The 2022 WHO classification of tumors of the pituitary gland: An update on aggressive and metastatic pituitary neuroendocrine tumors

Abstract

The vast majority of pituitary neuroendocrine tumors (PitNETs) are benign and slow growing with a low relapse rate over many years after surgical resection. However, about 40% are locally invasive and may not be surgically cured, and about one percentage demonstrate an aggressive clinical behavior. Exceptionally, these aggressive tumors may metastasize outside the sellar region to the central nervous system and/or systemically. The 2017 (4th Edition) WHO Classification of Pituitary Tumors abandoned the terminology "atypical adenoma" for tumors previously considered to have potential for a more aggressive behavior since its prognostic value was not established. The 2022 (5th Edition) WHO Classification of the Pituitary Tumors emphasizes the concept that morphological features distinguish indolent tumors from locally aggressive ones, however, the proposed histological subtypes are not consistent with the real life clinical characteristics of patients with aggressive tumors/carcinomas. So far, no single clinical, radiological or histological parameter can determine the risk of growth or malignant progression. Novel promising molecular prognostic markers, such as mutations in ATRX, TP53, SF3B1, and epigenetic DNA modifications, will need to be verified in larger tumor cohorts. In this review, we provide a critical analysis of the WHO guidelines for prognostic stratification and diagnosis of aggressive and metastatic PitNETs. In addition, we discuss the new WHO recommendations for changing ICD-O and ICD-11 codes for PitNET tumor behavior from a neoplasm either "benign" or "unspecified, borderline, or uncertain behavior" to "malignant" neoplasm regardless of the clinical presentation, histopathological subtype, and tumor location. We encourage multidisciplinary initiatives for integrated clinical, histological and molecular classification, which would enable early recognition of these challenging tumors and initiation of more appropriate and aggressive treatments, ultimately improving the outcome.

Keywords: PitNET; metastatic pituitary tumor; pituitary adenoma; pituitary carcinoma; pituitary neuroendocrine tumor.

FIGURE 1

Initial first surgery specimens from three different pituitary carcinomas showing a highly variable cell proliferation: A GH‐PRL producing carcinoma with no mitoses in haematoxylin‐eosin staining (A) and a low Ki‐67 index <1% (B), a corticotroph carcinoma with scattered mitoses (C) and moderately elevated Ki‐67 index 5%–8% (D), and a corticotroph carcinoma with high mitotic rate (E) and Ki‐67 > 40% (F). Hematoxylin–eosin microphotographs are taken with 400× magnification and Ki‐67 immunostaining captured with 200× magnification. Mitoses are highlighted with arrows.

FIGURE 2

Tumor size at the first presentation in 50 patients with pituitary carcinomas. Of the 12 non‐functioning PCs hormone immunohistochemistry was positive for prolactin (n = 1), growth hormone (3), adrenocorticotroph hormone (4), transcription factor PIT1 (2), and not investigated (2). Two of the silent somatotroph, and 3 of the silent corticotroph PCs subsequently became functioning.