Clinical Impact of the Current WHO Classification of Pituitary Adenomas.

WHO classifications should be used for comparing the results from different groups of pathologist and clinicians by standardized histopathological methods. Our present report describes the important parameters of pituitary adenoma pathology as demand of the WHO classification for correlation to endocrine data and prognosis. The combination of HE stain based structures with immunostainings for pituitary hormones allows subclassification of adenomas as the best method not only for correlations to clinical hyperfunctions but also for statements to the sensitivity of drug therapies (somatostatin analogs, dopamine agonists). GH-, PRL- and ACTH-secreting pituitary adenomas are further classified based on the size and number of their secretory granules by electron microscopy, or as is mostly the case nowadays by cytokeratin staining pattern, into densely and sparsely granulated. Granulation pattern may be considered for the prediction of treatment response in patients with GH-secreting adenomas, since the sparsely granulated subtype was shown to be less responsive to somatostatin analog treatment. For prognosis, it is important to identify aggressive adenomas by measurements of the Ki-67 index, of the number of mitoses, and of nuclear expression of p53. Among the criteria for atypical adenomas, high Ki-67 labeling index and invasive character are the most important adverse prognostic factors. Promising molecular markers have been identified that might supplement the currently used proliferation parameters. For defining atypical adenomas in a future histopathological classification system, we propose to provide the proliferative potential and the invasive character separately.

Emerging Histopathological and Genetic Parameters of Pituitary Adenomas: Clinical Impact and Recommendation for Future WHO Classification.

The review assesses immunohistochemical findings of somatostatin receptors and of metalloproteinases in different pituitary adenoma types and the significance of molecular genetic data. Current evidence does not support routine immunohistochemical assessment of somatostatin or dopamine receptor subtype expression on hormone-secreting or nonfunctioning pituitary adenomas. Further prospective studies are needed to define its role for clinical decision making. Until then we suggest to restrict membrane receptor profiling to individual cases or for study purposes. The problems of adenoma expansion and invasion are discussed. Despite partially contradictory publications, proteases clearly play a major role in permission of infiltrative growth of pituitary adenomas. Therefore, detection of at least MMP-2, MMP-9, TIMP-2, and uPA seems to be justified. Molecular characterization is important for familial adenomas, adenomas in MEN, Carney complex, and McCune-Albright syndrome and can gain insight into pathogenesis of sporadic adenomas.

Maximizing the extent of resection and survival benefit of patients in glioblastoma surgery: high-field iMRI versus conventional and 5-ALA-assisted surgery.

AIMS: A safe total resection followed by adjuvant chemoradiotherapy should be the primary goal in the treatment of glioblastomas (GBMs) to enable patients the longest survival possible. 5-aminolevulinic acid (5-ALA)- and intraoperative MRI (iMRI)-assisted surgery, have been shown in prospective randomized trials to significantly improve the extent of resection (EOR) and subsequently survival of patients with GBMs. No direct comparison of surgical results between both techniques has been published to date. We analyzed the additional value of iMRI in glioblastoma surgery compared to conventional surgery with and without 5-ALA. METHODS: Residual tumor volumes, clinical parameters and 6-month progression-free survival (6M-PFS) rates after GBM resection were analyzed retrospectively for 117 patients after conventional, 5-ALA and iMRI-assisted surgery. RESULTS: Mean residual tumor volume (range) after iMRI-assisted surgery [0.5 (0.0-4.7) cm(3)] was significantly smaller compared to the residual tumor volume after 5-ALA-guided surgery [1.9 (0.0-13.2) cm(3); p = .022], which again was significantly smaller than in conventional white-light surgery [4.7 (0.0-30.6) cm(3); p = .007]. Total resections were significantly more common in iMRI- (74%) than in 5-ALA-assisted (46%, p = .05) or white-light surgery (13%, p = .03). Improvement of the EOR by using iMRI was safely achievable as peri- and postoperative morbidities were comparable between cohorts. Total resections increased 6M-PFS from 32% to 45%. CONCLUSIONS: Analysis of residual tumor volumes, total resections and neurological outcomes demonstrate that iMRI may be significantly superior to 5-ALA and white-light surgery for glioblastomas at comparable peri- and postoperative morbidities. Longer 6M-PFS was observed in patients with total resections.

Long-term remission and recurrence rates after first and second transsphenoidal surgery for Cushing's disease: care reality in the Munich Metropolitan Region.

OBJECTIVE: Transsphenoidal surgery (TSS) presents the treatment of choice for Cushing's disease (CD). Remission and recurrence rates vary dependent on tumor size, extension, adenoma visibility on magnetic resonance imaging, and neurosurgical expertise. Other than published from single-surgeon neurosurgical series so far, we have aimed to describe long-term remission and recurrence rates of CD in a series incorporating different neurosurgeons, trying to reflect care reality in the Munich Metropolitan Region, which is accommodated by three tertiary university and multiple, smaller neurosurgical centers. DESIGN: We conducted a retrospective analysis of 120 patients who underwent first and 36 patients who underwent second TSS as treatment for CD between 1990 and 2012. METHODS: Patients were divided into three groups according to remission status. Potential risk factors for recurrence, pituitary function, and strategy in persistent disease were assessed. RESULTS: THREE OUTCOME GROUPS WERE IDENTIFIED ACCORDING TO REMISSION STATUS AFTER FIRST TSS (MEAN FOLLOW-UP 79 MONTHS): remission, 71% (85/120), disease persistence, 29% (35/120), and disease recurrence, 34% (29/85) (mean time to recurrence 54 months). After second TSS (n=36, mean follow-up 62 months), we documented remission in 42% (15/36), disease persistence in 58% (21/36), and disease recurrence in 40% (6/15) (mean time to recurrence 42 months). Postoperative hypocortisolism after first, though not after second, TSS was associated with a lower risk of suffering disease recurrence (risk=0.72; 95% CI 0.60-0.88; exact significance (two-sided) P=0.035). CONCLUSIONS: Our study shows higher recurrence rates of CD after first TSS than previously reported. Second TSS leads an additional 8% of the patients to long-term CD remission.

[Modern surgery of meningiomas affecting anterior visual pathways]. / Moderne Meningeomchirurgie im Bereich der vorderen Sehbahn.

Meningiomas are the most common form of primary intracranial tumors. If the anterior visual pathways are affected clinical visual compromise, visual field defects, oculomotor nerve disturbances or propotosis are predominant. Meningiomas of the anterior visual pathway remain therapeutically challenging due to the direct anatomical relationship to the circulus arteriosus cerebri, the cavernous sinus and cranial nerves. The therapy of choice is microsurgical resection. In many cases a curative approach can be achieved with modern surgical techniques and simultaneously maintaining patient quality of life. Problematic are cases in which resection would be associated with the risk of clinical impairment and in these cases radiotherapy is an important therapeutic option. In cases involving complex invasiveness an interdisciplinary treatment to control local clinical symptoms is favored.

[Meningiomas. Clinical case examples]. / Meningeome. Klinische Beispiele.

Using four case reports as examples the best treatment is discussed by considering the specific history and magnetic resonance imaging (MRI) findings. In many cases different therapeutic alternatives are possible for treatment of meningiomas.

Pituicytoma in a patient with Cushing's disease: case report and review of the literature.

Pituicytoma is an exceptionally rare low-grade glioma (WHO grade I) of the neurohypophysis and infundibulum. We are reporting the case of a 48-year-old man who presented with severe Cushing's syndrome. Endocrinological evaluation unequivocally confirmed pituitary-dependent Cushing's syndrome (=Cushing's disease). Cranial MR-imaging displayed a conspicuous area in the dorsal and basal pituitary gland and a minimal bulging of the pituitary gland paramedian of the pituitary stalk on the right side. Transsphenoidal inspection revealed a small tumor in the basal and dorsal pituitary gland. Surprisingly, the definite postoperative histopathological diagnosis of the removed tumor was pituicytoma and not pituitary adenoma. Hence, the microadenoma responsible for Cushing's disease was not yet removed and persistent hypercortisolism necessitated transsphenoidal re-operation. During re-operation, hemihypophysectomy was performed on the right side. The non-tumorous specimen of the adeno-hypophysis showed signs of Crooke's hyalinization consistent with Cushing's disease. Undetectable postoperative ACTH- and cortisol levels provided clear evidence that the underlying ACTH-source was successfully removed during re-operation. Coincidence of pituicytoma and pituitary-dependent Cushing's disease has not previously been reported.

Executive functions recover earlier than episodic memory after microsurgical transsphenoidal resection of pituitary tumors in adult patients--a longitudinal study.

Pituitary tumors may lead to cognitive dysfunction, and the most prevalent deficits are impaired memory and attention. To investigate whether memory and executive functions improve after surgical treatment we performed a prospective longitudinal study comprising 106 patients with pituitary tumors. Psychometric evaluation was performed with the d2-Letter Cancellation test, the Trail Making test, the Digit Span test and the Intelligence Structure test-Verbal Memory test at three timepoints: preoperatively, and at 3 months and 12 months after surgery. The preoperative and postoperative maximum suprasellar tumor extension and hormone status was assessed in all participants. The main finding was that concentration, working memory, and attentional speed improved significantly within the first 3 months after surgery (p<0.05), while improvement of episodic memory was not observed until 12 months after surgery (p<0.001). In the patients harbouring non-functioning adenomas, prolactinomas or other sellar lesions, the most important factor promoting improvement of neurocognitive function was the removal of the suprasellar tumor extension.

Histone acetylation patterns of typical and atypical pituitary adenomas indicate epigenetic shift of these tumours.

Pituitary adenomas are benign endocrine tumours of the anterior pituitary that are subclassified as typical (conventional) or atypical adenomas, with uncertain prognosis based on histopathological features. Clarifying epigenetic alterations of pituitary tumours, as well as the mechanisms underlying them, will hopefully open new windows to treatment and the classification of these tumours and maybe even prediction of patient survival. In the present study, using immunohistochemistry, we investigated the acetylation pattern of histone 3 lysine 9 (H3K9), an epigenetic marker of active chromatin state and gene transcription, in typical and atypical pituitary adenomas and the normal pituitary. We observed a significant increase in H3K9 acetylation from the normal pituitary to typical and atypical pituitary adenomas, which was associated with significant hyperacetylation of H3K9 in atypical adenomas (P < 0.0001). MIB-1 (Ki-67) overexpression was also highly associated with increased acetylation of H3K9, correlating prositively with tumour severity (P < 0.0001). p53 overexpression had a contributing effect on altered global H3K9 acetylation of atypical pituitary adenomas (P < 0.05). These data suggests that H3K9 acetylation status might serve as a relevant additional biomarker of tumour severity in pituitary adenomas, and also as a proper target for epigenetic-based therapies.

Surgical technique and validation of outcome assessment in sagittal synostosis.

BACKGROUND: Aim of the study was to evaluate the outcome of children operated for sagittal synostosis, with special attention paid to the postoperative aesthetic result, as seen from the parents' and the treating medical doctors' perspective, and to assess the time point for operative correction. METHODS: A retrospective chart review of 87 patients operated over 15 years was performed. Data included age at the time of operation, perioperative complications, duration of hospital stay, intraoperative blood loss, transfusion volume, neurological outcome, and postoperative skull growth. Aesthetic outcome was assessed at 6, 12 and 18 months after surgery separately by the treating medical team and the children's parents. RESULTS: Sagittal synostosis was diagnosed in 98.9% of cases in the first six months of life. We performed the same operative technique in all children with bilateral total removal of parietal bones. The median age at operation was 5 months. There was no correlation between age at the time of operation and blood loss (p<0.602). 5.7% of the children presented with significant postoperative skull asymmetries. All of these children had undergone operation in the first four months of life (p<0.01). The evaluation of the postoperative aesthetic outcome as seen by parents and doctors was highly convergent, with 79.3% of children in the excellent or good outcome group CONCLUSIONS: Our results suggest that the feasible time period for the method used by us is around the 5th - 6th month of life, with satisfying results. With regard to the aesthetic outcome assessment we recommend our approach using validation by parents as a valuable new principle.

Benign meningioma developing late lung metastases: case report and review of the literature.

Here we report the case of a 65-year-old female with a histologically benign parietal falcine meningioma who developed multiple lung metastases 15 years after tumor resection. The meningioma was initially incompletely resected due to invasion of the sagittal sinus. Since it was diagnosed as a benign meningothelial meningioma Grade I WHO, the residual tumor was followed with serial imaging without adjuvant treatment. The patient subsequently developed lung lesions later identified as metastases. The lung lesions were successfully removed surgically and histologically diagnosed as meningothelial meningioma Grade I WHO. A repeat brain MRI revealed the known residual meningioma with no signs of interval tumor growth, but did demonstrate occlusion of the sagittal sinus. In the further course, the residual meningioma was completely removed. A review of the literature revealed only 15 well-documented cases of benign meningiomas that metastasized in an interval of up to 12 years after primary tumor resection. This case illustrates that histologically benign meningiomas Grade I WHO with stable disease of the primary tumor have the potential to develop hematogenous metastases even after a long time interval.

Sellar neuroblastoma mimicking a pituitary tumour: case report and review of the literature.

Neuroblastomas of the sellar region are exceedingly rare. Only 2 cases have previously been reported. Management of these tumours depends on the tumour's primary site, the patient's age and histopathological features. We are reporting the case of a 43-year-old woman who developed progressive bitemporal hemianopsia and visual loss, accompanied by amenorrhea and hyponatremia. Laboratory findings revealed a slightly elevated prolactin level. Cranial MR-imaging displayed an intrasellar and suprasellar lesion with a maximum diameter of 2.5 cm that was suspicious for a pituitary adenoma or tuberculum sellae meningioma. The tumour was approached via a pterional trepanation. Intraoperatively, the tumour was highly vascularized and adhesive to the optic chiasm, the floor of the third ventricle, the hypothalamus and the hypophyseal stalk. Postoperatively, vision improved and prolactin dropped to normal values, but hyponatremia persisted. Histopathological examination revealed a neuroblastoma with strong positivity for synaptophysin and chromogranin, MAP-2 protein and NeuN-antigen in the immunohistochemistry. No pituitary hormone receptors were expressed. The MIB-1 labelling index was positive in 5% of the cell nucleoli. In the further course, the patient underwent radiotherapy of the neuroaxis. A brief review of the literature is presented.

Meningitis as a presentation of macroprolactinoma.

BACKGROUND: Cerebrospinal fluid (CSF) rhinorrhea and consecutive meningitis are well recognised clinical features of macroprolactinomas invading the skull base and are mainly observed under a dopamine-agonist therapy regimen. To our knowledge, a clinical case of primary meningitis due to an untreated macroprolactinoma, without any history of rhinorrhea, has not been reported previously in the English literature. CASE REPORT: A 64-year-old patient presented with acute meningitis. He had no prior episode of CSF rhinorrhea. Neuroradiological imaging revealed a pituitary tumour with invasion and destruction of the skull base. Massive hyperprolactinaemia was proof of a prolactinoma. The patient underwent transsphenoidal adenomectomy. The skull base defect was sealed with a fascia lata graft. In the postoperative course, no further episode of meningitis and no CSF rhinorrhea occurred. The invasive residual tumour was successfully treated with cabergoline. CONCLUSION: Macroprolactinomas can present with meningitis without any prior history of CSF rhinorrhea. Surgical repair of the skull base defect is the treatment of choice in order to prevent further episodes of meningitis. Pituitary tumours should be considered as a cause of otherwise unexplained meningitis.

No evidence for WT1 involvement in a beta-catenin-independent activation of the Wnt signaling pathway in pituitary adenomas.

The overexpression of Wilms' tumor gene product WT1, which acts as a tumor suppressor or oncogene, has been reported in various malignancies. Recent studies have shown that the interaction partner Wnt-4 is upregulated in pituitary adenomas dependent on the Pit-1 lineage (somatotrophs, lactotrophs, and thyrotrophs). However, no data on WT1 expression in nontumorous pituitary tissue or pituitary adenomas is available to date. We investigated WT1 expression in 90 paraffin-embedded pituitary adenomas, including eight atypical adenomas, and in 28 nontumorous pituitary glands by immunohistochemistry. WT1 is absent in epithelial cells of all nontumorous pituitary glands and in 87 out of 90 pituitary adenomas. Only two GHomas (including one atypical adenoma) and one gonadotropin-producing adenoma expressed WT1 in the cytoplasm of single tumor cells without nuclear staining. There is no evidence that WT1 does regulate the Wnt-4/beta-catenin-independent pathway which is activated in the Pit-1-expressing subset of pituitary adenomas.

Quantitative assessment of postoperative blood collection in brain tumor surgery under valproate medication.

BACKGROUND: The aim of the study was to evaluate whether valproate (VPA) increases the risk of bleeding complications in patients undergoing brain tumor surgery. METHODS: A retrospective chart review of 85 patients operated on between January and December 2005 was performed. 19 patients received VPA, 22 patients were given other anti-epileptic drugs (AEDs), 44 patients received no AEDs. Data analyzed included intraoperative blood loss, transfusion, important comorbidity factors and concomitant diseases. Preoperative and postoperative laboratory data included hemoglobin, hematocrit, fibrinogen, platelet count, INR, prothrombin time, partial thromboplastin time and RBC count. The tumor volume was evaluated by preoperative MRI and CT scans of the brain. All 85 patients underwent a native CT scan of the brain on the first day after the operation. The volume of the resection cavity and the volume of blood were documented. RESULTS: We could show that the volume of the tumor had a significant effect on the amount of blood in the tumor cavity, whereas VPA medication had no effect. CONCLUSIONS: In our dataset, we found that tumor size had a significant effect on postoperative blood volume. In contrast, no serious bleeding complications occurred in the patients receiving VPA. Therefore, the present study does not provide any evidence for the need to discontinue VPA medication prior to and during surgery.

Tuberculum sellae meningioma symptomatic during pregnancy: pathophysiological considerations.

A 31 year old woman in her second pregnancy presented in the 31st (+4) week of gestation with progressive visual impairment of the right eye. Magnetic resonance imaging (MRI) demonstrated a tuberculum sellae meningioma that was displaced upward by a markedly enlarged pituitary gland. Neuro-ophthalmological follow-up examinations showed a progressive decrease of visual acuity and right temporal field loss. Therefore, a caesarean section was performed in the 34th (+8) week. The meningioma was removed three days after childbirth via a right-sided pterional approach. Post-operatively, visual function was completely restored. Immunohistochemical examination showed positive staining for progesterone receptors (PR) in approximately 50% of tumour cells. Enlargement of the pituitary gland during late pregnancy in conjunction with a preexisting tuberculum sellae meningioma is the most likely pathophysiological factor responsible for visual loss. Enlargement of the PR-positive meningioma in the hormonal milieu of pregnancy might have contributed additionally to visual loss.