Hepatic adenomatosis.
Abstract: Hepatic adenomatosis was first described in 1985 by Flejou et al as multiple adenomas, arbitrarily more than 10, in an otherwise normal liver parenchyma. Several authors have suggested that it is a distinct entity from hepatic adenoma, which is predominantly seen in young women taking oral contraceptives. Although considered a benign disease, it can be associated with potentially fatal complications such as malignant transformation and intraperitoneal hemorrhage due to rupture. Although its etiology and natural history have not been fully elucidated, germline mutation of hepatocyte nuclear factor 1a, which is associated with maturity-onset diabetes of the young type 3, has recently been implicated in a subset of cases. Currently, there is no consensus on patient management. However, surgical removal of large lesions may significantly improve symptoms and reduce the risk of complications. Genetic counseling may now play an important role in case management.
Subject: Diabetes (Development and progression)
Contraceptives industry
Oral contraceptives
Authors: Greaves, Wesley O.C.
Bhattacharya, Baishali
Pub Date: 12/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: Dec, 2008 Source Volume: 132 Source Issue: 12
Product: Product Code: 2834127 Oral Contraceptives NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2834 Pharmaceutical preparations; 3069 Fabricated rubber products, not elsewhere classified
Accession Number: 230246897
Full Text: Hepatic adenoma (HA) is a benign neoplasm of the liver, seen predominantly in young women taking oral contraceptives in the third to fifth decades of life. Although it is typically a solitary lesion, (1,2) it can occasionally present as 2 to 3 nodules.

Hepatic adenomatosis was first described by Flejou et al in 1985 (1) as multiple adenomas in an otherwise normal liver parenchyma. At that time, the minimum number of adenomas required for diagnosis was arbitrarily designated as 10. However, given the increased clinical evidence related to the disease and the fact that patients with simple HAs rarely have more than 4 lesions, other authors have used 4 or 5 nodules as the cutoff. (3,4) Although its pathogenesis and natural history remain uncertain, hepatic adenomatosis is now considered to be a distinct clinicopathologic entity from HA.


Solitary HAs typically occur in the setting of hepatocellular stimulation. This is usually in the form of exogenous sex hormones with oral contraceptives (5) or anabolic androgenic steroids. (6) They can also arise in association with states of abnormal carbohydrate metabolism, such as familial diabetes mellitus, glycogen storage disease, and galactosemia. (7) They usually regress on cessation of the stimulus, and malignant transformation is rare. (7)

Hepatic adenomatosis, on the other hand, shows less frequent association with exogenous steroids. By definition, patients should not have a history of glycogen storage disease. In the original series of 13 cases reported by Flejou et al, (1) there was a low female-male ratio (8:5), as opposed to the overt female predominance in HA. However, subsequent series have demonstrated a clear female predominance. (8-10) In a case series report and review of the literature, Chiche et al (10) noted the association of oral contraceptive use in 46% of female patients with hepatic adenomatosis. Furthermore, adenomas regressed in 1 patient after discontinuation of oral contraceptive use. This suggested a possible role of oral contraceptives, at least in the evolution of some of these tumors. This finding was also contrary to the original report by Flejou et al. The exact role of exogenous steroids in the pathogenesis of hepatic adenomatosis remains to be clarified.

Hepatic adenomatosis is usually diagnosed in the fourth decade of life, with a mean age of 32 years. (10) However, it has been reported in teenagers as young as 13 years (10-12) and rarely in patients older than 60 years. (1,8)

Patients may be completely asymptomatic, and the diagnosis may only be made as an incidental finding by imaging studies. (13) Most patients, however, present because of complications of adenomas, such as chronic or acute abdominal pain as a result of intratumoral hemorrhage or necrosis, and hepatomegaly. A potentially devastating complication is intraperitoneal bleeding with hypovolemic shock. Liver enzymes, especially alkaline phosphatase and [gamma]-glutamyl transpeptidase, are often elevated owing to the numerous space-occupying lesions in the liver. However, they may also be normal. (8,10)

The imaging modalities commonly used in the diagnostic workup include ultrasound, computed tomography, and magnetic resonance imaging techniques. As in solitary hepatocellular adenomas, the individual lesions can have a wide range of radiologic appearances depending on the extent of intratumoral fat, necrosis, and hemorrhage. They typically show an arterial-type hypervascularized attenuation pattern on computed tomography and magnetic resonance imaging. (8,10) It is important to note, however, that other entities such as focal nodular hyperplasia (FNH) and hepatocellular carcinoma (HCC) may share similar features. (8) Notwithstanding the advances in modern imaging techniques, the definitive diagnosis is usually deferred to histologic examination. (8,10) Because percutaneous or transjugular liver biopsies may yield limited amounts of tissue in which it may be difficult to differentiate adenomas from low-grade HCC, a surgical resection specimen is usually preferred. (10)


Gross Features

On gross examination, the liver demonstrates numerous circumscribed soft nodules (typically unencapsulated) of varying sizes, ranging from a few millimeters to more than 10 cm in diameter. (1,10) The nonlesional liver is typically noncirrhotic (Figure 1). This is an important distinguishing feature because HCC usually arises in a setting of cirrhosis. The cut surface of the nodules may show varying shades of tan to yellow according to the degree of fat content. There may also be intratumoral hemorrhage and focal calcification.

Microscopic Features

Microscopically, the nodules consist of sheets of benign-appearing hepatocytes with varying degrees of steatosis and interspersed ectatic blood vessels (so-called floating vessels) in the background of a noncirrhotic liver (Figure 2, A and B). Portal tracts, including biliary structures, are typically absent within the lesions. However, it is important to note that bile ducts may become entrapped between adjacent expanding adenomas, and these should not be confused with bile ducts within the nodule. Reticulin stain highlights normal hepatocyte plate thickness of 1 to 2 cells (Figure 2, C).

Pathogenesis and Cytogenetics

Although the etiology of hepatic adenomatosis has not been entirely elucidated, some recent progress has been made in the understanding of the pathogenesis of this disease. Several authors have suggested an underlying abnormality of the hepatic circulation as a possible etiologic factor in benign nodular hepatocellular lesions including HAs, FNH, and nodular regenerative hyperplasia. (14-17) Kondo (14) suggested that although abnormal hepatic circulation alone may not be a sufficient etiologic explanation, the presence of various nontypical intermediate and transitional lesions (such as FNH and nodular regenerative hyperplasia or FNH and HA), which he called hepatocellular adenoma-like hyperplastic nodules, might be better explained by a single etiologic factor. He hypothesized that an increase or decrease in portal and/or arterial blood flow would cause hepatocyte hyperplasia and subsequent nodule formation. (14) However, further verification and validation of this hypothesis is needed.

Contrary to simple HA, withdrawal of exogenous steroids does not appear to result in involution or growth retardation of tumors in hepatic adenomatosis. (4) Although estrogen receptors have been identified in normal hepatocytes and simple adenomas, the exact role of sex hormones in the tumorigenesis and evolution of these lesions is still unknown. Ribeiro et al (4) performed immunohistochemical analysis of estrogen and progesterone receptors in 8 cases of hepatic adenomatosis. Interestingly, 6 of the 8 cases had estrogen receptor- and progesterone receptor-positive as well as estrogen receptor- and progesterone receptor-negative adenomas within the same liver. However, antiestrogenic therapy with tamoxifen or surgical oophorectomy did not prove to be effective in these patients. (4)

Other investigators noted a familial pattern of occurrence. (10,13,18,19) Chiche et al (10) reported 4 members of a family in 2 consecutive generations with hepatic adenomatosis. Interestingly, all affected members had diabetes (3 with insulin-dependent and 1 with non-insulin-dependent diabetes), suggesting an association between the 2 entities. More recently, Bacq et al (19) and Reznik et al (13) demonstrated the presence of germline mutations of hepatocyte nuclear factor (HNF1A) in members of 4 families with maturity-onset diabetes of the young type 3 and familial adenomatosis. HNF1A is a homeodomain containing transcription factor involved in hepatocyte differentiation and liver-specific expression of several genes including albumin, [beta]-fibrinogen, and [[alpha].sub.1]-antitrypsin. (20,21) Recently, Bluteau et al (21) demonstrated the biallelic inactivation of its encoding gene, HNF1A, located on chromosome 12q in HAs, thus characterizing it as a tumor suppressor gene. Germline mutations in HNF1A are associated with maturity-onset diabetes of the young type 3. (22) In the familial case reports by Bacq et al and Reznik et al, there was incomplete penetrance of the liver adenomatosis phenotype ranging from completely asymptomatic disease to the dramatic presentation of one 16-year-old patient with fatal hemorrhagic shock from intraperitoneal bleed. (13) In 3 of the families, there was a predominance of females with hepatic adenomatosis, whereas only males were affected in the fourth. Age at diagnosis ranged from 14 to 51 years and none of the cases developed malignant transformation.

Interestingly, Zucman-Rossi et al (23) demonstrated a predilection of malignant transformation in hepatocellular adenomas with [beta]-catenin mutations as opposed to those with HNF1A mutations, which do not seem to progress to HCC. These studies clearly demonstrate the genetic origin of a subset of hepatic adenomatosis and its link with diabetes.


The histopathologic differential diagnosis of hepatic adenomatosis mainly includes multifocal HCC, multiple FNH, nodular regenerative hyperplasia, and normal liver (particularly on needle biopsy specimens). Other rare lesions include epithelioid hemangioendothelioma and angiomyolipoma. In patients with cirrhosis, HCC would be of great concern. It is therefore critical to sample both lesional and nonlesional liver on biopsy specimens. Less frequently, HCC can also arise in a noncirrhotic liver. Features such as pleomorphic hepatocytes with increased nuclear-cytoplasmic ratio (Figure 3, A), prominent nucleoli, increased mitotic rate, increased hepatocyte plate thickness of more than 3 cells (Figure 3, B), and vascular invasion can be helpful in making the diagnosis.

Focal nodular hyperplasia occurs frequently in females of reproductive age. The lesion is classically characterized by a nodular growth pattern of hepatocytes surrounded by fibrous septa emanating from a central scar and the presence of malformed vessels and bile ductular proliferation. (2,24) Traditionally, these lesions have been considered to be hyperplastic rather than neoplastic and are usually conservatively managed with a wait-and-see approach. (7,24) They can also present as multiple lesions, particularly in the multiple FNH syndrome, which is defined as the presence of at least 2 FNH lesions and one or more of the following: liver hemangioma or arterial anomalies, central nervous system vascular malformation, meningioma, and astrocytoma. (7,25) In a report of 168 patients (305 lesions), Nguyen et al (24) proposed the classification of FNH into 2 distinct morphologic categories, namely classical and nonclassical FNH. Nonclassical lesions were characterized by the lack of 1 of the 2 classical features (namely nodular architecture or malformed vessels), with the presence of bile duct proliferation. Lesions in this category included the telangiectatic form, a mixed hyperplastic and adenomatous form (showing intermediate morphology between FNH and adenoma), and a subtype with cytologic atypia.




Clinical and morphologic overlap may occur between the nonclassical forms of FNH (particularly telangiectatic and mixed hyperplastic adenomatous types) and HAs, leading to some degree of diagnostic difficulty. For example, telangiectatic FNH lesions typically do not contain a macroscopic central scar and usually lack a nodular architecture at the microscopic level. (24) The presence of bile duct proliferation, highlighted by immunohistochemical staining for cytokeratin 7 or cytokeratin 19, was found to be the most helpful feature to distinguish between nonclassical FNH lesions and HAs. (24) Interestingly, Paradis et al (26,27) later demonstrated that a subset of telangiectatic FNH was monoclonal and had a low angiopoietin 1 to angiopoietin 2 (ANGPT1 and ANGPT2) mRNA ratio similar to HA. This was in contrast to typical FNH, which was polyclonal and had an increased ANGPT1 / ANGPT2 ratio, suggesting that telangiectatic FNH is more likely a neoplastic lesion and a variant of HA rather than a subtype of FNH.

Nodular regenerative hyperplasia is often seen as an autopsy finding. It usually arises in response to portal vein obstruction, which may be secondary to a myriad of underlying disorders such as myeloproliferative or lymphoproliferative disease and immunologic disorders. (7,14) Histologically, there are diffuse hyperplastic nodules of varying sizes with central portal tracts and no or few intervening fibrous septa. Other distinguishing features include internodular hepatocyte atrophy with reticulin collapse and sinusoidal dilatation.

On needle biopsy for a lesion, it is not uncommon to sample normal liver instead. This can be characterized by the normal acinar arrangement of hepatocytes with portal tracts and central veins.

Epithelioid hemangioendothelioma is a tumor of variable malignant potential with an unknown overall incidence. It is usually composed of epithelioid cells with intracytoplasmic lumina surrounded by myxoid stroma. Immunostaining with endothelial markers such as CD31, CD34, and factor VIII is helpful. Angiomyolipoma of the liver may rarely present as multiple lesions and may also be sharply demarcated but not encapsulated. The cut surface may appear yellow depending on the degree of fat content. By microscopy, the lesions consist of varying proportions of smooth muscle, vascular, and mature adipocytic components. The smooth muscle cells express HMB45, muscle-specific actin, and smooth muscle actin.


Hepatic adenomatosis is considered a benign entity. However, patients may rarely develop potentially fatal complications including hypovolemic shock due to rupture with intraperitoneal hemorrhage. (4,8,10,13) The overall rate of bleeding can be as high as 62.5%. (1,3,4) However, there are only 2 reported deaths as a result of intraperitoneal hemorrhage in the literature. (13,28)

There have been rare reports of progression to HCC. (1,29) Malignant transformation is estimated to occur in less than 10% of cases (3,18) and may be detected by elevated serum levels of tumor markers such as [alpha]-fetoprotein or rapid increase in tumor size on computed tomography or magnetic resonance imaging. (8) There are no described factors that increase the propensity of malignant progression. In one reported case, HCC developed 12 years after liver transplantation for multiple adenomas. (8)

Currently, there are no data on the optimal management of hepatocellular adenomatosis. Treatment options are therefore dictated by the likelihood of the development of complications. Although there have been conflicting reports on the role of sex hormones in the evolution of hepatic adenomatosis, (4,10) it is prudent to withdraw exogenous steroids as they have been associated with higher rates of bleeding. (3,10) Antiestrogenic therapy in the form of tamoxifen or surgical oophorectomy has been shown to be ineffective. (4)

Surgical removal of large or complicated (ie, rupture or hemorrhage) nodules in symptomatic patients has been shown to significantly improve symptoms. (3,4,10) Bleeding seems to be directly related to tumor size. (3,4,30) Ribeiro et al (4) found a decreased risk of rebleeding in patients in whom large adenomas (5 cm or more) were removed and therefore recommended the empirical removal of lesions greater than 5 cm even in patients who are asymptomatic as a preventative measure. Close follow-up in asymptomatic patients with at least yearly imaging of the liver and measurement of serum [alpha]-fetoprotein is crucial to monitor for the potential complications of hemorrhage and malignant transformation. (4)

Rarely, orthotopic liver transplantation may be required to treat severe disease with progressive liver failure or malignancy. (29)

Patients with maturity-onset diabetes of the young type 3 and their relatives should be screened for HNF1A mutation and silent hepatic adenomatosis. Likewise, genetic counseling should be offered to the relatives of patients with hepatic adenomatosis to search for germline HNF1A mutation. (13,23)


Hepatic adenomatosis is an uncommon disease characterized by multiple HAs in the background of a normal liver. It may occur sporadically, predominantly in women in the third and fourth decades of life. The familial form involves the germline mutation of HNF1A and is associated with maturity-onset diabetes of the young type 3. Although most patients have a benign clinical course, rare complications include intraperitoneal hemorrhage and progression to HCC. In light of this, careful surveillance of patients with imaging studies and serum [alpha]-fetoprotein is recommended. Genetic counseling to search for germline HNF1A mutation should be offered to all patients diagnosed with hepatic adenomatosis. The roles of exogenous steroids or an underlying abnormality in the hepatic circulation remain to be elucidated.


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Wesley O. C. Greaves, MD; Baishali Bhattacharya, MD

Accepted for publication April 9, 2008.

From the Department of Pathology, Rhode Island Hospital and Brown University, Providence.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Wesley O. C. Greaves, MD, Department of Pathology, APC 12, Rhode Island Hospital, Providence, RI 02903 (e-mail: wgreaves@ lifespan.org).
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