Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon
neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is
known about its molecular pathogenesis. For this study, a retrospective cohort of
n=66 tumor samples with the institutional diagnosis of ONB was analyzed by
immunohistochemistry, genome-wide DNA methylation profiling, copy number
analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated
genes. DNA methylation profiles were compared to those of relevant differential
diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation
data revealed 4 subgroups among institutionally diagnosed ONB. The largest group
(n=42, 64%, Core ONB) presented with classical ONB histology and no overlap with
other classes upon methylation profiling-based t-distributed stochastic neighbor
embedding (t-SNE) analysis. A second DNA methylation group (n=7, 11%) with CpG
island methylator phenotype (CIMP) consisted of cases with strong expression of
cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in
all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma
with IDH2 mutation. Four cases (6%) formed a small group characterized by an
overall high level of DNA methylation, but without CIMP. The fourth group consisted
of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin
expression in most cases. In t-SNE analysis these cases mostly grouped among
sinonasal adenocarcinoma, squamous cell carcinoma and undifferentiated
carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core
ONB with a high frequency of combined loss of chromosome 1-4, 8-10 and 12. NGS
sequencing did not reveal highly recurrent mutations in ONB, with the only
recurrently mutated genes being TP53 and DNMT3A.
In conclusion, we demonstrate that institutionally diagnosed ONB are a
heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the
mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the
precise classification of ONB