The Case
A 35-year-old man was referred to the urology clinic by his primary care physician for consultation regarding bilateral, multifocal renal masses. The patient reported a 3-month history of intermittent right flank pain and chronic right flank soreness not associated with nausea, vomiting, fevers, or chills. He denied any urinary complaints or hematuria. Physical examination was largely unremarkable, except for facial angiofibromas; urinalysis revealed no blood or infection. Postvoid residual urine volume per bladder scan was 26 mL. Vital signs were within normal limits. The patient denied any tobacco or alcohol abuse. He did have a known history of tuberous sclerosis complex, and had undergone resection of several brain tumors (giant cell astrocytomas) as a child.
Laboratory values, including results of a complete blood cell count with differential, liver function tests, coagulation panel, and basic chemistry panel, were unremarkable. A CT scan of the abdomen and pelvis with IV contrast was obtained, and it showed bilateral, multifocal, lipid-rich renal masses, possibly consistent with angiomyolipomas (Figure 1). On cross-sectional imaging, the largest renal mass on the right side measured 3.7 × 4.1 cm, and the largest renal mass on the left side measured 3.1 × 3.6 cm. Multiple smaller renal masses were present bilaterally throughout the parenchyma of both kidneys, ranging in size from 0.8 × 0.4 cm to 1.2 × 1.1 cm.
The patient underwent CT-guided needle biopsy of one of the renal masses for definitive diagnosis and to rule out a lipid-rich renal cell carcinoma with macroscopic fat due to osseous metaplasia. Microscopic examination of the tissue by the pathologist revealed mixed uniform spindle and adipose cells in the presence of small vascular channels (Figure 2A). Immunoperoxidase staining was positive for melanocyte antigen recognized by T cells–1 (MART1) (Figure 2B); and for alpha-smooth muscle actin (Figure 2C), which confirmed the smooth muscle origin of the spindle cells. This histopathology was consistent with a diagnosis of renal angiomyolipoma.
Which of the following is the recommended initial treatment strategy for this patient?
A. Observation only
B.Treatment with an mTOR inhibitor
C. Angiography and embolization
D. Partial nephrectomy
E. Total nephrectomy
Correct Answer: B
Discussion
Tuberous sclerosis complex is an autosomal dominant genetic disorder that typically results in the growth of hamartomas in multiple major organ systems.[1] Renal manifestations occur in 55% to 90% of patients with tuberous sclerosis complex, with angiomyolipomas occurring in up to 75% of patients.[2] Angiomyolipomas are composed of anomalous vessels, immature smooth muscle tissue, and adipocytes. Renal angiomyolipomas are the most common cause of mortality in patients with tuberous sclerosis complex because of associated hypertension, potential renal failure, or hemorrhage.[3] Because hemorrhage is a major cause of sudden death in adults with this disease, observation (Answer A) is not recommended.
The main nonpharmacologic options for renal angiomyolipomas are angiography with arterial embolization, nephron-sparing surgery (ie, partial nephrectomy), and complete nephrectomy. Angiomyolipomas, especially in patients with tuberous sclerosis complex, are often bilateral, multifocal, large, and difficult to target, which makes the potential for cure of arterial embolization (Answer C) and the success of nephron-sparing surgery (Answer D) low.[4] Moreover, patients with tuberous sclerosis complex who have angiomyolipomas often require re-treatment because of the high incidence of new and recurrent tumors; thus, these invasive procedures are limited to patients who fail first-line medical therapy or who have tumors greater than 4 or 5 cm and therefore are at high risk for rupture and intra-abdominal hemorrhage.[5,6] Prophylactic surgery with partial nephrectomy can be considered in relatively healthy patients with solitary or less numerous renal lesions, in whom the loss of kidney parenchyma after surgery and the duration of ischemia time during resection would both be minimized. Total nephrectomy (Answer E) leads to massive loss of normal renal parenchyma and renal function and is typically only recommended in a life-threatening emergency resulting from renal blood loss.
Because of the limits of surgical or invasive procedures in this disease, an effective pharmacologic treatment has been sought. In patients with tuberous sclerosis complex, mammalian target of rapamycin (mTOR) complex 1 is overactivated due to the loss of hamartin or tuberin protein.[7] Thus, agents that inhibit the mTOR signaling pathway (such as sirolimus or everolimus; Answer B) can theoretically suppress tumor growth in patients with tuberous sclerosis complex.[8]
In a systematic review by Peng and colleagues evaluating the efficacy and safety of the mTOR inhibitor sirolimus in the treatment of renal angiomyolipomas in patients with tuberous sclerosis complex, the overall response rate was 46.8% in the first year, and was 43.5% in the second year for those patients still being treated.[9] The response rate was defined as the percentage of patients who had a reduction in angiomyolipoma volume of more than 50% relative to baseline. Responses occurred after a minimum of 6 months of treatment. The overall mean reduction in renal angiomyolipoma volume ranged from 25% to 65% in the first year, and from 20% to 60% in the second year across study populations. The patients who stopped treatment after 1 year, however, had significant regrowth of their renal angiomyolipomas-back to baseline volumes-suggesting that lifelong mTOR inhibitor therapy may be required to prevent tumor regrowth. Reported side effects were tolerable, with most being mild or moderate in nature-eg, stomatitis, diarrhea, respiratory tract infection, urinary tract infection, hyperlipidemia, pain, skin lesions, irregular menses, bone marrow suppression (leukopenia, anemia), and proteinuria. Long-term data on survival have not been reported.
Sirolimus and everolimus have both shown effectiveness in the reduction of renal angiomyolipoma volume in patients with tuberous sclerosis complex.[8] In recent years, however, everolimus has been used more often because of its favorable pharmacokinetics, which include a favorable blood-brain partition coefficient, greater bioavailability, and greater solubility in water.[10] Bissler and colleagues conducted a multicenter, randomized, double-blinded, placebo-controlled clinical trial involving 118 patients with tuberous sclerosis complex and at least one renal angiomyolipoma measuring 3 cm or more at its greatest diameter based on radiologic assessment.[11] Patients were randomly assigned in a 2:1 fashion to receive oral everolimus, 10 mg/d, or placebo. The renal angiomyolipoma response rate was 42% (33 of 79 patients) for the everolimus group and 0% (0 of 39 patients) for the placebo group. Again, response was defined as a ≥ 50% reduction from baseline in the total volume of renal angiomyolipomas and the absence of new lesions. Much as with sirolimus, responses occurred after a minimum of 6 months of treatment. The most common adverse events were stomatitis, nasopharyngitis, and acne-like skin lesions. A follow-up study of this patient cohort at 4 years showed a durable response rate (58%) after all patients were allowed to receive open-label everolimus.[12] Long-term data on survival have not been reported.
KEY POINTS
- The majority of patients with tuberous sclerosis complex have bilateral, multifocal, large renal angiomyolipomas that are at risk for rupture, with subsequent life-threatening renal hemorrhage.
- Angiography with renal arterial embolization, as well as nephron-sparing surgery, have limited long-term effectiveness in this setting because of the recurrent nature of this disease; these approaches also carry a risk of loss of normal renal parenchyma and function.
- The overactivation of mammalian target of rapamycin (mTOR) due to the loss of hamartin or tuberin protein in persons with tuberous sclerosis complex makes this an ideal target for systemic pharmacologic therapy; mTOR inhibitors show a 50% response rate with at least a 50% reduction in renal angiomyolipoma volume after initiation of treatment.
As the studies cited here demonstrate, systemic treatment with an mTOR inhibitor can achieve an effective and durable treatment response in patients with multifocal, bilateral renal angiomyolipomas and tuberous sclerosis complex. Having an effective systemic option is especially advantageous in these patients, since invasive procedures or renal surgery carry a significant risk of morbidity or renal dysfunction due to the volume of disease present. In this particular patient, given the extensive and recurrent nature of his renal pathology, treatment with an mTOR inhibitor (Answer B) is the best, safest, and most effective long-term treatment option.
Despite the effectiveness of mTOR inhibition in reducing renal angiomyolipoma volume in patients with tuberous sclerosis complex, it is important to keep in mind that referral should be made for consideration of procedural intervention with tumor embolization or surgical resection in patients who cannot tolerate medical therapy or in whom it fails; who are noncompliant; who have tumors greater than 4 or 5 cm and are at high risk for rupture and intra-abdominal hemorrhage; or who have solitary, less complex, and less numerous renal lesions, such that the loss of kidney parenchyma after intervention and the duration of ischemia time during resection would both be minimal.[4]
Outcome of This Case
After initiating medical therapy with oral everolimus, 10 mg/d, the patient’s symptoms of intermittent right flank pain diminished. He had no significant adverse events from oral everolimus treatment and tolerated it well. Repeat cross-sectional CT imaging of the abdomen and pelvis with IV contrast after 3 months of everolimus therapy showed significant reduction of renal angiomyolipoma volume bilaterally. The total renal angiomyolipoma volume was reduced by approximately 50% compared with baseline imaging, with the largest tumor measuring 2.1 cm at its greatest diameter. Additionally, the patient has not had any episodes of hematuria or renal hemorrhage during treatment, because of the drastic reduction in renal angiomyolipoma size bilaterally. He has required no other invasive procedures or surgical interventions to date for his bilateral renal angiomyolipomas. Currently, he is continuing with oral everolimus therapy; repeat CT scan imaging is planned after 6 months of treatment.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
E. David Crawford, MD, serves as Series Editor for Clinical Quandaries. Dr. Crawford is Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology at the University of Colorado School of Medicine; Chairman of the Prostate Conditions Education Council; and a member of ONCOLOGY's Editorial Board.
If you have a case that you feel has particular educational value, illustrating important points in diagnosis or treatment, you may send the concept to Dr. Crawford at david.crawford@ucdenver.edu for consideration for a future installment of Clinical Quandaries.
References:
1. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355:1345-56.
2. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372:657-68.
3. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc. 1991;66:792-6.
4. Sooriakumaran P, Gibbs P, Coughlin G, et al. Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated. BJU Int. 2010;105:101-6.
5. Kothary N, Soulen MC, Clark TW, et al. Renal angiomyolipoma: long-term results after arterial embolization. J Vasc Interv Radiol. 2005;16:45-50.
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7. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005;37:19-24.
8. Curatolo P, Moavero R. mTOR inhibitors in tuberous sclerosis complex. Curr Neuropharmacol. 2012;10:404-15.
9. Peng ZF, Yang L, Wang TT, et al. Efficacy and safety of sirolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: a systematic review. J Urol. 2014;192:1424-30.
10. Franz DN. Everolimus in the treatment of subependymal giant cell astrocytomas, angiomyolipomas, and pulmonary and skin lesions associated with tuberous sclerosis complex. Biologics. 2013;7:211-21.
11. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013;381:817-24.
12. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus long-term use in patients with tuberous sclerosis complex: four-year update of the EXIST-2 study. PLoS One. 2017;12:e0180939.
