“…Rather than immediately sequencing questionable cases, repeating the IHC or performing IHC on the pretreatment biopsy will help resolve this issue. Decreased expression of PMS2 has also been reported in 30% of posttreatment rectal carcinomas [74]Fig. 4Immunohistochemistry for mismatch repair proteins in a patient that received neoadjuvant chemotherapy for rectal adenocarcinoma.…”
BackgroundMicrosatellite-unstable colorectal cancers (CRC) that are due to deficient DNA mismatch repair (dMMR) represent approximately 15% of all CRCs in the United States. These microsatellite-unstable CRCs represent a heterogenous group of diseases with distinct oncogenesis pathways. There are overlapping clinicopathologic features between some of these groups, but many important differences are present. Therefore, determination of the etiology for the dMMR is vital for proper patient management and follow-up.Main bodyEpigenetic inactivation of MLH1 MMR gene (sporadic microsatellite-unstable CRC) and germline mutation in an MMR gene (Lynch syndrome, LS) are the two most common mechanisms in the pathogenesis of microsatellite instability in CRC. However, in a subset of dMMR CRC cases that are identified by screening tests, no known LS-associated genetic alterations are appreciated by current genetic analysis. When the etiology for dMMR is unclear, it leads to patient anxiety and creates challenges for clinical management.ConclusionIt is critical to distinguish LS patients from other patients with tumors due to dMMR, so that the proper screening protocol can be employed for the patients and their families, with the goal to save lives while avoiding unnecessary anxiety and costs. This review summarizes the major pathogenesis pathways of dMMR CRCs, their clinicopathologic features, and practical screening suggestions. In addition, we include frequently asked questions for MMR immunohistochemistry interpretation.
“…Rather than immediately sequencing questionable cases, repeating the IHC or performing IHC on the pretreatment biopsy will help resolve this issue. Decreased expression of PMS2 has also been reported in 30% of posttreatment rectal carcinomas [74]Fig. 4Immunohistochemistry for mismatch repair proteins in a patient that received neoadjuvant chemotherapy for rectal adenocarcinoma.…”
BackgroundMicrosatellite-unstable colorectal cancers (CRC) that are due to deficient DNA mismatch repair (dMMR) represent approximately 15% of all CRCs in the United States. These microsatellite-unstable CRCs represent a heterogenous group of diseases with distinct oncogenesis pathways. There are overlapping clinicopathologic features between some of these groups, but many important differences are present. Therefore, determination of the etiology for the dMMR is vital for proper patient management and follow-up.Main bodyEpigenetic inactivation of MLH1 MMR gene (sporadic microsatellite-unstable CRC) and germline mutation in an MMR gene (Lynch syndrome, LS) are the two most common mechanisms in the pathogenesis of microsatellite instability in CRC. However, in a subset of dMMR CRC cases that are identified by screening tests, no known LS-associated genetic alterations are appreciated by current genetic analysis. When the etiology for dMMR is unclear, it leads to patient anxiety and creates challenges for clinical management.ConclusionIt is critical to distinguish LS patients from other patients with tumors due to dMMR, so that the proper screening protocol can be employed for the patients and their families, with the goal to save lives while avoiding unnecessary anxiety and costs. This review summarizes the major pathogenesis pathways of dMMR CRCs, their clinicopathologic features, and practical screening suggestions. In addition, we include frequently asked questions for MMR immunohistochemistry interpretation.
“…It is of note that the intensity of staining for all four markers, and especially for MSH6, may be reduced due to neoadjuvant treatment, which is most evident in rectal cancers after neoadjuvant chemoradiation. In these cases, pre-treatment endoscopic biopsies rather than operative material may be used as the primary material for immunohistochemistry [105]. Of note, reduced expression of MSH6 due to neoadjuvant treatment [106,107] should be differentiated from loss of MSH6 expression due to secondary frameshift mutations in the MSH6 gene in cancers with MLH1/PMS2 deficiency [107].…”
Section: Microsatellite Instability Testing In the Routine Settingmentioning
Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations of genetic events and epigenetic alterations. Chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) have been identified as the three major molecular characteristics, which interact with other significant mutations, such as mutations in the KRAS and BRAF genes. High-level MSI (MSI-H) is of eminent clinical importance. It is the seminal molecular feature for the identification of individuals with Lynch syndrome, but it may also occur in sporadic cancers with CIMP phenotype, which arise from serrated precursor lesions. MSI-H status is a marker of favorable prognosis and may be used for outcome prediction, that is, molecular grading. Among others, mucinous and medullary histology, signet-ring cell differentiation, and a marked anti-tumoral immune response are histological features suggesting MSI. Universal tumor testing is recommended and may be performed using immunohistochemistry (mismatch repair protein expression) or molecular analysis, as has recently been recommended by an international task force. In this review, we consider in detail the molecular pathogenesis of colorectal cancer, focusing on the diagnosis of MSI in both hereditary and sporadic tumors.
“…In the remaining cases (6.8%), the endoscopic material stained strongly positive while the resection material showed focal weak staining 35. A study by the same group involving 32 rectal cancers with paired preneoadjuvant and postneoadjuvant tissue and a control group of 39 patients with rectosigmoid cancer who did not receive neoadjuvant treatment demonstrated that quantitative scores of MMRP expression from the operative material were significantly lower in the neoadjuvant group than in the control (P<0.05 for all MMRPs) 34. Disagreement between the endoscopic biopsy and the operative material was evident in 18.5% in the neoadjuvant group compared with 7.7% in the control group (P=0.009).…”
Section: Discussionmentioning
confidence: 96%
“…The incorporation of the commercially available BRAF V600E antibody into this paradigm has the potential to further enhance this strategy44 as well as rapidly define aggressive tumours with poor prognosis 45. Regarding rectal cancer, where neoadjuvant chemoradiotherapy has become standard of care for locally advanced disease, performing MMR IHC on preoperative biopsies would allow determination of the MMR status in cases of pCR, where no residual tumour remains in resection specimens and also in tumours where neoadjuvant chemoradiation may have had a deleterious effect on IHC staining 34. Early results of the FOXTROT trial indicate that neoadjuvant chemotherapy may also become standard of care for locally advanced, operable colon cancer 38.…”
Section: Discussionmentioning
confidence: 99%
“…The pathway to the diagnosis of LS could be initiated preoperatively, allowing resultant genetic information to be used in consultation with the patient to inform management decisions 36 37. Moreover, rectal tumours treated with neoadjuvant chemoradiotherapy may undergo a complete pathological response (pCR), with no residual tumour available for testing, and in some instances, neoadjuvant therapy can alter the MMRP status of the tumour 34. In both these scenarios, the pretreatment biopsy would be a source of suitable, reliable testing material.…”
Endoscopic biopsies are a suitable source of tissue for MMR IHC analysis. This may provide a number of advantages to both patients and clinicians in the management of CRC.
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