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.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
ACCEPTED MANUSCRIPT
1
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,
5
Barry B. McGuire1, Kent T. Perry1, Robert B. Nadler1,*
RI PT
4
6 1
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL; 2Department of
8
Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL; 3Department of Radiology,
9
Northwestern University Feinberg School of Medicine, Chicago, IL
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7
10 11
*
12
675 North St. Clair Street, Suite 20-1502, Chicago, IL 60611
13
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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14 15 16
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Key words: Angiomyolipoma, Tuberous Sclerosis, Embolization, Partial Nephrectomy, mTOR
19
inhibitor
20
Running title: Diagnosis and Management of Renal Angiomyolipoma
21
Abstract count: 348
22
Word count: 3,929
23
Disclosure Statement: The listed authors have no conflicts of interest, disclosures, or financial
24
declarations specifically related to the production of this manuscript.
25
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18
ACCEPTED MANUSCRIPT
26
Abstract
27 Purpose: Advances in minimally-invasive therapies and novel targeted chemotherapeutics have
29
provided a breadth of options for the management of renal masses. The management of renal
30
angiomyolipoma has not been reviewed in a comprehensive fashion in over a decade. We
31
provide an updated review of the current diagnosis and management strategies for renal
32
angiomyolipoma.
33
Materials and Methods: A PubMed search of all available literature for renal or kidney
34
angiomyolipoma was conducted. Further sources were identified in the reference lists of
35
identified articles. Case series of partial nephrectomy, selective arterial embolization (SAE) and
36
ablative therapies as well as trials of mTOR inhibitors for AML from 1999 to 2014 were
37
specifically reviewed.
38
Results: Renal angiomyolipoma (AML) is an uncommon benign renal tumor. Although
39
associated with tuberous sclerosis complex (TSC) they occur sporadically. Risk of life
40
threatening hemorrhage underlies the main clinical concern. Due to their fat content, AML are
41
generally readily identifiable on computed tomography and magnetic resonance imaging (MRI);
42
however, fat-poor AML can present a diagnostic challenge. Novel research suggests that various
43
strategies using MRI, including chemical shift MRI, have the potential to differentiate fat-poor
44
AML from renal cell carcinoma (RCC). Active surveillance is the accepted management for
45
small asymptomatic masses. In general, symptomatic masses and masses of a size greater than
46
4cm should be treated; however, other relative indications may apply. Options for treatment have
47
traditionally included radical or partial nephrectomy, selective arterial embolization (SAE) and
48
ablative therapies including cryoablation and radiofrequency ablation (RFA) all of which are
AC C
EP
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M AN U
SC
RI PT
28
ACCEPTED MANUSCRIPT
reviewed and updated. Recent advances in the medical treatment of TSC associated AMLs with
50
mTOR inhibitors are reviewed. Specifically, trials of Everolimus for patients with TSC suggest
51
this agent may be safe and effective in managing AML tumor burden. A schema for the
52
suggested management of renal AML is provided.
53
Conclusions: Appropriately selected patients with renal AMLs can be managed with active
54
surveillance. For those patients requiring treatment; nephron-sparing approaches including
55
partial nephrectomy and selective arterial embolization are preferred options. For patients with
56
tuberous sclerosis complex, mTOR inhibitors may represent a viable approach to control tumor
57
burden while conserving renal parenchyma.
59 60
66 67 68 69 70 71
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61
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72
Introduction
73 74
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
76
Fischer first described the histopathology in 1911 as including the three components of
77
dysmorphic blood vessels, smooth muscle and mature adipose tissue from which the tumor
78
derives its name.1, 2 The term angiomyolipoma, however, did not come into wide use until the
79
middle of the 20th century.1 These tumors can occur sporadically or in association with the
80
tuberous sclerosis complex (TSC) or more rarely sporadic lymphangioleiomyomatosis (LAM).
SC
M AN U
81
RI PT
75
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
83
targeted chemotherapeutics have increased the options for management of AML. We provide an
84
up to date review of the current diagnosis and management of renal AML including a
85
management algorithm, which should be of value to the practicing urologist.
86
89
EP
88
Methods
A PubMed search of all available literature for renal or kidney angiomyolipoma was
AC C
87
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82
90
conducted. Further sources were identified in the reference lists of identified articles. Case series
91
(including at least 10 patients and most follow up data) of partial nephrectomy, selective arterial
92
embolization (SAE) and ablative therapies, as well as trials of mTOR inhibitors for the treatment
93
of AML from 1999 to 2014 were specifically reviewed. A management algorithm was
94
constructed using the available data.
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95 96
Epidemiology
97 Renal AML occur uncommonly in the general population with females more commonly
99
affected than males. A screening study for renal neoplasms using ultrasound in 17,941 Japanese
100
adults found an overall rate of renal AML of 0.13% with 0.22% of females affected versus 0.1%
101
of males.3 Historical series demonstrate a female to male ratio of 2:1.2 The proportion of AML
102
patients with TSC is around 20%.1 The tuberous sclerosis complex (TSC) is an autosomal
103
dominant disease with an estimated prevalence of 1 in 12,000 with a birth rate as high as 1 in
104
6,000.4 Rates of renal AML in association with TSC vary in the literature with most authors
105
citing a range from 55% up to as high as 90%.4, 5 Renal AML can also occur in 30-50% of
106
patients with sporadic lymphangioleiomyomatosis (LAM), a much more rare condition than TSC
107
that is almost exclusively seen in women.6 Age at presentation varies with TSC patients more
108
likely to present by their 20s-30s and sporadic AML patients in their 40s-50s.7, 8
109
112
EP
111
Pathophysiology
Renal AML can occur as part of TSC, sporadically or less commonly in association with
AC C
110
TE D
M AN U
SC
RI PT
98
113
sporadic LAM. The molecular genetics of TSC have been well characterized with mutations to
114
TSC1 found at chromosomal location 9q34 and TSC2 found at 16p13.3 identified.4, 5 Though
115
generally considered an autosomal dominant condition, up to two-thirds of patients have
116
sporadic mutations to TSC1 and TSC2.4 TSC1 and TSC2 encode proteins carrying the same
117
names, also known as hamartin and tuberin, respectively. These proteins interact with each other
ACCEPTED MANUSCRIPT
to form heterodimers, whose most important role is in the inhibition of the mammalian target of
119
rapamycin (mTOR) pathway.4, 5 Loss of TSC1 or TSC2 leads to unchecked activation of mTOR,
120
which leads to unregulated protein synthesis and increased cell growth and proliferation,
121
increased angiogenesis and changes in cell orientation and migration.5
122
RI PT
118
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
124
the central nervous system with over 90% of affected individuals having some combination of
125
epilepsy, neurocognitive impairment and autism due to cortical tubers, subependymal nodules
126
and subependymal giant-cell astrocytomas (SEGA).4, 5 The majority of TSC patients will also
127
have some combination of cutaneous manifestations which can include hypomelanotic macules,
128
facial angiofibromas, ungual fibromas and Shagreen patches.4, 5 The prevalence of renal AML in
129
TSC patients is high, (55-90% of patients) and these are generally multifocal and bilateral.4, 5
130
Forty percent of women with TSC will manifest some degree of pulmonary LAM leading to
131
pneumothorax, chylous pleural effusions and cystic lung disease.4, 5 Other major features of TSC
132
can include cardiac rhabdomyomas and retinal hamartomas.4, 5 To establish a diagnosis of TSC,
133
patients generally must have two major features of the syndrome or one major feature and two
134
minor features.4 Genetic testing serves to confirm the diagnosis and the specific mutation
135
involved in those who meet criteria, and can have utility in screening other family members in
136
the case of a sporadic mutation.4
138
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Diagnosis
139 140
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
143
shock less than 10% in contemporary series.7, 8 The classic triad of symptoms associated with
144
renal masses of flank pain, palpable mass and hematuria were historically found in 37-41%, 11-
145
35% and 11-24% of patients with AML.1, 2 More modern series demonstrate generally lower
146
rates of these symptoms, though Seyam et al. found 50% and 22% of their cohort presented with
147
pain and hematuria, respectively.7, 8 Tumors are more likely to be larger, multifocal and bilateral
148
at presentation in TSC patients with current series demonstrating mean sizes of 3.5-19.3cm in
149
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
154
finding with the incidence of fat containing renal cell carcinomas (RCC) low enough that
155
differentiating them from AML is rarely a dilemma.10, 11 On ultrasound (US), AMLs are almost
156
always hyperechoic compared to renal parenchyma due to the presence of macroscopic fat.
157
However, RCC also appears hyperechoic on US in approximately one third of cases.12 While
158
AML has relatively characteristic findings on US, the overall diagnostic reliability of US is not
159
high enough to allow it to be used confidently to distinguish AMLs. However, once a definitive
160
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
162
masses in general.13 Moreover, CT is rapid, cost effective, and widely available in clinical
163
practice. Even in small masses less than 2cm in size, macroscopic fat is often conspicuous
ACCEPTED MANUSCRIPT
enough to make the diagnosis of AML (Figure 1). Areas within a lesion of -15HU or less are
165
generally considered diagnostic of macroscopic fat.13 In 4-5% of AMLs, intra-lesional fat cannot
166
be detected on CT due to the small amount of fat within the lesion. These lesions are hyperdense
167
on CT and enhance after contrast administration. These AMLs represent a diagnostic challenge
168
as they can closely mimic RCC.14 Fat may also be obscured by hemorrhage within an AML. In
169
these instances, phase contrast MRI may be helpful.14 Lesions that contain both fat (macro or
170
microscopic) and calcification should steer one towards a diagnosis of RCC as AMLs rarely
171
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
174
(Figure 1).14 MRI, unlike CT, does not expose the patient to ionizing radiation. Moreover, the
175
diagnosis of AML can be made on non-contrast MRI, which is of particular utility in patients
176
with compromised renal function. The disadvantages of MRI are cost, time to complete a scan,
177
and reduced availability compared to CT in daily clinical practice. On MRI, comparing T1-
178
weighted images with and without frequency-selective fat suppression allows for the detection of
179
macroscopic fat within an AML. Masses that appear T1 hyperintense without fat-suppression
180
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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182
phase chemical shift sequences.17 Chemical shift imaging results in a sharp black (India ink
183
artifact) at the interface of macroscopic fat (contained in cells of AML) and water (contained in
184
the renal parenchyma) on the opposed-phase images (Figure 2).18 This is particularly useful in fat
185
poor AMLs or in lesions < 3cm in size in which the aforementioned typical T1 findings of AMLs
186
may not be readily apparent. Another imaging clue suggestive of fat poor AML over RCC is
ACCEPTED MANUSCRIPT
187
relatively T2 hypointensity of the lesion; this is the result of the predominance of the smooth
188
muscle component and paucity of fat in the AML.16
189
191
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190 Histopathology
Renal angiomyolipoma (AML) is a mesenchymal neoplasm composed of three
193
components in variable proportions: abnormal blood vessels, special spindle cells and mature
194
adipocytes. AML is believed to be derived from perivascualr epithelioid cells (PEC). Therefore
195
it is also called a PECOMA or at least considered part of the PECOMA family.
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SC
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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
198
yellow cut surface, depending its lipid content (Figure 3b). Hemorrhage can be seen with a red
199
cut surface but necrosis is uncommon. Histologically, a typical angiomyolipoma is composed of
200
three components (Figure 4a): vessels (angio); spindle cells (myo) and adipose tissue (lipo). The
201
Vessels are typically eccentric and thick-walled. Spindle tumor cells may grow around a vessel
202
(Figure 4b), have the features of smooth muscle and melanocytes. They range from mature-
203
appearing smooth muscle cells, immature spindle cells (Figure 4c), and epithelioid cells.
204
Adipocytes, which are intermingled with spindle cells, are mature without cytological atypia.
205
Immunohistochemically, HMB-45 and melanin A, melanocytic markers, are often positive in the
206
AML spindle cell component (Figure 4d). Smooth muscle markers such as smooth muscle actin
207
are also positive. Keratins and other epithelial markers are negative.
208 209
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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
ACCEPTED MANUSCRIPT
(Figure 5b) in an AML can be seen, which can be mistaken for a renal cell carcinoma or
211
sarcoma. However, these atypical features usually are not associated with malignant behavior.19
212
Hyalinization (Figure 5c), cystic changes or calcification can also be present in an AML. The
213
lipomatous component can be minimal or absent (Figure 5d), but these tumors are usually HMB-
214
45 positive. AMLs may co-exist with renal cell carcinoma. However, a true malignant AML is
215
very rare. There is some controversy over the diagnosis and behavior of epithelioid
216
angiomyolipoma. Based on our experience and published studies, the vast majority of renal
217
AMLs with focal epithelioid features are benign. Only pure epithelioid renal AML (PECOMA)
218
are potentially aggressive. The risk factors for a malignant AML include large size (>7cm),
219
tumor necrosis and epithelioid “carcinoma-like” pattern (Figure 6).20, 21
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220 221
Management
223 224
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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
226
also suggested an associated aneurysm size >5mm, concomitant TSC and poor access to follow
227
up or emergency care as additional considerations for treatment.1, 23 Figure 7 presents an updated
228
management schema based on the subsequent discussion.
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There have been no prospective randomized trials comparing surveillance versus
230
treatment for AML. Most series including patients with renal AML managed with active
231
surveillance include relatively small numbers of patients, the large majority of which have
232
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
234
between sporadic and TSC-associated lesions, Seyam et al. found an interval growth rate of 0.19
235
cm/yr for sporadic AMLs and 1.25 cm/yr (p4cm more often experienced
243
hemorrhage and other symptoms, had interval growth and required intervention than those with
244
AML 4cm.25 After 4 years mean follow up, only 13% of patients had discontinued
248
surveillance and undergone treatment, with 34% of the patients with lesions >4cm having
249
undergone treatment.25 Main indications were flank pain or interval tumor growth, though 35%
250
of those who failed had a retroperitoneal hemorrhage or gross hematuria.25 Predictors of failing
251
surveillance were symptoms at presentation and size >4cm. However, the authors argue that 67%
252
of symptomatic patients and 66% with tumors >4cm could be maintained on surveillance may
253
suggest following the historical criteria results in over-treatment.25 Importantly, no patient
254
surveilled who ultimately underwent surgical resection was found to have a malignancy on
255
pathologic examination.25
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The size of intralesional aneurysms associated with the AML has also been found to be a
257
factor predictive of hemorrhage. Yamakado et al. examined the tumor and aneurysm size on CT
258
and angiography of 23 patients treated for sporadic and TSC-associated AMLs.23 They found
259
that both increasing aneurysm (p
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.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
ACCEPTED MANUSCRIPT
1
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,
5
Barry B. McGuire1, Kent T. Perry1, Robert B. Nadler1,*
RI PT
4
6 1
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL; 2Department of
8
Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL; 3Department of Radiology,
9
Northwestern University Feinberg School of Medicine, Chicago, IL
M AN U
SC
7
10 11
*
12
675 North St. Clair Street, Suite 20-1502, Chicago, IL 60611
13
Email: [email protected]; Phone: 312-695-6124; Fax: 312-908-7275
Corresponding Author: Department of Urology; Northwestern University Feinberg School of Medicine;
TE D
14 15 16
EP
17
Key words: Angiomyolipoma, Tuberous Sclerosis, Embolization, Partial Nephrectomy, mTOR
19
inhibitor
20
Running title: Diagnosis and Management of Renal Angiomyolipoma
21
Abstract count: 348
22
Word count: 3,929
23
Disclosure Statement: The listed authors have no conflicts of interest, disclosures, or financial
24
declarations specifically related to the production of this manuscript.
25
AC C
18
ACCEPTED MANUSCRIPT
26
Abstract
27 Purpose: Advances in minimally-invasive therapies and novel targeted chemotherapeutics have
29
provided a breadth of options for the management of renal masses. The management of renal
30
angiomyolipoma has not been reviewed in a comprehensive fashion in over a decade. We
31
provide an updated review of the current diagnosis and management strategies for renal
32
angiomyolipoma.
33
Materials and Methods: A PubMed search of all available literature for renal or kidney
34
angiomyolipoma was conducted. Further sources were identified in the reference lists of
35
identified articles. Case series of partial nephrectomy, selective arterial embolization (SAE) and
36
ablative therapies as well as trials of mTOR inhibitors for AML from 1999 to 2014 were
37
specifically reviewed.
38
Results: Renal angiomyolipoma (AML) is an uncommon benign renal tumor. Although
39
associated with tuberous sclerosis complex (TSC) they occur sporadically. Risk of life
40
threatening hemorrhage underlies the main clinical concern. Due to their fat content, AML are
41
generally readily identifiable on computed tomography and magnetic resonance imaging (MRI);
42
however, fat-poor AML can present a diagnostic challenge. Novel research suggests that various
43
strategies using MRI, including chemical shift MRI, have the potential to differentiate fat-poor
44
AML from renal cell carcinoma (RCC). Active surveillance is the accepted management for
45
small asymptomatic masses. In general, symptomatic masses and masses of a size greater than
46
4cm should be treated; however, other relative indications may apply. Options for treatment have
47
traditionally included radical or partial nephrectomy, selective arterial embolization (SAE) and
48
ablative therapies including cryoablation and radiofrequency ablation (RFA) all of which are
AC C
EP
TE D
M AN U
SC
RI PT
28
ACCEPTED MANUSCRIPT
reviewed and updated. Recent advances in the medical treatment of TSC associated AMLs with
50
mTOR inhibitors are reviewed. Specifically, trials of Everolimus for patients with TSC suggest
51
this agent may be safe and effective in managing AML tumor burden. A schema for the
52
suggested management of renal AML is provided.
53
Conclusions: Appropriately selected patients with renal AMLs can be managed with active
54
surveillance. For those patients requiring treatment; nephron-sparing approaches including
55
partial nephrectomy and selective arterial embolization are preferred options. For patients with
56
tuberous sclerosis complex, mTOR inhibitors may represent a viable approach to control tumor
57
burden while conserving renal parenchyma.
59 60
66 67 68 69 70 71
EP
65
AC C
64
TE D
61
63
SC
M AN U
58
62
RI PT
49
ACCEPTED MANUSCRIPT
72
Introduction
73 74
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
76
Fischer first described the histopathology in 1911 as including the three components of
77
dysmorphic blood vessels, smooth muscle and mature adipose tissue from which the tumor
78
derives its name.1, 2 The term angiomyolipoma, however, did not come into wide use until the
79
middle of the 20th century.1 These tumors can occur sporadically or in association with the
80
tuberous sclerosis complex (TSC) or more rarely sporadic lymphangioleiomyomatosis (LAM).
SC
M AN U
81
RI PT
75
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
83
targeted chemotherapeutics have increased the options for management of AML. We provide an
84
up to date review of the current diagnosis and management of renal AML including a
85
management algorithm, which should be of value to the practicing urologist.
86
89
EP
88
Methods
A PubMed search of all available literature for renal or kidney angiomyolipoma was
AC C
87
TE D
82
90
conducted. Further sources were identified in the reference lists of identified articles. Case series
91
(including at least 10 patients and most follow up data) of partial nephrectomy, selective arterial
92
embolization (SAE) and ablative therapies, as well as trials of mTOR inhibitors for the treatment
93
of AML from 1999 to 2014 were specifically reviewed. A management algorithm was
94
constructed using the available data.
ACCEPTED MANUSCRIPT
95 96
Epidemiology
97 Renal AML occur uncommonly in the general population with females more commonly
99
affected than males. A screening study for renal neoplasms using ultrasound in 17,941 Japanese
100
adults found an overall rate of renal AML of 0.13% with 0.22% of females affected versus 0.1%
101
of males.3 Historical series demonstrate a female to male ratio of 2:1.2 The proportion of AML
102
patients with TSC is around 20%.1 The tuberous sclerosis complex (TSC) is an autosomal
103
dominant disease with an estimated prevalence of 1 in 12,000 with a birth rate as high as 1 in
104
6,000.4 Rates of renal AML in association with TSC vary in the literature with most authors
105
citing a range from 55% up to as high as 90%.4, 5 Renal AML can also occur in 30-50% of
106
patients with sporadic lymphangioleiomyomatosis (LAM), a much more rare condition than TSC
107
that is almost exclusively seen in women.6 Age at presentation varies with TSC patients more
108
likely to present by their 20s-30s and sporadic AML patients in their 40s-50s.7, 8
109
112
EP
111
Pathophysiology
Renal AML can occur as part of TSC, sporadically or less commonly in association with
AC C
110
TE D
M AN U
SC
RI PT
98
113
sporadic LAM. The molecular genetics of TSC have been well characterized with mutations to
114
TSC1 found at chromosomal location 9q34 and TSC2 found at 16p13.3 identified.4, 5 Though
115
generally considered an autosomal dominant condition, up to two-thirds of patients have
116
sporadic mutations to TSC1 and TSC2.4 TSC1 and TSC2 encode proteins carrying the same
117
names, also known as hamartin and tuberin, respectively. These proteins interact with each other
ACCEPTED MANUSCRIPT
to form heterodimers, whose most important role is in the inhibition of the mammalian target of
119
rapamycin (mTOR) pathway.4, 5 Loss of TSC1 or TSC2 leads to unchecked activation of mTOR,
120
which leads to unregulated protein synthesis and increased cell growth and proliferation,
121
increased angiogenesis and changes in cell orientation and migration.5
122
RI PT
118
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
124
the central nervous system with over 90% of affected individuals having some combination of
125
epilepsy, neurocognitive impairment and autism due to cortical tubers, subependymal nodules
126
and subependymal giant-cell astrocytomas (SEGA).4, 5 The majority of TSC patients will also
127
have some combination of cutaneous manifestations which can include hypomelanotic macules,
128
facial angiofibromas, ungual fibromas and Shagreen patches.4, 5 The prevalence of renal AML in
129
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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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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190 Histopathology
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
