The impact of multidisciplinary approaches on the outcomes of olfactory neuroblastoma treated with postoperative radiotherapy.

BACKGROUND: We investigated the outcomes of postoperative radiation therapy for olfactory neuroblastoma (ONB) and our cross-departmental collaboration to enhance the effectiveness of cancer treatment. METHODS: We retrospectively evaluated 22 patients with ONB who underwent postoperative radiotherapy after tumor resection. En bloc resection was performed; pathology specimens were prepared in coronal sections; and irradiation fields were determined after discussion with radiation oncologists, head and neck surgeons, and pathologists. RESULTS: The overall survival and local control rates were 95.5% and 100%, respectively, at a median 37-month follow-up. The 3- and 5-year disease-free survival (DFS) rates were 64.4% and 56.3%, respectively. Of the 22 patients, 9 (8 Kadish C and 1 Kadish B) had disease recurrence. Of the nine patients, five had positive margins and two had closed margins; cervical lymph node recurrence occurred in six, and distant metastasis with or without cervical lymph node recurrence occurred in three. DFS analysis of risk factors showed no statistically significant differences, but positive margins were a significant recurrence factor in multivariate analysis. CONCLUSIONS: The local control rate of ONB treated with postoperative radiation therapy was 100%. This may be attributed to cross-departmental cooperation between head and neck surgeons, pathologists, and radiation oncologists, which resulted in accurate matching of CT images for treatment planning with the location of the tumor and positive margins. Longer follow-up periods are required to evaluate the effectiveness of our strategy.

Treatment of unilateral olfactory neuroblastoma: Appropriate extent of surgical resection and potential for olfactory preservation.

Historically, comprehensive surgical resection for olfactory neuroblastoma has included the bilateral olfactory epithelium, cribriform plate, overlying dura, olfactory bulbs and tracts. This results in postoperative anosmia that may significantly impact a patient's quality of life without definitive added benefit in survival. The prevalence of occult intracranial disease is low, especially for Hyams grade I and II tumors. A unilateral approach sparing the contralateral cribriform plate and olfactory system can be considered for select cases of early stage, low-grade tumors when the disease does not cross midline to involve the contralateral olfactory cleft or septal mucosa and when midline dural margins can be cleared with frozen pathology. Approximately half of patients who undergo unilateral resection may have residual olfaction even with adjuvant unilateral radiation. Early data suggest favorable disease-free survival and overall survival for patients who underwent the unilateral approach; however, larger sample studies are needed to confirm comparability to bilateral resections regarding oncologic outcomes.

Update on olfactory neuroblastoma.

Olfactory neuroblastomas are uncommon malignancies that arise from olfactory receptor cells located high in the nasal cavity. Accurate diagnosis plays a crucial role in determining clinical results and guiding treatment decisions. Diagnosis can be a major challenge for pathologists, especially when dealing with tumours with poor differentiation. The discovery of several molecular and immunohistochemical markers would help to overcome classification difficulties. Due to the paucity of large-scale studies, standardisation of diagnosis, treatment and prediction of outcome remains a challenge. Surgical resection by endoscopic techniques with the addition of postoperative irradiation is the treatment of choice. In addition, it is advisable to consider elective neck irradiation to minimise the risk of nodal recurrence. Molecular characterisation will help not only to make more accurate diagnoses but also to identify specific molecular targets that can be used to develop personalised treatment options tailored to each patient. The present review aims to summarise the current state of knowledge on histopathological diagnosis, the molecular biology and management of this disease.

A multi-institutional retrospective study of 340 cases of sinonasal malignant tumor.

OBJECTIVE: Sinonasal malignant tumors (SNMT) are relatively rare among head and neck malignant tumors. Most are squamous cell carcinomas, and malignant melanomas, olfactory neuroblastomas, adenoid cystic carcinomas, sarcomas, and others also occur. The most common primary site of nasal sinus squamous cell carcinoma is the maxillary sinus. In recent years, a decrease in incidence of maxillary sinus squamous cell carcinoma (MSSCC) has been reported along with a decrease in the incidence of sinusitis. MSSCC is treated with a combination of surgery, radiation, and chemotherapy. Treatment decisions are made according to the progression of the disease, the patient's general condition, and the patient's own wishes. There are variations in treatment policies among facilities due to the specialty of staff and cooperation with other departments at each facility. We conducted a multi-institutional retrospective study to compare outcomes by treatment strategy. METHODS: In this study, 340 patients with SNMT who were treated at 13 Hospitals (Head and Neck Oncology Group (Kyoto-HNOG) ) during the 12-year period from January 2006 to December 2017 were included. There were 220 patients with squamous cell carcinoma, 32 with malignant melanoma, 21 with olfactory neuroblastoma, and 67 with other malignancies. Of the squamous cell carcinomas, 164 were of maxillary sinus origin. One hundred and forty cases of MSSCC that were treated radically were included in the detailed statistical analysis. RESULTS: There were 5 cases of cStage I, 9 cases of cStage II, 36 cases of cStage III, 74 cases of cStage IVa, and 16 cases of cStage IVb. There were 92 cases without clinical lymph node metastasis (cN(-)) and 48 cases with clinical lymph node metastasis(cN(+)). Primary tumors were treated mainly by surgery in 85 cases (Surg) and by radical radiation therapy (with or without chemotherapy) of 6-70 Gy in 55 cases(non-Surg). The 5-year overall/disease-free survival rate (OS/DFS) for MSSCC was 65.1%/51.6%. Old age, renal dysfunction, and clinical T progression were independent risk factors for OS, and renal dysfunction was an independent risk factor for DFS. In cN(-) patients, OS and DFS were significantly better in Surg group than in non-Surg group. In cN(+) patients, there was no significant difference in OS and DFS between Surg and non-Surg groups. CONCLUSION: For patients with MSSCC without lymph node metastasis, aggressive surgery on the primary tumor contributes to improved prognosis.

Multicenter Survival Analysis and Application of an Olfactory Neuroblastoma Staging Modification Incorporating Hyams Grade.

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.

Proceedings of the 2023 North American Society of Head and Neck Pathology Companion Meeting, New Orleans, LA, March 12, 2023: Navigating New Developments in High Grade Sinonasal Neuroendocrine and Neuroectodermal Neoplasms.

Although the definitions of sinonasal neuroendocrine and neuroectodermal neoplasms did not change substantially in the 5th edition WHO Classification of Head and Neck Tumours, the diagnosis of olfactory neuroblastoma (ONB), small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma remains quite challenging in practice. Ambiguities surrounding the amount of keratin expression allowable in ONB and the amount of neuroendocrine differentiation seen in sinonasal undifferentiated carcinoma (SNUC) lead to significant diagnostic discrepancies at the high grade end of this tumor spectrum. Furthermore, a group of problematic neuroepithelial tumors that show overlapping features of ONB and neuroendocrine carcinoma have never been recognized in formal classification schemes. Since publication of the 5th edition WHO, two new tumor entities have been proposed that help resolve these problems. Olfactory carcinoma is defined by high grade keratin-positive neuroectodermal cells with frequent intermixed glands and shows recurrent Wnt pathway, ARID1A, and RUNX1 alterations. IDH2-mutant sinonasal carcinoma is a molecularly-defined category that encompasses tumors with undifferentiated (SNUC), large cell neuroendocrine, and neuroepithelial phenotypes. This review will provide a practical overview of these emerging entities and their application to diagnostic challenges in the post-WHO sinonasal neuroendocrine and neuroectodermal tumor classification.

Olfactory Neuroblastoma-A Challenging Fine Line between Metastasis and Hematology.

Developing in a limited space, rare tumors located at the nose and paranasal sinuses are sometimes difficult to diagnose due to their modest clinical presentation, which is uncorrelated with anatomopathological diversity. This limits the preoperative diagnosis without added immune histochemical study; for that reason, we present our experience with these tumors with the intention of raising awareness. The patient included in our study was investigated by our department through clinical and endoscopic examination, imaging investigations, and an anatomic-pathological study. The selected patient gave consent for participation and inclusion in this research study in compliance with the 1964 Declaration of Helsinki.

Olfactory neuroblastoma with rhabdomyoblasts: A rare case report and review of the literature.

Herein we present a case of a 62-year-old male patient who was admitted with the chief complaints of nasal obstruction. The histopathological and immunohistochemical evaluation led to a diagnosis of olfactory neuroblastoma with rhabdomyoblasts. A review of the literature revealed that this is only the fourth case of olfactory neuroblastoma with rhabdomyoblasts. Thus, investigation of more cases and longer follow-up is necessary to understand the disease and identify the best treatment to improve prognosis.

Lymph node metastasis from olfactory neuroblastoma at presentation and as disease relapse: A systematic review and proportion meta-analysis of prevalence data and variables influencing regional control.

BACKGROUND: Aim of this study is to investigate the prevalence of cervical nodal metastasis at presentation and as disease relapse in primary, treatment-naive olfactory neuroblastoma (ONB), and to review treatment modalities, risk factors for regional failure and survival outcomes according to nodal status. METHODS: A systematic review and proportion meta-analysis were conducted following PRISMA guidelines based on PubMed, Web of Science, and Scopus. RESULTS: Eighteen articles were examined. The pooled proportion of patients with nodal metastasis at presentation (11.5%) was comparable to that of cN0 patients not receiving elective neck treatment developing nodal metastasis during follow-up (12.3%). Of the latter, most were Kadish stage C tumors (85.5%). CONCLUSIONS: Cervical involvement is common both at presentation and during follow-up of cN0 ONB. The highest risk of developing late nodal metastasis is seen in cN0 patients with Kadish stage C tumors not receiving elective neck treatment. Elective cN0 neck treatment should be encouraged in selected patients to increase regional control.

Operative Technique and Complication Management in a Case of Giant Esthesioneuroblastoma Resected by a Combined Transcranial and Endonasal Endoscopic Approach: Technical Case Report.

BACKGROUND AND IMPORTANCE: Esthesioneuroblastoma (ENB) is a rare anterior skull base tumor derived from olfactory epithelium. There are very few operative videos in the literature demonstrating the surgical resection techniques for giant ENB because of their rarity and complexity. In this technical report, we demonstrate the microsurgical resection of a very large and complex high-grade ENB, initially deemed unresectable, through a bifrontal craniotomy and extended subfrontal approach combined with an endonasal endoscopic approach. CLINICAL PRESENTATION: A 34-year-old woman presented with headaches, nasal congestion, and bloody nasal drainage. MRI showed a large nasal cavity mass with extension into the anterior cranial fossa and bifrontal lobes. There was significant bifrontal edema causing headaches and abutting the optic nerves. Initial management with surgical resection was offered to the patient for local tumor control and to preserve her vision. A combined bifrontal craniotomy and endonasal transsphenoidal approach was used for resecting this giant tumor. After achieving gross total resection, we reconstructed the anterior skull base in layers. She developed several postoperative complications which were appropriately managed. CONCLUSION: We demonstrate the surgical resection of a giant ENB through a combined transcranial and endonasal endoscopic approach. We discuss the several postoperative complications in this complex case and the lessons learned.

Molecular Evidence for Olfactory Neuroblastoma as a Tumor of Malignant Globose Basal Cells.

Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a sinonasal cancer with an underdeveloped diagnostic toolkit, and is the subject of many incidents of tumor misclassification throughout the literature. Despite its name, connections between the cancer and normal cells of the olfactory epithelium have not been systematically explored and markers of olfactory epithelial cell types are not deployed in clinical practice. Here, we utilize an integrated human-mouse single-cell atlas of the nasal mucosa, including the olfactory epithelium, to identify transcriptomic programs that link ONB to a specific population of stem/progenitor cells known as olfactory epithelial globose basal cells (GBCs). Expression of a GBC transcription factor NEUROD1 distinguishes both low- and high-grade ONB from sinonasal undifferentiated carcinoma, a potential histologic mimic with a distinctly unfavorable prognosis. Furthermore, we identify a reproducible subpopulation of highly proliferative ONB cells expressing the GBC stemness marker EZH2, suggesting that EZH2 inhibition may play a role in the targeted treatment of ONB. Finally, we study the cellular states comprising ONB parenchyma using single-cell transcriptomics and identify evidence of a conserved GBC transcriptional regulatory circuit that governs divergent neuronal-versus-sustentacular differentiation. These results link ONB to a specific cell type for the first time and identify conserved developmental pathways within ONB that inform diagnostic, prognostic, and mechanistic investigation.

Prognostic significance of PD-1, CTLA-4, CD4, and CD8 expression in olfactory neuroblastoma.

There are limited data regarding immune surveillance mechanisms in olfactory neuroblastoma. We investigated the expression of programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD4, and CD8 in olfactory neuroblastoma to identify potential therapeutic targets. Immunohistochemistry was used to detect PD-1 and CTLA-4 and measure the numbers of CD4+ and CD8+ T cells in 56 patients with olfactory neuroblastoma. The relationships between these molecules in tumor microenvironment, clinicopathological features, and survival were analyzed. The prevalence of PD-1 in Kadish C stage was 24.14%, significantly greater than in Kadish A and B stage. CD4+ T-cell and CD8+ T-cell levels correlated with higher Hyams histological grade and Kadish stage. In addition, PD-1 was related positively with CTLA-4, CD4+ T cells, and CD8+ T cells in olfactory neuroblastoma. Univariate survival analysis showed that higher PD-1 positivity, CD8+ T cells, and Hyams grade correlated with worse clinical outcome. Multivariate analysis showed that the expression of PD-1 was an independent parameter for poor prognosis. In conclusion, olfactory neuroblastoma with PD-1 expression had more aggressive clinicopathological features and worse prognosis. PD-1 may potentially predict the outcome of olfactory neuroblastoma patients.

Cytological diagnosis of olfactory neuroblastoma at metastatic sites, with emphasis on role of insulinoma-associated protein 1 immunocytochemistry.

BACKGROUND: Olfactory neuroblastoma (ONB) is a rare neuroectodermal tumor with a propensity for lymph node and distant metastases in a proportion of cases, presenting opportunities for cytological diagnosis. Insulinoma-associated protein 1 (INSM1) is a recently identified marker of neuroendocrine differentiation with higher sensitivity and specificity than traditional neuroendocrine immunostains used in diagnosis of ONB. METHODS: Archival aspirates diagnosed as metastatic ONB were retrieved and reviewed for described characteristics of ONB. Spare direct smears with sufficient cellular material from each case were selected, if available, and immunocytochemistry for INSM1 was performed on the destained alcohol-fixed smears. INSM1 was also performed on non-neuroendocrine malignant round cell tumors (MRCT). RESULTS: Seven fine needle aspirates (FNA) from five patients were identified, all of which showed a small round cell tumor with fine to coarse granular chromatin. Most cases had moderate to high cellularity, comprised of loosely cohesive clusters and dispersed cells. While two-cell pattern, nuclear streaking and moulding were frequent, background neuropil, fibrillary cytoplasm, and rosettes were uncommon. INSM1 immunostaining performed on spare direct smears showed strong positivity in 30%-100% of tumor cells (mean: 62%) in all aspirates tested (100%). In comparison with other immunostains, INSM1 showed more robust staining, and was easier to interpret. All non-neuroendocrine MRCTs were negative for INSM1. CONCLUSION: Metatstatic ONB can resemble other small round cell tumors, as all the diagnostic features of ONB may not be readily evident. INSM1 immunocytochemistry has high sensitivity and specificity and can reliably be used as a single marker to support the cytomorphology for a confirmatory diagnosis of ONB, even on direct smears if a cell block is not available.

Immunohistochemical Profiling and Staging in Esthesioneuroblastoma: A Single-Center Cohort Study and Systematic Review.

OBJECTIVE: Esthesioneuroblastoma (ENB) is a rare sinonasal malignant neoplasm with 40% 5-year survival. Because of the rarity of the tumor, the optimal treatment and subsequent prediction of prognosis are unclear. We studied a modern series of patients with ENB to evaluate the association of immunohistochemical (IHC) markers and clinical stages/grades with outcomes. METHODS: A single-center retrospective review of patients with ENB treated during a 25-year period was performed. A systematic literature review evaluating the prognostic benefits of current staging systems in evaluating survival outcomes in ENB was undertaken. RESULTS: Among 29 included patients, 25 (85%) were treated surgically at our institution, with 76% of those endoscopically resected; 7 (24.1%) received chemotherapy, and 18 (62.1%) received radiation therapy. The 5-year overall survival (OS) was 91.3%, and 10-year OS was 78.3%. Progression-free survival at 5 and 10 years was 85.6% and 68.2%, respectively. A total of 36 distinct IHC markers were used to diagnose ENB but were inconsistent in predicting survival. A systematic literature review revealed predictive accuracy for OS using the Kadish, TNM, and Hyams staging/grading systems was 68%, 42%, and 50%, respectively. CONCLUSIONS: This study reports the 5- and 10-year OS and progression-free survival in a modern series of patients with ENB. No traditional IHC marker consistently predicted outcome. Some novel reviewed markers show promise but have yet to enter clinical mainstream use. Our systematic review of accepted staging/grading systems also demonstrated a need for further investigation due to limited prognostic accuracy.

Expressions of NeuroD and GAP43 as diagnostic markers for olfactory neuroblastoma.

OBJECTIVE: Olfactory neuroblastoma (ONB) is often difficult to pathologically distinguish from other small round cell tumors (SRCTs) arising in the nasal cavities. Although there are several diagnostic markers used for differential diagnosis of ONB, these molecules are also expressed in various neuronal derived tumors. Here, we examined the expression of NeuroD, GAP43, and olfactory marker protein (OMP) in ONB and non-ONB SRCT to determine their utility in the differential diagnosis of ONB. METHODS: Twenty-six patients diagnosed with and treated for ONB at Kobe University Hospital between 1997 and 2017 with formalin-fixed, paraffin-embedded biopsy or surgical resection specimens were included. The expressions of NeuroD, GAP43, and OMP were immunohistochemically examined in these 26 ONB specimens and specimens from 13 SRCTs arising in the nasal cavities for reference. RESULTS: Among the 26 ONB samples, focal, patchy, and marked staining for NeuroD was observed in 4, 3, and 9 samples, respectively. Focal, patchy, and marked GAP43 staining was observed in 5, 3, and 11 samples, respectively. Consequently, marked positive staining for either NeuroD or GAP43 was observed in 54% (14/26) of ONBs. Among the 13 SRCTs, marked staining for NeuroD was observed in two small cell carcinomas, one undifferentiated carcinoma, and one neuroendocrine carcinoma, whereas marked positive staining for GAP43 was observed only in one undifferentiated carcinoma. No specimen in this study exhibited OMP staining. CONCLUSIONS: Our results suggest possible roles of GAP43 immunostaining in the differential diagnosis of ONB.

Metastatic esthesioneuroblastoma recurrence after 19 years of remission: A systematic review with case illustration.

PURPOSE: Esthesioneuroblastoma (ENB) is a rare malignant neoplasm of the olfactory epithelium with an estimated incidence of 0.4/million. It can directly extend along the cribriform plate in order to metastasize to the central nervous system. However, non-contiguous intracranial involvement without recurrence at the primary site is extremely uncommon. In this report, the authors review the literature and present a case of non-contiguous intracranial metastasis of ENB without recurrence at the primary site. To the best of our knowledge, this case presents the longest disease-free interval reported in the literature. METHODS: A systematic review of literature was conducted in accordance with the PRISMA guidelines. Additionally, the presentation, surgical management, and post-operative outcomes of an 82-year-old female with non-contiguous intracranial metastasis of ENB after 19 years of remission are described. RESULTS: A total of 137 deduplicated works were identified after the search. Of these, 6 papers satisfied our inclusion criteria for our systematic review. Average age at presentation was 50.8 years (range: 26-66) and 52.6% of patients were female. A majority of cases achieved gross-total resection and received adjuvant radiotherapy for initial treatment. The median interval to intracranial metastasis was 6 years from the time of primary tumor presentation. The median overall survival from ENB recurrence with non-contiguous intracranial metastasis was 11.5 months. CONCLUSIONS: ENB is a highly recurrent tumor and harbors the potential to involve the intracranial space even years after remission. Intracranial involvement entails poor overall survival. Lifetime radiographic follow-up should be considered in all patients with ENB.

Transcription Factor Expression in Sinonasal Neuroendocrine Neoplasms and Olfactory Neuroblastoma (ONB): Hyams' Grades 1-3 ONBs Expand the Spectrum of SATB2 and GATA3-Positive Neoplasms.

Sinonasal neuroendocrine neoplasms (SN-NENs) are rare and mostly include neuroendocrine carcinoma (NEC), whereas neuroendocrine tumor (NET) is exceptional in this site. Olfactory neuroblastoma (ONB) is a malignant neuroectodermal neoplasm arising in the nasal cavity. Albeit crucial for correct patients' management, the distinction of high grade ONB from NEC is challenging and requires additional diagnostic markers. The transcription factor SATB2 has been recently introduced in routine diagnostics as an immunohistochemical marker of distal intestine differentiation. No specific data are available about SATB2 and GATA3 expression in SN-NENs. GATA3, SATB2, and, for comparison, CDX2 expression were investigated in a series of epithelial and non-epithelial SN-NENs. We collected 26 cases of ONB and 7 cases of epithelial SN-NENs diagnosed and treated in our Institution. ONBs were graded according to Hyams' system and epithelial NENs were reclassified into 5 NECs, 1 MiNEN, and 1 amphicrine carcinoma. Immunohistochemistry was performed using standard automated protocols. Hyams' grades 1-3 ONBs stained diffusely and intensely for SATB2, whereas grade 4 ONBs and NECs were globally negative. The non-neuroendocrine component of MiNEN and the amphicrine carcinoma were strongly positive. GATA3 was heterogeneously and unpredictably expressed in Hyams' grades 1-3 ONBs, whereas grade 4 ONBs and NECs were completely negative. CDX2 was negative in all cases. Our study identifies, for the first time, SATB2 and GATA3 expression as features of Hyams' grades 1-3 ONBs, expands the spectrum of SATB2 and GATA3-positive neoplasms, and suggests that Hyams' grade 4 ONBs are not only clinically but also biologically different from low graded ONBs.