VOLUME

33

NUMBER

21

JULY

20

2015

JOURNAL OF CLINICAL ONCOLOGY

Olfactory Neuroblastoma With Hyponatremia

Introduction
Hyponatremia is a common electrolyte disorder in oncology.1
Hyponatremia in this context is often caused by the syndrome of
inappropriate antidiuretic hormone secretion (SIADH). In SIADH,
the secretion of vasopressin is said to be inappropriate when neither a
rise in serum osmolality nor intravascular volume depletion is responsible for the secretion of vasopressin.2 Both cancer and chemotherapy
can stimulate vasopressin inappropriately. In fact, the first patients
reported by Schwartz et al3 with SIADH had lung cancer. Since this
initial report, small-cell lung cancer has become the classic example of
a cancer with the potential to secrete vasopressin ectopically.4 Other
cancers that can produce vasopressin ectopically are pancreatic cancer
and olfactory neuroblastoma (also called esthesioneuroblastoma).5,6
Among the many chemotherapeutic agents that can cause hyponatremia as a result of SIADH, vincristine,7 ifosfamide,8 and cyclophosphamide9 are best recognized. In practice, hyponatremia often poses a
challenge in terms of differential diagnosis and selecting the optimal
correction rate.10 In contrast, hyponatremia has received little attention as an initial manifestation of underlying disease which may occur
in the case of diseases such as primary or secondary adrenal insufficiency,11 SIADH as a result of infectious disease,12 and paraneoplastic
SIADH.1 Similar to hyponatremia, hypertension is also a common

D I A G N O S I S

I N

O N C O L O G Y

paraneoplastic phenomenon, especially in cancers affecting the adrenal gland, such as Cushings syndrome or pheochromocytoma. Hypertension has also been observed as an adverse effect of newer
chemotherapeutic agents such as the tyrosine kinase inhibitor
sunitinib.13 Here, we present the case of a young woman who presented with hyponatremia and hypertension as the first and only
manifestations of a rare cancer, namely olfactory neuroblastoma.
Case Report
A 29-year-old pregnant woman was found to have hypertension
during her first prenatal visit at 12 weeks. Her blood pressure was
160/108 mmHg. Except for occasional nausea and vomiting, which
had started during the first weeks of pregnancy, she had no complaints. She had no previous medical history, no positive family history of hypertension or other diseases, and did not use any medication,
licorice, or licorice tea. She had no Cushingoid appearance, and there
was no edema. She was referred to a local hospital where blood tests
revealed severe hyponatremia (serum sodium, 117 mmol/L) with a
high urine sodium (168 mmol/L) and urine osmolality (610 mOsm/
kg, Table 1). Her serum sodium had never been measured before. Her
serum glucose, potassium, creatinine, and cortisol were within the
normal ranges, but she did have subclinical hypothyroidism (Table 1).
She was admitted to treat hypertension with labetalol and hyponatremia with hypertonic saline. A chest x-ray and abdominal ultrasound
were normal. A presumptive diagnosis of reset osmostat as a result of

Table 1. Laboratory and Blood Pressure Measurements of the Patient

Measurement
Blood
Sodium, mmol/L
Potassium, mmol/L
Osmolality, mOsm/kg
Creatinine, mol/L
Uric acid, mmol/L
Glucose, mmol/L
Urine
Sodium, mmol/L
Osmolality, mOsm/kg
Hormones
Thyroid stimulating hormone, mU/L
Free T4, pmol/L
Adrenocorticotropic hormone, ng/L
Cortisol, nmol/L
Vasopressin, ng/L
Renin, U/mL
Aldosterone, pg/mL
Urine metanephrine, mol/mmol creatinine
Urine normetanephrine, mol/mmol creatinine
Other
Blood pressure, mmHg

e88

2014 by American Society of Clinical Oncology

At Presentation
117
4.0
39
0.06
5.0
168
609
4.75
18.0
54.1
480

160/108

At Referral
126
4.0
252
53
0.17
4.6

Postoperatively

Reference Values

139
3.9

136-145
3.5-5.0
275-285
90
0.12-0.34
4.0-6.1

63
4.3

171
1,152

1.65
18.3

0.4-4.3
11-25
7.2-63.3
200-700
0-4.7
10-60
50-250
150
260

267
5.9
2.0
14.0
35
63
142/106

135/88

Journal of Clinical Oncology, Vol 33, No 21 (July 20), 2015: pp e88-e92

Downloaded from jco.ascopubs.org on July 2, 2016. For personal use only. No other uses without permission.
Copyright 2015 American Society of Clinical Oncology. All rights reserved.

Diagnosis in Oncology

pregnancy was made. During follow-up, she had an intrauterine fetal

death at 20 weeks for which no cause was found. In addition, hyponatremia recurred and could therefore no longer be ascribed to pregnancy. Magnetic resonance imaging (MRI) of her brain and pituitary
was normal. She was referred to our hospital for further analysis
(Table 1). SIADH was diagnosed on the basis of euvolemia, the absence of adrenal insufficiency or hypothyroidism, and inappropriately
concentrated urine (urine osmolality 1,152 mOsm/kg) during hypotonicity (serum sodium, 126 mmol/L; serum osmolality, 252 mOsm/
kg) with elevated levels of plasma vasopressin (5.9 pg/mL, Table 1).
Hyponatremia secondary to SIADH was treated with fluid restriction
and loop diuretics. Computed tomography (CT) scans of chest and
abdomen revealed no cause of SIADH or hypertension. CTangiography excluded the rare hyponatremic-hypertensive syndrome, which can be caused by renal artery stenosis.14 Hormone
analysis did not show abnormal production of aldosterone or catecholamines (Table 1). A literature search identified similar patients in
whom olfactory neuroblastoma, a rare tumor originating from neuroepithelial cells of the olfactory mucosa, was responsible for hyponatremia and hypertension.6,15 A subsequent MRI of the sinuses indeed
identified a gadolinium-positive lesion in the ethmoid sinus (Fig 1;

Fig 1.
www.jco.org

lesion indicated by white circle). Somatostatin receptor scintigraphy

showed slightly increased uptake in the right paranasal sinus (Fig 2;
lesion indicated by white circle; Fig 2A, somatostatin receptor scintigraphy; Fig 2B, single-photon emission CT; Fig 2C, CT). However,
clinical examination and nasal endoscopy did not reveal any mucosal
abnormalities. Endonasal ethmoidectomy was performed (Data
Supplement). The histology confirmed the presence of a welldifferentiated olfactory neuroblastoma with positive immunoreactivity to synaptophysin and S-100. In addition, immunohistochemical
staining of the olfactory neuroblastoma using a vasopressin antibody
(Abcam Anti-Vasopressin antibody ab39363; Abcam, Cambridge,
MA) was positive in particular regions (positive labeling in Figs 3A and
3C; boxed regions magnified in Figs 3B and 3D, respectively), including trabeculae or small round nests of cells (Figs 3E and 3F, respectively). This indicated that the tumor produced vasopressin
ectopically. Labeling was absent in other regions of similar structure in
the same tissue (Fig 3G; boxed area magnified in Fig 3H), or in the
absence of antibody (not shown). Immunohistochemical staining
with an antibody against tyrosine hydroxylase, a marker for catecholamine synthesis, was negative (data not shown). Blood pressure and
serum sodium normalized after surgery (Table 1). The tumor was
staged as Kadish B. The patient was treated with adjuvant radiotherapy. In retrospect, she denied complaints of anosmia, nasal obstruction, discharge, or epistaxis. At present, 16 months after therapy, she
remains normonatremic, without clinical or radiologic evidence
of recurrence.
Discussion
We report the case of a young woman in whom hyponatremia led
to the discovery of an olfactory neuroblastoma. A literature review
identified 20 previously reported cases of olfactory neuroblastoma
with hyponatremia (Table 2).6,15-31 We believe our patient and the
literature review illustrate a number of educational points. Patients
with olfactory neuroblastoma and hyponatremia were younger and
more often women (mean age of 38 years, 55% female) compared to a
cohort of 311 patients with olfactory neuroblastoma (mean age of 53
years, 45% female).32 In 16 of 21 patients (76%), hyponatremia preceded the diagnosis of olfactory neuroblastoma, as in our patient.
Because of its usual location in the olfactory cleft, olfactory neuroblastoma may remain asymptomatic for many years. Hyponatremia can
be the initial and only manifestation of olfactory neuroblastoma. This
case therefore emphasizes that in young patients, unexplained hyponatremia should not be considered idiopathic if none of the obvious
causes are present. However, in the elderly, SIADH is often idiopathic,
and this group may therefore not benefit from extensive diagnostic
testing.33 Previously we reported other patients for whom hyponatremia was also the first trigger for further investigation.11,12 Although
pregnancy may cause mild hyponatremia because of a reset of the
osmostat, serum sodium usually decreases to no more than 5 mmol/
L.34 Two previous patients with olfactory neuroblastoma and pregnancy have been reported.15,30 Both delivered normally and, in fact,
hyponatremia resolved during pregnancy in one patient, possibly
because she had superimposed diabetes insipidus of pregnancy.15 Although the visualization of the tumor with MRI ultimately led to the
diagnosis in our patient, it was of interest to see that there was also
uptake of somatostatin by the tumor during somatostatin receptor
scintigraphy (Fig 2). MRI is the imaging modality of choice in olfactory neuroblastoma; however, previous reports have indicated that
2014 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on July 2, 2016. For personal use only. No other uses without permission.
Copyright 2015 American Society of Clinical Oncology. All rights reserved.

e89

Hoorn et al

Fig 2.

this tumor expresses somatostatin receptors35,36 and can be detected

with somatostatin receptor imaging.37 We pursued specific staining
for vasopressin to confirm that hyponatremia was indeed caused by
the ectopic production of vasopressin by the tumor, as was done
previously.6,21,22 Hypertension also occurs commonly in patients with
olfactory neuroblastoma and hyponatremia (Table 2). Olfactory neuroblastoma can cause ectopic adrenocorticotropic hormone syndrome and therefore hypertension,38 but this was not present in our
patient. In the absence of ectopic adrenocorticotropic hormone syndrome, the pathogenesis of hypertension in olfactory neuroblastoma
remains unclear. In theory, high plasma vasopressin levels could exert
a pressor effect,39 although hypertension is uncommon in SIADH.
Alternatively, the tumor may produce other hypertensinogenic substances such as endothelin-1, as has been shown for other tumors.40 In
summary, unexplained hyponatremia led to the discovery of olfactory
neuroblastoma in this young woman, as documented by MRI, somatostatin receptor imaging, and immunohistochemistry for vasopressin (Figs 1 through 3).

Ewout J. Hoorn and Dominiek A. Monserez

Erasmus Medical Center, Rotterdam, the Netherlands

Robert A. Fenton
Center for Interactions of Proteins in Epithelial Transport, Aarhus University,
Aarhus, Denmark

Ilse Overdevest and Alfred J. Apperloo

St Elisabeth Hospital, Tilburg, the Netherlands

Robert Zietse and Jose A. Hardillo

Erasmus Medical Center, Rotterdam, the Netherlands

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES
1. Verbalis JG: Tumoral hyponatremia. Arch Intern Med 146:1686-1687, 1986
e90

2014 by American Society of Clinical Oncology

2. Ellison DH, Berl T: Clinical practice: The syndrome of inappropriate

antidiuresis. N Engl J Med 356:2064-2072, 2007
3. Schwartz WB, Bennett W, Curelop S, et al: A syndrome of renal sodium
loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 23:529-542, 1957
4. Coscia M, Brown HD, Miller M, et al: Ectopic production of antidiuretic hormone
(adh), adrenocorticotrophic hormone (ACTH) and beta-melanocyte stimulating hormone
(beta-MSH) by an oat cell carcinoma of the lung. Am J Med 62:303-307, 1977
5. Marks LJ, Berde B, Klein LA, et al: Inappropriate vasopressin secretion and
carcinoma of the pancreas. Am J Med 45:967-974, 1968
6. Osterman J, Calhoun A, Dunham M, et al: Chronic syndrome of inappropriate antidiuretic hormone secretion and hypertension in a patient with olfactory
neuroblastoma: Evidence of ectopic production of arginine vasopressin by the
tumor. Arch Intern Med 146:1731-1735, 1986
7. Cutting HO: Inappropriate secretion of antidiuretic hormone secondary to
vincristine therapy. Am J Med 51:269-271, 1971
8. Cantwell BM, Idle M, Millward MJ, et al: Encephalopathy with hyponatremia and inappropriate arginine vasopressin secretion following an intravenous
ifosfamide infusion. Ann Oncol 1:232, 1990
9. DeFronzo RA, Braine H, Colvin M, et al: Water intoxication in man after
cyclophosphamide therapy: Time course and relation to drug activation. Ann
Intern Med 78:861-869, 1973
10. Cluitmans FH, Meinders AE: Management of severe hyponatremia: Rapid
or slow correction? Am J Med 88:161-166, 1990
11. van der Hoek J, Hoorn EJ, de Jong GM, et al: Severe hyponatremia with
high urine sodium and osmolality. Clin Chem 55:1905-1908, 2009
12. Hoorn EJ, Hotho D, Hassing RJ, et al: Unexplained hyponatremia: Seek and
you will find. Nephron Physiol 118:66-71, 2011
13. Kappers MH, van Esch JH, Sluiter W, et al: Hypertension induced by the
tyrosine kinase inhibitor sunitinib is associated with increased circulating
endothelin-1 levels. Hypertension 56:675-681, 2010
14. Agarwal M, Lynn KL, Richards AM, et al: Hyponatremic-hypertensive
syndrome with renal ischemia: An underrecognized disorder. Hypertension
33:1020-1024, 1999
15. Renneboog B, Decaux G: Idiopathic hyponatremia in a young patient: Look
at the sinus. Am J Med 121:e5-e6, 2008
16. al Ahwal M, Jha N, Nabholtz JM, et al: Olfactory neuroblastoma: Report of
a case associated with inappropriate antidiuretic hormone secretion. J Otolaryngol 23:437-439, 1994
17. Bernard P, Vitrey D, Boursier C, et al: Olfactory esthesioneuroma manifesting as
Schwartz-Bartter syndrome[in French]. Rev Med Interne 21:278-281, 2000
18. Bouche J, Guiot G, Tessier P, et al: A further case of tumor of the olfactory
placode[in French]. Sem Hop 43:587-591, 1967
JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on July 2, 2016. For personal use only. No other uses without permission.
Copyright 2015 American Society of Clinical Oncology. All rights reserved.

Diagnosis in Oncology

Fig 3.

19. Cullen MJ, Cusack DA, OBriain DS, et al: Neurosecretion of arginine
vasopressin by an olfactory neuroblastoma causing reversible syndrome of
antidiuresis. Am J Med 81:911-916, 1986
20. Gray ST, Holbrook EH, Najm MH, et al: Syndrome of inappropriate
antidiuretic hormone secretion in patients with olfactory neuroblastoma. Otolaryngol Head Neck Surg 147:147-151, 2012
21. Kleinschmidt-DeMasters BK, Pflaumer SM, Mulgrew TD, et al: Sinonasal
teratocarcinosarcoma (mixed olfactory neuroblastoma-craniopharyngioma) presenting with syndrome of inappropriate secretion of antidiuretic hormone. Clin
Neuropathol 19:63-69, 2000
22. Miura K, Mineta H, Yokota N, et al: Olfactory neuroblastoma with epithelial
and endocrine differentiation transformed into ganglioneuroma after chemoradiotherapy. Pathol Int 51:942-947, 2001
23. Muller MB, Landgraf R, Keck ME: Vasopressin, major depression, and
hypothalamic-pituitary-adrenocortical desensitization. Biol Psychiatry 48:330-333, 2000
24. Myers SL, Hardy DA, Wiebe CB, et al: Olfactory neuroblastoma invading
the oral cavity in a patient with inappropriate antidiuretic hormone secretion. Oral
Surg Oral Med Oral Pathol 77:645-650, 1994
www.jco.org

25. Plasencia YL, Cortes MB, Arencibia DM, et al: Esthesioneuroblastoma

recurrence presenting as a syndrome of inappropriate antidiuretic hormone
secretion. Head Neck 28:1142-1146, 2006
26. Pope TL Jr, Morris JL, Cail WS, et al: Esthesioneuroblastoma presenting as
an intracranial mass. South Med J 73:643-645, 1980
27. Singh W, Ramage C, Best P, et al: Nasal neuroblastoma secreting
vasopressin: A case report. Cancer 45:961-966, 1980
28. Srigley JR, Dayal VS, Gregor RT, et al: Hyponatremia secondary to olfactory
neuroblastoma. Arch Otolaryngol 109:559-562, 1983
29. Wade PM Jr, Smith RE, Johns ME: Response of esthesioneuroblastoma to
chemotherapy: Report of five cases and review of the literature. Cancer
53:1036-1041, 1984
30. Senchak A, Freeman J, Ruhl D, et al: Low-grade esthesioneuroblastoma
presenting as SIADH: A review of atypical manifestations. Case Rep Otolaryngol
2012:582180, 2012
31. Maeda H, Tsuruya K, Yotsueda H, et al: A case report of syndrome of
inappropriate secretion of antidiuretic hormone with marked edema due to
administration of hypertonic saline. Ther Apher Dial 11:309-313, 2007

2014 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on July 2, 2016. For personal use only. No other uses without permission.
Copyright 2015 American Society of Clinical Oncology. All rights reserved.

e91

Hoorn et al

Table 2. Previously Reported Cases of Olfactory Neuroblastoma With Hyponatremia

Sex

Age (years)

Lowest Serum
Sodium (mmol/L)

Hyponatremia As
Presenting Feature

Accompanying Hypertension

Reference

M
F
F
F
F
F
M
M
F
M
F
M
M
M
F
M
F, F, M
F
F

34
56
17
59
33
26
28
27
79
59
34
22
47
56
28
61
25, 32, 29
28
29

116
112
110
124
110
115
107
108
125
113
128
107
110
109
116
112
110, 114, 115
112
117

No
No
No
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes

Not reported
Not reported
Yes
Not reported
No
Yes
Yes
No
Not reported
Not reported
No
Not reported
Not reported
Yes
No
Yes
Not reported
Not reported
Yes

18
26
27
29
28
19
6
16
24
21
25
17
23
22
15
31
20
30
This patient

32. Jethanamest D, Morris LG, Sikora AG, et al: Esthesioneuroblastoma: A

population-based analysis of survival and prognostic factors. Arch Otolaryngol
Head Neck Surg 133:276-280, 2007
33. Hirshberg B, Ben-Yehuda A: The syndrome of inappropriate antidiuretic
hormone secretion in the elderly. Am J Med 103:270-273, 1997
34. Davison JM, Shiells EA, Philips PR, et al: Influence of humoral and volume
factors on altered osmoregulation of normal human pregnancy. Am J Physiol
258:F900-F907, 1990
35. Freeman SR, Mitra S, Malik TH, et al: Expression of somatostatin receptors
in arginine vasopressin hormone-secreting olfactory neuroblastoma: Report of
two cases. Rhinology 43:61-65, 2005
36. Rostomily RC, Elias M, Deng M, et al: Clinical utility of somatostatin
receptor scintigraphic imaging (octreoscan) in esthesioneuroblastoma: A case

study and survey of somatostatin receptor subtype expression. Head Neck

28:305-312, 2006
37. Ramsay HA, Kairemo KJ, Jekunen AP: Somatostatin receptor imaging of
olfactory neuroblastoma. J Laryngol Otol 110:1161-1163, 1996
38. Kanno K, Morokuma Y, Tateno T, et al: Olfactory neuroblastoma causing
ectopic ACTH syndrome. Endocr J 52:675-681, 2005
39. Luft FC: Vasopressin, urine concentration, and hypertension: A new
perspective on an old story. Clin J Am Soc Nephrol 2:196-197, 2007
40. Yokokawa K, Tahara H, Kohno M, et al: Endothelin-secreting tumor.
J Cardiovasc Pharmacol 17:S398-S401, 1991 (suppl 7)

DOI: 10.1200/JCO.2013.49.1464; published online ahead of print at

www.jco.org on March 31, 2014

e92

2014 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on July 2, 2016. For personal use only. No other uses without permission.
Copyright 2015 American Society of Clinical Oncology. All rights reserved.