Department of Pathology, Yale University, New Haven, CT, USA.
Department of Pathology, Oregon Health and Science University, Portland, OR, USA.
Mod Pathol. 2019 May;32(5):650-658. doi: 10.1038/s41379-018-0179-3. Epub 2018 Nov 15.
Mismatch-repair deficiency testing plays a critical role in the identification of proband in Lynch Syndrome families and triaging patients with high stage or recurrent solid malignancies for check point inhibitor (Pembrolizumab) immunotherapy. We compared microsatellite shift patterns of microsatellite instability PCR analysis at 5 NCI recommended loci between microsatellite instability high endometrial carcinoma (n = 50) and microsatellite instability high colorectal cancer (n = 19). The endometrial cancer cohort included 45 endometrioid, 1 serous, and 4 clear cell carcinomas. Overall, 52% (26/50) of microsatellite instability high endometrial cancers showed minimal microsatellite shift (defined as a one to three nucleotide repeat shift at an involved locus) observed at least at one locus. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, the frequencies at each involved locus were D2S123 (21/21, 100%), D17S250 (10/11, 89%), D5S346 (11/12, 92%), BAT25 (9/12, 80%), and BAT26 (8/21, 45%). Noticeably, 11 of the 26 cases (42%) showed only minimal shift. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, 65% (17/26) had combined MLH1 and PMS2 loss, 8% (2/26) had combined MSH2 and MSH6 loss, 13% (3/26) had MSH6 loss and 15% (4/26) had loss of PMS2 by immunohistochemistry. In contrast, only 16% (3/19) had minimal microsatellite shift seen in colorectal cancer cohort with corresponding loss of MLH1/PMS2, MSH2/MSH6, or MSH6. Overall, 15% (7/50) of microsatellite instability high endometrial carcinomas showed isolated loss of MSH6 in contrast to 7% (1/15) seen in microsatellite instability high colorectal carcinomas. In conclusion, microsatellite instability high endometrial carcinomas have a significantly higher frequency of minimal microsatellite shift that coincides with a high percentage of combined loss of MLH1/PMS2. Microsatellite instability high endometrial cancers also have more frequent loss of MSH-6. Diagnostically, recognition of minimal microsatellite shift is crucial for accurate interpretation of microsatellite instability PCR data of endometrial carcinoma.
错配修复缺陷检测在林奇综合征家族中先证者的鉴定以及对高分期或复发性实体恶性肿瘤患者进行检查点抑制剂（派姆单抗）免疫治疗的分类中起着关键作用。我们比较了 5 个 NCI 推荐的微卫星不稳定 PCR 分析位点的微卫星不稳定性高子宫内膜癌（n=50）和微卫星不稳定性高结直肠癌（n=19）之间的微卫星转移模式。子宫内膜癌队列包括 45 例子宫内膜样癌、1 例浆液性癌和 4 例透明细胞癌。总体而言，52%（26/50）的微卫星不稳定性高子宫内膜癌显示出最小的微卫星转移（定义为至少一个受累位点出现一个至三个核苷酸重复转移）。在微卫星不稳定性高子宫内膜癌中，有最小微卫星转移的病例中，每个受累位点的频率为 D2S123（21/21，100%）、D17S250（10/11，89%）、D5S346（11/12，92%）、BAT25（9/12，80%）和 BAT26（8/21，45%）。值得注意的是，26 例中有 11 例（42%）仅显示最小转移。在微卫星不稳定性高子宫内膜癌中，有最小微卫星转移的病例中，65%（17/26）存在 MLH1 和 PMS2 联合缺失，8%（2/26）存在 MSH2 和 MSH6 联合缺失，13%（3/26）存在 MSH6 缺失，15%（4/26）存在 PMS2 免疫组化缺失。相比之下，结直肠癌队列中仅 16%（3/19）有最小微卫星转移，相应的 MLH1/PMS2、MSH2/MSH6 或 MSH6 缺失。总体而言，15%（7/50）的微卫星不稳定性高子宫内膜癌表现出孤立性 MSH6 缺失，而微卫星不稳定性高结直肠癌中仅为 7%（1/15）。结论：微卫星不稳定性高子宫内膜癌的最小微卫星转移频率明显更高，与 MLH1/PMS2 联合缺失的比例较高相一致。微卫星不稳定性高子宫内膜癌也更频繁地发生 MSH-6 缺失。诊断上，识别最小微卫星转移对于准确解释子宫内膜癌的微卫星不稳定 PCR 数据至关重要。
