Distinct Radiological and Clinical Appearance of Lymphocytic Hypophysitis

Kürsad Ünlühizarci, Fahri Bayram, Ramiz Çolak, Figen Öztürk, Ahmet Selçuklu, Ahmet Candan Durak and Fahrettin Kelestimur

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 Kelestimur, Department of Endocrinology and Metabolism, Erciyes University Medical School, Kayseri, Turkey.


    Introduction
 Top
 Introduction
 Case Reports
 Discussion
 References
 
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.


    Case Reports
 Top
 Introduction
 Case Reports
 Discussion
 References
 
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. 1Go, 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, 3.3–7); free T4, 19.3 pmol/L (normal, 9–24); TSH, 0.4 µIU/mL (normal, 0.3–4.1); PRL, 98 µg/L (normal, 5–25); 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, 190–660); ACTH, 7.9 pg/mL (normal, 1.3–12.3)], dynamic function tests of the pituitary gland were performed (Table 1Go), 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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Table 1. Serum levels of TSH, PRL, FSH, LH, GH, and cortisol after administration of TRH, LHRH, and insulin

 
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. 2Go). 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.

 
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 Sheehan’s 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, 2.2–4.6); free T4, 0.6 pmol/L (normal, 0.7–1.9); TSH, 0.7 µIU/mL (normal, 0.3–4.1)], 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, 190–660) 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 2Go. 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. 3Go, A and B). Histopathological examination of the pituitary gland established lymphocytic hypophysitis (Fig. 4Go). 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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Table 2. Serum levels of TSH, PRL, FSH, LH, and GH after administration of TRH, LHRH, and L-Dopa

 


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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.

 
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).


    Discussion
 Top
 Introduction
 Case Reports
 Discussion
 References
 
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 Sheehan’s 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 Sheehan’s syndrome, she was diagnosed as having lymphocytic hypophysitis.

Sheehan’s 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 Sheehan’s syndrome (17), we previously reported that Sheehan’s syndrome may be characterized by hyperprolactinemia (18). The lack of a typical medical history of suggesting Sheehan’s syndrome, such as postpartum hemorrhage, agalactorrhea, and amenorrhea during the postpartum period, clearly excludes Sheehan’s 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 Sheehan’s 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.


    References
 Top
 Introduction
 Case Reports
 Discussion
 References
 

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  13. Deleted in proof.
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