Lynch syndrome screening in colorectal cancer: results of a prospective 2-year regional programme validating the NICE diagnostics guidance pathway throughout a 5.
2-million populationAims: Screening all patients newly diagnosed with colorectal cancer (CRC) for possible Lynch syndrome (LS) has been recommended in the United Kingdom since the National Institute for Health and Care Excellence (NICE) released new diagnostics guidance in February 2017. We sought to validate the NICE screening pathway through a prospective regional programme throughout a 5.2-million population during a 2-year period. Methods and results: Pathology departments at 14 hospital trusts in the Yorkshire and Humber region of the United Kingdom were invited to refer material from patients with newly diagnosed CRC aged 50 years or over between 1 April 2017 and 31 March 2019 for LS screening. Testing consisted of immunohistochemistry for MLH1, PMS2, MSH2 and MSH6 followed by BRAF mutation analysis AE MLH1 promoter methylation test-ing in cases showing MLH1 loss. A total of 3141 individual specimens were submitted for testing from 12 departments consisting of 3061 unique tumours and 2791 prospectively acquired patients with CRC. Defective mismatch repair (dMMR) was observed in 15% of cases. In cases showing MLH1 loss, 76% contained a detectable BRAF mutation and, of the remainder, 77% showed MLH1 promoter hypermethylation. Of the patients included in the final analysis, 81 (2.9%) had an indication for germline testing. Conclusion: LS screening using the NICE diagnostics guidance pathway is deliverable at scale identifying significant numbers of patients with dMMR. This information is used to refer patients to regional clinical genetics services in addition to informing treatment pathways including the use of adjuvant/neoadjuvant chemotherapy and immunotherapy.
Colorectal cancer (CRC) is common with 3% of cases associated with germline mutations in the mismatch repair pathway characteristic of Lynch syndrome (LS). The UK National Institute for Health and Care Excellence recommends screening for LS in all patients newly diagnosed with CRC, irrespective of age. The Yorkshire Cancer Research Bowel Cancer Improvement Programme includes a regional LS screening service for all new diagnoses of CRC. In the first 829 cases screened, 80 cases showed deficient mismatch repair (dMMR) including four cases showing areas with loss of expression of all four mismatch repair proteins by immunohistochemistry. The cases demonstrated diffuse MLH1 loss associated with BRAF mutations and MLH1 promoter hypermethylation in keeping with sporadic dMMR, with presumed additional double hit mutations in MSH2+/−MSH6 rather than underlying LS. Recognition and accurate interpretation of this unusual phenotype is important to prevent unnecessary referrals to clinical genetics and associated patient anxiety.
Pathologists are an integral member of the colorectal multidisciplinary team and are able to closely interact with surgeons, radiologists and oncologists to facilitate improvements in surgical quality and patient outcomes. Accurate, high quality pathology reports containing all vital prognostic information are essential to ensure the patient receives optimal treatment. These reports should also integrate feedback to all members of the multidisciplinary team on the accuracy of preoperative staging, response to preoperative treatment, and the quality of surgery. Pathologists have played a key role in improving outcomes in patients with rectal cancer by recognising the prognostic importance of an involved circumferential resection margin. In addition, pathologists have described an assessment of the surgical planes of dissection as a marker of surgical quality and thereby a means of quality control. This article will review the current best practice for the pathological assessment of anterior resections and abdominoperineal excisions for rectal cancer and ultimately look at how pathologists can influence quality control in rectal cancer surgery.
Contributors MJK and JB were involved in the literature review and drafted the manuscript layout, text content and sourcing images. MJK, JB, RA and MTH were involved in revisions of the manuscript layout and content. AW and AC advised on histopathology input and provided the demonstrative histopathology image.
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