The 5th Edition of the WHO Classification of Pituitary Tumors: Strengths and limitations

The 5th Edition of the World Health Organization (WHO) Classification of Tumors of the Pituitary Gland, initially released as a chapter in Central Nervous System Tumors Book (CNS5) in 2021 [1] and then modified and revised in Endocrine and Neuroendocrine Tumors Book (ENDO5) (still online) in 2022 [2], has provided the community with a framework for classification of pituitary tumors. For the most common tumors involving the gland, the pituitary adenomas (now pituitary neuroendocrine tumors or PitNETs), the classification has endorsed the experience since ENDO4 of a cell lineage-based classification with description of distinct types and subtypes of tumors.

In this Mini-Symposium, four articles will discuss the strengths and weaknesses of the WHO pituitary tumors classification focusing on proposals for future classifications.

Goyal-Honavar and Chacko [3] discuss the challenges of a histopathological classification based solely on immunohistochemistry (IHC) of pituitary hormones and transcription factors. Some of the challenges include lack of criteria for positivity by IHC expression, costs and availability of antibodies worldwide, and precise diagnostic criteria for new tumor types/subtypes that have emerged since the widespread adaptation of the classification system, in particular the so-called multilineage tumors.

Villa et al. [4] analyze the several steps for grading and staging of PitNETs/adenomas and the challenges of fitting pituitary tumors in the overall scheme of grading/staging of other neuroendocrine neoplasms/tumors (NEN/NETs) as intended by the WHO classification. Most significantly, the authors comment on the need for clinical, biochemical, and radiological integration with the histopathology in a clinico-pathological classification of the tumors.

The discussion of aggressive PitNETs/adenomas is examined by Casar-Borota et al. [5] that dissect the clinical and pathological undertakings of diagnosing tumors that are beyond the so-called “benign adenoma,” including locally invasive, clinically aggressive, and metastatic tumors. The authors discuss the clinical, pathological, and molecular aspects of these more aggressive tumors and potential predictor factors for tumor recurrence and progression. They also provide a critical analysis of the controversial ICD-O coding system applied to PitNETs/adenomas in ENDO5.

Still focusing on the new WHO classification, Roncaroli and Giannini [6] discuss another group of pituitary tumors, the non-neuroendocrine tumors, focusing on the TTF-1 expressing tumors of the posterior pituitary and infundibulum, the newly described tumor with the proposed name of Primary Papillary Epithelial Tumor of the Sella (that also expresses nuclear TTF-1), and the rare sellar atypical teratoid/rhabdoid tumor (AT/RT). The authors describe in detail these entities clinical, pathological and molecular aspects, and the differences between CNS5 and ENDO5 regarding their classification and nomenclature.

Finally, Botelho, Andreiuolo et al. [7] deal with a distinct issue regarding the most requested targetable “marker” by clinicians for the treatment of specific pituitary tumors that are not cured by surgery. Clinicians utilized the expression of somatostatin receptors (SST or SSTR) in pituitary tumor tissue as a predictor for response to somatostatin analogs in somatotroph, lactotroph, and/or thyrotroph tumors. Pathologists are used to reporting on certain therapeutic targets, for instance PD-L1 in lung tumors, for the main purpose of medical treatment. Although SSTR expression has been utilized for several years in clinical practice, guidelines for reporting SSTR expression in pituitary tumors have not been established worldwide and no recommendation is given by the WHO classification for such procedure. The authors provide an overview of several reporting systems and experience in the literature of such issues.

Tumor pathological classifications are a dynamic process that should be modified constantly according to the escalating changes of disease knowledge. The recent accumulation of data on pituitary tumors molecular characterization [8, 9] and its integration with histopathological diagnosis [10] should play a significant role for the construction of new pituitary tumors classifications.

Likewise, understanding that histopathological classification of pituitary tumors, in particular PitNETs/adenomas, is only a portion of predictors of behavior and prognosis of pituitary tumors is essential. Unlike several other CNS tumor entities, many aspects independent of the pathological diagnosis play a role in clinical behavior and prognosis of these tumors. Consequently, the integration of clinical, laboratory, radiological, and histo-molecular information is essential for better prognostication of these tumors. As proposed by pathologists and clinicians that treat patients with pituitary tumors, multidisciplinary workflows and clinical-pathological classifications may provide better guidance for tumor prognosis and treatment of our patients [4, 11, 12].