Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations

Abstract

Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots of KRAS (8/22; 36%) and mutations or deletions of NF1 (7/22; 32%), followed by mutations of FGFR4 (2/22; 9%), NRAS (2/22; 9%), and amplification of EGFR (1/22; 5%). A germline DICER1 mutation was detected in two of five cases with constitutional DNA available. Notably, none of the patients showed evidence of a cancer-related syndrome at the time of diagnosis. In contrast to the genetic findings, the morphological features of these tumors were less distinctive, although rhabdomyoblasts or rhabdomyoblast-like cells could retrospectively be detected in all cases. The identified combination of genetic events indicates a relationship between the intracranial tumors analyzed and DICER1 predisposition syndrome-associated sarcomas such as embryonal rhabdomyosarcoma or the recently described group of anaplastic sarcomas of the kidney. However, the intracranial tumors in our series were initially interpreted to represent various tumor types, but rhabdomyosarcoma was not among the typical differential diagnoses considered. Given the rarity of intracranial sarcomas, this molecularly clearly defined group comprises a considerable fraction thereof. We therefore propose the designation "spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant" for this intriguing group.

Germline DICER1‐mutant intracranial sarcoma with dual chondroid and spindle cell morphology and pulmonary metastases treated with multimodal therapy

“…Sporadic reports of long‐term cure indicate that achieving GTR, immediate postoperative focal radiotherapy, and prolonged combination chemotherapy based on a “high‐risk” RMS backbone may be important. Effective regimens include VAC, platinum compounds, doxorubicin, etoposide, and high‐dose chemotherapy (melphalan, etoposide) followed by autologous rescue . Our patient had inoperable pulmonary metastases.…”

“…DICER1 syndrome, classically associated with pleuropulmonary blastoma, is an autosomal‐dominant condition with reduced penetrance, increasingly being recognized as predisposing to benign and malignant neoplasms, including CNS tumors such as pinealoblastoma, pituitary blastoma, and ciliary‐body medulloepithelioma, and genitourinary sarcomas . Recently, a group of DICER1‐mutant pediatric intracranial sarcomas were described, which are histologically heterogeneous, but homogeneous at the molecular level, with a characteristic methylation profile . Another series has reported pleomorphic differentiation with prominent eosinophilic cytoplasmic globules .…”

“…The clinical behavior of intracranial sarcoma, common in the frontal lobe and cerebellum, seems to be aggressive, with a mean survival of ∼9 months . Sporadic reports of long‐term cure indicate that achieving GTR, immediate postoperative focal radiotherapy, and prolonged combination chemotherapy based on a “high‐risk” RMS backbone may be important.…”

ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors

“…Germline nonsense pathogenic variants were then retrieved in both children: c.5053C>T / p.(Gln1685*) and c.1200G>A / p.(Trp400*) in case 1 and 2, respectively. Mutations in DICER1 in other tumor types commonly follow the same pattern of one germline truncating mutation and a somatic missense mutation in the RNase IIIb domain [2,5,7]. No feature of DICER1 syndrome was observed in either family, in accordance with its low penetrance (3).…”

“…Germline DICER1 pathogenic variants predispose to a broad spectrum of benign and malignant tumors [5]. Chondroid differentiation is a frequent feature in DICER1 associated tumors such as nasal chondromesenchymal hamartoma, rhabdomyosarcoma or anaplastic sarcoma of the kidney [2,5,7] and was observed in case 2 (Fig. 1kl).…”