In addition to liver cirrhosis, other factors such as, advanced age, hepatic steatosis, presence of chronic viral hepatitis even without cirrhosis, previous chemotherapy with oxaliplatin or irinotecan and transoperative hemorrhage impair the regenerative potential of the liver remnant 9 9 Clavien PA, Oberkofler CE, Raptis DA, Lehmann K, Rickenbacher A, El-Badry AM.
Patients with cirrhosis are generally not candidates for major partial hepatectomy. Child A patients without portal hypertension, especially those with small HCC, may be candidates for smaller partial hepatectomies. Whenever the location and size of the HCC allow, segmental or subsegmental resections are preferred Table 4.
The ideal surgical resection margin for HCC is 2 cm. Due to the high risk of liver failure and death, Child C patients should not be submitted to partial hepatic resections.
When CT volumetry of ther liver suggests that the remnant is insufficient, patients without cirrhosis or with Child A stage cirrhosis and without portal hypertension may be submitted to embolization of the main branch of the portal vein on the same side of the tumor.
Embolization is chosen to promote the growth of the hepatic remnant. The quality of the remnant should also be assessed. When major liver resections are planned, percutaneous biopsy of the hepatic lobe contralateral to the tumor may be utilized. In this procedure, the patient is submitted to laparotomy, ligation of the branch of the portal vein on the same side of the tumor and section hepatotomy of the area to be resected containing the tumor 1 1 Associating liver partition and portal vein ligation for staged hepatectomy ALPPS : tips and tricks.
J Gastrointest Surg. The abdomen is then closed, and the patient is reoperated one to four weeks later depending on the evaluation of remnant growth , when the parenchyma portion containing the tumor is removed.
Sorafenib in advanced hepatocellular carcinoma. However, its use as adjuvant therapy following partial post-hepatectomy for HCC is controversial. A randomized clinical trial comparing sorafenib to placebo involving patients submitted to adjuvant sorafenib therapy after partial hepatectomy or HCC ablation has been concluded 4 4 Bruix J, Takayama T, Mazzaferro V, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation STORM : a phase 3, randomised, double blind, placebo-controlled trial.
There was no statistical difference in survival between the group of patients receiving sorafenib and the control group. However, a meta-analysis evaluating a total of patients enrolled in three randomized clinical trials of hepatic intra-arterial epirubicin followed by intravenous chemotherapy demonstrated chemotherapy to provide poor outcomes as adjuvant treatment for HCC 25 25 Ono T, Yamanoi A, Nazmy El Assal O, Kohno H, Nagasue N. Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials.
Indian J Surg. A total of patients were included. However, this drug is not approved by the FDA and is not available for use in the US and most countries. Cirrhotic patients with HCC in the setting of advanced chronic liver disease are selectable for LT as long as not have distant metastases or nodal metastases are potential candidates for LT. Among those patients, those with single lesion up to 5 cm or up to three lesions of maximum 3 cm each Milan Criteria and absence of nodal or distant metastases may be listed at LT.
Liver Transplantation for the treatment of small hepatocelular carcinomas in patients with cirrhosis. N Engl J Med; Einstein Sao Paulo. The majority of patients whose sum of the size of the largest HCC with the total number of tumors does not exceed seven up-to-seven criteria may undergo neoadjuvant treatment by TAE or TACE. Such treatment may be able to control and even decrease tumor mass in several patients downstaging.
If the tumor disease responds well to neoadjuvant treatment and is reduced to fit within the Milan Criteria downstaging , these patients may be listed for LT. Hepatology ;. This equation uses serum INR, total bilirubin, and creatinine. MELD Score calculators are available on the internet. Although the degree of liver disease is not sufficient to give them an elevated calculated MELD score sometimes, neoplastic disease confers them a risk of death due to tumor spread.
After additional three months six after listing , the appealed MELD score is 31, being maintained at that value until LT or withdrawal of the patient from the waiting list by tumor progression or death. Waiting time for LT is variable according to the country. Different centers employ different treatments to control HCC growth according to estimated wait time for the LT.
Several invasive radiology procedures may be employed to control tumor disease. Intra-arterial treatment promotes ischemic necrosis coagulation necrosis in the tumor. It is utilized for patients awaiting LT and also as palliation patients not selectable for resection or LT.
It is contraindicated for Child C patients. It is indicated when there is more than one tumor nodule in a same hepatic lobe, for example. There are two forms of intra-arterial treatment: 1 transarterial embolization TAE : the embolizing agent [polyvinyl acetate PVA or microspheres] is selectively injected into the tumor circulation through coaxial microcatheterism; 2 transarterial chemoembolization TACE : lipiodol emulsified chemotherapy usually doxorubicin, mitomycin C and cisplatin or combination is selectively infused into the tumor circulation, followed by infusion of the embolizing agents PVA or microspheres.
Alternatively, the chemotherapy agent is infused simultaneously with specific drug-eluting beads, and interacts ionically with the chemotherapy agent. The response to intra-arterial treatment is monitored through abdominal CT scan with intravenous contrast. The treatment goal is to eliminate all neoplastic tissue inside the HCC nodule. Gastroenterol Res Pract. There are two techniques of percutaneous ablation: radiofrequency ablation RFA and chemical ablation with ethanol PEI or acetic acid.
Rochester, Minn. Hepatobiliary cancers. Plymouth Meeting, Pa. Accessed Feb. Related Infographic: Liver Cancer Liver cancer.
CDT New treatment options for those with liver cancer Dec. However, in most cases, vascular invasion is diagnosed only during histopathological analysis, i.
Unfortunately, currently available imaging methods are not sufficient for the diagnosis of tumoral thrombosis of small hepatic vessels. Serum AFP levels are also considered to be of prognostic value in three classifications. Due to the low general survival rates of the patients evaluated by these classifications, it is possible that selection of patients with advanced tumors occurred, since early HCC tend not to express high AFP levels.
One of the great benefits of tumor classification, in addition to providing an estimate of survival, is the selection of patients who can be submitted to treatment. The treatments currently used for HCC have shown an effect on patient survival, especially surgical and percutaneous therapies.
However, none of the classifications available considers this variable treatment. On this basis, the new classifications should evaluate the treatment options as a prognostic factor and correlate the tumor stages with the form of treatment to be adopted. However, this classification still awaits prospective validation. Regional multicenter studies on large patient series are needed to clarify the best time and types of treatment for each patient with HCC.
The main sites of HCC metastases are the adrenal glands, the bones and the lungs. Thus, it is imperative to perform bone scintigraphy and chest and abdomen tomography to rule out tumor dissemination. Although uncommon, brain metastasis may occur For patients who benefit from radical or curative treatment, mainly liver transplantation, we believe that skull tomography should be performed routinely to exclude the presence of brain metastases.
Thumbnail Table 1. Okuda classification of hepatocellular carcinomas 5. Thumbnail Table 2. Thumbnail Table 3. TNM classification of hepatocellular carcinomas Thumbnail Table 4. French classification of hepatocellular carcinomas Thumbnail Table 5. Thumbnail Table 6. The small number of patients with the same tumor stage impairs the execution of randomized and controlled studies, with a consequent difficulty in reaching a reliable conclusion about the best treatment for HCC.
However, the consensus is that for effective treatment the tumor must be detected in the early phases of development. A tumor is considered to be in an early stage when its size does not exceed 2 cm.
However, single tumors of less than 5 cm or up to three nodules, none of which exceeds 3 cm, are considered to be candidates for curative treatment. With follow-up programs for cirrhotic patients by US and AFP, the number of patients that can be submitted to curative treatment has increased.
Tumors diagnosed in advanced phases, with vascular invasion, multinodular, and with distant metastases cannot be treated with the objective of improving patient survival. The fibrolamellar variant of HCC is more common among non-cirrhotic young patients. Due to the slow evolution and low metastasis rates of this tumor, the treatment of choice is surgical resection even for tumors of large volume since the hepatic functional reserve needed for the procedure is maintained and the remaining liver in most cases is normal.
When the tumor is not resectable, liver transplantation may be indicated. However, most HCC are not of the fibrolamellar variant and occur in the presence of cirrhosis, with consequent impairment of treatment. Thus, we shall comment on the treatment of HCC in patients with cirrhosis.
Surgical treatments surgical resection and liver transplantation and percutaneous treatment alcoholization, radiofrequency and microwaves are considered to be curative or radical. Thumbnail Table 7. Survival after radical treatment of hepatocellular carcinoma. Surgical resection is considered to be the option of choice for the treatment of patients with HCC.
However, due to the frequent occurrence of postoperative hepatic decompensation, this treatment modality should be indicated only for patients with preserved hepatic function.
Non-judicious patient selection for surgical resection may not lead to increased survival when surgical treatment is compared to the natural history of HCC or even to other less invasive therapies The Child-Pugh classification and indocyanine green clearance have been used to assess the extent of liver function impairment before the indication of the surgical procedure.
This suggests that resection should be indicated for patients without portal hypertension. A single tumor measuring less than 5 cm in patients with preserved hepatic function and in sufficiently good clinical conditions to withstand the procedure is the criterion most often used to indicate resection. Nodules larger than 5 cm present a higher probability of invasion of the tumor capsule, with the presence of satellite nodules indicating local tumor dissemination.
Tumor localization, especially in a perihilar situation, may be a criterion for contraindication of resection regardless of the characteristics of the tumor. Intraoperative US should be routinely used both to define the safety margins and to exclude other lesions not visualized by preoperative imaging techniques When possible, conservative surgery should be performed, such as segmentectomy or sub-segmentectomy which will preserve a functioning liver mass.
Recurrence may be local or may consist of the appearance of metachronic tumors since the cirrhotic liver, especially when involved by extensive inflammatory activity, continues to be a risk factor. Liver transplantation is the treatment of choice in cases of HCC limited to the liver that cannot be submitted to surgical resection due to poor hepatic function or to technical impossibility. Liver transplantation not only eliminates the neoplasia, but can also cure the base liver disease.
Some authors adopt post-resection tumor recurrence as an indication for liver transplantation. Others adopt liver transplantation as the treatment of choice before resection. These survival rates are similar to those observed for liver transplantation in patients without neoplasias 41, Thus, the ideal candidate for liver transplantation is a patient with a single HCC smaller than 5 cm or with up to 3 nodules, none of them larger than 3 cm, without signs of neoplastic invasion of the portal system or of distant metastases.
Despite its advantages, the procedure also involves some disadvantages. The lack of donors with a consequent increase in the time on the waiting list, the high cost of the procedure, the possibility of tumor recurrence, the frequent postoperative infections, the high rates of perioperative morbidity, and the quality of postoperative life are aspects that should be taken into account at the time when the decision for an indication of liver transplantation is made.
Pre-liver transplantation co-adjuvant treatment in order to prevent tumor progression until the time for the surgical procedure has been adopted at some transplant centers where the time on the waiting list is more than 6 months. The real efficacy of these treatments for patient prognosis is still a matter of controversy.
Some groups use arterial embolization with or without chemotherapy as co-adjuvant pre-liver transplantation treatment and localized chemotherapy post-liver transplantation The combination of techniques, such as embolization and alcoholization, has demonstrated a satisfactory antitumoral effect and may be useful for co-adjuvant treatment before liver transplantation Strategies to increase the number of donors are of great importance. Living donor liver transplantation should also be considered for patients with HCC in groups in which time on the waiting list is more than 7 months The use of an "expanded" criterion for living donor liver transplantation in HCC has been discussed.
However, these criteria still need validation and should not be used in routine clinical practice. Immunosuppressive agents such as cyclosporine and tacrolimus are known to be stimulators of hepatic regeneration.
However, their interference with tumor progression is still a matter of controversy. Several types of percutaneous treatment are available for HCC, all of them aiming at destruction of the tumor with a safety margin of non-tumoral liver. The techniques most commonly used are alcoholization and radiofrequency. However, substances such as boiling saline solution and acetic acid can also be used.
Coagulation by radiofrequency, microwaves, laser therapy, and electrocauterization are percutaneous techniques used for the treatment of HCC. Percutaneous ethanol injection PEI is the technique for which most experience has been obtained, with various studies showing its efficacy. Absolute alcohol causes cell dehydration and extensive coagulative cell necrosis in addition to leading to thrombosis of the intratumoral vessels.
PEI is a procedure of easy execution, good tolerability and low cost, which can be applied during repeated sessions 48, Using ultrasound, the alcoholization needle is introduced until it reaches the nodule.
A G needle or a needle with specific side perforations for the procedure is used. After reaching the tumor, always under US visualization, the injection of absolute alcohol is started.
The amount of alcohol injected per session depends on tumor size and tolerability on the part of the patient, ranging from 1 to 10 ml, with an average of 5 ml per session. Larger volumes are inadvisable because of the risk of the occurrence of an extensive area of hepatic necrosis. However, injection of a large volume of alcohol in a single session without the occurrence of marked side effects has been reported in the literature.
The number of alcoholization sessions depends on the size and consistency of the tumor and on the distribution of alcohol through the tumor. The final objective of this treatment is to obtain total HCC necrosis. Serious complications are rare. Pain during the procedure is common and is related to alcohol reflux towards the hepatic capsule or to alcohol escape through the portal vein, visualized by US during the procedure.
In our routine we do not use sedation or systemic analgesia before PEI. There have been reports of hemoperitoneum, pleurisy, hemobilia, hepatic abscess, cholangitis, and hepatic decompensation Portal thrombosis may also occur after PEI as a consequence of vascular invasion by the tumor or of chemical thrombosis caused by alcohol. A single tumor smaller than 3 cm or up to three nodules, none of them larger than 3 cm, without extrahepatic metastases and with only slightly deteriorated hepatic functional reserve Child-Pugh A and B and without surgical indication 34,37,48 are the major indications for PEI.
The therapeutic efficacy of PEI depends on various factors. Vilana et al. PEI may have a therapeutic efficacy similar to resection or even to liver transplantation, especially when patients with poor hepatic function are selected for surgical treatment Radiofrequency has also been used successfully for patients with HCC. The indications are similar to those for PEI No randomized studies comparing the two percutaneous techniques in terms of antitumoral effect and patient survival are available.
The advantage of radiofrequency over PEI is the smaller number of sessions needed to obtain tumor necrosis. However, PEI is less expensive and is easy to perform, requiring no hospitalization. Thus, every attempt, including imaging follow-up or biopsy, should be made to characterize these nodules [ 55 ].
If the mass is large, central areas of necrosis may be seen that are typically hypodense during this imaging phase. In the hepatic arterial phase, HCCs typically are hyperdense relative to hepatic parenchyma and arterioportal shunt can occur as they are hypervascular tumors. Therefore, wedge-shaped perfusion abnormality due to arterioportal shunts can be seen and can result in a focal fatty change in the normal liver or focal fatty sparing in the diffusely fatty liver [ 56 ].
A halo of focal fatty sparing may also be seen around an HCC in an otherwise fatty liver [ 57 ]. The portal venous phase coincides with peak parenchymal enhancement is characterized by enhancement of hepatic veins as well as portal veins.
In this phase, small lesions may be isodense or hypodense and distinguish from the parenchyma is difficult, as the remainder of the liver increases in attenuation. Larger lesions with necrotic regions remain hypodense [ 58 ]. The portal venous and delayed phases can also evaluate nodule diameter, depicting hypovascular nodules including low- or high-grade dysplastic nodules, early HCCs, and well-differentiated HCC.
Portal blood flow may be maintained in some cases of dysplastic nodules and early HCC but reduced in other nodules, although the pathology remains because of early HCC, in which arterial blood flow has not yet increased.
In addition, these phases can also identify complication of HCC, such as portal venous or hepatic invasion and vascular thrombosis [ 59 ]. Moreover, CT can be assessed to establish for other complications such as bleeding and hemoperitoneum. On the other hand, false-negative CT imaging also can occur. In case of a cirrhotic liver with elevated AFP, and if the diagnosis is not absolute, MRI or other imaging modalities can assist in this differentiation.
HCC appearance varies on MRI depending on multiple factors, such as hemorrhage, degree of fibrosis, histologic pattern, degree of necrosis, and the amount of fatty change. HCC on T1-weighted images may be isointense, hypointense, or hyperintense relative to the liver. On T2-weighted images, HCC is usually hyperintense. MRI can help differentiate cirrhotic nodules from HCC: 1 If the mass is bright on T2-weighted images, it is HCC until proven otherwise; 2 if the mass is dark on T1- and T2-weighted images, it is a siderotic regenerative nodule or siderotic dysplastic nodule; 3 if the mass is bright on T1-weighted images and dark or isointense on T2-weighted images, it is a dysplastic nodule or low-grade HCC [ 61 ].
Hepatocyte-specific contrast-enhanced MRI including such as gadolinium-enhanced MRI typically demonstrates an increasing number of subcentimetre cirrhotic nodules and that are often confirmed as HCCs or high-grade dysplastic nodules by these techniques [ 62 ]. However, dysplastic nodules and, less likely, regenerative nodules can show similar enhancement. The degree of enhancement varies, particularly with the degree of necrosis in larger tumors.
Besides, keep in mind that gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy [ 63 ]. Recent studies showed that contrast agents other than gadolinium-based contrast media might demonstrate HCC.
Super paramagnetic iron oxide SPIO particles used alone or in conjunction with gadolinium-based contrast agents [ 64 ] have been shown to be highly sensitive for the detection of HCC, particularly for small tumors.
The technique, however, is of limited value for detecting and characterizing lesions smaller than 1 cm in diameter [ 67 ]. The only hepatocyte-selective contrast agent that has been approved for clinical use is mangafodipir trisodium can evaluate questionable lesions in the liver. Mangafodipir trisodium is taken up by normal hepatocytes and masses that contain hepatocytes, causing increased signal intensity on T1-weighted images.
This agent may help differentiate a tumor of hepatocellular origin, such as HCC, from secondary hepatic masses [ 68 ]. Although MRI is the most useful test to make a diagnosis, the nodules sometimes might not distinguish.
In case the nodules have not specific features of HCC and the diagnosis is still unclear, advance imaging modalities or histological examination is needed. Several studies have suggested a role for [18F] fluorodeoxyglucose FDG -PET scanning for the detection of primary HCCs, tumor staging, assessing response to therapy, and for predicting prognosis as an adjunct to CT [ 70 , 71 ]. However, FDG-PET might be a useful imaging modality for identifying extrahepatic metastases, although sensitivity is limited for lesions 1 cm or smaller [ 73 ].
Pathological diagnosis of HCC is recommended for all nodules occurring in non-cirrhotic livers, and for those patients with inconclusive or atypical imaging appearance in cirrhotic livers. However, there is no recommendation on prioritizing strategy for indeterminate nodules. The issue is also related to the need of risk stratification of atypical nodules in cirrhosis using ancillary findings. Pathological diagnosis is particularly complex for small nodules because minute biopsy specimens may not contain intratumoral portal tracts, thus precluding the detection of stromal invasion.
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