Pituitary neuroendocrine tumor classification

The 2022 World Health Organization classification of tumors of the pituitary gland

The 2022 World Health Organization classification of tumors of the pituitary gland provides detailed histological subtyping of a PitNET based on the tumor cell lineage, cell type, and related characteristics. The routine use of immunohistochemistry for pituitary transcription factors (PIT1, TPIT, SF1, GATA3, and ERα) is endorsed in this classification. The major PIT1, TPIT, and SF1 lineage-defined PitNET types and subtypes feature distinct morphologic, molecular, and clinical differences. The “null cell” tumor, which is a diagnosis of exclusion, is reserved for PitNETs with no evidence of adenohypophyseal lineage differentiation. Unlike the 2017 WHO classification, mammosomatotroph stem cell tumors and acidophil stem cell tumors represent distinct PIT1-lineage PitNETs. The diagnostic category of PIT1-positive plurihormonal tumor that was introduced in 2017 WHO classification is replaced by two clinicopathologically distinct PitNETs: the immature PIT1-lineage tumor (formerly known as silent subtype 3 tumors) and the mature plurihormonal PIT1-lineage tumor. Rare unusual plurihormonal tumors feature multi-lineage differentiation. The importance of recognizing multiple synchronous PitNETs is emphasized to avoid misclassification. The term “metastatic PitNET” is advocated to replace the previous terminology “pituitary carcinoma” in order to avoid confusion with neuroendocrine carcinoma (a poorly differentiated epithelial neuroendocrine neoplasm). Subtypes of PitNETs that are associated with a high risk of adverse biology are emphasized within their cell lineage and cell type as well as based on clinical variables. Posterior lobe tumors, the family of pituicyte tumors, include the traditional pituicytoma, the oncocytic form (spindle cell oncocytoma), the granular cell form (granular cell tumor), and the ependymal type (sellar ependymoma). Although these historical terms are entrenched in the literature, they are nonspecific and confusing, such that oncocytic pituicytoma, granular cell pituicytoma, and ependymal pituicytoma are now proposed as more accurate. Tumors with hypothalamic neuronal differentiation are classified as gangliocytomas or neurocytomas based on large and small cell sizes, respectively. This classification sets the standard for a high degree of sophistication to allow individualized patient management approaches 1).

The classification is based upon the size, invasion of adjacent structures, sporadic pituitary neuroendocrine tumor or familial pituitary neuroendocrine tumor cases, biochemical activity, clinical manifestations, morphological characteristics, response to treatment, and recurrence 2).

Current classification systems for PAs are based primarily on secretory characteristics of the tumor but are also classified on the basis of phenotypical characteristics, including tumor size, degree of invasiveness (e.g., Knosp grade), and immunohistological findings 3).

The anterior WHO classification system for PAs was refined to include designations for benign adenoma, atypical adenoma, and pituitary carcinoma on the basis of p53 immunoreactivity, MIB-1 index, mitotic activity, and the absence/presence of metastases 4) 5).

These tumor types can be microadenomas or macroadenomas and can either be functional or non-functional.

Pituitary microadenoma

Pituitary macroadenoma

Giant pituitary neuroendocrine tumor

Volume can be calculated using MRI-guided volumetrics and an ellipsoid approximation (TV × AP × CC/2) transverse (TV), antero-posterior (AP) and cranio-caudal (CC).

Functioning pituitary neuroendocrine tumor

Nonfunctioning pituitary neuroendocrine tumor

pituitary neuroendocrine tumors with gangliocytic component are rare tumors of the sellar region that are composed of pituitary neuroendocrine tumor cells and a ganglion cell component. Their histogenesis and hence nosology is not yet resolved because of the small number of cases reported and lack of large series in the literature 6).

Invasive pituitary neuroendocrine tumors and pituitary carcinomas are clinically indistinguishable until the identification of metastases.

Although most authors differentiate easily aspirated (soft) tumors from those that are not (fibrous, might require prior fragmentation), there is no universally accepted PA consistency classification. Fibrous PA tends to be hypointense on T2 weighted image and has lower apparent diffusion coefficient (ADC) values. Fibrous tumors seemed to present higher invasion into neighboring structures, including the cavernous sinus. Several articles suggest that dopamine agonists could increase PA consistency and that prior surgery and radiotherapy also make PA more fibrous. The anatomopathological studies identify collagen as being mainly responsible for fibrous consistency of adenomas.

Conclusions: Preoperative knowledge of PA consistency affords the neurosurgeon substantial benefit, which clearly appears to be relevant to surgical planning, risks, and surgery outcomes. It could also encourage the centralization of these high complexity tumors in reference centers. Further studies may be enhanced by applying standard consistency classification of the PA and analyzing a more extensive and prospective series of fibrous PA. 7).

Asa SL, Mete O, Perry A, Osamura RY. Overview of the 2022 WHO Classification of Pituitary Tumors. Endocr Pathol. 2022 Mar;33(1):6-26. doi: 10.1007/s12022-022-09703-7. Epub 2022 Mar 15. PMID: 35291028.
Syro LV, Rotondo F, Ramirez A, Di Ieva A, Sav MA, Restrepo LM, Serna CA, Kovacs K. Progress in the Diagnosis and Classification of pituitary neuroendocrine tumors. Front Endocrinol (Lausanne). 2015 Jun 12;6:97. doi: 10.3389/fendo.2015.00097. eCollection 2015. Review. PubMed PMID: 26124750; PubMed Central PMCID: PMC4464221.
Knosp E, Steiner E, Kitz K, Matula C: pituitary neuroendocrine tumors with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–618, 1993
Barnes L, Eveson JW, Reichart P, David Sidransky: World Health Organization Classification of Tumours: Pathology and Genetics of Head and Neck Tumours Lyon, IARC Press, 2005
Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V, Laws ER Jr: Atypical pituitary neuroendocrine tumors: incidence, clinical characteristics, and implications. J Neurosurg 114:336–344, 2011
Balci S, Saglam A, Oruckaptan H, Erbas T, Soylemezoglu F. pituitary neuroendocrine tumor with gangliocytic component: report of 5 cases with focus on immunoprofile of gangliocytic component. Pituitary. 2014 Jan 16. [Epub ahead of print] PubMed PMID: 24430434.
Acitores Cancela A, Rodríguez Berrocal V, Pian H, Martínez San Millán JS, Díez JJ, Iglesias P. Clinical relevance of tumor consistency in pituitary neuroendocrine tumor. Hormones (Athens). 2021 Jun 19. doi: 10.1007/s42000-021-00302-5. Epub ahead of print. PMID: 34148222.
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