*Department of Radiology, Shinshu University School of Medicine **PET Center, Departments of ***Pathology and ****Radiology, Aizawa Hospital

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1 ORIGINAL ARTICLE Annls of Nucler Medicine Vol. 20, No. 9, , 2006 Evlution of 2-deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomogrphy in gstric crcinom: reltion to histologicl subtypes, depth of tumor invsion, nd glucose trnsporter-1 expression Akir YAMADA,* Kzuhiro OGUCHI,** Mn FUKUSHIMA,*** Yutk IMAI**** nd Msumi KADOYA* *Deprtment of Rdiology, Shinshu University School of Medicine **PET Center, Deprtments of ***Pthology nd ****Rdiology, Aizw Hospitl Objective: Vrible uptke of 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) hs been noticed in positron emission tomogrphy (PET) studies of gstric crcinom ptients, with low uptke occurring especilly in some prticulr histologicl subtypes nd erly crcinoms. But this phenomenon hs not been dequtely explined. The im of the present study is to clrify FDG uptke in gstric crcinoms especilly focusing on histologicl subtypes, the depth of tumor invsion, nd glucose trnsporter-1 (GLUT-1) expression which is considered to be one of the mjor fctors for higher FDG uptke in humn mlignnt tumors. Methods: FDG-PET ws performed on 35 preopertive ptients with gstric crcinom. Forty mcroscopiclly distinguishble lesions on surgicl specimen were histologiclly clssified into two subtypes: Cohesive type (ppillry denocrcinom, tubulr denocrcinom, nd solid type poorly differentited denocrcinom) or Noncohesive type (signet-ring cell crcinom nd non-solid type poorly differentited crcinom). GLUT-1 expression ws immunohistochemiclly determined. Histologicl prmeters (GLUT-1 expression, histologicl subtypes, the depth of invsion, lymphtic permetion, venous invsion nd tumor size) were evluted, nd fctors for FDG uptke (detectbility nd the degree) nd GLUT-1 overexpression were determined by multiple regression nlysis. Results: Nineteen of 40 gstric crcinoms showed detectble FDG uptke (48%), multiple regression nlysis reveled tht both the depth of invsion nd histologicl subtypes re independent fctors tht influence the detectble FDG uptke in gstric crcinom (R 2 = 0.66). GLUT-1 expression ws seen from n erly cncer stge nd the cohesive type ws n independent fctor influencing the overexpression of GLUT-1 (R 2 = 0.66). GLUT-1 expression ws the most influentil fctor for the degree of FDG uptke in gstric crcinom (R 2 = 0.68). Conclusions: This study provided importnt informtion on the clinicl ppliction of FDG-PET in gstric crcinom tht erly or non-cohesive gstric crcinom my show lower FDG uptke. Therefore, the usefulness of FDG-PET for the detection of gstric crcinom is limited. But there is possibility tht FDG uptke ssocited with GLUT- 1 expression my serve s prognostic fctor of gstric crcinom representing tumor metbolism. Key words: gstric crcinom, denocrcinom, 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG), glucose trnsporter type 1 (GLUT-1), positron emission tomogrphy (PET) INTRODUCTION Received April 3, 2006, revision ccepted August 23, For reprint contct: Akir Ymd, M.D., Deprtment of Rdiology, Shinshu University School of Medicine, 3 1 1, Ashi, Mtsumoto, Ngno , JAPAN. E-mil: -ymd@hsp.md.shinshu-u.c.jp 2-Deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomogrphy (FDG-PET) is bsed on the theory tht mlignnt cells show incresed glucose uptke nd glycolysis (the Wrburg effect), 1 while overexpression of glucose trnsporter 1 (GLUT-1) is considered to ply mjor role in the higher FDG uptke by mlignnt cells. 2 5 GLUT-1 is the moleculr species tht ids FDG trnsit from outside the cncer cell to inside the cell. FDG-PET hs been proven to be useful in the evlution of vrious mlignnt neoplsms; 6 14 however, some Vol. 20, No. 9, 2006 Originl Article 597

2 prticulr histologicl subtypes nd erly gstric crcinoms re recognized to show low FDG uptke, with the mechnism underlying this is not yet clrified. 15 From the view point of histologicl subtype, the intestinl type of gstric crcinom ccording to Luren hs been reported to show higher FDG uptke compred to the non-intestinl type. 16,17 GLUT-1 expression in gstric crcinoms hs been lso considered to be ssocited with the intestinl type. 18,19 On the other hnd, dvnced gstric crcinom hs been reported to show higher FDG uptke nd GLUT-1 overexpression compred to erly gstric crcinom. 19,20 The reltionship between higher FDG uptke nd GLUT-1 overexpression hs been implied in gstric crcinom s well s other humn mlignnt tumors, but such reltionship hs not been fully investigted. The im of the present study is to clrify FDG uptke in gstric crcinoms especilly focusing on histologicl subtypes, depth of tumor invsion, nd GLUT-1 expression. MATERIALS AND METHODS Ptients This study group consisted of 40 lesions derived from 35 consecutive ptients (24 men, 11 women; ge, y; men ge, 67.7) with histologiclly proven gstric crcinom by surgicl excision between April nd December Mcroscopiclly distinguishble lesions in one surgicl specimen were counted s independent lesions. Ptients with dibetes mellitus nd/or previous nticncer therpy were excluded. All ptients underwent physicl exmintion, chest roentgenogrphy, double-contrst brium rdiogrphy, upper endoscopy, bdominl contrst enhnced CT, nd FDG-PET to determine the clinicl stge within 2 weeks before surgery. All ptients gve informed consent, nd the study protocol ws pproved by the hospitl ethics committee. PET imging All ptients fsted for t lest 4 hours before PET imging, nd the blood glucose level ws mesured before intrvenous injection of MBq FDG min fter injection of FDG, sttic whole-body PET scn ws performed using n Advnce Nxi PET scnner (Generl Electric Medicl Systems, Milwukee, WI). Emission scns were obtined with 2-min cquisition time t every tble position, requiring 6 or 7 bed positions to cover the ptient from the pelvis floor to the hed. After emission scnning, trnsmission scns were obtined using 68 Ge with 1-min cquisition time t every tble position. The PET imge ws reconstructed by ordered subset expnsion mximiztion (OSEM) lgorithm with segmented ttenution correction (SAC), with the resulting resolution being pproximtely 4.5 mm full-width t hlfmximum (FWHM). Imge nlysis PET imges were compred with the corresponding surgicl specimen nd vilble morphologicl studies (double-contrst brium rdiogrphy, upper endoscopy, bdominl contrst enhnced CT). The degree of FDG uptke of the tumor re ws evluted on subjective semiquntittive scle: no uptke, uncler uptke (diffusely incresed FDG ccumultion indistinguishble from physiologicl gstric uptke), low positive uptke nd high positive uptke. Foclly incresed FDG uptke compred with surrounding tissue ws considered to be positive. In the evlution of detectbility, no uptke nd uncler uptke were considered to be undetectble, nd low nd high positive uptkes were considered to be detectble. Histologicl exmintion Tissue sections were prepred from formlin fixed nd prffin-embedded tissues of gstric crcinom obtined t surgery from this study group. The histopthologicl prmeters (histologicl subtypes, depth of invsion, lymphtic permetion, venous invsion nd tumor size) were evluted ccording to the Generl Rules for the Clinicl nd Pthologicl Recording of Gstric Crcinom by the Jpnese Gstric Crcinom Society. 21 In ddition, we divided gstric crcinoms into two subtypes ccording to Uchino et l., 22 cohesive type, i.e., ppillry denocrcinom, tubulr denocrcinom, nd solid type poorly differentited denocrcinom, nd non-cohesive type, i.e., signet-ring cell crcinom nd non-solid type poorly differentited crcinom. Mucinous denocrcinom ws interpreted s either cohesive or non-cohesive, depending on the other predominnt elements. 21 Furthermore, to clrify the ssocition of GLUT-1 expression nd FDG uptke, we divided gstric crcinoms into four subgroups ccording to histologicl subtypes nd the depth of invsion, 1) erly non-cohesive gstric crcinom (ENGC), 2) erly cohesive gstric crcinom (ECGC), 3) dvnced non-cohesive gstric crcinom (ANGC), 4) dvnced cohesive gstric crcinom (ACGC). Erly gstric crcinom (EGC) is defined s lesion in which the depth of invsion is limited to the mucos, submucos, or both, regrdless of whether regionl lymph node metstsis is evident on histologicl exmintion. 21 This is equivlent to the pt1 ctegory in the ptnm (pthologic tumor/node/metstsis) system of the UICC (Interntionl Union Aginst Cncer) clssifiction. The others were clssified s dvnced gstric crcinom (AGC). Immunohistochemicl nlysis GLUT-1 trnsporters were detected by immunohistochemistry using the lbeled streptvidin biotin (LSAB) procedure. Three micrometer sections were cut from prffinembedded tissue blocks in the middle of the tumor re 598 Akir Ymd, Kzuhiro Oguchi, Mn Fukushim, et l Annls of Nucler Medicine

3 Tble 1 Results of GLUT-1 expression nd FDG uptke in 40 gstric crcinoms Ptient Age Gender Histology ly v T Size GLUT-1 FDG [mm] expression uptke 1 71 M Tub M Tub ± 3 63 M Tub ± 4 53 M Tub ± 5 73 F Por M Por F Por ± 8 73 F Sig ± 9 69 F Sig ± 10 b 66 F Sig Sig F Sig M Sig M Sig ± 14 b 76 M Sig ± Pp M Pp F Tub M Tub ± M Tub ± M Tub M Tub M Tub M Tub b 77 M Tub Tub ± Tub ± F Tub F Tub M Tub M Tub ± M Por F Por F Por M Por M Por M Por M Sig ± 35 b 56 M Sig ± Sig ± According to the Generl Rules for the Clinicl nd Pthologicl Recording of Gstric Crcinom by the Jpnese Gstric Crcinom Society. Pp = ppillry denocrcinom; Tub1 = well-differentited tubulr denocrcinom; Tub2 = modertelydifferentited tubulr denocrcinom; Por1 = solid type poorly differentited denocrcinom; Por2 = non-solid type poorly differentited denocrcinom; Sig = signet-ring cell crcinom; ly = lymphtic permetion; v = venous invsion T = depth of invsion, b Multiple lesions coexisted in one specimen. nd deprffinized. Before the immunohistochemicl procedures, ll sections were unmsked by the microwve method using citrte buffer, ph 6.0 for 40 min. Endogenous peroxidse ws neutrlized with 0.3% hydrogen peroxide for 30 minutes. The smples were then wshed nd incubted t room temperture for 1 hour in 1:50 dilution of the polyclonl rbbit ntihumn GLUT-1 ntibody (A3536; DAKO, Crpinteri, CA) rised ginst 12 mino cid synthetic peptide corresponding to the crboxyl terminus of humn GLUT-1. Prllel sections were incubted with helthy rbbit immunoglobulin G (Ig G) s negtive controls. The smples were then wshed off, nd biotinylted secondry ntibody (DAKO LSAB Kit, biotinylted nti-mouse, nti-rbbit, nd nti-got) ws pplied to the slides for 45 minutes in humidity chmber. The slides were gin wshed nd incubted with streptvidin peroxidse for n dditionl 45 minutes nd then submerged in DAB bth for 5 minutes. Tissues Vol. 20, No. 9, 2006 Originl Article 599

4 Tble 2 Comprison between histopthologicl prmeters nd FDG uptke in gstric crcinom Histopthologicl prmeters FDG uptke Undetectble Detectble p vlue No Uncler Low positive High positive GLUT-1 expression < Negtive Positive Histologic subtypes < 0.01 Non-cohesive type Cohesive type Depth of invsion < T T Lymphtic permetion < None Present Venous invsion < None Present Tumor size < 0.01 < 10 mm mm (< 0.01) b > 30 mm smller thn double of FWHM, b excluding the lesions smller thn double of FWHM were counterstined with hemtoxylin. All slides were exmined by light microscopy. We used the erythrocytes in the tissue sections for the positive control of GLUT-1 expression. Stining ws considered to be positive only when strong membrne ssocited immunorectivity ws observed. 18 GLUT-1-immunostining ws evluted without the clinicl informtion including FDG uptke for ech tumor. GLUT-1-immunorectivity ws evluted for ech tumor bsed on the percentge of tumor cells tht expressed GLUT-1 on subjective semiquntittive scle: no expression (0 1%), low positive expression: (2 30%), nd high positive expression (>30%). Sttisticl nlysis The nonprmetric sttisticl nlysis of FDG uptke nd histologicl prmeters were evluted by chi-squre test. The difference in FDG uptke between subgroups (ENGC, ECGC, ANGC, ACGC) ws evluted using the Kruskl Wllis test. The multiple regression nlysis of FDG uptke (detectbility nd the degree) nd GLUT-1 expression with the histologicl prmeters (lymphtic permetion, venous invsion, depth of invsion, tumor size, histologicl subtypes, nd GLUT-1 expression) were evluted by polytomous universl model using the SPSS softwre (SPSS Inc., Chicgo, IL). The correltion coefficient ws evluted for ech prmeter, nd correlted prmeters were represented by one prmeter to void multicollinerity in multiple regression nlysis of GLUT-1 expression nd detectble FDG uptke. This representtion ws not pplied in the multiple regression nlysis of the degree of FDG uptke to determine the most influentil fctor. Probbility vlues of less thn 0.05 were considered sttisticlly significnt. RESULTS Tble 1 summrizes the tumor chrcteristics, the results of immunohistochemicl findings nd the FDG-PET imging of 35 ptients. The correltions between the histologicl prmeters nd FDG uptke in gstric crcinom re shown in Tble 2. Immunohistochemicl stining of GLUT-1 Twenty-four of the 40 gstric crcinom lesions (60%) showed positive GLUT-1 expression. The positive rte of GLUT-1 expression ws 85% (22 of 26) in the cohesive type nd 14% (2 of 14) in the non-cohesive type. All of the 6 solid type poorly differentited denocrcinoms showed positive GLUT-1 expression (Fig. 1). GLUT-1 expression of gstric crcinom differed significntly between the cohesive nd non-cohesive types (p < ) (Fig. 2). Frequency of GLUT-1 expression in ech subgroup is shown in Tble 3. GLUT-1 expression ws seen from n erly cncer stge nd relted to the cohesive type of gstric crcinom. FDG-PET imging Nineteen of the 40 gstric crcinoms showed detectble FDG uptke (48%), with GLUT-1 overexpression seen in 17 of them (89%). FDG uptke in gstric crcinom 600 Akir Ymd, Kzuhiro Oguchi, Mn Fukushim, et l Annls of Nucler Medicine

5 Fig. 1 Ptient 14, cse of dvnced gstric crcinom, in which cohesive nd non-cohesive types coexisted. : Mcroscopic view of the surgicl specimen with distribution of crcinoms. Entire gstric wll thickening by signet ring cell crcinom infiltrtion nd protruded portion consisting of ppillry denocrcinom in the lesser curvtures (rrow) were observed. b, c: Coronl nd trnsxil imges of FDG PET. Elevted FDG uptke ws visulized in the protruded portion (rrow). No FDG uptke ws seen in the rest of the tumor. d: Corresponding trnsxil CT imge. e: Immunostining with ntiglut-1 showed positive GLUT-1 expression t ppillry denocrcinom component in the protruded portion. f: No GLUT-1 expression ws seen t signet ring cell crcinom component in the rest of the tumor. Fig. 2 Ptient 31, cse of dvnced gstric crcinom (solid type poorly differentited denocrcinom). : Mcroscopic view of the surgicl specimen with distribution of crcinoms. Ulcerted portion consisting of solid type poorly differentited denocrcinom (rrow) ws observed in nterior wll. b, c: Coronl nd trnsxil imges of FDG PET. Elevted FDG uptke ws visulized in the ulcerted portion (rrow) nd seprte lymph node metstses (rrowhed). d: Corresponding trnsxil CT imge. e: Solid type poorly differentited denocrcinom composed of tumor cells with n intimte cohesion, proliferting in solid nests ws observed on HE stining. f: Immunostining with ntiglut-1 showed positive GLUT-1 expression. differed significntly depending on GLUT-1 expression (p < 0.01). The detectble rte of FDG uptke in the cohesive type ws 65% (17 of 26), in contrst to 14% (2 of 14) in the non-cohesive type. All of the 6 solid type poorly differentited denocrcinoms showed detectble FDG uptke (Fig. 1). FDG uptke of gstric crcinom differed significntly between the cohesive nd non-cohesive types (p < 0.01) (Fig. 2). Sttisticl nlysis reveled significnt ssocitions between FDG uptke nd the depth of invsion, lymphtic permetion, nd vsculr invsion (Tble 2). Frequency of detectble FDG uptke in ech subgroup is shown in Tble 4. FDG uptke ws significntly different between subgroups (p < 0.001), nd higher in ACGC. Multiple regression nlysis of GLUT-1 expression nd FDG-PET uptke in gstric crcinom The correltion coefficient of histologicl prmeters in gstric crcinom is shown in Tble 5. The correltion coefficient between GLUT-1 expression nd histologicl subtype ws higher (r = 0.71). The depth of tumor invsion ws correlted to lymphtic permetion (r = 0.82), venous invsion (r = 0.66) nd tumor size (r = 0.58), but its correltion to GLUT-1 expression ws wek (r = 0.36). GLUT-1 expression ws represented by histologicl subtype, nd the other prmeters (lymphtic permetion, venous invsion nd tumor size) were represented by the depth of invsion, respectively in multiple regression nlysis of GLUT-1 expression nd detectble FDG uptke to void multicollinerity. Multiple regression nlysis reveled tht the cohesive type is n independent fctor tht influences the overexpression of GLUT-1 in gstric Vol. 20, No. 9, 2006 Originl Article 601

6 Tble 3 Frequency of positive GLUT-1 expression in gstric crcinom Histologicl subtype Depth of invsion EGC AGC b Non-cohesive 0% (0/9) 40% (2/5) Cohesive 75% (6/8) 89% (16/18) erly gstric crcinom, b dvnced gstric crcinom Tble 4 Frequency of detectble positive FDG uptke in gstric crcinom Histologicl subtype Depth of invsion EGC AGC b Non-cohesive 0% (0/9) 40% (2/5) Cohesive 25% (2/8) 83% (15/18) erly gstric crcinom, b dvnced gstric crcinom Tble 5 The correltion coefficient of histologicl prmeters in gstric crcinom Prmeters GLUT-1 subtype T b ly c v d Size GLUT subtype T b ly c v d Size cohesive or non-cohesive type, b the depth of invsion, c lymphtic permetion, d venous invsion Tble 6 The multiple regression nlysis of GLUT-1 expression with the histologicl prmeters in gstric crcinom Prmeters B p vlue Histologicl subtypes b Depth of invsion regression coefficient, b cohesive or non-cohesive type Tble 7 The multiple regression nlysis of FDG uptke with the histologicl prmeters in gstric crcinom Prmeters Detectble FDG uptke Degree of FDG uptke B p vlue B p vlue GLUT-1 expression Histologicl subtypes b Depth of invsion Lymphtic permetion Venous invsion Tumor size regression coefficient, b cohesive or non-cohesive type crcinom (p = 0.001) (R 2 = 0.66), but the correltion between the depth of tumor invsion nd GLUT-1 expression ws wek (p = 0.164) (Tble 6). Both the depth of invsion (p = 0.005) nd the cohesive type (p = 0.005) were independent fctors influencing the detectble FDG uptke in gstric crcinom (R 2 = 0.66) (Tble 7). Multiple regression nlysis lso reveled tht the GLUT-1 expression is the most influentil fctor for the degree of FDG uptke in gstric crcinom (p = 0.021) (R 2 = 0.68). DISCUSSION The results of this study clrify tht the degree of FDG uptke in gstric crcinom is relted to GLUT-1 overexpression. On the other hnd, the detectbility of gstric crcinom in FDG-PET depends on histologicl subtype nd the depth of tumor invsion. In other words, the non-cohesive type of gstric crcinom tends to be undetectble in FDG-PET becuse GLUT-1 overexpression is relted to the cohesive type of gstric crcinom. And lso erly gstric crcinom tends to be undetectble in FDG-PET regrdless of histologicl subtype or GLUT- 1 expression. The ssocition of GLUT-1 overexpression nd high FDG uptke hs been reported in vrious mlignncies. 2 5 In gstric crcinom, Kim et l. showed tht GLUT-1 expression is ssocited with the intestinl type of gstric crcinom. 18 On the other hnd, Sthl et l. reported tht the intestinl type shows high FDG uptke compred to the non-intestinl type. 16 These studies suggested n ssocition between FDG uptke nd GLUT-1 expression in gstric crcinom, while the present study clrified for the first time tht direct correltion exists between the two. Moreover, the mrked differences in FDG uptke nd GLUT-1 expression between solid type poorly differentited denocrcinom nd the other nonintestinl type of gstric crcinoms described in this study hve never been reported before. The reson for this difference in FDG uptke nd GLUT-1 expression between the cohesive nd non-cohesive types is uncler, but my be relted to oncogenic ltertions of glucose metbolism. Uchino et l. clssified gstric crcinoms into cohesive nd non-cohesive types nd showed tht p53 ltertion occurs selectively in the 602 Akir Ymd, Kzuhiro Oguchi, Mn Fukushim, et l Annls of Nucler Medicine

7 former from the intrmucosl cncer stge. 22 Solid type poorly differentited denocrcinom is included in the cohesive type nd thought to be trnsformed from the intestinl type The humn p53 gene is tumor suppressor gene, nd the ltertion is commonly seen in humn solid tumors where it plys role in tumor survivl from hypoxic cell deth. 26 The mechnism of p53 ltertion nd GLUT-1 overexpression is not fully clrified; however, the up-regultion of GLUT-1 expression medited by hypoxi-inducible trnscription fctor 1 lph (HIF-1α) ctivtion my be ssocited. 27 The ltertion of p53 is lso responsible for ctivting type-ii-hexokinse (HKII), which plys role in the initition nd mintennce of high rtes of glucose ctbolism in rpidly growing tumors. 28 The correltion of HKII overexpression nd high FDG uptke hs been reported in mlignnt tumors. 29 On the other hnd, p53 ltertion is rrely seen in the non-cohesive type of gstric crcinom. 22 Therefore metbolic dpttion including GLUT-1 overexpression my not occur nd result in low FDG uptke. The low tumor cell density nd rich strom could be nother possible reson of lower FDG uptke of noncohesive type of gstric crcinom. Our results lso showed higher FDG uptke in progressive gstric crcinoms represented s the depth of invsion, lymphtic permetion, vsculr invsion nd the tumor size. Incresed glycolysis to mintin cell division nd tumor growth is considered to be the cuse of higher FDG uptke in dvnced crcinom. 20 In this study group, the size of ll tumors ws lrger thn FWHM (4.5 mm), but two of the erly gstric crcinoms were smller thn double of FWHM (9.0 mm). Although erly crcinom tended to be smller thn dvnced crcinom (r = 0.58), the evlution of FDG uptke excluding these smller lesions showed significnt difference depending on the tumor size. Therefore not only the prtil volume effect nd the physiologicl mucosl FDG uptke including inflmmtion but lso lower tumor metbolism could be possible resons for the lower detection rte of FDG-PET study in erly gstric crcinom. 16,20 As our results showed, the degree of FDG uptke is well relted to GLUT-1 expression. There were lso significnt ssocitions between GLUT-1 positivity nd dverse tumor fetures nd survivl. 19 Therefore the degree of FDG uptke ssocited with GLUT-1 expression my be prognostic fctor of gstric crcinom representing tumor metbolism. A limittion of our study is tht the evlution of FDG uptke ws not mde by quntittive wy such s stndrdized uptke vlue (SUV). But gstric mucos often shows physiologiclly higher uptke nd sometimes the tumor re is difficult to distinguish from norml mucos. In this study group, more thn hlf of gstric crcinoms were undetectble mking it difficult to determine proper SUV. We decided this effect is not ignorble nd chose semiquntittive visul evlution for this study s prcticl wy. In our multiple regression nlysis, R 2 ws 0.68 for FDG uptke in gstric crcinom, which mens twothirds of the phenomenon cn be explined by the histologicl prmeters considered in this study, but the other third is of unknown fctors. Further investigtion of the ssocition of p53 ltertion nd glucose metbolism including the expression of HIF-1α, nd HKII is needed to clrify the mechnism of high FDG uptke in gstric crcinom. In conclusion, GLUT-1 overexpression is highly correlted to the cohesive type of gstric crcinom nd the most influentil fctor of higher FDG uptke. On the other hnd, the detectbility of gstric crcinom in FDG-PET depends on not only the histologicl subtype but lso the depth of tumor invsion. From these conclusions, this study provided importnt informtion on the clinicl ppliction of FDG-PET in gstric crcinom tht erly or non-cohesive gstric crcinom my show lower FDG uptke. Therefore, the usefulness of FDG-PET for the detection of gstric crcinom is limited. But there is possibility tht FDG uptke ssocited with GLUT-1 expression is prognostic fctor of gstric crcinom representing tumor metbolism, nd further investigtion is needed. ACKNOWLEDGMENTS The uthors re grteful to Drs. Kyoko Higuchi, Ktsunori Tuchi, nd Kzunobu Miyt for their co-opertion; Kouichi Anzi, Muneki Kimur, nd Kentrou Kinoshit for PET opertion; nd the stff of the PET center, Deprtments of Rdiology nd Pthology, Aizw Hospitl for their ssistnce. REFERENCES 1. Wrburg O. On the origin of cncer cells. Science 1956; 123: Brown RS, Whl RL. Over expression of Glut-1 glucose trnsporter in humn brest cncer: n immunohistochemicl study. Cncer 1993; 72: Higshi T, Tmki N, Hond T, Torizuk T, Kimur T, Inokum T, et l. FDG uptke, GLUT-1 glucose trnsporter nd cellulrity in humn pncretic tumors. J Nucl Med 1998; 39: Aloj L, Crco C, Jgod E, Eckelmn WC, Neumnn RD. 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