Changes in Uterine Cancer Incidence Rates in Egypt

Background Uterine cancer is one of the top-ranking cancers in women with wide international variations in incidence rates. Developed countries have higher incidence rates than the developing countries. Egypt has significantly lower incidence of uterine cancer than other countries in the Middle East. This study aimed at verifying the incidence rate of uterine cancer and characterizing the demographic and clinical profiles of patients residing in the Gharbiah province in the Nile delta region of Egypt. Methods Data from 660 uterine cancer patients diagnosed during the period of 1999 to 2010 were abstracted from the Gharbiah Cancer Registry, the only population-based registry in Egypt. The data included age, marital status, number of children, residence, smoking, occupation, date and basis of diagnosis, tumor topography, morphology, stage and grade, and treatment. Crude rate, age-standardized rate (ASR), and age-specific rate were calculated and associated with demographic and clinical characteristics of patients. Results The study confirmed the low ASR of uterine cancer in Egypt, (4.1 per 100,000 (95% CI: 3.8–4.4)). The incidence rate increased significantly over the 12-year period. The crude rate (CR) was 1.95, 95% CI (1.64–2.25) in 1999–2002; 2.9, 95% CI (2.5–3.2) in 2003–2006; and 3.5, 95% CI (3.1–3.9) in 2007–2010. The rate ratio was 1.5, 95% CI (1.2–1.8) in 2003–2006 and 1.8, 95% CI (1.5–2.2) in 2007–2010 compared to 1999–2002. The majority of patients (83%) were postmenopausal with the highest age-specific rate in the 60–69-year age group (22.07 per 100,000 (95% CI: 19.3–25.2). The majority of patients were diagnosed at early stages (60% localized and 5% regional), had adenocarcinoma (68%), and resided in urban areas (54%). Conclusions The study confirmed the low incidence rate of uterine cancer in the Gharbiah province of Egypt and significant increase in incidence in recent years. Future studies should focus on verifying the possible effect of hysterectomy on lowering the incidence, the factors related to the changes in rates between rural and urban areas, and the possible impact of nutritional and epidemiologic transitions on the increasing rates.


Introduction
Globally, uterine cancer is one of the top-ranking cancers that affect women [1,2]. Endometrial cancer arises from the inner layer (endometrium) of the uterus, the origin of approximately 90% of uterine cancers, followed by uterine sarcoma that arises from the outer layer (myometrium) (8%) and less frequent types of cancer (2%).
regions of the world. It is the most common gynecologic malignancy in developed countries and the second most common gynecologic malignancy in developing countries after cervical cancer [1,4]. North America and Central and Eastern Europe have the highest incidence of corpus uteri cancer in the world [1,3]. In contrast, some regions in Africa show the lowest incidence rate in the world [5][6][7]. e variation in uterine cancer incidence rates across the world can be explained by differences in exposure to risk factors and different levels of health care in the different regions [8].
Based on Globocan, corpus uteri cancer is ranked as the tenth most common cancer among women in Egypt. According to the Middle East Cancer Consortium (MECC) Report of 2006, the incidence rate of uterine cancer in Egypt (3.5/100,000) is the lowest compared to other countries in the Middle East such as Israeli Jews (13.8/100,000), Cypriots (11.8/100,000), Israeli Arabs (8.7/100,000), and Jordanians (5.8/100,000) [9]. In addition, the low stage at diagnosis of uterine cancer is high compared to other female cancers in Egypt [9].
is study incorporated the most recent data collected by the Egyptian registry after the published report on the data of [1999][2000][2001][2002]. We aimed at verifying the suspected increasing incidence rate of uterine cancer and characterizing the demographic and clinical profiles of patients residing in the Gharbiah province of Egypt during the period of 1999-2010.

e Study Population.
e study included all primary uterine cancers that were diagnosed in the Gharbiah province and collected by the Gharbiah Population-Based Cancer Registry (GPCR) from January 1999 through December 2010. e registry was founded in 1998 as a part of the Middle East Cancer Consortium. e Gharbiah Cancer Society is the home of GPCR in Tanta, which is the capital city of the Gharbiah province in the center of the Nile delta region. e registry uses the International Agency for Research on Cancer's (IARC) software CanReg4, and the data were actively collected from all hospitals and pathologic labs of the Gharbiah province. In addition, patients seeking medical care outside the Gharbiah province are tracked, and their data are abstracted and included in the registry.
e Gharbiah province is about 100 km north of Cairo in the Nile delta region. It is the tenth largest province in Egypt with a total area of 1,948 km 2 . Tumor grades were classified into 4 grades: Grade I, for well differentiated, Grade II, for moderately differentiated, Grade III, for poorly differentiated, and Grade IV, for undifferentiated anaplastic tumors, and lastly, the Unspecified Grade. Tumor stages were grouped into 4 stages: local, regional, distal, and unstaged. e incidence rate (IR) was calculated by dividing the number of events (E) by the total number of population at risk (P) per 100,000 women. e 95% confidence interval (CI) was calculated using the following formula: CI � IR ± 1.96 × IR/√E, and the 95% CI of rate ratio was calculated by using CI � exp (In (IR1/IR2)) ± 1.96 × √(1/E1 + 1/E2). e Egyptian census of 2006 was used to determine the number of women at risk. e incidence rate of uterine cancer was calculated for both pre-and postmenopausal women. e age of 50 years was used to determine the menopausal status. Due to the low number of cases, the incidence rates were compared over the 3 periods: 1999 to 2002, 2003 to 2006, and 2007 to 2010. e crude incidence rate was used to compare the incidence of uterine cancer over the entire time frame of the study to the initial incidence in the period of 1999 to 2002. e personyears at risk was calculated over the 12-year period based on the total population of Gharbiah women in the census of 2006. e world standard population (WHO 2000) was used to calculate the age-standardized rate.
Chi-square tests and t-tests were used to test the associations of categorical and continuous variables, respectively. For all the analyses, a two-sided p value of ≤0.05 was considered statistically significant. SAS version 9.4 (SAS Institute Inc., Cary, NC) was used in all statistical analysis.

Result
ere were 660 women diagnosed with primary uterine cancer in the Gharbiah province during the period of January 1999 through December 2010. Table 1 shows the distribution of demographic and clinical characteristics of the patients included in this study. About 83% of patients were postmenopausal, and 54% lived in urban areas. Most patients (93%) were diagnosed based on the histopathologic diagnosis. However, less than 5% of patients were diagnosed Obstetrics and Gynecology International with uterine cancer based on death records only. About 91% of the patients had corpus uteri cancer, and 9% had the diagnosis of "uterus NOS" (not otherwise specified). Adenocarcinoma and other carcinomas comprised 80% of the patients. Sarcoma represented 11% of the tumors, and 9% of all tumors were "unspecified malignant neoplasms." Surgery alone was the most offered treatment in 48% of treated patients, followed by surgery and adjuvant radiotherapy in 19% of patients who had treatment information reported. Treatment data showed that 23% of the patients either did not receive any kind of treatment because they were not fit for the treatment or treatment was not available or affordable. In addition, 27% of all patients' treatment data were missing because the treatment data were not available in the registry from the beginning, which resulted in "missing" in all those patients. e overall crude incidence rate of uterine cancer in Gharbiah was 2.8 per 100,000 with 95% CI (2.6-3.0). e age-standardized incidence rate was 4.1 per 100,000 with 95% CI (3.8-4.4). Unsurprisingly, the crude incidence rate of uterine cancer was 15.9 per 100,000 in postmenopausal women with 95% CI (14.6-17.3), whereas the premenopausal women were only 0.57 per 100,000 and 95% CI (0.46-0.67). e crude rate ratio was 28.1 and 95% CI (23.0-34.4). erefore, postmenopausal women had 28.1 times the odds to develop uterine cancer compared to premenopausal women. Table 2 shows the age-specific incidence rate of uterine cancer. Descriptively, the age-specific rate peaked at 22 per 100,000 and 95% CI (19.28-25.16) in the age group of 60-69 years, while the age-specific rate was lower in subsequent age groups.
e crude incidence rate of uterine cancer in the Gharbiah province over the period of 1999 through 2002 was 1.95 per 100,000 and 95% CI (1.  Table 3 shows the uterine cancer crude rate and the increment in the rate ratio over the time with the significant 95% CI. Corpus uteri cancer comprises the majority of uterine cancers in both pre-and postmenopausal women with proportions of 83% and 93%, respectively (Table 4). However, the NOS cancer has a higher proportion in premenopausal women (17%) than (7%) in postmenopausal women (p < 0.001).
Carcinomas were the most common type in pre-and postmenopausal women, 61% and 84%, respectively. e tumor grades have significant association with the menopausal status (p < 0.001). About 10% and 15% of pre-and postmenopausal, respectively, were in well-differentiated tumor grade. Moderately differentiated tumor comprised 38% of premenopausal and 47% of postmenopausal patients. Unspecified tumor grade had the highest percentage of premenopausal women (41%), whereas only 20% of postmenopausal women had unspecified tumor grade. Poorly and anaplastic tumor grade comprised 11% and 18% of preand postmenopausal patients, respectively.
Although the nulliparity was relatively high in both premenopausal and postmenopausal (52% and 48%, resp.), the parity levels did not show a significant difference by menopausal status (p � 0.35). Moreover, treatment, residential status, and employment status did not have any significant association with the menopausal status (Table 4). Table 5 displays the association of histopathologic types with different clinical characteristics of uterine cancer. About half the carcinoma patients were diagnosed with moderate tumor grade. Histopathologic types of cancer had significant differences across the levels of tumor grades, 59% of adenocarcinoma were moderately differentiated, 53% of other carcinoma were unspecified tumor grade, and 32% of sarcomas were diagnosed with poor and anaplastic tumor grade (p < 0.001). All sarcomas (100%) were diagnosed as corpus uteri, whereas 75% of other and unspecified malignancies were diagnosed as NOS uterine cancers. e highest proportions of all histopathologic types that were treated with surgery only were sarcomas (63%) followed by adenocarcinomas (48%). Histopathologic types of cancer had significant differences in relation to the given treatment (p < 0.001).

Discussion
is study revealed 3 interesting findings. First, uterine cancer ASR in this population was relatively low during the entire study period of 1999-2010; however, the crude and ASRs increased significantly by 2010. Second, the peak agespecific incidence rate of uterine cancer was in the age group of 60-69 years. ird, adenocarcinoma and other carcinomas comprised about 80% of all uterine cancers in this population.
ere are a limited number of studies examining ASR of uterine cancer in Egypt. e first population-based study was published by our group, for data from 1999 to 2001, in the monograph of the Middle East Cancer Consortium (MECC) [9]. e MECC report included the period 1999-2001 and showed an ASR of 3.5 per 100,000 in this population in Egypt compared to ASR of 5.8 per 100,000 for Jordan, ASR of 8.7 per 100,000 for Israeli Arabs, ASR of 13.8 per 100,000 for Israeli Jews, ASR of 11.8 per 100,000 for Cyprus, and ASR of 17.6 per 100,000 for SEER, USA [9]. A more recent study by members of our group showed a crude    [3]. Rates reported from developed countries in Europe and North America were significantly higher than the Egyptian rates (19.5, 17.0, and 13.9 per 100,000 for the US, France, and the U.K., resp.) [2]. In addition, the world uterine cancer ASR as reported in Globocan 2012 was 8.2 per 100,000 [2]. erefore, the results of this study clearly show that the Egyptian ASR of uterine cancer is considered one of the lowest uterine cancer incidence rates, globally.
Regarding the trend of increasing uterine cancer crude rates in Egypt in this study, other studies showed increasing trends of uterine cancer incidence in some European countries. For example, the incidence of uterine cancer increased significantly in the period of 1988 to 2008 in Norway, Ireland, the United Kingdom, and the Netherlands [13]. Some Asian countries also showed continuous increase in uterine cancer incidence rates. For example, 5 of the 6 population-based cancer registries in India showed an increase in uterine cancer trend over the period of 1982 to 2003 [14]. In addition, the increment in the uterine cancer trend was noticed also in Japan over the period of 1983 to 2005 [15]. In contrast, the rates declined in Austria, Sweden, and Germany [13]. In the US, the trend showed declining rates for 3 decades until the 1990, stability in the 1900s, then slight increase after 2007 [16]. e significant variations in ASRs across different countries could be explained by the variation in risk factors for uterine cancer or health care factors influencing the diagnosis of the disease [8].
e increasing rates in the Gharbiah province of Egypt over the study period could be Obstetrics and Gynecology International related to both risk factors and health systems factors. It is unlikely that improvement in the population-based registries has been a factor, since these have maintained consistently high standards verified by peer review [17,18]. Early age of menarche, late age of menopause, nulliparity, obesity, and diabetes mellitus are well-documented risk factors for uterine cancer in different countries.
Early age of menarche and late age of menopause are two risk factors related to increased risk for uterine cancer [19][20][21][22][23]. Average age of menarche in high-and low-SES girls in Egypt was reported in 1978 as 12.59 years and 13.89 years, for the 2 groups, respectively [24]. A more recent study showed that the mean age at menarche in Egypt declined to 12.49 years in the period of 2012-2013 [25]. Age of menopause has increased in Egypt over time. In 1986, a study from the Sharkia province in Egypt showed an average age of menopause of 45.2 years [26], and another study from Alexandria, Egypt, showed an average age of menopause of 45.8 years [27]. Studies from the rural province of Menoufia showed a lower average age of menopause of 43.1 years [28]. More recent studies showed a higher average age of menopause of 46.7 years and 50.84 years in Alexandria and Assiut, respectively [29][30][31].
Regarding the relationship between parity and uterine cancer, low parity has been considered a risk factor while high parity was considered a protective factor for the disease [32,33]. e fertility rate among Egyptian women (15-49 years) was 3.5 births per woman in 2014. [34]. Although the fertility rate declined from 5.3 to 3.5 births per woman during the period of 1980 to 2014, the rate is still higher than that of developed countries. For example, the fertility rates in the US, France, and the UK were reported as 1.9, 2.0, and 1.9, respectively, in 2011-2015 [35].
Obesity is considered an important risk factor for endometrial cancer for both pre-and postmenopausal women. [36][37][38][39][40][41]. About 39% of the risk of endometrial cancer can be attributed to overweight and obesity [42]. Egypt has been considered one of the countries with the highest overweight and obesity rates [43].
e Egyptian Demographic and Health Survey (EDHS) showed an increase in the proportion of obese women from 40.85 to 48.1% during the period from 2000 to 2014 [34,[44][45][46]. According to the WHO estimate for 2010-2014, prevalence of obesity (BMI ≥ 30) among Egyptian females aged 18+ years was 37.5% (95% CI 30.5-44.9) [43]. A hospital-based study from Alexandria, Egypt, showed abdominal obesity as a significant risk factor for endometrial cancer (OR � 13.58, 95% CI (4.0-46.6)) [47]. Moreover, diabetes mellitus is a well-known risk factor [48][49][50]. e prevalence of diabetes mellitus among Egyptian women increased from 8% in 1980 to 18.2% in 2014 [51]. erefore, the increase in some uterine risk factors over the past decades could explain the increasing incidence of uterine cancer in our study.
Egypt is one of the middle-income countries that have been undergoing epidemiologic and nutritional transitions [52][53][54]. For example, the prevalence of overweight and obesity was 28.2% and 7.6%, respectively, among Egyptian school girls of mean age of 13.2 during the period of 2006-2010 [40]. If increasing trends of overweight and obesity continue among Egyptian women, endometrial cancer might be expected to continue to increase in the future.
Although variations in risk factors may explain difference in incidence of uterine cancer between populations, protective factors may also play a role in variation in rates between countries. For instance, smoking is another risk factor that has been associated with low rates of uterine cancer in postmenopausal women [55][56][57] However, it should be noted that the smoking rate among Egyptian women is extremely low (0.5%) compared to the male population (37.7%) [58,59]. However, these studies did not address the possibility of exposure of women to passive smoking.
Oral contraceptive pills and injectable contraceptive methods are considered protective against endometrial cancer [60,61] e estimated prevalence of using birth control pills of Egyptian women of reproductive age (15-49 years) was 16.6% in 1980 and declined to 9.5% in 2000 then increased again to 16% in 2014 [62]. However, there has been a constant increase in the use of injectable contraceptive methods from 0.1% in 1988 to 8.5% in 2014 [34]. ese rates of usage are quite low compared to rates in developed countries that reach 40% [62]. In addition, the increase in physical activity was found protective against uterine cancer [63][64][65]. About 57% of women living in rural areas in our study region were engaged in daily activities and work in extensive farm-related physical work, which demanded a considerable amount of physical activity [10]. Moreover, the different exposures to environmental factors may affect uterine cancer incidence. For instance, exposure to xenoestrogens as a component of environmental estrogen may increase uterine cancer rates [12].
About 36% of the patients included in our registry were in the age group of 50-59 years, and the age-specific rate was the highest (22.07 per 100,000) among the age group of 60 to 69 years. is result does not differ from uterine cancer data worldwide [66,67]. e decrease in hormonal imbalance for both exogenous and endogenous hormones may explain the decline in uterine cancer incidence among elderly women [68]. Use of hormonal replacement therapy (HRT) by menopausal women is linked to increasing rates of uterine cancer [32,69,70]. However, HRT is rarely used in Egypt and is not known to most women in Egypt [30,71].
Egypt has a wide-spread system of primary health care, and access to medical care in primary care, hospitals, and private clinics is not a major barrier to receiving medical care [10]. Also, availability of resources for imaging and pathologic diagnosis of cancer has improved significantly in Egypt [17,18]. Whether these resources are available to physicians or underutilized for diagnosis of uterine cancer in this population is unknown.
Regarding the histopathologic types of uterine cancer, the majority of all types in this study were carcinomas and adenocarcinomas. e results of this study are in agreement with the classic presentation of adenocarcinoma among uterine cancer patients elsewhere. For example, adenocarcinomas comprise over 90% of all uterine cancers in the US [72]. However, in Tunisia, one of the North African countries, adenocarcinomas constituted about 63% of uterine cancers [73].

Obstetrics and Gynecology International
Most uterine cancers in this study were among postmenopausal women. is finding is consistent with studies from the US, where more than 90% of uterine cancer patients are postmenopausal [66]. e study has several strengths. e study builds on a track record of a reliable population-based cancer registry with validated data. e relatively long period of the study (12 years) adds to the strengths of the study. e coverage of medical care and accessibility to health care facilities in Egypt minimizes the chance of missed cases that had no access to medical care. Whether or not physicians histopathologically confirm the diagnosis of all uterine cancers could be a factor in underestimating uterine cancer in this population. Also, because of the low incidence of uterine cancer in this population, the relatively small sample size of this study might be a limitation.
In summary, while the uterine cancer incidence rate is low, but increasing over time in the Gharbiah province of Egypt compared to other countries, the postmenopausal Egyptian women comprised the vast majority of uterine cancer as in other countries. Future studies should focus on elucidating the impact of epidemiologic, demographic, and nutritional transitions on the future of uterine cancer in this population. Future studies should also investigate if uterine cancer is underestimated in this population, although this is unlikely due to population-wide accessibility to medical care in Egypt. Finally, research should explore if the increasing environmental pollution and environmental estrogens may have an impact on regional distribution of the disease in rural and urban regions of this population.

Data Availability
e data used for this study are available upon request.

Conflicts of Interest
e authors declare that they have no conflicts of interest.