Giant prolactinomas: clinical manifestations and outcomes of 16Arab cases

Mussa H. Almalki • Badurudeen Buhary • Saad Alzahrani •

Fahad Alshahrani • Safia Alsherbeni • Ghada Alhowsawi •

Naji Aljohani

� Springer Science+Business Media New York 2014

Abstract

Background The management of giant prolactinomas

remains a major challenge, despite dopamine agonists

being the first line of treatment, owing to its efficacy to

normalize prolactin levels and reduce tumor volume. The

aim of this study is to characterize the therapeutic aspects,

manifestations and outcomes of 16 cases of giant prolac-

tinomas admitted at a single tertiary center in Riyadh,

Saudi Arabia.

Methods Retrospective data collection involving 16

Saudi patients diagnosed with giant prolactinoma at the

Pituitary Clinic in King Fahad Medical City, Riyadh, Saudi

Arabia between January 2006 and July 2012.

Results A total of 16 patients (ten males; six females)

with age of diagnosis between 21 and 55 years (mean

34.9 years) were included in the analysis. The most com-

mon presenting features include headache, visual defects

and sexual dysfunction. Baseline mean serum prolactin

level were extremely high for both sexes which eventually

decreased by as much as 97 % after cabergoline treatment.

Serum prolactin concentrations completely normalized in

six patients and significantly decreased in five patients 3–5

times that of normal range. Tumor volume also decreased

by an average of 86 % for males and 87 % for females.

Two patients had no tumor size change with cabergoline

and required surgery.

Conclusion Findings indicate that cabergoline provides

dramatic clinical improvements with excellent safety pro-

file. Cabergoline should therefore be considered as the

primary therapy for giant prolactinomas.

Keywords Giant prolactinomas � Cabergoline �Pituitary tumor

Introduction

Prolactinomas are benign pituitary neoplasms accounting for

30–40 % of all pituitary adenomas. Recent epidemiologic

studies on clinically evident pituitary adenomas indicate that

prolactinomas account for [50 % for all cases with endo-

crine symptoms predominating, although this may not be

true for giant prolactinomas [1–4]. A giant prolactinoma is a

rare type accounting for *0.5–4.4 % of pituitary tumors [3,

5]. They are defined as a prolactin (PRL)-secreting pituitary

tumor, more than 4 cm, with very high circulating prolactin

levels [3, 5]. Because these tumors are commonly invasive

with a high possibility of neurological sequelae, the goals of

treatment extend beyond the suppression of excessive pro-

lactin secretion to include reducing tumor size and inhibiting

tumor growth [6]. Currently, the management of giant pro-

lactinoma is still a major challenge. Dopamine agonists

remain the first-line treatment, as they effectively normalize

PRL levels and reduce tumor volume [7]. Surgery alone is

not satisfactory and seldom results in total cure owing to size

and aggressiveness of tumors [8]. Surgery is however

remains reserved for intolerant or resistant cases. The pres-

ent study aims to describe for the first time, the clinical,

epidemiological characteristics, therapeutic aspects and

M. H. Almalki (&) � B. Buhary � S. Alzahrani �S. Alsherbeni � N. Aljohani

Obesity, Endocrine and Metabolism Center, King Fahad Medical

City, Riyadh, Saudi Arabia

e-mail: m2malki@yahoo.com

M. H. Almalki � S. Alzahrani � F. Alshahrani � G. Alhowsawi �N. Aljohani

College of Medicine, King Saud bin Abdulaziz University for

Health Sciences, Riyadh, Saudi Arabia

123

Pituitary

DOI 10.1007/s11102-014-0588-3

outcomes of giant prolactinomas among Saudi patients seen

at a single tertiary center in Riyadh, Saudi Arabia.

Patients and methods

In this retrospective study we included all patients admitted

and diagnosed with giant prolactinoma at the pituitary

clinic in King Fahad Medical City (KFMC), Riyadh, Saudi

Arabia, between January 2006 and July 2013 (mean period

of 31 months ranging from 6 to 78 months) and treated

with Dopamine agonists. Ethical approval was obtained

from the Institutional Review Board (IRB) of KFMC.

Charts were reviewed and clinical parameters which

include prolactin levels, clinical presentations and tumor

size pre- and post intervention were noted.

Imaging, biochemical assessments and definitions

Giant prolactinomas were defined as large tumors (MR

imaging with one measurable diameter [4 cm) with extra-

sellar involvement and higher prolactin concentrations [3, 5].

Tumor volume was determined using the Cavalieri principle

which takes into consideration tumor diameter measurements

in three orthogonal planes on MRI. Serum PRL levels were

measured by electrochemiluminescence immunoassay

(Elecsys Prolactin 11) (Roche Diagnostics, Indianapolis, IN,

USA). Normal range was 100–390 nmol/l. Total testosterone

was determined by electrochemiluminescence immunoassay

(Elecsys Testosterone 11) (Roche Diagnostics, Indianapolis,

IN, USA). Measuring range was 0.025–15 ng/mL

(0.087–52 nmo/l). Central hypothyroidism was defined as

low free T4 levels and either low or within the reference range

TSH concentrations. Hypogonadotropic hypogonadism was

defined as low testosterone concentrations with low or normal

LH and FSH levels. No echocardiogram was done.

Treatment protocol

All patients received oral cabergoline at a starting dose of

0.25 mg once or twice weekly with concomitant dose

increments based on serum prolactin levels as necessary.

With the exception of one case, whose dose was increased

to 10.5 mg/week, none of the subjects’ doses were

increased [3.5 mg/week (see Table 1 for individual

doses). Patients were scheduled to visit the clinic every

3–4 months to assess response to cabergoline management

and analyze serum prolactin level at each visit. Magnetic

resonance imaging (MRI) was performed at baseline,

6 months from medical therapy onset and annually to

monitor tumor size changes.

Statistical analysis

Data were analyzed using SPSS version 16.5 (SPSS Chi-

cago IL, USA). Data were expressed as mean ± standard

error for continuous variables and percentages (%) for

frequencies. Independent Student’s T test was done to

Table 1 Characteristics of the individual male and female patients pre- and post-treatment with cabergoline

Case Age at Dx PRL levels (nmol/l) Tumor size (cm3) Maximum dose

(mg/week)Pre- Post Change

(%)

Nadir

(months)

Pre- Post Decrease

(%)

Time

difference

Males

1 55 71,442 197 99.72 24 46.22 4.38 90.52 20 0.5

3 45 100,922 361 99.64 33 42.7 6.35 85.13 33 2.5

5 41 280,318 4,075 98.55 42 53.63 8.98 83.26 26 3.5

6 25 28,732 796 97.23 25 119.92 7.23 93.97 19 0.5

10 30 42,349 5,234 87.64 15 11.76 1.41 88.01 11 10.5

13 20 70,652 2 99.99 6 23.08 9.75 57.75 6 1.5

14 21 103,615 527 99.49 41 15.79 0.47 91.88 38 1.5

15 52 125,347 9,983 92.04 6 98.18 19.8 79.83 6 0.5

Females

2 46 10,800 88 99.18 39 45.22 11.10 75.45 35 1.0

7 46 201,000 1,694 99.16 50 17.62 2.51 85.75 45 2.0

8 21 53,117 1,780 96.64 65 13.73 1.19 91.33 60 1.5

11 23 37,184 1,094 97.06 7 10.11 1.41 86.05 6 2.0

12 43 14,290 409 97.14 10 22.28 0.21 99.06 6 1.0

16 28 298,002 11,935 95.99 6 39.56 5.42 86.30 6 1.0

Dx diagnosis, PRL prolactin; PRL normal range = 100–390 nmol/l

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compare normally distributed continuous variables and

Mann–Whitney U test for those with non-Gaussian distri-

bution. Chi Square tests were done to compare frequencies.

A p value \0.05 was considered significant.

Results

A total of 16 Saudi patients (ten males and six females) met

the diagnostic criteria for giant prolactinoma and were thus

included in this study. The mean age was 34.9 years (range

21–55). Baseline and post-treatment values of prolactin and

tumor volume for individual patients including the maxi-

mal dose given per week are presented in Table 1. Table 2

shows the clinical symptoms according to sex and reveals

that headache and visual disturbance were the most com-

mon complaints for both males and females. No significant

differences were noted for the rest of the symptoms.

Amenorrhea, which is a sex-specific symptom, was expe-

rienced 50 % (n = 3) female subjects. Mean values were

also compared with respect to PRL and tumor size values at

pre- and post-treatment and found no significant differ-

ences between males and females with the exception of

pre-treatment tumor size which was observed to be sig-

nificantly (borderline) higher in men than women

(63.09 ± 13.47 vs. 24.8 ± 5.9; p = 0.051).

Co-morbidities and symptoms

Headache was the most frequent symptom reported in 14

patients, which eventually resolved after treatment. Gal-

actorrhoea also disappeared in two patients who initially

presented with it. Among the 16 patients, five patients

presented with visual field defects (VFD) as detected by the

Goldmann–Friedmann perimetry. Four of them completely

improved after treatment. In all patients reported herein,

endocrine evaluation performed at baseline and after

treatment showed secondary hypogonadism in 50 %

(n = 5) of male patients; only two out of five reported

improvements in their sexual function after 4 months of

treatment. Five patients had GH deficiency with signifi-

cantly low GH and were subsequently confirmed to have

markedly low insulin growth factor (IGF)-I values for age

and sex in the context of other pituitary hormone

deficiency.

Four patients with secondary hypothyroidism continued

treatment with stable hormone profile. Secondary hypoa-

drenalism was found in one patient who had a morning

cortisol value \100 nmol/l confirmed by (1 lg) cosyntro-

pin test.

Hydrocephalus was reported in one patient who under-

went transcranial surgery. There were no deaths in this

series.

Table 2 Pre-treatment

symptoms and mean

comparisons of male and female

subjects

Data presented as frequencies

(percentages) for symptoms and

mean ± standard error for

continuous variables

PRL normal

range = 100–390 nmol/l;

p value significant at \0.05

NA not applicablea Non-Gaussian variableb Mean value for eight male

patients who responded to

cabergoline

Males Females p value

N 10 6

Pre-treatment symptoms

Visual change 6 (60.0) 3 (50.0) 0.55

Headache 10 (100.0) 4 (66.7) 0.12

Seizure 1 (10.0) 0 (0) 0.62

3rd Nerve palsy 1 (10.0) 2 (33.3) 0.52

Decreased libido 6 (60.0) 1 (16.7) 0.14

Decreased hearing 1 (10.0) 0 (0) 0.62

Memory loss 1 (10.0) 0 (0) 0.62

Personality change 1 (10.0) 0 (0) 0.62

Amenorrhea 0 (0) 3 (50.0) NA

Galactorrhea 1 (10.0) 2 (33.3) 0.30

Age, pre- and post PRL and tumor size

Age at diagnosis (years) 35.1 ± 3.99 34.5 ± 4.8 0.93

PRL pre-treatment (nmol/l)a 116020.5 ± 28339.6 102398.8 ± 48586.0 0.33

PRL post-treatment (nmol/l)a 2148.9 ± 1046.8 2833.3 ± 1841.1 0.45

PRL % change 97.4 ± 1.3 97.5 ± 0.5 0.94

Nadir (months)a 32.1 ± 7.0 29.5 ± 10.3 0.83

Pre-treatment tumor size (cm3)a 63.09 ± 13.47 24.8 ± 5.9 0.051

Post-treatment tumor size (cm3)a 6.9 ± 1.7 3.6 ± 1.7 0.18

Tumor size % decreasea 83.8 ± 4.1b 87.3 ± 3.2 0.96

Time difference (months)a 27.3 ± 6.1 26.3 ± 9.6 0.74

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Effects of cabergoline treatment

Cabergoline served as the primary therapy for all the

patients in the present study. Two patients subsequently

underwent transcranial surgery because of hydrocephalus

in one patient and mass effect with intratumoral bleeding in

other one. Rhinorrhea was seen in only one patient while

on treatment who was later treated with surgery. All

patients continued to receive cabergoline with good

response and tolerance to medication. The rest of the

patients reported no side effects common to the drug.

Effects of treatment on serum PRL

At baseline serum prolactin concentrations were extremely

high in all patients with mean a concentration of

114129.5 ± 24477.5 nmol/l (reference range 100–390 nmol/

l). At the last follow-up, both men and women had mean serum

prolactin levels reduced by 97 % except one (No. 10) with

complete normalization in six patients and decreased in five

patients to a level 3–5 times that of normal. For the two

patients who underwent surgery, prolactin level were 62,970

(case 9) and 273,858 nmol/l, (case 4) with further treat-

ment using cabergoline dropped to 208 and 106 nmol/l,

respectively.

Effects of treatment on tumor volume

Two patients submitted to surgery before medical treat-

ment for progression of the tumor and sign of increase in

ventricular volume (hydrocephalus) in one (case 4) and

mass effect and signs of intratumoral bleeding in another

(case 9). As result tumor volume decreased from 120.89

(case-4) and 98.73 (case-9) to 5.70 and 4.87 cm3, respec-

tively. The remaining 14 patients had significant decrease

in tumor volume (mean 85.3 %; range 57.75–99.06), which

was clearly evident between 6 and 60 months after starting

treatment (Table 2). All tumors measured had suprasellar

extension, and 50 % had evidence bilateral cavernous sinus

involvement.

Discussion

In this cohort, we described the clinical presentation, bio-

chemical and radiological response to cabergoline treat-

ment in Arab patients diagnosed with giant prolactinoma.

Sixteen patients with invasive giant prolactinoma were

identified (ten males and six females) suggesting male

preponderance. Such sex-discrepancy has been previously

reported [9, 10], with the most current available evidence

documenting a male to female ratio of 9:1 [11], consider-

ably lower than the present study (male to female ratio of

5:3). The over representation of women has been observed

elsewhere [12] and while we cannot ascertain such ratio

discrepancies, the male preponderance may be due to the

tumor’s aggressive nature, not merely due to delayed

diagnosis [13]. Consequently there was no difference in

treatment outcome between men and women.

In a previous study, 93 % of the patients who were treated

with bromocriptine experienced improvement in their visual

symptoms [14]. Similarly in another report, ten patients with

giant prolactinomas treated with only cabergoline reported

90 % tumor shrinkage with a complete disappearance of

visual defects in 30 % [5]. The rate of prolactin normalization

was documented in six patients and decreased in five patients

to a level 3–5 times that of normal, which is consistent with

other series in the literature. In other studies, the rate of pro-

lactin normalization was approximately 75–80 % in patients

with macroprolactinoma following 24–50 months of ca-

bergoline treatment [15, 16].

In a previous study of 26 patients with giant prolacti-

noma addressing the efficacy of cabergoline, prolactin

levels normalized in 18 and decreased by as much as 98 %

[5, 16, 17]. In another recent study involving ten patients,

cabergoline suppressed prolactin to normal levels in 75 %

of patients [18].

Our approach is consistent with current standards in

which medical treatment with dopamine agonists is the

corner stone of management for giant prolactinoma, but

surgical debulking may be performed to reverse optic

decompression or to prevent pituitary apoplexy in resistant

cases [19]. The dose of cabergoline used for all patients did

not exceed 3.5 mg/week, except for one case which

received up to 10.5 mg/week. With additional PRL-low-

ering benefits. Medical treatment with high-dosage of ca-

bergoline was associated with only one case of

cerebrospinal fluid leakage but no other potential compli-

cation namely chiasmal herniation, was reported. It is

worthy to note that two of our cases underwent surgery for

hydrocephalus in one and mass effect with signs of intra-

tumoral bleeding in other, but while surgical intervention is

usually associated with high mortality and morbidity rates

[20, 21], both cases survived, confirming that surgical

options for CAB-resistant prolactinomas may improve

outcome [22]. Larger dose of up to 20 mg daily was

reported in a patient with Parkinson’s disease without side

effects [23], but caution should still be exercised when

comparing efficacy rates for prolactinomas until standard

definitions are established [24].

Conclusion

In summary and to the best of our knowledge, this report is

considered the first of its kind in Saudi Arabia and probably

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123

in the (Gulf Cooperation Council) GCC area to report a

series of giant prolactinoma cases with up to 6-year follow

up. In such tumors, we propose cabergoline as the primary

therapy as it provides dramatic clinical improvement with

excellent safety profile.

Acknowledgments This study has been supported by a small grant

from the College of Medicine, King Fahad Medical City, Riyadh,

Saudi Arabia.

Conflict of interest The authors declare no conflict of interest.

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