Hepatic Tumors Flashcards
(97 cards)
1
Q
HCC
A
HCC is the most common primary malignant tumor of the liver.
It is the fifth most common cancer in men and the eighth most common in women, and it ranks fourth in annual cancer mortality rates
2
Q
HCC
A
Male predominance is, however, more obvious in populations at high risk for the tumor (mean male-to-female ratio, 3.7:1) than in those at low or intermediate risk (2.4:1)
3
Q
HBV
A
HBV DNA is integrated into cellular DNA in approximately 90% of HBV-related HCCs.1
4
Q
Risk Factors for HCC
A
MAJOR RISK FACTORS
Chronic HBV infection Chronic HCV infection Cirrhosis
NAFLD
5
Q
OTHER LIVER CONDITIONS
A
α1-Antitrypsin deficiency Hemochromatosis Membranous obstruction of the inferior vena cava Type 1 and type 2 glycogen storage disease Type 1 hereditary tyrosinemia Wilson disease
6
Q
INHERITED CONDITIONS NOT ASSOCIATED WITH LIVER DISEASE
A
Ataxia-telangiectasia
Hypercitrullinemia
7
Q
OTHER FACTORS
A
Cigarette smoking
Diabetes mellitus
Dietary exposure to aflatoxin B1 Oral contraceptive steroid use
8
Q
HCC
A
Possible direct carcinogenic effects include cis-activation of cellular genes as a result of viral integration, changes in the DNA sequences flanking the integrated viral DNA, transcriptional activation of remote cellular genes by HBV-encoded proteins (particularly the X protein), and effects resulting from viral mutations.
9
Q
The REACH-B (Risk Estimation for Hepatocellular Carcinoma
in Chronic Hepatitis B) score provides a
A
simple-to-use tool for
risk estimation for HCC among individuals with chronic HBV
infection and includes gender, age, serum ALT level, hepatitis B e antigen status, and serum HBV DNA level.
10
Q
HCV
A
In Japan, Italy, and Spain, HCV is the single most common etiologic factor for HCC, and in other industrialized countries, HCV infection, often in combination with alcohol abuse, has emerged as a major cause of the malignancy.
11
Q
HCV
A
Almost all HCV-induced HCCs arise in cirrhotic livers, and most of the exceptions are in livers with chronic hepatitis and fibrosis.
12
Q
Cirrhosis
A
Risk factors for HCC included
obesity, a low platelet count, and the presence of antibody to hepatitis B core antigen
13
Q
Aflatoxin B1
A
Dietary exposure to aflatoxin B1, derived from the fungi Aspergillus flavus and Aspergillus parasiticus, is an important risk factor for HCC in parts of Africa and Asia
14
Q
Other
A
Malignant transformation has been attributed to the cirrhosis but may also result from oxidant stress secondary to the accumulation of copper in the liver.
15
Q
HCC also may develop in patients with other inherited metabolic disorders that are complicated by cirrhosis,
A
such as α1-antitrypsin deficiency and type 1 hereditary tyrosinemia, and in patients with certain inherited diseases in the absence of cirrhosis—for example, type 1 glycogen storage disease
16
Q
Key Molecular Pathways Involved in Hepatocarcinogenesis
A
Angiogenic signaling Epigenetic promoter methylation and histone acetylation Growth factor-stimulated receptor tyrosine kinase JAK/STAT signaling PI3-kinase/AKT/mTOR p53 and cell cycle regulation Ubiquitin-proteasome Wnt/β-catenin
17
Q
Paraneoplastic Manifestations Associated with HCC
A
Carcinoid syndrome Hypercalcemia Hypertension Hypertrophic osteoarthropathy Hypoglycemia Neuropathy Osteoporosis Polycythemia (erythrocytosis) Polymyositis Porphyria Sexual changes—isosexual precocity, gynecomastia, feminization Thyrotoxicosis Thrombophlebitis migrans Watery diarrhea syndrome
18
Q
Diagnosis of HCC
A
The gold standard for the diagnosis of HCC is pathology.
Dysplastic nodules and even regenerative cirrhotic nodules can be seen on imaging studies and are potentially confused with HCC.
19
Q
Serum Tumor Markers
A
Serum tumor markers generally are not diagnostic for HCC by themselves but can be used in conjunction with imaging findings to diagnose HCC.
Additionally, they may raise the suspicion of HCC and lead to more sensitive and serial imaging of the liver.
Conventional liver biochemical tests do not distinguish HCC from other hepatic mass lesions or cirrhosis.
20
Q
AFP
A
AFP is an α1-globulin normally present in high concentrations in fetal serum but in only minute amounts thereafter.
21
Q
____can potentially be used for the diagnosis of HCC, surveillance, and prognostication.
A
Measurement of AFP
22
Q
can be considered diagnostic for HCC in an appropriate clinical context.
Although there is no specific diagnostic cutoff, values above 400 ng/mL in association with a liver mass can be considered diagnostic in most cases.
A
Clearly, markedly elevated AFP levels (>10,000 ng/mL to > 1,000,000 ng/mL)
23
Q
serum AFP levels appear to have some prognostic utility,
A
particularly with regard to LT, for which levels above 1000 ng/mL have been associated with poorer outcomes and higher rates of tumor recurrence.
24
Q
False-positive AFP results (for HCC)
A
also may occur in patients with tumors of endodermal origin, non-seminomatous germ cell tumors, pregnancy, and regenerating livers in the set- ting of ALF.
25
Fucosylated AFP
AFP is heterogeneous in structure. Its microheterogeneity results from differences in the oligosaccharide side chain and accounts for the differential affinity of the glycoprotein for lectins.
26
Des-γ-Carboxy Prothrombin
Serum concentrations of des-γ-carboxy prothrombin (DCP) (also known as prothrombin produced by vitamin K absence or antagonist II) are raised in most patients with HCC.
DCP is an abnormal prothrombin that is thought to result from a defect in the post-translational carboxylation of the prothrombin precursor in malignant cells
27
Imaging
The diagnosis of HCC generally requires imaging evidence of a focal lesion in the liver, although large infiltrating lesions can also be diagnostic.
Arterial hyperenhancement, particularly seen on dynamic contrast imaging of the liver, is observed because the blood supply of HCC comes from newly formed abnormal arteries (neoangiogenesis).
28
as a nodule transforms from low- to high-grade dysplasia and then to HCC, the primary blood supply shifts from portal to arterial;
new abnormal arterial branches produce characteristic findings on dynamic contrast imaging of the liver and subsequent hypoenhancement in the portal venous and delayed phases (“washout”)
HCC
29
European and American liver societies recommend
noninvasive diagnosis of HCC can be made in a nodule greater than 1 cm in diameter that demonstrates arterial hyperenhancement and portal venous or delayed washout.
30
The LI-RAD categories
assist the clinician in assessing the risk that a nodule is HCC, with LI-RAD 3 being intermediate risk, LI-RAD 4 probable HCC, and LI-RAD 5 definite HCC.
31
smaller tumors (<5 cm) are most often hypoechoic
and may demonstrate a thin peripheral fibrous capsule.
Small HCCs can also be uniformly hyperechoic and therefore indistinguishable from focal fat or a hemangioma
32
Multiphase (also called dynamic) multidetector CT
is the most popular imaging technique for the diagnosis of HCC
33
The classic and most diagnostic pattern for HCC is a combination of hyperenhancement in the arterial phase (with the uninvolved liver lacking enhancement), loss of central nodule enhancement compared with the enhancing uninvolved liver (washout), and capsular enhancement in the portal-venous and delayed phases
HCC
34
Guidelines recommend biopsy of lesions
larger than 1 cm and serial imaging for lesions smaller than 1 cm that do not have characteristic arterial enhancement and washout
35
Dynamic CT
is also useful for detecting invasion into the portal or hepatic veins and identifying the location and number of tumors; these findings are critical for planning treatment
36
Dynamic MRI using gadolinium contrast agents (extracellular)
provides another way of distinguishing HCC from normal liver
| tissue.
37
HCC may take 1 of 3 forms:
nodular, massive, or diffusely infiltrating.
38
The nodular variety of HCC
is most common and usually coexists with cirrhosis.
It is characterized by numerous round or irregular nodules of various sizes scattered throughout the liver;
some of the nodules are confluent.
39
The massive type
is characterized by a large circumscribed mass, often with small satellite nodules. This type of tumor is most prone to rupture and is more common in younger patients with a noncirrhotic liver. I
40
In the rare diffusely infiltrating variety,
a large part of the liver is infiltrated homogeneously by indistinct minute tumor nodules, which may be difficult to distinguish from the regenerative nodules of cirrhosis that are almost invariably present.
41
_____is the hallmark of HCC, regardless of the pattern.
Bile production
42
Moderately-Differentiated
Solid, sarcomatous, scirrhous, and clear cell varieties of HCC are described, as well as HCC with lymphoid stroma.
43
Progenitor cell activation is seen in
| association
with chronic viral hepatitis and cirrhosis, presumably
| related to senescence of hepatocytes.
44
Metastases
the most common sites are the lungs (up to 50% in some reports) and regional lymph nodes (≈20%). The adrenal glands are also frequently involved.
45
Fibrolamellar HCC
a distinct variant of HCC that typically occurs in young patients, has an approximately equal gender distribution, does not secrete AFP, is not caused by chronic hepatitis B or C, and almost always arises in a noncirrhotic liver.
46
Fibrolamellar HCC
has different immunohistochemical characteristics than usual HCC, occurring either with or without cirrhosis; therefore, fibrolamellar HCC is much less likely to stain positively for GPC3, although expression of CK7 is more abundant
47
Natural History and Prognosis
The natural history of HCC in its florid form is one of rapid progression, with increasing hepatomegaly, abdominal pain, wasting, and deepen- ing jaundice, and with death ensuing in 2 to 4 months.
48
Treatment
Additional treatments for advanced HCC include newer multikinase inhibitors and immune check- point inhibitors, including regorafenib, lenvatinib, cabozantenib, ramucirimab, nivolumab, and pembrolizumab.
49
Surgical Resection
For resection to be considered, the tumor should be confined to one lobe of the liver and favor- ably located, and ideally, the nontumorous liver tissue should not be cirrhotic
50
Resection indications
is also effective if the tumor is limited to the left lobe or a portion of the right lobe, thereby permitting a segmental resection if the patient has Child-Pugh class A cirrhosis, the serum bilirubin level is normal, and portal hypertension is not present (based on imaging, a normal platelet count, absence of varices on endoscopy, and a directly measured hepatic venous pressure gradient <10 mm Hg).
Child-Pugh class A patients without portal hypertension and with a MELD score of 9 or less
51
All the tumor nodules need to be removed,
with a negative margin of resection, and the patient needs to be left with enough functional liver volume (usually defined as ≥40% in a patient with cirrhosis) to
survive the postoperative period.
52
Surgical resection
Curative but limited to non-cirrhotic patients and cirrhotic patients without portal hypertension
May be technically difficult High recurrence rate
53
LT
Successful in selected patients (Milan criteria; see text and Chapter 97)
Requires lifelong immunosuppression
Expensive and not available worldwide
54
Radiofrequency ablation or ethanol injection
Potentially curative for small tumors, including multiple tumors
High recurrence rate
55
Transarterial chemoembolization
Prolongs survival in unresectable tumors if hepatic function is preserved; not curative
56
Chemotherapy
No clear benefit; palliative only Drug toxicity is common
57
Targeted molecular therapies
Sorafenib is the first such agent shown to improve patient survival Improvement in patient survival with
lenvatinib is similar to that with
sorafenib
Regorafenib, cabozantinib, and
ramucirumab (if AFP >400 ng/mL) improve survival after sorafenib failure
58
Immune checkpoint inhibitors
Nivolumab and pembrolizumab are associated with improved survival after failure of or intolerance to sorafenib
59
LT
is performed in patients in whom the tumor is not resectable but is confined to the liver or in whom advanced cirrhosis and poor liver function preclude resection
the ideal therapy for HCC because it provides the largest possible resection margin, removes the remaining liver, which is at high risk for de novo tumors, and replaces the dysfunctional liver.
60
Several large series have demonstrated that if one selects candidates based on the Milan criteria—
a single tumor up to 5 cm in size or 2 to 3 lesions, each up to 3 cm in size, with no large-vessel vascular invasion or metastasis—the 5-year survival rate is 70% to 75%, and the tumor recurrence rate is 10% to 15%.
61
If the estimated time to LT is greater than 6 months,
bridging therapy with RFA or transarterial chemoembolization (TACE) can often be performed to prevent tumor growth beyond Milan criteria
62
Local Ablation
potentially curative treatments for
patients with small tumors (usually <3 to 5 cm in diameter) that
are not amenable to resection or LT because of patient preference, the number and location of lesions, or significant hepatic
dysfunction (Child-Pugh class B or C
63
RFA has generally supplanted PEI because
it is more effective, particularly with
larger tumors (most effective in lesions up to 3 cm and effective
in those up to 5 cm), requires fewer sessions, and has similar com-
plication rates
64
Chemoembolization
palliative treatment reserved for patients with relatively intact hepatic function (Child-Pugh class A or B with a total bilirubin level <3 mg/dL), good performance status, and a tumor that is not amenable to local ablative treatments because of size, number, or location
65
Chemotherapy
Sorafenib, an inhibitor of Raf kinase and the tyrosine kinase activity of vascular endothelial growth factor receptors and platelet-derived growth factor receptor, is the first of these new agents to show modest improvement in survival compared with supportive care
The drug should be considered for patients with intact hepatic function (Child-Pugh class A or early class B) and portal vein thrombosis, extrahepatic tumor, or failure of other therapies
66
Levantinib,
a multikinase inhibitor, has been shown to be noninferior to sorafenib in the first-line treatment of advanced HCC.
67
are both, multikinase inhibitors, that have been shown to provide a modest improve- ment in survival for patients with Child-Pugh class A cirrhosis and advanced HCC who have had tumor progression after receiving sorafenib.
Regorafenib and cabozantinib
68
Nivolumab and pembrolizumab are, .
monoclonal antibodies to the programmed cell death receptor that have shown improved overall response rates and a trend toward better median survival in patients with HCC who progressed after sorafenib
69
An AASLD practice guideline published in 2005 and updated in 2011 and 2018 provides recommendations for surveillance
Patients at high risk for developing HCC should be entered into a surveillance program in which surveillance for HCC is performed using US at 6-month intervals.
```
HBV carrier with cirrhosis
HCV-related cirrhosis
PBC and stage 4 fibrosis
Hemochromatosis and cirrhosis
α1-Antitrypsin deficiency and cirrhosis
HBV carrier, Asian men > 40 yr
HBV carrier, Asian women > 50 yr
HBV carrier, family history of HCC
Unknown (higher than without family history)
HBV carrier, born in Africa
At least 0.5 (HCC occurs at a younger age)
HCV infection and stage 3 fibrosis
HBV carrier, <40 yr (men) and <50 yr (women)*
```
70
Intrahepatic Cholangiocarcinoma
malignant neoplasm arising from the biliary duct epithelium.
It often carries different names based on the particular portion of the biliary tract involved—small intra- hepatic bile ducts (peripheral cholangiocarcinoma), hepatic duct bifurcation (perihilar cholangiocarcinoma, or Klatskin tumor), and extrahepatic bile ducts (bile duct carcinoma).
71
Etiology and Pathogenesis
Although the underlying predisposing factor for most cases of cholangiocarcinoma is unknown, several risk factors have been recognized.
The strongest association is with Opisthorchis viverrini, a liver fluke endemic in parts of Southeast Asia and acquired by ingestion of raw or uncooked fish.
72
In patients with peripheral cholangiocarcinoma,
often only the serum alkaline phosphatase level is elevated.
CA 19-9 is the most frequently used serum tumor marker for cholangiocarcinoma but has significant limitations because CA 19-9 levels are also elevated in pancreatic, colorectal, gastric, and gynecologic cancers and in acute bacterial cholangitis
73
Peripheral cholangiocarcinoma
usually is a large and solitary tumor, but it may be multinodular
It is grayish-white, firm, and occasionally umbilicated and usually produces a focal hepatic mass; rarely, the tumor can grow alongside and infiltrate the bile ducts or occur as an intraductal papillary lesion.
The tumor is poorly vascularized and rarely bleeds internally or ruptures.
74
Microscopically, cholangiocarcinoma
exhibits acinar or tubular structures that resemble those of other adenocarcinomas.
75
Criteria for resection
absence of all the following:
evidence of extrahepatic metastasis, main portal vein or hepatic artery invasion or encasement, bilateral segmental bile duct involvement, and contralateral hepatic lobar atrophy.
76
Hepatoblastoma
In children, hepatoblastoma is the third most common malignant
tumor and the most common malignant hepatic tumor.
It occurs almost exclusively in the first 3 years of life,
77
Diagnosis Hepatoblastoma
AFP is present in high concentrations in the serum of 80% to
90% of patients with hepatoblastoma and is a useful clue to the
diagnosis.
CT and MRI are used to define the extent of the tumor and
plan definitive surgery. The tumor is seen as an avascular mass on hepatic arteriography.
78
Hepatoblastomas
Hepatoblastomas are rapidly progressive.
If the lesion is solitary and sufficiently localized to be resectable, surgery is often curative, with 5-year survival rates as high as 75%.
Cisplatin alone or in combination with other chemotherapeutic agents is effective against hepatoblastoma and is associated with 90% survival in selected patients
79
Hepatic Metastases
Foremost among the reasons for the high frequency of hepatic metastases are the double blood supply of the liver and the presence of fenestra- tions in the sinusoidal endothelium that facilitate penetration of malignant cells into the hepatic parenchyma.
80
Diagnosis
CT is the most useful imaging technique.210 Multiphase helical CT and CT during arterial portography are more sensitive than conventional CT.
Dynamic contrast-enhanced Doppler
US with IV infusion of CO2 microbubbles is also useful
81
BENIGN TUMORS
| Hepatocellular Adenoma
Hepatocellular adenomas (also termed hepatic adenomas and telangiectatic focal nodular hyperplasia [FNH] or adenomas) are rare benign epithelial tumors of the liver that occur predominantly in women in the second to fifth decades of life.
They are commonly associated with use of estrogen, including exogenous estrogens in oral contraceptive pills (OCPs), and can also be seen in the absence of exogenous estrogens and in men.
82
Hepatocellular Adenoma
Tumors that rupture are generally large (>5 cm) and solitary, although the most important determinant of rupture is a superficial location.
Often, the affected woman is menstruating at the time; rupture may also occur during pregnancy
The risk of malignant transformation is strongly associated with male gender, β-catenin activation, and a tumor diameter larger than 5 cm.
83
Dynamic MRI with a hepatocyte-specific contrast agent such as gadobenate dimeglumin or gadoxetic acid
the preferred imaging modality for diagnosis because it is most able to distinguish a hepatocellular adenoma from other benign or malignant masses in the liver; dynamic CT can also be helpful.
The tumor has a clearly defined margin and often has nearly parallel vessels entering it from the periphery (“spoke- wheel” appearance).
84
CT scan of Hepatocellular Adenoma
On portal venous and delayed images, enhancement tends to decrease, and the lesion can be isointense or hypointense (“washout”).
On late images (usually 20 minutes) using a hepato- cyte-specific contrast agent, almost all hepatocellular adenomas are hypointense compared with FNHs, which show homogenous diffuse hyperintensity or isointensity
85
Hepatocellular Adenoma
It is sharply circumscribed but does not have a true capsule, although a pseudocapsule is formed by compression of the surrounding liver tissue
86
range in diameter from 1 to 30 cm. They are larger on average in women taking OCPs than in those not taking them; the lesions usually occupy a subcapsular position and project slightly from the surface of the liver.
Adenomas
87
More recent series indicate that the risk of rupture is related to a size larger than 5 cm, although a few cases of hemorrhage have been reported in smaller lesions.
resection is now recommended for lesions larger than 5 cm or those with evidence of hemorrhage or other symptoms.
If the adenoma is not resected, pregnancy and exogenous estrogens should be avoided, although pregnancy without complications can be successful with careful monitoring for growth of the tumor, particularly for those smaller than 5 cm in diameter.
88
Cavernous Hemangioma
most common benign tumor of the liver and is found in as many as 7% of autopsies.
Cavernous hemangiomas affect persons of all ages, although they manifest most often in the third, fourth, and fifth decades of life.
89
Almost all cavernous hemangiomas can be diagnosed by contrast-enhanced CT or MRI with sequential scans
The center of the lesion remains hypodense, whereas the peripheral zone, which varies in thickness and may have a corrugated inner margin, is enhanced.
MRI has a high degree of specificity and a central role in the diagnosis of small hemangiomas.
90
Microscopically, hemangiomas
are composed of multiple vascular channels of varying sizes lined by a single layer of flat epithelium and supported by fibrous septa
91
TUMOR-LIKE HEPATIC LESIONS
| Focal Nodular Hyperplasia
FNH is a circumscribed, usually solitary lesion composed of nodules of benign hyperplastic hepatocytes surrounding a central stellate scar.
92
Focal Nodular Hyperplasia
FNH is more common than hepatocellular adenoma.
The lesion is seen more often in women than in men, although the gender difference is much less striking than that for hepatocellular adenoma.
93
Focal Nodular Hyperplasia
OCPs may accentuate the vascular abnormalities in FNH and cause the lesion to enlarge, become more symptomatic, and rarely rupture.
94
Gadoxetic acid
is thought to be the best choice of contrast agent for the diagnosis of FNH
95
FNH
The lesion of FNH usually occupies a subcapsular position and may be pedunculated.
It generally is solitary.
Larger lesions may show foci of hemorrhage or necrosis, although these features are seen less frequently than in hepatocellular adenomas.
The fibrous septa sometimes are poorly developed, and the central scar may be absent.
The lesion is sharply demarcated from the surrounding liver tissue, which is normal, but a true capsule is absent.
96
Contrast enhancement during the arterial phase of a multiphase CT or MRI study,
with subsequent washout during the portal venous or delayed phase, is considered diagnostic of HCC if the lesion is larger than 1 cm in diameter.
97
For a lesion smaller than 1 cm,
interval imaging at 3 to 6 months is recommended.
