Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ann Surg Oncol. 2020 Oct;27(10):3997-4006. doi: 10.1245/s10434-020-08209-y. Epub 2020 Feb 27.
Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking.
To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6.
In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 + tumor infiltrating lymphocytes in tumors with (mean = 685, median = 626) than without (mean = 227; median = 124) MMR deficiency (p < 0.0001), suggesting a role of MSI for immune response.
Our data suggest that MSI occurs early in a small subset of ductal adenocarcinomas of the pancreas and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate MMR status of the entire cancer mass.
微卫星不稳定性（MSI）已成为免疫检查点抑制剂治疗的预测生物标志物。癌症异质性是分析预测生物标志物的潜在障碍。已有报道称 MSI 存在于胰腺癌中，但关于肿瘤内异质性的可能程度的数据尚缺乏。
为了研究胰腺癌中的 MSI 异质性，使用针对错配修复（MMR）蛋白 MLH1、PMS2、MSH2 和 MSH6 的免疫组化方法对包含 597 个肿瘤的组织微阵列（TMA）进行筛选。
在 6 例可疑病例中，通过大切片免疫组化和微卫星分析（Bethesda 面板），在 480 例可解释的胰腺导管腺癌中鉴定出 4 例（0.8%）经证实的 MSI 病例。55 例 Vater 壶腹腺癌和 7 例腺泡细胞癌中不存在 MSI。MMR 缺陷总是伴有 MSH6 缺失，在 3 例中还伴有 MSH2 表达缺失。3 例为 MSI 高，1 例 MSH6 缺失的病例在 PCR 分析中为 MSS。对 44 个含肿瘤块的分析表明，受影响的肿瘤中 MMR 蛋白表达缺失总是同质的。CD8 免疫染色的自动数字图像分析显示，在 MMR 缺陷（平均=685，中位数=626）的肿瘤中 CD8+肿瘤浸润淋巴细胞明显高于无 MMR 缺陷（平均=227；中位数=124）（p<0.0001），表明 MSI 对免疫反应有作用。
我们的数据表明，MSI 早期发生在一小部分胰腺导管腺癌中，对有限的活检或细胞学材料进行免疫组化 MMR 分析可能足以估计整个癌块的 MMR 状态。
