Liver cancer by Dr. Basil Tumaini

Primary and Secondary
Liver Cancers
Basil Tumaini, MD
MMED (Int. Med.) Resident
Muhimbili University of Health and Allied Sciences
June 2017
1

Headings
• Introduction
• Epidemiology
• Clinical features
• Diagnosis ± staging
• Treatment
• Prognosis
± Prevention
•Introduction
•Primary liver cancers
HCC
Cholangiocarcinoma
Angiosarcoma
•Secondary liver cancers
2
Sub headings

Introduction
• A primary liver cancer arises from cells and/or
structures of the liver itself whereas a
secondary liver cancer spreads from other
organ to the liver
• When diagnosis is made late, as is often the
case, prognosis is poor
3

Primary liver cancers
• Hepatocellular carcinoma (hepatoma)
• Cholangiocarcinoma
• Angiosarcoma
• Others: embronal sarcoma, fibrosarcoma,
rhabdomyosarcoma
4

Primary liver cancers
Globally
– The 6th most frequent cancer
– The 2nd leading cause of cancer death
– In 2012, diagnosed in 782,000 people, caused
746,000 deaths
In US
– Five-year survival rates are 17%
5

http://www.wcrf.org/int/cancer-facts-figures/worldwide-data
6

Hepatocellular carcinoma (HCC)
• Arises from parenchymal cells (hepatocytes)
• Heterogeneous geographical distribution
• Prevalence is much higher in developing
countries (high prevalence of HBV infection,
aflatoxin B1 contamination of foods,
hepatotoxic drugs)
7

10

• Four times commoner in blacks
• More in rural areas
• Sex distribution, M:F ~ 2-6:1 (androgenic
trophic effect, hepatitis/exposure variation)
11

PROVEN PROBABLE POSSIBLE
Cirrhosis Alcohol Schistosomiasis
Hepatitis B, C Tobacco Hormonal factor
Aflatoxins Diabetes
Porphyria disease Obesity
Haemachromatosis
Nonalcoholic
steatohepatitis
(NASH)
Deficit of alfa-1
antitrypsin
Risk factors
12

• Cirrhosis of almost any cause, appearing 20-30
years after the initial insult
• 85% of Pts with HCC in the West have cirrhosis
• 3% with cirrhosis develop HCC annually
• The cause is hepatitis B in 39% of cases,
hepatitis C in 27% and alcoholism in 37%
• 25% of afflicted individuals have no risk
factors for the development of cirrhosis
13

Epidemiological Study of Carcinoma of
Liver in Dodoma Region
• In Dodoma Region, the populace consumes
large numbers of ground nuts which are
believed to predispose to liver cancer
• Of 939 clinically diagnosed malignancies in the
Region during 1972-1976, 256 (27 percent)
were hepatocellular carcinomas [P.R. Hiza]
14

In retrospective study of histopathologically confirmed cases of
hepatocellular carcinoma seen at Bugando Medical Center
between March 2009 and February 2013
• Seventy-four (52.1%) patients stated a history
of ingestion of foods stored in humid
conditions (a likely suspected source of aflatoxin B1
exposure)
• Eighty-five (59.9%) patients had a past history
of jaundice
• 32 (22.5%) had scarification marks
15
Jaka H, Mshana SE, Rambau PF, Masalu N, Chalya PL, Kalluvya SE. Hepatocellular
carcinoma: clinicopathological profile and challenges of management in a resource-
limited setting. World journal of surgical oncology. 2014 Aug 2;12(1):246.

In retrospective study of histopathologically confirmed cases of
hepatocellular carcinoma seen at Bugando Medical Center
between March 2009 and February 2013
• The use of traditional herbal concoctions was
documented in 82 (57.7%) patients
• A history of heavy alcohol consumption was
reported in 86 (60.6%) patients
• A past blood transfusion was documented in 28
(19.7%) patients
16

17

18

21

Treatment modalities
• All of the patients (100%) received supportive
therapy only because of the advanced nature
of the disease
• No patients received any curative treatment
such as liver transplantation, percutaneous
ethanol ablation, or radio frequency ablation
due to the lack of these treatment modalities
in our setting and due the advanced nature of
the disease at presentation
23

Investigations
• USS/Helical CT scan/MRI
• Hepatic arteriography
• Tumor markers: AFP, other markers
• Histopathology
• LFTs + liver enzymes: serum albumin, bilirubin
T+D, AST, ALT, ALP
• CBC:
• HBsAg, HCV Ab
• Ascitic fluid analysis
25

Ultrasound
 Used to assess tumor size, vascular invasion and
the existence of hilar adenopathies
 Sensitivity for tumors ˂ 1 cm is about 42%
reaching 95% for tumors of larger size .
 The combination of Doppler with US can be useful
for the identification of portal thrombosis in
patients with HCC, with 89 to 92% sensitivity and
100% specificity in the identification of tumor
thrombosis
26

Helicoidal/Spiral CT
 Suspicion of HCC by US in a patient with cirrhosis.
 The sensitivity of CT for the diagnosis of HCC is
similar to that of US
 Diagnostic efficacy depends on technical factors,
mainly the injection of contrast, and on factors
inherent to the tumor, the most tumor size and
vascularity
27

Helicoidal/Spiral CT
 CT should be performed by the spiral (or helicoidal)
technique with intravenous injection of contrast and
images should be obtained in the basal, arterial,
portal, and equilibrium phases
 Early arterial enhancement and delayed washout
(less enhancement than the rest of the liver) in the
venous or delayed phase of tri-phasic
multidetectorCT (the three phases are arterial,
venous, and delayed)
28

MRI
 MR has been used to obtain a better
characterization of hepatic lesions suggestive of
HCC and also for their differentiation from benign
lesions
 Sensitivity depends on tumor size
(eg for tumor ˂ 2cm =30% and tumors ˃2cm is
about 95%)
34

Hepatic arteriography
 The diagnostic efficacy of hepatic arteriography
depends on tumor size and on the extent of tumor
vascularization
 Small tumors tend to be well differentiated and
consequently present low vascularization, thus
being difficult to detect by this technique.
 For tumors smaller than 5 cm, HA has 82 to 93%
diagnostic sensitivity, 73% specificity and 89%
diagnostic accuracy
35

Tumor Markers: Alpha-1 fetoprotein
• Progressively increasing AFP concentrations
during screening are suggestive of HCC
• Considered to be diagnostic (400-500 ng/ml)
• 29% of patients with HCC may present serum
AFP levels within normal limits
• At the time of tumor diagnosis, AFP seems to
be of prognostic value
• Increase in pregnancy, chronic and other
regenerative liver disease
36

Cytology and/or histology
• Histopathological examination is the main
method for a sure diagnosis of HCC.
• FNAB is a safe technique with minimal risks of
complications and provides adequate material
when performed by trained personnel
• Diagnostic accuracy may vary from 60 to 90%
• The specificity and positive predictive value of
this technique are higher than 90%,
37

• Indications of Image-guided biopsy:
–Focal hepatic masses with atypical imaging
features
–Discrepant findings on CT and MRI
–Lesions detected in the absence of cirrhosis
• The risk of tumor seeding along the needle
track after biopsy in patients with suspected
hepatocellular carcinoma is low (2.7%)
39

Diagnosis of HCC according to the Barcelona-2000 Conference of
the European Association for the Study of the Liver (EASL)
40

Treatment
Stage-guided treatment
The choice of treatment
Cancer stage
Resources available
The level of practitioner expertise
41

Staging
• To determine the prognosis of the disease and
best therapeutic method
– Okuda
– TNM
– Barcelona Clinic of Liver Cancer (BCLC)
– French Classification
– Cancer of the Liver Italian Program
• BCLC is the only classification which correlates
prognostic data with treatment possibilities
42

Okuda 1= 11.5 months, Okuda 2 = 3 months, Okuda 3= 0.9 month
43

45
BCL
C
Performance
Status
Tumor Features Liver Fn Treatment option
A1 0 Single <5cm No PH Surgery/RFA
A2 0 Single <5cm PH, Bil
Normal
Surgery/RFA/
Transplant
A3 0 Single <5cm PH,
Abnormal
Bilirubin
RFA/Transplant
A4 0 3 tumors <3cm N/A Transplant/TACE
B 0 Large
multinodular
CP A-B TACE
C 1-2 Vascular
Invasion/Mets
CP A-B Sorafenib
D 3-4 Any CP C Supportive

7 stages (0-6) Stage 0=35 months, 2 =8months and 4-6 =3 months
47

HCC – Treatment: Surgical Resection
• Surgical resection is the treatment of choice in patients
without cirrhosis who are in the very early stage
• For patients with cirrhosis, resection produces the best
results when the tumor is small (<5 cm in diameter), portal
hypertension (a hepatic venous pressure gradient >10 mm
Hg) is absent, and the total bilirubin level is normal (≤1 mg
per deciliter [≤17.1 μmol per liter])*
• The 5-year risk of recurrence of hepatocellular carcinoma
after resection is as high as 70%*
• In the United States, less than 5% of patients are candidates
for hepatic resection, associated with an overall survival rate
of 90%
Llovet JM, Schwartz M, Mazzaferro V.
49

Surgical Resection
• Surgical resection should be considered for patients with
solitary tumors and no portal hypertension
• However, the most appropriate treatment for patients with
early-stage hepatocellular carcinoma is liver transplantation
• Patients with HCC who meet the Milan criteria for orthotopic
liver transplantation have an expected 4-year overall survival
rate of 85% and a recurrence-free survival rate of 92%*
• If transplantation is not possible, local ablation is the next
best option
MazzaferroV, Regalia E, Doci R, et al. 50

Local Ablation
• RFA, best treatment alternative for patients with early-stage
HCC who are not eligible for surgical resection or
transplantation
• Several recent randomized trials have shown radiofrequency
ablation to be more effective than ethanol injection in
treating patients with small hepatocellular tumors (2 to 3 cm
in diameter), with lower rates of local recurrence and higher
rates of overall and disease-free survival*
• Short-term outcomes are excellent, with overall survival rates
of 100% and 98% at 1 and 2 years, respectively*
Cho YK, Kim JK, Kim MY, Rhim H, Han JK. 51

Local Ablation
• 5-year recurrence rates as high as 70%
• The results of two randomized, controlled trials
comparing radiofrequency ablation and surgical
resection showed no significant differences in
overall or recurrence-free survival; as expected,
radiofrequency ablation was associated with lower
rates of complications and hospitalization*
Chen MS, Li JQ, Zheng Y, et al.
Livraghi T, Meloni F, Di Stasi M, et al. 52

Transarterial chemoembolization (TACE)
and Radioembolization
• Patients with compensated cirrhosis, but with large or
multifocal lesions but no vascular invasion are
considered to have intermediate-stage hepatocellular
carcinoma
• Improve survival among patients with preserved liver
function, who do not have extrahepatic metastases,
vascular invasion or prominent cancer-related
symptoms
53

Transarterial chemoembolization (TACE)
and Radioembolization
• A meta-analysis of randomized, controlled trials
assessing the use of arterial embolization,
chemoembolization, or both as primary palliative
treatment for hepatocellular carcinoma showed that
these procedures were associated with an improved 2-
year survival rate by 20 – 25% as compared with
conservative treatment*
56
Bruix J, Sala M, Llovet JM.

Transarterial Chemoembolization and
Radioembolization
• Neoadjuvant therapy or as a means of downstaging
a patient’s condition before liver transplantation
• Modalities include:
Selective TACE
Drug - eluting Beads (DB)-TACE,
Radioembolization or
combination approaches e.g., TACE and
radiofrequency ablation gave promising results
57

Radioembolization
• Embolization should not be performed without the use
of a chemotherapeutic agent, there are few data to
guide the choice of the chemotherapeutic agent
• In recent randomized, controlled trials, the use of a
drug-eluting bead that releases the drug in a controlled
fashion during TACE has been shown to be associated
with a reduction in both hepatic and systemic side
effects and with an increase in local tumor response*
Lammer J, Malagari K, Vogl T, et al.
Lencioni R. 58

• Radioembolization with yttrium-90 microspheres has
recently been used as palliative treatment for patients
with Child–Pugh class A cirrhosis and intermediate-
stage hepatocellular carcinoma
• However, there have been no controlled trials
comparing yttrium-90 radioembolization with TACE or
with other types of treatment
59
Radioembolization

Contraindications to TACE
60
Absolute contraindications
• Decompensated cirrhosis (Child-Pugh B ≥8) including:
– Jaundice
– Clinical encephalopathy
– Refractory ascites
– Hepatorenal syndrome
• Extensive tumor with massive replacement of both
entire lobes
• Severely reduced portal vein flow

Technical contraindications to hepatic
intra-arterial treatment
• Untreatable arteriovenous fistula
• Renal insufficiency (creatinine ≥2 mg/dl or
creatinine clearance <30 ml/min)
61

Relative contraindications to TACE
• Tumor size ≥10 cm
• Co-morbidities involving compromised organ
function:
– Active cardiovascular disease
– Active Lung disease
• Untreated varices at high risk of bleeding
• Bile-duct occlusion or incompetent papilla due to
stent or surgery
62

Sorafenib
• Patients with mild cancer-related symptoms,
vascular invasion, or extrahepatic spread are
considered to have advanced-stage disease and
are not suitable candidates for radical therapies
• TACE has increased the survival rate among well-
selected candidates, but the primary treatment
option for patients with this stage of disease is the
oral chemotherapeutic agent sorafenib
63
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A,
Schwartz M. Sorafenib in advanced hepatocellular carcinoma. New England journal of medicine. 2008
Jul 24;359(4):378-90.

• An oral multikinase inhibitor of the vascular endothelial
growth factor receptor, the platelet-derived growth factor
receptor
• Antiproliferative and antiangiogenic properties
• The only approved drug for Rx HCC BCLC –C stage
• 37% increase in overall survival as compared to placebo,
in patients with advanced HCC and compensated
cirrhosis*
Llovet JM, Ricci S, Mazzaferro V, et al.
65
Sorafenib

Indications
Pts unsuitable to TACE
Pts in whom TACE resulted in unacceptable toxicity
* Combination studies underway
66
Sorafenib

• Rash on the hands and feet
• Diarrhea
• Fatigue
• Other small molecules, brivanid, and erlotinib, and
monoclonal antibodies, bevacizumab and
cetuximab, are being studied
67
Sorafenib SEs

• Rash on the hands and feet
• Diarrhea
• Fatigue
 Other small molecules, brivanid, and erlotinib, and
monoclonal antibodies, bevacizumab and
cetuximab, are being studied
68
Sorafenib SEs

Supportive treatment
• Patients with terminal-stage disease present
with cancer symptoms related to liver failure,
vascular involvement, or extrahepatic spread
• The 1-year survival rate for such patients is
less than 10%, and they do not benefit from
the treatments mentioned above
69

Recurrence
• Cancer recurrence, generally in the hepatic
remnant, occurs in 70% to 100% of cases after
resection
• Accounts for the cause of death in 82.5% of
the patients while only 9% of deaths were due
to hepatic failure.
71

Recommendations: AASLD
• USS of the liver combined with measurement of serum
AFP levels every 6 to 12 months as surveillance for
HCC in patients with cirrhosis or advanced hepatic
fibrosis, irrespective of the cause
• Both are also useful in surveillance of HBV carriers
with or without cirrhosis if they are Africans older
than 20 years of age or Asians older than 40 years of
age or if they have a family history of HCC
• HCC is rare in HCV-infected patients with mild or no
hepatic fibrosis, surveillance is not recommended for
this group
72

Prevention
• In 2002, Tanzania introduced mandatory immunization of
Hepatitis B to all children under EPI
• Tanzania is an endemic area for viral hepatitis
 Immunization against Hepatitis B is very important to health
workers who are at higher risk and community at large
73

Cholangiocarcinoma
• Malignancies of the biliary duct system
• May originate in the
– intrahepatic bile ducts
– extrahepatic bile ducts
– distal extrahepatic bile ducts which terminate at
the ampulla of Vater
74

• Perihilar tumors (Klatskin tumors) are the
commonest cholangiocarcinomas and
intrahepatic cholangiocarcinomas are the least
common
• Klatskin tumors occur at the bifurcation of the
common hepatic duct (into right and left
hepatic ducts)
75

Epidemiology
• <2% of all human malignancies, 2nd most common
primary liver cancer
• Accounts for 6-10% of all primary liver cancer
• Highest incidence in S.E. Asia, associated with liver
fluke infection – Clonorchis sinensis and Opisthorchis
viverrini
• 2500 cases of cholangiocarcinoma each year, avg
incidence ranges from 2 - 6 cases per 100,000
people/year
76

Epidemiology
• Not associated with cirrhosis.
• Aggressive disease, median survival rate is
low (6 months)
• 90% are not eligible for curative resection
• M:F = 1:2.5 in patients (60 – 70s)
77

Risk factors
• Sclerosing cholangitis (7-42%)
• Congenital fibropolycystic diseases of the
biliarysystem-10% (particularly Caroli disease
and choledochal cysts )
• Previous exposure to Thorotrast (formerly
used in radiography of the biliarytract)
• In the Orient, the incidence rates are higher,
and it is due to chronic infection of the biliary
tract by liver flukes e.g., Clonorchis sinensis.
78

Risk factors
• IBD ( UC>CD)*
• Chemical exposures ( workers in aircraft, rubber,
and wood-finishing industries)
• Others: congenital diseases, bile duct adenomas,
α-1 antitrypsin deficiency, obesity
• Gallstones ,viral hepatitis and cirrhosis do not
appear to be risk factors
79

Pathophysiology
• Long-standing inflammation, as with PSC or chronic
parasitic infection
• Hyperplasia, cellular proliferation and malignant
transformation
• > 90% are adenocarcinoma, remainder are squamous
cell tumors
80

Clinical presentation
• Intrahepatic cholangiocarcinomais usually
detected late in its course
– as the result of obstruction to bile flow through
the hilum of the liver
– as a symptomatic liver mass
• 50 -75% metastasize to regional lymph nodes,
lungs, vertebrae, adrenals, brain, elsewhere at
autopsy
81

Clinical features
• Pruritus - 66%
• Abdominal pain - 30-50%
• Wt loss - 30-50%
• Fever - 20%
• Jaundice - 90%
• Hepatomegaly - 25-40%
• Palpable gallbladder (Courvoisier sign)
82

Diagnosis
• Pre operatively, dx is often difficult
• 1/3 of pts with symptoms and cholangiogram
suggestive of cholangiocarcinoma will have a
benign fibrosing disease or other metastasis
83

Diagnosis
• Elevated conjugated bilirubin, ALP, GGT
• Aminotransferases: normal or minimally
elevated
• LFT: normal in early disease
• Tumor markers,
– CA 19-9 > 180 ng/dl,
– CEA x 20 (Dx, Rx, and monitoring of HC with 89%
sensitivity and 86% specificity)
• Cholangiocarcinoma does not produce AFP
84

Imaging
• USS
• CT scan: benign vs. malignancy, resectability
• MRCP: 3-dimensional view of the biliary tree
• ERCP and PTC: assess local ductal extent of the
tumor while allowing for therapeutic biliary drainage
• PET scan: detect lymph node and distant metastases
• EUS: bile duct visualization and nodal evaluation,
aspirate for cytological studies
85

Treatment
• Standard therapy consists of extrahepatic bile duct
resection, hepatectomy and en bloc
lymphadenectomy
• Surgical resection
– Absence of retropancreatic and paraceliac nodal
metastases or distant liver metastases
– Absence of invasion of the portal vein or main
hepatic artery (although some centers support en
bloc resection with vascular reconstruction)
– Absence of extrahepatic adjacent organ invasion
– Absence of disseminated disease
89

Treatment
• Among patients undergoing complete resection, 5-
year overall survival rates are btn 15 and 40%
• Other treatment modalities include: Stenting,
Photodynamic therapy, Radiation therapy and
Chemotherapy
90

• Postop adjuvant therapy for +ve resection
margin (Fluoropyrimidine-based
chemotherapy)
• Radiochemotherapy if nodal positive
– In general, no single drug or combination has
consistently increased median survival beyond the
expected six to eight months
– The most active agents are 5-FU, gemcitabine,
cisplatin, and oxaliplatin
91

Prognosis
• Prognosis is poor
• The median time from diagnosis to death is 6
months
• Aggressive surgery remains the only treatment
offering hope for long-term survival
92

Hepatic angiosarcoma
• Hepatic angiosarcoma is a very rare disease,
accounting for only 2% of primary liver
malignancy
• Ranks in the third place in the list of most
common primary liver malignancies
• It originates from endothelial cells of the
blood vessels
• Difficult to diagnose in the early stage due to
unspecific symptoms
93

• Difficult to differentiate liver angiosarcoma
radiologically from other vascular tumors in
liver, such as hepatoma due hypervascularity
• No therapeutic guideline for liver
angiosarcoma has been set up
– partial liver resection to remove the tumor
radically still remains to be the cornerstone of
treatment options
95

• Prognosis of hepatic angiosarcoma is very
poor:
–rapid progression
–high recurrence rate
–resistant to traditional chemotherapy and
radiotherapy
• Even liver transplantation could not benefit
patients with liver angiosarcoma
96

Secondary liver cancers
• Metastatic involvement of the liver is commoner
(×20) than primary neoplasia
• In 50% of all cases the primary tumor is of the
GIT
• Other common primaries producing hepatic
metastases
– breast
– lung
• Any cancer in any site of the body may spread to
the liver including leukemias and lymphomas
97

Secondary liver cancers
• Typically, multiple nodular metastases are
found that often cause striking hepatomegaly
and may replace over 80% of existent hepatic
parenchyma
• The liver weight can exceed several kilograms
98

• Liver provides a fertile soil in which metastasis
may become established
– rich, dual blood supply
– humoral factors that promote cell growth
• The fenestrations in the sinusoidal
endothelium allow a foothold into the space
of Disse (perisinusoidal space) for tumor
emboli arriving via the blood stream
99

• 77% of pts both lobes are involved
• Growing metastases compress adjacent liver
parenchyma, causing atrophy and forming a
connective tissue rim
• Large metastases often outgrow their blood
supply, causing hypoxia and necrosis at the
centre of the lesion
100

Metastases to the Liver
• Factors influencing the incidence and pattern
of liver metastasis:
– Patients age and sex
– The primary site
– The histologic type
– Duration of the tumor
• The median survival time after the diagnosis
of hepatic metastasis was 75 days in one
series, and only 6.6% of pts survived longer
than one year
101

Symptoms & Signs
• Hepatomegaly
• Ascites
– 50% of pts have clinical signs of hepatomegaly or
ascites
• Tenderness
• Cachexia
• Jaundice
• Pyrexia
102

Investigations
• Level of serum ALP, AST, ALT is elevated or normal
– In 10% of patients ALP and GGT are elevated
• US/CT/MRI
– IOUS of the liver has the highest sensitivity 96%
– Duplex and color-flow imaging
– CT permits better evaluation of the involvement of
extrahepatic tissues including: bones, bowel, LN and
mesentery
– MRI allows effective localization of hepatic and
vascular invasion
* Ultrasound scan and CT scan can demonstrate
multiple filling defects
103

• Fluorodeoxyglucose (FDG) PET is the most
sensitive noninvasive imaging modality for the
diagnosis of liver metastasis
• Liver biopsy, US/CT guided
• Angiography – for planning vascular
intervention
104

Diagnosis
Limitations of imaging techniques
• Seldom enable a tissue diagnosis
• The differentiation of granulomatous lesions of the liver
from primary benign or malignant liver lesions may be
difficult
• Diagnostic difficulties may be encountered in the
characterization of atypical hemangiomas and FNH
• Hydatid liver disease may be a great mimic of liver
metastasis
• Focal fatty infiltration may also mimic liver metastasis
108

Treatment
Hepatic Resection
• Currently the most effective form of therapy for metastases
confined to the liver
• Resectability is defined as complete gross resection while retaining
a sufficient liver remnant with intact biliary drainage and
vasculature
• Anatomic or segmental resections are currently favored over large
wedge resections
• Accepted contraindications to metastasectomy include:
– Poor overall health
– Inadequate liver reserve
– Inability to achieve margin-negative resection
– Presence of extrahepatic disease
109

Treatment
• Ablative therapies (e.g. RFA) are also available for
patients with unresectable disease who do not have
apparent extrahepatic metastases
• Hepatic arterial infusion pump (HAIP) placement and
administration of chemotherapy (TACE)
• Fluorodeoxyuridine is the most common agent
administered by the intra-arterial route
• Other includes: IR and OX
110

• For most patients no effective treatment exists
because both lobes usually involved making
surgical resection impossible.
• Younger patients with metastases from CRC
confined to 1 lobe of liver and up to 4 in
number, may be treated by partial
hepatectomy
111

Liver cancer by Dr. Basil Tumaini

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