Journal of Pediatric Surgery 49 (2014) 539–542
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Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Biological characteristics of pediatric renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions Hong Cheng Song a, Ning Sun a,⁎, Wei Ping Zhang a, LeJian He b, Libing Fu b, ChengRu Huang a a b
Department of Urology, Beijing Children's Hospital of Capital Medical University, Beijing 100045, China Department of Pathology, Beijing Children's Hospital of Capital Medical University, Beijing 100045, China
a r t i c l e
i n f o
Article history: Received 12 June 2013 Received in revised form 9 October 2013 Accepted 9 October 2013 Key words: Children Xp11.2 translocation TFE3 gene Renal cell carcinoma
a b s t r a c t Purpose: To investigate the clinical features of pediatric Xp11.2 translocation renal cell carcinoma (RCC). Methods: A retrospective review of 22 cases over 35 years. Results: Xp11.2 translocation RCCs were identified in 13 boys and 9 girls with a median age of 10.5 years (range: 2.5–16 years). RCC presented with hematuria in 17, abdominal mass in 1, abdominal masses with hematuria in 2, abdominal pain with hematuria in 1, and as an incidental finding in 1 patient. Ten patients were classified stage I, 10 were stage III, and two were stage IV. Of the 10 patients with stage I RCCs, 3 patients with tumor measuring less than 7 cm had nephron-sparing surgery (NSS) and 17 patients underwent simple nephrectomy. A 15-cm tumor was incompletely removed in one patient and another patient with a 25cm × 18-cm × 15-cm tumor had gross residual. Of the 15 patients followed up between 6 months and 35 years, 13 were still living and 2 had died after surgery. Conclusions: Xp11.2 translocation RCC is the predominant form of pediatric RCC, associated with advanced stage at presentation. Nephrectomy is the usual treatment for RCC but NSS is an option for patients with tumors measuring b 7 cm. Patients with N + M0 maintained a favorable prognosis following surgery alone. © 2014 Elsevier Inc. All rights reserved.
Renal cell carcinoma (RCC) associated with Xp11.2 translocations/ TFE3 gene fusions was initially included in the WHO classification 2004 Edition [1]. It usually affects children more than adults with an incidence of 1.6% in adults, 15% in individuals under 45 years of age, and 20%–75% in children [2]. Because the disease has been reported only recently, its biological characteristics are largely unknown. We carried out a retrospective analysis (including clinical and pathological characteristics) of 22 cases of pediatric RCC associated with Xp11.2 translocations/TFE3 gene fusions at our institution over a 35-year period. 1. Materials and methods 1.1. Pathologic data Thirty patients were diagnosed with RCC in our hospital between 1973 and 2012. Two experienced pathologists performed TFE3 immunohistochemistry on preserved paraffin-embedded tumor tissue blocks and diagnosed 22 cases as RCC associated with Xp11.2 translocations/TFE3 gene fusions, according to tumor histology and the 2004 WHO classification of tumors of the urinary system and male genital organs. ⁎ Corresponding author. Department of Urology, Beijing Children's Hospital, Affiliated to Capital Medical University, Beijing 100045, China. Tel.: +1 13910515912. E-mail address: [email protected] (N. Sun). 0022-3468/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpedsurg.2013.10.005
1.2. General data The mean age of the 22 children with RCC associated with Xp11.2 translocations/TFE3 gene fusions was 10.5 years (range: 2.5– 16 years). Thirteen were male and 9 were female. The left kidney was involved in 12 cases and the right kidney in 10 cases. Clinical manifestations included 17 cases with painless gross hematuria (1 case with posttraumatic hematuria), 2 cases with hematuria and abdominal mass, 1 case with an abdominal mass, and 1 case with hematuria and abdominal pain, and 1 case was found incidentally during an ultrasound examination. Two cases with weight loss and anemia, and three cases with a palpable solid mass in the affected abdomen were found on physical examination. 1.3. Staging According to the 2010 TNM classification [3], T1N0M0 was found in 10 cases, T1N1M0 in 6 cases, T2N1M0 in 2 cases, T3N1M0 in 2 cases, and T4N1M0 in 2 cases. Ten cases were classified as stage I, 10 cases as stage III, and 2 cases as stage IV. 1.4. Diagnosis and treatment Abdominal sonography, contrast-enhanced computed tomography (CT) and intravenous urography (IVU) were used to diagnose renal tumor prior to surgery. On unenhanced CT, each mass had a
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density less than (or approximating) the density of normal renal parenchyma with cystic changes and calcification. In addition, each mass was surrounded by a membrane. Contrast-enhanced CT revealed mild tumoral enhancement (Fig. 1). The tumor diameter was less than 7 cm in 3 of 15 cases diagnosed as stage I RCC, for which nephronsparing surgery (NSS) was performed. In one case, intraoperative frozen section revealed a hamartoma, which was later proved to be RCC by postoperative pathological examination. In addition, as there were metastases in the perirenal fat and local lymph nodes in this patient, we performed a secondary nephrectomy. For the two patients classified as T4N1M0, subtotal tumor resection was performed for one patient with a tumor measuring N 15 cm in diameter, (which enveloped the abdominal aorta and the inferior vena cava.) In the other patient, the tumor measured 25 cm × 18 cm × 15 cm, the removed lymph nodes weighed 300 g, and gross residual tumor was observed during the surgery. Nephrectomy was performed on the affected kidney in the remaining 17 patients. The mean tumor diameter measured 7.2 cm (range: 2.5–25 cm). Postoperative radiotherapy was performed on two patients and postoperative chemotherapy administered over 6–15 months was performed on two other patients. One patient underwent postoperative interferon therapy and one patient underwent Nexavar (sorafenib) treatment. 2. Results Fifteen (68.2%) of 22 patients were followed up. The mean followup period was 12.25 years (range: 6 months to 35 years, median: 10.5 years). Postoperative recurrence occurred in two patients with T4N1M0 tumor. One of these two patients underwent a second operation and the other underwent a second surgery together with adjuvant sorafenib treatment. Both patients died approximately 1 year after the first surgery. Tumor-free survival was observed in 13 patients (86.6%). Seven patients survived more than 5 years without tumor recurrence, including three patients with T1N0M0 tumor, two with T1N1M0 tumor, and two with T2N1M0 tumor. Three of these patients (T1N0M0, T1N1M0, and T2N1M0) survived more than 20 years, and of these three, two patients married and raised children. One patient (T1N1M0) survived 4 years without tumor recurrence and one patient (T1N0M0) survived 3 years. Follow-up lasted less than 3 years in three patients (all T1N0M0). In the patient who underwent partial nephrectomy, IVU was carried out with excellent outcome.
translocation of its different subtypes [1]. The fusion of the TFE3 gene with several different genes, including ASPL(17q25), PRCC(1q21), PSF(1q34), NonO(Xq12) and CLTC(17q23) has been identified to date [4]. Another subset of renal carcinoma is associated with a translocation t(6;11)(p21;q12) involving the transcription factor EB (TFEB) transcription. The two most common Xp11 translocation RCCs are those bearing the t(X;1)(p11.2;q21) which fuses the PRCC and TFE3 gene [5] and the t(X;17)(p11.2;q25) which fuses the ASPL and TFE3 genes[6]. The renal carcinoma associated with translocation primarily affects children and adolescents. So far, 148 cases with TFE3 translocation renal carcinomas have been reported in the literature. TFEB renal carcinomas are even rare with 21 cases reported in the literature [7]. Twenty-two (73.3%) of 30 patients with RCC diagnosed at our institution had the Xp11.2 translocation. TFEB translocation RCC was not suspicious in our patients by molecular pattern; TFEB immunostainings has not been done. The Xp11.2 translocation renal carcinoma can occur secondary to chemotherapy. Argani et al. [8] reported on 39 patients with Xp11.2 translocation renal cell carcinoma, in which 6 patients had undergone chemotherapy before admission because of malignant tumor or autoimmune disease. The interval between chemotherapy and the time of diagnosis of renal carcinoma was between 4 and 13 years. In the current study, no children underwent chemotherapy before admission. There is no significant difference between Xp11.2 translocation RCC and other RCCs with regard to clinical manifestations and imaging characteristics. Gross hematuria is the main manifestation in children with RCC. The classical triad of flank pain, hematuria, and palpable abdominal mass is rarely seen. In the current study, painless gross hematuria was observed in 17 cases, accounting for 77.3% of cases. 3.1. Pathology of the Xp11.2 translocation RCC The gross morphology of the Xp11.2 translocation RCC is similar to that of other renal carcinomas, and on cross section, the tumor appears brown in color with associated necrosis and hemorrhage in the majority of cases (Fig. 2). The most characteristic pathological manifestation is a papillary structure composed of clear cells, which is rarely seen in adult patients and is often associated with nest-shaped structures composed of tumor cells containing eosinophilic granules (Fig. 3). Hyaline degeneration and psammoma body formation can be observed in the stroma (Fig. 4) [1].
3. Discussion Renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions was named according to the fusion gene formed by Xp11.2
Fig. 1. Contrast-enhanced CT, right renal lesion.
Fig. 2. The tumor appears brown in color with associated necrosis and hemorrhage.
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Fig. 3. Microscopic finding of Xp11.2 translocation RCC: typical papillary structure composed of clear cells (HE ×200).
Fig. 5. TFE3 immunohistochemistry of tumor cells shows nuclear labeling for TFE3 protein (HE ×400).
The diagnosis of an Xp11.2 translocation RCC is based on microscopic appearance, TFE3 immunostaining, and genetic analyses. Xp11.2 translocation RCC is characterized by chromosomal translocations including Xp11.2, which may result in gene fusions including the TFE3 transcription factor gene. These gene fusions ultimately express TFE3 fusion protein. The TFE3 fusion protein is an immunologic marker of RCC associated with Xp11.2 translocations/TFE3 gene fusions, and has a relatively high sensitivity (97.5%) and specificity (99.6 %) [9]. The positive expression in the nucleus of tumor cells (Fig. 5) together with the morphological characteristics of the tumor is a relatively accurate and convenient method for diagnosing this kind of RCC. However, its nuclear expression cannot directly indicate the translocation of the TFE3 gene. At the current time, fluorescence in situ hybridization (FISH) for TFE3 rearrangements is the optimal way to detect Xp11.2 translocation carcinomas [10].
be preserved [11]. In the current study, we performed NSS for three patients with a tumor diameter less than 7 cm. In one case, intraoperative frozen section revealed hamartoma, which was later proved to be RCC by postoperative pathological examination. In addition, there were metastases in the perirenal fat and local lymph nodes. We performed secondary nephrectomy in this patient and did not carry out any adjuvant therapy. This patient survived for 4 years without tumor recurrence. One of the other two patients survived 6 years without tumor recurrence and the other patient survived 1 year after surgery. Lymph node metastasis occurs commonly in patients with pediatric Xp11.2 translocation RCC. However, analysis of the data from the recent literature shows that children presenting with regional lymph node involvement and lack of hematogenous spread appear to have a favorable short-term prognosis. TFE3+N+M0 classification does not reduce survival. Geller et al. [2] reviewed 15 patients with TFE3+N+M0. The average follow-up duration was 6.3 years (range: 0.3–15.5 years) and tumor-free survival was observed in 13 cases (86.7%). Geller et al. concluded that only surgical resection was required for patients with pediatric TFE3+N+M0 and neither adjuvant therapy or lymph node dissection was needed because no effective, nontoxic medication was currently available. In the present study, among the six patients with N+M0 Xp11.2 translocation RCC, tumor-free survival was seen in 5 cases. Two patients have been followed up for more than 20 years and these patients married and are raising children. The prognosis for our cases was, therefore, similar to that of Geller's cases. We also felt that regional lymph node involvement did not affect prognosis for Xp11.2 translocation RCC cases. At present, simple surgery is felt to be sufficient for treatment without lymph node dissection and postoperative adjuvant treatment.
3.2. Treatment of the Xp11.2 translocation RCC Like other RCCs, Xp11.2 translocation RCC is not sensitive to radiotherapy or chemotherapy. Radical nephrectomy (RN) is the primary method of treatment. For localized RCC (T1-T2N0M0 RCC, traditionally known as early-stage RCC), numerous studies have shown that NSS can achieve satisfactory outcomes similar to RN for early-stage RCC less than 4–7 cm in diameter, and renal function can
3.3. Biological behavior of the Xp11.2 translocation RCC
Fig. 4. Psammoma body formation in the stroma (HE ×100).
Because Xp11.2 translocation RCC has only recently been identified as an independent subtype of RCC, few clinical studies have been performed. Thus, little is known concerning its biological behavior. It has been reported that this type of renal carcinoma is highly malignant in both children and adults. Argani et al. [12] reported on 28 adult patients with Xp11.2 translocation RCC, including 16 patients with stage III-IV cancers. Lymph node metastasis occurred in 11 of 13 patients who could be evaluated. In the current study, among 22 pediatric cases with Xp11.2 translocation RCC, 11 cases (52.4%) were high-grade tumors. We also treated eight patients with non-Xp11.2 translocation RCC at the same time. The clinical staging included six cases with T1N0M0, one with T2N1M0 and one with T4N1M1; i.e.,
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tumors in two cases (25%) were high grade. In a retrospective review by Geller et al. [2], among 75 patients with pediatric RCC, 40 were TFE + patients and 35 were TFE − patients. A total of 26 patients (65%) with TFE + disease presented with advanced stage disease and 12 TFE− patients (35%) presented with advanced stage disease. Combining our cases with the retrospective review by Geller et al., a total of 37 (60.6%) of 61 TFE3+ patients presented with advanced stage disease, and 14 (32.5%) of 43 TFE− patients presented with low-stage disease. The result of chi-square analysis demonstrated a P value less than 0.05 (P = 0.005); thus, there was a significant difference between TFE3+ and TFE3 − groups. Hence, patients with Xp11.2 translocation RCC have more advanced-stage disease compared to those with other types of renal cancer. At present, Xp11.2 translocation RCC has a high degree of invasiveness and a rapid disease course in adult patients. Komai et al. [13] reported on seven patients with adult Xp11.2 translocation RCC, in which five were classified as stagees III–IV and two patients died within 1 year. Meyer [14] reported on five patients with adult Xp11.2 translocation RCC. All five patients were in the late stage of their disease with distant metastasis, rapid disease course, and poor outcomes with an average survival of 18 months. However, according to recent studies, the biological behavior of pediatric Xp11.2 translocation RCC is relatively inert, and its prognosis is better than that of adult Xp11.2 translocation RCC [2,15]. According to the review by Armah and Parwani [15], clinical and pathological heterogeneity may exist between pediatric Xp11.2 translocation RCC and adult Xp11.2 translocation RCC, which require different treatments. Armah and Parwani also considered that Xp11.2 translocation RCC has a high degree of invasiveness, a rapid disease course, and a poor prognosis in adolescents and adults over the age of 16 years, compared to children. In our study, only one patient was over the age of 16 years and had a tumor size of 25 cm × 18 cm × 15 cm with 300 g of lymph nodes removed at surgery. Although we gave sorafenib after surgery, the patient died of recurrent tumor within 1 year. Tumor-free survival was observed in 8 of 11 of our patients with Xp11.2 translocation RCC during more than 3 years of follow-up, and all 7 patients with nonXp11.2 translocation-related RCC survived. The 3-year tumor-free survival rates were 74% (20/27) in children with Xp11.2 translocation RCC and 91% (33/36) in children with non-Xp11.2 translocationrelated RCC [2,16,17]. The result of chi-square test showed that the P value was more than 0.05 (P = 0.123); thus, there was no significant difference between pediatric Xp11.2 translocation RCC and other types of RCC with regard to prognosis. In conclusion, Xp11.2 translocation RCC is the predominant type of pediatric RCC. The Xp11.2 translocation RCC easily invades regional lymph nodes and is highly malignant. However, it is biologically inert in children and its prognosis is not significantly different from that of
other types of RCC. Since there are few studies on this type of renal carcinoma, additional studies with larger sample sizes should be carried out to fully characterize the biological activity of Xp11.2 translocation RCC. In addition, long-term follow-up is needed before the true outcome of this type of RCC can be determined, since these tumors have the capacity to occur late [18].
References [1] Argani P, Ladanyi M. Renal carcinomas associated with Xp11 translocations/TFE3 gene fusions. For: Eble JN, Sauter G, Epstein JI, et al, eds. World Health Organization classification of tumours: pathology and genetics of tumours of the urinary system and male genital organs. IARC Press, Lyon 2004,37-38. [2] Geller JI, Argani P, Adeniran A, et al. Translocation renal cell carcinoma: lack of negative impact due to lymph node spread. Cancer 2008;112:1607–16. [3] Edge SB, Byrd DR, Compton CC, et al. Kidney. AJCC cancer staging manual, 7th edn. Springer, 2010, NewYork. [4] Kuroda N, Mikami S, Pan CC, et al. Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on pathobiological aspect. Histol Histopathol 2012;27:133–40. [5] Argani P, Antonescu CR, Couturier J, et al. PRCC-TFE3 renal cell carcinomas: Morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X;1)(p11.2;q21). Am J Surg Pathol 2002;26:1553–66. [6] Argani P, Antonescu CR, Illei PB, et al. Primary renal cell neoplasms with the ASPLTFE3 gene fusion of alveloar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 2001;159:179–92. [7] Argani P, Yonescu R, Morsberger L, et al. Molecular confirmation of t(6;11)(p21; q12) renal cell carcinoma in archival paraffin-embedded material using a breakapart TFEB FISH assay expands its clinicopathlolgic spectrum. Am J Surg Pathol 2012;36:1516–26. [8] Argani P, Lae M, Ballard ET, et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 2006;24:1529–34. [9] Argani P, Lal P, Hutchinson B, et al. Aberrrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol 2003;27:750–61. [10] Green WM, Yonescu R, Morsberger L, et al. Utilization of a TFE3 break-apart FISH assay in a renal tumor consultation service. Am J Surg Pathol 2013;8:1150–63. [11] Manikandan R, Srinivasan V, Rane A. Which is the real goldstandard for small volume renal carcinoma? Radical nephrectomy versus nephron sparing surgery. J Endourol 2004;18:39–44. [12] Argani P, Semra O, Satish K, et al. Xp11.2 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007;31:1149–60. [13] Komai Y, Fujiwara M, Fujii Y, et al. Adult Xp11 translocation renal cell carcinoma diagnosed by cytogenetics and immunohistochemistry. Clin Cancer Res 2009;15: 1170–6. [14] Meyer PN, Clark JI, Flanigan RC, et al. Xp11.2 translocation renal cell carcinoma with very aggressive course in five adults. Am J Clin Pathol 2007;128:70–9. [15] Armah HB, Parwani AV. Xp11.2 translocation renal cell carcinoma. Arch Pathol Lab Med 2010;134:124–9. [16] Helmy T, Sarhan O, Sarhan M, et al. Renal cell carcinoma in children: single-center experience. J Pediatr Surg 2009;44:1750–3. [17] Selle B, Furtwangler R, Graf N, et al. Population-Based study of renal cell carcinoma in children in Germany, 1980–2005. Cancer,2006,107:2906–2914. [18] Ross H, Martignoni G, Argani P. Renal cell carcinoma with clear cell and papillary features. Arch Pathol Lab Med 2012;136:391–9.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Biological characteristics of pediatric renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions Hong Cheng Song a, Ning Sun a,⁎, Wei Ping Zhang a, LeJian He b, Libing Fu b, ChengRu Huang a a b
Department of Urology, Beijing Children's Hospital of Capital Medical University, Beijing 100045, China Department of Pathology, Beijing Children's Hospital of Capital Medical University, Beijing 100045, China
a r t i c l e
i n f o
Article history: Received 12 June 2013 Received in revised form 9 October 2013 Accepted 9 October 2013 Key words: Children Xp11.2 translocation TFE3 gene Renal cell carcinoma
a b s t r a c t Purpose: To investigate the clinical features of pediatric Xp11.2 translocation renal cell carcinoma (RCC). Methods: A retrospective review of 22 cases over 35 years. Results: Xp11.2 translocation RCCs were identified in 13 boys and 9 girls with a median age of 10.5 years (range: 2.5–16 years). RCC presented with hematuria in 17, abdominal mass in 1, abdominal masses with hematuria in 2, abdominal pain with hematuria in 1, and as an incidental finding in 1 patient. Ten patients were classified stage I, 10 were stage III, and two were stage IV. Of the 10 patients with stage I RCCs, 3 patients with tumor measuring less than 7 cm had nephron-sparing surgery (NSS) and 17 patients underwent simple nephrectomy. A 15-cm tumor was incompletely removed in one patient and another patient with a 25cm × 18-cm × 15-cm tumor had gross residual. Of the 15 patients followed up between 6 months and 35 years, 13 were still living and 2 had died after surgery. Conclusions: Xp11.2 translocation RCC is the predominant form of pediatric RCC, associated with advanced stage at presentation. Nephrectomy is the usual treatment for RCC but NSS is an option for patients with tumors measuring b 7 cm. Patients with N + M0 maintained a favorable prognosis following surgery alone. © 2014 Elsevier Inc. All rights reserved.
Renal cell carcinoma (RCC) associated with Xp11.2 translocations/ TFE3 gene fusions was initially included in the WHO classification 2004 Edition [1]. It usually affects children more than adults with an incidence of 1.6% in adults, 15% in individuals under 45 years of age, and 20%–75% in children [2]. Because the disease has been reported only recently, its biological characteristics are largely unknown. We carried out a retrospective analysis (including clinical and pathological characteristics) of 22 cases of pediatric RCC associated with Xp11.2 translocations/TFE3 gene fusions at our institution over a 35-year period. 1. Materials and methods 1.1. Pathologic data Thirty patients were diagnosed with RCC in our hospital between 1973 and 2012. Two experienced pathologists performed TFE3 immunohistochemistry on preserved paraffin-embedded tumor tissue blocks and diagnosed 22 cases as RCC associated with Xp11.2 translocations/TFE3 gene fusions, according to tumor histology and the 2004 WHO classification of tumors of the urinary system and male genital organs. ⁎ Corresponding author. Department of Urology, Beijing Children's Hospital, Affiliated to Capital Medical University, Beijing 100045, China. Tel.: +1 13910515912. E-mail address: [email protected] (N. Sun). 0022-3468/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpedsurg.2013.10.005
1.2. General data The mean age of the 22 children with RCC associated with Xp11.2 translocations/TFE3 gene fusions was 10.5 years (range: 2.5– 16 years). Thirteen were male and 9 were female. The left kidney was involved in 12 cases and the right kidney in 10 cases. Clinical manifestations included 17 cases with painless gross hematuria (1 case with posttraumatic hematuria), 2 cases with hematuria and abdominal mass, 1 case with an abdominal mass, and 1 case with hematuria and abdominal pain, and 1 case was found incidentally during an ultrasound examination. Two cases with weight loss and anemia, and three cases with a palpable solid mass in the affected abdomen were found on physical examination. 1.3. Staging According to the 2010 TNM classification [3], T1N0M0 was found in 10 cases, T1N1M0 in 6 cases, T2N1M0 in 2 cases, T3N1M0 in 2 cases, and T4N1M0 in 2 cases. Ten cases were classified as stage I, 10 cases as stage III, and 2 cases as stage IV. 1.4. Diagnosis and treatment Abdominal sonography, contrast-enhanced computed tomography (CT) and intravenous urography (IVU) were used to diagnose renal tumor prior to surgery. On unenhanced CT, each mass had a
540
H.C. Song et al. / Journal of Pediatric Surgery 49 (2014) 539–542
density less than (or approximating) the density of normal renal parenchyma with cystic changes and calcification. In addition, each mass was surrounded by a membrane. Contrast-enhanced CT revealed mild tumoral enhancement (Fig. 1). The tumor diameter was less than 7 cm in 3 of 15 cases diagnosed as stage I RCC, for which nephronsparing surgery (NSS) was performed. In one case, intraoperative frozen section revealed a hamartoma, which was later proved to be RCC by postoperative pathological examination. In addition, as there were metastases in the perirenal fat and local lymph nodes in this patient, we performed a secondary nephrectomy. For the two patients classified as T4N1M0, subtotal tumor resection was performed for one patient with a tumor measuring N 15 cm in diameter, (which enveloped the abdominal aorta and the inferior vena cava.) In the other patient, the tumor measured 25 cm × 18 cm × 15 cm, the removed lymph nodes weighed 300 g, and gross residual tumor was observed during the surgery. Nephrectomy was performed on the affected kidney in the remaining 17 patients. The mean tumor diameter measured 7.2 cm (range: 2.5–25 cm). Postoperative radiotherapy was performed on two patients and postoperative chemotherapy administered over 6–15 months was performed on two other patients. One patient underwent postoperative interferon therapy and one patient underwent Nexavar (sorafenib) treatment. 2. Results Fifteen (68.2%) of 22 patients were followed up. The mean followup period was 12.25 years (range: 6 months to 35 years, median: 10.5 years). Postoperative recurrence occurred in two patients with T4N1M0 tumor. One of these two patients underwent a second operation and the other underwent a second surgery together with adjuvant sorafenib treatment. Both patients died approximately 1 year after the first surgery. Tumor-free survival was observed in 13 patients (86.6%). Seven patients survived more than 5 years without tumor recurrence, including three patients with T1N0M0 tumor, two with T1N1M0 tumor, and two with T2N1M0 tumor. Three of these patients (T1N0M0, T1N1M0, and T2N1M0) survived more than 20 years, and of these three, two patients married and raised children. One patient (T1N1M0) survived 4 years without tumor recurrence and one patient (T1N0M0) survived 3 years. Follow-up lasted less than 3 years in three patients (all T1N0M0). In the patient who underwent partial nephrectomy, IVU was carried out with excellent outcome.
translocation of its different subtypes [1]. The fusion of the TFE3 gene with several different genes, including ASPL(17q25), PRCC(1q21), PSF(1q34), NonO(Xq12) and CLTC(17q23) has been identified to date [4]. Another subset of renal carcinoma is associated with a translocation t(6;11)(p21;q12) involving the transcription factor EB (TFEB) transcription. The two most common Xp11 translocation RCCs are those bearing the t(X;1)(p11.2;q21) which fuses the PRCC and TFE3 gene [5] and the t(X;17)(p11.2;q25) which fuses the ASPL and TFE3 genes[6]. The renal carcinoma associated with translocation primarily affects children and adolescents. So far, 148 cases with TFE3 translocation renal carcinomas have been reported in the literature. TFEB renal carcinomas are even rare with 21 cases reported in the literature [7]. Twenty-two (73.3%) of 30 patients with RCC diagnosed at our institution had the Xp11.2 translocation. TFEB translocation RCC was not suspicious in our patients by molecular pattern; TFEB immunostainings has not been done. The Xp11.2 translocation renal carcinoma can occur secondary to chemotherapy. Argani et al. [8] reported on 39 patients with Xp11.2 translocation renal cell carcinoma, in which 6 patients had undergone chemotherapy before admission because of malignant tumor or autoimmune disease. The interval between chemotherapy and the time of diagnosis of renal carcinoma was between 4 and 13 years. In the current study, no children underwent chemotherapy before admission. There is no significant difference between Xp11.2 translocation RCC and other RCCs with regard to clinical manifestations and imaging characteristics. Gross hematuria is the main manifestation in children with RCC. The classical triad of flank pain, hematuria, and palpable abdominal mass is rarely seen. In the current study, painless gross hematuria was observed in 17 cases, accounting for 77.3% of cases. 3.1. Pathology of the Xp11.2 translocation RCC The gross morphology of the Xp11.2 translocation RCC is similar to that of other renal carcinomas, and on cross section, the tumor appears brown in color with associated necrosis and hemorrhage in the majority of cases (Fig. 2). The most characteristic pathological manifestation is a papillary structure composed of clear cells, which is rarely seen in adult patients and is often associated with nest-shaped structures composed of tumor cells containing eosinophilic granules (Fig. 3). Hyaline degeneration and psammoma body formation can be observed in the stroma (Fig. 4) [1].
3. Discussion Renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions was named according to the fusion gene formed by Xp11.2
Fig. 1. Contrast-enhanced CT, right renal lesion.
Fig. 2. The tumor appears brown in color with associated necrosis and hemorrhage.
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Fig. 3. Microscopic finding of Xp11.2 translocation RCC: typical papillary structure composed of clear cells (HE ×200).
Fig. 5. TFE3 immunohistochemistry of tumor cells shows nuclear labeling for TFE3 protein (HE ×400).
The diagnosis of an Xp11.2 translocation RCC is based on microscopic appearance, TFE3 immunostaining, and genetic analyses. Xp11.2 translocation RCC is characterized by chromosomal translocations including Xp11.2, which may result in gene fusions including the TFE3 transcription factor gene. These gene fusions ultimately express TFE3 fusion protein. The TFE3 fusion protein is an immunologic marker of RCC associated with Xp11.2 translocations/TFE3 gene fusions, and has a relatively high sensitivity (97.5%) and specificity (99.6 %) [9]. The positive expression in the nucleus of tumor cells (Fig. 5) together with the morphological characteristics of the tumor is a relatively accurate and convenient method for diagnosing this kind of RCC. However, its nuclear expression cannot directly indicate the translocation of the TFE3 gene. At the current time, fluorescence in situ hybridization (FISH) for TFE3 rearrangements is the optimal way to detect Xp11.2 translocation carcinomas [10].
be preserved [11]. In the current study, we performed NSS for three patients with a tumor diameter less than 7 cm. In one case, intraoperative frozen section revealed hamartoma, which was later proved to be RCC by postoperative pathological examination. In addition, there were metastases in the perirenal fat and local lymph nodes. We performed secondary nephrectomy in this patient and did not carry out any adjuvant therapy. This patient survived for 4 years without tumor recurrence. One of the other two patients survived 6 years without tumor recurrence and the other patient survived 1 year after surgery. Lymph node metastasis occurs commonly in patients with pediatric Xp11.2 translocation RCC. However, analysis of the data from the recent literature shows that children presenting with regional lymph node involvement and lack of hematogenous spread appear to have a favorable short-term prognosis. TFE3+N+M0 classification does not reduce survival. Geller et al. [2] reviewed 15 patients with TFE3+N+M0. The average follow-up duration was 6.3 years (range: 0.3–15.5 years) and tumor-free survival was observed in 13 cases (86.7%). Geller et al. concluded that only surgical resection was required for patients with pediatric TFE3+N+M0 and neither adjuvant therapy or lymph node dissection was needed because no effective, nontoxic medication was currently available. In the present study, among the six patients with N+M0 Xp11.2 translocation RCC, tumor-free survival was seen in 5 cases. Two patients have been followed up for more than 20 years and these patients married and are raising children. The prognosis for our cases was, therefore, similar to that of Geller's cases. We also felt that regional lymph node involvement did not affect prognosis for Xp11.2 translocation RCC cases. At present, simple surgery is felt to be sufficient for treatment without lymph node dissection and postoperative adjuvant treatment.
3.2. Treatment of the Xp11.2 translocation RCC Like other RCCs, Xp11.2 translocation RCC is not sensitive to radiotherapy or chemotherapy. Radical nephrectomy (RN) is the primary method of treatment. For localized RCC (T1-T2N0M0 RCC, traditionally known as early-stage RCC), numerous studies have shown that NSS can achieve satisfactory outcomes similar to RN for early-stage RCC less than 4–7 cm in diameter, and renal function can
3.3. Biological behavior of the Xp11.2 translocation RCC
Fig. 4. Psammoma body formation in the stroma (HE ×100).
Because Xp11.2 translocation RCC has only recently been identified as an independent subtype of RCC, few clinical studies have been performed. Thus, little is known concerning its biological behavior. It has been reported that this type of renal carcinoma is highly malignant in both children and adults. Argani et al. [12] reported on 28 adult patients with Xp11.2 translocation RCC, including 16 patients with stage III-IV cancers. Lymph node metastasis occurred in 11 of 13 patients who could be evaluated. In the current study, among 22 pediatric cases with Xp11.2 translocation RCC, 11 cases (52.4%) were high-grade tumors. We also treated eight patients with non-Xp11.2 translocation RCC at the same time. The clinical staging included six cases with T1N0M0, one with T2N1M0 and one with T4N1M1; i.e.,
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tumors in two cases (25%) were high grade. In a retrospective review by Geller et al. [2], among 75 patients with pediatric RCC, 40 were TFE + patients and 35 were TFE − patients. A total of 26 patients (65%) with TFE + disease presented with advanced stage disease and 12 TFE− patients (35%) presented with advanced stage disease. Combining our cases with the retrospective review by Geller et al., a total of 37 (60.6%) of 61 TFE3+ patients presented with advanced stage disease, and 14 (32.5%) of 43 TFE− patients presented with low-stage disease. The result of chi-square analysis demonstrated a P value less than 0.05 (P = 0.005); thus, there was a significant difference between TFE3+ and TFE3 − groups. Hence, patients with Xp11.2 translocation RCC have more advanced-stage disease compared to those with other types of renal cancer. At present, Xp11.2 translocation RCC has a high degree of invasiveness and a rapid disease course in adult patients. Komai et al. [13] reported on seven patients with adult Xp11.2 translocation RCC, in which five were classified as stagees III–IV and two patients died within 1 year. Meyer [14] reported on five patients with adult Xp11.2 translocation RCC. All five patients were in the late stage of their disease with distant metastasis, rapid disease course, and poor outcomes with an average survival of 18 months. However, according to recent studies, the biological behavior of pediatric Xp11.2 translocation RCC is relatively inert, and its prognosis is better than that of adult Xp11.2 translocation RCC [2,15]. According to the review by Armah and Parwani [15], clinical and pathological heterogeneity may exist between pediatric Xp11.2 translocation RCC and adult Xp11.2 translocation RCC, which require different treatments. Armah and Parwani also considered that Xp11.2 translocation RCC has a high degree of invasiveness, a rapid disease course, and a poor prognosis in adolescents and adults over the age of 16 years, compared to children. In our study, only one patient was over the age of 16 years and had a tumor size of 25 cm × 18 cm × 15 cm with 300 g of lymph nodes removed at surgery. Although we gave sorafenib after surgery, the patient died of recurrent tumor within 1 year. Tumor-free survival was observed in 8 of 11 of our patients with Xp11.2 translocation RCC during more than 3 years of follow-up, and all 7 patients with nonXp11.2 translocation-related RCC survived. The 3-year tumor-free survival rates were 74% (20/27) in children with Xp11.2 translocation RCC and 91% (33/36) in children with non-Xp11.2 translocationrelated RCC [2,16,17]. The result of chi-square test showed that the P value was more than 0.05 (P = 0.123); thus, there was no significant difference between pediatric Xp11.2 translocation RCC and other types of RCC with regard to prognosis. In conclusion, Xp11.2 translocation RCC is the predominant type of pediatric RCC. The Xp11.2 translocation RCC easily invades regional lymph nodes and is highly malignant. However, it is biologically inert in children and its prognosis is not significantly different from that of
other types of RCC. Since there are few studies on this type of renal carcinoma, additional studies with larger sample sizes should be carried out to fully characterize the biological activity of Xp11.2 translocation RCC. In addition, long-term follow-up is needed before the true outcome of this type of RCC can be determined, since these tumors have the capacity to occur late [18].
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