;11:23 30. 14. Ucr E, Semerci E, Ustun H, Yetim T, Huzmeli C, Gullu M. Prognostic vlue of preopertive ce, c 19-9, c 72-4 nd fp levels in gstric cncer. Adv Ther 2008;25:1075 84. 15. Adchi Y, Tsuchihshi J, Shirishi N, Ysud K, Etoh T, Kitno S. fp-producing gstric crcinom: multivrite nlysis of prognostic fctors in 270 ptients. Oncology 2003;65:95 101. 16. Liu X, Cheng Y, Sheng W, et l. Anlysis of clinicopthologic fetures nd prognostic fctors in heptoid denocrcinom of the stomch. Am J Surg Pthol 2010;34:1465 71. 17. Nkjim K, Ochii T, Suzuki T, et l. Impct of preopertive serum crcinoembryonic ntigen, c 19-9 nd lphfetoprotein levels in gstric cncer ptients. Tumor Biol 1998;19:464 9. 18. Ishikur H, Fuksw Y, Ogswr K, Ntori T, Tsukd Y, Aizw M. An fp-producing gstric crcinom with fetures of heptic differentition. A cse report. Cncer 1985;56:840 8. 19. Kinjo T, Tniguchi H, Kushim R, et l. Histologic nd immunohistochemicl nlyses of α-fetoprotein producing cncer of the stomch. Am J Surg Pthol 2012;36:56 65. 20. Ngi E, Ueym T, Yo T, Tsuneyoshi M. Heptoid denocrcinom of the stomch. A clinicopthologic nd immunohistochemicl nlysis. Cncer 1993;72:1827 35. Correspondence to: Hwi-Jeng Lin, Division of Gstroenterology nd Heptology, Deprtment of Internl Medicine, Tipei Medicl University Hospitl, Tipei Medicl University, No. 252 Wuxing Street, Tipei 11031 Tiwn. E-mil: buddhistlerning@gmil.com * Division of Gstroenterology nd Heptology, Deprtment of Internl Medicine, Tipei Medicl University Hospitl, Tipei City, Tiwn. School of Medicine, Tipei Medicl University, Tipei City, Tiwn. Division of Gstroenterology, Deprtment of Medicine, Buddhist Dlin Tzu Chi Generl Hospitl, Chi-Yi, Tiwn. Buddhist Tzu Chi University, School of Medicine, Hulien City, Tiwn. Division of Generl Surgery, Veterns Generl Hospitl Tipei, Tipei City, Tiwn. # School of Medicine, Ntionl Yng-Ming University, Tipei City, Tiwn. ** Deprtment of Pthology, Veterns Generl Hospitl Tipei, Tipei City, Tiwn. e399