Role of liver transplantation in the management of unresectable neuroendocrine liver metastases

The use of OLT in the management of liver metastases of any origin is highly controversial, as most patients receiving a transplant for this indication display poor results owing to early tumor spread secondary to the effects of immunosuppression. However, as they have a better biological behavior, neuroendocrine (NE) tumors may be a good indication for OLT. Our aim was to present our experience in the management of unresectable liver metastases of tumors of NE origin. PATIENTS AND METHODS: Between January 1996 and April 2006, 10 patients underwent OLT for unresectable liver metastases of a neuroendocrine origin, accounting for 1.2% of all transplants performed to date in our unit (n = 626). The most common location of the primary tumor was the pancreas in six cases: three in the pancreatic tail--one carcinoid tumor, one gastrinoma, and one nonfunctioning NE [NF-NE] tumor; and three cases in the pancreatic head--three NF-NE tumors. In the remaining four cases, including three carcinoid tumours and one NF-NE tumors, two were located in the small bowel (at the ileum and ileocecal valve) and two in the lung. The liver metastases were synchronous with the primary tumor in seven cases and metachronous in three cases. RESULTS: The morbidity rate was 75% and the mortality rate, 10% (n = 1). The tumor recurrence rate was 33% with 1- and 3-year survival rates of 86% and 57%, respectively.     

Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors.

Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tumors metastatic only to the liver. In this consecutive series of 15 patients (5 multivisceral and 10 orthotopic liver transplantations) with well-differentiated carcinoids, or endocrine pancreatic tumors, we allowed higher proliferation rate (Ki67 <10%), large tumor burden, and higher age than previous studies. Liver transplantation offered good relief of symptoms, long disease-free intervals, and potential cure in individual patients. The survival of grafts and patients compared well with transplantation for benign disease. The overall 5-year survival was 90%. The recurrence-free survival of both multivisceral and liver transplantation related to the time after transplantation (about 20% at 5 years) despite inclusion of patients with higher risk. In conclusion, the critical prognosticators for long-term outcome still remain to be defined. The experience with multivisceral transplantation for patients with endocrine tumors of the pancreatic head is still limited.     

Liver transplantation for metastatic neuroendocrine tumors.

OBJECTIVE: This article describes the experience with liver transplantation in patients with irresectable neuroendocrine hepatic metastases. SUMMARY BACKGROUND DATA: Liver transplantation has become an established therapy in primary liver cancer. On contrast, there is little experience with liver transplantation in secondary hepatic tumors. So far, in the majority of patients being transplanted for irresectable liver metastases, long-term results have been disappointing because of early tumor recurrence. Because of their biologically less aggressive nature, the metastases of neuroendocrine tumors could represent a justified indication for liver grafting. METHODS: In a retrospective study, the data of 12 patients who underwent liver transplantation for irresectable neuroendocrine hepatic metastases were analyzed regarding survival, tumor recurrence, and symptomatic relief. RESULTS: Nine of 12 patients currently are alive with a median survival of 55 months (range, 11.0 days to 103.5 months). The operative mortality was 1 of 12, 2 patients died because of septic complications or tumor recurrences or both 6.5 months and 68.0 months after transplantation. all patients had good symptomatic relief after hepatectomy and transplantation. Four of the nine patients who are alive have no evidence of tumor with a follow-up of 2.0, 57.0, 58.0, and 103.5 months after transplantation. CONCLUSIONS: In selected patients, liver transplantation for irresectable neuroendocrine hepatic metastases may provide not only long-term palliation but even cure. Regarding the shortage of donor organs, liver grafting for neuroendocrine metastases should be considered solely in patients without evidence of extrahepatic tumor manifestation and in whom all other treatment methods are no longer effective.     

Aggressive surgery for metastatic liver neuroendocrine tumors

BACKGROUND: Neuroendocrine tumors of the gastrointestinal tract (carcinoids, pancreatic endocrine tumors) have low malignant potential but can decrease survival rates if they spread to the liver (LNET). METHODS: The records of 16 patients with LNET primarily from gastrointestinal carcinoids treated surgically were retrospectively reviewed. RESULTS: There were 12 women and 4 men. Median age was 56 years (range 25 to 75). Thirteen (81%) had a carcinoid tumor and 5 had gastrinoma. Two patients with multiple endocrine neoplasia type 1 had both a gastric carcinoid and a jejunal gastrinoma. Eight patients (50%) had the carcinoid syndrome. Each patient had all identifiable LNET either resected or ablated. Ten patients had liver wedge resections, 1 right trisegmentectomy, 5 left hepatic lobectomies, and 2 radiofrequency ablations. Thirteen (81%) patients had concomitant bowel resections. Two patients had concomitant total gastrectomies to remove stomach primaries. The final patient had an extraintestinal pelvic primary or a liver primary. There were no operative deaths, and all 8 (100%) patients with the carcinoid syndrome had amelioration of symptoms. The 5-year actuarial survival rate was 82% with a median follow-up of 32 months. CONCLUSIONS: This study demonstrates that liver and concomitant extrahepatic surgery can be performed safely in patients with liver metastases because of carcinoids or pancreatic endocrine tumors. It results in excellent long-term survival and amelioration of symptoms. Surgery should be the first-line therapy for patients with LNET.     

Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. A 31-case French multicentric report.

OBJECTIVE: The purpose of this study was to assess the value and timing of orthotopic liver transplantation (OLT) in the treatment of metastatic neuroendocrine tumors (NET). SUMMARY BACKGROUND DATA: Liver metastasis from NET seems less invasive than other secondary tumors. This observation suggests that OLT may be indicated when other therapies become ineffective. However, the potential benefit of this highly aggressive procedure is difficult to assess due to the scarcity and heterogeneity of NET. METHODS: A retrospective multicentric study was carried out, including all cases of OLT for NET performed in France between 1989 and 1994. There were 15 cases of metastatic carcinoid tumor and 16 cases of islet cell carcinomas. Hormone-related symptoms were present in 16 cases (55%). Only 5 patients (16%) had no previous surgical or medical therapy before OLT. Median delay from diagnosis of liver metastasis and OLT was 19 months (range, 2 to 120). RESULTS: The primary tumor was removed at the time of OLT in 11 cases, by upper abdominal exenteration in 7 cases and the Whipple resection in 3. Actuarial survival rate after OLT was 59% at 1 year, 47% at 3 years, and 36% at 5 years. Survival rates were significantly higher for metastatic carcinoid tumors (69% at 5 years) than for noncarcinoid apudomas (8% at 4 years), because of higher tumor- and non-tumor-related mortality rates for the latter. CONCLUSION: OLT can achieve control of hormonal symptoms and prolong survival in selected patients with liver metastasis of carcinoid tumors. It does not seem indicated for other NET.     

Indications and results of liver transplantation in patients with neuroendocrine tumors

Metastases from neuroendocrine (NE) tumors of the gastrointestinal tract, carcinoids, and endocrine pancreatic tumors (EPTs) can be confined to the liver for long periods and may exhibit slow growth. When considering liver transplantation (LTx) for patients with NE tumors, the expected results with conventional treatment must be weighed against the risk of LTx and immunosuppression. The following indications for LTx may be considered for patients with metastatic NE tumors limited to the liver: (1) tumors not accessible to curative surgery or major tumor reduction; (2) tumors not responding to medical or interventional treatment; and (3) tumors causing life-threatening hormonal symptoms. We excluded patients with poorly differentiated NE carcinoma or well differentiated NE carcinoma with a high proliferation index (Ki 67 > 10%). Over 4 years (1997–2001) we have performed transplants in nine patients (five with EPTs, four with carcinoids) with a mean ± SEM follow-up of 22 ± 5 months (range 4–45 months). Seven patients underwent orthotopic LTx and two multivisceral LTx. Eight patients are alive, six without clinical evidence of disease. Four patients developed recurrent tumors 9 to 36 months after LTx; two were detected at an early stage and underwent resection with curative intent. One patient with multivisceral Tx died after 4 months of posttransplant lymphoproliferative disease without tumor recurrence. In selected series LTx can offer good control of hormonal symptoms, a relatively long disease-free interval, and in individual cases potential cure.     

Liver transplantation for neuroendocrine tumors

Liver transplantation for the treatment of metastatic neuroendocrine tumors (NETs) is radical. Although cure is not impossible, it is improbable. The reported experience with transplantation for NETs is limited to less than 150 cases with widely varying results and few 5-year disease-free survivors. We reviewed our experience with transplantation for patients with NETs. Fourteen symptomatic patients with unresectable NET liver metastases who had failed medical management were listed for transplantation. Two patients listed for transplantation underwent prior right lobectomies. Three patients were listed but did not undergo transplantation: one was lost to follow-up, one died 14 months after listing, and one remains waiting over 4 years. Eleven patients underwent liver transplantation, three with living donor grafts. There were four men (36.4%) and seven women (63.6%) who had a mean age of 51.2 ± 6.3 years. Three patients had distal pancreatectomies and one patient had a Whipple procedure at the time of transplantation. There were six nonfunctioning tumors (54.6%), three carcinoid tumors (27.3%), and two (18.2%) Vipomas. In one patient, with fulminant hepatic failure, the NET was an incidental finding in the explant. The 1- and 5-year survival among transplanted patients is 73% and 36%, respectively, with a mean follow-up of 34 ± 40 months (range 0 to 119 months). Of the three patients surviving more than 5 years, only one was disease free. In carefully selected patients with metastatic NETs, liver transplantation may be an appropriate option. Presented in part at the Fourth Americas Congress of the American Hepato-Pancreatico-Biliary Association, Miami, Florida, February 28, 2003.     

Orthotopic liver transplantation for carcinoid tumour metastatic to the liver: anesthetic management

PURPOSE: To report the anesthetic management of a patient with carcinoid tumour metastatic to the liver who presented for orthotopic liver transplantation. Anesthetic implications of metastatic carcinoid tumour on liver transplantation and the use of octreotide are discussed. CLINICAL FEATURES: A 51-yr-old woman with intestinal carcinoid tumour metastatic to the liver presented for orthotopic liver transplantation, a recent treatment option for patients with extensive hepatic carcinoid metastases and disabling symptoms unresponsive to conventional therapy. Despite continuous administration of the somatostatin analogue octreotide via a hepatic artery infusate pump, the patient suffered from daily break through symptoms, which included flushing, palpitations, paroxysmal hypertension, and dyspnea. The patient presented to the operating room with sinus tachycardia and severe arterial hypertension. Octreotide and phentolamine were used to prevent further mediator release and to control the paroxysmal hypertension. Midazolam, fentanyl, thiopental, succinylcholine, vecuronium, and isoflurane were used to induce and maintain anesthesia safely. An intravenous octreotide infusion was initiated after induction and continued throughout the case. Infrequent and non-threatening peaks in arterial blood pressure were readily treated with small intravenous doses of vasoactive drugs and octreotide. No other manifestations of the carcinoid syndrome occurred. The patient had an uneventful recovery and was discharged on postoperative day #6. CONCLUSION: The patient safely underwent orthotopic liver transplantation for treatment of symptomatic carcinoid tumour metastatic to the liver. The anesthetic management followed recent recommendations favouring the use of octreotide to prevent patients from becoming symptomatic. Outlined dosing regimen for octreotide provided satisfactory hemodynamic stability.     

Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors

BACKGROUND: We reviewed 36 patients with liver metastases from islet cell tumors of the pancreas (n = 18) and carcinoid tumors (n = 18) who were treated with surgical resection (n = 16) or hepatic chemoembolization (n = 20). METHODS: All resections were complete and included 4 lobectomies, 6 segmental resections, and 6 wedge resections. There were no operative deaths. RESULTS: Median survival has not yet been reached, and the actuarial 5-year survival rate is 70%. Prognostic variables associated with improved disease-free survival included prior resection of the primary tumor and 4 or fewer metastases resected (P <.05). With an average of 3 chemoembolization procedures per patient, 17 of 20 patients (90%) demonstrated either a significant radiographic response (n = 5), stabilization of tumor mass (n = 2), or improvement of clinical symptoms (n = 10). Factors related to a sustained response (more then 1 year) included surgical resection of the primary tumor, 4 or more chemoembolization procedures, and liver metastases of 5 cm or smaller. Median survival after treatment was 32 months (range, 7-63 months), and the actuarial 5-year survival rate was 40%. CONCLUSIONS: Surgical resection of metastatic neuroendocrine tumors provides the best chance for extended survival. Chemoembolization effectively improves clinical symptoms and, in selected patients, may provide sustained tumor control.     

Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors

BACKGROUND: Patients suffering from hepatic metastases of neuroendocrine tumors (NET) are potential candidates for orthotopic liver transplantation. Because recurrence rates are high and outcome is variable, prognostic indicators are required. The aim of our study was to identify predictors of long-term survival with a focus on the impact of tumor biology. METHODS: We retrospectively analyzed 19 patients who received an orthotopic liver graft for metastatic NET at the Medizinische Hochschule Hannover. Expression of Ki67, E-cadherin, and p53 was studied immunohistochemically in metastases of neuroendocrine tumors of the explanted livers. RESULTS: Patients were followed up to 146 months after liver transplantation. Six patients died during follow-up. The resulting 1-, 5-, and 10-year survival rates are 89%, 80%, and 50%, respectively. All deaths during long-term follow-up were tumor-associated. Recurrence was diagnosed in 12 patients between 2 weeks and 48 months after liver transplantation. Three patients are without tumor recurrence more than 8 years after liver transplantation. Survival in the 5 patients with low Ki67 and regular E-cadherin staining was significantly better than in the 12 patients with high Ki67 or aberrant E-cadherin expression (7-year survival 100% vs. 0%, respectively, log rank P=0.007). p53 expression did not significantly improve prognostic accuracy. CONCLUSIONS: We conclude that analysis of Ki67 and E-cadherin expression may improve the identification of patients with a favorable prognosis after liver transplantation for metastatic neuroendocrine tumors.     

Surgical management of pancreatic neuroendocrine tumors

This study outlines the surgical management and clinicopathological findings of pancreatic neuroendocrine tumors (P-NETs). There are various surgical options, such as enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatoduodenectomy, and duodenum-preserving pancreas head resection. Lymph node dissection is performed for malignant cases. New guidelines and classifications have been proposed and are now being used in clinical practice. However, there are still no clear indications for organ-preserving pancreatic resection or lymph node dissection. Hepatectomy is the first choice for liver metastases of well-differentiated neuroendocrine carcinoma without extrahepatic metastases. On the other hand, cisplatin-based combination therapy is performed as first-line chemotherapy for metastatic poorly differentiated neuroendocrine carcinoma. Other treatment options are radiofrequency ablation, transarterial chemoembolization/embolization, and liver transplantation. Systematic chemotherapy and biotherapy, such as that with somatostatin analogue and interferon-α, are used for recurrence after surgery. The precise surgical techniques for enucleation of the tumor and spleen-preserving distal pancreatectomy are described.     

Surgery for metastatic neuroendocrine tumors with occult primaries

Introduction

Neuroendocrine tumors (NETs) frequently metastasize prior to diagnosis. Although metastases are often identifiable on conventional imaging studies, primary tumors, particularly those in the midgut, are frequently difficult to localize preoperatively.

Materials and methods

Patients with metastatic NETs with intact primaries were identified. Clinical and pathologic data were extracted from medical records. Primary tumors were classified as localized or occult based on preoperative imaging. The sensitivities and specificities of preoperative imaging modalities for identifying the primary tumors were calculated. Patient characteristics, tumor features, and survival in localized and occult cases were compared.

Results

Sixty-one patients with an intact primary tumor and metastatic disease were identified. In 28 of these patients (46%), the primary tumor could not be localized preoperatively. A median of three different preoperative imaging studies were utilized. Patients with occult primaries were more likely to have a delay (>6 mo) in surgical referral from time of onset of symptoms (57% versus 27%, P = 0.02). Among the 28 patients with occult primary tumors, 18 (64%) were found to have radiographic evidence of mesenteric lymphadenopathy corresponding, in all but one case, to a small bowel primary. In all but three patients (89%), the primary tumor could be identified intraoperatively.

Conclusion

The primary tumor can be identified intraoperatively in a majority of patients with metastatic NETs, irrespective of preoperative localization status. Referral for surgical management should not, therefore, be influenced by the inability to localize the primary tumor.     

Role of liver transplantation in management of esophageal variceal hemorrhage

The management of esophageal variceal hemorrhage ranges from conservative to surgical modalities. Before introduction of liver transplantation as a potentially curative therapy of the underlying etiology, decompressive portosystemic shunt operations have been the mainstay of mostly palliative procedures Our own experience with surgery for advanced hepatic disease and portal hypertension over 20 years includes 803 liver transplantations and 201 portosystemic shunts, emphasizing our primary objective of treatment. The results after shunt surgery were favorable in Child class A candidates when performed electively and with selective decompression. After liver replacement the clinical status of the patient, including hepatic function and extrahepatic complications, had a strong influence on postoperative outcome, with the chance of excellent long-term survival. The additional risk of previous shunt surgery for subsequent transplantation could be reduced over time. Based on this experience and reports from others there are enough reasonable arguments for shunt and transplantation. Instead of the choice being controversial, the two forms of therapy should supplement each other and be available in the same center that specializes in the treatment of patients with diseases that eventually lead to liver failure and portal hypertension Selection of either approach must depend on etiology, stage of the disease, and proper timing. Shunt procedures may be indicated in stable patients with the risk of bleeding after sclerotherapy failure, in those with contraindications to transplantation, or as a bridge to transplantation. The role of liver transplantation has been clearly established in patients with progressive or endstage (otherwise intractable) hepatobiliary disease.

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Resumen El manejo de la hemorragia por várices esofágicas va desde una modalidad conservadora hasta la intervención quirúrgica. Antes de la introducción del trasplante de hígado como una forma de terapia potencialmente curativa de la causa etiológica primaria, las operaciones de descompresión porta-sistémicas eran la modalidad de preferencia entre los procedimientos quirúrgicos fundamentalmente paliativos.Nuestra propia experiencia con la cirugía en pacientes con enfermedad hepática avanzada e hipertensión portal en más de 20 años, incluye 803 trasplantes hepáticos y 201 shunts porta-sistémicos. Los resultados de los shunts fueron favorables en pacientes Child A, cuando fueron realizados en forma electiva y fueron del tipo de la descompresión selectiva. Luego de trasplante hepático, el estado clínico, del paciente, incluyendo la función hepática y las complicaciones extrahepáticas, demostró tener una fuerte influencia sobre el resultado postoperatorio, con excelente posibilidad de sobrevida a largo plazo. Se ha logrado reducir el riesgo adicional que representa un shunt realizado con anterioridad al trasplante.Nuestra experiencia y los informes de otros autores constituyen suficiente y razonable argumentación en favor de la cirugía derivativa (shunts) y trasplante. En vez de plantear controversia, se considera que estas dos modalidades terapéuticas son complementarias.

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Résumé La gamme thérapeutique de l'hémorragie par rupture de varices oesophagiennes comprend des mesures les unes conservatrices et les autres chirurgicales. Avant d'envisager la transplantation comme un moyen potentiellement curateur de l'étiologie sousjacente, les interventions visant la décompression du système portocave restent l'essentiel de l'arsenal thérapeutique palliatif. Notre expérience dans le traitement des maladies hépatiques avancées et de l'hypertension portale sur ces 20 dernières années comporte 803 transplantations hépatiques et 201 anastomoses portocaves, mettant l'accent sur nos objectifs de traitement primaire des maladies hépatiques Les résultats des anastomoses sont favorables lorsqui'il s'agit d'anastomose de décompression sélective, réalisée électivement, chez les patients du stade Child A. Après transplantation, hépatique, l'état clinique du patient, sa fonction hépatique, et la survenue de complications extrahépatiques ont fortement influencé l'évolution à court et à long terme. Avec l'expérience le risque supplémentaire encouru par une chirurgie de décompression antérieure est réduite. D'après notre expérience et la littérature, il existe des arguments en faveur des deux formes de traitement, qui, en fait, sont complémentaires. Les deux modalités devraient être idéalement disponibles dans le même centre traitant des patients ayant une maladie susceptible d'évoluer soit vers une insuffisance hépatique ou une hypertension portale. La sélection d'un ou de l'autre des procédés dépend de l'étiologie, du stade de la maladie, et du moment évolutif où la thérapeutique se discute. Les anastomoses portocaves sont indiquées plutôt chez le patient stable ayant un risque d'hémorragie après sclérothérapie, en cas de contreindication ou en attendant la transplantation. Le rôle de la transplantation est bien établi chez le patient ayant une maladie hépatique évolutive ou terminale, autrement incurable.