Recently, the assessment of changes of white blood cell (WBC) subsets such as neutrophils, lymphocytes, monocytes, or ratio of neutrophil to lymphocyte counts (N/L) in peripheral blood has been identified as an easy, simple, inexpensive, and reliable prognostic index to determine host immunity (1-17). As immune cells, WBC subsets undergo changes in their proportion in peripheral blood by inhibition of apoptosis of neutrophils (1-4) and apoptosis of lymphocytes (7, 8) in certain psychological stress (9, 18), surgical trauma (10, 11), or advanced malignant tumors (1-4, 7, 8). It has been documented that the change of WBC subsets populations is a reliable prognostic index to predict survival rate and therapeutic benefit in cancer patients (1-8).

Major surgery produces tissue damage and acute inflammation, which are related with alterations in the immune status of patients (11, 19, 20). In already immune-changed cancer patients, surgical stress-induced suppression of cellular immunity may potentially accelerate the tumor growth and dissemination of residual cancer cells (21). Therefore, it is especially important to keep immune status of cancer patients competent after surgery.

Differences between men and women in endocrine reactions to the nature of the stress have been reported (18, 22, 23). Acute psychological stress activated the endocrine response more profoundly in male subjects than in female subjects (18). In contrast, physical stress stimulated greater increases in cortisol response in female subjects than in male subjects (22, 23). Although there is a close relationship between endocrine responses and immune changes, the effects of gender on the perioperative and postoperative perturbation of cellular immunity by surgical stress in cancer patients have not been reported.

Stomach cancer is one of the most common cancer and a leading cause of death from cancer in both sexes in Korea. Altered immune response to stomach cancer has been documented (13, 14). Therefore, the aim of the current study was to investigate the effects of gender on the changes in blood WBC subsets populations and N/L during hospitalization after surgical treatment between male and female patients with stomach cancer by analyzing blood WBC subset values and N/L from the database, retrospectively.

In response to total or subtotal gastrectomy in stomach cancer patients, increased neutrophils, decreased lymphocytes and monocytes, and increase of N/L in circulating blood were demonstrated. The alterations of these values were most significant at the immediate postoperative period and tended to be restored as time passes during the postoperative period in both sexes. We found significant gender effects on the changes of the percentage of blood WBC subsets following surgery in the large sample size of this study. Female patients had more circulating neutrophils, less lymphocytes, consequently higher N/L, and less monocytes, which indicate a more immune-compromised state, than male patients for a few days postoperatively. In the preoperative values, except for the total number of WBC and percentage of monocytes, there were no significant differences between sexes.

In the current study, database from 409 male patients and 212 female patients were available for analysis out of total 923 patients scheduled for total or subtotal gastrectomy from 1 January to 31 December in 2005. Exclusion criteria in the study were as follows: the patients with combined chemotherapy, combined medical disease that might have affected circulating WBC counts, or palliative surgery or combined surgery with other organs due to the correlation between surgical size and magnitude of immune suppression (19, 20), or postoperative complications such as pneumonia, urinary tract infection, and wound infection, or blood transfusion during surgery or postoperative period, or duration of hospital stay more than 10 days.

According to the stage of stomach cancer, the number of peripheral lymphocytes and lymphocyte subsets were suppressed in different degrees (13, 14). A quantitative change in circulating blood lymphocytes takes place in the advanced stage of stomach cancer (14). The immune status of the patients with stomach cancer in the current study might have been altered according to the cancer stage. We found that the ratio of cancer grading between advanced stage and early stage was exactly same as 42% and 58%, respectively, in both sexes in the current study. Furthermore, the mean age of the two groups in the current study (58 yrs of male patients vs. 57 yrs of female patients) was similar. A relative decrease of circulating lymphocytes has been observed as ages normally (16). In the study with patients admitted to intensive care unit, the degree of lymphopenia was well correlated with age (5). In the present study, we could clarify that the differences of WBC subsets percentage and N/L in the peripheral blood between the groups were not associated with cancer grading and age of patients. Although significantly shorter operation time and smaller amounts of fluid administration and bleeding were observed in female patients compared to male patients during surgery, these differences (8 min, 120 mL, and 17 mL, respectively) might have little influence on the immune response and do not seem to have any clinical effect. Therefore, the only noteworthy differences in WBC subsets values and N/L between the groups appeared to be gender-related factor.

Stomach cancer is the leading cause of cancer-related death in both male and female patients in Korea. Presurgical anxiety in patients waiting for gastrectomy due to stomach cancer clearly affect host immunity. Psychological distress in patients bearing digestive tract cancer was well related with suppressed immune function including increased neutrophils and decreased lymphocytes and monocytes in both sexes (15). Purely psychological stress such as in public speaking was also documented to cause the redistribution of circulating lymphocytes and their subsets (9). Because WBC subset values prior to the preoperative data were not available in this study, we could not demonstrate the extent of presurgical stress induced changes of WBC subsets levels. However, preoperative values of circulating blood WBC subsets, except the total number of WBC and percentage of monocytes, were not different between genders. The higher number of total WBC in male patients than in female patients may be related to potentially higher smoking population in male subjects than in female subjects in average age of 50s in Korea (17). In the study to investigate the relationship between acute psychological stress and immune response in elderly (55-75 yr) healthy individuals, adrenocorticotropic hormone (ACTH) and cortisol secretion by the activation of hypothalamic-pituitary-adrenal (HPX) axis were significantly increased in male subjects compared to female subjects (18). In contrast, the cortisol response to physical challenges, such as high intensity treadmill test (22) and lumbar puncture stress (23), has been greater in female subjects than in male subjects. Stimulation of HPX axis due to mental stress or physical stress increases blood concentrations of ACTH and cortisol, which induce redistribution of circulating WBC by inhibition of neutrophil apoptosis and activation of lymphocyte apoptosis (11). Concentrations of circulating WBC change continuously, so that a large sample size as in our current study is required to detect the differences of cellular immune response to active or passive stress between genders (24). Despite the no discernable gender differences in the percentage of peripheral neutrophils and lymphocytes, and N/L preoperatively, more increased percentage of neutrophils and decreased percentage of lymphocytes, and higher N/L in female patients than in male patients were observed postoperatively in this study.

Assessment of the absolute number or percentage of circulating blood WBC subsets has been advocated as an easy, simple, inexpensive, and reliable prognostic factor in critically ill patients with medical or surgical illnesses and malignancy. Depending on the study types and conditions, neutrophilia, lymphopenia, or N/L was identified as a predictive factor closely associated with mortality rate and therapeutic benefits. Both the lymphopenia and neutrophilia rather than total WBC count have been suggested as more sensitive parameters in adults admitted due to suspected bacteremia (5). An increased neutrophil count in peripheral blood has been suggested as a significant parameter to predict prognosis in patients with metastatic melanoma (4) and those with metastatic renal cell carcinoma (1-3). The degree of lymphopenia was correlated with host immunity and survival rate in advanced pancreatic cancer patients (7). Recently, N/L has been considered as a quick, simple and sensitive parameter to evaluate systemic inflammation and stress in critically ill patients following shock, multiple trauma, major surgery, or sepsis (6), and as the greatest predictive factor for increased cardiovascular risk (12). Preoperative N/L greater than 5 showed significantly higher cancer mortality in general compared to N/L lesser than 5 in patients with colorectal cancer (8). N/L in percutaneous fine-needle aspiration biopsy specimen was also found to be an independent prognostic factor for patients with advanced non-small cell lung carcinoma (25).

Although we observed suppressed cellular immunity only for 5 days after gastrectomy as a limitation of retrospective study, Ogawa et al. (11) showed significantly decreased lymphocyte number and function for 2 weeks postoperatively in patients with gastrointestinal cancer. When already immune suppressed cancer patients undergo operation, the host immunity could be depressed more seriously because surgeryinduced tissue damage and related acute inflammation cause decreases of immunocyte function. Because suppressed postoperative cellular immunity may accelerate remnant cancer cell growth or metastasis in cancer patients, particularly competent condition of host immunity should be considered (21).

In conclusion, in the current study female patients showed a more immune compromised pattern of immune cells in peripheral blood than male patients at least for a few days after gastrectomy due to gastric cancer. Further studies should determine whether and to what extent these postoperative changes of WBC subset populations and N/L affect long-term outcomes such as relapse of malignant tumor.