Mixed Hepatocellular Cholangiocarcinoma and Intrahepatic Cholangiocarcinoma in Patients Undergoing Transplantation for Hepatocellular Carcinoma

ArticleinLiver Transplantation 17(8):934-42 · August 2011with32 Reads
DOI: 10.1002/lt.22307 · Source: PubMed
Abstract
Mixed hepatocellular cholangiocarcinoma (HCC-CC) and intrahepatic cholangiocarcinoma (I-CC) are increasingly being reported in patients with cirrhosis. The aims of this study were (1) to evaluate the incidence, imaging features, and posttransplant outcomes for patients who underwent transplantation for hepatocellular carcinoma (HCC) and were found to have HCC-CC or I-CC in the explant and (2) to compare the outcomes of these patients with those of controls with HCC who were matched (1:3) by the tumor size and the number of nodules in the explant. In the explant specimens of 10 of 302 patients (3.3%) who underwent liver transplantation (LT) for HCC, mixed HCC-CC or I-CC was identified. There were 4 additional incidental cases of HCC-CC. After a median follow-up period of 32 months, 8 of the 14 patients (57%) suffered from tumor recurrence, and the median disease-free survival time was 8 months. The cumulative risk of tumor recurrence was 40% and 70% at 1 and 5 years, respectively, for these 14 patients. When the 4 incidental cases were excluded, the study group with HCC-CC or I-CC (n = 10) had a significantly lower incidence of well-differentiated tumors (11.1% versus 43.3%, P < 0.02) and a higher rate of recurrence (60% versus 16.7%, P = 0.008) in comparison with the control group of patients with HCC (n = 30). The 1- and 5-year cumulative risks of tumor recurrence were 42% and 65%, respectively, in the study group and 10% and 17%, respectively, in the control group (P < 0.002). The actuarial 1- and 5-year patient survival rates without recurrence were also significantly lower in the study group (79% and 32% in the study group and 90% and 62% in the control group, P < 0.03). Dynamic contrast-enhanced computed tomography or magnetic resonance imaging showed progressive contrast enhancement throughout the arterial and portal venous phases without washout in 8 of the 10 patients. In conclusion, HCC-CC and I-CC are associated with a poor prognosis and a high rate of tumor recurrence after LT, and both tumors exhibit radiographic features that are distinct from those observed with HCC.
    • Because the majority of recurrences after hepatic resection (66%)[65]are limited to the liver, overall recurrence rates are as low as less than 20% after liver transplantation[66]. Recurrence rates in further detail are demonstrated inTable 2HCC Hepatectomy 51%[67]; 54%[65]; 63%[68]HCC OLT 7.6%[69]; 15.3%[66]; 18.3%[70]PDA Pancreatectomy and adjuvant chemotherapy 75%–85%[71]; 81%–93% (Phase III RCT)[48]ICC Resection 62.2%[72]; 70%[73]Mixed HCC-CC/ICC Hilar/ICC OLT 60%[74]; 38%[75]ECC Distal Resection 39%[76]Hilar Resection, OLT 53%[77]; 68%[78]; After OLT: 20%[79]GBC Resection, resection and adjuvant chemotherapy 66%[78]; 81.4%[80]HCC: hepatocellular carcinoma; OLT: orthotopic liver tranplantation; PDA: pancreatic ductal adenocarcinoma; ICC: intrahepatic bile duct cholangiocarcinoma; HCC-CC: hepatocellular cholangiocarcinoma; ECC: extrahepatic bile duct cholangiocarcinoma; GBC: gallbladder cancer.
    [Show abstract] [Hide abstract] ABSTRACT: Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.
    Full-text · Article · Jan 2017
    • We found no significant difference in overall mortality with clear cell subtype relative to other subtypes. Mixed type represents an HCC subtype with combined features of HCC and cholangiocarcinoma that is typically associated with high recurrence rates and poor prognosis [16,17]. In our analysis, mixed subtypes tended to present as moderately advanced tumors with size greater than 2 cm and moderately or poorly differentiated histology.
    [Show abstract] [Hide abstract] ABSTRACT: Background: Histopathologic advancements have identified several rare subtypes of hepatocellular carcinoma (HCC), but the clinical significance of these distinctions is incompletely understood. Our aim was to investigate pathologic and treatment differences between HCC variants. Methods: The American College of Surgeons National Cancer Data Base (1998-2011) was queried to identify 784 patients with surgical management of six rare HCC subtypes: fibrolamellar (FL, n = 206), scirrhous (SC, n = 29), spindle cell (SP, n = 20), clear cell (CC, n = 169), mixed type (M, n = 291), and trabecular (T, n = 69). We examined associations between demographic, tumor and treatment-specific variables, and overall survival (OS). Results: Patients with FL-HCC were younger than other variants (median age 27 vs. 54-61, P < 0.001), more commonly female (56.3%, P < 0.001), and less likely to receive a transplant (3.66%, P < 0.001). Patients with FL- and Sp-HCC presented more frequently with larger tumors (>5 cm, P < 0.001) and node-positive disease (P < 0.001). Better OS was associated with lower pathologic stage, node-negative disease, FL-HCC, and liver transplant. Adjuvant therapy (11% of patients) was not associated with better OS. Conclusions: This largest series of recognized HCC variants demonstrates distinct differences in presentation, treatment, and prognosis. These findings can provide a valuable reference for clinicians and patients who encounter these rare clinical entities. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2015
    • This correlates to 0.5% incidence rate among all liver explants. Sapisochin et al. [33] found an incidence of 3.3% for these tumors over a 10-year period.
    [Show abstract] [Hide abstract] ABSTRACT: Background: Misdiagnosed or incidentally detected hepatocellular carcinoma (HCC) in liver explant is an undesirable surprise that might pose a medical challenge in the post-transplant setting. Material and methods: From May 2001 to the end of December 2013, 463 and 137 liver transplants for adult and pediatric patients, respectively, were performed at our center. Ten cases were found to have misdiagnosed or incidental malignant lesions on pathological examination of the explant. Results: We considered 105 patients for LT because of presence of HCC; 102 patients were accurately diagnosed by pretransplant imaging and the other 3 patients were misdiagnosed as HCC and then found to have mixed HCC-cholangiocarcinoma (CC) (2.9% misdiagnosis rate). Seven more patients were found to have i-HCC in explanted livers. Therefore, 109 patients were transplanted for presence of HCC (6.5% of them diagnosed incidentally). The overall rate of incidental HCC (i-HCC) among all liver explants was 1.2%. In the adult group no subjects had HCC recurrence, while only 1 subject had HCC recurrence in the pediatric group. All mixed HCC-CC lesions were found in adult patients. Two patients died from recurrence of cholangiocarcinoma after liver transplant. The other patient is still surviving with no recurrence at 13-month follow-up. Conclusions: Misdiagnosed or incidental malignancy is a rare but reported finding following liver transplantation. Their preoperative suspicion is quite challenging. A thorough explant pathology study is needed to diagnose this condition. It is evident that the outcome of this undesirable finding was judged mainly by tumor biology.
    Full-text · Article · Jun 2015
    • ''Very early'' iCCA 62 cm in diameter in cirrhotic patients may be able to undergo liver transplantation without recurrence[137]. Further data will be necessary to support these findings as well as to clarify if the prognosis of a mixed tumor is worse or not than for HCC[138][139][140][141]. In summary, while decades ago liver cancer was a field with grim perspectives and with limited clinical and research activity, it has evolved into a highly competitive field where advancements emerge at a constant rate.
    [Show abstract] [Hide abstract] ABSTRACT: The knowledge and understanding of all aspects of liver cancer [this including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA)] have experienced a major improvement in the last decades. New laboratory technologies have identified several molecular abnormalities that, at the very end, should provide an accurate stratification and optimal treatment of patients diagnosed with liver cancer. The seminal discovery of the TP53 hotspot mutation [1,2] was an initial landmark step for the future classification and treatment decision using conventional clinical criteria blended with molecular data. At the same time, the development of ultrasound, computed tomography (CT) and magnetic resonance (MR) has been instrumental for earlier diagnosis, accurate staging and treatment advances. Several treatment options with proven survival benefit if properly applied are now available. Major highlights include: i) acceptance of liver transplantation for HCC if within the Milan criteria [3], ii) recognition of ablation as a potentially curative option [4,5], iii) proof of benefit of chemoembolization (TACE), [6] and iv) incorporation of sorafenib as an effective systemic therapy [7]. These options are part of the widely endorsed BCLC staging and treatment model (Fig. 1) [8,9]. This is clinically useful and it will certainly keep evolving to accommodate new scientific evidence. This review summarises the data which are the basis for the current recommendations for clinical practice, while simultaneously exposes the areas where more research is needed to fulfil the still unmet needs (Table 1).
    Full-text · Article · Apr 2015
    • According to Sapisochin et al., when comparing the tumor size and tumor number among HCC-CC patients to a matched cohort of HCC patients, the HCC-CC cohort had significantly poorer 5-year recurrence-free survival (32% vs. 62%). Tumor recurrence was observed in 60% of patients with ICC-contained tumors, but in only 16.7% of the patients with HCC [43]. Groeschl et al. reported the outcomes of larger cohorts from the Surveillance, Epidemiology, and End Results database (n = 19) and the United Network for Organ Sharing database (n = 65).
    [Show abstract] [Hide abstract] ABSTRACT: The indication of liver transplantation for intrahepatic cholangiocarcinoma (ICC) is highly controversial. Initially, liver transplantation was embraced as a promising treatment for ICC, providing both a wider surgical margin and a potential cure for the underlying liver disease. However, the majority of transplant centers have abandoned liver transplantation for ICC due to poor long-term survival and high recurrence rates. Interestingly, these decisions were based on studies with highly inconsistent outcomes due to a limited number of patients, various patient selection criteria, and the use of nonstandardized adjunctive therapy protocols. Indeed, recent studies have revealed that ICC patients with small solitary tumors have excellent long-term survival after liver transplantation. Moreover, as seen in early-stage hilar cholangiocarcinoma, neoadjuvant and adjuvant therapy hold promise for improved long-term survival in patients with locally advanced ICC. As we work to expand treatment options for ICC, further evidence of success in this area is needed in order to justify the use of limited organ resources to treat ICC. Continued efforts to improve diagnosis of ICC, hone patient selection criteria, and implement standardized treatment protocols could provide certain patients with ICC access to potentially life-saving liver transplantation.
    Full-text · Article · Feb 2015
    • In mixed tumors, the presence of cholangiocarcinoma elements can be confirmed by a positive cytokeratin 19 (CK19) and cytokeratin 7 (CK7) staining by immunohistochemistry. With the recognition that patients can harbor mixed HCC-iCCA tumors [177,178], a liver biopsy should be considered for atypical lesions (lesions not diagnostic for HCC by classical imaging criteria on cross-sectional studies) prior to LT. Mixed HCC-iCCA lesions have worse outcomes following LT than patients with HCC [177,178] with a five-year recurrence rate of 65% [178] . Such patients should either not undergo transplantation or be enrolled in research protocols combining adjuvant or neoadjuvant therapy for iCCA in the transplant setting.
    Full-text · Article · Jun 2014
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