Purpose: Hepatocellular carcinoma (HCC) is associated with a propensity for vascular invasion and metastasis, which contribute to poor prognosis. Angiogenesis is a crucial process contributing to tumor growth and metastasis. Recently, Rac has been suggested to play a role in angiogenesis. However, the actual role of Rac in HCC angiogenesis remains unclear. Given that vascular endothelial growth factor (VEGF) is an important angiogenic factor in HCC, the purpose of this study was to evaluate the possible correlation between Rac activation and VEGF expression in HCC tumor samples, as well as the mechanism involved in Rac-induced HCC angiogenesis.

Experimental Design: We evaluated Rac and VEGF expression in the HCC tissue microarray of paired primary and metastatic HCC samples using immunohistochemical staining. The role of Rac-induced HCC angiogenesis was also evaluated in vitro in HCC cell lines.

Results: We first showed that activation of Rac was correlated with HCC metastasis (P < 0.001), and its expression was significantly correlated with VEGF expression by tissue microarray. Ectopic Rac-dominant active transfection in Hep3B cells increased VEGF secretion, which induced the morphologic change and proliferation of human umbilical vein endothelial cells, resulting in the promotion of angiogenesis. Rac induced the transcriptional activation of VEGF by direct interaction with hypoxia-inducible factor-1 (HIF-1) expression. In hypoxic conditions, Rac promoted angiogenesis through an increase in HIF-1 stabilization.

Conclusion: This study shows that Rac is a novel angiogenic factor for HCC through the enhancement of HIF-1 protein stability, which provides a possible therapeutic target in the development of inhibitors of angiogenesis.

Share This

The incidence of hepatocellular carcinoma is increasing in many countries. The estimated number of new cases annually is over 500,000, and the yearly incidence comprises between 2.5 and 7% of patients with liver cirrhosis. The incidence varies between different geographic areas, being higher in developing areas; males are predominantly affected, with a 2:3 male/female ratio. The heterogeneous geographic distribution reflects the epidemiologic impact of the main etiologic factors and environmental risk, which are the hepatitis B (HBV) and hepatitis C (HCV) viruses. The percentage of cases of hepatocellular carcinoma attributable to HBV worldwide is 52.3% and is higher in Asia where the seroprevalence of HBsAg in the population is high. However, the vaccination campaign against this virus in some eastern countries has tended to lower the incidence of new cases of hepatocellular carcinoma. The percentage of cases of hepatocellular carcinoma attributable to HCV is 25%, and it is more prevalent in Japan, Spain, and Italy where the association between hepatocellular carcinoma and antibodies to HCV ranges between 50 and 70%. In most cases hepatocellular carcinoma develops in cirrhotic livers, where the persistent proliferation of liver cells represents the key factor of progression to hepatocellular carcinoma independent of the etiology. Another minor risk factor is aflatoxin B1 consumption, which is responsible for most cases of hepatocellular carcinoma in Africa, where the consumption of contaminated foods is common. Other known risk factors are some hereditary diseases, such as hemochromatosis, porphyria cutanea tarda, hereditary tyrosinemia, and ₁ anti-trypsin deficiency. The natural history of hepatocellular carcinoma is heterogeneous and is influenced by nodule dimension, the mono- or plurifocality of lesions at diagnosis, the growth rate of the tumor, and the stage of the underlying cirrhosis. Available data to date suggest that tumor growth in a cirrhotic liver is variable and that the time in which a lesion in undetectable until it becomes 2 cm is between 4 and 12 months. Therefore, the suggested interval for surveillance screening with ultrasound in patients with liver cirrhosis has been set at 6 months. Patients who should benefit from screening programs are those who would be treated with curative therapy if diagnosed with hepatocellular carcinoma. Thus, the ideal target population should be limited to Child-Pugh’s class A cirrhotic patients without significant comorbidity.

Share This

Hepatocellular carcinoma accounts for 80 - 90% of all liver cancers. This type of cancer occurs more often in men than women, usually in people 50 to 60 years old. The disease is more common in parts of Africa and Asia than in North or South America and Europe.

The cause of liver cancer is usually cirrhosis (scarring of the liver). Cirrhosis may be caused by viral hepatitis, primarily hepatitis B and C, alcohol abuse, hemochromatosis, certain autoimmune diseases of the liver, and other diseases that result in chronic inflammation of the liver. The most common cause for cirrhosis in the United States is alcohol abuse.

Symptoms

·         Abdominal pain or tenderness, particularly in the right-upper quadrant

·         Enlarged abdomen

·         Easy bruising or bleeding

·         Jaundice (a yellow discoloration of the skin and eyes)

Share This

Hepatocellular carcinoma: A tumor in which the cancer starts during adulthood in cells in the liver. Also called adult primary liver cancer.

Primary liver cancer is different from cancer that has metastasized (spread) from another place in the body to the liver.

The signs and symptoms may include a hard lump just below the rib cage on the right side (from swelling of the liver), discomfort in the upper abdomen on the right side, pain around the right shoulder blade, or yellowing of the skin (jaundice).

There is often an increase in the blood levels of alpha-fetoprotein (AFP) and alkaline phosphatase. A rapid deterioration of liver function may be the only clue to the presence of the tumor.

Hepatocellular carcinoma is potentially curable by surgery, but surgery is the treatment of choice for only a small fraction of patients who have localized disease. Laparoscopy may detect metastatic disease, tumor in both lobes of the liver, or an inadequate liver remnant, and avoid the need for open surgery to explore the liver.

Therapy other than surgery is best as part of a clinical trial. Such trials evaluate the efficacy of systemic or infusional chemotherapy, hepatic artery ligation or embolization, percutaneous ethanol (alcohol) injection, radiofrequency ablation, cryotherapy (freezing the tumor), and radiolabeled antibodies, often in conjunction with surgical resection (removal) and/or radiation therapy.

The prognosis (outlook) depends on the degree of local tumor replacement and the extent of liver function impairment.

Primary liver cancer (hepatocellular carcinoma) is the most common cancer in some parts of the world. It is still relatively uncommon in the US but its incidence is rising, principally in relation to the spread of hepatitis B and hepatitis C. People who have a disease of the liver called cirrhosis are also more likely to get adult primary liver cancer.

Hepatitis B and C appear to be the most significant causes of hepatocellular carcinoma worldwide. People who have both hepatitis B and hepatitis C may be at a higher risk if they consume more than 3 oz. (80 grams) of alcohol a day. A first-degree relative with hepatocellular carcinoma also increases the risk.

Hepatocellular carcinoma is associated with cirrhosis in 50% to 80% of patients; 5% of cirrhotic patients eventually develop hepatocellular cancer.

Aflatoxin has also been implicated as a factor in the etiology (causation) of primary liver cancer in parts of the world where this mycotoxin occurs in high levels in food.

Workers exposed to vinyl chloride before controls on vinyl chloride dust were instituted developed sarcomas in the liver, most commonly angiosarcomas.

Common Misspellings: hepatocellular carcimona

Share This

Background:

Because hepatic cirrhosis is a major risk factor for hepatocellular carcinoma, recent guidelines by the European Association for the Study of the Liver (EASL) on clinical management of hepatocellular carcinoma recommend periodic ultrasound surveillance of cirrhotic patients with immediate workup for nodules >1 cm; an increase in the frequency of screening is considered sufficient for smaller lesions.

Aims:

To determine the actual risk of hepatocellular carcinoma associated with the latter lesions and to assess the role of ultrasound guided-fine needle biopsy in their diagnosis

Patients and methods:

Data were analysed for 294 new nodular lesions <20 mm, including 48 that were <10 mm, detected during a prospective multicentre study involving ultrasound surveillance of 4375 patients with hepatic cirrhosis. In the absence of fetoprotein (AFP) levels diagnostic of hepatocellular carcinoma, ultrasound guided-fine needle biopsy was performed (n = 274). AFP and fine needle biopsy diagnoses of malignancies (hepatocellular carcinoma and lymphoma) were considered definitive. Non-malignant fine needle biopsy diagnoses (dysplastic or regenerative nodule) were verified by a second imaging study. Diagnoses of hepatocellular carcinoma based on this study were considered definitive; non-malignant imaging diagnoses were considered definitive after at least one year of clinical and ultrasound follow up.

Results:

Overall, 258/294 (87.6%) nodules proved to be hepatocellular carcinoma, including 33/48 (68.7%) of those 10 mm. Overall typing accuracy of ultrasound guided-fine needle biopsy was 89.4%, and 88.6% for lesions 10 mm.

Conclusions:

In a screening population, well over half of very small nodules arising in cirrhotic livers may prove to be hepatocellular carcinoma, and approximately 90% of these malignancies can be reliably identified with ultrasound guided-fine needle biopsy.

Share This

PURPOSE: To evaluate the usefulness of power Doppler ultrasonography (US) with a microbubble contrast agent in assessing the therapeutic response of hepatocellular carcinomas (HCCs) treated with percutaneous radio-frequency (RF) ablation.

MATERIALS AND METHODS: Forty patients with 45 nodular HCC lesions 1.0–3.8 cm in diameter underwent power Doppler US before and after intravenous injection of a microbubble contrast agent. The same procedures were repeated after US-guided percutaneous RF ablation. The results of these studies were compared with those of three-phase helical computed tomography (CT) performed immediately after RF ablation.

RESULTS: Before RF ablation, nonenhanced power Doppler US demonstrated flow signals within tumor in 33 of 45 HCCs. After contrast agent administration, flow signals increased or newly appeared in all cases. After RF ablation, none of the ablated tumors showed intratumoral flow signals at nonenhanced power Doppler US, whereas six showed marginal intratumoral flow signals at contrast agent–enhanced power Doppler US. These six tumors were found to have small enhancing foci, suggestive of viable tumor, in corresponding areas at immediate follow-up CT. Additional RF ablation or transcatheter arterial chemoembolization was performed in these tumors.

CONCLUSION: The results of power Doppler US with a microbubble contrast agent in HCCs treated with RF ablation correlated well with those of contrast-enhanced CT. Preliminary data suggest that contrast-enhanced power Doppler US can be a promising noninvasive technique for assessing therapeutic response.

Share This

Hepatocellular carcinoma (HCC) is a major health problem worldwide. Currently, the only chance for obtaining a cure in patients with HCC is by either a surgical resection or liver transplantation. However, many HCCs with scattered tumors cannot be operated on. In such patients, effective alternative therapies need to be discovered in order to treat patients in the early stages of this disease.

An article to be published on 28 October in the World Journal of Gastroenterology proposes a new target for therapy. A study was conducted by Dr. Satoshi Mamori, of Jikei University, in which he evaluated tumor biopsies in order to confirm the diagnosis of HCC.

The immunohistochemical expression of survivin in liver tumor specimens obtained from 17 patients was studied. In addition, to determine the survivin expression in response to anti-cancer drugs in early stage HCC, the survivin expression was determined after treating HCC cells with anti-cancer drugs under hypoxic culture conditions.

Survivin is a member of a family of inhibitors of apoptosis protein (IAP), which has been implicated in both the control of cell division and the inhibition of apoptosis. Survivin is selectively expressed in most common human neoplasms and it also appears to be involved in tumor cell resistance to some anticancer agents and ionizing radiation. Several preclinical studies have demonstrated a down-regulation of the survivin expression/function by the use of anti-sense oligonucleotide, dominant negative mutants, ribozymes, small interfering RNAs and cyclin-dependent kinase inhibitors to increase the rate of apoptosis, while also reducing the tumor growth potential and sensitized tumor cells to various chemotherapeutic drugs and fx-irradiation using both in vitro and in vivo models of various types of human tumors.

The results and conclusions demonstrated survivin protein to be expressed in 64.7% of the cells in early HCC specimens (median). In early stage HCC with a tumor size > 10 mm, the expression rate ranged for 67.7 to 83.7%. Moreover, the survivin protein concentration in HCC cells increased with a combination of hypoxia and anti cancer drugs. With TACE, the conditions of hypoxia are maintained by embolisation over a long period of time. Therefore, this study suggests that survivin could be used as a potential useful therapeutic target for early HCC.

Share This

Abstract. The diagnosis of hepatocellular carcinoma (HCC) usually occurs at late stages in the disease when there are few effective treatment options. The measurement of the concentration of tumour markers in the serum of patients is a complementary tool frequently used for the interpretation of diagnostic imaging results. It is also used as a prognostic tool for the detection of cancer. Unfortunately, the sensitivity of tumour markers is still low and many times it yields normal results for cirrhotic and HCC patients. In the current work, the detection possibility of the structural changes in serum proteins accompanying cirrhosis and HCC is investigated using a low-angle x-ray scattering (LAXS) technique. The results show that there are significant differences in the LAXS profiles of cirrhosis and HCC lyophilized serum samples compared to normal. The changes in shape, total counts and position of the first scattering peak at 4.8°, which was previously reported to be sensitive to the structural changes in protein, showed the most characteristic deviations from normal serum. The present results are promising and would offer a potentially helpful complementary tool for monitoring cirrhosis and HCC.

Share This

CASE HISTORY

A 50-year-old man presented with a rapidly growing swelling over the sternum of two months duration. Except for this swelling, he had no other symptoms. Clinical examination revealed a 9 cm x 6 cm hard, fixed mass over the manubrium sterni. The overlying skin was erythematous with evidence of impending fungation. Thyroid gland, testes and regional lymph nodes were normal.

Computed tomography (CT) scan of the chest revealed an expansile destructive lesion of the upper sternum with extrathoracic as well as intrathoracic extension [Figure - 1]. A core biopsy of the lesion revealed presence of HCC without evidence of normal liver in the biopsy specimen [Figure - 2]. Immunohistochemistry showed tumour cell positive for á-fetoprotein (AFP), creatinine kinase (CK), and epithelial membrane antigen (EMA) and negative for vimentin and thyroglobulin.

Laboratory tests revealed a raised serum AFP (18302.8 ng/ml, normal range-0.5-35 ng/ml), normal serum beta HCG and liver enzymes. Hepatitis B surface antigen and hepatitis C virus antibodies were both negative. Scrotal ultrasound, done to rule out germ cell tumour of testes, revealed normal testes. A contrast enhanced CT scan of the abdomen revealed a normal liver with absence of mass lesion or coarse architecture or other obvious pathology in the liver. Skeletal scintigraphy showed increased uptake in the manubrium sternum, body of the left clavicle and left third rib anteriorly.

In view of the multiple bone lesions, only palliative radiotherapy (RT) was offered. The patient received 30 Gray external RT in 10 fractions via anterior portal and had a partial response, with reduction in the size of the lesion and erythema. He was started on tamoxifen and remained in good general health for three months, after which he developed breathlessness. A chest radiograph revealed extensive bilateral pulmonary metastases. He died within five months of diagnosis of his sternal tumour. At autopsy, except for multiple lung metastases, no other gross evidence of disease was present and the liver was normal without any evidence of metastases.

Discussion

HCC occurs frequently in sub-Saharan Africa. In Asia, the annual incidence is up to 500 cases per 100,000 population.[2] However, in Western Europe and in the United States it is much less common, accounting for one to two per cent of all malignant tumours.[2] The course of clinically apparent disease is rapid and if untreated most patients die within three to six months of diagnosis. The five-year survival in patients with symptomatic HCC is poor, 0.8% in men and 4.4% in women after the onset of symptoms.[2]

Metastases by dissemination through blood stream, are encountered in the lung (49%), bone (16%), adrenal glands (15%), pancreas (4%), kidney (3%), and the spleen (2%) in autopsy series.[3] In three to seven per cent cases of HCC, bone metastases represent the first symptoms of HCC.[1] Vertebrae, ribs, skull and long bones are the predominant sites of metastases and frequently multiple metastases are present.[4]

Bone metastases from unknown primary HCC are exceptional and only a few case reports have been documented.[1],[2],[3],[4] The hypothesis put forth for this unusual entity is that either metastases are from a microhepatocellular carcinoma, which has been destroyed by the immune system or there is a spontaneous regression of HCC, or from HCC developing de novo in ectopic liver tissue.[1],[5],[7],[8] Spontaneous regression of primary germ cell tumour is a well-documented entity but spontaneous regression of HCC is an extremely unusual phenomenon, and there is no case reported as yet where metastases have been growing after spontaneous regression of intrahepatic HCC.[9],[10]

Ectopic liver is a rare developmental error where liver tissue rests are found outside the liver. They may be attached to the mother liver by a stalk in which case it is called as accessory lobe. Ectopic liver tissue has been reported from various sites near the liver, such as the gall bladder, hepatic ligaments, omentum, retroperitoneum and the thorax.[6] The incidence of ectopic liver and accessory lobe in one study was 0.47% and 0.09% respectively.[5] Ectopic liver does not have a complete vascular and ductal system and when subjected to a carcinogenic factor might be functionally handicapped and more prone for hepatocarcinogenesis.[5]

In the present case, immunohistochemical staining for AFP, performed on formalin-fixed paraffin-embedded sections and a high serum level of AFP confirmed the hepatocellular nature of the tumour. The final diagnosis in our case was metastases from an unknown primary HCC. It is possible that a microhepatocellular carcinoma would have resulted in the bone metastases and the subsequent pulmonary metastases. The presence of multiple bone metastases probably excludes an ectopic HCC, as it is unlikely that an ectopic HCC of the sternum has metastasized to the bones in view of the very short history. Due to the small number of cases reported in the literature, the natural history of such lesions is not known, but aggressive treatment with combined modality has been performed with good long-term survival for solitary metastasis.[1],[2],[3],[4]

In conclusion, it is desirable to continue reporting new cases of this unusual entity as and when they occur in order to document their natural history. Treatment strategies can be then better formulated for the best possible outcome.

Share This

Background: Patients with hepatitis C virus (HCV) are at increased risk for hepatocellular carcinoma. Although serum -fetoprotein (AFP) is often used to detect hepatocellular carcinoma in HCV-infected individuals, its utility is unclear.

Purpose: To define the test characteristics of AFP for the diagnosis of hepatocellular carcinoma in patients with HCV.

Data Sources: MEDLINE search from 1966 to December 2002 for English- and non–English-language articles examining the test characteristics of AFP for identifying hepatocellular carcinoma.

Study Selection: Articles were included if they reported the sensitivity and specificity of AFP for detecting hepatocellular carcinoma in patients with HCV. Articles were excluded if the cause of hepatitis was ambiguous or if 50% or more of the study patients did not have HCV.

Data Extraction: Relevant articles were evaluated for quality of evidence; test characteristics were abstracted and calculated.

Data Synthesis: Five studies met all inclusion criteria and were analyzed. The overall quality of evidence was limited; only one study universally applied an acceptable gold standard test, and three of five studies used a case–control design that potentially overestimates diagnostic accuracy. By using the most commonly reported cutoff value of a positive test result for hepatocellular carcinoma (AFP level > 20 µg/L), the ranges of test characteristics were as follows: sensitivity, 41% to 65%; specificity, 80% to 94%; positive likelihood ratios, 3.1 to 6.8; and negative likelihood ratios, 0.4 to 0.6.

Conclusions: The paucity of high-quality data calls for more rigorous study of AFP and other diagnostic tests for detecting hepatocellular carcinoma in HCV-infected patients with an accepted gold standard applied to the entire cohort. Even if the “best-case” estimates of AFP sensitivity and specificity are accurate, AFP has limited utility for detecting hepatocellular carcinoma.

Share This