Q J Med 2013; 106:495–504
doi:10.1093/qjmed/hcs240 Advance Access Publication 16 January 2013
Review
Macroprolactinoma: a diagnostic and therapeutic update
P. IGLESIAS and J.J. DÍEZ
Address correspondence to Dr P. Iglesias, Department of Endocrinology, Hospital Ramón y Cajal, Ctra.
de Colmenar, Km 9, 28034 Madrid, Spain. email: piglo65@gmail.com
Summary
Prolactinomas are the most common type of pituitary adenomas. Macroprolactinomas are the name
used for these tumors when their size is 51 cm.
These tumors commonly cause symptoms due to
the excessive production of prolactin as well as
complaints caused by tumor mass and compression
of neural adjacent structures. Clinical diagnosis
and assessment of macroprolactinoma are based
on the measurement of serum prolactin concentrations and the morphological evaluation of the pituitary gland by magnetic resonance imaging.
Dopamine agonists are the first-line treatment
modality, with cabergoline being preferred to
bromocriptine, because of its better tolerance and
feasibility of administration. Cabergoline therapy
has been reported to achieve normalization of
prolactin levels and gonadal function and
reduction of tumor volume in >50% of patients
with
macroprolactinoma.
Resistance
or
intolerance to dopamine agonists are the main
indications for transsphenoidal adenomectomy in
patients with macroprolactinoma. External radiation therapy has been used in patients with poor
response to medical and surgical procedures.
Clinically significant tumor growth may occur
during pregnancy in women with macroprolactinomas, especially if they have not received prior surgical or radiation therapy. Visual fields should be
assessed periodically during pregnancy and therapy with dopamine agonists is indicated if symptomatic tumor growth occurs. Cystic and giant
prolactinomas as well as the rare cases of malignant prolactinomas have special peculiarities and
entail a therapeutic challenge.
Introduction
More than 90% of prolactinomas are microprolactinomas (<1.0 cm in diameter), whereas the rest
are macroprolactinomas (51.0 cm).3–6 Macroprolactinomas constitute approximately half of all functioning pituitary macroadenomas.7 Compared with
microprolactinomas, these tumors have a different
distribution frequency in the general population
and its biological behavior also differs according
to the age and sex of the patients. This review
focuses on the most updated and relevant clinical,
diagnostic and therapeutic aspects of the macroprolactinoma as well as several different special
clinical situations related to this type of tumor.
Prolactinoma is usually a benign tumor that appears
as a result of the monoclonal expansion of a cell line
of lactotrope cells of the adenohypophysis, probably
due to somatic mutations.1 It is the most common
pituitary tumor (50%) and usually appears in
women aged 20–50 years, with a female:male
ratio of 10:1 in that period. Its annual incidence is
6–10 cases per million of inhabitants and its prevalence of 60–100 cases per million, although recent
studies indicate that the prevalence may be three to
five times higher.2
! The Author 2013. Published by Oxford University Press on behalf of the Association of Physicians.
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From the Department of Endocrinology, Hospital Ramón y Cajal, Ctra. de Colmenar, Km 9, 28034
Madrid, Spain
496
P. Iglesias and J.J. Dı́ez
Macroprolactinoma according
to age and sex
Children and adolescents
Adults
Prolactinoma in adults occurs more frequently
(>70%) in women, mostly in the form of microprolactinoma (female:male ratio, 20:1). On the contrary, macroprolactinoma is more frequently
reported in males,3–7,19 with a macro-/microprolactinoma ratio of 5:1.19 Most (60%) of the adult
males with macroprolactinomas are diagnosed
before the age of 40 years; mainly in the fourth
decade of life, where about one-third of the patients
are diagnosed (Figure 1). Although macroprolactinomas are most common in young men, they have also
been reported in elderly males, sometimes presenting as authentic giant prolactinomas.20,21
Biology and clinical course of prolactinomas
seems to be different in men and women.
Although initially it was thought that the predominance of macroprolactinomas in males was due to a
delay in diagnosis, several studies have shown that
this fact could be because males frequently develop
tumors with greater mitotic activity and, therefore,
microprolacƟnomas (n=15, 16.1%)
macroprolacƟnomas (n=78, 83.9%)
Clinical features
The main complains at diagnosis in males with
macroprolactinoma are visual disturbances and
headaches, symptoms that are related to the compressive effect of the tumor mass.4,7,19,25 As it occurs
in men with microprolactinomas, the majority of patients (80%) show symptoms of hypogonadism
(erectile dysfunction associated or not to decreased
libido) as a result of hyperprolactinemia-induced
hypogonadism and compression of the gonadotrope
cells by the tumor.4,26 Partial or total hypopituitarism at diagnosis appears in 78% of males with
macroprolactinomas; the gonadal (74%) and somatotropic (31%) axes being the most frequently affected, followed by thyrotropic (25%) and
corticotropic (23%) axes.19 Anemia is frequently
(40–45%) found in men with prolactinomas.27,28
It is generally a mild normochromic normocytic
anemia (hemoglobin >11 g/dl), associated with the
presence of secondary hypogonadism or hypopituitarism. Usually, it improves after normalizing serum
PRL levels and increasing serum testosterone levels
with dopamine agonists (DA)27 and hormone replacement therapy.29
In women, the first clinical signs of macroprolactinomas are more frequently (70%) related with
hormonal dysfunction (amenorrhea and galactorrhea) than with the effect of the tumor mass.7,30 In
children and adolescents, macroprolactinomas present clinically with symptoms derived from tumor
growth such as headache and visual disturbances.9
Moreover, in adolescent women, these symptoms
manifest themselves together with primary or
secondary amenorrhea. Delayed puberty due to
hypogonadotropic hypogonadism induced by
hyperprolactinemia or by tumor effect on gonadotropic cells is another manifestation of macroprolactinoma in children.31 Finally, growth arrest is usually
not developed in this population due to the fact that
somatotropic axis is generally preserved.9
Percentage (%)
60
50
Diagnostic update
40
30
Morphological study
20
10
0
<40
40-60
>60
Age at diagnosis (yr)
Figure 1. Percentage distribution according to size
(micro- and macroprolactinoma) and age at diagnosis in
a group of 93 male adults (>18 years) with prolactinomas.
Magnetic resonance imaging (MRI) is the method of
choice for the morphological study of macroprolactinomas in both initial assessment and follow-up7
This technique provides information not only on
the size of the tumor but also on their relationship
with the surrounding brain structures and
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Pituitary adenomas are very uncommon (3% of all
brain tumors) in prepubertal children and, in most
cases, they are not functioning pituitary adenomas.8
Prolactinomas are therefore exceptional in children
and its clinical presentation may be different from
that of adults. Unlike adults, macroprolactinomas
are more common (60–80%) than microprolactinomas in children and adolescents.9–12 Furthermore, in
this age group, prolactinomas are more aggressive
and have increased proliferative capacity that in
adults, i.e. they are usually macroprolactinomas,
sometimes large, and some occasions manifesting
as authentic invasive giant prolactinomas.8,11–18
increased capacity of proliferation and invasiveness.22–24
Macroprolactinoma
497
Therapeutic update
Medical therapy
neuro-ophthalmological pathways. Also, the findings in the MRI are associated not only with serum
PRL concentration but also with clinical symptoms.7
These tumors show characteristic signs in the MRI;
they are isointense or slightly hyperintense on
T1-weighted images with an increase in signal
compared with normal pituitary tissue after administration of paramagnetic contrast and slightly hyperintense on T2-weighted images7 (Figure 2). MRI is
also useful in the follow-up of patients with macroprolactinomas treated with DA as it shows the
reduction of tumor size as well as other alterations
that can be associated with chronic medical treatment such as intratumoral hemorrhage, intraselar
chiasma and optic nerves invagination and empty
sella.7,19,32,33
Hormonal diagnosis
The degree of hyperprolactinemia is usually related
to the size of prolactinoma.34 Macroprolactinoma is
usually associated with serum PRL levels >250 ng/
ml. A serum PRL level >500 ng/ml makes the diagnosis of macroprolactinoma almost certain.35
Sometimes PRL levels may be normal or slightly
elevated in patients bearing macroprolactinomas.
This may be due to the ‘hook’ effect of the PRL, an
artifact of the PRL assay that can be observed when
serum PRL concentrations are very high and saturate
antibodies of the assay giving rise to falsely low
results. To avoid this phenomenon, repeating the
quantification of PRL in serum samples after dilutions of 1:100 is recommended, particularly in
male patients, with a mild–moderate PRL elevation
associated with a presumably non-functioning
pituitary macroadenoma.36,37
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Figure 2. MRI coronal section with a macroprolactinoma
showing a hyperintense signal on T1 after the administration of paramagnetic contrast.
The initial treatment of choice of the macroprolactinoma is currently DA.37–39 This therapy achieves a
reduction in the levels of PRL, restoration of the gonadal function and reduction of tumor size in a high
percentage of patients (Figure 3). Within this
pharmacologic group, cabergoline (CAB) is preferred due to a greater therapeutic efficiency, a
better tolerance and therefore, greater adherence
to treatment and, finally to a more convenience of
administration of the drug.35,37,38,40,41 A prospective
study of 26 patients (15 women and 11 men) with
previously untreated macroprolactinomas showed
that treatment with CAB (0.25–2.0 mg/week) was
followed by normoprolactinemia in 21 patients
(81%) and significant reduction in tumor size in
92% of patients after 6 months of treatment.26 In
this study, the therapeutic regimen achieved similar
effects in 94.7% and 42.1%, respectively, of patients
intolerant to bromocriptine (BRC). Similarly, 19 of
37 patients (51.3%) resistant to BRC and quinagolide achieved normoprolactinemia and 30.3% of
them showed a significant reduction in tumor size.26
DA are also the drugs of choice in the therapeutic
management
of
macroprolactinomas
in
men.4,19,25,42,43 In a 24-month prospective study,
treatment with CAB (0.25–3.5 mg/week) normalized
PRL levels in 76% of patients, significantly reduced
tumor size in all patients with a percentage reduction of the maximum tumor diameter of 84%, normalized serum testosterone in 60% and sperm
alterations in the majority (>90%) of patients.25
Given the effectiveness and tolerance of the DA,
this pharmacologic group, mainly CAB, also constitutes the initial therapy of choice in children and
adolescents with macroprolactinomas.9 These
drugs achieve the normoprolactinemia, the restoration of the gonadotropic axis function and the reduction in the tumor size in the majority of
patients.11,12,18
It has been reported that CAB, even at high doses,
does not normalize PRL in 18% of patients with
macroprolactinomas despite reducing the tumor
size. CAB doses exceeding 3 mg/week do not
seem to offer benefit on the control of the overproduction of PRL.40
Although cure of macroprolactinoma after
long-term treatment with DA has been reported,44
complete remission (normoprolactinemia associated
with absence of tumor image) is not easy to achieve.
A study showed a recurrence rate of hyperprolactinemia in 43.3% of patients with macroprolactinomas after 5 years of CAB withdrawal. In this study,
498
P. Iglesias and J.J. Dı́ez
2007
2010
tumor recurrence was 77.5% in those patients that
had small remnant tumor in MRI at the time of the
CAB withdrawal versus 32.6% in those showing no
evidence of tumor image at that time.45 Persistent
control of hyperprolactinemia without evidence of
tumor growth after 24–96 months of CAB withdrawal has been reported in 50% patients with
macroprolactinoma.46 Recurrences usually appear
in the first year following the withdrawal and one
study showed that the risk of recurrence was 18% by
millimeter tumor mass remaining before the withdrawal of the CAB.47 The probability of complete
cure is greater when treatment with DA has been
prolonged (>2 years) and there is no tumor rest in
MRI.37,48
Surgical therapy
Surgical treatment of macroprolactinoma is currently considered as second-line therapy after medical treatment with DA.37 Adenomectomy via
transsphenoidal (microscopic or endoscopic) approach is the main surgical technique used in the
majority of the macroprolactinomas. Craniotomy is
reserved for large tumors inaccessible to conventional procedures.49 The main surgical treatment indications include resistance, intolerance or lack of
adherence to medical treatment, cerebrospinal fistulas secondary to a reduction of tumor size after
therapy with DA, neuro-ophthalmologic defects
such as rapid loss of vision or cranial pars paralysis
due to intratumoral hemorrhage or pituitary apoplexy.37,39 A surgical series of 148 macroprolactinomas reported by Kreutzler et al.50 was accompanied
with initial remission (PRL normalization without
pharmacological treatment at least 4 weeks before
surgery on day 7 after surgery) in 42.6% of patients
with macroprolactinomas with suprasellar extension
and in 24.3% in those with parasellar and/or sphenoidal extension. Recurrence rate of hyperprolactinemia was 25.6% and 20%, respectively. In this study,
none of the 10 patients with giant prolactinoma
showed remission after surgery.
Radiotherapy
Given the excellent response of macroprolactinomas to DA, today the use of external radiotherapy
should be reserved for cases of resistance to medical
treatment and poor response to surgery and to malignant tumors.51 Although the addition of radiotherapy to medical treatment and surgery helps to
control the tumor size, hyperprolactinemia often
persists.19 The maximum therapeutic effect of radiotherapy requires long time, sometimes 10–20 years.
On the other hand, a recent study showed that treatment with radiotherapy in 14 men with macroprolactinomas was associated with hypopituitarism in
all cases after 12 years after radiotherapy.19
Finally, radiation therapy has been linked recently
with the development of a giant prolactinoma in a
young male, 15 years after its administration after
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Figure 3. MRI sagittal section that shows the morphological evolution of a macroprolactinoma in a male patient after
3 years of treatment with DA.
Macroprolactinoma
surgery of a pontine glioma, treated at 6 years of
age.52
Special situations
Hereditary macroprolactinomas
Familial isolated macroprolactinoma
Macroprolactinoma associated to MEN 1
MEN 1 is an autosomal dominant hereditary syndrome characterized by the coexistence of parathyroid, pituitary and gastroenteropancreatic (GEP)
tumors associated with mutations in the gene MEN
1, a suppressor gene located on chromosome 11q13
that encodes the menin protein.59,60 Primary hyperparathyroidism is the most common disorder (>90%)
associated to MEN 1, followed by GEP tumors
(30–75%), while pituitary tumors appear in
10–60% of patients.59,61 Among them, prolactinomas are most common (20%). In turn, prolactinomas are usually macroprolactinomas in 85% of the
patients and 30% of the cases being invasive macroprolactinomas.61 Some studies suggest that macroprolactinomas associated with MEN 1 are larger,
more aggressive and with poorer therapeutic
response than the sporadic macroprolactinomas
not associated with MEN.60–62
Macroprolactinoma and pregnancy
Due to the stimulating effect of placental estrogens
on the lactotrope cells, macroprolactinomas can
grow during pregnancy and therefore be accompanied by local complications (headache and/or visual
disturbances). The possibility of growth of macroprolactinoma during pregnancy varies according to
whether patients have been or not previously treated
with surgery and/or radiotherapy. In the first case,
growth is observed in 2.5–4.8% of pregnant women,
whereas in the second, the percentage increases to
9–31%.38,63–65 In women who do not tolerate DA or
not achieve an appropriate response with reduction
of tumor size with the pharmacological treatment,
surgery of the macroprolactinoma prior to pregnancy is recommended.37 Although the withdrawal
of treatment with DA before pregnancy is recommended, it is considered prudent to continue with
treatment, preferably with DA (BRC) throughout the
pregnancy in women who have not been operated
or irradiated previously, especially in invasive
tumors or located near the optic chiasm.37,66 The
occurrence of headaches or new alterations in the
visual field requires the realization of visual field
evaluation or assessment and MRI without paramagnetic contrast (gadolinium).37 In the case of symptomatic growth of the macroprolactinoma, one can
choose changing treatment from BRC to CAB67,68
and, in the absence of response, consider transesphenoidal surgery in the second trimester of pregnancy63,66 (Figure 4).
Cystic macroprolactinoma
Although in the majority of patients, macroprolactinomas are solid, sometimes, it may be cystic as consequence of the resolution of a previous
intratumoral hemorrhage, necrosis of the tumor or
other factors such as radiation therapy, steroid treatment, anticoagulation, trauma and DA treatment.69,70 Cystic macroprolactinomas may appear
in patients of any age. In fact, they have been reported in both children15,17 and adults.69,71 It has
been suggested that cystic macroprolactinomas do
not respond well to medical treatment due to the
absence of dopamine receptors in the cystic area
of the tumor. Therefore, some authors recommend
surgery as the first therapeutic option, especially if
there is a visual compromise.50,72 However, the
solid component of the tumor maintains responsiveness to DA, so treatment with these drugs contributes to a reduction of the tumor mass. A small
number of patients with cystic macroprolactinomas
treated only with DA has been reported so far.69,71
Results indicate that approximately half of the patients achieve normalization of seurm PRL, radiological cure and tumor size reduction.69 With
these results, medical treatment with DA should be
considered as the first-line therapy prior to surgery in
cystic macroprolactinomas. Finally, it should be
taken into account that the treatment with DA can
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Prolactinoma is the tumor most often (40%)
observed in familial isolated pituitary adenoma
(FIPA) syndrome.53,54 This disorder occurs when
two or more cases of pituitary adenomas appear in
the same family in the absence of multiple endocrine neoplasia type 1 (MEN 1) and Carney complex.55 Prolactinomas associated with FIPA are
macroprolactinomas in 36% cases of FIPA with
homogeneous clinical expression, i.e. when all
affected members of the same family have the
same type of pituitary adenoma. This percentage
significantly increases to 55.5% in families with heterogeneous FIPA, when different types of pituitary
adenomas are expressed in the same family.53 This
finding may be in relation to the presence of a
greater number of males in the latter group.53 AIP
(aryl hydrocarbon receptor-interacting protein) gene
mutations appear in 15% of patients with FIPA and
are associated with 10–20% of macroadenomas that
usually develop in children, adolescents and young
adults.56–58
499
500
P. Iglesias and J.J. Dı́ez
MacroprolacƟnoma under DA therapy
Previous surgery and/or
radiotherapy
DA intolerance or resistance
Yes
No
(low probability of tumor
growth)
(high probability of
tumor growth)
Intraselar
Invasive tumor or
located near opƟc
chiasm
hi
Yes
No
ConƟnue with DA (BRC)
Monitoring
T
Tumor
growth
h
No
Yes
Monitoring
Transesphenoidal surgery
Abbreviations: DA, dopamine agonists; BRC, bromocriptine
Figure 4. Therapeutic algorithm for macroprolactinoma before and during pregnancy.
give rise to the development of pituitary apoplexy in
cystic macroprolactinomas.73
Giant prolactinoma
Giant prolactinoma is defined as a macroprolactinoma with diameter 54 cm or more than 2 cm of
suprasellar extension. It is a rare tumor that occurs
mainly in males (85%), 25% of them being
macroprolactinomas and with an estimated frequency
of
0.5–4.4%
from
all
pituitary
tumors.19,74–76
Symptoms of giant prolactinoma depends not
only on the hyperprolactinemia but also on tumor
mass effect and are associated to neuroophthalmological complications.77 These patients
have an increased risk of pituitary apoplexy,78 intratumoral hemorrhage,7 cerebrospinal fluid fistula
with rhinoliquorrhea79,80 and other exceptional
complications as epistaxis,81 proptosis,82 nasal obstruction,83,84 recurrent sinusitis,84 seizures,85
hydrocephalia20 and even osteoarticular affection.86
Serum PRL levels associated with giant prolactinoma are very high, usually >1000 ng/ml, with
levels, occasionally exceeding 40 000 ng/ml.87,88
Sometimes PRL levels are so high that they can
appear in the urine in the form of nephrotic range
proteinuria.89 There is no correlation between tumor
size and PRL levels in giant prolactinoma.74
The treatment of choice, and therefore of first line,
of giant prolactinoma is medical treatment with DA,
especially CAB.17,35,74-76,83,87,88,90–96 Therapy with
CAB is associated to a normalization of PRL levels in
68%, a 73% of reduction of tumor size and an improvement of the visual field in 91% of the patients.75,76,83,88 Surgery should be indicated when
the patient is intolerant or tumor resistant to medical
treatment with DA and continues to grow causing
neuro-ophthalmological involvement or when it
produces a rapid loss of vision or paralysis of cranial
nerves due to intratumoral hemorrhage or pituitary
apoplexy.37,75,97 Radiotherapy has a limited role in
the treatment of giant prolactinoma; on the one
hand, due to its questionable efficacy98 and, on
the other hand, the good response to the DA and
the complications associated with radiotherapy,
especially hypopituitarism.19 Therefore, radiation
therapy would be reserved for patients with tumors
resistant to DA that cannot be treated surgically.
Although prolactinomas may express the subtypes
of receptors for somatostatin (SS) 2, 3 and 5, therapy
with SS analogs is generally ineffective; however,
recently it has been reported the first case of a
male with aggressive giant prolactinoma resistant
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DA withdrawal
Transesphenoidal surgery
before pregnancy
Macroprolactinoma
to DA that presented an appropriate response to
treatment with 111In-DTPA-octreotide.99
Finally, it must not be forgotten that the reduction
in tumor size induced by DA may be accompanied
by serious complications such as fistula of cerebrospinal fluid with rhinoliquorrhea14,79,100,101 or
otoliquorrhea,102 pituitary apoplexy,73 intratumoral
hemorrhage,32 cerebral and or optic chiasm herniation into the sella turcica associated with seizures
and/or visual alterations33 and, finally, tension
pneumocephalus.103
Macroprolactinoma may also have a malignant behavior. In this case it is considered as a PRL secreting pituitary carcinoma or malignant prolactinoma.
Pituitary carcinoma is defined by the presence of
distance metastasis. It is a rare entity with around
165 cases described so far,104,105 of which
about one-third are malignant prolactinomas.2,106
Clinically it shows no special signs to help distinguish it from the usual macroprolactinoma.
Occasionally, the morphological study shows similar images to those found in the macroadenoma.107
PRL levels are similar to the macroprolactinoma.
Diagnosis is suspected when the prolactinoma is
refractory to medical therapy or in those cases
with high rate of recurrence and the diagnosis is
established, when distant metastases are found, usually located at central nervous system.2,107,108
Although treatment with DA can be effective for
treating metastases, tumor regression may not
occur to be transient. The standard chemotherapy
or radiation therapy has not shown to be effective.109–112 The use of temozolomide (TMZ), an
alkylating agent used in the treatment of glioblastoma multiforme, has been accompanied by
good
results
obtaining
long-term
partial
responses.111,112
Conclusion
Macroprolactinoma is a rare tumor with increasing
incidence in young people and men, whose biological behavior seems to be more aggressive.
Clinically, it manifests in the form of visual disturbances and/or headaches due to the compressive
effect of the tumor and symptoms arising from the
hyperprolactinemia. PRL levels tend to be generally
>250 ng/ml and are correlated with the size of the
tumor. Treatment of choice, and therefore, of first
line for all macroprolactinomas regardless of size,
are DA, mainly CAB, achieving in a high percentage
of patients a significant reduction in PRL levels, the
restoration of the gonadal function and a significant
reduction in tumor size. Surgery should be relegated
to those cases of DA resistance, intolerance or lack
of adherence to medical treatment, neuroophthalmologic defects associated with intratumoral
hemorrhage or pituitary apoplexy. Radiation therapy
would be reserved to a poor response to surgical
treatment and in the case of malignant prolactinomas. TMZ has shown its effectiveness in the case of
malignant prolactinoma. Today, the use of DA (BRC)
is a therapeutic option in pregnant women bearing
macroprolactinomas not previously treated by surgery and/or radiotherapy, especially in invasive
macroprolactinomas and in those located near the
optic chiasm, due to the potential growth during
pregnancy.
Conflict of interest: None declared.
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