Esthesioneuroblastoma presenting with proptosis and bilateral neck metastasis: An unusual presentation.

Esthesioneuroblastoma (ENB) presenting simultaneously with proptosis and bilateral neck metastasis is a very rare presentation. ENB is a rare tumor arising from the olfactory epithelium of the nasal vault which frequently invades the cranial base, cranial vault and orbit. ENB has a bimodal age distribution between 11 and 20 years and between 51 and 60 years. ENB accounts for approximately 1 to 5% of intranasal cancers and no consensus has been reached yet regarding the treatment of this tumor. We are reporting a 17-year-old male patient who presented with right eye proptosis with loss of vision and bilateral neck metastasis. Contrast enhanced computed tomography (CECT) and magnetic resonance imaging (MRI) was done which showed Kadish stage C tumor. Nasal biopsy was done to make the diagnosis and the patient was subjected to radiotherapy. Tumor responded to radiotherapy and both the primary lesion and the cervical lymph node metastasis disappeared. The purpose of this study is to report the rare presentation of proptosis along with bilateral cervical lymph node metastasis in this rare sinonasal tumor.

Introduction

Esthesioneuroblastoma (olfactory neuroblastoma) (ENB) is a rare neuroepithelial tumor that arises from the olfactory epithelium in the cribriform plate or nasal cavity.[1] First described in 1924 by Berger and Luc,[2] it has a histological pattern similar to that of sympathetic ganglia, retina, and adrenal medulla[2] and only recently[3] became recognized as a distinct pathological entity, probably, as a result of immunohistochemistry and by means of electron microscopy techniques. They have helped to differentiate ENB from similar undifferentiated nasal cavity tumors.[3] ENB accounts for 1 to 5% of malignant neoplasms of the nasal cavity. Fewer than 1000 cases are reported in the world literature,[4] and most of the reports were in small series. Unlike most other neuroectodermal tumors, which manifest in childhood, ENB has a bimodal age distribution between 11-20 years and 51-60 years.[5] The symptoms are related to site of origin and invasion of the tumor. The staging system with stage A, B, and C based on tumor extension presented by Kadish et al.,[6] in 1976 has been widely accepted. Recently, Morita et al.,[7] justified a modified classification with stage D tumors, presenting metastases in cervical lymph nodes and at distant sites. Two other staging methods, the Biller method[8] and the Dulguerov method,[9] have also been described and used.

The optimal treatment modality for ENB continues to be debated because of limited cohort size case series and treatment inconsistencies for this rare tumor. Surgery and radiotherapy (RT) are still used by some institutions as single modalities despite the lack of support for single-modality treatment regimens,[810] while many other institutions favor surgery followed by RT.[11-13] The use of combined modality treatment with surgery, RT, and chemotherapy in various combinations has been increasingly adopted over the past few years.[1415] We are reporting on a rare presentation of ENB presenting with proptosis (without any nasal symptoms) along with bilateral cervical metastasis.

Case Report

A 17-year-old adolescent male patient presented to Ear, Nose and Throat Out-Patient Department (ENT OPD) with complaints of right eye proptosis and loss of vision for last 20 days [Figure 1]. There was no history of nasal obstruction or epistaxis. Patient also complained of bilateral non-tender neck swelling for last 7 days. On examination, nose was normal on anterior rhinoscopy, but perception of light in right eye was absent. The right globe was fixed in all directions and relative afferent papillary defect (RAPD) was also present. Left eye vision was normal. Coronal [Figure 2] and axial [Figure 3] cuts of contrast enhanced computerized tomography (CECT) scan of nose, paranasal sinus and orbit showed heterogeneously enhancing soft tissue density involving right nasal cavity, anterior and posterior ethmoids with erosion of cribriform plate and with right intraorbital extension. MRI of brain and orbit was done which showed Kadish stage C extension. Both T1 and T2 showed heterogenous signal intensity with dural enhancement along with involvement of right orbital apex and intraconal part of right eye. Patient underwent a nasal biopsy which was sent for histopathological examination (HPE). HPE report revealed small, round cell tumor forming Holmer-Wright rosettes suggestive of olfactory neuroblastoma. Fine needle aspiration cytology (FNAC) was also done from bilateral cervical level II lymph nodes which showed them as metastatic. In view of bilateral lymph nodes, radiotherapy consultation was sought and patient was put on external radiotherapy. The tumor responded very well to radiotherapy and both the metastatic lymph nodes and proptosis of right eye subsided within one month of starting radiotherapy. The patient received 66 gray radiation (Gy) in 33 fractions of 2 Gy a day for 5 fractions per week. Total treatment lasted for 7 weeks. At 1 month follow-up post radiotherapy, patient is clinically normal without palpable cervical lymph nodes and his proptosis has also decreased. He is on regular follow-up and according to the patient, his appetite and his weight has also improved after treatment.

Figure 1

Patient diagnosed as esthesioneuroblastoma presenting with proptosis and diminished vision in right eye

Figure 2

Coronal cuts of CECT showing homogeneously enhancing soft tissue involving right side of sinuses and orbit

Figure 3

Axial cut of CECT of the paranasal sinuses (PNS) showing hyperintense mass involving right side of nose and orbit

Discussion

ENB is a tumor of neural crest origin arising from the olfactory epithelium in the cribriform plate or nasal cavity.[1] Synonyms include olfactory esthesioneuroma, neuroesthesioma, olfactory neurocytoma, and olfactory esthesioneuroblastoma. First described in 1924 by Berger and Luc,[2] it has a histological pattern similar to that of sympathetic ganglia, retina, and adrenal medulla[2] and only recently[3] became recognized as a distinct pathological entity, probably, as a result of immunohistochemistry and by means of electron microscopy techniques. Histologically, there are a number of criteria that help in its diagnosis: neuroepithelial cells arranged in the classic pseudorosette pattern; fibrillar intracellular background; marked microvascularity; and round or fusiform cells approaching the size of lymphocytes with poorly defined, almost nonexistent cytoplasm.[116] Correct diagnosis often requires confirmatory examination with electron microscopy for the detection of neurosecretory granules. More recently, immunohistochemical methods for detection of neuron specific enolase (NSE) and S-100 protein with negative epithelial, muscle, and lymphoid antigens allowed further confirmation of ENB.[117] They have helped to differentiate ENB from similar undifferentiated nasal cavity tumors.[3] This tumor must be differentiated from other neoplasms of the nasal cavity and paranasal sinus, such as lymphoma, sarcoma, plasmacytoma, malignant melanoma, anaplastic carcinoma, rhabdomyosarcoma, and transitional cell carcinoma.[316]

ENB occurs with equal frequency in men and women. There is a bimodal age distribution with peaks at two age groups between 11-20 years and second in 51-60 year olds. Our patient belonged to first age group. The most common presenting symptoms are epistaxis and nasal obstruction,[5] contrary to our case in which the presenting symptom was right eye proptosis and decreased vision. The other symptoms can be headache, nasal pain, excessive lacrimation, anosmia, and visual disturbances.[5] The tumor can spread submucosally in all directions, thereby involving the nasal sinuses, nasal cavity and surrounding structures. Ear pain and otitis can result from tumor obstructing the Eustachian tube. Frontal headache suggests involvement of the frontal sinus. Cranial nerves may also be affected inducing nerve paralysis.[718] Alteration of mental status may be present if frontal lobe is invaded. This rare neoplasm is locally aggressive and can metastasize by lymphatic and hematogenous routes.[519] Local recurrence has been reported in upto 57% of patients. A metastatic rate of 10-30% is reported with the most common site being the cervical lymph nodes similar to our case. Bilateral cervical lymph node metastasis is very rare, contrary to our case. Other sites include the parotid glands, skin, lung, bone, liver, orbit, spinal cord, and spinal canal.[19]

The diagnosis and evaluation of staging of ENB can be done by CT, which provides the best information about the tumor invasion into bony structures.[17] The tumor presents as a homogeneous density mass, equal to or greater than the surrounding soft tissues. There are no tumor cysts or calcifications. Contrast enhancement is usually moderate and homogeneous. Coronal images are of value in evaluating extension to the orbit, through the cribriform plate and the anterior cranial fossa.[17] MRI shows tumor as hypointense to gray matter on T1-weighted images and iso or hyperintense on T2-weighted images. Gadolinium enhancement is observed to some degree in all cases. Fat saturated T1-weighted spin-echo images with and without gadolinium enhancement is of particular value in differentiating enhancing tumor from post-obstructive mucous debris and evaluating tumor extension to the non-enhancing orbital fat.[17] MRI is more accurate in depicting the exact margins of intracranial tumor extension because of its multiplanar display and superior tissue contrast.[17]

The Kadish system,[6] the classic staging system, used to predict overall morbidity and mortality from ENB, does not specifically mention retropharyngeal metastatic disease. Stage A tumors are those confined to the nasal cavity. Stage B tumors extend from the nasal cavity to the paranasal sinuses. Stage C tumors extend into the orbit, base of the skull, with or without intracranial extension.[6] This system has been advocated by some, because of its simplicity and acceptable prognostic efficacy. Other classifications have been proposed that specify which paranasal sinuses are involved, if there is extension into the cribriform plate, and the size of the tumor. Morita et al.,[7] proposed a Kadish D stage that adds further distinction to ENB involving the cervical lymph nodes like in our case. Two other staging methods, the Biller method[8] and the Dulguerov method,[9] have also been described and used.

Regardless of the staging system used, metastasis from ENB portends a poor prognosis. The 5-year survival rate of patients with cervical metastasis has been reported to be 0%, whereas the survival of those without positive distant metastasis was greater than 60%.[19] The incidence of local or distant metastatic disease from primary ENB has been reported at ranges between 10 to 40% in different study populations.[10] Recurrent metastatic disease to cervical lymph nodes has been reported in up to 18% of patients after initial treatment and up to 44% of patients with Kadish C disease at presentation.[89]

There are great variations in treatment for ENB. Some series advocate a protocol with surgery;[82023] radiotherapy[621] alone; combined surgery and pre-operative radiotherapy[20] and combined surgery and postoperative radiotherapy.[2023] The optimum management for ENB is probably surgery using the concept first described in 1971 by Doyle and Payton:[24] radical surgery with a combined craniofacial approach[17] done by craniofacial team, including neurosurgeon and head and neck surgeon. This technique has provided enhanced exposure and the possibility to achieve gross total resection. In patients without extension of tumors to the superior nasal vault or the cribriform plate, an intracranial exploration and removal of the floor of the anterior cranial fossa must be performed. This approach has a reduced incidence of local recurrence.[1] It is proved that the bone in this area may harbor tumor cells which are a potential cause of recurrence. Furthermore, the radiotherapy is recommended for palliative treatment.[21] The role of systemic chemotherapy in the treatment of ENB range from no response,[21] palliation,[2023] partial[7] or complete response.[25] In general, chemotherapy is usually reserved for tumor spreading beyond the nasal cavity and paranasal sinuses,[17] or in the treatment of distant metastases.[23]

The prognostic factors in the management of ENB are very controversial because of the small number of patients present in each series. Morita et al.,[7] advocated that the only reliable survival predictor is the tumor's pathological grade (Hyam's grading system[26]). Polin[22] was unable to find significant difference between survival of patients with low and high-grade tumors. Some authors[9] affirm that the negative prognostics include age, metastasis, recurrence, and extensions to the ethmoidal, nasopharyngeal and orbital area. They also noted that the absence of metastasis does not necessarily confer a good prognosis. Goldsweig[27] concluded that the degree of resectability of the tumor on primary surgery is the best predictor of long-term survival. Irish[1] determined a 100% 2-year survival rates in patients undergoing combined surgical and radiation treatment. Polin[22] determined the 5 and 10 years survival rates of 87% and 54%, respectively, and a 97% one-year survival. Patients with stage C disease have 96% one-year survival, 71% five years and 44% 10 years survival.[22] In literature, the 5-year recurrence free survival is reported to be between 52% and 90%.[9]

Conclusion

In conclusion, ENB is a very uncommon malignant tumor arising from olfactory epithelium that may have a long natural history characterized by frequent local or regional recurrences. It may have bizarre presentations including proptosis only or proptosis along with nasal symptoms. The presence of bilateral cervical lymph node metastasis in ENB has not been mentioned in the literature, contrary to our case, and it should be kept in mind in future. Radical craniofacial resections by a multidisciplinary surgical team combined with adjuvant radiotherapy with 50-60 Gy is probably the most usual treatment with some modifications according to the disease and the patient profile. The role of systemic chemotherapy in the treatment of distant metastasis should be further evaluated before being used as the standard treatment.