J E Oesterling, E K Fishman, S M Goldman, F F Marshall
The management of renal angiomyolipoma.
J Urol. 1986 Jun;135(6):1121-4. doi: 10.1016/s0022-5347(17)46013-7.
Abstract/Text
Yoshihiro Kitano, Toshiro Honna, Kenji Nihei, Jun Miyauchi, Kentarou Matsuoka, Tatsuo Kuroda, Kiyoshi Tanaka, Nobuyuki Morikawa, Yasushi Fuchimoto
Renal angiomyolipoma in Japanese tuberous sclerosis patients.
J Pediatr Surg. 2004 Dec;39(12):1784-6. doi: 10.1016/j.jpedsurg.2004.08.036.
Abstract/Text
PURPOSE: Renal angiomyolipoma (AML) is a benign neoplasm that may grow massive in tuberous sclerosis (TS) patients. The aim of this study was to document the characteristics of renal AML in Japanese TS patients.
METHODS: Medical records of 29 TS patients followed up at the authors' center were reviewed for the presence, size, symptom, and treatment of renal AML.
RESULTS: Twenty-four patients screened for renal AML were subdivided into 4 groups: group 0 (n = 8), no mass; group 1 (n = 5), AML less than 1 cm in diameter; group 2 (n = 4), AML 1 to 4 cm in diameter; group 3 (n = 7), AML greater than 4 cm in diameter. When present, AML always affected both kidneys and were multiple. All patients in groups 1 and 2 were symptom free, and the tumors seemed stable in size. All tumors in group 3 grew progressively causing various symptoms. Total or partial nephrectomy or transarterial embolization was performed in 5 patients with limited success.
CONCLUSIONS: AML in TS patients can be stable or aggressive. Pediatric surgeons aware of this problem should be involved in a follow-up program.
九州地方における腎血管筋脂肪腫の臨床的検討 －第14回九州泌尿器科共同研究－九州泌尿器科共同研究会 古賀成彦ほか 西日本泌尿器科69 (12) 698-706, 2007.
大庭康司郎, 古賀成彦, 錦戸雅春, 志田洋平, 竹原浩介, 野口満, 江口二郎, 金武洋 長崎大学大学院医歯薬学総合研究所腎泌尿器病態学、腎移植・血管外科15 (1): 28-31, 2003.
Raouf M Seyam, Nabil K Bissada, Said A Kattan, Alaa A Mokhtar, Muhammad Aslam, Wahib E Fahmy, Walid A Mourad, Ali A Binmahfouz, Hassan M Alzahrani, Kamal A Hanash
Changing trends in presentation, diagnosis and management of renal angiomyolipoma: comparison of sporadic and tuberous sclerosis complex-associated forms.
Urology. 2008 Nov;72(5):1077-82. doi: 10.1016/j.urology.2008.07.049. Epub 2008 Sep 21.
Abstract/Text
OBJECTIVES: To evaluate the changing management of sporadic renal angiomyolipoma and renal angiomyolipoma associated with the tuberous sclerosis complex (TSC) during the past 16 years.
METHODS: We retrospectively reviewed the charts of 60 patients with angiomyolipoma seen at our institutions.
RESULTS: The median age at presentation was 45 years (range 7-78). The presentation was pain in 30 patients and hematuria in 13; it was incidentally discovered in 17 patients. Of the 60 patients, 43 were females. TSC was present in 14 patients. The median tumor size was 4 cm (range 0.3-40, mean 6.5 +/- 1.1). Of the 60 patients, 31 were followed up expectantly. Surgery or intervention was needed for 29 patients to control hemorrhage or relieve pain or because of the suspicion of malignancy. Of these 29 patients, 12 underwent nephrectomy, 11 partial nephrectomy, and 6 embolization. The patients treated for hemorrhage had a median tumor diameter of 11 cm (range 2-21). Patients were followed up for a mean of 39.3 +/- 5.4 months. The lesions grew an average of 4.7 +/- 3.4 cm for TSC tumors and 0.6 +/- 0.2 cm for sporadic angiomyolipoma tumors. None of the patients developed renal impairment. Patients with TSC presented at a younger age, had larger and bilateral lesions, and were more symptomatic during follow-up. In the past 6 years, a significant trend was seen toward finding tumors in asymptomatic patients and toward the use of conservative or interventional (embolization) treatment.
CONCLUSIONS: Renal angiomyolipoma has a slow growth rate. The preservation of renal function was noted in all our patients. A recent shift was noted toward finding smaller tumors in asymptomatic patients and the use of conservative and interventional treatment.
J A Hamlin, D C Smith, F C Taylor, J M McKinney, H C Ruckle, H R Hadley
Renal angiomyolipomas: long-term follow-up of embolization for acute hemorrhage.
Can Assoc Radiol J. 1997 Jun;48(3):191-8.
Abstract/Text
OBJECTIVE: To determine if elective, angiographically directed embolization of enlarged renal angiomyolipomas can be used to prevent future hemorrhagic episodes in patients with tuberous sclerosis and thus avoid nephrectomy.
PATIENTS AND METHODS: Records were reviewed for all 5 patients who underwent elective, subtotal embolization of large, symptomatic angiomyolipomas at the authors' institution between 1975 and 1996.
RESULTS: All 5 patients had tuberous sclerosis and bilateral renal angiomyolipomas. Initial embolization in these patients was performed in 1975, 1981, 1993 (2 patients) and 1994. In 1 patient only a single embolization session was required. In another, initial embolization on the left side was followed by embolization on the right 13 months later. Two patients underwent 2 sessions, and 1 patient had 4 sessions over a 13-year period. Subtotal embolization with particulate material led to a decrease in size of the most severely affected portion of the kidney. One large angiomyolipoma underwent sterile liquefaction after embolization; percutaneous catheter drainage was required. The embolization allowed subsequent partial nephrectomy in this patient.
CONCLUSION: Embolization is effective for the long-term management of renal angiomyolipomas in patients with tuberous sclerosis; in this way nephrectomy and loss of renal function can usually be avoided.
橋本 政幸，神納 敏夫，大内 泰文ほか．腎血管筋脂肪腫に対するTAEの検討．臨床放射線． 2003；48：1201-1205.
Paris Pappas, Polytimi Leonardou, Stefanos Papadoukakis, George Zavos, Spyridon Michail, John Boletis, George Tzortzis
Urgent superselective segmental renal artery embolization in the treatment of life-threatening renal hemorrhage.
Urol Int. 2006;77(1):34-41. doi: 10.1159/000092932.
Abstract/Text
INTRODUCTION: Renal hemorrhage is a major life-threatening condition that can be caused by trauma, operation, biopsy, as well as sudden spontaneous rupture of renal tumors or aneurysms. We report our experience with superselective segmental renal artery catheterization and embolization as therapeutic options for such cases.
PATIENTS AND METHODS: Over the last 8 years, 28 patients with severe renal hemorrhage were admitted for evaluation and possible further treatment. Twenty of them had a history of previous biopsy (6 of them one of a transplanted kidney), 1 patient had a recent percutaneous nephrostomy, 4 patients presented with renal mass ruptures (2 patients renal cell carcinoma, 1 patient angiomyolipoma, 1 patient hemorrhagic cysts), 1 patient had rupture of a renal aneurysm during delivery, 1 patient suffered bleeding after partial nephrectomy, and 1 patient was hospitalized after a car accident. They all presented with clinical signs of hemodynamic instability. Angiographic investigation of the kidneys preceded further intervention in all cases. 26 out of the 28 patients underwent superselective embolization of the specific bleeding vessel with the use of microcoils and/or Gelfoam particles.
RESULTS: All patients treated by superselective segmental renal artery embolization had a successful outcome, including a steady renal function and a stable clinical course. No complications occurred.
CONCLUSION: Superselective segmental renal artery catheterization and embolization is a safe and efficient method for the treatment of patients with severe renal hemorrhage, preserving healthy renal parenchyma and renal function.
Sergio Fernández-Pello, Milan Hora, Teele Kuusk, Rana Tahbaz, Saeed Dabestani, Yasmin Abu-Ghanem, Laurence Albiges, Rachel H Giles, Fabian Hofmann, Markus A Kuczyk, Thomas B Lam, Lorenzo Marconi, Axel S Merseburger, Thomas Powles, Michael Staehler, Alessandro Volpe, Börje Ljungberg, Axel Bex, Karim Bensalah
Management of Sporadic Renal Angiomyolipomas: A Systematic Review of Available Evidence to Guide Recommendations from the European Association of Urology Renal Cell Carcinoma Guidelines Panel.
Eur Urol Oncol. 2020 Feb;3(1):57-72. doi: 10.1016/j.euo.2019.04.005. Epub 2019 Jun 4.
Abstract/Text
CONTEXT: Little is known about the natural history of sporadic angiomyolipomas (AMLs); there is uncertainty regarding the indications of treatment and treatment options.
OBJECTIVE: To evaluate the indications, effectiveness, harms, and follow-up of different management modalities for sporadic AML to provide guidance for clinical practice.
EVIDENCE ACQUISITION: A systematic review of the literature was undertaken, incorporating Medline, Embase, and the Cochrane Library (from 1 January 1990 to 30 June 2017), in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. No restriction on study design was imposed. Patients with sporadic AML were included. The main interventions included active surveillance, surgery (nephron-sparing surgery and radical nephrectomy), selective arterial embolisation, and percutaneous or laparoscopic thermal ablations (radiofrequency, microwaves, or cryoablation). The outcomes included indications for active treatment, AML growth rate, AML recurrence rate, risk of bleeding, post-treatment renal function, adverse events of treatments, and modalities of follow-up. Risk of bias assessment was performed using standard Cochrane methods.
EVIDENCE SYNTHESIS: Among 2704 articles identified, 43 were eligible for inclusion (zero randomised controlled trials, nine nonrandomised comparative retrospective studies, and 34 single-arm case series). Most studies were retrospective and uncontrolled, and had a moderate to high risk of bias.
CONCLUSIONS: In active surveillance series, spontaneous bleeding was reported in 2% of patients and active treatment was undertaken in 5%. Active surveillance is the most chosen option in 48% of the cases, followed by surgery in 31% and selective arterial embolisation in 17% of the cases. Selective arterial embolisation appeared to reduce AML volume but required secondary treatment in 30% of the cases. Surgery (particularly nephron-sparing surgery) was the most effective treatment in terms of recurrence and need for secondary procedures. Thermal ablation was an infrequent option. The association between AML size and the risk of bleeding remained unclear; as such the traditional 4-cm cut-off should not per se trigger active treatment. In spite of the limitations and uncertainties relating to the evidence base, the findings may be used to guide and inform clinical practice, until more robust data emerge.
PATIENT SUMMARY: Sporadic angiomyolipoma (AML) is a benign tumour of the kidney consisting of a mixture of blood vessels, fat, and muscle. Large tumours may have a risk of spontaneous bleeding. However, the size beyond which these tumours need to be treated remains unclear. Most small AMLs can be monitored without any active treatment. For those who need treatment, options include surgical removal of the tumour or stopping its blood supply (selective embolisation). Surgery has a lower recurrence rate and lower need for a repeat surgical procedure.
Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Thierry Krummel, Julien Garnon, Hervé Lang, Afshin Gangi, Thierry Hannedouche
Percutaneous cryoablation for tuberous sclerosis-associated renal angiomyolipoma with neoadjuvant mTOR inhibition.
BMC Urol. 2014 Sep 25;14:77. doi: 10.1186/1471-2490-14-77. Epub 2014 Sep 25.
Abstract/Text
BACKGROUND: Renal angiomyolipomas (AMLs) are frequent in tuberous sclerosis and are responsible for a significant proportion of the morbidity in adulthood, mainly from bleeding complications, which are correlated to the size of the AMLs. We describe the case of a 19-year-old female with multiple bilateral renal angiomyolipomas.
CASE PRESENTATION: The renal AMLs measured up to 6 cm in size. She was first treated with a low dose of the mammalian target of rapamycin (mTOR) inhibitor sirolimus (up to 3 mg/day over a 12-month period) and following significant AML size reduction, percutaneous cryoablation was performed. No side-effects of either treatment were reported. At 12 months post-cryoablation, no recurrence of the AML was noted.
CONCLUSION: This is the first report of this treatment strategy and the case study reveals that combining a low dose of an mTOR inhibitor with percutaneous cryoablation to treat small tumors mitigates the side-effects while providing a good clinical outcome. This therapeutic approach is a novel tool for the clinician involved in the management of patients with tuberous sclerosis.
Karina Trelborg, Tommy Kjærgaard Nielsen, Ernst Øyvind Østraat, Lars Henning Olsen
Laparoscopic cryoablation of angiomyolipomas in adolescents and young adults: A report of four cases associated with tuberous sclerosis and 1 case of sporadic origin.
J Pediatr Urol. 2016 Dec;12(6):384.e1-384.e6. doi: 10.1016/j.jpurol.2016.03.018. Epub 2016 Jun 11.
Abstract/Text
INTRODUCTION: Renal angiomyolipomas (AMLs) can be of sporadic origin or associated with tuberous sclerosis (TS). TS-associated AMLs often present in childhood, tend to be bilateral and multiple, and often exhibit a faster growth rate with an increased risk of hemorrhage. Renal cryoablation is well described in adults, whereas experiences with adolescents and young adults are limited. We present here for the first time a series of renal AMLs within adolescents and young adults treated with laparoscopic assisted cryoablation (LCA).
OBJECTIVE: The aim was to evaluate whether LCA of AMLs in adolescents and young adults is a safe and feasible treatment modality.
STUDY DESIGN: From October 2009 to September 2013 a total of five patients at our institution were diagnosed with AMLs requiring treatment. Four patients had TS and one had AML of sporadic origin, all five patients underwent LCA. Data were retrospectively collected by a systematic review of patient material and reassessment of renal imaging.
RESULTS: The median age was 16 years (range 13-27 years). Eight AMLs with a median size of 3.9 cm (range 2.1-7.7 cm) were treated in five patients because of tumor size and rapid growth. Follow-up was a median 37 months (range 20-62 months), and all tumors showed a reduction in tumor size, and no regrowth was recognized (see summary table). The procedure was well tolerated, with only few perioperative complications and no postoperative complications.
DISCUSSION: When considering the indication for treating AMLs, the origin (sporadic or TS associated) and size of the tumor are the decisive factors. To preserve renal function and prevent spontaneous hemorrhage caution should be intensified when tumors reach 4 cm, particularly if TS is present. After the diagnosis is established, patients should be monitored with renal imaging at regular intervals to identify rapid-growing tumors. As an alternative to current treatment modalities such as partial nephrectomy and super selective angioembolization, cryoablation is an emerging approach, although experience with pediatric patients is limited. For patients not requiring immediate surgery, pharmacological treatment with mTOR inhibitors is now being evaluated as an alternative treatment option or as neo-adjuvant therapy to ablative techniques.
CONCLUSION: Prophylactic treatment of large or rapid growing AMLs with LCA appears to be a safe and feasible nephron-sparing approach in adolescents and young adults. The low perioperative complication rate and promising effect on outcome might allow treatment of subclinical AMLs in order to minimize the risk of potentially life-threatening complications and preserve renal function.
Copyright © 2016 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
九州地方における腎血管筋脂肪腫の臨床的検討 －第14回九州泌尿器科共同研究－ 九州泌尿器科共同研究会 古賀成彦ほか 西日本泌尿器科68(10) 466-473, 2006.
Shen-Yang Lee, Hsiang-Hao Hsu, Yung-Chang Chen, Chen-Chih Huang, Yon-Cheong Wong, Li-Jen Wang, Cheng-Keng Chuang, Chih-Wei Yang
Embolization of renal angiomyolipomas: short-term and long-term outcomes, complications, and tumor shrinkage.
Cardiovasc Intervent Radiol. 2009 Nov;32(6):1171-8. doi: 10.1007/s00270-009-9637-0. Epub 2009 Jul 2.
Abstract/Text
This study retrospectively evaluated outcomes, complications, and tumor shrinkage in renal angiomyolipomas after transcatheter arterial embolization (TAE). All renal angiomyolipoma patients who underwent TAE between August 2000 and December 2008 and had short-term (6 months) follow-up images were evaluated. Complications and tumor relapse after TAE were reviewed. The sizes of embolized tumors were measured to calculate size reductions and reduction rates after TAE. Differences in tumor size, size reduction, and reduction rate between different time points (pre-TAE, short-term follow-up, and long-term follow-up) and groups (completely and incompletely embolized) were determined. Eleven renal angiomyolipoma patients who had undergone TAE were included. Seven (63.6%) patients had postembolization syndrome and one had abscess formation following TAE. Two patients had a tumor relapse (18.2%). The mean tumor size was 8.57+/-2.66 cm on pre-TAE images. The mean size reduction was 3.1 cm (33.3%) and 3.8 cm (43.0%) at short-term and long-term follow-up. Tumor sizes differed significantly between pre-TAE and short-term (p=0.004) or long-term images (p=0.022) but not between short-term and long-term images (p=0.059). Results stratified by the completeness of embolization indicate that only the short-term size reduction rate differed significantly (p=0.025), while the long-term reduction rate and short- and long-term follow-up tumor size and size reduction were comparable between the two groups. In conclusion, selective TAE is effective for tumor shrinkage in most renal angiomyolipomas, with acceptable complication and relapse rates. Tumor shrinkage occurring within 6 months after TAE may reflect the long-term effect of TAE.
J Lenton, D Kessel, A F Watkinson
Embolization of renal angiomyolipoma: immediate complications and long-term outcomes.
Clin Radiol. 2008 Aug;63(8):864-70. doi: 10.1016/j.crad.2008.02.005. Epub 2008 Apr 28.
Abstract/Text
AIMS: To report the outcomes of elective and emergency embolization of renal angiomyolipoma and describe an angiographic sign that will help localize the symptomatic aneurysm in emergency cases.
MATERIALS AND METHODS: A retrospective review of all patients undergoing embolization of renal angiomyolipoma at a two centres between 1998-2007. Indications for treatment and angiographic images were reviewed. Incidence of acute rupture during embolization was noted.
RESULTS: Seventeen patients underwent 23 episodes of embolization using polyvinyl alcohol (PVA) particles, bead block, and coils. Thirteen were elective procedures for large or symptomatic angiomyolipoma and 10 were acute procedures for patients presenting with retroperitoneal haemorrhage. Patients presenting acutely with haemorrhage tended to have extensive multifocal renal involvement. Active bleeding on diagnostic angiography was seen in a single patient who presented with retroperitoneal haemorrhage 48h after elective embolization with PVA alone. Seven out of 10 (70%) of the acute cases displayed splaying of adjacent vessels due to peri-aneurysmal haematoma, known locally as the "light bulb sign". This allowed treatment to be focused on the symptomatic aneurysm. The light bulb sign was not present in any patient undergoing elective embolization. Aneurysm rupture with active extravasation occurred following embolization of the distal tumour circulation with PVA in four of 10 (40%) of the patients in the acute group and three of 13 (23%) patients in the elective group. Five patients required a subsequent embolization, three at a different site. Two patients in the elective group required repeat embolization of the target site, one for delayed haemorrhage and the other whose tumour did not shrink following the initial incomplete treatment.
CONCLUSIONS: Embolization of renal angiomyolipoma produces durable results. The presence of the light bulb sign is a strong indicator of the site of haemorrhage within the kidney. We advocate using a combination of particulate material and coils, as embolization with PVA alone may predispose to acute haemorrhage occurring during or after embolization.
Y M Han, J K Kim, B S Roh, H Y Song, J M Lee, Y H Lee, S Y Lee, G H Chung, C S Kim, M H Sohn, K C Choi
Renal angiomyolipoma: selective arterial embolization--effectiveness and changes in angiomyogenic components in long-term follow-up.
Radiology. 1997 Jul;204(1):65-70. doi: 10.1148/radiology.204.1.9205224.
Abstract/Text
PURPOSE: To evaluate the efficacy of selective arterial embolization in symptomatic renal angiomyolipoma (AML) and the change in angiomyogenic components during long-term follow-up after embolization.
MATERIALS AND METHODS: Fourteen adult patients with symptomatic AMLs underwent 16 selective arterial embolizations. The embolic materials used were absolute alcohol with (n = 5) or without (n = 3) iodized oil, Gianturco coils (n = 4), and polyvinyl alcohol foam powder with gelatin sponge (n = 2). Follow-up ultrasonography and computed tomography (CT) were performed in six and 14 patients, respectively. The effectiveness of selective arterial embolization was evaluated on the basis of the area of the angiomyogenic components in the AML on initial and follow-up images and clinical improvement.
RESULTS: All patients showed devascularization of the tumor on the postembolization angiograms. In 13 patients, clinical symptoms disappeared. The follow-up period was 7-72 months (mean, 33 months). One patient underwent nephrectomy at 7 months after embolization because of a large cystic lesion found at 1 month. In long-term CT follow-up (> or =12 months) in 12 patients, nearly all angiomyogenic components disappeared, but fatty components partially shrank with liquefactive necrosis in tumors.
CONCLUSION: Selective arterial embolization is an effective and safe treatment of AML. The angiomyomatous components crucial for the prevention of bleeding were very sensitive to the embolization.
John J Bissler, Francis X McCormack, Lisa R Young, Jean M Elwing, Gail Chuck, Jennifer M Leonard, Vincent J Schmithorst, Tal Laor, Alan S Brody, Judy Bean, Shelia Salisbury, David N Franz
Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis.
N Engl J Med. 2008 Jan 10;358(2):140-51. doi: 10.1056/NEJMoa063564.
Abstract/Text
BACKGROUND: Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.
METHODS: We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.
RESULTS: Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.
CONCLUSIONS: Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)
2008 Massachusetts Medical Society
John J Bissler, J Christopher Kingswood, Elżbieta Radzikowska, Bernard A Zonnenberg, Michael Frost, Elena Belousova, Matthias Sauter, Norio Nonomura, Susanne Brakemeier, Petrus J de Vries, Vicky H Whittemore, David Chen, Tarek Sahmoud, Gaurav Shah, Jeremie Lincy, David Lebwohl, Klemens Budde
Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial.
Lancet. 2013 Mar 9;381(9869):817-24. doi: 10.1016/S0140-6736(12)61767-X.
Abstract/Text
BACKGROUND: Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata.
METHODS: In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400.
RESULTS: 118 patients (median age 31·0 years; IQR 18·0–61·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31–53%]) for everolimus and 0% (0 of 39 [0–9%]) for placebo (response rate difference 42% [24–58%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]).
INTERPRETATION: Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis.
FUNDING: Novartis Pharmaceuticals.
D Mark Davies, Petrus J de Vries, Simon R Johnson, Deborah L McCartney, Jane A Cox, Andreas L Serra, Peter C Watson, Christopher J Howe, Tim Doyle, Kate Pointon, Justin J Cross, Anne E Tattersfield, J Chris Kingswood, Julian R Sampson
Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial.
Clin Cancer Res. 2011 Jun 15;17(12):4071-81. doi: 10.1158/1078-0432.CCR-11-0445. Epub 2011 Apr 27.
Abstract/Text
PURPOSE: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders.
EXPERIMENTAL DESIGN: In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function.
RESULTS: The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus.
CONCLUSIONS: This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation.
©2011 AACR.
John J Bissler, John Christopher Kingswood, Elżbieta Radzikowska, Bernard A Zonnenberg, Michael Frost, Elena Belousova, Matthias Sauter, Norio Nonomura, Susanne Brakemeier, Petrus J de Vries, Noah Berkowitz, Sara Miao, Scott Segal, Severine Peyrard, Klemens Budde
Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial.
Nephrol Dial Transplant. 2016 Jan;31(1):111-9. doi: 10.1093/ndt/gfv249. Epub 2015 Jul 8.
Abstract/Text
BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are recommended as first-line treatment of renal angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sporadic LAM), but follow-up is limited. Longer term efficacy and tolerability data from a Phase 3, double-blind, placebo-controlled trial are presented.
METHODS: Following favorable results from the primary analysis (data cutoff 30 June 2011) of the EXIST-2 trial, patients still receiving study treatment were allowed to enter an open-label extension. Everolimus was initiated at 10 mg once daily and titrated based on tolerability. The primary outcome was angiomyolipoma response rate (≥ 50% reduction from baseline in target lesion volumes). Safety was a secondary endpoint.
RESULTS: As of the cutoff date (1 May 2013), 112 patients had received everolimus, and the response rate in 107 patients with angiomyolipoma (median duration of medication exposure of 28.9 months) was 54%. The proportion of patients achieving angiomyolipoma reductions of ≥ 30% and ≥ 50% increased over time, reaching 81.6% (62/76) and 64.5% (49/76), respectively, by Week 96. No everolimus-treated patients experienced renal bleeding. The long-term safety profile was consistent with previous reports; adverse events (AEs) were mostly Grade 1/2, and there were no new safety issues. The frequency of emerging AEs and severe AEs lessened over time.
CONCLUSIONS: Longer term everolimus treatment appeared safe and effective in patients with TSC- or sporadic LAM-associated renal angiomyolipoma not requiring surgical intervention. Continued reduction in angiomyolipoma volume was demonstrated, and there was no angiomyolipoma-related bleeding; AEs were predictable and generally manageable.
TRIAL REGISTRATION: clinicaltrialsgov identifier: NCT00790400 (http://clinicaltrials.gov/ct2/show/NCT00790400).
© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Brian J Siroky, Hong Yin, John J Bissler
Clinical and molecular insights into tuberous sclerosis complex renal disease.
Pediatr Nephrol. 2011 Jun;26(6):839-52. doi: 10.1007/s00467-010-1689-5. Epub 2010 Dec 9.
Abstract/Text
Patients with tuberous sclerosis complex are at great risk of developing renal lesions as part of their disease. These lesions include renal cysts and tumors. Significant advances in understanding the cell biology of these renal lesions has already led to clinical trials demonstrating that pharmacological interventions are likely possible. This review focuses on the pathology of these renal lesions, their underlying cell biology, and the possible therapeutic strategies that may prove to significantly improve care for these patients.
S K Rakowski, E B Winterkorn, E Paul, D J R Steele, E F Halpern, E A Thiele
Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors.
Kidney Int. 2006 Nov;70(10):1777-82. doi: 10.1038/sj.ki.5001853. Epub 2006 Sep 27.
Abstract/Text
Tuberous sclerosis complex is a genetic disorder characterized by hamartomatous lesions in multiple organs, frequently involving the kidney. We conducted a retrospective review of the clinical and radiographic records of 167 patients with tuberous sclerosis to determine the frequency of renal disease, the likelihood of significant renal morbidity, and the effects of genotype (TSC1 vs TSC2) and gender on renal phenotype. Renal lesions were seen in 57.5% of patients. Of these, angiomyolipoma (AML) occurred in 85.4%, cysts in 44.8%, and renal cell carcinoma in 4.2%. Both AML and cysts were significantly more common and more numerous in TSC2 than in TSC1. AML was significantly more common in female than in male patients, but cysts showed no correlation with gender. Eleven patients developed renal abnormalities during their care in this practice at an average age of onset of 11.3 years (range 3.8-23 years). The frequency and number of renal lesions were positively correlated with age. Interventions, including arterial embolization and nephrectomy, were performed in 11 (6.6%) patients. Among female patients with lymphangioleiomyomatosis, renal AML was universally present. Our findings confirm a high rate of renal involvement; a low rate of serious complications; significant associations between renal involvement, genotype, and gender; and a significant association between renal and pulmonary involvement in female patients.
Yoshiko Tokuyama, Tetsuo Fujita, Takahiro Hirayama, Masahiro Shirai, Akio Kazama, Masatsugu Iwamura, Shiro Baba
[Epithelioid angiomyolipoma of the kidney].
Hinyokika Kiyo. 2010 Feb;56(2):103-6.
Abstract/Text
A 50-year-old male was referred to our hospital for a left renal mass which was incidentally found during a medical check-up. Abdominal ultrasonography, computed tomography, and magnetic resonance imaging showed a weak enhancement tumor devoid of fat densities at the lower pole of the left kidney. Under the diagnosis of renal cell carcinoma, radical nephrectomy was performed. Histopathological examination revealed large epithelioid cells, and immunohistochemical staining showed strongly positive for HMB-45. The patient was diagnosed with epithelioid angiomyolipoma of the kidney. Epithelioid angiomyolipoma is a rare variant of angiomyolipoma, which is sometimes occurred aggressive clinical behavior. However, our case remains without evidence of recurrence or metastasis after radical nephrectomy, and showed relatively better prognosis than in previous reports.
Hakan Aydin, Cristina Magi-Galluzzi, Brian R Lane, Linda Sercia, Jose I Lopez, Brian I Rini, Ming Zhou
Renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association.
Am J Surg Pathol. 2009 Feb;33(2):289-97. doi: 10.1097/PAS.0b013e31817ed7a6.
Abstract/Text
The majority of renal angiomyolipoma (AML) is sporadic and occasionally it occurs as part of tuberous sclerosis complex (TSC). Epithelioid AML (EAML), an uncommon variant, is considered potentially malignant based on anecdotal case reports. The prognostic significance of epithelioid component in an otherwise typical AML is uncertain. We studied 194 AMLs for the clinicopathologic features of epithelioid and TSC-associated AMLs. Epithelioid component was present in 15 cases (7.7%) with an average amount of 51% (range: 10% to 100%). Histologically, the epithelioid tumor cells were categorized into small, intermediate, and large cell type based on the cell size. Worrisome histologic features were seen in many EAMLs, including coagulative tumor necrosis in 27% (4/15), nuclear atypia in 93% (14/15), mitosis in 47% (7/15), and atypical mitosis in 1 case. All 15 EAML patients had a mean follow-up time of 5.1 years and none had local recurrence or distant metastasis. Sixteen (8.2%) AMLs occurred in patients with definitive TSC. Three histologic features, namely microscopic AML foci, epithelioid component, and epithelial cysts, were present in 10 (62.5%), 4 (25%), and 44% (7/16), respectively, of TSC-associated AMLs, compared with 11 (6.2%), 11 (6.2%), and 6 (3.4%), respectively, in non-TSC-associated AMLs (P value all <0.01). In summary, all 15 cases of EAMLs in our study had benign clinical outcomes despite adverse pathologic features. Epithelioid component, epithelial cysts, and microscopic AML foci are strongly associated with TSC and the presence of all 3 features should raise strong suspicion for TSC.
Mitsuru Komeya, Tatsuya Matsumoto, Kiyoshi Fujinami, Yutaka Senga, Tomoyuki Asakura, Akihiko Goto
[Rupture of renal angiomyolipoma during pregnancy: a case report].
Hinyokika Kiyo. 2010 May;56(5):261-4.
Abstract/Text
A 39-year-old woman, who was followed because of a 4 cm asymptomatic angiomyolipoma (AML) in the left kidney, presented with an acute onset of lower left back pain in the 38th week of her first pregnancy. An ultrasound revealed an 8 cm mass suggestive of AML rupture and retroperitoneal hemorrhage. An emergency caesarean delivery was performed. A post-delivery computed tomographic scan confirmed the AML rupture and selective embolization was performed. This was a case in which the AML grew rapidly during the pregnancy ; therefore, we discuss the relationship between AML and pregnancy.
