Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups.

Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well-established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling, we demonstrate that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 nonredundant genes that significantly discriminate the tumor stroma from nontumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix, and transforming growth factor beta (TGFb) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increased expression of collagen 4A1/COL4A1, laminin gamma 2/LAMC2, osteopontin/SPP1, KIAA0101, and TGFb2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of osteopontin, TGFb2, and laminin in the stroma of ICC was significantly correlated with overall patient survival. More important, multivariate analysis demonstrated that the stromal expression of osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidate biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. (HEPATOLOGY 2013;58:1992-2000 I ntrahepatic cholangiocarcinomas (ICC) account for 5%-10% of liver primary cancers. 1 ICC usually arise from epithelial cells of the intrahepatic small bile ducts, although a recent report in mice suggested that ICC might also originate from the conversion of mature hepatocytes. 2 Over the last decade, the incidence of ICC has increased significantly in Western countries. 3,4 This trend could be related to a better histological diagnosis of ICC and/or to the rising incidence of the main risk factors for ICC: cholangitis, chronic hepatitis B and C, diabetes, and obesity. 5 Liver resection remains the only curative treatment for ICC but is associated with a high rate of recurrence. 6 Recently, we showed that hilar lymph node metastasis,

Satellite nodules, hilar lymph node metastases and perineural invasion are risk factors for recurrence following resection with curative intent for ICC. Repeat hepatectomy and labelled yttrium-90 radiotherapy may improve survival after intrahepatic recurrence.

For initially unresectable huge ICCs, chemotherapy with Ytt-90 radioembolization is an effective downstaging method that allows for secondary resectability.