Olfactory neuroblastoma (ONB) or esthesioneuroblastoma is a malignancy derived from the neuroendocrine cells. Infrequent in the sinonasal tract, it is possibly caused by mutations in the olfactory stem cells localized in the superior part of the nasal cavity. Particularly areas near the cribriform plate and olfactory nerve are affected [1].

Typical patients for ONB are those in the middle age (40-50 years of age), although patients may present almost at any decade of life [2]. They come with a unilateral nasal obstruction caused by a mass lesion which can provoke diplopia or proptosis if invasion into the orbit exists. Other symptoms include epistaxis and inability to sense smells (otherwise known as anosmia). Headaches and sinusitis can also be concluded [3].

Some cases may develop paraneoplastic syndromes (PS) typical for the neuroendocrine malignancies [3]. These syndromes arise when the tumor secretes hormones causing a certain effect on the target tissues. Syndrome of inappropriate antidiuretic hormone secretion (SIADH), ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), hypertension caused by catecholamine secretion and humoral hypercalcemia of malignancy (HHM) are documented. PS affecting the nervous system like opsoclonus-myoclonus-ataxia (OMA), can occur [4]. The mimicry between tumor cells and the body tissues may be observed, being responsible for autoimmune tissue degeneration [5].

• Swelling

  Facial symptoms include swelling, pain, and lack of sensation. Oral symptoms include loose teeth, and the loss of teeth, as well as ulcers in the mouth. [wisegeek.com]

  A patient presented with nasal swelling and left-sided nasal obstruction, epistaxis, and diplopia. Examination revealed broadening of the nasal dorsum with a fleshy pink mass in both nasal cavities. [ncbi.nlm.nih.gov]

  Olfactory Neuroblastoma Symptoms Symptoms of olfactory neuroblastoma include the following: nasal obstruction and epistaxis anosmia headache nausea facial swelling or pain ocular proptosis or decrease in vision with decreased movement of extraocular muscles [mountsinai.org]

• Fatigue

  However, we report the highly unusual case of a patient with an esthesioneuroblastoma who presented with atypical symptoms of headaches, sinus congestion, and fatigue before acutely losing consciousness. [experts.umn.edu]

  His main complaint was xerostomia, and he had anosmia, moderate fatigue, and frontal pressure headaches requiring opiate pain medication. [journals.plos.org]

• Anosmia

  Patients often present with nasal obstruction, rhinorrhea, recurrent epistaxis, hyposmia, or anosmia. [experts.umn.edu]

  Kallman's syndrome is an unusual clinical entity that includes anosmia and hypogonadotropic hypogonadism. We present a patient in whom an olfactory neuroblastoma was discovered during evaluation of his Kallman's syndrome. [ncbi.nlm.nih.gov]

  Clinical findings Bimodal age distribution, affecting those in the 2nd and 6th decades of life; presents as a unilateral nasal obstruction, epistaxis, anosmia and headache, accompanied by nonspecific symptoms similar to other intranasal lesions—i.e., [medical-dictionary.thefreedictionary.com]

• Rhinorrhea

  Patients often present with nasal obstruction, rhinorrhea, recurrent epistaxis, hyposmia, or anosmia. [experts.umn.edu]

  Most of the presenting symptoms include nasal obstruction, nasal bleeding, anosmia, rhinorrhea, and headache. In this present report, we describe a 79-year-old man who presented with bilateral nasal congestion for more than 1 year. [ncbi.nlm.nih.gov]

  She had a recent history of clear rhinorrhea and frequent nosebleeds. CT and MRI scan revealed a large mass in the left nasal cavity extending into the frontal lobe ( figure 1 ). [n.neurology.org]

  Esthesioneuroblastoma: Cerebrospinal fluid rhinorrhea and widespread metastasis. J Otolaryngol. 1986. 15: 80-4 [surgicalneurologyint.com]

  Other symptoms include headaches, pain, excessive lacrimation, rhinorrhea, anosmia and changes in vision. ON originates from olfactory epithelium; however, ON rarely causes anosmia (5%) ( 3, 4 ). [spandidos-publications.com]

• Nasal Congestion

  A 43-year-old female presented with persistent nasal congestion with intermittent epistaxis without resolution for the preceding 5 years. [ncbi.nlm.nih.gov]

  Symptoms Olfactory neuroblastomas typically cause loss of sense of smell (anosmia), epistaxis (nasal bleeding), nasal congestion/obstruction, vision loss and headache. [pacificneuroscienceinstitute.org]

• Hyposmia

  Patients often present with nasal obstruction, rhinorrhea, recurrent epistaxis, hyposmia, or anosmia. [experts.umn.edu]

  Less common symptoms include hyposmia (loss of smell), headache, rhinorrhea, vision loss, proptosis, facial pain, diplopia (double vision), masses in the neck and changes in mental status. [en.wikipedia.org]

  Hyposmia. Exophthalmos. Nasopharyngeal mass, which may have local extension into the orbits, sinuses, or frontal lobe. [es.oncolink.org]

• Nausea

  Olfactory Neuroblastoma Symptoms Symptoms of olfactory neuroblastoma include the following: nasal obstruction and epistaxis anosmia headache nausea facial swelling or pain ocular proptosis or decrease in vision with decreased movement of extraocular muscles [mountsinai.org]

  The symptoms of ENB can be classified into: Nasal - Obstruction, epistaxis, discharge, unilateral polyp, and anosmia Neurological - Headache and nausea Oral - Loose teeth, non-healing following tooth extraction and oral ulcers Facial - Swelling, pain, [skullbaseinstitute.com]

  Intracranial extension may lead to neurological symptoms such as changes in mental status, headaches, nausea and vomiting, seizures, and eventually coma and death. [med.uth.edu]

• Suggestibility

  Histological examination of a biopsy specimen suggested recurrence of the olfactory neuroblastoma. This type of recurrence is very unusual. [ncbi.nlm.nih.gov]

• Aggressive Behavior

  ENB recurs locally in up to 60% of patients who undergo surgery 15, and its locally aggressive behavior is the most common cause of death 44. Median survival after recurrences was only 12 months 45,46. [scielo.br]

  One study suggested that TP53 point mutations did not play an important role in the initial development of ONB as wild-type TP53 hyper-expression may lead to local aggressive behavior and a tendency for recurrence [31]. [journals.plos.org]

• Headache

  Only four cases of olfactory neuroblastoma isolated in the sphenoid sinus have been described in English literature and the frequency of presenting symptoms with cranial neuropathies and headache. [ncbi.nlm.nih.gov]

  However, we report the highly unusual case of a patient with an esthesioneuroblastoma who presented with atypical symptoms of headaches, sinus congestion, and fatigue before acutely losing consciousness. [experts.umn.edu]

Olfactory neuroblastoma is diagnosed after radiological examination and biopsy specimen analysis. These give valuable clues leading to this disease and provide objective information for future treatment strategy [6]. An endoscopy is used in visualizing the tumor inside the nasal cavity, providing first impressions of the possible size and location. It may resemble a polypoid mass located unilaterally [7].

Computed tomography (CT) and magnetic resonance imaging (MRI) are imperative in providing data about the size, localization, and grade of invasion into adjacent anatomical structures. Extension into the orbit, skull base, sinuses, etc. can be documented during the examination. CT reveals necrotic lesions seen heterogeneously on the scan. MRI findings are based on modality and include an emphasis on the lesions, which can appear calcific or include hemorrhages [7] [8].

A classification based on the invasion of the tumor has been created by Kadish et al. [9] and it contains three tiers:

• A group - tumor is restricted in the nasal cavity;
• B group - nasal cavity and paranasal sinuses are affected;
• C group - malignant lesion invades structures outside the limit of the two previous groups.

A biopsy is essential to confirm the diagnosis. ONB has distinguishing histopathological findings. The cells are pale, contain obscure borders, and are grouped into the nests forming lobules divided by fibrovascular tissues. These lobules can join together to create a layer of vascularized cells. Distinctive Flexner–Wintersteiner rosettes can indicate olfactory differentiation, pseudorosettes or Homer-Wright are identified too [10]. Immunohistochemistry will reveal positive reaction to neuroendocrine markers and those associated with ONB, which are S-100, CD56, calretinin, chromogranin, and synaptophysin. Moreover, olfactory neuroblastoma is generally negative for keratin [11].

Positron emission tomography (PET)-CT is useful in detecting distal metastases [7].

Combined treatment modality, including endoscopic endonasal surgery, achieved a better outcome than non-surgical approach. [ncbi.nlm.nih.gov]

In 13 patients, 61.5% were diagnosed as late T stage (T3/4), 69.2% late Kadish stage (C/D) and 53.8% were high Hyams grade (I/ II), which indicated poor prognosis. [ncbi.nlm.nih.gov]

Rescently left facial nerve palsy developed, of which etiology due to recurrence or treatment related fibrosis is unclear. Now, the authors are on study the etiology of left facial nerve palsy. [e-crt.org]

Methods: We present an atypical case and a review of the literature about the etiology, pathology, clinical manifestations, treatment options and prognosis of these tumours. [scitechnol.com]

No clear etiology for ENB has been discovered. Herrold in 1963 did produce ENB in Syrian hamsters by administering the auto industry solvent diethylnitrosamine (DENA) by various routes. [web.archive.org]

[…] roof of the nose to the area of the superior turbinate and a portion of the nasal septum. 3 The exact cell origin of OAN is controversial but recently, it is regarded as originating from the basal cells of the olfactory neuroepithelium and no clear etiologic [ispub.com]

Due to the rare and complex nature of ENB, multiple opinions exist regarding the etiology, optimal staging system, and treatment modalities. [emedicine.com]

We reviewed our material and literature reports to establish the epidemiology and origin, clinical and histological aspects and mainly the CT and MR features of olfactory neuroblastoma or aesthesioneuroblastoma. [moh-it.pure.elsevier.com]

Epidemiology Olfactory neuroblastoma is a very rare tumour ( Aetiology and Pathogenesis Unknown Natural History The tumour typically arises from the olfactory epithelium. [ozradonc.wikidot.com]

General Epidemiology: [1] Prognosis: poor. Wide age range with bimodal distribution - teens and 60s. No sex predilection. Clinical presentation: [1] Nasal obstruction ~ 70%. Epistaxis ~ 50%. Anosmia. Headache. [librepathology.org]

Epidemiology Olfactory neuroblastoma accounts for 1% to 5% of malignant nasal cavity neoplasms. Clinical features These tumours arise across a broad age range with a bimodal peak in the second and sixth decades of life. [e-immunohistochemistry.info]

A search of the National Cancer Database by Carey et al identified 1225 cases of ENB. [6] Similar incidence rates have been obtained through epidemiologic studies performed in Denmark. [7] No studies suggest a geographic variation in rates. [emedicine.com]

[…] to the cribriform plate and upper nasal vault; rarely in nasopharynx, maxillary or ethmoid sinus ( Mod Pathol 2017;30:S1, Head Neck Pathol 2009;3:252 ) May become locally invasive into paranasal sinuses, nasopharynx, palate, orbit, skull base, brain Pathophysiology [pathologyoutlines.com]

Department of Physiology and Pathophysiology University of Göttingen Federal Republic of Germany 4. Department of Neuropathology University of Mainz Federal Republic of Germany 5. [link.springer.com]

[…] rare malignant tumor, 15 cases of associated ISM have been reported [ Table 2 ],[ 1 4 5 9 12 14 15 16 17 18 21 22 23 24 26 ] with leptomeningeal dissemination recognized especially in high-grade ONB.[ 9 11 22 ] Although ISM has been reported as a rare pathophysiology [surgicalneurologyint.com]

Pathophysiology Esthesioneuroblastomas (ENBs) are undifferentiated tumors of neuroectodermal origin derived from the olfactory epithelium. [1] The tumor cells are mitotically active and are the precursor cells that develop into sustentacular and neuronal [emedicine.com]

One patient had residual intracranial disease due to coagulopathy preventing further resection. Twelve patients remain alive with 10 patients remaining disease-free (follow-up ranging from 11 to 64 months). [ncbi.nlm.nih.gov]

Prevention of Esthesioneuroblastoma or Olfactory Neuroblastoma Although no prevention method regarding any cancer has been proved to greatly prevent it from developing, the best prevention method in terms of preventing esthesioneuroblastoma or olfactory [epainassist.com]

Following a healthy diet and living as healthy a lifestyle as possible may play a role in your recovery, as well as preventing a recurrence of the cancer. [hopkinsmedicine.org]

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2. Bell D, Saade R, Roberts D, et al. Prognostic utility of Hyams histological grading and Kadish–Morita staging systems for esthesioneuroblastoma outcomes. Head Neck Pathol. 2015;9:51–59.
3. Shah K, Perez-Ordóñez B. Neuroendocrine Neoplasms of the Sinonasal Tract: Neuroendocrine Carcinomas and Olfactory Neuroblastoma. Head Neck Pathol. 2016;10(1):85-94.
4. Kunc M, Gabrych A, Czapiewski P, Sworczak K. Paraneoplastic syndromes in olfactory neuroblastoma. Contemp Oncol (Pozn). 2015;19(1):6-16.
5. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85:838–54.
6. Su SY, Bell D, Hanna EY. Esthesioneuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma: differentiation in diagnosis and treatment. Int Arch Otorhinolaryngol. 2014;18:S149–S156.
7. Leon-Soriano E, Alfonso C, Yebenes L, Garcia-Polo J, Lassaletta L, Gavilan J. Bilateral Synchronous Ectopic Ethmoid Sinus Olfactory Neuroblastoma: A Case Report. Am J Case Rep. 2016;17:268-273.
8. Dublin AB, Bobinski M. Imaging Characteristics of Olfactory Neuroblastoma (Esthesioneuroblastoma). J Neurol Surg B Skull Base. 2016;77(1):1-5.
9. Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer. 1976;37:1571–6.
10. Shah K, Perez-Ordóñez B. Neuroendocrine Neoplasms of the Sinonasal Tract: Neuroendocrine Carcinomas and Olfactory Neuroblastoma. Head Neck Pathol. 2016;10(1):85-94.
11. Bell D, Hanna EY, Weber RS, et al. Neuroendocrine neoplasms of the sinonasal region. Head Neck. 2015;PM:26041714.