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This manuscript describes the study of two cases of craniopharyngioma, which have been examined repeatedly over three separate centuries. This includes analysis by Josef Engel in 1839, who sought to uncover the physiological role of the pituitary gland; Jacob Erdheim in 1904, who initially described the disease we now call craniopharyngioma, and recent high resolution MRI and micro-CT imaging and attempted DNA analyses of the tumours. The cases highlight how, rightly or wrongly, our interpretation of data is shaped by the technologies, methodologies and prevailing theories of a given time., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Apps JR et al.)

Background: Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha., Methods: European Société Internationale d'Oncologie Pédiatrique and International Society for Pediatric Neurosurgery centers were contacted to submit a datasheet capturing pediatric patients with cystic craniopharyngiomas who had received intracystic interferon-alpha. Patient demographics, administration schedules, adverse events, and outcomes were obtained. Progression was clinical or radiological (cyst reaccumulation, novel cysts, or solid growth)., Results: Fifty-six children (median age, 6.3 y) from 21 international centers were identified. Median follow-up from diagnosis was 5.1 years (0.3-17.7 y). Lesions were cystic (n = 22; 39%) or cystic/solid (n = 34; 61%). Previous progression was treated in 43 (77%) patients before interferon use. In such cases, further progression was delayed by intracystic interferon compared with the preceding therapy for cystic lesions (P = 0.0005). Few significant attributable side effects were reported. Progression post interferon occurred in 42 patients (median 14 mo; 0-8 y), while the estimated median time to definitive therapy post interferon was 5.8 (1.8-9.7) years., Conclusions: Intracystic interferon-alpha can delay disease progression and potentially offer a protracted time to definitive surgery or radiotherapy in pediatric cystic craniopharyngioma, yet demonstrates a favorable toxicity profile compared with other therapeutic modalities-important factors for this developing age group. A prospective, randomized international clinical trial assessment is warranted., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

OBJECTIVE In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated. METHODS The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures. RESULTS In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA. CONCLUSIONS These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.

Background: Currently, no effective alternative treatment exists for progressive, regrowing, nonfunctioning pituitary adenomas (NFPA) that are resistant to conventional multimodality therapy. Temozolomide (TMZ) was proposed as a treatment option for pituitary carcinomas and aggressive pituitary adenomas. Recently, it was suggested that the responsiveness of pituitary tumors to TMZ depends on the immunoexpression of O(6)-methylguanine DNA methyltransferase (MGMT). Therefore, the authors of this report assessed MGMT expression in a series of patients with progressive, regrowing NFPAs to evaluate whether TMZ may serve as alternative treatment option., Methods: On the basis of postoperative magnetic resonance imaging, 45 patients with NFPAs were allocated to either a group with progressive, regrowing tumors (n = 24) or a tumor-free group (n = 21), which served as a control. MGMT expression was assessed semiquantitatively by immunohistochemistry (low expression was defined as 50% immunostained adenoma cells) and was compared between the 2 groups., Results: At the time of initial surgery, low MGMT expression was observed in 12 of 24 patients (50%) in the study group with progressive, regrowing NFPAs. In the control group of tumor-free patients, only 5 of 21 patients (24%) exhibited low MGMT expression. A comparable distribution of MGMT expression was observed in the specimens from repeat surgeries. A shorter interval to second surgery was observed in patients who had low MGMT expression., Conclusions: The current data has suggested that half of the patients with progressive, regrowing NFPAs exhibit low MGMT expression and are potential candidates for treatment with TMZ. These findings provide a rationale for the use of TMZ as an alternative treatment approach in this subgroup if conventional therapy, including reoperation, radiosurgery, and radiotherapy, fails., ((c) 2009 American Cancer Society.)

Objective: Virtual endoscopy (vE) is the navigation of a camera through a virtual anatomical space that is computationally reconstructed from radiological image data. Inside this three-dimensional space, arbitrary movements and adaptations of viewing parameters are possible. Thereby, vE can be used for noninvasive diagnostic purposes and for simulation of surgical tasks. This article describes the development of an advanced system of vE for endoscopic transsphenoidal pituitary surgery and its application to teaching, training, and in the routine clinical setting., Methods: The vE system was applied to a series of 35 patients with pituitary pathology (32 adenomas, three Rathke's cleft cysts) operated endoscopically via the transsphenoidal route at the Department of Neurosurgery of the Medical University Vienna between 2004 and 2006., Results: The virtual endoscopic images correlated well with the intraoperative view. For the transsphenoidal approach, vE improved intraoperative orientation by depicting anatomical landmarks and variations. For planning a safe and tailored opening of the sellar floor, transparent visualization of the pituitary adenoma and the normal gland in relation to the internal carotid arteries was useful., Conclusion: According to our experience, vE can be a valuable tool for endoscopic transsphenoidal pituitary surgery for training purposes and preoperative planning. For the novice, it can act as a simulator for endoscopic anatomy and for training surgical tasks. For the experienced pituitary surgeon, vE can depict the individual patient's anatomy, and may, therefore, improve intraoperative orientation. By prospectively visualizing unpredictable anatomical variations, vE may increase the safety of this surgical procedure.

Ki-67 antigen is used as a marker of proliferative activity that is linked to growth rate, invasiveness and prognosis of pituitary adenomas. So far the distribution of Ki-67 index within an individual adenoma has not been investigated. If Ki-67 antigen expression differs significantly within an individual pituitary adenoma, a sampling error may result when assessing small fragments of adenoma tissue. Such a potential error would diminish the value of Ki-67 as a tool for postoperative patient management considerations. The aim of the present study was to assess Ki-67 proliferation rates in different regions of pituitary adenomas and to statistically analyse these data for potential regional differences within each tumor. Ki-67 proliferation index was assessed in smear preparations of 100 specimens of 26 consecutive patients operated on for pituitary adenoma in the Department of Neurosurgery, Medical University Vienna. Depending on the size and extent of the tumor, a mean of 4 tissue samples (range 2-8) was selected intraoperatively from each adenoma from endosellar, suprasellar, parasellar, and basal sellar dural locations. Overall mean cell proliferation rate measured by Ki-67 was 1.81 +/- 0.90% (range 0.33-3.43%). Histologically invasive adenomas had significantly higher mean Ki-67 proliferation index in all samples from the same tumor than non-invasive adenomas (2.01 +/- 0.91% vs. 1.11 +/- 0.59%; P = 0.024). Multiregional sampling revealed a homogenous distribution of Ki-67 index throughout an individual adenoma with no significant differences between any two different regions on t-test. Our data confirm that location of a biopsy does not influence Ki-67 index. Therefore, Ki-67 index of a single biopsy is representative for the whole individual adenoma. Thus Ki-67 index can be considered a reliable parameter for assessment of cell proliferation rate in adenoma biopsies and may be used for postoperative patient management considerations.

Pituitary adenomas represent an inhomogeneous tumor entity in terms of growth rate, invasiveness and recurrence. To improve understanding of their different biological behaviour, tumor cell proliferation markers are applied. The aim of this study was to assess proliferation rates overall and in clinico-pathological subgroups using MIB-1 and the recently introduced cell proliferation marker anti-topoisomerase-IIalpha (Topo-IIalpha). Further, we correlated the two markers, and defined the clinical value of Topo-IIalpha in pituitary adenomas as compared to MIB-1. We analyzed tumor cell proliferation rates using MIB-1 and Topo-IIalpha antibodies on samples of 260 primary pituitary adenomas. We excluded recurrent cases and cases with drug pretreatment. Median patient age at the time of surgery was 47 years (range 14-86 years), the male:female ratio was 1:1. The total cohort comprised 110 non-functioning and 150 functioning cases. Subtyping was performed according to hormonal expression as defined by WHO. Tumor size and invasiveness were noted from surgical and/or radio logical reports in 95% of cases. Overall MIB-1 index was median 1.8% (range 0.2-23.6%), Topo-IIalpha index was median 1.0% (range 0-14.4%) with a strong correlation between the two markers ( R=0.837, P<0.001). As compared to MIB-1, mean Topo-IIalpha values were significantly lower by a factor 1.8. Only MIB-1 was significantly higher in invasive as compared to non-invasive adenomas, in tumors < or =3 cm in diameter, and in the age-group 21-40. Female gender had significantly higher MIB-1 and Topo-IIalpha indices than male. Silent ACTH-cell and PRL-producing adenomas had the highest, null-cell adenomas and gonadotropinomas the lowest proliferation values, respectively. Our data show a strong correlation between MIB-1 and Topo-IIalpha indices in pituitary adenomas. Only MIB-1 but not Topo-IIalpha demonstrated significantly higher values in invasive adenomas. Therefore, MIB-1 seems more useful than Topo-IIalpha for decisions regarding postoperative patient management.

Object: The aim of this study was to determine the value of high-field magnetic resonance (MR) imaging for diagnosis and surgery of sellar lesions., Methods: High-field MR images were obtained using a 3-tesla unit with emphasis on sellar and parasellar structures in 21 patients preoperatively to delineate endo-, supra-, and parasellar anatomical structures. Special attention was given to the medial border of the cavernous sinus and possible invasion of a sellar tumor therein, and to assessing the application of high-resolution images during intraoperative neuronavigation. The 3-tesla MR images were compared with the standard MR images already obtained and with intraoperative findings. Anatomical structures were studied in all 42 cavernous sinuses; in 32 of them comparisons with intraoperative findings were possible. The medial cavernous sinus border was rated intact in 53% on standard MR images, in 72% on 3-tesla MR images, and in 81% intraoperatively. With a positive correlation to surgical findings on 84% of 3-tesla MR images compared with 59% of standard MR images, a sensitivity of 83% compared with 67%, and a specificity of 84% compared with 58% (p = 0.016, McNemar test), 3-tesla MR imaging was superior for predicting tumor invasion through the medial cavernous sinus border. Although no difference was noted in delineation of the medial, superior, and inferior compartments, there was a better delineation of the lateral cavernous sinus compartment with 3-tesla MR imaging. This compartment was clearly visible on 40 sides (95%) on 3-tesla MR images compared with 34 sides (81%) on standard MR images. Identification of the cavernous sinus segments of the third, fourth, fifth (V1 and V2), and sixth cranial nerves was improved using high-resolution 3-tesla imaging compared with standard MR imaging. A mean of four cranial nerves was found as hypointense spots (range two-five spots) on 3-tesla MR imaging compared with a mean of three (range zero-four spots) on standard MR imaging. After addition of contrast agents, the anterior pituitary gland was found to be highly intense on 78% of T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo (MPRAGE) 3-tesla MR images compared with 73% of standard T1-weighted MR images. The optochiasmatic system displayed increased intensity on pre-contrast T1-weighted MPRAGE 3-tesla compared with standard T1-weighted MR images; it was hyperintense on 76% of 3-tesla compared with 15% of standard MR images, which was helpful for its delineation from suprasellar pituitary and tumor structures. Intraoperative navigation guided by fusion of 3-tesla MR images and computerized tomography (CT) scans was performed in seven patients. Whereas CT scanning was used during the transsphenoidal approach to depict the nasal bone structures, 3-tesla MR imaging was particularly useful for the visualization of parasellar tumor extension during microsurgical and/or endoscopic resection., Conclusions: Due to its higher resolution, 3-tesla MR imaging was found to be superior to standard MR imaging for the delineation of parasellar anatomy and tumor infiltration of the cavernous sinus, and this modality provided improved imaging for intraoperative navigation.

Objective: To support the opinion that transsphenoidal surgery can be an effective alternative to medical treatment for microprolactinomas in men., Design: Clinical study with retrospective data analysis., Patients and Methods: Of 46 men who were operated on for prolactinoma in the Department of Neurosurgery of the University of Vienna General Hospital between 1985 and 2000 a microadenoma was detected 11 times (24%)., Results: Median patient age was 41 years (range 32 to 54 years). Symptoms were of endocrine nature in all patients with erectile dysfunction, infertility and gynaecomastia being the initial complaints and having lasted for a median of 13 months (range 7-68 months). Preoperative median serum prolactin (PRL) was elevated to 120 ng/ml (range 41-1000 ng/ml). Radiography by MRI revealed microadenomas with a median diameter of 8 mm (range 4-10 mm). All patients were operated on via the transsphenoidal approach. Endocrine cure as defined by a serum PRL <25 ng/ml was achieved in 8 of 11 patients (73%) after a median follow-up of 7 years (range 2-13 years). In none of the 3 patients with preoperative serum PRL levels >150 ng/ml was a normoprolactinaemia obtained after surgery: 2 require further dopamine-agonist therapy after surgery, 1 after late follow-up. Surgery and medical treatment could restore potency and libido in all but 1 patient, 2 of 3 patients remain infertile., Conclusion: Prolactinomas in males are potentially curable by surgery if detected at an early stage. They most commonly present with insidious signs and symptoms of endocrine disturbances such as loss of libido, impotence and sterility. We stress the importance of early determination of serum prolactin and high resolution magnetic resonance tomography of the sella in male patients with hyperprolactinaemia as this may prevent the possible progression to larger tumours which are rarely curable by surgery and necessitate life-long medical therapy.

Due to their diversity, pituitary adenomas represent an interdisciplinary therapeutic challenge in regard to endocrinology, radiology and neurosurgery. Advanced radiological methods such as magnetic resonance imaging (MRI) and the possibility of three-dimensional reconstruction have profoundly improved surgical planning and intraoperative neuronavigation. With the application of modern surgical techniques like endoscope-assisted microsurgery or pure endoscopic surgery further improvements in the treatment of pituitary adenomas at difficult locations can be expected. Major prognostic factors predicting surgical outcome are extension of the adenoma and invasivity into adjacent structures. Both may be perfectly visualized by high-resolution MRI. The proliferation marker MIB-1 as a parameter of growth-rate and invasivity of pituitary adenomas provides information for postoperative management in terms of additional treatment and follow-up imaging. The current management of pituitary adenomas is discussed according to the different therapeutic options available and new developments are presented.

Seventy-six pituitary adenomas of akromegalic patients were investigated to find out the prognostic relevance of the intracytoplasmic distribution of cytokeratins (CK), immunohistochemically defined hormone production profile, proliferative activity and clinical presentation. CK distribution, growth fraction (MIB1 index) and hormone production profile were analyzed by means of immunohistochemistry. Apoptotic activity was investigated by the TUNEL method. Two different CK distribution patterns were seen: a dot-like pattern in 29 cases (type 1 adenomas), and a perinuclear fibrillary pattern in 47 cases (type 2 adenomas). Type 2 adenomas showed more prominent coexpression of prolactin (p < 0.0001), luteotrophic hormone (p < 0.002), follicle-stimulating hormone (p < 0.005), thyroid-stimulating hormone (p < 0.0001), and alpha-subunit (p < 0.005), as compared to type 1 adenomas. The mean MIB1 index was significantly higher in type 1 vs. type 2 tumors (4.23%, range: 1.93% - 9.83% vs. 2.07%, range: 0.67% - 4.87%, p < 0.0001). Apoptotic activity was too low in both examined groups to be used for balancing of tumor cell turnover. Clinical analysis of patients with type 1 adenomas revealed female predominance, younger age, larger tumor size, and more frequently aggressive growth with higher incidence of suprasellar extension (p < 0.0001) and cavernous sinus infiltration (p < 0.0001), as well as larger proportions of re-operations and incomplete resections (34.5% vs. 8.51%). Additionally, the interval until re-operation was shorter in type 1 adenomas (mean: 16 months, range: 9 - 21 months vs. mean: 57 months, range: 18- 158 months). We conclude that classification of adenomas of akromegalic patients based on intracytoplasmic CK distribution, combined with examination of proliferative activity, and immunohistochemically defined hormone production profile, provides important prognostic information for the management of akromegalic patients.

Pituitary apoplexy in patients with pituitary macroadenomas can occur either spontaneously or following various interventions. We present a case of a 71-year-old woman who developed third, fourth, and sixth cranial nerve palsies following administration of the four hypothalamic releasing hormones for routine preoperative testing of pituitary function. The MR examination showed interval tumor growth with impression of the floor of the third ventricle. There were also changes in signal intensity characteristics of the mass, suggestive of intratumoral bleeding. A transsphenoidal surgery with subtotal resection of the pituitary adenoma was performed. Microscopical examination revealed large areas of necrosis and blood surrounded by adenomatous tissue. Third, fourth, and sixth cranial nerve palsies completely resolved within 4 months. We conclude that MR imaging is useful in the demonstration of pituitary apoplexy following preoperative stimulation tests, but we suggest that these tests should be abandoned in patients with pituitary macroadenomas.

Despite its description in the literature there remains uncertainty about the incidence, the pathophysiological basis and the best management of a delayed visual deterioration in the presence of an empty sella after surgery for pituitary adenomas. Out of a series of 501 patients with pituitary adenomas operated on at our institution between 1984 and 1996, four patients (0.8%) developed a worsening of their visual function 3 to 37 months after surgery in the absence of tumour recurrence. None of the patients had received radiotherapy. Magnetic resonance imaging (MRI) ruled out compression by tumour and showed herniation of suprasellar structures into an empty sella. In three cases re-operation by a subfrontal approach with freeing of the optic structures from tethering scar tissue led to an improvement of visual deficits. In one case a spontaneous recovery was initiated by a minor head injury. Although apparently a rare event, our cases provide evidence for the occurrence of a potentially reversible delayed deterioration of visual function after surgery for pituitary adenomas. Based on our operative findings and our outcome we recommend re-operation by a transcranial approach in patients in whom repeated ophthalmological testing does not show spontaneous improvement within a short period of time.

The secretion of growth hormone (GH) stimulated by GH-releasing hormone ([GHRH] 100 micrograms intravenously [IV]) was determined in 33 patients with nonfunctioning pituitary macroadenomas before and after transsphenoidal adenomectomy and in 28 controls. Patients who needed substitution therapy for at least one additional pituitary hormone presented with lower GH secretion than the remaining patients with pituitary tumors. However, there was a marked overlap of stimulated GH secretion between these two groups (3.2 +/- 4.3 ng/mL and 7.2 +/- 6.6 ng/mL, respectively) and between either group with the control group (7.1 +/- 5.5 ng/mL). In an independent investigation, the effect of IV GHRH (100 micrograms) on the secretion of GH in seven healthy volunteers was shown to be comparable to that seen during an insulin tolerance test ([ITT] 0.1 U/kg IV). Thus, the GHRH stimulation test, a simple and comparatively unharmful procedure, is a useful alternative to the ITT in patients with potential pituitary defects. However, the pronounced overlap of stimulated serum GH concentrations in patients with pituitary macroadenomas and those estimated in healthy subjects and in patients with nonpituitary diseases underlines the difficulty in biochemically defining acquired GH deficiency in adults. We suggest that GH therapy in adults should primarily be instituted in patients with additional defects in anterior pituitary function.

Unlabelled: Epidepride is a novel benzamide derivative with high affinity for D2 receptors. Epidepride, in its 123I-labeled form, can be used for SPECT imaging of striatal and extrastriatal dopamine D2 receptors. The present study evaluated the usefulness of epidepride and SPECT for in vivo imaging of dopamine receptors in pituitary adenomas., Methods: SPECT imaging was performed in 19 patients with pituitary adenomas (among them 9 patients had prolactinoma, 4 acromegaly, 4 clinically nonfunctioning pituitary adenoma, 1 Cushing's disease and 1 Nelson's syndrome) and 7 control subjects 180 min after intravenous bolus injection of 3.9 +/- 1.1 mCi [123I]epidepride. The ratio target/cerebellum minus 1, reflecting specific/ nonspecific binding was used as semiquantitative measure of D2 receptor binding., Results: Eight of nine prolactinoma patients demonstrated specific binding within the adenoma. The adenoma/ cerebellum ratio 3 hr p.i. showed a wide variation with values from 2.5-33. In three prolactinomas, binding was higher than in the striatum. Specific binding within the lower range of prolactinomas (adenoma/cerebellum ratios 2 and 4.8) could be demonstrated in two of four GH-secreting adenomas. All four nonfunctioning tumors showed specific binding. The adenoma/cerebellum ratio was within the lower range of prolactinomas (5.2-7.5) in three of these patients but extremely high in one (52.3). No specific tracer uptake could be demonstrated in patients with Cushing's disease or Nelson's syndrome. The striatum/cerebellum ratio 3 hr p.i. in pituitary adenoma patients was not significantly different from control subjects (17.3 +/- 5.5 versus 17.8 +/- 6.6; patients versus control subjects)., Conclusion: Epidepride appears to be an excellent ligand for in vivo imaging of dopamine D2 receptors in pituitary adenomas. Epidepride SPECT could serve as a predictor for response to dopamine agonist treatment.

The McCune-Albright syndrome (MAS) comprises a triad of physical signs: localized bone lesions termed polyostotic fibrous dysplasia, café-au-lait pigmentation of the skin, and autonomous hyperfunction of multiple endocrine systems, including overproduction of GH and T4. A somatic activating point mutation in the gene for the alpha-subunit of the G-protein (Gs alpha) in the affected tissue has been claimed to be the underlying defect. A 29-yr-old patient with MAS, showing polyostotic fibrous dysplasia associated with acromegalic features, underwent endocrinological studies, including oral glucose tolerance test and pituitary stimulation test, and magnetic resonance imaging, revealing elevated plasma concentrations of GH, PRL, and secondary hyperthyroidism due to pituitary macroadenoma infiltrating the sphenoid cavity and extending to the suprasellar space. Subsequently, reduction of tumor mass by a transsphenoidal and a subsequent subfrontal operation led to only marginal amelioration of the excessive hormone production. Postsurgery octreotide and bromocriptine therapy induced near-normalization of hormone concentrations. Immunohistochemistry of tumor tissue confirmed the plurihormonal character, but DNA sequence analysis did not detect any of the two known activating mutations in the Gs alpha gene. Furthermore, biochemical tests revealed normal Gs alpha function, ruling out other mutations that lead to constitutive Gs alpha activation. Our study documents that MAS is a heterogeneous disease. Some, but clearly not all, patients have oncogenic mutations of the gene coding for Gs alpha. Any gene acting down-stream of Gs can theoretically be predicted to result in the same phenotype. In addition, hyperthyroidism of MAS may be secondary to a TSH-producing pituitary macroadenoma.