J Gastrointest Canc DOI 10.1007/s12029-014-9590-2

INVITED REVIEWS

Liver Transplantation for Malignancies Bijan Eghtesad & Federico Aucejo

# Springer Science+Business Media New York 2014

Abstract Liver transplantation (LT) has become an acceptable and effective treatment for selected patients with hepatocellular carcinoma with excellent outcomes. More recently, LT has been tried in different primary and secondary malignancies of the liver. The outcomes of LT for very selected group of patients with hilar cholangiocarcinoma (CCA) have been promising. Excellent results have been reported in LT for patients with unresectable hepatic epithelioid hemangioendothelioma (HEHE). In contrast to excellent results after LT for HEHE, results of LT for angiosarcoma have been disappointing with no long-term survivors. Hepatoblastoma (HB) is the most common primary liver cancer in pediatric age group. Long-term outcomes after LT in patients with unresectable tumor and good response to chemotherapy have been promising. Indication for LT for hepatic metastasis from neuroendocrine tumors (NETs) is mainly for patients with unresectable tumors and for palliation of medically uncontrollable symptoms. Posttransplant survival in those patients with low tumor activity index is excellent, despite recurrence of the tumor. More recent limited outcomes data on LT for unresectable hepatic metastases from colorectal cancer have claimed some survival benefit compared to the previous reports. However, due to the high rate of tumor recurrence in a very short time after LT, especially in the era of organ shortage, this indication has not been favored by the transplant community.

CEA HEHE NETs HB UNOS NANETS ENETS CC

Keywords Liver transplantation . Primary hepatic malignancies . Secondary hepatic malignancies

Liver Transplantation for Primary Liver Tumors

Abbreviations

HCC is the most common primary liver malignancy and a leading cause of death from cancer worldwide. Its incidence continues to rise globally due to its link to hepatitis B and C infection and nonalcoholic steatohepatitis (NASH) [1]. Despite the evolution of surgical, interventional, and systemic therapies, HCC is a very challenging disease to tackle. This is because most of HCCs arise in a background of cirrhosis, hampering the implementation of therapies, or due to its indolent course being diagnosed at late stages. In line with this, only 20 to 30 % of patients are potentially curable

LT HCC AFP

Liver transplantation Hepatocellular carcinoma Alpha-fetoprotein

B. Eghtesad (*) : F. Aucejo Hepato-pancreato-biliary/Liver Transplant Surgery, Cleveland Clinic, Desk A-100, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]

Carcinoembryonic antigen Hepatic epithelioid hemangioendothelioma Neuroendocrine tumors Hepatoblastoma United Network for Organ Sharing North American Neuroendocrine Tumor Society European Neuroendocrine Society cholangiocarcinoma

Orthotopic liver transplantation (LT) has been widely accepted as a treatment for hepatocellular carcinoma (HCC) in selected group of patients with excellent outcomes. This favorable result has expanded the LT indication for other primary and secondary malignancies of the liver like cholangiocarcinoma, hepatic epithelioid hemangioendothelioma (HEHE), hepatoblastoma (HB), neuroendocrine tumors (NETs), sarcomas, and more recently colorectal metastatic lesions. Although there are controversies in the use of LT the in treatment of these tumors, certain criteria have been developed to provide acceptable outcomes. This paper discusses the more recent reviews on the use of LT for primary and secondary hepatic malignancies.

Hepatocellular Carcinoma

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and this is via surgical interventions including liver resection or transplantation [2]. Liver resection is indicated in patients with minimal or no portal hypertension and is associated with a 5-year survival rate of >50 %. However, tumor recurrence after resection is very high due to untreated oncogenic liver background [3–5]. LT has the advantage of overcoming the presence of tumor and background of liver disease, but its main drawback is the scarcity of liver grafts. Despite this shortcoming, LT stands as the most important surgical therapy to treat patients with HCC and end-stage liver disease or those who failed liver resection [6]. The initial experience with LT for patients with HCC was dismal due to poor patient selection. Patients undergoing LT with large tumor burden or aggressive biology experienced high rates of post-LT recurrence and poor survival [7]. It was in a landmark study published in 1996 that survival similar to patients undergoing LT without HCC was observed in a selected group of transplant patients with HCC meeting the so-called Milan criteria. Patients undergoing LT with one HCC tumor ≤5 cm or three tumors 85 % and post-LT recurrence in the order of 8 % [8]. Due to the consistent reproducibility of similar outcomes among transplant centers, in 2002 the United Network of Organ Sharing (UNOS) adopted the Milan criteria for listing HCC patients for LT with 22 exception model of end-stage liver disease (MELD)-point and 3-point increment every 3 months on the waitlist until transplantation [9]. Despite this change in the dynamics of organ allocation, waitlist dropout in patients with HCC is as high as 10–20 % due to tumor progression or natural evolution of end-stage liver disease [10]. However, at the same time, the priority privilege to expedite transplantation in HCC patients has been pointed out as an element of unfairness of organ allocation for nonHCC patients. Therefore, the complexity of the issue of organ allocation for HCC patients in an era of severe organ scarcity continues to be a matter of debate [11]. Despite the excellent long-term outcomes observed in within the Milan criteria HCC patients undergoing LT, numerous worldwide single-center studies have been published arguing that the Milan criteria can be too strict and that a group of patients with HCC beyond these criteria could benefit from similar post-LT outcomes [12, 13]. One of the most popular proposed extended criteria is the University of California San Francisco (UCSF) criteria. Patients undergoing LT with a single tumor ≤6.5 cm, or up to three tumors with the largest being ≤4.5 cm with a total tumor diameter of ≤8 cm, exhibited 90 and 75 % 1- and 5-year survival rates, similar to patients with HCC within the Milan criteria [13]. When originally introduced, the USCF criteria was based on pathology analysis; however,

it was subsequently also validated when considered based on radiology analysis [14]. Many other studies proposing extended HCC criteria for LT have been published. Herrero et al. reported post-LT outcomes in patients with radiologic diagnosis of single tumor ≤6 cm or two to three tumors of ≤5 cm each equivalent to patients within the Milan criteria [15]. Roayaie et al. reported 55 % 5-year survival in patients undergoing LT with one or more tumors measuring 5 to 7 cm, also staged via imaging [16]. In another study, Kneteman et al. reported 83 % 4-year post-LT survival in patients with radiologic diagnosis of one tumor 3 cm, transperitoneal tumor biopsy, or metastatic disease or a history of prior malignancy experienced shorter survival [54]. Based on the documented body of evidence, it appears that in a much selected group of patients, LT for hilar CC could offer similar outcomes to patients undergoing LT with HCC within the Milan criteria. In line with this, the assigned MELD score adjustment in practice since 2010 at least appears to be adequate based on the observed dropout rate of 11.5 % per 3month increment. Emphasis in strict patient selection, evolution, and further standardization of neoadjuvant therapy, along with growing clinical and surgical experience and longer patient follow-up, will likely further clarify and improve the indication for LT in patients with CC. Special and delicate attention to these elements will be critical in upcoming times to continue fairly balancing the allocation of scarce liver grafts. Hepatic Epithelioid Hemangioendothelioma Hepatic epithelioid hemangioendothelioma (HEHE) is a rare malignant neoplasm, originating from the vascular endothelium. It predominantly affects females and has an unpredictable prognosis. The liver involvement is usually multifocal and bilobar and is mostly misdiagnosed as metastatic in origin. The variable malignant behavior of the tumor makes its presentation from a very slow-growing tumor to a rapidly fatal disease. Unlike most of the cases with hepatocellular carcinoma, HEHE appears on a background of normal liver histology, making resection an indicated treatment; however, the multifocal nature of the disease precludes this option in over 90 % of the cases. LT has become the treatment of choice in appropriately selected group of these patients with relatively favorable outcomes. Because of the rarity of the disease, different transplant centers have reported small case series with universally good outcomes. The report by Madariaga et al. from the University of Pittsburgh on LT in cases of HEHE showed an overall survival of 100, 88, and 71 at 1, 3, and 5 years with a disease-free survival of 81, 69, and 61 %, respectively, in the same intervals [55]. Similar results were published from the Cincinnati Cancer Transplant Registry [56]. The European Liver Transplant Registry [57] reported on 51 patients transplanted for HEHE with 1-, 5-, and 10-year survival of 93, 83, and 72 %, respectively. Furthermore, in a multicenter review of the literature on 128 patients, Mehrabi et al. reported a 1- and 5-year survival of 96 and 55 %, respectively [58]. Interestingly, involvement of hilar nodes, vascular invasion by the tumor, or presence of distant metastasis did not affect survival in these reports [57–59].

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Based on the available literature on HEHE, it seems that selected patients with this tumor, even in the presence of extrahepatic disease, may show favorable long-term survival after liver transplantation. Hepatoblastoma Hepatoblastoma (HB) is the most common primary hepatic malignancy in pediatric age group and accounts for up to 80 % of pediatric liver tumors. It usually presents with an asymptomatic abdominal mass in boys less than 3 years of age [60, 61]. It usually affects the right lobe, but bilobar disease can be seen in 35 % of the patients. Around 20 % of the patients may have distant metastasis at the time of diagnosis [62]. These patients may present with anemia and very high alpha-fetoprotein (AFP). Serum AFP of less than 100 ng/mL has been considered as a sign of poor prognosis in affected children [63, 64]. Surgical resection is considered the primary treatment for these children; however, approximately 60 % of these patients present with unresectable tumor [65]. The introduction of cisplatin-based chemotherapy has dramatically changed the prognosis of these tumors and has become the cornerstone of treatment in these patients. Response to chemotherapy is an important prognostic sign. Significant response can make an advanced tumor surgically resectable or make these patients a candidate for LT. A combination of chemotherapy and surgical resection is the preferred approach in these patients with approximately 80 % 5-year disease-free survival [65, 66]. Liver transplantation has a major role in the treatment of children with HB, either in the form of primary transplant or rescue therapy after incomplete resection or tumor recurrence after a curative resection. Post liver transplant recurrence-free survival has been shown in the range of 79 to 100 % with an overall 10-year survival of 85 % for primary LT and 40 % when LT was done as a rescue therapy [67–69]. In a review of outcomes of LT in HB from over 20 centers from North America, Europe, Asia, and Australia on 147 patients, recipients of primary LT showed 82 % survival at 6 years as compared to 30 % in those transplanted as a rescue therapy [69]. In a more recent report from King's College, 25 LTs were performed for HB over 14 years, of which 18 received cadaveric graft and 7 received left lateral segment from a living donor. Pretransplant chemotherapy was given to these patients based on the protocols. Patient and graft survival after cadaveric transplant was 91, 77.6, and 77.6 % at 1, 5, and 10 years, respectively with no retransplantation. Patient and graft survival after living donor LT was 100, 83.3, and 83.3 % at 1, 5, and 10 years. All surviving children except one remained disease-free, with a median follow-up of 6.87 years [70]. In another report from the USA on 135 patients transplanted for HB between 1987 and 2004, the actuarial 5- and 10-year survival was shown to be 69 and 66 % [71]. Similar results are reported from other centers. [72, 73].

Recurrence of HB is one of the main reasons for posttransplant patient loss. This is more pronounced in patients who underwent LT as a rescue therapy for HB. Use of chemotherapy after LT is the recommended practice in most transplant programs and is indicated in most of the reported series [74, 75]. In contrary, a review by Otte et al. did not show any significant difference in overall survival rates between children who received chemotherapy after LT and those who did not 77 versus 70 % [69]. Altogether, it seems that chemotherapy is indicated in patients with tumors with vascular invasion or distant metastasis at the time of LT. In summary, LT for HB is a viable option in unresectable cases or as a rescue therapy in patients with recurrence after liver resection. However, chemotherapy and liver resection are considered the primary treatment in patients with HB with relatively good outcomes. Sarcomas Angiosarcoma originates from the endothelium of blood vessels in the liver. It is the main differential diagnosis for HEHE, but unlike HEHE, this tumor is very aggressive, rapidly growing, and with poor prognosis, with a median survival of 6 months. It mostly happens in males, and death often occurs as a result of liver failure and hemorrhage due to tumor rupture. The tumor is not chemoresponsive, and no longterm survivors are reported after liver resection. In contrast to good response to LT for HEHE, transplantation for angiosarcoma has very poor outcomes with most of the transplanted patients died within a year with no survival beyond 30 months. The median survival 17 patients from the European Liver Transplant Registry transplanted for angiosarcoma was only 7 months [76]. Therefore, LT is not indicated in this group of patients [77].

Liver Transplantation for Secondary Liver Tumors Neuroendocrine Tumors NETs are a heterogeneous group of tumors originating in various locations, including pancreas, gastrointestinal tract, and lungs [78]. They represent 0.46 % of all malignant diseases with a rising incidence over the past few decades of 5–7 per 100,000 population [79–81]. In general, NETs originating from gastrointestinal tract are slow-growing tumors which are often discovered in the advance phase. About 40–80 % of patients present at diagnosis with metastases with liver as the most common site involved (40–93 %), bone (12–20 %), and lungs (8–10 %). As many as 75 % of small-bowel NETs and 30 to 85 % of pancreatic NETs present either synchronous or metachronous with liver metastases as their initial presentation [82, 83]. Furthermore, another 5 to 10 % of patients with

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NETs present with liver metastases with unknown origin of the disease [84]. The 5-year survival for patients with NETs is around 75 to 99 %. This rate decreases drastically when liver has been involved (13–54 %) [85, 86]. Prognostically, it seems that hepatic involvement in the disease is more important than the primary site of the tumor. Presence of bony lesions is suggestive of more aggressive tumor in these patients [87, 88]. Surgical resection for hepatic metastasis in patients with NET, if possible, is the primary line treatment option. Unfortunately, only 10 to 20 % of these patients are candidates for resection. When resection is possible, overall 5-year survival varies from 46 to 86 %, with a 10-year survival of 35 to 79 % in different reported series [89]. This wide range of variation is due to heterogeneity of tumor biology, and patient selection criteria [90]. The main goal for surgical resection is complete removal of all the tumor or cytoreductive operation to remove more than 90 % of the tumor burden. This is especially important in patients with functional tumor for relief of hormone-related symptoms [91, 92]. The relief of hormonerelated symptoms after cytoreductive surgery has been seen on average from 6 to 24 months [91, 93]. Currently, metastatic liver disease from NETs is considered the only indication for LT for a metastatic cancer. This is based on reports from single or multicenter case collections on the disease. In these reports, LT was found to be beneficial in certain categories of patients with NETs not amenable to liver resection to eliminate mass effect of the big liver or to eliminate hormone-related symptoms. The results of LT for metastatic NETs have been variable. In two separate large series on 85 and 103 patients, overall and recurrence-free 5-year survival was 36 and 47 %, and 17 and 24 %, respectively. In these series, patients with carcinoid tumors had much better 5-year survival versus noncarcinoid cancers (69 versus 8 %). The biologically favorable features of the tumor were looked at in another large single-center report. In this series, increased proliferation score as measured by Ki67 immunohistochemistry of more than 5 %, and presence of aberrant expression of E-cadherin was indicative of significantly less-favorable outcomes after liver transplantation for NETs [94–96]. In another more recent series reported on LT for NETs, it was noticed that duodenopancreatic location of the primary tumor and extensive involvement of the liver have a significant impact on 5-year overall survival in these patients (12 versus 68 %) [96]. In a report by [97] the authors looked at their criteria of inclusion for LT based on tumor grade, extent of the liver involvement, stability of the disease for minimum of 6 months, age of the patient, and surgical resection of the primary tumor before transplantation. Based on these stringent criteria, the authors reported the overall survival of 90 % and recurrencefree survival of 77 % at 5 years [97].

In a recent systematic review of the literature on LT for neuroendocrine tumors, 53 clinical studies were reviewed, and based on the data from 20 studies, 89 transplanted patients were included in the review. Sixty-nine patients had a primary tumor in the pancreas, with gastrinoma as the most frequent tumor (21 patients). Simultaneous pancreatic NET resection and liver transplantation was done in 45 cases. Cumulative 1-, 3-, and 5-year survival was 71, 55, and 44 %, respectively. With a calculated mean survival of 54±6 months. The patients with VIPomas (vasoactive intestinal peptide) had the best overall survival. Recipient age more or equal to 55 years and simultaneous pancreatic resection were found to be significant predictors of worse survival [98]. When comparing data from long-term follow-up of NETs patients, with postresection survival data based on tumor aggressiveness and extent of tumor burden of the liver on the outcomes of LT for NETs, there is no comprehensive answer to the question of efficacy of LT in patients with metastatic NETs to the liver. However, review of the available data is suggestive of the following predictors of posttransplant outcomes: (1) posttransplant survival is poorer in older patients (>55) [98]; (2) posttransplant survival is impaired when synchronous resection of the primary tumor is performed together with transplantation [98]; (3) tumors with differentiation index of low Ki-67 (less than 5 or preferably less than 2) do better [79, 81]; (4) patients with duodeno-pancreatic metastases in association with large tumor burden of the liver have are poor candidates for LT [96]; (5) at least 6 months of follow-up for evaluation of stability of the tumor before consideration of LT is appropriate [99]; and (6) patients with primary tumor originating from the stomach, pancreas, or intestine and liver metastasis are better candidates for LT [100]. Based on the outcomes reported on LT for NETs, major cancer and neuroendocrine tumor societies have made recommendations and guidelines for LT in this group of patients. The National Comprehensive Cancer Network recommends that LT for NET should be considered as “Investigational” and not a “routine care” at this time [101]. The North American Neuroendocrine Tumor Society (NANETS) (2013) guideline says: LT only be considered in a young patients with an unresectable and limited metastasis to the liver from a carcinoid primary tumor and without other risk factors [102, 103], and the European Neuroendocrine Society (ENETS) (2012) recommends that LT be considered in “selected patients” with low index of proliferation (Ki-67) and no extrahepatic spread of the tumor [104]. In summary, LT as a treatment of hepatic metastases of NETs is currently accepted for highly selected patients at some centers in the USA and Europe. However, varying criteria, heterogeneity of patients, and limited information on small number of patients in different single- and multicenter studies have not been able to completely define the role of LT in this group of patients.

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Metastatic Colorectal Tumors Colorectal cancer is one of the most frequent malignancies in the western world with an incidence of 700 per million population. About 25 % of these patients have liver involvement at the time of diagnosis, and another 25–50 % will develop liver metastasis through the course of disease. Unresectable metastatic colorectal cancer to the liver has been considered an absolute contraindication for LT. This is based on the poor results of transplantation in this group of patients reported in the early days of liver transplantation [105, 106]. Based on a report from the European Liver Transplant Registry on 58 patients registered as liver tumors of colorectal cancer origin, 1- and 5-year survival rates after liver transplantation were 62 and 18 %, respectively [107]. These outcomes from the liver transplant perspective and in the era of organ shortage were considered inferior and unacceptable when compared to other indications for liver transplantation. In a more recent prospective, pilot study from Norway, a selected group of patients with colorectal metastasis were transplanted. In a period of 4.5 years, from 2006 to 2011, 21 patients with unresectable colorectal metastasis underwent liver transplantation. The primary tumors had been resected previously and, at the time of transplant disease status in 16 of 21 patients (76 %), had progressed despite chemotherapy. The median number of metastatic lesions was 8 (range 4–40). In four patients, liver lesions were metachronous, and in the other, 17 liver lesions were present at the time of diagnosis of the primary cancer, with the median time from surgery of the primary lesion to transplantation being 36 months (16– 59 months) for metachronous lesions and 16 months (6– 36 months) for synchronous disease. The immunosuppressive regimen for these patients was consisted of sirolimus, mycophenolate mofetil, and corticosteroids, after induction with basiliximab. The overall 5-year survival rate was 60 % with a 1-year disease-free survival rate of 35 %, and no patients had long-term disease-free survival. Based on their outcomes, authors concluded that four parameters were significant for poor survival: diameter of the largest tumor (>5.5 cm), shorter than 2-year interval between the primary resection and liver transplant procedure, elevated CEA levels (more than 85) prior to the transplant, and patients with progressive disease on chemotherapy before liver transplantation. The number of liver metastasis did not have a significant impact on survival y [108]. With a short follow-up on these patients, with only 40 % of them evaluable at 3 years of follow-up after liver transplantation, and essentially all patients developing disease recurrence in 2 years, it is difficult to recognize a significant improvement in long-term outcomes of liver transplantation for metastatic colorectal cancer to the liver. This is in particular true that in most countries with shortage of organs, expectations for 5year survival after liver transplantation are around 70 % and

results of any new indication for transplantation should be essentially equivalent to other common indications for liver transplantation. Meaningful assessment of the results of liver transplantation for colorectal metastasis would be possible with better follow-up on these patients. This, very likely, would have an impact on consideration of liver transplantation in selective patients with metastatic colorectal cancer.

Summary Liver transplantation for primary and metastatic hepatic tumors has evolved dramatically. Hepatocellular carcinoma is now a common indication for transplantation with relatively good outcomes in selected group of patients following specific criteria. LT for hilar cholangiocarcinoma in a very selected group of patients has shown to be effective and with good outcomes under restrict protocols. In patients with hepatoblastoma, liver transplantation has been effective in two forms: as primary treatment in patients with unresectable lesions and favorable response to chemotherapy or as a rescue operation for tumor recurrence after liver resection. Liver transplantation for HEHE is an acceptable indication, even in the presence of limited extrahepatic spread of the tumor. Liver transplantation is considered a potential treatment in selected patients with metastatic neuroendocrine tumors to the liver. There is no general consensus in this regard, however, based on the experience on over 200 patients who received liver transplantation for this disease, it is known that results are better in patients younger than 50 years, with primary tumor completely resected more than 6 months before consideration for liver transplantation and no increase in aggressiveness of the disease and absence of extrahepatic disease and low proliferative index. Liver transplantation for metastatic colorectal cancers is in its early phases and quite immature. Almost universal recurrences in less than 2 years are not promising. Liver transplantation is contraindicated in sarcomas of the liver because of extremely poor outcomes.

Conflict of Interest The authors declare that they have no conflict of interest.

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