Review Article

Hepatocellular Carcinoma as an Emerging Morbidity in the

Thalassemia Syndromes: A Comprehensive Review
Hassan M. Moukhadder, MD1; Racha Halawi, MD, MS2; Maria Domenica Cappellini, MD3,4; and
Ali T. Taher, MD, PhD, FRCP1

The incidence of hepatocellular carcinoma (HCC) in patients with thalassemia is on the rise. The 2 well recognized HCC risk factors in
thalassemia are iron overload and chronic viral infection with hepatitis C. The carcinogenicity of iron is related to its induction of oxi-
dative damage, which results in genotoxicity, and to immunologic dysregulation, which attenuates cancer immune surveillance. Chron-
ic hepatitis B and C infections lead to necroinflammation, which can prompt progression to HCC, but an independent role of hepatitis
B virus in hepatic carcinogenesis among patients with thalassemia has not been demonstrated. Screening patients who have thalasse-
mia using magnetic resonance imaging-based liver iron concentration measurement and liver ultrasound is recommended for early
detection of iron overload and HCC, respectively. Prevention primarily resides in hepatitis B vaccination, donor blood screening, hepa-
titis treatment, and iron chelation. Although solid data is lacking on the outcomes of HCC treatment in patients with thalassemia, a
personalized approach tailored to the individual patient’s comorbidities remains necessary for treatment success. Treatment modali-
ties for HCC include surgical resection, chemoembolization, and liver transplantation, among others. Multicenter studies are needed
to better explore therapeutic targets that can improve the prognosis of these patients. Cancer 2017;123:751-8. V C 2016 American

Cancer Society.

KEYWORDS: hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, iron overload, thalassemia.

INTRODUCTION
The Thalassemia Syndromes
Thalassemia is a genetically transmitted, quantitative disorder of the hemoglobin.1 It is divided into 2 main categories,
a-thalassemia and b-thalassemia, in which the defect resides in a-chain and b-chain synthesis, respectively. Thalassemia is
a spectrum of syndromes classified according to clinical severity into asymptomatic carriers (a-thalassemia or
b-thalassemia minor), nontransfusion-dependent thalassemias (NTDTs) (which include b-thalassemia intermedia [TI]),
and transfusion-dependent thalassemias (TDTs) (which include b-thalassemia major [TM]).2

Hepatocellular Carcinoma in Thalassemia

Hepatocellular carcinoma (HCC) was not a common complication of thalassemia in the past, likely because patients with
thalassemia used to die at a young age secondary to anemia and heart failure.3 Better outcomes, particularly prevention of
heart disease after the advent of highly effective iron-chelating medicines, have greatly prolonged the survival of patients
with thalassemia, and patients currently live long enough to develop adverse complications like HCC.3,4 Although both
hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are established risk factors for the development of HCC
in the general population,5 the direct role of HBV in hepatic carcinogenesis in thalassemia is not well defined. In addition
to chronic hepatitis C, the other well recognized HCC risk factor in thalassemia is iron overload,6,7 which is the result of
chronic transfusional iron accumulation in patients with TDT as opposed to increased absorption of iron from the intes-
tine and release of recycled iron from the reticuloendothelial system in patients with NTDT.8 In this review, we describe

Corresponding author: Ali T. Taher, MD, PhD, FRCP, Department of Internal Medicine, American University of Beirut Medical Center, Cairo Street, PO Box 11-
0236, Riad El Solh 1107 2020, Beirut, Lebanon; Fax: (011) 961-1-370814; ataher@aub.edu.lb
1
Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 2Department of Internal
Medicine, Emory University School of Medicine, Atlanta, Georgia; 3Department of Internal Medicine, Foundation of the Scientific Institute for Research, Hospitali-
zation, and Health Care (IRCCS), Ca’ Granda Ospedale Maggiore Polyclinic, Milan, Italy; 4Department of Clinical Sciences and Community Health, University of Mi-
lan, Milan, Italy

The first 2 authors contributed equally to this work.

DOI: 10.1002/cncr.30462, Received: September 16, 2016; Revised: October 14, 2016; Accepted: October 17, 2016, Published online December 1, 2016 in Wiley
Online Library (wileyonlinelibrary.com)

Cancer March 1, 2017 751

Review Article
existing knowledge on the epidemiology and pathophysi-
ology of HCC in thalassemia, and we outline the most re-
cent recommended approaches to screening, prevention,
and management of this emerging morbidity.
INCIDENCE
The incidence of HCC in patients with thalassemia has
been increasing with time. For example, the number of
cases diagnosed in Italy steadily increased from 8 to 31 be-
tween 1993 to 1997 and 2008 to 2012.9 A prospective
study of 105 adults with TM identified a 2% incidence of
HCC during a 1-year observation period, which is almost
the same as the risk of HCC in the general population.10
It is noteworthy that the younger age at HCC diagnosis in
patients with thalassemia suggests the presence of risk fac-
tors unique to this population.11 In the general popula-
tion, the median age at HCC onset in developed countries
is approximately 70 years, with a 2.4:1 male-to-female
ratio12,13; on the other hand, most patients with thalasse-
mia develop HCC at age <50 years, and there is no
discernible difference in incidence between men and
women in this group of patients.9,10,14,15 It is worth men-
tioning that HCC seems to be more common in patients
with TI than TM, with a male-to-female ratio ranging
from 2:1 to 9.5:1.14-16 One possible explanation is that
patients who have TI usually have improved survival com-
pared with those who have TM, which enables them to
live long enough to develop HCC.14
RISK FACTORS
Iron Overload
Iron balance depends on intake and losses, and iron over-
load is generally the result of an overly positive iron bal-
ance. Hepcidin, a key regulator of iron balance, functions
by decreasing iron absorption from the gut and release
from the reticuloendothelial system.17 In states of abnor-
mally low hepcidin levels, such as NTDT, excess iron is
absorbed into the system and released into the circulation,
causing depletion of macrophage iron and preferential
portal and hepatocyte iron loading.18 The ultimate result
is an increase in free or nontransferrin-bound iron in the
blood, leading to end-organ damage, such as cardiomyop-
athy, endocrinopathies, cirrhosis, and even cancer.9 The
first mechanism by which free iron is believed to trigger
malignant transformation is the generation of reactive ox-
ygen species (ROS), which causes peroxidation of mem-
brane fatty acids and subsequent formation of toxic
byproducts that impair protein synthesis and disrupt
DNA, leading to mutations in tumor suppressor genes
(such as p53) and DNA repair genes.19 Iron overload may
752
also promote malignant transformation in the liver
through the acceleration of fibrosis to cirrhosis by activa-
tion of stellate cells and through the profibrogenic effects
of lipid peroxidation.7 Conversely, recent data supports
the finding that free iron is independently hepatocarcino-
genic, ie, in the absence of cirrhosis. For example, in a re-
cently described animal model, dietary iron overload was
associated with iron-free preneoplastic nodules and HCC
in the absence of cirrhosis, which may be caused by iron-
mediated oxidative stress, as detailed above.19 A recent
randomized trial demonstrated a decrease in the risk of
new visceral malignancy in a group of individuals who did
not have thalassemia or any other iron-loading disorder
but who underwent iron reduction compared to a control
group (hazard ratio 5 0.65).20
It also has been suggested that iron overload induces
immunologic aberrancies, which may contribute to cancer
formation. Growing evidence highlights the negative ef-
fect of iron and ferritin on the tumoricidal function of
macrophages in mice,21 in which it was specifically dem-
onstrated that iron overload decreased antibody-mediated
and mitogen-stimulated phagocytosis by monocytes and
macrophages.22 Moreover, lymphocyte proliferation is
inhibited independently by both nontransferrin-bound
iron and ferritin.19,23 Figure 1 summarizes the mecha-
nisms by which iron overload is believed to contribute to
the pathogenesis of HCC in patients with thalassemia.
Several reports in the literature have suggested the
hepatocarcinogenic role of iron in patients with thalasse-
mia. In fact, a number of case reports and case series have
described the development of HCC in patients with thal-
assemia who were negative for hepatitis B and C testing
but had significant hepatic iron overload.15,24,25 An
updated survey on the prevalence of HCC in Italian
patients with thalassemia highlighted the observation that
4 of the 62 reported patients had no evidence of exposure
to either HCV or HBV.9 All 4 patients had TI, and, in 3
of them, severe siderosis was reported in the biopsied liver
tissue.
HBV and HCV
Another risk factor for HCC in patients with thalassemia
is chronic viral infection, namely, with HCV or HBV, re-
lated to blood transfusion exposure. This applies mostly
to patients in their 30s or older because the risk of viral
transmission through blood transfusion was greatly re-
duced after the 1980s through blood donor screening.
The prevalence of anti-HCV antibodies in patients with
thalassemia ranges from 4.4% to 87%, with the highest
rates being reported from Italy.9,26-28 In an Italian study,9
Cancer March 1, 2017
 Hepatocellular Carcinoma in Thalassemia/Moukhadder et al
Figure 1. The pathophysiology of iron-mediated toxicity in hepatocellular carcinoma in thalassemia is illustrated. NTBI indicates
nontransferrin-bound iron; ROS, reactive oxygen species.
87% and 69% of patients were positive for HCV anti-
bodies and HCV-RNA, respectively. Data from the previ-
ous decade about the prevalence of HCC among multi-
transfused thalassemia patients in Italy and the United
Kingdom showed that 70–80% of individuals infected
with HCV will develop chronic hepatitis, approximately
20% of whom will develop cirrhosis with a risk that is di-
rectly related to the age at infection.14,26,29,30 Another
transfusion-transmitted infection is hepatitis B. The on-
cogenicity of HBV was first noted in the 1970s, when
chronic HBV infection was associated with an increased
incidence of HCC in the general population.31 Infection
with HBV is also encountered in patients with thalasse-
mia, in whom, for example, 5% of patients reported in
the updated Italian registry were positive for hepatitis B
surface antigen (HBsAg) and 58% had evidence of past
HBV infection.9
The direct role of HCV infection in progression to
HCC among patients with thalassemia is suggested by
Cancer March 1, 2017
several reports in the literature. In a recent report on
HCC incidence in a Greek thalassemia unit, HCC devel-
oped in 2 patients with TM who were not iron overloaded
but had HCV-related cirrhosis that failed to respond to
antiviral treatment.16 The results from this study suggest
that HCV infection is 1 of the main culprits of HCC de-
velopment in patients with TM. Indeed, transfusion-
related hepatitis C is a key factor in liver damage among
patients with TM through the increased risk of HCV-
associated cirrhosis.32 However, it was observed that
HCC also developed in a cirrhosis-free liver in an HCV-
infected female with TI in the presence of iron overload10;
and, in another account, HCC was witnessed in a noncir-
rhotic patient with thalassemia in the absence of iron over-
load.33 These observations suggest that HCV infection
might be an independent HCC risk factor in patients
with thalassemia. It is important to mention that chronic
hepatitis C and liver iron overload have been proposed to
work in synergy to increase the HCC risk, which is
753
Review Article
reflected by the fact that hepatic iron is often increased in
patients who have chronic HCV infection secondary to an
HCV-induced decrease in serum hepcidin levels.34,35 Al-
though chronic HBV infection accounts for approximate-
ly one-half of all HCC cases worldwide,36 the direct role
of chronic hepatitis B in hepatic carcinogenesis is not well
established for patients with thalassemia. To the best of
our knowledge, there are no reported cases in the litera-
ture of HCC in HBV-infected patients with thalassemia
in the absence of HCV serologic markers or significant
iron overload.
Transfusion-Associated Immunomodulation
Increasing evidence suggests that blood transfusions have
negative effects on the recipient’s immune system, most
likely as a result of chronic antigenic stimulation by the
transfused blood.37,38 Some of the reported immune ab-
normalities related to blood transfusions are impaired
B-lymphocyte differentiation and defective chemotaxis and
phagocytosis, which are important mechanisms in antiviral
immunity and anticancer immune surveillance.39-41 Several
studies have demonstrated the contributory effect of trans-
fusions to cancer progression or recurrence, particularly in
colorectal and lung cancers.42-44 However, to date, the pre-
cise role of transfusion-related immunomodulation in the
development of HCC in thalassemia has not been elucidat-
ed, and further studies are required for a better understand-
ing of this association.
MANAGEMENT
The management of HCC in patients with thalassemia
includes screening and prevention plans in addition to
treatment strategies that target the HCC risk factors.
Screening
The emergence of HCC as a pressing morbidity in thalas-
semia suggests the need for structured HCC screening
programs. Borgna-Pignatti et al reported nonspecific or
even completely absent symptoms in 82% of patients who
had thalassemia and were diagnosed with HCC, which
supports the usefulness of effective screening regimes tar-
geting early HCC detection.9 Iron overload, as discussed
above, is associated with a host of complications in
patients with thalassemia, including carcinogenesis, sug-
gesting that HCC surveillance strategies for patients with
thalassemia should include close monitoring of increased
iron burden which might put them at risk for developing
HCC. Although liver biopsy was previously used in
patients with thalassemia to estimate liver iron concentra-
tion (LIC), this practice has been abandoned, because of
754
the procedure’s inconvenience and potential side effects,
in favor of noninvasive LIC quantification with R2 or R2*
magnetic resonance imaging (MRI).9 However, the serum
ferritin assay, which is an easy and inexpensive method
compared with LIC measurement, remains to be heavily
relied upon in resource-poor areas where MRI technology
is not available.45 Although this marker is reflective of
iron stores in patients with TDT,46 serum ferritin levels
underestimate the true iron burden in NTDT patients,47
which can be explained by the finding that hyperabsorbed
iron in the latter group is accumulated in hepatocytes,
usually leading to lower serum ferritin levels.47,48 There-
fore, because LIC and total body iron are linearly related,
yearly LIC assessment using noninvasive MRI methodol-
ogies is the mainstay for accurately estimating total body
iron levels in all patients with thalassemia, but it may be
done on a more or less frequent basis, depending on the
extent of iron overload and its control.49
In addition to screening for iron overload, HCC can
be secondarily prevented in thalassemia if high-risk lesions
are detected early by timely radiographic testing. The
American Association for the Study of Liver Diseases rec-
ommends surveillance of cirrhotic patients in the general
population using biannual abdominal ultrasound, and it
recognizes that a-fetoprotein (AFP) measurement lacks
the sensitivity and specificity required for optimal HCC
detection.50-52 The inadequate sensitivity of AFP for
HCC screening is also apparent in patients with thalasse-
mia, in whom AFP levels were normal in 44% of patients
in an Italian study9 and in 100% of those in another study
by Greek investigators.16
The lack of clear-cut HCC screening guidelines for
thalassemia might be problematic, especially because the
HCC risk factors in these patients are different from those
in the general population. Various professional organiza-
tions have identified target populations that might benefit
from HCC surveillance plans, but the risk factors in the
thalassemia population are not clearly outlined in those
recommendations. On the basis of current evidence, it is
suggested that high-risk patients with thalassemia should
undergo biannual liver ultrasound for HCC screening,
with high-risk patients identified as patients with HCV
and/or HBV infection, NTDT with LIC 5 mg Fe/g dry
weight (dw), TDT with LIC 7 mg Fe/g dw or serum fer-
ritin 1000 ng/mL, or advanced cirrhosis.3,9,11,53-55
Prevention
The development of HCC can be avoided by preventing
or treating the HCC risk factors, namely, chronic viral
hepatitis and iron overload.3 In the general population,
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TABLE 1. Iron-Chelating Drugs in Transfusion-Dependent and Nontransfusion-Dependent Thalassemia
Variable Deferoxamine
Route of administration Parenteral
Indication
TDT  Ferritin level
consistently  1000 ng/mL
 10-15 transfusions
 LIC  7 mg Fe/g dw
NTDT Not approved
Abbreviations: dw, dry weight; LIC, liver iron concentration; NTDT, nontransfusion-dependent thalassemia; TDT, transfusion-dependent thalassemia.
HCC caused by HBV-related cirrhosis can be prevented
with vaccination.9 In addition, HCC caused by
transfusion-transmitted hepatitis B or C can be prevented
by donor blood screening with nucleic acid testing (NAT)
technology, the utility of which in developed countries is
minimal because of the low prevalence of HBV and HCV
infections in these nations.9 In the United States, HBsAg
and antibody against hepatitis B core antigen (anti-
HBcAg) screening are mandatory for whole blood dona-
tions based on current US Food and Drug Administration
recommendations, which also state that the use of NAT is
optional and cannot replace HBV serologic testing.56
Efforts to eradicate HCV infection should be imple-
mented once hepatitis C has developed.53 The recent in-
troduction of direct-acting antivirals (DAAs) for HCV
treatment has represented an enormous leap in the ap-
proach to HCV infection, with high sustained viral re-
sponse rates of approximately 90% to 95%.57 However,
all HCV-infected patients with thalassemia reported in
the literature had received pegylated interferon with or
without ribavirin, which used to be the standard treat-
ment for chronic HCV infection before the advent of
DAAs.58-60 Although some degree of efficacy has been
demonstrated in most of the trials investigating the use of
interferon alone or with ribavirin for the treatment of
chronic hepatitis C in thalassemia,3 the use of ribavirin in
thalassemia patients remains controversial because of
ribavirin-associated increased transfusion require-
ment.61,62 Another concern in HCV treatment is the need
to delay antiviral therapy pending appropriate iron chela-
tion, as suggested by some studies indicating that iron
overload reduces the response to interferon-a or com-
bined interferon plus ribavirin.63-65 Conversely, a recent
Cancer March 1, 2017
Hepatocellular Carcinoma in Thalassemia/Moukhadder et al
Iron-Chelating Drug
Deferiprone Deferasirox
Oral Oral
 Ferritin level  Ferritin level
consistently  1000 ng/mL consistently  1000 ng/mL
 10-15 transfusions  10-15 transfusions
 LIC  7 mg Fe/g dw  LIC  7 mg Fe/g dw
 Children aged > 6 y and adults
only if other chelators are not
tolerated or ineffective
Not approved  LIC  5 mg Fe/g dw
 Ferritin level  800 ng/mL in
patients aged >10 y (or > 15 y in
those with hemoglobin H disease)
prospective study demonstrated that LIC did not correlate
with virologic response to antiviral treatment in chronic
HCV-infected patients who had TM,66 which suggests
against delaying antiviral treatment in patients with thal-
assemia. Regarding the treatment of HBV in patients with
thalassemia, this has not been reported in the literature.
Currently approved drugs for chronic hepatitis B treat-
ment in the general population include interferons and
oral nucleoside/nucleotide analogs,67,68 but the safety and
efficacy of these agents in thalassemia remain to be
investigated.
Patients with thalassemia who are iron overloaded
should receive chelation therapy.3 Table 1 outlines the
different iron-chelation strategies and their indications in
the TDT and NTDT syndromes.2,54,55,69-71 It is also im-
portant to mention that blood transfusions, in light of
their putative immunomodulatory effects, should be re-
stricted to guidelines in TDT and only to instances when
they are indicated in NTDT. In addition, donor blood
should be leukoreduced to decrease its antigenic poten-
tial,71 but this is only a hypothesis given the lack of studies
establishing a correlation between blood transfusions and
HCC.
Treatment
Table 2 outlines the HCC cases in the literature among
patients with thalassemia reported to date along with the
therapies that were tried in them.9,14,16,53,72-74 It is im-
portant to note that, although little data has been pub-
lished on HCC treatment in thalassemia, the following
modalities have been proven both safe and effective in se-
lected patients with thalassemia: 1) surgical resection, 2)
chemoembolization, and 3) simultaneous percutaneous
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Review Article
TABLE 2. Summary of Hepatocellular Carcinoma in Patients With Thalassemia Reported in the Literature
and the Therapeutic Modalities Received
No. of
Reference Patients Type of Thalassemia
Zurlo 198972 1 TM
Borgna-Pignatti 200414 22 TM (n 5 8), TI (n 5 11), ST (n 5 3)
Modell 200873 2 Unspecified thalassemia
Fragatou 201016 5 TM (n 5 2) and TI (n 5 3)
Maakaron 201353 2 TI
Ansari 201374 1 Unspecified thalassemia
Borgna-Pignatti 20149a 62 TM (n 5 32), TI (n 5 28), ST (n 5 2)
Abbreviations: TI, thalassemia intermedia; TM, thalassemia major; ST, sickle thalassemia.
a
In the patients described by Borgna-Pignatti et al,9 all attempted treatments are outlined; some patients received more than 1 treatment strategy, and the
authors did not mention which patient received which treatment(s).
radiofrequency thermoablation and ethanol injec-
tion.3,10,33 Although it has been demonstrated that the ki-
nase inhibitor sorafenib significantly improves prognosis
in early stage HCC,75,76 it is not known whether this drug
is efficacious in treating HCC in patients with thalasse-
mia, because it was tried in 3 Italian thalassemia patients
but produced unclear outcomes.9,15
Thalassemia was previously considered a contraindi-
cation to liver transplantation, which has led to only a few
patients undergoing this procedure.11 In fact, liver trans-
plantation has long been considered an HCC treatment
option that improves survival in the general population.5
In an Italian case series of patients with TDT and NTDT,
the survival of the only patient who underwent transplan-
tation was 69 months, whereas the survival of the
8 untransplanted patients was 25.25 6 23.65 months
(range, 3-64 months).15 Two other patients with TDT
from a different Italian study underwent successful liver
transplantation with satisfactory post-transplantation out-
comes.3 Borgna-Pignatti et al reported 2 deaths among 3
patients who underwent transplantation but for reasons
not related to thalassemia, including 1 death from cirrhot-
ic liver failure possibly related to HCV recurrence and 1
from meningococcal sepsis.9 Given the promising results
highlighted above, thalassemia should no longer be con-
sidered a contraindication to liver transplantation in the
absence of significant comorbidities like heart disease and
pulmonary hypertension.3
CONCLUSION
HCC is an emerging complication in patients with thalas-
semia, but data is lacking with regard to its precise burden.
The incidence of HCC in the thalassemia syndromes
reflects an evolving morbidity that is increasingly compli-
756
Therapy
Not mentioned
Surgery (n 5 2); palliative therapy (n 5 20)
Not mentioned
Combined chemotherapy (n 5 3); chemoembolization (n 5 2)
Palliative therapy (n 5 1); percutaneous radioablation, sur-
gery, and palliative therapy (n 5 1)
Chemotherapy
Chemoembolization alone; thermoablation; surgery preced-
ed or followed by chemoembolization or thermoablation;
liver transplantation; palliative therapy; sorafenib
cating the course of the disease. It is noteworthy that the
significantly younger age at the diagnosis of HCC among
patients who have thalassemia compared with the general
population makes this a unique entity in which the con-
stellation of iron overload, chronic viral hepatitis, and
possibly transfusion-related immunomodulation are the
main risk factors for hepatic carcinogenesis.
Current approaches to screening for HCC in both
TDT and NTDT patients include liver ultrasonography
every 6 months in individuals with at least 1 HCC risk
factor (ie, HCV and/or HBV infection, iron overload, or
advanced cirrhosis) in addition to annual MRI-based LIC
measurement in all patients.3,9,11,53-55 Biannual liver ul-
trasonography is a shared recommendation with the gen-
eral population, but yearly LIC assessment is particular to
patients who have thalassemia because of their high risk of
iron overload, which is an established HCC risk factor as
described above. HCC prevention in patients with thalas-
semia might differ slightly from that in patients without
thalassemia, and extra care must be taken to ameliorate
the cancer risk factors unique to the former subgroup,
namely, chelation therapy for increased iron burden and
hepatitis treatment only with drugs that have been proven
both safe and efficacious in this patient population. To
date, there is no data supporting a different approach for
HCC treatment, including liver transplantation, in
patients who have thalassemia compared with those who
do not, provided that the treatment options are tailored to
the individual patient’s clinical status and coexisting mor-
bidities.3 It is paramount to stress the importance of
adopting a multidisciplinary approach that values the
patient’s quality of life, in which the hematologist, gastro-
enterologist, medical oncologist, surgeon, and mental
health provider all work together to optimize treatment
Cancer March 1, 2017

outcomes. On the other hand, ongoing research on HCC
in the thalassemia realm is lacking, although multiple
aspects about HCC in thalassemia are a nidus for future
investigation, such as the exact role of transfusional im-
mune dysregulation in hepatic carcinogenesis, the use of
DAAs in treating HCV-infected thalassemia patients, and
the utility of anti-HBV treatments in patients with thalas-
semia who concurrently have hepatitis B. Multicenter in-
ternational studies will be valuable to strengthen available
data on the aforementioned aspects and pave the way for
novel therapeutic targets in this special population, with
particular emphasis on the long-term outcomes of such
treatment modalities as tumor resection, percutaneous lo-
cal ablation, transarterial chemoembolization, liver trans-
plantation, and palliative therapy in the subgroup of
patients with HCC who also have thalassemia. An inter-
national registry tracking all HCC cases in patients with
thalassemia reported in the literature to date and incorpo-
rating additional accounts in the next 5 to 10 years may be
especially useful in outlining pathophysiologic and thera-
peutic trends unique to this patient population.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
Maria Domenica Cappellini and Ali T. Taher report grants from
Novartis Pharmaceuticals and Celgene Corporation outside the
submitted work.
AUTHOR CONTRIBUTIONS
Hassan M. Moukhadder and Racha Halawi wrote the article.
Maria Domenica Cappellini critically reviewed the article. Ali T.
Taher edited and critically reviewed the article. All authors read
and approved the final draft.
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