Alignment of stroma fibers, microvessel density and immune cell populations determine overall survival in pancreatic cancer - an analysis of stromal morphology –

Introduction: The aim of this study was to define histo-morphological stroma characteristics by analyzing stromal components, and to evaluate their impact on local and systemic tumor spread and overall survival in pancreatic ductal adenocarcinoma (PDAC). Methods and Materials: Patients who underwent oncologic resections with curative intent for PDAC were identified from a prospectively maintained database. Histological specimens were re-evaluated for morphological stroma features as stromal fibers, fibroblast morphology, stroma matrix density, microvessel density and distribution of immune cell populations. Results: A total of 108 patients were identified undergoing curative resection for PDAC in the period from 2011-2016. 33 (30.6%) patients showed parallel alignment of stroma fibers while 75 (69.4%) had randomly oriented stroma fibers. As compared to parallel alignment, random orientation of stroma fibers was associated with larger tumor size (median 3.62 cm vs. median 2.87cm, p=0.037), nodal positive disease (76.0% vs. 54.5%, p=0.040), higher margin positive resection rates (41.9% vs. 15.2%, p=0.008) and a trend for higher rates of T3/4 tumors (33.3% vs. 15.2%, p=0.064). In univariate analysis, patients with parallel alignment of stroma fibers had improved overall survival rates as compared to patients with random orientation of stroma fibers (42 months vs. 22 months, p=0.046). The combination of random orientation of stroma fibers and low microvessel density was associated with impaired overall survival rates (16 months vs. 36 months, p=0.019). A high CD4/CD3 ratio (16 months vs. 33 months, p=0.040) and high stromal density of CD163 positive cells were associated with reduced overall survival (27 months vs. 34 months, p=0.039). In multivariable analysis, the combination of random orientation of stroma fibers and low microvessel density (HR 1.592, 95%CI 1.098-2.733, p=0.029), high CD4/CD3 ratio (HR 2.044, 95%CI 1.203-3.508, p=0.028) and high density of CD163 positive cells (HR 1.596, 95%CI 1.367-1.968, p=0.036) remained independent prognostic factors. Conclusion: Alignment of stroma fibers and microvessel density are simple histomorphological features serving as surrogate markers of local tumor progression dissemination and surgical resectability and determine prognosis in PDAC patients. High CD4/CD3 ratio and CD163 positive cell counts determine poor prognosis.引言：本研究旨在通过分析胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）的间质成分，明确其组织形态学间质特征，并评估这些特征对肿瘤局部与远处播散以及患者总生存期的影响。 方法与材料：从前瞻性维护的数据库中筛选出2011-2016年间接受根治性肿瘤切除术的胰腺导管腺癌患者。对组织病理学标本的间质形态学特征进行重新评估，包括基质纤维、成纤维细胞形态、间质基质密度、微血管密度以及免疫细胞群的分布情况。 结果：本研究共纳入108例接受根治性切除术的胰腺导管腺癌患者。其中33例（30.6%）患者的基质纤维呈平行排列，75例（69.4%）患者的基质纤维呈随机定向排列。与基质纤维平行排列组相比，随机定向排列组患者的肿瘤体积更大（中位值3.62 cm vs 2.87 cm，p=0.037）、淋巴结阳性率更高（76.0% vs 54.5%，p=0.040）、切缘阳性切除率更高（41.9% vs 15.2%，p=0.008），且T3/4期肿瘤占比呈现升高趋势（33.3% vs 15.2%，p=0.064）。单因素分析显示，基质纤维平行排列组患者的总生存期优于随机定向排列组（42个月 vs 22个月，p=0.046）。基质纤维随机定向排列联合低微血管密度的患者总生存期更差（16个月 vs 36个月，p=0.019）。高CD4/CD3比值（16个月 vs 33个月，p=0.040）以及高CD163阳性细胞间质密度的患者总生存期显著缩短（27个月 vs 34个月，p=0.039）。多因素分析显示，基质纤维随机定向排列联合低微血管密度（风险比HR=1.592，95%置信区间CI=1.098-2.733，p=0.029）、高CD4/CD3比值（HR=2.044，95%CI=1.203-3.508，p=0.028）以及高CD163阳性细胞密度（HR=1.596，95%CI=1.367-1.968，p=0.036）均为独立预后因素。 结论：基质纤维排列方式与微血管密度是简便易行的组织形态学特征，可作为胰腺导管腺癌患者局部肿瘤进展、播散及手术可切除性的替代标志物，并可用于预测患者预后。高CD4/CD3比值与CD163阳性细胞计数可提示不良预后。