Clear cell sarcoma of the kidney in children: clinical characteristics and treatment results

Clear cell sarcoma of the kidney (CCSK) is a rare malignant renal tumor in children, which accounts for 2–5% of pediatric kidney malignancies. The aim of the study was to analyze the results of therapy of patients with CCSK treated in Dmitry Rogachev National Medical Research Center оf Pediatric Hematology, Oncology and Immunology. Retrospective analysis of patients with a histologically confirmed diagnosis of CCSK treated for the period 01.2012–02.2020 (98 months) was done. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI of the Ministry of Healthcare of the Russian Federation. Demographic characteristics, clinical symptoms, methods of diagnosis, and treatment modalities were analyzed. Patients were treated according to the protocols of the SIOP-RTSG group (SIOP 93-01, SIOP-2001, SIOP-RTSG-2016). The stage was assigned according to the SIOP classification. Overall and event-free survival was assessed by the Kaplan–Mayer method. The analysis of the results was carried out on 01.03.2021. The analysis included 10 patients with CCSK. The median age at the time of diagnosis of CCSK was 30.1 months (range 13.5–70.8 months). All patients were male. The duration from the onset of the first symptoms/detection of the tumor to the diagnosis was 0.8 months (range 0.1–3.2 months). The diagnosis was established on the basis of clinical and radiological data (n = 9) and biopsy (n = 1). Distant metastases at the time of diagnosis were detected in 1 (10%) patient (localization of metastases - lungs). The median tumor volume was 439 cm3 (range 256–996 cm3 ). Preoperative chemotherapy was performed in all patients (AV regimen (actinomycin D, doxorubicin) in 7 (70%) patients). Assessment of response after preoperative chemotherapy showed tumor regression in 3/10 (in 1/7 with AV regimen), tumor progression in 5 and stable disease in 2 patients. Surgical treatment in the extent of nephrectomy was performed in all patients. In 1 (10%) case, intraoperative tumor rupture was documented. Distribution of patients by local stages: I – 4/10 (40%), II – 2/10 (20%), III – 4/10 (40%) (including 1 patient with distant metastases). In 1 patient, a left thoracotomy was performed to exclude lung metastases. Adjuvant chemotherapy was performed in all patients in accordance with the relevant protocols of the high-risk group: 7 – 4–5-drug regimen, 3 – AVD regimen (actinomycin D, vincristine, doxorubicin). Radiation therapy was performed in 6/10 (60%) patients. Outcomes: 9/10 (90%) – alive, 1/10 (10%) patient died (non-tumor-related death). 3-year event-free survival and overall survival were 78.8% (95% confidence interval (CI) 52.5–100) and 90.0% (95% CI 71.4–100) respectively. Intensive program therapy in patients with CCSK allows to achieve satisfactory results of treatment.

Histopathological and Molecular Profiling of Clear Cell Sarcoma and Correlation with Response to Crizotinib: An Exploratory Study Related to EORTC 90101 “CREATE” Trial

Clear cell sarcoma (CCSA) is characterized by a chromosomal translocation leading to EWSR1 rearrangement, resulting in aberrant transcription of multiple genes, including MET. The EORTC 90101 phase II trial evaluated the MET inhibitor crizotinib in CCSA but resulted in only sporadic responses. We performed an in-depth histopathological and molecular analysis of archival CCSA samples to identify alterations potentially relevant for the treatment outcome. Immunohistochemical characterization of MET signaling was performed using a tissue microarray constructed from 32 CCSA cases. The DNA from 24 available tumor specimens was analyzed by low-coverage whole-genome sequencing and whole-exome sequencing for the detection of recurrent copy number alterations (CNAs) and mutations. A pathway enrichment analysis was performed to identify the pathways relevant for CCSA tumorigenesis. Kaplan–Meier estimates and Fisher’s exact test were used to correlate the molecular findings with the clinical features related to crizotinib treatment, aiming to assess a potential association with the outcomes. The histopathological analysis showed the absence of a MET ligand and MET activation, with the presence of MET itself in most of cases. However, the expression/activation of MET downstream molecules was frequently observed, suggesting the role of other receptors in CCSA signal transduction. Using sequencing, we detected a number of CNAs at the chromosomal arm and region levels. The most common alteration was a gain of 8q24.21, observed in 83% of the cases. The loss of chromosomes 9q and 12q24 was associated with shorter survival. Based on exome sequencing, 40 cancer-associated genes were found to be mutated in more than one sample, with SRGAP3 and KMT2D as the most common alterations (each in four cases). The mutated genes encoded proteins were mainly involved in receptor tyrosine kinase signaling, polymerase-II transcription, DNA damage repair, SUMOylation and chromatin organization. Disruption in chromatin organization was correlated with longer progression-free survival in patients receiving crizotinib. Conclusions: The infrequent activation of MET may explain the lack of response to crizotinib observed in the majority of cases in the clinical trial. Our work describes the molecular heterogeneity in CCSA and provides further insight into the biology of this ultra-rare malignancy, which may potentially lead to better therapeutic approaches for CCSA.

Corrigendum: Not always ‘squame’: The rare entity of follicular dendritic cell sarcoma of the tonsil presenting with cervical nodal metastases

No abstract available.