Neurosecretion of arginine vasopressin by an olfactory neuroblastoma causing reversible syndrome of antidiuresis

Neurosecretion of Argihne Vasopressin by an Olfactory Neuroblast;oma Causing Reversible Syndrome of Antidiuresis

MICHAEL J. CULLEN, M.A., M.B., BCti., M.R.C.P.I. DENIS A. CUSACK, M.B., M.R.C.P.I. D. SEAN O’BRIAIN, M.B., M.R.C.Path. JOHN B, DEVLIN, M.B.; B.A.(Mod), M.R.C.P.I. ANNE KEHELY, B.A., MB,, M.R.C.P.I. TERENCE A. LYONS, B.Sc. Dublin, Ireland

From the Departments of Endocrinology and Histopathology, and Sir Patrick Dun’s Research Laboratory, St. James’s Hospital and Trinity College, Dublin, Ireland. Requests for reprints should be addressed to Professor Michael J. Culten, Trinity Medical School, St. James’s Hospital, Dublin 8, Ireland. Manuscript submitted May 21, 1985, and accepted July 10, 1985.

A 26-year-old woman with the syndrome of inappropriate antidiuresis demonstrated complete recovery following the resection of an olfactory neuroblastoma. Tissue arginine vasopressin levels by radioimmunoassay, immunohistochemical staining of the tissue arginine vasopressin, postoperative normalization of plasma arginine vasopressin levels, and the clinical resolution are evidence in support of a neurally derived tumor being the direct source of neurosecretion of arginine vasopressin rather than neurohypophyseal secretion or secretion from non-neural tissues, as reported to date in the etiology of the syndrome of inappropriate antidiuresis. In 1957, Schwartz et al [l] first described the syndrome of inappropriate antidiuresis in patients with bronchogenic carcinoma. It has since been observed in a variety of malignancies and other diseases [2]. The source of the antidiuretic hormone (arginine vasopressin) has been found to be from non-neural tissues such as the lung or pancreas or assumed to be from neurohypophyseal neurosecretion. Formal evidence of arginine vasopressin production by tumors is often incomplete, whereas tumors of the nervous system not involving the neurohypophysis are currently assumed not to be a source of arginine vasopressin. We herein present evidence of a neural tumor being the direct source of arginine vasopressin in the syndrome of inappropriate antidiuresis. Our patient, a young woman, had unexplained hyponatremia for four years, but was otherwise well apart from a nasal polyp. Before and after polypectomy, measurements were made under metabolic conditions of serum sodium, serum osmolality, plasma arginine vasopressin levels, and urine osmolality. The syndrome of inappropriate antidiuresis resolved completely, and the polyp proved to be an olfactory neuroblastoma. Evidence from plasma radioimmunoassays, tumor electron microscopy, and direct tumor radioimmunoassay and immunohistochemical localization studies and the resolution of the syndrome of inappropriate antidiuresis after tumor resection all support the hypothesis that this neurally derived tumor was the source of arginine vasopressin. Previously, the blood pressure has been documented to be normal in the syndrome of inappropriate antidiuresis [3]. Nonetheless, we observed episodic hypertension with the syndrome of inappropriate antidiuresis that resolved on tumor removal. The role of arginine vasopressin in human hypertension is unclear [3-51. Features of the syndrome of inappropriate antidiuresis with serum sodium values of 108 to 115 mmol/liter with or without hypertension in otherwise apparently well young women in association with a nasal polyp that proves to be an olfactory neuroblastoma may constitute a new

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described nasal stuffiness for 10 years and had bilateral antral washouts in 1977. She had been taking 200 mg of metoprolol twice daily since 1981 for hypertension and 1 g of mefenamic acid four times daily during the times she had severe headache. On admission, she was distressed and vomiting. Her blood pressure was 190/120 mm Hg in both arms lying and standing. She did not have papilledema or any focal neurologic deficit. She had a right nasal polyp and adenoid speech. Her serum sodium concentration was 115 mmol/lit&, serum osmolality 233 mOsm/kg, urinary sodium 74 mmol/liter, and urine osmolality 833 mOsm/kg. Her urea level was 3.5 mmol/liter (21.0 mg/dl), and her creatinine level was 67 pmol/liter (0.8 mg/dl). An initial diagnosis of the syndrome of inappropriate antidiuresis was made, and fluid was restricted to 800 ml per day. However, a few hours after admission, she became disorientated and barely arousable. Emergency computed axial tomography of the brain showed no abnormality. With continued fluid restriction, her clinical condition returned to normal within 24 hours, and her serum sodium concentration rose to between 124 and 130 mmol/liter and serum osmolality to between 250 aild 256 mOsm/kg. Her urine osmolality remained inappropriately high-between 726 and 879 mOsm/kg-with continuing renal sodium excretion betweeir 56 and 82 mmol/litei-. The patient’s mental state and blood pressure returned to normal with fluid restriction to 800 ml per day. All medications had been discontinued on admission, and only paracetamol was prescribed for headache. Howe&, some 18 days later, she had paroxysmal hypertension of 200/90 mm Hg for several hours, which resolved spontaneously. Investigation revealed no cause for the syndrome of inappropriate antidiuresis, and repeated determinations of 24-hour urinary catecholamine values and fecal and urinary porphyrin values gave normal re’sults. Because the onset of these episodes cbincided with that of nasal stuffiness, we postulated that the polyp was the source of antidiuretic hormone. Polypectomy was performed, although complete removal was not histologically confirmed. Computed axial tomography showed no evidence of residual tumor. Following this, resolution of the syndrome of inappropriate antidiuresis occurred, and there were no further hypertensive episodes. Three months after surgicai resection, the patient was treated with radiotherapy with a total tumor dose of 5000 cgy administered iti 20 fractions over five weeks. One year after initial presentation, she remains healthy and asymptomatic. Laboratory Studies and Results. Arginine vasopressin was assayed by the radioimmunoassay method of Skowsky et al [6] at the Nichols Institute, Los Angeles, California. For plasma samples, when possible, EDTA plasma was frozen immediately and stored at -20% until assayed. Only heparinized p&ma samples that were frozen after a delay of six hours were available for the preoperative arginine vasopressin assays. Use of frozen heparinized plasma lowers results by approximately 50 percent in comparison with the results obtained with EDTA plasma, and no correction for this or for the delay in freezing has been made. The arginine vasopressin values are expressed in pmol/liter and compared with the normal range appropriate for a given

Figure 1. Olfactory neuroblastoma by /igbt microscopy. The tumor is composed of small round cells lying in a fibrillary background. These cells frequently cluster in semicircular Or circular formations typical of rosettes of the Homer Wiight-type (hematoxylin and eosin stain; magnification X 360).

clinical syndrom& The early recognition and treatment of this condition should lead to a better prognosis for this unusual tumor. CASE

REPORT

Clinical Course. A 26-year-old woman was admitted in July 1983 in a somnolent, precomatose but arousable state; she was orientated to time, person, and place. She had d two-week history of malaise anti lethargy and a one-day history of headache and vomiting. She had had multiple similar episodes in the previous 10 years with several hospital admissions. These had become more frequent in the past year, occurring monthly but not related to menses and lasting for one week. She had pre-eclamptic toxemia in 1973 and 1979. She delivered a live male child on the first occasion, and the pregnancy was terminated on the second, with resolution of the hypertension on both occasions. On the latter occasion, she had hyponatremia. Investigations for hematemesis in 1979 and for hypertension, vomiting, and hyponatremia in 1981 revealed no cause. She

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staining for arginine vasopressin was present as fine and coarse granules in the cytoplasm of tumor cell clusters. Occasional linear staining corresponding to cell processes was present in the fibrillar areas of the tumor. Control studies substituting non-immune rabbit serum for arginine vasopressin antibody gave negative results. 2) revealed tumor cells with Electron microscopy (Figure round nucleoli and small quantities of cytoplasm containing moderate amounts of rough endoplasmic reticulum and mitochondria. Cell processes were prominent and they contained microfilaments, microtubules, and abundant neurosecretory granules ranging in size from 50 to 110 nm. Occasional processes had bulbous terminal expansions, and a single cilium like structure was identified. Schwann cells were frequent and produced extensions to surround cell processes and cell clusters. Figure 3 illustrates the changes observed in serum sodi

-

radiotherapy Fluid

Intake

L/day

Serum

Figure 2. Olfactory neuroblastoma by transmission eleo Won microscopy. A group of tumor cells forms a rosette. Cell processes (neurites) are present in the lumen of the rosette, and multiple similar processes are present in the intercellular tissue (arrows) (magnif/cafion X 2,400; bar = 10 pf& Inset, portion of a cell process contains multiple membrane-bound neurosecretory granules (magnification X 30,000. Bar = 100 nM).

Sodium

mmol/

L

SerumOsmolality mOsm/kg

280 t

.----;

I

,.,, :;c/--9 **-.& ,..,/ .-.. .

*..a ------.

.

260 240 1000

serum osmolality. The sensitivity of the assay is 0.35 pmoi/liter (0.38 pg/ml). Tumor tissue removed at surgery was frozen and stored at -20°C. It was prepared for assay by the method of Coscia et al [7]. Fresh tissue was fixed in 10 percent formalin, processed routinely and stained with hematoxylin and eosin, periodic acid-Schiff, reticulin, Masson Fontana, and Grimelius stains. lmmunohistochemical analysis was performed on formalin-fixed paraffin-embedded material using the peroxidase antiperoxidase technique. Rabbit anti-serum to arginine vasopressin (UCB Bioproducts, SA; Brussels, Belgium) was used at a dilution of 1: 1,000. Non-immune rabbit serum was used as a negative control. Snap-frozen fresh tissue was examined for formaldehyde-in-duced fluorescence. For electron microscopy, fresh tissue fixed in 4 percent glutaraldehyde was embedded in Epon and stained with lead citrate and uranyl acetate following sectioning. By light microscopy, the tumor lay beneath the respiratory epithelium and was a typical olfactory neuroblastoma composed of sheets and nests of small round cells with 1). inconspicuous nucleoli and scanty cytoplasm (Figure Mitoses were rare. Homer Wright-type rosettes were frequent, and there was a prominent intercellular fibrillary background. Masson Fontana and Grimelius stains gave negative results. Formaldehyde-induced fluorescent studies revealed no catecholamines. lmmunohistochemical

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Urine

Osmolality

mOsm

/kg

500 0 15,

Plasma

--.-

AVP

-_----

. ..__._

pmol/L

0

5 Weeks

10’ Post

15

207

25

Presentation

igure 3. Clinical course in a patient with antidiuretic hormone-secreting olfactory neuroblastoma. The clinical course is shown with the time on the abscissa. The vertical arrow and line indicate the day of surgery, the upper horizontal arrows indicate the duration of radiotherapy, and the hatched area and lower horizontal arrows indicate the fluid intake. The ordinate shows the fluid intake, serum sodium concentration, serum and urine osmolality, and plasma arginine vasopressin level. Heparinized plasma arginine vasopressin levels are indicated by open dots, and EDTA plasma values are indicated by solid dots. The areas between the broken horizontal lines indicate the normal ranges and refer to the levels appropriate to the prevailing serum osmolality for plasma arginine vasopressin.

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rose to between 266 and 277 mOsm/kg. The urine osmolality showed the ability to dtjute to 260 mOsm/kg,The plasma arginine vasopressin level was 3.0 and 3.9 pmol/liter (3.3 and 4.3 pg/mi) on the seventh anti eighth postoperative days, whereas the exbected levels for the prevailing serum osmolality should have been less than’ 0.9 pmol/litdr (1 pg/ml). After 11 days, the patient tolerated increasing fluid intake to 2.3 liters per day, and at the same time, the serum sodium concentration continued to rise and remained riormal. The serum osmolality likewise was stable between 27-2 and 287 mOsm/kg. The urine osmolality responded to a 1.2 liter water challenge by dropping to 5Q rnOsmJkg and remaihed apbropriafe. Plasma arginine vasopressin levels decreased.to 0.8 to 3.2 pmol/liter (0.9 to 3.5 pg/ml); the expected levels for normally hydrated subjects with normal piasma osmolality range from 0.Q to 12.2 pmol/liter (1 to 13.3 .pg/ml). Radiotherapy had no effect on the serum sodium concentration or osmolality or plasma arginine vasopressin level. Fibwe 4 is included to iflustrate our values for plasma arginine vasopressin in comparison with the nomogram reported by Zerbe et al [2] relating plasma arginine vaso-

14 0 12

1 10 -

i ;; E a

8_

i-

0 0

0. > a

0

6. 4. 2_

0, L 250

I 260

I.

I

1

270

280

280

Serum Osrnolality mOsm/kg .~_

Figjure 4. Plasnia arginine vasopressin ‘levels related to serum osmolality. Preoperative heparir&ed plastha sati p/es (open dots), early postoperatiCe EQTA plasma sam p/es (split dots), and late postoperattve EDTA plasma sarnp/es (solid dots) are’ plotted. The shaded irea indicates the expected values of plasma arginine vasopressin in a normal subject, and the broken hdriz&ttal line indicates that the values should approach zero at serum os&olalities of less than 270 mOsm/kg [ 21.

pressin and osmolality. Removal of the tumor resulted in normalization of the arginine vasopressin levels. The tumor cdntained radioimmunoassayable arginine vasopressin in a concentration of 196 fmol/nig of dry tissue, comparable to the levels found in other arginine vasopressin-secreting tumor tissues (Table I). COMMENTS

urn concentration, serum osmolality, urihe osmolality, and plasma arginine vasopressin level over the seven-month period July i983 to January 1984. In the upper panel, the therapeutic interventions are indicated in terms of water intake per day and the timing of surgery and radiotherapy. In the preoperative period, with fluid restriction to 800 ml per day, the admission serum sodium concentration and osmolality were partially corrected from 115 mmol/liter and 233 mOsm/kg to about 127 mmol/liter and 255 mOsm/kg, respectively. The urine osmolaiity varied only slightly between 726 and 879 mOsm/kg. The plasma arginine vasopressin level was 6.4 to 13.1 pmol/iiter (7.0 to 14.3 pg/ml), although the expected arginine vasopressin levels for the prevailing serum osmolality should have been less than 0.9 pmol/liter (1 pg/ml). In the postoperative period, with continued water restriction to 800 ml per day, the serum sodium concentration rose to between 131 and 138 mmol/liter. Serum osmolality

TABLE I

Arginine V&opressin Tumor Tissues

Reference [12-15,231

“&Y This report

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Arginine Vasopressin Concentration (fmqllmg dry weight)

Concentrations

Pancreatic Olfactory

196

1986

in

Tissuesource Bronchogenic

36-3542 55,874,OOO 7,215-26,545

Olfactory neuroblastoma is a rare tumor affecting predominantly young adults. Five-year survival figures vary from 50 to 85 percent; however, late recurrence is common, and complete cure usually depends on early recognition followed by surgery and/or radiotherapy [8-IO]. Schwartz et al [l] demonstrated the presence of inappropriate antidiuresis in patients with carcinoma of the lung and suggested that it was due to the inappropriate secretion of antidiuretic hormone. Originally, a non-ectopic mechanism for this secretion was proposed, but later evidence for ectopic production of the hormone by malignant tumors was found [ 111, and it has since been described in a variety of tumors [2,7,12- 161 including multiple hormone-producing tumors [7,15]. Nonmalignant tissue has also been shown to contain arginine vasopressin [ 171. The syndrome of inappiopriate antidiuiesis associated with drugs and central nervous system disorders is thought to be due to an action on the hypothalamic neurohypophyseal system. Neuroblastomas are known to produce catecholamines and other compounds [ 181. Within the last IO years, olfactory neuroblastomas also have been shown to possess this property [ 191. Several investigators have found neurosecretory granules in olfactory neuroblastoma [20-221. Recently, the syndrome of inappropriate antidi-

carcinoma

carcinoma neuroblastoma I,

uresis has been associated

with olfactory

neuroblastoma

in two cases, each producing partial evidence for the

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TABLE II

Reference ;;:l’ This study

Clinical

Features

in Patients

Age/Sex

SerumSodium (mmol/liter)

17/F

110

33/F 26/F

108 115

with Olfactory

NeuroblaStoma

OF ARGININE

and Syndrome

VASOPRESSIN-CULLEN

df Inappropriate

Antidiuresis

TumorArginine Vasopressin ImmunoRadioimmuno- histochemical BloodPressure Plasma Arginine Vasopressin assay Analysis (mmW 140/95 Normal

Not assayed Not assayed

190/120

Inappropriate

ectopic production of arginine vasopressin by the tumor [23,24]. In one case, postmortem analysis of the tumor tissue revealed arginine vasopressin. In the second case, the syndrome of inappropriate antidiuresis was abolished by removal of the olfactory neuroblastoma, but arginine vasopressin levels were not measured in plasma or tumor. Our case provides additional evidence for the production of arginine vasopressin by an olfactory neuroblastoma. The syndrome of inappropriate antidiuresis was abolished and the increased plasma arginine vasopressin levels present before surgery returned to normal on removal of the tumor. The tumor was shown to contain arginine vasopressin by radioimmunoassay and immunohistochemical analysis. Ultrastructural study revealed neurosecretory granules consistent with arginine vasopressin granules. Although ectopic in location, unlike the well-recognized secretory carcinomas, the arginine vasopressin secretion in neuroblastomas originates in a neural tissue that morphologically mimics the normal mechanism of the neurohypophysis. It is likely that this arginine vasopressin secretion by the tumor is autonomous and so results in the syndrome of inappropriate antidiuresis. The relation between arginine vasopressin and hypertension is complex [3-51. Some investigators have reported elevated arginine vasopressin levels in the plasma of patients with mild hypertension, whereas others have reported such elevation in the plasma and the urine only in patients with severe hypertension [4]. Large doses of arginine vasopressin are required to elevate systemic blood pressure in humans. There is evidence that, with altered consciousness, baroreceptor mechanisms may be altered, so that in anesthesized subjects, for example, smaller doses of arginine vasopressin are sufficient to

Present Not assayed Present

Not done Not done Positive

ET AL

Excision Response Not excised Resolution

Resolution

raise blood pressure in a sustained way [25]. Nonetheless, patients with the syndrome of inappropriate antidiuresis generally have normal blood pressure [3]. Despite this, two of three patients with olfactory neuroblastoma and the syndrome of inappropriate antidiuresis have had hypertension, and in our patient, the hypertension was episodic and returned to normal after removal of the tumor. The finding of arginine vasopressin with other hormones in tumors has been noted [7,15]. It is possible that an unidentified hormonal substance may have been present in the tumor and caused the hypertension. Catecholamines were not found in this instance. Early recognition of this combination of findings-both clinical and biochemical (Table II)-and combined surgical and irradiation treatment with follow-up monitoring for residual or recurrent tumor may allow a better outcome for a curable neoplasm that has frequently proved fatal when recognition is delayed. As with other tumors that secrete hormones, there is a role for the measurement of plasma arginine vasopressin in the early diagnosis and follow-up of this condition. This constellation of features of the syndrome of inappropriate antidiuresis with profound hyponatremia in an otherwise healthy young wornan, together with nasal symptoms due to an arginine vasopressin-secreting olfactory neuroblastoma, seems to represent a distinct clinically recognizable syndrome. ACKNOWLEDGMENT

We are indebted to Mr. Walter Doyle-Kelly, ear, nose, and throat surgeon, for his assistance in the management of this patient and to Miss Mary Brightling for preparation of the manuscript.

REFERENCES 1.

2.

Schwartz WB, Bennett W, Curelop S, Bartter FC: A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957; 23: 529-542. Zerbe R, Stropes L, Robertson G: Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med 1980; 31: 315-327.

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Johnston Cl, Newman M, Woods R: Role of vasopressin in cardiovascular homeostasis and hypertension. Clin Sci 1981; 61: 129s-139s. Thibonnier M, Aldigier JC, Soto ME, et al: Abnormalities and drug-induced alterations of vasopressin in human hypertension. Clin Sci 1981; 61: 149s-152s. Padfield PL, Morton JJ, Brown JJ, Lever AF, Robertson JIS:

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Vasopressin in hypertenslon. In: Sleight P, Freis ED, eds. Cardiology, vol 1 (Hypertension). London: Butterworths _ International Medical Reviews, 1982; 183-198. Skowsky WR, Rosenbloom AA, Fisher DA: Radioimmunoassay measurement of arginine vasopressin in serum: development and application. J Clin Endocrinol Metab 1974; 38: 278-287. Coscia M, Brown RD, Miller M, et al: &topic production of sntidiuretic hormone, adrenocorticotrophic hormone and beta-melanocyte stimulating hormone by an oat cell carcinoma of the lung. Am J Med 1977; 62: 303-307. Bailey BJ, Barton S: Olfactory neuroblastoma. Arch Otolaryngol 1975; 101: 1-5. Kadish S, Goodman M, Wang CC: Olfactory neuroblastoma, a clinical analysis of 17 cases. Cancer 1976; 37: 1571-1576. Shah JP, Feghali J: Esthesioneuroblastoma. Am J Surg 1981; 142: 456-458. Amatruda TT, Mulrow PJ, Gallagher JC, Sawyer WH: Carcinoma of the lung with inappropriate antidiuresis. N Engl J Med 1963; 269: 544-549. Utiger RD: Inappropriate antidiuresis and carcinoma of the lung: detection of aiginine vasopiessin in tumor extracts by immunoassay. d Clin Endoorinol Metab 1966; 26: 970-974. Vorherr H, Massry SG, Utiger RD, Kleeman CR: Antidiuretic principle in malignant tumor extracts from patients with inappropriate ADH syndrome. J clin Endocrinol Metab 1968; 28: 162-168. George JM, Capen CC, Phillips AS: Biosynthesis of vasopressin in vitro and ultrastructure of a bronctiogenic carcinoma. J Clin Invest 1972; 51: 141-148.

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Hirata Y, Matsukura S, lmura H, et al: Two cases of multiple hormone-producing small cell carcinoma of the lung. Cancer 1976; 38: 2574-2582. Marks LJ, Berde B, Klein LA, et al: Inappropriate vasopressin secretion and oarcinoma of the pancreas. Am J Med 1968; 45: 967-974. Vorherr H, Massry SG, Sallet R, Kaplan L, Kleeman CR: Antidiuretic principle in tuberculous lung tissue of a patient with pulmonary tuberculosis and hyponatremia. Ann Intern Med 1970; 72: 383-387. UCLA Conference: Neuroblastoma: clinical perspectives, monoclonal antibodies, and retinoic acid. Ann Intern Med 1982; 97: 873-884. Micheau C, Guerinot F, Bohuon C, Brugere J: Dopaminebeta-hydroxylase and catecholamines in an olfactory esthesioneuroma. Cancer 1975; 35: 1309-1312. Kahn LB: Esthesioneuroblastoma: a light and electron microscopic study. Hum Pathol 1974; 5: 36-71/ Mackay B, Luna MA, Butler JJ: Adult neuroblastoma: electron microscopic observations in nine cases. Cancer 1976; 37: 1334-1351. Taxy JB, Hidvegi DF: Olfactory neuroblastoma: an uttrastructural study. Cancer 1977; 39: 131-138. Singh W, Ramage C, Best P, Angus B: Nasal neuroblastoma secreting vasopressin. Cancer 1980; 48: 961-966. Srigley JR, Dayal VS, Gregor RT, Love R, van Nostrand AWP: Hyponatremia secondary to olfactory neuroblastoma. Arch Otolaryngol 1983; 109: 559-562. Hays RM: Agents affecting the renal conservation of water. In: Gilman AG, et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutids, 6th ed. New York: Macmillan, 1980; 922.