Distal Bile Duct Adenocarcinoma Research Articles

Genome-Derived Ampullary Adenocarcinoma Classifier and Postresection Prognostication

Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use. To test external validity of the prognostic value of the hidden genome classifier of AA. This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020. The multilevel meta-feature regression model previously trained on a prospectively sequenced cohort of 3411 patients (1001 pancreatic adenocarcinoma, 165 distal bile duct adenocarcinoma, and 2245 colorectal adenocarcinoma) was applied to AA sequencing data to quantify the relative proportions of parental cell of origin. Genomic classification was correlated with immunohistologic subtype (intestinal [INT] or pancreatobiliary [PB]) and with overall survival (OS), using the log-rank test and Cox proportional hazard models. Among 192 patients with AA (median age, 69.0 [IQR, 60.0-74.0] years and 134 were male [64%]), concordance between immunohistologic and genomic subtypes was 55%. Most INT subtype tumors were categorized into the colorectal genomic subtype (43 of 57 [72.9%]). Of the 114 PB subtype tumors, 29 had a pancreatic genomic profile (25.4%) and 24 had a distal bile duct genomic profile (21.1%). Whereas the standard immunohistologic subtypes were not associated with survival (log rank P = .26), predicted genomic probabilities were correlated with survival probability. Genomic scores with higher colorectal probability were associated with higher survival probability; higher pancreatic and distal bile duct probabilities were associated with lower survival probability. The AA genomic classifier is reproducible with available molecular testing in a diverse international cohort of patients and improves stratification of the divergent clinical outcomes beyond standard immunohistologic classification. These data provide a molecular classification that may be incorporated into clinical trials for prospective validation.

Genome-Derived Classification Signature for Ampullary Adenocarcinoma to Improve Clinical Cancer Care.

The clinical behavior of ampullary adenocarcinoma varies widely. Targeted tumor sequencing may better define biologically distinct subtypes to improve diagnosis and management. The hidden-genome algorithm, a multilevel meta-feature regression model, was trained on a prospectively sequenced cohort of 3,411 patients (1,001 pancreatic adenocarcinoma, 165 distal bile-duct adenocarcinoma, 2,245 colorectal adenocarcinoma) and subsequently applied to targeted panel DNA-sequencing data from ampullary adenocarcinomas. Genomic classification (i.e., colorectal vs. pancreatic) was correlated with standard histologic classification [i.e., intestinal (INT) vs. pancreatobiliary (PB)] and clinical outcome. Colorectal genomic subtype prediction was primarily influenced by mutations in APC and PIK3CA, tumor mutational burden, and DNA mismatch repair (MMR)-deficiency signature. Pancreatic genomic-subtype prediction was dictated by KRAS gene alterations, particularly KRAS G12D, KRAS G12R, and KRAS G12V. Distal bile-duct adenocarcinoma genomic subtype was most influenced by copy-number gains in the MDM2 gene. Despite high (73%) concordance between immunomorphologic subtype and genomic category, there was significant genomic heterogeneity within both histologic subtypes. Genomic scores with higher colorectal probability were associated with greater survival compared with those with a higher pancreatic probability. The genomic classifier provides insight into the heterogeneity of ampullary adenocarcinoma and improves stratification, which is dictated by the proportion of colorectal and pancreatic genomic alterations. This approach is reproducible with available molecular testing and obviates subjective histologic interpretation.

Clinical, operative, and pathologic outcomes following neoadjuvant therapy versus upfront surgery for ampullary, duodenal and distal bile duct adenocarcinoma

Clinical, operative, and pathologic outcomes following neoadjuvant therapy versus upfront surgery for ampullary, duodenal and distal bile duct adenocarcinoma

Prognostic factors following surgical resection of distal bile duct cancer

PurposePrognostic factors for distal bile duct cancer are contentious. This study was conducted to analyze the prognostic factors of distal bile duct cancer after surgery with the aim of identifying those associated with diminished survival.MethodsTwo hundred forty-one patients who underwent pylorus-preserving pancreaticoduodenectomy (PPPD) or Whipple procedure in our tertiary hospital from February 1995 to June 2011 were retrospectively analyzed. All patients were pathologically proven to have distal bile duct adenocarcinoma. Postoperative complications, survival, and well-known prognostic factors after resection for distal bile duct cancer were investigated.ResultsPreoperative elevated carbohydrate antigen 19-9 (CA 19-9) level (P = 0.006), positive resection margin (P < 0.001), advanced T stage (P = 0.043), and lymph node metastasis (P = 0.002) were significantly independent worse prognostic indicators by multivariate analysis of resectable distal bile duct cancer.ConclusionR0 resection is the most important so that frozen sections should be utilized aggressively during each operation. For the distal bile duct cancer with elevated preoperative CA 19-9 level or advanced stage, further study on postoperative adjuvant treatment may be warranted.

Clinopathologic factors influencing syrvival of patients with distal bile duct adenocarcinoma

Clinopathologic factors influencing syrvival of patients with distal bile duct adenocarcinoma

Nrf2 target gene expression through the panin progression in pancreatic oncogenesis

s / Pancreatology 12 (2012) e1–e8 e4 Take-home message: Distal bile duct adenocarcinoma is a rare malignancy with not well known prognostic factors. In this large DBDA series has been shown that younger patients withwell differentiated DBDA and 2 or less involved LNs have longer survival post radical resection.

Intracellular localization of mesothelin predicts patient prognosis of extrahepatic bile duct cancer

Mesothelin is expressed in various types of malignant tumors, and we recently reported that the expression of mesothelin was related to unfavorable patient outcome in pancreatic ductal adenocarcinoma and gastric adenocarcinoma. In this study, we examined the clinicopathological significance of mesothelin expression in extrahepatic bile duct cancer (EHBDCA), especially in terms of its association with the staining pattern. Tissue samples from 61 EHBDCA (16hilar cholangiocarcinoma, 17 upper bile duct adenocarci-noma, 20 middle bile duct adenocarcinoma and 8 distal bile duct adenocarcinoma) were immunohistochemically examined. The expression levels of mesothelin in tumor cells was classified into the localization of mesothelin in luminal membrane and/or cytoplasm, in addition to high and low according to the staining intensity and proportion as a conventional analysis. 'High-level expression' of mesothelin (47.5%) was statistically correlated with liver metastasis (P=0.013) and poorer patient outcome (P=0.022), while 'luminal membrane positive' of mesothelin (52.5%) was more significantly correlated with liver metastasis (P=0.006), peritoneal metastasis (P=0.024) and unfavorable patient outcome (P=0.017). Moreover, we found that 'cytoplasmic expression' isolated from 'luminal membrane negative' of mesothelin represented the best patient prognosis throughout this study. We describe the expression pattern level of mesothelin, i.e., in luminal membrane or cytoplasm both high and low level, evidently indicate the patient prognosis of EHBDCA, suggesting the pivotal role of mesothelin in cancer promotion depending on its intracellular localization.

Adequate Lymph Node Assessment for Extrahepatic Bile Duct Adenocarcinoma

To examine the importance of adequate lymph node sampling in staging of extrahepatic bile duct cancer (EHBDCA). The American Joint Committee on Cancer staging manual (sixth edition) states that histologic examination of at least 3 lymph nodes is required for adequate N stage determination for EHBDCA. This recommendation has not been validated; however, there has been no comparative assessment of the proximal versus distal bile duct cancer. A total of 257 patients (144 hilar cholangiocarcinoma [HCCA] and 113 distal bile duct adenocarcinoma [DBDCA]) who underwent curative intent resection (1987-2007) were analyzed; patients with gallbladder cancer were excluded. Final disease staging, including lymph node status and total number of nodes examined (total lymph node count), was obtained from the final pathology report. Differences in disease-specific survival, according to nodal status, were compared using the log-rank test. R1 resections (n = 51) were excluded from this analysis. Metastasis to regional lymph nodes was noted in 89 patients (34.6%) and was an independent prognostic factor of poor survival (median disease-specific survival N0 vs. N1: 53.5 vs. 19.3 months, P < 0.0001, hazard ratio = 2.1 [95% CI: 1.4-3.2]). The median total lymph node count was 6 (range: 0-42), and was significantly lower for HCCA compared with DBDCA (median = 3 [range: 0-16] vs. 12 [range: 1-42], P < 0.001, respectively). For the entire cohort, patients who underwent R0 resection and were classified as N0, based on total lymph node count <11, had a disease-specific survival that was significantly worse than that of patients classified as N0 based on total lymph node count >or=11 (52.6 +/- 9.8 months vs. not reached, P = 0.008). The estimated optimal total lymph node count for HCCA differed from that of DBDCA (n = 7 vs. n = 11, respectively). Adequate lymph nodes assessment of EHBDCA, based on the current AJCC recommendations, results in understaging of these tumors. With respect to the optimal total lymph node count, HCCA, and DBDCA should be considered separately.

Portal annular pancreas, a notable pancreatic malformation: Frequency, morphology, and implications for pancreatic surgery

Portal annular pancreas (PAP) is a pancreatic anomaly in which the uncinate process of the pancreas extends and fuses to the dorsal surface of the body of the pancreas by surrounding the portal vein. To the best of our knowledge, there have only been 3 reports of PAP in the literature. 1 Sugiura Y. Shima S. Yonekawa H. Yoshizumi Y. Ohtsuka H. Ogata T. The hypertrophic uncinate process of the pancreas wrapping the superior mesenteric vein and artery. Japan J Surg. 1987; 17: 182-185 Crossref PubMed Scopus (28) Google Scholar , 2 Mizuma M. Suzuki M. Unno M. Katayose Y. Rikiyama T. Takeuti H. et al. A case of “portal annular pancreas” in that the ventral pancreas joins with the pancreatic body encircling the portal vein. Tan to sui. 2001; 22: 963-966 Google Scholar , 3 Savastano S. Alessi S. Fantozzi O. Corra S. Zonta L. MRI diagnosis of a periportal annular pancreas. Eur J Radiol Extra. 2004; 50: 93-95 Crossref Scopus (5) Google Scholar During pancreatic resection, the presence of a PAP significantly affects the procedure, including the pancreaticointestinal reconstruction. Thus, it is important to recognize a PAP preoperatively; however, the frequency and characteristics of the anomaly have yet to be precisely determined. Our experience of technical difficulty during a pancreaticoduodenectomy in a patient with a PAP and distal bile duct adenocarcinoma led us to determine the frequency of PAP and its morphologic features. To this end, we reviewed abdominal contrast-enhanced multidetector computed tomographies (MDCTs) to determine the incidence of PAP.

The mesopancreas is the primary site for R1 resection in pancreatic head cancer: relevance for clinical trials

PurposeThe prognosis of patients with pancreatic cancer remains poor, even after potentially curative R0 resection. This discrepancy may be due to the histopathological misclassification of R1 cases as curative resections (R0) in the past.Materials and methodsTo test this hypothesis, color coding of all resection margins and organ surfaces as part of a standardized histopathological workup was implemented and prospectively tested on 100 pancreatic head specimens.ResultsThirty-five patients were excluded from the analysis owing to the pathohistological diagnosis; only pancreatic ductal adenocarcinoma, distal bile duct adenocarcinoma, and periampullary adenocarcinoma were included. Applying the International Union Against Cancer criteria, 32 cancer resections were classified R0 (49.2%), while 33 cases turned out to be R1 resections (50.8%). The mesopancreas was infiltrated in 22 of the 33 R1 resection specimens (66.6%). It proved to be the only site of tumor infiltration in 17 specimens (51.5%). Applying the Royal College of Pathologists’ criteria, 46 resections were classified R1 (70.8%). As expected, the mesopancreas again was the most frequent site of noncurative resection (n = 27; 58.7%).ConclusionUsing the intensified histopathological workup for pancreatic head cancer specimens resulted in an increased rate of R1 resections and the mesopancreas represents the primary site for positive resection margins. Such results are of relevance for patients’ stratification in clinical trials.

Large-cell neuroendocrine carcinoma of the distal bile duct.

Large-cell neuroendocrine carcinoma (LCNEC) in the distal bile duct is very rare and different from common distal bile duct adenocarcinoma. A 77-year-old man was admitted with obstructive jaundice. Severe stenosis of the distal bile duct was revealed by percutaneous transhepatic cholangiography. Subtotal stomach-preserving pancreaticoduodenectomy was performed. A tumor measuring 1.8cm in diameter was located in the distal bile duct. Both histopathological and immunohistochemical examination of the resected specimen revealed features of LCNEC of the bile duct. The patient developed multiple liver metastases, lung metastases, and local recurrence and died of disease 3months after the operation. The clinical behavior of LCNEC in the distal bile duct appears to be highly aggressive with early metastases and a fatal outcome.

Recurrent disease after microscopically radical (R0) resection of periampullary adenocarcinoma in patients without adjuvant therapy

The survival rate after microscopically radical resection of pancreatic duct adenocarcinoma is still poor. Patients with ampulla of Vater and distal common bile duct adenocarcinoma indicate a much more favorable prognosis. Controversy exists as to whether adjuvant therapy could improve the outcome in these patients after resection. The aim of the present study was to analyze the pattern of recurrence in patients with periampullary adenocarcinoma after pancreatoduodenectomy. Between January 1992 and December 2002, all patients with an R0 resection were identified and used for this analysis. A total of 190 patients underwent a microscopically radical resection and received no adjuvant therapy. Of those, 72 patients were diagnosed with pancreatic duct adenocarcinoma, 86 patients were diagnosed with ampulla of Vater adenocarcinoma, and 31 patients were diagnosed with distal common bile duct adenocarcinoma. Recurrent disease was indicated in 81% of the patients with pancreatic duct adenocarcinoma, 50% of the patients with ampulla of Vater adenocarcinoma, and in 74% of the patients with bile duct adenocarcinoma. Multivariate analysis revealed that lymph node metastases were prognostic for recurrent disease in patients with pancreatic duct adenocarcinoma (P = 0.038). The depth of invasion (T4, P < 0.032) and lymph node metastases (P < 0.001) were prognostic in patients with ampulla of Vater adenocarcinoma. Poor tumor differentiation (P < 0.001) was prognostic in patients with distal bile duct adenocarcinoma. Selected patients with periampullary malignancies exhibited a high recurrence rate and should be encouraged to enroll in clinical trials for adjuvant treatment including local therapy (radiotherapy) according to the identified prognostic factors.

Should pancreaticoduodenectomy be performed in octogenarians?

As the population in the United States ages, an increasing number of elderly patients may be considered for pancreaticoduodenal resection. This high-volume, single-institution experience examines the morbidity, mortality, and long-term survival of 727 patients undergoing pancreaticoduodenectomy between December 1986 and June 1996. Outcomes of patients 80 years of age and older (n = 46) were compared to those of patients younger than 80 years. In these older patients, pancreaticoduodenectomy was performed for pancreatic adenocarcinoma (n = 25; 54%), ampullary adenocarcinoma (n = 9; 20%), distal bile duct adenocarcinoma (n = 5; 11%), duodenal adenocarcinoma (n = 2; 4%), crystadenocarcinoma (n = 2; 4%), cystadenoma (n = 1; 2%), and chronic pancreatitis (n = 2; 4%). When compared to the 681 concurrent patients younger than 80 years who were undergoing pancreaticoduodenectomy, the two groups were statistically similar with respect to sex, race, intraoperative blood loss, and type of pancreaticoduodenectomy performed. Patients 80 years of age or older had a shorter median operative time (6.4 hours vs. 7.0 hours; P = 0.02) but a longer postoperative length of stay (median = 15 days vs. 13 days; P = 0.01) and a higher complication rate (57% vs. 41%; P = 0.05) when compared to their younger counterparts. Pancreaticoduodenectomy in the older group resulted in a 4.3% perioperative mortality rate compared to 1.6% in the younger group ( P = NS). In the subset of patients undergoing pancreaticoduodenectomy for periampullary adenocarcinoma (n = 495), patients 80 years of age or older (n = 41) had a median survival of 32 months and a 5-year survival rate of 19%, compared to 20 months and 27%, respectively, in patients younger than 80 years (n = 454; P = 0.77). These data demonstrate that pancreaticoduodenectomy can be performed safely in selected patients 80 years of age or older, with morbidity and mortality rates approaching those observed in younger patients. Based on these data, age alone should not be a contraindication to pancreaticoduodenectomy.

Pylorus-preserving pancreatoduodenectomy. Is it an adequate cancer operation.

To assess the adequacy of pylorus-preserving pancreatoduodenectomy (PPPD) as a definitive surgical treatment for primary malignant diseases of the periampullary region. Retrospective review of the clinical records of patients undergoing PPPD for malignant diseases of the periampullary region. Median and 5-year actuarial survival by type and stage of cancer were determined. Survival data from this study were compared with those of patients undergoing a conventional Whipple operation. Lahey Clinic, Burlington, Mass. One hundred six patients undergoing PPPD for primary malignant disease of the periampullary region between November 1979 and June 1992. Pylorus-preserving pancreatoduodenectomy was performed with curative intent in the 106 patients. Ninety-five patients underwent proximal pancreatectomy; 11 patients, total pancreatectomy. Resection of the portal vein was performed in 10 patients. Long-term survival following PPPD was analyzed with respect to the type and stage of cancer. Median follow-up was 30 months (range, 6 to 156 months). Five-year actuarial survival rates were 45.4% for patients with ampullary adenocarcinoma; 6.6%, with pancreatic ductal adenocarcinoma; 33.3%, with distal bile duct adenocarcinoma; 75%, with pancreatic islet cell adenocarcinoma; and 0%, with pancreatic cystadenocarcinoma. An early cancer stage was associated with more favorable survival for ampullary and distal bile duct adenocarcinomas. For pancreatic ductal adenocarcinoma only, tumors less than 2 cm were associated with better survival. Duodenal resection margins were free of disease in all patients, while peripancreatic and retroperitoneal extension of the tumor was found in 20%. For patients with periampullary malignant disease, long-term survival following PPPD is similar to that following a conventional Whipple operation. The potential benefits of hemigastrectomy with perigastric lymphadenectomy are frequently obviated by the presence of positive margins and lymph nodes elsewhere, ie, in the retroperitoneum. We advocate PPPD as the procedure of choice for locally resectable malignant disease of the periampullary region, provided the duodenal margin is viable and tumor free.