Pituitary carcinoma: reclassification and implications in the NET schema

in Endocrine Oncology
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  • 1 Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio, USA
  • | 2 Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada

Correspondence should be addressed to S L Asa: Pathlady01@gmail.com
Open access

The entity known as pituitary carcinoma has been traditionally defined as a tumor of adenohypophysial cells that metastasizes systemically or craniospinally independent of the histological appearance of the lesion. Reported cases of pituitary carcinoma have clinically and histologically resembled their non-metastatic counterparts that were classified as adenomas; the majority of cases were initially diagnosed as adenomas, and with tumor progression and spread, the diagnosis was changed to carcinoma. This classification has been challenged since the definition of malignancy in most organs is not based only on metastatic spread. The extent of local invasion resulting in an inability to completely resect an adenohypophysial tumor can have serious consequences that can cause harm and are therefore not benign. To address this dilemma, it was proposed that pituitary tumors be classified as neuroendocrine tumors. This change in nomenclature is totally appropriate since these tumors are composed of classical neuroendocrine cells; as with other neuroendocrine tumors, they have variable behavior that can be indolent but can involve metastasis. With the new nomenclature, there is no requirement for a distinction between adenomas and carcinomas. Moreover, the WHO/IARC has provided an overarching classification for neuroendocrine neoplasms at all body sites; in this new classification, the term ‘neuroendocrine carcinoma’ is reserved for poorly differentiated high-grade malignancies that are clinically, morphologically and genetically distinct from well-differentiated neuroendocrine tumors. It remains to be determined if there are true pituitary neuroendocrine carcinomas.

Abstract

The entity known as pituitary carcinoma has been traditionally defined as a tumor of adenohypophysial cells that metastasizes systemically or craniospinally independent of the histological appearance of the lesion. Reported cases of pituitary carcinoma have clinically and histologically resembled their non-metastatic counterparts that were classified as adenomas; the majority of cases were initially diagnosed as adenomas, and with tumor progression and spread, the diagnosis was changed to carcinoma. This classification has been challenged since the definition of malignancy in most organs is not based only on metastatic spread. The extent of local invasion resulting in an inability to completely resect an adenohypophysial tumor can have serious consequences that can cause harm and are therefore not benign. To address this dilemma, it was proposed that pituitary tumors be classified as neuroendocrine tumors. This change in nomenclature is totally appropriate since these tumors are composed of classical neuroendocrine cells; as with other neuroendocrine tumors, they have variable behavior that can be indolent but can involve metastasis. With the new nomenclature, there is no requirement for a distinction between adenomas and carcinomas. Moreover, the WHO/IARC has provided an overarching classification for neuroendocrine neoplasms at all body sites; in this new classification, the term ‘neuroendocrine carcinoma’ is reserved for poorly differentiated high-grade malignancies that are clinically, morphologically and genetically distinct from well-differentiated neuroendocrine tumors. It remains to be determined if there are true pituitary neuroendocrine carcinomas.

Introduction

The pituitary is an endocrine gland composed of epithelial neuroendocrine cells that produce peptide hormones which regulate many aspects of homeostasis including growth, metabolism and reproduction. The seven normal neuroendocrine cell types are highly differentiated in structure and function. They are represented by members of three lineages dictated by expression of the transcription factors, PIT1, TPIT and SF1, and additional transcription factors ERα and GATA3, that regulate hormone synthesis (Asa & Perry 2020, Asa et al. 2021b). These neuroendocrine cells can give rise to pituitary neuroendocrine tumors (PitNETs) that generally are well differentiated and reflect normal cytology, but may also be composed of immature cells that do not exhibit normal cytodifferentiation. PitNETs have been the subject of intense investigation and have been classified in a highly elaborate scheme that has been shown to be of value in diagnosis, prognosis and prediction of therapeutic response (Table 1).

Table 1

Classification of PitNETs.

FamilyTumor typeTumor subtypeTranscription factor(s)HormonesOther biomarkers
TPITCorticotrophDensely granulatedTPITACTHKeratins
Sparsely granulatedKeratins
Crooke cellKeratin rings
PIT1SomatotrophDensely granulatedPIT1GH, αSUKeratins
Sparsely granulatedGHKeratin fibrous bodies
LactotophSparsely granulatedPIT1, ERPRL(Keratins)
Densely granulatedPRL(Keratins)
MammosomatotrophPIT1, ERGH>PRLKeratins
Mature plurihormonalPIT1, ER, GATA3GH>PRL, TSHKeratins
Immature PIT1-lineagePIT1 (ER, GATA3)(GH, PRL, TSH)(Keratins ± fibrous bodies)
Acidophil stem cellPIT1, ERPRL> GH(Keratins ± fibrous bodies)
ThyrotrophPIT1, GATA3TSH(Keratins)
SF1GonadotrophSF1, GATA3FSH, LH(Keratins ± follicular cells)
?Null cell(Keratins)
Unclassified plurihormonalTPIT/PIT1/SF1 combinationsACTH/GH/PRL/TSH/FSH/LHVariable

The behavior of PitNETs is extremely variable. Some are slow-growing small tumors that may be incidental findings or may be detected because of their role in creating hormone excess syndromes (Fig. 1), while others are rapidly growing and invasive tumors that involve vital structures around the sella turcica that surrounds the pituitary (Fig. 2). Some respond well to medical therapy or can be completely resected surgically; others are inoperable and require ancillary therapies including radiotherapeutic and pharmacologic approaches to restrain both tumor growth and hormone hypersecretion.

Figure 1
Figure 1

MRI of intrasellar PitNET. The sella shows asymmetry with enlargement of the left side that contains a tumor distorting half of the pituitary.

Citation: Endocrine Oncology 2, 1; 10.1530/EO-22-0041

Figure 2
Figure 2

MRI of large invasive PitNET. There is a large heterogeneous soft tissue tumor mass encasing the optic nerves centered on the clivus, sella and skull base with exophytic suprasellar lobulations. It also encases the internal carotid arteries bilaterally. There is posterior displacement of the cerebral peduncle on the left side with elevation of the basal ganglia. There is also displacement of the left temporal lobe with milder posterior displacement of the left mid brain and pons.

Citation: Endocrine Oncology 2, 1; 10.1530/EO-22-0041

The terminologies used for these neoplasms have undergone changes due to clarification of definitions and in accordance with the recent WHO/IARC proposal for a common classification framework for all neuroendocrine neoplasms (Rindi et al. 2018).

Historical definitions

The traditional classification of pituitary tumors identified the majority of neoplasms as adenomas. The criteria for a diagnosis of malignancy, called pituitary carcinoma, were very strict and required proof of systemic or craniospinal metastasis with no direct spread. In some previous classifications, there was a category of ‘atypical adenoma’ that was used to describe an invasive tumor with an elevated mitotic count, a Ki67 labeling index >3% and/or diffuse positive staining for p53 but no metastasis. However, the application of these criteria was inconsistent and failed to predict the most aggressive tumors (Asa & Ezzat 2016). Other proposals have tried to account for invasion and proliferation to predict the probability of post-operative complete remission or tumor progression (Trouillas et al. 2013, Raverot et al. 2015). These approaches failed to deal with the fundamental fact that almost any PitNET can be invasive of surrounding structures including surrounding adenohypophysis, therefore even small tumors can recur despite apparent complete resection and large tumors are often unresectable due to invasion into the cavernous sinus and around the carotid arteries and/or upwards invasion into the brain (Asa & Ezzat 2016). The application of a cut-off of 3% for the Ki67 labeling index has not been reproducible nor does it consistently associate with invasiveness and recurrence (Asa & Ezzat 2016, Mete et al. 2018).

The problem with this traditional approach is that tumors classified as adenomas are not always benign in behavior (Figs 3, 4 and 5). The term ‘benign’ means not harmful in effect and this does not apply to many pituitary tumors that are not metastatic. Moreover, the definition of ‘malignant’ is used to describe neoplasms that tend to invade normal tissues or recur after removal; it does not only imply metastatic behavior. Many pituitary tumor patients suffer from recurrent disease progression and growth, they require lifelong therapies that can be expensive and cause significant side effects as well as inconvenience, yet they are told that they have a benign problem and often do not receive the financial, psychosocial and healthcare support that they need and deserve.

Figure 3
Figure 3

Histology of corticotroph tumor. This well-differentiated tumor with solid architecture is composed of cells with basophilic cytoplasm that stains intensely for ACTH and keratins (CAM 5.2). It presented in a middle-aged woman with Cushing disease, was resected surgically but recurred several times, eventually giving rise to distant metastasis and ultimately causing the patient’s demise. The only unusual morphological finding was a Ki67 proliferation index that reached 10% in hotspots.

Citation: Endocrine Oncology 2, 1; 10.1530/EO-22-0041

Figure 4
Figure 4

Histology of lactotroph tumor. This tumor that caused hyperprolactinemia was treated with dopamine agonist but continued to grow; it was resected surgically and had the typical morphology of a sparsely granulated lactotroph tumor with dopaminergic effects: the small tumor cells are trapped in a fibrovascular stroma, they show nuclear reactivity for PIT1 and ER, and there is scant cytoplasmic PRL. Depsite two surgical sellar resections, she later developed metastases in brain and bone.

Citation: Endocrine Oncology 2, 1; 10.1530/EO-22-0041

Figure 5
Figure 5

Histology of Crooke cell tumor. This tumor is composed of large cells with abundant pale acidophillic hyaline cytoplasm that stains for ACTH with accentuation at the cell periphery and focally in the juxtanuclear area. The cytoplasm contains a striking ring-like intense positivity for keratins (CAM 5.2) corresponding to the hyaline material. This aggressive tumor with a Ki67 labeling index, that did not exceed 6%, invaded bony structures in and around the sella and ultimately caused the demise of the patient but there was no evidence of metastatic spread.

Citation: Endocrine Oncology 2, 1; 10.1530/EO-22-0041

The rationale for the traditional criteria is further challenged by the conundrum that most cases diagnosed as carcinoma are initially diagnosed as adenoma. These tumors clinically and histologically resemble non-metastatic tumors; while they may have high proliferative indices, this criterion alone is not able to predict metastasis, and thus far, there are no histologic, immunohistochemical or molecular features that can do so. Only with tumor progression and spread is the diagnosis changed to carcinoma, thus one is faced with a metastasizing adenoma, a contradictory term that cannot be supported.

Current definitions

Neuroendocrine tumors (NETs) in other body sites have been recognized to show a spectrum of behavior that varies from indolent to aggressive. As an example, small bowel NETs were initially called ‘carcinoid’ (meaning ‘carcinoma-like’) because they were described by Oberndorfer as lesions that looked like but were not carcinomas (Oberndorfer 1907). Subsequent evidence required a change in our understanding of these lesions that clearly have metastatic potential. NETs in different body sites have variable metastatic behavior ranging from the very rare spread of appendiceal NETs to the more common spread of small bowel and pancreatic NETs. Thus the terminology of ‘neuroendocrine tumor’ implies a well-differentiated neoplasm but with metastatic potential.

In 2017, the International Pituitary Pathology Club proposed to reclassify adenohypophysial tumors as PitNETs (Asa et al. 2017). This was followed by the WHO/IARC proposal for a common classification system for NETs at all body sites (Rindi et al. 2018); the pituitary proposal fits well within this framework. Despite some controversy, the proposal was adopted by the WHO fifth series; the first book to endorse this was the WHO classification of CNS tumors (WHO Classification of Tumours Editorial Board 2021) in which the term PitNET was introduced following adenoma (i.e. adenoma/PitNET). In the following WHO classification of endocrine and neuroendocrine tumors the terms are reversed, so that they are classified as PitNET/adenoma (WHO Classification of Tumours Editorial Board 2022), paving the way for the omission of the term ‘adenoma’ in the sixth series.

With the new terminology, there is no longer a need for the distinction of adenohypophysial carcinomas based strictly on metastatic spread; instead, lesions that spread are classified as ‘metastatic PitNETs’, obviating the need for a change in diagnosis when metastatic disease occurs.

The term carcinoma now has other implications, since the WHO/IARC proposal has recommended a clear distinction between well-differentiated NETs that generally harbor a specific pattern of molecular alterations (Asa et al. 2021a) and the poorly differentiated high-grade malignancies, classified as neuroendocrine carcinomas (NECs) that tend to have mutations in oncogenes and tumor suppressor genes that are the basis for adenocarcinomas in non-endocrine organs (Uccella et al. 2021). In the examples that have been studied carefully, this distinction can generally be identified by histological features as well as biomarkers of the mutational status. Most NECs have very high proliferation rates and are composed of cells that lack clear structural evidence of neuroendocrine differentiation but can express the common immunohistochemical biomarkers of neuroendocrine differentiation: INSM1, synaptophysin and, less so, chromogranins. Such tumors are very unusual as primary lesions in the pituitary; only recently has there been a report suggesting the possibility of a true primary pituitary NEC (Saeger et al. 2021).

Epidemiology of PitNETs

Like other NETs (Yao et al. 2008), PitNETs are now being diagnosed as more common disorders than initially thought. Adenohypophysial tumors have been described as incidental findings in 22.5–27% of routine autopsies (Costello 1936, Burrow et al. 1981) and approximately 20% of radiological studies (Elster 1993, Ezzat et al. 2004). While most of these apparently incidental findings have been considered to be clinically non-functioning, larger lesions can cause hypopituitarism (Freda et al. 2020), immunohistochemical studies have shown that many produce prolactin (Kovacs et al. 1980, McComb et al. 1983); occasional supposedly ‘incidental’ lesions are somatotroph or corticotroph tumors that can be associated with undiagnosed clinically relevant disease. More recent population studies have shown that the prevalence of clinically diagnosed pituitary tumors ranges from approximately 78–116 cases per 100,000 people (Daly et al. 2006, Fontana & Gaillard 2009, Fernandez et al. 2010, Agustsson et al. 2015). The annual incidence is about 3.9/100, 000 people (Tjornstrand et al. 2014); one study did a tumor-type analysis of annual incidence that identified 3.5 non-functioning, 1.6 lactotroph, 0.5 somatotroph and 0.2 corticotroph or thyrotroph tumors per 100,000 population per annum (Oh et al. 2021). Tumors causing hyperprolactinemia are consistently the most common PitNETs (Ezzat et al. 2004, Daly et al. 2006, Fontana & Gaillard 2009, Fernandez et al. 2010, Tjornstrand et al. 2014, Agustsson et al. 2015, Daly & Beckers 2020); since they are usually treated medically (Wilson & Dempsey 1978, Kovacs & Horvath 1986, Klibanski & Zervas 1991, Terada et al. 1995), the statistics are not reliably captured; so their exact incidence is unknown. Surgical resection is performed in over half of diagnosed patients (Daly et al. 2006). Among surgically resected PitNETs, more than a third are hormonally inactive tumors of SF1 lineage (Feldkamp et al. 1999, Mete et al. 2018), about 30% are of PIT1 lineage (more than half of those give rise to growth hormone excess) and approximately 15% are TPIT lineage tumors (Wilson & Dempsey 1978, Kovacs & Horvath 1986, Mindermann & Wilson 1994, Daly et al. 2006, Fernandez et al. 2010, Mete et al. 2018).

Metastatic behavior is exceptionally rare. Most reports publish single cases; the largest series includes 40 patients (McCormack et al. 2018). Metastatic PitNETs represented only 0.12% of the pituitary tumors in the German Pituitary Tumor Registry (Saeger et al. 2007) and 0.4% of surgically resected PitNETs in a published surgical series (Alshaikh et al. 2019). Metastases have been reported in patients of all ages, usually adults but a pediatric case has been reported (Guzel et al. 2008).

Molecular pathology of PitNETs

Like small bowel NETs (Karpathakis et al. 2016), the underlying basis for tumorigenesis in the vast majority of sporadic PitNETs falls broadly into epigenetic changes (Ezzat et al. 2018, Asa et al. 2021c) that include classical promoter methylation, histone tail modifications and non-coding RNAs (Bahreini et al. 2021, Gossing et al. 2021). A subset of sporadic somatotroph tumors harbor activating mutations of GNAS that result in constitutive activation of cyclic AMP signaling and some corticotroph tumors have mutations of the USP8 or USP48 genes (Ezzat et al. 2018, Asa et al. 2021c); occasional aggressive corticotroph tumors have been shown to harbor mutations in ATRX (Casar-Borota et al. 2021), similar to pancreatic NETs. A minority of PitNETs are caused by genetic changes that fall into the group of germline mutations linked with familial endocrine syndromes and associated with other NETs. These include multiple endocrine neoplasia types 1, 4 and 5 due to mutations in MEN1, CDKN1B and MAX, respectively, all of which are implicated in the development of NETs in other organs (Ezzat et al. 2018, Asa et al. 2021c). An unusual MEN1-like patient with acromegaly and hyperparathyroidism was attributed to germline mutation of CDC73 (Nachtigall et al. 2020). Rare PitNETs have been described in patients with mutations in genes encoding the various components of the succinate dehydrogenase complex. These genetic alterations are similar to those found in other NETs. Other familial genetic predisposition syndromes include Carney complex due to germline mutations in the PRKAR1Aα gene and the familial isolated pituitary adenoma syndromes attributed in about 50% of families to germline mutations in the AIP gene that encodes the aryl hydrocarbon-interacting protein. Recent evidence suggests a complex picture where components of heritable syndromes may be functionally important indirectly in sporadic tumors; the MEN2 syndrome associated RET proto-oncogene was shown to be involved in an apoptosis-dependent manner in AIP-deficient somatotroph tumors (Garcia-Rendueles et al. 2021). However, PitNETs generally have not been shown to carry mutations in classical proto-oncogenes. Rare aggressive and metastatic tumors have mutations in TP53 (Saeger et al. 2021, Uzilov et al. 2021) and may represent examples of tumors that qualify as NECs in the new WHO classification scheme.

Therapy of PitNETs

The management of PitNETs generally follows the guiding principles adopted for NETs of other body sites. This includes surgical eradication wherever technically feasible (Asa et al. 2021b). However, in the case of aggressive PitNETs and carcinomas, this goal is often not achievable. As such adjuvant therapies are often employed. These include systemic analogs of dopamine (Greenman & Bronstein 2021) and somatostatin (Asa et al. 2021b) that typically reduce hormone production and effectively diminish tumor progression. However, the more rapidly growing and/or invasive PitNETs often require additional approaches. Targeted therapies relying on mTOR signaling (Monsalves et al. 2014) with everolimus or multikinase inhibitors such as sunitinib represent the next level of PitNET pharmacotherapy (Alshaikh et al. 2019). For those PitNETs that evade such agents the use of the DNA methylation inhibitor temozolomide without or with capecitabine as part of the CAP/TEM combination chemotherapy has become a mainstay (Ishida et al. 2022). The application of peptide receptor radiotherapy taking advantage of somatostatin analog to chaperone intracellular delivery of beta-emitting lutetium 177 (Lu177) has also been reported for pituitary carcinomas (Alshaikh et al. 2019, Giuffrida et al. 2019). Progress in this strategic area of radiopharmaceuticals will undoubtedly facilitate the development of more potent agents for managing refractory PitNETs.

Future directions

The addition of PitNETs to the common classification system of NETs has brought to the fore the question of gradingthese tumors. Other NETs are classified into three grades based on their proliferation index, either mitotic count or Ki67 labeling. However, while some previous studies that address these biomarkers in pituitary tumors have shown some correlation with tumor size, invasiveness, recurrence and metastasis (Landolt et al. 1987, Knosp et al. 1989, Thapar et al. 1996, Salehi et al. 2009) other authors have not (Wierinckx et al. 2007, Salehi et al. 2009, de Aguiar et al. 2010, Zada et al. 2011, Mete et al. 2012, 2018, Tortosa & Webb 2016) and one study identified a Ki67 of 1.5% as the cut-off for more aggressive clinical follow-up (Chiloiro et al. 2014). There is clear evidence that tumor subtype is a more valuable predictor of tumor behavior in the pituitary (Gomez-Hernandez et al. 2015, Asioli et al. 2019, Asa et al. 2021b) and this model has also been shown to be valuable in other NETs such as pancreas and rectum (Asa et al. 2021b). Further work will be required to show whether tumor grade or subtype is more important for other NETs.

Given that adenohypophysial tumors were considered to be benign, there was never any need for a staging system. However, the change in terminology brings with it a recognition that these tumors deserve some attention to prognostic features that can predict long-term outcomes (Asa 2021). As indicated by previous surgical data, the extent of invasion including the degree of lateral extension into the cavernous sinus (Knosp classification) (Knosp et al. 1993) and also the degree of extra-sellar and vertical extension into supra-sellar regions (Hardy classification) (Hardy 1973) have value in predicting future requirements for multimodal therapies including repeat operations and/or radiotherapy (Mete et al. 2012, Tampourlou et al. 2017). Clearly, metastatic disease alters the prognosis even further. Thus, there is an opportunity to develop an evidence-based staging system based on tumor size and extent of invasion as well as the rare spread to lymph nodes and metastatic spread, both intracranially and systemically.

The approach to diagnosis of PitNETs should follow that used for other neoplasms that have any malignant potential, including synoptic reporting. This has been proposed (Nose et al. 2011, Villa et al. 2019) but is not currently the standard of care. Finally, the addition of PitNETs to the family of NETs should result in improved data collection in tumor registries.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Consent for publication

All authors consent to publication.

Author contribution statement

Conception and design: S L A, S E; data collection and analysis: S L A, S E; manuscript preparation and editing: S L A, S E; approval of final manuscript: S L A, S E.

References

  • Agustsson TT, Baldvinsdottir T, Jonasson JG, Olafsdottir E, Steinthorsdottir V, Sigurdsson G, Thorsson AV, Carroll PV, Korbonits M & Benediktsson R 2015 The epidemiology of pituitary adenomas in Iceland, 1955–2012: a nationwide population-based study. European Journal of Endocrinology 173 655664. (https://doi.org/10.1530/EJE-15-0189)

    • Search Google Scholar
    • Export Citation
  • Alshaikh OM, Asa SL, Mete O & Ezzat S 2019 An institutional experience of tumor progression to pituitary carcinoma in a 15-year cohort of 1055 consecutive pituitary neuroendocrine tumors. Endocrine Pathology 30 118127. (https://doi.org/10.1007/s12022-019-9568-5)

    • Search Google Scholar
    • Export Citation
  • Asa SL 2021 Challenges in the diagnosis of pituitary neuroendocrine tumors. Endocrine Pathology 32 222227. (https://doi.org/10.1007/s12022-021-09678-x)

    • Search Google Scholar
    • Export Citation
  • Asa SL & Ezzat S 2016 Aggressive pituitary tumors or localized pituitary carcinomas: defining pituitary tumors. Expert Review of Endocrinology and Metabolism 11 149162. (https://doi.org/10.1586/17446651.2016.1153422)

    • Search Google Scholar
    • Export Citation
  • Asa SL & Perry A 2020 Tumors of the pituitary gland. In AFIP Atlas of Tumor and Nontumor Pathology, Series 5, Fascicle 1. Arlington VA: ARP Press.

    • Search Google Scholar
    • Export Citation
  • Asa SL, Casar-Borota O, Chanson P, Delgrange E, Earls P, Ezzat S, Grossman A, Ikeda H, Inoshita N & Karavitaki N et al.2017 From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club Proposal. Endocrine-Related Cancer 24 C5C8. (https://doi.org/10.1530/ERC-17-0004)

    • Search Google Scholar
    • Export Citation
  • Asa SL, La Rosa S, Basturk O, Adsay V, Minnetti M & Grossman AB 2021a Molecular pathology of well-differentiated gastro-entero-pancreatic neuroendocrine tumors. Endocrine Pathology 32 169191. (https://doi.org/10.1007/s12022-021-09662-5)

    • Search Google Scholar
    • Export Citation
  • Asa SL, Mete O, Cusimano MD, McCutcheon IE, Perry A, Yamada S, Nishioka H, Casar-Borota O, Uccella S & La Rosa S et al.2021b Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification. Modern Pathology 34 16341650. (https://doi.org/10.1038/s41379-021-00820-y)

    • Search Google Scholar
    • Export Citation
  • Asa SL, Mete O & Ezzat S 2021c Genomics and epigenomics of pituitary tumors: what do pathologists need to know? Endocrine Pathology 32 316. (https://doi.org/10.1007/s12022-021-09663-4)

    • Search Google Scholar
    • Export Citation
  • Asioli S, Righi A, Iommi M, Baldovini C, Ambrosi F, Guaraldi F, Zoli M, Mazzatenta D, Faustini-Fustini M & Rucci P et al.2019 Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre. European Journal of Endocrinology 180 127134. (https://doi.org/10.1530/EJE-18-0749)

    • Search Google Scholar
    • Export Citation
  • Bahreini F, Jabbari P, Gossing W, Aziziyan F, Frohme M & & Rezaei N 2021 The role of noncoding RNAs in pituitary adenoma. Epigenomics 13 14211437.

  • Burrow GN, Wortzman G, Rewcastle NB, Holgate RC & Kovacs K 1981 Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. New England Journal of Medicine 304 156158. (https://doi.org/10.1056/NEJM198101153040306)

    • Search Google Scholar
    • Export Citation
  • Casar-Borota O, Boldt HB, Engstrom BE, Andersen MS, Baussart B, Bengtsson D, Berinder K, Ekman B, Feldt-Rasmussen U & Hoybye C et al.2021 Corticotroph aggressive pituitary tumors and carcinomas frequently harbor ATRX mutations. Journal of Clinical Endocrinology and Metabolism 106 11831194. (https://doi.org/10.1210/clinem/dgaa749)

    • Search Google Scholar
    • Export Citation
  • Chiloiro S, Bianchi A, Doglietto F, de Waure C, Giampietro A, Fusco A, Iacovazzo D, Tartaglione L, Di Nardo F & Signorelli F et al.2014 Radically resected pituitary adenomas: prognostic role of Ki 67 labeling index in a monocentric retrospective series and literature review. Pituitary 17 267276. (https://doi.org/10.1007/s11102-013-0500-6)

    • Search Google Scholar
    • Export Citation
  • Costello RT 1936 Subclinical adenoma of the pituitary gland. American Journal of Pathology 12 205216.1.

  • Daly AF & Beckers A 2020 The epidemiology of pituitary adenomas. Endocrinology and Metabolism Clinics of North America 49 347355. (https://doi.org/10.1016/j.ecl.2020.04.002)

    • Search Google Scholar
    • Export Citation
  • Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA & Beckers A 2006 High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. Journal of Clinical Endocrinology and Metabolism 91 47694775. (https://doi.org/10.1210/jc.2006-1668)

    • Search Google Scholar
    • Export Citation
  • de Aguiar PH, Aires R, Laws ER, Isolan GR, Logullo A, Patil C & Katznelson L 2010 Labeling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review. Neurological Research 32 10601071. (https://doi.org/10.1179/016164110X12670144737855)

    • Search Google Scholar
    • Export Citation
  • Elster AD 1993 Modern imaging of the pituitary. Radiology 187 114. (https://doi.org/10.1148/radiology.187.1.8451394)

  • Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML & McCutcheon IE 2004 The prevalence of pituitary adenomas: a systematic review. Cancer 101 613619. (https://doi.org/10.1002/cncr.20412)

    • Search Google Scholar
    • Export Citation
  • Ezzat S, Cheng S & Asa SL 2018 Epigenetics of pituitary tumors: pathogenetic and therapeutic implications. Molecular and Cellular Endocrinology 469 7076. (https://doi.org/10.1016/j.mce.2017.07.011)

    • Search Google Scholar
    • Export Citation
  • Feldkamp J, Santen R, Harms E, Aulich A, Modder U & Scherbaum WA 1999 Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas – results of a prospective study. Clinical Endocrinology 51 109113. (https://doi.org/10.1046/j.1365-2265.1999.00748.x)

    • Search Google Scholar
    • Export Citation
  • Fernandez A, Karavitaki N & Wass JA 2010 Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clinical Endocrinology 72 377382. (https://doi.org/10.1111/j.1365-2265.2009.03667.x)

    • Search Google Scholar
    • Export Citation
  • Fontana E & Gaillard R 2009 Epidemiology of pituitary adenoma: results of the first Swiss study. Revue Medicale Suisse 5 21722174.

  • Freda PU, Bruce JN, Khandji AG, Jin Z, Hickman RA, Frey E, Reyes-Vidal C, Otten M, Wardlaw SL & Post KD 2020 Presenting features in 269 patients with clinically nonfunctioning pituitary adenomas enrolled in a prospective study. Journal of the Endocrine Society 4 bvaa021. (https://doi.org/10.1210/jendso/bvaa021)

    • Search Google Scholar
    • Export Citation
  • Garcia-Rendueles AR, Chenlo M, Oroz-Gonjar F, Solomou A, Mistry A, Barry S, Gaston-Massuet C, Garcia-Lavandeira M, Perez-Romero S & Suarez-Farina M et al.2021 RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas. Oncogene 40 63546368. (https://doi.org/10.1038/s41388-021-02009-8)

    • Search Google Scholar
    • Export Citation
  • Giuffrida G, Ferrau F, Laudicella R, Cotta OR, Messina E, Granata F, Angileri FF, Vento A, Alibrandi A & Baldari S et al.2019 Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience. Endocrine Connections 8 528535. (https://doi.org/10.1530/EC-19-0065)

    • Search Google Scholar
    • Export Citation
  • Gomez-Hernandez K, Ezzat S, Asa SL & Mete Ö 2015 Clinical implications of accurate subtyping of pituitary adenomas: perspectives from the treating physician. Turk Patoloji Dergisi 31 (Supplement 1) 417. (https://doi.org/10.5146/tjpath.2015.01311)

    • Search Google Scholar
    • Export Citation
  • Gossing W, Aziziyan F, Frohme M, Rezaei N, Frohme M & Rezaei N 2021 The role of noncoding RNAs in pituitary adenoma. Epigenomics 13 14211437. (https://doi.org/10.2217/epi-2021-0165)

    • Search Google Scholar
    • Export Citation
  • Greenman Y & Bronstein MD 2021 Cabergoline should be attempted in progressing non-functioning pituitary macroadenoma. European Journal of Endocrinology 185 D11D20. (https://doi.org/10.1530/EJE-21-0344)

    • Search Google Scholar
    • Export Citation
  • Guzel A, Tatli M, Senturk S, Guzel E, Cayli SR & Sav A 2008 Pituitary carcinoma presenting with multiple metastases: case report. Journal of Child Neurology 23 14671471. (https://doi.org/10.1177/0883073808319078)

    • Search Google Scholar
    • Export Citation
  • Hardy J 1973 Transsphenoidal surgery of hypersecreting pituitary tumors. In Diagnosis and Treatment of Pituitary Tumors. International Congress Series No. 303, pp. 179198. Eds Kohler O, Ross GT. Amsterdam: Exerpta Medica.

    • Search Google Scholar
    • Export Citation
  • Ishida A, Shichi H, Fukuoka H, Inoshita N, Ogawa W & Yamada S 2022 Efficacy of temozolomide combined with capecitabine (CAPTEM) on refractory prolactinomas as assessed using an ex vivo 3D spheroid assay. Pituitary 25 238245. (https://doi.org/10.1007/s11102-021-01192-x)

    • Search Google Scholar
    • Export Citation
  • Karpathakis A, Dibra H, Pipinikas C, Feber A, Morris T, Francis J, Oukrif D, Mandair D, Pericleous M & Mohmaduvesh M et al.2016 Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumor. Clinical Cancer Research 22 250258. (https://doi.org/10.1158/1078-0432.CCR-15-0373)

    • Search Google Scholar
    • Export Citation
  • Klibanski A & Zervas NT 1991 Diagnosis and management of hormone-secreting pituitary adenomas. New England Journal of Medicine 324 822831. (https://doi.org/10.1056/NEJM199103213241207)

    • Search Google Scholar
    • Export Citation
  • Knosp E, Kitz K & Perneczky A 1989 Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery 25 927930. (https://doi.org/10.1227/00006123-198912000-00012)

    • Search Google Scholar
    • Export Citation
  • Knosp E, Steiner E, Kitz K & Matula C 1993 Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33 610617; discussion 617. (https://doi.org/10.1227/00006123-199310000-00008)

    • Search Google Scholar
    • Export Citation
  • Kovacs K & Horvath E 1986 Tumors of the pituitary gland. In Atlas of Tumor Pathology, Second Series, Fascicle 21. Washington, D.C.: Armed Forces Institute of Pathology.

    • Search Google Scholar
    • Export Citation
  • Kovacs K, Ryan N, Horvath E, Singer W & Ezrin C 1980 Pituitary adenomas in old age. Journal of Gerontology 35 1622. (https://doi.org/10.1093/geronj/35.1.16)

    • Search Google Scholar
    • Export Citation
  • Landolt AM, Shibata T & Kleihues P 1987 Growth rate of human pituitary adenomas. Journal of Neurosurgery 67 803806. (https://doi.org/10.3171/jns.1987.67.6.0803)

    • Search Google Scholar
    • Export Citation
  • McComb DJ, Ryan N, Horvath E & Kovacs K 1983 Subclinical adenomas of the human pituitary. New light on old problems. Archives of Pathology and Laboratory Medicine 107 488491.

    • Search Google Scholar
    • Export Citation
  • McCormack A, Dekkers OM, Petersenn S, Popovic V, Trouillas J, Raverot G, Burman P & ESE Survey Colla borators 2018 Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. European Journal of Endocrinology 178 265276. (https://doi.org/10.1530/EJE-17-0933)

    • Search Google Scholar
    • Export Citation
  • Mete O, Ezzat S & Asa SL 2012 Biomarkers of aggressive pituitary adenomas. Journal of Molecular Endocrinology 49 R69R78. (https://doi.org/10.1530/JME-12-0113)

    • Search Google Scholar
    • Export Citation
  • Mete O, Cintosun A, Pressman I & Asa SL 2018 Epidemiology and biomarker profile of pituitary adenohypophysial tumors. Modern Pathology 31 900909. (https://doi.org/10.1038/s41379-018-0016-8)

    • Search Google Scholar
    • Export Citation
  • Mindermann T & Wilson CB 1994 Age-related and gender-related occurrence of pituitary adenomas. Clinical Endocrinology 41 359364. (https://doi.org/10.1111/j.1365-2265.1994.tb02557.x)

    • Search Google Scholar
    • Export Citation
  • Monsalves E, Juraschka K, Tateno T, Agnihotri S, Asa SL, Ezzat S & Zadeh G 2014 The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas. Endocrine-Related Cancer 21 R331R344. (https://doi.org/10.1530/ERC-14-0188)

    • Search Google Scholar
    • Export Citation
  • Nachtigall LB, Guarda FJ, Lines KE, Ghajar A, Dichtel L, Mumbach G, Zhao W, Zhang X, Tritos NA & Swearingen B et al.2020 Clinical MEN-1 among a large cohort of patients with acromegaly. Journal of Clinical Endocrinology and Metabolism 105 e2271e2281. (https://doi.org/10.1210/clinem/dgaa142)

    • Search Google Scholar
    • Export Citation
  • Nose V, Ezzat S, Horvath E, Kovacs K, Laws ER, Lloyd R, Lopes MB & Asa SL 2011 Protocol for the examination of specimens from patients with primary pituitary tumors. Archives of Pathology and Laboratory Medicine 135 640646. (https://doi.org/10.5858/2010-0470-SAR1.1)

    • Search Google Scholar
    • Export Citation
  • Oberndorfer S 1907 Karzinoide tumoren des Dünndarms. Frankfurter Zeitschrift für Pathologie 1 425432.

  • Oh JS, Kim HJ, Hann HJ, Kang TU, Kim DS, Kang MJ, Lee JY, Shim JJ, Lee MR & Ahn HS 2021 Incidence, mortality, and cardiovascular diseases in pituitary adenoma in Korea: a nationwide population-based study. Pituitary 24 3847. (https://doi.org/10.1007/s11102-020-01084-6)

    • Search Google Scholar
    • Export Citation
  • Raverot G, Vasiljevic A, Jouanneau E & Trouillas J 2015 A prognostic clinicopathologic classification of pituitary endocrine tumors. Endocrinology and Metabolism Clinics of North America 44 1118. (https://doi.org/10.1016/j.ecl.2014.10.001)

    • Search Google Scholar
    • Export Citation
  • Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, de Krijger RR, Dietel M & El-Naggar AK et al.2018 A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Modern Pathology 31 17701786. (https://doi.org/10.1038/s41379-018-0110-y)

    • Search Google Scholar
    • Export Citation
  • Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ & Petersenn S 2007 Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. European Journal of Endocrinology 156 203216. (https://doi.org/10.1530/eje.1.02326)

    • Search Google Scholar
    • Export Citation
  • Saeger W, Mawrin C, Meinhardt M, Wefers AK & Jacobsen F 2021 Two pituitary neuroendocrine tumors (PitNETs) with very high proliferation and TP53 mutation – high-grade PitNET or PitNEC ? Endocrine Pathology [epub].

    • Search Google Scholar
    • Export Citation
  • Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV & Cusimano M 2009 Ki-67 in pituitary neoplasms: a review – part I. Neurosurgery 65 42943 7; discussion 437. (https://doi.org/10.1227/01.NEU.0000349930.66434.82)

    • Search Google Scholar
    • Export Citation
  • Tampourlou M, Ntali G, Ahmed S, Arlt W, Ayuk J, Byrne JV, Chavda S, Cudlip S, Gittoes N & Grossman A et al.2017 Outcome of nonfunctioning pituitary adenomas that regrow after primary treatment: a study from two large UK centers. Journal of Clinical Endocrinology and Metabolism 102 18891897. (https://doi.org/10.1210/jc.2016-4061)

    • Search Google Scholar
    • Export Citation
  • Terada T, Kovacs K, Stefaneanu L & Horvath E 1995 Incidence, pathology, and recurrence of pituitary adenomas: study of 647 unselected surgical cases. Endocrine Pathology 6 301310. (https://doi.org/10.1007/BF02738730)

    • Search Google Scholar
    • Export Citation
  • Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ, Murray D & Laws Jr ER 1996 Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38 99106; discussion 106. (https://doi.org/10.1097/00006123-199601000-00024)

    • Search Google Scholar
    • Export Citation
  • Tjornstrand A, Gunnarsson K, Evert M, Holmberg E, Ragnarsson O, Rosen T & Filipsson Nyström H 2014 The incidence rate of pituitary adenomas in western Sweden for the period 2001–2011. European Journal of Endocrinology 171 519526. (https://doi.org/10.1530/EJE-14-0144)

    • Search Google Scholar
    • Export Citation
  • Tortosa F & Webb SM 2016 Atypical pituitary adenomas: 10 years of experience in a reference centre in Portugal. Neurologia 31 97105. (https://doi.org/10.1016/j.nrl.2015.06.010)

    • Search Google Scholar
    • Export Citation
  • Trouillas J, Roy P, Sturm N, Dantony E, Cortet-Rudelli C, Viennet G, Bonneville JF, Assaker R, Auger C & Brue T et al.2013 A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathologica 126 123135. (https://doi.org/10.1007/s00401-013-1084-y)

    • Search Google Scholar
    • Export Citation
  • Uccella S, La Rosa S, Metovic J, Marchiori D, Scoazec JY, Volante M, Mete O & Papotti M 2021 Genomics of high-grade neuroendocrine neoplasms: well-differentiated neuroendocrine tumor with high-grade features (G3 NET) and neuroendocrine carcinomas (NEC) of various anatomic sites. Endocrine Pathology 32 192210. (https://doi.org/10.1007/s12022-020-09660-z)

    • Search Google Scholar
    • Export Citation
  • Uzilov AV, Taik P, Cheesman KC, Javanmard P, Ying K, Roehnelt A, Wang H, Fink MY, Lau CY & Moe AS et al.2021 USP8 and TP53 drivers are associated with CNV in a corticotroph adenoma cohort enriched for aggressive tumors. Journal of Clinical Endocrinology and Metabolism 106 826842. (https://doi.org/10.1210/clinem/dgaa853)

    • Search Google Scholar
    • Export Citation
  • Villa C, Vasiljevic A, Jaffrain-Rea ML, Ansorge O, Asioli S, Barresi V, Chinezu L, Gardiman MP, Lania A & Lapshina AM et al.2019 A standardised diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a European Pituitary Pathology Group (EPPG) proposal. Virchows Archiv 475 687692. (https://doi.org/10.1007/s00428-019-02655-0)

    • Search Google Scholar
    • Export Citation
  • WHO Classification of Tumours Editorial Board 2021 WHO Classification of Central Nervous System Tumours, 5th Series. Lyon, France: IARC.

  • WHO Classification of Tumours Editorial Board 2022 WHO Classification of Endocrine and Neuroendocrine Tumours, 5th Series. Lyon, France: IARC.

    • Search Google Scholar
    • Export Citation
  • Wierinckx A, Auger C, Devauchelle P, Reynaud A, Chevallier P, Jan M, Perrin G, Fevre-Montange M, Rey C & Figarella-Branger D et al.2007 A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocrine-Related Cancer 14 887900. (https://doi.org/10.1677/ERC-07-0062)

    • Search Google Scholar
    • Export Citation
  • Wilson CB & Dempsey LC 1978 Transsphenoidal microsurgical removal of 250 pituitary adenomas. Journal of Neurosurgery 48 1322. (https://doi.org/10.3171/jns.1978.48.1.0013)

    • Search Google Scholar
    • Export Citation
  • Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN & Rashid A et al.2008 One hundred years after ‘carcinoid’: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical Oncology 26 30633072. (https://doi.org/10.1200/JCO.2007.15.4377)

    • Search Google Scholar
    • Export Citation
  • Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V & Laws Jr ER 2011 Atypical pituitary adenomas: incidence, clinical characteristics, and implications. Journal of Neurological Surgery 114 336344. (https://doi.org/10.3171/2010.8.JNS10290)

    • Search Google Scholar
    • Export Citation

 

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    MRI of intrasellar PitNET. The sella shows asymmetry with enlargement of the left side that contains a tumor distorting half of the pituitary.

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    MRI of large invasive PitNET. There is a large heterogeneous soft tissue tumor mass encasing the optic nerves centered on the clivus, sella and skull base with exophytic suprasellar lobulations. It also encases the internal carotid arteries bilaterally. There is posterior displacement of the cerebral peduncle on the left side with elevation of the basal ganglia. There is also displacement of the left temporal lobe with milder posterior displacement of the left mid brain and pons.

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    Histology of corticotroph tumor. This well-differentiated tumor with solid architecture is composed of cells with basophilic cytoplasm that stains intensely for ACTH and keratins (CAM 5.2). It presented in a middle-aged woman with Cushing disease, was resected surgically but recurred several times, eventually giving rise to distant metastasis and ultimately causing the patient’s demise. The only unusual morphological finding was a Ki67 proliferation index that reached 10% in hotspots.

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    Histology of lactotroph tumor. This tumor that caused hyperprolactinemia was treated with dopamine agonist but continued to grow; it was resected surgically and had the typical morphology of a sparsely granulated lactotroph tumor with dopaminergic effects: the small tumor cells are trapped in a fibrovascular stroma, they show nuclear reactivity for PIT1 and ER, and there is scant cytoplasmic PRL. Depsite two surgical sellar resections, she later developed metastases in brain and bone.

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    Histology of Crooke cell tumor. This tumor is composed of large cells with abundant pale acidophillic hyaline cytoplasm that stains for ACTH with accentuation at the cell periphery and focally in the juxtanuclear area. The cytoplasm contains a striking ring-like intense positivity for keratins (CAM 5.2) corresponding to the hyaline material. This aggressive tumor with a Ki67 labeling index, that did not exceed 6%, invaded bony structures in and around the sella and ultimately caused the demise of the patient but there was no evidence of metastatic spread.

  • Agustsson TT, Baldvinsdottir T, Jonasson JG, Olafsdottir E, Steinthorsdottir V, Sigurdsson G, Thorsson AV, Carroll PV, Korbonits M & Benediktsson R 2015 The epidemiology of pituitary adenomas in Iceland, 1955–2012: a nationwide population-based study. European Journal of Endocrinology 173 655664. (https://doi.org/10.1530/EJE-15-0189)

    • Search Google Scholar
    • Export Citation
  • Alshaikh OM, Asa SL, Mete O & Ezzat S 2019 An institutional experience of tumor progression to pituitary carcinoma in a 15-year cohort of 1055 consecutive pituitary neuroendocrine tumors. Endocrine Pathology 30 118127. (https://doi.org/10.1007/s12022-019-9568-5)

    • Search Google Scholar
    • Export Citation
  • Asa SL 2021 Challenges in the diagnosis of pituitary neuroendocrine tumors. Endocrine Pathology 32 222227. (https://doi.org/10.1007/s12022-021-09678-x)

    • Search Google Scholar
    • Export Citation
  • Asa SL & Ezzat S 2016 Aggressive pituitary tumors or localized pituitary carcinomas: defining pituitary tumors. Expert Review of Endocrinology and Metabolism 11 149162. (https://doi.org/10.1586/17446651.2016.1153422)

    • Search Google Scholar
    • Export Citation
  • Asa SL & Perry A 2020 Tumors of the pituitary gland. In AFIP Atlas of Tumor and Nontumor Pathology, Series 5, Fascicle 1. Arlington VA: ARP Press.

    • Search Google Scholar
    • Export Citation
  • Asa SL, Casar-Borota O, Chanson P, Delgrange E, Earls P, Ezzat S, Grossman A, Ikeda H, Inoshita N & Karavitaki N et al.2017 From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club Proposal. Endocrine-Related Cancer 24 C5C8. (https://doi.org/10.1530/ERC-17-0004)

    • Search Google Scholar
    • Export Citation
  • Asa SL, La Rosa S, Basturk O, Adsay V, Minnetti M & Grossman AB 2021a Molecular pathology of well-differentiated gastro-entero-pancreatic neuroendocrine tumors. Endocrine Pathology 32 169191. (https://doi.org/10.1007/s12022-021-09662-5)

    • Search Google Scholar
    • Export Citation
  • Asa SL, Mete O, Cusimano MD, McCutcheon IE, Perry A, Yamada S, Nishioka H, Casar-Borota O, Uccella S & La Rosa S et al.2021b Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification. Modern Pathology 34 16341650. (https://doi.org/10.1038/s41379-021-00820-y)

    • Search Google Scholar
    • Export Citation
  • Asa SL, Mete O & Ezzat S 2021c Genomics and epigenomics of pituitary tumors: what do pathologists need to know? Endocrine Pathology 32 316. (https://doi.org/10.1007/s12022-021-09663-4)

    • Search Google Scholar
    • Export Citation
  • Asioli S, Righi A, Iommi M, Baldovini C, Ambrosi F, Guaraldi F, Zoli M, Mazzatenta D, Faustini-Fustini M & Rucci P et al.2019 Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre. European Journal of Endocrinology 180 127134. (https://doi.org/10.1530/EJE-18-0749)

    • Search Google Scholar
    • Export Citation
  • Bahreini F, Jabbari P, Gossing W, Aziziyan F, Frohme M & & Rezaei N 2021 The role of noncoding RNAs in pituitary adenoma. Epigenomics 13 14211437.

  • Burrow GN, Wortzman G, Rewcastle NB, Holgate RC & Kovacs K 1981 Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. New England Journal of Medicine 304 156158. (https://doi.org/10.1056/NEJM198101153040306)

    • Search Google Scholar
    • Export Citation
  • Casar-Borota O, Boldt HB, Engstrom BE, Andersen MS, Baussart B, Bengtsson D, Berinder K, Ekman B, Feldt-Rasmussen U & Hoybye C et al.2021 Corticotroph aggressive pituitary tumors and carcinomas frequently harbor ATRX mutations. Journal of Clinical Endocrinology and Metabolism 106 11831194. (https://doi.org/10.1210/clinem/dgaa749)

    • Search Google Scholar
    • Export Citation
  • Chiloiro S, Bianchi A, Doglietto F, de Waure C, Giampietro A, Fusco A, Iacovazzo D, Tartaglione L, Di Nardo F & Signorelli F et al.2014 Radically resected pituitary adenomas: prognostic role of Ki 67 labeling index in a monocentric retrospective series and literature review. Pituitary 17 267276. (https://doi.org/10.1007/s11102-013-0500-6)

    • Search Google Scholar
    • Export Citation
  • Costello RT 1936 Subclinical adenoma of the pituitary gland. American Journal of Pathology 12 205216.1.

  • Daly AF & Beckers A 2020 The epidemiology of pituitary adenomas. Endocrinology and Metabolism Clinics of North America 49 347355. (https://doi.org/10.1016/j.ecl.2020.04.002)

    • Search Google Scholar
    • Export Citation
  • Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA & Beckers A 2006 High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. Journal of Clinical Endocrinology and Metabolism 91 47694775. (https://doi.org/10.1210/jc.2006-1668)

    • Search Google Scholar
    • Export Citation
  • de Aguiar PH, Aires R, Laws ER, Isolan GR, Logullo A, Patil C & Katznelson L 2010 Labeling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review. Neurological Research 32 10601071. (https://doi.org/10.1179/016164110X12670144737855)

    • Search Google Scholar
    • Export Citation
  • Elster AD 1993 Modern imaging of the pituitary. Radiology 187 114. (https://doi.org/10.1148/radiology.187.1.8451394)

  • Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML & McCutcheon IE 2004 The prevalence of pituitary adenomas: a systematic review. Cancer 101 613619. (https://doi.org/10.1002/cncr.20412)

    • Search Google Scholar
    • Export Citation
  • Ezzat S, Cheng S & Asa SL 2018 Epigenetics of pituitary tumors: pathogenetic and therapeutic implications. Molecular and Cellular Endocrinology 469 7076. (https://doi.org/10.1016/j.mce.2017.07.011)

    • Search Google Scholar
    • Export Citation
  • Feldkamp J, Santen R, Harms E, Aulich A, Modder U & Scherbaum WA 1999 Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas – results of a prospective study. Clinical Endocrinology 51 109113. (https://doi.org/10.1046/j.1365-2265.1999.00748.x)

    • Search Google Scholar
    • Export Citation
  • Fernandez A, Karavitaki N & Wass JA 2010 Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clinical Endocrinology 72 377382. (https://doi.org/10.1111/j.1365-2265.2009.03667.x)

    • Search Google Scholar
    • Export Citation
  • Fontana E & Gaillard R 2009 Epidemiology of pituitary adenoma: results of the first Swiss study. Revue Medicale Suisse 5 21722174.

  • Freda PU, Bruce JN, Khandji AG, Jin Z, Hickman RA, Frey E, Reyes-Vidal C, Otten M, Wardlaw SL & Post KD 2020 Presenting features in 269 patients with clinically nonfunctioning pituitary adenomas enrolled in a prospective study. Journal of the Endocrine Society 4 bvaa021. (https://doi.org/10.1210/jendso/bvaa021)

    • Search Google Scholar
    • Export Citation
  • Garcia-Rendueles AR, Chenlo M, Oroz-Gonjar F, Solomou A, Mistry A, Barry S, Gaston-Massuet C, Garcia-Lavandeira M, Perez-Romero S & Suarez-Farina M et al.2021 RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas. Oncogene 40 63546368. (https://doi.org/10.1038/s41388-021-02009-8)

    • Search Google Scholar
    • Export Citation
  • Giuffrida G, Ferrau F, Laudicella R, Cotta OR, Messina E, Granata F, Angileri FF, Vento A, Alibrandi A & Baldari S et al.2019 Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience. Endocrine Connections 8 528535. (https://doi.org/10.1530/EC-19-0065)

    • Search Google Scholar
    • Export Citation
  • Gomez-Hernandez K, Ezzat S, Asa SL & Mete Ö 2015 Clinical implications of accurate subtyping of pituitary adenomas: perspectives from the treating physician. Turk Patoloji Dergisi 31 (Supplement 1) 417. (https://doi.org/10.5146/tjpath.2015.01311)

    • Search Google Scholar
    • Export Citation
  • Gossing W, Aziziyan F, Frohme M, Rezaei N, Frohme M & Rezaei N 2021 The role of noncoding RNAs in pituitary adenoma. Epigenomics 13 14211437. (https://doi.org/10.2217/epi-2021-0165)

    • Search Google Scholar
    • Export Citation
  • Greenman Y & Bronstein MD 2021 Cabergoline should be attempted in progressing non-functioning pituitary macroadenoma. European Journal of Endocrinology 185 D11D20. (https://doi.org/10.1530/EJE-21-0344)

    • Search Google Scholar
    • Export Citation
  • Guzel A, Tatli M, Senturk S, Guzel E, Cayli SR & Sav A 2008 Pituitary carcinoma presenting with multiple metastases: case report. Journal of Child Neurology 23 14671471. (https://doi.org/10.1177/0883073808319078)

    • Search Google Scholar
    • Export Citation
  • Hardy J 1973 Transsphenoidal surgery of hypersecreting pituitary tumors. In Diagnosis and Treatment of Pituitary Tumors. International Congress Series No. 303, pp. 179198. Eds Kohler O, Ross GT. Amsterdam: Exerpta Medica.

    • Search Google Scholar
    • Export Citation
  • Ishida A, Shichi H, Fukuoka H, Inoshita N, Ogawa W & Yamada S 2022 Efficacy of temozolomide combined with capecitabine (CAPTEM) on refractory prolactinomas as assessed using an ex vivo 3D spheroid assay. Pituitary 25 238245. (https://doi.org/10.1007/s11102-021-01192-x)

    • Search Google Scholar
    • Export Citation
  • Karpathakis A, Dibra H, Pipinikas C, Feber A, Morris T, Francis J, Oukrif D, Mandair D, Pericleous M & Mohmaduvesh M et al.2016 Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumor. Clinical Cancer Research 22 250258. (https://doi.org/10.1158/1078-0432.CCR-15-0373)

    • Search Google Scholar
    • Export Citation
  • Klibanski A & Zervas NT 1991 Diagnosis and management of hormone-secreting pituitary adenomas. New England Journal of Medicine 324 822831. (https://doi.org/10.1056/NEJM199103213241207)

    • Search Google Scholar
    • Export Citation
  • Knosp E, Kitz K & Perneczky A 1989 Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery 25 927930. (https://doi.org/10.1227/00006123-198912000-00012)

    • Search Google Scholar
    • Export Citation
  • Knosp E, Steiner E, Kitz K & Matula C 1993 Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33 610617; discussion 617. (https://doi.org/10.1227/00006123-199310000-00008)

    • Search Google Scholar
    • Export Citation
  • Kovacs K & Horvath E 1986 Tumors of the pituitary gland. In Atlas of Tumor Pathology, Second Series, Fascicle 21. Washington, D.C.: Armed Forces Institute of Pathology.

    • Search Google Scholar
    • Export Citation
  • Kovacs K, Ryan N, Horvath E, Singer W & Ezrin C 1980 Pituitary adenomas in old age. Journal of Gerontology 35 1622. (https://doi.org/10.1093/geronj/35.1.16)

    • Search Google Scholar
    • Export Citation
  • Landolt AM, Shibata T & Kleihues P 1987 Growth rate of human pituitary adenomas. Journal of Neurosurgery 67 803806. (https://doi.org/10.3171/jns.1987.67.6.0803)

    • Search Google Scholar
    • Export Citation
  • McComb DJ, Ryan N, Horvath E & Kovacs K 1983 Subclinical adenomas of the human pituitary. New light on old problems. Archives of Pathology and Laboratory Medicine 107 488491.

    • Search Google Scholar
    • Export Citation
  • McCormack A, Dekkers OM, Petersenn S, Popovic V, Trouillas J, Raverot G, Burman P & ESE Survey Colla borators 2018 Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. European Journal of Endocrinology 178 265276. (https://doi.org/10.1530/EJE-17-0933)

    • Search Google Scholar
    • Export Citation
  • Mete O, Ezzat S & Asa SL 2012 Biomarkers of aggressive pituitary adenomas. Journal of Molecular Endocrinology 49 R69R78. (https://doi.org/10.1530/JME-12-0113)

    • Search Google Scholar
    • Export Citation
  • Mete O, Cintosun A, Pressman I & Asa SL 2018 Epidemiology and biomarker profile of pituitary adenohypophysial tumors. Modern Pathology 31 900909. (https://doi.org/10.1038/s41379-018-0016-8)

    • Search Google Scholar
    • Export Citation
  • Mindermann T & Wilson CB 1994 Age-related and gender-related occurrence of pituitary adenomas. Clinical Endocrinology 41 359364. (https://doi.org/10.1111/j.1365-2265.1994.tb02557.x)

    • Search Google Scholar
    • Export Citation
  • Monsalves E, Juraschka K, Tateno T, Agnihotri S, Asa SL, Ezzat S & Zadeh G 2014 The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas. Endocrine-Related Cancer 21 R331R344. (https://doi.org/10.1530/ERC-14-0188)

    • Search Google Scholar
    • Export Citation
  • Nachtigall LB, Guarda FJ, Lines KE, Ghajar A, Dichtel L, Mumbach G, Zhao W, Zhang X, Tritos NA & Swearingen B et al.2020 Clinical MEN-1 among a large cohort of patients with acromegaly. Journal of Clinical Endocrinology and Metabolism 105 e2271e2281. (https://doi.org/10.1210/clinem/dgaa142)

    • Search Google Scholar
    • Export Citation
  • Nose V, Ezzat S, Horvath E, Kovacs K, Laws ER, Lloyd R, Lopes MB & Asa SL 2011 Protocol for the examination of specimens from patients with primary pituitary tumors. Archives of Pathology and Laboratory Medicine 135 640646. (https://doi.org/10.5858/2010-0470-SAR1.1)

    • Search Google Scholar
    • Export Citation
  • Oberndorfer S 1907 Karzinoide tumoren des Dünndarms. Frankfurter Zeitschrift für Pathologie 1 425432.

  • Oh JS, Kim HJ, Hann HJ, Kang TU, Kim DS, Kang MJ, Lee JY, Shim JJ, Lee MR & Ahn HS 2021 Incidence, mortality, and cardiovascular diseases in pituitary adenoma in Korea: a nationwide population-based study. Pituitary 24 3847. (https://doi.org/10.1007/s11102-020-01084-6)

    • Search Google Scholar
    • Export Citation
  • Raverot G, Vasiljevic A, Jouanneau E & Trouillas J 2015 A prognostic clinicopathologic classification of pituitary endocrine tumors. Endocrinology and Metabolism Clinics of North America 44 1118. (https://doi.org/10.1016/j.ecl.2014.10.001)

    • Search Google Scholar
    • Export Citation
  • Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, de Krijger RR, Dietel M & El-Naggar AK et al.2018 A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Modern Pathology 31 17701786. (https://doi.org/10.1038/s41379-018-0110-y)

    • Search Google Scholar
    • Export Citation
  • Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ & Petersenn S 2007 Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. European Journal of Endocrinology 156 203216. (https://doi.org/10.1530/eje.1.02326)

    • Search Google Scholar
    • Export Citation
  • Saeger W, Mawrin C, Meinhardt M, Wefers AK & Jacobsen F 2021 Two pituitary neuroendocrine tumors (PitNETs) with very high proliferation and TP53 mutation – high-grade PitNET or PitNEC ? Endocrine Pathology [epub].

    • Search Google Scholar
    • Export Citation
  • Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV & Cusimano M 2009 Ki-67 in pituitary neoplasms: a review – part I. Neurosurgery 65 42943 7; discussion 437. (https://doi.org/10.1227/01.NEU.0000349930.66434.82)

    • Search Google Scholar
    • Export Citation
  • Tampourlou M, Ntali G, Ahmed S, Arlt W, Ayuk J, Byrne JV, Chavda S, Cudlip S, Gittoes N & Grossman A et al.2017 Outcome of nonfunctioning pituitary adenomas that regrow after primary treatment: a study from two large UK centers. Journal of Clinical Endocrinology and Metabolism 102 18891897. (https://doi.org/10.1210/jc.2016-4061)

    • Search Google Scholar
    • Export Citation
  • Terada T, Kovacs K, Stefaneanu L & Horvath E 1995 Incidence, pathology, and recurrence of pituitary adenomas: study of 647 unselected surgical cases. Endocrine Pathology 6 301310. (https://doi.org/10.1007/BF02738730)

    • Search Google Scholar
    • Export Citation
  • Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ, Murray D & Laws Jr ER 1996 Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38 99106; discussion 106. (https://doi.org/10.1097/00006123-199601000-00024)

    • Search Google Scholar
    • Export Citation
  • Tjornstrand A, Gunnarsson K, Evert M, Holmberg E, Ragnarsson O, Rosen T & Filipsson Nyström H 2014 The incidence rate of pituitary adenomas in western Sweden for the period 2001–2011. European Journal of Endocrinology 171 519526. (https://doi.org/10.1530/EJE-14-0144)

    • Search Google Scholar
    • Export Citation
  • Tortosa F & Webb SM 2016 Atypical pituitary adenomas: 10 years of experience in a reference centre in Portugal. Neurologia 31 97105. (https://doi.org/10.1016/j.nrl.2015.06.010)

    • Search Google Scholar
    • Export Citation
  • Trouillas J, Roy P, Sturm N, Dantony E, Cortet-Rudelli C, Viennet G, Bonneville JF, Assaker R, Auger C & Brue T et al.2013 A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathologica 126 123135. (https://doi.org/10.1007/s00401-013-1084-y)

    • Search Google Scholar
    • Export Citation
  • Uccella S, La Rosa S, Metovic J, Marchiori D, Scoazec JY, Volante M, Mete O & Papotti M 2021 Genomics of high-grade neuroendocrine neoplasms: well-differentiated neuroendocrine tumor with high-grade features (G3 NET) and neuroendocrine carcinomas (NEC) of various anatomic sites. Endocrine Pathology 32 192210. (https://doi.org/10.1007/s12022-020-09660-z)

    • Search Google Scholar
    • Export Citation
  • Uzilov AV, Taik P, Cheesman KC, Javanmard P, Ying K, Roehnelt A, Wang H, Fink MY, Lau CY & Moe AS et al.2021 USP8 and TP53 drivers are associated with CNV in a corticotroph adenoma cohort enriched for aggressive tumors. Journal of Clinical Endocrinology and Metabolism 106 826842. (https://doi.org/10.1210/clinem/dgaa853)

    • Search Google Scholar
    • Export Citation
  • Villa C, Vasiljevic A, Jaffrain-Rea ML, Ansorge O, Asioli S, Barresi V, Chinezu L, Gardiman MP, Lania A & Lapshina AM et al.2019 A standardised diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a European Pituitary Pathology Group (EPPG) proposal. Virchows Archiv 475 687692. (https://doi.org/10.1007/s00428-019-02655-0)

    • Search Google Scholar
    • Export Citation
  • WHO Classification of Tumours Editorial Board 2021 WHO Classification of Central Nervous System Tumours, 5th Series. Lyon, France: IARC.

  • WHO Classification of Tumours Editorial Board 2022 WHO Classification of Endocrine and Neuroendocrine Tumours, 5th Series. Lyon, France: IARC.

    • Search Google Scholar
    • Export Citation
  • Wierinckx A, Auger C, Devauchelle P, Reynaud A, Chevallier P, Jan M, Perrin G, Fevre-Montange M, Rey C & Figarella-Branger D et al.2007 A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocrine-Related Cancer 14 887900. (https://doi.org/10.1677/ERC-07-0062)

    • Search Google Scholar
    • Export Citation
  • Wilson CB & Dempsey LC 1978 Transsphenoidal microsurgical removal of 250 pituitary adenomas. Journal of Neurosurgery 48 1322. (https://doi.org/10.3171/jns.1978.48.1.0013)

    • Search Google Scholar
    • Export Citation
  • Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN & Rashid A et al.2008 One hundred years after ‘carcinoid’: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical Oncology 26 30633072. (https://doi.org/10.1200/JCO.2007.15.4377)

    • Search Google Scholar
    • Export Citation
  • Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V & Laws Jr ER 2011 Atypical pituitary adenomas: incidence, clinical characteristics, and implications. Journal of Neurological Surgery 114 336344. (https://doi.org/10.3171/2010.8.JNS10290)

    • Search Google Scholar
    • Export Citation