Key Points
Question
Is incorporation of Hyams grade into olfactory neuroblastoma (ONB) staging systems associated with better prediction of disease recurrence?
Findings
In this multicenter case-control study of 256 patients with ONB, patients experienced excellent overall and disease-specific survival, although disease progression and recurrence were common. By incorporating Hyams grade, novel versions of tumor staging systems showed an excellent ability to estimate recurrence.
Meaning
These findings suggest that incorporation of Hyams grade into traditional ONB staging systems may increase these systems’ ability to estimate disease progression.
This case-control study describes survival variables for olfactory neuroblastoma and examines the association of incorporating Hyams tumor grade into existing staging systems.
Abstract
Importance
Current olfactory neuroblastoma (ONB) staging systems inadequately delineate locally advanced tumors, do not incorporate tumor grade, and poorly estimate survival and recurrence.
Objective
The primary aims of this study were to (1) examine the clinical covariates associated with survival and recurrence of ONB in a modern-era multicenter cohort and (2) incorporate Hyams tumor grade into existing staging systems to assess its ability to estimate survival and recurrence.
Design, Setting, and Participants
This retrospective, multicenter, case-control study included patients with ONB who underwent treatment between January 1, 2005, and December 31, 2021, at 9 North American academic medical centers.
Intervention
Standard-of-care ONB treatment.
Main Outcome and Measures
The main outcomes were overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) as C statistics for model prediction.
Results
A total of 256 patients with ONB (mean [SD] age, 52.0 [15.6] years; 115 female [44.9%]; 141 male [55.1%]) were included. The 5-year rate for OS was 83.5% (95% CI, 78.3%-89.1%); for DFS, 70.8% (95% CI, 64.3%-78.0%); and for DSS, 94.1% (95% CI, 90.5%-97.8%). On multivariable analysis, age, American Joint Committee on Cancer (AJCC) stage, involvement of bilateral maxillary sinuses, and positive margins were associated with OS. Only AJCC stage was associated with DFS. Only N stage was associated with DSS. When assessing the ability of staging systems to estimate OS, the best-performing model was the novel modification of the Dulguerov system (C statistic, 0.66; 95% CI, 0.59-0.76), and the Kadish system performed most poorly (C statistic, 0.57; 95% CI, 0.50-0.63). Regarding estimation of DFS, the modified Kadish system performed most poorly (C statistic, 0.55; 95% CI, 0.51-0.66), while the novel modification of the AJCC system performed the best (C statistic, 0.70; 95% CI, 0.66-0.80). Regarding estimation of DSS, the modified Kadish system was the best-performing model (C statistic, 0.79; 95% CI, 0.70-0.94), and the unmodified Kadish performed the worst (C statistic, 0.56; 95% CI, 0.51-0.68). The ability for novel ONB staging systems to estimate disease progression across stages was also assessed. In the novel Kadish staging system, patients with stage VI disease were approximately 7 times as likely to experience disease progression as patients with stage I disease (hazard ratio [HR], 6.84; 95% CI, 1.60-29.20). Results were similar for the novel modified Kadish system (HR, 8.99; 95% CI, 1.62-49.85) and the novel Dulguerov system (HR, 6.86; 95% CI, 2.74-17.18).
Conclusions and Relevance
The study findings indicate that 5-year OS for ONB is favorable and that incorporation of Hyams grade into traditional ONB staging systems is associated with improved estimation of disease progression.
Introduction
Olfactory neuroblastoma (ONB) is a rare sinonasal tumor, representing 2% to 6% of all sinonasal malignant neoplasms.1,2 Olfactory neuroblastomas arise from the olfactory epithelium adjacent to the cribriform plate, allowing for early intracranial extension.2 Surgery is the cornerstone of therapy, and many tumors are ideally suited for endoscopic resection due to their midline location along the ventral skull base.1,3 Adjuvant radiation therapy with or without chemotherapy is selected depending on tumor grade, margin status, and other clinical features.4,5,6 In select cases, induction chemotherapy may play a role for locally advanced tumors or for orbital preservation.7,8
Olfactory neuroblastoma is associated with favorable long-term survival, with a reported 5-year overall survival (OS) of 70% to 90%.1,4,6,9 However, recurrence is frequent, with a reported 10-year disease-free survival (DFS) of 51% to 62%.9,10,11,12 Recurrence often is delayed; the median time to recurrence has been reported to be 64 months after initial therapy.4 However, much of these data arises from historical institutional series across several treatment eras4,6,12 or from large database analyses,13,14,15 which may lack tumor and therapy details and may contain unreliable radiation therapy and systemic therapy data. For instance, the Surveillance, Epidemiology, and End Results (SEER) database now requires researchers to acknowledge the inaccuracies of the radiation therapy and chemotherapy SEER data, as recent work has shown a sensitivity of 80% for SEER radiation therapy data and 68% for SEER chemotherapy data compared with Medicare claims data.16
Given the unique dichotomy of ONB with favorable long-term survival but frequent recurrence, increased attention has been given to the ability of tumor staging systems to estimate both OS and DFS. The most widely accepted ONB-specific staging system, although unofficial, is the Kadish system.15 However, this system poorly delineates locally advanced tumors. Many institutional ONB series have reported that 60% to 70% of tumors are Kadish stage C.2,4,9,10,11 The modified Kadish (mKadish) system by Morita et al17 was developed to create an additional Kadish stage (mKadish stage D) for patients with metastatic disease. However, this system also does not delineate locally advanced tumors well and has been shown to be poorly associated with survival between stages.13,15 Moreover, other staging systems have been applied to ONB, including the Dulguerov T stage system18,19 and American Joint Committee on Cancer (AJCC) system.20,21 In a recent National Cancer Database study of 883 patients with ONB comparing the Kadish, AJCC, and Dulguerov staging systems, the authors concluded that all staging systems poorly depict patients’ prognosis over 10 years.15
Although the current staging systems for ONB may not effectively delineate between locally advanced tumors or optimally estimate survival and recurrence, Hyams tumor grade has consistently demonstrated an association with survival outcomes and recurrence.4,14,22,23 Moreover, many modern cancer staging systems have begun to incorporate histopathologic features and tumor grade. For instance, the updated AJCC cutaneous melanoma staging system incorporates both tumor thickness and the presence of histopathologic ulceration; this has shown an improved ability to estimate survival.24,25,26 Modifications of the AJCC breast cancer staging system have incorporated hormone receptor status in addition to anatomic features, also improving the ability to estimate long-term outcomes.27,28,29,30 However, to date, tumor grade or histopathologic findings have not been described in ONB staging. Thus, the primary aims of our multi-institutional study were to (1) examine the clinical covariates associated with survival and recurrence of ONB in the modern treatment era with widely available endoscopic approaches (2005 to present)31,32,33,34,35,36 and (2) incorporate Hyams tumor grade into existing staging systems and assess its ability to estimate OS, DFS, and disease-specific survival (DSS).
Methods
Study Population and Data Collection
In this case-control study, deidentified data originated from a retrospective review of electronic health records of patients who presented with confirmed diagnoses of ONB between 2005 and 2021 to the departments of otolaryngology–head and neck surgery at 9 academic referral centers in North America, including the Mayo Clinic Hospital, Medical College of Wisconsin, Oregon Health & Science University, Stanford University, University of North Carolina at Chapel Hill, Université Laval, University of Toronto, Loyola University Medical Center, and University of Pittsburgh Medical Center. Intervention criteria included patients with ONB who underwent treatment at the participating institutions. Patient age at diagnosis and sex, but not race and ethnicity, were included in the analysis. The institutional review board at each performance site provided expedited review and approval with a waiver of informed consent for this minimal-risk investigation of deidentified data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Source Data for Staging and Classification Systems
Compiled source data of interest included clinical TNM stage, as well as overall pathologic stage as defined by the AJCC.26,27 Staging specific for ONB was recorded using the Kadish, mKadish, and Dulguerov systems, as well as Hyams grade (eTable 1 in Supplement 1).
Available sinonasal diagnostic imaging was reviewed in order to characterize disease attributes, including laterality; sinus and skull base bone erosion or destruction on computed tomography; and orbital apex, cavernous sinus, and evidence of dural and brain involvement on magnetic resonance imaging. Postoperative permanent pathology reports were reviewed to ascertain evidence of tumor involvement of the dura, olfactory bulb and tract, and brain; perineural invasion; and final margin status.
To incorporate tumor grade and intrinsic biological tumor behavior into tumor staging, novel staging systems were defined a priori to incorporate Hyams grade as a dichotomous variable (low, grade 1 and 2; high, grade 3 and 4) into existing anatomic staging systems, including the Kadish, mKadish, Dulguerov, and AJCC systems (eFigure in Supplement 1). Hyams grade was selected due to its reflection of intrinsic biological behavior, wide use, simple dichotomous nature, and consistent correlation with survival and recurrence in the literature.1,4,23,37,38 Hyams grade of the tumor resection specimen was assigned by the institutional pathologist following surgical resection. If the patient underwent nonsurgical therapy, Hyams grade was assigned based on the biopsy specimen.
Survival Outcomes
Survival outcomes of interest included the OS, DFS, and DSS defined by the duration of observed time (in years) between the date of diagnosis and date of recorded event. Patients with no indication for the event were censored at last available follow-up date. Survival status at the last available clinical follow-up was categorized as alive, death from disease, or death from other causes.
Statistical Analysis
Overall survival, DFS, and DSS were estimated using the Kaplan-Meier method and summarized at 1, 2, 5, and 10 years after date of diagnosis. Risk for all-cause death, cancer disease progression, and cancer-specific death from disease were assessed using Cox proportional hazards regression models. Univariable associations with the outcomes were run for all explanatory variables of interest. All variables found to be significantly associated with each outcome were considered for multivariable analysis if P < .10. Manual backward selection of included features in the multivariable model was performed until each model retained only significant variables at P = .05. There were relatively few events in the mortality model (approximately 40 deaths), allowing only 4 variables to be retained. Repeated removal of the least significantly associated variable until only 4 were retained resulted in the model reported herein. For the disease progression model, however, after manual backward selection, only 1 variable was retained. Similarly for the cancer-specific death from disease outcome, only 1 variable was retained. T stage and Kadish score were considered for inclusion in the multivariable model for disease progression, but inclusion caused unbounded estimates for the hazard ratios (HRs), and this model was abandoned in favor of the simpler and more stable model including only AJCC stage.
Performance of models estimating OS, DFS, and DSS using various staging systems was assessed using Cox proportional hazards regression models and summarized using the Harrell C statistic. The C statistic is equivalent to the area under the receiver operating characteristic curve and summarizes the ability of the model to accurately classify patients who experienced the modeled outcome. Numbers of OS and DFS events were low, allowing for only uncomplicated models. Furthermore, to be consistent in assessing OS, DFS, and DSS, only univariable Cox proportional hazards regression models were used. C statistic values range from 0 to 1, with 0 denoting perfect anticoncordance, 0.5 denoting completely random assignments, and 1 denoting perfect concordance. Although not strictly defined, the following C statistic parameters are generally described: less than 0.5, poor model; 0.5, model is no better than random chance; greater than 0.7, good model; greater than 0.8, strong model; and greater than 0.9, near-perfect concordance, but highly unusual and interpreted with caution.39,40 The 95% CIs for the C statistic estimates were generated using the bootstrapping process. For each model, 1000 data sets were generated, consisting of patient records randomly sampled with replacement. The model used to generate the initial estimate was rerun for each of these randomly sampled data sets, and the resulting C statistic was recorded. The 2.5th and 97.5th percentiles of the distribution of C statistic output from these models were selected as the lower and upper bounds of the 95% CI for the initial estimate. Statistical analyses were performed using SAS, version 9.4 software (SAS Institute Inc).
Results
A total of 256 patients with ONB were included (mean [SD] age, 52.0 [15.6] years; 115 female [44.9%]; 141 male [55.1%]). Twenty-seven patients (10.9%) had Kadish A, 53 (21.4%) Kadish B, and 168 (67.7%) Kadish C tumors. Thirty-seven patients (14.4%) had regional nodal metastases at the time of presentation. Additional staging data are included in Table 1. Fifteen patients (8.0%) had Hyams 1, 99 (52.9%) Hyams 2, 56 (29.9%) Hyams 3, and 17 (9.1%) Hyams 4 tumor grade.
Table 1. Demographic, Clinical, and Treatment Characteristics.
| Characteristic | No. (%) (n = 256) |
| Age at diagnosis, y | |
| Mean (SD) | 52.0 (15.6) |
| Median (IQR) | 52.0 (43.0-63.0) |
| Range | 4.0-91.0 |
| Sex | |
| Female | 115 (44.9) |
| Male | 141 (55.1) |
| T stage | |
| T1 | 34 (13.3) |
| T2 | 30 (11.7) |
| T3 | 26 (10.2) |
| T4a | 40 (15.6) |
| T4b | 114 (44.5) |
| Tx | 12 (4.7) |
| N stage | |
| N0 | 188 (73.4) |
| N1 | 12 (4.7) |
| N2a | 3 (1.2) |
| N2b | 8 (3.1) |
| N2c | 12 (4.7) |
| N3 | 2 (0.8) |
| Nx | 31 (12.1) |
| M stage | |
| M0 | 220 (85.9) |
| M1 | 3 (1.2) |
| Mx | 33 (12.9) |
| AJCC overall stage | |
| I | 33 (13.5) |
| II | 29 (11.9) |
| III | 42 (17.2) |
| IVa | 38 (15.6) |
| IVb | 100 (41.0) |
| IVc | 2 (0.8) |
| Missing | 12a |
| Kadish | |
| A | 27 (10.9) |
| B | 53 (21.4) |
| C | 168 (67.7) |
| Missing | 8a |
| Modified Kadish | |
| A | 26 (10.5) |
| B | 52 (21.0) |
| C | 136 (54.8) |
| D | 34 (13.7) |
| Missing | 8a |
| Dulguerov stage | |
| T1 | 69 (28.0) |
| T2 | 32 (13.0) |
| T3 | 43 (17.5) |
| T4 | 102 (41.5) |
| Missing | 10a |
| Hyams grade | |
| 1 | 15 (8.0) |
| 2 | 99 (52.9) |
| 3 | 56 (29.9) |
| 4 | 17 (9.1) |
| Missing | 69a |
| Margins | |
| Negative | 154 (72.0) |
| Positive | 60 (28.0) |
| Missing | 42a |
| Local treatment | |
| Surgery alone | 41 (16.3) |
| Surgery plus radiation therapy | 137 (54.4) |
| Surgery plus chemoradiotherapy | 51 (20.2) |
| Chemoradiotherapy alone | 3 (1.2) |
| Radiation therapy alone | 2 (0.8) |
| Induction chemotherapy plus surgery then adjuvant therapy | 12 (4.8) |
| Induction chemotherapy plus chemoradiotherapy | 3 (1.2) |
| None or palliative | 3 (1.2) |
| Missing | 4a |
| Surgery (primary treatment) | |
| None | 8 (3.2) |
| Endoscopic only | 161 (64.1) |
| Open only | 29 (11.6) |
| Combined endoscopic and open surgery | 53 (21.1) |
| Missing | 5a |
| Neck radiation (primary treatment) | |
| None | 147 (72.8) |
| Unilateral radiation therapy | 13 (6.4) |
| Bilateral radiation therapy | 42 (20.8) |
| Missing | 54a |
| Neck dissection | |
| None | 228 (91.2) |
| Unilateral | 15 (6.0) |
| Bilateral | 7 (2.8) |
| Missing | 6a |
| Death | |
| No | 201 (78.5) |
| Yes | 55 (21.5) |
| Cancer progression or metastasis | |
| No | 178 (69.5) |
| Yes | 78 (30.5) |
| Site of recurrence | |
| None or not available | 178 (69.5) |
| Local (sinonasal or skull base) | 31 (12.1) |
| Intracranial (ie, brain metastasis, dural metastasis) | 7 (2.7) |
| Neck | 33 (12.9) |
| Distant | 7 (2.7) |
Abbreviation: AJCC, American Joint Committee on Cancer.
Missing data were not analyzed; therefore, no percentage is given.
Forty-one patients (16.3%) underwent surgery alone, 137 (54.4%) surgery plus radiation therapy, 51 (20.2%) surgery plus chemoradiotherapy, and 27 underwent a different procedure or had missing data (10.5%). Of patients undergoing surgery, 161 (64.1%) underwent a purely endoscopic approach, 53 (21.1%) a combined endoscopic and open approach, and 29 (11.6%) a purely open approach. The 5- and 10-year OS rates were 83.5% (95% CI, 78.3%-89.1%) and 66.7% (95% CI, 58.7%-75.8%), respectively. The 5- and 10-year DFS rates were 70.8% (95% CI, 64.3%-78.0%) and 53.1% (95% CI, 44.5%-63.5%), respectively. The 5- and 10-year DSS rates were 94.1% (95% CI, 90.5%-97.8%) and 89.4% (95% CI, 83.9%-95.4%), respectively. The event-free survival times for OS, DFS, and DSS are included in Table 2.
Table 2. Overall Survival, Disease-Free Survival, and Disease-Specific Survival Rates at 1, 2, 5, and 10 Years After Date of Diagnosis.
| Time, y | % (95% CI) | ||
|---|---|---|---|
| Overall survival | Disease-free survival | Disease-specific survival | |
| 1 | 95.8 (93.3-98.4) | 93.6 (90.5-96.8) | 99.1 (97.9-100.0) |
| 2 | 93.6 (90.5-96.8) | 87.0 (82.7-91.6) | 98.2 (96.5-100.0) |
| 5 | 83.5 (78.3-89.1) | 70.8 (64.3-78.0) | 94.1 (90.5-97.8) |
| 10 | 66.7 (58.7-75.8) | 53.1 (44.5-63.5) | 89.4 (83.9-95.4) |
On univariable analysis, the following factors were associated with OS: age, mKadish, Dulguerov stage, nodal status, positive margins, and locally directed therapy. Similarly, the following factors were associated with DFS: N stage, M stage, AJCC stage, Kadish stage, Dulguerov stage, orbital involvement, skull base bone involvement, Hyams grade (individual grades 1-4), Hyams grade (high vs low), positive margins, and dural involvement. The following factors were associated with DSS: N stage, mKadish, orbital apex involvement, and radiographic brain involvement (eTable 2 in Supplement 1). On multivariable analysis, age, AJCC stage, involvement of bilateral maxillary sinuses, and positive margins were associated with OS. Only AJCC stage was associated with DFS. Only N stage was associated with DSS (eTables 3-5 in Supplement 1).
Novel modifications of existing staging systems incorporating Hyams grade as described in the Methods section are delineated in the eFigure in Supplement 1. No models performed strongly in estimating mortality (OS) in this cohort. The worst-performing model for estimation of OS was the Kadish system (C statistic, 0.57; 95% CI, 0.50-0.63). The best-performing model was the novel modification of the Dulguerov system (C statistic, 0.66; 95% CI, 0.59-0.76). However, compared with the unmodified Dulguerov system (C statistic, 0.63; 95% CI, 0.57-0.71), the novel modification did not perform significantly better, as indicated by the almost complete overlap in the CIs for these 2 estimates (Table 3). The mKadish system had the worst predictive value for recurrence (DFS) (C statistic, 0.55; 95% CI, 0.51-0.66), while a novel modification of the AJCC staging incorporating Hyams grade had the highest predictive value (C statistic, 0.70; 95% CI, 0.66-0.80). In fact, the C statistic estimates for the unmodified systems are outside the bounds of the CIs of the modified systems; for example, the unmodified Kadish model for DFS had a C statistic of 0.56 (95% CI, 0.51-0.63), which is outside the bounds of the mKadish model (C statistic, 0.67; 95% CI, 0.59-0.74), indicating the increased discriminatory ability of models that include the Hyams grade for estimating DFS. Regarding estimation of death from disease (DSS), the mKadish system was the best-performing model overall (C statistic, 0.79; 95% CI, 0.70-0.94), and the unmodified Kadish performed worst (C statistic, 0.56; 95% CI, 0.51-0.68). Similar to the predictive models for DFS, addition of the Hyams grade into models predicting DSS showed notable improvement in their performance, again as indicated by comparing the C statistic estimates in the unmodified models with the 95% CIs for the modified systems.
Table 3. C Statistic Analysis of Original and Novel Staging System Variables Associated With Mortality, Disease Progression, and Death From Disease.
| Variable | Mortality | Progression | Death from disease | |||
|---|---|---|---|---|---|---|
| C statistic | 95% CI | C statistic | 95% CI | C statistic | 95% CI | |
| Original staging system | ||||||
| Kadish | 0.57 | (0.50-0.63) | 0.56 | (0.51-0.63) | 0.56 | (0.51-0.68) |
| Modified Kadish | 0.61 | (0.54-0.69) | 0.55 | (0.51-0.66) | 0.66 | (0.58-0.85) |
| Dulguerov | 0.63 | (0.57-0.71) | 0.61 | (0.55-0.68) | 0.67 | (0.60-0.80) |
| AJCC | 0.59 | (0.54-0.69) | 0.61 | (0.56-0.69) | 0.58 | (0.53-0.78) |
| Novel staging system | ||||||
| Novel Kadish | 0.60 | (0.54-0.69) | 0.67 | (0.59-0.74) | 0.68 | (0.60-0.82) |
| Novel modified Kadish | 0.62 | (0.57-0.73) | 0.67 | (0.61-0.77) | 0.79 | (0.70-0.94) |
| Novel Dulguerov | 0.66 | (0.59-0.76) | 0.68 | (0.63-0.77) | 0.77 | (0.72-0.89) |
| Novel AJCC | 0.63 | (0.60-0.77) | 0.70 | (0.66-0.80) | 0.77 | (0.73-0.91) |
Abbreviation: AJCC, American Joint Committee on Cancer.
Hazard ratio estimates from progression-free survival (PFS) models for the novel staging systems are shown in Table 4. In the novel Kadish staging system, patients with Kadish C, high Hyams grade disease were approximately 7 times as likely to experience disease progression as patients with Kadish A, low Hyams grade disease (HR, 6.84, 95% CI, 1.60-29.20). Results were similar for the novel mKadish D, high Hyams grade system (HR, 8.99; 95% CI, 1.62-49.85) and the novel Dulguerov T4, high Hyams grade system (HR, 6.86; 95% CI, 2.74-17.18). The HR model for PFS for the novel AJCC staging system performed more poorly. Of note, within the novel mKadish staging system, patients with mKadish C, high Hyams grade disease (HR, 6.41; 95% CI, 1.49-27.57) were more likely to experience disease progression than those with mKadish D, low Hyams grade disease (HR, 3.64; 95% CI, 0.60-22.12). For comparison, eTable 6 in Supplement 1 shows HR estimates from PFS models for the original staging systems not including Hyams grade.
Table 4. Estimates From Progression-Free Survival Models for the Novel Staging Systems.
| Parameter | HR (95% CI) |
|---|---|
| Novel Kadish | |
| Stage I: Kadish A, low Hyams grade | 1 [Reference] |
| Stage II: Kadish A, high Hyams grade | NA |
| Stage III: Kadish B, low Hyams grade | 1.81 (0.35-9.35) |
| Stage IV: Kadish B, high Hyams grade | 1.02 (0.09-11.25) |
| Stage V: Kadish C, low Hyams grade | 3.98 (0.93-17.01) |
| Stage VI: Kadish C, high Hyams grade | 6.84 (1.60-29.20) |
| Novel modified Kadish | |
| Stage I: modified Kadish A, low Hyams grade | 1 [Reference] |
| Stage II: modified Kadish A, high Hyams grade | NA |
| Stage III: modified Kadish B, low Hyams grade | 1.62 (0.31-8.35) |
| Stage IV: modified Kadish B, high Hyams grade | 0.85 (0.08-9.42) |
| Stage V: modified Kadish C, low Hyams grade | 3.65 (0.85-15.76) |
| Stage VI: modified Kadish C, high Hyams grade | 6.41 (1.49-27.57) |
| Stage VII: modified Kadish D, low Hyams grade | 3.64 (0.60-22.12) |
| Stage VIII: modified Kadish D, high Hyams grade | 8.99 (1.62-49.85) |
| Novel Dulguerov | |
| Stage I: Dulguerov T1, low Hyams grade | 1 [Reference] |
| Stage II: Dulguerov T1, high Hyams grade | NA |
| Stage III: Dulguerov T2, low Hyams grade | 2.15 (0.68-6.85) |
| Stage IV: Dulguerov T2, high Hyams grade | 1.83 (0.38-8.82) |
| Stage V: Dulguerov T3, low Hyams grade | 1.82 (0.53-6.24) |
| Stage VI: Dulguerov T3, high Hyams grade | 2.42 (0.81-7.22) |
| Stage VII: Dulguerov T4, low Hyams grade | 2.62 (1.02-6.73) |
| Stage VIII: Dulguerov T4, high Hyams grade | 6.86 (2.74-17.18) |
Abbreviation: HR, hazard ratio; NA, not applicable.
The association of several patient and disease characteristics with the site of recurrence or metastasis is shown in eTable 7 in Supplement 1. Sex, T stage, mKadish stage, and Hyams grade were significantly associated with site of recurrence.
Discussion
Olfactory neuroblastoma is a rare neuroendocrine tumor, making it challenging to study. Historical institutional studies are hampered by inclusion of patients over a long period with vast shifts in treatment modalities, thus limiting conclusions on interventions and outcomes. An alternative attempt to pool larger numbers of patients with ONB is to use large databases, such as the National Cancer Database and SEER. However, as we have noted, these databases contain limited treatment details, and information on radiation therapy and chemotherapy has been shown to be inaccurate.16 The current study attempted to overcome these institutional limitations by pooling data on 256 patients from multiple North American centers in the modern endoscopic era from 2005 to 2021, thus selecting a more homogenous era of therapeutics while allowing a reasonable time frame for long-term follow-up. In addition, pooled institutional-level data allow for a thorough and accurate review of therapeutic details, including surgical details, imaging, and staging.
Cancer staging systems are intended to clearly delineate long-term prognosis by stage, ideally for both survival and recurrence.41,42 With this goal in mind, the current ONB staging systems have been shown to inadequately delineate tumor stage and poorly estimate prognosis for both survival and recurrence.13,15 Some data suggest that increasing Kadish and Dulguerov stages are associated with worse survival, but Kadish stage C has been noted to be heterogenous with regard to prognosis and survival.43 A recent modification of the mKadish staging system, including the anatomic designation of dural invasion, has been shown to improve the mKadish system’s ability to estimate both OS and DFS.10
However, many modern cancer staging systems are increasingly using histopathologic features or tumor grade, in addition to traditional anatomic factors.24,25,26,27,28,29,44 The rationale for this inclusion is that tumor grade reflects the intrinsic biological features of the tumor and likely reflects the ability of the tumor to metastasize or recur.45,46 Within the realm of ONB, the Hyams grading system has been widely accepted and used and has consistently been shown to correlate with survival and recurrence.1,4,23,37,38 Thus, we created modifications of the most used ONB staging systems to include a low Hyams grade (1-2) or high Hyams grade (3-4) for each individual stage. Across all ONB staging systems (Kadish, mKadish, Dulguerov, AJCC), the addition of Hyams grade status improved each system’s ability to estimate both survival and recurrence. Interestingly, although the novel modification of the original staging systems improved their ability to estimate the outcome of interest as measured by C statistics, these novel systems had the tightest CIs in their ability to estimate recurrence, not all-cause mortality or death from ONB (Table 3). This finding may reflect the rarity of death from this disease but the commonality of recurrence, thus allowing the DFS model to have more end points to fit. From a practical application standpoint, the novel Dulguerov system may be most suited to clinical practice. It performed well across all outcomes of interest (all-cause mortality, recurrence, and death from disease). In addition, it contains 8 stages, as opposed to the 14 stages of the novel AJCC system.
The findings from the novel mKadish system analysis to estimate PFS highlights the importance of Hyams grade in estimating outcomes. Within this analysis, patients with mKadish C, high Hyams grade disease (HR, 6.41; 95% CI, 1.49-27.57) were more likely to experience disease progression than those with mKadish D, low Hyams grade disease (HR, 3.64; 95% CI, 0.60-22.12). Stated differently, patients with mKadish C, high Hyams grade disease were more likely to experience progression of their ONB than patients with regional or metastatic disease at presentation with low Hyams grade. This finding builds on previous evidence that suggested the importance of Hyams grade to estimate both survival and recurrence.23,38
Within our modern-era pooled data, the ONB dichotomy of excellent long-term survival but frequent recurrence was confirmed, with 5- and 10-year OS rates of 83.5% and 66.7%, respectively, along with 5- and 10-year DFS rates of 70.8% and 53.1%, respectively. When recurrence occurs, it is often delayed, with a reported median time to recurrence of more than 5 years,4 and is most commonly to the cervical lymph nodes, although sinonasal, intracranial, and distant metastases may also occur.1,2,4,17 The etiology for delayed recurrence is not well understood, although a recent suggestion is that ONB cells may reside in the dural lymphatics and eventually lead to locoregional recurrence.47,48,49 Marinelli et al47 showed that dural invasion was associated with the laterality of cervical lymph node metastasis in both initial presentation and delayed metastasis after treatment. A recent imaging study also showed connections between human brain lymphatic channels and the cervical lymph nodes.49 Dural lymphatics have been implicated in the spread of other malignant neoplasms and inflammatory conditions.50,51,52
Limitations
This study has several limitations. First, data were collected retrospectively, which can be subject to selection bias of the treating institution and the accuracy of the medical record. Second, given the retrospective nature of the data, certain patient data points were not available for all patients. We attempted to overcome this limitation by collating a large volume of patients from several centers across North America using standardized data collection parameters. Third, a measure of the overall burden of comorbidities was not included in the model. When developing prognostic staging systems where OS is an end point, excluding a comorbidity measure limits the performance of the model. Fourth, given the relatively few patients who died in this cohort (overall and disease-specific mortality), the multivariable models for survival contained only a few select variables due to the rarity of the outcome of interest.
Conclusions
Traditional ONB staging systems have been shown to poorly estimate survival and recurrence. The findings of this case-control study suggest that incorporation of Hyams grade into traditional ONB staging systems may improve these systems’ ability to estimate disease progression.
eTable 1. Staging Systems for Olfactory Neuroblastoma
eTable 2. Univariable Cox Proportional Hazards Models of Time to Death and Time to Disease Progression
eTable 3. Multivariable Cox Proportional Hazards Model of Risk of Mortality
eTable 4. Multivariable Cox Proportional Hazards Model of Disease Progression
eTable 5. Multivariable Cox Proportional Hazards Model of Death From Disease
eTable 6. Hazard Ratio Estimate From Progression-Free Survival Models for the Original Staging Systems (Without Inclusion of Hyams Grade)
eTable 7. Associations of Patient and Disease Characteristics With Site of Recurrence or Metastases
eFigure. Novel Modifications Incorporating Hyams Grade for the Original Kadish, Modified Kadish, Dulguerov, and American Joint Commission on Cancer Staging Systems
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Staging Systems for Olfactory Neuroblastoma
eTable 2. Univariable Cox Proportional Hazards Models of Time to Death and Time to Disease Progression
eTable 3. Multivariable Cox Proportional Hazards Model of Risk of Mortality
eTable 4. Multivariable Cox Proportional Hazards Model of Disease Progression
eTable 5. Multivariable Cox Proportional Hazards Model of Death From Disease
eTable 6. Hazard Ratio Estimate From Progression-Free Survival Models for the Original Staging Systems (Without Inclusion of Hyams Grade)
eTable 7. Associations of Patient and Disease Characteristics With Site of Recurrence or Metastases
eFigure. Novel Modifications Incorporating Hyams Grade for the Original Kadish, Modified Kadish, Dulguerov, and American Joint Commission on Cancer Staging Systems
Data Sharing Statement