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ORIGINAL ARTICLE
Year : 2021  |  Volume : 24  |  Issue : 12  |  Page : 1814-1823

Do tumor localization, microsatellite instability and mismatch repair deficiency have an impact on the prognosis of colorectal cancer?


1 Department of General Surgery, İzmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, Turkey
2 Department of Biostatistics, İzmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, Turkey
3 Department of Pathology, İzmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, Turkey

Date of Submission21-Jun-2020
Date of Acceptance02-Jul-2021
Date of Web Publication09-Dec-2021

Correspondence Address:
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_371_20

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   Abstract 


Background: Recent reports have shown that left-and right-sided colon cancers display different clinical and biological features. Chromosomal instability, epigenetic alterations, and defects in the deoxyribonucleic acid (DNA) mismatch repair (MMR) system may lead to the development of colorectal cancer (CRC). Besides microsatellite instability (MSI) caused by DNA MMR activity degradation increases the risk for CRC. Aim: We aimed to show the differences between CRCs in different locations, to research the cause of these differences, to present whether there is a relation between MMR and MSI, and to evaluate their effects on prognosis. Patients and Methods: 641 CRC cases were divided into three groups: Group 1 (right-sided), Group 2 (left-sided), and Group 3 (rectum). Demographics, cancer stages, location of the tumors, number of the lymph nodes removed, MMR deficiency or proficiency, MSI status, and survival were assessed by retrospective review of the patients. Results: Among 641 patients, 64.9% were males. Group 1, 2, and 3 comprised 31.2%, 45.7%, and 23.1% of all the cases, respectively. There was a significant difference in terms of survival and location only in stage II tumors. Stage II left colon cancer (LCCs) had a statistically significant lower survival rate. There was no significant difference in survival between both MSI and MMR statuses. In addition, cases were also stratified by stages. According to this data, 10.1, 45.7, and 44.2% of the patients had stages I, II, and III disease, respectively. Conclusions: Although it was not statistically significant, tumors with MMR deficiency (dMMR) and high microsatellite instability (MSI-H) are more common in right-sided colon tumors.

Keywords: Colorectal cancer prognosis, localization, microsatellite instability, mismatch repair, survival


How to cite this article:
Acar T, Acar N, Kamer E, Cengiz F, Tekindal M A, Bağ H, Atahan K, Ekinci N, Dilek O N. Do tumor localization, microsatellite instability and mismatch repair deficiency have an impact on the prognosis of colorectal cancer?. Niger J Clin Pract 2021;24:1814-23

How to cite this URL:
Acar T, Acar N, Kamer E, Cengiz F, Tekindal M A, Bağ H, Atahan K, Ekinci N, Dilek O N. Do tumor localization, microsatellite instability and mismatch repair deficiency have an impact on the prognosis of colorectal cancer?. Niger J Clin Pract [serial online] 2021 [cited 2022 Jan 20];24:1814-23. Available from: https://www.njcponline.com/text.asp?2021/24/12/1814/332078




   Background Top


Colorectal cancer (CRC) is one of the most common cancers and the fourth most common cause of cancer-related deaths worldwide.[1.2] The major risk factors for CRC are excessive consumption of red meat, smoked and/or low-fiber nutrients, alcohol, overweight, hormone replacement therapy, smoking, and long-term usage of non-steroidal anti-inflammatory drugs.[3.4]

Recent reports have shown that left-and right-sided colon cancers display different clinical and biological features.[5.6] Especially right-sided colon cancer is predominant in females and elderly patients, while left-sided cancer is predominant in males and middle-aged patients.[7.8] Although the demographics, hereditary, and environmental characteristics of the cases have been researched, the cause of this condition is still unclear, assuming that this may be dependent on the biological feature of the tumor.[9]

Colorectal cancer is a heterogeneous disease that can occur with different molecular pathological pathways. The possible defined pathways in which CRC can occur are chromosomal instability (CIN), epigenetic alterations, and defects in the DNA mismatch repair (MMR) system. Microsatellite instability (MSI) represents phenotypic evidence that the MMR system is not functioning normally, and it exists in around 15% of all CRCs.

There are also reports in the literature supporting that high MSI (MSI-H) CRCs have a better prognosis compared to low MSI (MSI-L) or microsatellite-stable (MSS) CRCs.[10] Also, the risk for developing non-polyposis colorectal cancer (HNPCC) is increased in patients who have a heterozygous germline mutation in one of the MLH1, MSH2, MSH6, or PMS2 DNA MMR genes.[11] However, there is no definite information on whether it is dependent on tumor localization or not.

In this study, we aimed to show the differences between CRCs in different locations, to investigate the cause of these differences, to present whether there is a relation between MMR and MSI, and to evaluate their effects on prognosis and survival.


   Methods Top


Ethics

The retrospective study protocol was approved by the Institutional Ethics Committee. Written informed consent was obtained from each patient. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patients

A total of 641 cases with CRC who had undergone surgery in our Department of General Surgery between January 2011 and July 2017 were included in the study.

The patients were divided into three groups: right-sided colon tumors (Group 1), left-sided colon tumors (Group 2), and rectal tumors (Group 3).

The inclusion criteria were (1) patients with pathologically confirmed CRC, (2) patients who had undergone curative surgical resection, and (3) patients with stages I–III CRC. We excluded the patients who had (1) undergone preoperative chemotherapy or radiotherapy, (2) two or more primary tumors, (3) carcinoma in situ (CIS) tumors, (4) patients with stage IV disease, and/or (5) peritoneal carcinomatosis. Staging of the disease was performed according to the fifth edition of the American Joint Committee on Cancer (AJCC) TNM classification. The patients' demographic and clinicopathological characteristics were collected from a medical data platform by trained staff who used standardized data collection and quality-control procedures.

The following parameters were analyzed for all the patients: age at diagnosis, sex, tumor location, tumor differentiation, tumor-node-metastasis (TNM) stage, histological subtype, carcinoembryonic antigen (CEA) (mean: <2.5 ng/mL) level, lymphovascular-neural invasion, presence of mucinous subtype, and MSI. The cases which were negative for the expression of human mutL homolog 1 (hMLH1), human mutS homolog 2 (hMSH2), and/or human mutS homolog 6 (hMSH6) were defined as having mismatch repair deficiency (dMMR), and the remaining patients were defined as having mismatch repair proficiency (pMMR). The primary explanatory variable was the tumor location: Right colon cancer (RCC), left colon cancer (LCC), and rectal cancer (RECC). RCCs included the tumors in the caecum, ascending colon, hepatic flexure, and transverse colon. LCCs included the tumors in the splenic flexure, descending colon, and sigmoid colon.

Microsatellite Instability

Microsatellite instability (MSI) is a change that occurs in the DNA of certain cells (such as tumor cells) in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different than the number of repeats that was in the inherited DNA. The cause of MSI may be a defect in the ability to repair the mistakes made when the DNA is copied in the cell.

It should be noted that MSI testing is not a genetic test, but it rather helps to stratify the risk of having an inherited cancer predisposition syndrome and identifies patients who might benefit from subsequent genetic testing. Immunohistochemistry is available as an add-on to this test (IHC/Mismatch Repair (MMR) Protein Immunohistochemistry Only, Tumor).

Evaluation of MSI may also be valuable for clinical decision-making. Colon cancers that demonstrate defective DNA mismatch repair (MSI-H) have a significantly better prognosis compared to those with intact mismatch repair (MSS/MSI-L). Additionally, the current data indicate that stages II and III CRCs with defective MMR (MSI-H) may not benefit from treatment with fluorouracil (5-FU) alone or in combination with leucovorin (LV). These findings are most likely to impact the management of patients with stage II disease.

Follow-up

Follow-up data were collected from the follow-up platform of our hospital. The overall survival (OS) was defined as the time from the initial surgical resection until death for any reason. Disease-free survival (DFS) was defined as the time from the initial surgical resection to the detection of any recurrence or metastasis of CRC. The median duration of the follow-up for all participants was 31.3 months (range: 0.1–85.7 months).

Statistics analysis

For discrete and continuous variables, descriptive statistics (mean, standard deviation, n, and percentile) were given. In addition, the homogeneity of the variances, which is one of the prerequisites of parametric tests, was checked through Levene's test. The assumption of normality was tested via the Shapiro–Wilk's test.

To compare the differences between three or more groups, a one-way analysis of variance was used when the parametric test prerequisites were fulfilled, and the Kruskal–Wallis test was used when such prerequisites were not fulfilled. The Bonferroni correction method, which is a multiple comparison test, was used to evaluate the significant results concerning three or more groups.

The Chi-square test was used for determining the relationships between two discrete variables. When the expected sources were less than 20%, the values were determined through the Monte Carlo Simulation Method in order to include such sources in the analysis. The survival analysis for using the Kaplan–Meier method, the comparison of the variables of the survival times of the factors between the categories was evaluated by the Logrank Mantel–Cox test.

The data were evaluated via SPPS 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). P < 0.05 and P < 0.01 were taken as significance levels.


   Results Top


Among 641 patients, 64.9% were males. The age range, that the cases were commonly diagnosed, was between 51 and 75 years (65.1%). When the histological types were assessed, 67.2% of the tumors were moderately differentiated and 19.7% were poorly differentiated. Moderate differentiation was more frequent in RECCs, while poor differentiation was in LCCs. A majority of the cases were diagnosed with stage II CRC (45.7%), which was followed by stage III CRC (44.1%). Although early-stage tumors were mostly localized in the rectum, there was no statistically significant difference between the groups regarding the distribution of the tumor stage. The dMMR subset accounted for 24.6% of the patients whose data of MMR status was available, and 54.6% of the cases who had available data of MSI status had high-frequency MSI. While the lymphovascular invasion was more frequent in LCCs (34.8%), the mucinous subtype was more frequent in RCCs (30%). A vast majority of the patients underwent elective surgery (81.7%). The most common tumor localization of the emergent cases was the left colon (25.9%).

Postoperative complications, most notably anastomotic leakage and wound infection, were mostly observed in RECCs (20.3%), and consequently, the longest hospital stay belonged to group 3 (12.66 ± 7.84).

The median duration of follow-up for all the participants was 31.3 months (range: 0.1–85.7 months). The recurrence and/or metastasis rate of 11.6% (n: 76) was observed during the follow-up, and the majority (n: 38) of these recurrent cases were from group 1.

Among all the cases, 45.7% (n = 293) had LCC, 31.2% (n = 200) had RCC, and 23.1% (n = 148) had RECC. There were significant differences between the tumor locations regarding sex, histological subtype, presence of lymphovascular invasion, presence of mucinous component, operating condition, morbidity, duration of hospital stay, and recurrence (all, **P < 0.01).

Compared to LCC and RCC, RECC cases were more likely to be males (76.4% vs. 65.5% and 55.5%). Group 1 exhibited higher frequencies of poorly differentiated tumors (32% vs. 14.7% and 12.8%) and mucinous subtype (30% vs. 13% and 17.6%, respectively), while group 3 had a lower frequency of LVI (25% vs. 34.8% and 33.5% [Table 1].
Table 1: Demographic and clinicopathological features of patients with colorectal cancer

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About 10.1% (n = 65) of the patients had stage I, 45.7% (n = 293) had stage II, and 44.2% (n = 283) had stage III disease. The patients' characteristics by stage and tumor location are shown in [Table 2].
Table 2: Demographic and clinicopathological features of patients stratified by stages

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Survival analyses by tumor location, stage, MSI status, and MMR status

The mean survival time was 475.212 days, and the median survival time was 376 days. The Kaplan–Meier survival analyses of all the patients are shown in [Figure 1].
Figure 1: Kaplan–Meier survival analyses of all patients

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The Kaplan–Meier survival curves revealed that there was no significant difference between OS and the tumor location [Figure. 2].
Figure 2: Kaplan–Meier survival analyses of tumor localization

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The results of OS according to the tumor location, and OS according to the stages are shown in [Figure 3]a, [Figure 3]b, [Figure 3]c, respectively. There was a significant difference in both the survival and location only in stage II (P < 0.05) tumors. Stage II LCCs had a significantly lower survival rate.
Figure 3: Kaplan–Meier survival analyses by tumor stage and location. (a) OS of stage I patients; (b) OS of stage II patients; (c) OS of stage III patients

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In addition, there was no significant difference in survival between both MSI and MMR statuses [Figure 4]a and [Figure 4]b.
Figure 4: Kaplan–Meier survival analyses (a) OS of MMR (b) OS of MSI

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   Discussion Top


In many previous studies subjecting the differences in the mortality rates between RCCs and LCCs, researchers excluded RECCs or counted them in the same group with LCCs.[9.12] On the other hand, studies evaluating all three different locations also had other limitations on MMR, MSI status, and/or tumor recurrence. In our study, the clinicopathological features of different locations of CRC, the impact of MSI and dMMR on location, and mortality were assessed. Furthermore, we also compared the clinicopathological features by both tumor location and stage. Most findings of the subgroup analyses were statistically significant (with similar trends), although no significant difference was observed for age in stage I, and gender and mucinous subtype in stages I and III.

The risk of CRC is higher in males, and its incidence significantly increases in older age. According to the studies on the relation between demographics and tumor location, RCC is more common among the elderly and females, while LCC is predominant in young people and males.[7],[13],[14] In our study, the number of CRC patients over 50 years was significantly higher, and age was observed to be independent of location. In addition, the male population was significantly higher, and the left colon was the most common location for CRC in both sexes.

There are differences in terms of demographics, clinical and biological (tumor) factors among patients with RCC, LCC, and RECCs.[15],[16] These differences affect the prognosis for sure. Various previous studies have evaluated the impact of CRC location on survival (mostly emphasizing histopathological findings) and revealed that the tumor size, high grade, poorly differentiated, lymphovascular invasion, mucinous and signet ring cell tumors were frequently seen in the RCCs.[9],[16],[17],[18] This fact is still unclear and requires further studies.[19]

Our stage-based analysis demonstrated that moderate differentiation was the most common histopathologic type among all three locations, and the mucinous component was detected more frequently in RCCs. No significant difference was found in terms of neural invasion whereas lymphovascular invasion was found at least in RECCs.

Colorectal cancer is a disease deriving from genetic alterations which involve changes in the DNA of oncogenes and/or tumor suppressor genes. Mismatch repair and such penetration mutations in other oncogenes are relatively rare, and most familial CRCs are likely due to the low penetrance polymorphism of other genes. According to a Scandinavian study, hereditary factors affect 35% of CRCs, while high-penetration mutations in genes such as APC, MLH-1, and MSH-2 affect only 2–6%.[20]

RCCs and LCCs also display great differences in molecular and cellular features.[21.22] A CRC, originating from the hereditary MSI pathway, usually results from a germline mutation of the MMR gene.[21] Loss of functions of the MMR gene causes replication failure in DNA, which also results in MSI-positive tumors.[22] Our results revealed that MSI-H was more common among RCCs, yet this was not statistically significant.

V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations and MSI have important prognostic values, and both of them have higher rates in RCCs.[23],[24],[25] MSI-L CRCs have better and non-MSI-H CRCs with BRAF mutations have a poorer prognosis.[23],[24],[25]

Some authors introduced that the inconsistent data on the relationship between mortality and tumor location may be associated with MSI.[6.26] Liu et al.'s[6] subgroup analyses showed that RCC presented with a shorter OS in patients who were between 51 and 65 years old and had dMMR. They also reported that RCC had a worse prognosis for DFS in dMMR subset and a better prognosis in the pMMR subset. Our results did not support this hypothesis since there was no significant difference when the survival analysis was performed comparing MSI statuses (MSS, MSI-L, and MSI-H) and MMR statuses (pMMR and dMMR). Sargent et al.[27] reported that the MMR status was not solely associated with the duration of the disease-free period. In contrast, Sinicrope et al.[28] proved that dMMR showed an improved outcome compared with pMMR for time to recurrence, DFS, and OS in stage II and stage III disease. However, most studies in the literature did not analyze the relation between MMR/MSI status, tumor location, and CRC survival. In addition to its prognostic involvement, MSI may also be the answer for the relations between tumor location, treatment, and prognosis.[29]

Although MSI-H does not have a regular distribution according to the stage, MSI-H tumors are associated with a lower stage (21% in stage II vs. 14% stage III and 4% stage IV).[18.30] Furthermore, previous studies have shown that they have different effects on different molecular subgroups. For instance, while MSI-H tumors get less benefit from fluorouracil-based chemotherapy, patients with stage III MSI-H tumors benefit more from oxaliplatin.[31.32]

Our results revealed that dMMR and MSI-H were more common in RCCs than LCCs, yet this was not statistically significant. This may be related to different pathological pathways that CRCs in various locations follow.

Surgical resection of non-metastatic CRC remains the most common treatment option for all localization of colorectal cancer. Since LCCs are more predisposed to obstruction, emergency surgery is more frequent among them.[33.34] RCCs have lower complication rates, lower incidence of surgical site infection, shorter duration of hospitalization, and lower cost rates when compared to LCCs and RECCs.[35]

Different biologic patterns, which also vary according to the location of the tumor, may have an effect on OS as well as they have in the efficacy of treatment after recurrence. In a study by Benedix et al.,[36] the 5-year survival rate was found to be higher in LCCs than RCCs (RCC 67% vs. LCC 71%). Also, other authors have found similar results, reporting a better OS in LCC. [37, 38] In a study of 53.801 patients with stages I–III primary CRC by Weiss et al. revealed that RCC had the worst survival outcome compared to all the stages of LCC.[27] Meguid et al. also reported that RCC was related to an increased risk of mortality, however, it had a better survival outcome compared to stage II LCCs.[19] This difference in the survival rates is unclear. The fact that advanced age, poorly differentiated and mucinous tumors are more frequent in RCCs may be considered as possible causes.[9] These results are consistent with our findings. Most of the cases that underwent emergency surgery in our study had LCC. RCCs had lower postoperative morbidity and shorter duration of hospital stay, while they had higher rates of recurrence and/or metastasis when compared to LCCs and RECCs. In terms of the effect of location on survival, all three locations were evaluated as distinct groups, and our univariate analysis revealed shorter OS in stage II of the LCCs (vs. RCCs and RECCs, P<0.001;0.001), although RECCs and RCCs exhibited similar OS. In stages I and III, there was similar OS in all three groups.

Besides its distinguished aspects, there are also a few limitations of this study. The study population was identified using linked administrative databases that do not include information regarding various known prognostic factors in colon cancer, such as smoking status, diet, or race/ethnicity. In addition, information on performance status was not collected. BRAF mutation and p53 expression were unknown due to the working protocols of our hospital. The number of patients in which MMR could be evaluated was low, and all the patients were from a single center. Therefore, residual confounding is a major limitation in this study.

Consequently, tumor location does not have a direct impact on prognosis and survival. However, stage II LCCs have a statistically significant lower survival rate. This can be explained by the result showing that the patients with stage II LCC had undergone emergency surgery at a significantly higher rate compared to other locations in stage II. Although the general opinion accepts dMMR and MSI-H as negative prognostic factors, our study revealed that these statuses had no impact on survival. Further studies should be conducted to support this conclusion.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgements

The authors thank all the general surgery staff for their cooperation.

All the authors read and approved the paper.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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