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Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Cellular Classification

Table 1. Indications for Germline Genetic Analysis (Screening) of Children and Adolescents with Renal Cell Carcinoma (RCC)a

Indication for TestingTumor HistologyGene TestRelated Syndrome
VHL = von Hippel-Lindau.
a Adapted from Linehan et al.[56]
Multifocal RCC or VHL lesionsClear cellVHLgenevon Hippel-Lindau syndrome
Family history of clear cell RCC or multifocal RCC with absent VHL mutationClear cellChromosome 3 gene translocationsHereditary non-VHL clear cell RCC syndrome
Multifocal papillary RCC or family history of papillary RCCPapillaryMETgeneHereditary papillary RCC syndrome
Multifocal RCC or cutaneous fibrofolliculoma or pulmonary cysts or spontaneous pneumothoraxChromophobe or oncocytic or clear cellGermline sequenceBHDgeneBirt-Hogg-Dubé syndrome
Personal or family history of early-onset uterine leiomyomata or cutaneous leiomyomataType 2 papillary orcollecting duct carcinomaFHgeneHereditary leiomyomata/RCC syndrome
Multifocal RCC or early-onset RCC or presence of paraganglioma/pheochromocytoma or family history of paraganglioma/pheochromocytomaClear cell or chromophobeSDHBgene,SDHCgene,SDHDgeneHereditary 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.[57] 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.[38,58] 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.[59,60,61] Recurrences have been reported 20 to 30 years after the initial resection of the translocation-associated RCC.[54] VEGFR-targeted therapies and mTOR inhibitors seem to be active in Xp11 translocation metastatic RCC.[62]

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