Classification of lymph node groups in the management of carcinoma of the distal bile duct. They are as follows: 7, left gastric artery; 8, common hepatic artery; 9, celiac trunk; 11, splenic artery; 12, hepatoduodenal ligament; 13, posterior pancreaticoduodenal; 14, superior mesenteric artery; 15, middle colic artery; 16, para-aortic; and 17, anterior pancreaticoduodenal.
Survival rates after pancreatoduodenectomy with extended lymph node dissection in 26 patients with distal bile duct cancer.
Survival rates of patients with 0, 1 or 2, and 3 or more involved lymph nodes. Significant differences existed between patients with no involved nodes and those with 3 or more involved nodes (P<.001) and between those with 1 or 2 involved nodes and those with 3 or more involved nodes (P = .04). Significant difference was absent between patients with no involved nodes and those with 1 or 2 involved nodes (P = .61).
Yoshida T, Matsumoto T, Sasaki A, Morii Y, Aramaki M, Kitano S. Prognostic Factors After Pancreatoduodenectomy With Extended Lymphadenectomy for Distal Bile Duct Cancer. Arch Surg. 2002;137(1):69–73. doi:10.1001/archsurg.137.1.69
Since 1995, we have been performing pancreatoduodenectomy with regional and para-aortic lymph node dissection for patients with distal bile duct cancer. Prognostic indicators after extended lymphadenectomy have not been fully understood.
Pancreatoduodenectomy with extended lymphadenectomy and adjuvant chemotherapy is the treatment of choice for patients with distal bile duct cancer.
In a retrospective study, univariate and multivariate models were used to analyze the effect of patient demographics, tumor characteristics, and treatment factors on long-term survival.
Oita Medical University and its affiliated hospitals in Japan.
From 1995 to 1999, 27 patients with distal bile duct cancer underwent pancreatoduodenectomy with extended lymphadenectomy. In 9 patients fluorouracil (500 mg/d) was infused continuously for 14 days after surgery as adjuvant chemotherapy.
Main Outcome Measures
Clinicopathologic characteristics and long-term results.
In 6 patients (22%) major surgical complications occurred including 1 in-hospital death (3.7%). For 26 patients, the survival rates were 65% for 1 year and 37% for 3 and 5 years. Univariate analysis found that the absence of lymph node metastasis, no more than 2 involved nodes, and negative resection margins were predictors of survival. Multivariate analysis with a Cox proportional hazards regression model revealed that favorable factors for survival included up to 2 positive nodes, negative resection margins, and the use of postoperative adjuvant chemotherapy.
Patients with up to 2 positive lymph nodes had a more favorable prognosis than that of other patients. We recommend pancreatoduodenectomy with extended lymphadenectomy and adjuvant chemotherapy for the treatment of patients with distal bile duct cancer.
IN PATIENTS with distal bile duct cancer, lymph node metastasis is associated significantly with treatment outcomes.1- 4 The extent of dissection and histological examination of lymph nodes, however, varies between countries, and this variation may result in erroneous nodal staging and may account for differences in surgical results. In Japan, some surgeons advocate the complete removal of the primary bile duct cancer with connective tissue clearance, including lymph node and neural plexus dissection.4- 6 Since 1995, we have been performing pancreatoduodenectomy with regional and para-aortic lymph node dissection for patients with distal bile duct cancer.7- 9 The goal of this radical surgery with extended lymphadenectomy is to primarily achieve locoregional control and to secondarily obtain accurate tumor staging.
Results from randomized controlled trials of patients with adenocarcinoma of the pancreatic head indicated that extended lymphadenectomy and retroperitoneal soft tissue clearance with pancreatoduodenal resection might be accepted as the procedure of choice in the treatment of node-positive patients with similar morbidity and mortality to standard dissection.10,11 The use of postoperative adjuvant chemoradiotherapy and intraoperative blood loss are considered independent prognostic factors.12 Because of its rarity, there are a few detailed reports about treatments for distal bile duct cancer.1- 5,13,14 This retrospective study identifies prognostic factors after pancreatoduodenectomy with extended lymphadenectomy in patients with distal bile duct cancer, using a series of 27 patients, a sufficiently large population to allow for statistical evaluation, and relating to a single center, to minimize the problem of homogeneity of treatment and follow-up.
Between January 1, 1995, and December 31, 1999, at the First Department of Surgery, Oita Medical University, Oita, Japan, and its affiliated hospitals, 100 patients with malignant tumors underwent pancreatoduodenectomy with systematic lymph node dissection including regional and para-aortic nodes. The patient population consisted of 27 patients with distal bile duct cancer, 24 with pancreatic head cancer, 21 with ampullary cancer, and 28 with other malignancies. Distal bile duct cancer was defined as adenocarcinoma arising from the intrapancreatic bile duct. Pancreatic head, ampullary, and other adenocarcinomas were excluded from this study. Of the 27 patients with distal bile duct cancer, 16 were treated by pancreatoduodenectomy with conventional gastrectomy, and 11 underwent a pylorus-preserving procedure. Four patients underwent portal vein resection and reconstruction. Para-aortic lymph node dissection extended from the celiac axis to the inferior mesenteric artery and from the right margin of the inferior vena cava to the left margin of the abdominal aorta. One patient died of an intra-abdominal abscess after the operation and was excluded from survival analysis. The remaining 26 patients included 16 men and 10 women who had a mean age of 63.5 years (age range, 35-80 years).
The resected specimens with attached choledochal and peripancreatic lymph nodes were examined by the preparation of serial tissue sections at 5-mm intervals and were stained with hematoxylin-eosin. All specimens were reviewed by a single surgical pathologist (A.S.) according to the General Rules for Surgical and Pathological Studies on Cancer of the Biliary Tract15 outlined by the Japanese Society of Biliary Surgery. Local extent of the primary tumor was classified into 2 groups with the classification based on the presence of pancreatic parenchymal invasion.7- 9 Predominant histological grading was adopted as the differentiation. Lymph nodes were considered positive if any lymph node in the resected specimen contained metastatic foci. The number and location of involved nodes were carefully recorded. Lymph nodes were classified according to the General Rules for Surgical and Pathological Studies on Cancer of the Biliary Tract15: 5 indicates suprapyloric; 6, infrapyloric; 7, left gastric artery; 8, common hepatic artery; 9, celiac trunk; 11, splenic artery; 12, hepatoduodenal ligament; 13, posterior pancreaticoduodenal; 14, superior mesenteric artery; 15, middle colic artery; 16, para-aortic; and 17, anterior pancreaticoduodenal (Figure 1). Resection margins were considered positive if infiltrating adenocarcinoma was present at the pancreatic neck, proximal bile duct, or periductal soft tissue margins. The lymphatic, venous, and perineural permeations were examined routinely with cut sections.
Intraoperative blood loss, transfused units of erythrocytes, and operative time were investigated by reviewing the medical records. Patients were offered 2 options for postoperative treatment—chemotherapy or no chemotherapy—according to their condition. As adjuvant chemotherapy, fluorouracil (500 mg/d) was infused continuously and systemically for 14 days after the pancreatoduodenectomy.16
Follow-up to December 31, 2000, was obtained for all 26 patients and ranged from 12 to 71 months (mean duration of follow-up, 52.2 months; median duration of follow-up, 54.0 months). Patient demographics, tumor characteristics, and treatment factors were evaluated using univariate and multivariate models to determine their effect on long-term survival. The cumulative survival rate was calculated by the Kaplan-Meier method, and the survival curves were compared using the Mantel-Haenszel test. Multivariate analysis was performed using the stepwise forward Cox proportional hazards regression model. Differences were considered statistically significant at P<.05.
Major surgery-related complications occurred in 6 (22%) of 27 patients, including leakage of the pancreaticojejunostomy in 5 (1 death), delayed bleeding in 2, myocardial infarction in 1, and obstruction of the efferent loop of gastrojejunostomy in 1. One patient, in whom adjuvant chemotherapy was not administered, died of intra-abdominal sepsis due to leakage of the pancreaticojejunostomy after 38 postoperative days. The in-hospital death rate was 3.7%. Two patients with delayed intraperitoneal hemorrhage were treated successfully with transcatheter arterial embolization and conservative treatment.17 Reoperation was needed 20 days after pancreatoduodenectomy in 1 patient with obstruction of the efferent loop of gastrojejunostomy.
In 15 patients (58%), metastatic adenocarcinoma was identified in resected lymph nodes (Table 1). Of the 15 node-positive patients, 6 had 1 or 2 nodes involved, and 9 had 3 or more nodes involved. All node-positive patients had involved lymph nodes in the groups classified as 12, 13, and/or 17. Seven patients had metastatic nodes in group 8 or 14 or both. Para-aortic lymph node involvement was observed in 5 patients.
There were 12 tumors (46%) without pancreatic invasion and 14 (54%) with pancreatic invasion (Table 2). Four patients (15%) had positive resection margins (proximal bile duct in 2 and periductal soft tissue margins in the other), and 22 (85%) had negative margins. Most carcinomas either were well differentiated in 15 (58%) or moderately differentiated in 7 (27%). The median intraoperative blood loss was 1000 mL, the median units of erythrocytes transfused was 1, and the median operative time was 7 hours. Nine patients who underwent adjuvant chemotherapy had no chemotherapy-related complications.
The survival rates (Figure 2) were 65% for 1 year and 37% for 3 and 5 years with survival time ranging from 4 to 64 months (mean, 26.4 months; median, 20.5 months). Of 26 patients, 16 (4 with positive and 12 with negative margins) died of either the tumor or a recurrence. The cause of death was peritoneal dissemination in 5, liver metastases in 4, local recurrence due to positive resection margins in 4, and retroperitoneal recurrence in 3. In 9 patients with postoperative adjuvant chemotherapy, 2 had local and 2 had retroperitoneal recurrences. Liver metastases occurred only in patients who did not receive adjuvant chemotherapy.
Univariate analysis (Table 2) found prognostic factors for survival to include the absence of lymph node metastasis (P = .02), no more than 2 involved lymph nodes (P<.001), and negative resection margins (P = .002). For patients without positive lymph nodes, survival rates were 91% for 1 year and 61% for 3 and 5 years (Figure 3). For patients with up to 2 positive nodes, survival rates were 83% for 1 year and 50% for 3 and 5 years. The survival rate for patients with 3 or more positive nodes was 22% for 1 year, and it decreased to 0% by 3 years. Survival rates were statistically similar between patients without positive nodes and those with 1 or 2 positive nodes (P = .61). Significant differences existed between patients with 3 or more positive nodes and those without positive nodes (P<.001) as well as those with 1 or 2 involved nodes (P = .04).
Multivariate analysis with a stepwise regression model showed that prognostic factors for survival included the number of lymph nodes involved, the status of resection margins, and the use of postoperative adjuvant chemotherapy (Table 3). Although the use of adjuvant chemotherapy was a significant prognostic factor for survival by multivariate analysis, no difference was found by the Mantel-Haenszel test (P = .12).
The presence of lymph node metastasis is reportedly significantly associated with the outcome of patients with distal bile duct cancer.1- 4 In our study, however, the 5-year survival rate for node-positive patients was 20%, and lymph node involvement failed to affect survival adversely if no more than 2 positive nodes were detected. These results suggest that the extent of lymph node dissection is an important component of radical surgery. In patients with distal bile duct cancer, extended lymph node dissection can contribute to locoregional control and accurate nodal staging and result in favorable outcomes.4
We found no record of technical difficulties with the extended lymphadenectomy that included regional and para-aortic nodes. Our results of median intraoperative blood loss, median transfused units of erythrocytes, and median operative time are almost comparable with those of other reports.10- 12 With this procedure, early postoperative complications are problematic although recent occurrences are lacking. We only have performed lymph node dissection around the superior mesenteric artery with either total circular or left hemicircular preservation of the nerve plexus, and this helps to prevent intractable diarrhea and digestive malnutrition.4,18 Intraoperative blood loss of less than 700 mL and the absence of intraoperative blood transfusion were previously reported as predictors of improved survival in patients with pancreatic head cancer.12 In our study, however, intraoperative blood loss and blood transfusion failed to be important prognostic factors; this may have been owing to the small sample size.
In the past, staging systems for malignancy determined the nodal status by the location of lymph node metastases associated with the primary tumor. At present, a pathologic N category has been defined as the number of involved nodes in the stomach (N1 indicates 1-6 positive nodes; N2, 7-15 positive nodes; and N3, ≥16 positive nodes) and colorectum (N1 indicates 1-3 positive nodes; N2, ≥4 positive nodes), and this has been accepted as a simple and useful classification system.19,20 In addition, ampullary carcinoma patients with up to 2 positive nodes have a better survival rate than that of other patients.21,22 We, therefore, analyzed the number of involved nodes in distal bile duct cancer. A lymph node staging system based on the number of involved nodes may be applied to pancreatoduodenal malignancies after further investigation.
Tumor involvement of the surgical margins is an important prognostic factor in patients with cancer of the pancreatic head and distal bile duct.1,4,12 Our results show that the survival rates for patients with negative resection margins are significantly higher than those for patients with positive surgical margins and that the status of the resection margins is an independent prognostic factor. Of 27 patients, 2 (7.4%) had a positive proximal bile duct transection margin owing to superficial spreading of more than 30 mm from the main papillary tumor, and these patients died of anastomotic recurrence. Although major hepatic resection with pancreatoduodenectomy may allow for a negative proximal bile duct transection margin, careful assessment and treatment are necessary because of high morbidity and mortality rates.23- 25
Locoregional recurrence and distant (mainly hepatic) metastasis are major causes of treatment failures. Several studies of patients with pancreatic cancer reported that adjuvant chemotherapy or chemoradiotherapy after curative pancreatectomy improved survival by decreasing hepatic metastasis.12,16 These results led us to believe that radical resection with wide lymphadenectomy needed to be combined with an additional therapy to prevent hepatic metastasis. Therefore, in 1995, we began adjuvant chemotherapy for patients in whom distal bile duct cancer was resected by extended operation according to their condition. In our present study, the use of adjuvant chemotherapy was a prognostic factor by multivariate analysis although no difference was found by univariate analysis. Further investigations are needed that examine larger groups of patients who undergo adjuvant chemotherapy and are observed for long-term follow-up periods. To confirm our results, a prospective, randomized trial should be undertaken.
Although the limited number of cases observed does not allow for definite conclusions, the results of this study would seem to recommend pancreatoduodenectomy with extended lymphadenectomy and adjuvant chemotherapy as the treatment of choice in the surgical management of patients with distal bile duct cancer. Lymph node involvement failed to affect survival adversely if no more than 2 positive nodes were detected.
This investigation was supported in part by Grant-in-Aid for Scientific Research C-2-11671255 from the Ministry of Education, Science, and Culture of Japan, Tokyo.
Presented in part at the 101st Congress of the Japan Surgical Society, Sendai, Japan, April 12, 2001.
Corresponding author and reprints: Takanori Yoshida, MD, Department of General Surgery, Nakatsu Municipal Hospital, 173 Shimoikenaga, Nakatsu, Oita 871-8511, Japan.