Pituitary

This chapter covers the pituitary gland. It starts with the anatomy and physiology, then moves on to imaging, and pituitary function. It then covers common tests, including ITT, glucagon, ACTH stimulation, arginine, clomiphene, hCG, and TRH. It then begins to cover disorders of pituitary function, with treatment, hormone replacement, and investigation all included. Pituitary tumours are described, along with investigation, diagnosis, and treatment. Other disorders, including Cushing’s disease, cysts, inflammatory conditions are all included. Complications from other conditions are also described.

Molecular Pathways in Prolactinomas: Translational and Therapeutic Implications

Prolactinoma has the highest incidence rate among patients with functional pituitary tumours. Although mostly benign, there is a subgroup that can be aggressive. Some clinical, radiological and pathology features have been associated with a poor prognostic. Therefore, it can be considered as a group of heterogeneous tumours. The aim of this paper is to give an overview of the molecular pathways involved in the behaviour of prolactinoma in order to improve our approach and gain deeper insight into the better understanding of tumour development and its management. This is essential for identifying patients harbouring aggressive prolactinoma and to establish personalised therapeutics options.

An aggressive poorly differentiated plurihormonal Pit-1-positive adenoma

Summary In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20–30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue. Learning points Poorly differentiated plurihormonal Pit-1-positive adenoma is a potentially aggressive subtype of pituitary tumours. This subtype can express somatostatin receptors, allowing treatment with somatostatin analogues. A multidisciplinary approach involving an endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist and medical oncologist is key for the management of patients with aggressive pituitary tumours, allowing the successful application of multimodality treatment. Temozolomide is first-line chemotherapy for aggressive pituitary tumours and carcinomas. Further development of novel targeted therapies, such as peptide receptor radionuclide therapy (PRRT), vascular endothelial growth factor (VEGF) receptor-targeted therapy, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors, is needed.

Pituitary Tumours

The chapter focuses on understanding the latest classification of the pituitary adenomas in light of immuno-histological and molecular signatures as envisaged in the latest WHO classification guidelines. It further looks into evaluating and analysing the symptoms of the adenoma locally and at distant organs. Imaging and hormonal analysis has been discussed in detail for both functional, non-functional and pituitary apoplexy. Further, the therapeutic options- medical, surgical and their outcomes have been highlighted.

Characteristics and treatment responsiveness of patients with acromegaly and a paradoxical GH increase to oral glucose load

Objectives: We aimed to investigate the clinical, biochemical, histological and radiological characteristics as well as the response to somatostatin analogs (SSA) in a large cohort of acromegaly patients with a paradoxical GH response (PR) to oral glucose tolerance test (OGTT). Design: retrospective study. Methods: Of 110 patients with acromegaly included in our study, 30 (PR+; 27%) had a paradoxical GH increase of more than 25% relative to basal GH levels during OGTT. Results : At diagnosis, PR+ patients were older than PR- patients (52 ± 16 vs 44 ± 14 years, p<0.05) and had smaller pituitary tumours (40% microadenomas vs 19%, p<0.05), which were less often invasive (17 vs 35%, p<0.05), overall more secreting (IGF-1/tumoural surface: 2.35 ULN/cm² [0.28-9.06] vs 1.08 [0.17- 7.87], p=0.011), and more often hypointense on T2-weighted MRI (92 vs 48%, p=0.001). While the rate of remission after surgery was similar in the two groups (69%), a better response to SSA treatment was observed in PR+ patients, either before (IGF-1 reduction of > 50% after 3-6 months in 77 vs 49%, p=0.023) or after surgery (normalization of IGF-1 in 100 vs 44%, p=0.011). Conclusions: Our study demonstrates that in acromegaly, a paradoxical GH increase during OGTT is associated with particular features of somatotroph adenomas and with a better prognosis in terms of response to somatostatin analogs.

Transcription factor immunohistochemistry in the diagnosis of pituitary tumours

Objective: The clinical utility and prognostic value of WHO 2017 lineage-based classification of pituitary tumours have not been assessed. This study aimed to (1) determine the clinical utility of transcription factor analysis for classification of pituitary tumours and (2) determine the prognostic value of improved lineage-based classification of pituitary tumours. Methods: This was a retrospective evaluation of patients who underwent surgical resection of pituitary tumours at St Vincent’s Public and Private Hospitals, Sydney, Australia between 1990 and 2016. Included patients were at least 18 years of age and had complete histopathological data, forming the “histological cohort”. Patients with at least 12 months of post-surgical follow up were included in the subgroup “clinical cohort”. The diagnostic efficacy of transcription factor immunohistochemistry in conjunction with hormone immunohistochemistry was compared with hormone immunohistochemistry alone. The prognostic value of identifying “higher risk” histological subtypes was assessed. Results: There were 171 patient tumour samples analyzed in the histological cohort. Of these, there were 95 patients forming the clinical cohort. Subtype diagnosis was changed in 20/171 (12%) of tumours. Within the clinical cohort, there were 21/95 (22%) patients identified with higher risk histological subtype tumours. These were associated with tumour invasiveness (p=0.050), early recurrence (12-24 months, p=0.013), shorter median time to recurrence (49 [IQR 22.5-73.0] v 15 [IQR 12.0-25.0] months, p=0.005) and reduced recurrence-free survival (p=0.031). Conclusions: Application of transcription factor analysis, in addition to hormone immunohistochemistry, allows for refined pituitary tumour classification and may facilitate an improved approach to prognostication.