Annals of Oncology 11: 891-895, 2000.
© 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical case
Diabetes insipidus in metastatic cancer: Two case reports with
review of the literature
D. ten Bokkel Huinink,1 G. A. M.Veltman,2 T. W. J. Huizinga,3 F. Roelfsema4 & H. J. Keizer1
Departments of ^Clinical Oncology, Rheumatology, 4Endocrinology', Leiden University Medical Center, Leiden; 2Department of Internal
Medicine, Hospital De Baronie, Breda, The Netherlands
Key words: cancer, diabetes insipidus, metastases, pituitary gland
tration was elevated with 1.03 umol/1 and remained at a
level of 1.13 umol/1 after stimulation. The serum growth
Tumour metastases may cause a number of endocrine hormone concentration rose from 4.6 to 55 mU/1 after
syndromes. One of these syndromes is diabetes insipidus injection of 50 ug growth hormone-releasing hormone.
caused by metastatic infiltration of the hypothalamic- Computed tomography (CT) showed enlargement of the
pituitary region. Although these metastases are rarely pituitary gland with bulging of the diaphragma sellae.
recognised ante mortem, diabetes insipidus is a well Magnetic resonance imaging (MRI) showed a mass
recognised complication, in particular in patients with lesion in the neurohypophysis, with deviation of the
advanced cancer of the breast and lung [1-3, 24]. Yet pituitary stalk to the left, and increased contrast endiabetes insipidus is rarely mentioned as manifesta- hancement of the stalk with gadolineum. The ocular
tion of metastases in the major oncological text books fundus appeared normal. There were no visual field
defects. A 99mTc-diphosphate bone scan revealed bone
[4-6].
Here, we describe and discuss the clinical presenta- metastases in the convexity of the skull, spine, ribs,
tion, diagnosis, treatment and outcome in two patients sternum, left clavicle, left humerus and femora. Ultrawith cancer in whom diabetes insipidus developed. In sonography of the abdomen showed a lesion suspect
for a metastasis in the liver. Based upon the clinical
addition a review of the literature is presented.
Introduction
Case A
Table 1. Laboratory results patient A and B.
Laboratory results
In a 53-year-old, postmenopausal woman a carcinoma
of the breast was diagnosed (stage pTiN0M0, estrogen
receptor positive). She was treated with breast conserving
surgery and radiotherapy.
After a disease-free interval of 32 months she complained about polyuria, polydipsia and loss of weight.
She did not have a headache or visual complaints.
Physical examination was unremarkable. The results of
laboratory tests are presented in Table 1. She had a large
volume of 24-hour urine production (5 1) with a very
low urine-osmolality (147 mosm/kg) compared to that
of the plasma (292 mosm/kg). Endocrinological evaluation was performed. A thyrotropin-releasing hormone
(TRH) stimulation test with 200 ug TRH was normal,
showing serum TSH rising from 1.19 to 6.59 mU/1 and
serum prolactin rising from 15 to 29 ug/1 after 30 minutes.
During a corticotrophin-releasing hormone (CRH) test
with 100 ug CRH the serum adrenocorticotropic hormone (ACTH) concentration was 25 ng/1 and rose to 83
ng/1 after 15 minutes. The basal serum cortisol concen-
Serum
Sodium (mmol/1)
Potassium (mmol/1)
Calcium (mmol/1)
Urea (mmol/1)
Creatinine (umol/1)
Albumin (mmol/1)
Osmolality (mosm/kg)
Thyroxine (nmol/1)
TSH (mU/1)
LH (1U/1)
FSH (IU/1)
Prolactin (ug/1)
ADH (ng/1)
Urine
Volume (1/24 h)
Osmolality (mosm/kg)
Specific gravity
Patient A
Patient B
Normal value
145
4.5
2.55
5.5
95
46
292
113
0.94
28.6
46
8.8
ND
150
3.5
3.73
4.5
60
37
287-313
111
0.67
1.5
2.3
16
<0.3
136-144
3.6-4.8
2.25-2.60
3.5-5.5
2.5-7.5
70-133
285-295
70-160
<7
>20"
>20 a
<10
<0.3
5
147
1.007
7.3
136
1.007
Abbreviation: ND - not determined.
For postmenopausal women.
a
892
symptoms, laboratory results and radiological findings,
the diagnosis diabetes insipidus was made without
compromising anterior pituitary function, presumably
caused by a metastasis in the dorsal part of the pituitary
gland. She was treated with l-desamino-8-D-arginine
vasopressin (DDAVP), an oral dose of 0.1 mg twice
daily. Anti-tumour therapy with tamoxifen was started.
Two months later, MRI showed regression of the lesion
in the pituitary gland. The oral dose of DDAVP could
be decreased to 0.05-0.075 mg daily. Tamoxifen was
stopped after 7 months, because of progression of bone
metastases. New metastases were found in the lungs.
Chemotherapy was given, first CMF (cyclophosphamide, methotrexate and 5-fluorouracil (5-FU)). At subsequent progressive disease second-line chemotherapy
(doxorubicin) was started later. Serum prolactin levels
rose further to 30 ug/1 and serum luteinising hormone
(LH) and follicle-stimulating hormone (FSH) levels
dropped to less than 0.1 IU/1 probably due to progressive
disease. A third MRI showed less enhancement and less
thickening of the stalk. Serum prolactin levels dropped
to 15 ug/1 and serum LH and FSH levels rose to 5.4 and
21 IU/1 a year after chemotherapy was started, which
corresponds with the response seen at the third MRI.
Nineteen months after the diagnosis diabetes insipidus
she died of metastatic disease. Autopsy was not permitted.
CaseB
In a 46-year-old woman bilateral breast cancer was
diagnosed (stage pT3NiM0 left; pTiN0M0 right, estrogen receptor positive). She was treated with bilateral
modified radical mastectomy and loco-regional radiotherapy on the left side. Two years later a local recurrence on the left side was treated with local excision
followed by radiotherapy.
At the age of 60 years metastases were found in ribs
and pleura. Hormonal treatment with tamoxifen was
started. The pleural effusion was positive for malignant
cells and was treated with drainage and pleurodesis. Two
years later she had a total hysterectomy with bilateral
salpingo-oophorectomy as treatment for an endometrium
carcinoma. Tamoxifen was discontinued on request of
the patient. A year later she complained about polyuria,
polydypsia and loss of weight. Other problems were
constipation, loss of appetite and drowsiness. She did not
have a headache or visual disturbances. Physical examination showed signs of dehydration. Laboratory results
showed hypercalcemia (3.73 mmol/1). Further laboratory results are shown in Table 1. A 99mTc-diphosphate
bone scan revealed metastases in the spine, ribs and
femurs. Ultrasonography of the abdomen showed lesions
in the liver suspect for metastases. A X-ray of the chest
showed pleural effusion, a broad mediastinum, pleural
metastases and signs of lymphangitis carcinomatosa.
The diagnoses metastatic cancer of the breast with
hypercalcemia was made. She was treated with isotonic
saline and pamidronate intravenously. After correction
of hypercalcemia, polyuria and polydipsia persisted. A
water deprivation test was done. Despite the retrieval of
water the diuresis persisted with a urine osmolality of
136 mosm/kg and a rapid fall in body weight. A TRH
stimulation test showed an almost normal response:
serum TSH rose from 0.76 to 4.52 mU/1 after 15 minutes
and serum prolactin rose from 15 to 25 ug/1 after 15
minutes. With 100 ug luteinizing hormone-releasing
hormone (LHRH) serum LH level rose from 2.3 to 7.7
IU/1 after 20 minutes and to 13.2 IU/1 after 60 minutes.
Serum FSH level rose from 2.41 to 4.8 IU/1 after 60
minutes and to 5.8 IU/1 after 90 minutes. A CT- and
MRI-scan with gadolineum of the hypothalamic-pituitary region did not show any abnormalities. The ocular
fundus and visual fields were normal. The diagnosis
diabetes insipidus probably caused by micrometastases
in the hypothalamic-pituitary region was made. She was
treated with DDAVP at an oral dose of 0.1 mg twice
daily. Anti-tumour therapy with tamoxifen was started.
This resulted in an objective remission of metastases.
However, endocrine parameters did not change and the
dose of DDAVP could not be reduced. Because of progressive disease in the liver tamoxifen was stopped after
30 months. Serum LH and FSH levels rose to 8.7 and
7.6 IU/1, respectively. Other endocrine parameters did
not change. A CT- or MRI-scan of the hypothalamicpituitary region was not repeated. Second-line hormonal therapy (aminoglutethimide) was given without
success. Chemotherapy including cyclophosphamide,
methotrexate, 5-FU and later doxorubicin was administered. Both induced a tumour response, temporarily.
Forty-three months after the diagnosis of diabetes
insipidus she died of metastatic disease. Autopsy was
not permitted.
Discussion
Over a period of 10 years 8 patients were admitted to our
hospital with clinical suspicion of metastases in the
hypothalamic-pituitary region. All these patients presented with diabetes insipidus. One of them had a
metastasis of a melanoma and the other suffered of
metastatic breast cancer. Metastases in the hypothalamic-pituitary region are usually an incidental postmortem finding, most frequently found in patients with
advanced cancer, in particular of the breast and lung. In
a serie of 500 consecutive autopsies of cancer patients,
pituitary metastases were found in 18 (3.6%) patients.
Six patients had breast cancer. Only one patient had
clinical symptoms [6]. The incidence of metastases in
the hypothalamic-pituitary region in patients with breast
cancer at autopsy is higher and varies from 5.3%—28%
[8, 9]. Clinical manifestations of hypothalamic-pituitary
metastases are rare and this may be the explanation for
the lack of attention for diabetes insipidus or metastases
in the hypothalamic-pituitary region in textbooks of
oncology. It was however the presenting symptom for
893
metastatic disease in our patient A. Pituitary metastases
have been found in a variety of solid tumours, leukaemia
and lymphoma. Rarely, it is the first sign of malignancy
[1, 3, 7,10-14],
Location of metastases
The anterior pituirary gland produces GH, prolactin,
LH, FSH, TSH and ACTH. Vasopressin also mentioned
antidiuretic hormone (ADH) and oxytocin are produced
in neurons of the hypothalamus and stored in the posterior lobe of the pituitary gland.
In our two patients diabetes insipidus was the only
clinical manifestation of metastases in the hypothalamic-pituitary region. The low concentration of gonadotrophins with a moderate and delayed response LHRH
in patient B, a postmenopausal woman, was the first
sign of partial (secondary) anterior pituitary failure.
If metastases to the hypothalamic-pituitary region are
symptomatic during life, diabetes insipidus is the usual
clinical manifestation [1-4, 7-10, 14, 24]. Metastases
have a preference for the posterior part of the pituitary
gland and will present therefore with clinically diabetes
insipidus [1, 2, 7]. In a review of 178 cases of pituitary
metastases involvement of the posterior lobe only was
found in 52%, the posterior and anterior lobe in 27%
and the anterior lobe only in 21%. 159 of the 178 patients
reviewed were asyptomatic [7]. The preference of metastases for the posterior part might be explained by the
fact that this part obtains its blood supply directly from
the systemic circulation in contrast to the anterior part.
In addition, a close relationship between the posterior
part and the dura mater supports local spread of metastases from contiguous bone sites [1, 2, 7, 12]. A third
possibility is invasion of the suprasellar cistern by
leptomeningeal tumour [2, 7]. Extension from adjacent
bone metastases may also result in diabetes insipidus
due to the close relationship of the posterior lobe to the
dura covering the pituitary gland [4]. Therefore, metastases in the hypothalamic-pituitary region are likely to
be associated with advanced disease and bone metastases similar to our patients. Moreover, the incidence
of intracerebral metastases outside the hypothalamicpituitary region and meningitis carcinomatosa is high
[2, 12, 14]. Clinically, anterior pituitary failure is rare in
patients with metastases in the hypothalamic-pituitary
region and if present it is usually accompanied by diabetes
insipidus [1-3, 7,13,14]. Also other clinical manifestations
of metastases in the hypothalamic-pituitary region like
extra-ocular nerve palsies, visual disturbances due to
chiasmatic and optic nerve involvement and headache
are seldomly seen and even less frequent than diabetes
insipidus [7, 11, 14, 24].
Imaging techniques
A CT of the hypothalamic-pituitary region was normal
in our patients. MRI-scan with gadolineum contrast
suggested a lesion in the posterior part of the pituitary
gland, thickening and deviation of the stalk in patient A,
but was normal in patient B. Most series of pituitary
metastases were described prior to CT- and MRI-scan.
Plain X-ray imaging is not able to detect the majority of
metastases [3]. CT- and MRI-scan have increased the
sensitivity of detecting pituitary tumours [16-19]. MRI
is now the technique of choice for imaging the hypothalamic-pituitary region. MRI findings described in
series with a small number of patients are various and
include contrast-enhancing pituitary lesions, relatively
isodense to the brain in T r and T2-weighed images, loss
of the normal high signal from the posterior lobe of the
pituitary gland, intra- and supra-sellar lesions with only
a small bridge of tissue connecting the intra- and suprasellar portions (dumbbell lesions), supra-sellar lesions,
involvement of the infundibulum or cavernous sinus or
thickening of the pituitary stalk [14, 16-19].
Differential diagnosis
The differential diagnosis of metastases in the hypothalamic-pituitary region and pituitary adenoma may be
difficult [7, 15]. In contrast to 3.6% pituitary metastases
in 500 consecutively autopsied patients with cancer,
1.8% pituitary adenomas were found [7]. However, in
general clinical manifestations of metastases in the hypothalamic-pituitary region and pituitary adenoma
differ. Metastases present with diabetes insipidus or,
less commonly, with extra-ocular nerve palsies [7, 12,
15]. These symptoms occur in less than 2% of patients
with pituitary adenoma [20]. MRI may help to differentiate between metastases and pituitary adenoma [18,
25].
The final diagnosis can be made by histological
examination only. Autopsy was done in only one of the
eight patients identified in our hospital suffering from
diabetes insipidus due to metastatic disease. In this
patient the hypothalamic-pituitary region was normal
at macroscopic examination, but at microscopic investigation metastases were found. A normal hypothalamicpituitary region at macroscopic investigation has been
described by others too [1, 7-9, 12]. Microscopic metastases might explain the normal MRI of patient B.
Treatment
Treatment with DDAVP achieved symptomatic relief in
our patients, who also received systemic anti-tumour
therapy because of metastatic disease. Treatment of
the underlying disease depends upon the distinction
between metastases and other lesions as pituitary
adenoma and the prognosis of the patient. If diabetes
insipidus or ocular nerve dysfunction suggests metastases, radiotherapy may be the first choice of treatment
[2, 3, 7, 10, 12, 14]. Resection of metastases in the
hypothalamic-pituitary region is indicated if the diagnosis needs to be clarified especially when suprasellar
extension causes progressive deterioration of vision [14].
However, reports of surgery of pituitary metastases
894
indicate that the lesions are diffuse, invasive and therefore difficult to resect completely [26]. If the patient's
cancer has already led to systemic metastases, local
radiotherapy and systemic therapy or systemic therapy
only might be a better choice. In patient A during treatment with tamoxifen a drop in serum gonadotrophin
levels was seen. It was a larger drop than the decrease of
approximately 50% in postmenopausal patient reported
by others during treatment with tamoxifen. This may be
explained by a selective estrogenic effect of tamoxifen
[21, 23]. MRI showed regression of the tumour in the
pituitary gland and later a decrease in enhancement and
thickening of the stalk. These observations and the
relatively low dose of DDAVP needed during follow-up
can be explained by partial compression of the pituitary
stalk. However, metastases outside the hypothalamicpituitary region were progressive. Patient B responded
well to treatment with tamoxifen and subsequent chemotherapy, but she remained DDAVP dependent until
death. Serum gonadotrophin levels were too low for a
postmenopausal woman, and stayed at a low level
during treatment. Elevated serum prolactin levels did
not drop as has been described in most postmenopausal
patients responding to tamoxifen [21, 22]. This might be
explained by lesions of the hypothalamus or pituitary
stalk. Interruption of the pituitary stalk is followed by
reduction of the release of GH, LH, FSH and ACTH
from the anterior lobe. In contrast, the level of prolactin
rises after interruption of the stalk implying the inhibiting influence for prolactin secretion by the hypothalamic. So this could explain the high prolactin and the low
gonadotrophin levels in patient B.
Effects of anti-tumour therapy and prognosis
In patients reported in the literature diabetes insipidus
was usually irreversible after anti-tumour therapy only.
In a series of 19 patients with metastases in the hypothalamic-pituitary region diabetes disappeared in only
one patient after treatment with radiotherapy [3]. In a
group of 39 patients with breast cancer, resolution of
diabetes insipidus appeared in 4 patients treated with
chemotherapy or hormonal intervention [2]. In the two
patients described in detail in this paper, diabetes
insipidus during systemic therapy was mild. The patients
required a moderate amount of DDAVP to control this
disorder.
Our patients had a survival of 19 and 43 months,
respectively, from presentation with diabetes insipidus.
Little is known about survival after development of
diabetes insipidus caused by metastases. A mean survival
of 7 months, with a range of 3 days to 25 months, was
found in a group of 11 patients. Eight of them had
metastatic breast cancer [10]. In a group of 14 patients
treated with transsphenoidal surgery after a mean follow-up of 20 months, 5 patients were still alive. The 9
patients who had died of their disease did so after 1-86
months following surgery and had a mean survival of
22 months [15]. Another study reviewing 36 patients
with symptomatic pituitary report a mean survival of
6 months.
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Received 18 February 2000; accepted 24 March 2000.
Correspondence to:
D. ten Bokkel Huinink, MD
Leiden University Medical Center
P.O. Box 9600
2300 RC Leiden
The Netherlands
E-mail: [email protected]