Endocrine Pathology (2022) 33:6–26

https://doi.org/10.1007/s12022-022-09703-7

Overview of the 2022 WHO Classification of Pituitary Tumors

Sylvia L. Asa1   · Ozgur Mete2   · Arie Perry3   · Robert Y. Osamura4 

Accepted: 2 January 2022 / Published online: 15 March 2022

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

Abstract
This review summarizes the changes in the 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors
that relate to the pituitary gland. The new classification clearly distinguishes anterior lobe (adenohypophyseal) from posterior
lobe (neurohypophyseal) and hypothalamic tumors. Other tumors arising in the sellar region are also discussed. Anterior lobe
tumors include (i) well-differentiated adenohypophyseal tumors that are now classified as pituitary neuroendocrine tumors
(PitNETs; formerly known as pituitary adenomas), (ii) pituitary blastoma, and (iii) the two types of craniopharyngioma.
The new WHO classification provides detailed histological subtyping of a PitNET based on the tumor cell lineage, cell
type, and related characteristics. The routine use of immunohistochemistry for pituitary transcription factors (PIT1, TPIT,
SF1, GATA3, and ERα) is endorsed in this classification. The major PIT1, TPIT, and SF1 lineage-defined PitNET types
and subtypes feature distinct morphologic, molecular, and clinical differences. The “null cell” tumor, which is a diagnosis
of exclusion, is reserved for PitNETs with no evidence of adenohypophyseal lineage differentiation. Unlike the 2017 WHO
classification, mammosomatotroph and acidophil stem cell tumors represent distinct PIT1-lineage PitNETs. The diagnostic
category of PIT1-positive plurihormonal tumor that was introduced in the 2017 WHO classification is replaced by two
clinicopathologically distinct PitNETs: the immature PIT1-lineage tumor (formerly known as silent subtype 3 tumor) and
the mature plurihormonal PIT1-lineage tumor. Rare unusual plurihormonal tumors feature multi-lineage differentiation. The
importance of recognizing multiple synchronous PitNETs is emphasized to avoid misclassification. The term “metastatic
PitNET” is advocated to replace the previous terminology “pituitary carcinoma” in order to avoid confusion with neuroen-
docrine carcinoma (a poorly differentiated epithelial neuroendocrine neoplasm). Subtypes of PitNETs that are associated
with a high risk of adverse biology are emphasized within their cell lineage and cell type as well as based on clinical vari-
ables. Posterior lobe tumors, the family of pituicyte tumors, include the traditional pituicytoma, the oncocytic form (spindle
cell oncocytoma), the granular cell form (granular cell tumor), and the ependymal type (sellar ependymoma). Although
these historical terms are entrenched in the literature, they are nonspecific and confusing, such that oncocytic pituicytoma,
granular cell pituicytoma, and ependymal pituicytoma are now proposed as more accurate. Tumors with hypothalamic neu-
ronal differentiation are classified as gangliocytomas or neurocytomas based on large and small cell size, respectively. This
classification sets the standard for a high degree of sophistication to allow individualized patient management approaches.

Keywords  Pituitary neuroendocrine tumor · Pituitary adenoma · PitNET · Pituitary blastoma · Craniopharyngioma ·
Pituicytoma · Gangliocytoma · Neurocytoma

3
* Sylvia L. Asa Departments of Pathology and Neurological Surgery,
[email protected] University of California San Francisco, San Francisco, CA,
USA
1
Department of Pathology, University Hospitals Cleveland 4
Department of Pathology, Nippon Koukan Hospital,
Medical Center, Case Western Reserve University,
Kawasaki and Keio University School of Medicine, Tokyo,
Cleveland, OH, USA
Japan
2
Department of Pathology, University Health Network,
University of Toronto, Toronto, ON, Canada

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Endocrine Pathology (2022) 33:6–26 7

Introduction neuroendocrine neoplasms [6]. They have for many years

been classified as adenomas based on the rarity of meta-
The pituitary is a complex organ that is composed of ade- static behavior. However, adenomas are, by definition,
nohypophyseal hormone-secreting neuroendocrine cells, benign, and benign implies a disease that is not harmful,
posterior lobe pituicytes that are modified glia, axonal which does not threaten health or life and that has no sig-
extensions of hypothalamic neurons that secrete hormones nificant impact on the host. These are not features of a
into the bloodstream, and stromal cells that include blood significant number of pituitary tumors. In fact, pituitary
vessels, nerves, meninges, bone, and other connective tis- tumors are often invasive neoplasms that can infiltrate into
sue elements [1]. The sella turcica is the site of tumors surrounding structures, not unlike carcinomas. Moreover,
that arise from all of these various cell types. Because of when they do metastasize, there are no morphologic or
the fascination with hormone excess syndromes, such as molecular features that can predict metastatic spread; using
acromegaly, Cushing disease, central hyperthyroidism, and traditional nomenclature, the initial diagnosis is “adenoma”
hyperprolactinemia, pituitary tumor studies have mainly and only when the metastasis is identified is the diagnosis
focused on hormone production. However, the develop- changed to “carcinoma.” It should be clear that there is no
ment of molecular tools that facilitate better understand- such thing as a metastasizing adenoma; therefore, the term
ing of the mechanisms responsible for cell differentiation is not appropriate for tumors of adenohypophyseal cells.
has provided further clarity, and the field has advanced Another important point is that the approach to manage-
significantly over the last 20 years [2]. It is now clear that ment of unresectable pituitary tumors involves the same
there are specific cell lineages that are terminally differ- therapies as used for neuroendocrine tumors in other sites.
entiated, while other cell types are more fluid, providing Based on these many issues in pituitary pathology, a pro-
access to transdifferentiation [3–5] as required for changes posal was made to rename these lesions PitNETs [7]. This
in physiology. approach fits well with the aim to provide a uniform clas-
The 5th edition of the WHO Classification of Endo- sification system for all neuroendocrine neoplasms (NENs)
crine and Neuroendocrine Tumors has made significant [8]. This classification divides epithelial NENs into well-
advances in recognizing the progress made by the differentiated neuroendocrine tumors (NETs) and poorly
application of advanced tools to characterize tumors of the differentiated neuroendocrine carcinomas (NECs). Since
sellar region beyond the conventional hormonal activity PitNETs can have metastases and since even metastatic
that has been the basis for classification in past editions. lesions generally do not become poorly differentiated, there
Tumors are now classified based on cell lineage as deter- is no rationale to use the term “carcinoma”; instead, one
mined by expression of transcription factors, hormones, can now classify PitNETs as primary and metastatic lesions.
and other biomarkers. As with the other 5th edition WHO Sometimes, NETs from extra-pituitary sites such as pancreas
series, a specific tumor entity is now referred to as a tumor or the digestive system may metastasize to the pituitary and
“type,” whereas variants are considered “subtypes.” mimic the histology of PitNET [9–11]; the correct diagnosis
In this review, we adopt a question–answer model to requires the use of pituitary transcription factors to ensure
summarize the most important changes that will allow that PitNETs are distinguished from other NETs [12].
more accurate classification, better understanding of
molecular and functional implications, and as a conse-
quence, a more targeted approach to therapy. Question 2: What Are the New Diagnostic
Categories of Pituitary Neuroendocrine
Tumors?

Question 1: What Is the Significance The new classification, summarized in Table  1, places

of the Nomenclature Change from Pituitary an emphasis on the various cell types and their subtypes,
Adenoma to Pituitary Neuroendocrine as well as on tumors that do not show features of normal
Tumor? What Happened to Pituitary cell differentiation. The adenohypophysis is composed of
Carcinoma? at least six normal cell types: somatotrophs, lactotrophs,
mammosomatotrophs, and thyrotrophs are of PIT1 lineage,
A major nomenclature change from the previous edition corticotrophs are of TPIT lineage, and gonadotrophs are
of the WHO classification is the transition from “ade- of SF1 lineage. In the previous 2017 WHO classification,
noma” to “pituitary neuroendocrine tumor” (PitNET). mammosomatotroph tumors were not classified as a dis-
The hormone-secreting cells of the adenohypophysis tinct type, but in the new edition, they assume a position
are neuroendocrine cells and their tumors are therefore of relevance.

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8 Endocrine Pathology (2022) 33:6–26

Table 1  The 2022 WHO classification of pituitary neuroendocrine tumors (PitNETs)

PitNET Type Subtype Transcription factors Hormones LMWK

PIT1-lineage PitNETs
Somatotroph tumors Densely granulated somatotroph PIT1 GH, α-subunit Perinuclear
tumor
Sparsely granulated somatotroph PIT1 GH Fibrous bodies (> 70%)
tumor
Lactotroph tumors Sparsely granulated lactotroph PIT1, ERα PRL (paranuclear dot-like) Weak or negative
tumor
Densely granulated lactotroph PRL (diffuse cytoplasmic) Weak or negative
tumor
Mammosomatotroph PIT1, ERα GH (predominant), PRL, Perinuclear
tumor α-subunit
Thyrotroph tumor PIT1, GATA3 α-subunit, βTSH Weak or negative
Mature plurihormonal PIT1, ERα, GATA3 Monomorphic tumor cells with Perinuclear
PIT1-lineage tumor predominant GH expression
and variable PRL, βTSH, and
α-subunit
Immature PIT1-lineage PIT1 (ERα, GATA3) Monomorphic tumor cells with Focal/variable
tumor focal/variable staining for no
hormones, or one or more
of GH, PRL, βTSH, and/or
α-subunit
Acidophil stem cell PIT1, ERα Monomorphic tumor cells with Scattered fibrous
tumor PRL (predominant) and GH bodies
(focal/variable)
Mixed somatotroph and PIT1, ERα** Somatotroph tumor component: Tumor subtype charac-
lactotroph tumor* GH ± α-subunit depending teristics
on tumor subtype; lactotroph
tumor component: PRL (diffuse
or paranuclear depending on the
subtype)
TPIT-lineage PitNETs
Corticotroph tumors Densely granulated corticotroph TPIT ACTH and other POMC Strong, always diffuse
tumor derivates
Sparsely granulated corticotroph Variable (often diffuse)
tumor
Crooke cell tumor Perinuclear ring–like
cytoplasmic
SF1-lineage PitNETs
Gonadotroph tumor SF1, ERα, GATA3 α-subunit, βFSH, βLH, or none Variable or negative
PitNETs with no distinct cell lineage
Plurihormonal tumor Multiple combinations Multiple combinations in Variable
a monomorphous tumor
population
Null cell tumor None None Variable

LMWK low molecular weight cytokeratin, PitNET pituitary neuroendocrine tumor

*
 These tumors are composed of two morphologically and immunohistochemically distinct tumor cell populations; **positive in the lactotroph
tumor component

The subtypes of PitNETs are discussed within the frame- counterparts and are usually highly hormonally active,
work of the normal cell counterparts, highlighting the fea- whereas the sparsely granulated tumors are more aggres-
tures that are important in their diagnosis. Somatotroph, sive, likely because they present at a later, more advanced
lactotroph, and corticotroph tumors are subtyped as sparsely stage due to less florid hormonal symptomatology. The
and densely granulated; the densely granulated forms of reverse is true of lactotroph tumors that are far more com-
somatotroph and corticotroph tumors resemble their normal monly sparsely granulated, reflecting the normal status of

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Endocrine Pathology (2022) 33:6–26 9

lactotrophs. An unusual and aggressive subtype of cortico- cell type, and hormone production as well as other ancillary
troph PitNET is the Crooke cell tumor that illustrates the features that allow characterization of subtypes (Table 1).
dichotomy of hormone feedback and growth control; these The approach to this need for extensive immunohisto-
atypical lesions have Crooke’s hyaline change suggesting chemistry varies based on resource availability. In the ideal
feedback suppression of hormone synthesis and secretion, yet setting, all PitNETs should be stained for at least the three
they are highly proliferative, aggressive tumors. Only thyro- main transcription factors, PIT1, TPIT, and SF1 [1]; ide-
troph and gonadotroph tumors have no recognized subtypes. ally, this panel should also include ERα and GATA3 [18].
There are now also examples of PitNETs that are thought Staining for hormones should include ACTH, GH, PRL,
to represent tumors of precursor cells. These include the aci- βTSH, βFSH, and βLH as well as the α-subunit of glyco-
dophil stem cell tumor and the immature PIT1-lineage tumor. protein hormones (αSU), although some pathologists do not
These tumors are often (but not always) plurihormonal and stain for βFSH and βLH given the high sensitivity of SF1
do not show terminal differentiation based on morphology, for detecting gonadotroph tumors [19]. The importance of
immunoprofile, ultrastructure, and function. Importantly, the keratins in determining cell type and tumor subtype must
original description of the immature plurihormonal tumors also be emphasized [20]; the most widely used antibody is
used the nomenclature “poorly differentiated” to describe the CAM5.2 clone but others including AE1/AE3 and CK18
the cytology that was not characteristic of any differenti- are also satisfactory. As with other NETs, Ki67 is a part of
ated PIT1-lineage cell [13]. However, in the context of the the assessment but unlike other NETs, these tumors are not
WHO/IARC common classification system for NENs, the graded based on proliferation indices.
term “poorly differentiated” is used for NECs, and these The ideal approach is to perform the complete panel of stains.
tumors are not nearly so undifferentiated; therefore, the term However, in some places, this is not feasible; there is a proposal
has been changed to “immature PIT1-lineage” to clarify this to use a tiered approach, starting with pituitary transcription
potential source of confusion. Another important addition is factors [21, 22] followed by the relevant hormones applicable
the mature plurihormonal PIT1-lineage tumor that resembles for the transcription factors identified. This approach is more
a mammosomatotroph tumor but also is responsible for secre- cost-effective and can be used for small specimens that may not
tion of TSH in addition to GH and PRL. have sufficient tissue for a full workup [23, 24], but might miss
As in previous editions, the term “null cell” is used to unusual tumors that require more detailed evaluation [25].
describe PitNETs that have no evidence of adenohypophyseal
lineage-specific differentiation based on complete lack of reac-
tivity for not only pituitary hormones, but also PIT1, TPIT, Question 4: What Are the Pathological
SF1, and GATA3. As predicted at the time of their inception Correlates of Acromegaly?
[14], these tumors are becoming much more rare with the use
of more sophisticated tools to identify lineage determination. It has long been recognized that acromegaly is not one disease
There are very rare tumors that are composed of a single [26] but rather is attributed to a group of neoplasms including
cell population that exhibits features of multiple adenohy- rare ones outside the pituitary.
pophyseal lineages [15, 16]; these unusual plurihormonal The commonest tumor associated with acromegaly is the
PitNETs are accounted for as a separate type. densely granulated somatotroph tumor (Fig. 1) [19, 27].
In previous editions, mixed tumors were recognized in This tumor is composed of densely granulated, strongly
the somatotroph category, but it is now evident that multi- acidophilic cells that closely resemble nontumorous soma-
ple synchronous PitNETs occur more often than previously totrophs. They are usually highly hormonally active, and
thought [17]; this point has been highlighted by the use of the patients present with florid disfigurement that is read-
transcription factor immunohistochemistry that allows the ily appreciated on cursory examination. The tumor cells
detection of discrete cells types in tumors that might other- express PIT1, GH, and αSU and have a characteristic peri-
wise be classified as “unusual plurihormonal” lesions. nuclear pattern of keratin staining. Because of their hormo-
nal activity, they are usually diagnosed at a younger age and
when smaller than their related sparsely granulated subtype
Question 3: Which Ancillary Tools Are that may go undetected until they create symptoms of a
Required for the Assessment of Pituitary mass and are, therefore, often extrasellar at diagnosis.
Neuroendocrine Tumors? The sparsely granulated somatotroph tumor (Fig. 2) is com-
posed of chromophobic cells that have few secretory granules
As is evident from the new WHO classification, there is an and may be negative or only focally weakly positive for GH,
absolute need to identify tumor cell expression of transcription but they have a characteristic cytoplasmic globule that can be
factors and hormones [12]. The role of IHC cannot be over- seen on H&E staining and is decorated by stains for keratins
emphasized. All PitNETs must be classified based on lineage, such as CAM5.2, CK18, and AE1/AE3 [20]. In addition to this

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10 Endocrine Pathology (2022) 33:6–26

Fig. 1  Densely granulated
somatotroph tumor. These
tumors are composed of large
cells with acidophilic cyto-
plasm, nuclear positivity for
PIT1, diffuse strong cytoplasmic
reactivity for GH, and intense
perinuclear keratins using the
CAM 5.2 stain

keratin pattern, they express PIT1 diffusely but they are usually is associated with additional hormone hypersecretion includ-
negative for αSU and all other pituitary transcription factors ing hyperprolactinemia that is greater than expected from
and hormones. The fibrous body is present in the vast majority hypothalamic interruption and, in the case of the plurihor-
of tumor cells and is the hallmark of this PitNET. monal tumor, hyperthyroidism.
Densely granulated somatotroph tumors are highly enriched In contrast, the immature PIT1-lineage tumor and the acido-
for tumors with GNAS activating mutations [28] and the high phil stem cell tumor represent less differentiated cells that do
cAMP levels that are characteristic of this tumor account for not resemble any terminally differentiated “mature” cells that
the consistent expression of αSU and explain the sensitivity of are known to exist in the mature normal gland. Both of these
these tumors to somatostatin inhibition, whereas the sparsely immature tumor types have unusual keratin profiles that vary
granulated subtype tends to be more resistant to this therapeu- from diffuse to focal and they may have scattered fibrous bodies.
tic approach [27]. These tumor subtypes can be distinguished Immature PIT1-lineage tumors (Fig. 5) are composed of
preoperatively based on the clinical and biochemical features polygonal or even spindle-shaped chromophobic cells that
as well as their radiological features including the hyperinten- more closely resemble thyrotrophs; these tumors may be
sity of sparsely granulated tumors on T2-weighted magnetic clinically silent or may cause acromegaly, hyperprolactine-
resonance imaging (MRI) [26, 27]. Occasional tumors have mia, and/or central hyperthyroidism; they consistently stain
the predominant morphology of densely granulated tumors but for PIT1 but may have variable, usually only focal positivity
contain scattered fibrous bodies associated with diffuse peri- for one or more than one PIT1-lineage hormones including
nuclear keratin staining; these so-called “intermediate” forms GH, PRL (associated with ERα), and/or βTSH (associated
are clinically, biochemically, radiologically, and prognostically with GATA3); and they tend to be relatively aggressive, with
indistinguishable from densely granulated tumors [29] and are large unresectable tumors at presentation.
therefore classified within that category. Acidophil stem cell tumors (Fig. 6) are also large tumors
Other PitNETs can also cause acromegaly. These include at presentation and are usually associated with hyperprol-
mammosomatotroph tumors (Fig. 3) that not only resemble actinemia but less than expected for the size of the tumor;
densely granulated somatotroph tumors but also express they may also give rise to a very subtle “fugitive acromeg-
ERα and PRL in many tumor cells and mature plurihor- aly” [23]. Unlike in the 2017 WHO classification, the acido-
monal PIT1-lineage tumors (Fig. 4) that not only are simi- phil stem cell tumor is separated from the lactotroph tumor
lar but also express variable GATA3 and βTSH. These are family and now stands out as a distinct PIT1-lineage tumor.
both strongly acidophilic tumors that resemble nontumorous These tumors have characteristic oncocytic cytology with
mammosomatotrophs and give rise to florid acromegaly that massive dilated “giant” mitochondria that can be seen as

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Endocrine Pathology (2022) 33:6–26 11

Fig. 2  Sparsely granulated
somatotroph tumor. These
tumors are composed of large
cells with chromophobic cyto-
plasm that harbors pale round
structures (arrows) that cor-
respond to keratin aggresomes
known as fibrous bodies. They
have nuclear positivity for PIT1
but only scant variable cyto-
plasmic reactivity for GH and
incomplete weak membranous
staining for SSTR2

cytoplasmic vacuoles on H&E staining. They stain for PIT1 tumor composed of gangliocytoma with a somatotroph
and ERα, have extensive PRL but only focal GH immuno- tumor, usually a sparsely granulated somatotroph tumor.
reactivity, and generally do not express αSU. Ectopic GH results in no pituitary enlargement, so the gland
The category of mixed somatotroph-lactotroph tumors is is not usually biopsied, but ectopic GHRH can be missed
used to describe tumors that are composed of two distinct and considered to be primary pituitary disease because of
populations of tumor cells that can be recognized, usu- the resulting somatotroph hyperplasia. Pituitary hyperpla-
ally on H&E but certainly on immunoprofiling. They are sia should be considered when the imaging identifies uni-
most often composed of densely granulated somatotrophs form sellar enlargement with no distinction between a non-
and sparsely granulated lactotrophs (see next section), but enhancing neoplasm and an enhancing normal rim, but this
occasional tumors are composed of sparsely granulated is occasionally overlooked and the pathologist is responsible
somatotrophs and sparsely granulated lactotrophs. for making the diagnosis of hyperplasia. The importance
Acromegaly can rarely be caused by eutopic or ectopic of reticulin or collagen IV staining is emphasized for this
production of GH-releasing hormone (GHRH) [10, 11, 30, distinction [1] that will lead to a workup for the primary
31] and even less commonly by ectopic GH [32]. Eutopic dis- source of disease that can be in the lung, pancreas, adrenal,
ease takes the form of either a gangliocytoma or a composite or other sites.

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12 Endocrine Pathology (2022) 33:6–26

Fig. 3  Mammosomatotroph
tumor. Like densely granulated
somatotroph tumors, these
tumors are composed of large
cells with acidophilic cyto-
plasm, nuclear positivity for
PIT1, diffuse strong cytoplas-
mic reactivity for GH, and
intense perinuclear keratins (not
shown), but they also express
ER (not shown) and PRL

Question 5: What Are the Pathological dot-like staining pattern that corresponds to the Golgi complex.
Correlates of Hyperprolactinemia? These tumors are negative for GH, αSU, βTSH, and other pitui-
tary transcription factors including GATA3. CAM5.2 expression
Hyperprolactinemia is a feature of almost any mass lesion in is often variable. Interestingly, these tumors tend to be indolent
the sella that interferes with the transmission of dopamine to the in women but are more aggressive in men [34].
adenohypophysis; this so-called "stalk section effect" is respon- A very rare lactotroph tumor subtype is the densely granu-
sible for moderate elevations in circulating PRL that is regu- lated lactotroph tumor (Fig. 8) that tends to present as a very
lated by tonic inhibition from the hypothalamus. This can be large mass with very high prolactin levels that can be resistant
seen with any PitNET that does not synthesize or secrete pro- to dopamine agonist therapy. These tumors are distinguished
lactin, with tumors in the sella that do not completely destroy from their sparsely granulated counterparts by the presence of
the adenohypophysis (such craniopharyngiomas, meningiomas, diffuse cytoplasmic PRL expression.
and soft tissue tumors) as well as with inflammatory conditions Other PIT1-lineage PitNETs can synthesize and secrete
that cause sellar enlargement, the various forms of hypophysitis PRL, sometimes with other hormones, but the correlation
[1]. Hyperprolactinemia due to a prolactin-secreting PitNET with tumor size is not nearly as clear. These include mam-
comes in many flavors. The term “prolactinoma” is meaning- mosomatotroph tumors, mature plurihormonal PIT1-lineage
less for histopathological tumor classification. tumors, mixed somatotroph-lactotroph tumors (all three with
The vast majority of these tumors are pure lactotroph tumors acromegaly), immature PIT1-lineage tumors (that may also
that comprise almost half of cases in almost every epidemiologic have unusual presentations including acromegaly and/or
series [6, 33] but not in surgical series [19]. These are sparsely hyperthyroidism or may be clinically silent with hyperprol-
granulated lactotroph tumors (Fig. 7) that usually respond actinemia in the range of stalk effect), and the acidophil stem
exquisitely to dopamine agonist therapy with normalization of cell tumor that usually is unassociated with other hormone
hormone levels and tumor shrinkage. One of the clues to this excess but may give rise to very subtle or “fugitive” acro-
diagnosis is the exceptional correlation between tumor size and megaly. Other rare mixed tumors may also have a lactotroph
prolactin level. Sparsely granulated lactotroph tumors are com- component that would not cause hyperprolactinemia pro-
posed of chromophobic tumor cells that express PIT1, ERα, and portional to tumor size because the other components alter
PRL; the PRL staining has a highly characteristic juxtanuclear the tumor size without being responsible for PRL secretion.

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Endocrine Pathology (2022) 33:6–26 13

Fig. 4  Mature PIT1-lineage
tumor. Like mammosomato-
troph tumors, these tumors are
composed of large cells with
acidophilic cytoplasm, nuclear
positivity for PIT1, diffuse
strong cytoplasmic reactivity
for GH, variable positivity for
ER (not shown) and PRL, and
intense perinuclear keratins
(CAM 5.2), but they also
express TSH and GATA3 (not
shown)

Question 6: What Are the Pathological traditionally considered to be aggressive with extensive fibrosis
Correlates of TSH Excess? and invasive behavior that precludes gross total surgical resec-
tion; however, the inclusion of immature PIT1-lineage tumors
One of the most important changes in the new classification is that have those specific features of aggressive behavior is likely
the emphasis on the various types of PitNETs that can secrete responsible for this fallacy, as most mature thyrotroph tumors
TSH. These include thyrotroph tumors (Fig. 9), immature may be fibrotic but are not really highly invasive.
PIT1-lineage PitNETs, mature plurihormonal PIT1-lineage An important differential diagnosis that is often seen clini-
PitNETs, any of these tumors in the context of multiple syn- cally is thyrotroph hyperplasia due to primary thyroid failure with
chronous PitNETs, and unusual plurihormonal PitNETs. hypothyroidism. This results from an incomplete biochemical
Much of the literature is filled with case reports and series assessment and poor radiology interpretation that fails to rec-
of “TSHomas” a term that may be clinically relevant but is ognize complete sellar enlargement with no enhancing rim of
meaningless as a biological tumor classification [35]. These normal tissue that is seen as a feature of PitNETs [1]. In this situ-
series include pure thyrotroph tumors as well as mature pluri- ation, the pathologist should recognize the expanded but intact
hormonal PIT1-lineage tumors that often cause acromegaly and reticulin framework as well as the presence of intermixed nontu-
hyperthyroidism [23, 24] and immature PIT1-lineage tumors morous cells of all types. This is one rationale for the proposal to
that may have unusual presentations including hyperthyroidism perform reticulin or collagen IV stains as a matter of routine and
[13] but may also be clinically silent with hyperprolactinemia to perform the complete battery of immunostains for all pituitary
in the range of stalk effect. TSH-producing tumors have been transcription factors and hormones.

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14 Endocrine Pathology (2022) 33:6–26

Fig. 5  Immature PIT1-lineage
tumor. These unusual tumors
are composed of spindle and
epithelioid cells with nuclear
pleomorphism and prominent
nuclear inclusions known as
spheridia. The only consistent
immunohistochemical finding is
diffuse nuclear PIT1 positivity.
They can have variable GH, PRL,
and/or TSH in any combination,
with ER (not shown) and GATA3
expression correlating with PRL
and TSH, respectively

Question 7: What Are the Pathological and strongly PAS-positive tumors with nuclear TPIT, cyto-
Correlates of Cushing Disease? plasmic ACTH, and very intense keratin reactivity. The big-
gest challenge with these tumors is due to their small size;
The clinical diagnosis of Cushing disease varies from a they may not be visible on MRI, resulting in the need for
florid disorder that can be diagnosed at first glance to one of inferior petrosal vein sampling to localize them; they may
the most challenging scenarios in which multiple complex be missed because of a larger incidental “decoy” lesion [37].
tests are required. As with acromegaly, there are subtypes of Often the surgeon will try to identify them by filleting the
corticotroph tumors that are associated with distinct clini- gland in situ, and they may be lost to suction used to clear the
cal features and have different prognosis and responses to hemorrhagic operative field; it is therefore recommended that
therapy [1, 36]. As in the 2017 WHO classification, corti- the suction apparatus have a trap to catch all tissue. Despite
cotroph tumors are classified based on the extent and distri- this precaution, occasional patients will not have a detect-
bution of their secretory granules as well as distribution of able tumor yet they are cured by surgery; the diagnosis is
their cytoplasmic keratin filaments into three subtypes: (i) supported by the presence of Crooke’s hyaline change in the
densely granulated corticotroph tumor, (ii) sparsely granu- nontumorous gland that is both diagnostic of cortisol excess,
lated corticotroph tumor, and (iii) Crooke cell tumor. excluding the differential diagnosis of a pseudo-Cushing dis-
Densely granulated corticotroph tumors (Fig. 10) tend to order, and predictive of better outcome [38].
be very small and associated with florid clinical manifesta- Sparsely granulated corticotroph tumors (Fig. 11) are
tions of cortisol excess. These are characteristic basophilic usually larger and associated with less obvious Cushingoid

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Fig. 6  Acidophil stem cell

tumor. These are oncocytic
tumors whose cells can have
large dilated mitochondria
that are visible as cytoplas-
mic vacuoles on routine
microscopy. They consistently
express nuclear PIT1 and ER
(not shown) and cytoplasmic
PRL, but they often have scant
variable GH as well as focal
fibrous bodies with CAM 5.2.
The antimitochondrial antibody
(AMA) yields strong positivity
that highlights the dilated forms

features. There is some confusion in the literature about Crooke cell tumor (Fig. 12) is a rare subtype of cortico-
these lesions that have been classified as “silent” by some troph tumor. It is composed of tumor cells with Crooke’s
when they have no obvious clinical features but there is hyaline change, providing evidence of hormonal feedback
biochemical evidence of cortisol excess; a purist definition inhibition. Paradoxically, these tumors are among the most
requires no evidence of cortisol excess for the diagnosis of proliferative and aggressive, invasive, recurrent, and meta-
a silent tumor. These tumors can be described as “whisper- static PitNETs. They are composed of large cells with baso-
ing”; the accuracy of diagnosis is dependent on the degree philic, PAS-, and ACTH-positive granules sequestered at
of acuity of the clinician. These tumors are composed of the cell periphery or immediately next to the nucleus, while
chromophobic cells that have strong nuclear TPIT staining, the cytoplasm is filled with a ring of pale hyaline material
variable, often focal and weak PAS and ACTH positivity, that is intensely reactive for keratins using CAM5.2, AE1/
and intense cytoplasmic keratin reactivity. They too are AE3, or CK18 [20].
associated with Crooke’s hyaline change of nontumorous As with acromegaly, the cause of ACTH-dependent cor-
corticotrophs when functional, but not when silent. The dis- tisol excess may be outside the pituitary, and while the most
tinction of a functioning tumor from a true silent one can common situation is ectopic ACTH that has no pituitary
also be confirmed using the biomarker p27 that is usually enlargement, occasional patients have ectopic CRH that
lost in functioning tumors but shows intact nuclear staining causes corticotroph hyperplasia; the radiologic features and
in silent tumors [19]. reticulin changes are similar to those of somatotroph and

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16 Endocrine Pathology (2022) 33:6–26

Fig. 7  Sparsely granulated
lactotroph tumor. These tumors
composed of cells with chromo-
phobic cytoplasm have a highly
characteristic pattern of juxta-
nuclear staining for PRL. They
exhibit strong nuclear reactivity
for PIT1 and ER

thyrotroph hyperplasia discussed above. Primary cortico- gonadal steroids [39–41]. The most common scenario is that
troph hyperplasia as a cause of Cushing disease is a novel of a premenopausal woman with menstrual irregularity,
but rare disorder that can be very difficult to confirm, but is infertility, polycystic ovaries, and even symptoms of ovar-
supported by the lack of Crooke’s hyaline change in nontu- ian hyperstimulation such as abdominal pain and bloating.
morous corticotrophs [38]. Very rare cases of precocious puberty have been described.
However, the majority of tumors associated with gonadotro-
pin excess cause paradoxical hypogonadism. These tumors
Question 8: What Are the Pathological are not morphologically different from the far more common
Correlates of Gonadotropin Excess? clinically silent gonadotroph tumors. The chromophobic cells
can have solid or nesting architecture, but many have pseudo-
Gonadotropin excess is exceptionally uncommon. While gon- papillary growth and they may form characteristic pseudoro-
adotroph tumors (Fig. 13) are the most frequently resected settes around vascular channels. It is important to distinguish
PitNETs representing around 40% of these tumors [19], they these tumors that are often negative for hormones from meta-
are usually clinically silent. Rare functioning PitNETs are static NETs from non-pituitary primary sites, emphasizing
associated with elevated gonadotropins in the face of elevated the importance of transcription factor immunohistochemistry.

Fig. 8  Densely granulated
lactotroph tumor. These very
rare tumors are composed of
loosely cohesive cells with pale
chromophobic to acidophilic
cytoplasm; they express nuclear
PIT1 (not shown) and ER and
diffuse cytoplasmic PRL

13
Endocrine Pathology (2022) 33:6–26 17

Fig. 9  Thyrotroph tumor. The

typical thyrotroph tumor is com-
posed of spindle shaped cells
that stain for nuclear PIT1 and
cytoplasmic TSH

These tumors stain for SF1, GATA3, and ERα, while staining incidental findings or present with symptoms of a sellar
for βFSH, βLH, and αSU is variable. Around 40% of these mass including headache, visual field defects, and hypo-
tumors lack keratin expression [19, 20], a finding that should pituitarism. The most common lesion is a gonadotroph
not be mistaken for a sellar paraganglioma given their com- tumor as described above; they constitute about 70–75% of
mon GATA3 expression. clinically non-functioning PitNETs [19, 42]. In adults, the
second most common clinically silent PitNETs are silent
Question 9: What Is the Classification corticotroph tumors that can be densely or sparsely granu-
of Clinically Nonfunctioning PitNETs lated and can be distinguished morphologically from func-
and Does It Matter? tioning tumors only by the lack of Crooke’s hyaline change
in the surrounding nontumorous tissue and the presence of
The clinical term “non-functioning” is not a diagnosis but intact nuclear p27 [19]. In patients younger than 25 years,
rather a description of a clinical scenario that has many immature PIT1-lineage tumors are also common findings
differential diagnoses. These are tumors that are either in patients with non-functioning PitNETs [43]. Occasional

Fig. 10  Densely granulated cor-

ticotroph tumor. These classical
basophilic tumors are composed
of round tumor cells that have
intense cytoplasmic ACTH and
keratin (CAM 5.2) positivity
and nuclear TPIT (not shown).
When associated with Cushing
disease, they are negative for
p27 (with the normal endothe-
lial and stromal cells serving as
positive controls for the stain), a
feature that is not seen in clini-
cally silent tumors

13
18 Endocrine Pathology (2022) 33:6–26

Fig. 11  Sparsely granulated
corticotroph tumor. These
tumors are composed of round
tumor cells that have chromo-
phobic cytoplasm with only
variable ACTH but intense
keratin (CAM 5.2) positivity
and nuclear TPIT (not shown).
These tumors also are negative
for p27 when clinically func-
tional (see Fig. 10)

tumors with morphological features of a PitNET but no large and includes metastatic NETs that can be easily con-
biomarkers of lineage determination are classified as null fused without the application of transcription factors and
cell tumors; these are decreasing in incidence as the tools hormones that assist in determination of site of origin [6].
used to classify these tumors improve [42, 44]. Other tumors The importance of accurate diagnosis lies not only in the
can also present this way; the differential diagnosis is very exclusion of metastatic disease, which can portend a dismal

Fig. 12  Crooke cell tumor.

These tumors are composed
of corticotrophs that show
evidence of glucocorticoid
feedback suppression, the
accumulation of pale pink
hyaline cytoplasmic mate-
rial that stains intensely for
keratins (CAM 5.2), pushing
the ACTH-immunoreactive
cytoplasmic secretory granules
to the cell periphery, or trapping
it in a perinuclear location.
Electron microscopy shows the
concentric bundles of interme-
diate filaments that represent the
keratin material

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Endocrine Pathology (2022) 33:6–26 19

Fig. 13  Gonadotroph tumor.
These tumors composed of
chromophobic cells can form
sheets, ribbons, trabecula, or
rosettes around vascular chan-
nels. They have strong nuclear
positivity for SF1 and GATA3
but hormone reactivity can
be variable or absent; in this
example there is only focal FSH
staining

prognosis, but also in stratifying the prognosis of the Pit- Question 11: What Are the Relative
NET, determining the needs for ancillary therapies such as Clinico‑pathological Risks of the Various
external beam radiation, gamma knife radiosurgery, and pep- PitNET Tumor Types?
tide receptor radiotherapy. These treatments are not usually
indicated for gonadotroph tumors but may be required for Unlike other NETs, PitNETs are not stratified into grades
the more aggressive silent corticotroph tumors and immature based on their Ki67 proliferation index; this is because
PIT1-lineage tumors [6, 25, 28]. there are far better biomarkers of aggressive behavior [48].
In fact, the classification of tumor type and subtype is of
major clinical significance [49]. The stratification of tumors
Question 10: How Can You Verify within each tumor lineage and cell type has been proven by
the Diagnosis of Multiple Synchronous clinical data as described in the sections above. For instance,
PitNETs? among patients with acromegaly, it is recognized that
sparsely granulated somatotroph tumors are more aggres-
The incidence of multiple synchronous PitNETs has increased sive than densely granulated ones. Among patients with
in the last 15 years due to the application of transcription fac- Cushing disease, sparsely granulated corticotroph tumors
tor immunohistochemistry [17, 45, 46]. The identification of are more aggressive than densely granulated corticotroph
a PitNET with multiple transcription factor profiles (Fig. 14) tumors and Crooke cell tumors are exceptionally aggressive.
should prompt careful analysis of the distribution of the Patients with pituitary tumor-dependent hyperthyroidism are
immunoreactivity that is usually accompanied by correspond- stratified with immature PIT1-lineage tumors as the most
ing hormone positivity [12]. While there are exceptionally aggressive cause. Among patients with hyperprolactinemia,
rare tumors that express transcription factors and hormones the story is more complex with patient demographics play-
of multiple lineages in a single cell type [15, 16], it is far more ing a role in modifying tumor classification: while sparsely
common to have multiple synchronous neoplasms. These can granulated lactotroph tumors tend to be very indolent and
only be diagnosed using a thorough immunohistochemical responsive to medical therapy, they can be aggressive in
approach [12], and one must be careful to ensure that all cases men, whereas the rare densely granulated subtype is gener-
are clinically diagnosed appropriately, and that research is ally always aggressive. Immature PIT1-lineage tumors tend
performed on properly characterized samples [47]. to be aggressive irrespective of their clinical presentation,

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20 Endocrine Pathology (2022) 33:6–26

Fig. 14  Double PitNET. The

coexistence of multiple PitNETs
is not uncommon. Double
tumors are most common,
such as this one composed of a
PIT1-lineage densely granulated
somatotroph tumor on the right
and a SF1-positive gonadotroph
tumor on the left. Triple tumors
may occur (not shown)

whether it be acromegaly, hyperthyroidism, hyperprolactine- document the occurrence of pituitary blastoma in young
mia or as a clinically non-functioning tumor. Among clini- adults [52, 53]. Careful review of follow-up data under-
cally non-functioning tumors, silent corticotroph and silent scores that treatment-related complications rather than dis-
PIT1-lineage tumors including the non-functional immature ease progression were the source of most deaths in affected
PIT1-lineage tumors are more aggressive than the more patients [53, 54].
common silent gonadotroph tumors.
It should be noted that as yet, there is no staging sys-
tem for PitNETs; however, the extent of tumor is a critical Question 13: What Is the Rationale
factor in determining prognosis. Microtumors that can be for Consolidating Posterior Lobe Tumors?
completely surgically resected have a much better prognosis
than a tumor that extends into locations where it cannot be Tumors arising in the posterior lobe have now been con-
resected, such as the lateral cavernous sinus. solidated in the new WHO classification. In the past, the
existence of multiple tumors of uncertain histogenesis
Question 12: What Is New in the Pathological gave rise to a nomenclature that is nonspecific and con-
Correlates of Pituitary Blastoma? fusing. Tumors classified as “spindle cell oncocytomas”
were originally thought to be derived from folliculos-
Pituitary blastoma (Fig.  15) is one of the hallmarks of tellate (sustentacular) cells of the anterior lobe. Gran-
DICER1 syndrome caused by pathogenic DICER1 variants. ular cell tumors were of unknown origin. Tumors with
This rare embryonal sellar tumor is composed of three dis- ependymal morphology were called sellar ependymomas
tinct components including small undifferentiated/primitive without any evidence of ependymal cells in the normal
blastemal cells, cuboidal/columnar Rathke’s pouch epithe- pituitary. Only pituicytomas were thought to derive from
lium with rosette or gland/follicle formation, and adeno- the glial-like cells that comprise the posterior lobe. How-
hypophyseal neuroendocrine cells. Neuroendocrine cells ever, with the recognition that pituicytes normally have
tend to show predominant corticotroph cell differentiation; subtypes that can be oncocytic, granular, or resembling
this likely reflects the fact that corticotrophs are the first ependymal cells, and using TTF1 as a biomarker of origin
cell type to differentiate in the fetal pituitary [50, 51]. This in the medial basal hypothalamus/posterior pituitary, it
entity was initially restricted to infantile Cushing disease was proposed several years ago that these unusual tumors
with onset prior to 2 years of age; however, recent reports are all subtypes of pituicytoma (Fig. 16) [55]. Studies of
their genetics and epigenetic methylation profiles have

13
Endocrine Pathology (2022) 33:6–26 21

Fig. 15  Pituitary blastoma. This

rare tumor is composed of small
undifferentiated blastemal cells,
cuboidal and columnar Rathke’s
pouch epithelium that can form
rosettes, glands and follicles,
and adenohypophyseal neuroen-
docrine cells that are most often
positive for ACTH

supported this hypothesis and have expanded on prognos- of vasopressin on corticotrophs [60]. These tumors expand
tic subgroups in these tumors [56]. the spectrum of neuroendocrine neoplasia to include TTF1-
positive neuronal lesions.

Question 14: What Is the Significance

of the Sellar Neuronal Tumors? Question 15: How Important Is
the Pathologist in Identifying Germline
One of the more exciting areas of this classification is the Predisposition to Pituitary Tumors?
incorporation of hormone-producing neuronal tumors
(Fig. 17). This area represents a true transition between Pituitary tumors are a part of the spectrum of familial dis-
neuronal and neuroendocrine neoplasia. The existence of orders known as the multiple endocrine neoplasia (MEN)
ganglion cell tumors in this region has been recognized for syndromes [28]. PitNETs are a primary component of
many years, and some of these gangliocytomas have been MEN1 (due to MEN1 mutations), MEN4 (due to CDKN1B
associated with hypersecretion of hypothalamic (GHRH mutations), and the recently described MEN5 (due to
and CRH) and pituitary (GH, ACTH) hormones, resulting MAX mutations), as well as manifestations of SDH defi-
in acromegaly or Cushing disease, as well as occasional ciency syndromes (due to mutations in the SDH complex
tumors causing other hormonal manifestations [57–59]. genes) and Carney complex (due to PRKR1α mutations);
More recently, there have been reports of a number of a patient with a germline pathogenic CDC73 mutation
tumors composed of small neurons, classified as neurocyto- also had an atypical MEN1-like syndrome with a PitNET.
mas, associated with vasopressin excess and the syndrome PitNETs are now being identified in patients with Lynch
of inappropriate diuresis [60]. Interestingly, an intrasellar syndrome (due to deficiencies of MLH1, MSH2, MSH6, or
gangliocytoma producing small amounts of vasopressin PMS2); pituitary blastoma is pathognomonic of DICER1
caused Cushing disease, consistent with the known impact syndrome.

13
22 Endocrine Pathology (2022) 33:6–26

Fig. 16  Pituicytomas. Tumors
that arise from pituicytes of the
posterior lobe can have variable
morphology, resembling spindle
cell light and dark, oncocytic,
granular, or ependymal pitui-
cytes. The traditional pituicy-
toma is a spindle cell tumor (top
row); the tumor formerly called
spindle cell oncocytoma (mid-
dle and bottom rows) is now
recognized to be an oncocytic
subtype of pituicytoma. All
pituicytomas feature nuclear
TTF1 positivity and have
variable S100 positivity. The
oncocytic tumors have abundant
AMA reactivity

Sporadic germline mutations in GNAS give rise to McCune- immunohistochemistry such as staining for menin in MEN1,
Albright syndrome with pituitary neoplasms as a main com- p27 in MEN4, SDHB in SDH deficiency syndromes, parafi-
ponent. PitNETs occur as isolated tumors in families with the bromin in HPTJT syndrome, and mismatch repair enzymes
familial isolated pituitary adenoma (FIPA) syndrome due to AIP (MLH1, MSH2, MSH6, and PMS2) in Lynch syndrome. Loss
mutations and in children with X-linked acrogigantism (X-LAG). of immunoreactivity for these tumor suppressor proteins with
Some of these associations are characterized by specific tumor intact internal positive controls confirms a pathogenesis that
types. For example, patients with Carney complex, McCune- should prompt germline testing. At this time, there is no high-
Albright syndrome, and X-LAG tend to have acromegaly due to quality staining for MAX protein that allows the detection of
mammosomatotroph tumors, whereas those with AIP mutations MEN5, but this is surely on the horizon. A young patient with
usually manifest sparsely granulated somatotroph tumors. acromegaly or gigantism and a sparsely granulated somatotroph
The only association that allows the morphologic tumor type tumor is at high suspicion for germline AIP mutation; how-
to predict a genetic alteration is that of pituitary blastoma with ever in this setting, loss of AIP immunoreactivity is not help-
DICER1 syndrome; however, while the vast majority of ful, since most sporadic tumors of this type exhibit epigenetic
patients with pituitary tumors have sporadic disease, the downregulation of AIP [61]. Of course, any young child with
pathologist can play an important role in identifying those early onset gigantism should be assessed for X-LAG. In any
who should be considered for genetic testing. Any young patient of the syndromic disorders, the association of a PitNET with
(under 30 years of age) with a pituitary tumor is a candidate another qualifying lesion should immediately prompt genetic
for molecular testing, some of which can be approached with evaluation with counselling for the patient and the family.

13
Endocrine Pathology (2022) 33:6–26 23

Fig. 17  Hypothalamic neu-
roendocrine tumors. Tumors
composed of hypothalamic
neurons occur in and around the
sella turcica. Those composed
of large mature ganglion cells
are known as gangliocytomas;
they may be pure neuronal
neoplasms (top left) or admixed
with a PitNET, most commonly
a sparsely granulated somato-
troph tumor (top right). Those
composed of small neurons are
known as neurocytoma (middle
and bottom rows). These tumors
can be identified by their strong
expression of neurofilaments;
they usually exhibit at least
focal TTF1 nuclear reactivity,
reflecting their origin from the
ventral medial hypothalamus.
These tumors may express
hypothalamic hormones;
vasopressin (VP) is the most
frequent product of neurocy-
tomas

Conclusion to consider the development of a staging system for pituitary

tumors. As we continue to work on these aspects of pituitary
The new WHO classification has incorporated tremendous pathology to improve patient care, we face the challenge of
advances in the understanding of the cytogenesis and patho- addressing the pathogenesis of the majority of these lesions
genesis of pituitary tumors of all types. While the advances that remain enigmatic despite so many years of study [28].
in the field of craniopharyngiomas are not discussed here,
the ability to classify these lesions based on immunohisto-
chemistry for BRAF V600E mutant protein versus nuclear Author Contribution  Conception and design: SLA, OM; data collec-
tion and analysis: SLA, OM, AP, RYO; manuscript preparation and
β-catenin expression has made correct diagnosis available editing: SLA, OM, AP, RYO; approval of final manuscript: SLA, OM,
to all pathologists with access to these tools [62] and in a AP, RYO.
subset, paves the way for targeted therapies [63]. Multiple
chapters in the new classification discuss rare but important Declarations 
mesenchymal and stromal tumors, the unusual hematolym-
phoid lesions that occur in the sella, germ cell tumors that Ethics Approval  Not applicable.
can mimic gonadotropin excess, and the metastases that
Consent for Publication  All authors consent to publication.
occur in this region.
The major transformation to PitNETs raises the opportunity Competing Interests  Dr. Ozgur Mete is the editor in chief of Endocrine
to implement structured reporting of these tumors [64, 65] and Pathology. This article was handled by an independent senior editor

13
24 Endocrine Pathology (2022) 33:6–26

and peer-reviewed as per the journal standards. Other authors have no of Routine Analysis of Pituitary Transcription Factors. Endocr
competing interests to disclose. Pathol 31: 330-336. https://​doi.​org/​10.​1007/​s12022-​020-​09646-x
13. Mete O, Gomez-Hernandez K, Kucharczyk W, Ridout R, Zadeh
G, Gentili F, Ezzat S, Asa SL (2016) Silent subtype 3 pituitary
adenomas are not always silent and represent poorly differenti-
ated monomorphous plurihormonal Pit-1 lineage adenomas. Mod
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