Toshiyuki Kokatsu Mamoru Tsukuda
Department of Otorhinolaryngology, Yokohama City University, School of Medicine, Yokohama, Japan
Hypopituitarism and Hyponatremia in a Case with Nasopharyngeal Carcinoma
Key Words
Nasopharyngeal carcinoma Hypopituitarism Hyponatremia Syndrome of inappropriate secretion of antidiuretic hormone
Abstract
We report a case of nasopharyngeal carcinoma (NPC) accompanied by hypo- natremia and polyuria which was induced by tumor invasion into the pituitary gland. Magnetic resonance imaging showed the pituitary gland pushed upward by NPC. Hypopituitarism due to an intracranial tumor and the extracellular volume excess due to chemotherapy caused hyponatremia and polyuria. As the intracranial tumor was diminished by chemotherapy and irradiation, pitu- itary hormones were normalized. In patients with T4 NPC, pituitary-adreno- cortical function should be endocrinologically evaluated before treatment.
It has been reported that the use of antitumor drugs can induce the manifestation of the syndrome of inappro- priate secretion of antidiuretic hormone (SIADH) and also hyponatremia [1-3]. We encountered a patient with nasopharyngeal carcinoma (NPC) complicated by pitu- itary dysfunction due to intracranial invasion by the tumor. We treated this patient with a cisplatin (CDDP)- based multidrug chemotherapy regimen which aug- mented the manifestation of pituitary dysfunction.
Report of a Case
A 57-year-old man began to notice double vision in March 1991; in September he complained of hardness of hearing in the left car, a headache developed and subsequently the patient was referred to our institute. A nasopharyngeal tumor was biopsied and diagnosed pathologically as an undifferentiated squamous cell carcinoma. The patient was hospitalized on November 19. In the nasopharynx. a tumor having a coarse, granular surface was scen to occupy the space from the opening of the left eustachian tube to the midline of the tectorium. Magnetic resonance imaging (MRI) using gadolinium showed an invasion of the NPC into the skull (fig. 1b), with extensive infiltration from the pontine cistern to the suprasellar cistern. The
pituitary gland appeared to be pushed from the anteroinferior direc- tion (fig. la). This patient’s stage was diagnosed as T4N2bMO (UICC, 1987) with roentgenography, ultrasonography and scintigra- phy.
Physical examination and hematological findings were normal except for mild anemia. The serum electrolytes were all normal. The urinalysis results showed a urine volume of 1,000-1,200 ml/day, spe- cific gravity of 1.015 (1.003-1.030: reference values at our institute). a urine creatinine value of 0.15 mm . kg-1/day (0.13-0.22 mmol. kg-1/day) and a serum creatinine clearance value of 0.87 ml/s/m2 (0.87-1.34 ml/s/m2).
Course of Treatment
At our institute, randomized studies on the efficacy of two courses of different types of chemotherapy, including CDDP and 5- fluorouracil (5-FU), were performed on previously untreated cases with advanced squamous cell carcinomas of the head and neck. One type was CDDP followed by 120-hour continuous 5-FU infusion giv- en in the conventional way and the other was CDDP administration 72 h after the initiation of continuous 5-FU infusion (modified). In this study, modified CDDP plus 5-FU combination chemotherapy was a more efficacious regimen than the conventional one to achieve high complete response rate [4]. Based on these results, head and neck carcinoma patients have been treated by this modified regimen at our department. Beginning on November 22, 5-FU was adminis- tered in a dosage of 1,000 mg/m2/day in 2,500 ml supplementary
a
b
Prednisolone 5 mg/day
CDDP
Į CBDCA WWW.Į 5-FU
CBDCA
WWWWĮ 5-FU
WWW.Į 5-FU
600
☒ Urine volume
☐ Serum Na value
(ml/day)
400
☐ Plasma osmolality
200
☐ Supplementary fluid volume
0
☒ Water intake volume
11/20
20
30
12/5
10
15
20
25
(date)
1/5
10
15
20
160
☒ · Urinary Na value
140
Urinary osmolality
(mmol/l)
120
100
80
60
0
(date)
350
(mosm/kg)
300
250
200
0
(date)
Cortisol
(nmol/l)
100
ACTH
30
1
(ng/l)
20
10
0
TSH·
(mU/I)
5
0
FSH
(IU/I)
5
0
LH
(IU/I)
5
0
(ng/l)
1
1
ADH
11/25
12/2
12/5
12/26
1/8
1/22
(Date)
3
4
infusion fluid by continuous intravenous drip infusion for 5 consecu- tive days. On the 3rd day from the start of chemotherapy. the patient showed urinary incontinence and manifested abnormal behavior.
The serum electrolytes were determined as follows: Na 116 mmol/l (139-146 mmol/l), K 4.6 mmol/l (3.7-4.9 mmol/l), CI 74 mmol/l (104-112 mmol/l), and Ca 2.1 mmol/l (2.1-2.5 mmol/l). indicating severe hyponatremia. In addition, the serum osmolality was found to be low, 248 mmol/kg (285-295 mmol/kg), while the urine osmolality. 318 mmol/kg, and the urinary sodium valuc. 85 mmol/l, were both high.
To correct the serum sodium level, intravenous administration of physiological saline as fluid supplementation was performed and NaCl was orally administered daily (fig. 2). Since we thought the elec- trolyte disorder was caused by the pressure of the advanced tumor on the pituitary gland, chemotherapy was continued. The patient was administered 5-FU on the 4th and 5th days, and CDDP (60 mg/m2) on the 4th day, loading with 4.500 ml of supplementary infusion fluid under clinically strict control. However, on the 11th day the laboratory tests showed that the serum value of sodium had de- creased again to 110 mmol/l. In order to make a diagnosis of SIADH the hormones of the pituitary gland were measured: serum cortisol level at 8 a.m. was 28 nmol/l (112-500 nmol/l), scrum ACTH at 8 a.m. below 10 ng/l (30-60 ng/l). TSH 1.1 mU/l (0.6-5.1 mU/l), FSH 1.2 IU/1 (1.8-13.6 IU/1), LH 0.5 IU/1 (1.1-8.8 IU/l), and GH 0.9 ug/1 (below 5 µg/l). Plasma aldosterone level (supine) was found to be 0.00 nmol/l (0.08-0.28 nmol/l). i.c., secondary adrenocortical hypofunc- tion was diagnosed. However, the serum level of antidiuretic hor- mone (ADH) was normal at 1.3 ng/l (1-3 ng/l).
Laboratory examinations of December 5 showed a plasma aldo- sterone level of 0.07 nmol/l (supine) and low values for anterior pitu- itary hormones (fig. 3). Because the patient was considered to be at risk of shock caused by acute adrenal failure, 5 mg/day of predniso- lone was orally administered.
The second chemotherapy was continued, since the decrease of pressure exerted by the tumor on the pituitary gland was thought to be necessary. We changed the combined CDDP chemotherapy regi- men to 5-FU and carboplatin (CBDCA) at 300 mg/m2/day, which would not require supplementary fluid loading.
On January 22 pituitary and adrenocortical hormones had recov- cred to normal levels (fig. 2), while the scrum level of ADH showed a normal range. After the patient was treated with radiation therapy (70 Gy), the urine volume decreased to 2,000-3,000 ml/day, and MRI using gadolinium showed complete disappearance of the tumor that had been pressing upward on the pituitary gland (fig. 4). Clini- cally, the tumor showed a complete response. This patient is alive in July, 1993 with normal pituitary-adrenocortical function and there is no evidence of tumor recurrence.
Discussion
We speculated about the mechanism behind the devel- opment of hyponatremia manifested by this patient (fig. 5). It is surmised that prior to the administration of chemotherapy, the nasopharyngeal tumor pressed on the
Pituitary gland
Tumor
Pressure on pituitary gland by nasopharyngeal carcinoma
Large volume of i.v. supplementary fluid due to chemotherapy
Hyposecretion of pituitary anterior lobe hormones
Hyposecretion of ACTH
Hyposecretion of cortisol
Decreased reabsorption of Na by renal tubules
Increase in extracellular fluid
☒ Polyuria
Hyponatremia
pituitary gland, thereby causing a dysfunction of the pitu- itary anterior lobe and leading to a state of chronic sec- ondary adrenal hypofunction. The cortisol secretion was decreased, accordingly the reabsorption of sodium by the renal tubules was reduced and a state of renal sodium loss was established. In addition, it is suspected that the intra- venous infusion of a large volume of supplementary fluid in association with the combined CDDP chemotherapy caused an increase in extracellular fluid. This resulted in a complication of a low serum sodium concentration and aggravated hyponatremia.
After the administration of CDDP with a large volume of fluid the laboratory tests showed a low value of serum sodium for the serum osmolality regardless of normal plasma ADH level, while the urine osmolality was high considering the amount of fluid intake. It is thought that these values were caused by the decreased reabsorption of sodium by the renal tubules, which was a result of the decreased secretion of cortisol and aldosterone.
In normal health, an increase in extracellular fluid vol- ume would trigger activation of the renin-angiotensin sys- tem, resulting in the promotion of aldosterone secretion and subsequent maintenance of the level of serum sodi- um. In contrast, in this case, the plasma aldosterone level on December 9 was slightly lower than the normal value. In the normal state, a decrease in the serum osmolality would suppress the secretion of ADH. In the present patient, as well, the decrease in the serum osmolality was
accompanied by a slight decrease in the serum ADH level. Therefore, it is surmised that the secretion of pituitary posterior lobe hormones remained normal in this pa- tient.
The most common cause of pituitary hypofunction is pituitary adenomas, followed by Sheehan’s syndrome, craniopharyngiomas and pinealomas. There have been a few cases with pituitary hypofunction accompanying NPC, but all of them had manifested during or after radiation therapy [5-8]. Kavanagh et al. [9] reported a case with NPC which produced ADH and they surmised that SIADH was caused by heterotopic secretion of vaso- pressin by the tumor.
The possible side effect of CDDP-containing chemo- therapy might cause this hormonal dysfunction. We have administered CDDP plus 5-FU chemotherapy to patients with advanced head and neck carcinoma, since this che- motherapy regime has shown a high response rate and a high complete response rate [10]. Kurtzberg et al. [11] reported that the administration of CDDP resulted in an impaired reabsorption of electrolytes from Henle’s loop in the kidney. It is suspected that the administration of CDDP might have upset the balance between water and serum electrolytes, consequently causing the enhance- ment of the already existing conditions of hyponatremia and polyuria.
There is no report of SIADH induced by the adminis- tration of 5-FU. Ritch [12] reported a case of a lung cancer patient with persistent SIADH caused by CDDP adminis- tration. Littlewood and Smith [13] and Porter [14] have reported that the period from the administration of CDDP to the manifestation of SIADH is as short as 1 day. Abe et al. [15] reported a case of a patient with NPC in which pituitary hypofunction manifested during the course of radiation therapy. They reported that computed tomography is efficacious for diagnosing bone destruction at the base of the skull due to the tumor and they also stated that MRI is superior for evaluating the stereoscopic site of occupation of the tumor in the skull and for judging the compression of the pituitary gland.
On the basis of the treatment of this case, we conclude that, when performing chemotherapy and radiation thera- py for patients with NPC, MRI should be employed to make an overall assessment of the direction of advance of the tumor and the relationship of the pituitary gland. Fur- thermore, in patients with invasion to the pituitary gland, the serum levels of pituitary-adrenal hormones should be evaluated before therapy.
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Announcements
| 30th Postgraduate Course in Ear Surgery | Sixth International Symposium on Recent Advances in Otitis Media |
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