CLINICAL CASE SEMINAR Distinct Radiological and Clinical Appearance of Lymphocytic Hypophysitis

KU¨ RS¸AD U¨ NLU¨ HIZARCI, FAHRI BAYRAM, RAMIZ C¸ OLAK, FIGEN O¨ ZTU¨ RK, AHMET SELC¸ UKLU, AHMET CANDAN DURAK, AND FAHRETTIN KELES¸ 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

Lymphocytic hypophysitis is a rare inflammatory lesion of immunostaining) pituitary tissue heavily infiltrated by lymphocytes the pituitary gland. The disease shows a striking female (positively stained by leukocyte common antigen), and the diagnosis predilection of approximately 9:1 and commonly affects was panhypophysitis (Fig. 2). During her follow-up, PRL levels pro- gressively increased, and a disturbing galactorrhea could be managed young women during late pregnancy or in the postpartum by high doses (up to 20 mg/day) of bromocriptine SRO (5 mg bro- period. Clinical presentation and radiological findings may mocriptine mesylate as slow releasing tablets). Also, in addition to mimic pituitary adenoma. We have reviewed the literature conjugated estrogen (0.625 mg/day), medroxyprogesterone acetate (5 ␮ and report two cases of lymphocytic hypophysitis, neither of mg/day), and desmopressin acetate (10 U/day) intranasally, l-T4 (100 ␮g/day) therapy was given for the management of secondary hypo- whom was neither pregnant or in the postpartum period; one thyroidism developed after operation. Six months after the replacement of them (case 1) was a unique patient with empty sella as- therapy, she was well, with normal PRL and thyroid hormone levels and sociated with lymphocytic hypophysitis and diabetes insip- without any sign or symptom of secondary adrenal failure. The dose of idus established as a suprasellar mass. bromocriptine SRO was lowered gradually (until 5 mg/day), and the patient was invited to regular clinical controls. Case Reports Case 2 Case 1 A 72-yr-old woman with eight children presented with fatigue, an- A 47-yr-old woman with two children presented with a 5-month orexia, and headache for 1 yr. She was first seen (omitted) by a local history of poliuria-polydipsia (ϳ15 liter/day), galactorrhea, and head- physician who noted low levels of free T3, free T4, TSH, LH, and FSH ache. She had been postmenopausal for 5 yr without hormone replace- and symptoms suggestive of Sheehan’s syndrome. She was referred to ment therapy. Medical history showed that she lactated and had regular the Endocrinology Clinic of Erciyes University. Medical history showed menses after the second delivery and had no history of peripartum or that she had her last delivery when she was 43 yr old and did not lactate postpartum hemorrhage. On physical examination body mass index was 2 and had no regular menses after this parturition. 40 kg/m . The results of the physical examination were normal, except On physical examination, vital signs were stable, the patient was pale, the patient was described as obese. Visual field test evaluated by com- and physical examination was unremarkable. The findings of the he- puterized perimetry was normal. mogram were normal, except for a slightly reduced hemoglobin value Magnetic resonance (MR) of the pituitary gland showed a suprasellar (11.5 g/L). Baseline hormonal investigations showed secondary hypo- mass (11 ϫ 7 ϫ 8 mm in diameter) with empty sella (Fig. 1, A and B). thyroidism [free T3, 1.2 pmol/L (normal, 2.2–4.6); free T4, 0.6 pmol/L Central diabetes insipidus (DI) was diagnosed by the appropriate test. (normal, 0.7–1.9); TSH, 0.7 ␮IU/mL (normal, 0.3–4.1)], secondary hy- After the blood samples were obtained for baseline hormone values [free pogonadism [FSH, 2.9 IU/L (normal, Ͼ22 for postmenopausal woman); T3, 4.8 pmol/L (normal, 3.3–7); free T4, 19.3 pmol/L (normal, 9–24); TSH, Ͼ ␮ ␮ LH, 0.7 IU/L (normal, 20 for postmenopausal woman); estradiol, 18 0.4 IU/mL (normal, 0.3–4.1); PRL, 98 g/L (normal, 5–25); FSH, 3.2 pmol/L (normal, Ͻ108 for postmenopausal woman)], and normal basal IU/L (normal, Ͼ22 for postmenopausal woman); LH, 0.2 IU/L (normal, Ͼ Ͻ cortisol (258 nmol/L; normal, 190–660) level and adequate cortisol re- 20 for postmenopausal woman); estradiol, 36 pmol/L (normal, 108 sponse (peak cortisol, 690 nmol/L) to standard ACTH stimulation test. for postmenopausal woman); cortisol, 913 nmol/L (normal, 190–660); The results of the dynamic function tests of the pituitary gland are shown ACTH, 7.9 pg/mL (normal, 1.3–12.3)], dynamic function tests of the in Table 2. The patient had no any symptom suggestive of DI, and tests pituitary gland were performed (Table 1), and hyperprolactinemia, sec- for assessment of posterior pituitary gland function were not performed. ondary hypogonadism, and GH deficiency were diagnosed. MR of the sella showed an enlarged pituitary gland and a thickened She was operated on by the transcranial approach because of a small infundibulum (Fig. 3, A and B). Histopathological examination of the increment in the size of the tumor on MR performed at 6-month inter- pituitary gland established lymphocytic hypophysitis (Fig. 4). In the vals. A mass lesion arising from the infundibulum and adherent to the postoperative period the patient had secondary adrenal failure and was right optic nerve was detected. The lesion could not be removed com- prescribed prednisolone (5 mg/day) and l-T4 (gradually increased to pletely, and a biopsy was performed. Histopathological examination 100 ␮g/day); she was invited to regular clinical controls. showed anterior and posterior (established by chromogranin and S-100 Diagnosis Received April 25, 2000. Revision received August 11, 2000. Rerevi- sion received December 21, 2000. Accepted January 14, 2001. Lymphocytic hyphophysitis mainly affects women and typically pre- Address all correspondence and requests for reprints to: Prof. Dr. sents during pregnancy or the postpartum period with symptoms re- Fahrettin Keles¸timur, Department of Endocrinology and Metabolism, ferable to pituitary enlargement and later those of hypopituitarism (1). Erciyes University Medical School, Kayseri, Turkey. E-mail: fktimur Commonly, lymphocytic hyphophysitis presents with features of a mass @erciyes.edu.tr. lesion, with variable loss of anterior pituitary function and rarely with

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FIG. 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.

TABLE 2. Serum levels of TSH, PRL, FSH, LH, and GH after administration of TRH, LHRH, and L-Dopa

Min 0 306090120 TSH (␮U/mL) 0.9 2.5 2.1 1.9 1.8 PRL (␮g/L) 5.6 7.1 7.1 5.5 4.1 FSH (IU/mL) 2.4 3.4 4.4 4.5 5.2 LH (IU/mL) 1.3 1.4 2.3 2.3 2.4 GH (␮g/L) 0.4 0.4 0.5 0.5 0.5

pophysitis are enlarged pituitary mass, which is characterized by ho- mogenous 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 mark- ers, and the diagnosis depends on the clinical suspicion and can only be clearly established by histological examination (1, 6).

Discussion

FIG. 1. A, Patient 1. The coronal MR image demonstrates empty sella Lymphocytic hyphophysitis is a rare inflammatory disease of and suprasellar mass. B, Patient 1. The sagittal MR image demon- the anterior pituitary gland. The disease was first described by strates the thickening of the pituitary stalk, suprasellar mass, and Goudie and Pinkerton in 1962 (7); since then, more than 120 empty sella. cases have been reported. Although the etiology remains un- TABLE 1. Serum levels of TSH, PRL, FSH, LH, GH, and cortisol known, considerable evidence exists for an autoimmune patho- after administration of TRH, LHRH, and insulin genesis (8, 9). In lymphocytic hyphophysitis, the abnormalities appear to be confined to the anterior pituitary, with a small Min number of patients having clinical evidence of DI (1, 10), but, 0306090120rarely, lymphocytic hyphophysitis may also involve the infun- TSH (␮U/mL) 2.9 7.0 4.8 3.1 2.7 dibuloneurohypophyseal region (11). ␮ Ͼ Ͼ Ͼ Ͼ PRL ( g/L) 141 400 400 400 400 Lymphocytic hyphophysitis shows a striking female pre- FSH (IU/L) 3.6 6.3 7.7 7.5 9.6 LH (IU/L) 2.8 4.2 3.3 3.3 4.6 dilection of approximately 8.5:1 and commonly affects young GH (␮g/L) 1.6 1.7 1.5 1.4 1.0 women during late pregnancy or in the postpartum period Cortisol (nmol/L) 607 1106 1311 1738 938 (1, 12). However, it has also been described in postmenopausal women (2, 4, 13, 14). These two patients were neither posterior pituitary involvement (2). In a few cases, chronic lymphocytic pregnant nor in the postpartum period, and they are addi- infiltration occurs in both hypophysis and infundibuloneurohypophysis tional examples of lymphocytic hyphophysitis during the (3). The most common radiological features of the lymphocytic hy- postmenopausal period. We think that the occurrence of LYMPHOCYTIC HYPOPHYSITIS AS A SUPRASELLAR MASS 1863

FIG. 4. Photograph of hematoxylin-eosin-stained tissue from case 2, showing lymphocytic infiltration of anterior pituitary tissue.

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 combina- tion 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

FIG. 3. A, Patient 2. The coronal MR image demonstrates homoge- to TRH stimulation have been reported as diagnostic and neous uptake of gadolinium of pituitary gland. B, Patient 2. The screening procedures in patients with Sheehan’s syndrome sagittal MR image of thickened pituitary stalk and diffuse homoge- (17), we previously reported that Sheehan’s syndrome may neous uptake of gadolinium. be characterized by hyperprolactinemia (18). The lack of a typical medical history of suggesting Sheehan’s syndrome, such as postpartum hemorrhage, agalactorrhea, and amen- lymphocytic hyphophysitis without associated pregnancy is orrhea during the postpartum period, clearly excludes Shee- more frequent than that previously considered. han’s syndrome as a diagnosis in the first patient. The as- Besides partial or total hypopituitarism, hyperpro- sociation of empty sella with lymphocytic hyphophysitis in lactinemia may be present in patients with lymphocytic this patient led us to speculate that at least in some patients, hyphophysitis, and in many of the patients elevated PRL lymphocytic hyphophysitis may be an underlying disorder levels may represent an endocrine marker of the disease in patients with presumed Sheehan’s syndrome. To support (1). Although the second patient was normoprolactinemic, this hypothesis, we believe that patients with lymphocytic this suggestion is also supported in the first case with hyphophysitis should be followed for the development of partial hypopituitarism and hyperprolactinemia. Stalk empty sella. Empty sella may be primary or secondary in compression resulting in decreased dopamine delivery to origin (19). Secondary empty sella is usually related to sur- the anterior pituitary may be a reason for hyperprolactine- gical treatment, radiotherapy, spontaneous infarction of pi- mia in this patient. However, an autoimmune mechanism tuitary tumors, bromocriptine therapy in prolactinoma, and 1864 U¨ NLU¨ HIZARCI ET AL. JCE&M• 2001 Vol. 86 • No. 5

T4 therapy in patients with primary hypothyroidism (20, 21). References None of these causes was the case in the first patient. 1. Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S. 1995 It has been reported that lymphocytic hyphophysitis Lymphocytic hypophysitis: clinicopathological findings. J Clin Endocrinol should be strongly suspected if 1) symptoms occur during Metab. 80:2302–2311. 2. Jenkins PJ, Chew SL, Lowe DG, et al. 1995 Lymphocytic hypophysitis: un- or soon after pregnancy; 2) ACTH and/or TSH deficiency usual features of a rare disorder. Clin Endocrinol (Oxf). 42:529–534. is present with normal gonadotropin and GH secretion; 3. Hashimoto K, Takao T, Makino S. 1997 Lymphocytic adenohypophysitis and and 3) contrast enhancement scans of the pituitary gland lymphocytic infundibuloneurohypophysitis. Endocr J. 44:1–10. 4. Vanneste JAL, Kamphorst W. 1987 Lymphocytic hypophysitis. Surg Neurol. are positive (particularly gadolinium contrast on MR scan- 28:145–149. ning) (10). These two cases represent an unusual presen- 5. Baskın DS, Townsend JJ, Wilson CB. 1982 Lymphocytic adenohypophysitis tation of lymphocytic hyphophysitis with preserved of pregnancy simulating a pituitary adenoma: a distinct pathological entity. J Neurosurg. 56:148–153. ACTH and TSH secretion, but not gonadotropins, at the 6. Naik RG, Ammini A, Shah P, Sarkar C, Mehta VS, Berry M. 1994 Lympho- time of diagnosis. To our knowledge, lymphocytic hypho- cytic hypophysitis. J Neurosurg. 80:925–927. 7. Goudie RB, Pinkerton PH. 1962 Anterior hypophysitis and Hashimoto’s dis- physitis, confirmed by histological diagnosis and empty ease in a young woman. J Pathol Bacteriol. 83:584–585. sella, was not reported previously. Additionally, empty 8. Bayram F, Keles¸timur F, O¨ ztu¨ rk F, Selçuklu A, Patırog˘lu TE, Beyhan Z. 1998 sella associated with panhypophysitis characterized by Lymphocytic hypophysitis in a patient with Graves’ disease. J Endocrinol Invest. 21:193–197. suprasellar mass and DI has never been reported previ- 9. Pestell RG, Best JD, Alford FP. 1990 Lymphocytic hypophysitis. The clinical ously. This unusual case provides additional insights into spectrum of the disorder and evidence for an autoimmune pathogenesis. Clin the presentation of lymphocytic hyphophysitis. Endocrinol (Oxf). 33:457–466. 10. Powrie JK, Powell M, Ayers AB, Lowry C, So¨nksen PH. 1995 Lymphocytic Both spontaneous recovery of pituitary gland function adenohypophysitis: magnetic resonance imaging features of two new cases and progressive and permanent hypopituitarism have and a review of the literature. Clin Endocrinol (Oxf). 42:315–322. been reported. Although the administration of bromocrip- 11. Nussbaum CE, Okawara SH, Jacobs LS. 1991 Lymphocytic hypophysitis with involvement of the cavernous sinus and hypothalamus. Neurosurgery. tine can lower the high PRL level, the beneficial impact of 28:440–444. this drug on the course of the disease is unproven (22). 12. Lee JH, Laws ER, Guthrie BL, Dina TS, Nochomovitz LE. 1994 Lymphocytic Addition of the deficient hormones is essential in the man- hypophysitis: occurence in two men. Neurosurgery. 34:159–163. 13. Deleted in proof. agement of patients with lymphocytic hyphophysitis. Cor- 14. Cosman F, Post KD, Holub DA, Wardlaw SL. 1989 Lymphocytic hypophy- ticosteroid therapy has been advocated and has been ef- sitis. Report of 3 new cases and review of the literature. Medicine. fective in some patients. Transsphenoidal surgery is both 68:240–256. 15. Cebelin MS, Velasco ME, De Las Mulas JM, Druet RL. 1981 Galactorrhea diagnostic and therapeutic. However, surgical interven- associated with lymphocytic adenohypophysitis. Br J Obstet Gynaecol. tion may result in further deterioration of pituitary gland 88:675–680. ¨ ˙ functions. It has been suggested that in the cases of sus- 16. Ozbey N, Inanç S, Aral F, et al. 1994 Clinical and laboratory evaluation of 40 patients with Sheehan’s syndrome. Isr J Med Sci. 30:826–829. pected hypophysitis, a frozen section should be performed 17. Shahmanesh M, Ali Z, Pourmand M, Nourmand I. 1980 Pituitary function to confirm the diagnosis and to avoid aggressive resection tests in Sheehan’s syndrome. Clin Endocrinol (Oxf). 12:303–311. 18. Keles¸timur F. 1992 Hyperprolactinemia in a patient with Sheehan’s syndrome. of potentially viable pituitary tissue (1, 22). South Med J. 85:1008–1010. In conclusion, lymphocytic hyphophysitis is a rare dis- 19. Bonneville JF, Cattin F, Dieteman JL. 1989 Hypothalamic-pituitary region: order, and empty sella may be associated with this syn- computed tomography imaging. Endocrinol Metab Clin North Am 3:35–72. 20. Lopin I, Santen RJ. 1975 Empty sella syndrome: sequela of the spontaneous drome. It should be considered in the differential diag- remission of acromegaly. Arch Intern Med. 135:1519–1521. nosis of any pituitary mass that may extend to the 21. Keles¸timur F, Selçuklu A, O¨ zcan N. 1992 Empty sella developing during suprasellar region, and lymphocytic hyphophysitis should throxine therapy in a patient with primary hypothyroidism and hyperprolactinemia. Postgrad Med J. 68:589–591. be suspected in the patients with empty sella, hyperpro- 22. Ezzat S, Josse RG. 1997 Autoimmune hypophysitis. Trends Endocrinol Metab. lactinemia, and hypopituitarism. 8:74–80.