Orthotopic liver transplantation after extended bile duct resection as treatment of hilar cholangiocarcinoma First long-terms results

Abstract Although the surgical treatment of hilar cholangiocarcinoma represents the only potentially curative option, survival figures remain low over the long term. After hilar and partial hepatic resections for hilar cholangiocarcinoma, loco-regional tumor recurrence appears as the primary site of failure. From April 1992 to April 1996, 14 patients underwent extended bile duct resections. Extended bile duct resections combine total hepatectomy, partial pancreatoduodenectomy, and liver transplantation in an attempt to eradicate the entire biliary tract without dissecting the hepatoduodenal ligament. The postoperative 60-day mortality rate was 14% ( n = 2). The rate of curative resections was 93% (13 of 14 extended bile duct resections). One- and 4-year survival rates after curative resections were 56% and 30%, respectively. The rate of curative resections increased by combining total hepatectomy, partial pancreatoduodenectomy, and liver transplantation, i.e., extended bile duct resection. However, survival figures have not improved accordingly. Therefore, this extended surgical procedure has to be implemented with caution and possibly not without modifications (e.g., multimodal treatment).     

Surgical treatment in proximal bile duct cancer. A single-center experience.

OBJECTIVES: The authors evaluated the experience and results of a single center in surgical treatment of proximal bile duct carcinoma. SUMMARY BACKGROUND DATA: Whenever feasible, surgery is the appropriate treatment in proximal bile duct carcinoma. To improve survival rates and with special regard to liver transplantation, the extent of surgical radicalness remains an open issue. PATIENTS AND METHODS: Retrospective analysis of 249 patients who underwent surgery for proximal bile duct carcinoma via the following procedures: resection (n = 125), liver transplantation (n = 25), and exploratory laparotomy (n = 99). Survival rates were calculated according to the Kaplan-Meier method, uni- and multivariate analysis of prognostic factors, and log rank test (p < 0.05). RESULTS: Survival rates after resection and liver transplantation are correlated with international Union Against Cancer (UICC) tumor stage (resection: overall 5-year, 27.1%; stage I and II, 41.9%; stage IV, 20.7%; liver transplantation: overall 5-year, 17.1%; stage I and II, 37.8%; stage IV, 5.8%). Significant univariate prognostic factors for survival after liver resection were lymph node involvement (N category), tumor stage, tumor-free margins, and vascular invasion; for transplantation, they were local tumor extent, N category, tumor stage, and infiltration of liver parenchyma. For resection and transplantation, a multivariate analysis showed prognostic significance of tumor stage and tumor-free margins. CONCLUSION: Resection remains the treatment of choice in proximal bile duct carcinoma. Whenever possible, decisions about resectability should be made during laparotomy. With regard to the observation of long-term survivors, liver transplantation still can be justified in selected patients with stage II carcinoma. It is unknown whether more radical procedures, such as liver transplantation combined with multivisceral resections, will lead to better outcome in advanced stages. With regard to palliation, surgical drainage of the biliary system performed as hepatojejunostomy can be recommended.     

Carcinoma of the distal and middle bile duct: surgical results, prognostic factors, and long-term follow-up

BACKGROUND/PURPOSE: Carcinoma of the distal bile duct is associated with poor prognosis. Surgical resection remains the only potentially curative treatment. We conducted a retrospective study to identify prognostic factors determining longterm survival. METHODS: From 1990 to 2006, 95 patients with distal and/or middle bile duct carcinoma had resections. Fifty-four patients underwent pylorus-preserving pancreaticoduodenectomy (57%) and 41 patients underwent standard Kausch-Whipple pancreaticoduodenectomy (43%). Nine patients underwent pancreaticoduodenectomy including portal vein resection (9%). RESULTS: Overall 1-, 3-, and 5-year survival rates were 60%, 36%, and 29%, respectively. Five-year survival after R0 resection was 34%, and after R1 resection it was 0%. Four patients died during their hospital stay (4%). Multivariate analysis showed negative resection margins (P = 0.040), lymphatic vessel invasion (P = 0.036), and portal vein infiltration (P = 0.027) as strong predictors for survival, whereas the location of the tumor (distal bile duct vs middle bile duct) and lymph node status were not identified as independent prognostic factors. CONCLUSIONS: Five-year survival depends strongly on negative resection margins, independent of nodal status. Portal vein resections in patients with portal vein involvement fail to ameliorate long-term survival. Primary tumor site--middle bile duct or distal bile duct--did not determine prognosis.     

Liver transplantation for hilar cholangiocarcinoma

Hilar cholangiocarcinoma was accepted as an indication for liver transplantation at the beginning of the transplantation era. Owing to disappointing long-term results for this indication, and in parallel, encouraging results in patients with benign disease, hilar cholangiocarcinoma has generally not been accepted as an indication for liver transplantation in recent years. To improve results, more aggressive approaches have been used: “abdominal organ cluster transplantation” and “extended bile duct resection”, which lead to increased long-term survival rates. However, with improving results after conventional extrahepatic bile duct resection in combination with partial hepatectomy, extended procedures in combination with liver transplantation never became a real option in the treatment of hilar cholangiocarcinoma. However, new awareness of liver transplantation in the treatment of this cancer has been raised for patients with hilar cholangiocarcinoma in the context of underlying liver diseases such as primary sclerosing cholangitis, which preclude liver resection. Current results show increased survival figures, in particular in well-selected patients with early tumor stages. Further improvements in long-term survival may be reached with new adjuvant and neoadjuvant protocols. Patients with neoadjuvant radiochemotherapy show long-term results similar to those for liver transplantation for other indications. Also, photodynamic therapy and the use of new antiproliferative immunosuppressive agents may be an approach for further improvement of the long-term results. Currently, liver transplantation for the treatment of hilar cholangiocarcinoma should be restricted to centers with experience in the treatment of this cancer and should be taken into consideration in patients with contraindications to liver resection.     

Zentrales Gallengangskarzinom (Klatskin-Tumor)

Perihilar cholangiocarcinoma or Klatskin tumors are a rare entity arising from the extrahepatic bile duct bifurcation. Considering the close anatomical relationship of the bile duct bifurcation with the portal vein bifurcation and hepatic arteries, surgical treatment is demanding. With an incidence of only 2–4 cases/100,000 population/year patients should be referred to a specialized center. The tumors are usually poorly differentiated adenocarcinomas growing diffusely along the duct and also the perineural sheath. Only radical surgery offers a curative option and currently surgical strategy usually consists of en bloc resection of the bile duct, extended liver resection and portal vein resection. Proximal and lateral safety margin R0 resections are technically very demanding procedures because of the local anatomy.     

Gibt es eine nichtchirurgische Therapie der Gallenwegskarzinome?

Nonsurgical treatment aims at controlling disease and improving survival and quality of life in patients with nonresectable, recurrent metastatic cholangiocarcinomas. After R0 resection, percutaneous or intraluminal radiotherapy with adjuvant radiochemotherapy may improve survival. Available data, however, are still unsatisfactory, and the efficacy of adjuvant radiochemotherapy after R0 resection remains to be confirmed. Exclusive chemotherapy fails to improve survival postoperatively while, in adequate patients, neoadjuvant chemotherapy can improve R0 resection results. Palliative chemotherapy yielded improved survival and quality of life in only one small prospective randomized trial and cannot be generally recommended at present. Previous biliary stenting for relieving jaundice is mandatory. Beyond established regimens employing 5-fluorouracil/leukovorin and gemcitabine plus platin-based agents, ongoing trials are focussing on topoisomerase-and thyrosine kinase inhibitors. Palliative stenting of malignant bile duct stenoses may eliminate or at least relieve jaundice and pruritus. Single stenting is sufficient for distal bile duct stenoses. In patients with liver metastasis and life expectancy of <6 months, temporary plastic prostheses with 4-6-month patency are sufficient. When the prognosis is for >6 months, self-expanding permanent metal stents, with their significantly longer patency, are superior. In hilar tumors, obstruction of plastic prostheses occurs earlier than in distal bile duct stenoses. Thus, patients with Bismuth II-IV tumors benefit from self-expanding metal stents. These may be inserted by an endoscopic, retrograde approach, percutaneously, or by a combined rendez-vous maneuver. The superiority of bilateral vs unilateral stenting has yet to be proven in Bismuth II-IV tumors. Photodynamic therapy followed by stenting appears to improve survival rates by delaying stent occlusion rather than by regression of the tumoric disease itself.     

Primary and secondary hepatic manifestation of neuroendocrine tumors

BACKGROUND: In comparison with most other malignancies, in the treatment of metastatic neuroendocrine tumors one also has to consider endocrine symptoms and natural progression of disease. Since hepatic metastasis predominates and endocrine symptoms correlate with functional tumor mass, hepatic resection may improve prognosis or even cure patients. PATIENTS AND METHODS: We reviewed 41 consecutive patients with metastatic neuroendocrine tumors and four patients with primary hepatic disease presenting between 1989 and 1999. The neuroendocrine tumors were classified according to their origin, pattern of metastasis, endocrine activity, and histology. Operative therapy including hepatic resections of different extent, liver transplantation, and removal of the primary tumor was analyzed. The median survival after initial diagnosis and after hepatic resection were major parameters of outcome. RESULTS: There were 26 low-grade malignant, 12 high-grade malignant, 2 biphasically differentiated neuroendocrine carcinomas, and 5 pancreatic endocrine tumors. Hepatic resections were performed in 25 patients, resections of the primary tumor in 40 patients. The median survival after initial diagnosis was 49 months; 50.5 months in patients with hepatic resection versus 47 months in those with no liver surgery. CONCLUSION: Hepatic resection improved the outcome of patients with liver metastasis due to neuroendocrine tumors tendentiously but not significantly.     

A combination surgical-radiological approach for the treatment of carcinoma of the hepatic duct bifurcation with involvement of both hepatic duct trunks]

The only curative treatment to proximal bile duct cancers with involvement of both hepatic ducts is liver transplantation. A curative resection with wide lateral clearance is limited due to the neighbourhood of vital anatomic structures in the liver hilum. The majority of patients with bile duct cancers is over 60 years of age and due to concomitant disease, they do not fulfill the requirements for liver transplantation. Our treatment strategy in adequate cases is palliative tumor resection and reconstruction of bile passage by sutureless biliodigestive anastomosis as proposed by Rodney Smith. We treated 11 patients with this method, in 5 patients an additive combined radiotherapy by percutaneous radiation and intraluminal after-loading therapy was performed. Our results indicate that this strategy leads to effective palliation in cases provided that only microscopic residual tumor is left in situ (R1-resection). Our observed survival times compare favorably to survival times after liver transplantation (average survival time 11.5 months median survival time 10 months).     

H2-receptor antagonists and the incidence of gastroduodenal ulcer perforation and hemorrhage. An epidemiological study

The only curative treatment to proximal bile duct cancers with involvement of both hepatic ducts is liver transplantation. A curative resection with wide lateral clearance is limited due to the neighbourhood of vital anatomic structures in the liver hilum. The majority of patients with bile duct cancers is over 60 years of age and due to concomitant disease, they do not fulfill the requirements for liver transplantation. Our treatment strategy in adequate cases is palliative tumor resection and reconstruction of bile passage by sutureless biliodigestive anastomosis as proposed by Rodney Smith. We treated 11 patients with this method, in 5 patients an additive combined radiotherapy by percutaneous radiation and intraluminal after-loading therapy was performed. Our results indicate that this strategy leads to effective palliation in cases provided that only microscopic residual tumor is left in situ (R1-resection). Our observed survival times compare favorably to survival times after liver transplantation (average survival time 11.5 months median survival time 10 months).     

Hepatic resection for primary and metastatic tumors

Thirty-four hepatic resections were performed on 33 patients. These included 4 trisegmentectomies, 14 lobectomies, 7 segmentectomies, and 9 wedge resections. Twenty patients had metastatic colorectal cancer, 4 had a primary liver tumor, 2 had giant cavernous hemangioma, 1 had metastatic leiomyosarcoma, 5 had various benign lesions including focal nodular hyperplasia, and 1 patient had resection for trauma. Operative morbidity included four subphrenic abscesses, one bile leak, one bile duct injury, one case of cholestasis, and one case of phlebitis. There were no operative deaths. The median survival of the patients with metastatic colorectal cancer was 40 months, and the 5-year actuarial survival rate was 35 percent. Survival rates were not significantly different between patients with a solitary metastasis and those with multiple lesions and was not influenced by size of the metastases. However, survival was significantly better in patients whose primary colorectal lesion was Dukes' B as compared with those whose lesion was Dukes' C. The results indicate that liver resection can be performed safely with acceptable morbidity and improved long-term survival.     

Prognosis and therapy of primary epithelial liver tumors. Evaluating a personal patient sample

Prognostically relevant factors and treatment were analysed in 103 patients suffering from primary epithelial liver tumors (88 HCC, 15 CCC). Ninety of them underwent operations: 14 liver transplantations, 32 resections, 44 explorative laparotomies. The resection rate was 38%, the 30-day mortality in transplantation 14%, in resection 22%. The 5-year survival after resection was about 25%. Liver transplantation resulted in 50% 1-year and 40% 2-year survival. Long-term prognosis was positively influenced by cirrhosis and formation of a tumor capsule. Indications for operative management depend only on extension of tumor growth and concomiting liver cirrhosis as biology of epithelial liver tumors is poorly understood.     

Resective operations for biliary carcinoma

Records of 25 consecutive patients who underwent resection for proximal bile duct tumor (3 extended right hepatic lobectomies, 6 left hepatic lobectomies, 16 skeletonization resections) and records of 21 patients who underwent pancreatoduodenectomy for distal bile duct carcinoma were reviewed to assess the value of resective therapy. The operative mortality rate for patients with resected proximal bile duct tumor was 4 per cent (0 per cent for liver resection) and that of distal bile duct tumor, 4.6 per cent. The 3- and 5-year actuarial survival rates for patients with proximal bile duct tumor were 44 per cent and 35 per cent, respectively; all except one patient eventually died of disease. Survival was better for patients who had curative resection (margins microscopically free of tumor). The 5-year actuarial survival rate for patients with distal bile duct carcinoma was 58±12 (SE) per cent, with patients who had negative nodes surviving longer than patients with positive nodes. When major hepatic resection and pancreatoduodenectomy can be performed in selected patients with low operative mortality, patients with bile duct carcinoma should be assessed by an experienced hepatobiliary multidisciplinary group before a decision is made in favor of palliative, endoscopic, or percutaneous techniques because surgical resection appears to offer the best possible long-term survival and probably the best quality of palliation. This report is the basis of a paper read by R.L.R. at the 90th Annual Meeting of the Japanese Surgical Society, Sapporo, Japan, 1990     

One hundred and eleven liver resections for hilar bile duct cancer

A positive correlation between absence of residual tumor at resection margins and long-term survival in the treatment of hilar bile duct carcinoma has encouraged some surgeons to use a more radical approach, including liver/portal vein resection and combined pancreatoduodenectomy. However, if liver resection is associated with significant morbidity and mortality, it may not produce any overall benefit. This review was undertaken in an attempt to determine whether liver resection is a safe procedure and whether if has any beneficial effect over that of local bile duct excision alone, in terms of achieving curative resection and long-term survival. The records of 151 patients with hilar bile duct carcinoma surgically treated between June 1989 and December 1997 at the Asan Medical Center, Seoul, were retrospectively analyzed. Surgical resection was possible in 128 patients. The remaining 23 patients had surgical palliative drainage. Local bile duct excision alone was performed in 17 patients. Liver resection for tumor extending to secondary bile ducts or hepatic parenchyma was performed in 111 patients; portal vein resection was necessary in 29 of these 111 patients (26.1%) and pancreatoduodenectomy was combined in 18 patients (16.2%). Seven patients died during hospitalization after liver resection, an operative mortality of 6.3%. Margins of bile duct resection were free of tumor on histologic examination in 4 of the 17 local bile duct excisions, but in 86 of the 111 liver resections. The cumulative survival rate after local bile duct excision was 85.7% at 1 year, 42.9% at 2 years, 21.4% at 3 years, and 0% at 4 years. However, the survival rate after liver resection (excluding operative mortality) was 97.1% at 1 year, 72.8% at 2 years, 55.3% at 3 years, and 24.0% at 5 years. Survival and the percentage of patients with tumor-free resection margins after liver resection were superior to those after local bile duct excision. Resection of hilar bile duct carcinoma offers long-term survival only when surgery is aggressive and includes liver resection. Received for publication on July 2, 1998; accepted on July 5, 1998     

胆管类癌32例并文献复习

目的探讨肝外胆管类癌的临床特征和临床诊治。方法报告2例胆总管类癌并结合文献报道30例;对32例肝外胆管类癌进行分析。结果肝外胆管类癌临床少见,32例中女性23例,男性9例,发病年龄平均为49岁(19～79)岁。临床表现梗阻黄疸最为常见,占55%。肿瘤局限于胆管内为71%,诊断时己有远处转移的为29%,其肿瘤局限于胆管内病例3年存活率为100%。结论肝外胆管类癌与胆管腺癌不同,其发病年龄年轻(平均为49岁),并好发于女性。肿瘤的局部浸润为主,很少发生远处转移,根治切除后可获长期生存,对胆管类癌应行积极的根治切除。     

Incidence and management of bile leakage after hepatic resection for malignant hepatic tumors

BACKGROUND: Bile leakage is one of the frequent and disturbing complications of hepatic resection. STUDY DESIGN: Clinical records of the 363 patients who underwent hepatic resections without biliary reconstruction for hepatic cancers between January 1994 and June 2001 were reviewed. Postoperative bile leakage was defined as continuous drainage with a bilirubin concentration of 20 mg/dL or 1,500 mg/d lasting 2 days. Leakage that continued longer than 2 weeks or that required surgical intervention was defined as uncontrollable. Differences in incidence and frequency of uncontrollable leakage for the different types of hepatic resection, tumors, and underlying liver disease were investigated. Outcomes after treatment for uncontrollable bile leakage were also reviewed. RESULTS: Postoperative bile leakage occurred in 26 of 363 patients (7.2%). Although the incidence in patients with cholangiocellular carcinoma (3/9 [33%]) was higher (p = 0.03) than in patients with hepatocellular carcinoma, rates of occurrence were similar among the different types of hepatic resection and underlying liver disease. Eight of the 26 patients (31%) had uncontrollable leakage. Two patients required reoperation to control leakage; one of these developed hepatic failure and died 2 months after surgery. Four patients underwent endoscopic nasobiliary drainage 21 to 34 days after hepatectomy, and the leakage resolved within 3 to 21 days. Fibrin glue sealing was effective in two patients whose leaking bile ducts were not connected to the common bile duct. CONCLUSIONS: Although meticulous surgical technique can minimize the risk of postoperative bile leakage, some instances of leakage are unavoidable. Nonsurgical treatments, such as nasobiliary drainage or fibrin glue sealing, are preferable to reoperation.     

Liver resection and transplantation — Therapeutic concepts in surgical treatment of hepatic metastases

Summary Background: Surgical procedures such as liver resection or liver transplantation are the only treatment modalities that provide a chance of cure for patients with liver metastases. Methods: This report reviews results of liver resection and liver transplantation for liver metastases from colorectal cancer and neuroendocrine tumors as compared to the natural course. Results: Overall 5 year survival after curative liver resection for colorectal metastases ranges between 25 and 48%. The operative mortality is between 0 and 5%. Risk factors for tumor recurrence are more or less defined. Reresections of metastases can be performed with comparable mortality rates and results. Liver transplantation for unresectable colorectal metastases offers a median survival of 28 months, but the chance of cure only for individual patients. Exclusion of patients with positive lymph nodes of the primary tumor improves median survival. As there are alternative treatment options for neuroendocrine metastases, indication for liver resection or transplantation is not clearly defined, but the chance of cure by means of surgical treatment should not be missed. Curative resections of neuroendocrine liver metastases can achieve 5-year survival rates of more than 80%. Conclusions: Radical surgical removal of liver metastases from colorectal and neuroendocrine cancer can improve the prognosis for selected patients. Further improval is expected from a multimodal approach.      

肝叶切除术在肝门部胆管癌治疗中的作用

目的探讨肝叶切除术在肝门部胆管癌治疗中的作用。方法回顾性分析了１９９１年１月～１９９５年１２月间收治的５２例肝门部胆管癌的临床资料。结果５２例中手术切除１７例,切除率３２７％,手术死亡率为５９％。切除组中１４例兼行不同范围的肝叶切除,其中８例为治愈性切除,治愈性切除组与姑息性切除组平均生存期为２１１个月和７５个月（Ｐ＜０．０５）。切除组与引流组疗效有显著性差异（Ｐ＜０．０５）。结论联合肝叶切除术可提高肝门部胆管癌的治愈性切除率,改善术后病人的预后。     

Multimodal treatment strategies for advanced hilar cholangiocarcinoma

Cholangiocarcinoma (CCA) is the second most common primary malignancy of the liver arising from malignant transformation and growth of biliary ductal epithelium. Approximately 50–70 % of CCAs arise at the hilar plate of the biliary tree, which are termed hilar cholangiocarcinoma (HC). Various staging systems are currently employed to classify HCs and determine resectability. Depending on the pre-operative staging, the mainstays of treatment include surgery, chemotherapy, radiation therapy, and photodynamic therapy. Surgical resection offers the only chance for cure of HC and achieving an R0 resection has demonstrated improved overall survival. However, obtaining longitudinal and radial surgical margins that are free of tumor can be difficult and frequently requires extensive resections, particularly for advanced HCs. Pre-operative interventions may be necessary to prepare patients for major hepatic resections, including endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, and portal vein embolization. Multimodal therapy that combines chemotherapy with external beam radiation, stereotactic body radiation therapy, bile duct brachytherapy, and/or photodynamic therapy are all possible strategies for advanced HC prior to resection. Orthotopic liver transplantation is another therapeutic option that can achieve complete extirpation of locally advanced HC in judiciously selected patients following standardized neoadjuvant protocols.     

Resective operations for biliary carcinoma

Records of 25 consecutive patients who underwent resection for proximal bile duct tumor (3 extended right hepatic lobectomies, 6 left hepatic lobectomies, 16 skeletonization resections) and records of 21 patients who underwent pancreatoduodenectomy for distal bile duct carcinoma were reviewed to assess the value of resective therapy. The operative mortality rate for patients with resected proximal bile duct tumor was 4 per cent (0 per cent for liver resection) and that of distal bile duct tumor, 4.6 per cent. The 3- and 5-year actuarial survival rates for patients with proximal bile duct tumor were 44 per cent and 35 per cent, respectively; all except one patient eventually died of disease. Survival was better for patients who had curative resection (margins microscopically free of tumor). The 5-year actuarial survival rate for patients with distal bile duct carcinoma was 58 +/- 12 (SE) per cent, with patients who had negative nodes surviving longer than patients with positive nodes. When major hepatic resection and pancreatoduodenectomy can be performed in selected patients with low operative mortality, patients with bile duct carcinoma should be assessed by an experienced hepatobiliary multidisciplinary group before a decision is made in favor of palliative, endoscopic, or percutaneous techniques because surgical resection appears to offer the best possible long-term survival and probably the best quality of palliation.     

Macroscopic intrabiliary growth of liver metastases from colorectal cancer

BACKGROUND: The clinicopathologic features of colorectal liver metastases that invade the bile duct were evaluated. METHODS: From 1992 to 1996, 149 patients who underwent a first hepatic resection were studied for a total of 377 colorectal liver metastases. Twenty-one second hepatic resections in these patients were also analyzed. RESULTS: Bile duct invasion was histologically observed in 62 (42%) of 149 patients with first colorectal liver metastasis. Eighteen patients (12%) had gross extension of the tumor in the bile duct ranging from 4 mm to 42 mm (median 17.0 mm). Histologically, two thirds (12 of 18) of the tumors with macroscopic bile duct invasion were well-differentiated adenocarcinomas with a tendency for less vascular involvement. The actuarial 3- and 5-year survivals were 62% and 57% for patients with no bile duct invasion, 56% and 48% for patients with microscopic bile duct invasion, and 94% and 80% for patients with macroscopic bile duct invasion. The 5-year survival rate was better for patients with macroscopic bile duct invasion than for those with only microscopic (P = .02) or no bile duct invasion (P = .03). In a multivariate analysis, macroscopic bile duct invasion was an independent prognostic variable for favorable outcome after hepatic resection. CONCLUSIONS: Macroscopic bile duct invasion of colorectal liver metastases may reflect an indolent biologic behavior, warrants an aggressive surgical approach, and confers a better prognosis.