Esthesioneuroblastoma

Esthesioneuroblastoma (olfactory neuroblastoma) is a rare malignant neuroectodermal tumour arising from the olfactory neuroepithelium in the upper nasal cavity, at the cribriform plate and the roof of the nasal vault. It accounts for about 2 to 3 percent of sinonasal tumours (incidence 0.4 per million per year).

It has a bimodal age distribution (peaks in the second and sixth decades) and affects both sexes equally.

Histology shows lobules or nests of small round blue cells with neurofibrillary stroma and Homer Wright rosettes (in about 30 percent) or Flexner-Wintersteiner rosettes (rare), with S100 positive sustentacular cells at the periphery. Staining is positive for neuron specific enolase, synaptophysin, chromogranin and CD56, and negative for cytokeratin (usually negative or focal).

This distinguishes it from sinonasal undifferentiated carcinoma, neuroendocrine carcinoma, melanoma, lymphoma, and rhabdomyosarcoma.

Grading is by Hyams (grade I to IV). Grades I and II are less aggressive. Grades III to IV have high mitotic rate, necrosis and pleomorphism, and are more aggressive.

Staging systems:

• Kadish system: A is confined to the nasal cavity; B is nasal cavity and paranasal sinuses; C is extension beyond the nasal cavity and sinuses to the orbit, skull base, intracranial, or metastases; D was added by Morita for regional nodal or distant metastasis.
• Dulguerov (TNM) system (T1 to T4).

Presentation is late (months to years). Cervical node metastases occur in 5 to 20 percent initially and 20 to 30 percent in the later course. Distant metastases occur in 10 to 30 percent. Late recurrences occur (up to 10 to 15 years or more).

• Unilateral nasal obstruction (about 70 percent) and epistaxis (about 50 percent), the commonest symptoms, with anosmia or hyposmia (about 5 to 10 percent as a presenting symptom, which often goes unnoticed).
• Headache, rhinorrhoea, facial pain or swelling, and tearing (epiphora), proptosis, diplopia, and visual changes (orbital extension).
• Rarely, ectopic hormone secretion: syndrome of inappropriate antidiuretic hormone secretion and Cushing syndrome (ectopic adrenocorticotropic hormone).
• Intracranial extension: headache, personality change, cranial nerve palsies, and seizures; a mass in the nasal cavity (pink grey, polypoid and friable) on endoscopy, usually in the upper nasal cavity near the olfactory cleft.
• Cervical lymphadenopathy.

• Nasal endoscopy: a polypoid, vascular, friable mass in the superior nasal vault, olfactory cleft, with biopsy for histology; immunohistochemistry (neuroendocrine markers positive: synaptophysin, chromogranin, CD56; S100 sustentacular cells; cytokeratin variable) and exclusion of the differentials.
• MRI of the sinuses, skull base and brain with gadolinium (the best study): a dumbbell shaped mass at the cribriform plate with intracranial and nasal components ("waist" at the cribriform plate), with avid enhancement.
• MRI also shows peritumoral cysts at the tumour brain interface (characteristic), dural and brain involvement, and orbital invasion. CT of the sinuses and skull base shows bone erosion or remodelling.
• Staging: CT or PET-CT of the neck and chest and abdomen, and MRI neck for cervical lymph node assessment (in high grade tumours); somatostatin receptor imaging (68Ga-DOTATATE PET-CT) can be useful.
• Endocrine assessment if there are features of Cushing syndrome or hyponatraemia.
• Staging by Kadish and Hyams grading for therapeutic planning and prognostic assessment.

Optimal treatment is multimodal: surgery with postoperative radiotherapy for most tumours, within a multidisciplinary skull base team.

• Surgery: craniofacial resection (a combined transcranial transfacial approach, via a bifrontal craniotomy and a lateral rhinotomy) with removal of the cribriform plate, olfactory bulbs and tracts, the involved dura, and the tumour with negative margins. This was the traditional gold standard.
• Endoscopic endonasal resection (with or without a craniotomy) with skull base reconstruction (multilayer: fascia lata or collagen matrix inlay, with a vascularised nasoseptal flap onlay) has equivalent oncological outcomes in appropriately selected tumours (Kadish A to C without extensive orbital or brain parenchymal invasion), and lower morbidity.
• Complications of surgery: cerebrospinal fluid leak (3 to 8 percent), meningitis, pneumocephalus, anosmia, bleeding, and frontal lobe injury.
• Radiotherapy: postoperative radiotherapy for Kadish B and C (or all stages for high grade), at a dose of 60 to 65 Gy in 30 to 33 fractions (2 Gy per fraction), improves local control.
• Definitive radiotherapy (65 to 70 Gy) with or without chemotherapy is used for unresectable tumours. Proton therapy and stereotactic radiosurgery (for residual or recurrent) are used to spare adjacent structures (optic chiasm, brainstem). Elective neck irradiation in high risk patients (high grade, nodal disease) is considered.
• Chemotherapy: neoadjuvant or adjuvant chemotherapy for high grade tumours (Hyams III to IV), Kadish C, unresectable, and metastatic disease. Regimens are cisplatin 60 to 80 mg/m2 on day 1 with etoposide 100 mg/m2 on days 1 to 3 every 3 weeks (4 to 6 cycles), or cyclophosphamide-doxorubicin-vincristine.
• The combination of cisplatin and etoposide produces responses in about 50 to 70 percent of cases. Neoadjuvant therapy may downstage unresectable tumours.
• Somatostatin analogues (octreotide) and peptide receptor radionuclide therapy (177Lu-DOTATATE) are used in some for somatostatin receptor positive recurrent tumours.
• Cervical lymph node metastases: neck dissection (selective or modified radical) and radiotherapy. The role of prophylactic neck treatment is controversial.
• Recurrent disease (about 30 to 50 percent overall, with local recurrences being the commonest): salvage surgery and/or re-irradiation, and systemic therapy.
• Follow up: lifelong, with nasal endoscopy and MRI at 3 to 4 months postoperatively, then every 3 to 6 months for 2 to 3 years, then every 6 to 12 months for at least 10 to 15 years (given late recurrences), and neck imaging.
• Prognosis: 5-year survival of about 75 to 80 percent overall (90 percent for Kadish A, 70 to 80 percent for B, 40 to 60 percent for C), and a 10-year survival of about 50 to 60 percent.
• Grade is a major prognostic factor (Hyams grade I to II 5-year survival of 80 to 90 percent; III to IV 40 to 50 percent).