Clinical Implications of Accurate Subtyping of Pituitary Adenomas: Perspectives from the Treating Physician

Abstract

Pituitary adenomas comprise a heterogenous group of adenohypophyseal tumours with distinct clinicopathological features across both the clinically functioning and silent groups. Although, predicting a clinically aggressive course remains challenging, accurate subtyping of pituitary adenomas offers valuable prognostic information that together with other clinical and radiological information serves as a platform for tailored treatment and follow-up. For instance, silent subtype 3 pituitary adenomas, silent corticotroph adenomas, acidophil stem cell adenomas, Crooke cell adenomas, and sparsely granulated somatotroph adenomas show more invasive growth. This review has been formulated as a set of practical questions that address the distinct clinical behaviour of a selected group of pituitary adenoma subtypes.

Full text

doi: 10.5146/tjpath.2015.01311
Review
4
Receved : 09.06.2015 Accepted : 10.06.2015
Correspondence: Özgür METE
200 Elizabeth Street, 11th Floor, Department of Pathology,
University Health Network, TORONTO, ON, CANADA
E-mail: ozgur.mete2@uhn.ca Phone: +1 416 340 3004
(Turk Patoloji Derg 2015, 31(Suppl):4-17)
ABSTRACT
Ptutary adenomas comprse a heterogenous group of adenohypophyseal tumours wth dstnct clncopathologcal features across both the
clncally functonng and slent groups. Although, predctng a clncally aggressve course remans challengng, accurate subtypng of ptutary
adenomas oers valuable prognostc nformaton that together wth other clncal and radologcal nformaton serves as a platform for talored
treatment and follow-up. For nstance, slent subtype 3 ptutary adenomas, slent cortcotroph adenomas, acdophl stem cell adenomas, Crooke
cell adenomas, and sparsely granulated somatotroph adenomas show more nvasve growth. s revew has been formulated as a set of practcal
questons that address the dstnct clncal behavour of a selected group of ptutary adenoma subtypes.
Key Words: Ptutary adenoma, Acromegaly, Hyperthyrodsm, Cushng syndrome
Clinical Implications of Accurate Subtyping of Pituitary
Adenomas: Perspectives from the Treating Physician
Karen GOMEZ-HERNANDEZ1, Shereen EZZAT1, Sylva L. ASA2, Özgür METE2
Department of 1Medicine and 2Pathology, University Health Network, University of Toronto, TORONTO, ONTARIO, CANADA
INTRODUCTION
As members of the multidisciplinary endocrine oncology
team providing care for patients with pituitary disease we
have oen been intrigued by the relative scarcity of studies
in the eld that describe the clinical relevance of accurate
pituitary adenoma subtyping. Certainly, in other elds of
endocrine oncology such as thyroid cancer, the description
of clinicopathological features has emerged as pivotal
elements in disease risk stratication and management.
Although ancillary tests that distinguish aggressive
pituitary adenomas from pituitary carcinomas are still
unavailable, the accurate subtyping of pituitary adenomas
in association with selected biomarkers is still considered
the best predictor and prognosticator (1-5). Modern
approaches to the classication of pituitary adenomas use
a panel approach by integrating adenohypophyseal cell-
lineage specic transcription factors (Pit-1, Tpit, SF-1, and
ER), monoclonal antibodies against adenohypophyseal
hormones (Growth hormone: GH, Prolactin: PRL, beta-
thyroid stimulating hormone: beta-TSH, beta-follicle
stimulating hormone: beta-FSH, beta-luteinizing hormone:
beta-LH, Adrenocorticotropic hormone: ACTH, and
alpha-subunit), low molecular weight keratin (CAM5.2
or cytokeratin 18), and Ki-67 (MIB-1) (1-3,5,6). p53
immunohistochemistry is also a part of this panel in some
practices (5). is approach identies tumours that are more
frequently associated with invasive growth (Hardys’ grade
III/IV and Knosp’s grade III/IV), higher recurrent rates, and
a distinct response to therapy (Table 1). Importantly, this
morphologic categorization into aggressive subtypes has
been suggested to be complementary and in some instances
perhaps even superior to the designation of atypical
pituitary adenomas, which are invasive adenomas showing
p53 positivity and/or a MIB-1 labeling index >3%. In this
brief review that has been formulated as a set of questions
we will address the distinct behaviour of a selected group
of pituitary adenoma subtypes in selected clinical settings.
A. CLINICALLY NONFUNCTIONING PITUITARY
ADENOMAS
Question for the Pathologist: Which type of adenoma is
it?
Clinical Relevance: Certain clinically non-functioning
pituitary adenomas are characterized by more aggressive
behaviour.
Although all pituitary adenoma subtypes can potentially
present as clinically non-functioning, based on recent
surgical series, gonadotroph adenomas are the most
frequent (7). Amongst the less common pituitary adenomas
that may present as clinically silent tumours, silent
corticotroph adenomas and silent subtype 3 adenomas have
more aggressive clinical behaviour in terms of size, invasive
growth, and recurrence rates (7,8). ese tumour subtypes
also present at an earlier mean age than gonadotroph
adenomas (7,8). Null cell adenomas have also been
recognized as more invasive than gonadotroph adenomas

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GOMEZHERNANDEZ K et al: Pituitary Adenomas
Vol. 31, Suppl, 2015; Page 4-17
Table I: Subtyping of pituitary adenomas
Adenoma subtype Distinct clinical features Hormones, transcription factors, and CAM5.2
Pit-1 family tumours
PRL-producing adenomas
Sparsely granulated lactotroph adenoma
Densely granulated lactotroph adenoma
Acidophil stem cell adenoma
GH-producing adenomas
Densely granulated somatotroph adenoma
Intermediate granulated somatotroph adenoma
Sparsely granulated somatotroph adenoma
Mammosomatotroph adenoma
Mixed somatotroph and lactotroph adenoma
TSH-producing adenomas
yrotroph adenoma
Monomorphous plurihormonal adenoma
Silent subtype 3 adenoma
Common subtype, responsive to dopamine agonists
Likely more resistant to dopamine agonists
Likely more resistant to dopamine agonists
Likely to respond to somatostatin analogues
Behave like densely granulated somatotroph adenomas
More resistant to somatostatin analogues
Aggressive tumours; central hyperthyroidism
Present in younger individuals when compared to
gonadotroph adenomas; invasive and recurrent
Pit-1, ER, PRL (golgi pattern)
Pit-1, ER, PRL (diuse)
Pit-1, ER, PRL (diuse), GH (variable), CAM5.2 (few brous bodies)
Pit-1, GH (diuse), α-SU, CAM5.2 (perinuclear)
Pit-1, GH (diuse), α-SU, CAM5.2 (brous bodies <70%))
Pit-1, GH (weak), CAM5.2 (brous bodies >70%)
Pit-1, ER, GH, PRL, α-SU
Pit-1, ER, GH, PRL, α-SU
Pit-1, GATA-2, β-TSH, and α-SU
Pit-1, ER (variable), α-SU (variable), and GH/PRL/β-TSH (variable)
Tpit family tumours
Densely granulated corticotroph adenoma
Sparsely granulated corticotroph adenoma
Crooke cell adenoma
If excised completely cure is possible
Aggressive tumours
Typically present with normal or mildly elevated
ACTH; Aggressive tumours
Tpit, ACTH (strong, diuse), CAM5.2 (strong, diuse)
Tpit, ACTH (weak, variable), CAM5.2 (strong, diuse)
Tpit, ACTH (juxtanuclear and peripheral), CAM5.2 (ring-like)
SF-1 family tumours
Hormone-negative gonadotroph adenoma
Hormone-positive gonadotroph adenoma
Most common clinically non-functioning adenoma;
hormone status is of no clinical signicance
SF-1, ER, GATA-2, α-SU, β-FSH and/or β-LH, CAM5.2 (-/+)
SF-1, ER, GATA-2, CAM5.2 (-/+)
Polymorphous Plurihormonal adenoma
Plurihormonal adenoma Extremely rare Multiple
Transcription factor and hormone negative
adenoma
Null cell adenoma
Tumours that have been shown to grow rapidly
preoperatively will continue to show rapid growth
of residual disease; more invasive than gonadotroph
adenomas.
Negative for all adenohypophyseal transcription factors and
hormones; CAM5.2 (-/+).
Pit-1: Pituitary transcription factor-1, ER: Estrogen Receptor, SF-1: Steroidogenic factor-1, GH: Growth hormone, PRL: Prolactin, β-TSH: Beta-thyroid stimulating hormone, ACTH:
Adrenocorticotrophic hormone, α-SU: alpha-subunit, β-FSH: Beta-follicle stimulating hormone, β-LH: Beta-luteinizing hormone.

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Vol. 31, Suppl, 2015; Page 4-17
with mass eects (13), invasion (7), and a high frequency
of pituitary apoplexy (acute hemorrhagic necrosis) (12,
14, 15). In a study that directly compared gonadotroph
adenomas (dened based on immunoreactivity for beta-
FSH, beta-LH or alpha-subunit) to SCA, it was shown that
SCA have higher and earlier recurrences (13). Also, when
compared to other clinically silent adenomas (mainly null
cell adenomas and gonadotrophs adenomas), patients
younger than 30 years of age with silent corticotroph
adenomas more oen have multiple recurrences (>2) and
late recurrences (more than ve years aer initial resection)
(15). It has been suggested that interactions between tumour
cells and extracellular matrix may be one of the mechanisms
leading to distinct behaviour by these pituitary adenomas;
it may be that osteopontin plays a role in the invasiveness
of SCAs, whereas MMP-1 is more frequently expressed in
gonadotroph adenomas (16).
e morphologic distinction of corticotroph origin in a
non-functioning pituitary adenoma is not sucient to
complete a diagnosis, since corticotroph adenomas are a
heterogeneous group of neoplasms. Densely granulated
corticotroph adenomas typically present with a basophilic
cytoplasm correlating with diuse strong PAS positivity
and immunoreactivity for ACTH (Figure 2B); in contrast,
sparsely granulated corticotroph adenomas display focal
PAS staining and weak positivity for ACTH (1-3,17,18).
Regardless of PAS and/or ACTH positivity, both types
of corticotroph adenoma are diusely positive for Tpit
(1,3,5,17,18). Silent densely and sparsely granulated
(9) and to rapidly grow aer surgery if they had shown a
rapid pattern of growth preoperatively (10).
Null Cell Adenomas
e appropriate classication of an adenohypophyseal
tumour into the null cell pituitary adenoma category
requires negativity of cell-type specic dierentiation
using adenohypophyseal hormones and pituitary
transcription factors. e reason this type of adenoma
was overrepresented in older surgical series is that without
the use of pituitary transcription factors, a signicant
proportion of gonadotroph adenomas, which were negative
for beta-FSH and beta-LH, were mistakenly subtyped as
“null cell adenomas”. In fact, the use of SF-1 and ER has
improved the detection of gonadotroph dierentiation in
hormone-negative pituitary adenomas (Figure 1A,B). e
distinction of null cell adenoma is of clinical relevance.
Firstly, true null cell adenomas that grow rapidly before
surgery will continue to show rapid growth of residual or
recurrent disease postoperatively (10), a feature that dictates
a close surveillance strategy. Secondly, null cell adenomas
also seem to show more cavernous sinus invasion than
gonadotroph adenomas (7) which as expected predicts
residual disease (10).
Silent Corticotroph Adenomas
Clinically, silent corticotroph adenomas are characterized by
the lack of clinical signs or symptoms of Cushing’s syndrome
and normal cortisol and ACTH levels (11,12). ese tumors
oen present as macroadenomas (Figure 2A) associated
Figure 1: SF-1 immunohistochemistry helps to distinguish gonadotroph dierentiation in hormone negative adenomas. A) is
photomicrograph illustrates a pituitary adenoma that was negative for all adenohypophyseal hormones. B) Positivity for SF-1 conrms
gonadotroph cell dierentiation in this tumor.
A B

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Vol. 31, Suppl, 2015; Page 4-17
corticotroph adenomas are classied as type 1 (Figure 2A)
and type 2 SCAs, respectively. It has been shown that type 2
SCAs have a higher expression prole of factors regulating
tumor cell invasion/ migration and proliferation, such
as MMP-1, β1-integrin, and FGFR4, compared with type
I SCAs16. Corticotroph adenomas with Crooke’s hyaline
change, also known as “Crooke cell adenomas”, have also
been associated with aggressive behaviour (19, 20).
Silent Subtype 3 Pituitary Adenomas
Silent subtype 3 pituitary adenomas are monomorphous
plurihormonal Pit-1 lineage adenomas that may be
clinically silent (3, 5). However, the term “silent” is a
misnomer, since these tumours can cause acromegaly,
hyperprolactinemia (albeit generally due to stalk eect)
or hyperthyroidism (8,21-23). ese tumours tend to be
invasive macroadenomas or giant adenomas (Figure 3A)
and they present at an earlier mean age than gonadotroph
adenonomas(7, 8, 22, 23). Also, recurrence and tumour-
free status may be as low as a third of treated patients (8).
Not surprisingly, radiotherapy is required in a substantial
number of cases (8) and it appears to achieve control of
disease (22). Somatostatin receptor expression has been
shown in some of these tumours and tumour stability on
long acting octreotide has been previously reported in two
individuals with residual disease (22).
Pathologists should distinguish these neoplasms by
demonstrating variable positivity for one or more Pit-
1-lineage hormones (GH, PRL, and beta-TSH) together
with diuse Pit-1 nuclear reactivity (Figure 3B-D) (3, 5).
It is important to distinguish true tumor cell hormone
expression from scattered positivity that represents
entrapped nontumorous adenohypophyseal cells.
Ultrastructural examination of silent subtype 3 adenomas
reveals characteristic nuclear inclusions known as
“spheridia” (3, 5, 22).
B. ADENOMAS CAUSING PROLACTIN EXCESS
Question for the Pathologist: Is it a sparsely granulated
lactotroph adenoma (most common subtype) or a less
frequent and potentially more aggressive subtype?
Clinical Relevance: Sparsely granulated lactotroph
adenomas usually respond to dopamine agonist therapy. In
patients with acidophil stem cell adenomas, the diagnosis
of GH excess may be missed due to a clinical picture that is
dominated by symptoms related to prolactin excess.
Most “prolactinomas” are sparsely granulated lactotroph
adenomas; densely granulated lactotroph adenomas and
acidophil stem cell adenomas are rare (3). While acidophil
stem cell adenomas are typically associated with prolactin
excess, concomitant GH-excess may occur causing
acromegaly or gigantism (24-26). Given the predominance
of hyperprolactinemia related symptoms, the diagnosis of
GH-excess may be missed if the GH axis is not appropriately
evaluated; this has been described as “fugitive acromegaly”.
Hyperprolactinemia in the setting of acidophil stem
cell adenomas is dierent from that observed in sparsely
A B
Figure 2: Silent corticotroph adenoma. A) Magnetic resonance image showing invasive growth of a silent subtype 2 adenoma; most
silent corticotroph adenomas are invasive macroadenomas (arrow) with a predilection of cavernous sinus invasion, B) Diuse ACTH
expression in a type 1 silent corticotroph adenoma (densely granulated corticotroph adenoma lacking any biochemical or clinical
evidence of excess ACTH) is illustrated.

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Vol. 31, Suppl, 2015; Page 4-17
that are correlated with lack of therapeutic responsiveness
have not provided a detailed morphologic characterization
of the prolactin-producing adenomas and have instead
classied them according to size, i.e., macroprolactinomas
vs microprolactinomas (31,32). In our own experience and
as illustrated by the previous report of two pediatric cases
(33), acidophil stem cell adenomas tend to be resistant
to dopamine agonist therapy both in terms of prolactin
reduction and tumour shrinkage. is clinical observation
is supported by in vitro studies showing bromocriptine
resistance in cells of acidophil stem cell adenomas (34).
granulated lactotroph adenomas in that is not as
proportional to tumour size, i.e., larger acidophil stem
cell adenomas produce less prolactin than similar size
sparsely granulated lactotroph adenomas. Another distinct
characteristic of acidophil stem cell adenomas is that they
are usually invasive macroadenomas (27,29).
Although the vast majority of “prolactinomas” show a
good response to dopamine agonist therapy (30); there
are instances in which a reduction in tumour size and
prolactin concentrations is dicult to achieve. Studies that
have aimed at characterizing the relevant clinical features
Figure 3: Magnetic resonance image and histopathology of a silent subtype 3 adenoma. A) e magnetic resonance image shows a
macroadenoma with suprasellar extension and invasion into the le cavernous sinus; this patient had presented with hypopituitarism
and visual eld disturbances. B) Silent subtype 3 adenomas are diusely positive for Pit-1. C-D) Variable positivity for GH, PRL, and
beta-TSH render the diagnosis of these tumours (GH: C; PRL: D).
A
C
B
D

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GOMEZHERNANDEZ K et al: Pituitary Adenomas
Vol. 31, Suppl, 2015; Page 4-17
It has also been our experience that densely granulated
lactotroph adenomas are relatively rare; they are usually
larger and more invasive than sparsely granulated lactotroph
adenomas.
From a pathological perspective, paranuclear Golgi-type
PRL staining distinguishes sparsely granulated lactotroph
adenomas from acidophil stem cell adenomas and densely
granulated lactotroph adenomas, which oen display
diuse cytoplasmic PRL expression (3,5). Oncocytic change
with dilated mitochondria is one of the characteristics of
acidophil stem cell adenomas in addition to scattered brous
bodies and concomitant focal GH expression (3,5, 35).
When compared to controls, MEN-1 patients more
frequently harbour plurihormonal pituitary adenomas as
well as multiple adenomas (36). Plurihormonality in this
setting most oen includes GH and PRL expression. On
the other hand, when multiple synchronous adenomas
are present they are frequently a combination of PRL- and
ACTH-producing adenomas. PRL-producing tumours in
MEN-1 also tend to be larger (37) and more prone to be
resistant to dopamine agonists (37, 38).
C. ADENOMAS CAUSING GROWTH HORMONE
EXCESS
C1. Question for the Pathologist: Is the somatotroph
adenoma sparsely granulated or densely granulated?
Clinical Relevance: Dierential therapeutic responsiveness
to somatostatin analogues and clinical behaviour.
Pure (isolated) GH-producing pituitary adenomas are
histologically classied into densely granulated and sparsely
granulated somatotroph adenomas. Densely granulated
somatotroph adenomas are the most frequent subtype and
they generally respond better to somatostatin analogues
(39-42). Part of the explanation for the dierential response
is that sparsely granulated somatotroph adenomas tend
to be larger and more invasive (42-45) (Figure 4A) while
also showing relatively lower SSTR2 expression (46,47).
Also, albeit discordant reports in the literature (41,47-49),
it appears that a higher proportion of densely granulated
somatotroph adenomas have high intracellular cAMP levels
due to activation of the protein kinase-A pathway making
them excellent targets for cAMP suppression via SSTR,
whereas the mechanisms underlying sparsely granulated
somatotroph adenomas appear to involve the STAT
signaling pathway2,3. Interestingly, aected individuals
with familial isolated somatotroph adenomas (some of
which harbour germline mutations in the aryl hydrocarbon
receptor interacting gene) tend to have invasive adenomas
with less response to somatostatin analogues (50,51).
Not surprisingly, the proportion of sparsely granulated
somatotroph adenoma is overrepresented in this syndrome
(50,51). It also appears that sparsely granulated somatotroph
adenomas are overrepresented in the subgroup of
sporadic somatotroph adenomas associated with low aryl
hydrocarbon receptor interacting protein expression and
poor response to somatostatin analogue therapy (52).
Pathologists distinguish these two neoplasms by assessing
the staining characteristics of low molecular weight keratin
(CAM5.2 or CK18), GH, and alpha-subunit (Figure 4B-D).
Sparsely granulated somatotroph adenomas typically show
focal or weak GH expression, no alpha-subunit expression,
and prominent (>70% of the tumor cells) juxtanuclear
globular reactivity for low molecular weight keratin,
corresponding to intermediate lament aggresomes known
as “brous bodies” (3,5,44). Unlike sparsely granulated
somatotroph adenomas, densely granulated somatotroph
adenomas display diuse and strong positivity for GH and
alpha-subunit, and low molecular weight keratin stains in
a perinuclear pattern (3,5). Scattered brous bodies can be
identied in some cases within the phenotype of densely
granulated somatotroph adenomas; while these neoplasms
are considered to represent an intermediate form of
somatotroph adenoma, their biologic features including
treatment response to somatostatin do not dier from
densely granulated somatotroph adenomas (44).
C2. Questions for the Pathologist: Is the adenoma not
a pure somatotroph adenoma? Is there any evidence of
underlying somatotroph hyperplasia or multifocal disease?
Clinical Relevance: Other pituitary adenomas can also
cause excess GH in addition to other hormones, mainly
prolactin. e coexistence of multicentric disease and/or
associated hyperplasia should alert the physician to the
possibility of GHRH-producing tumors, Carney Complex
or McCune Albright syndrome.
In contrast to somatotroph adenomas, mammosomatotroph
adenomas (53,54), mixed somatotroph and lactotroph
adenomas, and other plurihormonal adenomas (silent
subtype 3 adenomas, acidophil stem cell adenomas,
and GH-producing plurihormonal adenomas) may co-
secrete GH and PRL. Currently, it is unclear whether in
acromegalic patients there is a dierential response to
dopamine agonist therapy between these tumours and
pure somatotroph adenomas. It is important to mention
though that baseline prolactin levels do not seem to predict
response to dopamine agonist therapy (55).

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Mammosomatotroph adenomas most commonly cause GH
excess leading to acromegaly or gigantism while prolactin
is usually only mildly elevated (34,53,56,57). Interestingly,
mammosomatotroph hyperplasia coexisting with
adenomas is frequently found in patients with acromegaly
in the setting of Carney complex (58-60). Precisely because
of the diuse pituitary involvement in which hyperplasia
and small tumours coexist, these patients tend to have
pituitary imaging that does not clearly identify the presence
of an adenoma. e National Institute of Health group has
been successful at treating these imaging-negative Carney
complex acromegalics with somatostatin analogues (60).
e pituitaries of acromegalic patients with McCune Al-
bright Syndrome also show areas of hyperplasia (somato-
troph/mammosomatotroph) together with areas of fully
developed adenoma (somatotroph/mammosomatotroph)
(61,62). erefore, especially in young individuals with
gigantism or acromegaly, a surgical pathology report indi-
Figure 4: Sparsely granulated somatotroph adenoma. A) Magnetic resonance image showing an invasive sparsely granulated
somatotroph adenoma; typically as shown here these tumours are hyperintense in T2-weighed imaging (arrows indicate the adenoma).
B) Careful examination of the hematoxylin-eosin stained slides can highlight the presence of juxtanuclear globular brous bodies
(arrows indicate brous bodies). C) Densely granulated somatotroph adenomas show diuse alpha-subunit and perinuclear CAM5.2
expression. D) Sparsely granulated somatotroph adenomas show prominent brous bodies on CAM5.2.
A
C
B
D

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GOMEZHERNANDEZ K et al: Pituitary Adenomas
Vol. 31, Suppl, 2015; Page 4-17
cating the presence of coexisting hyperplasia and adenoma
should alert the clinician to the possibility of either of these
multiple endocrine neoplasia syndromes.
Outside of Carney complex and McCune Albright
Syndrome, very early childhood onset of pituitary gigantism
(<4 years old) caused by diuse mammosomatotroph
hyperplasia has been described (63,64).
Finally, in some patients a combined pituitary neoplasm
consisting of GHRH-producing gangliocytoma and a
somatotroph adenoma can be identied in the background
of somatotroph hyperplasia (65). However, the more
frequent source of GHRH leading to somatotroph and/
or mammosomatotroph hyperplasia is ectopic GHRH
produced by a neuroendocrine tumor of the lung, pancreas,
adrenal or other sites (66,67).
D. ADENOMAS CAUSING ACTH EXCESS
A detailed surgical pathology report is particularly relevant
in the setting of Cushing disease as it provides very useful
prognostic information. It may also alert the clinician as
to the possibility of an incorrect diagnosis, i.e. pseudo-
Cushing’s syndrome.
D1. Questions for the Pathologist: Was an adenoma
identied? Did the nontumorous corticotrophs show
Crooke’s hyaline change?
Clinical Relevance: Lack of identication of a corticotroph
adenoma in the surgical pathology specimen is associated
with non-remission aer pituitary surgery. Identication of
Crooke’s hyaline change in the nontumorous corticotrophs
conrms pathological hypercortisolemia.
Corticotroph adenomas tend to be microadenomas that
sometimes can be quite small and dicult to localize.
Lack of corticotroph adenoma identication in a surgical
pathology specimen of a patient with Cushing disease is
more frequently observed in patients in whom remission
is not achieved (68, 69). ere are several possibilities as
to why an adenoma is not detected on surgical pathology:
(a) it was missed by the surgeon, (b) it was destroyed
during the procedure, (c) the diagnosis of Cushing disease
was incorrect, (d) Cushing’s syndrome was caused by
corticotroph hyperplasia, but not by an adenoma.
Diuse corticotroph hyperplasia can be due to ectopic
CRH production (70); therefore, a surgical pathology
specimen in which this type of hyperplasia is observed
should prompt the clinician to initiate investigations to
localize the responsible tumour. However, both diuse and
nodular forms of corticotroph hyperplasia may also be a
rare aetiology of pituitary Cushing disease (71, 72).
e distinction between hyperplasia and adenoma is per-
formed by assessing characteristics of the reticulin network
surrounding microacinar units of the adenohypophysis.
While pituitary adenoma shows loss of reticulin network,
hyperplasia presents with an intact but expanded reticulin
framework. Glucocorticoid excess results in Crooke’s hya-
line change of the non-tumorous corticotrophs (Figure 5
A,B), reecting the negative inhibition of excess glucocor-
ticoids on non-tumorous pituitary corticotrophs54,55. While
this can easily be identied on haematoxylin and eosin-
stained slides, PAS along with ACTH and low molecular
weight keratin can be used to highlight this cellular altera-
tion (Figure 5 A,B). Of note, Crooke’s hyaline change is typ-
ically absent in diuse corticotroph hyperplasia (due to lack
of normal corticotrophs), in pseudo-Cushing syndrome, as
well as in the non-tumorous corticotrophs of patients with
silent corticotroph adenomas. If the specimen fails to show
a corticotroph adenoma or diuse corticotroph hyperpla-
sia, the presence or absence of Crooke’s hyaline change can
provide important insights for treating physicians for the
diagnosis of a pseudo-Cushing state (3).
D2. Question for the Pathologist: Which type of adenoma
is it?
Clinical Relevance: Distinct clinical features
Tumours that produce ACTH can be classied as clinically
non-functioning (silent subtype 1 and silent subtype 2
corticotroph adenomas reviewed above) or as clinically
functioning (sparsely granulated corticotroph adenomas,
densely granulated corticotroph adenomas, and Crooke
cell adenomas). Amongst these adenomas causing
Cushing disease, Crooke cell adenomas (Figure 6 A,B) are
considered an aggressive histologic variant (19,20). ese
tumours are usually invasive macroadenomas with a high
recurrence rate that can be as high as 60% aer a mean
follow up of 6.7 years (20). In our experience, sparsely
granulated corticotroph adenomas are also associated with
more aggressive behaviour than their densely granulated
counterpart.
E. ADENOMAS CAUSING TSH EXCESS
Question for the Pathologist: Is the adenoma a thyrotroph
adenoma?
Clinical Relevance: Not all pituitary adenomas causing
TSH excess are thyrotroph adenomas “TSHomas”; however,
most adenomas leading to excess TSH are as a group
aggressive tumours.
Most physicians link central hyperthyroidism to a “TSHoma”.
In fact, silent subtype III adenomas (monomorphous

12
Turkish Journal of Pathology GOMEZHERNANDEZ K et al: Pituitary Adenomas
Vol. 31, Suppl, 2015; Page 4-17
Figure 5: Crooke’s hyaline change of the nontumorus corticotrophs. A) While this cellular alteration can easily be identied on
haematoxylin and eosin-stained slides (arrows). B) PAS along with ACTH and low molecular weight keratin is used to highlight this
nding; the translocation of ACTH containing granules to the cell membrane and juxtanuclear region is accompanied by a ring like
(arrows) low molecular weight keratin expression.
A B
Figure 6: Crooke cell adenoma. A) ese rare tumors are oen invasive pituitary adenomas (arrows) and B) display a predominant
Crooke’s hyaline change.
A B
plurihormonal Pit-1 lineage adenomas), unusual
plurihormonal adenomas, and thyrotroph adenomas can
all result in TSH excess. TSH expressing adenomas are
characteristically invasive brotic macroadenomas that
present with mass eect and central hyperthyroidism (73-
76). Not surprisingly, residual/recurrent disease is frequent;
of additional note, recurrences do not seem to correlated
with the Ki67 labeling index that reects proliferation
(73). Fortunately, for tumours that are not curable with
surgery, somatostatin analogues have proven to be eective
in the management of hyperthyroidism and in some cases
treatment with these agents also results in tumour shrinkage
(76,77).
F. THYROTROPH HYPERPLASIA MIMICKING
A PITUITARY ADENOMA: AN EXAMPLE OF A
PREVENTABLE CLINICAL ERROR
Questions for the Clinician: Does the patient with a
diusely enlarged pituitary have baseline pituitary function
tests that rule out primary hypothyroidism?

13
Turkish Journal of Pathology
GOMEZHERNANDEZ K et al: Pituitary Adenomas
Vol. 31, Suppl, 2015; Page 4-17
Clinical Relevance: yrotroph hyperplasia resolves with
treatment of primary hypothyroidism
Unfortunately, and as previously reported (78-80), we have
seen surgically resected pituitaries containing thyrotroph
hyperplasia with or without lactotroph hyperplasia due to
longstanding primary hypothyroidism. Diuse pituitary
enlargement (with or without mass eect) associated
with mild hyperprolactinemia (due to TRH stimulation
of lactotrophs or stalk eect) may be misdiagnosed as a
prolactinoma (78,79). is underscores the relevance of
complete baseline anterior pituitary function assessment
for all patients with a suspected pituitary macroadenoma.
It is the clinician and not the pathologist who should make
the diagnosis of hypothyroidism. Radiology can be helpful
as well, since hyperplastic pituitaries show symmetrical
enlargement with no localized gadolinium enhancement
that distinguishes non-tumorous from adenomatous
adenohypophysis. With appropriate treatment of the
primary hypothyroidism, thyrotroph and lactotroph
hyperplasia regress, requiring months to up to two years,
but ultimately magnetic resonance imaging of the pituitary
returns to normal (81, 82).
G. PITUITARY CARCINOMA
Questions for the Pathologist and the Clinician: What
denes a pituitary carcinoma? Where does an atypical
adenoma stand in this spectrum? What are the potential
treatments for pituitary carcinoma?
ere are several factors that support the belief that pituitary
carcinomas arise mainly from transformed adenomas,
namely, the initial presentation of pituitary carcinomas
as aggressive adenomas, the generally long time required
for the progression to carcinoma development, and the
progressive accumulation of genetic abnormalities (83).
However, it is important to emphasize that the diagnosis of
pituitary carcinoma is not based on morphologic criteria,
instead it is established by the identication of metastatic
disease (Figure 7), which may be cerebrospinal or systemic
(84).
e categorization of an adenoma as “atypical” does not
predict malignant behaviour. Furthermore, pituitary
adenomas with invasive growth do not necessarily exhibit
a high proliferation rate as determined by the Ki67 labeling
index. erefore, an approach that integrates accurate
subtyping of the pituitary adenoma, biomarkers such as Ki67
and p53, intraoperative and radiologic ndings of invasion,
and response to therapy is warranted. Trouillas et al. (85)
have shown that pituitary adenomas that are classied based
on clinicopathologic features as “invasive and proliferative”
have a probability of tumour persistence that is 25 times
higher than “non-invasive and non-proliferative” tumours.
Furthermore, the probability of recurrence was 12 times
higher in the “invasive and proliferative group”.
Unfortunately, eective therapies for pituitary carcinomas
and recurrent invasive macroadenomas resistant to
conventional modalities are still lacking. However,
temozolomide, an O6 and N7 guanine-alkylating agent
approved for the treatment of glioblastomas and anaplastic
astrocyomas (86), has emerged as a therapeutic option
in those settings. It is unclear which individuals are most
likely to benet from the use of temozolomide but given its
mechanism of action, it would seem logical to assume that
patients with a faulty DNA repair enzymes would be better
candidates for treatment. Nevertheless, studies evaluating
O6-alkylguanine DNA alkyltransferase (MGMT) expression
have yielded inconsistent results. Perhaps, rather than the
qualitative observation of low or high MGMT expression,
a more quantitative approach will provide more reliable
information; in this regard, a recent study has shown
that MGMT staining below 50% is associated with a high
likelihood of treatment response (87).
Figure 7: Pituitary carcinoma. e magnetic resonance image
shows a metastatic focus in the cerebellopontine angle identied
5 years aer pituitary adenoma diagnosis.

14
Turkish Journal of Pathology GOMEZHERNANDEZ K et al: Pituitary Adenomas
Vol. 31, Suppl, 2015; Page 4-17
CONCLUSION
Accurate subtyping of pituitary adenomas allows for
diagnostic conrmation of clinically suspected disease
conditions. Furthermore, it allows for the identication of
patients that may be at higher risk of recurrent disease and
in some circumstances may dictate therapeutic responses.
Pathologists play an essential role in the multidisciplinary
endocrine oncology team by accurately classifying pituitary
tumours as standard practice.
CONFLICT OF INTEREST
e authors have declared no conict of interest.
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