Clinical behavior and management of three types of renal angiomyolipomas

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Journal of the Formosan Medical Association (2018) xx, 1e8

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.jfma-online.com

Original Article

Clinical behavior and management of three types of renal angiomyolipomas Kun-Han Lee a, Han-Yu Tsai b, Yu-Ting Kao a, Hsin-Chia Lin a, Yi-Chun Chou c, Shih-Huan Su b, Cheng-Keng Chuang b,* a Chang Gung Memorial Hospital, School of Medicine, Chang Gung University, No.5, Fusing St., Gueishan, Taoyuan 333, Taiwan b Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, School of Medicine, Chang Gung University, No.5, Fusing St., Gueishan, Taoyuan 333, Taiwan c Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, No. 5, Fusing St., Gueishan, Taoyuan 333, Taiwan

Received 28 September 2017; received in revised form 14 February 2018; accepted 23 February 2018

KEYWORDS Angiomyolipoma; Renal; Tuberous sclerosis complex; Hemorrhage; Epithelioid; Angioembolization; Nephrectomy

Objectives: To analyze and present the demography, clinical behavior, especially the risk factors of tumor hemorrhage and management of sporadic angiomyolipoma (SAML), tuberous sclerosis complex associated angiomyolipoma (TSCAML) and epithelioid angiomyolipoma (EAML) in our institution. Methods: A retrospective study of 587 patients who were diagnosed with renal angiomyolipoma in our institution between January 2000 and May 2015 was done. The AMLs were diagnosed by ultrasonography, CT, or MRI. EAML was confirmed by histopathology. Medical records and follow-up results were analyzed using the SPSS version 22 software. Results: Out of 587 cases of renal AMLs, 87.4% were SAMLs, 8.7% were TSCAMLs and 3.9% were EAMLs. Most of the AML patients were asymptomatic. The most common presenting symptoms included flank pain and abdominal pain. The median tumor size of SAML, TSCAML, EAML were 4.7, 2.7, 10.5 cm respectively. Approximately half of SAMLs were conservatively treated, almost all TSCAMLs were treated conservatively, while all EAMLs were surgically treated. The median tumor size of hemorrhagic SAML cases was 8 cm versus non-hemorrhagic cases of 4.1 cm. The optimal cut-off point on the ROC curve for predicting SAML tumor hemorrhage was 7.35 cm. Conclusions: A larger tumor size, younger patient’s age and higher BMI value correlated with a higher risk of tumor hemorrhage. For tumor sizes less than 7.35 cm, we recommend active

* Corresponding author. E-mail addresses: [email protected] (K.-H. Lee), [email protected] (H.-Y. Tsai), [email protected] (Y.-T. Kao), [email protected] (H.-C. Lin), [email protected] (Y.-C. Chou), [email protected] (S.-H. Su), [email protected] (C.-K. Chuang). https://doi.org/10.1016/j.jfma.2018.02.012 0929-6646/Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Lee K-H, et al., Clinical behavior and management of three types of renal angiomyolipomas, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/j.jfma.2018.02.012

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K.-H. Lee et al. surveillance or TAE for hemorrhage prevention. We also suggest that surgical management should be considered for patients with tumors larger than 7.35 cm, symptomatic and progressive AML, or suspicious EAML. Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Introduction Renal AML is a benign mesenchymal tumor composed of blood vessels, smooth muscle, and adipose tissue. Most renal AMLs are sporadic, while some are associated with TSC.1 The renal EAML is a rare variant of AML with malignant potential.2 Clinically, renal AML used to be categorized into SAML and TSCAML.3 Histologically, it was categorized into classic AML (CAML) and EAML.4 The World Health Organization (WHO) classification of Renal Neoplasms defines EAML as a potentially malignant mesenchymal neoplasm, characterized by the proliferation of predominantly epithelioid cells.4,5 Most renal AMLs can be diagnosed by ultrasonography showing hyperechoic images due to the presence of adipose tissue in the tumor. Computed tomography (CT), or magnetic resonance imaging (MRI) may be needed if ultrasound alone is insufficient to make a diagnosis.6 Most renal AMLs are asymptomatic, but common clinical manifestations include flank pain, hematuria, and abdominal pain.7 As the tumor grows, hemorrhage may occur and result in poor outcomes, with tumor hemorrhage being the biggest morbidity risk of AML. The current consensus states that active surveillance is suggested for small (<4 cm) asymptomatic AMLs; while the presence of tumor hemorrhage, symptoms, tumor greater than 4 cm or EAML histology require more active management.6 Some studies showed that obesity has been linked to increased risk of renal neoplasms, even more so in women.8,9 While others showed that high body mass index (BMI) is an independent risk factor for renal cancer equally strong in both sexes,10,11 therefore the roles of AMLs and obesity remains unknown. Many studies have been done on renal AMLs, however there has been no study making comparisons between SAML, TSCAML and EAML at the same time to date. Thus, we retrospectively analyzed the differences between the three AMLs’ clinical presentations, diagnosis, and management. We also compared the characteristics between hemorrhagic and non-hemorrhagic SAML tumors in order to offer clinicians more risk factors of AML to beware of.

Methods With the approval of the Institutional Research Board, 887 cases were collected from the registration coding system, after those cases with coding mistake or missing data, a total of 587 renal AMLs were recruited for analysis. The AMLs were diagnosed by ultrasonography, CT, or MRI. EAML was confirmed by histopathology. Data collection on the patients’ age, sex, BMI, symptoms, associated underlying diseases, diagnostic methods,

tumor number, site, and size, management, laboratory data and follow-up condition were done. We defined tumor size as the greatest diameter recorded on radiological imaging or pathology report. The priority of methods to record the tumor size is pathologic report, MRI, CT and echo. The patients were divided into 3 groups based on clinical features and histology: SAML, TSCAML and EAML. We used analysis of variance of variance (ANOVA) with Scheffe test and cross-tabulation with Pearson square for analysis of continuous and categorical variables, respectively. p Values were considered significant at p < 0.05. All p-values were 2sided. We used the Statistical Package for Social Sciences software, version 22 (SPSS 22), for statistical analysis.

Results As shown in Table 1, retrospective review of the medical records, radiological images of 587 renal AML cases in our institution over the period between January 2000 and May 2015. SAML, TSCAML and EAML constituted 513 (87.4%), 51 (8.7%) and 23 (3.9%) amongst all AML cases respectively. All types of AML used ultrasonography as the first line diagnostic tool. 81.4% of SAML, 47.1% of TSCAML and 78% of EAML were diagnosed by ultrasonography and CT. 1% of SAML, 7.8% of TSCAML and 21.7% of EAML were diagnosed by ultrasonography and MRI. All of the EAML was confirmed by histopathology. Only 0.8% of SAML was diagnosed using all three of ultrasonography, CT and MRI. We defined tumor size as the greatest diameter recorded on radiological imaging or pathology report. Since not all cases utilized the same imaging modality, for the purpose of this research, we first looked at CT and MRI, with sonogram considered only when the previous two are not available. The median age of SAML, TSCAML and EAML patients at diagnosis were 53 (18e100), 18 (0.4e58), and 46 (18e64) years old respectively (p < 0.001). Female patients constituted 80.5%, 49.0%, and 69.6% among each group. The median BMI was 23.8 (15.1e44.1), 20.1 (10.9e34.8), and 24.3 (18.0e44.5) kg/m2 respectively (p < 0.001). Multiple tumor presentations were seen in 22% (n Z 113) of SAML, 94.1% (n Z 48) of TSCAML, and 13% (n Z 3) of EAML (p < 0.001). There were 20 cases of pure EAMLs, 2 cases of EAML combined with SAML, and 1 case of EAML combined with clear cell RCC. Similar ratio of multiple tumors in hemorrhagic and non-hemorrhagic SAML (25.6%, 21.3%) was also noted. Bilateral involvement was found in 3.9% (n Z 20), 90.2% (n Z 46), and 4.3% (n Z 1) of each AML type. The median tumor size in SAML, TSCAML, EAML were 4.7 (0.3e32.4), 2.7(0.3e8.4), 10.5(1.6e21) cm respectively (p Z 0.005). The hemorrhage rate was 16% (n Z 82), 13.7% (n Z 7), 4.3% (n Z 1), respectively. In addition, the median tumor size in

Please cite this article in press as: Lee K-H, et al., Clinical behavior and management of three types of renal angiomyolipomas, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/j.jfma.2018.02.012

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Three types of renal angiomyolipomas Table 1

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The characteristics of AML, SAML, TSCAML and EAML patients.

Case number Diagnostic tool Echo Echo + CT Echo + MRI Echo + CT+MRI Age Median(Range) Average Gender Male Female BMI (kg/m2) Median(Range) Average Number Single Multiple Site Left Right Bilateral Size(cm) Median(Range) Average Hemorrhage Yes No Hb(g/dL) Median(Range) Creatinine(mg/dL) Median(Range) Last time follow-up Creatinine Median(Range) Management Conservative AS TAE Surgery NSS Nx

All AML

SAML

TSCAML

EAML

587

513(87.4%)

51(8.7%)

23(3.9%)

108(18.7%) 453(78.2%) 14(2.4%) 4(0.7%)

85(16.8%) 411(81.4%) 5(1%) 4(0.8%)

23(45.1%) 24(47.1%) 4(7.8%) 0

0 18(78.3%) 5(21.7%) 0

51(0.4e100) 50.1

53(18e100) 53.5

18(0.4e58) 19.4

46(18e64) 42.8

133(22.7%) 454(77.3%)

100(14.5%) 413(80.5%)

26(51%) 25(49%)

7(30.4%) 16(69.6%)

23.6(10.9e44.5) 24.0

23.8(15.1e44.1) 24.3

20.1(10.9e34.8) 21.1

24.3(18e44.5) 25.3

422(72.1%) 164(27.9%)

400(78%) 113(22%)

3(5.9%) 48(94.1%)

20(87%) 3(13%)

260(44.3%) 260(44.3) 67(11.4%)

246(48) 247(48.1) 20(3.9%)

3(5.9%) 2(3.9%) 46(90.2%)

11(47.8) 11(47.8) 1(4.3%)

4.7(0.3e32.4) 6.0

4.7(0.3e32.4) 5.8

2.7(0.3e8.4) 5.9

10.5(1.6e21) 9.5

90(15.3%) 497(84.7%)

82(16%) 431(84%)

7(13.7%) 44(86.3%)

1(4.3%) 22(95.7%)

12.6(4.7e16.6)

12.5(5.6e15.6)

12.9(4.7e15.7)

11.5(7.4e15.1)

0.8(0.1e11.4)

0.8(0.3e11.4)

0.57(0.1e3.3)

0.8(0.4e2.2)

0.76(0.3e13.2)

0.77(0.3e13.2)

0.69(0.3e5.4)

0.86(0.5e6.3)

256(43.9%) 182 74 327(56.1%) 240 87

214(42%) 146 68 296(58%) 230 66

42(84%) 36 6 8(16%) 2 6

0(0%) 0 0 23(100%) 8 15

p- Value

<0.001

<0.001

<0.001

<0.001

<0.001

0.005

0.3

0.252 0.202 0.252

AS Z active surveillance. TAE Z trans-arterial embolization. NSS Z nephron-sparing nephrectomy. Nx Z radical nephrectomy. Conservative treatment included AS and TAE.

hemorrhagic (8 cm) and non-hemorrhagic (4.1 cm) SAML was significantly different (p < 0.001). There was no significant difference between the three types of AML in patient’s hemoglobin (p Z 0.252) and creatinine (p Z 0.202) levels. The median values were all within the normal range. However, hemoglobin levels of hemorrhagic SAML patients were significantly lower than non-hemorrhagic SAML patients (p < 0.001). As shown in Table 2, half of the AML patients were asymptomatic (50.5%, n Z 259). The most common symptom of SAML patients was flank pain (25.7%), followed by abdominal pain (12.1%), hematuria (6%), flank soreness

(5.1%), nausea/vomiting (2.3%), abdominal distension (1.4%) and others (testis pain, weight loss, urinary frequency). Bleeding renal AML results in higher morbidity. As shown in Table 3, the hemorrhage SAML patients had younger age (median 49 years old), higher BMI (median BMI 26.1) and larger tumor (median 8 cm). A multivariate analysis between age, gender, BMI and tumor size in hemorrhage SAML patients showed that tumor size was the most important parameter associated with bleeding. The area under the receiver-operating characteristic (ROC) curve (AUC) of SAML tumor size was 0.746. The optimal cut-off point on

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K.-H. Lee et al. Table 2

The initial symptoms of SAML patients. Symptom of SAML patient

Symptom

Frequency

Percentage

Asymptomatic Flank pain Abdominal pain Hematuria Flank soreness Nausea/vomit Abdominal distension Other

259 132 62 31 26 12 7 2

50.5% 25.7% 12.1% 6.0% 5.1% 2.3% 1.4% 0.4%

the ROC curve for predicting SAML tumor hemorrhage was 7.35 cm (Fig. 1). Fig. 2 is the flow chart of management protocol of hemorrhagic SAML in our institution. There were 82 patients presented with hemorrhagic SAML, with three transferred to other hospitals. A total of 79 patients were analyzed, and among the 38 patients who had unstable vital signs (mean arterial pressure < 70 mmHg or received blood transfusion), 33 patients received TAE as first treatment (87%, 33/38) and 21 patients received TAE followed by surgery (8 received NSS Table 3

and 13 received nephrectomy). For the 41 patients with stable vital sign, 21 received surgery (14 received NSS and 7 received nephrectomy); 15 received TAE, with only one patient requiring further surgery of NSS; and 5 remained under close observation. In summary, TAE is effective in kidney preservation for all stable hemorrhagic SAML patients and for 61% (20/33) of unstable hemorrhagic SAML patients.

Discussion TSCAML had a significantly higher rate of tumors presenting in multiple form (94.1%) and presenting in bilateral kidneys (90.2%) compared to SAML and EAML. This result was consistent with previous studies.12,13 Due to above character of TSCAML, clinical doctors should highly suspect TSCAML when bilateral renal tumors with multiple form was found. Our result also corresponded to previous studies that reported TSCAMLs usually being diagnosed at a younger age than SAML.12,14 SAML and EAML patients were predominantly female from our data. This result also corresponded to previous studies that showed the ratio of female: male ranging from 3:1 to 16:1.14e19 Henske, E.P., et al. and Boorjian, S.A., et al. proposed that female sex hormones might be the cause for a higher proportion of women

The characteristics of hemorrhagic and non-hemorrhagic SAML.

Age Median (Range) Average Gender Male Female BMI Median (Range) Average Number Single multiple Site Left Right Bilateral Size (cm) Median (Range) Average Hb(g/dL) Median (Range) Creatinine(mg/dL) Median (Range) Management AAD Conservative (AS þ TAE) Active surveillance TAE Surgery Nephron-sparing Radical nephrectomy

Non-hemorrhagic SAML (n Z 431,84%)

Hemorrhagic SAML (n Z 82,16%)

54 (18e100) 54.3

49 (19e87) 49.4

74 (17.2%) 357 (82.8%)

26 (31.7%) 56 (68.3%)

23.6 (15.1e44.1) 24.1

26.1 (16e40.1) 25.8

339 (78.7%) 92 (21.3%)

61 (74.4%) 21 (25.6%)

208 (48.3%) 206 (47.8%) 167 (3.9%)

38 (46.3%) 41 (50%) 3 (3.7%)

4.1 (0.3e32.4) 5.2

8 (1e25.5) 8.8

12.7 (7.2e16.6)

10.8 (5.6e16.0)

0.78 (0.3e11.4)

0.9 (0.4e9.62)

183 140 43 248 205 43

3 31 5 26 48 25 23

p- Value 0.004

0.003

0.046

0.236

0.934

<0.001

<0.001 0.048

0.343

0.343

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Three types of renal angiomyolipomas

5 m2.25 Patients that formed our data group were all within the normal range of BMI. The association between high BMI and AML incidence was low from our data. However, it was interesting to note that higher BMI was associated with a higher risk of tumor hemorrhage (26.1 vs 23.6). In our study, the median tumor size of SAML, TSCAML, EAML were 4.7, 2.7, 10.5 cm respectively. However, in Sooriakumaran et al.’s study, the median size of TSCAML was larger than SAML tumors (3.5 cm versus 1.2 cm),26 which is different from our results. This could be because nearly half of our SAML was asymptomatic and the TSCAML was found due to other clinical presentations of tuberous sclerosis complex. In Sooriakumaran series,9 32% (8/32) of SAML patient (median size 1.2 cm) were symptomatic. Our cases had a higher percentage of symptomatics than Sooriakumaran series. Due to mass effect, the larger the lesion is, the greater the probability of clinical symptoms. This could explain why the median size of SAML in our data is larger than theirs. In other studies,12,16,27e29 the mean size of SAML ranged from 1.8 to 6.5 cm. EAML exhibited the largest size compared to the other two types of AML, as was shown in previous studies.30,31 Of the total 513 SAML cases, 50.5% (n Z 259) SAML were asymptomatic. Since asymptomatic patients do not voluntary visit physicians for examination, these cases were discovered when they received regular health check-ups or when they received abdominal examination for other dis-

Figure 1 The area under the receiver-operating characteristic (ROC) curve (AUC) of SAML tumor size was 0.746. The optimal cut-off point on the ROC curve for predicting SAML tumor hemorrhage is 7.35 cm.

Hemorrhagic SAML (79)

Unstable vital sign

Stable vital sign

symptomac (38)

asymptomac (41)

Operaon(5)

NSS(2)

TAE(33)

Nx(3)

AS(12)

Observe (5)

TAE(15)

NSS(1)

Nx(0)

Operaon(21)

NSS(8)

Operaon (21)

AS(14)

NSS(14)

Nx(7)

Nx(13)

Figure 2 We have 82 patients with hemorrhage SAML, 3 refused treatment from our hospital and transferred to other hospital. (NSS Z nephron-sparing surgery; Nx Z radical nephrectomy).

developing AMLs compared to men.20,21 The female-tomale ratio of EAML in this study was 2.29: 1, and other studies recorded gender ratio of: 1.6: 1,22 0.72: 1,23 0.9: 1.24 Therefore, EAML does appear to exhibit less difference in gender distribution than SAML. Obesity has previously been linked to an increased risk of renal neoplasm, even more so in women.8,9 A high BMI is an independent risk factor for renal cancer equally strong in both sexes.10,11 However, the role that obesity plays in renal angiomyolipoma is still unknown. Normal BMI is defined by the World Health Organization in 2004 as 18.50e24.99 kg/

comforts. In 82 hemorrhagic SAML cases, 72 cases (87.8%) of hemorrhagic AML were diagnosed at first presentation. Ten cases (12.2%) with SAML were followed for a period and ruptured afterwards; only 4 received regular follow up at our hospital. These cases (n Z 10) were followed for an average of 43.7 months (3.6 years) prior to rupture. Since 87.8% of hemorrhagic AML in our data were diagnosed at first presentation, we can conclude that most hemorrhage AML were incidental findings where patients had no prior knowledge of their AML. Therefore, routine renal echo examination may be necessary.

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6 The most dangerous complication of AML is tumor hemorrhage. In severe cases, it can cause hemodynamic instability and lead to shock. Therefore, the prediction of the possibility of AML hemorrhage is a crucial clinical issue. Many studies have indicated that the vascularity and the size of tumor are related to the risk of tumor hemorrhage.32e34 The median sizes of hemorrhagic and nonhemorrhagic SAML were 8 cm versus 4.1 cm from our study. The tumors with hemorrhage have significantly bigger size than tumors without hemorrhage (p Z 0.004). In Prando’s study,33 the mean tumor sizes of hemorrhaging and nonhemorrhaging AML rates were 11.4 cm and 5.0 cm, suggesting that the bigger the size of the tumor, the higher the risk of hemorrhage. The cut-off point of tumor size for conservative or invasive management has been 4 cm for many years.35 From our cases, the hemorrhage rates of SAML 4 cm and <4 cm were 23.6% and 4.8% respectively. The tumor size 4 cm or larger had 4.92 times higher risk of hemorrhage than tumors less than 4 cm. The optimal cutoff point on the ROC curve for predicting SAML tumor hemorrhage was 7.35 cm in our study. The hemorrhage rate of SAML larger than 7.35 cm and SAML larger than 4 cm was 36.3% and 23.6%. The hemorrhage rate is higher in SAML larger than 7.35 cm. The hemorrhage rate of SAML between 4 cm and 7.35 cm was 13.2%. If the patient’s vital sign was stable with asymptomatic or non-hemorrhagic tumor, active surveillance or TAE could be considered as first-line management in SAML between 4 cm and 7.35 cm. This could increase the percentage of kidney preservation for patients. In Kuusk T el. study,27 the prevalence of major bleeding was high in sporadic AMLs with a diameter of >6 cm. They suggested that conservative treatment can be considered in AMLs of <6 cm in diameter. The role of TAE is to reduce blood flow to the tumor, resulting in tumor ischemia and necrosis. It could stop bleeding and prevent re-bleeding in hemorrhage AML and slow the growth rate of tumor.36 In our study, If the vital sign was stable, there was higher chance of kidney preservation. When patients received TAE prior to surgical operation, 93.3% were able to preserve their kidney; If TAE was not performed prior to operation, 33.3% of patients require radical nephrectomy. We recommended hemorrhage SAML patients to receive TAE first, irregardless of vital sign conditions because it could elevate the percentage of kidney preservation. Patient could receive TAE only without subsequent operation. Even if further operation was required, most cases require only partial nephrectomy. The consensus was that symptomatic renal AML mainly due to hemorrhage should be treated by TAE, and surgery should be regarded as second-line treatment37 In our study, one third of hemorrhagic SAML received surgery as first line treatment instead of TAE, most probably due to factors such as limited radiologist availability, surgeon’s favor for surgeries, and patient’s preference and condition. Male patients and patients with younger age were at higher risk of hemorrhage. We speculated that young men are more prone to partake in strenuous exercise, which has a larger impact on physiology and hemodynamics. This might have resulted in a higher risk of tumor hemorrhage for young male. From the multivariate analysis, we deduced that tumor size was the most important factor

K.-H. Lee et al. affecting tumor hemorrhage, and the other parameters were associated to a lesser extent when compared with tumor size. Therefore, tumor size should be the main factor to consider when determining whether more aggressive management was required clinically. From our results, the hemorrhage rate of TSCAML (13.7%) is lower than SAML (16%), which differed from previous studies that reported TSCAML having a higher rate of spontaneous hemorrhage than SAML.38,39 This may be because TSCAML was diagnosed at a younger age at our institution, leading to early prophylactic management and active surveillance. Initial clinical manifestations and tumor size were important factors for decisions on the management plan of AML.40 Patients with bigger tumor size and who were symptomatic, should have more aggressive treatment. TAE was recommended as the first-line therapy after AS has been discontinued.40 In our study, the major determinants that lead to invasive treatment were larger tumor size and the physician’s decision to prevent tumor hemorrhage. In our data, the median tumor size of patients who received invasive management and non-invasive management was 5.5 vs 3 cm (p < 0.001). Many non-hemorrhagic patients received invasive treatment because of a large tumor size, and for tumor hemorrhage prevention. The majority of TSCAML cases were conservatively treated, as we found that most of the TSCAMLs presented as multiple tumors and in bilateral kidneys. In consideration of nephron-sparing, we opted to choose conservative treatment. In Murray, Doyle, and Lee’s studies, TAE of AML has a high success rate (93.3%), with the mean tumor size reduction of 3.4 cm, and re-treatment rate of 20.9%.41 Chang et al. had reported that urgent superselective TAE was an effective management for emergency patients with hemorrhagic AML, with no need for emergency surgery after embolization.42 Clinical physicians will need to regularly follow up on any changes to patients’ tumor via kidney echo. Based on their prior experiences and professional judgement, clinical physicians can choose to perform TAE or surgery for the patients if: tumor size is too large, tumor growth is too fast, symptoms (such as flank pain) continue to irritate patient, it is the patient’s desired form of treatment, or patient is of a high risk rupture group (young male, favors extreme sports, etc). Among EAML cases in our study, only one case was diagnosed as EAML by tumor biopsy before operation. Renal cell carcinoma was suspected in 20 cases, and 3 cases were impressed as large SAML. All 23 cases were confirmed EAML by histopathology. EAML should be taken into consideration by clinicians if the patient is of young age and the renal tumor size is large. A preoperative biopsy might be considered. Due to the malignant potential of renal epithelioid angiomyolipoma, conservative treatment is not suitable. Also, the preoperative distinction between RCC and epithelioid angiomyolipoma might not be important since both lesions were generally treated with surgical resection.43 We are still working on a preoperative diagnostic study focusing on the malignant behavior of EAML. According to the study done by Liu Y,44 when encountering a solid lesion with hyper-density on unenhanced CT, with or without fat component, that demonstrated a rapid wash-in

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Three types of renal angiomyolipomas to slow wash-out dynamic enhancement pattern, EAML should be suspected. Pre-operative renal biopsy is required for more precise decision making and further treatment options such as the use of mTOR inhibitors. In Zheng S el. study,24 a larger tumor size, the presence of tumor necrosis and invasive tumor edge may be potential indicators for malignant EAML. Due to the retrospective nature of our study, we can only analyse the pre-existing case data available. There were some limitations in our study. We did not use an uniform method to record tumor size and that may result in measurement bias. In this retrospective study, not all the patients with AML received surgery or tumor biopsy, so EAML might be underestimated. Future research and further data collection will be required to generate more clinically meaningful suggestions.

Conclusion SAML and EAML were more common in middle-aged patients, while TSCAML was more common in pediatric/ adolescent aged groups. SAML and EAML were female predominant but TSCAML had equal gender ratio. The most common initial symptoms of AML patients were flank pain, abdomen pain, and hematuria, but nearly half of the AML patients were asymptomatic. TSCAML has significantly higher rate of tumors presenting in multiple form and tumors presenting in bilateral kidneys. Clinical doctors should highly suspect TSCAML when bilateral renal tumors with multiple form was found. Younger patient’s age, bigger tumor size and higher BMI value correlate to an increased the risk of tumor hemorrhage. The tumor size was the most important factor affecting the tumor hemorrhage. The optimal cut-off point on the ROC curve for predicting SAML tumor hemorrhage is 7.35 cm. For tumor sizes less than 7.35 cm, we recommend active surveillance or TAE for preventing hemorrhage. However, surgical management should still be applied in large tumor sizes, suspicious EAML, symptomatic and progressive AML. Nephron-sparing surgery may be considered in selective cases.

Conflict of interest The authors have no conflicts of interest relevant to this article.

Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The IRB number of this research is 104-7555C. For this type of study formal consent is not required.

Acknowledgments We thank the NSC Grant No. NSC-105-2314-B-182-024MY3, for funding this study and thank Professor Cheng-

7 Keng Chuang the guidance and the direction. And we would like to thank reviewers and the editor for their comments.

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Please cite this article in press as: Lee K-H, et al., Clinical behavior and management of three types of renal angiomyolipomas, Journal of the Formosan Medical Association (2018), https://doi.org/10.1016/j.jfma.2018.02.012