Original Clinical Science
Tumors With Intrahepatic Bile Duct Differentiation in Cirrhosis: Implications on Outcomes After Liver Transplantation Marcelo E. Facciuto,1 Manoj K. Singh,1 Nir Lubezky,1 Motaz A. Selim,1 Dorothy Robinson,1 Leona Kim-Schluger,1 Sander Florman,1 Stephen C. Ward,2 Swan N. Thung,2 MariaIsabel Fiel,2 and Thomas D. Schiano1 Background. The role of liver transplantation (LT) in the management of cirrhotic patients with tumors exhibiting intrahepatic bile
duct differentiation remains controversial. The objective of this study was to characterize the spectrum of these tumors and analyze post-LT outcomes. Methods. Retrospective pathology database search of explant histology analysis of liver transplants between April 1993 and November 2013. Results. Thirty-two patients were analyzed, 75% were men with a mean age of 60 years. Seven patients had nodules demonstrating intrahepatic cholangiocarcinoma (I-CCA), nine had I-CCA nodules occurring concomitantly with hepatocellular carcinoma (HCC), and 16 had mixed HCC-CCA nodules. The median number of tumors was 1 and size was 2.5 cm. Overall patient survival post-LT at 1 and 5 years was 71% and 57%, respectively. Patients within Milan criteria, especially with I-CCA features, showed a 5-year tumor recurrence rate (10%) and 5-year survival rate (78%) comparable with other patients having HCC within Milan criteria. Conclusion. This series showed that patients with CCA within Milan criteria may be able to achieve acceptable long-term post-LT survival. (Transplantation 2014;99: 151–157)
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holangiocarcinoma (CCA) is a primary hepatobiliary malignant neoplasm arising from epithelial cells of the intra-and extrahepatic bile ducts.1 The American Joint Committee on Cancer, in the seventh edition of the American Joint Committee on Cancer Staging Manual, has a novel staging system for intrahepatic bile duct cancer, independent of the staging system for hepatocellular carcinoma (HCC), and extrahepatic bile duct malignancy, including hilar bile duct cancers.2 The staging system for intrahepatic bile duct
Received 26 February 2014. Revision requested 24 March 2014. Accepted 5 May 2014. 1
Recanati Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY.
2
The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, New York, NY.
The authors declare no funding or conflicts of interest. M.E.F. participated in research design, data analysis, and writing of article. M.K.S. participated in performance of research, data analysis, and writing of article. N.L. participated in performance of research and article writing. M.A.S. participated in performance of research and data collection. D.R. participated in performance of research and data collection. L.K.-S. participated in research and review of article. S.F. participated in research and review of article. S.C.W. participated in research and writing of article. S.N.T. participated in research and writing of article. M.I.F. participated in research and writing of article. T.D.S. participated in research design and writing of article. Correspondence: Marcelo E. Facciuto, MD, MPH, Recanati/Miller Transplantation Institute, One Gustave L. Levy Place, Box 1104, New York, NY 10029. (marcelo. [email protected]) Copyright © 2014 Wolters Kluwer Health, Inc. All right reserved. ISSN: 0041-1337/15/9901-151 DOI: 10.1097/TP.0000000000000286
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tumors applies to carcinomas of the intrahepatic bile ducts. These include intrahepatic CCA (I-CCA), and the rare combined HCC and CCA (mixed HCC-CCA). Intrahepatic cholangiocarcinoma represents 5% to 10% of CCAs and typically present as an intrahepatic mass.3-6 Mixed HCC-CCA is an uncommon form of primary liver cancer arising from the epithelial cells of the liver (hepatocytes and cholangiocytes).7 It accounts for 1% to 14% of all primary liver tumors.8-10 Mixed HCC-CCA have histologic features of both HCC and CCA, believed to originate from hepatic progenitor cells, and have a strong correlation with the presence of underlying liver disease, especially hepatitis C virus infection and advanced fibrosis.11 Although this variant is well described histopathologically, the clinical and radiologic features have not been well characterized and so far are not distinctive.9 Because the diagnosis of mixed HCC-CCA is challenging preoperatively to make, most of these tumors are managed as HCC or CCA, only to be diagnosed as mixed HCC-CCA incidentally on resected specimens, liver explant, or at autopsy.12 Data on the incidence of mixed HCC-CCA and I-CCA in pretransplant patients are lacking because of the inability to differentiate these tumors from HCC by imaging. Chan et al.13 reported an overall incidence of 0.7% for mixed HCC-CCA based on explant pathologic analysis among predominantly hepatitis B-infected patients who underwent liver transplantation (LT). Sapisochin et al.14 reported an incidence of 3.3% in their series, Panjala et al.15 reported 12 patients with mixed HCC-CCA tumor found on explant among patients who underwent LT for HCC over a 10-year period. There is no clear consensus as to the best treatment strategy for patients with this spectrum of tumors exhibiting intrahepatic bile duct differentiation. Surgical resection is www.transplantjournal.com
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regarded as the primary curative treatment of selected patients. Unfortunately, overall 5-year survival rates range from 20% to 40% in those patients undergoing potential curative surgical resection.16-23 Although surgical resection is the treatment of choice, many patients have unresectable tumors because of associated underlying liver disease. For these patients, LT remains the only option. Thus, LT provides the option of wide resection margins, thereby expanding the indication of surgical intervention to patients who otherwise would not be candidates for surgery because of lack of functional hepatic reserve. However, results with LT in intrahepatic bile duct tumors have not been dramatically different compared with those of surgical resection, with 5-year survival rates ranging from 30% to 36%.24-28 The suboptimal results of LT for these tumors are mainly because of the high tumor recurrence rate.29-31 The Cincinnati Transplant Tumor Registry has reported a 28% 5-year survival with a 51% tumor recurrence rate.26 The goal of this study was to provide an in-depth and accurate assessment of the impact of tumor staging and histopathologic features of intrahepatic bile duct tumors on long-term outcome after LT. RESULTS This study involved 32 patients with explant pathology diagnosis of tumors with intrahepatic bile duct differentiation and cirrhosis. Patient clinical characteristics are listed in Table 1. Most of the patients were men, with a mean age of 60 years at LT. Most patients had hepatitis C virus (50%), and none of them had primary sclerosing cholangitis. Twenty-eight patients had the presumptive preoperative diagnosis of HCC, and only four patients had biopsy-proven I-CCA, preoperatively. Twenty-two patients (69%) received preoperative tumor ablation therapy. Twelve patients received transarterial chemoembolization (TACE), one patient radiofrequency ablation (RFA), six patients received a combination of TACE+RFA, one patient received stereotactic body radiation therapy (SBRT), and two patients received combination of TACE+SBRT. Tumor characteristics are listed in Table 1. Patients within Milan criteria had an average I-CCA tumor size of 1.97 cm, ranging from 0.8 to 4.8, with only one tumor greater than 2.5 cm. Patients outside Milan criteria had an average I-CCA tumor size of 3.8 cm, ranging from 1 to 12 cm. Seven patients had only nodules demonstrating I-CCA, in a background of hepatitis B virus (three cases), NASH (one case), and ETOH (three cases). Nine patients had Goodman type I nodules: I-CCA concomitantly with other HCC nodules. The remaining 16 patients were classified as Goodman type II, including four patients with mixed HCC-CCA nodules and 12 patients with mixed HCC-CCA nodules and concomitant HCC nodules. Cholangiocarcinoma vascular invasion was demonstrated in 41% of the patients, and median nodule size was 2.5 cm. Pathologic tumor staging included all tumors, and was based on the American Liver Tumor Study Group (ALTSG) system; 31% of the patients were considered within Milan criteria (ALTSG stages I and II), whereas 69% of the patients fell outside the Milan criteria (ALTSG stages III and above). Patients with only I-CCA and Goodman type I nodules were equally distributed within and outside Milan criteria (50% within, 50% outside Milan criteria), but accounted for most of the patients within Milan criteria (8 of 10). Patients with
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TABLE 1.
Clinical characteristics of patients with tumors having intrahepatic bile duct differentiation and cirrhosis Patient demographics
Patients (n) Age (mean, yr) Male (n) Origin HCV (n) Other (n) (HBV, NASH, ETOH) MELD score (median) Preoperative ablation (n) Tumor characteristics Largest tumor (median, cm) Nodules (median, n) Microvascular invasion, CCA (n) Differentiation grade, CCA (n) Well Moderate Poor Histologic type (n) Only I-CCA Goodman type I (I-CCA and HCC in separate nodules) Goodman type II (Mixed HCC-CCA in same nodule) (Mixed HCC-CCA+concomitant HCC nodules) Grouped histologic type features (n) Patients with I-CCA features Only I-CCA+Goodman type I Patients with mixed HCC-CCA features Goodman type II Microvascular invasion, HCC (n) pALTSG classification for all nodules (n) I II III IV A1 IV A2 IV B pMilan classification for all nodules (n) Within (ALTSG I, II) Outside (ALTSG>II)
32 60 24 (75%) 16 (50%) 16 (50%) 13.5 22 (69%) 2.5 (0.8-12) 1 (1-5) 13 (41%) 7 (24%) 14 (48%) 8 (28%) 7/32 (22%) 9/32 (50%)
4/32 (13%) 12/32 (38%) 16/32 (50%) 16/32 (50%) 14/22 (64%) 4 (13%) 6 (19%) 7 (22%) 11 (34%) 3 (9%) 1 (3%) 10/32 (31%) 22/32 (69%)
HCV, hepatitis C virus; HBV, hepatitis B virus; MELD, model for end-stage liver disease; ALTSG, American Liver Tumor Study Group; CCA, cholangiocarcinoma; I-CCA, intrahepatic CCA; HCC, hepatocellular carcinoma.
Goodman type II nodules were predominantly outside Milan criteria (two patients were within Milan criteria [12%], and 14 patients were outside Milan criteria [88%]). The difference on overall tumor staging for only I-CCA and Goodman type I versus Goodman type II was statistically significant (P=0.02). Patients were followed for a mean of 47 months and a median of 28 months (range, 3-199 months). Tumor Recurrence
Tumor recurrence occurred in 12 patients (38%) at a median time of 5 months. Five were CCA recurrences (two originated from I-CCA, one in Goodman type I, and two in Goodman type II), and seven were HCC recurrences.
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All five patients with CCA recurrence showed bad tumor prognostic factors on CCA nodules: all had vascular invasion, two had poor differentiation, two had a size greater than 5 cm, and four of five were outside Milan criteria. By logistic regression analysis, vascular invasion of the CCA component was found to be an independent factor for CCA recurrence after LT (P=II)
CCA
HCC matched control group
32 60 24 (75%)
64 60 53 (83%)
16 (50%) 16 (50%)
33 (51%) 31 (49%)
4 6 7 11 3 1
8 12 14 22 6 2
10 (31%) 22 (69%)
20 (31%) 44 (69%)
P
0.77 0.37 0.89
1
1
HCV, hepatitis C virus; ALTSG, American Liver Tumor Study Group; CCA, cholangiocarcinoma; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HBV, hepatitis B virus.
staging and histopathologic characteristics on patient outcomes after LT. Intrahepatic cholangiocarcinoma and mixed HCC-CCA are considered aggressive tumors with survival rates after surgical resection of 35% to 68% and 23% to 38% at 3 years; 28% to 35% and 8% to 24% at 5 years, respectively, with median survival ranging from 23 to 37 months for I-CCA and 10 to 32 months for mixed HCC-CCA.32-36 The role of LT in the management of intrahepatic bile duct tumors is not well defined to date. Previously reported results of LT for CCA have been disappointing with 3-year survival rates of 20% to 40% and disease recurrence rates of 50% to 60%.26,30,37 Sapisochin et al.14 reported the UCSF experience in 14 patients transplanted for mixed HCC-CCA and I-CCA, four of them with incidental tumors. They found a 57% incidence of tumor recurrence. After a median followup of 14 months from LT, the 1-year and 5-year survival was 76% and 51%, respectively. Patients with mixed HCC-CCA showed a trend toward worse prognosis, a higher rate of tumor recurrence, and a shorter period of DFS in comparison with the patients having only I-CCA or Goodman type I tumors. In our series, the overall recurrence rate was 38%. Recurrences were similarly distributed among CCA or HCC recurrences. Patients with early stage tumors (within Milan criteria) had a lower recurrence rate as opposed to patients with advanced stage (outside Milan criteria) tumors (10% vs. 50%). Even though we did not find a difference in recurrence rate between histopathologic tumor types, we should bear in mind that 80% of patients within Milan criteria had nodules with I-CCA features, who in fact, did not develop recurrence. This observation suggests that favorable outcomes for tumors with I-CCA features within Milan are achievable. On the contrary, nearly 90% of mixed HCC-CCA nodules were found in patients outside Milan criteria. Mixed HCCCCA tumors were historically associated with a worse prognosis.14 However, this less favorable natural history may not be in fact because of more aggressive behavior in mixed histology tumors, but rather a reflection of a more advanced tumor stage at the time of transplant.
Post-LT DFS was associated with overall tumor staging. Patients within Milan criteria had significantly improved DFS, along with the findings of significantly lower recurrence rates. In several published studies of patients undergoing liver resection, mixed HCC-CCA patients were found to have shorter periods of DFS and a poorer prognosis as compared to CCA patients32,33,38 and HCC patients.38 Because it has been postulated that HCC, I-CCA, and mixed HCC-CCA tumors have a common carcinogenic pathway from hepatic progenitor cells,39,40 poor outcomes of patients with mixed HCC-CCA could a be reflection of an overall more advanced tumor staging. The overall 5-year survival in our series was 57%, with a 44% 5-year tumor-free survival after LT. We found that patients with early stage tumors (within Milan criteria), most of them having I-CCA features, tended to have an acceptable post-LT outcome: 78% 5-year survival. This series, which is one of the largest to date, suggests that this
FIGURE 3. OS comparison between patients with CCA and the HCC matched control group. Five-year OS: within Milan criteria (78% for CCA vs. 79% for HCC only, P=0.61), outside Milan criteria (48% for CCA vs. 53% for HCC only, P=0.12). OS, overall survival; HCC, hepatocellular carcinoma; CCA, cholangiocarcinoma.
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subgroup of patients should be considered for LT. These observations are similar to ones made by Sotiropoulos et al. in their series of liver transplants for patients having I-CCA, in which three patients who “falsely” fulfilled the Milan criteria were alive with no tumor recurrence at 30, 35, and 42 months after LT, respectively.41 Recently, a multicenter study published a nomogram to predict long-term survival after resection for I-CCA, and found tumor size, among others, as a factor predictive of survival.42 Along with these observations, the limited availability of donor organs necessitates improved selection of the increasing number of patients with presumptive diagnosis of HCC considered for LT. Can we more accurately predict which patients will have better chances of survival and hence achieve a fairer allocation of scarce organs? Although several clinicopathologic HCC variables, such as tumor number, tumor size, microscopic and macroscopic-vascular invasion, and lymph node involvement, have been identified as predictors of recurrence,43-47 there is no consensus on how to best predict an individuals risk for tumor recurrence after LT for HCC. In most liver transplant centers, directed biopsy of presumed HCC lesions noted on imaging studies is not standard practice, unless there is diagnostic uncertainty as to the nature of the lesion. Thus, there has been some inherent bias in the pretransplant diagnosis of these lesions on needle biopsy with the assumption being that the biopsy was carried out to establish histologic diagnosis in the setting of unclear imaging. The current data will help liver transplant programs decide moving forward regarding the feasibility of transplantation of such tumors. This will become even more important as we approach the era of molecular diagnostic assessment and prognostication of liver lesions pre-LT. In patients with hilar CCA, neoadjuvant multimodality therapy protocols have shown encouraging results after LT. Rea et al.48 have reported 3-year and 5-year survival rates of 82% after LT for hilar CCA that combined neoadjuvant chemoradiation and LT. Can we take a similar approach as with hilar CCA and consider it into the decision making for the management of I-CCA? LT for I-CCA may need to be reevaluated in the setting of neoadjuvant chemoradiation protocols, particularly for those patients having tumors with I-CCA features within Milan criteria diagnosed preoperatively. In summary, accurate pretransplant diagnosis of tumors with intrahepatic bile duct differentiation in cirrhosis is difficult based on imaging alone or tumor markers. The subgroup of patient with tumors within Milan criteria, especially with I-CCA features may face a better long-term prognosis post-LT to justify consideration for LT. In view of the benefits of neoadjuvant therapy with hilar CCA, future research should be directed to evaluate potential utility of the combination of neoadjuvant and surgical therapies for I-CCA. The role of LT for tumors with intrahepatic bile duct differentiation remains to be defined, but our findings warrant further investigation into the natural history and outcomes of this group of patients. MATERIALS AND METHODS All patients with cirrhosis and explant pathologic diagnosis of tumors with intrahepatic bile duct differentiation undergoing LT between April 1993 and September 2013 at our institution were identified in a database search, and
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retrospectively evaluated. During that period, a total of 3,073 patients were transplanted, and 32 patients were found to have cirrhosis and pathologic diagnosis of intrahepatic bile duct tumor on explant review, and were included in this analysis. Patients with hilar CCA (Klatskin tumors), CCA in noncirrhotics, and incidental CCA nodules not identified in preoperative imaging but found on explants were excluded. The exclusion of incidental tumors was based on the presumption that small, not identified, tumors on imaging, would have better survival rates and could improve outcome on known tumors preoperatively. Data were obtained from hospital and office records. Patient characteristics (age, sex, origin, preoperative tumor treatment), tumor variables (number, size, grade, vascular invasion, histopathologic characteristics), and outcome variables (tumor recurrence, patient survival after LT) were analyzed. Appropriate IRB approval was obtained. Liver function was estimated on the basis of the ChildPugh-Turcotte classification.49 All patients had preoperative radiologic tumor diagnosis based on at least two abdominal imaging studies, including computed tomography (CT) and magnetic resonance imaging (MRI). All patients had the preoperative presumptive diagnosis of HCC, excluding four who had biopsy-proven I-CCA. Extrahepatic metastases were excluded before LT based on chest and abdominal CT or MRI, as well as bone scintigraphy performed within 6 months before surgery. Patients listed for LT were considered for locoregional antitumoral procedures to prevent tumor progression including a combination of TACE, percutaneous ethanol injection or RFA and SBRT. Nodules with I-CCA resemble adenocarcinoma from other sites with tumor cells that are usually arranged in tubules and glands that are embedded in dense fibrous stroma. Mixed HCC-CCA nodules have unequivocal areas of both HCC and CCA that comprise the tumor. Hepatocellular carcinoma characteristics include a trabecular, pseudoglandular, or solid pattern of growth, with bile production, whereas the cholangiocellular characteristics are those of glandular pattern and mucin production embedded within dense connective tissue.11 Patients were classified according to the Goodman classification8 including type I for I-CCA nodules occurring concomitantly with HCC nodules in the same liver and type II for mixed HCC-CCA nodules. For statistical comparison, patients were further grouped as with I-CCA features (only I-CCA and Goodman type I) and with mixed HCC-CCA features (Goodman type II). In addition, a separate matched control group of patients with explant pathology showing only HCC, and transplanted during the same period was obtained with the purpose of comparing outcomes with the entire treatment group of patients with CCA. The control group was established at 2:1 ratio, matching for patient age, origin, and tumor stage. Pathologic tumor staging was based on the ALTSG modified Tumor-Node-Metastasis classification, current allocation system for patients with HCC awaiting LT in the United States.50 Macroscopic vascular invasion was defined as invasion of the branches of the main portal vein (right or left, not including sectoral branches) or of one or more of the three hepatic veins (right, middle, or left). Multiple tumors include the presence of satellite nodules, multifocal tumors, and intrahepatic metastases.2 After LT, protocol postoperative immunosuppressive therapy consisted of a triple-drug regimen of
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cyclosporine or tacrolimus, corticosteroids, and mycophenolate mofetil. Corticosteroids were gradually tapered to discontinuation at 3 to 6 months after LT. All patients were followed up after surgery with CT scans of the chest and abdomen every 3 months for the first 2 years and every 6 months thereafter. Additional imaging techniques (MRI, bone scintigraphy) were performed if recurrent tumor was suspected. Statistics
Descriptive statistics are expressed as mean (standard deviation) or median. Chi-square test or Fisher’s test, where appropriate, were used for univariate comparisons. Logistic regression analysis was performed to predict the probability of tumor recurrence as a binary-outcome variable. For univariate survival analysis, plots were calculated by the Kaplan-Meier method and comparisons made by the logrank test. Statistical differences were considered significant at P less than or equal to 0.05. Perioperative death was included in the survival analysis for the treatment group. All statistical analyses were performed using Stata 11 Statistics/ Data Analyses (StataCorp, College Station, TX). ACKNOWLEDGMENTS The authors sincerely thank Dr Spiros Hiotis, Vice Chairman for Surgical Research for the Department of Surgery, Mount Sinai Medical Center, for his thoughtful review of the article and his insightful comments. REFERENCES 1. Renshaw K. Malignant neoplasms of the extra-hepatic biliary ducts. Ann Surg 1922;76:205. 2. Edge SB, Byrd DR, Compton CC, et al. eds. AJCC Cancer Staging Handbook. 7th ed. New York, NY: Springer; 2010. 3. Burke EC, Jarnagin WR, Hochwald SN, et al. Hilar cholangiocarcinoma: pattern of spread, the importance of hepatic resection for curative operation and a presurgical clinical staging system. Ann Surg 1998;228:385. 4. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar and distal tumors. Ann Surg 1996;224:463. 5. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115. 6. Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2006;3:33. 7. Allen RA, Lisa JR. Combined liver cell and bile duct carcinoma. Am J Pathol 1949;25:647. 8. Goodman ZD, Ishak KG, Langloss JM, et al. Combined hepatocellularcholangiocarcinoma. A histologic and immunohistochemical study. Cancer 1985;55:124. 9. Kassahun WT, Hauss J. Management of combined hepatocellular and cholangiocarcinoma. Int J Clin Pract 2008;62:1271. 10. Kim KH, Lee SG, Park EH, et al. Surgical treatments and prognoses of patients with combined hepatocellular carcinoma and cholangiocarcinoma. Ann Surg Oncol 2009;16:623. 11. Sempoux C, Jibara G, Ward SC, et al. Intrahepatic cholangiocarcinoma: new insights in pathology. Semin Liver Dis 2011;31:49. 12. Aoki K, Takayasu K, Kawano T, et al. Combined hepatocellular carcinoma and cholangiocarcinoma: clinical features and computed tomographic findings. Hepatology 1993;18:1090. 13. Chan AC, Lo CM, Ng IO, et al. Liver transplantation for combined hepatocellular cholangiocarcinoma. Asian J Surg 2007;30:143. 14. Sapisochin G, Fidelman N, Roberts JP, et al. Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transpl 2011;17:934. 15. Panjala C, Senecal DL, Bridges MD, et al. The diagnostic conundrum and liver transplantation outcome for combined hepatocellular-cholangiocarcinoma. Am J Transplant 2010;10:1263.
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16. Pichlmayr R, Weimann A, Klempnauer J, et al. Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg 1996;224:628. 17. Gerhards MF, van Gulik TM, Bosma A, et al. Long-term survival after resection of proximal bile duct carcinoma (Klatskin tumors). World J Surg 1999;23:91. 18. Neuhaus P, Jonas S, Bechstein WO, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg 1999;230:808. 19. Hemming AW, Reed AI, Fujita S, et al. Surgical management of hilar cholangiocarcinoma. Ann Surg 2005;241:693. 20. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234:507. 21. D’Angelica MI, Jarnagin WR, Blumgart LH. Resectable hilar cholangiocarcinoma: surgical treatment and long-term outcome. Surg Today 2004;34:885. 22. Konstadoulakis MM, Roayaie S, Gomatos IP, et al. Aggressive surgical resection for hilar cholangiocarcinoma: is it justified? Audit of a single center’s experience. Am J Surg 2008;196:160. 23. Munoz L, Roayaie S, Maman D, et al. Hilar cholangiocarcinoma involving the portal vein bifurcation: long-term results after resection. J Hepatobiliary Pancreat Surg 2002;9:237. 24. Thelen A, Neuhaus P. Liver transplantation for hilar cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2007;14:469. 25. Iwatsuki S, Todo S, Marsh JW, et al. Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg 1998;187:358. 26. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients. Transplantation 2000;69:1633. 27. Robles R, Figueras J, Turrion VS, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg 2004;239:265. 28. Jonas S, Mittler J, Pascher A, et al. Extended indications in livingdonor liver transplantation: bile duct cancer. Transplantation 2005;80 (1 Suppl): S101. 29. Shimoda M, Farmer DG, Colquhoun SD, et al. Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature. Liver Transpl 2001;7:1023. 30. Goldstein RM, Stone M, Tillery GW, et al. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 1993;166:768. 31. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992;215:31. 32. Jarnagin WR, Weber S, Tickoo SF, et al. Combined hepatocellular and cholangiocarcinoma: demographic, clinical and prognostic factors. Cancer 2002;94:2040. 33. Yano Y, Yamamoto J, Kosuge T, et al. Combined hepatocellular and cholangiocarcinoma: a clinicopathologic study of 26 resected cases. Jpn J Clin Oncol 2003;33:283. 34. Zuo HQ, Yan LN, Zeng Y, et al. Clinicopathological characteristics of 15 patients with combined hepatocellular carcinoma and cholangiocarcinoma. Hepatobiliary Pancreat Dis Int 2007;6:161. 35. Tickoo SK, Zee SY, Obiekwe S, et al. Combined hepatocellularcholangiocarcinoma: a histopathologic, immunohistochemical, and in situ hybridization study. Am J Surg Pathol 2002;26:989. 36. Liu CL, Fan ST, Lo CM, et al. Hepatic resection for combined hepatocellular and cholangiocarcinoma. Arch Surg 2003;138:86. 37. Brandsaeter B, Isoniemi H, Broome U, et al. Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy. J Hepatol 2004;40:815. 38. Lee JH, Chung GE, Yu SJ, et al. Long-term prognosis of combined hepatocellular and cholangiocarcinoma after curative resection. Comparison with hepatocellular carcinoma and cholangiocarcinoma. J Clin Gastroenterol 2011;45:69. 39. Yeh MM. Pathology of combined hepatocellular-cholangiocarcinoma. J Gastroenterol Hepatol 2010;25:1485. 40. Tanaka S, Yamamoto T, Tanaka H, et al. Potentiality of combined hepatocellular and intrahepatic cholangiocellular carcinoma originating from a hepatic precursor cell: immunohistochemical evidence. Hepatol Res 2005;32:52. 41. Sotiropoulos GC, Kaiser GM, Lang H, et al. Liver transplantation as a primary indication for intrahepatic cholangiocarcinoma: a single-center experience. Transplant Proc 2008;40:3194. 42. Hyder O, Marques H, Pulitano C, et al. A nomogram to predict long-term survival after resection for intrahepatic cholangiocarcinoma: an eastern and western experience. JAMA Surg 2014.
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43. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693. 44. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394. 45. Tung-Ping Poon R, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg 2000;232:10. 46. Itamoto T, Nakahara H, Tashiro H, et al. Indications of partial hepatectomy for transplantable hepatocellular carcinoma with compensated cirrhosis. Am J Surg 2005;189:167.
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47. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 2002;8:765. 48. Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar holangiocarcinoma. Ann Surg 2005;242:451. 49. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646. 50. United Network for Organ Sharing. Liver Transplant Candidates with hepatocellular carcinoma (HCC) Policy 3.6.4.4. In., 2002.
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Tumors With Intrahepatic Bile Duct Differentiation in Cirrhosis: Implications on Outcomes After Liver Transplantation Marcelo E. Facciuto,1 Manoj K. Singh,1 Nir Lubezky,1 Motaz A. Selim,1 Dorothy Robinson,1 Leona Kim-Schluger,1 Sander Florman,1 Stephen C. Ward,2 Swan N. Thung,2 MariaIsabel Fiel,2 and Thomas D. Schiano1 Background. The role of liver transplantation (LT) in the management of cirrhotic patients with tumors exhibiting intrahepatic bile
duct differentiation remains controversial. The objective of this study was to characterize the spectrum of these tumors and analyze post-LT outcomes. Methods. Retrospective pathology database search of explant histology analysis of liver transplants between April 1993 and November 2013. Results. Thirty-two patients were analyzed, 75% were men with a mean age of 60 years. Seven patients had nodules demonstrating intrahepatic cholangiocarcinoma (I-CCA), nine had I-CCA nodules occurring concomitantly with hepatocellular carcinoma (HCC), and 16 had mixed HCC-CCA nodules. The median number of tumors was 1 and size was 2.5 cm. Overall patient survival post-LT at 1 and 5 years was 71% and 57%, respectively. Patients within Milan criteria, especially with I-CCA features, showed a 5-year tumor recurrence rate (10%) and 5-year survival rate (78%) comparable with other patients having HCC within Milan criteria. Conclusion. This series showed that patients with CCA within Milan criteria may be able to achieve acceptable long-term post-LT survival. (Transplantation 2014;99: 151–157)
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holangiocarcinoma (CCA) is a primary hepatobiliary malignant neoplasm arising from epithelial cells of the intra-and extrahepatic bile ducts.1 The American Joint Committee on Cancer, in the seventh edition of the American Joint Committee on Cancer Staging Manual, has a novel staging system for intrahepatic bile duct cancer, independent of the staging system for hepatocellular carcinoma (HCC), and extrahepatic bile duct malignancy, including hilar bile duct cancers.2 The staging system for intrahepatic bile duct
Received 26 February 2014. Revision requested 24 March 2014. Accepted 5 May 2014. 1
Recanati Miller Transplantation Institute, The Mount Sinai Medical Center, New York, NY.
2
The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, The Mount Sinai Medical Center, New York, NY.
The authors declare no funding or conflicts of interest. M.E.F. participated in research design, data analysis, and writing of article. M.K.S. participated in performance of research, data analysis, and writing of article. N.L. participated in performance of research and article writing. M.A.S. participated in performance of research and data collection. D.R. participated in performance of research and data collection. L.K.-S. participated in research and review of article. S.F. participated in research and review of article. S.C.W. participated in research and writing of article. S.N.T. participated in research and writing of article. M.I.F. participated in research and writing of article. T.D.S. participated in research design and writing of article. Correspondence: Marcelo E. Facciuto, MD, MPH, Recanati/Miller Transplantation Institute, One Gustave L. Levy Place, Box 1104, New York, NY 10029. (marcelo. [email protected]) Copyright © 2014 Wolters Kluwer Health, Inc. All right reserved. ISSN: 0041-1337/15/9901-151 DOI: 10.1097/TP.0000000000000286
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tumors applies to carcinomas of the intrahepatic bile ducts. These include intrahepatic CCA (I-CCA), and the rare combined HCC and CCA (mixed HCC-CCA). Intrahepatic cholangiocarcinoma represents 5% to 10% of CCAs and typically present as an intrahepatic mass.3-6 Mixed HCC-CCA is an uncommon form of primary liver cancer arising from the epithelial cells of the liver (hepatocytes and cholangiocytes).7 It accounts for 1% to 14% of all primary liver tumors.8-10 Mixed HCC-CCA have histologic features of both HCC and CCA, believed to originate from hepatic progenitor cells, and have a strong correlation with the presence of underlying liver disease, especially hepatitis C virus infection and advanced fibrosis.11 Although this variant is well described histopathologically, the clinical and radiologic features have not been well characterized and so far are not distinctive.9 Because the diagnosis of mixed HCC-CCA is challenging preoperatively to make, most of these tumors are managed as HCC or CCA, only to be diagnosed as mixed HCC-CCA incidentally on resected specimens, liver explant, or at autopsy.12 Data on the incidence of mixed HCC-CCA and I-CCA in pretransplant patients are lacking because of the inability to differentiate these tumors from HCC by imaging. Chan et al.13 reported an overall incidence of 0.7% for mixed HCC-CCA based on explant pathologic analysis among predominantly hepatitis B-infected patients who underwent liver transplantation (LT). Sapisochin et al.14 reported an incidence of 3.3% in their series, Panjala et al.15 reported 12 patients with mixed HCC-CCA tumor found on explant among patients who underwent LT for HCC over a 10-year period. There is no clear consensus as to the best treatment strategy for patients with this spectrum of tumors exhibiting intrahepatic bile duct differentiation. Surgical resection is www.transplantjournal.com
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regarded as the primary curative treatment of selected patients. Unfortunately, overall 5-year survival rates range from 20% to 40% in those patients undergoing potential curative surgical resection.16-23 Although surgical resection is the treatment of choice, many patients have unresectable tumors because of associated underlying liver disease. For these patients, LT remains the only option. Thus, LT provides the option of wide resection margins, thereby expanding the indication of surgical intervention to patients who otherwise would not be candidates for surgery because of lack of functional hepatic reserve. However, results with LT in intrahepatic bile duct tumors have not been dramatically different compared with those of surgical resection, with 5-year survival rates ranging from 30% to 36%.24-28 The suboptimal results of LT for these tumors are mainly because of the high tumor recurrence rate.29-31 The Cincinnati Transplant Tumor Registry has reported a 28% 5-year survival with a 51% tumor recurrence rate.26 The goal of this study was to provide an in-depth and accurate assessment of the impact of tumor staging and histopathologic features of intrahepatic bile duct tumors on long-term outcome after LT. RESULTS This study involved 32 patients with explant pathology diagnosis of tumors with intrahepatic bile duct differentiation and cirrhosis. Patient clinical characteristics are listed in Table 1. Most of the patients were men, with a mean age of 60 years at LT. Most patients had hepatitis C virus (50%), and none of them had primary sclerosing cholangitis. Twenty-eight patients had the presumptive preoperative diagnosis of HCC, and only four patients had biopsy-proven I-CCA, preoperatively. Twenty-two patients (69%) received preoperative tumor ablation therapy. Twelve patients received transarterial chemoembolization (TACE), one patient radiofrequency ablation (RFA), six patients received a combination of TACE+RFA, one patient received stereotactic body radiation therapy (SBRT), and two patients received combination of TACE+SBRT. Tumor characteristics are listed in Table 1. Patients within Milan criteria had an average I-CCA tumor size of 1.97 cm, ranging from 0.8 to 4.8, with only one tumor greater than 2.5 cm. Patients outside Milan criteria had an average I-CCA tumor size of 3.8 cm, ranging from 1 to 12 cm. Seven patients had only nodules demonstrating I-CCA, in a background of hepatitis B virus (three cases), NASH (one case), and ETOH (three cases). Nine patients had Goodman type I nodules: I-CCA concomitantly with other HCC nodules. The remaining 16 patients were classified as Goodman type II, including four patients with mixed HCC-CCA nodules and 12 patients with mixed HCC-CCA nodules and concomitant HCC nodules. Cholangiocarcinoma vascular invasion was demonstrated in 41% of the patients, and median nodule size was 2.5 cm. Pathologic tumor staging included all tumors, and was based on the American Liver Tumor Study Group (ALTSG) system; 31% of the patients were considered within Milan criteria (ALTSG stages I and II), whereas 69% of the patients fell outside the Milan criteria (ALTSG stages III and above). Patients with only I-CCA and Goodman type I nodules were equally distributed within and outside Milan criteria (50% within, 50% outside Milan criteria), but accounted for most of the patients within Milan criteria (8 of 10). Patients with
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TABLE 1.
Clinical characteristics of patients with tumors having intrahepatic bile duct differentiation and cirrhosis Patient demographics
Patients (n) Age (mean, yr) Male (n) Origin HCV (n) Other (n) (HBV, NASH, ETOH) MELD score (median) Preoperative ablation (n) Tumor characteristics Largest tumor (median, cm) Nodules (median, n) Microvascular invasion, CCA (n) Differentiation grade, CCA (n) Well Moderate Poor Histologic type (n) Only I-CCA Goodman type I (I-CCA and HCC in separate nodules) Goodman type II (Mixed HCC-CCA in same nodule) (Mixed HCC-CCA+concomitant HCC nodules) Grouped histologic type features (n) Patients with I-CCA features Only I-CCA+Goodman type I Patients with mixed HCC-CCA features Goodman type II Microvascular invasion, HCC (n) pALTSG classification for all nodules (n) I II III IV A1 IV A2 IV B pMilan classification for all nodules (n) Within (ALTSG I, II) Outside (ALTSG>II)
32 60 24 (75%) 16 (50%) 16 (50%) 13.5 22 (69%) 2.5 (0.8-12) 1 (1-5) 13 (41%) 7 (24%) 14 (48%) 8 (28%) 7/32 (22%) 9/32 (50%)
4/32 (13%) 12/32 (38%) 16/32 (50%) 16/32 (50%) 14/22 (64%) 4 (13%) 6 (19%) 7 (22%) 11 (34%) 3 (9%) 1 (3%) 10/32 (31%) 22/32 (69%)
HCV, hepatitis C virus; HBV, hepatitis B virus; MELD, model for end-stage liver disease; ALTSG, American Liver Tumor Study Group; CCA, cholangiocarcinoma; I-CCA, intrahepatic CCA; HCC, hepatocellular carcinoma.
Goodman type II nodules were predominantly outside Milan criteria (two patients were within Milan criteria [12%], and 14 patients were outside Milan criteria [88%]). The difference on overall tumor staging for only I-CCA and Goodman type I versus Goodman type II was statistically significant (P=0.02). Patients were followed for a mean of 47 months and a median of 28 months (range, 3-199 months). Tumor Recurrence
Tumor recurrence occurred in 12 patients (38%) at a median time of 5 months. Five were CCA recurrences (two originated from I-CCA, one in Goodman type I, and two in Goodman type II), and seven were HCC recurrences.
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All five patients with CCA recurrence showed bad tumor prognostic factors on CCA nodules: all had vascular invasion, two had poor differentiation, two had a size greater than 5 cm, and four of five were outside Milan criteria. By logistic regression analysis, vascular invasion of the CCA component was found to be an independent factor for CCA recurrence after LT (P=II)
CCA
HCC matched control group
32 60 24 (75%)
64 60 53 (83%)
16 (50%) 16 (50%)
33 (51%) 31 (49%)
4 6 7 11 3 1
8 12 14 22 6 2
10 (31%) 22 (69%)
20 (31%) 44 (69%)
P
0.77 0.37 0.89
1
1
HCV, hepatitis C virus; ALTSG, American Liver Tumor Study Group; CCA, cholangiocarcinoma; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HBV, hepatitis B virus.
staging and histopathologic characteristics on patient outcomes after LT. Intrahepatic cholangiocarcinoma and mixed HCC-CCA are considered aggressive tumors with survival rates after surgical resection of 35% to 68% and 23% to 38% at 3 years; 28% to 35% and 8% to 24% at 5 years, respectively, with median survival ranging from 23 to 37 months for I-CCA and 10 to 32 months for mixed HCC-CCA.32-36 The role of LT in the management of intrahepatic bile duct tumors is not well defined to date. Previously reported results of LT for CCA have been disappointing with 3-year survival rates of 20% to 40% and disease recurrence rates of 50% to 60%.26,30,37 Sapisochin et al.14 reported the UCSF experience in 14 patients transplanted for mixed HCC-CCA and I-CCA, four of them with incidental tumors. They found a 57% incidence of tumor recurrence. After a median followup of 14 months from LT, the 1-year and 5-year survival was 76% and 51%, respectively. Patients with mixed HCC-CCA showed a trend toward worse prognosis, a higher rate of tumor recurrence, and a shorter period of DFS in comparison with the patients having only I-CCA or Goodman type I tumors. In our series, the overall recurrence rate was 38%. Recurrences were similarly distributed among CCA or HCC recurrences. Patients with early stage tumors (within Milan criteria) had a lower recurrence rate as opposed to patients with advanced stage (outside Milan criteria) tumors (10% vs. 50%). Even though we did not find a difference in recurrence rate between histopathologic tumor types, we should bear in mind that 80% of patients within Milan criteria had nodules with I-CCA features, who in fact, did not develop recurrence. This observation suggests that favorable outcomes for tumors with I-CCA features within Milan are achievable. On the contrary, nearly 90% of mixed HCC-CCA nodules were found in patients outside Milan criteria. Mixed HCCCCA tumors were historically associated with a worse prognosis.14 However, this less favorable natural history may not be in fact because of more aggressive behavior in mixed histology tumors, but rather a reflection of a more advanced tumor stage at the time of transplant.
Post-LT DFS was associated with overall tumor staging. Patients within Milan criteria had significantly improved DFS, along with the findings of significantly lower recurrence rates. In several published studies of patients undergoing liver resection, mixed HCC-CCA patients were found to have shorter periods of DFS and a poorer prognosis as compared to CCA patients32,33,38 and HCC patients.38 Because it has been postulated that HCC, I-CCA, and mixed HCC-CCA tumors have a common carcinogenic pathway from hepatic progenitor cells,39,40 poor outcomes of patients with mixed HCC-CCA could a be reflection of an overall more advanced tumor staging. The overall 5-year survival in our series was 57%, with a 44% 5-year tumor-free survival after LT. We found that patients with early stage tumors (within Milan criteria), most of them having I-CCA features, tended to have an acceptable post-LT outcome: 78% 5-year survival. This series, which is one of the largest to date, suggests that this
FIGURE 3. OS comparison between patients with CCA and the HCC matched control group. Five-year OS: within Milan criteria (78% for CCA vs. 79% for HCC only, P=0.61), outside Milan criteria (48% for CCA vs. 53% for HCC only, P=0.12). OS, overall survival; HCC, hepatocellular carcinoma; CCA, cholangiocarcinoma.
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subgroup of patients should be considered for LT. These observations are similar to ones made by Sotiropoulos et al. in their series of liver transplants for patients having I-CCA, in which three patients who “falsely” fulfilled the Milan criteria were alive with no tumor recurrence at 30, 35, and 42 months after LT, respectively.41 Recently, a multicenter study published a nomogram to predict long-term survival after resection for I-CCA, and found tumor size, among others, as a factor predictive of survival.42 Along with these observations, the limited availability of donor organs necessitates improved selection of the increasing number of patients with presumptive diagnosis of HCC considered for LT. Can we more accurately predict which patients will have better chances of survival and hence achieve a fairer allocation of scarce organs? Although several clinicopathologic HCC variables, such as tumor number, tumor size, microscopic and macroscopic-vascular invasion, and lymph node involvement, have been identified as predictors of recurrence,43-47 there is no consensus on how to best predict an individuals risk for tumor recurrence after LT for HCC. In most liver transplant centers, directed biopsy of presumed HCC lesions noted on imaging studies is not standard practice, unless there is diagnostic uncertainty as to the nature of the lesion. Thus, there has been some inherent bias in the pretransplant diagnosis of these lesions on needle biopsy with the assumption being that the biopsy was carried out to establish histologic diagnosis in the setting of unclear imaging. The current data will help liver transplant programs decide moving forward regarding the feasibility of transplantation of such tumors. This will become even more important as we approach the era of molecular diagnostic assessment and prognostication of liver lesions pre-LT. In patients with hilar CCA, neoadjuvant multimodality therapy protocols have shown encouraging results after LT. Rea et al.48 have reported 3-year and 5-year survival rates of 82% after LT for hilar CCA that combined neoadjuvant chemoradiation and LT. Can we take a similar approach as with hilar CCA and consider it into the decision making for the management of I-CCA? LT for I-CCA may need to be reevaluated in the setting of neoadjuvant chemoradiation protocols, particularly for those patients having tumors with I-CCA features within Milan criteria diagnosed preoperatively. In summary, accurate pretransplant diagnosis of tumors with intrahepatic bile duct differentiation in cirrhosis is difficult based on imaging alone or tumor markers. The subgroup of patient with tumors within Milan criteria, especially with I-CCA features may face a better long-term prognosis post-LT to justify consideration for LT. In view of the benefits of neoadjuvant therapy with hilar CCA, future research should be directed to evaluate potential utility of the combination of neoadjuvant and surgical therapies for I-CCA. The role of LT for tumors with intrahepatic bile duct differentiation remains to be defined, but our findings warrant further investigation into the natural history and outcomes of this group of patients. MATERIALS AND METHODS All patients with cirrhosis and explant pathologic diagnosis of tumors with intrahepatic bile duct differentiation undergoing LT between April 1993 and September 2013 at our institution were identified in a database search, and
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retrospectively evaluated. During that period, a total of 3,073 patients were transplanted, and 32 patients were found to have cirrhosis and pathologic diagnosis of intrahepatic bile duct tumor on explant review, and were included in this analysis. Patients with hilar CCA (Klatskin tumors), CCA in noncirrhotics, and incidental CCA nodules not identified in preoperative imaging but found on explants were excluded. The exclusion of incidental tumors was based on the presumption that small, not identified, tumors on imaging, would have better survival rates and could improve outcome on known tumors preoperatively. Data were obtained from hospital and office records. Patient characteristics (age, sex, origin, preoperative tumor treatment), tumor variables (number, size, grade, vascular invasion, histopathologic characteristics), and outcome variables (tumor recurrence, patient survival after LT) were analyzed. Appropriate IRB approval was obtained. Liver function was estimated on the basis of the ChildPugh-Turcotte classification.49 All patients had preoperative radiologic tumor diagnosis based on at least two abdominal imaging studies, including computed tomography (CT) and magnetic resonance imaging (MRI). All patients had the preoperative presumptive diagnosis of HCC, excluding four who had biopsy-proven I-CCA. Extrahepatic metastases were excluded before LT based on chest and abdominal CT or MRI, as well as bone scintigraphy performed within 6 months before surgery. Patients listed for LT were considered for locoregional antitumoral procedures to prevent tumor progression including a combination of TACE, percutaneous ethanol injection or RFA and SBRT. Nodules with I-CCA resemble adenocarcinoma from other sites with tumor cells that are usually arranged in tubules and glands that are embedded in dense fibrous stroma. Mixed HCC-CCA nodules have unequivocal areas of both HCC and CCA that comprise the tumor. Hepatocellular carcinoma characteristics include a trabecular, pseudoglandular, or solid pattern of growth, with bile production, whereas the cholangiocellular characteristics are those of glandular pattern and mucin production embedded within dense connective tissue.11 Patients were classified according to the Goodman classification8 including type I for I-CCA nodules occurring concomitantly with HCC nodules in the same liver and type II for mixed HCC-CCA nodules. For statistical comparison, patients were further grouped as with I-CCA features (only I-CCA and Goodman type I) and with mixed HCC-CCA features (Goodman type II). In addition, a separate matched control group of patients with explant pathology showing only HCC, and transplanted during the same period was obtained with the purpose of comparing outcomes with the entire treatment group of patients with CCA. The control group was established at 2:1 ratio, matching for patient age, origin, and tumor stage. Pathologic tumor staging was based on the ALTSG modified Tumor-Node-Metastasis classification, current allocation system for patients with HCC awaiting LT in the United States.50 Macroscopic vascular invasion was defined as invasion of the branches of the main portal vein (right or left, not including sectoral branches) or of one or more of the three hepatic veins (right, middle, or left). Multiple tumors include the presence of satellite nodules, multifocal tumors, and intrahepatic metastases.2 After LT, protocol postoperative immunosuppressive therapy consisted of a triple-drug regimen of
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cyclosporine or tacrolimus, corticosteroids, and mycophenolate mofetil. Corticosteroids were gradually tapered to discontinuation at 3 to 6 months after LT. All patients were followed up after surgery with CT scans of the chest and abdomen every 3 months for the first 2 years and every 6 months thereafter. Additional imaging techniques (MRI, bone scintigraphy) were performed if recurrent tumor was suspected. Statistics
Descriptive statistics are expressed as mean (standard deviation) or median. Chi-square test or Fisher’s test, where appropriate, were used for univariate comparisons. Logistic regression analysis was performed to predict the probability of tumor recurrence as a binary-outcome variable. For univariate survival analysis, plots were calculated by the Kaplan-Meier method and comparisons made by the logrank test. Statistical differences were considered significant at P less than or equal to 0.05. Perioperative death was included in the survival analysis for the treatment group. All statistical analyses were performed using Stata 11 Statistics/ Data Analyses (StataCorp, College Station, TX). ACKNOWLEDGMENTS The authors sincerely thank Dr Spiros Hiotis, Vice Chairman for Surgical Research for the Department of Surgery, Mount Sinai Medical Center, for his thoughtful review of the article and his insightful comments. REFERENCES 1. Renshaw K. Malignant neoplasms of the extra-hepatic biliary ducts. Ann Surg 1922;76:205. 2. Edge SB, Byrd DR, Compton CC, et al. eds. AJCC Cancer Staging Handbook. 7th ed. New York, NY: Springer; 2010. 3. Burke EC, Jarnagin WR, Hochwald SN, et al. Hilar cholangiocarcinoma: pattern of spread, the importance of hepatic resection for curative operation and a presurgical clinical staging system. Ann Surg 1998;228:385. 4. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar and distal tumors. Ann Surg 1996;224:463. 5. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115. 6. Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2006;3:33. 7. Allen RA, Lisa JR. Combined liver cell and bile duct carcinoma. Am J Pathol 1949;25:647. 8. Goodman ZD, Ishak KG, Langloss JM, et al. Combined hepatocellularcholangiocarcinoma. A histologic and immunohistochemical study. Cancer 1985;55:124. 9. Kassahun WT, Hauss J. Management of combined hepatocellular and cholangiocarcinoma. Int J Clin Pract 2008;62:1271. 10. Kim KH, Lee SG, Park EH, et al. Surgical treatments and prognoses of patients with combined hepatocellular carcinoma and cholangiocarcinoma. Ann Surg Oncol 2009;16:623. 11. Sempoux C, Jibara G, Ward SC, et al. Intrahepatic cholangiocarcinoma: new insights in pathology. Semin Liver Dis 2011;31:49. 12. Aoki K, Takayasu K, Kawano T, et al. Combined hepatocellular carcinoma and cholangiocarcinoma: clinical features and computed tomographic findings. Hepatology 1993;18:1090. 13. Chan AC, Lo CM, Ng IO, et al. Liver transplantation for combined hepatocellular cholangiocarcinoma. Asian J Surg 2007;30:143. 14. Sapisochin G, Fidelman N, Roberts JP, et al. Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transpl 2011;17:934. 15. Panjala C, Senecal DL, Bridges MD, et al. The diagnostic conundrum and liver transplantation outcome for combined hepatocellular-cholangiocarcinoma. Am J Transplant 2010;10:1263.
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43. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693. 44. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394. 45. Tung-Ping Poon R, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg 2000;232:10. 46. Itamoto T, Nakahara H, Tashiro H, et al. Indications of partial hepatectomy for transplantable hepatocellular carcinoma with compensated cirrhosis. Am J Surg 2005;189:167.
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47. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl 2002;8:765. 48. Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar holangiocarcinoma. Ann Surg 2005;242:451. 49. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646. 50. United Network for Organ Sharing. Liver Transplant Candidates with hepatocellular carcinoma (HCC) Policy 3.6.4.4. In., 2002.
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