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TABLE 1 Comparison of Imaging Findings for the Five Most Commonly Encountered Benign Liver Lesions
Lesion US CT MRI
Simple cyst Round, through-transmission,
generally lacks septations
Heterogeneity seen with
hemorrhage
Biliary cystadenoma Round, anechoic, thick cyst wall,
internal septations
May have mural and septal
nodules
Hemangioma Homogenous, hyperechoic,
posterior acoustic enhancement
Blood flow rarely observed
Adenoma Well-circumscribed,
heterogeneous, variable
echogenicity
Focal nodular hyperplasia Variable echogenicity, central scar
rarely observed
Unreliable modality for diagnosis
Well circumscribed, homogenous,
hypoattenuated
Limited contrast enhancement
Well circumscribed, isoattenuated
noncontrast
Mural and nodular enhancement
with contrast
Well circumscribed, homogenous
Asymmetric peripheral pools of
enhancement in arterial phase
Centripetal enhancement and
washout delayed phase
Isoattenuated noncontrast
Hyperattenuated arterial phase,
loss of contrast enhancement
delayed phases (return to
isoattenuation)
Heterogeneous if necrosis or
hemorrhage
Hyperattenuated signal if active
hemorrhage
Isoattenuated or hypoattenuated
noncontrast
Hyperattenuated arterial phase,
central scar remains enhanced
during venous phase
Loss of contrast enhancement
in delayed phases (return to
isoattenuation)
Well circumscribed, homogenous
T1: hypointense
T2: very hyperintense
Limited contrast enhancement
Well circumscribed, heterogenous
T1: hypointense
T2: hyperintense
Mural and nodular enhancement
with contrast
Well circumscribed, homogenous
T1: hypointense
T2: very hyperintense
Gadolinium enhancement pattern
similar to CT
T1: isointense to hyperintense
T2: isointense to hyperintense
Gadolinium enhancement pattern
similar to CT
Eovist not retained in delayed,
hepatobiliary phase
Fat saturation sequences
demonstrate intracellular fat
T1: hypointense
T2: hyperintense with
hyperintense central scar
Gadolinium enhancement pattern
similar to CT
Eovist retention in delayed,
hepatobiliary phase
Simple liver cysts are usually small (<3 cm in diameter) and remain
stable in size, although growth may be observed because of continued production of serous fluid. Simple cysts are rarely symptomatic
and nearly universally benign.
Presentation
Simple liver cysts occur in approximately 18% of the population.
They are most often observed in adults and are usually discovered
incidentally. There is a slight female predominance (1.5:1), and
although cysts may occur throughout the liver, they are found more
often in the right lobe. Simple liver cysts are asymptomatic in the
vast majority of cases. Occasionally, larger cysts are associated with
pain, shortness of breath, early satiety, nausea, or vomiting. Complications such as infection, hemorrhage, or biliary obstruction caused
by compression or rupture are rare. Liver function tests are usually
within normal limits. Occasionally, large cysts might be palpable on
physical examination. A self-limiting bleed into a simple cyst is more
common in patients on anticoagulation, and it typically causes acute
upper abdominal pain that spontaneously resolves over hours to
days. Polycystic liver disease is discussed in a separate chapter.
Imaging
In the majority of cases, US alone may be used to establish the diagnosis of a simple cyst, which appears as a circular or oval anechoic
lesion with clearly defined smooth borders, posterior acoustic
enhancement, minimal septations, and absence of internal vascularity. Fluid layering, heterogeneity, and internal echoes mimicking
septations may indicate cyst hemorrhage, whereas debris within
the cyst fluid can be associated with infection or a prior bleed. The
presence of internal septations or a thickened, irregular cyst wall
with mural nodules and papillary projections or calcifications is
concerning for MCN, which is associated with an increased risk of
malignant transformation that requires surgical resection. In certain cases, CT or MRI may be necessary to confirm the diagnosis
of a simple cyst. On CT, simple cysts appear as well-circumscribed,
homogeneous, hypoattenuated lesions that do not enhance with
contrast injection (Fig. 1A). On MRI, simple cysts are hypointense
with T1-weighted imaging and hyperintense with T2-weighted
imaging (Fig. 1B). Similar to CT findings, cysts lack contrast
enhancement and appear as well circumscribed and homogeneous
on MRI.
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FIG. 1 (A) Axial CT scan demonstrating a simple liver cyst in the left lobe of the liver in a 54-year-old woman. (B) Axial T1-weighted MRI scan after cyst
fenestration shows minimal hypointense, residual fluid in the cyst cavity.
Management
Asymptomatic simple cysts require no treatment or follow-up
imaging. For patients with symptoms, surgical fenestration is the
treatment of choice. Percutaneous aspiration with injection of
sclerosing agents (sclerotherapy) is associated with rare but severe
complications and thus is best reserved for patients with a high
surgical risk. Cyst aspiration is associated with a high rate of recurrence and is rarely indicated as definitive therapy for symptomatic
cases in which the patient is unable to undergo other treatment
modalities. Because it typically takes several days for cyst fluid to
reaccumulate, however, cyst aspiration may be used as a diagnostic
maneuver to determine whether symptoms are attributable to the
cyst. In case there is diagnosis uncertainty (e.g., imaging features
suspicious for MCN), follow-up imaging or surgical intervention
may be necessary.
With surgical fenestration, part of the cyst wall is resected to
establish a permanent communication between the cyst and the
peritoneal cavity for drainage. Fenestration should be performed
with a minimally invasive approach (laparoscopic or robotic) when
possible. The minimally invasive approach is associated with reduced
hospital stay, decreased postoperative pain, and reduced blood loss
compared with an open procedure. An energy device (e.g., harmonic
scalpel) or surgical stapler is commonly used to cut through the cyst
wall and liver tissue to minimize the likelihood of postoperative
bleeding. In open operations, the resection margin can instead be
oversewn with a running locked suture. The resected cyst wall is sent
for pathologic evaluation to rule out a neoplasm. A mobilized omental flap can be placed into the opened cyst to reduce the risk of recurrence, which is caused by other tissue walling off the opened cyst
(e.g., diaphragm). Complete cyst wall resection is rarely indicated
and is reserved for instances when there is a high suspicion for MCN.
Complete resection can generally be performed with either a wedge
or segmental resection. Recurrence rates are comparable between
fenestration and complete resection, both between 5% and 15%.
Morbidity for surgical fenestration or resection is approximately
15%, and mortality is less than 1%. Main complications include postoperative ascites, bile leak, hematoma, and surgical site infection. For
patients with high surgical risk, sclerotherapy can be used to destroy
the biliary epithelial lining of the cyst wall, which is the source of
fluid production. A catheter is placed into the cyst cavity under US
guidance, and contrast is injected to evaluate for communication
with the biliary tree, which is a contraindication to sclerotherapy.
Sclerosing agents (ethanol, minocycline hydrochloride, or ethanolamine oleate) are injected into the cyst cavity and aspirated after 2
to 4 hours. Sclerotherapy is associated with a lower morbidity and
mortality rate, but the recurrence rate is 20% within the first year.
Postprocedural pain is common, though self-limiting. Additional
contraindications to sclerotherapy include intracystic bleeding and
fistula to the gastrointestinal tract or peritoneum.
MUCINOUS CYSTIC NEOPLASM
Pathogenesis
MCNs, previously referred to as biliary cystadenomas, are cystic
neoplasms of the biliary ductular system that may occur throughout the biliary tree, including both intrahepatic and extrahepatic
locations. MCNs typically present as a solitary, multilocular mass
with fluid contents. Histologically, MCNs are lined by biliary-type
mucus-secreting cuboidal or columnar epithelium, supported by a
mesenchymal stroma-resembling ovarian tissue and surrounded by
a less cellular layer of collagen. Unlike biliary intraductal papillary
mucinous neoplasms, no papillary projections are found in MCNs.
Malignant transformation or the presence of an invasive carcinoma
(previously referred to as cystadenocarcinoma) has been described in
approximately 15% of cases.
Presentation
MCNs typically occur as a single cystic mass, predominately in adult
women (90%). The majority of these tumors are identified incidentally, although some patients may present with abdominal pain or
distention. Cyst rupture and hemorrhage are rare complications.
Imaging
On US, MCNs are multilocular anechoic lesions with a thick wall.
Intracystic debris are frequently observed. Mural and septal nodules
may be associated with malignant transformation. On CT, MCNs
have low attenuation but, unlike simple cysts, the walls are thickened and/or nodular and show enhancement on contrast injection.
Similar cyst wall findings are also seen on MRI (Fig. 2). The degree
of T1 signal intensity in the cyst fluid indicates the degree of protein
and debris. Magnetic resonance cholangiopancreatography (MRCP)
may identify a communication between the cyst and the biliary tree.
Although mural nodules are more commonly seen in patients with
malignant transformation, the diagnosis of invasive carcinoma cannot be reliably made on imaging findings.
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FIG. 2 (A) Axial T2-weighted MRI demonstrating a cystadenoma in the left lobe of the liver in a 57-year-old woman. (B) Axial T1-weighted imaging of the
same lesion reveals a hypoattenuated, septated mass with clear borders.
Management
MCNs should be completely resected with negative margins
because of the risk of malignant transformation within the cyst.
Aspiration and fenestration are not recommended as the definitive
treatment because premalignant or malignant tissue is left behind.
In addition, aspiration is associated with high recurrence rates
(80%–90%). For intrahepatic disease, technical factors including
cyst location and size should determine the type and extent of liver
resection. Peripheral lesions should be managed with partial liver
resection. For more central lesions near major vessels, enucleation
is an acceptable alternative if formal resection is not possible. In
extremely rare cases, orthotropic liver transplant can be used in the
treatment of MCN.
HEPATIC HEMANGIOMA
Pathogenesis
Hepatic hemangiomas are the most common benign liver lesion,
occurring in 5% to 20% of the population. They are congenital
malformations comprising blood-filled cavernous spaces lined by a
single layer of endothelial cells and separated by fibrous tissue. They
are round, well-encapsulated, and may contain thrombi or calcifications. Hemangiomas have no potential for malignant transformation
and, in contrast with adenomas, have an extremely low risk of spontaneous hemorrhage or rupture. Most hemangiomas exhibit either
slow growth or no growth over time. Although hemangiomas have
no estrogen receptors, estrogen exposure may result in higher rates
of enlargement with no increase in risk of rupture.
Presentation
Hemangiomas occur predominately in women 20 to 50 years of
age. Most patients present with a single lesion, with only 10% of
patients presenting with multifocal disease. The majority of cases
are incidentally found, with lesions ranging from several millimeters to several centimeters in diameter. Lesions greater than
10 cm are referred to as giant hemangiomas. Symptoms are rarely
present and include abdominal pain and early satiety resulting from
compression of the upper gastrointestinal tract. Giant hemangiomas in children may also result in a consumptive process called
Kasabach-Merritt syndrome, characterized by thrombocytopenia,
hypofibrinogenemia, elevated fibrin degradation products, and
coagulopathy.
Imaging
On US imaging, hemangiomas appear as well-demarcated, homogeneous, hyperechoic lesions with posterior acoustic enhancement. On
cross-sectional imaging, hemangiomas appear as well-circumscribed
lesions with peripheral nodular enhancement in the early phase
followed by a progressive centripetal enhancement and washout on
delayed phases (Fig. 3B). These lesions are hypointense on T1-weighted
MRI and markedly hyperintense on T2-weighted MRI (Fig. 3A).
Management
Asymptomatic patients with small lesions for which the diagnosis
of hemangioma is clear on imaging do not need any additional
follow-up. For larger lesions (i.e., >5 cm) and/or diagnostic uncertainty, follow-up imaging is recommended in 3 to 6 months. Significant growth or presence of significant symptoms are indications
for surgical treatment. In the exceedingly rare situation when the
patient presents with rupture or hemorrhage, surgery is indicated.
However, preoperative hepatic arterial embolization is typically done
before resection to control bleeding. Embolization may also be done
before resection of giant hemangiomas to mitigate intraoperative
bleeding and for symptomatic patients who are not candidates for
surgery. Hemangiomas can be resected through enucleation or liver
resection based on the size and location of the lesion, preferably with
minimally invasive approaches, if technically feasible. Enucleation
is possible because hemangiomas have a large pseudocapsule that
can be separated from the liver parenchyma as crossing vascular
structures are controlled. Mortality for resection of hemangioma is
low (<1%). Enucleation is associated with lower risk of postoperative
complications compared with liver resection.
HEPATIC ADENOMA
Pathogenesis
Hepatic adenomas are encapsulated tumors composed of large plates
of adenoma cells that are larger than hepatocytes and contain glycogen
and lipids. Grossly, they appear as soft, tan lesions perfused by peripheral arteries on their outer surface, sometimes with central necrosis
or hemorrhage, and they generally occur in patients with a normal
liver, although steatosis and steatohepatitis are risk factors. Other risk
factors include estrogen exposure such as those in oral contraceptives,
anabolic steroids, and types I and III glycogen storage diseases. Adenomas may be categorized into three distinct subtypes: hepatocyte
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A
T1 T2
B
FIG. 3 (A) Hemangiomas appear hypointense on T1-weighted MRI and hyperintense on T2-weighted images, as shown by this large left hepatic lobe mass
in a 51-year-old woman. (B) MRI demonstrates centripetal contrast enhancement over time, which is pathognomonic for hemangioma.
nuclear factor (HNF)-1 alpha–inactivated adenoma, inflammatory
adenoma, and beta-catenin activated adenoma, although not all
adenomas can be classified within these categories. The HNF1alpha–inactivated subtype comprises 30% to 50% of adenomas and
is characterized by diffuse steatosis and lack of inflammatory infiltrates. Inflammatory adenomas account for up to 50% of cases and
are characterized by lymphocytic infiltrates, sinusoidal dilation and
hemorrhage, and abnormal activation of the JAK/STAT pathway.
Inflammatory adenomas are associated with obesity-induced nonalcoholic steatohepatitis. Adenomas with beta-catenin activation are
observed less often, in approximately 10% of cases, but they are the
most common subtype in men and are associated with androgen use.
These lesions exhibit greater cellular atypia in addition to pseudoglandular formation. Hepatic adenomas are at risk for malignant transformation, mainly among those with beta-catenin activation. Because of
the lack of a capsule, there is also risk of spontaneous bleeding and
rupture with life-threatening intraabdominal hemorrhage. Bleeding
is especially common with inflammatory adenomas.
Presentation
Adenomas can present as single or multiple simultaneous lesions and
can range from a few millimeters to greater than 10 cm in diameter.
The presence of 10 or more adenomas is referred to as adenomatosis.
Adenomas occur most often in women 20 to 40 years of age and less
commonly in men. Most adenomas are incidentally found during
abdominal imaging for other indications. However, some patients
present with acute-onset right upper quadrant or epigastric pain
secondary to spontaneous hemorrhage, which can be self-limiting
or, more rarely, associated with hypovolemic shock and hemoperitoneum. Other symptoms include sporadic abdominal pain, early
satiety, and, very rarely, jaundice resulting from biliary obstruction.
Imaging
Adenomas appear as well-demarcated, heterogeneous masses with
variable echogenicity on US imaging. Because the appearance is
nonspecific, additional imaging is recommended. On CT, adenomas are isodense relative to the surrounding liver parenchyma. On
MRI, adenomas appear isointense to hyperintense on both T1-and
T2-weighted sequences (Fig. 4B). Multiphasic enhancement with
contrast will show adenomas to enhance during the early arterial
phase, which disappears in the later phases. Depending on the
degree of necrosis or hemorrhage, adenomas may have heterogenous
attenuation (Fig. 4A). Gadoxetic acid contrast can help distinguish
FNH from adenoma as this contrast will be retained during the late
(hepatobiliary) phase in FNHs but not typically in adenomas, with
the exception of inflammatory adenomas.
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FIG. 4 (A) Axial CT scan of a 21-year-old woman with two large adenomas with foci of hemorrhage. (B) Axial T2-weighted image of the same lesions
shows a mixed-intensity signal that correlates with regions of hemorrhage.
Management
Resection of the adenoma is recommended for patients with symptoms and those at risk of bleeding and/or malignant transformation.
Because of the high risk of malignant transformation, all men with
adenomas should be considered for surgical resection, regardless
of the size of the lesion. For an adenoma less than 5 cm in diameter
in a female patient, the initial management strategy is cessation of
estrogen or anabolic steroids if present. Obese patients with fatty
liver disease should be counseled on lifestyle modifications for weight
loss. The main goal with risk mitigation is to avoid further growth.
Although regression of the adenoma is possible, disappearance is
unlikely, thus long-term surveillance is indicated. Pregnant women
are at risk of hormone-induced growth and rupture. Therefore, closer
follow-up should be performed in these patients (monthly as opposed
to 6–12 months). For women in whom the adenoma continues to
grow or becomes symptomatic or for adenomas greater than 5 cm,
surgical resection is recommended. Transarterial embolization may
be used before surgery to reduce the size of the lesion and is the treatment of choice for bleeding control in cases of acute rupture. After
the bleeding is controlled, the patient is referred for surgical resection, except in the rare cases in which there is no residual lesion on
follow-up MRI. Embolization and thermal ablation can also be used
as definitive treatment of adenoma, but experience with these modalities is limited. Surgical resection is typically accomplished through
liver resection, although enucleation can also be used. Resection
should be parenchymal-sparing and done minimally invasively when
possible, based on the location and size of the lesion. For patients with
multiple adenomas or unresectable lesions, close surveillance with
MRI is recommended. Growth or worrisome changes on MRI of any
specific lesion is an indication to resect that single lesion. For patients
who present with acute hemorrhage from a ruptured adenoma for
which embolization fails or is not an option, emergent laparotomy is
indicated. Liver packing and inflow control with Pringle’s maneuver
are used for bleeding control. Resection may be performed at the
same operation, but patients with acidosis, coagulopathy, or hypothermia may require resuscitation before the definitive operation.
FOCAL NODULAR HYPERPLASIA
Pathogenesis
FNH is thought to be a hyperplastic lesion of the hepatocytes
surrounding a congenital arteriovenous malformation and thus
not a true neoplasm. Histologically, FNH is characterized by proliferation of mature hepatocytes and bile ducts in a stellate pattern
often surrounding a central scar composed of fibrous tissue and
malformed vessels. In FNH, the beta-catenin pathway is activated
but, unlike in other beta-catenin–activated lesions (adenoma,
hepatocellular carcinoma), activating mutations of CTNNB1 are
not observed. FNH shows a characteristic maplike pattern on
immunohistochemical staining for glutamine synthetase. Although
the presence of this immunohistochemical pattern can help differentiate FNH from other lesions, its differentiation from diffuse
glutamine synthetase staining, characteristic of other beta-catering
activated tumors, can be difficult in small biopsy specimens. These
lesions have no malignant potential and an extremely low risk of
bleeding.
Presentation
FNH is the second most common benign liver lesion after hemangioma and occurs most often in reproductive-age women 20 to
50 years of age. These lesions are typically incidental. When symptomatic, vague right upper quadrant or epigastric pain are the most
common symptom. FNH usually presents as a single lesion, although
multiple lesions may be observed in rare cases and are sometimes
associated with a syndrome of vascular malformations.
Imaging
US is an unreliable modality for the diagnosis of FNH. Contrast-enhanced CT and MRI are the standard of care for diagnosing FNH.
On noncontrast CT images, FNH will appear isoattenuated or
hypoattenuated relative to the surrounding liver parenchyma, and in
some cases a hypoattenuated central scar is visible. On T1-weighted
MRI, FNH appears hypointense throughout, while on T2-weighted
sequences, FNH is hypointense with a hyperintense central scar
(Fig. 5A). After contrast injection, FNH will have enhancement in
the early, arterial phase (Fig. 5B), which disappears in the venous
phase. If a central scar is present, it will remain enhanced in the
venous phase. In the absence of a central scar, these findings overlap with those of adenoma and fibrolamellar carcinoma. Retention
of gadoxetic acid on delayed hepatobiliary phase in FNH may be
helpful in distinguishing it from adenoma. However, retention of
gadoxetic acid on delayed hepatobiliary phase can also be seen in
inflammatory adenomas.
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A
T1 T2
B
FIG. 5 (A) Focal nodular hyperplasia (FNH) appears hypointense throughout on T1-weighted MRI, whereas on T2-weighted sequences FNH is hypointense
with a hyperintense central scar (white arrow). (B) FNH displays early arterial enhancement with rapid washout. During the venous phase, FNH is isointense, while the central scar remains enhanced.
Management
Surgical resection is indicated in the presence of significant symptoms. In addition, surgery may be necessary when the lesion cannot
be differentiated from an adenoma or fibrolamellar carcinoma. In the
absence of a central scar, a biopsy may be helpful to establish the diagnosis. However, because the typical maplike staining for glutamine
synthetase is not always seen on biopsy, the diagnosis of adenoma
may be impossible to rule out without resection. In these situations,
management will be dictated by the possible risk of bleeding and/or
malignant transformation in case the lesion turns out to be an adenoma. When resection of FNH is recommended, minimally invasive
approaches are favored. The lesion can be resected with either enucleation or liver resection, based on the size and location of the lesion.
SUMMARY
There has been a substantial increase in the frequency of incidentally
discovered liver lesions because of the increased use of axial imaging.
The majority of these lesions are benign and include simple cysts,
MCNs, hemangiomas, adenomas, and FNH. Management is dictated
by the presence of symptoms and the risk of complications, which
include bleeding and malignant transformation. Risk of malignant
transformation is seen in MCNs and adenoma, therefore, surgical
resection is recommended for all patients when MCN is suspected.
When the suspicion is low (i.e., presence of internal septations in
the absence of wall enhancement/thickening), surveillance is an
acceptable alternative to surgery. Adenomas >5 cm in women or of
any size in men should be resected. Smaller adenomas in women
should be followed long-term with imaging to monitor growth while
addressing risk factors (e.g., estrogen and anabolic steroid exposure,
obesity). In addition to malignant transformation, adenomas >5 cm
are at risk of spontaneous bleeding, which could result in rupture
with life-threatening hemoperitoneum. Finally, surgery may be
indicated if the diagnosis cannot be confirmed with imaging with
or without a core biopsy. This is more commonly seen in patients
with hypervascular lesions with imaging features that are common
to both FNHs and adenomas. This is especially true in trying to
differentiate an FNH with no central scar from an inflammatory
adenoma because the retention of gadoxetic acid in the hepatobiliary
phase of the MRI, characteristic of FNHs, has also been described in
inflammatory adenomas. Moreover, the maplike staining for glutamine synthetase, pathognomonic for FNH, sometimes is not seen on
core biopsy because of sampling limitations. When surgical resection
is recommended for benign liver lesions, enucleation is preferred
in most cases if technically feasible, except in benign liver cysts,
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when fenestration is possible, and when there is a risk of malignancy
(e.g., MCNs and fast-growing adenomas). The minimally invasive
approach should be used when technically possible, and the risk of
perioperative complications is typically low. Because establishing a
causal relationship between symptoms and the liver lesion is often
difficult, patients whose surgical resection is recommended based
on the presence of symptoms alone should be counseled on the possibility that symptoms may not improve after surgery. The ability of
surgeons to diagnose and appropriately manage benign liver lesions
has taken on greater importance given the increased frequency of
incidentally identified liver lesions, a current trend that is likely to
continue in the future.
S u g g e S t e d R e a d i n g S
Arnaoutakis DJ, Kim Y, Pulitano C, et al. Management of biliary cystic
tumors: a multi-institutional analysis of a rare liver tumor. Ann Surg.
2015;261(2):361–367.
Management of
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Bioulac-Sage P, Sempoux C, Balabaud C. Hepatocellular adenomas: morphol-
ogy and genomics. Gastroenterol Clin North Am. 2017;46(2):253–272.
European Association for the Study of the Liver (EASL). EASL Clinical
Practice Guidelines on the management of benign liver tumours. J
Hepatol. 2016;65(2):386–398.
Ibrahim S, Chen CL, Wang SH, etal. Liver resection for benign liver tumors:
indications and outcome. Am J Surg. 2007;193(1):5–9.
McInnes MD, Hibbert RM, Inácio JR, Schieda N. Focal nodular hyperplasia
and hepatocellular adenoma: accuracy of gadoxetic acid–enhanced MR
imaging—A systematic review. Radiology. 2015;277(3):927.
Miura JT, Amini A, Schmocker R, et al. Surgical management of hepatic
hemangiomas: a multi-institutional experience. HPB. 2014;16(10):924–
928.
Tsilimigras DI, Rahnemai-Azar AA, Ntanasis-Stathopoulos I, etal. Current
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2019;23(1):199–209.
be achieved with a variety of intraarterial therapies, including hepatic
arterial bland embolization (HAE), transarterial chemoembolization
(TACE), or radioembolization with yttrium-90.
Danielle K. DePeralta, MD, and Matthew J. Weiss, MD, MBA
alignant tumors of the liver are grouped into two categories:
primary and metastatic. The most common primary malig-
M
nant tumors of the liver include hepatocellular carcinoma (HCC)
and intrahepatic cholangiocarcinoma (ICC). In the Western world,
metastatic liver tumors such as colorectal, pancreatic, gastric, and
neuroendocrine are significantly more common than primary liver
tumors. Colorectal metastases are among the most frequent indications for liver resection.
Surgical resection is the mainstay of treatment for hepatic malignancies. Appropriate patient selection requires evaluation of overall
health status, oncologic appropriateness, and resectability of the
disease. A lesion is considered resectable if negative margins can be
obtained while leaving an adequate amount of functional liver parenchyma with intact hepatic arterial and portal venous inflow, hepatic
venous outflow, and biliary drainage. In patients without underlying
liver disease or extensive exposure to systemic chemotherapy, this
typically requires two contiguous segments of remaining liver parenchyma. If this cannot be achieved, other local (ablation, external
beam radiation) or regional (tumor embolization, hepatic artery
infusion pump) therapies are frequently possible.
Thermal tumor ablation has evolved significantly over time and
is most frequently accomplished with microwave ablation (MWA),
which can be performed percutaneously, laparoscopically, or during
an open operation. Traditionally, radiofrequency ablation (RFA) and
cryoablation were commonly employed, but MWA is more efficient
and efficacious. Nonthermal ablation with irreversible electroporation (IRE) is a newer option for tumors adjacent to major vessels or
critical structures that could be potentially damaged by thermal ablation. IRE uses short-duration, high-voltage pulses to create defects in
the lipid bilayer that ultimately results in cell death. This avoids the
heat-sink effect associated with loss of thermal energy when used
in close proximity to major blood vessels. In addition to surgical
resection and ablation, external beam radiation—either conformal or
stereotactic—is an option for local therapy. Tumor embolization can
PRIMARY LIVER TUMORS
Hepatocellular Carcinoma
HCC is the most common primary malignant liver tumor worldwide. Although the incidence is highest in Asia and sub-Saharan
Africa, the incidence in the United States is rising. Risk factors
include cirrhosis and chronic liver disease from any cause, including
viral hepatitis, alcohol use, and fatty liver disease. Patients with hepatitis C disease typically develop HCC in the setting of long-standing
cirrhosis, but those with hepatitis B may develop HCC without
antecedent cirrhosis. A less common subtype, known as fibrolamellar HCC, often occurs in younger patients and those without
preexisting liver disease or cirrhosis. In the setting of chronic liver
disease, CT and MRI are typically diagnostic for HCC and biopsy is
not indicated unless additional tissue is needed for molecular analysis to guide systemic therapy. Imaging findings include homogenous
hyperenhancement in the arterial phase with portal venous washout.
The Liver Imaging Reporting and Data System (LI-RADS) standardizes terminology and serves as a classification system to characterize
liver lesions in patients with chronic liver disease at risk for HCC. A
LI-RADS 5 lesion is diagnostic of HCC.
In most cases, HCC must be managed in parallel with chronic
liver disease. In addition to the American Joint Committee on
Cancer (AJCC) staging system, the Barcelona Clinic Liver Cancer
(BCLC) and Okuda staging systems are frequently used. These alternative staging systems also incorporate the extent of chronic liver
disease. Staging workup includes a thorough history and physical
exam, thorough investigation for extent of chronic liver disease and
portal hypertension, laboratory studies including alpha-fetoprotein
(AFP) (CA 19-9 and CEA should be included if the diagnosis is
unclear), chest CT, and abdominal CT or MRI. Bone scans should be
considered selectively. The most common sites of metastatic spread
include the lung, peritoneum, bone, spleen, adrenal gland, and brain.
In appropriately selected patients, liver transplantation addresses
both the underlying liver disease and the malignancy and therefore
is the treatment of choice in patients with advanced cirrhosis and
relatively limited HCC. It also addresses the “field defect” present
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in a cirrhotic liver and mitigates the risk of new HCC formation
by removing the entire diseased liver. Transplantation is limited by
organ availability and transplant-associated risks, including organ
rejection and complications of immunosuppression. Several other
treatment modalities are often employed either as definitive therapy
or as a bridge to transplantation.
Surgical resection of HCC is an excellent option in patients with
limited underlying liver disease and/or those with tumors beyond
criteria for transplant. The presence and degree of hepatic fibrosis/
cirrhosis correlates with the risk of posthepatectomy liver failure and
long-term survival. Major hepatectomy is generally only an option
for patients without underlying cirrhosis or cirrhosis classified as
Child-Pugh A (Table 1) with no evidence of portal hypertension.
Perioperative mortality in these patients is less than 5% but increases
significantly in patients with Child-Pugh B or C cirrhosis, or portal
hypertension. A detailed discussion comparing resection and transplantation is available in a separate chapter.
In patients who are medically fit for an operation, resection is
only indicated if negative margins can be achieved. Ideally, anatomic
resections of portal territories including sectionectomy, segmentectomy, and subsegmentectomy should be performed because HCC
tends to spread along portal venous tributaries. Anatomic resection
is associated with improved recurrence-free survival and overall
survival in patients with HCC. Although bulky portal adenopathy
is often present in the setting of chronic liver disease, formal portal
lymphadenectomy is typically not necessary. Presently, there are no
good options for adjuvant systemic therapy in resected HCC.
If a patient is not fit for surgery, ablation is often an excellent
option for local tumor control. Based on multiple randomized trials,
thermal ablation of small (<2–3 cm) HCC has long-term outcomes
similar to surgical resection with less morbidity and mortality. However, these data should be interpreted with caution as these trials had
small sample sizes and were not designed as noninferiority trials.
Furthermore, they were primarily conducted in Asian populations
with much higher incidence of hepatitis B compared with Western
populations.
Intra-arterial embolization (bland HAE, TACE, or radioembolization with yttrium-90) is reserved for patients who are not
candidates for potentially curative therapy with transplantation,
resection, or ablation. Embolization is often employed as a bridge to
transplantation or before attempted ablation of larger tumors measuring 3 to 5 cm. Although transplantation and surgical resection are
typically contraindicated in patients with extrahepatic metastasis,
TABLE 1 Child-Turcotte-Pugh Score
Measure 1 Point 2 Points 3 Points
Total bilirubin,
mg/dL
Serum albumin,
g/L
PT/INR <1.7 1.71–2.30 >2.30
Ascites None Mild Moderate to
Hepatic
encephalopathy
PT/INR, Prothrombin time/international normalized ratio.
*The score uses five clinical measures: class A, 5–6 points; class B, 7–9
points; class C, 10–15 points.
<2 2–3 >3
>35 28–35 <28
None Grades I–II
(suppressed with
medication)
*
severe
Grades
III–IV
(refractory)
other liver-directed therapies may be considered in the setting of
liver-dominant disease. Systemic therapy should be considered in
patients with more extensive extrahepatic disease. In recent years,
systemic options for HCC have increased. The multikinase inhibitors
sorafenib and lenvatinib, as well as the anti PD-1 agent nivolumab,
are options in the first-line setting. Regorafenib, cabozantinib, ramucirumab, and nivolumab/pembrolizumab are available second-line
treatment options.
Intrahepatic Cholangiocarcinoma
ICC is the second most common primary malignant liver tumor and
accounts for 10% to 20% of cases. Biliary tract cancers arise from
cholangiocytes and can be classified into four types: ICC, hilar cholangiocarcinoma, distal cholangiocarcinoma, and gallbladder cancer.
Risk factors for cholangiocarcinoma include sclerosing cholangitis
(8%–20% lifetime risk), choledochal cysts (3%–28% lifetime risk),
and cirrhosis. There are three gross subtypes of ICC, which include
mass forming, periductal infiltrating, and intraductal. The periductal infiltrating type is most common and associated with the worst
prognosis.
Staging workup includes thorough history and physical exam,
laboratory studies including CA 19-9 (as well as AFP and CEA if the
diagnosis is in question), chest CT, and abdominal pelvic CT or MRI.
Easily resectable tumors are often resected without a biopsy, but in
cases where a neoadjuvant therapy approach is under consideration,
a biopsy is necessary. Diagnostic laparoscopy is often helpful to evaluate for occult peritoneal metastasis at the time of planned resection
to avoid unnecessary laparotomy, particularly in patients with large
tumor or significantly elevated CA 19-9.
Surgical resection with negative margins is the only curative
option. Approximately one-third of patients will have nodal metastasis to the porta hepatitis at the time of resection, and formal portal
lymphadenectomy is necessary for all patients with suspected biliary
tract cancer. This is in contrast to HCC, where portal lymphadenectomy is rarely indicated. Five-year survival after surgical resection
is approximately 40% to 60%. Adjuvant chemotherapy is recommended for most patients, even in the setting of early-stage disease.
Adjuvant radiation may provide additional locoregional control for
patients with positive margins, involved lymph nodes, or inadequate
lymphadenectomy.
METASTATIC LIVER TUMORS
Colorectal Liver Metastasis
Colorectal cancer is the third most frequent malignancy with approximately 150,000 new cases diagnosed annually in the United States.
Half of all patients diagnosed with colorectal cancer will develop liver
metastasis, either at the time of initial diagnosis (synchronous) or
months and even years after initial diagnosis (metachronous). Consequently, colorectal liver metastases (CRLM) are far more common
than primary liver tumors.
Surgical resection, when feasible, is the best curative option in
patients with CRLM. The goal is to remove all disease with microscopically negative margins. Whenever feasible, parenchymal-sparing
resection is preferred as this is associated with less morbidity and
increased options for salvage in the event of recurrence. In the case
of bilateral CRLM, formal hepatic lobectomy can be combined with
parenchymal-sparing resection, as well as thermal ablation to treat
all sites of disease. The extent of resection that can be performed at
the time of a single operation is dictated by the volume of anticipated
future liver remnant (FLR) and patient comorbidities. Many of these
patients have been treated with chemotherapy before liver resection,
with resultant chemotherapy-associated liver injury. This must
be considered when calculating the volume of FLR and planning
resection. If the anticipated FLR is less than 30% in a patient treated
with chemotherapy (or 20% in a patient with a healthy liver), a
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two-stage resection is generally recommended, typically with portal
vein embolization (PVE) between stages. An alternative to two-stage
hepatectomy is associating liver partition and portal vein ligation
(ALPPS), which may increase resection rates with comparable surgical margins, complications, and short-term morbidity.
In patients with synchronous CRLM, the primary tumor and liver
metastasis can be resected at the same time or in staged operations.
Sequencing will also include a period of systemic therapy. In general,
extensive hepatectomy in combination with complex colorectal resection, for example, those requiring extensive pelvic resection or low
rectal anastomosis, are best avoided. Several factors are considered
in sequencing these operations. If the primary tumor is symptomatic
with evidence of bleeding or obstruction, it should be addressed
first. If the primary tumor is asymptomatic, a “liver first” approach
is favored by many centers. In patients with rectal cancer, short- or
long-course radiation will also be necessary, and this must be carefully sequenced with systemic therapy and planned surgical resection.
Unlike primary liver tumors, limited extrahepatic metastasis
is not necessarily a contraindication to hepatic metastasectomy if
the extrahepatic disease can be treated completely. This reflects the
excellent response rates to systemic therapy in patients with colorectal cancer. Preoperative chemotherapy is typically administered
to assess tumor response and to address potential micrometastatic
disease not visible on imaging. A large randomized, controlled trial
of perioperative chemotherapy for CRLM demonstrated improved
progression-free survival compared with patients who underwent
resection alone. However, prolonged chemotherapy can be associated with significant liver injury. Specifically, irinotecan-based
regimens are associated with steatohepatitis, and oxaliplatin-based
regiments are associated with sinusoidal congestion. “Disappearing”
liver metastases are an additional consideration because they will
eventually recur in up to 80% of patients if not resected. Careful
coordination among members of the multidisciplinary team is necessary to determine sequencing of all therapy. In general, preoperative
systemic therapy should be limited to 4 to 6 cycles or 2 to 3 months.
In the case of unresectable disease, additional locoregional therapies
including ablation, transarterial embolization, and placement of
a hepatic artery infusion pump can be considered. Hepatic artery
infusion pumps may also be utilized to convert from unresectable to
resectable disease and as adjuvant therapy following resection.
Prognostic factors for patients who undergo curative-intent
resection include the disease-free interval between diagnosis of the
primary tumor and hepatic metastasis, size of the largest hepatic
tumor, presence of extrahepatic metastasis, mutation status (e.g.,
RAS, BRAF), and nodal status of the primary tumor. Five-year overall and disease-free survival range from 30% to 60% and 20% to 40%,
respectively.
PREOPERATIVE EVALUATION
Patients should undergo preoperative optimization and risk stratification tailored to their comorbidities and performance status. Liver
function is assessed with evaluation of total bilirubin, prothrombin
time, albumin, presence of ascites, and history of encephalopathy.
The Child-Pugh scoring system (see Table 1) is associated with
perioperative mortality rates of 5%, 30%, and 80% in patients with
class A, B, and C cirrhosis, respectively. Thrombocytopenia (platelets
<100,000 mm
of portal hypertension, which is associated with prohibitive rates of
perioperative mortality after hepatectomy.
The location of the liver lesions and their relationship to major
vascular and biliary structures are determined by high-quality,
contrast-enhanced CT scan or MRI. The volume of the FLR is
calculated to estimate the risk of posthepatectomy liver failure. In
the absence of underlying hepatic dysfunction, an FLR of 20% of
the standardized total liver volume is typically sufficient. Patients
with some degree of liver dysfunction, such as those who have
been treated with cytotoxic chemotherapy, should have an FLR of
3
), splenomegaly, and esophageal varices are indicative
at least 30%, and patients with cirrhosis need an FLR of at least
40%. Volumetry is calculated with three-dimensional CT scan or
MRI. The volume of nonfunctional liver (parenchyma that is either
nonperfused or replaced by tumor) is subtracted from the total liver
volume, which is especially important for patients with large lesions.
Alternatively, the estimated liver volume can be calculated from the
patient’s body weight or body surface area (i.e., total liver volume in
3
cm
= −794.41 = 1267.28 × body surface area in m²). Patients with
insufficient FLR should undergo PVE of the branches of the segments
planned for resection to induce hypertrophy of the contralateral liver.
Volumetry is repeated about 4 weeks after PVE and in a few more
weeks if the minimal recommended FLR has not been achieved.
ALPPS, an alternative to two-stage hepatectomy, was first described
in 2011. This consists of a short interval two-stage resection with the
first stage typically involving right portal vein ligation and parenchymal transection. This induces rapid contralateral hypertrophy, with
the goal of completing the second stage during the same hospitalization in 1 or 2 weeks. This approach is only recommended in highly
experienced centers because morbidity and mortality can be high.
TECHNICAL CONSIDERATIONS
Liver resections are classified into anatomic and nonanatomic. Anatomic resections include segmentectomy, sectionectomy, hemihepatectomy, and trisectionectomy. Small peripheral lesions are usually
amenable to parenchymal-sparing nonanatomic resections. Larger or
more centrally located lesions often require anatomic resection. This
can be performed though an open or minimally invasive approach.
Positioning, Incision, and Exposure
Patients are placed in the supine position with arms extended at
90 degrees. Intravenous fluids are restricted until the parenchymal
transection is complete to decrease blood loss from hepatic veins.
Central venous cannulation is often unnecessary but should be considered in patients with extensive comorbidities, especially if major
hepatectomy is planned. If measured, a central venous pressure less
than 5 cm HO is recommended. Once the parenchymal transection
is complete, intravascular volume is restored to achieve euvolemia.
In an open technique, a right subcostal incision with an upper
midline extension provides adequate exposure for most cases.
Alternative incisions include a midline, inverted “L” (Makuuchi’s
incision) or bilateral subcostal with midline extension (Mercedes
Benz incision). If necessary, the xiphoid is removed to facilitate visualization of the suprahepatic inferior vena cava (IVC). The peritoneal
cavity is explored for extrahepatic metastasis. The round ligament is
divided and the falciform is dissected along the anterior surface of
the liver up to the hepatic venous outflow. The gastrohepatic ligament is opened to expose the caudate lobe with care not to injure an
accessory or replaced left hepatic artery. Intraoperative ultrasound is
performed to identify all lesions, including any that may have been
occult on preoperative imaging. Furthermore, ultrasound is used to
define tumor relationship with vascular and biliary structures and
define the resection plane.
Inflow and Outflow and Outflow Control
For major hepatic resections, hepatic and portal venous inflow can
be dissected and controlled in the hilum of the liver, intraparenchymally, or through small hepatotomies (Fig. 1). The latter approach
should be avoided if the tumor is within 2 cm of the hilum. Inflow
control before parenchymal resection will result in a vascular demarcation line that will guide the correct transection plane. It is our
practice to divide the inflow structures in the hepatic hilum using
a vascular stapler or sutures. After inflow has been controlled, the
hepatic venous outflow is controlled. This can also be done extrahepatically, which is our preference whenever feasible, or within the
parenchyma during the transection.
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FIG. 1 (A) For the right portal pedicle to be accessed, hepatotomies are made in the gallbladder fossa (2) and in the caudate process (1). The pedicle is
encircled with a renal pedicle clamp, and a vessel loop is passed around it. The vessel loop is used to retract the main portal vein/left portal vein to the left
as a TA stapler is passed and fired (B) to divide the right portal pedicle. (From Fong Y, Blumgart LH. Useful stapling techniques in liver surgery. J Am Coll Surg.
1997;185:93.)
5
tape
6
I
FIG. 2 (A) For division of the liver parenchyma, two stay sutures are placed for traction. The parenchyma is sequentially crush-clamped with a Kelly clamp;
this demonstrates various size pedicles and veins. Those <5 mm are sealed and divided with the LigaSure device. (B) If the structure is >5 mm, the endovascular stapler, clips, and ties are used. (From Patrlj L, Tuorto S, Fong Y. Combined blunt-clamp dissection and LigaSure ligation for hepatic parenchyma dissection: postco-
agulation technique. J Am Coll Surg. 2010;210:39.)
We also generally apply umbilical tape with a Rummel tourniquet
to the porta hepatitis, which can be tightened in the event a Pringle’s
maneuver is needed to control bleeding from the contralateral inflow
structures.
and hepatic veins that can be controlled with a combination of
energy devices (Fig. 2), clips, ties, and firings of a vascular stapler.
An alternative method is the two-surgeon technique, in which one
surgeon dissects with the Cavitron Ultrasonic Surgical Aspirator
(CUSA) and the other surgeon divides the vasculature and provides
Parenchymal Transection
Multiple tools and techniques are available for parenchymal transection. There are no compelling data to support one method over
another and thus is left to the discretion, expertise, and comfort
of the surgeon. A simple and frequently employed technique is
the crush-clamp method in which the liver parenchyma is gently
“crushed” with a Kelly clamp exposing branches of portal pedicles
exposure. Regardless of technique, small vessels less than 3 mm can
be divided with electrocautery, medium vessels are controlled with
titanium clips, and larger vessels greater than 5 mm are divided
with suture or a vascular stapler. Caution should be given to overuse of linear staplers in the absence of meticulous parenchymal
dissection as this technique can lead to inadvertent biliary or
vascular injury, especially in the setting of significant bleeding and
poor exposure.
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