Liver transplantation for nonhepatocellular malignant disease

Overview

Liver transplantation (LT) is considered standard of care for select patients with hepatocellular carcinoma (HCC) arising in the setting of cirrhosis (see Chapter 108A ). The role of LT in treatment of other malignancies arising in the liver such as hilar and intrahepatic cholangiocarcinoma (CCA), hepatic epithelioid hemangioendothelioma (HEHE), or tumors metastatic to the liver such as neuroendocrine cancer (NEC) and colorectal cancer (CRC) continues to evolve. Herein we review the results of LT for these malignancies—specifically hilar and intrahepatic CCA, metastatic NEC, HEHE, and metastatic CRC—with an aim to suggest guidelines for the application of LT in the treatment of these diseases.

Hilar cholangiocarcinoma (see Chapter 51 )

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, ^, and the prevalence of intrahepatic disease appears to be on the rise. CCA can arise within the liver, in the perihilar location, or along the extrahepatic bile duct (see Chapters 50 and 51 ). 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 of the difficulty achieving a tumor-free (R0) margin of resection. Radical resection with partial hepatectomy has been shown to improve survival 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 ). LT appeared promising for the treatment of intrahepatic and hilar CCA; LT 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 LT for the treatment of CCA were uniformly poor. LT for both hilar and intrahepatic 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. 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 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% after OLT in a PSC population with early-stage CCA.

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 (UCLA) has reported reasonable survival outcomes in incidental CCA detected in the explant after OLT. 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. A similar experience was recently reported by Neuhaus’ team in Berlin. Sixteen patients with CCA were treated by combined LT and pancreatoduodenectomy (PD) between 1992 and 1998, and results were compared with those achieved for 8 patients who did not undergo PD, which at the time of LT was associated with significantly higher morbidity than transplantation alone. Long-term survival (>4 years) was achieved in only 3 of 20 patients without lymph node–involvement 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 LT for these tumors, intrahepatic and hilar CCA became widely recognized as absolute contraindications for LT. 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 overall poor results with LT alone, some patients with favorable hilar CCA, such as those with negative resection margins and no regional lymph node metastases, did benefit from transplantation. In addition, a small group of patients at Mayo Clinic treated with primary radiotherapy and chemosensitization alone, without resection, had 22% 5-year survival. Based on the known palliative efficacy of radiotherapy for CCA—and knowledge that CCA resection failures are usually because of locoregional recurrence rather than distant metastases —the transplant team at the University of Nebraska pioneered a strategy of high-dose neoadjuvant brachytherapy and chemotherapy followed by LT for patients with unresectable hilar CCA.

The initial Nebraska protocol used high-dose intrabiliary brachytherapy, 6000 cGy, followed by daily intravenous (IV) 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, 2.8–14.5 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 medical and radiation oncologists, hepatologists, and surgeons. The general concept is that neoadjuvant therapy and LT should provide the best possible control of local disease. The rationale for the protocol is based on several factors: (1) the known CCA tumor response to high-dose radiotherapy; (2) hepatotoxicity of radiotherapy is obviated by LT; (3) LT achieves radical resection, including removal of residual disease after neoadjuvant therapy; (4) LT is not limited by underlying liver disease (PSC), vascular involvement, or concern about intrahepatic extension of disease; (5) neoadjuvant therapy before operative staging and transplantation might avoid tumor dissemination during operation; and (6) careful patient selection with operative staging before LT could exclude patients with advanced disease and regional lymph node metastases that are destined to develop distant metastatic disease.

Inclusion and exclusion criteria

Criteria for protocol enrollment are designed to select those patients least likely to develop metastatic disease, most likely to respond to neoadjuvant therapy, and who have a high probability for survival after transplantation. Appropriate patients include those with early-stage hilar CCA determined to be unresectable or those who have underlying PSC because CCA arising in the setting of PSC has a very poor natural history after standard resection (see Chapters 41 and 51 ).

Criteria for anatomic unresectability include bilateral segmental ductal extension, encasement of the main portal vein (PV), unilateral segmental ductal extension with contralateral vascular encasement, and unilateral atrophy with either contralateral segmental ductal or vascular involvement. Because of the difficulty of assessing extent of disease along the bile duct, especially in the setting of PSC, no longitudinal limits exist for bile duct involvement (see Chapters 41 , 51 , and 119B ).

Original criteria required that hilar CCA not extend lower than the cystic duct, but it was subsequently found that early CCA arising in PSC with unsuspected common bile duct (CBD) involvement found at transplantation was amenable to transplantation with PD; however, patients with CCA extending below the cystic duct on cholangiography are excluded because they have larger tumors that are more likely to abut the PV and be less amenable to complete extirpation during transplantation.

Vascular encasement of the hilar vessels is not a contraindication to transplantation. The upper limit of tumor size is 3 cm in radial diameter (perpendicular to the biliary duct at the site of origin) when a mass is visible on cross-sectional imaging studies, and there must be no evidence of intrahepatic or extrahepatic metastases by chest computed tomography (CT), abdominal CT or magnetic resonance imaging (MRI), ultrasonography, or bone scan. Endoscopic ultrasound (EUS) is performed before neoadjuvant therapy to exclude patients with regional lymph node metastases.

The Mayo Clinic protocol specifically excludes patients with evidence of intrahepatic or extrahepatic metastases or gallbladder involvement. Surgical intervention and any type of transperitoneal biopsy or fine-needle aspiration have emerged as absolute contraindications to enrollment. These procedures result in an unacceptable rate of peritoneal seeding, which has been discovered during operative staging or recurrence after transplantation (unpublished data). Candidates must have no active infections or medical conditions that preclude either neoadjuvant therapy or OLT. These exclusion criteria are quite restrictive and select for patients with early-stage disease. Indeed, a recent review of 732 patients with CCA in the Netherlands found that 154 (21%) patients had potentially resectable disease, 335 (46%) patients had regional lymph node or distant metastases, and only 84 (11%) met tumor criteria. Of those 84 patients, only 34 (5% of the total number of CCA patients) were deemed to have been potential candidates as the others were above their age limit of 70 years.

Tumor diagnosis

Diagnostic criteria for neoadjuvant therapy and LT require a malignant-appearing stricture on cholangiography and either visualization of a mass on cross-sectional imaging at the site of the stricture, cytologic or histologic confirmation of CCA by transluminal brushing or biopsy, elevation of carbohydrate antigen (CA19-9) greater than 100 U/mL in the absence of acute bacterial cholangitis, or polysomy by fluorescence in situ hybridization (FISH). Patients with indeterminate diagnostic criteria—such as FISH trisomy (7 or 3), dysplasia from brushings, FISH polysomy in the absence of a malignant-appearing stricture, or a malignant-appearing stricture in the absence of a mass lesion are followed closely with repeat endoscopic retrograde cholangiography (ERCP) with brushings, cross-sectional imaging, and laboratory testing. Patients with PSC and multifocal FISH polysomy are especially of concern because over 80% of these patients develop CCA within 3 years.

Neoadjuvant therapy

Neoadjuvant therapy is administered by external beam radiation (40–45 Gy), followed by transcatheter radiation (20–30 Gy) with iridium wires. Wires are placed preferentially by ERCP and percutaneous transhepatic cholangiography (PTC) when ERCP is technically not possible. Occasionally, brachytherapy is not possible, and a comparable dose of radiation is administered as a localized boost. IV 5-FU is administered for chemosensitization during radiation therapy, and capecitabine is administered afterward, while patients await transplantation.

Staging operation

All patients undergo operative staging before OLT. Operative staging includes a thorough abdominal exploration with careful palpation of the liver to identify small, previously undetected intrahepatic metastases, biopsy of any suspicious nodules, and excision of a proximal proper hepatic artery lymph node (at the takeoff of the gastroduodenal artery) and a pericholedochal lymph node (posterior to the CBD just superior to the pancreas). The caudate process and retrohepatic vena cava are assessed for suitability of a caval-sparing hepatectomy, which is necessary for recipients of living-donor liver grafts. Extrahepatic or intrahepatic metastases, lymph node involvement, or locally extensive disease preclude transplantation. Survival for patients with these findings beyond a year is very rare. The staging operation was initially performed through a right subcostal incision with extension along the future LT incision as necessary. During the past decade, most procedures have been accomplished by hand-assisted laparoscopy using a smaller, right subcostal incision and several separate port insertion sites. The staging procedure is initiated as a laparoscopic survey of the abdomen followed by placement of a hand port to facilitate palpation of the liver and perihepatic region and excision of the hepatic artery and pericholedochal lymph nodes. Seprafilm (Sanofi-Aventis, US, LLC) has been used to try to prevent adhesions for patients that stage negative and are awaiting deceased-donor liver transplantation (DDLT).

Timing of the staging operation depends on the possibility of living-donor liver transplantation (LDLT) or the anticipated waiting time for DDLT. The staging procedure is performed 1 to 2 days before LDLT or as time nears for DDLT. Patients with underlying cirrhosis from PSC or liver dysfunction from cholestasis are at risk for decompensation after the staging procedure. Liver decompensation may lead to an increase in a patient’s calculated Model for End-Stage Liver Disease (MELD) score and advance their position on the deceased-donor waiting list, but it also leads to an increase in perioperative morbidity and mortality. Unfortunately, only supportive care is possible for those patients who decompensate after a positive staging operation, and few survive the perioperative period. An occasional patient is too sick to undergo operative staging as a separate operation, usually because of liver decompensation with a high MELD score or medically refractory ascites. Operative staging can be done when a donor liver becomes available, but this approach requires close coordination with the donor organ procurement organization (OPO) and arrangements for a back-up patient in the event that the findings of the staging procedure preclude LT.

Before 2003, 30% to 40% of patients had findings during the staging operation that precluded LT. EUS-guided aspiration of regional nodes (not the primary tumor) was implemented to exclude patients with lymph node metastases before initiation of neoadjuvant therapy. Initial findings from 47 patients identified 8 (17%) with metastases. No morphologic features of the lymph nodes were found at EUS that predicted microscopic disease. Thus it is important to sample the regional lymph nodes even if they appear benign on endoscopic ultrasound. Since routine use of EUS was implemented in 2003, the percentage of patients with a positive staging exploration has been reduced to 20% overall, 14% for patients with CCA arising in PSC, and 26% for patients with CCA arising de novo. EUS avoids the morbidity and mortality of high-dose neoadjuvant therapy and prevents an unnecessary operation for patients destined to fall out at operative staging.

Liver transplantation

The technical difficulty and nuances of transplantation for patients with CCA and neoadjuvant radiotherapy exceed those of standard OLT (see Chapter 125 ). Hilar dissection is avoided to prevent tumor manipulation and to reduce the possibility of intraoperative dissemination. There is typically extensive scar tissue in the hepatoduodenal ligament because of the neoadjuvant therapy and the previous staging procedure, which can make the dissection very difficult. The irradiated native hepatic artery is avoided during transplantation with a deceased-donor liver, and arterial inflow is established with a segment of deceased-donor iliac artery sewn to the infrarenal aorta. This approach was initially applied to LDLT but unfortunately resulted in an unacceptable rate of hepatic artery thrombosis. Better results have been achieved using the native artery, which is sewn directly to the living-donor artery despite prior radiation therapy. Use of the irradiated artery is associated with more frequent hepatic artery stenosis and thrombosis, but surveillance with Doppler ultrasound effectively enables early detection and intervention if problems arise.

The CBD is transected as close to the pancreas as possible, and it may be possible to enucleate a short segment of additional CBD from the head of the pancreas. The margin is submitted for frozen section examination. Microscopic tumor involvement at this margin occurs in 10% to 15% of patients with PSC but rarely with CCA arising de novo. The possibility of PD is discussed with all PSC patients before initiation of neoadjuvant therapy. Bilioenteric continuity is restored with a standard Roux-en-Y hepaticojejunostomy (living-donor graft) or choledochojejunostomy (deceased-donor graft).

The PV may be somewhat brittle and fragile because of the neoadjuvant therapy, and an injury may be difficult to control. The PV is divided as low as possible and is not dissected free up into the hilus of the liver. Despite low division, the deceased-donor PV is almost always long enough for an end-to-end anastomosis. A segment of a deceased-donor iliac vein is often used as an interposition graft between a living-donor right or left PV and the native vein during LDLT. We used to think it was important to insert a short vein graft for living-donor right livers to enable intervention after transplantation (discussed later), but a graft is now used only when necessary to make up the distance between the donor and recipient PVs. A caval-sparing hepatectomy is performed in most cases, and the donor suprahepatic vena cava is sewn to the left/middle hepatic vein trunk or the retrohepatic cava during DDLT; the right or left/middle hepatic vein trunk is reconstructed in an end-to-end fashion during LDLT along with implantation of infrahepatic and caudate veins larger than 0.5 cm and reconstruction of segment V and VII veins if necessary. If there is concern for tumor extension into the caudate, which is usually detectable during the staging operation, the retrohepatic cava is excised, and the donor retrohepatic vena cava is sewn to the suprahepatic and infrahepatic cavae as an interposition graft, usually with use of portovenous and venovenous bypass.

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