|Year : 2017 | Volume
| Issue : 4 | Page : 126-131
Microsatellite instability profile of colorectal cancers in Kano Northwestern Nigeria
Dahiru M. C. Aminu1, Yawale Iliyasu2, Ibrahim Yusuf3
1 Department of Pathology, Federal Medical Centre, Yola, Adamawa State, Nigeria
2 Department of Pathology, Ahmadu Bello University/ABUTH, Zaria, Nigeria
3 Department of Pathology, Bayero University/Aminu Kano Teaching Hospital, Kano, Nigeria
|Date of Web Publication||29-Oct-2018|
Dr. Ibrahim Yusuf
Department of Pathology, Aminu Kano Teaching Hospital, P.M.B. 3452, Kano
Source of Support: None, Conflict of Interest: None
Background: Published reports indicate that clinicopathologic profile of colorectal cancer (CRC) in Africa is different from that of the developed world. This study investigates microsatellite instability (MSI) status of CRC in relation to clinicopathologic profiles of our patients.
Patients and Methods: This was a 2 year (2014-15) retrospective study of CRCs diagnosed at the pathology department of a tertiary hospital. Relevant bio-data of the CRC cases (age, sex and site) were obtained from records. Immunohistochemistry for MLH1 and MSH2 were done on corresponding archived CRC tissue blocks. The results were analyzed with SPSS software and presented in tabular form. Correlations between MSI tumours and clinicopathologic features were done using Fishers exact test (P < 0.05).
Results: 53 cases of CRC comprised 37 (69.8%) males and 16 (30.2%) females with a M:F ratio of 2.3:1. The average age of patients was 45.0±15.3 years. Of the 53 cases, 28 (52.8%) exhibited MSI. M:F ratio for MSI CRCs was 3:1. Patients ≤50 years comprised 67.9% (19/28cases) of MSI CRCs (P > 0.05). MSI was detected in 80% of poorly differentiated and 60% of mucinous carcinoma. MSI tumours were mostly located in the left colon (23/28, 82.1%). However, correlation between sex, age, grade, site and MSI status was not statistically significant (P > 0.05)
Conclusion: This study provides useful baseline data for future studies. Over half (53%) of CRCs in our study had MSI. Given the fact MSI CRCs are said to have better prognosis, this portends improved survival of our patients if diagnosis is made early.
Keywords: Cancer, colorectal, microsatellite instability
|How to cite this article:|
Aminu DM, Iliyasu Y, Yusuf I. Microsatellite instability profile of colorectal cancers in Kano Northwestern Nigeria. Arch Int Surg 2017;7:126-31
| Introduction|| |
Globally, colorectal carcinoma (CRC) is the third commonest cancer among males and the second among females. GLOBOCAN 2012 reports that most colorectal cancers (55%) were in developed countries, while most CRC deaths (52%) were in less developed countries. Only 1.6% of CRC deaths were in Africa.
CRC is not uncommon in Nigeria, with various studies across the country reporting an average incidence of 12.5–32.3 cases per year.,,,, It is the most common gut malignancy in the country, constituting 3.9%–7% of all histologically diagnosed cancers.,
Significant epidemiologic differences have been documented between colorectal cancer in Africans and the western world. Black African patients are reported to have higher prevalence of high-grade tumors (poorly differentiated, mucinous, signet ring) and tend to be younger., In Nigeria, the average age of presentation varies across the country from 42 to 53 years as reported in different series.,,
There are two major pathways in oncogenesis of colorectal cancer – APC/β-catenin and microsatellite instability (MSI). APC/β-catenin pathway occurs due to mutations that dysregulate WNT signaling resulting in classic adenoma–carcinoma sequence. The less frequent MSI pathway results from defects in DNA mismatch repair leading to accumulation of oncogenic mutations.,
There has been no comprehensive study of both the APC/β-catenin and MSI pathways in northern Nigeria to determine the relative proportions of both molecular pathways. Ideally, such a study should assay both pathways; however, this study will focus on MSI pathway. MSI tumors are reported to have better prognosis and in recent times new anti-cancer drug therapies have been based on peculiar molecular abnormalities in tumor cells. Consequently, MSI tumors are potential candidates for targeted therapy. Ascertaining the molecular profile of our colorectal cancers is therefore potentially useful for better clinical management of this malignancy.
The aim of this study is to document MSI statuses of patients with CRC by evaluating MutL-Homologue 1 (MLH1) and MutS-homologue 2 (MSH2) immunohistochemistry profiles and their relationship with clinicopathologic features of the patients.
| Patients and Methods|| |
This was a 2-year retrospective study of MLH 1/MSH 2 immunoprofile of all CRCs diagnosed at pathology department of a tertiary teaching hospital between January 2014 and December 2015.
The laboratory request cards of the cases were retrieved and relevant clinical information including age, sex, and tumor site were extracted. Corresponding histology slides were retrieved and reviewed by the authors. The tumors were categorized according to World Health Organization classification of carcinomas of the colon and rectum.
CRC cases with insufficient tissue in paraffin blocks for immunohistochemistry or with missing tissue blocks were excluded. The remaining archived CRC tissue blocks of the corresponding slides were retrieved, sectioned, and stained with hMLH1/hMSH2 antibodies using Thermo-Fisher Scientific UltraVision Quanto Detection System. Nuclear MLH1/MSH2 immunostaining of tumor cells was considered positive and microsatellite stable (MSS), whereas tumors negative for both or either MLH1 or MSH2 were considered microsatellite unstable (MSI). Adjacent non-neoplastic epithelial cells and lymphocytes were used as positive internal controls. SPSS version 20 was used for data analysis. Fisher's exact test was applied to evaluate any correlation between MLH1/MSH2 expression and clinicopathologic parameters. The results were considered to be statistically significant with P values <0.05.
| Results|| |
In all, 53 cases satisfied the criteria for inclusion in the study out of 61 CRC cases received during the study period. Eight cases were excluded due to insufficient tissue in paraffin blocks for immunohistochemistry. Of the 53 cases, there were more males (37/53 cases, 69.8%) than female patients (16/53 cases, 30.2%) with a male-to-female ratio of 2.3:1 and a mean age of 45 ± 15.3 years [Table 1]. CRC was more common in individuals below the age of 50 years (32/53 cases, 60.0%), than those older than 50 years of age (21/53 cases, 40.0%).
Left-sided tumors were vastly more preponderant (44/53 cases, 83%), than the right-sided tumors (9/53 cases, 17%). The rectum was by far the commonest tumor site with 33 cases (62.3%), followed by sigmoid colon (10 cases 18.9%), cecum (7 cases, 13.2%), ascending, transverse, and descending colons with 1 (1.9%) case each.
Adenocarcinoma was the most frequent histological variant [Figure 1] and [Figure 2]. Other histological types, their frequencies, and age distribution are as depicted in [Table 1].
|Figure 1: Colon adenocarcinoma showing infiltrating malignant glands H&E ×100|
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|Figure 2: Same lesion shown in Figure 1. showing positive nuclear staining for MSH 2 IHC ×100|
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With regard to MLH1/MSH2 immunoprofile, 28 (52.8%) of the 53 cases of CRC exhibited MSI as evident from absence of nuclear staining in both or either of the proteins [Figure 3] and [Figure 4]. Thirteen (46.4%) of these 28 MSI tumors were negative for both proteins (MLH1 and MSH2), 11 (39.3%) were negative for only MSH2, whereas 4 (14.3%) were negative for only MLH1 [Table 2] and [Table 3].
|Figure 3: Colon adenocarcinoma showing infiltrating malignant glands H&E ×100|
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|Figure 4: Same lesion in Figure 3 showing microsattellite instability and negative nuclear MSH2 staining. IHC×100|
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As shown in [Table 2], MSI tumors were three times more common in males (21/28 cases, 75%) than females (7/28 cases, 25%). However, no statistically significant correlation was found between sex and MSI status (P > 0.05) [Table 4].
|Table 4: Correlation between MSI tumours and sex, age, tumour grade and site|
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Over two-thirds (19/28 cases, 67.9%) of MSI tumors were in patients ≤50 years, whereas the remaining (9 cases, 32.1%) occurred in patients >50 years. Age and MSI status show no significant correlation (P > 0.05) [Table 4].
Well and moderately differentiated adenocarcinoma comprised 35.7% and 32.1% of the MSI tumors, respectively. Other histological variants and frequencies of their MSI statuses are shown in [Table 3]. Low-grade tumors (well and moderately differentiated adenocarcinomas) form the majority of MSI tumors (19/28, 68.0%), whereas high-grade tumors (poorly differentiated, mucinous, signet ring, and medullary carcinomas) comprised the remaining (9/28, 32.0%). Correlation between histologic grade and MSI was not statistically significant (P > 0.05) [Table 4].
In the left colon, 82.1% (23/28 cases) were MSI tumors, whereas in the right colon only 17.9% (5/28 cases) of the tumors showed MSI. Tumor site and MSI status were not significantly correlated (P > 0.05) [Table 4].
| Discussion|| |
This study found a male predominance in CRC, an average patient's age of 45 years, adenocarcinoma as the most frequent histologic type, and preponderance of distally located tumors. Similar to a multicenter study which documented 52.0% prevalence of MSI colorectal tumors among West Africans, this study also showed MSI tumors constituting 52.8%. Other similar studies conducted in Nigeria recorded lower prevalence for MSI tumors. In a study by Duduyemi et al., and more recently by Irabor et al. both in Ibadan, MSI tumors comprised 23% and 43%, respectively, of the CRC cases reviewed, while Adegoke et al. in Ile-Ife found a prevalence of 34.5%.,, A prevalence of 41% for MSI tumor was reported among Ghanaians in West Africa., However, prevalence of MSI tumors is much lower outside Africa and in the developed regions of the world. These studies documented figures ranging from 12% to 20.3%. Twelve percent was reported in the United States, 18.7% in India, 18.7% in Malaysia, and 20.3% in Italy.,,,
Some of the reported global disparities in prevalence of MSI CRC can be attributed partly to differences in analytical techniques. Several studies used polymerase chain reaction to detect MSI, whereas others used immunohistochemistry to evaluate mismatch repair proteins expression. Absence of standardized reporting format for MSI immunohistochemistry may also result in wide interobserver variability.
In this study, the mean age was 45 years and 60% of patients presented at less than 50 years of age. The relatively younger average age at presentation observed in our study supports the assertion that CRC presents two decades earlier in Black Africans compared with Caucasians. For instance in the United States, the average age at diagnosis was 64 years, whereas in the United Kingdom more than 70% of CRCs are diagnosed in people age 65 years or older and cases peak in the ninth decade., In a systematic review of more than 2000 CRC cases reported over 53 years in Nigeria, the average age of incidence reported was 46 years, a figure which concurs with our finding. Similarly, a study of the Black population in South Africa reported a mean age of 54.3 years, and 28% of the patients presenting with tumor were less than 40 years.
The high prevalence of MSI CRC among younger age group (68% of patients less than 50 years) in this series is in agreement with reports from different authors across the globe that suggests a high MSI prevalence among relatively younger patients with CRC. Liu et al. reported MSI tumors in 58% of patients younger than 35 years. Similarly, Lurkish et al. in the United States found 47% MSI CRC cases in patients less than 40 years. However, other studies reported relatively lower frequencies in younger patients. In Ontario, Canada, only 20% of MSI CRCs were found in patients less than 50 years. It is therefore valid to say that MSI CRC is more likely to occur in patients less than 50 years of age. The younger age of presentation and high prevalence of MSI tumors among younger patients in Nigeria compared with Caucasians pose important implications in etiopathogenesis of CRC in our setting. Perhaps our cases arise through a different molecular pathway due to differences in genetic and environmental factors.
More males were affected than females with an overall male-to-female ratio of 2.3:1. This male preponderance is in keeping with the findings of other studies within Nigeria which documented a male-to-female ratio ranging from 1.3 to 2.5:1.,, Similarly, in more developed regions, such as Australia, New Zealand, United States, Canada, and United Kingdom, the age-standardized incidence rate in men exceeds that of women.,,
The relationship between MSI tumors and gender has been contentious with some authors documenting a statistically significant correlation while others did not find any significant correlation. Our study showed no correlation between gender and MSI status. In agreement with this finding, studies conducted in Ibadan and Ile-Ife both in Nigeria and review of 150 CRC cases in India did not find significant relationship between gender and MSI status., However, Ward et al. in Sydney documented a significant relationship between female gender and MSI status in their series of 302 patients with colorectal cancer. Evaluating a larger sample size is therefore imperative to substantiate MSI status of CRC cases and gender.
In this study, adenocarcinoma was the most frequent (84.9%) histologic type with moderately differentiated adenocarcinoma being the most common histologic subtype (41.5%). This is comparable to the findings of other researchers both within the country and reports from high incident areas.,,, MSI was observed in 35.7% and 32.1% of well- and moderately differentiated adenocarcinomas, respectively, whereas poorly differentiated adenocarcinoma and mucinous carcinoma represented 14.3% and 10.7% of MSI CRC, respectively. Studies from Italy, Australia, and the United States showed high histologic grade carcinomas, particularly poorly differentiated adenocarcinoma and mucinous carcinoma were strongly associated with MSI CRC.,, In our study however, poorly differentiated adenocarcinoma and mucinous carcinoma showed MSI in 80% (4/5 cases) and 60% (3/5 cases) of the CRC cases, respectively, but these figures failed to achieve statistical significance in associating these high-grade tumors with presence of MSI probably due to small sample size. In addition, histologic diagnosis of mucinous carcinoma requires up to 50% of mucinous phenotype within tumor. Thus, unrepresentative sampling of non-mucinous component of mucinous carcinoma as may occur in tiny colonoscopy biopsies may lead to erroneous misclassification and under-representation of these tumors.
Worldwide, left-sided tumors are more predominant with the rectum as the most common site for CRC. In the high incidence populations, approximately 60% of CRC also arise in the left colon and this is similar to our findings and that of CRC reports from other studies in Nigeria.,
Although a majority (82%) of left colon tumors in our study showed MSI, this finding showed no statistically significant correlation between tumor site and MSI status. Other authors documented a strong correlation between MSI and right-sided CRC.,,, In this study, we have demonstrated that our cases of CRC were overwhelming left-sided, and consequently most of the cases in this series came from left-sided tumors. This, compounded with small sample size may have presented us with fewer right-sided CRC tumors and this may have impacted on statistical analysis.
| Conclusion|| |
A majority of CRC in our study showed MSI occurring in relatively younger patients. This highlights the importance of defect in DNA mismatch repair genes in the pathogenesis of our CRC cases and may portend improved survival for patients if diagnosis is made early since MSI tumors have better prognosis. However, given the small sample size of this study, only tentative conclusions can be reached. A national screening program with improved gastroenterology/colonoscopy services is therefore imperative for prevention and treatment of CRC.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]