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.