Pediatric Renal Cell Carcinoma: Clinical, Pathologic, and Molecular Abnormalities Associated With the Members of the MiT Transcription Factor Family

Abstract and Introduction

Abstract

We describe the clinical features, outcome, pathology, cytogenetics, and molecular aspects of 13 pediatric papillary renal cell carcinomas during a 19-year period. Seven cases (54%) had translocations involving Xp11.2 (TFE3). They were identified by cytogenetic, molecular, and/or immunohistochemical analyses. All Xp11.2+ translocations were TFE3+ by immunostaining. Cytogenetic and/or polymerase chain reaction analyses identified 3 cases with t(X17) and 1 case with t(1;17), and all had additional translocations. Histologic features in common in TFE3+ tumors also were present in some TFE3– tumors. One TFE3– tumor had complex cytogenetic abnormalities, 55XY,+2, del(3)(p14),+7,+8,+12,+13,+16,+17,+20[11], and 2 cases had normal karyotypes. None had t(6;11)/TFEB+ immunostaining. Five cases had focal, weak MITF tumor immunostaining.

The key clinical findings were as follows: (1) The presence of an Xp11.2 (TFE3) translocation frequently is associated with advanced stage at initial examination. (2) All patients who underwent complete, partial nephrectomy with clear margins (adequate only for stage 1) and resection of metastases were alive and relapse-free at last follow-up. (3) The mean ± SD event-free survival and overall survival rates at 5 years were both 92% ± 7.4%. (4) One patient with a TFE3+ and MITF+ tumor and 66-87,XXY,der(1)t(1;8)del(4)(q?) der(11)t(11;15)der17t(X;17) abnormalities died 9 months after diagnosis.

Introduction

Renal cell carcinoma (RCC) is a rare childhood tumor constituting fewer than 0.3% of all tumors and 2.6% of renal neoplasms in children and adolescents younger than 15 years,^[1] and, given its rarity, it has been difficult to determine whether pediatric RCC differs from its adult counterpart. However, reports suggest that the clinical and pathologic features of pediatric RCC are different from those seen in older adolescents and young adults.^[2] In children, most cases consist of papillary histologic features,^[3] whereas among the 4 types of RCC (clear cell, papillary, chromophobe, and collecting duct), the clear cell type predominates in adults (75%); in younger adults (18-45 years), Cao et al^[4] found that 53% were clear cell, 12% were papillary, 8% were chromophobe, 2% were oncocytoma, and 26% were in a miscellaneous group (that comprised Xp11.2 translocation carcinoma, renal medullary carcinoma, primitive neuroectodermal tumor, cystic nephroma, metanephric biphasic tumor, and mucinous tubular and spindle cell carcinoma).

Cytogenetic and molecular studies have suggested that abnormalities in the Xp11.2 region involving the TFE3 gene might account for a significant proportion of pediatric RCC, with these tumors representing a subset of papillary RCC. Therefore, RCC associated with Xp11.2 translocations/TFE3 gene fusion is listed as a separate entity in the World Health Organization (WHO) classification of tumors of the urinary system.^[5] Moreover, multiple chromosomal translocation partners can be fused to TFE3 at Xp11.2 in this subset of RCCs. The 2 most common forms are the t(X;17)(p11.2;q25) translocation that fuses the transcription factor gene TFE3 with the ASPL gene on 17q25,^[6-15] and the t(X;1)(p11.2;q21) or the t(X;1)(p11.2;p34) that fuses the TFE3 transcription factor gene on Xp11.2 with the PRCC gene at 1q21.2^[14-27] or the PSF gene on 1p34.^{[6,8,14,28-31]} The rarer forms of chromosomal abnormalities that involve TFE3 at Xp11.2 are the TFE3 fusions with NonO at Xq12,^[31] del(X)(p11),^[31] inv(X)(p11.2),^[31] and an unknown gene at 10q23.^[8]

TFE3 is 1 of 4 closely related members of the transcription factor family MiT (a subfamily of basic helix-loop-helix-leucine zipper transcription factors).^[32] The other members are MITF, TFEB, and TFEC. These MiT members share virtual perfect homology in their DNA binding domains and bind a common DNA motif.^[33] Another MiT member, TFEB, also has been found to be involved in chromosomal translocation in a subset of RCCs. This subset of RCC harbors t(6;11)(q21;q13) that results in the fusion of one of the MiT members, Alpha-TFEB.^[34] Seven cases have been reported in adolescents and adults (ages 9-33 years; median, 17 years).^[35] In this chromosomal translocation, promoter substitution led to the up-regulation of TFEB.^[36] Structural genetic abnormalities that involve the remaining 2 MiT transcription factor family members, MITF and TFEC, have not been reported.

In the cytogenetic studies of papillary RCC, mostly in adults, other chromosomal abnormalities have been found. These are complex numeric chromosomal abnormalities and unique patterns of allelic imbalances that often reveal gains of chromosomes 7, 8, 12q, 16q, and 20q and losses of chromosomes 1p, 4q, 6q, 9p, 11p, 13q, 14q, 18, 21q, X, and Y.^[37-43] Their prevalence in pediatric RCC is less well known. To better elucidate the characteristics of pediatric RCC, we embarked on a retrospective review of 13 consecutive cases of pediatric RCC seen at our center. We describe the clinical features, outcome, histopathologic features, and cytogenetic and molecular abnormalities associated with the members of the MiT transcription factor family in this patient population.