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Dramatic effect of sirolimus on renal angiomyolipomas in a patient with tuberous sclerosis complex
European Journal of Internal Medicine 18 (2007) 76 – 77 www.elsevier.com/locate/ejim
Brief report
Dramatic effect of sirolimus on renal angiomyolipomas in a patient with tuberous sclerosis complex ☆ Isabelle Herry a , Catherine Neukirch a , Marie-Pierre Debray b , Françoise Mignon c , Bruno Crestani a,⁎ a
Service de pneumologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France, Université Paris 7, France Service de radiologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France, Université Paris 7, France c Service de néphrologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France, Université Paris 7, France b
Received 23 February 2006; received in revised form 24 May 2006; accepted 6 July 2006
Abstract Angiomyolipomas are very common in patients with tuberous sclerosis complex (TSC) and cause substantial morbidity. Until now, arterial embolization has been the recommended treatment for symptomatic patients. We report the case of a woman with TSC and giant angiolipomas in whom sirolimus induced a dramatic reduction in bilateral renal tumors. © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Angiomyolipomas; Tuberous sclerosis complex; Lymphangioleiomyomatosis; Sirolimus
1. Introduction
2. Case report
Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease with multivisceral involvement. Cutaneous adenomas, cerebral lesions, epilepsy, and mental retardation occur in most cases and renal angiomyolipomas are common. Pulmonary involvement has been reported to occur in 1% of patients and is similar to pulmonary lymphangioleiomyomatosis (LAM) [1,2]. Angiomyolipomas arise in up to 80% of patients with tuberous TSC and are the cause of substantial morbidity. Arterial embolization is currently the first choice of intervention when symptoms develop [3]. Activation of the mammalian target of rapamycin (mTOR) signalling pathway has been observed in renal angiomyolipoma [4]. We report herein the case of a woman in whom sirolimus (rapamycin, Rapamune®) induced a dramatic improvement in renal angiomyolipomas.
A 38-year-old female was followed in Hôpital BichatClaude Bernard for LAM associated with bilateral renal angiomyolipomas, brain lesions, and epilepsy in the context of TSC. Giant angiomyolipomas caused recurrent abdominal pain requiring frequent medical advice. The patient's creatinine blood level was stable between 1999 and 2003 (115 μmol/L). Arterial embolization was considered, but refused by the patient. Sirolimus was started in June 2003 (6 mg once daily) as a possible treatment for angiomyolipomas. Blood sirolimus levels were maintained between 8 and 10 ng/ml. The treatment was well tolerated. Abdominal pain disappeared within 3 months after initiation of sirolimus. Abdominal computed tomography (CT) performed 1 and 2 years after continuous sirolimus treatment demonstrated a dramatic reduction in the volume of angiomyolipomas (Fig. 1A–C). The size of both the right and left kidneys was greatly reduced within the first year of therapy and stabilized thereafter (left kidney: 205 mm before sirolimus, 126 mm after 1 year, 120 mm after 2 years; right kidney: 115 mm before sirolimus, 104 mm after 1 year, 100 mm after 2 years). Creatinine level was unchanged, as were lung CT
☆ The authors certify that they have no involvement in any organization with a direct financial interest in the subject of the manuscript. ⁎ Corresponding author. Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard 75877 Paris cedex 18, France. E-mail address: [email protected] (B. Crestani).
0953-6205/$ - see front matter © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2006.07.017
I. Herry et al. / European Journal of Internal Medicine 18 (2007) 76–77
77
Fig. 1. Computed tomography of the kidneys disclosing angiomyolipomas (A) before treatment, (B) after 1 year of treatment, (C) after 2 years of treatment, and (D) 6 months after the end of treatment with sirolimus.
and lung function tests. Sirolimus was stopped after 2 years of continuous treatment. Six months later, abdominal CT showed stable angiomyolipomas (Fig. 1D).
4. Learning point Sirolimus may be considered as an alternative to arterial embolization for symptomatic angiomyolipomas.
3. Discussion References To the best of our knowledge, this is the first case to be reported with such a dramatic improvement in renal angiomyolipomas with sirolimus treatment. TSC is caused by inactivating mutations of the TSC1 and TSC2 genes, which encode hamartin and tuberin, respectively. Under normal circumstances, these proteins heterodimerize and inhibit the mTOR. Inactivating mutations result in an unregulated activation of mTOR and lead to phosphorylation of S6 kinase and of signal transducer and activator of transcription (STAT) proteins, with major transcriptional effects and secondary changes in cellular proliferation and apoptosis processes [5,6]. Activation of a mTOR metabolic pathway has been demonstrated in angiomyolipomas from five TSC patients [4,6] and probably explains the efficacy of sirolimus in this patient. Intensive management is generally recommended for angiomyolipomas associated with TSC. This case illustrates the potentially therapeutic effect of sirolimus. Therapeutic trials with sirolimus for TSC patients are currently under way. Their results may improve our therapeutic approach to this disease and allow us to confirm its effect on renal tumor growth and, perhaps, on the course of pulmonary disease in this setting.
[1] Castro M, Sheperd CW, Gomez MR, Lie JT, Ryu JH. Pulmonary tuberous sclerosis. Chest 1995;107:189–95. [2] Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, Brooks PG, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001;164:669–71. [3] Harabayashi T, Shinohara N, Katano H, Nonomura K, Shimizu T, Koyanagi T. Management of renal angiomyolipomas associated with tuberous sclerosis complex. J Urol 2004;171:102–5. [4] El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 2003;361:1348–9. [5] Lee L, Sudentas P, Donohue B. Efficacy of a rapamycin analog (CCI779) and INF-γ in Tuberous Sclerosis Mouse Models. Genes Chromosomes Cancer 2005;42:213–27. [6] El-Hashemite N, Zhang H, Walker V, Hoffmeister KM, Kwiatkowski DJ. Perturbed INF-gamma-Jak-Signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of Rapamycin-INF-gamma treatment. Cancer Res 2004;64:3436–43.
Brief report
Dramatic effect of sirolimus on renal angiomyolipomas in a patient with tuberous sclerosis complex ☆ Isabelle Herry a , Catherine Neukirch a , Marie-Pierre Debray b , Françoise Mignon c , Bruno Crestani a,⁎ a
Service de pneumologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France, Université Paris 7, France Service de radiologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France, Université Paris 7, France c Service de néphrologie, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France, Université Paris 7, France b
Received 23 February 2006; received in revised form 24 May 2006; accepted 6 July 2006
Abstract Angiomyolipomas are very common in patients with tuberous sclerosis complex (TSC) and cause substantial morbidity. Until now, arterial embolization has been the recommended treatment for symptomatic patients. We report the case of a woman with TSC and giant angiolipomas in whom sirolimus induced a dramatic reduction in bilateral renal tumors. © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Angiomyolipomas; Tuberous sclerosis complex; Lymphangioleiomyomatosis; Sirolimus
1. Introduction
2. Case report
Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease with multivisceral involvement. Cutaneous adenomas, cerebral lesions, epilepsy, and mental retardation occur in most cases and renal angiomyolipomas are common. Pulmonary involvement has been reported to occur in 1% of patients and is similar to pulmonary lymphangioleiomyomatosis (LAM) [1,2]. Angiomyolipomas arise in up to 80% of patients with tuberous TSC and are the cause of substantial morbidity. Arterial embolization is currently the first choice of intervention when symptoms develop [3]. Activation of the mammalian target of rapamycin (mTOR) signalling pathway has been observed in renal angiomyolipoma [4]. We report herein the case of a woman in whom sirolimus (rapamycin, Rapamune®) induced a dramatic improvement in renal angiomyolipomas.
A 38-year-old female was followed in Hôpital BichatClaude Bernard for LAM associated with bilateral renal angiomyolipomas, brain lesions, and epilepsy in the context of TSC. Giant angiomyolipomas caused recurrent abdominal pain requiring frequent medical advice. The patient's creatinine blood level was stable between 1999 and 2003 (115 μmol/L). Arterial embolization was considered, but refused by the patient. Sirolimus was started in June 2003 (6 mg once daily) as a possible treatment for angiomyolipomas. Blood sirolimus levels were maintained between 8 and 10 ng/ml. The treatment was well tolerated. Abdominal pain disappeared within 3 months after initiation of sirolimus. Abdominal computed tomography (CT) performed 1 and 2 years after continuous sirolimus treatment demonstrated a dramatic reduction in the volume of angiomyolipomas (Fig. 1A–C). The size of both the right and left kidneys was greatly reduced within the first year of therapy and stabilized thereafter (left kidney: 205 mm before sirolimus, 126 mm after 1 year, 120 mm after 2 years; right kidney: 115 mm before sirolimus, 104 mm after 1 year, 100 mm after 2 years). Creatinine level was unchanged, as were lung CT
☆ The authors certify that they have no involvement in any organization with a direct financial interest in the subject of the manuscript. ⁎ Corresponding author. Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard 75877 Paris cedex 18, France. E-mail address: [email protected] (B. Crestani).
0953-6205/$ - see front matter © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2006.07.017
I. Herry et al. / European Journal of Internal Medicine 18 (2007) 76–77
77
Fig. 1. Computed tomography of the kidneys disclosing angiomyolipomas (A) before treatment, (B) after 1 year of treatment, (C) after 2 years of treatment, and (D) 6 months after the end of treatment with sirolimus.
and lung function tests. Sirolimus was stopped after 2 years of continuous treatment. Six months later, abdominal CT showed stable angiomyolipomas (Fig. 1D).
4. Learning point Sirolimus may be considered as an alternative to arterial embolization for symptomatic angiomyolipomas.
3. Discussion References To the best of our knowledge, this is the first case to be reported with such a dramatic improvement in renal angiomyolipomas with sirolimus treatment. TSC is caused by inactivating mutations of the TSC1 and TSC2 genes, which encode hamartin and tuberin, respectively. Under normal circumstances, these proteins heterodimerize and inhibit the mTOR. Inactivating mutations result in an unregulated activation of mTOR and lead to phosphorylation of S6 kinase and of signal transducer and activator of transcription (STAT) proteins, with major transcriptional effects and secondary changes in cellular proliferation and apoptosis processes [5,6]. Activation of a mTOR metabolic pathway has been demonstrated in angiomyolipomas from five TSC patients [4,6] and probably explains the efficacy of sirolimus in this patient. Intensive management is generally recommended for angiomyolipomas associated with TSC. This case illustrates the potentially therapeutic effect of sirolimus. Therapeutic trials with sirolimus for TSC patients are currently under way. Their results may improve our therapeutic approach to this disease and allow us to confirm its effect on renal tumor growth and, perhaps, on the course of pulmonary disease in this setting.
[1] Castro M, Sheperd CW, Gomez MR, Lie JT, Ryu JH. Pulmonary tuberous sclerosis. Chest 1995;107:189–95. [2] Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, Brooks PG, et al. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001;164:669–71. [3] Harabayashi T, Shinohara N, Katano H, Nonomura K, Shimizu T, Koyanagi T. Management of renal angiomyolipomas associated with tuberous sclerosis complex. J Urol 2004;171:102–5. [4] El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 2003;361:1348–9. [5] Lee L, Sudentas P, Donohue B. Efficacy of a rapamycin analog (CCI779) and INF-γ in Tuberous Sclerosis Mouse Models. Genes Chromosomes Cancer 2005;42:213–27. [6] El-Hashemite N, Zhang H, Walker V, Hoffmeister KM, Kwiatkowski DJ. Perturbed INF-gamma-Jak-Signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of Rapamycin-INF-gamma treatment. Cancer Res 2004;64:3436–43.