Jaundice, Cirrhosis and a Liver Mass
Meghan Ho BSc, (University of Toronto 1T2)*
Stephen G.F. Ho MD, FRCP(C)1
Zamil Karim MD, FRCPC2 (University of Toronto 0T7)
Nancy Fu BPharm, MD2
Yuan Yuan Chan PhD, MD2
Eric M. Yoshida MD, MHSc, FRCPC2, (University of Toronto Medical School Class 8T6)
From the University of Toronto Faculty of Medicine*, the UBC Department of Radiology1 and
the UBC Division of Gastroenterology2, University of British Columbia, Vancouver, BC,
Canada.
Address Correspondence to:
Ms. Meghan Ho
meghan.ho@mail.utoronto.ca
Abstract
A 40-year-old woman with decompensated cirrhosis, manifested by marked jaundice,
coagulopathy and hypoalbuminemia, presented with a large liver mass suspicious for
hepatocellular carcinoma. Atypical radiologic features were noted. The case is reviewed, and
possible therapeutic modalities for a diagnosis of hepatocellular carcinoma are discussed.
Keywords: Liver mass, hepatocellular carcinoma, cirrhosis, jaundice
Case History
A 40-year-old woman with a history of hypothyroidism, gestational diabetes and pre-diabetes,
and a ureteric stone, presented to a community hospital with a two week history of painless jaundice
and a one week history of nausea, vomiting, and general malaise. There was no history of significant
travel, blood transfusion or recreational drug use. She had a remote smoking history, and alcohol
consumption was 4-5 drinks per week for 15 years. The family history revealed two first-degree
relatives with alcoholic liver disease but was negative for autoimmune disease or malignancy. Her
physical examination showed scleral icterus, as well as multiple spider angiomata on her face. She
was noted to be obese. Laboratory investigations revealed a hemoglobin of 109 g/L (normal 135-160),
platelet count of 88 x 109/L (normal 150-300), creatinine of 67 µmol/L, INR of 2.0 (normal < 1.2), total
bilirubin of 355 µmol/L (normal < 22), GGT of 229 U/L (normal < 55), AST of 206 U/L (normal < 35),
and albumin of 24 g/L (normal 35-45). ALT and ALP were within normal limits. HIV, Hepatitis B and
Hepatitis C serology were all negative; EBV, CMV and Hepatitis A were all IgG seropositive indicating
past exposure. The alpha fetoprotein was 259 µg/L (normal < 11). An autoimmune work-up was
negative, including anti-smooth muscle antibody, anti-cardiolipin antibody, anti-neutrophil cytoplasmic
antibody, liver kidney microsomal type 1 antibody, anti-mitochondrial antibodies, and anti-nuclear
antibodies. Iron profile revealed a ferritin of 1,562, but an iron saturation of 3% and serum iron of 8.
Abdominal ultrasound showed hepatomegaly of 26 cm, fatty infiltration of the liver, and
splenomegaly of 15 cm, with minimal ascites. Sludge was present within the gall bladder but there was
no evidence of cholelithiasis or intrahepatic bile duct dilatation. Abdominal computed tomographic
(CT) scan with single portal venous phase showed hepatomegaly, heterogeneous liver enhancement
and three ill-defined, hypodense liver masses (the largest being 6.8 cm x 4.7 cm) suspicious for
malignancy. There was evidence of portal hypertension, with moderate splenomegaly, variceal
formation in the splenic hilum, and recanalization of the umbilical vein. The pancreas, kidneys, and
adrenal glands were within normal limits.
At the community hospital, a low-grade fever was treated with ceftriaxone despite negative
culture results of blood and urine. An ultrasound-guided liver biopsy revealed non-specific
inflammation, with evidence of cirrhosis (bridging portal fibrosis and perivenular fibrosis) and steatosis,
moderate neutrophilic infiltration in the parenchymal lobules, moderate portal inflammation, but no
evidence of malignancy or Mallory hyaline bodies. The patient was started on methylprednisolone 60
mg BID for treatment of presumed alcoholic hepatitis based on the liver biopsy, and transferred to a
tertiary care facility for further management.
At the tertiary care hospital, a triphasic CT scan of the liver with arterial, portal venous and
delayed phase imaging was obtained, showing multiple low-attenuation, ill-defined liver lesions on
arterial phase imaging, the largest being 6.2 cm. The lesions were less well-defined on portal venous
imaging. Due to suboptimal examination, an MRI was recommended to rule-out multifocal
hypovascular hepatocellular carcinoma (HCC). The MRI revealed a large subcapsular mass in
segment 6 that remained suspicious for HCC, measuring 6 cm x 3.5 cm, and without significant
arterial enhancement or washout of the contrast on the portovenous phase.
The patient was judged to have severe liver disease secondary to either alcoholic liver disease
or, more likely, non-alcoholic hepatosteatosis (NASH), with a Child-Pugh Class C and Model for EndStage Liver Disease, MELD Score of 26, with multiple, large (>3 cm) focal lesions noted on imaging.
The presence of such severe parenchymal disease makes the management of her focal liver lesions
more challenging. If the mass were in fact a HCC, locoregional therapy such as transarterial
chemoembolization (TACE) therapy would not be feasible given the degree of hepatic
decompensation. Therefore, a workup for possible liver transplant was initiated and she was
discharged home with a plan for further follow-up with the liver transplant program.
Figure 1: A focal, partially exophytic lesion with contour abnormality in segment VI (white arrows)
demonstrated no significant enhancement on arterial phase (not shown). This post gadolinium
enhanced image obtained at 3 minutes demonstrates similar signal intensity of the lesion to
surrounding liver.
Discussion
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality;
worldwide, it is the fourth most common cause of cancer-related death (1). Moreover, the incidence of
HCC is on the rise (2) both world-wide and in Canada (3), where the incidence has been increasing for
the past three decades. Although cirrhosis from chronic hepatitis B and C are well known to be
associated with HCC, it is important to appreciate that patients with cirrhosis of any etiology are also at
increased risk (4). The finding of a liver mass in a patient with known liver disease can present a
conundrum in terms of establishing a precise diagnosis. A liver biopsy can be associated with
bleeding, and in the setting of HCC, it is well-known that malignant cells from HCC can track along the
path of the biopsy needle, converting a previously contained HCC to a metastatic situation (5). As a
result, a radiologic diagnosis of HCC on CT scan or MRI is acceptable for a definitive diagnosis (6).
HCCs are hypervascular tumours that, unlike the rest of the liver parenchyma, are not perfused by the
portal venous blood flow. Hence, on definitive imaging, the HCC enhances on the arterial phase and
washes out on the portal venous phase (6).
Therapeutic Options for HCC
Assuming that our patient’s liver mass is an HCC, what would be the possible treatment
options? Since 80-90% of HCC patients have liver cirrhosis, their functional hepatic reserve is limited,
and this is an important consideration of management (7). Treatment options for HCC, which range
widely and vary based on extent of disease and the degree of underlying liver cirrhosis, include
surgical resection, transplantation, loco-regional therapy including radiofrequency ablation (RFA)
(either percutaneous or at laparotomy) and embolic therapies such as transarterial chemoembolization
(TACE), as well as systemic pharmacologic treatments such as the multikinase inhibitor agent
sorafenib. Currently, the surgical therapies (resection or transplantation), and RFA for optimal lesions,
are the only curative treatments available for HCC, with 5-year survival rates of 60-70% (8).
Surgical Resection and Liver Transplantation
Localized resection of small tumours is most beneficial in patients without underlying liver
cirrhosis, resulting in 5-year survival rates of up to 74% (2). Resection may be contraindicated in
patients with compromised liver function, as it may lead to liver failure (1). Large tumour size or
multiple tumour foci may also limit resection as a treatment option due to the increased risk of vascular
spread compared with well-circumscribed, solitary lesions (2). Post-resection recurrence rates have
been reported as high as 70% after five years, with the majority of cases being due to dissemination
from the primary tumour (2). Thus, both the risk of recurrence and the overall surgical risk, based on
tumour characteristics, must be weighed when considering surgical resection. Risk factors for
recurrence include tumour rupture, venous invasion, cirrhosis, high viral replication in hepatitis, and
multiple tumour foci (1). For cases of recurrence post-resection, the best treatment options may be
salvage liver transplantation or other localized, non-surgical therapies (2).
For non-resectable HCC, liver transplantation with or without TACE or RFA is the most suitable
surgical treatment. Patients must undergo thorough evaluation to determine the appropriateness of
and eligibility for transplantation. The validated Milan criteria are currently considered the international
standard by which to judge transplant eligibility: patients are eligible for transplant if their tumour
burden consists of a single tumour < 5 cm, or up to 3 tumours, each < 3 cm in size, and without
vascular or extrahepatic involvement (9). However, studies on the usage of expanded criteria
(University of California San Francisco criteria of solitary lesions up to 6.5 cm or up to 3 lesions each
less than 4.5 cm in size with combined size < 8 cm) have reported similar survival outcomes to the
Milan criteria of over 70% at 5 years (10). In addition, downstaging protocols in which patients are first
treated with localized invasive therapy such as TACE or RFA to downsize the tumour burden until
transplant criteria are met have resulted in similarly successful results (2). The most important
predictor of transplant success (survival and lack of recurrence) has been found to be the diameter of
the largest tumour, rather than the number of nodules (1). The largest barrier to transplantation as a
definitive therapy for HCC remains the significant shortage of organ donors (11).
Loco-Regional Therapies
Percutaneous therapies include ethanol injection (PEI) to directly destroy tumour cells or
ablation by radiofrequency or microwaves. These therapies can be used to treat early-stage HCC
(small, solitary tumours), or be used pre-transplantation. RFA is the preferred therapy over PEI, as it is
better tolerated, requires fewer treatments, and has better survival outcomes (2). Microwave ablation
is an emerging therapy with theoretical advantages over RFA that has as of yet shown no significant
differences in efficacy when compared with RFA, but is currently undergoing further comparative trials
(2).
TACE is the first-line treatment for large or multi-focal HCC, or tumours not amenable to
surgical or ablative therapies without vascular invasion or extrahepatic spread (2). This procedure
involves the specific placement of an angiographic catheter to administer chemotherapy, typically
doxorubicin, to the hepatic artery feeding the tumour, followed by embolization of the feeding hepatic
artery and resulting selective tumour ischemia. More recently, drug-eluting microspheres containing
doxorubicin, known as drug eluting beads (DEB), in the absence of HCC artery embolization have
shown a better safety profile and greater response rates compared with conventional TACE (2).
Advances in catheter design minimize the risks of non-selective chemoembolization and injury to
collateral tissues, including liver failure, cholecystitis, and upper gastrointestinal bleeding (7). Yttrium90-labeled microspheres take advantage of the hypervascularity of HCC in a similar manner to TACE,
allowing for targeted radiation to the tumour (2). Randomized controlled trials are needed to compare
Y90 treatment with the other HCC treatment modalities.
In addition to being used for downstaging, percutaneous strategies such as RFA and TACE
may be used to control the tumour while the patient waits for liver transplantation, or may be used as
neoadjuvant treatments pre-transplant to improve transplant outcomes (1).
Pharmacologic Therapies
The anti-angiogenic drug sorafenib, a multikinase inhibitor used for advanced HCC, is the first
systemic chemotherapy that has demonstrated a survival advantage, albeit modest (approximately 3
months) in patients with compensated liver disease who have HCC (12). Consequently, sorafenib is
the first-line therapy for unresectable HCC with preserved liver function for whom there are no other
options (2).
Future Therapies
Bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, sunitinib, a
multi-tyrosine kinase inhibitor, and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
such as erlotinib, are currently being investigated for use in HCC treatment. In addition, mTOR
(mammalian target of rapamycin) inhibitors are undergoing early phase clinical trials after positive
preclinical data showed reduced tumour growth (8). Following transplantation for HCC, sirolimus, an
mTOR inhibitor and immunosuppressive agent, has been demonstrated to improve outcomes (13).
Phase I clinical trials have been done on the use of bone marrow-derived stem cells to improve liver
function (7). Beneficial effects on serum bilirubin and albumin were observed up to 1 year, suggesting
stem cells as another potential pre-transplantation downstaging therapy (7).
Back to the Case: Final Clinical Comments
Our patient with decompensated cirrhosis presented with a large liver mass that was atypical
for HCC on imaging, but was still clinically suspicious for HCC. If the large mass was a HCC, she was
not a feasible candidate for any therapy besides liver transplantation. It was elected to follow her with
serial imaging as per the American Association for Study of Liver Disease (AASLD) guidelines (6). A
follow-up MRI approximately three months later revealed that the 6 cm mass was unchanged, with no
arterial enhancement or portal venous washout, therefore being less suggestive of HCC (Figure 1).
The patient is currently undergoing assessment for liver transplantation.
Conflicts of Interest: None.
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