Stroma Amount in Human Cancer

Abstract

Background: The development of a reactive tumor stroma is a hallmark of tumor progression. Based on a large number of smaller studies, using different methods, desmoplasia is generally considered associated with poor prognosis. The variability between tumor types regarding stroma fraction, and its prognosis associations, have not been systematically analyzed. Methods: We quantified the tumor stroma in 16 solid cancer types from 2732 patients. The tissue segmentation into stromal and epithelial compartment was performed using objective machine-learning method, driven by a combination of pan-cytokeratin staining, tissue autofluorescence patterns and nuclei characteristics. Findings: Stroma fraction was highly variable within and across the tumor types. Survival analysis in individual tumor types revealed both positive and negative associations of the tumor stroma fraction with survival. A meta-analysis across all cancer types indicated an association of higher stroma fraction with longer survival. Interpretation: Findings strongly argue against the commonly promoted simplistic view of a general associations between high stroma abundance and poor prognosis. Findings also suggest that full exploitation of the prognostic potential of tumor stroma requires analyses that go beyond determination of stroma abundance. Funding Statement: This study was partly supported by The Swedish Cancer Society, The Lions Cancer Foundation Uppsala, Sweden, The Swedish Government Grant for Clinical Research, The Mrs Berta Kamprad Foundation, Sweden, Sellanders foundation, P. O. Zetterling Foundation, and The Sjoberg Foundation, Sweden. Image annotation was provided by HistoOne AB, Uppsala, Sweden (https://histo.one). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statements: Colon Cancer (CC) and Rectal Cancer (RC) patient cohort - (Ethical approval Uppsala, 116/07; 419/15). Pariampullary Cancer of intestinal (PACi) and pancreatobiliary (PACpb) type patient cohort - (Ethical approval Lund, 445/07). Ovarian Cancer (OVC) patient cohort - (Ethical approval Lund, 445/07). High Grade Serous Ovarian Cancer (HGSC) patient cohort - (Ethical approval Stockholm, 2016/551–32). Renal Clear Cell (RCC) patient cohort - (Ethical approval Malmo, 282/07). Urine Bladder Cancer (UBC) patient cohort - (Ethical approval Uppsala, 2005/143). Endometrial Cancer (ENC) patient cohort - (Ethical approval Helsinki, 2016/010). Non Small Cell Lung Cancer presented as Lung Squamous Cell Carcinoma (LUSC) and Lung Adenocarcinoma (LUAD) patient cohort - (Ethical approval Uppsala, 532/12). Gastroesophageal Junction Adenocarcinoma (GECA) and Stomach Cancer (SC) patient cohort - (Ethical approval Lund, 445/07). Prostate Cancer (PC) patient cohort - (Ethical approval Lund, 494/05). Breast Cancer (BRC ER- and ER+) patient cohort - (Ethical approval Uppsala, Umea, 2005/118/2).