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J Neurosurg 104:54–61, 2006
Bromocriptine treatment of invasive giant prolactinomas
involving the cavernous sinus: results of a
long-term follow up
ZHE BAO WU, M.D., CHUN JIANG YU, M.D., ZHI PENG SU, M.D., QI CHUAN ZHUGE, M.D.,
JIN SEN WU, M.D., AND WEI MING ZHENG, M.D.
Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical College, Wenzhou; and
Department of Neurosurgery, Fu Xing Hospital, Capital University of Medical Science, Beijing,
People’s Republic of China
Object. The aim of this study was to observe long-term clinical outcomes in a group of patients treated with bromocriptine for invasive giant prolactinomas involving the cavernous sinus.
Methods. Data from 20 patients with invasive giant prolactinomas at the authors’ institutions between July 1997 and
June 2004 were retrospectively reviewed. The criteria to qualify for study participation included: 1) tumor diameter
greater than 4 cm, invading the cavernous sinus to an extent corresponding to Grade III or IV in the classification
scheme of Knosp and colleagues; 2) serum prolactin (PRL) level greater than 200 ng/ml; and 3) clinical signs of hyperprolactinemia and mass effect. Among the 20 patients who met the criteria, six had undergone unsuccessful transcranial or transsphenoidal microsurgery prior to bromocriptine treatment and 14 patients received bromocriptine as the
primary treatment. Eleven of the 20 patients underwent adjuvant radiotherapy.
After a mean follow-up period of 37.3 months, the clinical symptoms in all patients improved by different degrees.
Tumor volume on magnetic resonance images was decreased by a mean of 93.3%. In 11 patients, the tumor had almost
completely disappeared; in the other nine patients, residual tumor invaded the cavernous sinus. Visual symptoms improved in 13 of the patients who had presented with visual loss. Eight patients had normal PRL levels. The postoperative PRL level was more than 200 ng/ml in seven patients. During the course of drug administration, cerebrospinal
fluid leakage occurred in one patient, who subsequently underwent transsphenoidal surgery. No case of apoplexy occurred during bromocriptine treatment.
Conclusions. Dopamine agonist medications are effective as a first-line therapy for invasive giant prolactinomas, because they can significantly shrink tumor volume and control the PRL level. Tumor mass vanishes in some
patients after bromocriptine treatment; in other patients with localized residual tumor, stereotactic radiosurgery is a viable option so that unnecessary surgery can be avoided. The application of radiotherapy does not reliably shrink tumor
volume.
KEY WORDS • giant prolactinoma • invasiveness • bromocriptine • cavernous sinus
P
ROLACTIN-SECRETING adenoma, the most common type
of hyperfunctioning pituitary adenoma, accounts for
approximately 50 to 60% of all functional pituitary
tumors.52 Significant advances in the last few decades have
contributed to the effective management of prolactinomas,
including pharmacological therapies, microsurgical and endoscopic techniques, and stereotactic radiosurgery. Giant
prolactinomas with cavernous sinus invasion, a rare subcategory of prolactinomas, occurring with characteristics
of hyperprolactinemia and invasive growth remain one of
the greatest challenges in neurosurgery. Hyperprolactinemia
commonly causes reproductive and sexual dysfunction. Because of invasive growth, giant adenomas can compress or
destroy adjacent structures, resulting in neurological dysfunction such as visual loss, cavernous sinus compression,
and so forth. The aim of treatment has two aspects: to normalize the hyperprolactinemic state and preserve residual
pituitary function, and to eliminate mass effect and prevent
Abbreviations used in this paper: CSF = cerebrospinal fluid;
MR = magnetic resonance; PRL = prolactin.
54
tumor recurrence. Improving the quality of life through the
amelioration of sexual dysfunction and reproductive difficulties is also an important factor. Treatment is a complex
issue because of the involvement of the cavernous sinus as
well as other parasellar and basal forebrain structures. Pharmacological therapy with a dopamine agonist remains the
mainstay of treatment. We report on a group of patients with
invasive giant prolactinomas involving the cavernous sinus
who had undergone long-term follow-up review after bromocriptine treatment.
Clinical Material and Methods
Patient Population and Inclusion Criteria
Giant pituitary adenomas have been previously defined
as those measuring 4 cm or larger in diameter. We adopted
the classification system of Knosp, et al.,26 and defined invasiveness as Grade III or IV according to this scheme. Criteria for inclusion in the present study consisted of the following: 1) tumor size larger than 4 cm in diameter with
invasion of the cavernous sinus corresponding to Grade III
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Bromocriptine treatment of invasive giant prolactinomas
TABLE 1
Pretreatment disease manifestations in 20 patients
with invasive giant prolactinomas
Pretreatment Symptom
visual change
headache
decreased libido
impotence
amenorrhea
galactorrhea
vertigo
intracranial hypertension
nasal obstruction & hemorrhage
facial numbness
episodic facial pain
axillary & pubic hair loss
obesity
No. of Patients (%)
14 (70)
10 (50)
9 (56)*
3 (19)*
4 (100)†
2 (50)†
2 (10)
2 (10)
1 (5)
1 (5)
1 (5)
4 (20)
2 (10)
* In male patients, the incidence of decreased libido and impotence was
nine of 16 and three of 16, respectively.
† In female patients, the incidence of amenorrhea and galactorrhea was
four of four and two of four, respectively.
or IV, in the classification system of Knosp and associates;
2) serum PRL level greater than 200 ng/ml; and 3) clinical neurological symptoms of hyperprolactinemia and mass
effect. Twenty patients with diagnosed invasive giant prolactinomas involving the cavernous sinus were treated at
our hospitals between July 1997 and June 2004. Our sample accounted for approximately 2% of the 1000 pituitary
tumors diagnosed during this same period. Long-term follow-up outcomes following bromocriptine treatment were
thoroughly analyzed. The cohort consisted of 16 male and
four female patients, whose ages ranged from 15 to 53 years
(mean age 32 years) and whose disease lasted from 1 month
to 8 years (mean course 3.5 years). A visual deficit was the
most common symptom, with an incidence of 70% (14
of 20 patients). Amenorrhea was the initial manifestation in
all four women; in nine men (56% of men in our cohort),
decreased libido was the primary symptom. Headache occurred in 10 cases. The most frequent symptoms and signs
are detailed in Table 1, and changes in visual function in
Table 2.
Neuroradiological and Endocrinological Evaluation
Multiple follow-up MR imaging studies were available
in all patients in the series. According to these images, tumor diameters ranged from 37 to 97 mm, with a mean maximal diameter of 59 mm. Tumor sizes and invaded parasellar areas are listed in Table 3. Invasion of the bilateral
cavernous sinuses occurred in 11 cases, of a unilateral cavernous sinus in the other nine cases. Using MR imaging
studies to assess tumor volume, we measured the largest diameter of the lesion in three orthogonal planes (a, b, and
c) and we used the following formula, designed to calculate
the volume of an ellipsoid: V = 4pabc 3 23/3. In Table
3, the numerical values of the three diameters of the tumors
(a, b, and c) are listed in the column labeled tumor volume.
In cases in which residual tumors were divided into several
separate areas after treatment, each area was calculated individually. All PRL levels were greater than 200 ng/ml before treatment and exceeded 4000 ng/ml in nine cases. Because of difficulties at the laboratory, accurate PRL levels
were not available in some cases.
J. Neurosurg. / Volume 104 / January, 2006
TABLE 2
Pretreatment and posttreatment visual field statuses in patients
with invasive giant prolactinomas*
Pre-Tx VF
Post-Tx VF†
Case
No.
OD
OS
OD
OS
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
anopsia
TH
TH
anopsia
anopsia
anopsia
N
T
TH
TH
T
T
TH
N
TH
N
T
N
N
N
anopsia
TH
TH
TH
N
N
N
N
TH
TH
N
anopsia
N
N
TH
N
T
N
N
N
TH
N
N
N
N
N
N
N
TH
N
TH
TH
N
N
N
N
T
N
N
N
anopsia
N
N
N
N
N
N
N
TH
N
N
anopsia
N
N
N
N
N
N
N
N
* N = normal; OD = oculus dexter; OS = oculus sinister; T = tubular;
TH = temporal hemianopia; Tx = treatment; VF = visual field.
† Most recent finding.
Treatment Methods
Six patients who had undergone unsuccessful surgery at
other hospitals received bromocriptine treatment at our hospital. Four patients were treated using craniotomy (Cases 6,
7, 11, and 13), one transsphenoidal surgery (Case 20), and
one transnasal surgery (Case 2). According to postoperative
MR imaging and endocrinological examination data, these
six patients met the diagnostic criteria for invasive giant
prolactinomas, and therefore were included in our study. To
determine the outcomes of bromocriptine treatment, tumor
volume based on postoperative MR images was calculated in the same manner as the volume before bromocriptine
treatment. The other 14 patients initially received bromocriptine treatment. Eleven patients in our study group underwent adjuvant radiotherapy. Bromocriptine was orally
administered before sleep at night at an initial dose of 2.5
mg/day to reduce the occurrence of orthostatic hypotension.
Within 2 to 3 weeks, the dose was gradually increased to 7.5
mg/day (that is, 2.5 mg three times/day), which was the effective treatment dose. In cases in which patients experienced adverse effects (such as gastrointestinal discomfort,
dizziness, and so forth) after taking bromocriptine only half
of a tablet (1.25 mg) was subsequently administered, and
the dose was slowly increased; for example, 1.25 mg/day
was added every week, and most patients was able to tolerate the entire dose after the gradual adaptation.29
Results
Posttreatment Courses
All patients were closely followed up by the first author
(Z.B.W.) between 7 and 71 months posttreatment (mean
follow up of 37.3 months; Figs. 1–4). Follow-up examina55
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Z. B. Wu, et al.
TABLE 3
Summary of characteristics in 20 patients with invasive giant prolactinomas treated with bromocriptine*
PRL Level (ng/ml)
Case Age (yrs),
No.
Sex
Pre-Tx Post-Tx†‡
Tumor Vol (mm3)†
Pre-Tx
Post-Tx‡
Range of Tumor Invasion
% Vol
Change
Follow
Up (mos)
Treatment
Method
75, 68, 80
30, 20, 3
95
41
BRC 1 RT
205
769
58, 49, 51
72, 52, 48
~0, ~0, ~0
70, 39, 26
99.9
61
32
7
S 1 BRC 1 RT
BRC
341.5
19
15
19
86
226
60, 54, 50
97, 67, 40
56, 45, 40
72, 40, 38
44, 34, 26
73, 60, 54
0, 0, 0
38, 30, 28
0, 0, 0
0, 0, 0
0, 0, 0
23, 15, 20
100
88
100
100
100
97
31
9
62
57
37
36
BRC
BRC 1 RT
S 1 BRC 1 RT
S 1 BRC
BRC 1 RT
BRC 1 RT
125
55, 37, 30
81
15
BRC
3154.8
.8000
.200
1100
.4000
.200
.200
18
11.5
4.74
312
9
250
37
40, 34, 30
65, 55, 45
41, 23, 32
42, 20, 20
55, 52, 38
52, 50, 38
72, 48, 45
100
88
100
100
95
76
85
25
46
63
34
71
42
26
S 1 BRC 1 RT
BRC 1 RT
S 1 BRC
BRC
BRC
BRC 1 RT
BRC 1 RT
.4000
.8000
.200
258
34
16
63, 40, 45
46, 32, 30
40, 35, 30
25, 14, 23/
24, 10, 16§
0, 0, 0
40, 30, 30
0, 0, 0
0, 0, 0
30, 16, 11
30, 31, 25
28, 15, 40/
23, 12, 22§
~0, ~0, ~0
0, 0, 0
0, 0, 0
99.9
100
100
17
39
56
BRC
BRC
S 1 BRC 1 RT
1
18, M
7938.8
2
3
33, M
15, M
.6000
16000
4
5
6
7
8
9
48, M
22, F
17, M
24, M
53, M
37, F
1431.4
.200
.200
.200
.4000
.8000
10
20, M
.470
11
12
13
14
15
16
17
40, M
49, M
37, M
25, F
26, M
26, F
42, M
18
19
20
49, M
17, M
37, M
77.35
Pre-Tx
bilat-CS, SS, Cl, TV
& IPC; bilat-FL & TL
bilat-CS, SS, Cl, TV, & NC
bilat-CS, SS, Cl, TV,
& IPC; lt-TL
bilat-CS, & TV; rt-TL
lt-CS, SS, Cl, TV, & LV
rt-CS, SS, & Cl
bilat-CS, SS, & Cl
rt-CS, SS, Cl, & TV
rt-CS, SS, Cl, TV
& IPC; rt-TL
bilat-CS & TV
rt-CS & TV
lt-CS, SS, Cl, & TV; lt-TL
lt-CS, SS, & Cl
rt-CS & TV
bilat-CS, Cl, & TV
rt-CS, Cl, & IPC; rt-TL
bilat-CS, SS, Cl,
TV & LI
bilat-CS, SS, Cl, & TV
bilat-CS & Cl
bilat-CS, SS, & Cl
Post-Tx‡
lt-CS
bilat-CS, SS,
& Cl
lt-CS, SS, & Cl
rt-CS
rt-CS
lt-CS & IS
lt-CS
rt-CS
bilat-CS
* BRC = bromocriptine; Cl = clivus; CS = cavernous sinus; FL = frontal lobe; IPC = interpeduncular cistern; IS = intrasellar; LV = lateral ventricle; NC = nasal
cavity; RT = radiotherapy; S = surgery; SS = sphenoidal sinus; TL = temporal lobe; TV = third ventricle.
† Values represent those for tumor areas a, b, and c, respectively.
‡ Most recent finding.
§ Residual tumors were divided into two separate areas after treatment.
tion took place mainly in the outpatient clinic and was supplemented by telephone interview. The 3-month, 6-month,
and 1-year follow ups were conducted after bromocriptine
treatment; thereafter, a follow up was undertaken every 1 to
2 years. The follow-up examination included cranial MR
imaging with contrast, endocrinological laboratory tests, vision and visual field checks, and so forth. If the patient’s
state of health deteriorated, he or she had the opportunity to
visit the doctor immediately. Initially, three patients experienced different degrees of bromocriptine-related side effects, such as nausea, gastrointestinal discomfort, orthostatic dizziness, fatigue, nasal congestion, and so forth. A lower
drug dose was administered, and the dose was subsequently increased gradually; each of the three patients was able to
tolerate the entire dose following this strategy.
On Day 140 after bromocriptine administration, CSF
leakage occurred in the patient in Case 3. He continued to
take the drug and was simultaneously given conservative
treatment, with no effect. Transsphenoidal surgery was performed to excise the greater part of the tumor and to repair
the CSF leak. Two months after the administration of bromocriptine in the patient in Case 12, the tumor decreased in
size by 88%. One year after taking the drug consistently, the
patient’s residual tumor shrank no further and was localized
in the sella, involving the left cavernous sinus. In October
2002, the patient underwent transsphenoidal surgery for tumor excision and continued to take bromocriptine postoperatively. At present, the tumor has disappeared completely
56
and the patient’s PRL level is normal. No instance of tumor
apoplexy occurred while taking bromocriptine.
Effects of Treatment on Presenting Symptoms and
Visual Fields
In the 14 patients with visual loss—excluding the patient
in Case 9 whose visual deterioration was considered to be
related to radiotherapy—the visual symptoms were improved in 93% to various extents. Visual field impairment
was ameliorated in all of these patients, as shown in Table
2. In the 10 patients with headaches, symptoms disappeared
in eight and were ameliorated in the other two. In nine patients with sexual dysfunction and a decrease in PRL levels, sexual function improved to various degrees; in six, a
normal sex life was regained. In two patients with galactorrhea, the relevant symptoms vanished. In four patients with
amenorrhea, menstruation resumed in one patient (Case
5); amenorrhea remained in the other three (Cases 9, 14,
and 16).
Prolactin Levels
In eight patients, PRL levels decreased to less than 25
ng/ml after bromocriptine treatment, as shown in Table 3. In
seven patients, levels continued to exceed 200 ng/ml. In five
patients, PRL levels were between 25 and 200 ng/ml. Normal pituitary function was preserved in all patients, without
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Bromocriptine treatment of invasive giant prolactinomas
FIG. 1. Case 2. Magnetic resonance images obtained in a 33year-old man. A and B: The patient displayed a giant sellar tumor
that extensively invaded the nasal cavity and skull base. He had undergone resection at another hospital to remove the nasal cavity tumor. Results of a postoperative pathological examination revealed
an invasive pituitary tumor, and radiotherapy after patient discharge
was suggested. One month later, after radiotherapy, the patient was
admitted to our hospital. C and D: The tumor before bromocriptine treatment. E and F: Gadolinium-enhanced T1-weighted MR
images obtained 16 months after initiating bromocriptine treatment.
G and H: Gadolinium-enhanced T1-weighted MR images obtained
25 months after initiating bromocriptine treatment. The latter four
images show a nearly total disappearance of the lesion, with only a
residual tumor envelope. Recently, the PRL level in this patient was
205 ng/ml and he has continued to take 2.5 mg/day bromocriptine.
evidence of panhypopituitarism. No case of diabetes insipidus was observed.
Tumor Volume Change on MR Imaging
After treatment with bromocriptine, tumor volume decreased dramatically in all patients, with a mean reduction
of 93.3% (range 61–100%; Table 3). On MR images obtained in 11 patients, the tumor had almost completely disappeared; on images obtained in the other nine, residual tumor remained in the cavernous sinus areas. Among the 20
patients, tumors involved 31 lateral cavernous sinuses; durJ. Neurosurg. / Volume 104 / January, 2006
FIG. 2. Case 18. A and B: Pretreatment T1-weighted MR images with Gd enhancement demonstrating a giant sellar tumor with
suprasellar, sphenoidal sinus, clival, and parasellar extension. C
and D: Gadolinium-enhanced T1-weighted MR images obtained
6 months after initiation of bromocriptine treatment, showing suprasellar and sphenoidal sinus lesion shrinkage, as well as residual
tumor located in the bilateral cavernous sinus. E and F: Gadolinium-enhanced T1-weighted MR images obtained 13 months after
initiation of bromocriptine treatment, demonstrating a near total disappearance of tumor despite a PRL level of 258 ng/ml.
ing follow up, the lesion disappeared in 20 sinuses. In the
course of tumor reduction, lesions in the suprasellar area
commonly shrank first, followed by those in the sphenoid
sinus and the intrasellar region. Tumors in the cavernous sinus area were always the last to shrink.
Discussion
Effectiveness of Bromocriptine in the Treatment of
Invasive Giant Prolactinomas
Dopamine agonist medication is the first consideration in
the treatment of prolactinomas. Bromocriptine can normalize the serum PRL level in more than 90% of cases and reduce tumor volume in approximately 85% of cases.3,6,13,17,
37,42,54
Its main mechanism involves the dopamine D2 receptors on the cell membrane of PRL cells, which is selec57
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Z. B. Wu, et al.
FIG. 3. Case 17. A–C: Pretreatment T1-weighted MR images
with Gd enhancement demonstrating a giant sellar lesion with suprasellar, sphenoidal sinus, clival, and parasellar extension. D: A
T1-weighted unenhanced MR image obtained 2 months after initiation of bromocriptine treatment together with adjuvant radiotherapy, demonstrating obvious shrinkage of a suprasellar tumor. E
and F: Gadolinium-enhanced T1-weighted MR images obtained 11
months after initiation of bromocriptine treatment, showing a small
residual tumor mainly located in the bilateral cavernous sinus.
tively activated; thus, the transcription and expression of the
PRL gene and the metabolism of PRL cells are inhibited,
leading to decreased synthesis and secretion of PRL. In addition, the involution of the endoplasmic reticulum and Golgi apparatus and the suppression of cell proliferation cause
a reduction in tumor volume.2,38,49,50 With the reduction in lesion volume and the control of the PRL level, clinical symptoms are ameliorated. Headache and sexual dysfunction are
improved to differing degrees. The extent and rate of the reduction in tumor volume can be astonishing; for example,
during the mean follow-up period of 37 months in the present study, tumor volumes decreased by a mean of 93.3%
overall and lesions almost disappeared in 11 patients, according to MR imaging studies (Figs. 1 and 3). Shrivatava
and colleagues47 reported on 10 cases of giant prolactinomas that had been treated with bromocriptine, only five of
which involved the cavernous sinus. During a mean followup period of 6.7 years, tumor volume decreased by a mean
of 69%. Other authors have reported that cabergoline—
which has a much longer duration of action, fewer side effects, and greater efficacy compared with bromocriptine—
is a first-line drug in the treatment of prolactinomas.9,10,15
In our study, however, successful treatment effects were
achieved using bromocriptine. Most authors have reported
58
FIG. 4. Case 16. A: Pretreatment T1-weighted MR image with
Gd enhancement showing a giant tumor with obvious right cavernous sinus extension. B–D: Three T1-weighted MR images obtained 12, 28, and 40 months after initiation of bromocriptine treatment, respectively, demonstrating obvious shrinkage (76%) of a
giant tumor. Residual tumor existed mainly in the right cavernous
sinus.
that in cases of giant prolactinomas, visual symptoms improve several days to several weeks after treatment with
bromocriptine. Posttreatment visual improvement was not
significantly different after drug administration compared
with that following surgery.7,30,35,39,48,53,55 If, after drug administration, the tumor had obviously diminished but vision and
visual fields had not improved, ocular defects were rarely
improved by subsequent surgery.18 The blood supply to the
optic nerve and chiasm can be impaired during the surgical
separation of adhesions between the giant tumor and the optic nerve. Bromocriptine treatment gradually reduces tumor
volume and therefore does not contribute to acute damage
of the optic nerve and chiasm. In 13 (93%) of 14 patients
with visual deterioration, visual symptoms improved. After
taking bromocriptine, vision initially improved in the patient in Case 9; 6 months after radiotherapy, however, the
patient’s vision deteriorated. Hence, visual loss was attributed to radiotherapy. Visual improvement usually occurred
within several weeks after beginning bromocriptine treatment and has occurred even on the 1st day after commencing treatment.55
Influence of Sex on Treatment Effects
Compared with those in women, the tumors in men are
larger, PRL levels are higher, and tumors invade the cavernous sinus more often.51 In the present study, most patients
were male, with a ratio of 4:1 (male/female). Among the
four female patients, excluding the woman in Case 5, PRL
levels continued to exceed 200 ng/ml after treatment, and
amenorrhea did not improve. Among the 16 male patients,
PRL levels decreased to within normal range in seven cases,
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Bromocriptine treatment of invasive giant prolactinomas
but exceeded 200 ng/ml in four cases. Rates of PRL level
control in both sex groups were statistically analyzed, and
there was no significant difference (p . 0.05). In the four
female patients, tumor volume decreased by a mean of 90%,
during a mean follow-up period of 30 months. In the 16
male patients, tumor volume decreased by a mean of 94%
during a mean follow up of 39 months. There was no significant difference in tumor volume reduction between the
sexes.
Correlation Between PRL Level Decrease and Tumor
Volume Shrinkage
Do tumor volume and PRL level decrease at the same
rate? Does the PRL level always decrease to a normal level
after tumor disappearance? Data in our study showed that
in 11 patients in whom tumors had either completely or almost vanished according to MR imaging, the PRL level was
normalized (, 25 ng/ml) in five and was not normalized in
the other six. Of the latter six patients, four had PRL levels
higher than 200 ng/ml. In patients who continued to demonstrate a high PRL level, tumor disappearance on MR images
did not necessarily indicate complete lesion resolution, because the tumor had invaded adjacent structures or the bone
matrix and possessed a strong ability to excrete PRL (Figs.
1 and 2). These patients not only continued to take bromocriptine, but were also closely monitored, because once administration of the drug was terminated, the tumor could recur immediately.37 On the other hand, among eight patients
whose PRL levels decreased to normal, the tumor remained
visible on MR images obtained in three patients. In five patients whose MR imaging studies were negative for tumor
and whose PRL levels were normal, it was suggested that
bromocriptine therapy be withdrawn. Close monitoring for
recurrent hyperprolactinemia and renewed tumor growth
was established.8 Tumor volume shrinkage and controlled
PRL levels were not equally sensitive to bromocriptine, and
there was no positive correlation between tumor size and
PRL level.37,47
Sequence of Tumor Volume Shrinkage
During follow up, we found an interesting phenomenon:
after treatment with bromocriptine, tumors growing into the
suprasellar area shrank first (for example, tumors protruding into the third ventricle or the temporal lobe). In the nine
patients with residual tumors, the remnant always involved
the cavernous sinus (Fig. 3). In three patients (Cases 5, 9,
and 16), tumor volume was reduced within several weeks
to several months after taking the drug. As drug therapy
was prolonged, the tumor diminished slowly, particularly
any residual tumor involving the cavernous sinus. In the patient in Case 16 (Fig. 4), tumor volume shrank by 76% 12
months after initial bromocriptine administration. In the
subsequent 2 years, the tumor shrank no further, and the
PRL level was not satisfactorily controlled. This condition
could be considered late resistance and may have occurred
for the following reasons. 1) After drug administration, tumor fibrosis becomes progressive and, to a certain extent,
the tumor can shrink no further. 2) The absence, lower expression level, or a postreceptor defect of the dopamine D2
receptors on the surface of tumor cells may contribute to
this condition.41 Caccavelli, et al.,5 considered drug resistance to be strongly associated with the decrease in D2 reJ. Neurosurg. / Volume 104 / January, 2006
ceptor gene transcription, resulting in a fourfold decrease in
the number of D2 receptors on the cell membrane.
Indications for Surgery in Patients With Invasive
Giant Prolactinomas
Pituitary tumors with lateral extension into the cavernous
sinus pose a formidable surgical challenge. Recently, authors have sought to modify the standard transsphenoidal approach to resect pituitary adenomas with cavernous
sinus invasion.12,20,22,25,44 Note, however, that surgical outcomes were rather unsatisfactory in patients with pituitary
adenomas of Grade III or IV, according to the classification
of Knosp and colleagues.26 Losa, et al.,34 reported on 19
PRL-secreting pituitary adenomas with cavernous sinus invasion; the disease was cured in just one patient through
early surgery. Increasingly, many investigators have chosen
to perform selective tumor removal with subsequent radiosurgical treatment of residual adenoma within the cavernous sinus to avoid complications of cranial neuropathies. In
treating PRL-secreting adenomas, shrinking the tumor volume and controlling the PRL level are equally important.
As a result of the tumor’s intrusive growth and cavernous
sinus invasion, it is usually impossible to achieve complete
resection through a single operation. Similarly, controlling
the PRL level by using a biological cure cannot usually be
achieved through a single operation.21,43 As mentioned earlier, bromocriptine first shrinks the part of a tumor that aggressively extends into the suprasellar space and compresses the optic nerve (as in Cases 4, 5, 8, and 17); therefore,
bromocriptine treatment, as a first-line therapy for invasive
giant prolactinomas, can reduce the necessity for surgery
and associated risks and costs.23 The cure rate following
bromocriptine treatment for invasive giant prolactinomas
involving the cavernous sinus has not been previously reported. The following conditions are still indications for
surgery: 1) intolerance or resistance to bromocriptine; 2) occurrence of CSF leakage while taking bromocriptine which
cannot be conservatively treated; and 3) tumor apoplexy
causing significant clinical symptoms, such as sudden severely decreased vision.1,14,43,45,47,48 If the clinical symptoms
in a patient with tumor apoplexy are not prominent, bromocriptine treatment can still be effective.4,32 In the patient in
Case 12, the tumor shrank during the 2nd month of bromocriptine therapy. After 1 year of subsequent drug therapy, residual tumor was localized in the sella turcica and the left
cavernous sinus, without further reduction; transsphenoidal
surgery was performed to excise the remnant. The patient
has continued to take bromocriptine postoperatively, and at
present, the tumor has vanished completely and the PRL
level is normal.
Timing of Radiotherapy
Because of potential side effects, radiotherapy is presently regarded as an adjunctive therapy after surgery or drug
treatment.16,19,31,36,56 In our series, 11 patients underwent radiotherapy within 2 months of starting bromocriptine to accelerate shrinkage of the tumor volume and to enhance control of the PRL level. Positive effects were achieved during
a mean follow-up period of 37.5 months: tumor volume
shrank by a mean of 93.5%. However, the use of radiotherapy should be carefully considered. In patients with hypopituitarism and sharply decreased vision and in young wom59
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Z. B. Wu, et al.
en who wish to remain fertile, radiotherapy is not a feasible
choice. In the nine patients who did not undergo radiotherapy, tumor volume shrank by a mean of 93% during a mean
follow up of 37 months, and there was no significant difference between the groups with or without adjuvant radiotherapy. In other words, traditional radiotherapy did not enhance tumor volume shrinkage. Given the positive effects
of bromocriptine treatment on invasive giant prolactinomas
and the potential side effects of traditional radiotherapy, the
latter method is selected more and more cautiously.40 On the
other hand, after bromocriptine treatment, if the tumor is localized to limited areas and continuous drug administration
does not shrink the tumor, one might perform gamma knife
surgery, which could control the residual tumor with cavernous sinus invasion.24,27,28,46 Some authors have proposed
a technique for pituitary gland transposition,11,33 which involves transposing the normal pituitary gland away from
the cavernous sinus tumor and interposing a fat graft between the gland and the tumor. This process increases the
distance between the two to facilitate radiosurgical treatment of residual tumor, thereby reducing the effective biological dose to the normal pituitary gland.
Conclusions
We reported on 20 patients with invasive giant prolactinomas in the cavernous sinus who had experienced successful treatment outcomes. In summary, bromocriptine can
dramatically reduce tumor volumes and control prolactinoma levels in a relatively short treatment period. During a
mean follow up of 37.3 months, the tumors in 11 patients
disappeared almost completely on MR images; in the other
nine patients, tumor volume shrank by 61 to 97%, with residual tumor involving the cavernous sinus. If a localized
residual tumor does not demonstrate additional shrinkage
with continuous drug therapy, gamma knife surgery may be
a good option.
Acknowledgment
We are grateful to Edward Laws Jr., M.D., for the critical evaluation and linguistic revision of this manuscript.
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Manuscript received April 1, 2005.
Accepted in final form July 17, 2005.
Address reprint requests to: Zhe Bao Wu, M.D., Department
of Neurosurgery, First Affiliated Hospital of Wenzhou Medical
College, Wenzhou 325000, People’s Republic of China. email:
[email protected].
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