681

Review

www.expert-reviews.com ISSN 1744-6651© 2009 Expert Reviews Ltd10.1586/EEM.09.37

General features of autoimmune hypophysitisAutoimmune (lymphocytic) hypophysitis (AH), is a chronic inflammation of the pituitary gland caused or accompanied by pituitary autoimmu-nity [1,2]. It can be classified etiologically into two groups: primary and secondary hypophysitis.

Primary hypophysitis is, by definition, of unknown etiology. It is diagnosed on clinical and radiological grounds or, when available, by pathological examination. Pathology classifies primary hypophysitis into three forms: lym-phocytic, granulomatous and xanthomatous, although some patients have mixed lympho-cytic and granulomatous or granulomatous and xanthomatous forms, so that the relationship between these entities remains to be established. Lymphocytic hypophysitis is the most common form and the topic of this review. Granulomatous hypophysitis is characterized by an infiltration of multinucleated giant cells and histiocytes, sur-rounded by lymphocytes, mainly T cells [3], and plasma cells. Xanthomatous hypophysitis is very rare; it was originally described in 1998 in three women [4], and in eight additional patients there-after [3,5–8]. It features cystic-like areas of liquifi-cation, infiltrated by lipid-rich foamy histiocytes and lymphocytes.

Secondary hypophysitis is caused by local or systemic processes. Local processes that arise within or around the pituitary gland and are

associated with lymphocytic infiltration of the pituitary gland include germinoma [9], ruptured Rathke cleft cyst [10], pituitary adenoma [11], and craniopharyngioma [12]. Systemic processes that involve the pituitary are most commonly associated with a granulomatous reaction and include Wegener granulomatosis [13], sarcoidosis [14], Langerhans cell histiocytosis [15] and, more rarely nowadays, TB [16]. In the last 5 years a new entity has emerged in this group: hypophysitis secondary to the administration of an antibody that blocks cytotoxic T-lymphocyte antigen (CTLA)-4 [17], an entity that will be explored in detail in this review.

Autoimmune hypophysitis was first reported in 1962 in a young woman who died 14 months after delivery of her second child because of severe adrenal insufficiency [18]. Only 12 addi-tional patients, mainly post-mortem, appeared in the literature during the following 20 years. The first two ante-mortem patients diagnosed by CT scan were reported in 1980 [19,20] and the first one diagnosed by MRI in 1988 [21]. The widespread use of MRI and greater awareness of AH in the medical community have signifi-cantly increased the number of published AH patients (Figure 1). Many others are diagnosed but not published, and even more patients remain undiagnosed because of varying clinical pres-entations and courses. Thus, although AH has been traditionally considered a rare disease, it

Angelika Gutenberg, Melissa Landek-Salgado, Shey-Cherng Tzou, Isabella Lupi, Abby Geis, Hiroaki Kimura and Patrizio Caturegli††Author for correspondenceDepartment of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Tel.: +1 443 287 8911 Fax: +1 410 614 3548 pcat@jhmi.edu

Autoimmune hypophysitis is an increasingly recognized disorder that enters in the differential diagnosis of nonfunctioning pituitary masses. The differential diagnosis of these conditions is challenging because of similar clinical presentations and radiological signs. This review describes the essential features of hypophysitis and the other nonfunctioning pituitary masses. It also emphasizes a recently described feature of hypophysitis: its appearance with unexpectedly high frequency in patients receiving treatments that abrogate the function of cytotoxic T lymphocyte antigen 4.

Keywords: autoimmunity • CTLA-4 blockade • hypophysitis • monoclonal antibodies • MRI • nonfunctioning sellar masses

Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockadeExpert Rev. Endocrinol. Metab. 4(6), 681–698 (2009)

For reprint orders, please contact reprints@expert-reviews.com

Expert Rev. Endocrinol. Metab. 4(6), (2009)682

ReviewN

um

ber

of

pat

ien

ts w

ith

pri

mar

y A

H

Year of publication

40

30

20

10

0

1960 1970 1980 1990 2000 2010

Firs

t CT

cas

es

Firs

t MR

I cas

e

Gutenberg, Landek-Salgado, Tzou et al.

is probably underestimated [22]. At Johns Hopkins we maintain a database of published patients with primary AH that, as of October 15 2009, includes 522 cases downloadable from our website [201]. Patients have been reported from several countries, but predominantly Japan and the USA (Figure 2). Within these countries, reporting is, as expected, greatest in areas rich in aca-demic centers. Many authors have written about AH, creating a total of 630 articles as of October 15 2009. The articles have all been scanned and are now freely downloaded from our website [201]. The top-five publishing centers currently are Federico II University of Naples, Naples, Italy (De Bellis A, 19 articles); Gunma University, Gunma, Japan (Kobayashi I, 13 articles); Kochi Medical School, Kochi, Japan (Hashimoto, K, 12 articles); Johns Hunter Children’s Hospital, New South Wales, Australia (Crock P, ten articles); and Johns Hopkins University, MD, USA (Caturegli P, ten articles).

Autoimmune hypophysitis can affect just the anterior pituitary lobe (adenohypophysitis), just the posterior lobe and the stalk (infundibulo-neruohypophysitis) or both (panhypophysitis). It is unclear whether these conditions represent different diseases or a spectrum of the same disease. The distinction can also be mis-leading because a biopsy of both the anterior and posterior lobes is only rarely performed, or specified in the published reports.

Autoimmune hypophysitis is approximately three-times more common in females than males (389 female and 138 male; ratio: 2.8:1), especially when it affects preferentially the anterior lobe (273 female and 65 male; ratio: 4.2:1). The disease is most com-mon during the fourth decade of life, with a mean age at presen-tation of 39 (median 35) years. As is common for such diseases, AH tends to occur together with other autoimmune diseases, most frequently with those affecting the thyroid gland [1].

The diagnosis of AH remains difficult because it mimics the clinical and even radiological features of all other nonsecreting pituitary masses of a reasonable size [23]. The symptoms of AH are mainly neurological and endocrinological. Neurological symp-toms stem from compression of the structures surrounding the pituitary gland, and thus include headache (meninges), visual disturbances (optic chiasma) and diplopia (oculomotor nerves). Endocrinological symptoms are due to compression or invasion of the normal anterior pituitary (leading to adrenal insufficiency, hypothyroidism and hypogonadism), posterior pituitary (diabetes insipidus) or pituitary stalk (hyperprolactinemia).

The treatment of AH is, at the moment, only symptomatic. It aims to reduce the size of the pituitary mass and replace the defi-cient hormones. High-dose glucocorticoids (prednisolone 60 mg daily, tapering the dose every 5 days) are generally recommended as first-line treatment in cases suspected for AH where vision is not endangered by the pituitary mass. Improvement under glucocorticoids, however, is sometimes incomplete, transient or even lacking, especially in cases that have a granulomatous or xantho matous component [23]. If vision is endangered or symp-toms worsen, trans-sphenoidal surgery has to be performed. In addition to reducing the mass size, this procedure also yields pituitary tissue for pathological analysis, which is still consid-ered the gold standard for diagnosing AH. Given the diffuse nature of the pituitary lesion in AH, neurosurgical decompression should not be radical. Follow-up intervals after surgery should be short and include endocrinological and radiological updates as recurrence of AH following trans-sphenoidal surgery is well described [24]. In AH patients with aggressive course that have not responded to the two treatments indicated above (glucocorti-coids, and trans-sphenoidal surgery), other approaches have been successfully applied. These include lympholytic drugs other than glucocorticoids, such as azathioprine [25], methotrexate [26,27] or rituximab [28], stereotactic radiotherapy [29] and, more recently, g-knife surgery [30].

The natural history of AH is variable. Most patients improve after reduction of the pituitary mass (obtained through surgery or gluco-corticoid therapy), and either require long-term hormonal replace-ment therapy (73%) or no medication (17%). Glucocorticoids, when started early during the disease course, can significantly amel-iorate the patient’s status and even halt the progression to a chronic phase. The hypopituitarism developing in the early phases of AH can, in fact, occur via two mechanisms: the direct destruction of the endocrine cells induced by the lymphocytic infiltrate, and the compression and impairment of the endocrine cells secondary to the inflammatory edema. The latter mechanism is corrected by glucocorticoid administration. Indeed, a clinical response to gluco-corticoids is a good indication that the diagnosis of a nonbiopsied pituitary mass is indeed AH. A few AH patients improve spontane-ously without treatment (4%). The remaining patients (6%) die because of an irreversible, late-diagnosed adrenal insufficiency. The most recent patient reported as an autopsy case was published in March 2009 [31], and showed a clinical history not dissimilar from that of the first patient reported in 1962, reminding us that AH can still be a lethal disease if unrecognized.

Figure 1. Distribution of 522 published patients with primary AH according to the year of publication.AH: Autoimmune hypophysitis; CT: Computed tomography.

www.expert-reviews.com 683

Review

US

A10

0

Can

ada

20

Mex

ico

1

Bra

zil

2

Arg

entin

a4

Aus

tral

ia18

New

Zea

land

2

Japa

n15

4C

hina 9

Sou

th K

orea

21

Indi

a9

Taiw

an6

Sou

th A

fric

a2

Sen

egal

1

Tuni

sia

3

Isra

el5Le

bano

n1

Om

an 1

UK

35Bel

gium

3The

Net

herla

nds

5S

wed

en3

Den

mar

k2

Ger

man

y54

Pol

and

1 Aus

tria

4C

roat

ia1

Gre

ece

2Tu

rkey

12

Irel

and

2Fr

ance

14

Spa

in17

Por

tuga

l1 Ita

ly 5

Sw

itzer

land

2

WA

1

CA

15C

O 1

TX 2

MO 3 LA 3AR 1

MS 2

AL 1

TN

3

FL 2SC 3NC

2

IL 1

WI

6M

I 5O

H 4

PA 4N

Y 9

MA

10

CT

2

MD

2

DC

5

VA

13

Kin

ki39

Kan

to41

Kyu

shu

17

Shi

koku

26

Chu

goku

5

Chu

bu13

Toho

ku8

Hok

kaid

o5

Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

Fig

ure

2. D

istr

ibu

tio

n o

f 52

2 p

ub

lish

ed p

atie

nts

wit

h p

rim

ary

auto

imm

un

e h

ypo

ph

ysit

is a

cco

rdin

g t

o t

he

geo

gra

ph

ic lo

cati

on

of

the

firs

t au

tho

r. W

orld

wid

e,

USA

and

Jap

anes

e di

strib

utio

ns.

Expert Rev. Endocrinol. Metab. 4(6), (2009)684

Review

Tumor-associated macrophage

TNF-αCSF-1VEGF

Myeloid-derived suppressor cell Tolerogenic dendritic cell

Suppressorlymphocyte (Treg)

FoxP3

Hypoxia

ARGNOS

Recruitment of:

Release of:TGF-βPGE2VEGF

Absence of:B7-1B7-2

Cancer cell

IL-10

CTLA-4CD25

CD4

B7

1

2

3

4

Depletion of:L-tryptophan (IDO )L-arginine (ARG /NOS )

Antigen-presenting cell

B7

CD28 CTLA-4 CD4

T cell

MHC II

TCR

Signal+ -

Expert Rev. Endocrinol. Metab. © Future Science Group (2009)

Gutenberg, Landek-Salgado, Tzou et al.

Autoimmune hypophysitis has at least three features that are intellectually challenging and stimulating. First, it shows a striking but unexplained temporal association with pregnancy. Second, it remains one of the few organ-specific autoimmune diseases where the autoantigens have not yet been identified. Lastly, it develops with unexpectedly high frequency in patients receiving treatments that block CTLA-4. This review will focus on the differential diagnosis of AH, emphasizing its expansion to include CTLA-4 blockade.

Association of CTLA-4 blockade & AHIt is now well established that the immune system recognizes can-cer cells and plays an important role in their control, so much so that humans and animals with a defective immune system are at greater risk of developing cancer [32]. Cancer cells, however, evade such immune surveillance in most patients. Despite enor-mous efforts and resources being dedicated to the development of immunotherapies, none of them are currently indicated as a standard, first-line anti cancer treatment [33]. Cancer cells escape the immune system surveillance using four main types of mechanisms illustrated in Figure 3. The first mechanism, directly relevant to this review, involves the recruitment to the tumor site and draining lymph nodes of suppressor T cells (Tregs), tolerogenic dendritic cells [34], myeloid-derived suppressor cells [35] and tumor-associated macrophages (Figure 3) [36].

Tregs are a subset of CD4 T lymphocytes that suppress the activ-ity of CD8 effector T lymphocytes, CD4 helper T lymphocytes and antigen-presenting cells. Tregs are mainly characterized by the intracellular expression of the forkhead box P3 transcription factor [37]. They also express constitutively CTLA-4, CD25 (the a chain of the IL-2 receptor) and the glucocorticoid-induced TNF receptor; secrete the immunosuppressive cytokines IL-10 and TGF-b; and have minimal levels of effector cytokines (e.g., IFN-g and TNF-a) and cytotoxic molecules (e.g., granzyme B) [37]. Tregs are beneficial in that they keep autoimmunity in check, but they are also detrimental in tumor immunology because they inhibit the anti-tumor action of effector T cells. Notably, there is a strong inverse correlation between the number of intratumoral Tregs and the extent of tumor necrosis: the higher the number of intratumor Tregs the smaller the capacity of CD8 T cells to induce tumor necrosis (reviewed in [38]).

CTLA-4 (Figure 3, inset) is a regulatory molecule expressed con-stitutively on the surface of Tregs. It binds to the costimulatory molecule B7 on dendritic cells, sending inhibitory signals that ultimately impair the immune-activating capacities of dendritic cells [39]. CTLA-4 is also expressed on effector T cells but only after T-cell activation; it is inititally found in cytosolic vesicles located near the immunologic synapse, and then on the cell sur-face peaking at 2–3 days after activation [40]. Thus, CTLA-4 acts bidirectionally (on both dendritic cells and effector T cells) to

Figure 3. Mechanisms used by cancer cells to escape recognition by the immune system. Inset: function of CTLA-4.ARG: Arginine; CSF: Cerebrospinal fluid; CTLA: Cytotoxic T lymphocyte antigen; NOS: Nitric oxidase synthase; PG: Prostaglandin; TCR: T-cell receptor.

www.expert-reviews.com 685

ReviewAutoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

ultimately inhibit T-cell function and prevent the development of autoimmunity. Deletion of Ctla-4 in mice leads to aggressive autoimmune reactions characterized by lymphoproliferation and multiorgan failure [41], secondary to defective Treg activity and unopposed effector T-cell activation. Similarly, in humans, poly-morphisms in the CTLA-4 gene that decrease its RNA stability and function have been associated with increased susceptibility to Type 1 diabetes mellitus and autoimmune thyroiditis [42].

Considering the inhibitory effects of CTLA-4 on lymphocyte function and the notion that immune responses against cancer cells are usually inhibited, investigators have blocked CTLA-4 with the intent of inducing a general immune stimulation. That is, inhibiting an inhibitor such as CTLA-4 should ultimately result in an overall enhanced immune response, and thus also in an enhanced immune response against cancer cells. Inhibition of CTLA-4 is achieved in patients by the injection of a mono-clonal antibody that disrupts the CTLA-4/B7 interaction, ulti-mately abrogating CTLA-4 function [43]. This treatment regi-men, combined or not with vaccination protocols against cancer antigens, is being tested in patients with malignant melanoma, renal cell carcinoma, ovarian cancer, prostate cancer and other solid tumors [44–46].

There are currently two anti-CTLA-4 monoclonal antibodies in Phase I clinical trials: ipilimumab (MDX-010, by Medarex and Bristol Myers Squibb) and tremelimumab (or ticilimumab [CP-675,206] by Pfizer) [47]. The largest experience is with ipili-mumab [48]. CTLA-4 blockade is an effective anticancer treat-ment. It induces, on average, cancer regression in approximately 15% of the patients, although results are variable among trials [44]. CTLA-4 blockade promotes anticancer responses via at least two mechanisms. Blocking CTLA-4 on tumor-specific effector T cells avoids their inhibition, promoting their clonal expansion [49]. Blocking CTLA-4 on Tregs leads to their depletion, thus releas-ing the brake that Tregs place on effector T cells, both tumor specific and nontumor specifc [50]. Several randomized Phase III clinical trials based on CTLA-4 blockade are currently ongoing (listed at [202]).

The expected ‘side effect’ of CTLA-4 blockade, known as immune breakthrough event or immune-related adverse event (IRAE), is the induction of autoimmune diseases. They are reported in up to 43% of patients [51] and have a variable and unpredictable course. In some cases the course is fulminant, such as the development of diffuse colitis with crypt abscess formation 7 days after the first dose of ipilimumab [52]. The most common IRAEs due to anti-CTLA-4 therapy are inflammatory bowel dis-ease (colitis), hypophysitis, skin reactions and hepatitis, although numerous others are described [17].

Autoimmune hypophysitis secondary to CTLA-4 blockade was first reported in eight out of 163 (5%) melanoma patients pub-lished by the National Cancer Institute [53,54], and its appearance was associated with a favorable response in five out of the eight patients. AH incidence ranges from a minimum of 1.8% [55] to a maximum of 17% [56], both in trials of patients with meta-static melanoma. The clinical description of AH manifestations in these case series is limited, but more recently four individual

publications have described a total of seven patients [17,57–59]. The clinical presentation is similar and indistinguishable from that of patients with classic AH: patients complain of headache and symp-toms of anterior pituitary hormone deficiencies. Furthermore, the MRI is similar, showing a diffuse enlargement of the pituitary gland [57]. The diagnostic hint for this form of secondary AH is the underlying cancer and the use of CTLA-4-blocking anti-bodies. AH symptoms usually improve upon discontinuation of CTLA-4 blockade, and with the use of immunosuppressive doses of glucocorticoids [58]. The endocrine defects are long-lasting and require a prolonged follow-up, so much so that specific algorithms should be included in anti-CTLA-4 therapy protocols [17].

It remains unknown why AH, a disease traditionally considered to be very rare, appears preferentially in the settings of CTLA-4 blockade. Efforts aimed at unraveling this association can greatly

Table 1. Classification of sellar (intrasellar and parasellar) masses.

Disease % of sellar masses

Hormone-secreting pituitary adenomas 56

PRL-secreting adenomaACTH-secreting adenomaGH-secreting adenomaTSH-secreting adenoma

42851

Nonfunctioning sellar masses 44

Benign tumorsNonfunctioning pituitary adenomaChordomaMeningioma

32.01.200.96

Developmental lesionsRathke’s cleft cystCraniopharyngiomaArachnoid cystDermoid and epidermoid cysts

3.961.920.480.36

Malignant tumorsMetastasis (mainly from breast and lung cancer)GerminomaLymphomaAstrocytoma

1.200.240.120.15

Autoimmune and inflammatory lesionsHypophysitis (lymphocytic and granulomatous)Sphenoidal sinus mucoceleSarcoidosisWegener granulomatosisLangerhans cell histiocytosis

0.840.120.120.060.06

Infectious lesionsTBPituitary abscess

0.120.12

Vascular lesionsPituitary apoplexyIntrasellar aneurysm

0.060.06

ACTH: Adrenocorticotropic hormone; GH: Growth hormone; TSH: Thyroid-stimulating hormone. Data derived and simplified from [60,72].

Expert Rev. Endocrinol. Metab. 4(6), (2009)686

Review Gutenberg, Landek-Salgado, Tzou et al.

advance our understanding of AH pathogenesis and auto immunity. At the very least, the CTLA-4/AH association is contributing to an increased awareness of AH in the medical community.

Differential diagnosis of nonfunctioning sellar massesMasses that arise within (intrasellar) or around (parasellar) the sella turcica, so-called sellar masses, can be of neoplastic, develop-mental, inflammatory, infectious or vascular origin (Table 1) [60,61]. The most common sellar mass is the hormone-secreting pituitary adenoma, representing more than half (56%) of all sellar masses. Its diagnosis is greatly facilitated by the signs and symptoms that arise as a consequence of the hormonal hypersecretion.

Nonfunctioning sellar masses represent a heterogenous group of approximately 20 diseases (Table 1), among which the nonfunctioning pituitary adenoma predominates.

All nonfunctioning sellar masses, despite their diverse etiology, present very similarly but require quite diverse treatments. For example, surgery is indicated for a nonfunctioning pituitary ade-noma that impinges upon the optic chiasma causing loss of vision, radiotherapy for a germinoma and glucocorticoids for AH. The presentation is characterized by neurologic and/or hypo pituitary symptoms caused by the mass effect. Neurologic symptoms result from compression of the structures surrounding the pituitary: headache (meninges); visual field and acuity defects (optic chi-asm); and diplopia (oculomotor nerves). Hypopituitarism results from compression of the normal anterior pituitary, and more rarely, the posterior pituitary (causing diabetes insipidus) or the stalk (causing hyperprolactinemia).

The differential diagnosis of nonfunctioning sellar masses should be based on a multidisciplinary approach and, in an ideal setting, it should be obtained before trans-sphenoidal surgery. In the following section we will discuss the clinical and radio-logical features that can be used to distinguish AH from the other nonfunctioning sellar masses before surgery. This distinction is crucial for patient care because AH can often be managed with lympholytic medications alone whereas many of the other sellar masses require surgical resection [62].

Autoimmune hypophysitisAutoimmune hypophysitis has a well-established autoimmune pathogenesis. AH is, in fact, reproducible in mice by immuni-zation with pituitary proteins [63], has the pathological features typical of autoimmune diseases (formation of tertiary lymphoid follicles within the target organ), responds to immuno suppressive therapies (such as glucocorticoids), occurs in the same patient with other diseases of proven autoimmune nature and is accompanied by pituitary antibodies.

For AH, however, the main criteria used to establish a diagno-sis of autoimmune disease (unique clinical features, presence of specific autoantibodies and pathological findings) are not easily applicable. In fact, the clinical features of AH are often indistin-guishable from those of other nonfunctioning masses arising in the sella turcica; the pituitary antibodies as currently measured are not specific (covered in the next section); and to biopsy the pitui-tary gland requires an expensive and invasive surgical procedure.

It is, therefore, not surprising that many AH patients are misdi-agnosed and undergo trans-sphenoidal surgery for a presumptive diagnosis of nonfunctioning pituitary adenoma [26].

Autoimmune hypophysitis should be suspected when the neuro-logic and/or hypopituitary symptoms described above appear in relation with pregnancy or post-partum, especially if the woman suffers from additional autoimmune diseases, such as thyroiditis, Addison disease, Sjögren syndrome and Type 1 diabetes mellitus. Lack of symptoms, that is presentation of the mass as incidenta-loma, is very rare for AH [64]. It has been proposed that the degree of hypopituitarism is disproportionate to the size of the pituitary mass [65], although the criterion has not been formally tested on a large number of cases and controls. Similarly, it has been proposed that the order in which anterior pituitary hormones are lost in AH is different from that observed in pituitary adenomas where gonado-tropins and growth hormone are the first to be impaired [66]. In AH, the hypopituitarism mainly involves the adrenal and thyroid axis, although it is important to emphasize that pituitary hormones were not systematically measured in all reported AH patients, thus ascertainment bias is possible. Overall, the measurement of ante-rior pituitary hormones is useful and needed to establish a baseline reference for future treatments, but does not help substantially in distinguishing AH from the other nonfunctioning pituitary masses.

MRI of the sella turcica is currently the best diagnostic tool, closely reflecting the pathological changes of a pituitary gland targeted by the autoimmune attack. We have recently published a study that systematically analyzed the MRI features of AH in comparison with those of nonfunctioning pituitary adenomas [67]. In keeping with the inflammatory changes and hypervascularity seen during the florid phase of hypophysitis, AH appears on MRI as a symmetrical enlargement of the pituitary gland, homogeneous on T1- and T2-weighted images, both before and after the intense gadolinium enhancement [67,68]. Two additional MRI features indicative of AH are the loss of the normal bright appearance of the posterior pituitary [69] and the thickening of the stalk, probably indicating an autoimmune involvement of the neurohypophysis, even if the patient has not yet developed clinical diabetes insipidus.

Nonfunctioning pituitary adenomaNonfunctioning pituitary adenomas lack clinical or biochemical manifestations of hormonal excess. They derive most commonly from the gonadotrophs [70], although each pituitary cell type can give rise to tumors that remain clinically silent [71,72]. They present with headache (48%), visual field and acuity defects (48%) and hypogonadism (35%) [73]. Modest hyperprolactinemia secondary to hypothalamic–pituitary stalk compression is common (47%) [73], whereas diabetes insipidus is extremely rare (<1%) [74]. The duration of symptoms before diagnosis is long, 23 ± 35 months, and it is not unusual even for large tumors to remain asymptomatic and be discovered incidentally after a cranial imaging study is per-formed for unrelated reasons [73]. Trans-sphenoidal surgery and removal of the adenoma is mandatory if vision is endangered [75].

Nonfunctioning pituitary adenomas are usually macroadeno-mas when they are symptomatic (diameter >10 mm) and often extend upwards into the suprasellar cistern, or even the third

www.expert-reviews.com 687

ReviewAutoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

ventricle and the foramen of Monroe. This upward extension provides the tumor a typical snowman or figure-of-eight appear-ance [76]. Their MRI appearance is clearly dishomogenous, par-ticularly on fast T2-weighted images where disseminated areas of signal hyperintensity reflecting cystic or necrotic portions are seen [76]. After gadolinium injection, the adenomatous tissue usu-ally enhances slightly in comparison to the cavernous sinus or normal pituitary tissue. Strong enhancement is to be expected only in the presence of secondary inflammatory changes, which are found in approximately 3% of pituitary adenomas [77]. In adenomas, the stalk is often deviated laterally, and the normal posterior pituitary bright spot is almost invariably conserved [67].

CraniopharyngiomaCraniopharyngiomas account for approximately 2% of all sellar masses (Table 1) [78]. They are thought to arise from epithelial rem-nants of the craniopharyngeal duct or the Rathke pouch (ada-mantinomatous type) or from metaplasia of squamous epithelial cell remnants of the part of the stomadeum that form the buccal mucosa (squamous papillary type) [79,80]. The age at presenta-tion follows a bimodal distribution, with a first peak between 5 and 14 years of age and a second between 65 and 74 years [79]. Craniopharyngiomas are often diagnosed late, sometimes years after the initial symptom appearance. The clinical picture at diagnosis is dominated by headache (62%), visual impairment (67–75%) and various degrees of hypopituitarism (52–87%) [81]. Hyperprolactinemia is found in approximately a third of patients and diabetes insipidus in 6–19% [81]. Characteristic of cranio-pharyngiomas is the presence of psychiatric deficits, loss of short-term memory and personality changes, which are described in approximately a third of the patients [80]. Currently, surgical exci-sion followed by external-beam irradiation is the main treatment option for residual tumor [82].

Craniopharyngiomas appear as large masses (>20 mm in diam-eter) in part cystic and in part solid and calcified, located in the suprasellar (75%), supra- and intra-sellar (20%) or intrasellar (5%) regions [83]. Tumoral calcification, which may be best appreciated on CT scan, is particularly common and is seen in 70–90% of childhood craniopharyngiomas and 40–60% of adult tumors [26]. Postcontrast MRI shows a heterogeneous gadolinium uptake in the solid part of approximately 60% of craniopharyngioma [78].

Rathke cleft cystRathke cleft cysts are cystic sellar and suprasellar lesions. They probably arise from the incomplete obliteration of the Rathke pouch, which develops as a rostral outpouching of the primitive oral cavity during the third or fourth week of embryogenesis and are characteristically lined by a single layer of ciliated cuboidal or columnar epithelium with goblet cells. Rathke cleft cysts are twice as common in women than men and usually occur between 30 and 60 years of age [84]. They present with headache (65%), hypopituitarism (39–81%) and visual loss caused by compression of the optic chiasm (38%). Hyperprolactinemia is found in 39% of the patients and diabetes insipidus in 9% [81]. Treatment of Rathke cleft cyst is by trans-sphenoidal surgery [85].

Rathke cleft cysts are smoothly marginated and vary in size from a few millimeters to 10–20 mm. They can be completely intrasellar (40%), or have some suprasellar extension (60%), whereas completely suprasellar cysts are rare [86]. Rathke cleft cysts vary widely in their radiological appearance. Cysts with low protein content are isointense with cerebrospinal fluid on all sequences, but become hyperintense on T1-weighted images as the protein content increases. On T2-weighted images, these cysts are hyperintense in 70% of cases and iso- or hypo-intense in the remaining 30% [86]. A small nonenhancing intracystic nodule is considered a virtually pathognomonic sign of Rathke cleft cyst [78]. These nodules show high signal intensity on T1-weighted images and low signal intensity on T2-weighted images, and lack enhancement, although an enhancing rim of displaced and compressed pituitary gland is present in approxi-mately half of the cases [86]. Calcification is a rarity in Rathke cleft cysts [86].

Arachnoid cystArachnoid cysts arise most commonly (40–50%) in the supra-tentorial compartment, and rarely (9–15%) in the sellar region [87]. They can be congenital or acquired. Sellar arachnoid cysts are attributed to herniation of the arachnoid membrane through an incompetent diaphragma [88]. The mean age at presentation is 45 years (range: 16–80 years) and the time from symptom appearance to diagnosis can vary from 2 weeks to 5 years [89]. Main symptoms include headache (41%) and visual distur-bances (55%), whereas hypopituitarism, usually involving the gonadotropic axis, is less common [90]. Hyperprolactinemia is found in 21% and diabetes insipidus in less than 2% of cases [90]. Symptomatic arachnoid cysts are resected via the trans-sphenoidal route.

Arachnoid cysts appear ovoid, smoothly marginated and extending to the suprasellar region [89]. Their signal intensity is the same as that of the cerebrospinal fluid in all sequences, although hemorrhage, high protein content or lack of flow within the cyst may complicate the MRI appearance [86]. Arachnoid cysts show a hypodense signal on T1-weighted sequences and a high signal on T2-weighted images. There is no enhancement of any part of the lesion after contrast agent administration. The normal anterior pituitary can often be recognized only on sagittal planes, and the pituitary stalk is sometimes deviated [89].

Epidermoid cystEpidermoid cysts arise from ectodermal inclusion during neu-ral tube closure in the third to fifth week of embryogenesis [91]. Acquired epidermoid cysts may develop as a result of trauma but are uncommon in the brain [92]. Epidermoid cysts are present at birth but, because of their slow growth rate, typically remain silent until the second to fourth decade of life [93]. They can occur in numerous locations throughout the brain, including the sellar region, although they are predominantly found in the cerebello–pontine angle cistern. Thus, their clinical presentation varies according to their location. Surgical removal is preferably performed via the trans-sphenoidal route [94].

Expert Rev. Endocrinol. Metab. 4(6), (2009)688

Review Gutenberg, Landek-Salgado, Tzou et al.

Most epidermoid cysts are isointense or slightly hyperintense to the cerebrospinal fluid on both T1- and T2-weighted images and typically do not enhance, although some minimal rim enhance-ment occurs in approximately 25% of cases. Rare ‘white epider-moids’ have high protein content and show high signal intensity on T1- and low signal intensity on T2-weighted images [86].

MeningiomaMeningiomas are three times more common in women than men and peak in incidence during the sixth decade of life [40]. They can originate from any dural surface, including the tuberculum sellae, olfactory groove, sphenoid wing, diaphragma sellae and sella turcica [95]. Purely intrasellar meningiomas are rare [96]. A meningioma originating from the inner surface of the diaphragma sellae grows into the pituitary fossa, mimicking closely a non-functioning pituitary adenoma [96]. Meningiomas originating from the outer layer, by contrast, extend mainly to the supra- and para-sellar regions [96]. Patients with tuberculum sellae meningi-omas often present with severe visual disturbance, and frontal and orbital headaches (5–20%), but not hypopituitarism; mild-to-moderate hyperprolactinemia may be found at presentation in as many as 50% of patients [97] and the mean duration of symptoms before surgery is approximately 2 years [98]. Sellar meningiomas are known to increase in size and become symptomatic during menses or pregnancy [99]. Progesterone receptor positivity is a risk factor for meningiomas and is found in 81% of female patients versus 40% of male patients [100]. For surgical resection the fron-tolateral and pterional approach is advocated [98,101]. Postoperative residual and/or recurrent tumor, especially within the cavernous sinus, is best controlled by g-knife radiosurgery [102].

Intrasellar meningiomas typically appear as masses that are hypointense to isointense with respect to the gray matter on both T1- and T2-weighted sequences [103]. They enhance markedly after gadolinium administration in a homogeneous fashion in more than 90% of the cases [103]. Intrasellar meningiomas are commonly associated with sellar enlargement and rarely with an enhancing dural tail [96]. The single most useful finding in differentiating intrasellar meningiomas from AH and pituitary adenomas is to identifiy the pituitary gland as separate from the mass [95]. Visualization of a cerebrospinal fluid cleft between the tumor mass and the gland, although uncommon, is indicative of meningioma [103]. Hyperostosis of the sellar floor or adjacent bony structures also favors a diagnosis of meningioma, a feature present in approximately a third of the cases [103].

ChordomaChordomas arise from embryonic remnants of the primitive noto-chord and are found entrapped within bone in midline locations, such as the clivus, parasellar region and craniocervical junction (45% of the cases), or the sacrococcygeal region (55%) [104,105]. Intracranial chordomas are more common in females and the young (<26 years of age) [106]. They typically infiltrate and destroy the bone, causing symptoms that vary according to their location. The most common initial complaints are headache, usually reported in occipital or retro-orbital locations, and diplopia, usually caused by

palsy of the abducent nerve [105]. Hypopituitarism is rare, although mild dysfunction and hyperprolactinemia have been reported [60]. Trans-sphenoidal surgery followed by radiotherapy is the generally accepted treatment [107].

Intracranial chordomas appear on high-resolution CT as a cen-trally located, well-circumscribed, soft-tissue mass that arises from the clivus and is associated with extensive lytic bone destruction [60]. Intratumoral calcifications are common but considered to represent inclusions from bone destruction rather than dystrophic calcifications within the tumor itself [105]. MRI is the procedure of choice for detecting a clival chordoma and determining the extent of the tumor and involvement of adjacent structures. Chordomas are iso- to hypo-intense to gray matter on T1- weighted images [108], and have a high signal intensity on T2-weighted images, a finding probably reflecting the high fluid content of vacuolated cellular components [108]. Most intracranial chordomas enhance moderately to markedly after gadolinium administration, with a pattern sometimes referred to as ‘honeycomb’ [109]. Use of the fat suppression technique allows the differentiation of enhanced tumor margins from adjacent bright fatty bone marrow, and better demarcation of intraclival chordomas [110].

Pituitary metastasisMetastases to the pituitary gland via hematogenous spread typi-cally localize in the posterior pituitary, and thus present as diabetes insipidus [111], considering that the posterior pituitary receives blood directly from the systemic circulation whereas the anterior pituitary is served by the portal system. Metastasis can also occur via menin-geal spread through the suprasellar cistern, via the portal circulation from a hypothalamo–hypophyseal or infundibular metastasis, and via extension from a juxtasellar and skull base metastasis. Pituitary metastases are most commonly caused by breast and lung cancer, and are usually found in elderly patients during the sixth or seventh decade of life [112]. Pituitary symptoms are rare because pituitary metastases tend to occur in end-stage cancer patients. Following diabetes insipidus, which is present in approximately 50% of the patients, symptoms include hypo pituitarism (25%), bilateral hemi-anopsia (25%) and headaches (15%); hyperprolactinemia is rare (6% of pituitary metastases) [112].

On MRI, pituitary metastases appear as sellar or suprasellar masses, sometimes with a dumb-bell shape, which are often iso- or hypo-intense to the gray matter on T1-weighted images, and of increased T2 signal [60,95,112]. Masses enhance after gadolin-ium administration, with a homogeneous, heterogeneous or rim pattern [95]. Thickening of the stalk (21%), erosion of the sellar bone (15%), invasion of the cavernous and sphenoidal sinuses (10%) and loss of the posterior pituitary bright spot (9%) are also described [95,112].

Germ cell tumorGerm cell tumors of the brain (intracranial germ cell tumors) occur mainly in prepubertal children [113]. Intracranial germ cell tumors include germinomas (65%), of which 85% are considered ‘pure’ germinomas and 15% are germinomas with syncytio trophoblast giant cells [114], teratomas (18%), embryonal carcinomas (5%),

www.expert-reviews.com 689

ReviewAutoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

endodermal sinus tumors (7%) and choriocarcinomas (5%) [115]. Germinomas primarily involving the sellar region are rare and have a predilection for females [116]. They present with diabetes insipidus (60–90%), hypopituitarism (75–90%) and visual field defects [117–119]. Hyperprolactinemia, deficiency of growth hor-mone (GH), adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH) are reported in 50, 41.7, 16.7 and 8.3% of the patients, respectively [120]. Sellar germinomas can be difficult to differentiate from AH, even after examination of the pituitary biopsy, since they can show a diffuse lymphocytic infiltration of the pituitary gland similar to that typically seen in AH and are mostly negative for human chorionic gonadotropin (b-hCG), both in the serum and cerebrospinal fluid [114,121,122]. b-hCG, a glycoprotein produced by placental trophoblastic cells, is elevated in choriocarcinomas and in the minority of germinomas that contain syncytiotrophoblast giant cells [114,123]. b-hCG-secret-ing germinomas are thought to be more aggressive than nonse-creting germinomas, but this notion is controversial [114,123]. We have recently described a girl with intrasellar germinoma initially misdiagnosed as AH [9], and found in the literature eight simi-lar cases reported during the last decade [124–131]. The therapy of choice is irradiation after a confirmatory biopsy is performed [121].

Loss of the normal posterior pituitary bright spot on T1-weighted images is one of the earliest signs in sellar germinomas [95,118], followed by swelling of the stalk and subsequent mass forma-tion, which may displace the enhancing pituitary gland anteri-orly [95]. Sellar/suprasellar germ cell tumors have a non specific image. They are isointense to cerebral cortex on T1-weighted images (~70%) and enhance solidly. Variable intensities are seen on T2-weighted images [118]. Intratumoral cysts are revealed by MRI in approximately half of the cases [118]. Calcifications may be seen in bigger tumors [95]. Teratomas show a mixed signal intensity with fat and calcifications [60].

Pituitary lymphomaLymphomas may arise in the CNS directly or through spread from other sites during the natural history of the disease, which is usually associated with progressive widespread systemic disease. Primary CNS lymphoma is defined as a lymphoma limited to the cranio-spinal axis without evidence of systemic disease [132,133]. It represents up to 2% of all primary CNS malignancies and is practically always of the non-Hodgkin type, with the majority being B-cell lymphoma [134]. Pituitary lymphomas are exceedingly rare and are more common in males during the sixth decade of life [133]. Headache is the most common presenting symptom, and results from erosion of the bony sella turcica or stretching of the diaphragma sellae. Like any other nonfunctioning sellar mass, pituitary lymphomas may also present with symptoms of hypopi-tuitarism, which often follows a characteristic sequence character-ized by gonadotropin, GH, TSH and, finally, ACTH deficiency [133]. Hypopituitarism, visual field defects, diabetes insipidus and hyperprolactinemia are present at the time of diagnosis in 50, 50, 40 and 20% of the patients, respectively [133]. Cranial nerve involvement owing to lateral extension of the pituitary lymphoma into the cavernous sinus has also been reported [133]. Interestingly,

AH has been proposed as a risk factor for subsequent development of pituitary lymphoma [135]. Treatment for this rare malignancy consists of whole-brain radiotherapy [136], combined with systemic chemotherapy and intracranial methotrexate [137].

Sellar lymphomas appear on MRI specifically as homogeneously or heterogeneously enhancing sellar masses, that are iso- to hypo-intense relative to gray matter on T2-weighted images [95]. Their appearance, however, varies according to whether the patient has normal or suppressed immunity [95]. In patients with a normal immune system, CNS lymphoma appears as a solitary mass with intermediate-to-low signal intensity relative to gray matter on both T1- and T2-weighted sequences; enhancement with gadolinium is seen in nearly all cases and is homogenous in approximately three quarters of cases [95,134]. The relative lack of T2 prolongation in CNS lymphoma is generally attributed to dense cellularity and a high nucleus-to-cytoplasm ratio, a feature that may be helpful in distinguishing lymphomas from other CNS tumors. This feature, however, has low sensitivity, being present in just over 50% of cases [134]. Calcification and hemorrhage in CNS lymphoma are rare [60,95].

SarcoidosisSarcoidosis is a systemic disorder of unknown etiology, charac-terized histologically by the presence of noncaseating epithelioid granulomas. It is more common in African–American females during the fourth decade of life, where the annual incidence is 107 cases per 100,000 persons [138]. Sarcoidosis of the CNS is evident clinically in approximately 5% of patients [139,140] and at autopsy in approximately 20% [141]. The most common CNS sites of disease activity are the basal meninges and hypothalamus, fol-lowed by pituitary stalk and pituitary gland [141,142]. Owing to the hypothalamic involvement, diabetes insipidus is the most common presenting symptom [143], accompanied by other signs of hypotha-lamic dysfunction, such as impaired thirst, temperature, sleep or weight regulation. Hypopituitarism is rare, a consequence of defec-tive hypothalamic releasing factors [144], and mainly involving the gonadotropin axis [145,146]. Headache (16%), visual dysfunction (10%), diplopia (8–12%) and hyperprolactinaemia (3–32%) are also rare in CNS sarcoidosis. Therapy consists of immunosuppres-sive agents (e.g., cyclophosphamide, azathioprine or methotrexate) and should be initiated with corticosteroids [147,148].

On MRI, the meningeal, intraparenchymal or sellar lesions of sarcoidosis appear isointense on T1-weighted images and variable on T2-weighted images [60]. These lesions enhance after contrast administration [139], typically accompanied by leptomeningeal enhancement. The pituitary stalk is thickened and enhanced in approximately 50% of patients [145,149], with loss of the normal pos-terior pituitary bright spot [143,145]. Very rarely, pituitary sarcoidosis shows a cystic appearance [150,151].

Wegener granulomatosisWegener granulomatosis is a vasculitis of small and medium-sized vessels associated with the presence of antineutrophil cyto-plasmic antibodies [152]. It favors Caucasians (90% of patients) [153], equally in males and females [154], and has a mean age at

Expert Rev. Endocrinol. Metab. 4(6), (2009)690

Review Gutenberg, Landek-Salgado, Tzou et al.Ta

ble

2. K

ey c

linic

al a

nd

rad

iolo

gic

al f

eatu

res

of

no

nfu

nct

ion

ing

pit

uit

ary

mas

ses.

Dif

fere

nti

al d

iag

no

sis

M:F

ra

tio

Mea

n a

ge

(yea

rs)

Hea

dac

he

(%)

Vis

ual

co

mp

rom

ise

(%)

DI

(%)

An

teri

or

pit

uit

ary

dys

fun

ctio

nC

ran

ial

ner

ve

pal

sy (

%)

Un

iqu

e fe

atu

res

Aut

oim

mun

e hy

po

phys

itis

1:3

3253

435

0A

CTH

(57

%),

FSH

/LH

(52

%),

TSH

(49

%),

GH

(3

8%

), h

yper

pro

lact

inem

ia (2

3%

)3

–16

Ass

oci

atio

n w

ith

preg

nanc

y

Non

func

tion

ing

pitu

itar

y ad

enom

a1:

15

04

8-6

842

<2

FSH

/LH

(43

%),

GH

(36%

), h

yper

pro

lact

inem

ia

(28

%),

AC

TH (2

6%),

TSH

(24

.5%

) 7

N/A

Cra

nio

phar

yngi

oma

1.1

5–1

4 an

d 65

–74

6267

–75

6–9

AC

TH (3

2–5

0%

) FSH

/LH

(59

%),

GH

(39

%),

TS

H (3

9%

), h

yper

pro

lact

inem

ia (3

2%)

Rar

ePs

ychi

atri

c d

efici

ts

in 3

3%

Rat

hke

clef

t cy

st1:

23

0–

60

653

89

AC

TH (

57%

), G

H (3

5%),

FSH

/LH

(53

%),

TSH

(3

5%),

hyp

erpr

ola

ctin

emia

(39

%)

Rar

eN

/A

Epid

erm

oid

cys

t1:

120

–40

>5

0>

50

Rar

e>

50

% (

no p

refe

rred

axe

s)Ye

sN

/A

Sella

ara

chno

id c

yst

1:1

4541

55<

2FS

H/L

H (

43%

), G

H (3

8%

), A

CTH

(36%

),

hyp

erpr

ola

ctin

emia

(21%

), T

SH (<

7%),

N

/A

Sella

r m

enin

giom

a1:

362

5-2

0>

50

Rar

eH

yper

pro

lact

inem

ia >

50

%, o

ther

axe

s ra

reYe

sPr

ogr

essi

on

durin

g pr

egna

ncy

Cho

rdom

a1:

2<

26U

sual

Rar

eR

are

Unu

sual

30

N/A

Ger

m c

ell t

umor

1:2

Prep

uber

tal a

ge

Usu

alU

sual

60

–9

0H

yper

pro

lact

inem

ia (

50

%),

GH

(42

%),

AC

TH

(17%

), T

SH (

8%

) R

are

N/A

Pitu

itar

y ly

mph

oma

2:1

Imm

uno

com

prom

ised

: 3

0–4

0;

imm

uno

com

pet

ent:

6

0–7

0

755

04

0FS

H/L

H >

GH

> T

SH >

AC

TH4

0N

/A

Pitu

itar

y m

etas

tase

s1:

16

0–7

015

2545

Part

ial o

r gl

oba

l defi

cien

cy o

f an

teri

or lo

be

in

25%

, hyp

erpr

ola

ctem

ia (

6%)

Rar

eN

/A

Pitu

itar

y tu

ber

culo

sis

1:2

36

.791

46

11D

efici

ency

in 7

7% w

itho

ut p

refe

rent

ial

invo

lvem

ent,

hyp

erpr

ola

ctin

emia

(23

%)

23.1

N/A

Sarc

oid

osi

s1:

233

.716

1033

Hyp

erpr

ola

ctin

emia

(3–3

2%),

ant

erio

r pi

tuit

ary

dys

func

tion

is r

are,

but

FSH

/LH

mo

stly

aff

ecte

d8

–12

Afr

ican

s ha

ve a

th

reef

old

in

crea

sed

risk

Weg

ener

gra

nulo

mat

osi

s1:

14

8Ye

sYe

s10

0H

yper

pro

lact

inem

ia (

42%

), T

SH (

42%

),

FSH

/LH

(33

%),

AC

TH (1

7%),

GH

(17%

) R

are

>9

0%

are

C

auca

sian

Lang

erha

ns c

ell

hist

iocy

tosi

s3

:135

, but

70

% u

nder

ag

e of

17

Yes

Rar

e>

90

GH

(4

0–

67%

), F

SH/L

H (

58

%),

AC

TH (

42%

),

TSH

(42

%)

Rar

eN

/A

AC

TH: A

dre

no

cort

icot

rop

ic h

orm

on

e; D

I: D

iab

etes

insi

pid

us;

FSH

: Fo

llicl

e-st

imu

lati

ng

ho

rmo

ne;

GH

: Gro

wth

ho

rmo

ne;

LH

: Lu

tein

izin

g h

orm

on

e; N

/A: N

ot a

pp

licab

le; T

SH: T

hyro

tro

pin

.

www.expert-reviews.com 691

ReviewAutoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

diagnosis of 48 years [155]. The major targets of disease activity are the upper respiratory tract, lungs and kidneys [156]. The PNS is frequently affected, with symmetrical sensory–motor polyneu-ropathy or mononeuritis multiplex [154]. CNS involvement is less common and caused by three different mechanisms [157]: direct intracranial extension of the granulomatous process from the sinuses, orbits or mastoid air cells; vasculitis of the cerebral ves-sels with subsequent ischemic and/or hemorrhagic infarctions; or formation of granulomas directly within the brain parenchyma, remote from the primary disease site.

The pituitary gland is rarely a target of Wegener granulomatosis [158], most often described as thickening of the gland and stalk [155,158–160]. The lesions are typically granulomatous on patho-logical examination, but pure lymphocytic infiltration of the pitu-itary gland has been described [23]. Diabetes insipidus is present in all patients affected by Wegener granulomatosis of the pituitary gland [161]. Hypopituitarism is characterized by hypothyroidism (42%), hypogonadism (33%) and GH and ACTH deficiencies (17%) [161]. Hyperprolactinemia is seen in 42% of cases. Visual disturbances [158], ophthalmoplegia [162] or meningitis [163] are rare. Currently, a regimen consisting of daily cyclophosphamide and corticosteroids, which induces complete remission in the majority of patients, is considered standard therapy [164].

The MRI findings of Wegener granulomatosis of the CNS vary widely, reflecting the three mechanisms of CNS involve-ment highlighted above. The most common findings are thickening and enhancement of the meninges (65%), cerebral infarctions owing to vasculitis (24%), pituitary enlargement (12%), and supra- or infra-tentorial granuloma (<1%) [155]. The pituitary mass most commonly extends to the suprasellar region, although purely intrasellar masses are described [160]. The mass is hypointense on T1- and hyperintense on T2-weighted-images [155,159] and enhances markedly after gadolinium in a homo-geneous [155] or heterogeneous fashion depending on the presence of infarction and hemorrhage [159]. Cystic sellar masses that do not enhance with gadolinium are also described [165]. Contrary to what one would predict based on the presence of diabetes insipidus, thickening of the pituitary stalk and loss of the normal posterior bright spot are rarely noticed [159].

Langerhans cell histiocytosisLangerhans cell histiocytosis is the pathological infiltration of several organs by Langerhans cells [166]. It is most common in children and young adults, so that approximately 70% of the cases occur before 17 years of age. The point prevalence per 100,000 individuals is 0.27 for males and 0.07 for females [167]. The disease most commonly involves bone, skin, lungs, liver, lymph nodes and the hypothalamo–pituitary axis [168]. Diabetes insipidus is the most common endocrine abnormality (>90%) [169], followed by GH deficiency [170]. Hypothyroidism is also common, and can be both secondary to pituitary infiltration [171] or primary because of thyroid infiltration [172]. ACTH deficiency usually occurs in the context of panhypopituitarism but isolated ACTH deficiency is also described [171]. In a study of 12 adult patients with histologi-cally proven Langerhans cell histiocytosis and diabetes insipidus,

Kaltsas et al. found deficiency of GH, follicle stimulating hor-mone, luteinizing hormone, TSH and ACTH in 67, 58, 42 and 42% of the patients, respectively [15]. Hyperprolactinema is rare [15]. Systemic chemotherapy appears to be of little benefit in con-trolling the progression of the disease over the long term, although

focal radiotherapy may halt local disease progression in terms of mass effects [15].

A pituitary mass caused by Langerhans cell histiocytosis is hypointense on T1-weighted images and hyperintense on T2-weighted images, and enhances brightly after contrast [173]. Loss of the normal posterior pituitary bright spot is seen in all patients with diabetes insipidus [15] and infundibular thickening in over 50% [174]. Infundibular atrophy (29%) and pronounced hypothalamic mass lesion (10%) are less common.

Pituitary tuberculosisThere has been a resurgence of TB during the past three decades due to the HIV/AIDS epidemic, increased travel and migration. The annual incidence per 100,000 persons varies from four cases in the USA to over 100 cases in Asia and Africa. Approximately 10% of TB cases have CNS involvement [175], which may present as meningitis or parenchymal space-occupying lesion. Pituitary TB is extremely rare, with approximately 60 cases reported since the original 1940 description by Coleman and Meredith [176]. Females are affected more frequently than males (2:1) with a mean age at presentation of 37 years [177]. Only a third of the cases have a past or concurrent history of extrasellar tubercular involve-ment [176]. Headache is the most common presenting symptom (91%), followed by visual disturbances (46%) and cranial nerve palsy, especially the abducens nerve (23%). Fever is common in children and rare in adults [176]. Hypopituitarism is present in 77% of the patients, without preferential involvement of any hormonal axis, and can be disproportionate to the size of the sellar lesion [178]. Hyperprolactinemia and diabetes insipidus are found in 23 and 11% of the patients, respectively [176].

The treatment of cerebral tuberculosis, like that of other forms of TB, is aimed at killing both intracellular and extracellular organ-isms and preventing the development of drug resistance by using several drugs in combination The first-line anti-tubercular drugs are isoniazid, pyrazinamide, ethionamide, and cycloserine which penetrate into the cerebrospinal fluid well. Rifampicin, strepto-mycin and ethambutol penetrate in adequate concentrations are only used when the meninges are inflamed [179]. Surgical inter-vention is required in cases of intracranial tuberculous empyema to reduce the mass effect, as well as when serious complications such as hydrocephalus, tuberculomas and tuberculous abscesses develop [179].

Pituitary tuberculomas are usually isointense on T1-weighted images, but can be hyperintense owing to high protein content [180]. They enhance avidly after contrast, except in areas of casea-tion, which appear cystic. Pituitary tuberculomas show a supra-sellar extension in 74% of cases, but are limited to the sella in the remaining 26% [176,177]. The sella is enlarged and the stalk is almost always thickened owing to chronic inflammation [180]. Sometimes, the suprasellar extension can make evaluation of the

Expert Rev. Endocrinol. Metab. 4(6), (2009)692

Review

Pre

vale

nce

of

pit

uit

ary

auto

anti

bo

die

s (%

po

siti

ve)

Hea

lthy

Non

auto

imm

une

dise

ase

Oth

er a

utoi

mm

une

dise

ase

Oth

er p

ituita

rydi

seas

e

Isol

ated

def

icie

ncie

s

Clin

ical

AH

Bio

psy

AH

100

90

80

70

60

50

40

30

20

10

0

Gutenberg, Landek-Salgado, Tzou et al.

stalk difficult. Other MRI findings described with pituitary TB are peripheral ring enhancement of the mass, enhancement of the adjacent dura and basal enhancing exudates owing to meningi-tis [180]. Isolated stalk thickening, sellar/suprasellar calcification, apoplexy and erosion of the sellar floor have also been reported in pituitary tuberculomas [176].

The aforementioned clinical and radiological features of non-functioning pituitary masses are summarized in Table 2. Overall, it is difficult to establish before surgery a diagnosis of certainty, which can be obtained in the majority of the patients only after pathological examination of the pituitary biopsy obtained via trans-sphenoidal surgery.

Pituitary antibodiesThe presence of immunoglobulins in the serum reacting against self-antigens is one of the cardinal features of autoimmune dis-eases. Autoantibodies are undoubtedly the most widely used tool to diagnose, monitor and, more recently, predict autoimmune diseases. With a few exceptions, where autoantibodies are the cause of the clinical phenotype (e.g., the acetycholine receptor antibodies in myasthenia gravis and thyrotropin receptor antibod-ies in Graves disease), the role of autoantibodies in the pathogen-esis of autoimmune-mediated pathology remains unknown. It has now become clear that autoantibodies are present several years before the clinical diagnosis. Pioneer studies in this regard are the ones performed by Arbuckle and col-leagues in systemic lupus erythematosus [181]. The authors have taken advantage of the worlds largest serum repository, main-tained by the USA Department of Defense, which has over 40 million sera collected longitudinally from military personnel. The authors have shown that lupus anti-bodies are present several years before the clinical diagnosis and follow a predictable course with progressive accumulation of different specificities. Independently of their role in disease initiation, there is universal agreement on the fact that auto-antibodies can be used as disease mark-ers, bystander spectators of the underlying autoimmune process.

Pituitary autoantibodies only partially fulfill this role of disease markers. The main reason for their currently low clinical utility is that the pituitary autoantigens targeted by the immune system during AH remain unknown. This lack of knowledge has ham-pered the development of antigen-specific antibody assays and, therefore, current approaches to detect pituitary antibodies in patient sera rely on nonantigen-specific methods, such as indirect immunofluores-cence. These methods have low sensitivity

and specificity, and are poorly quantitative. A discussion of pituitary antigens and antibodies have been presented in detail in previous reviews (e.g., [182–184]).

When measured by indirect immuno fluorescence, pituitary autoantibodies are found in a variety of conditions, ranging in increasing frequency from normal subjects to patients with histo-logically proven AH (Figure 4). At present, pituitary auto antibodies remain of limited value to the clinician for differentiating pituitary masses. Nonetheless, pituitary antibodies can suggest a diagnosis of AH when histopathological examination of the pituitary is not feasible and they have been associated with impairment of pituitary secretions, such as growth hormone [185–187] and gonado tropins [188]. Further studies are needed to elucidate the role of pituitary antibodies in the differential diagnosis of pituitary masses.

Expert commentaryDuring the past 5 years, the awareness of AH has increased sig-nificantly in the medical community, mainly owing to the emer-gence of a new form of AH secondary to anti-CTLA-4 therapy. Advances have also been made on the clinical side with a bet-ter characterization of the various AH phenotypes and its MRI features, as well as in basic research through the generation of a mouse model of AH.

Figure 4. Prevalence of pituitary autoantibodies in healthy controls and in the following disease categories: biopsy-proven AH, clinically suspected AH, isolated deficiencies of anterior pituitary hormones, other pituitary diseases different from AH, other autoimmune diseases different from AH, and diseases of nonautoimmune pathogenesis. AH: Autoimmune hypophysitis. Modified from [182].

www.expert-reviews.com 693

ReviewAutoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

References1 Caturegli PC, Newschaffer A, Olivi MG,

Pomper PC, Burger, Rose NR. Autoimmune hypophysitis. Endocr. Rev. 26(5), 599–614 (2005).

2 De Bellis, AG, Ruocco, M Battaglia et al. Immunological and clinical aspects of lymphocytic hypophysitis. Clin. Sci. (Lond.) 114(6), 413–421 (2008).

3 Gutenberg AR, Buslei R, Fahlbusch R, Buchfelder M, Bruck W. Immunopathology of primary hypophysitis: implications for pathogenesis. Am. J. Surg. Pathol. 29(3), 329–338 (2005).

4 Folkerth RD, Price DL Jr, Schwartz M, Black PM, Girolami U De. Xanthomatous hypophysitis. Am. J. Surg. Pathol. 22(6), 736–741 (1998).

5 Burt MG, Morey AL, Turner JJ, Pell M, Sheehy JP, Ho KK. Xanthomatous pituitary lesions: a report of two cases and review of the literature. Pituitary 6(3), 161–168 (2003).

6 Cheung CC, Ezzat S, Smyth HS, Asa SL. The spectrum and significance of primary hypophysitis. J. Clin. Endocrinol. Metab. 86(3), 1048–1053 (2001).

7 Deodhare SS, Bilbao JM, Kovacs K et al. Xanthomatous hypophysitis: a novel entity

of obscure etiology. Endocr. Pathol. 10(3), 237–241 (1999).

8 Tashiro T, Sano T, Xu B et al. Spectrum of different types of hypophysitis: a clinicopathologic study of hypophysitis in 31 cases. Endocr. Pathol. 13(3), 183–195 (2002).

9 Gutenberg A, Bell JJ, Lupi I et al. Pituitary and systemic autoimmunity in a case of intrasellar germinoma. Pituitary DOI: 10.1007/s11102-009-0187-x (2009) (Epub ahead of print).

10 Janeczko, C, McHugh J, Rawluk D, Farrell M, Brennan P, Delanty N. Hypophysitis secondary to ruptured Rathke’s cyst mimicking neurosarcoidosis. J. Clin. Neurosci. 16(4), 599–600 (2009).

11 Cuthbertson DJ, Ritchie D, Crooks D et al. Lymphocytic hypophysitis occurring simultaneously with a functioning pituitary adenoma. Endocr. J. 55(4), 729–735 (2008).

12 Puchner MJ, Ludecke DK, Saeger W. The anterior pituitary lobe in patients with cystic craniopharyngiomas: three cases of associated lymphocytic hypophysitis. Acta Neurochir. (Wien) 126(1), 38–43 (1994).

13 McIntyre EA, Perros P. Fatal inflammatory hypophysitis. Pituitary 10(1), 107–111 (2007).

14 Takano, K. Sarcoidosis of the hypothalamus and pituitary. Intern. Med. 43(10), 894–895 (2004).

15 Kaltsas GA, Powles TB, J Evanson et al. Hypothalamo–pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment. J. Clin. Endocrinol. Metab. 85(4), 1370–1376 (2000).

16 Rao S, Rajkumar A, Kuruvilla S. Sellar lesion: not always a pituitary adenoma. Indian J. Pathol. Microbiol. 51(2), 269–270 (2008).

17 Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary DOI: 10.1007/s11102-009-0193-z (2009) (Epub ahead of print).

18 Goudie RB, Pinkerton PH. Anterior hypophysitis and Hashimoto’s disease in a woman. J. Pathol. Bacteriol. 83, 584–585 (1962).

19 Mayfield RK, Levine JH, Gordon L, Powers J, Galbraith RM, Rawe SE. Lymphoid adenohypophysitis presenting as a pituitary tumor. Am. J. Med. 69, 619–623 (1980).

Key issues

• Autoimmune hypophysitis (AH) is an increasingly recognized endocrine disease that has intriguing features, such as its temporal association with pregnancy.

• AH remains difficult to diagnose with certainty before surgery because it clinically and radiologically mimics the presentation of the other 20 or so nonfunctioning sellar masses.

• AH is the only nonfunctioning sellar mass that has an autoimmune pathogenesis. It should, therefore, be possible to distinguish AH from the other masses once the specific pituitary antigens that are targeted in AH are discovered and antibody-based assays are developed.

• In recent years, a new form of AH has emerged: the form secondary to immunological therapies that block the inhibitory molecule cytotoxic T lymphocyte antigen (CTLA)-4.

• The CTLA-4-induced form of hypophysitis is increasing the awareness of AH in the medical community, and can shed light on the mechanisms leading to AH development.

However, the differential diagnosis of nonfunctioning pituitary masses remains challenging and can be obtained with certainty only after an invasive surgery and pathological examination of the pituitary biopsy. It is possible that discovery of AH-associated pituitary autoantigen(s) will allow the development of immuno-logical assays that can provide us with a further tool to use in the study of pituitary lesions.

Five-year viewDespite AH being first reported almost five decades ago, the path-ogenic pituitary antigen(s) targeted by the patient’s immune sys-tem during AH remain(s) to be discovered or confirmed. Such a discovery will allow the development of antigen-specific antibody

assays that should be useful in the differential diagnosis of non-functioning pituitary masses. In addition, understanding the link between CTLA-4 blockade and development of AH will promote understanding of autoimmune diseases in general.

Financial disclosure and acknowledgmentsThis work was supported by NIH grant DK080351 to Patrizio Caturegli, and by the Heidenreich-von-Siebold grant of the Georg-August-University of Göttingen, Germany to Angelika Gutenberg. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Expert Rev. Endocrinol. Metab. 4(6), (2009)694

Review Gutenberg, Landek-Salgado, Tzou et al.

20 Quencer RM. Lymphocytic adenohypophysitis: autoimmune disorder of the pituitary gland. AJNR Am J. Neuroradiol. 1(4), 343–345 (1980).

21 Levine SN, Benzel EC, Fowler MR, Shroyer JV, Mirfakhraee M. Lymphocytic adenohypophysitis: clinical, radiological, and magnetic resonance imaging characterization. Neurosurgery 22(5), 937–941 (1988).

22 Bellastella A, Bizzarro A, Coronella C, Bellastella G, Sinisi AA, De Bellis A. Lymphocytic hypophysitis: a rare or underestimated disease? Eur. J. Endocrinol. 149(5), 363–376 (2003).

23 Gutenberg A, Hans V, Puchner MJ et al. Primary hypophysitis: clinical–pathological correlations. Eur. J. Endocrinol. 155(1), 101–107 (2006).

24 Tsagarakis S, Vassiliadi D, Malagari K, Kontogeorgos G, Thalassinos N. Lymphocytic hypophysitis: late recurrence following successful transsphenoidal surgery. Endocrine 25(2), 85–90 (2004).

25 Lecube A, Francisco G, Rodriguez D et al. Lymphocytic hypophysitis successfully treated with azathioprine: first case report. J. Neurol. Neurosurg. Psychiatry 74(11), 1581–1583 (2003).

26 Leung GK, Lopes MB, Thorner MO, Vance ML, Laws ER. Primary hypophysitis: a single-center experience in 16 cases. J. Neurosurg. 101(2), 262–271 (2004).

27 Tubridy N, Saunders D, Thom M et al. Infundibulohypophysitis in a man presenting with diabetes insipidus and cavernous sinus involvement. J. Neurol. Neurosurg. Psychiatry 71(6), 798–801 (2001).

28 Postema PTE, van Hagen PM, de Herder WW. Treatment of aggressive, recurrent lymphocytic hypophysitis with rituximab. Presented at: 90th Annual Meeting of the Endocrine Society. San Francisco, CA, USA, 12–15 June 2008 (Abstract P1-394).

29 Selch MT, DeSalles AA, Kelly DF et al. Stereotactic radiotherapy for the treatment of lymphocytic hypophysitis. Report of two cases. J. Neurosurg. 99(3), 591–596 (2003).

30 Ray DK, Yen CP, Vance ML, Laws ER, Lopes B, Sheehan JP. g knife surgery for lymphocytic hypophysitis. Neurosurg. J. DOI: 10.3171/2009.6.JNS081176 (2009) (Epub ahead of print).

31 Gonzalez-Cuyar LF, Tavora F, Shaw K, Castellani RJ, Dejong JL. Sudden unexpected death in lymphocytic hypophysitis. Am. J. Forensic Med. Pathol. 30(1), 61–63 (2009).

32 Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer Immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3(11), 991–998 (2002).

33 Choudhury A, Mosolits S, Kokhaei P, Hansson L, Palma M, Mellstedt H. Clinical results of vaccine therapy for cancer: learning from history for improving the future. Adv. Cancer Res. 95, 147–202 (2006).

34 Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

35 Serafini P, Borrello I, Bronte V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin. Cancer Biol. 16(1), 53–65 (2006).

36 Lucas T, Abraham D, Aharinejad S. Modulation of tumor associated macrophages in solid tumors. Front. Biosci. 13, 5580–5588 (2008).

37 Kryczek I, Liu R, Wang G et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res. 69(9), 3995–4000 (2009).

38 Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 9, 3 (2009).

39 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005).

40 Subudhi SK, Alegre ML, Fu YX. The balance of immune responses: costimulation verse coinhibition. J. Mol. Med. 83(3), 193–202 (2005).

41 Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5), 541–547 (1995).

42 Ueda H, Howson JM, Esposito L et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423(6939), 506–511 (2003).

43 Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat. Rev. Cancer 7(2), 95–106 (2007).

44 Beck KE, Blansfield JA, Tran KQ et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J. Clin. Oncol. 24(15), 2283–2289 (2006).

45 Hodi FS, Mihm MC, Soiffer RJ et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc. Natl Acad. Sci. USA 100(8), 4712–4717 (2003).

46 Phan GQ, Yang JC, Sherry RM et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100(14), 8372–8377 (2003).

47 Weber JS. The clinical utility of cytotoxic T lymphocyte antigen 4 abrogation by human antibodies. Melanoma Res. 16(5), 379–383 (2006).

48 Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol. Immunother. 58(5), 823–830 (2009).

49 Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J. Immunol. 175(11), 7746–7754 (2005).

50 Wing K, Onishi Y, Prieto-Martin P et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899), 271–275 (2008).

51 Hodi FS. Cytotoxic T-lymphocyte-associated antigen-4. Clin. Cancer Res. 13(18 Pt 1), 5238–5242 (2007).

52 Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 12(7), 864–872 (2007).

53 Blansfield JA, Beck KE, Tran K et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J. Immunother. 28(6), 593–598 (2005).

54 Yang JC, Hughes M, Kammula U et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. 30(8), 825–830 (2007).

55 Weber JS, O’Day S, Urba W et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J. Clin. Oncol. 26(36), 5950–5956 (2008).

www.expert-reviews.com 695

ReviewAutoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

56 Maker AV, Yang JC, Sherry RM et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J. Immunother. 29(4), 455–463 (2006).

57 Carpenter KJ, Murtagh RD, Lilienfeld H, Weber J, Murtagh FR. Ipilimumab-induced hypophysitis: MR imaging Findings. AJNR Am. J. Neuroradiol. 30(9), 1751–1753 (2009).

58 Kaehler KC, Egberts F, Lorigan P, Hauschild A. Anti-CTLA-4 therapy-related autoimmune hypophysitis in a melanoma patient. Melanoma Res. 19(5), 333–334 (2009).

59 Shaw SA, Camacho LH, McCutcheon IE, Waguespack SG. Transient hypophysitis after cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade. J. Clin. Endocrinol. Metab. 92(4), 1201–1202 (2007).

60 Freda PU, Post KD. Differential diagnosis of sellar masses. Endocrinol. Metab. Clin. North Am. 28(1), 81–117 (1999).

61 Glezer A, Paraiba DB, Bronstein MD. Rare sellar lesions. Endocrinol. Metab. Clin. North Am. 37(1), 195–211 (2008).

62 Caturegli P. Autoimmune hypophysitis: an underestimated disease in search of its autoantigen(s). J. Clin. Endocrinol. Metab. 92(6), 2038–2040 (2007).

63 Tzou SC, Lupi I, Landek M et al. Autoimmune hypophysitis of SJL mice: clinical insights from a new animal model. Endocrinology 149(7), 3461–3469 (2008).

64 Lidove O, Piette JC, Charlotte F, Cassoux N, Correas JM, Papo T. Lymphocytic hypophysitis with lachrymal, salivary and thyroid gland involvement. Eur. J. Intern. Med. 15(2), 121–124 (2004).

65 Guay AT, Agnello V, Tronic BC, Gresham DG, Freidberg SR. Lymphocytic hypophysitis in a man. J. Clin. Endocrinol. Metab. 64(3), 631–634 (1987).

66 Cosman F, Post KD, Holub DA, Wardlaw SL. Lymphocytic hypophysitis. Report of 3 new cases and review of the literature. Medicine 68(4), 240–256 (1989).

67 Gutenberg A, Larsen J, Lupi I, Rohde V, Caturegli P. A radiological score to distinguish autoimmune hypophysitis from non-secreting pituitary adenoma pre-operatively. AJNR Am. J. Neuroradiol. 30(9), 1766–1772 (2009).

68 Ahmadi J, Meyers GS, Segall HD, Sharma OP, Hinton DR. Lymphocytic adenohypophysitis: contrast-enhanced MR imaging in five cases. Radiology 195(1), 30–34 (1995).

69 Lee MH, Choi HY, Sung YA, Lee JK. High signal intensity of the posterior pituitary gland on T1-weighted MR images. Correlation with plasma vasopressin concentration to water deprivation. Acta Radiol. 42(2), 129–134 (2001).

70 Chanson P, Brochier S. Non-functioning pituitary adenomas. J. Endocrinol. Invest. 28(11 Suppl.), 93–99 (2005).

71 Asa SL. Practical pituitary pathology: what does the pathologist need to know? Arch. Pathol. Lab. Med. 132(8), 1231–1240 (2008).

72 Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German pituitary tumor registry. Eur. J. Endocrinol. 156(2), 203–216 (2007).

73 Drange MR, Fram NR, Herman-Bonert V, Melmed S. Pituitary tumor registry: a novel clinical resource. J. Clin. Endocrinol. Metab. 85(1), 168–174 (2000).

74 Lamberts SW, de Herder WW, van der Lely AJ. Pituitary insufficiency. Lancet 352(9122), 127–134 (1998).

75 Ferrante E, Ferraroni M, Castrignano T et al. Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors. Eur. J. Endocrinol. 155(6), 823–829 (2006).

76 Choi SH, Kwon BJ, Na DG, Kim JH, Han MH, Chang KH. Pituitary adenoma, craniopharyngioma, and Rathke cleft cyst involving both intrasellar and suprasellar regions: differentiation using MRI. Clin. Radiol. 62(5), 453–462 (2007).

77 Heshmati HM, Kujas M, Casanova S et al. Prevalence of lymphocytic infiltrate in 1400 pituitary adenomas. Endocr. J. 45(3), 357–361 (1998).

78 Rao VJ, James RA, Mitra D. Imaging characteristics of common suprasellar lesions with emphasis on MRI findings. Clin. Radiol. 63(8), 939–947 (2008).

79 Bunin GR, Surawicz TS, Witman PA, Preston-Martin S, Davis F, Bruner JM. The descriptive epidemiology of craniopharyngioma. J. Neurosurg. 89(4), 547–551 (1998).

80 Garnett MR, Puget S, Grill J, Sainte-Rose C. Craniopharyngioma. Orphanet J. Rare Dis. 2, 18 (2007).

81 Shin JL, Asa SL, Woodhouse LJ, Smyth HS, Ezzat S. Cystic lesions of the pituitary: clinicopathological features distinguishing craniopharyngioma, Rathke’s cleft cyst, and arachnoid cyst. J. Clin. Endocrinol. Metab. 84(11), 3972–3982 (1999).

82 Karavitaki N, Cudlip S, Adams CB, Wass JA. Craniopharyngiomas. Endocr. Rev. 27(4), 371–397 (2006).

83 Van Effenterre R, Boch AL. Craniopharyngioma in adults and children: a study of 122 surgical cases. J. Neurosurg. 97(1), 3–11 (2002).

84 Voelker JL, Campbell RL, Muller J. Clinical, radiographic, and pathological features of symptomatic Rathke’s cleft cysts. J. Neurosurg. 74(4), 535–544 (1991).

85 Kasperbauer JL, Orvidas LJ, Atkinson JL, Abboud CF. Rathke cleft cyst: diagnostic and therapeutic considerations. Laryngoscope 112(10), 1836–1839 (2002).

86 Osborn AG, Preece MT. Intracranial cysts: radiologic–pathologic correlation and imaging approach. Radiology 239(3), 650–664 (2006).

87 Rengachary SS, Watanabe I. Ultrastructure and pathogenesis of intracranial arachnoid cysts. J. Neuropathol. Exp. Neurol. 40(1), 61–83 (1981).

88 Harrison MJ, Morgello S, Post KD. Epithelial cystic lesions of the sellar and parasellar region: a continuum of ectodermal derivatives? J. Neurosurg. 80(6), 1018–1025 (1994).

89 Dubuisson AS, Stevenaert A, Martin DH, Flandroy PP. Intrasellar arachnoid cysts. Neurosurgery 61(3), 505–513 (2007).

90 Mohn A, Schoof E, Fahlbusch R, Wenzel D, Dorr HG. The endocrine spectrum of arachnoid cysts in childhood. Pediatr. Neurosurg. 31(6), 316–321 (1999).

91 Kaido T, Okazaki A, Kurokawa S, Tsukamoto M. Pathogenesis of intraparenchymal epidermoid cyst in the brain: a case report and review of the literature. Surg. Neurol. 59(3), 211–216 (2003).

92 Green AJ, Roberts DR, Swanson RA. Post-traumatic epidermoid cyst presenting with headache. Neurology 64(9), 1657 (2005).

93 Yamakawa K, Shitara N, Genka S, Manaka S, Takakura K. Clinical course and surgical prognosis of 33 cases of intracranial epidermoid tumors. Neurosurgery 24(4), 568–573 (1989).

94 Oge K, Ozgen T. Transsphenoidal removal of an intra- and suprasellar epidermoid cyst. Neurochirurgia (Stuttg.) 34(3), 94–96 (1991).

95 Huang BY, Castillo M. Nonadenomatous tumors of the pituitary and sella turcica. Top. Magn. Reson. Imaging 16(4), 289–299 (2005).

Expert Rev. Endocrinol. Metab. 4(6), (2009)696

Review Gutenberg, Landek-Salgado, Tzou et al.

96 Kinjo T, al-Mefty O, Ciric I. Diaphragma sellae meningiomas. Neurosurgery 36(6), 1082–1092 (1995).

97 Gokalp HZ, Arasil E, Kanpolat Y, Balim T. Meningiomas of the tuberculum sella. Neurosurg. Rev. 16(2), 111–114 (1993).

98 Schick U, Hassler W. Surgical management of tuberculum sellae meningiomas: involvement of the optic canal and visual outcome. J. Neurol. Neurosurg. Psychiatry 76(7), 977–983 (2005).

99 Ebner FH, Bornemann A, Wilhelm H, Ernemann U, Honegger J. Tuberculum sellae meningioma symptomatic during pregnancy: pathophysiological considerations. Acta Neurochir. (Wien) 150(2), 189–193 (2008).

100 Jhawar BS, Fuchs CS, Colditz GA, Stampfer MJ. Sex steroid hormone exposures and risk for meningioma. J. Neurosurg. 99(5), 848–853 (2003).

101 Nakamura M, Roser F, Struck M, Vorkapic P, Samii M. Tuberculum sellae meningiomas: clinical outcome considering different surgical approaches. Neurosurgery 59(5), 1019–1028(2006).

102 Kuo JS, Yu C, Giannotta SL, Petrovich Z, Apuzzo ML. The Leksell g knife Model U versus Model C: a quantitative comparison of radiosurgical treatment parameters. Neurosurgery 55(1), 168–172 (2004).

103 Donovan JL, Nesbit GM. Distinction of masses involving the sella and suprasellar space: specificity of imaging features. AJR Am. J. Roentgenol. 167(3), 597–603 (1996).

104 Dahlin DC, Maccarty CS. Chordoma. Cancer 5(6), 1170–1178 (1952).

105 Erdem E, Angtuaco EC, Van Hemert R, Park JS, Al-Mefty O. Comprehensive review of intracranial chordoma. Radiographics 23(4), 995–1009 (2003).

106 McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM. Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control 12(1), 1–11 (2001).

107 Thodou E, Kontogeorgos G, Scheithauer BW et al. Intrasellar chordomas mimicking pituitary adenoma. J. Neurosurg. 92(6), 976–982 (2000).

108 Bonneville F, Narboux Y, Cattin F, Rodiere E, Jacquet G, Bonneville JF. Preoperative location of the pituitary bright spot in patients with pituitary macroadenomas. AJNR Am. J. Neuroradiol. 23(4), 528–532 (2002).

109 Doucet V, Peretti-Viton P, Figarella-Branger D, Manera L, Salamon G. MRI of intracranial chordomas. Extent of tumour

and contrast enhancement: criteria for differential diagnosis. Neuroradiology 39(8), 571–576 (1997).

110 Sze G, Uichanco LS 3rd, Brant-Zawadzki MN et al. Chordomas: MR imaging. Radiology 166(1 Pt 1), 187–191 (1988).

111 Hermet M, Delevaux I, Trouillier S, Andre M, Chazal J, Aumaitre O. [Pituitary metastasis presenting as diabetes insipidus: a report of four cases and literature review]. Rev. Med. Interne 30(5), 425–429 (2009).

112 Komninos J, Vlassopoulou V, Protopapa D et al. Tumors metastatic to the pituitary gland: case report and literature review. J. Clin. Endocrinol. Metab. 89(2), 574–580 (2004).

113 Surawicz TS, McCarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG. Descriptive epidemiology of primary brain and CNS tumors: results from the central brain tumor registry of the United States, 1990–1994. Neuro Oncol. 1(1), 14–25 (1999).

114 Inamura T, Nishio S, Ikezaki K, Fukui M. Human chorionic gonadotrophin in CSF, not serum, predicts outcome in germinoma. J. Neurol. Neurosurg. Psychiatry 66(5), 654–657 (1999).

115 Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J. Neurosurg. 63(2), 155–167 (1985).

116 Frank G, Galassi E, Fabrizi AP, Frank F, Manetto V. Primary intrasellar germinoma: case report. Neurosurgery 30(5), 786–788 (1992).

117 Fields JN, Fulling KH, Thomas PR, Marks JE. Suprasellar germinoma: radiation therapy. Radiology 164(1), 247–249 (1987).

118 Kanagaki M, Miki Y, Takahashi JA et al. MRI and CT findings of neurohypophyseal germinoma. Eur. J. Radiol. 49(3), 204–211 (2004).

119 Nada R, Mohan H, Dhir SP, Mukherjee KK, Kak VK. Suprasellar malignant mixed germ cell tumour presenting as craniopharyngioma. Neurol. India 48(4), 381–384 (2000).

120 Oka H, Kawano N, Tanaka T et al. Long-term functional outcome of suprasellar germinomas: usefulness and limitations of radiotherapy. J. Neurooncol. 40(2), 185–190 (1998).

121 Bamberg M, Kortmann RD, Calaminus G et al. Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J. Clin. Oncol. 17(8), 2585–2592 (1999).

122 Shibamoto Y, Takahashi M, Sasai K. Prognosis of intracranial germinoma with syncytiotrophoblastic giant cells treated by radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 37(3), 505–510 (1997).

123 Utsuki S, Kawano N, Oka H, Tanaka T, Suwa T, Fujii K. Cerebral germinoma with syncytiotrophoblastic giant cells: feasibility of predicting prognosis using the serum hCG level. Acta Neurochir. (Wien) 141(9), 975–977 (1999).

124 Bettendorf M, Fehn M, Grulich-Henn J et al. Lymphocytic hypophysitis with central diabetes insipidus and consequent panhypopituitarism preceding a multifocal, intracranial germinoma in a prepubertal girl. Eur. J. Pediatr. 158(4), 288–292 (1999).

125 Endo T, Kumabe T, Ikeda H, Shirane R, Yoshimoto T. Neurohypophyseal germinoma histologically misidentified as granulomatous hypophysitis. Acta Neurochir. (Wien) 144(11), 1233–1237 (2002).

126 Fehn M, Bettendorf M, Ludecke DK, Sommer C, Saeger W. Lymphocytic hypophysitis masking a suprasellar germinoma in a 12-year-old girl. A case report. Pituitary 1(3–4), 303–307 (1999).

127 Houdouin L, Polivka M, Henegar C, Blanquet A, Delalande O, Mikol J. Pituitary germinoma and lymphocytic hypophysitis: a pitfall. Report of two cases. Ann. Pathol. 23(4), 349–354 (2003).

128 Kim G, Park SA, Hwang HJ et al. A case of suprasellar germinoma misdiagnosed as lymphocytic hypophysitis. J. Korean Med. Sci. 73(2), 210–215 (2007).

129 Mikami-Terao Y, Akiyama M, Yanagisawa T et al. Lymphocytic hypophysitis with central diabetes insipidus and subsequent hypopituitarism masking a suprasellar germinoma in a 13-year-old girl. Childs Nerv. Syst. 22(10), 1338–1343 (2006).

130 Ozbey N, Sencer A, Tanyolac S et al. An intrasellar germinoma with normal cerebrospinal fluid b-HCG concentrations misdiagnosed as hypophysitis. Hormones (Athens) 5(1), 67–71 (2006).

131 Torremocha F, Hadjadj S, Menet E et al. Pituitary germinoma presenting as a pseudotumoral lymphocytic hypophysitis in a man. Ann. Endocrinol. (Paris) 63(1), 13–17 (2002).

132 Fine HA, Mayer RJ. Primary central nervous system lymphoma. Ann. Intern. Med. 119(11), 1093–1104 (1993).

www.expert-reviews.com 697

ReviewAutoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade

133 Giustina A, Gola M, Doga M, Rosei EA. Clinical review 136: primary lymphoma of the pituitary: an emerging clinical entity. J. Clin. Endocrinol. Metab. 86(10), 4567–4575 (2001).

134 Johnson BA, Fram EK, Johnson PC, Jacobowitz R. The variable MR appearance of primary lymphoma of the central nervous system: comparison with histopathologic features. AJNR Am. J. Neuroradiol. 18(3), 563–572 (1997).

135 Singh S, Cherian RS, George B, Nair S, Srivastava A. Unusual extra-axial central nervous system involvement of non-Hodgkin’s lymphoma: magnetic resonance imaging. Australas. Radiol. 44(1), 112–114 (2000).

136 Nelson DF, Martz KL, Bonner H et al. Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology group (RTOG): RTOG 8315. Int. J. Radiat. Oncol. Biol. Phys. 23(1), 9–17 (1992).

137 DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group study 93-10. J. Clin. Oncol. 20(24), 4643–4648 (2002).

138 Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am. J. Epidemiol. 145(3), 234–241 (1997).

139 Christoforidis GA, Spickler EM, Recio MV, Mehta BM. MR of CNS sarcoidosis: correlation of imaging features to clinical symptoms and response to treatment. AJNR Am. J. Neuroradiol. 20(4), 655–669 (1999).

140 Porter N, Beynon HL, Randeva HS. Endocrine and reproductive manifestations of sarcoidosis. Q JM 96(8), 553–561 (2003).

141 Stern BJ, Krumholz A, Johns C, Scott P, Nissim J. Sarcoidosis and its neurological manifestations. Arch. Neurol. 42(9), 909–917 (1985).

142 Sherman JL, Stern BJ. Sarcoidosis of the CNS: comparison of unenhanced and enhanced MR images. AJNR Am. J. Neuroradiol. 11(5), 915–923 (1990).

143 Loh KC, Green A, Dillon WP Jr, Fitzgerald PA, Weidner N, Tyrrell JB. Diabetes insipidus from sarcoidosis confined to the posterior pituitary. Eur. J. Endocrinol. 137(5), 514–519 (1997).

144 Stuart CA, Neelon FA, Lebovitz HE. Hypothalamic insufficiency: the cause of hypopituitarism in sarcoidosis. Ann. Intern. Med. 88(5), 589–594 (1978).

145 Bihan H, Christozova V, JL Dumas et al. Sarcoidosis: clinical, hormonal, and magnetic resonance imaging (MRI) manifestations of hypothalamic–pituitary disease in 9 patients and review of the literature. Medicine (Baltimore) 86(5), 259–268 (2007).

146 Bullmann C, Faust M, A Hoffmann et al. Five cases with central diabetes insipidus and hypogonadism as first presentation of neurosarcoidosis. Eur. J. Endocrinol. 142(4), 365–372 (2000).

147 Nowak DA, Widenka DC. Neurosarcoidosis: a review of its intracranial manifestation. J. Neurol. 248(5), 363–372 (2001).

148 Scott TF, Yandora K, Valeri A, Chieffe C, Schramke C. Aggressive therapy for neurosarcoidosis: long-term follow-up of 48 treated patients. Arch. Neurol. 64(5), 691–696 (2007).

149 Inaba H, Suzuki S, Shigematsu S, Kobayashi S, Nishio S, Hashizume K. Spontaneous remission of diabetes insipidus due to CNS sarcoidosis. Intern. Med. 48(4), 225–229 (2009).

150 Guoth MS, Kim J, de Lotbiniere AC, Brines ML. Neurosarcoidosis presenting as hypopituitarism and a cystic pituitary mass. Am. J. Med. Sci. 315(3), 220–224 (1998).

151 Sato N, Sze G, Kim JH. Cystic pituitary mass in neurosarcoidosis. AJNR Am. J. Neuroradiol. 18(6), 1182–1185 (1997).

152 Rao JK, Weinberger M, Oddone EZ, Allen NB, Landsman P, Feussner JR. The role of antineutrophil cytoplasmic antibody (c-ANCA) testing in the diagnosis of Wegener granulomatosis. A literature review and meta-analysis. Ann. Intern. Med. 123(12), 925–932 (1995).

153 Abdou NI, Kullman GJ, Hoffman GS et al. Wegener’s granulomatosis: survey of 701 patients in North America. Changes in outcome in the 1990s. J. Rheumatol. 29(2), 309–316 (2002).

154 de Groot K, Gross WL, Herlyn K, and Reinhold-Keller E. Development and validation of a disease extent index for Wegener’s granulomatosis. Clin. Nephrol. 55(1), 31–38 (2001).

155 Murphy JM, Gomez-Anson B, Gillard JH et al. Wegener granulomatosis: MR imaging findings in brain and meninges. Radiology 213(3), 794–799 (1999).

156 Anderson G, Coles ET, Crane M et al. Wegener’s granuloma. A series of 265 British cases seen between 1975 and 1985. A report by a sub-committee of the British Thoracic Society Research Committee. Q JM 83(302), 427–438 (1992).

157 Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann. Neurol. 33(1), 4–9 (1993).

158 Goyal M, Kucharczyk W, Keystone E. Granulomatous hypophysitis due to Wegener’s granulomatosis. AJNR Am. J. Neuroradiol. 21(8), 1466–1469 (2000).

159 Katzman GL, Langford CA, Sneller MC, Koby M, Patronas NJ. Pituitary involvement by Wegener’s granulomatosis: a report of two cases. AJNR Am. J. Neuroradiol. 20(3), 519–523 (1999).

160 Roberts GA, Eren E, Sinclair H et al. Two cases of Wegener’s granulomatosis involving the pituitary. Clin. Endocrinol. (Oxf.) 42(3), 323–328 (1995).

161 Rosete A, Cabral AR, Kraus A, Alarcon-Segovia D. Diabetes insipidus secondary to Wegener’s granulomatosis: report and review of the literature. J. Rheumatol. 18(5), 761–765 (1991).

162 Inoue T, Kaneko Y, Mannoji H, Fukui M. Giant cell granulomatous hypophysitis manifesting as an intrasellar mass with unilateral ophthalmoplegia – case report. Neurol. Med. Chir. (Tokyo) 37(10), 766–770 (1997).

163 Yasuhara T, Fukuhara T, Nakagawa M et al. Wegener granulomatosis manifesting as meningitis. Case report. J. Neurosurg. 97(5), 1229–1232 (2002).

164 White ES, Lynch JP. Pharmacological therapy for Wegener’s granulomatosis. Drugs 66(9), 1209–1228 (2006).

165 Garovic VD, Clarke BL, Chilson TS, Specks U. Diabetes insipidus and anterior pituitary insufficiency as presenting features of Wegener’s granulomatosis. Am. J. Kidney Dis. 37(1), E5 (2001).

166 Arico M, Clementi R, Caselli D, Danesino C. Histiocytic disorders. Hematol. J. 4(3), 171–179 (2003).

167 Watanabe R, Tatsumi K, Hashimoto S, Tamakoshi A, Kuriyama T. Clinico–epidemiological features of pulmonary histiocytosis X. Intern. Med. 40(10), 998–1003 (2001).

Expert Rev. Endocrinol. Metab. 4(6), (2009)698

Review Gutenberg, Landek-Salgado, Tzou et al.

168 Arico M, Egeler RM. Clinical aspects of Langerhans cell histiocytosis. Hematol. Oncol. Clin. North Am. 12(2), 247–258 (1998).

169 Makras P, Samara C, Antoniou M et al. Evolving radiological features of hypothalamo–pituitary lesions in adult patients with Langerhans cell histiocytosis (LCH). Neuroradiology 48(1), 37–44 (2006).

170 Maghnie M, Bossi G, Klersy C, Cosi G, Genovese E, Arico M. Dynamic endocrine testing and magnetic resonance imaging in the long-term follow-up of childhood langerhans cell histiocytosis. J. Clin. Endocrinol. Metab. 83(9), 3089–3094 (1998).

171 Broadbent V, Gadner H. Current therapy for Langerhans cell histiocytosis. Hematol. Oncol. Clin. North Am. 12(2), 327–338 (1998).

172 Thompson LD, Wenig BM, Adair CF, Smith BC, Heffess CS. Langerhans cell histiocytosis of the thyroid: a series of seven cases and a review of the literature. Mod. Pathol. 9(2), 145–149 (1996).

173 Maghnie M, Arico M, Villa A, Genovese E, Beluffi G, Severi F. MR of the hypothalamic–pituitary axis in Langerhans cell histiocytosis. AJNR Am. J. Neuroradiol. 13(5), 1365–1371 (1992).

174 Prayer D, Grois N, Prosch H, Gadner H, Barkovich AJ. MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. AJNR Am. J. Neuroradiol. 25(5), 880–891 (2004).

175 da Rocha AJ, Maia AC Jr, Ferreira NP, do Amaral LL. Granulomatous diseases of the central nervous system. Top. Magn. Reson. Imaging 16(2), 155–187 (2005).

176 Sunil K, Menon R, Goel N et al. Pituitary tuberculosis. J. Assoc. Physicians India 55, 453–456 (2007).

177 Arunkumar MJ, Rajshekhar V. Intrasellar tuberculoma presenting as pituitary apoplexy. Neurol. India 49(4), 407–410 (2001).

178 Singh S. Pituitary tuberculoma: magnetic resonance imaging. Neurol. India 51(4), 548–550 (2003).

179 Katti MK. Pathogenesis, diagnosis, treatment, and outcome aspects of cerebral tuberculosis. Med. Sci. Monit. 10(9), RA215–RA229 (2004).

180 Patankar T, Patkar D, Bunting T, Castillo M, Mukherji SK. Imaging in pituitary tuberculosis. Clin. Imaging 24(2), 89–92 (2000).

181 Arbuckle MR, McClain MT, Rubertone MV et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349(16), 1526–1533 (2003).

182 Caturegli P, Lupi I, Landek-Salgado M, Kimura H, Rose NR. Pituitary autoimmunity: 30 years later. Autoimmun. Rev. 7(8), 631–637 (2008).

183 Crock PA, Bensing S, Smith CJA, Burns C, Robinson PJ. Pituitary autoantibodies. Curr. Opin. Endocrinol. Diabet. 13, 344–350 (2006).

184 De Bellis A, Bizzarro A, Bellastella A. Pituitary antibodies and lymphocytic hypophysitis. Best Pract. Res. Clin. Endocrinol. Metab. 19(1), 67–84 (2005).

185 De Bellis A, Bizzarro A, Conte M et al. Antipituitary antibodies in adults with apparently idiopathic growth hormone deficiency and in adults with autoimmune endocrine diseases. J. Clin. Endocrinol. Metab. 88(2), 650–654 (2003).

186 De Bellis A, Salerno M, Conte M et al. Antipituitary antibodies recognizing growth hormone (GH)-producing cells in children with idiopathic GH deficiency and in children with idiopathic short stature. J. Clin. Endocrinol. Metab. 91(7), 2484–2489 (2006).

187 Manetti L, Lupi I, Morselli LL et al. Prevalence and functional significance of antipituitary antibodies in patients with autoimmune and non-autoimmune thyroid diseases. J. Clin. Endocrinol. Metab. 92(6), 2176–2181 (2007).

188 De Bellis A, Sinisi AA, Conte M et al. Antipituitary antibodies against gonadotropin-secreting cells in adult male patients with apparently idiopathic hypogonadotropic hypogonadism. J. Clin. Endocrinol. Metab. 92(2), 604–607 (2007).

Websites

201 Hypophysitis research centerhttp://pathology2.jhu.edu/hypophysitis

202 Clinical trials database http://clinicaltrials.gov

Affiliations• Angelika Gutenberg, MD, PhD

Department of Neurosurgery, Georg-August University, Goettingen, Germany Tel.: +49 551 391 4027 Fax: +49 551 398 794 agutenberg@med.uni-goettingen.de

• Melissa Landek-Salgado Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Tel.: +1 443 287 8911 Fax: +1 410 614 3548 mlandek1@jhmi.edu

• Shey-Cherng Tzou, PhD Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Tel.: +1 443 287 8911 Fax: +1 410 614 3548 sctzou.tw@yahoo.com.tw

• Isabella Lupi, MD Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy Tel.: +39 050 995 010 Fax: +39 050 995 086 isabellalupi@yahoo.it

• Abby Geis Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Tel.: +1 443 287 8911 Fax: +1 410 614 3548 abbydawson@hotmail.com

• Hiroaki Kimura, PhD Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Tel.: +1 443 287 8911 Fax: +1 410 614 3548 hkimura1@jhmi.edu

• Patrizio Caturegli, MD, MPHDepartment of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Tel.: +1 443 287 8911 Fax: +1 410 614 3548 pcat@jhmi.edu