—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 3 - Hepatic Adenomatosis

Elizabeth M. Brunt
St. Louis University
St. Louis, Missouri


Click on each slide thumbnail image for an enlarged view
Clinical History:
A 35 year old woman presented to the Saint Louis University Liver Clinic for re-evaluation of abdominal discomfort. Prior evaluation at an outside hospital for severe abdominal pain 3 months before included numerous imaging studies of the abdomen and pelvis. CT scan showed a 16 cm subcapsular hematoma in the right lobe of the liver, and multiple hyperdense lesions throughout the liver, that ranged from a few millimeters to 5 centimeters. The latter were considered unusual for hemangioma or adenomas and the interpretation of the scan was metastatic disease. A primary source could not be identified and no further treatment was given. When the patient came to SLU, further history and tests were obtained. The PMH was significant for 4 children (ages 7-15 years old). Other than occasional alcohol use, there was no history of drug or medication use. Liver tests were normal, and serum tumor markers were negative. Repeat CT scan confirmed the subcapsular hemorrhage and organized hematoma; however, the hyperdense lesions were considered consistent with adenomas. Further questioning found estrogen-based oral contraception use for three years, 21 years ago. Two years prior to the current presentation, a subcutaneous levonorgestrel implant (Norplant) was placed in her arm. Because of concern of further bleeding and/or rupture, the patient underwent resection of the hematoma and two of the larger separate lesions.


Case 3 - Figure 1 - Low power of interface between lesion and surrounding parenchyma
Case 3 - Figure 2 - Medium power of lesion. Note the naked arterioles
Case 3 - Figure 3 - High power of lesion. Note the pseudoacinar formation.

Pathology
The specimens consisted of a partial right hepatic lobectomy with an 8 cm encapsulated organized clot, and two oval 1.2 cm diameter specimens labeled as "caudate" and "liver mass". Cut sections of the larger specimen away from the clot showed numerous (more than 20) non-encapsulated, poorly defined pale foci, some subcapsular, in the otherwise unremarkable hepatic parenchyma. The two separately submitted specimens also showed paler parenchyma. None of the lesions were bulging, bile-stained, necrotic or contained a central scar.

Microscopic evaluation of the encapsulated hemorrhage showed organized clot within a thick capsule in which foci of recent and remote hemorrhage were noted. The only liver parenchyma found in multiple sections within this lesion was unremarkable. Examination of lesions within the parenchyma away from this mass and in the two separately submitted specimens showed distinct, but poorly demarcated regions of hepatocytes, some with steatosis, with easily noted "naked arteries" and altered reticulin and iron staining. Several foci of pseudoacinar rosettes were noted. Rare non-caseating, non-necrotizing granulomas were present. Fibrovascular septa were uncommon, but noted within the lesions; none contained bile ducts or cytokeratin positive epithelial cells. a -SMA immunostain highlighted artery walls in the parenchyma and in the fibrovascular septa; CD34 immunohistochemical stain highlighted endothelium of arteries, the vessels within fibrovascular cores and the sinusoids immediately adjacent to the latter. Diffuse CD34 reactivity was not seen. Other immunostains were negative ( a FP, estrogen receptor, progesterone receptor) or noninformative (pCEA).

Diagnosis: Hepatic Adenomatosis

Discussion
Benign neoplasms of the liver are much less common than malignant tumors. Hepatic adenoma is considered the most significant benign tumor due to the known potential for hemorrhage and rupture. Hepatic adenoma, defined as a tumor arising in an otherwise unremarkable liver, is most often noted in women with a long-term use of oral contraceptives; other associations include glycogen storage disease, androgenic/anabolic steroids, diabetes, familial adenomatous polyposis, and others as reviewed.1  Most commonly, hepatic adenoma is a single mass, but there may be 2-3 adenomas. Intratumoral hemorrhage and the risk of rupture mitigate surgical resection when possible. Case reports of hepatocellular carcinoma arising in an hepatic adenoma have established this uncommon, but recognized complication.2  Histologically, adenoma is characterized by benign clonal proliferation of hepatocytes; with sinusoids, unaccompanied arteries, and separate venous structures, but without portal tracts or bile ducts. Epithelioid granulomas and other lesions, including those of "steatohepatitis" may be seen. Liver cell dysplasia may be present, but mitoses are few to none and there may be difficulty in distinguishing adenoma from well-differentiated hepatocellular carcinoma.1 

Hepatic adenomatosis is even more uncommon and is characterized, as the name implies, by multiple adenomas throughout an otherwise unremarkable liver. The exact number of adenomas that classify as adenomatosis in the literature ranges from >3 3 to >10.4  Ribeiro et al suggested the former due to the rarity of >3 adenomas and the proclivity for new lesions to occur in patients with >4 lesions.3  As in our case,6  the number of lesions is far greater than 10; "innumerable" 5 or >50 4 lesions are noted. The differential diagnosis for numerous lesions detected by imaging includes abscess, metastatic tumor, multifocal HCC, multiple FNH, and adenomatosis.

The clinical presentation of adenomatosis is reviewed in recent series;3-5  briefly, abdominal pain is common, as are intratumoral or intraperitoneal hemorrhage. The lack of female gender and oral contraceptive use noted in Flejou et al's review of 13 total cases (8 in the literature, 5 of their own) in 1984 4 was revised by a subsequent review in 2000 by Chiche et al 5 of 38 cases (30 in the literature, 8 of their own). The latter group found 74% of reported patients were women, 46% of whom had taken oral contraceptives. This study also documented diabetes in all cases and a familial association of adenomatosis in four. Our patient had neither diabetes nor an elicited family history of similar liver disease. Our patient had a documented history of oral contraceptive use for 3 years 21years ago, had had 4 subsequent pregnancies, and was managed with levonorgestrel (Norplant) implant for the most recent previous 2 years.

The histologic findings in adenomatosis are similar to those of adenoma, including the presence of granulomas, as noted in our case, in some.7  Interestingly, all cases in Chiche's series had steatosis; our case likewise was characterized by steatosis in the adenomas. Chiche et al 5 and LeBail et al 7 noted the presence of dysplasia in adenomatosis; this finding was present in our case as well. In addition to pseudoacini and nuclear crowding, we considered the iron-free nature of these lesions, albeit subtle, suggestive of dysplasia. Estrogen and progesterone receptors were studied by immunohistochemistry in our case and in 23 lesions from 8 patients in the Mayo Clinic series.3  In our case, none of the lesions were positive for either receptor.In the Mayo experience, 8 were ER positive, 9 were PR positive but neither ER nor PR results were uniform. All positive results were noted to be weak and differing results were shown within lesions from the same liver.3  The role of the contraceptive history, the prior pregnancies and the recent use of the progestational agent, levonorgestrel, in our case is unknown, but intriguing. Kalra et al 8 reported adenomatosis in 2 renal failure patients receiving norethisterone to control uterine bleeding.

Laboratory values typically reflect the results of hemorrhage or mass effect in the liver. Imaging studies may vary due to the variable presence of steatosis and/or hemorrhage within the lesions; one group recommends sonography and MRI for diagnostic evaluation.5  Calcifications have been noted in the tumors.9 

Management of adenomatosis, as can be seen in this case, is challenging. The risk of hemorrhage is high and is greater in the larger lesions;3  this is often the underlying cause of presenting symptoms, and associated with morbidity and mortality.3,5  Therefore, resection of the larger and/or bleeding tumors is recommended by these groups.3,5  The unresectable nature of numerous parenchymal hepatic lesions "poses a monumental dilemma" 10 for management, however. The Mayo Clinic review noted that the lack of routine imaging and long-term follow-up in reported cases precludes determination of prediction of development of new lesions.3  In their series, 4 patients developed new lesions or growth of lesions following surgery; one developed re-bleeding that required emergent treatment. Regression of tumors with tamoxifen in a case of ER-positive lesions has been reported.3 

An algorithm for managing asymptomatic and symptomatic cases has been proposed by the Mayo group; discontinuing oral contraceptives is recommended in all cases, as is close observation with frequent ultrasound and resection of large lesions. The final pathway in all cases of concern is ablative or surgical therapy when possible, and consideration of liver transplantation in cases with post-surgical complications of bleeding, tumor growth or HCC are detected.3  The risk of progression to hepatocellular carcinoma in adenomatosis has been debated,11  but is reported in only 2 cases to date.10,12  In glycogen storage disease 13 and anabolic steroid-related adenomatosis,14,15  HCC is a more common, but still rare, complication. a FP values are recommended while being acknowledged as not ideal.5 

Finally, the use of liver transplantation for treatment of adenomatosis is discussed as a theoretic choice by the Mayo Clinic.3  OLT has been undertaken in 2 patients in Chiche's series of 8,5  and Yoshidome et al report that a total of 6 patients have been managed with liver transplantation.16 

References

  1. MacSween, RN, Burt, AD, Portmann, BC, Ishak, KG, Scheuer, PJ, Anthony, PP (eds): Pathology of the Liver, Churchill Livingstone, London, 2002, p 713-715.
  2. Ferrell, LD. Hepatocellular carcinoma arising in a focus of multilobular adenoma. Am J Surg Pathol 1993: 17:525-529.
  3. Ribeiro A, Burgart LJ, Nagorney DM, et al. Management of liver adenomatosis: results with a conservative surgical approach. Liver transplantation and surgery 1998;4:388-398.
  4. Flejou JF, Barge J, Menu Y, et al. Liver adenomatosis. An entity distinct from liver adenoma?. Gastroenterology 1985;89:1132-8.
  5. Chiche L, Dao T, Salame E, et al. Liver adenomatosis: reappraisal, diagnosis, and surgical management. Ann Surg 2000;231:74-81.
  6. Suarez AA, Brunt EM, Di Bisceglie AM. A 35 year old woman with progesterone implant contraception and multiple liver masses. Semin in Liver Disease 2001; 21: 453-459.
  7. 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;16:982-7.
  8. Kalra PA, Guthrie JA, Dibble JB, et al. Hepatic adenomas induced by norethisterone in patients receiving renal dialysis. British Med J 1987;294:808.
  9. Khan SS, Fink M, King S. Liver adenomatosis presenting as multiple calcified masses. Clin Radiol 1992;45:206-7.
  10. Foster JH, Berman MM. The malignant transformation of liver cell adenomas. Arch Surg 1994;129:712-7.
  11. Propst A, Propst T, Waldenberger P, et al. A case of hepatocellular adenomatosis with a follow-up of 11 years. Am J Gastroenterol 1995;90:1345-6.
  12. Leese T, Farges O, Bismuth H. Liver cell adenomas. A 12-year surgical experience from a specialist hepato-biliary unit. Ann Surg 1988;208:558-64.
  13. Howell RR, Stevenson RE, Ben-Menachem Y, et al. Hepatic adenomata with type 1 glycogen storage disease. JAMA 1976;236:1481-4.
  14. Sale GE, Lerner KG. Multiple tumors after androgen therapy. Arch Pathol Lab Med 1977;101:600-3.
  15. Boyd PR, Mark GJ. Multiple hepatic adenomas and a hepatocellular carcinoma in a man on oral methyl testosterone for eleven years. Cancer 1977;40:1765-70.
  16. Yoshidome H, McMasters KM, Edwards MJ. Management issues regarding hepatic adenomatosis. Am J Surg 1999;65: 1070-1076.