Esthesioneuroblastoma

Synonyms and related keywords: esthesioneuroblastoma, ENB, olfactory neuroblastoma, esthesioneuroepithelioma, olfactory esthesioneuroma, esthesioneurocytoma


INTRODUCTION

Background: Esthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of the nasal vault, believed to arise from the olfactory epithelium. In 1924, Berger and Luc first described the tumor in the French medical literature under the name esthésioneuroépithéliome olfactif. Because of the uncertainty surrounding its precise histological origin, various names have been ascribed to this tumor, but the only 2 terms used in recent publications are esthesioneuroblastoma and olfactory neuroblastoma.

Beyond the most appropriate naming, multiple opinions exist regarding its origin, diagnosis, and management. The source of this controversy stems primarily from the rarity of this unusual tumor and the fact that almost no individual clinician or even institution will treat more than a few patients each year with this diagnosis. Three other factors contribute to the controversy surrounding this neoplasm. First, this tumor exhibits varying biologic activity ranging from indolent growth with patients surviving with known tumor more than 20 years, to a highly aggressive neoplasm capable of rapid widespread metastasis and patient survival limited to a few months. The second factor involves problems with precise histologic diagnosis since esthesioneuroblastoma is often confused with other small, round cell undifferentiated neoplasms of the nasal cavity. Third, no universally accepted staging system is available (see Staging).

Pathophysiology: The exact cell of origin of esthesioneuroblastoma has been controversial. While a neuronal-neural crest origin is supported by the presence of neurofilaments in ENB, until recently, few arguments linked ENB directly to the olfactory epithelium.

The olfactory epithelium is a peculiar neurosensory organ because dying olfactory neurons are replaced by new ones, which exhibit a progressive maturation, not only during embryogenesis but also physiologically and when injured by trauma or environmental insults. The globose basal cells constitute a precursor population and express neural cell adhesion molecule (NCAM) and proteins coded by the mammalian analogue of Drosophila achaete-scute (MASH) gene. These progenitor cells differentiate in olfactory neurosensory cells, which exhibit a progressive maturation from the basal membrane to the epithelial surface. Each layer can be characterized by specific olfactory- and neuron-specific markers. Immature olfactory cells express GAP43, a 24-kd membrane-associated protein kinase C involved in polyphosphoinositide turnover. As these cells mature, they migrate toward the surface, send axons to the olfactory bulb, and express olfactory marker protein (OMP) and NCAM, but not GAP43.

In the mid 1990s, ENB was found to express HASH, the human homologue of the MASH gene, while staining negative for other olfactory epithelium markers. Further indirect evidence that ENB originates from olfactory stem cells can be derived from transgenic mice in which the SV40T oncogene was inserted under the OMP gene promoter region: these mice did not develop ENB but adrenal and sympathetic ganglia neuroblastoma. Therefore, the currently available evidence links ENB with the basal progenitor cells of the olfactory epithelium.

Inclusion of ENB within the Ewing sarcoma family of tumors or the primitive neuroectodermal tumors (PNET) was proposed because of the identification, in certain cases, of translocation t(11:22), which is regarded as a specific molecular abnormality for Ewing sarcoma. Recent studies using fluorescent in situ hybridization and reverse transcriptase polymerase chain reaction (PCR) have failed to confirm this translocation in ENB. Therefore, ENB should be seen as a distinct entity from PNET and the Ewing sarcoma family of tumors.

Most of the olfactory neuroepithelium is located at the cribriform plate; however, islands of olfactory mucosa may be found in the upper turbinates and the upper one third of the nasal septum as well as on the entire middle turbinate. On rare occasions, olfactory mucosa has been found in the inferior turbinates and in the maxillary sinus. This probably explains why a small percentage of early-stage tumors appear to be completely free of the cribriform plate.

Frequency:

• In the US: ENB remains a rare disease.

• Internationally: In an extensive literature review, Broich et al found about 1000 new cases reported; however, several multiple publications on the same patients were included. Most cases (80%) were reported within the last 20 years. This is certainly the result of better recognition of this disease entity by pathologists, although the possibility of a rising incidence cannot be ruled out entirely.

  In view of the lack of precise epidemiologic studies, the authors' data suggest an incidence of 1 case per 1,000,000 per year. Similar incidence figures were recently obtained in Denmark. Thus, the authors tend to think that ENB represents about 5% of all nasal malignant tumors.

Race:

• ENB does not show familial prevalence and has been reported in all races and on all continents.

Sex:

• ENB affects males and females with similar frequency.

Age:

• ENB occurs in all age groups.

CLINICAL

History: Esthesioneuroblastoma (ENB) does not cause specific symptoms, similarly to most other nasal and paranasal malignancies. The symptoms can be classified into nasal, facial, oral, ophthalmic, neurological, and cervical. The unilateral nature of symptoms should raise the suspicion of a possible neoplasia. Symptoms of nasal and paranasal cancers are as follows:

• Nasal - Obstruction, epistaxis, discharge, unilateral polyp, anosmia

• Neurological - Headache, nausea

• Oral - Mobile tooth, nonhealing tooth extraction, ill-adapted dental prostheses, ulceration

• Facial - Swelling, pain, anesthesia, trismus

• Cervical - Mass

• The average delay between the appearance of the first symptom and the diagnosis is 6 months. The most frequent symptoms are a unilateral nasal obstruction (70%), followed by epistaxis (46%). These are banal symptoms, occurring in common nasal diseases, including long-term rhinosinusitis or allergic polypoid sinus disease. Many of these patients undergo sinus surgery, only to have the diagnosis established as an unexpected pathological finding. The importance of sending the totality of removed tissue during sinus surgery and the vigilance of the pathologist cannot be overemphasized.

• Further growth of the tumor can be directed laterally within the orbit and results in proptosis, extraocular movement paralysis, and blindness, or, it superiorly produces intracranial complications. Facial and oral symptoms are rare.

• Early referral for an intranasal biopsy is key to early diagnosis. A patient with a unilateral nasal obstruction and/or a recurrent epistaxis lasting longer than 1-2 months should undergo a thorough nasal evaluation by an otolaryngologist, although the cost-effectiveness of this approach has not been evaluated.

Physical: A nasal examination, particularly if aided by endoscopy, reveals a reddish-gray tumor arising in the upper nasal fossa, which bleeds easily during instrumentation. Although the aspect is strictly different from the white glistening appearance of benign nasal polyps, little differentiates ENB from other nasal malignancies.

Causes: No clear etiologic agent or exposure has been documented in humans. However, ENB can be consistently induced by nitrosamine compounds in rodents. In cats with spontaneous ENB or in transgenic mice developing ENB, type C retroviral particles have been demonstrated and classified as feline and murine leukemia virus, respectively. The role of retrovirus sequences in human ENB remains to be evaluated.

DIFFERENTIALS

Lymphoma, Non-Hodgkin
Malignant Melanoma
Metastatic Cancer, Unknown Primary Site
Plasmacytoma, Extramedullary

Other Problems to be Considered:

Nasal and paranasal squamous cell carcinoma
Sinonasal polyposis
Choanal polyp
Juvenile angiofibroma
Neuroendocrine carcinoma
Embryonal rhabdomyosarcoma
Undifferentiated sinonasal carcinoma
Ewing sarcoma

WORKUP

Lab Studies:

• No specific lab studies confirm the diagnosis of esthesioneuroblastoma (ENB). Because surgery often is contemplated and because open nasal procedures are associated with significant bleeding and may involve blood transfusions, a CBC count could be obtained, and the patient should be advised about preoperative blood donation.

Imaging Studies:

• CT scan

• Standard radiographs do not have a role in the evaluation of ENB. A direct coronal fine-cut CT scan (ie, 3 mm) is the initial radiological study of choice.

• ENB lacks a specific radiological appearance and appears as a homogeneous soft tissue mass with uniform and moderate contrast enhancement.

• CT images are essential for correct staging and should be evaluated carefully for erosion of the lamina papyracea, cribriform plate, and fovea ethmoidalis.

• Obstruction of the sinus-draining ostia results in an accumulation of nasal secretions, which tend to be difficult to differentiate from tumor tissue when viewed by a CT scan.

• MRI

• MRI often is necessary to better delineate sinonasal and intraorbital extension or an intracerebral extension.

• Using MRI, ENB appears as hypointense to gray matter on T1-weighted images and isointense or hyperintense to gray matter on T2-weighted images.

• Because details of bony erosion are better demonstrated by CT images, both studies usually are required in the majority of patients.

• Octreoscan

• Imaging with an Octreoscan is based on the binding of the radiolabeled somatostatin analog, 111In-pentoctreotide (111In-DTPA-D-Pheoctreotide), to a subset of somatostatin receptors.

• In few reported cases, this imaging modality was found useful, although its sensitivity and specificity remain unclear.

• Since most ENB express somatostatin receptors, Octreoscan is promising.

Other Tests:

• No other diagnostic tests are necessary.

Procedures:

• Biopsy

• Grossly, ENB appears as a gray-to-red mass in the nasal vault. The color usually is related to the extent of tumor vascularization, raising the possibility of profuse nasal bleeding following the biopsy procedure.

• Taking a biopsy specimen should be deferred until completion of the radiologic studies to avoid swelling effects and the inadvertent biopsy of other nasal tumors of neurogenic origin.

• Biopsy is performed after topical anesthesia under direct vision through a rigid endoscope. The specimen should be sent for regular staining as well as for immunohistochemistry and possibly electron microscopy.

Histologic Findings: Well-differentiated ENBs exhibit homogenous small cells with uniform round-to-oval nuclei with rosette or pseudorosette formation and eosinophilic fibrillary intercellular background material. True rosettes (ie, Flexner-Wintersteiner [FW]) refer to a ring of columnar cells circumscribing a central oval-to-round space, which appears clear on traditional pathological sections. Pseudorosettes or Homer Wright (HW) rosettes are characterized by a looser arrangement and the presence of fibrillary material within the lumen. Fibrils have been shown by electron microscopy to represent cellular cytoplasmic processes.

In undifferentiated ENB characterized by anaplastic hyperchromatic small cells with numerous mitoses and scant cytoplasm, differentiation from other small-cell nasal neoplasms via light microscopy becomes difficult. Immunohistochemical staining and electron microscopy are essential for establishing the pathological diagnosis of sinonasal small cell neoplasms, which include malignant melanoma, embryonal rhabdomyosarcoma, malignant lymphoma, extramedullary plasmocytoma, and, especially, sinonasal undifferentiated carcinoma and sinonasal neuroendocrine carcinoma. No specific immunocytologic stain identifies ENB, but a typical staining profile can be very helpful. With ENB, the stain is positive for S-100 protein and/or neuron-specific enolase, while the stain usually is negative for cytokeratin, desmin, vimentin, actin, glial fibrillary acidic protein, UMB 45, and the common leukocytic antigen. For difficult cases, electron microscopy can be useful.

ENB can be distinguished from melanoma by the lack of UMB 45 immunopositivity and the pattern of S-100 staining, which is scattered and peripheral in ENB, but, in melanoma, the staining is diffuse and strong. ENB can be distinguished from rhabdomyosarcoma by the lack of cross-striated cells (ie, rhabdomyoblasts) and an absence of immunostaining with desmin, vimentin, and actin. ENB can be distinguished from lymphoma by the lack of common leukocyte antigen immunostaining.

ENB can be distinguished from sinonasal undifferentiated carcinoma through histology (ie, absence of numerous mitotic figures, areas of necrosis, vascular invasion, glandular differentiation) and immunohistochemistry (ie, lack of staining with cytokeratin antibodies). ENB can be distinguished from neuroendocrine sinonasal carcinoma by the lack of cytokeratin immunopositivity, which, in neuroendocrine carcinoma, tends to assume a punctate paranuclear distribution upon electron microscopy. ENB can be distinguished from Ewing sarcoma (rare within the paranasal sinuses) by the lack of myc-2 protein immunostaining.

In summary, the pathological distinction of poorly differentiated small neoplasms of the nasal cavity is difficult and is based on a panel of immunohistochemical stains and, if necessary, electron microscopy. The reactions used should include S-100 protein, neuron-specific enolase, chromogranin and/or synaptophysin, cytokeratin, desmin, actin, UMB 45, common leukocytic antigen, and myc-2 protein.

The demonstration of HASH gene expression, although still investigational, could become the diagnostic procedure of choice. Mhawech et al were able to distinguish ENB from other sinonasal, poorly differentiated tumors by real-time PCR assay of hASH1 mRNA levels. In addition, as an inverse association was noted between the grade of ENBs and hASH1 mRNA levels.

Histopathologic Grading According to Hyams (1988)

Grade	Lobular Architecture Preservation	Mitotic Index	Nuclear Polymorphism	Fibrillary Matrix	Rosettes	Necrosis
I	+	Zero	None	Prominent	HW rosettes	None
II	+	Low	Low	Present	HW rosettes	None
III	+/-	Moderate	Moderate	Low	FW rosettes	Rare
IV	+/-	High	High	Absent	None	Frequent

Staging: From a limited series of 17 patients, Kadish et al were the first to propose a staging classification for ENB. Patients were divided into 3 categories: groups A, B, and C. Group A is limited to tumors of the nasal fossa; in group B, extension is to the paranasal sinuses; group C is defined as extension beyond the paranasal sinuses.

The Kadish classification has several shortcomings. Recognizing these inadequacies, a proposed classification is based on the Tumor Node Metastasis (TNM) system, which is predicated on CT scan and MRI findings that can be elucidated before treatment. Thus, patients treated by primary or preoperative radiation can be staged as reliably as surgical candidates. Although this classification system has gained popularity, attempts have been made to modify the Kadish system for ENB.

• TNM system where T = tumor, N = node, and M = metastasis

• T1 - Tumor involving the nasal cavity and/or paranasal sinuses (excluding sphenoid), sparing the most superior ethmoidal cells

• T2 - Tumor involving the nasal cavity and/or paranasal sinuses (including the sphenoid), with extension to or erosion of the cribriform plate

• T3 - Tumor extending into the orbit or protruding into the anterior cranial fossa, without dural invasion.

• T4 - Tumor involving the brain

• N0 - No cervical lymph node metastasis

• N1 - Any form of cervical lymph node metastasis

• M0 - No metastasis

• M1 - Distant metastasis

TREATMENT

Medical Care: The role of an accurate histopathological diagnosis before initiating treatment for ENB cannot be overemphasized. Classic treatment strategies of ENB are based on surgery or radiotherapy as unique modalities or a combination of surgery and radiation therapy. More recently, chemotherapy has been introduced in the therapeutic armamentarium. The optimal treatment sequence varies in different institutions. Because of the lack of any randomized trial comparing these treatment protocols, the available data can be summarized as follows:

• Surgery or radiation versus combined therapy
  • The literature gives little support to single-regimen treatments because few studies advocate either surgery or radiation alone. The authors' meta-analysis clearly provided lower recurrence rates for combined treatment.
  • The only conceivable indication for single-modality treatment would be a patient with a small tumor located well below the cribriform plate (eg, Dulguerov T1 stage).
  • 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
  • Most institutions favor surgery as the first treatment modality, followed by postoperative irradiation. The authors have found that preoperative radiation results in the usual loss of definable tumor borders, which makes an en-bloc resection problematic.
  • The theoretical advantage that preoperative radiation will convert an unresectable tumor to resectable status is not supported by most head and neck oncologic surgeons.
  • Preoperative radiotherapy as a standard protocol for all patients has been promoted by some institutions.

• 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 5500-6500 cGy and, in most cases, is more than 6000 cGy. These doses are close or exceed the radiation dose admitted to sensitive structures such as the optic nerve, optic chiasma, brainstem, retina, and lens.
  • A possible role of proton beam radiotherapy, intensity-modulated radiotherapy, and stereotactic radiation has been suggested recently, but it remains to be convincingly demonstrated.

• Role of chemotherapy
  • The use of chemotherapy has been advocated by publications from the University of Virginia. 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 and at the Gustave-Roussy Institute in France, but, 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. 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. Eight of 12 patients receiving a combination of cyclophosphamide, doxorubicin, and vincristine with continuous-infusion cisplatin and etoposide, with radiation achieved complete response. Toxicity was acceptable according to the authors.
  • Isolated case reports exist of survival after chemotherapy treatment of metastatic disease.

• Conclusion
  • Low-grade and low-stage tumors should be treated by surgery followed, in most cases, by radiation therapy.
  • This treatment regimen should be applied to the majority of ENB, with the possible exception of T4 and the highest Hyams grade cases. In these advanced and poorly differentiated cases, the role of preoperative chemotherapy and radiation should be decided on an individual basis.
  • The authors do not see a role for chemotherapy in the routine treatment of ENB. However, for patients with advanced or metastatic disease, systemic chemotherapy as part of multimodality therapy could be an option.

Surgical Care: Endocranial extension and the close relationship to the ethmoidal roof and cribriform plate require a combined transfacial and neurosurgical approach. A craniotomy probably is not justified for T1 tumors, where clear radiological evidence of a normal cribriform plate and upper ethmoid cells exist. All other patients should be treated by a transfacial approach combined with a bifrontal craniotomy. In the authors' data, craniofacial resection resulted in much better local control than other surgical resections (ie, 100% vs 40%), and other series tend to support these findings.

• Craniofacial resection permits en-bloc resection of the tumor, with better 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 has prevented 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.

• Neck metastasis at presentation occurs in 5±7% of patients. When neck disease is diagnosed at the initial presentation, it should be treated surgically.

• In their literature review, Beitler et al found an incidence of delayed neck metastasis of 19%, but half of these patients also presented a local recurrence. 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% incidence rate of a delayed neck recurrence represents justification for elective neck dissection in all cases of ENB.

Consultations: Usually, patients with head and neck tumors are discussed in university centers, within multidisciplinary tumor boards. Head and neck tumor boards usually include a head and neck surgeon and radiation and medical oncologists. 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 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. In addition, ophthalmologists could be helpful if contemplating partial intraorbital resection. Dacryocystorhinostomy usually is performed during surgery, and ophthalmologists could help in this procedure and/or the postoperative evaluation of the lacrimal system.

• If contemplating an associated palate resection, 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 following tissue scarring and/or retraction that take place within 6 months after completion of treatment.

Diet: No specific postoperative dietary restrictions are required for patients with ENB.

• Following major surgery, patients only tolerate 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 base of skull repair to heal.

Activity:

• Some surgeons routinely place a lumbar drain to decrease pressure on the dural repair. The authors' tend to restrict CSF decompression to cases with important dural sacrifice and 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 let the air out during sneezing to avoid the creation of pneumocephalus.

MEDICATION

Routine chemotherapy for ENB is not recommended.


FOLLOW-UP

Further Inpatient Care:

• In the first 48 hours following craniofacial resection, regular neurosurgical evaluation is required. ICU monitoring for at least 24 hours also is necessary. Duration of the lumbar drainage is controversial, varying from intraoperative only to as long as 7 days.

• Aspiration of the nasal trumpets should be performed several times a day. Nasal packing is left in place for 5-7 days. Removal of large nasal packing is uncomfortable, and some pain medication could be administered before the procedure.

Further Outpatient Care:

• Craniotomy sutures are removed 7-10 days after surgery. If a facial incision has been used, sutures are removed after 5 days.

• Nasal irrigation with sterile isotonic sodium chloride solution begins within a few days after packing removal. Nasal crusting removal should be performed regularly during initial postoperative visits. This problem is aggravated during radiotherapy but decreases in most patients after 1-2 years. It is a lifelong burden for which no good treatment or prevention is available.

In/Out Patient Meds:

• This procedure usually is performed under antibiotic prophylaxis started before skin incision, using coverage for gram-positive bacteria. Because good intracerebral doses are preferred, ceftriaxone often is a good choice. The authors continue antibiotics while the nasal packing remains in place.

Complications:

• Craniofacial resection for esthesioneuroblastoma (ENB) has been associated with a complication rate of 10-15%.

• The most frequent problems are infections, including abscess surrounding the bone flap, meningitis, and, less often, subdural or epidural abscess.

• Meningitis sometimes is related to the presence of a cerebrospinal fluid leak because the closure of the anterior skull base is not always watertight.

• Pneumocephalus has been another difficult problem to prevent. Although self-limiting in most cases, pneumocephalus can result in brain compression and requires needle aspiration through the trephine bony holes.

• Blindness secondary to optic nerve injury and death, either from intracerebral bleeding or internal carotid injury, has become exceptional.

• Inform patients that olfactory function should be either altered or absent after surgery. In addition, nasal crusting is a long-lasting problem that requires daily nasal irrigation for several years.

• Delayed complications include necrosis of the frontal bone flap, lacrimal drainage obstruction, and frontal sinus mucocele.

• Radiation-related complications also are rare and include lacrimal duct blockage and tearing, postradiation cataract, osteoradionecrosis of the frontal bone flap, radiation retinopathy, and blindness.

Prognosis:

• Treatment results before the availability and use of modern diagnostic techniques were flawed, probably by the inclusion of cases of sinonasal undifferentiated carcinoma and sinonasal neuroendocrine carcinoma, two aggressive diseases associated with poor survival. The importance of correctly differentiating these cancers is highlighted in a recent report by Rosenthal et al.

• In recent series, the 5-year patient survival rate varies from 50-80%, with the majority of large studies indicating patient survival rates of higher than 70%. In the authors' meta-analysis, the average 5-year survival was 45 ± 22 % (range, 0-86%).

• Whether the Kadish classification system has a definitive prognostic value remains unknown, but the available survival data for stages A, B, and C are 72%, 59%, and 47%, respectively. According to the Dulguerov staging system, the survival rates were 81% for T1, 93% for T2, 59% for T3, and 48% for T4.

• Prognostic survival factors that emerged in the authors' meta-analysis include lower Hyams histopathologic grade (56% for grades I-II vs 25% for grades III-IV) and absence of neck lymph node metastasis (64% for N0 vs 29% for N+).

• Other reasonable but undemonstrated prognostic factors include a low proliferative index, the completeness of the surgical resection, and tumor shrinkage after induction chemotherapy.

• Survival data according to treatment modality favored regimens including surgery.

• The most frequent recurrence is local, with rates from 20-40% (29% in the meta-analysis). Craniofacial resection followed by radiation seems to result in fewer recurrences, a rate of approximately 10%. Salvage after local recurrence is possible in one third to one half of cases.

• Regional recurrence, while the primary site is under control, occurs in 15% of cases and is salvageable by further treatment in 25-50% of cases. Distant metastasis with locoregional control is not frequent (8%) and carries a dismal prognosis.

• Note that recurrence could occur years after the completion of treatment, often more than 10 years; therefore, prolonged follow-up is required, although the exact frequency of medical visits and the necessity of radiological studies has not been precisely studied.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to inform the patient that treatment of ENB can be associated with serious complications, as previously outlined, can be problematic because ENB is a cancer located in an area surrounded by essential structures, including the eye and optic nerve, internal carotid artery, and the brain.