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World Journal of
Hepatology
ISSN 1948-5182 (online)
World J Hepatol 2021 October 27; 13(10): 1203-1458
Published by Baishideng Publishing Group Inc
WJH https://www.wjgnet.com IOctober 27, 2021 Volume 13 Issue 10
World Journal of
Hepatology
W J H
Contents Monthly Volume 13 Number 10 October 27, 2021
EDITORIAL
Transition of an acronym from nonalcoholic fatty liver disease to metabolic dysfunction-associated fatty
liver disease
1203
Alam S, Fahim SM
OPINION REVIEW
Non-invasive real-time assessment of hepatic macrovesicular steatosis in liver donors: Hypothesis, design
and proof-of-concept study
1208
Rajamani AS, Rammohan A, Sai VR, Rela M
REVIEW
Impact of COVID-19 pandemic on liver, liver diseases, and liver transplantation programs in intensive
care units
1215
Omar AS, Kaddoura R, Orabi B, Hanoura S
In the era of rapid mRNA-based vaccines: Why is there no effective hepatitis C virus vaccine yet?
1234
Echeverría N, Comas V, Aldunate F, Perbolianachis P, Moreno P, Cristina J
Pediatric non-cirrhotic portal hypertension: Endoscopic outcome and perspectives from developing
nations
1269
Sarma MS, Seetharaman J
MINIREVIEWS
Acute-on-chronic liver failure in children
1289
Islek A, Tumgor G
Coronavirus disease 2019 in liver transplant patients: Clinical and therapeutic aspects
1299
Loinaz-Segurola C, Marcacuzco-Quinto A, Fernández-Ruiz M
Pediatric vascular tumors of the liver: Review from the pathologist’s point of view
1316
Cordier F, Hoorens A, Van Dorpe J, Creytens D
Autoimmune hepatitis in genetic syndromes: A literature review
1328
Capra AP, Chiara E, Briuglia S
Assessing the prognosis of cirrhotic patients in the intensive care unit: What we know and what we need
to know better
1341
da Silveira F, Soares PHR, Marchesan LQ, da Fonseca RSA, Nedel WL
Liver transplantation for pediatric inherited metabolic liver diseases
1351
Vimalesvaran S, Dhawan A
WJH https://www.wjgnet.com II October 27, 2021 Volume 13 Issue 10
World Journal of Hepatology
Contents Monthly Volume 13 Number 10 October 27, 2021
Liver and COVID-19: From care of patients with liver diseases to liver injury
1367
Gaspar R, Castelo Branco C, Macedo G
ORIGINAL ARTICLE
Basic Study
Direct modulation of hepatocyte hepcidin signaling by iron
1378
Yu LN, Wang SJ, Chen C, Rausch V, Elshaarawy O, Mueller S
Serum zonulin levels in patients with liver cirrhosis: Prognostic implications
1394
Voulgaris TA, Karagiannakis D, Hadziyannis E, Manolakopoulos S, Karamanolis GP, Papatheodoridis G, Vlachogiannakos
J
Retrospective Cohort Study
Impact of biliary complications on quality of life in live-donor liver transplant recipients
1405
Guirguis RN, Nashaat EH, Yassin AE, Ibrahim WA, Saleh SA, Bahaa M, El-Meteini M, Fathy M, Dabbous HM, Montasser
IF, Salah M, Mohamed GA
Retrospective Study
Machine learning models for predicting non-alcoholic fatty liver disease in the general United States
population: NHANES database
1417
Atsawarungruangkit A, Laoveeravat P, Promrat K
Acute liver failure with hemolytic anemia in children with Wilson’s disease: Genotype-phenotype
correlations?
1428
Pop TL, Grama A, Stefanescu AC, Willheim C, Ferenci P
Observational Study
Clinical outcomes of patients with two small hepatocellular carcinomas
1439
Pham AD, Vaz K, Ardalan ZS, Sinclair M, Apostolov R, Gardner S, Majeed A, Mishra G, Kam NM, Patwala K, Kutaiba N,
Arachchi N, Bell S, Dev AT, Lubel JS, Nicoll AJ, Sood S, Kemp W, Roberts SK, Fink M, Testro AG, Angus PW, Gow PJ
CASE REPORT
Focal nodular hyperplasia associated with a giant hepatocellular adenoma: A case report and review of
literature
1450
Gaspar-Figueiredo S, Kefleyesus A, Sempoux C, Uldry E, Halkic N
WJH https://www.wjgnet.com III October 27, 2021 Volume 13 Issue 10
World Journal of Hepatology
Contents Monthly Volume 13 Number 10 October 27, 2021
ABOUT COVER
Editorial Board Member of World Journal of Hepatology, Julio Coelho, MD, PhD, Professor, Department of Surgery,
Federal University of Parana, Curitiba 80240-110, Parana, Brazil. coelhojcu@yahoo.com.br
AIMS AND SCOPE
The primary aim of World Journal of Hepatology (WJH, World J Hepatol) is to provide scholars and readers from
various fields of hepatology with a platform to publish high-quality basic and clinical research articles and
communicate their research findings online.
WJH mainly publishes articles reporting research results and findings obtained in the field of hepatology and
covering a wide range of topics including chronic cholestatic liver diseases, cirrhosis and its complications, clinical
alcoholic liver disease, drug induced liver disease autoimmune, fatty liver disease, genetic and pediatric liver
diseases, hepatocellular carcinoma, hepatic stellate cells and fibrosis, liver immunology, liver regeneration, hepatic
surgery, liver transplantation, biliary tract pathophysiology, non-invasive markers of liver fibrosis, viral hepatitis.
INDEXING/ABSTRACTING
The WJH is now abstracted and indexed in PubMed, PubMed Central, Emerging Sources Citation Index (Web of
Science), Scopus, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal
Database (CSTJ), and Superstar Journals Database. The 2021 edition of Journal Citation Reports® cites the 2020
Journal Citation Indicator (JCI) for WJH as 0.61. The WJH’s CiteScore for 2020 is 5.6 and Scopus CiteScore rank
2020: Hepatology is 24/62.
RESPONSIBLE EDITORS FOR THIS ISSUE
Production Editor: Xu Guo; Production Department Director: Xiang Li; Editorial Office Director: Xiang Li.
NAME OF JOURNAL INSTRUCTIONS TO AUTHORS
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FREQUENCY PUBLICATION ETHICS
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EDITORS-IN-CHIEF PUBLICATION MISCONDUCT
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Submit a Manuscript: https://www.f6publishing.com World J Hepatol 2021 October 27; 13(10): 1450-1458
DOI: 10.4254/wjh.v13.i10.1450 ISSN 1948-5182 (online)
CASE REPORT
Focal nodular hyperplasia associated with a giant hepatocellular
adenoma: A case report and review of literature
Sérgio Gaspar-Figueiredo, Amaniel Kefleyesus, Christine Sempoux, Emilie Uldry, Nermin Halkic
ORCID number: Sérgio Gaspar-
Figueiredo 0000-0002-0883-9690;
Amaniel Kefleyesus 0000-0002-7951-
4041; Christine Sempoux 0000-0003-
1375-3979; Emilie Uldry 0000-0002-
2493-0750; Nermin Halkic 0000-
0002-0117-0453.
Author contributions: Gaspar-
Figueiredo S and Kefleyesus A
performed the literature review,
collected all the data related to the
case report, and recorded/edited
the video-vignette related to the
case report; Sempoux C did the
anatomopathological
examination/appraisal; Halkic N
and Uldry E did the surgical
appraisal; all authors have read
and approved the final manuscript.
Informed consent statement:
Informed written consent was
obtained from the patient for
publication of this report and any
accompanying images.
Conflict-of-interest statement: All
authors declare no conflicts-of-
interest related to this article.
CARE Checklist (2016) statement:
The authors have read the CARE
Checklist (2016), and the
manuscript was prepared and
revised according to the CARE
Checklist (2016).
Open-Access: This article is an
open-access article that was
Sérgio Gaspar-Figueiredo, Amaniel Kefleyesus, Emilie Uldry, Nermin Halkic, Department of
Visceral Surgery, Lausanne University Hospital, Lausanne 1011, Switzerland
Christine Sempoux, Department of Pathology, Lausanne University Hospital, Lausanne 1011,
Switzerland
Corresponding author: Nermin Halkic, MD, PhD, Chief Doctor, Professor, Department of
Visceral Surgery, Lausanne University Hospital, Rue du Bugnon 46, Lausanne 1011,
Switzerland. nermin.halkic@chuv.ch
Abstract
BACKGROUND
Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are well-
known benign liver lesions. Surgical treatment is usually chosen for symptomatic
patients, lesions more than 5 cm, and uncertainty of diagnosis.
CASE SUMMARY
We described the case of a large liver composite tumor in an asymptomatic 34-
year-old female under oral contraceptive for 17-years. The imaging work-out
described two components in this liver tumor; measuring 6 cm × 6 cm and 14 cm
× 12 cm × 6 cm. The multidisciplinary team suggested surgery for this young
woman with an unclear HCA diagnosis. She underwent a laparoscopic left liver
lobectomy, with an uneventful postoperative course. Final pathological
examination confirmed FNH associated with a large HCA. This manuscript aimed
to make a literature review of the current management in this particular situation
of large simultaneous benign liver tumors.
CONCLUSION
The simultaneous presence of benign composite liver tumors is rare. This case
highlights the management in a multidisciplinary team setting.
Key Words: Liver; Focal nodular hyperplasia; Hepatocellular adenoma; Composite tumor;
Video vignette; Case report
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Gaspar-Figueiredo S et al. Simultaneous benign liver tumors
WJH https://www.wjgnet.com 1451 October 27, 2021 Volume 13 Issue 10
selected by an in-house editor and
fully peer-reviewed by external
reviewers. It is distributed in
accordance with the Creative
Commons Attribution
NonCommercial (CC BY-NC 4.0)
license, which permits others to
distribute, remix, adapt, build
upon this work non-commercially,
and license their derivative works
on different terms, provided the
original work is properly cited and
the use is non-commercial. See: htt
p://creativecommons.org/License
s/by-nc/4.0/
Manuscript source: Unsolicited
manuscript
Specialty type: Gastroenterology
and hepatology
Country/Territory of origin:
Switzerland
Peer-review report’s scientific
quality classification
Grade A (Excellent): A
Grade B (Very good): 0
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
Received: April 25, 2021
Peer-review started: April 25, 2021
First decision: June 4, 2021
Revised: June 15, 2021
Accepted: August 31, 2021
Article in press: August 31, 2021
Published online: October 27, 2021
P-Reviewer: Beraldo RF
S-Editor: Gong ZM
L-Editor: A
P-Editor: Guo X
Core Tip: Focal nodular hyperplasia and hepatocellular adenoma (HCA) are frequent
but non-malignant tumors. There is rarely indication for surgery. Combination of these
two masses is a very unusual situation. Their diagnosis is mainly based on radiology.
Oral contraception is a risk factor for HCA. Malignant transformation of HCA is the
predominant argument for surgery. All these cases, especially composite tumors, must
be discussed in a multidisciplinary team.
Citation: Gaspar-Figueiredo S, Kefleyesus A, Sempoux C, Uldry E, Halkic N. Focal nodular
hyperplasia associated with a giant hepatocellular adenoma: A case report and review of
literature. World J Hepatol 2021; 13(10): 1450-1458
URL: https://www.wjgnet.com/1948-5182/full/v13/i10/1450.htm
DOI: https://dx.doi.org/10.4254/wjh.v13.i10.1450
INTRODUCTION
Focal nodular hyperplasia (FNH) has become a pretty well-known disease in the past
two decades. It is defined by a benign hyperplasic nodule with a central scar,
appearing in the normal liver parenchyma, and is composed of normal hepatocytes in
a multinodular structure[1]. Its incidence is between 0.6%-3%, predominantly affecting
females patients (80%-90%) in their third or fourth decade. The pathophysiology is
thought to be due to an increased arterial flow that leads to secondary hepatocellular
hyperplasia[2,3]. The correlation with oral contraceptives (OCs) is unproven but very
likely, given that OCs are taken almost exclusively by women (sex ratio 9:1) and the
proven correlation between OCs and change in lesion size[4,5].
Hepatocellular adenoma (HCA) is a benign lesion with a malignant potential
between 4% and 8%, according to recent works of Farges et al[6] and Sempoux et al[7].
It classically arises in a noncirrhotic liver, in young females with an OC background.
However, the understanding of HCA has evolved dramatically and we now know that
it can also develop in patients with non-alcoholic steatohepatitis, certain vascular
malformations, or alcoholic cirrhosis. Moreover, there are a wide variety of subtypes of
this complex disease, making it very difficult to establish treatment guidelines[8-10].
In this present article, we aimed to describe the detailed management of a rare
simultaneous case of FNH and HCA and a brief review of the literature.
CASE PRESENTATION
Chief complaints
A 34-year-old woman in general good health, with a medical history of oral contra-
ceptives (desogestrel, ethinylestradiol) for 17 years consulted her general practitioner
(GP) for a check-up.
History of present illness
She was completely asymptomatic.
History of past illness
She had no past illness.
Personal and family history
The patient had no past medical history except a knee orthopedic surgery 1 year
before, had a stable weight with normal body mass index (21.1 kg/m2) and no familial
medical history.
Physical examination
During the examination, her GP found a mobile and palpable abdominal mass of more
than 10 cm in diameter, with no skin bulging at the Valsalva's maneuver (Figure 1).
Gaspar-Figueiredo S et al. Simultaneous benign liver tumors
WJH https://www.wjgnet.com 1452 October 27, 2021 Volume 13 Issue 10
Figure 1 Pre-operative patient’s supine and stand-up picture – no external signs of tumor.
Laboratory examinations
The blood exams were normal, except for an elevation in alkaline phosphate level of
519 U/L (normal range = 36-108). Tumoral markers were normal.
Imaging examinations
Abdominal ultrasound revealed an aspecific giant mass next to the left hepatic lobe. A
computed tomography (CT scan) revealed a double mass attached to the left lobe of
the liver. The first one had the typical characteristics of FNH and the second one of
uncertain dignity. Further magnetic resonance imaging (MRI) confirmed a 6 cm x 6 cm
mass suggestive of FNH in the inferior part of segment III. This 6 cm lesion was right
next to a second one measuring 14 cm × 12 cm × 6 cm which dignity was unclear. The
differential diagnosis was between an HCA, a hepatocellular carcinoma (fibrolamellar
variant), or an atypical FNH (Figures 2-5).
FINAL DIAGNOSIS
The pathologist’s report confirmed the diagnosis of 6 cm FNH resected with good
margin and showed a non-beta-catenin–mutated HCA (inflammatory subtype with
more risk of malignant transformation) (Figure 6).
TREATMENT
Indication for surgery was retained during a multidisciplinary team (MDT) meeting as
the first option for definitive diagnosis and treatment.
The surgery was completed without complication. We summarize hereafter the key
points of the minimally invasive procedure. After inserting 4 trocars for the
laparoscopy (para-umbilical, right and left flank, subxiphoid) and staying away from
the large dual mass which limited the range movements, we performed an ultrasound
confirming a pedunculated mass (FNH) highly vascularized attached to segment III
and a second component pedunculated between segment II and III. The mass showed
no adhesion with the segment IV and the gallbladder allowing a left lobectomy.
Dissection was performed with ultrasonic shears (Ultracision Harmonic, Ethicon Inc.,
NJ, United States) and transsection was completed with a 60mm stapler (tri-staple
vascular cartridge, Endo-GIA, Medtronic, Minneapolis, MN, United States). We
extracted the specimen with both lesions through a suprapubic (Pfannenstiel) incision.
The operative time was 122 min. Blood loss was minimal (50 mL) (Video 1).
The postoperative course was uneventful and the patient was discharged on
postoperative day 3.
Gaspar-Figueiredo S et al. Simultaneous benign liver tumors
WJH https://www.wjgnet.com 1453 October 27, 2021 Volume 13 Issue 10
Figure 2 Preoperative drawing – tumor and liver major vessels’ relationship (credits: Dr. Giulia Piazza). FNH: Focal nodular hyperplasia; HCA:
Hepatocellular adenoma.
Figure 3 Ultrasonography with a sagittal view of focal nodular hyperplasia and hepatocellular adenoma. D1: Greater axis length. FNH: Focal
nodular hyperplasia; HCA: Hepatocellular adenoma.
OUTCOME AND FOLLOW-UP
The MDT meeting proposed a 1-year MRI follow-up with oral contraceptive discon-
tinuation.
One month after surgery, the patient was good without any complaint, her scar
evolution was satisfactory and there was no sign of an early incisional hernia.
DISCUSSION
The interest of this case lies in the simultaneous discovery of 2 adjacent but patholo-
gically different benign liver lesions: the first one (FNH) without a strong indication
for surgery and the second one requiring surgery because of its uncertain diagnosis.
Gaspar-Figueiredo S et al. Simultaneous benign liver tumors
WJH https://www.wjgnet.com 1454 October 27, 2021 Volume 13 Issue 10
Figure 4 Computed tomography late portal phase, with a multiplanar reconstruction of focal nodular hyperplasia and hepatocellular
adenoma.
Figure 5 Magnetic resonance imaging – T2 sequence. Orange arrow: Focal nodular hyperplasia; White arrow: Hepatocellular adenoma.
FNH has no recognized risk of malignant transformation or bleeding and usually
has an uneventful course. Therapeutic abstention is usually recommended for
asymptomatic patients with a definitive diagnosis[11]. Surgical management is
reserved for symptomatic patients or with diagnosis uncertainty despite a complete
workup[12,13]. Twelve cases of spontaneous rupture of FNH are described and
considering these extremely rare events, conservative treatment is the actual well-
established standard of care [English-language literature until 2019; NCBI.gov with
terms “spontaneous; rupture; FNH]. Close follow-up is however recommended for
FNH more than 5 cm. Some authors advocate for upfront surgery with FNH larger
than 5 cm[14-16]. However, we do not recommend a surgical resection in our daily
practice but advocate for a close follow-up strategy. In the present case report, the
diagnosis of FNH of the segment III lesion was radiologically typical and in the
absence of the HCA component, a 1-year MRI follow-up would have been
recommended.
On the contrary, the risk of malignant transformation of HCA is 4%-5%. As reported
by Sempoux et al[7], risk factors for complications of HCA (bleeding or malignant
transformation) are the size (> 5 cm), male gender, activating mutation in β-catenin,
Gaspar-Figueiredo S et al. Simultaneous benign liver tumors
WJH https://www.wjgnet.com 1455 October 27, 2021 Volume 13 Issue 10
Figure 6 Anatomopathological pictures (top: fresh sample; bottom: formalin-fixed sample), sagittal section plane. Yellow arrow: Focal nodular
hyperplasia; Green arrow: Hepatocellular adenoma; Orange arrow: Left liver (segment II).
and specific clinical background (glycogen storage disease, androgens, vascular
diseases). The resulting recommendations for surgery are based on initial size (> 5 cm),
imaging or histological signs of malignancy, size progression after OC discontinuation,
and male patients. Selected patients and those who are not fit for surgery can benefit
from embolization[17-19]. When the diagnosis cannot be achieved with imaging, a
percutaneous biopsy or resection may be required[20].
Moreover, Bröker et al[21] 2012 advocated the surgery for adenoma greater than 5
cm with patients who had planned a pregnancy. Our patient didn’t have a pregnancy
plan but size and uncertainty of diagnosis were our principal arguments for surgery.
We made a literature review of the simultaneous cases of FNH and HA. Although
there is some case reports in the eighties, the article was not available for consulting
[22-25]. Table 1 summarizes the other cases with enough data.
Case 1 was operated on because of the lack of obvious radiological evidence[26].
The authors of case 2 don’t clearly explain the indication for the operative procedure
but they interestingly explain the possible same pathophysiological etiology for 4
different simultaneous hepatic masses[27].
Shih et al[28] made a left hepatectomy for a case with common features between
FNH and HA and operate for the uncertainty of diagnosis.
The French group of Laurent et al[29] found in their records 5 over 30 patients
operated for “benign hepatocytic nodules" with simultaneous HNF and adenoma. All
of them went under surgery when the radiology reports an HA or unidentified mass.
The diagnosis of FNH was already known at the time of the surgical procedure except
for one case where the FNH was too small[29].
Concerning the surgical technique, the laparoscopic approach is relatively recent.
Unfortunately, Shih et al[28] didn’t report this in their paper although they did the
same procedure for a similar patient. Despite the lack of high-level evidence data
(randomized control trials, meta-analysis), current literature about laparoscopic vs
open liver surgery for benign tumors suggests an advantage for the minimal-invasive
technique[30,31]. On the other hand, evidence for laparoscopic malign liver resection is
much more consistent. Furthermore, safety, feasibility, and long-term results
confirmed the advantages of laparoscopy for malign liver tumors[32-34].
Gaspar-Figueiredo S et al. Simultaneous benign liver tumors
WJH https://www.wjgnet.com 1456 October 27, 2021 Volume 13 Issue 10
Table 1 Summary of current literature review
No. Ref. Sex, age OC Pathology - Size
(cm) Location (segment) Symptoms Treatment
FNH – 2.5 S3 Wedge resection#1 Dimitroulis et al
[26], 2012
F, 18 yr No
HA – 6 S5-6
RUQ pain
Lt S5-6
FNH – < 5 S4 En bloc (+ gallbladder)
HA – NA S4 Enucleation
HH – > 4 S2 Enucleation
#2 Di Carlo et al[27],
2003
F, 25 yr No
HCy – NA S5
RUQ pain
En bloc (+ gallbladder)
FNH – 6 III#3 Shih et al[28], 2015 F, 40 yr Yes
HA – 9.5 & small ones
(max 1.5 cm)
III for the largest, small
ones on both lobes
Abdominal pain LH
FNH – 1 S3 Lt S3 segmentectomy +
wedge
F, 45 yr Yes
HA – NA S7
Fatigue
Lt RH
FNH – 5 S6 Biopsy
FNH – 4 S7 Biopsy
NA – 3 Left lobe
None
Lt LH
F, 40 yr Yes
HA – 3 Left lobe Lt LH
F, 38 yr Yes HA surrounded by
FNH –13
Right lobe None Lt RH
HA – 5 × 1 S1 (bleeding), S2, 3, 7, 8F, 29 yr Yes
FNH – 1 S6
Abdominal pain +
shock
Lt LH + S1
HA – 1 RL
#4 Laurent et al[29],
2003
F, 41 yr Yes
FNH – 1 RL
Abdominal pain Lt RH
#5 Our case-report F, 38 yr Yes 6 × 614 × 12 × 6 S3 None Ls LL
FNH: Focal nodular hyperplasia; HA: Hepatic adenoma; HCy: Hepatic hydatid cyst; HH: Hepatic hemangioma; RL: Right lobectomy; LH: Left
hepatectomy; LH: Left hepatectomy; LL Left lobectomy; RUQ: Right upper quadrant; Lt: Laparotomy; Ls: Laparoscopic; F: Female; OC: Oral contraception.
CONCLUSION
We hereby report a laparoscopic resection of a macro-adenoma associated with focal
nodular hyperplasia. The review of the literature shows that the simultaneous
presence of these two masses is rare and that every case must be discussed in a
multidisciplinary board. Factors like age, pregnancy wish, size, and uncertainty of
diagnosis must be considered for shared decision in the setting of a multidisciplinary
team. The laparoscopic approach should be preferred as much as possible.
ACKNOWLEDGEMENTS
We thank Dr. Giulia Piazza for her graphic representation of the case (Figure 2) which
she has kindly drawn and for her courtesy in publishing it.
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