Prospective Comparison of Hepatic Malignancy Detection Techniques

This report presents a comprehensive analysis of various imaging techniques used in the detection of primary hepatic malignancy, specifically focusing on patients undergoing liver transplants. The study critically evaluates the diagnostic performance of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasonography (USG) in identifying hepatocellular carcinoma (HCC). The introduction highlights the prevalence and challenges of HCC, emphasizing the importance of early and accurate detection for effective patient management. A detailed literature review explores the principles, advantages, and limitations of each imaging modality, including CT's multi-phasic contrast imaging, PET's use of tracers, MRI's detailed imaging capabilities, and the accessibility of ultrasonography. The methodology section outlines the comparative analysis of these techniques, aiming to determine the most effective and efficient methods for HCC detection. The report also discusses the clinical presentation, diagnostic approaches, and staging examinations associated with HCC, providing a holistic view of the disease and its detection. Finally, the conclusion summarizes the findings, offering insights into the optimal imaging strategies for diagnosing HCC in the context of liver transplantation, and provides a basis for future research in the field. The report is a valuable resource for medical professionals and students alike, providing a detailed overview of the current landscape of HCC detection methods.

Running Head: DETECTION OF PRIMARY HEPATIC MALIGNANCY
Study Developing Detection of Primary Hepatic Malignancy in Liver Transplant Patient:
Prospective Comparison of CT, MR Imaging, Ultrasound and PET
Name of the University:
Name of the Student:
Authors Note:
Table of Content

1Detection of Primary Hepatic Malignancy
s
1.0 Introduction.....................................................................................................................3
1.1 Aims.........................................................................................................................4
1.2 Objectives....................................................................................................................5
2.0 Hypothesis.......................................................................................................................5
3.0 Literature Review............................................................................................................5
3.1 CT................................................................................................................................5
3.2 PET..............................................................................................................................7
3.3 MRI.............................................................................................................................8
3.4 Ultra sonography.........................................................................................................9
4.0 Methodology.................................................................................................................10
Hepatocarcinogenesis......................................................................................................10
Clinical presentation of Hepatocellular carcinoma.........................................................12
Diagnostic Approach.......................................................................................................14
AFP in diagnosis of HCC............................................................................................17
Imaging of the Hepatocellular Carcinoma......................................................................18
Survey examinations.......................................................................................................19
Staging Examinations......................................................................................................20
Characterization of the Hepatic Lesion...........................................................................22
Conclusion...........................................................................................................................23
Summary.............................................................................................................................25

2Detection of Primary Hepatic Malignancy
5.0 References.....................................................................................................................27

3Detection of Primary Hepatic Malignancy
1.0 Introduction
Hepatocellular Carcinoma (HCC) is the most common and prevalent type of liver cancer
that affects majority of patients around the world (Johnson et al. 2015). There are multiple
health conditions due to which patients suffer from this critical health condition such as liver
cirrhosis, due to the critical infection by hepatitis B or hepatitis C (Halazun et al. 2017). The
risk factors of hepatocellular carcinoma are associated with higher consumption of alcohol or
are suffering from critical viral infections. As per Geissler et al. (2018), the cancer cells of
HCC are developed due to the epigenetic alterations which then affects the machinery of the
cellular system and hence, replicates in huge numbers due to which it develops critical heath
conditions. As per Piscaglia et al. (2016), one of the most effective intervention that could
help to prevent the risk of HCC is to conduct orthotic transplantation of liver so that by
removing the carcinogenic liver, another liver could be included in the human body. Further,
it is considered as the most effective treatment process that is implement in patients that are
suffering from HCC. As per Mittal et al. (2016), this process not a new intervention that is
implemented upon patients that suffer from HCC. However, there are cases that indicates that
the rate of infection or other complication arises due to orthotic transplantation in patients
suffering from HCC. Hence, these are the reasons due to which multiple researches are being
conducted so that the rate of survival in patients affected with liver cancer could be
understood. Multiple researches identified that the patients that suffer from critical health
condition such as solitary 5cm or smaller Hepatocellular Carcinoma as well as tumor nodules
less than 3 cm are able to overcome their liver cancer related conditions through proper
transplantation of liver (Sapisochin and Bruix 2017). However, it was also seen that multiple
patients that have already gone through critical conditions associated with their liver
carcinoma are affected with cholangial carcinoma faces poor outcome due to the adverse
conditions as the rate of tumor recurrence becomes higher in those patients. Hence, from

4Detection of Primary Hepatic Malignancy
these critical conditions, it could be understood that to overcome these severe health
complications, proper health screening should be conducted so that they could overcome their
critical health conditions and their eligibility to undergo critical health conditions could be
identified. Further, it should also be conducted to analyze or match the liver profiles of the
donor and the recipient effectively (Mittal et al. 2015).
As per Johnson et al. (2015), it is also important to assess the presence of HCC among
patients so that the accurate diagnosis method of identification of HCC could be identified.
As per the research of Sapisochin and Bruix (2017), it was seen that the there are two kind of
diagnosis method that could be used for the successful diagnosis of the HCC condition
among the patients and as per Zoller and Tilg (2016), CT and MR is considered as the most
effective tools in HCC detection. Hence, the primary aim of this paper was to analyze the
type of detection and identification processes, which is important for the identification and
analysis of the HCC and the type of transplant they need to undergo while suffer from critical
health conditions (Sapisochin and Bruix 2017). The diagnosis processes that this paper would
be assessing is the analysis of magnetic resonance imaging (MRI), computed tomography
scan (CT), Ultrasonography or USG, or positron emission tomography (PET) which could be
considered as the processes that would be used as the process for analysis. Hence, through the
analysis of these imaging technologies or identification process it is estimated that the
successful detection of Hepatocellular Carcinoma (HCC) among the patients of liver
transplant could be identified.
1.1 Aims
The aim of the research is to comparatively study the detection and analysis of the imaging
of the hepatocellular carcinoma exploiting various imaging techniques like positron emission
tomography (PET), computed tomography (CT), ultrasonography (USG), magnetic resonance
imaging (MRI)

5Detection of Primary Hepatic Malignancy
1.2 Objectives
The objective of the research is to analyze and compare the diagnostic performance of the
imaging techniques exploited like Positron emission tomography, ultrasonography, computed
tomography and magnetic resonance imaging. This research exploits the effectiveness of the
imaging techniques in the efficiency to detect the hepatocellular carcinoma among individual
opting for the liver transplant.
2.0 Hypothesis
The hypothesis of this research article is to comparatively analyze the imaging technique
exploited by computed tomography (CT), positron emission tomography (PET), magnetic
resonance imaging (MRI) and ultrasonography. And based on the literature review detect the
most advanced inexpensive mode of detection of the hepatocellular carcinoma.
3.0 Literature Review
3.1 CT
Computed Tomography are special X-ray tests which produces cross-sectional images of
the body exploiting X-rays and a computer. Computed tomography is also referred to as
computerized axial tomography (Kojima et al., 2016). It was established as early as 1974. It
aids to the comfort of the patient since the scan can executed quickly. Exploiting high
resolution of the image formation ensures efficient diagnosis of the disease. Computed
tomography is considered non-invasive, safe as well as effectively tolerated (Yamakawa and
Kojima, 2017). The resolution imaging ensures detailed look at the different body parts. The
design of the scanner rarely makes the patient feel claustrophobic since it is an open donut
shaped scanner.
The patient is exposed to radiation when undergoing CT scan even though it is in the safe
levels. A dye is exploited in the computed tomography as called as a contrast can pose a

6Detection of Primary Hepatic Malignancy
potential risk for the patient as it can cause serious allergic reaction (Kurokawa and Tsubota,
2019). But the contrast aids in distinguishing normal from the abnormal tissues. It also aids in
differentiating blood vessels from lymph nodes.
The evaluation of the CT imaging for patients with suspected hepatocellular carcinoma
should be executed by exploiting hepatic multiphasic contrast imaging. After fast intravenous
infusion of the contrast, imaging is executed at different intervals of time that corresponds to
the enhancement of the phase of contrast (Lee et al., 2015). Triphasic computed tomography
indicates liver imaging performed before contrast, during the arterial and the venous phases.
Hepatocellular carcinoma tumours acquires blood flow predominantly from arteries in the
liver and this has the tendency to enhance in the arterial phase or about 2 to 40 seconds post
contrast infusion (Tang et al., 2017). The hepatic parenchyma surrounding it utilises 75 to
80% of the blood flow through the portal vein and is best observed in the time span of 50 to
90 seconds after infusion of contrast in the portal phase. The enhancement of the arterial
phase can elevate the detection of the hepatocellular carcinoma tumour detection by 10%
(Roberts et al., 2018). In the CT imaging the HCC appears to be heterogeneous in nature that
reflects the intra-tumoural fibrous stranding, necrosis, fatty metamorphosis or calcifications.
Another characteristic exhibited is the occurrence of the satellite nodule in the close
proximity to main lesion. The fibrous structures that encapsulate or is present within the
lesion retains the contrast as well as it enhances readily on the delayed imaging which can be
3 to 10 minutes post infusion (Castilla-Lièvre et al., 2016).
In the literature studies it is described that hepatic lesions can imitate hepatocellular
carcinoma on the CT imaging (Sasikumar et al., 2016). The lesions may include
haemangiomas, regenerating nodules, peliosis and focal fat. The speed of the imaging is
directly proportional to the accuracy of the imaging, this promotes quicker administration of
the contrast media which dramatically impacts the enhancement of the contrast. The

7Detection of Primary Hepatic Malignancy
increased speed as well as the flexibility of the multidetector CT promotes better quality,
thin-section imaging with capabilities of three-dimension (Galle et al., 2018). The computed
tomography arteriography is an invasive as well as effective option to enhance the accuracy
as a result of the greater quantity of the contrast that is administered at a rapid rate. But it
should be noted that this technique is expensive and this acts as a limitation to its use. The
computed tomography arteriography as well as the portography is more frequently used in the
Far East in order to define the liver vasculature prior to surgical interventions (Mulazzani et
al., 2019).
3.2 PET
Positron emission tomography scan is an imaging test that is exploited to detect the
diseases in the body. It exploits the use of dyes that have radioactive tracers. These
radioactive tracers are either swallowed, inhaled or injected into the vein based on the part of
the body that is being examined (Preshlock, Tredwell and Gouverneur, 2016). These tracers
are absorbed by the tissues and organs of the body. These tracers enable doctors to diagnose
any abnormality in the body. The radioactive tracers accumulate in the regions of high
chemical activity and they show up as a bright spot in the scanner. PET scans are mostly
exploited to detect cancer, heart issues and brain disorders including the central nervous
system (Kawai et al., 2017).
In case of the cancer detection since the areas exhibiting carcinogenesis have high
chemical activity they show up as bright spots in the PET scan. PET scans are scanning
techniques that show metabolic changes that occur at the cellular level in an organ or tissue.
This is indeed a vital consideration as the disease usually starts at the cellular level. This is
the reason why PET scan is advantageous over the computed tomography and MRI scanning
techniques (Chalaye et al., 2018).

8Detection of Primary Hepatic Malignancy
PET scan exposes the patient to radioactivity even though it is in the minimal quantity.
The tracer is essentially a glucose molecule that is attached with a radioactive component.
Positron emission tomography plays a prominent role in the Hepatocellular carcinoma
HCC, management. In order to detect the primary tumor, non-FDG PET exploiting [11C]
acetate, [11C]CH or [18F] FCH has a higher sensitivity in comparison to [18F] FDG PET. The
technique of dual-tracer in PET utilizing FDG as well as a non-FDG tracers for the evaluation
of the two in-vivo types of metabolism causes optimization of diagnostic performance. The
several types of hepatocellular carcinoma exhibit differential uptake levels of the tracer
molecules based on the tumor differentiation degree. Presently there has been no literature
studies that can compare the combination of the dual tracers or against technique of
exploiting single tracer with an adjunct imaging of hepatic perfusion. [18F] FDG PET is
comparatively considered as more sensitive in the detection of the extra hepatic metastases
and can be utilized in the evaluation of the high-risk patients, but performing PET for the
purpose of preliminary staging is yet to reach a global agreement. [18F] FDG PET can be
exploited for the pre-treatment prognostication that can include evaluation of the pre-
transplantation which can thus influence the selection of patient. The evidence for the
evaluation of the post-treatment or the detection of the recurrence is comparatively less and it
is also observed in the retrospective studies mostly, with little data that is prospective is
reported in abstracts. The complexity of the hepatocellular carcinoma with respect to the
tumor biology, staging strategies, and the options in treatment warrants the further
prospective research for confirming the role of the positron emission tomography and specific
radiotracers as well as the management course, and also the analysis that is considered cost-
effective to guide the healthcare decisions (Hernandez et al., 2016).

9Detection of Primary Hepatic Malignancy
3.3 MRI
Magnetic resonance imaging exploits the use of a strong magnetic field as well as radio
waves to create a detailed cross-sectional image of the tissues and organs of the body. MR is
considered to be a non-invasive and painless procedure (Wahlstrand et al., 2017). It does not
exploit the usage of potentially harmful ionizing radiation. It is not common that patient who
undergo MRI scan experiences any side effects. But the contrast dye exploited in this
scanning technique can cause nausea, headaches as well as pain or burning at the region
where the dye has been injected. But allergic symptoms are rarely observed in case of MRI
scanning (Tsonton and Thompson, 2016). But some patients may feel claustrophobic while
undergoing MRI scanning.
3.4 Ultra sonography
Ultrasonography is the most common and the frequent imaging modality that is exploited
to analyze and evaluate the parenchymal organs of the abdomen since it is comparatively less
expensive, widely available and non-invasive. The efficacy of the detection of the
hepatocellular carcinoma varies in the individual affected with liver disease with a sensitivity
of 33-96% and the specificity reaches over 90%. There are variety of guidelines that
recommends Ultrasonography as the first-line surveillance modality for the HCC in patients
with high risk. The high- risk patients may include cirrhotic patients as well as the non-
cirrhotic patients with chronic hepatitis B and hepatitis C infection or may have elevated
levels of HBV-DNA levels. Patients with non-cirrhotic family history of hepatocellular
Carcinoma and Non-Alcoholic fatty liver disease should be encouraged to undergo the
routine surveillance. Based on the literature studies it can be inferred that the ultrasonography
has a low rate of sensitivity but comparatively a high rate for specificity. The screening
interval for the hepatocellular carcinoma is approximately 6 months. The recommended
screening interval for HCC is 6 months. In case of the cirrhotic patients, the sub-centimeter

10Detection of Primary Hepatic Malignancy
nodules (< 1 cm) that are detected by the ultrasonography should be followed every 3to 4
months during the initial year followed by every 6 months post the first year (Hernandez et
al., 2016). The nodules that are over 1 cm should be tested for imaging work-ups as well as
biopsy for the characterization of the same. The performance of the US is greatly dependent
on quality of the equipment and the expertise of the operator. US comparatively less sensitive
than the other techniques discussed in this report for the detection of the early-stage of
hepatocellular carcinoma.
4.0 Methodology
Hepatocarcinogenesis
The process of the hepatocellular carcinoma is called as hepatocarcinogenesis and it is the
most common and prevalent cancer that impacts all populations worldwide. Several health
complexities can lead to this chronic health compromised condition. The factors may be
hepatitis b and hepatitis C infections. The risk factor involves excessive consumption of the
alcohol as well as viral infections that are critical can be a risk. It should also be noted that in
most cases this hepatocellular carcinoma can arise silently and progress hence making the
diagnosis challenging at the early stages (Sapisochin and Bruix 2017) (Mittal et al. 2015).
Hepatocarcinogenesis is defined as a complex multistep process that impacts the
molecular, cellular as well as the histologic levels. The liver cells can develop epigenetic
alterations that impacts the system at the cellular level. The chronic inflammation of the liver
can cause repeated cell injury, death and regeneration cycles, this leads to subsequent
epigenetic and genetic in the hepatocytes (Kojima et al., 2016). Considering the molecular
level, the important oncogenes like MYC and the tumour suppressor genes like TP53, E-
cadherin, PTEN, and RASSF1 either undergo mutation or are aberrantly regulated because of
structural genetic alterations and several signalling pathways that are functioning abnormally

11Detection of Primary Hepatic Malignancy
like Ras, epithelial growth factor receptor and insulin-like growth factor receptor 1 signalling.
Post the malignant transformation of the mature liver cells or the intrahepatic stem cells
hepatocellular carcinoma develops at the cellular level. The phenotypically abnormal
precursor lesions in the liver, which includes cirrhotic nodules, high-grade dysplastic nodules
(HGDN) low-grade dysplastic nodules (LGDN), at the histological level dedifferentiate and
evolve to form early and eventually progressed hepatocellular carcinoma. This process can
impact at various rates in several hepatic parts. There are various key alterations that happen
during the process of hepatocarcinogenesis. Firstly, the distinct hemodynamic changes take
place during the multistep process. The blood supply of the nodules diverges with the
malignant transformation: there is a reduction in the number of intra-nodular portal tracts
gradually but there is an increase in the number of unpaired arteries. The hepatic artery
system supplies the hepatocellular carcinoma via the abnormal unpaired arteries. This causes
characteristic enhancement of the pattern of the hepatic arterial phase hyper enhancement and
portal venous phase or the delayed phases wash-out relative to background liver on the
contrast enhanced multiphasic MRI and CT. Additionally, the venous drainage of the nodules
evolves from the hepatic veins to sinusoids as well as the portal veins, that explains why
HCC majorly spreads through the portal venous system than the hepatic veins (Kojima et al.,
2016).
Secondly, the most prominent features morphologically during the hepatocarcinogenesis are
formation of the fibrous tumour capsule which is a smooth, uniform and enhancing rim
formed surrounding most of the nodule or all of the nodule as well as the “nodule-in-nodule”
architecture is also formed which is the formation of smaller nodules with considerably
different imaging features present within the outer larger nodule (Yamakawa and Kojima,
2017). It should be noted that since the cirrhotic nodules, the dysplastic nodules and the early
hepatocellular carcinoma are rarely present with a fibrous capsule, the appearance of the

12Detection of Primary Hepatic Malignancy
capsule is considered as a progressive stage of the HCC (Sapisochin and Bruix 2017). The
architecture of “nodule-in-nodule” can result from a successively dedifferentiated clonal
populations or excessive fat development nodules inside a bigger outer nodule. It is observed
that the fat can develop within the dysplastic nodule in the early HCC but it should be noted
that there is regression in the content of the fat accumulated in the nodule as the
hepatocellular carcinoma progresses (Mittal et al. 2015).
Thirdly, the expression of various protein transporters gets altered significantly in the process
of hepatocarcinogenesis. The family of organic anionic transporting polypeptides (OATP)
involves the proteins which are expressed on the sinusoidal membranes of the liver cells and
aids in transportation of the bile salts. The hepatobiliary contrast agents in the MRI technique
are predominantly taken up by human hepatocytes via the OATP8 also called as OATP1B1/3
(Yamakawa and Kojima, 2017). During the hepatocarcinogenesis, there is decrease in the
expression of OATP8, progressively. In most cases involving hepatocellular carcinoma,
numerous HGDNs, as well as some of the LGDNs are present with OATP8 under expression
relative to the background liver that results in the hypointense nodules that are observed in
the hepatobiliary phase (HBP) in the MRI imaging. Moreover, the emerging data also suggest
that there is a reduction in the level of OATP8 expression before reduction in the portal tracts
followed by increase in the unpaired arteries. Therefore, the hepatobiliary agents aid in
improving the sensitivity in detecting the early small HCCs. Additionally, it is observed that
the OATP8 expression is inversely correlated with the HCC tumour grade and its
aggressiveness (Mittal et al. 2015).
Clinical presentation of Hepatocellular carcinoma
It is observed that hepatocellular carcinoma arises classically and grows in a silent fashion,
thus making the discovery of the disease challenging before development of the later stage.

13Detection of Primary Hepatic Malignancy
The different clinical presentations which generally relate to the extent of hepatic reserve at
the time of diagnosis. It is observed that the cirrhotic patients have comparatively lesser
tolerance for the hepatic malignant infiltration and frequently presents nonspecific symptoms
and signs of decompensation of the liver like hepatic encephalopathy, jaundice and anasarca.
Ascites, variceal bleeding as well as other findings consistent with the portal hypertension
indicates malignant invasion of hepatocellular carcinoma into the portal structures (Chalaye
et al., 2018). The abnormal laboratory values are not specific for the chronic liver disease and
may reflect effects of the commonly prescribed medications for cirrhotic like spironolactone.
Non-cirrhotic patients with hepatocellular carcinoma typically exhibits a different
mannerism, as is commonly observed in the sub-Saharan Africa and other high incidence
areas. Their tumors advance in a manner which is not restricted. Symptoms are inclined to the
long-standing malignancy as well as the tumour growth that involves malaise, distension,
anorexia and pain in the right upper quadrant abdomen (Bruix et al., 2016). Physically
examining such cases reveal that there is a presence of an abdominal mass with irregular and
hard borders which may depict vascular bruit. Encroachment of tumour on the near vicinity
extra hepatic biliary structures can show up symptoms of obstructive jaundice that is
considered painless. There might occur catastrophic incidence of rupturing of the tumour
which is though a rare case and occurs large vascular tumour located on the hepatic periphery
outgrows the blood supply. Such internal issues causes severe pain in the abdomen of the
patient, hypotension and peritoneal irritation. Abdominal laparotomy and peritoneal lavage
confirms the diagnosis in such cases.
Extra hepatic manifestations of the HCC are related to distant metastases or to paraneoplastic
phenomena. Advanced hepatocellular carcinoma can metastasize to any organ system
through the haematogenous or lymphatic routes, and it is observed to frequently spread to the
bone, lung and the abdominal viscera. There are several characteristics that relate to the bone

14Detection of Primary Hepatic Malignancy
metastases like pain in the bone which are considered to be the initial signs. Paraneoplastic
manifestations can occur rarely in case of HCC and it includes symptoms like hypoglycemia,
feminization syndrome, hypocalcaemia and polycythaemia (Bruix et al., 2016). Cirrhosis as
well as hepatocellular carcinoma has a common syndrome of watery diarrhoea which is not
frequently observed in cases of only cirrhosis and hence watery diarrhoea can be considered
as the initial symptom. Elevated rate of production of the intestinal secretory substances like
gastrin and vasoactive intestinal peptide (VIP) are regarded as the probable reason for the
cause (Khalaf et al., 2017) (Conti et al., 2016). There are several cutaneous features that are
described well in hepatocellular carcinoma like Leser-Trelat sign, dermato-myositis,
pemphigus foliaceus, and pityriasis rotunda, it should be considered that such symptoms does
not aim at a particular disease occurrence. Advances in the chronic hepatitis can lead to the
occurrence of porphyria cutanea tarda (PCT) is observed frequently. Evidence based studies
have shown that such scenario can cause hepatocellular carcinoma (Chalaye et al., 2018).
The detection of the asymptomatic hepatocellular carcinoma in the high risk patients are by
routine surveillance is common. In these cases the tumors are identified much prior to the
advance of the liver decompensation or similar complexities should be subjected to
aggressive invasion to promote higher rates of survival for these patients (Khalaf et al.,
2017).
Diagnostic Approach
Patients at higher risk for hepatocellular carcinoma – The patients who are at greater risk
for acquiring hepatocellular carcinoma can undergo the process of diagnosis with aid of
dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging
(MRI) specific for the evaluation of the hepatic lesion. In case of the solitary lesions,

15Detection of Primary Hepatic Malignancy
Contrast-enhanced abdominal ultrasound (US) can be used as well. The follow ups can lead
to a biopsy if the imaging of the hepatic lesion exhibits specific characteristics.
The patients with increased risk of hepatocellular carcinoma are the subjected to
surveillance. These high-risk patients may have cirrhosis and also patients who are suffering
from chronic hepatitis B virus infection (Bruix et al., 2016).
Surveillance exploits the usage of Ultrasonography (US) which may be without or without
the alpha-fetoprotein (AFP) at the regular intervals for the detection of the tumor in the
preliminary stage, which can also be stated as the stage that is potentially curable. The
imaging with US may exhibit characteristic lesion which leads to suspection of the detection
of hepatocellular carcinoma (Chalaye et al., 2018).
The diagnostic approach to a hepatic lesion in case of a patient at high risk of
hepatocellular carcinoma, is analyzed by the size of the solid lesion that can be detected on
the surveillance Ultrasonography.
 Lesions <1 cm – the lesions that measure less than 1 cm in diameter are considered
very small that can be definitively diagnosed by further imaging techniques or by
biopsy. These small lesions must be monitored in short intervals like within a span of
three to six months for a time span of one or two years. If the size of the lesion
remains 1 cm or the lesion disappears, the patient can resume the routine surveillance
of imaging in an interval of six month. But if the size of the lesion is more than 1 cm,
or if there is a development of a new lesion of size around 1 cm or more, or if the
level of AFP rises, then the hepatic lesion characterization should be analyzed with
the aid of dynamic contrast enhanced computed tomography (CT) or magnetic
resonance imaging (MRI). Though contrast enhanced ultrasonography may also be

16Detection of Primary Hepatic Malignancy
exploited for this diagnosis but the analyzation of the burden of the tumor in the liver
would require a CT or MRI imaging (Balogh et al., 2016).
 Lesions ≥1 cm – In case of the patients that are under high risk with an
ultrasonography exhibiting solid, dominant lesion of the size greater than 1 cm is
proved to be a haemangioma in a contrast enhanced imaging research study exploiting
the imaging techniques of contrast enhanced CT or MRI. As per the guidelines of the
Liver Imaging Reporting and Data System (LI-RADS) doing a biopsy for the
histologic confirmation is not necessary if the diagnosed lesion meets the typical
criteria for imaging for detection of HCC (Conti et al., 2016). But if there is a
suspicion of malignancy in the diagnosis even though it is not certain and the report
might impact the management of the patient then a followed-up biopsy is suggested.
But it should be noted that the decision to do biopsy should be inferred based on
context of multidisciplinary discussion considering the preferences of the patient
preferences, the co-morbidities as well as the other factors that are relevant (Balogh et
al., 2016).
Patients with no cirrhosis but non-viral, chronic liver disease— In case of the patients
who acquired noncirrhotic, non-viral, chronic hepatic disease, and are suspected of liver
lesion on ultrasonography, an abdominal contrast-enhanced CT or MRI aiming for hepatic
lesion imaging and AFP for more evaluation and confirmation should be executed.
If imaging characteristics are consistent with hepatocellular carcinoma and the level of
AFP is greater than 400 ng/mL, then there is no requirement for a biopsy in the patient and
specifically if the lesion appears resectable (Balogh et al., 2016).
If there is still uncertainty in the diagnosis even post the options of advanced imaging
technologies and the size of the lesion is greater than 1 cm, then the diagnosis may proceed
with a biopsy if the reports impact the patient's management. If the size of the lesion is less

17Detection of Primary Hepatic Malignancy
than 1 cm, then the advanced imaging of the lesion should be done in a span of three to six
months since the yield from a biopsy report is less in this setting (Clark et al., 2015). The
advanced imaging technique to monitor the lesion should continue as the mentioned time
intervals for a total of at least 24 months, considering the fact that there is no evident change
in the size and appearance of the lesion. But if the size of the lesion increases and is almost
around 1cm or more, then a non-invasive imaging diagnosis should be done or even a biopsy
can be exploited based on the impact of patient management (Balogh et al., 2016).
Patients without chronic liver disease — Metastases from the extrahepatic malignancy
frequently impacts the noncirrhotic livers in comparison to the cirrhotic livers. The diagnostic
approach for the detected lesions in the patients who do not have any liver disease involves
evaluating the tumor markers like CA 19-9, AFP and carcinoembryonic antigen, an
evaluation of the serology or the previously undiagnosed liver disease and imaging
techniques that includes an abdominal contrast-enhanced CT or MRI tailored for the
evaluation of the hepatic lesion. If the diagnosis is uncertain then a biopsy can be executed if
the results impact the patient’s management (Clark et al., 2015).
AFP in diagnosis of HCC
Evidences show that Alfa-fetoprotein (AFP) correlates to the size of the tumor and the
volume at time of diagnosis. A Thailand based study stated that hepatocellular carcinoma
patients with AFP levels more than 400 ng/ml tend to have bigger size, bilobar involvement,
portal vein thrombosis as well as reduced rate of survival. If this condition is left untreated
the tumors producing AFP increases in their size over time which coincides with the
progression of the disease. Tumors that lack effective differentiation with more aggressive
features is frequently observed in patients with high alfa-fetoprotein levels. There is a
reduction in the prognosis when the AFP levels are higher than 1000 ng/ml, but there might
be exceptions to this. Tumors that have normal AFP levels at time of diagnosis tend to remain

18Detection of Primary Hepatic Malignancy
the same even in the advanced stage of the disease. The tumor AFP level inconsistencies
reflect the variables that are associated with its synthesis in hepatocellular carcinoma and this
pose a challenge in the making of systematic assumptions on tumor characteristics depeding
on the level of AFP level only (Chalaye et al., 2018).
In case of recurrent disease the monitoring of the level of AFP is considered to be helpful.
But this is limited to the patients with tumors that produces AFP. Efficient removal of the
tumor by means of surgery is usually accompanied by a rapid fall in the level of AFP to the
normal values, as the half-life is considered to be 3.4 to 5 days(Clark et al., 2015) . If the
level of AFP is persistent without any reduction it means that there is presence of residual
disease or incomplete resection. But it should also be taken into consideration that the
normalized levels does not infer that there is no possibility of remaining disease. If the level
of AFP rises gradually it is often consistent with recurrence of the disease. The levels of AFP
mimics the responsiveness of tumor to therapies like chemotherapy which are nonsurgical.
Evidence based studies show that patients with low levels of AFP post chemotherapy is
considered to have an advantage of higher survival rates than those patients who exhibit rapid
fall in the level of AFP or there is absolutely no response (Clark et al., 2015).
Imaging of the Hepatocellular Carcinoma
Hepatocellular carcinoma is most commonly observed as a solitary tumor of the size of
20mm in diameter or a multifocal lesion. These multifocal lesions in the early stage appears
as a single focus lesion than can be equal to or similar to 20mm in diameter and
comparatively has a better prognosis with 90% of the five-year survival rate if effective
treatment with complete re-sectioning or liver transplant is carried out (Ayuso et al., 2018).
Hepatocellular carcinoma is characterized by an elevated rate of local invasiveness with the
potential to cause infiltration of the portal vein branches and biliary tracts though it is less
frequent in order to form abnormal arteriovenous connections and results in presentation of

19Detection of Primary Hepatic Malignancy
the tumor emboli within vessels especially in the portal vein system (Tang et al., 2018). This
infiltration of the portal vein followed by formation of tumor emboli facilitates intrahepatic
metastasis even if it is in the early stage of the disease. An independent risk factor of the
multifocal tumor growth is the extensive damage of the numerous hepatocytes due to the
toxic and viral factors.
The article mainly aimed at comparatively analysing the imaging technique that can be
used to detect the hepatocellular carcinoma with less or almost negligible number of false
positive results. The non-invasive imaging techniques are only discussed in this article. The
techniques namely are computed tomography, magnetic resonance imaging, ultrasonography
and positron emission tomography. It is observed based on the literature study that the non-
invasive imaging technique of ultrasonography is considered as the first line imaging
modality that is exploited for the detection of the hepatocellular carcinoma (Mittal et al.
2015). The imaging observed in case of the computed tomography indicates that
hepatocellular carcinoma is heterogeneous in appearance, it also aids in detecting presence of
satellite nodule that is present in the close proximity of the main lesion. It should be noted
that hepatocellular carcinoma mimics hepatocellular lesion in case of computed tomography.
The development of the imaging technique of CT formed the computed tomography
arteriography which is invasive and efficacious in comparison to CT but it is expensive and
limited in availability (Hernandez et al., 2016). PET is positron emission tomography that
exploits the use of radioactive tracers that are readily absorbed by the highly active cells and
show up as bright spots in the imaging process. Magnetic resonance imaging is a noninvasive
technique exploiting the magnetic field and the radiowaves as well. MRI and CT imaging
techniques are comparatively more sensitive and has highr resolution than the
ultrasonography imaging technique and these are more commonly used when compared to
PET because of the high cost involved (Tsonton and Thompson, 2016).

20Detection of Primary Hepatic Malignancy
The characteristic development of the hepatocellular carcinoma in the liver cirrhosis is a
multiphasic process that starts with the regeneration nodule followed by low grade dysplastic
nodule and high-grade dysplastic nodule that progresses to hepatocellular carcinoma focus
within the dysplastic nodule and this leads to the early stage of hepatocellular carcinoma. The
progressive stage of the same is called mature form of hepatocellular carcinoma.
Imaging modalities for the hepatocellular carcinoma includes ultrasonography, computed
tomography, magnetic resonance imaging and positron emission tomography. Computed
tomography and magnetic resonance tomography provide images with higher resolution in
comparison to ultrasonography. But they are also expensive and when computed tomography
is considered it leads to exposure to radiation as well. Hepatocellular carcinoma is considered
as a hyper vascular lesion, CT and MRI are performed with contrast agents that are
characterized by arterial enhancement. There is microbubble enhanced ultrasonography that
can be exploited but the enhancing agents exploited in the ultrasonography have not been
approved by the FDA, Food and Drug Administration and the microbubbles are present in the
hepatic cells for only a short interval.
Survey examinations
CT and MRI scans show the internal organs as well as the tissue level images. But PET
scan shows an image of the complex systemic disease from the cellular level. PET exploits
the use of positron unlike CT scans as well as MRI scans. The patients detected with extra-
hepatic malignancy regularly go through survey exploiting the abdominal examinations to
diagnose liver metastases, involvement of the lymph node and local involvement (Kim et al.,
2015) (Yu, 2016). During the analysis of the liver, the main aim is to analyze the presence or
the absence of the metastasis in the hepatic cells and aids in providing gross estimation of the
burden of the liver tumor. Surveys that involve such examinations exploit the usage of
contrast enhanced CT because CT has a high sensibility (93%) as well as specificity (100%)

21Detection of Primary Hepatic Malignancy
for the detection of the hepatic metastases. The Computed Tomography is preferred over
Ultrasonography and Magnetic resonance imaging since both these techniques have similar
rates of accuracy and the CT scan images out-performs the other two techniques for the
evaluation of the extra hepatic abdomen. Computed Tomography has other benefits as well
which includes easy accessibility and it is widely available and the protocol for imaging with
CT is comparatively patient friendly since it allows imaging of the chest-abdomen-pelvis in a
time span lesser than 20 seconds by holding the breath exploiting the multidetector CT
technique. Mostly the examination of the patients involves portal venous phase imaging for
the examination of the pelvis and the abdomen. Some of the complex cases like various
vascular tumors for examples neuroendocrine tumors, renal carcinoma cells and melanoma.
The accuracy of the CT is compromised if the radiographic contrast media is not used. If
radiographic contrast media cannot be administered due to iodine allergy or renal
insufficiency, the accuracy of CT is poor and an MRI should be performed to fully evaluate
the liver. In a similar way MRI should be executed in the presence of hepatic fatty infiltration
because the hepatic metastases can be obscured in the presence of hepatic steatosis. The
function of fluorine-18-labelled fluorodeoxyglucose (FDG)–PET imaging for the evaluation
of the colon rectal cancer in the abdomen and in the patients detected with ovarian cancer
(Kim et al., 2015). A combination of the PET and CT imaging techniques can be exploited as
it ensures anatomic localization of the hotspots for the characterization. But PET is an
expensive technique and it is also limited in terms of the availability hence it is not
considered at present for the routine analysis of the abdominal survey. There is another major
disadvantage of PET is the heterogeneous uptake of the radiopharmaceutical FDG by the
liver prevents the exclusion of the small hepatic metastases. There are evidence-based
literature studies that state that contrast enhanced MRI is comparatively efficacious than PET.
But it should be noted that PET plays a vital role in the preliminary diagnosis of the staging

22Detection of Primary Hepatic Malignancy
of the carcinoma since it has a comparatively higher sensitivity for the detection of the extra
hepatic foci of the metastases in the areas in which the CT exhibits suboptimal sensitivity like
metastases in the non-enlarged lymph nodes (Yu, 2016).
Staging Examinations
The liver staging examinations, unlike the survey examinations are executed in patients
who have a known liver malignancy which may be primary or secondary in which the liver
resectioning is taken into consideration. This examination is comparatively crucial since the
number and the location that is determined in the course of the examination determines
whether to proceed for surgical therapy for the patient. To execute this operation, it is
observed that liver specific contrast agent enhanced MRI examination is more superior over
the contrast enhanced computed tomography and the non-contrast MRI techniques. The pre-
and post-contrast gadoxetate MRI provides improved sensitivity for the detection of the liver
lesion in comparison to the pre-contrast MRI as well as the dual-phase CT which also has
similar sensitivity and in case of the pre- and post gadoxetate MRI there are lesser false
positive results comparatively. Therefore, it can be stated that the Computed Tomography is
not required for the accurate staging study during the arterial phase imaging.
There are several chemicals that are specific for the hepatic imaging are available to
execute the hepatic MRI (Vilgrain et al., 2016). The hepato-specific agents are water soluble
and paramagnetic in nature chelates with the uptake by the hepatocyte like mangafodipir,
gadobenate and gadoxetate and there are reticuloendothelial specific compounds like
ferumoxide and ferucarbotran. Post administration of the iron compounds intravenously they
are readily taken up by the reticuloendothelial system. These iron compounds aid in the MRI
images by reducing the signal intensity of the normal regions of the liver on the T2 weighted
images (Lu et al., 2018). The MRI images that are taken without the reticuloendothelial
specific compounds have shown unchanged signals. Thus, it can be inferred that the usage of

23Detection of Primary Hepatic Malignancy
the reticuloendothelial specific compounds intensifies the detection of the liver metastases
and thus aids in improved detection of the liver metastases. But hepatocyte targeted
compounds are tolerated at a rate better than that of the iron containing compounds (Vilgrain
et al., 2016).
The staging followed by the treatment of hepatocellular carcinoma is dependent on the
tumor spread or extension assessment. Dynamic contrast-enhanced, multiphasic MRI is
considered as the most efficacious imaging technique for detection of hepatocellular
carcinoma and staging of the same (Scott et al., 2018). To determine the bone metastases,
bone scintigraphy may be used. The complete work-up of the patients detected with HCC
involves dynamic contrast-enhanced MRI or CT, chest CT and the bone scintigraphy. PET
imaging is considered effective for the staging of the entire body and also for the resolving of
doubtful metastases or certain atypical features. There are different staging systems that are
available and the Barcelona Clinic Liver Cancer (BCLC) classification is endorsed by the
AASLD and EASL-EORTC guidelines (Joo et al., 2015). The classification of BCLC
includes status of the tumor, hepatic function as well as health performance status and the
variables that are treatment-dependent variables (Scott et al., 2018) (Choi et al., 2016). The
size and multicentricity of the main nodule define the status of the tumor. The non-invasive
imaging techniques involving CT and MRI plays a crucial role in proving the fact tumors
remain single and are solitary with negligible macrovascular involvement. The detection of
the initial stage tumors classified as BCLC stage A have a better survival rate with surgical
resection, local ablation or liver transplantation in selected patients. The Intermediate HCCs
classified as BCLC stage B can usually be treated with the process of chemoembolization as
well as advanced chemotherapy for treating hepatocellular carcinoma (Choi et al., 2016).

24Detection of Primary Hepatic Malignancy
Characterization of the Hepatic Lesion
There is great prevalence of the benign hepatic tumors like focal nodular hyperplasia,
cysts and haemangioma this makes characterization of the hepatic lesion an integral part of
the detection. The contrast enhanced CT effectively characterizes the haemangioma mostly in
the portal phase (Rui et al., 2017). Cysts are readily characterized by the delayed or the
equilibrium phase scans. A dynamic contrast enhanced MRI with gadolinium chelates
effectively aids in the lesion characterization when the lesion detection is indeterminate using
the contrast enhanced CT (Renzulli et al., 2018). The nonspecific extracellular gadolinium
chelates are used as the contrast agents most commonly since they are cheap, inexpensive,
safe to be used, is effectively tolerated by the patient and they can be efficaciously exploited
for determination of the variety of hepatic diseases. The optimal imaging technique should
exploit the imaging to be executed in the arterial, portal as well as the equilibrium phases. For
patients who are undergoing the staging studies exploiting liver specific contrast agent-
enhanced MRI, which is a dynamic scan using the gadolinium chelates can be done almost
immediately after administering a second injection, hence it results in a dual contrast study
(Renzulli et al., 2018) (Choi et al., 2016).
Conclusion
The hepatocellular carcinoma is considered as a vital public health concern worldwide.
The non-invasive imaging techniques impart significant roles as observed in this article in the
surveillance, diagnosis, characterization, staging, prognosis and evaluation of the
hepatocellular carcinoma. The first line of imaging modality that is considered presently is
ultrasonography. Contrast enhanced dynamic multiphasic computed tomography as well as
the magnetic resonance imaging are considered as the diagnostic tools for HCC based on
characteristic enhancement patterns which does not exploit histopathologic confirmation. The
functional MRI techniques include DWI, MRI utilising hepatobiliary contrast agents, MRE as

25Detection of Primary Hepatic Malignancy
well as perfusion imaging. These techniques show promising reports and provides important
information with respect to the tumour biological behaviour. Additionally, there are variety of
imaging features based on different imaging modalities that enable the prediction of patient
recurrence, MVI and survival.
The prognosis of the HCC is largely dependent on which stage the tumour is detected;
early detection along with accurate assessment is considered critical for the patient
management and the survival of the patient. Nevertheless, it can be inferred that early
diagnosis of hepatocellular carcinoma is indeed considered as one of the most challenging
areas for hepatic imaging. And the comprehensive prediction models for the preoperative
evaluation of the HCC prognosis are required on an urgent basis. Therefore there should be
further studies involving the exploration of the biological behaviours of the hepatocellular
carcinoma and to develop the comprehensive diagnostic as well as the predictive models that
are based on serological, imaging, texture and radio-genomic parameters.

26Detection of Primary Hepatic Malignancy
Summary
Hepatocellular carcinoma is a malignant epithelial tumour that occurs in the hepatocytes.
The HCC is the fifth most common type of the cancer and the second most leading cause of
mortality related to cancer globally. It is assumed that almost 70%-90% of the HCC occurs
due to established liver cirrhosis and advanced fibrosis. The risk factors for the disease
includes non-alcohol fatty liver disease, hepatitis B and C virus as well as alcohol abuse.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major
public health concern worldwide. Hepatocellular carcinoma (HCC) is a leading cause of
cancer that is related to elevated mortality rates worldwide that exploits immense
geographical variation (Chou et al., 2014). The process of hepatocellular carcinoma also
known as hepatocarcinogenesis is a complex multistep process at the cellular, histologic and
the histologic levels with prime alternations that are exposed by the non-invasive imaging
modalities. Hence, imaging techniques play a major role in detection, characterization,
staging, surveillance as well as prognosis evaluation of the HCC. Presently, ultrasound is the
first line imaging modality for the screening and surveillance purpose of the disease. The
objective of this article is to exploit the current state-of-art and the recent advances in the
comprehensive non-invasive imaging evaluation of the HCC (Jiang et al., 2018).
It is of utmost importance to accurately execute the diagnosis process to be eligible for the
curative therapy. It is observed that most of the cases are detected at a later stage. The
detection is achieved with the aid of applicable screening modalities (Makuuchi et al., 2008).
Based on the literature many organizations all around the world has developed several
guidelines exploiting the evidence based data to execute the screening of hepatocellular
carcinoma. The aim of the dissertation is to review the screening modalities of the
hepatocellular carcinoma for assisting gastroenterologists as well as the providers engaged in

27Detection of Primary Hepatic Malignancy
the management of the hepatocellular carcinoma (Jiang et al., 2018). The screening methods
is subjected to changes based on the condition of the patient. The main fact to be considered
is the cost-effectiveness and screening modality that plays an important role in influencing
the variation in survival.
This article exploits the non-invasive imaging modalities that include ultrasound (US),
computed tomography (CT) and magnetic resonance imaging (MRI) play pivotal roles in
detecting hepatocellular carcinoma in the recent decades. There are several clinical practice
guidelines that recommend this non-invasive imaging techniques as the first-line tool for the
screening, diagnosis, staging and surveillance of the disease (Jiang et al., 2018). The
detection of the hepatocellular carcinoma can be done exploiting the characteristic
enhancement pattern on the dynamic multiphasic CT or MRI, this detection methods does not
require further histopathologic confirmation. Microbubble enhanced US, perfusion and dual-
energy CT as well as similar techniques has led to improved diagnostic accuracies as well as
enhanced characterization of the disease.
The prognosis of the hepatocellular carcinoma is inclined on the stage at which the disease
has been detected. Hence it is of utmost importance to detect the disease at the early stages
and ensure accurate characterization are critical in the management of the HCC disease. Thus
the imaging modalities that exploit ultrasound (US), computed tomography (CT) and
magnetic resonance imaging (MRI) play a vital role in the non-invasive diagnosis of the
hepatocellular carcinoma (Chou et al., 2014). The risk of bias that is the quality included
studies that was assessed, data were extracted and the results were quantitatively as well as
qualitative analysis. The analysis is stratified by the types of imaging as well as the unit of
analysis. Randomized trials and comparative observational studies on the effects of imaging
on clinical decision making, clinical outcomes and the harms caused (Sapisochin and Bruix
2017).

28Detection of Primary Hepatic Malignancy
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