Indications for germline genetic testing of children and adolescents with RCC to screen for a related syndrome are described in Table 1.
Table 1. Indications for Germline Genetic Analysis (Screening) of Children and Adolescents with Renal Cell Carcinoma (RCC)a
VHL = von Hippel-Lindau.
a Adapted from Linehan et al.
| Indication for Testing||Tumor Histology||Gene Test||Related Syndrome|
|Multifocal RCC or VHL lesions||Clear cell||VHL gene||von Hippel-Lindau syndrome|
|Family history of clear cell RCC or multifocal RCC with absent VHL mutation ||Clear cell ||Chromosome 3 gene translocations|| Hereditary non-VHL clear cell RCC syndrome|
|Multifocal papillary RCC or family history of papillary RCC||Papillary||MET gene||Hereditary papillary RCC syndrome|
|Multifocal RCC or cutaneous fibrofolliculoma or pulmonary cysts or spontaneous pneumothorax||Chromophobe or oncocytic or clear cell||Germline sequence BHD gene||Birt-Hogg-Dube syndrome|
|Personal or family history of early-onset uterine leiomyomata or cutaneous leiomyomata ||Type 2 papillary or collecting duct carcinoma||FH gene||Hereditary leiomyomata/RCC syndrome|
|Multifocal RCC or early-onset RCC or presence of paraganglioma/pheochromocytoma or family history of paraganglioma/pheochromocytoma||Clear cell or chromophobe||SDHB gene, SDHC gene, SDHD gene||Hereditary paraganglioma/pheochromocytoma syndrome|
Pediatric RCC differs histologically from the adult counterparts. Although the two main morphological subgroups of papillary and clear cell can be identified, about 25% of RCCs show heterogeneous features that do not fit into either one of these categories. Childhood RCCs are more frequently of the papillary subtype (20%-50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor, metanephric adenoma, and metanephric adenofibroma.
Translocation-positive carcinomas of the kidney are recognized as a distinct form of RCC and may be the most common form of RCC in children. They are characterized by translocations involving the transcription factor E3 (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:
- ASPSCR in t(X;17)(p11.2;q25).
- PRCC in t(X;1)(p11.2;q21).
- SFPQ in t(X;1)(p11.2;p34).
- NONO in inv(X;p11.2;q12).
- Clathrin heavy chain (CLTC) in t(X;17)(p11;q23).
Another less common translocation subtype, t(6;11)(p21;q12), involving a fusion Alpha/TFEB, induces overexpression of transcription factor EB (TFEB). The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry. Prior exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. The postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[33,50] Controversy exists as to the biological behavior of the translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a higher stage (III/IV) than TFE-RCC, a meta-analysis reports that these patients have poorer outcomes.[51,52,53] Recurrences have been reported 20 to 30 years after the initial resection of the translocation-associated RCC. VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11 translocation metastatic RCC.