Hepatic Angiomyolipoma Open Access

Hepatic angiomyolipoma (AML) is a rare, benign, hepatic mesenchymal neoplasm, first described in 1976 by Ishak.1,2 To date, approximately 200 hepatic AMLs have been reported.3 The tumor consists of 3 components: smooth muscle cells (SMCs), adipose tissue, and vessels. These components can vary greatly within the lesion. This heterogeneity makes the preoperative diagnosis by imaging, needle biopsy, and other techniques difficult.

It is possible to misdiagnose hepatic AML as a number of entities, both benign and malignant. Commonly confused entities include lipoma, hepatocellular adenoma and carcinoma, sarcoma, or other metastatic neoplasms. Hepatic AML has been reported in patients from many ethnicities, including whites, Asians (Chinese and Japanese), and blacks.1,4,5 Hepatic AML has not been proven, at this time, to be associated with any virus or genetic abnormality. When tested or reported, none or only a very small proportion (8%) of the patients from studied cases were positive for hepatitis viral markers or had abnormal liver function tests.6,7 Uncommonly, there have been lesions in patients with tuberous sclerosis reported (6%–10%); however, that association is far more common in renal AML (20%–40%).1,8,9 Most patients with hepatic AML do not have tuberous sclerosis. There is no proven association between hepatic and renal AML.1,2 Although hepatic AML can be confused with many entities, the diagnosis can be made reliably and definitively on histologic examination along with immunohistochemical analysis, specifically with homatropine methylbromide–45 (HMB-45).

Although the exact etiology of hepatic AML has yet to be definitively proven, a number of proposals have been made. One of the major components of hepatic AML is the SMC; a defining and consistent feature of hepatic AML is SMC positivity for the immunohistochemical stain HMB-45. HMB-45 is an antibody that reacts with an oncofetal premelanosome–associated glycoprotein 2, found in neoplastic (but not normal) melanocytes, as well as other cells bearing those structures.1,10 ,Perivascular epithelioid cell (PEC) is a term proposed to describe the SMCs found in hepatic AML, which are always positive for HMB-45, and has been postulated as the underlying neoplastic mesenchymal cell.1,9–11 These cells share some common features with melanocytes, neuroendocrine, and muscle cells.11 PECs are also found in pulmonary lymphangiomyomatosis and clear cell (“sugar”) tumors of the lung. PECs are HMB-45 positive in these lesions as well. Therefore, it has been proposed that these tumors and hepatic AMLs belong to a family referred to as PEComas, but that theory has not yet been solidified.1,5–7,9,11,12 A possible origin from neural crest cells has been postulated as well.9 

Hepatic AML can be found in both males and females, with a female preponderance, and is found in adult patients ranging from 26 to 86 years of age.1,2,4–9,11–13 Most patients with hepatic AML are asymptomatic, and the lesions are found incidentally on imaging for other medical issues or at autopsies. Large lesions may cause symptoms related to mass effect.1,7 Other reported symptoms include abdominal discomfort and mild fever.1,4,11 Acute tumor rupture, although uncommon, has been reported.1,6 

Angiomyolipoma occurs most commonly in the kidneys. Hepatic AMLs represent the second most common site of involvement. Rare occurrences at many other sites have been reported, including the uterus, retroperitoneum, mediastinum, renal capsule, the nasopharyngeal cavity, the buccal mucosa, the hard palate, penis, vagina, fallopian tube, abdominal wall, skin, stomach, and spinal cord.5,11,12 Invasive growth has been reported as exceedingly rare, and these lesions do not show malignant potential and most do not metastasize. To date, 2 metastatic lesions have been reported—to the omentum and lung.14,15 

Multiple modalities have been used to aid in the diagnosis of hepatic AML. Laboratory tests, such as viral markers for hepatitis, α-fetoprotein, carcinoembryonic antigen, and liver function, when reported, have been negative or have not proven to be specific or helpful in reaching a diagnosis of hepatic AML.6,7 Several imaging modalities have proven to be helpful, but a definitive diagnosis cannot be made on these tests alone. On ultrasound examination, most lesions show a heterogeneous high echo, but on ultrasound alone, this lesion may by indistinguishable from hemangioma.8 Color Doppler sonography shows a punctiform or filiform vascular distribution pattern. Contrast-enhanced spiral computed tomography shows marked enhancement of the soft tissue components in the arterial phase and enhancement in the portal venous phase. Magnetic resonance imaging is the most specific imaging entity for the detection of lipomatous components; however, because hepatic AML can have such variation in the amount of adipose tissue present, detection varies based on the percentage of the lesion that is composed of adipose tissue. Magnetic resonance imaging findings include the presence of hypointensity or hyperintensity of T1-weighted images and hyperintensity on T2-weighted images.2,4,8,16 Angiography may demonstrate hypervascularity.6 Although these tools may aid in the diagnosis, the definitive diagnostic tool remains the histologic examination of the surgically resected lesion coupled with immunohistochemical stains.

Hepatic AML can range in size from 0.1 cm to greater than 36 cm.1–9,11,12 On gross examination, the lesion is usually solitary, although a few patients had multiple lesions. Hepatic AMLs are well circumscribed but not encapsulated. Some studies report several lesions that are partially encapsulated.1,5 The cut surface is described as soft, with color descriptions ranging from yellow to tan or gray, and areas of hemorrhage and necrosis can be present. The surrounding liver parenchyma is not cirrhotic or fibrotic.

Hepatic AML has a wide spectrum of morphologic and histologic appearances. Hepatic AML has 3 main histologic components, which may be present in varying proportions within each lesion. The 3 main components are SMCs, adipose tissue, and blood vessels. Another commonly present component, although not necessary for diagnosis, is hematopoietic tissue. It should be emphasized that the SMCs are the only specific and diagnostic component of hepatic AML and are characteristically positive for HMB-45 and Melan-A. Hepatic AMLs are classified based on the line of differentiation and the predominant tissue component. The most common type of hepatic AML is the mixed lipomatous type, where the tumor is composed of at least 70% adipose tissue. The myomatous type has as much as 10% adipose tissue; there are also lipomatous and angiomatous types composed predominately of adipose and vascular structures, respectively.1 Each of these types has a heterogeneous mix of the 3 types of cells, the most important being the SMCs. The SMCs can have varying morphology, ranging from epithelioid to spindled, with an intermediate type falling between the former two designations in the morphologic spectrum. The tumors that are composed predominately of myomatous elements (myomatous subtype) are the type most likely to cause diagnostic confusion. On preoperative imaging, the lack of adipose tissue often presents a diagnostic dilemma.8,16,17 

The most important cells for diagnosis, the SMCs, are arranged in sheets and are most commonly described as epithelioid. The SMCs are large, polygonal or spheroid cells, with clear cytoplasm (Figure 1, A). At the periphery of the cells, the cytoplasm is clear, leaving eosinophilic granular cytoplasm at the center of the cell. These cells can be vacuolated and are often described as having a “spider web” morphology. The nuclei are round to oval and normochromatic, with a single nucleoli. Moderate pleomorphism can be present, but mitoses are usually rare. Some epithelioid SMCs can have eosinophilic cytoplasm. Spindled SMCs are uncommon. The intermediate variant of the SMCs, which can be confused with leiomyoma cells, are plump and pale and have a peripheral rim of eosinophilic cytoplasm. They have round to oval, pale nuclei, and lack features typical of leiomyoma (deeply eosinophilic cytoplasm and elongated, dark nuclei).1 There are variants of the SMCs described as well. They can be clear, oncocytic, or pleomorphic. The oncocytic variant is typically devoid of adipose tissue, and the cells are considered degenerated. The pleomorphic variant can have bizarre or multinucleated cells, but the nuclear-cytoplasmic ratio is preserved and there are no mitoses. The adipocytes are mature, but occasional lipoblast-like cells have been described.1 These cells have been shown to contain fat and glycogen, and are D-PAS–positive eosinophilic hyaline globules. In one series, all cases showed occasional intranuclear inclusions with intranuclear cytoplasmic inclusions.1 Brown pigment composed of melanocytic pigment or hemosiderin can be present. Mature adipose tissue comprises the second component. The third component of hepatic AML, the vascular, consists of abnormal vessels showing tortuosity and thick walls. Hematopoietic elements, when present, are normal findings, but can be completely absent, and are not present in renal AML.13 The presence of hematopoietic elements is most likely related to the liver's hematopoietic function during fetal life and the continued potential it retains. Necrosis and hemorrhage are not uncommon findings.

In addition to the many morphologies of the cellular components, hepatic AML can also assume various patterns, including trabecular, pelioid, or inflammatory.1 The trabecular pattern shows epithelioid SMCs in trabeculae with intervening sinusoids lined by endothelial cells, but lacks a reticulin network. Increased hematopoietic elements and a decrease in adipose tissue have been described within this pattern. The pelioid pattern has dilated spaces lacking an endothelial lining filled with pale, eosinophilic serous fluid. These pelioid spaces are often associated with hemorrhage. The inflammatory pattern has prominent, dense lymphoid aggregates. The lesions are described as having pushing borders on the surrounding nonneoplastic liver parenchyma. Recently, tumors with invasive features have been described. There is no current, uniform definition for invasive features or malignant hepatic AML. In one study of 39 hepatic AML patients,5 24 tumors showed invasive features. Invasive features described included tumor cells, some atypical, replacing hepatocytes and extension into portal areas or infiltration around vessels; however, none of these 24 patients showed metastatic lesions in follow-up. In another study of 49 patients with hepatic AML,7 3 tumors showed invasive features, with no recurrences or metastases in follow-up. In one case14 of reported malignant hepatic AML with omental metastases, there was vascular and lymphatic invasion. Another author15 reported a case of recurrence and lung metastases. In renal AML, invasion into the renal vein, inferior vena cava, and regional lymph node involvement are not considered malignant features, and only 5 cases of malignant renal AML have been reported, to our knowledge.14 Malignant features in renal AML include cellular atypia and multicentricity.7 Malignant features in hepatic AML are poorly defined; suggested features include increased mitoses, atypia, invasive features, and recurrences. Metastases are a definite feature.5–7,14,15 However, most lesions are described as noninvasive.

Immunohistochemical studies are essential to the diagnosis of hepatic AML and will readily differentiate it from other hepatic tumors. In immunohistochemical study, the SMCs (the tumor cells) are characteristically strongly positive for HMB-45 (Figure 1, B) and Melan-A, but negative for cytokeratin (CAM 5.2 and AE1/AE3) (Figure 1, C) and HepPar-1. The SMCs are also negative for S100 (Figure 1, D), whereas mature adipose cells are mostly positive for S100. The angiomatous elements characteristically stain positive for CD34 and factor VIII. Electron microscopy examination shows cytoplasmic bound granules consistent with premelanosomes as well as intracytoplasmic filaments that aggregate to produce dense bodies.1,2,5 The presence of adipose tissue can be very helpful in differentiating this lesion from malignant entities. Diagnosis on needle biopsy is again difficult because of the heterogeneity of the lesion, because the lipomatous component is variable, and because the lipomatous region may or may not be sampled. Flow cytometric studies performed on specimens demonstrated diploid DNA ploidy.2 There have been few molecular studies. Although clonality has been demonstrated, a specific molecular defect has not been discovered. In tuberous sclerosis–associated renal AMLs, loss of heterozygosity and microsatellite instability play a role in the pathogenesis. In a study of 40 patients with hepatic AMLs, neither loss of heterozygosity nor microsatellite instability were demonstrated.7 

There are many entities in the differential diagnosis of hepatic AML, and the distinction can become problematic as the adipose component decreases. Some of the lesions considered in the differential diagnosis include hepatocellular carcinoma, hepatic adenoma, leiomyoma, hepatoblastoma (especially when hematopoietic elements are present), melanoma, angiosarcoma, and gastrointestinal stromal tumors. In one series, 50% of tumors were originally misdiagnosed as carcinomas or sarcomas.1 Histologically, hepatocellular carcinoma is especially difficult to discern from hepatic AML when the trabecular growth pattern is present in myomatous-dominant tumors. This distinction is difficult on imaging as well as histologic diagnosis. Immunostaining with HMB-45 remains the most useful diagnostic tool because there are no other primary hepatic lesions that are positive for HMB-45. In addition, the SMCs do not express S100 as metastatic melanoma cells do.1 

If the diagnosis of hepatic AML has been comfortably made, conservative treatment may be recommended. The tumor can be followed with imaging modalities when clinicians are comfortable with and alert to this entity. Surgical resection may be suggested when a malignant lesion cannot be ruled out with imaging techniques, fine needle aspiration, or needle biopsy, when the patient is having symptoms, or when the risk of rupture is a possibility because the lesion has increased in size significantly with continued observation.4 Overall, hepatic AML is a benign lesion with a favorable prognosis, with 4 recurrences and 1 omental and 1 lung metastasis reported in the literature to date.14,15 

Hepatic AML is a rare, benign liver tumor composed of varying amounts of SMCs, adipose tissue, and vessels. The SMC component is the most specific to the diagnosis and characteristically stains with HMB-45 and Melan-A but not with S100. This staining pattern differentiates this lesion from other malignant and benign liver lesions that it can resemble histologically and on imaging. Hepatic AML can be treated with complete surgical resection and shows no propensity for metastases or malignant potential.