Download Pituitary adenomas in adolescence: diagnostic approach

Pituitary adenomas in adolescence:
diagnostic approach and therapeutic
strategy
4° Joint Meeting on
Adolescence Medicine
Catanzaro, 14-16 October 2010
Piernicola Garofalo
Graziella Malizia
U.O.C Endocrinologia A.O.O.R. Villa Sofia-Cervello
Palermo
Pituitary adenomas
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Pituitary adenomas are rarely diagnosed in childhood and adolescence, but
their mass effect and endocrine abnormalities can compromise both quality
and length of life. Many signs or symptoms of pituitary adenoma,
complained of in adulthood, not became evident during adolescence,
suggesting true prevalence of this tumor in teenagers is higher than
expected.
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Pituitary adenoma occuring during adolescence are associated with features or
therapeutic needs sometimes different from those occuring in adulthood. At
the onset of disease, delay in growth was rarely observed in teenagers with
pituitary adenomas.

Many girls complain of oligoamenorrhoea and galactorrhoea, while
headache and delay in pubertal development are the most commons features
in boys.
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Hypopituitarism is occasionally encountered in adolescence.
Early diagnosis and appropriate choice of therapy are necessary to avoid
permanent endocrine complications of disease and its treatment.
Pituitary adenomas
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The estimated incidence of pituitary adenoma in children is still unknown
since most published series included patients with onset of symptoms before
the age of 20 years as pediatric patients.
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Pituitary adenomas constitute less than 3% of supratentorial tumors in
children and 2.3-6% of all pituitary tumors treated surgically.
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The average annual incidence of pituitary adenoma in children has been
estimated to be 0.1/million.
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Pituitary carcinomas are rare in adults and extremely rare in children

In children, more frequently than in adults, pituitary tumors may be a
manifestation of genetic conditions such as multiple endocrine neoplasia
type 1 (MEN 1), Carney complex, familial isolated pituitary adenoma (FIPA),
and McCune-Albright syndrome.
Pituitary adenomas
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Prolactinoma is indeed the most frequent adenoma histotype in children,
followed by the ACTHoma and the somatotropinoma.

Non-functioning pituitary adenomas, TSH-secreting, and
gonadotropin-secreting adenomas are very rare in children accounting for
only 3-6% of all pituitary tumors.

ACTH secreting adenomas have earlier onset and predominate in the prepubertal period.

GH secreting adenomas are very rare before puberty.

Similar to adults, presenting symptoms are generally related to the endocrine
dysfunction rather than to mass effect.
Function

Anterior Lobe:
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FSH
LH
ACTH
TSH
Prolactin
GH
Posterior Lobe:
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ADH
Oxytocin
Prolactin secreting adenomas

Prolactinomas are the most frequent tumors both in childhood and in
adulthood, and their frequency varies with age and sex, occurring more
frequently in females (until 42-68 % in differents study).

Prolactinomas are usually diagnosed at the time of puberty or in the
postpubertal period and clinical manifestations vary in keeping with the age
and sex of the child. Although growth arrest is typically seen in children
and adolescents before ephiphyseal fusion is completed.

Pre-pubertal children generally present with a combination of headache,
visual disturbances, growth failure.

Growth failure is not a common symptom. Impairment of other pituitary
hormone secretion was found only in a minority of patients (27%).

Spontaneous or provoked galactorrhea is seen in 50% of children.
Prolactin secreting adenomas
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Macroadenomas at presentation are more likely in boys than in girls.
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Young hyperprolactinemic men were shown to have a more severe
impairment of BMD than patients in whom hyperprolactinemia occurred at
an older age.
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In another series of patients, occurrence of hyperprolactinemia during
adolescence has a lower BMD than those having adult onset tumors
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Females may present with pubertal delay, amenorrhea, and other symptoms
of hypogonadism.
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In males, macroprolactinomas are more frequent; accordingly, males with
prolactinomas also have a higher incidence of neurological and
opthalmological abnormalities (i.e. cranial nerve compression, headaches,
visual loss), growth or pubertal arrest and other pituitary dysfunctions.
Prolactin secreting adenomas
Treatment strategy

In the absence of complications needing immediate surgery,
such as visual loss, hydrocephalus or cerebrospinal fluid leak,
pharmacotherapy with dopamine agonists should be considered
the first treatment approach.
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In children, cabergoline (CBA) has been used successfully by
several investigators at doses starting at 0.25 mg twice weekly
and ranging from 0.5-3.5 mg/week orally.
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The easily weekly administration makes CAB an excellent
therapeutic approach to children .
Prolactin secreting adenomas
“Clinical tips”
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Hyperprolactinemic children expressed a wide variety
of initial clinical presentations. The most common were
growth and puberty disorders and obesity.
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PRL determination should be included in investigation
protocols of obese and short stature children.
Horm. Res. Paediatr. 2010;73(3):187-92.
ACTH-secreting adenomas

Between 11 and 15 years of age, ACTH secreting adenomas are the most
frequent cause of adrenal hyperfunction and the second most frequent
pituitary adenoma after prolactinomas. A macroadenoma is rarely the cause
of Cushing's disease (CD) in children.
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The clinical manifestations of CD are mostly the consequence of
excessive cortisol production. The clinical presentation is highly variable
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The diagnosis is generally delayed since a decrease in growth rate may be
the only symptom for a long time. Growth failure in CD may be due to a
decrease of free IGF1 levels and/or a direct negative effect of cortisol on
the growth plate.
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In children with CD, the direct negative effect of hypercortisolism on bone
formation is further worsened by concomitant hypogonadism and GH
deficiency, both of which are associated with decreased BMD.
ACTH-secreting adenomas
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Children with CD may have impaired carbohydrate tolerance, while
overt diabetes mellitus is uncommon.
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Excessive adrenal androgens may cause acne and excessive hair
growth, or premature sexual development in the first decade of life.
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Hypercortisolism may cause pubertal delay in adolescent patients.
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Peculiarly, young patients with CD may present neuropsychiatric
symptoms which differ form those of adult patients. Frequently they
tend to be obsessive and are high performers at school.
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The differential diagnosis of CD includes adrenal tumors, ectopic
ACTH production, and ectopic CRH producing tumors. However,
ectopic ACTH secretion is extremely rare in the pediatric age.
ACTH-secreting adenomas
Diagnosis
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In a child/adolescent with suspected CD the diagnosis is based on
measurement of levels of cortisol and ACTH.
Measurement of 24-h urinary free cortisol is elevated, and a low dose of
dexamethasone (15 µg/Kg) at midnight does not induce suppression of
morning serum cortisol concentrations as in normal subjects.
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Suppression of the spontaneous circadian variations of serum cortisol is
another feature of CD.
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Suppression of cortisol by more than 50% after high dose dexamethasone
(150 µg/Kg) given at midnight will confirm that hypercortisolism is due to
an ACTH-secreting pituitary adenoma
ACTH-secreting adenomas
Differential diagnosis of Cushing’s disease
ACTH-secreting adenomas
Different aetiologies of paediatric CS from the literature (n= 398 cases)
shown at ages of peak incidence
Storr et al. Trends Endocrinol Metab 2006;18:167-174
ACTH-secreting adenomas
Treatment strategy
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Trans sphenoidal adenomectomy is the treatment of choice
for ACTH secreting adenomas. Surgical remission is successful
in the majority of children, with initial remission rates of 7098% and long term cure of 50-98% in most studies.
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Surgery is usually followed by adrenal insufficiency and patients
require hydrocortisone replacement for a few months. After
normalization of cortisol levels, resumption of normal growth
or even catch up growth can be observed. Generally, final
height is compromised compared to target weight.
ACTH-secreting adenomas
“Clinical Tips”
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The management of pediatrics CD patients after
cure also presents challenges for optimizing
growth, bone health, reproduction and
composition from childhood into and during
adult life.
Pituitary. 2007;10(4):365-71
Growth hormone secreting adenomas
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In childhood, GH-secreting adenomas account for 5-15% of all pituitary
adenomas. In less than 2% of the cases excessive GH secretion may depend
on a hypothalamic or ectopic GH releasing hormone (GHRH) - producing
tumor (gangliocytoma, bronchial or pancreatic carcinoid), which causes
somatotroph hyperplasia or a well-defined adenoma.
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Chronic GH hyper secretion is characterized by local bone overgrowth, while
in children and adolescents it leads to gigantism because of the associated
secondary hypogonadism which delays epiphyseal closure, thus allowing
continued bone growth.
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All growth parameters are affected although not necessarily symmetrically,
mild to moderate obesity occurs frequently, and macrocephaly has been
reported.
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In girls, menstrual irregularity can be present while glucose intolerance and
diabetes mellitus are rare.
Growth hormone secreting adenomas
Diagnosis
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The diagnosis is usually clinical, and can be readily confirmed by measuring
GH levels, which in more than 90% of patients are above 10 mg/l. The
OGTT is the simplest and most specific dynamic test for both the diagnosis
and the evaluation of the optimal control of GH excess. IGF1 values should
be referred to pubertal stage.
Treatment strategy
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The objectives of treatment of GH excess are tumor removal with
resolution of its eventual mass effect, restoration of normal basal and
stimulated GH secretion, relief of symptoms directly caused by GH
secretion, relief of symptoms directly caused by GH excess and prevention
of progressive disfigurement, bone expansion, osteoarthritis and
cardiomyopathy which are disabling long-term consequences, as well as
prevention of hypertension, insulin resistance, lipid abnormalities that are risk
factors for vascular damage.
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Surgery, radiotherapy and pharmacological suppression of GH levels are
the currently available treatment options
Growth hormone secreting adenomas
Treatment strategy
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Transphenoidal adenomectomy remains the first treatment for GHsecreting tumors. Currently, cure criteria are serum GH levels below 2.5 mg/l,
glucose suppressed GH levels below 1 mg/l together with age-normalized
IGF-1 levels.
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Treatment with somatostatin analogs is very effective in patients with GH
hypersecretion, although few data in adolescent patients have been reported.
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Promising new therapeutic agents have recently emerged in the form of
competitive GHRH and GH antagonists which have been shown to
effectively suppress GH and/or IGF-1 levels.
TSH-secreting adenomas
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This tumor type is rare in very rare in childhood and adolescence with
only a few cases reported so far. It is frequently a macroadenoma presenting
with mass effect symptoms such as headache, visual disturbances, together
with variable signs and symptoms of hyperthyroidism.
It must be differentiated from the syndrome of thyroid hormone resistance .
Treatment strategy
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TSS is the first treatment approach to these tumors. In adults, radiotherapy is
recommended as routine adjunctive therapy. However, due to high frequency
of post-radiotherapy hypopituitarism, in children pharmacotherapy is the
preferred second choice.
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Chronic treatment with SR-lanreotide reduced plasma TSH and normalized
fT4 and fT3 levels, suggesting its use in the long-term medical treatment of
these adenomas
Nonfunctioning adenomas
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FSH and LH-secreting tumors with a clinical picture of hormone
hypersecretion are very rare. The majority of FSH/LH-producing adenomas
are clinically asymptomatic. In pediatric patients they represent account
for less than 4-6% of cases.
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The clinical presentation included visual field defects, headache and some
degree of pituitary insufficiency since invariably all patients had
macroadenoma.
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In the pediatric population, these adenomas need to be differentiated from
other sellar/parasellar masses such as cysts, craniopharyngioma and
dysgerminoma.
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Therefore, the MRI of the sella and parasellar structure is the basic step in the
diagnosis.
Nonfunctioning adenomas
Treatment strategy
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The first approach to these adenomas is trans sphenoidal surgery (TSS) to
remove tumor mass and decompress parasellar structures.
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After surgery, these patients partially recover from hypopituitarism.
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Postoperative radiotherapy is applied in patients with subtotal tumor
removal to prevent tumor regrowth and reduce residual tumors, but is
burdened by high prevalence of panhypopituitarism.
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Positive effects of cabergoline were observed in some patients with a
subunit secreting adenomas, mostly in patients with tumor expressing high
number of dopamine D2 receptors.
Craniopharyngiomas
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Craniopharyngiomas comprise the majority (80 to 90%) of neoplasms
found in the pituitary fossa of children: up to 15% of all intracranial tumors
in childhood are craniopharyngiomas.
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These tumors have a bimodal age-specific incidence: they occur most
frequently at age 5 to 14 years and rarely in the fifth decade of life.
Incidence does not vary with gender or race.
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Most craniopharyngiomas (70% of the total) give symptoms they are
extended in both the intrasellar and suprasellar regions; 30% of the tumors
may be either intra- or suprasellar in location.
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Craniopharyngiomas typically present with endocrine dysfunction,
decreased vision, and an intense headache or other symptoms related to
increased intracranial pressure.
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By histology, these tumors are benign; however, craniopharyngiomas can
behave aggressively through papillae that invade surrounding bony structures
and tissues. In addition, they can have cystic components that may enlarge
and compress adjacent structures.
Case report 1
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G.L. female patient was born on
26/9/74
Menarche at 13 years with regular
menses until May 1994, since then
amenorrhea, six months after treated
with estro-progestogens.
November '95: persists amenorrhea and
galactorrhea is reported that both
spontaneous and provoked is
hospitalized: PRL: 186 ng/ml. Perform
brain MRI pituitary: “…extensive
process to expansive character with
prevailing intra-and suprasellar
location, roughly oval, with diameter.
max of about 17 x18x15, that appears to
occupy the spaces aditus sellae, but with
expanded storage of the profile of
dorsun sellae and extends to occupy the
upper reservoir space Ferner and
characterized extensively the optic
chiasm, located up ... do not recognize,
in relation to ' extension of the
expansion process, the pituitary stalk…”
Case report 1
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February ‘96: Begin therapy with 10 mg/day of
bromocriptine. Perform ophthalmologic
examination and campimetric, results were
normal.
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April ’96: PRL: 101-105 ng/ml
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December ’96: PRL: 120-122 ng/ml
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August '97: resumption of menses with
oligomenorrhea
Case report 1
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June '97: MRI brain-pituitary "gland
morphofunctional alteration
with presence in the right half of the
hypointense area of basic weights and
which becomes, after contrast medium,
even more markedly hypointense with
respect to the remaining gland ... This
lesion (significantly reduced volume than
'95) leads to a slight imprint on the sellar floor
and the tank overflows cranially sovrasellare
right and may be attributable to regression to
the area of necrosis of the previous
macroadenoma. There is a modest shift of the
pituitary stalk to the left and a portion of the
lesion, which manifests itself above the carotid
siphon signal that has typical adenomatous
tissue. Not invasion of cavernous sinuses”.
Case report 1
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January 98: PRL: 83 ng/ml. Stopped bromocriptine and started
cabergoline 1.5 mg/w.
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October 99: MRI brain pituitary "gland volume in the standard. Persistence
of areola mildly hypointense on T1 on the right for possible persistence of
residual adenomatous and/or residue regressive“.
Case report 1
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December ’99: PRL: 17,4 ng/ml
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March 2001: PRL: 17,3
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July 2000: PRL: 21,3
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Maj 2001: PRL: 19,6
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Gennuary 2002: PRL: 17,3
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February 2003: PRL: 13,3
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October 2003: PRL: 28,4
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March 2005: PRL: 8-8,5-8,9
Case report 1
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October 2005: MRI brain-pituitary: "... gland volume in
the physiological range, with only a minimal persistence of
altered signal areola, subtle hypointense ...
Case report 1
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December 2006: PRL: 12,2
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December 2007: PRL: 9,3
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December 2008: PRL: 4,4
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July 2010: PRL: 3,1 ng/ml.
Echocardiography were normal. Continued
cabergoline therapy.
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Pituitary MRI: Sellar normal volume.
Case report 2
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M.G. female patient was born on 03/04/1996, Target 157 cm, birth weight
3.050 kg, the age of 4 years early isolated pubarche.
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Due to a marked increase in weight (+ 10 kg), was referral for clinical
evaluation.
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October 2004: H 128.7 cm (51 centile), weight 45 kg, BMI: 27.1. Facio-truncal.
Obesity. Achantosis nigricans in the neck and roots of the limbs.
PH3/B1 pubertal stage.
ACTH at 8: 19 pg/ml, at 20: 7.6, Cortisol at 8: 24 mcg/dl, at 20: 13, after
over night suppression test with dex: 2.8, after simple suppression test : 2.7,
CLU: 400 mcg/24 h (88-359). 17OHP basal and after Synacthen, total and free
testosterone, LH, FSH, E2, thyroid hormones, pelvic ultrasound: normal for
age. IRI after OGTT in 60 'peak of 345.6 mcU / ml.
Rx left hand and wrist: bone age equivalent to 8 years.
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January 2005: ACTH at 8: 32, 20:34, cortisol 8: 23,4, 20: 37, CLU: 549 ,
cortisol after over night suppression test: 17,24 mcg/dl
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CT adrenal glands: normal
Case report 2
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January 2005: MRI pituitary: "... no images certanly to refer to
adenoma".
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February 2005: cortisol: 8: 33,5, CLU: 285-335 -484
CRF Test: ACTH: 30-113-95-60-39-32, cortisol: 35,8-44,2-47,4-56,2-48,437,8. Dex test, Cortisol: 4,5, dex 4 days cortisol: 1,8.

February 2005: MRI pituitary (Niguarda): "... the adenohypophysis has a
concave profile, the pituitary stalk median ... after MDC welcomes small
and heterogeneous hypointensity of the right half of the gland, not surely
due to pituitary adenoma.
CT thorax: normal.

March 2005: TNS surgery. Immunohistochemistry: ACTH positive, some
cells positive for GH, PRL negative proliferative index (KI67/MIB-1)
<1%. Start therapy Cortone acetate at a dose of 25 mg ½ + ¼ + ¼
H 128.3 cm, weight 45 kg, circumference 79 cm away. PH4/B2 pubertal
stage.
Case report 2
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April 2005: H 130.9 cm, 42.8 kg, LH, FSH, E2, PRL, TSH: normal. IGF1:
345.
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June 2005: stop taking cortone. H 134.5 cm (55th percentile), kg 40.800, BMI
22.6, waist circumference 70 cm, vc: 10.9 cm/year.
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October 2005: CLU: 36 nmol/L, ACTH: 13 Cortisol: 12,5
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February 2006: H 137.7 cm, kg 41.800, waist 71cm, FT4, TSH, PRL
normal, ACTH at 8: 13, Cortisol 8: 9,46, CLU: 66, bone age 10.5 years.

March 2006: MRI brain-pituitary: "... regular morphology saddled with
reduced expression of pituitary asymmetrical right half of the gland with
asymmetric depth of the tank-type configuration with sovrasellar
aracnoidocele. Pituitary stalk in line…”
Case report 2
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March 2006: MRI brain-pituitary
Case report 2
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July 2006: H 140.8 cm (69th percentile), 44.600 kg, BMI: 22.5, waist
circumference 71 cm, PH4/B3, vc: 7.5 cm/year. Menarche.
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November 2006: H 143.3 cm (71th percentile), kg 51.700, BMI: 25.2, waist
circumference 74 cm, vc: 6.6 cm/year PH5/B4. ACTH: 6.8, Cortisol: 15,
CLU: 67, oligomenorrhea
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January 2008: H 148.1 cm (46th percentile), kg 57.700, BMI: 26.3, waist
circumference 75 cm, vc: 3.1 cm/year. Eumenorrea/oligomenorrhea. IGF1,
LH, FSH, E2, TSH normal. ACTH at 8: 30 pg/ml, at 20: 34. Cortisol, 8: 5.7
ug/dl (1-39), 20: 4.9 (3-18), fasting IRI: 13 nU/ml,
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July 2009: H 148.8 cm (5th centile), kg 58.800, BMI 26.6, waist circumference
67.5 cm. Hirsutism from about 6 months, IFG: 13. Complained of
aheadache. ACTH 8: 28, cortisol 8: 14.2, cortisol after over night
suppression test: 6.1, LH, FSH, E2, PRL, total testosterone, free testosterone,
DHEAS: normal, androstenedione: 3.1 ng/ml (0.3 to 3).
Case report 2
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August 2009: MRI Brain-pituitary: “…
Recurrent microadenoma the left half
of the pituitary gland…”
Case report 2
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January 2010: H 148.8 cm, kg 51.200, waist circumference 62 cm, ACTH 8:
64 pg/ml, 20: 73.2, Cortisol at 8: 10.67 ug/dl, 20: 13.6, CLU: 340,2
nmol/24h (38-208), cortisol after over night suppression test: 8.28

March 2010: MRI Brain-pituitary ... marked reduction in thickness with a
small focal area of signal CSF dependent adenoipophysis right half as a result
of surgery, the left half of the gland is appreciated with a profile along the
top and also the dynamic study with contrast medium allows detection of
hypointense parenchymal inhomogeneity of 0.5 cm… pituitary
microadenoma. Small deviation to the right side of the pituitary stalk ...
Case report 2
March 2010: Brain-pituitary MRI
Case report 2

April 2010: TNS endoscopic surgery: removal of diseased tissue, white, soft
laterosellare sn, pituitary gland observed. Immunohistochemistry: fragments
of parenchyma pituitary FSH + LH + + GH, PRL + ACTH +, Ki67 (MIBI):
<1%.

May 2010: CLU: 434 mcg/24 h (28-213), ACTH: 25.3, cortisol: 8: 34, 20:
16.

May 2010: TNS surgery by removal of some small fragments of pituitary
parenchyma and fibrous tissue. Immunohistochemistry: fragments of
parenchyma pituitary FSH + LH + + GH, PRL + ACTH +

July 2010: CLU: 876.5, ACTH: 49.2, cortisol 8: 22, 20: 35.
What therapy?
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First-line treatment for Cushing disease in childhood is always surgical;
transsphenoidal adenomectomy or hemihypophysectomy in situations
where the surgical exploration is negative has been shown to be nearly 90%
curative.
Radiation or gamma-knife therapy is reserved for these patients in whom
surgical intervention failed.
Bilateral adrenalectomy may be considered for inoperable or recurrent
cases; however it is associated with a significant risk of development of
Nelson's syndrome.
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What is Pasireotide (SOM230) ?
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