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Autoimmune : expanding the differential diagnosis to CTLA-4 blockade

Expert Rev. Endocrinol. Metab. 4(6), 681–698 (2009)

Angelika Gutenberg, is an increasingly recognized disorder that enters in the differential Melissa Landek- diagnosis of nonfunctioning pituitary masses. The differential diagnosis of these conditions is Salgado, Shey-Cherng challenging because of similar clinical presentations and radiological signs. This review describes Tzou, Isabella Lupi, 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 Abby Geis, frequency in patients receiving treatments that abrogate the function of cytotoxic T lymphocyte Hiroaki Kimura and antigen 4. Patrizio Caturegli† † Author for correspondence Keywords: • CTLA-4 blockade • hypophysitis • monoclonal antibodies • MRI • nonfunctioning Department of Pathology, The sellar masses Johns Hopkins University School of Medicine, Baltimore, MD, USA General features of associated with lymphocytic infiltration of the Tel.: +1 443 287 8911 autoimmune hypophysitis include germinoma [9], ruptured Fax: +1 410 614 3548 Autoimmune (lymphocytic) hypophysitis (AH), Rathke cleft cyst [10], [11], [email protected] is a chronic of the pituitary gland and craniopharyngioma [12]. Systemic processes caused or accompanied by pituitary autoimmu- that involve the pituitary are most commonly nity [1,2]. It can be classified etiologically into two associated with a granulomatous reaction and groups: primary and secondary hypophysitis. include Wegener granulomatosis [13], sarcoidosis Primary hypophysitis is, by definition, of [14], Langerhans cell histiocytosis [15] and, more unknown etiology. It is diagnosed on clinical rarely nowadays, TB [16]. In the last 5 years a new and radiological grounds or, when available, by entity has emerged in this group: hypophysitis pathological examination. Pathology classifies secondary to the administration of an antibody primary hypophysitis into three forms: lym- that blocks cytotoxic T-lymphocyte antigen phocytic, granulomatous and xanthomatous, (CTLA)-4 [17], an entity that will be explored in although some patients have mixed lympho- detail in this review. cytic and granulomatous or granulomatous and Autoimmune hypophysitis was first reported xanthomatous forms, so that the relationship in 1962 in a young woman who died 14 months between these entities remains to be established. after delivery of her second child because of Lymphocytic hypophysitis is the most common severe [18]. Only 12 addi- form and the topic of this review. Granulomatous tional patients, mainly post-mortem, appeared hypophysitis is characterized by an infiltration of in the literature during the following 20 years. multinucleated giant cells and histiocytes, sur- The first two ante-mortem patients diagnosed rounded by lymphocytes, mainly T cells [3], and by CT scan were reported in 1980 [19,20] and the plasma cells. Xanthomatous hypophysitis is very first one diagnosed by MRI in 1988 [21]. The rare; it was originally described in 1998 in three widespread use of MRI and greater awareness women [4], and in eight additional patients there- of AH in the medical community have signifi- after [3,5–8]. It features cystic-like areas of liquifi- cantly increased the number of published AH cation, infiltrated by lipid-rich foamy histiocytes patients (Figure 1). Many others are diagnosed but and lymphocytes. not published, and even more patients remain Secondary hypophysitis is caused by local or undiagnosed because of varying clinical pres- systemic processes. Local processes that arise entations and courses. Thus, although AH has within or around the pituitary gland and are been traditionally considered a rare disease, it www.expert-reviews.com 10.1586/EEM.09.37 © 2009 Expert Reviews Ltd ISSN 1744-6651 681 Review Gutenberg, Landek-Salgado, Tzou et al.

The diagnosis of AH remains difficult because it mimics the clinical and even radiological features of all other nonsecreting 40 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 30 disturbances (optic chiasma) and diplopia (oculomotor nerves). Endocrinological symptoms are due to compression or invasion of the normal (leading to adrenal insufficiency, 20 and ), () or pituitary stalk (hyperprolactinemia). The treatment of AH is, at the moment, only symptomatic. It First MRI case aims to reduce the size of the pituitary mass and replace the defi- 10 First CT cases cient . High-dose glucocorticoids (prednisolone 60 mg daily, tapering the dose every 5 days) are generally recommended

Number of patients with primary AH as first-line treatment in cases suspected for AH where vision is not endangered by the pituitary mass. Improvement under 0 glucocorticoids, however, is sometimes incomplete, transient or 1960 1970 1980 1990 2000 2010 even lacking, especially in cases that have a granulomatous or Year of publication xantho­matous component [23]. If vision is endangered or symp- toms worsen, trans-sphenoidal surgery has to be performed. In Figure 1. Distribution of 522 published patients with addition to reducing the mass size, this procedure also yields primary AH according to the year of publication. AH: Autoimmune hypophysitis; CT: Computed tomography. pituitary tissue for pathological analysis, which is still consid- ered the gold standard for diagnosing AH. Given the diffuse is probably underestimated [22]. At Johns Hopkins we maintain nature of the pituitary lesion in AH, neurosurgical decompression a database of published patients with primary AH that, as of should not be radical. Follow-up intervals after surgery should October 15 2009, includes 522 cases downloadable from our be short and include endocrinological and radiological updates website [201]. Patients have been reported from several countries, as recurrence of AH following trans-sphenoidal surgery is well but predominantly Japan and the USA (Figure 2). Within these described [24]. In AH patients with aggressive course that have countries, reporting is, as expected, greatest in areas rich in aca- not responded to the two treatments indicated above (glucocorti- demic centers. Many authors have written about AH, creating a coids, and trans-sphenoidal surgery), other approaches have been total of 630 articles as of October 15 2009. The articles have all successfully applied. These include lympholytic drugs other than been scanned and are now freely downloaded from our website glucocorticoids, such as azathioprine [25], methotrexate [26,27] or [201]. The top-five publishing centers currently are Federico II rituximab [28], stereotactic radiotherapy [29] and, more recently, University of Naples, Naples, Italy (De Bellis A, 19 articles); g-knife surgery [30]. Gunma University, Gunma, Japan (Kobayashi I, 13 articles); The natural history of AH is variable. Most patients improve after Kochi Medical School, Kochi, Japan (Hashimoto, K, 12 articles); reduction of the pituitary mass (obtained through surgery or gluco- Johns Hunter Children’s Hospital, New South Wales, Australia corticoid therapy), and either require long-term hormonal replace- (Crock P, ten articles); and Johns Hopkins University, MD, USA ment therapy (73%) or no medication (17%). Glucocorticoids, (Caturegli P, ten articles). when started early during the disease course, can significantly amel- Autoimmune hypophysitis can affect just the anterior pituitary iorate the patient’s status and even halt the progression to a chronic lobe (adenohypophysitis), just the posterior lobe and the stalk phase. The developing in the early phases of AH (infundibulo-neruohypophysitis) or both (panhypophysitis). It is can, in fact, occur via two mechanisms: the direct destruction of unclear whether these conditions represent different diseases or the endocrine cells induced by the lymphocytic infiltrate, and the a spectrum of the same disease. The distinction can also be mis- compression and impairment of the endocrine cells secondary to leading because a biopsy of both the anterior and posterior lobes the inflammatory edema. The latter mechanism is corrected by is only rarely performed, or specified in the published reports. glucocorticoid administration. Indeed, a clinical response to gluco- Autoimmune hypophysitis is approximately three-times more corticoids is a good indication that the diagnosis of a nonbiopsied common in females than males (389 female and 138 male; ratio: pituitary mass is indeed AH. A few AH patients improve spontane- 2.8:1), especially when it affects preferentially the anterior lobe ously without treatment (4%). The remaining patients (6%) die (273 female and 65 male; ratio: 4.2:1). The disease is most com- because of an irreversible, late-diagnosed adrenal insufficiency. The mon during the fourth decade of life, with a mean age at presen- most recent patient reported as an case was published in tation of 39 (median 35) years. As is common for such diseases, March 2009 [31], and showed a clinical history not dissimilar from AH tends to occur together with other autoimmune diseases, most that of the first patient reported in 1962, reminding us that AH frequently with those affecting the gland [1]. can still be a lethal disease if unrecognized.

682 Expert Rev. Endocrinol. Metab. 4(6), (2009) Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade Review 2 w Zealand Worldwide, Ne orea 21 South K 154 pa n Ja an 18 6 ustralia A iw Ta 8 ohoku T 41 Kanto 9 5 China Hokkaido u 13 9 39 India Chub Kink i y ia 1 man oku 54 l 1 26 4 ustr Lebanon 5 Ger Oman Shik A 1 5 1 Israe k land Po Croatia Chugoku 2 2 17 Greece Denmar ushu Ky key ica 12 3 r Tu 2 Sweden lands South Afr 5 3 unisia T 3 The Nether 35 UK Belgiu m DC 5 13 VA MA 10 CT 2 MD 2 2 Ireland 14 ance 5 9 1 NY 17 Italy Fr 1 tugal Spain 2 3 NC 2 Senegal FL 4 PA SC land r Po er 2 4 OH 1 5 Switz MI AL 2 TN 3 Brazil 2 1 IL MS 6 WI 4 3 1 3 LA AR MO Argentina 2 TX 20 100 Canada USA CO 1 xico 1 Me 1 WA 15 CA Figure 2. Distribution of 522 published patients with primary autoimmune hypophysitis according to the geographic location of the first author. USA and Japanese distributions.

www.expert-reviews.com 683 Review Gutenberg, Landek-Salgado, Tzou et al.

Autoimmune hypophysitis has at least three features that Tregs are a subset of CD4 T lymphocytes that suppress the activ- are intellectually challenging and stimulating. First, it shows a ity of CD8 effector T lymphocytes, CD4 helper T lymphocytes striking but unexplained temporal association with pregnancy. and antigen-presenting cells. Tregs are mainly characterized by Second, it remains one of the few organ-specific autoimmune the intracellular expression of the forkhead box P3 transcription diseases where the autoantigens have not yet been identified. factor [37]. They also express constitutively CTLA-4, CD25 (the a Lastly, it develops with unexpectedly high frequency in patients chain of the IL-2 ) and the glucocorticoid-induced TNF receiving treatments that block CTLA-4. This review will focus receptor; secrete the immunosuppressive cytokines IL-10 and on the differential diagnosis of AH, emphasizing its expansion to TGF-b; and have minimal levels of effector cytokines (e.g., IFN-g include CTLA-4 blockade. and TNF-a) and cytotoxic molecules (e.g., granzyme B) [37]. Tregs are beneficial in that they keep autoimmunity in check, but they Association of CTLA-4 blockade & AH are also detrimental in tumor immunology because they inhibit It is now well established that the immune system recognizes can- the anti-tumor action of effector T cells. Notably, there is a strong cer cells and plays an important role in their control, so much so inverse correlation between the number of intratumoral Tregs and that humans and animals with a defective immune system are the extent of tumor necrosis: the higher the number of intratumor at greater risk of developing cancer [32]. Cancer cells, however, Tregs the smaller the capacity of CD8 T cells to induce tumor evade such immune surveillance in most patients. Despite enor- necrosis (reviewed in [38]). mous efforts and resources being dedicated to the development CTLA-4 (Figure 3, inset) is a regulatory molecule expressed con- of immunotherapies, none of them are currently indicated as a stitutively on the surface of Tregs. It binds to the costimulatory standard, first-line anti­cancer treatment [33]. Cancer cells escape the molecule B7 on dendritic cells, sending inhibitory signals that immune system surveillance using four main types of mechanisms ultimately impair the immune-activating capacities of dendritic illustrated in Figure 3. The first mechanism, directly relevant to this cells [39]. CTLA-4 is also expressed on effector T cells but only review, involves the recruitment to the tumor site and draining after T-cell activation; it is inititally found in cytosolic vesicles lymph nodes of suppressor T cells (Tregs), tolerogenic dendritic located near the immunologic synapse, and then on the cell sur- cells [34], myeloid-derived suppressor cells [35] and tumor-associated face peaking at 2–3 days after activation [40]. Thus, CTLA-4 acts macrophages (Figure 3) [36]. bidirectionally (on both dendritic cells and effector T cells) to

Hypoxia CD25 CTLA-4 CD4 TNF-α ARG CSF-1 NOS B7 VEGF

Tumor-associated Myeloid-derived FoxP3 macrophage suppressor cell Tolerogenic dendritic cell

Suppressor lymphocyte (Treg) IL-10 4 Absence of: B7-1 B7-2 1 Recruitment of: Antigen-presenting cell 2 Depletion of: MHC II L-tryptophan (IDO ) B7 L-arginine (ARG /NOS )

3 Release of: TCR TGF-β CD28 CTLA-4 CD4 PGE2 VEGF Signal Cancer cell + - Expert Rev. Endocrinol. Metab. © Future Science Group (2009)

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.

684 Expert Rev. Endocrinol. Metab. 4(6), (2009) Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade Review

ultimately inhibit T-cell function and prevent the development publications have described a total of seven patients [17,57–59]. The of autoimmunity. Deletion of Ctla-4 in mice leads to aggressive clinical presentation is similar and indistinguishable from that of autoimmune reactions characterized by lymphoproliferation and patients with classic AH: patients complain of headache and symp- multiorgan failure [41], secondary to defective Treg activity and toms of anterior pituitary deficiencies. Furthermore, the unopposed effector T-cell activation. Similarly, in humans, poly- MRI is similar, showing a diffuse enlargement of the pituitary morphisms in the CTLA-4 gene that decrease its RNA stability gland [57]. The diagnostic hint for this form of secondary AH is and function have been associated with increased susceptibility to the underlying cancer and the use of CTLA-4-blocking anti- mellitus and autoimmune thyroiditis [42]. bodies. AH symptoms usually improve upon discontinuation of Considering the inhibitory effects of CTLA-4 on lymphocyte CTLA-4 blockade, and with the use of immunosuppressive doses function and the notion that immune responses against cancer of glucocorticoids [58]. The endocrine defects are long-lasting and cells are usually inhibited, investigators have blocked CTLA-4 require a prolonged follow-up, so much so that specific algorithms with the intent of inducing a general immune stimulation. That should be included in anti-CTLA-4 therapy protocols [17]. is, inhibiting an inhibitor such as CTLA-4 should ultimately It remains unknown why AH, a disease traditionally considered result in an overall enhanced immune response, and thus also in to be very rare, appears preferentially in the settings of CTLA-4 an enhanced immune response against cancer cells. Inhibition blockade. Efforts aimed at unraveling this association can greatly of CTLA-4 is achieved in patients by the injection of a mono- clonal antibody that disrupts the CTLA-4/B7 interaction, ulti- Table 1. Classification of sellar (intrasellar and mately abrogating CTLA-4 function [43]. This treatment regi- parasellar) masses. men, combined or not with vaccination protocols against cancer Disease % of sellar antigens, is being tested in patients with malignant melanoma, masses renal cell carcinoma, ovarian cancer, prostate cancer and other Hormone-secreting pituitary adenomas 56 solid tumors [44–46]. There are currently two anti-CTLA-4 monoclonal antibodies PRL-secreting adenoma 42 in Phase I clinical trials: (MDX-010, by Medarex ACTH-secreting adenoma 8 and Bristol Myers Squibb) and tremelimumab (or ticilimumab GH-secreting adenoma 5 [CP‑675,206] by Pfizer) [47]. The largest experience is with ipili- TSH-secreting adenoma 1 mumab [48]. CTLA-4 blockade is an effective anticancer treat- Nonfunctioning sellar masses 44 ment. It induces, on average, cancer regression in approximately Benign tumors 15% of the patients, although results are variable among trials [44]. Nonfunctioning pituitary adenoma 32.0 CTLA-4 blockade promotes anticancer responses via at least two Chordoma 1.20 mechanisms. Blocking CTLA-4 on tumor-specific effector T cells Meningioma 0.96 avoids their inhibition, promoting their clonal expansion [49]. Developmental lesions Blocking CTLA-4 on Tregs leads to their depletion, thus releas- Rathke’s cleft cyst 3.96 ing the brake that Tregs place on effector T cells, both tumor Craniopharyngioma 1.92 specific and nontumor specifc [50]. Several randomized Phase III Arachnoid cyst 0.48 clinical trials based on CTLA-4 blockade are currently ongoing Dermoid and epidermoid cysts 0.36 (listed at [202]). Malignant tumors The expected ‘side effect’ of CTLA-4 blockade, known as Metastasis (mainly from breast and lung cancer) 1.20 immune breakthrough event or immune-related adverse event Germinoma 0.24 (IRAE), is the induction of autoimmune diseases. They are Lymphoma 0.12 reported in up to 43% of patients [51] and have a variable and Astrocytoma 0.15 unpredictable course. In some cases the course is fulminant, such Autoimmune and inflammatory lesions as the development of diffuse colitis with crypt abscess formation Hypophysitis (lymphocytic and granulomatous) 0.84 7 days after the first dose of ipilimumab [52]. The most common Sphenoidal sinus mucocele 0.12 IRAEs due to anti-CTLA-4 therapy are inflammatory bowel dis- Sarcoidosis 0.12 Wegener granulomatosis 0.06 ease (colitis), hypophysitis, skin reactions and hepatitis, although Langerhans cell histiocytosis 0.06 numerous others are described [17]. Autoimmune hypophysitis secondary to CTLA-4 blockade was Infectious lesions TB 0.12 first reported in eight out of 163 (5%) melanoma patients pub- Pituitary abscess 0.12 lished by the National Cancer Institute [53,54], and its appearance was associated with a favorable response in five out of the eight Vascular lesions 0.06 patients. AH incidence ranges from a minimum of 1.8% [55] to Intrasellar aneurysm 0.06 a maximum of 17% [56], both in trials of patients with meta- ACTH: Adrenocorticotropic hormone; GH: Growth hormone; TSH: Thyroid- static melanoma. The clinical description of AH manifestations stimulating hormone. in these case series is limited, but more recently four individual Data derived and simplified from [60,72]. www.expert-reviews.com 685 Review Gutenberg, Landek-Salgado, Tzou et al. advance our understanding of AH pathogenesis and auto­immunity. It is, therefore, not surprising that many AH patients are misdi- At the very least, the CTLA-4/AH association is contributing to an agnosed and undergo trans-sphenoidal surgery for a presumptive increased awareness of AH in the medical community. diagnosis of nonfunctioning pituitary adenoma [26]. Autoimmune hypophysitis should be suspected when the neuro­ Differential diagnosis of nonfunctioning sellar masses logic and/or hypopituitary symptoms described above appear in Masses that arise within (intrasellar) or around (parasellar) the relation with pregnancy or post-partum, especially if the woman sella turcica, so-called sellar masses, can be of neoplastic, develop- suffers from additional autoimmune diseases, such as thyroiditis, mental, inflammatory, infectious or vascular origin(T able 1) [60,61]. Addison disease, Sjögren syndrome and Type 1 diabetes mellitus. The most common sellar mass is the hormone-secreting pituitary Lack of symptoms, that is presentation of the mass as incidenta- adenoma, representing more than half (56%) of all sellar masses. loma, is very rare for AH [64]. It has been proposed that the degree Its diagnosis is greatly facilitated by the signs and symptoms that of hypopituitarism is disproportionate to the size of the pituitary arise as a consequence of the hormonal hypersecretion. mass [65], although the criterion has not been formally tested on a Nonfunctioning sellar masses represent a heterogenous group of large number of cases and controls. Similarly, it has been proposed approximately 20 diseases (Table 1), among which the nonfunctioning that the order in which anterior pituitary hormones are lost in AH pituitary adenoma predominates. is different from that observed in pituitary adenomas where gonado­ All nonfunctioning sellar masses, despite their diverse etiology, tropins and growth hormone are the first to be impaired [66]. In present very similarly but require quite diverse treatments. For AH, the hypopituitarism mainly involves the adrenal and thyroid example, surgery is indicated for a nonfunctioning pituitary ade- axis, although it is important to emphasize that pituitary hormones noma that impinges upon the optic chiasma causing loss of vision, were not systematically measured in all reported AH patients, thus radiotherapy for a germinoma and glucocorticoids for AH. The ascertainment bias is possible. Overall, the measurement of ante- presentation is characterized by neurologic and/or hypo­pituitary rior pituitary hormones is useful and needed to establish a baseline symptoms caused by the mass effect. Neurologic symptoms result reference for future treatments, but does not help substantially in from compression of the structures surrounding the pituitary: distinguishing AH from the other nonfunctioning pituitary masses. headache (meninges); visual field and acuity defects (optic chi- MRI of the sella turcica is currently the best diagnostic tool, asm); and diplopia (oculomotor nerves). Hypopituitarism results closely reflecting the pathological changes of a pituitary gland from compression of the normal anterior pituitary, and more targeted by the autoimmune attack. We have recently published rarely, the posterior pituitary (causing diabetes insipidus) or the a study that systematically analyzed the MRI features of AH in stalk (causing hyperprolactinemia). comparison with those of nonfunctioning pituitary adenomas [67]. The differential diagnosis of nonfunctioning sellar masses In keeping with the inflammatory changes and hypervascularity should be based on a multidisciplinary approach and, in an ideal seen during the florid phase of hypophysitis, AH appears on MRI setting, it should be obtained before trans-sphenoidal surgery. as a symmetrical enlargement of the pituitary gland, homogeneous In the following section we will discuss the clinical and radio­ on T1- and T2-weighted images, both before and after the intense logical features that can be used to distinguish AH from the other gadolinium enhancement [67,68]. Two additional MRI features nonfunctioning sellar masses before surgery. This distinction is indicative of AH are the loss of the normal bright appearance of crucial for patient care because AH can often be managed with the posterior pituitary [69] and the thickening of the stalk, probably lympholytic medications alone whereas many of the other sellar indicating an autoimmune involvement of the neurohypophysis, masses require surgical resection [62]. even if the patient has not yet developed clinical diabetes insipidus.

Autoimmune hypophysitis Nonfunctioning pituitary adenoma Autoimmune hypophysitis has a well-established autoimmune Nonfunctioning pituitary adenomas lack clinical or biochemical pathogenesis. AH is, in fact, reproducible in mice by immuni- manifestations of hormonal excess. They derive most commonly zation with pituitary proteins [63], has the pathological features from the gonadotrophs [70], although each pituitary cell type can typical of autoimmune diseases (formation of tertiary lymphoid give rise to tumors that remain clinically silent [71,72]. They present follicles within the target organ), responds to immuno­suppressive with headache (48%), visual field and acuity defects (48%) and therapies (such as glucocorticoids), occurs in the same patient with hypogonadism (35%) [73]. Modest hyperprolactinemia secondary other diseases of proven autoimmune nature and is accompanied to hypothalamic–pituitary stalk compression is common (47%) by pituitary antibodies. [73], whereas diabetes insipidus is extremely rare (<1%) [74]. The For AH, however, the main criteria used to establish a diagno- duration of symptoms before diagnosis is long, 23 ± 35 months, sis of (unique clinical features, presence of and it is not unusual even for large tumors to remain asymptomatic specific autoantibodies and pathological findings) are not easily and be discovered incidentally after a cranial imaging study is per- applicable. In fact, the clinical features of AH are often indistin- formed for unrelated reasons [73]. Trans-sphenoidal surgery and guishable from those of other nonfunctioning masses arising in removal of the adenoma is mandatory if vision is endangered [75]. the sella turcica; the pituitary antibodies as currently measured are Nonfunctioning pituitary adenomas are usually macroadeno- not specific (covered in the next section); and to biopsy the pitui- mas when they are symptomatic (diameter >10 mm) and often tary gland requires an expensive and invasive surgical procedure. extend upwards into the suprasellar cistern, or even the third

686 Expert Rev. Endocrinol. Metab. 4(6), (2009) Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade Review ventricle and the foramen of Monroe. This upward extension Rathke cleft cysts are smoothly marginated and vary in size provides the tumor a typical snowman or figure-of-eight appear- from a few millimeters to 10–20 mm. They can be completely ance [76]. Their MRI appearance is clearly dishomogenous, par- intrasellar (40%), or have some suprasellar extension (60%), ticularly on fast T2-weighted images where disseminated areas whereas completely suprasellar cysts are rare [86]. Rathke cleft of signal hyperintensity reflecting cystic or necrotic portions are cysts vary widely in their radiological appearance. Cysts with seen [76]. After gadolinium injection, the adenomatous tissue usu- low protein content are isointense with cerebrospinal fluid on ally enhances slightly in comparison to the cavernous sinus or all sequences, but become hyperintense on T1-weighted images normal pituitary tissue. Strong enhancement is to be expected as the protein content increases. On T2-weighted images, these only in the presence of secondary inflammatory changes, which cysts are hyperintense in 70% of cases and iso- or hypo-intense are found in approximately 3% of pituitary adenomas [77]. In in the remaining 30% [86]. A small nonenhancing intracystic adenomas, the stalk is often deviated laterally, and the normal nodule is considered a virtually pathognomonic sign of Rathke posterior pituitary bright spot is almost invariably conserved [67]. cleft cyst [78]. These nodules show high signal intensity on T1-weighted images and low signal intensity on T2-weighted Craniopharyngioma images, and lack enhancement, although an enhancing rim of Craniopharyngiomas account for approximately 2% of all sellar displaced and compressed pituitary gland is present in approxi- masses (Table 1) [78]. They are thought to arise from epithelial rem- mately half of the cases [86]. Calcification is a rarity in Rathke nants of the craniopharyngeal duct or the Rathke pouch (ada- cleft cysts [86]. mantinomatous type) or from metaplasia of squamous epithelial cell remnants of the part of the stomadeum that form the buccal Arachnoid cyst mucosa (squamous papillary type) [79,80]. The age at presenta- Arachnoid cysts arise most commonly (40–50%) in the supra­ tion follows a bimodal distribution, with a first peak between 5 tentorial compartment, and rarely (9–15%) in the sellar region and 14 years of age and a second between 65 and 74 years [79]. [87]. They can be congenital or acquired. Sellar arachnoid cysts Craniopharyngiomas are often diagnosed late, sometimes years are attributed to herniation of the arachnoid membrane through after the initial symptom appearance. The clinical picture at an incompetent diaphragma [88]. The mean age at presentation diagnosis is dominated by headache (62%), visual impairment is 45 years (range: 16–80 years) and the time from symptom (67–75%) and various degrees of hypopituitarism (52–87%) [81]. appearance to diagnosis can vary from 2 weeks to 5 years [89]. Hyperprolactinemia is found in approximately a third of patients Main symptoms include headache (41%) and visual distur- and diabetes insipidus in 6–19% [81]. Characteristic of cranio­ bances (55%), whereas hypopituitarism, usually involving the pharyngiomas is the presence of psychiatric deficits, loss of short- gonadotropic axis, is less common [90]. Hyperprolactinemia term memory and personality changes, which are described in is found in 21% and diabetes insipidus in less than 2% of approximately a third of the patients [80]. Currently, surgical exci- cases [90]. Symptomatic arachnoid cysts are resected via the sion followed by external-beam irradiation is the main treatment ­trans-sphenoidal route. option for residual tumor [82]. Arachnoid cysts appear ovoid, smoothly marginated and Craniopharyngiomas appear as large masses (>20 mm in diam- extending to the suprasellar region [89]. Their signal intensity eter) in part cystic and in part solid and calcified, located in the is the same as that of the cerebrospinal fluid in all sequences, suprasellar (75%), supra- and intra-sellar (20%) or intrasellar (5%) although hemorrhage, high protein content or lack of flow within regions [83]. Tumoral calcification, which may be best appreciated the cyst may complicate the MRI appearance [86]. Arachnoid cysts on CT scan, is particularly common and is seen in 70–90% of show a hypodense signal on T1-weighted sequences and a high childhood craniopharyngiomas and 40–60% of adult tumors [26]. signal on T2-weighted images. There is no enhancement of any Postcontrast MRI shows a heterogeneous gadolinium uptake in part of the lesion after contrast agent administration. The normal the solid part of approximately 60% of craniopharyngioma [78]. anterior pituitary can often be recognized only on sagittal planes, and the pituitary stalk is sometimes deviated [89]. Rathke cleft cyst Rathke cleft cysts are cystic sellar and suprasellar lesions. They Epidermoid cyst probably arise from the incomplete obliteration of the Rathke Epidermoid cysts arise from ectodermal inclusion during neu- pouch, which develops as a rostral outpouching of the primitive ral tube closure in the third to fifth week of embryogenesis [91]. oral cavity during the third or fourth week of embryogenesis and Acquired epidermoid cysts may develop as a result of trauma but are characteristically lined by a single layer of ciliated cuboidal are uncommon in the brain [92]. Epidermoid cysts are present or columnar epithelium with goblet cells. Rathke cleft cysts are at birth but, because of their slow growth rate, typically remain twice as common in women than men and usually occur between silent until the second to fourth decade of life [93]. They can 30 and 60 years of age [84]. They present with headache (65%), occur in numerous locations throughout the brain, including hypopituitarism (39–81%) and visual loss caused by compression the sellar region, although they are predominantly found in the of the optic chiasm (38%). Hyperprolactinemia is found in 39% cerebello–pontine angle cistern. Thus, their clinical presentation of the patients and diabetes insipidus in 9% [81]. Treatment of varies according to their location. Surgical removal is preferably Rathke cleft cyst is by trans-sphenoidal surgery [85]. performed via the trans-sphenoidal route [94]. www.expert-reviews.com 687 Review Gutenberg, Landek-Salgado, Tzou et al.

Most epidermoid cysts are isointense or slightly hyperintense to palsy of the abducent nerve [105]. Hypopituitarism is rare, although the cerebrospinal fluid on both T1- and T2-weighted images and mild dysfunction and hyperprolactinemia have been reported [60]. typically do not enhance, although some minimal rim enhance- Trans-sphenoidal surgery followed by radiotherapy is the generally ment occurs in approximately 25% of cases. Rare ‘white epider- accepted treatment [107]. moids’ have high protein content and show high signal intensity Intracranial chordomas appear on high-resolution CT as a cen- on T1- and low signal intensity on T2-weighted images [86]. trally located, well-circumscribed, soft-tissue mass that arises from the clivus and is associated with extensive lytic bone destruction Meningioma [60]. Intratumoral calcifications are common but considered to Meningiomas are three times more common in women than men represent inclusions from bone destruction rather than dystrophic and peak in incidence during the sixth decade of life [40]. They calcifications within the tumor itself[105] . MRI is the procedure of can originate from any dural surface, including the tuberculum choice for detecting a clival chordoma and determining the extent sellae, olfactory groove, sphenoid wing, diaphragma sellae and of the tumor and involvement of adjacent structures. Chordomas sella turcica [95]. Purely intrasellar meningiomas are rare [96]. A are iso- to hypo-intense to gray matter on T1- weighted images meningioma originating from the inner surface of the diaphragma [108], and have a high signal intensity on T2-weighted images, a sellae grows into the pituitary fossa, mimicking closely a non­ finding probably reflecting the high fluid content of vacuolated functioning pituitary adenoma [96]. Meningiomas originating cellular components [108]. Most intracranial chordomas enhance from the outer layer, by contrast, extend mainly to the supra- and moderately to markedly after gadolinium administration, with para-sellar regions [96]. Patients with tuberculum sellae meningi- a pattern sometimes referred to as ‘honeycomb’ [109]. Use of the omas often present with severe visual disturbance, and frontal and fat suppression technique allows the differentiation of enhanced orbital headaches (5–20%), but not hypopituitarism; mild-to- tumor margins from adjacent bright fatty bone marrow, and better moderate hyperprolactinemia may be found at presentation in as demarcation of intraclival chordomas [110]. many as 50% of patients [97] and the mean duration of symptoms before surgery is approximately 2 years [98]. Sellar meningiomas Pituitary metastasis are known to increase in size and become symptomatic during Metastases to the pituitary gland via hematogenous spread typi- menses or pregnancy [99]. Progesterone receptor positivity is a risk cally localize in the posterior pituitary, and thus present as diabetes factor for meningiomas and is found in 81% of female patients insipidus [111], considering that the posterior pituitary receives blood versus 40% of male patients [100]. For surgical resection the fron- directly from the systemic circulation whereas the anterior pituitary tolateral and pterional approach is advocated [98,101]. Postoperative is served by the portal system. Metastasis can also occur via menin- residual and/or recurrent tumor, especially within the cavernous geal spread through the suprasellar cistern, via the portal circulation sinus, is best controlled by g-knife radiosurgery [102]. from a hypothalamo–hypophyseal or infundibular metastasis, and Intrasellar meningiomas typically appear as masses that are via extension from a juxtasellar and skull base metastasis. Pituitary hypointense to isointense with respect to the gray matter on both metastases are most commonly caused by breast and lung cancer, T1- and T2-weighted sequences [103]. They enhance markedly and are usually found in elderly patients during the sixth or seventh after gadolinium administration in a homogeneous fashion in decade of life [112]. Pituitary symptoms are rare because pituitary more than 90% of the cases [103]. Intrasellar meningiomas are metastases tend to occur in end-stage cancer patients. Following commonly associated with sellar enlargement and rarely with diabetes insipidus, which is present in approximately 50% of the an enhancing dural tail [96]. The single most useful finding in patients, symptoms include hypo­pituitarism (25%), bilateral hemi- differentiating intrasellar meningiomas from AH and pituitary anopsia (25%) and headaches (15%); hyperprolactinemia is rare adenomas is to identifiy the pituitary gland as separate from the (6% of pituitary metastases) [112]. mass [95]. Visualization of a cerebrospinal fluid cleft between the On MRI, pituitary metastases appear as sellar or suprasellar tumor mass and the gland, although uncommon, is indicative masses, sometimes with a dumb-bell shape, which are often iso- of meningioma [103]. Hyperostosis of the sellar floor or adjacent or hypo-intense to the gray matter on T1-weighted images, and bony structures also favors a diagnosis of meningioma, a feature of increased T2 signal [60,95,112]. Masses enhance after gadolin- present in approximately a third of the cases [103]. ium administration, with a homogeneous, heterogeneous or rim pattern [95]. Thickening of the stalk (21%), erosion of the sellar Chordoma bone (15%), invasion of the cavernous and sphenoidal sinuses Chordomas arise from embryonic remnants of the primitive noto- (10%) and loss of the posterior pituitary bright spot (9%) are also chord and are found entrapped within bone in midline locations, described [95,112]. such as the clivus, parasellar region and craniocervical junction (45% of the cases), or the sacrococcygeal region (55%) [104,105]. Germ cell tumor Intracranial chordomas are more common in females and the young Germ cell tumors of the brain (intracranial germ cell tumors) occur (<26 years of age) [106]. They typically infiltrate and destroy the mainly in prepubertal children [113]. Intracranial germ cell tumors bone, causing symptoms that vary according to their location. The include germinomas (65%), of which 85% are considered ‘pure’ most common initial complaints are headache, usually reported in germinomas and 15% are germinomas with syncytio­trophoblast occipital or retro-orbital locations, and diplopia, usually caused by giant cells [114], teratomas (18%), embryonal carcinomas (5%),

688 Expert Rev. Endocrinol. Metab. 4(6), (2009) Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade Review

endodermal sinus tumors (7%) and choriocarcinomas (5%) [115]. AH has been proposed as a risk factor for subsequent development Germinomas primarily involving the sellar region are rare and of pituitary lymphoma [135]. Treatment for this rare malignancy have a predilection for females [116]. They present with diabetes consists ofwhole-brain radiotherapy [136], combined with systemic insipidus (60–90%), hypopituitarism (75–90%) and visual field chemotherapy and intracranial methotrexate [137]. defects [117–119]. Hyperprolactinemia, deficiency of growth hor- Sellar lymphomas appear on MRI specifically as homogeneously mone (GH), adrenocorticotropic hormone (ACTH), and thyroid- or heterogeneously enhancing sellar masses, that are iso- to hypo- stimulating hormone (TSH) are reported in 50, 41.7, 16.7 and intense relative to gray matter on T2-weighted images [95]. Their 8.3% of the patients, respectively [120]. Sellar germinomas can appearance, however, varies according to whether the patient has be difficult to differentiate from AH, even after examination of normal or suppressed immunity [95]. In patients with a normal the pituitary biopsy, since they can show a diffuse lymphocytic immune system, CNS lymphoma appears as a solitary mass with infiltration of the pituitary gland similar to that typically seen in intermediate-to-low signal intensity relative to gray matter on both AH and are mostly negative for human chorionic gonadotropin T1- and T2-weighted sequences; enhancement with gadolinium is (b-hCG), both in the serum and cerebrospinal fluid [114,121,122]. seen in nearly all cases and is homogenous in approximately three b-hCG, a glycoprotein produced by placental trophoblastic cells, quarters of cases [95,134]. The relative lack of T2 prolongation in is elevated in choriocarcinomas and in the minority of germinomas CNS lymphoma is generally attributed to dense cellularity and a that contain syncytiotrophoblast giant cells [114,123]. b-hCG-secret- high nucleus-to-cytoplasm ratio, a feature that may be helpful in ing germinomas are thought to be more aggressive than nonse- distinguishing lymphomas from other CNS tumors. This feature, creting germinomas, but this notion is controversial [114,123]. We however, has low sensitivity, being present in just over 50% of have recently described a girl with intrasellar germinoma initially cases [134]. Calcification and hemorrhage in CNS lymphoma are misdiagnosed as AH [9], and found in the literature eight simi- rare [60,95]. lar cases reported during the last decade [124–131]. The therapy of choice is irradiation after a confirmatory biopsy is performed[121] . Sarcoidosis Loss of the normal posterior pituitary bright spot on T1-weighted Sarcoidosis is a systemic disorder of unknown etiology, charac- images is one of the earliest signs in sellar germinomas [95,118], terized histologically by the presence of noncaseating epithelioid followed by swelling of the stalk and subsequent mass forma- granulomas. It is more common in African–American females tion, which may displace the enhancing pituitary gland anteri- during the fourth decade of life, where the annual incidence is orly [95]. Sellar/suprasellar germ cell tumors have a non­specific 107 cases per 100,000 persons [138]. Sarcoidosis of the CNS is image. They are isointense to cerebral cortex on T1-weighted evident clinically in approximately 5% of patients [139,140] and at images (~70%) and enhance solidly. Variable intensities are seen autopsy in approximately 20% [141]. The most common CNS sites on T2-weighted images [118]. Intratumoral cysts are revealed by of disease activity are the basal meninges and , fol- MRI in approximately half of the cases [118]. Calcifications may lowed by pituitary stalk and pituitary gland [141,142]. Owing to the be seen in bigger tumors [95]. Teratomas show a mixed signal hypothalamic involvement, diabetes insipidus is the most common intensity with fat and calcifications [60]. presenting symptom [143], accompanied by other signs of hypotha- lamic dysfunction, such as impaired thirst, temperature, sleep or Pituitary lymphoma weight regulation. Hypopituitarism is rare, a consequence of defec- Lymphomas may arise in the CNS directly or through spread tive hypothalamic releasing factors [144], and mainly involving the from other sites during the natural history of the disease, which gonadotropin axis [145,146]. Headache (16%), visual dysfunction is usually associated with progressive widespread systemic disease. (10%), diplopia (8–12%) and (3–32%) are Primary CNS lymphoma is defined as a lymphoma limited to the also rare in CNS sarcoidosis. Therapy consists of immunosuppres- cranio-spinal axis without evidence of systemic disease [132,133]. sive agents (e.g., cyclophosphamide,azathioprine or methotrexate) It represents up to 2% of all primary CNS malignancies and is and should be initiated with corticosteroids [147,148]. practically always of the non-Hodgkin type, with the majority On MRI, the meningeal, intraparenchymal or sellar lesions of being B-cell lymphoma [134]. Pituitary lymphomas are exceedingly sarcoidosis appear isointense on T1-weighted images and variable rare and are more common in males during the sixth decade of on T2-weighted images [60]. These lesions enhance after contrast life [133]. Headache is the most common presenting symptom, and administration [139], typically accompanied by leptomeningeal results from erosion of the bony sella turcica or stretching of the enhancement. The pituitary stalk is thickened and enhanced in diaphragma sellae. Like any other nonfunctioning sellar mass, approximately 50% of patients [145,149], with loss of the normal pos- pituitary lymphomas may also present with symptoms of hypopi- terior pituitary bright spot [143,145]. Very rarely, pituitary sarcoidosis tuitarism, which often follows a characteristic sequence character- shows a cystic appearance [150,151]. ized by gonadotropin, GH, TSH and, finally, ACTH deficiency [133]. Hypopituitarism, visual field defects, diabetes insipidus and Wegener granulomatosis hyperprolactinemia are present at the time of diagnosis in 50, Wegener granulomatosis is a vasculitis of small and medium- 50, 40 and 20% of the patients, respectively [133]. Cranial nerve sized vessels associated with the presence of antineutrophil cyto­ involvement owing to lateral extension of the pituitary lymphoma plasmic antibodies [152]. It favors Caucasians (90% of patients) into the cavernous sinus has also been reported [133]. Interestingly, [153], equally in males and females [154], and has a mean age at www.expert-reviews.com 689 Review Gutenberg, Landek-Salgado, Tzou et al. Unique features Association with pregnancy N/A Psychiatric deficits in 33% N/A N/A N/A Progression during pregnancy N/A N/A N/A N/A N/A Africans a have threefold increased risk >90% are Caucasian N/A 12 – Cranial nerve palsy (%) 3–16 7 Rare Rare Yes Yes 30 Rare 40 Rare 23.1 8 Rare Rare

32%), anterior32%), pituitary – Anterior pituitary dysfunction ACTH (57%), FSH/LH (52%), TSH (49%), GH (38%), hyperprolactinemia (23%) FSH/LH (43%), GH (36%), hyperprolactinemia (28%), ACTH (26%), TSH (24.5%) ACTH (32–50%) FSH/LH (59%), GH (39%), TSH (39%), hyperprolactinemia (32%) ACTH (57%), GH (35%), FSH/LH (53%), TSH (35%), hyperprolactinemia (39%) >50% (no preferred axes) FSH/LH (43%), GH (38%), ACTH (36%), hyperprolactinemia TSH (<7%), (21%), Hyperprolactinemia >50%, other axes rare Unusual Hyperprolactinemia (50%), GH (42%), ACTH TSH (8%) (17%), FSH/LH > GH > TSH > ACTH Partial or global deficiencyof anterior lobe in 25%, hyperprolactemia (6%) Deficiency without in 77% preferential involvement, hyperprolactinemia (23%) Hyperprolactinemia (3 dysfunctionbut FSH/LH rare, is mostly affected Hyperprolactinemia (42%), TSH (42%), FSH/LH GH (17%) (33%), ACTH (17%), GH (40–67%), FSH/LH (58%), ACTH (42%), TSH (42%) DI (%) 50 <2 6–9 9 Rare <2 Rare Rare 60– 90 40 45 11 33 100 >90 Visual compromise (%) 43 42 67–75 38 >50 55 >50 Rare Usual 50 25 46 10 Yes Rare Headache (%) 53 48-68 62 65 >50 41 5-20 Usual Usual 75 15 91 16 Yes Yes Mean age (years) 32 50 and 65–74 5–14 30–60 20–40 45 62 <26 Prepubertal age Immunocompromised: 30–40; immunocompetent: 60–70 60–70 36.7 33.7 48 but 70% under35, age 17 of M:F ratio 1:3 1:1 1.1 1:2 1:1 1:1 1:3 1:2 1:2 2:1 1:1 1:2 1:2 1:1 3:1 Table 2. Key clinical 2. and Key radiologicalTable features nonfunctioning of pituitary masses. Differential diagnosis Autoimmune hypophysitis Nonfunctioning pituitary adenoma Craniopharyngioma cleftRathke cyst Epidermoid cyst Sella arachnoid cyst Sellar meningioma Chordoma Germ cell tumor Pituitary lymphoma Pituitary metastases Pituitary tuberculosis Sarcoidosis Wegener granulomatosis Langerhans cell histiocytosis ACTH: Adrenocorticotropic hormone; DI: Diabetes insipidus; FSH: Follicle-stimulating hormone; GH: Growth hormone; LH: ; N/A: Not applicable; TSH: Thyrotropin.

690 Expert Rev. Endocrinol. Metab. 4(6), (2009) Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade Review

diagnosis of 48 years [155]. The major targets of disease activity Kaltsas et al. found deficiency of GH, follicle stimulating hor- are the upper respiratory tract, lungs and kidneys [156]. The PNS mone, luteinizing hormone, TSH and ACTH in 67, 58, 42 and is frequently affected, with symmetrical sensory–motor polyneu- 42% of the patients, respectively [15]. Hyperprolactinema is rare ropathy or mononeuritis multiplex [154]. CNS involvement is less [15]. Systemic chemotherapy appears to be of little benefit in con- common and caused by three different mechanisms [157]: direct trollingthe progression of the disease over the long term, although intracranial extension of the granulomatous process from the focal radiotherapy may halt local disease progression in terms of sinuses, orbits or mastoid air cells; vasculitis of the cerebral ves- mass effects [15]. sels with subsequent ischemic and/or hemorrhagic infarctions; or A pituitary mass caused by Langerhans cell histiocytosis formation of granulomas directly within the brain parenchyma, is hypointense on T1-weighted images and hyperintense on remote from the primary disease site. T2-weighted images, and enhances brightly after contrast [173]. The pituitary gland is rarely a target of Wegener granulomatosis Loss of the normal posterior pituitary bright spot is seen in all [158], most often described as thickening of the gland and stalk patients with diabetes insipidus [15] and infundibular thickening [155,158–160]. The lesions are typically granulomatous on patho­ in over 50% [174]. Infundibular (29%) and pronounced logical examination, but pure lymphocytic infiltration of the pitu- hypothalamic mass lesion (10%) are less common. itary gland has been described [23]. Diabetes insipidus is present in all patients affected by Wegener granulomatosis of the pituitary Pituitary tuberculosis gland [161]. Hypopituitarism is characterized by hypothyroidism There has been a resurgence of TB during the past three decades (42%), hypogonadism (33%) and GH and ACTH deficiencies due to the HIV/AIDS epidemic, increased travel and migration. (17%) [161]. Hyperprolactinemia is seen in 42% of cases. Visual The annual incidence per 100,000 persons varies from four cases disturbances [158], ophthalmoplegia [162] or meningitis [163] are rare. in the USA to over 100 cases in Asia and Africa. Approximately Currently, a regimen consisting of daily cyclophosphamide and 10% of TB cases have CNS involvement [175], which may present corticosteroids, which induces complete remission in the majority as meningitis or parenchymal space-occupying lesion. Pituitary of patients, is considered standard therapy [164]. TB is extremely rare, with approximately 60 cases reported since The MRI findings of Wegener granulomatosis of the CNS the original 1940 description by Coleman and Meredith [176]. vary widely, reflecting the three mechanisms of CNS involve- Females are affected more frequently than males (2:1) with a ment highlighted above. The most common findings are mean age at presentation of 37 years [177]. Only a third of the cases thickening and enhancement of the meninges (65%), cerebral have a past or concurrent history of extrasellar tubercular involve- infarctions owing to vasculitis (24%), pituitary enlargement ment [176]. Headache is the most common presenting symptom (12%), and supra- or infra-tentorial granuloma (<1%) [155]. The (91%), followed by visual disturbances (46%) and cranial nerve pituitary mass most commonly extends to the suprasellar region, palsy, especially the abducens nerve (23%). Fever is common although purely intrasellar masses are described [160]. The mass in children and rare in adults [176]. Hypopituitarism is present is hypointense on T1- and hyperintense on T2-weighted-images in 77% of the patients, without preferential involvement of any [155,159] and enhances markedly after gadolinium in a homo­ hormonal axis, and can be disproportionate to the size of the sellar geneous [155] or heterogeneous fashion depending on the presence lesion [178]. Hyperprolactinemia and diabetes insipidus are found of infarction and hemorrhage [159]. Cystic sellar masses that do in 23 and 11% of the patients, respectively [176]. not enhance with gadolinium are also described [165]. Contrary The treatment of cerebral tuberculosis, like that of other forms of to what one would predict based on the presence of diabetes TB, is aimed at killing both intracellular and extracellular organ- insipidus, thickening of the pituitary stalk and loss of the normal isms and preventing the development of drug resistance by using posterior bright spot are rarely noticed [159]. several drugs in combination The first-line anti-tubercular drugs are isoniazid, pyrazinamide, ethionamide, and cycloserine which Langerhans cell histiocytosis penetrate into the cerebrospinal fluid well. Rifampicin, strepto- Langerhans cell histiocytosis is the pathological infiltration of mycin and ethambutol penetrate in adequate concentrations are several organs by Langerhans cells [166]. It is most common in only used when the meninges are inflamed [179]. Surgical inter- children and young adults, so that approximately 70% of the cases vention is required in cases of intracranial tuberculous empyema occur before 17 years of age. The point prevalence per 100,000 to reduce the mass effect, as well as when serious complications individuals is 0.27 for males and 0.07 for females [167]. The disease such as hydrocephalus, tuberculomas and tuberculous abscesses most commonly involves bone, skin, lungs, liver, lymph nodes and develop [179]. the hypothalamo–pituitary axis [168]. Diabetes insipidus is the Pituitary tuberculomas are usually isointense on T1-weighted most common endocrine abnormality (>90%) [169], followed by images, but can be hyperintense owing to high protein content GH deficiency[170] . Hypothyroidism is also common, and can be [180]. They enhance avidly after contrast, except in areas of casea- both secondary to pituitary infiltration[171] or primary because of tion, which appear cystic. Pituitary tuberculomas show a supra­ thyroid infiltration [172]. ACTH deficiency usually occurs in the sellar extension in 74% of cases, but are limited to the sella in context of panhypopituitarism but isolated ACTH deficiency is the remaining 26% [176,177]. The sella is enlarged and the stalk also described [171]. In a study of 12 adult patients with histologi- is almost always thickened owing to chronic inflammation [180]. cally proven Langerhans cell histiocytosis and diabetes insipidus, Sometimes, the suprasellar extension can make evaluation of the www.expert-reviews.com 691 Review Gutenberg, Landek-Salgado, Tzou et al. stalk difficult. Other MRI findings described with pituitary TB and specificity, and are poorly quantitative. A discussion of pituitary are peripheral ring enhancement of the mass, enhancement of the antigens and antibodies have been presented in detail in previous adjacent dura and basal enhancing exudates owing to meningi- reviews (e.g., [182–184]). tis [180]. Isolated stalk thickening, sellar/suprasellar calcification, When measured by indirect immuno­fluorescence, pituitary apoplexy and erosion of the sellar floor have also been reported in autoantibodies are found in a variety of conditions, ranging in pituitary tuberculomas [176]. increasing frequency from normal subjects to patients with histo- The aforementioned clinical and radiological features of non- logically proven AH (Figure 4). At present, pituitary auto­antibodies functioning pituitary masses are summarized in Table 2. Overall, remain of limited value to the clinician for differentiating pituitary it is difficult to establish before surgery a diagnosis of certainty, masses. Nonetheless, pituitary antibodies can suggest a diagnosis which can be obtained in the majority of the patients only after of AH when histopathological examination of the pituitary is not pathological examination of the pituitary biopsy obtained via feasible and they have been associated with impairment of pituitary trans-sphenoidal surgery. secretions, such as growth hormone [185–187] and gonado­tropins [188]. Further studies are needed to elucidate the role of pituitary Pituitary antibodies antibodies in the differential diagnosis of pituitary masses. The presence of immunoglobulins in the serum reacting against self-antigens is one of the cardinal features of autoimmune dis- Expert commentary eases. Autoantibodies are undoubtedly the most widely used tool During the past 5 years, the awareness of AH has increased sig- to diagnose, monitor and, more recently, predict autoimmune nificantly in the medical community, mainly owing to the emer- diseases. With a few exceptions, where autoantibodies are the gence of a new form of AH secondary to anti-CTLA-4 therapy. cause of the clinical phenotype (e.g., the acetycholine receptor Advances have also been made on the clinical side with a bet- antibodies in and thyrotropin receptor antibod- ter characterization of the various AH phenotypes and its MRI ies in Graves disease), the role of autoantibodies in the pathogen- features, as well as in basic research through the generation of a esis of autoimmune-mediated pathology remains unknown. It mouse model of AH. has now become clear that autoantibodies are present several years before the clinical 100 diagnosis. Pioneer studies in this regard are ) the ones performed by Arbuckle and col- 90 leagues in systemic erythematosus [181]. The authors have taken advantage of 80 the worlds largest serum repository, main- tained by the USA Department of Defense, 70 which has over 40 million sera collected 60 longitudinally from military personnel. The authors have shown that lupus anti- 50 bodies are present several years before the clinical diagnosis and follow a predictable 40 course with progressive accumulation of different specificities. Independently of 30 their role in disease initiation, there is 20 universal agreement on the fact that auto­ alence of pituitary autoantibodies (% positive antibodies can be used as disease mark- v 10

ers, bystander spectators of the underlying Pre autoimmune process. 0 y Pituitary autoantibodies only partially y fulfill this role of disease markers. The main Health disease disease reason for their currently low clinical utility disease Biopsy AH is that the pituitary autoantigens targeted Clinical AH Other pituitar

by the immune system during AH remain Nonautoimmune Other autoimmune

unknown. This lack of knowledge has ham- Isolated deficiencies pered the development of antigen-specific Figure 4. Prevalence of pituitary autoantibodies in healthy controls and in the following antibody assays and, therefore, current disease categories: biopsy-proven AH, clinically suspected AH, isolated deficiencies of approaches to detect pituitary antibodies anterior pituitary hormones, other pituitary diseases different from AH, other in patient sera rely on nonantigen-specific autoimmune diseases different from AH, and diseases of nonautoimmune pathogenesis. methods, such as indirect immunofluores- AH: Autoimmune hypophysitis. cence. These methods have low sensitivity Modified from [182].

692 Expert Rev. Endocrinol. Metab. 4(6), (2009) Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade Review

However, the differential diagnosis of nonfunctioning pituitary assays that should be useful in the differential diagnosis of non- masses remains challenging and can be obtained with certainty functioning pituitary masses. In addition, understanding the link only after an invasive surgery and pathological examination of between CTLA-4 blockade and development of AH will promote the pituitary biopsy. It is possible that discovery of AH-associated understanding of autoimmune diseases in general. pituitary autoantigen(s) will allow the development of immuno- logical assays that can provide us with a further tool to use in the Financial disclosure and acknowledgments study of pituitary lesions. This work was supported by NIH grant DK080351 to Patrizio Caturegli, and by the Heidenreich-von-Siebold grant of the Georg-August-University Five-year view of Göttingen, Germany to Angelika Gutenberg. The authors have no other Despite AH being first reported almost five decades ago, the path- relevant affiliations or financial involvement with any organization or entity ogenic pituitary antigen(s) targeted by the patient’s immune sys- with a financial interest in or financial conflict with the subject matter or tem during AH remain(s) to be discovered or confirmed. Such a materials discussed in the manuscript apart from those disclosed. discovery will allow the development of antigen-specific antibody No writing assistance was utilized in the production of this manuscript.

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.

References of obscure etiology. Endocr. Pathol. 10(3), 14 Takano, K. Sarcoidosis of the 237–241 (1999). hypothalamus and pituitary. Intern. Med. 1 Caturegli PC, Newschaffer A, Olivi MG, 8 Tashiro T, Sano T, Xu B et al. Spectrum of 43(10), 894–895 (2004). Pomper PC, Burger, Rose NR. different types of hypophysitis: a 15 Kaltsas GA, Powles TB, J Evanson et al. Autoimmune hypophysitis. Endocr. Rev. clinicopathologic study of hypophysitis in Hypothalamo–pituitary abnormalities in 26(5), 599–614 (2005). 31 cases. Endocr. Pathol. 13(3), 183–195 adult patients with langerhans cell 2 De Bellis, AG, Ruocco, M Battaglia et al. (2002). histiocytosis: clinical, endocrinological, Immunological and clinical aspects of 9 Gutenberg A, Bell JJ, Lupi I et al. Pituitary and radiological features and response to lymphocytic hypophysitis. Clin. Sci. and systemic autoimmunity in a case of treatment. J. Clin. Endocrinol. Metab. (Lond.) 114(6), 413–421 (2008). intrasellar germinoma. Pituitary 85(4), 1370–1376 (2000). 3 Gutenberg AR, Buslei R, Fahlbusch R, DOI: 10.1007/s11102-009-0187-x (2009) 16 Rao S, Rajkumar A, Kuruvilla S. Sellar Buchfelder M, Bruck W. Immunopathology (Epub ahead of print). lesion: not always a pituitary adenoma. of primary hypophysitis: implications for 10 Janeczko, C, McHugh J, Rawluk D, Farrell Indian J. Pathol. Microbiol. 51(2), 269–270 pathogenesis. Am. J. Surg. Pathol. 29(3), M, Brennan P, Delanty N. Hypophysitis (2008). 329–338 (2005). secondary to ruptured Rathke’s cyst 17 Dillard T, Yedinak CG, Alumkal J, Fleseriu 4 Folkerth RD, Price DL Jr, Schwartz M, mimicking neurosarcoidosis. J. Clin. M. Anti-CTLA-4 antibody therapy Black PM, Girolami U De. Xanthomatous Neurosci. 16(4), 599–600 (2009). associated autoimmune hypophysitis: hypophysitis. Am. J. Surg. Pathol. 22(6), 11 Cuthbertson DJ, Ritchie D, Crooks D et al. serious immune related adverse events 736–741 (1998). Lymphocytic hypophysitis occurring across a spectrum of cancer subtypes. 5 Burt MG, Morey AL, Turner JJ, Pell M, simultaneously with a functioning pituitary Pituitary DOI: 10.1007/s11102-009-0193-z Sheehy JP, Ho KK. Xanthomatous adenoma. Endocr. J. 55(4), 729–735 (2009) (Epub ahead of print). pituitary lesions: a report of two cases and (2008). 18 Goudie RB, Pinkerton PH. Anterior review of the literature. Pituitary 6(3), 12 Puchner MJ, Ludecke DK, Saeger W. The hypophysitis and Hashimoto’s disease in a 161–168 (2003). anterior pituitary lobe in patients with woman. J. Pathol. Bacteriol. 83, 584–585 6 Cheung CC, Ezzat S, Smyth HS, Asa SL. cystic craniopharyngiomas: three cases of (1962). The spectrum and significance of primary associated lymphocytic hypophysitis. Acta 19 Mayfield RK, Levine JH, Gordon L, hypophysitis. J. Clin. Endocrinol. Metab. Neurochir. (Wien) 126(1), 38–43 (1994). Powers J, Galbraith RM, Rawe SE. 86(3), 1048–1053 (2001). 13 McIntyre EA, Perros P. Fatal inflammatory Lymphoid adenohypophysitis presenting as 7 Deodhare SS, Bilbao JM, Kovacs K et al. hypophysitis. Pituitary 10(1), 107–111 a pituitary tumor. Am. J. Med. 69, 619–623 Xanthomatous hypophysitis: a novel entity (2007). (1980).

www.expert-reviews.com 693 Review Gutenberg, Landek-Salgado, Tzou et al.

20 Quencer RM. Lymphocytic 31 Gonzalez-Cuyar LF, Tavora F, Shaw K, 44 Beck KE, Blansfield JA, Tran KQ et al. adenohypophysitis: autoimmune Castellani RJ, Dejong JL. Sudden Enterocolitis in patients with cancer after disorder of the pituitary gland. unexpected death in lymphocytic antibody blockade of cytotoxic AJNR Am J. Neuroradiol. 1(4), 343–345 hypophysitis. Am. J. Forensic Med. Pathol. T-lymphocyte-associated antigen 4. J. Clin. (1980). 30(1), 61–63 (2009). Oncol. 24(15), 2283–2289 (2006). 21 Levine SN, Benzel EC, Fowler MR, 32 Dunn GP, Bruce AT, Ikeda H, Old LJ, 45 Hodi FS, Mihm MC, Soiffer RJ et al. Shroyer JV, Mirfakhraee M. Lymphocytic Schreiber RD. Cancer Immunoediting: Biologic activity of cytotoxic T adenohypophysitis: clinical, radiological, from immunosurveillance to tumor lymphocyte-associated antigen 4 antibody and magnetic resonance imaging escape. Nat. Immunol. 3(11), 991–998 blockade in previously vaccinated characterization. Neurosurgery 22(5), (2002). metastatic melanoma and ovarian 937–941 (1988). 33 Choudhury A, Mosolits S, Kokhaei P, carcinoma patients. Proc. Natl Acad. Sci. 22 Bellastella A, Bizzarro A, Coronella C, Hansson L, Palma M, Mellstedt H. Clinical USA 100(8), 4712–4717 (2003). Bellastella G, Sinisi AA, De Bellis A. results of vaccine therapy for cancer: 46 Phan GQ, Yang JC, Sherry RM et al. Lymphocytic hypophysitis: a rare or learning from history for improving the Cancer regression and autoimmunity underestimated disease? Eur. J. future. Adv. Cancer Res. 95, 147–202 induced by cytotoxic T lymphocyte- Endocrinol. 149(5), 363–376 (2003). (2006). associated antigen 4 blockade in patients 23 Gutenberg A, Hans V, Puchner MJ et al. 34 Steinman RM, Hawiger D, Nussenzweig with metastatic melanoma. Proc. Natl Acad. Primary hypophysitis: clinical–pathological MC. Tolerogenic dendritic cells. Annu. Sci. USA 100(14), 8372–8377 (2003). correlations. Eur. J. Endocrinol. 155(1), Rev. Immunol. 21, 685–711 (2003). 47 Weber JS. The clinical utility of cytotoxic 101–107 (2006). 35 Serafini P, Borrello I, Bronte V. Myeloid T lymphocyte antigen 4 abrogation by 24 Tsagarakis S, Vassiliadi D, Malagari K, suppressor cells in cancer: recruitment, human antibodies. Melanoma Res. 16(5), Kontogeorgos G, Thalassinos N. phenotype, properties, and mechanisms of 379–383 (2006). Lymphocytic hypophysitis: late immune suppression. Semin. Cancer Biol. 48 Weber J. Ipilimumab: controversies in its recurrence following successful 16(1), 53–65 (2006). development, utility and autoimmune transsphenoidal surgery. Endocrine 25(2), 36 Lucas T, Abraham D, Aharinejad S. adverse events. Cancer Immunol. 85–90 (2004). Modulation of tumor associated Immunother. 58(5), 823–830 (2009). 25 Lecube A, Francisco G, Rodriguez D et al. macrophages in solid tumors. Front. Biosci. 49 Maker AV, Attia P, Rosenberg SA. Analysis Lymphocytic hypophysitis successfully 13, 5580–5588 (2008). of the cellular mechanism of antitumor treated with azathioprine: first case report. 37 Kryczek I, Liu R, Wang G et al. FOXP3 responses and autoimmunity in patients J. Neurol. Neurosurg. Psychiatry 74(11), defines regulatory T cells in human tumor treated with CTLA-4 blockade. 1581–1583 (2003). and autoimmune disease. Cancer Res. J. Immunol. 175(11), 7746–7754 (2005). 26 Leung GK, Lopes MB, Thorner MO, 69(9), 3995–4000 (2009). 50 Wing K, Onishi Y, Prieto-Martin P et al. + Vance ML, Laws ER. Primary 38 Oble DA, Loewe R, Yu P, Mihm MC Jr. CTLA-4 control over Foxp3 regulatory hypophysitis: a single-center experience in Focus on TILs: prognostic significance of T cell function. Science 322(5899), 16 cases. J. Neurosurg. 101(2), 262–271 tumor infiltrating lymphocytes in human 271–275 (2008). (2004). melanoma. Cancer Immun. 9, 3 (2009). 51 Hodi FS. Cytotoxic T-lymphocyte- 27 Tubridy N, Saunders D, Thom M et al. 39 Greenwald RJ, Freeman GJ, Sharpe AH. associated antigen-4. Clin. Cancer Res. Infundibulohypophysitis in a man The B7 family revisited. Annu. Rev. 13(18 Pt 1), 5238–5242 (2007). presenting with diabetes insipidus and Immunol. 23, 515–548 (2005). 52 Weber J. Review: anti-CTLA-4 antibody cavernous sinus involvement. J. Neurol. 40 Subudhi SK, Alegre ML, Fu YX. The ipilimumab: case studies of clinical Neurosurg. Psychiatry 71(6), 798–801 balance of immune responses: response and immune-related adverse (2001). costimulation verse coinhibition. J. Mol. events. Oncologist 12(7), 864–872 28 Postema PTE, van Hagen PM, Med. 83(3), 193–202 (2005). (2007). de Herder WW. Treatment of aggressive, 41 Tivol EA, Borriello F, Schweitzer AN, 53 Blansfield JA, Beck KE, Tran K et al. recurrent lymphocytic hypophysitis with Lynch WP, Bluestone JA, Sharpe AH. Cytotoxic T-lymphocyte-associated rituximab. Presented at: 90th Annual Loss of CTLA-4 leads to massive antigen-4 blockage can induce Meeting of the Endocrine Society. lymphoproliferation and fatal multiorgan autoimmune hypophysitis in patients with San Francisco, CA, USA, 12–15 June 2008 tissue destruction, revealing a critical metastatic melanoma and renal cancer. (Abstract P1-394). negative regulatory role of CTLA-4. J. Immunother. 28(6), 593–598 (2005). 29 Selch MT, DeSalles AA, Kelly DF et al. Immunity 3(5), 541–547 (1995). 54 Yang JC, Hughes M, Kammula U et al. Stereotactic radiotherapy for the treatment 42 Ueda H, Howson JM, Esposito L et al. Ipilimumab (anti-CTLA4 antibody) of lymphocytic hypophysitis. Report of Association of the T-cell regulatory gene causes regression of metastatic renal cell two cases. J. Neurosurg. 99(3), 591–596 CTLA4 with susceptibility to autoimmune cancer associated with enteritis and (2003). disease. Nature 423(6939), 506–511 hypophysitis. J. Immunother. 30(8), 30 Ray DK, Yen CP, Vance ML, Laws ER, (2003). 825–830 (2007). Lopes B, Sheehan JP. g knife surgery for 43 Melero I, Hervas-Stubbs S, Glennie M, 55 Weber JS, O’Day S, Urba W et al. lymphocytic hypophysitis. Neurosurg. J. Pardoll DM, Chen L. Immunostimulatory Phase I/II study of ipilimumab for patients DOI: 10.3171/2009.6.JNS081176 (2009) monoclonal antibodies for cancer therapy. with metastatic melanoma. J. Clin. Oncol. (Epub ahead of print). Nat. Rev. Cancer 7(2), 95–106 (2007). 26(36), 5950–5956 (2008).

694 Expert Rev. Endocrinol. Metab. 4(6), (2009) Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade Review

56 Maker AV, Yang JC, Sherry RM et al. 69 Lee MH, Choi HY, Sung YA, Lee JK. High 82 Karavitaki N, Cudlip S, Adams CB, Wass Intrapatient dose escalation of anti- signal intensity of the posterior pituitary JA. Craniopharyngiomas. Endocr. Rev. CTLA-4 antibody in patients with gland on T1-weighted MR images. 27(4), 371–397 (2006). metastatic melanoma. J. Immunother. Correlation with plasma vasopressin 83 Van Effenterre R, Boch AL. 29(4), 455–463 (2006). concentration to water deprivation. Acta Craniopharyngioma in adults and children: 57 Carpenter KJ, Murtagh RD, Lilienfeld H, Radiol. 42(2), 129–134 (2001). a study of 122 surgical cases. J. Neurosurg. Weber J, Murtagh FR. Ipilimumab- 70 Chanson P, Brochier S. Non-functioning 97(1), 3–11 (2002). induced hypophysitis: MR imaging pituitary adenomas. J. Endocrinol. Invest. 84 Voelker JL, Campbell RL, Muller J. Findings. AJNR Am. J. Neuroradiol. 30(9), 28(11 Suppl.), 93–99 (2005). Clinical, radiographic, and pathological 1751–1753 (2009). 71 Asa SL. Practical pituitary pathology: what features of symptomatic Rathke’s cleft 58 Kaehler KC, Egberts F, Lorigan P, does the pathologist need to know? Arch. cysts. J. Neurosurg. 74(4), 535–544 (1991). Hauschild A. Anti-CTLA-4 therapy- Pathol. Lab. Med. 132(8), 1231–1240 85 Kasperbauer JL, Orvidas LJ, Atkinson JL, related autoimmune hypophysitis in a (2008). Abboud CF. Rathke cleft cyst: diagnostic melanoma patient. Melanoma Res. 19(5), 72 Saeger W, Ludecke DK, Buchfelder M, and therapeutic considerations. 333–334 (2009). Fahlbusch R, Quabbe HJ, Petersenn S. Laryngoscope 112(10), 1836–1839 (2002). 59 Shaw SA, Camacho LH, McCutcheon IE, Pathohistological classification of pituitary 86 Osborn AG, Preece MT. Intracranial cysts: Waguespack SG. Transient hypophysitis tumors: 10 years of experience with the radiologic–pathologic correlation and after cytotoxic T lymphocyte-associated German pituitary tumor registry. Eur. J. imaging approach. Radiology 239(3), antigen 4 (CTLA4) blockade. J. Clin. Endocrinol. 156(2), 203–216 (2007). 650–664 (2006). Endocrinol. Metab. 92(4), 1201–1202 73 Drange MR, Fram NR, Herman-Bonert V, 87 Rengachary SS, Watanabe I. Ultrastructure (2007). Melmed S. Pituitary tumor registry: a novel and pathogenesis of intracranial arachnoid 60 Freda PU, Post KD. Differential diagnosis clinical resource. J. Clin. Endocrinol. cysts. J. Neuropathol. Exp. Neurol. 40(1), of sellar masses. Endocrinol. Metab. Clin. Metab. 85(1), 168–174 (2000). 61–83 (1981). North Am. 28(1), 81–117 (1999). 74 Lamberts SW, de Herder WW, van der 88 Harrison MJ, Morgello S, Post KD. 61 Glezer A, Paraiba DB, Bronstein MD. Rare Lely AJ. Pituitary insufficiency.Lancet Epithelial cystic lesions of the sellar and sellar lesions. Endocrinol. Metab. Clin. 352(9122), 127–134 (1998). parasellar region: a continuum of North Am. 37(1), 195–211 (2008). 75 Ferrante E, Ferraroni M, Castrignano T ectodermal derivatives? J. Neurosurg. 80(6), 62 Caturegli P. Autoimmune hypophysitis: an et al. Non-functioning pituitary adenoma 1018–1025 (1994). underestimated disease in search of its database: a useful resource to improve the 89 Dubuisson AS, Stevenaert A, Martin DH, autoantigen(s). J. Clin. Endocrinol. Metab. clinical management of pituitary tumors. Flandroy PP. Intrasellar arachnoid cysts. 92(6), 2038–2040 (2007). Eur. J. Endocrinol. 155(6), 823–829 (2006). Neurosurgery 61(3), 505–513 (2007). 63 Tzou SC, Lupi I, Landek M et al. 76 Choi SH, Kwon BJ, Na DG, Kim JH, Han 90 Mohn A, Schoof E, Fahlbusch R, Wenzel Autoimmune hypophysitis of SJL mice: MH, Chang KH. Pituitary adenoma, D, Dorr HG. The endocrine spectrum of clinical insights from a new animal model. craniopharyngioma, and Rathke cleft cyst arachnoid cysts in childhood. Pediatr. Endocrinology 149(7), 3461–3469 (2008). involving both intrasellar and suprasellar Neurosurg. 31(6), 316–321 (1999). regions: differentiation using MRI. Clin. 64 Lidove O, Piette JC, Charlotte F, Cassoux 91 Kaido T, Okazaki A, Kurokawa S, Radiol. 62(5), 453–462 (2007). N, Correas JM, Papo T. Lymphocytic Tsukamoto M. Pathogenesis of hypophysitis with lachrymal, salivary and 77 Heshmati HM, Kujas M, Casanova S et al. intraparenchymal epidermoid cyst in the thyroid gland involvement. Eur. J. Intern. Prevalence of lymphocytic infiltrate in brain: a case report and review of the Med. 15(2), 121–124 (2004). 1400 pituitary adenomas. Endocr. J. 45(3), literature. Surg. Neurol. 59(3), 211–216 65 Guay AT, Agnello V, Tronic BC, Gresham 357–361 (1998). (2003). DG, Freidberg SR. Lymphocytic 78 Rao VJ, James RA, Mitra D. Imaging 92 Green AJ, Roberts DR, Swanson RA. hypophysitis in a man. J. Clin. Endocrinol. characteristics of common suprasellar Post-traumatic epidermoid cyst presenting Metab. 64(3), 631–634 (1987). lesions with emphasis on MRI findings. with headache. Neurology 64(9), 1657 66 Cosman F, Post KD, Holub DA, Wardlaw Clin. Radiol. 63(8), 939–947 (2008). (2005). SL. Lymphocytic hypophysitis. Report of 3 79 Bunin GR, Surawicz TS, Witman PA, 93 Yamakawa K, Shitara N, Genka S, Manaka new cases and review of the literature. Preston-Martin S, Davis F, Bruner JM. The S, Takakura K. Clinical course and surgical Medicine 68(4), 240–256 (1989). descriptive epidemiology of prognosis of 33 cases of intracranial 67 Gutenberg A, Larsen J, Lupi I, Rohde V, craniopharyngioma. J. Neurosurg. 89(4), epidermoid tumors. Neurosurgery 24(4), Caturegli P. A radiological score to 547–551 (1998). 568–573 (1989). distinguish autoimmune hypophysitis from 80 Garnett MR, Puget S, Grill J, Sainte-Rose 94 Oge K, Ozgen T. Transsphenoidal removal non-secreting pituitary adenoma pre- C. Craniopharyngioma. Orphanet J. Rare of an intra- and suprasellar epidermoid operatively. AJNR Am. J. Neuroradiol. Dis. 2, 18 (2007). cyst. Neurochirurgia (Stuttg.) 34(3), 94–96 30(9), 1766–1772 (2009). 81 Shin JL, Asa SL, Woodhouse LJ, Smyth (1991). 68 Ahmadi J, Meyers GS, Segall HD, Sharma HS, Ezzat S. Cystic lesions of the pituitary: 95 Huang BY, Castillo M. Nonadenomatous OP, Hinton DR. Lymphocytic clinicopathological features distinguishing tumors of the pituitary and sella turcica. adenohypophysitis: contrast-enhanced MR craniopharyngioma, Rathke’s cleft cyst, Top. Magn. Reson. Imaging 16(4), 289–299 imaging in five cases. Radiology 195(1), and arachnoid cyst. J. Clin. Endocrinol. (2005). 30–34 (1995). Metab. 84(11), 3972–3982 (1999).

www.expert-reviews.com 695 Review Gutenberg, Landek-Salgado, Tzou et al.

96 Kinjo T, al-Mefty O, Ciric I. Diaphragma and contrast enhancement: criteria for 122 Shibamoto Y, Takahashi M, Sasai K. sellae meningiomas. Neurosurgery 36(6), differential diagnosis. Neuroradiology Prognosis of intracranial germinoma with 1082–1092 (1995). 39(8), 571–576 (1997). syncytiotrophoblastic giant cells treated by 97 Gokalp HZ, Arasil E, Kanpolat Y, Balim 110 Sze G, Uichanco LS 3rd, Brant-Zawadzki radiation therapy. Int. J. Radiat. Oncol. T. Meningiomas of the tuberculum sella. MN et al. Chordomas: MR imaging. Biol. Phys. 37(3), 505–510 (1997). Neurosurg. Rev. 16(2), 111–114 (1993). Radiology 166(1 Pt 1), 187–191 (1988). 123 Utsuki S, Kawano N, Oka H, Tanaka T, 98 Schick U, Hassler W. Surgical management 111 Hermet M, Delevaux I, Trouillier S, Andre Suwa T, Fujii K. Cerebral germinoma with of tuberculum sellae meningiomas: M, Chazal J, Aumaitre O. [Pituitary syncytiotrophoblastic giant cells: involvement of the optic canal and visual metastasis presenting as diabetes insipidus: feasibility of predicting prognosis using outcome. J. Neurol. Neurosurg. Psychiatry a report of four cases and literature review]. the serum hCG level. Acta Neurochir. 76(7), 977–983 (2005). Rev. Med. Interne 30(5), 425–429 (2009). (Wien) 141(9), 975–977 (1999). 99 Ebner FH, Bornemann A, Wilhelm H, 112 Komninos J, Vlassopoulou V, Protopapa D 124 Bettendorf M, Fehn M, Grulich-Henn J Ernemann U, Honegger J. Tuberculum et al. Tumors metastatic to the pituitary et al. Lymphocytic hypophysitis with sellae meningioma symptomatic during gland: case report and literature review. central diabetes insipidus and consequent pregnancy: pathophysiological J. Clin. Endocrinol. Metab. 89(2), 574–580 panhypopituitarism preceding a multifocal, considerations. Acta Neurochir. (Wien) (2004). intracranial germinoma in a prepubertal girl. Eur. J. Pediatr. 158(4), 288–292 150(2), 189–193 (2008). 113 Surawicz TS, McCarthy BJ, Kupelian V, (1999). 100 Jhawar BS, Fuchs CS, Colditz GA, Jukich PJ, Bruner JM, Davis FG. Stampfer MJ. Sex steroid hormone Descriptive epidemiology of primary brain 125 Endo T, Kumabe T, Ikeda H, Shirane R, exposures and risk for meningioma. and CNS tumors: results from the central Yoshimoto T. Neurohypophyseal J. Neurosurg. 99(5), 848–853 (2003). brain tumor registry of the United States, germinoma histologically misidentified as granulomatous hypophysitis. Acta 101 Nakamura M, Roser F, Struck M, Vorkapic 1990–1994. Neuro Oncol. 1(1), 14–25 Neurochir. (Wien) 144(11), 1233–1237 P, Samii M. Tuberculum sellae (1999). (2002). meningiomas: clinical outcome considering 114 Inamura T, Nishio S, Ikezaki K, Fukui M. different surgical approaches. Neurosurgery Human chorionic gonadotrophin in CSF, 126 Fehn M, Bettendorf M, Ludecke DK, 59(5), 1019–1028(2006). not serum, predicts outcome in Sommer C, Saeger W. Lymphocytic hypophysitis masking a suprasellar 102 Kuo JS, Yu C, Giannotta SL, Petrovich Z, germinoma. J. Neurol. Neurosurg. Psychiatry germinoma in a 12-year-old girl. A case Apuzzo ML. The Leksell g knife Model U 66(5), 654–657 (1999). report. Pituitary 1(3–4), 303–307 versus Model C: a quantitative comparison 115 Jennings MT, Gelman R, Hochberg F. (1999). of radiosurgical treatment parameters. Intracranial germ-cell tumors: natural Neurosurgery 55(1), 168–172 (2004). history and pathogenesis. J. Neurosurg. 127 Houdouin L, Polivka M, Henegar C, Blanquet A, Delalande O, Mikol J. 103 Donovan JL, Nesbit GM. Distinction of 63(2), 155–167 (1985). Pituitary germinoma and lymphocytic masses involving the sella and suprasellar 116 Frank G, Galassi E, Fabrizi AP, Frank F, hypophysitis: a pitfall. Report of two cases. space: specificity of imaging features. AJR Manetto V. Primary intrasellar Ann. Pathol. 23(4), 349–354 (2003). Am. J. Roentgenol. 167(3), 597–603 (1996). germinoma: case report. Neurosurgery 128 Kim G, Park SA, Hwang HJ et al. A case 104 Dahlin DC, Maccarty CS. Chordoma. 30(5), 786–788 (1992). of suprasellar germinoma misdiagnosed as Cancer 5(6), 1170–1178 (1952). 117 Fields JN, Fulling KH, Thomas PR, Marks lymphocytic hypophysitis. J. Korean Med. JE. Suprasellar germinoma: radiation 105 Erdem E, Angtuaco EC, Van Hemert R, Sci. 73(2), 210–215 (2007). Park JS, Al-Mefty O. Comprehensive therapy. Radiology 164(1), 247–249 (1987). 129 Mikami-Terao Y, Akiyama M, review of intracranial chordoma. 118 Kanagaki M, Miki Y, Takahashi JA et al. Yanagisawa T et al. Lymphocytic Radiographics 23(4), 995–1009 (2003). MRI and CT findings of neurohypophyseal hypophysitis with central diabetes germinoma. Eur. J. Radiol. 49(3), 204–211 106 McMaster ML, Goldstein AM, Bromley insipidus and subsequent hypopituitarism (2004). CM, Ishibe N, Parry DM. Chordoma: masking a suprasellar germinoma in a incidence and survival patterns in the 119 Nada R, Mohan H, Dhir SP, Mukherjee 13-year-old girl. Childs Nerv. Syst. 22(10), United States, 1973–1995. Cancer Causes KK, Kak VK. Suprasellar malignant mixed 1338–1343 (2006). Control 12(1), 1–11 (2001). germ cell tumour presenting as 130 Ozbey N, Sencer A, Tanyolac S et al. An craniopharyngioma. Neurol. India 48(4), 107 Thodou E, Kontogeorgos G, Scheithauer intrasellar germinoma with normal 381–384 (2000). BW et al. Intrasellar chordomas mimicking cerebrospinal fluid b-HCG concentrations pituitary adenoma. J. Neurosurg. 92(6), 120 Oka H, Kawano N, Tanaka T et al. misdiagnosed as hypophysitis. Hormones 976–982 (2000). Long-term functional outcome of (Athens) 5(1), 67–71 (2006). suprasellar germinomas: usefulness and 108 Bonneville F, Narboux Y, Cattin F, Rodiere 131 Torremocha F, Hadjadj S, Menet E et al. limitations of radiotherapy. J. Neurooncol. E, Jacquet G, Bonneville JF. Preoperative Pituitary germinoma presenting as a 40(2), 185–190 (1998). location of the pituitary bright spot in pseudotumoral lymphocytic hypophysitis patients with pituitary macroadenomas. 121 Bamberg M, Kortmann RD, Calaminus G in a man. Ann. Endocrinol. (Paris) 63(1), AJNR Am. J. Neuroradiol. 23(4), 528–532 et al. Radiation therapy for intracranial 13–17 (2002). (2002). germinoma: results of the German 132 Fine HA, Mayer RJ. Primary central cooperative prospective trials MAKEI 109 Doucet V, Peretti-Viton P, Figarella- nervous system lymphoma. Ann. Intern. 83/86/89. J. Clin. Oncol. 17(8), Branger D, Manera L, Salamon G. MRI of Med. 119(11), 1093–1104 (1993). intracranial chordomas. Extent of tumour 2585–2592 (1999).

696 Expert Rev. Endocrinol. Metab. 4(6), (2009) Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade Review

133 Giustina A, Gola M, Doga M, Rosei EA. 144 Stuart CA, Neelon FA, Lebovitz HE. 156 Anderson G, Coles ET, Crane M et al. Clinical review 136: primary lymphoma of Hypothalamic insufficiency: the cause of Wegener’s granuloma. A series of 265 the pituitary: an emerging clinical entity. hypopituitarism in sarcoidosis. Ann. Intern. British cases seen between 1975 and 1985. J. Clin. Endocrinol. Metab. 86(10), Med. 88(5), 589–594 (1978). A report by a sub-committee of the 4567–4575 (2001). 145 Bihan H, Christozova V, JL Dumas et al. British Thoracic Society Research 134 Johnson BA, Fram EK, Johnson PC, Sarcoidosis: clinical, hormonal, and Committee. QJM 83(302), 427–438 Jacobowitz R. The variable MR appearance magnetic resonance imaging (MRI) (1992). of primary lymphoma of the central manifestations of hypothalamic–pituitary 157 Nishino H, Rubino FA, DeRemee RA, nervous system: comparison with disease in 9 patients and review of the Swanson JW, Parisi JE. Neurological histopathologic features. AJNR Am. literature. Medicine (Baltimore) 86(5), involvement in Wegener’s granulomatosis: J. Neuroradiol. 18(3), 563–572 (1997). 259–268 (2007). an analysis of 324 consecutive patients at 135 Singh S, Cherian RS, George B, Nair S, 146 Bullmann C, Faust M, A Hoffmann et al. the Mayo Clinic. Ann. Neurol. 33(1), 4–9 Srivastava A. Unusual extra-axial central Five cases with central diabetes insipidus (1993). nervous system involvement of non- and hypogonadism as first presentation of 158 Goyal M, Kucharczyk W, Keystone E. Hodgkin’s lymphoma: magnetic resonance neurosarcoidosis. Eur. J. Endocrinol. Granulomatous hypophysitis due to imaging. Australas. Radiol. 44(1), 112–114 142(4), 365–372 (2000). Wegener’s granulomatosis. AJNR (2000). 147 Nowak DA, Widenka DC. Am. J. Neuroradiol. 21(8), 1466–1469 136 Nelson DF, Martz KL, Bonner H et al. Neurosarcoidosis: a review of its (2000). Non-Hodgkin’s lymphoma of the brain: intracranial manifestation. J. Neurol. 159 Katzman GL, Langford CA, Sneller MC, can high dose, large volume radiation 248(5), 363–372 (2001). Koby M, Patronas NJ. Pituitary therapy improve survival? Report on a 148 Scott TF, Yandora K, Valeri A, Chieffe C, involvement by Wegener’s granulomatosis: prospective trial by the Radiation Therapy Schramke C. Aggressive therapy for a report of two cases. AJNR Am. J. Oncology group (RTOG): RTOG 8315. neurosarcoidosis: long-term follow-up of 48 Neuroradiol. 20(3), 519–523 (1999). Int. J. Radiat. Oncol. Biol. Phys. 23(1), treated patients. Arch. Neurol. 64(5), 160 Roberts GA, Eren E, Sinclair H et al. Two 9–17 (1992). 691–696 (2007). cases of Wegener’s granulomatosis 137 DeAngelis LM, Seiferheld W, Schold SC, 149 Inaba H, Suzuki S, Shigematsu S, involving the pituitary. Clin. Endocrinol. Fisher B, Schultz CJ. Combination Kobayashi S, Nishio S, Hashizume K. (Oxf.) 42(3), 323–328 (1995). chemotherapy and radiotherapy for primary Spontaneous remission of diabetes insipidus 161 Rosete A, Cabral AR, Kraus A, Alarcon- central nervous system lymphoma: Radiation due to CNS sarcoidosis. Intern. Med. 48(4), Segovia D. Diabetes insipidus secondary to Therapy Oncology Group study 93-10. 225–229 (2009). Wegener’s granulomatosis: report and J. Clin. Oncol. 20(24), 4643–4648 (2002). 150 Guoth MS, Kim J, de Lotbiniere AC, review of the literature. J. Rheumatol. 138 Rybicki BA, Major M, Popovich J Jr, Brines ML. Neurosarcoidosis presenting as 18(5), 761–765 (1991). Maliarik MJ, Iannuzzi MC. Racial hypopituitarism and a cystic pituitary 162 Inoue T, Kaneko Y, Mannoji H, Fukui M. differences in sarcoidosis incidence: a mass. Am. J. Med. Sci. 315(3), 220–224 Giant cell granulomatous hypophysitis 5-year study in a health maintenance (1998). manifesting as an intrasellar mass with organization. Am. J. Epidemiol. 145(3), 151 Sato N, Sze G, Kim JH. Cystic pituitary unilateral ophthalmoplegia – case report. 234–241 (1997). mass in neurosarcoidosis. AJNR Am. J. Neurol. Med. Chir. (Tokyo) 37(10), 139 Christoforidis GA, Spickler EM, Recio Neuroradiol. 18(6), 1182–1185 (1997). 766–770 (1997). MV, Mehta BM. MR of CNS sarcoidosis: 152 Rao JK, Weinberger M, Oddone EZ, Allen 163 Yasuhara T, Fukuhara T, Nakagawa M correlation of imaging features to clinical NB, Landsman P, Feussner JR. The role of et al. Wegener granulomatosis manifesting symptoms and response to treatment. AJNR antineutrophil cytoplasmic antibody as meningitis. Case report. J. Neurosurg. Am. J. Neuroradiol. 20(4), 655–669 (c-ANCA) testing in the diagnosis of 97(5), 1229–1232 (2002). (1999). Wegener granulomatosis. A literature 164 White ES, Lynch JP. Pharmacological 140 Porter N, Beynon HL, Randeva HS. review and meta-analysis. Ann. Intern. therapy for Wegener’s granulomatosis. Endocrine and reproductive manifestations Med. 123(12), 925–932 (1995). Drugs 66(9), 1209–1228 (2006). of sarcoidosis. Q JM 96(8), 553–561 (2003). 153 Abdou NI, Kullman GJ, Hoffman GS et al. 165 Garovic VD, Clarke BL, Chilson TS, 141 Stern BJ, Krumholz A, Johns C, Scott P, Wegener’s granulomatosis: survey of 701 Specks U. Diabetes insipidus and Nissim J. Sarcoidosis and its neurological patients in North America. Changes in anterior pituitary insufficiency as manifestations. Arch. Neurol. 42(9), outcome in the 1990s. J. Rheumatol. 29(2), presenting features of Wegener’s 909–917 (1985). 309–316 (2002). granulomatosis. Am. J. Kidney Dis. 37(1), 142 Sherman JL, Stern BJ. Sarcoidosis of the 154 de Groot K, Gross WL, Herlyn K, and E5 (2001). CNS: comparison of unenhanced and Reinhold-Keller E. Development and 166 Arico M, Clementi R, Caselli D, Danesino enhanced MR images. AJNR Am. J. validation of a disease extent index for C. Histiocytic disorders. Hematol. J. 4(3), Neuroradiol. 11(5), 915–923 (1990). Wegener’s granulomatosis. Clin. Nephrol. 171–179 (2003). 143 Loh KC, Green A, Dillon WP Jr, Fitzgerald 55(1), 31–38 (2001). 167 Watanabe R, Tatsumi K, Hashimoto S, PA, Weidner N, Tyrrell JB. Diabetes 155 Murphy JM, Gomez-Anson B, Gillard JH Tamakoshi A, Kuriyama T. Clinico– insipidus from sarcoidosis confined to the et al. Wegener granulomatosis: MR epidemiological features of pulmonary posterior pituitary. Eur. J. Endocrinol. imaging findings in brain and meninges. histiocytosis X. Intern. Med. 40(10), 137(5), 514–519 (1997). Radiology 213(3), 794–799 (1999). 998–1003 (2001).

www.expert-reviews.com 697 Review Gutenberg, Landek-Salgado, Tzou et al.

168 Arico M, Egeler RM. Clinical aspects of 180 Patankar T, Patkar D, Bunting T, Castillo Affiliations Langerhans cell histiocytosis. Hematol. M, Mukherji SK. Imaging in pituitary • Angelika Gutenberg, MD, PhD Oncol. Clin. North Am. 12(2), 247–258 tuberculosis. Clin. Imaging 24(2), 89–92 Department of Neurosurgery, Georg- (1998). (2000). August University, Goettingen, Germany 169 Makras P, Samara C, Antoniou M et al. 181 Arbuckle MR, McClain MT, Rubertone Tel.: +49 551 391 4027 Evolving radiological features of MV et al. Development of autoantibodies Fax: +49 551 398 794 hypothalamo–pituitary lesions in adult before the clinical onset of systemic lupus [email protected] patients with Langerhans cell histiocytosis erythematosus. N. Engl. J. Med. 349(16), • Melissa Landek-Salgado (LCH). Neuroradiology 48(1), 37–44 1526–1533 (2003). Department of Pathology, The Johns (2006). 182 Caturegli P, Lupi I, Landek-Salgado M, Hopkins University School of Medicine, 170 Maghnie M, Bossi G, Klersy C, Cosi G, Kimura H, Rose NR. Pituitary Baltimore, MD, USA Genovese E, Arico M. Dynamic endocrine autoimmunity: 30 years later. Autoimmun. Tel.: +1 443 287 8911 testing and magnetic resonance imaging in Rev. 7(8), 631–637 (2008). Fax: +1 410 614 3548 the long-term follow-up of childhood 183 Crock PA, Bensing S, Smith CJA, Burns C, [email protected] langerhans cell histiocytosis. J. Clin. Robinson PJ. Pituitary autoantibodies. • Shey-Cherng Tzou, PhD Endocrinol. Metab. 83(9), 3089–3094 Curr. Opin. Endocrinol. Diabet. 13, Department of Pathology, The Johns (1998). 344–350 (2006). Hopkins University School of Medicine, 171 Broadbent V, Gadner H. Current therapy 184 De Bellis A, Bizzarro A, Bellastella A. Baltimore, MD, USA for Langerhans cell histiocytosis. Hematol. Pituitary antibodies and lymphocytic Tel.: +1 443 287 8911 Oncol. Clin. North Am. 12(2), 327–338 hypophysitis. Best Pract. Res. Clin. Fax: +1 410 614 3548 (1998). Endocrinol. Metab. 19(1), 67–84 (2005). [email protected] 172 Thompson LD, Wenig BM, Adair CF, 185 De Bellis A, Bizzarro A, Conte M et al. • Isabella Lupi, MD Smith BC, Heffess CS. Langerhans cell Antipituitary antibodies in adults with Department of Endocrinology and histiocytosis of the thyroid: a series of seven apparently idiopathic growth hormone , University of Pisa, Pisa, Italy cases and a review of the literature. Mod. deficiency and in adults with autoimmune Tel.: +39 050 995 010 Pathol. 9(2), 145–149 (1996). endocrine diseases. J. Clin. Endocrinol. Fax: +39 050 995 086 173 Maghnie M, Arico M, Villa A, Genovese Metab. 88(2), 650–654 (2003). [email protected] E, Beluffi G, Severi F. MR of the 186 De Bellis A, Salerno M, Conte M et al. • Abby Geis hypothalamic–pituitary axis in Langerhans Antipituitary antibodies recognizing Department of Pathology, The Johns cell histiocytosis. AJNR Am. J. Neuroradiol. growth hormone (GH)-producing cells in Hopkins University School of Medicine, 13(5), 1365–1371 (1992). children with idiopathic GH deficiency and Baltimore, MD, USA 174 Prayer D, Grois N, Prosch H, Gadner H, in children with idiopathic short stature. Tel.: +1 443 287 8911 Barkovich AJ. MR imaging presentation of J. Clin. Endocrinol. Metab. 91(7), Fax: +1 410 614 3548 intracranial disease associated with 2484–2489 (2006). [email protected] Langerhans cell histiocytosis. AJNR Am. J. 187 Manetti L, Lupi I, Morselli LL et al. • Hiroaki Kimura, PhD Neuroradiol. 25(5), 880–891 (2004). Prevalence and functional significance of Department of Pathology, The Johns 175 da Rocha AJ, Maia AC Jr, Ferreira NP, antipituitary antibodies in patients with Hopkins University School of Medicine, do Amaral LL. Granulomatous diseases of autoimmune and non-autoimmune thyroid Baltimore, MD, USA the central nervous system. Top. Magn. diseases. J. Clin. Endocrinol. Metab. 92(6), Tel.: +1 443 287 8911 Reson. Imaging 16(2), 155–187 (2005). 2176–2181 (2007). Fax: +1 410 614 3548 [email protected] 176 Sunil K, Menon R, Goel N et al. Pituitary 188 De Bellis A, Sinisi AA, Conte M et al. tuberculosis. J. Assoc. Physicians India 55, Antipituitary antibodies against • Patrizio Caturegli, MD, MPH 453–456 (2007). gonadotropin-secreting cells in adult male Department of Pathology, The Johns Hopkins University School of Medicine, 177 Arunkumar MJ, Rajshekhar V. Intrasellar patients with apparently idiopathic Baltimore, MD, USA tuberculoma presenting as pituitary hypogonadotropic hypogonadism. J. Clin. Feinstone Department of Molecular apoplexy. Neurol. India 49(4), 407–410 Endocrinol. Metab. 92(2), 604–607 Microbiology and Immunology, The Johns (2001). (2007). Hopkins Bloomberg School of Public 178 Singh S. Pituitary tuberculoma: magnetic Health, Baltimore, MD, USA resonance imaging. Neurol. India 51(4), Websites Tel.: +1 443 287 8911 548–550 (2003). Fax: +1 410 614 3548 179 Katti MK. Pathogenesis, diagnosis, 201 Hypophysitis research center [email protected] treatment, and outcome aspects of cerebral http://pathology2.jhu.edu/hypophysitis tuberculosis. Med. Sci. Monit. 10(9), 202 Clinical trials database RA215–RA229 (2004). http://clinicaltrials.gov

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