Hepatic Angiomyolipoma: A Clinicopathological Analysis And Molecular Pathological Study

BackgroundPerivascular epithelioid cell tumors are mesenchymal tumors included in the softtissue of WHO in2002,and it is characterized by the epithelioid cells which could speciallyexpress both melanoma cell and muscle cell markers, the epithelioid cells around the bloodvessels was organ-like radial distribution. AML is the most common type of the PEComasfamily, which often occurs on the kidney and liver,and it can also be found in otherlocation, such as heart, lung, mediastinum, roof of the mouth, vagina and so on.It isIshank who first reported HAML in1976, The first case diagnosed in our hospital was1992. WHO classified tumors with perivascular epithelioid cell differentiation as belongingto the family of undetermined differentiation tumors.Since Dalle reported the firstmalignant HAML in2000,more and more patients with malignant HAML werediscovered. HAMLs have a unique pathological characteristics and biological behavior,however, it is still difficult to predict the malignant potential as there is no specificmorphological indicators currently.According to the Department of pathology of ourhospital data on file, from2001January to2012November,244Cases of HAML withoperation resection were collected.Objective⑴The aim of the study was to investigate the relashionship between HAML clinicalfeatures and pathology features which was in the largest single center series, and to providea histopathological basis for the clinical and pathology diagnosis.(2) To investigate the clinicopathologic features and microvesel desity of HAML andanalysis the relationship between them,which could provide basis for tumor development.(3)To Explore the role of genetic instability in HAML development and understandthe the molecular mechanism.Method(1)This study selecte244cases of HAML patients who received hepatectomy and hadcomplete clinical data from January2000to December2012, in Eastern HepatobiliarySurgery Hospital, Shanghai. Gender, age, clinical symptoms and other clinical parametersderived from medical records.According to the WHO standards of HAML,the details ontumor size, composition, and immune staining are from the pathology reports.To studydiffrencec between clinicopathologic features, patients are divided into different groups according above factors.(2)34HAML cases of2012are selected randomly to stain with vascular endothelialmarker CD34,we difine the quantitation of sinusoid-like vessels as microvessel density(MVD), MVD is compared between the tumor and the liver tissue adjacent to the tumorand analyzed with pathological features.To analyze the relationship betweenclinicopathological features and MVD.(3)Select gene INPP4b and IGF1overexpressed in HAML,FN gene underexpressed.In addition, according to the statistics of the pre-clinical data, we find the higher incidenceof HAML in women, so human androgen receptor (AR) gene is detected. The HAMLoccurs often acompanied with tuberous sclerosis syndrome, therefore we select the TSCgene loci. The epithelioid component of HAML is the object of study, to find whetherthere is relationship between HAMLand genomic instability.Result（1）During the past10years the incidence of HAML is increasing, and the numberof female patients is always more than men.Among the244patients, the number of femalepatients with72.13percent is obviously larger than the number of male patients with27.87percent.Age ranges from17to79years old (average44.28±9.70),the age of femalepatients is from30to60years old, the male patients were mainly more than60years old.Most of patients have no obvious clinical symptoms. There are significant differencesin body mass index between men and women,female patients are mainly in the group ofBMI<18.5and18.5~BMI~24with86.4percent and66.3percent, patients with BMI＞24are all male. Blood indicators of HAML patients are normal. The size of the tumor isclosely related to occurrence of intratumoral hemorrhage, the number of HAML withintratumoral hemorrhage increase significantly when the tumor diameter is greater than5cm. Whether the tumor is single or multiple also has a relationship with size of tumor,majority of the tumor is single.（2）MVD is closely related to the size of tumor, the difference is significant betweenthe group of diameter≤5cm and diameter>5cm(t=3.64,P＜0.01). This shows that MVDwas significantly higher when the tumor is larger than5cm. The MVD is significantlyhigher in tumor compared with peritumoral liver tissue (t=13.81,P＜0.01).(3) In the30HAML patients,22（73.3%）patients are microsatellite instability,14（46.7%） patients are loss of heterozygosity.25cases (83.3%) is microsatellite variation.5cases (16.7%) occurred microsatellite stable,21cases (70%) are low frequency microsatellite instability, four cases (13.3%) occurred the middle frequency microsatelliteinstability, no high-frequency microsatellite instability occurs. High-frequencymicrosatellite instability loci is RH78451on FN gene, D2S2635, RH102231and D4S826loci are middle frequency microsatellite instability, all of the rest are the low frequency ofmicrosatellite instability.21cases (70%) is FN variation,13cases (43.3%) is IGF1variation,10cases (33.3%) is INPP4b variation,5cases (16.7%) is TSC1variation,3cases (10%) is AR variation.ConclusionFirst,HAML patients often occurs in middle-aged women, and nearly10years thenumber of female patients is always larger than men during the last decade.It is suggestedthat the occurrence of HAML may be gender-related.There is not microsatellite variationon AR,it might lead to cancer though other way. There is significant difference about BMIbetween different gender, female patients always more than male when BMI is under24,it appears only in men when BMI is above24. Biological behavior is closely related totumor size, therefore, it is necessary to pay attention when the tumor diameter is greaterthan five cm.So far,the best way to the treat HAML is operation resection Second,angiogenesis plays an important role in the the HAMLdevelopment, MVD issignificantly increased when tumor diameter is larger than five cm. Compared with theliver tissue adjacent to the tumor, the tumor MVD was significantly increased.Third, though there are change on expression of IGF1, FN and INPP4b inHAML,there does not appear obvious genomic instability.It is suggested that all genes maynot play a major role in HAML.83.3%of cases occur microsatellite variation (MSI/LOH), and it suggested thatgenetic variation is related to HAML. It is need to strengthen the postoperative follow-upespecially in cases with intermediate frequency microsatellite instability, in order to detectthe early recurrence of lesions. RH78451on FN gene is high-frequency microsatelliteinstability loci, suggesting that this marker may be useful for the diagnosis of HAML.Allof the selected gene from FN, IGF1, INPP4b, TSC1,to AR,and their mutation is decreased,highest rate of gene mutation may be closely associated with tumorigenesis, how thesegene cause tumor needs further study.