Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population

Abstract

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Keywords: EU-RHAB registry; RTPS1; RTPS2; SMARCB1; atypical teratoid rhabdoid tumors; extracranial malignant rhabdoid tumor; germline mutation.

Figure 1

Anatomical localizations of infants with malignant rhabdoid tumor. Anatomical localization of infants with MRT (n = 100), included n = 17 synchronous tumors, registered between 2005 and 2020 in EU-RHAB database. The most common localization detected in this series, are highlighted in bold.

Figure 2

The 5-year overall survival (OS) of 93 consecutive patients treated according to the EU-RHAB consensus therapy. (A) The 5-year OS was 35.8 ± 7.4 % for female and 11 ± 5% for male patients. (B) The 5-year OS was 36.2 ± 7.4% for patients with localised disease without loco-regional lymph node involvement (M0, LN−), 40 ± 21.9 % for patients with loco-regional lymph node involvement (M0, LN+), 6.1 ± 5.4% for patients with metastasis (M+) at diagnosis and 7.1 ± 6.9% for patients with synchronous tumors (SYN). (C) The 5-year OS was 7.7 ± 4.2% for patients diagnosed with germline mutation (GLM+) and 45.7 ± 8.6% for those without (GLM−).

Figure 3

Response to standardized chemotherapy of infants with extensive primary eMRT, imaging results. (A) Diagnostic imaging at 3 months of age with inoperable, liver eMRT (8.2 × 8.4 × 7.4 cm), without distant metastasis, without germline mutation. Before GTR (gross total resection), one course ICE (ifosfamide, carboplatin, etoposide) according to EU-RHAB was given. The patient achieved CR (complete remission) and the chemotherapy was continued according to EU-RHAB with four courses of DOX (doxorubicin), three courses of VCA (vincristine, cyclophosphamide, actinomycin) and four courses of ICE. The patient survived 60 months after diagnosis in continuing CR (complete remission). (B) Diagnostic imaging at 3 months of age with inoperable, neck eMRT (4.9 × 5 × 6.4 cm), without distant metastasis, without germline mutation. The tumor was resected subtotally (2.5 × 1.2 × 1 cm), and 50% to 25% decrease in tumor volume (IMP–improvement) was detected. After subtotal resection, therapy was continued according to EU-RHAB with two courses of DOX, two courses of ICE, and one course of VCA, and GTR (gross total resection) was performed. After GTR the patient received one course of VCA, high dose chemotherapy (HDCT) and maintenance therapy according to EU-RHAB. The patient achieved CR (complete remission), and one year later RTx was given to tumor bed up to 19.8 Gy with boost up to 16.2 Gy. The patient survived 111 months after diagnosis in continuing CR (complete remission).

Figure 3

Response to standardized chemotherapy of infants with extensive primary eMRT, imaging results. (A) Diagnostic imaging at 3 months of age with inoperable, liver eMRT (8.2 × 8.4 × 7.4 cm), without distant metastasis, without germline mutation. Before GTR (gross total resection), one course ICE (ifosfamide, carboplatin, etoposide) according to EU-RHAB was given. The patient achieved CR (complete remission) and the chemotherapy was continued according to EU-RHAB with four courses of DOX (doxorubicin), three courses of VCA (vincristine, cyclophosphamide, actinomycin) and four courses of ICE. The patient survived 60 months after diagnosis in continuing CR (complete remission). (B) Diagnostic imaging at 3 months of age with inoperable, neck eMRT (4.9 × 5 × 6.4 cm), without distant metastasis, without germline mutation. The tumor was resected subtotally (2.5 × 1.2 × 1 cm), and 50% to 25% decrease in tumor volume (IMP–improvement) was detected. After subtotal resection, therapy was continued according to EU-RHAB with two courses of DOX, two courses of ICE, and one course of VCA, and GTR (gross total resection) was performed. After GTR the patient received one course of VCA, high dose chemotherapy (HDCT) and maintenance therapy according to EU-RHAB. The patient achieved CR (complete remission), and one year later RTx was given to tumor bed up to 19.8 Gy with boost up to 16.2 Gy. The patient survived 111 months after diagnosis in continuing CR (complete remission).

Figure 4

The 5-year overall (OS) and event free survival (EFS) of 93 patients infants with MRT. 7 patients did not receive any chemotherapy, not included in this analysis. The 5-year overall survival (OS) of 93 infants with MRT (ATRT = 41, eMRT = 28, RTK = 9, SYN = 15) was 23.5 ± 4.6%, while the 5-year event free survival (EFS) of the same cohort was 19 ± 4.1%.