A prospective study of tumor-stroma ratio in resected intrahepatic mass-forming cholangiocarcinoma: prognostic value and correlation with gadoxetic acid-enhanced MRI.

To assess whether gadoxetic acid-enhanced MRI could be used as a prognostic factor for intrahepatic mass-forming cholangiocarcinomas (IMCCs). Forty-one patients with pathologically proven IMCCs who underwent preoperative gadoxetic acid-enhanced MRI were included. The signal intensity of the IMCCs on hepatobiliary phase (HBP) MRI was qualitatively analyzed by two radiologists, and categorized into intermediate or hypointense groups. Analysis of clinicopathological prognostic factors and correlations of imaging and histology were also performed. Survival time and time to recurrence (TTR) were analyzed. Of the 41 IMCCs, 23 were in the intermediate group and 18 were in the hypointense group on HBP MRI. IMCCs in the intermediate group were associated with shorter survival time (P = 0.048) and TTR (P = 0.002) than the IMCCs of the hypointense group. Only the intermediate group on HBP MRI had a significantly shorter TTR on multivariate analysis (P = 0.012). The IMCCs of the intermediate group showed a tendency for more abundant tumour fibrous stroma than those of the hypointense group (P = 0.027). The enhancement of IMCCs on HBP gadoxetic acid-enhanced MRI appears to correlate with tumour aggressiveness and outcomes due to the tumour fibrous stromal component. Thus, HBP images could be a useful prognostic factor for IMCCs after surgery. • The enhancement of IMCCs on HBP correlates with the tumour fibrous stroma. • The enhancement of IMCCs on HBP MRI appears to correlate with prognosis. • Gadoxetic acid-enhanced MRI is helpful for predicting prognosis of IMCCs after surgery.

To examine the differential features of combined hepatocellular and cholangiocarcinoma (HCC-CC) from mass-forming intrahepatic cholangiocarcinoma (ICC) on gadoxetic acid-enhanced MRI. Forty patients with pathologically proven combined HCC-CC (n = 20) and ICCs (n = 20) who had undergone gadoxetic acid-enhanced MRI were enrolled in this study. MR images were analyzed for the shape of lesions, hypo- or hyperintense areas on the T2-weighted image (T2WI), rim enhancement during early dynamic phases, and central enhancement with hypointense rim (target appearance) on the 10-min and 20-min hepatobiliary phase (HBP). The significance of these findings was determined by the χ(2) test. Irregular shape and strong rim enhancement during early dynamic phases, and absence of target appearance on HBP favored combined HCC-CCs (P < 0.05). Lobulated shape, weak peripheral rim enhancement, and the presence of complete target appearance on the 10-min and 20-min HBP favored ICCs (P < 0.05). However, 10 CC-predominant type of combined HCC-CC showed complete or partial target appearance on 10-min HBP. The shape of tumors, degree of rim enhancement during early dynamic phases, and target appearance on HBP were valuable for differentiating between combined HCC-CC and mass-forming ICC on gadoxetic acid-enhanced MRI.

BackgroundThe tumour–stroma ratio (TSR) is identified as a promising prognostic parameter for breast cancer, but the cutoff TSR value is mostly assessed by visual assessment, which lacks objective measurement. The aims of this study were to optimize the cutoff TSR value, and evaluate its prognosis value in patients with breast cancer both as continuous and categorical variables.MethodsMajor clinicopathological and follow-up data were collected for a series of patients with breast cancer. Tissue microarray images stained with cytokeratin immunohistochemistry were evaluated by automated quantitative image analysis algorithms to assess TSR. The potential cutoff point for TSR was optimized using maximally selected rank statistics. The association between TSR and 5-year disease-free survival (5-DFS) was assessed by Cox regression analysis. Kaplan–Meier analysis and log-rank test were used to assess the significance in survival analysis.ResultsThe optimal cut-off TSR value was 33.5%. Using this cut-off point, categorical variable analysis found that low TSR (i.e., high stroma, TSR ≤ 33.5%) predicts poor outcomes for 5-DFS (hazard ratio [HR] = 2.82, 95% confidence interval [CI] = 1.81–4.40, P = 0.000). When TSR was considered as a continuous parameter, results showed that increased stroma content was associated with worse 5-DFS (HR = 1.71, 95% CI = 1.34–2.18, P = 0.000). Similar results were also obtained in three molecular subtypes in continuous and categorical variable analyses. Moreover, in the Kaplan–Meier analysis, log-rank test showed that low TSR displayed a worse 5-DFS than high TSR (P = 0.000). Similar results were also obtained in patients with triple-negative breast cancer, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and luminal–HER2-negative breast cancer.ConclusionTSR is an independent predictor for 5-DFS in breast cancer with worse survival outcomes in low TSR. The prognostic value of TSR was also observed in other three molecular subtypes.

The objective of this study was to examine the imaging features of classic mass-forming intrahepatic cholangiocarcinoma (MICC) and nonclassic hypervascular MICC on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging. Twenty pathologically confirmed MICCs were included. Two radiologists retrospectively reviewed the imaging characteristics on T2-weighted imaging, diffusion-weighted imaging, dynamic contrast-enhanced images, and hepatobiliary phase (HBP) of each MICC. For the morphologic feature of defect, HBP signal intensity (SI) ratio was calculated by dividing the SI of the MICC by nearby normal liver parenchyma SI. Classic MICCs (n = 14) showed classic rim or peripheral enhancement at arterial dominant phase with centripetal enhance in the delayed phases. Hypervascular MICCs (n = 6) showed complete (n = 4) or near-complete (n = 2) arterial enhancement and washout (n = 6) on delayed phases. On HBP, 13 classic MICCs (93%) and 2 hypervascular MICCs (33%) showed cloud-like SI in the center ("EOB cloud") with peripheral defect. Mean SI ratio was 0.77 in classic MICCs and 0.59 in hypervascular MICC (P = 0.057). Classic MICCs (70%) frequently showed progressive centripetal enhancement on dynamic phase, and central EOB-cloud appearance with distinct peripheral defect on HBP. Nonclassic hypervascular MICCs comprised 30% of the MICCs in this study. Compared with classic MICCs, hypervascular MICCs showed wash-in on arterial dominant phase and washout on delayed phase.

Tumour budding and tumour-stroma ratio in hepatocellular carcinoma.

Introduction:Tumor-stroma ratio (TSR) is prognostic in multiple cancers, while its role in high-grade serous ovarian cancer (HGSOC) remains unclear. Despite the prognostic insight gained from genetic profiles and tumor-infiltrating lymphocytes (TILs), the prognostic use of histology slides remains limited, while it enables the identification of tumor characteristics via computational pathology reducing scoring time and costs. To address this, this study aimed to assess TSR’s prognostic role in HGSOC and its association with TILs. We additionally developed an algorithm, Ovarian-TSR (OTSR), using deep learning for TSR scoring, comparing it to manual scoring.Methods:340 patients with advanced-stage who underwent primary debulking surgery (PDS) or neo-adjuvant chemotherapy (NACT) with interval debulking (IDS). TSR was assessed in both the most invasive (MI) and whole tumor (WT) regions through manual scoring by pathologists and quantification using OTSR. Patients were categorized as stroma-rich (≥ 50% stroma) or stroma-poor (< 50%). TILs were evaluated via immunohistochemical staining.Results:In PDS, stroma-rich tumors were significantly associated with a more frequent papillary growth pattern (60% vs 34%), while In NACT stroma-rich tumors had a lower Tumor Regression Grading (TRG 4&5, 21% vs 57%) and increased pleural metastasis (25% vs 16%). Stroma-rich patients had significantly shorter overall and progression-free survival compared to stroma-poor (31 versus 45 months; P < 0.0001, and 15 versus 17 months; P = 0.0008, respectively). Combining stromal percentage and TILs led to three distinct survival groups with good (stroma-poor, high TIL), medium (stroma-rich, high TIL, or; stroma-poor, Low TIL), and poor(stroma-rich, low TIL) survival. These survival groups remained significant in CD8 and CD103 in multivariable analysis (Hazard ratio (HR) = 1.42, 95% Confidence-interval (CI) = 1.02–1.99; HR = 1.49, 95% CI = 1.01–2.18, and HR = 1.48, 95% CI = 1.05–2.08; HR = 2.24, 95% CI = 1.55–3.23, respectively). OTSR was able to recapitulate these results and demonstrated high concordance with expert pathologists (correlation = 0.83).Conclusions:TSR is an independent prognostic factor for survival assessment in HGSOC. Stroma-rich tumors have a worse prognosis and, in the case of NACT, a higher likelihood of pleural metastasis. OTSR provides a cost and time-efficient way of determining TSR with high reproducibility and reduced inter-observer variability.

Prognostic value of tumor-stroma ratio in early stage cervical adenocarcinoma

The precise differentiation of intrahepatic cholangiocarcinoma (ICC) from atypical hepatocellular carcinoma (HCC) is vital for treatment strategy and prognostic prediction. In clinical practice, nearly 40% of HCCs demonstrate atypical manifestations, particularly HCCs with rim arterial phase hyperenhancement (APHE), which is challenging to differentiate from mass-forming ICC. Thus, we aimed to develop a diagnostic regimen of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) contrast-enhanced magnetic resonance imaging (MRI) combined with serum tumor markers in differentiating mass-forming ICC from atypical HCC in at-risk patients with the hepatitis B virus (HBV). This study enrolled 129 patients with pathologically proven mass-forming ICCs (n=53) and atypical HCCs (n=76) who had undergone preoperative Gd-EOB-DTPA contrast-enhanced MRI. The clinical data and imaging findings were analyzed. Univariate and multivariate logistic analyses were performed to identify the independent predictors for differentiating mass-forming ICCs from atypical HCCs. The diagnostic performance was evaluated using receiver operating characteristic (ROC) curves, and DeLong test was used to compare the areas under curves of all independent predictors. Univariate logistic regression analysis revealed normal alpha fetoprotein (AFP), elevated carbohydrate antigen 19-9 (CA19-9) level, elevated carcinoma embryonic antigen (CEA) level, central hyperintensity on T2-weighted imaging (T2WI), central hypointensity on T2WI, and targetoid sign on hepatobiliary phase (HBP) and targetoid restriction on diffusion-weighted imaging (DWI) were more likely to be significant predictors favoring mass-forming ICCs (all P values <0.05). In contrast, multifocal hyperintensity on T2WI and capsule sign were more frequently seen in patients with atypical HCC (all P values <0.05). Multivariate analysis revealed normal AFP, elevated CA19-9 level, targetoid sign on HBP, and targetoid restriction on DWI (all P=0.001) were independent predictors for differentiating mass-forming ICCs from atypical HCCs; DeLong test showed that the area under curve (AUC) increased to 0.949 when the above predictors were combined (all P values <0.05), and the sensitivity, specificity, and accuracy of the combined independent predictors were 88.7%, 93.4%, and 91.5%, respectively. A diagnostic regimen integrating tumor markers (AFP, CA19-9) and imaging biomarkers (targetoid restriction on DWI and/or targetoid sign on HBP) using Gd-EOB-DTPA-enhanced MRI could help to differentiate mass-forming ICCs from atypical HCCs and achieve high diagnostic performance of mass-forming ICCs in at-risk patients with the HBV. Mass-forming intrahepatic cholangiocarcinoma (mass-forming ICC); atypical hepatocellular carcinoma (atypical HCC); magnetic resonance imaging (MRI); gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA); hepatobiliary phase (HBP).

The tumor-stroma ratio (TSR) has shown a prognostic value in various cancers, including colon cancer. This retrospective, multicenter cohort study aimed to investigate the prognostic value of TSR in a screened stage II colon cancer population, both independently and in combination with tumor budding. The cohort included 497 patients who underwent surgical resection for stage II colon cancer. TSR was determined based on the procedures proposed by van Pelt et al, and tumor budding was evaluated according to the guidelines from the International Tumor Budding Consensus Conference. Our findings demonstrate that patients with tumors categorized as having a high proportion of stroma (>50% stroma area) had a shorter 5-year time to recurrence (hazard ratio [HR], 1.95; P = .05), recurrence-free survival (HR, 1.63; P = .02), and overall survival (HR, 1.05; P = .07) compared with those with tumors categorized as having a low proportion of stroma (≤50% stroma area). The prognostic effect was specific to TSR determination at the deepest invasive front of tumor and lost significance as the examination area expanded. Combining TSR and tumor budding further improved prognostic stratification. Tumors with high stromal content and high-grade budding exhibited a significantly more aggressive risk profile and poorer 5-year survival outcomes compared with those with stroma-low and budding-low tumors (time to recurrence: HR, 4.47; P < .01; recurrence-free survival: HR, 2.71; P < .01; and overall survival: HR, 2.20; P = .01). The study highlights the importance of standardized procedures for TSR assessment and suggests that evaluating both TSR and tumor budding could improve prognostic accuracy and aid in clinical decision-making.

To investigate the utility of Liver Imaging Reporting and Data System (LI-RADS) v2014 for intrahepatic mass-forming cholangiocarcinomas (IMCC) on gadoxetic acid-enhanced magnetic resonance imaging (MRI). This retrospective study was approved by our Institutional Review Board with waiver of informed consent. Pathologically confirmed IMCCs (n = 35) and hepatocellular carcinomas (HCCs) (n = 71) in patients with chronic hepatitis B or cirrhosis who had undergone gadoxetic acid-enhanced 3.0T or 1.5T MRI were included. Three radiologists independently assigned LI-RADS categories for each IMCC or HCC. Diagnostic performances of LR-M (probable malignancy, not specific for HCC) and LR-5/5v (definitely HCC) were investigated, and imaging features were compared between IMCCs of LR-M and non-LR-M. In all, 88.6% (31/35), 80.0% (28/35), and 74.3% (26/35) of IMCCs and 12.7% (9/71), 22.5% (16/71), and 16.9% (12/71) of HCCs were assigned as LR-M by the three reviewers with substantial interobserver agreements (kappa = 0.664-0.741). Among IMCCs, 2.9% (1/35), 5.7% (2/35), and 11.4% (4/35) were categorized as LR-5/5v. IMCCs of non-LR-M (n = 8, using the consensus method) were significantly smaller (24.1 ± 17.4 vs. 62.8 ± 30.6 mm, P = 0.002) and showed higher frequencies of arterial hyperenhancement (75.0% (6/8) vs. 7.4% (2/27), P < 0.001) and lower frequencies of non-HCC malignancy-favoring features such as peripheral enhancement (12.5% (1/8) vs. 77.8% (21/27), P = 0.002) or the target appearance on the hepatobiliary phase (0% (0/8) vs. 81.5% (22/27), P < 0.001) than IMCCs of LR-M (n = 27). Using LI-RADS, the majority of IMCCs can be accurately categorized as LR-M on gadoxetic acid-enhanced MRI; however, caution is warranted, as some atypical IMCCs may be assigned as LR-5/5v resulting in a false-positive diagnosis of HCC. J. Magn. Reson. Imaging 2016;44:1330-1338.

To investigate the correlation between tumor stroma ratio (TSR) and survival in patients with alveolar soft part sarcoma (ASPS), and the application of apparent diffusion coefficient (ADC) histogram parameters in assessing TSR. This retrospective study collected 61 patients from May 2015 to December 2018. TSR was classified as stroma-rich (low TSR) or stroma-poor (high TSR) based on histology. The correlation between TSR and clinicopathological characteristics was analyzed. Prognostic value for 5-year progression-free survival (5-PFS) and 5-year overall survival (5-OS) were assessed using Kaplan-Meier analysis, log-rank test, and Cox regression. Independent sample t-tests or Mann-Whitney U-test and receiver operating characteristic curve analysis examined TSR and ADC histogram parameters. Sixty-one patients met the inclusion criteria (mean age 25.5 ± 12.2 years; 30 males, 31 females). Low TSR was significantly associated with lymph node metastasis (p = 0.048). In multivariate analysis, low TSR was an independent adverse prognostic factor for 5-PFS (hazard ratios [HR] and 95% = 10.456, 95% confidence intervals [CI]: 1.816-60.208, p = 0.009) and 5-OS (HR = 4.789, 95% CI: 1.164-19.708, p = 0.030). Significant differences were found in ADC25th, ADC50th, and ADCmean between TSR groups (p < 0.05). The combination of the three ADC values improved diagnostic efficiency (area under the curve = 0.781, sensitivity = 81.48%, specificity = 82.35%), with a Youden index of 0.638. TSR is an independent prognostic factor for PFS and OS in ASPS patients. ADC histogram parameters serve as imaging biomarkers for evaluating TSR. Question The prognostic value of TSR in ASPS remains unclear, with limited imaging biomarkers available for assessment. Findings Low TSR is associated with poorer 5-PFS and OS. ADC histogram parameters aid in TSR evaluation. Clinical relevance TSR as a prognostic factor, assessed through ADC histogram parameters, offers a non-invasive imaging method that may be useful in predicting the progression of alveolar soft tissue sarcoma.

To establish a non-invasive diagnostic system for intrahepatic mass-forming cholangiocarcinoma (IMCC) via decision tree analysis. Totally 1008 patients with 504 pathologically confirmed IMCCs and proportional hepatocellular carcinomas (HCC) and combined hepatocellular cholangiocarcinomas (cHCC-CC) from multi-centers were retrospectively included (internal cohort n = 700, external cohort n = 308). Univariate and multivariate logistic regression analyses were applied to evaluate the independent clinical and MRI predictors for IMCC, and the selected features were used to develop a decision tree-based diagnostic system. Diagnostic efficacy of the established system was calculated by the receiver operating characteristic curve analysis in the internal training-testing and external validation cohorts, and also in small lesions ≤ 3cm. Multivariate analysis revealed that female, no chronic liver disease or cirrhosis, elevated carbohydrate antigen 19-9 (CA19-9) level, normal alpha-fetoprotein (AFP) level, lobulated tumor shape, progressive or persistent enhancement pattern, no enhancing tumor capsule, targetoid appearance, and liver surface retraction were independent characteristics favoring the diagnosis of IMCC over HCC or cHCC-CC (odds ratio = 3.273-25.00, p < 0.001 to p = 0.021). Among which enhancement pattern had the highest weight of 0.816. The diagnostic system incorporating significant characteristics above showed excellent performance in the internal training (area under the curve (AUC) 0.971), internal testing (AUC 0.956), and external validation (AUC 0.945) cohorts, as well as in small lesions ≤ 3cm (AUC 0.956). In consideration of the great generalizability and clinical efficacy in multi-centers, the proposed diagnostic system may serve as a non-invasive, reliable, and easy-to-operate tool in IMCC diagnosis, providing an efficient approach to discriminate IMCC from other HCC-containing primary liver cancers. This study established a non-invasive, easy-to-operate, and explainable decision tree-based diagnostic system for intrahepatic mass-forming cholangiocarcinoma, which may provide essential information for clinical decision-making. • Distinguishing intrahepatic mass-forming cholangiocarcinoma (IMCC) from other primary liver cancers is important for both treatment planning and outcome prediction. • The MRI-based diagnostic system showed great performance with satisfying generalization ability in the diagnosis and discrimination of IMCC. • The diagnostic system may serve as a non-invasive, easy-to-operate, and explainable tool in the diagnosis and risk stratification for IMCC.

In recent years, the tumor-stroma ratio (TSR) has attracted increasing attention as an independent prognostic factor for several solid tumors. However, the importance of the stromal compartment has not been investigated yet in gallbladder cancer (GBC). The objective of this study is to investigate the prognostic value of TSR in GBC and the relationship between TSR and other known prognostic parameters. A total of 51 patients who underwent operations for gallbladder carcinoma were selected for this study. TSR was determined on haematoxylin and eosin (H et E)-stained sections by two independent investigators. Stromal ratio groups were classified as stroma-poor (ratio of stroma 50%). The Mann-Whitney test, the Chi-squared test, the Kaplan-Meier method, and the Cox proportional hazards model were used to analyze the data. The median survival time for patients in the stroma-rich group was 6.00 months (95% CI, 4.47-7.54). In contrast, for the stroma-poor group, the median survival time was 17.00 months (95% CI, 3.64-30.36). The 3-year overall survival rate was 19.7% in the stroma-poor group and 7.2% in the stroma-rich group. Patients with stroma-rich tumors had a worse prognosis than those with stroma-poor tumors (log-rank P = 0.004). According to the univariate analysis, the TSR, differentiation grade, pTNM stage, and operative methods were shown to be related to overall survival (OS) with statistical significance. The hazard ratio (HR) of TSR was 2.428 (95% CI, 1.29-4.58; P = 0.006). However, the TSR did not prove to be an independent prognostic factor in the multivariate analysis. Our study demonstrated that the tumor-stroma ratio (TSR) is an important prognostic parameter for gallbladder cancer (GBC). Stroma-rich tumors were associated with poor overall survival.

The tumor–stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin‐stained tissue slides of 1,794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence‐free survival (RFS; HR 1.35, 95% CI 1.10–1.66, p = 0.004). The interaction term was statistically significant for grade and triple‐negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43–2.51, p < 0.001) and triple‐negative tumors (HR 1.86, 95% CI 1.10–3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple‐negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma‐high tumor had a worse prognosis compared to patients with a stroma‐low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple‐negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification.

Intrahepatic metastasis of intrahepatic cholangiocarcinoma (ICC) has not been evaluated in detail. We report a case of mass-forming type ICC with micrometastasis to the distant portal tract in a 40-year-old woman. In 2006, she was given a diagnosis of mass-forming type ICC, 4cm in diameter, and right hepatectomy with lymph node dissection was performed. Macroscopic findings showed an irregular white mass-forming type lesion with two small daughter lesions and portal vein invasion in the S5 subsegment. Microscopically, other cancer cells within vessels had proliferated in the peripheral portal tract of the S8 subsegment, and these cancer cells in the portal tract had invaded the vessel wall. The endothelial cells of the vessels around the cancer cells were positive for CD34, but negative for D2-40 and CK19 on immunohistochemical analysis. Therefore, intrahepatic metastasis of cancer cells through the portal vein was diagnosed. Intrahepatic metastasis of cancer cells through the portal vein was demonstrated in a patient with mass-forming ICC.