Liver transplantation in patients with incidental hepatocellular carcinoma/cholangiocarcinoma and intrahepatic cholangiocarcinoma: a single-center experience

Cleveland, USA

Liver transplantation in patients with incidental hepatocellular carcinoma/cholangiocarcinoma and intrahepatic cholangiocarcinoma: a single-center experience

Mohammed Elshamy, Naftali Presser, Abdulrahman Y Hammad, Daniel J Firl, Christopher Coppa, John Fung and Federico N Aucejo

Cleveland, USA

BACKGROUND: Reports of liver transplantation (LT) in patients with mixed hepatocellular carcinoma/cholangiocarcinoma (HCC/CC) and intrahepatic cholangiocarcinoma (ICC) are modest and have been mostly retrospective after pathological categorization in the setting of presumed HCC. Some studies suggest that patients undergoing LT with small and unifocal ICC or mixed HCC/CC can achieve about 40%-60% 5-year post-transplant survival. The study aimed to report our experience in patients undergoing LT with explant pathology revealing HCC/CC and ICC.

METHODS: From a prospectively maintained database, we performed cohort analysis. We identified 13 patients who underwent LT with explant pathology revealing HCC/CC or ICC.

RESULTS: The observed recurrence rate post-LT was 31% (4/13) and overall survival was 85%, 51%, and 51% at 1, 3 and 5 years, respectively. Disease-free survival was 68%, 51%, and 41% at 1, 3 and 5 years, respectively. In our cohort, four patients would have qualified for exception points based on updated HCC Organ Procurement and Transplantation Network imaging guidelines.

CONCLUSIONS: Lesions which lack complete imaging characteristics of HCC may warrant pre-LT biopsy to fully eluci-date their pathology. Identified patients with early HCC/CC or ICC may benefit from LT if unresectable. Additionally, incorporating adjunctive perioperative therapies such as in the case of patients undergoing LT with hilar cholangiocarcinoma may improve outcomes but this warrants further investigation.

(Hepatobiliary Pancreat Dis Int 2017;16:264-270)

mixed hepatocellular carcinoma/ cholangiocarcinoma; liver transplantation; survival outcomes

Introduction

Mixed hepatocellular carcinoma/cholangiocarcinoma (HCC/CC) and intrahepatic cholangiocarcinoma (ICC) are two pathological subgroups of primary liver tumors that can be observed in patients undergoing liver transplantation (LT).[1,2]Reports of LT in patients with these tumor subtypes are modest and have been mostly retrospective after pathological categorization in the setting of presumed HCC.[3,4]Although initially embraced as a mean of cure for a disease with a dismal prognosis, early experience with LT for ICC was hampered by high recurrence rates and low overall survival such that ICC became a contraindication for LT.[5,6]Nevertheless, some experience would suggest that patients undergoing LT with small and unifocal ICC (presumed HCC) can have adequate post-transplant survival.[7]

Similarly, the natural history of mixed HCC/CC is as yet incompletely defined with studies revealing conflicting results as to the behavior of these lesions.[8,9]Since HCC/CC lies somewhere between pure HCC and ICCfrom a tumor biology standpoint, LT could be considered as a surgical option in selected patients who are not candidates for resection. Scarce published data about LT in patients with mixed tumors appear to be supportive of this assumption.[5,10]Of note, no standard adjunctive therapies in the setting of LT for HCC/CC or ICC have been established and whether that would improve survival in this subset of patients remains uncertain. Herein we report our center’s experience in patients undergoing LT with explant pathology revealing HCC/CC and ICC, and a review of the literature about this subject.

Methods

A Cleveland Clinic prospectively maintained and Institutional Review Board approved LT and liver tumor related database was queried. Medical records of patients undergoing LT from January 2005 to December 2015 were reviewed and patients who underwent LT with explant pathology of mixed HCC/CC or ICC were included. Histopathologic characteristics of mixed HCC/CC and ICC including number and size, degree of differentiation and presence of vascular invasion were analyzed. Patient demographics, underlying liver diseases, model for endstage liver disease (MELD) score, pre-transplant diagnosis of HCC and pre-transplant locoregional therapy were assessed. Radiologic pre-transplant tumor characteristics were addressed using computed tomography (CT) and/or magnetic resonance imaging (MRI), the results of which were reviewed by one experienced radiologist (Coppa C). Pre-transplant tumor markers including alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) levels were analyzed. Follow-up was calculated from time of LT to last clinic visit or death. Post-LT overall survival and disease-free survival were assessed. For patients who developed disease recurrence, time from LT to disease recurrence, site of recurrence, treatment and outcome were described. Categorical variables were expressed as number and continuous variables were expressed as mean±standard error measurement (SEM). Analysis of overall survival and disease-free survival was performed utilizing the Kaplan-Meier method. Statistical analysis was performed with SPSS (version 17, SPSS Inc., Chicago, IL, USA).

Results

Table 1 summarizes the characteristics of 13 identified HCC/CC or ICC cases from our 1341 transplants over the interval examined. Nine patients had HCC/CC and four had ICC. Patients and tumor characteristics are described in Tables 1 and 2. Eight patients were male (62%), mean age was 60.0±1.7 years, and hepatitis C virus was the most common etiology of cirrhosis (n=5). The four patients with ICC had underlying cirrhosis from primary sclerosing cholangitis (n=2), secondary sclerosing cholangitis (1) and autoimmune hepatitis (1) (Table 1).

Explant histopathology

Thirteen patients had 20 tumors on explant histopathology. Four patients had just one HCC/CC tumor,three patients had just one ICC tumor and five patients had multifocal tumor including ICC, pure HCC and ICC, or pure HCC and HCC/CC. One patient had multiple microscopic foci of ICC.

Table 1. Demographic and tumor characteristics of patients receiving liver transplant with incidental findings of HCC/CC or ICC on explant pathology

Pre-LT imaging and pre-LT treatments

Preoperative imaging was examined. Four patients had lesions that ful filled Organ Procurement and Transplantation Network (OPTN) class 5 lesion characteristics for four pure HCC lesions (two patients) and one HCC/ CC lesion (two patients). In five patients, there were lesions that did not meet OPTN class 5 criteria: three ICC, one pure HCC and one HCC/CC. Due to insuf ficient imaging technique, no OPTN class 5 designation was reported in three patients (two patients with just one HCC/CC and one patient with two pure HCC and one ICC). Two patients with ICC did not have pre-LT imaging of a mass and underwent transplantation for chronic end-stage liver disease (Table 2).

Seven (54%) patients underwent pre-LT locoregional therapy via chemoembolization. One patient underwent left lateral segmentectomy for recurrent cholangitis with imaging findings showing segmental biliary dilatation and left lateral segment atrophy.

Post-LT follow-up

Mean post-LT follow-up was 35.6±8.0 months. Overall survival was 85%, 51% and 51% at 1, 3 and 5 years,respectively. Disease-free survival was 68%, 51% and 41% at 1, 3 and 5 years, respectively (Fig.).

Table 2. Radiologic and pathologic features of liver tumors

Table 2. Radiologic and pathologic features of liver tumors

Fig. Kaplan-Meier curves showing the overall survival (A) and disease-free survival (B) in patients with HCC/CC and ICC.

Seven (54%) patients died. Three patients died from tumor recurrence. One patient developedde novogastric adenocarcinoma, one died from chronic rejection and sepsis, one died as a result of chronic kidney disease, and one died as a consequence of chronic neurological disease.

Treatment of tumor recurrence

Overall tumor recurrence rate was 31% (4 patients). One patient (HCC/CC) had a recurrence 12.2 months after LT, deferred systemic chemotherapy and died 2.2 months later. One patient (ICC) developed pulmonary metastasis 2 months post-LT and died 18 months post-LT after receiving systemic chemotherapy. One patient (HCC/CC) developed bone metastases 65 months post-LT, and was undergoing chemo-radiation at the last date of follow-up. One patient (HCC/CC) developed pulmonary metastases 2.8 months post-LT and died 3 months later after receiving systemic chemotherapy.

Discussion

About a third of patients undergoing LT carry the diagnosis of HCC; and in patients within Milan criteria (single lesion ≤5 cm, or up to 3 lesions ≤3 cm each) post-LT survival is equivalent to patients undergoing LT without HCC.[11]In contrast, as opposed to hilar cholangiocarcinoma for which LT is an accepted therapy in selected patients, ICC has been considered a contraindication for LT due to poor outcomes.[12-14]There is however rather anecdotal experience demonstrating that small unifocal ICC or incidentally found ICC on explant histopathology can be associated with acceptable post-LT outcome.[6]Additionally, a small subgroup of patients with mixed HCC/CC underwent LT with presumed diagnosis of HCC.[3,6,13]Since mixed HCC/CC may have different biological behavior than HCC, and have demonstrated inferior outcomes post-LT compared to pure HCC patients, it is important to recognize these tumors pre-LT.[8]

Several classifications for HCC/CC have been proposed. Allen and Lisa[15]described a type A variant with two distinctly separate lesions, each having histology of either HCC or CC, type B variant (collision lesions) with distinct sub-areas that develop into CC and HCC; and type C variant which are hybrid lesions where histological elements of HCC and CC are truly intermingled. The histopathology of combined hepatobiliary tumors is progressively being elucidated lying between classical HCC lesions and CC. These lesions often express cellular markers of both CC and HCC. Serum AFP and CA19-9 levels, typically associated with HCC and CC respectively can both be elevated. In line with this, these “mixed” lesions likely represent a spectrum between the two diseases.[16]

Diagnosis of HCC relies mainly on characteristic imaging features and organ allocation hinges on these pathognomonic findings. Before the implementation of the new OPTN HCC radiologic criteria, the American Association for the Study of Liver Disease (AASLD) guidelines relied fundamentally on the presence of arterial phase hyper-vascularity or enhancement with subsequent portal venous phase or delayed phase “washout” on cross-sectional contrasted studies to presume diagnosis of HCC.[17]Washout is based on the premise that HCC contains mostly arterial blood and by the time of delayed imaging has relatively less observed compared to normal liver, thus appearing hypo-attenuating. In contrast, CC tend to demonstrate delayed enhancement. However, the imaging characteristics of HCC/CC are less well defined.

In one recent study, sensitivity of both CT and MRI imaging for detecting HCC/CC was about 33% with lesions being mistaken for both HCC and CC; thus highlighting the diagnostic challenges associated with this diagnosis.[17]The current OPTN guidelines for the imaging diagnosis of HCC are as follows: for lesions 1-2 cm characteristic arterial enhancement with both portal/ venous phase contrast washout and pseudo-capsule enhancement are required while either washout or pseudocapsule enhancement suffice for lesions 2-5 cm. Alternately, if these conditions are not fulfilled, demonstration of ＞50% growth over 6 months allows for a diagnosis of HCC. These OPTN class 5 lesions qualify for MELD ex-ception points in current organ allocation schema. In our series with patients presenting with pre-transplant liver masses, after excluding one patient where pre-LT imaging could not be retrieved, three patients fulfilled none of the OPTN class 5 imaging criteria, two patients did not fully fulfill OPTN class 5 criteria and were reported to be indeterminate or atypical and only four fulfilled all criteria for OPTN class 5 HCC diagnosis. Thus, four lesions would have qualified for exception points based on updated HCC imaging guidelines.[17,18]Of note, CT imaging protocols used at the time when several patients in our series were imaged did not incorporate delayed phase imaging, which is now mandated by OPTN and helps to appreciate wash-out and delayed enhancement used to differentiate HCC and CC.

Table 3. Summary of published reports of LT for ICC and HCC/CC

Some reports suggest that HCC/CC trend towards decreased survival compared with pure HCC.[10,19]Recent studies[20,21]have corroborated these findings with survival curves for mixed tumors falling between pure HCC and ICC, showing relatively poorer and better survival, respectively.

While LT along with neoadjuvant therapy in selected patients with hilar cholangiocarcinoma has become promising, the applicability of LT for non-resectable small unifocal ICC or HCC/CC remains to be fully elucidated.[22-24]One of the largest prospective series to date describes 42 patients with 27 ICC and 15 HCC/CC. Recurrence rates for HCC/CC were similar to HCC controls (1-, 3- and 5-year recurrence rates of 7%, 7% and 7%, respectively vs 0%, 4% and 4% for controls;P=0.6), as was actuarial survival (HCC/CC 1-, 3- and 5-year overall survival 93%, 78% and 78% vs 97%, 86% and 86% for the HCC controls;P=0.9).[3]ICC tended to have higher recurrence rates than HCC controls (12%, 25% and 36% vs 0%, 2% and 2%, respectively;P〈0.001) and lower overall survival (78%, 66% and 51% vs 100%, 98% and 93%, respectively;P〈0.001). This study’s conclusion was in support of LT for patients with HCC/CC.[3]In contrast, an analysis of the Surveillance, Epidemiology, and End Results (SEER) database reviewed 3378 patients undergoing resection or transplant for HCC of which 54 were found on pathology to have HCC/CC with conflicting results.[10]Patients undergoing resection were found to have 3-year survival of 46% vs 55% (P=0.4), respectively for HCC/CC vs HCC controls while survival after LT for HCC/CC vs HCC controls was 48% vs 78%, respectively (P=0.01). These lower rates of survival for HCC/CC after LT are consistent with outcomes of ICC and as such the study investigators questioned the indication of transplant for patients with HCC/CC (Table 3).[3,10,25-28]Additionally, a recent study[28]looking at ICC suggested that further differentiation in outcomes are demonstrable between different levels of pathological differentiation of ICC with improved outcomes in the setting of well differentiated tumors (vs moderate differentiation). This lends another layer of complexity when considering transplantation for such patients.

The ongoing conundrum for this subset of patients is two-fold. First, most are diagnosed on pathological assessment post-LT. Second, in the event of correct preoperative diagnosis organ allocation to such patients is questionable based on limited reported outcomes.

Optimally, increased suspicion will be raised in the future when liver lesions don’t completely fulfill the new OPTN HCC diagnosis criteria leading to an increasing number of these lesions being identified preoperatively. Lesions which lack complete imaging characteristics of HCC may warrant pre-LT biopsy to fully elucidate their pathology. Additionally, incorporating adjunctive perioperative therapies for HCC/CC and ICC, similar to the case of patients undergoing LT with hilar cholangiocarcinoma may improve outcomes. This assumption will nevertheless require further investigation.

Contributors:EM, PN, HAY and FDJ performed the research, collected and analyzed the data. CC read and interpreted the radiological imaging. All authors contributed to the design and interpretation of the study. The final version of the manuscript has been read and approved by all of the authors. AFN is the guarantor.

Funding:None.

Ethical approval:This study was approved by Cleveland Clinic Institutional Review Board.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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October 4, 2016

Accepted after revision February 28, 2017

Author Affiliations: Hepatobiliary and Transplant Surgery, Digestive Disease and Surgery Institute (Elshamy M, Presser N, Hammad AY, Firl DJ, Fung J and Aucejo FN), and Imaging Institute (Coppa C), Cleveland Clinic, Cleveland, OH, USA

Federico N Aucejo, MD, Hepatobiliary and Transplant Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, 9500 Euclid Ave. /A100, Cleveland, OH 44195, USA (Tel: +216-445-8021; Email: aucejof@ccf.org)

? 2017, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(17)60016-X

Published online May 3, 2017.