Everett Jessica N, Raymond Victoria M, Dandapani Monica, Marvin Monica, Kohlmann Wendy, Chittenden Anu, Koeppe Erika, Gustafson Shanna L, Else Tobias, Fullen Douglas R, Johnson Timothy M, Syngal Sapna, Gruber Stephen B, Stoffel Elena M
JAMA Dermatol. 2014 Dec;150(12):1315-21. doi: 10.1001/jamadermatol.2014.1217.
IMPORTANCE Sebaceous neoplasms (SNs) define the Muir-Torre syndrome variant of Lynch syndrome (LS), which is associated with increased risk for colon and other cancers necessitating earlier and more frequent screening to reduce morbidity and mortality.Immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in SNs can be used to screen for LS, but data on subsequent germline genetic testing to confirm LS diagnosis are limited.OBJECTIVE To characterize the utility of IHC screening of SNs in identification of germline MMR mutations confirming LS.DESIGN, SETTING, AND PARTICIPANTS Retrospective study at 2 academic cancer centers of 86 adult patients referred for clinical genetics evaluation after diagnosis of SN.MAIN OUTCOMES AND MEASURES Results of tumor IHC testing and germline genetic testing were reviewed to determine positive predictive value and sensitivity of IHC testing in diagnosis of LS. Clinical variables, including age at diagnosis of SN, clinical diagnostic criteria for LS and Muir-Torre syndrome, and family history characteristics were compared between mutation carriers and noncarriers.RESULTS Of 86 patients with SNs, 25 (29%) had germline MMR mutations confirming LS.Among 77 patients with IHC testing on SNs, 38 (49%) had loss of staining of 1 or more MMR proteins and 14 had germline MMR mutations. Immunohistochemical analysis correctly identified 13 of 16 MMR mutation carriers, corresponding to 81% sensitivity. Ten of 12 patients(83%) with more than 1 SN had MMR mutations. Fifty-two percent of MMR mutation carriers did not meet clinical diagnostic criteria for LS, and 11 of 25 (44%) did not meet the clinical definition of Muir-Torre syndrome. CONCLUSIONS AND RELEVANCE Immunohistochemical screening of SNs is effective in identifying patients with germline MMR mutations and can be used as a first-line test when LSis suspected. Abnormal IHC results, including absence of MSH2, are not diagnostic of LS and should be interpreted cautiously in conjunction with family history and germline genetic testing. Use of family history to select patients for IHC screening has substantial limitations,suggesting that universal IHC screening of SNs merits further study. Clinical genetics evaluation is warranted for patients with abnormal IHC test results, normal IHC test results with personal or family history of other LS-associated neoplasms, and/or multiple SNs.
重要性 皮脂腺肿瘤（SNs）定义了林奇综合征（LS）的穆尔-托里综合征变异型，该综合征与结肠癌和其他癌症风险增加相关，因此需要更早且更频繁地进行筛查以降低发病率和死亡率。对SNs进行错配修复（MMR）蛋白的免疫组织化学（IHC）染色可用于筛查LS，但关于后续进行种系基因检测以确诊LS的相关数据有限。目的 描述对SNs进行IHC筛查在识别确诊LS的种系MMR突变中的作用。设计、地点和参与者 在2个学术性癌症中心对86例诊断为SN后转诊进行临床遗传学评估的成年患者进行回顾性研究。主要结局和测量指标 回顾肿瘤IHC检测和种系基因检测结果，以确定IHC检测在诊断LS中的阳性预测值和敏感性。比较突变携带者和非携带者之间的临床变量，包括SN诊断时的年龄、LS和穆尔-托里综合征的临床诊断标准以及家族史特征。结果 在86例SN患者中，25例（29%）存在确诊LS的种系MMR突变。在77例对SN进行了IHC检测的患者中，38例（49%）有1种或更多MMR蛋白染色缺失，其中14例有种系MMR突变。免疫组织化学分析正确识别出16例MMR突变携带者中的13例，敏感性为81%。12例有1个以上SN的患者中有10例（83%）存在MMR突变。52%的MMR突变携带者不符合LS的临床诊断标准，25例中有11例（44%）不符合穆尔-托里综合征的临床定义。结论和相关性 对SNs进行免疫组织化学筛查可有效识别有种系MMR突变的患者，在怀疑有LS时可用作一线检测。异常的IHC结果，包括MSH2缺失，不能诊断为LS，应结合家族史和种系基因检测谨慎解读。利用家族史选择患者进行IHC筛查有很大局限性，提示对SNs进行普遍的IHC筛查值得进一步研究。对于IHC检测结果异常、IHC检测结果正常但有其他LS相关肿瘤的个人或家族史和/或有多个SN的患者，有必要进行临床遗传学评估。
