Typing of inflammatory lesions of the pituitary.

Inflammatory pituitary lesions account for 1.8% of all specimens from the German Pituitary Tumor Registry. They occure in 0.5% of the autoptical specimens and in 2.2% of the surgical cases. Women are significantly more often affected than men and are often younger when first diagnosed. In general, primary and secondary inflammation can be distinguished, with secondary types occurring more frequently (75.1%) than idiopathic inflammatory lesions (15.4%). In primary inflammation, the lymphocytic type is more common (88.5%) than the granulomatous type of hypophysitis (11.5%). The most common causes of secondary inflammation are Rathke's cleft cysts (48.6%), followed by tumors (17.4%) such as the craniopharyngioma (9.1%), adenoma (5.5%) or germinoma (2.0%). More causes are tumor-like lesions (7.1%) such as xanthogranuloma (3.5%) or Langerhans histiocytosis (3.5%), abscesses (5.5%), generalized infections (5.1%), spreaded inflammations (4.7%) and previous surgeries (4.0%). In 1.6% of all specimens the reason for the inflammation remains unclear. The described classification of hypophysitis is important for specific treatment planning after surgery.

Venous thromboembolic complications with and without intermittent intraoperative and postoperative pneumatic compression in patients with glioblastoma multiforme using intraoperative magnetic resonance imaging. A retrospective study.

OBJECTIVE: To evaluate the effectiveness of intraoperative and postoperative intermittent pneumatic compression (IPC) as a method used to decrease the incidence of deep venous thrombosis (DVT), in comparison to the standard use of graduated compression stockings, low-molecular weight heparin (LMWH) and physiotherapy during the hospital stay. All patients in this study underwent intracranial surgery for glioblastoma multiforme (GBM) using intraoperative magnetic resonance imaging (MRI) guidance. PATIENTS AND METHODS: We performed a single center retrospective study of a cohort of 153 patients who underwent surgery for GBM aided by intraoperative MRI from October of 2009 to January of 2015 at the International Neuroscience Institute (INI), Hannover, Germany. Out of all patients, 75 in comparison to 78 were operated with and without the additional use of IPC, respectively. Both groups received graduated compression stockings, LMWH and physiotherapy postoperatively as a basic thromboprophylaxis. Postoperatively the patients were screened for DVT by Doppler ultrasonography of the limbs and pulmonary embolism (PE) by CT-scan of the chest. RESULTS: DVTs were found in 6 patients with IPC and in 3 patients without IPC. The incidence of developing DVTs was therefore not significantly increased with the application of IPC from 3.9% to 8% (P-value: 0.33). No statistically significant differences were found in the probability of occurrence of pulmonary embolism (PE) with a reduction from 2.6% to 1.3% (P-value: 0.59). CONCLUSION: Our results demonstrate, that the surgical intervention and the subsequent patient immobilization, as well as the thromboprophylactic techniques used have a relatively low influence on the occurrence of thromboembolic complications than we expected. Our findings might be attributed to the overall low number of these complications in a glioblastoma multiforme patient population expected to be at a high risk for coagulopathy. In other words, in order to produce statistically significant results, we would need to increase the patient cohort. By doing so we may better detect a positive therapeutic effect. Alternatively, because of the multitude of possible complex risk-factors leading to coagulopathy in a glioblastoma patient population it might be the case that IPC has little or no effect and that there is a different underlying mechanism responsible for the observed coagulopathy.

Expression pattern of neuronal intermediate filament α-internexin in anterior pituitary gland and related tumors.

PURPOSE: α-Internexin (INA) is a class IV neuronal intermediate filament protein that maintains the morphogenesis of neurons. It is expressed in developing neuroblasts and represents the major component of the cytoskeleton in cerebellar granule cells of adult central nervous system tissue. Data concerning INA expression in the human frontal pituitary lobe and related adenomas (PA) is missing. METHODS: Using immunohistochemistry we examined the distribution pattern of INA in a large cohort of 152 PA, 11 atypical PA, 4 pituitary carcinomas and 20 normal pituitaries (overall n = 187). Quantity of INA protein expression was semi-quantitatively evaluated and grouped into five categories (0 = 0%; 1 = >0-5%; 2 = >5-35%; 3 = >35-80%; 4 = >80% of cells). RESULTS: Cellular staining intensity of INA appeared significantly higher in gonadotropinomas (Go, n = 62), null cell adenomas (NC, n = 7) and thyrotropinomas (TSHomas, n = 7) compared to the other tumor subtypes (p ≤ 0.001). Furthermore, Go and NC showed a peculiar pseudorosette-like staining pattern surrounding blood vessels in 85.5% (59/69) of cases. Interestingly, areas exhibiting homogenous INA staining were often associated with oncocytic cell changes and decreased immunohistochemically detectable hormone expression. Only 8.5% (8/94) of other PA showed a comparable INA distribution (p ≤ 0.001). CONCLUSION: Go, NC as well as TSHomas exhibit high levels of intracellular INA protein indicating neuronal transdifferentiation. A possible impact on pathogenesis and endocrine activity needs further investigation.

No effect of the PPAR-gamma agonist rosiglitazone on ACTH or cortisol secretion in Nelson's syndrome and Cushing's disease in vitro and in vivo.

OBJECTIVE: Surgical tumor resection remains the primary treatment strategy in ACTH-secreting pituitary adenomas, i.e. Cushing's disease (CD) and Nelson's syndrome (NS). However, an effective long-term pharmacological regime is not available in patients with persistent ACTH-hypersecretion. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma) is abundantly expressed in most pituitary adenomas. First encouraging data reported that the PPAR-gamma ligand rosiglitazone antagonizes ACTH hypersecretion and exerts also antiproliferative effects in pituitary cell lines. Herein, we studied the potential therapeutical effects of rosiglitazone in patients with ACTH-secreting pituitary adenomas in vitro and in vivo. MATERIALS AND METHODS: Seven patients with persistent ACTH-hypersecretion (3 with NS, 4 with persistent CD) were treated 5 months with rosiglitazone (4 - 16 mg/day). In vitro assays were performed in primary cell cultures obtained from eight additional patients with ACTH-secreting pituitary adenomas applying 80 microM rosiglitazone repeatedly over a time period of 14 days. RESULTS: Our long-term clinical trial with the PPAR-gamma activator rosiglitazone showed no amelioration of clinical symptoms nor an inhibiting effect on ACTH-secretion in vivo. In vitro, rosiglitazone treatment led to a statistically significant decrease of ACTH levels in 2 out of 8 primary cell cultures after 14 days compared to untreated controls. CONCLUSION: In contrast to the initially promising laboratory data gathered in pituitary cell line experiments and nude mice models, our experimental data obtained in primary human ACTH-expressing pituitary adenoma cell cultures as well as our clinical experience with a long-term rosiglitazone trial in approved antidiabetic doses support the recently reported disappointing reports on acute or short-term medical treatment of ACTH-hypersecretion with PPAR-gamma activators.

Late endocrine sequelae after radiotherapy of pediatric brain tumors are independent of tumor location.

INTRODUCTION: Irradiation of brain tumors (BT) in children can lead to the loss of pituitary function, predominantly manifesting as deficiencies in GH and ACTH. OBJECTIVE: To assess the incidence and nature of pituitary deficiency in relation to initial tumor location in children after radiotherapy of BT. METHODS: Twenty survivors (16 males and 4 females) of radiation-treated BT aged 1.4-10.9 (median 3.6) yr at diagnosis were studied, 10 with supratentorial and 10 with infratentorial BT. Radiation doses to the hypothalamus- pituitary (HP) area ranged from 30 to 54 (median 45) Gray. Follow-up was 9.4-16.9 (median 12.2) yr. Basal pituitary hormone levels were measured every 6 months. When growth failure became evident or pituitary deficiency was suspected, provocation tests of the HP axis were performed to assess GH, ACTH, and TSH function. RESULTS: GH deficiency (GHD) developed in 17/20 (85%) children. In 10 patients, it occurred 4 yr after radiotherapy and in 2, 11 and 12 yr after radiotherapy. Six (30%) patients developed secondary hypothyroidism and 4 (20%) developed ACTH deficiency. Precocious puberty occurred in 2 girls. The course of development and the severity of hormone deficiencies were similar for supratentorial and infratentorial tumors. CONCLUSION: The major hormonal effect of BT irradiation in children is GHD, which may sometimes take more than 10 yr to manifest. We confirm findings by others that ACTH insufficiency occurs less frequently in children than reported for adults. Tumor location has no prognostic significance regarding the loss of HP function.

Surgical management of giant craniopharyngiomas.

INTRODUCTION: Multimodal treatment in the management of giant craniopharyngiomas (>4 cm in diameter) is necessary to obtain optimal results, and includes conservative or palliative treatment and "aggressive" removal. The significance of a new treatment algorithm including direct surgical resection with the intent to avoid radiation therapy and regrowth will be discussed here. MATERIALS AND METHODS: Between January 1996 and January 2005 16 patients were diagnosed with giant craniopharyngiomas. Two of them underwent only cyst aspiration because of their advanced age and/or lack of improvement of neuropsychological deficits. One patient underwent transsphenoidal operation and in the remaining 13 transcranial surgery was performed. Four additional patients underwent surgery for recurrence. The prospective protocol included pre- and post-operative dynamic endocrine tests, high field 1.5 T MRI and ophthalmological as well as neuropsychological examinations. RESULTS: In resectable tumours, the rate of total removal was ten out of 12 with two recurrences. In the remaining two patients with recurrences this intention was abandoned because of a firm tumour or a deteriorating neuropsychological status prior to the scheduled additional operation. There was no mortality and the morbidity rate was 6.3%. Visual function improved in 11, was unchanged in one and deteriorated in two patients. Secretion of different adenohypophyseal hormones deteriorated after tumour resection in one to three patients, and new diabetes insipidus occurred in six patients. There was no permanent deterioration of neuropsychological function. CONCLUSION: Special reference is given to direct resection of tumours at an optimal timing within this management. If hypothalamic disturbances are absent or improving due to pre-treatment (medical therapy, symptomatic surgery), giant craniopharyngiomas can be surgically removed in more than two of three patients with low morbidity and only moderate deterioration of endocrine function. The latter has to be accepted when curative surgery is intended, but even then, recurrences cannot be prevented. Contraindication for curative surgery is persisting hypothalamic damage necessitating conservative treatment modalities.

A simplified direct endonasal approach for transsphenoidal surgery.

Having the experience of more than 4,000 hypophysectomy operations (150 cases per year on the average) by the senior author, initially performed via an intracranial, then a transseptal approach, now a direct endonasal approach, as a minimal invasive technique, is introduced to reduce the complications and for better comfort of the patient. It is the least traumatic route to the sella turcica, it avoids brain retraction, and it provides excellent visualization of the pituitary gland and lesions related to that structure. The brilliant increased vision of the surgical target offered by the endoscope can enable a more effective removal of the lesion, followed by superior clinical results and a reduction in the incidence of complications.

Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients.

OBJECTIVE: Medical therapy with dopamine agonists (DA) is the primary treatment of choice in most patients with prolactinomas. 'Classical' surgical indications are intolerance or lack of efficiency of DA therapy. Focusing on a possible shift of recent indications, we retrospectively analyzed our results of surgical treatment in prolactinomas. PATIENTS AND METHODS: Between 1990 and 2005, we have operated on 212 consecutive patients with prolactinomas. Surgical indications were divided into 'classical' indications and 'modern' indications defined as cystic prolactinomas or patients with microprolactinomas who individually decided on a primary surgical treatment. RESULTS: Initial overall remission was accomplished in 53.2% including giant prolactinomas. However, in microadenomas, the remission rate was significantly higher with 91.3%. Overall remission at the latest follow-up was 42.7%, but 72.5% in intrasellar tumors, 80% in cystic prolactinomas, and 84.8% in microprolactinomas. The overall recurrence rate was 18.7%. Relapse of hyperprolactinemia in microprolactinomas was 7.1%. In our series, continually less patients were surgically treated for 'classical' indications. By contrast, the number of patients who individually decided on a primary surgical therapy has increased considerably. CONCLUSION: Remission rates after surgical treatment of prolactinomas remain excellent, particularly in microadenoma and intrasellar macroadenomas, whereas morbidity of transsphenoidal surgery is low in the hands of experienced pituitary surgeons. Our remission rates not only confirm the already interdisciplinarily accepted surgical indications, but also emphasize the value of primary transsphenoidal surgery as a discussion-worthy alternative to dopaminergic therapy in young patients with microprolactinomas or cystic tumors.

Intraoperative brainstem auditory evoked potential pattern and perioperative vasoactive treatment for hearing preservation in vestibular schwannoma surgery.

OBJECTIVE: In vestibular schwannoma surgery, four different intraoperative brainstem auditory evoked potential (BAEP) patterns (stable BAEP, abrupt loss, irreversible progressive loss, reversible loss) can be identified and correlated with postoperative hearing outcome. Patients with reversible loss significantly benefit from postoperative vasoactive treatment consisting of hydroxyethyl starch and nimodipine. The present study investigates the treatment effect in the remaining three BAEP patterns. METHODS: A retrospective analysis was performed in 92 patients operated on for vestibular schwannoma between 1997 and 2005. Between 1997 and 2001, only patients with reversible loss of BAEP received vasoactive medication. Subsequently, all patients operated on between 2001 and 2005 received a 10 day course of therapy, regardless of the BAEP pattern. Serial audiological examinations before, after surgery and after 1 year were performed in all patients. RESULTS: All 30 patients with reversible loss of BAEP received medication, and postoperative hearing preservation was documented in 21 patients. All 13 patients with stable waves showed hearing preservation, regardless of treatment. In all 24 patients with abrupt loss and in all 25 patients with irreversible progressive loss, postoperative anacusis was documented, regardless of treatment. CONCLUSION: In patients with reversible loss of BAEP, a disturbed microcirculation of the cochlear nerve seems to be the underlying pathophysiological factor. In patients with abrupt or irreversible progressive loss, additional mechanical injury of nerve fibres determines hearing outcome. The study provides evidence that for the purpose of hearing preservation, only patients with reversible loss of BAEP benefit from vasoactive treatment.

Alveolar rhabdomyosarcoma of the clivus with intrasellar expansion: Case report.

Rhabdomyosarcomas are common tumors of the head and neck region in children. However, a primarily intracranial localization of this tumor entity is rare. We report on a 3-year-old boy presenting with double vision due to left VI (th) nerve palsy. No other neurological deficits were recognized by clinical inspection. MRI scans visualized an enhancing mass lesion in the upper clivus compressing the cavernous sinus and the pituitary gland. Transsphenoidal biopsy was performed and histopathological examination as well as molecular diagnostics confirmed the diagnosis of an alveolar rhabdomyosarcoma (ARMS). Staging identified a metastatic lesion in the fourth thoracic vertebra resulting in the diagnosis of stage IV disease. Treatment modality included stereotactic radio- and chemotherapy.

Intraoperative high-field MRI: anatomical and functional imaging.

Intraoperative high-field magnetic resonance (MR) imaging with integrated microscope-based navigation is at present one of the most sophisticated technical methods providing a reliable immediate intraoperative quality control. It enables intraoperative imaging at high quality that is up to the standard of up to date pre- and postoperative neuroradiological routine diagnostics. The major indications are pituitary tumor surgery and glioma surgery. In pituitary tumor surgery intraoperative MRI helps to localize hidden tumor remnants that would be otherwise overlooked. The same is true for glioma surgery, where the optimal extent of resection by simultaneous preservation of functional integrity can be achieved. This is possible since high-field MR imaging offers various modalities beyond standard anatomical imaging, such as MR spectroscopy, diffusion tensor imaging, and functional MR imaging which may also be applied intraoperatively, providing not only data on the extent of resection and localization of tumor remnants but also on metabolic changes, tumor invasion, and localization of functional eloquent cortical and deep-seated brain areas.

[CranioNet -- an interdisciplinary strategy for craniopharyngioma]. / CranioNet -- eine interdisziplinäre Strategie für das Kraniopharyngeom.

In patients with craniopharyngioma, pituitary failure and often lifelong hormone replacement therapy, persisting ophthalmological problems with impaired vision, cranial nerve palsies, and psychoneurological deficits will lead to a persisting impairment in quality of life and social competence. Some patients completely depend on assistance. To prevent this, a major goal is an early diagnosis and limitation of operative radicality to minimize postoperative complications. Surgery in centers with special expertise is mandatory. Radiotherapeutical strategies are relatively safe and improve the outcome and recurrence-free survival after incomplete surgical resection or after local recurrence. Multidisciplinary concepts and prospective data acquisition are desirable with regard to therapy and outcome in patients with craniopharyngioma. Problems in the follow-up period are the development of atherosclerotic complications and metabolic syndrome as a consequence of occasionally excessive obesity, which may impair the long-term survival of the patients. Cause and progression of these complications are not fully understood, therapeutical strategies for the morbid obesity are not available. Only interdisciplinary co-operation will help to develop and evaluate therapeutical concepts for the management of this rare disease.

Craniopharyngioma in a female adolescent presenting with symptoms of anorexia nervosa.

BACKGROUND: Tumours of the central nervous system mostly present with neurological symptoms and signs of intracranial hypertension. Several reports of cerebral tumors in adolescents outline initial symptoms of anorexia and emaciation, leading to the diagnosis of anorexia nervosa. PATIENT: We report on a 15.5-year-old girl with a craniopharyngioma. The girl had a 2 year history of weight loss, dystrophy, no onset of puberty, and a 6 year history of headache. These symptoms had led initially to the clinical diagnoses of migraine and anorexia nervosa, since unenhanced computed tomography of the brain was normal. At presentation, physical examination showed short stature (height SDS - 3.6) and Tanner stage I. Bone age delay was about four years. Laboratory analyses showed hypopituitarism. The diagnosis of craniopharyngioma was made by repeated imaging, depicting an intrasellar and parasellar mass, which was totally removed by neurosurgery. Hormonal substitution with hGH, L-thyroxine, hydrocortisone, and estrogens led to normal physiological development and final height within upper target height. CONCLUSIONS: The reported case illustrates that the diagnosis of craniopharyngioma is often delayed due to unspecific clinical symptoms. Careful evaluation of anthropometrics, ophthalmologic, and endocrine data in patients with suspected eating disorders may give additional clues to the diagnosis of a craniopharyngioma.

DNA-flow cytometry of 207 pituitary adenomas: ploidy, proliferation, and prognosis.

The principal factors involved in pituitary adenoma formation are unknown. DNA-flow cytometry is a useful study providing an estimation of a tumor proliferative rate. In this study, DNA-flow cytometry was performed to evaluate its capability to both assess prognosis and predict recurrence. Two hundred and seven fresh pituitary adenoma specimens were assessed by flow cytometry. Pre-operative endocrine function, previous medical treatment, radiographic appearance, surgical findings and immunohistochemistry were recorded for each patient. Patient outcomes were assessed at a mean follow-up of 5.3 +/- 3.1 yr. Endocrinologically inactive pituitary adenomas were predominantly euploids (50.8%). The highest proliferation rates occurred in Nelson's syndrome and the lowest in Cushing's disease. A significant difference in proliferation was observed with prolactinomas and acromegaly when a medical treatment was performed before primary surgery. Massive histological invasiveness was directly associated with a significant increase in proliferation rate. Radiotherapy did not affect the recurrence rate (4.4%) statistically. In conclusion, DNA-flow cytometry was found to be useful for determining ploidy and obtaining an overview of cell cycle status. It was helpful in identifying patients requiring closer follow-up, such as those with invasive adenomas and Nelson's syndrome. No single parameter revealed by DNA-flow cytometry could predict tumor prognosis or recurrence in the follow-up of 7.5 +/- 1.3 yr.

Neurovascular relationship at the trigeminal root entry zone in persistent idiopathic facial pain: findings from MRI 3D visualisation.

BACKGROUND: Patients with atypical neuralgia or atypical facial pain have been surgically treated with microvascular decompression (MVD) of the trigeminal root entry zone (TREZ). There are no data regarding the sensitivity and specificity of a vessel-TREZ relationship as a cause of pain in patients with persistent idiopathic facial pain (PIFP) according to the definition given by the International Headache Society (IHS). METHODS: The TREZ was visualised by 3D CISS MRI in 12 patients with unilateral PIFP according to the IHS criteria. RESULTS: The frequency of artery-TREZ, vein-TREZ, or vessel (artery/vein)-TREZ contacts on the symptomatic and asymptomatic sides did not differ significantly. On the symptomatic side, vessel-TREZ contact was found in 58% of patients (sensitivity). On the asymptomatic side, vessel-TREZ contact was absent in 33% of patients (specificity). CONCLUSIONS: On the basis of the low sensitivity and specificity found in the present study, PIFP cannot be attributed to a vessel-TREZ contact, and therefore, pain relief after MVD cannot be expected.

Visualization of the pyramidal tract in glioma surgery by integrating diffusion tensor imaging in functional neuronavigation.

OBJECT: The aim of this study was to investigate whether diffusion tensor imaging (DTI) can be integrated into functional navigation for the intraoperative visualization of the pyramidal tract. METHODS: A single-shot spin-echo diffusion-weighted echo planar imaging sequence on a 1.5 T magnetic resonance (MR) scanner was used for DTI. One null image and six diffusion-weighted images (high B value 1 000 mm/s (2)) were obtained. Color-encoded fractional anisotropy maps of the principal eigenvector rendered as a boxoid within each voxel were used for segmentation of the pyramidal tract. The segmented images were rigidly registered with a T(1)-weighted gradient echo 3D dataset for navigation in 16 patients with gliomas. In tumors adjacent to the motor cortex (n = 6) data from functional MR imaging were co-registered. RESULTS: The whole DTI processing lasted about 25-30 minutes in each case. In all cases DTI could be integrated into the navigational dataset resulting in an intraoperative visualization of the pyramidal tract by microscope-based navigation. Navigational accuracy measured as the target registration error was 1.2 +/- 0.46 mm. Registration of fractional anisotropy maps with the 3D navigational dataset was possible with an error of less than 2 mm. Co-registration with fMRI was consistent with DTI data. A neurological deterioration was observed only in one patient. CONCLUSIONS: DTI can be reliably integrated into navigational datasets. Thus, microscope-based neuronavigation can be used for an intraoperative visualization of the course of the pyramidal tract. However, a possible shifting of the pyramidal tract has to be taken into account after major tumor parts are removed.

An automated robotic approach with redundant navigation for minimal invasive extended transsphenoidal skull base surgery.

BACKGROUND: The aim of this work was to determine the feasibility of a robotic-assisted and fully automated approach to the sphenoid sinus. An image-guided robotic system was designed to address potential human errors in performing transsphenoidal sinus surgery by combining the reproducible accuracy of a robotic system with standard computer navigation. METHODS: A six-degrees of freedom robotic assistance system and an opto-electrical navigation system were combined for image-guided assistance with redundantly controlled robotics. Newly designed endoscopic instruments for robotic surgery have been developed and are described. Telemanipulatory, as well as fully automated procedures, were tested on cadaveric heads as part of a preclinical trial. RESULTS: A fully automated sphenoidotomy as well as a telemanipulatory sphenoidectomy were performed successfully on cadaveric heads. Intraoperative performance, accuracy assessment studies, as well as possible sources of stereotactic offsets are described. The mean measured robotic reproducibility accuracy was 0.056 mm (range: 0.02 - 0.14 mm) and the mean overall navigated robotic accuracy, including all transformation and registration errors was 1.53 mm (range: 1.13 - 1.89 mm) respectively. CONCLUSION: A system for robot-guided surgery in combination with redundant navigational control was developed. It allows highly accurate maneuvers, performed either in a telemanipulation mode as master-slave system or in a fully automated fashion. A sphenoidectomy on cadaveric heads was performed in both telemanipulation and fully automated modes. The overall intraoperative accuracy was in the range of the resolution of the CT images and stereotactic offsets were caused mainly due to deflections of the endoscopic operating instrument.

Analysis of secretory, immunostaining and clinical characteristics of human "functionless" pituitary adenomas: transdifferentiation or gonadotropinomas?

In this study, the central technique of in vitro culture has been used to further investigate whether LH/FSH-expressing, but clinically "functionless" pituitary adenomas are gonadotropinomas or whether their hormone secretion is due to transdifferentiation events. 664 "functionless" pituitary adenomas were examined for hormone secretion by in vitro culture and for hormone content by immunostaining. The results were correlated with the clinical findings. 40 % of the tumours (n = 263) secreted at least one of the gonadotropins alone, 8 % (n = 53) exhibited various patterns of anterior pituitary hormones, whilst the remaining 52 % of tumours were not associated with any hormone. In the secretory tumours, immunostaining revealed only a few scattered hormone-containing cells (5 to 15 %). Mild hyperprolactinaemia was observed in some cases, presumably because of pressure effects of the tumours. The majority of the patients suffered clear cut hypopituitarism (p < 0.05). Pre-operatively, gonadotropin hypersecretion was observed in 3 cases, but only one of these secreted hormones in culture. Interestingly, a higher proportion of tumours removed from patients with hypopituitarism showed secretory activity in vitro than those tumours removed from patients showing no hormonal dysfunction or hyperprolactinaemia. We conclude that the term "gonadotropinoma" to describe functionless pituitary tumours associated with LH and/or FSH secretion is a misnomer, because the presence of LH and/or FSH confirmed by in vitro methods in the present series is a result of only a few scattered cells. We suggest that primary pituitary tumour cells differentiate into a secretory type (transdifferentiation), possibly in response to altered serum hormone levels such as decreased steroids. Further work is required to identify the factors which trigger the altered cells' characteristics.

Immunopathology of primary hypophysitis: implications for pathogenesis.

The etiology of primary hypophysitis is still not fully elucidated. Histologically, primary hypophysitis includes three different main subtypes: lymphocytic (LYH), granulomatous (GRH), and xanthomatous (XH) hypophysitis. Clinical and laboratory findings suggest an autoimmune basis in primary hypophysitis. Controversy still exists about the composition of the inflammatory infiltrate and the relevant immunopathogenic effector mechanisms. Therefore, 21 cases of primary hypophysitis of different subtypes were analyzed with respect to the expression of lymphocyte and macrophage antigens as well as MHC class I and II molecules of the inflammatory infiltrate and the resident pituitary acinar cells. Lymphocyte infiltration in LYH (n = 15), but also in GRH (n = 4) and XH (n = 2), mainly consisted of T cells, while B cells were rare. Independent from the histopathologic subtype, T cell subsets showed equal ratios of CD4+ to CD8+ T cells. Highest numbers of activated CD8+ T cells were observed in LYH presenting during pregnancy, surrounding or even infiltrating preserved pituitary acinar cells. Moreover, an increased rate of activated CD8+ T cells correlated with a shorter duration of clinical symptoms. In LYH, aberrant expression of MHC class II antigens as well as overexpression of MHC class I molecules on pituitary cells were observed. Independent of the histologic subtype, macrophages mostly expressed markers of chronic activation and showed MHC class II positivity. LYH, GRH, and XH, although heterogeneous in their histologic appearance and in age distribution, exhibit a similar if not identical immunohistologic profile. It is highly likely that direct T cell-mediated cytotoxicity through CD8+ T cells, with the initial help of CD4+ T cells, is pivotal in the pathogenesis of primary hypophysitis, implicating a target autoantigen expressed by pituitary cells.