The

n e w e ng l a n d j o u r na l

of

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case records of the massachusetts general hospital

Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor
Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor
Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor
Christine C. Peters, Assistant Editor

Case 37-2008: A 17-Year-Old Boy with

a Pituitary Tumor and Skull Abnormalities
Edward R. Smith, M.D., Jay Loeffler, M.D., Madhusmita Misra, M.D.,
Stuart R. Pomerantz, M.D., Anat Stemmer-Rachamimov, M.D.,
and Miriam D. Post, M.D.

Pr e sen tat ion of C a se

A 17-year-old boy was seen at this hospital because of a pituitary tumor and radiologic evidence of bony abnormalities in the skull. The patient was well until approximately 12 years of age, when headaches developed. The pain ranged from
dull to stabbing (up to 8 on a scale of 1 to 10, with 10 indicating the most severe
pain), was located primarily in the left frontal region (medial and posterior to his left
eye), and occurred one to two times per month, with no precipitating factors. Nausea, without vomiting, occurred occasionally in the morning. His peripheral vision
and visual acuity decreased, and his performance at school declined. Approximately 2 years before this evaluation, his growth stopped; his parents noted mood
changes and angry outbursts, and he was referred to a psychiatrist. Buspirone was
administered. During the next 18 months, the frequency increased to one or two
headaches per week, with fatigue, occasional somnolence, cold intolerance, darkening of the skin over his elbows and neck, and occasional epistaxis. There was no
constipation, dry skin, or hair loss. During the 3 years before this evaluation, he
gained 13.6 kg in weight, and stretch marks developed on his abdomen.
Approximately 3 months before this evaluation, the headaches became consistently stabbing and increased in severity; the patient rated the pain as 10. Computed
tomography (CT) of the sinuses, performed without the administration of contrast
material at another hospital, revealed normal sinuses but a moth-eaten appearance
of the skull base and clivus, with destruction of cortical bone. Magnetic resonance
imaging (MRI) of the head with the administration of gadolinium revealed an expansile, cystic-appearing lesion, 2 cm in diameter, in the sellar and suprasellar region, which compressed the optic chiasm, and a solid mass, with mixed signal intensity and heterogeneous enhancement, that involved the entire clivus, extended
into the petrous bones, indented the midpons, and expanded into the right cerebellomedullary angle.
Ten weeks before the current evaluation, the patient saw a neurosurgeon at another hospital. On examination, there was a mild right sixth-nerve palsy; bitemporal
hemianopia; positive Hoffmanns sign (in which sudden flexion of the third finger
by flicking the nail induces extension of the distal interphalangeal joint of that finger and flexion of the thumb) on the right side; striae on the shoulders, axillae, and

From the Department of Neurosurgery,

Childrens Hospital of Boston (E.R.S.);
the Departments of Radiation Oncology
(J.L.), Pediatrics (M.M.), Radiology (S.R.P.),
and Pathology (A.S-R., M.D.P.), Massachusetts General Hospital; and the Departments of Surgery (E.R.S.), Radiation
Oncology (J.L.), Pediatrics (M.M.), Radiology (S.R.P.), and Pathology (A.S.-R.,
M.D.P.), Harvard Medical School.
N Engl J Med 2008;359:2367-77.
Copyright 2008 Massachusetts Medical Society.

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waist; and an area of hyperpigmentation on the

right shoulder. There was no facial or chest hair,
and the patient was at Tanner stage 4 for puberty.
Results of laboratory tests are shown in Table 1.
Ophthalmologic examination showed noncongruous bitemporal hemianopia, with complete
temporal hemianopia on the right side and a less
severe left temporal visual-field defect. Visual acuity was 20/50 in both eyes, correcting to 20/30 in
the right and 20/25 in the left. On endocrinologic
evaluation, the patient reported that pubic hair,
adult body odor, and acne had developed at the age
of 13 years. The weight was 82.4 kg, the height
168 cm, and the body-mass index (the weight in
kilograms divided by the square of the height in
meters) 29.2; the vital signs were normal. There
was mild facial acne and acanthosis nigricans of
the neck and axillae. A grade 2/6 systolic ejection
murmur was present at the left sternal border,
and the liver edge was palpated at 5 to 6 cm; the
remainder of the examination was normal. Neuropsychological evaluation revealed high-average
overall abilities, some difficulties with short-term
memory, and more developed nonverbal than verbal skills. Test results are shown in Table 1. Treatment with levothyroxine was begun.
The patient was admitted to the other hospital. Laboratory-test results are shown in Table 1.
The sellar component of the mass was resected
through a transsphenoidal approach, with biopsy
of the clivus. Pathological examination revealed a
prolactin-secreting pituitary adenoma. Two days
after the operation, MRI of the brain and spine
with gadolinium revealed decompression and resection of the cystic hemorrhagic component in
the sellar region. The patient was discharged on
the fourth hospital day; medications included ca
bergoline, dexamethasone, levothyroxine, buspi
rone, and ranitidine.
Two weeks after the operation, the patient reported improvement in his vision and infrequent
mild, dull headaches. Visual acuity was 20/25 in
both eyes, and the visual fields were normal. Results of laboratory tests performed 3 weeks postoperatively are shown in Table 1. Positron-emission tomography (PET) of the whole body and
head, with 18F fluorodeoxyglucose (18F-FDG) as a
tracer, revealed variable but generally low 18F-FDG
avidity of the residual mass and no evidence of
disease elsewhere. A lumbar puncture was normal.
Four weeks postoperatively, the patient was
seen in the pediatric endocrinology and radiation2368

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oncology clinics of this hospital, for consideration

of proton-beam irradiation to the bone lesion. His
energy level had improved, and the headaches had
diminished in frequency and severity. The patient
had been adopted at the age of 5 months. Early
development had been normal. He lived with his
adoptive parents. A junior in high school, he was
a good student and active in sports. No history
of the health of his biologic family was available.
The vital signs were normal, and the findings
on physical examination were unchanged and
consistent with pubertal development at Tanner
stage 4. Results of laboratory tests are shown in
Table 1. The dose of cabergoline was increased to
0.5 mg twice weekly. Repeated MRI of the brain
with the administration of gadolinium again revealed a large, heterogeneously enhancing mass
centered in the clivus, with extension into the petrous bones, effacement of the prepontine cistern
with indenting of the pons, and narrowing of the
right cerebellomedullary angle.
A diagnostic procedure was performed.

Differ en t i a l Di agnosis
Dr. Edward R. Smith: This 17-year-old boy presented
with headache, progressive vision loss, mood
changes, worsening academic performance, fatigue, cold intolerance, and weight gain.
Examination disclosed bitemporal hemianopia;
decreased visual acuity; a positive Hoffmanns sign
on the right side; normal strength, sensation, and
other reflexes; striae on the trunk; an absence of
chest and facial hair; and mild obesity. Although
I saw the patient for the first time after the radiographic studies had been performed, it is pertinent
to review the findings in his history and physical examination that might indicate the presence
of an intracranial mass lesion.
Findings Suggestive of an Intracranial
Process

The patients problems can be grouped into the

following three categories: headache, visual changes, and symptoms related to endocrine dysfunction. Headaches are common in his age group,
with nearly one third of adolescents reporting
weekly headaches.1 One of the most difficult issues facing pediatricians in the evaluation of children with headache is identifying the approximately 4% of such children who actually have
intracranial lesions. Performing imaging studies

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case records of the massachusetts gener al hospital

Table 1. Results of Laboratory Tests.*

Reference Range,
Adults

Variable

First Hospital
10 Wk
Earlier

Sodium (mmol/liter)

135145

Potassium (mmol/liter)

3.44.8
100108

102

23.031.9

27

Osmolality (mOsm/kg)

280296

293

142
3.3
103
26.7
308

298

299
107

825

12

0.61.5

Calcium (mg/dl)

8.510.5

Prolactin (ng/ml)

0.015.0

675.7

Macroprolactin

Negative

Negative (90.6%,
where >60% is considered negative)

0.405.00

Thyroxine (g/dl)

1.0
9.8

1.84
3.83 (ref 4.612)

Free thyroxine (ng/dl)

1 Day after
Presentation

70110

Creatinine (mg/dl)

Thyrotropin (U/ml)

This Hospital

7 Days
Earlier

4.3

Carbon dioxide (mmol/liter)

Urea nitrogen (mg/dl)

4 Wk
Earlier

144

Chloride (mmol/liter)

Glucose (mg/dl)

Second Hospital
4.5 Wk
Earlier

0.91.8

Thyroglobulin antibody

684

641.6

28.95

1.89

2.52

1.38

3.8

4.6

8.3

0.7

19.8

1.29
1.5

Negative

Thyroglobulin-binding index

1.04
(ref 0.881.08)

Luteinizing hormone (U/liter)

2.012.0 (men)

Follicle-stimulating hormone (U/liter)

1.012.0 (men)

Testosterone (ng/dl)

2701070

Corticotropin (pg/ml)

676

Estradiol (pg/ml)

0.9

0.6

1.3 (ref 1.512.5)

2.1
99

38

129
19

12 (ref 1045 in men)

Human chorionic gonadotropin

Negative

Somatomedin C (IGF-I) (ng/ml)

249

IGF-binding protein 3 (mg/liter)

2.54.8 (1618 yr )

2.5 (ref 2.24.2)

227
2.9

Cortisol (g/dl)
Morning

525 (8 a.m.noon)

12

60 min after stimulation with 250 g

of corticotropin (cosyntropin)

10.2
26.1

* All values are serum or blood levels. IGF-I denotes insulin-like growth factor I, and ref reference range. To convert the values for glucose to
millimoles per liter, multiply by 0.05551. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for calcium to millimoles per liter, multiply by 0.250. To
convert the values for thyroxine to nanomoles per liter, multiply by 12.87. To convert the values for free thyroxine to picomoles per liter,
multiply by 12.87. To convert the values for testosterone to nanomoles per liter, multiply by 0.0347. To convert the values for corticotropin
to picomoles per liter, multiply by 0.2202. To convert the value for estradiol to picomoles per liter, multiply by 3.671. To convert the values
for cortisol to nanomoles per liter, multiply by 27.59.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They
may therefore not be appropriate for all patients.
Reference ranges for somatomedin C (IGF-I) at this hospital are based on the Tanner stage in men (Tanner stage 1, 109 to 485 ng per milliliter; stage 2, 174 to 512 ng per milliliter; stage 3, 230 to 818 ng per milliliter; stage 4, 396 to 776 ng per milliliter; and stage 5, 402 to 839 ng
per milliliter).
For the first hospital, this test was performed at Quest Diagnostics, and for this hospital, it was performed at Esoterix Laboratory Services.

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in all patients with headache is not practical because of cost constraints on resource allocation,
the risk associated with sedation in younger children, and the risk associated with radiation (with
the performance of CT).2 Predictors of a mass lesion include sleep-related headache, vomiting, confusion, focal neurologic abnormalities, the absence
of typical migrainous visual phenomena and of a
family history of migraines, and the presence of
headache for less than 6 months. There is no
family history in this case, since the patient was
adopted. The presence of visual deficits, the absence of features of migraine, and the progressive nature of his symptoms suggest the need for
neuroimaging.
Localization of the Lesion

In this patient, bitemporal hemianopia strongly

suggests involvement of the optic chiasm, where
compression of crossing fibers from nasal retinal
fields can cause this deficit. Decreased acuity suggests long-standing compression of the optic apparatus or injury from increased intracranial
pressure. Fatigue, delayed secondary sexual characteristics, and cold intolerance suggest endocrine
dysfunction. These features direct the clinician to
the sella turcica, with a probable diagnosis of a
slowly enlarging mass involving the pituitary gland
and optic chiasm.
Sellar lesions may cause headache by anatomical deformation of structures with pain receptors
(dura) and global increases in intracranial pressure, as well as effects on the trigeminovascular
system through alterations in dopamine metabolism by hormonally active tumors.3 Although
headache alone is a poor localizing finding, it is
of more concern in the case of this patient with
Hoffmanns sign, which is usually indicative of
compression of corticospinal tracts or upper-
motor-neuron lesions. The chronic progressive
nature of his symptoms and the history of headache, worse in the morning, lead one to suspect
a large, slow-growing lesion, associated with increased intracranial pressure or compression of
the brain stem or cervicomedullary junction. May
we review the imaging studies?
Dr. Stuart R. Pomerantz: CT of the paranasal sinus shows an extensive destructive process of the
basisphenoidal and basioccipital portions of the
skull base, with diffuse expansion and destruction of cortical bone but no frank pattern of osteoid or chondroid matrix (Fig. 1A).
MRI of the skull base reveals two distinct com2370

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Figure 1 (facing page). CT and MRI Studies of the

Skull Base.
A CT scan of the paranasal sinus shows an extensive
destructive process of the basisphenoid (Panel A, arrow). There is a diffusely expanded and moth-eaten appearance of the osseous structures, including destruction of cortical bone, but no frank pattern of osteoid or
chondroid matrix is evident. MRI of the skull base reveals two distinct components of the lesion. An axial
T1-weighted image (Panel B) shows that in the sellar
and suprasellar regions, there is a hyperintense, cysticappearing expansile mass, approximately 2 cm in diameter (arrow), with bright and dark fluid levels on T2 weighted sequences (Panel C, arrow), findings that are
suggestive of hemorrhagic or proteinaceous material.
Smaller multicystic changes are seen in the adjacent
osseous component (arrowhead). A coronal T1-weighted image reveals a suprasellar extension compressing
the optic chiasm, more on the left (Panel D, arrow),
and invasion of the cavernous sinuses, more on the
right (arrowhead). A sagittal T1-weighted image obtained after the administration of contrast material
(Panel E) reveals a larger osseous mass that is solidappearing, with mixed signal intensity and heterogeneous gadolinium enhancement extending from the
sellar floor to the foramen magnum, with mass effect
on the ventral aspect of the pons (arrow). An axial T1weighted image obtained after the administration of
contrast material reveals extension into the right petrous bone (Panel F, arrow) and partial effacement of
the cistern of the right cerebellomedullary angle (arrowhead).

ponents. In the sellar and suprasellar region, there

is a cystic-appearing expansile lesion, approximately 2 cm in diameter (Fig. 1B, 1C, and 1D), that
shows hyperintensity on T1- and T2-weighted sequences, with fluid levels suggestive of hemorrhagic or proteinaceous material. There is a suprasellar extension compressing the optic chiasm,
worse on the left, and invasion of the cavernous
sinuses, worse on the right. The larger, osseous
portion of the mass (Fig. 1E and 1F) appears
solid, with mixed signal intensity and heterogeneous gadolinium enhancement, and extends from
the sellar floor to the foramen magnum and into
the petrous bones bilaterally, more extensively
on the right where there is also mastoid involvement. The lesion indents the ventral aspect of the
midpons and partially occupies the cistern of the
right cerebellomedullary angle. The basilar artery
is displaced laterally without frank encasement
or stenosis.
Sellar Lesions

Dr. Smith: The differential diagnosis of lesions in

the region of the sella turcica is extensive (Table 2).

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In this patient, a key finding was an elevated se- these causes do not lead to prolactin levels that
rum prolactin level. Elevated prolactin levels may are above 100
to 2001stng per milliliter, and levels
RETAKE
AUTHOR Smith
ICM
have several causes, includingREGpharmacologic
of
500
ng
per
milliliter
2nd or higher, as seen in this
F FIGURE
1a-f
3rd
agents (particularly neurolepticCASE
drugs),
comprespatient,
are
usually
indicative
of a prolactinoma.
TITLE
Revised
EMail
sion of the infundibulum or pituitary
gland (the Tumor
size
Line
4-C and serum prolactin levels have a diSIZE
Enon
5 Extraordinarily high levels of proARTIST:
mst
H/T correlation.
H/T
stalk effect, whereby compression
of the piturect
FILL
33p9
Combo
itary gland or stalk interferes with the delivery of lactin can occasionally but rarely result in artifactuAUTHOR, PLEASE NOTE:
dopamine from the hypothalamus
tohas
the
pitutestbeen
results
Figure
been
redrawnally
and low
type has
reset. (the hook effect). If high levels
itary), or normal processes (e.g., pregnancy, Please
nurs-check
arecarefully.
suspected, the testing of serial dilutions of the
ing, and nipple stimulation). However,
many of serumISSUE:
will circumvent
this effect. The finding of
11-27-08
JOB: 35922
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Table 2. Differential Diagnosis of Sellar Lesions in Children.

Vascular
Aneurysm (interior cerebral artery, anterior cerebral artery, or basilar)
Cavernous malformation
Carotidcavernous fistula
Infectious or inflammatory
Lymphocytic hypophysitis

of

m e dic i n e

cams razor suggests that an invasive pituitary adenoma or pituitary carcinoma would be most likely.
Other possibilities include craniopharyngioma (10
to 20 times as common as adenomas in this age
group), sarcomas (accounting for 77% of pediatric tumors of the skull base), and chordoma.4,8
Less likely would be primary bone lesions, such
as osteoblastoma or fibrous dysplasia.

Sarcoidosis

Diagnostic and Therapeutic Approach

Langerhans-cell histiocytosis

My leading diagnosis was a prolactinoma, either

invasive or associated with a second, distinct pathologic process. The first line of treatment for prolactinomas is usually pharmacologic, but in this
case, the need for a tissue diagnosis in a patient
with visual-field defects warranted surgical intervention. Surgical indications typically include pituitary apoplexy, cerebrospinal rhinorrhea, adverse
events in association with dopamine-agonist therapy, and visual-field deficits in patients with macroadenomas (particularly cystic tumors) that are
rapidly progressive or do not respond to medical
therapy. I used a transsphenoidal approach to decompress the optic apparatus and obtain tissue
from the lesions of both the sellar region and the
skull base. This approach is not associated with
a high rate of adverse effects, but risks include
cerebrospinal fluid leakage (in 3% of cases), infection, hypopituitarism (in 18 to 87% of cases),
and injury to the internal carotid arteries or cranial nerves.9 Of critical importance is the administration of supplemental (stress dose) corticoste
roids in patients with physiological stressors such
as surgery, in order to avoid hypocortisolism.6,7,10

Granuloma (in association with tuberculosis)

Cysticercosis
Abscess or mucocele
Congenital
Arachnoid cyst
Epidermoid or dermoid
Rathkes cleft cyst
Hypothalamic hamartoma
Encephalocele
Lipoma
Neoplastic
Nonpituitary
Craniopharyngioma (the most common sellar-region tumor in
children)*
Optic or hypothalamic glioma
Germ-cell tumor
Rare in children: metastasis, meningioma, lymphoma, chordoma,
sarcoma, schwannoma
Pituitary
Pituitary adenoma
Functional
Nonfunctional
Pituitary carcinoma
* The information is from Lafferty and Chrousos.4

Dr . Edwa r d R . Smi ths Di agnosis

Prolactinoma, probably invasive; rule out a primary osseous lesion.

a serum prolactin level that is higher than 500 ng

Pathol o gic a l Discussion
per milliliter in the absence of confounding agents
strongly suggests the diagnosis of a prolactino- Dr. Anat Stemmer-Rachamimov: Review of the slides
ma in this case.6,7
from the other hospital disclosed a cellular tumor
with a diffuse growth pattern (Fig. 2A). Tumor cells
Lesions of the Skull Base
display marked nuclear pleomorphism with promComplicating this case is the extensive involve- inent nucleoli, occasional bizarre cells, and mitotic
ment of the skull base with a complex process. The figures (Fig. 2B). The unusual histologic appearbrain-stem compression seen on imaging provides ance led to a broad differential diagnosis and a
an explanation for the upper-motor-neuron find- large panel of immunostains was performed to
ings on examination. The differential diagnosis help establish a diagnosis. Immunostaining for piof lesions of the skull base in this patients age tuitary hormones (Fig. 2C) showed strong, difgroup is shown in Table 3. The principle of Oc- fuse staining for prolactin and focal, weak stain2372

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case records of the massachusetts gener al hospital

ing for human growth hormone. The proliferation

index, assessed with Ki67, was 3%, and immunostaining highlighted rare p53-positive cells.
The presence of occasional cells that were positive for human growth hormone raises the possibility of an acidophilic stem-cell adenoma, a rare
aggressive pituitary adenoma characterized by intracytoplasmic vacuoles, cytokeratin whorls, and
abnormal, giant mitochondria on electron microscopy. Cytokeratin immunostaining did not highlight fibrous bodies in this case, and ultrastructural examination did not reveal abnormal
mitochondria.11 In summary, this is a prolactinsecreting pituitary adenoma with atypical features,
including mitotic activity, prominent nucleoli, and
an elevated proliferation fraction, which have been
associated with aggressive behavior.12,13
Dr. Smith: We concluded that the patient had
an atypical, invasive pituitary adenoma. Pharmacologic therapy of the lesion was begun, and he
was referred to the radiation-oncology clinic to
discuss the possibility of radiotherapy to the bone
lesion.
Dr. Jay Loeffler: The bone lesion was one of the
most extensive tumors seen by our neuroendocrine
group in the past 20 years. The large size of the
residual disease suggests that a substantial amount
of the tumor must be poorly differentiated; otherwise the prolactin level would be considerably
higher (thousands of nanograms per milliliter).
Radiation therapy is now rarely used in the management of prolactin-secreting pituitary adenomas
because of the availability of effective dopamineagonist therapy and is reserved for patients with
resistance to or adverse events in association with
dopamine agonists and those with inoperable disease (e.g., invasion of the cavernous sinus or bones
of the skull base). The invasion of the cranial base
in this patient led us to recommend aggressive
conformal proton therapy.
Proton-therapy planning was performed with
contrast-enhanced MRI and CT. Tumor volume
and critical normal structures were outlined on
the axial MRI study and fused with the CT study.
A plan was developed that used four proton fields
to deliver 54 CGE (cobalt gray equivalents) in 30
fractions over a period of 6 weeks. The final treatment plan and images were presented at our
weekly proton-review conference. Dr. Norbert
Liebsch, who directs the skull-base section of the
Department of Radiation Oncology at this hospital, commented that the expansile bony component with both lytic and blastic components was

Table 3. Differential Diagnosis of Skull-Base Lesions in Children.

Benign
Juvenile nasopharyngeal angiofibromas
Glomus tumors
Mature teratomas
Osteoblastoma or osteoid osteoma
Fibrous dysplasia (risk of malignant degeneration, consider the McCune
Albright syndrome)
Intermediate or non-neoplastic
Invasive pituitary adenoma
Invasive craniopharyngioma
Aneurysmal bone cyst
Langerhans-cell histiocytosis
Infection
Malignant
Sarcoma (Ewings sarcoma, rhabdomyosarcoma, myofibroblastic sarcoma, chondrosarcoma)
Chordoma
Esthesioneuroblastoma
Giant-cell tumor
Pituitary carcinoma (by definition, metastatic)

more suggestive of an indolent primary bone process, such as fibrous dysplasia or osteoblastoma,
than a bone invaded by tumor.
We contacted Dr. Smith, who also had concerns that the extensive bone involvement was not
typical for a pituitary adenoma and for this reason had performed a biopsy of the clivus. We
recommended that a biopsy specimen be obtained
through the retromastoid space, since tissue from
that site would be far enough away from the pituitary that a definitive diagnosis might be made.
Dr. Nancy Lee Harris (Pathology): Dr. McKenna,
would you describe the diagnostic procedure?
Dr. Michael McKenna (Massachusetts Eye and
Ear Infirmary): A decision was made to perform
a biopsy of the mastoid component of the bone
lesion, through a transmastoid approach. Dissection was carried out into the region of the jugular foramen. An abnormal bony mass was encountered. A biopsy specimen was obtained, and a
frozen section was prepared so that we could be
certain that it contained diagnostic tissue.
Dr. Miriam D. Post: The specimen consisted of
fragments of normal, reactive, and neoplastic bone
(Fig. 3A), with sharp demarcation between the
neoplastic and non-neoplastic bone, indicating a
slow-growing process. The tumor was composed

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Figure 2. Transsphenoidal-Biopsy Specimen of the

Mass in the Sella Turcica.
The tumor is cellular, with scattered mitotic figures
RETAKE
1st
AUTHORcellsSmith
andICM
pleomorphic
(Panel A, hematoxylin
and eo2nd
F FIGURE
2a-cshows tumor cells that have
sin).REG
Smear
preparation
3rd
CASE
TITLE
large, irregular nuclei with prominent nucleoli
(Panel
Revised
EMail
Line
4-C show strong,
B, hematoxylin and eosin). Tumor
cells
SIZE
Enon
ARTIST:staining
mst forH/T
H/T
diffuse, positive
prolactin
(Panel C, immu16p6
FILL
Combo
nohistochemical stain for prolactin).
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.

of haphazardly arranged, connected trabeculae of

35922
ISSUE: 11-27-08
bone,JOB:
fibrous
tissue with prominent
capillaries,
and bland-appearing osteoblasts arrayed along the
bone-forming surface (Fig. 3B). These histologic
features, in combination with the radiologic findings of a circumscribed, expansile, heterogeneous
mass, support a diagnosis of osteoblastoma. Care2374

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m e dic i n e

ful reevaluation of the previous biopsy specimen

showed a minute fragment of tissue that most
likely represents a tiny piece of osteoblastoma.
There was, however, insufficient material in the
specimen to have made this diagnosis.
The base of the skull is an unusual site for
osteoblastoma, a rare, benign bone-forming neoplasm that occurs most commonly in the spine.
When osteoblastoma involves the skull, it generally occurs in the mandible and maxilla.14,15 The
histologic differential diagnosis in this case included osteoid osteoma (which is histologically
identical but is characterized by a size of less than
2 cm in diameter), osteosarcoma, and fibrous dysplasia. This patients tumor is well circumscribed,
unlike osteosarcoma, which typically shows infiltrative borders, and does not have malignant
cytologic features. On the basis of the imaging
findings, fibrous dysplasia was the major differential diagnosis, but it is characterized by fibrous
tissue with bland spindle cells and curvilinear
trabeculae of bone, which do not show the osteoblastic rimming seen in this case.16
Treatment of osteoblastoma typically consists
of curettage, although en bloc resection may be
performed if the tumor is large and readily accessible. The prognosis is excellent; however, approximately 20% of tumors recur, generally when
they are curetted out of sites that are difficult to
access surgically.17
Dr. Harris: Dr. Misra, would you discuss the
management of the prolactinoma?
Dr. Madhusmita Misra: This patient had hyperprolactinemia (prolactin level, 675 ng per milliliter) in the macroadenoma range,18 without gynecomastia, galactorrhea, decreased libido, or erectile
dysfunction. He had laboratory evidence of secondary hypothyroidism and hypogonadism and
low insulin-like growth factor I (IGF-I) levels for
his pubertal stage, suggestive of growth hormone
deficiency. Although the tumor stained for both
growth hormone and prolactin, the growth chart
did not show accelerated growth and the IGF-I
level did not suggest a cosecreting adenoma. Even
after adjustment for age and duration of symptoms, there is a higher prevalence of macroadenomas in pubertal boys than in pubertal girls,
which has been attributed to the ease of diagnosis in girls on the basis of menstrual irregularities.
Overall, tumors in boys are larger, more resistant
to medical therapy, and more invasive,19 indicating sex-specific differences in tumor biology.

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case records of the massachusetts gener al hospital

Since prolactin secretion is inhibited by the

binding of dopamine to D2 receptors on lactotropes, children with prolactinomas such as this
patient have excellent responses to medical therapy
with dopamine agonists, typically bromocrip
tine20,21 and cabergoline.22 We generally recommend cabergoline, since it involves less frequent
dosing, has fewer side effects, and more often results in normalization of prolactin levels and reduction of tumor size in patients with either microprolactinomas or macroprolactinomas.22,23 Our
major concern is that high cumulative doses of
cabergoline in patients with Parkinsons disease
are associated with the risk of the development
of clinically significant cardiac valvular regurgitation.24 The risk with the much lower doses typically used in prolactinomas remains to be definitively determined; recently, an increased risk of
moderate tricuspid regurgitation was reported
when the cumulative dose exceeded 280 mg,25 but
overall, the data show no increased risk of clinically significant regurgitation.26-28 For this reason, echocardiography was performed in this
patient; he has trivial pulmonic and tricuspid regurgitation, which is being followed annually.
After surgery for the described indications and
at a cabergoline dose of 0.25 mg twice weekly,
prolactin levels fell to nearly normal. A dose increase to 0.5 mg twice weekly led to complete
normalization of prolactin levels, and the levels
have remained at the low end of the normal range.
We looked for deficiencies of thyrotropin, corticotropin, antidiuretic hormone, and growth hormone to determine which hormone replacements
were necessary. Levothyroxine (75 g daily) was
begun preoperatively, and the patient has remained
euthyroid with this dose. A preoperative morning cortisol level indicated sufficient basal secretion, and a postoperative cosyntropin stimulation
test indicated a normal peak cortisol level, at
26.1 g per deciliter (720 nmol per liter). Diabetes insipidus did not develop. IGF-I levels continued to be in the low-normal range for age and were
low for pubertal stage (225 to 240 ng per milliliter), but a growth hormone stimulation test at
18.7 years of age was normal. At a chronologic age
of 17 years and a height standard-deviation score
of 1.16, the bone age was 18 years, indicating
completion of statural growth.
The patients hypogonadism improved gradually, and current morning testosterone levels are
in the low-normal range. He has no evidence of

Figure 3. Transmastoidal-Biopsy Specimen

of the Petrous Bone (Hematoxylin and Eosin).
On low magnification (Panel A), a clear delineation beRETAKE
1st
AUTHOR Smith
ICM
tween reactive bone (arrowheads) and neoplastic bone
2nd
REG F FIGURE
3a&b
(arrow) is evident. This provides support for a diagno3rd
CASE
TITLE
Revised magsis of
a slow-growing, benign process. On higher
EMail
Line
4-C
nification
(Panel B), bland osteoblasts are seen
within
SIZE
Enon
ARTIST: mst
H/T
H/T
the FILL
loose fibrous connectiveCombo
tissue, rimming16p6
the neoplastic bony trabeculae (arrows), a finding that is charAUTHOR, PLEASE NOTE:
acteristic
of osteoblastoma.
Thistype
is one
of the
main
Figure
has been redrawn and
has been
reset.
Please check
features that distinguishes
thiscarefully.
entity from fibrous dysplasia.
JOB:

35922

ISSUE:

11-27-08

hyperparathyroidism or a pancreatic tumor, which

would raise concern about multiple endocrine neoplasia type 1. Annual MRI has revealed no growth
of the pituitary adenoma or of the osteoblastoma. The z score for bone mineral density at the
spine was 1.8 soon after surgery and 1.7 after
a year of therapy with a dopamine agonist. He has
been offered the option of switching to bromocriptine but has elected to continue with cabergoline.
Dr. Harris: The occurrence of two uncommon,
unrelated tumors adjacent to each other in this
child stretches credulity and understandably led
his caregivers to assume a unifying diagnosis of
an aggressive pituitary adenoma invading bone.
Two unifying diagnoses could be considered. First,
the McCuneAlbright syndrome is associated with
both pituitary adenomas and benign fibro-os-

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2375

The

n e w e ng l a n d j o u r na l

seous bone lesions; could this syndrome account

for both of this patients tumors? Second, could
hyperprolactinemia have been caused by impingement by osteoblastoma on the pituitary stalk, with
cystic degeneration of the pituitary gland?
Dr. Misra: We considered the McCuneAlbright
syndrome, when the differential diagnosis of the
skull-base lesion was broadened to include a primary bone process such as fibrous dysplasia. The
McCuneAlbright syndrome, caused by activating
mutations of GNAS1, which encodes for Gs, is associated with caf au lait spots, polyostotic fibrous
dysplasia, and one or more conditions of hormone
excess, including precocious puberty, growth hormone excess (with or without hyperprolactinemia), hyperthyroidism, hyperparathyroidism, and
hypercortisolism. There are no reports of isolated
prolactinomas or even isolated hyperprolactinemia in the McCuneAlbright syndrome. Our patient had no evidence of growth hormone excess
or any other features of the disease. Finally, the
McCuneAlbright syndrome is associated with fi-

of

m e dic i n e

brous dysplasia, not osteoblastoma. Thus, this diagnosis is unlikely. Elevated prolactin levels due
to compression of the pituitary stalk do not usually exceed 200 ng per milliliter. Our patients
highly elevated prolactin levels, together with the
pathological findings, confirm the diagnosis of a
prolactin-secreting pituitary adenoma.
Dr. Harris: So instead of Occams razor, we are
left with Hickams dictum, which states that a
patient can have as many diagnoses as he darn
well pleases.29

A nat omic a l Di agnose s

Pituitary adenoma, prolactin secreting, with atypical features and a high proliferation fraction.
Osteoblastoma of the skull.
Dr. Loeffler reports receiving consulting fees or being on the paid
advisory boards of TransMolecular and Procore and having equity
ownership in Procore; Dr. Misra, receiving grant support from Tercica and Ortho-McNeil Pharmaceutical, and Dr. Pomerantz, receiving lecture fees and grant support from GE HealthCare. No other
potential conflict of interest relevant to this article was reported.

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