Embryonal tumor with multilayered rosettes located in the brainstem: Promising results after multimodal treatment including interstitial brachytherapy

Embryonal tumors with multilayered rosettes (ETMR; CNS WHOº4) represent rare malignant tumors affecting predominantly infants.¹ Supratentorial location is more frequent than the posterior fossa (70% vs 30%), and 30% show CNS metastases at first diagnosis. ETMR are characterized by true multilayered rosettes and expression of LIN28A.² Furthermore, about 90% of ETMR harbor a C19MC microRNA cluster amplification¹ and another 5% a DICER1 germline mutation.^1,3

A generally recommended therapeutic approach comprises maximal safe surgical resection, irradiation, and induction and tandem high-dose chemotherapy with autologous stem-cell transplantation (HDCT/ASCT).⁴ However, regarding brainstem tumors in young children, surgery and radiation therapy present particular challenges.

Despite multimodal treatment, prognosis particularly for brainstem ETMR remains poor, with a reported median overall survival of 10–12 months.^4,5

Here, we present a 19-month-old boy diagnosed with a brainstem ETMR, who underwent multimodal treatment including surgical resection, intravenous and intrathecal chemotherapy, followed by stereotactic interstitial brachytherapy (SBT) and HDCT/ASCT. At diagnosis, the boy refused to walk; soon afterwards he developed a somnolent state with episodic, bradycardia and sinus arrhythmia, and right-sided hemiparesis. Magnetic resonance imaging (MRI) showed a pontine, predominantly T2-hyperintense, 40 × 31 mm lesion without strong contrast enhancement compressing the 4th ventricle (Figure 1A). A frame-based stereotactic biopsy was performed, but further rapid clinical deterioration leading to a sporadic state required debulking surgery. Thereafter, the boy recovered quickly and postoperative MRI showed a sufficient decompression of infratentorial structures (Figure 1B). Central neuropathological review established the diagnosis of a LIN28-positive ETMR with evidence of a C19MC amplification (DNA methylation class “embryonal tumor with multilayered rosettes, c19 Mc altered”; calibrated score 0.99; brain tumor classifier version 12.5).

Figure 1.

The course throughout the applied treatment regimes on T1- and T2-weighed magnetic resonance imaging (MRI): (A) at first diagnosis, (B) after partial tumor debulking, (C) after 3 cycles of induction chemotherapy, (D) after brachytherapy, and (E) at the last follow-up 24 months after first diagnosis. The tumor volume decreased from 11.7 ml prior to interstitial brachytherapy (C) to 3.6 ml in the most recent MRI (E). The distribution of the isodoses (F) from the implanted seeds in axial and sagittal planes and in a view along the trajectory. We applied 50 Gy to the surface of the tumor over 95 days with an initial dose rate of 3.6 cGy/h. The red line represents the outlined surface of the tumor, the orange line the 150 Gy isodose, the green the 50 Gy (therapeutic isodose), and the dark blue line the 10 Gy isodose. The 50 Gy isodose covered 95.92% of the visible tumor.

A medulloblastoma-type induction chemotherapy with systemic carboplatin and etoposide in combination with intraventricular methotrexate via a Rickham reservoir was initiated.⁴ After 3 cycles, the tumor showed no treatment response (Figure 1C); therefore, early radiotherapy was discussed. Due to the circumscribed appearance of the tumor and the patient’s young age SBT was considered the best available option. Feasibility and benefit of SBT were previously reported for infants but not for this entity.⁶ The patient underwent stereotactically guided temporary implantation of low-dose-rate 125-iodine seeds with a surface dose of 50 Gy over 95 days (initial dose rate 0.87 Gy/d) (Figure 1F) in between 2 systemic chemotherapy cycles. Twenty-seven days after SBT, HDCT with cisplatin and etoposide was applied and followed by ASCT. Cranial MRI 2 months after SBT showed ≥50% reduction in tumor volume (Figure 1D). The patient proceeded with the second HDCT with thiotepa and cyclophosphamide followed by another ASCT. At last visit, 24 months after initial diagnosis, the boy presented without neurological deficits, excellent quality of life, and age-appropriate development. The MRI showed radiation-induced image changes but no evidence of tumor progression or metastatic disease (Figure 1E). Thus, the reported maximum survival of 10 months for brainstem ETMR has been surpassed more than twofold up to now.⁴

SBT is associated with a highly inhomogeneous dose distribution, where cumulative doses of ≥200 Gy are achieved in the tumor core; therefore, it represents an effective treatment in incompletely resected ETMR, an entity, knowingly responsive to radiation therapy. The sequential combination with intrathecal chemotherapy may effectively prevent the formation of CNS metastases. Notably, SBT reduces the time of treatment and does not greatly interfere with the systemic chemotherapy schedule compared to conventional irradiation.

The combination of SBT to intense chemotherapy might therefore constitute the key to the unusually favorable outcome observed here. We propose that combining conventional therapeutic concepts with SBT constitutes a promising therapeutic approach to enhance the dismal outcome of patients with ETMR and should nourish further investigation.