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Hepatocellular Carcinoma
George Barreto, Shailesh V Shrikhande, Parul J Shukla
 
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death in the world. With a high prevalence of hepatitis B and C viral related chronic liver disease in India (Tata Memorial Hospital Registry recorded 103 cases of HCC in 2001) and also the common occurrence of food contamination with aflatoxins, an increasing incidence of HCC is noted. An evidence based review on HCC and its management is presented.
 

Introduction
Better understanding of the natural
history, aetiology, and prevention of HCC coupled with better laboratory and radiologic diagnostic modalities have scantly but definitely improved the detection rate of HCC and the various treatment options.

Epidemiology
HCC is the 5th most common neoplasm in the world and the 3rd most common cause of cancer death worldwide.1 South East Asian countries account for the major bulk of the disease. This variability is also shared by the aetiological factors for the disease across the world. The incidence in the South East Asian countries was estimated to be 10 – 20 per 1,00,0002, while Australia, North America and Europe have the lowest incidence of 1-3 per 100,000. In the United States, it is estimated that there will be 18,510 new cases diagnosed in 2006 and 16,200 deaths. 3 Chronic hepatitis accounts for 0.46% incidence of HCC cases. It was estimated around 12,750 new patients would be diagnosed in India thus comprising 1.6% of all incident cancers. About 80% of Indian patients with HCC have hepatitis virus-associated liver disease.
Aetiology (Table 1)4 - 8
Classification of Hepatocellular Carcinoma
I Carcinoma
1) Hepatoma
2) Cholangioma
3) Mixed and Anaplastic
II Sarcoma
1) Haemangioendothelioma
2) Rhabdomyosarcoma
3) Leiomyosarcoma
4) Lymphoma
III Metastatic
IV Malignant Teratoma
Grossly, HCC shows four major patterns and two special forms:
The major patterns are:
1) Expanding
2) Spreading
3) Multifocal
4) Indeterminate
The two special forms are:
a) Fibrolamellar
b) Cholangiocellular

Staging Systems
AJCC Staging Of HCC and Intrahepatic Cholangiocarcinoma

Stage Tumour Node Metastasis

The various other staging systems include:
1) Child – Pugh Score9 (Table 2) – This system, introduced in 1973, continues to be an important system of classification of patient into prognostic groups.
2) Okuda system10 - It is a simple and effective staging system that scores patients on the basis of tumour size, ascites, albumin, and serum bilirubin levels.
The other staging systems include Cancer of the liver Italian Programme (CLIP),11 Barcelona Clinic Liver Cancer staging for HCC 12 and the French System.13
In a recent review comparing the Okuda, CLIP and BCLC staging systems, it was found that both, CLIP and BCLC scores were more effective than the Okuda score in stratifying patients into different risk groups with early- intermediate HCC. However, the BCLC scoring system gave a better prediction of prognosis in patients with disease diagnosis at a very early stage.14

Clinical Presentation
The incidence increases with age with a tendency to fall off in the elderly. The recent trend in the younger age of incidence of HCC i.e. around 10 years younger is probably due to the association of HCC with the viral hepatitis B and C. The neoplasm is predominant in the male gender, where it is characterized also by a worse prognosis than in females. Also, the rate of DNA synthesis in the cirrhotic liver is higher in men than in women.15 HCC presents late because of lack of symptoms in the early stages. Symptoms include:
1) Pain in the right upper abdomen, weight loss and presence of a right hepatic mass – constitute the most commonly encountered triad in HCC
2) Anorexia, malaise, weight loss, lethargy
3) Sudden decompensation in an otherwise well compensated cirrhotic
4) Shoulder pain
5) Budd Chiari Syndrome
6) Jaundice and fever
7) Tumour rupture causing an abdominal emergency
8) Paraneoplastic syndromes
9) GI bleeds – secondary to haemobilia, varices and gastropathy

Diagnosis
A more systematic approach to a patient with HCC would thus be as follows:
I] Confirm the diagnosis and determine the extent of local and distant disease16 (Fig.1).
Preoperative FNAC has no statistically significant adverse effect on the operability, possibility of extra-hepatic tumour spread, or long-term survival of patients with HCC.19
If the lesion is potentially operable, then biopsy of the non-tumour liver may be required to determine the best treatment option. A recent study20 comparing breath hold magnetic resonance angiography and triphasic CT has shown a statistically significant difference in the diagnosis of lesions between 10 – 20 mm in favour of MRA. However, there wasn’t any statistical difference for lesions > 20 mm. This however needs randomized controlled trials to confirm the reproducibility.
II] Assess the general condition of the patient
The investigations include : Chest X-ray, complete blood count, liver and renal function Tests, cardiopulmonary assessment for all patients > 65 years and full clotting profile.
III] Assess functional liver reserve
A definite risk in cirrhotic liver resection is the danger of postoperative liver insufficiency. While Bismuth 21 deduced that a normal liver can tolerate up to 80% resection of functional liver parenchyma, even minor resections in a cirrhotic liver can result in life threatening liver insufficiency.

Assessment techniques
i) Clinical assessment and blood tests

  • Serum Bilirubin – single most important prognostic factor
  • Two-fold rise has been suggested by Hasegawa22 to be an absolute contraindication for liver resection
    • Childs Pugh Score

ii) Dynamic Tests
Included in this group are two types of tests of liver function:
  • Flow limited – Indocyanine green – exclusively cleared by the liver
  • Capacity limited – evaluate specific metabolic capacity of the entire liver mass
    1) Galactose Elimination Capacity – measured in blood or breath
    2) [14C] aminopyrine breath test – evaluates specific metabolic capacity of the entire liver mass
iii) CT volumetric study Combined with ICG15, this test could help predict the safe limits of resection in patients with impaired liver function. This test has recently been shown to accurately assess the extent of liver resections.
iv) Redox tolerance index
This index, presumed to correlate with hepatic microsomal function, is derived from the hepatic ketone body ratio and changes in glucose levels after an oral glucose load. However, this test has not consistently been proven to be effective in predicting survival after hepatic resection.23
v) Laparoscopic assessment of liver
Staging laparoscopy with laparoscopic ultrasonography optimizes patient selection for liver resection with curative intent. The initial laparoscopy identifies patients with factors that would preclude a surgical resection while the ultrasonography helps identify liver tumours not identified during laparoscopy.
vi) Preoperative investigations facilitating post op follow up
Alpha fetoprotein
  • Post op protocol – 2 weekly estimates for the first 6 months
  • Rising titre – Chest X-ray and Ultrasound. If suspicious, do a CT or a Hepatic angiography

Treatment Options (Table 3) Before describing the treatment options for HCC, a review of the surgical anatomy as defined by systems is as follows:

Surgical Anatomy of the Liver
 The system of defining the liver as per Couinaud,24 also known as the French system, divides the liver into eight segments that combine to form four sectors separated by three scissurae containing the hepatic veins. A branch of the portal pedicle supplies each segment. By this system, the liver is divided into the right and the left livers by the main portal scissurae that contains the middle hepatic vein in the Cantlie’s line that runs from the fossa of the gall bladder to the left of the Inferior Vena Cava. The right liver is then divided by the right portal scissura (right hepatic vein) into two sectors viz., anteromedial or anterior and posteromedial or posterior. The anterior sector contains the segments V inferiorly and VIII superiorly, while the posterior sector contains the segments VI inferiorly and VII superiorly. The left liver is divided by the left portal scissurae (left hepatic vein) into anterior or superior and posterior sectors. The superior sector is divided by the umbilical fissure into the quadrate lobe (segments IV) and segment III, while the inferior sector is the only sector to contain a single segment i.e. segments II. Segment I or the caudate lobe lies independently posteriorly embracing the retro hepatic inferior vena cava. In 2000, at the World Congress of IHPBA in Brisbane, the following terminology was introduced for liver anatomy:25 (Table 4)



Liver Resection
Curative resection has been defined as “complete removal of tumour tissues plus a clear resection margin ³ 1 cm on pathological examination”26 in which negative findings by angiography followed by Lipiodol CT and ultrasound one or two months after resection are included. Resections for malignancy of the liver are predominantly the partial and the total hepatectomies along with liver transplantation. These surgeries offer the only options for cure. Surgical resection is considered the first treatment option for early stage patients. It is reserved for patients with solitary tumours without portal hypertension and normal bilirubin.
Criteria for resection:

  • Exclusion of extrahepatic metastasis
  • Adequate hepatic functional reserve
  • Anatomic intrahepatic accessibility of tumour
Anatomical resections should be performed since they are technically easier and they avoid damaging the vessels and bile ducts.
Important steps in Hepatic Resections
Inflow control – This refers to the control of the hepatic artery and the portal venous blood supply to the portion of the liver to be removed. This can be achieved by extrahepatic dissection and alternatively by transecting the relevant pedicles within the liver substance. This inadvertently involves control of the relevant biliary radicles. For right-sided lesions, it is advisable to achieve control of the inflow by extrahepatic biliary dissection owing to the anatomical variations of the major right sectoral ducts at their junction with the main biliary channel. For left sided resections, it is advisable to dissect within or at the base of the umbilical fissure and well to the left of the hilar bifurcation.
The vascular inflow control can be achieved by:
1) Clamping of the hepatic pedicle (Pringle manoeuvre)
Indications: minor and major hepatic resections provided that the trunk end of the major hepatic veins and/or the inferior vena cava are not involved
2) Hemihepatic Vascular clamping
Indications: small hepatic tumours located peripherally in an abnormal liver parenchyma
3) Segmental vascular clamping
Indication: Small HCCs associated with abnormal liver parenchyma
4) Ischaemic preconditioning
Surgical resection has the best outcomes in patients who are Childs Pugh score A
Vascular inflow and outflow control
This isolates the liver from the circulation and aims to prevent bleeding and air embolism from injuries to major hepatic veins and/or the inferior vena cava. This is indicated in major hepatic resections for lesions involving the cavo-hepatic junction or when significant back flow bleeding occurs due to an inability to lower the central venous pressure.
Parenchymal Transection – The Glissons capsule is scored with the diathermy and the parenchyma is then transected by any one of the following techniques:
1) “Kelly clysis”
2) Cavitron ultrasonic surgical aspirator (CUSA)
3) Water jet Dissector
4) Finger fracture
5) Radiofrequency (Tissue link)
6) Harmonic Scalpel

Intraoperative ultrasound
Use:
1) Define the number, location, anatomical relationships of lesions within the liver
2) Performance of guided needle biopsy of small deeply placed lesions
For a curative resection, the lesion together with the entire parenchymal area supplied by its main portal branch should be removed since dissemination of HCC occurs via retrograde invasion of distal portal branches. The resection thus encompasses any satellite nodules.
The major types of resections according to the IHPBA guidelines are:27
1) First – order division
2) Second – order division (based on bile ducts and hepatic artery)
3) Third – order division
4) Alternative second - order division (based on portal vein)
The results of a liver resection can now be improved by various advances in surgery and interventional radiology.
1. En bloc resection of adjacent organs involved by the tumour
This has been propounded that the morbidity and the 3- and 5- year survivals of patients with diaphragmatic involvement and who underwent en bloc resections of the liver lesion and the diaphragm were the same as those without diaphragmatic involvement.28 Yamanaka29 has shown that portal venous thrombosis associated with the HCC can be dealt with at the time of liver resection by combining it with thrombus extraction. The real worth of this surgery in terms of outcomes is debatable considering that these patients are at increased risk of disseminated disease.
2. Shrinkage of large tumours and compensatory hypertrophy of the noninvolved liver
This aims at reducing the size of the liver lesion and inducing a compensatory hypertrophy in the rest of the liver, thus enabling a safe resection especially in cirrhotic livers. This will enable a proper surgical resection of a 1 cm margin without the need of compromise on resection margins. The techniques used are as in Table 5.
The use of preoperative portal venous embolisation to induce compensatory hypertrophy of the liver in patients was studied and found to be effective in allowing safer hepatic resections.36 However, a recent study37 has shown that the incidence of extrahepatic liver metastasis in patients with advanced HCC undergoing preoperative portal venous embolisation was found to be more frequent. The explanation offered for this is that due to portal venous embolisation, the hepatic veins act as main drainage veins. As a result, manipulation during surgery may facilitate the spread of tumour cells. This aspect thus requires further investigation involving a larger patient population.

Prognostic Factors and Long Term Outcome After Hepatectomy38
Factors influencing post-recurrence survival are:
1) Multiple initial tumours
2) Disease free survival < 12 months
3) Multiple recurrent tumours
4) Recurrent tumour size > 2 cm
5) Extrahepatic recurrence
6) Non resectional treatment
Concept of Recurrence
The origin of recurrence can be divided into two sources: 39
1) Unicentric – intrahepatic metastatic recurrence or residual tumour; occurs approximately 12 months after liver resection.
2) Multicentric – newly developed lesion in the cirrhotic liver; occurs approximately 3 years after liver resection

 Strategies To Reduce Recurrence
50- 90% deaths after liver resection are due to disease recurrence.40 Thus any treatment that can decrease or delay the incidence of recurrence may improve the results of liver resection.
A recent review on randomized controlled trials evaluating preventive approaches for recurrence after curative resection of HCC was published.41
Summary of data on preoperative and / or postoperative TACE (Table 6) suggests that preoperative TACE is not helpful in decreasing recurrence after resection of resectable HCC. In contrast, postoperative TACE is only beneficial to patients with invasive HCC, but not effective and perhaps even harmful to the patients after a curative resection.
A Summary of locoregional or systemic chemotherapy (Table 7) shows that systemic chemotherapy is not effective and can even be harmful as an adjuvant treatment in patients after resection of HCC according to a recently published meta analysis.46 However, there are reports that still show a favourable outcome for systemic chemotherapy.47
Post operative adoptive immunotherapy (Table 8)
In the early 1990s, a series of experiments were conducted on animals to demonstrate the efficacy of immunotherapy.52 Following the success of these experiments, interest in the use of immunotherapy in humans began to grow but was met with less than expected success.53
The basis for the success of immunotherapy is based on its presumed capabilities to eliminate micrometastasis in the remnant liver thus inhibiting recurrence after resection at least in the first few years. However, further randomized trials are required to confirm this concept.

Postoperative interferon (IFN) treatment (Table 9)
The basis for the use of interferons in HCC came from the findings of HCV related HCC.
1) The incidence of HCC was lower in HCV patients treated with interferons
2) Recurrence after curative resection of HCC developed from multicentric origin that is closely related to HCC viraemia status.
3) Interferon had an anti-cancer effect on the early stage tumours – micrometastasis

Postoperative acyclic retinoid acid (Table 10)
Retinoid acid is an inducer of differentiation. Acyclic retinoic acid (ARA) given postoperatively has been studied and shown to produce improvements in overall survival and disease free survival in patients with HCV related HCC. The proposed mechanism of action is through inhibition of second primary liver cancer by liver cancer by deletion of a latent clonal hepatoma cells.60
Role of Surgery in Recurrent Hcc
Repeat hepatic resection is the treatment of choice for:62
1) Patients who have undergone resection of a single HCC at primary surgery
2) Disease free survival (DFS) ³ 1 year
3) Recurrent tumour with no portal invasion

Role of Transplantation in HCC
Transplantation has the potential to replace a cirrhotic liver with a normal liver, thus, preventing the onset of metachronous tumour in a cirrhotic liver. It also serves to cure portal hypertension and its sequelae. In the right indications, the tumour free survival after three years of follow up has shown definite advantages over resection.63
Indications:64 The Milan Criteria
1) Solitary tumour < 5 cm,
2) Up to 3 nodules < 3 cm, in the absence of vascular invasion
Best results are obtained in Fibrolamellar HCC, small tumours with cirrhosis, and small incidental tumours found incidentally in the explanted liver.
Factors influencing negative outcome:65
1) Size of the nodule ³ 35 mm66
2) Advanced stage of the disease
3) Presence of an involved resection margin
4) Microscopic and macroscopic vascular invasion
5) Bilobar disease
Limitations of transplantation:
1) Expensive
2) Long term immunosuppression post transplant
3) Scarcity of donors
4) High recurrence of HCC post transplantation*
*Numerous attempts to reduce the incidence include the use of pretransplant chemotherapy, preoperative radiotherapy and posttransplant chemotherapy.
With the advent of anti viral drugs, hepatitis B is not a contraindication to transplantation.67

Radiofrequency Ablation
Radiofrequency ablation refers to the induction of thermal energy due to frictional heat generated by ionic agitation of particles within tissue following the application of alternating current that is applied within the radiofrequency range (200 – 1200 Mhz).
Indications:
1) Upto 3 nodular HCC lesions, preferably < 3 cm68
2) Bridge to liver transplantation69 to decrease patient drop out rates in transplant waiting lists caused by scarcity of organs and disease progression70
3) Unresectable HCC71 or metastatic colorectal metastasis
4) Adjuvant modality to treat residual disease that cannot be easily removed at the time of partial hepatectomy

Efficacy:
Based on the results of a study72 on patients undergoing percutaneous RFA prior to transplant, thereby enabling a true examination of the explanted liver and the efficacy of RFA, it was proven that RFA was an effective treatment of small i.e.< 3 cm HCC. A systematic review73 confirmed RFA to be more effective than other treatments in terms of less recurrence of HCC and could be as safe, although the present evidence is insufficient. Compared to alcohol injection, Livraghi et al. concluded that RFA had a higher success rate but noted that the complication rate was also higher.74

Percutaneous Ethanol Injection
This technique was first advocated by Suguira et al75 in 1983.
Technique
Under imaging control, absolute alcohol is injected into the tumour thereby inducing cellular dehydration, coagulative necrosis and vascular thrombosis leading to tumour cell death. The firm to hard consistency of the surrounding cirrhotic liver enables the localization of the injected solution. Also, the hypervascular nature of HCC allows the entry of the ethanol into the vessels and the consequent thrombosis of the vessels. It has the advantages of being safe, inexpensive, repeatable and easy to perform.
Indications
1) Tumours < 3 in number and < 3 cm in size
2) Isolated tumour recurrence after surgery
Contraindications include ascites (increases likelihood of intraperitoneal bleeding by decreasing the chance for adhesion formation between the liver and abdominal wall76 and also carries the temporary problem of leak of fluid from the puncture site), bleeding and obstructive jaundice
Complications encountered include the risk of tumour seeding, bleeding, cholangitis and portal venous thrombosis.
The side effects, though minimal, included pain, fever, and a transient rise in liver enzymes i.e. SGPT, SGOT and GGT.

Efficacy
Most published series where comparisons with historical controls were made, showed little difference in survival rates between resection, transplantation and PAI in tumours < 3 cm in diameter. A study of 260 tumours < 5 cm in diameter in Child’s A cirrhosis showed a 3 year survival rate of 79% after surgery, 71% after PAI and 26% in the absence of any treatment.77 Most centres thus still regard surgery as the best-proven therapy, providing a chance of cure. While the largest retrospective analysis78 did not find PEI comparable to surgery in efficacy for small HCCs, a recent prospective study has shown comparable results with both modalities.79
Other agents also used are acetic acid80 and Yttrium 90.81

Hepatic Arterial Embolization
Since the liver has a dual blood supply and the supply to the tumour tissue is predominantly derived from the hepatic artery, the idea of embolising the hepatic artery and destroying the tumour without affecting the normal liver (supplied by the portal vein) evolved.
Indications for HAE
1) Good symptomatic control for well selected cases
2) Management of pain and tumour rupture82
Side effects of HAE include pain, fever, nausea and a transient elevation in liver enzymes – due to enzymes released by the tumour cells.

Transarterial Chemotherapy (TAC)
Drugs used are those with high liver extraction rates and short plasma half-life, i.e. 5-FU, 5FUDR, cisplatin, doxorubicin, 4’ – epidoxorubicin. The best agents remain the fluoropyrimidines, 5-FU and 5FUDR, as they have a high rate of systemic clearance and a prolonged drug exposure to hepatic tumours. Studies on combination chemotherapy 83,84 have shown that efficacy wise TAC is associated with a better response rate than mono-agent TAC or systemic chemotherapy. This advantage, though, is offset by the toxicities – bone marrow suppression and cholangitis, as well as, the need for an arterial port for infusion of the drugs.

Transarterial Chemoembolization
Modalities : Transarterial Chemotherapy + embolisation (TACE)
Rationale – to increase drug exposure to the tumour after hepatic intraarterial chemotherapy, slowing down of arterial blood flow by temporary or permanent occlusion of the artery by gel foam pellets or ivalon particles.
After two systematic reviews,85,86 both comparing survival benefits after arterial embolisation with or without chemotherapy versus conservative management or suboptimum treatments showed discrepant results, a sequential, multicentre, randomized controlled trial87 assessing the survival benefits showed that chemoembolisation along with lipiodol improved survival of stringently selected patients with unresectable HCC.
High intensity focused ultrasound ablation is a conformal extracorporeal treatment administered by extracorporeal motion of a therapeutic transducer leading to a well delineated coagulation necrosis at depth in the focal area of the ultrasound beam, through the intact skin. It has been combined with TACE in the treatment of stage IV A HCC and evaluated.88 The initial results are promising but large scale randomized clinical trials are necessary for confirmation.
Transarterial chemotherapy and lipiodolization (L-TAC)
Lipiodol or ethiodol is an oily X-ray contrast medium derived from poppy seed oil found to be retained selectively by HCC for many weeks after intra-arterial administration into the liver.89
Madden90 found no survival benefit but rather an increased morbidity for patients treated with lipiodol – epirubicin. Yoshikawa,91 however, did note a benefit in the duration of survival though the difference in the treated and control arms did not reach statistical significance.

Transarterial chemotherapy, lipiodolization and embolisation (L-TACE)
The treatment involves the intra-arterial administration of hydrophilic drugs (60 mg of doxorubicin) mixed with lipiodol (15 ml) in an emulsion followed by temporary or permanent occlusion of the hepatic artery by gel foam pellets (0.5-1 mm), ivalon particles or starch particles.
Llovet has shown that patients with small tumours and good liver function benefit from this treatment. The efficacy has also been confirmed by Lo.92 A meta analysis published by Camma93 has shown that TACE significantly improved overall 2-year survival compared with nonactive treatment, but the magnitude of the benefit is relatively small.

Transarterial Radiotherapy
Conventional radiotherapy has a limited role in the treatment of HCC because of the adverse effects of irradiation to the accompanying liver tissue leading to radiation hepatitis. Selective internal radiation therapy using yttrium 90 microspheres is effective for selected cases of nonresectable HCC and is well tolerated. The objective response rate in terms of drop in tumour marker levels is higher than that based on reduction in tumour volume shown by computed tomography. The non-tumourous liver appears to be more tolerant to internal radiation than external beam radiation therapy. Selective internal radiotherapy may convert nonresectable tumours to resectable ones.
Systemic Chemotherapy
HCC is relatively resistant to chemotherapeutic agents. The most commonly studied ones include cisplatin, doxorubicin, 5-FU and interferons. The role in preoperative down staging has already been summarized. (vide supra).

Other Agents
The other agents tried in cases of advanced HCC include tamoxifen, anti androgens like flutamide and leuprorelin, megestrol, octreotide and thalidomide.94 These agents have shown variable results in the studies evaluating their efficacy.

Laparoscpic Liver Resections
Liver resections of up to two segments can be performed by laparoscopy using the same technique as that used during open surgery. It is preferred in patients with small tumours located in the left lateral segments or anterior segments of the right liver. The complication rate is low as compared to patients with HCC in cirrhotic liver. Using laparoscopic ultrasound, a 1-cm margin should routinely be obtained.95 However, the benefits observed compared with open surgery appear to be limited so far.96
The stage-based management is summarized in Fig. 2.

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EMERGENCE AND RESURGENCE OF MRSA

‘The onus is...on health-care authorities to develop not only surveillance systems that are able to monitor the clonal dynamics of MRSA...but also to provide the resources for early recognition of MRSA carriers through rapid screening.’
Staphylococcus aureus is a gram positive bacterium that colonises the skin and is present in the anterior nares in about 25-30% of healthy people, with the ability to cause a range of diseases in man. The bacterium readily acquires resistance against all classes of antibiotics. Of all the resistance traits S aureus has acquired, meticillin resistance is clinically the most important. In a review, Hajo Grundmann and colleagues discuss the history and evolution of meticillin resistant staphylococcus aureus (MRSA) as well as the worldwide burden it presents today, along with methods of control and future perspectives.

Lancet, 2006; 874.
 
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