Bobby R. Alford Department of
Otolaryngology-Head and Neck Surgery

Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.

Esthesioneuroblastoma
Mark Zafereo, M.D.
January 10, 2008

PF is a 72-year-old gentleman with a 2-year history of nasal obstruction and mucoid rhinorrhea.  He had previously seen an outside otolaryngologist and was originally thought to have right-sided nasal polyposis.  He had no previous sinonasal surgery, and his past medical history was otherwise only remarkable for diabetes mellitus.  He denied epistaxis, diplopia, facial numbness, or anosmia.

Physical examination revealed a flesh-colored mass in the right nasal vault.  All cranial nerves including pupils, extraocular muscles, and facial sensation were intact, and there was no lymphadenopathy.

A CT scan, followed by an MRI, were obtained, showing a large mass involving the bilateral sinonasal vault, predominately on the right side.  There was erosion of the cribriform plate and extension through the anterior skull base into the anterior cranial fossa with mass effect on the inferior frontal lobes of the brain, but no edema in the frontal lobes.  The mass impinged on the medial wall of the orbits, particularly on the right side, without apparent involvement of the orbital contents.

An intranasal biopsy revealed this tumor to be esthesioneuroblastoma (ENB), and he was staged Kadish C and UCLA T4, and underwent a bifrontal craniotomy with intracranial, intradural resection of the tumor from the frontal lobe combined with a transnasal endoscopic ethmoidectomy, orbital decompression with removal of the lamina papyracea and right periorbita, and sphenoidotomy.  The anterior skull base defect was closed with a pericranial flap.  I’ll come back to this patient for follow-up at the conclusion of the presentation.

Today I’ll be reviewing esthesioneuroblastoma including anatomy and histology; etiology, incidence, and clinical features; histopathologic diagnosis; differential diagnosis; imaging and staging; treatment and outcomes; and finally present a 25-year retrospective review of this disease at the Cleveland Clinic Foundation, a study which is currently in press for Otolaryngology – Head and Neck Surgery.

The olfactory neuroepithelium is situated on the cribrifrom plate, and also segments of the superior septum and both the superior and middle turbinates, and in rare cases, even the inferior turbinate and maxillary sinus.  It occupies an area of 1.5 square cm.  The pseudostratified columnar ciliated olfactory neuroepithelium differs noticeably from the ordinary respiratory epithelium which lines most of the upper respiratory tract. It is thicker and has many more nuclei. The olfactory neuroepithelium is a specialized epithelium and neurosensory organ with three basic cell types.

Basal cells are small, pyramid-shaped cells located against the base of the epithelial basement membrane.  These are a type of stem cell and the precursors to the other two types of cells.  Sustentacular cells are columnar cells with a narrow base with microvilli.  These cells are thought to secrete mucus and support and nourish the olfactory cells, which are the 3rd type of cell.  Olfactory cells are bipolar chemosensory neurons with modified upper and lower cytoplasmic processes.

In the left picture, there is a faint line of cilia and surface mucus.  The nuclei in the outermost layer belong to the sustentacular cells, while the olfactory cell nuclei are located in the lower two-third’s of the membrane.  Then you can see Bowman’s glands, the mucus secreting glands, in the lamina propria.

The top right is an immunohistochemical stain, the red line marks the olfactory sensory neurons, and the point to make about this is that it’s not a continuous layer, but is interspersed in some areas with the respiratory epithelium of the nasal cavity.  Bottom right is a drawing of the olfactory neuroepithelium over the cribriform plate showing the three cell types in the inset.  And this is better illustrated on the next slide.

L'esthesioneuroepitheliome olfactif, a term coined by Berger and Lu in 1924, was originally used to describe a nasal mass that exhibited cellular rosettes and fibrils. The astonishing observation made by these authors was the realization that esthesioneuroblastomas developed from the olfactory placode, which develops into the olfactory region of the sinonasal cavity.  

The picture shows again the 3 cell types of the olfactory neuroepithelium: the olfactory cells, the sustentacular or supporting cells, and the basal cells, and it’s from the basal cells that ENB’s are thought to arise.  Axons of the olfactory cells reach the olfactory bulbs through pores in the cribriform plate, while a single dendrite passes to the apical surface, terminating in an olfactory vesicle which contains a tuft of nonmotile cilia which form a chemosensory membrane. 

In the past, due to uncertainty about the precise histological origin, there have been various names for this tumor, but currently in the literature, it’s often referred to as esthesioneuroblastoma by clinicians or olfactory neuroblastoma by pathologists.

Esthesioneuroblastoma is estimated to represent a few percent of sinonasal malignancies with a bimodal peak in the second and sixth decades.  The picture here is a large pink infiltrating ENB growing from the nasal cavities through the cribriform plate into the frontal lobe.  Even in the US, average time from development of the first symptom to diagnosis is 6 months.  The most common symptoms are unilateral nasal obstruction, recurrent epistaxis, and anosmia, with anosmia being more common with cribriform erosion. Others include otalgia, serous otitis media, and frontal headache.   And diplopia, proptosis, and epiphora can occur with orbital or retroorbital involvement.

It’s a fairly vascular tumor, and they can bleed profusely with biopsy.   This is an angiogram showing a highly vascular ENB on both sides of the cribriform plate.  Biologic activity varies from indolent growth with long-term survival even with persistent disease or recurrence to highly-aggressive tumors with widespread metastases.

These are H&E stains showing the small, round, and blue tumor cells of ENB.  It is histologically similar to other small round cell tumors including SNUC, NEC, melanoma, lymphoma, pituitary adenoma, and rhabdomyosarcoma.  Diagnosis is more straightforward with differentiated or low-grade tumors.  The presence of a fibrous intercellular background in conjunction with Homer-Wright pseudorosettes in an upper nasal neoplasm is considered to be diagnostic for ENB.  Arrows in the bottom left and top right pictures indicate Homer-Wright pseudorosettes, which are glandlike arragements of tumor cells around an eosinophilic, central area that contains neurofibrils but lacks a true lumen.  They indicate evidence of neuroblastic differentiation and are present in medulloblastomas and primitive neuroectodermal tumors as well as 50% of ENB’s.  The lobular architecture, as in the bottom right picture, creates a nest-like appearance of tumor cells, and nuclear pleomorphism, increased mitotic figures, and necrosis are uncommon in low-grade lesions.

ENB’s are graded according to the Hyams system.  Grade 1 indicates well-differentiated, grade 4 indicates no evidence of neuronal or neuroendocrine differentiation.  The Hyams grade is based on routine H & E stains, but immunohistochemistry and electron microscopy are really needed to differentiate ENB from the other small, round, blue cell tumors of the sinonasal cavity.  The Flexner-Wintersteiner rosette is illustrated in the two pictures, consisting of tumor cells surrounding a true lumen.  These are rare but can be seen in Hyams grade 3 esthesioneuroblastomas.

In a 1993 study by Morita and others in Neurosurgery examining prognostic factors, the pathologic Hyams grade was found to be the most significant prognostic factor, with an 80% 5-year survival for 32 patients with low-grade tumors, and a 40% 5-year survival for 15 patients with high-grade tumors.

Higher Hyams grades have little architecture as well as areas of necrosis, and the important point is that this makes them very difficult to distinguish from a laundry list of other small, round, blue cell undifferentiated malignancies of the sinonasal tract on routine H&E.

Sinonasal undifferentiated carcinoma (SNUC), sinonasal lymphoma, sinonasal melanoma, and neuroendocrine carcinoma (NEC) are all high-grade tumors with frequent mitotic figures and pleomorphic nuclei that look a lot like high-grade ENB on routine H&E stains.  So immunohistochemistry is almost always necessary to distinguish these tumors.

Synaptophysin, which is stained in the two pictures, is a synaptic vesicle glycoprotein present in neuroendocrine cells, and acts as a marker for neuroendocrine tumors, so it’s also positive in neuroendocrine carcinomas.  Chromogranin and neuron-specific enolase are also markers for neuroendocrine differentiation in tumors.  Most ENB’s express S-100, but the pattern is scattered and peripheral, as compared to the diffuse and strong pattern in melanoma. Few ENB’s express HMB-45, which is another marker for melanoma.  Vimentin, desmin, and actin are often expressed with rhabdomyosarcoma but not usually expressed with esthesioneuroblastoma.  Common leukocyte antigen is expressed by lymphoma, and myc-2 is expressed by Ewing’s sarcoma.

This is a chart from a  2002 MDACC study in which they took 12 consecutive patients who were referred with the diagnosis of olfactory neuroblastoma and the pathologists there only confirmed the diagnosis of ENB  in 2/12 cases.  Lesions in 10 patients were therefore misdiagnosed as those listed here, and 8/10 of these patients who were misdiagnosed required a significant alteration in their treatment plan.

The chart summarizes some of the immunohistochemical differences between ENB and some of the other sinonasal tumors.  Of all the paranasal sinus tumors, it is most difficult to differentiate ENB from NEC, and immunohistochemistry and often electron microscopy are needed to differentiate the two.  These are pictures from the same study.  Synaptophysin and cytokeratin are stained red.  Synaptophysin is postive in both ENB and NEC but negative in SNUC.   Cytokeratins, which are found in the cytoskeleton of epithelial tissue, are negative in ENB but positive in NEC and SNUC.

In addition to immunohistochemical markers, there is also an interesting molecular marker for ENB. The HASH gene is critical in olfactory neuronal differentiation and expressed in immature or poorly differentiated olfactory cells.  In 2004, Mhawech, et al from Swizterland looked at the HASH gene as a molecular marker for ENB.  They had 24 cases, 5 ENB (3 high-grade and 2 low-grade) and 19 other poorly differentiated tumors of the nasal cavity, including nasopharyngeal carcinoma, large B cell lymphoma, and melanoma.  The diagnoses were confirmed by immunohistochemistry, and then HASH mRNA levels were measured by PCR in the tumor.  4/5 cases of ENB were identified correctly and all 19 of the other poorly differentiated tumors of the nasal cavity were correctly found not to be ENB.  The cases of low-grade ENB are columns 15 and 21 and high-grade ENB are columns 22-24.  25 and 26 are small cell lung cancer, which is also known to express HASH, and was used as a positive control, and 27 is a T cell lymphoma which was used as a negative control.  All 3 high-grade ENB’s were easily identified as their HASH expression was high. And it makes sense that the high-grade, poorly differentiated tumors would have more HASH as this is a gene which is expressed in immature olfactory cells.  1 of 2 low-grade ENB were identified.  But in lower-grade tumors, the diagnosis is more easily made with light microscopy and immunohistochemistry, so HASH may become a diagnostic procedure of choice for the higher-grade tumors.  One major limitation of the study was that it did not include any cases of SNUC or NEC, and since HASH has been shown to be expressed in neuroendocrine malignant neoplasms, it may also be expressed in these tumors. 

The other small, round, blue cell tumors which can be histopathologically very similar to ENB are bolded in this diagram, and include malignant epithelial tumors, malignant nonepithelial tumors, and lymphoreticular tumors, but if any of the tumors listed here are high-grade and poorly differentiated, they will be in the differential diagnosis for ENB.

So I’ll quickly go through a few of the other tumors in the differential when considering esthesioneuroblastoma.  NEC originates from the exocrine glands.  As opposed to ENB, this tumor usually originates lower in the nasal vault and seldom involves the cribriform plate.  As previously mentioned, NEC stains positive for cytokeratin antibodies.   SNUC is a generally more aggressive tumor than ENB.  Overall cure rate for SNUC is 20% and most patients die within 1.5 years of diagnosis.
Again, SNUC can be differentiated from ENB by cytokeratin antibodies.  Sinonasal lymphoma is most common in Asian populations, although the B-cell phenotype is more common in Western populations.
Over ¾’s of sinonasal lymphomas occur in the maxillary sinus, although a minority, like the one in the picture, occur in the superior nasal vault.  The top picture shows an immunohistochemical stain with strong positivity of large neoplastic lymphoid cells for the B-cell marker CD20, and the bottom picture illustrates infiltration of the sinus mucosa by scattered large neoplastic lymphoid cells which are illustrated by the arrow.

Sinonasal melanoma is most common in the anterior septum and inferior and middle turbinates, although they can grow quite large, making it difficult to determine the site of origin as in the picture.  Sun exposure is not a risk factor, though cutaneous melanoma metastasizes to mucosa in 2-9% of cases, so metastatic lesions should always be excluded.  It’s generally more aggressive than esthesioneuroblastoma, with a 1997 metaanalysis by Branchwein and others reporting 5-year survival in only about a third of patients.  Picture A above shows an S-100 stain for a sinonasal melanoma, while B shows an S-100 stain for an ENB to illustrate that the pattern is strong and diffuse with sinonasal melanoma and scattered and peripheral with the ENB.

Pituitary tumors of the nasal cavity most commonly arise from an intrasellar origin.  Ectopic pituitary adenomas are speculated to develop from ectopic cells that have been entrapped along the pathway of the craniopharyngeal duct during embryonic development or an aberrant migration of these cells.

The coronal MRI shows a primary ectopic pituitary adenoma in the nasal cavity extending to the frontal cranial fossa (white arrows).  With invasive pituitary tumors, there is expression of proliferating cell nuclear antigen (PCNA), illustrated in the top picture, and the left picture is an H&E stain showing tumor cells with the characteristics of chromophobe cells in the pituitary gland.

CT scan is the initial study of choice with esthesioneuroblastoma.  As seen here in these axial, postcontrast CT scans, ENB often presents as a homogeneous soft-tissue mass with relatively uniform enhancement.  It can have an expansile or destructive growth pattern, which can be seen here with some bone erosion and molding of the septum and medial wall of the maxillary sinus.  Intralesional calcification in a sinonasal tumor is nearly pathognomonic for ENB.  The coronal CT shows a mass pushing the nasal septum to the right and invading the maxillary sinus with diffuse calcifications.

The presence of a superior tumor margin cysts in the anterior cranial fossa also yields a definitive diagnosis, which is illustrated on an upcoming slide.

MRI is almost always helpful with advanced esthesioneuroblastomas, as it allows better delineation of intraorbital and/or intracranial extension.  Esthesioneuroblastomas are hypo- to isointense on T1 and iso- to hyperintense on T2, and generally enhance with variable uniformity with gadolinium contrast.  The MRI also allows better differentiation between obstructed, fluid-filled sinuses and tumor.

As an illustration of how an MRI can help differentiate between blocked nasal secretions and tumor, this is an axial T1 MRI with contrast.   There is a small esthesioneuroblastoma of the right nasal cavity showing some enhancement and it’s pushing the nasal septum in all directions as denoted by the small arrowheads.  The sinuses show varying signal intensities which could easily be confused with tumor.  Numbers 1, 2, and 3 represent the left sphenoid, a left posterior ethmoid, and the right spenoid, and indicate obstructed fluid-filled sinuses with different signal intensities depending on the particular protein content of the fluid, but it’s important to differentiate these obstructed, fluid-filled sinuses from actual tumor.

On the left, a sagital T1W post-gadolinium contrast MRI.  The tumor extends cephalad through the cribriform plate into the anterior cranial fossa and there’s a tumor margin cyst in the anterior cranial fossa, which again is pathognomonic for ENB.

On the right, a coronal T2 MRI demonstrating an isointense tumor extending both intraorbitally and intracranially with extensive edema in the right frontal lobe.

From a limited series of 17 patients in 1976, Kadish and others at Mass Eye and Ear came up with the first formal staging system for ENB, and the disease-free survival was 100, 80, and 40% for the 3 groups, respectively.  This is a coronal CT showing an expansile right nasal fossa mass obstructing the right ethmoid and maxillary sinuses.  The lesion is limited to the sinonasal cavity and thus Kadish A.  Stage B involves the paranasal sinuses, and stage C extends beyond the paranasal sinuses.  The Kadish system was modified by Morita, et al. in 1993 to include cervical lymph nodes and distant metastases as stage D. 
They found the modified Kadish stage to correlate better with overall survival, but this did not reach statistical significance.

The Kadish system has correlated with outcomes in some studies, and in others it has not, and it has been criticized as not being detailed enough to correspond well to clinical outcomes.  Biller and others published a paper in Laryngoscope in 1990 suggesting a new staging system based on the TNM format, and then Dulgerov and Calcaterra from UCLA wrote a landmark paper published in 1992 modifiying the Biller TNM staging system.  They looked at 26 patients and found that their staging system better predicted disease-free survival than the Kadish or Biller system.

This is a graphic representation of the UCLA T staging system in the horizontal (a) and coronal (b) planes. Stage TI is depicted in green, T2 in blue, T3 in red, and T4 in yellow:
T1 representing nasal/paranasal disease
T2 including sphenoid and/or extension to the cribriform plate
T3 indicating orbital or anterior cranial fossa invasion without dural invasion
T4 indicating dural invastion

There is no consensus on the best staging system.  Some prefer the Kadish or modified Kadish, and others prefer the TNM staging system.  Staging is based on imaging, so one case in point.  Again esthesio’s are usually iso- or hypointense to muscle and mucosa on T1W images and heterogeneously hyperintense on T2W images.  The picture to the left is a T1 axial MRI showing invasion of the sphenoid sinus.  Mass is isointense on T1.  The picture on the right is a T2 axial MRI.  The mass is hyperintense on T2.  T1 sagitals are illustrated here: the left is without contrast, and the right is with gadolinium contrast. 

There is no evidence of cribriform plate destruction or intracranial invasion, as there’s a clear line of separation between tumor and brain.  A coronal T2 on the left shows a hyperintense mass and again a line of separation between the mass and the brain.  On the right is a T1 with contrast with heterogenous moderate enhancement.  This patient is therefore a UCLA T2 because the tumor involves the sphenoid and extends to the cribriform plate but does not extend to the anterior cranial fossa.
It’s a Kadish B because it involves the nasal cavity and paranasal sinus.

The most common treatment for ENB is the combination of surgery and radiotherapy (XRT). This table comes from a meta-analysis published in The Lancet in 2001.  This analysis included 26 studies published between 1990 and 2000, so it excluded some of the older data with questionable pathology.

Surgery plus radiation was the most frequent treatment modality, so statistical analyses looked at differences between this treatment regimen and other treatment modalities.  Because of a still relatively small sample size, only comparison of surgery plus radiaton, compared to radiation alone, was statistically significant.  But looking at clinical significance, there’s a 65% survival of surgery plus radiation, which was by far the highest of all the groups, versus a 48% survival for surgery alone, even though you may expect that these tumors treated without XRT may represent earlier stage disease.  And in fact the difference in survival between the surgery plus radiotherapy group is 15-20% higher when compared to any of the other treatment regimens.Based on this data, Dulguerov argues that the only conceivable indication for single modality treatment is a small tumor located well below the cribriform plate, i.e., a Kadish A or T1 tumor. 

Most institutions favor surgery followed by postoperative radiotherapy  However, the University of Virginia (UVA), who have probably published more on this tumor than any other institution, have excellent results with preoperative radiotherapy.  They took 34 consecutive patients with ENB between 1976 and 1994 and published the results in Neurosurgery in 1998.  Of these 34, 31 received preoperative XRT, and for 21 of these patients, there were pre- and posttreatment images available for retrospective analysis.  Kadish A and B were treated with preoperative XRT alone, and Kadish C were treated with preoperative chemoradiotherapy.  2/3’s of studied patients had at least 20% response to adjuvant therapy and almost half had at least a 50% reduction in tumor volume.  The table compares disease state at last follow-up with response to preoperative therapy, and the bottom line is that patients with response to neoadjuvant therapy demonstrated a significantly lower rate of disease-related mortality.  One example of tumor response from this study, this is a contrast-enhanced axial CT scan.  Picture A shows preoperative imaging demonstrating large intracranial extension and Kadish stage C disease.  Picture B is after preoperative chemoraditotherapy.   A 74% reduction in overall size and an 89% reduction in intracranial size was observed. The patient then underwent surgery, and at 92 months from diagnosis, the patient had no evidence of disease.

At MD Anderson Cancer Center (MDA), the treatment paradigm is surgery with postoperative XRT.  In advanced cases, they give induction chemotherapy.  They perform surgery and if there is deep orbital invasion, brain parenchyma invasion, or known residual gross disease, they’ll often give postoperative chemotherapy in addition to XRT.

Comparing the MDA experience with the UVA experience, both demonstrate excellent survival with two different treatment regimens, MDA being primarily postoperative XRT +/- chemotherapy and Virginia preoperative XRT +/- chemotherapy.

Regarding surgical therapy, Walter Dandy, the renowned neurosurgeon from Hopkins and pictured top center, first described the craniofacial resection for orbital tumors with central nervous system extension in 1941. However, the initial application of this technique toward sinonasal tumors was reported by Robert Smith (pictured bottom center) and others in 1954.  In this procedure, a frontal or subfrontal craniotomy (illustrated in the pictures to the left) is combined with lateral rhinotomy (pictured bottom right) or midfacial degloving. If dural resection is performed, the defect can be sealed with a pericranial flap. As reported in 1986, the advent of the craniofacial resection resulted in a more than two-fold increase in survival for ENB patients at the University of Virginia.

While traditional craniofacial resection remains the gold standard, endoscopic approaches have become increasingly utilized, whether a complete endoscopic approach, termed minimally invasive endoscopic resection, or a combined approach with a craniotomy from above and endoscopic resection from below, termed endoscopic-assisted cranionasal resection.

However, regardless of approach, what really seems to matter is achieving clear surgical margins. Whatever technique allows the surgeon to completely resect all local disease with the least morbidity is the technique of choice.  In a recent 1,300-patient international collaborative study on malignant skull base tumors by Dr. Patel and others, the local recurrence rate doubled and survival was cut in half for patients with positive surgical margins.

In advanced cases involving the cribriform plate, resection should include the entire ipsilateral cribriform plate and crista galli.  The olfactory bulb and overlying dura should be removed with the specimen.  Preservation of the contralateral olfactory system, when possible, has resulted in a preserved sense of smell in a few cases.  Tumor that does not penetrate the orbit can be taken out with resection of the lamina papyracea or even small segments of orbital periosteum as a margin.

Minimally invasive endscopic resection (MIER) for ENB without the need for open craniotomy was first described by Stammberger and colleagues in 1999.   In a series of 8 patients, all were alive and disease-free with a mean follow-up of 37 months.  In 2001, Casiano and others in Miami described 5 patients, Kadish A and B, with this approach, 4 of whom were disease free at 31 months.  And the Italians, Suriano and others, in 2007, reported 9 patients, also Kadish A and B, all alive and without disease after 43 months.  Complications in these studies were few and temporary.  These are essentially preliminary results with small numbers and relatively short follow-up time for this disease, and larger studies with longer follow-up will be required for better comparison to the traditional craniofacial resection.

Management of the neck is another debated topic.  Neck metastases at presentation are reported as 5%, and these patients should receive a neck dissection with consideration for postoperative XRT. 

However, the debate really lies in the N0 neck, especially in patients with advanced disease, such as the patient presented today.  The cumulative metastatic rate, that is the rate at presentation + those who later developed cervical metastases, calculated by Ferlito and others from a meta-analysis of almost 500 cases from 26 institutions, was 23%.  And these patients commonly present with cervical metastases years after diagnosis, even with control at the primary site.  Furthermore, it has been shown that cervical metastases are significantly associated with distant failure. 

There is no clear evidence in the literature to suggest how to handle the N0 neck, and some institutions recommend elective neck dissection or elective irradiation with advanced disease because of the high association between delayed cervical metastases and distant metastases, while others favor watching the neck and operating with gross disease.

Prognosis and prognostic indicators based on a meta-analysis by Dulguerov: overall and disease-free 5-year survival averaged 45% and 41%.   And these numbers are lower than some of the numbers quoted from some of the larger individual studies earlier.  Rates of local (29%) and regional (16%) recurrences, as well as distant metastases (17%) are high.  Surgical margins, as well as Hyams grade and presence of cervical lymph node metastases have been reported to be important prognostic factors

Finally, I’ll speak briefly about a study that I presented as an oral presentation at the 2007 Academy annual meeting in Washington D.C. of patients at the Cleveland Clinic.  This was a retrospective analysis including all patients presenting between 1980 and 2004.  There were 18 patients treated over this 25-year period with both traditional open craniofacial resection and minimally invasive endoscopic resection.

Almost 2/3’s were male, mean age was approximately 60,  mean time from onset of symptoms to diagnosis was almost 1 year, and there was 5 and 1/2 years average follow-up.  Nasal obstruction followed by epistaxis were the most common presenting symptoms.  Incidence of neck disease at presentation was 22%.  Analyzing this patient population with both of these staging systems, about half of patients presented with advanced disease.  17/18 patients underwent surgery in the treatment of their disease, most of whom also underwent XRT, while chemotherapy was reserved for patients with advanced disease.  Only one patient, a patient who presented with recurrence, did not undergo surgery, receiving palliative chemoXRT.

Over the 25-year period, there were 13 traditional craniofacial resections and four endoscopic surgeries, 1 endoscopic assisted cranionasal resection (EA-CNR) and 3 minimally invasive endoscopic resections (MIERs) with image guidance.  This is a graph depicting disease-specific, overall recurrence-free, and local recurrence-free survival.  Follow-up time is in months.  There were 5 recurrences, 3 local and 2 regional.  Overall recurrence-free survival was 62 and 46% at 5 and 10 years, respectively. There were 3 deaths, 2 of disease and 1 of other cause without disease, with a 10-year disease-specific survival of 80%.

We examined several prognostic variables.  Increasing TNM stage, but not Kadish stage, correlated negatively with disease-specific survival.  Positive surgical margins were negatively associated with both disease-specific and recurrence-free survival. Neck disease and surgical approach, i.e. traditional craniofacial resection versus endoscopic, did not influence survival.

In order to compare craniofacial versus endoscopic resection, we looked at all 10 patients who presented with early stage disease.  There were four endoscopic resections and 6 traditional craniofacial resections with similarly staged disease.  There was one local recurrence in the endoscopic group in a patient who presented with Kadish B, TNM T2 disease and did not undergo radiotherapy.  There was 100% overall survival in both groups and overall few complications, with no complications among patients who underwent MIER, 1 pneumocephalus in a patient who underwent EA-CNR, and 1 pneumocephalus and 2 persistent CSF leaks in the craniofacial resection (CFR) group.

Based on the results of the study, we developed institutional treatment paradigms based on TNM tumor stage and neck disease.  We suggested minimally invasive endoscopic resection for T1 and T2 disease.  These tumors do not involve the anterior cranial fossa or orbit, and therefore CSF leaks which result from a small violation of the dura during resection of the cribriform plate can be handled in the same fashion as handling anterior skull base CSF leaks encountered during more routine endoscopic sinus surgery.  XRT should be considered in all patients, even those with early disease.  For large T3 or T4 lesions, like the UVA experience, we suggested preoperative chemoradiotherapy, to allow for a potentially less invasive and less morbid surgical resection.

Regarding regional treatment, we suggested no elective treatment for those with early stage disease but consideration for elective neck dissection for patients with advanced disease.  We also recommended neck dissection for patients with N+ disease, and postoperative radiotherapy to the neck for patients with extracapsular spread, high-grade hisopathological features, or greater than one positive node.

So this was a retrospective review with particular attention to surgical approach, demonstrating that both endoscopic and traditional CFR were successful in treating early disease with 100% survival and low rates of surgical complications.

The results support that an endoscopic approach can provide an effective and less morbid surgical approach in select patients, and these patients can then be easily followed with surveillance endoscopy for early detection of recurrence.

Finally, to follow-up on the case presentation today.  The patient had been presented at neurosurgery tumor board, and the original plan was for the aforementioned surgery followed by XRT.  However, he had a prolonged recovery from surgery with frontal lobe symptoms and generalized deconditioning, and he and his family decided against the postoperative XRT. 

He remained without definitive evidence of disease with serial MRI’s for 4 years following surgical resection, whereupon he presented with a right level 2 neck mass, seen bottom right.  FNA found recurrent esthesioneuroblastoma. 

There was also some concern of a very slowly growing recurrence of the right anterior skull base near the posterior orbital apex at the junction with the sphenoid sinus.  So, Dr. Oghali performed a combined endoscopic and external transfacial resection of the sinonasal recurrence in conjunction with a right neck dissection performed by Dr. Donovan.  The patient then received 60 Gy to the surgical bed and the bilateral neck, which he completed several months ago. 

So this case illustrates well many points concerning this disease including the rather indolent growth of this tumor with propensity for local and regional recurrences years after initial therapy and some of the different surgical approaches that can be performed with both primary and recurrent disease.

Case Presentation:

PF is a 72-year-old gentleman who presents with a 2-year history of right nasal obstruction and mucoid rhinorrhea.  He had previously seen an outside otolaryngologist and was originally thought to have right-sided nasal polyposis.  He has had no previous sinonasal surgery, and his past medical history is otherwise only remarkable for diabetes mellitus.  He denies epistaxis, diplopia, facial numbness, or anosmia. 

Fiberoptic nasoscopy reveals a flesh-colored mass in the right superior nasal vault without necrosis or bleeding.  The left sinonasal cavity and nasopharynx are without visible abnormality.  Cranial nerves including pupils, extraocular muscles, and facial sensation are intact, and there is no proptosis.  There are no palpable cervical masses or lymphadenopathy.

A CT scan, followed by an MRI, are obtained, showing a large mass involving the bilateral sinonasal vault, predominately on the right side.  There is erosion of the cribriform plate and extension through the anterior skull base into the anterior cranial fossa with mass effect on the inferior frontal lobes of the brain, but no edema in the frontal lobes.  The mass impinges on the medial wall of the orbits, particularly on the right side, without apparent involvement of the orbital contents.

A biopsy is performed with histopathologic examination consistent with esthesioneuroblastoma.  He is staged Kadish C, UCLA T4.  He undergoes a bifrontal craniotomy with intracranial, intradural resection of the tumor from the frontal lobe combined with a transnasal endoscopic ethmoidectomy, orbital decompression with removal of the lamina papyracea and right periorbita, and sphenoidotomy.  The anterior skull base defect is closed with a pericranial flap.

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