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Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (1 April 2021) | Viewed by 28982

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Dr. Luca Di Tommaso

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Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy
Interests: liver; hepatocarcinogenesis; hepatocarcinoma (HCC); early HCC; angiogenesis; tissue; biomarkers; digital pathology; artificial intelligence

Special Issue Information

Liver cancers are among the most common malignant tumors. They include primary liver lesions, mostly represented by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), and secondary lesions, particularly metastatic colorectal cancer (mCCR). These three types of tumors vary greatly in their pathogenesis, behavior, and prognosis. Accordingly, their treatment rests on the evaluation of several elements, warranted by a multidisciplinary approach. Among others, surgical treatment is the most important approach for achieving long-term survival in these patients.

This Special Issue aims to review the current status of surgery for HCC, CC and mCCR, to present research data prompting innovative surgical solutions, and to discuss how pathology can address the challenges raised by these advances

Dr. Luca Di Tommaso
Guest Editor

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Keywords

liver
hepatocarcinoma
cholangiocarcinoma
metastases
treatment
surgery
pathology
diagnosis

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Published Papers (9 papers)

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Research

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17 pages, 4028 KiB

Open AccessArticle

The Presence of Small Nerve Fibers in the Tumor Microenvironment as Predictive Biomarker of Oncological Outcome Following Partial Hepatectomy for Intrahepatic Cholangiocarcinoma

by Jan Bednarsch, Xiuxiang Tan, Zoltan Czigany, Dong Liu, Sven Arke Lang, Shivan Sivakumar, Jakob Nikolas Kather, Simone Appinger, Mika Rosin, Shiva Boroojerdi, Edgar Dahl, Nadine Therese Gaisa, Marcel den Dulk, Mariëlle Coolsen, Tom Florian Ulmer, Ulf Peter Neumann and Lara Rosaline Heij

Cancers 2021, 13(15), 3661; https://doi.org/10.3390/cancers13153661 - 21 Jul 2021

Cited by 8 | Viewed by 2728

Abstract

The oncological role of the density of nerve fibers (NFs) in the tumor microenvironment (TME) in intrahepatic cholangiocarcinoma (iCCA) remains to be determined. Therefore, data of 95 iCCA patients who underwent hepatectomy between 2010 and 2019 was analyzed regarding NFs and long-term outcome. Extensive group comparisons were carried out and the association of cancer-specific survival (CSS) and recurrence-free survival (RFS) with NFs were assessed using Cox regression models. Patients with iCCA and NFs showed a median CSS of 51 months (5-year-CSS = 47%) compared to 27 months (5-year-CSS = 21%) in patients without NFs (p = 0.043 log rank). Further, NFs (hazard ratio (HR) = 0.39, p = 0.002) and N-category (HR = 2.36, p = 0.010) were identified as independent predictors of CSS. Patients with NFs and without nodal metastases displayed a mean CSS of 89 months (5-year-CSS = 62%), while patients without NFs or with nodal metastases but not both showed a median CCS of 27 months (5-year-CSS = 25%) and patients with both positive lymph nodes and without NFs showed a median CCS of 10 months (5-year-CSS = 0%, p = 0.001 log rank). NFs in the TME are, therefore, a novel and important prognostic biomarker in iCCA patients. NFs alone and in combination with nodal status is suitable to identify iCCA patients at risk of poor oncological outcomes following curative-intent surgery. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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15 pages, 821 KiB

Open AccessArticle

Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection

by Francesco Ardito, Francesco Razionale, Lisa Salvatore, Tonia Cenci, Maria Vellone, Michele Basso, Elena Panettieri, Maria Alessandra Calegari, Giampaolo Tortora, Maurizio Martini and Felice Giuliante

Cancers 2021, 13(9), 2148; https://doi.org/10.3390/cancers13092148 - 29 Apr 2021

Cited by 8 | Viewed by 2345

Abstract

If KRAS mutation status of primary colorectal tumor is representative of corresponding colorectal liver metastases (CRLM) mutational pattern, is controversial. Several studies have reported different rates of KRAS discordance, ranging from 4 to 32%. Aim of this study is to assess the incidence of discordance and its impact on overall survival (OS) in a homogenous group of patients. KRAS mutation status was evaluated in 107 patients resected for both primary colorectal tumor and corresponding CRLM at the same institution, between 2007 and 2018. Discordance rate was 15.9%. Its incidence varied according to the time interval between the two mutation analyses (p = 0.025; Pearson correlation = 0.2) and it was significantly higher during the first 6 months from the time of primary tumor evaluation. On multivariable analysis, type of discordance (wild-type in primary tumor, mutation in CRLM) was the strongest predictor of poor OS (p < 0.001). At multivariable logistic regression analysis, the number of CRLM >3 was an independent risk factor for the risk of KRAS discordance associated with the worst prognosis (OR = 4.600; p = 0.047). Results of our study suggested that, in the era of precision medicine, possibility of KRAS discordance should be taken into account within multidisciplinary management of patients with metastatic colorectal cancer. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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11 pages, 1555 KiB

Open AccessArticle

Risk Stratification of Cholangiocarcinoma Patients Presenting with Jaundice: A Retrospective Analysis from a Tertiary Referral Center

by Ana Lleo, Francesca Colapietro, Patrick Maisonneuve, Monia Aloise, Vincenzo Craviotto, Roberto Ceriani, Lorenza Rimassa, Salvatore Badalamenti, Matteo Donadon, Vittorio Pedicini, Alessandro Repici, Luca Di Tommaso, Antonio Voza, Guido Torzilli and Alessio Aghemo

Cancers 2021, 13(9), 2070; https://doi.org/10.3390/cancers13092070 - 25 Apr 2021

Cited by 7 | Viewed by 1979

Abstract

Cholangiocarcinomas (CCAs) are a heterogeneous group of tumors that arise from the biliary tract. Jaundice is a common clinical presentation; however, the prognostic impact of this symptom is poorly understood, and current management recommendations lack solid evidence. We aim to assess the clinical outcomes and predictive factors of CCA patients presenting with jaundice in the Emergency Room (ER). We retrospectively analyzed all consecutive ER cases presenting with jaundice between January 2010 and December 2017. During the study period, 403,766 patients were admitted to the ER, 1217 (0.3%) presented with jaundice, and in 200 (0.049%), the diagnosis was CCA. CCA cases increased during the study period (p for trend 0.026). Most of them presented with advance disease (stage III 46.5%, stage IV 43.5%) and median survival was 4.5 months (95% CI 3.4–6.0). Factors associated with better survival were age, stage of disease, presence of jaundice at the moment of diagnosis, and lack of concomitant viral hepatitis. A nomogram was constructed that significantly predicts 1-month, 6-month, and 1-year survival after patients’ admission. In conclusion, the majority of CCA patients presenting with jaundice to the ER have advanced disease and poor prognosis. Risk stratification of these patients can allow tailored management. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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12 pages, 6610 KiB

Open AccessArticle

Prognostic Value of Metabolic Imaging Data of ¹¹C-choline PET/CT in Patients Undergoing Hepatectomy for Hepatocellular Carcinoma

by Matteo Donadon, Egesta Lopci, Jacopo Galvanin, Simone Giudici, Daniele Del Fabbro, Ezio Lanza, Vittorio Pedicini, Arturo Chiti and Guido Torzilli

Cancers 2021, 13(3), 472; https://doi.org/10.3390/cancers13030472 - 26 Jan 2021

Cited by 6 | Viewed by 2369

Abstract

¹¹C-choline positron emission tomography/computed tomography (PET/CT) has been used for patients with some types of tumors, but few data are available for hepatocellular carcinoma (HCC). We queried our prospective database for patients with HCC staged with ¹¹C-choline PET/CT to assess the clinical impact of this imaging modality. Seven parameters were recorded: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), liver standardized uptake value (SUVliver), metabolic tumor volume (MTV), photopenic area, metabolic tumor burden (MTB = MTVxSUVmean), and SUVratio (SUVmax/SUVliver). Analysis was performed to identify parameters that could be predictors of overall survival (OS). Sixty patients were analyzed: fourteen (23%) were in stage 0-A, 37 (62%) in stage B, and 9 (15%) in stage C of the Barcelona classification. The Cox regression for OS showed that Barcelona stages (HR = 2.94; 95%CI = 1.41–4.51; p = 0.003) and MTV (HR = 2.11; 95%CI = 1.51–3.45; p = 0.026) were the only factors independently associated with OS. Receiver operating characteristics curve analysis revealed MTV ability in discriminating survival (area under the curve (AUC) = 0.77; 95%CI = 0.57–097; p < 0.001: patients with MTV ≥ 380 had worse OS (p = 0.015)). The use of ¹¹C-choline PET/CT allows for better prognostic refinement in patients undergoing hepatectomy for HCC. Incorporation of such modality into HCC staging system should be considered. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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11 pages, 561 KiB

Open AccessArticle

Hepatic and Extrahepatic Colorectal Metastases Have Discordant Responses to Systemic Therapy. Pathology Data from Patients Undergoing Simultaneous Resection of Multiple Tumor Sites

by Luca Vigano, Pio Corleone, Shadya Sara Darwish, Nicolò Turri, Simone Famularo, Lorenzo Viggiani, Lorenza Rimassa, Daniele Del Fabbro, Luca Di Tommaso and Guido Torzilli

Cancers 2021, 13(3), 464; https://doi.org/10.3390/cancers13030464 - 26 Jan 2021

Cited by 7 | Viewed by 2226

Abstract

Background: Systemic therapy is the standard treatment for patients with hepatic and extrahepatic colorectal metastases. It is assumed to have the same effectiveness on all disease foci, independent of the involved organ. The present study aims to compare the response rates of hepatic and extrahepatic metastases to systemic therapy. Methods: All consecutive patients undergoing simultaneous resection of hepatic and extrahepatic metastases from colorectal cancer after oxaliplatin- and/or irinotecan-based preoperative chemotherapy were analyzed. All specimens were reviewed. Pathological response to chemotherapy was classified according to tumor regression grade (TRG). Results: We analyzed 45 patients undergoing resection of 134 hepatic and 72 extrahepatic metastases. Lung and lymph node metastases had lower response rates to chemotherapy than liver metastases (TRG 4–5 95% and 100% vs. 67%, p = 0.008, and p = 0.006). Peritoneal metastases had a higher pathological response rate than liver metastases (TRG 1–3 66% vs. 33%, p < 0.001) and non-hepatic non-peritoneal metastases (3%, p < 0.001). Metastases site was an independent predictor of pathological response to systemic therapy. Conclusions: Response to chemotherapy of distant metastases from colorectal cancer varies in different organs. Systemic treatment is highly effective for peritoneal metastases, more so than liver metastases, while it has a very poor impact on lung and lymph node metastases. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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Review

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12 pages, 878 KiB

Open AccessReview

Vascular Resection in Perihilar Cholangiocarcinoma

by Alejandro Serrablo, Leyre Serrablo, Ruslan Alikhanov and Luis Tejedor

Cancers 2021, 13(21), 5278; https://doi.org/10.3390/cancers13215278 - 21 Oct 2021

Cited by 17 | Viewed by 2794

Abstract

Among the cholangiocarcinomas, the most common type is perihilar (phCC), accounting for approximately 60% of cases, after which are the distal and then intrahepatic forms. There is no staging system that allows for a comparison of all series and extraction of conclusions that increase the long-term survival rate of this dismal disease. The extension of the resection, which theoretically depends on the type of phCC, is not a closed subject. As surgery is the only known way to achieve a cure, many aggressive approaches have been adopted. Despite extended liver resections and even vascular resections, margins are positive in around one third of patients. In the past two decades, with advances in diagnostic and surgical techniques, surgical outcomes and survival rates have gradually improved, although variability is the rule, with morbidity and mortality rates ranging from 14% to 76% and from 0% to 19%, respectively. Extended hepatectomies and portal vein resection, or even right hepatic artery reconstruction for the left side tumors are frequently needed. Salvage procedures when arterial reconstruction is not feasible, as well as hepatopancreatoduodenectomy, are still under evaluation too. In this article, we discuss the aggressive surgical approach to phCC focused on vascular resection. Disparate results on the surgical treatment of phCC made it impossible to reach clear-cut conclusions. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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10 pages, 824 KiB

Open AccessReview

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

by Berend R. Beumer, Roeland F. de Wilde, Herold J. Metselaar, Robert A. de Man, Wojciech G. Polak and Jan N. M. Ijzermans

Cancers 2021, 13(15), 3730; https://doi.org/10.3390/cancers13153730 - 24 Jul 2021

Cited by 12 | Viewed by 2559

Abstract

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. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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15 pages, 4360 KiB

Open AccessReview

Histological Heterogeneity of Primary Liver Cancers: Clinical Relevance, Diagnostic Pitfalls and the Pathologist’s Role

by Mina Komuta

Cancers 2021, 13(12), 2871; https://doi.org/10.3390/cancers13122871 - 8 Jun 2021

Cited by 21 | Viewed by 4524

Abstract

Primary liver cancers (PLCs) mainly comprise hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and cHCC-CCA. Combined HCC-CCA and small duct type iCCA show similar clinical presentations, and their histological features are more complex than seen in HCC. Therefore, while their treatment strategy differs, it is difficult to properly diagnose these tumors. Currently, HCC is the only tumor that can be treated by liver transplantation. In addition, small duct type iCCA harbors IDH1/2 mutations and FGFR2 fusions, which can be used for targeted therapy. Thus, improving diagnostic accuracy is crucial. A further point to note is that PLCs often present as multiple liver tumors, and they can be a combination of different types of PLCs or HCCs. In the case of HCCs, two different scenarios are possible, namely intrahepatic metastasis, or multicentric occurrence. Therefore, it is essential to characterize the type of multiple liver tumors. This review aims to clarify the pathological features of HCC, iCCA and cHCC-CCA, including their diagnostic pitfalls and clinical relevance. It is designed to be of use to clinicians who are dealing with PLCs, to provide a better understanding of the pathology of these tumors, and to enable a more accurate diagnosis and optimal treatment choice. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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27 pages, 1521 KiB

Open AccessReview

Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy

by Valentina Cazzetta, Sara Franzese, Claudia Carenza, Silvia Della Bella, Joanna Mikulak and Domenico Mavilio

Cancers 2021, 13(9), 2184; https://doi.org/10.3390/cancers13092184 - 1 May 2021

Cited by 26 | Viewed by 6430

Abstract

Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients. Full article

(This article belongs to the Special Issue Surgical Treatment and Pathological Diagnosis of Liver Cancers: Current Status and Novel Perspectives)

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