Image Sources
Authors
Ali Ahmad, MD
Complex General Surgical Oncology Fellow
Roger Williams Medical Center
Providence, Rhode Island
Disclosure: Ali Ahmad, MD, has disclosed no relevant financial relationships.
Itzhak Nir, MD, FACS
Director of Regional Cancer Therapies
UNM Cancer Center;
Assistant Professor of Surgery
University of New Mexico
Albuquerque, New Mexico
Disclosure: Itzhak Nir, MD, FACS, has disclosed no relevant financial relationships.
Editor
Olivia Wong, DO
Section Editor
Medscape Drugs & Diseases
New York, New York
Disclosure: Olivia Wong, DO, has disclosed no relevant financial relationships.
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Ali Ahmad, MD; Itzhak Nir, MD, FACS | April 30, 2015
Hepatic tumors are a diverse group of masses that include malignant and benign subtypes.[1] Their presentation can vary from localizing signs/symptoms, such as jaundice and right upper quadrant pain, to vague signs/symptoms, such as fatigue, weight loss, and anorexia. Many hepatic tumors are discovered incidentally on medical imaging studies.[2,3] Additionally, the liver is a common site for metastasis,[4] and metastases to the liver are significantly more common than primary liver tumors.[5,6]
Image of a large liver tumor from a 50-year-old male courtesy of Wikimedia Commons/Haitham Alfalah.
The incidence of primary liver cancer (including intrahepatic bile duct cancer) is steadily increasing in the United States (shown) and worldwide. Primary liver cancer is the 13th most common cancer type in the United States[8] but the fifth most common cause of cancer death in US men and the ninth most common cause of cancer death in US women.[9] In 2014, there were approximately 33,190 new cases of liver cancer in the United States, with an estimated 23,000 deaths[8]—making liver cancer one among a rare group of cancers with a high mortality.[10] The 2015 estimated new cases and deaths, respectively, from liver and intrahepatic bile duct cancer are 35,660 and 24,550.[11]
Globally, liver cancer is the third leading cause of cancer death after cancers of the lung and the stomach.[12] The highest incidence of hepatocellular carcinoma (HCC) is in China, representing about 50% of HCC cases worldwide, with most of the cases associated with hepatitis B virus (HBV) infection. Cholangiocarcinoma also has a disproportionate geographical distribution, with Thailand having the highest global rates due to the presence of liver flukes.[12]
Image courtesy of the National Cancer Institute's (NCI's) Surveillance, Epidemiology, and End Results (SEER) Program.[9]
Common malignant liver tumors include the following[7]:
Common benign liver tumors include the following[7]:
Image of abdominal organs courtesy of NCI.[5]
Hepatocellular carcinoma (HCC) (shown) is the most common primary malignant liver tumor in adults.[7,13,14] It occurs predominantly in patients with underlying chronic liver disease and cirrhosis,[7,9,13] thus, there is a strong association between the development of HCC and infection with HBV and hepatitis C virus (HCV).[2,5,9,11,13]
Typically, the pattern of HCC spread is local expansion, but it can also metastasize via the hematogenous route and it can be multifocal.[7] In general, these tumors are discovered either during routine screening in cirrhotic patients or when the lesions are symptomatic owing to their size or location.
Image courtesy of Arief Suriawinata, MD, Department of Pathology, Dartmouth Medical School.
For HCC, favorable factors associated with better prognosis include low stage, encapsulation, solitary lesion,[6] tumor size smaller than 5 cm,[6] fibrolamellar variant,[7] no underlying cirrhosis, no vascular invasion, and surgical resectability with negative margins.[11]
Histologically, high-grade HCC demonstrates hyperchromasia with increased nuclear-to-cytoplasmic ratios.[15] In addition, the tumor cells distort the normal trabecular structure of the liver.
Image A shows a gross specimen of a surgically resected liver from a patient with HCC. Image B depicts a micrograph showing HCC fibrosis (blue collagen), nuclear atypia, loss of normal liver architecture, and the presence of Mallory bodies (arrow).
Images courtesy of Ali Ahmad, MD (A) and Wikimedia Commons/Nephron (B).
Once a diagnosis of HCC is suspected, workup should begin with an evaluation of the patient's baseline liver function and obtaining viral hepatitis serology studies and serum alpha fetoprotein (AFP) levels.[7] AFP levels greater than 400 ng/mL are virtually diagnostic for HCC in the setting of appropriate imaging correlates.[13,16] Thus, a biopsy is not always necessary.[7,16]
Image A reveals a hepatic mass during the noncontrast phase of a triple-phase computed tomography (CT) scan. Triple-phase CT scanning has a high sensitivity and specificity for the diagnosis of HCC; magnetic resonance imaging (MRI) studies can also be used to make the diagnosis.[2,11] Classic CT scan findings include a hypervascular pattern with arterial enhancement (B) and rapid washout during the portal venous phase (C).[2,17] On MRI (D), other characteristics that support the diagnosis of HCC include visualization of a tumor capsule (shown), demonstration of an internal mosaic resulting from variable attenuation within the tumor (shown), and portal vein branch invasion.
Images courtesy of Ali Ahmad, MD.
Although an estimated 10%-23% of patients with HCC may be surgical candidates for curative-intent treatment,[11] advances in surgical techniques and perioperative care have resulted in a dramatic reduction in perioperative morbidity and mortality.
Liver resection is the preferred treatment in noncirrhotic patients[7,13] with tumors smaller than 5 cm; these patients can often tolerate major resections. However, in cirrhotic patients, the ability to tolerate a formal liver resection is limited by the degree of cirrhosis.[7]
Consider liver transplantation in patients with established cirrhosis and a single HCC lesion (≤5 cm in diameter) or up to three HCC lesions (all ≤3 cm in diameter).[7,13,18] With this criteria (the Milan criteria), a 4-year overall survival (OS) rate of 85% and a tumor-free survival (TFS) rate of 92% may be seen after transplantation.[18]
Patients with advanced disease or those who are otherwise not candidates for liver resection or transplantation may be offered chemotherapy, radiotherapy, targeted therapy, embolization, chemoembolization, or local ablative treatments.[7,11]
Image A shows HCC in a patient with underlying cirrhosis (asterisk). Image B (inset) depicts a gross liver cross-section of a resected HCC. Note the encapsulated appearance of the tumor.
Images courtesy of Ali Ahmad, MD.
Cholangiocarcinoma, or bile duct carcinoma, is a relatively rare liver tumor that is primarily classified as an adenocarcinoma.[18-21] In the United States, an annual 2,000-3,000 people develop this disease,[18] with the most common risk factor being primary sclerosing cholangitis (PSC) (5%-20% lifetime risk of patients with PSC developing cholangiocarcinoma).[19,21]
In general, cholangiocarcinomas have a very aggressive biology and are usually metastatic at the time of presentation.[18-21] These tumors are classified into three major subtypes on the basis of their location, as follows[21]:
The image shows a resected cholangiocarcinoma (asterisk). This tumor extended into the intrahepatic biliary tree, thereby necessitating a formal hepatectomy.
Image courtesy of Ali Ahmad, MD.
Complete surgical resection of cholangiocarcinoma is the only option for potential cure.[18,19,21,22] Unfortunately, fewer than 30% of patients present with limited disease and are amenable to surgical resection.[19,21] Intrahepatic and some perihilar tumors require liver resection; however, this may not be an option for older patients with comorbid conditions. Liver transplantation may be considered for select patients with proximal tumors who are not candidates for surgical resection due to underlying cirrhosis.[23]
Radiation therapy, usually in conjunction with chemotherapy, may be used in an attempt to make borderline resectable tumors into resectable lesions.
Image A shows a gross specimen of resected cholangiocarcinoma involving the intrahepatic bile ducts (arrow). Image B is a micrograph that reveals atypical bile ductlike cells (bottom of image) with abundant desmoplastic stroma (asterisk) in a cholangiocarcinoma specimen. A normal portal triad (top of image) is seen with a histologically normal bile duct (arrow).
Images courtesy of Wikimedia Commons and Fidel22 (A) and Nephron (B).
As noted earlier, metastatic liver disease is far more common than primary liver tumors.[5,6] This is due to the liver's rich dual blood supply. Most of these metastatic tumors are detected on staging after a primary tumor has been found in another organ, and colorectal liver metastases are the most prevalent in this group (60%-70%).[24] Extragastrointestinal tumors that can metastasize to the liver include melanomas, genitourinary and gynecologic malignancies, breast cancer, and lung cancer.[5,6]
For most tumor types, liver metastasis is considered stage IV disease in the American Joint Committee on Cancer (AJCC) Staging System.[7,11] However, the management of these tumors has evolved significantly over the past decade and is usually dictated by the type of primary tumor, the size and number of lesions, and the patient's clinical condition.[24] For example, tumors of colorectal and renal origin can be resected, but pancreatic adenocarcinomas and gastric adenocarcinomas are not. Local ablative therapies such as microwave ablation (MWA), radiofrequency ablation (RFA), transarterial chemoembolization (TACE), and irreversible electroporation (IRE) continue to evolve and have important roles in the management of unresectable tumors.
Images A and C are intraoperative photographs of, respectively, a metastatic rectal gastrointestinal stromal tumor (GIST) and a metastatic uveal melanoma. Images B and D show, respectively, a gross cross-section of a resected liver segment with intrahepatic satellitosis from HCC and a gross specimen of a resected melanoma metastasis.
Images courtesy of Ali Ahmad, MD.
Hepatic metastases may appear in a multitude of ways on CT scans. The majority of these lesions are hypovascular (hypoattenuating) in comparison with the surrounding parenchyma (A) (arrow).[6]
Contrast-enhanced CT scans and MRIs reportedly have a greater than 90% sensitivity and specificity for diagnosing liver metastases,[25] although the ranges vary.[26-29] MRI is more sensitive and specific than CT scanning[26-29] and can be utilized in atypical cases when the diagnosis is in doubt or to differentiate malignant tumors from other benign etiologies.
Although the accuracy of transabdominal ultrasonography ranges from 50% to 76%,[26] intraoperative ultrasonography (IOUS) of the liver, with or without contrast, has the highest sensitivity (95%-98%) for the detection of focal liver abnormalities.[27-29]
The CT scans reveal a hypodense metastatic tumor during the noncontrast phase (A); an unenhanced tumor depicting hypovascularity during the arterial phase (B); and a persistently unenhanced tumor during the portal venous phase (C).
Images courtesy of Ali Ahmad, MD.
Hepatic hemangiomas (or, hepatic venous malformations, hepatic cavernous hemangiomas) (gross specimen shown) are the most common benign tumors affecting the liver.[2,7,30-33] Their etiology remains unknown,[2] but these tumors are mesenchymal in origin,[32] usually solitary,[33] have a female preponderance (5:1),[2] and are associated with some genetic syndromes (eg, Kassabach-Merritt syndrome, Osler-Weber-Rendu disease).[30,34] Most of these lesions are asymptomatic and discovered incidentally on imaging studies.[2,7,30-33]
Hepatic hemangiomas present a diagnostic challenge because they can be mistaken for other malignant hypervascular tumors of the liver. Triple-phase CT scanning or MRI can accurately characterize these tumors and differentiate them from other lesions.[2,33] Whenever possible, biopsy should be avoided due to the risk of hemorrhage.[2] Histologically, hepatic hemangiomas have variably sized vascular spaces lined by flat endothelial cells and myxoid or fibrous stroma (inset).[32]
Due to their benign nature and no known malignant potential, hepatic hemangiomas generally do not require treatment.[2,31,33] For large, symptomatic hemangiomas that affect the patient's quality of life or when the diagnosis is in doubt, surgery may be considered.[2,33]
Images courtesy of Ali Ahmad, MD (gross specimen) and Wikimedia Commons/Nephron (inset).
Focal nodular hyperplasia (FNH) (shown) is the second most common benign tumor of the liver after hepatic hemangiomas.[2,31,35,36] It is generally found incidentally and affects women more often than men. Although patients are rarely symptomatic, FNH can cause abdominal pain and vague upper gastrointestinal symptoms.[35,37]
FNH may be confused with other tumors of the liver[2,7,35-37]; however, with the improved quality of imaging studies, the need for invasive diagnostic procedures has diminished. Macroscopically, these tumors are characterized by the presence of a depressed, grayish-white scar; this stellate scar is found in about 50%-80% of all FNH nodules,[37,38] but its presence is regarded as pathognomonic.[2,31,36,39] Microscopically, the most common pattern is a lobular proliferation of bland-appearing hepatocytes with bile duct proliferation and the presence of malformed vessels within a fibrous scar.[36,37]
Intraoperative image of a large, symptomatic FNH courtesy of Ali Ahmad, MD.
With regard to imaging studies for FNH, MRI is more sensitive and specific than conventional ultrasonography or CT scanning, but Doppler ultrasonography and contrast-enhanced US (CEUS) can greatly improve the accuracy of the diagnosis.[2] As noted earlier, the presence of a central or stellate scar is considered pathognomonic.[2,31,36,39] FNH demonstrates increased uptake on technetium-99m (99mTc) sulfur colloid scanning due to the presence of Kupffer cells.[35] Historically, this imaging modality was used to distinguish FNH from other tumors (eg, adenomas).
FNH is not considered a premalignant condition; once a correct diagnosis has been made, there is no indication for surgery in most cases, and treatment includes conservative clinical follow-up in asymptomatic patients. Surgery is generally reserved only for large symptomatic FNH or when the diagnosis is in doubt.[2,7,31,35-37] Some authors advocate surgical resection for tumors that demonstrate progressive growth or those greater than 10 cm in size.[10]
The gadolinium-enhanced T1-weighted MRIs reveal FNH. There is an ill-defined low-signal-intensity mass in the precontrast phase (top left). The mass enhances intensely in the arterial phase after the administration of contrast medium (top right). Minor enhancement persists in the portal venous phase (bottom left), and the lesion becomes isointense relative to the liver on delayed images (bottom right).
Images courtesy of Medscape.
Hepatic adenoma, or hepatocellular adenoma, (shown) is a rare, usually benign tumor that occurs mostly in women of childbearing age; it is strongly associated with the use of oral contraceptive pills (OCPs).[2,7,31,37,41] In men, hepatic adenoma is associated with the use of anabolic steroids.[2,7,36,37]
The clinical presentation may vary from an incidental finding on imaging studies to hemoperitoneum from rupture.[2,7,31,37,41] Although uncommon, there is a potential for malignant transformation to HCC,[2,36,41] and the risk is higher for tumors larger than 5 cm. There have been some reports of hepatic adenomas with beta-catenin mutation having an increased risk for malignant transformation.[2,36,37,42]
The gross lesions usually appear tan or yellow, smooth, well circumscribed, and fleshy; their size varies from 1 to 30 cm.[2,36,41] Microscopically, hepatic adenomas consist of sheets of hepatocytes without bile ducts or portal areas.[2,36]
Intraoperative image of a left-lobe hepatic adenoma courtesy of Ali Ahmad, MD.
Hepatic adenoma may be differentiated from other lesions with the use of triple-phase CT scanning or MRI. The lesion appears as a nonspecific, well-circumscribed mass that has a low density (A) (arrow), with a marked centripetal pattern of enhancement during the arterial phase (B and C). The density then fades to isodensity in the delayed phase (D). Hepatic adenoma can also have a central necrotic area or calcifications.[43]
Biopsy is usually not indicated unless the appearance is atypical.[2]
Once diagnosed, patients with hepatic adenoma should discontinue OCPs or any anabolic steroids. Ruptured adenomas may require emergent intervention for hemorrhagic control.[2,7,31,36,41] Surgical resection is classically indicated for symptomatic hepatic adenomas or those larger than 5 cm.[2,37]
Image A is a T1-weighted MRI shown during the precontrast phase. The three postcontrast T1 MRIs are shown at 15 seconds (B), at 1 minute (C), and at 3 minutes (D).
Images courtesy of Ali Ahmad, MD.
Simple hepatic cysts are benign and have no malignant potential.[2,44,45] These large simple cysts appear to affect women slightly more than men. Simple hepatic cysts may be asymptomatic, or they can produce right upper quadrant or flank pain; rarely, the tumors can cause biliary obstruction or intracystic hemorrhage.[2,44,45]
Management of hepatic cysts relies on accurate diagnosis by imaging studies, primarily with ultrasonography; CT scanning and MRI are also useful for the diagnosis.[2,44] In general, the cysts appear as round or ovoid, smooth, anechoic lesions on ultrasonography.[2,44,46] If a cyst appears to have septations or a mixed appearance, it should be thoroughly worked up to rule out a neoplastic or infectious process.[2,46] Simple cysts do not require a biopsy for confirmation.
Surgical intervention, usually cyst unroofing (or, open surgical cyst fenestration, marsupialization), is offered in symptomatic cases; needle aspiration and sclerotherapy are also options, but these are associated with higher rates of recurrence.[2,45] Complete cyst excision or hepatectomy may be performed when the diagnosis is in doubt.[45,46]
Intraoperative image of a hepatic cyst with intracystic hemorrhage courtesy of Ali Ahmad, MD.
Surgery remains the mainstay of treatment for most liver tumors.[11,47] Perioperative outcomes of hepatic resection have improved over time due to the advancements in surgical techniques as well as improved perioperative care.[48] Outcomes are improved in centers with high volume and surgeons experienced in treating these lesions.
The liver is anatomically divided into eight functional segments; segments one through four compose the left liver, and segments five through eight comprise the right lobe.[48] Various types of hepatic resections exist, including anatomic (segmental; usually involve ≥2 hepatic segments) and nonanatomic (wedge; resection of the tumor with a margin of uninvolved tissue).[48] Types of hepatectomies include formal right or left hepatectomy, segmentectomy, trisegmentectomy, sectorectomy (meaning two segments), and nonanatomic resection.
Decision making regarding which specific type of resection is appropriate is complex and multifactorial. In addition to the relevant anatomy, factors that dictate the extent of hepatectomy include the patient's overall condition, the type of tumor, and any previous treatments the patient has received.
The intraoperative photograph of the liver was obtained prior to a hepatectomy. The line dividing the left lobe from the right (Cantlie line) is marked by electrocautery (yellow arrow). A red vessel loop surrounds the portal triad (green asterisk).
Image courtesy of Ali Ahmad, MD.
This intraoperative photograph was obtained following a formal right hepatectomy. The right adrenal gland (asterisk), the inferior vena cava (hashtag), and the diaphragm (X) are seen after the removal of the right liver. The cut surface of the liver (right of image) is retracted, and a stapled right inflow pedicle can be seen (arrow).
Image courtesy of Ali Ahmad, MD.
Ablation refers to the local destruction of tumors without surgical resection.[7,49] Most of these techniques are used in tumors that are otherwise unresectable. Multiple different techniques have evolved over the past several years, including the following:
Although each technique offers advantages and disadvantages over the others, all require the placement of probes directly into the tumor. Percutaneous and surgical approaches are acceptable for these ablative techniques.[49,51]
The image shows an RFA probe inserted directly into a liver tumor in a patient with advanced cirrhosis. Multiple tumors are noted (arrows) and can be ablated.
Image courtesy of Ali Ahmad, MD.
Regional therapies are used in the setting of widespread intrahepatic tumor burden that is not amenable to surgical resection.[7,49] Although multiple techniques have gained significance in the past several years, regional therapies are usually delivered intraarterially to the liver, with the advantage of conveying high dosages with minimal extrahepatic toxicity.
Common techniques for regional therapies of the liver include the following:
These techniques can still have regional and/or hepatic side effects, thereby making the selection of the appropriate technique complex. Success rates have varied across different tumor types.[51]
The image shows a catheter surgically placed into the gastroduodenal artery (GDA). The catheter is connected to a subcutaneous port for easy access (not shown). Meticulous dissection of the GDA is performed with ligation of all collateral vessels to avoid spillage of high-dose chemotherapy into the surrounding tissues. After placement of the catheter, it is tested with methylene blue injection (shown). Any undesired flow into surrounding tissues can be seen (arrow).
Image courtesy of Ali Ahmad, MD.
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