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

Corresponding Author: 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.

doi: 10.1016/S1499-3872(17)60016-X

Published online May 3, 2017.

 

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.

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 elucidate 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)

 

KEY WORDS: mixed hepatocellular carcinoma/cholangiocarcinoma; liver transplantation; survival outcomes

 

 

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 ICC from 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.

 

 

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 end-stage 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).

 

 

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).

 

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.

 

Preoperative imaging was examined. Four patients had lesions that fulfilled 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 insufficient 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.

 

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.).

 

Seven (54%) patients died. Three patients died from tumor recurrence. One patient developed de novo gastric 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.

 

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.

 

 

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 pseudo-capsule 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 exception 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.

 

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.

 

 

1 Vilchez V, Shah MB, Daily MF, Pena L, Tzeng CW, Davenport D, et al. Long-term outcome of patients undergoing liver transplantation for mixed hepatocellular carcinoma and cholangiocarcinoma: an analysis of the UNOS database. HPB (Oxford) 2016;18:29-34. PMID: 26776848

2 Hashimoto K, Miller CM. Liver transplantation for intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci 2015;22:138-143. PMID: 25214036

3 Sapisochin G, de Lope CR, Gastaca M, de Urbina JO, López-Andujar R, Palacios F, et al. Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study. Ann Surg 2014;259:944-952. PMID: 24441817

4 Sapisochin G, Facciuto M, Rubbia-Brandt L, Marti J, Mehta N, Yao FY, et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment. Hepatology 2016;64:1178-1188. PMID: 27481548

5 Goldstein RM, Stone M, Tillery GW, Senzer N, Levy M, Husberg BS, et al. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 1993;166:768-772. PMID: 8273866

6 Pichlmayr R, Weimann A, Oldhafer KJ, Schlitt HJ, Klempnauer J, Bornscheuer A, et al. Role of liver transplantation in the treatment of unresectable liver cancer. World J Surg 1995;19:807-813. PMID: 8553670

7 Sapisochin G, Rodríguez de Lope C, Gastaca M, Ortiz de Urbina J, Suarez MA, Santoyo J, et al. “Very early” intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am J Transplant 2014;14:660-667. PMID: 24410861

8 Yin X, Zhang BH, Qiu SJ, Ren ZG, Zhou J, Chen XH, et al. Combined hepatocellular carcinoma and cholangiocarcinoma: clinical features, treatment modalities, and prognosis. Ann Surg Oncol 2012;19:2869-2876. PMID: 22451237

9 O’Connor K, Walsh JC, Schaeffer DF. Combined hepatocellular-cholangiocarcinoma (cHCC-CC): a distinct entity. Ann Hepatol 2014;13:317-322. PMID: 24756005

10 Groeschl RT, Turaga KK, Gamblin TC. Transplantation versus resection for patients with combined hepatocellular carcinoma-cholangiocarcinoma. J Surg Oncol 2013;107:608-612. PMID: 23386397

11 Figueras J, Jaurrieta E, Valls C, Benasco C, Rafecas A, Xiol X, et al. Survival after liver transplantation in cirrhotic patients with and without hepatocellular carcinoma: a comparative study. Hepatology 1997;25:1485-1489. PMID: 9185772

12 Becker NS, Rodriguez JA, Barshes NR, O’Mahony CA, Goss JA, Aloia TA. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2008;12:117-122. PMID: 17963015

13 Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000;69:1633-1637. PMID: 10836374

14 Goss JA, Shackleton CR, Farmer DG, Arnaout WS, Seu P, Markowitz JS, et al. Orthotopic liver transplantation for primary sclerosing cholangitis. A 12-year single center experience. Ann Surg 1997;225:472-483. PMID: 9193175

15 Allen RA, Lisa JR. Combined liver cell and bile duct carcinoma. Am J Pathol 1949;25:647-655. PMID: 18152860

16 Roncalli M, Park YN, Di Tommaso L. Histopathological classification of hepatocellular carcinoma. Dig Liver Dis 2010;42:S228-234. PMID: 20547308

17 Wald C, Russo MW, Heimbach JK, Hussain HK, Pomfret EA, Bruix J. New OPTN/UNOS policy for liver transplant allocation: standardization of liver imaging, diagnosis, classification, and reporting of hepatocellular carcinoma. Radiology 2013;266:376-382. PMID: 23362092

18 Fowler KJ, Sheybani A, Parker RA 3rd, Doherty S, M Brunt E, Chapman WC, et al. Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast-enhanced CT and MRI. AJR Am J Roentgenol 2013;201:332-339. PMID: 23883213

19 Cao J, Huang L, Liu C, Li J, Zhang X, Shen J, et al. Double primary hepatic cancer (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) in a single patient: a clinicopathologic study of 35 resected cases. J Gastroenterol Hepatol 2013;28:1025-1031. PMID: 23425127

20 Tang D, Nagano H, Nakamura M, Wada H, Marubashi S, Miyamoto A, et al. Clinical and pathological features of Allen’s type C classification of resected combined hepatocellular and cholangiocarcinoma: a comparative study with hepatocellular carcinoma and cholangiocellular carcinoma. J Gastrointest Surg 2006;10:987-998. PMID: 16843869

21 Koh KC, Lee H, Choi MS, Lee JH, Paik SW, Yoo BC, et al. Clinicopathologic features and prognosis of combined hepatocellular cholangiocarcinoma. Am J Surg 2005;189:120-125. PMID: 15701504

22 Yoon YI, Hwang S, Lee YJ, Kim KH, Ahn CS, Moon DB, et al. Postresection outcomes of combined hepatocellular carcinoma-cholangiocarcinoma, hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Gastrointest Surg 2016;20:411- 420. PMID: 26628072

23 Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B Jr, McCashland T, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant 2002;2:774-779. PMID: 12243499

24 Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Pedersen R, Kremers W, et al. Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006;82:1703-1707. PMID: 17198263

25 Panjala C, Senecal DL, Bridges MD, Kim GP, Nakhleh RE, Nguyen JH, et al. The diagnostic conundrum and liver transplantation outcome for combined hepatocellular-cholangiocarcinoma. Am J Transplant 2010;10:1263-1267. PMID: 20420633

26 Hu XX, Yan LN. Retrospective analysis of prognostic factors after liver transplantation for intrahepatic cholangiocarcinoma in China: a single-center experience. Hepatogastroenterology 2011;58:1255-1259. PMID: 21937390

27 Sapisochin G, Fidelman N, Roberts JP, Yao FY. Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transpl 2011;17:934-942. PMID: 21438129

28 Takahashi K, Obeid J, Burmeister CS, Bruno DA, Kazimi MM, Yoshida A, et al. Intrahepatic cholangiocarcinoma in the liver explant after liver transplantation: histological differentiation and prognosis. Ann Transplant 2016;21:208-215. PMID: 27068242