Pathogenesis and Pathology

The prevalence of hemangioma in the general population ranges from 1% to 20% (Semelka & Sofka, 1997), but it is predominant in women by a 5 : 1 ratio (Mergo & Ros, 1998; Trotter & Everson 2001; Biecker et al, 2003). In adults, hemangiomas are usually found in patients at a mean age of 50 years and equally in the left and right lobes of the liver; the majority are less than 5 cm in diameter and are rarely pediculated, but hemangiomas measuring 10 cm or more are referred to as giant hemangiomas and can present with fibrosis, thrombosis, and calcifications (Fig. 79A.1).

FIGURE 79A.1 Giant hemangioma. Portal-venous phase helical computed tomographic and centripetal contrast enhancement.

The pathogenesis of hemangioma is not well understood. Some of these tumors have estrogen receptors, and accelerated growth has been observed with high-estrogen states, such as those associated with puberty, pregnancy, oral contraceptive use, and with androgen treatment. These findings suggest that hormonal effect may be one of the pathogenic mechanisms (Trotter & Everson, 2001; Cobey & Salem, 2004). Macroscopic examination demonstrates well-delineated, flat lesions of red-blue color that may partially collapse on sectioning. Some degree of fibrosis, calcification, and thrombosis may be observed, most commonly in the largest lesions (Fig. 79A.2). Microscopically, hemangiomas are made of cavernous vascular spaces lined by flattened endothelium underlying fibrous septa of various widths (Fig. 79A.3). Small hemangiomas may become entirely fibrous, appearing as a solitary fibrous nodule.

FIGURE 79A.2 Macroscopic view of hemangioma.

FIGURE 79A.3 Microscopic view of hemangioma showing cavernous vascular spaces lined by flattened endothelium underlying fibrous septa of various widths. The vascular spaces are filled with red blood cells.

Clinical and Biologic Data

The vast majority of hemangiomas are less than 5 cm and are found incidentally during ultrasound (US) or computed tomography (CT) examination of the abdomen for unrelated reasons (Trotter & Everson, 2001). Hemangiomas remain stable in size (Takayasu et al, 1990) or demonstrate minimal increase in diameter over time (Nghiem et al, 1997). Pain related to an uncomplicated hemangioma is most probably due to associated disorders, such as gallbladder disease, liver cysts, gastroduodenal ulcers, or a hiatal hernia (Farges et al, 1995). Large hemangiomas may be asymptomatic or may manifest with an abdominal mass or pain (Erdogan et al, 2007). Large lesions located in the left lobe of the liver may cause pressure effects on adjacent structures with resulting symptoms. Jaundice as a result of compression of bile ducts by hemangioma has also been observed, but this is rare (Losanoff & Millis, 2008).

Liver biologic tests, including alkaline phosphatase and γ-glutamyltransferase (GGT), are normal. Normal laboratory tests associated with a large hepatic tumor with mild symptoms could be of help in the diagnosis of hemangioma.

Complications are mostly observed in large hemangiomas and can be divided into 1) alterations of internal architecture, such as with inflammation; 2) coagulation abnormalities, which could lead to systemic disorders such as hemorrhage and subsequent hemoperitoneum; and 3) compression of adjacent structures.

Some cases of inflammatory processes complicating giant hemangioma have been reported (Bornman et al, 1987; Takayasu et al, 1990), and the prevalence is probably underestimated. Signs and symptoms of an inflammatory process include low-grade fever, weight loss, abdominal pain, accelerated erythrocyte sedimentation rate, normal white blood cell count, anemia, thrombocytosis, and increased fibrinogen level. The imaging features are those of giant hemangioma. Clinical and laboratory abnormalities disappear after surgical excision of the mass (Bornman et al, 1987; Pateron et al, 1991; Pol et al, 1998).

Kasabach-Merritt syndrome is an exceptional complication of hepatic hemangioma in adults (Hall, 2001; see Chapter 82). This coagulopathy consists of intravascular coagulation, clotting, and fibrinolysis within the hemangioma, and it may progress to secondary increased systemic fibrinolysis and thrombocytopenia (Concejero et al, 2009); the syndrome is reversible after removal of the hemangioma. Although rarely encountered in hepatic hemangioma, intratumoral hemorrhage can occur spontaneously or after anticoagulation therapy. Spontaneous rupture of a hemangioma is exceptional, and very few indisputable cases have been reported (Corigliano et al, 2003); taking into account the high prevalence of these tumors, the extremely low incidence of this complication should not interfere with the therapeutic management, nor should it influence the specific advice to patients, who are often worried by the presence of a vascular liver tumor (Plackett & Lin-Hurtubise, 2008).

Imaging

The vast majority of hemangiomas are diagnosed accurately by imaging studies alone because of characteristic imaging features. On US the classic appearance of hemangioma is that of a homogeneous hyperechoic mass less than 3 cm in diameter with acoustic enhancement and sharp margins (Fig. 79A.4; see Chapter 13). No vascular pattern is usually identified on color Doppler. Other investigations are required when US does not show typical patterns. Contrast-enhanced US reveals peripheral globular enhancement in the portal phase and isoechoic pattern on the late phase in most atypical hemangiomas (Quaia et al, 2002).

FIGURE 79A.4 Hemangioma. A, Ultrasound shows a hypoechoic liver lesion with posterior acoustic enhancement. B and C, Contrast-enhanced ultrasound demonstrates peripheral puddling followed by complete and delayed enhancement.

On CT, the criteria for the diagnosis of hemangioma are the following: 1) low attenuation on noncontrast CT, 2) peripheral and globular enhancement of the lesion followed by a central enhancement on contrast CT, and 3) contrast enhancement of the lesion on delayed scans (Freeny & Marks, 1986; see Chapter 16). Among these criteria, the presence of peripheral puddles on the arterial phase has a sensitivity of 67%, a specificity of 99%, and a positive predictive value of 86% for hemangioma (Nino-Murcia et al, 2000). Magnetic resonance (MR) imaging is the key imaging modality in the characterization of liver hemangiomas (Itai et al, 1985; Starck et al, 1985; see Chapter 17). The classic appearance of a liver hemangioma is that of a hypointense lesion on T1-weighted sequences, a strongly hyperintense lesion on heavily T2-weighted sequences, with a “lightbulb” pattern (Fig. 79A.5). Dynamic multiphasic T1-weighted sequences after gadolinium chelate administration show findings similar to that of contrast-enhanced CT phases (Fig. 79A.6; Semelka et al, 1994). Hemangiomas can be multiple in 10% of cases, and in exceptional cases, the presence of innumerable hemangiomas are called hemangiomatosis (Ishak & Rabin, 1975; Keegan et al, 2001).

FIGURE 79A.5 Hemangioma. T2-weighted magnetic resonance imaging shows typical bright signal.

FIGURE 79A.6 Typical hemangioma. A and B, Precontrast T2- and T1-weighted magnetic resonance imaging shows typical bright signal on T2 and low signal on T1. Gadolinium-enhanced T1-weighted MR imaging obtained at the arterial, portal, and delayed phase (C to E) shows typical peripheral enhancement with progressive and complete filling over time.

The two most common imaging atypias are found in giant hemangiomas and in rapidly filling hemangiomas. Giant hemangiomas, which are defined when they exceed 6 or 12 cm in diameter, are often heterogeneous with marked central areas that correspond to thrombosis, extensive hyalinization, and fibrosis (Danet et al 2003; Coumbaras et al, 2002). However, usually the typical early, peripheral, nodular enhancement is observed along with strong hyperintensity on T2-weighted MR images at the periphery. Although present, the progressive centripetal enhancement of the lesion does not lead to complete filling. Rapidly filling hemangiomas are not uncommon and occur significantly more often in small lesions (42% of hemangiomas are <2 cm in diameter) (Hanafusa et al, 1995). CT and MR imaging show an immediate homogeneous enhancement in the arterial phase, which makes differentiation from other hypervascular tumors difficult. Their diagnosis is based on strong hyperintensity on T2-weighted images, the parallel enhancement with arterial structures, and the persistent enhancement on delayed-phase imaging; it is important to note that these rapidly filling hemangiomas may induce arterial–portal venous shunts (Kim et al, 2001). The other atypical hemangiomas are very uncommon and include very slow filling, calcified, hyalinized cystic and pedunculated hemangiomas, those with fluid-fluid levels, and hemangiomas with capsular retraction.

Hemangiomas associated with inflammatory response syndrome are usually due to acute thrombosis of a part or all the hemangioma. These can be diagnosed by showing spontaneous hyperattenuation on unenhanced CT scans. Hemangiomas developing in abnormal liver are difficult to diagnose, and those in fatty liver usually appear isoechoic or hypoechoic at US and hyperattenuating at unenhanced CT (Marsh et al, 1989). MR imaging with fat-suppressed, in-phase and opposed-phase T1-weighted sequences is the key to the diagnosis and is more helpful than CT; strong hyperintensity on T2-weighted images is also a reliable finding.

With progressive cirrhosis, hemangiomas are likely to decrease in size and become more fibrotic and difficult to diagnose radiologically (Brancatelli et al, 2001). In this clinical setting, US cannot be used to confidently make the diagnosis of hemangioma, as half of the hyperechoic lesions are hepatocellular carcinomas (HCCs) (Caturelli et al, 2001). The association of hepatic hemangioma and FNH can be observed in about 25% of cases and is not fortuitous (Mathieu et al, 1989; Vilgrain et al, 2003). FNH is considered to be a hyperplastic response as a result of focal increased arterial flow in the hepatic parenchyma and, like hemangioma, it is thought to have a vascular origin.

Imaging, and especially MR imaging, is therefore able to diagnose liver hemangiomas in nearly all cases, and liver biopsy should be restricted to exceptional cases. Liver hemangioma, which has been considered a contraindication to needle biopsy for many years, is possible without significant risk of hemorrhage (Heilo & Stenwig, 1997; Caldironi et al, 1998). However, as in other tumors, a cuff of normal hepatic parenchyma should be interposed between the capsule and the margin of the hemangioma.

Management

Whatever the size, there is no treatment for asymptomatic hemangioma. When the diagnosis is established, it is not necessary to adopt therapeutic or specific measures. The patient should be reassured about the rare occurrence of growth and the extremely low risk of complication; therefore oral contraceptives need not be interrupted, nor should the patient be counseled to avoid pregnancy or discontinue any sporting activity, and follow-up is not justified. Although in specialized centers, liver resection mortality for benign lesions is essentially nil, there is a risk of intraoperative bleeding and postoperative biliary fistula, which should be considered unacceptable given the benign nature of these lesions; indeed, it could be stated that the main complication of hemangioma is surgical operation.

Indications for treatment include severe symptoms, complications, and inability to exclude malignancy (Yoon et al, 2003; Duxbury & Garden, 2010). Symptoms are more frequently encountered with huge hemangioma (Erdogan et al, 2007). Surgical resection remains the definitive treatment, but other less effective options include hepatic artery ligation and radiation therapy; radiation therapy can reduce the size of the lesion (Gaspar et al, 1993), but long-term effects of radiation therapy on the liver and adjacent structures can be deleterious. In addition, relief of symptoms is not well documented. Arterial embolization, which may be considered for the temporary control of hemorrhage, has limited success and is occasionally associated with morbidity (Reading et al, 1988). Arterial ligation may be considered during surgical procedures to allow manual decompression of large hemangiomas and facilitate their manipulation and enucleation (Yoon et al, 2003).

When indicated, the only treatment to be considered is resection (Herman et al, 2005; Erdogan et al, 2007), and it should be performed in specialized units, where a variety of techniques and approaches can be used. The choice between enucleation and resection requires consideration of the size and anatomic location of the lesion. Hemangioma located in the peripheral liver area is preferably treated by enucleation, whereas tumors deeply located are more safely resected with a formal anatomic liver resection (Kuo et al, 1994; Gedaly et al, 1999; Fu et al, 2009). In the majority of cases, patients showed symptoms relief after resection of a symptomatic hemangioma (Erdogan et al, 2007). Although laparoscopic resection is safe for peripheral hemangioma (Karahasanoglu et al, 2001; Jiang et al, 2007), this approach should not extend the rare indication for surgery. Liver transplantation has also been used successfully to treat symptomatic patients with a technically unresectable, complicated giant hemangioma or hemangiomatosis with cardiopulmonary complications (Browers et al, 1997; Tapetes et al, 1995; Ferraz et al, 2004; Keegan et al, 2001; Ercolani et al, 2010).

Pathogenesis and Pathology

FNH accounts for the second most common benign liver process, after hemangioma. It is a benign, tumor-like condition predominantly diagnosed in women 30 to 50 years of age, and it is not influenced by oral contraceptives (International Working Party, 1995; Ishak, 1979). FNH is considered a hyperplastic reaction resulting from arterial malformation (Wanless et al, 1985). This hypothesis, suggesting that increased arterial flow hyperperfuses the local liver parenchyma and leads to secondary hepatocellular hyperplasia, has been reinforced by molecular data showing that FNH is a polyclonal regenerative process (Gaffey et al, 1996; Paradis et al, 1997; Rebouissou et al, 2008). This regenerative process induced in a specific vascular territory could explain the absence of size changes in the vast majority of cases. However, an involution of this lesion is possible after menopause (Kuo et al, 2009), which explains the occurrence of this lesion in patients with vascular disorders of the liver, including Budd-Chiari syndrome (Cazals-Hatem et al, 2003), hereditary hemorrhagic telangiectasia (Gincul et al, 2008), congenital absence of portal flow (Kim T, et al, 2004), or portal thrombosis with subsequent hepatic arterialization (Bureau et al, 2004).

Such focal regenerative processes are also described in cirrhotic tissue with the so-called FNH-like macronodules. FNH displays a typical pathologic pattern for both radiologists and pathologists. Grossly, it is a well-circumscribed, unencapsulated, usually solitary mass characterized by a central fibrous scar that radiates into the liver parenchyma (Fig. 79A.7). Histologically, FNH is composed of benign-appearing hepatocytes arranged in nodules, usually partially delineated by fibrous septa that originate from the central scar. The main diagnostic feature is the presence of large and dystrophic vessels in the fibrous septa, which can be accompanied by several degrees of ductular proliferation and inflammatory cells. The hepatocytes are hyperplastic, arranged in liver plates of normal or slightly increased thickness (see Chapter 78). Hepatocytes may be hydropic, related to cholestatic changes, or they may display some degree of steatosis.

FIGURE 79A.7 A, Macroscopic view of focal nodular hyperplasia (FNH); it is well circumscribed and displays a central, fibrous scar that radiates and delineates liver parenchyma nodules. B, Adjacent liver is normal on trichrome staining; fibrous bands spread across the FNH, delineating hepatocellular nodules. Vascular spaces are observed inside the fibrous tissue. C, On hematoxylin and eosin staining, large and dystrophic vessels and inflammatory cells are observed in the fibrous bands.

Performance of biopsy in the diagnosis of FNH is often a challenge, because fibrous septa and thick abnormal arteries are usually missing on biopsy specimen (Makhlouf et al, 2005). In that context, glutamine synthetase showing focal positive hepatocellular areas, usually centered by hepatic veins and described as a maplike pattern, is a helpful surrogate marker (Bioulac-Sage et al, 2009a).

Besides this classic form of FNH, several variant lesions are described with increased frequency and commonly classified as nontypical FNH by radiologists. This group of lesions is somewhat heterogeneous, including FNH without a central fibrous scar and FNH containing fat (Nguyen et al, 1999). However, molecular studies have demonstrated that in this group of atypical FNH, lesions that display telangiectatic changes, the so-called telangiectatic form of FNH, are clonal processes that should be rather regarded as a variant form of liver cell adenoma; it is classified as a specific subgroup of adenoma other than FNH (Paradis et al, 2004; Bioulac-Sage et al, 2005).

Clinical and Biologic Data

FNH represents the second most frequent benign lesion, with an estimated prevalence around 1% (Vilgrain, 2006); it is seen predominantly in women (9 : 1) and often is discovered in patients aged 30 to 40 years, although men with FNH are usually older than 40 years (Nguyen et al, 1999). The vast majority of FNH is asymptomatic, usually discovered incidentally during liver US examination. In a few patients with large tumors, FNH can be discovered by abdominal pain or discomfort. Large lesions located in the left lobe of the liver may cause pressure effects on adjacent structures with resulting symptoms. The lesion may be felt when it is pedunculated, and it can be responsible for acute episodes of pain because of torsion on the pedicle. Large FNH below the Glisson capsule could also be responsible for pain (Buetow et al, 1996), but in most cases pain related to FNH is probably due to associated disorders.

Complications of FNH, such as rupture or bleeding, are exceptional and are usually related to atypical forms of FNH with specific imaging and biologic features, the so-called telangiectatic FNH, which should be classified as an adenoma. No malignant transformation of FNH has been demonstrated. A reduction in size after menopause may be observed, but in the vast majority of cases, FNH remains stable in size, even after interruption of oral contraception or after pregnancy (Mathieu et al, 2000).

Liver biologic test results are normal in nearly 80% of cases (Belghiti et al, 1993). Abnormalities include mild elevation of GGT and alkaline phosphatase in patients with a large FNH that caused extrinsic compression of intrahepatic biliary ducts. The presence of a slight elevation of serum transaminase levels could be due to the presence of associated steatosis in the underlying liver parenchyma.

Imaging

FNH is usually slightly hypoechoic or isoechoic at US (see Chapter 13). Some lesions are only detected because they displace the surrounding vessels. Lobulated contours and a hypoechoic halo are often observed; the central scar is slightly hyperechoic but is often difficult to visualize at US (20% of cases; Shamsi et al, 1993). Typical findings at color Doppler include the presence of a central feeding artery with a stellate or spoke-wheel pattern that corresponds to the artery running from the central scar to fibrous septa (Fig. 79A.8). Doppler spectral analysis shows, in most cases, an intralesional pulsatile waveform with high diastolic flow and low resistive index (Uggowitzer et al, 1997). Large draining vessels may be identified in the periphery at the tumor margins. US contrast agents and nonlinear continuous imaging modes at a low mechanical index are very interesting tools to better characterize FNH. Most lesions enhance at the arterial phase (Kim MJ, et al, 2004; Dietrich et al, 2005) with a central vascular supply and a centrifugal filling to the periphery. The lesion becomes homogeneously isoechoic in the late portal and delayed phases in the vast majority of the cases (Kim MJ, et al, 2004), and very little FNH is evident with washout; when the central scar is detected, it appears hypoechoic on both arterial and portal phases. By showing centrifugal enhancement with radiated vascularization, differentiation from hepatocellular adenoma is possible in most cases (Kim T, et al, 2008).

FIGURE 79A.8 Typical focal nodular hyperplasia (FNH). A, Contrast-enhanced ultrasound demonstrates strong and homogeneous enhancement apart from the central scar, which remains hypoechoic. Precontrast T2- and T1-weighted magnetic resonance (MR) imaging shows two hyperplastic focal nodules, which are isointense on T2 (B) and hypointense on T1 (C). Gadolinium-enhanced T1-weighted MR imaging obtained at the arterial and delayed phase (D and E) shows strong and homogeneous enhancement of the lesion with progressive fading. The central scar is hyperintense on T2 and enhances on delayed imaging. Note that the central scar is more evident in the large FNH.

On precontrast CT scans, FNH is demonstrated as a focal hypodense or isodense mass. A central hypodense scar is depicted in only one third of the patients (Shamsi et al, 1993). Calcifications within the central scar are very rare and are observed in only about 1% (Caseiro-Alves et al, 1996). Because of the prominent arterial supply to the FNH, the lesion enhances rapidly at the arterial phase of contrast-enhanced CT in most cases (Brancatelli, et al 2001). Lesion enhancement decreases at the portal venous phase, and the lesion may be either isodense or slightly hyperdense relative to normal liver. Additional findings are lesion homogeneity, a lobulated contour, and the absence of a capsule. A central scar is observed more often in large lesions than in small ones, and it enhances over time (Carlson et al, 2000). It has been shown that the enhancement of FNH in the arterial phase is significantly higher than in HA (Ruppert-Kohlmayr et al, 2001).

On MRI, typical FNH is isointense or hypointense on T1-weighted images and isointense or slightly hyperintense on T2-weighted images (Vilgrain et al, 1992; Buetow et al, 1996; see Chapter 17). The central scar is hypointense on T1-weighted images and strongly hyperintense on T2-weighted images (Mortelé et al, 2000; Kehagias et al, 2001). Another key finding is the lesion homogeneity apart from the central scar. After administration of gadolinium chelates, the enhancement is similar to that observed on contrast-enhanced CT. On delayed-phase imaging, 5 to 10 minutes after injection, the central scar shows high signal intensity because of the accumulation of contrast material in the fibrous tissue. Hepatobiliary contrast agents can be used to highlight the hepatocellular origin of the lesions and to differentiate FNH from hepatocellular adenomas; however, the biokinetics are different among those specific contrast agents (Ba-Ssalamah et al, 2002; Grazioli et al, 2005). On diffusion-weighted MR sequences, FNH is often hyperintense on high b values, but their apparent diffusion coefficient (ADC) values are close to that of the liver.

Atypical forms of FNH that are difficult to diagnose include FNH without a scar, especially in lesions measuring less than 3 cm in diameter. In some cases, scars do not enhance on delayed imaging, or they are hypointense on T2-weighted images; this leads the clinician to suspect the diagnosis of fibrolamellar carcinoma. Other atypical findings include hyperintensity on T1-weighted imaging, which may be caused by various pathologic changes that include fat deposition (mostly in patients with steatosis; Stanley et al, 2002). FNH heterogeneity is exceptional and should make the diagnosis doubtful.

Although FNH is mainly a solitary lesion, multiple FNH lesions may be observed in 20% of cases and may be associated with hemangiomas or more seldom with HA (Mathieu et al, 1989; Vilgrain et al, 2003; Laurent et al, 2003). Accuracy of contrast-enhanced US has been established, and MR imaging has the higher sensitivity (70%) and specificity (98%) (Soussan et al, 2010). However, the diagnosis of FNH is based on a combination of features, and none of them are specific for FNH. When imaging cannot establish a firm diagnosis, liver biopsy plays a role in diagnosing FNH (Fabre et al, 2002; Makhlouf et al, 2005).

Management

Whatever the size and number of lesions, no treatment is necessary for asymptomatic FNH, when the diagnosis has been firmly established. This lesion should be considered a regenerative procedure rather than a tumor. In addition, the occurrence of this lesion in men should not modify the indication of conservative treatment; FNH has no risk of malignant potential and no risk of complications. The patient should be reassured about the absence of potential complications and the natural history of this lesion, which remains stable; advise that it could decrease and even disappear after the fifth decade; therefore no argument can even be made for interrupting oral contraceptives or avoiding pregnancy, and a follow-up is not justified.

Surgical resection is restricted to symptomatic patients. Symptomatic patients with confirmed FNH should be thoroughly investigated to exclude other pathology before attributing symptoms to the liver lesion. The development of a liver laparoscopic approach should not extend the indication for resection, which should be performed in specialist hepatobiliary units, as it is clearly indicated in patients with large, symptomatic FNH located in the left liver and in those with a pedunculated lesion. The safer resection procedure is liver resection with a surgical margin, rather than enucleation, because large veins often surround FNH, which renders enucleation difficult. In some symptomatic patients with large FNH located in the right liver or in segment I and necessitating difficult or risky resection, transarterial embolization has been advocated to determine the relationship between the lesion and symptoms (De Rave & Hussain, 2002; Kehagias et al, 2001). Data in the literature (Amesur et al, 2009) and our experience have shown that this is an attractive treatment with reduction of size in conjunction with relief of symptoms (Fig. 79A.9). Percutaneous radiofrequency ablation (RFA) has also been described as an effective treatment modality for symptomatic FNH (Hedayati et al, 2010).

FIGURE 79A.9 Focal nodular hyperplasia (FNH) before and after arterial embolization. A, Abdominal computed tomographic scan with contrast injection on arterial and portal phases. Homogeneous centrohepatic FNH shows an immediate and intense enhancement during the arterial phase (white arrows). B, Postembolization aspect of the lesion. Note the size decrease and complete devascularization of the center of the lesion, appearing as a homogeneous unenhanced central area (black arrows).

Pathogenesis and Pathology

Hepatocellular adenoma (HA) is a rare, benign liver neoplasm strongly associated with oral contraceptive (OC) use (Rosenberg, 1991). The most important complications of HA are hemorrhage and malignant transformation into HCC. HA is mainly observed in women of childbearing age, and it is rare in men (sex ratio 9 : 1). Its incidence is estimated to be 0.1 per year per 100,000 in non-OC users, and it reaches 3 to 4 per 100,000 in long-term OC users (Wittekind, 1995). HA is directly related to OC use, and the risk for developing adenoma increases with the duration and estrogen content of the medication (Rosenberg, 1991; Dokmak et al, 2009). This tumor can also occur in men receiving anabolic steroids (Socas, et al 2005), or it may be associated with underlying metabolic disease, including type 1 glycogen storage disease, and iron overload related to β-thalassemia and hemochromatosis (Barthelemes & Tait, 2005; Bioulac-Sage et al, 2008). The prevalence of obesity was high in patients with HA (Dokmak et al, 2009), and it was recently described in patients with nonalcoholic fatty liver disease (Watkins et al, 2009). HA can also occur in patients with portacaval shunt or portal deprivation, and familial cases have been reported in patients with mellitus onset diabetes type 3 (Chiche et al, 2000; Bioulac-Sage et al, 2008).

HA is usually solitary, sometimes pedunculated, with a diameter that can vary from a few millimeters up to 30 cm. The widespread use and technical progress in imaging techniques has revealed that one third of patients have multiple HAs (Dokmak et al, 2009; Deneve et al, 2009; Bioulac-Sage et al, 2009b). Patients with more than 10 HAs are subclassified as having liver adenomatosis, considered to be more common in men and to have an increased risk of complications (Fléjou et al, 1985). However, review of the literature and our experience do not support this arbitrary classification based on clinical and imaging characteristics (Ribeiro et al, 1998; Jovine et al, 2004; Barthelemes & Tait, 2005; Dokmak et al, 2009; Bioulac-Sage et al, 2008). The risk of bleeding and of malignant transformation is similar to that in patients with solitary adenoma and is mainly related to the size and subtype of tumors (Dokmak et al, 2009; Bioulac-Sage et al, 2008; Deneve et al, 2009; Stoot et al, 2010). It also appears that the prevalence of HA is rising in men, mainly as a result of the rising incidence of metabolic syndrome (Farges et al, 2011). Such HA displays a significantly higher risk of malignant transformation to HCC, reaching 47% in the last few years in our experience (Farges et al, 2011); therefore patients should not be managed according to the number of HAs, but rather according to the risk of complications, which is related to sex, the histologic subtype, and mainly to the size of the HA.

Large subcapsular vessels are commonly found on macroscopic examination. On cut sections, the tumor is well delineated, sometimes encapsulated, and has a fleshy appearance; it ranges in color from white to brown (Fig. 79A.10). HA frequently displays heterogeneous areas of necrosis and hemorrhage. Histologically HA consists of a proliferation of benign hepatocytes arranged in a trabecular pattern; however, the normal liver architecture organization is absent (Chapter 78). Hepatocytes may have intracellular fat or increased glycogen. Malignant transformation to HCC may be difficult to assess, especially on biopsy specimen (Deneve et al, 2009; Stoot et al, 2010), but it is observed in 4% to 10% of cases in published series (Barthelemes & Tait, 2005; Bioulac-Sage, 2008; Deneve et al, 2009; Zucman-Rossi et al, 2006).

FIGURE 79A.10 Macroscopic aspect of hepatocellular adenoma. The lesion is well delineated, unencapsulated, and tan to yellow with some vascular changes.

Four subtypes of HA could be named according to genotype/phenotype classification (Bioulac-Sage et al, 2009). Group 1 includes HA with mutation in the hepatocyte nuclear factor (HNF)-1α gene (H-HA). Observed in approximately 35% to 40% of patients, almost exclusively in women and often with multiple HAs, this group corresponds to a histologically homogeneous group of tumors characterized by marked steatosis, no cytologic abnormalities, no inflammatory infiltrates, and a very low risk of complications. Group 2 includes HA with mutation of the β-catenin gene. Observed in approximately 10% of cases, mostly in men, this group is characterized by the presence of cytologic abnormalities with the greater risk of malignant transformation. Group 3 corresponds to telangiectatic/inflammatory HA. Observed in more than 50% of cases, these lesions usually occur in overweight women patients with inflammatory syndrome; tumors are characterized morphologically by the presence of inflammatory infiltrates, marked sinusoidal dilation or congestion, and numerous isolated or clustered arteries. The risk of complication in this group is high. The last group corresponds to HA that does not express any of the above-mentioned phenotypic or morphologic features. Besides the morphologic features associated with the different subtypes of HA, additional immunohistochemical markers have been described that provide significant assistance in the classification of HA, especially in biopsy specimens (Bioulac-Sage et al, 2009).

Clinical and Biological Data

Although patients with HA can come to medical attention with symptoms, the majority are asymptomatic, especially if they have small tumors (Trotter & Everson, 2001; Weimann et al, 2000; Bioulac-Sage et al, 2009; Dokmak et al, 2009). Tumors are discovered during diagnostic workup of elevated liver enzymes or during liver imaging monitoring in pregnancy or for other reasons. A large adenoma may cause a sensation of right upper quadrant fullness or discomfort.

Adenoma is of clinical importance because of its tendency to bleed spontaneously and result in hemorrhage and infarction in the tumor. The risk of spontaneous bleeding is likely to be between 20% and 40% (Barthelemes & Tait, 2005; Dokmak et al, 2009; Bioulac-Sage et al, 2009; Deneve et al, 2009). Although the risk of bleeding is increased in pregnant women and in those taking OC, this risk is quite exclusively observed in patients with lesions larger than 5 cm (Dokmak et al, 2009; Deneve et al, 2009). About 10% of patients are seen with acute, severe abdominal pain from intraperitoneal rupture and hemoperitoneum, which may be associated with hypovolemic shock. Hemorrhage results in acute pain and discomfort accompanied by anorexia, nausea, vomiting, and fever. Although tumor rupture with hemoperitoneum represents an alarming manifestation, hemodynamic instability is rare, except in patients treated with anticoagulation (Marini et al, 2002). The presence of sudden right upper quadrant pain with some respiratory manifestation leads some clinicians to erroneously suspect the diagnosis of pulmonary embolism; they then treat the patient with anticoagulant therapy, which can exacerbate the bleeding.

The risk of malignant transformation of HA in women is on the order of 5% (Barthelemes & Tait, 2005; Bioulac-Sage et al, 2009; Deneve et al, 2009; Dokmak et al, 2009; Stoot et al, 2010). No clinical or radiologic signs can predict preoperatively the diagnosis of degenerated HA; it is almost exclusively made on the pathologic specimen of resected HA. Malignancy displays well-differentiated HCC, and vascular extension or satellite nodules are exceptional. α-Fetoprotein (AFP) level is usually normal. Most cases of HCC develop at the site of the liver cell adenoma. The risk of malignancy is very high in men (50%), whatever the size of the tumor, and in women with a large HA (>8 cm) (Dokmak et al, 2009; Stoot et al, 2010; Farges et al, 2011). Moreover, HA with β-catenin activation carries a higher risk of malignant transformation (Bioulac-Sage et al, 2009; Farges et al, 2011). These cases of malignancy developed in HA should be differentiated from exceptional cases of multiple degenerated HA occurring in young women with symptomatic hepatomegaly associated with severe asthenia and high AFP level. The prognosis is poor, because surgical resection is not feasible, and liver transplantation is inevitably followed by rapid and fatal relapse of the disease.

In two thirds of cases, liver function tests are abnormal, including elevated cholestatic enzymes and mild elevation of transaminases (Dokmak et al, 2009). In case of malignancy, serum AFP is generally normal.

Imaging

For years, imaging features of HA were nonspecific and unlikely for FNH. Now, it is well established that the different molecular features correspond to distinct phenotypic features.

The key imaging feature of HNF-1α–inactivated HA is the presence of marked and diffuse fat within the lesion. Fat is responsible for lesion hyperechogenicity on US and strong hypoattenuation on unenhanced CT scan (see Chapter 16). Because of the fat content, the lesion does not enhance markedly and shows rapid washout on multiphasic examination. MR plays a crucial role in demonstrating the presence of diffuse fat (see Chapter 17). The striking finding is a diffuse and homogeneous signal dropout on chemical-shift T1-weighted sequences with a high specificity (Laumonier et al, 2008; Fig. 79A.11).

FIGURE 79A.11 hepatocyte nuclear factor-1α–inactivated hepatocellular adenoma. A, Ultrasound shows a hyperechoic liver lesion. B, Portal-venous phase computed tomography shows a lesion that exhibits washout. The lesion is isointense on fat-suppressed T2- and in-phase T1-weighted magnetic resonance (MR) imaging (C and D). E, Signal intensity strongly drops in opposed-phase T1-weighted MR imaging. Gadolinium-enhanced T1-weighted MR imaging obtained at the arterial and delayed phases (F and G) shows strong lesion enhancement on the arterial phase and washout on the delayed phase.

The key imaging feature of telangiectatic/inflammatory HA is the presence of telangiectatic components (Fig. 79A.12). The lesion is often hyperechoic at US but is also heterogeneous, and Doppler signals are commonly seen. Unlike other HAs, central arteries that could mimic FNH may be seen on contrast-enhanced US (Soussan et al, 2010). On unenhanced CT, telangiectatic/inflammatory HAs are hypoattenuating but often heterogeneous. The characteristic lesion behavior on multiphasic examination is a strong arterial enhancement and a persistent enhancement in the delayed phase (Laumonier et al, 2008). MR imaging is also very important because it shows a strong hyperintense signal on T2-weighted images. On T1-weighted sequences, lesion signal intensity is variable and is often hyperintense. This hyperintensity is not related to fat and persists on fat-suppressed and opposed-phase sequences (Attal et al, 2003; Lewin et al, 2006). Considering two imaging findings—a markedly hyperintense signal on T2-weighted images and persistent enhancement on the delayed phase—Laumonier and colleagues (2008) observed a positive predictive value for the diagnosis of telangiectatic/inflammatory hepatocellular adenoma of 88.5%, a negative predictive value of 84%, a sensitivity of 85.2%, and a specificity of 87.5%. Some of telangiectatic/inflammatory HAs may contain some fat deposition. The two other subtypes, β-catenin–activated and unclassified HA, are less characteristic on imaging. To note, some telangiectatic/inflammatory HA may display β-catenin activation and may therefore have imaging findings similar to classic telangiectatic/inflammatory HA. The others share findings of hepatocellular tumors, strong arterial enhancement with no delayed enhancement after gadolinium injection, and may have heterogeneous content.

FIGURE 79A.12 Telangiectatic/inflammatory hepatocellular adenomas. The two large lesions (one in the caudate and the other in the left liver lobe) are hyperintense on fat-suppressed T2-weighted and on in- and opposed-phase T1-weighted MR imaging (A and C). Gadolinium-enhanced T1-weighted magnetic resonance imaging obtained at the arterial and delayed phases (D and E) shows strong lesion enhancement on the arterial phase and persistent enhancement on the delayed phase. Other small lesions are seen in the right liver.

Treatment

The management of patients with HA should be mainly tailored according to the patient’s gender and the size of the tumor. The follow-up and treatment in some patients can also be influenced by the histologic classification of their HA.

Whatever the size, HA in men represents an indication for resection because of the high risk of malignancy. Whatever the number of HAs, women with small lesions less than 5 cm in diameter have a low risk of complication and could be safely observed after cessation of OC; however, the influence of the discontinuation of OC on the regression of HA is a subject of debate (Gordon et al, 1986), justifying serial imaging examinations in patients with HA managed conservatively. Indeed, long-term follow-up evaluation for nearly 20 years of patients with small residual HAs after surgery showed that HA remains stable or involved in more than 90% of cases (Dokmak et al, 2009). Regression and even disappearance of HAs seem to occur more frequently in older patients. Reappearance or increase in size occurs in 15% of patients, but serious complications are rarely described in this subgroup (Dokmak et al, 2009). It was usually recommended that pregnancy be avoided in patients with a history of HA (Deneve et al, 2009); however, in our experience, pregnancies in several women treated for HA were not associated with reappearance or enlargement of residual HA; this led us to not contraindicate pregnancy in patients with HA (Dokmak et al, 2009).

Resection of HA greater than 5 cm is indicated. The operative approach should be tailored to the location and the size of the tumor. A large resection margin is not needed, allowing complete resection through a laparoscopic approach when feasible (Descottes et al, 2003). In some patients with large bilobar tumors, resection could be performed in two steps. Tumors located in one lobe are resected during a first procedure, followed some weeks later by a second procedure to resect tumors located in the remnant liver. Small tumors need not be resected, and liver transplantation is no longer indicated in patients with multiple HAs (Dokmak et al, 2009). Malignant transformation is often discovered on the pathologic analysis of the resected specimen, because no radiologic features are specific, and AFP level is almost always normal. Vascular invasion is absent, and lymph nodes are not involved. Complete resection of malignant HA is a safe and efficient therapeutic option.

Although surgical resection remains the standard of care of HA, other treatment modalities such as arterial embolization (Kobayashi et al, 2009; Stoot et al, 2007), percutaneous RFA (Atwell et al, 2005), or combinations of both are performed more and more with encouraging results in recent publications. Such modes of treatment are now proposed for tumors around 5 cm in diameter, in case of recurrence after surgical resection, and if the estimated risk of malignancy is very low (see Chapter 83, Chapter 85A, Chapter 85B, Chapter 85C, Chapter 85D ).

Patients with ruptured HA should be treated electively. After stabilization of the patient and selective hepatic artery embolization, the patient can be observed for several months, until resorption of the hematoma surrounding the tumor (Terkivatan et al, 2001; Marini et al, 2002). The absorption of the hematoma surrounding the tumor allows an easier and parenchyma-sparing elective liver resection with a low risk of transfusion (Marini et al, 2002; Deneve et al, 2009). The involvement of these hemorrhagic HAs, which decrease dramatically in size and even disappear after embolization, may even bring into question the need for subsequent resection, because exceptional cases of hemorrhagic HA had a malignant component.

The impact of the genotype/phenotype classification on the management of HA remains unclear (Terkivatan & Ijzermans, 2009). We are in favor of preoperative biopsy in patients with large (>5 cm) steatotic HA, considering a conservative approach with observation if the HA belongs to group 1, with H-HA mutation. Patients with HA approximately 5 cm, which could be treated by transarterial embolization or RFA, should undergo a biopsy before employing a conservative approach, so that close follow-up or even systematic resection can be considered if the HA belongs to group 2 with β-catenin mutation.

Fatty Lesions of the Liver

Angiomyolipoma

Hepatic angiomyolipoma is a rare, benign mesenchymal tumor composed of smooth muscle cells, adipose tissue, and proliferating blood vessels in various combinations. It belongs to the group of tumors derived from the perivascular epithelioid cell, referred to as perivascular epithelial cell tumors or PEComas (Tsui et al, 1999). Hepatic angiomyolipoma occurs frequently in the kidney but rarely in liver. This rare tumor may occur as a solitary mass (Zhou et al, 2008; Zeng et al, 2010) or as an associated finding with tuberous sclerosis (Hooper et al, 1994), which is present in about 15% of cases. In this situation, angiomyolipomas are usually multiple.

Hepatic angiomyolipoma predominantly affects women between 30 and 50 years of age, and lesions are often larger than 5 cm in diameter (Yang et al, 2007), and it can increase in size (Zeng et al, 2010). This tumor was once considered benign, but malignant transformation has been reported (Zhou et al, 2008; Rouquie et al, 2006; Dalle et al, 2000). Patients usually have no symptoms, and liver tests are normal; most of these tumors are found incidentally on routine imaging studies. The accuracy of preoperative diagnosis is low as a result of variable imaging appearance because of the varying content of the three components and the rarity of the lesion. The fat component of angiomyolipoma varies between 10% and 90% (Hooper et al, 1994).

Typically, angiomyolipoma appears hyperechoic and hypoattenuated on unenhanced CT scans and markedly enhanced on the arterial phase with central vascular opacification (Fig. 79A.13). The presence of large central vessels, the so-called macroaneurisms, within the lesion is characteristic of angiomyolipoma. On contrast-enhanced US, the vast majority of angiomyolipomas enhance on the arterial phase without washout on the portal or delayed phase (Wang et al, 2010). MRI is also an important diagnostic technique that allows fat suppression and multiphase dynamic contrast-enhanced scanning. In general, MR shows a marked hypersignal in T1-weighted images, which drops on fat-suppressed sequences. However, the lesions have various imaging characteristics because of the different proportions of smooth muscle, fat, and vessels (Yan et al, 2002). The amount of fat may be too small to be detected (<5%), and some angiomyolipomas, especially those with a prominent epithelioid myoid component, may mimic hepatocellular lesions, mostly HA and HCC (Arblade et al, 1996). The accuracy of needle biopsy is reinforced by using the antibody anti–HMB-45, which stains the myoid component (Arblade et al, 1996); the positivity of this antibody in the cytoplasm of smooth cells is characteristic of angiomyolipoma (Arblade et al, 1996). When the diagnosis is established, careful observation with serial follow-up is recommended in asymptomatic patients with lesions less than 5 cm (Hoffman et al, 1997; Sawai et al, 1998). Because some degenerated cases have been reported in patients with large tumors, especially when major epithelioid content was present, liver resection is indicated in large (>5 cm) hepatic angiomyolipoma (Zeng et al, 2010; Fig. 79A.14).

FIGURE 79A.13 Typical angiomyolipoma. Precontrast computed tomography shows a heterogeneous lesion that contains fat.

FIGURE 79A.14 Large hepatic angiomyolipoma requiring resection for the risk of malignant components. Lesion heterogeneity is well demonstrated on magnetic resonance imaging.

Lipoma

Hepatic lipoma is a very rare liver tumor that can mimic angiomyolipoma. Lesions of hepatic lipoma are homogeneous and circumscribed, show fat attenuation on CT, and do not enhance after intravenous (IV) administration of contrast material. On MRI imaging, lipomas are hyperintense on T1-weighted images and moderately hyperintense on T2-weighted images. The key finding is the drop in signal intensity on fat-suppressed MR sequences (Horton et al, 1999). Unlike hepatocellular tumors that contain fat, lipomas do not drop in signal intensity on opposed-phase T1-weighted MR images. Microscopic analysis shows well-differentiated adipose tissue without any significant changes. There is no need to resect lipomas (Nakamura et al, 2009).

Bile Duct Adenoma

Bile duct adenoma, also called benign cholangioma, is a benign and asymptomatic mass that is typically discovered incidentally at imaging studies, surgery, or at autopsy (Kim et al, 2010). This rare benign lesion of the liver is usually a well-circumscribed, subcapsular nodule with a diameter of less than 1 cm consisting of a proliferation of noncystic biliary structures within a dense, fibrous stroma (Allaire et al, 1988). No relationship between this tumor and cholangiocarcinoma has been shown, and resection is unnecessary; its only clinical significance lies in the possible confusion with metastatic carcinoma during surgery (Hornick et al, 2005).

Biliary Hamartoma

This lesion, also known as a Von Meyenburg complex, is a development anomaly of small intrahepatic bile ducts composed of bile ductules, inflammatory cells, and fibrosis (Table 79A.1; Neri et al, 2004). The main practical problem raised by this tumor is for the pathologist, because its possible discovery during surgery for carcinoma of another abdominal organ leads the surgeon to perform a biopsy for frozen-section diagnosis (Guiu et al, 2009). The pathologist who is unaware of this rare entity may be puzzled and may be tempted to call the lesion metastatic carcinoma. Otherwise, hamartomas are easily recognized on heavily T2-weighted MR images and appear as multiple small lesions that are strongly hyperintense. The presentation is often mistaken for Caroli disease, but the lesions in biliary hamartoma do not communicate with bile ducts (Thomé-Noun et al, 2008). Treatment is not required.

Inflammatory Pseudotumors

Inflammatory pseudotumor of the liver (IPL) is a rare benign tumor that can mimic cholangiocarcinoma (Deng et al, 2010; see Chapter 48). Commonly found in the lung, IPL is a reactive fibroblastic proliferation infiltrated by polymorph inflammatory cells: plasmocytes, lymphocytes, and histiocytes. IPLs are also referred to as inflammatory myofibroblastic tumors, plasmocytic granuloma, histiocytoma, fibroxanthoma, pseudolymphoma, and necrotic tumor of the liver (Milias et al, 2009). They are more common in men than in women, are more frequently seen in the non-European population, and have an average age at presentation of 50 years (Goldsmith et al, 2009). The majority of patients with IPL typically experience vague constitutional symptoms such as fever (50%), abdominal pain (48%), weight loss (37%), and jaundice (Zamir et al, 1998; Goldsmith et al, 2009). Hematologic tests are generally normal, but one third of patients are seen with inflammatory syndrome. Liver function tests are abnormal in 15% of cases with mild elevations in cholestatic tests (alkaline phosphatase and GGT). The etiology of this pathology is not well known, but the predominantly inflammatory pattern and the associated systemic reaction suggest an underlying infectious agent (Koea et al, 2003) with microorganisms coming from the gut to the liver via the portal vein (Jover Díaz et al, 2009). This etiology can explain the response to antibiotics in some cases. Some authors have suggested an autoimmune etiology such as immunoglobulin G (IgG)-4 sclerosing cholangitis with histologic findings similar to autoimmune pancreatitis (Uchida et al, 2007), and in this case, treatment with steroids can be effective (Anthony, 1993; Kamisawa & Okamoto, 2008). In the tumoral hypothesis, authors suggest that some IPL may be of follicular dendritic cell origin (Shek et al, 1998).

Imaging studies often show diffuse and infiltrative large tumors, although multiple forms can be found (Jover Díaz et al, 2009). The majority of these lesions are located near the gallbladder or are related to the biliary tree, sometimes mimicking a malignant biliary stricture (Koea et al, 2003; Locke et al, 2005; Terada, 2010).

According to clinical and morphologic presentations, three different forms can be distinguished:

1) Inflammatory form: Revealed by abdominal pain and fever, inflammatory syndrome can be found in half of patients; weight loss, nausea, and vomiting may also occur but are rare. At imaging, the lesion is generally solitary, ill-defined, large, heterogeneous, and hypervascular. On MRI, the lesion is hypointense on T1-weighted sequences and isointense or hyperintense on T2-weighted sequences. At histology, spindle cells with a dense inflammatory and polymorphic population are seen, associated with anomalies of the portal branches in contact with the lesion (fibrotic portal endophlebitis).

2) Encapsulated form: Clinically, this lesion is small and is usually discovered fortuitously. Inflammatory syndrome is absent. At CT, the lesion is hypoattenuating and presents with a peripheral capsule, and no enhancement is depicted within the lesion. On MRI, the lesion is well limited, hypointense on T1 imaging, isointense on T2 imaging, and surrounded by a capsule that enhances on delayed phase. This encapsulated form resembles a lesion called a solitary necrotic nodule of the liver (Abbey-Toby et al, 2003), and it can be a chronic sequela of an inflammatory process that has partially healed, circumscribed by a fibrotic capsule.

3) Infiltrating periportal form: Frequently revealed by jaundice (Venkataraman et al, 2003), this is a poorly demarcated lesion with periportal infiltration on imaging. The lesion is hypointense on T1-weighted sequences and moderately hyperintense on T2-weighted sequences with dilated bile ducts (Venkataraman et al, 2003). A progressive enhancement is seen after injection of gadolinium chelates. Lymphadenopathy can be observed along the hepatoduodenal ligament and in the retroperitoneum, mimicking cholangiocarcinoma (Fig. 79A.15; Chirica et al, 2005). On histology, periportal inflammation is associated with destruction of bile ducts and intrahepatic extension of inflammatory processes.

FIGURE 79A.15 Inflammatory pseudotumor of the liver. A, Solid and necrotic appearance on post–gadolinium T1-weighted magnetic resonance imaging sequence. B, Macroscopic analysis shows a subcapsular, well-limited, trefoil-shaped white lesion corresponding to necrosis. A thin, fibrous capsule is observed at the border of the lesion. C, Aggressive pattern mimicking cholangiocarcinoma on computed tomography.

On gross sections, IPL is tan, usually unencapsulated, and may show indistinct borders with the surrounding parenchyma. When the diagnosis is suspected, a liver biopsy is often necessary to differentiate IPL from other tumors.

The optimal management has not been well established, with many types of treatment described, from simple observation to surgical resection and even liver transplantation (Milias et al, 2009). In the literature, most patients have been surgically treated, because the diagnosis was not made preoperatively because of the possible destructive nature of IPL, or because its malignant potential leads some authors to propose liver resection (Li et al, 1989). The outcome of patients treated surgically is very good (Goldsmith et al, 2009), but IPL can be associated with some risk, especially IPL that occurs as hilar lesions, necessitating major liver resection. Recurrence can be observed after resection (Lopez-Tomassetti Fernandez et al, 2006). However, IPLs are benign lesions with no malignant potential; once the diagnosis has been made, medical treatment by antibiotics, steroids (Maze et al, 1999), or observation can be undertaken with very good results. A number of reports exist that suggest the natural history of these lesions is of spontaneous complete resolution or regression (Levy et al, 2001; Koea et al, 2003; Goldsmith et al, 2009); therefore IPL can be safely managed nonoperatively.

Rare Tumors and Pseudotumors

Hepatic Pseudolesions

The development of imaging techniques using thin slices and multiphasic study permits the discovery of many intrahepatic anomalies, especially after injection of contrast material on CT scan and MRI; some anomalies are not really liver lesions but can mimic liver tumors.

1) Perfusion disorders: These anomalies are the result of hyperarterialization of a liver segment as a result of decreased or absent portal vein flow. These anomalies are seen on CT after injection of contrast; they predominate on arterial or portal phase images and disappear or attenuate on the delayed phase. These perfusion disorders result from portal obstruction, compression, or arterioportal shunt (Tamura et al, 1997). In general, they have typical straight borders that correspond to segmental or subsegmental locations. The diagnosis can be more difficult in patients with small peripheral or central “pseudonodular” lesions, such as in cirrhotic patients as a result of arterioportal shunts. In patients with hepatic vein obstruction, these abnormalities are not systematized (mosaic form) because of the rapid development of interhepatic venous shunts (Vilgrain et al, 2007).

2) Localized parenchymal compression: This can display aspects of pseudolesion because of impaired enhancement in the compressed territory in the portal phase but without hyperarterialization on the arterial phase. In this case, the pseudolesion has no vascular topography and can be exacerbated by deep inspiration with compression by the ribs and diaphragm (Vilgrain et al, 2007).

3) Confluent fibrosis: This lesion can also mimic a tumor, and it is mainly observed in chronic liver disease; it corresponds to parenchymal extinction and is located in segments IV and VIII with capsular retraction (Vilgrain et al, 2007).

4) Radiation: Pseudolesion of liver parenchyma can be observed after radiation exposure. Previous history of radiation therapy and the appearance of straight borders without anatomic distribution are highly suggestive of this etiology. As a result of associated fibrosis, atrophy of the involved segment can be observed with compensatory hypertrophy (Vilgrain et al, 2007).

Peliosis

Peliosis is a rare condition characterized by multiple, small, blood-filled pools in liver parenchyma that vary from 1 mm to several centimeters without lobular systematization. This lesion results from focal rupture of sinusoidal walls and is mostly observed in adult patients after systemic chemotherapy for colorectal liver metastases using oxaliplatin (Rubbia-Brandt et al, 2010). It can also be associated with androgenic anabolic steroids (Tsirigotis et al, 2007), OC use (Gutiérrez Santiago et al, 2007), HIV infection (Radin & Kanel, 1991), or severe tuberculosis and malignancies such as Hodgkin’s lymphoma (Kleger et al, 2009).

Imaging findings often mimic those of true tumors, because lesions are well limited and strongly hyperintense on T2- weighted MR images, and they enhance with arterial phase CT or MR. The persistent contrast uptake within the lesion is due to the blood-pooled condition (Verswijvel et al, 2003). This lesion can lead to extensive fibrosis resulting from parenchymal destruction and collapse (Cavalcanti et al, 1994), which is revealed on histology.

In general, this lesion is asymptomatic, but severe complications such as liver rupture, subsequent bleeding (Choi et al, 2009; Wang et al, 2001; Fidelman et al, 2002), and hepatopulmonary syndrome have been reported (Kallel et al, 2008). Treatment includes withdrawal of the possible causative agents, which can lead to regression of the disease.

Focal Fatty Changes

Hepatic steatosis is generally a diffuse process; however, heterogeneous focal fat distribution seen as spared liver areas, without steatosis, or areas that are fattier than the rest of liver parenchyma may also be present (Wanless, 2002). Although the pathogenesis is not well understood, regional hypoxia of hepatic tissue is thought to play a role (Zeppa et al, 2002). The majority of patients have underlying disease such as diabetes, obesity, hepatitis C, nonalcoholic steatohepatitis, and malnutrition; lesions are often discovered incidentally on imaging studies. Focal steatosis is mainly localized in segment IV, around the gallbladder and the round ligament (Vilgrain et al, 2007). A nodular aspect can mimic liver metastasis (Tom, et al 2004; Rubaltelli et al, 2002).

Nodular Regenerative Hyperplasia

Nodular regenerative hyperplasia (NRH) is a relatively rare, benign, diffuse micronodular transformation of the liver that has been referred to by many names in the literature, including nodular transformation, noncirrhotic nodulation, and partial nodular transformation. It is a distinct disease entity characterized by diffuse involvement of the liver with nodules composed of hyperplastic hepatocytes, and it should not be confused with the regenerative nodules of cirrhosis or FNH (Federle & Brancatelli, 2001).

The pathogenesis of NRH is not well known, but one of the proposed theories hypothesizes that a primary vascular process leads to obliteration of portal vein, which in turn induces ischemia, atrophy of hepatocytes in the central zone, and the proliferation of hepatocytes (Al-Mukhaizeem et al, 2004). The other theory proposes that a preneoplastic process leads to NRH in association with the reported high prevalence of hepatocyte dysplasia (20% to 42%) and HCC formed in livers of patients with NRH (Nzeako et al, 1996; Dogan et al, 2003). The prevalence of NRH was reported to be around 2% (Biecker et al, 2003).

NRH was classically associated with a wide spectrum of systemic diseases, processes, and drugs; these include myeloproliferative and lymphoproliferative disorders, chronic vascular disorders, rheumatologic and collagen vascular diseases (rheumatoid arthritis, Felty syndrome, polyarteritis nodosa, amyloidosis, and primary biliary cirrhosis) (Morris et al, 2010), primary hypogammaglobulinemia (Malamut et al, 2008), HIV infection (Tateo et al, 2008; Bihl et al 2010), hereditary hemorrhagic telangiectasia (Brenard et al, 2010), hepatoportal sclerosis, congenital absence of the portal vein (Peker et al, 2009), portal veinopathy (Hillaire et al, 2002), malignant disease (Al-Hamoudi et al, 2009), and after solid organ transplantation (Devarbhavi et al, 2007). NRH is also associated with the use of drugs such as steroids (Mortelé & Ros, 2002), azathioprine for inflammatory bowel disease (Vernier-Massouille et al, 2007; Seksik et al, 2010), and chemotherapeutic agents. This lesion is considered the most severe induced histologic liver lesion in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases, with an incidence up to 24% (Hubert et al, 2007; Wicherts et al, 2010; Rubbia-Brandt et al, 2010); it can be associated with high postoperative morbidity in cases of major liver resection (see Chapter 65).

Clinically, NRH usually causes no symptoms, and lesions are discovered incidentally, mainly on liver biopsy. More than two thirds of reported patients had abnormal liver test results, but liver function was preserved (Arvanitaki & Adler, 2001; Morris et al, 2010); the risk of liver insufficiency leading to liver transplantation is rare (Tateo et al, 2008). The main clinical presentation is portal hypertension, observed in 30% of patients, with subsequent esophageal varices, splenomegaly, and ascites (Arvanitaki & Adler, 2001; Dogan et al, 2003; Morris et al, 2010). Fatal bleeding from varices has been observed (Morris et al, 2010), but the risk of transformation to HCC is rare (Nzeako et al, 1996; Kataoka et al, 2006). Because of these clinical features, the diagnosis of NRH should be considered in patients with clinical signs of portal hypertension and normal or mildly abnormal liver function test results, in whom other causes of portal hypertension have been excluded.

Imaging findings are not specific for NRH. On imaging, three presentations are possible: first, liver imaging is unremarkable; second, imaging shows signs of noncirrhotic portal hypertension without any liver nodules, because the nodules are typically very small; third, NRH appears as multiple liver nodules with or without portal hypertension. In most cases, imaging shows normal hepatic parenchyma. When nodules are seen, they have a variable enhancement, and they are hyperintense on T1-weighted images and isointense or hypointense to normal liver on T2-weighted images (Clouet et al, 1999; Mortelé & Ros, 2002; Casillas et al, 1997; Horita et al, 2002). Contrary to FNH, the central scar is lacking. Differences between these two lesions are mainly based on the presence of multiple small nodules, signs of portal hypertension, and clinical context. Accurate diagnosis should be confirmed with histologic examination prior to treatment. In highly suspicious cases, percutaneous needle biopsy can establish the diagnosis (Hubert et al, 2007). In doubtful cases with negative percutaneous biopsy, open biopsy is indicated to obtain an adequate sample of hepatic tissue, because percutaneous needle biopsies may give falsely normal results (Biecker et al, 2003).

Management depends on the clinical symptoms. In asymptomatic patients, no treatment is recommended. The effect of the withdrawal or specific treatment of the possible causative disease or agents on the course of this entity is not well known. In patients with complications of portal hypertension, appropriate management includes drug therapy, endoscopic therapy, transjugular intrahepatic shunt, or portacaval shunt if necessary (Biecker et al, 2003). Rarely, patients may progress to liver failure and may ultimately require liver transplantation (Trotter & Everson, 2001; Tateo, 2008). Because of the high postoperative morbidity with major liver resection in cases of NRH associated with oxaliplatin-based chemotherapy (Wicherts et al, 2010), it is recommended in this group of patients, who underwent many cycles of preoperative chemotherapy, to perform a liver biopsy—either systematically or in case of portal hypertension—to search for NRH. If NRH is diagnosed, major liver resection should be avoided or prepared for by portal vein embolization.

FNH-like Lesions

FNH-like lesions histopathologically resemble FNH but are seen in patients with liver disease or liver vessel abnormalities. The most common causes of liver diseases responsible for the development of FNH-like lesions are Budd-Chiari syndrome (Cazals-Hatem et al, 2003), hereditary hemorrhagic telangiectasia (Gincul et al, 2008), and congenital hepatic fibrosis (Vilgrain et al, 1999; Zeitoun et al, 2004; Buscarini et al, 2004). All these diseases induce severe liver flow alterations with decreased portal vein blood flow and marked increased hepatic artery blood flow (Kim et al, 2004; Bureau et al, 2004). FNH-like lesions may be a hepatic response to increased arterial inflow. Similarly, FNH-like lesions have been reported in patients with cavernous transformation of the portal vein (Bureau et al, 2004); imaging findings of FNH-like lesions are similar to the FNH that arises on normal liver, and they may contain a central scar. Because the liver signal is abnormal in Budd-Chiari syndrome, the FNH-like lesions are mostly hyperintense on T1- and hypointense on T2-weighted images; however, they still enhance strongly at the arterial phase. Unlike most FNH, they may become more numerous and grow over time.