Few studies have been conducted on sex differences in the incidence, pathophysiology, and prognosis of gastric cancer (GC).

To analyze the differences in GC characteristics according to sex in patients who underwent surgical treatment for GC.

A total of 2983 patients diagnosed with gastric adenocarcinoma who received surgical treatment at the Seoul National University Bundang Hospital between 2003 and 2017 were included. Baseline clinicopathological characteristics, histologic type of GC, overall and GC-specific survival rates, and associated risk factors were analyzed.

Among the 2983 patients, 2005 (67.2%) and 978 (32.8%) were males and females, respectively. The average age of the female group (59.36 years) was significantly younger than that of the male group (61.66 years; P < 0.001). Cancer of the gastric body (P < 0.001) and diffuse-type histology (P < 0.001) were more common in females than in males. This trend was more prominent in females younger than 60 years of age, with a significantly higher proportion of diffuse-type cancer than in the male group. Regardless of sex, diffuse-type GC was more common in younger patients, and the proportion of intestinal-type GC increased with age. The overall survival rate was significantly higher in females (P < 0.001). However, this difference disappeared for GC-specific survival (P = 0.168), except for the poor GC-specific survival rate in advanced-stage cancer (stage III or above) in females (P = 0.045). The risk factors for GC-related mortality were older age, upper location of GC, and diffuse- or mixed-type histology. In terms of comorbidities, more males died from diseases other than GC, including other malignancies such as lung cancer, hepatocellular carcinoma, and pancreatic cancer, and respiratory diseases such as interstitial lung disease and chronic obstructive pulmonary disease, while there were relatively more cardiovascular or cerebrovascular deaths in females.

Sex-based differences in GC were observed in clinicopathological features, including age at diagnosis, tumor location, histologic type, survival rate, and comorbidities.

Gastric cancer (GC) is the fifth most common cancer and the third most common cause of cancer-related deaths worldwide[1]. Age-standardized incidence rates are approximately twice as high in males than in females[2]. Major risk factors for developing GC include Helicobacter pylori (H. pylori) infection, family history of GC, dietary habits, ionizing radiation, smoking, alcohol, and pernicious anemia, and the difference in incidence between males and females is likely due to the difference in exposure to these risk factors[3-5]. However, these factors alone do not fully explain the different characteristics of GC between the sexes. Recent research has revealed the role of sex hormones in various diseases and the resulting sex differences. It is well known that sex differences exist in the location and prognosis of various cancers, including colorectal cancer[6,7], renal cell carcinoma[8], and bladder cancer[9]. In addition, sex differences are also known in central nervous system diseases such as cognitive disorders, Alzheimer’s disease[10], Parkinson’s disease[11], and autoimmune diseases[12]. However, the role of sex hormones such as testosterone and estrogen in the etiology, response to therapy, and survival of patients with GC, and the involved mechanisms and pathways remain unclear. Also, few studies to date have detailed the epidemiological and prognostic differences in GC between males and females.

Lauren classification is an independent prognostic factor in patients with GC[13]. That is, intestinal-type GC shows better clinicopathological characteristics and prognosis than diffuse-type GC. Diffuse-type cancer exhibits a higher recurrence rate than intestinal-type cancer, and the clinical appearance and survival of mixed-type cancers are known to be similar to those of diffuse-type GC[14]. Environmental factors reportedly play an important role in the development of intestinal-type versus diffuse-type GC[15]. There is also a sex-based difference in the histologic type of GC. That is, there is a marked predominance of older age and male sex in intestinal-type GC and a younger female predominance in diffuse-type GC. Younger female patients seem to exhibit a higher percentage of diffuse-type GC, resulting in more aggressive tumor behavior[14]; therefore, treatment methods may vary according to the Lauren type[16]. From this point of view, we hypothesized that an accurate analysis of sex-based differences in GC is possible in a well-designed surgical cohort with regular follow-up observations, clear histologic results, accurate information on family history, and social history such as smoking and alcohol consumption. Based on this background, the aim of this study was to analyze the sex-based differences in clinicopathological features and staging in GC, and to investigate prognostic factors including survival and death.

To the best of our knowledge, this study is the first to provide evidence of sex differences in GC with exact histologic diagnosis and long-term follow-up in nearly 3000 patients. In our data, a statistically significant overall survival benefit in females and a non-significant GC-specific survival in males were observed. In both males and females, a high proportion of diffuse-type cancers was observed among younger patients, while intestinal-type cancer became more prominent with increasing age. However, more females of all ages had diffuse-type cancer, while the ratio of diffuse-type to intestinal-type cancer was higher in females until the age of 60 years. In addition, the incidence of higher proportion of diffuse-type and gastric body cancers in females, compared to intestinal-type and antral cancers in males could be the reasons for higher N stage and poor GC-specific survival in females. Furthermore, there were also differences in comorbidities, including causes of death other than GC, between males and females.

There are few studies on the prognosis of GC by sex, and sex-based differences in GC are not clear, as in other cancers such as colorectal cancer[6,7]. A recent study based on the Surveillance, Epidemiology, and End Results (SEER) database in the United States reported survival advantages in females[20]. A female advantage was observed in both overall survival and GC-specific survival, and the prognosis of GC and the risk of developing GC were significantly worse in males than in females in that study, so the authors insisted on the necessity for early intervention in high-risk male patients due to their relatively poor prognosis[20]. However, this difference from our results could be due to a difference in the histologic type of GC, with a higher proportion of adenocarcinoma and a lower proportion of signet ring cell carcinoma (SRC), especially in females. In a large meta-analysis of data obtained from the Korea Central Cancer Registry and National Statistical Office reported by Song et al[21], the prognosis of female GC patients was also better than that of male GC patients, with differential incidence and mortality patterns among age groups. However, females tend to have a worse prognosis when they are diagnosed later than 40 years of age. In that study, the histologic type or anatomic subsites of GC could not be identified. Since the 2000s, many early GC (EGC) patients have been identified and treated through a national endoscopic surveillance project in Korea, possibly showing different results from data prior to the 2000s[22]. Contrary to earlier results, a recent study in Korea reported poor prognosis in females[23], similar to the present study. The authors concluded that female GC patients were significantly younger, had more poorly differentiated adenocarcinomas, and were more likely to have SRC than male GC patients. In addition, females with advanced GC (AGC) and SRC had significantly poorer overall survival rates. In our data, among patients with advanced-stage disease (stage III or above), females had significantly lower GC-specific survival rates than males. In our data, the ratio of diffuse-type (undifferentiated) GC was relatively high, especially among younger females. Diffuse-type GC is known to be related to genetic factors such as E-cadherin mutations, feature a poorer prognosis due to rapid growth and poor treatment response, and is generally more common in younger patients[24,25]. Comparing the characteristics of GC in Korea and the United States, more upper-third and differentiated cancers were observed in the United States, while Korean patients showed fewer upper-third cancers with poorer cancer differentiation, deeper invasion, and poorer prognosis; hence, a difference in GC characteristics between Korean and United States populations is suspected[26].

The same results have been shown in previous studies in relation to histologic type and GC location, as more diffuse-type, gastric body location cases were noted in females versus more intestinal-type, stomach antrum location cases in males[27,28]. Based on previous reports on GC location, the distribution was reported as cardia 4%-8%, body 15%-30%, and antrum 60%-80% in a study of EGC in Korea[29]. In another Korean study of patients who underwent endoscopic resection for EGC, the most common location for EGC was the antrum (57.5%) and lesser curvature (37.8%), and body cancers were associated with younger patient age, larger tumor size, and more frequent poorly differentiated or SRC histology than cancers at other sites[30]. Our data are consistent with those of the aforementioned studies, and this relation to histologic type and GC location is believed to be due to differences in the composition of gastric mucous cells, such as the gastric body with a large distribution of parietal cells and the antrum with a large distribution of G cells[31].

The effects of sex hormones may cause this sex-based difference in GC. Epidemiological studies have reported that exogenous sex hormone exposure reduces the risk of esophageal adenocarcinoma[32,33] and esophageal squamous cell carcinoma[34], and a decrease in the risk of GC[35] and colorectal cancer[33,36] have been reported in females taking oral contraceptives or hormone replacement therapy. A large cohort study in Japan also reported that females in early menarche had a decreased risk of GC, especially differentiated-type GC, in subgroup analyses of histologic subtypes[37]. In addition, in a Chinese study of approximately 2000 surgically treated GC patients, the proportion of female GC patients showed a decreasing tendency, and the proportion of male GC patients showed an increasing tendency with age, but this trend stopped after 60 years of age[38]. Furthermore, a recent study in Korea reported that no premenopausal females had intestinal-type GC and that the ratio of intestinal-type GC increased in females after menopause and became similar to that of males about 10 years after menopause; this parity was associated with an increased risk of intestinal-type GC in females after menopause[27].

These results suggest that estrogen plays a role in curbing the development of GC in females, especially in intestinal-type GC. However, the specific mechanisms of estrogen in different histologic subtypes have not yet been established. Several studies have attempted to explain this by investigating the role of estrogen receptors (ER) in GC. First, Yi et al[39] showed that ERα expression was associated with diffuse-type GC and shorter disease-free survival. Wang et al[40] reported that well-differentiated gastric adenocarcinoma has a higher expression rate of ERβ and that poorly differentiated gastric adenocarcinoma is associated with a reduction or loss of ERβ. According to previous studies, diffuse-type GC may be initiated by the downregulation of E-cadherin by 17β-estradiol (E2), the most potent isoform of estrogen, through ERα[41-43].

In addition to the action of estrogen, Gan et al[44] reported that the four sex hormone receptors, ERα, ERβ, progesterone receptor, and androgen receptor (AR), were expressed independently and showed a decreased expression pattern in gastric tumors compared to adjacent normal tissues, suggesting that sex hormone receptors may be partly involved in gastric carcinogenesis. Jukic et al[2] reported a significantly higher frequency of cases with AR-positive cells in the stroma of intestinal-type GC in males than in females, which may be the reason for the greater invasiveness of this cancer type in males and presented the possibility of AR-targeted agents in GC treatment. Another study by Hsu et al[45] showed that males were more likely to develop tumor recurrence and liver metastasis than females, especially in cases of stage III GC. The authors suggested that the cause was higher programmed death ligand 1 expression in males and GC patients aged 65 years or older, and supporting data suggest that sex hormones are the basis of these differences[46,47].

The changes in the proportion of intestinal-type and diffuse-type cancers in the present study suggest that estrogen might have a protective effect on intestinal-type GC[27,28]. Thus, intestinal-type GC is much less common in young females than in males, and the prevalence of intestinal-type GC increases in females after menopause, which is likely to be similar to males about 20 years after menopause according to our data (approximately 70 years of age). Additional in-depth studies are needed to confirm the role of sex hormones, including estrogen, in the pathogenesis and progression of GC, depending on the tissue type.

The pattern of P53 overexpression also differed by sex; P53 overexpression was more frequent in males and intestinal-type GC patients. In our previous report on P53 overexpression, the clinical and prognostic significance differed by histological type of GC; P53 overexpression was more common in intestinal-type GC, but was associated with a poor prognosis for diffuse-type GC[18]. Therefore, it is also likely to act as a factor that affects GC prognosis differently in males and females.

Our study has several limitations. First, the enrolled subjects were patients who underwent surgical treatment after receiving a diagnosis of GC; therefore, early cases treated with endoscopic resection and advanced inoperable cases were not included. Hence, in terms of GC-related survival and mortality, the data from our study are likely to be slightly different from those of all patients with GC. To compensate for this limitation, we are conducting a follow-up study of patients diagnosed with and treated for over 14000 GC in SNUBH. The results of our data analyses to this point showed no significant differences between males and females according to the treatment method. Second, there are no data on estrogen exposure such as menopause, childbirth, and breastfeeding in this study, making it difficult to provide additional evidence that estrogen has protective effects against intestinal-type cancer. Further research, including a history of sex hormone use, is required. Third, the eradication of H. pylori was not confirmed in all patients, although postoperative H. pylori eradication treatment may affect prognosis or survival[17]. In the future, additional research is needed that considers both H. pylori infection and sex. In contrast, our research has several strengths over existing studies. Studies involving subjects before the year 2000 reported that the prognosis of GC was relatively good in females; however, these studies did not reflect the situation in East Asia, where the prevalence of GC is high[20], or the exact histologic type of GC was not analyzed[21]. A relatively recent large-scale Korean study reflecting histological types reported that the prognosis of GC was poorer in females than in males, similar to our results[23]. In this study, the changes in the histology of GC according to age was examined, and the change in the ratio according to aging and menopause was confirmed, suggesting that female hormones would affect the development and progression of GC. However, we further analyzed the comorbidities of GC patients with respect to survival.

In conclusion, differences in the epidemiology of GC incidence, including a higher proportion of diffuse-type histology and mortality, and poorer survival in AGC in females, were observed. The proportion of diffuse-type cancer was found to be higher in younger patients, the frequency of intestinal-type histology increased with age, and the ratio of diffuse-type cancer was higher until the age of 60 years in females. Differences in Lauren histologic type and tumor location by sex were also observed, with a high proportion of diffuse-type and gastric body location in females. Comorbidities, including other malignancies and respiratory diseases, are more common in males. These differences may originate from hormonal factors and should be considered in the diagnosis, treatment, and prediction of prognosis of GC in individuals.