Molecular analysis of clonality of sporadic angiomyolipoma

Saxena, Anurag; Alport, Edward C.; Custead, Savita; Skinnider, Leo F.

doi:10.1002/(sici)1096-9896(199909)189:1<79::aid-path366>3.0.co;2-c

Cited by 35 publications

(20 citation statements)

References 27 publications

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“…Renal AML have already been proven to be monoclonal neoplasms. 3,4 Loss of heterozygosity in the region of the tuberous sclerosis genes TSC1 (9q24) or TSC2 (16p13.3) has been shown in AML and several other "hamartomas" of TSC patients. 5,6 Malignant AML of the kidney have been described in exceptional cases.…”

supporting

confidence: 53%

“…The strong evidence for monoclonality not only in the monophasic tumors but also in one case with polyphasic cellularity supports the hypothesis of clonal proliferation of an uncommitted stem cell, able to evolve towards different cell types already suspected in renal AML. 3,4 One of our cases revealed identical X-chromosomal inactivation patterns in each of 5 separate intrahepatic nodules. This finding points to an intrahepatic spread probably representing metastasis of a single primary tumor.…”

Section: Resultsmentioning

confidence: 99%

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Common and epithelioid variants of hepatic angiomyolipoma exhibit clonal growth and share a distinctive immunophenotype

Flemming¹,

Lehmann²,

Becker³

et al. 2000

Hepatology

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In contrast to the common renal angiomyolipoma (AML), 1 AML of the liver is very rare and has been recognized only since 1976. 2 Liver AML are usually unifocal tumors without the background of tuberous sclerosis (TSC). Until recently, AML was generally thought to be a hamartoma, composed of several tissue components. Renal AML have already been proven to be monoclonal neoplasms. 3,4 Loss of heterozygosity in the region of the tuberous sclerosis genes TSC1 (9q24) or TSC2 (16p13.3) has been shown in AML and several other "hamartomas" of TSC patients. 5,6 Malignant AML of the kidney have been described in exceptional cases. 7,8 AML of the liver displays a considerable morphologic heterogeneity. The epithelioid variant closely resembles liver cell adenomas. To find out whether a different phenotype reflects a different nature of a hamartoma or a true neoplasm, we analyzed clonality within a series of hepatic AML in female patients using the human androgen receptor (HUMARA) gene. 9 Furthermore, a broad panel of monoclonal antibodies was applied to assess heterogeneity and find useful markers in diagnostically puzzling cases, particularly the recently described monophasic epithelioid variant. MATERIALS AND METHODSAML samples were derived from archival tissue from the Institute of Pathology, Hannover Medical School. Tumor tissue had been fixed in neutral buffered formalin and embedded in paraffin. The material available ranged from 1 (needle biopsies) to 20 paraffin blocks. Slides only were maintained from 2 patients. A series of 17 antibodies was applied for immunohistochemical analysis on serial sections of 5 m thickness using the alkaline-phosphatase-anti-alkaline-phosphatase method after microwave antigen retrieval as described. 10 The extent of staining was graded on a scale from faint to moderate to strong.DNA Extraction. Formalin-fixed, paraffin-embedded tissues were serially sectioned at 15 m and mounted on glass slides. Tumor and normal liver were selectively sampled by microdissection. DNA was extracted by overnight digestion at 56°C with proteinase K followed by extensive organic extraction and ethanol precipitation. Approximately 100 ng genomic DNA was incubated overnight with 10 units HpaII according to the manufacturer's instructions (MBI Fermentas, St. Leon-Rot, Germany). As a negative control, DNA was incubated with restriction buffer only. After digestion samples were incubated for 15 minutes at 65°C to inactivate the restriction enzyme.Assessment of Clonality. Clonality at the HUMARA locus was assessed by polymerase chain reaction (PCR) essentially as described. 11 One tenth of the restriction digest was amplified using 2.5 pmol each of the primers AR-C sense and AR-C antisense in a total volume of 25 L for 40 cycles in the presence of 3 mmol/L MgCl 2 , 200 mmol/L dNTP, and 0.25 units RedTaq-Polymerase (Sigma, Deisenhofen, Germany). The sense primer was fluorescence-labeled (IRD-700; MWG BioTech, Ebersberg, Germany) and the PCR products were separated and detected in a 6% denaturing polyacrylamide ge...

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supporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Common and epithelioid variants of hepatic angiomyolipoma exhibit clonal growth and share a distinctive immunophenotype

Flemming¹,

Lehmann²,

Becker³

et al. 2000

Hepatology

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“…AMLs have been regarded as hamartomas; however, clonality assays performed in a recent study of renal AMLs has shown the myoid and the vascular components to be monoclonal, implying a neoplastic proliferation (15,16). The adipose tissue component of the AML was found to be polyclonal and the authors speculate that the fat is metaplastic or a reactive change in the neoplasm.…”

Section: Discussionmentioning

confidence: 97%

Multiple Angiomyolipomata of the Liver: A Case Report

et al. 2002

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Angiomyolipoma (AML) is a rare benign tumor that occurs most commonly in the kidney. Occasionally it may be found in the liver. Lesions in the liver are usually solitary. Multiple AMLs are extremely rare and are typically seen in patients with tuberous sclerosis. We now report an unusual case of a 46-year-old woman with multiple hepatic AMLs. There were more than 15 lesions distributed predominantly in the right hepatic lobe. The tumors ranged from 0.2 to 6 cm in size and consisted of a variable admixture of proliferating blood vessels, adipose tissue, and smooth muscle. There was no clinical evidence of tuberous sclerosis in this patient. Polymerase chain reaction amplification of the highly polymorphic human androgen receptor gene (HU-MARA) was performed and the pattern of X chromosome inactivation was analyzed. Three of the five representative AML nodules showed a preferential loss of one of the two HUMARA alleles indicating a clonal proliferation with involvement of different alleles. Histologic examination of the corresponding lesions showed clonal lesions to be predominantly composed of epithelioid myoid cells while the polyclonal lesions were predominantly composed of adipose tissue. While the histologic diagnosis of AML in a surgical resection specimen is often straightforward, the radiographic, cytologic and intraoperative interpretation of a case with multiple lesions presents a considerable challenge.

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“…Genetic analyses of sporadic AMLs have demonstrated that these tumors are clonally derived, but the studies have not provided consistent results with respect to an underlying genetic mechanism [27][28][29] . Trisomy 7 has been independently reported in sporadic AMLs.…”

Section: Discussionmentioning

confidence: 99%

Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms

et al. 2007

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Angiomyolipomata (AML) belong to a family of tumors known as perivascular epithelioid cell tumors (PEComas) that share a common immunophenotypic profile of muscle and melanocytic differentiation. These tumors are clonal in nature and have a strong association with tuberous sclerosis. Genetic analyses have reported allelic imbalance at the TSC2 locus on 16p13. In the context of non-TSC, non-LAM associated AMLs and non-renal PEComas, the functional status of the TSC2 signaling pathway has not been reported. Studies over the last several years have uncovered a critical role of the TSC1/2 genes in negatively regulating the Rheb/mTOR/p70S6K cascade. Here, we examined the activity of this pathway in sporadic AMLs and PEComas using immunohistochemical and biochemical analyses. We found increased levels of phospho-p70S6K, a marker of mTOR activity, in 15 of 15 non-TSC AMLs. This was accompanied by reduced phospho-AKT expression, a pattern that is consistent with the disruption of TSC1/2 function. Western blot analysis confirmed mTOR activation concurrent with the loss of TSC2 and not TSC1 in sporadic AMLs. Similarly, elevated phospho-p70S6K and reduced phospho-AKT expression was detected in 14/15 cases of extra-renal PEComas. These observations provide the first functional evidence that mTOR activation is common to sporadic, non-TSC-related AMLs and PEComas. This suggests the possibility that mTOR inhibitors such as rapamycin may be therapeutic for this class of disease.

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Molecular analysis of clonality of sporadic angiomyolipoma

Cited by 35 publications

References 27 publications

Common and epithelioid variants of hepatic angiomyolipoma exhibit clonal growth and share a distinctive immunophenotype

Common and epithelioid variants of hepatic angiomyolipoma exhibit clonal growth and share a distinctive immunophenotype

Multiple Angiomyolipomata of the Liver: A Case Report

Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms

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