ORIGINAL ARTICLE
Dynamic Computed Tomographic Features of Adult Renal Cell Carcinoma Associated With Xp11.2 Translocation/TFE3 Gene Fusions: Comparison With Clear Cell Renal Cell Carcinoma Jian He, MD,* Weidong Gan, MD,† Song Liu, MD,* Kefeng Zhou, MD,* Gutian Zhang, MD,† Hongqian Guo, MD,† and Bin Zhu, MD* Objective: To investigate the dynamic contrast-enhanced computed tomography (CT) characteristics of renal cell carcinoma associated with Xp11.2 translocation and TFE gene fusion (Xp11.2 RCC) by comparison with clear cell renal cell carcinoma (CCRCC). Methods: Dynamic contrast-enhanced CT images and clinical and pathological records of 20 adult patients with Xp11.2 RCC confirmed by TFE3 immunohistochemical and fluorescence in situ hybridization assay were retrospectively analyzed and compared with the findings of 21 contemporary CCRCCs. Results: Renal cell carcinoma associated with Xp11.2 translocation and TFE gene fusions often occurred in young (30.6 ± 8.6 years) patients with hematuria (9/20). They presented as well-defined (17/20) cysticsolid (17/20) mass with hemorrhage (8/20) and circular/rim calcifications (6/20). Dynamic contrast-enhanced CT showed heterogeneous moderate prolonged enhancement. A tumor-to-cortex attenuation ratio in corticomedullary phase less than 0.62 gave a sensitivity of 90.0% and a specificity of 92.9% in differentiating Xp11.2 RCC from CCRCC (area under the receiver operating characteristic curve = 0.957, P < 0.001). Conclusions: Computed tomographic characteristics and dynamic contrastenhanced patterns and index can differentiate Xp11.2 RCC from CCRCC. Key Words: carcinoma, renal cell, adult, multidetector computed tomography, diagnosis, differential, in situ hybridization, fluorescence (J Comput Assist Tomogr 2015;39: 730–736)
R
enal cell carcinoma (RCC) associated with Xp11.2 translocation/ TFE3 gene fusion (Xp11.2 RCC) was introduced as a genetically distinct entity into the World Health Organization classification of renal neoplasms in 2004.1 Although Xp11.2 RCC is predominantly found in children and rare in adults, it seems more advanced and aggressive in adults than in children.2 Also, Xp11.2 RCC has a poorer prognosis than non–Xp11.2 RCC in children and young adults based on a meta-analysis.3 From the Departments of *Radiology and †Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. Received for publication February 1, 2015; accepted March 11, 2015. Correspondence to: Weidong Gan, MD, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Rd, Nanjing 210008, China (e‐mail: [email protected]). Bin Zhu, MD, is to be contacted at Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Rd, Nanjing 210008, China. This work was supported by the National Natural Science Foundation of China (ID: 21377052), the Natural Science Foundation of Jiangsu Province (ID: BK20131281), the Fundamental Research Funds for the Central Universities (ID: 20620140664), and Nanjing City Young Health Personnel Training Project (third level; ID: QRX11178). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/RCT.0000000000000263
730
www.jcat.org
The diagnosis of Xp11.2 RCC is usually established by postoperative histology and immunohistochemical (IHC) staining. Because of the property of overexpressed transcription factor E3 (TFE3) fusion protein, IHC staining with TFE3 antibody makes a useful diagnostic tool.4 However, there were false-positive and equivocal findings of IHC results in some patients.5 Fluorescence in situ hybridization (FISH) assay proved a more reliable test for Xp11.2 RCC.6 Several reports on computed tomography (CT) and/or magnetic resonance findings of Xp11.2 RCC were published in the past 3 years.7–12 Based on those studies, primary characteristics of this rare lesion on CT/magnetic resonance imaging (MRI) had been described. However, some imaging features remains uncertain or contradictory to each other. Their sample size was relatively small (5–12 patients), even including children and adult patients together. Also, the diagnosis of Xp11.2 RCC was only made by IHC staining in previous studies, and there may be potential false-positive cases. In this study, we focused on dynamic contrast-enhanced CT features of adult patients with Xp11.2 RCC. A total of 20 patients were included, and all diagnoses of Xp11.2 RCC were established by both IHC and FISH assay. Furthermore, CT findings of Xp11.2 RCC were compared with those of clear cell RCC (CCRCC), which is the most common histologic subtype of RCC in adults.
MATERIALS AND METHODS Participants This retrospective study was approved by the institutional review board of our hospital. All patients provided written informed consent for this study and CT examination. From January 2007 to July 2014, a total of 23 patients (20 adults ≥18 years old, 3 children) with Xp11.2 RCC undergone radical or partial nephrectomy in our institution were retrospectively included. The children younger than 18 years were excluded, and 20 adults with Xp11.2 RCC served as the participants of this investigation. There were a total of 783 patients diagnosed as having CCRCC based on microscopic findings, 52 patients from whom were younger than 50 years. From those 52 patients, 21 patients of CCRCC with a definite negative FISH assay result were selected for comparative study. The other 31 patients failed to undergo FISH analysis due to lack of tissue specimens. They were excluded in this study because a diagnosis of Xp11.2 RCC cannot be excluded solely based on microscopic findings. None of the patients included had received local or systematic therapy before CT scanning and surgery.
Clinical, Treatment, and Pathological Information A total of 20 Xp11.2 RCCs and 21 CCRCCs were included in this study. Each patient had 1 lesion. Clinical, radiologic, and
J Comput Assist Tomogr • Volume 39, Number 5, September/October 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Comput Assist Tomogr • Volume 39, Number 5, September/October 2015
pathological records of the 2 RCC subtypes were shown in Table 1. No history of malignancy, chemotherapy, or toxic exposure was recorded in the 2 groups. Open or laparoscopic radical operation served as the main treatment for patients with Xp11.2 RCC (16/20), and the remaining 4 of 20 patients with Xp11.2 RCCs underwent laparoscopic partial nephrectomy, whereas many patients (10/21) with CCRCC underwent laparoscopic partial nephrectomies. None of the patients in 2 groups died during the operation. Gross pathological record of the specimen was reviewed by 2 pathologists to confirm the tumor's location, boundary, capsule, shape, necrotic and cystic components, hemorrhage, and tumor thrombosis observed on CT imaging. Microscopically, tumor cells showed abundant clear or eosinophilic cytoplasm, irregular nuclei with vesicular chromatin, and prominent nucleoli with papillary, nested, alveolar, or tubular architectures in Xp11.2 RCC. Immunohistochemical staining with TFE3 antibody demonstrated strong TFE3 nuclear staining in 19 cases and suspicious positivity in 1 case. Then a self-designed polyclonal break-apart probe was used for FISH assay. All sections were successfully examined our FISH probes. The split red and green signals within a single nucleus were found simultaneously in 20 cases of Xp11.2 RCC, including the one with suspicious positive TFE3. The diagnosis of Xp11.2 RCC was ruled out in other 2 patients with strong positive TFE3 (+2-+3) but negative FISH results. Clear cell RCC showed nests of epithelial cells with clear cytoplasm and a distinct cell
DCECT of Xp11.2 RCC Compared With CCRCC
membrane, separated by a delicate branching network of vascular tissue. Both TFE3 staining and FISH assay were negative in all CCRCC cases.
CT Examination All patients underwent unenhanced and dynamic contrastenhanced kidney CT scans on a multidetector CT scanner (LightSpeed; GE Healthcare, Princeton, NJ) with a 5.0-mm slice thickness at 40, 70 to 80, and 180 seconds to obtain corticomedullary, nephrographic, and delayed phases after injection of 1.2-mL/kg body weight of contrast media (Omnipaque 350 mg I/mL; GE Healthcare) at a rate of 3.0 mL/s followed by 40 mL saline solution using a power injector (Medrad Stellant, Indianola, PA). Images were obtained at a tube voltage of 120 kVp and a tube current of 240 mA, with a rotation time of 0.6 seconds, a helical pitch of 1.375, a field of view of 35 to 40 cm, and a matrix of 512 512.
Image Interpretation All CT images were reviewed in consensus by 2 radiologists (J.H. and K.Z. with 5 and 10 years’ experience in abdominal CT diagnosis, respectively). The images were reviewed on a picture archiving and communication system workstation (GE AW4.3 workstation). Computed tomographic attenuation values (in Hounsfield unit, or HU) of the tumor and kidney were measured
TABLE 1. The Clinical and Pathological Details and Tumor Characteristics on CT in Xp11.2 RCC and CCRCC Groups
Sex (male/female) Age range, y Mean age, y Gross hematuria Palpable mass Flank discomfort Location (left/right) Location (upper/center/lower/whole) Location (cortical/cortical-medullary/medullary) Diameter, cm Boundary (clear/unclear) Capsule sign (pseudocapsule) Shape (regular/irregular) Nature (solid/cystic-solid/cystic) Hemorrhage Circular calcifications Fat Tumor thrombosis Lymph node metastasis Distant metastasis Treatment (OR/LR/LP/RA) TFE3 (+++ to ++++) FISH (+) Stage (I/II/III/IV) Median months of follow-up (range) Survival rate
Xp11.2 RCC (n = 20)
CCRCC (n = 21)
P
8/12 19–51 30.6 ± 8.6 9 (45.0%) 2 (10.0%) 4 (20.0%) 7/13 4/7/8/1 1/18/1 5.5 ± 2.4 17/3 10 (50%) 11/9 2/17/1 8 (40.0%) 6 (30.0%) 0 3 (15.0%) 3 (15.0%) 1 (5.0%) 6/10/4/0 19 (95.0%) 20 (100.0%) 13/1/4/2 33 (1–78) 17 (85.0%)
13/8 30–47 40.6 ± 4.6 0 1 (4.8%) 3 (14.3%) 12/9 5/10/6/0 9/11/1 4.1 ± 1.9 17/4 10 (47.6%) 16/5 11/10/0 5 (23.8%) 3 (14.3%) 0 0 1 (4.7%) 0 5/3/10/3 0 0 19/0/1/1 31 (19–60) 21 (100%)
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Dynamic Computed Tomographic Features of Adult Renal Cell Carcinoma Associated With Xp11.2 Translocation/TFE3 Gene Fusions: Comparison With Clear Cell Renal Cell Carcinoma Jian He, MD,* Weidong Gan, MD,† Song Liu, MD,* Kefeng Zhou, MD,* Gutian Zhang, MD,† Hongqian Guo, MD,† and Bin Zhu, MD* Objective: To investigate the dynamic contrast-enhanced computed tomography (CT) characteristics of renal cell carcinoma associated with Xp11.2 translocation and TFE gene fusion (Xp11.2 RCC) by comparison with clear cell renal cell carcinoma (CCRCC). Methods: Dynamic contrast-enhanced CT images and clinical and pathological records of 20 adult patients with Xp11.2 RCC confirmed by TFE3 immunohistochemical and fluorescence in situ hybridization assay were retrospectively analyzed and compared with the findings of 21 contemporary CCRCCs. Results: Renal cell carcinoma associated with Xp11.2 translocation and TFE gene fusions often occurred in young (30.6 ± 8.6 years) patients with hematuria (9/20). They presented as well-defined (17/20) cysticsolid (17/20) mass with hemorrhage (8/20) and circular/rim calcifications (6/20). Dynamic contrast-enhanced CT showed heterogeneous moderate prolonged enhancement. A tumor-to-cortex attenuation ratio in corticomedullary phase less than 0.62 gave a sensitivity of 90.0% and a specificity of 92.9% in differentiating Xp11.2 RCC from CCRCC (area under the receiver operating characteristic curve = 0.957, P < 0.001). Conclusions: Computed tomographic characteristics and dynamic contrastenhanced patterns and index can differentiate Xp11.2 RCC from CCRCC. Key Words: carcinoma, renal cell, adult, multidetector computed tomography, diagnosis, differential, in situ hybridization, fluorescence (J Comput Assist Tomogr 2015;39: 730–736)
R
enal cell carcinoma (RCC) associated with Xp11.2 translocation/ TFE3 gene fusion (Xp11.2 RCC) was introduced as a genetically distinct entity into the World Health Organization classification of renal neoplasms in 2004.1 Although Xp11.2 RCC is predominantly found in children and rare in adults, it seems more advanced and aggressive in adults than in children.2 Also, Xp11.2 RCC has a poorer prognosis than non–Xp11.2 RCC in children and young adults based on a meta-analysis.3 From the Departments of *Radiology and †Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. Received for publication February 1, 2015; accepted March 11, 2015. Correspondence to: Weidong Gan, MD, Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Rd, Nanjing 210008, China (e‐mail: [email protected]). Bin Zhu, MD, is to be contacted at Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Rd, Nanjing 210008, China. This work was supported by the National Natural Science Foundation of China (ID: 21377052), the Natural Science Foundation of Jiangsu Province (ID: BK20131281), the Fundamental Research Funds for the Central Universities (ID: 20620140664), and Nanjing City Young Health Personnel Training Project (third level; ID: QRX11178). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/RCT.0000000000000263
730
www.jcat.org
The diagnosis of Xp11.2 RCC is usually established by postoperative histology and immunohistochemical (IHC) staining. Because of the property of overexpressed transcription factor E3 (TFE3) fusion protein, IHC staining with TFE3 antibody makes a useful diagnostic tool.4 However, there were false-positive and equivocal findings of IHC results in some patients.5 Fluorescence in situ hybridization (FISH) assay proved a more reliable test for Xp11.2 RCC.6 Several reports on computed tomography (CT) and/or magnetic resonance findings of Xp11.2 RCC were published in the past 3 years.7–12 Based on those studies, primary characteristics of this rare lesion on CT/magnetic resonance imaging (MRI) had been described. However, some imaging features remains uncertain or contradictory to each other. Their sample size was relatively small (5–12 patients), even including children and adult patients together. Also, the diagnosis of Xp11.2 RCC was only made by IHC staining in previous studies, and there may be potential false-positive cases. In this study, we focused on dynamic contrast-enhanced CT features of adult patients with Xp11.2 RCC. A total of 20 patients were included, and all diagnoses of Xp11.2 RCC were established by both IHC and FISH assay. Furthermore, CT findings of Xp11.2 RCC were compared with those of clear cell RCC (CCRCC), which is the most common histologic subtype of RCC in adults.
MATERIALS AND METHODS Participants This retrospective study was approved by the institutional review board of our hospital. All patients provided written informed consent for this study and CT examination. From January 2007 to July 2014, a total of 23 patients (20 adults ≥18 years old, 3 children) with Xp11.2 RCC undergone radical or partial nephrectomy in our institution were retrospectively included. The children younger than 18 years were excluded, and 20 adults with Xp11.2 RCC served as the participants of this investigation. There were a total of 783 patients diagnosed as having CCRCC based on microscopic findings, 52 patients from whom were younger than 50 years. From those 52 patients, 21 patients of CCRCC with a definite negative FISH assay result were selected for comparative study. The other 31 patients failed to undergo FISH analysis due to lack of tissue specimens. They were excluded in this study because a diagnosis of Xp11.2 RCC cannot be excluded solely based on microscopic findings. None of the patients included had received local or systematic therapy before CT scanning and surgery.
Clinical, Treatment, and Pathological Information A total of 20 Xp11.2 RCCs and 21 CCRCCs were included in this study. Each patient had 1 lesion. Clinical, radiologic, and
J Comput Assist Tomogr • Volume 39, Number 5, September/October 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Comput Assist Tomogr • Volume 39, Number 5, September/October 2015
pathological records of the 2 RCC subtypes were shown in Table 1. No history of malignancy, chemotherapy, or toxic exposure was recorded in the 2 groups. Open or laparoscopic radical operation served as the main treatment for patients with Xp11.2 RCC (16/20), and the remaining 4 of 20 patients with Xp11.2 RCCs underwent laparoscopic partial nephrectomy, whereas many patients (10/21) with CCRCC underwent laparoscopic partial nephrectomies. None of the patients in 2 groups died during the operation. Gross pathological record of the specimen was reviewed by 2 pathologists to confirm the tumor's location, boundary, capsule, shape, necrotic and cystic components, hemorrhage, and tumor thrombosis observed on CT imaging. Microscopically, tumor cells showed abundant clear or eosinophilic cytoplasm, irregular nuclei with vesicular chromatin, and prominent nucleoli with papillary, nested, alveolar, or tubular architectures in Xp11.2 RCC. Immunohistochemical staining with TFE3 antibody demonstrated strong TFE3 nuclear staining in 19 cases and suspicious positivity in 1 case. Then a self-designed polyclonal break-apart probe was used for FISH assay. All sections were successfully examined our FISH probes. The split red and green signals within a single nucleus were found simultaneously in 20 cases of Xp11.2 RCC, including the one with suspicious positive TFE3. The diagnosis of Xp11.2 RCC was ruled out in other 2 patients with strong positive TFE3 (+2-+3) but negative FISH results. Clear cell RCC showed nests of epithelial cells with clear cytoplasm and a distinct cell
DCECT of Xp11.2 RCC Compared With CCRCC
membrane, separated by a delicate branching network of vascular tissue. Both TFE3 staining and FISH assay were negative in all CCRCC cases.
CT Examination All patients underwent unenhanced and dynamic contrastenhanced kidney CT scans on a multidetector CT scanner (LightSpeed; GE Healthcare, Princeton, NJ) with a 5.0-mm slice thickness at 40, 70 to 80, and 180 seconds to obtain corticomedullary, nephrographic, and delayed phases after injection of 1.2-mL/kg body weight of contrast media (Omnipaque 350 mg I/mL; GE Healthcare) at a rate of 3.0 mL/s followed by 40 mL saline solution using a power injector (Medrad Stellant, Indianola, PA). Images were obtained at a tube voltage of 120 kVp and a tube current of 240 mA, with a rotation time of 0.6 seconds, a helical pitch of 1.375, a field of view of 35 to 40 cm, and a matrix of 512 512.
Image Interpretation All CT images were reviewed in consensus by 2 radiologists (J.H. and K.Z. with 5 and 10 years’ experience in abdominal CT diagnosis, respectively). The images were reviewed on a picture archiving and communication system workstation (GE AW4.3 workstation). Computed tomographic attenuation values (in Hounsfield unit, or HU) of the tumor and kidney were measured
TABLE 1. The Clinical and Pathological Details and Tumor Characteristics on CT in Xp11.2 RCC and CCRCC Groups
Sex (male/female) Age range, y Mean age, y Gross hematuria Palpable mass Flank discomfort Location (left/right) Location (upper/center/lower/whole) Location (cortical/cortical-medullary/medullary) Diameter, cm Boundary (clear/unclear) Capsule sign (pseudocapsule) Shape (regular/irregular) Nature (solid/cystic-solid/cystic) Hemorrhage Circular calcifications Fat Tumor thrombosis Lymph node metastasis Distant metastasis Treatment (OR/LR/LP/RA) TFE3 (+++ to ++++) FISH (+) Stage (I/II/III/IV) Median months of follow-up (range) Survival rate
Xp11.2 RCC (n = 20)
CCRCC (n = 21)
P
8/12 19–51 30.6 ± 8.6 9 (45.0%) 2 (10.0%) 4 (20.0%) 7/13 4/7/8/1 1/18/1 5.5 ± 2.4 17/3 10 (50%) 11/9 2/17/1 8 (40.0%) 6 (30.0%) 0 3 (15.0%) 3 (15.0%) 1 (5.0%) 6/10/4/0 19 (95.0%) 20 (100.0%) 13/1/4/2 33 (1–78) 17 (85.0%)
13/8 30–47 40.6 ± 4.6 0 1 (4.8%) 3 (14.3%) 12/9 5/10/6/0 9/11/1 4.1 ± 1.9 17/4 10 (47.6%) 16/5 11/10/0 5 (23.8%) 3 (14.3%) 0 0 1 (4.7%) 0 5/3/10/3 0 0 19/0/1/1 31 (19–60) 21 (100%)
0.113 —
