Pituitary society expert Delphi consensus: operative workflow in endoscopic transsphenoidal pituitary adenoma resection.

PURPOSE: Surgical workflow analysis seeks to systematically break down operations into hierarchal components. It facilitates education, training, and understanding of surgical variations. There are known educational demands and variations in surgical practice in endoscopic transsphenoidal approaches to pituitary adenomas. Through an iterative consensus process, we generated a surgical workflow reflective of contemporary surgical practice. METHODS: A mixed-methods consensus process composed of a literature review and iterative Delphi surveys was carried out within the Pituitary Society. Each round of the survey was repeated until data saturation and > 90% consensus was reached. RESULTS: There was a 100% response rate and no attrition across both Delphi rounds. Eighteen international expert panel members participated. An extensive workflow of 4 phases (nasal, sphenoid, sellar and closure) and 40 steps, with associated technical errors and adverse events, were agreed upon by 100% of panel members across rounds. Both core and case-specific or surgeon-specific variations in operative steps were captured. CONCLUSIONS: Through an international expert panel consensus, a workflow for the performance of endoscopic transsphenoidal pituitary adenoma resection has been generated. This workflow captures a wide range of contemporary operative practice. The agreed "core" steps will serve as a foundation for education, training, assessment and technological development (e.g. models and simulators). The "optional" steps highlight areas of heterogeneity of practice that will benefit from further research (e.g. methods of skull base repair). Further adjustments could be made to increase applicability around the world.

Pituitary society guidance: pituitary disease management and patient care recommendations during the COVID-19 pandemic-an international perspective.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain that has caused the coronavirus disease 2019 (COVID-19) pandemic, has presented healthcare systems around the world with an unprecedented challenge. In locations with significant rates of viral transmission, social distancing measures and enforced 'lockdowns' are the new 'norm' as governments try to prevent healthcare services from being overwhelmed. However, with these measures have come important challenges for the delivery of existing services for other diseases and conditions. The clinical care of patients with pituitary disorders typically involves a multidisciplinary team, working in concert to deliver timely, often complex, disease investigation and management, including pituitary surgery. COVID-19 has brought about major disruption to such services, limiting access to care and opportunities for testing (both laboratory and radiological), and dramatically reducing the ability to safely undertake transsphenoidal surgery. In the absence of clinical trials to guide management of patients with pituitary disease during the COVID-19 pandemic, herein the Professional Education Committee of the Pituitary Society proposes guidance for continued safe management and care of this population.

Pituitary pathology in traumatic brain injury: a review.

PURPOSE: Traumatic brain injury most commonly affects young adults under the age of 35 and frequently results in reduced quality of life, disability, and death. In long-term survivors, hypopituitarism is a common complication. RESULTS: Pituitary dysfunction occurs in approximately 20-40% of patients diagnosed with moderate and severe traumatic brain injury giving rise to growth hormone deficiency, hypogonadism, hypothyroidism, hypocortisolism, and central diabetes insipidus. Varying degrees of hypopituitarism have been identified in patients during both the acute and chronic phase. Anterior pituitary hormone deficiency has been shown to cause morbidity and increase mortality in TBI patients, already encumbered by other complications. Hypopituitarism after childhood traumatic brain injury may cause treatable morbidity in those survivors. Prospective studies indicate that the incidence rate of hypopituitarism may be ten-fold higher than assumed; factors altering reports include case definition, geographic location, variable hospital coding, and lost notes. While the precise pathophysiology of post traumatic hypopituitarism has not yet been elucidated, it has been hypothesized that, apart from the primary mechanical event, secondary insults such as hypotension, hypoxia, increased intracranial pressure, as well as changes in cerebral flow and metabolism may contribute to hypothalamic-pituitary damage. A number of mechanisms have been proposed to clarify the causes of primary mechanical events giving rise to ischemic adenohypophysial infarction and the ensuing development of hypopituitarism. CONCLUSION: Future research should focus more on experimental and clinical studies to elucidate the exact mechanisms behind post-traumatic pituitary damage. The use of preventive medical measures to limit possible damage in the pituitary gland and hypothalamic pituitary axis in order to maintain or re-establish near normal physiologic functions are crucial to minimize the effects of TBI.

Physicians' awareness of gadolinium retention and MRI timing practices in the longitudinal management of pituitary tumors: a "Pituitary Society" survey.

PURPOSE: In view of mounting attention related to possible brain retention of gadolinium-based contrast agents (GBCAs) in patients with normal renal function, our purpose was to detail results from a survey of pituitary experts to assess: 1) the timing interval and frequency of pituitary magnetic resonance imaging (MRI) following surgical and/or medical and/or radiation therapy of pituitary tumors, 2) awareness of the types of GBCAs used and their possible safety issues. METHODS: The Pituitary Society Education Committee composed a survey with 12 multiple choice questions, 8 of which specifically addressed the time interval and frequency of MRI in the longitudinal management of pituitary tumors. The survey was distributed at two meetings; the International Pituitary Neurosurgeons Society conference in San Diego, CA, on February 18th, 2018, and the Pituitary Society Membership and Career Development Forum, Chicago, IL on March 18th, 2018. RESULTS: There is consensus among pituitary endocrinologists and neurosurgeons that long-term repeated imaging is recommended in most pituitary tumors, although the precise strategy of timing varied depending on the specialist group and the specific clinical context of the adenoma. The data also suggest that International Pituitary Neurosurgeons Society neurosurgeons, as well as Pituitary Society neuroendocrinologists, are sometimes unaware of which contrast agents are used by their institution, and many are also unaware that evidence of long-term brain retention has been reported with the use of GBCAs in patients with normal function. CONCLUSIONS: International pituitary endocrinologists and pituitary neurosurgeons experts suggest ongoing MRIs for the management of pituitary tumors; strategies vary based on clinical context, but also on individual experience and practice.

Pathology of GH-producing pituitary adenomas and GH cell hyperplasia of the pituitary.

INTRODUCTION: Histologic, immunohistochemical and electron microscopic studies have provided conclusive evidence that a marked diversity exists between tumors which secrete growth hormone (GH) in excess. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH-releasing hormone secreting tumors or in familial pituitary tumor syndromes. MATERIALS AND METHODS: A literature search was performed for information regarding pathology, GH-producing tumors and acromegaly. RESULTS: This review summarizes the current knowledge on the morphology of GH-producing and silent GH adenomas, as well as GH hyperplasia of the pituitary. CONCLUSION: The importance of morphologic classification and identification of different subgroups of patients with GH-producing adenomas and their impact on clinical management is discussed.

Arginine vasopressin (AVP): a review of its historical perspectives, current research and multifunctional role in the hypothalamo-hypophysial system.

INTRODUCTION: This publication reviews the function of arginine vasopressin and focuses on the morphologic and functional correlation between the hormone and its effect on stress, the hypophysial-adrenocortical axis, neuroimmune responses, renal function and corticotroph pituitary tumors. MATERIALS AND METHODS: A literature review was performed using various search engines for information regarding the morphology and the multifunctional role of arginine vasopressin. RESULTS: Although a large number of studies were published discussing these interactions, there are several important areas that are still obscure. CONCLUSION: The questions of how does arginine vasopressin affect the morphology and function of these various areas, and how does the secretion of ACTH and adrenocortical hormones influence the morphology of arginine vasopressin-producing cells and their hormone secretion requires further investigation.

Current status on histological classification in Cushing's disease.

INTRODUCTION: Managing Cushing's disease remains a challenge. Surgery is the first option of treatment and it offers a high success rate. Even in cases where biochemical remission is not achieved, it is crucial to obtain surgical tissue for morphological diagnosis because the therapeutic approach can be modified according to the findings. MATERIALS AND METHODS: A literature search was performed using PubMed for information regarding pathology and Cushing's disease. RESULTS: The histopathological features found in the pituitary gland of patients with Cushing's disease are presented. CONCLUSION: Different subtypes of ACTH-producing pituitary tumors are recognized and characterized. The significance of finding a normal pituitary gland with or without Crooke's changes is also discussed.

STRESS IN THE CLASSIFICATION OF PITUITARY TUMORS. FOCUS ON AGGRESSIVE PITUITARY ADENOMAS.

After a brief summary of the stress concept and the contribution of Dr. Hans Selye, this publication focuses on the classification of pituitary neoplasms and the difficulties to provide conclusive information on the prognosis of various pituitary tumor types. The term "aggressive pituitary tumors" was introduced. These tumors have a rapid cell proliferation rate. At present, the assessment of Ki-67 nuclear labeling index appears to be the simplest and most reliable method to evaluate tumor cell multiplication. Further studies on pituitary tumor biomarkers are needed.

Pituitary stem cells: candidates and implications.

The pituitary is the master endocrine gland of the body. It undergoes many changes after birth, and these changes may be mediated by the differentiation of pituitary stem cells. Stem cells in any tissue source must display (1) pluripotent capacity, (2) capacity for indefinite self-renewal, and (3) a lack of specialization. Unlike neural stem cells identified in the hippocampus and subventricular zone, pituitary stem cells are not associated with one specific cell type. There are many major candidates that are thought to be potential pituitary stem cell sources. This article reviews the evidence for each of the major cell types and discuss the implications of identifying a definitive pituitary stem cell type.

Melanoma of the sellar region mimicking pituitary adenoma.

We report here the case of an 82-year-old woman who presented with visual disturbance. MRI demonstrated a sellar mass. The diagnosis of pituitary adenoma was made. She underwent transnasal surgery. Histologic, immunohistochemical and ultrastructural studies indicated that the tumor was a melanoma. Despite an exhaustive search for a primary lesion elsewhere, none was found. The sellar tumor was considered a primary lesion, although extrasellar primary tumor imaging cannot be excluded with 100% certainty. Reported examples of melanoma affecting the sellar region are few. They exhibit morphologic features identical to those of melanomas arising elsewhere. Although very rare, primary melanomas enter into the differential diagnosis of sellar lesions.

Pituitary immunoexpression of ghrelin in anorexia nervosa.

Ghrelin, an orexigenic hormone, is known to occur in the normal anterior pituitary where its physiologic role is uncertain but may include promotion of appetite. We sought to investigate anticipated differences in adenohypophysial and neurohypophysial ghrelin immunoexpression between normal subjects and patients with anorexia nervosa who had succumbed to complications of the disease. We hypothesized that the glands of anorexia nervosa patients would show relative diminished action in ghrelin content. The study included 12 autopsy-derived pituitaries of anorexia nervosa and 10 control glands. The streptavidin-biotin-peroxidase complex method and double immunohistochemical staining method were used to determine which cell types expressed both ghrelin and adenohypophysial hormones. Nontumorous control pituitaries were also obtained at autopsy. In anorexia nervosa and control adenohypophyses, ghrelin was mainly localized in somatotrophs and to a lesser extent in corticotrophs and gonadotrophs. Ghrelin accumulated within nerve fibers and Herring bodies in the neurohypophysis and pituitary stalk. In the controls, ghrelin expression was apparent in only a few cases. It was mild and only along few nerve fibers. In the adenohypophyses of anorexia nervosa patients, ghrelin was not depleted. It appears that in these patients, ghrelin is transported in excess from the hypothalamic neurohypophysial tract to the neurohypophysis.

Anti-VEGF therapy in pituitary carcinoma.

We report the case of a 44-year-old male patient with an aggressive silent corticotroph cell pituitary adenoma, subtype 2. In that it progressed to carcinoma despite temozolomide administration, anti-VEGF therapy was begun. MRI, PET scan and pathologic analysis were undertaken. After 10 months of anti-VEGF (bevacizumab) treatment no progression of the lesion was noted. The tumor was biopsied and morphological analysis showed severe cell injury, vascular abnormalities and fibrosis. Bevacizumab treatment has continued for additional 16 months to present with stabilization of disease as documented on serial MRI and PET scans. This is the first case of a bevacizumab-treated pituitary carcinoma with long-term, now 26 months, control of disease. The present findings are promising in that anti-angiogenic therapy appears to represent a new option in the treatment of aggressive pituitary tumors.

Somatotroph pituitary adenoma with acromegaly and autosomal dominant polycystic kidney disease: SSTR5 polymorphism and PKD1 mutation.

A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0-5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48-255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Pathologic, cytogenetic, molecular and in silico analysis was undertaken. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.142C>A (p.L48M, rs4988483) in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subjected to extensive morphological, ultrastructural, cytogenetic and molecular studies. The physical proximity of the PKD1 and SSTR5 genes on chromosome 16 suggests a causal relationship between ADPKD and somatotroph adenoma.

Clinical Biology of the Pituitary Adenoma.

All endocrine glands are susceptible to neoplastic growth, yet the health consequences of these neoplasms differ between endocrine tissues. Pituitary neoplasms are highly prevalent and overwhelmingly benign, exhibiting a spectrum of diverse behaviors and impact on health. To understand the clinical biology of these common yet often innocuous neoplasms, we review pituitary physiology and adenoma epidemiology, pathophysiology, behavior, and clinical consequences. The anterior pituitary develops in response to a range of complex brain signals integrating with intrinsic ectodermal cell transcriptional events that together determine gland growth, cell type differentiation, and hormonal production, in turn maintaining optimal endocrine health. Pituitary adenomas occur in 10% of the population; however, the overwhelming majority remain harmless during life. Triggered by somatic or germline mutations, disease-causing adenomas manifest pathogenic mechanisms that disrupt intrapituitary signaling to promote benign cell proliferation associated with chromosomal instability. Cellular senescence acts as a mechanistic buffer protecting against malignant transformation, an extremely rare event. It is estimated that fewer than one-thousandth of all pituitary adenomas cause clinically significant disease. Adenomas variably and adversely affect morbidity and mortality depending on cell type, hormone secretory activity, and growth behavior. For most clinically apparent adenomas, multimodal therapy controlling hormone secretion and adenoma growth lead to improved quality of life and normalized mortality. The clinical biology of pituitary adenomas, and particularly their benign nature, stands in marked contrast to other tumors of the endocrine system, such as thyroid and neuroendocrine tumors.

Ghrelin immunoexpression in pituitary adenomas.

Ghrelin, an orexigenic hormone, is normally produced mainly in stomach. In addition, it has been demonstrated in gastric carcinoid tumors and less often in other neuroendocrine tumors. We investigated ghrelin expression by immunohistochemistry (streptavidin-biotin-peroxidase complex method) in the full spectrum of resected pituitary adenoma subtypes. Quantification of staining considered both the frequency of ghrelin-reactive tumor cells as well as their staining intensity. Cytoplasmic ghrelin immunopositivity was identified in several adenoma subtypes. Cellular staining varied considerably. In addition, the intensity of cell staining differed within the same tumor and between adenoma subtypes. The highest scores were noted in GH producing adenomas exposed to long-acting somatostatin analogs. In decreasing order, lower scores were encountered in ACTH adenomas in Cushing disease, silent subtype 3 adenomas, untreated GH adenomas, silent corticotroph adenomas of subtypes 1 and 2, dopamine agonist-treated PRL adenomas, ACTH adenomas in Nelson syndrome, and gonadotroph adenomas. No significant immunoreactivity was noted in TSH, untreated PRL, and null cell adenomas. The high immunoexpression of ghrelin in GH adenomas exposed to long-acting somatostatin analogs remains unexplained, but may be due to either increased ghrelin production or to suppression of its release. Based on our findings, it appears that ghrelin immunopositivity does not serve as a biomarker of biologic behavior, prognosis and therapeutic responsiveness in pituitary adenomas.

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

MGMT immunoexpression in aggressive pituitary adenoma and carcinoma.

Recent case reports have documented the efficacy of temozolomide therapy in some aggressive pituitary adenomas and pituitary carcinomas resistant to multimodality therapy. Evidence suggests that low O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression correlates with response to temozolomide chemotherapy. Herein, we aimed to study MGMT immunoexpression in a spectrum of pituitary tumors, indolent, aggressive and malignant. A literature review of the use of temozolomide in pituitary tumors was also performed. Immunohistochemistry for MGMT was performed on 60 pituitary tumors identified in the Mayo Clinic Tissue Registry and the consultation files of one of us (BWS). The group included 30 pituitary carcinomas (15 ACTH, 10 PRL, 1 FSH/LH, 1 TSH, 1 silent subtype 3 and 2 null cell). Tissue from recurrences was available in 17 cases. In addition, 30 functionally different pituitary adenomas were studied, including 15 invasive and 15 non-invasive adenomas. Overall, 32 cases of pituitary tumors (54%) demonstrated low MGMT immunoexpression. This included 17 of 30 (57%) carcinomas, 9 of 15 (60%) invasive adenomas, and 6 of 15 cases (40%) of non-invasive pituitary adenomas. There was no significant change in MGMT immunoexpression between primary and recurrent tumors. Prolactin-producing carcinomas had the highest proportion of tumors (80%) with low expression. A significant proportion of pituitary adenomas and carcinomas demonstrate low MGMT immunoexpression. In an effort to anticipate the likelihood of a temozolomide response, all cases of aggressive pituitary tumors should be assessed for MGMT expression.

Collision tumors of the sella: craniopharyngioma and silent pituitary adenoma subtype 3: case report.

Collision tumors of the sella turcica are rare and consist mainly of more than one type of pituitary adenoma, usually a corticotropin- and a prolactin-producing adenoma. The association of a craniopharyngioma and a pituitary adenoma is rare. Herein, we report the first case of an association between craniopharyngioma and silent pituitary adenoma subtype 3. It involved a 12-year-old boy who underwent a frontal craniotomy with surgical removal of a calcified sellar tumor. Histology revealed an adamantinomatous craniopharyngioma; however, by electron microscopy, there was conclusive evidence of adenoma cells showing the ultrastructural features of silent pituitary adenoma subtype 3. Endocrine and neuroimaging as well as detailed immunohistochemical and ultrastructural studies were undertaken. The literature is also reviewed.

Pituitary adenoma with peliosis: a report of two cases.

Peliosis is characterised by multiple blood-filled lakes or cavities within parenchymatous organs. Typically found in the liver, spleen, bone marrow and lymph nodes, it has also been described in other organs such as lungs, kidneys, parathyroids and pancreas. The mechanism responsible for the development of peliosis remains unknown. (1) A 69 year-old man with a 6-year history of acromegaly underwent transsphenoidal surgery for pituitary adenoma. Morphologic findings demonstrated a plurimorphous plurihormonal pituitary adenoma consisting of somatotrophs, lactotrophs and mammosomatotrophs. The tumor contained several blood-filled cavities characteristic of peliosis. (2) A 61-year-old man with a prolactin-producing pituitary adenoma who underwent transsphenoidal surgery. In the tumor, peliosis was noted. Peliosis in a pituitary adenoma is an intriguing finding. The question arises whether it represents vasculogenic mimicry.

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.