Classically, ONBs are characterized by small, round, blue cells slightly larger than mature lymphocytes, with a very high ratio of nucleus to cytoplasm, arranged in a lobular pattern (Fig. 38.3a, b).

ONB is often graded according to Hyams criteria, which range from Grade I to Grade IV [12]. These criteria are based on several features, including architecture, pleomorphism, neurofibrillary matrix, rosettes, mitoses, necrosis, glands, and calcification. Grade I ONB is characterized by lobular cytoarchitecture, little pleomorphism, prominent neurofibrillary matrix, Homer-Wright pseudorosettes, no mitoses or necrosis, and variable calcification. On the other extreme, Grade IV ONB is characterized by loss of lobular cytoarchitecture, marked pleomorphism, necrosis, mitoses, Flexner-Wintersteiner rosettes, and absent calcification [12].

ONBs are typically positive for synaptophysin (Fig. 38.3c), chromogranin, CD56, neuron-specific enolase, neurofilament protein (NFP), and S100 protein [2].

The Ki-67 proliferative index is usually high, ranging between 10 and 50 % [2].

Depending on the stage of disease at the time of diagnosis and the degree of tumor resection, multimodality treatment consisting of surgery, radiation, and chemotherapy is often implemented.

One large meta-analysis showed no difference in survival between patients who underwent surgery alone and those who underwent surgery plus radiotherapy at 5 years (78 % vs. 75 %) or 10 years (67 % vs. 61 %) [13].

Survival has been associated with Kadish stage and Hyams stage [11, 13]. According to the original Kadish staging, patients with Kadish A tumors had a 5-year survival of 75–91 %, compared with 41–47 % for patients harboring Kadish C tumors [11].

Surgical resection may be performed via standard open craniotomy, craniofacial approaches, or more recently, extended endoscopic endonasal approaches [14].

In a series of 11 patients by Gallia et al. [14], complete endoscopic endonasal surgical resection was possible in all patients, with no patients demonstrating recurrence at 28 months follow-up.

Recent meta-analyses have lent support to equal or more favorable outcomes following endoscopic resection compared with open surgery, although some selection bias exists in the surgical approaches assigned to varying Kadish ONB subtypes [15, 16].

The benefits of adjuvant radiation have been debated; some studies have shown a beneficial effect [17] and others have shown no major benefits [13].