Magnetic Resonance Imaging and Computed Tomography Characteristics of Renal Cell Carcinoma Associated with Xp11.2 Translocation/TFE3 Gene Fusion

Purpose To characterize Xp11.2 translocation renal cell carcinoma (RCC) using magnetic resonance imaging (MRI) and computed tomography (CT). Methods This study retrospectively collected the MRI and CT data of twelve patients with Xp11.2 translocation RCC confirmed by pathology. Nine cases underwent dynamic contrast-enhanced MRI (DCE-MRI) and 6 cases underwent CT, of which 3 cases underwent MRI and CT simultaneously. The MRI and CT findings were analyzed in regard to tumor position, size, hemorrhagic, cystic or necrotic components, calcification, tumor density, signal intensity and enhancement features. Results The age of the 12 patients ranged from 13 to 46 years (mean age: 23 years). T2WI revealed heterogeneous intensity, hyper-intensity, and slight hypo-intensity in 6 cases, 2 cases, and 1 case, respectively. On DCE-MR images, mild, moderate, and marked rim enhancement of the tumor in the corticomedullary phase (CMP) were observed in 1, 6, and 2 cases, respectively. The tumor parenchyma showed iso-attenuation (n = 4) or slight hyper-attenuation (n = 1) compared to the normal renal cortex on non-contrast CT images. Imaging findings were suggestive of hemorrhage (n = 4) or necrosis (n = 8) in the tumors, and there was evidence of calcification in 8 cases by CT (n = 3) and pathology (n = 8). On dynamic contrast-enhanced CT images, 3 cases and 1 case manifested moderate and strong CMP enhancement, respectively. Nine tumors by MRI and 4 tumors by CT showed prolonged enhancement. Three neoplasms presented at stage I, 2 at stage II, 3 at stage III, and 4 at stage IV according the 2010 AJCC staging criteria. Conclusions XP11.2 translocation RCC should be considered when a child or young adult patient presents with a renal tumor with heterogeneous features such as hemorrhage, necrosis, cystic changes, and calcification on CT and MRI and/or is accompanied by metastatic evidence.


Introduction
Renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE 3 gene fusion (Xp11.2/TFE 3 RCC or Xp11.2 translocation RCC) is an uncommon subtype of RCC that is now accepted as a distinct entity according to the 2004 World Health Organization renal tumor classification [1]. These tumors are defined by several different translocations in chromosome Xp11.2, resulting in gene fusions in the TFE3 gene. Although some cases have been reported in older patients, Xp11.2/TFE RCC primarily affects children and young adults, and this condition is more common in women than men [1][2][3][4][5]. Although Xp11.2 translocation RCCs are less common among adult RCCs than pediatric RCCs, adult Xp11.2 translocation RCCs still outnumber pediatric cases [6]. Macroscopically, Xp11.2 translocation RCCs usually manifest tan/yellow and are often accompanied by necrosis and hemorrhage [7]. The associated histopathologic characteristics include clear cell carcinoma with papillary architecture [8]. The most distinctive immunohistochemical feature of this type of tumor is nuclear immunoreactivity for TFE3 protein [8,9].
Xp11.2 translocation RCC is typically presented as an asymptomatic, painless renal mass and is often identified accidentally by abdominal imaging. Local signs include gross hematuria, flank pain, or a palpable abdominal mass. Initial clinical data suggest an indolent clinical course despite advanced stage. However, recent reports have indicated that adult cases of Xp11.2 translocation RCC have a more aggressive clinical course, and the prognosis of these tumors in adult patients is poor compared to other types of RCC [10][11][12]. The liver, lungs, and retroperitoneal lymph nodes are common sites of metastasis [3].
Radiologic examination may be valuable for the diagnosis of XP11.2 translocation RCC [13]. However, due to the rarity of XP11.2 translocation RCC, only a few case reports focusing on its imaging features are available [11,[13][14][15][16][17]. MRI is suggested to be superior to CT due to the increased soft-tissue contrast and multiple imaging weights of MRI, which better reveal the heterogeneous composition (such as hemorrhage or necrosis) of this type of tumor [18]. However, the macroscopic characteristics of XP11.2 translocation RCC are still not well defined by radiological examination due to the small number of imaging reports, and MRI examination is extremely rare. As a result, the noninvasive diagnosis of this type of tumor is difficult, particularly at the early stage.
This study retrospectively collected a relatively large sample of cases of Xp11.2 translocation RCC that had undergone MRI (9 cases) and CT (6 cases) to characterize their imaging features.

Ethics statement
This retrospective study was approved by the Institutional Review Board of The Fudan Cancer Hospital. All patients provided written informed consent to participate in this study.

Patients
From January 2009 to June 2013, twelve patients with pathologically proven Xp11.2/TFE RCC were recruited in this study. Eleven of the 12 cases were confirmed by partial or radical nephrectomy and 1 by biopsy (Tables 1-2). One patient died of intraoperative cardiac arrest. None of these patients had received treatment with chemotherapy, surgery, or radiation before the radiological examination. Of the 12 patients, 9 underwent dynamic contrast-enhanced MRI (DCE-MRI) and 6 underwent kidney CT (only 4 were assessed by dynamic contrast-enhanced CT). Three patients underwent MRI and CT simultaneously.

CT and MRI examinations
The parameters of the MRI and CT protocols varied due to the multiple imaging systems used and the retrospective nature of the study.
MR acquisition. Seven patients were examined with a 3.0 T whole-body MR system (Signa; GE Medical Systems), and two patients were examined with a 1.5 T twin-speed superconducting MR system (GE Signa with EXCITE II) with 5-8 mm slice thickness and 0.5-2.0 mm gap spacing. MRI sequences included in-phase (IP, TR = 150-230 ms, TE = 1.4-2.4 ms) and opposedphase (OP, TR = 150-240 ms, TE = 3.2-4.6 ms) T1-weighted axial spoiled gradient echo imaging (SPRG) sequences and fatsaturated T2-weighted axial fast spin echo (FSE) sequences (TR = 3200-4000 ms, TE = 78-92 ms). Intravenous dynamic contrast-enhanced images were obtained in all 9 patients. For the 3T MRI scanner, dynamic contrast-enhanced images were acquired using liver acquisition with a volume acceleration (LAVA) sequence (TR = 2.6-3.2 ms, TE = 1.2-1.5 ms); for the 1.5 T MRI scanner, dynamic contrast-enhanced images were obtained using the T1-weighted FSPGR sequence (TR = 150-180 ms, TE = 1.4-1.7 ms) with fat suppression. The delay time was 20 seconds for CMP, 60 seconds for Nephrographic phase (NP), and 120 seconds for the coronal delayed phase after the intravenous injection of 15 ml of Magnevist (0.1 mmol/kg; Bayer Schering, Pharma AG, Berlin, Germany) at a rate of 2 ml/s. CT acquisition. Six patients were examined with a multidetector spiral CT machine (Sensation 64, Siemens Medical Systems). Images were obtained at 120 kV and 200 mA with a collimation of 1 mm (n = 4) or 5 mm (n = 5). In 4 of 6 cases, plain (non-contrast) and dynamic contrast images were obtained. Contrast images were acquired in both CMP and NP (n = 4) or Excretory phase (EP) (n = 1). In 1 case, only NP images were acquired, and in 1 patient, only non-contrast CT images were available (patient 9, who also underwent DCE-MRI). The delay time for the contrast-enhanced CT images was 30-35 seconds for CMP, 65-70 seconds for NP and 24 minutes for EP after the intravenous injection of 90 ml iohexol (Omnipaque 300; General Electric) at a rate of 3 ml/s.

Image interpretation
The imaging characteristics of MRI and CT were retrospectively analyzed by 2 genitourinary radiologists. Both readers were aware that all patients had Xp11.2 translocation RCC but were unaware of the clinical and radiological findings. The images were reviewed on a picture archiving and communication system workstation (GE Aw4.3 workstation).
The evaluated parameters included the tumor position and size, tumor density on unenhanced, CMP, NP or EP CT scans, tumor intensity on T2WI, T1WI or CMP or NP MRI scans, cystic and necrotic changes, hemorrhage, calcification, and metastasis. Readers recorded the size of all renal masses on axial images. The location of the tumor was defined as medullary, cortical, exophytic, or renal pelvis, depending on the relationship of the tumor with the perinephric fat, renal parenchyma, and renal sinus fat. The presence or absence of a tumor boundary was observed and evaluated on the contrast-delayed phase as a clearly defined or poorly defined border. The enhancement pattern of the tumor was classified as homogeneous or heterogeneous, hypo-intense, isointense, or hyper-intense. The tumor was classified as a solid or cystic mass depending on the nature of the parenchyma. Intratumoral hemorrhage was considered present if a mass was visually hyper-dense relative to the normal renal parenchyma on non-contrast CT images [19]. Necrosis was defined as the presence of irregular cavitation on contrast-enhanced images [19,20].
The region of interest (ROI) was defined in the solid portion of the mass to avoid partial volume effects [21]. Each 10-mm ROI was measured 3 times for each image, and the mean value was used. Intratumoral calcification and cystic or necrotic components were excluded from the ROI. The density values of the tumor, normal renal cortex, and medulla were measured on non-contrast and CMP, NP, or EP CT images. Tumor attenuation on unenhanced CT images was classified as 'mildly high' if .10 HU, 'high' if .30 HU, 'iso-dense' if equal to the renal parenchyma, and 'low' if ,10 HU compared to the normal renal parenchyma [14].
Advanced-stage disease was considered if the images revealed an invasion of the renal vein, a local adenopathy, or distant metastases. Local adenopathy was defined as retroperitoneal nodal enlargement with a short-axis diameter .10 mm [19]. Based on the 2010 AJCC staging criteria, all the renal neoplasms presented at stages I-IV [22].
One primary investigator, Dr. Ding, who was not one of the readers, collected the data and correlated the findings with all available clinical, imaging, and histopathological records, including findings on follow-up imaging and surgery.

Clinical and general characteristics of the patients
The patients' medical records were reviewed to evaluate their clinical and general characteristics (Table 1). Follow-up information was also available for 8 cases ( Table 1). The age of these patients ranged from 13 to 46 years (mean age: 23 years), and the female to male ratio was 7:5. Of the 12 patients, 3 patients (25%) were younger than 20 years old, 5 patients (42%) were between 20 and 29 years, 2 patients (17%) were between 30 and 39 years, and 2 patients (17%) were older than 40 years. Most patients (67%) were younger than 30 years of age. Using the 2010 AJCC staging criteria, 3 cases presented at stage I, 2 at stage II, 3 at stage III, and 4 at stage IV.

CT and MRI features
The imaging characteristics of the 12 patients are summarized in Tables 2 and 3. The representative cases are illustrated in Figures 1, 2, 3, 4, 5, 6.
The imaging characteristics of 6 patients who underwent CT are summarized in Tables 2 and 3. The solid portion of 5 tumors that underwent plain CT showed iso-attenuation (4 cases, 80%) or slight hyper-attenuation (1 case, 20%) compared to the normal renal cortex (Fig. 3-6). On enhanced CT images, 3 of the 4 tumors (75%) showed mild to moderate enhancement, 1 tumor (25%) showed marked enhancement on CMP, and all 4 tumors showed prolonged enhancement (Fig. 3-5). The density was inhomogeneous in 2 cases of plain CT images and in 3 cases of enhanced CT images.

Discussion
Clinical characteristics of Xp11.2 translocation RCC Xp11.2 translocation RCC is a rare subtype that usually affects children and adolescents [23][24][25], with only a few reported adult cases to date [6,26]. In our study, the age of the patients ranged from 13 to 46 years (67% were younger than 30 years old), which demonstrated a greater average age than that in some reports (median age 13 years) [26,27] while consistent with that in others [5,8,28]. Thus, the presence of RCC in a child or young adult should increase the level of suspicion for Xp11.2 translocation RCC. In our study, the ratio of males to females was 1:1.4 (5:7), with a slight female predominance, which is consistent with previous reports [14,27], although different from the male predominance reported by Dang et al [17]. Little is known about the clinical behavior of these carcinomas [8]. In our study, the symptoms in 75% (9/12) of the patients were nonspecific, and the other 25% (3/12) were detected incidentally. However, most Xp11.2 translocation RCC cases were associated with aggressive clinical course, advanced stage, and relatively poor prognosis in our study. Most of the patients (58%) were at an advanced stage (stage III-IV) although the tumors were small. Adult-onset Xp11.2 translocation RCCs, unlike those with onset during childhood, demonstrate more aggressive clinical course and poorer prognosis, most likely because majority of the adult patients are diagnosed at an advanced clinical stage and do not receive effective systemic therapy [2,27,29].

Imaging characteristics of Xp11.2 translocation RCC
To date, reports on the imaging features of Xp11.2 translocation RCCs are very few. Furthermore, most of them have focused on CT features while only few included MRI [5,6,11,[13][14][15][16][17]. In this study, we analyzed the imaging manifestations of Xp11.2 translocation RCC using a relatively large sample (9 MRI cases and 6 CT cases); moreover, the combination of MRI and CT may provide additional information regarding this type of RCC. These merits helped to reveal the general imaging features.
First, Xp11.2 translocation RCCs mainly involved the renal medullary tissue. Xp11.2 translocation RCCs originate from the renal medulla and are within the contour of the kidney [6]. In our study, most Xp11.2 translocation RCCs were located in the renal medullary tissue or in both the medullary and cortical tissues and within the contour of the kidney, suggesting that these RCCs originated from the renal medulla. The involvement of the pelvic region is occasionally observed, as in our study (1 case) and one early case report [6].
Second, the signal intensity on MRI and the density on CT of Xp11.2 translocation RCCs was inhomogeneous, regardless of the tumor size. This may reflect the heterogeneous components within the tumors, such as hemorrhage, necrosis, cystic changes, or calcification [13,17]. In our study, the CT density of 3 tumors (3/6, 50%) and the MRI signal of 9 tumors (100%) were inhomogeneous. Only a few studies reported that Xp11.2/TFE RCC presents as a homogenously hyper-intense or mildly hyper-intense, dense solid tumor on plain CT images [14]. On plain CT, most of these tumors showed iso-attenuation or slight hyper-attenuation compared to the normal renal cortex. Such hyper-attenuation is thought to be due to hemorrhagic or proteinaceous fluid, densely packed cellular components, or a combination of these factors [13,16]. MRI provided important information on the tumor parenchyma. Most tumors present heterogeneous mixed signal intensity on T2WI or T1WI because of hemorrhage, necrosis, or cystic changes [17].
Third, most of these tumors appeared as a well-defined mass. All 12 cases of XP11.2 translocation RCCs demonstrated complete or near-complete boundaries on MRI/CT (capsule sign), which was best observed during the delayed phase. On T2WI, low-intensity capsule signs were also detected, and ill-defined margins appeared to break the capsule (Fig. 3).
Fourth, Xp11.2 translocation RCCs are hypo-vascular tumors and manifest mild/moderate and prolonged enhancement on CT or MRI. On enhanced CT, most tumors in the study were moderately enhanced on CMP and showed prolonged enhancement, and the enhancement of the tumor parenchyma was lower than that of the surrounding normal renal cortex. After the intravenous injection of contrast media on MRI, most tumors (7 of 9) showed heterogeneous enhancement, presenting with cystic-solid changes due to intra-tumoral hemorrhage or necrosis and prolonged enhancement on the solid portion of the tumors. Additionally, the fibrous capsule revealed a gradual rim-like enhancement, which was also consistent with a previous report [13,17]. Peripheral irregular rims were also present in the tumors around the areas of internal necrosis or hemorrhage, particularly in the larger tumors.
Fifth, calcification is an important concomitant sign of Xp11.2 translocation RCCs. In our study, calcifications were detected in 3 of 5 tumors by CT, and 8 of the total 12 cases were confirmed as having calcification by pathology, which was in agreement with previous reports [6,13]. These calcifications clearly presented as punctate or patchy on CT but were poorly detected by MRI (Fig. 4, Fig. 6). However, calcification is not required to diagnose this subtype, as more than half of the cases did not demonstrate calcification on pathology; one previous study also showed no calcification on unenhanced CT images [14].
Finally, cystic and necrotic changes are usually detected in Xp11.2 translocation RCCs. One previous report indicated a unilocular cystic mass with multiple mural nodules on MRI in the right kidney of a 26-year-old pregnant female with Xp11.2/ TFE RCC [15]. In our study, most of the tumors demonstrated cystic-solid changes, while none showed such multiple mural nodules. Another early report has shown that tumors contain macroscopic focal fat, which is presumed to be the result of adipose tissue metaplasia [13]. However, no fat component was demonstrated in any of our 12 tumors.

Differential diagnosis of Xp11.2 translocation RCCs
The differential diagnosis of Xp11.2 translocation RCCs includes clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe cell RCC (chRCC), collecting duct carcinoma (CDC) and angiomyolipoma (AML) with minimal fat. Most subtypes of RCCs occurs more often in mean ages 50 to 60, and it is rare that patients with Xp11.2 translocation RCCs demonstrate disease at a later age.
ccRCCs have several distinguishing features, including necrosis and hemorrhage, which are commonly associated with lymph node metastasis and renal vein infiltration [23,27,28,30,31], similar to Xp11.2 translocation RCCs. However, ccRCCs are hyper-vascular tumors and exhibit significantly greater enhancement in the CMP [32]. Stronger enhancement equivalent to the renal cortex is shown only in ccRCCs while not in other subtypes [33]. However, Xp11.2 translocation RCCs present as hypovascular tumors with weak prolonged enhancement and clearly differ from ccRCCs.
There are considerable overlaps in morphology between Xp11.2 translocation RCCs and pRCCs, as pRCCs also typically appear hypo-vascular. Homogeneity, small size, regular shape, low-level enhancement, and peripheral location are indicative of a well-differentiated pRCC [30,34]. pRCCs typically appear as a mass with homogeneous low signal intensity on T2WI, possibly due to cytoplasmic or interstitial histiocytic hemosiderin deposition in the tumor cells [19,30,[35][36][37]. However, in our study, most XP11.2 translocation RCCs showed heterogeneous signal intensity on T2WI. If pRCCs are poorly differentiated, they can present with heterogeneous attenuation or signal intensity due to necrosis or hemorrhage within the tumor [38], which makes the differential diagnosis with Xp11.2 translocation RCCs difficult. chRCCs typically localize in the periphery and present as welldefined, large, solid masses without necrosis or calcification; they are commonly diagnosed at an early stage [39][40][41]. In our study, only 1 case (Patient 9 in Table 3) presented with homogenous iso-  attenuation and without calcification on plain CT images, which was difficult to distinguish from chRCC. chRCCs also present as hypo-vascular masses, with heterogeneous T2 signal intensity and homogeneous enhancement [18,40,41]. Some chRCCs show cystic or necrotic changes in the tumor parenchyma [41,42], microvascular invasion, local extension, or metastasis, and they are therefore difficult to distinguish from XP11.2 translocation RCCs [43].
CDC is a rare subtype of RCCs that is generally located in the central region of the kidney and typically infiltrates the renal sinus fat. Most of the Xp11.2 translocation RCCs in our study originated in the renal medulla, within the kidney contour. A recent report indicated that the density of Xp11.2 translocation RCCs on unenhanced CT was greater than that of CDC tumors [14].
AMLs with minimal fat are generally hyper-vascular. They typically present with low signal intensity on T2WI and manifest a homogeneously marked and prolonged enhancement pattern on   Table 1   CT [19,44]. Intra-tumoral calcification can be detected in XP11.2 translocation RCCs, whereas this characteristic is rare in AML.
This study had several limitations. First, because Xp11.2 translocation RCC is an uncommon RCC subtype, selection bias was inevitable. Second, because this study was retrospective, which precluded the careful design of the radiological plans, only routine MRI and CT images were available. Thus, larger samples with advanced MRI techniques, such as diffusion-weighted imaging, perfusion-weighted imaging, and MR spectroscopy, are preferred to improve the imaging diagnostics of this subtype of tumor.
In conclusion, XP11.2 translocation RCC should be considered when a child or young adult patient presents with a renal tumor with the following characteristics: (1) located in the renal medullary tissue; (2) inhomogeneous signal intensity (density) on plain MRI or CT; (3) a well-defined boundary with a fibrous or false capsule; (4) mild/moderate and prolonged inhomogeneous enhancement on CT or MRI; (5) punctate or patchy calcification; (6) necrotic or cystic changes; and (7) signs of advanced stage such as retroperitoneal adenopathy, venous invasion, and distant metastasis. Although this study provides important macroscopic findings for Xp11.2 translocation RCC, the final diagnosis should still be based on microscopic pathology.