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Keywords:

  • bleeding;
  • hepatocellular carcinoma;
  • liver;
  • liver cell adenoma;
  • oral contraceptive;
  • tumor

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Hepatocellular adenoma (HCA) is a benign liver neoplasm with a risk of spontaneous bleeding and malignant transformation. The aim of this review article is to review all the case reports and case series of patients with HCA from 1998 to 2008 in China and other parts of the world in order to compare clinical presentation, surgical management and outcomes. A search for all reports of HCA in the world literature from 1998 to 2008 was performed. A total of 356 patients were identified, including 191 patients from China, 104 from Europe, 46 from North America, and 15 from South–East Asia. A female predominance was not observed in Chinese patients in contrast to the other regions. Acute/chronic abdominal pain was the main clinical presentation in all regions. Twenty patients were diagnosed with coexistent hepatocellular carcinoma (HCC), and hepatitis B virus infection (HBV) was found among six of them. The management of HCA consisted of resection in most cases. The clinical presentation of HCA in China differed from other parts of the world regarding male predominance and a higher incidence of coexistent HCC in China. This might be the result of the birth control policy in China, limited oral contraceptive use, and the higher incidence of HBV.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Hepatocellular adenoma (HCA) is a rare, benign neoplasm of the liver. HCA has significant etiological association with oral contraceptive use in young women.1,2 The estimated incidence for long-term contraceptive users is three to four per 100 000/year,3 as opposed to only one per million for non-users or women with less than 2 years of exposure.4 Over the past few decades, our understanding of its incidence, pathogenesis, and natural history has expanded.5–9 However, the paucity of case series reported worldwide and the lack of controlled studies have hampered the development of a defined approach to the diagnosis and management of this condition.

The diagnosis of HCA is difficult and is usually based on imaging studies. This often leads to confusion, exposing patients to unnecessary delay in diagnosis and appropriate treatment. In China, HCA was thought to be infrequent in the past; however, it has been increasingly reported in recent years, drawing attention to its clinical significance and natural history in this part of the world.

We reviewed all the case reports and case series of HCA from 1998 to 2008, published in Chinese and other language literature. The aim of this study was to assess clinical presentation, surgical management, and outcomes of HCA in China according to this literature, and to compare these with other regions of the world.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The Chinese Biology and Medicine Database, China Hospital Knowledge Database, and the Chinese Periodical Database of Science and Technology were used as search sources. Key words used for the searches were “liver” combined with “adenoma”. From January 1998 to December 2008, 191 cases were extracted from 75 articles reported in China.

A PubMed search of all languages from January 1998 to December 2008 was performed using the Mesh terms: adenoma and liver cell, and the key words, liver cell adenoma, liver adenoma, HCA and hepatic adenoma. Articles were considered after reviewing the titles and abstracts when available. From this initial body of literature, we identified additional articles using the bibliographies of the original set.

Attention was paid to clinical presentation and the diagnostic and treatment modalities used by the various authors. Articles with insufficient information regarding these items were excluded from this study, as well as case reports of patients diagnosed with liver adenomatosis. Only those reports were included in which the diagnosis of HCA was confirmed histologically, either using percutaneous biopsy or the resection specimen.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Reports from China

A total of 191 patients with HCA were reported in China between 1 January 1998, and 31 December 2008. The male : female ratio was 1.65 (119:72). The mean age at diagnosis was 39.3 (range: 5–79) years. Among the 72 women, only eight had been taking oral contraceptives for 3–20 years. Twelve patients had been admitted with acute abdominal pain caused by intratumoral bleeding or necrosis of one of the adenomas. Seven patients presented with a bleeding and rupture into the peritoneal cavity. Two of them died before laparotomy could be performed and the diagnosis was made at necropsy; the others underwent urgent surgery. In 14 patients, the tumor was found during evaluation of a palpable mass in the right upper quadrant. In four of these patients with tumors located centrally in the liver, the bile duct was compressed, causing jaundice, which necessitated surgical treatment.

Reports from Europe, North America, and South-East Asia

A total of 165 cases from 93 reports dating back to 1998 were examined. Of these, 46 cases were reported by US authors (Table 1), 104 cases were reported by European authors (Table 1), and 15 cases by authors from East Asia (Japan/South Korea) (Table 1). Patient characteristics are shown in Table 2.

Table 1.  Reported cases of hepatocellular adenoma in North America, Europe, and South-East Asia
North America
Study (by first author)YearPatientsNo. femalesOCC/AnaSize (cm)TreatmentComplications
  1. OCC/Ana, oral contraceptives/anabolic androgenic steroids; OLT, orthotopic liver transplantation; RFA, radiofrequency ablation; TAE, transcatheter arterial embolization.

Nicole (World J. Gastroenterol. 14: 4573)20081  9.9Resection 
Heeringa (Am. Surg. 67: 927)200111+6.5Resection 
Abhasnee (J. Gastroenterol. and Hepatol. 20: 653)200511 12Resection 
Dorothy (J. Pediatr. Surg. 41:1149)20061  3.5RFA 
Ashish (J. Pediatr. Hematol. Oncol. 26: 16)20041 +8Conservative 
Lautz (J. Pediatr. Surg. 43:751)200811+18Resection 
Adusumilli (Am. Surg. 68: 582)20021  10Resection 
Silvana (AJR. 182: 1520)200411+10Resection 
Joseph (Dig. Surg. 17: 640)200011+4.3Resection 
Lefian (AJR. 165: 1426)199911+17Resection 
Franco1 (J. Inherit. Metab.Dis. 28: 153)200511  RFA 
Maria (J. Pediatr. Gastroenterol. Nutr. 44: 640)200711+5.5Resection 
Morotti (Semin. Liver Dis. 27:427)200711+5TAE 
Rahul (Urology 70: 1008)200711+9Resection 
Jabbour (Am. Surg. 71: 354)200511+9Resection 
Caballesa (Int. J. Gynaecol Obstet. 64: 177)199911+ Resection 
Kimberly (Pediatr. Radiol. 29: 92)19991   Resection 
Wesley (J. Pediatric. Surgery. 42: 23)20071  21Resection 
Delgado (J. La. State Med. Soc. 151(9): 474)199911+7Resection 
Riedenauer (J. Pediatr. Surg. 42: 23)200711+10Resection 
Suárez-Peñaranda (Am. J. Forensic. Med. Pathol. 22: 275)200111 24 Death
Anita (Human Pathology 39: 1370)20081   Conservative 
Thomas (AJR. 184: 828)200533+5RFA 
Naduka (J. Am. Board Fam. Pract. 12: 337)199911+3Resection 
Hashimoto (Hepatogastroenterology 51: 837)200411+3Resection 
Frederick (Am. J. Surgery 187: 181)20041   Resection 
Michael (ModPathol. 15: 189)20021514+ ResectionBile leakage
Evlampia (J. Magn. Reson. Imaging. 22: 258)20052  17Conservative 
Srinevas (J. Hepatology. 47: 658)200711  Resection 
Europe
Gray (Ulster. Med. J. 69: 65)200011+5Resection 
Bork (J. Hepatol. 36: 707)200211+14Resection 
Nicola (Dig. Dis. Sci. 50: 1818)200511+9Resection 
Csepregi (J. Gastroenterol. Hepatol. 22: 759)200711+5RFA 
Aude (Med. Pediatr. Oncol 36: 659)200111 4Resection 
Terracciano (Arch. Pathol. Lab. Med. 128: 222)200411 10Resection 
Huguet (Rev. Esp. Enferm. Dig. 98:53)200611 20Resection 
Posthuma (Peritoneal Dialysis International 18: 444)199811 17Resection 
Bartley (Arch. Gynecol. Obstet. 269: 290)200411+5.5Resection 
Toso (Liver Int. 23: 35)200311 13ResectionBiloma
Franka (Med. Klin. 96: 676)200111++Resection 
Lim (Br. J. Radiol. 75: 695)200211+5Conservative 
Emmanuelle (J. Hepatol. 45: 883)200611+7Resection 
Giusti (Dig Liver Dis. 37: 200)20051  18Resection 
Handra (Histopathology 48: 309)200611+8.5TAE 
Bartolotta (Radiol. Med. 101: 219)200111+4.5Conservative 
Socas (Br. J. Sports Med. 39: 27)20052  12Conservative 
Konrad (Lancet 353: 1066)199931+13Resection 
Burria (Eur. J. Gastroenterol. Hepatol. 18: 437)200611+8Resection 
Capussotti (Hepatogastroenterology 54: 1557200711 5Resection 
Patrick (Gastroenterol. Clin. Biol. 30: 304)200611+9Resection 
Debaere (Can. Assoc. Radiol. J. 50: 161)199911  Conservative 
Terkivatan (Liver 20: 186)200022+7.5Conservative 
Dietrich (Br. J. Radiol. 78: 704)200588+1.5–5.5Conservative 
Posthuma (Peritoneal Dialysis International 18: 446)199811+17Resection 
Fulya (Eur. J. Gastroenterol. Hepatol. 14: 463)200211 11ResectionInfection
Abdulkader (Int. J. Surg. Pathol. 12: 245)200433+10Resection 
Donati (Dig. Liver Dis. 37: 200)20051  17Resection 
Jan (Dig. Surg. 23: 155)200611  TAE 
Ozenne (Eur. J. Gastroenterol. Hepatol. 20: 1036)20082  5.1Conservative 
Garrido (Gastroenterol. Hepatol. 6: 665)200311 7.5Resection 
Faivre (J. Inherit. Metab. Dis. 22: 723)199912+10OLT 
Volkert (World J. Gastroenterol. 12: 6059)200611+7RFA 
Kirti (Indian J. Gastroenterol. 24: 274)20051  11.5Resection 
Suarez (Semin. Liver Dis. 21: 453)200111 24 Death
Deha (Cardiovasc. Intervent. Radiol. 30: 1252)200766+4–18TAE 
Carlo (J. Gastroenterol. Hepatology 18: 227)200311 4Resection 
Menge (Med. Klin. [Munich]. 96: 676)200111+8Resection 
Nicolaleone (Dig. Dis. Sci. 50: 10)200532+9Resection 
Ruiz (Aten. Primaria. 35: 109)200533+2.4–5RFA 
Croes (Ned. Tijdschr. Geneeskd. 142: 2463)199888+ Conservative 
Bestard (Nefrología. 1: 93)200811+5ResectionSepsis
Dargent (Histopathology 37: 287)200011  Resection 
Peddua (Clinical Radiology 63: 329)200811+4.2Conservative 
Suriawinata (Semin. Liver Dis. 19: 339)199911+14Resection 
(N. Z. Med. 116: U444)200311 8.5Resection 
Teeuwen (Ned. Tijdschr. Geneeskd. 151: 1321)200722+5Resection 
Bagia (N.Z. J. Surg. 70: 686)20001 + Resection 
Nadir (Am. J. Surg. Pathol. 24: 1429)20002  7–9Resection 
Terkivatan (Br. J. Surg. 88: 207)200011+9Resection 
Erdogan (Liver Int. 26: 433)20062222+2.2–15.2Resection 
South-East Asia
Fujita (J. Gastroenterol. Hepatol. 21: 1351)200622+2–5Resection 
Hsu (World J. Gastroenterol. 9: 627)20031  2,4Resection 
Chung (Am. J. Gastroenterol. 101: 2160)200611 19Resection 
Masahide (J. Gastroenterol. 36:52)200111 2.6Resection 
Koizumi (J. Gastroenterol. Hepatol. 21: 619)200611 5Resection 
Tadashi (J. Gastroenterol. 38: 516)200311 21Resection 
Chung (J. Gastroenterol. Hepatology 19: 710)200411+6Resection 
Gong (World J. Gastroenterol. 12: 2125)200611 2Resection 
Yasuhiro (J. Nippon Med. Sch. 68: 6)20011  4.5Resection 
Masahiro (World J. Gastroenterol. 9: 2379)200311 10Resection 
Nakao (J. Gastroenterol. 35: 557)200311 5.5Resection 
Lim (Clin. Nucl. Med. 27: 270)20021 +3.5Resection 
Oshita (J. Hepatobiliary Pancreat. Surg. 15: 200)200821 3Conservative 
Table 2.  Clinical features of reported hepatocellular adenoma cases during 1998–2008
 ChinaEuropeSouth-East AsiaNorth America
  1. FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; IPB, intraperitoneal bleeding; ITB, intratumoral bleeding; ITN, intratumoral necrosis; OCC, oral contraceptives.

No. cases1911041546
Age (years)39.3 (5–79)36.2 (9–69)34.8 (11–70)28.9 (0–56)
Male/female119/729/954/1110/36
OCC case8 (4.2%)74 (71.2%)3 (20%)30 (65.2%)
Presentation    
 Incidental43 (22.5%)37 (35.6%)7 (46.7%)9 (19.6%)
 Acute pain52 (27.2%)33 (31.7%)2 (13.3%)12 (26.1%)
 Chronic pain65 (34%)22 (21.1%)06 (13%)
 Palpable mass14 (7.3%)2 (1.9%)1 (6.7%)2 (4.3%)
 Gastrointestinal symptoms13 (6.8%)8 (7.7%)5 (33.3%)2 (4.3%)
 OtherJaundice/4 (2%)Unknown/2 (1.9%)0Unknown/15 (32.6%)
Tumor size (mean)8.32 (2–31)8.37 (2–24)7.95 (2–19)9.65 (2.4–21)
Tumor number    
 Multiple (%)12 (6.3%)53 (50.9%)3 (20%)16 (34.8%)
 Solitary (%)179 (93.7%)51 (49.1%)12 (80%)30 (65.2%)
Tumor location    
 Right (%)100 (52.4%)49 (47.1%)9 (60%)26 (56.5%)
 Left (%)82 (42.9%)31 (29.8%)5 (33.3%)15 (32.6%)
 Bilateral (%)9 (4.7%)24 (23.1%)1 (6.7%)5 (10.9%)
Bleeding    
 ITB44 (23%)40 (38.5%)8 (5.3%)9 (19.6%)
 ITN39 (20.4%)17 (16.3%)1 (6.7%)6 (13%)
 IPB7 (3.7%)11 (10.6%)03 (6.5%)
Histopathology    
 HCC13 (6.8%)3 (2.9%)1 (6.7%)3 (6.5%)
 FNH2 (1%)4 (3.8%)1 (6.7%)2 (4.3%)
 Steatosis1 (0.5%)62 (59.6%)6 (40%)26 (56.5%)
 Other1 (1%)01 (6.7%)0

Among these three regions, a female preponderance was observed (86%, 142:165), and of all women, 75.4% (107:142) had been taking oral contraceptives for 3–20 years, which differs from the Chinese data (Table 2). The North American patients showed the lowest mean age (29 years), whereas in Europe and South-East Asia, a similar mean age was found (i.e. 35 and 36 years, respectively). The main mode of presentation within these three regions was acute/chronic abdominal pain, which is comparable with the cases reported in China. Fourteen patients presented with bleeding and rupture into the peritoneal cavity (11 from Europe, 3 from the USA). One died before laparotomy could be performed; the others underwent urgent surgery. In the reports from Europe, 50.9% of patients had two or more lesions, whereas in China, South-East Asia, and North America, HCA most frequently presented as a solitary lesion (Table 2).

Diagnostic modalities

In the literature of all regions, laboratory studies revealed non-specific results. A slight increase in serum aminotransferase was observed in some cases. Otherwise, the medical workup was normal or showed a twofold or threefold increase in serum alkaline phosphatase or γ-glutamyl transpeptidase levels.

In China, considering the high prevalence of liver cancer, laboratory analyses usually included hepatitis B serology tests (hepatitis B surface antigen, antihepatitis B core antigen) and levels of α-fetoprotein as a surrogate marker for hepatocellular carcinoma (HCC). Of all 191 Chinese patients, 25 tested positive for hepatitis B. Thirteen of them also had clinical symptoms of hepatitis. Thirteen patients were diagnosed with HCC, five of whom had coexistent hepatitis B virus (HBV) infection. Only six of the patients with HCC demonstrated high levels of α-fetoprotein (> 200 ng/mL). In the other three regions, hepatitis B serology testing is not a standard procedure, and only two patients were diagnosed as HBV positive.10,11 HCC was diagnosed in one patient with HBV co-infection.

The radiological investigations commonly used in all regions consisted of ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and angiography. In China, like the other three groups, the CT and MRI scans were the preferred diagnostic modalities. In all four regions, 74.5% of hepatic adenomas were isodense or slightly hyperdense, and became 100% visible in the arterial phase of contrast-enhanced CT scans. Upon MRI, 56.7% of these HCA were isointense or slightly hyperintense, as compared to the surrounding liver upon T1-weighted images. While the presence of HCA was suggestive in most cases, the diagnosis could not be made with certainty using CT and/or MRI in all four regions.

Overall, in 52.4% of the Chinese patients, lesions compatible with HCA were located in the right hemiliver, in 42.9% in the left hemiliver, and in 4.7% in both liver lobes. In contrast, 23.1% of the European patients had tumors located in both liver lobes, and 60% of the South-East Asian patients showed tumors only in the right liver lobe (Table 2). Of all 191 Chinese patients, only 6.3% (12 patients) were diagnosed with more than one lesion. Among the other three groups, 44% patients had multiple lesions. The number and location of the adenomas are shown in Table 2.

Management and outcome

All women diagnosed with HCA in the four regions were reported to have stopped using oral contraceptives. Overall, 53 patients were treated conservatively; 39 of them were European (73.6%). Thirty-seven patients in all the regions received non-surgical treatments, including selective transarterial embolization (TAE; n = 22), ethanol injection (n = 1), and percutaneous radiofrequency ablation (RFA; n = 14) (Table 3).

Table 3.  Management and mortality of reported hepatocellular adenoma cases during 1998–2008
 ChinaEuropeSouth-East AsiaNorth America
  1. OLT, orthotopic liver transplantation; RFA, radiofrequency ablation; TAE, transcatheter arterial embolization.

Management    
 Resection175 (91.6%)47 (45.2%)14 (93.3%)32 (71.1%)
 Conservative7 (3.7%)39 (37.5%)1 (6.7%)6 (13.3%)
 TAE7 (3.7%)13 (12.5%)02 (4.4%)
 RFA1 (0.5%)8 (7.7%)05 (11.1%)
 OtherEthanol injection/1 (0.5%)1/OLT (0.97%)00
Complications    
 Bleeding6 (3.4%)001 (3.1%)
 Bile leakage3 (1.7%)2 (4.3%)00
 Infection2 (1.1%)1 (2.1%)00
 Other4 (2.3%)1 (2.1%)1/unknown0
Mortality4 (2.1%)003 (6.5%)

Surgical procedures consisted of hemihepatectomy or a segmental or local resection in all the regions. In case of multiple tumors, resection of the largest tumor was performed, unless all tumors were located in the same segment or lobe. To assess surgical morbidity, all complications requiring treatment were included in the analysis (Table 3).

Of the Chinese patients with non-ruptured HCA, 170 underwent elective surgery. Major hepatic resections were performed in 40 patients (23.5%), including (extended) right and left hemihepatectomies. Non-anatomic resections (tumorectomy or wedge resection) were performed in 77 patients, and a (bi)segmental resection was performed in 53 patients. In addition to hepatic resection, nine patients underwent additional local resections to remove more than one HCA. Seven patients underwent a second resection because of tumor recurrence. Of these patients, three patients with large tumors had a recurrence at the site of previous excision, and four had developed a new lesion. Five patients presenting with ruptured HCA underwent emergency laparotomy. Of these, three patients underwent hemihepatectomy; the other two were treated with local excision.

The overall postoperative mortality rate in China was 1.1% (2/175). One patient died because of persistent bleeding, and the other of a severe pulmonary infection. The overall morbidity rate was 8.6% (15/175 patients). In five patients, a surgical reintervention was required due to rebleeding (n = 3) or because of severe bile leakage (n = 2).

More than 93.3% of patients reported in South-East Asia underwent surgical treatment, which was the highest rate of the four regions. Anatomic resections (segmentectomy or hemihepatectomy) were the most performed operations among the three regions (59%), and a major hepatic resection was performed in 35.4% patients (33/93), including (extended) right and left hemihepatectomies. Seven patients underwent additional local resections because of multiple lesions. Tumor recurrence was diagnosed in two patients12,13 who had developed new lesions in the residual liver. Of the three regions outside China, 13 patients presenting with ruptured HCA underwent emergency laparotomy. Of these, eight underwent hemihepatectomy; the other five were treated with local excision. The data pertaining to surgical management in all four regions are listed in Table 1.

Histopathological examination

Histopathological examination of the resected specimen or of percutaneous biopsy material was taken as the gold standard for confirmation of the diagnosis. In most HCA cases, a well-encapsulated gray or tan liver mass with a pseudocapsule was found upon gross examination. Microscopic examination revealed hepatocytes rich in glycogen and lipid, arranged in sheets and cords with aberrant feeding arterioles lacking an acinar architecture. Atypia, vascular invasion and mitotic figures were absent, and the reticulin architecture was generally preserved. In all patients (Table 4), histopathological evaluation of the tumors met with the abovementioned criteria for HCA.

Table 4.  Hepatocellular adenoma coexistent with hepatocellular carcinoma
Region/case no.AgeSexHBVα-fetoprotein (> 200 ng/mL)Tumor size (cm)
  1. m, multiple tumors; s, solitary tumor.

China
130MaleYes 8.0 × 7.0 × 6.0/s
262MaleYesYes5.0 × 4.0 × 4.0/s
371MaleYes 5.0 × 4.5 × 4.0/s
428Female Yes12.0 × 11.0/s
562Male Yes5.9 × 5.9/m
645Male  31.0 × 23.5/s
767Male  14.0 × 13.0/s
853MaleYesYes5.2 × 3.8/m
936Male  13.8 × 16.6/s
1050Male Yes30 × 25 × 20/m
1131Male  17.0/s
1239MaleYes 7.8 × 5.2/m
1336Female YesUnknown
Europe
114Female  10 × 9/m
240Female  8.0/s
344Male  5.0/s
South-East Asia
166MaleYes Unknown
North America
123Female  4.0/s
225Female  9.5/s
333Female  8.5/s

Among Chinese patients, focal necrosis and microscopic foci of hemorrhage were present in 39 and 44 patients, respectively. Thirteen of the 191 Chinese patients (7%) had evidence of malignancy within the lesion. In two patients, coexistent focal nodular hyperplasia was found in the same lesion.

Patients from the other three regions shared similar histopathological characteristics with the Chinese patients (Table 2). The percentage of focal necrosis and microscopic foci was roughly the same. Coexistent steatosis in these three regions was much more common than in Chinese patients (59.6%, 56.5%, and 40% in the European, US, and South-East Asian groups, respectively, vs 0.5% in the Chinese group, Table 1), while HCC was found in only seven patients, which was significantly different from the Chinese group (Table 4). Among all patients, the mean size of the tumor with HCC was 11.2 cm (range: 5–31 cm), whereas the mean tumor diameter for benign HCA in the four regions was 7.8 cm (range: 1.5–25 cm).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Demographics

In the present study, we report the largest review so far of 356 patients with HCA (191 from China, 104 from Europe, 46 from the USA, and 15 from South-East Asia), collected from all case reports and case series published in 1998–2008. Only a descriptive analysis was performed because of the heterogeneous data. In Europe, North America, and South-East Asia, a female predominance was obvious (91.3%, 78.3%, and 73.3%, respectively). This female predominance has frequently been mentioned in literature.14 In contrast, after analyzing the Chinese literature, only 37.7% (72/191) of patients in China were female and only eight of them had a history of oral contraceptive/anabolic steroid use. There are two reasons to explain this difference. First, because of the birth control policy, as became effective in China in 1980, oral contraceptives are commonly used by women before they get married. After they have had their first and only baby, most Chinese women use the intrauterine device as a routine birth control method. This is compulsory in many provinces of mainland China. Second, the criterion for the surgical treatment of HCA might be more rigorous in China, considering the large prevalence of liver cancer. Surgeons would rather advise tumor resection even if the presumptive diagnosis is adenoma, especially in male patients.

Clinical presentation

Symptomatic patients usually present with chronic upper abdominal pain due to the mass effect of larger HCA or acute pain secondary to bleeding within an HCA.15 In this study, most patients had acute/chronic abdominal pain as their main complaint both in China (61.2%, 117/191) and in Europe or North America (52.9% vs 58.1%, 55/104 vs 18/31). The data from the South-East Asian group differed, with 47.7% of HCA detected as an incidental finding. This was the highest of all groups, as the rate of incidental findings in China, Europe and the USA, was 22.5%, 36.3%, and 29%, respectively.

HCA mostly presents as a solitary nodule. Occasionally, two or more tumors are found. Tumor size is variable, with a range of 1–30 cm (usually 8–15 cm).16 In our study, 93.7% of the Chinese patients were diagnosed with a solitary lesion. In patients from South-East Asia and North America, the rate of solitary lesions was 80% and 65.2%, respectively. In the European reports, more than half of the patients (50.9%) had multiple lesions. The reason for this difference is unclear, but a referral bias should be considered.

HCA is of clinical importance because of its tendency to bleed and to rupture spontaneously.17 Fourteen cases in the European/US groups were reported with catastrophic rupture and intraperitoneal bleeding, while among the patients from China, seven suffered spontaneous rupture of the lesions. Four deaths occurred: two in the Chinese and two in the North American group. There was no mortality in the South-East Asian group. Although there was no conclusive evidence to prove a correlation of the size of HCA and rupture, some authors reported an increased risk of rupture in tumors more than 6.5 cm in size.18 In our series, 21 cases of ruptured HCA were found; the mean diameter of the lesions in China, Europe, and North America were 10.8, 12.4, and 14 cm, respectively (Table 5).

Table 5.  Clinical features of patients with or without intraperitoneal bleeding (IPB)
 IPBNon-IPB
ChinaEuropeUSA
Sex (male/female)4/30/112/1136/188
Age51.937.522.736.7
Tumor size10.812.4148.33

Management

The management of benign hepatic tumors ranges from routine resection to observation. Given the difficulty in distinguishing HCA from well-differentiated HCC and the risk of spontaneous rupture and malignant transformation, large HCA are generally resected.19 Because of the claimed safety and efficacy, RFA and TAE are rapidly evolving as widely-accepted methods for treating HCA.20–22 Twenty-two patients in this review underwent TAE treatment, and 14 RFA, with no severe complications reported. RFA and TAE can provide a reasonable alternative for resection in selected cases.23

Well-recognized indications for surgery are the presence of symptoms; lesions larger than 5 cm; complications, such as bleeding; or the need to establish a definitive diagnosis. Most of the patients in our review underwent resection. In patients from South-East Asia, 93.9% underwent resection; in the Chinese, European, and US groups, the rate was 91.6%, 46.2%, and 69.6%, respectively. Chinese surgeons tend to advise resection, especially in males or in patients with coexisting HBV infection and in lesions larger than 2.5 cm, although nowadays, more strict criteria for resection are used, as applied in Europe and the USA. In cases of major liver resection, the operative risk should be carefully balanced against the benefits to be expected from resection. The morbidity associated with liver resection for HCA is limited. Mortality, which might be underreported in the literature, must be considered unacceptable, taking into account the benign nature of the tumor.

Malignant transformation of HCA

The malignant transformation of HCA to HCC has been described in the literature by several groups.10,24–26 The issue of when HCA develops into malignancy and which factors influence malignant degeneration are still being investigated. In our data, a total of 20 patients (5.6%) had evidence of HCC within an adenoma upon final pathology. The mean size of the tumor with HCC was larger than the mean tumor diameter in benign HCA (11.2 cm vs 7.8 cm). Our data, derived from the world literature, suggests that small tumors (<4 cm) are unlikely to become malignant. Among the 20 patients with HCC, only seven were female. Therefore, HCA size and sex appear as possible risk factors for malignant transformation. Our study also shows that HCA occurs in patients with HBV infection. In all four groups, malignant transformation was reported in 20 patients, six of whom had coexisting HBV infection (5 from China, 1 from Korea). Although only 30% (6/20) of patients with malignant transformation in our series had high α-fetoprotein levels (>200 ng/mL), we recommend this tumor marker as an adjunct to imaging studies in identifying the malignant degeneration of HCA. In addition, since it is not clear whether all HCA eventually can transform into HCC, and at which time point this transformation will occur, it is important that patients are observed, especially male patients with HBV infection.

Conclusion

We compared the literature on HCA in China, Europe, North America, and South-East Asia. To our knowledge, this is currently the largest review of HCA from 1998 to 2008. The most remarkable findings can be summarized as follows:

  • 1
    A male predominance of HCA was observed in China. This male predominance could be the result of the birth control policy in China and the limited use of oral contraceptives.
  • 2
    Acute/chronic abdominal pain was the main clinical presentation in all groups.
  • 3
    Management consisted of resection in most reported cases.
  • 4
    HCA combined with chronic HBV infection could increase the risk of malignant transformation.
  • 5
    Tumors more than 10 cm in size indicate an increased risk of rupture and malignant transformation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References