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Management of the focal nodular hyperplasia of the liver: evaluation of the surgical treatment comparing with observation only
The American Journal of Surgery (2012) 204, 689 – 696
Clinical Science
Management of the focal nodular hyperplasia of the liver: evaluation of the surgical treatment comparing with observation only Aristotelis Perrakis, M.D.a,*, Resit Demir, M.D.a, Volker Müller, M.D.a, Jürgen Mulsow, M.D.a, U¨nal Aydin, M.D.b, Sedat Alibek, M.D.c, Werner Hohenberger, M.D.a, Süleyman Yedibela, M.D.a a
Department of Surgery, Department of Hepatobiliary and Transplant Surgery, and bDepartment of Radiology, University of Erlangen-Nuremberg, Erlangen, Germany; cDepartment of Surgery, University of Gaziantep, Sehitkamil/Gaziantep, Turkey KEYWORDS: Focal nodular hyperplasia; Surgical treatment; Observation; Liver resection
Abstract BACKGROUND: Long-term results of both surgery and observation for patients with focal nodular hyperplasia (FNH) in a large single-center experience do not exist. Accordingly, the aim of this study was to compare long-term outcomes in patients with FNH who underwent either elective hepatectomy or observation alone. METHODS: A retrospective single-institution analysis of 185 patients with FNH, treated from 1990 to 2009, was performed. RESULTS: Seventy-eight patients underwent elective hepatectomy and 107 patients observation alone, with a median follow-up period of 113 months. There was no perioperative mortality. Postoperative complications were recorded in 12 patients, and 92% of patients reported symptomatic reductions. Among observation patients, 9 (13%) developed additional symptoms; tumor enlargement was seen in 3 patients (4%). CONCLUSIONS: Elective liver resection for FNH is a safe procedure at high-volume centers. This single-center experience showed that 13% of observed patients had protracted symptoms. This justifies the therapeutic algorithm that elective surgery should be considered in symptomatic patients or in those with marked enlargement. © 2012 Elsevier Inc. All rights reserved.
Focal nodular hyperplasia (FNH) is the second most common benign nodular disease of the liver, and its exact etiology and pathogenesis are not completely understood.1 FNH is considered a truly benign formation, which does not P.A. and R.D. contributed equally to this article. * Corresponding author. Tel.: 49-9131-8533296; fax: 49-91318539227. E-mail address: [email protected] Manuscript received August 28, 2011; revised manuscript February 26, 2012
0002-9610/$ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2012.02.006
undergo a malignant transformation.2 It appears predominantly in women during their reproductive years (female/ male ratio, 80:20). In most patients, these lesions are discovered incidentally during ultrasound examination. Whether oral contraceptives play a role in the growth of the lesions remains an open matter.3,4 Some authors have emphasized that oral contraceptives lead to an intense vascularization of FNH, increasing the risk for rupture and acute bleeding.5 Liver function test results are in most cases normal, and ␣-fetoprotein is not present.6 Contrast-enhanced magnetic
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resonance imaging (MRI) has been shown to be the most sensitive modality for characterizing FNH, while triplephase spiral computed tomography (CT) and contrast-enhanced ultrasonography can be used as further diagnostic tools.6 –17 Because of the benign nature of FNH, observation remains in the foreground, and the indication for surgical treatment is controversial. However, the rapid progress of the disease, the occurrence of symptoms, the obstruction of large vessels, jaundice, and the uncertainty of the diagnosis can be accepted as indications for surgical treatment. Several studies have reported nonsurgical management or observation of FNH.1,2,7 However, there is an absence of large studies with adequate numbers of patients reporting longterm results of both nonsurgical and surgical treatment.2,5,8,9,10 Here, we report our single-center experience in the management of FNH, including patients who underwent elective surgical therapy or observation alone. Our aims were to review the long-term outcomes of these patients and to clarify the indications for surgical treatment.
Methods Study population Between January 1990 and December 2009, 185 patients diagnosed with FNH were evaluated in the Surgical Department of the University of Erlangen-Nuremberg. Patients were identified from a prospective database and analyzed in 2 groups: group A (n ⫽ 78) included patients who underwent elective surgical treatment and group B (n ⫽ 107) those who were observed alone or those who refused to undergo surgery despite the occurrence of symptoms and marked enlargement of their tumors during follow-up (Fig. 1). One hundred twenty-one patients had no symptoms, 64 reported about abdominal discomfort, and 11 symptomatic patients refused to undergo surgical treatment. Our final analysis involved 147 patients who underwent complete follow-up through December 2009 or until death. The treatment algorithm for all patients at our institution is illustrated in Figure 1. We analyzed demographic data, health status according the EQ-5D questionnaire,18 laboratory liver values, number and sizes of the lesions, diagnostic methods used, mode of surgical treatment, and postoperative outcome with perioperative and postoperative complications.
Demographic parameters and diagnostic imaging The median age of the patients was 34 years (range, 19 –53 years). Ninety-two percent were women. The ratios of women to men were 86% to 14% in group A and 98% to 2% in group B. Diagnostic workup included ultrasonography, contrast-enhanced triphasic CT, and MRI (Table 1). The imaging findings of the surgical group (group A, n ⫽
78) were compared with the outcomes of the histopathologic examinations of the resected specimens. The latter were taken as the gold standard for confirmation of the diagnosis. Tumor biopsy was performed preoperatively in 10 patients (percutaneously in 6 patients and laparoscopically in 4 patients). Liver serum tests included aspartate aminotransferase, alanine aminotransferase, bilirubin, ␥-glutamyltransferase, alkaline phosphatase, and ␣-fetoprotein (Table 2).
Surgical procedures and indication criteria Indications for surgical treatment included abdominal discomfort (n ⫽ 53), marked tumor enlargement with a rate of growth of ⬎.5 cm/y or ⬎ 3 cm in comparison with initial diameter (n ⫽ 13), and uncertainty of diagnosis (n ⫽ 12) (Table 3). All patients who underwent surgery for uncertainty of diagnosis were treated in the early 1990s, when imagining modalities did not offer sufficient results. Patients for whom the indication for surgery was given as tumor enlargement (n ⫽ 13) showed marked enlargement of FNH in a time frame from 3 to 51 months (mean, 23 months). Patients with tumor enlargement or uncertainty of diagnosis (n ⫽ 25) were initially in the observation group and underwent hepatectomy a mean of 32 months after initial referral (range, 3– 63 months). Ninety-six patients without any symptoms and 11 patients who reported abdominal discomfort but refused to undergo surgical treatment were included in group B. We evaluated the outcomes of the patients in both groups. In group A, all patients underwent anatomically oriented liver resection. The extent of the hepatectomy was classified according to the Brisbane criteria.11 The parameters assessed were blood loss and blood transfusion in the perioperative phase and early postoperative course, hepatic and extrahepatic complications, 90-day morbidity and mortality, lengths of stay in the intensive care unit and the hospital, and symptom relief after surgical treatment. The observation parameters for the patients in group B were reductions of symptoms, symptom progression, tumor enlargement, tumor-related morbidity and mortality, and health status according to the EQ-5D questionnaire. Statistical analysis was performed using SPSS for Windows version 17.0 (SPSS, Inc, Chicago, IL) and Excel 2007 (Microsoft Corporation, Redmond, WA), and all data were checked for significance using unpaired Student’s t tests. P values ⬍ .05 were considered statistically significant. Continuous variables are reported as mean ⫾ SD.
Results Twenty-two percent of the patients in group A had histories of cancer (n ⫽ 17), and 60% (n ⫽ 47) had received
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Management of focal nodular hyperplasia
Symptomatic n=64
691
Asymptomatic n=121
Observation n=132
n=11
Abdominal discomfort n=53
Uncertain diagnosis n=12
Tumor enlargement n=13
Surgery n=78
n=69
Follow-up n=147
Lost cases n=38
Figure 1
Therapy algorithm for all patients (n ⫽ 185).
hormonal therapy before the diagnosis. Mean levels of alanine aminotransferase, aspartate aminotransferase, bilirubin, and ␥-glutamyltransferase were within the normal ranges in both groups (Table 2). Only mean alkaline phosphatase level was elevated in group A (109.9 U/L; reference range ⬍ 80 U/L) (Table 2). In group A, mean tumor diameter was 7.9 cm (range, 1–20 cm), and in group B, it was 5.2
Table 1 Imaging modality and the rates of diagnosis in the surgical group (group A) Modality
n
Correct
Uncertain
Incorrect
Ultrasound CT MRI
78 63 47
40 (51%) 48 (76%) 41 (87%)
21 (27%) 12 (19%) 4 (9%)
17 (22%) 3 (5%) 2 (4%)
cm (range, 1–12 cm) (Table 2). Twenty-two patients in group A had multiple lesions (n ⫽ 28). By contrast, multiple nodules were diagnosed in 15 patients in group B. Four patients in group A developed increasing jaundice because of compression of the intrahepatic and/or extrahepatic bile ducts by the nodules. Five patients had additional findings, including hemangioma (n ⫽ 2) or hepatocellular adenomas (n ⫽ 3). In all patients with the diagnosis of FNH, there was a cessation of consumption of contraceptives after the first referral to our department.
Diagnostic studies All patients who were treated surgically underwent abdominal ultrasonography. In 40 of 78 patients (51%), the diagnosis was established correctly. In 21 patients (27%),
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Table 2
Pretreatment demographic data
Variable Age (y), median (range) Gender Male Female Tumor diameter (cm), mean (range) Number of lesions Solitary Multiple History of cancer No Yes Previous hormonal therapy No Yes Mean ASAT (U/L) Mean ALAT (U/L) ␥-glutamytransferase (U/L) Bilirubin (mg/dL) Alkaline phosphatase (U/L)
Surgery
Observation
All Patients
(n ⫽ 78)
(n ⫽ 107)
(n ⫽ 185)
37 11 67 7.9
30
33 (17–53)
P NS
2 105 5.2
13 (7%) 172 (93%) 6.7 (1–20)
.003 .043 NS
56 22
91 16
147 (79%) 38 (21%)
NS NS
61 17
103 4
164 (89%) 21 (11%)
NS NS
46 (25%) 139 (75%) 12.9 ⫾ 1.52* 14.8 ⫾ 1.86* 43.7 ⫾ 4.75* .7 ⫾ .42* 76.7 ⫾ 4.83*
.004 .046 NS NS .003 NS .004
31 47 14.3 18.9 65.4 .67 109.9
15 92 11.7 12.1 28.3 .71 53.3
ALAT ⫽ alanine aminotransferase; ASAT ⫽ aspartate aminotransferase. *First ambulant aftercare.
there was uncertainty of the diagnosis. In 17 patients (22%), the ultrasound examinations did not offer the correct diagnosis: in 8 the diagnosis of a malignant tumor (primary liver tumor or metastasis) and in 5 the diagnosis of hemangioma were established; in 4 patients, hepatocellular adenomas were suspected. Contrast-enhanced triphasic CT was performed in 63 patients (80%) and established the correct diagnosis in 48 patients (76%). In 19% of these patients (n ⫽ 12), there was uncertainty of the diagnosis, and in 3 patients (5%) there were incorrect diagnoses. In these 3 patients, hepatocellular adenomas were suspected. The vast majority of the patients (n ⫽ 45) were referred to our department with abdominal CT already performed; in the rest of the patients (n ⫽ 18), CT was performed because of uncertain diagnoses or suspected malignancies. In all patients with uncertain or discrepant diagnosis after ultrasound and CT (n ⫽ 47), contrast-enhanced MRI was performed. The diagnosis was accurate in 41 patients (87%), uncertain in 4 (9%), and incorrect in 2 (4%) (Table 1). In these 2 patients, the diagnosis of hepatocellular adenoma was given. With regard to the accuracy of the diagnostic studies, the diagnostic studies were defined as accurate regarding the histopathologic workup of the resected specimens. In the observation group, diagnosis of FNH was based on the synopsis of complementary imaging findings. Overall, 107 patients underwent abdominal ultrasonography, 23 underwent contrast-enhanced triphasic CT, and in 78 patients, FNH was diagnosed on contrast-enhanced MRI.
Surgical treatment Because most FNHs are asymptomatic and to exclude other disorders and a malignancy, all symptomatic patients in group A underwent symptom-oriented complementary diagnostic evaluations using esophagogastroduodenoscopy, colonoscopy, and rectoscopy before surgery to exclude other disorders and malignancies. Patients with jaundice underwent endoscopic retrograde cholangiopancreatography to exclude disorders of the intrahepatic and extrahepatic bile ducts. None of the patients was diagnosed with a malignancy at the time of the extensive preoperative evaluation. All patients in group A underwent elective liver resection. Segmentectomy or bisegmentectomy was performed in 52 patients (67%), right or left hemihepatectomy in 10 patients (23%), and extended right or left hemihepatectomy in 8 patients (10%). Temporal occlusion of the hepatoduodenal ligament (Pringle maneuver) was performed in 31 patients. Perioperative blood loss of ⬎500 mL was regis-
Table 3
Indication for resection of FNH
Indication
n*
Abdominal discomfort Uncertainty of diagnosis Tumor enlargement† Jaundice
53 13 12 4
*Multiple indications were permitted. †Growth rate .5 cm/y or ⬎3 cm in comparison with initial size.
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693
Table 4 Intraoperative features and postoperative outcomes after liver resection for FNH (n ⫽ 78)
Table 6
Variable
Variable
Mode of operation Segmentectomy/bisegmentectomy Right/left hemihepatectomy Extended right/left hepatectomy Blood loss (%) ⬍500 mL ⱖ500 mL Blood transfusion (%) No substitution 1–3 erythrocyte concentrates ⱖ4 erythrocyte concentrates Postoperative complications (%)* Grade I Grade II Grade IIIa Grade IIIb Grade IV Complications (%) Biliary leakage Extrahepatic complications Perioperative death Relief of symptoms Length of hospital stay (d), mean (range) Length of intensive care unit stay (d), mean (range)
Value 52 (67%) 10 (23%) 8 (10%) 56 (72%) 22 (28%) 68 (87%) 9 (12%) 1 (1%) 5 15 1 0 0
(6%) (19%) (1%) (0%) (0%)
1 11 0 72
(1%) (14%) (0%) (92%)
10.4 (4–25) .9 (0–8)
*Clavien-Dindo classification.
tered in 22 patients (28%). The remaining patients in group A (n ⫽ 56 [72%]) had blood loss ⬍ 500 mL. Intraoperative or postoperative blood transfusion was required in 10 patients (1–3 erythrocyte concentrates in 9 patients [13%], ⬎ 4 erythrocyte concentrates in 1 patient) (Table 4).
Histology Diagnosis of FNH was confirmed in all resected specimens. In all cases, the tumors were removed completely, without disruption of the tumor capsules. Central scars were diagnosed in 52 patients (67%). Intratumoral bleeding occurred in 2 patients, both of whom reported long-term consumption of contraceptives. According to the histopathologic results of all resected specimens, in none of the
Table 5 Course of disease in patients with FNH and observation alone (n ⫽ 69) Variable
Value
Symptom relief Additional symptoms Tumor enlargement Tumor-related complications Death
12 9 3 0 0
(17%) (13%) (4%) (0%) (0%)
EQ-5D
Mobility No problems Moderate Immobility Self-reliance Full Moderate No Pain/discomfort (scale 0–10) No Moderate (1–5) Extreme (6–10) Mean health status (mean)*
Surgery
Observation
(n ⫽ 78)
(n ⫽ 69)
P
78 (100%) 0 (0%) 0 (0%)
69 (100%) 0 (0%) 0 (0%)
NS
78 (100%) 0 (0%) 0 (0%)
69 (100%) 0 (0%) 0 (0%)
NS
72 (92%) 6 (8%) 0 (0%) 93%
60 (87%) 9 (13%) 0 (0%) 91%
NS NS NS NS
*On a scale ranging from 0% (worst) to 100% (best).
patients who underwent surgery with the preoperative diagnosis of FNH was a malignant disease found.
Outcomes Patient follow-up as of December 2009 or until time of death ranged from 0 to 248 months (median, 109 months; mean, 113 months). None of the patients who underwent surgical therapy were lost to follow-up. These patients underwent follow-up examinations every 6 months: clinical examination, imaging modalities (ultrasound and/or MRI), and face-to-face interviews to gather information about their health status after surgery or during observation (Table 5). We used the EQ-5D health questionnaire19 (Table 6). There was no perioperative or postoperative mortality in our study. Postoperative complications were recorded in 12 patients (15%). One patient had biliary leakage, which was treated using endoscopic retrograde cholangiopancreatography, placement of a nasobiliary tube, and a biliary stent. Extrahepatic complications, including pleural effusion (n ⫽ 2), pneumonia (n ⫽ 3), wound infection (n ⫽ 4), and seroma (n ⫽ 2,) occurred in 11 patients (14%) and were treated conservatively (Table 4). All recorded complications were graded as mild or moderate (Table 4). The mean hospital stay was 10.4 days (range, 4 –25 days), and the mean length of stay in the intensive care unit was .9 days (range, 0 – 8 days). Twenty-one patients in group A (27%) and 19 in group B (18%) died during follow-up because of concomitant nonhepatic malignant diseases (n ⫽ 12 in group A and n ⫽ 3 in group B), cardiovascular diseases (n ⫽ 7 in group A and n ⫽ 6 in group B), or other unknown reasons (n ⫽ 2 in group A and n ⫽ 10 in group B). None of the patients who underwent operative treatment developed late postoperative complications or disease recurrence. Symptom relief was recorded in 72 of 78 patients (92%) in group A. The other 6 patients reported continuing abdominal discomfort.
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In the observation group (group B), 69 of 108 patients (64%) underwent complete follow-up. The remaining patients declined follow-up or were referred to other centers and were lost to follow-up. The lost patients were all asymptomatic and had tumor diameters ⱕ 3 cm. All patients underwent ultrasonography every 6 months. In cases in which ultrasonography did not offer reliable diagnoses in terms of the dimensions of the lesions, patients underwent MRI. Overall, 20 patients reported abdominal discomfort during follow-up, while 12 patients (17%) had symptom relief (Table 5). Tumor enlargement was registered in 3 patients (4%). Despite symptoms, these patients declined surgical treatment. Furthermore, neither symptoms nor the sizes of FNH lesions regressed after the cessation of hormone therapy according to imaging modalities during follow-up. Additionally, none of the patients in group B underwent surgical treatment during follow-up. Neither tumor-related major complications such as rupture nor disease-related mortality was recorded. We used the EQ-5D questionnaire to evaluate the health status of patients after surgery and during follow-up. Patients in the surgical group had a mean of 93% in terms of current health status. Furthermore, 92% of patients stated that they were free of pain and any other symptoms. In contrast, patients who were followed up had a mean of 91% in terms of current health status, and 87% of them were free of any symptoms (pain, discomfort, etc; Table 6).
Comments FNH is the second most common benign focal lesion of the liver. FNH is characterized as a nodular, hyperplastic lesion and is not a true neoplasm but rather a local hyperplastic response to increased blood flow within an intrahepatic arteriovenous malformation.17 FNH presents as a solitary lesion in 70% of patients. In 30% of patients, multiple lesions are present.14 In our series, the observed rate of multiple lesions was 19% (Table 1). In 20% of patients, there is an association between multiple FNH meningiomas, astrocytomas, and liver hemangiomas.20 In our series, we observed additional benign liver tumors such as hemangiomas and hepatocellular adenomas in 3 (4%) and 2 (3%) patients, respectively. An association between FNH and neoplasms (gastrointestinal stromal tumors, pheochromocytomas) of other organs has also been described.13,20,21 According to our results, we did not observe these associated lesions. The predominant symptoms are abdominal pain, discomfort in the right upper abdominal quadrant, and nausea.2,8 Palpable masses are observed in 2% to 4% of patients. Other symptoms, such as fever and infection, are rare (⬍1%).7,22 Abnormalities in the liver serum tests are present in 10% to 14% of patients.6,7,16 Some authors consider the risk for complications due to FNH minimal and discourage surgical treatment, emphasizing the potential risk for perioperative and postoperative
complications, and suggest conservative treatment and observation.3 We present our results as counterevidence to this argument. Although 18 patients (33%) (Table 4) underwent advanced hepatectomy, the rate of morbidity was low, and the outcomes of these patients were excellent in our series (Table 4). Because of the lack of randomized clinical trials assessing the benefits of surgical treatment, the management algorithm of FNH of the liver remains controversial.6,7,15–17 It is generally accepted that small, asymptomatic FNH without a tendency for enlargement should be managed conservatively.2 By contrast, liver lesions of unknown etiology, especially in patients with histories of cancer, should be treated surgically, even if small in size. In particular, the development of symptoms and marked tumor enlargement (⬎3– 4 cm or .5 cm/y) during follow-up are indications for surgical treatment.2,3,5,6 The risk for tumor rupture should also be considered when deciding on management. The risk, although exceedingly rare, clearly exists.23,24 Besides these objective criteria, patients’ anxiety must be taken into account. Patient concerns due to the presence of the tumor in the liver should not be dismissed. Some patients develop depressive signs and retreat from normal life activities.16 Focal lesions of the liver are often an incidental finding, because they remain asymptomatic for a long time.1,2,3,7,12 Therefore, the diagnosis of a hepatic nodule requires a further reliable diagnostic approach to discriminate a malignant from a benign liver lesion. The most reliable imaging methods are MRI (specificity, 95%–98%; sensitivity, 65%–70%), triple-phase spiral CT and contrast-enhanced ultrasonography.3,12,13 However, despite detailed radiologic and histologic workup after a liver biopsy, the histopathology of liver tumors remains unclear in some patients. The main difficulty in the diagnosis exists in the differentiation among FNH, hepatocellular adenoma, and fibrolamellar carcinoma.3,9,13,14 This aspect, together with the occurrence of symptoms and other criteria such as enlargement of the tumor(s), compression of central vessels or of the bile duct, or hepatic vein thrombosis, must be considered when considering surgical resection.1,7,15,16 In our study, all patients who underwent hepatectomy were treated using these criteria (Table 3). Pain and abdominal discomfort were the most common symptoms of patients with this lesion. The majority of patients with uncertain diagnoses in our series were treated at the beginning of the 1990s. Radiologic imaging is the most meaningful and noninvasive diagnostic method. In many studies, the final diagnosis was often based only on imaging and follow-up, although most patients did not undergo biopsies to obtain definitive histopathologic diagnosis.12–14 Many authors have demonstrated that MRI and multiphase dynamic CT have high diagnostic accuracy for identifying FNH. The diagnosis of FNH is based on MRI of the central scar, which demonstrates delayed enhancement and increased signal intensity on T2-weighted images, while an accurate differ-
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entiation between FNH and hepatic adenoma can be achieved on delayed T1-weighted imaging after the administration of gadobenate dimeglumine.13,14 In this study, the sensitivity of MRI in the surgical group was acceptable but not optimal (87%). The use of contrast-enhanced ultrasound, particularly to differentiate between FNH and hepatocellular adenoma, might be a useful addition to the diagnostic workup.12 CT-guided or ultrasound-guided percutaneous biopsy is generally recommended to define the entity of a liver nodular lesion, but obtaining a biopsy specimen for the diagnosis of hypervascular hepatic tumors is controversial.25 The main indication for such a procedure is to exclude the presence of a fibrolamellar carcinoma.8 Many authors do not believe that there is an indication to perform a liver biopsy, because of the small dimensions of the specimens, which cause difficulties in histopathologic clarification, particularly between FNH and hepatocellular adenoma.3,7 Moreover, the high risk for bleeding from a hypervascularized tumor such as FNH must be considered.7 Therefore, we performed preoperative biopsies in only 10 patients, mainly between 1990 and 1995. Four patients underwent laparoscopic biopsies. In our series, there were no complications associated with tumor biopsy. In our series, we were able to demonstrate that surgical therapy is associated with low morbidity. One of our main aims was to minimize intraoperative blood loss. The key to successful surgical therapy is anatomic liver resection along the avascular planes according to the definition of Couinaud.26 Such a resection results in reduced trauma to the hepatic parenchyma and a marked reduction of perioperative blood loss (Table 4). Given our results and experience with anatomic liver resection for other indications with low morbidity and mortality,27,28 this procedure has been established for benign liver diseases at our institution. The risk for perioperative and postoperative complications and their grade (Clavien-Dindo grades I–IIIa; Table 4)19 in our series were very low (n ⫽ 12 [15%]; Table 6). All postoperative complications were treated successfully, without the need for reoperation. The mean hospital stay in the postoperative phase was 10.4 days and was comparable with that found in other studies, which reported hospital stays of 9 to 14 days.2,3,7 Also of great importance was the fact that no mortality was registered. In group A, we noted a marked benefit due to symptom relief in 72 of 78 patients (92%). This result confirms the opinion of other authors who believe that symptom relief and patient satisfaction in addition to a correct indication justify (major) liver resection for benign focal lesions of the liver.7,16 As far as the patients in the observation group were concerned, we could not demonstrate any definitive trend. In 13% of the observed patients (n ⫽ 9), additional symptoms appeared; in contrast, 17% of patients (n ⫽ 12) reported symptom relief. Furthermore, tumor enlargement was diagnosed in 3 patients (4%). Neither a major complication such as acute intraperitoneal bleeding nor mortality
695 was observed. These findings are similar to those of other studies.8,9 Bonney et al suggested surgical treatment when symptoms develop but reported no follow-up of patients who were observed and did not undergo an operation.2 Weimann et al9 followed up a similar number of patients (n ⫽ 54), and their results support our thesis, concluding that the occurrence of a major complication such as acute bleeding or malignant transformation is unlikely. It has also been reported that patients under observation had no significant growth of their tumors. These findings are similar to those of other studies with observed patients for FNH.10,29,30 Major problems are demonstrated in patients on follow-up for histories of malignancy in whom previously undiagnosed liver lesions, with features consistent with hemangioma or FNH, are detected. In the experience of the Memorial Sloan-Kettering Cancer Center, this was reported to occur in 25.0% of surgically treated hemangiomas, and in 38.0% of them, definitive diagnosis were possible only after surgical resection.31 In our series, this occurred in 17 patients (22%). One limitation of the present study was its retrospective nature. Nevertheless, the data reported included all patients who underwent elective surgery with no exclusions and underline the importance of elective treatment and the several parameters in favor of surgery. Another limitation was that this study was performed at a single institution, and the results obtained might not be comparable with those at other centers. Single-center studies, however, have the advantage of reducing the number of possible differences in surgical technique. On the basis of the results of our study, we firmly believe that FNH should be treated and managed in a manner similar to hepatic hemangioma. The strategy of management of such a benign tumor ranges from observation to an elective operation. Surgical treatment is an integral part of this work flow, while the initial size of the lesion must not be the major indication criterion for surgery. Once symptoms appear, abnormal behavior of the lesion is demonstrated, or a marked enlargement of the FNH is diagnosed, liver resection should be considered. Furthermore, we would advise surgical therapy to establish a definite diagnosis in case of inconclusive results on radiologic imaging and histologic examination.
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4. Mathieu D, Kobeiter H, Maison P, et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 2000;119: 560 – 4. 5. Chen MF. Hepatic resection for benign tumors of the liver. J Gastroenterol Hepatol 2000;15:587–92. 6. Belghiti J, Pateron D, Panis Y, et al. Resection of presumed benign liver tumors. Br J Surg 1993;80:380 –3. 7. Terkivatan T, de Wilt JHW, de Man RA, et al. Indications and long-term outcome of treatment for benign hepatic tumors. Arch Surg 2001;136:1033– 8. 8. Hsee LC, McCall JL, Koea JB. Focal nodular hyperplasia: what are the indications for resection? HPB 2005;7:298 –302. 9. Weimann A, Ringe B, Klempnauer J, et al. Benign liver tumors: differential diagnosis and indications for surgery. World J Surg 1997; 21:983–91. 10. Pain JA, Gimson AES, Williams R, et al. Focal nodular hyperplasia of the liver: results of treatment and options in management. Gut 1991; 32:524. 11. Strasberg SM. Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J Hepatobiliary Pancreat Surg 2005;12:351–5. 12. Dietrich CF, Schuessler G, Trojan J, et al. Differentiation of focal nodular hyperplasia and hepatocellular adenoma by contrast-enhanced ultrasound. Br J Radiol 2005;78;704 –7. 13. Finley AC, Hosey JR, Noone TC, et al. Multiple focal nodular hyperplasia syndrome: diagnosis with dynamic, gadolinium-enhanced MRI. Magn Reson Imaging 2005;23;511–3. 14. Grazioli L, Morana G, Kirchin MA, et al. Accurate differentiation of focal nodular hyperplasia from hepatic adenoma at gadobenate dimeglumine-enhanced MR imaging: prospective study. Radiology 2005; 236:166 –77. 15. Reddy KR, Kligerman S, Levi J, et al. Benign and solid tumors of the liver: relationship to sex, age, size of tumors and outcome. Am Surg 2001;67:173– 8. 16. Fioole B, Kokke M, Van Hillegersberg R, et al. Adequate symptom relief justifies hepatic resection for benign disease. BMC Surg 2005; 5:7.
17. Maillete de Buy Wenniger L, Terpstra V, Beuers U. Focal nodular hyperplasia and hepatic adenoma: epidemiology and pathology. Dig Surg 2010;27:24 –31. 18. EuroQol Group. EQ-5D. Available at: http://www.euroqol.org. Accessed April 24, 2012. 19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13. 20. Wanless IR, Albrecht JB, Frei JV, et al. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol 1989;2;456 – 62. 21. Colle I, Beeck BOD, Hoorens A, et al. Multiple focal nodular hyperplasia. J Gastroenterol 1998;33:904 – 8. 22. Shawcross DL, Naoumov N, Pachiadakis I, et al. Should a biopsy precede liver resection or transplantation for presumed hepatocellular carcinoma when alfa fetoprotein is normal. Transplantation 2004;77:637–8. 23. Becker YT, Raiford DS, Webb L, et al. Rupture and hemorrhage of hepatic nodular hyperplasia. Am Surg 1995;61:210 – 4. 24. Kleespies A, Settmacher U, Neuhaus P. Spontanruptur einer fokal nodulären Hyperplasie der Leber. Zentralbl Chir 2002;127:326 – 8. 25. Durand F, Regimbeau JM, Belghiti J, et al. Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma. J Hepatol 2001;35:254. 26. Couinaud C. Le foie. Etudes anatomiques et chirurgicales. Paris: Masson; 1957. 27. Scheele J. Anatomical and atypical liver resections. Chirurg 2001;72: 113–24. 28. Yedibela S, Demir R, Zhang W, et al. Surgical treatment of massforming intrahepatic cholangiocarcinoma: an 11-year Western singlecenter experience in 107 patients. Ann Surg Oncol 2009;16:404 –12. 29. Dagradi AD, Mangiante GL. Focal nodular hyperplasia of the liver: a single institution experience. Acta Chir Aust 1994;26:109 –12. 30. Nagorney DM. Benign hepatic tumors: focal nodular hyperplasia and hepatocellular adenoma. World J Surg 1995;19:13– 8. 31. Yoon SS, Charny CK, Fong Y, et al. Diagnosis, management, and outcome of 115 patients with hepatic hemangiomas. J Am Coll Surg 2003;197:392– 402.
Clinical Science
Management of the focal nodular hyperplasia of the liver: evaluation of the surgical treatment comparing with observation only Aristotelis Perrakis, M.D.a,*, Resit Demir, M.D.a, Volker Müller, M.D.a, Jürgen Mulsow, M.D.a, U¨nal Aydin, M.D.b, Sedat Alibek, M.D.c, Werner Hohenberger, M.D.a, Süleyman Yedibela, M.D.a a
Department of Surgery, Department of Hepatobiliary and Transplant Surgery, and bDepartment of Radiology, University of Erlangen-Nuremberg, Erlangen, Germany; cDepartment of Surgery, University of Gaziantep, Sehitkamil/Gaziantep, Turkey KEYWORDS: Focal nodular hyperplasia; Surgical treatment; Observation; Liver resection
Abstract BACKGROUND: Long-term results of both surgery and observation for patients with focal nodular hyperplasia (FNH) in a large single-center experience do not exist. Accordingly, the aim of this study was to compare long-term outcomes in patients with FNH who underwent either elective hepatectomy or observation alone. METHODS: A retrospective single-institution analysis of 185 patients with FNH, treated from 1990 to 2009, was performed. RESULTS: Seventy-eight patients underwent elective hepatectomy and 107 patients observation alone, with a median follow-up period of 113 months. There was no perioperative mortality. Postoperative complications were recorded in 12 patients, and 92% of patients reported symptomatic reductions. Among observation patients, 9 (13%) developed additional symptoms; tumor enlargement was seen in 3 patients (4%). CONCLUSIONS: Elective liver resection for FNH is a safe procedure at high-volume centers. This single-center experience showed that 13% of observed patients had protracted symptoms. This justifies the therapeutic algorithm that elective surgery should be considered in symptomatic patients or in those with marked enlargement. © 2012 Elsevier Inc. All rights reserved.
Focal nodular hyperplasia (FNH) is the second most common benign nodular disease of the liver, and its exact etiology and pathogenesis are not completely understood.1 FNH is considered a truly benign formation, which does not P.A. and R.D. contributed equally to this article. * Corresponding author. Tel.: 49-9131-8533296; fax: 49-91318539227. E-mail address: [email protected] Manuscript received August 28, 2011; revised manuscript February 26, 2012
0002-9610/$ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2012.02.006
undergo a malignant transformation.2 It appears predominantly in women during their reproductive years (female/ male ratio, 80:20). In most patients, these lesions are discovered incidentally during ultrasound examination. Whether oral contraceptives play a role in the growth of the lesions remains an open matter.3,4 Some authors have emphasized that oral contraceptives lead to an intense vascularization of FNH, increasing the risk for rupture and acute bleeding.5 Liver function test results are in most cases normal, and ␣-fetoprotein is not present.6 Contrast-enhanced magnetic
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resonance imaging (MRI) has been shown to be the most sensitive modality for characterizing FNH, while triplephase spiral computed tomography (CT) and contrast-enhanced ultrasonography can be used as further diagnostic tools.6 –17 Because of the benign nature of FNH, observation remains in the foreground, and the indication for surgical treatment is controversial. However, the rapid progress of the disease, the occurrence of symptoms, the obstruction of large vessels, jaundice, and the uncertainty of the diagnosis can be accepted as indications for surgical treatment. Several studies have reported nonsurgical management or observation of FNH.1,2,7 However, there is an absence of large studies with adequate numbers of patients reporting longterm results of both nonsurgical and surgical treatment.2,5,8,9,10 Here, we report our single-center experience in the management of FNH, including patients who underwent elective surgical therapy or observation alone. Our aims were to review the long-term outcomes of these patients and to clarify the indications for surgical treatment.
Methods Study population Between January 1990 and December 2009, 185 patients diagnosed with FNH were evaluated in the Surgical Department of the University of Erlangen-Nuremberg. Patients were identified from a prospective database and analyzed in 2 groups: group A (n ⫽ 78) included patients who underwent elective surgical treatment and group B (n ⫽ 107) those who were observed alone or those who refused to undergo surgery despite the occurrence of symptoms and marked enlargement of their tumors during follow-up (Fig. 1). One hundred twenty-one patients had no symptoms, 64 reported about abdominal discomfort, and 11 symptomatic patients refused to undergo surgical treatment. Our final analysis involved 147 patients who underwent complete follow-up through December 2009 or until death. The treatment algorithm for all patients at our institution is illustrated in Figure 1. We analyzed demographic data, health status according the EQ-5D questionnaire,18 laboratory liver values, number and sizes of the lesions, diagnostic methods used, mode of surgical treatment, and postoperative outcome with perioperative and postoperative complications.
Demographic parameters and diagnostic imaging The median age of the patients was 34 years (range, 19 –53 years). Ninety-two percent were women. The ratios of women to men were 86% to 14% in group A and 98% to 2% in group B. Diagnostic workup included ultrasonography, contrast-enhanced triphasic CT, and MRI (Table 1). The imaging findings of the surgical group (group A, n ⫽
78) were compared with the outcomes of the histopathologic examinations of the resected specimens. The latter were taken as the gold standard for confirmation of the diagnosis. Tumor biopsy was performed preoperatively in 10 patients (percutaneously in 6 patients and laparoscopically in 4 patients). Liver serum tests included aspartate aminotransferase, alanine aminotransferase, bilirubin, ␥-glutamyltransferase, alkaline phosphatase, and ␣-fetoprotein (Table 2).
Surgical procedures and indication criteria Indications for surgical treatment included abdominal discomfort (n ⫽ 53), marked tumor enlargement with a rate of growth of ⬎.5 cm/y or ⬎ 3 cm in comparison with initial diameter (n ⫽ 13), and uncertainty of diagnosis (n ⫽ 12) (Table 3). All patients who underwent surgery for uncertainty of diagnosis were treated in the early 1990s, when imagining modalities did not offer sufficient results. Patients for whom the indication for surgery was given as tumor enlargement (n ⫽ 13) showed marked enlargement of FNH in a time frame from 3 to 51 months (mean, 23 months). Patients with tumor enlargement or uncertainty of diagnosis (n ⫽ 25) were initially in the observation group and underwent hepatectomy a mean of 32 months after initial referral (range, 3– 63 months). Ninety-six patients without any symptoms and 11 patients who reported abdominal discomfort but refused to undergo surgical treatment were included in group B. We evaluated the outcomes of the patients in both groups. In group A, all patients underwent anatomically oriented liver resection. The extent of the hepatectomy was classified according to the Brisbane criteria.11 The parameters assessed were blood loss and blood transfusion in the perioperative phase and early postoperative course, hepatic and extrahepatic complications, 90-day morbidity and mortality, lengths of stay in the intensive care unit and the hospital, and symptom relief after surgical treatment. The observation parameters for the patients in group B were reductions of symptoms, symptom progression, tumor enlargement, tumor-related morbidity and mortality, and health status according to the EQ-5D questionnaire. Statistical analysis was performed using SPSS for Windows version 17.0 (SPSS, Inc, Chicago, IL) and Excel 2007 (Microsoft Corporation, Redmond, WA), and all data were checked for significance using unpaired Student’s t tests. P values ⬍ .05 were considered statistically significant. Continuous variables are reported as mean ⫾ SD.
Results Twenty-two percent of the patients in group A had histories of cancer (n ⫽ 17), and 60% (n ⫽ 47) had received
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Management of focal nodular hyperplasia
Symptomatic n=64
691
Asymptomatic n=121
Observation n=132
n=11
Abdominal discomfort n=53
Uncertain diagnosis n=12
Tumor enlargement n=13
Surgery n=78
n=69
Follow-up n=147
Lost cases n=38
Figure 1
Therapy algorithm for all patients (n ⫽ 185).
hormonal therapy before the diagnosis. Mean levels of alanine aminotransferase, aspartate aminotransferase, bilirubin, and ␥-glutamyltransferase were within the normal ranges in both groups (Table 2). Only mean alkaline phosphatase level was elevated in group A (109.9 U/L; reference range ⬍ 80 U/L) (Table 2). In group A, mean tumor diameter was 7.9 cm (range, 1–20 cm), and in group B, it was 5.2
Table 1 Imaging modality and the rates of diagnosis in the surgical group (group A) Modality
n
Correct
Uncertain
Incorrect
Ultrasound CT MRI
78 63 47
40 (51%) 48 (76%) 41 (87%)
21 (27%) 12 (19%) 4 (9%)
17 (22%) 3 (5%) 2 (4%)
cm (range, 1–12 cm) (Table 2). Twenty-two patients in group A had multiple lesions (n ⫽ 28). By contrast, multiple nodules were diagnosed in 15 patients in group B. Four patients in group A developed increasing jaundice because of compression of the intrahepatic and/or extrahepatic bile ducts by the nodules. Five patients had additional findings, including hemangioma (n ⫽ 2) or hepatocellular adenomas (n ⫽ 3). In all patients with the diagnosis of FNH, there was a cessation of consumption of contraceptives after the first referral to our department.
Diagnostic studies All patients who were treated surgically underwent abdominal ultrasonography. In 40 of 78 patients (51%), the diagnosis was established correctly. In 21 patients (27%),
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Table 2
Pretreatment demographic data
Variable Age (y), median (range) Gender Male Female Tumor diameter (cm), mean (range) Number of lesions Solitary Multiple History of cancer No Yes Previous hormonal therapy No Yes Mean ASAT (U/L) Mean ALAT (U/L) ␥-glutamytransferase (U/L) Bilirubin (mg/dL) Alkaline phosphatase (U/L)
Surgery
Observation
All Patients
(n ⫽ 78)
(n ⫽ 107)
(n ⫽ 185)
37 11 67 7.9
30
33 (17–53)
P NS
2 105 5.2
13 (7%) 172 (93%) 6.7 (1–20)
.003 .043 NS
56 22
91 16
147 (79%) 38 (21%)
NS NS
61 17
103 4
164 (89%) 21 (11%)
NS NS
46 (25%) 139 (75%) 12.9 ⫾ 1.52* 14.8 ⫾ 1.86* 43.7 ⫾ 4.75* .7 ⫾ .42* 76.7 ⫾ 4.83*
.004 .046 NS NS .003 NS .004
31 47 14.3 18.9 65.4 .67 109.9
15 92 11.7 12.1 28.3 .71 53.3
ALAT ⫽ alanine aminotransferase; ASAT ⫽ aspartate aminotransferase. *First ambulant aftercare.
there was uncertainty of the diagnosis. In 17 patients (22%), the ultrasound examinations did not offer the correct diagnosis: in 8 the diagnosis of a malignant tumor (primary liver tumor or metastasis) and in 5 the diagnosis of hemangioma were established; in 4 patients, hepatocellular adenomas were suspected. Contrast-enhanced triphasic CT was performed in 63 patients (80%) and established the correct diagnosis in 48 patients (76%). In 19% of these patients (n ⫽ 12), there was uncertainty of the diagnosis, and in 3 patients (5%) there were incorrect diagnoses. In these 3 patients, hepatocellular adenomas were suspected. The vast majority of the patients (n ⫽ 45) were referred to our department with abdominal CT already performed; in the rest of the patients (n ⫽ 18), CT was performed because of uncertain diagnoses or suspected malignancies. In all patients with uncertain or discrepant diagnosis after ultrasound and CT (n ⫽ 47), contrast-enhanced MRI was performed. The diagnosis was accurate in 41 patients (87%), uncertain in 4 (9%), and incorrect in 2 (4%) (Table 1). In these 2 patients, the diagnosis of hepatocellular adenoma was given. With regard to the accuracy of the diagnostic studies, the diagnostic studies were defined as accurate regarding the histopathologic workup of the resected specimens. In the observation group, diagnosis of FNH was based on the synopsis of complementary imaging findings. Overall, 107 patients underwent abdominal ultrasonography, 23 underwent contrast-enhanced triphasic CT, and in 78 patients, FNH was diagnosed on contrast-enhanced MRI.
Surgical treatment Because most FNHs are asymptomatic and to exclude other disorders and a malignancy, all symptomatic patients in group A underwent symptom-oriented complementary diagnostic evaluations using esophagogastroduodenoscopy, colonoscopy, and rectoscopy before surgery to exclude other disorders and malignancies. Patients with jaundice underwent endoscopic retrograde cholangiopancreatography to exclude disorders of the intrahepatic and extrahepatic bile ducts. None of the patients was diagnosed with a malignancy at the time of the extensive preoperative evaluation. All patients in group A underwent elective liver resection. Segmentectomy or bisegmentectomy was performed in 52 patients (67%), right or left hemihepatectomy in 10 patients (23%), and extended right or left hemihepatectomy in 8 patients (10%). Temporal occlusion of the hepatoduodenal ligament (Pringle maneuver) was performed in 31 patients. Perioperative blood loss of ⬎500 mL was regis-
Table 3
Indication for resection of FNH
Indication
n*
Abdominal discomfort Uncertainty of diagnosis Tumor enlargement† Jaundice
53 13 12 4
*Multiple indications were permitted. †Growth rate .5 cm/y or ⬎3 cm in comparison with initial size.
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693
Table 4 Intraoperative features and postoperative outcomes after liver resection for FNH (n ⫽ 78)
Table 6
Variable
Variable
Mode of operation Segmentectomy/bisegmentectomy Right/left hemihepatectomy Extended right/left hepatectomy Blood loss (%) ⬍500 mL ⱖ500 mL Blood transfusion (%) No substitution 1–3 erythrocyte concentrates ⱖ4 erythrocyte concentrates Postoperative complications (%)* Grade I Grade II Grade IIIa Grade IIIb Grade IV Complications (%) Biliary leakage Extrahepatic complications Perioperative death Relief of symptoms Length of hospital stay (d), mean (range) Length of intensive care unit stay (d), mean (range)
Value 52 (67%) 10 (23%) 8 (10%) 56 (72%) 22 (28%) 68 (87%) 9 (12%) 1 (1%) 5 15 1 0 0
(6%) (19%) (1%) (0%) (0%)
1 11 0 72
(1%) (14%) (0%) (92%)
10.4 (4–25) .9 (0–8)
*Clavien-Dindo classification.
tered in 22 patients (28%). The remaining patients in group A (n ⫽ 56 [72%]) had blood loss ⬍ 500 mL. Intraoperative or postoperative blood transfusion was required in 10 patients (1–3 erythrocyte concentrates in 9 patients [13%], ⬎ 4 erythrocyte concentrates in 1 patient) (Table 4).
Histology Diagnosis of FNH was confirmed in all resected specimens. In all cases, the tumors were removed completely, without disruption of the tumor capsules. Central scars were diagnosed in 52 patients (67%). Intratumoral bleeding occurred in 2 patients, both of whom reported long-term consumption of contraceptives. According to the histopathologic results of all resected specimens, in none of the
Table 5 Course of disease in patients with FNH and observation alone (n ⫽ 69) Variable
Value
Symptom relief Additional symptoms Tumor enlargement Tumor-related complications Death
12 9 3 0 0
(17%) (13%) (4%) (0%) (0%)
EQ-5D
Mobility No problems Moderate Immobility Self-reliance Full Moderate No Pain/discomfort (scale 0–10) No Moderate (1–5) Extreme (6–10) Mean health status (mean)*
Surgery
Observation
(n ⫽ 78)
(n ⫽ 69)
P
78 (100%) 0 (0%) 0 (0%)
69 (100%) 0 (0%) 0 (0%)
NS
78 (100%) 0 (0%) 0 (0%)
69 (100%) 0 (0%) 0 (0%)
NS
72 (92%) 6 (8%) 0 (0%) 93%
60 (87%) 9 (13%) 0 (0%) 91%
NS NS NS NS
*On a scale ranging from 0% (worst) to 100% (best).
patients who underwent surgery with the preoperative diagnosis of FNH was a malignant disease found.
Outcomes Patient follow-up as of December 2009 or until time of death ranged from 0 to 248 months (median, 109 months; mean, 113 months). None of the patients who underwent surgical therapy were lost to follow-up. These patients underwent follow-up examinations every 6 months: clinical examination, imaging modalities (ultrasound and/or MRI), and face-to-face interviews to gather information about their health status after surgery or during observation (Table 5). We used the EQ-5D health questionnaire19 (Table 6). There was no perioperative or postoperative mortality in our study. Postoperative complications were recorded in 12 patients (15%). One patient had biliary leakage, which was treated using endoscopic retrograde cholangiopancreatography, placement of a nasobiliary tube, and a biliary stent. Extrahepatic complications, including pleural effusion (n ⫽ 2), pneumonia (n ⫽ 3), wound infection (n ⫽ 4), and seroma (n ⫽ 2,) occurred in 11 patients (14%) and were treated conservatively (Table 4). All recorded complications were graded as mild or moderate (Table 4). The mean hospital stay was 10.4 days (range, 4 –25 days), and the mean length of stay in the intensive care unit was .9 days (range, 0 – 8 days). Twenty-one patients in group A (27%) and 19 in group B (18%) died during follow-up because of concomitant nonhepatic malignant diseases (n ⫽ 12 in group A and n ⫽ 3 in group B), cardiovascular diseases (n ⫽ 7 in group A and n ⫽ 6 in group B), or other unknown reasons (n ⫽ 2 in group A and n ⫽ 10 in group B). None of the patients who underwent operative treatment developed late postoperative complications or disease recurrence. Symptom relief was recorded in 72 of 78 patients (92%) in group A. The other 6 patients reported continuing abdominal discomfort.
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In the observation group (group B), 69 of 108 patients (64%) underwent complete follow-up. The remaining patients declined follow-up or were referred to other centers and were lost to follow-up. The lost patients were all asymptomatic and had tumor diameters ⱕ 3 cm. All patients underwent ultrasonography every 6 months. In cases in which ultrasonography did not offer reliable diagnoses in terms of the dimensions of the lesions, patients underwent MRI. Overall, 20 patients reported abdominal discomfort during follow-up, while 12 patients (17%) had symptom relief (Table 5). Tumor enlargement was registered in 3 patients (4%). Despite symptoms, these patients declined surgical treatment. Furthermore, neither symptoms nor the sizes of FNH lesions regressed after the cessation of hormone therapy according to imaging modalities during follow-up. Additionally, none of the patients in group B underwent surgical treatment during follow-up. Neither tumor-related major complications such as rupture nor disease-related mortality was recorded. We used the EQ-5D questionnaire to evaluate the health status of patients after surgery and during follow-up. Patients in the surgical group had a mean of 93% in terms of current health status. Furthermore, 92% of patients stated that they were free of pain and any other symptoms. In contrast, patients who were followed up had a mean of 91% in terms of current health status, and 87% of them were free of any symptoms (pain, discomfort, etc; Table 6).
Comments FNH is the second most common benign focal lesion of the liver. FNH is characterized as a nodular, hyperplastic lesion and is not a true neoplasm but rather a local hyperplastic response to increased blood flow within an intrahepatic arteriovenous malformation.17 FNH presents as a solitary lesion in 70% of patients. In 30% of patients, multiple lesions are present.14 In our series, the observed rate of multiple lesions was 19% (Table 1). In 20% of patients, there is an association between multiple FNH meningiomas, astrocytomas, and liver hemangiomas.20 In our series, we observed additional benign liver tumors such as hemangiomas and hepatocellular adenomas in 3 (4%) and 2 (3%) patients, respectively. An association between FNH and neoplasms (gastrointestinal stromal tumors, pheochromocytomas) of other organs has also been described.13,20,21 According to our results, we did not observe these associated lesions. The predominant symptoms are abdominal pain, discomfort in the right upper abdominal quadrant, and nausea.2,8 Palpable masses are observed in 2% to 4% of patients. Other symptoms, such as fever and infection, are rare (⬍1%).7,22 Abnormalities in the liver serum tests are present in 10% to 14% of patients.6,7,16 Some authors consider the risk for complications due to FNH minimal and discourage surgical treatment, emphasizing the potential risk for perioperative and postoperative
complications, and suggest conservative treatment and observation.3 We present our results as counterevidence to this argument. Although 18 patients (33%) (Table 4) underwent advanced hepatectomy, the rate of morbidity was low, and the outcomes of these patients were excellent in our series (Table 4). Because of the lack of randomized clinical trials assessing the benefits of surgical treatment, the management algorithm of FNH of the liver remains controversial.6,7,15–17 It is generally accepted that small, asymptomatic FNH without a tendency for enlargement should be managed conservatively.2 By contrast, liver lesions of unknown etiology, especially in patients with histories of cancer, should be treated surgically, even if small in size. In particular, the development of symptoms and marked tumor enlargement (⬎3– 4 cm or .5 cm/y) during follow-up are indications for surgical treatment.2,3,5,6 The risk for tumor rupture should also be considered when deciding on management. The risk, although exceedingly rare, clearly exists.23,24 Besides these objective criteria, patients’ anxiety must be taken into account. Patient concerns due to the presence of the tumor in the liver should not be dismissed. Some patients develop depressive signs and retreat from normal life activities.16 Focal lesions of the liver are often an incidental finding, because they remain asymptomatic for a long time.1,2,3,7,12 Therefore, the diagnosis of a hepatic nodule requires a further reliable diagnostic approach to discriminate a malignant from a benign liver lesion. The most reliable imaging methods are MRI (specificity, 95%–98%; sensitivity, 65%–70%), triple-phase spiral CT and contrast-enhanced ultrasonography.3,12,13 However, despite detailed radiologic and histologic workup after a liver biopsy, the histopathology of liver tumors remains unclear in some patients. The main difficulty in the diagnosis exists in the differentiation among FNH, hepatocellular adenoma, and fibrolamellar carcinoma.3,9,13,14 This aspect, together with the occurrence of symptoms and other criteria such as enlargement of the tumor(s), compression of central vessels or of the bile duct, or hepatic vein thrombosis, must be considered when considering surgical resection.1,7,15,16 In our study, all patients who underwent hepatectomy were treated using these criteria (Table 3). Pain and abdominal discomfort were the most common symptoms of patients with this lesion. The majority of patients with uncertain diagnoses in our series were treated at the beginning of the 1990s. Radiologic imaging is the most meaningful and noninvasive diagnostic method. In many studies, the final diagnosis was often based only on imaging and follow-up, although most patients did not undergo biopsies to obtain definitive histopathologic diagnosis.12–14 Many authors have demonstrated that MRI and multiphase dynamic CT have high diagnostic accuracy for identifying FNH. The diagnosis of FNH is based on MRI of the central scar, which demonstrates delayed enhancement and increased signal intensity on T2-weighted images, while an accurate differ-
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entiation between FNH and hepatic adenoma can be achieved on delayed T1-weighted imaging after the administration of gadobenate dimeglumine.13,14 In this study, the sensitivity of MRI in the surgical group was acceptable but not optimal (87%). The use of contrast-enhanced ultrasound, particularly to differentiate between FNH and hepatocellular adenoma, might be a useful addition to the diagnostic workup.12 CT-guided or ultrasound-guided percutaneous biopsy is generally recommended to define the entity of a liver nodular lesion, but obtaining a biopsy specimen for the diagnosis of hypervascular hepatic tumors is controversial.25 The main indication for such a procedure is to exclude the presence of a fibrolamellar carcinoma.8 Many authors do not believe that there is an indication to perform a liver biopsy, because of the small dimensions of the specimens, which cause difficulties in histopathologic clarification, particularly between FNH and hepatocellular adenoma.3,7 Moreover, the high risk for bleeding from a hypervascularized tumor such as FNH must be considered.7 Therefore, we performed preoperative biopsies in only 10 patients, mainly between 1990 and 1995. Four patients underwent laparoscopic biopsies. In our series, there were no complications associated with tumor biopsy. In our series, we were able to demonstrate that surgical therapy is associated with low morbidity. One of our main aims was to minimize intraoperative blood loss. The key to successful surgical therapy is anatomic liver resection along the avascular planes according to the definition of Couinaud.26 Such a resection results in reduced trauma to the hepatic parenchyma and a marked reduction of perioperative blood loss (Table 4). Given our results and experience with anatomic liver resection for other indications with low morbidity and mortality,27,28 this procedure has been established for benign liver diseases at our institution. The risk for perioperative and postoperative complications and their grade (Clavien-Dindo grades I–IIIa; Table 4)19 in our series were very low (n ⫽ 12 [15%]; Table 6). All postoperative complications were treated successfully, without the need for reoperation. The mean hospital stay in the postoperative phase was 10.4 days and was comparable with that found in other studies, which reported hospital stays of 9 to 14 days.2,3,7 Also of great importance was the fact that no mortality was registered. In group A, we noted a marked benefit due to symptom relief in 72 of 78 patients (92%). This result confirms the opinion of other authors who believe that symptom relief and patient satisfaction in addition to a correct indication justify (major) liver resection for benign focal lesions of the liver.7,16 As far as the patients in the observation group were concerned, we could not demonstrate any definitive trend. In 13% of the observed patients (n ⫽ 9), additional symptoms appeared; in contrast, 17% of patients (n ⫽ 12) reported symptom relief. Furthermore, tumor enlargement was diagnosed in 3 patients (4%). Neither a major complication such as acute intraperitoneal bleeding nor mortality
695 was observed. These findings are similar to those of other studies.8,9 Bonney et al suggested surgical treatment when symptoms develop but reported no follow-up of patients who were observed and did not undergo an operation.2 Weimann et al9 followed up a similar number of patients (n ⫽ 54), and their results support our thesis, concluding that the occurrence of a major complication such as acute bleeding or malignant transformation is unlikely. It has also been reported that patients under observation had no significant growth of their tumors. These findings are similar to those of other studies with observed patients for FNH.10,29,30 Major problems are demonstrated in patients on follow-up for histories of malignancy in whom previously undiagnosed liver lesions, with features consistent with hemangioma or FNH, are detected. In the experience of the Memorial Sloan-Kettering Cancer Center, this was reported to occur in 25.0% of surgically treated hemangiomas, and in 38.0% of them, definitive diagnosis were possible only after surgical resection.31 In our series, this occurred in 17 patients (22%). One limitation of the present study was its retrospective nature. Nevertheless, the data reported included all patients who underwent elective surgery with no exclusions and underline the importance of elective treatment and the several parameters in favor of surgery. Another limitation was that this study was performed at a single institution, and the results obtained might not be comparable with those at other centers. Single-center studies, however, have the advantage of reducing the number of possible differences in surgical technique. On the basis of the results of our study, we firmly believe that FNH should be treated and managed in a manner similar to hepatic hemangioma. The strategy of management of such a benign tumor ranges from observation to an elective operation. Surgical treatment is an integral part of this work flow, while the initial size of the lesion must not be the major indication criterion for surgery. Once symptoms appear, abnormal behavior of the lesion is demonstrated, or a marked enlargement of the FNH is diagnosed, liver resection should be considered. Furthermore, we would advise surgical therapy to establish a definite diagnosis in case of inconclusive results on radiologic imaging and histologic examination.
References 1. Cherqui D, Rahmouni A, Charlotte F, et al. Management of the focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological and pathological correlations. Hepatology 1995;22:1674 – 81. 2. Bonney GK, Gomez D, Al-Mukhtar A, et al. Indication for treatment and long term outcome of focal nodular hyperplasia. HPB 2007;9: 368 –72. 3. Herman P, Pugliese V, Machado MAC, et al. Hepatic adenoma and focal nodular hyperplasia: differential diagnosis and treatment. World J Surg 2000;24;372– 6.
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