Author's Accepted Manuscript An Update on the Diagnosis and Management of Renal Angiomyolipoma Andrew S. Flum , Nabeel Hamoui , Mohammed A. Said , Ximing J. Yang , David D. Casalino , Barry B. McGuire , Kent T. Perry , Robert B. Nadler

PII: DOI: Reference:

S0022-5347(15)05256-8 10.1016/j.juro.2015.07.126 JURO 13120

To appear in: The Journal of Urology Accepted Date: 11 July 2015 Please cite this article as: Flum AS, Hamoui N, Said MA, Yang XJ, Casalino DD, McGuire BB, Perry KT, Nadler RB, An Update on the Diagnosis and Management of Renal Angiomyolipoma, The Journal of Urology® (2015), doi: 10.1016/j.juro.2015.07.126. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

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An Update on the Diagnosis and Management of Renal Angiomyolipoma

2 3 Andrew S. Flum1, Nabeel Hamoui1, Mohammed A. Said1, Ximing J. Yang2, David D. Casalino3,

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Barry B. McGuire1, Kent T. Perry1, Robert B. Nadler1,*

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Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL; 2Department of

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Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL; 3Department of Radiology,

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Northwestern University Feinberg School of Medicine, Chicago, IL

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675 North St. Clair Street, Suite 20-1502, Chicago, IL 60611

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Email: [email protected]; Phone: 312-695-6124; Fax: 312-908-7275

Corresponding Author: Department of Urology; Northwestern University Feinberg School of Medicine;

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Key words: Angiomyolipoma, Tuberous Sclerosis, Embolization, Partial Nephrectomy, mTOR

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inhibitor

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Running title: Diagnosis and Management of Renal Angiomyolipoma

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Abstract count: 348

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Word count: 3,929

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Disclosure Statement: The listed authors have no conflicts of interest, disclosures, or financial

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declarations specifically related to the production of this manuscript.

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Abstract

27 Purpose: Advances in minimally-invasive therapies and novel targeted chemotherapeutics have

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provided a breadth of options for the management of renal masses. The management of renal

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angiomyolipoma has not been reviewed in a comprehensive fashion in over a decade. We

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provide an updated review of the current diagnosis and management strategies for renal

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angiomyolipoma.

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Materials and Methods: A PubMed search of all available literature for renal or kidney

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angiomyolipoma was conducted. Further sources were identified in the reference lists of

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identified articles. Case series of partial nephrectomy, selective arterial embolization (SAE) and

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ablative therapies as well as trials of mTOR inhibitors for AML from 1999 to 2014 were

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specifically reviewed.

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Results: Renal angiomyolipoma (AML) is an uncommon benign renal tumor. Although

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associated with tuberous sclerosis complex (TSC) they occur sporadically. Risk of life

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threatening hemorrhage underlies the main clinical concern. Due to their fat content, AML are

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generally readily identifiable on computed tomography and magnetic resonance imaging (MRI);

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however, fat-poor AML can present a diagnostic challenge. Novel research suggests that various

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strategies using MRI, including chemical shift MRI, have the potential to differentiate fat-poor

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AML from renal cell carcinoma (RCC). Active surveillance is the accepted management for

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small asymptomatic masses. In general, symptomatic masses and masses of a size greater than

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4cm should be treated; however, other relative indications may apply. Options for treatment have

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traditionally included radical or partial nephrectomy, selective arterial embolization (SAE) and

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ablative therapies including cryoablation and radiofrequency ablation (RFA) all of which are

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reviewed and updated. Recent advances in the medical treatment of TSC associated AMLs with

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mTOR inhibitors are reviewed. Specifically, trials of Everolimus for patients with TSC suggest

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this agent may be safe and effective in managing AML tumor burden. A schema for the

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suggested management of renal AML is provided.

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Conclusions: Appropriately selected patients with renal AMLs can be managed with active

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surveillance. For those patients requiring treatment; nephron-sparing approaches including

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partial nephrectomy and selective arterial embolization are preferred options. For patients with

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tuberous sclerosis complex, mTOR inhibitors may represent a viable approach to control tumor

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burden while conserving renal parenchyma.

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Introduction

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Renal angiomyolipoma (AML) is an uncommon tumor that though benign in most cases can present difficult management decisions. It was first referenced as an entity in 1900 and

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Fischer first described the histopathology in 1911 as including the three components of

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dysmorphic blood vessels, smooth muscle and mature adipose tissue from which the tumor

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derives its name.1, 2 The term angiomyolipoma, however, did not come into wide use until the

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middle of the 20th century.1 These tumors can occur sporadically or in association with the

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tuberous sclerosis complex (TSC) or more rarely sporadic lymphangioleiomyomatosis (LAM).

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The diagnosis and management of renal AML has not been reviewed in a comprehensive fashion in over a decade.1 In that time, advances in minimally-invasive therapies and novel

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targeted chemotherapeutics have increased the options for management of AML. We provide an

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up to date review of the current diagnosis and management of renal AML including a

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management algorithm, which should be of value to the practicing urologist.

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Methods

A PubMed search of all available literature for renal or kidney angiomyolipoma was

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conducted. Further sources were identified in the reference lists of identified articles. Case series

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(including at least 10 patients and most follow up data) of partial nephrectomy, selective arterial

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embolization (SAE) and ablative therapies, as well as trials of mTOR inhibitors for the treatment

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of AML from 1999 to 2014 were specifically reviewed. A management algorithm was

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constructed using the available data.

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Epidemiology

97 Renal AML occur uncommonly in the general population with females more commonly

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affected than males. A screening study for renal neoplasms using ultrasound in 17,941 Japanese

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adults found an overall rate of renal AML of 0.13% with 0.22% of females affected versus 0.1%

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of males.3 Historical series demonstrate a female to male ratio of 2:1.2 The proportion of AML

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patients with TSC is around 20%.1 The tuberous sclerosis complex (TSC) is an autosomal

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dominant disease with an estimated prevalence of 1 in 12,000 with a birth rate as high as 1 in

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6,000.4 Rates of renal AML in association with TSC vary in the literature with most authors

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citing a range from 55% up to as high as 90%.4, 5 Renal AML can also occur in 30-50% of

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patients with sporadic lymphangioleiomyomatosis (LAM), a much more rare condition than TSC

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that is almost exclusively seen in women.6 Age at presentation varies with TSC patients more

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likely to present by their 20s-30s and sporadic AML patients in their 40s-50s.7, 8

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Pathophysiology

Renal AML can occur as part of TSC, sporadically or less commonly in association with

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sporadic LAM. The molecular genetics of TSC have been well characterized with mutations to

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TSC1 found at chromosomal location 9q34 and TSC2 found at 16p13.3 identified.4, 5 Though

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generally considered an autosomal dominant condition, up to two-thirds of patients have

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sporadic mutations to TSC1 and TSC2.4 TSC1 and TSC2 encode proteins carrying the same

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names, also known as hamartin and tuberin, respectively. These proteins interact with each other

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to form heterodimers, whose most important role is in the inhibition of the mammalian target of

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rapamycin (mTOR) pathway.4, 5 Loss of TSC1 or TSC2 leads to unchecked activation of mTOR,

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which leads to unregulated protein synthesis and increased cell growth and proliferation,

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increased angiogenesis and changes in cell orientation and migration.5

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These downstream effects of unchecked mTOR activation lead to the variety of clinical manifestations associated with TSC. Most common among these manifestations are those seen in

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the central nervous system with over 90% of affected individuals having some combination of

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epilepsy, neurocognitive impairment and autism due to cortical tubers, subependymal nodules

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and subependymal giant-cell astrocytomas (SEGA).4, 5 The majority of TSC patients will also

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have some combination of cutaneous manifestations which can include hypomelanotic macules,

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facial angiofibromas, ungual fibromas and Shagreen patches.4, 5 The prevalence of renal AML in

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TSC patients is high, (55-90% of patients) and these are generally multifocal and bilateral.4, 5

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Forty percent of women with TSC will manifest some degree of pulmonary LAM leading to

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pneumothorax, chylous pleural effusions and cystic lung disease.4, 5 Other major features of TSC

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can include cardiac rhabdomyomas and retinal hamartomas.4, 5 To establish a diagnosis of TSC,

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patients generally must have two major features of the syndrome or one major feature and two

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minor features.4 Genetic testing serves to confirm the diagnosis and the specific mutation

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involved in those who meet criteria, and can have utility in screening other family members in

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the case of a sporadic mutation.4

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Diagnosis

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Clinical Presentation

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With the increased use of cross-sectional imaging over 80% of AMLs are now discovered incidentally with hemorrhage at presentation (Wunderlich syndrome) seen in less than 15% and

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shock less than 10% in contemporary series.7, 8 The classic triad of symptoms associated with

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renal masses of flank pain, palpable mass and hematuria were historically found in 37-41%, 11-

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35% and 11-24% of patients with AML.1, 2 More modern series demonstrate generally lower

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rates of these symptoms, though Seyam et al. found 50% and 22% of their cohort presented with

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pain and hematuria, respectively.7, 8 Tumors are more likely to be larger, multifocal and bilateral

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at presentation in TSC patients with current series demonstrating mean sizes of 3.5-19.3cm in

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TSC patients versus 1-4cm in sporadic AML patients.7, 8

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Imaging

The diagnosis of renal angiomyolipoma (AML) can reliably be made on computed tomography (CT) or magnetic resonance imaging (MRI).9 The presence of fat is the hallmark

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finding with the incidence of fat containing renal cell carcinomas (RCC) low enough that

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differentiating them from AML is rarely a dilemma.10, 11 On ultrasound (US), AMLs are almost

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always hyperechoic compared to renal parenchyma due to the presence of macroscopic fat.

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However, RCC also appears hyperechoic on US in approximately one third of cases.12 While

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AML has relatively characteristic findings on US, the overall diagnostic reliability of US is not

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high enough to allow it to be used confidently to distinguish AMLs. However, once a definitive

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diagnosis of AML has been made (i.e. via CT), US may be used to follow AML.12

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CT has excellent sensitivity, specificity, PPV and NPV with regards to AML and renal

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masses in general.13 Moreover, CT is rapid, cost effective, and widely available in clinical

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practice. Even in small masses less than 2cm in size, macroscopic fat is often conspicuous

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enough to make the diagnosis of AML (Figure 1). Areas within a lesion of -15HU or less are

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generally considered diagnostic of macroscopic fat.13 In 4-5% of AMLs, intra-lesional fat cannot

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be detected on CT due to the small amount of fat within the lesion. These lesions are hyperdense

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on CT and enhance after contrast administration. These AMLs represent a diagnostic challenge

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as they can closely mimic RCC.14 Fat may also be obscured by hemorrhage within an AML. In

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these instances, phase contrast MRI may be helpful.14 Lesions that contain both fat (macro or

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microscopic) and calcification should steer one towards a diagnosis of RCC as AMLs rarely

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contain calcifications.15

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MRI, like CT, is accurate and specific for AML and is essentially equivalent in accuracy

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to CT in the diagnosis of AML and can be particularly helpful in diagnosing fat-poor AMLs

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(Figure 1).14 MRI, unlike CT, does not expose the patient to ionizing radiation. Moreover, the

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diagnosis of AML can be made on non-contrast MRI, which is of particular utility in patients

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with compromised renal function. The disadvantages of MRI are cost, time to complete a scan,

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and reduced availability compared to CT in daily clinical practice. On MRI, comparing T1-

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weighted images with and without frequency-selective fat suppression allows for the detection of

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macroscopic fat within an AML. Masses that appear T1 hyperintense without fat-suppression

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and T1 hypointense after frequency selective fat suppression are consistent with AML.16

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Another set of MRI sequences that are useful in diagnosing AML are in and opposed-

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phase chemical shift sequences.17 Chemical shift imaging results in a sharp black (India ink

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artifact) at the interface of macroscopic fat (contained in cells of AML) and water (contained in

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the renal parenchyma) on the opposed-phase images (Figure 2).18 This is particularly useful in fat

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poor AMLs or in lesions < 3cm in size in which the aforementioned typical T1 findings of AMLs

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may not be readily apparent. Another imaging clue suggestive of fat poor AML over RCC is

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relatively T2 hypointensity of the lesion; this is the result of the predominance of the smooth

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muscle component and paucity of fat in the AML.16

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Renal angiomyolipoma (AML) is a mesenchymal neoplasm composed of three

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components in variable proportions: abnormal blood vessels, special spindle cells and mature

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adipocytes. AML is believed to be derived from perivascualr epithelioid cells (PEC). Therefore

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it is also called a PECOMA or at least considered part of the PECOMA family.

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Grossly, AMLs are located in the renal parenchyma (Figure 3a), rather than the capsule or perinephric tissue. The tumor is typically a well-circumscribed mass with a tan-white, pink or

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yellow cut surface, depending its lipid content (Figure 3b). Hemorrhage can be seen with a red

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cut surface but necrosis is uncommon. Histologically, a typical angiomyolipoma is composed of

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three components (Figure 4a): vessels (angio); spindle cells (myo) and adipose tissue (lipo). The

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Vessels are typically eccentric and thick-walled. Spindle tumor cells may grow around a vessel

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(Figure 4b), have the features of smooth muscle and melanocytes. They range from mature-

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appearing smooth muscle cells, immature spindle cells (Figure 4c), and epithelioid cells.

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Adipocytes, which are intermingled with spindle cells, are mature without cytological atypia.

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Immunohistochemically, HMB-45 and melanin A, melanocytic markers, are often positive in the

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AML spindle cell component (Figure 4d). Smooth muscle markers such as smooth muscle actin

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are also positive. Keratins and other epithelial markers are negative.

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AML may display a wide range of histological variations that can make pathologic diagnosis difficult. Focal degenerative cytological atypia (Figure 5a) or epithelial appearance

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(Figure 5b) in an AML can be seen, which can be mistaken for a renal cell carcinoma or

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sarcoma. However, these atypical features usually are not associated with malignant behavior.19

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Hyalinization (Figure 5c), cystic changes or calcification can also be present in an AML. The

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lipomatous component can be minimal or absent (Figure 5d), but these tumors are usually HMB-

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45 positive. AMLs may co-exist with renal cell carcinoma. However, a true malignant AML is

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very rare. There is some controversy over the diagnosis and behavior of epithelioid

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angiomyolipoma. Based on our experience and published studies, the vast majority of renal

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AMLs with focal epithelioid features are benign. Only pure epithelioid renal AML (PECOMA)

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are potentially aggressive. The risk factors for a malignant AML include large size (>7cm),

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tumor necrosis and epithelioid “carcinoma-like” pattern (Figure 6).20, 21

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Management

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Active Surveillance and Indications for Intervention Historically the criteria for intervention in cases of renal AML have been symptomatic lesions, size >4cm, suspicion for malignancy and women of childbearing age.1, 2, 22 Authors have

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also suggested an associated aneurysm size >5mm, concomitant TSC and poor access to follow

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up or emergency care as additional considerations for treatment.1, 23 Figure 7 presents an updated

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management schema based on the subsequent discussion.

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There have been no prospective randomized trials comparing surveillance versus

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treatment for AML. Most series including patients with renal AML managed with active

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surveillance include relatively small numbers of patients, the large majority of which have

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sporadic non-TSC associated AMLs. These sporadic AMLs tend to exhibit a much slower

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growth rate over time as compared to AMLs in TSC patients.7 In comparing growth rates

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between sporadic and TSC-associated lesions, Seyam et al. found an interval growth rate of 0.19

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cm/yr for sporadic AMLs and 1.25 cm/yr (p4cm more often experienced

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hemorrhage and other symptoms, had interval growth and required intervention than those with

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AML 4cm.25 After 4 years mean follow up, only 13% of patients had discontinued

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surveillance and undergone treatment, with 34% of the patients with lesions >4cm having

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undergone treatment.25 Main indications were flank pain or interval tumor growth, though 35%

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of those who failed had a retroperitoneal hemorrhage or gross hematuria.25 Predictors of failing

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surveillance were symptoms at presentation and size >4cm. However, the authors argue that 67%

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of symptomatic patients and 66% with tumors >4cm could be maintained on surveillance may

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suggest following the historical criteria results in over-treatment.25 Importantly, no patient

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surveilled who ultimately underwent surgical resection was found to have a malignancy on

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pathologic examination.25

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The size of intralesional aneurysms associated with the AML has also been found to be a

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factor predictive of hemorrhage. Yamakado et al. examined the tumor and aneurysm size on CT

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and angiography of 23 patients treated for sporadic and TSC-associated AMLs.23 They found

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that both increasing aneurysm (p

Update on the Diagnosis and Management of Renal Angiomyolipoma.

Advances in minimally invasive therapies and novel targeted chemotherapeutics have provided a breadth of options for the management of renal masses. M...
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