The main microscopic characteristic of hepatocellular carcinoma is its resemblance to the normal liver, both in its plate-like growth pattern separated by sinusoids and its cytological appearances (Figure 4). Certain architectural and cytological variants have been recognized in the World Health Organisation classification (Ishak et al., 1994) which are helpful for diagnosis but have no other, i.e. clinical or biological, significance.
The commonest architectural pattern is the plate-like or, as seen in two-dimensional histological sections, trabecular. Tumour cells grow in cords that vary in thickness from two to three to many cells. These are separated by sinusoids lined by flat endothelial cells. Kupffer cells are absent or reduced in number. Collagen fibres are increased in Disse's space surrounding the sinusoids and a basement membrane forms, i.e. they become 'capillarized'. The pseudoglandular pattern may result from dilatation of bile canaliculi or from central breakdown of cells in otherwise solid trabecula; the contents are bile or proteinaceous fluid. Compact, solid or scirrhous patterns are rare and develop from compression, scarring and chemo-radiotherapy. The term 'sclerosing hepatic carcinoma' has been applied to tumours associated with hypercalcaemia.
The commonest cytological variant is hepatic or liverlike. Tumour cells are polygonal, with vesicular nuclei and prominent nucleoli. The cytoplasm is finely granular and more basophilic than that of normal liver cells. Bile
canaliculi may be seen. Pleomorphic cells show marked variation in nuclear size, shape and staining. Clear cells have a seemingly empty cytoplasm. This may be due to accumulation of water, fat or glycogen. Sarcomatoid tumours form spindle and giant cells. Recently, a small-cell variant has also been described. Recognition of these cytological variants is diagnostically important so that they can be distinguished from metastatic tumours of similar appearance: renal cell carcinoma, soft tissue sarcoma and carcinoma of the lung, respectively.
A number of intracellular inclusions may be seen. Globular hyaline bodies are small, round and often acidophilic. They usually consist of a-1-antitrypsin. Mallory bodies, similar to those seen in alcoholic liver disease, are made up of altered cytokeratins.
Grading of hepatocellular carcinoma into well-, moderately and poorly differentiated tumours is traditional but it is less important than stage for prognosis.
Special staining techniques commonly employed include silver impregnation, which demonstrates the deficiency of the reticulin framework in hepatocellular carcinoma in contrast to normal or cirrhotic liver and hepatocellular adenoma in which it is normal or increased (Figure 5). Others are the PAS reaction for the demonstration of glycogen and trichrome methods for cytoplasmic inclusions.
Electron microscopy is relatively little used nowadays owing to the need for fresh tissue, long time of preparation and expense. However, the ultrastructural features of hepatocellular carcinoma are useful for diagnosis. Numerous mitochondria, a well-developed endoplasmic reticu-lum and, most of all, the presence of intercellular bile canaliculi are pathognomonic.
Immunocytochemistry, however, has replaced electron microscopy in the investigation of liver tumours. It can be done on formalin-fixed, paraffin-embedded tissues and it
is quick and cheap. The demonstration of normal 'export' proteins such as a-1-antitrypsin, albumin, fibrinogen, ferritin and methallothionein is useful in identifying a tumour as being of liver cell origin. Normal adult liver cells express cytokeratins Nos 8 and 18 as defined in Moll's catalogue whereas bile duct cells contain these and Nos 7 and 19 in addition. The latest addition to liver cell markers is Hep Par1 (Leong et al., 1998). The specificity of a-fetoprotein is high but its sensitivity is low. It is usually only demonstrable in tumour tissue when the serum levels are high, in excess of 5000 ngmL-1. Car-cinoembryonic antigen is widely distributed in glandular tissues in the body and polyclonal antibodies raised against it react with biliary glycoproteins. This allows the demonstration of bile canaliculi without recourse to electron microscopy (Figure 6).
Fine needle aspiration cytology is a useful diagnostic aid in expert hands, especially when smears are combined with histology of centrifuged needle washings which may contain tiny tissue fragments.
Hepatic carcinogenesis has been extensively studied for many years in experimental animals, usually rodents, by the use of chemicals. Results have led to the concept of multistep neoplastic development from initiation through promotion to progression. This is summarized in Table 4. Most of the chemicals used are not likely to play a part in the pathogenesis of human hepatocellular carcinoma, the experiments were short term and the phenotypic changes seen in animals are not definitely identified in humans. As evidence for the causative role of viruses began to emerge, attention has switched to mechanisms of viral carcinogen-esis. These are presented in Figure 7. The possible
pathways of hepatitis B and C viruses and of aflatoxin have been discussed already. Both Tables 4 and Figure 7 are somewhat wishful and idealized since such evidence as we have is patchy. Broadly speaking, the genetic changes in carcinogenesis at any site are multiple and cumulative and their phenotypic expressions are not easily identified. What we have at present is an incomplete mosaic from which most of the pieces are missing. However, they can be broken down into alterations in cell cycle regulation, growth factors, oncogenes, tumour-suppressor genes and epigenetic changes, such as telomerase activity. All of these have been investigated in hepatocellular carcinoma and found to be acting abnormally in a varying proportion of cases (Feitelson and Duan, 1997; Geissler et al., 1997; Idilman et al., 1998; Chen and Chen, 1999; Hirohashi et al., 2000).
Completion of the cell cycle requires the successive activation of cyclin-dependent protein kinases which are opposed by their inhibitors. The latter allow for DNA repair. Altered expression leads to the uncontrolled growth of liver cells. Growth factors are generally poly-peptides that act at short range via signal transduction pathways across cell membranes. Insulin-like growth factor II (IGF-II) may be an early marker of malignant transformation whilst transforming growth factor a (TGFa) may play a role in its maintenance. Transformed hepatocytes are resistant to transforming growth factor fl (TGFfl), which inhibits cell proliferation. In human hepatocellular carcinoma, oncogene (ras, myc, fos families) activation is a rare and tumour-suppressor gene (p53, Rb) activation is a late event. The most important epige-netic change perhaps is increased telomerase activity which immortalizes the cell.
None of these changes are 'stand-alone' events: they interlock and co-act to produce genomic instability which is amply supported by many chromosomal abnormalities found in hepatocellular carcinoma.
Table 4 Chemical hepatic carcinogenesis (multistep Initiation
Metabolic conversion of proximate to ultimate carcinogen Damage to DNA, organelles, membranes Fixation of abnormality by cell proliferation Inhibition/selection: clonal expansion Altered cell populations: Enzyme changes Hyperplastic nodules Autonomous neoplastic nodules Metastases and death Increased cell turnover all-important
DNA virus RNA virus
Reverse transcriptase DNA copy
Activation of oncogenes Inactivation of anti-oncogenes ras, myc, fos p53, rb
Genomic instability Neoplasia
Figure 7 Viral hepatic carcinogenesis
The outlook for hepatocellular carcinoma patients presenting with symptoms is poor, most specialized centres reporting a < 5% survival rate amongst those considered suitable for treatment. Better results can be obtained in patients with small, asymptomatic tumours. Good prognostic indicators are a serum a-fetoprotein level below 100ngmL_1, a solitary tumour, size <5 cm and preferably < 2 cm, lack of portal or hepatic vein involvement, early stage in terms of the TNM classification and well-preserved liver function (Okuda, 1993; Akriviadis et al., 1998; Schafer and Sorrell, 1999).
Presentation, Clinical Diagnosis and Management
In Western countries and particularly in Japan, patients are middle aged or elderly, have had cirrhosis for years and the onset of malignancy is heralded by a sudden deterioration of their condition. In tropical Africa and Asia, patients are often young adults and cirrhosis is first discovered at the same time as the tumour, which is often large and the course is fulminant. Common presenting features are lethargy, pain, hepatomegaly or a mass, fever, weight loss and, in the case of large tumours, rupture and intraperitoneal haemorrhage. Some patients experience a variety of paraneoplastic syndromes such as hypoglycaemia, ery-throcytosis and hypercalcaemia.
The most useful laboratory test is a serum a-fetoprotein level over 2-400 ngmL-1, which is found in ^80% of cases. Frequently used imaging methods are ultrasound, computed tomography and magnetic resonance imaging (Okuda, 1993; Akriviadis et al, 1998; Curley, 1998).
Treatment modalities include surgical resection, hepatic artery embolization or chemotherapy, percutaneous injection of alcohol and total hepatectomy followed by liver transplantation. The respective roles of local attempts at tumour removal or destruction and hepatectomy with transplantation have not been finally determined yet and each has its advocates. Once the tumour has spread outside the liver, no form of therapy is effective.
An intriguing aspect of hepatocellular carcinoma is spontaneous regression which has been reported on occasions over the years.
This is a distinctive type of hepatocellular carcinoma that affects adolescents and young adults of either gender. It is not associated with cirrhosis, serum a-fetoprotein is seldom raised and < 10% of patients show evidence of HBV or HCV infection. Despite all this, fibrolamellar carcinoma is of liver cell origin (Anthony, 1994; Ishak et al., 1994; Hirohashi et al., 2000).
Patients present with malaise, weight loss and a palpable mass, which is usually solitary and often large, 5-25 cm. The tumour cells are large, with vesicular nuclei and granular, pink cytoplasm, due to the presence of numerous mitochondria. Cytoplasmic globules and 'pale bodies' commonly represent a-1-antitrypsin and fibrinogen, respectively. Bile droplets, copper and copper-associated protein may be present. Bile canaliculi may be difficult to demonstrate. An abundant fibrous stroma, arranged as lamellae of coarse collagen is characteristic and is a sine qua non requirement for diagnosis. This fibrous incarceration of the tumour has been held to be responsible for its slow growth and favourable prognosis.
The surgical resectability rate is high and the 5-year survival figures are in the region of 50%.
This is the most frequently occurring liver tumour in children with a peak incidence in the second year of life. A few present at birth or develop in early adolescence. Males are twice as commonly affected as females. Hepa-toblastoma consists of immature liver cells in varying stages of development and a mesenchymal component that is frequently osteoid (Anthony, 1994; Ishak et al, 1994; Stocker and Conran, 1997). One-third of patients with hepatoblastoma have a congenital anomaly (hemi-hypertrophy, cleft palate, talipes, cardiac or renal malformation), a syndrome (Beckwith-Widemann and Down) or other childhood tumour (nephroblastoma). There is also an increased incidence in familial adenomatous polyposis. Chromosomal abnormalities are common.
The usual presentation is with failure to thrive, loss of weight and a rapidly enlarging abdominal mass. The serum «-fetoprotein level is almost invariably high. Virilization is seen in a small minority, due to production of chorionic gonadotrophin by the tumour. Increased urinary excretion of cystathionine occurs in about half of cases.
Hepatoblastoma usually forms a single mass and is often large when first detected, up to 25 cm. It is well circumscribed, with a thin capsule and a partly solid, partly cystic, fibrous, gelatinous or haemorrhagic cut surface. The epithelial component consists of embryonal, foetal, occasionally adult-like liver cells or glandular structures and keratinizing squamous cells. The commonest mesen-chymal elements are undifferentiated spindle cells and osteoid but cartilage, bone and striated muscle may be seen. Rarely, anaplastic small cells, neuroendocrine differentiation and melanin production are present. Extramedullary haematopoiesis is common. Immunocytochemistry shows a wide range of differentiation pathways.
Most hepatoblastomas fall into the epithelial or mixed epithelial and mesenchymal categories (Figure 8) but a more detailed classification defines six categories: epithelial (pure foetal, combined foetal and embryonal, macrotrabecular, small cell undifferentiated), mixed epithelial and mesenchymal and mixed with teratoid features (Stocker and Conran, 1997). These categories have limited prognostic significance.
Although half of patients are inoperable at presentation and one-fifth have pulmonary metastases, pre-operative
chemotherapy allows local resection or total hepatectomy followed by transplantation to be carried out in > 90% of cases. The overall survival rate is 65-70%. A rapid fall of serum «-fetoprotein levels after surgery is a particularly good prognostic sign.
CHOLANGIOCARCINOMA (INTRAHEPATIC AND HILAR BILE DUCT CARCINOMA)
Cholangiocarcinoma is a malignant tumour composed of structures resembling bile ducts (Ishak et al., 1994). It may be intrahepatic, arising from small bile ducts within the liver or hilar, arising from large bile ducts near the porta hepatis. The clinical presentation is somewhat different according to location. The pathology is simple: all these tumours are mucus secreting adenocarcinomas (Anthony, 1989, 1994; Nakanuma et al, 2000).
Cholangiocarcinoma is much less common than hepato-cellular carcinoma and constitutes about 15% of all liver cancers (Parkin et al., 1997). It is distributed equally throughout the world except in South-East Asia, particularly Thailand, Laos, Korea, Hong Kong and Canton, where its incidence is increased. This is due to the high prevalence of liver fluke infestation in these areas. Patients are middle aged to elderly, there is no gender difference and the tumour is not associated with cirrhosis.
Liver Fluke Infestation
Infestation with the liver flukes Opistorchis viverrini in Thailand and Laos and Clonorchis sinensis in
Korea, Hong Kong and Canton is the major cause of cholangiocarcinoma in these high-incidence areas. The life cycle of liver flukes requires poor environmental conditions with infested human waste discharged into stagnant water, take-up by snails as intermediate hosts and the habit of eating raw or undercooked fish which themselves have become infested. A heavy parasite load is acquired over many years and results in cho-langitis, liver abscess and cholangiocarcinoma. The presence of liver flukes may not, in itself, be carcinogenic and nitrosamines, derived from diet, may act as cofactors.
Intrahepatic biliary stones are frequently associated with clonorchiasis but not with opistorchiasis. Cystic lesions of bile ducts may also be complicated by stones.
Chronic Inflammatory Bowel Disease
Cholangiocarcinoma is a significant complication of long-standing ulcerative colitis commonly preceded by sclerosing cholangitis.
These include cystic dilatation of the biliary tree or Caroli disease, choledochal cysts, biliary microhamartomas and anomalies of the union between the main pancreatic and common bile ducts.
This once commonly used radiological contrast medium is best known for causing angiosarcoma of the liver but, in recent years, cholangiocarcinomas have also been observed.
Precancerous Changes, Screening and Prevention
The best studied precancerous changes are those associated with liver flukes and biliary stones (Figure 9). These consist of adenomatous hyperplasia, dysplasia with multilayering, nuclear enlargement and hyperchromasia and carcinoma-in-situ without invasion (Nakanuma et al., 2000). Cell kinetic studies have shown increasing proli-ferative activity along this sequence and the acquisition of genetic abnormalities.
There is no effective screening method for cholangio-carcinoma and prevention consists of reducing the incidence of liver fluke infestation, surveillance of individuals with known high-risk factors and surgical removal of choledochal cysts which carry a particularly high risk of malignant change.
Macroscopic and Microscopic Pathology
The gross appearance of intrahepatic tumours is of a grey-white, tough, scirrhous type of growth which is often solitary but may be multinodular, or a combination of both. Central necrosis, scarring and calcification may be seen. Finger-like extensions around the main mass represent spread along portal tracts. Metastatic spread is common, to regional lymph nodes, lungs and the peritoneum. Tumours in the hilum present as ill-defined nodules, strictures or, rarely, as an intraductal papillary growth. The flow of bile from the liver is often obstructed and the liver is stained green whilst the gall bladder and common bile ducts are empty.
Microscopic Features: Histological Patterns, Ultrastructure and Special Techniques
Most cholangiocarcinomas are mucus-secreting adeno-carcinomas of a tubular pattern and an abundant fibrous stroma is characteristic (Figure 10) (Colombari and Tsui, 1995). PAS diastase-resistant or mucicarmine-positive mucus is readily demonstrable and tumour cells express carcinoembryonic antigen in their cytoplasm as well as on their luminal border. The tumour may also grow in solid cords and form papillae. Rarely, it is of signet ring or clear cell type. Large amounts of extracellular mucus are sometimes formed in which tubulopapillary fragments of tumour appear to float freely. Tumours associated with stones, cysts or bile duct anomalies may be adenosqua-mous or purely squamous. Sarcomatoid cholangiocarci-noma is rare.
Electron microscopy is seldom used in the diagnosis of cholangiocarcinoma. It shows glandular characteristics: lack
of organelles, presence of tonofilaments and a basal lamina.
Immunocytochemistry is used mainly to distinguish cholangiocarcinoma from metastatic adenocarcinoma and, less commonly, from hepatocellular carcinoma. The most useful are demonstration of different cytokeratin patterns for the former and Hep Par 1 for the latter (Leong et al., 1998).
Mutations of the ras oncogene and the p53 tumour-suppressor gene are the most common genetic abnormalities in cholangiocarcinoma followed by over-expression of c-erbB-2 (Nakanuma et al., 2000).
Early detection of cholangiocarcinoma is difficult and most patients present with advanced tumours. Lymph node involvement, positive margins and bilobar distribution are associated with high recurrence rates after surgical resection. Patients with unrelieved obstruction of major hepatic ducts and those with cysts and stones may die of complications, e.g. sepsis or liver failure, before the tumour itself becomes evident.
Presentation, Clinical Diagnosis and Management
Malaise, abdominal pain and weight loss are common symptoms of intrahepatic tumours whilst hilar tumours cause unremitting obstructive jaundice. Ultrasound and computer-assisted tomography show the location of the tumour which can then be biopsied for a definitive diagnosis. Only a small minority of patients are suitable for surgical resection and other forms of treatment, e.g. radio-or chemotherapy, are ineffective.
These are rare tumours. Their pathology is virtually identical with that of similar tumours seen in the ovary and, occasionally, in the pancreas. Most are mucinous and a minority are serous. Patients present with solitary masses which may be fairly large but they are usually amenable to surgical resection and the results are good.
MIXED HEPATOCELLULAR CARCINOMA AND CHOLANGIOCARCINOMA
The presence of both bile secretion and mucus production must be present, supported by appropriate immuno-cytochemical markers, for such a diagnosis to be made. Effective treatment is seldom possible and the prognosis is poor.
These are nearly always secondary carcinomas and the common primary sites are the colon, rectum, upper gastrointestinal tract, pancreas, lung and breast. Liver metastases indicate advanced disease and most patients die within a few weeks or at most months. Colonic and, especially, rectal carcinoma metastases may be solitary or few in number and worthwhile results have been achieved by partial hepatectomy.
SARCOMAS OF THE LIVER
These are all rare but angiosarcoma, childhood sarcomas and malignant lymphoma are the most important (Ishak, 1997).
The cause of this tumour is unknown in most cases but a minority are associated with exposure to the once popular radiological contrast agent Thorotrast (thorium dioxide), arsenic and the industrial contaminant vinyl chloride monomer. Thorium is radioactive with a half-life of approximately 400 years and, when injected, most of it is taken up by the liver. In addition to angiosarcoma, hepato-cellular carcinoma and cholangiocarcinoma have also been observed. Particles of Thorotrast are readily visualized in histological sections as coarse, pink--brown granules
Angiosarcoma of the liver is always fatal and at autopsy it appears as ill-defined, spongy and haemorrhagic, or greyish--white fibrous nodules which replace the entire
liver (Figure 12). The histological appearances are variable but the most characteristic is a scaffold-like or tectorial growth of spindle cells on the surface of liver cell plates which eventually atrophy and disappear (Figure 13). Immunocytochemistry shows that tumour cells react with endothelial markers such as CD31, CD34 and Factor VIII related antigen or von Willebrand factor.
Another, distinctive form of malignant vascular tumour is epithelioid haemangioma, which occurs in the liver, lung, skin and bone and has a much better prognosis than angiosarcoma.
These are embryonal sarcoma and rhabdomyosarcoma. They are much less common than hepatoblastoma. Their prognosis has been hopeless until recently but aggressive treatment combining surgical excision, chemotherapy and radiation has led to 5-year survival rates of around 15%.
Primary Malignant Lymphoma
All types of lymphoma may secondarily involve the liver in their advanced stage and the prognosis is then poor. However, it is increasingly recognized that lymphoma can also be primary in the liver and the outcome, with appropriate treatment, is much more favourable. They are all non-Hodgkin lymphomas of B or T cell lineage. Some have been associated with HBV or HCV infections and AIDS.
The most important benign tumour of the liver is hepato-cellular adenoma. The majority of cases occur in young to middle-aged women who have taken oral contraceptive steroids for years or in individuals of either gender on long-term treatment with androgenic/anabolic steroids. Hepatocellular adenoma is often symptomatic, may grow to a large size, and rupture, giving rise to life-threatening intraperitoneal haemorrhage. The relationship of focal nodular hyperplasia to oral contraceptive steroids is much less certain and is often an asymptomatic, incidental finding. Inflammatory myofibroblastic tumour is an intriguing entity, the nature of which is not fully understood, i.e. whether inflammatory or neoplastic, but surgical excision is curative. Many other types of benign tumour have been described but they are all rare or clinically unimportant (Anthony, 1994).
TUMOURS OF THE GALL BLADDER
Nearly all tumours at this site are mucus secreting adenocarcinomas (Albores-Saavedra and Henson, 1986).
The incidence of carcinoma of the gall bladder is variable in different parts of the world and amongst ethnic groups. Overall, it ranks fourth amongst cancers of the digestive tract, after those of the colo-rectum, stomach and pancreas. The highest frequency is seen in South West American Indians and it is also common in Mexico, Chile, Bolivia and Israel.
South West American Indians apart, who seem to have a genetic predisposition to gall bladder carcinoma, the most important predisposing factor in most countries is chronic inflammation of the gall bladder associated with stones (cholelithiasis). Secondary factors are old age, female gender, obesity, abnormalities of bile and lipoprotein metabolism and multiple pregnancies which, themselves, predispose to gall stone formation. There is also a link with chronic inflammatory bowel disease, anomalous pancrea-ticobiliary duct union and the typhoid carrier state.
Carcinoma of the gall bladder is commonly preceded by epithelial hyperplasia, dysplasia and carcinoma-in-situ. Malignant change may also develop in tubular or villous adenomas. Rarely, biliary papillomatosis affects the gall bladder, the intra- and extrahepatic bile ducts and even the pancreatic duct system and carcinomas can arise at any of these sites.
There is no effective screening method for gall bladder carcinoma and the only means of prevention is prophylactic cholecystectomy which has been advocated for high-risk groups such as American Indian females beyond middle age.
Carcinoma of the gall bladder is often a silent disease and the tumour is discovered incidentally at cholecys-tectomy or else the symptoms are those of cholecystitis or cholelithiasis. These include intolerance of fatty meals, right upper quadrant abdominal pain and intermittent nausea or vomiting. Weight loss and jaundice are indicative of advanced disease. Ultrasonography and computed tomography are used in the assessment of patients with symptoms attributable to gall bladder disease.
Macroscopically, carcinoma of the gall bladder may appear as diffuse thickening of the wall, an ill-defined nodule or a polyp. Microscopically, most tumours are well to moderately differentiated adenocarcinomas with a tubular or tubulo-papillary pattern. Mucus secretion is nearly always demonstrable. Intestinal (with endocrine, Paneth and goblet cells), mucinous (with much extracellular mucin), signet ring, clear and small-cell variants are recognized. Ultrastructural or immunocytochemical studies are not particularly useful for diagnosis: the features are those of an adenocarcinoma occurring at many sites.
The majority of gall bladder carcinomas express mutated p53 tumour-suppressor gene. Ras and other oncogene mutations are late events. Amplification of the c-erbB-2 gene has also been found.
Surgical excision is the only effective method of treatment. The best results are obtained before the gall bladder wall has been breached. Direct extension into the liver and regional lymph node metastasis are indicators of a poor prognosis. Ultimately, patients die of disseminated disease with direct, lymphatic and blood-borne spread to many possible sites in the body.
As in the gall bladder, the commonest tumour in the extrahepatic bile ducts is an adenocarcinoma. About half arise in the common hepatic, cystic and upper common bile ducts, one quarter in the middle and one-tenth in the lower common bile duct; the rest are diffuse or multiple tumours. In general, the prognosis is worse for carcinomas of the proximal than of the middle or distal segments of the extrahepatic biliary tree. Most patients are elderly and males are more commonly affected than females, in contrast to carcinoma of the gall bladder. Cholelithiasis is not a risk factor. Ulcerative colitis, malunion of the main pancreatic and common bile ducts, congenital malformations such as choledochal cyst, pre-existing adenomas and papillomas are well-known predisposing factors. The onset of invasive malignancy may be preceded by dysplasia and carcinoma-in-situ, which are sometimes seen next to it in operative specimens. Most patients present with obstructive jaundice, some with ascending cholangitis and a few with blood in the bile (haemobilia). At laparotomy, extrahepatic bile duct carcinoma appears as a polyp, a stricture or a diffuse thickening. Histologically, most are tubular or tubulo-papillary adenocarcinomas with a fibrous stroma. A good histological grade has been claimed to confer a prognostic advantage but this is not universally accepted. Spread to adjacent structures or lymph node metastasis are indicative of a poor prognosis. The only effective treatment is complete surgical excision.
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