Surgical treatment of hepatocellular carcinoma

Abstract

Surgery for hepatocellular carcinoma (HCC) includes partial liver resection (LR) and liver transplantation (LT). Although LT represents the most efficient treatment in patients with small HCC, <30% of patients are eligible for LT because of restrictive criteria (one nodule <5 cm or two to three nodules <3 cm without macroscopic vascular invasion), graft unavailability and the high cost of the procedure. For large HCC, LR remains the only potential curative treatment. LR is now safer, with a low rate of mortality. Selective preoperative morphological assessment, preoperative use of portal vein embolization for increasing future remnant liver volume and the improvement of surgical techniques such as the use of intermittent clamping and anterior approach are factors that improve the safety and tolerance of LR. In patients with small HCCs and a preserved liver function (Child-Pugh grade A), good long-term survival can be achieved after anatomical resection that removes the tumor(s) and its portal vein territory. These good results of LR for small HCC and the increasing duration of the waiting list for candidates of LT have renewed the place of LR as a bridge treatment before LT.

Introduction

Surgery, including liver transplantation (LT), remains the most efficient treatment of patients with hepatocellular carcinoma (HCC). However, <30% of patients with HCC are eligible for surgery, mainly because of the multiplicity of the lesions which often occurs on a background of chronic liver disease ¹,²,³. Over the past 10 years, there has been considerable progress in the diagnosis and surgical treatment of HCC. The tumors are more often identified at an early stage, in particular through the screening of high-risk patients ⁴,⁵,⁶,⁷. Surgery is safer, with an acceptable overall mortality rate in cirrhotic patients (<5%); also, good long-term survival, up to >50%, is achieved after adequate anatomical resections ⁸,⁹. Partial resection is associated with a high incidence of tumor recurrence, mainly due to the presence of the chronic underlying liver disease which is a preneoplastic state ³,¹⁰. Therefore, because LT removes the tumor(s) and the preneoplastic underlying chronic liver disease, LT appears to be the treatment of choice for small HCCs ²,¹¹. However, to avoid tumor recurrence, LT indications for HCC are restrictive and the limited availability of grafts and the cost of the LT represent the main potential limiting factors for its development ¹².

Partial liver resection of HCC

HCC without chronic liver disease

In the vast majority of cases, HCC develops in the setting of cirrhosis, but 5–15% of patients have no underlying chronic liver disease ¹³,¹⁴. Usually, the etiology of HCC developed in normal liver or minimal fibrosis is undetermined, but in some cases a chronic hepatitis B virus infection or hemochromatosis are present. Fibrolamellar carcinoma, which frequently occurs in patients with normal liver, represents a variant of HCC with specific pathological and clinical features ¹³. The tumor is hypervascularized with eosinophilic cells surrounded by a dense fibrous stroma. The tumors are frequently observed in the western hemisphere, in white females at a younger age (20–40 years), more often located in the left liver with positive lymph nodes, and alfa-fetoprotein (AFP) is rarely elevated ¹⁵,¹⁶.

HCC tumors in patients with normal liver are often large (>10 cm) and diagnosed when tumors are symptomatic ¹⁷,¹⁸,¹⁹. The only curative treatment is major hepatectomy, which is often well tolerated in the absence of underlying liver disease and the good regenerative capacity of the remnant liver. The long-term results of resection of HCC without chronic liver disease are much better than in patients with cirrhosis, with disease-free 5-year survival rates as high as 50% ²⁰,²¹. These favorable results observed in both fibrolamellar and nonfibrolamellar HCC variants suggest that the absence of underlying liver disease is a major factor in short- and long-term prognosis ³,²⁰.

HCC with chronic liver disease

The selection of patients with HCC associated with cirrhosis includes two main principles: surgery should be curative, and it should not place the patient at risk of operative death.

Indications for hepatectomy

In terms of tumor status, liver resection is usually contraindicated when one of the following criteria is present: (a) extrahepatic metastasis; (b) multiple and bilobar tumors; (c) involvement of the main bile duct; (d) presence of portal thrombus in the main portal vein and/or the vena cava. Preoperative evaluation of patients includes: ultrasonography (US) and thoracoabdominal helical multiphase contrast CT scan. The accuracy of new generation CT scan with vascular reconstruction has restricted the indication for angiography mainly to patients who are planned for preoperative transcutaneous arterial chemoembolization (TACE). Despite the fact that TACE can in some cases down-stage HCC, prospective trials have failed to show any significant benefit of this treatment before surgery ²²,²³,²⁴.

Patients with HCC and tumor thrombus in the vena cava or in the portal trunk have a poor prognosis ²⁵. This major vascular involvement is generally associated with a large tumor for which no treatment could be anticipated. It was shown that in a selected group of patients with normal liver function and excellent general status, extensive liver resection associated with removal of the vascular thrombus can achieve favorable survival results ²⁵,²⁶.

The role of hepatic resection for treatment of multiple and bilobar HCCs is more controversial ²⁷,²⁸,²⁹,³⁰,³¹. Bilobar HCCs may represent advanced disease with intrahepatic metastasis from one lobe to the other or may represent multifocal HCCs. However, in some selected patients with good liver function, the presence of a small solitary lesion in the contralateral lobe cases should not contraindicate the resection of the main tumor, and in selected cases major hepatic resection can be associated with wedge resection or local ablative therapy (if the lesion is not superficial) ³¹,³².

Spontaneous rupture of HCC occurs in 5–15% of patients ³³,³⁴,³⁵. This complication is observed particularly in patients with large superficial or protruding tumors; it is associated with hypovolemic shock in less than half of the patients ³³,³⁶. In case of hemo-peritoneum, transcutaneous arterial embolization represents the best hemostasis procedure ³⁴,³⁵,³⁷. In patients with good liver function and single tumor, rupture of HCC should not be regarded as a contraindication to subsequent elective surgical treatment ³³,³⁵,³⁸.

A great proportion of patients with chronic liver disease continue to present with advanced large tumors. Large tumor size alone should not be considered as a contraindication for hepatic resection ¹⁸,²¹,³⁸,³⁹. It is proven that hepatic resection for HCCs >10 cm in diameter without macroscopic venous invasion is a safe and an effective option ¹⁷,¹⁸,³⁸. However, the postoperative regenerative process can be impaired in the presence of cirrhosis, especially in the presence of small size of the future liver remnant (FLR) (<40% of the functional whole liver volume) ⁴⁰,⁴¹. Therefore, the use of preoperative portal vein embolization (PVE), the aim of which is to induce hypertrophy of the FLR, was developed mainly to improve the safety and tolerance in major liver resections of both normal and injured liver parenchyma ⁴²,⁴³. Previously, there were concerns about the regenerative capacity of fibrotic or cirrhotic liver parenchyma to hypertrophy after technically successful PVE. Later, further studies showed that preoperative PVE induces significant hypertrophy of the FLR even in patients with chronic liver disease ⁴⁰,⁴⁴,⁴⁵. Furthermore, it was shown that preoperative PVE inducing significant hypertrophy of the FLR could improve the safety and tolerance of major liver resections ⁴¹,⁴⁶,⁴⁷ in patients with chronic liver disease (fibrosis and cirrhosis) ⁴⁵. Moreover, the absence of hypertrophy of the nonembolized liver (FLR) following technically successful PVE, became a dynamic test and an indicator of the absence or low capacity of the injured liver to regenerate and therefore contraindicate major liver resection in these patients ⁴⁵.

Preoperative evaluation of liver functional reserve

In addition to the evaluation of tumor status and to avoid postoperative liver failure, the preoperative liver functional reserve assessment in cirrhotic patients is critical for patient selection ⁸. The overall incidence of in-hospital death following liver resection for HCC in studies published in the 1990s ranges between 1% and 10% (Table I). In most studies, hospital mortality was significantly higher in patients with liver cirrhosis than in patients without cirrhosis. The predominant cause of death in cirrhotic patients is liver failure, which is mainly assessed by Child-Pugh classification ⁴⁸, which was originally designed for predicting the prognosis of patients with portal hypertension undergoing shunting operations. In the vast majority of western centers, resection is contraindicated in grade C cirrhotic patients and rarely limited resection is possible in grade B cirrhotic patients ²⁰. However, even in grade A cirrhotic patients, with apparently normal liver function, the risk of liver surgery is increased and more sophisticated quantitative liver function tests have been developed. The indocyanine green clearance (ICG) test seems the best single test for predicting mortality after hepatectomy ⁴⁹,⁵⁰. It is generally admitted that ICG retention at 15 minutes of <15% identified patients who could tolerate a major resection while those with a value of >20% could only tolerate limited resection. Other factors predicting postoperative liver failure are: (a) a volume of FLR estimated on CT volumetry below 40% of the whole liver volume; (b) a grade 4 fibrosis assessed by biopsy of the nontumorous liver; (c) a high portal pressure assessed by grade 2 or 3 esophageal varices or measured by transjugular pressure, and (d) the presence of a superimposed active hepatitis assessed by preoperative elevated transaminase level more than twice normal ²¹,⁵¹,⁵²,⁵³. Although those criteria were not commonly accepted, there are strong arguments showing that patients with either one of these criteria should not undergo a major liver resection without preoperative PVE. In patients with chronic liver disease, the degree of hypertrophy of the future remnant liver after PVE is variable. It has been suggested that selective TACE before PVE could improve the rate of hypertrophy ⁵⁴.

Table I. Series of liver resection for HCC.

Author, year of publication	Study Period	Number of patients	Cirrhosis (%)	Diameter <5 cm (%)	In-hospital mortality (%)	1 year (%)	3 years (%)	5 years (%)
Results after curative surgical resection of HCC in Asian series
Nagasue, 1993	1980–90	229	77	75	11	80	51	26
Kawasaki, 1995	1990–93	112	68	83	2	92	79
Takenada, 1996	1985–93	280	52		2	88	70	50
Chen, 1997	1983–94	382	45	40	4	71	52	46
Makuuchi, 1998	1990–97	352			<1	92	73	47
Poon, 2001	1989–94	136	50	29	13	68	47	36
	1994–99	241	43	45	2.5	82	62	49
Shimozawa, 2004	1987–2001	135	71	100	2	95	73	55
Results after curative surgical resection of HCC in Western series
Franco, 1990	1983–88	72	100	60	7	68	51
Vauthey, 1995	1970–92	106	33	17	6			41
Nagorney, 1996		120	22		8	82	44	31
Llovet, 1999	1989–97	77	100	75		85	62	51
Fong, 1999	1991–98	154	65	24	4.5	81	54	37
Belghiti, 2002	1990–99	300	82	47	6	81	57	37
Ercolani, 2003	1983–99	224	100	81	3	83	63	42
Cha, 2003	1990–2001	164	40		4	79	51	40

Extent of resection

The two main aims of hepatic resection, especially in cirrhotic liver, seem to be opposite: one is to resect all of the malignant tissue (tumor, satellite nodules, and portal vein territory) with effective clearance; the other is to leave enough nontumorous liver parenchyma to prevent postoperative liver failure. This explains why most centers perform limited resections for small HCC, especially in patients with poor liver function. The other argument for performing limited resections is the pattern of postoperative recurrence, which results in part from the development of new tumors in the remnant liver ³,⁵⁵,⁵⁶,⁵⁷,⁵⁸,⁵⁹. However, the main risk of limited resections is tumor recurrence by local metastasis and particularly by tumor cell seeding in the adjacent or distal liver segments through tumor portal venous territory ⁸,⁶⁰,⁶¹,⁶². Anatomical resections according to the architecture of the portal vein have the potential to remove undetected cancerous foci (portal vein metastases and satellite nodules) disseminated from the primary gross tumor. The segmental or subsegmental portal venous drainage areas of the segment containing the tumor are identified by intraoperative US ⁶³. Several studies demonstrated that anatomical resections of small solitary HCC achieve a significant better overall and disease-free survival than limited resections, without increasing the postoperative risk ⁶⁰,⁶²,⁶⁴,⁶⁵. Therefore, when possible, anatomical resection should be the treatment of choice and considered as the reference surgical treatment when comparing it to other treatments. Moreover, when anatomical resection does not seem to be possible, either because of the tumor location and/or the degree of the liver function, other therapeutic options such as LT and/or percutaneous treatments are discussed.

Improvement of surgical resection

Twenty years ago, the mortality rate for hepatectomy in cirrhotic patients was >10%. Substantial improvements in the surgical techniques of hepatic resection in the past decade have resulted in a dramatic decline in the operative mortality of hepatic resection for HCC and allowed major resections in selected cirrhotic patients (Table I).

Intermittent inflow occlusion

During liver resection, reducing blood loss and transfusion are essential. Several methods designed to limit bleeding from inflow occlusion by portal triad clamping to complete vascular exclusion have been used ⁶⁶. The poor tolerance of cirrhotic liver to warm ischemia led many authors to contraindicate inflow occlusion in patients with cirrhosis. However, it has been demonstrated that intermittent inflow occlusion with periods of 15 minutes of clamping and 5 minutes of unclamping was well tolerated ⁶⁷. This method, which minimizes intraoperative bleeding, can be repeated safely for up to 90 minutes in cirrhotic patients with good liver function ⁶⁴.

Anterior approach

When liver tumors are large, the use of conventional techniques usually requires forceful retraction and mobilization of the liver with possible disadvantages including compression of both right and left lobes and tumor dissemination. Interestingly, two new techniques which do not require liver mobilization are now available: (1) the anterior approach ⁶⁸,⁶⁹ and (2) the ‘hanging maneuver’ ⁷⁰. In the anterior approach, after hilar control of the vascular inflow, and without prior mobilization of the right lobe containing the tumor, the parenchymal plane is transected directly from the anterior surface of the liver down to the anterior surface of the inferior vena cava (IVC). After anterior approach of the parenchyma, and the control of all venous tributaries including the right hepatic vein, the right lobe is mobilized and resected without forceful retraction of both the right and left lobes. This approach reduces the intraoperative blood loss, blood transfusion, hospital death rate, pulmonary metastases, and recurrence as compared with the conventional approach ⁶⁹. The hanging maneuver is an expansion of the anterior approach ⁷⁰. During this maneuver, the liver is raised away from the anterior surface of the IVC by a tape. The antero-posterior parenchymal transection is then facilitated by an upward traction on the tape (hanging the liver parenchyma anteriorly) placed in front of the retro-hepatic vena cava. This allows the surgeon to follow a direct plane and it facilitates exposure and hemostasis of the transected posterior parenchymal in front of the IVC. This technique can be used both in patients with normal or chronic liver disease and is contraindicated for large tumors invading the vena cava and in the presence of multiple adhesions between the prehepatic liver parenchyma and the anterior surface of the retrohepatic vena cava.

Recurrence following resection of HCC

The rate of recurrence following resection of HCC is around 80% at 5 years ²⁹,⁵⁶,⁶⁵,⁷¹,⁷²,⁷³. The predominant cause of tumor recurrence is metachronous carcinogenesis, as the precursor condition (cirrhosis) persists after surgery ⁷⁴. Greater incidence of recurrence is associated with the following factors: presence and severity of an underlying cirrhosis; presence of multiple nodules; tumor of >5 cm in diameter; lack of a capsule; moderately or poorly differentiated HCC; presence of daughter nodules; venous invasion; infiltrating rather than expansive tumor; insufficient cancer-free margin; and intraoperative blood transfusion ⁶⁵,⁷²,⁷³,⁷⁵. Thus, any neoadjuvant or adjuvant therapy that can decrease or delay the incidence of intrahepatic recurrence should be considered after partial hepatectomy ¹,⁷⁶.

Although recurrence following resection of HCC is associated with a poor outcome in most cases, there is growing evidence that some patients will benefit from more aggressive approaches, especially if the recurrence is limited to the liver ⁷⁷,⁷⁸,⁷⁹. Multimodality therapy including TACE, percutaneous ablative therapy, and re-resection could result in prolonged survival with an overall 5-year survival rate of 20% ³⁰,⁷¹,⁷³,⁸⁰,⁸¹.

Results of liver resection

The largest report of resected patients comes from the Liver Cancer Study Group in Japan, which has reported 1-, 3-, 5-, and 10-year survival rates of 85%, 64%, 45%, and 21%, respectively, in 6785 cirrhotic patients treated by hepatic resection between 1988 and 1999 ⁸². Comparable results have been reported by other groups worldwide without differences between Western and Asian studies (Table I). Survival rates as high as 60% at 5 years may be achieved in Child grade A patients with well-encapsulated tumors of ≤2 cm in diameter. Although <10% of patients fit these selection criteria, such results, obtained in patients with good liver function who underwent anatomical resection, could be favorably compared with those of liver transplantation ⁸³,⁸⁴.

Liver transplantation

LT is obviously the most attractive therapeutic option for HCC because it removes both detectable and undetectable tumor nodules together with the preneoplastic lesions that are present in the cirrhotic liver. In addition, it simultaneously treats the underlying cirrhosis and prevents the development of postoperative or distant complications associated with portal hypertension and liver failure.

Three distinct periods of LT for HCC can be identified (Table II). Before 1996, LT was initially performed in patients in whom partial liver resection could not be contemplated because of the high number and/or large size of the tumors. The results of LT for large unresectable tumors were disappointing, with a high rate of recurrence within the first months or years post-transplant ⁸⁵. After the publication of criteria proposed by Mazzaferro et al.¹¹ from the Milan group (i.e. a single nodule <5 cm or two or three nodules each <3 cm without vascular invasion) several groups have published remarkable improved results. Therefore, LT was considered as a first-line option for patients with limited tumor(s) ¹¹,⁸⁶. However, during the most recent period various series showed a significant decrease of long-term survival in patients who underwent LT for HCC, with a high rate of recurrence. It must be noted that the use of (nonspecific) immunosuppressive treatments markedly accelerated the course of recurrence. The decline of survival during the last period could be related to two factors: the increase in the waiting list and the extension of the size criteria. Some authors considered the Milan criteria to be too restrictive, they expanded the indications for LT ⁸⁷,⁸⁸. The increase in waiting time is associated with tumor progression and especially development of vascular invasion. Accordingly, strategies to increase the donor pool and diminish the tumor progression rate became a priority in many centers. In the United States, the United Network for Organ Sharing proposed a new system to allocate patients on the list according to the MELD score ⁸⁹. This change gives a priority to patients to minimize drop-out rates.

Table II. Series of liver transplantations for HCC in cirrhotic patients.

Authors	Year	n	3-year survival (%)
Iwatsuki	1991	105	40
Bismuth	1993	60	49
McPeake	1993	87	10
Mazzaferro	1996	48	84
Llovet	1998	58	74
Figueras	2000	85	74
Hemming	2001	112	63
Adam	2001	195	66
Roayaie	2002	43	58

Additional organs might be used by accepting marginal livers (advanced age or steatotic organs). Living donor LT has emerged as the most feasible alternative to cadaveric LT. It has been shown that the benefits of living donor LT for early HCC compared with cadaveric LT are reached in waiting times exceeding 7 months ⁹⁰. The availability of living donor LT has opened the potential for an expansion of the criteria beyond those conventionally applied. However, it can be anticipated that a massive extension of the criteria for transplantation to patients with larger tumors may significantly impair the results of transplantation in general. Because the morbidity-mortality of the donor is a major concern, it is highly questionable to take a donor risk for an uncertain recipient prognosis ⁹¹.

The tumor management while awaiting transplantation includes several modalities such as percutaneous radiofrequency ablation, TACE, and hepatic resection. The two nonsurgical treatments are widely used, but their impact on survival is unproved. We have demonstrated that surgical resection before LT does not increase the surgical risk nor impair the survival ⁸³. Therefore resection and transplantation could be associated rather than opposed. Resection could be used as a bridge to transplantation, especially for tumors located in the upper part of the right liver, which can be easily and completely removed through a transthoracic incision ⁹². Similarly, some superficial tumors which are not easily accessible by a percutaneous approach could be resected through a laparoscopic approach. Such previous resection allows a better selection of transplant candidates ⁸³,⁸⁴. As a matter of fact, markers other than size and number have recently emerged as significant prognostic variables-such as differentiation and the presence of satellite nodules. These factors can only be fully ascertained upon the complete examination of the resected specimen ⁸³. The strategy that combines resection and transplantation opens a completely new field of investigation and will certainly evolve with time ⁷²,⁸³,⁸⁴. We are currently speeding up the transplantation process if markers of early recurrence are present in the resected specimen, whereas we tend to consider resection as the first-line treatment in their absence and perform transplantation as salvage once recurrence occurs, as suggested by Poon et al. ⁷². This latter option has been shown not to be associated with a loss of chance in HBV patients (who are the most frequent in Hong Kong) and we are currently investigating whether the same holds true in HCV patients (who predominate in the West and Japan).