第一部分：林奇综合征与散发性微卫星不稳定结直肠癌患者临床病理特征分析

【目的】探讨散发性微卫星不稳定(MSI)结直肠癌与林奇综合征(LS)患者临床病理特征及预后差异。

【方法】收集2015年1月至2017年12月中国医学科学院肿瘤医院确诊的338例连续性MSI结直肠癌术后病例，其中LS组105例，散发性MSI结直肠癌组233例，回顾性分析其临床病理学特点。

【结果】LS患者确诊年龄明显小于散发性MSI结直肠癌患者(t=4.179, P<0.001)，错配修复蛋白缺陷类型更倾向为3型(x²=28.036, P<0.001)或4型(x²=4.325,P=0.038)。散发性MSI患者更容易发生启动子甲基化(x²=22.388, P<0.001)及BRAF突变(x²=13.005, P<0.001)。二组在组织学形态上差异无统计学意义，总生存期(x²=1.035，P=0.305)与无进展生存期(x²=0.008，P=0.928)的差异无统计学意义。高危组织学成分如微乳头及印戒细胞是MSI结直肠癌患者无病生存的独立预后因素(HR=4.075, P<0.05)。

【结论】LS与散发性MSI结直肠癌的临床病理特征存在差异性，其对免疫治疗的反应性差异的分子机制需要进一步研究。

第二部分：MLH1缺陷型林奇综合征与MLH1缺陷型散发性微卫星不稳定结直肠癌免疫微环境研究

【目的】探讨MLH1缺陷型散发性微卫星不稳定(MSI)结直肠癌与MLH1缺陷型林奇综合征(LS)患者免疫微环境的差异。

【方法】随机纳入40例2015年1月至2017年12月中国医学科学院肿瘤医院原发、连续的通过分子检测确诊为MLH1缺陷型微卫星不稳定结直肠癌患者，林奇综合征组与散发性微卫星不稳定结直肠癌各20例。两名病理医师对入组病例连续的石蜡包埋肿瘤切片进行复阅后挑选切片进行全自动多重免疫荧光染色检测，以识别CD3+、CD8+、CD45RO+、FoxP3+和PD-1+T细胞，并采用数字病理图像及人工智能图像分析软件将肿瘤浸润免疫细胞进行量化分析及免疫评分，同时分析免疫评分与生存预后的关系。

【结果】与散发性微卫星不稳定结直肠癌相比，林奇综合征肿瘤区域内具有更多的CD45RO+T细胞(P=0.002)及更少的FoxP3+T细胞(P=0.001)浸润，而其他免疫标志物的差异不明显：CD3+(P=0.449)、CD8+(P=0.130)、PD-1+(P=0.766)。免疫细胞百分比在两组间显示同样的结果：CD45RO+(P=0.006)、FoxP3+(P<0.001)、CD3+(P=0.194)、CD8+(P=0.387)、PD-1+(P=0.607)。此外，散发性微卫星不稳定结直肠中浸润的CD45RO+T细胞生物活性强于林奇综合征(P=0.025)。林奇综合征的免疫评分较散发性微卫星不稳定结直肠癌高，差异具有统计学意义(P=0.013)，且低免疫评分的总生存期(P=0.380)及无进展生存期(P=0.604)均较高免疫评分组短，但差异不具有统计学意义。

【结论】MLH1缺陷型林奇综合征与MLH1缺陷型散发性微卫星不稳定结直肠癌肿瘤免疫微环境存在差异。

PART Ⅰ: Analysis of clinical and pathological characteristics of Microsatellite Instability Colorectal Cancer

Objectives: To explore the differences in clinicopathological features and prognosis between sporadic Microsatellite Instability (MSI) colorectal cancer and Lynch syndrome(LS) patients.

Methods: A total of 338 consecutive postoperative cases of MSI colorectal cancer diagnosed at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2015 to December 2017 were collected, including 105 cases of LS and 233 cases of sporadic MSI colorectal cancer. The clinicopathological characteristics were retrospectively analyzed, and relevant literature was reviewed.

Results: LS patients were significantly younger at the time of diagnosis compared to sporadic MSI colorectal cancer patients(t=4.179, P<0.001), and the type of mismatch repair protein deficiency tended to be more of type 3(x²=28.036, P<0.001) or type 4(x²=4.325, P=0.038). Sporadic MSI patients were more likely to experience promoter methylation(x²=22.388, P<0.001) and BRAF mutation(x²=13.005, P<0.001). There was no significant difference in histological morphology between the two groups, and the differences in overall survival(x²=1.035，P=0.305) and progress-free survival(x²=0.008，P=0.928) were not statistically significant. High-risk histological components such as micropapillary and signet ring cells were significant independent prognostic factors for progress-free survival in MSI colorectal cancer patients(HR=4.075, P<0.05).

Conclusion: LS and sporadic MSI colorectal cancers display differences in clinicopathological characteristics, and the molecular mechanisms behind their varied responses to immunotherapy warrant further investigation.

PART Ⅱ: Study on the Immune Microenvironment of MLH1-Deficient Lynch Syndrome and MLH1-Deficient Sporadic Microsatellite Instability Colorectal Cancer

Objectives: To explore the differences in Immune microenvironment between MLH1-Deficient Sporadic Microsatellite Instability (MSI) colorectal Cancer and MLH1-Deficient Lynch Syndrome (LS) Patients.

Methods: A total of 40 consecutive primary colorectal cancer patients with MLH1-deficient Microsatellite Instability confirmed by molecular testing at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2015 to December 2017 were randomly enrolled, including 20 cases each in the Lynch syndrome group and the sporadic Microsatellite Instability colorectal cancer group. Two pathologists reviewed the consecutive paraffin-embedded tumor sections of the enrolled cases and selected sections for fully automated multiplex immunofluorescence staining to identify CD3+, CD8+, CD45RO+, FoxP3+, and PD-1+ T cells. Digital pathology imaging and artificial intelligence-based image analysis software were used to quantify tumor-infiltrating immune cells and calculate immune scores, while analyzing the relationship between immune scores and survival prognosis.

Results: Compared with sporadic Microsatellite Instability colorectal cancer, Lynch syndrome tumor regions exhibited significantly higher infiltration of CD45RO+ T cells (P=0.002) and lower FoxP3+ T cells (P=0.001), while other immune markers showed no significant differences: CD3+ (P=0.449), CD8+ (P=0.130), PD-1+ (P=0.766). The percentages of immune cells demonstrated the same pattern between the two groups: CD45RO+ (P=0.006), FoxP3+ (P<0.001), CD3+ (P=0.194), CD8+ (P=0.387), PD-1+ (P=0.607). Additionally, the biological activity of infiltrating CD45RO+ T cells was stronger in sporadic Microsatellite Instability colorectal cancer than in Lynch syndrome (P=0.025). The immune score of Lynch syndrome was statistically higher than that of sporadic Microsatellite Instability colorectal cancer (P=0.013). Although patients with low immune scores showed shorter overall survival (P=0.380) and progression-free survival (P=0.604) compared to those with high immune scores, these differences were not statistically significant.

Conclusion: MLH1-deficient Lynch syndrome exhibits differences in the tumor immune microenvironment compared to MLH1-deficient sporadic Microsatellite Instability colorectal cancer.