Prognostic Evaluation and Survival Prediction for Combined Hepatocellular-Cholangiocarcinoma Following Hepatectomy.

Purpose: This study aimed to assess prognostic factors associated with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and to predict 5-year survival based on these factors. Materials and Methods: Patients who underwent definitive hepatectomy from 2006 to 2022 at a single institution was retrospectively analyzed. Inclusion criteria involved a pathologically confirmed diagnosis of cHCC-CCA. Results: A total of 80 patients with diagnosed cHCC-CCA were included in the analysis. The median progression-free survival (PFS) was 15.6 months, while distant metastasis-free survival (DMFS), hepatic progression-free survival (HPFS), and overall survival (OS) were 50.8, 21.5, and 85.1 months, respectively. In 52 cases of recurrence, intrahepatic recurrence was the most common initial recurrence (34/52), with distant metastasis in 17 cases. Factors associated with poor DMFS included tumor necrosis, lymphovascular invasion (LVI), perineural invasion and histologic compact type. Postoperative CA19-9, tumor necrosis, LVI, and close/positive margin were associated with poor overall survival. LVI emerged as a key factor affecting both DMFS and OS, with a 5-year OS of 93.3% for patients without LVI compared to 35.8% with LVI. Based on these factors, a nomogram predicting 3-year and 5-year DMFS and OS was developed, demonstrating high concordance with actual survival in the cohort (Harrell C-index 0.809 for OS, 0.801 for DMFS, respectively). Conclusion: The prognosis of cHCC-CCA is notably poor when combined with lymphovascular invasion. Given the significant impact of adverse features, accurate outcome prediction is crucial. Moreover, consideration of adjuvant therapy may be warranted for patients exhibiting poor survival and increased risk of local recurrence or distant metastasis.

Intraductal papillary neoplasm of the bile duct: diagnostic value of MRI features in differentiating pathologic subclassifications-type 1 versus type 2.

OBJECTIVES: To identify MRI features for differentiating type 2 from type 1 intraductal papillary neoplasms of bile duct (IPNB) and assessing malignant potential of IPNB. METHODS: This retrospective study included 60 patients with surgically proven IPNB who had undergone preoperative MRI between January 2007 and December 2020. All surgical specimens were reviewed retrospectively to classify types 1 and 2 IPNBs and assess tumor grade. Significant MRI features for differentiating type 2 (n = 40) from type 1 IPNB (n = 20); and for IPNB with an associated invasive carcinoma (n = 43) from intraepithelial neoplasia (n = 17) were determined using logistic regression analysis. RESULTS: An associated invasive carcinoma was more frequently found in type 2 than in type 1 IPNB (85.0% [34/40] vs. 45.0% [9/20], p = 0.003). At univariable analysis, MRI features including extrahepatic location, no dilatation of tumor-bearing segment of bile duct, isolated upstream bile duct dilatation, and single lesion were associated with type 2 IPNB (all p ≤ 0.012). At multivariable analysis, significant MRI findings for differentiating type 2 from type 1 IPNB were extrahepatic location and no dilatation of tumor-bearing segment of bile duct (odds ratio [OR], 7.24 and 46.40, respectively). At univariable and multivariable analysis, tumor size ≥ 2.5 cm (OR, 8.45), bile duct wall thickening (OR, 4.82), and irregular polypoid or nodular tumor shape (OR, 6.44) were significant MRI features for differentiating IPNB with an associated invasive carcinoma from IPNB with intraepithelial neoplasia. CONCLUSION: MRI with MR cholangiopancreatography may be helpful in differentiating type 2 IPNB from type 1 IPNB and assessing malignant potential of IPNB. CLINICAL RELEVANCE STATEMENT: Preoperative MRI with MR cholangiopancreatography may be helpful in differentiating type 2 intraductal papillary neoplasms of bile duct (IPNB) from type 1 IPNB and assessing malignant potential of IPNB. KEY POINTS: • In terms of tumor grade, the incidence of invasive carcinoma was significantly higher in type 2 intraductal papillary neoplasm of the bile duct (IPNB) than in type 1 IPNB. • At MRI, extrahepatic location and no dilatation of tumor-bearing segment are significant features for differentiating type 2 IPNBs from type 1 IPNBs. • At MRI, large tumor size, bile duct wall thickening, and irregular polypoid or nodular tumor shape are significant features for differentiating IPNB with an associated invasive carcinoma from IPNB with intraepithelial neoplasia.

Thymidylate synthase accelerates Men1-mediated pancreatic tumor progression and reduces survival.

Clinical studies of cancer patients have shown that overexpression or amplification of thymidylate synthase (TS) correlates with a worse clinical outcome. We previously showed that elevated TS exhibits properties of an oncogene and promotes pancreatic neuroendocrine tumors (PanNETs) with a long latency. To study the causal impact of elevated TS levels in PanNETs, we generated a mouse model with elevated human TS (hTS) and conditional inactivation of the Men1 gene in pancreatic islet cells (hTS/Men1-/-). We demonstrated that increased hTS expression was associated with earlier tumor onset and accelerated PanNET development in comparison with control Men1-/- and Men1+/ΔN3-8 mice. We also observed a decrease in overall survival of hTS/Men1+/- and hTS/Men1-/- mice as compared with control mice. We showed that elevated hTS in Men1-deleted tumor cells enhanced cell proliferation, deregulated cell cycle kinetics, and was associated with a higher frequency of somatic mutations, DNA damage, and genomic instability. In addition, we analyzed the survival of 88 patients with PanNETs and observed that high TS protein expression independently predicted worse clinical outcomes. In summary, elevated hTS directly participates in promoting PanNET tumorigenesis with reduced survival in Men1-mutant background. This work will refocus attention on new strategies to inhibit TS activity for PanNET treatment.

Performance of LI-RADS Version 2018 on CT for Determining Eligibility for Liver Transplant According to Milan Criteria in Patients at High Risk for Hepatocellular Carcinoma.

BACKGROUND. LI-RADS has been investigated primarily in terms of detection of hepatocellular carcinoma (HCC), with less attention given to its performance, particularly on CT, in determining eligibility for liver transplant (LT). OBJECTIVE. The purpose of our study was to assess the performance of LI-RADS version 2018 (v2018) on CT for the diagnosis of HCC and determination of LT eligibility according to the Milan criteria (MC). METHODS. This retrospective study included 136 patients (110 men, 26 women; mean age, 53.9 ± 8.1 [SD] years) at high-risk for HCC who underwent liver protocol CT within 3 months before LT between January 2010 and December 2018. Two radiologists independently reviewed CT examinations using LI-RADS v2018; Organ Procurement and Transplantation Network (OPTN) classes were constructed from the LI-RADS interpretations. Histopathologic analysis of liver explants served as the reference standard for determining the presence of HCC and LT eligibility based on MC. Diagnostic performance was evaluated. Overall survival (OS) was assessed based on medical record review. RESULTS. Based on histopathologic evaluation of liver explants in the 136 patients, 27 patients had no malignancy, 77 were eligible for LT due to HCC within MC, and 32 were unsuitable for LT (i.e., HCC beyond MC in 16 patients, HCC with macrovascular invasion in 12, non-HCC malignancy in four). LR-5 exhibited per-lesion sensitivity and PPV for HCC of 55.9% and 92.8%, respectively, for reader 1 and 39.8% and 86.5% for reader 2. When considering LR-5 observations to represent HCC in assessing MC, LI-RADS had accuracy for determining LT eligibility of 92.7% for reader 1 and 85.3% for reader 2; OPTN criteria had accuracy for determining LT eligibility of 89.0% for reader 1 and 84.4% for reader 2. Five-year OS for patients within MC versus 5-year OS for patients unsuitable for LT was 92.2 months versus 56.0 months for LI-RADS, 92.6 months versus 47.6 months for OPTN criteria, and 93.3 months versus 55.1 months for histopathologic assessment of liver explants. CONCLUSION. LI-RADS v2018, as evaluated on CT in high-risk patients, shows high PPV for HCC detection and high accuracy for determining LT eligibility based on MC. LT eligibility based on preoperative LI-RADS evaluation is associated with post-LT survival. CLINICAL IMPACT. These findings support the use of LI-RADS on CT in assessing eligibility in patients who are candidates for LT.

LI-RADS Tumor in Vein at CT and Hepatobiliary MRI.

Background Diagnostic performance of the Liver Imaging Reporting and Data System tumor in vein (LR-TIV) category at CT and/or MRI has not yet been evaluated, to the knowledge of the authors. Purpose To assess the diagnostic performance of the LR-TIV category in detecting macroscopic tumors in veins (TIVs) at CT and hepatobiliary contrast agent-enhanced (HBA) MRI, with pathologic results used as the reference standard. Materials and Methods Between January 2010 and December 2019, consecutive patients with or without macroscopic TIV who underwent both CT and HBA MRI before hepatic resection or liver transplant were retrospectively included. Three radiologists independently assessed the LR-TIV features of enhancing soft tissue in vein and features suggestive of TIV (FSTIV) and reached a consensus. Macroscopic TIV at pathologic examination was the reference standard. Sensitivities and specificities of the LR-TIV category without and with FSTIV were calculated, and the added value of FSTIV was evaluated by using the McNemar test. Results In the 1322 patients with (n = 101) or without (n = 1221) macroscopic TIV (median age, 64 years [interquartile range, 58-70 years]; 1053 men), without consideration of FSTIV, the sensitivity and specificity of enhancing soft tissue in vein for detecting macroscopic TIV at pathologic examination were 64.4% (65 of 101) and 99.8% (1218 of 1221) with CT and 62.4% (63 of 101) and 99.8% (1218 of 1221) with HBA MRI, respectively. With consideration of FSTIV, the sensitivity and specificity of the LR-TIV category became 67.3% (68 of 101 patients) and 99.7% (1217 of 1221 patients) at both CT and HBA MRI. No difference was found between measurements without and with FSTIV (sensitivity, 62% vs 67% for CT [P = .45] and 64% vs 67% for HBA MRI [P = .18]; specificity, 99% for both CT and HBA MRI [P > .99 for both]). Conclusion The Liver Imaging Reporting and Data System tumor in vein category showed moderate sensitivity and high specificity in the detection of macroscopic tumors in veins at both CT and hepatobiliary contrast agent-enhanced MRI, with pathologic examination used as the reference standard. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Morrell in this issue.

How to approach pancreatic cancer after neoadjuvant treatment: assessment of resectability using multidetector CT and tumor markers.

OBJECTIVES: To investigate clinical and CT factors associated with local resectability in patients with nonmetastatic pancreatic cancers after neoadjuvant chemotherapy ± radiation therapy (CRT). METHODS: This retrospective study included consecutive patients with nonmetastatic pancreatic cancers who underwent neoadjuvant CRT between June 2009 and June 2019. Tumor size, tumor-vascular contact with artery/vein, and local resectability categories (resectable, borderline resectable, or locally advanced) were assessed at baseline and post-CRT CT. Baseline and post-CRT carbohydrate antigen (CA) 19-9 levels were also assessed. Clinical or imaging features related to R0 resection were determined using logistic regression analysis. RESULTS: A total of 179 patients (mean age, 62.4 ± 9.3 years; 92 men) were included. After neoadjuvant CRT, 105 (58.7%) patients received R0 resection, while 74 (41.3%) did not. R0 resection rates were significantly different according to post-CRT CT resectability categories (p < 0.001): 82.8% (48/58), 70.1% (47/67), and 18.5% (10/54) for resectable, borderline resectable, and locally advanced disease, respectively. For post-CRT borderline resectable disease, ≥ 50% decrease in CA 19-9 was significantly associated with R0 resection (odds ratio (OR), 3.160; p = 0.02). For post-CRT locally advanced disease, small post-CRT tumor size ≤ 2 cm (OR, 9.668; p = 0.026) and decreased tumor-arterial contact (OR, 24.213; p = 0.022) were significantly associated with R0 resection. CONCLUSION: Post-CRT CT resectability categorization may be useful for the assessment of R0 resectability in patients with pancreatic cancer following neoadjuvant CRT. Additionally, ≥ 50% decrease in CA 19-9 was associated with R0 resection in post-CRT borderline resectable disease, while small post-CRT tumor size and decreased tumor-arterial contact were with locally advanced disease. KEY POINTS: • R0 resection rates following neoadjuvant chemotherapy ± radiation therapy (CRT) were 82.8%, 70.1%, and 18.5% in resectable, borderline resectable, and locally advanced disease, respectively, at post-CRT CT (p < 0.001). • For post-CRT borderline resectable disease, ≥ 50% decrease in carbohydrate antigen (CA) 19-9 was significantly associated with R0 resection. • For post-CRT locally advanced disease, small post-CRT tumor size ≤ 2 cm and decreased tumor-arterial contact were significantly associated with R0 resection.

Simultaneous evaluation of perfusion and morphology using GRASP MRI in hepatic fibrosis.

OBJECTIVES: To determine if golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced (DCE)-MRI allows simultaneous evaluation of perfusion and morphology in liver fibrosis. METHODS: Participants who were scheduled for liver biopsy or resection were enrolled (NCT02480972). Images were reconstructed at 12-s temporal resolution for morphologic assessment and at 3.3-s temporal resolution for quantitative evaluation. The image quality of the morphologic images was assessed on a four-point scale, and the Liver Imaging Reporting and Data System score was recorded for hepatic observations. Comparisons were made between quantitative parameters of DCE-MRI for the different fibrosis stages, and for hepatocellular carcinoma (HCCs) with different LR features. RESULTS: DCE-MRI of 64 participants (male = 48) were analyzed. The overall image quality consistently stood at 3.5 ± 0.4 to 3.7 ± 0.4 throughout the exam. Portal blood flow significantly decreased in participants with F2-F3 (n = 18, 175 ± 110 mL/100 mL/min) and F4 (n = 12, 98 ± 47 mL/100 mL/min) compared with those in participants with F0-F1 (n = 34, 283 ± 178 mL/100 mL/min, p < 0.05 for all). In participants with F4, the arterial fraction and extracellular volume were significantly higher than those in participants with F0-F1 and F2-F3 (p < 0.05). Compared with HCCs showing non-LR-M features (n = 16), HCCs with LR-M (n = 5) had a significantly prolonged mean transit time and lower arterial blood flow (p < 0.05). CONCLUSIONS: Liver MRI using GRASP obtains both sufficient spatial resolution for confident diagnosis and high temporal resolution for pharmacokinetic modeling. Significant differences were found between the MRI-derived portal blood flow at different hepatic fibrosis stages. KEY POINTS: A single MRI examination is able to provide both images with sufficient spatial resolution for anatomic evaluation and those with high temporal resolution for pharmacokinetic modeling. Portal blood flow was significantly lower in clinically significant hepatic fibrosis and mean transit time and extracellular volume increased in cirrhosis, compared with those in no or mild hepatic fibrosis. HCCs with different LR features showed different quantitative parameters of DCE-MRI: longer mean transit time and lower arterial flow were observed in HCCs with LR-M features.

Preoperative immune landscape predisposes adverse outcomes in hepatocellular carcinoma patients with liver transplantation.

Immune class in hepatocellular carcinoma (HCC) has been shown to possess immunogenic power; however, how preestablished immune landscapes in premalignant and early HCC stages impact the clinical outcomes of HCC patients remains unexplored. We sequenced bulk transcriptomes for 62 malignant tumor samples from a Korean HCC cohort in which 38 patients underwent total hepatectomy, as well as for 15 normal and 47 adjacent nontumor samples. Using in silico deconvolution of expression mixtures, 22 immune cell fractions for each sample were inferred, and validated with immune cell counting by immunohistochemistry. Cell type-specific immune signatures dynamically shifted from premalignant stages to the late HCC stage. Total hepatectomy patients displayed elevated immune infiltration and prolonged disease-free survival compared to the partial hepatectomy patients. However, patients who exhibited an infiltration of regulatory T cells (Tregs) during the pretransplantation period displayed a high risk of tumor relapse with suppressed immune responses, and pretreatment was a potential driver of Treg infiltration in the total hepatectomy group. Treg infiltration appeared to be independent of molecular classifications based on transcriptomic data. Our study provides not only comprehensive immune signatures in adjacent nontumor lesions and early malignant HCC stages but also clinical guidance for HCC patients who will undergo liver transplantation.

Evaluation of LI-RADS Version 2018 Treatment Response Algorithm for Hepatocellular Carcinoma in Liver Transplant Candidates: Intraindividual Comparison between CT and Hepatobiliary Agent-enhanced MRI.

Background The Liver Imaging Reporting and Data System (LI-RADS), version 2018, treatment response algorithm (TRA) is used to assess hepatocellular carcinoma (HCC) after local-regional therapy (LRT). However, its diagnostic performance has not yet been fully compared between CT and hepatobiliary agent (HBA)-enhanced MRI in patients who have undergone liver transplant (LT). Purpose To compare the diagnostic performance of LI-RADS TRA when using CT versus using HBA-enhanced MRI in an intraindividual manner according to pathologic results. Materials and Methods Between January 2011 and September 2019, 165 patients with 237 clinically suspected HCCs underwent LRT followed by LT and were retrospectively included. All patients underwent both CT and HBA-enhanced MRI after LRT and before LT. Three radiologists independently assessed tumor viability with both modalities by using LI-RADS TRA and reached a consensus. Pathologic tumor viability categorized as either completely (100%) or incompletely (<100%) necrotic obtained from the explanted liver served as the reference standard. Sensitivity and specificity of the LI-RADS TRA in the consensus reading were then compared between CT and HBA-enhanced MRI by using the ratio estimator approach. Interobserver agreements were calculated by using Fleiss κ statistics. Results There were 165 patients (mean age, 62 years ± 9 [standard deviation]; 135 men) with a total of 237 lesions, of which 107 were viable tumors (45.1%) at pathologic evaluation. With the LI-RADS TRA, sensitivity and specificity of the viable category for detection of viable HCCs at pathologic evaluation were 42.1% (45 of 107 lesions) and 95.4% (124 of 130 lesions) with CT and 52.3% (56 of 107 lesions) and 93.9% (122 of 130 lesions) with HBA-enhanced MRI, with a significant difference in sensitivity but not specificity (P = .009 and P = .42, respectively). Interobserver agreements for the LI-RADS TRA were substantial for both CT and HBA-enhanced MRI (κ, 0.69 for both). Conclusion In patients who underwent local-regional therapy for hepatocellular carcinoma before liver transplant, hepatobiliary agent-enhanced MRI was more sensitive than CT in evaluating tumor viability with the Liver Imaging Reporting and Data System, version 2018, treatment response algorithm. ©RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Bashir and Mendiratta-Lala in this issue.

Peritumoral lymph nodes in pancreatic cancer revisited; is it truly equivalent to lymph node metastasis?

BACKGROUND: Lymph node (LN) metastasis is a well-known poor prognostic factor of pancreatic cancer. LN metastasis, through direct invasion of tumor cell to peritumoral lymph nodes (PTLN), is treated as the same as those which spread through lymphatic channels. This study aimed to evaluate the impact of PTLN invasion on the oncologic outcome of pancreatic cancer. METHODS: Five hundred and six patients who underwent operation for pancreatic ductal adenocarcinoma from 2012 to 2018 were reviewed. PTLN invasion was defined as direct invasion of tumor cells in contact with main tumor. RESULTS: Among the 506 patients, 112 patients (22.1%) had PTLN invasion. PTLN invasion group (PTLNI) showed better disease-free survival than regional LN metastasis group (RLNM) and combined LN metastasis group (CLNM) (PTLNI 21 vs RLNM 11 vs CLNM 12 months, P = .003). There was no significant difference between N0 and PTLNI (PTLNI 21 vs N0 23 months, P = .999). In multivariate analysis, conventional LN metastasis was a significant factor compared to N0, but PTLN invasion was not (hazard ratio 0.786 [0.507-1.220], P = .283). CONCLUSION: Because PTLN invasion does not adversely affect survival in the same way as LN metastasis does, pancreatic cancer-may be overstaged if PTLN invasion were dealt in the same manner as a metastatic LN. Therefore, PTLN invasion should be disregarded from current nodal staging system.

Preoperative assessment of the resectability of pancreatic ductal adenocarcinoma on CT according to the NCCN Guidelines focusing on SMA/SMV branch invasion.

OBJECTIVES: For patients with pancreatic adenocarcinoma (PAC), adequate determination of disease extent is critical for optimal management. We aimed to evaluate diagnostic accuracy of CT in determining the resectability of PAC based on 2020 NCCN Guidelines. METHODS: We retrospectively enrolled 368 consecutive patients who underwent upfront surgery for PAC and preoperative pancreas protocol CT from January 2012 to December 2017. The resectability of PAC was assessed based on 2020 NCCN Guidelines and compared to 2017 NCCN Guidelines using chi-square tests. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using log-rank test. R0 resection-associated factors were identified using logistic regression analysis. RESULTS: R0 rates were 80.8% (189/234), 67% (71/106), and 10.7% (3/28) for resectable, borderline resectable, and unresectable PAC according to 2020 NCCN Guidelines, respectively (p < 0.001). The estimated 3-year OS was 28.9% for borderline resectable PAC, which was significantly lower than for resectable PAC (43.6%) (p = 0.004) but significantly higher than for unresectable PAC (0.0%) (p < 0.001). R0 rate was significantly lower in patients with unresectable PAC according to 2020 NCCN Guidelines (10.7%, 3/28) than in those with unresectable PAC according to the previous version (31.7%, 20/63) (p = 0.038). In resectable PAC, tumor size ≥ 3 cm (p = 0.03) and abutment to portal vein (PV) (p = 0.04) were independently associated with margin-positive resection. CONCLUSIONS: The current NCCN Guidelines are useful for stratifying patients according to prognosis and perform better in R0 prediction in unresectable PAC than the previous version. Larger tumor size and abutment to PV were associated with margin-positive resection in patients with resectable PAC. KEY POINTS: • The updated 2020 NCCN Guidelines were useful for stratifying patients according to prognosis. • The updated 2020 NCCN Guidelines performed better in the prediction of margin-positive resection in unresectable cases than the previous version. • Tumor size ≥ 3 cm and abutment to the portal vein were associated with margin-positive resection in patients with resectable pancreatic adenocarcinoma.

Hepatic fibrosis grading with extracellular volume fraction from iodine mapping in spectral liver CT.

PURPOSE: To determine whether hepatic extracellular volume fraction (ECV) obtained from iodine density map (ECV-iodine) can be used to estimate hepatic fibrosis grade and to compare performance with ECV measured using Hounsfield units (ECV-HU). METHODS: From December 2016 to March 2019, patients who underwent liver resection or biopsy within four weeks after spectral liver CT were included. ECV-iodine and ECV-HU were calculated using the equilibrium phase. Within each of these, comparison of ECVs was made for different fibrosis grades (F0 - 1 vs. F2 - 3 vs. F4) and also for patients with compensated and decompensated cirrhosis. The diagnostic performance of ECVs in detecting clinically significant fibrosis (≥ F2) and cirrhosis (F4) was assessed using ROC analysis. RESULTS: A total of 144 patients (men = 98, mean age 58.1 ± 11.5 years) were included. The ECV-iodine value was significantly higher in cirrhosis (33.6 ± 6.8 %) than those with F0 - 1 (25.0 ± 3.7 %) or F2 - 3 (28.3 ± 3.4 %, P < 0.001 for all). It was significantly higher in decompensated cirrhosis than those with compensated cirrhosis (36.5 ± 7.2 % vs. 30.7 ± 5.0 %, respectively; P < 0.001). The AUC of ECV-iodine was 0.82 for detecting F2 or above (cut-off value, > 26.9 %) and 0.81 for detecting cirrhosis (cut-off value, > 29 %). ECV-iodine had a significantly higher AUC than ECV-HU for detecting F2 or above (AUC: 0.69, P < 0.001) and cirrhosis (AUC: 0.74, P = 0.04). CONCLUSIONS: ECV-iodine from spectral CT was able to detect clinically significant hepatic fibrosis and cirrhosis.

A comparison of outcomes in patients with intracholecystic papillary neoplasms or conventional adenocarcinomas of the gallbladder.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) of the gallbladder (GB) is an exophytic intraepithelial neoplasm. This study aimed to investigate clinicopathologic findings, prognosis and recurrence patterns of patients with ICPN as compared to those patients with conventional adenocarcinoma of the gallbladder (GBC). METHODS: Patients who underwent surgical resection for suspected GB cancer between 2000 and 2018 were included. ICPN was defined as an exophytic papillary mass within the GB lumen with a size ≥1.0 cm. RESULTS: Of 607 patients, 241 patients (40%) were pathologically diagnosed with ICPN. Of the 241 patients with ICPNs, 110 (46%) were T1 or less. Following T stage-matched analysis, the rate of lymph node metastases were comparable (50 [52%] vs. 37 [49%], P = 0.581). The five-year survival rate was higher in ICPN, but after T stage-matching, they were comparable (69.1 vs. 63.2%, P = 0.171). Overall recurrence rates were also comparable, with the exception of lower peritoneal seeding in patients with ICPN. CONCLUSION: Patients with ICPN who underwent resection were more likely to have an earlier T stage. There was no significant difference in prognosis and recurrence between ICPN and conventional GBC after stage matching. Therefore, the treatment strategy for ICPN should follow the same protocols used for conventional GBC.

Natural history and optimal treatment strategy of intraductal papillary mucinous neoplasm of the pancreas: Analysis using a nomogram and Markov decision model.

BACKGROUND/PURPOSE: With the increase in detection of intraductal papillary mucinous neoplasms (IPMN), a tailored approach is needed. This study was aimed at exploring the natural history of IPMN and suggest optimal treatment based on malignancy risk using a nomogram and Markov decision model. METHODS: Patients with IPMN who underwent surveillance or surgery were included. Changes in worrisome features/high-risk stigmata and malignancy conversion rate were assessed. Life expectancy and quality-adjusted life year (QALY) were compared using a nomogram predicting malignancy. RESULTS: Overall, 2006 patients with histologically confirmed or radiologically typical IPMN were enrolled. Of these, 1773 (88.4%), 81 (4.0%), and 152 (7.6%), respectively, had branch duct (BD)-, main duct-, and mixed-type IPMN at initial diagnosis. The cumulative risk of developing worrisome feature or high-risk stigmata was 19.0% and 35.0% at 5- and 10-year follow-up, respectively. The progression of malignancy rate at 10-year follow-up was 79.9% for main and mixed IPMNs and 5.9% for BD-IPMN. Nomogram-based malignancy risk prediction is well correlated with natural history based on pathologic biopsy and shows good stratification of survival. The decision model recommends surgery to maximize survival and QALY especially in those with >35% malignancy risk. CONCLUSIONS: Compared with main duct- and mixed-type IPMN, which have a high risk of malignancy (79.9%), BD-IPMN is very indolent (5.9%). The nomogram-based decision model suggests surgery rather than surveillance for patients with a high malignancy risk. The optimal treatment strategy between surgery and surveillance should consider patients' health status, malignancy risk, and centers' experience.

Prediction of tumor recurrence and poor survival of ampullary adenocarcinoma using preoperative clinical and CT findings.

OBJECTIVES: To predict poor survival and tumor recurrence in patients with ampullary adenocarcinoma using preoperative clinical and CT findings. MATERIALS AND METHODS: A total of 216 patients with ampullary adenocarcinoma who underwent preoperative CT and surgery were retrospectively included. CT was assessed by two radiologists. Clinical and histopathological characteristics including histologic subtypes were investigated. A Cox proportional hazard model and the Kaplan-Meier method were used to identify disease-free survival (DFS) and overall survival (OS). A nomogram was created based on the multivariate analysis. The optimal cutoff size of the tumor was evaluated and validated by internal cross validation. RESULTS: The median OS was 62.8 ± 37.9, and the median DFS was 54.3 ± 41.2 months. For OS, tumor size (hazard ratio [HR] 2.79, p < 0.001), papillary bulging (HR 0.63, p = 0.049), organ invasion on CT (HR 1.92, p = 0.04), male sex (HR 1.59, p = 0.046), elevated CA 19-9 (HR 1.92, p = 0.01), pT stage (HR 2.45, p = 0.001), and pN stage (HR 3.04, p < 0.001) were important predictors of survival. In terms of recurrence, tumor size (HR 2.37, p = 0.04), pT stage (HR 1.76, p = 0.03), pN stage (HR 2.23, p = 0.001), and histologic differentiation (HR 4.31, p = 0.008) were important predictors of recurrence. In terms of tumor size on CT, 2.65 cm and 3.15 cm were significant cutoff values for poor OS and RFS (p < 0.001). CONCLUSION: Preoperative clinical and CT findings were useful to predict the outcomes of ampullary adenocarcinoma. In particular, tumor size, papillary bulging, organ invasion on CT, male sex, and elevated CA 19-9 were important predictors of poor survival after surgery. KEY POINTS: • Clinical staging based on preoperative clinical information and CT findings can be useful to predict the prognosis of ampullary adenocarcinoma patients. • In terms of survival, tumor size (HR 2.79), papillary bulging (HR 0.63), organ invasion on CT (HR 1.92), male sex (HR 1.59), and elevated CA 19-9 (HR 1.92) were important clinical predictors of poor survival. • Tumor size on CT was of special importance for both poor overall survival and disease-free survival, with optimal cutoff values of 2.65 cm and 3.15 cm, respectively (p < 0.001).

Important CT and histopathological findings for recurrence and overall survival in patients with pancreatic ductal adenocarcinoma who underwent surgery after neoadjuvant FOLFIRINOX.

OBJECTIVES: To investigate important factors for recurrence-free survival (RFS) and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDA) who underwent surgery after neoadjuvant FOLFIRINOX using CT and histopathological findings. MATERIALS AND METHODS: Sixty-nine patients with PDA who underwent surgery after neoadjuvant FOLFIRINOX were retrospectively included. All patients underwent baseline and first follow-up CT. Two reviewers assessed the CT findings and resectability based on the NCCN guideline. They graded extrapancreatic perineural invasion (EPNI) using a 3-point scale focused on 5 routes. Clinical and histopathological results, such as T- and N-stage, tumor regression grade (TRG) using the College of American Pathology (CAP) grading system, and resection status, were also investigated. Kaplan-Meier methods were used for RFS and OS. The Cox proportional hazard model and logistic regression model were used to identify significant predictive factors. RESULTS: There were 57 patients (82.6%) without residual tumors (R0) and 12 patients (17.4%) with residual tumors (R1 or R2). The median RFS was 13 months (range 0~22 months). For RFS, EPNI on baseline CT (hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.116-5.733, p = 0.026) and TRG (HR 1.76, 95% CI 1.000-3.076, p = 0.046) were important predictors of early recurrence. The mean OS was 48 months (range 11~35 months). For OS, TRG (HR 1.05, 95% CI 1.251-6.559, p = 0.013) was a significant factor. However, there were no independent predictors for residual tumors according to the CT findings. CONCLUSION: EPNI on baseline CT and TRG were important prognostic factors for tumor recurrence. In addition, TRG was also an important prognostic factor for OS. KEY POINTS: • CT and histopathological findings are helpful for predicting early recurrence and poor survival. • EPNI on baseline CT (HR 2.53, p = 0.026) is an important predictor of early recurrence. • The TRG is an important prognostic factor for early recurrence (HR 1.76, p = 0.046) and poor survival (HR 1.05, p = 0.013).

Clinical meaning of the World Health Organization morphologic classification (flat vs. tumoral) of gallbladder intraepithelial neoplasm as a prognostic factor in gallbladder cancer.

BACKGROUND: In the World Health Organization (WHO) classification, gallbladder (GB) intraepithelial lesions are grouped as flat or tumoral, according to their morphological features. The purpose of this study was to investigate the relationship between the morphologies and clinical features of GB cancer (GBC) and to examine the feasibility of using morphologic classification as a prognostic factor. METHODS: From January 2000 to December 2012, the available pathologic slide reviews of 381 patients were analyzed at the Seoul National University Hospital. All pathologic slides were evaluated by two pancreato-biliary tract pathology experts. GBCs were categorized into eight groups (Flat: F1-2, Borderline, Tumoral: Tu1-5), according to the thickness of the mucosal lesion, histologic patterns of the mucosa under microscopy, invasion extent, and patient history of premalignant lesions. According to the morphologic classification, clinical features were compared and survival analysis was performed. RESULTS: In three groups, flat lesions comprised 179 (46.9%) cases and borderline and tumoral comprised 97 (25.4%) and 105 (27.5%) cases, respectively. More favorable pathologic and clinical results were found within the tumoral group. The borderline group had an intermediate tendency between flat and intraluminal in clinicopathologic parameters. In the curative resected T2 stage group, the borderline group demonstrated an intermediate trend compared to that of the flat and tumoral groups, but this was statistically insignificant (P=0.08). CONCLUSIONS: Flat type GBCs show worse prognosis than tumoral GBCs. The morphological classifications between flat and tumoral on the basis of 1 cm and by papillary feature is feasible. Tumor morphology can be used as a reference while deciding the treatment plan, especially in T2 GBC.

Pancreatic acinar cell carcinomas and mixed acinar-neuroendocrine carcinomas are more clinically aggressive than grade 1 pancreatic neuroendocrine tumours.

Acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MAcNECs) of the pancreas are extremely rare carcinomas with a significant component with acinar differentiation. To date, the clinicopathological behaviours of these neoplasms remain unclear. In this study, we evaluated the histopathological and molecular characteristics of 20 ACCs and 13 MAcNECs and compared them to a cohort of 269 well-differentiated pancreatic neuroendocrine tumours (PanNETs). Compared to PanNETs, both ACCs and MAcNECs had an advanced pT classification (p<0.001), as well as more prevalent lymphovascular and perineural invasion (p=0.002) and lymph node and distant metastases (p<0.001). Patients with MAcNECs had worse overall (p<0.001) and recurrence-free survival (p<0.001) than those with PanNETs, but no significant difference with those with ACCs. Subgroup analyses revealed that patients with ACCs and MAcNECs had significantly worse recurrence-free survival than those with grade 1 PanNET (p<0.001), and patients with MAcNECs also had worse overall survival than those with grade 1 and 2 PanNETs (p<0.001, and p=0.001). ACCs presented more commonly with intraductal growth (p=0.014) than MAcNECs, while MAcNECs more often had lymph node metastasis (p=0.012) than ACCs. The telomere maintenance mechanism Alternative Lengthening of Telomeres (ALT) was assessed by telomere-specific FISH, and ALT was detected in 1 of 20 ACCs and in three of the 13 MAcNECs. Patients with MAcNECs and ACCs had worse survival and more aggressive behaviour than those with grade 1 PanNETs; thus, the clinicopathological behaviour of MAcNECs resembles ACCs rather than PanNETs. Combined neuroendocrine and acinar cell immunohistochemical markers are helpful for differentiating these different tumour types.

Risk Factors of Tumor Recurrence After Liver Transplantation for Combined Hepatocellular Carcinoma and Cholangiocarcinoma.

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is commonly diagnosed as hepatocellular carcinoma (HCC) preoperatively. Therefore, unexpected recurrence occurs in some patients after liver transplantation (LT). The aim of this study was to identify the risk factors of recurrence. METHODS: We retrospectively reviewed the data of 20 patients who underwent LT for cHCC-CC from January 2005 to December 2015. RESULTS: Of the 20 patients, 11 (55%) had concurrent HCC and 10 (50%) had multiple cHCC-CCs. Before LT, 13 patients had undergone transarterial chemoembolization (TACE, n = 9), radiofrequency ablation, and TACE (n = 3) or surgical resection (n = 1). Four of the patients (20%) had the classical type, whereas 16 (80%) had subtypes with stem cell features. Six of the 16 patients (37.5%) with subtypes with stem cell features and 3 of the 4 patients (75%) with the classical type showed recurrence after LT. In multivariate analysis, the classical type was significantly associated with poorer recurrence-free survival (RFS) (hazard ratio [HR]: 8.65, confidence interval [CI]: 1.25-60.05, P = .03) and poorer overall survival (HR: 8.89, CI: 1.37-57.84, P = .02). Spontaneous tumor necrosis also showed significance on RFS (P = .03) among 11 patients with nontreated lesions. CONCLUSION: In cHCC-CC, the classical type and spontaneous tumor necrosis were associated with recurrence. If these risk factors are found after LT, short-interval follow-up and strategies such as chemotherapy and/or use of mammalian target of rapamycin inhibitors to prevent recurrence are needed.

Tumor-Associated Protein Profiles in Kaposi Sarcoma and Mimicking Vascular Tumors, and Their Pathological Implications.

We investigated protein profiles specific to vascular lesions mimicking Kaposi sarcoma (KS), based on stepwise morphogenesis progression of KS. We surveyed 26 tumor-associated proteins in 130 cases, comprising 39 benign vascular lesions (BG), 14 hemangioendotheliomas (HE), 37 KS, and 40 angiosarcomas (AS), by immunohistochemistry. The dominant proteins in KS were HHV8, lymphatic markers, Rb, phosphorylated Rb, VEGF, and galectin-3. Aberrant expression of p53, inactivation of cell cycle inhibitors, loss of beta-catenin, and increased VEGFR1 were more frequent in AS. HE had the lowest Ki-67 index, and the inactivation rates of cell cycle inhibitors in HE were between those of AS and BG/KS. Protein expression patterns in BG and KS were similar. Clustering analysis showed that the 130 cases were divided into three clusters: AS-rich, BG-rich, and KS-rich clusters. The AS-rich cluster was characterized by high caveolin-1 positivity, abnormal p53, high Ki-67 index, and inactivated p27. The KS-rich cluster shared the features of KS, and the BG-rich group had high positive expression rates of galectin-3 and low bcl2 expression. In conclusion, although the rate was different, AS and HE tended to have less cell cycle marker expression than KS, and features of BG and activated KS cell signaling were similar.