Renal angiomyolipomas: At least two diseases. A series of patients treated at two European institutions

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Renal angiomyolipomas: At least two diseases. A series of patients treated at two European institutions J.-B. Delhorme a, A. Fontana b, A. Levy c, P. Terrier d, M. Fiore b, D. Tzanis e, D. Callegaro b, C. Dratwa f, A. Gronchi b,g, S. Bonvalot e,g,* a b

Department of Surgical Oncology, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France Department of Surgical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian, 1, 20133, Milano, Italy c Department of Radiation Oncology, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif, France d Department of Pathology, Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif, France e Department of Surgical Oncology, Institut Curie, PSL University, 26 rue d’Ulm, 75248, Paris, France f Department of Radiology, Institut Curie, PSL University, 26 rue d’Ulm, 75248, Paris, France Accepted 17 November 2016 Available online - - -

Abstract Objective: The aim of this study is to analyze the outcome of renal angiomyolipomas (AML) at two European institutions. Methods: The data were collected from patients with a primary AML who were treated at Gustave Roussy, Villejuif, France and Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy from 1998 to 2014. The specimens were classified as classic AML (C AML) or epithelioid AML (E AML) based on the percentage of epithelioid cells. Results: There were 40 patients identified for the study (35 C AML, 5 E AML). One patient had an associated tuberous sclerosis complex. Six patients (15%) had bilateral AML. The imaging results were significantly different between C/E AML. E AML was associated with fewer bilateral lesions, more renal vein/vena cava extension, and more poor or non-fatty aspects. Surgery/active surveillance (AS)/chemo radiation were applied for 28/11/1 patients, respectively. The median tumor size was significantly smaller (3.75 cm) in patients receiving AS (median 15 cm when surgically resected). The median patient follow-up was 43 months. The three-year overall survival was significantly better for patients with C AML than E AML (100% versus 50%, p < 0.0001). The univariate analysis identified the OS prognostic factors were E AML histologic subtype (p < 0.001), poor/non fatty features (p ¼ 0.002), and renal vein extension on imaging (p ¼ 0.01). Conclusion: AML manifests as at least two different entities with significantly different outcomes. Epithelioid subtype, poor/non-fatty features, and renal vein involvement are all associated with worse survival. Ó 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Keywords: Angiomyolipoma; Epithelioid angiomyolipoma; Active surveillance; Surgery; Prognostic factors

Introduction Angiomyolipoma (AML) is a mesenchymal tumor1 within the family of perivascular epithelioid cell tumors (PEComa).2 The majority of AMLs occur in the kidney. However, tumors can also be found in the liver and rarely in other organs.3,4 The * Corresponding author. Institut Curie, 26 rue d’Ulm, 75005 Paris, France. E-mail address: [email protected] (S. Bonvalot). g Same contribution.

overall prevalence of AMLs in the general population is 0.44% and they account for approximately 3% of all renal tumors.3 Although 80% of AML are sporadic and the majority of tumors are inconsequential, approximately 20% are associated with tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM).3 TSC is an autosomal dominant syndrome that arises from inactivating mutations in either TSC1 or TSC2 genes. Renal AMLs occur in up to 80% of TSC patients and are frequently bilateral and multifocal. The primary cause of TSC-related mortality is chronic kidney disease from increasing tumor burden.5 Renal AML patients

http://dx.doi.org/10.1016/j.ejso.2016.11.012 0748-7983/Ó 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Please cite this article in press as: Delhorme J-B, et al., Renal angiomyolipomas: At least two diseases. A series of patients treated at two European institutions, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.11.012

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have a mean age of diagnosis of 50 years for non-TSC patients and 30 years for TSC patients. The female to male ratio is 3:1.3 There are two histologic tumor subtypes described; a classic type (C AML) composed of variables degrees of vascular, smooth muscle and adipose tissue components, and an epithelioid type (E AML) composed of a large contingent of epithelioid cells with no or a minimal amount of adipose tissue. In contrast to C AML, which is considered benign, E AML is a potentially malignant mesenchymal neoplasm and approximately one-third of patients experience metastases.1,6 There is no consensus on the percentage of epithelioid cells required for diagnosing E AML. However, previous studies have suggested that at least 20% of cells must exhibit epithelioid histology.7 “Typical” AML can be diagnosed by identifying macroscopic fat with ultrasound, computed tomography, or magnetic resonance imaging.6 Approximately 5% of AMLs do not show the fat attenuation on imaging and cannot be differentiated from renal cell carcinoma (RCC) and are termed “fat poor AMLs”. The clinical outcomes of these tumors were reported to be excellent in several retrospective series.8e11 E AMLs typically present as large masses with intratumoral hemorrhage and necrosis. The tumors can have a fat component and demonstrate a rapid wash-in to slow wash-out dynamic enhancement pattern.12 A percutaneous biopsy may guide the treatment decisions for lesions with unusual growth and imaging characteristics.9 The treatment options range from nephrectomy to kidneysparing surgery, surveillance or ablative therapies in cases of bilateral lesions. Patients with TSC can be treated with mTOR inhibitors as a viable approach to control tumor burden while conserving renal parenchyma.13e16 The objective of this study was to analyze the outcome of renal AML patients in two European institutions with expertise in the management of mesenchymal tumors. Patients and method Study outline and definitions The data were collected from patients with primary AML who were treated at the Institut Gustave Roussy, Villejuif, France and Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy from 1998 to 2014. The patient characteristics included gender, age, symptoms, and past medical history. Diagnostic data collected imaging characteristics (site, size, bilaterality and fatty aspect, extent of the tumor in the renal vein or vena cava, and presence of metastasis at diagnosis) and biopsy when performed. The pathological diagnosis was centrally reviewed by a specialized pathologist. Histologically, tumors were categorized using the 2016 World Health Organization criteria17 according to microscopic features and immunohistochemistry (smooth muscle actin, h-caldesmon, desmin, and HMB-45). Each specimen was classified as C AML or E AML based on the percentage of epithelioid cells. In this study, the morphologic criteria for designating tumors as E AML were defined

by proliferation of predominantly epithelioid cells with enlarged vesicular nuclei. The treatment strategies were categorized as surveillance, surgery, chemotherapy, and embolization. The surgical procedures and extent of kidney surgery were recorded. Surgical resections were classified as macroscopically complete (R0 or R1) or incomplete (R2) according to the UICC “R” classification.18 Postoperative complications were graded according to the DindoeClavien classification.19 Morbidity grade III or higher was considered to be major morbidity. The patients were followed-up with clinical evaluation and CT scan every 6e12 months for the first five years and then again annually. Statistical analysis The cutoff date for survival analyses was December 31st 2014 for the censored data analysis. The categorical variables were compared within groups using the Chi-squared and Fisher’s exact test. The patient follow-up, overall survival (OS), and disease-free survival (DFS) rates were estimated using the KaplaneMeier method.20 The survival curves were compared using the log-rank test. The patient OS was computed from the date of diagnosis to the date of death, regardless of cause. All statistical analyses were performed using IBM SPSS statistics software, version 20.0. The data were expressed as the means  the standard error of the mean unless otherwise stated. All reported p-values are two sided and values less than 0.05 were considered significant. Results Clinicopathologic features There were 40 patients identified for this study (35 C AML, 5 E AML). The clinicopathological characteristics are shown in Table 1. Six patients (15%) with C AML had a past history of other cancers (1 leiomyosarcoma, 1 well-differentiated liposarcoma, 1 rectal carcinoma, 1 pseudomyxoma peritonei, 1 breast carcinoma and 1 melanoma). One patient had associated TSC. One E AML patient had lung metastasis at diagnosis. The median patient age at diagnosis was 56 years. The median tumor size was 10 cm (range 1e30). There were six patients (15%) with bilateral AML, and the median size of the contralateral lesion was 2.25 cm (range 0.7e4.5). The diagnosis was based on percutaneous biopsy for 12 patients (11 C AML, 1 E AML). The surgical specimen was used for diagnosis in 28 patients (24 C AML and 4 E AML). The imaging results were significantly different (p < 0.001) between C AML/E AML. E AML was associated with fewer bilateral lesions, more renal vein/vena cava extension, and more poor or non-fatty aspects. Main treatment Active surveillance (AS) was used in 11 patients affected by C AML. Surgery was performed as the first

Please cite this article in press as: Delhorme J-B, et al., Renal angiomyolipomas: At least two diseases. A series of patients treated at two European institutions, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2016.11.012

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Table 1 Clinicopathologic features and main treatments.

Gender Male Female Age average years (range) Past medical history Past cancer Past renal cancer Tuberous sclerosis complex Lymphangioleiomyomatosis Clinical presentation Symptomatic - Pain - Flank mass - Bleeding - Urinary infection Incidental diagnosis Unknown Radiological features Unilateral Bilateral “Beak sign”/renal origin Renal vein involvement Vena cava involvement Poor/non fatty AML Median tumor size (cm, range) Synchronous metastasis Lymph node Lung First line treatment Surgery Radio-chemotherapy alone Active surveillance (AS) Surgical treatment After failure AS Kidney conservation Partial nephrectomy Multi visceral resection DindoeClavien grade IeII III UICC “R” classification R0eR1 R2 Immunohistochemistry Smooth muscle actin h-Caldesmon Desmin HMB-45 Progression/Recurrence Operated patients Local Distant metastasis Both Non operated patients Local (after AS) Distant metastasis (patient treated by radio-chemotherapy alone) Death

Full series

Subgroup analysis Histologic subtype

n ¼ 40

CAML n ¼ 35

EAML n ¼ 5

7 (17.5) 33 (82.5) 56 (28e85)

6 (17.2) 29 (82.8) 56 (28e85)

1 (20) 4 (80) 54 (45e67)

6 (15) 0 1 (2.5) 0

6 (17.1) 0 1 (2.8) 0

0 0 0 0

19 (47.5) 12 3 2 (5) 2 17 (42.5) 4 (10)

18 (51.4) 11 3 2 2 16 (45.7) 1

1 (20) 1 (20) 0 0 0 1 (20) 3 (60)

34 (85) 6 (15) 37 (92.5) 3 (7.5) 1 (2.5) 5 (12.5) 10 (0.8e30)

29 (82.8) 6 (17.1) 32 (91.4) 0 0 1 (2.8) 10 (0.8e30)

5 0 5 3 1 4 9

2 (5) 1 (2.5)

1 (2.8) 0

1 (20) 1 (20)

28 (70) 1 (2.5) 11 (27.5) 29 (72.5) 1 (3.5) 3 (10.3) 2 (6.9) 5 (17.2)

24 (68.6) 0 11 (31.4) 25 (71.4) 1 3 2 3

4 (80) 1 (20) 0 4 (80) 0 0 0 2

16 (40) 0

15 (60) 0

1 (20) 0

26 (90) 1

25 (100) 0

1 (25) 1 (25)

21 (52.5) 9 (22.5) 11 (27.5) 24 (60) 8 (20) 5 2 2 1 3 2 1 3 (7.5)

21 (60) 9 (25.7) 10 (28.6) 23 (65.7) 3 (8.6) 1 1 0 0 2 2 0 0

0 0 1 1 5 4 1 2 1 1 0 1 3

p 1

0.64 1

1

<0.001 (100) (100) (60) (20) (80) (6.3e21)

0.89 0.33

0.053

1

0.33

0.07

0,62

(20) (20) (100)

<0.001

(60)

0.001

Results presented as numbers unless specified. Brackets: the proportions unless specified. p: p-value.

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line treatment for 28 patients and after progression under AS for one patient with C AML. One patient (E AML) with lung metastasis at diagnosis was treated with radiotherapy (50 Gy) and cisplatinum, which was then followed by systemic chemotherapy. The treatment decision in C AML was significantly different based on tumor size (median tumor size 15 cm (range: 1e30) for surgical resection and 3.75 cm (range: 0.8e7.7) for surveillance). The median hospital stay in patients who were operated on was 8 days (range: 5e18). There was no postoperative major morbidity or mortality observed. Survival and relapse The median follow-up was 43 months (range: 1e205 months) in the entire cohort. At the final follow-up, 31 patients were disease free or without disease progression, 8 patients were alive with disease progression or recurrence, and 1 patient was lost to follow-up. Among the twelve nonoperated patients, 2/11 C AML patients progressed after surveillance and 1 E AML patient with synchronous metastasis progressed after a first line CT. Among the 28 operated patients; 1 C AML patient developed a local recurrence after a partial nephrectomy and all E AML patients developed recurrences (local n ¼ 1, metastatic n ¼ 2, both n ¼ 1). The 3-year OS was 91.1% (IC 95% [79.9e100]), and the 3-year DFS was 81% (IC 95% [66.5e98.1]). The sites of metastasis were lung n ¼ 3 and liver n ¼ 1. Three E AML patients died of disease progression. Among the two patients who progressed after surveillance, one was affected by with TSC and was treated by radiofrequency ablation and 1 patient without TSC was treated surgically. Prognostic factors The three-year OS was significantly higher for patients with C AML than patients with E AML (100% versus 50%, p < 0.0001). The three-year DFS for C AML patients was 100% and was significantly higher than E AML patients, which was 0% (p < 0.0001, Fig. 1). The univariate analysis found the OS prognostic factors were E AML histologic subtype (p < 0.001), poor/non-fatty features (p ¼ 0.002), and renal vein extension on imaging (p ¼ 0.01). In the univariate analysis of DFS, the prognostic factors were E AML histologic subtype (p < 0.001), poor/non-fatty features (p ¼ 0.002), renal vein extension on imaging (p ¼ 0.01), and incomplete surgical resection (p ¼ 0.001). Tumor size was not a prognostic factor. The multivariate analysis did not identify prognostic factors for OS or DFS. Discussion In this bicentric case series we confirm that “AML” describes at least two very different diseases co-existing with an ill-defined border. We found that C AML exhibits an acceptable prognosis and the 3 year OS is 100%. However,

100% CAML

Disease free survival

4

EAML

75%

50%

25%

0% 0

24

48

72

96

120

5

2

Time (months)

Patients at risk: CAML 35 EAML 5

21 2

12

9

Figure 1. Disease free survival according to AML subtype (C/E AML).

the OS was approximately half for patients with E AML. These results are consistent with previous studies.6,21 It is crucial to accurately diagnose the correct tumor type because the management and follow-up are different. The classic variant is suitable for a more conservative approach including AS and does not require a specific follow up when resected; while the epithelioid variant may benefit from a more aggressive approach upfront. Another concern is the recognition of patients with TSC because using a nephron sparing strategy is critical. As in previous studies, the majority of AMLs in our series were sporadic. Nevertheless, previous series had higher rates of TSC overall, which ranged from 5% to 20%.13,14,22 Our data confirm the middle age propensity and female predominance. Half of our patients exhibited symptomatic lesions and this result is consistent with the findings of a previous large surgical study.8 However, this percentage may be lower according to the inclusion criteria. A recent imaging study analyzing patients who were identified with a radiology report that included a reference to renal AML23 showed more than 90% were discovered incidentally. However, in the latest study the median tumor size was smaller. We observed only 5% bleeding that revealed renal AML, which is the most severe complication. A recent pooled analysis of individual patient data24 found 12% of patients presented with major retroperitoneal bleeding. These patients had significantly larger tumors (10 cm) than patients without bleeding (6 cm). This case series confirms that imaging features of C/E AML are significantly different. The imaging findings of C AML include a fatty component within a renal mass that is characterized by negative density on CT-scan. These features are not found in E AML because the tumors are significantly more often fat-poor or have minimal-fat. A retrospective series found the characteristic imaging features of E AML12

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included higher density (than normal renal parenchyma) by unenhanced CT, bulging contour of the affected kidney, and markedly heterogeneous enhancement. Additionally, renal vein involvement is significantly associated with E AML. Vessels are often present within the C AML and this finding helps to distinguish huge exophytic C AML from well differentiated liposarcoma (WDLPS). In WDLPS the kidney is frequently encased in the fat and the tumor rarely originates in the kidney, which is the opposite of AML. The major imaging feature that helps distinguish AML from liposarcoma is the ‘‘beak sign’’ at the interface of the mass with the kidney and indicates a renal origin.9 However, these features are not specific and we recommend a percutaneous biopsy every time the imaging features are not pathognomonic, approximately 1/3 cases in our series. E AMLs may mimic RCC, renal sarcoma, or C AML with minimal or absent fat on imaging evaluation. These features may lead to an incorrect diagnosis.4 The clinicopathologic parameters that predict malignant outcome of AML are not well known. Epithelioid histology is a reliable parameter associated with recurrence, metastasis, or death in the literature.7,25 However, the percentage of epithelioid cells required for a diagnosis of E AML is not well defined and there are various prognoses based on the threshold. In a study by Aydin et al.,25 they define E AML as tumors with at least 10% epithelioid component. In our study, E AML was defined as “predominantly epithelioid cells” and we found that the patients had similar survival as the patients reported by Nese et al.26 The authors studied “pure epithelioid AML” tumors that were composed of purely epithelioid cells with minimal or no adipocytic component. The results showed half of the patients developed metastatic disease and one-third of the patients died of the disease. We found that epithelioid subtype, poor/non-fatty features, and renal vein involvement on imaging were significant tumor prognostic factors associated with poor survival. These adverse prognostic parameters are consistent with findings from other studies.6,21,26 Other factors including severe atypia, higher mitotic count, atypical mitotic figures, and necrosis have also been reported.21 In a study specifically of E AML the association with TSC, tumor size (>7 cm), carcinoma-like morphologic pattern, and presence of necrosis were also adverse prognostic factors.26 E AML (8860/1) and AML (8860/0) are now classified distinctly in the WHO 2016 classification of tumors of the urinary system.17 The behavior is coded /1 when the evolution is uncertain because the morphologic criteria is not able to predict a precise outcome. Thus, the development of new molecular biomarkers would be helpful. In the present series, approximately one-fourth of patients were treated by AS and there were only two failures. This intervention rate is higher than in the most recent series23,27 (22, 27) and reflects a limitation of our study. Our patient collection period was long and there is a selection bias concerning patient referrals in tertiary centers. As a

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result, the median tumor size was 10 cm and half of our patients exhibited symptomatic lesions. The management of renal AMLs is typically based on suspected malignancy, associated symptoms and radiographic size. Indeed, major bleeding is the most severe complication and increases with tumor size.24 However, the size threshold for prophylactic treatment rises with time. The historical recommendation for intervention was AMLs larger than 4 cm. However, Ouzaid27 reported on 130 patients receiving AS and 29% had masses larger than 4 cm. In this latest group, only one-third had discontinued AS and underwent active treatment. In the large study of Bhatt,23 5.6% of patients who were initially observed were actively treated and 91% of AMLs did not grow or grew slowly. There was no difference between tumors smaller/larger than 4 cm and the average growth rate was only 0.02 cm/yr. Surgery is now challenged by more recent options such as cryoand radio-frequency ablation14 and selective arterial embolizations28 that were used once in our series. Kidney disease is the leading cause of death in patients with TSC.28,29 Thus, nephron sparing approaches are particularly important for these patients. Conclusion In this study, AML displayed at least two different entities with significantly different outcomes. The epithelioid subtype shows poor/non-fatty features and renal vein involvement that are associated with poor survival. Thus, additional predictive molecular biomarkers suitable for routine use would help to better distinguish tumor types. Source of funding None. Conflict of interest statement The authors have no potential conflicts of interest to disclose.

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