Yonago Acta medica 2013;56:73–78

Original Article

Clinicopathologic Characteristics and Prognosis of Advanced Gastric Cancer
Simulating Early Gastric Cancer
Hiroaki Saito, Kozo Miyatani, Seigo Takaya, Tomoyuki Matsunaga, Yoji Fukumoto, Tomohiro Osaki, Toshiro
Wakatsuki and Masahide Ikeguchi
Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504,
Japan

ABSTRACT

Key words

gastric cancer.2, 3 On the other hand, Japanese gastriccancer treatment guidelines recommend gastrectomy
with limited lymph node dissection as a curative treatment for early gastric cancers,4 since lower incidence oflymph node metastasis is expected in early gastric cancer.5, 6, 7, 8 The accurate diagnosis of tumor depth prior tosurgery is important since surgeons must decide on thetreatment strategy based on the preoperative findings.
However, the accuracy of preoperative diagnosis of earlygastric cancer is limited and has been reported as 92.4%
to 95.4%.9, 10 This finding suggests that substantial numbers of patients who were clinically diagnosed earlygastric cancer are actually advanced gastric cancer andmight require D2 lymph node dissection as a curative
treatment. Theoretically, additional surgery to achieve
D2 lymph node dissection is required for patients withclinically early but pathologically advanced gastriccancer following gastrectomy with limited lymph nodedissection. However, the feasibility of this additional surgery has not been investigated thus far.
The gross type of gastric cancer is classified into 6
types, 0 to 5, according to the Japanese Classification of
Gastric Cancer (JCGC).11 Types 1, 2, 3 and 4 are basedon the Borrmann classification. Most advanced gastriccancers show Borrmann type appearance while mostearly gastric cancers show type 0 appearance. However,it was reported that some advanced cancers show type 0
appearance like early gastric cancer, namely advanced
gastric cancer simulating early gastric cancer (AGC
simulating EGC).12 The clinicopathologic features andprognosis of Borrmann type advanced gastric cancer,
especially Borrmann type 4 gastric cancer, has been
well characterized thus far.13, 14, 15 However, the clinicopathologic features and prognosis of AGC simulating EGC still remain unclear thus far. Of importance

Gastric cancer is one of the most common cancers inAsia and its mortality still ranks second among all cancer deaths worldwide.1 In Japan, gastrectomy with D2
lymph node dissection is performed safely and is widely
accepted as a standard treatment for locally advanced

Corresponding author: Hiroaki Saito, MD
sai10@med.tottori-u.ac.jp
Received 2013 June 24
Accepted 2013 July 30
Abbreviations: AGC simulating EGC, advanced gastric cancer
simulating early gastric cancer; I-type, infiltrative type; JCGC,
Japanese Classification of Gastric Cancer; L-type, localized type;
LAG, laparoscopy-assisted gastrectomy; MP, muscularis propria;SE, serosa; SS, subserosa

Background Although the clinicopathologic featuresand prognosis of Borrmann type advanced gastriccancer has been well characterized, those of advanced
gastric cancer simulating early gastric cancer (AGC
simulating EGC) still remains unclear.
Methods We reviewed 1985 gastric cancer patients
who had undergone gastrectomy at our hospital to determine the clinicopathologic characteristics, susceptible
sites for lymph node metastasis, and prognosis of AGC
simulating EGC in comparison with Borrmann type advanced gastric cancer.
Results
Among 102 patients with AGC simulating
EGC, 100 patients (98%) had tumors with depressed
type appearance. The frequencies of serosal invasion,
lymph node metastasis, lymphatic vessel invasion, bloodvessel invasion, and liver metastasis were significantly
lower in AGC simulating EGC than in Borrmann typetumors. The prognosis of AGC simulating EGC was significantly better than that of the Borrmann type tumors.
Multivariate analysis indicated that the gross appearance
was an independent prognostic factor. In patients with
AGC simulating EGC which invaded to the the muscularis propria (MP), most lymph node metastasis was restricted with the perigastric lymph nodes (1st-titer lymph
nodes) and lymph node metastasis to 2nd-titer lymph
nodes was only observed at station 8a.
Conclusion AGC simulating EGC is less advanced incomparison with Borrmann type advanced gastric cancer. Based on the results of susceptible sites for lymph
node metastasis in the current study, limited lymph nodedissection could be indicated for AGC simulating EGC
whose depth of invasion is MP.

gastric cancer; gross appearance; lymph
node dissection; prognosis73

H. Saito et al.
Table 1. Clinicopathologic characteristics of AGCs according to gross type appearance
Variable

AGC simulating EGC(n = 102)

Localized type(n = 303)

Infiltrated type(n = 590)

Age, mean (SD), yr		Size, mean (SD), cm		GenderMale
FemaleHistology
DifferentiatedUndifferentiatedSerosal invasion
AbsentPresent
Lymph node metastasis
AbsentPresent
Lymphatic vessel invasion
AbsentPresent
Blood vessel invasion
AbsentPresent
Peritoneal metastasis
AbsentPresent
Liver metastasis
AbsentPresent
Curability
Curative
Non-curative

58.9 (12.5)*
4.7 (2.3)*‡
62 (60.8%)40 (39.2%)
33 (32.4%)*
69 (67.6%)
72 (70.6%)*‡30 (29.4%)
64 (62.7%)*‡38 (37.3%)
48 (47.1%)*‡54 (52.9%)
69 (67.6%)*‡33 (32.4%)
100 (98.0%)‡
2 (2.0%)96 (94.1%)*‡6 (5.9%)97 (95.1%)*‡5 (4.9%)65.6 (11.1)†
6.6 (3.0)†
194 (64.0%)
109 (36.0%)
151 (49.8%)†152 (50.2%)
127 (41.9%)†176 (58.1%)
89 (29.4%)†
214 (70.6%)
67 (22.1%)
236 (77.9%)
93 (30.7%)†
210 (69.3%)
291 (96.0%)†
12 (4.0%)
256 (84.5%)
47 (15.5%)
255 (84.2%)†
48 (15.8%)

60.5 (12.5)
9.7 (4.7)354 (60.0%)236 (40.0%)
144 (24.4%)
446 (75.6%)
104 (17.6%)
486 (82.4%)
117 (19.8%)473 (80.2%)
107 (18.1%)
483 (81.9%)230 (39.0%)
360 (61.0%)474 (80.3%)
116 (19.7%)
509 (86.3%)
81 (13.7%)400 (67.8%)
190 (32.2%)

AGC simulating ECG, advanced gastric cancer simulating early gastric cancer; differentiated, papillary or tubular adenocarcinoma; undifferentiated, poorly differentiated or mucinous adenocarcinoma, or signet-ring cell carcinoma.
* AGC simulating EGC versus localized type; P < 0.05.
† Infiltrated type versus localized type; P < 0.05.
‡ AGC simulating EGC versus infiltrated type; P < 0.05.

is that AGC simulating EGC is likely to be clinicallydiagnosed as early gastric cancer prior to operation.
As a result, limited lymph node dissection might beperformed for those patients, which might be an insufficient treatment according to the Japanese gastric cancer
treatment guidelines. On the other hand, there might bea difference in the 5-year survival rate and clinicopathological characteristics, including susceptible site and theincidence of the lymph node metastasis, between AGC
simulating EGC and Borrmann type advanced gastriccancer. Moreover, if AGC simulating EGC is associatedwith lower incidence of lymph node metastasis and better prognosis, gastrectomy with limited lymph node dissection may provide a suitable curative treatment option.
In the present study, we investigated the clinicopathological characteristics and long-term survival outcomeof AGC simulating EGC and Borrmann type advanced
gastric cancer. Furthermore, the susceptible sites for
lymph node metastasis in AGC simulating EGC werealso evaluated to clarify whether limited lymph nodedissection could be indicated in these patients.

undergone gastrectomy at our institution between January 1975 and December 2000. Ages ranged between
20 and 93 years with an average age of 62 years. The
clinicopathological findings were determined according
to JCGC.11 All had undergone distal partial gastrectomy,
proximal partial gastrectomy or total gastrectomy with
regional lymph node dissection to group 1 (D1), group 2(D2) or group 3 (D3).
At the time of analysis, the median follow-up for1074 survivors was 108 months. Of the 911 deaths, 560
were related to recurrence of gastric cancer, 57 were due
to another malignancy and 279 were due to another disease or accident. The cause of death was unknown in 15
patients.
AGC simulating EGC was defined as advanced gastric cancer with early gastric cancer-like gross appearance (type 0). According to JCGC, the endoscopic classification is as follows: elevated type, I (protruded) and IIa(superficial elevated); flat type, IIb; or depressed type,
IIc (superficial depressed) and III (excavated). There arealso mixed types of tumor, such as IIc + III, IIa + IIc,
etc. The first designation indicates the dominant macroscopic type in the description of a mixed type of tumor.
When the elevated lesion had a depressed area, as in theIIa + IIc type, we classified it as a depressed type tumor
in the present study.

MATERIALS AND METHODSPatients

This study examined 1985 consecutive gastric adenocarcinoma patients, 1266 male and 719 female, who had
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AGC simulating EGC

Statistical analysis

The significance of the differences among the means
was determined by the Mann-Whitney U test. Survival
curves were calculated according to the Kaplan-Meiermethod. Survival data shown in the current study were
for cancer-specific survival. To this end, deaths not fromgastric cancer were considered as lost to follow-up as oftime of death. Differences between survival curves were
examined with the log rank test. Multivariate analysis ofprognostic factors related to survival was performed using the Cox proportional hazards model and a step-wiseprocedure. The accepted level of significance was P <0.05. Stat View software (Abacus Concepts, Berkeley,CA) was used for all statistical analyses.

Fig. 1. The 5-year survival rates in early gastric cancer with invasion to SM, AGC simulating EGC, L-type and I-type tumors, respectively. The prognosis of AGC simulating EGC is significantly
better than that of L-type and I-type, and significantly worse thanthat of early gastric cancer with invasion to SM. AGC simulating
EGC, advanced gastric cancer simulating early gastric cancer; Itype, infiltrative type; L-type, localized type; SM, submucosa.

RESULTS
There were 102 patients (9.4%) with AGC simulating
EGC, 30 patients (2.8%) with Borrmann type 1, 273
patients (25.3%) with Borrmann type 2, 396 patients(36.6%) with Borrmann type 3 and 194 patients (17.9%)
with Borrmann type 4 tumors. Borrmann type 1 and2 tumors were considered localized type (L-type) andBorrmann type 3 and 4 were considered infiltrative type(I-type) in the analysis. Among 102 patients with AGC
simulating EGC, IIa was observed in 2 patients, IIa +IIc in 10 patients, IIc in 74 patients and IIc + III in 16
patients, indicating that 100 patients (98%) with AGC
simulating EGC showed depressed type tumors.
Table 1 shows the correlation between gross appearance and clinicopathologic factors. Patients with AGC
simulating EGC were significantly younger than thosewith L-type tumors. The tumor size of AGC simulating
EGC was significantly smaller than that of L-type andI-type tumors. Undifferentiated carcinoma was more

frequently observed in AGC simulating EGC than in Ltype tumors. The frequency of serosal invasion, lymph
node metastasis, lymphatic vessel invasion, blood vessel
invasion and liver metastasis were significantly lower in
AGC simulating EGC than in L-type and I-type tumors.
Peritoneal metastasis was less frequently observed in
AGC simulating EGC than in I-type tumors. Moreover,a curative operation could be performed more frequently
in patients with AGC simulating EGC than in those with
L-type and I-type tumors.
The 5-year survival rates were 87.8%, 60.7% and32.4% in AGC simulating EGC, L-type and I-type
tumors, respectively (Fig. 1). The prognosis of AGC

Table 2. Association of various factors with survival determined by the Cox proportional hazards model and a
stepwise procedure
Prognostic factor

P value

Hazard ratio

95% CIAge*		
Tumor size*		
Depth of invasion (t2–t4)† 		
Lymph node metastasis (n0–n3)‡
Lymphatic vessel invasion (ly0–ly3)§		
Peritoneal metastasis (absent or present)
Liver metastasis (absent or present)		
Curability (curative or noncurative)
Gross appearance
AGC simulating EGC (versus I-type)L-type (versus I-type)0.00130.0004< 0.0001< 0.0001
0.0108< 0.0001< 0.0001< 0.0001
0.00140.0007

1.013
1.036
1.484
1.460
1.118
1.332
1.446
0.358
0.437
0.677

1.005–1.021
1.016–1.056
1.261–1.748
1.340–1.591
1.026–1.218
1.186–1.496
1.263–1.656
0.278–0.460
0.263–0.727
0.540–0.849

AGC simulating EGC, advanced gastric cancer simulating early gastric cancer; CI, confidence interval; I-type, infiltrative type; L-type,
localized type.
*Continuous variable.
†t2, tumor has invaded the muscularis propria or the subserosa; t3, penetrating the serosa; t4, invading adjacent organs.
‡n0, no regional lymph node metastasis; n1, n2 and n3, metastasis in groups 1, 2 and 3 lymph nodes, respectively.
§Lymphatic invasion: ly0–ly3, grade of lymphatic vessel invasion.

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H. Saito et al.

simulating EGC was significantly better than that of Ltype and I-type. There were 448 early gastric cancer
patients with invasion to the submucosa during the same
period. The 5-year survival rate of these patients was
97.9%, which was significantly better than that of AGC
simulating EGC (Fig. 1). To determine whether AGC
simulating EGC is an independent prognostic factor inadvanced gastric cancer, multivariate analysis using Cox
proportional hazard model and a stepwise procedure
was applied. Multivariate analysis indicated that thegross appearance was an independent prognostic factor
as well as age, tumor size, depth of invasion, lymph nodemetastasis, lymphatic vessel invasion, peritoneal metastasis, liver metastasis and curability (Table 2).
With regard to the mode of recurrence, peritoneal
recurrence (7.8%) was the most frequent site, followed
by hematogenous (5.9%) and lymph node recurrence(1.7%) in patients with AGC simulating EGC (Fig. 2).
Peritoneal recurrence (34.7%) occurred significantly
more than hematogenous (13.7%) or lymph node recurrence (10.5%) in patients with I-type advanced cancer.
On the other hand, hematogenous recurrence (15.5%)
occurred significantly more than peritoneal (8.9%) or
lymph node recurrence (7.6%) in patients with L-typeadvanced cancer.
Figure 3 shows the frequency of lymph node metastasis of AGC simulating EGC according to the depthof invasion. In patients with tumors which invade themuscularis propria (MP), most lymph node metastasis
was restricted with the perigastric lymph nodes (1st-titerlymph nodes) and lymph node metastasis to 2nd-titerlymph nodes was only observed at station 8a. On theother hand, lymph node metastasis to 2nd-titer lymph
nodes was observed at stations 9, 11 and 12a as well as
station 8a in patients with tumor that invaded the subserosa (SS) or penetrated the serosa (SE).

Fig. 2. The site of recurrence in each type of tumor. Peritoneal
recurrence is the most frequent site, followed by hematogenous
and lymph node sites in patients with either AGC simulating EGC
or I-type tumors. On the other hand, hematogenous recurrenceis the most frequent site, followed by peritoneal or lymph noderecurrence in patients with L-type tumors. AGC simulating EGC,
advanced gastric cancer simulating early gastric cancer; I-type,infiltrative type; L-type, localized type.

DISCUSSION
The classification of advanced gastric cancer into 4 grossmorphological types by Borrmann in 192616 is presently
accepted by many surgeons throughout the world.17 This
reflects unique characteristics of each type of tumor ingastric cancer. For instance, Borrmann type 4 gastriccancer can be characterized by a high incidence of poorly differentiated tumor and peritoneal metastasis, andextremely poor prognosis.14, 15 Chen et al. reported that
Borrmann type 1 gastric cancer could be characterized
by its presence in the upper stomach, a high incidence ofFig. 3. The frequency of lymph nodemetastasis at each lymph node stationaccording to the depth of invasion. In
patients with MP tumors, most lymph
node metastasis was restricted with theperigastric lymph nodes (1st-titer lymph
nodes) and lymph node metastasis to 2ndtiter lymph nodes was only observed atstation 8a. On the other hand, lymph nodemetastasis to 2nd-titer lymph nodes wasobserved at stations 9, 11 and 12a as well
as station 8a in patients with SS and SE
tumors. MP, muscularis propria; SE, serosa; SS, subserosa.

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AGC simulating EGC

intestinal type, a less advanced stage and good prognosis.13
In the present study, we demonstrated that the frequencies of serosal invasion, lymph node metastasis,
lymphatic vessel invasion, blood vessel invasion andliver metastasis were significantly lower in AGC simulating EGC than in L-type and I-type tumors. Peritoneal
metastasis was less frequently observed in AGC simulating EGC than in I-type tumors. Furthermore, the prognosis of AGC simulating EGC was significantly better
than that of L-type and I-type tumors. These results
indicate that AGC simulating EGC is less advanced incomparison with Borrmann type advanced gastric cancer. On the other hand, the dominant histological type of
AGC simulating EGC was undifferentiated type, whichis consistent with a previous report.12 With regard to thesite of recurrence, peritoneal recurrence was the mostfrequent site, followed by hematogenous and lymph
node sites in patients with AGC simulating EGC. This
trend was similar to I-type AGC although the recurrence rate was lower in AGC simulating EGC than in Itype AGC. Therefore, AGC simulating EGC has similar
clinicopathologic characters to I-type AGC, indicating
the possibility that AGC simulating EGC might progress
to I-type AGC.
With regard to the differences in biological character, Ichiyoshi et al. demonstrated that the incidence of
p53 overexpression in Borrmann type cancer was higher
than that in AGC simulating EGC in gastric cancer invading the MP. They also demonstrated that the proliferating activity measured by MIB-1 labeling percentage
was higher in Borrmann type cancer than in AGC simulating EGC.18 These results indicate that Borrmann typecancer and AGC simulating EGC are distinct in theirinherent biological nature.
The extent of lymph node dissection is different
depending on the depth of invasion according to theJapanese gastric cancer treatment guidelines.4 In fact,
lymph node dissection of group 1 and group 2 nodes(D2) has been a standard procedure for advanced gastriccancer in Japan. On the other hand, lesser lymph nodedissection is carried out for early gastric cancer patientsto reduce postgastrectomy disorders, because only afew patients have lymph node metastasis. Furthermore,
laparoscopy-assisted gastrectomy (LAG) has increasingly been performed as a minimally invasive surgicaltreatment option for the treatment of early gastric cancer
in Japan.19 The treatment strategy must be decided basedon the preoperative findings. The problem is that the accuracy of preoperative diagnosis of early gastric cancer
is limited. Although intraoperative findings indicating
signs of advanced gastric cancer are often helpful inchanging treatment strategies, it is generally difficult todistinguish pT1 and pT2 gastric cancer, particularly during laparoscopic surgery in which manipulation of thetumor is limited. As a result, we occasionally encountera situation in which the results of a pathological examination of a resected specimen indicate T2 advanced gastric cancer, despite a clinical diagnosis of T1 gastric cancer. Of importance is that AGC simulating EGC can beunderstaged endoscopically and by gross examination,
indicating that LAG with limited lymph node dissection
might be performed for those patients. Theoretically,
additional surgery to achieve D2 lymph node dissection
is required for those patients, followed by gastrectomy
with limited lymph node dissection. In patients with MP
tumors, however, most lymph node metastasis was restricted with the perigastric lymph nodes (1st-titer lymph
nodes) and lymph node metastasis to 2nd-titer lymph
nodes was only observed at station 8a in the present
study. On the other hand, lymph node metastasis to 2ndtiter lymph nodes was observed at stations 9, 11 and 12a
as well as station 8a in patients with SS and SE tumors.
Considering better prognosis of AGC simulating EGC
than that of Borrmann type advanced gastric cancer andresults of susceptible sites for lymph node metastasis,
limited lymph node dissection could be indicated for
AGC simulating EGC whose depth of invasion is MP.
In conclusion, AGC simulating EGC is less advanced
than Borrmann type advanced gastric cancer. Based on
the results of susceptible sites for lymph node metastasis
in the present study, limited lymph node dissection could
be indicated for AGC simulating EGC whose depth ofinvasion is MP.
The authors declare no conflict of interest.
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