Endocrine Journal 1999, 46 (4), 505-512

Lymphocytic and Infundibuloneurohypophy- sitis; Clinical and Pathological Evaluations

NURI KAMEL, SEN DAOcI ILGIN, SEVIMGULLU, VEDIACESUR TONYUKUK AND HALUKDEDA*

Department of Endocrinology and Metabolic Diseases, Ankara University Medical School, Ankara, Turkey * Department of Neurosurgery , Ankara University Medical School, Ankara, Turkey

Abstract. This report describes the clinical and pathological characteristics of two patients with lymphocytic hypophysitis (LHy) and two with infundibuloneurohypophysitis (INHy). Two of the patients were women and two were men, and their ages were between 27 and 38 years old. This disease was not associated with either pregnancy or the postpartum period in the female patients. Two of the patients presented with , one with panhypopituitarism and right abducens paralysis and one with headache and galactorrhea. At presentation three of the patients had mild to moderate hyperprolactinemia and one had low levels. All four had abnormal magnetic resonance imaging (MRI): focal nodular enlarging of the infundibulum and normal hypophysis in one, expanding sellar masses in two, and diffusely thickened stalk with slightly enlarged in one. Three cases showed no sign of adenohypophysial deficiency with stimulation tests. One patient had associated chronic lym- phocytic thyroiditis. Of the first three patients, one patient underwent transcranial and two underwent transnasal transsphenoidal (TNTS) surgery for mass excisions since they were thought to have pituitary tumors. Endoscopic endonasal transsphenoidal biopsy was performed in the last one with a suspicion of LHy. The pathological and immunohistochemical examinations revealed lymphocytic infiltration. Hyperprolactinemia resolved with surgery in two patients and one developed diabetes insipidus as a complication. We conclude that LHy and infun- dibuloneurohypophysitis should be considered in the differential diagnosis of the mass lesions of the sellar region and also should be kept in the mind for the etiopathogenesis of cases of hyperprolactinemia, galactorrhea and diabetes insipidus. In suspected cases endoscopic endonasal biopsy for the histopathological diagnosis can be a safe ap- proach.

Key words: Lymphocytic hypophysitis, Infundibuloneurohypophysitis (Endocrine Journal 46: 505-512, 1999)

LYMPHOCYTIC hypophysitis (LHy), which is a disorders and can mimic nonfunctioning pituitary rare inflammatory lesion of the pituitary gland, was adenomas. first described in 1962 by Goudie and Pinkerton [1] Infundibuloneurohypophysitis (INHy), which was and more than 100 cases have been documented since first described by Imura et al. [25], is a different entity then. Although LHy has been reported to be a dis- and involvement of the posterior pituitary and/or ease of females related to pregnancy or the post- pituitary stalk involvement may result in diabetes in- partum period [2-12], it can occur in nonpregnant sipidus (DI) [20, 26, 27]. The etiology of LHy and women and even in men [13-24]. The disease can INHy remains obscure but some evidence exists for cause complete or partial and visual an autoimmune pathogenesis because of its associa- tion with other autoimmune diseases including thyroiditis, adrenalitis, pernicious anemia, lympho- Received: November 13, 1998 cytic parathyroiditis, atrophic gastritis, retroperi- Accepted: March 12, 1999 Correspondence to: Dr. Sevim GULLU, Ibn-i Sina Hastanesi, toneal fibrosis and the existence of circulating anti- Endokrinoloji ve Metabolizma Hastahklari Bilim Dali, 10. pituitary antibodies [1, 10, 14, 15, 21, 22, 24, 28-31]. Kat, D-Blok, 06100, Samanpazari, Ankara, Turkey In this report we describe four distinct cases with 506 KAMEL et al.

either LHy or INHy. All the patients were diag- and 48.0 ng/ml). He had normal serum free T3, free nosed histopathologically. Because three of them T4 and TSH levels and he was negative for thyroid were suspected of having tumors, they all underwent antibodies (Anti-microsomal antibody and antithyro- surgical explorations with initial diagnoses of pituita- globulin antibody). ry neoplasms, but the fourth patient biopsied had a The plasma ACTH, serum cortisol, FSH, LH, free preoperative diagnosis of LHy. The clinical, radio- and total testosterone levels were normal (Table 1). logical and histological features of the patients are Partial hypopituitarism was excluded by means of described. insulin induced hypoglycemia testing with adequate plasma cortisol and growth hormone responses. Case 1 Thyrotropin releasing hormone stimulation test responses were also normal. A 27-year-old man was admitted with a two month His plain lateral sella turcica film was normal. history of polydipsia, and fatigue. He had T1-weighted magnetic resonance imaging (MRI) had a diagnosis of major depression three years reveled a focal nodular thickening of the infundibu- previously. He had used amitriptyline and lithium lum and a normal hypophysis (Fig. 1). The nodular for two years but stopped the medication over six lesion was enhanced after iv gadolinium administra- months before the presenting complaints. He denied tion. Since the patient was thought to have a tumor head trauma or operation. of this region, right pterional craniotomy was per- His vital signs were normal. There was no res- formed. At operation the pituitary stalk was ob- triction of his visual field and his systemic examina- served to be thicker than normal. An incision was tion was normal. made on the stalk. A gray-white mass was detected His white blood cell count, hematocrit and in the stalk and normal stalk structures were dissected erythrocyte sedimentation rate were normal. Other from this mass and the lesion was removed while acute phase reactants were also found to be negative. protecting the pituitary stalk. No complication oc- Apart from hypernatremia (158 mEq/L), all bio- curred during and after the operation. By light chemical tests were normal. Daily urine volume microscopy, hematoxylin and eosin stained sections was 10.5 L and urine osmolality was 52.7 mOsm/kg, exhibited a diffuse lymphoplasmacytic (mainly lym- Water deprivation and desmopressin tests indicated a phocytic) infiltration (Fig. 2). There was no evidence partial central DI. His serum prolactin levels were of granulomas, giant cells or neoplastic tissue. On found to be high (on two measurements 22.3 ng/ml, immunohistochemical evaluation, the inflammatory

Table 1. Preoperative and postoperative hormonal findings of the patients. LYMPHOCYTIC HYPOPHYSITIS 507

and chronic headache. She had regular menses and she was not pregnant or in the postpartum period. On physical examination no abnormality could be detected apart from bilateral galactorrhea. Her visual field evaluation was normal. Laboratory evaluation demonstrated a normal white blood cell count, hematocrit and erythrocyte sedimentation rate. Her biochemical tests were in the normal ranges. She had normal urinary output and normal urine specific gravity. Her serum prolactin level was found to be slightly high (84.0 ng/ml). Both basal (Table 1) and stimulated adenohypophysial and target tissue hor-

Fig. 1. Coronal view of MRI of Case 1. Focal nodular mones were normal. thickening of the stalk and a normal hypophysis. Her plain sella film revealed an enlarged sella tur- cica and MRI showed an enlarged pituitary with cells were found to be a polyclonal population of T suprasellar extension (Fig. 3) which was enhanced and B cells with positivity for CD45 (pan leukocyte diffusely after contrast injection. She was operated antigen, 80-85%) and CD20 (B-cell antigen, 15-200%) on by transnasal transsphenoidal (TNTS) surgery. respectively. The diagnosis was lymphocytic infun- After opening the dura a gray-white non-bleeding dibuloneurohypophysiti s . mass was detected. A normal pituitary gland was The patient's prolactin levels returned to normal not detected in the sellar region. It did not seem to and no additional hormonal deficiency occurred be a . A frozen section of the (Table 1) after the operation, but his diabetes insipi- mass was reported to be lymphocytic hypophysitis, dus continued. The patient is now receiving replace- and sellar decompression was achieved. ment doses of desmopressin acetate (20 pg/day, The specimens were stained with hematoxylin and bid, via the intranasal route) and he has had no eosin. Light microscopy showed a generalized lym- symptoms along with the treatment. This case was phocytic infiltration. On immunohistochemical reported before [321. evaluation the inflammatory cells were positive for CD45 (100%), CD20 (10%) and negative for CD3 (T- Case 2 cell antigen). After the operation the patient's prolactin levels A 42-year-old woman, sought medical attention six returned to normal and her galactorrhea disappeared months before she was referred to us for galactorrhea and no new hormonal deficiency occurred, but she

Fig. 2. The histologic appearance of LHy. Lymphoplasma- Fig. 3. Coronal view of MRI of Case 2. Enlarged pituitary cytic infiltration of the stalk (Hematoxylin-eosin) with suprasellar extension. 508 KAMEL et al. developed DI. After replacement therapy with des- mopressin (20 rig/day, bid, via the intranasal route) her urinary output returned to normal.

Case 3

A 35-year-old man with an approximately 15 year history of panhypopituitarism was admitted to our hospital with fatigue, headache, diplopia and loss of libido. He had been receiving replacement therapy with L-thyroxine (100 pg, daily, po), prednisolone (7.5 mg, daily, po) and testosterone (depot testoster- one 250 mg, monthly, IM) since 1993 and discon- Fig. 4. Enlarged pituitary gland showing hyper and isoin- tinued to use testosterone three months before ad- tensity with thickening of dura on the upper and mission. bottom sides of the gland, indicating dura infiltration On physical examination he had a eunuchoid (MRI of Case 3). habitus and a dry-pale skin with diminished body hair. His visual field evaluation showed bilateral Case 4 concentric narrowing and he had right abducens paralysis. A 38-year-old woman was admitted for two He had normal urine output and urine specific months with polyuria and polydipsia. Her past gravity. All of his biochemical tests and complete medical history revealed no abnormality and she was blood count were normal. In addition to the low not taking any medication. She had regular menses levels of adenohypophyseal and target tissue hor- and had her last pregnancy 13 years previously. mones, was also found (Table 1). Her vital signs were normal and physical examina- His plain sella film showed an enlarged and dis- tion revealed no abnormality apart from grade Ib torted sella turcica. MRI revealed a pituitary mass, diffuse hyperplasia of the thyroid gland. showing hyper- and isointensive areas and expanding The blood count, erythrocyte sedimentation rate to half of the clivus, with thickening of the dura on and routine biochemical tests were found to be nor- the upper and bottom sides indicating dura infiltra- mal. Her daily urine output was 8 to 10 liters with a tion (Fig. 4). He was suspected of having nonfun- urinary osmolality of 103 mosm per liter, and the ctioning pituitary adenoma and for surgery the TNTS plasma osmolality was 301-310 mosm per liter. Se- route was used. The dura was very hard and thick rum basal and target tissue hor- and was so infiltrated by the mass so it could not be mones were all within the normal range. Prolactin separated from the mass. Half of the clivus was re- moved with a high speed drill. The mass was re- moved until adequate surgical decompression was achieved. On light microscopy predominant lymphocytic infiltration was noted. Immunohistochemical ex- amination showed diffuse CD45, focal CD20 and minimal CD3 positivity. His diplopia and panhypopituitarism continued after the operation. No surgical complication was observed. He is on replacement therapy with L- thyroxine (150 sag/day, po), prednisolone (7.5 mg/day, po) and testosterone (depot testosterone 250 mg, monthly, IM). Fig. 5. Slightly enlarged pituitary gland and diffusely thick- ened stalk of patient 4 on MRI. LYMPHOCYTIC HYPOPHYSITIS 509

levels were found to be high on two measurements a rare feature of the disease and has been reported in (29 and 52 ng/ml) (Table 1). Insulin hypoglycemia only six cases up to the present time [4, 10, 24, 34, 37, and thyrotropin releasing hormone tests revealed no 38]. anterior pituitary deficiency. Her thyroid autoanti- INHy was reported to be an entity distinct from bodies were found to be high (anti-M 139IU/ml; LHy. This disease is confined to the hypothalamus normal < 50, anti-Tg 324 IU/ml: normal < 50). and/or stalk and/or posterior pituitary [20, 25-27]. Water deprivation and desmopressin tests indicated Diabetes insipidus is the major clinical presentation central diabetes insipidus. of this disorder. Our two cases (cases 1 and 4) were Her plain lateral sella film was normal but the MRI regarded as having INHy since they had the evidence showed diffuse thickening of the stalk with a slightly of stalk and posterior pituitary involvement on MRI enlarged pituitary gland (increased convexity, Fig. 5). and diabetes insipidus. Growth hormone deficiency As lymphocytic hypophysitis was suspected, en- was suggested as a feature of INHy by some authors doscopic endonasal transsphenoidal biopsy was per- but we could not observe this condition in our formed from the posterior pituitary. On pathologi- patients on provocative tests. cal examination apparent lymphocytic infiltration Mild to moderate hyperprolactinemia, which was was observed. The lymphocytes were positive for observed in three of the presented cases, was reported CD45 (100%), CD20 (25%) and CD9 (5%) on im- in most of the patients with LHy and INHy [19, 22, munohistochemical staining. 24, 34, 45-47]. In a review article by Hashimoto et She is under medical supervision with desmopres- al. [48] hyperprolactinemia was found to be reported sin nasal solution for one year and her anterior pit- in 32.4% of the cases. The hyperprolactinemia in uitary hormone levels have all remained within the our cases was attributed to stalk involvement and/or normal range. compression. On the other hand, hypoprolactine- mia was reported in 36.1% of the cases [48]. Hypoprolactinemia in our case 3 probably occurred Discussion as a result of extensive destruction of the pituitary gland, including lactotrophs, by lymphocytic LHy is classically considered to be an autoimmune infiltration, since he had panhypopituitarism and reaction in the anterior pituitary and is predominant- cavernous sinus involvement. ly a disease of females and frequently associated One of the MRI findings in lymphocytic hypophy- with pregnancy or presenting during the postpartum sitis is an enhancing pituitary mass with or without period, but its occurrence in nonpregnant women suprasellar extension and was observed in two of our has also been reported [1-9, 11, 12, 14, 16, 17, 19]. cases. Stalk enlargement, which was present in two The case (case 2) with LHy presented in this paper cases (cases 2 and 4), has been reported to be was a nonpregnant woman who was also not in characteristic of LHy and INHy [17, 18, 25, 34]. the postpartum period. Observation of LHy in Marked contrast enhancement in images is a sign of men is rare and about 15 male patients have been inflammatory lesions of the pituitary [17, 23, 43, 49]. reported [10, 13-15, 17, 18, 23, 24, 26, 33, 34]. Our A diffusely enlarged pituitary gland with enhance- third patient was a male patient with LHy. ment can be a clue in diagnosing. In addition, a Adenohypophysial hypofunction characterized by nodular lesion in the stalk with a normal pituitary total or partial hypopituitarism and a pituitary mass image in MRI as in case 1 should be kept in mind are the most common clinical presentations in [32]. patients with LHy [2-19, 21-24, 28, 33-44]. Several Several findings suggest that autoimmunity is in- endocrine deficiencies including those of ACTH, volved in the pathogenesis of LHy and probably also TSH, LH, FSH and growth hormone, alone or in in the pathogenesis of INHy. Circulating antipitui- combination have been reported. Pituitary in- tary antibodies have been reported but the exact sufficiency was present in one patient of ours as relationship to the pathogenesis still remains obscure. panhypopituitarism (case 3). This case also showed A 20-50% incidence of coexistent autoimmune dis- signs of cavernous sinus involvement presenting as orders is also found in the literature in patients with lateral rectus palsy. Cavernous sinus involvement is LHy [1, 10, 14, 15, 21, 28-30, 37, 42]. As one 510 KAMEL et al.

patient with INHy (case 4) in the present report had minimal morbidity we suggest this approach for the Hashimoto thyroiditis, although accepted as a differ- diagnosis of both LHy and INHy. With the in- ent disorder, we suggest that patients with INHy creasing number of reports and with the awareness of should also be examined for the existence of other the different clinical presentations of disorders, the autoimmune diseases. number of such cases may increase. Although the Pituitary surgery is both diagnostic and in some diagnosis of LHy and INHy mainly depends on instances therapeutic in cases of LHy. Amelioration histological findings, unnecessary major resections of the symptoms of sellar mass, hyperprolactinemia can be avoided in this way. and pituitary dysfunction have been reported with Histologic examination represents the basis for surgery [3, 4, 7, 9, 11, 12, 29, 34, 37, 41, 46, 47, 50- confirming the diagnosis of LHy and INHy. Evalu- 52]. Among our patients hyperprolactinemia was ation of all four affected pituitaries examined in the resolved in two cases (cases 1 and 2) with surgery. present series revealed a typical polyclonal inflam- The procedure remained diagnostic for case 3 since matory infiltrate with a mixed T and B cell popula- his clinical status, panhypopituitarism and sixth tion as reported by other investigators [19, 24, 47]. cranial nerve palsy, did not improve with the opera- Care must be taken to distinguish LHy from a rare tion. Although the procedure is accepted to be safe, but similar condition, granulomatous hypophysitis. diabetes insipidus, which was developed after the Although the clinical presentation is usually pituitary operation in one of our cases, may occur as a com- insufficiency associated with a pituitary mass, this plication of surgery [9,14]. In addition development condition is characterized by nodular collection of of hypopituitarism and worsening of the existing epithelioid histiocytes and multinucleated giant cells clinical status were reported after extensive surgery but no lymphoid follicles [17, 31]. The pathological [9-11 ], so such aggressive procedures should be and immunohistochemical evaluations in all of our avoided in patients with LHy and INHy. four cases revealed polyclonal lymphoplasmacytic The correct preoperative diagnosis of INHy was infiltrate and some showed lymphoid follicles, and suspected in only one of our patients (case 4). In our since no granulomatous formations were detected in review of the literature we observed that preoperative any of the specimens, the diagnosis of granulomatous consideration of the diagnosis was very rare [4, 11, hypophysitis was excluded. 21, 24, 52] and that most of the patients underwent In conclusion, LHy and INHy should be consi- surgery with a preoperative diagnosis of tumoral in- dered in the differential diagnosis of lesions of the volvement as in our first three cases. But because of sellar region both in nonpregnant women and men. the extent of our experience of the disorders, a Clinical presentations of the disorders vary. Pitui- preoperative diagnosis of lymphocytic hypophysitis tary hypofunction with growing pituitary masses was suspected in the fourth case and an endoscopic and compressive symptoms, diabetes insipidus and endonasal transsphenoidal biopsy was performed. hyperprolactinemia with galactorrhea must be in- This procedure has been performed for lesions of the cluded in this spectrum of the diseases. Although sellar region, especially for the treatment of pituitary the diagnosis can only be established by histological adenomas [53-55]. This approach facilitates faster examinations, suspicion alone may avoid aggressive postoperative recovery, shortens the hospital stay, pituitary surgery, and endoscopic transnasal trans- and avoids traditional incision and postoperative sphenoidal pituitary biopsy can be a safe and alter- nasal packing. This technique was preferred for native way for the histopathological diagnosis of these reasons in our patient since she was suspected such cases. of having LHy before operation. Since it has

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