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High-risk pituitary adenomas are aggressive. They show clinical and imaging features similar to those of carcinomas, including infiltration of the surrounding brain structures, but lack cerebrospinal or systemic metastases. In addition, they display distinct behavior, including tendency for fast growth and frequent recurrences, which are difficult to control. The term "high-risk" adenoma was first introduced in the 4th edition of the World Health Organization Classification of Endocrine Tumors in 2017. Five defined adenoma types belong to this category, including sparsely granulated somatotroph, lactotroph in men, Crooke cell, silent corticotroph, and plurihormonal PIT-1 positive adenomas. The morphological and immunohistochemical characteristics of high-risk adenomas are herein described in detail. In addition, the clinical features and the treatment options are presented. This review focuses on predictive markers assessed by immunohistochemistry, which help clinicians to design the appropriate treatment strategies for high-risk adenomas. Somatostatin receptor status predicts effectiveness of postsurgical treatment with somatostatin analogs, and MGMT expression predicts response to treatment with temozolomide. This comprehensive review presents the clinical and pathological features of high-risk pituitary adenomas, underlines the contribution of immunohistochemistry, and emphasizes the leading role of pathology in the design of optimal clinical management., (© 2021. Hellenic Endocrine Society.)

Objectives: Thyrotroph adenomas are the most infrequent adenohypophysial tumors. Somatostatin (SST) inhibits hormone secretion and suppresses cell proliferation. SST receptors (sstr) belong to a family of 5 types of G-coupled membrane proteins, which show high binding affinity to SST. Currently, SST analogs used to treat pituitary adenomas, have a preferential binding activity to sstr2 and sstr5. The aim of this study was to evaluate the status of all active sstrs on cell membrane of thyrotroph adenomas., Patients: Nine cases of thyrotroph adenomas were studied for all types of sstrs. All patients were clinically associated with hyperthyroidism. The adenomas were initially diagnosed and classified by histology and immunohistochemistry for all pituitary hormones and two of them were examined by electron microscopy., Methods: For sstr immunohistochemistry, antisera against all sst types (1, 2A, 2B, 3, 4 and 5) were used. To enhance sensitivity, the tyramide amplification technique was applied. This is the first report investigating the full spectrum of sstrs in thyrotroph adenomas by immunohistochemistry., Results: All tumors were immunoreactive for β-subunit of thyroid-stimulating hormone and for α-subunit of glycoprotein hormones. The sst2A, sst2B and sstr5 were co-expressed in all adenomas. The sstr1 and sstr3 were noted in 8 and sstr4 in 7 adenomas respectively. High scores 2+ and 3+ were prominent in sstr2A, sstr2B, sstr3 and sstr5. High score 3+ for sstr4 was also noted in one tumor, while score 3+ for sstr1 was not observed., Conclusions: Knowledge of the sstr status may contribute to a better selection of patients, anticipating benefit from treatment with SST analogs. Given that multiligand SST analogs have a broader ability to bind other sstrs, such as sstr1 and sstr3, patients with thyrotroph adenomas expressing these receptors may benefit from novel sstr targeting therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Temozolomide (TMZ) is currently considered as a rational therapeutic option for patients with progressively aggressive pituitary adenomas and carcinomas not responding to conventional therapies. Administration of TMZ results in clinical response and improvement in survival of many of these patients depending upon the expression of the DNA repair enzyme O-6 methylguanine DNA transferase (MGMT). Low or negative MGMT immunoreactivity predicts responsiveness to TMZ therapy. Therefore, MGMT serves as a criterion to select candidate patients anticipating response to treatment., Materials and Methods: The MGMT expression was investigated in 25 pituitary adenomas with Ki-67 labeling index more that 3% and p53 expression, using various antigen retrieval protocols. After direct application of the antibody, only one adenoma yielded positive for MGMT. However, after pretreatment of tissue sections with antigen retrieval protocols, another 3 adenomas, initially negative turned to positive., Conclusions: These findings could explain lack of response to TMZ treatment in patients with false negative MGMT immunohistochemistry. Evaluation of tumor samples for MGMT expression should carefully be carried-out using the optimum immunohistochemical protocol to obtain consistent and reliable results that help to identify patients that could respond to TMZ therapy.

Double and multiple adenomas of the pituitary are composed of two or more distinct tumors located in the same gland. They represent uncommon lesions measuring less than 1 cm, reported as having a low incidence in autopsies and occurring even more infrequently in surgical series. The histological diagnosis of double adenomas in surgical material is often extremely difficult, and confirmation requires immunohistochemistry and, occasionally, electron microscopy. Fragmented tissue material submitted for histology after transsphenoidal resection complicates the diagnosis. Difficulties in demonstrating double or multiple adenomas by imaging techniques contribute to diagnostic failure. Magnetic resonance imaging (MRI) techniques may disclose two separate adenomas located in the same pituitary gland. Intraoperative MRI and imaging ultrasonography, together with positron emission computed tomography, more accurately identify sites of residual tumors. These techniques might also detect postoperatively a residual tumor belonging to the second component of double adenoma. Double adenomas may also create extreme clinical diagnostic challenges. It is almost impossible to suspect functioning double adenomas with combined hormone secretion, each one secreting a different hormone, and distinguish them from an isolated plurihormonal adenoma, simultaneously secreting more than one hormone. Double adenomas may underlie surgical failure when one adenoma is removed while the other is left behind. Despite the low frequency of double adenomas, identification and resection of both of them is of major importance for the achievement of biochemical cure.

Objective: The term "null cell" adenoma was first proposed in 1980 to designate pituitary adenomas lacking clinical, biochemical and morphological markers to disclose their cell origin., Design: The aim of this study was to investigate the presence of α- and β-gonadotropin subunits in clinically nonfunctioning pituitary tumors, which were initially immunonegative and thus diagnosed as null cell adenomas. For this reason, we reapplied immunohistochemistry using a more sensitive method comprising a tyramide signal amplification technique, combined with a polymer antibody immunohistochemical detection system., Results: With this approach, all these previously negative tumors became positive for α- and β-gonadotropin hormone subunits., Conclusions: Our results prove that so-called "null cell" adenomas produce α-SU or/and β-FSH or β-LH and therefore are gonadotrph adenomas in origin.

We present a unique case of a prolactin (PRL)-producing pituitary adenoma showing incomplete neuronal differentiation without ganglion cells. A 27-year-old man presented with nausea, headaches, and instability over the last 2 months. Clinical examination revealed obesity with no other endocrinological signs. His serum PRL levels were slightly elevated (38 ng/ml), whereas concentrations of the other adenohypophysial hormones were within normal range. Histology revealed an unusual pituitary adenoma containing many hypocellular areas with fibrillar appearance. The sizable tumor cells were polyhedral or elongated harboring an ovoid, vesicular nucleus with prominent nucleolus, lacking, however, the typical features of ganglion cells. By immunohistochemistry, many adenoma cells were positive for PRL. Immunostain for neurofilament protein revealed variable amounts of fibrils dispersed throughout the stroma, mostly in the hypocellular areas. In addition, neurofilament protein and chromogranin were strongly reactive in approximately 15% of the tumor cell population, whereas reactivity for synaptophysin was uniform throughout the tumor. These findings led to the conclusion that part of the tumor-cell population expressed a hybrid immunoprofile of adenoma-neuronal cell. Our case is the first PRL-producing pituitary adenoma showing incomplete neuronal differentiation lacking mature ganglion cells.