hepatic angiomyolipoma ( haml ) is a rare benign mesenchymal liver tumor first described by ishak   in 1976 ; it belongs to a group of perivascular epithelioid cell tumors called pecoma . until date ,
approximately 300 cases have been reported [ 310 ] ; however , its natural history has not been clarified .
the tumor composed of blood vessels , smooth muscle , and adipose cells and due to the variety of predominance of these tissues , its patterns in imaging studies have resulted in a difficulty in diagnosis and misdiagnosis of the tumor as hepatocellular carcinoma ( hcc ) in some cases [ 6 , 11 ] .
therefore , the preoperative correct diagnosis has been difficult ; however , recent advances in imaging diagnosis through a combination of ultrasonography ( us ) , computed tomography ( ct ) , magnetic resonance imaging ( mri ) , and angiography and specific immunohistochemical analysis of this tumor using human melanoma black-45 antigen ( hmb-45 ) staining have resulted in accurate diagnosis and it is reported that the current accurate preoperative diagnosis was made in 25%52% of cases [ 8 , 9 ] .
the majority of these tumors are believed to be clinically benign during a mean follow - up period of 6.8 years ; however , an increasing number of cases and aggressive changes including growth in size , recurrence after surgical resection , metastasis , and invasive growth pattern into the parenchyma and along the vessels have been reported . in this paper
, we have focused on the characteristic features of this tumor shown in imaging studies and by histological analysis , summarized these cases showing aggressive patterns , and discussed management of the patients and indications for surgical treatment .
most cases were found as incidental liver tumors upon health screening or imaging examinations for other diseases .
it usually follows a benign clinical course while some patients visited hospitals with unspecific symptoms of abdominal discomfort , fullness , and other such complaints .
more than half of the renal aml are considered to be associated with tuberous sclerosis which features the loss of heterozygosity at tsc1 ( 9q34 ) and tsc2 ( 16p13 ) , while it is estimated to be 515% in the liver .
thus the etiology of most of these tumors in the liver is unknown ; most cases have no history of liver diseases or specific symptoms , and no changes in laboratory data are seen .
moreover , serum levels of the tumor markers alpha - fetoprotein , protein induced by vitamin k absence or antagonist ii , carcinoembryonic antigen , and carbohydrate antigen 19 - 9 were normal .
since this tumor is composed of various tissues , such as lipomatous , myomatous , and angiomatous tissue in various proportions , the imaging studies show a wide array of features depending on the predominance of each tissue . the tumor showing the predominance of lipomatous tissue is likely to be correctly diagnosed ; however , myomatous and angiomatous variant poses diagnostic problems since it is difficult to be distinguished from malignant tumors .   us images may vary depending on the tissue components affected by the tumor .
high echogenic lesions can be observed because of lipomatous and myomatous tissue , and angiomatous tissue may result in low echoic lesions in tumor images ( figure 1(a ) ) .
if the tumor has predominance of lipomatous tissue , the differential diagnosis with hepatic hemangioma is difficult by sonography alone .
color doppler sonography shows punctiform or filiform vascular distribution pattern if the tumor has predominance of angiomatous tissue .
recent reports showed the diagnostic effectiveness of contrast - enhanced us ( ceus ) [ 10 , 13 ] .
reported that ceus revealed the typical imaging characteristics of haml , that is , an inhomogeneous hyperenhancing pattern in the arterial phase and prolonged enhancement during the portal and kupffer phases .  
plain ct showed homogeneous or heterogeneous low - density lesions , and contrast - enhanced dynamic ct showed highly enhanced lesions in the arterial phase , prolonged enhancement in the portal phase , and , occasionally , defective lesions in the late venous phase depending on the component of the tumor tissue .
a density of less than 20 hounsfield units in plain ct is useful to determine the involvement of lipomatous tissue .
the difficulty is , however , to diagnose the tumor that is myomatous tissue and angiomatous variant .
for this point , modification of size of region of interest in ct was reported to be effective for accurately diagnose renal angiomyolipoma from renal cell carcinoma .
abdominal angiography showed marked tumor staining in the arterial phase , which remained in the portal phase ( figure 1(b ) ) . in some tumors , drainage of the hepatic veins can be observed in the late vascular phase . the first phase of ct during hepatic arteriography showed significant hypervascular lesions in the tumor ( figure 1(c ) ) , and the second phase showed the remains of staining and defective lesions in other areas ( figure 1(d ) ) .
ct during arterial portography showed areas of defective tumors ( figure 1(d ) ) .  
mri is considered to be the best modality to determine the components of the tumor .
hyperintensity on the t2-weighted image and hyper- or hypointensity on the t1-weighted image are observed depending on the component of tumor tissue [ 810 ] .
lipomatous lesions may be determined as hyperintensity on the t1-weighted image ; they may also be determined by the chemical shift imaging technique .
contrast - enhanced dynamic mri using gadolinium or the hepatocyte - specific contrast agent gadolinium - ethoxybenzyl - diethylenetriamine pentaacetic acid showed early enhancement in the arterial phase followed by the prolonged enhancement in the portal phase and defective lesions in the hepatobiliary phase .
macroscopic and magnifying glass view of the tumor showed a soft , white to yellow , and well - circumscribed tumor and range in size from 0.1  cm to greater than 36  cm .
no signs of chronic inflammation or fibrosis were seen in the surrounding liver tissue . because haml comprises lipomatous , myomatous , and angiomatous tissues , microscopic examination showed a mixture of blood vessels , specialized smooth muscle cells , and adipose cells with atypical changes in classic haml ( figures 2(a ) and 2(b ) ) .
this variation of mixture levels in one tumor reflected the differences in imaging studies and made accurate diagnosis difficult .
it is believed that majority of the hamls behave in a benign fashion and even if some cases showed invasive growth pattern into the adjacent hepatic parenchyma , portal triad ( figure 2(c ) ) , and hepatic vein .
tumor cells , especially myomatous cells , were stained positive for hmb-45 in most tumors ( figure 2(d ) ) , for cd34 in the endothelial cells of the blood vessels and for smooth muscle actin in spindle smooth muscle cells .
hmb-45 is an antibody that reacts with an oncofetal premelanosome - associated glycoprotein 2 , found in neoplastic melanocytes .
also cd63 , cd67 , desmin , s100 , and ema may also be positive but not specific .
these cells were negative for cytokeratin 18 , cytokeratin 19 , cam 5.2 , hepatocyte paraffin-1 .
therefore , the identification of lipomatous , myomatous , and angiomatous tissue by a positive reaction to hmb-45 currently provides the only evidence of haml [ 46 , 18 ] and can be useful for defining from the other liver tumors such as hcc after the tumor biopsy and surgical resection followed by these immunohistochemical stainings .
although favorable prognosis can be expected for this tumor since the majority of the tumors are benign , however recently , the number of reports of haml showing malignant potential has increased [ 3 , 5 , 8 , 9 , 12 , 1624 ] which revealed significant growth , recurrence , metastasis , and poor prognosis summarized in table 1 . among those cases ,
deng et al . reported in their case that haml showed atypical angiomatous , epithelioid components with pleomorphic and frequent mitosis in the center of the large tumor displayed p53 immunoreactivity , and mutation at exon 7 for p53 and resulted in vascular invasion , distant metastasis , and fatal outcomes .
these results indicate that the hmb-45 staining , mitotic analysis by mib-1 ( ki67 ) , and p53 reactivity following the fine - needle biopsy of the tumor might be useful for the diagnosis of the tumor and its malignant potential .
since haml usually follows benign clinical courses , the majority of the cases can be conservatively treated .
however , as not a few cases showed aggressive pattern in their courses [ 3 , 5 , 8 , 9 , 12 , 1624 ] and because of the low level of accurate diagnoses by imaging studies , and because of the possibility of dissemination of tumor cells into the peritoneal cavity if a tumor is malignant , tumor biopsy has been avoided , and many hamls have been surgically resected [ 3 , 8 , 9 ] . with the increasing number of resected samples , careful comparisons of imaging studies and pathological findings
therefore , once haml has been diagnosed by imaging studies , a fine - needle biopsy should be performed to make an accurate diagnosis   and to confirm the predominance of the tissue components , the existence of pleomorphic nuclei with high proliferation activity , p53 immunoreactivity , and mutation in p53 if possible . if the aggressive patterns such as vascular invasion , high proliferation of the tumor cells , p53 immunoreactivity were marked , or when the imaging findings and biopsy can not provide a definitive diagnosis , or if the patients have abdominal symptoms , surgical resection should be considered .
haml is considered to be a benign mesenchymal tumor , and nonsurgical treatment with conservative management involving close followup is therefore suggested for patients with asymptomatic tumors smaller than 5  cm , which have been proved to be a typical haml by fine - needle aspiration biopsy . as a fact the renal angiomyolipoma often showed perirenal invasion , involvement of the renal vein , and the inferior vena cava , that are not considered as signs of malignant behavior and the angiomatous
, epithelioid monophasic or pleomorphic variant might be associated with the aggressive behavior and cellular atypia , mitotic activity , and metastatic lesions are the criteria for the malignant renal angiomyolipoma . however , due to the difficulties in diagnosis by imaging studies , many hamls have been surgically resected and have been followed closely for a long period .
in addition , by careful analysis of these recent cases [ 3 , 5 , 8 , 9 , 12 , 1624 ] summarized in table 1 , it was revealed that , although rare , hamls may have malignant potential , which may be distinguished by aggressive patterns characterized by ( 1 ) significant changes in size in short period ; ( 2 ) a change of tumor composition ( cases 1 , 2 , 5 , and 6 ) [ 9 , 16 , 17 , 19 ] ; ( 3 ) metastases to the other organs ( cases 1 , 9 , and 10 ) [ 17 , 22 , 23 ] ; ( 4 ) recurrence after curative surgical resection ( cases 3 , 7 , 9 , 10 , 11 , 12 , and 13 ) [ 3 , 8 , 18 , 20 , 2224 ] ; and ( 5 ) invasive growth into the vessels ( cases 2 , 4 , 8 , 9 , and 10 ) [ 12 , 17 , 2123 ] .  
ohmori et al . reported the first possibly malignant case , which showed that a significant increase in the tumor size resulted in liver dysfunction .
fatal progression was observed in nine cases listed by multiple recurrences [ 3 , 8 , 18 , 20 , 2224 ] and metastases to the liver , peritoneum , retroperitoneal region , gastrohepatic omentum , pancreas , and lung [ 17 , 22 , 23 ] .
the cases reported by chang , rouquie , and us   underwent surgical resection , with a suspicious of aggressive patterns and no recurrence has occurred .
we also reported that portal thrombosis , that is , high - grade portal vein invasion , found in five cases in table 1 ( cases 2 , 8 , 9 , 10 , and 11 ) [ 3 , 17 , 2123 ] may be a clinical marker of the malignant potential and transformation of haml   as it resulted in a significantly aggressive disease and fatal course in 4 cases with multiple recurrences and metastases .
this finding might be able to be detected by imaging studies as similar to hcc .
in addition , pathological findings of atypical epithelioid component with high proliferation activity , p53 immunoreactivity , and mutation in p53 might be predictive markers for malignant transformation . based on these reports , as recommended by previous papers [ 3 , 8 , 9 ] ,
long - term follow - up of haml is necessary after its diagnosis by imaging studies and biopsy specimens and curative surgical treatment .
the majority of hamls behave as a benign tumors and conservative follow - up may be recommended ; however , with increasing number of the reports showing potentially malignant behavior , prompt surgical resection is essential for better prognosis of this tumor .
we have reviewed noninvasive imaging studies and the role of histological diagnosis showing distinctive characteristics of haml to increase the rate of accurate diagnoses .
in addition , we summarized the cases that showed progressive patterns of the tumor and concluded that a careful followup of the tumor even after the final diagnosis is necessary .
we propose that tumor resection is indicated in the following scenarios : ( 1 ) the patients show symptoms ; ( 2 ) the tumor shows an aggressive growth ; ( 3 ) the tumor shows invasive growth into the vessels evidenced by fine - needle biopsy or imaging studies ; ( 4 ) the component of the tumor shows atypical epithelioid pattern , high proliferation activity , and/or p53 immunoreactivity ; and ( 5 ) a definitive diagnosis can not be made by imaging and pathological studies from malignant tumors .
 angiomyolipoma ( aml ) is a benign mesenchymal tumor that is frequently found in the kidney and , rarely , in the liver . 
 the natural history of hepatic aml has not been clarified , and , because of the similar patterns in imaging studies , such as ultrasonography , computed tomography , and magnetic resonance imaging , some of these tumors have been overdiagnosed as hepatocellular carcinoma in the past . with an increase in the number of case reports showing detailed imaging studies and immunohistochemical staining of the tumor with human melanoma black-45 
 , the diagnostic accuracy is also increasing . in this paper , we focused on the role of noninvasive imaging studies and histological diagnosis showing distinctive characteristics of this tumor . 
 in addition , because several reports have described tumor progression in terms of size , recurrence after surgical resection , metastasis to other organs , and portal thrombosis , we summarized these cases for the management and discussed the indications for the surgical treatment of this tumor . 
1. Introduction
2. Natural History and Laboratory Findings
3. Imaging Studies
4. Pathological Findings
5. Patient Management
6. Discussion
7. Conclusion