Malignant Prolactinoma Discovered by D2 Receptor Imaging
P. Petrossians,
W. De Herder,
D. Kwekkeboom,
G. Lamberigts,
A. Stevenaert and
A. Beckers
Departments of Endocrinology (P.P., A.B.) and Neurosurgery (A.S.),
University Hospital, B-4000 Liege, Belgium; Departments of Internal
Medicine (W.D.H.) and Nuclear Medicine (D.K.), University Hospital,
3015 Rotterdam, The Netherlands; and Department of
Endocrinology, AZ St. Jan (G.L.), B-8000 Brugge, Belgium
Address all correspondence and requests for reprints to: Prof. Albert Beckers, Service dEndocrinologie, CHU de Liege, Domaine universitaire du Sart Tilman, B-4000, Liege, Belgium.
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Introduction
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Malignant prolactinomas are extremely rare (1, 2).
The diagnosis of these carcinomas is mainly based on the patients
medical history and the detection of metastases. Nuclear medicine
offers new imaging modalities for the detection of metastases of
pituitary carcinomas. These techniques may have serious consequences
for subsequent investigations and therapy. The case presented here
shows the clinical behavior of a malignant prolactinoma. The usefulness
of dopamine D2 receptor scintigraphy for establishing the diagnosis and
subsequently directing the therapeutic approach is illustrated.
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Case Report
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A 43-yr-old man presented with a macroprolactinoma in 1984. He was
operated on by a transfrontal approach in 1984 and by two
transsphenoidal approaches in 1985. Postoperatively, serum PRL levels
did not normalize. The patient showed partial resistance to dopamine
agonists; serum PRL levels decreased from 212 µg/L (normal, <20
µg/L) at baseline to 57 µg/L with bromocriptine
therapy. From 19841991, a progressive rise in serum PRL levels was
noted despite treatment with high doses of bromocriptine
(55 mg/day) and thereafter quinagolide (0.8 mg/day). When he was
referred to us in 1991, his serum PRL level was 757 µg/L on
quinagolide and 1575 µg/L without treatment. Pituitary magnetic
resonance imaging (MRI) showed a pituitary macroadenoma with bilateral
extrasellar extension to the cavernous sinuses. Surgery was repeated
using a transcranial approach. However, postoperative serum PRL values
remained elevated (2181 µg/L). External pituitary irradiation was
administered (total dose, 5000 rads), and treatment with
cabergoline was started. From 19911993, a progressive
decrease in PRL levels was observed (to 84 µg/L) while the patient
was still being treated with cabergoline (2.0 mg every 2
days). After this period of relative efficacy of this drug, a
progressive rise in serum PRL levels was observed again. The patient
was then treated four times with
-knife radiosurgery (in 1994, 1995,
1996, and 1997). The last
-knife treatments were less effective than
the first ones (Fig. 1
). The patient
underwent two additional pituitary explorations in 1997 and 1998 via
the transcranial route in another center, which did not reveal further
tumorous tissue. He was then referred back to us. At the last hospital
admission (July 1998), 2 months after the last operation and
discontinuation of cabergoline treatment, serum PRL levels
were much higher than previously observed (7163 µg/L). Nevertheless,
MRI study did not reveal important tumor residue. Because the clinical
evolution of the patient strongly suggested a malignant prolactinoma,
nuclear imaging studies were performed.

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Figure 1. Evolution of PRL levels. Quinagolide doses
do not appear in the graph due to the scale used to represent the
entire biological history. RxTh, Radiotherapy.
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Imaging studies
Dopamine D2 receptor scintigraphy. Epidepride scintigraphy was
performed as recently described (2). Potassium iodide (100 mg daily)
was administered for 5 days, starting 24 h before
radiopharmaceutical injection. [123I]Epidepride
was obtained from Dr. Angelberger, Osterreichisches Forschungszentrum
Seibersdorf GmbH (Seibersdorf, Austria), and was distributed by IDB
Holland BV (Baarle-Nassau, The Netherlands).
[123I]Epidepride (185 megabecquerels) was
administered iv, and images were obtained after 3 h. Single photon
emission computed tomography images of the head were obtained
using a three-headed camera (Picker 3000 xp, Picker International,
Cleveland, OH) equipped with a medium energy collimator. The pulse
height analyzer was centered over the energy peak (159 keV); the window
width was 20%. Acquisition parameters were one scan, 36 s/frame, 120
projections, 360° rotation, 64 x 64 matrix. Images were
reconstructed using a Metz filter. Whole body images (from head to
upper legs) were obtained using a two-headed camera (Prism 2000, Picker
International). Acquisition time was 40 min. There was no uptake of
[123I]epidepride in the pituitary region. Faint
uptake that could correspond to a tumor remnant was noticed close to
the basal ganglia (Fig. 2
). At whole body
imaging, normal uptake was seen in the urinary bladder, liver, gall
bladder, intestines, and lung. However, pathological uptake was seen
caudal in the left thorax (possibly a rib), at multiple sites in the
lower thoracic and lumbar spine, and in the mediastinum and right femur
(Fig. 3
).

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Figure 2. Coronal slices from the sellar region during
epidepride scintigraphy. Slices run from dorsal to ventral. Intense
uptake in the basal ganglia and slightly increased uptake below the
left basal ganglion are shown.
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Figure 3. Total body scintigraphy 3 h after the
injection of [123I]epidepride. Normal accumulation of
radioactivity in the basal ganglia, thyroid, lungs, liver, bowel, and
urinary bladder in a control patient (left images are
anterior and posterior views, respectively). Pathological uptake
projecting over the left anterior thorax, possibly in a rib (third
image from left), and in multiple sites in the spine and right femur
(rightmost image) in the study patient.
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MRI. Total spine MRI was performed using T2 before gadolinium
injection and T1 weighted images before and after gadolinium injection.
Multiple lesions suggestive of metastases were seen along the thoracic
(T1, T3, T5, T6, T7, T8, T10, and T12) and lumbar vertebrae (L1, L2,
L4, and L5; Fig. 4
).

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Figure 4. Sagittal T1 spin echo sequences with
gadolinium showing hyperintensities involving the body of T5 and T6,
the left pedicle of T10, the T12 processus spinosus, and the body of L2
corresponding to metastases. A, Median slices (left); B,
left lateral slices (right).
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Clinical follow-up
Considering the nature and the extent of the metastatic lesions,
further palliative treatment was decided. Cabergoline was
restarted despite its ineffectiveness in normalizing serum PRL levels.
However, a significant decrease in serum PRL levels was observed again,
and we hoped that this treatment might also slow down tumor
progression. Local external radiotherapy was applied to the back to
prevent pain and peripheral nerve palsy.
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Discussion
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Pituitary carcinoma is one of the traps presenting to
endocrinologists. These tumors are very rare, and a review of the
literature only reveals 96 cases (for 2 recent reviews, see Refs. 1, 2), which included 28 malignant prolactinomas (1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), 25
ACTH-producing carcinomas, 12 GH-producing carcinomas, 1 TSH-producing
carcinoma, and 30 gonadotropin-producing or clinically nonfunctioning
carcinomas (2). At the University Hospital of Liege, this was the first
pituitary carcinoma among 1200 pituitary tumors.
The distinction between carcinomas and invasive adenomas is difficult.
Malignant prolactinomas do not present with distinct clinical signs
that distinguish them from benign tumors. Initially, the radiological
appearance may mimic that of an adenoma. Histological examination, even
using tumor markers, does not allow easy differentiation between
adenomas and well differentiated carcinomas. The diagnosis is usually
suspected because of multiple recurrences and progressive inefficacy of
treatment. However, these features can also occur in drug-resistant and
aggressive adenomas. Therefore, the final diagnosis is often made after
metastases have been discovered.
In the present case, the early clinical features were compatible with a
recurrent adenoma.
Knife radiotherapy was very efficient at first.
The loss of efficacy of radiotherapy and radiosurgery in the later
stages of the disease was attributed to either resistance or increasing
aggressiveness of the tumor. However, retrospectively, this probably
was the first manifestation of extracranial metastases that were not
yet suspected and, therefore, not treated at that time. This hypothesis
is supported by the fact that at the last two operations no tumor
remnants were found in the sellar region. The persistence of increased
serum PRL levels despite dopamine agonist therapy, the lack of efficacy
of additional radiotherapy, and the finding of an empty sella at
surgery led to the search for metastases.
Malignant prolactinomas usually metastasize to the central
nervous system and arachnoidal tissues. Distant metastases are rare.
However, they have been reported in the skeleton in two cases (1, 3),
in lymph nodes in four cases (1, 12, 18), in the lung in two
cases (11, 13), and in the liver or ovaries in three cases (1, 11, 16).
Some researchers suggest that metastases may have been grafted by
surgery because they have been found on the surgical route in some
cases (16).
Scintigraphy can sometimes be very useful for demonstrating
metastases and, therefore, for the confirmation of the malignant
character of a tumor. Somatostatin receptor imaging has been reported
to be useful for the detection of metastatic deposits in a GH-secreting
carcinoma (21). The use of this technique in a case of a malignant
prolactinoma may be worthwhile, because PRL-secreting cells may have
somatostatin receptors. However, these cells usually possess
somatostatin receptor subtype 5 (sst5) (22),
whereas [111In]pentetreotide
binds with high affinity to somatostatin receptor subtype 2
(sst2) and with only moderate to low affinity to
sst5. Therefore, [123I]epidepride,
a radioisotope with high affinity for D2 receptors, was used (23).
[123I]Epidepride scintigraphy finally revealed
areas of pathological uptake corresponding to extracranial metastases.
This is the first case in the literature in which D2 receptor imaging
demonstrated extracranial metastases of a pituitary carcinoma. This
technique may prove useful in future difficult cases, especially when
dopamine D2 receptors instead of high affinity somatostatin receptors
are likely to be present in the tumor, such as prolactinomas or their
malignant counterparts.
Pathological examination of malignant prolactinomas reveals only
a slight degree of cytological atypia. Mitotic activity is higher, and
the tumor cells are usually aneuploid. Labeling indexes for
proliferation markers MIB-1 and proliferating cell nuclear
antigen are higher in primary and metastatic tumors than in
adenomatous cells. There is also a greater expression of p53 protein in
these cells (1). Little is known about the tumorigenesis of
pituitary carcinomas. Loss of retinoblastoma susceptibility gene
has been demonstrated in an ACTH-secreting pituitary carcinoma
(24). In another study, no mutations were detected in the p53 tumor
suppressor gene or in N- or K-ras G-protooncogenes, but
point mutations were identified in the H-ras gene (25).
The midterm evolution of patients presenting with PRL-secreting
carcinomas is pejorative. Only 50% of the cases described in the
literature showed a survival of more than 1 yr. Surgery may be useful
in debulking the lesion and relieving the local compression effect.
However, it cannot be repeated indefinitely despite the recurrence of
the tumor. Dopamine agonists are widely used in the treatment of
prolactinomas. In the case of malignant tumors, they may slightly
reduce the tumor size, but without changing the final outcome. Some
researchers have used cytotoxic chemotherapy with a transient
improvement in the illness. The treatment consisted of different
combinations of procarbazine, vincristine, etoposide, cisplatine, and
lomustine. The use of tamoxifen alone has been successful in one case
(16). Radiotherapy remains one of the more efficient treatments.
Despite the lack of a definite cure, it can be helpful either in partly
relieving the local complications of the tumor or as a palliative
treatment for pain.
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Note Added in Proof
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The patient presented in this case died in September 1999. The
last PRL level measured before his death was 45,500 µg/L.
Received June 21, 1999.
Revised August 12, 1999.
Accepted August 24, 1999.
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