Recurrent Pituitary Tumors Research Articles

Elevated Expression of Programmed Death Ligand1 in Human Pituitary Tumors

Pituitary tumors are the third most common intracranial neoplasms. Treatment for pituitary tumors involves surgery, radiation therapy, hormone regulation and chemotherapy. However, it remains challenging to treat pituitary tumors that are recurrent, aggressive, or resistant to conventional treatments. Over the last several years, checkpoint blockade immunotherapy approaches targeting the PD-1/PD-L1 axis have shown tremendous promise in treating a range of malignancies, and durable objective responses have been observed in these settings. The Programmed death ligand 1 (PD-L1, also known as B7-H1 and CD274) plays a major role in suppressing T cell responses in the immune system but has also emerged as a key biomarker whose expression predicts favorable responses to anti-PD-1/PD-L1 therapies. . We therefore explored the possibility that PD-L1 was overexpressed in pituitary tumors and potentially represent a biomarker for patients with particularly refractory tumors who may be suitable candidates for immunotherapeutic approaches. To determine the PD-L1 mediated tumor immune status of pituitary tumors and its correlation with tumor classification, PD-L1 expression in ninety-two pituitary tumors were evaluated by RNAscope in situ hybridization and immunohistochemistry for RNA and protein levels, respectively. Both PD-L1 RNA and protein expression were significantly increased in non-functioning and functioning pituitary tumors, especially in hGH- secreting tumors, compared with normal pituitary tisssue. PD-L1 level was observed in both slowly and actively-dividing tumors, with high expression in tumors MIB less than 3 and over 3. In addition to its enhanced expression in typical pituitary tumors, PD-L1 was also dramatically increased in the atypical type which is more aggressive and invasive. Moreover, PD-L1 was not only expressed highly in primary tumors but also increased significantly in recurrent pituitary tumors. Together, these findings demonstrated significantly elevated PD-L1 expression in a broad range of human pituitary tumors irrespective of tumor hormone secretion, mitosis, aggressiveness level, or recurrence status. These data therefore raise the possibility that patients with high pituitary PD-L1 expression may represent candidates for anti-PD-1/PD-L1 therapy in surgically-refractory settings.

Endoscopic endonasal surgery for recurrent pituitary tumors: technical challenges to the surgical approach.

Objective To review our experience in a series of patients who underwent revision endoscopic pituitary surgery. Methods Retrospective chart review. Results A total of 27 patients were included in the study. Of the 21 patients who required nasoseptal flap reconstruction, a left-sided nasoseptal flap was successfully used in 13 patients. Gross total or near-total resection of tumor was achieved in 74.1%. Cavernous sinus invasion and presentation with residual disease were identified as factors limiting extent of resection (p = 0.002 and 0.009, respectively). A statistically significant difference (p = 0.027) was noted between mean largest tumor dimension in patients with gross total resection and those with near-total or subtotal resection. Complications occurred in 22% and included postoperative temporary diabetes insipidus (n = 2), postoperative hypotension (n = 2), new anterior pituitary insufficiency (n = 1), and right-sided abducens palsy (n = 1). Conclusions Revision endoscopic pituitary surgery is advantageous but technically challenging. Cavernous sinus invasion and presentation with residual disease were significant factors limiting extent of resection. Suprasellar extension was not a factor limiting extent of resection and may prove to be an advantage over microscopic speculum-based approaches. Because of the right-sided scarring from prior surgery, a left-sided nasoseptal flap is reliable and advantageous.

Management of aggressive pituitary adenomas and pituitary carcinomas

Pituitary tumors are benign but not uncommonly invade locally into adjacent tissues such as the cavernous sinus and dura. Some of these invasive tumors exhibit varying degrees of resistance to standard therapy and tend to recur. Early prediction of which pituitary tumors will recur and/or exhibit an invasive phenotype remains difficult despite introduction of several tissue-based molecular markers. Management of these recurrent invasive pituitary tumors usually comprises combination medical, surgical and radiation therapy but in some instances is suboptimal. Earlier diagnosis of invasive/recurrent pituitary tumor and application of aggressive multi-modal therapy at presentation may be advantageous in some cases. Clinical trials to develop additional therapeutic options are needed for this subgroup of pituitary tumors. Although it is not yet possible to diagnose at presentation, the subset of pituitary tumors that will become invasive and/or recurrent pituitary tumors, broader use of molecular markers and standardization of histopathological criteria for "atypical" pituitary tumor features have assisted earlier diagnosis. Aggressive therapy early in disease may be warranted and exploration of recently available targeted therapies may improve disease management.

Radioterapia nos tumores da hipófise – atualizações e controvérsias

IntroductionRadiotherapy is an effective treatment for residual or recurrent pituitary tumors with tumor volume control and decrease or normalization of excess hormone secretion in the clinically functioning adenomas. The risks of long-term toxicity, being the hypopituitarism the most frequent, make radiation therapy a rarely used second-line treatment. ObjectivesTo describe efficacy, safety and role of conventional external beam radiotherapy, as well as radiosurgery in the treatment of pituitary tumors. Material and MethodsSearch of original or review papers published until January 2012 with the following keywords“pituitary radiotherapy”, “radiotherapy for pituitary adenomas”, “stereotactic radiotherapy”, “pituitary radiosurgery”, “radiation therapy”, “radiotherapy for Cushing's Disease”, “radiotherapy for acromegaly”, “radiotherapy for non-functioning pituitary adenomas”, “radiotherapy for prolactin-secreting pituitary tumors”. ConclusionsRadiotherapy still has a complementary role to surgical resection, although it could be appropriate as a first-line treatment in selected cases. The new modalities of radiation treatment show promising results in the reduction of toxicity as well as in the latency of hormonal response; however more studies are necessary to prove long-term efficacy and safety.

Recurrent pituitary tumor: the importance of a functional classification at diagnosis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Treatment of Aggressive Pituitary Adenomas and Carcinomas—An Overview

Most pituitary tumors are non-invasive, benign adenomas that remain confined to the sella turcica. Some of them recur, have a rapid growth rate, and invade surrounding tissues. These adenomas, considered aggressive pituitary tumors, are difficult to manage and present problems due to incomplete resection. A pituitary carcinoma is diagnosed when craniospinal and/or systemic metastases are documented. Treatment options for pituitary adenomas are surgery, radiation, and drugs. Recent publications report the efficacy of temozolomide in the treatment of aggressive pituitary adenomas and carcinomas. Indications for, results with, and side effects of temozolomide therapy in aggressive pituitary tumors and pituitary carcinomas are reviewed here. Alternative treatment options for resistant or recurrent pituitary tumors are also discussed.

Treatment of Aggressive Pituitary Adenomas and Carcinomas – An Overview

Most pituitary tumours are non-invasive, benign adenomas that remain confined to the sella turcica. Some of them recur, have a rapid growth rate, and invade surrounding tissues. These adenomas, considered aggressive pituitary tumours, are difficult to manage and present problems due to incomplete resection. A pituitary carcinoma is diagnosed when craniospinal and/or systemic metastases are documented. Treatment options for pituitary adenomas are surgery, radiation and drugs. Recent publications report the efficacy of temozolomide in the treatment of aggressive pituitary adenomas and carcinomas. Indications for, results with, and side effects of temozolomide therapy in aggressive pituitary tumours and pituitary carcinomas are reviewed here. Alternative treatment options for resistant or recurrent pituitary tumours are also discussed.

Endoscopic Endonasal Surgery in Recurrent and Residual Pituitary Adenomas after Microscopic Resection

Background Despite the increasing interest in endoscopic techniques for pituitary surgery, little has been published on the endoscopic approach for recurrent and/or residual pituitary adenomas. We report the outcome of purely endoscopic endonasal surgery for a series of recurrent and/or residual pituitary tumors after a previous microscopic resection. Methods We reviewed all of the patients in our institution who underwent endoscopic resection for recurrent and/or residual pituitary tumors after previous microscopic resection. All patients had clinical and magnetic resonance imaging follow-up of at least 3 months postoperatively. Careful attention was given to the operative reports documenting the degree of previous microscopic exposure. Our results were compared with published reports of surgery for recurrent and residual pituitary tumors. Results Thirty-nine patients met our inclusion criteria. The mean follow-up was 21 months. Tumors were comprised of 19 nonfunctional, 10 adrenocorticotropic hormone, 9 growth hormone, and 1 prolactin-secreting adenoma. The endoscopic procedure revealed limited previous exposure of the sphenoidal and sellar structures in 30 cases (76%). Sphenoidotomy and sellar opening, in terms of working area and angle of view, were significantly restricted in 64% and 61% of the cases, respectively. Gross total removal was achieved in 46% of cases. Seventeen patients had frank cavernous sinus invasion. Conclusions The restricted exposure of sphenoidal and sellar structures by the microscopic approach may be a contributing factor to incomplete tumor resection. The results observed in this setting make the endoscopic technique a valid option in recurrent and residual pituitary adenomas treated initially by microscopic surgery.

Endoscopic Endonasal Surgery for Recurrent Pituitary Tumors: Technical Challenges to the Surgical Approach

Endoscopic Endonasal Surgery for Recurrent Pituitary Tumors: Technical Challenges to the Surgical Approach

Identification of somatostatin 5 receptor gene variants associated with recurrence of pituitary adenoma and other disease phenotypes in acromegaly patients

Pituitary tumors are characterized by increased expression of somatostatin receptor (SSTR) 2 and 5 subtypes that are acting as mediators of the somatostatin induced growth hormone inhibition. The aim of the study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of identified polymorphisms with acromegaly and different disease characteristics as well as responsiveness to somatostatin analogs. In total 20 SNPs were identified in SSTR5 gene coding region and 2000bp upstream region by direct sequencing. 3 SNPs (C633T, T1004C and G1044A) were significantly associated with presence of acromegaly comparing 48 patients with acromegaly and 96 controls. These SNPs were further analyzed in the same group of acromegaly patients and 475 age and sex matched controls. The allele frequencies was significantly (p<0.001) different between the acromegaly patients and control group for two SNPs. Haplotype reconstruction revealed two possible risk haplotypes determined by 633T and 1044A alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared to controls (P<0.001). In addition C633T was significantly associated with recurrent pituitary adenoma (higher number of adenoma resections) (P=0.0001), younger age at acromegaly diagnosis (P=0.002), increased BMI (P=0.004) and more aggressive adenoma proliferation in presence of somatostatin analogues therapy (P=0.014). We have thus identified the genetic variants of SSTR5 that may promote the pituitary adenoma development by low level suppression of tumor growth. These data suggest the important role of SSTR5 in the progression of acromegaly as well as possible identification of genetic markers that can be used to predict the recurrent pituitary tumors and potential choice of therapy.

Immunohistochemical detection of prothymosin alpha in pituitary adenomas--a new marker of tumor recurrence?

Forty pituitary adenomas were immunostained with an antibody raised against the C-terminal fragment (101-109) of human prothymosin alpha (PT alpha). The strong positive immunostaining was found in the subpopulation of cell nuclei and intratumoral vessel walls, while the cytoplasm of adenoma cells was slightly immunopositive. The significantly higher percentage of PT alpha-positive cell nuclei was found in recurrent pituitary adenomas as compared with primary tumors. However, there was no correlation between the percentage of PT alpha-positive cell nuclei and Ki-67 indices. Gonadotropinomas were characterized by higher nuclear PT alpha expression in comparison to other pituitary adenomas, which is probably linked with the high recurrence rate of these tumors. It is suggested that PT alpha immunostaining may be helpful in predicting the pituitary tumor recurrence. However, this conclusion needs to be confirmed in further prospective studies. Moreover, PT alpha may be also useful as an immunohistochemical marker of the intratumoral microvasculature.

Effect of Temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma

The patient was a 70-year-old man with a recurrent pituitary tumor. Three surgeries were performed but the tumor recurred. Based on histologic, immunohistochemical and ultrastructural studies, the diagnosis of oncocytic gonadotrophic pituitary adenoma was made. The tumor was a macroadenoma partly immunopositive for LH. Immunohistochemistry for O6 Methylguanine-DNA Methyl-Transferase (MGMT) showed an admixture of immunopositive and immunonegative cells. After recurrence following operations, the patient was treated with Temozolomide, an imidazotetrazine derivative, DNA-alkylating drug. Following Temozolomide administration the MRI demonstrated significant tumor necrosis. A few months later, the patient died of massive pulmonary embolism. No autopsy was performed. The present case indicates that benign, typically slow-growing pituitary adenomas of oncocytic gonadotrophic type may respond to Temozolomide even when the tumor consists of an admixture of MGMT immunopositive and immunonegative cells.

Pituitary tumors

Pituitary adenomas are the most common intrasellar tumors. With the exception of prolactinomas, first-line treatment is almost always surgical. Prolactinomas are usually treated with dopamine agonists such as cabergoline or bromocriptine. Somatostatin analogues, such as octreotide and lanreotide, can be adjunctive to surgical therapy in acromegaly, although they can be used as primary therapy in selected cases. Pegvisomant, a growth hormone receptor antagonist, is reserved for acromegalic patients who are resistant to treatment with somatostatin analogues. No effective medical therapy is available for adenomas that secrete adrenocorticotropic hormone, and occasionally bilateral adrenalectomy is required to resolve severe hypercortisolemia. Radiation therapy (fractionated or radiosurgery) can be used for residual or recurrent pituitary tumors. Asymptomatic, nonfunctioning pituitary adenomas may be followed without any intervention, but surgery is typically indicated if there are symptoms of mass effect on the optic chiasm or endocrine dysfunction. In the hands of an experienced pituitary neurosurgeon, the prognosis for endocrinologic recovery and visual improvement is good.

NOVALIS INTENSITY-MODULATED RADIOSURGERY

ABSTRACT OBJECTIVE The Novalis stereotactic radiotherapy system (BrainLAB, Heimstetten, Germany) allows for precise treatment of cranial base tumors with single-fraction radiosurgery. In some cases, however, proximity of the optic nerve and chiasm is a concern. In these cases, intensity-modulated stereotactic radiosurgery (IMRS) can be used to limit the dose to these structures. IMRS planning can be labor intensive, which poses a problem when it is performed on the day of treatment. We describe our methods and results of preprocedure planning for IMRS for patients with lesions in the cavernous sinus or parasellar regions in whom the dose to the optic nerve or chiasm might exceed our acceptable tolerance dose (8 Gy). METHODS Patients whose lesions were more than 4 mm from the optic nerve and chiasm on standard magnetic resonance imaging scans but who were questionable candidates for radiosurgery because of concerns of dose to the optic nerve or chiasm were considered for IMRS. Preprocedure imaging (computed tomography and magnetic resonance imaging) was fused and analyzed using the BrainLAB BrainScan 5.3 treatment planning system. Dynamic conformal arc plans for stereotactic radiosurgery and IMRS were evaluated. Doses to the planning target volume and optic apparatus were assessed by dose-volume histograms and conformality index calculated to characterize the quality of the different plans. When IMRS was used, the preplan allowed for a rapid recalculation on the treatment day, minimizing the time patients were in the head frame before treatment. RESULTS We describe three patients with recurrent pituitary tumors and three with meningiomas. Doses were 1500 to 2000 cGy prescribed to the 80 to 96% isodose line delivered by eight to 22 fields. Tumor volumes ranged from 2.70 to 8.82 cm3 (mean, 5.7 cm3). In five of the six patients, the dynamic conformal arc plan precluded delivery of therapeutic dose without exceeding optic nerve tolerance. On the basis of 95% coverage of target volume, maximum prescription doses of 7.7 to 20.64 Gy were possible with the dynamic conformal arc plans without exceeding 8 Gy to the optic apparatus. IMRS allowed maximum doses of 20 to 31 Gy using the same optic apparatus dose restriction. No complications have occurred, and all tumors have remained stable since treatment (mean follow-up period, 30 mo). CONCLUSION We believe this pretreatment technique streamlines the process for IMRS, allowing for better patient comfort and efficient physician time use.

Endoscopic Endonasal Transethmoidal Transcribriform Transfovea Ethmoidalis Approach to the Anterior Skull Base and Anterior Cranial Fossa

The endoscopic transethmoidal transcribriform approach is an alternative minimal access route to the anterior skull base. Traditional approaches require significant brain retraction, can be cosmetically disfiguring, and often require complex cranial base reconstruction and a high risk of cerebrospinal fluid (CSF) leak, meningitis, and skin necrosis. A purely endoscopic endonasal approach was used to treat pathology of the anterior skull base in a series of 24 patients. There were 12 encephalocoeles, 3 olfactory groove meningiomas, 2 esthesioneuroblastomas, 1 rhabdomyosarcoma, 1 malignant salivary tumor, 1 juvenile angiofibroma, 1 hemangiopericytoma, 1 osteoma, 1 recurrent pituitary tumor, and 1 papilloma. The dura and cribriform plate were reconstructed using a multilayer closure. Lumbar drains were placed intraoperatively in 9 cases. Eight patients required only a transethmoidal approach while 16 additionally required either a transcribriform or transfovea ethmoidalis approach. Of the tumors, gross total resection (GTR) was obtained in 7 patients and 98% resection in 5. Two patients had CSF leaks immediately after surgery which stopped with lumbar drainage. After a mean follow-up of 12.5 months, there was 1 recurrent CSF leak. There were no postoperative infections. A purely endoscopic endonasal transethmoidal transcribriform approach is a feasible alternative to craniofacial approaches to the anterior skull base. The risks of CSF leak and infection are low.

Image-Guided Endonasal Transsphenoidal Microsurgical Treatment of Recurrent Microadenomas of the Pituitary Gland

Neuronavigation is a commonly used technology that provides continuous, three-dimensional information for the precise localization of and surgical trajectory to brain lesions. This study was performed to evaluate the role that navigation can play in assisting microsurgical transsphenoidal surgery for precise localization and removal of recurrent pituitary tumours while simultaneously preserving pituitary gland function. During a 6-month period -- July 2004 until December 2004 -- 9 patients with recurrent pituitary tumours (5 female and 4-male) were treated with navigation-guided transsphenoidal microsurgical resection. Surgery was performed via a paraseptal or endonasal transsphenoidal approach. The navigation system Vector Vision (Brain Lab, Heimstetten, Germany) allowed precise localization of the tumours (7 hormonal active and 2 inactive microadenomas) in respect to the pituitary gland, the carotid arteries and the cavernous sinus. Postoperative MRI investigations of the 9 patients treated with image-guided transsphenoidal microsurgery, showed total tumour removal in 7 (77 %) patients and subtotal removal in 2 patients (23 %). One patient (11 %) developed a cerebral spinal fluid (CSF) leak and was treated conservatively. One patient (11 %) had preoperative insufficiency of the corticotrope axis which remained unchanged postoperatively. Of the remaining 8 patients who did not have preoperative endocrinological disturbance, only one (12 %) developed postoperative insufficiency of the corticotrope axis. Out of the 7 patients with hormone active tumours, 5 (72 %) patients showed no more postoperative hormonal activity. Microneurosurgical transsphenoidal techniques combined with image-guided systems can precisely define the localization and removal of lesions in the sella region with respect to the margins of important anatomical structures in the neighbourhood and the endocrinological functionality of the pituitary gland.

Treatment of Pituitary Tumors: Radiation

In this paper, the role of conventional radiotherapy and radiosurgery in the management of pituitary tumors is reviewed. After a short summary of the mechanism of action of irradiation therapy and the types of different irradiation techniques, the therapeutic effects and side effects are analyzed in patients with different types of pituitary tumors, including our own experience with conventional radiotherapy and radiosurgery in patients with acromegaly. Conventional fractionated radiotherapy has long been used to control growth and/or hormonal secretion of residual or recurrent pituitary tumors. However, patient selection for conventional radiotherapy still remains a controversial issue, because a number of potentially significant side effects, including hypopituitarism and other complications, have been described. Stereotactic radiotherapy/radiosurgery methods have several potential advantages over conventional radiotherapy, including their use in patients with residual or recurrent pituitary tumors who had previously been treated by conventional radiotherapy, but long-term follow-up data with these relatively new techniques are still limited.

Role of bifrontal basal interhemispheric approach in recurrent suprasellar tumors; craniopharyngioma and pituitary tumors

Recurrent suprasellar tumors, including craniopharyngiomas and pituitary tumors, can be approached with minimal brain retraction, a wider operative field with better orientation and a good view of important neurovascular structures via a bifrontal basal interhemispheric approach (BFBIHA). The authors present their experience of using BFBIHA for removal of recurrent suprasellar tumors, during which they recorded the size and location of each tumor and the degree of tumor extension. Two hundred fifty-four cases of pituitary tumors and 80 cases of craniopharyngiomas were operated on. Recurrent cases were 25 (9.8%) in pituitary tumors and 14 (17.5%) in craniopharyngiomas. Among recurrent cases, nine patients (five recurrent pituitary tumors, four recurrent craniopharyngiomas) were included. Preoperatively, suprasellar extension of the tumors was measured with the aid of radiological images (MRI, MRA, CT). Using line C (mid-sella), the tumors were divided into three groups according to the direction of tumor growth. Group I (one case) contained those with a prechiasmatic location, group II (two cases), those with a suprasellar location, and group III (five cases), those with a retrochiasmatic location. All of the recurrent patients underwent operations by the same approach. All tumors but one were totally resected. There was no operative mortality. In our experience, recurrent suprasellar tumors were safely manipulated with this BFBIHA, preserving important neurovascular structures and hypothalamo–pituitary functions.

Hypophysial transposition (hypophysopexy) for radiosurgical treatment of pituitary tumors involving the cavernous sinus

Stereotactic radiosurgery (SRS) is performed with increasing frequency in the treatment of residual or recurrent pituitary adenomas. Its major associated risk in these cases of residual or recurrent pituitary tumor adjacent to normal functional pituitary gland is radiation exposure to the pituitary, which frequently leads to the development of hypopituitarism. The authors describe a technique of pituitary transposition to reduce the radiation dose to the normal pituitary gland in cases of planned radiosurgical treatment of residual pituitary adenoma within the cavernous sinus. A sellar exploration for tumor resection is performed, the pituitary gland is transposed from the region of the cavernous sinus, and a fat and fascia graft is interposed between the normal pituitary gland and the residual tumor in the cavernous sinus. The residual tumor may then be treated with SRS. The increased distance between the normal pituitary gland and the residual tumor facilitates treatment of the tumor with radiosurgery and reduces radiation exposure to the normal pituitary gland.

Conventional Radiotherapy for Pituitary Tumors

Radiosurgery for pituitary adenomas is clearly attaining a more prominent position in the spectrum of management of these lesions. It is our belief that improvements in radiosurgical technology can significantly enhance the outcome for patients with these lesions.