J Gastrointest Canc (2012) 43:36–39

DOI 10.1007/s12029-010-9205-5

REVIEW ARTICLE

Hepatocellular Carcinoma in Non-cirrhotic Liver

Without Evidence of Iron Overload in a Patient
with Primary Hemochromatosis. Review
Parminder Singh & Harneet Kaur & Robert G. Lerner &
Roshan Patel & Shamudheen M. Rafiyath &
Gurpreet Singh Lamba

Published online: 28 September 2010

# Springer Science+Business Media, LLC 2010

Abstract exposure should be monitored closely for any sign and

Background We report a case of a 70-year-old male with
hepatocellular carcinoma (HCC) with a history of hemo-
chromatosis but with no evidence of cirrhosis or iron
overload and with a history of exposure to atomic bomb
radiation. It is very rare to see hepatocellular carcinoma in
the absence of evidence of liver injury.
Methods We did an extensive review of current English
medical literature through Pubmed from 1980 to 2009 and
found 14 case reports of patient with hepatocellular cancer
in absence of cirrhosis. The details of these cases were
reanalyzed as reported and documented for review.
Results There are 14 previous case reports of HCC
developing in hemochromatosis in absence of cirrhosis
but ten of them had evidence of iron overload in the non-
tumorous livers. Our case is the fifth case of Hepatocellular
cancer in hemochromatosis in absence of cirrhosis and iron
overload.
Conclusion Hepatocellular carcinoma is a very rare in
absence of cirrhosis but patient with other risk factors like
hemochromatosis, viral infections, radiation, and toxin
P. Singh (*) : R. G. Lerner : S. M. Rafiyath : G. Singh Lamba
Department of Hematology and Oncology,
Westchester Medical Center,
Valhalla, NY, USA
e-mail: Drparminder.singh@gmail.com
H. Kaur
Department of Internal Medicine, Westchester Medical Center,
Valhalla, NY, USA
R. Patel
Department of Pathology, Westchester Medical Center,
Valhalla, NY, USA
symptoms suggestive of malignancy.
Keywords Hepatocellular carcinoma . Hemochromatosis .
Non-cirrhotic liver . Radiation exposure
Introduction
Hemochromatosis has been associated with increased risk of
Hepatocellular carcinoma (HCC) esp. due to iron overload
and cirrhosis [1]. Radiation-induced liver cancer has been
reported in the epidemiologic studies in atomic bomb
survivors [2]. Studies in patients who received thorotrast as
a radiological contrast also showed increased incidence of
liver cirrhosis and carcinoma. We report a patient with well
controlled hemochromatosis who developed HCC in the
absence of cirrhosis, iron overload, and viral hepatitis and
with a history of exposure to atomic bomb radiation.
Case
A 70-year-old caucasian man with a 35-year history of well-
controlled hemochromatosis with frequent phlebotomies pre-
sented to his medical doctor (MD) for regular follow-up and
phlebotomy. He complained of slowly progressive discomfort
in the right upper abdomen for the last 4–6 weeks. The pain
was usually a feeling of sting and then a continuous
annoyance. The pain will respond briefly to Tylenol. He also
noticed gradual weight loss of 10–12 lbs over 6–8-month
period. He has no history of any fevers, nausea, malaise,
anorexia, and easy bruisability. The MD ordered an ultra-
J Gastrointest Canc (2012) 43:36–39 37

sound which showed a liver mass. He was referred to our

center for evaluation and further management. From the
records available, the patient had a past medical history of
hemochromatosis with an average ferritin of 91.6 ng/ml (14–
235 ng/ml) and serum iron 175 mcg/ml (35–140 mcg/ml). He
had regular evaluation and phlebotomies at 6–12-week
interval depending on his ferritin and serum iron values. He
also had hypertension, hypothyroidism, and gout which were
well controlled.
His mother and one brother were affected by the disease
though his children were not affected by the disease. The
patient worked in the army and was witness to the atomic test
code name ‘Orange’ on 12 August 1958 off the shores of
Johnson islands. He was stationed on the aircraft carrier and
observed the testing without any protection from the radiation.
He later on moved to construction but denied working with
any form of chemicals. He never smoked or drank alcohol. On
physical examination, he did not have any stigmata of liver Fig. 1 MRI of the abdomen showing solitary mass in the right hepatic
lobe
disease but had mild hepatomegaly. Initial laboratory work-
up showed slight elevations of liver enzymes with normal
ferritin and serum iron. His viral serologies for hepatitis B 45 years or under the age of 10. Hepatocellular carcinoma
virus (HBV) and polymerase chain reaction for HCV were was the main subtype observed after atomic radiation exposure,
negative. MRI done preoperatively showed large 6.5×8.5 cm with overall rate of HCC 6.44 (4.51, 9.51) times higher than
heterogeneously enhancing lesion without washout. This was that of cholangiocarcinoma (p<0.001). Interestingly, our
not characteristic of HCC (Fig. 1). Other studies showed no patient was exposed when he was in his 20s and was
evidence of metastatic disease in the chest abdomen and diagnosed with cancer at age 70.
pelvis. Similar observations were made in cohort of Mayak
On gross examination during surgery, the patient’s liver workers [3] and also animal models [4]. On the contrary,
looked normal in texture and contour with no external internal radiation exposure by thorotrast, a radiological
evidence of cirrhosis or fatty liver (Fig. 2). Histopathology contrast medium used in the 1930s and 1940s, known to
showed moderate to poorly differentiated hepatocellular deposit in connective tissue surrounding intrahepatic ductal
carcinoma in segment 6 and 7 of liver (Fig. 3). Vascular
invasion was absent. The non-neoplastic liver showed no
evidence of cirrhosis (Fig. 4). World Health Organization
(WHO) grade 1–2 fibrosis and non-specific portal triaditis
was present. Steatosis and any large cell dysplasia were
absent. The normal liver was negative for iron staining.
Immuno-histochemistry for HBV virus on the tissue was
negative. The patient is alive without recurrence on 6 months
follow-up CT scans.

Discussion

External and internal radiation, both are associated with

increased incidence of liver cancer. In their epidemiologic
study of atomic bomb survivors in Hiroshima and Naga-
saki, Cologne et al [2] noticed overall increase in incidence
of HCC. The higher incidence [3.3{CI: (2.7, 4)} times] was
noticed in males than females. Peak incidence in males
occurred around age 70. Most of the excess risk was
noticed among those exposed between the age 10 and 30, Fig. 2 Gross specimen of resected liver showing tumor which is tan
with no excess risk among those exposed over the age of yellow color with hemorrhagic foci
38
Fig. 3 Histopathology of liver showing malignant tissue and normal liver. Note normal liver with minimal periportal fibrosis and absent iron stain
system can induce cholangiocarcinoma more commonly than
other forms of liver cancer. Thorotrast after deposition
continuously emits α-particles which over years induces
malignancy [5].
The pathophysiology of hepatocarcinogenesis is linked
tightly to the evolution of cirrhosis. Several mechanisms at
the cirrhosis stage appear to accelerate cancer formation
including the following (a) telomere dysfunction inducing
chromosomal instability, (b) a growth inhibitory environ-
ment selecting for proliferative cells, and (c) alterations of
the microenvironment and macroenvironment stimulating
cellular proliferation.
Hemochromatosis is associated with 220-fold increased
risk of HCC [1]. However, occurrence of HCC in absence
of cirrhosis is very rare. Our case represents the fifth case of
HCC developing in hemochromatosis in absence of
cirrhosis and iron overload (Table 1).
Trevisani et al. in his largest series of HCC, evaluated
HCC in non-cirrhotic patients, found only one patient out
of 102 had hemochromatosis but did not comment on iron
Fig. 4 Uninvolved liver with minimal periportal fibrosis
J Gastrointest Canc (2012) 43:36–39
overload in that patient [6]. They also noticed that larger
solitary lesion was more common in absence of cirrhosis
and that they have extensive disease because of the late
presentation.
HCC in non-cirrhotic usually presents as a symptom
complex of right upper quadrant pain or discomfort, malaise,
fever, anorexia, and weight loss as compared to cirrhotic
which present with signs and symptom of liver cell failure.
Grando-lemaire, in his case series of HCC in non-cirrhotic
in French patients [15], found some evidence of liver injury in
terms of fibrosis (85%), active inflammation (67%), steatosis
(67%), iron overload (64%), and large cell dysplasia (40%).
Our patient had minimal evidence periportal fibrosis of WHO
grade 1–2 and non-specific triaditis.
There are 14 previous case reports of HCC developing in
hemochromatosis in absence of cirrhosis but ten of them
had evidence of iron overload in the non-tumorous livers.
Role of iron in mutagenesis has been studied extensively in
animals and in vitro studies. Shires in their studies on rat
hepatic nucleic subjected to iron-induced lipid peroxidation
showed that it can cause breaks in DNA [7]. Similarly,
Hann showed that iron-enhanced hepatocellular carcinoma
cell growth in vitro and its deprivation caused tumor cell
death. There is evidence that ferritin plays a role in
carcinogenesis by suppressing the immune system [8].
Interestingly, Deuginer in their largest series of HCC in
primary hemochromatosis noticed what they called ‘Iron
free Foci’, these were lobular and sublobular clusters of
iron-devoid hepatocytes in an overloaded liver, that had
preneoplastic changes in form of large dysplastic cells. Iron
depletion was previously proposed as an earliest hall mark
of morphological modifications in neoplastic cells [9].
These cases represent a very small subset of patients with no
evidence of cirrhosis and iron overload, progressing to HCC.
Explanation may lie in multistep process and combination of
many factors including age, sex, genetic mutation of HFE gene,
J Gastrointest Canc (2012) 43:36–39 39

Table 1 Details of non-cirrhotic patients with cirrhosis reported in the literature

Ref Age/sex Age of diagnoses Previous Iron Hepatitis B Hepatitis C C282Y AFP Radiation
hemochromatosis cirrhosis overload mutation levels exposure

Fellows [11] 58/m 53 No Nil NT NT NT 554 No mention

Fellows [11] 76/m 65 No Nil -ve NT NT 2350 No mention
Blumberg [10] 67/m 35 Yes Nil -ve NT NT NT No mention
Goh et Al [13] 56/m 39 No Nil -ve -ve NT 9400 No mention
Our case 70/m 35 No Nil -ve -ve homozygous 46 present

NT not tested

initial iron overload and underlying chronic damage to liver. Our
case also had a history of atomic bomb radiation which could
have been one of the steps that finally lead to its development.
Male predominance of these patients is also noted.
Controversy persists whether this subgroup of patient with
genetic hemochromatosis undergoing venesection should be
regularly screened for HCC. It is generally accepted that
aggressive management of hemochromatosis improves sur-
vival and decreases the risk of complications. Some case
reports have shown reversal of fibrosis and cirrhosis after
phlebotomy [10]. The incidence of HCC in cirrhotic
hemochromatosis patient has been estimated to be as high
as 19% [5]; however, similar rates cannot be extrapolated to
well-treated patients. It is also known that once fibrosis and
cirrhosis supervene, the depletion of iron alone does not
prevent development of HCC [9, 11–13]. Normal AFP in our
case and in cases presented by others [10] precludes its use
as a standard of care for surveillance. Recent meta-analysis
showed pooled sensitivity of annual surveillance ultrasound
to detect any stage HCC in patient with cirrhosis is 94%,
before clinical symptoms arise [14]. However, ultrasound
was less effective for detecting early HCC with a sensitivity
of 63%. We feel that clinicians following such patients
should have a low threshold for ordering ultrasound on onset
of symptoms or clinical deterioration of liver function.
Further studies at centers following hemochromatosis patient
may help formulate guidelines for surveillance in these
patients especially with associated risk factors of viral
infections, exposure to radiation, and toxins.
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