Lymphocytic Hypophysitis

Mise au point thématique

A review of 145 cases

N. BERESSI (1), J.-P. BERESSI (2), R. COHEN (1), E. MODIGLIANI (1)

Lymphocytic hypophysitis (LH) is a new clinico patho- Lymphocytic hypophysitis is a recently individualized logical entity, first described in 1962 by Goudie [46]. autoimmune endocrinopathy, similarto Hashimoto’s thyroi- With recent advances in radiological investigation and ditis. The frequency of the disease is probably underesti- technical refinements of trans-sphenoidal surgery, LH mated and some cases of idiopathic pituitary insufficiency cases are being reported with increasing frequency. A of adults or primary idiopathic empty sella syndrome might total of 145 cases have been reported to date, 102 of them be related to previously ignored LH. since 1990, with 121 histologically proven. LH is an autoimmune endocrinopathy characterized by an extensive infiltration of the anterior pituitary gland by chronic inflammatory cells, which can cause pituitary Pathological definition expansion and a variable degree of hypopituitarism closely mimicking the features observed in pituitary Thedefinitionoflymphocytichypophysitisremainshisto- adenoma. Involvement of the neurohypophysis rarely logical. In its classical form, adenohypophysis is infiltrated, occurs in LH. The disease mostly occurs at the end of in a focal or diffuse way, by chronic inflammatory cells, gestation or during the early post partum, but not exclusi- chiefly lymphocytes and macrophages [159]. Sometimes vely: 23 cases of men and 13 cases of menopausal women neutrophilic and eosinophilic polynuclear cells coexist with have been reported in the literature. When no diagnosis is avariabledegreeoffibrosis.Nomicro-organismisobserved. made, the sometimes insidious clinical course can Neurohyphophysis is usually spared by the disease, but in progress towards hypopituitarism and can result in a lethal 8 cases,involvementoftheinfundibulum,neurohypophysis, outcome. Better known since the last five years, clinical and pituitary stalk, by the same pathological lesion was management remains a question of debate. Up to now, the observed [3, 108, 112, 158]. majority of cases of adenohypophysitis were surgically treated leading to severe secondary endocrine deficien- cies. Recently some authors (including in one personal MACROSCOPIC FINDINGS case report) reported a new approach with corticosteroid therapy, which was successful in reversing the hypophy- The gland can be normal, grossly enlarged or atro- seal mass and the pituitary endocrine insufficiency. phied. These different aspects are probably related to different stages of the natural course of the disease, similar to that observed in autoimmune thyroiditis. At trans-sphenoidal surgery, the gland is unusually firm, (1) Service d’Endocrinologie, Hôpital Avicenne, 93009 Bobi- tough in its appearance and at palpation. The color gny. varies from white or gray to yellow. When the lesion is (2) Service d’Endocrinologie, Hôpital Saint-Louis, Paris. encapsulated, it is wrapped in a dense pituitary capsule and if not, it appears adherent to the wall of the sella Correspondence and reprint requests: N. BERESSI, at the address above. and is difficult to remove. Total extirpation of the mass is thus impossible in the majority of the cases [6, 81] Article reçu le 1er décembre 1998 ; acceptation définitive le 4 as LH is difficult to shell out from normal pituitary janvier 1999. tissue. 328 N. BERESSI ET AL.

HISTOLOGICAL CRITERIA [27, 51, 61, 83, 158]. In LH, diabetes insipidus (DI) is uncommon, and neurohypophysis has been reported to be The anterior pituitary gland shows a diffuse lympho- histologically normal in most cases [27]. Unlike LINH, cytic infiltration seen in hematoxylin and eosin stain with the inflammation is localized to the neurohypophyseal a withdrawal of the normal pituitary architecture. This system and the disease is known to be a cause of central extensive cellular infiltration consists chiefly of lympho- ID [61, 75, 163, 165]. In some cases, these 2 diseases cytes accompanied by some plasma and mononuclear seem to be dissociated: adenohypophysis appears to be cells; a few spotted eosinophil cells has been even seen [3, spared on MRI [61, 75] and histological biopsy [165] with 27]. While follicles with a germinal center can often be features distinct from LH, but in some cases they may be noted [6], no giant cell granuloma has been observed. The concomitant events, with a sellar mass localized in the lesion is global, but mostly inhomogeneous in the majo- neurohypophysis associated with inflammation of the rity of cases. The residual gland shows foci of uninvolved adenohypophysis [109, 163]. pituitary tissue which appears morphologically normal. Various degrees of edema and fibrosis are seen, but no adenoma feature is found and no microorganism is observed. The pituitary destruction is not confined to a Clinical findings particular cell type, as showed by immunocytochemical staining. Up to February 1998, 145 cases have been published in The lymphocytic infiltrate, studied by various authors [1, the English literature: 103 were diagnosed from surgical 6, 27, 40, 50, 51, 61, 66, 75, 83, 108, 119, 134], is made of material, 15 were diagnosed at autopsy, 27 were not histo- activated T cells, with a dominant expression of CD4 gically proven [37, 57, 161, 178]. Clinical, morpholo- marker (CD4 +/CD8 +, ratio 2: 1) and macrophages expres- gical, and radiological findings will be now discussed, as sing the MT1 marker [66, 83]. The predominance of T cells well as the evolution of medical and surgical treatment, over B cells is in agreement with the characteristics of the following the presentation of a personal case, treated with infiltrate observed in other autoimmune diseases such as success by corticosteroids [8]. IDDM and Hashimoto’s thyroiditis [18, 32]. A 27-year-old woman developed chronic headache 13 months after giving birth. Her pregnancy was unremar- kable and she had a normal delivery. Persistent headache, ELECTRON MICROSCOPIC FEATURES associated with visual symptoms and amenorrhea, with galactorrhea led to a cranial CT-scan and magnetic reso- The electron microscopic characteristics have been nance imaging (MRI). MRI revealed a markedly enlarged studied by various authors [1, 6, 50, 108]: in the most pituitary gland with a supra-sellar extension without any dense areas of inflammatory cell infiltration, pituitary erosion of the dorsum sellae. Because of mild hyperpro- cells show interdigitations with activated lymphocytes at lactinemia, bromocriptine was prescribed at the dose of their common interface. Some of these pituitary cells 5mg/daily and was soon followed by the transient appea- contain large lysosomal bodies fusing with secretory rance of menstruation. After two years of follow-up loss, granules as well as an increased number of swollen mito- panhypopituitarism was revealed by acute adrenal insuffi- chondria indicating a possible oncocytic transformation. ciency, without hyperprolactinemia (table I). Magnetic No immune complex deposits are identified, and the resonance imaging showed that the pituitary mass was the vessels examined are usually normal. same as previously described, with a superior triangular shape displacing the optic chiasm. A homogenous mass enhancement was observed after gadolinium injection PIT FALLS OF PER SURGERY BIOPSY ANALYSIS (fig. 1A). In general per surgery pathological analysis is not The occurrence of hypopituitarism with transient hyper- contributive. Diagnosis is usually fibrous adenoma [23, prolactinemia a few months after pregnancy, associated 54], normal hypophysis with rare lymphocytes infiltration with previously described radiological aspects led us to [144], or non specific chronic inflammatory process. consider the diagnosis of LH. Nuclear antibodies were Diagnosis is even more difficult during the post partum negative, as well as pituitary antibodies. Human leukocyte period in the presence of lactotroph cell hyperplasia, antigen serological class II typing was DR3/DR4. which can mimic prolactinoma [10]. Nevertheless, in Because of the absence of any visual complications, and three cases [7, 81, 97] frozen sections gave the correct the patient refusal to surgery, prednisone was given at a diagnosis, thus allowing limited surgery. Thus, the benefit daily dose of 60mg for three months, then progressively of per surgery analysis seems to be limited. decreased for the next six months. With this treatment, a clinical improvement consisting of disappearance of headaches and return of menstruation DIAGNOSIS WITH LYMPHOCYTIC INFUDIBULO- was observed. The biological feature showed a gradual NEUROHYPOPHYSITIS (LINH) recovery of all hormonal pituitary axis (table I). The MRI done after 3 months showed a substantial reduction of the Lymphocytic adenohypophysitis and lymphocytic pituitary mass reaching 70% after six month and sustained infundibulo-neurohypophysitis are distinctly specific enti- at 9 months (fig. 1B). Five months after interruption of ties, probably caused by different autoimmune processes steroid treatment, the patient relapsed with panhypopitui-

LYMPHOCYTIC HYPOPHYSITIS 329

Table I. Ð Endocrine investigation before and after steroid treatment (60 mg/d) with prednisone during 3 months, then tapered for 6 months: baseline values and response of LH, FSH, ACTH, cortisol, and prolactin to the injection of LHRH, CRH, and TRH*. Before After Hormones treatment treatment June March January 1990 1992 1993 ** LH (1-7UI/L) 1.6 1 0.7 Peak after LHRH  3.2 1.6 FSH (3-8UI/L) 5 5.6 4.2 Peak after LHRH  6.8 4 Estradiol (37-730pM/L)  68 151 TSH (0.2-4.5mUI/ml) 0.88 5.9 1.79 Peak after TRH  8.8  FT4 (10-30pM/L) 11.8 1.4 8.1 ACTH (10-50pg/ml)  24 14 Peak after CRH  134 32 Cortisol (345-662nM/L)  32 101 Peak after TRH  107 156 Prolactin (130-700mU/L) 1440 376 646 Peak after TRH  342 1074 *LH: luteinizing hormone; FSH: follicule stimuling hormone; ACTH: adreocorticotropic hormone; TSH: thyroid-stimulating hormone; TRH: thyroid releasing hormone; LHRH: luteinizing hormone-releasing hormone; CRH: corticotropin-releasing hormone; FT4: free thyroxine. **After withdrawal of levothyroxine for 30 days, of prednisone for 15 days, and of hydrocortisone for 1 day.

tarism and an increase of pituitary volume. Steroid therapy was resumed and a trans-sphenoidal pituitary biopsy was performed, confirming the diagnosis of LH. The patient still receives steroid therapy.

A SPECIFIC BACKGROUND AND ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES

The disease shows a striking female predilection with a sex ratio of approximately 5. 3 female for 1 male; it commonly affects young women during late pregnancy or Fig. 1. Ð a) coronal Gd-DTPA-enhanced, T1-weighted image (550/22/1) at the time of admission after gadolinium infusion. the postpartum period, in two third of the cases. The mean There is a large pituitary mass with a symmetrical extension age at presentation is 31 years in females compared with and homogeneous enhancement. Compression of the optic 42 years in males, with a range from 14 to 74 years. chiasma by a suprasellar extension of the mass is seen. Note Patients with LH are more likely to have other autoim- an unusually thickened and elevated diaphragma sellae as a mune diseases, as an association is found in 20% of cases discrete hypointense line outlined by the enhancement. b) Coronal Gd-DTPA-enhancement T1-weighted image, 6 (28 cases out of 145), principally with autoimmune months after therapy. The mass in the pituitary fossa has thyroid diseases (82% of cases) [11, 46, 62, 66, 99, 102, significantly decreased in size. Enhancement extends upward 113, 118, 122, 135, 138, 148, 158, 167]. Other autoim- to a distal thickened stalk. mune diseases can precede or follow LH by a few years. LH is now part of the autoimmune polyendocrinopathies syndrome (APS) [101]. Among published cases, three cases of Addison disease were reported [78, 135, 140] including one associated with hypoparathyroidism [78] case of autoimmune hepatitis associated with Hashi- and one associated with retroperitoneal fibrosis and moto’s thyroiditis. Hashimoto’s thyroiditis [148]; 2 cases of pernicious Idiopathic retroperitoneal fibrosis is a rare systemic anemia were noted [58, 92], including one associated with autoimmune disease [74, 117, 130]. Fibrosis can occur in Hashimoto’s thyroiditis [58], as well as 2 cases of a few organs including the hypophysis [47]. In the case Raynaud’s syndrome [34, 123], 1 case of IDDM and 1 reported by Sobrinho [148], autopsy revealed a fibrotic 330 N. BERESSI ET AL.

Table II. Ð Clinical features in lymphocytic hypophysitis ding to the CSF space or a passive dissemination of (n=145). inflammatory cells. Symptoms Frequency (%) femal gender 84 Endocrine disorders relationship with pregnancy or post partum 68 post partum agalactia 33 Symptoms resulting from partial or complete anterior amenorrhea 40 pituitary hypofunction are present in nearly 85% of tumoral syndrome 60 hyperprolactinemia 30 patients. The degree of endocrine failure is not correlated anterior pituitary insufficiency 85 to the radiological volume of the mass in opposition to the diabetes insipidus 18 data found in pituitary adenomas. In patients with LH, associated autoimmune diseases 20 hypopituitarism is present with small mass or even unen- larged pituitary, while in patients with tumor it is unusual to see such a degree of panhypopituitarism except when the mass is very large [27]. Biological panhypopituitarism is found in 32% of patients, after complete hormonal retroperitoneal mass involving iliac vessels, mainly investigation (38 cases out of 117). The endocrine deficits composed of dense, sometimes hyalin collagen contai- are usually dissociated. ning foci of lymphocytes clustered around vessels and forming rare germinal centers. The other histologic lesions Gonadal function concerned the endocrine organs with massive lymphocytic infiltration of thyroid, adrenals and hypophysis. In 40% of females (85% of affected subjects), the first clinical symptom reported is amenorrhea, the origin is variable. The association of amenorrhea and galactorrhea CLINICAL PRESENTATION is not frequent, encountered only in 10% of cases, contrary to prolactinoma. As LH occurs mostly during Duration of the symptoms rangesfrom 1 month to 5 years, pregnancy or postpartum period in 68% of affected but the rather rapid onset of hypopituitarism can distinguish women, an insufficiency in breast feeding was observed LH from adenomas. Most of the patients have completed in 33% of these women (n=74). In males, biological hypo- hypopituitarism in less than one year, except in 5 cases gonadism is present in 82% of cases (19 cases out of 23). whereaslowcourseoftwoyears[8,109,173]andfiveyears [65, 123] was observed. The clinical presentation involves two categories of symptoms, those resulting from mass Hyperprolactinemia effects, which occur in 60% of patients, and the variable Despite the relatively low occurrence of amenorrhea- degree of hypopituitarism associated or not with hyperpro- galactorrhea syndrome, hyperprolactinemia is found in lactinemia which is found in 85% of patients (table II). 30% of patients with LH, galacthorrea was present only in 13 patients (12%) [25, 131]. Its interpretation remains Tumoral syndrome controversial. Prolactin hypersecretion is a physiologic feature during pregnancy and postpartum period. In cases with The tumoral syndrome is characterized by its sudden expanding supra-sellar mass, hyperprolactinemia might be occurrence and its rapid course. a consequence of the compression of the pituitary stalk, Headache and impaired vision are the most frequent which prevents the inhibitory regulation of prolactin release symptoms reported. Headache is observed in 60% of by hypothalamic dopamine. But, as suggested by Bottazzo, cases; onset is noted during the third trimester of pre- the role of anti-PRL secreting cell antibodies could be gnancy and is exacerbated after delivery. Headache is comparable to what is observed with TSH receptor stimu- localized to the frontal, temporal or retro-orbital region. lating antibodies in Graves’disease [15]. Its frequency is higher than reported in adenoma [60, 93]. Various visual disturbances are observed in 40% of Adrenal axis cases, including visual field defects, decreased acuity, blurring and diplopia. Among them a chiasmal syndrome, ACTH deficiency is the most frequent endocrine failure as temporal hemianopsia or superior quadranopsia, is in patients with proven LH. Such deficiency is present in found in 77% of cases [89]. A loss or decrease of visual 65% of patient (n=141) and is responsible for the severity acuity is observed in 40% [70], and 7 patients present of the disease as in 12 patients death was directly related to diplopia arising from an extension of the process into the acute adrenal insufficiency [34, 42, 43, 46, 58, 87, 88, 135, cavernous sinus with a sixth nerve palsy [2, 112, 156]. 139, 158]. Hypoglycemic comas were reported in 4 of these Acute degradation of blurring vision is often the reason patients. The corticotrophin deficit was isolated in 14 cases for surgery emergency. [2, 37, 85, 102, 122, 135, 158, 167, 169]. Selective loss of Occasionally, aseptic meningitis or CSF leucocytosis is corticotrop cells on histological study has been reported by observed secondary to the pituitary lesion [56, 166]. CSF few authors [66, 90, 135] and was well correlated with the reaction, may represent an autoimmune reaction exten- clinical presentation of cortisol deficiency. LYMPHOCYTIC HYPOPHYSITIS 331

Thyroid dysfunction resolution of the mass and non correlated partial or total recovery of adenohypophyseal function [12, 20, 24, 44, Clinical symptoms of thyroid dysfunction were observed 60, 86, 94, 99, 113, 62, 118, 122, 123, 138, 158, 178]. in 18% of patients with LH (26 cases out of 145). Autoim- Occasionnaly, the pituitary may become strikingly and mune thyrotoxicosis episodes were noted in 10 patients, cli- atrophic at the chronic stage [27] and may eventually nical hypothyroidism in 15 cases, and myxoedematous coma cause empty sella syndrome [104, 113]; such a course was in one patient. A biological thyreotroph deficiency was observed in 7 patients within a delay of 3 months to found in 60% of patients (71 cases out of 117). Among them, 6 years [62, 65, 99, 111, 113, 127]. Resumption of normal isolated thyreotroph deficiency has been described [84]. hormonal function is rare and does not correlate with the mass regression. Somatotroph axis The long-term course of LH is not well documented. The somatotroph axis has been rarely documented. The disease course can be long. In our case [8], the tumo- Basal GH levels were low in 54% of the patients tested ral syndrome was present with hyperprolactinemia up to (n=87). Insulin-induced hypoglycemia revealed a GH two years before surgical procedure and hypopituitarism insufficiency in 17 cases out of 18 studied [13, 37, 40, 51, occurred progressively. Naik [103] reported a case of LH 77, 84, 90, 97, 100, 109, 111, 118, 119, 142, 176, 178]. In in which pituitary gland enlargement persisted for more five of those, diabetes insipidus was associated with GH than 10 years. In another case, reported by Nishokia deficiency [61]. [110], recurrence of LH occurred after a long free interval. In men, a decreased libido and sexual impotence were A prompt corticosteroid treatment was dramatically effec- the most frequently observed symptom. Endocrine inves- tive on visual defect with significant reduction of the lesion tigation revealed 56% panhypopituitarim (13 cases out of on MRI. But the possibility of recurrence after steroid 23) and 82% hypogonadism (19 cases out of 23) withdrawal was noted in a few cases reports [8, 90, 102]. Thus LH frequently result in isolated ACTH deficien- These observations suggest that long-term follow-up cies or combinated adrenal and thyreotroph deficits unlike with endocrinological and radiological examination is endocrine failure patterns observed in non-secreting ade- necessary for surveillance of patients with LH, as no pre- noma and Sheehan syndrome, where amenorrhea and dictive factors regarding the time course of the disease has somatotroph insufficiency are most frequent. been identified so far [120]. Nevertheless, it is important to underline that there is no early serological marker of the disease, as reported in Neuro-endocrine disorders IDDM and Hashimoto’s thyroiditis, which would be lin- ked to the onset of the autoimmune process. Although it has been reported that diabetes insipidus is uncommon in LH, Thodou et al. reported it in 14% to 19%. To our knowledge, 26 cases were reported [1, 3, 26, LH and pregnancy 56, 63, 77, 99, 109, 113, 158, 173]. In these cases, thicke- No data on the natural history of the disease in a subse- ning of the stalk and loss of T1 hyperintense signal of the quent pregnancy is available so far. Six patients conceived posterior pituitary was frequently noted on MRI. Neuro- spontaneously, three months to five years after diagnosis, hypophyseal dysfunction may be attributed to direct with no apparent adverse influence of LH on pregnancy inflammatory cell invasion, destruction or compression of [11, 20, 66, 82, 83, 164]. Pregnancy did not have any either the posterior lobe or pituitary stalk. adverse effect on the course of the disease. Moreover the resolution of the pituitary lesion was noted in one case Inflammation parameters [164]. LH should not be considered a contraindication to pregnancy if close neuro-ophtalmological and endocrine In the majority of published cases, parameters of inflam- follow-up is planned [164]. mation were not documented. In 15 cases moderate increase in sedimentation rate (30/60mm/h) was observed [50, 56, 79, 118, 119, 132, 142, 148, 164, 176]. Neuroradiological findings Lymphocytosis and eosinophilia were seen in one male case [49]. In a single case immunoelectrophoresis showed The specific radiological abnormalities of LH may an increased IgG and a slightly increased IgM ratio [148]. suggest the diagnosis before neurosurgical intervention. Lumbar puncture, detected lymphocytes in the CSF [56, 166] or an increased leukocyte count in the CSF [79], but in most cases results of lumbar puncture were normal [108]. SKULL RADIOGRAPHS Thepituitaryfossamaybeslightlyenlarged[7,50,56,90, Natural course of the disease 99, 124, 169], but surprisingly normal size is frequent even when the pituitary mass is relatively large. Minimal abnor- A total of 13 deaths were disease-related (acute adrenal malities may be observed: thinning or decalcification of the insufficiency or hypopituitarism) [42]. Inversely, 19 spon- dorsum sellae withoutobviousballooning. A flat sellar floor taneous regressions of the mass have been also reported is mostly observed which contrasts with the unilateral with sometimes a dissociation between the radiological depression generally found in pituitary adenomas. 332 N. BERESSI ET AL.

MAGNETIC RESONANCE IMAGING (MRI) FINDINGS “dural tail “, no enhancement of the adjacent dura mater is observed in most cases of pituitary adenoma [2]. Typical aspects of LH on MRI The lack of specificity of images Some MRI characteristics may help in LH diagnosis in the early, presumably active, phase of the disease, because Any inflammatory mass has interstitial spaces and they are quite different from those of typical pituitary ade- increased water content in the acute phase of inflamma- noma and despite the physiologicpituitary enlargementthat tion, explaining relatively low signal on T1 weighted ima- occurs during pregnancy [35, 45]. The first MRI was reali- ges and less mass effect on adjacent structures than a solid zed by Levine in 1988 for the diagnosis of LH. The pitui- tumor. Pituitary stalk enlargement and thickening are also tary mass has a suprasellar extension, deplacing the optic observed in neurosarcoidosis and are probably due to chiasma upward in 64% of cases (77 cases out of 120) and inflammation, hyperemia and stalk edema. Marked showing a symmetrical and often triangular aspect. enhancement, as typically found in inflammatory lesion of The pituitary mass gives relatively low signal on pre- the pituitary [156], can be attributed to the increased contrast T1 weighted images, and is iso-intense to gray interstitial space with free diffusion of contrast medium matter. However a relatively high signal on T2 weighting into the extra cellular space, where an increased number may be a significant finding in LH, although not specific. of water protons is available [138]. Involvement of the cavernous sinus is rare, and was observed only in 7 cases [2, 112, 123, 156, 158, 169]. The posterior lobe is generally normal but the loss of hyperintense “bright spot” signal of the normal posterior Pathogenesis pituitary on sagittal view [41], and thickening of the pituitary stalk have been reported in several cases of clinical DI CLINICAL BACKGROUND [1, 2, 26, 61, 97, 109, 113, 138, 173]. Pituitary stalk enlargement and thickening, although not reported as classical The autoimmune nature of LH is supported on the radiological features of LH, were encountered in 15% of presence of typical pathologicinflammatoryfeatures, circu- the cases (18 cases out of 120) [1, 3, 56, 79, 109, 112, 113, lating organ specific autoantibodies and other coexisting 158, 166, 173]; in all the cases a stalk deviation was repor- autoimmune diseases [15, 101]. For various authors, LH is ted [137]. It is not clear, whether the stalk enlargement is part of the type I autoimmune polyglandular syndrome [69, a non specific reaction or an extension of the lesion along 101, 106]. Various clinical, biological, experimental and the pituitary stalk. anatomopathological evidence [39, 67, 121, 125, 151, 171] Gadolinium contrast enhanced MR images reveal an favors the autoimmune origin of the disease. intense homogeneously triangular enhancement of the High incidence of the disease during the third trimester pituitary mass [2] associated with an abnormal dural of pregnancy or in the post-partum period are in favor of an enhancement, that seems to be pathognomonic of LH, it autoimmune process [5]. The alteration of the immune is described as a “dural tail”, consisting of strips of abnor- system during this period explains the exacerbation of mal enhancing tissue along the dura mater. An abnormal autoimmune disease (AID), as observed in lupus erythema- enhancement along the posterior side of the infundibulum tosus [149]. Various hypotheses concerning the mechanism extending to the hypothalamus floor was also observed have been proposed: decreasing levels of helper T cells [2]. Extrapituitary components such as focal sub mucosa with loss of immune surveillance and self recognition sphenoidal sinus enhancement consistent with an inflam- [171], or loss of “fetal suppressorfactor” in the post-partum matory reaction probably spreading from the pituitary period which allows an autoimmune reaction to occur. fossa to the sinus [2, 3, 5] or involvement of the cavernous Therefore in cases with temporal relationship to pregnancy, sinus were also noted [2, 112]. symptoms may worsen in the post-partum period. The coexistence of lymphocytic hypophysitis with other autoimmune disorders (AID) is found in 20% of the MRI in the differential diagnosis with adenoma 145 cases described, as already emphasized by Cosman [27] and Lee [79]. The most frequent associated AID are In adenoma the mass is on one side and not symmetrical. thyroid autoimmune disease (cumulating cases n=21) The stalk is not thickened, but often deviated. A low signal such as Hashimoto’s thyroiditis, post partum thyroiditis, on precontrast T1 weighted images is uncommon in solid painless thyroiditis or Graves’disease. Another prominent pituitary macroadenomas [2, 138]. In the case of macroade- feature of AID is the presence of autoimmune multiple nomas, a posterior pituitary lobe may occasionally be seen, organ failure found as Biermer anemia, Addison disease, but is often deformed or displaced. After injection of gado- primary hypoparathyroidism, and insulin dependent linium, pituitary adenoma usually shows only moderate diabetes mellitus (IDDM) in the same individual [43, 46, enhancement. Occasionally, a ring-like enhancement con- 58, 78, 135]. sistent with a central necrosis aspect is observed in pituitary In the few cases where the major histocompatibility adenomas complicated by hemorrhage, necrosis, or infarc- complex (MHC) class II antigens were studied (17 cases), tion. These aspects are rare in LH and were reported in only class II typing was DR4 (41%), as usually observed in 5 cases [21, 56, 64, 164, 169]. In opposition to the LH other AID [8, 53, 123, 150, 156, 176]. DR5 was also LYMPHOCYTIC HYPOPHYSITIS 333 reported, in 4 cases (23%) [40, 49, 122, 142], usually the assay is difficult to perform, its sensitivity is low and found in Graves’disease and thyroiditis in the Japanese its specificity and predictability in LH are poor. The population [48, 147]. multiplicity of target auto-antigens used for the assay, Theautoimmunepathogenesisisfurthersupportedbyultra because the specific one is still unknown, makes the assay structural analysis, showing that cytotoxic lymphocytes are not as reliable as the other antibodies used in autoimune intimately in contact with anterior pituitary cells [6, 7]. endocrine diseases as IDDM, Hashimoto’s thyroiditis and Graves’disease.

EXPERIMENTAL MODELS Techniques Experimental animal models have been useful in showing that LH is a transferable autoimmune disease: The first description of Ab directed against the pituitary Ð Triplett observed that LH can be induced by the reim- was made by Engelberth and Jezkova in 1965 [36]. These platation of autologous pituitary tissue in frogs, after authors used complement consumption test, with homoge- surgical removal. In this model, the pituitary graft was nate prepared from anterior lobes of human pituitaries. acutely rejected and the pathological analysis of the reim- They tested the serum of 128 post-partum women three planted tissue showed comparable results as the one times: at the end of pregnancy, at delivery, and at the fifth observed in LH. These results are in favor of a loss of or seventh day after birth. The Ab became positive only tolerance after primary removal of the pituitary [162]. after five days in 18% of parturients. Among them, 25% Ð Levine [80] has, in 1967, used a model of adenohypo- progressed towards adenohypophysis insufficiency, ver- physitis induced by the subcutaneous injection in rats, of sus 4% in the group without Ab. Since this first descrip- pituitary anterior lobes homogenates, with complete tion, multiple techniques have been described, but the Freund’s adjuvant. In this model, LH is observed two to specificity and sensitivity of the methods were not always three weeks after the injection of homogenates and seems clearly defined (table III). The most widespread techni- limited to the pituitary, sparing other endocrine glands. ques are the indirect immunofluorescence assay using, in The pituitary cellular infiltrate is made of mononuclear initial experiments, unfixed frozen section of fresh human cells, monocytes, lymphocytes and a few epithelioid cells. pituitary gland obtained at hypophysectomy for advanced The disease appeared more severe in a small subgroup of carcinoma of the breast [36], followed by techniques pregnant and postpartum rats and has been related to the using rat pituitaries [126], and in recent publications, hypervascularization of the pituitary gland during this cultured rodent pituitary-derived cell lines (corticotrophin period as well as to high estrogen levels. secreting mouse AT20 cell and GH-PRL secreting rat Ð Klein [71] has used rabbit females injected with GH3 cells) [153, 154]. According to the technique used, homologous pituitary homogenates with adjuvant. Out of Ab directed against all varieties of pituitary cells (PRL, the seven animals, five developed a lymphocytic infiltra- GH, ACTH), may be found, the prolactin-secreting cell tion limited to the anterior pituitary gland. Four affected being the predominant type. rabbits had a positive lymphoblastic transformation test in Therefore, as it depends on the type of techniques used, presence of pituitary tissue in vitro. Interestingly, the the interpretation of the published results is difficult. severity of the infiltrate correlated with the level of radioelement incorporation during the transformation test. But in vivo no circulating pituitary autoantibodies were Sensitivity found in immunized rabbits serum. Ð Rubella virus has been used as a triggering factor Because circulating antipituitary Ab measurement is inducing LH in the animal model of Yoon [177]. In the difficult to perform and not routinely available, Ab were Syrian hamster, the injection of Rubella recombinant detected in only a minority of patients with LH: among glycoproteins, E1 and E2, is followed after two weeks by the 145 cases reported in the English literature, 38 were the appearance of LH in 50% of the animals studied and tested for pituitary Ab and 8 (21% of cases) were positive the production of antibodies directed towards pituitary [19, 62, 44, 90, 111, 118, 142, 174]. Suguira noted that cells. Furthermore, the disease is prevented by neonatal the presence of Ab against pituitary depended on the tech- thymectomy, suggesting the role of T lymphocytes at the nique used [153]. Moreover the sensitivity seems to origin of disease. decrease when human pituitary tissue is used [126]. Out All these results are consistent with the role of an of 18 IDDM patients, the percentage of anti-pituitary Ab autoimmune reaction in the genesis of human lympho- varied from 16.7% to 66.7% depending on the type of the cytic hypophysitis. pituitary cell line (respectively GH3 and AT20) used for the assay [154]. However, a longitudinal study [68] in patients with hypopituitarism indicated that anti-pituitary ROLE OF PITUITARY AUTOANTIBODIES Ab titers fluctuate and may disappear during the course of the disease without any improvement of pituitary func- In many endocrine autoimmune diseases, serum autoan- tion. Interestingly in this same study, Ab were also found tibodies (Ab) act as serological markers of the disease. in patient relatives, suggesting a hereditary background But anti-pituitary Ab set up a particular problem because for such autoimmune disease. 334 N. BERESSI ET AL.

Table III. Ð Techniques of anti pituitary Ab assay. Authors Year Antigen used Cell target Method Clinical context % positive Engelberth 1965 human pituitary complement consumption test Sheehan syndrome (n=128) 18 Bottazzo 1975 human pituitary prolactin indirect immunofluorescence polyglandular disease (n=287) 6.6 Bottazzo 1980 prolactin indirect immunofluorescence growth disorders (n=483) 6 Pouplard 1982 guinea pig pituitary indirect immunofluorescence pituitary deficiency (n=54) 44.4 human pituitary indirect immunofluorescence pituitary deficiency (n=54) 13 Scherbaum 1987 human fetal pituitary ACTH/LH indirect immunofluorescence Cushing’s disease (n=51) 25.5 Sugiura 1987 AtT20 (mouse) indirect immunofluorescence IDDM (n=18) 66.7 GH3 (rat) indirect immunofluorescence IDDM (n=18) 16.7 AtT20 (mouse) indirect immunofluorescence ACTH deficiency (n=5) 100 Kobayashi 1988 rat pituitary indirect immunofluorescence Hashimoto’s thyroiditis (n=34) 55.8 rat pituitary indirect immunofluorescence Graves’disease (n=28) 7.1 Komatsu 1988 AtT20 (mouse) indirect immunofluorescence primary empty sella (n=32) 75 GH3 (rat) indirect immunofluorescence primary empty sella (n=32) 47 GH3 (rat) indirect immunofluorescence GH adenoma (n=9) 11 AtT20 et GH3 indirect immunofluorescence prolactinoma (n=9) 22 Kajita 1991 GH3 (rat) indirect immunofluorescence ACTH deficiency (n=7) 57 Crock 1993 human pituitary immunoblotting (titres up 1/1000) idiopathic GH deficit (n=19) 16 human pituitary immunoblotting (titres up 1/1000) secondary GH deficit (n=14) 7

Specificity sera of 118 patients with IDDM had anti-prolactin cell antibodies. In recent study, Kobayashi et al. [73] found a In addition to the previous unsolved technical problems, frequency of pituitary Ab higher in IDDM (56%) and non pituitary Ab appear to be less specific or predictive of the IDDM (24%) patients than in healthy control subjects LH than other antibodies in autoimmune endocrine (6%). Similar results were found in patients with Hashi- diseases as IDDM, Hashimoto’s thyroiditis and Gra- moto’s thyroiditis and Graves’disease [72, 155]. ves’disease. They have been found in various non autoimmune pituitary diseases: pituitary adenoma [76, 126], Cushing’s Identification of the target autoantigen disease prior to surgery [141], Sheehan syndrome [36], empty sella syndrome [76], isolated growth hormone defi- Bottazzo et al. [14], showed that pituitary Ab were direc- ciency [28], and idiopathic hypopituitarism [68]. Komatsu ted against a cytosolic fraction involved in the synthesis in 1988 [76] showed, in 75% of 32 patients with primary and transport of hormone rather than the hormone itself. empty sella syndrome, the presence of pituitary Ab using Yabe et al. [175], showed evidence by Western blot analy- indirect immunofluorescence with AT20 cells and in 47% sis that the sera from 6 patients (which showed various stai- using GH3 cells. No correlation with hypopituitarism was ning patterns by IF methods) reacted with various found in these patients. The frequency of positivity for components of the rat pituitary membrane and cytosolic pituitary Ab was still higher in patients with the empty fraction of different molecular weight (the 97.5 kDa, 65 sella syndrome than in patients with pituitary adenoma and 47 kDa bands correlated to one staining pattern) reflec- (12% and 16%, respectively with the two methods) or dia- ting possible different pituitary antigens. Only anti-ACTH betes insipidus (33% with the two methods). In 1980, Bot- antiserum recognized several bands between 22-110 kDa; tazzo [16] investigated 483 children with various growth other specific rat pituitary hormone Ab (LH, FSH GH) did disorders, and 6% of the sera reacted with isolated pitui- not recognize rat pituitary antigens. Recently, Crock [28] tary cells. Thus, despite some methodological restrictions, reported the detection of anti-pituitary Ab, by immunoblot- the presence of pituitary Ab seems to be correlated with ting with human pituitary tissues as antigens. A 45 kDa an evolution towards hypopituitarism only in the post-par- pituitary specific membrane protein was identified as an tum period [36, 95]. It remains unclear whether these Ab autoantigen in one of 19 patients with idiopathic growth have any diagnosis or predictive value for hypopitutarism, hormone deficiency associated with an empty sella syn- as there is still no definite correlation between the drome. A 43 kDa, pituitary and brain membrane protein presence of pituitary Ab and a corresponding pituitary was identified as an autoantigen in two patients with hormone deficiency. growth hormone deficiency. Pituitary Ab can even be found in the absence clinical Thus, the exact role of the Ab in the pathogenesis of LH pituitary disease, as in patients with other autoimmune remains largely unknown. Unlike the passive transmission diseases. The presence of anti-prolactin cell Ab is obser- of AID by serum such as experimental myasthenia [160] ved in 7% of the serum of patients with autoimmune or experimental autoimmune thyroiditis [170], data polyglandular disease associated with primary hypopara- concerning experimental hypophysitis do not demonstrate thyroidism, but without evidence of pituitary dysfunction an important role for pituitary autoAb in pathogenesis of [14]. Bottazzo and Doniach [17, 96] found that 15% of the LH [177]. Contrary to other AID, sensitivity and specifi- LYMPHOCYTIC HYPOPHYSITIS 335 city of pituitary Ab do not allow early diagnosis of the of disease after tapering or withdrawal of corticosteroid disease as in IDDM, and do not shed light on the natural [3, 8, 56, 112, 123]. Duration of treatment and doses used history of the disease. are not the subject of a general agreement, however high doses (2 mg/kg) should be preferred in order to quickly evaluate the response to such therapy. Although its effi- cacy in this disease remains uncertain [108, 134, 158] Management and treatment conservative treatment with corticosteroids has been recommended when there is no gross visual disturbance As the natural course of the disease, seems variable and [2, 8, 12, 27, 40, 128, 150]. Corticosteroids seem also the sometimes of long duration, the management of LH most logical treatment of LH occurring during pregnancy remains controversial. or post-partum, where the disease may improve late after pregnancy.

SURGERY Other immunosuppressive drugs Two-thirds of the published cases underwent surgery because preoperative diagnosis was pituitary adenoma Others immunosuppressive drugs such as cyclosporine with chiasmal compression. After surgical removal of LH, or FK506 (Tacrolimus) have not been used in the treat- recovery of hormonal pituitary deficiency is rare. Surgery ment of LH. Their potential benefit in the treatment of the is deleterious on the endocrine function since approxima- disease has yet to be demonstrated. tely one third of operated patients have total or partial post-surgical hypopituitarism requiring hormonal replace- SURVEILLANCE WITH HORMONAL REPLACEMENT ALONE ment. Except when partial removal or limited biopsy of the lesion was performed, allowing in some cases a favo- The natural history of autoimmune hypophysitis rable outcome, pituitary function improved in only 15% suggests that the inflammation would eventually subside. of cases after surgery [83, 86]. Honneger [56] noted that The case of Brandes [20], reporting a 17-year old female no recurrence was reported after radical surgery leaving whose pituitary mass with supra sellar extension and ante- the patient with anterior pituitary insufficiency. Nishokia rior pituitary deficiency regressed to an empty sella over [110] estimates that LH surgery should be performed only 5 years, illustrates that abstention might be mandatory, when mandated by the presence of visual impairment or except in the presence of progressive visual impairment. other potentially irreversible neurologic signs, when Moreover, spontaneous radiological resolution, during progression of the mass is rapid despite corticosteroid short term follow-up has been well documented in the therapy or when atypical symptoms such as ID or sinus literature (16 cases) [24, 60, 86, 108, 113, 116, 158]. An cavernous involvement are present. evolution toward empty sella syndrome, noted in 5 cases further justifies this attitude. In case of presurgical imaging diagnosis, complete antehypophyseal surgical MEDICAL TREATMENT resection should be avoided because of the self-limited course of the disease, especially if vision is not compro- Bromocriptine mised [8, 128].

Bromocriptine has been used for treatment of hypophysitis misdiagnosed for prolactinoma in patients with hyperprolactinemia [6, 13, 21, 40, 83, 84, 85, 112, 123, Differential diagnosis 127, 134, 150, 158, 166, 169, 174]. Various results have been observed in this small group of patients (17 cases) Review of the literature indicates that the principal such as normalization of prolactinemia, or reversed galac- misdiagnosis is prolactin secreting pituitary adenoma or torrhea and amenorrhea. In three cases only, an improve- non-secreting adenoma [7, 27, 59, 81, 90]. Preoperative ment of visual field defects was observed [6, 84, 158]. diagnosis between these two entities is necessary as already discussed, and can be suggested on the basis of endocrine and MRI features. The distinction is mandatory Corticosteroids because of specific therapeutic issues (surgery or medical) in each diseases, since in LH extensive resection may The use of corticosteroids appears to be the logical exacerbate the often preexisting hypopituitarism [27, 81]. treatment of hypopohysitis as it as been used with success Pituitary abscesses are rarely confusing with LH, as in various autoimmune diseases. Thirty patients unde- background and radiological findings are different. The rwent such a treatment in the literature [8, 145]. Results clinical symptoms of pituitary abscess typically include are not always available, but a benefit on the visual symp- hypopituitarism and sometime visual disturbances, with at tom or headache and a decrease of tumoral size have been MRI a cystic formation, which can be misdiagnosed as observed in 18 cases. An impairment of hormonal pitui- Rathke’s cleft cyst or cystic pituitary adenoma. In the tary function was noted for 7 patients, whereas it should majority of cases, pituitary abscess develops in a setting be pointed out that most of cases showed a recurrence of bacterial meningitis, sinusitis, sepsis or immunosup- 336 N. BERESSI ET AL. pression. Some cases develop as a late complication after cells might be seen as a manifestation of a granulomatous pituitary surgery [105]. Pituitary abscess was also foreign-body type reaction. described in association with craniopharyngioma [114], Recently Sautner has reported [139], a new classifica- Rathke’s cleft cyst or pituitary adenoma [105]. In these tion of pituitary inflammatory diseases, which account for cases the previous necrosis of the tumor may induce the 0.5% of the sellar diseases, introducing “secondary hypo- pituitary abscess formation [105]. physitis” as a new entity. Secondary hypophysitis consists Specific granulomatous hypophysitis (SGH) is characte- of inflammatory extension into the pituitary gland from a rized by the presence of a granuloma, made of multinu- tumor localized in the sellar region. As noted by a few clear giant cells and histiocytes with epithelioid cells in authors [4, 55, 82, 129], the origin of the mechanism response to systemic syphilis, tuberculosis, sarcoidosis or leading to hypophysitis seems to be clearly different from histiocystosis X [30, 31, 107]. In the serie of Rickards LH or granulomatous hypophysitis. In secondary hypo- [136], out of 113 autopsy cases of hypophysis granuloma, physitis, the affected area is composed of fibrous tissue 23 were a specific granulomatous hypophysitis. In SGH, and granulation tissue, B and T lymphocytes are present a general inflammatory syndrome is present, and pituitary in equal amount, and there is no granuloma. symptoms are not isolated but are associated with specific abnormalities of chest X-ray, biological inflammatory syndrome, including increase of sedimentation rate, increased polyclonal serum gammaglobulins, and increase Conclusion of serum angiotensin-converting enzyme (ACE). In sarcoidosis, central nervous system is involved in 3.5 Lymphocytic hypophysitis is a rare autoimmune lesion to 5% of the reported cases and is exceptionally the only of the pituitary gland, histopathogically characterized by sign [22, 91]. The inflammatory infiltrate, reaches the lymphocytic infiltration and destruction of the anterior neurohypophysis in 90% of cases, inducing diabetes insi- pituitary. Nearly 145 cases have been reported since the pidus (DI) [152]. One case of LH associated with pulmo- first description of the entity in 1962 by Goudie [46]. nary and eye sarcoidosis was reported, but no histological Patients may present with symptoms of an expanding feature of sarcoidosis was observed in the pituitary [53]. intrasellar mass or with varying degrees of pituitary Sellar tuberculosis is today extremely rare in clinical dysfunction. 84% of affected subjects are female and two practice. Three cases have been reported by Esposito [38], thirds of cases occur during pregnancy or postpartum and Berger [9] reported a series of 9 well documented period. Adrenal and thyreotroph insufficiency are the observations. Recently Ranjan [133] reported five patients most frequent endocrine failure, whereas the gonadotrop with biopsy proven intrasellar tuberculoma with supra- axis is relatively preserved. An important element of diagnosis is the radiological aspect consisting of a sellar extension. In these cases the triad of headaches, symmetrical pituitary mass, with gadolinium homoge- fever and visual symptoms was present. Endocrine insuf- neous enhancement. Despite the diagnosis can be ficiencies were usually dissociated and might occur, a few suspected from the medical history and imaging studies, years after the initial episode of acute meningitis. biopsy is necessary if a trial course of steroid therapy Moreover calcifications of hypothalamus region were fails. The surgery should be limited to a biopsy only or if frequent [29]. needed to decompress the optic chiasm. The natural Idiopathic granulomatous hypophysitis (IGH), identi- course of LH is still imprecise but spontaneous regression fied by giant cells, was first described in 1917 by of intra sellar mass is not infrequent, thus favoring the Simmons [146]. It has been rediscovered for several hypothesis that some apparently idiopathic pituitary insuf- years, but remains not well known [3, 52, 143, 157]. ficiencies or empty sella turcica may in fact be the final Clinical evaluation must exclude specific granulomas term of initially undiagnosed LH. (sarcoidosis, tuberculosis or fungal infection). The preva- lence of the disease is low, approximately 28 cases being reported in the literature [33, 115, 140]. Various findings References differentiate this disease from LH: there is no sex ratio in favor of female, it does not occur during pregnancy and there is no relation with an autoimmune process [168]. 1. ABE T, MATSUMOTO K, SANNO N, OSAMURA Y: Lympho- cytic hypophysitis: case report. Neurosurgery, 1995; 36: Moreover, DI seems frequent, in opposition to LH, but 1016-1019. only pathological analysis can establish the diagnosis. 2. 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ALBINI CH, MC GILLIVRAY MH, FISHER JE, VOORHESS pathological processes involving the parasellar region, ML, KLEIN DM: Triad of hypopituitarism, granulomatous chromophobe adenoma [55], Rathke cyst [4, 172], sphe- hypophysitis, and ruptured Rathke’s cleft. Neuro Surg, noidal mucocele [140] suggests that the inflammatory 1988; 22: 133-136. LYMPHOCYTIC HYPOPHYSITIS 337

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