The classification of pediatric and young adult renal cell carcinomas registered on the children's oncology group (COG) protocol AREN03B2 after focused genetic testing

Abstract

Background: Renal cell carcinomas (RCCs) are rare in young patients. Knowledge of their pathologic and molecular spectrum remains limited, and no prospective studies have been performed to date in this population. This study analyzes patients diagnosed with RCC who were prospectively enrolled in the AREN03B2 Children's Oncology Group (COG). The objective was to classify these tumors with the aid of focused genetic testing and to characterize their features.

Methods: All tumors registered as RCC by central review were retrospectively re-reviewed and underwent additional ancillary studies. Tumors were classified according to the 2016 World Health Organization classification system when possible.

Results: In total, 212 tumors were identified, and these were classified as microphthalmia transcription factor (MiT) translocation RCC (MiT-RCC) (41.5%), papillary RCC (16.5%), renal medullary carcinoma (12.3%), chromophobe RCC (6.6%), clear cell RCC (3.3%), fumarate hydratase-deficient RCC (1.4%), and succinate dehydrogenase-deficient RCC (0.5%). Other subtypes included tuberous sclerosis-associated RCC (4.2%), anaplastic lymphoma kinase (ALK)-rearranged RCC (3.8%), thyroid-like RCC (1.4%), myoepithelial carcinoma (0.9%), and unclassified (7.5%). MiT-RCCs were classified as either transcription factor E3 (TFE3) (93.2%) or EB (TFEB) (6.8%) translocations, and characterization of fusion partners was possible in most tumors.

Conclusions: The current study delineates the frequency of distinct RCC subtypes in a large prospective series of young patients and contributes knowledge to the diagnostic, clinical, and genetic features of MiT-RCC, the most common subtype among this age group. The identification of rare subtypes expands the spectrum of RCC in young patients, supporting the need for a thorough diagnostic workup. These studies may aid in the introduction of specific therapies for different RCC subtypes in the future. Cancer 2018. © 2018 American Cancer Society.

Keywords: pediatric renal tumor; renal cell carcinoma; transcription factor E3 (TFE3) gene; transcription factor EB (TFEB) gene; translocation renal cell carcinoma.

Figure 1

MiT-RCC and PRCC. Nuclear TFE3 immunohistochemical staining in a tumor positive for TFE3 rearrangement (A, 200X). MiT-RCC showing a combination of nested and papillary architecture, variable amounts of clear and eosinophilic cytoplasm and psammoma bodies (B and C). Two main cytological patterns are appreciated, one with voluminous cytoplasm and well-defined cell membranes (B, H&E 200X), and one with smaller cells with less distinct cell membranes (C, H&E 100X). Biphasic cell population consisting of large and small cells seen in a T-RCC with a TFEB fusion transcript (D, H&E 200X). Type 1 papillary RCC with papillary structures lined by a single layer of cuboidal epithelium with scant cytoplasm (E, H&E 100X). Type 2 papillary RCC showing pseudostratification of the papillae and eosinophilic cytoplasm (F, H&E 200X).

Figure 2

Other RCC subtypes. Renal medullary carcinoma composed of cells with eosinophilic cytoplasm and high nuclear grade frequently arranged in a reticular growth pattern with prominent neutrophilic inflammation (A, H&E 200X). Chromophobe RCC showing cells with pale eosinophilic cytoplasm and perinuclear halos (B, H&E 200X). Clear cell RCC with clear cells arranged in a solid growth pattern (C, 100X). Fumarate hydratase-deficient RCC with cells showing prominent nucleoli and perinucleolar clear halos lining papillary structures (D, 400X). Succinate dehydrogenase-deficient RCC showing cells with eosinophilic cytoplasm and intracytoplasmic vacuoles containing pale eosinophilic material (E, 400X). Tuberous sclerosis-associated RCC composed of cells with granular eosinophilic cytoplasm in a solid and nested growth pattern (F, 200X). ALK-rearranged RCC characterized with cells containing abundant eosinophilic cytoplasm, intracytoplasmic lumina and vesicular chromatin (G, 400X). Thyroid-like RCC with follicular structures containing eosinophilic material, reminiscent of thyroid follicles (H, 100X). Myoepithelial carcinoma showing small epithelioid cells embedded in a myxoid stroma (I, 200X).