Pituicytoma and Cushing’s Disease in a
7-Year-Old Girl: A Mere Coincidence?
Paola Cambiaso, MDa, Donato Amodio, MDb, Emidio Procaccini, MDc, Daniela Longo, MDd, Stefania Galassi, MDd,
Francesca Diomedi Camassei, MD, PhDe, Marco Cappa, MDa
abstract
a
Endocrinology and Diabetology Unit, University
Department of Pediatrics, bImmune and Infectious Diseases
Unit, University Department of Pediatrics, University of Rome
Tor Vergata, cNeurosurgery Unit, Department of
Neuroscience, dNeuroradiology Unit, Department of Imaging,
and ePathology Unit, Department of Laboratories, Bambino
Gesù Children’s Hospital, IRCCS, Rome, Italy
Drs Cambiaso and Amodio took care of patient and
drafted the initial manuscript; Dr Procaccini took
care of patient, and critically reviewed the
manuscript; Drs Longo, Galassi, and Diomedi
Camassei critically reviewed the manuscript; Dr
Cappa reviewed and revised the manuscript; and all
authors approved the final manuscript as
submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2015-0638
DOI: 10.1542/peds.2015-0638
Accepted for publication Aug 24, 2015
Address correspondence to Donato Amodio, Immune
and Infectious Diseases Unit, University Department
of Pediatrics, University of Rome Tor Vergata,
Bambino Gesù Children’s Hospital, IRCCS, Piazza
Sant’Onofrio, 4 00165 Rome, Italy. E-mail: don.
[email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright © 2015 by the American Academy of
Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated
they have no financial relationships relevant to this
article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have
indicated they have no potential conflicts of interest
to disclose.
CASE REPORT
Pituicytoma is a tumor extremely rare in childhood, with only 4 cases reported
in literature. It is thought to arise from the specialized glial elements called
“pituicytes.” The association of pituicytoma and Cushing’s disease (CD) has been
described only once so far, in an adult patient. A 7-year-old girl was referred
for clinical signs of hypercortisolism, and a diagnosis of CD was made. MRI
revealed 2 pathologic areas in the pituitary gland. The patient underwent
surgery, with microscopic transsphenoidal approach, and a well-circumscribed
area of pathologic tissue was identified and removed. Surprisingly, histologic
and immunohistochemical study provided unequivocal evidence of pituicytoma.
No pituitary adenoma could be identified. For persistent hypercortisolism, the
patient necessitated transsphenoidal endoscopic reintervention and 2 other
lesions were removed. By immunohistological examination, these lesions were
confirmed to be corticotropin-secreting adenoma. Unfortunately, there was no
postoperative decrease in corticotropin and cortisol levels, and the patient
underwent bilateral laparoscopic adrenalectomy. Considering that we report
a second case of association of pituicytoma and corticotropin-secreting
adenoma, that CD is infrequent, and pituicytoma is extremely rare in childhood,
the coexistence of these 2 tumors should not be considered a mere coincidence.
To date, there is no conclusive evidence about the origin of these different
subtypes of pituitary tumors. This case supports the hypothesis that these
tumors share a common progenitor cell, which could be the folliculostellate cell.
To better delineate neoplasm
manifesting in the neurohypophysis
and pituitary stalk, the World Health
Organization, in 2007, proposed to add
a new entity, the pituicytoma, to the
international classification of human
tumors. This extremely rare neoplasm
is thought to arise from the specialized
glial elements called “pituicytes.”
According to the current World Health
Organization classification of central
nervous system tumors, pituicytoma is
considered a rare, low grade, glial
neoplasm of adults with low
proliferative potential and possibility
of cure after surgical resection alone.1
Histologically, it is composed of solid
sheets of elongate bipolar spindle cells
arranged in fascicles or with storiform
pattern. Pituicytomas usually express
vimentin and S100 protein, whereas
the expression of glial fibrillary
acidic protein (GFAP) is variable.
Clinical signs and symptoms are
related to mass effect, with
compression of the optic chiasm and
pituitary gland, and consequent
headache, visual disturbance, and
hypopituitarism. To our knowledge,
a total of 75 cases of pituicytoma
have been reported and, among
them, only 1 occurred in association
with Cushing’s disease (CD) 2 and 2
with not clearly defined
hypercortisolism. 3,4 Only 4 pediatric
patients 5 with pituicytoma have
been described so far. We report the
first case of a 7-year-old girl with
pituicytoma in association with
corticotropin secreting adenoma.
PEDIATRICS Volume 136, number 6, December 2015
CASE REPORT
A 7-year-old girl was referred to our
department for precocious pubarche,
reduced growth velocity, increasing
weight gain, and progressive
muscular weakness. On clinical
examination, she showed moon face,
central obesity, and generalized
hypertrichosis. Her height was 108.7
cm (22.6 SD), her weight 25.8 kg (0.9
SD), with a BMI of 21.89 (2.5 SD). The
resting blood pressure was 90/60
mm Hg. Midnight serum cortisol and
corticotropin levels were elevated,
respectively, 24.26 mg/dL (669.28
nmol/L) and 33.7 pg/mL (7.41 pmol/L),
as well as urinary free cortisol
(897.6 mg/24 hours). Overnight 1-mg
and low-dose dexamethasone
suppression test (30 µg/kg per day
for 2 days) were unable to suppress
serum cortisol. Three Tesla MRI (MRI
3T) of the pituitary gland, before and
after intravenous gadolinium
administration, revealed an enlarged
pituitary gland associated to a bulged
and convex profile of the diaphragma
sellae and a shortened pituitary stalk.
A small hyperintense (T2-weighted
images) area on the mesial and upper
portion of the gland and a small
hypointense (T1-VIBE dynamic
study) area in its median and
paramedian left side were also
detected (Fig 1 A, B, C, and D). The
patient underwent bilateral inferior
petrosal sinus blood sampling, before
and after corticotropin-releasing
hormone administration. The central/
peripheral plasma corticotropin
gradient after corticotropin-releasing
hormone (1.53) was not diagnostic,
and intersinus gradient (1.04) was
suggestive of a midline lesion. At
surgery (microscopic transsphenoidal
approach), after dural opening and
careful inspection of the gland, no
frank adenoma was found; a wellcircumscribed area of pathologic
tissue on the left side of the pituitary
was identified anyway and removed.
Histologically, the pathologic tissue
revealed a compact architecture
consisting of elongate spindle cells
arranged in a storiform pattern;
immunohistochemical staining of the
tumor demonstrated strong positivity
for vimentin and S-100 protein; some
cells were positive for GFAP.
Chromogranin A stained adjacent
normal pituitary gland cells, but not
pituicytoma cells. Epithelial
membrane antigen and
synaptophysin were negative too
(synaptophysin highlighted residual
neurohypophysis parenchyma). No
cytoplasmic granularity or
vacuolization were found, and only
rare mitotic figures were identified
(MIB-1 labeling index ,1%; Fig 2).
These findings provided unequivocal
FIGURE 1
A–D, Presurgical MRI study. A, T2-weighted image coronal plane reveals an enlarged gland with convex superior border and focal hyperintensity area in
the median/superior surface (red arrows). B and C, T1-weighted coronal plane, before and after gadolinium, confirms gland enlargement with
homogeneous glandular enhancement. D, T1 VIBE dynamic study reveals focal hypointense area in the median/paramedian left side of the pituitary gland
(red arrow). E–H, Postsurgical MRI study. E, T2-weighted image coronal plane reveals marked reduction of gland size with persistent hyperintense area in
its median region. F and G, T1-weighted before and after gadolinium coronal plane reveal homogeneous glandular enhancement. H, T1 VIBE image after
gadolinium reveals a spot slightly hypointense in the median/paramedian left side of pituitary gland referable to microadenoma (red arrow).
PEDIATRICS Volume 136, number 6, December 2015
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FIGURE 2
A, Mild proliferation of spindle cells with abundant cytoplasm and uniform nuclei. A fascicular pattern of growth is evident. B, Focal GFAP-positivity
indicating the glial nature of proliferating cells. C, Very low proliferative index (anti-MIB-1 immunostain). D and G, Strong positivity for vimentin and S-100
protein. E, Chromogranin A stained adjacent normal pituitary gland cells, but not pituicytoma cells. F and H, Epithelial membrane antigen and
synaptophysin were negative.
evidence of pituicytoma. No pituitary
adenoma could be identified. The
postoperative corticotropin and
cortisol levels did not return to the
normal range, and a second MRI-3T
with dynamic study was performed.
The study revealed a reduction in the
size of adenohypophysis,
a hyperintense area in the region of
the removed pituicytoma in T2weighted images (considered
a consequence of surgery), and the
persistence of the smaller
hypointense area previously
described (Fig 1 E, F, G, and H). Even
if the absence of a significant central/
peripheral plasma ratio does not
necessarily imply ectopic secretion of
corticotropin,6 positron emission
tomography was preoperatively
performed for additional exclusion of
ectopic corticotropin source, without
any identification of neoplastic areas.
During the following endoscopic
reintervention, pathologic whitish
tissue, localized in the context of the
e1634
median/paramedian left side of the
pituitary gland, was found and
removed, together with an additional
pathologic area in the context of the
paramedian right side of the pituitary
gland. Histologic examination
revealed a solid cellular proliferation
composed by biphasic population:
groups large cells with abundant
cytoplasm containing basophilic
secretory granules positive for
corticotropin and sheets of mediumsized cells containing eosinophilic
granules, positive for growth
hormone (not shown). Few cells were
positive for prolactin. Thyrotropin,
luteinizing hormone, and folliclestimulating hormone resulted
negative. As mild nuclear atypia and
low proliferative index (0% to 1%)
FIGURE 3
A, Solid cellular proliferation composed by groups large cells with abundant cytoplasm and sheets
of medium-sized cells containing eosinophilic granules. B, Basophilic secretory granules positive for
corticotropin.
CAMBIASO et al
were observed, a grade I pituitary
adenoma diagnosis was formulated
(Fig 3 A and B). Unfortunately, there
was no postoperative decrease in
corticotropin and cortisol levels.
Considering the young age of the patient
and the available therapeutic options,
bilateral laparoscopic adrenalectomy
was performed. The histologic
examination revealed a diffuse
adrenocortical hyperplasia secondary to
excessive corticotropin production.
DISCUSSION
Pituicytoma is a rare neoplasm of the
sellar and suprasellar region, arising
from the pituicytes of the
neurohypophysis or the
infundibulum.1 To date,
approximatively only 75 cases have
been reported.3,7 The most frequent
symptoms of pituicytoma are visual
impairment and headache. Patients
can also present endocrine
disturbances, such as
hyperprolactinemia,
hypogonadotropic hypogonadism, or
hypopituitarism. In just a few
patients, pituicytoma was incidentally
discovered.8 Uncommon in adults, it
is extremely rare in childhood, with
just 4 cases described so far, in
children of age between 7 and 17
years.3,5 All these children presented
with visual impairment and headache,
whereas short stature, as a possible
sign of endocrine disturbance, was
reported only in 1.5
It is well known that pituicytoma is not
a secreting tumor and that the
endocrine symptoms, related to its
presence, are due to the loss of
pituitary function, caused by mass
effect, rather than to pituitary
hyperfunction. However, slightly
elevated serum corticotropin levels
were found in 1 patient,4 and
symptomatic corticotropin
hypersecretion, resolved by removing
a pituicytoma, has been recently
described in another 24-year-old man.3
Differently from these cases, in our
patient there was a coexistence of
PEDIATRICS Volume 136, number 6, December 2015
asymptomatic pituicytoma and
corticotropin-secreting adenoma. The
former should be considered
incidentally discovered, because the
girl manifested only symptoms of CD
obviously persisting after the surgical
removal of the pituicytoma. The same
tumor association has been recently
reported, for the first time, in an adult
man. As in our case, the pituicytoma
was asymptomatic and incidentally
detected during operation for CD.2
The authors wondered whether an
association between pituicytomas
and endocrine tumors actually exists
or whether, in their case, it was
coincidental. Considering that we
report a second case of this
association, that CD is infrequent, and
pituicytoma is extremely rare in
childhood, the coexistence of these 2
tumors should not be considered
a mere coincidence.
It is generally considered that
pituicytomas are primary tumors of
the neurohypophysis, presumably
arising from the pituicytes. Pituicytes
are GFAP immunoreactive spindle or
stellate cells that are believed to
regulate neurohypophysial hormone
secretion. However, ultrastructural
findings from a single case, revealing
transitional features between
a pituicytoma and a pituitary
adenoma, suggested, for the first time,
its possible origin from
adenohypophysis folliculostellate
cells (FSCs).9 FSCs are S-100immunoreactive spindle to stellateshaped cells that are believed to
regulate the activity of anterior
pituitary endocrine cells through the
production of cytokines and growth
factors. In the normal pituitary gland,
FSCs are concentrated near the center
of adenohypophyseal lobules and are
the only cells expressing bcl-2, an
oncoprotein that inhibits apoptosis
and plays a role in the progression of
various tumor types. Moreover, some
cases of pituicytomas revealing focal
expression of bcl-2 have been
reported.10,11 Ulm et al10 speculate
that, if a potential for multilineage
differentiation can be definitively
demonstrated for FSCs, neoplastic
transformation of such a cell might
lead to different subtypes of pituitary
tumors, including adenomas, spindle
cell oncocytomas (SCOs), and even
pituicytomas. More recently, other
findings consistent with the idea of
a common histogenesis for
pituicytomas and SCOs have been
reported,7 and SCOs are usually
considered as derived from FSCs.
To date, there is no conclusive
evidence about the origin of these
different subtypes of pituitary
tumors. We think that this case can
contribute to the debate on the origin
of pituicytoma. The association of
corticotropin-secreting adenoma and
the pituicytoma in both our case
and the case in Schmalisch et al,2
supports the hypothesis that these
tumors share a common progenitor
cell, which could be FSC.
ABBREVIATIONS
CD: Cushing’s disease
FSC: folliculostellate cell
GFAP: glial fibrillary acidic protein
SCO: spindle cell oncocytoma
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