Dados do Resumo

Título

STUDY OF CLEAR CELL RENAL CELL CARCINOMA DISSEMINATION THROUGH VENOUS TUMOR THROMBUS USING A PATIENT-DERIVED XENOGRAFT MODEL

Introdução

An uncommon hallmark of renal cell carcinoma (RCC) is its propensity for vascular invasion, leading to the development of a venous tumor thrombus (VTT) within the renal vein or inferior vena cava (IVC) in up to 25% of cases. The current standard of care for RCC with VTT is radical nephrectomy with IVC thrombectomy, a procedure associated with significant surgical morbidity and mortality, typically resulting in a median survival of only 5 months.

Objetivo

Thus, this project aimed to study and characterize a case of dissemination of clear cell renal carcinoma, through the formation of tumor thrombi and metastases, generated in immunodeficient animals.

Métodos

The sample used in the present study was obtained from a female patient who underwent left radical nephrectomy at the A.C.Camargo Cancer Center. Tumor fragments were implanted orthotopically (in the renal capsule) into immunodeficient NOD Scid Gamma (NSG) mice. The animals were monitored by palpation, and when the tumors showed signs of growth, the animals were anesthetized, the tumor removed and serially passed (P2). Tumor fragments were cryopreserved, and part was submitted to histological analysis (immunohistochemistry), and sequencing of genomic targets.

Resultados

The animals showed tumor growth one month after implantation of the fragments. The patient's tumor had a high histological grade (ISUP 4), pathological stage pT3a. The neoplasm measurements were 9.5 x 9.0 x 9.0 cm and histopathological analysis determined the presence of a sarcomatoid and rhabdoid component (more than 50%), in addition to the presence of necrosis. The patient had infiltration of the renal capsule, perirenal fat, sinus, renal artery and veins, with thrombus formation in the renal vein and inferior vena cava. PDX recapitulated the phenotype of the patient's previously diagnosed vena cava tumor thrombus extension and metastasis formation. PDX recapitulated metastases in the peritoneum, lymph node, and lung. PDX showed ectopic tumor growth and sample viability after cryopreservation. A cell line was established from the primary culture of this case (CCR26), capable of recapitulating the formation of tumor thrombi in animals. The characterization by immunohistochemistry indicates that PDXs and the established cell lineage preserve CCR phenotypes, including the expression of PAX8, Carbonic Anhydrase IX (CAIX) and Cytokeratin 7 (CK7), over successive passages in the animals. The genes found altered were VHL; BAP1 and FAT1. This case was characterized by exome genomic sequencing.

Conclusões

PDX recaptured the genetic signatures observed in the primary tumor. The mechanisms that lead to the formation of tumor thrombi are still poorly understood and these results are still unpublished. PDX was efficient in preserving the histological, genomic and immunohistochemical phenotype of the primary tumor. The presence of high histological grade and high pathological staging are related to a worse clinical prognosis. Reducing VTT formation holds promise for improving outcomes in patients with locally advanced RCC, who currently face a poor prognosis and limited treatment options.

Palavras Chave

Patient-derived xenografts; Tumor thrombus formation; Clear cell renal cell carcinoma