DP02 Improving Lynch syndrome screening in sebaceous neoplasms: integrating the Mayo Muir–Torre score to overcome limitations of mismatch repair immunohistochemistry

Abstract

Sebaceous neoplasms can be associated with Lynch syndrome, but mismatch repair (MMR) immunohistochemistry (IHC) on sebaceous neoplasms often shows deficient MMR even in the absence of germline disease. This reduces its reliability as a single screening tool. We compared the predictive value of the Mayo Muir–Torre syndrome (MTS) score with IHC results and examined how restricting germline testing to only patients with deficient IHC introduces clinical verification bias. This cohort included 119 cases of SN with 33 sebaceous carcinomas, documenting MMR IHC findings and the minimum Mayo MTS score. In total, 32 patients had constitutional Lynch syndrome. We assessed the diagnostic accuracy for different Mayo thresholds and calculated the positive predictive value (PPV) within the IHC-deficient subgroup. All 32 germline-tested patients had MMR-deficient IHC, but only 13 (41%) had confirmed Lynch syndrome, indicating a high false positive rate for IHC. Because only IHC-deficient patients were referred for genetic testing, IHC specificity could not be measured, and its sensitivity was overestimated. Conversely, Mayo score demonstrated precision (area under the curve 0.97) and provided meaningful stratification within the IHC-deficient group: the PPV was 5.9% for Mayo 0–1, 60% for Mayo 2, and 90% for Mayo ≥ 3. Mayo ≥ 2 provided the best balance of sensitivity (92.3%), specificity (84.2%), PPV (80%) and negative predictive value (94.1%), while Mayo ≥ 3 increased the PPV but missed more patients with Lynch syndrome. Using IHC alone leads to systematic over-referral and verification bias, as most IHC-deficient sebaceous neoplasms were not caused by constitutional variants in MMR genes. The Mayo MTS score, especially at a threshold of ≥ 2, showed better accuracy and effectively distinguished high-risk patients from those unlikely to have Lynch syndrome. A pathway that prioritizes Mayo scoring, either before or alongside IHC, would reduce unnecessary germline testing while improving LS detection in sebaceous neoplasms.