Colorectal cancer (CRC) is globally the second leading cause of cancer death and the third most common cancer [1,2]. In 2020, GLOBOCAN reported that CRC was responsible for 0.94 million deaths and more than 1.9 million new incident cases [3]. CRC is currently an indicator of epidemiological change and socioeconomic transition. Current global evidence shows that CRC incidence and mortality rates in developing low-income and middle-income countries are on the rise, while such rates are decreasing in developed high-income countries [3,6].

Due to the consumption of a high-fibre diet in Sub-Saharan Africa, CRC has historically been considered to be an uncommon diagnosis [7,8]. While data are limited from Sub-Saharan Africa, over the last few decades, there has been an increase in CRC rates. The age-standardized rates of CRC per 100,000 population have increased in Uganda according to the Kampala Cancer Registry, especially for women. In Uganda, the Kampala Cancer Registry showed that the age-standardized incidence rate has increased from 5.2 per 100,000 population for 1991-1995 to 9.0 per 100,000 population for 2006-2010 in females [9]. Between 1998 and 2007, the age-standardized incidence rate increased in females from 8.2 to 9.9 per 100,000 population, while for male patients, it increased from 7.6 to 8.2 per 100,000 population [10]. In Bomet, which is located in south eastern Kenya, there has been an increase from 2.0 in 1998-2002 to 9.6 in 2013-2017. In Tanzania, over the past decade, there has been a six-fold increase in the CRC incidence rate, which is 4.4 per 100,000 population in Kilimanjaro [10].

This steady increase in the incidence rates in Uganda and the rest of Sub-Saharan Africa should make the medical community realize that CRC is not uncommon in this part of the world. The introduction of a Western diet in these communities, urbanization and inactivity are some of the major risk factors contributing to this observation [7,11].

However, unexplored genetic factors and infectious causes that may contribute to the aetiology of CRC need to be investigated in our population [12]. Exploring these factors in our Ugandan population may explain the observed trend of younger patients presenting with CRC at an advanced stage and also the general increase in the incidence of CRC in our community [13-15].

A record review using data from the Kampala Cancer Registry and recruited CRC participants from 2008-2021 was carried out in our study. The aim of our study was to document the burden of CRC focusing on demographics, stage at presentation and perspectives and challenges associated with the increase of CRC in Uganda.

We conducted a descriptive cross-sectional study and obtained all clinical records of patients diagnosed with colorectal adenocarcinoma between 2008-2021. The retrospective arm of the study involved participants who were diagnosed between 2008 and 2019 in the Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University. Colorectal cancer tissues were received by the Department of Pathology at Makerere University, which has a catchment from hospitals in different regions of the country. The prospective arm involved colorectal cancer participants who were recruited in 2019-2021 from the Department of Surgery of Masaka Regional Referral Hospital, Mulago National Referral Hospital, Uganda Martyrs’ Hospital Lubaga and Mengo Hospital.

Patient’s with histologically diagnosed colorectal adenocarcinoma were included, while patients with missing demographic data or incomplete or unavailable data were excluded. Colorectal cancer tissue for histopathology was obtained either through colonoscopy or during surgery a biopsy or resection from the patients as part of routine standard clinical management.

For all participants, we extracted data using a standard data extraction form for the following variables: age, sex, location of primary tumour, type of operation, year of diagnosis and radiological stage. The TNM AJCC 8^th edition was used to classify the radiological stage for all patients included [16,17].

Data on whether colonoscopy was carried out were obtained in the first 128 participants from the prospective arm of the study. The presence or absence of colorectal adenomas and the site of the CRC were obtained from the colonoscopy reports.

Statistical Analysis

We summarized continuous variables using either the means (standard deviation) or median (interquartile range – IQR) depending on the distribution, and categorical variables by frequencies and percentages. We derived and showed proportions of cases by selected patient characteristics as the number of cases of CRC with that characteristic divided by the total number of CRC cases, and we have presented these statistics in tables and graphs. We showed the trend in CRC cases by plotting cases diagnosed by calendar year and used the Cochran-Armitage chi-square test to determine any deviations from the linear trend. We assessed for a statistical association between histories of CRC and GI cancers and the likelihood of having adenomatous polyps using logistic regression. In all statistical tests, we assumed a p-value of less than 0.05 as statistically significant.

Between 2008 and 2021, a total of 404 cases were obtained from the Kampala Cancer Registry and the clinical records of the Department of Surgery of Masaka Regional Referral Hospital, Mulago National Referral Hospital, Uganda Martyrs’ Hospital Lubaga and Mengo Hospital. The median (IQR) age of all the patients was 54 (43-67) years, and 38.9% were ≤49 years of age, while patients who were 60-69 years were 88 (21.8%) of CRC patients. Two hundred (49.5%) were males, 266 (65.8%) had a colorectal resection, and 138 (34.2%) had a biopsy during proctosigmoidoscopy or colonoscopy.

Number of Colorectal Cancer Cases

Figure 1 shows a steady increase in the frequency of CRC from 2008-2021. In 2008, the frequency of cases diagnosed with CRC was 17, which steadily increased in 2017, 2018, 2019, 2020 and 2021 to 32, 22, 46, 75, 75 and 72 CRC cases, respectively. However, there was no linear trend; Cochran-Armitage trend test, p=0.807.

Figure 1: Trend in CRC cases from 2008 to 2021 based on the age categories ≤54 years and ≥54 years (N=404). The median (IQR) age at diagnosis was 54(43-67) years.

Table 1 shows that advanced stage (stage III and IV) constituted 217 (60.8%) of CRC cases whilst early stage CRC constituted 140 (39.2%) of CRC cases.

Table 1: Staging of all CRC patients.

Figure 2: Pie chart showing the anatomical distribution of all colorectal tumours.

Figure 2 is a pie chart showing that the commonest CRC tumour was found in the rectum 212 (53%), followed by sigmoid colon tumours 65(16%) and the least were hepatic flexure tumours 1 (0.3%).

Table 2: Frequency and detection of adenomas at colonoscopy of CRC patients.

Data on the availability of colonoscopy were only available for 128 prospectively recruited CRC participants. Out of the 128 CRC participants, only 56 (43.8%) had a colonoscopy. Twenty-four (18.8%) CRC participants only had a proctoscopy/proctosigmoidoscopy, and 72 (56.2%) had no colonoscopy. There were 5 (8.9%) CRC patients (3 female and 2 male CRC patients) who had colorectal adenomas identified at colonoscopy.

Table 3: Analysis of the association between family history of CRC and gastrointestinal cancer and colorectal adenomatous polyps.

A family history of CRC was associated with the presence of colorectal adenomatous polyps, and this association reached statistical significance (p=0.004). A family history of gastrointestinal cancer was also associated with the presence of adenomatous polyps, which reached statistical significance (p=0.047) (Table 3).

Table 4: Topography of CRC based on the findings at colonoscopy.

The majority of CRC lesions detected at colonoscopy were left-sided colon lesions and included rectal 22 (39%) followed by sigmoid colon 10 (18%) out of the 56 CRC participants who underwent a colonoscopy (Table 4). Out of the 128 CRC participants, 80 (22.9%) had a biopsy. These included 24 (18.8%) CRC participants who had a proctoscopy/proctosigmoidoscopy and 56(43.8%) who had a colonoscopy. Of these 56 (43.8%) colonoscopy patients, 22 (39.3%) had rectal tumours.

Table 5: Type of initial operation for CRC participants.

Out of 404 participants, the distribution for the type of operation was available for 270(66.8%) CRC participants and is shown in Table 5. Low anterior resection was the most common operation for rectal cancer patients (30%), followed by abdominoperineal resection (17.4%). Sigmoid colectomy was the next most common type of operation (18.1%), which is a left-sided colon tumour. Palliative colostomy which did not involve colorectal resection constituted 4.1% of CRC participants.

Our study highlights three important observations from the findings presented. The first important finding is the late-stage presentation of CRC patients; second is the high frequency of young patients affected with CRC; and the third is the low rate of diagnostic colonoscopies which were performed on CRC patients with none detected by screening colonoscopy. The CRC incidence rate is increasing in Uganda, with a significant shift observed resulting in an increase in noncommunicable diseases. From our records there was an increase in the frequency of CRC cases observed from 2008-2021. Hence, this indicates that the incidence of CRC is increasing in Uganda. A major challenge has been observed in the health care system of our country and the rest of East Africa with this increase in the burden of CRC.

Compared to developed high-income countries, a younger age of CRC diagnosis has been seen in countries in Sub-Saharan Africa [13,18,19]. Single centre studies from Sub-Saharan Africa have reported that the proportion of CRC patients younger than 40 years of age is between 19%-38% [13]. In our study, 18.6% of CRC patients were <40 years of age, with some patients even presenting at 15 years of age. However, in developed high-income countries only 3%-7% are under the age of 40 years [20,21].

This difference may be explained by a younger population with short life expectancy. However, a difference in tumour biology, particularly a distinct molecular profile, may be responsible for the rising incidence rate of young CRC patients [22-24]. Young patients with CRC present at an advanced stage with an increased frequency of metastasis and faster disease progression and are associated with a poorer prognosis [20,25,26].

National screening guidelines in Uganda are still being conceptualized, and therefore, very few patients have CRC detected through screening [27,28]. In our study, none of the patients had their CRC diagnosed by screening colonoscopy. These findings show that if the initial screening age for CRC in Uganda is at 50 years of age, as in Western countries, then this will potentially miss 39% of individuals affected with CRC in our setting. Therefore, screening guidelines that are suited for our population are necessary. Studies from the USA have recommended lowering the initial age of screening for African individuals due to an increase in the incidence of early-onset colorectal cancer [29,30]. Early-onset CRC develops at a younger age and is more common in African patients than in white patients [31,32]. In developing low-income countries these challenges make the management of CRC even more difficult than in developed high-income countries. Hypothesis for early-onset CRC has been proposed, which includes the contribution from colonic microbiota and hence the association of infectious agents with CRC. Familial factors and genetic predisposition are also other factors that need to be considered and may contribute to the aetiology of CRC in the African setting [12].

Asymptomatic patients are very rarely screened for CRC in Uganda, and essentially all of our CRC patients presented with symptoms of colorectal cancer. Before being referred or seeking definitive treatment, our patients experienced a long duration of CRC symptoms. Since the time from the onset of symptoms is strongly correlated with late-stage colorectal cancer, many of our patients presented with late-stage CRC [33]. In low-resource settings in Uganda, there are many reasons for this delay in receiving treatment, which is due to reduced access to care, resulting from difficulty and expense of travel, referral to distant regional referral hospitals and inadequate patient education [10,27]. Therefore, these factors need further investigation in resource-limited settings to improve the diagnosis and management of CRC. Therefore, opportunities to develop an effective strategy to detect CRC at an earlier stage are necessary to prevent presentation at an advanced stage due to prolongation of the duration of symptoms [19]. Effective strategies also need to be developed to refer patients to specialized canters of care in Uganda.

Another observation in our study was that only 43.8% of patients had a colonoscopy performed for diagnostic purposes, and none in our hospitals in central Uganda were detected by screening colonoscopy. Colonoscopy rates may differ in other studies as patients’ access health care either during screening programmes or during surveillance [34]. Minimal screening with colonoscopy is being carried out in referral hospitals in Uganda partly due to a lack of national screening guidelines. Colonoscopy should be offered for individuals presenting with symptoms that are suggestive of a diagnosis of CRC. Educating patients and improving the referral system is important to reduce the long duration between the commencement of symptoms and presentation with CRC.

In Uganda, the feasibility and appropriateness of screening programmes need further investigation. Studies that include mathematical modelling in Sub-Saharan Africa have shown that colonoscopy is a cost-effective strategy to detect CRC, with other studies showing an improved survival rate [35,36]. However, in our limited-resource setting, there are limited endoscopic capabilities, and endoscopic skill needs to be developed through proper infrastructure and training [37]. The hospitals from which we recruited the CRC patients in central Uganda have been training surgeons and physicians to perform colonoscopies and carry out therapeutic manoeuvers such as polypectomy. However, to meet demand, these efforts need to be increased in other Ugandan hospitals in rural settings. In Uganda, as in other parts of Sub-Saharan Africa, training non-physician endoscopists to carry out colonoscopies should be explored. Our study showed that in Uganda, most CRCs are rectal and left-sided colon cancers, which makes it easier to carry out screening in our population. However, in Sub-Saharan Africa, the sigmoid colon is prone to volvulus and is long and tortuous, making it more challenging to carry out screening colonoscopies [38].

In our resource-limited setting, establishing endoscopy facilities would have a high cost and would be most accessible only from regional referral hospitals, hence missing a number of patients attending District General Hospitals. Scarcity of endoscopy equipment and skilled endoscopists to perform colonoscopies together with lack of sensitization of the community to screening are some of the main factors responsible for the low rate of colonoscopies Providing district and regional referral hospitals in Uganda, the trained endoscopists and endoscopy equipment together with the implementation of CRC screening programmes may have a significant impact on the early detection of CRC. This development requires collaboration at national, regional and local levels and has been shown to improve the survival of CRC.

Most of the patients recruited in this study first attended district general hospitals and health centers that do not have the infrastructure for performing endoscopy. Providing these hospitals with investigative capabilities and trained staff will have an important impact on the early detection and surveillance of CRC. An important observation is that when CRC mortality is considered, the discrepancy between CRC incidence in developing low-income countries and developed high-income countries diminishes [2]. Therefore this provides further reason to increase trained staff and infrastructure for CRC in Uganda and the rest of Sub-Saharan Africa.

Another limiting factor for screening colonoscopy is that in our hospitals in central Uganda, it may take 2-4 weeks to obtain histopathology results, as some hospitals rely on other institutions for the histopathological diagnosis of CRC. To obtain results in a timelier manner, high-resolution micro-endoscopy is a cheaper solution that may be adopted [39]. A major difference between cases in developed high-income countries and developing low-income countries is the tumour site of CRC. Developed high-income countries have reported that over time, lesions are more frequently being reported in the proximal colon; hence, these countries have found a right-shift in the incidence of CRC [40]. This may be due to an aging population where CRC is more common in the proximal colon and there is a decrease in the incidence of distal CRC [41]. In keeping with findings from other Sub-Saharan African countries, our study has shown a predominance of left-sided colon tumours, particularly rectal tumours, followed by sigmoid colon tumours. To date, no plausible explanation has been reported. However, this may be due to a lack of screening programmes, as rectal tumours tend to present early with rectal bleeding, rectal pain and changes in bowel habits [7]. This is in contrast to right-sided colon cancers, which tend to grow to a larger size before becoming symptomatic [7,10].

The prevalence rates of colorectal polyps detected at colonoscopy are relatively low in Sub-Saharan African countries compared to the rates reported in Asia and Western countries [42-49]. Colorectal polyps may be classified as nonneoplastic (inflammatory, hamartomatous, hyperplastic) or neoplastic. Neoplastic colorectal polyps (adenomas) originate from colonic epithelial cells that are mucous secreting [50]. The significance of adenomatous polyps is that they are precursors to CRC. Colon carcinogenesis is a multistep pathway that takes several years and involves hyperproliferation of normal epithelial cells to form adenomas and eventually the formation of invasive CRC [51]. At colonoscopy, these precancerous adenomatous polyps may be removed, leading to a reduction in mortality and incidence of CRC, which has been observed in studies involving patients who have undergone polypectomy [50].

Between different groups, there is a wide variation in the prevalence of colonic polyps. In Africa, a low rate of colonic polyps between 10-15% is observed; however, it is estimated that 30% of Western populations have colonic polyps [52,53]. Studies have shown that compared to women, men have a higher frequency of colonic polyps. The colon adenoma rate from the patients who had a colonoscopy in our study was 8.9%, which is similar to the rate of 6.8% obtained in Ile-Ife in Nigeria but higher than that found in Lagos in Nigeria (4.8%) and Ghana (2.9%) [42,48,49]. These adenoma rates in Sub-Saharan African countries are lower than those in the United States (31%), Germany (19.4%) and France (17.7%) [54-56]. Factors influencing adenoma detection rates include age (over 50 years) and sex, overall procedure time, bowel preparation, history of cigarette smoking and the level of experience of the endoscopist [57-63].

Curative resection is the main aim of surgeons managing colorectal adenocarcinoma. A number of surgical interventions have been reported in East Africa due to many patients presenting at an advanced stage. In this study, the majority of surgical operations for rectal cancer were low anterior resections (63.3%), however, other studies in East Africa have shown that abdomino-perineal resections are performed in up to 54%-71% of patients [64,67] due to the advanced stage of presentation of rectal tumours. Between 22%-26% of patients have anterior resections for rectal tumours due to a lack of facilities to provide radiotherapy and chemotherapy preoperatively for advanced-stage rectal cancer in East Africa. In this study, many of our patients in central Uganda were referred for chemotherapy and radiotherapy in the last few years, making rectal cancer more amenable to low anterior resection.

Table 5 shows the frequency of operations in this study. The frequency of palliative colostomy was only 4.1%. A colostomy itself may lead to social stigma and psychological distress, which may lead to suicide [68]. A higher risk of suicide has been found in >70-year-old patients with a single marital status [68,69]. Erectile impotence may occur due to psychological reasons or due to disruption of the pelvic nerves [70,71]. The impact on psychological well-being needs to be factored in when treatment options are being considered since many rectal cancer operations occur in young Africans who are sexually active.

The only chance for cure is complete resection with adjacent involved lymph nodes in early-stage CRC [70,72]. Since many patients present with advanced-stage CRC in Uganda and the rest of East Africa, only palliative surgery in the form of a colostomy is possible. Cure by surgical resection is only possible in approximately 3.3% of patients, in keeping with studies from developing countries [73-75]. Other reasons for not undergoing surgery for colorectal resection are the financial constraints and clinical deterioration on admission as many patients present to the hospital with stage IV CRC disease in our population.

In Uganda and other resource-poor countries in East Africa, a major challenge in the treatment of CRC is limited access to chemotherapy. The main reasons for the lack of adherence to this form of treatment are financial difficulties and the drug side effects associated with chemotherapy [72]. In locally advanced rectal cancer, local control rates are improved when radiotherapy is administered preoperatively or postoperatively. However, studies have shown that few patients in the East African region have access to this treatment modality, with only 7.2% of CRC patients having access to radiotherapy [72,76,77].

In resource-limited settings, there are numerous challenges in determining the true incidence of CRC. Consistent with observations made from the rest of Sub-Saharan Africa, colorectal cancer is increasing in Uganda. These shifts in the burden of CRC should be made a priority in public health and drive the Ministry of Health and other stakeholders to increase endoscopic and surgical infrastructure to improve the ability to screen, diagnose and manage CRC. Of great concern is the high number of young individuals affected with CRC; hence adopting screening guidelines from western countries which recommend a cut-off age of ≥50 years may not be applicable in our setting. Lack of patient education to present early with symptoms and lack of national screening guidelines lead to a late-stage presentation which affects the mortality and morbidity of CRC patients. Therefore, age-appropriate national screening guidelines and education campaigns are necessary for Uganda and the rest of East Africa. These observations have implications not only for Uganda but also for East Africa and the wider global community.

The limitations of this study included the following:

• Hospital-based studies may not be representative of the entire population; however, in this study, there was a fair representation of participants from all major regions of the country, giving a high level of confidence about the generalizability of the findings in this study.
• The Kampala Cancer Registry archives data on already known CRC patients. This limited our analyses to the presentation of CRC frequencies and not incidence cases since the risk population was unknown.
• Another limitation was the underestimation of the stage of CRC. Staging of CRC in the years 2008-2018 mostly involved a plain chest-X-ray and abdominal ultrasound scanning with some having a CT abdomen and pelvis. In developing low-income countries such as ours, CT scanning is also largely inaccessible for many patients, especially those from rural parts of the country. Therefore, the CRC stage at diagnosis was likely to be under-assessed with inadequate high-precision staging capacity. Another reason for underestimating the CRC TNM stage in this study is that the stage was radiological at diagnosis and not pathological.
• The Kampala Cancer Registry located in the Department of Pathology was used for CRC case identification between 2008 and 2018, as it is reliable in capturing the majority of CRC patients who attended hospitals in central Uganda. The medical records of the Department of Pathology were also used to capture CRC cases outside the catchment of the Kampala Cancer Registry from other regions of the country. However, when using this approach, we may have missed clinically diagnosed CRC that did not undergo resection or biopsy.
• Some CRC patients may not have been included in the study due to missing information. However, we believe that these patients were comparable in age, sex and stage to the analysed patients. The reasons for missing patients included the following: a) some clinical files had missing information on patients’ demographics, clinical data or operative findings and were difficult to characterize beyond knowing that they actually had the disease; b) with the transfer of patients to other oncologic services, some clinical files may have been misplaced; and c) referral of colorectal tissue samples sent for histopathology from other hospitals may have had missing clinical information.

Ethical Considerations

This work was part of the PhD study, which was approved by the Higher Degrees Research and Ethics Committee, School of Biomedical Sciences, College of Health Sciences, Makerere University (reference number: SBS-HDREC-630) and Uganda National Council for Science and Technoology (reference number: HS-2574). A waiver of consent was obtained for the retrospective arm of the study to abstract data from the Kampala Cancer Registry and the case files in the respective hospitals. The patient data, which were obtained from the Kampala Cancer Registry and the case files in the respective hospitals, were anonymised and maintained with confidentiality.

Consent to Participate in the Study

Written informed consent was obtained to participate in the study for patients recruited from the hospitals in the prospective arm of the study.

Competing Interests

The authors have declared that they have no conflicts of interest and no competing interests.

Authors’ Contributions

Richard Wismayer conceived the concept, collected data, performed data analysis and wrote the first draft. Julius Kiwanuka performed data analysis and provided statistical support. Michael Odida and Henry Wabinga performed critical reviews of the manuscript for intellectual content. All authors approved the final manuscript.

Funding

The corresponding author personally funded this part of his PhD research project. The authors declare that they received no specific funding for this work. No payment was received by the authors to write and publish this article.

Acknowledgements

This was part of the PhD work, which was approved by the Doctoral Committee and Higher Degrees Research and Ethics Committee of the School of Biomedical Sciences, College of Health Sciences, Makerere University for the corresponding author. Final approval of this research study was obtained from the Uganda National Council for Science and Technology.

The authors wish to thank Sarah Nambooze and Mary Phoebe Amulen, research assistants in the Kampala Cancer Registry, Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University for abstracting data from the Kampala Cancer Registry and abstracting data from the medical records of the study participants in the respective hospitals.

The authors also wish to thank the clinical staff and research assistants, particularly Dr. Sulaiman Ishaq Mahmud and Dr. Justus Atuhaire, who recruited the participants from the Department of Surgery of Masaka Regional Referral Hospital, Mulago National Referral Hospital, Uganda Martyrs’ Hospital Lubaga and Mengo Hospital for their support in this research project.

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