1 Benign Liver Lesions RONALD S. CHAMBERLAIN, MD, MPA DOUGLAS DECORATO, MD WILLIAM R. JARNAGIN, MD Benign liver lesions are often found serendipitously on evaluation of unrelated conditions whereas some patients with known hepatic malignancies will have coexistent benign hepatic lesions. Symptoms related to these lesions will bring them to attention in some patients; in rare cases, the first manifestation will be a catastrophic event such as spontaneous rupture and hemorrhage. In most instances, 83 percent of liver lesions identified serendipitously are benign.1–2 In nearly all of these instances, the surgeon will be called upon to make decisions regarding further work-up and therapeutic options. The appropriate treatment of benign liver lesions requires a thorough knowledge of their natural history and mature clinical judgment. Benign liver lesions may be solid or cystic and may arise from hepatocellular or biliary epithelial cells or mesenchymal cells. A number of miscellaneous disorders that may masquerade as liver tumors have also been described (Table 1–1). The relative frequency of different types of hepatic tumors is difficult to determine, but more than 50 percent of incidentally discovered hepatic lesions are hemangiomas or focal nodular hyperplasias (FNH) (Table 1–2), and simple cysts account for another large proportion. Several other benign liver tumors have been described, but nearly all are extraordinarily uncommon and are unlikely to be encountered in general practice. While patients with symptoms directly attributable to a benign hepatobiliary tumor should be considered for resection, the majority are asymptomatic, and resection or other interventions are seldom warranted. However, certain benign tumors are associated with life-threatening complications (eg, hemorrhage) or malignant transformation and should be resected even in the absence of symptoms. Establishing a firm diagnosis relies heavily on the radiographic appearance of these lesions, which in turn requires highquality imaging studies and experienced radiologists. Advances in imaging technology have greatly improved the clinician’s ability to differentiate among the various benign lesions, but diagnostic uncertainty remains a persistent problem. Indeed, a common indication for resecting “benign” liver tumors is the inability to exclude a malignancy or to exclude a Table 1–1. BENIGN LIVER TUMORS Cell of Origin Epithelial Hepatocellular Cholangiocellular Other Mesenchymal Endothelial Tumor Focal nodular hyperplasia Hepatocellular adenoma Regenerative nodule Biliary adenoma Biliary cystadenoma Simple cyst Epitheliod leiomyoma Hemangioma Hemangioendothelioma (adult, infantile) Mesothelial Solitary fibrous tumor (benign mesothelioma, or fibroma) Adipocyte Lipoma Myelolipoma Angiomyolipoma Other Tumor Pseudotumor Biliary hamartoma Focal fatty infiltration Adrenal neoplasm Inflammatory pseudotumor 1 2 HEPATOBILIARY CANCER Table 1–2. DIAGNOSTIC FREQUENCY OF INCIDENTAL LIVER TUMORS Tumor Relative Frequency (%) Hemangioma Focal nodular hyperplasia Metastatic tumor Hepatocellular adenoma Focal fatty infiltration Hepatocellular carcinoma Extrahepatic process (abscess, adrenal tumor) Other benign hepatic process 52 11 11 8 8 6 3 1 Reprinted with permission from Little JM. Benign tumors of the liver. In: Terblanche J, editor. Hepatobiliary malignancies: its multidisciplinary management. London: Edward Arnold; 1994. p. 235–49. benign lesion that should be resected (eg, liver cell adenoma). In our experience with over 155 patients with benign hepatic tumors, inability to exclude malignancy was the indication for resection in 46 percent of patients (Table 1–3).3 Risk of malignant transformation or rupture and a tumor that has ruptured are less common indications for surgical intervention. Patients with newly diagnosed hepatic lesions should be approached systematically and all information reviewed critically to avoid premature and erroneous diagnoses. A careful history may provide some useful information, such as information about the patient’s previous or current use of oral contraceptives. In patients with symptoms possibly related to the tumor, specific details are important since such symptoms may be arising from a coexistent condition, such as peptic ulcer disease or cholecystitis, and may be entirely unrelated to the liver lesion. Physical examination is typically unrevealing unless the tumor is quite large; in this setting, pain or abdominal discomfort is often present. Laboratory tests, including liver function tests, are gener- ally normal in patients with asymptomatic liver tumors and are therefore usually not helpful for establishing the diagnosis. Serum tumor markers such as α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and CA-19-9 are almost never elevated in benign liver tumors. Any previous computed tomography (CT) scans should be obtained for comparison since benign tumors frequently evolve over many years. Radiologic studies are critical in evaluating benign hepatic processes and often provide a precise diagnosis based on the characteristic appearance of the lesion. In most situations, multiple studies providing complementary data are required (Table 1–4). Ultrasonography (US) is the most common initial study and effectively differentiates cystic and solid lesions. Contrast-enhanced CT with precontrast images, arterial dominant-phase images, and delayed imaging (a so-called triple-phase CT scan) may provide precise diagnostic information while also determining the location and extent of the lesion. Magnetic resonance imaging (MRI) may be the most useful imaging modality for differentiating between benign and malignant tumors and also for distinguishing among the various types of benign solid tumors. Although angiography was previously a common imaging technique, it has generally been replaced by noninvasive imaging modalities. Angiography occasionally may be useful for distinguishing hepatic adenoma from FNH, which is an important distinction since treatment recommendations are different. In our experience, the majority of benign hepatobiliary lesions can be diagnosed accurately without invasive studies. Strategies for evaluating patients with incidentally discovered hepatic lesions are described in detail in Chapter 2. Table 1–3. EXPERIENCE IN MANAGING PATIENTS WITH BENIGN LIVER TUMORS BETWEEN 1992 AND 1999* Diagnosis Hemangioma FNH Adenoma Cystadenoma Total Patients Mean Age 97 42 12 4 155 52 38 34 45 47 Resected (%) 39 18 8 3 68 (40) (43) (67) (75) (44) ? Malignant (%)† 13 11 6 1 31 (13) (25) (50) (25) (46) Symptoms (%)† 48 18 8 2 36 (49) (44) (67) (50) (53) *Experience at Memorial Sloan-Kettering Cancer Center. † The percentage of the total number submitted to resection. FNH = focal nodular hyperplasia. Reprinted with permission from Charny CK, Jarnagin WR, Schwartz LH, et al. Benign liver tumors: radiologic and surgical management. Br J Surg 2000. [In press] Benign Liver Lesions 3 Table 1–4. RADIOGRAPHIC IMAGING OF COMMON BENIGN LIVER TUMORS Imaging Modality Tumor US CT MRI Tc-99m RBC Scan Tc-99m SC Scan Hemangioma Hyperechoic Well demarcated Increased vascular flow Central venous pooling Delayed central filling Very sensitive Isodense on noncontrast scan Contrast-enhanced scan shows delayed nodular enhancement from the periphery of the lesion Very sensitive Isodense on T1 Highly specific Very sensitive Not indicated Hyperdense on T2 Gadolinium-enhanced scan has similar findings to contrast CT Blood pooling of radionucleotide Nonspecific ?Hyperechoic Isodense on noncontrast CT May be well demarcated on contrast CT, with central scar—often isodense Isodense on T1 and T2 Early hyperdense appearance after gadolinium Not indicated Nonspecific Hyperechoic Nonspecific Hyperechoic Nonspecific Focal nodular hyperplasia Hepatic adenoma Nonspecific ?Hyperechoic Increased blood flow on duplex scanning Takes up Tc-99 SC Contains bile ducts and Kupffer’s cells Nonspecific Generally does not take up Tc-99 SC because of lack of bile ducts and Kupffer’s cells Nonspecific CT = computed tomography; MRI = magnetic resonance imaging; T1 = T1-weighted MRI; T2 = T2-weighted MRI; Tc-99m RBC = technetium-99m-labeled red blood cell; Tc-99m SC = technetium-99m sulfur colloid; US = ultrasonography. SOLID TUMORS Hemangiomas Hemangiomas, the most common benign solid tumors of the liver (see Table 1–2),4–6 occur in two variants, capillary and cavernous. Capillary hemangiomas are far more common but are clinically insignificant. They tend to be small hypervascular lesions (< 2 cm) encountered at the time of laparotomy and may be the source of considerable diagnostic uncertainty. Establishing the diagnosis and excluding a malignancy are all that is required. Cavernous hemangiomas are more relevant clinically because of the potential for complications and associated symptoms.4,7,8 Cavernous hemangiomas may vary in size from less than 1 cm to 30 to 40 cm or more (“giant hemangiomas”)9 (Fig. 1–1). The size of the lesion appears to correlate with symptoms, and it is the large pedunculated tumors that are most commonly symptomatic and that are encountered at operation.4,7,10 These tumors are usually sharply demarcated from surrounding liver tissue and may be partly necrotic or fibrotic (Fig. 1–2). In some instances, infarct of the hemangioma may cause fibrosis or calcification, making it difficult to distinguish from other benign or malignant tumors. The acute nature of some symptoms related to hemangiomas may not be related to increase in size but rather to thrombosis and infarction of part of the tumor. The incidence of cavernous hemangiomas has been documented to be as high as 7 percent in one autopsy series,5 and these tumors occur more commonly in adults than in children.4 Their etiology is unclear, but cavernous hemangiomas appear to represent progressive growth of congenital lesions. The incidence has been reported as between 1.3 to 6 times higher in women than in men,4,7,8 prompting some researchers to suggest that sex hormones are somehow involved in stimulating growth and producing symptoms. However, sex hormones have not been etiologically linked to the development of hemangioma, and autopsy series have reported a nearly equal sex incidence.10 Pathology Hemangiomas are typically well demarcated and distinct from the surrounding hepatic parenchyma. The sharp interface between the tumor and the normal liver parenchyma permits surgical enucleation in most cases. However, not all of these tumors can 4 HEPATOBILIARY CANCER be enucleated, and it is the histologic features of the tumor-liver interface that defines how easily a parenchymal-sparing technique may be utilized. In our experience, over half of these lesions were amenable to enucleation while the remainder required formal hepatic resection.3 Histologically, four variants of the interface between the hemangioma and normal liver have been described. A fibrolamellar interface, characterized by a capsule-like fibrous ring of variable thickness, is most common. In this situation, blood vessels either traverse the fibrous lamella or parallel the A B Figure 1–1. Intraoperative views of a giant hemangioma during enucleation. A, Intraoperative view of a giant hemangioma involving the left liver. The tumor is held upward to reveal the porta hepatis. A loop (blue) has been passed around the left hepatic artery, and the gallbladder is visible between the tumor and the normal-appearing right liver. B, A different view, showing the full extent of the tumor. Benign Liver Lesions periphery of the hemangioma. The normal hepatic parenchyma may be atrophic, and a plane between the hemangioma and the normal liver tissue can be well defined. A second variant, the “interdigiting” pattern, is marked by the lack of a fibrous lamella surrounding the hemangioma, the lamella being replaced by an ill-defined plane between the normal liver tissue and the vascular channels of the hemangioma. This tumor can be quite hazardous to remove 5 without a formal resection. Unfortunately, the presence of this variant is usually only manifest after an initial attempt at enucleation results in unanticipated bleeding. The other two histologic variants of the hemangioma-liver interface are a compression interface, in which the periphery of the tumor is well demarcated in the absence of a fibrous lamella and in which the surrounding liver parenchyma demonstrates marked atrophy, and an irregular or spongy A B Figure 1–2. Cavernous hemangioma. A, The gross appearance of a cavernous hemangioma on cut section. B, A sponge-like architecture with venous lakes is the characteristic histologic appearance. 6 HEPATOBILIARY CANCER interface characterized by an ill-defined margin. The latter variant may appear to be intercalated into the surrounding liver parenchyma at various points, making enucleation difficult. Despite the invasive appearance of this histologic variant, hemangiomas are not premalignant lesions. Generally, the histologic diagnosis of a cavernous hemangioma is straightforward (see Fig. 1–2). Rarely, an atypical hemangioma may be mistaken for other liver conditions including peliosis hepatis, hemorrhagic telangiectasia (Osler-WeberRendu disease), hemangioendothelioma, and other malignant vascular tumors. Appropriate correlation with the patient’s age, sex, medication history, and clinical condition normally resolves such diagnostic dilemmas. Although the diagnosis of cavernous hemangioma can be made on histologic review, a percutaneous biopsy should be avoided as this may result in uncontrollable hemorrhage. Symptomatic, large, or indeterminate lesions should be managed surgically. Clinical Presentation and Evaluation The true incidence of symptoms caused by hemangiomas is unclear but is probably lower than that reported in most surgical series as the presence of symptoms is a major indication for resection. In our experience, approximately half of patients presented with symptoms.3 Thus, many patients are asymptomatic, and the tumors are discovered incidentally when a radiologic investigation or laparotomy is performed for other indications. According to literature reports, the majority of hemangiomas that come to medical attention are found in young women (mean age of 45 years). The most commonly reported symptoms associated with hemangioma are abdominal pain, increasing abdominal girth, early satiety, nausea, vomiting, and/or prolonged fever. Rare presentations have been reported, including obstructive jaundice, biliary colic, torsion of a pedunculated lesion, gastric obstruction, pulmonary embolism, and spontaneous rupture with intraperitoneal hemorrhage.4,7,8 Severe thrombocytopenia and the development of a consumptive coagulopathy have also been associated with cavernous hemangioma of the liver. Although the term Kasabach-Merritt syndrome was initially used to describe thrombocytopenia and afibrinogenemia associated with hemangiomas of the skin and spleen in infants, this term is now often used to describe similar coagulopathies in children and adults (rare) with hemangiomas of the liver.11 Symptoms from hepatic hemangioma are generally attributed to rapid expansion of the tumor or to thrombosis and infarction that result in stretching or inflammation of Glisson’s capsule. A very large hemangioma may occasionally present as a palpable nontender mass in the right upper quadrant; more often, physical examination reveals only a vague upper abdominal tenderness with no mass. It may be possible to detect a bruit over the liver if the hemangioma is large, but this is not pathognomonic. In rare cases, a hemangioma may rupture, resulting in a hemoperitoneum and shock requiring emergency treatment.4,12,13 In many cases, the symptom complex associated with hemangioma is nonspecific, and a diagnostic investigation is begun. Although hemangiomas may grow to huge proportions (see Fig. 1–1), they typically do not compromise normal liver function, and unless an acute complication such as thrombosis or intraparenchymal hemorrhage has occurred, all serologic tests are generally normal. The initial radiologic evaluation of a suspected hemangioma is often dictated by the clinical presentation. In many situations, hemangiomas are discovered incidentally on a study performed for other reasons, and the degree of diagnostic certainty provided by this study may obviate the need for additional testing. If a patient presents with dull nonspecific right-upper-quadrant complaints, ultrasonography (US) is typically the first study performed. The quality of the US study, unlike that of most other imaging modalities, depends on the operator rather than on the technology. Hemangiomas appear on US imaging as hyperechoic masses clearly demarcated from the surrounding liver; the addition of duplex US can provide further information on peripheral blood flow and central pooling of venous blood. In spite of the skill of many ultrasonographers, US imaging cannot definitively exclude other diagnostic possibilities, and a CT scan is often the next study requested. Hemangiomas are hypodense on noncontrast abdominal CT scans and have a characteristic pattern of Benign Liver Lesions irregular peripheral nodular enhancement after the initial injection of contrast material. Delayed CT scanning (several minutes after contrast injection) demonstrates central filling of the hypodense lesion; the filling persists for some time and is felt to be diagnostic14,15 (Fig. 1–3). High-quality dynamic CT may provide a conclusive diagnosis in many cases. However, MRI is considered to be the most sensitive and the most specific diagnostic study. A T2weighted image demonstrates a characteristic hyperintense pattern (Fig. 1–4). The administration of gadolinium demonstrates similar peripheral nodular enhancement with delayed central filling as was described with CT (Fig. 1–5). Although the cost of MRI was previously prohibitive, it has considerably decreased, and in our opinion, MRI with gadolinium is the preferred study for the evaluation of most hepatic lesions. Scintigraphy with technetium-99m-labeled red blood cells (Tc-99m RBC scan) has historically been considered the gold standard for diagnostic evaluation of hemangiomas14,16 (Fig. 1–6). However, advances in diagnostic axial imaging techniques such as MRI and CT, combined with the additional staging information these studies offer with regard to assessing the remainder of the abdomen, have led to less reliance on red blood cell (RBC) scintigra- 7 phy. In our opinion, RBC scintigraphy can be misleading, and we do not use it routinely. Selective hepatic angiography demonstrates a characteristic neovascularity to these lesions that is often described as “corkscrewing.” Rapid filling of the central portion of hemangiomas from the neovascular periphery yields a “cotton wool” appearance to these lesions (Fig. 1–7). Despite the use of angiography in characterizing hemangiomas, the diagnostic yield of less invasive studies is much greater, and arteriography is seldom warranted. At many institutions, MRI is not readily available or is otherwise prohibitive; in this situation, dynamic CT may be a good substitute.17 Given the risk of low but nonetheless significant bleeding, fine-needle aspiration (FNA) should be avoided if hemangioma remains a diagnostic possibility, in which case an MRI should be performed. As discussed elsewhere, MRI may in fact be sufficient to provide a conclusive diagnosis and thus obviate the need for a biopsy. While needle biopsy may be necessary in a few patients when imaging studies are inconclusive, it should be used sparingly. Furthermore, it must be stressed that over-reliance on negative or inconclusive FNA results, particularly if malignancy cannot be excluded, is ill-advised.14–18 As a rule, a biopsy is unnecessary unless a histologic diagnosis will alter planned therapy. Figure 1–3. Hemangioma. Computed tomography image of the liver after contrast administration demonstrates a mass with peripheral nodular enhancement (arrow). This pattern of enhancement is diagnostic of a hemangioma. 8 HEPATOBILIARY CANCER Treatment In nearly all cases of asymptomatic hemangiomas, observation is the most appropriate treatment. To date, there has been no documented case in which a hemangioma has spontaneously ruptured while being observed. Trastek and colleagues observed 36 patients with cavernous hemangiomas for up to 15 years (mean, 5.5 years).15 One adult patient was treated with external beam radiation and showed marked reduction in the size of the lesion. The other 33 patients were observed, with no other treatment. There were no spontaneous ruptures and—most important—no changes in symptoms over the course of the follow-up. In 4 patients, the size of the hemangioma increased; in 3 patients, the size decreased. Foster observed 44 patients with hemangiomas for a period ranging from 2 months to 12 years. There were no reports of rupture, death, or changes in clinical symptoms in their series.16 In the absence of clinical symptoms, careful observation is the recommendation of most experienced liver surgeons. In symptomatic patients, some form of treatment is frequently required. Patients with disabling pain, pressure symptoms, or acute symptoms related to hemangioma should undergo resection.19,20 In general, the likelihood of symptoms increases with tumor size. In our series, tumors in symptomatic patients had a mean size of 10 ± 8 cm versus 6.8 ± 5.8 cm for tumors in asymptomatic patients Figure 1–4. Hemangioma seen on magnetic resonance imaging (MRI) of the liver, demonstrating a mass in hepatic segment III. The mass is hyperintense on T2-weighted images (arrow). This mass maintained increased signal on the heavily T2-weighted images and demonstrated peripheral nodular enhancement (see Fig. 1–5) consistent with a hemangioma. (p = .03), and patients with tumors ≥ 10 cm were much more likely to report symptoms.3 It must be emphasized, however, that vague symptoms or symptoms inconsistent with the lesion should be thoroughly investigated to exclude other causes. Resection is also indicated when there is diagnostic uncertainty or the possibility of a malignancy. On the other hand, resection solely to avoid the risk of rupture and intra-abdominal hemorrhage is not indicated even for large hemangiomas. Although Shumacker reported that the estimated lifetime risk of rupture for a hemangioma is 19.7 percent, this is inconsistent with other published reports.19 Henson and colleagues observed 35 patients with hepatic hemangiomata for 10 years and reported no ruptures,10 and Trastek and colleagues reported no spontaneous hemorrhage among 49 patients with hepatic hemangiomas observed for a mean of 5.5 years.15 A review of the literature reveals only 21 cases of spontaneous rupture reported since 1898. Although cautious observation seems the most appropriate initial therapy for most patients, this does not equate to a recommendation in favor of therapeutic nihilism in the management of all hepatic hemangiomas. Patients with large hemangiomas should be carefully observed, and if a change in size or symptoms occurs either abruptly or over time, reconsideration of surgical resection is appropriate. The location of the hemangioma often dictates the operative approach, and full assessment of the Benign Liver Lesions tumor’s extent is critical. While most lesions are amenable to enucleation, a formal anatomic resection may be the safest approach in some cases. Large central lesions that abut the portal vein, hepatic outflow tract, or inferior vena cava over a long distance may pose a prohibitive surgical risk even in experienced hands. In these situations, alternative therapeutic modalities might be considered. Although radiotherapy has been used successfully to treat symptoms and induce involution of hemangioma in some situations, the rarity of this occurrence makes the results difficult to interpret. On the whole, data justifying the use of radiotherapy for hemangioma are scant. However, radiotherapy seems a reasonable 9 alternative approach to the treatment of symptomatic hemangioma if surgical therapy is not possible.21 Resection for hemangioma should be approached as would any other hepatic resection. The surgeon should have extensive knowledge of the anatomy and vascular supply of the liver and should be prepared to perform a major resection if necessary. Wide exposure and full mobilization of the liver are required. Unlike a malignant lesion, a hemangioma need not be resected with a margin of normal tissue around the tumor. Enucleation is therefore the most appropriate treatment for most hemangiomas since it will remove essentially no functional parenchyma. Ligation and division of the principal hepatic arterial inflow Figure 1–5. Hemangioma seen on magnetic resonance imaging (MRI). A, T1-weighted images of the same patient studied in Fig. 1–4 demonstrate the mass (arrow) to be hypointense with respect to hepatic parenchyma. B, Images after gadolinium enhancement demonstrate peripheral nodular enhancement (arrow) (as also seen on computed tomography images), characteristic of a hemangioma. A B 10 HEPATOBILIARY CANCER parenchyma. As the dissection proceeds, pedicle and hepatic venous branches extending from the tumor to the liver parenchyma will be encountered and should be controlled with clips or ties. The effectiveness of hepatic artery ligation or embolization as primary treatment for hemangioma has been described anecdotally; however, the benefit of either procedure is likely transient.22,23 On the other hand, these approaches play a pivotal role in temporarily controlling hemorrhage from a hemangioma that has ruptured spontaneously and thus allow stabilization and definitive surgical treatment. Special Issues: Hemangioma in Children Figure 1–6. Tagged red blood cell (RBC) scintiscan of a cavernous hemangioma of the liver, 2 minutes (top) and 45 minutes (bottom) after injection of radionuclide-tagged RBCs. Note the early lack of filling of the hemangioma and the late pooling of the tagged RBCs within the lesion. should be done early in the operation, especially for very large tumors, as this procedure may result in significant tumor decompression and may facilitate resection. Enucleation is performed by defining the plane between the tumor and hepatic parenchyma. The majority of hemangiomas requiring resection are contained within a tough fibrous capsule that can be grasped firmly with a clamp, which can be used for retraction. Careful dissection within the proper plane allows the tumor to be separated from the normal In general, hepatic hemangiomas of infancy and childhood are different from those seen in adults.24–27 The lesion is typically large, and symptoms are rarely subtle. The vast venous lakes within the lesion can function as tremendous siphons for a large proportion of the total cardiac output, leading to congestive heart failure and death. In children who develop high-output cardiac failure, the initial treatment usually consists of digitalis, diuretics, oxygen, corticosteroids, and ligation of the hepatic artery.2,25,27 Radiation treatment is often employed and may result in improved cardiac performance.21,26 The risk of spontaneous rupture of a hepatic hemangioma in infancy is much greater than that of such tumors in adults.25 Similarly, Kasabach-Merritt syndrome, associated with lifethreatening thrombocytopenia and afibrinogenemia, occurs much more frequently in infants than in adults and is a common cause of morbidity and mortality. The treatment of hemangioma in infants and children (in contrast to that in adults) often requires a lifesaving operation, and such cases should be referred immediately to an experienced tertiary pediatric center. Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH), the second most common benign tumor of the liver, was initially described by Edmundson in 1958.28 Like hepatic adenoma, FNH is most often found in women of reproductive age. It is usually asymptomatic and is Benign Liver Lesions often discovered incidentally during a radiologic investigation for other reasons. In rare instances, FNH may present as a palpable abdominal mass on physical examination. Although FNH was rarely seen prior to the 1960s, its incidence has increased markedly in the last three decades. The rise in the number of cases has occurred concurrently with the introduction and widespread use of both US and CT in clinical practice. Whether the increased reporting of FNH represents a true change in incidence or merely reflects the proficiency of scanning in identifying these lesions is not clear, but the latter is probably the case. Klatskin and Vana and colleagues each reported collective series of FNH; both studies suggested an etiologic relationship between oral contraceptive pill (OCP) usage and the development of both FNH and hepatic adenoma.29,30 However, the numerous reports of FNH before the 1960s and the high frequency of FNH in the absence of OCP use suggest that there is probably no cause-and-effect relation- 11 ship. The potential effect of pregnancy on FNH remains poorly understood. In one provocative report, Scott and colleagues described a 36-year-old woman who had used OCPs for 11 years prior to developing FNH,31 which regressed after cessation of the medication but subsequently increased in size during a later pregnancy. Other than such anecdotal reports, there are no firm data linking pregnancy and changes in the size or symptoms of FNH, and meaningful conclusions are therefore not possible. Unlike hepatic adenoma, FNH carries little risk of spontaneous rupture and no risk of malignant transformation,32 which underscores the importance of distinguishing these lesions. Pathology Macroscopically, FNH is a pale firm lesion distinct from the surrounding liver (Fig. 1–8). Histologically, FNH is sharply demarcated from the normal liver but lacks a true capsule. The architecture of the Figure 1–7. Hemangioma seen by catheter angiography; a conventional angiogram of the hepatic artery of a patient with a large hepatic mass. The mass demonstrates peripheral puddling of contrast material (arrows), characteristic of a hemangioma. (Image courtesy of Dr. George Getrajdman) 12 HEPATOBILIARY CANCER lesion suggests a regenerative rather than a neoplastic process; as such, the lesion can be difficult to distinguish histopathologically from cirrhosis with regenerating nodules. This difficulty can be readily overcome by informing the pathologist of the diagnostic imaging findings and providing a sample of normal-appearing liver tissue away from the mass. Unlike in hepatic adenoma, bile duct hyperplasia and Kupffer’s cells are prominent in FNH. This feature is the basis for using labeled sulfur colloid scans to distinguish FNH from other lesions as Kupffer’s cells will take up the radiolabel while tumors with a paucity of Kupffer’s cells (such as adenoma) will not. Radiographically, FNH is described as having a “central scar.” The central portion of an FNH is composed of fibrous septae containing a round cell infiltrate and prominent thick-walled blood vessels,32,33 which may give the appearance of a scar on imaging studies. This finding, however, is by no means constant or pathognomonic. A B Figure 1–8. Focal nodular hyperplasia (FNH). A, On cross section, this FNH appears as a yellowtan lesion sharply demarcated from the normal liver in the absence of a true capsule. B, The gross and microscopic architecture of these lesions suggests a regenerative rather than a neoplastic process. Bile duct hyperplasia and Kupffer’s cells are prominent. Benign Liver Lesions Clinical Presentation and Evaluation Focal nodular hyperplasia usually presents as a solitary hepatic mass but may be multiple in up to 20 percent of patients33,34 and may occur in association with other benign tumors of the liver, such as hemangioma.35,36 The lesion is typically small and intraoperatively appears as firm nodules, pale red to brown, with prominent blood vessels on the surface. Larger lesions can be particularly difficult to distinguish from well-differentiated hepatocellular carcinoma (HCC). Tumors of FNH are frequently asymptomatic, and spontaneous rupture is extremely rare. In our experience, less than half of patients with FNH were symptomatic,3 and (like hemangiomas) the likelihood of symptoms increases with tumor size. Furthermore, there were no cases of spontaneous hemorrhage in patients who were observed. By contrast, Mays and Christopherson reported a 9.2 percent incidence of rupture in a series of 98 patients with FNH; however, this percentage is extraordinarily high compared to other large series in which no spontaneous ruptures were reported.35–38 Making a definitive diagnosis of FNH can be difficult. The lesion is visible by US but exhibits no characteristic features. Technetium-99m-labeled sulfur colloid scintigraphy may be helpful in demonstrating the presence of Kuppfer’s cells within a hepatic tumor; however, a positive result is not specific enough to make the diagnosis conclu- 13 sively. CT may demonstrate a well-demarcated enhancing lesion with enhancement of the central scar during the portal venous phase (Fig. 1–9). Magnetic resonance imaging may be more sensitive than CT, but the characteristic MRI features of FNH are subtle and require high-quality imaging studies and an experienced radiologist. Precontrast images may reveal a lesion that is hypointense or even isointense with respect to the surrounding liver tissue on T1-weighted images. Features on T2weighted images are also subtle, with the lesion being isointense to mildly hyperintense with respect to the liver. Focal nodular hyperplasia usually enhances early and appears hyperintense on the immediate postgadolinium images and becomes gradually isointense on the delayed sequences. Like CT, contrast MRI images may demonstrate a central scar, but this finding is less reliable than the overall appearance of the lesion on pre- and postcontrast sequences (Fig. 1–10). The use of reticuloendothelial agents (such as Ferridex), which are taken up selectively by Kupffer’s cells, can increase the specificity of both CT and MRI; however, the results are not specific to FNH. Angiography typically demonstrates a hypervascular mass with enlarged peripheral vessels and a single central feeding artery (Fig. 1–11). This so-called wheelspoke appearance with the vessels radiating out from the center of the tumor may help distinguish FNH from hepatic adenoma (see below). Figure 1–9. Focal nodular hyperplasia. Noncontrast computed tomography image of the liver demonstrates a mass (straight arrows) similar in attenuation to the surrounding hepatic parenchyma. Note that there is an area of low attenuation centrally consistent with a central scar (curved arrow). 14 HEPATOBILIARY CANCER Treatment As with all benign hepatic tumors, symptoms and the clinician’s inability to exclude malignancy are the most common reasons for resection of FNH. Inability to exclude malignancy is particularly common with FNH and was the reason for operation in 61 percent of those with FNH who were submitted to resection in our series.3 In many cases, diagnostic uncertainty prompts a percutaneous needle biopsy. The results of these biopsies are seldom diagnostic and are often misleading. One should therefore use caution when making treatment recommendations based on biopsy results alone. If the lesion is defin- Figure 1–10. Magnetic resonance imaging (MRI) of focal nodular hyperplasia. A, T1weighted image demonstrates a mass (arrows) that is isointense to hepatic parenchyma. B, T2weighted image of the liver demonstrates a mass (arrows) that is isointense to hepatic parenchyma. A B itively shown to be an FNH at the time of operation, enucleation of the tumor is sufficient treatment. More often, a firm histologic diagnosis is not available before operation and cannot be reliably obtained on frozen-section histologic study. In such cases, a formal resection with a rim of normal tissue is required in the unfortunate event that the final pathology demonstrates a malignant lesion. When the diagnosis of FNH can be made confidently by imaging criteria, particularly if the tumor is small and centrally located, a trial of close observation with repeat imaging every 3 to 4 months is rational. Any change in size, number, or symptoms of the lesion(s) should prompt reconsideration of surgical Benign Liver Lesions resection. Even in the absence of strong evidentiary data, discontinuation of OCP use in all patients with resected or unresected FNH seems prudent. Hepatic Adenomas Hepatic adenomas are generally solitary lesions but may be multiple in up to 30 percent of cases.35 As with FNH, the incidence of hepatic adenoma has increased since the late 1960s. Baum and colleagues were the first to suggest a cause-and-effect link between the development of a hepatic adenoma and OCP use, although the effects of exogenous estrogen on hepatic parenchyma had been previously reported.37 After starting OCP, 40 percent of women will develop hepatocellular dysfunction, manifested by increased retention of bromsulphothalein; rare patients will develop cholestatic jaundice.35,38–40 Alterations in hepatocyte architecture and trafficking have also been documented in association with OCP usage and pregnancy, and these changes appear to be related to dose and to duration of treatment. Klatskin and colleagues suggested that alterations in hepatic vasculature occur following OCP administration and may be the primary 15 mechanism through which the effects of OCP on the liver are mediated.41 A persuasive body of information now exists in support of an etiologic link between OCP use and the development of hepatic adenoma,40–43 which supports the initial observation by Baum and colleagues. The risk of developing hepatic adenoma appears commensurate with the duration of OCP use and with age of over 30 years. Ninety percent of patients who develop hepatic adenoma have used OCPs, and the incidence of hepatic adenoma among those who have used OCP for more than 2 years is 3 to 4 per 100,000. The risk of developing a hepatic adenoma while taking OCP may be related to the amount of estrogen in the OCP preparation. If this is true, then the recent trend of marketing low-estrogen OCP should affect the future incidence of hepatic adenoma. Regression of hepatic adenoma once OCP has been stopped is well documented; however, this is not a universal occurrence as tumor growth despite the stopping of medication has been reported.44–45 There is no convincing evidence linking pregnancy to the development of hepatic adenoma, but pregnancy may increase the incidence of associated complications. Rooks and colleagues documented Figure 1–11. Angiogram of focal nodular hyperplasia (FNH). Catheter angiogram of the hepatic artery demonstrates a hypervascular mass with a wheel-spoke pattern (arrows) of vessels characteristic of FNH. (Image courtesy of Dr. Karen Brown) 16 HEPATOBILIARY CANCER ruptures of hepatic adenomas in 5 of 6 women who either were currently pregnant or had recently given birth.43 This rate of rupture is alarmingly high in comparison to a rupture rate of less than 30 percent reported for nonpregnant women with hepatic adenomas.35 In addition to estrogens, several other hormones used as therapies, including androgens, clomiphene, danazol, and human growth hormone, have been linked to the development of hepatic adenoma and other benign liver tumors.46–51 Additional reports of an increased incidence of hepatic adenoma in patients with type I glycogen storage disease, galactosemia, Klinefelter’s syndrome, and Turner’s syndrome has led to significant speculation as to whether hepatic adenoma may be the result of an inborn genetic error in carbohydrate metabolism. Hepatic adenomas are capable of malignant transformation, but this appears to be an uncommon occurrence. Several authors have reported cases of hepatocellular carcinoma (HCC) arising adjacent to or within pre-existing hepatic adenomas.33,52–55 Similarly, Rooks and colleagues reported a patient who developed HCC in the same area where a hepatic adenoma had been removed 5 years earlier.43 By contrast, Tao and colleagues, after careful review of the histologic differences between adenomatous and dysplastic liver lesions, suggested that malignant transformation may not occur.54,55 However, given the difficulty inherent in differentiating between these entities, and given the significant anecdotal evidence in the literature, all hepatic adenomas should be considered to potentially harbor dysplastic changes or frank cancer until pathologic review of the entire tumor (and not a limited biopsy) proves otherwise. Pathology Hepatic adenomas are typically small (< 5 cm) solitary soft tumors that may or may not be encapsulated. The gross specimen appears pale yellow on the cut surface and may have a variegated appearance secondary to internal hemorrhage. Microscopically, hepatic adenomas are composed of monotonous sheets of hepatocytes, often containing considerable glycogen (Fig. 1–12). Unlike FNH, portal triads and bile ducts are absent, and the exist- ing blood vessels are thin-walled. Venous lakes (the so-called peliosis hepatis) are common. Areas of necrosis with “ghost cells” are characteristic of many hepatic adenomas. However, there is little evidence of an inflammatory reaction, fibrosis, or regeneration. Histologic differentiation of a hepatic adenoma from a well-differentiated HCC or a fibrolamellar HCC can be very difficult.55,56 Distinguishing an adenoma from a fibrolamellar HCC may be quite difficult also because both tumors occur most commonly in females of reproductive age who have no risk factors for chronic liver disease. In some series, small foci of HCCs were found in association with up to 10 percent of hepatic adenomas. Clinical Presentation and Diagnosis Because adenoma and FNH are common in young women and may have similar appearances on radiographic studies, they are often confused. Distinguishing these lesions is critical, however, because the recommended treatment for each is often different. There are often differences in presentation, which may be helpful, but these are generally not specific enough to be diagnostic. While the majority of FNHs are small and asymptomatic, hepatic adenomas tend to be large and symptomatic. In our series, two-thirds of patients with adenomas reported symptoms, compared with less than half of those with FNHs.3 Up to one-third of all patients with hepatic adenoma initially present with an acute rupture and intraperitoneal bleeding30,33,38,39,43 although the true incidence of this catastrophic complication is unclear. Additional complaints can include abdominal pain, pressure, and nonspecific gastrointestinal symptoms. Results of liver function tests are usually normal or only mildly abnormal. Tumor markers such as carcinoembryonic antigen (CEA) and α-fetoprotein are not elevated. Distinguishing hepatic adenoma from FNH or well-differentiated HCC radiographically remains a difficult problem. The findings on US are of a tumor with mixed echogenicity and an overall heterogeneous appearance—generally nonspecific. Computed tomography can yield a wide spectrum of disparate findings but typically demonstrates a hypodense lesion on noncontrast imaging, with a Benign Liver Lesions variegated appearance following contrast administration. Although MRI findings may be similarly nonspecific, we have increasingly used this modality to help distinguish adenoma from FNH. Adenomas are typically heterogenous but are usually hyperintense in T1-weighted images and isointense to mildly hyperintense on T2-weighted images. Additionally, these masses tend to enhance early on gadolinium-enhanced MRI (Fig. 1–13). In the past, technetium-99m sulfur colloid scans have been used to distinguish hepatic adenoma from FNH. Hepatic adenomas usually contain fewer Kupffer’s cells than FNH and will therefore not concentrate the radiola- 17 beled material and will appear as a cold nodule. However, sulfur colloid scans lack sufficient specificity and sensitivity to be clinically useful. Angiography, once commonly used, may still have a role in the occasional patient. Angiography of a hepatic adenoma typically reveals a hypervascular lesion with areas of necrosis and hemorrhage and tortuous vessels penetrating the tumor from the periphery. By contrast, the classic FNH angiogram demonstrates multiple vessels radiating from a large central vessel (the so-called central scar). Although imaging studies may provide evidence that is suggestive of the diagnosis, diagnostic uncertainty is often the rule. A B Figure 1–12. Hepatic adenoma. A, Hepatic adenomas grossly appear as soft, tan lesions. B, Microscopically, hepatic adenomas are composed of monotonous sheets of hepatocytes containing considerable glycogen. Portal triads and bile ducts are absent, and the existing blood vessels have thin walls. Venous lakes and zones of necrotic ghost cells are characteristic. 18 HEPATOBILIARY CANCER A B Figure 1–13. Magnetic resonance imaging of a hepatic adenoma. A, T1-weighted image demonstrates a mass (arrowheads) that is mildly heterogeneous with respect to hepatic parenchyma. Note that there is a focus in the mass that is hyperintense (arrow) from prior hemorrhage. B, T2-weighted image demonstrates the mass (arrow) to be mildly hyperintense compared to hepatic parenchyma. C, Arterial dominant-phase images through the mass demonstrate it to be hypervascular (arrow) compared to background parenchyma. C Benign Liver Lesions Treatment Because of the significant risk of spontaneous hemorrhage and the low but apparently real risk of malignant transformation, all patients suspected of having hepatic adenoma should be considered for resection. Enucleation may be a reasonable operative approach, especially if there is considerable doubt regarding the diagnosis, but most presumed adenomas should be approached as if they harbor an unsuspected malignancy. In this regard, surgical resection of these tumors is advised, with an adequate margin of normal tissue. Control of bleeding from a ruptured hepatic adenoma may be achieved surgically or with hepatic artery embolization. If surgical exploration is not feasible, angiographic embolization can be a temporary lifesaving maneuver until transfer to a center with surgical capability is possible. Intraoperatively, hepatic artery ligation can similarly be a lifesaving procedure in the presence of ongoing hemorrhage. All women diagnosed with hepatic adenoma should be advised to stop OCP use for life. Recurrence of hepatic adenoma after resection or enucleation has not been a problem, provided that OCPs are discontinued. Yearly follow-up with imaging is advised for all patients and is mandatory in patients with hepatic adenoma not causally linked to OCP use. Although data are sparse, some reports suggest that pregnancy increases the risk of spontaneous rupture. Given the high mortality associated with this complication, women with untreated adenomas should be advised to avoid becoming pregnant or to undergo resection beforehand. Hepatic artery embolization, radiofrequency ablation, or cryoablation may be useful in some settings. However, experience with these nonoperative modalities has been insufficient for the making of any firm recommendations regarding their use as primary treatment for hepatic adenomas. Other Liver Tumors5,6,35,42,55,56 Epithelial Tumors (Biliary Hamartomas and Adenomas) Bile duct adenomas and hamartomas are common tumors. They are particularly noteworthy since they may appear grossly and radiographically indistinguishable from metastatic lesions and are often mis- 19 takenly interpreted as such by the operating surgeon. Clinically silent, these tumors are manifest only at the time of operation or autopsy. Biliary hamartomas are small gray-white nodules scattered throughout the liver.57 They are often multiple and may be associated with liver cysts or other benign hepatic pathology. Microscopically, they are composed of dilated mature bile ducts surrounded by fibrous tissue. Bile duct adenomas are small white masses that are usually solitary and subcapsular. Their bile ducts are narrow with little or no lumen and may be surrounded by fibrosis. Biliary hamartomas and adenomas are easily distinguished from FNH on microscopic review due to their lack of hyperplasia and cellular proliferation. When encountered, biopsies on one or more lesions should be performed to confirm the diagnosis and exclude the possibility of malignancy. Mesenchymal Tumors Solitary Fibrous Tumor (Benign Mesothelioma, Fibroma). Solitary fibrous tumors are rare mesenchymal tumors that can often be mistaken for metastatic lesions because of their radiographic and intraoperative appearance (Fig. 1–14). The clinical course of these lesions appears to vary considerably, with some behaving like benign tumors while others are more aggressive. Moran and colleagues recently reported on nine cases of primary solitary fibrous tumors of the liver.57 The patients were seven women and two men and were between the ages of 32 and 83 years (mean, 57.5 years). Most of the tumors were large and symptomatic. Five tumors were palpable on physical examination. Grossly, the tumors varied in size from 2 to > 20 cm in greatest dimension and were described as firm, white to gray, and well to ill defined. Eight tumors were intraparenchymal lesions, two were necrotic, and one was attached by a pedicle to the liver capsule. Most of the tumors had a bland histologic appearance, with the classic short storiform (so-called patternless) pattern and an absence of cellular atypia, mitoses, and necrosis. In two cases, however, there was marked cellular atypia and mitotic figures varying from 2 to 4 mitoses per 10 high-power field (hpf) (Fig. 1–15). Immunohistochemically, all of the tumors showed a strong pos- 20 HEPATOBILIARY CANCER itive reaction against antibodies for CD34 and vimentin. The diagnosis of either a benign or malignant solitary fibrous tumor is impossible without definitive histologic review, and surgical resection is indicated in all circumstances. Lipoma (Myelolipoma or Angiomyolipoma). Fatty tumors of the liver are extraordinarily rare. Several reports of primary lipomas have appeared, but there are no reports to date of a primary hepatic liposarcoma. Most benign fatty hepatic tumors have been encountered at the time of autopsy, with rare reports of operative resection of these tumors.5 Multiple Figure 1–14. Imaging of a solitary fibrous tumor. A, Computed tomography examination of the liver demonstrates a large heterogeneous mass (arrows). B, T2-weighted magnetic resonance image of the same patient demonstrates the mass (arrows) to be heterogeneous with respect to hepatic parenchyma. A B variants, including myelolipoma, angiolipoma, and angiomyolipoma, have been described.5,58 The term “pseudolipoma” has been given to an extracapsular fatty tumor with involutional changes. This lesion probably results when a free-floating piece of fat (eg, an appendix epiploica) becomes trapped between the diaphragm and the surface of the liver.59 Definitive diagnosis requires resection to exclude malignancy. Mesenchymal Hamartoma. Mesenchymal hamartomas are extremely rare liver tumors that are seen most commonly in infants less than 1 year of age.60 Benign Liver Lesions Unlike biliary hamartomas that are clinically insignificant, mesenchymal hamartomas can reach enormous size, resulting in significant impairment of hepatic function. Microscopically, mesenchymal hamartomas display a background of edematous fibrous and myxoid mesenchyme with random groupings of hepatic cells, bile ducts, blood vessels, 21 and cysts. The cystic component is generally the most prominent feature, resulting in a honeycomb appearance. Although benign, mesenchymal hamartomas can result in death due to mass effect and/or hepatic insufficiency. Therefore, all mesenchymal hamartomas should be completely excised if feasible. If complete resection is not possible or is pro- A B Figure 1–15. A, Gross appearance of a resected solitary fibrous tumor. The tumor measured 18 cm in diameter. B, Histopathologically, the tumor has a bland appearance, with little or no cellular atypia and no necrosis. 22 HEPATOBILIARY CANCER hibitive for other reasons, surgical debulking may be sufficient as there have been no reports of recurrence after an incomplete surgical resection.35 Myxoma. A primary hepatic myxoma is exceptional. To date, there are only three reports of such lesions in the literature. Two hepatic myxomas were resected from children, one of which proved to be invasive. Both children remained free of disease at the time of report.36 There has been only one reported case of a hepatic myxoma in an adult; this involved a 58-year-old man with a left-lobe myxoma that ruptured. Definitive diagnosis was not made until autopsy 4 months later.29 Teratoma. At least seven benign primary teratomas of the liver have been reported.61,62 Most occur in children. Teratomas may be cystic and are usually encapsulated and easily resected. Resection is indicated to exclude malignancy. Secondary teratomas may be seen in the liver after systemic chemotherapy to treat testicular cancer. Resection is usually undertaken to remove residual disease that may be malignant, and the diagnosis of teratoma is made only after resection. NONPARASITIC CYSTIC TUMORS Cystic lesions of the liver and biliary tree are common, although many are not neoplasms in the true sense. Cystic lesions are discussed apart from solid benign tumors because such a finding within the liver leads to a different group of diagnostic possibilities. A complete discussion of all cystic diseases of the liver is beyond the scope of this section, which will focus on the most common of these lesions. Nonparasitic cystic lesions of the liver and intrahepatic biliary tree differ in many respects but share some common features.63 First, these tumors appear to result from congenital malformations of the intrahepatic biliary radicles and, as such, may be classified as epithelial in origin. Second, these lesions are predominantly or entirely cystic in nature, which distinguishes them from nearly all of the solid benign tumors. Cystic lesions may be further subcategorized as simple or complex with respect to their radiographic appearance, an important distinction that will dictate treatment recommendations (see below). The finding of a complex cyst is potentially more ominous; in general, these lesions should be resected, even in the absence of symptoms. Simple Cyst Simple hepatic cysts (also known as benign hepatic cysts, congenital hepatic cysts, or unilocular cysts) are round or ovoid cystic formations containing serous fluid. The size of simple cysts ranges from a few millimeters to 20 cm or more. Small cysts are surrounded by normal hepatic parenchyma. Larger cysts may cause atrophy of adjacent hepatic parenchyma, and huge cysts may result in significant lobar atrophy with compensatory contralateral hypertrophy. Simple cysts are considered to be congenital malformations resulting from an aberrant bile duct that has lost its communication with the biliary tree and that slowly but progressively accumulates fluid and dilates. Thus, simple cysts have no communication with the biliary tree and are lined by a single layer of uniform cuboidal or columnar epithelium resembling biliary epithelium. In the absence of spontaneous intracystic hemorrhage or previous aspiration, the cyst fluid is clear and is similar in composition to the normal secretion of biliary epithelial cells. Approximately 50 percent of patients with nonparasitic cystic disease have a single cyst while the remainder will have two or more.64 A small number of patients will have multiple cysts, reminiscent of the hepatic cysts seen in adult polycystic kidney disease. However, while some of these patients have one or a few renal cysts, they must not be regarded as having polycystic kidney disease. In most cases, simple cysts are asymptomatic and are discovered incidentally on evaluation of other conditions. Such findings may cause considerable consternation because they may be mistaken for evidence of metastatic disease, especially in patients with a known malignancy elsewhere who are undergoing an evaluation for extent of disease. This is particularly true for small cysts that may be difficult to characterize radiographically. Furthermore, distinguishing simple cysts from other cystic lesions, specifically cystadenoma and hydatid disease, is critical. The latter two conditions are treated with Benign Liver Lesions resection in most cases, while asymptomatic simple cysts require no specific therapy beyond serial follow-up examinations. Ultrasonography is a simple and effective method for confirming the diagnosis of simple hepatic cysts. The ultrasonographic appearance is that of a circular or oval anechoic area, well circumscribed and with sharp smooth borders and a strong posterior wall echo, indicating a welldefined tissue-fluid interface65 (Fig. 1–16). Magnetic resonance imaging has also proven valuable in diagnosing simple cysts, which appear very bright on T2-weighted images (Fig. 1–17) Computed tomography confirms the presence of one or several round or oval thin-walled water-dense lesions without internal septations; it appears to be less useful for evaluating smaller cysts. In most cases, simple cysts are readily distinguished from other hepatic lesions by routine imaging studies. Occasionally, however, simple cysts may be difficult to distinguish from cystadenomas or hydatid disease. While hydatid cysts are usually complex and contain multiple septations and calcification, these features may be absent. Also, serologic tests for ecchinococcal infestation are not always positive, and 23 the disease can be acquired in areas where it is not endemic. Furthermore, simple cysts with intracystic hemorrhage and clotting, which may occur spontaneously (Fig. 1–18) or after instrumentation (Fig. 1–19), may be radiographically indistinguishable from hydatid disease or cystadenomas. When the distinction between hydatid disease and simple cysts cannot be made on radiographic grounds, microscopic examination of the cyst fluid obtained by aspiration may be useful.66 Likewise, tumors suspected of being cystadenomas should be treated as such rather than risk inappropriate treatment for a lesion that may be premalignant or that may already contain a focus of malignancy (see below). Most simple cysts are asymptomatic, even when large, and therefore require no specific therapy. Serial imaging of these lesions may show no appreciable enlargement over several years. A small number of patients may experience rapid enlargement, which may be associated with severe pain; intracystic hemorrhage may also result in sudden and severe pain. Symptoms are much more likely to occur in women over 50 years of age.64 The most effective therapy for symptomatic simple cysts is wide fenestration of the Figure 1–16. Ultrasonography of the liver, demonstrating a simple hepatic cyst (arrow). The lesion is well circumscribed and is hypoechoic with increased through transmission. This constellation of findings is characteristic of a simple cyst. 24 HEPATOBILIARY CANCER cyst wall performed at laparotomy or laparoscopy. Percutaneous aspiration by itself is ineffective treatment; reaccumulation of cyst fluid is generally rapid.67 However, aspiration combined with infusion of alcohol is more effective in preventing recurrence and may be an alternative to fenestration for patients who cannot tolerate general anesthesia.68–71 Biliary Cystadenoma Biliary cystadenoma, also known as hepatobiliary cystadenoma, is an uncommon tumor that has a tenFigure 1–17. Magnetic resonance imaging of a simple cyst. A, T2-weighted image demonstrates small well-circumscribed markedly hyperintense masses (arrow). B, Postcontrast images fail to demonstrate enhancement within these masses (arrow), consistent with simple cysts. A B dency to recur if incompletely resected and that also has potential for malignant transformation. It is therefore essential that cystadenoma not be mistaken for a simple cyst and disregarded or (worse) subjected to fenestration. Cystadenomas are generally solitary and often large, ranging in size from 10 to 20 cm (Fig. 1–20). The pathogenesis is uncertain, although a congenital origin from an abnormal intrahepatic bile duct is generally favored.72 These lesions are most commonly seen in women over 40 years of age.72 Patients with large tumors may experience abdominal discomfort or pain, anorexia, or other Benign Liver Lesions symptoms related to tumor compression of adjacent organs. Smaller tumors often cause no symptoms and may be discovered only on evaluation of elevated liver enzymes. The diagnosis is suggested on the basis of imaging studies. Unlike simple cysts, cystadenomas usually have irregular margins, with multiple internal septations delimiting locules of various sizes. Papillary growths arising from the cyst wall and extending into the cyst lumen are also common.73 Cystadenomas are sometimes difficult to distinguish from hydatid cysts or (rarely) from a cluster of contiguous simple cysts. 25 Cystadenomas tend to progress slowly. Complications such as cholestasis from bile duct compression,74 intracystic hemorrhage, rupture, or bacterial infection that will bring otherwise asymptomatic lesions to medical attention have been described. Malignant transformation is the potential complication of greatest concern. Cystadenocarcinomas arise almost exclusively within pre-existing cystadenomas. Malignancy may affect the entire epithelial lining; more often, only part of the cyst is involved. The finding of abundant and large papillary projections on imaging studies suggests the presence of malignancy.75–77 Figure 1–18. Magnetic resonance imaging of a hemorrhagic cyst. A, T1-weighted image demonstrates a mass with a hyperintense rim (arrows). B, T2-weighted image demonstrates the mass to be hyperintense, with the rim being hypointense (arrow), consistent with hemorrhage. The lesion failed to enhance after contrast administration. A B 26 HEPATOBILIARY CANCER Because of the risk of malignant transformation, all suspected cystadenomas must be excised completely. Enucleations or partial excisions expose the patient to the risk of recurrent cystadenoma or late development of cystadenocarcinoma and are therefore not appropriate. CONCLUSION The key to managing patients with benign liver tumors is an accurate diagnosis and a knowledge of the natural history of the untreated lesion. Although radiologists have made great strides in identifying Figure 1–19. Computed tomography scan of a patient with multiple simple cysts. A, A large cyst within the right lobe and dome of the liver, causing respiratory symptoms. This cyst was aspirated percutaneously to relieve symptoms. Notice the thickened wall and the homogenous nature of the cyst fluid, consistent with intracystic hemorrhage. B, Lower cuts, showing additional simple cysts. Notice the typical sharp borders, thin wall, and homogenous nature of the cyst fluid in contrast to the previously instrumented cyst. A B and characterizing the features of benign hepatic tumors and although gastroenterologists have developed greater skill in diagnosing these lesions, the final burden of responsibility for both diagnosis and therapy rests with the surgeon. Increasing experience, improved techniques, and better support systems have made hepatic surgery a safe and effective therapeutic modality. However, as we have learned more about the prognoses of certain lesions (particularly hemangioma and FNH), a more conservative attitude has evolved, particularly since improvements in noninvasive imaging now permit careful follow-up by serial examinations. On the other hand, Benign Liver Lesions 27 A B C Figure 1–20. Magnetic resonance imaging of cystadenoma. A, T1-weighted image demonstrates a heterogeneous mass (arrow) with a fluid-fluid level. The mass has components that are both hypo- and hyperintense to hepatic parenchyma. B, T2-weighted image demonstrates the mass (arrow) to be well circumscribed, with similar levels of differing intensity. C, Postgadolinium images fail to demonstrate enhancement within the mass. 28 HEPATOBILIARY CANCER while some benign tumors may be safely observed, others require resection, and it is ultimately the surgeon’s responsibility to determine the most appropriate course of action. As discussed above, such decisions are not always simple or straightforward and often require significant experience and mature clinical judgment. An otherwise fit patient with a symptomatic benign hepatic tumor should be considered for resection, provided that the tumor can be removed safely. It is imperative to ensure that the symptoms are indeed related to the tumor and do not arise from some other abdominal pathology. Preoperative needle biopsies may be dangerous, are often inaccurate, and should not be performed as a matter of routine. Needle biopsies should be considered only after the diagnosis of hemangioma has been excluded and then only in asymptomatic patients who are not candidates for resection, to exclude a malignancy if warranted on the basis of imaging studies or if the biopsy results will otherwise alter management. 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