Incidence and Long-term Outcome of Young Patients With Gastric Carcinoma According to Sex: Does Hormonal Status Affect Prognosis?

Background  We investigated the clinicopathological features and evaluated the prognostic impact of age and sex on patients with gastric cancer.

Design  Retrospective study from 1993 to 2000.

Setting  Korea University Medical Center.

Patients  A total of 1299 patients with gastric cancer were divided into young (n = 175 [13.5%]) and older (n = 1124 [86.5%]) groups with an age cutoff of 40 years.

Main Outcome Measures  Clinicopathological characteristics were investigated and survival analysis was performed according to sex for each age group.

Results  Tumor differentiation was significantly different between the 2 age groups. Among male patients, the young group had more undifferentiated tumors than the older group (P < .001) but, in female patients, both differentiation (P < .001) and operative methods (P = .008) were significantly different between the young and older groups. In male patients, the 10-year survival rate of the young group was higher (62.5%) than that of the older group (44.6%) (P = .03). Although it was not statistically significant, the survival rate of the older female group was higher than that of the young group (56.2% vs 51.9%). On multivariate analysis, tumor stage (P < .001) and sex (P = .042) were proved to be independent prognostic factors.

Conclusions  Only tumor differentiation was an important difference between the 2 age groups, and prognosis was not affected by age. However, when sex was added to age as a factor, the older male and young female groups had an unfavorable prognosis. Therefore, we propose that sex hormones such as estrogens contribute to the survival differences, and further studies are needed to confirm this possibility.

Gastric carcinoma is usually a disease of the aged, with a mean age of approximately 50 to 60 years¹; patients younger than 40 years represent 2% to 8% of all patients with gastric carcinoma.² The question of whether gastric carcinoma in young patients is different from that in older patient has been raised but remains unresolved. Some authors have suggested that young patients have a worse prognosis, and this is thought to be due to delayed diagnosis and more aggressive tumor behavior. Others have shown that age is not an independent factor for survival.^3-8

Recently, the prognostic effect of sex hormones in the development of gastric carcinoma has been studied,⁹ and the presence of estrogen receptors has been shown to be associated with poor survival in young patients with gastric carcinoma.^10,11 In other reports, the presence of androgen receptors was found to be an independent unfavorable prognostic factor in gastric cancer.¹² Therefore, the relationship between sex hormones and the prognosis of gastric cancer remains unclear.

Although there is a difference according to sex, the status of sex hormones is dependent on age. Thus, both age and sex should simultaneously be considered to precisely evaluate the impact of sex hormones on the prognosis of gastric cancer. Therefore, in this study, we retrospectively analyzed the clinical and pathological factors for young patients with gastric cancer and compared the findings with those of their counterparts according to sex.

From January 1, 1993, to December 31, 2000, a total of 1299 patients with gastric carcinoma underwent surgery at the Department of Surgery, Korea University Medical Center. Of these patients, 175 were 40 years or younger, and they were classified as the young group; the remaining 1124 patients were classified as the older group. We then compared the clinical and pathological features between the young group and the older group according to sex.

The features compared were operative method (gastric resection, gastrojejunal bypass, and no surgical procedure [opening and closure]), tumor location, histologic differentiation, curability, depth of invasion, lymph node metastasis, and TNM stage.

A survival analysis was performed, and the 10-year survival rate was compared according to age and sex. Finally, we performed multivariate analysis to determine the independent prognostic factors by Cox proportional hazards regression model.

For the statistical analysis, SPSS 13.0 for Windows (SPSS Inc, Chicago, Illinois) was used. The clinical variables were analyzed with the χ² test and the independent paired t test. The survival rates were calculated by the Kaplan-Meier method, and outcomes of treatment were compared with the log-rank test. P<.05 was considered statistically significant.

Of 1299 patients, 175 (13.5%) (100 male [7.7%] and 75 female [5.8%]) were classified in the young group, and the male to female ratio was 1.33. The remaining 1124 patients (86.5%) (765 male [58.9%] and 359 female [27.6%]) were classified as the older group, and the male to female ratio was 2.13. In total, 865 (66.6%) were male and 434 (33.4%) were female, and the sex ratio was 1.99.

For both sexes, the young group had more undifferentiated tumors (63.0% in males and 93.3% in females) than the older group (40.1% in males and 58.2% in females), and this difference was statistically significant (P < .001) (Table 1). For male patients, the histologic differentiation was the only statistically significant factor (P < .001). For females, both histologic differentiation and operative methods were significantly different between the young and the older groups (P < .001 and P = .008, respectively). For female patients, no surgical procedure (opening and closure) was performed in 8 patients (10.7%) in the young group and 11 patients (3.1%) in the older group because of multiple seeding of the peritoneum.

Other variables, such as tumor location, curability, depth of invasion, lymph node metastasis, and overall TNM stage, were not statistically significantly different between the 2 groups for either sex (Table 1).

When the 10-year survival rate was compared between the 2 age groups in all patients, the young group showed a better overall survival than the older group; however, this difference was not statistically significant (P = .10). When the 10-year survival rate was compared between sexes, female patients showed a better survival rate than males, but this difference was not statistically significant (P = .08). When all patients were divided into 4 groups according to age and sex and the 10-year survival rates were compared, for male patients the overall 10-year survival rate was best for the young male group (62.5%) and worst for the older males (44.6%), and this difference was statistically significant (P = .03) (Figure 1). In contrast, however, the survival rate for female patients in the older group was higher than that of the young group, but this difference was not statistically significant (56.2% vs 51.9%; P = .33) (Figure 2).

When the survival rates of patients who underwent curative resection were compared, there was a significant difference between the young male and older male patients in favor of the young group (P = .03) (Figure 3). However, the survival result was reversed between the older and young female patients, although the difference was not significant (P = .30) (Figure 4).

On univariate survival analysis, the statistically significant prognostic factors were sex, age, tumor differentiation, and cancer stage. By Cox proportional hazards model, cancer stage and sex were proved to be statistically significant (Table 2).

Surgery is the only potentially curative modality for patients with localized gastric tumors, and it has been shown that curative resection offers the only chance of long-term survival in patients with this disease.^1,13

In this study, we performed curative resection in 82% of the patients in the young group and in 79% of the patients in the older group; however, this difference was not statistically significant.

A comparative study in Japan demonstrated different features of gastric cancer between patients younger than 40 years and patients older than 70 years.¹³ In our study, we chose 40 years of age as the cutoff between the young and older groups. Generally, the average perimenopausal age range is 45 to 55 years. In our analyses, the average age of the young female group was about 34 years and that of the older group was 59 years. This suggests the possibility of sex hormone differences between the 2 age groups in our study. Also, we performed additional survival analyses by moving the cutoff age by 10 years, but there were no survival differences or other relevant findings, so we kept the cutoff value at 40 years in our study.

Earlier reports showed a higher incidence of gastric cancer in males and in patients with advanced age but a higher proportion of females among younger patients than older patients. Our study supports this finding of a relatively higher proportion of female patients in the young group.^4,7,14-16 In our series, the male to female ratio for all patients 40 years or younger was 1.33, and it was 2.13 for the remaining patients. The reason for this high number of female patients in the young group is not known. Nevertheless, male patients might have more frequent and prolonged exposure to environmental carcinogens than females, which might explain the male preponderance among the older patients.¹⁷

In the present study, comparison of histologic differentiation showed that the young group had more poorly differentiated tumor types in both sexes, this finding being in agreement with studies by several other groups.^2,4,15,18 Nakamura et al¹⁵ analyzed the pathological findings and prognosis of gastric carcinoma in young and elderly patients and found that 45.5% of early gastric carcinomas in elderly patients were well-differentiated adenocarcinomas, whereas a greater incidence of poorly differentiated adenocarcinoma was identified in the young patients. In agreement with other studies, young age at onset of gastric cancer appears to be associated with the diffuse type by the Lauren classification.^4,19 In our study, we could not comment on the Lauren classification; nevertheless, our findings suggest that the diffuse type would be more prominent in young patients with gastric cancer.

Earlier reports showed that the prognosis of patients with early onset of gastric carcinoma was poor, with a short survival potential, especially in patients who presented with advanced gastric carcinoma.^15,20,21 Delay in diagnosis and more aggressive biological behavior of gastric carcinoma in young patients have been suggested as possible causes of the poor prognosis.^6-8 In a few reports, however, the prognosis of patients with early-onset gastric cancer who underwent gastrectomy was better than that of older patients.^22,23 In our cases, the 10-year survival rates were 58.1% in the young group and 48.1% in the older group. When curative resection was performed, the 10-year survival rates were 64.8% and 53.2% in the young and older groups, respectively. Therefore, the survival for the young patients with gastric cancer in our study was superior to that of the older group; however, these differences were not statistically significant. Although we did not match the survival outcome with the stage of disease, the findings indicate better outcome with surgical resection in younger patients with gastric cancer. By contrast, recent reports show no difference in surgical outcomes between older and younger patients with gastric cancer^2-5,21; therefore, age does not appear to be an independent risk factor. However, when the survival was analyzed between the age groups by sex, we found that the young group had a better survival outcome for males and the older group had a better survival outcome for females. Yamachika et al²⁴ reported that expression of the intestinal trefoil factor was correlated with a poor prognosis in patients with gastric cancer. Intestinal trefoil factor expression appears to be induced by estrogens in breast cancer cells.²⁵ Although women are more likely to express intestinal trefoil factor, its expression in men has also been correlated with more aggressive tumor phenotype and significantly poorer survival. Furthermore, some studies have reported pregnancy as a poor prognostic factor for patients with gastric cancer.^26,27

Hormonal differences, therefore, appeared to be an important factor for prognosis in patients with gastric cancer. Harrison et al²⁸ proposed that estradiol is trophic to gastric cancer cell lines in in vitro experiments and suggested that the estradiol receptor D5 antibody could be an independent negative prognostic factor for patients with gastric cancer.¹¹ Matsui et al¹⁰ immunohistologically investigated sex hormone receptors in 107 patients with gastric cancer who underwent curative resection and found that the estrogen receptor–positive rate was slightly higher in young females and in patients with poorly differentiated gastric cancer. Others proposed a suppressive effect of sex hormones on the spreading of stomach cancer; Furukawa et al²⁶ suggested that female sex hormones or their analogues may play a suppressive role in carcinogenesis or progression of stomach cancer, and that pregnancy and delivery may accelerate growth of stomach cancer cells. In a 2004 report, Lindblad et al²⁹ proposed a reduced risk of gastric cancer in a male cohort exposed to estrogens, thus supporting the hypothesis that estrogens may play a preventive role in gastric cancer. The foregoing studies strongly suggest that sex hormones, especially estrogens, affect the invasiveness and progression of gastric cancer, and that our results are consistent with these findings. In multivariate analyses, the independent prognostic survival factor was sex. Also, the survival shown in this study was not disease-adjusted but overall survival. Therefore, we hypothesized that the survival difference in male patients is due to the impact of age, but in female patients it may be due to a hormonal effect.

In Korea, gastric cancer is a leading cause of cancer-related death, and several studies have shown epidemiologic factors associated with the prognosis of gastric cancer, especially in regard to age. Our surgical outcomes for gastric cancer may reflect those of other cancer treatment institutions in Korea because of the large number of cases (1299) and the long-term follow-up period of approximately 10 years.

In this study, we performed comparative and survival analyses of the prognostic effect of age and sex, and the present findings strongly suggest that a single age factor does not appear to be meaningful for epidemiologic evaluation of gastric carcinomas in regard to prognosis.

When the clinical and pathological factors were compared between young and older patients with gastric cancer, tumor differentiation was the only significant factor. The prognosis for patients with gastric cancer was the best for the young male group and the poorest in the older male group. For female patients with gastric cancer, the prognosis for the older group was better than that for the young group. There may be important hormonal influences on the prognosis of gastric cancer, and further investigation is needed for a deeper understanding of hormonal influences on gastric cancer.

Correspondence: Sung-Soo Park, MD, PhD, Department of Surgery, Korea University College of Medicine, Korea University Anam Hospital, Anam-dong 5-ga Seongbuk-gu, Seoul, 136-705, Korea (kugspss@korea.ac.kr).

Accepted for Publication: May 4, 2007.

Author Contributions:Study concept and design: J.-H. Kim, S.-S. Park, C.-S. Kim, and Mok. Acquisition of data: J.-H. Kim, Boo, J.-M. Park, S.-S. Park, and S.-J. Kim. Analysis and interpretation of data: J.-H. Kim and S.-S. Park. Drafting of the manuscript: J.-H. Kim, Boo, J.-M. Park, S.-S. Park, and Mok. Critical revision of the manuscript for important intellectual content: J.-H. Kim, S.-S. Park, S.-J. Kim, and C.-S. Kim. Statistical analysis: J.-H. Kim and S.-S. Park. Obtained funding: J.-H. Kim and S.-S. Park. Administrative, technical, and material support: J.-H. Kim, S.-S. Park, and Mok. Study supervision: J.-H. Kim and S.-S. Park.

Financial Disclosure: None reported.