Esthesioneuroblastoma (ENB) or olfactory neuroblas-toma is a rare malignant tumour that arises from olfactory neuroepithelium, a structure that originates from neural crest and is found in upper part of nasal cavity [1,2]. ENB was first described by Berger in 1924 and constitutes 3-6% of all intranasal tumours with an incidence of 0.4/million population and approximately 1,200 cases reported to date [3,4]. There are no recorded risk factors as of now [5]. Bimodal age distribution that peaks in sixth and second decade (smaller peak) has been observed with a mean age of 53-54 years without any gender predisposition [3].

ENB behaves as a ‘great imposter’ due to variable clinical presentation which have insidious onset. Diagnosis is often made in late stage as a result of non-specific symptoms including nasal obstruction, epistaxis, sinusitis, anosmia and headache [6]. Less frequently, symptoms due to intra-orbital or intracranial extension of tumour can lead to confusion with oculo-orbital or brain tumour [7]. Clinical examination may reveal a reddish-brownish polypoid mass in the nasal cavity. ENB tends to be locally aggressive and has potential to recur or meta-stasize years later [3]. Rarely, ENB may be associated with paraneoplastic syndromes (PNS) including endocrinolo-gical syndrome of inappropriate ADH secretion (SIADH), ectopic ACTH syndrome, humoral hypercalcemia of malignancy, hypertension due to catecholamine secretion by tumour and neurological (opsoclonus-myoclonus-ataxia; cerebellar degeneration) [6].

Incidence of syndrome of inappropriate ADH secretion (SIADH) with cancer is infrequent with a rate of 1-2% [8]. Moreover, less than 50 cases of SIADH in ENB have been reported in literature and they had either prior or concomitant onset of SIADH [9]. Here, we describe a pediatric case of ENB in whom SIADH detected during ongoing primary treatment reflected disease progression that was confirmed radiologically.

A 16 year old female with no known comorbidities presented with nasal blockage, intermittent nasal bleeding, eye pain and headache with a 2×2 cm palpable left level II cervical lymph node.

Contrast enhanced computed tomography (CECT) of para-nasal sinus and contrast enhanced magnetic resonance imaging (CEMRI) of orbits showed a large lobulated enhancing mass epicentred in right nasal cavity, causing its expansion with extension in right maxillary, ethmoid and sphenoid sinus. There was bony destruction of nasal septum, lateral nasal wall and nasal turbinates. Lesion extended intracranially in anterior cranial fossa. Scalloping and erosion of medial wall of right orbit was noted with mass effect on underlying medial rectus muscle which was displaced towards optic nerve. Mass effect was also seen on right optic nerve in its intra-canalicular and adjacent intracranial part (Fig. 1). Biopsy of nasal mass showed features of olfactory neuroblastoma, Hyams grade II that was immunopositive for chromogranin, INSM1, synaptophysin and focally for NKX2.2. Prominent fibro-vascular stroma was present. However, rosettes, calcification and necrosis was absent.

Figure 1. Heterogenously enhancing mass in right nasal cavity with extension in right maxillary, ethmoid and sphenoid sinus. There was bony destruction of nasal septum, lateral nasal wall, nasal turbinates and medial wall of right orbit. Lesion extended intracranially in anterior cranial fossa. There was mass effect on underlying medial rectus muscle which was displaced towards optic nerve.

As the tumour was locally advanced, patient was planned for 3 cycles of chemotherapy with cisplatin and capecitabine. Subjective and radiological response was present after three cycles of chemotherapy with enhancing lesion present in posterior aspect of right nasal cavity extending to bilateral sphenoid sinus and erosion of sinus well.

However, after receiving 5 cycles patient developed recurrent episodes of hyponatremia with one episode of generalised seizure. Blood and urine investigations showed- hemoglobin- 12.0 g/dL, total leucocyte count- 8,700/µL, platelet- 314×10³/mL, blood urea nitrogen- 14 mg/dL, serum (S) creatinine- 0.7 mg/dL, total bilirubin- 0.7 mg/dL, S. aspartate transaminase- 26 U/L, S. alanine transami-nase- 13 U/L, S. alkaline phosphatase- 97 U/L, S. sodium- 106 mmol/L, S. potassium- 3.9 mmol/L, S. osmolality- 200 mosmol/kg, urine potassium- 16.06 mmoL/L, urine sodium- 121 mmoL/L, urine osmolality- 382 mosm/kg/water.

CEMRI of brain and paranasal sinus was done for evaluation and disease status that revealed progressive disease with the mass in nasopharynx extending into sella region causing erosion of sella and into clivus with its erosion. It was also extending into cavernous sinus, middle cranial fossa and causing erosion of bilateral medial temporal bones with involvement of right temporal dura. Lesion was encasing bilateral extraorbital optic nerves (Fig. 2).

Figure 2. Heterogenously enhancing sift tissue mass in nasopharyngeal wall extending into sella, clivus, sphenoid and cavernous sinus, nasal cavity that is encasing extra orbital optic nerve and infiltrating into anterior and middle cranial fossa.

Diagnosis of ENB is difficult due to its rarity, asymptomatic early stage, and non-specific symptoms in later stages [8]. Histopathologically, it is a small blue round cell tumour that has lobular architecture composed of primitive neuroblastoma cells in a dense neurofibrillary background with high nucleus/cytoplasmic ratio and scant cytoplasm. Homer-Wright rosettes and Flexner-Wintersteiner rosettes can be seen. It should be differentiated from other lesions with neuro-endocrine differentiation as they have poor loco-regional and distant control thus requiring adjuvant chemotherapy (Table 1) [10]. Workup includes clinical examination of sino-nasal region and diagnostic biopsy along with CECT and CEMRI of paranasal sinus to differentiate from other causes and stage the disease. A positron emission tomography - computed tomography (PET-CT) can be done for metastatic workup and has been found to upstage in 36% of cases [4]. Neurological and ophthalmological examination should be done [3].

Table 1 . Comparison of lesions with neuro-endocrine differentiation [8,11].

Features	Esthesioneuroblastoma	Sinonasal undifferentiated carcinoma	Sinonasal neuroendocrine carcinoma	Small cell carcinoma
Histopathology	Lobules of uniform cells with indistinct cell borders and background fibrillary material Homer-Wright (pseudo-) or Flexner–Wintersteiner (true) rosettes +/−	Malignant tumour with no squamous or glandular differentiation Nuclei are medium to large but uniformMitoses and necrosis are prominent	Sheets of monotonous, small to medium “undifferentiated” cells Abrupt and focal squamous differentiation
Synaptophysin	Positive	Negative	Negative	Weakly positive
Chromogranin	Positive	Weakly positive	Negative	Weakly positive
Epithelial markers	Weakly positive	Positive	Positive	May be positive
Arginine vasopression - neurophysin	May be positive	Negative	Negative	Negative

ENB has 3 grading systems [1]: Hyams’ grading, based on architecture, pleomorphism, neurofibrillary matrix, rosettes, mitoses, necrosis, glands, and calcification classifies into four grades - I,II (low grade) and III, IV (high grade); Kadish staging - In group A, the tumour is limited to the nasal cavity; in group B, the tumour is localized to the nasal cavity and paranasal sinuses; and in group C, the tumour extends beyond the nasal cavity and paranasal sinuses. Morita modified this system, adding a fourth group D to include local and distant metastases (Table 2) [6]. Also, TNM staging of ENB is classified according to Dulguerov staging (Table 3) [2]. Approximately, 10-30% patients have nodal or distant metastasis [5].

Table 2 . Kadish stage group and suggested treatment [4].

Stage	Description	Treatment
A	Tumour confined to the nasal cavity	Surgery, in selected cases combined with radiotherapy
B	Tumour confined to the nasal cavity and paranasal sinuses	Radiotherapy before or after surgery, to the primary tumour site and subclinical lymph nodes with elective nodal irradiation. Adjuvant chemotherapy may be added depending on the degree of differentiation of the tumour
C	Tumour extent beyond nasal cavity and paranasal sinuses, including involvement of the cribriform plate, base of the skull, orbit, or intracranial cavity	Preoperative chemotherapy and/or radiotherapy followed by surgery or Surgery may be followed by chemoradiotherapy with elective nodal irradiation
D	Tumour with metastasis to cervical lymph nodes or distant sites

Table 3 . Dulguerov modified TNM staging [2].

T stage	Description
T1	Nasal cavity/paranasal sinuses (not sphenoid or superior most ethmoid)
T2	Includes sphenoid with extension to/erosion of cribriform plate
T3	Extends into orbit or anterior cranial fossa without dural invasion
T4	Tumour involving brain
N stage
N0	No cervical lymph node metastasis
N1	Cervical lymph node metastasis present
M stage
M0	No metastasis
M1	Distant metastasis

WHO classified sinonasal neuroendocrine carcinoma (NEC) and tumours with predominantly neural features such as Ewing’s sarcoma/primitive neuroectodermal tumour, mucosal malignant melanoma, melanotic neuroectodermal tumour of infancy, heterotopic central nervous system tissue (nasal glioma), and ectopic pituitary adenoma that are differentials of NEC. Table 1 compares pathological features of lesions with neuro-endocrine differentiation [11].

As ENB is rare, there are no standard treatment guidelines [6]. Complete surgical removal by anterior cranio- facial resection or endoscopically with adjuvant radiation in low to moderate grade lesions is generally fol-lowed. Depending on the setting of radiation (RT), dose varies [7]. For pre-operative radiation, 45 Gy while for post-operative doses of 50-60 Gy in 1.8 Gy to 2.0 Gy fractions is prescribed. Preoperative RT has been shown to improve chances of resection, whereas post-operative RT has decreased local recurrence rates to 0-40%. In inoperable tumours, dose can go upto 70 Gy. Concurrent chemotherapy is preferred as the tumour is both chemosensitive and radiosensitive [3].

Chemotherapy with cyclophosphamide, vincristine, dox-orubicin or combination of etoposide and cisplatin or ifosfamide has shown some benefit and is reserved for patients with high grade, margin positive, Kadish C & D disease and recurrent cases (Table 2) [6,12]. The reported 5 yr and 10 yr overall survival rates for ENB are 61.1% and 45.6% respectively [11]. Older age (>65 years) and node positive disease are poor prognostic factors. Recur-rences are observed in approximately 30% of cases that may be as late as after 15 years of initial diagnosis [5].

Most ENB are non-functioning tumours [6]. Associ-ation with PNS is rare however, SIADH remains the most common PNS [1]. Moreover, there is a high chance that this correlation has been missed [1]. Hyponatremia has preceded diagnosis of ENB in 76% of cases of SIADH associated ENB with a mean duration of 3.5 years [13]. Most of the cases are reported in young age patients [14]. Exact mechanism of SIADH in ENB is unclear. However, it may be a result of ectopic production of ADH from tumour as arginine vasopressin immunopositive has been observed in ENB [1]. SIADH is a result of presence of ADH in excess amounts that results in hyponatremia and elevated urine osmolalilty, lack of edema, and normal renal function [6,8]. Symptoms of SIADH are mostly neurological and depends on rate and degree of hyponatremia. When it is gradual, patient can be asymptomatic or have non-specific symptoms while when it is rapid, symptoms are severe. Fall of serum sodium <120 mEq or serum osmolality >240 mOsm/kg can lead to cerebral edema [6].

It has been observed that treatment of primary tumour usually resolves the associated PNS as well. Hence, patient in whom SIADH does not resolve after completion of adjuvant treatment should be evaluated for residual or recurrent disease [1]. Furthermore, SIADH in follow up period can indicate late recurrences hence, any inci-dence of hyponatremia should be followed up with workup for recurrence [13,15].

Follow-up is mandatory to detect recurrences early. Clinical examination and radiological investigations are used for follow up. Measurement of serum sodium should form a part of follow up in all patients of ENB as it is an easy and cost effective method of follow up to detect a few of recurrent cases. Patients need to be followed up lifelong as ENB has a long natural history and recurrences tend to occur late [14-16].

Also, in the opposite situation when patient presents with idiopathic SIADH, clinical and radiological evaluation of sinonasal region should not be forgotten.

This case is an unusual case of ENB in a 16 year old where SIADH onset occurred during treatment and it reflected disease progression that was confirmed by radiological imaging. This suggests that in locally advanced cases serum sodium monitoring during treatment can assist in response evaluation.

ENB is a unique malignancy with reports of long standing SIADH prior to its diagnosis. SIADH can occur months to years before the diagnosis of ENB, can infrequently also be at the time of presentation or years later prior to recurrence. However, any new onset SIADH during treatment can represent disease progression as seen in this case has not been reported before. Serum sodium estimation is a cost effective test and should be a part of monitoring and routine follow up.

The patient details presented in this case report were submitted as an abstracted and presented as a Yound oncologist case report poster display at the annual European Society of Medical Oncology conference held in Singapore on 3 December 2022. The abstract has since been rewritten. The case report is not a repetition of the material included in the poster and has since been re-conceptualised and presented as an original piece of research.

The authors have no conflict of interest to declare.