Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
Mod Pathol. 2022 Nov;35(11):1723-1731. doi: 10.1038/s41379-022-01095-7. Epub 2022 May 19.
Mucinous adenocarcinoma (MAD), the most common subtype of colonic adenocarcinoma (CA), requires >50% intratumoral mucin. There is limited data regarding the impact of MAD on key lymphocyte subsets and therapeutically critical immune elements. In this study we address: (1) the definition of MAD, (2) grading of MAD, and (3) the impact of MAD and extracellular mucin on intratumoral immune milieu. Estimation of the percentage of intratumoral mucin was performed by two pathologists. Tissue microarrays were stained for immune markers including CD8, CD163, PD-L1, FoxP3, β2 microglobulin, HLA class I, and HLA class II. Immunohistochemistry for BRAF V600E was performed. MMR status was determined on immunohistochemistry for MSH2, MSH6, MLH1, PMS2. Manual and automated HALO platforms were used for quantification. The 903 CAs included 62 (6.9%) MAD and 841 CA with ≤ 50% mucin. We identified 225 CAs with mucinous differentiation, defined by ≥10% mucin. On univariate analysis neither cut point, 50% (p = 0.08) and 10% (p = 0.08) mucin, correlated with disease-specific survival (DSS). There were no differences in key clinical, histological and molecular features between MAD and CA with mucinous differentiation. On univariate analysis of patients with MAD, tumor grade correlated with DSS (p = 0.0001) while MMR status did not (p = 0.86). There was no statistically significant difference in CD8 (P = 0.17) and CD163 (P = 0.05) positive immune cells between MAD and conventional CA. However, deficient (d) MMR MADs showed fewer CD8 (P = 0.0001), CD163 (P = 0.0001) and PD-L1 (P = 0.003) positive immune cells compared to proficient (p)MMR MADs, a finding also seen with at 10% mucin cut point. Although MAD does not impact DSS, this study raises the possibility that the immune milieu of dMMR MADs and tumors with > =10% mucin may differ from pMMR MADs and tumors with <10% mucin, a finding that may impact immune-oncology based therapeutics.
黏液腺癌（MAD）是结直肠腺癌（CA）最常见的亚型，需要 >50%的肿瘤内黏液。关于 MAD 对关键淋巴细胞亚群和治疗性关键免疫成分的影响的数据有限。在这项研究中，我们解决了以下问题：（1）MAD 的定义，（2）MAD 的分级，以及（3）MAD 和细胞外黏液对肿瘤内免疫微环境的影响。两名病理学家通过对肿瘤内黏液的百分比进行评估。组织微阵列用于免疫标志物的染色，包括 CD8、CD163、PD-L1、FoxP3、β2 微球蛋白、HLA Ⅰ类和 HLA Ⅱ类。进行 BRAF V600E 的免疫组化染色。通过 MSH2、MSH6、MLH1、PMS2 的免疫组化来确定 MMR 状态。使用手动和自动化 HALO 平台进行定量分析。在 903 例 CA 中，包括 62 例（6.9%）MAD 和 841 例黏液含量≤50%的 CA。我们确定了 225 例具有黏液分化的 CA，定义为≥10%的黏液。在单变量分析中，50%（p=0.08）和 10%（p=0.08）的黏液含量与疾病特异性生存率（DSS）均无相关性。MAD 和具有黏液分化的 CA 之间在关键的临床、组织学和分子特征方面没有差异。在 MAD 患者的单变量分析中，肿瘤分级与 DSS 相关（p=0.0001），而 MMR 状态则无相关性（p=0.86）。MAD 中 CD8（P=0.17）和 CD163（P=0.05）阳性免疫细胞之间没有统计学差异。然而，与功能正常（p）的 MAD 相比，功能缺陷（d）的 MAD 中 CD8（P=0.0001）、CD163（P=0.0001）和 PD-L1（P=0.003）阳性免疫细胞较少，在 10%黏液含量截点时也观察到了这一发现。尽管 MAD 不影响 DSS，但这项研究提出了一种可能性，即 dMMR MAD 和黏液含量> =10%的肿瘤的免疫微环境可能与 pMMR MAD 和黏液含量<10%的肿瘤不同，这一发现可能会影响基于免疫肿瘤学的治疗。
