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Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
HEP_25874_sm_SuppFig1.tif12954KSupporting Figure 1. Histological diagnosis of combined epatocellular-cholangiocarcinoma. (A) Intermediate area showing combination of features of hepatocellular carcinoma (HCC, asterisk) and intrahepatic cholangiocellular carcinoma (ICC, arrow) embedding in stomal. For differential diagnosis, representative examples of the separated HCC and CC are shown: (B) Separated HCC and CC with synchronous but distinct HCC showing trabecular pattern (left, asterisk) and ICC showing malignant ductular structures (right, arrow) which are embedded in an inflamed fibrous stroma. (C) “collision tumor” showing nodules with distinct histological features separated by fibrosis. (D) Mucus lakes (Alcian blue-PAS staining, with nuclei staining with PCNA) in lumens of malignant ductular structures. (A-D bar=50µm) (E-F) HCC area is showing biliary differentiation confirmed by immunohistochemistry on sequential sections: (E), HepPar1 and (F) K7 stain (bar=100µm). (G-H) ICC area is also showing intermediate phenotype on sequential sections: (G), HepPar1 and (H) K7 stain (bar=50µm).
HEP_25874_sm_SuppFig2.tif880KSupporting Figure 2. Relative recurrence risk as a continuous function of HPCs related quantifications. The continuous function is represented by termplots for (A) PI-DR; (B) number of HPCs. The dashed curves indicate the risk scores ± standard errors.
HEP_25874_sm_SuppFig3.tif1135KSupporting Figure 3. Assessment of established Cox proportional hazards models for OS and DFS (Model A). (A) Plots of the deviance residuals for global models of OS (left) and DFS (right) show no wildly deviant observations. (B) Plots of the rescaled Schoenfeld residuals to assess the proportional hazards assumption for covariates in both OS and DFS models. Flat smooth curve confirmed by P>0.05 indicates a reasonable assumption.
HEP_25874_sm_SuppFig4.tif1126KSupporting Figure 4. Assessment of established Cox proportional hazards models for OS and DFS (Model B). (A) Plots of the deviance residuals for global models of OS (left) and DFS (right) show no wildly deviant observations. (B) Plots of the rescaled Schoenfeld residuals to assess the proportional hazards assumption for covariates in both OS and DFS models. Flat smooth curve confirmed by P>0.05 indicates a reasonable assumption.
HEP_25874_sm_SuppFig5.tif1038KSupporting Figure 5. PI-DR impacts recurrence of combined hepatocellular-cholangiocarcinoma, but in different pattern with K7-DR as well as inflammatory status. (A) Kaplan-Meier curves for cumulative recurrence hazard by severity of K7-DR (left), PI-DR (Right) in CHC patients with curative hepatectomy (n=70). Black curves showed overall recurrence, red curves showed late recurrence (K7 reactive DR, >20 months; PCNA index for DR, >10 months). (B) Kaplan-Meier curves for cumulative recurrence hazard by Ishak grade (left), NLR (Right) in CHC patients with curative hepatectomy (n=70). Black curves showed overall recurrence, red curves showed late recurrence (>10 months).
HEP_25874_sm_SuppFig6.tif3296KSupporting Figure 6. Univariate analysis of associations with “multicentric occurrence” (MO) of hepatocellular carcinoma component in combined hepatocellular-cholangiocarcinoma. (A) Representative photomicrograph of a patient with “MO” feature is shown in HCC-like area (bar=150µm). (B-C) Associations between present of MO and background liver related (B) or tumor related (C) factors are shown: PI-DRs, EpCAM expression in tumor (IOD) and OV-6 expressions (IOD) are represented by mean with SEM bar. Distribution of histological grading and staging of background liver diseases as well as presence of microvascular invasion (MVI) are shown by stacked column with percentage. Tumor sizes are shown by mean with SEM bar.

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