Liver Transplantation for Unresectable Intrahepatic Cholangiocarcinoma: The Role of Sequencing Genetic Profiling

Intrahepatic cholangiocarcinoma (iCCA) is a rare and aggressive primary liver tumor, characterized by a range of different clinical manifestations and by increasing incidence and mortality rates even after curative treatment with radical resection. In recent years, growing attention has been devoted to this disease and some evidence supports liver transplantation (LT) as an appropriate treatment for intrahepatic cholangiocarcinoma; evolving work has also provided a framework for better understanding the genetic basis of this cancer. The aim of this study was to provide a clinical description of our series of patients complemented with Next-Generation Sequencing genomic profiling. From 1999 to 2021, 12 patients who underwent LT with either iCCA or a combined hepatocellular and cholangiocellular carcinoma (HCC-iCCA) were included in this study. Mutations were observed in gene activating signaling pathways known to be involved with iCCA tumorigenesis (KRAS/MAPK, P53, PI3K-Akt/mTOR, cAMP, WNT, epigenetic regulation and chromatin remodeling). Among several others, a strong association was observed between the Notch pathway and tumor size (point-biserial rhopb = 0.93). Our results are suggestive of the benefit potentially derived from molecular analysis to improve our diagnostic capabilities and to devise new treatment protocols, and eventually ameliorate long-term survival of patients affected by iCCA or HCC-iCCA.

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Proposal of a New Definition of “Very Early” Intrahepatic Cholangiocarcinoma—A Retrospective Single-Center Analysis

Journal of Clinical Medicine ◽

10.3390/jcm10184073 ◽

2021 ◽

Vol 10 (18) ◽

pp. 4073

Author(s):

Oliver Beetz ◽

Angelica Timrott ◽

Clara A. Weigle ◽

Andreas Schroeter ◽

Sebastian Cammann ◽

...

Keyword(s):

Liver Transplantation ◽

Intrahepatic Cholangiocarcinoma ◽

Tumor Size ◽

Tumor Biology ◽

Extrahepatic Disease ◽

Term Outcome ◽

Term Survival ◽

Long Term Outcome ◽

Definition Of

Intrahepatic cholangiocarcinoma (ICC) is a rare disease with poor outcome, despite advances in surgical and non-surgical treatment. Recently, studies have reported a favorable long-term outcome of “very early” ICC (based on tumor size and absence of extrahepatic disease) after hepatic resection and liver transplantation, respectively. However, the prognostic value of tumor size and a reliable definition of early disease remain a matter of debate. Patients undergoing resection of histologically confirmed ICC between February 1996 and January 2021 at our institution were reviewed for postoperative morbidity, mortality, and long-term outcome after being retrospectively assigned to two groups: “very early” (single tumor ≤ 3 cm) and “advanced” ICC (size > 3 cm, multifocality or extrahepatic disease). A total of 297 patients were included, with a median follow-up of 22.8 (0.1–301.7) months. Twenty-one (7.1%) patients underwent resection of “very early” ICC. Despite the small tumor size, major hepatectomies (defined as resection of ≥3 segments) were performed in 14 (66.7%) cases. Histopathological analyses revealed lymph node metastases in 5 (23.8%) patients. Patients displayed excellent postoperative outcome compared to patients with “advanced” disease: intrahospital mortality was not observed, and patients displayed superior long-term survival, with a 5-year survival rate of 58.2% (versus 24.3%) and a median postoperative survival of 62.1 months (versus 25.3 months; p = 0.013). In conclusion, although the concept of a “very early” ICC based solely on tumor size is vague as it does not necessarily reflect an aggressive tumor biology, our proposed definition could serve as a basis for further studies evaluating the efficiency of either surgical resection or liver transplantation for this malignant disease.

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Somatic Mutation Profiling of Intrahepatic Cholangiocarcinoma: Comparison between Primary and Metastasis Tumor Tissues

Journal of Oncology ◽

10.1155/2020/5675020 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Shi-Feng Xu ◽

Yuan Guo ◽

Xin Zhang ◽

Xiao-Dan Zhu ◽

Ning Fan ◽

...

Keyword(s):

Drug Resistance ◽

Intrahepatic Cholangiocarcinoma ◽

Notch Pathway ◽

Treatment Strategies ◽

Immune Gene ◽

Platinum Drug ◽

Clinical Prognosis ◽

Resistance Pathway ◽

Incidence And Mortality ◽

Platinum Drug Resistance

Introduction. Intrahepatic cholangiocarcinoma (ICC) exhibited increasing incidence and mortality around the world, with a 35% five-year survival rate. In this study, the genetic alteration of primary ICC and metastasis ICC was exhibited to discover novel personalized treatment strategies to improve the clinical prognosis. Methods. Based on 153 primary and 49 metastasis formalin-fixed paraffin-embedded ICC samples, comprehensive genomic profiling was carried out. Results. In primary tumor samples (PSs) and metastasis tumor samples (MSs), the top alteration genes were TP53 (41.8% vs 36.7%), KRAS (30.7% vs 36.7%), and ARID1A (22.2% vs 14.2%). In the top 20 most frequent alteration genes, BRAF showed lower mutation frequency in MSs as compared to PSs (0 vs 11.1%, P=0.015), while LRP1B exhibited opposed trend (22.4% vs 10.4%, P=0.032). In PSs, patients with MSI-H showed all PDL1 negative, and patients with PDL1 positive exhibited MSS both in PSs and MSs. It was found that the Notch pathway had more alteration genes in MSI-H patients (P=0.027). Furthermore, the patients with mutated immune genes in PSs were more than that in MSs (28.8% vs 8.2%, P=0.003, odd ratio = 0.2). Interestingly, the platinum drug resistance pathway was only enriched by mutated genes of MSs. Conclusions. In this study, the identification of two meaningful mutated genes, BRAF and LRP1B, highly mutated immune gene harbored by primary ICC patients. Both in PSs and MSs, no patients with MSI-H showed PDL1 positive. The Notch pathway had more alteration genes in patients with MSI-H. And the enrichment of the platinum drug resistance pathway in MSs might offer reference for the novel therapeutic strategy of ICC.

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Liver Transplantation for Cholangiocarcinoma

European Oncology & Haematology ◽

10.17925/eoh.2012.08.3.173 ◽

2012 ◽

Vol 08 (03) ◽

pp. 173

Author(s):

Armin Thelen ◽

Christoph Benckert ◽

Sven Jonas ◽

◽

...

Keyword(s):

Liver Transplantation ◽

Long Term Results ◽

Treatment Modalities ◽

Neoadjuvant Radiochemotherapy ◽

Organ Shortage ◽

Remnant Liver ◽

Term Survival ◽

Treatment Protocols ◽

Long Term Survival

The treatment of intra- and extrahepatic cholangiocarcinomas remains a medical challenge. Due to the poor efficacy of conventional chemotherapy, surgical treatment modalities represent the only chance of attaining long-term survival and cure. The introduction of new procedures, in particular extended liver resections – which were enabled by increasing surgical expertise and the implementation of multimodal treatment protocols – led to an increasing number of curatively treated patients and significant improvements in long-term results after curative resection. However, numerous patients are not suitable for radical resection because of local tumour growth, intrahepatic metastases, infiltration of main vascular and biliary structures or insufficient remnant liver function. In unresectable tumours, liver transplantation is a curative treatment option for many patients and represents the only chance to achieve long-term survival and cure. Yet, cholangiocarcinomas are not currently a standard indication for liver transplantation, because of the organ shortage and the resulting necessity to allocate available organs to patients with the best prognosis. In recent years, the results of liver transplantation for the different types of cholangiocarcinoma have improved following the application of new treatment protocols. The most promising long-term results were achieved in hilar cholangiocarcinoma by using neoadjuvant radiochemotherapy prior to transplantation. Long-term survival rates were not inferior to those seen in patients receiving a transplantation for benign liver diseases or early-stage hepatocellular carcinoma. The improved long-term outcomes of transplantation for intra- and extrahepatic cholangiocarcinomas have led to a renewed interest for liver transplantation as a treatment for these tumour entities.

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Surgical Treatment of Cholangiocellular Carcinoma

Swiss Surgery ◽

10.1024/1023-9332.5.3.111 ◽

1999 ◽

Vol 5 (3) ◽

pp. 111-115 ◽

Cited By ~ 1

Author(s):

Hanack ◽

Lorf ◽

Binder ◽

Braun ◽

Oestmann ◽

...

Keyword(s):

Liver Transplantation ◽

Surgical Treatment ◽

Early Stage ◽

Therapeutic Option ◽

Bile Duct Carcinoma ◽

Neoadjuvant Treatment ◽

Treatment Modalities ◽

Duct Carcinoma ◽

Treatment Protocols ◽

Primary Liver Tumor

Cholangiocarcinoma is a primary liver tumor arising from the small bile ducts within the liver. According to its different location, clinical features, frequency of metastases, treatment modalities and prognosis, intrahepatic cholangiocarcinoma should well be differentiated from proximal bile duct carcinoma. To date, there is no therapeutic measure with curative potential apart from surgical treatment. Partial hepatectomy is the treatment of choice. It is of overriding importance to achieve microscopically tumor-free margins. However, only few patients treated in an early stage have a prolonged recurrence-free survival or a chance for cure. Liver transplantation is not an alternative therapeutic option for unresectable cholangiocarcinoma, due to early tumor recurrence in almost all recipients. Liver transplantation has a place in preventing cholangiocarcinoma in primary sclerosing cholangitis, although the timing of replacement is still a matter of debate. Results of surgery need further improvement by adjuvant or neoadjuvant treatment protocols.

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The Role of Surgical Resection and Liver Transplantation for the Treatment of Intrahepatic Cholangiocarcinoma

Journal of Clinical Medicine ◽

10.3390/jcm10112428 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2428

Author(s):

Guergana Panayotova ◽

Jarot Guerra ◽

James V. Guarrera ◽

Keri E. Lunsford

Keyword(s):

Liver Transplantation ◽

Surgical Resection ◽

Intrahepatic Cholangiocarcinoma ◽

Locally Advanced ◽

Tumor Biology ◽

Future Liver Remnant ◽

Patient Treatment ◽

Term Survival ◽

Liver Remnant

Intrahepatic cholangiocarcinoma (iCCA) is a rare and complex malignancy of the biliary epithelium. Due to its silent presentation, patients are frequently diagnosed late in their disease course, resulting in poor overall survival. Advances in molecular profiling and targeted therapies have improved medical management, but long-term survival is rarely seen with medical therapy alone. Surgical resection offers a survival advantage, but negative oncologic margins are difficult to achieve, recurrence rates are high, and the need for adequate future liver remnant limits the extent of resection. Advances in neoadjuvant and adjuvant treatments have broadened patient treatment options, and these agents are undergoing active investigation, especially in the setting of advanced, initially unresectable disease. For those who are not able to undergo resection, liver transplantation is emerging as a potential curative therapy in certain cases. Patient selection, favorable tumor biology, and a protocolized, multidisciplinary approach are ultimately necessary for best patient outcomes. This review will discuss the current surgical management of locally advanced, liver-limited intrahepatic cholangiocarcinoma as well as the role of liver transplantation for select patients with background liver disease.

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Nab-Paclitaxel Combined With Gemcitabine Adjuvant Chemotherapy After Radical Resection of Intrahepatic Cholangiocarcinoma

Case Medical Research ◽

10.31525/ct1-nct04077983 ◽

2019 ◽

Author(s):

Keyword(s):

Adjuvant Chemotherapy ◽

Intrahepatic Cholangiocarcinoma ◽

Radical Resection

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Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

Current Cancer Drug Targets ◽

10.2174/1568009620666200520084415 ◽

2020 ◽

Vol 20 (9) ◽

pp. 720-727

Author(s):

Jianguo Qiu ◽

Wei Tang ◽

Chengyou Du

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Immune Checkpoint ◽

Graft Rejection ◽

Checkpoint Inhibitors ◽

Liver Graft ◽

Immune Checkpoints ◽

Term Survival ◽

Liver Preservation ◽

Programmed Death

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied. Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT. Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed. Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival. Conclusions: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

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The Treatment Effect of Liver Transplantation versus Liver Resection for HCC: A Review and Future Perspectives

Cancers ◽

10.3390/cancers13153730 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3730

Author(s):

Berend R. Beumer ◽

Roeland F. de Wilde ◽

Herold J. Metselaar ◽

Robert A. de Man ◽

Wojciech G. Polak ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Liver Resection ◽

Early Stage ◽

Disease Free Survival ◽

Milan Criteria ◽

Term Survival ◽

Equal Distribution ◽

Intention To Treat ◽

Treat Analysis

For patients presenting with hepatocellular carcinoma within the Milan criteria, either liver resection or liver transplantation can be performed. However, to what extent either of these treatment options is superior in terms of long-term survival is unknown. Obviously, the comparison of these treatments is complicated by several selection processes. In this article, we comprehensively review the current literature with a focus on factors accounting for selection bias. Thus far, studies that did not perform an intention-to-treat analysis conclude that liver transplantation is superior to liver resection for early-stage hepatocellular carcinoma. In contrast, studies performing an intention-to-treat analysis state that survival is comparable between both modalities. Furthermore, all studies demonstrate that disease-free survival is longer after liver transplantation compared to liver resection. With respect to the latter, implications of recurrences for survival are rarely discussed. Heterogeneous treatment effects and logical inconsistencies indicate that studies with a higher level of evidence are needed to determine if liver transplantation offers a survival benefit over liver resection. However, randomised controlled trials, as the golden standard, are believed to be infeasible. Therefore, we suggest an alternative research design from the causal inference literature. The rationale for a regression discontinuity design that exploits the natural experiment created by the widely adopted Milan criteria will be discussed. In this type of study, the analysis is focused on liver transplantation patients just within the Milan criteria and liver resection patients just outside, hereby ensuring equal distribution of confounders.

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The Role of Conventional and Stereotactic Microwave Ablation for Intrahepatic Cholangiocarcinoma

Journal of Clinical Medicine ◽

10.3390/jcm10132963 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2963

Author(s):

Corina Kim-Fuchs ◽

Daniel Candinas ◽

Anja Lachenmayer

Keyword(s):

Literature Review ◽

Intrahepatic Cholangiocarcinoma ◽

Microwave Ablation ◽

Treatment Options ◽

Tumor Biology ◽

Tumor Ablation ◽

Curative Treatment ◽

Complication Rates ◽

Curative Therapy ◽

Incidence And Mortality

Background: The incidence and mortality of intrahepatic cholangiocarcinoma (ICCA) is increasing worldwide and curative treatment options are limited due to the aggressive tumor biology and often late diagnosis. Resection of the primary tumor remains the only curative therapy available, as the benefit of palliative chemotherapy and radiotherapy is relatively small. In contrast to hepatocellular carcinoma, minimal-invasive thermal tumor ablation, and in particular stereotactic tumor ablation for small primary cancers or metastases, is not established and data are scarce. Methods: We conducted a literature review in the field of ICCA ablation and retrospective analysis of 10 patients treated by stereotactic microwave ablation (SMWA) for either primary ICCA or liver metastases of ICCA. Results: While current guidelines have no consensus for ablation of primary ICCA, some state that it might be an option in inoperable patients or those with recurrent disease. The literature review revealed 11 studies on microwave ablation for ICCA reporting that MWA for ICCA ≤ 5 cm might be safe and could be a treatment option for patients who are not candidates for surgery. No data has been published on stereotactic microwave ablation (SMWA) for ICCA. The analyses of our own data of 10 patients treated by SMWA for primary ICCA (n = 5) or recurrent ICCA (n = 5) show that the treatment is safe and efficient with short hospital stays and low complication rates. Conclusion: Although thermal ablation, and in particular SMWA, might be a minimally invasive and tissue-sparing curative treatment alternative for small ICCA in the diseased liver and ICCA metastases, the oncologic benefit still needs to be shown in larger studies with longer follow-up.

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