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Oncology

hanging Trends in Presentation,iagnosis and Management of Renalngiomyolipoma: Comparison of Sporadic anduberous Sclerosis Complex-associated Forms

aouf M. Seyam, Nabil K. Bissada, Said A. Kattan, Alaa A. Mokhtar, Muhammad Aslam,ahib E. Fahmy, Walid A. Mourad, Ali A. Binmahfouz, Hassan M. Alzahrani, andamal A. Hanash

BJECTIVES To evaluate the changing management of sporadic renal angiomyolipoma and renal angiomyo-lipoma associated with the tuberous sclerosis complex (TSC) during the past 16 years.

ETHODS We retrospectively reviewed the charts of 60 patients with angiomyolipoma seen at our insti-tutions.

ESULTS The median age at presentation was 45 years (range 7-78). The presentation was pain in 30patients and hematuria in 13; it was incidentally discovered in 17 patients. Of the 60patients, 43 were females. TSC was present in 14 patients. The median tumor size was 4 cm(range 0.3-40, mean 6.5 � 1.1). Of the 60 patients, 31 were followed up expectantly. Surgeryor intervention was needed for 29 patients to control hemorrhage or relieve pain or becauseof the suspicion of malignancy. Of these 29 patients, 12 underwent nephrectomy, 11 partialnephrectomy, and 6 embolization. The patients treated for hemorrhage had a median tumordiameter of 11 cm (range 2-21). Patients were followed up for a mean of 39.3 � 5.4 months.The lesions grew an average of 4.7 � 3.4 cm for TSC tumors and 0.6 � 0.2 cm for sporadicangiomyolipoma tumors. None of the patients developed renal impairment. Patients withTSC presented at a younger age, had larger and bilateral lesions, and were more symptomaticduring follow-up. In the past 6 years, a significant trend was seen toward finding tumors inasymptomatic patients and toward the use of conservative or interventional (embolization)treatment.

ONCLUSIONS Renal angiomyolipoma has a slow growth rate. The preservation of renal function was noted in all ourpatients. A recent shift was noted toward finding smaller tumors in asymptomatic patients and the use

of conservative and interventional treatment. UROLOGY 72: 1077–1082, 2008. © 2008 Elsevier Inc.

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enal angiomyolipoma (AML) is a rare benigntumor. It is significant because of its character-istic radiologic appearance, occasional suspi-

ion of malignancy, and its potential association withevere complications.1-7 We report on 60 patients withML treated at our referral centers during a 16-year

eriod. Our aim was to compare sporadic AMLSAML) and AML associated with tuberous sclerosisomplex (TSC), patients who underwent surgical vs

rom the Department of Urology, Suez Canal University Faculty of Medicine, Ismailia,gypt; Departments of Urology and Pathology, King Faisal Specialist Hospital andesearch Centre, Riyadh, Saudi Arabia; Department of Urology, University of Arkan-

as for Medical Sciences, Little Rock, AR; and Urology and Nephrology Center,ansoura University, Mansoura, EgyptReprint requests: Raouf M. Seyam, M.D., Department of Urology, King Faisalospital and Research Center, P.O. Box 3354, MBC 83, Riyadh 11211 Saudi

Prabia. E-mail: rmseyam@yahoo.comSubmitted: March 2, 2008, accepted (with revisions): July 21, 2008

2008 Elsevier Inc.ll Rights Reserved

onservative treatment, and patients presenting in 2ifferent periods.

ATERIAL AND METHODS

e retrospectively reviewed the charts of 60 patients with theiagnosis of renal AML who presented from January 1990 toune 2006. We recorded their treatment, outcomes, and long-erm follow-up. The tumor size was identified as the greatestimension recorded on radiologic investigation at presentation.he growth of the lesions was calculated using the last imaging

tudy. We divided the patients into 2 groups according to theedian tumor size and compared both groups for symptoms,

herapy type, follow-up, and complications. We used 1-waynalysis of variance and cross-tabulation with Fisher’s exactests for analysis of continuous and categorical variables, respec-ively. P values were considered significant at P � .05. All

values were 2-sided. The SE is reported. We used the Statis-

0090-4295/08/$34.00 1077doi:10.1016/j.urology.2008.07.049

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ESULTS

emographicstotal of 60 charts had complete records. The median

ge at presentation was 45 years (range 7-78); 43 (71.7%)ere females and 17 (28.3) were males. TSC was present

n 14 patients (23.3%).

linical Picturehe presenting symptom was pain in 30 patients (50%),of whom developed shock owing to massive retroperi-

oneal hemorrhage. The lesion was incidentally discov-red in 17 patients (28.3%) and was found secondary toematuria in 13 patients (21.7%). Thirteen patients withumors �4 cm were symptomatic at presentation, 4 withematuria and 9 with flank pain. Hydrocephalus was theresenting symptom in a young boy with TSC and bilateralenal AML. The methods of diagnosis included computedomography in 32 (53.3%), surgical pathologic examinationn 9 (15%), fine needle aspiration in 3 (5%), ultrasonogra-hy in 12 (20%), and magnetic resonance imaging in 46.7%). The median tumor size was 4 cm (range 0.3-40,ean 6.5 � 1.1). Most of the lesions were solitary and

nilateral (n � 38, 63.3%). Patients with TSC presented atyounger age, had larger and bilateral lesions, demonstratedgreater growth rate, and were more symptomatic during

ollow-up than were the patients with SAML (Table 1).

Table 1. Differences between tuberous sclerosis-associat

Variable Tub

Age at presentation (y)Lesion size (cm) 1Growth of lesion at follow-up (cm)Duration of growth (mo) 4Rate of growth/y (cm)Multiple bilateral (n)Symptomatic at follow-up or mortality (n)

Data presented as mean � SE or numbers, with percentages in p

Table 2. Effect of tumor size on symptoms and treatment

Variable �4

Patients (n) 24Age � SE (y) 50.6 �Mean size � SE (cm) 1.5 �Size range (cm) 0.3Symptomatic at presentation (n)‡ 13 (5TSC (n)‡ 0 (0Surgical intervention (n)‡ 3 (1Embolization 0 (0

TSC � tuberous sclerosis complex.* A 7-year-old child with TSC had multiple bilateral large tumors.† Smallest size associated with symptoms due to angiomyolipom‡ Percentage within size category.

arger tumors were found in younger patients, who pre- d

078

ented with more symptoms, included more patients withSC, required more surgical treatment (Table 2), and in-luded the only mortality in our series.

reatmentxpectant management (pain relief medications and/or

ollow-up examinations) was applied to 31 patients51.7%). The indications for surgical or interventionalreatment included severe hemorrhage or shock in 12,arge tumor size in 3, suspicion of malignancy in 9, andntractable pain in 5. Gross hematuria was an indicationor intervention when severe, resulted in shock, or wasssociated with severe pain. Three patients with tumors4 cm (range 2-3) underwent surgery between 1992 and

997 for suspicion of malignancy, intractable pain, orersistent hematuria.Nephrectomy was performed in 12 (20%), partial ne-

hrectomy or tumor enucleation in 11 (18.3%), andmbolization in 6 (10%). All embolizations were per-ormed in the last 6 years of the study period. The medianumor size treated surgically or by embolization for severeemorrhage was 11 cm (range 2-21; 12 patients). Only 1atient underwent partial nephrectomy for a tumor �4m (2 cm) because of severe hemorrhage. Patients whonderwent embolization as a primary treatment (n � 6)ad lesions 4-19 cm in diameter and were followed up for-120 months. Embolization was successful in 5 of thesepatients. The change in size varied from �35% at 6onths to 0% after 120 months. Embolization for hem-

rrhage failed in 1 patient after 6 months, and she un-

nd sporadic angiomyolipoma

Sclerosis Sporadic P Value

� 3.2 49.4 � 2 �.001� 4.8 4.1 � 0.7 �.001� 3.4 0.6 � 0.2 �.05� 10.9 38.4 � 6 .7.25 0.19100) 6 (13) �.00142.9) 4 (8.7) �0.01

theses.

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Tumor Size (cm)

P Value�4

3642.1 � 3.2* �.05

† 11.4 � 1.6 �.0014-40

31 (86.1) �.0114 (38.9) �.00119 (52.8) �.01

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ion embolization with no significant complications.mbolization was adopted as a second-line treatment in 1enal unit remaining after primary surgical interventionor TSC AML to control 3 subsequent hemorrhagic ep-sodes.

Patients treated surgically or by embolization had sig-ificantly more tumors �4 cm (86%, n � 25/29 vs 35%,� 11/31, P � .01) and included more symptomatic

atients at presentation (94%, n � 40/43 vs 61%, n �3/17, P � .05) compared with patients treated conser-atively. The median tumor size for suspected renal cellarcinoma (RCC) was 7 cm (range 2-9) with only 1easuring �4 cm. Most of these suspicious lesions were

ymptomatic, and the tumors were detected during in-estigations for flank pain or hematuria. Only 2 tumorsreated as RCC were discovered incidentally. None ofhese lesions showed fat content during imaging.

The decade of presentation had a significant effect onhe clinical presentation and management. In the mostecent 6 years, more patients presented with incidentalumors (41%, n � 14/34 vs 8%, n � 2/26; P � .01), theumor size was significantly smaller (4.5 � 0.8 cm vs 9.8 �.4 cm, P � .05), and had a lesser growth rate (0.02 �.31 cm vs 3.5 � 1.5 cm, P � .01) compared with thearlier decade. A significant shift was found toward con-ervative treatment (66% n � 25/38 vs 27%, n � 6/22,� .05) and the use of embolization (16%, n � 6/38 vs

%, n � 0/22) compared with the earlier decade.

ollow-uphe mean follow-up was 39.3 � 5.4 months. A total of0 patients (83.3%) remained asymptomatic. Nine pa-ients continued to have persistent pain at follow-up. Ofhe 29 who had undergone surgery or intervention, 26ere asymptomatic at follow-up. Of the 3 patients who

emained symptomatic, 2 had TSC and were treated foremorrhage by embolization and partial nephrectomynd 1 had SAML and underwent partial nephrectomy forain. One patient with TSC and bilateral 20-cm largeenal AMLs died of rupture of his tumor and intractableemorrhage at 24 years of age. The average overall lesionrowth during the follow-up period was 1.4 � 0.7 cm4.7 � 3.4 cm for TSC tumors and 0.6 � 0.2 cm forAML tumors). TSC-associated lesions grew an averagef 1.25 cm/y and SAML lesions grew an average of 0.19m/y. None of the 60 patients developed renal impair-ent.Since submission of this report, 7 new patients have

een treated at our institution. One of these patients was60-year-old man who required lifelong anticoagulation

or a cardiac valve prosthesis. He developed massiveemorrhage of his single, 4-cm SAML and underwentmbolization that failed and was followed by urgent ne-

hrectomy. r

ROLOGY 72 (5), 2008

OMMENTe report on 60 patients with AML who presented at

ur institutions during 16-year period. Our series reflectshe changing spectrum and management of renal AMLnd highlights the differences between SAML and AMLssociated with TSC.

We used an orthogonal diameter measurement to de-ermine AML size. A more accurate method describedecently is to calculate the volume of the lesion.8 Thisight be useful in detecting minor differences in size and

rowth rates, particularly within a short follow-up period.owever, the size obtained with volumetric techniques

nd that obtained by measuring the orthogonal diametersas a high correlation coefficient (r � 0.81; P � .001).8

he statistical significance of the measurements obtainedhrough either method was similar.8

ifference between TSC and SAMLsignificant difference was found in the clinical spec-

rum of the 2 forms of AML in the age at presentation,umor size, and growth rate (Table 1). These findingsorrelate with those of previous studies.1,2 We reported aelatively large average tumor size for TSC AML (19.1m diameter, range 10-40) compared with 6.6 cm re-orted by Harabayashi et al.7 and 8.9 cm in the poolednalysis of Nelson and Sanda.1 The molecular character-stics of the 2 clinical entities can explain these differ-nces and provide novel approaches to their mana-ement. Patients with TSC-associated AML have autation of the TSC1 and TSC2 genes. In contrast, onlyutations of the TSC2 gene are found in SAML.9-12 The

aried growth pattern of AML is characteristic.13-15 Theoss of heterozygosity of TSC1 or TSC2 occurs in renalMLs in patients with TSC and could explain the tu-ors’ variable growth.10 It is not yet known whether

dentification of the molecular structure of AML can besed to predict tumor growth and anticipate complica-ions. Recently, suppression of mTOR signaling reducedhe size of AML lesion in patients with TSC and ame-iorated the clinical spectrum of sporadic lymphangio-eiomyomatosis of the lungs.8

reatment Indicationse actively treated patients with AML for suspicion ofalignancy and to control for severe symptoms or bleed-

ng. Prophylactic intervention in asymptomatic patientss dictated by the size and vascular characteristics of theesion and the presence of medical conditions that mightncrease the risk of hemorrhage.

Many investigators have indicated that the tumor sizes a significant predictor for the necessity of treat-ent.2,16-21 Our data, using the median tumor size, sup-

ort the need for intervention if the tumor size increaseso �4 cm in diameter. Patients who required activentervention for hemorrhage had a median tumor size of1 cm. A cutoff size associated with a significantly high

isk of complications was difficult to reach within our

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mall sample size. Another parameter that needs to bessessed in larger series is the growth rate of the lesions as aredictor for the need for intervention. Recently, our indi-ations for prophylactic intervention in asymptomatic tu-ors �4 cm have included radiologic evidence of large

ascular aneurysms, women planning pregnancy, patientsequiring prolonged anticoagulation, and patients with noapid access to an appropriate medical care facility.

An interesting group included 3 patients with tumors

igure 1. Imaging studies of 21-year-old woman who presencan showing right solid renal tumor with no fat content. (Bcans confirming diagnosis of solid renal tumor with no fat coyperechogenic pattern of angiomyolipoma. (F) Color Dopplhis woman might have angiomyolipoma is presence of muadical nephrectomy for suspicion of malignancy.

4 cm in diameter who were treated surgically for p

080

uspicion of malignancy (1992), persistent hematuria1997), or intractable pain (1992). This reflects the fre-uent reliance on surgical treatment in the earlier eraefore the emergence of more conservative approaches inecent years.

ear of Malignancyhe fear of malignancy remains a major concern for some

ith right flank pain. (A) Noncontrast computed tomographyweighted and (C) T2-weighted magnetic resonance imagingt. (D,E) Ultrasound scan showing absence of characteristicdy of tumor showing its high vascularity. (G) Only clue that

e fat-containing echogenic lesions in liver. She underwent

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urgical intervention in many of them.4,5,22,23 Nine pa-ients in our series underwent surgery for RCC and had anique feature of a low fat content. The tiny amount ofat could be detected only by histopathologic examina-ion. In our series, no significant change was found be-ween the early decade and the most recent 6 years withespect to the number of lesions removed on the suspi-ion of malignancy, despite the improved imaging stud-es. Recent reports are controversial regarding the reli-bility of novel radiologic techniques and image analysiso rule out RCC in histologically proven fat-poorML.24,25 Establishing such a technique would be of

reat diagnostic value. Even with recent imagining mo-alities, the reported increased incidence of benign le-ions is �20% for tumors �7 cm removed on radiologicuspicion of RCC.26 Therefore, some urologists advocate areater role for preoperative core biopsy of selected renalumors.27 Faced with a solid renal tumor and no fat contentn the imaging studies, we still consider it RCC and treat its such. A typical case is illustrated in Figure 1.

reatment Methodse performed total or partial nephrectomy in 23 patients

38.3%) compared with 54% reported by others.1,2 Be-ore 2000, 47.5% of patients underwent surgery; however,n the past 6 years, the percentage decreased to 10%.everal factors have led to a more conservative treatmentpproach in recent years. The increased number of inci-entally discovered SAML of small size resulted in moreatients being observed. The treatment of patients withSC-associated AML has changed from surgery in therevious decade to embolization more recently. Two fac-ors played a role in this change. Nephrectomy for non-ife-threatening bleeding reduced the management op-ions for the remaining solitary kidney, mandating aonservative approach subsequently. Nephron-sparingurgery proved difficult to achieve in patients with TSC-ssociated AML because of the multiplicity of the lesionsn the kidney, eventually ending in nephrectomy in 1atient to control the bleeding.The role of embolization in the management of exist-

ng or impending hemorrhage in patients with SAML orML associated with TSC is expanding. Six of our

atients were treated by this modality. Both embolizationnd nephron-sparing surgery have been reported withxcellent success and minimal complications.28-30 Toetter define the role of embolization vs nephron-sparingurgery in the management of AML, a prospective head-o-head comparison between these 2 modalities iseeded. At present, we recommend embolization as therimary treatment of choice for both forms of AML inatients with a conclusive diagnosis who require inter-ention. Laparoscopic partial nephrectomy might have aole in selected cases in the future.

enal Functionone of our patients developed renal impairment during

ollow-up. Despite surgical intervention, repeated embo-

ROLOGY 72 (5), 2008

ization, or large tumor size, the renal units retaineddequate function to maintain the serum creatinineithin the normal range. This was probably because of a

ack of compression exerted by the growing lesion on theormal parenchyma, an adequate blood supply, and thebsence of tumor replacement of the remaining normalissue of the kidney.

ONCLUSIONSsignificant difference was found in the presentation,

eed for intervention, outcomes, and prognosis betweenAML and TSC-associated AML. Long-term observa-ion of the patients with SAML indicated a slow growthate and preservation of renal function. Recently, morexpectant management for small and asymptomatic le-ions, as well as the increasing use of embolization inymptomatic lesions, has decreased the need for surgicalntervention in patients with AML. Most patientsreated for AML remained symptom free during follow-p. However, symptomatic control is still a problem inome patients with TSC. Better diagnosis and a refinedbility to exclude the presence of malignancy are neededo avoid unnecessary surgical interventions in some pa-ients. Additional areas of research need to address theole of prophylactic intervention in patients with largeML, define the role of embolization vs nephron-sparing

urgery, and use the differences between variants of AMLn genetic structure and growth rate to predict the clin-cal course and assess the need and type of additionalntervention.

cknowledgment. To Susan E. Railey for reviewing the ar-icle.

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