|Year : 2018 | Volume
| Issue : 4 | Page : 520-525
|Prevalence estimation of microsatellite instability in colorectal cancers using tissue microarray based methods – A tertiary care center experience
Sonali Susmita Nayak1, Paromita Roy1, Neeraj Arora2, Indu Arun1, Manas Kumar Roy3, Sudeep Banerjee3, Indranil Mallick4, Mohandas K Mallath5
1 Department of Pathology, Tata Medical Centre, Kolkata, West Bengal, India
2 Department of Laboratory Medicine and Molecular Genetics, Tata Medical Centre, Kolkata, West Bengal, India
3 Department of Surgical Oncology, Tata Medical Centre, Kolkata, West Bengal, India
4 Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal, India
5 Department of GI Medicine, Tata Medical Center, Kolkata, West Bengal, India
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|Date of Web Publication||10-Oct-2018|
| Abstract|| |
Aim: Microsatellite instability (MSI) pathway is known to be implicated in carcinogenesis of 15% colorectal carcinomas (CRC), including 2%–3% of cases of Lynch syndrome, as per western literature. MSI status has important prognostic and therapeutic implications. The prevalence of MSI in Indian CRC patients is unknown. We aimed to determine the prevalence by studying 231 consecutive unselected cases of CRC. Methods: Tissue microarrays using duplicate cores per case for 141 cases, and whole tissue sections for 90 cases, were used. Immunohistochemistry with four mismatch repair (MMR) markers – MLH1, MSH2, MSH6, and PMS2 was performed. Molecular analysis for MSI status was performed in 18 randomly selected cases. Correlation with various clinical and histopathological features was done using univariate and multivariate analysis. Results: Loss of MMR immunohistochemical (IHC) was seen in 53/231 cases, i.e. 22.94% (95% confidence interval 17.52%–28.36%). MLH1-PMS2 dual loss comprised 13.9%, MSH2-MSH6 7.4%, and isolated PMS2 loss in 1.73% of cases. Univariate analysis showed significant association with age (<60 years), right-sided tumor location, histologic type, high grade, the presence of severe intratumoral lymphocytic (ITL) and peri-tumoral lymphocytic response, and N0 nodal stage. On multivariate analysis, independent variables were age < 60 years, right-sided location, and severe ITL. Molecular testing for MSI corroborated with the IHC results. Conclusion: The study results show a slightly higher prevalence of MSI-H phenotype, compared to Western literature, stressing the need for more widespread testing for better clinical management and identification of possible hereditary colon cancer syndrome.
Keywords: Colorectal carcinoma, microsatellite instability, mismatch repair protein
|How to cite this article:|
Nayak SS, Roy P, Arora N, Arun I, Roy MK, Banerjee S, Mallick I, Mallath MK. Prevalence estimation of microsatellite instability in colorectal cancers using tissue microarray based methods – A tertiary care center experience. Indian J Pathol Microbiol 2018;61:520-5
|How to cite this URL:|
Nayak SS, Roy P, Arora N, Arun I, Roy MK, Banerjee S, Mallick I, Mallath MK. Prevalence estimation of microsatellite instability in colorectal cancers using tissue microarray based methods – A tertiary care center experience. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Nov 27];61:520-5. Available from: https://www.ijpmonline.org/text.asp?2018/61/4/520/242977
| Introduction|| |
Colorectal carcinoma (CRC) is the third most common cancer in men and second most common cancer in women worldwide. In India, it ranks 9th among the most common cancers both in males and females, with the highest age-adjusted incidence rate for CRC's being recorded as 4.1 for men and 5.2 for women. Development of colorectal neoplasia most commonly occurs through chromosomal instability pathway (75%), followed by microsatellite instability (MSI) pathway (15%)., The third major pathway is the CpG island methylator phenotype causing epigenetic gene silencing, in 10% CRCs.,, Approximately 15% of the MSI associated cancers are inherited as hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome (LS), whereas the rest (85%) are sporadic.,, These have better prognosis and reduced recurrence rates, and in Stage II CRCs, 5FU-based chemotherapy does not provide additional survival benefit., Testing for MSI is directed toward detecting the change in length of microsatellites using polymerase chain reaction (PCR)-based assays. National Cancer Institute recommends using 5 mononucleotide microsatellite markers, which has greater sensitivity.,
Alternatively, mismatch repair (MMR) gene functionality is tested, either by immunohistochemical (IHC) assessment of protein expression or by gene sequencing or promoter hypermethylation analysis. The recommended panel includes markers against protein products of the four MMR genes (mutL homolog 1, MLH1; mutS homologs 2 and 6, MSH2 and MSH6; postmeiotic segregation increased 2, PMS2).
In spite of the huge therapeutic significance, in India, there is currently no published series on the prevalence of MSI in CRC. In this study, we aimed to detect the feasibility of detection of MMR deficiency using immunohistochemical techniques, for MSI prevalence estimation, in CRC.
| Methods|| |
The study comprised a retrospective analysis of 236 consecutive cases of CRC, treated at our hospital over a period of 4 years (May 2011–April 2015). These included patients operated at our center and cases where surgery was done at an outside hospital and slides and blocks were submitted for review at our hospital. Among the rectal primaries, where neoadjuvant chemoradiotherapy (NACRT) was given, only cases where pre-NACRT biopsies were available for IHC testing, were included in the study. This was to avoid aberrant IHC staining in post-NACRT tissue. To assess prevalence with a precision of 5%, (which is the standard value used in most calculations), with 95% confidence intervals (CIs), at a sensitivity of 97% and specificity of 99%, a sample size of 218 cases is required. For a better precision rate than 5%, our goal was to include at least 230 cases, for this study.
The study was approved by the Institutional Review Board Ethics Committee. All information relating to patient demographics, family history, and radiological characteristics were retrieved from the records of our hospital information system. The histological parameters evaluated were the predictors of MSI phenotype, which include tumor histologic subtype of adenocarcinoma (conventional, mucinous, signet ring, medullary or mixed/heterogeneous pattern), grade (low or high), intra-tumoral lymphocytic response (ITL; graded as absent, mild (0–3 lymphocytes/high power field [hpf]), or severe (>3 lymphocytes/hpf), and peri-tumoral lymphocytic response (PTL; graded as absent, mild, or severe (>3 follicles/hpf). Also recorded was the extent of tumor invasion, tumor and nodal stage, margin status, lymphovascular invasion, and perineural invasion. The histological assessment was done blinded to the MSI status.
Archived formalin-fixed paraffin-embedded tumor tissue blocks were used. One representative block from each case was selected for tissue microarray (TMA) construction, after circling the area of tumor on the slide and corresponding block. TMAs were manually constructed with 141 cases, using duplicate cores of 2 mm diameter, taken from the same block, per case. A 14G bone marrow biopsy needle was used, after making holes in premade paraffin block with a half size smaller gauged needle. Each TMA block contained 17 cores comprising of eight cases and one coding core of normal liver tissue. These blocks were regularly sectioned at a thickness of 3–4 μ. Cases where the internal control was unsatisfactory on a TMA core, whole tissue sections were used for IHC testing. In 95 cases, whole tumor sections were used for IHC testing.
Mouse monoclonal concentrated antibody markers used in this study, are from Biocare Medical, USA, comprising of MLH1antibody (Clone G168-15) at 1/50 dilution, MSH2 antibody (Clone FE11) at 1/100 dilution, MSH6 antibody (Clone BC/44) at 1/100 dilution and PMS2 antibody (Clone A16-4) at 1/250 dilution. Staining was done on the Leica BONDMAX automated IHC platform, and antibody detection was done by using biotin-free bond polymer defined detection system (Leica Microsystems). Normal colonic epithelium was used as external control per batch. Validation was done using known positive and negative cases. The testing met the standards of the external quality control program conducted by NORDIQC (run 49).
The interpretation of IHC staining was same for TMA and whole tumor sections and was carried out independently by two pathologists. Any nuclear staining was considered as positive (intact expression). Cases with weak focal nuclear staining (in <10% tumor cells), were noted separately. The complete absence of nuclear staining in the presence of positive internal control (lymphocytes and stromal cells) was considered negative (loss of expression). Aberrant staining patterns included cytoplasmic staining or nuclear staining in <10% cells, in which IHC was repeated with construction of new TMA blocks taking tumor tissue from a different area of the donor block or whole sections. If the aberrant staining pattern persisted after repeat IHC, it was considered non-contributory. Cases where internal control did not work even after repeat TMA or whole tumor section staining, were regarded as noncontributory and excluded from the study.
A fluorescent PCR-based assay was used to detect MSI using five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24, and MONO-27) and two pentanucleotide repeat markers (Penta C and Penta D) (PROMEGA MSI Analysis System, Version 1.2). This test was done in a randomly selected cohort of 18 cases where the molecular pathologist was blinded to the IHC results. The tumor was classified as MSI-H (MSI-high) when, two or more (≥30%) of the markers exhibit instability, MSI-L (MSI-low) if one (1%-29%) of the markers exhibit instability), and microsatellite stable (MSS) if none of the markers are unstable.,,,
All data were analyzed using (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Univariate analysis of clinical and histopathological features predicting MSI was done using the Chi-square test and Fischer's exact test wherever applicable. A binary logistic regression was performed for multivariate analysis to determine factors which are independently predictive of MSI. A probability of <0.05 was considered statistically significant.
| Results|| |
Out of the 236 cases of CRC analyzed, 33 cases were subjected to repeat IHC due to aberrant staining pattern or lack of internal control staining. Five cases continued to show noncontributory IHC results, even after repeat IHC using a different block, and were excluded from the study.
The demographic and clinical profile is listed in [Table 1]. Although there were more left-sided colonic tumors in this study, the most common presenting site was the ascending colon (40.3%).
The histopathological features of CRC are detailed in [Table 2]. Histological predictors of MSI phenotype (at least one or more criteria) was identified in 55.8% of cases. In 28 cases (12.1%) conventional adenocarcinoma was seen in combination with mucinous/signet ring or medullary type carcinoma (mixed pattern). The most common stage was stage II or pT2/T3 N0, seen in 98/231 (42%) cases. In 14 cases of post-NACRT rectal cancer, which were included in the study, the postregression pathological stage was not considered for statistical analysis.
Immunohistochemical details of pattern of MMR protein deficiency are tabulated in [Table 3]. MMR deficient status was observed in 22.9% of cases. The most common age group for MMR deficiency was fourth and fifth decade, while the MSS tumors were more common in the sixth decade.
The clinico-pathological parameters predictive of MSI are depicted in [Table 4] and [Table 5]. On univariate analysis, the features predictive of MSI in the revised Bethesda guidelines, were found to be highly correlating. These variables include age(<60 years), right-sided tumor location, mucinous/signet ring/medullary/mixed tumor histology, high tumor grade, and presence of moderate to severe ITL and PTL response. The pathological nodal stage also correlated significantly, with most of the MSI cases presenting with node-negative (N0) disease, although tumor stage and gender showed no correlation. On multivariate analysis, significant independent variables associated with MSI, were age <60 years, right-sided colonic location and the presence of severe ITL. Other factors such as nodal stage, tumor histology, grade, and PTL were not independently predictive.
|Table 4: Univariate analysis of clinicopathological factors predicting microsatellite instability|
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In the 18 cases where molecular analysis of MSI was done, there was a 100% concordance with the IHC results. Eight cases of MMR deficient phenotype on IHC showed MSI-H phenotype on PCR as well. Nine cases with MMR proficient phenotype, were MSS on PCR. While one case with intact MMR protein expression showed variation in one of the mono-nucleotide markers on PCR, consistent with MSI-L.
| Discussion|| |
Methods of microsatellite instability evaluation
Molecular and immunohistochemical methods of evaluation of deficient MMR are two completely distinct modalities of investigation where one is directed towards identifying microsatellite sequences and the other is a direct phenotypic reflection of the MMR gene, respectively. In our small cohort where microsatellite testing was done, there was complete concordance between the IHC results of MMR deficiency and presence of MSI-H on PCR analysis. Validation on a larger cohort could not be done due to financial constraints. However, review of literature shows that though neither test is 100% accurate in detecting defective MMR machinery independently, they do show excellent concordance. IHC estimation of MMR deficiency has similar efficacy to PCR based MSI with a sensitivity close to 95% and specificity of 98%., This is much improved with four MMR IHC markers, over earlier studies using two antibody panels (MLH1 and MSH2)., However, the slightly lower sensitivity of IHC as compared to PCR method is attributed to the lower sensitivity in detecting MLH1 missense mutations which result in catalytically inactive but antigenically active mutant proteins, producing a false normal staining pattern. Also, non-truncating mutations lying outside the interacting domain of MMR proteins and mutations in other MMR genes are also not picked up by IHC, though these cases comprise an insignificant minority.,
Although we took presence of nuclear stain (>10%) to be considered as positive, in four cases of MLH1, one case each of MSH2 and PMS2 and three cases of MSH6, we found focal (<10%) weak nuclear staining. Other investigators like Ohrling et al. have also noted weak focal MLH1 staining, limiting IHC interpretation. Shia et al. have showed weak staining may be representative of instability, especially for MSH6 antibody.
Staining in five cases could not be interpreted even after repeat on whole sections, and had to be excluded from this study. We noted in all these cases that blocks were received from outside referral laboratories, and inadequate formalin fixation limited accurate staining with these markers.
Microsatellite instability prevalence
The only published Indian study attempting prevalence estimation of MSI in Indian patients, is by Pandey et al. They studied a smaller series of 46 cases, and observed MMR deficiency (using two markers MLH1 and MSH2) in seven cases (15.7%). The same cohort was tested for MSI by PCR using a five-mono-nucleotide panel, which showed MSI-H phenotype in only two cases (4.3%). There are only three other reported studies on MSI in CRC,,, all of which have fewer case numbers. Kanth et al., studied 91 such cases, and frequency of MSI-H phenotype observed was 48.4%. Another study by Rajkumar et al., observed MSI of 67.74%, using 31 cases. Both of these studies only selected cases fulfilling the Bethesda criteria. The study by Singh et al. was done with 30 cases, where two IHC markers (MLH1 and MSH2) were used and observed frequency of MMR deficiency was 63.3%.
The study was based on a larger unselected cohort of all consecutive CRC cases (n = 231), employing a more sensitive panel of four antibodies and we observed an increased percentage of MMR protein loss of 22.9% (95% CI 17.52%–28.36%). Although this is in concordance with many western studies reported in the literature, it is marginally higher, and further testing in a larger series is warranted to understand if this may be representative of different tumor biology. A deficient MMR IHC based study done in Singapore, also quoted a higher prevalence of 21% in Asian patients. We could not include all the rectal cancers treated in our hospital, as the majorities were presurgically treated with neoadjuvant chemoradiation, and we did not have at our disposal the diagnostic biopsy blocks of all the patients who were biopsied in the community. If we remove the rectal cancers from the analysis, MSI was found in 50/172 (29.07%, 95% CI 22.28%–35.86%) evaluable colon cancer patients.
Microsatellite instability and Lynch syndrome
The prevalence of germline mutation (HNPCC) is also unknown in our population, and our preliminary results highlight the need for further evaluation. The loss of MSH2-MSH6, in 17/53 cases along with four cases of isolated PMS2 loss (overall prevalence of 9%), indicates a strong probability of LS. However, only four out of 17 cases had a documented clinical family history fulfilling Amsterdam criteria. The exact cause is difficult to determine in this retrospective audit. It could reflect incomplete disclosure by the patient, and a lack of awareness about the significance and prevalence of LS leading to the suboptimal documentation of family history in routine clinics.
BRAF (V600E) mutation is frequently present in sporadic colorectal cancers with MLH1 hypermethylation and not in LS. Further testing of our cases with MMR deficiency, for BRAF IHC and germline testing of MMR genes, is proposed as a follow-up study.
Correlation of clinico-pathological parameters with microsatellite instability status
Among the parameters studied, most known histological factors predictive of MSI, showed significant association on univariate analysis [Table 4]. In 24% cases with MMR deficiency, no histological indicator of MSI was identified. Age <60 years, right-sided colonic location, high histologic grade, and presence of severe ITL were the only features which showed significant association with MSI on multivariate analysis [Table 5]. These findings reflect the importance of MSI testing in all colorectal cases and not just those showing histological evidence.
Microsatellite instability and prognosis
Data from various randomized clinical trials and meta-analyses have shown that MMR deficient tumors have a better prognosis, including overall survival rates, and reduced recurrence rates. Merok et al. have showed the positive prognostic impact of MSI on stage II colorectal cancers. In our study, we observed a frequent occurrence of MSI-H phenotype in stage II CRC cases, although not statistically significant.
| Conclusion|| |
Although our study is a 4 years retrospective study, the prognosis of these patients which would require a follow-up period could not be assessed.
The study is the first attempt at determining the frequency of MSI-H phenotype in CRC in India, using a validated four IHC panel. With a higher frequency in our population and limitations of relying on MSI-H histology, IHC can serve as an easily available, cost-efficient method in identifying patients with MSI-H phenotype. This vital test should be incorporated into a mandatory panel for all CRC, to guide testing for LS, and gather prognostic and predictive information for better patient care.
This work was being carried out during the fellowship period of Dr. Sonali Susmita Nayak at Tata Medical Centre, Kolkata. She is currently affiliated to Department of Pathology, Homi Bhabha Cancer Hospital and Research Center, Visakhapatnam, India. We also acknowledge the contribution of Mr. Pradip Kumar for his excellent technical skills in manual TMA preparation and performance of immunohistochemistry, and Mr. Biswajoy Pal for his technical assistance in the molecular study. This study would not have been possible without their meticulous effort.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Tata Medical Centre, 14 MAR (E-W), New Town, Rajarhat, Kolkata - 700 160, West Bengal
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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