While there have been many advances in the field of minimally invasive and targeted therapies for renal tumors in the past few years, there have been few updates on the review of renal vascular smooth muscle lipoma (AML). Professor Flum et al. from Northwestern University provided a thorough review of the epidemiology, pathophysiology, clinical presentation, diagnosis and differential diagnosis, and management strategies of renal AML, which was published online in the Journal of Urology in November of this year.
Epidemiology
Studies in Japan have shown that the incidence of renal AML is about 0.13%, with 0.22% in women and 0.1% in men, and the incidence in women is two times higher than that in men. According to the incidence, renal AML is usually divided into two categories: the simple disseminated type and the type with tuberous sclerosis (TSC) or lymphangioleiomyomatosis (LAM). Since TSC is more common than LAM in clinical practice, only TSC is briefly described in this article.
Tuberous sclerosis
TSC is an autosomal dominant disease with a prevalence of 1/14,000 to 1/12,000 in children under 10 years of age and 1/6000 in newborns in the U.K. Approximately 55% of patients with TSC have renal AML, and it has been reported in the literature that the percentage can reach 90%. Renal AML with TSC is more common in 20-30 year olds, while disseminated renal AML is more common in 40-50 year olds.
The genes closely related to TSC are TSC1 and TSC2, each encoding hamartin and tuberin, which interact to form heterodimers and inhibit the abnormal activation of the mTOR pathway. According to statistics, 2/3 of TSC patients have mutations in TSC1 and TSC2, which can lead to deregulation of cell growth, proliferation, migration, and vascularization, leading to tumorigenesis.
Other clinical manifestations of TSC include cardiac rhabdomyosarcoma, retinal malformations, desmoplakia, sharkskin spots, and facial angiofibromas. Genetic testing not only helps to confirm the diagnosis of TSC, but also provides early screening of family members with TSC.
Clinical presentation
Due to the availability of CT and MRI, more than 80% of renal AML is detected incidentally, with less than 15% of patients presenting with hematuria and less than 10% with shock. The classic triad of renal cancer (RCC) – back pain, hematuria, and palpable mass – is present in 37% to 41%, 11% to 35%, and 11% to 24% of renal AML, respectively.
In sporadic renal AML, the maximum tumor diameter usually does not exceed 4 cm, while in TSC with renal AML, the tumor is not only larger in diameter (3.5-19.3 cm), but also more likely to involve both kidneys.
Imaging
CT and MRI have become the most common and important tools for the diagnosis of renal AML because of the low specificity of symptoms. If a kidney mass contains fat, renal AML is the first thought, as the presence of fat in RCC is very unlikely. Ultrasound is not generally recommended for the diagnosis of renal AML, but can be used as a follow-up test if the diagnosis of renal AML is clear on CT.
CT is now the preferred test for renal AML because of its excellent sensitivity and specificity, as well as its efficiency and rapidity. Even in masses smaller than 2 cm, the presence of fat can be distinguished from the image (see Figure 1). A CT value of less than -15 Hu is usually considered to be a fat component, but in 4% to 5% of renal AML the typical hypointense shadow is not seen on CT because the fat content is too low or because the tumor is obscured by hemorrhage. In this case, it can be easily confused with RCC.
MRI has a unique diagnostic value for renal AML with low fat content (see Figure 1). If phase contrast MRI is used and both fat and calcification are seen in the image, then RCC is more likely, as calcification is extremely rare in renal AML. In contrast to CT, MRI has no risk of ionizing radiation and does not require enhancement scans, making it particularly suitable for patients with renal insufficiency.
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Figure 1. (a) Enhanced CT shows an exophytic mass in the anterior middle portion of the right kidney, which is predominantly fatty; (b) T2 on MRI at the same level as CT, the mass is hyposignal due to fibrosis; (c) T1 on MRI at the same level as CT, the mass is high-signal with a fatty component, which is typical of AML; (d) enhanced T1 lipid compression sequence with reduced signal in the fatty area, which is also a feature of AML imaging. (d) post-enhancement T1 lipid compression sequence with reduced signal in the fatty area is also a feature of AML imaging.
If the mass appears as T1 high signal on MRI and becomes low signal after fat compression, it suggests a high probability of renal AML. AML with low fat content may show relatively low T2 signal because it has abundant smooth muscle cells.
The sharp black shadow at the fat-water junction seen on recent MRI chemical shift iso- and antiphase imaging (see Figure 2) is also a typical sign for the diagnosis of renal AML, especially if the mass is fat-poor and the tumor is <3 cm. However. MRI takes longer to complete and is more expensive than CT.
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Figure 2. (a) Coronal enhancement CT image, showing a 1.4 cm occupancy of the lower pole of the right kidney with enhancement in its inferior lateral aspect (45 Hu difference in CT values before and after enhancement) and a punctate hypointense shadow in the middle, which is suspected to be a fat component and needs to be distinguished from fat-deprived AML and RCC; (b) without enhancement, the high signal shadow indicated by the white arrow on T1, which is consistent with the CT view; (c) after enhancement, the mass is enhanced on the T1 (c) after enhancement, the mass is enhanced on the T1 lipid compression sequence; (d) a sharp black shadow at the fat-water junction is seen on MRI chemical shift iso- and antiphase imaging, which is a fat
Pathology
Histologically, renal AML is of mesenchymal origin and consists of 3 components: heterogeneous blood vessels, spindle-shaped myocytes and mature fat, usually with a highly variable ratio of these 3 components. It is currently believed that renal AML originates from perivascular epithelial-like cells. Therefore, it has been suggested that renal AML is a member of the PECOMA family (WHO definition of PECOMA: mesenchymal neoplasm composed of perivascular epithelioid cells with histologic and immunohistochemical features).
Renal AML is most commonly seen in the renal parenchyma and less frequently in the perinephric and perirenal tissues. The typical pathology of AML is shown grossly and microscopically in Figures 3 and 4, respectively. immunohistochemistry detects HMB45, melanin A and melanocyte-associated markers on spindle-shaped myocytes in renal AML (see Figure 4d), whereas keratin and epithelial cell-associated markers are generally negatively expressed.
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Figure 3. Gross section of renal AML (a) AML in the renal parenchyma, which is brittle and easily ruptured; (b) yellow-white cross-section
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Figure 4. Typical histologic features of AML (a) fat, vascular, and smooth muscle tissues are visible (100×); (b) spindle-shaped myocytes radiating from the vessel wall to the periphery (100×); (c) immature spindle-shaped myocytes in AML (200×); (d) positive expression of HMB-45 in AML (200×)
As mentioned previously, the proportions of the 3 components that make up renal AML vary, and sometimes the fatty component is difficult to see microscopically. The presence of focal cellular anisotropy, epithelioid changes, vitreous changes, cystic changes, and calcifications does not indicate malignant renal AML, but is often mistaken for RCC or sarcoma by the pathology department.
Although renal AML can also occur in conjunction with RCC, the probability of malignancy in renal AML is very low. The risk factors for malignancy in renal AML are: maximum diameter >7 cm, tumor necrosis, and epithelioid carcinoid type. Only simple renal epithelioid malignancies are potentially aggressive. The vast majority of scholars believe that renal AML with focal epithelioid changes should remain in the benign category.
Management strategy
When a diagnosis of renal AML has been made, the question of whether or when to intervene as early as possible, and what specific therapeutic measures are available, is the focus of the next discussion.
Previously, indications for treatment of renal AML were: maximum diameter >4 cm, suspected malignancy, and women of childbearing age. However, the authors of this article suggest that the indications should also include the presence of a combined aneurysm >5 mm, patients with TSC, non-adherent follow-up, and emergency patients.
From the current data, the vast majority of patients followed are with disseminated, non-TSC-associated renal AML, and Professor Seyam et al. found that disseminated renal AML grew at an average rate of 0.19 cm/year compared to 1.25 cm/year for TSC. There is no unanimous opinion on how often renal AML should be followed up, and the authors believe that the decision should depend on the size of AML and whether it is combined with TSC.
Some studies have shown that renal AML larger than 4 cm is more likely to have bleeding or other symptoms, and also grows faster during the follow-up period. Therefore, any tumor larger than 4 cm, especially in combination with TSC, should be treated with interventions. However, this option has not been fully accepted.
Ouzaid et al. followed 130 patients with renal AML (mean follow-up 4 years), 80% of whom were initially asymptomatic and 38 with a maximum tumor diameter >4 cm. 17 patients were treated during this period, including 13 patients with an initial diameter >4 cm. Although the study suggests that the presence of pain or hematuria at the time of initial diagnosis and a tumor diameter >4 cm were both predictors of discontinuation of follow-up, it also suggests that 2/3 of the patients were overtreated even with these risk factors.
The size of the aneurysm in renal AML is an important factor in determining whether the aneurysm bleeds. Also, the size of the aneurysm was positively correlated with the size of the renal AML aneurysm. In renal AML with a maximum diameter of >4 cm, aneurysms >5 mm are more likely to rupture and bleed. Such patients should be adequately informed of the risks associated with conservative observation.
Although rupture of renal AML during pregnancy has been reported only in isolated cases, the consequences are quite serious, and Professor Boorjian et al. detected expression of estrogen receptors and progesterone and even androgens in renal AML, so aggressive treatment is the first choice for women of childbearing age who are planning to become pregnant.
As for the specific treatments, the main ones include surgical resection, arterial embolization, percutaneous ablation and oral mTOR inhibitors.
1.Surgical resection
Surgical resection occupies the majority of the treatment for renal AML. As the status of kidney-sparing surgery (NSS) has gradually increased in the treatment of RCC, it has also been extended to the treatment of renal AML. Especially for those with multiple AML in both kidneys in TSC, NSS can be a great comfort to patients by maximizing the function of their residual kidneys.
The complication rate and tumor recurrence rate after NSS for sporadic renal AML are low. Boorjian et al. reported a 12% complication rate after open NSS and a 3.4% recurrence rate within 8 years. Common complications include urinary leakage/fistula, bleeding, and bowel obstruction. Intraoperative blood loss, ischemic time, and hospital days increase with larger tumor volumes. As with RCC, the safety and efficacy of lumpectomy NSS in the management of renal AML is satisfactory.
If NSS is not possible due to the undesirable location of the tumor, renal subtotal surgery or embolization may be considered.
2. Arterial embolization
In recent years, selective arterial embolization (SAE) has also become more popular among urologists. SAE has even become the treatment of choice, especially in cases of hemodynamic instability due to ruptured hemorrhage (see Figure 5). The main embolic agents used in SAEs today are ethanol, polyvinyl alcohol (PVA), and gel microspheres (Embospheres), and there is a lack of data comparing the safety of these three embolic agents in the treatment of renal AML.
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Figure 5. (a) CT shows a large hematoma in the retroperitoneum with a hypodense shadow near the front, which is considered to be fatty, and combined with the patient’s history of dystocia and hypertension, the patient was diagnosed with right renal AML rupture; (b) digital subtraction angiography (DSA) shows a lobulated aneurysm at a branch of the right renal artery, which is considered to be the source of bleeding and is embolized; (c) DSA after embolization, the bleeding site is closed and the patient’s The patient’s blood pressure returned to normal after the procedure.
The recurrence rate after SAE is higher than that after NSS, ranging from 11% to 40% in the literature. For TSC, lifelong follow-up is generally recommended. However, SAEs are associated with shorter hospital stays and less blood loss than surgical treatment. Common complications include post-embolization syndrome, vascular injury, septic kidney or even renal infarction, and non-target vessel embolization. Post-embolization syndrome, which refers to fever, dystocia and leukocytosis, has been reported in the literature in about 80% of patients, but can be recovered with conservative treatment.
3. Percutaneous ablation
Percutaneous ablation is not yet widely used and is usually limited to asymptomatic patients with small tumors. Patients who underwent radiofrequency ablation (RFA) consisted of two groups: those who were initially suspected of RCC and then biopsied lumpectively to suggest renal AML, and those who underwent RFA directly after the imaging diagnosis was clear. This also indicates that ablation therapy still has some prospects.
4. Drug treatment
For patients with TSC and LAM who cannot undergo surgery, embolization or ablation, oral mTOR drug therapy is the only option.
The target of mTOR inhibitors is the mTOR signaling pathway. The drug not only prevents further tumor growth, but also shrinks some tumors. Sirolimus was one of the first mTOR inhibitors, and the four known phase II clinical trials on this drug included 94 patients with TSC or LAM who had renal AML. In the end, 50% of patients were found to have reduced tumor size and 46.8% achieved partial remission at 12 months after treatment.
In 2 of the clinical trials, there was no significant difference in tumor volume and maximum diameter between the two groups of patients taking sirolimus for 24 months and 12 months, respectively, does this indicate that patients reached peak efficacy at 12 months on sirolimus? If so, what should be the treatment after 12 months of treatment? These are the questions we face today.
The side effects of sirolimus are mainly stomatitis (52%), hyperlipidemia (40%), skin lesions (30%), respiratory tract infections (29%) and proteinuria (18%). To date, only one patient has been reported to have died from a severe respiratory infection.
Another new mTOR inhibitor, everolimus, has been approved by the FDA for the treatment of metastatic RCC that has failed TKI therapy, in addition to being shown to be effective for renal AML in the EXIST-2 study.
EXIST-2 is a multicenter randomized, double-blind controlled trial that included 118 patients with renal AML with TSC or LAM who were randomized to oral everolimus and placebo for a median observation period of 38 weeks and were considered to have responded to a 50% or greater reduction in tumor volume. A response rate of 42% was found in the everolimus group compared to 0% in the placebo group, and the 12-month tumor progression-free rate was 92% in the everolimus group and 25% in the placebo group.
Common side effects of everolimus included stomatitis (48%), nasopharyngitis (24%), acneiform lesions (22%), headache (22%), cough (20%), and hypercholesterolemia (20%).
Although many studies have shown the efficacy and safety of everolimus in the treatment of TSC-related renal AML to be poor, it is unknown whether its efficacy is long-lasting, how long a dosing regimen is required, and how toxic side effects are managed. Whether everolimus has the same efficacy in disseminated renal AML also needs to be clarified by clinical trials.
Conclusion
Renal AML is a relatively rare benign tumor that can be disseminated or combined with TSC or LAM, and due to the popularity of CT, MRI and other impact examinations, it is now mostly found incidentally, and clinical manifestations such as hematuria are rare. However, some renal AML with less fat content is not easily detected by CT and MRI, so MRI with chemical shift isotropic and antiphase imaging is needed to clarify.
For asymptomatic renal AML with tumor size <4 cm, active follow-up is the first choice, while only those with clinical symptoms such as hematuria, large tumor size and easy rupture and bleeding should be considered for interventional treatment. Surgical resection and arterial embolization are currently the most used treatments, but all should be decided on a case-by-case basis for each patient.
In patients with renal AML combined with TSC and LAM with poor residual renal function, oral mTOR inhibitors have been shown to be effective in slowing disease progression, and patients tolerate the side effects reasonably well. Of course, there are still many unknowns regarding the treatment of renal AML, and for the time being, the combination of TSC or LAM should be determined first, and then the treatment plan should be tailored to the patient’s condition.