JOURNAL OF MAGNETIC RESONANCE IMAGING 40:440–447 (2014)
Original Research
Renal Carcinomas Associated With Xp11.2 Translocations/TFE3 Gene Fusions: Findings on MRI and Computed Tomography Imaging Kefu Liu, MD, PhD,1,2* Ping Xie, MS,1 Weijun Peng, MD, PhD,2 and Zhengrong Zhou, MD, PhD2 Purpose: To retrospectively analyze MRI and computed tomographic (CT) findings from renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions (Xp11-RCC).
MRI images relative to the renal cortex except for 1 tumor that showed significant hemorrhage and a relative hyperintensity. For 3 cases who were imaged with CT, two tumors imaged using nonenhanced CT images showed mild hyperdensity relative to the renal cortex. Calcification was noted in all three tumors. All tumors showed mild, persistent enhancement.
Materials and Methods: Institutional review board permission was obtained to review patient medical records, and the requirement for informed consent was waved . The clinical and MRI/CT features of five cases with Xp11RCC that were confirmed by pathology were analyzed retrospectively. The image characteristics included the lesion location and size, contribution of cystic and solid components, intratumoral necrosis or hemorrhage, invasion of perinephric tissue and renal sinus, lymphadenopathy, major venous or arterial vascular invasion, pattern of the tumor growth, intratumor calcification and lipids, homogeneity of SI on T2-weighted images, attenuation and SI of the mass with respect to the normal renal cortex on precontrast and contrasted CT/MRI images, tumor SIs, tumor attenuations and tumor-to-cortex indices, homogeneity of enhancement on the contrasted images.
Conclusion: Typical Xp11-RCC manifests as an advanced, solid renal mass with mild persistent enhancement, a prevalence of intertumor hemorrhage/calcification, and a cortical epicenter location. The predilection for children and young adults is a useful clinical feature when confirming a diagnosis of Xp11-RCC. Key Words: renal cell carcinoma; Xp11.2 translocation; TFE3 gene fusion; CT; MRI J. Magn. Reson. Imaging 2014;40:440–447. C 2013 Wiley Periodicals, Inc. V
Results: The mean age was 32 years (range, 15–47 years). Most patients (4/5) were women. All tumors showed a cortical location. The average tumor size was 9 cm (range, 4–18 cm). Four tumors comprised a predominantly solid lesion with focal necrosis, and one tumor comprised a solid lesion with significant necrosis. All tumors showed intertumor hemorrhage, infiltrative growth and invasion of the perirenal adipose/renal sinus. Four cases showed retroperitoneal lymphadenopathy, of which one case showed simultaneous mediastinal and supraclavicular lymphadenopathy. All tumors from four cases showed mild hyperintensity on T1-weighted MRI images, and three tumors showed hypointensity on T2-weighted
1 Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China. 2 Department of Radiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. *Address reprint requests to: K.L., Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, No. 242, Guang Ji Road, Suzhou, Jiangsu, 215008, China. E-mail: [email protected]. Received May 10, 2013; Accepted July 29, 2013. DOI 10.1002/jmri.24349 View this article online at wileyonlinelibrary.com. C 2013 Wiley Periodicals, Inc. V
RENAL CELL CARCINOMA (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11-RCC) was identified and listed as a separate entity in the 2004 World Health Organization (WHO) classification of kidney tumors (1,2). The most distinctive histopathologic appearance of Xp11-RCC is that of a carcinoma with a papillary architecture composed of clear cells; however, these tumors frequently show a more nested architecture and often feature cells with a granular eosinophilic cytoplasm (1). Nuclear labeling for TFE3 is specific to Xp11.2-RCC (3). This carcinoma predominantly affects children and young adults in the second and third decades of life, although some cases of older patients have recently been described, and shows no gender preference (4). Approximately 15% of RCCs in children are of the clear cell subtype; however, Xp11-RCCs accounts for one-third of pediatric RCCs (5). In adults, Xp11RCCs are associated with a poor prognosis, they present at an advanced stage and are frequently associated with lymph node metastasis upon diagnosis (1,2,4–6). Hence, we describe the computed tomography (CT) and MRI findings from five cases with Xp11-RCC.
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Xp11-RCC MRI and CT Findings
MATERIALS AND METHODS Patients Six patients with pathology-confirmed Xp11-RCC were revealed upon a retrospective search of our pathology department database between January 2010 and June 2012. The pathology was confirmed based on pathological morphology and immunohistochemistry (2). One case (female, 73 years) was excluded from the study due to a lack of preoperative imaging. Thus, five patients were included in this study. MRI images were available for four cases, and CT images were available for three cases. Institutional review board permission was obtained to review the patients’ medical records, and patient informed consent was not required.
Imaging Techniques In our study, three patients had available, preoperative CT images. One case underwent non-contrast CT imaging and contrast enhanced CT imaging, including corticomedullary-phase and nephrographic-phase imaging (6 days before surgery), one case only had excretory-phase contrasted CT images (4 days before surgery), and one case underwent plain CT imaging (13 days before surgery). The CT examinations were performed using a multislice CT scanner (Somaton Sensation 40 or 64, Siemens, Germany). The tube voltage was set to 120 kVp, the tube current was adjusted for each subject based on the tissue size and density, the rotation time was 0.5 s, the pitch was 1.4 (60 0.6 or 40 0.6), and the reconstructive slice thickness was 5 mm. A bolus of nonionic contrast material (300 mg I/mL of iopamidol at 1.5 mL/kg body weight) was injected intravenously at a rate of 3 mL/s using an automated injector. Four patients in this study had available, preoperative MRI images. MR imaging was performed at 5, 7, 13, and 14 days before surgery. MRI examinations were performed using a 3.0 Tesla (T) scanner (Signa HDxt, General Electric Medical Systems, Milwaukee, WI) using a standard renal MRI protocol that included an axial in-and-opposed-phase two-dimensional (2D) T1-weighted gradient-echo (repetition time ms/echo time ms, 230/1.1, 2.2; field of view, 38 cm; section thickness, 7–8 mm; intersection gap, 2 mm; and matrix, 320 160), axial respiratory-triggered fat-saturation 2D T2-weighted gradient-echo (repetition time ms/echo time ms, 6300/85, field of view, 38 cm; section thickness, 7–8 mm; intersection gap, 2 mm; and matrix, 320 160) followed by axial 3D fat-saturation T1-weighted gradient-echo sequences obtained during the corticomedullary, nephrographic (repetition time ms/echo time ms, 2.5/1.2, field of view, 38 cm; section thickness, 6 mm; and matrix, 260 220) and coronal 3D fat-saturation T1-weighted gradient-echo sequences during excretory phases (repetition time ms/echo time ms, 3.6/1.5, field of view, 38 cm; section thickness, 6 mm; and matrix, 260 220) of enhancement after intravenous administration of gadopentate dimeglumine (0.1 mmol/kg body weight;
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Magnevist, Schering, Berlin, Germany) at 2 mL/s using an injector (Mallinckrodt, Ohio). Image Analysis Two radiologists with 15 and 12 years’ experience in abdominal MRI evaluated the tumors’ image features based on the following criteria: (i) Tumor’s location, which was defined as either medullary, cortical or exophytic depending on the location of the center of the tumor. (ii) Size of the tumor (maximum axial diameter). (iii) Relative contribution of cystic and solid components. (iv) Presence of intratumor necrosis or hemorrhage. (v) Presence of an invasion of perinephric tissue and renal sinus. (vi) Presence of lymphadenopathy, which was defined as when the diameter of a lymph node had enlarged by >1 cm. (vii) The presence of distant metastatic disease (based on CT or MRI images). (viii) Presence of major venous or arterial vascular invasion, which were defined as when the tumor was found in the lumen of the renal vein or the inferior vena cava. (ix) Pattern of the tumor growth (infiltrative or expansive); infiltrative growth was characterized by the lack of clear borders between the tumor and the normal renal parenchyma, whereas expansive growth was characterized by well-defined, bulging tumor margins that displaced the normal parenchyma. (x) Presence of intratumor calcification on CT images. (xi) Presence of microscopic lipids on MRI images (an area of increased signal intensity (SI) on in-phase T1-weighted images (T1WI) that visually showed a decrease in SI on opposed-phase T1WI). (xii) Homogeneity of SI on T2-weighted images (homogeneous or heterogeneous. (xiii) Predominant attenuation and SI of the mass with respect to the normal renal cortex on precontrast and contrasted CT/MRI images. (xiv) Tumor SIs, tumor attenuations and tumor-tocortex indices, which were calculated for those sequences with same parameters (corticomedullaryand nephrographic-phase images for MRI and each phase for CT). Tumor-to-cortex indices were calculated for both the corticomedullary- and nephrographic-phase images as the SI for MRI and attenuation for CT of the tumor divided by those of the renal cortex. The intratumor ROI was placed within the region demonstrating the most marked contrast enhancement based on visual assessment. The renal cortical ROI was placed within a portion of the renal cortex of the ipsilateral kidney that did not show a tumor. (xv) Homogeneity of enhancement on the contrasted images (homogeneous or heterogeneous).
RESULTS The clinical features of the five cases with Xp11-RCC are recorded in Table 1. Patients presented with symptoms including abdominal pain and an abdominal mass in two cases, left supraclavicular lymphadenopathy in one case, gross hematuria in one case, and gross hematuria with abdominal pain and an abdominal mass in one case. The mean age was 32
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Table 1 Clinical Features of Five Cases With Xp11-RCC No. Gender Age (year) Symptom
1
2
3
4
5
Female 15 Abdominal pain and abdominal mass
Female 45 Gross hematuria
Male 33 Abdominal pain, abdominal mass and gross hematuria
Female 22 Abdominal pain and abdominal mass
Female 47 Supraclavicular lymphadenopathy
years (range, 15–47 years). Four patients were women, and one was a man. None of the cases had a history of prior exposure to chemotherapy. All five patients underwent surgical resection of their tumors: one patient died of arrhythmia while the incision was being sutured during the operation, one patient was lost to follow-up immediately after surgery, and the remaining three patients were alive as of the time of writing this article, having lived 75, 150, and 375 days. The CT and MRI findings from the five cases with Xp11-RCC are described in Table 2. All tumors
showed a cortical location (Figs. 1–5). Tumors occurred in the right kidney in three cases (Figs. 2–4) and the left kidney in two cases (Figs. 1,5). The average tumor size was 9 cm (range, 4–18 cm). Four tumors comprised a predominantly solid lesion with focal necrosis (Figs. 1–3, 5), and 1 tumor comprised a solid lesion with significant necrosis at the center ( 70%) that did not show lymphadenopathy (Fig. 4). All tumors showed intertumor hemorrhage, infiltrative growth and invasion of the perirenal adipose/renal sinus (Figs. 1–5). Four cases showed retroperitoneal lymphadenopathy (Figs. 1–3, 5), of which one case
Table 2 CT and MRI Features of Five Cases With Xp11-RCC No. Side Size (cm) Location Solid/cyst Pattern of tumor growth Necrosis Intertumor hemorrhage Invasion of the perirenal adipose Involvement of renal sinus Lymphadenopathy Vascular invasion Distant metastatic disease Microscopic lipid Heterogeneity of SI on T2-weighted images SI relative to renal cortex on in-phase T1-weighted images SI relative to renal cortex on opposed-phase T1-weighted images SI relative to renal cortex on T2-weighted images Enhancement heterogeneity Enhancement of the mass relative to the normal renal cortex at the corticomedullary phase Enhancement of the mass relative to the normal renal cortex at the nephrographic phase Enhancement of the mass relative to the normal renal cortex at the excretory phase CT Plain CT Calcification Heterogeneous enhancement Enhancement of the mass relative to the normal renal cortex at the corticomedullary phase Enhancement of the mass relative to the normal renal cortex at the nephrographic phase Enhancement of the mass relative to the normal renal cortex at the excretory phase SI, signal intensity.
1
4
5
Left Right Right 18 4 6 Cortical Cortical Cortical Solid Solid Solid Infiltrative Infiltrative Infiltrative Focal Focal Focal Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No No No No No No No Yes Yes Yes Hyperintensity Hyperintensity Hyperintensity
Right 11 Cortical Cyst Infiltrative Center Yes Yes Yes No No No No Yes Hyperintensity
Left 7 Cortical Solid Infiltrative Focal Yes Yes Yes Yes No Yes No images No images No images
Hyperintensity Hyperintensity Hyperintensity
Hyperintensity
No images
Hypointensity Hyperintensity Hypointensity Yes Yes Yes Hypointensity Hypointensity Hypointensity
Hypointensity Yes Hypointensity
No images No images No images
Hypointensity
Hypointensity
Hypointensity
Hypointensity
No images
Hypointensity
Hypointensity
Hypointensity
Hypointensity
No images
No No No No
images images images images
2
3
No No No No
images images images images
No images Yes Yes No images
Mild hyperdensity Mild hyperdensity Yes Yes No images Yes No images Hypodensity
No images
No images
No images
No images
Hypodensity
No images
No images
Hypodensity
No images
Hypodensity
Xp11-RCC MRI and CT Findings
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Figure 1. A 15-year-old female with Xp11-RCC of the left kidney. The tumor shows mild hyperintensity on precontrast inphase T1-weighted images (a), mild hypointensity on precontrast opposed-phase T1-weighted images (b), and a hypointense appearance on T2-weighted images (c). A retroperitoneal lymphadenopathy, an invasion of the perinephric tissue, and renal sinus and intertumor hemorrhage are found on MRI images (A,C). The enhancement of the mass relative to the normal renal cortex is hypointense on the corticomedullary- (d), nephrographic- (e), and excretory-phase images (f), and this tumor shows a mild persistent enhancement (d–f). The tumor appears to show a papillary architecture with clear cells and nested architecture. The tumor cells feature granular eosinophilic cytoplasm. Local hemorrhage was noted in the tumor (g). Some tumor cells were positive for TFE3 protein (h).
showed simultaneous mediastinal and supraclavicular lymphadenopathy (Fig. 5). Vascular invasion was not found on the CT and MRI images. For the 4 cases with MRI images, all tumors showed a mild hyperintensity on T1-weighted images, and 3 tumors showed a hypointensity relative to the renal cortex on T2-weighted images (Figs. 1, 3, 4) except for 1 tumor that showed a significant hemorrhage and relative hyperintensity (Fig. 2). Microscopic lipids were not found in any of these four tumors. Tumors showed
hypointensity relative to the renal cortex at the corticomedullary, nephrographic, and excretory phase (Figs. 1–4). For the cases with CT images, two tumors with plain CT images showed a mild hyperdensity relative to the renal cortex (Figs. 4,5). Calcification was found in all three tumors (Figs. 3–5). Two tumors with contrasted CT images showed heterogeneity (Figs. 3,5). Tumors showed hypointensity relative to the renal cortex at the corticomedullary, nephrographic, and excretory phase (Figs. 3,5).
Figure 2. A 45-year-old female with Xp11-RCC of the right kidney. The tumor shows mild hyperintensity on precontrast inphase T1-weighted images (a), a mild hypointensity on precontrast opposed-phase T1-weighted images (b), and a hypointense appearance on T2-weighted images (c). Retroperitoneal lymphadenopathy, invasion of the perinephric tissue and renal sinus and intertumor hemorrhage are found on MRI images (a,c). The enhancement of the mass relative to the normal renal cortex is hypointense on the corticomedullary- (d), nephrographic- (e), and excretory-phase images (f), and the tumor shows mild persistent enhancement (d–f). Local hemorrhage was noted in the tumor (g). Some tumor cells were positive for TFE3 protein (h).
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Figure 3. A 33-year-old male with Xp11-RCC of the right kidney. The tumor showed mild hyperintensity on precontrast inphase T1-weighted images (a), mild hypointensity on precontrast, opposed-phase T1-weighted images (b), and a hypointense appearance on T2-weighted images (c). Retroperitoneal lymphadenopathy, invasion of the perinephric tissue, and renal sinus and intertumor hemorrhage were noted in MRI images (a,c). The enhancement of the mass relative to the normal renal cortex is hypointense on corticomedullary- (d), nephrographic- (e), and excretory-phase images (f), and the tumor shows mild persistent enhancement (D–F). A CT image of the excretory phase of this tumor also shows its hypodense appearance relative to the normal renal cortex, and calcifications were observed in this tumor (g).
The tumor MRI SIs, CT attenuations and tumor-tocortex indices on each CT and MRI sequence using the same parameters are shown in Table 3. For cases with MRI images, the average SI of the tumors was 501 and 493 at the corticomedullary and nephrographic phase, respectively; the tumor-to-cortex indices were 0.60
and 0.55 at the corticomedullary and nephrographic phase, respectively. For the cases with CT images, the average attenuation of the tumor was 43 HU, 71 HU, 80 HU, and 69 HU at the plain, corticomedullary, nephrographic, and excretory phases, respectively; the tumor-to-cortex indices were 1.40, 0.54, 0.47,
Figure 4. A 22-year-old female with Xp11-RCC of the right kidney. The tumor shows significant center necrosis (>70%) and mild hyperintensity on precontrast in-phase T1-weighted images (a), mild hypointensity on precontrast, opposed-phase T1weighted images (b), and a hypointense appearance on T2-weighted images (c). Invasion of the perinephric tissue and renal sinus and intertumor hemorrhage were noted on MRI images (a,c). The enhancement of the mass relative to the normal renal cortex shows hypointensity on the corticomedullary- (d), nephrographic- (e), and excretory-phase images (f), and the tumor shows mild persistent enhancement (D–F). On a plain CT image, this tumor shows a mild hyperdense appearance relative to the normal renal cortex, and calcifications were noted in this tumor (g).
Xp11-RCC MRI and CT Findings
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Figure 5. A 47-year-old female with Xp11-RCC of the left kidney. The tumor is predominantly a solid mass and shows a mild hyperdense appearance on a precontrast CT image (a,b). Invasion of the perinephric tissue and renal sinus, calcification, and intertumor hemorrhage were found (a–c). The enhancement of the mass relative to the normal renal cortex was hypointense on the corticomedullary (c) and nephrographic phase (d), and the tumor shows mild persistent enhancement (c,d). On a plain CT image, supraclavicular and mediastinal lymphadenopathy were noted (e,f).
and 0.57 at the plain, corticomedullary, nephrographic, and excretory phases, respectively. All tumors showed mild persistent enhancement.
DISCUSSION Xp11.2-RCC is caused by several different translocations involving chromosome Xp11.2 that all result in gene fusions involving the TFE3 gene (2). TFE3 is a member of the basic-helix-loop-helix family of
transcription factors (2). Both the PRCC-TFE3 and ASPL-TFE3 fusion proteins retain the TFE3 DNAbinding domain, localize to the nucleus, and can act as aberrant transcription factors (2). The expression levels of TFE3 fusion proteins appear aberrantly high compared with native TFE3, perhaps because the fusion partners of TFE3 are ubiquitously expressed, and their promoters regulate the fusion proteins (2,7). The TFE3 immunohistochemical assay has been demonstrated to be very sensitive and specific for neoplasms bearing
Table 3 Xp11-RCC SIs From MRI Images, Tumor Attenuations From CT Images, and Tumor-to-Cortex Indices From Each CT and MRI Sequence Using the Same Parameters No. MR The SI of the renal cortex at the corticomedullary phase The SI of the tumor at the corticomedullary phase Tumor-to-cortex index at the corticomedullary phase The SI of the renal cortex at the nephrographic phase The SI of the tumor at the nephrographic phase Tumor-to-cortex index at the nephrographic phase CT The attenuation of renal cortex on the precontrast images The attenuation of the tumor in precontrast images Tumor-to-cortex index in precontrast images The attenuation of renal cortex at the corticomedullary phase The attenuation of the tumor at the corticomedullary phase Tumor-to-cortex index at the corticomedullary phase The attenuation of the renal cortex at the nephrographic phase The attenuation of the tumor at the nephrographic phase Tumor-to-cortex index at the nephrographic phase The attenuation of the renal cortex at the excretory phase The attenuation of the tumor at the excretory phase Tumor-to-cortex index at the excretory phase
1
2
3
4
5
849 529 0.62 933 486 0.52
927 555 0.59 958 514 0.53
653 406 0.62 673 406 0.60
925 513 0.55 1032 566 0.55
No images No images None No images No images None
No images No images None No images No images None No images No images None No images No images None
No images No images None No images No images None No images No images None No images No images None
No images No images None No images No images None No images No images None 69 121 0.57
33 44 1.33 No images No images None No images No images None No images No images None
28 41 1.46 131 71 0.54 168 80 0.47 No images No images None
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TFE3 gene fusions. Using moderate and strong immunoreactivity as a positive score, the sensitivity was 97.5% and the specificity was 99.6% (2,3). Prior exposure to chemotherapy is currently the only known risk factor for the development of Xp11-RCC. A review showed that up to 15% of patients with these tumors had a history of prior chemotherapy exposure. The postchemotherapy interval ranged from 4 to 13 years (6,8,9). However, in our study, none of the cases had a history of prior chemotherapy exposure. Xp11.2-RCC accounts for 1% of all renal cell carcinomas and approximately 20% of RCCs in the pediatric and adolescent age groups (2). In our study, the mean age was 32 years (range, 15–47 years), and four patients were adults. Recent literature has shown that the frequency of Xp11-RCC in adults may have been previously underestimated due to its morphological overlap with conventional clear cell RCC. Adult Xp11-RCC cases may vastly outnumber pediatric Xp11-RCC cases due to the much higher incidence of RCC in the adult population (5,6). Specifically, our results showed a prevalence of women (four of five), which is not consistent with past literature that showed no gender preference (4). Due to its indolent course, adult cases with Xp11RCCs often present at advanced stages (1,4,6), which is consistent with our results. Furthermore, the tumors in our cases were relatively large (9 cm), and most cases (four of five) showed lymphadenopathy. All five tumors showed an invasion of the perirenal adipose/renal sinus. However, vascular invasion was not found in our series. In our study, most tumors (four of five) were predominantly solid with a mild heterogeneous appearance that reflects the histological features, which are typically a tan-yellow mass with focal necrosis and hemorrhage (5,10,11). MRI did not reveal microscopic lipids in any case imaged, which is consistent with a previous case (5). Calcification was found in all three Xp11-RCCs imaged with CT. All Xp11-RCCs in our study showed infiltrative growth, which suggests that this tumor may be a clinically aggressive tumor, as reported previously by Sukov et al (12). Our results are similar to previous reports (10,11) but are not consistent with Kato et al, who showed a well-demarcated mass (5). In our study, the mean tumor size was 9 cm, which was significantly larger than the tumor size reported by Kato et al. We presume that the larger tumor size is related to their more infiltrative appearance. On noncontrast images, the tumors showed mild hyperintensity on T1-weighted images and mild hyperdensity relative to the renal cortex on CT images, which is consistent with a previous case (5). This feature is considered to be due to hemorrhagic, proteinaceous fluid or a densely packed cellular component or a combination of both (5,7). Most tumors in our series showed hypointensity relative to the renal cortex on adipose-suppressed T2-weighted images, which was similar to a past case (5,7). One tumor showed hyperintensity relative to the renal cortex on adipose-suppressed T2-weighted images, which may be due to significant sub-acute hemorrhage.
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The tumors in our study showed hypointensity relative to the renal cortex at the corticomedullary, nephrographic, and excretory phases and showed mild persistent enhancement, similar to a past case (5). Clear cell RCC is the most common histologic RCC subtype, and it typically shows significant heterogeneous enhancement and a significant washout (7,13–17). These features are different from Xp11RCC, which shows predominantly solid lesions of a mild heterogeneous appearance and with mild, persistent enhancement. Kim et al noted that clear cell RCC showed enhancement of more than 84 HU at the corticomedullary phase and 44 HU at the excretory phase (with a specificity of 100% and 91%, respectively) (14), which contrast with our data that showed that the tumor enhancement was 71 HU at the corticomedullary phase and 69 HU at the excretory phase. Additionally, our MRI data showed that the tumorto-cortex indices of the corticomedullary phase and the nephrographic phase were 0.60 and 0.55, respectively, which were different from those of renal clear cell RCC, which shows a tumor-to-cortex enhancement index at the corticomedullary phase and nephrographic phase of 1.43 and 0.87, respectively. Additionally, clear cell RCC appears iso- to hyperintense on T2-weighted MR images, which contrasts with findings from Xp11-RCC, which shows hypointensity (5,7). Other types of nonclear cell RCC, such as papillary RCC, chromophobe RCC, collecting duct carcinoma, and renal medullary carcinoma, must also be included in the differential diagnosis. The features described below are useful for the differential diagnosis. Xp11-RCC typically mimics the papillary subtype of RCC; however, papillary RCC is typically hypovascular and shows homogeneous enhancement, and these features can be used for differentiating Xp11RCC, which shows a mild heterogeneous appearance (7,13). Chromophobe RCC and collecting duct carcinoma often occur in older adults; collecting duct carcinoma often locates to the epicenter of the medulla; renal medullary carcinoma is typically associated with caliectasis, although it appeared as an infiltrative, heterogeneous mass with a medullary epicenter and a relatively high prevalence in young men (7,18). One tumor in our study appeared as a solid lesion with significant necrosis in its center (>70%), which might mimic papillary RCC and multilocular cystic RCC (19). Multilocular cystic RCC is a multiseptated cystic lesion with a fibrous capsule, and it occurs predominantly in older males (5,7,10,11). These characteristics differ from Xp11-RCC, which shows an infiltrative mass with center necrosis and presents predominantly in children and young, female adults. In the case of cystic papillary RCCs, some features, such as the enhanced, peripheral, soft-tissue mural nodules and its bilateral/multifocal occurrence (particularly in hereditary syndromes), may be used to differentiate it from Xp11-RCC (7). This study was limited by its small sample size because Xp11-RCC is encountered rarely. Moreover, all patients did not have both MR and CT images and the differences in technique were from patient to
Xp11-RCC MRI and CT Findings
patient. Therefore, further studies of larger numbers of cases are required. In conclusion, typically, Xp11-RCC manifests as an advanced, solid, renal mass with mild persistent enhancement, prevalent intertumor hemorrhage/calcification, and cortical epicenter localization. The predilection for children and young adults is a possible useful clinical feature for confirming a diagnosis of Xp11-RCC. REFERENCES 1. Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004 WHO classification of the renal tumors of the adults. Eur Urol 2006;49: 798–805. 2. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004. p 37–38. 3. Argani P, Lal P, Hutchinson B, Lui MY, Reuter VE, Ladanyi M. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003;27:750–761. 4. Moch H. An overview of renal cell cancer: pathology and genetics. Semin Cancer Biol 2012;23:3–9. 5. Kato H, Kanematsu M, Yokoi S, et al. Renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion: radiological findings mimicking papillary subtype. J Magn Reson Imaging 2011;33:217–220. 6. Ross H, Argani P. Xp11 translocation renal cell carcinoma. Pathology 2010;42:369–373. 7. Prasad SR, Humphrey PA, Catena JR, et al. Common and uncommon histologic subtypes of renal cell carcinoma: imaging spectrum with pathologic correlation. Radiographics 2006;26:1795– 1806; discussion 1806–1810. 8. Rais-Bahrami S, Drabick JJ, De Marzo AM, et al. Xp11 translocation renal cell carcinoma: delayed but massive and lethal metas-
447 tases of a chemotherapy-associated secondary malignancy. Urology 2007;70:178.e3–6. 9. Argani P, Lae M, Ballard ET, et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 2006; 24:1529–1534. 10. Franzini A, Picozzi SC, Politi PL, et al. A case of renal cancer with TFE3 gene fusion in an elderly man. Clinical, radiological and surgical findings. Urol Int 2007;78:179–181. 11. Koie T, Yoneyama T, Hashimoto Y, et al. An aggressive course of Xp11 translocation renal cell carcinoma in a 28-year-old man. Int J Urol 2009;16:333–335. 12. Sukov WR, Hodge JC, Lohse CM, et al. TFE3 rearrangements in adult renal cell carcinoma: clinical and pathologic features with outcome in a large series of consecutively treated patients. Am J Surg Pathol 2012;36:663–670. 13. Jung SC, Cho JY, Kim SH. Subtype differentiation of small renal cell carcinomas on three-phase MDCT: usefulness of the measurement of degree and heterogeneity of enhancement. Acta Radiol 2012;53:112–118. 14. Kim JK, Kim TK, Ahn HJ, Kim CS, Kim KR, Cho KS. Differentiation of subtypes of renal cell carcinoma on helical CT scans. AJR Am J Roentgenol 2002;178:1499–1506. 15. Yoshimitsu K, Irie H, Tajima T, et al. MR imaging of renal cell carcinoma: its role in determining cell type. Radiat Med 2004;22: 371–376. 16. Zhang J, Lefkowitz RA, Ishill NM, et al. Solid renal cortical tumors: differentiation with CT. Radiology 2007;244:494–504. 17. Kim JH, Bae JH, Lee KW, Kim ME, Park SJ, Park JY. Predicting the histology of small renal masses using preoperative dynamic contrast-enhanced magnetic resonance imaging. Urology 2012; 80:872–876. 18. Pickhardt PJ, Siegel CL, McLarney JK. Collecting duct carcinoma of the kidney: are imaging findings suggestive of the diagnosis? AJR Am J Roentgenol 2001;176:627–633. 19. Suzigan S, Drut R, Faria P, et al. Xp11 translocation carcinoma of the kidney presenting with multilocular cystic renal cell carcinoma-like features. Int J Surg Pathol 2007;15:199–203.
Original Research
Renal Carcinomas Associated With Xp11.2 Translocations/TFE3 Gene Fusions: Findings on MRI and Computed Tomography Imaging Kefu Liu, MD, PhD,1,2* Ping Xie, MS,1 Weijun Peng, MD, PhD,2 and Zhengrong Zhou, MD, PhD2 Purpose: To retrospectively analyze MRI and computed tomographic (CT) findings from renal carcinomas associated with Xp11.2 translocations/TFE3 gene fusions (Xp11-RCC).
MRI images relative to the renal cortex except for 1 tumor that showed significant hemorrhage and a relative hyperintensity. For 3 cases who were imaged with CT, two tumors imaged using nonenhanced CT images showed mild hyperdensity relative to the renal cortex. Calcification was noted in all three tumors. All tumors showed mild, persistent enhancement.
Materials and Methods: Institutional review board permission was obtained to review patient medical records, and the requirement for informed consent was waved . The clinical and MRI/CT features of five cases with Xp11RCC that were confirmed by pathology were analyzed retrospectively. The image characteristics included the lesion location and size, contribution of cystic and solid components, intratumoral necrosis or hemorrhage, invasion of perinephric tissue and renal sinus, lymphadenopathy, major venous or arterial vascular invasion, pattern of the tumor growth, intratumor calcification and lipids, homogeneity of SI on T2-weighted images, attenuation and SI of the mass with respect to the normal renal cortex on precontrast and contrasted CT/MRI images, tumor SIs, tumor attenuations and tumor-to-cortex indices, homogeneity of enhancement on the contrasted images.
Conclusion: Typical Xp11-RCC manifests as an advanced, solid renal mass with mild persistent enhancement, a prevalence of intertumor hemorrhage/calcification, and a cortical epicenter location. The predilection for children and young adults is a useful clinical feature when confirming a diagnosis of Xp11-RCC. Key Words: renal cell carcinoma; Xp11.2 translocation; TFE3 gene fusion; CT; MRI J. Magn. Reson. Imaging 2014;40:440–447. C 2013 Wiley Periodicals, Inc. V
Results: The mean age was 32 years (range, 15–47 years). Most patients (4/5) were women. All tumors showed a cortical location. The average tumor size was 9 cm (range, 4–18 cm). Four tumors comprised a predominantly solid lesion with focal necrosis, and one tumor comprised a solid lesion with significant necrosis. All tumors showed intertumor hemorrhage, infiltrative growth and invasion of the perirenal adipose/renal sinus. Four cases showed retroperitoneal lymphadenopathy, of which one case showed simultaneous mediastinal and supraclavicular lymphadenopathy. All tumors from four cases showed mild hyperintensity on T1-weighted MRI images, and three tumors showed hypointensity on T2-weighted
1 Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China. 2 Department of Radiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. *Address reprint requests to: K.L., Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, No. 242, Guang Ji Road, Suzhou, Jiangsu, 215008, China. E-mail: [email protected]. Received May 10, 2013; Accepted July 29, 2013. DOI 10.1002/jmri.24349 View this article online at wileyonlinelibrary.com. C 2013 Wiley Periodicals, Inc. V
RENAL CELL CARCINOMA (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11-RCC) was identified and listed as a separate entity in the 2004 World Health Organization (WHO) classification of kidney tumors (1,2). The most distinctive histopathologic appearance of Xp11-RCC is that of a carcinoma with a papillary architecture composed of clear cells; however, these tumors frequently show a more nested architecture and often feature cells with a granular eosinophilic cytoplasm (1). Nuclear labeling for TFE3 is specific to Xp11.2-RCC (3). This carcinoma predominantly affects children and young adults in the second and third decades of life, although some cases of older patients have recently been described, and shows no gender preference (4). Approximately 15% of RCCs in children are of the clear cell subtype; however, Xp11-RCCs accounts for one-third of pediatric RCCs (5). In adults, Xp11RCCs are associated with a poor prognosis, they present at an advanced stage and are frequently associated with lymph node metastasis upon diagnosis (1,2,4–6). Hence, we describe the computed tomography (CT) and MRI findings from five cases with Xp11-RCC.
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Xp11-RCC MRI and CT Findings
MATERIALS AND METHODS Patients Six patients with pathology-confirmed Xp11-RCC were revealed upon a retrospective search of our pathology department database between January 2010 and June 2012. The pathology was confirmed based on pathological morphology and immunohistochemistry (2). One case (female, 73 years) was excluded from the study due to a lack of preoperative imaging. Thus, five patients were included in this study. MRI images were available for four cases, and CT images were available for three cases. Institutional review board permission was obtained to review the patients’ medical records, and patient informed consent was not required.
Imaging Techniques In our study, three patients had available, preoperative CT images. One case underwent non-contrast CT imaging and contrast enhanced CT imaging, including corticomedullary-phase and nephrographic-phase imaging (6 days before surgery), one case only had excretory-phase contrasted CT images (4 days before surgery), and one case underwent plain CT imaging (13 days before surgery). The CT examinations were performed using a multislice CT scanner (Somaton Sensation 40 or 64, Siemens, Germany). The tube voltage was set to 120 kVp, the tube current was adjusted for each subject based on the tissue size and density, the rotation time was 0.5 s, the pitch was 1.4 (60 0.6 or 40 0.6), and the reconstructive slice thickness was 5 mm. A bolus of nonionic contrast material (300 mg I/mL of iopamidol at 1.5 mL/kg body weight) was injected intravenously at a rate of 3 mL/s using an automated injector. Four patients in this study had available, preoperative MRI images. MR imaging was performed at 5, 7, 13, and 14 days before surgery. MRI examinations were performed using a 3.0 Tesla (T) scanner (Signa HDxt, General Electric Medical Systems, Milwaukee, WI) using a standard renal MRI protocol that included an axial in-and-opposed-phase two-dimensional (2D) T1-weighted gradient-echo (repetition time ms/echo time ms, 230/1.1, 2.2; field of view, 38 cm; section thickness, 7–8 mm; intersection gap, 2 mm; and matrix, 320 160), axial respiratory-triggered fat-saturation 2D T2-weighted gradient-echo (repetition time ms/echo time ms, 6300/85, field of view, 38 cm; section thickness, 7–8 mm; intersection gap, 2 mm; and matrix, 320 160) followed by axial 3D fat-saturation T1-weighted gradient-echo sequences obtained during the corticomedullary, nephrographic (repetition time ms/echo time ms, 2.5/1.2, field of view, 38 cm; section thickness, 6 mm; and matrix, 260 220) and coronal 3D fat-saturation T1-weighted gradient-echo sequences during excretory phases (repetition time ms/echo time ms, 3.6/1.5, field of view, 38 cm; section thickness, 6 mm; and matrix, 260 220) of enhancement after intravenous administration of gadopentate dimeglumine (0.1 mmol/kg body weight;
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Magnevist, Schering, Berlin, Germany) at 2 mL/s using an injector (Mallinckrodt, Ohio). Image Analysis Two radiologists with 15 and 12 years’ experience in abdominal MRI evaluated the tumors’ image features based on the following criteria: (i) Tumor’s location, which was defined as either medullary, cortical or exophytic depending on the location of the center of the tumor. (ii) Size of the tumor (maximum axial diameter). (iii) Relative contribution of cystic and solid components. (iv) Presence of intratumor necrosis or hemorrhage. (v) Presence of an invasion of perinephric tissue and renal sinus. (vi) Presence of lymphadenopathy, which was defined as when the diameter of a lymph node had enlarged by >1 cm. (vii) The presence of distant metastatic disease (based on CT or MRI images). (viii) Presence of major venous or arterial vascular invasion, which were defined as when the tumor was found in the lumen of the renal vein or the inferior vena cava. (ix) Pattern of the tumor growth (infiltrative or expansive); infiltrative growth was characterized by the lack of clear borders between the tumor and the normal renal parenchyma, whereas expansive growth was characterized by well-defined, bulging tumor margins that displaced the normal parenchyma. (x) Presence of intratumor calcification on CT images. (xi) Presence of microscopic lipids on MRI images (an area of increased signal intensity (SI) on in-phase T1-weighted images (T1WI) that visually showed a decrease in SI on opposed-phase T1WI). (xii) Homogeneity of SI on T2-weighted images (homogeneous or heterogeneous. (xiii) Predominant attenuation and SI of the mass with respect to the normal renal cortex on precontrast and contrasted CT/MRI images. (xiv) Tumor SIs, tumor attenuations and tumor-tocortex indices, which were calculated for those sequences with same parameters (corticomedullaryand nephrographic-phase images for MRI and each phase for CT). Tumor-to-cortex indices were calculated for both the corticomedullary- and nephrographic-phase images as the SI for MRI and attenuation for CT of the tumor divided by those of the renal cortex. The intratumor ROI was placed within the region demonstrating the most marked contrast enhancement based on visual assessment. The renal cortical ROI was placed within a portion of the renal cortex of the ipsilateral kidney that did not show a tumor. (xv) Homogeneity of enhancement on the contrasted images (homogeneous or heterogeneous).
RESULTS The clinical features of the five cases with Xp11-RCC are recorded in Table 1. Patients presented with symptoms including abdominal pain and an abdominal mass in two cases, left supraclavicular lymphadenopathy in one case, gross hematuria in one case, and gross hematuria with abdominal pain and an abdominal mass in one case. The mean age was 32
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Table 1 Clinical Features of Five Cases With Xp11-RCC No. Gender Age (year) Symptom
1
2
3
4
5
Female 15 Abdominal pain and abdominal mass
Female 45 Gross hematuria
Male 33 Abdominal pain, abdominal mass and gross hematuria
Female 22 Abdominal pain and abdominal mass
Female 47 Supraclavicular lymphadenopathy
years (range, 15–47 years). Four patients were women, and one was a man. None of the cases had a history of prior exposure to chemotherapy. All five patients underwent surgical resection of their tumors: one patient died of arrhythmia while the incision was being sutured during the operation, one patient was lost to follow-up immediately after surgery, and the remaining three patients were alive as of the time of writing this article, having lived 75, 150, and 375 days. The CT and MRI findings from the five cases with Xp11-RCC are described in Table 2. All tumors
showed a cortical location (Figs. 1–5). Tumors occurred in the right kidney in three cases (Figs. 2–4) and the left kidney in two cases (Figs. 1,5). The average tumor size was 9 cm (range, 4–18 cm). Four tumors comprised a predominantly solid lesion with focal necrosis (Figs. 1–3, 5), and 1 tumor comprised a solid lesion with significant necrosis at the center ( 70%) that did not show lymphadenopathy (Fig. 4). All tumors showed intertumor hemorrhage, infiltrative growth and invasion of the perirenal adipose/renal sinus (Figs. 1–5). Four cases showed retroperitoneal lymphadenopathy (Figs. 1–3, 5), of which one case
Table 2 CT and MRI Features of Five Cases With Xp11-RCC No. Side Size (cm) Location Solid/cyst Pattern of tumor growth Necrosis Intertumor hemorrhage Invasion of the perirenal adipose Involvement of renal sinus Lymphadenopathy Vascular invasion Distant metastatic disease Microscopic lipid Heterogeneity of SI on T2-weighted images SI relative to renal cortex on in-phase T1-weighted images SI relative to renal cortex on opposed-phase T1-weighted images SI relative to renal cortex on T2-weighted images Enhancement heterogeneity Enhancement of the mass relative to the normal renal cortex at the corticomedullary phase Enhancement of the mass relative to the normal renal cortex at the nephrographic phase Enhancement of the mass relative to the normal renal cortex at the excretory phase CT Plain CT Calcification Heterogeneous enhancement Enhancement of the mass relative to the normal renal cortex at the corticomedullary phase Enhancement of the mass relative to the normal renal cortex at the nephrographic phase Enhancement of the mass relative to the normal renal cortex at the excretory phase SI, signal intensity.
1
4
5
Left Right Right 18 4 6 Cortical Cortical Cortical Solid Solid Solid Infiltrative Infiltrative Infiltrative Focal Focal Focal Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No No No No No No No Yes Yes Yes Hyperintensity Hyperintensity Hyperintensity
Right 11 Cortical Cyst Infiltrative Center Yes Yes Yes No No No No Yes Hyperintensity
Left 7 Cortical Solid Infiltrative Focal Yes Yes Yes Yes No Yes No images No images No images
Hyperintensity Hyperintensity Hyperintensity
Hyperintensity
No images
Hypointensity Hyperintensity Hypointensity Yes Yes Yes Hypointensity Hypointensity Hypointensity
Hypointensity Yes Hypointensity
No images No images No images
Hypointensity
Hypointensity
Hypointensity
Hypointensity
No images
Hypointensity
Hypointensity
Hypointensity
Hypointensity
No images
No No No No
images images images images
2
3
No No No No
images images images images
No images Yes Yes No images
Mild hyperdensity Mild hyperdensity Yes Yes No images Yes No images Hypodensity
No images
No images
No images
No images
Hypodensity
No images
No images
Hypodensity
No images
Hypodensity
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Figure 1. A 15-year-old female with Xp11-RCC of the left kidney. The tumor shows mild hyperintensity on precontrast inphase T1-weighted images (a), mild hypointensity on precontrast opposed-phase T1-weighted images (b), and a hypointense appearance on T2-weighted images (c). A retroperitoneal lymphadenopathy, an invasion of the perinephric tissue, and renal sinus and intertumor hemorrhage are found on MRI images (A,C). The enhancement of the mass relative to the normal renal cortex is hypointense on the corticomedullary- (d), nephrographic- (e), and excretory-phase images (f), and this tumor shows a mild persistent enhancement (d–f). The tumor appears to show a papillary architecture with clear cells and nested architecture. The tumor cells feature granular eosinophilic cytoplasm. Local hemorrhage was noted in the tumor (g). Some tumor cells were positive for TFE3 protein (h).
showed simultaneous mediastinal and supraclavicular lymphadenopathy (Fig. 5). Vascular invasion was not found on the CT and MRI images. For the 4 cases with MRI images, all tumors showed a mild hyperintensity on T1-weighted images, and 3 tumors showed a hypointensity relative to the renal cortex on T2-weighted images (Figs. 1, 3, 4) except for 1 tumor that showed a significant hemorrhage and relative hyperintensity (Fig. 2). Microscopic lipids were not found in any of these four tumors. Tumors showed
hypointensity relative to the renal cortex at the corticomedullary, nephrographic, and excretory phase (Figs. 1–4). For the cases with CT images, two tumors with plain CT images showed a mild hyperdensity relative to the renal cortex (Figs. 4,5). Calcification was found in all three tumors (Figs. 3–5). Two tumors with contrasted CT images showed heterogeneity (Figs. 3,5). Tumors showed hypointensity relative to the renal cortex at the corticomedullary, nephrographic, and excretory phase (Figs. 3,5).
Figure 2. A 45-year-old female with Xp11-RCC of the right kidney. The tumor shows mild hyperintensity on precontrast inphase T1-weighted images (a), a mild hypointensity on precontrast opposed-phase T1-weighted images (b), and a hypointense appearance on T2-weighted images (c). Retroperitoneal lymphadenopathy, invasion of the perinephric tissue and renal sinus and intertumor hemorrhage are found on MRI images (a,c). The enhancement of the mass relative to the normal renal cortex is hypointense on the corticomedullary- (d), nephrographic- (e), and excretory-phase images (f), and the tumor shows mild persistent enhancement (d–f). Local hemorrhage was noted in the tumor (g). Some tumor cells were positive for TFE3 protein (h).
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Figure 3. A 33-year-old male with Xp11-RCC of the right kidney. The tumor showed mild hyperintensity on precontrast inphase T1-weighted images (a), mild hypointensity on precontrast, opposed-phase T1-weighted images (b), and a hypointense appearance on T2-weighted images (c). Retroperitoneal lymphadenopathy, invasion of the perinephric tissue, and renal sinus and intertumor hemorrhage were noted in MRI images (a,c). The enhancement of the mass relative to the normal renal cortex is hypointense on corticomedullary- (d), nephrographic- (e), and excretory-phase images (f), and the tumor shows mild persistent enhancement (D–F). A CT image of the excretory phase of this tumor also shows its hypodense appearance relative to the normal renal cortex, and calcifications were observed in this tumor (g).
The tumor MRI SIs, CT attenuations and tumor-tocortex indices on each CT and MRI sequence using the same parameters are shown in Table 3. For cases with MRI images, the average SI of the tumors was 501 and 493 at the corticomedullary and nephrographic phase, respectively; the tumor-to-cortex indices were 0.60
and 0.55 at the corticomedullary and nephrographic phase, respectively. For the cases with CT images, the average attenuation of the tumor was 43 HU, 71 HU, 80 HU, and 69 HU at the plain, corticomedullary, nephrographic, and excretory phases, respectively; the tumor-to-cortex indices were 1.40, 0.54, 0.47,
Figure 4. A 22-year-old female with Xp11-RCC of the right kidney. The tumor shows significant center necrosis (>70%) and mild hyperintensity on precontrast in-phase T1-weighted images (a), mild hypointensity on precontrast, opposed-phase T1weighted images (b), and a hypointense appearance on T2-weighted images (c). Invasion of the perinephric tissue and renal sinus and intertumor hemorrhage were noted on MRI images (a,c). The enhancement of the mass relative to the normal renal cortex shows hypointensity on the corticomedullary- (d), nephrographic- (e), and excretory-phase images (f), and the tumor shows mild persistent enhancement (D–F). On a plain CT image, this tumor shows a mild hyperdense appearance relative to the normal renal cortex, and calcifications were noted in this tumor (g).
Xp11-RCC MRI and CT Findings
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Figure 5. A 47-year-old female with Xp11-RCC of the left kidney. The tumor is predominantly a solid mass and shows a mild hyperdense appearance on a precontrast CT image (a,b). Invasion of the perinephric tissue and renal sinus, calcification, and intertumor hemorrhage were found (a–c). The enhancement of the mass relative to the normal renal cortex was hypointense on the corticomedullary (c) and nephrographic phase (d), and the tumor shows mild persistent enhancement (c,d). On a plain CT image, supraclavicular and mediastinal lymphadenopathy were noted (e,f).
and 0.57 at the plain, corticomedullary, nephrographic, and excretory phases, respectively. All tumors showed mild persistent enhancement.
DISCUSSION Xp11.2-RCC is caused by several different translocations involving chromosome Xp11.2 that all result in gene fusions involving the TFE3 gene (2). TFE3 is a member of the basic-helix-loop-helix family of
transcription factors (2). Both the PRCC-TFE3 and ASPL-TFE3 fusion proteins retain the TFE3 DNAbinding domain, localize to the nucleus, and can act as aberrant transcription factors (2). The expression levels of TFE3 fusion proteins appear aberrantly high compared with native TFE3, perhaps because the fusion partners of TFE3 are ubiquitously expressed, and their promoters regulate the fusion proteins (2,7). The TFE3 immunohistochemical assay has been demonstrated to be very sensitive and specific for neoplasms bearing
Table 3 Xp11-RCC SIs From MRI Images, Tumor Attenuations From CT Images, and Tumor-to-Cortex Indices From Each CT and MRI Sequence Using the Same Parameters No. MR The SI of the renal cortex at the corticomedullary phase The SI of the tumor at the corticomedullary phase Tumor-to-cortex index at the corticomedullary phase The SI of the renal cortex at the nephrographic phase The SI of the tumor at the nephrographic phase Tumor-to-cortex index at the nephrographic phase CT The attenuation of renal cortex on the precontrast images The attenuation of the tumor in precontrast images Tumor-to-cortex index in precontrast images The attenuation of renal cortex at the corticomedullary phase The attenuation of the tumor at the corticomedullary phase Tumor-to-cortex index at the corticomedullary phase The attenuation of the renal cortex at the nephrographic phase The attenuation of the tumor at the nephrographic phase Tumor-to-cortex index at the nephrographic phase The attenuation of the renal cortex at the excretory phase The attenuation of the tumor at the excretory phase Tumor-to-cortex index at the excretory phase
1
2
3
4
5
849 529 0.62 933 486 0.52
927 555 0.59 958 514 0.53
653 406 0.62 673 406 0.60
925 513 0.55 1032 566 0.55
No images No images None No images No images None
No images No images None No images No images None No images No images None No images No images None
No images No images None No images No images None No images No images None No images No images None
No images No images None No images No images None No images No images None 69 121 0.57
33 44 1.33 No images No images None No images No images None No images No images None
28 41 1.46 131 71 0.54 168 80 0.47 No images No images None
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TFE3 gene fusions. Using moderate and strong immunoreactivity as a positive score, the sensitivity was 97.5% and the specificity was 99.6% (2,3). Prior exposure to chemotherapy is currently the only known risk factor for the development of Xp11-RCC. A review showed that up to 15% of patients with these tumors had a history of prior chemotherapy exposure. The postchemotherapy interval ranged from 4 to 13 years (6,8,9). However, in our study, none of the cases had a history of prior chemotherapy exposure. Xp11.2-RCC accounts for 1% of all renal cell carcinomas and approximately 20% of RCCs in the pediatric and adolescent age groups (2). In our study, the mean age was 32 years (range, 15–47 years), and four patients were adults. Recent literature has shown that the frequency of Xp11-RCC in adults may have been previously underestimated due to its morphological overlap with conventional clear cell RCC. Adult Xp11-RCC cases may vastly outnumber pediatric Xp11-RCC cases due to the much higher incidence of RCC in the adult population (5,6). Specifically, our results showed a prevalence of women (four of five), which is not consistent with past literature that showed no gender preference (4). Due to its indolent course, adult cases with Xp11RCCs often present at advanced stages (1,4,6), which is consistent with our results. Furthermore, the tumors in our cases were relatively large (9 cm), and most cases (four of five) showed lymphadenopathy. All five tumors showed an invasion of the perirenal adipose/renal sinus. However, vascular invasion was not found in our series. In our study, most tumors (four of five) were predominantly solid with a mild heterogeneous appearance that reflects the histological features, which are typically a tan-yellow mass with focal necrosis and hemorrhage (5,10,11). MRI did not reveal microscopic lipids in any case imaged, which is consistent with a previous case (5). Calcification was found in all three Xp11-RCCs imaged with CT. All Xp11-RCCs in our study showed infiltrative growth, which suggests that this tumor may be a clinically aggressive tumor, as reported previously by Sukov et al (12). Our results are similar to previous reports (10,11) but are not consistent with Kato et al, who showed a well-demarcated mass (5). In our study, the mean tumor size was 9 cm, which was significantly larger than the tumor size reported by Kato et al. We presume that the larger tumor size is related to their more infiltrative appearance. On noncontrast images, the tumors showed mild hyperintensity on T1-weighted images and mild hyperdensity relative to the renal cortex on CT images, which is consistent with a previous case (5). This feature is considered to be due to hemorrhagic, proteinaceous fluid or a densely packed cellular component or a combination of both (5,7). Most tumors in our series showed hypointensity relative to the renal cortex on adipose-suppressed T2-weighted images, which was similar to a past case (5,7). One tumor showed hyperintensity relative to the renal cortex on adipose-suppressed T2-weighted images, which may be due to significant sub-acute hemorrhage.
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The tumors in our study showed hypointensity relative to the renal cortex at the corticomedullary, nephrographic, and excretory phases and showed mild persistent enhancement, similar to a past case (5). Clear cell RCC is the most common histologic RCC subtype, and it typically shows significant heterogeneous enhancement and a significant washout (7,13–17). These features are different from Xp11RCC, which shows predominantly solid lesions of a mild heterogeneous appearance and with mild, persistent enhancement. Kim et al noted that clear cell RCC showed enhancement of more than 84 HU at the corticomedullary phase and 44 HU at the excretory phase (with a specificity of 100% and 91%, respectively) (14), which contrast with our data that showed that the tumor enhancement was 71 HU at the corticomedullary phase and 69 HU at the excretory phase. Additionally, our MRI data showed that the tumorto-cortex indices of the corticomedullary phase and the nephrographic phase were 0.60 and 0.55, respectively, which were different from those of renal clear cell RCC, which shows a tumor-to-cortex enhancement index at the corticomedullary phase and nephrographic phase of 1.43 and 0.87, respectively. Additionally, clear cell RCC appears iso- to hyperintense on T2-weighted MR images, which contrasts with findings from Xp11-RCC, which shows hypointensity (5,7). Other types of nonclear cell RCC, such as papillary RCC, chromophobe RCC, collecting duct carcinoma, and renal medullary carcinoma, must also be included in the differential diagnosis. The features described below are useful for the differential diagnosis. Xp11-RCC typically mimics the papillary subtype of RCC; however, papillary RCC is typically hypovascular and shows homogeneous enhancement, and these features can be used for differentiating Xp11RCC, which shows a mild heterogeneous appearance (7,13). Chromophobe RCC and collecting duct carcinoma often occur in older adults; collecting duct carcinoma often locates to the epicenter of the medulla; renal medullary carcinoma is typically associated with caliectasis, although it appeared as an infiltrative, heterogeneous mass with a medullary epicenter and a relatively high prevalence in young men (7,18). One tumor in our study appeared as a solid lesion with significant necrosis in its center (>70%), which might mimic papillary RCC and multilocular cystic RCC (19). Multilocular cystic RCC is a multiseptated cystic lesion with a fibrous capsule, and it occurs predominantly in older males (5,7,10,11). These characteristics differ from Xp11-RCC, which shows an infiltrative mass with center necrosis and presents predominantly in children and young, female adults. In the case of cystic papillary RCCs, some features, such as the enhanced, peripheral, soft-tissue mural nodules and its bilateral/multifocal occurrence (particularly in hereditary syndromes), may be used to differentiate it from Xp11-RCC (7). This study was limited by its small sample size because Xp11-RCC is encountered rarely. Moreover, all patients did not have both MR and CT images and the differences in technique were from patient to
Xp11-RCC MRI and CT Findings
patient. Therefore, further studies of larger numbers of cases are required. In conclusion, typically, Xp11-RCC manifests as an advanced, solid, renal mass with mild persistent enhancement, prevalent intertumor hemorrhage/calcification, and cortical epicenter localization. The predilection for children and young adults is a possible useful clinical feature for confirming a diagnosis of Xp11-RCC. REFERENCES 1. Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004 WHO classification of the renal tumors of the adults. Eur Urol 2006;49: 798–805. 2. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004. p 37–38. 3. Argani P, Lal P, Hutchinson B, Lui MY, Reuter VE, Ladanyi M. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003;27:750–761. 4. Moch H. An overview of renal cell cancer: pathology and genetics. Semin Cancer Biol 2012;23:3–9. 5. Kato H, Kanematsu M, Yokoi S, et al. Renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion: radiological findings mimicking papillary subtype. J Magn Reson Imaging 2011;33:217–220. 6. Ross H, Argani P. Xp11 translocation renal cell carcinoma. Pathology 2010;42:369–373. 7. Prasad SR, Humphrey PA, Catena JR, et al. Common and uncommon histologic subtypes of renal cell carcinoma: imaging spectrum with pathologic correlation. Radiographics 2006;26:1795– 1806; discussion 1806–1810. 8. Rais-Bahrami S, Drabick JJ, De Marzo AM, et al. Xp11 translocation renal cell carcinoma: delayed but massive and lethal metas-
447 tases of a chemotherapy-associated secondary malignancy. Urology 2007;70:178.e3–6. 9. Argani P, Lae M, Ballard ET, et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 2006; 24:1529–1534. 10. Franzini A, Picozzi SC, Politi PL, et al. A case of renal cancer with TFE3 gene fusion in an elderly man. Clinical, radiological and surgical findings. Urol Int 2007;78:179–181. 11. Koie T, Yoneyama T, Hashimoto Y, et al. An aggressive course of Xp11 translocation renal cell carcinoma in a 28-year-old man. Int J Urol 2009;16:333–335. 12. Sukov WR, Hodge JC, Lohse CM, et al. TFE3 rearrangements in adult renal cell carcinoma: clinical and pathologic features with outcome in a large series of consecutively treated patients. Am J Surg Pathol 2012;36:663–670. 13. Jung SC, Cho JY, Kim SH. Subtype differentiation of small renal cell carcinomas on three-phase MDCT: usefulness of the measurement of degree and heterogeneity of enhancement. Acta Radiol 2012;53:112–118. 14. Kim JK, Kim TK, Ahn HJ, Kim CS, Kim KR, Cho KS. Differentiation of subtypes of renal cell carcinoma on helical CT scans. AJR Am J Roentgenol 2002;178:1499–1506. 15. Yoshimitsu K, Irie H, Tajima T, et al. MR imaging of renal cell carcinoma: its role in determining cell type. Radiat Med 2004;22: 371–376. 16. Zhang J, Lefkowitz RA, Ishill NM, et al. Solid renal cortical tumors: differentiation with CT. Radiology 2007;244:494–504. 17. Kim JH, Bae JH, Lee KW, Kim ME, Park SJ, Park JY. Predicting the histology of small renal masses using preoperative dynamic contrast-enhanced magnetic resonance imaging. Urology 2012; 80:872–876. 18. Pickhardt PJ, Siegel CL, McLarney JK. Collecting duct carcinoma of the kidney: are imaging findings suggestive of the diagnosis? AJR Am J Roentgenol 2001;176:627–633. 19. Suzigan S, Drut R, Faria P, et al. Xp11 translocation carcinoma of the kidney presenting with multilocular cystic renal cell carcinoma-like features. Int J Surg Pathol 2007;15:199–203.
