This review focuses on discussing the main changes on the upcoming fourth edition of the WHO Classification of Tumors of the Pituitary Gland emphasizing histopathological and molecular genetics aspects of pituitary neuroendocrine (i.e., pituitary adenomas) and some of the non-neuroendocrine tumors involving the pituitary gland. Instead of a formal review, we introduced the highlights of the new WHO classification by answering select questions relevant to practising pathologists. The revised classification of pituitary adenomas, in addition to hormone immunohistochemistry, recognizes the role of other immunohistochemical markers including but not limited to pituitary transcription factors. Recognizing this novel approach, the fourth edition of the WHO classification has abandoned the concept of “a hormone-producing pituitary adenoma” and adopted a pituitary adenohypophyseal cell lineage designation of the adenomas with subsequent categorization of histological variants according to hormone content and specific histological and immunohistochemical features. This new classification does not require a routine ultrastructural examination of these tumors. The new definition of the Null cell adenoma requires the demonstration of immunonegativity for pituitary transcription factors and adenohypophyseal hormones Moreover, the term of atypical pituitary adenoma is no longer recommended. In addition to the accurate tumor subtyping, assessment of the tumor proliferative potential by mitotic count and Ki-67 index, and other clinical parameters such as tumor invasion, is strongly recommended in individual cases for consideration of clinically aggressive adenomas. This classification also recognizes some subtypes of pituitary neuroendocrine tumors as “high-risk pituitary adenomas” due to the clinical aggressive behavior; these include the sparsely granulated somatotroph adenoma, the lactotroph adenoma in men, the Crooke’s cell adenoma, the silent corticotroph adenoma, and the newly introduced plurihormonal Pit-1-positive adenoma (previously known as silent subtype III pituitary adenoma). An additional novel aspect of the new WHO classification was also the definition of the spectrum of thyroid transcription factor-1 expressing pituitary tumors of the posterior lobe as representing a morphological spectrum of a single nosological entity. These tumors include the pituicytoma, the spindle cell oncocytoma, the granular cell tumor of the neurohypophysis, and the sellar ependymoma.

Overview of the 2017 WHO Classification of Pituitary Tumors

Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with pituitary adenomas.

Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene

Abstract 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.

Clinical Biology of the Pituitary Adenoma

Context: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports. Objective: To improve the knowledge of MEN1 natural history before 21 years old. Methods: Obtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the “Groupe d'etude des Tumeurs Endocrines” MEN1 cohort. Results: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-NET in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before a...

/pdf/men1-disease-occurring-before-21-years-old-a-160-patient-2w031s9rdq.pdf

MEN1 Disease Occurring Before 21 Years Old: A 160-Patient Cohort Study From the Groupe d'étude des Tumeurs Endocrines

Recently, a number of novel genetic alterations have been identified that predispose individuals to pituitary adenomas. Clinically relevant pituitary adenomas are relatively common, present in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior lobe of the pituitary gland, and cause disease due to hormonal alterations and local space-occupying effects. The pathomechanism of pituitary adenomas includes alterations in cell-cycle regulation and growth factor signaling, which are mostly due to epigenetic changes; somatic and especially germline mutations occur more rarely. A significant proportion of growth hormone- and adrenocorticotrophin-secreting adenomas have activating somatic mutations in the GNAS and USP8 genes, respectively. Rarely, germline mutations predispose to pituitary tumorigenesis, often in a familial setting. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and McCune-Albright syndrome. Pituitary tumors have also been described in association with neurofibromatosis type 1, DICER1 syndrome, and SDHx mutations. Pituitary adenomas with no other associated tumors have been described as familial isolated pituitary adenomas. Patients with AIP or GPR101 mutations often present with pituitary gigantism either in a familial or simplex setting. GNAS and GPR101 mutations that arise in early embryonic age can lead to somatic mosaicism involving the pituitary gland and resulting in growth hormone excess. Senescence has been suggested as the key mechanism protecting pituitary adenomas turning malignant in the overwhelming majority of cases. Here we briefly summarize the genetic background of pituitary adenomas, with an emphasis on the recent developments in this field. Clin Cancer Res; 22(20); 5030-42. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "ENDOCRINE CANCERS REVISING PARADIGMS".

/pdf/novel-genetic-causes-of-pituitary-adenomas-3w0qify5az.pdf

Novel Genetic Causes of Pituitary Adenomas.

Context: Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age %30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population. Objective: We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age %30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. Design: The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. Patients and settings: One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study. Results: Twenty-one out of 174 (12%) patients had AIP (nZ15, 8.6%) or MEN1 (nZ6, 3.4%) mutations. In pediatric patients (age %18 years old), AIP/MEN1 mutation frequency reached nearly 22% (nZ10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (nZ3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. Conclusion: Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

/pdf/genetic-analysis-in-young-patients-with-sporadic-pituitary-1aisnk2ove.pdf

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis

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Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis