Benign Hepatocellular Tumors (Adenomatosis) in Nonalcoholic Steatohepatitis: A Case Report

Hepatic adenomatosis is a very rare condition of multiple benign hepatocellular tumors involving a noncirrhotic liver.[1] [2] The definition is exclusive of glycogen storage disease or androgen use, as these conditions are known for their potential to give rise to multiple hepatocellular tumors, some of which may be adenomas or hepatocellular carcinomas (HCCs).[3] [4] [5] A review of the literature from 1963 to 2003[1] [2] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] shows that adenomatosis is more common in women but, unlike adenomas, has a variable relationship to oral contraceptive use (Table [1]). Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of the metabolic syndrome (obesity, insulin resistance, hyperlipidemia, and hypertension); NASH may progress to cirrhosis, and cases of HCC in cirrhotic NASH have been reported.[26] [27] [28] [29] [30] [31] To our knowledge, benign hepatocellular neoplasms have not been reported in association with NASH. In this report, we document a case of hepatic adenomatosis arising in a noncirrhotic liver with steatohepatitis.

Table 1 Review of the Literature on Adenomatosis Author, Year, Cases (n), Ages (yrs) M:F Oral Contraceptive Use and/or Para Diabetes/Familial Steatosis, HCC, and Other Liver Lesions Monaco, 19646 21 F N/A Para: 0 No/ N/A Resection: multiple tumors 0.8-3.5 cm, some steatotic; no steatosis in uninvolved parenchyma Brander, 19767 24 F High dose for DUB, 6 years Para: 0 No/N/A Rupture of liver; multiple tumors; no steatosis Edmondson, 19778 n = 2 (32, 35) 0:2 100% (4, 5 years) Para: 0, 6 N/A Tissue dx: no mention of steatosis Kalra, 198710 n = 2 (23, 33) 0:2 DUB, renal tx N/A Tissue dx: no mention of steatosis Foster, 19789 n = 3 (15,17,43) 1:2 Not stated 43 years/o was mother 3/3 Steatosis not mentioned Liu, 198011 39 F No Para: 4 No/ N/A Steatosis not mentioned Sinha, 198212 37 F No Para: 3 N/A Steatotic nodules but not in nontumor liver Chen, 198313 28 F No Para: 0 N/A Presented at age 12: liver tumors (adenomas) bxd; no steatosis. Died 15 years later, congenital heart disease; 10 lesions 1-12 cm; one FNH Le Bail, 199214 39, 52 2F 100% (12, 18 years) Para: 3, 2 N/A Mild zone 1 steatosis in one case Propst, 199515 30 F N/A N/A Steatosis not mentioned Gokhale, 199616 17 F No Para: 0 N/A Tissue bx: steatosis in tumors Arsenault, 199617 41 F No N/A N/A Tissue bx: mild steatosis in lesion Ye, 199918 42 F 25 years N/A One tumor with central HCC. Steatosis not mentioned Suarez, 200119 35 F 3 years; 21 years prior; Norplant, 2 years No/No Steatosis in adenomas; none in nontumor liver Flejou, 198520 n = 5 (13-75) Review of lit: 8 cases 3:2 No N/A No steatosis mentioned in nodules or in nontumor liver Leese, 198821 n = 2 (16, 45) 1:1 No 0 and N/A Steatosis not mentioned. Multiple HCCs in explant Ribeiro, 19981 n = 8 (37-48) Review of lit: 22 cases 0:8 88% N/A and 0 Steatosis not mentioned Yoshidome, 199922 n = 2 (29, 53) Review of lit: 30 cases 0:2 1, remote past N/A “Mild steatosis” in nontumor parenchyma in both cases Chiche, 20002 n = 8 (14-45) Review of lit: 30 cases 1:7 43% (1, 6, 15 years) 4/4 Steatosis in all adenomas; not mentioned in nontumor liver. FNH (2), portal vein agenesis (1) Grazioli, 200023 n = 15 (19-66) 1:14 36% (2-15 years) N/A Mild steatosis in a minority of tumors; not mentioned in nontumor liver. FNH (2); portal vein thrombosis (1); portal vein absence (2), p-h shunt (2); HCC in explant (1) and in allograft (1) Bluteau, 200224 n = 7 (27-49) 1:6 66% females Para: not known Not specified; some family members of adenomatosis cases Steatosis not mentioned Bacq, 200325 n = 5 (14-42) 2:3 66% females Para: one female, 1 Two families with affected members Steatosis in adenomas in 3; diffuse steatosis in one relative without tumor Total cases n = 71 10:61 OC use:42% See above Steatosis in nontumor liver: 4 HCC: 4 bx, biopsy; DUB, dysfunctional uterine bleeding; dx, diagnosis; FNH, focal nodular hyperplasia; HCC, hepatocellular carcinoma; OC, oral contraceptive; p-h, portal-hepatic; tx, treatment; N/A, not assessed.

REFERENCES

• 1 Ribeiro A, Burgart L J, Nagorney D M, Gores G J. Management of liver adenomatosis: results with a conservative surgical approach.  Liver Transpl Surg. 1998;  4 388-398
• 2 Chiche L, Dao T, Salame E et al.. Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature.  Ann Surg. 2000;  231 74-81
• 3 Boyd P R, Mark G J. Multiple hepatic adenomas and a hepatocellular carcinoma in a man on oral methyl testosterone for eleven years.  Cancer. 1977;  40 1765-1770
• 4 Sale G E, Lerner K G. Multiple tumors after androgen therapy.  Arch Pathol Lab Med. 1977;  101 600-603
• 5 Howell R R, Stevenson R E, Ben-Menachem Y, Phyliky R L. Hepatic adenomata with type 1 glycogen storage disease.  JAMA. 1976;  236 1481-1484
• 6 Monaco A P, Hallgrimsson J, McDermott W V. Multiple adenoma (hamartoma) of the liver treated by subtotal (90%) resection: morphological and functional studies of regeneration.  Ann Surg. 1964;  159 513-519
• 7 Brander W L, Vosnides G, Ogg C S, West I E. Multiple hepatocellular tumours in a patient treated with oral contraceptives.  Virchows Arch A Pathol Anat Histol. 1976;  370 69-76
• 8 Edmondson H A, Reynolds T B, Henderson B, Benton B. Regression of liver cell adenomas associated with oral contraceptives.  Ann Intern Med. 1977;  86 180-182
• 9 Foster J H, Donohue T A, Berman M M. Familial liver cell adenomas and diabetes mellitus.  N Engl J Med. 1978;  299 239-241
• 10 Kalra P A, Guthrie J A, Dibble J B, Turney J H, Brownjohn A M. Hepatic adenomas induced by norethisterone in patients receiving renal dialysis.  Br Med J (Clin Res Ed). 1987;  294 808
• 11 Liu A FK, Hiratzka L F, Hirose F M. Multiple adenomas of the liver.  Cancer. 1980;  45 1001-1004
• 12 Sinha M R, Prasad S B. Multiple adenomas of the liver.  J Indian Med Assoc. 1982;  79 16-18
• 13 Chen K TK, Bocian J J. Multiple hepatic adenomas (letter).  Arch Pathol Lab Med. 1983;  107 274-275
• 14 Le Bail B, Jouhanole H, Deugnier Y et al.. Liver adenomatosis with granulomas in two patients on long-term oral contraceptives.  Am J Surg Pathol. 1992;  16 982-987
• 15 Propst A, Propst T, Waldenberger P, Vogel W, Judmaier G. A case of hepatocellular adenomatosis with a follow-up of 11 years.  Am J Gastroenterol. 1995;  90 1345-1346
• 16 Gokhale R, Whitington P F. Hepatic adenomatosis in an adolescent.  J Pediatr Gastroenterol Nutr. 1996;  23 482-486
• 17 Arsenault T M, Johnson C D, Gorman B, Burgart L J. Hepatic adenomatosis.  Mayo Clin Proc. 1996;  71 478-480
• 18 Ye M Q, Suwinata A, Hain M B, Parsons R, Schwartz M. A 42 year old woman with liver masses and long-term use of oral contraceptives.  Semin Liver Dis. 1999;  19 339-344
• 19 Suarez A A, Brunt E M, Di Bisceglie A M. A 35 year old woman with progesterone implant contraception and multiple liver masses.  Semin Liver Dis. 2001;  21 453-459
• 20 Flejou J F, Barge J, Menu Y et al.. Liver adenomatosis. An entity distinct from liver adenoma?.  Gastroenterology. 1985;  89 1132-1138
• 21 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
• 22 Yoshidome H, McMasters K M, Edwards M J. Management issues regarding hepatic adenomatosis.  Am Surg. 1999;  65 1070-1076
• 23 Grazioli L, Federle M P, Ichikawa T, Balzano E, Nalesnik M, Madariaga J. Liver adenomatosis: clinical, histopathologic, and imaging findings in 15 patients.  Radiology. 2000;  216 395-402
• 24 Bluteau O, Jeannot E, Bioulac-Sage P et al.. Bi-allelic inactivation of TCF1 in hepatic adenomas.  Nat Genet. 2002;  32 312-315
• 25 Bacq Y, Jacquemin E, Balabaud C et al.. Familial liver adenomatosis associated with hepatocyte nuclear factor 1α inactivation.  Gastroenterology. 2003;  125 1470-1474
• 26 Cotrim H P, Parana R, Braga E, Lyra L. Nonalcoholic steatohepatitis and hepatocellular carcinoma: natural history?.  Am J Gastroenterol. 2000;  95 3018-3019
• 27 Ludwig J, McGill D B, Lindor K D. Nonalcoholic steatohepatitis.  J Gastroenterol Hepatol. 1997;  12 398-403
• 28 Orikasa H, Ohyama R, Tsukada N, Eyden B P, Yamazaki K. Lipid-rich clear-cell carcinoma arising in nonalcoholic steatohepatitis in a patient with diabetes mellitus.  J Submicrosc Cytol Pathol. 2001;  33 195-200
• 29 Powell E E, Cooksley W G, Hanson R, Searle J, Halliday J W, Powell L W. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.  Hepatology. 1990;  11 74-80
• 30 Shimada M, Hashimoto E, Taniai M et al.. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.  J Hepatol. 2002;  37 154-160
• 31 Zen Y, Katayanagi K, Tsuneyama K, Harada K, Araki I, Nakanuma Y. Hepatocellular carcinoma arising in non-alcoholic steatohepatitis.  Pathol Int. 2001;  51 127-131
• 32 Brunt E M. Benign tumors of the liver.  Clin Liver Dis. 2001;  5 1-15
• 33 Calle E E, Rodriguez C, Walker-Thurmond K, Thun M J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.  N Engl J Med. 2003;  348 1625-1638
• 34 Balkau B, Kahn H S, Courbon D, Eschwege E, Ducimetiere P. Hyperinsulinemia predicts fatal liver cancer but is inversely associated with fatal cancer at some other sites.  Diabetes Care. 2001;  24 843-849
• 35 Nair S, Mason A, Eason J, Loss G, Perillo R P. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?.  Hepatology. 2002;  36 150-155
• 36 Lagiou P, Kuper H, Stuver S O, Tzonou A, Trichopoulos D, Adami H O. Role of diabetes mellitus in the etiology of hepatocellular carcinoma.  J Natl Cancer Inst. 2000;  92 1096-1099
• 37 El-Serag H B, Tran T, Everhart J E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.  Gastroenterology. 2004;  126 460-468
• 38 Marchesini G, Bugianesi E, Forlani G et al.. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.  Hepatology. 2003;  37 917-923
• 39 Bugianesi E, Leone N, Vanni E et al.. Expanding the natural history of non-alcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.  Gastroenterology. 2002;  123 134-140
• 40 Ratziu V, Bonyhay L, Di Martino V et al.. Survival, liver failure and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis.  Hepatology. 2002;  35 1485-1493
• 41 Marrero J A, Fontana R J, Su G L, Conjeevaram H S, Emick D M, Lok A S. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.  Hepatology. 2002;  36 1349-1354
• 42 Clark J M, Brancati F L, Diehl A M. Nonalcoholic fatty liver disease.  Gastroenterology. 2002;  122 1649-1657
• 43 Ruhl C E, Everhart J E. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States.  Gastroenterology. 2003;  124 71-79