The World Health Organization classifications of pituitary neuroendocrine tumours: a clinico-pathological appraisal

Abstract

The classification of tumours of the pituitary gland has recently been revised in the 2021 5th edition World Health Organization (WHO) Classification of Central Nervous System Tumours (CNS5) and 2022 5th edition WHO Classification of Endocrine and Neuroendocrine Tumours (ENDO5). This brief review aims to appraise the most relevant changes and updates introduced in the two classifications. A new nomenclature has been introduced in CNS5 and ENDO5 to align adenohypophyseal tumours with the classification framework of neuroendocrine neoplasia. The term Pituitary Neuroendocrine Tumour (PitNET) with subtype information has therefore been adopted and preferred to adenoma. Pituitary carcinoma has been replaced by metastatic PitNET. The ICD-O coding has been changed from benign to malignant in line with NETs from other organs. Histological typing and subtyping based on immunohistochemistry for lineage restricted pituitary transcription factors is regarded as the cornerstone for an accurate classification. Such approach does not fully reflect the complexity and dynamics of pituitary tumorigenesis and the variability of transcription factors expression. ENDO5 does not supported a grading and/or staging system and argues that histological typing and subtyping is more robust than proliferation rate and invasiveness to stratify tumours with low or high risk of recurrence. However, the prognostic and predictive relevance of histotype is not fully validated. Recent studies suggest the existence of clinically relevant molecular subgroups and emphasize the need of a standardized, histo-molecular integrated approach to the diagnosis of PitNETs to further our understanding of their biology and overcome the unsolved issue of grading and/or staging system.

A clinicopathological study of non-functioning pituitary neuroendocrine tumours using the World Health Organization 2022 classification

“…Moreover, pituitary tumorigenesis is a complex process that cannot be simply explained by three transcription factors alone. Interplay between transcription factors, variability of protein expression, as well as trans-differentiation of tumours is still not well understood ( 19 ). Whether tumours with expression of two transcription factors without immunostaining of corresponding hormones should be regarded as a plurihormonal PitNET, and strategies to overcome incongruent expression of IHC of transcription factors and hormones, remained to be elucidated in further studies ( 6 , 19 ).…”

“…A major limitation of the current WHO classification of PitNET is that it relies on tumour histotype as the sole prognostic marker for PitNET without incorporating any grading or stratification system ( 19 ). Evidence suggests that the biological determinants of aggressive PitNET is not only based solely on transcription factor subtype, but also relies on an interplay of different proliferative, radiological and molecular factors.…”

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors

“…Two groups of patients were enrolled: (1) a prospective, unselected collection of patients ( n = 66) who presented to MSKCC for pituitary surgery and provided written informed consent to the sequencing study prior to surgery, and (2) a retrospective collection of pituitary patients ( n = 26) whose tumors had either demonstrated aggressive, treatment-refractory behavior as defined by progression on MRI following standard treatments including a first course of external beam radiation (22/26, 85%) or were considered at a higher risk as per the 2017 and/or 2022 World Health Organization classification of pituitary tumors [ 52 ]: a silent corticotroph PitNET, lactotroph PitNET in a man, Crooke’s cell PitNET, or immunonegative PitNET (4/26, 15%). Corticotroph tumors were considered biochemically silent by fulfilling one of the following criteria: (1) normal 24 h urine free cortisol, (2) diagnosis of adrenal insufficiency requiring glucocorticoid replacement, or (3) confirmation by referring endocrinologist.…”

Ectopic Pituitary Neuroendocrine Tumors/Adenomas Around the Sella Turcica

“…The change in the nomenclature of the tumor in the fifth edition of the World Health Organization (WHO) Classification 2021 and 2022 WHO Classification of Endocrine and Neuroendocrine Tumors can be attributed to its variable clinical and pathological features such as aggressive behavior, recurrence after treatment, and occasional metastasis. 16 , 17 , 18 , 19 Additionally, neuroendocrine proteins such as chromogranin A, insulinoma-like protein 1, CD56, and synaptophysin are expressed by PitNETs, which are suggestive of neuroendocrine tumors. 20 …”