Universal Tumor Screening in Colorectal Cancer: Role of MMR Immunohistochemistry for Lynch Syndrome and Early-Onset CRC.

Mismatch repair deficiency detected by immunohistochemistry, followed by reflex BRAF testing and MLH1 promoter methylation analysis before germline panel testing.

The authors retrospectively analysed 1,022 consecutive colorectal cancer patients undergoing surgical resection at the University Hospital of Padua between 2015 and 2023, with mismatch repair status assessed by immunohistochemistry, reflex BRAF testing and MLH1 promoter methylation analysis for deficient tumours, followed by germline multigene panel testing where Lynch syndrome was suspected. Testing was performed in 875 patients (85.6%), coverage rising from 67.0% in 2015-2017 to 97.4% in 2021-2023, and deficiency was identified in 139 tumours (15.9%), independently associated with age 70 years or older, colonic location and stage 0-II. Of 22 confirmed Lynch syndrome cases, 13 (59.1%) were newly identified through universal tumour screening, and family history was not significantly associated with Lynch status on univariate analysis. Deficiency prevalence was numerically higher in early- than late-onset disease (20.0% versus 15.4%), approaching significance after adjustment (OR 1.90; 95% CI 0.99-3.64; P = 0.054), and markedly rarer in rectal than colonic cancer (4.1% versus 22.5%; P < 0.0001).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Thirteen of twenty-two Lynch syndrome cases identified only through universal screening, with family history showing no significant association: this is the most direct argument against selective criteria, including age-based ones. The most counter-intuitive result is the association of deficiency with age 70 years or older, a reminder that immunohistochemistry also and mainly picks up somatic MLH1 silencing and that reflex BRAF / methylation testing is in no way optional. A single-centre series, but consecutive and with test coverage raised to 97%, which makes the subgroup comparisons credible.

Analysis by Dr Thibaut Benquey