Supplementary Material for: IMMUNOHISTOCHEMISTRY, MOLECULAR BIOLOGY AND CLINICAL SCORING FOR THE DETECTION OF MUIR-TORRE SYNDROME IN CUTANEOUS SEBACEOUS TUMORS: WHICH STRATEGY?

Background
Sebaceous neoplasms (SNs) always raise the possibility of an association with Muir-Torre syndrome (MTS) and permit to screen internal malignancies, colorectal and endometrial carcinomas, before they become symptomatic. Immunohistochemistry (IHC), molecular biology and clinical examination are different approaches for detection of MTS. We conducted a retrospective analysis of non-selected SNs in order to determine the optimal tools to implement for MTS screening.
Methods
Deficient MMR phenotype (dMMR) was determined by either IHC using antibodies directed to four mismatch repair (MMR) antigens on tissue-microarray or molecular biology using pentaplex PCR. The Mayo-Clinic-Risk score of MTS was calculated from medical records. Sensibility and specificity of each test for the detection of MTS was determined.
Results
We included 107 patients, 8 with multiple SNs, for a total of 123 SNs (43 sebaceous adenomas, 19 sebaceomas and 61 sebaceous carcinomas (SC)). Loss of at least one MMR protein was observed in 70.7% of tumors while 48% had a microsatellite instable phenotype. Concordance between both techniques was 92.9%, with a 0.85 Cohen’s kappa coefficient. Nineteen patients (20.2%) had a ≥2 points Mayo-Clinic-Risk-Score, one having a pMMR SC. Among the 13 patients with confirmed MTS, 2 had a low Mayo-Clinic-risk score (1 point). IHC had the highest sensitivity for MTS screening (100%) with a specificity of 34.1% while a >2 points Mayo-Clinic-Risk-Score had a lower sensitivity (92%) but a higher specificity (89%).
Conclusion
To detect MTS in SNs patients, first line Mayo-Clinic-risk-score followed by IHC appears the most accurate strategy with lower cost for society. This strategy should be adapted to the medico-economic resources of each country.

# 背景
皮脂腺肿瘤（Sebaceous neoplasms, SNs）常与穆尔-托雷综合征（Muir-Torre syndrome, MTS）相关联，可在患者出现临床症状前，筛查其潜在的结直肠癌与子宫内膜癌等内脏恶性肿瘤。目前用于检测MTS的手段包括免疫组化（Immunohistochemistry, IHC）、分子生物学技术及临床检查。本研究对连续纳入的未经过预先筛选的SNs病例开展回顾性分析，旨在明确用于MTS筛查的最优实施方案。

# 方法
错配修复缺陷表型（Deficient MMR phenotype, dMMR）的检测方式分为两种：一是通过组织微阵列切片上靶向四种错配修复（mismatch repair, MMR）抗原的抗体开展免疫组化检测；二是采用五重聚合酶链式反应（pentaplex PCR）进行分子生物学检测。研究人员从患者病历中提取数据，计算梅奥诊所MTS风险评分，并评估各项检测手段用于MTS筛查的敏感性与特异性。

# 结果
本研究共纳入107例患者，其中8例存在多发皮脂腺肿瘤病灶，总计123个SNs病灶（43个皮脂腺腺瘤、19个皮脂腺瘤及61个皮脂腺癌（Sebaceous carcinomas, SC））。70.7%的病灶至少存在1种错配修复蛋白缺失，48%的病灶呈现微卫星不稳定表型（microsatellite instable phenotype）。两种检测方法的一致性达92.9%，科恩kappa系数为0.85。19例患者（20.2%）的梅奥诊所风险评分≥2分，其中1例患者的病灶为错配修复完整表型（proficient MMR, pMMR）皮脂腺癌。在13例确诊MTS的患者中，2例的梅奥诊所风险评分为1分，属于低风险范畴。免疫组化用于MTS筛查的敏感性最高（100%），特异性为34.1%；而梅奥诊所风险评分＞2分的筛查方案敏感性为92%，但特异性更高（89%）。

# 结论
针对皮脂腺肿瘤患者的MTS筛查，先采用梅奥诊所风险评分进行初筛、再辅以免疫组化检测的策略，兼具较高准确性与社会成本效益，该方案应结合各国的医疗经济资源进行本土化调整。