Discussion
Olfactory neuroblastoma (ONB) is a rare malignant tumor of neural crest origin, arising from the olfactory epithelium of the nasal vault [
3]. It is a relatively uncommon neoplasm, and its clinicopathological presentation remains unclear. Berger and Luc first described this uncommon neoplasm in 1924. Since then, approximately 1200 cases of ONB have been identified [
2]. However, ONB centered in the posterior right orbit with prominent orbital protrusion reported in this case is even rare. This disease has a higher degree of malignancy, and the younger the age, the worse the prognosis. Given the pathway of the olfactory nerve, ONB can possiblely invade adjacent structures, such as the ethmoidal sinus, anterior skull base, orbit, and even across the midline to the contralateral nasal cavity [
1]. If metastatic, ONB may involve local lymph nodes, with distant metastasis to lungs, liver, and bone.
The most common presenting symptoms are unilateral nasal obstruction (70%), and epistaxis (50%). Other symptoms include anosmia, headache, pain, excessive lacrimation, and rhinorrhea. In particular, patients with periorbital extension may present with proptosis, periorbital edema and decrease visual acuity, just like the rare case we reported. Uncommonly, ONB may be associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH) with dilutional hyponatremia or ectopic adrenocorticotropic hormone (ACTH) production leading to Cushing syndrome [
4].
ONB may histologically mimic a number of types of tumor within the sinonasal tract, making it much difficult to diagnosis [
5]. Multi-modality imaging is essential to correctly assess the extent of the disease in the management of this infrequent tumor [
6]. CT and MRI with and without contrast is the first line for evaluation of ONB. The imaging pathway in this case was typical, with CT and MRI complementing each other in maximizing tumor delineation [
7]. The CT scan is a helpful initial study to identify the lesion but more importantly, it has superior definition in reviewing bony involvement of the cribriform plate, orbit, and air sinuses [
3]. Typically, on CT, a homogenous mass with necrotic nonenhancing areas is observed. As to MRI, ONB usually appears hypointense on T1-weighted sequences and intermediate to hyperintense on T2-weighted sequences. Contrast enhancement is avid and homogeneous, except for areas of necrosis or hemorrhage. MRI has superiority in evaluating the extent of soft tissue invasion and establishing tumor boundaries against post obstruction fluid in the paranasal sinuses. Typically, a dumbbell shaped mass extending across the cribriform plate is one of the most characteristic findings of this tumor [
8]. The upper portion of the dumbbell-shaped mass is in the anterior cranial fossa whereas the lower portion is in the nasal cavity with the waist at the cribriform plate [
9]. Another characteristic imaging feature of ONB is the presence of peritumoral cysts at the tumor brain interface [
2]. In this case, we can also see a dumbbell-shaped mass with the waist at the cribriform plate and peritumoral cyst, which is helpful in the accurate diagnosis of ONB.
Histologically, ONB typically have a high nucleus/cytoplasm ratio, with scant, poorly defined cytoplasm. High-grade tumors characteristically present with nuclear pleomorphism, mitotic figures (> 2 per high-power microscope field), and necrosis [
10]. Homer Wright rosettes are present in up to 30% of cases and Flexner–Wintersteiner rosettes are seen in up to 5%. The ultrastructural features of ONB are dense membrane-bound neurosecretory granules with neurofilaments and micro-tubules in the cytoplasm and nerve processes. They typically stain positive for NSE, neurofilament protein, synaptophysin, chromograinin, CD56, and LEU-7. S-100 protein staining seen along the periphery of the neoplastic lobules, also seen in our case, is the characteristic manifestation of ONB. Hematolymphoid markers (CD45, B cell, and T cell), myogenic markers (myoglobin, desmin, myogenin), melanoma markers (HMB 45, melan A, tyrosinase) and Ewing’s sarcoma markers (CD99/MIC2) are absent in most ONB cases. Epithelial markers including EMA, SMA and carcinoembryonic antigen (CEA) are also absent in ONB.
The diagnosis of ONB is extremely challenging as several sinonasal neoplasms must be excluded. The differential diagnosis is widely broad including rhabdomyosarcoma, lymphoma, undifferentiated carcinoma, neuroendocrine carcinoma, melanoma and Ewing’ s sarcoma [
11]. The differential diagnosis of ONB and neuroendocrine carcinoma was considered as ONB is non-reactive with CK and TTF-1. ONB can be separated from Ewing’ s sarcoma by the presence of an S100 positive sustentacular network in most cases as well as diffuse positivity for neuroendocrine markers and negativity for CD99 [
12]. But untypically in this case, the tumor cells were positive for CD99. In addition, the maximum standardized uptake value in the initial PET/CT may be an adjunct to the differential diagnosis of ONB and sinonasal undifferentiated carcinoma [
13]. Furthermore, magnetic resonance diffusion kurtosis imaging (DKI) and dynamic contrast enhanced MRI (DCE-MRI) are helpful in distinguishing ONB from nasal squamous cell carcinoma for significantly higher K values and lower V
e values in ONB [
1]. In particular, ONB can be differentiated from intracranial immature teratoma for the absence of some increased substances including AFP, b-HCG, and PLAP in serum and cerebrospinal fluid [
14]. The diagnosis of ONB can be established after a careful evaluation of radiological study, histopathological examination, immunohistochemistry, and cytogenetic analysis [
11].
Kadish et al. and Dulguerov et al. proposed ONB classifications based on primary tumor extension and clinicoradiographic data, respectively. Kadish et al. were the first to propose a staging classification for ONB [
8]. Morita et al. modified the Kadish staging to include 4 groups. The modified Kadish staging classification is the most commonly used approach to classify the anatomic extent of the tumor (Table
1). According to modified Kadish staging, our case belongs to group C. The Dulguerov system (Table
2), which uses the TNM classification and includes the imaging data, is preferred by some oncologists and surgeons for recognizing the early involvement of the cribriform plate in the T2 stage and identifying the true brain involvement. ONB is divided into 4 grades by Hyams based on the following microscopic features: cellular architecture and pleomorphism; mitotic activity; and presence of necrosis, calcification, gland proliferation, and neurofibrillary matrix or rosettes [
15]. Histopathology is considered a potentially important prognostication, Hyams grades III and IV are associated with a poor prognosis.
Table 1
Modified Kadish staging classification and Hyams histologic grading system for olfactory neuroblastoma
Modified Kadish classification |
A | Tumor confined to the nasal cavity |
B | Tumor extension to the paranasal sinuses |
C | Tumor beyond the nasal cavity and paranasal sinuses, including involvement of the cribriform plate, base of the skull, intracranial cavity, and/or orbit |
D | Tumor with metastases to cervical lymph nodes and/or distant sites |
Hyams histologic grading system |
Cytoarchitecture | Lobular | Lobular | ± | ± |
Mitotic rate | 0 | Low | Moderate | High |
Nuclear Pleomorphism | Absent | Slight | Moderate | Marked |
Rosettes | ± | ± | True Rosettes | None |
Necrosis | Absent | Absent | Mild | Extensive |
Table 2
The Dulguerov staging system for olfactory neuroblastoma
Primary tumor |
T1 | Tumor involving the nasal cavity and/or paranasal sinuses (excluding sphenoid), sparing the most superior ethmoid |
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 involvement |
T4 | Tumor involving the brain |
Lymph nodes |
N0 | No cervical lymph node metastasis |
N1 | Any form of cervical lymph node metastasis |
Distant metastasis |
M0 | No metastases |
M1 | Distant metastases |
The management of ONB usually requires craniofacial surgical approach, trephination procedure, which is technically challenging and achieving good results are difficult. Recently, authors have come to an agreement that a multimodal approach is necessary to treat patients with ONB. Treatment modalities for ONB are enbloc resection, extra cranial resection or surgery combined with radiotherapy and/or chemotherapy. But unfortunately, the patient did not take adjuvant radiotherapy and chemoradiation and post-operative examination because of poor economic condition.
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