|Year : 2019 | Volume
| Issue : 4 | Page : 302-308
Prognostic and predictive significance of microsatellite instability in stage II colorectal carcinoma: An 8-year study from a tertiary center in South India
Roopa R Paulose1, Divya A Ail1, Shital Biradar1, Anu Vasudevan2, KR Sundaram2
1 Department of Pathology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
2 Department of Biostatistics, Amrita Institute of Medical Sciences, Kochi, Kerala, India
|Date of Web Publication||11-Oct-2019|
Roopa R Paulose
Department of Pathology, Amrita Institute of Medical Sciences, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
BACKGROUND: Microsatellite instability (MSI) accounts for 15–20% of colorectal cancer (CRC) and is considered to have favorable stage-adjusted prognosis compared to Microsatellite stable (MSS) CRCs. Determination of MSI in stage II CRC is important for management decisions regarding adjuvant chemotherapy administration. The aim of this study was to determine the prognostic and predictive significance of MSI in stage 2 CRC in the Indian scenario.
MATERIALS AND METHODS: A total of 195 patients who underwent curative surgery for stage II CRC from 2010 to 2017 were included. MSI testing by immunohistochemistry (DNA MisMatch Repair proteins) was performed in all. Various clinicopathological factors and disease-free survival and overall survival were assessed between MSI and MSS groups. The effect of treatment in terms of survival benefits with adjuvant therapy in the MSI group was also assessed.
RESULTS: 27.1% of the CRCs' showed MSI. Younger age (<50 years), family history of cancer, synchronous/metachronous malignancies, proximal (right sided) location, poor morphological tumour differentiation, mucin production, and presence of peritumoral (Crohn's-like) lymphocytic response showed statistically significant association with MSI. Majority (56%) of our patients showed combined loss of MLH1 and PMS2. Overall, survival among the MSI patients was significantly higher (76.6 ± 4.149 months) than the MSS patients (65.05 ± 3.555)P= 0.04. MSI patients did not show any differences in survival with or without treatment.
CONCLUSION: This study highlights the distinct clinicopathological features of MSI-related CRC and the relevance of MSI testing of stage II CRC for management decisions and prognostication.
Keywords: Colorectal cancer, deficiency of MisMatch Repair Proteins, DNA Mismatch repair, microsatellite instability, microsatellite stable
|How to cite this article:|
Paulose RR, Ail DA, Biradar S, Vasudevan A, Sundaram K R. Prognostic and predictive significance of microsatellite instability in stage II colorectal carcinoma: An 8-year study from a tertiary center in South India. Indian J Cancer 2019;56:302-8
|How to cite this URL:|
Paulose RR, Ail DA, Biradar S, Vasudevan A, Sundaram K R. Prognostic and predictive significance of microsatellite instability in stage II colorectal carcinoma: An 8-year study from a tertiary center in South India. Indian J Cancer [serial online] 2019 [cited 2019 Nov 18];56:302-8. Available from: http://www.indianjcancer.com/text.asp?2019/56/4/0/267598
| » Introduction|| |
Colorectal carcinoma (CRC) is one of the leading malignancies among both men and women in the world. It has lower mortality rates in the West owing to screening protocols and improved standards of care. The incidence of CRC in India has been ranked 10th among all cancers by population-based cancer registries , and has a 5-year survival rate of <40%.
UICC TNM stage of tumor is the universally accepted parameter used for management decisions and to predict prognosis. However due to significant variability in the disease outcome within the same stage contributed by tumour heterogeneity, molecular differences, immune response, tumour host environment, etc., substaging is now becoming increasingly relevant., Role of adjuvant therapy in advanced stage of CRC (III/IV) is well established. However, controversy remains in treating Stage II CRC and adjuvant therapy is offered to those with unfavourable histological features (pT4, <12 lymph nodes examined, poor differentiation, bowel perforation/obstruction, lymphovascular/perineural invasion).
The molecular basis of CRC commonly follows two major mechanisms of genetic instability: Chromosomal instability and microsatellite instability (MSI) pathway. Chromosomal instability is responsible for most cases of CRC and due to the accumulation of mutations in the tumour suppressor genes and oncogenes (TP53, KRAS, BRAF) along with chromosomal abnormalities (APC). 5–20% of colorectal carcinoma is due to MSI which has two arms to its genesis: Lynch syndrome (LS) which results from germline mutation of any of the MMR genes accounting for approximately 5% of CRC. The remaining majority are sporadic cases which can be due to somatic mutations in the MMR genes or epigenetic inactivation of MLH1 gene commonly in the context of CpG island methylation resulting in truncated/nonfunctional/loss of protein , [Figure 1].
MSI-H or MMR deficient CRCs are phenotypically distinct and seen more frequently in stage II CRC (20%) compared to stage III (12%). They are associated with favorable prognosis and require different management strategy especially in stage II CRC, as they are not benefitted by 5-FU-based adjuvant chemotherapy., MSI testing therefore is becoming relevant in early CRC. Determining MSI status also helps in identifying patients with LS, who have a predisposition for CRC and other extracolonic cancers like endometrial, gastric, ovarian, urothelial hepatobilary, pancreatic, small intestinal, and skin.,, Studies on molecular aspects of CRC in the Indian population are limited.
The aim of this study is to analyse the predictive and prognostic significance of MSI in stage II CRC and to understand the association of various clinicopathological features of MSI related CRC, in the Indian scenario. The study also aims to determine the effect of adjuvant chemotherapy in MSI-related stage II CRC in terms of patient survival.
| » Materials and Methods|| |
After Institutional Review Board approval, all patients who underwent curative surgery at Amrita Institute of Medical Sciences a tertiary center in South India for Stage II colorectal adenocarcinoma between 2010 and 2017 were selected from the files of the Department of Pathology. Patients who received neoadjuvant chemo/radiotherapy and all other stages of CRCs were excluded. Information regarding patient demographics, family history of cancer, presence/absence of synchronous/metachronous malignancy, details about adjuvant therapy were obtained from hospital information system and Cancer Registry database. All patients were followed up till the end of November 2017.
Histopathological assessment of the surgical specimen was done as per the RCPath guidelines. The following parameters were recorded:
- Location of tumor-Tumors of cecum, ascending colon, and transverse colon closer to the hepatic flexure were categorised as proximal (right sided) and those in splenic flexure, descending colon, sigmoid colon, and rectum were categorized as distal (left sided)
- Tumor differentiation- Well and moderately differentiated adenocarcinoma was categorized together and poorly differentiated/signet ring cell type were categorized separately. Tumors with more than 50% mucin production were classified as mucinous carcinoma. Tumors with <50% mucin were considered as adenocarcinoma with mucinous change
- Invasive front of the tumor: viz- infiltrative/pushing or both
- Tumor infiltrating lymphocytes (TIL) and peritumoral (Crohns-like) lymphocytic response (CLR) were graded according to CAP guidelines as: None/mild to moderate/marked 
- Presence of background polyps/tumors: In case of synchronous malignancies, parameters of the most advanced tumor were used for the analysis.
Patients in the MSI group were randomly selected for adjuvant (5-FU based) chemotherapy following surgery, whereas all the patients in the microsatellite stable (MSS) group received adjuvant chemotherapy unless they were lost to follow-up.
Immunohistochemistry (IHC) for DNA MisMatch Repair (MMR) proteins:
Formalin-fixed paraffin-embedded 3 micron thick tissue sections containing tumor and normal colonic mucosa were selected and stained using prediluted monoclonal mouse antibodies against MMR proteins:- MLH1 (clone 4c9c7 thermoscientific), PMS2 (clone ERP3947, thermoscientific), MSH2 (clone 25D12, thermoscientific), and MHS6 (clone ERP3945, thermoscientific). Antigen retrieval was done by HEAR technique. Biogenex horse radish peroxidase was used as secondary antibody kit.
Interpretation of IHC: [Figure 2] and [Figure 3].
|Figure 2: IHC (MMR proteins) shows colonic adenocarcinoma with deficiency/loss of expression of MLH1 and PMS2 and intact MSH2 and MSH6, in keeping with Microsatellite Instability (MSI). Staining of normal colonic mucosa serves as internal control|
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|Figure 3: IHC (MMR proteins) in a patient with colonic adenocarcinoma shows deficiency/loss of expression of MSH2 and MSH6 with intact MLH1 and PMS2 in keeping with Microsatellite instability (MSI)|
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Loss of nuclear expression of one or more of MMR proteins in the neoplastic cells was considered as deficiency of MMR protein (dMMR) - MSI [Figure 2] and [Figure 3].
Nuclear expression of all four MMR proteins in the tumor cells was considered as intact/proficiency of MMR protein - MSS.
Nuclear expression of the proteins in lymphocytes, stromal cells, and normal colonic mucosa (base of crypts) was taken as positive internal control.
Chi-square test was used to investigate the statistical correlation between MSI and MSS groups with various clinicopathological parameters (age, gender, family history of cancer, synchronous/metachronous malignancies, site, tumour differentiation, mucin production, tumour edge, intratumoral and peritumoral lymphocytes). T test was used to compare the mean of numerical variables between groups, independent to the sample.
The date of primary histopathological diagnosis was considered as the entry point for determining the disease-free survival (DFS) and overall survival (OS). The date of disease progression and date of disease-related death or date of last follow-up was the end-point for DFS and OS, respectively. Kaplan–Meier method was used to calculate the DFS and OS for groups and log rank test was applied to know the strength of association between the DFS and OS with each of the parameters. For all the continuous variables the results were given as mean ± standard deviation and for categorical variables as percentage.
P value less than 0.05 was considered statistically significant. The data were analyzed using IBM SPSS 20, IBM, Armonk, NY, United States of America.
| » Results|| |
Colorectal carcinoma was diagnosed in 1366 patients during the 8 year study period. A total of 195 patients of stage II colorectal adenocarcinoma were included in the study. IHC for MSI (MMR proteins) was performed on all cases.
Patient demography [Table 1]
Of the 195 patients, 27.1% belonged to the MSI group and 72.9% belonged to MSS group. Mean age of the patients in MSI group was 56 ± 12.052 years. Age <50 years, female preponderance, family history and presence of synchronous/metachronous malignancy were significantly associated with MSI. Synchronous/metachronous malignancy was higher among MSI patients (22.9%) than MSS patients (6.1%), P = 0.001.
|Table 1: Association of various clinical and pathological parameters with the MSI/MSS|
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Pathological and histological features
Right-sided tumors were common among the MSI group (60.4%), whereas left-sided tumors were frequent in MSS group (79.6%) (P = <0.001). Both groups had a relatively uniform distribution of well/moderately differentiated tumours, while poorly differentiated and mucinous carcinoma was significantly associated with the MSI group (P = 0.002). Mucin producing tumors were also more common in the MSI group (50.9%) as compared to MSS group (16.9%), P = <0.001. Type of tumor edge was not specific to any group. Intratumoral lymphocytic infiltration was seen in both groups (P = 0.931). Peritumoral CLR was more frequently seen in MSI group (P = 0.047) [Table 1].
Analysis of the data between the MSI patients with and without family history of cancer did not reveal any significant association with the above described clinicopathological parameters.
The distribution of MMR protein loss (dMMR) in the present study is shown in [Figure 4]. Majority (56%) of our patients showed combined loss of MLH1 and PMS2. Mutational analysis was not done.
DFS and OS survival analysis [Table 2] and [Figure 5]
There was disease recurrence in 6.4% and 8.1% of MSI and MSS patients, respectively. The mean DFS in MSI group was 74.7 ± 3.496 months compared to 69.2 ± 3.631 months in MSS group. Disease-related death was seen in 2.3% and 15.7% of patients in MSI and MSS group, respectively, P = 0.042. The mean OS of MSI patients was 76.6 ± 4.149 months as compared to 65.05 ± 3.555 months in MSS patients (P = 0.04).
|Table 2: Comparison of mean disease-free survival and overall survival between MSI and MSS patients|
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Of the 53 MSI patients, 17 patients received adjuvant 5 FU-based chemotherapy and 26 did not receive any further treatment. Statistical analysis showed no difference in the overall survival between the two groups (P = 0.237). The mean value of the overall survival could not be calculated as there was no disease-related death in one group.
| » Discussion|| |
The DNA MMR system maintains genomic stability by repairing base–base mispairs and insertions/deletions introduced into microsatellites (which are short tandemly repeated sequences) during DNA synthesis. MMR proteins form functional heterodimers. MSH2 dimerizes with either MSH6 or MSH3, and then recruits heterodimers of MLH1 and PMS2 or MLH1 and PMS1 to excise the mismatched nucleotides. Mutations in the MMR system lead to accumulations of errors in DNA, resulting in Microsatellite instability (MSI). Currently, MSI is detected indirectly by demonstrating loss of expression of MMR proteins by IHC, or directly by polymerase chain reaction (PCR)-based amplification of specific microsatellite repeats. Both methods are largely concordant (97.80 concordance, exact 95% CI (96.27-98.82).,,
MSI by PCR
Testing of the tumour DNA for MSI should be done using a minimum panel of 5 microsatellite markers i.e., Two mononucleotide repeats (BAT25, BAT 26) and three dinucleotide repeats (D5S346, D2S123, D17S250) as recommended by Bethesda guidelines. A larger panel has been suggested for better sensitivity. Test results are categorised with criteria as follows:(i) MSI-high (MSI-H), indicating instability at two or more loci (or >30% of loci if a larger panel of markers is used); (ii) MSI-low (MSI-L), indicating instability at one locus (or in 10%-30% of loci in larger panels); (iii) Microsatellite stable (MSS), indicating no loci with instability (or <10% of loci in larger panels).
MSI by IHC
This method assesses the expression of MMR proteins using commercially available antibodies MLH1, MSH2, MSH6 and PMS2. Loss of expression of one or more of these proteins suggest deficient MMR and can indicate the gene harbouring a germline mutation or inactivation by hypermethylation, latter commonly with MLH1. MSH2 and MLH1 proteins are the common subunits of their respective heterodimeric complexes, and when mutated, a loss of the subunits (MSH2/MLH1) and their associated partner proteins (MSH6/PMS2 respectively) is typically observed. Rarely there could be isolated germline mutations of MSH6 or PMS2 resulting in isolated loss of staining of MSH6 or PMS2. A subset of LS is due to deletion of EpCam, a gene upstream of MSH2. This can cause loss of expression of MSH2 due to somatic hypermethylation of MSH2. Musulen et al. have shown that lack of EpCam immunostaining in MSH2 negative CRC is indicative of EpCam gene alterations with 100% specificity.
Comparison of IHC and PCR for MSI
Both methods are sensitive and specific as stated above. The advantage of IHC is that it is rapid, cost effective and has the key advantage in directing specific gene testing. One large study had shown that a predictive value of IHC for MSS/MSI-L was 96.4% and for MSI-H phenotype was 100%.
MSI testing in CRC is useful for diagnosis of LS and for recognition of sporadic CRC with MSI due to implications regarding cancer prevention, management and surveillance. MSI CRC have favourable stage-adjusted prognosis compared to MSS CRC, and require a different management strategy in stage II CRC patients as they are not benefitted by 5-FU based adjuvant chemotherapy. Stage II CRCs' are heterogeneous tumours, with five-year survival (OS) ranging from 58.4% to 87.5%. MSI is uncommon in metastatic CRC (4%), confer poor prognosis and can indicate role of immunotherapy., Patients with LS have higher risk of developing extracolonic malignancies and therefore require more intensive cancer surveillance to help reduce cancer related death in these patients.
Demography and clinical parameters:
MSI constitutes 12%-20%and 6%-13% of CRCs in Western and Eastern countries, respectively. In our study population, 27.1% of patients had MSI CRC. A similar Indian study reported incidence of 22.2% and another Indian study reported prevalence of 40% in stage 2 CRC. Similar studies from Malaysia and China and some Middle Eastern countries have reported incidence of 19% -24%,, suggesting a higher incidence in Asian population.
MSI tumours (both LS and sporadic tumors) have higher incidence in young patients with female preponderance  as also noted in this study. Gandhi et al., showed no significant gender predilection for MSI cancers.,
Proximal (right sided) location, mucinous component and poorly differentiated morphology are typical features of MSI -H tumors  and was also noted in our study. Rectum (left side) has also been described as being a common site of MSI CRC in young patients., Despite the poor morphological differentiation/signet ring morphology and mucin production, they have favourable prognosis in Stage II CRC.
The advancing front of the tumour described as pushing and infiltrative margins was not found to be a predictive factor in this study and other studies, implying that MSI tumours are not characterized by a particular type of invasive front.
The immunological characteristics of tumour microenvironment is an emerging hallmark of cancer, and its assessment has significant impact on clinical outcome in terms of new prognostic markers and personalized treatment. Tumour infiltrating lymphocytes (TIL) and Peritumoral Crohn's like response (CLR) are considered as histological features of predicting MSI in CRC and an independent prognostic factor. The deficiency of MMR system in MSI tumors causes accumulation of frame-shift mutations that causes the transcription and translation of neoantigens that are presented by Human Leukocyte Antigen(HLA) class I and are recognized by cytotoxic T cells. The survival advantage of MSI CRC may be partly attributed to the high lymphocytic response., Our study showed MSI tumors had increased peritumoral lymphocytic response than MSS tumors. Ogino et al., who studied the association of lymphocytic reaction score with MSI, also demonstrated a statistically significant association of peritumoral CLR than other lymphocytic scores with MSI and with survival advantage. The specific immune molecules expressed may act as the potential target for future therapeutic modalities.
Treatment and prognosis
Several meta-analyses have shown that MSI CRC cases have good prognosis in terms of disease-free survival, and overall survival regardless of the stage, whereas others have shown the benefit of knowledge of MSI status only in stage 2 and 3 CRCs. Data also highlight that in a recurrent or metastatic setting the MSI tumors tends to have negative prognostic role with reduced OS as compared to the MSS CRC., This study showed higher disease-free survival and mean overall survival in MSI group, the latter being 76.6 months compared to 65.05 months in the MSS group, in concordance with literature.
Studies on role of adjuvant chemotherapy in randomly selected patients with early stage MSI CRC have shown no significant difference in overall and disease-free survival. Likewise, we also found no significant difference in the survival of patients with or without treatment in stage II CRC.
MSI and Lynch syndrome
MSI is the molecular hallmark of LS accounting for 5% of CRC and characterized by autosomal dominant germline mutations of any one of MMR genes. Mutations in MLH1, MSH2, MSH6, and PMS2 are found in 32%, 38%, 14%, and 15% of LS, respectively. The sensitivity of Amsterdam and modified Bethesda criteria used for screening LS is 50% and 70%, respectively. In our study, 56% of patients showed loss of staining for MLH1 and PMS2, [Figure 2] which may be due to acquired somatic hypermethylation of the MLH1 gene or BRAF mutation (Sporadic) or due to MLH1 germline mutation (LS). Combined loss of MSH2 and MSH6 (30% in our study) or the rare isolated loss of PMS2 (3% in our study) or MSH6 (1% in our study) are more likely to be due to LS with germline mutations in one of these genes.
Algorithm for molecular testing for LS in patients with CRC is shown in [Figure 6].
|Figure 6: Testing algorithm for Lynch syndrome and sporadic microsatellite instability colorectal cancer. MSI: Microsatellite instability; IHC: Immunohistochemical staining; CRC: Colorectal cancer; EpCAM: Epithelial cell adhesion molecule|
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| » Conclusion|| |
MSI-related CRC has a distinct clinico-pathological profile, favorable prognosis, and adjuvant therapy does not improve survival. Universal MSI testing is recommended in all CRC patients, especially in stage II for management decision and prognostication.
We would like to thank Mr P. Gangadharan and his team, Cancer Registry for their help and support in obtaining the data regarding the follow-up of the patients in the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]