CASE REPORT

63Acta Med Indones - Indones J Intern Med • Vol 51 • Number 1 • January 2019

Immunohistochemical Staining on an Excision Biopsy
Specimen as a Diagnostic Modality for Rare Idiopathic
Hepatocellular Adenoma: A Case Report

Juferdy Kurniawan1,2, Andri Sanityoso1,2, Toar J.M Lalisang1,3,
Ening Krisnuhoni1,4, Sahat Matondang1,5, Abirianty P. Araminta1, Lutfie1

1 National Hepatopancreatobiliary Center, Jakarta, Indonesia.
2 Department of Internal Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
3 Department of Surgery, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
4 Department of Pathology Anatomy, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
5 Department of Radiology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.

Corresponding Author:
Juferdy Kurniawan, MD. Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine Universitas
Indonesia - Cipto Mangunkusumo Hospital. Jl. Diponegoro no. 71 Jakarta 10430, Indonesia. email: juferdy.k@
gmail.com.

ABSTRAK
Adenoma hepatoselular merupakan tumor jinak hati yang sangat jarang, dengan predominasi pada wanita

usia muda. Estimasi insidens 3-4 kasus per 1.000.000 populasi setiap tahunnya menjadikan kondisi ini memiliki
tantangan diagnostik tersendiri. Melalui naskah ini kami melaporkan seorang wanita berusia 30 tahun dengan
adenoma hepatoselular tanpa faktor risiko klasik. Rangkaian metode diagnostik telah dikerjakan untuk dapat
menegakkan diagnosis dan hanya biopsi eksisi dari reseksi segmental yang menunjukkan kemaknaan nilai
diagnostik. Kasus ini mengilustrasikan peran dari pulasan imunohistokimia pada biopsi eksisi sebagai modalitas
diagnostik terbaik untuk adenoma hepatoselular, sekaligus sebagai modalitas terapeutik untuk mencegah
transformasi keganasan.

Kata kunci: adenoma hati, tumor jinak hati, diagnosis, penanda imunohistokimia, reseksi.

ABSTRACT
Hepatocellular adenoma is an extremely rare benign tumor of the liver which predominantly in young

women. Its rare incidence with estimated 3-4 cases per 1.000.000 annually makes it a diagnostic challenge.
Here we present a 30-year-old female patient with hepatocellular adenoma without classic risk factors. A
series of work up tools have been performed in order to diagnose the condition. None but excision biopsy
from segmental resection had been showed to increase diagnostic confidence. This case illustrates the role of
immunohistochemical staining from excision biopsy as the best diagnostic modality of hepatocellular adenoma
as well as therapeutic modality to prevent malignant transformation.

Keywords: liver adenoma, benign liver tumor, diagnosis, immunohistochemical marker, resection.

Juferdy Kurniawan Acta Med Indones-Indones J Intern Med

INTRODUCTION
Hepatocellular adenoma (HCA), also

known as hepatic adenoma, are rare, benign,
hormonal induced hepatic tumors. Commonly
found in childbearing-aged women, HCA
has been strongly correlated with the use of
oral contraceptives.1 Incidence of HCA is
approximately 1/1.000.000 in women without
history of oral contraceptives compare to 30-
40/1.000.000 in long-term users.2,3 Nevertheless,
the mechanism of estrogen-induced HCA is
not completely understood. Other etiologies
inducing the development of HCA include long-
term use of anabolic androgenic steroids and
glycogen storage diseases.4

The clinical presentation of hepatic adenomas
varies widely. About 25-50% patients with hepatic
adenomas reported with pain in the right upper
quadrant or epigastric region. Lesions may be
palpable or incidentally found during abdominal
imaging study for other study. Bordeaux
classification of hepatic adenomas is currently
being evaluated. The classification consists of
hepatocyte nuclear factor 1α-inactivated HCA
(HNF1α HCA 30-35%), β cateninmutated HCA
(β-cat HCA 10-15%), inflammatory HCA (50%),
and a subgroup of less than 10% that remains
unclassified.5

Basically, HCA is diagnosis made by excluding
other differential diagnosis. Serological test are
performed to exclude other possible diagnosis.
Serum aminotransferase levels may be mildly
elevated due to the mass effect of the tumor. Most
patients with hepatic adenoma have normal range
of serum alpha-fetoprotein (AFP). An elevation in
AFP levels is correlated with primary carcinoma or
malignant transformation of adenoma. Radiologic
findings are nondiagnostic because the mass
commonly found in solitary and well demarcated
lesion. Advances in contrast-enhanced MRI
and contrast-enhanced ultrasonography may
be helpful to distinguish hepatic adenoma and
possibly determined Bordeaux classification
subtypes.6 Immunohistochemistry may be
performed to further characterize lesion under
the new Bordeaux classification while results
of histologic evaluation with liver biopsy are
nondiagnostic and insensitive.5 The prognostic

for hepatic adenoma is not well established.
While complete resolution is uncommon, the risk
of malignant transformation still remains even
after oral contraceptive or steroid use has been
discontinued. All symptomatic tumors should
be resected. Asymptomatic adenomas smaller
than 5 cm in size may be managed with close
monitoring.7

CASE ILLUSTRATION
A 30-year-old female was referred with

abdominal pain in the right upper quadrant over
the preceding one year. The pain was described
as localized, episodic, and non-triggered by food
or activity. She had not complained of nausea,
vomit, dark-colored stool urine, black stool,
abdominal enlargement, bloating or weight loss.
She could still carry on daily activity without
restriction. She had no history of jaundice,
blood transfusions, hepatitis, excessive alcohol
consumption, or long-term oral contraception.
Clinical examination revealed no abnormalities,
no abdominal palpable mass found.

Laboratory tests were within normal limits.
Tests for hepatitis B surface antigen and hepatitis
C antibodies were all non-reactive. Serum tumor
markers (AFP, CEA, Ca 19-9, Ca 125) were all
within normal range. Multiphase abdominal multi
slice computed tomography (MSCT) showed a
focal mass in right lobe liver, segment 5, with size
of 6.3 cm x 5.2 cm x 5 cm. The mass was shown
as iso-hypodense lesion with slight enhancement
in arterial phase, followed by heterogeneous
enhancement in portovenous phase and contrast
washed out in delayed phase (Figure 1).
The CT findings suggested hepatocellular
carcinoma with differential diagnosis of
adenoma, adenocarcinoma. Liver core biopsy
was then performed to ensure the diagnosis. Core
biopsy findings suggested liver adenoma with
differential diagnosis hepatocellular carcinoma
grade 1. Immunohystochemical staining was
performed following core biopsy, with findings
of positive granular cytoplasm with expression
of glypican 3, complete expression of CD 34,
positive expression of CD10, and less than 5%
of expression of Ki67 (Figure 2). The findings
suggested hepatocellular carcinoma grade 1.

Vol 51 • Number 1 • January 2019 Immunohistochemical staining on excision biopsy specimen as diagnostic

The patient underwent open laparotomy.
Medial laparotomy incision from xiphoid process
to two fingers below umbilicus, passing through
cutis, sub cutis, and linea alba. Intraoperative
ultrasonography (USG) was performed and
showed solid lesion of 3 x 3 x 3 cm in hepatic
segment V. Tumor resection margins were
determined with the use of USG guidance. Liver
mobilization began by releasing the liver from
the falciform ligament, coronary ligament, and
triangular ligament. Hepatoduodenal ligament
was identified and released from surrounding
tissues at right hepatic artery, right portal vein
and common bile duct using Pringle maneuver.
To treat the lesion, hepatectomy of segment V
was performed.

The specimen was brown-black colored,
spongy, measuring 10 x 7 x 4.5 cm. The mass
itself measured 7 x 6 x 3 cm, yellow-brown
colored, firm and tender. A 2.5 x 2 x 1.5 cm
hollow with inner irregular surface was shown
in division of the mass (Figure 3). Microscopic
examination showed tumor tissues with partly
poor-circumscribed edges. Neovascularization
was also seen. Tumor cells showed hepatocytes
differentiation consists of trabecular tissue of 2-4
cells/field in depth, common uniform nucleated
tumor cells, some with vivid nucleolus, and
mitosis was hardly found (Figure 4). Microscopic
examination showed the lesion was hepatocellular
adenoma. The specimen was consulted and sent
to Groningen, Netherlands and New York, USA,
of which both confirmed the diagnosis was
hepatocellular adenoma. Mutation examination
revealed it was inactivated hepatocellular
adenoma through evaluation of HNF-1α.

Figure 1. Multiphase abdominal MSCT of the patient
(clockwise from top left): non-contrast, arterial phase, venous
phase, delayed phase.

Figure 2. Histopathology finding and immunohistochemical
staining on core biopsy specimen (clockwise from top left):
stained with Hematoxylin & Eosin (H&E), CD34, glypican-3,
and Ki67.

Figure 3. Macroscopic specimen of liver mass.

Figure 4. H&E staining on excision biopsy specimen
showing hepatocellular adenoma characterized by sinusoidal
dilatation and cluster of small arteries surrounded by
inflammation.

No signs of liver failure were shown after
surgery. The patient was discharged one week

Juferdy Kurniawan Acta Med Indones-Indones J Intern Med

after surgery. The patient was advised for follow-
up ultrasound examination six months after the
operation.

DISCUSSION
The differential diagnosis of benign liver

cell tumors requires understanding of the
clinical, radiological, and pathological features
of the liver lesions. A detailed history, physical
examinations, hepatic tests, imaging, and
histopathological studies are necessary for
precise diagnosis. There are several points of
approach for the lesion which may be beneficial
as the clues of establishing HCA diagnosis,
differentiating it with focal nodular hyperplasia
(FNH) or hepatocellular carcinoma (HCC).

Patients with liver adenomatosis range in
age from 12 to 75 years, with a mean age of 34
years.8 Eighty-eight percent of them are women,
as well as those with FNH (80-90%), meanwhile
HCC predominates in men.9 Patients diagnosed
with HCA are typically young women with long-
standing oral contraceptive use or with history of
glycogen storage diseases.9 In the present case,
the diagnosis is difficult to be determined and
distinguished from other possible diagnosis due
to absence of classic risk factors from neither
HCA nor HCC (viral, alcoholic, metabolic
syndrome) and FNH (local or systemic vascular
anomalies). HCA typically occurs in noncirrhotic
livers.8 However, a recent case of HCA was
observed in a hepatitis B virus or alcoholic-
associated cirrhotic liver.10

The majority of the tumors are in the size
range of 5 to 15 cm at the time diagnosis, but they
can be < 0,5 or > 30 cm. Clinical presentation is
usually related to the size of the tumors, with size
of ≥ 5 cm tend to be more likely simptomatic,
presented with acute abdominal pain (43%) and
hemorrhagic complications (46%).8

Several diagnostic modalities have been
performed. Unlike in HCC, both HCA and FNH
were usually presented with normal function
liver test results and no or minimal elevation in
serum tumor markers, such as α-fetoprotein.10
Although the laboratory test results in our case
appeared within normal range, hepatocellular
carcinoma was suggested from radiologic
findings.

Radiological findings for HCA are similar
with those in HCC or FNH. Adenomas are
sharply marginated (85%), nonlobulated (95%),
sometimes encapsulated (30%), and rarely
calcified (10%), demonstrated with homogenous
or nearly homogenous enhancement in 80% of
cases.11 While most of adenomas were presented
in a single mass that may contain area of fat or
hemorrhage, we have found none in our case.
Also, the accurate differentation of the HCA
lesion often can be better interpreted with
magnetic resonance imaging (MRI) or contrast
enhanced ultrasonography (CEUS).8,9

S e v e r a l p r i m a r y h e p a t i c t u m o r s ,
including HCC, FNH and HCA, are classified
as hypervascular tumors, on the basis of
helical multiphasic CT observations and
pathophysiology, and therefore a confident
preoperative diagnosis of HCA are difficult
based on the radiologic observations.12,13 FNH
usually comes with diagnostic pointer of central
scar with centrifugal or eccentric enhancement,8
whereas well-differentiated HCC is usually large,
heterogenous, and lobulated, with large, central,
or eccentric scars and radiating fibrous septa,
calcifications (40-68%), as well as abdominal
lymphadenopathy (65%).11

Distinction between HCA and HCC are
obviously of paramount clinical importance in
determining appropriate therapy and assessing
prognosis, unless often can usually be achieved
only on histologic grounds. We found that the
histopathology examination of core biopsy from
our patient indicated benign lesion. The later
immunohistochemical staining with glypican
3, CD34, CD10 and Ki67 of core biopsy
specimen indicated HCC lesion. However,
distinguishing HCA from well-differentiated
HCC can be extremely challenging when the
diagnostic material is a small needle biopsy.8
Nonetheless, the efficacy of percutaneous liver
biopsy is limited with preoperative accuracy
about 50%.13,14

Conservative treatment was the initial
treatment for HCA < 5 cm in diameter. A tumor
size ≥ 5 cm and abdominal complaints, as found
in our case, were major criteria for surgical
resection. Among all HCAs, 9% may transform
into HCC with risk factors including male sex,

Vol 51 • Number 1 • January 2019 Immunohistochemical staining on excision biopsy specimen as diagnostic

androgen use, size ≥ 5 cm, and ß-catenin-mutated
HCA. In these complicated cases, early surgical
removal may improve patient outcomes.15 As an
alternative, several reports also demonstrated
the efficacy of radiofrequency ablation (RFA),
especially in cases not amenable to surgery or
in patients who would require major hepatic
resection otherwise.16 Our patient was then
decided to undergone surgery with hepatectomy
for diagnostic and therapeutic purpose.

Immunohistochemical examination of
glutamine synthetase, beta-catenin, serum
amyloid A and C-reactive protein, and liver
fatty-acid binding protein on surgical specimen
determined the lesion as of non-inflammatory
HCA or specifically HNF-1α HCA. Among all
HCAs, the HNF-1α HCA is the least aggressive
subtype with almost no risk for the development
of malignancy.

CONCLUSION
As illustrated in this case, similar findings

of HCA and well-differentiated HCC as well as
FNH in radiologic findings can be a challenge
in distinguishing the diagnosis. Because
management of these tumors is different,
confident preoperative diagnosis is essential.
Although documented in low statistic number,
HCA could occur in individual without classic risk
factor. Atypical features such as heterogeneous
enhancement should be evaluated with additional
imaging, such as MRI; or biopsy; even surgical
resection. In such cases, all possible diagnosis
must be excluded. Resection and histopathology
examination remains the best modality in
diagnosing HCA, as well as therapeutic option
to exclude malignant neoplasm.

ACKNOWLEDGMENTS
We thank Professor Annette S.H.Gouw,

MD, PhD from University Medical Centre,
Groningen, Netherlands and Professor Swan
N Thung, MD, FAASLD from Mount Sinai
Hospital, New York for the consultation on
histopathology and immunohistochemical
staining on surgical resection.

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