Distinct Radiological and Clinical Appearance of Lymphocytic Hypophysitis
Kür
ad Ünlühizarci,
Fahri Bayram,
Ramiz Çolak,
Figen Öztürk,
Ahmet Selçuklu,
Ahmet Candan Durak and
Fahrettin Kele
timur
Departments of Endocrinology and Metabolism (K.U., F.B., R.C.,
F.K.), Pathology (F.O.), Neurosurgery (A.S.), and Radiology (A.C.D.),
Erciyes University Medical School, Kayseri, Turkey
Address all correspondence and requests for reprints to: Prof. Dr. Fahrettin Kele
timur, Department of Endocrinology and Metabolism, Erciyes University Medical School, Kayseri, Turkey.
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Introduction
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Lymphocytic hypophysitis is a rare inflammatory lesion of the
pituitary gland. The disease shows a striking female predilection of
approximately 9:1 and commonly affects young women during late
pregnancy or in the postpartum period. Clinical presentation and
radiological findings may mimic pituitary adenoma. We have reviewed the
literature and report two cases of lymphocytic hypophysitis, neither of
whom was neither pregnant or in the postpartum period; one of them
(case 1) was a unique patient with empty sella associated with
lymphocytic hypophysitis and diabetes insipidus established as a
suprasellar mass.
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Case Reports
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Case 1
A 47-yr-old woman with two children presented
with a 5-month history of poliuria-polydipsia (
15 liter/day),
galactorrhea, and headache. She had been postmenopausal for 5 yr
without hormone replacement therapy. Medical history showed that she
lactated and had regular menses after the second delivery and had no
history of peripartum or postpartum hemorrhage. On physical examination
body mass index was 40 kg/m2. The results of the
physical examination were normal, except the patient was described as
obese. Visual field test evaluated by computerized perimetry was
normal.
Magnetic resonance (MR) of the pituitary gland showed a suprasellar
mass (11 x 7 x 8 mm in diameter) with empty sella (Fig. 1
, A and B). Central diabetes
insipidus (DI) was diagnosed by the appropriate test. After the blood
samples were obtained for baseline hormone values [free
T3, 4.8 pmol/L (normal, 3.37); free
T4, 19.3 pmol/L (normal, 924); TSH, 0.4
µIU/mL (normal, 0.34.1); PRL, 98 µg/L (normal, 525); FSH, 3.2
IU/L (normal, >22 for postmenopausal woman); LH, 0.2 IU/L (normal,
>20 for postmenopausal woman); estradiol, 36 pmol/L (normal, <108 for
postmenopausal woman); cortisol, 913 nmol/L (normal, 190660); ACTH,
7.9 pg/mL (normal, 1.312.3)], dynamic function tests of the
pituitary gland were performed (Table 1
),
and hyperprolactinemia, secondary hypogonadism, and GH deficiency were
diagnosed.

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Figure 1. A, Patient 1. The coronal MR image
demonstrates empty sella and suprasellar mass. B, Patient 1. The
sagittal MR image demonstrates the thickening of the pituitary stalk,
suprasellar mass, and empty sella.
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She was operated on by the transcranial approach because of a small
increment in the size of the tumor on MR performed at 6-month
intervals. A mass lesion arising from the infundibulum and adherent to
the right optic nerve was detected. The lesion could not be removed
completely, and a biopsy was performed. Histopathological examination
showed anterior and posterior (established by chromogranin and S-100
immunostaining) pituitary tissue heavily infiltrated by lymphocytes
(positively stained by leukocyte common antigen), and the diagnosis was
panhypophysitis (Fig. 2
). During her
follow-up, PRL levels progressively increased, and a disturbing
galactorrhea could be managed by high doses (up to 20 mg/day) of
bromocriptine SRO (5 mg bromocriptine
mesylate as slow releasing tablets). Also, in addition to conjugated
estrogen (0.625 mg/day), medroxyprogesterone acetate (5 mg/day), and
desmopressin acetate (10 µU/day) intranasally,
L-T4 (100 µg/day) therapy was given
for the management of secondary hypothyroidism developed after
operation. Six months after the replacement therapy, she was well, with
normal PRL and thyroid hormone levels and without any sign or symptom
of secondary adrenal failure. The dose of bromocriptine
SRO was lowered gradually (until 5 mg/day), and the patient was invited
to regular clinical controls.

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Figure 2. Photograph of hematoxylin-eosin-stained
histological section of the pituitary gland from case 1, showing the
heavy lymphocytic infiltration. Only a few nests of normal pituitary
cells remain.
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Case 2
A 72-yr-old woman with eight children presented with fatigue,
anorexia, and headache for 1 yr. She was first seen (omitted) by a
local physician who noted low levels of free T3,
free T4, TSH, LH, and FSH and symptoms suggestive
of Sheehans syndrome. She was referred to the Endocrinology Clinic of
Erciyes University. Medical history showed that she had her last
delivery when she was 43 yr old and did not lactate and had no regular
menses after this parturition.
On physical examination, vital signs were stable, the patient was pale,
and physical examination was unremarkable. The findings of the hemogram
were normal, except for a slightly reduced hemoglobin value (11.5 g/L).
Baseline hormonal investigations showed secondary hypothyroidism [free
T3, 1.2 pmol/L (normal, 2.24.6); free
T4, 0.6 pmol/L (normal, 0.71.9); TSH, 0.7
µIU/mL (normal, 0.34.1)], secondary hypogonadism [FSH, 2.9 IU/L
(normal, >22 for postmenopausal woman); LH, 0.7 IU/L (normal, >20 for
postmenopausal woman); estradiol, 18 pmol/L (normal, <108 for
postmenopausal woman)], and normal basal cortisol (258 nmol/L; normal,
190660) level and adequate cortisol response (peak cortisol, 690
nmol/L) to standard ACTH stimulation test. The results of the dynamic
function tests of the pituitary gland are shown in Table 2
. The patient had no any symptom
suggestive of DI, and tests for assessment of posterior pituitary gland
function were not performed. MR of the sella showed an enlarged
pituitary gland and a thickened infundibulum (Fig. 3
, A and B). Histopathological
examination of the pituitary gland established lymphocytic hypophysitis
(Fig. 4
). In the postoperative period the
patient had secondary adrenal failure and was prescribed prednisolone
(5 mg/day) and L-T4 (gradually
increased to 100 µg/day); she was invited to regular clinical
controls.

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Figure 3. A, Patient 2. The coronal MR image
demonstrates homogeneous uptake of gadolinium of pituitary gland. B,
Patient 2. The sagittal MR image of thickened pituitary stalk and
diffuse homogeneous uptake of gadolinium.
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Figure 4. Photograph of hematoxylin-eosin-stained
tissue from case 2, showing lymphocytic infiltration of anterior
pituitary tissue.
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Diagnosis
Lymphocytic hyphophysitis mainly affects women and typically
presents during pregnancy or the postpartum period with symptoms
referable to pituitary enlargement and later those of hypopituitarism
(1). Commonly, lymphocytic hyphophysitis presents with
features of a mass lesion, with variable loss of anterior pituitary
function and rarely with posterior pituitary involvement
(2). In a few cases, chronic lymphocytic infiltration
occurs in both hypophysis and infundibuloneurohypophysis
(3). The most common radiological features of the
lymphocytic hypophysitis are enlarged pituitary mass, which is
characterized by homogenous enhancement after gadolinium injection and
thickened infundibulum on MR (1, 4, 5). Empty sella is an
uncommon radiological appearance of lymphocytic hypophysitis, and to
date, few patients have been reported (3). There are no definite
biochemical or serological markers, and the diagnosis depends on the
clinical suspicion and can only be clearly established by histological
examination (1, 6).
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Discussion
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Lymphocytic hyphophysitis is a rare inflammatory disease of
the anterior pituitary gland. The disease was first described by Goudie
and Pinkerton in 1962 (7); since then, more than 120 cases
have been reported. Although the etiology remains unknown, considerable
evidence exists for an autoimmune pathogenesis (8, 9). In
lymphocytic hyphophysitis, the abnormalities appear to be confined to
the anterior pituitary, with a small number of patients having clinical
evidence of DI (1, 10), but, rarely, lymphocytic
hyphophysitis may also involve the infundibuloneurohypophyseal region
(11).
Lymphocytic hyphophysitis shows a striking female predilection of
approximately 8.5:1 and commonly affects young women during late
pregnancy or in the postpartum period (1, 12). However, it
has also been described in postmenopausal women (2, 4, 13, 14). These two patients were neither pregnant nor in the
postpartum period, and they are additional examples of lymphocytic
hyphophysitis during the postmenopausal period. We think that the
occurrence of lymphocytic hyphophysitis without associated pregnancy is
more frequent than that previously considered.
Besides partial or total hypopituitarism, hyperprolactinemia may
be present in patients with lymphocytic hyphophysitis, and in many of
the patients elevated PRL levels may represent an endocrine marker of
the disease (1). Although the second patient was
normoprolactinemic, this suggestion is also supported in the first case
with partial hypopituitarism and hyperprolactinemia. Stalk compression
resulting in decreased dopamine delivery to the anterior pituitary may
be a reason for hyperprolactinemia in this patient. However, an
autoimmune mechanism involving the production of stimulating antibodies
by plasma cells may lead to increased PRL secretion
(15).
It was suggested that if inflammation of the pituitary gland is
left untreated, the enlarged gland that produces a mass effect in the
initial stages of the disease may shrink as glandular tissue is
destroyed (6). It has been reported that some patients
with presumed Sheehans syndrome but no clear history of postpartum
hemorrhage or sepsis may have lymphocytic hypophysitis
(1). In the second patient, although the medical history
of inability to lactate and having no menses after the last delivery in
combination with partial pituitary hormone deficiency is suggestive of
Sheehans syndrome, she was diagnosed as having lymphocytic
hypophysitis.
Sheehans syndrome, which occurs as a result of ischemic pituitary
necrosis due to severe postpartum hemorrhage, is almost always
characterized by empty sella and rarely DI (16). Although
PRL deficiency and an absent PRL response to TRH stimulation have been
reported as diagnostic and screening procedures in patients with
Sheehans syndrome (17), we previously reported that
Sheehans syndrome may be characterized by hyperprolactinemia
(18). The lack of a typical medical history of suggesting
Sheehans syndrome, such as postpartum hemorrhage, agalactorrhea, and
amenorrhea during the postpartum period, clearly excludes Sheehans
syndrome as a diagnosis in the first patient. The association of empty
sella with lymphocytic hyphophysitis in this patient led us to
speculate that at least in some patients, lymphocytic hyphophysitis may
be an underlying disorder in patients with presumed Sheehans
syndrome. To support this hypothesis, we believe that patients with
lymphocytic hyphophysitis should be followed for the development of
empty sella. Empty sella may be primary or secondary in origin
(19). Secondary empty sella is usually related to surgical
treatment, radiotherapy, spontaneous infarction of pituitary tumors,
bromocriptine therapy in prolactinoma, and
T4 therapy in patients with primary
hypothyroidism (20, 21). None of these causes was the case
in the first patient.
It has been reported that lymphocytic hyphophysitis should be
strongly suspected if 1) symptoms occur during or soon after pregnancy;
2) ACTH and/or TSH deficiency is present with normal gonadotropin and
GH secretion; and 3) contrast enhancement scans of the pituitary gland
are positive (particularly gadolinium contrast on MR scanning)
(10). These two cases represent an unusual presentation of
lymphocytic hyphophysitis with preserved ACTH and TSH secretion, but
not gonadotropins, at the time of diagnosis. To our knowledge,
lymphocytic hyphophysitis, confirmed by histological diagnosis and
empty sella, was not reported previously. Additionally, empty sella
associated with panhypophysitis characterized by suprasellar mass and
DI has never been reported previously. This unusual case provides
additional insights into the presentation of lymphocytic
hyphophysitis.
Both spontaneous recovery of pituitary gland function and
progressive and permanent hypopituitarism have been reported. Although
the administration of bromocriptine can lower the high PRL
level, the beneficial impact of this drug on the course of the disease
is unproven (22). Addition of the deficient hormones is
essential in the management of patients with lymphocytic hyphophysitis.
Corticosteroid therapy has been advocated and has been effective in
some patients. Transsphenoidal surgery is both diagnostic and
therapeutic. However, surgical intervention may result in further
deterioration of pituitary gland functions. It has been suggested that
in the cases of suspected hypophysitis, a frozen section should be
performed to confirm the diagnosis and to avoid aggressive resection of
potentially viable pituitary tissue (1, 22).
In conclusion, lymphocytic hyphophysitis is a rare disorder, and
empty sella may be associated with this syndrome. It should be
considered in the differential diagnosis of any pituitary mass that may
extend to the suprasellar region, and lymphocytic hyphophysitis should
be suspected in the patients with empty sella, hyperprolactinemia, and
hypopituitarism.
Received April 25, 2000.
Revised August 11, 2000.
Revised December 21, 2000.
Accepted January 14, 2001.
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