DISCUSSION

EAML was first described by Mai et al in 1996 [4]. It is a rare mesenchymal tumor which has been gradually recognized and accepted as a distinct entity in recent years . Renal EAML is a rare renal neoplasm accounting for less than 1 % of renal epithelial neoplasms, with a male to female ratio of 1:3 [5]. The current World Health Organization Classification of Renal Neoplasms classifies renal EAML as “a potentially malignant mesenchymal neoplasm” with adverse outcomes in approximately one-third of cases. TSC is an autosomal dominant multi- system disease that can manifest with seizures, mental retardation, autism, and tumors in the brain, retina, kidneys and heart, and is caused by germline mutations in either TSC1 or TSC2 genes located on chromosomes 9 and 16, respectively. With renal involvement being the main cause of mortality and morbidity in patients older than 30 years [6, 7]. The TSC1 and TSC2 genes encode proteins that form the hamartin and tuberin tumor suppressor complex, which restricts the activation of mammalian target of rapamycin complex 1 (mTORC1) [7]. Everolimus is a rapamycin derivative that inhibits the mTOR pathway by acting on mTORC1 [8]. In AML, the first study demonstrating the effect of mTOR inhibitors was in 2008, in which patients were treated with sirolimus over a 12-month period [9]. All patients showed a reduction in AML size. This first study was followed by a large, multicenter, prospective randomized trial (EXIST-2) evaluating the effect of everolimus on AML. With 118 adult patients, of whom 79 were treated with everolimus 10 mg/day and 39 received placebo. After 24 weeks, 55 % of patients in the treatment group showed a >50 % reduction in AML volume compared with 0 % in the control group [10]. Results of the EXIST-2 trial led to the approval of everolimus for TSC associated AML worldwide. Thus, everolimus therapy is the primary recommended treatment, allowing patients to avoid surgical procedures and preserving their kidneys [11, 12]. In our case, everolimus showed simply stability of the hepatic metastasis and renal EAML size. Even if the trough blood concentrations of everolimus were low no recommendation exist to adjuste the dosage on blood concentrations. However we switched to temsirolimus 8 months later after failure of everolimus. Yet, even this switch did show any sign of clinical nor radiological improvement on the patient. Since many of TSC patients suffer from seizures, they are kept on antiepileptic drugs and sometimes on carbamazepine. Which was the case in our patient. Carbamazepine is an inducer of CYP3A4, which increase clearance of everolimus and sirolimus, thus decreasing their effect. Temsirolimus is converted to the major metabolite sirolimus by deesterification (a non-cytochrome process). As we increased the dose of temsirolimus to the therapeutic zone, we started to see positive results. In subgroup analysis of EXIST-2 study, TSC AML patients under anti-epileptic medication presented with everolimus trough levels of 3.8 ng/ml, compared with 8.2 ng/ml for patients without anti- epileptic medication. This shows, like in our case, the undesired drug interaction between mTOR inhibitors and anti-epileptic medications. But no effect was observed on the efficacity of Everolimus [10]. Furthermore, drug interactions are real and can alter the whole management plan for certain patients. Thus, as in our case, awareness is necessary when using mTOR inhibitors with CYP450 3A4 enzyme inducing drugs.