Renal Epithelioid Angiomyolipoma Undergoing Aggressive Clinical Outcome: The MDM2 Expression in Tumor Cells of Two Cases

Abstract

Epithelioid angiomyolipoma (EAML) has been known as a potentially malignant tumor which occasionally recur and/or metastasize to other organs, and clinically and pathologically recognized as distinct entity. However, the mechanisms of recurrence and/or metastasis (recurrence/metastasis) has still remained unknown. Here, we report two cases of renal EAML associated with recurrence/metastasis, and three cases of EAML in kidney or liver without recurrence/metastasis. According to the previous histological predictive models of EAML, the primary tumor was classified as low risk group in one of the cases with recurrence/metastasis in spite of its malignant behavior. Therefore, we considered that further investigation about the mechanisms of recurrence/metastasis in EAML is required for a malignancy prediction. We focused on some cell-cycle modulators, including mouse double minute 2 homolog (MDM2), which is ubiquitin ligase well-known to promote malignant behaviors by p53 ubiquitination and degradation, and also other cellular processes including genomic instability and epithelial-mesenchymal transition in p53-independent manners in various human malignancies. Immunohistochemical evaluation revealed that MDM2 protein expression increased stepwise throughout every steps of metastasis/recurrence in both cases, although it was negative in primary tumors. In conclusion, this is the first study demonstrating that MDM2 could play an important role in the molecular mechanisms of recurrence/metastasis of EAML. Further analyses focusing on MDM2 pathway could contribute to the identification of novel prognostic factors and/or therapeutic targets in EAML patients.

Clinical challenges and management of primary renal epithelioid angiomyolipoma of duplex kidney with paraneoplastic syndrome

“…Inoue et al. 20 reported that the MDM2 protein was negative in primary EAML and showed a gradually increasing trend in two patients with metastasis or recurrence. These findings indicate the likelihood of new prognostic factors as treatment targets for EAML.…”

“…18 Kenerson et al 19 found that the mTOR pathway was abnormally activated during the growth and progression of renal EAML; thus, the application of mTOR inhibitors such as rapamycin, everolimus, and others might lead to tumor reduction. Inoue et al 20 reported that the MDM2 protein was negative in primary EAML and showed a gradually increasing trend in two patients with metastasis or recurrence. These findings indicate the likelihood of new prognostic factors as treatment targets for EAML.…”

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

“…Several interesting studies relevant to this topic are discussed here. IHC evaluation revealed that MDM2 protein expression increased stepwise throughout every steps of metastasis/recurrence in the two cases of Renal Epithelioid Angiomyolipoma (EAML) studied, although it was negative in primary tumors [ 118 ]. This study suggests that MDM2 could play an important role in the recurrence/metastasis of renal EAML.…”

The recurrence of well-differentiated liposarcoma from benign giant intramuscular lipoma

“…MDM2 and chromosome 12 centromere (CEP12) using the Vysis LSI MDM2 Spectrum Orange Probe nd Vysis DNA FISH probe CEP12 (Abott Molecular/Vysis, Des Plaines, IL, USA) were examined, and. [ 13 ] results of MDM2-FISH showed focally positive and 5.96 of MDM2/CEP12 ratio, suggesting that MDM2 gene amplification indicated the lipomatous tumor as WDLS.…”