Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6,000, affecting an estimated 1 million individuals worldwide [1]. TSC can affect almost every organs in the body and has variable clinical presentations [1]. TSC is an autosomal dominant condition caused by mutation in the TSC-1 or TSC-2 genes, which encode the proteins hamartin and tuberin [1]. These proteins form a complex which further activates the GTPase-activating protein Rheb, ultimately inhibiting the mammalian target of rapamycin (mTOR). The inhibition or inactivation of mTOR leads to an overproduction of proteins and increased cellular metabolism, differentiation, and growth in various tissues [1].

The diagnostic criteria for tuberous sclerosis were updated in 2021. This updated diagnostic criteria was based on genetic criteria, i.e., identifying mutation of tumor suppressor genes TSC-1 and TSC-2; and clinical criteria, which have been summarized in Table 1 [2]. The clinical diagnosis of TSC is described by a set of major and minor criteria: 1) definitive TSC; 2 major or 1 major+2 minor features and 2) possible TSC; 1 major or ≥2 minor features.

Table 1 . Diagnostic criteria for TSC.

Major criteria	Minor criteria
Hypomelanotic macules (≥3; at least 5 mm in diameter)	“Confetti lesions”
Angiofibroma (≥3) or fibrous cephalic plaque	Dental enamel pits (≥3)
Ungual fibromas (≥2)	Intraoral fibromas (≥2)
Shagreen patch	Retinal achromic patch
Multiple retinal hamartomas	Multiple renal cysts
Multiple cortical tubers and/or radial migration lines	Non-renal hamartomas
Subependymal nodule (≥2)	Sclerotic bone lesions
Subependymal giant cell astrocytoma	-
Cardiac rhabdomyoma	-
LAM	-
Angiomyolipomas (≥2)	-

Definite TSC: Two major features or 1 major feature with 2 minor features. Possible TSC: Either 1 major feature or ≥2 minor features. Genetic diagnosis: A pathogenic variant in TSC-1 or TSC-2 is diagnostic for TSC (most TSC-causing variants are sequence variants that clearly prevent TSC-1 or TSC-2 protein production. Some variants compatible with protein production (e.g., missense changes) are well established as disease causing; other variant types should be considered with caution. A combination of the two major clinical features, LAM and angiomyolipomas, with other features does not meet the criteria for a definite diagnosis..

TSC, tuberous sclerosis complex; LAM, lymphangiomatosis..

Although neurological and cutaneous manifestations, such as epilepsy, giant cell astrocytoma, hydrocephalus, neurodevelopmental impairment, cortical tubers, and facial angiofibromas, are the most common symptoms of TSC; approximately 70% to 80% of patients with TSC are also affected by renal angiomyolipomas (AMLs) [1]. AMLs are benign tumors comprising blood vessels, adipose tissue, and smooth muscle [1]. They can be accurately diagnosed by computed tomography (CT) and magnetic resonance imaging (MRI) with intralesional fat as the hallmark feature [3]. AMLs smaller than 4 cm are typically asymptomatic, while larger lesions may cause lumbar pain, anemia, and hematuria [4].

Management strategies include selective embolization of the tumor, nephrectomy in severe cases, and medical approaches such as mTOR inhibitors [5,6].

Despite the correlation between TSC and renal AML, and the reports of a high risk of AML-related complications in patients with TSC in literature, disease awareness in clinical practice remains low. Therefore, we present a case series of three patients with TSC and renal AML successfully managed with renal artery embolization, a procedure that preserved the renal parenchyma and function. Institutional Review Board approval was waived due to retrospective case report. Informed consent was obtained from the patients.

1) Case 1

A 21-year-old woman presented with bilateral vague flank pain for the past 6 months, accompanied by recurrent urinary tract infection and hematuria. She had undergone bilateral double J stent placement at another hospital, although medical records were unavailable. She had also experienced epilepsy since the age of four and was on antiepileptic medications.

On physical examination, multiple facial angiofibromas were observed (Fig. 1A). Laboratory investigations revealed hemoglobin levels of 11 gm/dL, numerous red and white blood cells in the urine, and normal renal function. Ultrasonography (USG) showed bilateral lobulated, enlarged kidneys suggestive of renal AML. Based on the TSC diagnostic criteria, she had two major features indicative of tuberous sclerosis: (1) facial angiofibromas >3, and (2) bilateral renal AML. She did not undergo genetic testing.

Figure 1. Case 1: A 21-year-old woman with definite tuberous sclerosis complex having two major features, i.e., facial angiofibromas and bilateral renal angiomyolipoma. (A) Clinical photograph showing facial angiofibromas. (B) Contrast-enhanced computed tomography of bilateral kidneys showing renal angiomyolipoma (red arrows) and in situ Double J stents (blue arrow).

Contrast-enhanced computed tomography (CECT) showed bilateral renal masses involving the upper lobe of the left kidney and the upper and middle lobes of the right kidney. The size of the left kidney was 19×8 cm, whereas the right kidney measured 20×9 cm. (Fig. 1B) The masses contained fat and soft tissue components, with multiple macroaneurysms (1-3 mm in size) and a large arteriovenous (AV) shunt noted in the left kidney (Fig. 2A, C). Normal renal parenchyma was compressed and displaced inferiorly in both kidneys.

Figure 2. Pre- and post-embolization angiograms of Case 1. The arrows denote the description.(A) Angiogram showing left renal angiomyolipoma with micro and macroaneurysms. (B) Angiogram showing coil embolization of the left side macroaneurysm. (C) Angiogram showing right renal angiomyolipoma with microaneurysm. (D) Angiogram showing glue embolization performed for the right side microaneurysm.

The patient underwent staged angioembolization of tumors. First stage included coil embolization (Nester^® Embolization Coil; Cook Medical, three coils of size 18-14-8 and one coil of size 18-14-10) of the AV shunt (Fig. 2B), followed by embolization with glue (Histoacryl+Lipidol) and polyvinyl alcohol (PVA) particles to tackle the macro and microaneurysms of the left renal AML. The right renal AML was embolized using glue and PVA particles in the second stage (Fig. 2D).

Post-procedure recovery was uneventful except for transient bilateral flank pain. Hematuria resolved, and renal function remained within normal limits. At the 1-year follow-up, there was no recurrence of the AML.

2) Case 2

A 37-year-old woman was referred to our center with an ultrasonography report showing bilateral renal masses suggestive of AML. She reported no genitourinary symptoms.

On physical examination she exhibited multiple confetti lesions (minor criteria) on her entire body and more than three hypomelanotic patches (major criteria) larger than 5 mm (Fig. 3A, C). Her renal function tests and routine urinalysis results were normal. Based on clinical diagnostic criteria, a definite diagnosis of TSC was made, as she had two major features, i.e., bilateral renal angiolipoma and hypomelanotic macules, and one minor feature, i.e., confetti skin lesions. The patient did not undergo genetic testing.

Figure 3. Case 2: A 37-year-old woman with definite tuberous sclerosis complex, presenting two major features, i.e., bilateral renal angiolipoma and hypomelanotic macules and one minor feature, i.e., confetti skin lesions. The arrows show the description provided. (A) Hypomelanotic macules and confetti lesions on the back of the patient. (B) Abdominal contrast-enhanced computed tomography showing bilateral renal angiomyolipomas with macroaneurysm on the right side. (C) Hypomelanotic macules and confetti lesions on the right upper limb of the patient.

Abdominal CECT performed at our center showed tumor masses involving the upper poles of both kidneys (left, 6×5 cm; right, 10×7 cm) comprising fat and soft tissues with macroaneurysms, a maximum 3 mm in size, on the right side (Fig. 3B). Although she was asymptomatic, the large size of the tumors posed a significant risk of spontaneous rupture and life-threatening hemorrhage. After counseling, the patient agreed to and subsequently underwent selective embolization of the tumor masses.

The upper polar branches of both kidneys were selectively canulated using a microcatheter, and the tumors were embolized with PVA particles (Fig. 4). Postoperatively, the patient experienced fever, mild flank pain, and nausea, suggestive of post-embolization syndrome. These symptoms were managed conservatively with analgesics, antipyretics, and antiemetics. She was discharged on the third postoperative day. Follow-up evaluations at 1 and 3 years revealed no tumor recurrence or symptoms.

Figure 4. Pre- and post-embolization angiograms of Case 2. (A) Angiogram showing left renal angiomyolipoma with microaneurysm (arrow). (B) Angiogram showing embolization of the left tumor with obliteration of aneurysm (arrow). (C) Angiogram showing right renal angiolipoma with macroaneurysm (arrow). (D) Angiogram showing embolization of the right macroaneurysm with its subsequent obliteration (arrow).

3) Case 3

A 40-year-old woman with a known diagnosis of TSC-1 gene mutation and bilateral renal AMLs was admitted for a hysterectomy due to abnormal uterine bleeding. On examination, she had multiple facial angiofibromas (Fig. 5A). Abdominopelvic examination revealed an enlarged uterus. She had a history of epilepsy since the age of eight, managed with regular antiepileptic medication. Ten years earlier, the patient had undergone coil embolization of left renal artery for spontaneous hematuria. At present, she reported no urinary symptoms. She underwent open hysterectomy with an uneventful postoperative recovery.

Figure 5. Case 3: A 40-year-old woman with known tuberous sclerosis complex-1 gene mutation, bilateral renal angiomyolipomas, and multiple facial angiofibromas. (A) Facial angiofibromas. (B) Abdominal contrast-enhanced computed tomography showing bilateral renal angiomyolipomas (arrows).

During the preoperative investigative work-up for the hysterectomy, abdominal CECT revealed bilateral enlargement of the kidneys (left, 16×8 cm; right, 18.0×8.5 cm) (Fig. 5B) along with coils of previous embolization.

One month post hysterectomy, the patient underwent bilateral renal angiography which revealed AML involving all three lobes of both kidneys (Fig. 6A, B). The coils were visualized in the left middle and lower polar branches, but flow was intact (Fig. 6B). Evidence of any micro or macroaneurysms was absent; hence, the patient was advised conservative management with regular follow up. The option of treatment with everolimus was discussed with the patient; however, she declined this approach.

Figure 6. Angiograms of Case 3. The arrows are showing the description provided. (A) Angiogram of right kidney showing renal angiomyolipoma with soft tissue components and no vascular aneurysms. (B) Angiogram of left kidney showing renal angiomyolipoma with soft tissue components, no vascular aneurysms, and previously inserted coils in the left middle and lower polar branches.

The summary of all cases is provided in Table 2.

Table 2 . Clinicodemographic summary of the cases.

Clinicodemographic characteristic	Case 1	Case 2	Case 3
Age (y)	21	37	40
Genitourinary symptoms	+	–	+
Diagnostic criteria met	Two major	Two major+one minor	Two major
Genetic testing	–	–	TSC-1 mutation+
CECT findings	Bilateral renal mass: left, 19×8 cm; right, 20×9 cm	Bilateral renal mass: left, 6×5 cm; right, 10×7 cm	Bilateral renal enlargement: left, 16×8 cm; right, 18.0×8.5 cm
Duration of follow-up (y)	1	1 and 3	10

CECT, contrast-enhanced computerized tomography; TSC, tuberous sclerosis complex..

Renal AML is a common benign kidney tumor, classified as either sporadic or TSC-associated (TSC-AML) [1]. Sporadic AMLs are indolent in growth and active surveillance is generally conducted for patients with tumor size <4 cm [4]. Contrary to its sporadic counterparts, TSC-AMLs tend to present early in childhood and adolescence, are multicentric and large, and frequently associated with hemorrhage [3,7]. Enlargement of AMLs can impair the renal parenchyma, leading to chronic kidney disease [8]. Approximately 500,000 TSC patients worldwide have stage 1 chronic kidney disease [8]. Retroperitoneal hemorrhage or bleeding into the renal collecting system are the most severe complications [4]. Seyam et al. [7] reported a yearly growth rate of 1.25 cm for TSC-AML vs. 0.19 cm of sporadic AML. Currently, criteria defining the frequency of imaging studies to be performed during surveillance are absent. The International Tuberous Sclerosis Complex Consensus Conference (ITSCCC) for TSC-AML recommends that abdominal MRI or USG should be performed every 1-3 years throughout the lifetime of a patient to assess tumor growth [2]. The ITSCCC also recommends concomitant hematological evaluation and urinalysis along with imaging [2].

The main treatment goals for TSC-AML are to maintain renal function and prevent rupture and enlargement of the tumor [8,9]. Treatment options include medical management with mTOR inhibitors, partial or total nephrectomy (PN/TN), selective arterial embolization (SAE) of the renal artery, and ablative therapy.

1) mTOR inhibitors

Everolimus is an approved drug for the treatment of TSC-AML, and its effect was investigated in the everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2) and extension studies [9]. The EXIST-2 study reported a ≥50% reduction in TSC-AML volume in 55% of patients [9]. Based on these results, the ITSCCC recommended mTOR inhibitors as the first-line treatment for AML ≥3 cm in size, even when asymptomatic [2]. SAE and PN were recommended as second-line treatments [2].

The EXIST-2 extension study has reported the following main adverse effects of everolimus: nasopharyngitis (43%), stomatitis (43%), and headache (30%) [9]. Similarly, Cai et al. [10] reported oral mucositis (100%), irregular menstrual cycles (91%), and abdominal pain (77.8%) as common adverse effects. Wang et al. [11] reported TSC-AML volume reduction of 55.6% with everolimus and 30.5% with sirolimus, concluding that everolimus 10 mg daily might be more effective than sirolimus 2 mg daily for medical management.

While mTOR inhibitors reduce TSC-AML volume, the optimal duration of therapy remains unclear. Moreover, everolimus cannot cure AMLs and its long-term use increases the risk of gonadal dysfunction, interstitial lung disease, and immunosuppression-related complications [12]. A recent review from Japan suggested that the use of everolimus for TSC-associated renal AML is weakly recommended and its dose reduction can be considered during the follow up period [13]. An appropriate management of the adverse effects of mTOR inhibitors is also necessary.

2) Nephrectomy

Surgical treatment for AML includes PN or TN, depending on the size of the tumor. Surgery is typically reserved for cases with suspected malignancy or high hemorrhage risk [2]. An advantage of surgical treatment is the availability of tissue for a histological diagnosis. The advantages of PN include its feasibility, low complication rates, and preservation of renal function [14,15]. PN can be performed by open, laparoscopic, or robotic-assisted techniques and studies have reported similar surgical outcomes with each method [13,14].

In a report on PN for sporadic AML, Boorjian et al. [14] described a local recurrence rate of 3.4%, with no cases of chronic renal insufficiency. In comparison to sporadic AMLs, TSC-AMLs are often multifocal, bilateral, and exhibit a high recurrence rate [3]. It is therefore imperative to adopt a broader treatment strategy for TSC-AML. Preoperative therapy with mTOR inhibitors may reduce the TSC-AML size, enable PN, and decrease recurrence rates. Staehler et al. [15] described three TSC-AML cases with 6 months of neoadjuvant sirolimus therapy prior to PN. They found that the tumor volume decreased by 38%-95%, facilitating easier PN with no recurrence and well preserved renal function postoperatively [15].

A TN may be necessary in cases with very large AML or severe bleeding following rupture; however, this carries the risk of renal insufficiency [15]. Despite the pros and cons, surgical treatment continues to play an important role in managing AML.

3) Embolization

One of the major complications of AML is hemorrhage following rupture, which can be catastrophic and life threatening. SAE is recommended as a first-line treatment for bleeding AMLs [2]. SAE enables hemostasis, tumor shrinkage, and preservation of renal function. Embolization can be performed with absolute alcohol, metallic coils, triacyl gelatin microspheres, or n-butyl-2-cyanoacrylates. SAE is also widely used as a preventive strategy for AML rupture and is recommended as the first choice for managing AMLs >4 cm in size, which are at high risk of rupture [2,4]. Compared to surgical treatment, SAE has several advantages, including being minimally invasive, having low complication rates, sparing renal function, and achieving satisfactory short-term (<5 years) outcomes [5].

In a clinical study by Ewalt et al. [16], the AML size after SAE decreased in 13 of 16 patients within 3 months post-treatment, and no tumor regrowth was observed in 7 patients imaged 3 to 9 years later. In our clinical series (Cases 1 and 2), post-embolization follow up at 1 and 3 years, respectively, revealed no regrowth of the AMLs. In Case 3, presentation 10 years after the initial coil embolization showed no AV aneurysms and only fat and soft tissue components of the tumor.

In another study, the recurrence rate of TSC-AML after SAE was as high as 60% [17]. Thus, long-term follow-up is necessary after SAE. Some authors have reported the effect of everolimus for TSC-AML recurrence after SAE, with AML volume decreasing in all patients. A 50% reduction in volume was observed in 57% (8 of 14) of the cases, with a mean reduction rate of 53% [17].

Post-embolization syndrome, the most common complication of SAE, occurs in up to 80% of cases [18]. The symptoms, including high fever, flank pain, nausea, or leukocytosis, can be treated conservatively. Among our cases, only one patient experienced post-embolization syndrome, which was treated conservatively. This case series highlights that SAE is a good option for emergent situations like AML rupture or hemorrhage. However, embolization carries the risk of deterioration of renal function and tumor recurrence. Notably, in this case series, the tumors were treated successfully without these complications.

4) Ablation

Ablative therapies for AML are mainly reserved for small, symptomatic tumors or for patients with a solitary kidney [19]. The ablative techniques include radiofrequency ablation, microwave ablation, and cryoablation. Krummel et al. [20] described a case of TSC-AML managed with CT-guided percutaneous cryoablation combined with a low-dose mTOR inhibitor. They reported that the combined treatment strategy mitigated side effects and reduced the tumor size [20].

A cohort of 15 patients with AML with a mean tumor size of 2.6 cm, who underwent either laparoscopic or CT-guided percutaneous radiofrequency ablation were described by Castle et al. [19]. They observed minimal intraoperative and postoperative complications with no recurrence in a mean follow-up period of 21 months [19]. Although further studies are needed to validate the use of ablation therapy as a management option for AMLs, they appear to be effective for small AMLs [13].

In summary, tuberous sclerosis complex-associated AMLs tend to present at a young age, are multicentric and large, and frequently associated with hemorrhage. SAE is a safe, minimally invasive, and effective strategy to prevent the rupture and life-threatening hemorrhage associated with AMLs.

None.

The author has nothing to disclose.

Concept and design: all authors. Analysis and interpretation: all authors. Data collection: all authors. Writing the article: GGG, MPT. Critical revision of the article: GGG, MPT. Final approval of the article: all authors. Statistical analysis: none. Obtained funding: none. Overall responsibility: all authors.