Esthesioneuroblastoma Treatment & Management

Due to the rarity and complexity of esthesioneuroblastoma (ENB), there exists considerable heterogeneity in treatment. Complete surgical resection of the tumor followed by radiation therapy is recognized by most studies as the optimal treatment. However, some institutions report success with alternative treatment sequences, including surgery without radiation. More recently, chemotherapy has been introduced in the therapeutic armamentarium. Because of the lack of any randomized trial comparing these treatment protocols, the available data can be summarized as follows:

• Single-modality therapy versus combined treatment

  • The literature gives little support to single-modality treatments; few studies advocate either surgery or radiation alone. Dulguerov’s 2001 meta-analysis clearly showed lower recurrence rates for the combination of surgery and radiotherapy.^[18]
  • Some institutions advocate surgery alone for Kadish stage A tumors, whereas most suggest adjuvant radiotherapy for these lesions.
  • A few studies advocate neoadjuvant chemotherapy for Kadish C lesions.
  • Unlike most surgical specimens from the head and neck, specimens from the nasal cavity and paranasal sinuses, even en bloc, are difficult to orient, and surgical margins are difficult to analyze. Because one can rarely be completely confident of the adequacy of surgical margins, postoperative radiation to minimize the risk of local recurrence seems justified in almost all patients.
• Timing of surgery and radiation in combined therapy

  • Most institutions favor surgery as the first treatment modality, followed by postoperative irradiation.
  • Preoperative radiation results in the usual loss of definable tumor borders, which makes an en-bloc resection problematic. However, it has been noted that a theoretical advantage to preoperative radiation therapy is to convert an inoperable tumor to one that is amenable to resection. This theory is not widely supported.
• Radiation technique

  • Standard techniques include external megavoltage beam and a 3-field technique; an anterior port is combined with wedged lateral fields to provide a homogeneous dose distribution. The radiation portals are nowadays planned by integrating pretreatment CT or MRI imaging within the radiotherapy software.
  • The dose varies from 5500-6500cGy. The majority of patients receive < 6000 cGy. These doses are close to or exceed the maximum radiation dose recommended for sensitive structures such as the optic nerve, optic chiasma, brainstem, retina, and lens. Therefore, those patients are susceptible to cataract formation and glaucoma.
  • A possible role of proton beam radiotherapy, intensity-modulated radiotherapy, and stereotactic radiation has been suggested.^{[19, 20]} Several institutions have reported that intensity-modulated radiotherapy can provide good tumor control with low rates of radiation-induced toxicity, in children as well as in adults.^{[21, 22]} There are case reports describing the use of CT-guided interstitial high-dose-rate brachytherapy.^[23] However, prospective clinical trials confirming the efficacy of these modalities have not yet been completed.
• Role of chemotherapy

  • Chemotherapy is not recommended for routine treatment of ENB. Exceptions include palliative treatments or as part of a multimodality treatment in patients with advanced or metastatic disease.^[24]
  • The use of chemotherapy has been advocated by authors from the University of Virginia.^[25] In their protocol, patients with advanced disease (eg, Kadish stage C) are treated first with 2 cycles of cyclophosphamide (300-650 mg/m²) and vincristine (1-2 mg) with or without doxorubicin, followed by 50 Gy of radiotherapy, which then is followed by a craniofacial resection. With this regimen, the 5-year and 10-year actuarial survival rates are 72% and 60%, respectively. Similar results have been obtained without chemotherapy, and how much chemotherapy contributed to the cure rates is unclear.
  • Cisplatin-based regimens are preferred at the Mayo Clinic^{[26, 27]} and at the Gustave-Roussy Institute in France,^[28] but even if ENBs are responsive to cisplatin, chemotherapy for high-grade tumors in the advanced setting is not curative.
  • At Harvard, the selected regimen is cisplatin (33 mg/m²/d) and etoposide (100 mg/m²/d) for 3 days. This has been followed by proton radiation in 9 patients, with excellent results.^[19] This is probably the only study that demonstrates convincingly the possibility of a nonsurgical treatment of ENB, although the patient population is small.
  • A more aggressive chemotherapy regimen was reported by Mishima et al.^[29] In 8 of 12 patients receiving a combination of cyclophosphamide, doxorubicin, vincristine, and continuous-infusion cisplatin and etoposide followed by radiation, a complete response was achieved. Toxicity was acceptable, according to the authors. Turano et al achieved success in treating advanced anult tumors by alternating cisplatin and etoposide with doxorubicin, ifosafimide, and vincristine.^[30]

Surgery remains the primary treatment for esthesioneuroblastoma (ENB) and offers the best chance for locoregional control as well as survival. Both open and endoscopic craniofacial resection have achieved complete surgical resection with tumor-free margins. In the last 20 years, craniofacial resection followed by radiation therapy has been repeatedly referred to as the “gold standard” for treatment, and thus, other treatment modalities should be measured against it. Open craniofacial resection permits en-bloc resection of the tumor, with assessment of any intracranial extension and protection of the brain and optic nerves.

• The en-bloc resection should include the entire ipsilateral cribriform plate and crista-galli.
• The olfactory bulb and overlaying dura should be removed with the specimen.
• Preservation of the contralateral olfactory system, when possible, results in a preserved sense of smell in a few cases.
• A tumor that does not penetrate the orbit can be encompassed by resecting the lamina papyracea or even small segments of orbital periosteum.
• To avoid late frontal sinus mucocele formation, the posterior table of the frontal sinus should be taken down, the mucosa removed, and the cranial contents allowed to fill the defect.
• Repair of the dura is facilitated by the added exposure afforded by craniotomy. Although cranial floor defects as large as 4 cm may be present, bone grafts have not been necessary. The cranial floor is repaired by various techniques, including a pericranium flap, temporalis muscle and fascia transposition, or a layer of fascia lata held with thrombin glue. This prevents the herniation of cranial contents into the nasal cavity and the occurrence of cerebrospinal fluid leaks.
• Pneumocephalus has been prevented in the immediate postoperative period by the placement of a nasal trumpet in the operated nasal fossa, along with necessary packing, to vent any coughed or pressurized air away from the cranial cavity.
• Postoperative complications have been reported in 15-40% of cases. Major complications include (but are not limited to) frontal lobe abscess, infection, and intercranial hemorrhage.

Endoscopic craniofacial resection (ECFR)

• ECFR is being successfully performed and is now a widely accepted treatment modality.
• Multiple studies have shown it to be a safe, feasible, and oncologically sound technique.^{[31, 32, 33, 34]}
• Initially, an endoscopic approach was limited to Kadish stages A and B; however, successful resections have been performed on stage C tumors.^[31]
• The benefits of an endoscopic approach include decreased time in surgery, blood loss, morbidity, postoperative complications, and cost.
• Excess bleeding can hinder the endoscopic approach.
• Endoscopic resection followed by gamma-knife stereotactic radiosurgery has demonstrated positive outcomes.
• Key features unique to the endoscopic approach include the following:

  • Creating generous sphenoidotomies and drilling off the sphenoid rostrum to make a common sphenoid sinus cavity allowing exposure to the planum sphenoidale.
  • A Draf type III, Lothrop-type, frontal sinusotomy communicating both frontal sinuses across the midline to expose a common frontal sinus cavity.
  • Using a high-speed cutting bur, performing an anterior fossa craniotomy bilaterally, from the planum posteriorly to the posterior wall of the frontal sinus anteriorly.
  • The dura is resected and a complete anterior fossa resection is performed. This includes bilaterally transecting the olfactory tracts.
  • A multi-layered dural reconstruction is performed, which includes an intradural inlay and overlay Alloderm graft, abdominal fat, and sealant. The multi-layered reconstruction is supported intranasally, with placement of packing under direct visualization and the balloon of a Foley catheter.

Neck metastasis at presentation occurs in 5–7% of patients. When neck disease is diagnosed at the initial presentation, it should be treated surgically.^[35]

In their literature review, Beitler et al found an incidence of delayed neck metastasis of 19%, but half of these patients also presented with local recurrence.^[36] Salvage treatment was successful in 70% of these patients. Contrary to the conclusion of Beitler et al, the authors do not consider that a 10% rate of delayed neck recurrence represents justification for elective neck dissection in all cases of ENB.

The goal of surgery is to achieve complete tumor resection with negative margins. The number of studies reporting success with the endoscopic approach without compromising effectiveness in the short term is increasing. Short-term prognosis of both methods is comparable; however, the long-term outcomes of the endoscopic approach have yet to be evaluated. The decision between endoscopic versus craniofacial resection should be evaluated on an individual case basis. Considerations should include the extent of tumor progression as well as the histopathologic and morphologic characteristics of the tumor.

Usually, patients with head and neck tumors are treated in academic centers with broad expertise with prospective treatment programs outlined in the multidisciplinary tumor board. Head and neck tumor boards usually include a head and neck surgeon and radiation and medical oncologists. Speech language pathologists, psychosocial oncologists, nutritional and social work support, and dental consultations are available. Maxillofacial and prosthetic consultants are incorporated as needed. The treatment protocol is decided in common, and each specialist performs his or her own specific task as described above.

• A craniofacial team, in which neurosurgeons form an essential part, usually manages an esthesioneuroblastoma (ENB) surgically. Most of the important complications after surgery concern the brain and calvarium; thus, close neurosurgical follow-up is necessary.
• For ENB, a preoperative ophthalmology evaluation is mandatory because the optic nerves are at risk during either radical surgery or radiation therapy. In addition, ophthalmologists can be helpful if partial intraorbital resection is contemplated. Dacryocystorhinostomy usually is performed during surgery, and ophthalmologists can provide help in this procedure and/or the postoperative evaluation of the lacrimal system.
• If an associated palate resection is contemplated, the upper dental prosthesis should be made before surgery and placed at the end of the procedure. This usually achieves a separation of the oral cavity from the nasal cavity and allows adequate oral nutrition. Adjustments of this prosthesis are required after ablation of the nasal packing and in response to tissue scarring and/or retraction that take place within 6 months after completion of treatment.

No specific postoperative dietary restrictions are required for patients with esthesioneuroblastoma (ENB).

• Following major surgery, patients tolerate only light meals during the first postoperative days.
• Patients with a history of constipation should be given stool softeners for the first postoperative week to prevent undue straining and allow the skull base repair to heal.

• Some surgeons routinely place a lumbar drain to decrease pressure on the dural repair. The authors tend to restrict CSF decompression to cases with significant dural sacrifice and replacement and/or when the base of skull repair is deemed fragile. As long as the drain remains in place, patients require strict bed rest.
• Otherwise, patients usually are out of bed on the first postoperative day.
• Patients should be advised to not blow their noses for several days and to open their mouth during sneezing and coughing to avoid the creation of pneumocephalus.