Extrahepatic Biliary Malignancy Consortium Research Articles

ASO Visual Abstract: Prognostic Utility of Systemic Immune-Inflammation Index After Resection of Extrahepatic Cholangiocarcinoma-Results from the US Extrahepatic Biliary Malignancy Consortium.

ASO Visual Abstract: Prognostic Utility of Systemic Immune-Inflammation Index After Resection of Extrahepatic Cholangiocarcinoma-Results from the US Extrahepatic Biliary Malignancy Consortium.

ASO Author Reflections: Is Systemic Immune-Inflammation Index a Useful Biomarker After Resection of Extrahepatic Cholangiocarcinoma: Results from the U.S. Extrahepatic Biliary Malignancy Consortium.

ASO Author Reflections: Is Systemic Immune-Inflammation Index a Useful Biomarker After Resection of Extrahepatic Cholangiocarcinoma: Results from the U.S. Extrahepatic Biliary Malignancy Consortium.

Prognostic Utility of Systemic Immune-Inflammation Index After Resection of Extrahepatic Cholangiocarcinoma: Results from the U.S. Extrahepatic Biliary Malignancy Consortium.

We sought to define the association of the systemic immune inflammation index (SII) with prognosis and adjuvant therapy benefit among patients undergoing resection of extrahepatic cholangiocarcinoma (eCCA). The impact of SII on overall (OS) and recurrence-free survival (RFS) following resection of eCCA was assessed and compared with other inflammatory markers and traditional prognostic factors. Propensity score matching (PSM) was used to determine the impact of adjuvant therapy (AT) on OS and RFS relative to low versus high SII. Patients with high versus low SII had worse 5-year OS (15.9% vs. 27.9%) and RFS (12.4% vs. 20.9%) (both p < 0.01). On multivariate analysis, high SII remained associated with worse OS (HR = 1.50, 95% CI 1.20-1.87) and RFS (HR = 1.46, 95% CI 1.18-1.81). Patients with T1/2 disease and a high-SII had worse 5-year OS versus individuals with T3/4 disease and low-SII (5-year OS: T1/2 & low-SII 35.6%, T1/2 & high-SII 16.4%, T3/4 & low-SII 22.1%, T3/4 & high-SII 15.6%, p < 0.01). Similarly, 5-year OS was comparable among individuals with N0 and high-SII versus N1 and low-SII (5-year OS: N0 & high-SII 23.2%, N1 and low-SII 19.8%, p = 0.95). On PSM, AT improved OS and RFS among patients with high SII (5-year OS: 22.5% vs. 12.3%, p < 0.01, 5-year RFS: 19.0% vs. 12.5%; p = 0.01) but not individuals with low SII (5-year OS: 22.9% vs. 26.9%; p = 0.98, 5-year RFS: 18.5% vs. 19.9%; p = 0.94). SII was independently associated with postoperative OS and RFS following curative-intent resection of eCCA. High SII up-staged patients relative T- and N-categories and identified patients with high SII as the most likely to benefit from AT.

Using Machine Learning to Preoperatively Stratify Prognosis among Patients with Gallbladder Cancer: A Multi-Institutional Analysis

Background: Gallbladder cancer (GC) is often aggressive and carries significant chance of recurrence and mortality. Thus, risk stratification and patient selection are critical to providing patient-centered care. We aimed to generate prognostic groups of GC patients based only on preoperative characteristics. Methods: Patients undergoing curative-intent resection of GC were identified using the US Extrahepatic Biliary Malignancy Consortium multi-institutional database. A machine-based classification and regression tree (CART) was used to identify four homogenous groups relative to overall survival (OS) using preoperative factors. Results: Among 320 patients, CART analysis identified tumor size, biliary drainage procedures, serum carbohydrate antigen 19-9 (CA19-9) levels, and neutrophil-lymphocyte ratio (NLR) as the strongest predictors of OS. Four groups of patients were identified: Group 1 (n=109): NLR £ 1.5, CA19-9 £ 20, no drainage, tumor size < 5.0 cm; Group 2 (n=88): NLR > 1.5, CA19-9 £ 20, no drainage, tumor size < 5.0 cm; Group 3 (n=46): CA19-9 > 20, no drainage, tumor size < 5.0 cm; Group 4 (n=77): tumor size < 5.0 cm with drainage OR tumor size ³ 5.0 cm. Median overall survival decreased incrementally among groups (Figure 1b, Group 1: 59.5 mo, Group 2: 27.6 mo, Group 3: 20.6 mo, Group 4: 12.1 mo; p < 0.0001). Conclusions: A machine-based CART model identified four groups of GC patients with distinct outcomes based on preoperative characteristics. Characterizing patients preoperatively with machine learning tools may help physicians in patient selection and in providing patient-centered care.

ASO Author Reflections: Development and Validation of Distal Cholangiocarcinoma Early Recurrence (DICER) Score: Results from the US Extrahepatic Biliary Malignancy Consortium.

ASO Author Reflections: Development and Validation of Distal Cholangiocarcinoma Early Recurrence (DICER) Score: Results from the US Extrahepatic Biliary Malignancy Consortium.

Survival benefit of lymphadenectomy for gallbladder cancer based on the therapeutic index: An analysis of the US extrahepatic biliary malignancy consortium.

BackgroundThe survival benefit of lymphadenectomy among patients with gallbladder cancer (GBC) remains poorly understood.MethodsPatients who underwent resection for GBC between 2000 and 2015 were identified from a US multi‐institutional database. The therapeutic index (LNM rate multiplied by 3‐year overall survival [OS]) was determined to assess the survival benefit of lymphadenectomy.ResultsAmong 449 patients, less than half had LNM (N = 183, 40.8%). The median number of evaluated and metastatic lymph nodes (LNs) was 3 (interquartile range [IQR]: 1‐6) and 1 (IQR: 0‐1), respectively. 3‐year OS among patients with LNM in the entire cohort was 26.8%. The therapeutic index was lower among patients with T4 (5.9) or T1 (6.0) tumors as well as carbohydrate antigen (CA19‐9) ≥200 UI/mL (6.0). Of note, a therapeutic index difference ≥10 was noted relative to CA19‐9 (<200: 18.7 vs ≥200: 6.0), American Joint Committee on Cancer T Stage (T1: 6.0 vs T2: 17.8 vs T4: 5.9) and number of LNs examined (1‐2: 6.9 vs ≥6: 16.9). Concomitant common bile duct resection was not associated with a higher therapeutic index among patients with either T2 or T3 disease.ConclusionCertain clinicopathological factors including T1 or T4 tumor and CA19‐9 ≥200 UI/mL were associated with a low therapeutic index. Resection of six or more LNs was associated with a meaningful therapeutic index benefit among patients with LNM.

Association of Perioperative Transfusion with Recurrence and Survival After Resection of Distal Cholangiocarcinoma: A 10-Institution Study from the US Extrahepatic Biliary Malignancy Consortium.

Perioperative allogeneic blood transfusion is associated with poor oncologic outcomes in multiple malignancies. The effect of blood transfusion on recurrence and survival in distal cholangiocarcinoma (DCC) is not known. All patients with DCC who underwent curative-intent pancreaticoduodenectomy at 10 institutions from 2000 to 2015 were included. Primary outcomes were recurrence-free (RFS) and overall survival (OS). Among 314 patients with DCC, 191 (61%) underwent curative-intent pancreaticoduodenectomy. Fifty-three patients (28%) received perioperative blood transfusions, with a median of 2 units. There were no differences in baseline demographics or operative data between transfusion and no-transfusion groups. Compared with no-transfusion, patients who received a transfusion were more likely to have (+) margins (28 vs 14%; p = 0.034) and major complications (46 vs 16%; p < 0.001). Transfusion was associated with worse median RFS (19 vs 32months; p = 0.006) and OS (15 vs 29months; p = 0.003), which persisted on multivariable (MV) analysis for both RFS [hazard ratio (HR) 1.8; 95% confidence interval (CI) 1.1-3.0; p = 0.031] and OS (HR 1.9; 95% CI 1.1-3.3; p = 0.018), after controlling for portal vein resection, estimated blood loss (EBL), grade, lymphovascular invasion (LVI), and major complications. Similarly, transfusion of ≥ 2 pRBCs was associated with lower RFS (17 vs 32months; p < 0.001) and OS (14 vs 29months; p < 0.001), which again persisted on MV analysis for both RFS (HR 2.6; 95% CI 1.4-4.5; p = 0.001) and OS (HR 4.0; 95% CI 2.2-7.5; p < 0.001). The RFS and OS of patients transfused 1 unit was comparable to patients who were not transfused. Perioperative blood transfusion is associated with decreased RFS and OS after resection for distal cholangiocarcinoma, after accounting for known adverse pathologic factors. Volume of transfusion seems to exert an independent effect, as 1 unit was not associated with the same adverse effects as ≥ 2 units.

Association of perioperative transfusion with survival and recurrence after resection of gallbladder cancer: A 10-institution study from the US Extrahepatic Biliary Malignancy Consortium.

Perioperative blood transfusion is associated with poor outcomes in several malignancies. Its effect in gallbladder cancer (GBC) is unknown. All patients with GBC who underwent curative-intent resection at 10-institutions from 2000 to 2015 were included. The effect of blood transfusion on overall survival (OS) and recurrence-free (RFS) was evaluated. Of 262 patients with curative-intent resection for GBC, 61 patients (23%) received blood transfusions. Radical cholecystectomy was the most common procedure (80%), but major hepatectomy was more frequent in the transfusion versus no-transfusion group (13% vs 4%; P = 0.02). The transfusion group was less likely to have incidentally discovered disease (57% vs 74%) and receive adjuvant therapy (29% vs 48%), but more likely to have preoperative jaundice (23% vs 11%), T3/T4 tumors (60% vs 39%), LVI (71% vs 40%), PNI (71% vs 48%), and major complications (39% vs 12%) (all P < 0.05). Transfusion was associated with lower median OS compared to no-transfusion (20 vs 32 mos; P < 0.001), which persisted on multivariable (MV) analysis (HR:1.9; 95%CI 1.1-3.5; P = 0.035), controlling for comorbidities, serum albumin, INR, preoperative jaundice, major hepatectomy, incidental discovery, margin status, T-Stage, LN status, and major complications. Median RFS of transfused patients was 13mo compared to 49mo for non-transfused patients (P = 0.1). Transfusion, however, was an independent predictor of decreased RFS on MV analysis (HR:2.3; 95%CI 1.1-5.1; P = 0.035). Perioperative blood transfusion is associated with decreased OS and RFS after resection for GCC, accounting for other adverse factors. Transfusions should thus be administered with well-defined protocols.

Is primary sclerosing cholangitis-related gallbladder cancer associated with worse survival? Results from the U.S. extrahepatic biliary malignancy consortium

Is primary sclerosing cholangitis-related gallbladder cancer associated with worse survival? Results from the U.S. extrahepatic biliary malignancy consortium

Defining Early Recurrence of Hilar Cholangiocarcinoma After Curative-intent Surgery: A Multi-institutional Study from the US Extrahepatic Biliary Malignancy Consortium.

Time to tumor recurrence may be associated with outcomes following resection of hepatobiliary cancers. The objective of the current study was to investigate risk factors and prognosis among patients with early versus late recurrence of hilar cholangiocarcinoma (HCCA) after curative-intent resection. A total of 225 patients who underwent curative-intent resection for HCCA were identified from 10 academic centers in the USA. Data on clinicopathologic characteristics, pre-, intra-, and postoperative details and overall survival (OS) were analyzed. The slope of the curves identified by linear regression was used to categorize recurrences as early versus late. With a median follow-up of 18.0months, 99 (44.0%) patients experienced a tumor recurrence. According to the slope of the curves identified by linear regression, the functions of the two straight lines were y=-0.465x+16.99 and y=-0.12x+7.16. The intercept value of the two lines was 28.5months, and therefore, 30months (2.5years) was defined as the cutoff to differentiate early from late recurrence. Among 99 patients who experienced recurrence, the majority (n=80, 80.8%) occurred within the first 2.5years (early recurrence), while 19.2% of recurrences occurred beyond 2.5years (late recurrence). Early recurrence was more likely present as distant disease (75.1% vs. 31.6%, p=0.001) and was associated with a worse OS (Median OS, early 21.5 vs. late 50.4months, p<0.001). On multivariable analysis, poor tumor differentiation (HR 10.3, p=0.021), microvascular invasion (HR 3.3, p=0.037), perineural invasion (HR 3.9, p=0.029), lymph node metastases (HR 5.0, p=0.004), and microscopic positive margin (HR 3.5, p=0.046) were independent risk factors associated with early recurrence. Early recurrence of HCCA after curative resection was common (~35.6%). Early recurrence was strongly associated with aggressive tumor characteristics, increased risk of distant metastatic recurrence and a worse long-term survival.

The impact of caudate lobe resection on margin status and outcomes in patients with hilar cholangiocarcinoma: a multi-institutional analysis from the US Extrahepatic Biliary Malignancy Consortium

BackgroundThe objective of this study was to determine the impact of caudate resection on margin status and outcomes during resection of extrahepatic hilar cholangiocarcinoma. MethodsA database of 1,092 patients treated for biliary malignancies at institutions of the Extrahepatic Biliary Malignancy Consortium was queried for individuals undergoing curative-intent resection for extrahepatic hilar cholangiocarcinoma. Patients who did versus did not undergo concomitant caudate resection were compared with regard to demographic, baseline, and tumor characteristics as well as perioperative outcomes. ResultsA total of 241 patients underwent resection for a hilar cholangiocarcinoma, of whom 85 underwent caudate resection. Patients undergoing caudate resection were less likely to have a final positive margin (P = .01). Kaplan-Meier curve of overall survival for patients undergoing caudate resection indicated no improvement over patients not undergoing caudate resection (P = .16). On multivariable analysis, caudate resection was not associated with improved overall survival or recurrence-free survival, although lymph node positivity was associated with worse overall survival and recurrence-free survival, and adjuvant chemoradiotherapy was associated with improved overall survival and recurrence-free survival. ConclusionCaudate resection is associated with a greater likelihood of margin-negative resection in patients with extrahepatic hilar cholangiocarcinoma. Precise preoperative imaging is critical to assess the extent of biliary involvement, so that all degrees of hepatic resections are possible at the time of the initial operation.

Adjuvant therapy is associated with improved survival after curative resection for hilar cholangiocarcinoma: A multi-institution analysis from the U.S. extrahepatic biliary malignancy consortium.

Curative-intent treatment for localized hilar cholangiocarcinoma (HC) requires surgical resection. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall (OS) and recurrence free survival (RFS) in patients undergoing curative resection. We reviewed patients with resected HC between 2000 and 2015 from the ten institutions participating in the U.S. Extrahepatic Biliary Malignancy Consortium. We analyzed the impact of AT on RFS and OS. The probability of RFS and OS were calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis. A total of 249 patients underwent curative resection for HC. Patients who received AT and those who did not had similar demographic and preoperative features. In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.58, P = 0.013), and this was maintained in a propensity matched analysis (HR 0.66, P = 0.033). The protective effect of AT remained significant when node negative patients were excluded (HR 0.28, P = 0.001), while it disappeared (HR 0.76, P = 0.260) when node positive patients were excluded. AT should be strongly considered after curative-intent resection for HC, particularly in patients with node positive disease.

Outcomes after vascular resection during curative-intent resection for hilar cholangiocarcinoma: a multi-institution study from the US extrahepatic biliary malignancy consortium

BackgroundSurgical resection is the cornerstone of curative-intent therapy for patients with hilar cholangiocarcinoma (HC). The role of vascular resection (VR) in the treatment of HC in western centres is not well defined. MethodsUtilizing data from the U.S. Extrahepatic Biliary Malignancy Consortium, patients were grouped into those who underwent resection for HC based on VR status: no VR, portal vein resection (PVR), or hepatic artery resection (HAR). Perioperative and long-term survival outcomes were analyzed. ResultsBetween 1998 and 2015, 201 patients underwent resection for HC, of which 31 (15%) underwent VR: 19 patients (9%) underwent PVR alone and 12 patients (6%) underwent HAR either with (n = 2) or without PVR (n = 10). Patients selected for VR tended to be younger with higher stage disease. Rates of postoperative complications and 30-day mortality were similar when stratified by vascular resection status. On multivariate analysis, receipt of PVR or HAR did not significantly affect OS or RFS. ConclusionIn a modern, multi-institutional cohort of patients undergoing curative-intent resection for HC, VR appears to be a safe procedure in a highly selected subset, although long-term survival outcomes appear equivalent. VR should be considered only in select patients based on tumor and patient characteristics.

Evaluating the American College of Surgeons National Surgical Quality Improvement project risk calculator: results from the U.S. Extrahepatic Biliary Malignancy Consortium

BackgroundThe objective of this study is to evaluate use of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) online risk calculator for estimating common outcomes after operations for gallbladder cancer and extrahepatic cholangiocarcinoma. MethodsSubjects from the United States Extrahepatic Biliary Malignancy Consortium (USE-BMC) who underwent operation between January 1, 2000 and December 31, 2014 at 10 academic medical centers were included in this study. Calculator estimates of risk were compared to actual outcomes. ResultsThe majority of patients underwent partial or major hepatectomy, Whipple procedures or extrahepatic bile duct resection. For the entire cohort, c-statistics for surgical site infection (0.635), reoperation (0.680) and readmission (0.565) were less than 0.7. The c-statistic for death was 0.740. For all outcomes the actual proportion of patients experiencing an event was much higher than the median predicted risk of that event. Similarly, the group of patients who experienced an outcome did have higher median predicted risk than those who did not. ConclusionsThe ACS NSQIP risk calculator is easy to use but requires further modifications to more accurately estimate outcomes for some patient populations and operations for which validation studies show suboptimal performance.

Pathologic and Prognostic Implications of Incidental versus Nonincidental Gallbladder Cancer: A 10-Institution Study from the United States Extrahepatic Biliary Malignancy Consortium

Most gallbladder cancers (GBCs) are discovered incidentally after routine cholecystectomy. The influence of timing of diagnosis on disease stage, treatment, and prognosis is not known. Patients with GBC who underwent resection at 10 institutions from 2000 to 2015 were included. Patients diagnosed incidentally (IGBC) and nonincidentally (non-IGBC) were compared. Primary outcome was overall survival (OS). Of 445 patients with GBC, 266 (60%) were IGBC and 179 (40%) were non-IGBC. Compared with IGBC, non-IGBC patients were more likely to have R2 resections (43% vs 19%; P < 0.001), advanced T-stage (T3/T4: 70% vs 40%; P < 0.001), high-grade tumors (50% vs 31%; P < 0.001), lymphovascular invasion (64% vs 45%; P = 0.01), and positive lymph nodes (60% vs 43%; P = 0.009). Receipt of adjuvant chemotherapy was similar between groups (49% vs 49%). Non-IGBC was associated with worse median OS compared with IGBC (17 vs 32 months; P < 0.001), which persisted among stage III patients (12 vs 29 months; P < 0.001), but not stages I, II, or IV. Despite accounting for other adverse pathologic factors (grade, T-stage, lymphovascular invasion, margin, lymph node), adjuvant chemotherapy was associated with improved OS only in stage III IGBC, but not in non-IGBC. Compared with incidental discovery, non-IGBC is associated with reduced OS, which is most evident in stage III disease. Despite being well matched for other adverse pathologic factors, adjuvant chemotherapy was associated with improved survival only in stage III patients with incidentally discovered cancer. This underscores the importance of timing of diagnosis in GBC and suggests that these two groups may represent a distinct biology of disease, and the same treatment paradigm may not be appropriate.

Evaluating the American College of Surgeons national surgical improvement project risk calculator in extrahepatic biliary malignancy: results from the U.S. extrahepatic biliary malignancy consortium

Objective: To assess the accuracy of the ACS NSQIP calculator for estimating risk after operation for gallbladder cancer and extrahepatic cholangiocarcinoma. Methods: Adult patients with gallbladder cancer, distal or hilar cholangiocarcinoma who underwent curative-intent, complete resection January, 2000–December, 2014 were included. The ability of the NSQIP calculator to accurately predict a particular outcome was assessed using the c-statistic (0.7 or above score for reasonable models) and Brier score (zero score for perfect models). Results: 854 adult patients were included. The most commonly performed procedures included right or left hepatic lobectomy (254, 29.7%), pancreaticoduodenectomy (132, 15.5%) and trisegmentectomy (118, 13.8%). 185 patients experienced surgical site infection (SSI) (21.7%, median predicted risk of 9.6%, range: 1.9–36.6%). There was 2.1% mortality (median predicted risk of 0.5%, range: 0–19.4%). There were 57 (6.7%) reoperations (median predicted risk of 3.3%, range: 0.9–13.2%). 169 (19.7%) patients were readmitted (median predicted risk of 9.1%, range: 2.6–32.2%). The median length of stay in the cohort was 8 days (Range: 0 119 days) and the median predicted length of stay was 6.5 days (Range: 2.5–25.5 days). The c-statistics for SSI, mortality, reoperation and readmission were 0.64, 0.74, 0.68 and 0.57 and Brier scores were 0.17, 0.02, 0.06 and 0.16 respectively (FIGURE). Conclusion: The ACS NSQIP Risk Calculator estimates the risk of mortality reasonably well for patients with gallbladder and extrahepatic biliary malignancy but generally underestimates risk of several other postoperative complications. Future modifications of the calculator for some patient populations are needed before widespread use of the tool can be encouraged.

Effect of perioperative transfusion on survival and recurrence after resection of gallbladder cancer: a 10-institution study from the U.S. extrahepatic biliary malignancy consortium

Effect of perioperative transfusion on survival and recurrence after resection of gallbladder cancer: a 10-institution study from the U.S. extrahepatic biliary malignancy consortium

Outcomes after vascular resection during curative resection for hilar cholangiocarcinoma: a multi-institution analysis from the US extrahepatic biliary malignancy consortium

Outcomes after vascular resection during curative resection for hilar cholangiocarcinoma: a multi-institution analysis from the US extrahepatic biliary malignancy consortium

Routine port-site excision in incidentally discovered gallbladder cancer is not associated with improved survival: A multi-institution analysis from the US Extrahepatic Biliary Malignancy Consortium.

Current data on the utility of port-site excision (PSE) during re-resection for incidentally discovered gallbladder cancer (IGBC) in the US are conflicting and limited to single-institution series. All patients with IGBC who underwent curative re-resection at 10 institutions from 2000 to 2015 were included. Patients with and without PSE were compared. Primary outcome was overall survival (OS). Of 449 pts with GBC, 266 were incidentally discovered, of which 193(73%) underwent curative re-resection and had port-site data; 47 pts(24%) underwent PSE, 146(76%) did not. The PSE rate remained similar over time (2000-2004: 33%; 2005-2009: 22%; 2010-2015:22%; P = 0.36). Both groups had similar demographics, operative procedures, and post-operative complications. There was no difference in T-stage (T1: 9 vs. 11%; T2: 52 vs. 52%; T3: 39 vs. 38%; P = 0.96) or LN involvement (36 vs. 41%; P = 0.7) between groups. A 3-year OS was similar between PSE and no PSE groups (65 vs. 43%; P = 0.07). On univariable analysis, residual disease at re-resection (HR = 2.1, 95% CI 1.4-3.3; P = 0.001), high tumor grade, and advanced T-stage were associated with decreased OS. Only grade and T-stage, but not PSE, persisted on multivariable analysis. Distant disease recurrence-rate was identical between PSE and no PSE groups (80 vs. 81%; P = 1.0). Port-site excision during re-resection for IGBC is not associated with improved overall survival and has the same distant disease recurrence compared to no port-site excision. Routine port-site excision is not recommended.

Histologic classification and grading enhances gallbladder cancer staging: A population-based prognostic score validated by the U.S. Extrahepatic Biliary Malignancy Consortium.

356 Background: Beyond the most common adenocarcinoma type, several gallbladder cancer (GBC) histologies have been described as being associated with more favorable (papillary) or less favorable outcome (adenosquamous, mucinous, signet ring). We sought to examine the added value of histologic type and grade on the existing AJCC staging system for resected GBC. Methods: Patients who underwent resection of GBC from 1988-2013 were identified using the Surveillance Epidemiology End Results (SEER) registry. A prognostic score was created by assigning points for T stage, N stage, grade and histology based on the regression coefficient in multivariate analysis. The score was externally validated using the US Extrahepatic Biliary Malignancy Consortium (USEBMC) database (2000-2015) and compared with the AJCC staging system. Results: Of 7,915 patients identified in SEER, 83% had adenocarcinoma, 7% papillary, 4% adenosquamous, 4% mucinous, and 2% signet ring. In the USEBMC database, the frequencies of the respective histologies were 86, 9, 2, 1 and 2%. Median survival per histologic type, for SEER and USEBMC respectively, were 45 and 110 mos for papillary, 16 and 24 mos for adenocarcinoma, 14 and 12mos for mucinous, 8 and 4mos for adenosquamous, and 9 and 15mos for signet ring (P between histologies &lt; 0.001 for both cohorts). On multivariate analysis, T stage, N stage, grade and histology were independent predictors of survival. The developed prognostic score, based on points for each of these 4 variables, showed excellent discriminatory ability both in the SEER and USEBMC cohorts. The AUC for the prognostic score was significantly improved compared with the AJCC system (0.69 vs. 0.64,both P &lt; 0.001 using SEER, and 0.76 vs. 0.66,both P &lt; 0.001 using USEBMC). Conclusions: The incorporation of histology and grade into the TNM system allows for a simple and accurate tool to determine prognosis following resection of GBC. [Table: see text]