BACKGROUND
According to the 2016 edition of the World Health Organization (WHO) classification of renal tumors, Xp11.2 translocation renal cell carcinoma (Xp11.2RCC ) is accepted as a distinct entity with unique biologic and pathologic characteristics and classified in the microphthalmia transcription factor (MIT) family, resulting in various gene fusions involving the TFE3 transcription factor gene.[ 1–3 ] These translocations result in novel chimeric proteins, and the most common chimeric proteins are ASPL-TFE3 and PRCC-TFE3 .[ 4 , 5 ] At present, the accepted standard method for the diagnosis of Xp11.2 RCC is a break-apart fluorescence in situ hybridization (FISH) assay.[ 6 ]
Xp11.2RCC is a rare tumor that accounts for approximately 4.2% of adult RCCs[ 7 ] but almost 20% of pediatric RCCs.[ 8 ] Even, if the incidence rates are lower, Xp11.2RCC is more common in adults by orders of magnitude[ 9 ] and more malignant in adults than in children.[ 10 ]
Xp11.2RCC ’s symptoms are nonspecific, such as abdominal mass, abdominal pain, and hematuria. Some tumors are incidentally found by physical examination.[ 11 ] There are few imaging review studies on Xp11.2RCC in the recent literature, and most studies are mainly focused on CT characteristics. Imaging findings on MR have rarely been reported.[ 12–15 ] Additionally, due to the rarity of Xp11.2 RCC, most studies focusing on this tumor have been case reports.[ 10 , 16 , 17 ]
We report the imaging and clinical findings of 28 cases of Xp11.2RCC and analyze the relationship between the pathological features and imaging findings, which will help improve the understanding of Xp11.2RCC for radiologists and clinicians.
METHODS
Patients
This study was approved by the Biomedical Research Ethics Committee of our hospital (SWYX: NO. 2021-358). The requirement for written informed consent was waived for this retrospective analysis.
At the screening stage, a search of the pathology and PACS systems was performed to search for patients. From August 2013 to November 2019, 2659 cases of renal carcinoma were identified, of which 30 patients were diagnosed with Xp11.2RCC by histopathology. Clinical data, radiological data, and pathological records were reviewed. One patient was excluded because of missing imaging data.
Next, specimens of the remaining patients were examined pathologically, including via light microscopy and immunohistochemistry, tumor specimens (bilateral renal tumors in one patient) were diagnosed after partial or complete nephrectomy (n = 25), needle biopsy (n = 4), and renal exploration (n = 1). Because the accepted standard method for the diagnosis of Xp11.2 RCC is break-apart fluorescence in situ hybridization (FISH) assays, so we did FISH assays on all pathological specimens. The pathological records were reviewed by a specialist consultant histopathologist, one patient with equivocal immunostaining was excluded because of a negative FISH assay.
Finally, 28 out of 2659 RCC patients were identified as Xp11.2RCC .
Argani P et al .[ 8 ] reported that Xp11.2 RCC has a higher incidence in children and adolescents than in adults. To verify the distinction of the incidence rates, we searched the number of all RCC cases in the same period from the pathology system of our hospital, and all cases were divided into two groups (adolescent and pediatric group (≤ 18 y) and adult group (≥18 y)) based on age. Twenty-eight patients were divided into two groups.
CT and MR technique
Twenty-four patients underwent renal CT examination, and CT examination was performed using one of several MDCT scanners (Discovery CT750 HD; Somatom Definition, Siemens Flash). Scans ranged from the domes of the diaphragm to the pubic symphysis. The parameters were as follows: tube voltage of 100–120 kV, tube current of 80–120 mAS, and pitch of 1/1.5. Enhanced scans were performed by injecting a bolus of 80–100 ml of contrast agent into the elbow vein at a rate of 3 ml/s after unenhanced scanning. Multiphase images were acquired at the corticomedullary phase (25–30 s), nephrographic phase (80–90 s), and excretory phase (180–240 s). The images were reconstructed with a thin-slice thickness of 1 mm.
Five patients underwent MR examination, and MR examination was performed using one of several MR systems (Siemens Magnetom Verio 3.0T; Philips Ingenia 3.0T). T1-weighted axial scans, T2-weighted axial scans, in-phase, and opposed-phase diffusion-weighted imaging (DWI) scans were obtained first. Dynamic contrast-enhanced images were obtained after intravenous injection of gadolinium (0.1 mmol/kg; 2.5 ml/s).
Qualitative analysis
Two experienced radiologists with more than 10 years of experience in image reading reviewed the CT and MRI images retrospectively and obtained consensus on a PACS system. Reviewers evaluated the imaging parameters of each tumor, including the tumor position, size, capsule sign, presence of calcification presence of fat, cystic component/necrosis, capsule disruption, and lymph node/distant metastasis. The prognosis was carried out by telephone follow-up. Calcification was considered small punctate, irregular coarse hyperdense on unenhanced CT images, iso- or hypointense on T1WI and hypointense or very low hypointense on T2WI with no enhancement. Cystic component/necrosis was considered when there was cavitation on unenhanced CT images and there was no enhancement following contrast enhancement.[ 18 , 19 ] Fat was considered a very low-density area (CT value: −20 ~ −120 HU) on CT images or an area showed hyperintense on T1WI and T2WI, and with a decreased signal on fat-saturated T2-weighted sequences. The presence of a capsule was defined as a clear boundary with delayed enhancement during the nephrographic and excretory phases.[ 11 , 13 ] Capsule disruption was defined as a tumor breaking the renal capsule.
Quantitative analysis
The region of interest (ROI) was measured (diameter, 10 mm) on the solid of the tumor, taking the average value of three times to avoid the impact of a partial-volume effect.[ 14 ] The CT values were assessed using Hounsfield values (HU) including the tumor, normal renal cortex, and medulla in every phase.[ 13 ]
The unenhanced CT values of tumors were assessed as “mildly hyperdense” if greater than 10 HU; “hyperdense” if greater than 30 HU; “isodense” if equal to the renal parenchyma; and “hypodense” if lower than 10 HU to the normal renal parenchyma.[ 12 ]
For contrast-enhanced CT scans, the degree and peak phase of the enhancement were assessed, including the values of the tumor, normal renal cortex, and medulla. The degree of enhancement was classified as mild enhancement (<20 HU), moderate enhancement (20–40 HU), and marked enhancement (>40 HU).
Statistical analysis
Statistical analysis was performed with IBM SPSS statistics software (version: 22.0). First, the consistency between the two radiologists was checked by the kappa correlation coefficient study, with a kappa value of >0.75 indicating “excellent,” a kappa value between 0.4 and 0.75 indicating “good” and a kappa value of <0.4 indicating “weak.” Furthermore, tumor incidence in the two groups and their imaging features (capsule, calcification, cystic component/necrosis, fat, capsule disruption, metastases) were analyzed using the Chi-square test. Differences were considered statistically significant when P < 0.05.
Quantitative analysis of the enhancement degree of the solid tumor and the tumor index (CT values of the solid tumor divided by the CT values of the renal cortex) was performed. The CT value is based on the average ± standard deviation.
RESULTS
Clinical features and prognosis
The general clinical characteristics and radiology examination of the patients are shown in Table 1 . Patients (18 males and 10 females) ranged from 3 to 83 years old, and the median age was 47 years. Patients presented with hematuria (n = 8); lower back pain (n = 7); medical examination (n = 8); neck pain, shoulder pain (n = 3); trauma (n = 1); and hip pain (n = 1). Bilateral renal tumors were detected in 1 patient, and unilateral renal tumors were detected in the remaining 27 patients. Out of 29 tumors, 13 were in the left kidneys, and 16 were in the right kidneys.
Table 1: General clinical characteristics and radiology examination of patients
Ten patients were identified with lymph node/distant metastasis (8 patients in the adult group; 2 patients in the adolescent and pediatric groups) at the time of diagnosis. From the follow-up date to March 06, 2021, among the 5 patients in the adolescent and pediatric groups, 1 patient (abandoned treatment) died, and 4 patients remained alive. Among 23 patients in the adult group, 6 patients died, 13 patients remained alive, and 4 patients were lost to follow-up.
Among the 2 patients with metastases in the adolescent and pediatric groups, 2 patients (100%) remained alive (follow-up times were 52 months and 24 months, respectively). Among the 8 patients with metastases in the adult group, 1 patient remained alive (follow-up time was 21 months), 5 patients died (follow-up times were 36 months, 21 months, 24 months, 6 months, and 33 months), and 2 patients were lost to follow-up.
Imaging findings
General characteristics
The kappa correlation coefficient study showed that the consistency between the two radiologists was excellent (kappa = 0.872). The differentials were reached by consensus.
Twenty-four tumors in 24 patients were detected by CT examination, and 6 tumors in 5 patients were detected by magnetic resonance (MR), of which 1 tumor in 1 patient was detected by CT and MR simultaneously. The size of the tumors ranged from 2.2 cm × 2.5 cm to 20.0 cm × 9.7 cm. Tumors were analyzed for cystic component/necrosis (100%, 29/29), renal capsule disruption (55%, 16/29), capsule (62%, 18/29), calcification (52%, 15/29), fat (14%, 4/29), and lymph node/distant metastasis (34%, 10/29). Among ten metastasis patients, five patients (50%, 5/10) had retroperitoneal metastasis; one patient (10%, 1/10) had vertebral body metastasis; one patient (10%, 1/10) had inferior vena cava metastasis; two patients (20%, 2/10) had renal vein metastasis; and one patient (10%, 1/10) had cervical lymph node metastasis.
CT Qualitative analysis
CT imaging findings are shown in Table 2 . Twenty-four patients underwent renal CT examination. On unenhanced CT examination, 14 tumors (58.3%, 14/24) were mildly hyperdense [Figure 1a and b ], 6 tumors (25.0%, 6/24) were isodense, 2 tumors (8.3%, 2/24) were hyperdense, and 2 tumors (8.3%, 2/24) were hypodense. Cystic component/necrosis [Figure 1b ] was found in every tumor (100%, 24/24). Small punctate and irregular coarse calcifications [Figure 1a ] were seen inside 12 tumors (50%, 12/24), and fat components were found in 3 tumors (12.5%, 3/24). Fifteen tumors (62.5%, 15/24) broke through the renal capsule. Enhanced scanning showed that 13 tumors (54.2%, 13/24) exhibited a clear boundary with delayed enhancement during the nephrographic and excretory phases.
Table 2: CT and MR imaging findings
Figure 1: Male, 10 years old, an oval mass with a clear boundary at the upper pole of the right kidney, the tumor maximum size was 7.1 × 6.8 cm (a), multiple calcification and patchy areas of low density were seen on unenhanced CT image (a and b), moderate enhancement during the corticomedullary phase, delayed enhancement during nephrographic phase and excretory phase (c-e)
Quantitative analysis
CT values of the renal cortex, medulla, and tumor in every phase and index of the tumor are shown in Table 3 .
Table 3: CT values of renal cortex, medulla and tumor in every phase and index of the tumor
The tumor enhancement curve [Figure 2 ] showed that the solid part of the tumors exhibited moderate enhancement during the corticomedullary phase and delayed enhancement during the nephrographic phase and excretory phase [Figure 1c -e ]. The enhancement of the solid part of the tumor was lower than that of the renal cortex during every phase, and the peak was demonstrated in the nephrographic phase.
Figure 2: Enhanced curve of tumor, renal cortex, and medulla. The enhancement of the tumor was lower than that of the renal cortex during every phase and higher than that of the renal medulla during the renal corticomedullary phase; the peak was demonstrated in the nephrographic phase (1, unenhanced; 2, renal corticomedullary phase; 3, renal nephrographic phase; 4, excretory phase)
The box plot [Figure 3 ] showed that the index of the tumor was highest during the unenhanced phase and had the largest discretization trend. With the injection of contrast agent, the tumor index reached the maximum in the renal nephrographic phase and was relatively concentrated. The tumor index was the most concentrated in the excretory phase.
Figure 3: Box-plot of the index of the tumor. The index of the tumor was highest in the unenhanced phase and had the largest discretization trend. The maximum was reached on nephrographic phase. The trend was relatively concentrated in the nephrographic phase and reached its highest concentration in the excretory phase
MRI
MR imaging findings are shown in Table 2 . Five patients underwent MR examination; among 5 patients, bilateral renal tumors were detected in 1 patient. On T1WI, 1 tumor (16.7%, 1/6) was isointense, 3 tumors (50%, 3/6) were iso, hypointense, and 2 tumors (33.3%, 2/6) were isointense and hyperintense [Figure 4a ]. On T2WI, 3 tumors (50%, 3/6) were hypointense, 2 tumors (33.3%, 2/6) were isointense, and 1 tumor (16.7%, 1/6) was mixed intense [Figure 4b ]. Remarkably, the solid part of the tumors was hypointense on T2WI. One tumor (16.7%, 1/6) showed a decreased signal on fat-saturated T2-weighted sequences. Four tumors (66.7%, 4/6) showed obvious diffusion limitation on DWI [Figure 4c ], with 2 tumors (33.3%, 2/6) showing unobvious diffusion limitation (apparent diffusion coefficient (ADC) value of 6 tumors: 0.948; 0.866; 2.908; 0.711; 0.841; 2.747; × 10- 3 mm2/s).
Figure 4: Female, 34 years old, an irregular mass at the upper pole of the left kidney, the tumor maximum size was 4.0 × 2.6 cm, MR examination showed an inhomogeneous mass, in overall signal, tumor showed as iso-intense on T1-weighted image (a), and hypo-intense on T2-weighted image, the septum inside of the tumor was showed as slightly hyperintense on T1-weighted image and hypo-intense on T2-weighted image (a and b), cystic hyperintense was observed on T2-weighted image (b), obvious diffusion limitation on DWI (c), uneven enhancement during the corticomedullary phase (d), delayed enhancement during the nephrographic phase (e), delayed enhancing septum on 5 min delayed phase (f)
Enhanced scanning showed that the solid part of the tumor exhibited mild enhancement during the corticomedullary phase [Figure 4d ], the enhancement of the tumor was lower than that of the renal cortex, the contrast agent was further filled, and delayed enhancement was observed during the nephrographic phase [Figure 4e ]. A delayed enhancing septum was also seen in the 5 min delayed phase [Figure 4f ].
Histologic, immunohistochemistry, and FISH
The overall view of the tumor is oval, indicating a dark red or brown color [Figure 5a ], with areas of hemorrhage and necrosis visible inside the tumor [Figure 5b ]. The tumor cells were arranged in a typical papillary structure [Figure 5c ], with some tubular, septae, and solid structures; some cytoplasm exhibited vesicle-like structures [Figure 5d ], large patchy areas of hemorrhage [Figure 5e ] were observed in the surroundings, and psammoma bodies were observed locally. Furthermore, typical foam cells and collagen bodies were observed. The tumor stroma was made of fibrous stroma, and peripheral inflammatory cell infiltration was observed [Figure 5f ]. Immunohistochemically, the nuclei of tumor cells showed TFE3 expression [Figure 5g ].
Further FISH analysis showed a positive result including only a single pair of separated green and red signals or a single green or red signal in male patients. In female patients, a positive result included a fused or closely approximated green–red signal pair (representing the uninvolved copy of the X chromosome) and a pair of split signals or a single green or red signal [Figure 5h ].
Figure 5: Male, 10 years old, an oval mass with a clear boundary at the upper pole of the right kidney, Tumor was oval in shape, dark red or brownish in surface (a), areas of hemorrhage and necrosis (b), tumor cells were arranged in typical papillary structure (HE10*40) (c), the clear cytoplasm of the tumor cells, partly calcified collagen bodies, large patchy areas of hemorrhage and psammoma bodies (HE10*20 ~ 40) (d and e) fibrous stroma and inflammatory cells (HE10*40) (f), Nuclei of tumor cells were expressed as brown by the immunohistochemical analysis, TFE3(+) (HE10*40) (g), TFE3 break-apart probe assay, a pair of split red and green signals and fusion red–green signals in this patient (h)
Intergroups analysis
Among 5 tumors in the adolescent and children group, tumors showed cystic component/necrosis (100%, 5/5), renal capsule disruption (80%, 4/5), capsule (80%, 4/5), calcification (60%, 3/5), fat (20%, 1/5); among 24 tumors in adult group, tumors showed cystic component/necrosis (100%, 24/24), renal capsule disruption (50%, 12/24), capsule (58%, 14/24), calcification (50%, 12/24), and fat (13%, 3/24). From August 2013 to November 2019, we searched 2,659 RCC patients, in which the incidence of Xp11.2RCC was 1.05%. The incidence rate in the adult group was 0.89% (23/2593), and in the adolescent group was 7.58% (5/66). The Chi-square test results showed that the aforementioned imaging characteristics of Xp11.2 RCC did not have significant correlation with age, whereas the incidence, that is, the incidence of the adolescent and child groups, was higher than that of the adult group. Of these, there were more adults in the patient group, and we further analyze this in the Discussion section. The incidence statistics between the two groups are shown in Table 4 .
Table 4: Incidence statistics between two groups
DISCUSSION
Xp11.2 RCC is a rare RCC subtype that is characterized by multiple ectopic Xp11.2 genes that cause fusion of the TFE3 gene. Xp11.2 RCC was first reported by De Jong in 1986.[ 16 ] It is insidious, with various nonspecific clinical symptoms, such as abdominal mass, abdominal pain, hematuria and some are found by physical examination.[ 13 , 16 ] In this study, 8 patients presented with gross hematuria; however, 20 patients were diagnosed with nonspecific symptoms, and 8 patients were identified upon physical examination, which is consistent with previous reports in the literature.
Patients in this study were aged 3 to 83 years old, with an average age of 47 years old. In addition, the average age of the adult group, which was 46.7 years old, was older than that in most previous studies. Our result is consistent with studies by Woo et al. ,[ 9 ] which might be related to the general hospital setting to which we belong rather than children’s hospitals. Of the 28 patients, 18 patients were male and 10 patients were female, consistent with the male-dominated report[ 20–22 ] and conflicting with female-dominated reports.[ 21 , 23–25 ]
In our study, among 8 patients with metastases in the adult group, only 1 patient remained alive; meanwhile, among 2 patients with metastases in the adolescent and pediatric groups, both underwent surgical clipping and had a good prognosis. This suggests that Xp11.2 RCC in adolescent and pediatric patients is less aggressive than that in adults.[ 10 , 26 ] Xp11.2 RCC in adolescent and pediatric patients who receive early treatment usually has a good prognosis even if metastases exist.
Moreover, we found that retroperitoneal lymph node metastasis existed in 5 patients (50%, 5/10), including two adolescent and pediatric patients. It was reported that Xp11.2RCC has a strong tendency to metastasize to retroperitoneal lymph nodes in one study, and it also indicated that the probabilities were approximately 33–50% in pediatric patients. Our results are consistent with the literature.[ 20 ]
We analyzed the incidence of contemporaneous whole Xp11.2RCC in our hospital in different age groups, and our result was consistent with previous reports. However, there were significantly more adults than children and adolescents, which might be related to the overall high incidence of renal cell carcinoma in adults. The results of the Chi-square test also showed that the imaging characteristics of Xp11.2 RCC had no significant correlation between the two groups. This may be related to the fact that the number of Xp11.2 RCC patients in this study was still small.
The imaging findings, including CT and MRI manifestations, reflected the histologic composition based on different imaging technologies; histologic features dictated the radiological features of the tumor. We hope to find a correlation between the imaging and histological findings to better understand the unique imaging manifestation of Xp11.2RCC .
First, the tumor stroma was made of fibrous stroma and peripheral inflammatory cell infiltration.[ 8 , 17 , 27–29 ] The tight arrangement linking cells under microscopy was assumed to be a focal solid component with hyperdensity on CT images[ 30 ] and hypointensity on T2-weighted MRI. Previous studies reported that hypointensity on T2WI was a characteristic feature of Xp11.2 RCC, in our study, interestingly, the sold component of all 6 tumors was consistent with previous reports in the literature.[ 9 , 11 , 27 ] In our opinion, this was related to the alignment of the tight arrangement linking cells and fiber stroma, and further evaluation is warranted to analyze this typical imaging characteristic by combining radiology and pathology.
Second, tumors showed cystic component/necrosis (100%, 29/29) on CT and MR images. This result suggested that cystic component/necrosis is an independent characteristic that has no relationship with age or tumor size, which is consistent with previous studies. This suggests that cystic component/necrosis is the most frequent change in imaging findings and could be one of the diagnoses of Xp11.2RCC .
Third, the other two common imaging findings were calcification and capsule.[ 24 ] Psammoma bodies under microscopy were considered small puncta and irregularly coarse hyperdense on CT images, with speckled dots hypointense on T1WI and T2WI. For the latter, a local fibrous component between the cells under microscopy was found as the enhanced septum in the excretory phase. The tumor capsule was composed of the fibrous stroma and showed as a delayed enhancement on the CT and MR images relative to the tumor solid; histologically, it was associated with a lower blood supply than the tumor solid. Small punctate, irregular coarse calcifications existed in 15 of 29 tumors, and capsules existed in 18 of 29 tumors, which would be one of the main diagnostic bases as well.
Fourth, we also found fat components in 4 tumors. Consistent with our results, several previous studies indicated that fat components may be associated with increased fatty metaplasia.[ 30 ] The imaging findings indicate that the fat component is important but not specific for diagnosis, especially the differential diagnosis with renal angiomyolipoma. Therefore, it is necessary to shorten the revision period for patients with atypical renal angiomyolipoma.
Finally, the tumor enhancement curve showed that the tumors were hypovascular, exhibited moderate enhancement during the corticomedullary phase and delayed enhancement during the nephrographic phase and excretory phase. The density and degree of the enhancement of tumors may be related to the compression of vasculature by fibrous tissues. Because of the large age span of our patients and because this was a retrospective study, the imaging examination used conventional scanning rather than individual scanning, and the tumor enhancement curve may have deviated, even if the result of the tumor enhancement curve was consistent with the previous literature.[ 11 ] The tumor index solved this problem well, and the box plot showed that the index tended to be concentrated after injection of the contrast agent and reached the maximum value in the nephrographic phase even if the discretization trend was still large during the unenhanced phase. This is a good indication that the peak value of the tumor occurs in the renal nephrographic phase.
The imaging findings of Xp11.2RCC often overlap with other tumors, which need to be combined with imaging and clinical features. RCC (renal clear cell carcinoma), as the most common renal tumor,[ 31–35 ] is easy to distinguish from Xp11.2RCC . The enhancement of RCC is usually higher than the renal cortex, the degree of enhancement is a good distinguishing characteristic. By contrary, CDC (renal collecting duct carcinoma) showed less enhancement than the renal medulla during every enhanced phases.[ 12 , 36 ] We found the enhancement of Xp11.2 RCC was higher than CDC. Papillary RCC is considered to be similar to Xp11.2 RCC. In previous studies, it was considered that large size, cystic/necrosis and calcification may be a good differential feature between tumors. Our study shows that may be a good distinguishing characteristic.[ 9 ] Papillary RCC is supposed to be small size (< 2 cm) and homogeneous density.[ 11 ] In addition, a clear boundary may also be a distinguishing characteristic from tumors without a clear boundary, such as CDC and poorly differentiated papillary RCC. Tumors in children should be distinguished from nephroblastoma. Studies have shown that the onset age of nephroblastoma is younger, with a peak of 2–3 years old. In this study, the onset age of Xp11.2RCC is significantly older.
Compared to the imaging analysis of Xp11.2RCC in previous studies, our study involved a comparison analysis between imaging features and histological features, which has helped radiologists and clinicians in their understanding of the disease. Second, given the rare incidence rates of Xp11.2RCC , we collected 28 patients from August 2013 to November 2019, which is more than the number included in most previous studies, although the number of cases is still low.
There are several limitations to our study. First, the number of patients was small due to the rarity of the tumor, but the number of patients in our study was larger than that in other radiologic studies. Second, the follow-up time was too short. Third, this is a retrospective study; only routine scanning images were available, and scanning parameter biases were inevitable.
Overall, the main imaging findings were cystic component/necrosis, capsule, calcification, renal capsule disruption, and metastases, especially lymph node metastasis, hypointense solid parts on T2WI, moderately enhancing solid parts in the tumors during the corticomedullary phase and delayed enhancement during the nephrographic phase and excretory phase, delayed capsular enhancement on CT and MRI and so on. When the aforementioned imaging features are revealed for a renal tumor, the Xp11.2 RCC diagnosis should be considered, especially in children or adolescents.
Ethical statement
The study design was approved by the Biomedical Research Ethic Committee of Shandong Provincial Hospital (SWYX: NO.2021-358).
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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