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Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 3094-3103 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.08.987 Clinicopathologic Behavior of Gastric Adenocarcinoma in Hispanic Patients: Analysis of a Single Institution's Experience Over 15 YearsFrom the Departments of Gastrointestinal Medical Oncology, Biostatistics and Applied Mathematics, Medical Informatics, Radiation Oncology, Surgical Oncology, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to James C. Yao, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jyao{at}mdanderson.org
PURPOSE: To determine the clinicopathologic behavior of gastric adenocarcinoma in Hispanics by comparing Hispanic and non-Hispanic patients treated at a single cancer center.
PATIENTS AND METHODS: Medical records of patients with invasive gastric cancer treated from 1985 to 1999 were reviewed. Diagnoses were pathologically confirmed. Differences in categorical variables were assessed using the RESULTS: Of 1,897 patients, 301 (15.9%) were Hispanic. Hispanics were significantly younger at diagnosis than non-Hispanic whites (53.1 ± 14.4 years v 59.4 ± 12.7 years, respectively; P < .005) or African Americans (57.6 ± 15.3 years, P < .005). Hispanics were less likely to have proximal gastric cancers compared with whites (38.9% v 59.5%, respectively; P < .005). Hispanics were more likely to have mucinous/signet-ring type histology (42.5%) than whites (27.4%) and African Americans (32.5%; P < .005). Hispanics were more likely to require total gastrectomy (51%) compared with whites (38%), African Americans (38%), and Asians (36%; P = .039). Among patients with metastases at diagnosis, Hispanics were less likely to have liver metastasis than whites (30% v 44%, respectively; P = .009) but more likely to have peritoneal metastasis than whites and African Americans (54% v 41% and 47%, respectively; P = .002). In Cox analyses, Asian race, earlier stage, papillary/tubular histology, distal location, and younger age were favorable predictors of survival. CONCLUSION: Hispanic ethnicity does not impact survival in gastric adenocarcinoma. However, histology, metastasis pattern, tumor localization, and other clinical parameters differ sufficiently to warrant further investigation into the epidemiology, pathogenesis, and molecular biology of gastric cancer in this population.
Gastric cancer, the second leading cause of cancer-related deaths worldwide, is more commonly diagnosed in Hispanics than in non-Hispanic whites in the United States.1 Hispanics are the largest minority group in the United States, and their population is projected to double by 2030.2 Although the overall gastric cancer rate and the rates in non-Hispanic whites and African Americans have declined in the United States over the past few years, the rate in Hispanic Americans has remained rather steady in a dramatically increasing population.3 However, the clinicopathologic features of gastric cancer in this population are not well defined, with most published studies on the effect of race on gastric cancer focusing on Asians or African Americans. Despite its declining incidence in Western Europe and the United States,4 gastric cancer continues to have a major negative impact on public health. Differences in survival have been reported between different countries and between different racial and ethnic groups within a given country or countries. Most literature of the past decade has dealt with apparent survival advantage of Asian populations5-10 and worse prognosis experienced by African Americans.7,11,12 Several theories have been proposed to explain the racial and ethnic differences associated with gastric adenocarcinoma, including ethnicity-related tumor biology. For example, Asian patients may develop tumors that are less aggressive and confer superior survival.9,13 Additionally, Helicobacter pylori infection, which is associated with the development of gastric adenocarcinoma development, may be more prevalent in African American and Hispanic populations.14,15 Stage migration has also been suggested as a partial explanation for the markedly superior survival observed in Japanese populations compared with American and European populations. Because Japanese pathologists diagnose malignancy based on nuclear and structural criteria in the absence of invasion16 and because Japanese patients are much more likely to have had a D2-level lymph node dissection and a pathologic analysis of their additional lymph nodes,5,6 cancer in Japanese patients is more likely to be assigned to a higher stage than equivalent non-Japanese patients, and thus, Japanese patients will have superior survival when stratified by stage.9 Hispanic patients have been described as having an increased risk for gastric cancer compared with the risk in other ethnic groups1; associations with H pylori infection, intestinal metaplasia,17 and Epstein-Barr virus18 have been proposed as possible causes. Currently, the available data on gastric cancer in Hispanic patients concern only incidence, prevalence, mortality, and postsurgical outcome. Differences in presentation and survival between Hispanics and persons of other races and ethnicities remain incompletely delineated. Therefore, we attempted to better define these differences by analyzing the effect of race and ethnicity on gastric adenocarcinoma in patients who were treated over a 15-year period at The University of Texas M.D. Anderson Cancer Center (Houston, TX), a comprehensive cancer center with a diverse patient population including Hispanic, African American, Asian, and non-Hispanic white patients.
Patients All patients with invasive gastric adenocarcinoma who were treated from 1985 to 1999 at The University of Texas M.D. Anderson Cancer Center were identified, and their data were entered into a confidential retrospective database. Histologic confirmation of gastric adenocarcinoma was obtained from the Department of Pathology. Other gastric tumors, such as neuroendocrine tumors, lymphoma, sarcoma, or adenocarcinoma in situ, were excluded from this analysis. The study was approved by the Institutional Review Board of the M.D. Anderson Cancer Center. Following the classification system used by the Surveillance, Epidemiology, and End Results program,19 we divided patients into five racial and ethnic groups, namely, non-Hispanic white, Hispanic, African American, Asian, and Native American.
Study Design
Statistical Analyses
Median survival duration was determined by the Kaplan-Meier method. Cumulative survival of all ethnicities and of individual pairs of ethnic categories was compared using the log-rank test. A multivariate Cox proportional hazards model was constructed to assess the effects of race and/or ethnicity, AJCC stage, WHO histology, tumor location, age at diagnosis, and sex on survival. Adjusted hazard ratios with associated 95% CIs were calculated. Furthermore, patients who had undergone surgery were compared by ethnic category for differences in the location and type of surgery and the extent of node dissection by
Patients Of the 1,920 patients with gastric adenocarcinoma eligible for our study, we included 1,897; 19 patients were excluded because of missing ethnicity data, and four patients who were either American Indians or Alaskan Natives were excluded because of their small numbers. The largest group was non-Hispanic white patients (n = 1,352, 71.3%). The rest of the patients were Hispanic (n = 301, 15.9%), African American (n = 163, 8.6%), or Asian (n = 81, 4.3%; Table 1). Men (n = 1,292, 68.1%) outnumbered women (n = 605; 31.9%) overall and within each racial or ethnic group. Significant differences between races and/or ethnicities were noted in sex distribution of disease, mean age at diagnosis, tumor location, WHO histology, and AJCC stage (P < .005; Table 1).
Age at Diagnosis Hispanics were younger then all other racial or ethnic groups at time of diagnosis. Although the mean age of all patients was 58 years (standard deviation = 13.6), the mean age of Hispanics was 53 years (standard deviation = 14.4). Compared separately, Hispanics were significantly younger than non-Hispanic whites (mean difference, –6.32 years; P < .005) and African Americans (mean difference, –4.51; P = .003) at diagnosis.
Cancer Localization and WHO Histology Compared with all other races combined, Hispanics had a borderline significantly higher rate of involvement of the whole stomach (P = .054). This borderline statistical difference was most pronounced between Hispanics and non-Hispanic whites (P = .057). Hispanics had the highest frequency of mucinous/signet-ring pathology (42.5%; P < .005). Comparatively, mucinous/signet-ring histology was present in 27.4% of non-Hispanic white patients. Whites and African Americans had a higher frequency of poorly differentiated or tubular papillary histology (Table 1).
AJCC Stage
Therapy for Patients With Locoregional Disease A total of 1,247 surgical procedures in the 1,897 patients were recorded. Of these, 587 were performed at M.D. Anderson, and 660 were performed at other institutions. No significant differences were observed in the percentage of patients receiving preoperative therapy. In the time period that this data was collected (1985 to 1999), postoperative adjuvant therapy was not used to treat gastric cancer at our institution. There were no significant differences in the extent of node dissection between different racial and ethnic groups (Table 2); there were also no significant differences between groups in rates of resection, whether performed at M.D. Anderson or elsewhere, reflecting a similar proportion of referrals for early-stage versus late-stage disease in the different ethnic groups. Hispanics, however, were more likely to require total or extended gastrectomy than were the other groups (P = .039; Table 2), which is a possible reflection of the more infiltrative growth pattern observed for mucinous/signet-ring histology.
As suggested by the data on stage at diagnosis, Asians were more likely to undergo potentially curative resection, whereas African Americans were more likely to have nontherapeutic laparotomy because of unresectable disease (P = .004). Hispanic and non-Hispanic whites had similar rates of potentially curative resections. Among patients whose resections were curative in intent, no differences in rates of R0 (microscopically and grossly negative surgical margins) resections were observed between the groups (Table 2).
Sites of Metastases
Sites of Metastases at Diagnosis
Liver and Peritoneal Metastasis The most common sites of metastases at diagnosis were the liver and peritoneal cavity. To explore the clinicopathologic parameters associated with metastasis to the liver or peritoneal cavity, we examined the records of patients whose first site of metastasis was either of these two sites; 408 patients had liver metastasis, 400 had peritoneal metastasis, and 63 had liver and peritoneal metastases found at the same time. We performed multivariate analyses comparing patients with liver metastasis with those with peritoneal metastasis. Ethnicity, histology, age, and sex were included in the model. Sex and histology were predictors of liver or peritoneal metastasis (Table 4). Compared with females, males were significantly more likely to have liver metastasis (OR = 2.68; 95% CI, 1.80 to 3.99) and less likely to have peritoneal metastasis (OR = 0.35; 95% CI, 0.25 to 0.50).
As expected, the histology was the strongest predictor of liver or peritoneal metastasis. Tumors of patients whose first site of metastasis was the peritoneal cavity were more likely to have a poorly differentiated, mucinous/signet-ring, or mixed histopathology, whereas the converse was observed for patients with liver metastases as first site of distant disease (Table 4). Although Hispanics were more likely to have peritoneal metastases, according to univariate analyses, ethnicity was not a statistically significant predictor when adjusted for covariates. This suggests that the ethnic differences in sites of metastasis that we observed may result from differences in the frequencies of various histologies.
Survival
Other factors with a significant effect on survival in the univariate analysis were cancer stage, histologic designation, tumor location, and age. Multivariate Cox regression analyses (Table 5) indicated that stage was the dominant predictor of survival. Asians had a better prognosis than the other groups (P = .02). Poorly differentiated and mucinous/signet-ring histologies, proximal cancer localization, and age greater than 60 years were associated with an inferior probability of survival.
In analyzing the clinicopathologic behavior of gastric adenocarcinoma in patients treated over 15 years at a single comprehensive cancer center with a diverse racial and ethnic population, we observed significant differences in the pattern of gastric cancer among Hispanic patients. Compared with patients from most other races and ethnicities, Hispanic patients were younger at diagnosis, had a lower rate of proximal cancer localization, and had the highest rate of tumors with a mucinous or signet-ring type. However, despite these differences, overall survival and stage at presentation of gastric cancer among Hispanics were similar to overall survival and stage in non-Hispanic whites. In the United States, although the overall incidence of gastric cancer continues to decrease, the incidences of proximal gastric cancer and gastroesophageal junction cancer are increasing.20-23 Nonproximal gastric cancer is more commonly found among minority groups and women, whereas proximal gastric cancer and gastroesophageal junction cancer are most commonly found in non-Hispanic white men.24 Historically, a variety of host-related factors have been associated with gastric cancer. Compelling data suggest that environmental factors causing conditions, such as atrophic gastritis,25 pernicious anemia,26-28 and H pylori infection affect patients' risk for the intestinal type of gastric cancer. H pylori infection has been linked to a three- to five-fold increase in the risk for gastric cancer.29-32 Furthermore, the increased risk conferred by H pylori infection seems to be specific for nonproximal gastric cancer.33 Transition studies of immigrants to the United States from areas such as Japan, South America, and Eastern Europe, all of which have a high incidence of gastric cancer, showed that their descendants' risk for gastric cancer decreased after two or three generations.34,35 Dietary and environmental factors, particularly those encountered early in life, also seem to influence risk.35,36 Refrigeration has been credited by many for the reduction in the incidence of gastric cancer. One possibility is that refrigeration has reduced exposure to nitrates and nitrites by reducing bacterial and fungal contamination of foods. Another possibility is that refrigeration led to decreased consumption of smoked, cured, and salted foods. Increased consumption of fresh fruits has been correlated with a lower rate of gastric cancer.37 Several investigators have reported a worse prognosis for patients who have proximal gastric cancer than for those whose cancer is located in the mid or distal portion of the stomach.38-40 Obesity may play a role in the pathogenesis of proximal gastric cancer. For example, in two case-control studies conducted in the United States and one conducted in Sweden, associations between a high body mass index and adenocarcinoma of the gastric cardia were observed.23,41,42 Tobacco use has also been reported to increase the risk of proximal gastric cancer.41,43-45 A study in Japan also found that a Western-type diet increases the likelihood of proximal gastric cancer.43 As mentioned previously, the tumors of Hispanics had a higher rate of mucinous/signet-ring histology than tumors of non-Hispanic whites or African Americans. Characterized as diffuse under the Lauren classification system, a tumor with a mucinous/signet-ring histology was the strongest clinicopathologic predictor of peritoneal dissemination in patients with distant metastasis. Consequently, Hispanics were more likely than their non-Hispanic white and African American counterparts to have peritoneal dissemination. Published data suggest that divergent molecular pathogenic pathways lead to the development of papillary/tubular (intestinal) and diffuse (mucinous) types of gastric cancer typical of Hispanic populations. For example, defects in the APC and DCC genes46-51 and microsatellite instability and hypermethylation of the promoter for the hMHL1 gene52-54 have been associated with the intestinal type of gastric cancer. However, the diffuse type of gastric cancer is characterized by aberrant cellular adhesion. The cadherins, in conjunction with catenins, play a critical role in cell adhesion and polarity.55 Mutation, deletion, and promoter hypermethylation have been described methods of E-cadherin inactivation in diffuse gastric cancer.56-59 Race and ethnicity are constructed categories that may reflect history, origin, cultural identity, and socioeconomic status in addition to genetic and biologic factors to varying degrees. From a biologic point of view, human geneticists and anthropologists generally agree that human races do not exist per se60 but are, instead, social constructs that are maintained by internal and external racial identification.61 Different racial and ethnic groups, whatever their origins, have different incidences, natural histories, access to screening and treatment, and outcomes for various human diseases.62 Investigating these differences has inherent value because it allows biologic differences to be separated from environmental and socioeconomic factors. An understanding of the biologic and molecular basis of gastric cancer will allow oncologic therapy to be tailored to the unique characteristics of a patient's individual tumor. The M.D. Anderson Cancer Center may be particularly suited to explore such differences. The patient population at M.D. Anderson is diverse, both in terms of the racial and ethnic mix and the financial background of patients. Clinical departments are made up of physicians who make treatment decisions based on departmental protocols and multidisciplinary evaluation. Faculty are paid a salary, with no fee-for-service arrangement. All patients entered into the M.D. Anderson system are eligible for full treatment, up to and including chemotherapy, radiation therapy, and oncologic surgery. Despite these considerations, the limitations of analyses based on race and ethnicity are evident. For example, Asians in our study were largely American citizens of Chinese, Japanese, and Filipino descent, but there were also international Asian patients and patients from the Indian subcontinent. Non-Hispanic white patients were of Anglo-Saxon, Jewish, Mediterranean, and other descent. African Americans may have had ancestors who were identified as white or Caucasian, and many white participants may have had black ancestors. Data from the 2000 US Census show that almost seven million people identified themselves as members of more than one race; approximately 800,000 respondents said they were both white and black.63 And Hispanics can be of any race. At M.D. Anderson, most Hispanic patients are from Mexico and Central and South America. Nonetheless, despite this wide variation, Hispanics are identified in this country by themselves and by others as a distinct group with particular medical issues and needs. Because Hispanics have recently overtaken African Americans as the largest minority group in the United States,64 the proportion of Hispanic patients treated in the US healthcare system for gastric and other cancers will continue to grow. Discrete categories, such as race and ethnicity, are, by necessity, oversimplifications. An ethnicity-based analysis of gastric cancer, such as our study, must necessarily acknowledge the intersection of biology, socioeconomic factors, and access to health care with the natural history of the disease. Although we acknowledge the well-known potential limitations of retrospective analyses, as well as the inherent referral bias because of M.D. Anderson's status as a tertiary referral center, the goal of our study was to understand the clinical pathologic behavior of gastric cancer among Hispanics. An understanding of the effects of race and ethnicity on gastric cancer will allow us to better understand gastric adenocarcinoma as a whole and its effects on individual patients. In the future, as genetic, environmental, cultural, and healthcare access issues are better understood, clinicians may have the ability to customize gastric cancer treatment based on individual patient and tumor profiles.
The authors indicated no potential conflicts of interest.
We thank Sharon Robinson for expert help in the preparation of this manuscript and Ellen M. McDonald for editorial comments.
Supported by the Cantu, Caporella, and Smith families and by a grant from the River Creek Foundation. This work was presented in part at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA, January 22-24, 2004, and at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Logistic regression was used for multivariate analyses. Median survival was estimated using the Kaplan-Meier method. Cox proportional hazards modeling was used to assess the impact of covariates. 
30 years, 31 to 60 years, and > 60 years), patients age 31 to 60 years had the best prognosis; however, in the multivariate analysis, age was significant only for patients older than 60 years (P < .005). 
