EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Liver transplant is now an acceptable and effective treatment for specific nonhepatocellular malignancies. Worldwide, hilar cholangiocarcinoma accounts for 3% of all primary gastrointestinal malignancies and for 10% of primary hepatobiliary malignancies. For patients who have early-stage, unresectable cholangiocarcinoma, liver transplant preceded by neoadjuvant radiotherapy can result in tumor-free margins, accomplish a radical resection, and treat the underlying primary sclerosing cholangitis when present. Hepatic epithelioid hemangioendothelioma is a rare tumor of vascular origin with a variable malignant potential. Excellent results have been reported with liver transplant for patients with unresectable hepatic epithelioid hemangioendothelioma, with 1-year and 10-year survival rates of 96% and 72%. Hepatoblastoma is the most common primary hepatic malignancy in children. The long-term survival rate after transplant ranges from 66% to 77% in patients with unresectable tumors and good response to chemotherapy. Metastatic liver disease is not an indication for liver transplant, with the exception of cases in which the primary tumor is a neuroendocrine tumor. Indication for liver transplant for hepatic metastasis from neuroendocrine tumors 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. Some recent data on liver transplant for unresectable hepatic metastases from colorectal cancer have reported limited survival benefits compared with previous reports. However, due to the high rate of tumor recurrence in a very short time after liver transplant, especially in the era of organ shortage, this indication has not been favored by the transplant community. The indications for liver transplant for nonhepatocellular carcinoma malignancy and its limitations have evolved dramatically over the past decades and will continue to be redefined through future research and investigations.

Key words : Cholangiocarcinoma, Hepatic epithelioid hemangioendothelioma, Hepatoblastoma, Metastatic liver disease

Liver transplant (LT) is the only curative treatment option for patients with irrevocable acute or chronic liver failure, and, during the past 4 decades, it has developed from an experimental approach with high mortality to an almost routine procedure with good short- and long-term survival rates. During the past 15 years, survival rates worldwide have been relatively stable, with an overall survival (OS) of > 80% in the first year and > 70% at 5 years.^1,2

In 1967, Starzl and associates performed the first successful LT for a patient diagnosed with hepatoblastoma.³ Liver transplant is currently incorporated into treatment regimens for specific nonhepatocellular malignancies. Table 1 summarizes indications and contraindications for LT in patients with malignancies.⁴ In addition to hepatocellular carcinoma (HCC), hepatoblastoma and epithelioid hemangioendothelioma are also standard indications for LT. Investigational indications include cholangiocarcinoma and neuroendocrine liver metastases. However, hepatoblastoma with uncontrolled extrahepatic disease is a contraindication for LT.

Cholangiocarcinoma
Cholangiocarcinoma is the second most common primary hepatobiliary malignancy in the United States; worldwide, it accounts for 3% of all primary gastrointestinal malignancies and for 10% of primary hepatobiliary malignancies.⁵ The mortality rate for untreated cholangiocarcinoma ranges from 50% to 70% within 12 months⁶; therefore, aggressive treatment is warranted. Surgical resection is the mainstay of treatment for periductal cholangiocarcinoma and yields 5-year survival rates of 27% to 44%.^7,8

Risk factors associated with cholangiocarcinoma are presence of primary sclerosing cholangitis, ulcerative colitis, choledochus cysts, hepatic tremadodes, hepatolithiasis, and hepatitis C virus. In contrast to HCC, cholangiocarcinoma originates in the bile duct epithelium and can be defined as intrahepatic, perihilar, or distal cholangiocarcinoma.⁴

Invasion into the main portal vein, common hepatic artery, or into 1 lobe of the liver with invasion of the contralateral branch of the portalvein or hepatic artery are criteria for unresectability.^9,10 In an analysis of various studies about survival after LT for cholangiocarcinoma, Castaldo and associates¹¹ showed that 5-year OS rates were between 0% and 42% (range, 0%-83%). The group established that cholangiocarcinoma is a poor indication in general for transplant due to high disease recurrence with few long-term survivors. This observation helped stimulate a more selective approach to transplant forcholangiocarcinoma, although some studies showed that LT for early-stage hilar cholangiocarcinoma in selected individuals can nevertheless be effective.¹¹

In their review of selected single-center series of resection for intrahepatic cholangiocarcinoma, Rana and associates showed that mortality rate was 9.5% at most, although 3-year and 5-year survival rates remained poor at 18% to 52% and 10% to 31%. However, the investigators concluded that, for unresectable intrahepatic cholangiocarcinoma, orthotopic LT in combination of neoadjuvant therapy inappropriately selected patients led to improved tumor recurrence-free survival after transplant. As such, expansion of LT criteria for treatment of intrahepatic cholangiocarcinomais recommended.¹²

In 2012, a first meta-analysis of 605 patients undergoing LT for cholangiocarcinomashowed pooled 1-year OS of 75%, 3-year OS of 42%, and 5-year OS of 39%. Importantly, in patients transplanted after neoadjuvant therapy, 5-year OS was 65%,which is thus comparable to survival rates of LT for HCC within the Milan criteria.¹³ Groeschl and associates analyzed the outcomes of the largest cohort to date of patients who underwent LT for combined HCC and cholangiocarcinoma (n = 19) using the Surveillance, Epidemiology, and End Results database (1973 to 2007). The 3-year survival rate was in the 50% range, which was worse than that forHCC (78%).¹⁴

Recently, a multicenter study from Spain depicted more promising results, with a 5-year survival rate of approximately 80% for a combined HCC-cholangiocarcinoma cohort (n = 15), equivalent to a 1:2 matched cohort of HCC (n = 30). Furthermore, no significant differences were observed in the 5-year cumulative risk of recurrence between the 2 cohorts (7% for HCC versus 4% for cholangiocarcinoma). This lower recurrence rate than previous reports could be attributed to the fact that 67% of patients had a single tumor and <20% showed microvascular invasion or satellite lesions. The authors concluded that a preoperative biopsy resulting in a diagnosis of combined HCC-cholangiocarcinoma should not exclude patients from LT.¹⁵

Hepatic epithelioid hemangioendothelioma
Hepatic epithelioid hemangioendothelioma was first described and characterized in 1982 as a low-grade malignant soft tissue tumor.¹⁶ This disease has an incidence of 1per million, and diagnosis is often challenging.¹⁷ Its clinical presentation is nonspecific and includes abdominal pain, hepatomegaly, and fatigue.^18,19 The clinical course of hepatic epithelioid hemangioendothelioma varies between almost benign behavior, like hemangioma, to rapid progress, like angiosarcoma.²⁰

Liver transplant remains the only potentially curative approach for unresectable hepatic epithelioid hemangioendothelioma with or without extrahepatic tumor manifestation. Liver transplant has been proposed for patients with hepatic epithelioid hemangioendothelioma having a diffuse disease pattern, tumor size >10 cm, >10 nodules, and greater than 4 segments of hepatic involvement.²¹

In an analysis of several series involving more than 5 patients and 2 reviews analyzing LT for hepatic epithelioid hemangioendothelioma, including synopses of United Network for Organ Sharing (UNOS), European, and Canadian databases, Hackl and associates concluded that, with 5-year OS at 83% (even in the presence of extrahepatic disease) and 5-year diease-free survival at 46% to 82%, the outcome of LT for hepatic epithelioid hemangioendothelioma is comparable with nonmalignant indications for LT.⁴ Therefore, LT should be offered to all patients with unresectable hepatic epithelioid hemangioendothelioma or resectable hepatic epithelioid hemangioendothelioma with unfavorable predictors.⁴

Hepatoblastoma
Hepatoblastoma is the most common primary hepatic malignancy in children, first described in 1954 by Debre and colleagues.²² Incidence of hepatoblastoma is 1 to 2 per million.²³ The long-term survival rate after transplant ranges from 66% to 77% in patients with unresectable tumors, a quite promising result, especially in those with good response to chemotherapy.

In the same study, Hackl and associates also analayzed data of LT for hepatoblastoma. They found that long-term OS after transplant ranged from 65% to 87%, even in the presence of extrahepatic, chemoresponsive disease. The group thus concluded that LT should be offered to all patients with unresectable hepatoblastoma. In borderline-resectable hepatoblastoma, LT should be considered since long-term OSwas shown to be 85% to 90% in patients receiving primary LT for hepatoblastoma compared with 25% to 40% in rescue transplant for recurrent disease after prior liver resection.⁴

Neuroendocrine liver metastases
Neuroendocrine carcinomas were first described in 1907 by Siegfried Oberndorfer.²⁴ Neuroendocrine carcinomas have an incidence of ≤ 5 per 100 000, show variable locations, and have a variable natural course of the disease.²⁵

According to the World Health Organization, neuroendocrine tumors should beclassified by mitotic index and Ki-67 labeling index as follows: low-grade (G1) tumors have a mitotic index < 2 per 10 high-powered fields (HPFs) and Ki-67 positivity of < 3%, intermediate-grade (G2) tumors havea mitotic index of 2 to 20 per 10 HPFs and Ki-67 positivity of 3% to 20%, and high-grade (G3) tumors have amitotic index of > 20 per 10 HPFs and Ki-67 positivity of > 20%.²⁶

Treatment strategies for neuroendocrine liver metastases include antihormonal therapy, interferon and chemotherapeutic treatment, regional ablation, and surgery.^27,28 Analyses of the Surveillance, Epidemiology, and End Result database have shown 5-year OS rates of 35% in G1 and G2 neuroendocrine tumors and of < 5% for G3 tumors. However, a 5-year OS rate of > 50% has been described incertain G1 patients after combined medical-surgical therapy without LT.²⁹

Together with the 2 preexisting guidelines, LT should be considered a viable option in patients with well-differentiated neuroendocrine tumors (G1/G2), a Ki-67 index of <10%, up to 75% liver involvement, no extrahepatic disease, age <55 years, primary tumor removed before LT, and stable disease for at least 6 months, with no major extrahepatic resection to be performed concurrently with LT.^29,30

In their analysis of neuroendocrine liver metastases in series with > 100 patients, including a synopsis of UNOS and European databases, Hackl and associates reported 5-year OS rates of 47% to 58%. In the most comprehensive reports from UNOS and European databases, 5-year overall survival was 49% and 52%. Of significance from these analyses, patients who received LT for neuroendocrine liver metastases had previously undergone nontransplant medical and surgical therapy, and, in the European database analysis, 5-year OS rates from first diagnosis were 73% (84% for patients diagnosed after 2000). In the UNOS database, the 5-year OS rates after LT were comparable to the 5-year OS rates of 4693 patients transplanted for HCC during the same period. Current National Comprehensive Cancer Networkguidelines define LT for neuroendocrine liver metastasesas an investigational procedure, with research ongoing to define predictors for patient selection.⁴

Colorectal cancer liver metastasis
The primary metastatic site for patients diagnosed with colorectal cancer is the liver, with 60% to 70% of metastatic recurrences in patients with colorectal cancer occurring in the liver and up to 35% of metastatic colorectal cancer patients having metastases only in this organ.³¹ Up to now, colorectal liver metastasis is a contraindication for LT due to (1) allocation justice in light of deceased-donor organ shortages and (2) high rates of tumor recurrence after transplant.^32,33

Hagness and colleagues performed LT for 21 patients diagnosed with unresectable colorectal liver metastasis and reported estimated 1-year OS of 95%, 3-year OS of 68%, and 5-year OS of 60%. In addition, patients reported good quality of life during the first year after transplant.³⁴ Furthermore, equivalent to the Milan criteria, prognostic factors such as maximum hepatic tumor diameter < 5.5 cm, time from colorectal cancer surgery > 2 years, carcinoembryonic antigen level of < 80 μg/L, and stable disease or partial response after chemotherapy before LT were defined.³⁴ The group concluded that thesemay serve as future criteria for selecting patients with colorectal liver metastasis who are eligible for LT.³⁴

Başkent University Experience
Between December 8, 1988 and October 31, 2016, Baskent University performed 526 LT procedures. Of these, 12 patients hadLT for non-HCCmalignancy. As shown in Table 2, 6 patients had hepatoblastoma, 2 had cholangiocarcinoma, and 2 had angiosarcoma. Half of the patients died, with others to date alive. Survival rates were between 3 months and 3 years.

To increase evidence-based indications for LT, further clinical trials are needed for the (1) comparison of long-term oncologic and overall outcomes of living-donor versus deceased-donor LT in malignant disease; (2) establishment of predictive criteria to select patients whocan benefit the most from LT; (3) standardization of organ allocation rules outside the Model for End-Stage Liver Disease criteria for defined malignancies; (4) establishment of standard perioperative chemotherapeutic regimens combined with LT; and (5) improvement of long-term antiproliferative immunosuppressive therapy.⁴

The indications for LT for non-HCC malignancy and its limitations have evolved dramatically over the past decades and will continue to be redefined through future research and investigation.

Volume: 15 Issue: 2 March 2017 - Supplement - 2

FULL TEXT