Renal Angiomyolipoma

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Continuing Education Activity

Renal angiomyolipomas (AMLs) are considered the most prevalent benign renal tumor. Renal AMLs are generally composed of blood vessels, smooth muscles, and adipose tissues. Although most of these tumors are found incidentally on radiological imaging, symptomatic presentations such as flank pain, gross hematuria, or severe retroperitoneal hemorrhage may also exist. Imaging plays a central role in the diagnosis and management of these tumors. This activity reviews the evaluation, treatment, complications, and prognosis of renal angiomyolipomas and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

  • Describe the epidemiology of renal angiomyolipoma.
  • Review the evaluation of a renal angiomyolipoma.
  • Summarize the treatment of a renal angiomyolipoma.
  • Outline the complications associated with renal angiomyolipoma.

Introduction

Renal angiomyolipomas (AMLs) are the most prevalent benign renal tumor.[1] First described by Grawitz in 1900, they are generally highly vascular, primarily composed of smooth muscle and adipose tissues, and are distinguished by perivascular epithelioid differentiation.[2] Although most of these tumors are found incidentally on radiological imaging, symptomatic presentations also exist. Typical symptoms would include flank pain, gross hematuria, and retroperitoneal hemorrhage, which can be severe.[3] 

Angiomyolipomas are sometimes mistakenly referred to as hamartomas. While both are benign, the difference is that an angiomyolipoma is a true tumor, while a hamartoma is defined as a disorganized collection of normal local tissue and cells that are usually the result of a trauma, infection, infarction, obstruction, or hemorrhage. Although first described by Grawitz, angiomyolipomas are distinct from Grawitz tumors which are malignant renal cell carcinomas and hypernephromas.

Imaging plays a central role in the diagnosis and management of renal angiomyolipomas.[4] The tumors contain variable amounts of the same three tissue elements (vascular, muscular, and adipose). Variations will have different pathological, radiological, and clinical features.[5] 

The fundamental diagnostic criterion of classic angiomyolipoma is detecting a large amount of adipose tissue on radiological imaging.[6] Although considered benign, the tumors may extend into the surrounding perirenal fat or renal sinus and nearby organs and lymphatics.[7] There are also rare, isolated reports of tumor thrombi extending through the renal vein into the vena cava.[8][9]

The management of angiomyolipomas is generally based on the clinical manifestations, tumor size, number, growth pattern, and malignant potential.[2][5] For example, epithelioid angiomyolipoma of the kidney is considered an uncommon subtype of angiomyolipoma, which is potentially malignant.[10]

Etiology

Renal angiomyolipomas most often occur as "sporadic" cases (80%), which are isolated but may also be associated with certain "hereditary" conditions (20%) such as tuberous sclerosis and pulmonary lymphangioleiomyomatosis.[3][5] The exact reason behind the sporadic cases is not fully known, but some researchers postulate that it results from a spontaneous genetic mutation.[6] 

Hereditary angiomyolipomas, associated with tuberous sclerosis complex or pulmonary lymphangioleiomyomatosis, are caused by a genetic mutation in the TSC1 or TSC2 genes.[5][11] These mutations affect mTOR (mammalian target of rapamycin), which explains the response of these angiomyolipomas to mTOR inhibitors like sirolimus and everolimus.[12]

Compared to the more common sporadic type, hereditary angiomyolipomas (associated with tuberous sclerosis or lymphangioleiomyomatosis) are likely to be larger, begin at an earlier age, be multicentric and bilateral, grow more quickly, hemorrhage, develop chronic renal failure, and undergo malignant transformation.[13][14]

Tuberous sclerosis is a rare, familial, autosomal dominant genetic disorder that causes benign tumors to develop in various body parts, usually affecting the brain, eyes, heart, lungs, and kidneys. It is also associated with adenoma sebaceum, epilepsy, and mental deficiencies.[15] The overall incidence of tuberous sclerosis is estimated at about 1 per 10,000 population, although it is thought to be significantly underdiagnosed.[15] There is no racial or sexual preference for tuberous sclerosis.[15] More than 50% of patients with tuberous sclerosis will develop angiomyolipomas.[5] (See our companion article on Tuberous Sclerosis.)[15]

Patients with tuberous sclerosis tend to have larger angiomyolipomas when diagnosed (32% will be >3 cm), are more likely to have bilateral and multifocal lesions, and have twice the rate of tumors that increase in size over time compared to non-tuberous sclerosis AML patients.[16][17][18] They are also more likely to have the epitheliod variant type of angiomyolipoma, which is more likely to become malignant.[19] Among women with tuberous sclerosis, 40% will demonstrate some degree of pulmonary lymphangioleiomyomatosis, which is described below.[16][20][21]

Pulmonary lymphangioleiomyomatosis is an exceedingly rare genetic disease often associated with angiomyolipomas that may sometimes be associated with tuberous sclerosis. The overall incidence is about 5 cases per one million women.[22] It typically affects women of childbearing age by causing abnormal smooth muscle cell growth in the lungs, lymph nodes, and kidneys. In the lungs, it causes cysts which can affect pulmonary function resulting in dyspnea. In the kidneys, 45 to 60% of patients will develop angiomyolipomas that tend to be multiple and bilateral.[23][24][25] Pulmonary lymphangioleiomyomatosis should be suspected in younger women with interstitial lung disorders. Lymphangioleiomyomatosis can be diagnosed by a biopsy or an elevated serum vascular endothelial growth factor D (VEGF-D).[26]

All patients newly diagnosed with lymphangioleiomyomatosis should receive renal imaging as screening for angiomyolipomas. However, due to its rarity, routine VEGF-D testing for lymphangioleiomyomatosis is not necessary or recommended for most female patients with angiomyolipomas but should be considered in younger women with multiple renal AMLs, especially if they also have pulmonary issues. (See our companion article on lymphangioleiomyomatosis.)[23]

Epidemiology

Renal angiomyolipomas are rare kidney tumors that account for only 0.3 to 3% of all renal neoplasms.[2][27] The overall prevalence rate of renal angiomyolipomas ranges from 0.13 to 2.2%, with over eighty percent isolated and sporadic cases.[6][28][29][30] The other twenty percent develop in association with pulmonary lymphangioleiomyomatosis or tuberous sclerosis complex.[28][31] 

Renal angiomyolipomas tend to occur in females more than males, possibly due to estrogenic effects.[5] The size of the tumors also tends to be larger in females than males. There is an increased growth rate of angiomyolipomas in pregnant women and a higher risk of hemorrhagic complications.[32][33][34][35] Exogenous estrogen therapy also appears to increase the risk of bleeding from angiomyolipomas.[36]

At least 50 to 75% of patients with tuberous sclerosis will be found to have renal angiomyolipomas.[5][37][38][39] In these patients, the incidence of renal angiomyolipomas increases with age, while the initial presentation of the tumors tends to be younger (13 years vs. 24 years).

Pathophysiology

The exact reason for sporadic renal angiomyolipoma is not fully known.[5][28] It appears that all three tissue types are derived from pericytes (microcirculatory mural cells) as they all express pericyte markers except for the endothelial cell components that develop independently.[40][41]

Hereditary renal angiomyolipomas are caused by a mutation in either the TSC1 or TSC2 gene.[2][11] These two genes encode the essential proteins hamartin and tuberin, respectively.[3][5] The interaction between these two proteins forms a tumor suppressor complex.[5] This tumor suppressor complex inhibits the Mammalian Target of Rapamycin (mTOR) pathway, which is crucial for cell growth, angiogenesis, and protein synthesis.[5][28]

Deficient or defective TSC1 or TSC2 gene activity will lead to unchecked activation of the mTOR pathway resulting in the formation of angiomyolipomas.[5][16][42] 

Angiomyolipomas are generally considered benign and will only very rarely become malignant.[16] The majority of angiomyolipomas are asymptomatic and tend to remain stable in size. Only about 9% tend to enlarge over time.[43] Larger tumors (>6 cm) are more likely to enlarge and grow, hemorrhage, and cause symptoms.[43]

Histopathology

Renal angiomyolipomas can be classified histologically as either typical (triphasic) or atypical (monophasic or epithelioid).[3][44] Triphasic angiomyolipomas usually contain three tumor components (blood vessels or vascular, smooth muscle cells, and mature adipocytes). Monophasic angiomyolipomas usually consist of one major component, while other elements are typically present only in minimal amounts.[3][6][44]

Gross Pathology Descriptions

  • The mean tumor size is 6 cm, but the range varies from 0.5 to 25 cm.[3]
  • A "large" tumor would be >6 cm. (Historically, this was previously 4 cm.)
  • Circumscribed, not encapsulated.[45]
  • Tumors rarely have a cystic component.[44]
  • Tumors are usually unifocal and unilateral but could be bilateral or multiple, suggesting underlying tuberous sclerosis.[44]
  • The cut surface appearance could be gray-white (smooth muscle component), red (vascular component), or yellow (adipose component); the typical golden-yellow appearance depends on the fat content.[4]
  • It may or may not invade the local perinephric fat, lymphatics, or renal sinus.[3]
  • May rarely invade the renal vein and develop a tumor thrombus similar to malignant renal tumors with possible intracardiac extensions and pulmonary embolisms.[8][9]
  • Epitheliod variant tends to have minimal fat and may show metastasis in a third of cases.[46]

Microscopic Pathology Descriptions

  • The classic triphasic renal angiomyolipoma contains thick-walled dysmorphic, disorganized hyalinized blood vessels without elastic lamina.[47] 
  • The tumor also contains mature adipose tissue and myoid spindle cells.[45]
  • Epithelioid variant usually contains predominant polygonal cells with densely eosinophilic cytoplasm. Hemorrhage, necrosis, epithelioid cellular proliferation, and mitotic figures are typically common.[45][48]
  • In renal angiomyolipomas with epithelial cysts, the cysts are lined by cuboidal or hobnail epithelial cells.[45]

Biomarkers

Renal angiomyolipomas are comprised of three cell types, all originating from pericytes.[5][40] The three cell types are atypical smooth-muscle-like, adipocyte-like, and epithelioid cells.[5] Accordingly, they express pericyte markers.[40][45] The expressed pericyte markers are angiotensin II type 1 receptor, platelet-derived growth factor receptor-beta, desmin, calponin, alpha-smooth muscle actin, and vascular endothelial growth factor receptor 2.[40] However, the endothelial cell or adipocyte markers, including CD31 and S-100, are not expressed.[40]

Renal angiomyolipomas typically stain strongly positive for estrogen, progesterone, and androgen receptors which partly explains the increased incidence in females and the accelerated growth in patients on hormonal therapy.

Melanocytic markers for spindle cells (HMB-45 and Melan-A) can help differentiate angiomyolipomas from various sarcomas.[16][48]

Malignant angiomyolipomas are extremely rare. Risk factors would include fat-invisible lesions on imaging, pure epithelioid histology, a size greater than 7 cm, and the presence of intralesional necrosis.[16][49][50]

History and Physical

Renal angiomyolipomas are mostly asymptomatic and typically diagnosed incidentally.[5] Advances in imaging technology have significantly increased the likelihood of diagnosing more cases.[44] 

Historically, up to 15% of patients would present with a spontaneous retroperitoneal hemorrhage (also called Wunderlich syndrome). This can be severe and lead to shock in about one-third of patients.[5] Therefore, the main clinical concern in a patient newly diagnosed with renal angiomyolipoma is the risk of potentially life-threatening bleeding.[5] (Spontaneous retroperitoneal bleeding can also be caused by renal cell cancers, nephritis, and polyarteritis nodosa, but angiomyolipomas are the most common etiology.)

Possible clinical signs and symptoms include flank pain, palpable abdominal mass, urinary tract infection, hematuria, anemia, severe renal insufficiency, and shock.[5][6] Classic renal angiomyolipomas have a benign prognosis, but the epithelioid variant can undergo malignant transformation.[16]

Renal angiomyolipomas associated with tuberous sclerosis complex or pulmonary lymphangioleiomyomatosis tend to be more aggressive, occur at an earlier age, are likelier to be bilateral and multifocal, and are larger at initial diagnosis than the more common sporadic variety.[4][5][51]

Evaluation

In clinical practice, angiomyolipomas appear as either fat-rich, fat-poor, or fat-invisible masses.[52] About 5% of angiomyolipomas will be of the fat-poor or fat-invisible variety.[53][54][55]

CT scanning is generally used first, often for unrelated reasons, and may be sufficient. If not, an MRI will be more sensitive in identifying fat-poor angiomyolipomas.[43][56] CT scans also have the advantages of wide availability, lower cost, easier access, and can be performed quickly. For fat-invisible lesions, no imaging study will suffice, and it will require either a percutaneous biopsy or surgical intervention.[43]

The cornerstone for identifying renal angiomyolipoma is diagnostic imaging. A  biopsy is not generally required to diagnose an angiomyolipoma but might be needed to exclude malignancy in difficult or complex cases such as fat-invisible renal mass lesions. Several imaging modalities help diagnose this condition as described below:

Ultrasonography: Hyperechoic lesion associated with a posterior acoustic shadowing is the typical feature of a fat-rich angiomyolipoma.[6] Renal masses might be iso or hyperechogenic, and a significant percentage (up to 30%) of smaller renal cell cancers can appear similarly.[5][6][57] 

The lesion's echogenicity directly correlates with the total fat content.[31] Fat-poor angiomyolipomas have a mixed echogenicity.[4][5] Fat-invisible angiomyolipomas are homogeneously isoechoic.[6] 

Unfortunately, about a third of renal cell carcinomas can demonstrate a similar appearance on ultrasound.[57] Accordingly, the ultrasonographic findings in angiomyolipomas are often inconclusive, and further investigations are still required.[5][6] Overall diagnostic accuracy of ultrasound in the initial diagnosis of angiomyolipomas is only about 78%.[58] 

The combination of tumor size with ultrasonic image-based quantitative textural analysis improves the ability of ultrasonography to differentiate hyperechoic renal cell carcinomas from angiomyolipomas with a higher degree of accuracy.[59]Ultrasonography can be most useful in tracking the progress of known lesions as it is cost-efficient and minimizes ionizing radiation exposure.[16][60]

A CT or MRI is suggested if the ultrasound shows significant growth (>2.5 mm/year) or a potentially serious change. (It is helpful to repeat the same imaging modality used to make the original diagnosis so the comparison can be more precise.) For these reasons, a baseline ultrasound is suggested for newly diagnosed angiomyolipomas if not already obtained. The combination of tumor size with ultrasound image-based quantitative textural analysis improves the ability of ultrasonography to differentiate hyperechoic renal cell carcinomas from angiomyolipomas with a higher degree of accuracy.[59]

Computed Tomography: The presence of a region of interest on CT scanning that contains attenuations of –10 Hounsfield Units or less is considered a dependable and reliable sign of fatty tissue, which is easily seen in most fat-rich angiomyolipomas.[5][6] The CT scan may not show a hypoattenuating area that measures less than –10 HU in fat-poor angiomyolipomas.[61] 

For this reason, proper placement of the region of interest (ROI) is essential to detect the fatty tissue component of suspicious renal masses. This is because the attenuation values will be higher if the ROI is placed on the muscular or vascular component than if placed on fatty tissue.[5][6] 

Fat-poor angiomyolipomas appear heterogeneously hyperattenuating or iso-attenuating. Fat-invisible angiomyolipomas appear homogenously hyperattenuating because there is insufficient adipose tissue to show any decreased density. In these cases, an MRI is usually the next recommended step. In selected cases, a contrast-enhanced CT scan may be indicated if there is a high suspicion of active bleeding, as it is necessary to find tortuous blood vessels prone to hemorrhage before a therapeutic embolization can be performed.[5][6][62]

Magnetic Resonance Imaging:  There is little difference in accuracy between MRI and CT scans for detecting most renal angiomyolipoma although MRI is considered superior in fat-poor lesions.[5][6][31] 

In one study of 98 pathologically confirmed fat-poor angiomyolipomas, 23% were identifiable on MRI but not CT scan.[63] The classical approach for diagnosing this condition is locating the fatty component inside the mass.[5] The best way to find the fatty area is by comparing the T1-weighted MRI images with and without selective fat suppression.[6]

Fat-rich angiomyolipomas show T1-hypointensity (dark) with fat suppression and T1-hyperintensity (bright) without fat suppression. It is important to note that this T1-hyperintensity is also present in other conditions like renal cell carcinomas and hemorrhagic cysts so it is not a specific, definitive, diagnostic manifestation of angiomyolipomas.[6][31] 

The main difficulty is to diagnose the fat-invisible mass, which contains too little fat to manifest the hypointensity on the fat-suppressed images required for making the diagnosis.

The application of MRI artifacts had been proposed for improved evaluation of the fat content in renal tumors. One of these is the India ink artifact which makes a black line at the boundary between fat and water. Applying this type of artifact helps diagnose small tumors and fat-poor angiomyolipomas—phase versus opposed phase chemical shift MRI assists in differentiating fat-poor angiomyolipomas and renal cell carcinomas. T2-weighted images are also beneficial for diagnosing renal angiomyolipomas.[5][6] 

Fat-rich angiomyolipomas are usually hyperintense while fat-poor angiomyolipomas manifest as heterogeneous or homogeneously hypointense in comparison to renal tissues.[5][16] Fat-invisible angiomyolipomas are homogenously hypointense compared to the renal parenchyma due to their minimal amount of fat.[62][64] 

Gadolinium contrast is generally not needed for diagnosis but can help identify internal aneurysms and determine general vascularity. Overall sensitivity and specificity of MRI for diagnosing fat-poor angiomyolipomas have been reported as 83% and 90%, respectively.[56] A biopsy may be necessary if a definitive diagnosis cannot be made by MRI imaging.

Percutaneous Biopsy: Percutaneous renal biopsies are mainly indicated to differentiate malignant renal lesions from benign masses.[5] As the vast majority of renal masses show characteristic signs of malignancy and benign lesions, such as angiomyolipomas, are usually diagnosed reliably with imaging, routine percutaneous biopsies are not generally required or recommended. Lesions that raise the suspicion of malignancy will typically demonstrate necrosis, intralesional calcifications, or lymphadenopathy; in these cases, it is reasonable to proceed directly to surgical resection.[17] 

The purpose of a percutaneous renal biopsy is mainly to identify benign lesions that would not require aggressive treatment in those rare equivocal cases where imaging modalities alone are unable to make a definitive diagnosis.[5][31][65]     

A percutaneous renal biopsy is typically only used to differentiate a renal cell carcinoma from a fat-invisible or low-fat angiomyolipoma if both MRI and CT scan images are inconclusive or indecisive.[5][66] On a CT scan, a fat-invisible angiomyolipoma usually manifests as a hyperattenuating lesion that enhances homogeneously.[5][63] 

Although this imaging presentation is unusual for a renal cell carcinoma, both lesions may look identical.[5][63] In this situation, the lesion should first be evaluated by MRI to get further information.[5][63] While fat-invisible angiomyolipomas appear hypointense homogenously on T2-weighted images on MRI, renal cell carcinomas (clear cell subtype) manifest as hyperintense lesions.[5][63] The main issue is the papillary renal cell carcinoma which also appears as a hypointense mass.[5][63] 

A percutaneous renal biopsy may be necessary to differentiate between the papillary subtype of renal cell carcinoma and fat-invisible angiomyolipomas if the lesion is small (considered as less than 3 cm) and appears T2-hypointense on MRI without any evidence of fat inside the tumor.[5][65] If there is a high possibility of bleeding or the mass is particularly large, proceeding directly to a suitable surgical treatment could be the best option to avoid hemorrhagic complications.[5][6] 

The risk of significant bleeding following a percutaneous biopsy in fat-invisible angiomyolipomas is no greater than for other renal masses.[67]

Renal nuclear scanning utilizing technetium-99m (Tc) mercaptoacetythiglycine (MAG3) renography is not generally used in the routine evaluation of angiomyolipomas and other renal masses. It evaluates relative renal function, which can be helpful before nephron-sparing surgery. It may also be useful in differentiating renal masses and pseudomasses in cases where other imaging modalities are ambiguous.

Evaluation Summary:

  • Ultrasonography can be useful for the initial detection of a renal mass or for tracking but is not reliable enough for an initial diagnosis.
  • CT scanning is generally used first in the initial evaluation of renal masses, usually for unrelated reasons, and is often sufficient for diagnosis.
  • CT scans also have the advantages of wider availability, lower cost, easier access, and can be performed quickly.
  • An MRI will be more sensitive in identifying fat-poor angiomyolipomas if the CT scan is inconclusive.[43][56] 
  • For fat-invisible lesions, no imaging study will suffice, and a definitive diagnosis will require either a percutaneous biopsy or direct surgical intervention.[43] 
  • If any of these means cannot determine a reliable diagnosis, the mass lesion should be treated as a renal malignancy.

Treatment / Management

Indications for Treatment

Most angiomyolipoma cases are asymptomatic and usually do not require treatment, but therapeutic interventions are required in the minority of cases.[5] 

In the past, the main indications for intervention were the presence of the symptoms, suspicion of malignancy, the presence of the tumor in women of childbearing age, and a size larger than 4 cm.[5] 

Recently, the historical 4 cm size threshold has been questioned. Some recent studies do not support the 4 cm size criterion because only 30% of renal angiomyolipomas larger than 4 cm were symptomatic.[5] 

Other studies revealed that using the 4 cm criterion as a predictor of hemorrhage has lower specificity than the tumoral aneurysm size of 5 mm.[5][31] The degree and complexity of the lesion's vascularity (multiple, large, tortuous vessels, aneurysms) is a better general indicator of the need to require an intervention to prevent significant bleeding.[31] 

This evidence suggests that the vascularity of the angiomyolipoma and the size of any related aneurysms are ultimately more significant than the tumor size alone.[31] Increasing the size criteria to >6 cm avoided presumed overtreatment in 65% of patients.[68]

Angiomyolipomas can be especially troubling during a pregnancy given the high levels of estrogen receptors in these lesions, which causes them to enlarge, and the relatively high rate of reported hemorrhage.[69][70][71] 

The European Association of Urology and the Canadian Best Practice Report recommend that the treatment of angiomyolipomas be considered and discussed with women of reproductive age who have been found to have these lesions.[72][73][69]

If an angiomyolipoma is found in a pregnant lady, it should be managed similarly to other renal tumors, and the treatment should be highly individualized.[74]

Currently, the European Association of Urology and the Canadian Urological Association recommend that intervention is required in well-selected cases and should consider the following criteria:[72][73][13]

  • Symptoms from the tumor(s) such as persistent pain
  • Large lesions (>6 cm, formerly >4 cm)
  • Multiple lesions
  • Lesions that are enlarging >2.5 mm per year (>5 mm yearly is considered high risk)
  • Intralesional aneurysms >5 mm
  • Poor access to emergency care or follow-up
  • Poor patient compliance 
  • Presence of a tumor in women of childbearing age 
  • High-risk occupations such as commercial airline pilots
  • Female patients who must continue hormonal therapy

Possible interventions include medical treatment with mTOR inhibitors, thermal ablation (radiofrequency ablation and cryotherapy), selective renal artery embolization, and surgical excision (total nephrectomy, partial nephron-sparing surgery).[5]

Medical Treatment: Hereditary renal angiomyolipomas (those associated with tuberous sclerosis and/or pulmonary lymphangioleiomyomatosis) are caused by a mutation in the TSC1 or TSC2 genes resulting in unchecked activation of the mTOR pathway. This results in cell overgrowth and the formation of angiomyolipomas.[11][12] 

Medications that inhibit the mTOR pathway can interrupt tumor progression and promote the reversion of the existing lesions.[5][12] It has been suggested that all hereditary angiomyolipoma lesions >3 cm be treated with mTOR inhibitor medications even if asymptomatic.[1][5]

Sirolimus was the first mTOR inhibitor used to treat hereditary angiomyolipomas.[75] Initial studies with sirolimus showed a greater volume reduction in fat-poor compared to fat-rich angiomyolipomas. This was most obvious in the more highly vascularized and low-fat areas of the tumor. Excessive tumoral vascularity and related aneurysms were markedly reduced by 75% to 100%.[76]

Everolimus (also an mTOR inhibitor) was approved by the U.S Food and Drug Administration (FDA) for treating hereditary angiomyolipomas in the setting of tuberous sclerosis complex.[5][16][28][77][78] An average 55% reduction in tumor size has been reported with everolimus.[79] The standard starting dose is 10 mg daily.

The use of everolimus in sporadic angiomyolipomas is more problematic. A 2020 phase II multi-institutional prospective trial reported good efficacy in patients who were given 4 to 6 cycles of monthly everolimus therapy based on response and tolerability. Over 50% of the patients demonstrated a reduction in tumor size of 25% or more, but almost 50% developed side effects or toxicities that required modification or discontinuation of therapy.[80] This compares favorably with the EXIST-2 trial of everolimus use in hereditary angiomyolipomas.[81]

It is important to recognize that mTOR inhibitors are not risk-free and have many reported side effects.[14] Dose adjustment or even drug discontinuation may be required if the patient manifests any severe side effects.[82] The following encompasses the most likely side effects associated with these medications:[14]

  • Amenorrhea
  • Delayed wound healing
  • Dyslipidemia
  • Fatigue
  • Hyperglycemia
  • Hypophosphatemia
  • Infections
  • Lymphopenia
  • Microcytic anemia
  • Non-infectious pneumonitis
  • Proteinuria
  • Stomatitis
  • Thrombocytopenia

Thermal Ablation

Thermal ablative therapy (radiofrequency ablation, cryotherapy, etc.) has been recommended by the American Urological Association Guidelines for small renal masses (<3 cm).[83] 

Specific selection depends on patient characteristics, tumor size, and specific location, as well as local experience and expertise. Thermal ablative therapy has the advantage of being able to perform simultaneous percutaneous renal biopsies and being effective regardless of the underlying nature of the tumor. This gives them a significant advantage over selective angiographic embolization, where the diagnosis has to be clear and definitive before treatment, although embolization remains the preferred minimally invasive procedure for angiomyolipomas. The most commonly used thermal ablative modalities include cryotherapy and radiofrequency ablation.

  • Cryotherapy has been used very successfully in small numbers of angiomyolipoma patients, but there is insufficiently reported data to recommend its routine use.[31][83][84][85] 
    • Cryotherapy has some unique advantages, which include minimal damage to surrounding renal tissue, a well-defined area of ablation, the ability to obtain a tissue biopsy during the same procedure, percutaneous accessibility, minimally invasive technology, and the delivery of definitive treatment to the mass regardless if it is eventually determined to be a benign or malignant lesion.
    • In institutions that have experience with this modality, cryotherapy may be a very reasonable option, especially where arterial embolization has failed or is not technically feasible, as well as in situations where the absolute minimal loss of renal function is desired or there is some remaining doubt about the diagnosis. This would also include patients with pre-existing renal failure or extensive bilateral disease as an alternative to surgical resection.
    • If renal cryoablation of the tumor is being considered, it would be best to include it within a clinical trial if possible. No data is yet available on the possible combination of angiographic embolization together with renal cryotherapy, but it might theoretically provide superior results for larger tumors.
  • Radiofrequency ablation of angiomyolipomas has demonstrated minimal complications with good efficacy. This minimally invasive technique is most suitable for small-sized tumors which are asymptomatic but could also target large masses.[5][31] 
    • Radiofrequency ablation targets the vascular and solid elements of the tumor mass without damaging normal renal tissue. The efficacy of radiofrequency ablation for renal angiomyolipomas has been assessed for small angiomyolipomas in relatively small series.[5] 
    • In one study, 15 small renal angiomyolipomas were treated successfully with complete disappearance of tumoral enhancement on CT scan and a low complication rate (13.3%) at a mean follow-up of 21 months.[86] 
    • Another study reported a reduction in tumor size from 4.5 cm to 2.9 cm after radiofrequency ablation of a sporadic angiomyolipoma in a patient with a solitary kidney without any complications or tumor recurrence at the 12-month follow-up.[87][88] 
    • Four large angiomyolipomas were treated by radiofrequency ablation in another study, and no complications or hemorrhagic events were reported. This study also showed, during a follow-up of 48 months, a significant decrease in the mean soft-tissue-to-total tumor ratio, but the total tumor volume did not significantly change.[88][89] CT scans usually guide the procedure, but ultrasonography is a possible alternative.[5] 
    • CT scan guidance is required for tumors that cannot be easily and safely targeted by ultrasonography. Superselective renal artery embolization combined with radiofrequency ablation has produced excellent success rates in a small number of studies.[90] Further studies are needed to determine if this is superior long-term to alternative treatment.

Selective Renal Artery Embolization: In the past, the main treatment for angiomyolipoma was surgical excision because tumor malignancy could not be excluded.[3][16] Currently, selective transarterial embolization is considered the first-line treatment, especially if there is a risk of acute bleeding, active hemorrhaging, or hemodynamic instability.[5][14][31][72][91] 

Selective renal artery embolization is the preferred procedural option reserving surgery and possibly thermal ablative therapies for patients with vascular malformations, uncontrollable symptoms, embolization failures, or diagnostic uncertainty.[5][14] The overall success rate of selective renal artery embolization is 93%, with an average reduction in tumor size of 38%.[5][14]

When the surgical option is indicated, preoperative embolization of the tumor may be considered to reduce the complications and the difficulty of the operation.[4][5][31] Embolization is not a risk-free option, and it is associated with a relatively high rate of side effects (42.8%).[5] 

Most of these side effects are related to a post-embolization syndrome characterized by flank pain, fever, vomiting, nausea, and leucocytosis during the first three days after the procedure.[5][16] 

These side effects are generally managed conservatively with standard supportive care. Prescribing antipyretics, antiemetics, and analgesia prophylactically could play a major role in minimizing and controlling these symptoms.[5][16][72] Thirty percent of cases treated with selective arterial embolization will need a second treatment due primarily to tumor revascularization.[14][73]

Surgical Excision: Total or partial nephrectomy is the only treatment option that totally eradicates the entire renal mass.[3] Every surgical operation should use a nephron-sparing approach whenever possible.[3][14] 

Parenchymal preservation is especially important in patients with hereditary angiomyolipomas because of the higher recurrence rate, faster growth rate, and multifocal disease pattern.[5] 

Nephrectomy is usually indicated when the suspicion of malignancy is high and the renal mass is particularly large or when other treatment modalities cannot be performed.[5] However, in an emergency, a nephrectomy can be a lifesaving option.[5][11][92] 

Surgical excision has the advantage of a higher cure rate and the need for fewer follow-up procedures with reduced surveillance compared with arterial embolization.

Active Surveillance and Follow-up

Generally, active surveillance is used to monitor the ongoing progression of known tumors and the development of new ones when the diagnostic evaluations are completed and the indications for treatment are not present.[5][43] The overall rate of spontaneous bleeding from angiomyolipomas is only 2%, so surveillance in most cases is reasonable.[73]

There are currently no definitive guidelines for sporadic angiomyolipomas regarding the frequency of imaging studies or which imaging modality should be used for that reason.[5][31] The decisions should be guided according to the individual clinical scenario and history.[31][93] 

An annual repeat of imaging may be appropriate for small and solitary lesions.[6] Biannual (twice annual) imaging is generally recommended at least initially for hereditary tumors (associated with tuberous sclerosis or lymphangioleiomyomatosis), multiple, bilateral, and larger lesions, as some have been found to grow up to 1.5 cm a year.[43][94]

For hereditary angiomyolipomas, the International Tuberous Sclerosis Complex Consensus highly recommends using the MRI yearly to monitor the condition because of its higher sensitivity in detecting adipose tissue.[5] Most published protocols start with biannual imaging. If there is little change, this is then modified to annual screenings.[43] It is also highly recommended to check the blood pressure and renal function in these cases annually.[5] 

Ultrasound is usually sufficient for monitoring with a CT scan or MRI if significant changes are found. With long-term follow-up, it is reasonable to avoid routine CT scanning to minimize radiation exposure.

Treatment Summary

  • Most angiomyolipomas do not need any treatment.
  • The need for treatment is based on current symptoms, size (>6 cm), growth >2.5 mm/yr, intratumoral aneurysms >5 mm, high-risk situations, and potential lack of access to healthcare.
  • The least invasive treatment modality should be used whenever possible, which minimizes complications and loss of renal function.
  • Everolimus has shown efficacy in controlling tumor growth and promoting shrinkage in hereditary angiomyolipomas. Its use in the more common sporadic angiomyolipomas is uncertain, but early studies suggest it can be effective. 
  • Thermal therapies such as radiofrequency ablation and cryotherapy allow percutaneous biopsies to be performed simultaneously and will be effective for both benign and malignant lesions. They should certainly be considered for smaller tumors (<3 cm) depending on local experience, expertise, and availability.
  • Selective angiographic embolization is the treatment of choice for active bleeding and prophylaxis of high-risk angiomyolipomas. However, there is a high retreatment rate of 30%, and it requires a definitive diagnosis before treatment.
  • Surgery is the most definitive, curative therapy reserved for situations that cannot be better managed with less invasive modalities. Nephron-sparing techniques are recommended.

Differential Diagnosis

It is essential to know that renal angiomyolipoma has different types ( fat-rich angiomyolipoma, fat-poor angiomyolipoma, and fat-invisible angiomyolipoma).[31] Fat-rich angiomyolipomas are diagnosed easily on imaging due to the high amount of adipose tissue inside the mass.[5] The main issue is correctly diagnosing other angiomyolipomas where fat visualization is poor or invisible.[5] 

It is necessary to exclude the other differential diagnoses before deciding on treatment.[5] The possible differential diagnoses of renal angiomyolipoma are listed below [95][96]

  • Renal cell carcinoma 
  • Oncocytoma
  • Wilms tumor
  • Retroperitoneal liposarcoma
  • Adrenal myelolipoma
  • Tumors metastatic to the kidney

The recent high use of high-resolution imaging modalities has raised the detection of small renal masses. Many of these small renal lesions are found incidentally, are assumed to be possible renal cell carcinomas, and are managed accordingly.[5] About 21.5 percent of those renal masses are ultimately diagnosed as benign lesions after surgical removal, and renal angiomyolipomas account for about half of these.[5] 

Differentiating renal cell carcinomas from angiomyolipomas can sometimes be challenging in routine clinical practice.[61][97][98] Apart from the classic angiomyolipoma, which could be featured from renal cell carcinoma by detecting a sufficient amount of fat on a CT scan, the main issue is differentiating the fat-poor or fat invisible angiomyolipoma from renal cell carcinoma.[5] 

Clinical information that favors the diagnosis of angiomyolipoma includes female gender, younger age, and asymptomatic clinical manifestations.[5] Imaging results that increase the possibility of angiomyolipoma include multiple lesions, no calcifications, T2-weighted hypointensity on MRI, and hyperattenuation on CT scan.[5] However, because these features do not necessarily exist in every case and there are many exceptions, no solitary clinical finding or imaging modality is perfect in all cases.[5][99][100][101]

Retroperitoneal liposarcomas may also appear similar to larger angiomyolipomas. Since angiomyolipomas are renal parenchymal tumors, there will be an indentation or dimple where the mass originated, while a liposarcoma will tend to envelop and compress the entire kidney with no specific originating marker.[102][103]

When a renal mass lesion cannot be reliably determined to be an angiomyolipoma from imaging alone but is considered suspicious for AML, a percutaneous biopsy is reasonable, especially for high-risk patients, as it will avoid the risks and potential complications of surgery.[66] 

If there are indications of malignancy (such as internal necrosis, calcifications, or local lymphadenopathy), it should be treated as a malignancy unless proven benign by percutaneous renal biopsy.[5][6][66] If the diagnosis remains uncertain, the lesion should be treated as a malignancy.

Lesions suspicious of possible malignancy (tumoral necrosis or calcifications, regional lymphadenopathy, metastasis, perinephric extension) should generally be treated surgically.[17]

Prognosis

Small angiomyolipomas and those without aneurysms usually have a good prognosis as the risk of spontaneous bleeding are low, at only 2%.[5][73]  Renal angiomyolipomas that contain aneurysms >5 mm or the size of the tumor is larger than 6 cm pose a significant risk of spontaneous rupture and bleeding, which is considered a life-threatening condition.[16][104] 

Another important prognostic factor is the malignant potential, as some types of angiomyolipoma have a greater tendency for this transformation.[5]  

There is a need for updated clinical guidelines to help guide physicians to optimal management in each of these rare and unusual cases. Improved treatments or even a potential cure will require ongoing translational research in genomics, immunotherapy, and other new treatment technologies.[105]

Complications

Renal angiomyolipoma is a rare benign neoplasm, but it may still impose significant morbidity and mortality due to the tumor's unique vascular characteristics and the possible complications associated with treatment.[5]

The risk of bleeding associated with renal angiomyolipomas is a challenging factor in saving the patient's life while preserving renal function.[5] Several studies have documented that large tumors (more than 6 cm) and tuberous sclerosis complex-associated lesions are considered more susceptible to bleeding than small sporadic lesions, raising the need for prophylactic treatment.[16] 

Another important complication includes the need for long-term surveillance and the potential for renal impairment over time associated with renal angiomyolipomas.[11]

Consultations

The management of renal angiomyolipoma and its complications requires a multidisciplinary team.[5] This team can consist of the following specialties:

  • Nephrologist
  • Radiologist
  • Interventional radiologist
  • Oncologist
  • Urologist
  • Pathologist 
  • Clinical pathologist
  • Vascular surgeon
  • General surgeon
  • Genetics counselor
  • Primary care

Deterrence and Patient Education

Patients with renal angiomyolipoma should be informed about this disease's benign nature.[5] Health professionals should clarify that available medications and minimally invasive treatments can stop the disease's progression and lower the spontaneous bleeding risk.[5] 

Health care providers also have to advise the patients about the importance of medication adherence and compliance and the need for long-term surveillance.[16] 

Any woman of childbearing age diagnosed with renal angiomyolipoma who plans to become pregnant should seek consultation to discuss the management of her condition before and during the pregnancy. Pregnancy is considered a significant risk factor for disease progression and complications as the tumor mass will likely grow and may rupture while she is carrying.[5][11]

Pearls and Other Issues

  • Over 90% of all angiomyolipomas never need treatment.
  • A number of experts recommend an evaluation of all patients with newly diagnosed angiomyolipomas for tuberous sclerosis.
  • Conversely, all patients with tuberous sclerosis should be screened for angiomyolipomas.
  • All patients with lymphangioleiomyomatosis should receive renal imaging for angiomyolipomas.
  • Asymptomatic patients with <2 lesions smaller than 4 cm are unlikely to have tuberous sclerosis.
  • Consider a biopsy if the diagnosis cannot be reliably made from CT and MRI scanning alone.
  • If the diagnosis is still in doubt, treat the lesion as a malignancy.
  • Ultrasound is not sufficiently detailed to make a definitive diagnosis but can track previously diagnosed lesions.
  • The risk of a percutaneous biopsy is no greater for patients with low-fat or invisible-fat angiomyolipomas than for other renal tumors.
  • MRI imaging is more sensitive in detecting fat than CT and is, therefore, most useful for fat-poor lesions. (No imaging will show a fat-invisible lesion.)
  • If all measures have failed to confirm a diagnosis reliably, treating the lesion as malignant is recommended.
  • Active bleeding is best controlled with selective angiographic embolization, but there is a 30% retreatment rate.
  • Surgical intervention with minimally invasive ablative techniques should be considered when possible.
  • Women of childbearing age should consider prophylactic treatment of angiomyolipomas due to the high risk of complications during pregnancy.

Enhancing Healthcare Team Outcomes

Managing renal angiomyolipoma requires the collaboration of the entire interprofessional healthcare team.[16] The primary healthcare provider should be aware of this disease, especially if the patient presents with flank pain and palpable abdominal mass.[5] 

The role of the radiologist and interventional radiologist is crucial to confirm the diagnosis and monitor the disease progression through imaging.[5] Few cases require a percutaneous renal biopsy to confirm the diagnosis if the imaging modalities cannot confirm it.[31] 

All medical efforts should focus on preserving renal function while preventing disease progression and associated complications.[5][11] Other specialists, as detailed above, may be called in to consult on the case.

The nursing staff plays a crucial role in patient counseling, assisting in surgery, coordinating contacts and interventions between specialties, and answering patient questions. If medical therapy is part of the treatment plan, the pharmacist will counsel the patient on proper dosing and administration and perform medication reconciliation, contacting the ordering or prescribing clinician if any problems are noted.

All interprofessional team members must provide meticulous documentation of their activities and interventions in the patient's medical record so all team members have access to the same up-to-date, accurate information. All interprofessional team members should likewise be able to engage in open communication regarding the case with all other team members so the best therapeutic options can be implemented. This interprofessional approach will drive optimal patient outcomes. [Level 5]



(Click Image to Enlarge)
Angiomyolipoma
Angiomyolipoma
Contributed by D. Kabir MD
Article Details

Article Author

Younus M. Shamam

Article Editor:

Stephen W. Leslie

Updated:

11/28/2022 7:20:38 PM

PubMed Link:

Renal Angiomyolipoma

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