Case Report Received: November 12, 1996 Accepted: April 15, 1997
Dig Surg 1998;15:75–78
Massimo Cristaldi a Marco Rovati a Dario Conte c Marco Elli a Alessandro Lesma a Maurizio Mezzabotta a Luca Vago b Angelo Maria Taschieri a a b
c
Divisione di Chirurgia generale e Anatomia Patologica, Università degli Studi di Milano, Ospedale Luigi Sacco Milano, e Istituto di Scienze mediche, IRCCS Ospedale Maggiore di Milano, Italia
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Key Words Liver Neoplasm Adenoma Adenomatosis
Primary Liver Adenomatosis Report of Two Cases and Literature Review
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Abstract Background/Aims: Liver adenomatosis is an uncommon condition and so far only 13 cases fulfilling the requirements for its diagnosis have been reported in the literature. Optimal treatment of the disease and follow-up criteria are still the subject of debate. Methods: We report on 2 cases of liver adenomatosis. In both cases definite diagnosis was obtained only intraoperatively on biopsy. Results: In neither case was liver transplantation done, due either to patient refusal or foreseeable poor compliance. Prolonged strict follow-up failed to demonstrate malignant changes. Conclusions: Removal of the huge masses often responsible for abdominal pain is the only real indication for resective surgery. Orthotopic liver transplantation should be reserved for those cases in which malignant changes are suspected due to elevation of the ·-fetoprotein concentration or gross modifications in the shape of the hepatic lesions. OOOOOOOOOOOOOOOOOOOOOO
Introduction Liver adenomatosis is defined as the presence of more than 10 hepatic cell adenomas in an otherwise normal liver [1, 2]. It occurs in patients with no previous history of oral contraceptives or any other hormonal therapy, virilizing ovarian tumors, metabolic conditions as type-I glycogen storage disease, diabetes and iron overload in thalassemic patients [1]. So far only 13 such cases have been reported in the literature [1, 3–10] (table 1). Differential diagnosis is made by hepatocellular adenomas which, on the contrary, are usually solitary [7]: three or more synchronous liver adenomas are an extremely rare condition. Elevation in hepatic function tests has been reported in 80% of cases with liver adenomatosis, while they are usually normal in patients with liver adenomas [1].
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Progression of the disease is very slow, with an unpredictable risk of rupture, bleeding and malignant transformation, which stimulates debate on therapeutic options [1, 10]. Occasionally liver transplantation has been done for the condition [11]. Two cases of liver adenomatosis are reported. Both were referred for treatment to the Division of General Surgery and the Department of Internal Medicine of the State University of Milan.
Case Reports Case 1 In a 40-year-old caucasian woman with no history of oral contraceptives or other hormonal therapy, many hyperechoic lesions (diameters ranging from 0.5 to 2 cm) were found incidentally throughout the liver on abdominal ultrasonography 4 years prior to admis-
Angelo M. Taschieri, MD, Professor of Surgery Luigi Sacco Hospital, Via G.B. Grassi, 74 I–20157 Milan (Italy) Tel. (2) 3567413, Fax (2) 38200232 E-Mail
[email protected]
Table 1. Clinical, pathologic findings, therapy and outcome in 13 cases (plus 2 additional cases of the present series) of liver adenomatosis unrelated to contraceptive or hormonal use reported in the literature References
Sex
Age at diagnosis years
Symptoms
Surgery
Intratumorous or intraperitoneal bleeding
Outcome and follow-up months
Monges et al. [3] Monaco et al. [4] Caquet et al. [6] Lui et al. [7] Chen and Bocian [8] Flejou et al. [1]
M F M F F M M M F F
56 21 49 39 13 31 13 75 45 38 30 40 40 26
EP, HM HM EP, HM EP AP EP, HM AP EP, HM AP EP, HM = AP AP EP
H H H H WR WR H WR WR H WR H WR WR
No No No Yes No No Yes No Yes No No Yes No Yes
Well, 17 Well, 10 Well, 6 Death, pulmonary emboli Sudden death Well, 11 Well for 34 months then OLT for HCC Well, 7 Well, 28 Well, 15 Well, 36 Well, 132 Well, 72 Well, 18
Khan et al. [9] Propst et al. [10] Present report
F M
EP = Epigastric pain; AP = abdominal pain; HM = hepatomegaly; OLT = orthotopic liver transplantation; H = hepatectomy; WR = wedge resection; HCC = hepatocellular carcinoma.
sion. The patient was symptom free and a diagnosis of multiple liver hemangiomas was entertained at the time: no therapy was instituted and yearly liver ultrasonography was suggested. On admission to our department for right upper quadrant abdominal pain, a non-tender palpable right upper quadrant mass was found. Ultrasonography, computed tomography (CT), dynamic CT and nuclear magnetic resonance were done. CT scan was positive for multiple solid nodules with a hypodense appearance scattered throughout the liver (fig. 1). Ultrasound scan showed numerous hyperechoic nodules, as reported at previous controls, and in addition revealed the presence of a solid hyperechoic mass 8 cm in diameter, located in liver segment IV. Liver function tests were normal except for a mild increase in Á-glutamyltranspeptidase (Á-GT) and alkaline phosphatase. Hemoglobin was 11.1 g/l. Hepatitis B and C markers were negative. The patient was scheduled for surgery. At laparotomy several yellowish, round nodules, ranging from 0.5 to 8 cm in diameter, were seen all over the surface of the liver. The masses were soft in consistency. Intraoperative ultrasound revealed more than 50 other hyperechoic nodules within the liver parenchyma, which were undetectable by simple palpation. The largest lesion (n 8 cm), located in liver segment IV, was removed by wedge resection, together with many satellite nodules: the main lesion was surrounded by a rim of compressed hepatic parenchyma, free of neoplastic invasion. There was no macroscopically visible capsule. At histology large plates of benign-looking hepatocytes were described, with nuclei uniform in shape and size, and diffuse micro- and macrovesicular steatosis. No mytoses or cellular atypias were reported. Well-formed portal tracts and central veins were absent. Foci of necrosis or intratumoral bleeding were also absent. A thin and discontinous fibrous capsule circumscribed the tumors, but no remarkable alterations were found in the surrounding hepatic tissue except for mild steatosis (fig. 2). We compared the his-
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tology with other liver adenomas previously observed in our institution and found them strikingly similar. Once discharged in good general condition, the patient was considered for orthotopic liver transplantation and the usual pretransplant work up was done. The celiac arteriography was negative for hypervascular lesions suggesting malignant changes within the liver; during the venous phase no abnormalities or displacement of the intrahepatic portal vein were seen. The hepatic veins were patent on color Doppler study. After discussion with the patient, who had remained in excellent condition, the conservative option was preferred and liver transplantation was cancelled. A close follow-up by ultrasound scans and ·-fetoprotein levels was done at yearly intervals. 72 months after surgery the patient is in satisfactory condition, with an unchanged ultrasound picture and normal levels of ·-fetoprotein. Case 2 An extensive work up had been done elsewhere for this 26-yearold caucasian man with history of dyspepsia for 1 year. At abdominal ultrasound the liver was completely subverted by numerous hyperechogenic areas: the diameter of the lesions ranged from 2 to 8 cm and their margins were irregular. At CT scan hyperdense nodules were scattered throughout the liver; shortly after the administration of contrast medium, they became hypodense and maintained a central impregnation in the late films, consistent with a radiological diagnosis of hemangiomas. At angiography large vascular lesions were observed. The patient came to our institute 1 year later in December 1995. On physical examination he presented only a slight tenderness at deep palpation in the right hypochondrium and at deep inspiration the inferior edge of the liver could be palpated 5 cm below the costal margin. Laboratory data were all within normal limits except for a mild increase in Á-GT levels (76 IU/l, normal 7–32).
Cristaldi/Rovati/Conte/Elli/Lesma/ Mezzabotta/Vago/Taschieri
Fig. 1. Case 1. Computed tomography shows multiple hypodense nodules diffused throughout the liver.
Hepatitis B and C viral markers were negative. Chest X-ray was normal. At contrast abdominal CT scan diffuse hypodense areas were seen with partial intrahepatic vein occlusion secondary to compression by the tumors (fig. 3). The remaining hepatic parenchyma was normal and the liver was only slightly enlarged. The spleen was moderately enlarged. The findings were confirmed by nuclear magnetic resonance. An ultrasound-guided liver biopsy was initially scheduled but the risk of intraperitoneal bleeding was deemed too high. The patient underwent exploratory celiotomy and biopsy under vision. At surgery several round nodules, ranging from 1 to 10 cm in diameter, were seen throughout the hepatic parenchyma. A wedge resection was performed on the third hepatic segment, encompassing a large lesion of 6.5 cm in diameter and several hepatic satellite nodules. The masses were soft in consistency and well demarcated from the surrounding normal liver. The pathology report described the presence of several non-capsulated nodules formed by normal-looking hepatocytes arranged in plates of various thickness. The cells showed no mytoses or cellular atypias. A large number of blood vessels with sporadic intralesional bleeding was observed. The postoperative course was uneventful and the patient was discharged home on postoperative day 7. Presently he remains well, free of pain and with a normal ·-fetoprotein level.
2
Discussion Hepatocellular adenomas are uncommon benign neoplasms usually occurring in young women on oral contraceptives. Before the widespread use of the birth-control pill, they were rare tumors: in the Edmonson’s [12] review of 50,000 autopsies at Los Angeles County Hospital from 1918 to 1954 only two liver adenomas were found. Baum et al. [13] were the first to suggest the possible etiologic relationship between liver adenomas and the birth-con-
Fig. 2. Microphotograph showing the boundary of the hepatic adenoma (on the right) separated from the normal liver tissue (on the left) by a thin fibrous capsule (arrows). HE. !100. Fig. 3. Case 2. Computed tomography reveals diffuse hypodense areas partly confluent and associated with intraparenchymal occlusive venopathy manifestations.
Primary Liver Adenomatosis
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trol pill. Since then more than 750 reports of hepatic adenomas have been reported [10]. Female predominance, number of nodules less than 3, intraperitoneal or intratumoral bleeding, and rare but unpredictable malignant transformation have also been described as the main clinical features of liver adenomas [1, 2, 10]. On the contrary, an equal incidence in males and females with no relationship to oral contraceptives, multiple liver nodules (arbitrarily 1 10 but in most cases 40–50), mild elevation of Á-GT and alkaline phosphatase, and abdominal pain as the main presenting symptom made Flejou et al. [1] suggest in 1985 that liver adenomatosis is a different entity from multiple liver adenomas. Its progression seems very slow: 1 patient in the series of Flejou et al. [1] complained of liver enlargement 50 years before clinical diagnosis was entertained, and 1 case of hepatocellular adenomatosis with a follow-up of 11 years has recently been reported [10]. So far malignant transformation in liver adenomatosis has been diagnosed in only 1 patient originally belonging to the above-mentioned series reported by Flejou et al. [1]: 5 years after surgical resection, the ·-fetoprotein concentration, which had previously been normal, rose to 300,000 IU/l without changes in hepatic lesions detectable on ultrasound and CT scans. The patient underwent orthotopic liver transplantation but the reported followup was inadequate. Multiple areas of well-differentiated hepatocarcinoma among histologically proved adenomas were found in the native liver [11]. Due to the small number of cases reported and the still short follow-ups, the occurrence of malignant changes in liver adenomatosis remains as unpredictable as the likelihood of bleeding.
Due to the great number of nodules, ultrasonography and CT are often inadequate to detect hepatocellular foci of carcinoma arising in an adenomatous liver. In asymptomatic patients, malignant changes can be more easily detected by assessment of the ·-fetoprotein concentration combined with ultrasonography at yearly intervals as confirmed by Leese et al. [11]. CT scan examination should be reserved to confirm gross changes in the morphology or dimensions of the hepatic lesions and in those cases in which rupture or peritoneal hemorrhage are clinically suspected. Hemorrhage has been described in 4 patients among those reported in the literature: in 2 it occurred in the tumor mass and in the remaining 2 in the peritoneum. Laparotomy and partial liver resection have been performed to achieve a correct diagnosis in all reported cases. In a few instances excision of the major hepatic lesions relieved abdominal pain [1]. In our opinion, removal of huge masses often responsible for abdominal pain is the only real indication for resective surgery. Orthotopic liver transplantation should be reserved for those cases in which malignant changes are suspected due to elevation of the ·-fetoprotein concentration or gross modifications in shape of the hepatic lesions. It should be stressed that in all cases reported in the literature a definite diagnosis was achieved only by histology of the specimen obtained at surgery. The 6-year follow-up of 1 of the 2 patients discussed is the second longest observation of liver adenomatosis, after the report of an 11-year observation of a comparable case by Propst et al. [10].
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References 1 Flejou JF, Barge J, Menu Y, Degott C, Bismuth H, Potet F, et al: Liver adenomatosis: An entity distinct from liver adenoma? Gastroenterology 1985;89:1132–1138. 2 Shortell CK, Schwartz SI: Hepatic adenoma and focal nodular hyperplasia. Surg Gynecol Obstet 1991;173:426–431. 3 Monges H, Payan H, Legrè M, Vignoli R: Considérations sur un cas d’adénome bénin du foie à forme multinodulaire. Arch Mal Appar Dig 1963;52:725–737. 4 Monaco AP, Hallgrimsson J, McDermott WV: Multiple adenoma (hamartoma) of the liver treated by subtotal (90%) resection: Morphological and functional studies of regeneration. Ann Surg 1964;159:513–519.
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5 Bisson A, Duron JJ, Fagniez PL, Pinadeau Y, Germain A: Adénomatose hépatique et contraceptifs oraux. Aspects chirurgicaux. Nouv Presse Méd 1974;3:2079–2082. 6 Caquet R, Guillausseau PJ, Louvel A, D’larzn JJ, Laroche C, Leger L: Polyadénomatose hépatique. Un nouveau cas. Nouv Presse Méd 1976; 5:1474–1476. 7 Lui AFK, Hiratzka LF, Hirose FM: Multiple adenomas of the liver. Cancer 1980;45:1001– 1004. 8 Chen KTK, Bocian JJ: Multiple hepatic adenomas. Arch Pathol Lab Med 1983;107:274– 275. 9 Khan SS, Fink M, King S: Case Report: Liver adenomatosis presenting as multiple calcified masses. Clin Radiol 1992;45:206–207.
10 Propst A, Propst T, Judmaier G: A case of hepatocellular adenomatosis with a follow-up of 11 years. Am J Gastroenterol 1995;90:1345– 1346. 11 Leese T, Farges O, Bismuth H: Liver cell adenomas. A 12-year surgical experience from a specialist hepato-biliary unit. Ann Surg 1988; 208:558–564. 12 Edmondson HA: Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, fasc 25. Washington, Armed Forces Institute of Pathology, 1958. 13 Baum JK, Bookstein JJ, Holz F, Klein EW: Possible association between benign hepatomas and oral contraceptives. Lancet 1973;ii: 926–929.
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