Does Hyams Grade Impact Outcomes in Olfactory Neuroblastoma?

Olfactory neuroblastoma (ONB), or esthesioneuroblastoma, is a rare neuroectodermal malignancy originating from olfactory neuroepithelium in the superior nasal cavity. Accounting for approximately 2%–6% of all sinonasal tumors, ONB ranges from indolent tumors to aggressive neoplasms with a propensity for locoregional invasion and distant metastasis. The disease often presents insidiously, with vague symptoms of nasal obstruction, epistaxis, or anosmia, delaying diagnosis. Multiple staging systems have historically been employed to stratify disease severity in ONB. These include the original Kadish classification, the modified Kadish system proposed by Morita et al., the Dulguerov TNM system, and the AJCC staging system. While each describes the anatomic extent of disease, they do not incorporate histologic differentiation or tumor biology. These anatomy-based systems have demonstrated limitations in accurately predicting recurrence and survival, particularly in cases of locally advanced disease. The Hyams grading system classifies ONB into four grades based on microscopic features, including growth pattern, nuclear pleomorphism, mitotic activity, necrosis, rosette formation, neurofibrillary matrix, and calcification. Low Hyams grades (I–II) indicate well-differentiated tumors with more favorable behavior, while high grades (III–IV) are characterized by poor differentiation and more aggressive behavior. Despite its inclusion in nearly all ONB pathology reports, Hyams grade has only recently been incorporated into standardized staging systems. This review evaluates current evidence on the prognostic significance of Hyams grade in ONB and clinical practice implications. The prognostic relevance of Hyams grade in ONB has been substantiated in several studies. Collectively, these investigations demonstrate that higher Hyams grades are associated with worse survival, increased recurrence rates, and greater metastatic risk. McMillan et al. [1] conducted a single-institution series of 143 patients treated over a 60-year period at a tertiary care center. Their analysis emphasized oncologic outcomes and the prognostic significance of Hyams grade, modified Kadish staging, and surgical margin status. On multivariate analysis, high Hyams grade (III-IV) was an independent predictor of worse overall survival (OS), progression-free survival (PFS), and distant metastasis–free survival. Notably, 5-year OS in the entire cohort reached 82.3%, yet patients with lower-grade tumors consistently exhibited more favorable outcomes. The study reinforces the role of histologic differentiation in esthesioneuroblastoma and affirms that Hyams grade refines risk stratification beyond anatomic staging alone. Kaura et al. [2] addressed the role of Hyams grade in patients with advanced-stage (Kadish C) disease. Their cohort included 20 patients with Kadish C ONB who underwent craniotomy for tumor resection. Patients with low-grade Hyams (LGH) tumors had a 5-year OS of 86% compared to 56% in those with high grade Hyams (HGH) tumors. PFS was significantly prolonged in LGH patients; 2-year PFS was 86% and 5-year PFS was 65% in comparison to 73% and 49% in patients with HGH, respectively. Notably, even among patients with aggressive anatomic disease, histologic grade was the most reliable predictor of survival and recurrence. Bell et al. [3] examined the prognostic utility of Hyams grading in a retrospective review of 124 patients with ONB treated at a large academic center. Hyams grade, rather than Kadish-Morita staging, was significantly associated with DFS. OS at 5 years was 75% across the cohort, but DFS was significantly reduced in patients with HGH tumors. The authors concluded that Hyams grade should be considered in treatment planning and surveillance, given its stronger association with recurrence risk than traditional staging. Goshtasbi et al. [4] analyzed data from 57 studies published between 1993 and 2018, including 563 ONB patients with reported survival outcomes. The analysis stratified patients into LGH (grades I–II) and HGH (grades III–IV) groups. Neck metastasis occurred in 18.2% of HGH patients versus 7.9% in LGH (p = 0.03); distant metastasis rates were similarly elevated in HGH tumors (20.7% vs. 8.9%, p = 0.03). LGH tumors exhibited superior 5-year (81.2% vs. 60.9%, p < 0.001) and 10-year (64.0% vs. 40.6%, p < 0.001) OS rates compared to HGH tumors. Pooled odds ratios demonstrated that patients with HGH tumors were over twice as likely to develop metastases and had a significantly increased risk of death at 5 and 10 years. HGH tumors more often exhibited histopathologic features of poor differentiation, increased mitotic activity, and necrosis, correlating with more aggressive clinical behavior. In a large multicenter retrospective study, Choby et al. [5] analyzed outcomes from 256 patients with ONB treated at nine North American academic centers between 2005 and 2021. When Hyams grade was incorporated into traditional staging frameworks, the ability to predict disease progression improved markedly. On multivariate analysis, AJCC stage, bilateral maxillary sinus involvement, and positive surgical margins were independently associated with decreased OS. Importantly, Hyams grade was incorporated into novel staging models, particularly a modified Dulguerov system, resulting in improved discrimination between low- and high-risk groups. Patients with stage VI disease in these models, typically characterized by high-grade tumors, had an approximate 7- to 9–fold increased risk of progression compared to patients with stage I disease. Based on current evidence, Hyams grade should be integrated into counseling, prognostic models, and treatment planning for ONB patients. Histopathologic evaluation: All ONB specimens should undergo thorough histopathologic assessment with assignment of Hyams grade by a pathologist experienced in sinonasal neoplasms. Risk stratification/staging: Patients with HGH tumors should be considered high risk, even if the anatomic stage is lower (e.g., Kadish B). Risk stratification should integrate Hyams grade in combination with anatomic staging and nodal status. Specific recommendations regarding surgical approach, selection or type of adjuvant therapy, and management of the neck are beyond the scope of this review. However, the available literature suggests that integrating Hyams histologic grading into clinical decision-making may provide valuable prognostic information. Given its association with disease aggressiveness and recurrence patterns, Hyams grading has the potential to inform individualized treatment planning and risk stratification. Further studies, including randomized controlled trials, are warranted to define the optimal use of this grading system in therapeutic algorithms across different clinical settings. Many studies evaluating the prognostic impact of Hyams grade are retrospective, with levels of evidence ranging from II to III. Multicenter cohorts and meta-analyses involving retrospective series provide Level II evidence [1, 2], while single-institution retrospective cohorts represent Level IV evidence [3-5]. E.C.K. is a consultant for Stryker and 3D Matrix, and receives royalties from Springer. E.W.W. is a consultant for Stryker and NIH-NIAD. These relationships are not relevant to the current work. The authors declare no conflicts of interest.