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Okafor et al. Mini-invasive Surg 2024;8:28 https://dx.doi.org/10.20517/2574-1225.2023.128 Page 9 of 15

presentation was associated with poor prognosis while orbital and dural invasion exhibited significantly
worse disease-free survival [53,58,66] . Lechner et al. conducted a multicenter retrospective analysis of clinical
staging, prognosis and treatment outcomes of 404 patients diagnosed with olfactory neuroblastoma and the
[53]
role of targeted SSTR therapy . Results highlighted the prognostic implications of stratifying Kadish C
patients based on orbital involvement, intracranial extension or dural invasion, revealing that dural invasion
serves as a significant prognostic indicator of worse survival outcomes. In addition, among patients
presenting with Kadish D staging who were stratified based on cervical nodal disease versus distant disease,
those with distant metastasis exhibited significantly worse outcomes, further illustrating the worsened
prognosis and shortened survival associated with distant metastatic disease.

Ultimately, long-term surveillance is crucial for all cases of olfactory neuroblastoma due to its tendency for
late recurrences which can occur up to 15 years after initial treatment [19,26,107,108] . It is recommended that close
monitoring should involve ongoing physical and endoscopic imaging examinations as well as imaging
evaluations for at least ten years after treatment. Unfortunately, there are no clear guidelines in place for
surveillance recommendations. PET-CT offers great value in detecting recurrences that may not be
[109]
apparent through other routine imaging methods . However, the advent and increased use of [68Ga]-
DOTATATE PET as an imaging modality and surveillance tool have illustrated the benefits and sensitivity
of this imaging modality compared to that of routine PET/CT and MRI [28,110,111] . Although these studies
involve a small cohort of patients, findings are promising and illustrate the need for larger prospective trials
in efforts to develop a standardized guideline recommendation. Nonetheless, long-term surveillance with
[68Ga]-DOTATATE PET should be highly considered given its documented superiority in detection of
tumors compared to that of PET/CT .
[53]

FUTURE THERAPEUTIC DIRECTIONS
Olfactory neuroblastoma is increasingly recognized as a heterogenous disease composed of various cell
lineage-specific elements from the normal olfactory epithelium. One study performed bulk transcriptomics
on 19 olfactory neuroblastomas and found that tumors could be grouped into either neural or basal
[112]
categories based on cell gene signatures . Follow-up studies have expanded on this notion and provide
evidence for tumor cells expressing either known neuronal, sustentacular, or glandular markers [52,113] . It may
make sense, then, for a possible combination therapeutic approach to target components of each of these
cell type-specific lineages. For example, enhancer of zeste homolog 2 (EZH2) is widely expressed in
neuronal cells of olfactory neuroblastoma, helps coordinate normal olfactory neurogenesis, and plays a role
[52]
in proliferation in other cancers . A future trial of tazemetostat, a Food and Drug Administration (FDA)-
approved EZH2 inhibitor, in olfactory neuroblastoma patients, might therefore be a viable, mechanistically-
based option. Recently, a mouse model of olfactory neuroblastoma was developed and validated .
[114]
Interestingly, mouse tumors recapitulated heterogeneity observed in human tumors, including a neural
population expressing EZH2; however, it was shown that high-grade olfactory neuroblastoma exhibits
plasticity, with the potential to shift between neural and non-neuronal lineages . This emphasizes the
[114]
potential importance of targeted combination therapies.

Another therapeutic direction involves adapting treatment approaches from better-studied neuroendocrine
cancers. A recent study showed that 82.4% of olfactory neuroblastoma cases expressed the SSTR2, which is
commonly upregulated in many neuroendocrine cancers . In a pilot cohort part of the larger LUTHREE
[53]
trial, three metastatic olfactory neuroblastoma patients were treated with an SSTR2-targeted
radionucleotide, which was well-tolerated and led to stable disease . Hasan et al. documented a
[53]
retrospective trial with a cohort of seven patients with Kadish D unresectable disease treated with 177Lu-
DOTATATE surface SSTRs and noted a median progression-free survival of 17 months and a median