Endocrine Pathology (2021) 32:3–16

https://doi.org/10.1007/s12022-021-09663-4

Genomics and Epigenomics of Pituitary Tumors: What Do Pathologists

Need to Know?
Sylvia L. Asa1,2   · Ozgur Mete2,3 · Shereen Ezzat4

Accepted: 4 January 2021 / Published online: 12 January 2021

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021

Abstract
Molecular pathology has advanced our understanding of many tumors and offers opportunities to identify novel therapies. In
the pituitary, the field has uncovered several genetic mutations that predispose to pituitary neuroendocrine tumor (PitNET)
development, including MEN1, CDKN1B, PRKRIα, AIP, GPR101, and other more rare events; however, these genes are only
rarely mutated in sporadic PitNETs. Recurrent genetic events in sporadic PitNETs include GNAS mutations in a subset of
somatotroph tumors and ubiquitin-specific peptidase mutations (e.g., USP8, USP48) in some corticotroph tumors; to date,
neither of these has resulted in altered management, and instead, the prognosis and management of PitNETs still rely more
on cell type and subtype as well as local growth that determines surgical resectability. In contrast, craniopharyngiomas have
either CTNNB1 or BRAFV600E mutations that correlate with adamantinomatous or papillary morphology, respectively; the
latter offers the opportunity for targeted therapy. DICER1 mutations are found in patients with pituitary blastoma. Epige-
netic changes are implicated in the pathogenesis of the more common sporadic pituitary neoplasms including the majority
of PitNETs and tumors of pituicytes.

Keywords  Pituitary neuroendocrine tumor · Pituicytoma · Craniopharyngioma · Pituitary blastoma · Mutation · Epigenetics

Introduction somatotrophs, lactotrophs, mammosomatotrophs,

The pituitary is a complex endocrine gland. The anterior
lobe is composed of epithelial neuroendocrine cells; the
posterior lobe is composed of pituicytes (modified glia) and
the terminals of hypothalamic neuronal hormone-secreting
cells [1]. Together, they are responsible for synthesis and
secretion of peptide hormones which regulate metabolism,
growth, and reproduction. In the adenohypophysis, there are
seven known terminally differentiated epithelial cell types
in three lineages: TPIT-lineage corticotrophs, PIT1-lineage
* Sylvia L. Asa
pathlady01@gmail.com
1
Department of Pathology, University Hospitals Cleveland
Medical Center, Case Western Reserve University,
Cleveland, Ohio, USA
2
Department of Pathology, University Health Network,
Toronto, ON, Canada
3
Department of Laboratory Medicine and Pathobiology,
University of Toronto, Toronto, ON, Canada
4
Department of Medicine, University Health Network
and University of Toronto, Toronto, ON, Canada
and thyrotrophs, and SF1-lineage gonadotrophs.
Corticotrophs produce pro-opiomelanocortin (POMC)
that is cleaved into several hormones, the most critical
being adrenocorticotropin (ACTH) that regulates adrenal
glucocorticoid production; other products of POMC include
melanocyte-stimulating hormone (MSH), endorphins and
enkephalins that modulate pain and anxiety perception, and
several other bioactive peptides. The PIT1 family of cells
is complex. Somatotrophs are responsible for production
of growth hormone (GH) that is required for normal
somatic growth in childhood and for maintenance of lean
body mass in adults. With the additional expression of
estrogen receptor-alpha (ER), PIT1-lineage cells become
mammosomatotrophs that also produce prolactin (PRL), a
hormone that is required for lactation but also plays a role
in emotional health including bonding. Both GH and PRL
also have been implicated in immune regulation. Mature
lactotrophs arise from mammosomatotrophs with the
additional expression of an uncharacterized GH repressor
and produce only PRL. PIT1-lineage cells that also express
GATA2/3 develop into thyrotrophs that produce thyrotropin
(thyroid-stimulating hormone, TSH). There is evidence of

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fluidity of the PIT1-lineage cells that can transdifferentiate
under physiological conditions. Somatotrophs predominate
during childhood and adolescence but transform into
mammosomatotrophs then lactotrophs during pregnancy
and lactation, with evidence of reversal after lactation is
terminated [2]. Animal studies have shown that somatotrophs
can reversibly transform into thyrotrophs in hypothyroidism
[3]. The third lineage, SF1-directed gonadotrophs, produces
both gonadotropins, follicle-stimulating hormone (FSH) and
luteinizing hormone (LH). An interesting complexity is that
TSH, FSH, and LH are all dimeric glycoprotein hormones
that have a common alpha-subunit and distinct beta-subunits
that confer specificity; their various cell types also rely on
expression of GATA2/3 in addition to PIT1 for thyrotrophs
and SF1 for gonadotrophs.
Tumors of these adenohypophyseal neuroendocrine
cells, now classified as pituitary neuroendocrine tumors
(PitNETs) [4], recapitulate the normal cell types, but in
addition, they may develop distinct morphologic subtypes
[1]; these include sparsely and densely granulated variants
of corticotrophs, somatotrophs, and lactotrophs, as well as
tumors that are less terminally differentiated, such as the
so-called “poorly differentiated PIT1-lineage” and “acidophil
stem cell” tumors. Rare pituitary tumors have features of
neuroendocrine cells but lack any lineage determination
and are classified as “null cell” tumors. PitNETs show
a spectrum of clinical behaviors that vary from indolent
prolactinomas with exquisite responsiveness to medical
therapy to aggressive infiltrative tumors that invade brain
and surrounding sinuses and persistent hormone excess with
life-threatening complications. Very rarely they metastasize.
In the posterior lobe, tumors derived from pituicytes,
modified glia, are known as pituicytomas; they have
several variants that reflect the normal spectrum of
pituicytes, including oncocytic tumors known as spindle
cell oncocytoma, granular cell tumors, and ependymal
variants [5]. Tumors of the hypothalamic neurons that
form the hormone-containing posterior pituitary include
gangliocytomas and neurocytomas, recapitulating the
neurons of the magnocellular and parvocellular nuclei of the
hypothalamus [6]. These tumors all express TTF1 that is a
feature of the basal hypothalamus; the neurons also produce
vasopressin and oxytocin.
Tumors of Rathke’s cleft that is the developmental
pr imordium of t he adenohypophysis include
craniopharyngiomas and pituitary blastomas [1].
The addition of molecular diagnostics has had
significant impact on the practice of surgical pathology.
In some areas, for example some parts of neuropathology
and hematopathology, some tumor diagnoses cannot
be confirmed without a molecular test. However, in
the classification of pituitary neoplasia, this is not the
case. There are indeed specific mutations that have
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been identified in some tumor subtypes [7–8], and the
importance of recognizing genetic predisposition to these
neuroendocrine tumors should not be overlooked; however,
the most important role of the pathologist is to accurately
subtype pituitary lesions to guide the management of the
individual patient [9]. As will become evident, there are
structural features that correlate with specific mutations but
morphologic classification along with clinical and radiologic
data remains the best predictor of patient prognosis and can
predict therapeutic responsiveness [1].
In this review, we will summarize the molecular altera-
tions that predispose to the development of pituitary tumors,
the sporadic genetic events that have been described, and
conclude with a discussion of the epigenetic changes that
seem to be more critical [10] and may represent features
that can be modulated to prevent the development of these
increasingly common neoplasms.
Genetics of Inherited Pituitary Tumors
A small proportion of PitNETs occur in patients who have
germline genetic alterations that predispose them to PitNET
development (Table 1). In general, these patients present at
a younger age than patients with sporadic tumors [11–15].
The first example, multiple endocrine neoplasia type 1
(MEN1), was originally described by Wermer in 1954 [16].
The gene responsible for this autosomal dominant disorder
with incomplete penetrance, MEN1 at 11q13, encodes
the 610 amino acid protein menin, a scaffold protein that
regulates gene transcription through interactions with
multiple partners and regulates a number of signaling
pathways. Mutations that inactivate menin must be
associated with loss of heterozygosity (LOH) of the normal
allele to give rise to neoplasia. Interestingly, menin is
ubiquitously expressed but tissues that most commonly
develop tumors are the pituitary, parathyroids, and endocrine
pancreas. Patients with MEN1 are also more susceptible to
the development of adrenal cortical lesions [17] and breast
cancer [18]. Approximately two-thirds of mutation carriers
develop a PitNET. Most kindreds have had a predominance
of tumors of PIT1 lineage, including typical prolactinomas,
tumors that produce growth hormone (GH) or GH and
PRL [11, 19–21] and poorly differentiated tumors of PIT1
lineage [22], but examples of almost any adenohypophyseal
tumor type have been reported. Some reports have identified
multiple and multicentric neoplasms in the pituitary [21, 23].
A rare syndrome that mimics MEN1 clinically can
result from defects in CDKI genes. This so-called MEN4
syndrome has been reported in patients with mutations
in the CDKN1B/p27Kip1 gene [24,  25] or the CDKN2C/
p18INK4c gene [26, 27]. In addition to PitNETs, parathyroid,
and pancreatic endocrine proliferations, these mutations
Endocrine Pathology (2021) 32:3–16 5

Table 1  Genetic susceptibility in pituitary neuroendocrine tumors

Syndrome/condition Gene(s) PitNETs Other NETs Other non-neuroendocrine
lesions

MEN1 syndrome MEN1 PIT1-lineage Parathyroid NET Adrenal cortical neoplasms

most common Pancreatic NET Breast carcinoma
All types reported Duodenal NET
Pulmonary NET
Thymic NET
MEN4 syndrome CDKN1B Parathyroid NET Lymphoma
Pancreatic NET Breast carcinoma
Small Intestinal NET
Carney complex PRKRIα Densely granulated Pigmented nodular adrenocor-
Other (unknown) somatotroph tumors tical disease
Mammosomato- Testicular tumors
troph tumors Mucosal nevi
Cardiac and other myxomas
Malignant melanotic nerve
sheath tumors
Familial isolated pituitary AIP Sparsely granu- Pancreatic NET Scant morphologic data
adenoma (isolated familial Other (unknown) lated somatotroph Duodenal (ampullary type)
somatotropinoma) tumor most common NET
All types reported
SDHx-related familial paragan- SDHx  Acidophil stem cell Pheochromocytomas and para- Gastrointestinal stromal tumors
glioma syndromes tumors gangliomas Renal cell carcinoma
Pancreatic ­NETa
Hyperparathyroidism jaw tumor CDC73 Somatotropha Parathyroid NETs Ossifying fibromas of bone
syndrome Renal cell carcinoma
Uterine tumors
DICER syndrome DICER1 Pituitary blastoma  Pleuropulmonary blas-
toma; thyroid follicular
neoplasms;Sertoli-Leydig
cell tumors; sarcomas
Lynch syndrome (HNPCC) MLH1 Multiple types Pancreatic NET Colorectal cancer
MSH2, Endometrial cancer
MSH6 Gastric cancer
PMS2 Biliary and pancreatic cancer
Urinary tract cancers
X-linked acrogigantism Xq26 Densely granulated
microduplication somatotroph tumors
GPR101 Mammosomato-
troph tumors
McCune-Albright GNAS Densely granulated Adrenal and thyroid adenomas
somatotroph tumors Polyostotic fibrous dysplasia
Mammosomato- Cafe-au-lait skin pigmentation
troph tumors Precocious puberty
a
 Single case reported

predispose to small intestinal neuroendocrine tumors,
lymphoma, and breast cancer [28]. Similarly, MEN1-like
acromegaly and hyperparathyroidism were associated in a
patient with a germline mutation of CDC73 [29].
Carney’s complex (CNC) [30] is an autosomal dominant
disorder in which about 50% of patients have germline
mutations in the PRKAR1Aα gene that encodes the protein
kinase A regulatory subunit 1Aα. This results in unrestrained
cAMP signaling [31,  32] (Fig.  1) that manifests in the
pituitary with GH-secreting hyperplasia and neoplasia. Other
features include pigmented nodular adrenocortical disease,
testicular tumors, spotty pigmentation due to nevi involving
mucosal surfaces including the lips, cardiac and other
myxomas, and malignant melanotic nerve sheath tumors [30].
The isolated familial somatotropinoma (IFS) syndrome
[33], now known as familial isolated pituitary adenoma
(FIPA) syndrome [34] since other PitNETs also occur, is
a familial disorder attributed in about 50% of families to
germline mutations in the AIP gene that encodes the aryl
hydrocarbon-interacting protein (AIP); this chaperone
protein modulates expression of the aryl hydrocarbon
receptor (Fig. 1), which mediates the carcinogenic effects

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6 Endocrine Pathology (2021) 32:3–16
Fig. 1  Molecular pathogenesis of pituitary somatotroph tumors.
Sporadic or germline activating mutations in GNAS result in constitu-
tive activation of the Gsα that upregulates adenylyl cyclase resulting
in increased cAMP, causing phosphorylation of CREB and synthesis
of GH as well as αSU. In patients with Carney Complex mutations
inactivating PRKR1A have the same effect by enhancing CREB
of dioxins [35, 36] thereby acting as a tumor suppressor
[15, 34, 37]. The commonest tumor type is the sparsely
granulated somatotroph tumor, and evidence suggests that
germline AIP mutations are identified more frequently in
pediatric and young adults (<  30  years) with sparsely
granulated somatotroph tumors [12].
Rare PitNETs have been described in patients with
mutations in the genes encoding the various components
of the succinate dehydrogenase (SDH) complex; these
mutations primarily cause familial pheochromocytomas and
paragangliomas, gastrointestinal stromal tumors (GISTs),
and renal carcinomas [38, 39]. Another familial syndrome
associated with occasional PitNETs is Lynch syndrome due
to mutation in one of the mismatch repair enzymes, MLH1,
MSH2, MSH 6, or PMS2, that is usually associated with
colorectal carcinomas, ovarian and endometrial carcinomas,
as well as several other tumor types [40].
Inherited or sporadic Xq26 microduplications and
GPR101 mutation are the cause of a rare form of early
childhood X-linked acrogigantism (X-LAG) [41]; patients
with this disorder have mammosomatotroph or somatotroph
hyperplasia and/or mammosomatotroph PitNET [42].
Pituitary blastomas are rare tumors that are composed
of adenohypophyseal neuroendocrine cells admixed with
primitive Rathke’s pouch epithelium and folliculostellate cells
13
activation. Tumors with these alterations have a densely granulated
phenotype and respond well to somatostatin analog therapy that
reduces cAMP. In contrast, changes shown on the right including
AIP mutation or silencing, GHR inactivation, or other mechanisms of
reducing STAT signaling, result in sparsely granulated somatotroph
tumors that have fibrous bodies (modified from (7))
[43]. These tumors occur almost exclusively in patients with
germline mutations of the DICER1 gene [44, 45] and may
be associated with other phenomena of that syndrome that is
also known as “pleuropulmonary blastoma-familial tumor and
dysplasia syndrome” or simply DICER1 syndrome.
Genetic Alterations in Sporadic Pituitary
Tumors
The majority of PitNETs are sporadic tumors; the genes
implicated in familial syndromes discussed above are not
commonly altered in these sporadic neoplasms. While
chromosomal alterations seem to vary based on tumor
functionality in PitNETs [46], there are specific mutations
that have been identified in subsets of the more common
tumors. The molecular alterations are summarized in Table 2.
The molecular features of the unusual plurihormonal tumors
and multiple PitNETs are largely unknown given their rarity.
A subset of somatotroph tumors has activating mutations
of GNAS. This gene is associated with several other endocrine
tumors including functioning thyroid adenomas, adrenal
cortical adenomas, and gonadal tumors. The protein product of
this gene, Gsα, mediates signaling from seven transmembrane
domain G-protein coupled receptors (including the receptors
Endocrine Pathology (2021) 32:3–16 7

Table 2  Common sporadic Gene(s) PitNETs Clinical correlates

genetic alterations in pituitary
tumors
GNAS Densely granulated somatotroph/mammosoma- Florid acromegaly
totroph tumors T2 hypointensity on MRI
Somatostatin responsiveness
USP8 Densely granulated corticotroph Florid Cushing disease
USP48 Pasireotide responsiveness
ATRX Corticotroph tumors Aggressive, recurrent, metastatic
CTNNB1 Adamantinomatous craniopharyngioma
BRAFV600E Papillary craniopharyngioma Targeted therapy

for GHRH, TSH, ACTH, and MSH) to activate cyclic
AMP (Fig. 1). Familial transmission of this mutation is not
recognized since germline mutation is embryonic lethal;
however, sporadic mosaicism gives rise to McCune-Albright
syndrome, which manifests these various endocrinopathies
as well as fibrous dysplasia of bone and cafe-au-lait spots
of the skin. In isolated sporadic somatotroph tumors, this
mutation is associated with smaller tumors that give rise to
florid acromegaly and high GH and IGF1 levels and predicts
responsiveness to somatostatin analogs. Several studies have
shown that this mutation is most often seen in tumors with a
densely granulated somatotroph phenotype [47, 48] but not
all densely granulated tumors harbor GNAS mutations and the
correlation is not perfect [49, 50]; nevertheless, histopathology
remains the best predictor of therapeutic responsiveness
[51]. For this reason, molecular testing is not recommended
as a routine analysis. Transcriptome profiling of pituitary
neuroendocrine tumors with GH and PRL co-expression
segregated along with somatotroph tumors in a recent study
[46]; this may be at least partially attributable to the frequency
of GNAS-related alterations in mammosomatotroph tumors
which clinically and morphologically resemble densely
granulated somatotroph tumors but also express ER and PRL.
An unusual germline SSTR5 inactivating mutation
was reported in a patient with acromegaly [52]. Growth
hormone autoregulation may also be implicated in
somatotroph pathophysiology. Mouse studies have shown
that loss of GH signaling through either deletion of the
GHR or expression of a dominant negative GH results
in somatotroph hypertrophy and hyperplasia [53]. In
human tumors, treatment with a dominant negative GH,
pegvisomant, in vitro caused the formation of fibrous bodies,
and a somatic mutation in the extracellular domain of the
GH receptor (GHR) that impairs receptor glycosylation,
reducing GH-ligand binding, was identified in sparsely
granulated somatotroph tumors that feature this keratin
aggresome [54]. This suggests that impaired hormone auto-
feedback may be implicated in the pathogenesis of these
tumors and subcellular structures [54]. This mutation has not
been identified in other studies but the inhibitory effect of
a GH agonist confirmed GH autoregulation in somatotroph
tumors that were not characterized for tumor subtype [55]
and STAT-3 upregulation has been shown to correlate
with GH expression in somatotroph tumors [56] (Fig. 1),
supporting the hypothesis that an altered GHR signaling
pathway may play a role in the pathogenesis of sparsely
granulated somatotroph tumors and their fibrous bodies.
Dopamine is the major regulator of prolactin synthesis
and secretion through tonic inhibition. While most lactotroph
tumors respond to dopamine, it has been suggested that loss
of activity of the type 2 dopamine receptor, D2R, may be
the cause of dopamine resistance in some tumors. However,
mutations in the D2R gene have not been identified. D2R
expression is dependent on nerve growth factor (NGF)
binding to the NGF receptor p75, and some authors have
suggested that NGF alterations may explain dopamine
resistance [57]. A recent study of sporadic lactotroph tumors
identified large-scale somatic copy number alterations,
especially gains, as well as sequence variants in 15 genes
including DRD2, PRL, TMEM67, and MLH3 that are possibly
involved in tumorigenesis [58]. In a study of 38 high-risk
histological subtypes of PitNETs, homozygous CDKN2A
deletion using FISH was reported in densely granulated
lactotroph tumors that also exhibited increased proliferative
activity [59]; this finding suggests a possible utility of p16
immunohistochemistry in this group of PitNETs.
Thyroid hormone receptors (TRs) are important
regulators of thyrotroph function and proliferation. TRα and
TRβ, which each undergo alternative splicing to generate
2 isoforms, are ubiquitously expressed [60]; however, the
β2 isoform is of particular importance in the pituitary. The
β-isoforms are underexpressed in clinically silent tumors,
but the significance of this may be more related to the fact
that most of these tumors are composed of gonadotrophs
[60]. Novel missense mutations have been reported in some
thyrotroph tumors and occasional clinically silent tumors
[61, 62].
Some corticotroph tumors, especially those with
biochemical functionality, have mutations of USP8, a gene
encoding a member of the ubiquitin protease family that
is thought to alter EGFR signaling but more recently has
been suggested to affect POMC and ACTH degradation
[63]. This mutation has been reported mainly in small
densely granulated corticotroph tumors [64–67] and is

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8 Endocrine Pathology (2021) 32:3–16
thought to be predictive of pasireotide response [66] but
has not yet reached clinical relevance. Pathogenic germline
USP8 variants have also been recently defined in pediatric
Cushing disease [68]. Somatic USP48 [69] and BRAFV600E
mutations [69] have also been identified in a few USP8-
wild-type corticotroph tumors. BRAF mutations were shown
to enhance POMC transcription in functional studies [69].
ATRX mutations with LOH and loss of immunoreactivity
have been reported in aggressive and metastatic corticotroph
tumors [70-71]. PTEN has also been suggested to play a
role in metastatic spread of these tumors [71]. While this
clarifies the basis of these more aggressive tumors, there is
no predictive value for therapeutic guidance.
Germline mutation of the GCR​ gene encoding the
glucocorticoid receptor was identified in a small number of
patients with pituitary Cushing’s disease [72] and somatic
mutations in GCR​were found in some sporadic tumors [73],
suggesting that diminished glucocorticoid inhibition may
play a role in the development of some of these tumors.
Apart from these small subsets of tumors, the majority of
sporadic PitNETs lack recurrent mutations, and molecular
studies have shown only variable genomic instability with
copy number variations [58, 74–76].
Mutations in codon 12 of H-RAS have been reported in
only a few PitNETs including an aggressive prolactinoma
and a few rare metastatic tumors [77, 78].
While RB-deficient mice develop pituitary tumors of
the corticotroph lineage, mutations in this gene are not
implicated in human tumors. A single report suggested
that loss of RB expression may play a role in metastatic
progression [79]. The role of the TP53 oncogene is also
unclear; p53 immunoreactivity was initially reported
in carcinomas [80-81], but this is also the case in non-
metastatic PitNETs where it became a standard feature to
report [82]. This is now known to be wild-type expression
Fig. 2  Molecular pathogenesis of craniopharyngioma. Adamanti-
nomatous craniopharyngioma (left) is characterized by mutations of
β-catenin that can be identified by nuclear translocation of the pro-
13
and mutation of TP53 has been reported in only a very few
documented cases [80;83–87]. While there may be some
prognostic value of p53 staining [80], this is controversial
and there is no consistent correlation between p53 indices
and tumor invasion or recurrence [88].
Craniopharyngiomas represent the one tumor type
with a clear-cut molecular basis [89]. These tumors have
two distinct morphologic variants. Adamantinomatous
craniopharyngiomas resemble the dental ameloblastic
organ and adamantinoma; the majority of these lesions
harbor mutations of the CTNNB1 gene that encodes beta-
catenin [89–92] resulting in aberrant nuclear localization
of immunohistochemical reactivity for β-catenin (Fig. 2a);
however, nuclear staining tends to be only focal, most
often found in morular structures. In contrast, papillary
craniopharyngiomas that are less common and rare in children
are composed of more regular squamous epithelium that
harbors BRAFV600E mutations in nearly all cases [89, 93], a
mutation that can be detected using the VE1 antibody (Fig. 2b)
[94]. The identification of BRAFV600E mutation has paved the
way for medical therapy with targeted BRAF inhibition for
recurrent tumors that cannot be resected surgically [95–97].
There is currently no evidence of germline susceptibility
to the development of pituicyte-derived posterior lobe tumors
including conventional pituicytomas, spindle cell oncocytomas,
granular cell tumors, and sellar ependymomas. Although
a single case of pituicytoma has been linked to pathogenic
BRAFV600E, NF1, and TSC1 variants [98], these tumors usually
lack BRAF and IDH1 mutations that are more frequent in
low-grade astrocytomas [5]. Somatic copy number alterations
involving 1p, 5p, 14q, and 22q have been identified in a
pituicytoma [99]. The limited data on molecular alterations
suggested somatic alterations leading to the activation of the
MAPK pathway (e.g., HRAS, FAT1, SND1) in conventional
and oncocytic pituicytomas [98, 100].
tein on immunohistochemistry. Papillary craniopharyngiomas (right)
harbor BRAFV600E mutations that can be identified with the VE1
antibody
Endocrine Pathology (2021) 32:3–16
Epigenetic Alterations Underlying Pituitary
Neoplasia
Epigenetic dysregulation is more frequent than structural
genetic alterations in sporadic pituitary neoplasms (Fig. 3)
[10].
Dysregulated Growth Factor Signaling
A number of growth factors play important roles in
pituitary cell growth and hormone secretion, and there
is evidence of altered expression of these growth factors
and/or their receptors in PitNETs. Transforming growth
factor-α (TGF-α) is expressed in PitNETs as well as in
normal adenohypophyseal cells [101]; it may mediate the
proliferative effects of estrogen [102] and causes tumor
development in mice [103]. Epidermal growth factor (EGF)
is expressed in adenohypophyseal cells and all types of
functional and nonfunctional PitNETs. EGF stimulates
PRL and ACTH synthesis and secretion. The EGF-receptor
(EGF-R) family that mediates signaling of TFG-α and EGF
includes four members, EGF-R (ErbB1, HER1), p185
Her2/neu (ErbB2 or HER2), ErbB3 (HER3), and ErbB4
(HER4). EGF-R appears to be critical for somatotroph
development as shown by transgenic mice overexpressing
Fig. 3  Epigenetic alterations in pituitary neuroendocrine tumors.
Nuclear transcription is regulated by menin, DNMTs, Ikaros, and
HMGAs. Alterations in these proteins, by mutation and LOH of
menin in MEN1 or by dysregulation in the other factors in sporadic
tumors, change chromatin accessibility to decrease expression of
tumor suppressors such as CDKIs, Rb, p53, GADD45γ, MEG3,
9
a dominant-negative EGF-R [104]. All four receptors
are expressed by human PitNETs and are upregulated in
invasive and recurrent tumors [105] with the exception of
ErbB4 [106], and despite the fact that there is no evidence of
amplification or mutation of EGF-R family members in these
neoplasms, pharmacotherapeutic targeting of ErbB2 has been
proposed for treatment [107]. Indeed, the only rationale for
this would be to target the putative augmented signaling of
EGF-R in corticotroph tumors with USP8 mutations.
Fibroblast growth factors (FGFs) and their receptors
(FGFRs) regulate development, growth, and angiogenesis
in many organ systems. There are at least 23 FGFs. The
original FGFs include acidic FGF1 and basic FGF2; the
latter was originally isolated from the bovine pituitary and
was subsequently shown to be produced by folliculo-stellate
cells [108, 109]. FGFs are critical for pituitary development
[110–112] and blockade of FGF signaling using a dominant
negative receptor in mice abrogates pituitary formation
[113]. FGF2 is expressed by human and rodent PitNETs
[114-116] and elevated circulating FGFs are found in
patients with PitNETs [114,  117]. FGFs signal through
four receptors, FGFR1 through FGFR4, each of which has
multiple isoforms. Mutation in FGFR1 has been associated
with combined pituitary hormone deficiency [118] and two
FGFRs have been shown to be altered pituitary tumors [119].
or PTAG, and dysregulate growth factors, releasing cells into
proliferation. Changes in miRNAs also affect expression levels
of important cell cycle regulators, growth factors, and adhesion
molecules that restrain growth and enhance invasion, which is also
enhanced by a polymorphism in the MMP-1 promoter
13
10
FGFR2-IIIb is a receptor isoform that is expressed in
the normal pituitary but is subject to promoter methylation
and down-regulation in pituitary tumors [119]. FGFR2-IIIb
inhibits pituitary tumor cell proliferation [120] and silences
expression of the cancer/testis-melanoma-associated
antigens (MAGE-A) [121]. In contrast to the expression
of FGFRs 1, 2, and 3 in the normal gland, FGFR4 is not
normally expressed but is identified in PitNETs [119].
Epigenetic changes causing alternative transcription
initiation [122, 123] result in expression of a truncated ptd-
FGFR4 that displaces N-cadherin from the cell membrane,
disrupting cell adhesion [124,  125] and expression of
FGFR4 is associated with aggressive behavior [126–128].
This mechanism of altering cell adhesion is also suggested in
reports that PSA-NCAM expression enhances tumor growth
and invasiveness [129], since PSA-NCAM would also
disrupt the tri-protein FGFR4.N-cadherin-NCAM complex.
The FGFR4 gene has a polymorphism, FGFR4-G488R,
which alters signaling of this receptor; the FGFR4-R388
isoform has been associated with more aggressive behavior
in a number of epithelial malignancies. In the pituitary, it
enhances cell growth and impairs normal hormone regulation
in corticotrophs and somatotrophs [130, 131], providing a
possible genetic basis for the development of larger tumors
with less hormonal activity, that is, sparsely granulated
variants of corticotroph and somatotroph tumors. It may also
modulate response to somatostatin analog therapy [132].
Another polymorphism that has been implicated in
invasiveness of PitNETs is in the MMP-1 promoter where
insertion of a guanine residue increases the risk of tumor
invasion [133].
Dysregulated Tumor Suppressors
Epigenetic silencing of several tumor suppressor genes has
been documented in PitNETs [8-10].
The retinoblastoma (RB1) tumor suppressor gene on
chromosome 13q has long been a target of investigation,
since RB1-deficient mice develop pituitary intermediate
lobe tumors [134]. RB1 mutations, including in the promoter
region, are not identified in human PitNETs [135–137], but
instead, RB1 promoter methylation causing gene silencing
has been described [136] as well as LOH at 13q in tumors
with unmethylated RB1 [138]. The ARF tumor suppressor
may modulate RB1-mediated tumorigenesis [139], and the
inhibitor of differentiation Id2 also interacts with RB1 [140]
and vascular endothelial growth factor (VEGF) [140] but no
mutations have been described in these genes in PitNETs.
Cyclins promote mitosis through cyclin-dependent
kinases (CDKs) that are inhibited by CDK inhibitors
(CDKIs) [141]. Knockout of cyclins and CDKIs in mice
consistently result in pituitary tumors; these include
­p27kip1–null mice [142–144], ­p18ink4c–null mice [145] and
13
Endocrine Pathology (2021) 32:3–16
double knockout mice [145]. No mutations of these genes
have been reported in sporadic tumors but protein levels
of p27 are reduced in functioning corticotroph tumors
[146,  147]; interestingly, this is not the case in silent
corticotroph tumors [128], suggesting that glucocorticoid
excess mediates protein stability [148]. Expression of
­p16ink4A is also silenced by promoter methylation [149, 150].
Similarly, GADD45γ (growth arrest and DNA damage-
inducible 45γ) and MEG3 (a human homolog of the mouse
maternally imprinted Gtl2 gene) are downregulated in
PitNETs by CpG island promoter methylation [151–153].
Another gene involved in the DNA damage repair response,
CHEK2, is upregulated in corticotroph tumors and
suppressed in somatotroph tumors [154]. Pituitary tumor
apoptosis gene (PTAG), on chromosome 22, was identified
as a methylation-sensitive anti-apoptotic gene expressed in
PitNETs [155]..
Epigenetic Regulators Implicated in Pituitary
Tumors
The striking epigenetic changes resulting in silencing of tumor
suppressors in pituitary tumors have led to studies of epigenetic
regulators in these tumors. Indeed, menin, the protein product
of the MEN1 gene, is itself a nuclear scaffold protein that
regulates gene transcription by chromatin remodeling.
Other factors that regulate gene expression include DNA
methyltransferase (DNMT) enzymes [10]. Studies have shown
that DNMT1 and DNMT3a are not altered but DNMT3b is
overexpressed in pituitary tumor cells, and it is implicated in
the silencing of pRB1, p21, and p27 [10, 156].
In addition to DNA methylation, chromatin remodeling
is mediated, in part, through post-translational histone
modifications that control access of DNA to transcription
factors. One of the factors that is involved in chromatin
remodeling in the pituitary is Ikaros, originally described
in lymphoid cells [157]. Ikaros in both the wild-type
and dominant-negative (dn) isoforms are expressed in
hypothalamic and pituitary neuroendocrine cells. Ikaros is
required for normal development of the pituitary TPIT lineage
[158] as well as hypothalamic GHRH neurons that are required
for pituitary somatotroph growth and function [159]. It also
may regulate PIT1-lineage cell functional differentiation by
modulating GH and PRL hormone gene expression [160]. A
dominant negative isoform of Ikaros is expressed in pituitary
tumors [123] where it activates the Bcl-XL promoter [161],
enhancing pituitary cell survival and evasion of apoptosis.
Ikaros also can regulate cholesterol uptake through the low-
density lipoprotein receptor (LDL-R) and sterol-regulatory
element binding protein 2 (SREBP2) to provide lipid required
for synthesis of secretory granule membranes [162].
Chromatin remodeling is also regulated by the high
mobility group (HMG) proteins containing AT-hook
Endocrine Pathology (2021) 32:3–16
domains (HMGA). Mice overexpressing HMGA1 or
HMGA2 develop pituitary tumors of the PIT1 lineage
[163, 164], thought to be through silencing of pRB and
induction of E2F1 [165] and upregulation of cyclin B2[166].
HMGA1 [166-167] and HMGA2 [168] have been found
to be amplified and overexpressed in a small number of
prolactinomas.
Non-coding RNAs are implicated in the epigenetics of
neoplasia. MicroRNAs (miRs) are endogenous small RNAs
that play important roles in the regulation of expression of
genes that control cell proliferation, differentiation, and
apoptosis. For example, the altered expression of HMGA2
in primary tumors without amplification of this gene may
be due to altered microRNA expression, particularly of
let-7 [169]. An increasing number of aberrantly expressed
miRNAs is currently being discovered in human pituitary
tumor studies [10].
Gene expression can also modulate the invasive growth
in PitNETs [170]. PITX2, a homeobox gene product, is
significantly overexpressed in non-functional PitNETs with
cavernous sinus invasion [171]. Similarly, protein expression
studies on invasiveness of silent corticotroph tumors
identified different patterns than in other non-functional
PitNETs [172]. These findings underscore the importance
of the regulation of cell-to-extracellular matrix interactions
that are likely related to epigenetic dysregulation.
Epigenetic alterations including distinct miRNA profiling
were noted in oncocytic pituicytomas with recurrent disease
[173]. In addition, transcriptome profiling of oncocytic
pituicytomas underscored the role of cell cycle and its
regulators as well as metabolic alterations [173].
Conclusions
Molecular pathology has led to advances in the
understanding of many tumors and offers opportunities
to identify novel therapies. In the pituitary, the field has
uncovered a number of genetic mutations that predispose
to PitNET development, including MEN1, CDKN1B,
PRKRIα, AIP, and other rarer events, but these genes are
rarely mutated in sporadic tumors. Recurrent genetic
events in sporadic PitNETs include GNAS mutations in a
subset of somatotroph tumors as well as USP8 and USP48
mutations in some corticotroph tumors; to date, neither of
these has resulted in altered management, and instead, the
prognosis and management of PitNETs relies more on cell
type and subtype as well as local growth that determines
surgical resectability. In contrast, craniopharyngiomas have
either CTNNB1 or BRAFV600E mutations that correlate with
adamantinomatous or papillary morphology, respectively;
the latter offers the opportunity for targeted therapy. DICER1
mutations are found in patients with pituitary blastoma.
11
Epigenetic changes are implicated in the pathogenesis of
the more common sporadic pituitary neoplasms including
the majority of PitNETs and tumors of pituicytes.
Funding  This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Compliance with Ethical Standards 
Conflict of Interest  The authors declare that they have no conflict of
interest.
References
1. Asa SL, Perry A. Tumors of the Pituitary Gland. Atlas of Tumor
nd Nontumor Pathology, Series 5, Fascicle 1. Arlington VA: ARP
Press, 2020.
2. Asa SL, Penz G, Kovacs K, Ezrin C. Prolactin cells in the human
pituitary. A quantitative immunocytochemical analysis. Arch
Pathol Lab Med 1982; 106:360–363.
3. Horvath E, Lloyd RV, Kovacs K. Propylthiouracyl-induced
hypothyroidism results in reversible transdifferentiation of
somatotrophs into thyroidectomy cells. A morphologic study
of the rat pituitary including immunoelectron microscopy. Lab
Invest 1990; 63:511–520.
4. Asa SL, Casar-Borota O, Chanson P et  al. From pituitary
adenoma to pituitary neuroendocrine tumor (PitNET): an
International Pituitary Pathology Club proposal. Endocr Relat
Cancer 2017; 24(4):C5-C8.
5. Mete O, Lopes MB, Asa SL. Spindle cell oncocytomas and
granular cell tumors of the pituitary are variants of pituicytoma.
Am J Surg Pathol 2013; 37(11):1694-1699.
6. Asa SL, Mete O. Hypothalamic Endocrine Tumors: An Update.
J Clin Med 2019; 8(10).
7. Asa SL, Ezzat S. The pathogenesis of pituitary tumors. Annu Rev
Pathol 2009; 4:97-126.
8. Ezzat S, Asa SL. Mechanisms of disease: The pathogenesis
of pituitary tumors. Nat Clin Pract Endocrinol Metab 2006;
2(4):220-230.
9. Gomez-Hernandez K, Ezzat S, Asa SL, Mete O. Clinical
Implications of Accurate Subtyping of Pituitary Adenomas:
Perspectives from the Treating Physician. Turk Patoloji Derg
2015; 31 Suppl 1:4-17.
10. Ezzat S, Cheng S, Asa SL. Epigenetics of pituitary tumors:
Pathogenetic and therapeutic implications. Mol Cell Endocrinol
2018; 469:70-76.
11. Trouillas J, Labat-Moleur F, Sturm N et al. Pituitary tumors and
hyperplasia in multiple endocrine neoplasia type 1 syndrome
(MEN1): a case-control study in a series of 77 patients
versus 2509 non-MEN1 patients. Am J Surg Pathol 2008;
32(4):534-543.
12. Beckers A, Aaltonen LA, Daly AF, Karhu A. Familial
isolated pituitary adenomas (FIPA) and the pituitary adenoma
predisposition due to mutations in the aryl hydrocarbon receptor
interacting protein (AIP) gene. Endocr Rev 2013; 34(2):239-277.
13. Daly AF, Tichomirowa MA, Petrossians P et  al. Clinical
characteristics and therapeutic responses in patients with
germ-line AIP mutations and pituitary adenomas: an
international collaborative study. J Clin Endocrinol Metab 2010;
95(11):E373-E383.
13
12
14. Tahir A, Chahal HS, Korbonits M. Molecular genetics of the aip
gene in familial pituitary tumorigenesis. Prog Brain Res 2010;
182:229-253.
15. Georgitsi M, De Menis E, Cannavo S et al. Aryl hydrocarbon
receptor interacting protein (AIP) gene mutation analysis in
children and adolescents with sporadic pituitary adenomas. Clin
Endocrinol (Oxf) 2008; 69(4):621-627.
16. 16. Wermer P. Genetic aspects of adenomatosis of endocrine
glands. Am J Med 1954; 16:363-371.
17. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and
type 4 (MEN4). Mol Cell Endocrinol 2014; 386(1-2):2-15.
18. Brennan P. Breast cancer risk in MEN1 - a cancer genetics
perspective. Clin Endocrinol (Oxf) 2015; 82(3):327-229.
19. DeLellis RA. Multiple endocrine neoplasia syndromes revisited.
Clinical, morphologic and molecular features. Lab Invest 1995;
72:494–505.
20. Ezzat S, Asa SL. The multiple endocrine neoplasia syndromes.
In: Kovacs K, Asa SL, editors. Functional Endocrine Pathology.
Boston: Blackwell Science, 1998: 952-966.
21. Scheithauer BW, Laws ER, Jr., Kovacs K, Horvath E, Randall
RV, Carney JA. Pituitary adenomas of the multiple endocrine
neoplasia type I syndrome. Semin Diagn Pathol 1987;
4(3):205-211.
22. Mete O, Gomez-Hernandez K, Kucharczyk W et  al. Silent
subtype 3 pituitary adenomas are not always silent and represent
poorly differentiated monomorphous plurihormonal Pit-1 lineage
adenomas. Mod Pathol 2016; 29(2):131-142.
23. Shintani Y, Yoshimoto K, Horie H et al. Two different pituitary
adenomas in a patient with multiple endocrine neoplasia type 1
associated with growth hormone-releasing hormone-producing
pancreatic tumor: clinical and genetic features. Endocr J 1995;
42:331-340.
24. Pellegata NS, Quintanilla-Martinez L, Siggelkow H et al. Germ-
line mutations in p27Kip1 cause a multiple endocrine neoplasia
syndrome in rats and humans. Proc Natl Acad Sci U S A 2006;
103(42):15558-15563.
25. Georgitsi M, Raitila A, Karhu A et al. Germline CDKN1B/
p27Kip1 mutation in multiple endocrine neoplasia. J Clin
Endocrinol Metab 2007; 92(8):3321-3325.
26. Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in
cyclin-dependent kinase inhibitor genes in multiple endocrine
neoplasia type 1 and related states. J Clin Endocrinol Metab
2009; 94(5):1826-1834.
27. Georgitsi M. MEN-4 and other multiple endocrine neoplasias
due to cyclin-dependent kinase inhibitors (p27(Kip1) and
p18(INK4C)) mutations. Best Pract Res Clin Endocrinol Metab
2010; 24(3):425-437.
28. Alrezk R, Hannah-Shmouni F, Stratakis CA. MEN4 and
CDKN1B mutations: the latest of the MEN syndromes. Endocr
Relat Cancer 2017; 24(10):T195-T208.
29. Nachtigall LB, Guarda FJ, Lines KE et  al. Clinical MEN-1
Among a Large Cohort of Patients With Acromegaly. J Clin
Endocrinol Metab 2020; 105(6).
30. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The
complex of myxomas, spotty pigmentation, and endocrine
overactivity. Medicine (Baltimore) 1985; 64(4):270-283.
31. Kirschner LS, Carney JA, Pack SD et al. Mutations of the gene
encoding the protein kinase A type I-alpha regulatory subunit in
patients with the Carney complex. Nat Genet 2000; 26(1):89-92.
32. Yin Z, Williams-Simons L, Parlow AF, Asa S, Kirschner
LS. Pituitary-specific knockout of the Carney complex gene
prkar1a leads to pituitary tumorigenesis. Mol Endocrinol 2008;
22(2):380-387.
33. Soares BS, Frohman LA. Isolated familial somatotropinoma.
Pituitary 2004; 7(2):95-101.
13
Endocrine Pathology (2021) 32:3–16
34. Beckers A, Daly AF. The clinical, pathological, and genetic
features of familial isolated pituitary adenomas. Eur J Endocrinol
2007; 157(4):371-382.
35. Pesatori AC, Baccarelli A, Consonni D et al. Aryl hydrocarbon
receptor-interacting protein and pituitary adenomas: a
population-based study on subjects exposed to dioxin
after the Seveso, Italy, accident. Eur J Endocrinol 2008;
159(6):699-703.
36. Stiles CE, Korbonits M. Familial Isolated Pituitary Adenoma.
2000.
37. Vierimaa O, Georgitsi M, Lehtonen R et al. Pituitary adenoma
predisposition caused by germline mutations in the AIP gene.
Science 2006; 312(5777):1228-1230.
38. Gill AJ. Succinate dehydrogenase (SDH)-deficient neoplasia.
Histopathology 2018; 72(1):106-116.
39. Xekouki P, Stratakis CA. Succinate dehydrogenase (SDHx)
mutations in pituitary tumors: could this be a new role for
mitochondrial complex II and/or Krebs cycle defects? Endocr
Relat Cancer 2012; 19(6):C33-C40.
40. Bengtsson D, Joost P, Aravidis C et al. Corticotroph Pituitary
Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary
Tumors in a Nationwide LS Cohort. J Clin Endocrinol Metab
2017; 102(11):3928-3932.
41. Trivellin G, Daly AF, Faucz FR et al. Gigantism and acromegaly
due to Xq26 microduplications and GPR101 mutation. N Engl J
Med 2014; 371(25):2363-2374.
42. Moran A, Asa SL, Kovacs K et al. Gigantism due to pituitary
mammosomatotroph hyperplasia. N Engl J Med 1990;
323:322-327.
43. Scheithauer BW, Kovacs K, Horvath E et al. Pituitary blastoma.
Acta Neuropathol 2008; 116(6):657-666.
44. de Kock L, Sabbaghian N, Plourde F et al. Pituitary blastoma:
a pathognomonic feature of germ-line DICER1 mutations. Acta
Neuropathol 2014; 128(1):111-122.
45. Sahakitrungruang T, Srichomthong C, Pornkunwilai S et al.
Germline and somatic DICER1 mutations in a pituitary blastoma
causing infantile-onset Cushing’s disease. J Clin Endocrinol
Metab 2014; 99(8):E1487-E1492.
46. Neou M, Villa C, Armignacco R et al. Pangenomic Classification
of Pituitary Neuroendocrine Tumors. Cancer Cell 2020;
37(1):123-134.
47. Spada A, Arosio M, Bochicchio D et al. Clinical, biochemical and
morphological correlates in patients bearing growth hormone-
secreting pituitary tumors with or without constitutively active
adenylyl cyclase. J Clin Endocrinol Metab 1990; 71:1421-1426.
48. Asa SL, Kucharczyk W, Ezzat S. Pituitary acromegaly: not one
disease. Endocr Relat Cancer 2017; 24(3):C1-C4.
49. Bakhtiar Y, Hirano H, Arita K et  al. Relationship between
cytokeratin staining patterns and clinico-pathological features
in somatotropinomae. Eur J Endocrinol 2010; 163(4):531-539.
50. Larkin S, Reddy R, Karavitaki N, Cudlip S, Wass J, Ansorge O.
Granulation pattern, but not GSP or GHR mutation, is associated
with clinical characteristics in somatostatin-naive patients with
somatotroph adenomas. Eur J Endocrinol 2013; 168(4):491-499.
51. Ezzat S, Caspar-Bell GM, Chik CL et al. Predictive markers for
postsurgical medical management of acromegaly: a systematic
review and consensus treatment guideline. Endocr Pract 2019;
25(4):379-393.
52. Ballare E, Persani L, Lania AG et al. Mutation of somatostatin
receptor type 5 in an acromegalic patient resistant to
somatostatin analog treatment. J Clin Endocrinol Metab 2001;
86(8):3809-3814.
53. Asa SL, Coschigano KT, Bellush L, Kopchick JJ, Ezzat S.
Evidence for growth hormone (GH) autoregulation in pituitary
somatotrophs in GH antagonist-transgenic mice and GH
receptor-deficient mice. Am J Pathol 2000; 156(3):1009-1015.
Endocrine Pathology (2021) 32:3–16
54. Asa SL, DiGiovanni R, Jiang J et al. A growth hormone receptor
mutation impairs growth hormone autofeedback signaling in
pituitary tumors. Cancer Res 2007; 67(15):7505-7511.
55. Cuny T, Zeiller C, Bidlingmaier M et al. In vitro impact of
pegvisomant on growth hormone-secreting pituitary adenoma
cells. Endocr Relat Cancer 2016; 23(7):509-519.
56. Zhou C, Jiao Y, Wang R, Ren SG, Wawrowsky K, Melmed
S. STAT3 upregulation in pituitary somatotroph adenomas
induces growth hormone hypersecretion. J Clin Invest 2015;
125(4):1692-1702.
57. Fiorentini C, Guerra N, Facchetti M et al. Nerve growth factor
regulates dopamine D(2) receptor expression in prolactinoma
cell lines via p75(NGFR)-mediated activation of nuclear factor-
kappaB. Mol Endocrinol 2002; 16(2):353-366.
58. De Sousa SMC, Wang PPS, Santoreneos S et al. The Genomic
Landscape of Sporadic Prolactinomas. Endocr Pathol 2019;
30(4):318-328.
59. Kara M, Tokat F, Pamir MN, Danyeli AE. Frequency and Role
of CDKN2A Deletion in High-Risk Pituitary Neuroendocrine
Tumors. Endocr Pathol 2020; 31(2):166-173.
60. Gittoes NJL, McCabe CJ, Verhaeg J, Sheppard MC, Franklyn
JA. Thyroid hormone and estrogen receptor expression in normal
pituitary and nonfunctioning tumors of the anterior pituitary. J
Clin Endocrinol Metab 1997; 82:1960-1967.
61. Ando S, Sarlis NJ, Krishnan J et al. Aberrant alternative splicing
of thyroid hormone receptor in a TSH- secreting pituitary tumor
is a mechanism for hormone resistance. Mol Endocrinol 2001;
15(9):1529-1538.
62. McCabe CJ, Gittoes NJ, Sheppard MC, Franklyn JA. Thyroid
receptor alpha1 and alpha2 mutations in nonfunctioning pituitary
tumors. J Clin Endocrinol Metab 1999; 84(2):649-653.
63. Sesta A, Cassarino MF, Terreni M et  al. Ubiquitin-Specific
Protease 8 Mutant Corticotrope Adenomas Present Unique
Secretory and Molecular Features and Shed Light on the Role of
Ubiquitylation on ACTH Processing. Neuroendocrinology 2020;
110(1-2):119-129.
64. Ballmann C, Thiel A, Korah HE et  al. USP8 Mutations in
Pituitary Cushing Adenomas-Targeted Analysis by Next-
Generation Sequencing. J Endocr Soc 2018; 2(3):266-278.
65. Reincke M, Sbiera S, Hayakawa A et  al. Mutations in the
deubiquitinase gene USP8 cause Cushing’s disease. Nat Genet
2015; 47(1):31-38.
66. Hayashi K, Inoshita N, Kawaguchi K et al. The USP8 mutational
status may predict drug susceptibility in corticotroph adenomas
of Cushing’s disease. Eur J Endocrinol 2015.
67. Ma ZY, Song ZJ, Chen JH et al. Recurrent gain-of-function USP8
mutations in Cushing’s disease. Cell Res 2015; 25(3):306-317.
68. Cohen M, Persky R, Stegemann R et  al. Germline USP8
Mutation Associated With Pediatric Cushing Disease and Other
Clinical Features: A New Syndrome. J Clin Endocrinol Metab
2019; 104(10):4676-4682.
69. Chen J, Jian X, Deng S et al. Identification of recurrent USP48
and BRAF mutations in Cushing’s disease. Nat Commun 2018;
9(1):3171.
70. Casar-Borota O, Boldt HB, Engstrom BE et al. Corticotroph
aggressive pituitary tumours and carcinomas frequently harbour
ATRX mutations. J Clin Endocrinol Metab 2020.
71. Guo F, Wang G, Wang F, Xu D, Liu X. Identification of Novel
Genes Involved in the Pathogenesis of an ACTH-Secreting
Pituitary Carcinoma: A Case Report and Literature Review. Front
Oncol 2018; 8:510.
72. Karl M, Lamberts SWJ, Koper JW et  al. Cushing’s disease
preceded by generalized glucocorticoid resistance: clinical
consequences of a novel dominant-negative glucocorticoid
receptor mutation. Proc Assoc Am Physicians 1996;
108:296-307.
13
73. Karl M, von Wichert G, Kempter E et al. Nelson’s syndrome
associated with a somatic frame shift mutation in the
glucocorticoid receptor gene. J Clin Endocrinol Metab 1996;
81:124-129.
74. Newey PJ, Nesbit MA, Rimmer AJ et  al. Whole-exome
sequencing studies of nonfunctioning pituitary adenomas. J Clin
Endocrinol Metab 2013; 98(4):E796-E800.
75. Bi WL, Horowitz P, Greenwald NF et al. Landscape of Genomic
Alterations in Pituitary Adenomas. Clin Cancer Res 2017;
23(7):1841-1851.
76. Hage M, Viengchareun S, Brunet E et al. Genomic Alterations
and Complex Subclonal Architecture in Sporadic GH-Secreting
Pituitary Adenomas. J Clin Endocrinol Metab 2018;
103(5):1929-1939.
77. Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A,
Jameson JL. Ras mutations in human pituitary tumors. J Clin
Endocrinol Metab 1992; 74:914-919.
78. Cai WY, Alexander JM, Hedley-Whyte ET et al. Ras mutations
in human prolactinomas and pituitary carcinomas. J Clin
Endocrinol Metab 1994; 78:89-93.
79. Hinton DR, Hahn JA, Weiss MH, Couldwell WT. Loss of Rb
expression in an ACTH-secreting pituitary carcinoma. Cancer
Lett 1998; 126(2):209-214.
80. Thapar K, Scheithauer BW, Kovacs K, Pernicone PJ, Laws
ER, Jr. p53 expression in pituitary adenomas and carcinomas:
Correlation with invasiveness and tumor growth fractions.
Neurosurgery 1996; 38:765-771.
81. Pernicone PJ, Scheithauer B, Sebo TJ et al. Pituitary carcinoma:A
clinicopathologic study of 15 cases. Cancer 1997; 79:804-812.
82. DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and
Genetics of Tumours of Endocrine Organs. Lyons, France: IARC
Press, 2004.
83. Tanizaki Y, Jin L, Scheithauer BW, Kovacs K, Roncaroli F, Lloyd
RV. P53 gene mutations in pituitary carcinomas. Endocr Pathol
2007; 18(4):217-222.
84. Buckley N, Bates AS, Broome JC et al. p53 protein accumulation
in Cushings adenomas and invasive non-functional adenomas. J
Clin Endocrinol Metab 1994; 79:1513-1516.
85. Sumi T, Stefaneanu L, Kovacs K, Asa SL, Rindi G.
Immunohistochemical study of p53 protein in human and animal
pituitary tumors. Endocr Pathol 1993; 4:95-99.
86. Levy A, Hall L, Yeundall WA, Lightman SL. p53 gene mutations
in pituitary adenomas: rare events. Clin Endocrinol (Oxf) 1994;
41:809-814.
87. Kawashima ST, Usui T, Sano T et al. P53 gene mutation in an
atypical corticotroph adenoma with Cushing’s disease. Clin
Endocrinol (Oxf) 2009; 70(4):656-657.
88. Amar AP, Hinton DR, Krieger MD, Weiss MH. Invasive pituitary
adenomas: significance of proliferation parameters. Pituitary
1999; 2(2):117-122.
89. Goschzik T, Gessi M, Dreschmann V et al. Genomic Alterations
of Adamantinomatous and Papillary Craniopharyngioma. J
Neuropathol Exp Neurol 2017; 76(2):126-134.
90. Sekine S, Shibata T, Kokubu A et al. Craniopharyngiomas of
adamantinomatous type harbor beta-catenin gene mutations. Am
J Pathol 2002; 161(6):1997-2001.
91. Buslei R, Nolde M, Hofmann B et al. Common mutations of
beta-catenin in adamantinomatous craniopharyngiomas but
not in other tumours originating from the sellar region. Acta
Neuropathol 2005; 109(6):589-597.
92. Oikonomou E, Barreto DC, Soares B, De Marco L, Buchfelder
M, Adams EF. Beta-catenin mutations in craniopharyngiomas
and pituitary adenomas. J Neurooncol 2005; 73(3):205-209.
93. Brastianos PK, Taylor-Weiner A, Manley PE et  al. Exome
sequencing identifies BRAF mutations in papillary
craniopharyngiomas. Nat Genet 2014; 46(2):161-165.
13
14
94. Fukuhara N, Iwata T, Inoshita N et al. Immunohistochemistry
or Molecular Analysis: Which Method Is Better for Subtyping
Craniopharyngioma? Endocr Pathol 2020.
95. Brastianos PK, Shankar GM, Gill CM et al. Dramatic Response of
BRAF V600E Mutant Papillary Craniopharyngioma to Targeted
Therapy. J Natl Cancer Inst 2016; 108(2).
96. Roque A, Odia Y. BRAF-V600E mutant papillary
craniopharyngioma dramatically responds to combination BRAF
and MEK inhibitors. CNS Oncol 2017; 6(2):95-99.
97. Rostami E, Witt NP, Libard S, Wikstrom J, Casar-Borota O,
Gudjonsson O. Recurrent papillary craniopharyngioma with
BRAFV600E mutation treated with neoadjuvant-targeted therapy.
Acta Neurochir (Wien ) 2017; 159(11):2217-2221.
98. Viaene AN, Lee EB, Rosenbaum JN, Nasrallah IM, Nasrallah
MP. Histologic, immunohistochemical, and molecular features
of pituicytomas and atypical pituicytomas. Acta Neuropathol
Commun 2019; 7(1):69.
99. Phillips JJ, Misra A, Feuerstein BG, Kunwar S, Tihan T.
Pituicytoma: characterization of a unique neoplasm by
histology, immunohistochemistry, ultrastructure, and array-based
comparative genomic hybridization. Arch Pathol Lab Med 2010;
134(7):1063-1069.
100. Miller MB, Bi WL, Ramkissoon LA et al. MAPK activation and
HRAS mutation identified in pituitary spindle cell oncocytoma.
Oncotarget 2016; 7(24):37054-37063.
101. Ezzat S, Walpola IA, Ramyar L, Smyth HS, Asa SL. Membrane-
anchored expression of transforming growth factor-a in human
pituitary adenoma cells. J Clin Endocrinol Metab 1995;
80:534-539.
102. Liu SC, Sanfilippo B, Perroteau I, Derynck R, Salomon DS,
Kidwell WR. Expression of transforming growth factor a (TGFa)
in differentiated rat mammary tumors: estrogen induction of TGFa
production. Mol Endocrinol 1987; 1:683-692.
103. McAndrew J, Paterson AJ, Asa SL, McCarthy KJ, Kudlow JE.
Targeting of transforming growth factor-a expression to pituitary
lactotrophs in transgenic mice results in selective lactotroph
proliferation and adenomas. Endocrinology 1995; 136:4479-4488.
104. Roh M, Paterson AJ, Asa SL, Chin E, Kudlow JE. Stage-sensitive
blockade of pituitary somatomammotrope development by
targeted expression of a dominant negative epidermal growth
factor receptor in transgenic mice. Mol Endocrinol 2001;
15(4):600-613.
105. LeRiche V, Asa SL, Ezzat S. Epidermal growth factor and
its receptor (EGF-R) in human pituitary adenomas: EGF-R
correlates with tumor aggressiveness. J Clin Endocrinol Metab
1996; 81:656-662.
106. Cooper O, Vlotides G, Fukuoka H, Greene MI, Melmed S.
Expression and function of ErbB receptors and ligands in the
pituitary. Endocr Relat Cancer 2011; 18(6):R197-R211.
107. Liu X, Kano M, Araki T et al. ErbB receptor-driven prolactinomas
respond to targeted lapatinib treatment in female transgenic mice.
Endocrinology 2015; 156(1):71-79.
108. Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G.
Structural characterization and biological functions of fibroblast
growth factor. Endocr Rev 1987; 8:95-114.
109. Ferrara N, Schweigerer L, Neufeld G, Mitchell R, Gospodarowicz
D. Pituitary follicular cells produce basic fibroblast growth factor.
Proc Natl Acad Sci USA 1987; 84:5773-5777.
110. Scully KM, Rosenfeld MG. Pituitary development:
regulatory codes in mammalian organogenesis. Science 2002;
295(5563):2231-2235.
111. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families.
Trends Genet 2004; 20(11):563-569.
112. De Moerlooze L, Spencer-Dene B, Revest J, Hajihosseini
M, Rosewell I, Dickson C. An important role for the IIIb
isoform of fibroblast growth factor receptor 2 (FGFR2) in
13
Endocrine Pathology (2021) 32:3–16
mesenchymal-epithelial signalling during mouse organogenesis.
Develop 2000; 127(3):483-492.
113. Celli G, LaRochelle WJ, Mackem S, Sharp R, Merlino G. Soluble
dominant-negative receptor uncovers essential roles for fibroblast
growth factors in multi-organ induction and patterning. EMBO J
1998; 17(6):1642-1655.
114. Ezzat S, Smyth HS, Ramyar L, Asa SL. Heterogeneous in vivo
and in vitro expression of basic fibroblast growth factor by human
pituitary adenomas. J Clin Endocrinol Metab 1995; 80:878-884.
115. Li Y, Koga M, Kasayama S et  al. Identification and
characterization of high molecular weight forms of basic
fibroblast growth factor in human pituitary adenomas. J Clin
Endocrinol Metab 1992; 75:1436-1441.
116. Heaney AP, Horwitz GA, Wang Z, Singson R, Melmed S. Early
involvement of estrogen-induced pituitary tumor transforming
gene and fibroblast growth factor expression in prolactinoma
pathogenesis. Nature Medicine 1999; 5:1317-1321.
117. Zimering MB, Katsumata N, Sato Y et  al. Circulating basic
FGF-1 like substance in multiple endocrine neoplasia type 1
and acromegaly. Fibroblast Growth Factor Family Meeting,San
Diego,CA , 40. 1991 (Abstract)
118. Correa FA, Trarbach EB, Tusset C et al. FGFR1 and PROKR2
rare variants found in patients with combined pituitary hormone
deficiencies. Endocr Connect 2015; 4(2):100-107.
119. Abbass SAA, Asa SL, Ezzat S. Altered expression of fibroblast
growth factor receptors in human pituitary adenomas. J Clin
Endocrinol Metab 1997; 82:1160-1166.
120. Zhu X, Lee K, Asa SL, Ezzat S. Epigenetic silencing through
DNA and histone methylation of fibroblast growth factor
receptor 2 in neoplastic pituitary cells. Am J Pathol 2007;
170(5):1618-1628.
121. Zhu X, Asa SL, Ezzat S. Fibroblast Growth Factor 2 and Estrogen
Control the Balance of Histone 3 Modifications Targeting
MAGE-A3 in Pituitary Neoplasia. Clin Cancer Res 2008;
14(7):1984-1996.
122. Yu S, Asa SL, Weigel RJ, Ezzat S. Pituitary tumor AP-2alpha
recognizes a cryptic promoter in intron 4 of fibroblast growth
factor receptor 4. J Biol Chem 2003; 278(22):19597-19602.
123. Ezzat S, Yu S, Asa SL. Ikaros isoforms in human pituitary tumors:
distinct localization, histone acetylation, and activation of the 5’
fibroblast growth factor receptor-4 promoter. Am J Pathol 2003;
163(3):1177-1184.
124. Ezzat S, Zheng L, Asa SL. Pituitary tumor-derived fibroblast
growth factor receptor 4 isoform disrupts neural cell-adhesion
molecule/N-cadherin signaling to diminish cell adhesiveness: a
mechanism underlying pituitary neoplasia. Mol Endocrinol 2004;
18(10):2543-2552.
125. Ezzat S, Zheng L, Winer D, Asa SL. Targeting N-Cadherin
through Fibroblast Growth Factor Receptor-4: Distinct
Pathogenetic and Therapeutic Implications. Mol Endocrinol 2006;
20(11):2965-2975.
126. Qian ZR, Sano T, Asa SL et  al. Cytoplasmic expression of
fibroblast growth factor receptor-4 in human pituitary adenomas:
relation to tumor type, size, proliferation, and invasiveness. J Clin
Endocrinol Metab 2004; 89(4):1904-1911.
127. Morita K, Takano K, Yasufuku-Takano J et al. Expression of
pituitary tumour-derived, N-terminally truncated isoform of
fibroblast growth factor receptor 4 (ptd-FGFR4) correlates
with tumour invasiveness but not with G-protein alpha subunit
(gsp) mutation in human GH-secreting pituitary adenomas. Clin
Endocrinol (Oxf) 2008; 68(3):435-441.
128. Mete O, Cintosun A, Pressman I, Asa SL. Epidemiology and
biomarker profile of pituitary adenohypophysial tumors. Mod
Pathol 2018; 31(6):900-909.
129. Daniel L, Trouillas J, Renaud W et al. Polysialylated-neural cell
adhesion molecule expression in rat pituitary transplantable
Endocrine Pathology (2021) 32:3–16
tumors (spontaneous mammotropic transplantable tumor in
Wistar-Furth rats) is related to growth rate and malignancy.
Cancer Res 2000; 60(1):80-85.
130. Nakano-Tateno T, Tateno T, Hlaing MM et  al. FGFR4
polymorphic variants modulate phenotypic features of Cushing
disease. Mol Endocrinol 2014; 28(4):525-533.
131. Tateno T, Asa SL, Zheng L, Mayr T, Ullrich A, Ezzat S. The
FGFR4-G388R Polymorphism Promotes Mitochondrial STAT3
Serine Phosphorylation to Facilitate Pituitary Growth Hormone
Cell Tumorigenesis. PLoS Genet 2011; 7(12):e1002400.
132. Ezzat S, Wang R, Pintilie M, Asa SL. FGFR4 polymorphic
alleles modulate mitochondrial respiration: A novel target for
somatostatin analog action in pituitary tumors. Oncotarget 2017;
8(2):3481-3494.
133. Altas M, Bayrak OF, Ayan E et al. The effect of polymorphisms
in the promoter region of the MMP-1 gene on the occurrence and
invasiveness of hypophyseal adenoma. Acta Neurochir (Wien )
2010; 152(9):1611-1617.
134. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA,
Weinberg RA. Effects of an Rb mutation in the mouse. Nature
1992; 359:295-300.
135. Cryns VL, Alexander JM, Klibanski A, Arnold A. The
retinoblastoma gene in human pituitary tumors. J Clin Endocrinol
Metab 1993; 77:644-646.
136. Woloschak M, Yu A, Xiao J, Post KD. Abundance and state of
phosphorylation of the retinoblastoma gene product in human
pituitary tumors. Int J Cancer 1996; 67(1):16-19.
137. Pei L, Melmed S, Scheithauer B, Kovacs K, Benedict WF,
Prager D. Frequent loss of heterozygosity at the retinoblastoma
susceptibility gene (RB) locus in aggressive pituitary tumors:
Evidence for a chromosome 13 tumor suppressor gene other than
RB. Cancer Res 1995; 55:1613-1616.
138. Bates AS, Farrell WE, Bicknell EJ et al. Allelic deletion in
pituitary adenomas reflects aggressive biological activity and
has potential value as a prognostic marker. J Clin Endocrinol
Metab 1997; 82:818-824.
139. Tsai KY, MacPherson D, Rubinson DA et al. ARF mutation
accelerates pituitary tumor development in Rb+/- mice. Proc
Natl Acad Sci U S A 2002; 99(26):16865-16870.
140. Lasorella A, Rothschild G, Yokota Y, Russell RG, Iavarone A.
Id2 mediates tumor initiation, proliferation, and angiogenesis in
Rb mutant mice. Mol Cell Biol 2005; 25(9):3563-3574.
141. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-
dependent kinases. Genes Dev 1995; 9:1149-1163.
142. Nakayama K, Ishida N, Shirane M et al. Mice lacking p­ 27Kip1
display increased body size,multiple organ hyperplasia, retinal
dysplasia, and pituitary tumors. Cell 1996; 85:707-720.
143. Kiyokawa H, Kineman RD, Manova-Todorova KO et  al.
Enhanced growth of mice lacking the cyclin-dependent kinase
inhibitor function of ­p27Kip1. Cell 1996; 85:721-732.
144. Fero ML, Rivkin M, Tasch M et al. A syndrome of multiorgan
hyperplasia with features of gigantism, tumorigenesis, and
female sterility in ­p27Kip1-deficient mice. Cell 1996; 85:733-744.
145. Franklin DS, Godfrey VL, Lee H et  al. CDK inhibitors
p18(INK4c) and p27(Kip1) mediate two separate pathways to
collaboratively suppress pituitary tumorigenesis. Genes Dev
1998; 12(18):2899-2911.
146. Bamberger CM, Fehn M, Bamberger AM et  al. Reduced
expression levels of the cell-cycle inhibitor p27Kip1 in human
pituitary adenomas. Eur J Endocrinol 1999; 140(3):250-255.
147. Dahia PL, Aguiar RC, Honegger J et al. Mutation and expression
analysis of the p27/kip1 gene in corticotrophin- secreting
tumours. Oncogene 1998; 16(1):69-76.
148. Liu W, Asa SL, Ezzat S. Vitamin D and its analog EB1089
induce p27 accumulation and diminish association of p27 with
15
Skp2 independent of PTEN in pituitary corticotroph cells.
Brain Pathol 2002; 12(4):412-419.
149. Woloschak M, Yu A, Post KD. Frequent inactivation of the
p16 gene in human pituitary tumors by gene methylation. Mol
Carcinog 1997; 19(4):221-224.
150. Frost SJ, Simpson DJ, Clayton RN, Farrell WE. Transfection
of an inducible p16/CDKN2A construct mediates reversible
growth inhibition and G1 arrest in the AtT20 pituitary tumor
cell line. Mol Endocrinol 1999; 13(11):1801-1810.
151. Zhang X, Sun H, Danila DC et  al. Loss of expression of
GADD45 gamma, a growth inhibitory gene, in human pituitary
adenomas: implications for tumorigenesis. J Clin Endocrinol
Metab 2002; 87(3):1262-1267.
152. Bahar A, Bicknell JE, Simpson DJ, Clayton RN, Farrell
WE. Loss of expression of the growth inhibitory gene
GADD45gamma, in human pituitary adenomas, is associated
with CpG island methylation. Oncogene 2004; 23(4):936-944.
153. Zhao J, Dahle D, Zhou Y, Zhang X, Klibanski A.
Hypermethylation of the promoter region is associated with
the loss of MEG3 gene expression in human pituitary tumors.
J Clin Endocrinol Metab 2005; 90(4):2179-2186.
154. Metin-Armagan D, Comunoglu N, Bulut G et  al. A Novel
Expression Profile of Cell Cycle and DNA Repair Proteins
in Nonfunctioning Pituitary Adenomas. Endocr Pathol 2020;
31(1):2-13.
155. Bahar A, Simpson DJ, Cutty SJ et  al. Isolation and
characterization of a novel pituitary tumor apoptosis gene. Mol
Endocrinol 2004; 18(7):1827-1839.
156. Zhu X, Mao X, Hurren R, Schimmer AD, Ezzat S,
Asa SL. Deoxyribonucleic acid methyltransferase 3B
promotes epigenetic silencing through histone 3 chromatin
modifications in pituitary cells. J Clin Endocrinol Metab 2008;
93(9):3610-3617.
157. Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros
gene in lymphocyte development and homeostasis. Annu Rev
Immunol 1997; 15:155-176.
158. Ezzat S, Mader R, Yu S, Ning T, Poussier P, Asa SL. Ikaros
integrates endocrine and immune system development. J Clin
Invest 2005; 115(4):1021-1029.
159. Ezzat S, Mader R, Fischer S, Yu S, Ackerley C, Asa SL. An
essential role for the hematopoietic transcription factor Ikaros
in hypothalamic-pituitary-mediated somatic growth. Proc Natl
Acad Sci U S A 2006; 103(7):2214-2219.
160. Ezzat S, Yu S, Asa SL. The zinc finger Ikaros transcription
factor regulates pituitary growth hormone and prolactin gene
expression through distinct effects on chromatin accessibility.
Mol Endocrinol 2005; 19(4):1004-1011.
161. Ezzat S, Zhu X, Loeper S, Fischer S, Asa SL. Tumor-derived
Ikaros 6 acetylates the Bcl-XL promoter to up-regulate a
survival signal in pituitary cells. Mol Endocrinol 2006;
20(11):2976-2986.
162. Loeper S, Asa SL, Ezzat S. Ikaros modulates cholesterol
uptake: A link between tumor suppression and differentiation.
Cancer Res 2008; 68(10):3715-3723.
163. Fedele M, Battista S, Kenyon L et al. Overexpression of the
HMGA2 gene in transgenic mice leads to the onset of pituitary
adenomas. Oncogene 2002; 21(20):3190-3198.
164. Fedele M, Pentimalli F, Baldassarre G et  al. Transgenic
mice overexpressing the wild-type form of the HMGA1
gene develop mixed growth hormone/prolactin cell pituitary
adenomas and natural killer cell lymphomas. Oncogene 2005;
24(21):3427-3435.
165. Fedele M, Visone R, De M, I et al. HMGA2 induces pituitary
tumorigenesis by enhancing E2F1 activity. Cancer Cell 2006;
9(6):459–471.
13
16
166. De Martino I, Visone R, Wierinckx A et al. HMGA proteins
up-regulate CCNB2 gene in mouse and human pituitary
adenomas. Cancer Res 2009; 69(5):1844-1850.
167. Evans CO, Moreno CS, Zhan X et al. Molecular pathogenesis
of human prolactinomas identified by gene expression
profiling, RT-qPCR, and proteomic analyses. Pituitary 2008;
11(3):231-245.
168. Finelli P, Pierantoni GM, Giardino D et al. The High Mobility
Group A2 gene is amplified and overexpressed in human
prolactinomas. Cancer Res 2002; 62(8):2398-2405.
169. Qian ZR, Asa SL, Siomi H et al. Overexpression of HMGA2
relates to reduction of the let-7 and its relationship to
clinicopathological features in pituitary adenomas. Mod Pathol
2009; 22(3):431-441.
170. Mete O, Ezzat S, Asa SL. Biomarkers of aggressive pituitary
adenomas. J Mol Endocrinol 2012; 49(2):R69-R78.
13
Endocrine Pathology (2021) 32:3–16
171. Tamura R, Ohara K, Morimoto Y et al. PITX2 Expression in
Non-functional Pituitary Neuroendocrine Tumor with Cavernous
Sinus Invasion. Endocr Pathol 2019; 30(2):81-89.
172. Mete O, Hayhurst C, Alahmadi H et al. The role of mediators
of cell invasiveness, motility, and migration in the pathogenesis
of silent corticotroph adenomas. Endocr Pathol 2013;
24(4):191-198.
173. Krokker L, Nyiro G, Reiniger L et al. Differentially Expressed
miRNAs Influence Metabolic Processes in Pituitary Oncocytoma.
Neurochem Res 2019; 44(10):2360-2371.
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