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Essay: Hepatocellular carcinoma (HCC) (liver cancer)

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Epidemiology

Liver cancer in adult men is the fifth most frequently diagnosed cancer worldwide, and is the second leading cause of cancer-related death in the world.

The number of deaths per year in HCC is virtually identical to the incidence throughout the world, underscoring the high case fatality rate of this aggressive disease (Jemal et al.,2011).

In adult women, it is the seventh most commonly diagnosed cancer and the sixth leading cause of cancer death. In the United States (US), the annual incidence of hepatocellular carcinoma (HCC) was at least 6 per 100,000 in 2010 (El-Serag and Kanwal, 2014).

HCC is a national health concern in Egypt; with rising incidence in the past decade. The annual incidence rate of HCC in Egypt is the highest in Middle Eastern countries ranging from 21.9/100,000 in males to 4.5/100,000 in females according to Population-Based Cancer Registry Data for Middle Eastern Countries (Salim et al.,2009).

The burden of HCC has been increasing in Egypt with doubling in the incidence rate in the past 10 years (Lehman and Wilson, 2009)

Race

A population-based study in the US identified racial and ethnic variations in the incidence of HCC (Wong and Corley,2008)
The incidence was highest among Asians, nearly double that of white Hispanics (11 versus 6.8 per 100,000/year) and four times higher than Caucasians (2.6 per 100,000/year).

In another database analysis from the US, the incidence rates among Asians/Pacific Islanders, blacks, Native Americans/Alaska Natives, and whites were 7.8, 4.2, 3.2, and 2.6 per 100,000 persons, respectively (CDC,2010).

The reasons for these differences are likely related to the underlying cause of liver disease, genetic, and environmental factors

Sex and age distribution

In all parts of the world, men are more likely than women to develop HCC.

In Northern America, the incidence rates for males and females were 6.8 and 2.2 per 100,000 persons, respectively, in 2008 (Jemal et al.,2011).

Geographic variation

The incidence of HCC varies widely according to geographic location (table 1) (Jemal et al.,2011).

(table 1)

The distribution of HCC also differs among racial and ethnic groups within the same country, and between regions within the same country (El-Serag and Kanwal,2014).

These extreme differences in distribution of HCC are probably due to regional variations in exposure to hepatitis viruses and environmental pathogens.

RISK FACTORS

1-Hepatitis B

Viral load

The risk of HCC is much greater in patients with high serum levels of HBV DNA compared with those who have low levels (<10,000 copies/mL) (figure 1) (Tseng et al.,2012). Figure1)) Cumulative incidence of hepatocellular carcinoma Reproduced from: Chen CF, Lee WC, Yang HI, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology 2011; 141:1240.

Sex

Men who are HBsAg positive appear to be at increased risk for HCC compared with women (Tseng et al.,2012). In a prospective cohort study that followed 23,820 residents of Taiwan who were between the ages of 30 and 65, the cumulative lifetime incidence of HCC for patients who were positive for HBsAg was higher in men than in women (27 versus 8 percent) (Huang et al.,2011). Coinfection with HCV or HDV In a population-based study from Sweden, the risk of HCC was higher among patients coinfected with HBV and HDV compared with those with HBV alone (Ji et al.,2012). Other factors associated with HCC in patients with HBV Other risk factors associated with HCC include older age, habitual alcohol consumption, cigarette smoking, elevated serum ALT levels (figure 1), the presence of core and precore mutations, coinfection with HCV, and possibly family history of HCC (Loomba et al.,2013). In addition, a study from China suggested that compared with blood group O, male patients with blood group A or B may be at increased risk for HCC, whereas women with blood group AB or B may be at decreased risk (Li et al.,2012). 2-Hepatitis C A strong association between chronic HCV infection and HCC has been observed, but the mechanisms involved in carcinogenesis remain unclear (Omland et al.,2012). An important clinical observation is that HCC in patients with HCV occurs almost exclusively in patients with advanced stages of hepatic fibrosis or cirrhosis (Lok et al.,2009). However, in up to 10 percent of patients with HCV infection who undergo resection for HCC, only mild degrees of fibrosis are found (Lewis et al.,2013). Hepatitis C virus infection is a major etiology risk factor that predisposes to HCC in Egypt, taking into consideration that Egypt has the highest HCV prevalence in the world with a ratio of about 14.7% among 15’59 years age group (Mohamoud et al.2013). In a prospective cohort study that followed 23,820 residents of Taiwan between the ages of 30 and 65, the cumulative lifetime incidence of HCC for patients with HCV alone was 24 percent for men and 17 percent for women (Huang et al.,2011). Patients who were also positive for hepatitis B surface antigen had a cumulative incidence of 38 percent for men and 27 percent for women. Among patients with HCV, the differences in HCC rates between men and women were not significantly different. In addition, higher viral loads were associated with an increased risk of HCC. A 186-gene signature on gene expression profile analysis has also been associated with an increased risk of HCC among patients with HCV and Child-Pugh class A cirrhosis (Hoshida et al.,2013). The degree of inflammation in the liver of patients with HCV also correlates with prognosis once HCC is diagnosed. Several oxidative stress and inflammation markers, including CD68+ cells, 8-hydroxydeoxyguanosine (8-OHdG) DNA adducts, and 4-hydroxynonenal (HNE) protein adducts, have been examined in noncancerous liver tissue in patients who had both HCV and HCC. Patients with higher levels of these markers were found to have a worse prognosis (Maki et al.,2007). The host immune response may also be an important factor associated with a risk for progression to cirrhosis and cancer (Suruki et al.,2006). Several other factors have been implicated: ‘Animal models have suggested that increased hepatic iron stores observed in chronic HCV infection result in increased reactive oxygen species, leading to increased inflammation and cell turnover (Furutani et al.,2006). ‘A meta-analysis found an association with HCV genotype 1b, but data from individual studies are mixed (Lee et al.,2014). and this association has not been confirmed. ‘Concomitant heavy alcohol use, diabetes mellitus, and obesity were found in various reports to increase the risk of HCC. ‘HCC was associated with older age, black race, lower platelet count, higher alkaline phosphatase, presence of esophageal varices, and smoking in a report from the HALT-C trial, a prospective study which was designed to evaluate the impact of long-term low dose peginterferon in patients with advanced fibrosis (Lok et al.,2009). ‘Latent HBV infection or exposure to HBV appears to increase the risk of HCC in patients with HCV and cirrhosis in some regions (Ikeda et al.,2007). but such exposures do not appear to be an important risk factor for HCC among HCV-infected individuals in the United States (Lok et al.,2011). Successful treatment of HCV has been associated with a decreased risk of HCC. In a meta-analysis of observational studies, patients who achieved a sustained virologic response had a lower risk of developing HCC than those who were treated but did not achieve a sustained virologic response (relative risk 0.24, 95% CI 0.18-0.31). It appears that much of the residual risk is found in patients who had underlying cirrhosis prior to initiating therapy (George et al.,2009). 3-Chronic hepatitis and cirrhosis Compensated cirrhotics are thought to have a 1 to 8 percent annual incidence of HCC (depending upon the etiology of the cirrhosis), and those with chronic hepatitis have an approximate annual risk of 1 percent (table 2). (Table 2) HCC: hepatocellular carcinoma; NAFLD: nonalcoholic fatty liver disease. Reproduced with permission from: Bruix J, Sherman M. Management of Hepatocellular Carcinoma: An Update. Hepatology 2010. Copyright ” 2010 John Wiley & Sons. 4-Environmental toxins At least two environmental toxins, aflatoxin and contaminated drinking water, may contribute to the pathogenesis of HCC. However, their contribution to the worldwide disease burden of HCC (compared with other risk factors such as HBV infection) is minimal. Furthermore, they are probably not important independent etiologic factors, but rather may contribute to HCC development in individuals with other risk factors. Aflatoxin Aflatoxin is a mycotoxin that commonly contaminates corn, soybeans, and peanuts. High rates of dietary aflatoxin intake have been associated with HCC (table 3) (table 3) Adapted from: Van Rensburg SJ, Cook-Mozaffari P, van Schalkwyk DJ, et al. Br J Cancer 1985; 51:713. Contaminated drinking water Several studies conducted in rural China have noted a higher mortality rate from HCC among people who drink pond-ditch water compared with those who drink well water (100 versus fewer than 20 deaths per 100,000 population per year) (Yu,1995). The blue-green algal toxin Microcystin commonly contaminates these ponds and is thought to be a strong promoter of HCC (Ueno et al.,1996). 5-Betel nut chewing Case control trials have suggested that Betel nut chewing, which is widespread in certain regions of Asia, may be an independent risk factor for the development of cirrhosis and HCC (Tsai et al.,2004). 6-Tobacco and alcohol abuse Cigarette smoking has been shown to be a risk factor for HCC. Alcohol intake has been linked to HCC in many reports (Trichopoulos et al.,2011). Although the threshold dose and duration of use are unclear. The relationship between ethanol and HCC could be a direct toxic effect, or an indirect one, since alcohol represents an important risk factor. 7-Diabetes mellitus Epidemiologic studies suggest a possible link between diabetes mellitus and HCC (Chen et al.,2013). A systematic review that included a total of 49 case-control and cohort studies estimated that the risk was increased by approximately 2.2-fold (risk ratio 2.2; 95% CI 1.7-3.0), although few studies adjusted for diet and obesity (Wang et al.,2012). A meta-analysis of 14 prospective epidemiologic studies also found an increased risk of HCC among patients with diabetes (relative risk 1.9; 95% CI 1.2-2.3) (Yang et al.,2011). In addition, a study found that the presence of the metabolic syndrome (defined by the presence of three of the following: elevated waist circumference/central obesity, dyslipidemia, hypertension, and impaired fasting glucose) was a risk factor for HCC (adjusted odds ratio 2.1) (Welzel et al.,2011). A large population-based cohort study confirmed the findings of the systematic review and meta-analysis. The study included 19,349 patients with newly diagnosed diabetes and 77,396 patients without diabetes (Lai et al.,2012). The incidence of HCC was significantly higher among patients with diabetes compared with those without diabetes (21.0 versus 10.4 per 10,000 person-years), with an adjusted hazard ratio [HR] of 1.7 (95% CI 1.5-2.0). The use of a thiazolidinedione or metformin was associated with a decreased risk of HCC among patients with diabetes (adjusted HR 0.56 and 0.49, respectively). However, associations between diabetes and HCC should be interpreted with caution. In many cases, the onset of glucose intolerance results from the development of cirrhosis, so “diabetes” in this context may be a surrogate for cirrhosis, which increases the risk of HCC. In addition, many patients with diabetes also have nonalcoholic fatty liver disease (NAFLD), which has also been associated with an increased risk of HCC. Whether the use of antidiabetic medications alters the risk of HCC has been evaluated in a meta-analysis of 10 studies with 334,307 patients with type 2 diabetes mellitus (Singh et al.,2013). 8-Nonalcoholic fatty liver disease There is growing evidence that NAFLD represents an increasingly frequent underlying liver disease in patients with HCC (Yasui et al.,2011). It is likely that NAFLD causes HCC via cirrhosis, although the exact pathogenesis has not yet been determined. One study found that HCC in NASH was associated with obesity, diabetes, hypertension and male sex (Yasui et al.,2011). 9-Alpha-1 antitrypsin deficiency Alpha-1 antitrypsin deficiency has been associated with an increased risk of HCC, which can occur in patients without cirrhosis. 10-Acute intermittent porphyria Studies suggest that there may be an increased risk of HCC in patients with acute intermittent porphyria (AIP), including those without evidence of cirrhosis. Reported rates of HCC in patients with AIP have ranged from 0 to 27 percent (Stewart, 2012). 11-Gallstones and cholecystectomy An increased risk of primary liver cancer (including HCC) was noted in a meta-analysis of 15 studies with over 4 million subjects (Liu et al., 2014). 12-Epidermal growth factor polymorphisms and receptor expression Certain polymorphisms of the epidermal growth factor (EGF) gene have been associated with an increased risk of HCC in patients with cirrhosis (Abu Dayyeh et al.,2011). In addition, the receptor for EGF is a cofactor for HCV entry into cells (Lupberger et al.,2011). Overexpression of epidermal growth factor in the liver has been associated with HCC in animal models, providing a rationale for the observed association. In the aforementioned HALT-C study in HCV-infected individuals, logistic regression analysis of clinicopathologic parameters identified sex, age, tobacco status, alkaline phosphatase level, platelet count, and EGF polymorphisms to independently contribute to the risk for HCC. In addition, these factors can be used to stratify HCV patients into low, intermediate, and high-risk categories for developing of HCC (Abu Dayyeh et al.,2011). 13-Dietary factors Some studies have suggested that consumption of red meat and saturated fat are associated with an increased risk of HCC (Freedman et al.,2010). PROTECTIVE FACTORS 1-Statin use Statin use has been associated with a lower risk of hepatocellular carcinoma (HCC) (Hsiang et al.,2015). This was demonstrated in a population-based study from China that included 33,413 patients with HBV (Tsan et al.,2012). Compared with patients who did not use statins, patients with 28 to 90 cumulative defined daily doses (cDDDs) of a statin had a hazard ratio (HR) for HCC of 0.66 (95% CI 0.44-0.99), those with 91 to 365 cDDDs had an HR of 0.41 (95% CI 0.27-0.61), and those with >365 cDDDs had an HR of 0.34 (95% CI 0.18-0.67). Similar results were seen in a study that included more than 260,000 patients with HCV (Tsan et al.,2013).

The association of statins use with a decreased risk of HCC was also demonstrated in a meta-analysis that included 10 studies with 1.6 million patients (Singh et al.,2013).

Compared with patients who did not use statins, patients who took statins had a 37 percent decrease in their odds of developing HCC (odds ratio 0.63; 95% CI 0.52-0.76).

2-Dietary factors

A population-based study and meta-analysis suggested that consumption of white meat may be associated with a reduced risk (Luo et al.,2014). In addition, the consumption of fish, omega-3 fatty acids, and vegetables has been associated with a reduced risk (Bamia et al.,2015).

Higher dietary intake of vitamin E has also been associated with a decreased risk of liver cancer among patients both with and without a self-reported history of liver disease or a family history of liver cancer (Zhang et al.,2012).

Several observational studies have implicated coffee consumption as a protective factor for liver cancer, including HCC. A meta-analysis estimated that consumption of two or more cups per day was associated with a 43 percent reduction of liver cancer (95% CI 0.49-0.67) (Larsson and Wolk,2007).

The benefit was observed in individuals with and without liver disease. The authors noted that coffee contains large amounts of antioxidants, suggesting biological plausibility for the protective effect. They also noted that coffee and caffeine have been linked to lower aminotransferase levels and a reduced risk of cirrhosis, potentially further contributing to biological plausibility.
Similar conclusions were reached in a second meta-analysis and in a subsequent large, population-based cohort study (Setiawan et al.,2015).

Clinical features

Patients who develop hepatocellular carcinoma (HCC) usually have no symptoms other than those related to their chronic liver disease. Suspicion for HCC should be heightened in patients with previously compensated cirrhosis who develop decompensation such as ascites, encephalopathy, jaundice, or variceal bleeding. These complications are often associated with extension of the tumor into the hepatic or portal veins or arteriovenous shunting induced by the tumor (Yuki et al.,2003).

Some patients may have mild to moderate upper abdominal pain, weight loss, early satiety, or a palpable mass in the upper abdomen. These symptoms often indicate an advanced lesion (Garfein et al.,2004).

Other uncommon presentations include:

‘Obstructive jaundice caused by invasion of the biliary tree, compression of the intrahepatic duct, or rarely, as a result of hemobilia.

‘Diarrhea (Stevens et al.,1975).

‘Bone pain or dyspnea due to metastases.

‘Intraperitoneal bleeding due to tumor rupture.

Tumor rupture is often associated with sudden onset of severe abdominal pain with distension, an acute drop in the hematocrit and hypotension, and is most commonly diagnosed by peritoneal lavage and laparotomy.

A computed tomography (CT) scan typically demonstrates a liver mass and free intraperitoneal blood (Beasley et al.,1982).
This is a life-threatening complication, and control of bleeding may require emergent angiography and embolization of the bleeding vessel, or even surgery (Coursaget et al.,1987).

Although the risk of peritoneal dissemination is high, delayed resection may be considered, if feasible.

‘Fever may develop in association with central tumor necrosis.

‘Paraneoplastic syndromes.

‘Pyogenic liver abscess (very rare) (Tassopoulos et al.,1987).

The physical findings in most patients with HCC (splenomegaly, ascites, jaundice, or other manifestations of decompensated cirrhosis) reflect the underlying liver disease (Kumar et al.,2007).

Hepatomegaly or a bruit heard over the liver are occasionally present.

Laboratory examination is usually nonspecific. The majority of patients who develop HCC have cirrhosis, and may have thrombocytopenia, hypoalbuminemia, hyperbilirubinemia, and hypoprothrombinemia. Patients are often mildly anemic and may have electrolyte disturbances (eg, hyponatremia, hypokalemia, metabolic alkalosis) associated with defective water handling or with diuretic use. Serum aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase are often abnormal in a nonspecific pattern (Lok and Lai,1989).

Paraneoplastic syndromes

Patients with HCC occasionally develop a paraneoplastic syndrome that can manifest as hypoglycemia, erythrocytosis, hypercalcemia, or severe watery diarrhea. The presence of any of these manifestations, other than erythrocytosis, is generally associated with a poor prognosis (Guillevin et al.,1995).

Hypoglycemia, which usually occurs in advanced HCC, is thought to result from the tumor’s high metabolic needs. The hypoglycemia is typically mild and produces no symptoms; however, more severe reductions in the plasma glucose can occur, resulting in lethargy and confusion.

Less than 5 percent of tumors secrete insulin-like growth factor-II, which can cause severe symptomatic hypoglycemia, sometimes early in the course of the disease (Johnson and Couser,1990).

Erythrocytosis :

Erythrocytosis in HCC is probably due to tumor secretion of erythropoietin (EPO).

Although raised serum EPO levels may be present in up to 23 percent of patients with HCC, elevations in hemoglobin concentration or packed cell volume are uncommon, and most patients are anemic at diagnosis because of other effects of the tumor (Li,1991).

Hypercalcemia

Although hypercalcemia is sometimes associated with osteolytic metastases, it may be present in the absence of bony metastasis due to secretion of parathyroid hormone-related protein (Lok,1992).

Watery diarrhea

Patients with HCC may present with watery diarrhea. In one study, for example, diarrhea was significantly more common among cirrhotic patients with HCC compared to matched cirrhotic controls (48 versus 9 percent) (Stevens et al.1975).

Rarely, diarrhea may be severe and intractable, leading to hypokalemia and achlorhydria (Chang et al.1988).

Cutaneous features

Several cutaneous manifestations have been described in association with HCC; however, none is specific for the diagnosis (Lok and Lai,1988). These include:

  • Dermatomyositis.
  • Pemphigus foliaceus, a superficial blistering disease similar to pemphigus vulgaris except it rarely involves the mucous membranes. Blisters often appear as shallow erosions associated with erythema, scale and crust formation, which may resemble severe seborrheic dermatitis.
  • The sign of Leser-Trelat, which refers to the sudden appearance of multiple seborrheic keratoses, often with an inflammatory base in association with skin tags and acanthosis nigricans.
  • Pityriasis rotunda, which is characterized by multiple, round or oval, sharply demarcated scaling patches. It can be a useful diagnostic sign suggesting the possibility of HCC, especially in South African blacks with chronic hepatitis B (Andreani et al.,2007).
  • Porphyria cutanea tarda (PCT), in which exposure to the sun and/or minor trauma leads to skin erythema and the development of vesicles and bullae that may become hemorrhagic.

Although PCT has been recognized in patients with HCC related to a variety of risk factors, PCT in patients with HCC may be a marker for underlying hepatitis C virus infection (Hui et al.,2007).

Patterns of metastatic spread

Extrahepatic spread is present at the time of diagnosis in only approximately 5 to 15 percent of cases (Bertoletti and Kennedy, 2015).
Extrahepatic metastases are more common in patients with Advanced stage primary tumors (>5 cm, large vessel vascular invasion) (Chang et al.,1995).

Extrahepatic disease spread is also uncommon as a component of disease recurrence after locoregional therapy (5 to 24 percent) (McMahon et al.,2001).

The most common sites are lung, intra-abdominal lymph nodes, bone, and adrenal gland, in that order. Brain metastases are rare overall (0.2 to 2 percent), although a higher rate has been reported in patients with advanced disease (Chu et al.,1989).
Perihepatic lymphadenopathy should not be assumed to represent extrahepatic spread. In patients with cirrhosis, benign nodal enlargement is frequent and most often involves the porta hepatis and portacaval space.

Pathology

Gross

HCC may form a large solitary circumscribed nodule with or without adjacent smaller satellite nodules. In the presence of cirrhosis, HCC may be multinodular within one lobe, consist of multiple nodules scattered throughout the liver, or may infiltrate the liver diffusely without forming circumscribed nodules. Classifications based upon gross morphology (ie, nodular, diffuse, expansive, infiltrative, multifocal, etc) have been proposed (Nakashima and Kojiro, 1987).

HCCs are usually soft, tan to yellow, often bile-stained, and show areas of necrosis and hemorrhage. Large vessel vascular invasion can be identified on gross examination, and the frequency increases with tumor size. The portal vein and hepatic veins as well as the vena cava may be involved (picture 1). Invasion of major bile ducts is an uncommon finding, but when present, it can cause biliary obstruction .

Small tumors (<5 cm if solitary, or up to three nodules, each smaller than 3 cm) have a better prognosis (Mazzaferro et al.,1996). while the presence of satellite nodules (Plessier et al.,2004). and major vessel invasion are adverse features (D’Amico et al.,2009). For patients undergoing tumor resection, the main predictor of poor outcome is incomplete resection (Lauwers and Vauthey, 1998).

Histology

Invasive HCC

The cells of HCC resemble hepatocytes in function, cytologic features, and growth patterns. The degree of differentiation reflects the resemblance of tumor cells to normal hepatocytes:

‘Well-differentiated HCCs are often small (<2 cm) and composed of cells with mild atypia, arranged in a thin trabecular pattern with rare pseudoglandular structures (picture 2). The tumor cells are typically polygonal with granular and eosinophilic cytoplasm (picture 2). The tumor cells may secrete bile (picture 3) and contain fat (picture 4), glycogen (picture 5), Mallory-Denk hyalins (picture 6), hyalin globules, or fibrinogen (picture 7) mimicking or in exaggeration of normal hepatocyte function. A large amount of cytoplasmic fat and/or glycogen causes a clear cell appearance, which may be difficult to distinguish from metastatic clear cell renal cell carcinoma. Most often the tumor grows in a trabecular pattern with thickened cords of cells separated by vascular sinusoids that are lined by endothelial cells (picture 8), mimicking the cell plates and sinusoids of normal liver. Expansion of the trabeculae may compress the sinusoids and form a solid or compact pattern of growth. Occasional dilated bile canaliculi, often containing bile and producing a pseudoglandular pattern (picture 9), may be seen in the centers of trabeculae. Connective tissue stroma is typically sparse, and reticulin fibers are significantly reduced or absent. ‘Moderately-differentiated HCCs are usually larger tumors (>3 cm), and they are composed of polygonal tumor cells in thick trabecular pattern with frequent pseudoglandular pattern (picture 10).

‘Poorly-differentiated HCCs are composed of pleomorphic tumor cells in a solid or compact growth pattern (picture 11).

Variants

There are several uncommon histologic subtypes of HCC, including scirrhous, spindle cell, giant cell, inflammatory lymphoepithelioma-like, undifferentiated, and small cell variants:

  • The scirrhous variant is morphologically composed of tumor cells in a background of dense fibrous stroma rather than the sinusoids that are typical for HCC (picture 12). This HCC subtype should be differentiated from cholangiocarcinoma, which typically shows abundant dense desmoplastic fibrous stroma.
  • The spindle cell variant mimics metastatic sarcoma (picture 13), but extensive sampling may yield polygonal cells that are diagnostic of HCC.
  • The giant cell variant is considered to be a poorly-differentiated form of HCC and is composed of large multinucleated giant cells (picture14) It should be differentiated from metastatic giant cell carcinoma from other organs.
  • The inflammatory lymphoepithelioma-like variant contains pleomorphic tumor cells in a syncytial growth pattern with a lymphocyte-rich background.
  • The small cell variant often demonstrates neuroendocrine differentiation similar to other small cell neuroendocrine carcinomas arising in other organs; a metastatic small cell carcinoma (usually of lung origin in smokers, but occasionally extrapulmonary) should be in the differential diagnoses.
  • Extensive sampling of these uncommon HCC variants may demonstrate minor areas of typical HCC. In addition, these special HCC subtypes may lose HCC-specific antigenicity usually seen in conventional HCC and may not stain with the usual immunohistochemical reagents.

Dysplastic focus

Dysplastic focus is an expansile focus of hepatocytes with cytologic changes indicative of dysplasia and measuring less than 1 cm (International Working Party,1995). Dysplasia as a premalignant change in hepatocarcinogenesis takes the form of small cell change (Le et al.,1997).

Which is cytologically recognized as hepatocytes with decreased cytoplasmic volume, cytoplasmic basophilia, mild nuclear pleomorphism and hyperchromasia, and increased nuclear cytoplasmic ratio (picture 15). According to the original definition, dysplastic focus measured <1 mm in diameter, but this arbitrary size criterion was related to the fact that the microscopic lesions were usually contained within a single cirrhotic nodule (Theise et al.,2010).

A dysplastic focus is often iron free in a liver with hemochromatosis (Deugnier et al.,1993).

Unlike small cell change, large cell change (picture 16) is not directly related to hepatocarcinogenesis (in other words it is not a premalignant lesion), but it has been linked to cellular senescence and it is more prevalent in cirrhotic livers with HCC (Lee et al., 1997).

Large cell transformation is an important independent risk factor for the subsequent development of HCC, and its presence may be used to identify a subgroup of patients at high risk for HCC requiring more intensive screening (Koo et al.,2008).

Dysplastic nodules

Dysplastic nodules are considered preneoplastic lesions, supported by the accumulation of evidence that points to the existence of a sequence of events in dysplastic nodules that precedes the emergence of HCC (Llovet et al.,2006).

The evolution of dysplastic nodules into early carcinoma includes induction of an arterial blood supply and stromal invasion (Kojiro and Roskams, 2005).

They are usually (but not exclusively) detected in cirrhotic livers. On cut surface, dysplastic nodules bulge and differ from the surrounding cirrhotic liver.

Dysplastic nodules are classified into low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs) based upon cytologic and architectural atypia as seen on microscopic examination:

  • In LGDN, the hepatocytes rarely show a clonal population, and there is minimal nuclear atypia and only a slight increase in the nuclear:cytoplasmic ratio. Large cell change is often present, but mitotic figures are absent. Without obvious clonal population, the distinction between LGDN and a large regenerative nodule is difficult and does not carry any practical consequences as long as the nodules lack the features of HGDN.
  • HGDN shows cytologic and/or architectural atypia but is insufficient for the diagnosis of HCC. Small cell change and architectural atypia, such as thick plates (up to three cells thick) and occasional pseudoglandular structures, are common in HGDN.

Small and early hepatocellular carcinoma

Small HCCs up to 2 cm in diameter are classified into distinctly nodular type and vaguely nodular type. Distinctly nodular HCCs (also known as progressed HCCs) are mostly moderately differentiated, lack portal tracts, and show evidence of microvascular invasion. Vaguely nodular HCCs (also known as early HCCs or small HCC with indistinct margins) retain the basic architecture of the background cirrhotic liver, and the neoplastic cells grow in and replace the nonneoplastic liver cords. The small neoplastic cells (reminiscent of small cell change) are arranged in irregular, thin trabeculae with pseudoglandular structures or fatty changes. A fibrous capsule is lacking, and the tumor contains ‘entrapped’ portal tracts (picture 17). The tumor cells grow around preexisting portal tractsand/or invade the portal tracts (stromal invasion).

Most vaguely nodular HCCs are well-differentiated HCCs. Most of these nodules are clinically hypovascular because of the insufficient development of unpaired tumor arteries and incomplete sinusoidal capillarization.

Distinctly nodular HCC or progressed HCC is biologically more advanced and usually of higher grade, and there are typical HCC features and well-developed unpaired tumor arteries, which facilitate their detection by contrast enhanced imaging methods.
Small nodules with a ‘nodule-in-nodule’ appearance are either HGDN with a subnodule of HCC, or a well-differentiated HCC with a subnodule of moderately-differentiated HCC.

The former is commonly completely hypovascular, but the latter is usually detected as a hypovascular nodule containing a hypervascular focus on contrast images (Efremidis et al.,2007).

Stromal invasion, as an important criterion of a carcinoma, is easier to identify in distinctly nodular HCC but is obscured in the vaguely nodular type. The absence of cytokeratin (CK)7-positive duct staining is a feature of areas of stromal invasion in small HCC and can be helpful in distinguishing small HCCs from minimally invasive HCCs of the vaguely nodular type, and overtly invasive HCCs of the distinctly nodular type.

Immunohistochemistry

Immunohistochemistry can aid in the diagnosis and differential diagnosis. In well-differentiated and moderately-differentiated tumors, the trabeculae are lined directly by CD34 or CD31-positive endothelial cells (picture 18). The presence of bile canaliculi may be highlighted by polyclonal carcinoembryonic antigen (pCEA) or CD10 (picture 19) (Wang et al.,2006).

The canalicular pattern of staining for pCEA or CD10 indicates hepatocellular differentiation and is diagnostic of HCC. The tumor cells may also contain alpha-fetoprotein (AFP) or alpha-1-antitrypsin or fibrinogen that can be demonstrated by immunohistochemical staining. However, high serum levels of the tumor marker AFP do not correlate with positive AFP immunostaining. AFP immunostaining is positive in less than 40 percent of HCCs (Wang et al.,2006).

Immunohistochemically, most well to moderately well-differentiated HCC’s are positive for hepatocyte paraffin 1 (HepPar1) (picture 20), cytoplasmic thyroid transcription factor-1 (TTF1) (picture 21), glutamine synthetase, GPC3, and CK8 and 18 (Lei et al.,2006).
CK19 staining is a surrogate marker for progenitor cell origin, and its positivity in HCC indicates activation of the epidermal growth factor signaling pathway, which correlates with aggressive behavior, the presence of lymph node and extrahepatic metastasis, and early relapse (Yoneda et al.,2011).

Immunostaining with a combination of GPC3, HSP-70, and glutamine synthetase may aid the distinction between HGDNs and HCCs (Roskams and Kojiro, 2010).

At least two diffusely positive stains out of the three markers are seen in early or well-differentiated HCC.

Poorly-differentiated HCC’s may occasionally lose immunoreactivity to some of the hepatocellular differentiation markers above, such as HepPar1, canalicular CEA or CD10, and AFP; and therefore, the diagnoses must often rely on imaging studies to exclude other primaries and clinical history of chronic hepatitis.

Stromal invasion, as an important criterion of a carcinoma, is easier to identify in distinctly nodular HCC but is obscured in the vaguely nodular type. The absence of CK7-positive ductular reaction is a feature of areas of stromal invasion in small HCC and can be helpful in distinguishing small HCCs from dysplastic nodules, minimally invasive HCCs of the vaguely nodular type, and overtly invasive HCCs of the distinctly nodular type (Park et al.,2007).

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