Surgical Therapy for Primary Liver Tumors – Resection and Transplantation
The two most common malignant liver tumors are hepatocellular carcinoma (HCC) and intrahepatic cholangiocellular carcinoma (“intrahepatic cholangiocellular adenocarcinoma”
[iCCA]). Primary liver tumors can basically arise from all histogenetic cell elements present in the liver. HCC is a primary liver-specific tumor with hepatocytic differentiation, the cell of origin is the hepatocyte in different stages of differentiation, iCCA is defined as an intrahepatically located malignancy with biliary differentiation [1]. Intrahepatic cholangiocarcinomas can arise in any part of the intrahepatic bile duct, from segmental bile ducts to the smallest branches of the bile ducts and tubular structures [2].
HCC are relatively rare, but due to the previously relatively poor prognosis, they are among the ten most common causes of cancer death [3]. In Germany, around 8300 new cases occur per year, with an approximately equal number of deaths. The median age at diagnosis is 70 years in men and 74 years in women [1].
According to large statistics, iCCA account for about 5–10 % of all primary malignant liver tumors, with prevalence showing a large geographical variation. High-incidence areas are in Asia, where the endemic occurrence of etiologically relevant worms (Opisthorchis viverrini and Clonorchis sinensis) is documented. In the United States, classified as a low-incidence area, 1–2 new cases/100,000 inhabitants are assumed (these numbers could be similar to ours). The average age of patients with an iCCA is 55 years. Men are generally affected more frequently than women. The incidence of iCCA is steadily increasing [1].
Surgical Therapy for iCCA
iCCA often remain asymptomatic for a long time and therefore usually have a considerable size and extent at the time of diagnosis [4, 5, 6]. A distinction is made between the two rare periductal-infiltrating and intraductal growing forms as well as the more common mass-forming type [7]. The two aforementioned variants are usually noticeable due to obstruction of the downstream bile ducts (jaundice), whereas the mass-forming type clinically usually presents as a large solitary or multifocal, often confluent mass, which frequently has contact with large vessels or infiltrates them. Cholestasis with jaundice is rare and is usually due to compression of the hepatic bifurcation, less often to direct tumor infiltration [4, 5, 8, 9].
Currently, radical surgical removal of the tumor tissue represents the only curative treatment for iCCA. Since iCCA predominantly arise in a non-cirrhotic liver, the required extensive resections are often possible. Across all tumor stages, 5-year survival rates between 21 and 45 % are achieved after R0 resection [5, 6, 9, 10, 11, 12]. Distant metastasis, multifocality, lymph node metastases and vascular invasion are important prognostic factors after R0 resection of an iCCA [6, 9, 12, 13, 14].
Analogous to other gastrointestinal tumor diseases, surgical therapy for iCCA is increasingly embedded in multimodal concepts. In the BILCAP study (“Capecitabine compared with observation in resected biliary tract cancer”), a median survival of 53 months was found after resection + adjuvant therapy compared to 36 months after surgical therapy alone [15]. Adjuvant chemotherapy with capecitabine is currently considered the standard. Data are also available on the effectiveness of neoadjuvant therapy. In a French multicenter analysis, comparable results were found after secondary resection of initially irresectable or borderline resectable iCCA compared to resection of initially resectable iCCA, but significantly better results than after systemic chemotherapy alone [11]. Further studies also indicate that R1 resection in combination with subsequent chemotherapy can achieve superior survival data compared to chemotherapy alone. The indication for palliative resection (debulking, R2 resection) is only given in individual cases [5, 6, 10, 16].
In isolated intrahepatic tumor recurrences after potentially curative resection (usually within the first 2 years in about half of the patients), in recent years, alternatives to systemic therapy have increasingly been treated with local ablation or surgery. This has achieved results comparable to primary resection [10, 17].
Liver transplantation (LTX) currently has only minor importance in iCCA. In patients with so-called “very early stage iCCA” (solitary iCCA < 2 cm), 5-year survival rates of 65 % can be achieved [18]. In the current guidelines of the German Medical Association on organ transplantation, LTX in patients with a CCA is only recommended within the framework of clinical studies [19].
Surgical Therapy for HCC
HCC arise in over 85 % of cases in a cirrhotic liver. The presence and degree of cirrhosis as well as the underlying disease are decisive for diagnosis, therapy and prognosis [8, 16, 20].
The German HCC guideline, which is currently under revision, as well as the European guideline recommend HCC in cirrhosis LTX as the therapy of choice [16, 20]. It is contraindicated in extrahepatic tumor manifestations as well as in imaging-detectable infiltration of large liver vessels [19].
In still compensated liver function, resection represents an alternative to transplantation. Due to the limited functional reserve, more extensive resections are only rarely possible. Resections in liver cirrhosis are also associated with an increased perioperative risk, which is particularly increased by portal hypertension. Studies indicate that morbidity can be reduced by a laparoscopic approach [21]. Analyses report 5-year survival rates after resection of small and solitary HCC between 30 and 55 %, in highly selected subgroups even up to over 75 % [22, 23, 24]. Depending on the cause of liver cirrhosis, the recurrence risk within 5 years after resection is 60 – 80 %, since the resection cures the HCC lesion but not the underlying disease (hence the recommendation for LTX). An effective adjuvant therapy after R0 resection in HCC in cirrhosis is largely lacking so far. There is no solid evidence for neoadjuvant therapy to date [25]. Recurrences after HCC resection in cirrhosis are often limited to the liver, so that in these cases a repeat resection or LTX can be performed individually. 5-year survival rates of 60 % for repeat resection and up to 80 % after salvage LTX are reported [20, 26, 27].
For HCC in non-cirrhotic liver, resection represents the therapy of choice. In stage M1, there is usually no indication for resection anymore, isolated lung or adrenal metastases may be an exception. After R0 resection of an HCC in non-cirrhotic liver, 5-year survival rates between 26 and 60 % are described [8].
Despite potentially curative resection, tumor recurrence occurs in more than half of the patients with HCC within the first 2 years. Usually, multifocal intrahepatic or combined intra- and extrahepatic recurrences are found. Isolated intrahepatic tumor recurrences that can be resected again are rare. In case of irresectability of locally advanced tumors or tumor recurrences, LTX can also be considered for HCC in non-cirrhotic liver. A European multicenter analysis with over 100 patients has shown a 5-year survival of 49 % and a disease-free survival of 43 % after LTX in these cases [28].
Technical Aspects in the Surgery of iCCA and HCC
In resections of primary liver tumors, all technical possibilities of liver surgery are utilized, taking into account the functional residual capacity of the liver [5, 6, 8, 9, 10, 12]. In a healthy liver, up to 80 % of the liver volume can be resected.
The standard procedure for HCC and iCCA in non-cirrhotic liver is anatomical liver resection. In addition to the classic (extended) hemihepatectomy, segmentectomies and less common techniques such as sectorectomies or mesohepatectomies can be considered for smaller tumors [5, 6, 7, 8, 9, 10, 11, 12]. The goal is R0 resection with adherence to a safety margin, for whose size, however, no solid evidence exists.
Especially in non-cirrhotic parenchyma, the liver can be conditioned for resection, achieving hypertrophy rates of the FLR (functional liver remnant volume) of up to 40 %. Common techniques are portal vein embolization, rarely operative portal vein ligation [29]. The procedure of “in-situ split” or “associating liver partition and portal vein ligation for staged hepatectomy” (ALPPS), which enables volume increases of the FLR of 60 to over 100 % within a week, is performed very cautiously due to the sometimes considerable perioperative complication rate [30].
In addition to extensive liver resections, vascular and especially in iCCA bile duct resections are often indicated [5, 6, 8, 12, 31, 32]. If a curative overall concept seems achievable, these surgical extensions nowadays no longer represent a contraindication to resection, but they do entail a not insignificant perioperative mortality of up to 10 %.
For HCC in cirrhosis, predominantly small resections and segmentectomies, less often hemihepatectomies, are performed [22, 23, 24].
In primary liver carcinomas, lymphadenectomy primarily has diagnostic-prognostic significance. In resectable HCC, the incidence of LN metastasis is overall low at 5 – 10 %, with lymphatic metastasis being less common in HCC in cirrhosis [8, 13, 14]. In iCCA, the incidence of lymph node metastases is significantly higher at about 20–40% than in HCC.
For the resection of hepatobiliary tumors, lymphadenectomy is predominantly required, although the underlying data is weak. Since the lymphatic drainage of the liver is very complex and variable, there is still no standardization of lymphadenectomy for liver tumors. Various studies have shown that the detection of LN metastases has a negative impact on the prognosis of tumors of the liver (including liver metastases), pancreas, and bile ducts [13, 33]. In addition to the total number of affected lymph nodes, the ratio of affected to examined LN (LN ratio) seems to have prognostic significance at least in intrahepatic (ICC) and perihilar cholangiocarcinoma (PHCC, Klatskin).
Nevertheless, it is consensus that in lymphadenectomy, the hepatic hilum should always be included. However, there is uncertainty as to how “aggressively” the dissection of the lymphatic and connective tissue in the hepatic hilum should be performed.
In liver cirrhosis, hilar lymphadenectomy is associated with increased morbidity: venous bleeding due to portal congestion, frequent respiratory or cardiovascular complications, wound and intra-abdominal infections [13]. Occasionally, pronounced lymph leaks or massive ascites development occur in the postoperative course. Due to the diverse postoperative risks, in liver cirrhosis, a very precise weighing of benefit and risk of lymphadenectomy is necessary.