DNA Methylation Profiling Distinguishes Adamantinoma-Like Ewing Sarcoma From Conventional Ewing Sarcoma

Area of Science:

• Oncology
• Molecular Pathology
• Genetics

Background:

• Adamantinoma-like Ewing sarcoma (ALES) has been considered a variant of Ewing sarcoma due to shared EWSR1::FLI1 fusions and keratin/p40 positivity.
• However, shared translocations across tumor types suggest ALES may be a distinct entity.

Purpose of the Study:

• To investigate the relationship between Ewing sarcoma and ALES using DNA methylation profiling.
• To determine if ALES represents a separate tumor entity based on molecular and immunophenotypic characteristics.

Main Methods:

• Searched institutional archives for ALES cases.
• Performed DNA methylation profiling on ALES and compared to conventional Ewing sarcoma.
• Analyzed genetic fusions (EWSR1::FLI1, FUS::FLI1) and immunophenotypes (keratins, p40, CD99, p63, S100).

Main Results:

• Twelve ALES cases were identified, occurring in various head and neck sites.
• All ALES cases showed a distinct methylation profile, segregating them from conventional Ewing sarcoma.
• Immunoprofiles included keratin, CD99, and p40/p63 positivity; genetic fusions varied.

Conclusions:

• DNA methylation profiling reveals a distinct signature for ALES, differentiating it from Ewing sarcoma.
• The unique methylation profile, combined with distinct immunophenotypic features, supports classifying ALES as a separate entity.
• This research redefines the classification of ALES, moving away from its consideration as a mere variant of Ewing sarcoma.