Hepatic Adenoma and Focal Nodular Hyperplasia

8/6/2019 Hepatic Adenoma and Focal Nodular Hyperplasia

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Hepatic Adenoma and Focal NodularHyperplasia: Diagnosis and Criteriafor Treatment

Luciano De Carlis,* Vincenzo Pirotta,* GianFranco Rondinara,*

Cosimo V. Sansalone,* Giovanni Colella,* Giuseppe Maione,*Abdallah O. Slim,* Antonio Rampoldi, Alberto Cazzulani,Luca Belli, and Domenico Forti*

Focal nodular hyperplasia (FNH) and adenomaare rare benign hepatic tumors, and the standardsfor diagnosis and treatment still remain controver-sial. Usually adenoma is an indication for resec-tion, due to its tendency to bleed and to degener-ate; FNH, on the contrary, may be treatedconservatively. Preoperation differential diagno-sis is, however, difficult, often impossible. Materi-als and methods. Thirty-eight patients with pre-

sumed hepatic adenoma and/or FNH were studiedat our department from 1984 to 1996. Preoperativeassessment included clinical evaluation andsymptoms, laboratory tests, liver biopsy, ultra-sound scan, computed tomography scan, mag-netic resonance imaging, scintigraphy, and angi-ography. Thirteen patients had a presumeddiagnosis of FNH, 16 of adenoma, and 9 of unde-termined benign lesions; 27 had hepatic resec-tions (3 with laparoscopic technique), and 11 werenot operated on and are actually under a strictfollow-up observation. Results. The final diagno-sis was 19 FNH and 19 adenomas (2 of which

contained areas of hepatocarcinoma). Presumeddiagnosis was confirmed in 71% of cases. Use oforal contraceptives, abdominal symptoms, andpathologic liver test results were more frequent inpatients with adenomas. There were no deathsafter surgery. All resected patients were tumorfree during the follow-up, and in 10 of the 11nonoperated cases, the size of the nodules re-mained unchanged. We conclude that precise

diagnosis of these benign liver tumors remainsdifficult and sometimes impossible, despite newimaging techniques. Hepatic resections can beperformed under very safe conditions; laparo-scopic surgery may play a role in selected cases.Adenomas and uncertain cases are clear indica-tions for surgery. Only when a diagnosis of FNHcan be firmly confirmed in asymptomatic patientsis strict observation without surgery recom-mended.Copyrightr 1997 by theAmericanAssociation forthe Study of Liver Diseases

I n contrast with hemangioma,1 focal nodular

hyperplasia (FNH) and hepatic adenoma are

very uncommon benign lesions affecting the liver,

and their diagnosis and differentiation may be

difficult. Moreover, their natural history is not well

defined. Because of all these considerations, their

surgical indication and treatment remain controver-

sial. As a consequence of the widespread use of

improved imaging modalities, these tumors are

now recognized more frequently, and more informa-

tion is available on their behavior.2 In particular, a

strict correlation exists between these tumors and

the use of oral contraceptives.3,4 Hepatic adenomas

have the tendency to grow to conspicuous sizes,

and spontan eous ruptu res or bleeding are relatively

frequent. Malignant degeneration has been re-

ported in some cases, and resection is therefore

advisable.5 On the contrary, FNH is often an

incidental finding, and to date there is no convinc-

ing report showing that these tumors can bleed or

degenerate. Because of this, resection may be

avoided when the diagnostic assessment evidences

FNH.2 In clinical practice, computed tomography

(CT), magnetic resonance imaging (MRI), ultra-

sound (US), and angiography are used in an

attempt to determine the nature of the solitary

masses of t he liver, but accurate distinction be-

tween adenoma and FNH before surgery is often

difficult.6-10 Furthermore, percutaneous needle bi-

opsy cannot differentiate these tumors with accu-

racy.11,12

From the *Department of Surgery and Abdominal Transplanta-

tion, the Department of Radiology, and the Department of

Hepatology, Niguarda Hospital, Milan, Italy.

Address reprints request to Luciano De Carlis, MD, Divisione di

Chirurgia Generale e dei Trapianti Addominali, Pizzamiglio 27,

Ospedale Niguarda, 20162 Milano, Italy.

Copyrightr 1997 by the American Association for the Study of

Liver Diseases

1074-3022/97/0302-0009$3.00/0

Liver Transplantation andSurgery, Vol 3, No 2 (March), 1997:pp 160-165160


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The authors report herein their experience in

the treatment of these benign lesions of the liver.

Preoperative findings were matched with definite

diagnoses and with th e results of surgery; when

surgery was unadvisable, the clinical courses of

these patients were closely followed up throughtime. The aim of this study was both to define the

diagnostic criteria and establish in which cases

surgical treatment of these tumors is indicated.

Materials and Methods

From January 1984 to May 1996, 38 patients with either hepatic

adenoma or FNH were observed in our surgical department.

Nine patients were observed in the first 6 years, whereas the

remaining 29 were referred to u s between 1990 and 1996.

The patient population included 37 women and 1 man,

ranging in age from 21 to 57 years (average age, 32.6). No

chronic liver diseases nor abnormalities in serum alpha-

fetoprotein levels were detected in any patients. Thirty women

(78.9%) had a history of oral contraceptive consumption for an

average time of 5.8 years (range, 7 months to 12 years) before

diagnosis.

Ten (26.3%) patients were completely asymptomatic, and

the lesions were discovered during periodic routine examina-

tions (8 cases) or laparotomies (2 cases) performed for different

medical reasons; 23 (60.5%) complained of abdominal pain,

which was acute in 9 (23.6%); 11 (28.9%) had a palpable mass,

and 15 ( 39.4%) suffered from vague digestive troubles with

fatigue and sense of heaviness in the right abdomen.

All patients were evaluated with routine laboratory analyses,

including liver tests. Only alkaline phosphatase, gamma-

glutamyl transpeptidase, and red blood cell count showed some

abnormalities in 14 cases (36.8%). US scan, liver scintigraphy,

CT, and selective hepatic angiography were performed in all

cases. MRI, available to u s since 1990, was employed in th e last

28 patients (Figs. 1, 2). The diagnosis was made by adopting

predefined criteria, slightly modified by the authors. (Table

1).10,11,12

Percutaneous fine-needle liver biopsies were performed in

all except 3 patients, where fresh frozen section specimens were

obtained during laparotomy.

FNH was preoperatively diagnosed in 13 cases and adenom a

in 16. In 9 patients, a differential diagnosis could not be

obtained. Two symptomatic patients with diagnosis of FNH, 16

with diagnosis of adenoma, and 9 with uncertain diagnosis

underwent liver resection. Eleven patients were not operated on

because preoperative stud y, including h istology, showed the

typical features of FNH; in 8 of these cases no clinical symptoms

were evident, and in 7, moreover, the lesions were not easily

resectable because of their central location in the liver paren-

chyma. All 11 of these lesions were the only lesion in each

patient, with an average size at CT of 4.2 cm (range 2.5 to 5.5).

Right hepatectomy was performed in 3 cases, left hepatec-

tomy in 2, left lateral lobectomy in 4, and segmentectomy or

enucleation in 18. An intraoperative USscan was used rout inely

to determine the location of the tumor and its relationship with

the vascular system.

Three superficial nodules, two located in the third and one

in the sixth liver segment were excised by laparoscopic tech-

nique. Nodules were solitary in 35 of 38 patients ( 92.1%),

whereas 3 patients had multiple tumors: Two had two FNH and

1 had three adenomas. The size of the different nodules ranged

from 2.5 to 22 cm (mean, 8.7 cm). Intratumor hemorrhage was

noted in five nodules. All the lesions were submitted to

extensive evaluation by a trained path ologist. Follow-up was

completed in 100% of cases and ranged from 2 months to 12

years (average, 46 months). Patients underwent an annual

check-up with clinical examination, US scan, and biochemical

Figure 1. Typical CT appearance of an adenomaof the left liver lobe. (A) A hypodense area on theleft lateral hepatic segments is present beforecontrast administration. (B) A typical marked con-trast enhancement is evident in the early arterialphase.

Hepatic Adenoma and FNH 161


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data; CT and/or MRI were performed only when indicated.

Statistical analysis was based on the Students t-test, assuming

significance when P , .05. The therapeutic protocol wasapproved by the ethical committee of the hospital, and an

informed consent was obtained from each patient included in

the study.

Results

The final diagnosis in the resected cases was FNH

in 8 patients and hepatic adenoma in 19. These

results appear in Table 2. In 2 patients, an accurate

pathological examination revealed areas of well-

differentiated hepatocarcinoma within the adeno-

matous n odules. Two presumed adenomas were

determined to be FNH, whereas in the nine undeter-

mined cases, four were diagnosed as FNH and five

as adenomas. All presumed FNH were confirmed

both by pathological examinations and by fol-

low-up data. The 11 patients with unresected FNH

are regularly followed in our outpatient clinic, as

mentioned earlier (average follow-up, 23.7 month s;

range, 5 to 39), and the clinical courses were

uneventful except for 1. All 11 patients presented

typical CT, MRI, angiographic, and/or histological

features of FNH. In one case the nodule size

increased from 4.5 to 5.5 cm and is now under

strict evaluation. Preoperative biopsy and postop-

Figure 2. Focal nodular hyperplasia of the leftliver lobe. (A) MRI shows an isointense mass witha little hyperintense central scar on T2-weightedimages. (B) At selective angiography a markedhypervascular lesion appears; the feeding arteryis evident with rapid contrast filling from thecenter to the periphery of the node.

Table 1. Diagnostic Criteria for Adenoma and FNH

Adenoma FNH

Enlarging nodules

At CT, ipodensity followed

by a marked contrast

enhancement, calcifica-

tions, capsule, and fat

infiltration

At angiography, vascular

supply from the

periphery to the center

of the node

At biopsy, sheets of

normal hepatocytes

without bile ducts and

Kupffer cells

At CT, isodensity with an

iperdense central scar

(50% of cases)

At angiography, a central

feeding artery with

rapid visualization of

the suprahepatic vein

At MRI, isointense lesion

on T1T2 with hyperin-

tense central scar on

T2

At scintigrams, normal or

increased uptake

At biopsy, normal hepato-

cytes separated by

fibrous septa, prolifer-

ating vessels, bile

ducts, and inflamma-tory cells

Table 2. Comparison Between Presumed and

Definitive Diagnosis in the 38 Considered Patients

FNH Adenoma Uncertain

Presumed diagnosis 13 16 9

Final diagnosis

FNH 13* 2 4

Adenoma 0 14 5

*Including the 11 nonresected patients.Including the 2 cases with areas of HCC.

De Carlis et al162


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erative surgical pathologic evaluation or follow-up

data (in the nonoperated cases) were in agreement,

thus allowing a definite diagnosis in 19 of 35 cases

(54.2%). All preoperative studies showed a diagnos-

tic accuracy of 71% (27/38 patients).

Oral contraceptive use was more frequent in thepatients with adenoma (17/19 or 89.4%) than in

those with FNH (13/19 or 68.4%; P5 ns). Acute

pain (possibly related to intranodular bleeding)

and pathologic liver test results were significantly

more frequently associated with the presence of an

adenoma or an hepatocarcinoma (P, .05). All

hemorrhagic nodules were adenomas. Other clini-

cal features of our patient population are shown in

Table 3.

No perioperative deaths occurred in the patients

who underwent liver resection. Three p atients had

subdiaphragmatic fluid collections: One was reop-

erated and a small biliary fistula was sealed; theother 2 maintained percutaneous drainages for a

few days. Minor complications occurred in 5 other

patients including pleural effusion in 2, pneumon ia

in 1, and wound suppuration in 2: All were treated

conservatively. The average hospitalization time

was 10.9 days (range, 625). The 3 patients oper-

ated with the laparoscopic technique showed no

postoperative problems and were discharged from

hospital on the 4th postoperative day. During t he

follow-up, one patient died in a traffic accident 3

years after the resection. All the others are alive

with no evidence of tumor recurrence. All patients

had discontinued oral contraceptive use.

Discussion

Our experience seems to confirm that FNH, whencorrectly diagnosed, may be managed conserva-

tively and monitored with repeated US scans.13,14,15

Problems may exist in obtaining a certain differen-

tial diagnosis between FNH and adenoma and, in

some cases, between benign and malignant tumors.

From our data, only 15/19 (78.9%) of FNH had a

correct preoperative diagnosis with accurate imag-

ing techniques. US scan is nonspecific in the

differentiation of these lesions but h as a great value

as a noninvasive method in the follow-up of both

resected and nonresected patients. CT permits

diagnosis in typical cases when a central scar

within the nodule or a feeding vessel can beobserved, but these characteristic pictures are pres-

ent only in 50% of patients. Moreover, fibrolamel-

lar carcinoma may present an important fibrotic

component, similar to the central scar described as

typical for FNH. MRI has an accuracy comparable

to CT, and when used together, th ey may add 10%

to 15% to specificity. Selective hepatic angiography

was performed routinely in this series of patients,

giving excellent diagnostic confirmation without

any related complications. Concern exists about its

extensive utilization for benign hepatic lesions

because it has the disadvantage of being an invasive

procedure. The preference for angiography results

from our extensive experience in the treatment of

portal hypertension, in which it proved to be

extremely safe and exhaustive. Furthermore, th e

importance of angiography is incomparable for

technical reasons when planning a liver resection.

The procedure has diagnostic value for FNH when

a feeding artery to the mass is demonstrable: This

was the case in 11 of 19 (57.8%) of our patients

with FNH, and in all, this diagnosis was confirmed

either by postoperative pathologic evaluation or by

follow-up data. In our experience, in t he typical

cases, a suprahepatic vein selectively draining themass was usually rapidly seen along with the

feeding artery (Fig. 3). To our knowledge, this

observation is n ot reported in the literature and

seems to be a pathognomonic picture of FNH; no

patient with adenoma or other hepatic masses

evidenced such angiographic features. Scintigra-

phy shows normal uptake in all cases of FNH due

to the presence of Kupffer cells, but recent data

Table 3. Clinical Features of the Patients

FNH

(n 5 19)

Adenoma

(n 5 19*)

P

Value

Age (mean 1

range) 33.4 (23-57) 31.8 (21-43) ns

Oral contraceptive

use 13 (68.4%) 17 (89.4%) ns

Symptoms

None 8 (42.1%) 2 (10.5%) ns

Abdominal pain 8 (42.1%) 15 (78.9%) ns

Acute pain 0 (0%) 9 (47.3%) ,.05Palpable mass 5 (26.3%) 6 (31.5%) ns

Vague 5 (26.3%) 10 (52.6%) ns

Biochemical

alterations 2 (10.5%) 12 (63.4%) ,.05

Single lesion 19 (100%) 16 (84.2%) ns

Size (mean) 9.2 7.9 ns

*Including two cases with areas of HCC.



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demonstrate normal uptake also in 25% of cases of

adenoma; four of our cases confirmed this find-

ing.6,8,13 Laboratory tests and symptoms are not

diagnostic. In case of FNH, however, there is a

tendency to observe asymptomatic masses, inciden-

tally seen, without any biochemical abnormalities.

Adenoma was correctly diagnosed in 12 of 19

cases (63.1%); patients had symptoms present in a

higher percentage of cases, especially when bleed-

ing or sudden growth occurred13,14 (Fig. 4). Labora-

tory tests in most cases show alterations in stasis

indexes. In our series, these signs had statisticalsignificance in the differentiation between ad-

enoma and FNH. CT and MRI frequently demon-

strate the presence of necrosis or hemorrhage

within the nodules (five cases in our series; Fig. 4);

these findings, however, may be encountered also

in malignant lesions, such as large hepatomas.7,9,10

Either an enlarging lesion or anemia on subsequent

controls may indicate the presence of an adenoma.

On scintigram a reduced uptake is usually evident,

but not always.

Percutaneous liver biopsy alone is reported to be

of little value in the diagnosis of these benign

tumors due to the frequent lack of specific featuresin a small specimen; moreover, th e material is often

inadequate, and typical signs were p resent in only

54.2% of our cases.11,12 Other problems are related

to the fact that biopsy may be contraindicated in

hemorrhagic lesions, and the distinction between

adenoma and well-differentiated h epatocellular car-

cinoma remains difficult.11 Our study confirms the

strict correlation between adenoma and the use of

oral contraceptives; less evident is the correlation

in cases of FNH, but it un doubtedly seems that the

incidence in patients u sing sex hormones who

manifested FNH is higher than the percentage of

Figure 3. Typical angiographic images of focalnodular hyperplasia of the right liver lobe. (A)Early arterial phase showing a hypervascularmass with a central feeding artery: The contrastdye rapidly fills the node from the center to theperiphery. (B) In late phases the node is com-pletely opacified, and a suprahepatic vein, selec-tively draining the node, is well evidenced.

Figure 4. A 27-year-old female with double he-patic adenoma. CT scan showed an enormoushemorrhagic and necrotic mass arising from theleft liver lobe and occupying the whole left hypo-condrium. Another nonhemorrhagic, contrast-enhanced lesion is evident on the fourth liversegment.

De Carlis et al164


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women in the general population in Italy using

these drugs (68.4% v. 30%). This fact may reflect a

selection bias in the study but is, in our opinion, an

interesting finding.

In the last 10 years, hepatic surgeons have

largely improved their results, and hepatic resec-tions are now performed safely, with low morbidity

and very low mortality rates. In specialized surgical

units these operations are done without any need

of transfusions and with reduced hospitalization

time.5,13-16 Laparoscopic surgery may, in very se-

lected cases (superficial plongeantlesions), be an

operative option.17 The prolonged duration of

laparoscopic procedures compared with lapa-

rotomic techniques is still a major concern; never-

theless the duration of the operation usually does

not affect the recovery of patients in overall good

condition, and hospitalization time is reduced (4 v.

10.9 days in our series).An important area on which to focus when

studying these lesions is the risk of not identifying

malignant tumors. Two patients in our series had

adenomas containing degenerated areas of hepato-

carcinoma. Malignant transformation of adenoma

is a rare event, but recent reports point out this

possibility in an increasing percentage of cases.18

In conclusion, all the diagnostic preoperative

studies in our series led to the right diagnosis in

71% of cases, with more than one quarter being

misdiagnosed. It is our opinion that this is the

actual limit in the treatment of these tumors. Our

philosophy, therefore, is to resect all lesions preop-eratively classified as adenoma, independent of

their location and size. In cases of undetermined

diagnosis, we usually resect all easily resectable

lesions and keep under close observation those in

which the risks of resection seem high; any in-

crease in size or in imaging characteristics should

be signal for excision. Asymptomatic patients who

have a diagnosis of FNH based on the aforemen-

tioned typical signs are also under repeated clinical

and ecographic controls.19

The extensive use of hepatic resection in such

cases can be justified by offering patients the

guarantee of a higher recovery rate, as well as fewer

complications, which specialized liver centers offer

today.

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Sheedy PF. Hepatic adenoma and focal nodular hyper-

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Hepatic Adenoma and Focal Nodular Hyperplasia