Adult Workshop 1

HORMONE Horm Res 2007;68(suppl 5):145–150 Published online: December 10, 2007 RESEARCH DOI: 10.1159/000110611

Lymphocytic Hypophysitis

Mark E. Molitch Mary P. Gillam

Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Ill. , USA

Key Words cated as a means of attenuating inflammation, but given the ,Lymphocytic hypophysitis ؒ Sellar mass ؒ ؒ uncertainty of its efficacy and the known adverse effects Pregnancy such therapy does not seem justified for most patients. The optimal surgical strategy involves partial resection of the mass to decompress the surrounding structures. All patients Abstract with lymphocytic hypophysitis require appropriate replace- Background: Lymphocytic hypophysitis is a disorder of the ment therapy for deficient hormones. Long-term follow-up that presents as a sellar mass lesion and/or is mandatory to monitor for the development of other hor- hypopituitarism. It causes pituicyte destruction and hypopi- monal deficits. Copyright © 2007 S. Karger AG, Basel tuitarism and is speculated to have an autoimmune basis. Diagnosis: Lymphocytic hypophysitis should be considered in the differential diagnosis of pituitary masses and/or hypo- pituitarism in females who are pregnant or in the early post- Introduction partum period, especially in cases associated with other autoimmune diseases or unusual patterns of hormone defi- Lymphocytic hypophysitis is an unusual disorder of ciencies. A definitive diagnosis requires tissue biopsy. A pre- the pituitary gland that presents as a sellar mass lesion sumptive clinical diagnosis can be made based on a history and/or hypopituitarism, most often associated with preg- of gestational or postpartum hypopituitarism, a contrast-en- nancy and the postpartum period. Since the original de- hancing sellar mass with imaging features characteristic of scription by Goudie and Pinkerton [1] , almost 400 cases lymphocytic hypophysitis, a pattern of pituitary hormone of biopsy-proven lymphocytic hypophysitis have been re- deficiency with early loss of adrenocorticotrophic hormone ported [2–5] . The true incidence of lymphocytic hypoph- and thyroid-stimulating hormone unlike that typically found ysitis is unknown as it is likely to be underestimated due with macroadenomas, relatively rapid development of hy- to confusion with Sheehan syndrome and spontaneous popituitarism and a degree of pituitary failure dispropor- recovery of undiagnosed cases. The earliest descriptions tionate to the size of the mass. Symptoms resulting from par- of lymphocytic hypophysitis emphasized its exclusive as- tial or panhypopituitarism occur in approximately 80% of sociation with pregnancy and the postpartum period. cases and multiple deficiencies are found in approximately However, cases have also been reported both in men and 75% of cases. Management: Appropriate management re- in women having no relationship to pregnancy. mains controversial. Corticosteroid therapy has been advo-

© 2007 S. Karger AG, Basel Mark Molitch, MD 0301–0163/07/6811–0145$23.50/0 Northwestern University Medical School (Tarry 15-731) Fax +41 61 306 12 34 Center for Endocrinology, Metabolism and Molecular Medicine E-Mail [email protected] Accessible online at: 303 E. Chicago Avenue, Chicago, IL 60611 (USA) www.karger.com www.karger.com/hre Tel. +1 312 503 4130, Fax +1 312 908 9032, E-Mail [email protected] Classification and Pathology Pathogenesis

Hypophysitis may be classified by its anatomic distri- The etiology of lymphocytic hypophysitis is unknown, bution and whether it is a primary or secondary finding. but it has been speculated to have an autoimmune basis With respect to anatomic classification, the most com- [2–5, 9]. Nearly 30% of patients have a history of coexist- mon form of lymphocytic hypophysitis is confined to the ing autoimmune diseases such as Hashimoto thyroiditis, anterior pituitary and causes pituicyte destruction and Addison disease, type 1 diabetes and pernicious anemia hypopituitarism; (DI) is uncommon [2–5, 7] , and the condition is now considered a compo- [2–5] . Much less commonly, hypophysitis may primarily nent of the type 1 polyglandular syndrome [2–5, 14] . The involve the infundibulum and posterior pituitary, caus- epidemiologic association of lymphocytic hypophysitis ing DI and hyperprolactinemia from stalk dysfunction; with pregnancy has been proposed as circumstantial ev- however, anterior pituitary function is usually preserved idence supporting an autoimmune pathogenesis [15, 16] . [2–6] . Lymphocytic infundibulo-panhypophysitis is even Limited experimental animal studies have supported more rare, with lymphocytic infiltration and destruction the autoimmune theory of lymphocytic hypophysitis present in both the anterior and posterior pituitary. These with hypophyseal infiltrates developing after injections patients present with a combination of DI and anterior of pituitary extracts [17–20] . However, the pathology in pituitary deficiency [2–5] . these experimental conditions does not exactly mimic There are three primary forms of hypophysitis: lym- that seen in humans [3] . phocytic, granulomatous and xanthomatous. Lympho- Although antipituitary antibodies have been demon- cytic hypophysitis is characterized by dense lymphocytic strated in some patients with lymphocytic hypophysitis, infiltration of the anterior pituitary and destruction of their specificity for hypophysitis is poor, as they are also the normal pituitary architecture and replacement with present in patients with nonautoimmune pituitary dis- fibrosis [2–5, 7, 8] . Some studies have shown that the lym- ease and other nonpituitary autoimmune disease [15, 21– phocytes are predominantly cytotoxic T-lymphocyte 24] and in normal postpartum women who do not de- (CD8+) cells, suggesting that T cell-mediated cytotoxic- velop hypophysitis [25] . Taken together, the preponder- ity is critical in the pathogenesis of the disorder [9] . Gran- ance of evidence supports an autoimmune basis, but this ulomas and multinucleated giant cells are not found in remains to be proved. lymphocytic hypophysitis and, if observed, suggest an alternative diagnosis of granulomatous hypophysitis, which is a much rarer disorder occurring at an incidence P r e s e n t a t i o n of ! 1/1,000,000. Granulomatous hypophysitis occurs in men and women with equal frequency and is not particu- When associated with pregnancy, lymphocytic hy- larly associated with pregnancy. It also presents as a mass pophysitis typically presents in the third trimester of lesion with hypopituitarism and is characterized by giant pregnancy or within 1 year postpartum, with symptoms cell granulomas [2–5, 7, 9]. The final major variant is xan- usually related to a pituitary mass (headaches or visual thomatous hypophysitis, of which less than a dozen cases symptoms) or hypopituitarism ( table 1 ). The disorder is have been reported. The pathology of xanthomatous hy- often brought to attention due to failure of either lacta- pophysitis is characterized by a predominance of foamy tion or menses following delivery [2–5, 26] . Neurohypo- macrophages, some lymphocytes and single plasma cells physial involvement, manifesting as DI, occurs in 15% of [3, 9]. Other more rare types of hypophysitis appear to be cases [2–5, 7, 26] . Other rare presentations of lympho- part of a more generalized inflammatory process and in- cytic hypophysitis include meningeal irritation [27] , dip- clude Rosai-Dorfman disease [10] and fibrosing inflam- lopia due to cavernous sinus involvement [27] and occlu- matory pseudotumor (also called Tolosa-Hunt syndrome sion of the internal carotid arteries [28] . and parasellar chronic inflammatory disease) [11–13] . Symptoms resulting from partial or panhypopituita- Although hypophysitis is usually thought of as a pri- rism occur in approximately 80% of cases [2–5, 7, 26], and mary process, it may occur secondarily in relation to in- multiple deficiencies are found in approximately 75% of fection (viral, bacterial, fungal, tuberculosis, syphilis) or cases [2–5, 7, 26]. There is an inexplicable unique predilec- other processes such as Langerhans cell histiocytosis, tion for the corticotrophs and thyrotrophs to be affected sarcoidosis, Wegener granulomatosus, Crohn disease, while the gonadotrophs may be spared. levels Takayasu disease and ruptured cysts [2–5] . range from unmeasurable to elevated: low levels are at-

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Table 1. Lymphocytic hypophysitis: clinical symptoms at presen- acteristics distinguish hypophysitis from a macroade- tation noma ( table 2 ). With hypophysitis, the gland is gener- ally symmetrically enlarged, and administration of gad- Symptoms Frequency, % olinium homogeneously enhances the gland. By contrast, Mass effects in adenomas gadolinium enhances the gland more fo- Headache 60 cally. In lymphocytic hypophysitis, the pituitary dis- Visual disturbance 40 plays a relative low signal on T 1- and a relatively high Bitemporal hemianopsia 32 signal on T -weighted images. By comparison, in mac- Impaired visual acuity 2 Diplopia <5 roadenomas a low signal on T1 -weighted images is un- common, but a high signal on T2 -weighted images is oc- Endocrine dysfunction 80 casionally seen [32] . Often, the dura mater adjacent to 65 Hypothyroidism 60 the mass in lymphocytic hypophysitis shows a unique, Growth hormone deficiency 54 marked contrast enhancement referred to as a ‘dural Hypogonadism 40 tail’. In late stages, these MRI findings may be absent Hyperprolactinemia 30 due to shrinkage of the mass with resolution of the in- Diabetes insipidus 15 flammatory process, and fibrotic changes and an empty Data abstracted from Beressi et al. [26], based on analysis of sella may be seen [33] . 145 cases of clinically suspected and biopsy-proven lymphocytic hypophysitis. Diagnosis

Lymphocytic hypophysitis should be considered in Table 2. Magnetic resonance imaging features of lymphocytic hy- the differential diagnosis of pituitary masses and/or hy- pophysitis and pituitary macroadenomas popituitarism in females who are pregnant or in the ear- ly postpartum period. This is especially true in cases MRI characteristic Hypophysitis Macroadenoma associated with other autoimmune diseases or unusual patterns of hormone deficiencies. In the past many indi- Signal intensity on T1 Relatively low Isointense viduals with postpartum hypopituitarism who lacked a Signal intensity on T2 High Usually isointense Contrast enhancement Marked Moderate history of hypovolemic shock were inadvertently labeled Pattern of enhancement Homogeneous Focal as having Sheehan syndrome when, in fact, they had hy- Shape Symmetric Dumbbell pophysitis [8] . Dural enhancement Common Rare A definitive diagnosis of lymphocytic hypophysitis re- quires tissue biopsy. However, it may be possible to make Data abstracted from Saiwai et al. [32]. a presumptive clinical diagnosis in patients who meet the following criteria: (1) a history of gestational or postpar- tum hypopituitarism, especially after a delivery uncom- plicated by hemorrhage or hypotension; (2) a contrast- tributable to destruction of the lactotrophs, while hyper- enhancing sellar mass with imaging features characteris- prolactinemia is expected during pregnancy and the ear- tic of lymphocytic hypophysitis; (3) a pattern of pituitary ly postpartum period. However, elevated prolactin levels hormone deficiency with early loss of adrenocortico- have been reported in cases of lymphocytic hypophysitis trophic hormone (ACTH) and thyroid-stimulating hor- in men and nonpregnant women [7, 29, 30], which is like- mone (TSH) unlike that typically found with macroad- ly secondary to compression of the pituitary. enomas (i.e., sequential loss of growth hormone, lutein- izing hormone/follicle-stimulating hormone, ACTH, and TSH; (4) relatively rapid development of hypopituita- R a d i o l o g y rism in contrast to the expected slow development typical of an adenoma; and (5) a degree of pituitary failure dis- In 85–95% of hypophysitis cases, magnetic resonance proportionate to the size of the mass. Nevertheless, bi- imaging (MRI) shows an enlarged pituitary gland, and opsy may be required in situations in which a distinction suprasellar extension is common [2–5, 31] . Certain char- cannot be made between lymphocytic hypophysitis and

Lymphocytic Hypophysitis Horm Res 2007;68(suppl 5):145–150 147 a nonfunctioning macroadenoma or prolactinoma and failed to improve with glucocorticoid therapy [7, 43, 44] . when neurologic signs develop. There are also a few documented cases of improvement in symptoms with administration of corticosteroids fol- Lymphocytic Infundibulo-Neurohypophysitis lowed by a relapse when therapy was discontinued [45– Lymphocytic hypophysitis and infundibulo-neurohy- 47] . It is unclear, however, whether improvement in the pophysitis likely represent distinctly separate pathologic clinical course is directly attributable to corticosteroid entities, as the latter tends to occur in older patients and treatment or simply reflects the natural course of the dis- is less likely to be associated with pregnancy [2–6] . Lym- ease [33, 37–39, 48] . Given the uncertainty regarding the phocytic infundibulo-neurohypophysitis causes central efficacy of corticosteroid treatment and its known ad- DI and spares the anterior pituitary as a result of an in- verse effects, such therapy does not seem justified for flammatory process confined to the stalk and posterior most patients. pituitary [6, 34–36] . Patients with a presumed diagnosis of lymphocytic hypophysitis should be observed closely and undergo se- rial visual field examinations or an MRI if they are man- Management aged medically. Surgical decompression of the pituitary mass is required if the patient fails conservative therapy The natural history of lymphocytic hypophysitis is as demonstrated by progressive radiologic or neurologic variable and unpredictable. Typically, it follows a pro- deterioration or by signs of optic nerve compression, gressive course in which the pituitary initially becomes though in this situation some would argue for a short inflamed, edematous and enlarged, and the patient de- course of steroids [2–5, 7, 44] . The optimal surgical strat- velops symptoms secondary to mass effects. With de- egy involves only partial resection of the mass to decom- struction of pituicytes, the parenchyma is replaced by fi- press the surrounding structures via a transsphenoidal brosis with pituitary atrophy leading to hypopituitarism. approach, rather than an attempt at complete resection In some cases, the course is aggressive and neurologic because surgery rarely improves endocrine dysfunction. deficits progress rapidly [2–5, 7]. However, cases of spon- All patients with lymphocytic hypophysitis require taneous partial or full recovery of pituitary function, as appropriate replacement therapy for deficient hormones. well as resolution of pituitary masses in the absence of Long-term follow-up is mandatory to monitor for the de- any intervention, have been well documented [33, 37– velopment of other hormonal deficits. Because hypopitu- 39] . itarism is temporary in a subset of patients, a careful at- Because the natural history of lymphocytic hypophy- tempt should be made to withdraw hormone replacement sitis is so variable, appropriate management remains con- after resolution of the inflammatory stage if progression troversial. Controlled trials are not feasible due to the rar- to fibrosis does not result in irreversible hypopituita- ity of the disorder and our inability to make definitive rism. diagnoses without histologic proof, which requires surgi- cal intervention. Until recently, preoperative suspicion of the diagnosis was rare due to underrecognition, and the Conclusions traditional diagnostic and therapeutic approach involved transsphenoidal biopsy, exploration and/or pituitary re- Lymphocytic hypophysitis is a pituitary disorder that section. Consequently, cases illustrating only transient causes pituicyte destruction and hypopituitarism. It compressive effects and endocrine dysfunction support a should be considered in the differential diagnosis of pitu- case for conservative management. With a greater knowl- itary masses and/or hypopituitarism in females who are edge of the course of lymphocytic hypophysitis and the pregnant or in the early postpartum period, especially in ability to make a presumptive diagnosis in highly sugges- cases associated with other autoimmune diseases or un- tive cases, it is possible to avoid routine neurosurgical ex- usual patterns of hormone deficiencies. A definitive di- ploration in many cases. agnosis requires tissue biopsy. Symptoms resulting from Corticosteroid therapy has been advocated as a means partial or panhypopituitarism occur in approximately of attenuating inflammation and in some patients has 80% of cases, and multiple deficiencies are found in ap- been associated with return of pituitary function and re- proximately 75% of cases. Corticosteroid therapy has duction of the mass [27, 40–42]. Conversely, cases have been advocated as a means of attenuating inflammation, also been reported in which lymphocytic hypophysitis though such therapy does not seem justified for most pa-

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tients. The optimal surgical strategy involves partial re- Disclosure Statement section of the mass to decompress the surrounding struc- tures. All patients with lymphocytic hypophysitis require M.E.M. has a relevant financial relationship with a commer- cial interest. He is an independent contractor of Sanofi-Aventis, appropriate replacement therapy for deficient hormones, Amgen, Ardana and Tercica, has been teaching/speaking at Sano- and long-term follow-up is mandatory to monitor for de- fi-Aventis, Merck and Abbott, and is a member of the Advisory velopment of other hormonal deficits. Committee/Review Panel of Sanofi-Aventis and Abbott. Consult- ing fees have been received from Sanofi-Aventis and Abbott. Honoraria have been received from Sanofi-Aventis, Abbott and Merck. M.P.G. declares no conflict of interest.

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