Propensity‐Matched Analysis of Patients with Mixed Hepatocellular‐Cholangiocarcinoma and Hepatocellular Carcinoma Undergoing Liver Transplantation†

Abstract

Mixed hepatocellular-cholangiocarcinomas (HCC-CCAs) are rare tumors with both hepatocellular and biliary differentiation. While liver transplantation (LT) is the gold standard treatment for patients with unresectable hepatocellular carcinoma (HCC), it is contraindicated in known HCC-CCA because of concerns of poor prognosis. We sought to compare posttransplant oncologic outcomes for HCC-CCA and a matched cohort of HCC LT recipients. A retrospective, single-center analysis (1984-2015) identified 12 patients with mixed HCC-CCA who were matched 1:3 to patients with HCC on both pretransplant (radiologic diameter and alpha-fetoprotein) and explant (pathologic diameter, grade/differentiation, and vascular invasion) tumor characteristics. Compared with HCC patients matched on pretransplant characteristics (n = 36), HCC-CCA had higher explant tumor grade, more poorly differentiated tumors, but similar T stage and vascular invasion. HCC-CCA recipients trended toward inferior recurrence-free survival at 5 years (28% versus 61%; P = 0.12) and greater recurrence (HCC-CCA: 50%, median time to recurrence 297 days versus HCC: 22%, median time to recurrence 347 days; P = 0.07). However, when matched to a separate HCC cohort with similar explant pathology, HCC-CCA had similar 5-year recurrence-free survival (42% versus 44%; P = 0.45) and posttransplant recurrence (50% versus 27%; P = 0.13). All 6 HCC-CCA recurrences occurred with poorly differentiated tumors (median survival 21.3 months), without a single recurrence in 5 of the 12 HCC-CCA patients with well-moderately differentiated tumors (median survival 60.2 months). Mixed HCC-CCA tumors are more likely poorly differentiated tumors compared with HCC with similar pretransplant characteristics. However, compared with HCC with similar pathologic characteristics, they display similar recurrence-free survival and are not inherently more aggressive tumors. Low-grade, well-moderately differentiated HCC-CCAs have excellent survival with a low risk for post-LT recurrence, and they should not be excluded from LT. Improved pretransplant identification of pathologic characteristics in HCC-CCA may allow for successful utilization of LT in this subset of patients.

Development and Validation of a Nomogram for Differentiating Combined Hepatocellular Cholangiocarcinoma From Intrahepatic Cholangiocarcinoma

“…A previous study demonstrated that the molecular biology features of cHCC are more similar to those of hepatocellular carcinoma (HCC) than of iCCA, therefore, multitargeted inhibitors, including lenvatinib, regorafenib, and cabozantinib, may have potential for benefit in cHCC due to frequent alterations in RTK/Ras/PI3‐kinase pathways ( 22 ). Moreover, liver transplantation might also bring potential survival benefits to patients with cHCC ( 23 , 24 ). However, due to the current controversy over the value of liver transplantation for iCCA and the lack of indications for liver transplantation that meet the characteristics of the disease, liver transplantation has not been recommended as a routine treatment for iCCA.…”

Analysis of Liver Resection Versus Liver Transplantation on Outcome of Small Intrahepatic Cholangiocarcinoma and Combined Hepatocellular‐Cholangiocarcinoma in the Setting of Cirrhosis

“…When compared with the LR group, patients who underwent LT were younger (59 versus 63 [48-80] years; P = 0.03) and had a lower BMI (27 versus 29 [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] kg/m 2 ; P = 0.046; Table 1). A significantly higher rate of diabetes was seen in transplanted patients (23 [47%] versus 6 [23%]; P = 0.04), and they had a significantly higher MELD score (12 versus 7 [6][7][8][9][10][11][12][13][14]; P < 0.001).…”

“…(10) Lee et al found that both early iCCA (≤2 cm) and advanced iCCA (>2 cm or multifocal tumors or involving vascular invasion) had similar outcomes after LT compared with patients with HCC T2 within the Milan criteria. (24) The 5-cm cutoff point seems clinically relevant because a tumor size between 5 and 10 cm was significantly associated with a lower survival rate in patients who underwent either LR or LT. (25) Moreover, improvements in radiological techniques, the systematic use of magnetic resonance imaging, and greater suspicion in the event of radiographic findings not typical of HCC (26) will increase the preoperative diagnosis of iCCA and cHCC-CCA, which is easier in tumors up to 5 cm. In our series, cHCC-CCA was found more frequently in LT patients, even though patients with cHCC-CCA experienced the same recurrence rate as those with iCCA in both the LR and LT groups.…”

Should We Reevaluate Liver Transplantation as an Alternative to Resection for the Treatment of Intrahepatic Cholangiocarcinoma?

“…Emerging data have challenged this premise. ( 4‐7 ) Sapisochin et al first presented compelling data for LT in the setting of iCCA and HCC‐CCA, reporting 5‐year OS of 62% with a 16.7% risk of recurrence for small incidental or misdiagnosed tumors in patients with underlying cirrhosis. ( 6 ) This series was subsequently expanded to include retrospective data from 17 international centers.…”