Overview

Liver transplantation for malignancies other than hepatocellular carcinoma (HCC) remains highly controversial. Nonhepatocellular carcinomas most commonly treated with liver transplantation include cholangiocarcinoma (CCA), metastatic neuroendocrine cancer (NEC), and hepatic epithelioid hemangioendothelioma (HEHE). Single-center and multicenter results have been equivocal with discrepancies in survival and efficacy. Herein we review the results of liver transplantation for these malignancies—specifically CCA, metastatic NEC, and HEHE—with an aim to suggest guidelines for the application of liver transplantation in the treatment of these diseases.

Hilar Cholangiocarcinoma (See Chapter 50B)

CCA, the second most common primary malignant tumor of the liver, arises from the cholangiocytes of the intrahepatic and extrahepatic bile ducts. The incidence of this tumor has been estimated at 3000 to 5000 cases per year (de Groen et al, 1999; Olnes & Erlich, 2004), and the prevalence of intrahepatic disease appears to be on the rise (Shaib et al, 2004). CCA can arise within the liver, in the perihilar location, or along the extrahepatic bile duct (see Chapters 50A and 50B). CCA has three growth patterns: 1) mass-forming tumors are usually intrahepatic, 2) sclerosing tumors arise in the perihilar and extrahepatic bile ducts, and 3) polypoid tumors grow within the major intrahepatic and extrahepatic ducts. Surgical extirpation has been the standard treatment for all three tumor types.

The treatment of hilar CCA has been most troublesome because it is impossible to achieve a tumor-free (R0) margin of resection. Radical resection with partial hepatectomy was shown to improve survival (Launois et al, 1979) for patients with hilar CCA, but few patients come to medical attention with disease amenable to complete resection. Indeed, fewer than 30% of patients are candidates for resection at diagnosis because of either bilateral liver involvement, encasement of hilar vascular structures, involvement of sectoral bile ducts, and/or underlying liver disease, such as primary sclerosing cholangitis (PSC; see Chapter 41). Liver transplantation appears promising for the treatment of intrahepatic and hilar CCA, because the procedure affords a radical resection, is not limited by bilateral ductal or vascular involvement, and treats underlying liver disease.

Early Experience with Liver Transplantation

Unfortunately, early experiences with liver transplantation for the treatment of CCA were uniformly poor. Liver transplantation for both intrahepatic and hilar CCA was fraught with high recurrence rates and poor patient survival. The Cincinnati Tumor Registry reported a large multicenter analysis for patients transplanted from 1968 to 1997, wherein 1-, 3-, and 5-year patient survival rates were only 72%, 48%, and 23%, respectively (Meyer et al, 2000). The recurrence rate was 51% with a median time to recurrence of only 9.7 months. Local recurrence within the allograft was the most common initial site of recurrence (47%) followed by distant metastases to the lung (30%). Recurrence of tumor portended an extremely poor prognosis, with a median survival of only 2 months. Adjuvant therapy was not found to be beneficial, and no difference was reported in the survival rate of known tumors versus incidental tumors found at the time of orthotopic liver transplantation (OLT); results were poor for both intrahepatic and hilar tumors.

A multitude of retrospective studies have confirmed these findings. A Spanish multicenter study reported similar results for 59 patients who underwent OLT for CCA from 1988 to 2001 (Robles et al, 2004) and found 5-year survival was 30% with a 53% recurrence rate for 39 patients with hilar CCA. Results were equally poor for 23 patients with intrahepatic CCA, for which 5-year survival was 42%, and the recurrence rate was 35%. Similarly, a Scandinavian study reported a 5-year survival of 30% following OLT in a primary sclerosing cholangitis (PSC) population with early-stage CCA (Brandsaeter et al, 2004).

Several centers have reported their outcomes with incidental tumors discovered in patients undergoing transplantation for chronic liver disease. Ghali and colleagues (2005) reviewed the Canadian experience from 1996 through June 2003 and identified 10 cases, 8 arising in patients with PSC. Most of these tumors had favorable characteristics that included small size (<1 cm) and absence of perihepatic lymph node involvement; 90% were well differentiated, and 60% arose in the extrahepatic or hilar ducts. Despite the favorable characteristics, 3-year survival was only 30%. Only the University of California–Los Angeles has reported reasonable survival outcomes in incidental CCA detected in the explant after OLT (Goss et al, 1997). Ten patients with incidental CCA had a 5-year survival of 87%, which was comparable to PSC patients without CCA, although pathologic characteristics were not included in the paper. As with all other experiences, the 4 patients transplanted with known CCA had poor outcomes, and none were alive at 5 years.

A more radical approach with cluster abdominal transplantation reported by the University of Pittsburgh had equally poor results: a 3-year survival of 20% and a 57% recurrence rate (Alessiani et al, 1995). A similar experience was recently reported by Neuhaus’ team in Berlin (Seehofer et al, 2009). Sixteen patients with CCA were treated by combined liver transplantation and pancreatoduodenectomy (PD) between 1992 and 1998, and results were compared to those achieved for 8 patients who did not undergo PD, which at the time of liver transplantation was associated with significantly higher morbidity than transplantation alone. Long-term survival (>4 years) was achieved in only 3 lymph node–negative patients of 20 patients who survived the perioperative period. Neuhaus and colleagues concluded that “there is no good evidence that more radical resections alone are able to markedly improve long-term results.”

With uniformly poor results of liver transplantation for these tumors, intrahepatic and hilar CCA became widely recognized as absolute contraindications for liver transplantation. Both intrahepatic and hilar CCA are best treated by resection; unresectable disease has a prohibitively high recurrence rate after transplantation and warrants additional or palliative therapy.

Neoadjuvant Therapy and Liver Transplantation

Despite the poor results with liver transplantation alone, some patients with favorable hilar CCA—that is, those with negative margins and no regional lymph node metastases—did benefit from transplantation (Shimoda et al, 2001). In addition, a small group of patients at the Mayo Clinic treated with primary radiotherapy and chemosensitization alone, without resection, had a 5-year survival of 22% (Foo et al, 1997). Based on the known palliative efficacy of radiotherapy for CCA—and knowledge that CCA resection failures are usually due to locoregional recurrence, rather than distant metastases (Jarnagin et al, 2003)—the transplant team at the University of Nebraska pioneered a strategy of high-dose neoadjuvant brachytherapy and chemotherapy followed by liver transplantation (Sudan et al, 2002) for patients with unresectable hilar CCA.

The initial Nebraska protocol utilized high-dose intrabiliary brachytherapy, 6000 cGy, followed by daily intravenous 5-fluorouracil (5-FU) until OLT. Patients underwent operative staging when a donor liver became available for transplantation. At operation, the patients were assessed for extrahepatic metastases or regional lymph node involvement. Either finding precluded transplantation, and the donor liver was reallocated to another patient. Seventeen patients received neoadjuvant brachytherapy: 2 patients died from disease progression, and 4 were found to have extrahepatic disease at exploration; 11 patients underwent transplantation. Median survival after transplantation was 25 months; 5 (45%) were alive and disease-free at a median of 7.5 years (range, 2.8 to 14.5 years) after transplantation, 2 patients died from recurrent disease, and 4 patients died from perioperative complications. Overall survival was 30% for the 17 patients 5 years after the start of neoadjuvant therapy.

Mayo Clinic Experience

The transplant team at the Mayo Clinic embraced the concept pioneered by the team at the University of Nebraska and implemented a protocol in 1993 through a collaborative effort of oncologists, hepatologists, and surgeons. The general theory is that neoadjuvant therapy and liver transplantation should provide the best possible control of local disease. The rationale for the protocol was based on several factors: 1) the known CCA tumor response to high-dose radiotherapy; 2) hepatotoxicity of radiotherapy is obviated by liver transplantation; 3) liver transplantation achieves radical resection, including removal of residual disease following neoadjuvant therapy; 4) liver transplantation is not limited by underlying liver disease (PSC), vascular involvement, or concern about intrahepatic extension of disease; 5) neoadjuvant therapy prior to operative staging and transplantation might avoid tumor dissemination during operation; and 6) careful patient selection with operative staging prior to liver transplantation could exclude patients with advanced disease and regional lymph node metastases that are destined to develop distant metastatic disease.

Results

One hundred ninety-six patients were enrolled in the Mayo Clinic protocol from 1993 until April 10, 2010 (Fig. 97E.1). Sixteen patients died, became too debilitated for transplantation, or had disease progression prior to operative staging. Three patients underwent transplantation at other centers, and five were receiving neoadjuvant therapy and/or awaiting operative staging. One hundred seventy-two patients underwent operative staging, and 38 patients (22%) had findings precluding transplantation. After staging, 1 patient died from hepatic decompensation, 1 developed intrahepatic metastases, and 3 patients underwent transplantation at other centers. The remaining 126 patients underwent transplantation, 84 with deceased-donor grafts, 41 with living-donor grafts, and one with a domino familial amyloid donor graft.

FIGURE 97E.1 Mayo Clinic neoadjuvant therapy and liver transplantation for hilar cholangiocarcinoma, 1993 through 2010.

Overall patient survival from enrollment in the protocol (intention-to-treat analysis) was 56% ± 4% at 5 years after the start of neoadjuvant therapy (Fig. 97E.2), 63% ± 5% for patients with underlying PSC, and 44% ± 7% for patients with de novo CCA. Five-year survival after transplantation was 74% ± 5%; 80% ± 5% for patients with underlying PSC and 64% ± 8% for patients with de novo CCA (Fig. 97E.3). No difference in survival was reported among patients undergoing LDLT versus DDLT.

FIGURE 97E.2 Patient survival after start of neoadjuvant therapy. PSC, primary sclerosing cholangitis.

FIGURE 97E.3 Patient survival after transplantation. PSC, primary sclerosing cholangitis.

Thirty-eight patients (22%) had findings at the staging operation that precluded transplantation. The majority of these findings were regional lymph node (n = 17) and peritoneal (n = 14) metastases; 8 patients had invasion of adjacent organs/tissues, and 5 had intrahepatic metastases that had not been detected by preoperative imaging studies. Findings were missed in 4 patients found to have gallbladder involvement (n = 1) and invasion of neuroconnective tissue (n = 3) during transplantation within several weeks of their staging operations. Remarkably, the patient with gallbladder involvement also had microscopic disease at the common bile duct margin. She did not undergo PD, as it was not technically possible, and she is alive and disease-free 6.5 years after transplantation. The three patients with neuroconnective tissue involvement underwent reexcision during the transplant operation and are alive at 13, 32, and 66 months after transplantation. The patient at 13 months has a very high CA19-9 level and presumably will develop detectable recurrent disease. The other 2 patients show no evidence of recurrent disease.

Twenty-nine patients (23%) died after transplantation: 7 from surgical complications (1 to 5 months) and 17 from recurrent CCA. Other causes of death were graft-versus-host disease (n = 2 at 1 and 4 months), posttransplant lymphoproliferative disease (23 months), an indeterminate hematologic disorder (31 months), and uterine cancer (45 months).

Pancreatoduodenectomy and Transplantation

The addition of a PD greatly increases the technical complexity of transplantation and has a significant impact on postoperative morbidity and mortality. A 5-year survival rate of 56% (±17%, compared with 75% ± 5% overall) was reported in 11 patients who underwent OLT with concomitant PD, and 9 of 67 PSC patients (13%) were found to have microscopic involvement of the common bile duct margin at the time of transplantation, and 8 of these patients (5 deceased donor, 2 living donor, and one amyloid donor) underwent PD. Currently, 5 are alive and disease free at 9 months to 11 years after transplantation; however, 2 patients died within 3 months from hepatic artery thrombosis (deceased-donor graft) and hepatic artery thrombosis with pseudoaneurysm (living-donor graft), and adhesions precluded PD in the remaining patient, who was also found to have gallbladder involvement; remarkably, this patient is alive and without evidence of disease 6.5 years after transplantation.

Two patients with previous biliary operations underwent OLT with en bloc PD. One patient is alive and disease-free 7 years after transplantation; the other patient died 45 months after transplantation from uterine cancer. Additionally, one PSC patient known to have positive brushings in the common bile duct in addition to a hilar CCA underwent planned OLT with en bloc PD and is alive and disease-free at 13 months. No patient with de novo hilar CCA has had a positive common bile duct margin at the time of transplantation.

Vascular Complications

Late vascular complications are much more common after transplantation for CCA than after other indications because of the neoadjuvant therapy (Mantel et al, 2007). Use of the irradiated native common hepatic artery is avoided during DDLT in lieu of a deceased-donor iliac artery graft from the infrarenal aorta. This strategy was initially implemented in LDLT but resulted in an unacceptable rate of acute hepatic artery thrombosis. Subsequently, the native hepatic artery has been used for arterial inflow in LDLT; this strategy reduced early hepatic artery thrombosis but it is associated with a 20% late stenosis/thrombosis rate. Likewise, there is also a 20% rate of late portal vein stenosis (with or without thrombosis) seen with both living- and deceased-donor transplantation. A deceased donor iliac vein is used as an interposition graft during LDLT, and the stenosis has always involved the native portal vein and its anastomosis with the interposition graft.

All patients undergo Doppler US and contrast CT examination 4 months after transplantation. These imaging studies enable detection of an asymptomatic stenosis that is usually amenable to angioplasty with or without stent insertion. Arterial complications are treated by a transarterial approach, and portal complications are treated transhepatically. Fortunately, the Mayo group has not lost a graft from a portal stenosis or an arterial stenosis detected prior to thrombosis.

Medical and Neoadjuvant Complications

The effect of neoadjuvant radiotherapy on the liver is profound (Fig. 97E.4). Widespread necrosis is found in the hilus with necrotic debris in the major ducts (Fig. 97E.5); thus pretransplant infectious complications related to neoadjuvant therapy are very common and require continuous care and frequent hospitalization for patients awaiting transplantation. Nearly all patients have one or more episodes of cholangitis with occasional development of intrahepatic abscesses. Cholecystitis is treated nonoperatively with antibiotics, although severe cases may require endoscopic placement of a cystic duct stent or percutaneous cholecystostomy. Several patients have developed gallbladder necrosis with rupture that required emergency operations. Gastritis, duodenitis, and poor gastric emptying are also common and can persist after transplantation, which can lead to difficulties with nutrition. Several patients have required operative intervention for duodenal perforation or life-threatening hemorrhage from duodenitis and peptic ulceration.

FIGURE 97E.4 Explanted liver after neoadjuvant therapy showing radiation effect.

FIGURE 97E.5 Explanted liver after neoadjuvant therapy showing duct necrosis and intraductal debris.

CCA patients are hypercoaguable and at risk for deep venous thrombosis (DVT) and pulmonary embolism, as observed with other types of malignancies. Thus, they receive DVT prophylaxis whenever hospitalized for nonbleeding complications and especially during the perioperative period following operative staging.

Neuroendocrine Cancer (See Chapter 81B)

Gastroenteropancreatic neuroendocrine cancers (NECs) are a rare, diverse group of tumors with an incidence of one to two cases per 100,000 per year with a slight female predominance (Taal & Visser, 2004). These tumors are characteristically indolent in nature and are frequently found to be metastatic at the time of diagnosis. The liver is the most common site for metastases, and widespread hepatic dissemination is the leading cause of death in these patients (Frilling et al, 2009). Fortunately, these cancers are often confined to the liver for protracted periods of time with 5-year survival of 13% to 54% even without treatment (Godwin, 1975; Thompson et al, 1988; Que et al, 1995).

Various therapeutic options have been utilized for NEC with hepatic metastases; such treatments include transarterial chemoembolization (TACE), radiofrequency and cryoablation, systemic chemotherapy, peptide receptor radionuclide therapy (see Chapters 84A, 84B, 85A and 85B), cytoreductive resection, surgical resection (see Chapter 81B), and liver transplantation. Surgical extirpation with an R0 resection is the most effective therapy for metastatic NEC confined to the liver; however, only 10% to 57% of these tumors are amenable to compete resection (Chen et al, 1998; Elias et al, 2003; Frilling et al, 2009; Grazi et al, 2000; Mazzaferro et al, 2007; Musunuru et al, 2006; Yao et al, 2001).

Liver transplantation is an option for treatment of patients with a low probability of achieving an R0 resection. The goals of liver transplantation are to 1) achieve palliation by alleviating symptoms for patients with functioning NEC; 2) achieve palliation by delaying death as a result of tumor replacement of the liver, taking advantage of the slow progression and the time it will take to replace the new liver with tumor, “resetting the clock”; and 3) achieve a cure. Liver transplantation is highly effective at relieving symptoms for patients with functioning NEC. There are several single-center (Florman et al, 2004; Frilling et al, 2006; Mazzaferro et al, 2007; Rosenau et al, 2002) and multicenter (Le Treut et al, 2008) studies reporting 36% to 90% patient survival at 5 years. The possibility of achieving a cure, however, is very low. Disease-free survival is only 20% to 77% at 5 years, and tumor recurrence after 5 years is common.

Widespread acceptance of OLT as a reasonable option for the treatment of this disease remains limited and controversial for multiple reasons that include the scarcity of deceased-donor organs available for OLT and the availability of other treatment modalities that can also provide palliation. Furthermore, reliable selection criteria have not been identified, and long-term data are limited because of the low incidence of the disease. Most importantly, it remains difficult to determine the actual benefit derived from OLT as a result of the protracted course of metastatic disease and unknown natural history of disease for those patients selected as candidates for transplantation.

The Mayo Clinic developed a protocol in 2002 designed to assess efficacy of liver transplantation for patients with metastatic NEC confined to the liver and regional hepatic lymph nodes (van Vilsteren et al, 2006). The clinical inclusion/exclusion criteria are summarized in Box 97E.1. Each patient was screened for locally recurrent and extrahepatic disease with chest, abdomen, and pelvic CT scans, bone scan, and somatostatin receptor scintigraphy within 60 days of preliminary registration for transplantation. Prior treatment modalities did not exclude patients, as long as they did not technically prohibit OLT. Patients were observed for 6 months following resection of the primary NEC to exclude extrahepatic disease progression. Reevaluation for metastatic disease prior to liver transplantation was performed every 4 months via laboratory tests, tumor marker assays, and abdominal imaging studies. Extrahepatic metastases were excluded via operative staging with laparoscopy prior to OLT.

The results were published with short follow-up. Since that time, 23 patients with metastatic NEC have undergone transplantation at the Mayo Clinic, with 76% patient survival and 37% disease-free survival at 5 years (unpublished data). Consistent with information in the literature, patients with carcinoid tumors fared slightly better than those with islet cell tumors originating in the pancreas. Patient and disease-free survival at 5 years was 86% and 45% for 10 patients with carcinoid tumors, 78% and 44% for 9 patients with islet cell tumors, and 50% and 0% for 3 patients with gastrinoma and one patient with glucagonoma. Thirteen patients developed recurrent disease, and survival after recurrence was less than 30% at 4 years, 50% for those with carcinoid or islet cell tumors, and 0% for those with gastrinoma or glucagonoma. As a result, patients with metastatic glucagonoma and gastrinoma are no longer considered for transplantation.

In summary, liver transplantation effectively alleviates symptoms for patients with diffuse, functioning NEC liver metastases. Liver transplantation may improve patient survival for those destined to succumb to liver replacement by tumor, but no studies actually demonstrate efficacy. Recurrence is common following transplantation, and results with metastatic gastrinoma and glucagonoma are poor, so transplantation should not be done for these types of tumors. Indications for transplantation and optimal timing in the course of disease remain ill defined, and the absence of prioritization (MELD score adjustment) in the United States precludes widespread application.

Hepatic Epithelioid Hemangioendothelioma (See Chapter 78B)

HEHE, first described in 1982, is a rare neoplasm that originates from vascular endothelium, and it has unpredictable malignant potential (Weiss & Enzinger, 1982). Ishak and colleagues (1984) first reported liver involvement in a series of 32 patients with HEHE, which arises between the second and ninth decades with a 3 : 2 female/male predominance (Mehrabi et al, 2006). The etiology of HEHE remains elusive, although a multitude of conditions have been proposed to contribute to its development; these include viral hepatitis, liver trauma, oral contraceptives, primary biliary cirrhosis, alcohol consumption, and exposure to vinyl chloride, asbestos, and Thorotrast (Darras et al, 1988; Dean et al, 1985; Lauffer et al, 1996; Makhlouf et al, 1999; Mehrabi et al, 2006; Soslow et al, 1997).

The most common clinical manifestations of HEHE are right upper quadrant pain, hepatomegaly, and weight loss. Weakness, anorexia, epigastric mass, ascites, nausea, jaundice, and fatigue are additional symptoms. Up to 25% of these lesions are detected as incidental findings (Lauffer et al, 1996; Mehrabi et al, 2006).

Two variants of HEHE have been described, nodular and diffuse. In actuality, the variants represent early- and late-stage disease. The nodular type is seen early with a highly variable number of 1- to 12-cm lesions arising throughout the liver. The lesions are typically hypodense on CT scan with high-density contrast uptake in the periphery. Individual nodules increase in size by spreading along the hepatic or portal veins, and they eventually coalesce to form diffuse peripheral lesions. The CT appearance of the later diffuse type is typically a large, slow-growing lesion resulting from coalescence of smaller lesions. Flattening of the capsule may occur because of fibrosis, peripheral enhancement of contrast may be seen with many hypervascular central lesions, and hypertrophy of the unaffected segments of the liver may be apparent (Fulcher & Sterling, 2002; Lyburn et al, 2003; Miller et al, 1992).

Definitive radiographic diagnosis of the HEHE is usually not possible, especially in the nodular form, because of the similarity of this tumor with primary epithelial liver tumors and hepatic metastases. In a review of 434 cases of HEHE, the majority of patients (87%) had multifocal disease involving both lobes of the liver at the time of presentation. Extrahepatic disease at diagnosis was common (36.6%) with involvement of the lung (8.5%), regional lymph nodes (7.7%), peritoneum (6.1%), spleen (3.2%), and diaphragm (1.6%) (Mehrabi et al, 2006).

Histologically, HEHE may resemble other conditions such as venoocclusive disease, CCA, hemangioma, angiosarcoma, and metastatic signet ring cell carcinoma (Corrin et al, 1979). Furthermore, immunohistochemical staining may suggest a tumor of neuroendocrine origin. Histologic findings are consistent with epithelioid or histiocytoid morphology and intracytoplasmic lumina containing red blood cells. Immunohistochemical staining is positive for factor VIII–related antigen and endothelial cell markers (CD31, CD34) and negative for mucin, bile, carcinoembryonic antigen, and α-fetoprotein. Ultrastructural findings are characterized by a well-developed basal lamina, pinocytotic vesicles, and Weibel-Palade bodies (Ishak et al, 1984; Lauffer et al, 1996; Mehrabi et al, 2006).

Treatment of HEHE is difficult. Resection is often not possible because of the presence of multifocal bilobar disease at the time of diagnosis. In the review by Mehrabi and colleagues (2006), only 9.4% of patients were amenable to resection. Patient survival was 100% at 1 year and 75% at 5 years. For many patients, observation alone is reasonable, because progression may be extremely slow, if it occurs at all. Others have reported poorer results (Ben-Haim et al, 1999) and have suggested that resection should be limited to patients presenting with unilobar, liver-confined disease (Mosoia et al, 2008).

Liver transplantation is an option for patients with extensive intrahepatic disease. Several series have reported outcomes equivalent to those for liver transplantation for other diagnoses. In a report from the European Liver Transplant Registry (ELTR), patient survival rates at 1, 5, and 10 years were 93%, 82%, and 72% with 90%, 82%, and 64% disease-free survival, respectively. Neither disease-free survival nor patient survival was influenced by neoadjuvant therapy, lymph node status, or the presence of extrahepatic disease; however, vascular invasion had a negative impact on patient survival (Lerut et al, 2007). A multicenter Canadian experience with 11 patients reported 5-year survival of 82% with a 36.4% recurrence rate (Nudo et al, 2008). A recent query of the UNOS database identified 110 patients who underwent OLT for HEHE in the United States between 1987 and 2005 (Rodriguez et al, 2008). Patient survival was 80% and 64% at 1 and 5 years. In their survey of the available literature, Mehrabi and colleagues (2006) reported 1- and 5-year patient survival of 96% and 54.5%, respectively, after OLT.

The Mayo Clinic recently reviewed its experience with 30 patients treated for HEHE between 1984 and 2007 (Grotz et al, 2010) and found a 2 : 1 female predominance with a mean age at diagnosis of 46 years (range, 21 to 79 years). The diagnosis of HEHE was confirmed in all cases by immunohistochemical staining for factor VIII–related antigen, CD31, and CD34. Patients were divided into groups based on the number and size of nodules present within the liver: half had 10 or fewer nodules, and half had more than 10 nodules; the largest lesion was smaller than 5 cm in 43%, it was 5 to 10 cm in 30%, and it was larger than 10 cm in 27% of cases. Extrahepatic disease was present at diagnosis in 37% of patients (n = 11). Sites of metastases included lung (n = 8), peritoneum (n = 2), bone (n = 2), brain (n = 1), and skin (n = 1), and one third of the patients had multiple sites of extrahepatic involvement.

Therapeutic management included OLT (n = 11), primary resection (n = 11), systemic chemotherapy (n = 5), and no medical treatment (n = 3). Median follow-up was 41.6 months (range, 0 to 243), and in this time, 12 deaths (40%) were reported, one patient died within 2 years of primary resection, six patients died after OLT (1 month to 11 years), and five patients treated nonsurgically died 1 month to 4 years after diagnosis. Patient survival following primary resection at 1, 3, and 5 years was 100%, 86%, and 86%, respectively, compared with 91%, 73%, and 73%, respectively, for patients treated with OLT. Patient survival following nonoperative management was 57%, 43%, and 29% at 1, 3, and 5 years, respectively. Disease-free survival following primary resection was 78%, 62%, and 62% at 1, 3, and 5 years, respectively, compared with 64%, 46%, and 46% after OLT. Although no significant differences were seen in patient survival (P = .128) or disease-free survival (P = .405), patients who underwent primary resection had significantly fewer tumor nodules and less diffuse liver involvement compared with those who underwent OLT (P = .004).

Morphologic features associated with prolonged disease-free survival were nodular disease pattern (P = .01) and largest hepatic lesion 10 cm or smaller (P = .003). Patients with 10 or fewer tumor nodules showed a trend toward better survival (P = .052). Factors associated with decreased overall patient survival were tumor size larger than 10 cm (P = .0007, hazard ratio [HR], 10.97; 95% confidence interval [CI], 2.76 to 43.68), more than 10 nodules (P = .023; HR, 5.83; CI, 1.27 to 26.8), diffuse disease pattern (P = .0076; HR, 8.14; CI, 1.75 to 37.91), and involvement of more than four liver segments (P = .041; HR, 4.92; CI, 1.06 to 22.77). The presence of extrahepatic disease did not have an impact on patient survival (P = .5).

The Mayo Clinic findings demonstrate that primary resection and liver transplantation achieve comparable survival for patients with HEHE. Resection is favored for patients with 10 or fewer lesions, involvement of four or fewer liver segments, and disease amenable to complete extirpation of tumor. Transplantation is recommended for those with more than 10 lesions, involvement of more than four liver segments, and unresectable disease.

Summary

Liver transplantation is appropriate therapy for selected patients with malignancies other than HCC. Excellent results have been achieved for patients with unresectable hilar CCA and hilar CCA arising in the setting of PSC. Success requires rigorous adherence to protocol with careful selection of patients with early stage disease confined to the hilus along with neoadjuvant chemoradiotherapy and operative staging to exclude patients with regional lymph node metastases. Liver transplantation without prior neoadjuvant therapy is rarely successful and should not knowingly be performed for patients with CCA.

The role of liver transplantation in the treatment of metastatic NEC remains unclear. Experience to date shows that most patients develop recurrent disease; however, transplantation may prolong survival by delaying death from tumor replacement of the liver. Because of the indolent nature of the disease, survival beyond 5 years is achievable, but the actual benefit—that is, the difference in survival with and without transplantation—remains unknown.

Liver transplantation achieves results comparable to resection for patients with HEHE, and transplantation should be considered for patients with more than 10 nodules, involvement of more than four liver segments, or tumors not amenable to resection. Additional experience is necessary to confirm reports that transplantation is beneficial for patients with limited extrahepatic disease.