Departments of Anatomic Pathology.
Medicine and Bioregulatory Science.
Am J Surg Pathol. 2018 Feb;42(2):172-182. doi: 10.1097/PAS.0000000000000947.
Synchronous colorectal carcinoma (CRC) is a unique disease associated with a high prevalence (∼35%) of microsatellite instability and occasionally with Lynch syndrome. The clinicopathologic and molecular features of synchronous CRC are poorly understood, particularly in Japanese patients. We examined 118 Japanese patients (236 tumors) with synchronous CRC and 117 Japanese patients (117 tumors) with solitary CRC with immunohistochemical staining for TP53 and mismatch repair (MMR) protein (MLH1, MSH2, PMS2, and MSH6) and mutation analyses of KRAS and BRAF genes. The results revealed no significant differences in clinicopathologic, histologic, and molecular findings between the synchronous and solitary CRC groups. Among the 118 synchronous CRC patients, 15 (12.7%) showed loss of MMR protein(s) expression in at least 1 tumor, whereas 103 (87.3%) showed intact expression of all 4 MMR proteins in both tumors. Of note, all patients with MMR deficiency had excellent prognoses. The 15 patients were further subdivided into 2 groups: the Concordant group, with concordant MMR loss (n=9, 7.6%) and the Discordant group, with discordant MMR loss (n=6, 5.1%). The Concordant patients showed concurrent MLH1/PMS2 loss (n=3), concurrent MSH2/MSH6 loss (n=4) and isolated MSH6 loss (n=2) in both tumors, whereas the Discordant patients showed concurrent MLH1/PMS2 loss (n=2), isolated PMS2 loss (n=2) and isolated MSH6 loss (n=2) in a single tumor. On the basis of the MMR expression pattern and BRAF mutation, the Concordant and Discordant groups were suspected to include Lynch syndrome, Lynch-like syndrome and sporadic MLH1 promoter hypermethylated CRC. In addition, KRAS mutation was present in only 1 tumor in a single patient in each group. In conclusion, the frequency of MMR protein deficiency in synchronous CRC in the Japanese population may be lower compared with the reported data from Western populations. MMR protein loss and KRAS and BRAF mutations in synchronous CRCs were heterogenous even in an individual patient.
同步结直肠癌（CRC）是一种独特的疾病，与高发病率（约 35%）相关，其特征为微卫星不稳定，偶尔与林奇综合征相关。同步 CRC 的临床病理和分子特征尚未被充分了解，尤其是在日本患者中。我们检测了 118 例日本同步 CRC 患者（236 个肿瘤）和 117 例日本单发 CRC 患者（117 个肿瘤），采用免疫组化方法检测 TP53 和错配修复（MMR）蛋白（MLH1、MSH2、PMS2 和 MSH6），并对 KRAS 和 BRAF 基因进行突变分析。结果显示，同步 CRC 组和单发 CRC 组在临床病理、组织学和分子特征方面无显著差异。在 118 例同步 CRC 患者中，有 15 例（12.7%）至少有 1 个肿瘤中存在 MMR 蛋白缺失，而 103 例（87.3%）两个肿瘤中均存在 4 种 MMR 蛋白完整表达。值得注意的是，所有 MMR 缺陷患者均有良好的预后。这 15 例患者进一步分为两组：一致性组，有 9 例（7.6%）存在 MMR 缺失一致；不一致组，有 6 例（5.1%）存在 MMR 缺失不一致。一致性组的患者在两个肿瘤中均存在 MLH1/PMS2 缺失（n=3）、MSH2/MSH6 缺失（n=4）或仅 MSH6 缺失（n=2），而不一致组的患者在单个肿瘤中存在 MLH1/PMS2 缺失（n=2）、仅 PMS2 缺失（n=2）或仅 MSH6 缺失（n=2）。根据 MMR 表达模式和 BRAF 突变情况，推测一致性组和不一致组包括林奇综合征、林奇样综合征和散发 MLH1 启动子高甲基化 CRC。此外，每组仅在单个肿瘤中存在 1 例 KRAS 突变。总之，与西方人群的报告数据相比，日本人群同步 CRC 中 MMR 蛋白缺失的频率可能较低。即使在单个患者中，同步 CRC 中的 MMR 蛋白丢失以及 KRAS 和 BRAF 突变也存在异质性。
