Colorectal carcinoma: correlation between age gender and subsite distribution

Introduction
The etiology of colorectal cancer (CRC), defined as a malignant neoplasm involving the intestine extending from the cecum to the anus (large intestine), is of great interest. The possible environmental and genetic risk factors vary with race, gender, age, country of birth and migration, dietary factors, and anatomic location in the large intestine (1-5).
Epidemiological studies suggest that the incidence of CRC differs worldwide, including differences in incidence observed within one country (6). Several studies have also shown geographical variations in the frequencies of right-sided and left-sided CRC over-all with a proximal shift in its subsite distribution (1, 6-9). Coupled with the knowledge that the potential for screening for CRC is largely dependent on the anatomic location of the premalignant or early phase of the tumor, fiberoptic complete colonoscopy and CT-guided colonography are currently the most cost-effective means of screening average-risk adults for CRC (1, 2) with the advantage of biopsy and removal of premalignant lesions during colonoscopy.
Population-based epidemiologic studies may provide information that will further increase our understanding of the demographic patterns of CRC prevalence and their relationship to the etiology of CRC. In addition, increased knowledge of variations in the anatomic distribution of CRC according to gender and age of patients may have important implications for screening strategies used for the prevention of CRC. This retrospective case-control study was therefore undertaken in order to analyze the interrelationships between anatomical tumor location and gender, age, and incidence rates for CRC in a tertiary University Hospital in an area of Northern Greece (Evros region,150.000 inhabitants), between 1982 and 1997.

Materials and Methods
Data were obtained from the First Department of Surgery and the Endoscopy Unit of the University General Hospital of Alexandroupolis, which is the tertiary referral hospital in an area of Northern Greece (Evros region,150.000 inhabitants). Registry data for the years 1982-1997 for CRC, including the year of diagnosis, incidence and anatomic subsite of CRC, age at diagnosis and gender, were recorded and analyzed, and two time periods (1982-1989 and 1990-1997) were compared, while the population remained almost stable during this time.
During that time interval, the same team of specialists was involved in the diagnosis and treatment of the patients.
The study was limited to patients with histologically confirmed first primary adenocarcinomas of the colon or rectum. Data excluded from analysis were carcinoma of the anal canal, carcinoma with unspecified site, and carcinoma found in multiple sites of the colorectum.
The anatomical subsite was defined as the right colon (RC), left colon (LC), and rectum (Re). The RC subsite included the cecum, ascending colon, hepatic flexure, transverse colon, and splenic flexure; the LC subsite included the descending colon and sigmoid; and the Re subsite included the rectum and rectosigmoid junction, with the latter location defined as the peritoneal reflection, approximately 15 cm from the anal orifice.
A total of 143 patients with CRC were registered in this study. The anatomic locations of their tumors were RC in 41 cases (28.7%), LC in 51 cases (35.7%), and Re in 51 cases (35.7%).

Results
The anatomic distribution of CRCs in all cases from the entire study period 1982-1997 are summarized in table 1: of the 143 cases of CRC included in these analyses, 71 were male and 72 female, and 41 (28,7%) were classified as RC, 51 (35,7%) as LC and 51 (35,7%) as Re.
As indicated in table 2, the number of patients diagnosed with CRC increased significantly from 1982-1989 to 1990-1997 among both genders (by up to 50%; p<0.001). In addition, analysis by gender revealed in the entire cohort an increase in the proportion of females with CRC (by 17.32%; p=0.474) and a corresponding decrease in the proportion of males with CRC (by 14.52%; p=0.474) (table 3).
The anatomic distribution of CRC between colon and rectum did not differ significantly with gender (x2 test, p=0,477). Colon carcinoma was found in 52,2% of the females and 47,8% of the males, while rectal carcinoma was found in 47,1% of the females and 52,9% of males (table 4).
Consequently, differences in the proportions of cancer at each subsite were detected between the two study periods. Dividing the colorectal subsites into proximal and distal between the descending colon and sigmoid colon, including the rectum distally, revealed that at the second time period (1990-1997) there was an increase (of up to 22.36%) in the incidence of tumors diagnosed in the proximal (right) colon, which was linked to a decrease (of up to 6.6%) in the incidence of distal CRC (x2 test, p=0.495; table 5).
With respect to differences in the distribution of CRC with gender, RC occurred more frequently among the women, while LC occurred more frequently among the men, while there was no significant change between the two study periods in the frequency of Re in either gender (table 6).
The interactions observed between gender and subsite location of proximal (right) vs distal CRC over study periods are summarized in table 6. Specifically, the frequency of tumors diagnosed in the proximal colon (RC) increased in both genders, with a highly significant increase (of up to 119%) in the proportion of female patients with proximal CRC (x2 test, p=0.025).
The age of patients with CRC increased significantly from 1982-1989 to 1990-1997 (mean age 65.4 years vs 67.8 years, respectively; p=0.002), particularly in patients with RC (mean age 69.8 years vs 73.4 years, respectively; p=0.001) and those with Re (mean age 67.5 years vs 69.9 years, respectively; p=0.002). There was also a progressive increase in the incidence rates with increasing age in both genders (p=0.001), with the risk being higher for females than for males (mean ages: females, 70.1 years; males, 68.9 years).

Discussion
The results of this study demonstrate that in our region in Northern Greece, the frequency of CRC is rising, as is the mean age of patients diagnosed with CRC, findings that concur with those of many other studies in other regions (1, 2, 3, 10-12). However, there are also reports of either a declining (13) or static (14, 15) overall incidence of CRC. These differences can be explained by the documented worldwide variability in the average annual rates of increase in the incidence of CRC (16, 17).
We found that the proportions of new diagnoses of CRC rose significantly (p<0.001) between 1982 and 1997. In the entire cohort, the most common tumors were LC and Re (in the same proportion: 51 patients in each location, 35.7%), followed by RC (41 patients, 28.7%). No significant differences were observed between genders and location of colon carcinoma vs rectal carcinoma. In contrast, the differences with age were significant (p=0.002).
Many authors have reported a migration in the occurrence of CRC toward a proximal colonic location (1, 7, 9-12, 14, 15, 18, 19). The present study confirmed this increasing shift from left-sided to right-sided CRC, and showed that this shift was linked to a reduction in the incidence of distal colon cancer tumors, coupled with the aging of the population, as evidenced by previous reports (7, 14, 17, 20-22). In addition, several publications have dealt with the issues of race, gender, and age as determinants of anatomic subsite CRC risk (1, 2, 23). Although the results have been variable, and in some cases difficult to interpret, these epidemiological studies have revealed significant interactions between the subsite location of tumors and race, gender, and age (1, 3-5, 8, 23-28).
Differences between genders have been reported in the distribution of CRC, with right-sided tumors being more common among women and left-sided tumors more common among men (29). In our experience the proximal migration of tumors in the second time period of the study was identified for both genders (p=0.495). However, the analysis of our data showed that the right-sided CRC population included a significantly higher proportion of females (p=0.025). Moreover, in our experience the frequency of right-sided tumors increased significantly with patient age (p=0.001), and other published studies have shown that if the population includes a higher number of elderly patients, a greater proportion of right-sided CRCs can be expected (1, 18, 23).
The authors must emphasize that there are currently no screening programs in Thrace, and either sigmoidoscopy or total colonoscopy is performed only in patients with symptoms. This may explain why diagnoses of CRC have not become earlier in the stage of disease, and some of the differential results compared with other studies.
As reported previously (1, 7, 9, 18, 30), we consider that the proximal migration of CRC has important implications for the choice of screening techniques, especially the use of total colonoscopy versus flexible sigmoidoscopy. On the basis of the findings presented here (i.e., increased frequency of CRC with a significant predominance of right-sided tumors in aged patients and females), sigmoidoscopy may be the primary screening strategy of choice for patients of both genders aged under 60 years, who are more likely to have left-sided colonic and rectal tumors. Conversely, total colonoscopy should be the procedure of choice for the identification of CRC but also for premalignant lesions especially in patients aged over 60 years who are more likely to have right-sided colon tumors.
The results of the current study suggest that epidemiological studies emphasizing differences among races, genders, and ages according to the subsite of CRC will yield important clues as to CRC etiology and facilitate further prevention of the disease.

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