**Abstract**

In this chapter we aim at presenting the state of the art in liver surgery. After a brief introduction about natural evolution of hepatocellular carcinoma (HCC) either in cirrhotic or non-cirrhotic patients, this manuscript will focus on planning and timing surgery: CT evaluation of the remnant liver; biopsy and ultrasonography (US) evaluation of liver disease; intraoperative US; surgical techniques, such as major and limited hepatectomies and two-stage hepatectomies, each of them in open or mini-invasive approach; and their possible complications. Follow-up and further interventions during expected recurrences will be highlighted. Our chapter will also treat topics such as patient's quality of life, importance of multidisciplinary evaluation and the role of surgeon in it.

**Keywords:** HCC, liver cirrhosis, liver surgery, open surgery, laparoscopic liver surgery, robotic liver surgery, HCC management, HCC follow up, staged hepatectomy, ALPSS

#### **1. Introduction**

Hepatocellular carcinoma (HCC) accounts for about 75–85% of primary liver malignancy. Being the most common histotype of liver cancer, it contributes significantly to global disease and mortality. Liver cancer ranks sixth for worldwide incidence and third for worldwide mortality. In Europe it ranks 14th for incidence and 8th for mortality [1]. In cirrhotic patients it remains one of the major causes of death [2, 3].

HCC incidence is worldwide heterogeneous because of the distribution of its main risk factors: hepatitis B, hepatitis C, alcoholic hepatitis, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) (**Table 1**) [4] chronic liver disease is the main background in which HCC arises (70–90% of all patients) [2]. It usually develops in cirrhotic liver, even if 10–20% of cases involve patients not yet cirrhotic [3]. These ones tend to receive a late diagnosis, due to the lack of symptomatology in early stage and/or inadequate surveillance [3].


#### **Table 1.**

*HCC incidence in cirrhotic and non-cirrhotic patients per risk factor.*

Clinical evaluation and multidisciplinary approach are fundamental to submit patients to the most appropriate treatment. Assessment must consider patients' characteristics (general conditions, performance status, physiological age, life expectancy, treatment tolerability), HCC stage, oncological principles and liver status [4].

Several approaches, both surgical and non-surgical, are available for HCC treatment. Surgery is the first-line treatment in terms of overall survival and diseasefree survival [5].

Surgical approaches include liver resections (LRs) and liver transplantation (LT). LR is the gold standard in non-cirrhotic liver, whereas cirrhotic patients should be properly selected because of higher risk of complications [5].

LT allows radical tumor removal (R0) combined with the cure of underlying liver disease [6]. It is the treatment of choice in patients unsuitable for resective surgery that fall within the Milan criteria [5]. LT is indicated in patients ≤65 years (extended to 70 and 70+ patients, in some cases) [7] with severe cirrhosis (MELD > 15). According to the Milan criteria, patients should have a single nodule ≤5 cm or up to three nodules measuring ≤3 cm [8, 9], with no macroscopic vascular invasion nor extrahepatic metastases [5, 9]. After some years of experience, the Milan criteria were extended, developing up-to-seven criteria, in which patients are considered eligible for liver transplant when the sum of the size (in cm) of the largest tumor and the number of lesions is ≤7, in the absence of microscopic vascular invasion [10]. Up-to-seven criteria should be used carefully because overall survival decreases as the number and size of tumor grows [11]. This principle is called "Metro ticket" [12]. Because of organs' low availability, lower recurrence risk patients shall be selected for transplantation in order to optimize organ allocation [12]. Resection and noninvasive therapies could be performed to control lesion progression during waiting period (bridging) or in order to downstage HCC [5, 6]. Liver function in waiting list is commonly evaluated through Child-Pugh (CTP), MELD and MELD-Na scores [13]. The latter is a good predictor of waitlist mortality in cirrhotic patients, so it shall be taken into account to improve organ allocation system [14]. Pretransplant mortality rate in liver malignancy accounts for about 10 deaths per 100 patient years of waiting [15].

Non-surgical approaches include percutaneous radiofrequency thermoablation (RFA), microwave thermoablation (MWA), drug-eluting bead transarterial chemoembolization (DEB-TACE), transarterial radioembolization (TARE), percutaneous ethanol injection (PEI), cryoablation and laser ablation (LA). Except from thermoablations, which are considered curative in small lesion (≤2 cm), non-surgical approaches are commonly palliative [16]. Elderly, very elderly and frail patients, either at presentation or in the case of recurrences, may benefit from these techniques in terms of survival and quality of life [4].

RFA and MWA are the most appropriate treatment in patients with BCLC 0 and A tumors not eligible for surgery [5, 17]. RFA induces coagulative necrosis in tumor

**77**

necessary [4, 27].

failure [5].

rate [5, 24].

*HCC in Cirrhotic and Non-cirrhotic Liver: Timing to Surgery and Outcome - State of the Art*

cells and in a "safety ring" of peritumoural tissue using frictional heat generated by high-frequency alternating current. Lesions adjacent to the vessels and biliary tree or in subcapsular positions could compromise RFA effectiveness and safety [5, 18, 19]. However, microwave ablation has been recognized as effective in this kind of lesions, due to damage concentration and less heat dispersion [17, 20]. MWA uses electromagnetic energy to induce a larger necrotic area than RFA thanks to faster heating and higher temperature [17]. Overall, RFA and MWA provide similar

DEB-TACE induces tumor necrosis through intraarterial delivery of microspheres fulfilled with chemotherapic drug that may vary in size and chemotherapic agent to treat different types of HCC [21]. This technique profits from the presence of a singular artery feeding the tumor. TACE is a palliative treatment indicated in patients not eligible for surgery or percutaneous ablation, with tumor at stage BCLC B (Child-Pugh ≤ B8; PS < 2). HCC nodule >10 cm, macroscopic vascular invasion, extrahepatic disease, untreatable ascites, jaundice and kidney disfunction strongly contraindicate TACE [4, 5]. Potential adverse effects are liver enzyme abnormalities (18.1%), fever (17.2%), hematological/bone marrow toxicity (13.5%), pain (11%), vomiting (6%) and even death (0.6%) for liver

RFA can be used as a complementary technique with TACE, to treat residual neoplastic tissue [22]. Patients with bigger nodules (>3 cm) and with capillary

TARE is also called selective internal radiation therapy (SIRT). It is a palliative brachytherapy that uses radioactive substances (Y90-microspheres) injected into tumor-feeding arteries. This complex procedure is indicated in patients with conserved liver function (Child-Pugh ≤ 8, bilirubin ≤ 2.0 mg/dl, no ascites) and locally advanced HCC, not eligible for surgery or TACE (portal system invasion or unencapsulated large lesions). Pulmonary shunt and other vascular anomalies

PEI induces tumor cell necrosis through dehydration, protein denaturation and small tumor vessel disruption. It is indicated in patients not eligible neither for resection nor for other forms of ablation, especially in HCC nodules ≤3 cm in the hepatic hilum area. The application of this procedure is restricted because it allows only an incomplete necrosis in lesions >3 cm and leads to high recurrence

Cryoablation induces tumor cell necrosis using recurring applications of freezing temperature. Despite its good efficacy, this procedure is barely used because it is associated with high risk of life-threatening complications such as cryoshock, cold

Surgical and non-surgical treatments, and the possibility of combined approach,

Follow-up is fundamental in HCC patients, both in cirrhotic and non-cirrhotic ones, in order to promptly identify possible recurrences and to treat them in the best way. Intrahepatic recurrences, far from previously treated lesions, are always possible and generated by chronic hepatopathy; therefore, lifelong surveillance is

The aim of this chapter is to illustrate the state of the art in liver surgery to achieve the best treatment for patients suffering from hepatocellular carcinoma.

LA induces tissue necrosis through conversion of absorbed light (usually infrared) into heat. It can be used to treat up to five lesions, measuring ≤5 cm, located in the deep parenchyma and distant from the vessels, biliary ducts, bowel or diaphragm, when patients are not eligible for resection [26]. It is rarely used because

vascularization receive higher benefit from this combination [5, 23].

*DOI: http://dx.doi.org/10.5772/intechopen.86638*

contraindicate to this technique [4, 5].

injury to adjacent organs and massive bleeding [25].

of difficulties in the technique's management [5].

should be carefully evaluated aiming for a tailored therapy.

results in terms of local control and survival rates [17].

#### *HCC in Cirrhotic and Non-cirrhotic Liver: Timing to Surgery and Outcome - State of the Art DOI: http://dx.doi.org/10.5772/intechopen.86638*

cells and in a "safety ring" of peritumoural tissue using frictional heat generated by high-frequency alternating current. Lesions adjacent to the vessels and biliary tree or in subcapsular positions could compromise RFA effectiveness and safety [5, 18, 19]. However, microwave ablation has been recognized as effective in this kind of lesions, due to damage concentration and less heat dispersion [17, 20]. MWA uses electromagnetic energy to induce a larger necrotic area than RFA thanks to faster heating and higher temperature [17]. Overall, RFA and MWA provide similar results in terms of local control and survival rates [17].

DEB-TACE induces tumor necrosis through intraarterial delivery of microspheres fulfilled with chemotherapic drug that may vary in size and chemotherapic agent to treat different types of HCC [21]. This technique profits from the presence of a singular artery feeding the tumor. TACE is a palliative treatment indicated in patients not eligible for surgery or percutaneous ablation, with tumor at stage BCLC B (Child-Pugh ≤ B8; PS < 2). HCC nodule >10 cm, macroscopic vascular invasion, extrahepatic disease, untreatable ascites, jaundice and kidney disfunction strongly contraindicate TACE [4, 5]. Potential adverse effects are liver enzyme abnormalities (18.1%), fever (17.2%), hematological/bone marrow toxicity (13.5%), pain (11%), vomiting (6%) and even death (0.6%) for liver failure [5].

RFA can be used as a complementary technique with TACE, to treat residual neoplastic tissue [22]. Patients with bigger nodules (>3 cm) and with capillary vascularization receive higher benefit from this combination [5, 23].

TARE is also called selective internal radiation therapy (SIRT). It is a palliative brachytherapy that uses radioactive substances (Y90-microspheres) injected into tumor-feeding arteries. This complex procedure is indicated in patients with conserved liver function (Child-Pugh ≤ 8, bilirubin ≤ 2.0 mg/dl, no ascites) and locally advanced HCC, not eligible for surgery or TACE (portal system invasion or unencapsulated large lesions). Pulmonary shunt and other vascular anomalies contraindicate to this technique [4, 5].

PEI induces tumor cell necrosis through dehydration, protein denaturation and small tumor vessel disruption. It is indicated in patients not eligible neither for resection nor for other forms of ablation, especially in HCC nodules ≤3 cm in the hepatic hilum area. The application of this procedure is restricted because it allows only an incomplete necrosis in lesions >3 cm and leads to high recurrence rate [5, 24].

Cryoablation induces tumor cell necrosis using recurring applications of freezing temperature. Despite its good efficacy, this procedure is barely used because it is associated with high risk of life-threatening complications such as cryoshock, cold injury to adjacent organs and massive bleeding [25].

LA induces tissue necrosis through conversion of absorbed light (usually infrared) into heat. It can be used to treat up to five lesions, measuring ≤5 cm, located in the deep parenchyma and distant from the vessels, biliary ducts, bowel or diaphragm, when patients are not eligible for resection [26]. It is rarely used because of difficulties in the technique's management [5].

Surgical and non-surgical treatments, and the possibility of combined approach, should be carefully evaluated aiming for a tailored therapy.

Follow-up is fundamental in HCC patients, both in cirrhotic and non-cirrhotic ones, in order to promptly identify possible recurrences and to treat them in the best way. Intrahepatic recurrences, far from previously treated lesions, are always possible and generated by chronic hepatopathy; therefore, lifelong surveillance is necessary [4, 27].

The aim of this chapter is to illustrate the state of the art in liver surgery to achieve the best treatment for patients suffering from hepatocellular carcinoma.

*Liver Disease and Surgery*

free survival [5].

*Desai et al. [3].*

**Table 1.**

years of waiting [15].

niques in terms of survival and quality of life [4].

Clinical evaluation and multidisciplinary approach are fundamental to submit patients to the most appropriate treatment. Assessment must consider patients' characteristics (general conditions, performance status, physiological age, life expectancy, treatment tolerability), HCC stage, oncological principles and liver status [4]. Several approaches, both surgical and non-surgical, are available for HCC treatment. Surgery is the first-line treatment in terms of overall survival and disease-

NAFLD-NASH 6.48% from a single study 6.45% from a single study

**Parameter Mean incidence in cirrhotic liver Mean incidence in non-cirrhotic liver**

HBV 41.65% 30.60% HCV 44.18% 14.36% Alcoholic hepatitis 30% 21.77%

Surgical approaches include liver resections (LRs) and liver transplantation (LT). LR is the gold standard in non-cirrhotic liver, whereas cirrhotic patients should

LT allows radical tumor removal (R0) combined with the cure of underlying liver disease [6]. It is the treatment of choice in patients unsuitable for resective surgery that fall within the Milan criteria [5]. LT is indicated in patients ≤65 years (extended to 70 and 70+ patients, in some cases) [7] with severe cirrhosis (MELD > 15). According to the Milan criteria, patients should have a single nodule ≤5 cm or up to three nodules measuring ≤3 cm [8, 9], with no macroscopic vascular invasion nor extrahepatic metastases [5, 9]. After some years of experience, the Milan criteria were extended, developing up-to-seven criteria, in which patients are considered eligible for liver transplant when the sum of the size (in cm) of the largest tumor and the number of lesions is ≤7, in the absence of microscopic vascular invasion [10]. Up-to-seven criteria should be used carefully because overall survival decreases as the number and size of tumor grows [11]. This principle is called "Metro ticket" [12]. Because of organs' low availability, lower recurrence risk patients shall be selected for transplantation in order to optimize organ allocation [12]. Resection and noninvasive therapies could be performed to control lesion progression during waiting period (bridging) or in order to downstage HCC [5, 6]. Liver function in waiting list is commonly evaluated through Child-Pugh (CTP), MELD and MELD-Na scores [13]. The latter is a good predictor of waitlist mortality in cirrhotic patients, so it shall be taken into account to improve organ allocation system [14]. Pretransplant mortality rate in liver malignancy accounts for about 10 deaths per 100 patient

Non-surgical approaches include percutaneous radiofrequency thermoablation (RFA), microwave thermoablation (MWA), drug-eluting bead transarterial chemoembolization (DEB-TACE), transarterial radioembolization (TARE), percutaneous ethanol injection (PEI), cryoablation and laser ablation (LA). Except from thermoablations, which are considered curative in small lesion (≤2 cm), non-surgical approaches are commonly palliative [16]. Elderly, very elderly and frail patients, either at presentation or in the case of recurrences, may benefit from these tech-

RFA and MWA are the most appropriate treatment in patients with BCLC 0 and A tumors not eligible for surgery [5, 17]. RFA induces coagulative necrosis in tumor

be properly selected because of higher risk of complications [5].

*HCC incidence in cirrhotic and non-cirrhotic patients per risk factor.*

**76**
