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New WHO classification of pituitary adenomas (4th edition): assessment of

pituitary transcription factors and the prognostic histological factors

Article  in  Brain Tumor Pathology · January 2018

DOI: 10.1007/s10014-017-0307-7

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New WHO classification of pituitary
adenomas (4th edition): assessment of
pituitary transcription factors and the
prognostic histological factors

Hiroshi Nishioka & Naoko Inoshita

Brain Tumor Pathology

ISSN 1433-7398
Volume 35
Number 2

Brain Tumor Pathol (2018) 35:57-61

DOI 10.1007/s10014-017-0307-7

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Brain Tumor Pathology (2018) 35:57–61
https://doi.org/10.1007/s10014-017-0307-7

REVIEW ARTICLE

New WHO classification of pituitary adenomas (4th edition):

assessment of pituitary transcription factors and the prognostic
histological factors
Hiroshi Nishioka1,3 · Naoko Inoshita2,3

Received: 20 December 2017 / Accepted: 26 December 2017 / Published online: 9 January 2018
© The Japan Society of Brain Tumor Pathology 2018

Abstract
WHO classification of pituitary adenomas was revised in 2017. The two major and significant changes are discussed. (1) The
new classification focuses on adenohypophysial-cell lineage for the designation of adenomas, and thus, assessment of pitui-
tary transcription factors is recommended. Its appropriate use has a complementary role in obtaining an accurate diagnosis,
particularly in hormone-negative adenomas. Subclassification of nonfunctioning adenomas was revised accordingly and,
consequently, null cell adenomas became quite rare. (2) “Atypical adenoma”, a previous category, was eliminated due to the
poor reproducibility and predictive value. Assessment of tumor proliferation marker and other clinical parameters such as
invasion are recommended to predict aggressiveness. “High-risk adenomas” are those with rapid growth, radiological inva-
sion, and a high Ki-67 proliferation index, whereas some special adenoma subtypes commonly show aggressive behavior.

Keywords  Aggressive adenomas · Nonfunctioning adenomas · Pituitary adenomas · Transcription factor · WHO
classification

Introduction “aggressive” adenomas are discussed, whereas a previous

“WHO classification of tumours of endocrine organs” was
revised in 2017 (4th edition). 13 years have passed since the
last 3rd edition in 2004. There are several changes in the new
classification of pituitary adenomas according to the recent
new knowledge including tumor development and prognosis
[1–3]. In this article, the two major and significant changes
are focused. (1) For the new classification, a novel approach
according to adenohypophysial-cell lineages was introduced.
Assessment of pituitary transcription factors is required in
some adenomas for the accurate subclassification, particu-
larly for nonfunctioning adenomas. (2) Clinical and patho-
logical prognostic parameters for predicting “high-risk” and
* Hiroshi Nishioka
nishioka@tokyo‑med.ac.jp
1
Department of Hypothalamic and Pituitary Surgery,
Toranomon Hospital, 2‑2‑2 Toranomon, Minatoku,
Tokyo 105‑8470, Japan
2
Department of Pathology, Toranomon Hospital, Tokyo, Japan
3
Okinaka Memorial Institute for Medical Research, Tokyo,
Japan
category “atypical” adenoma was eliminated. The benefits
and misleading of the new classification are also discussed.
Pituitary transcription factors
The recent advances in molecular biology have clarified
the cytodifferentiation pathways involved in the develop-
ment of adenohypophysial cells. During development,
an organized, complex process of cell differentiation is
orchestrated by specific transcription factors. The pituitary
transcription factors also have a role in determining the
cytodifferentiation and hormone production of pituitary
adenomas and, thus, can serve as diagnostic markers [4–6].
The new WHO classification proposed the application of
transcription factors immunohistochemistry to determine
adenohypophysial cell lineages for the accurate subclas-
sification of pituitary adenomas [1–3]. There are three
main pathways of adenohypophysial cell differentiation
and the determined transcription factors (Fig. 1): (1) cor-
ticotrophs determined by the t-box pituitary transcription
factor (Tpit), (2) somatotrophs/lactotrophs/mammosoma-
totrophs/thyrotrophs determined by pituitary transcription

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Fig. 1  Adenohypophysial cell
lineage and the transcription
factors
factor 1 (Pit-1), and (3) gonadotrophs determined by ster-
oidogenic Factor-1 (SF-1) and/or GATA-2 in the presence
of estrogen Receptor-α (ERα). At present, however, there
are still no reliable commercial antibodies for Tpit.
Approximately, 30–40% of all surgically treated pitui-
tary adenomas are clinically nonfunctioning adenomas
since they lack clinical and biochemical evidence of
adenohypophyseal hormone excess. Morphologically
they are heterogeneous and have been traditionally clas-
sified into several histological subtypes by various meth-
ods including immunohistochemistry using antibodies
against adenohypophysial hormones, electron microscopy,
in situ hybridization, or reverse hemolytic plaque assay. It
became evident that there are some differences in clinical
behavior and prognosis for each subtype. However, there
are limitations in achieving accurate classification using
hormone immunohistochemistry alone. An appropriate
use of immunohistochemistry for pituitary transcription
factors has a complementary role in obtaining an accu-
rate diagnosis for hormone-negative adenomas and, thus,
can prevent them from being mistakenly classified as null
cell adenomas [5, 6]. Subclassification of nonfunctioning
adenomas was revised accordingly. In clinical practice, an
accurate histological diagnosis should be obtained particu-
larly in nonfunctioning adenoma in young patients, with
frequent recurrence, and with aggressive clinical features
[6, 7].
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Brain Tumor Pathology (2018) 35:57–61
Gonadotroph adenomas
Gonadotroph adenomas are the most common subtype of
nonfunctioning adenomas (approximately three quarters in
our series [6]). Although many of them are either negative
or faintly positive for very few scattered cells or groups of
cells for gonadotropins, they can be reliably detected by
nuclear immunoreactivity for SF-1 (Fig. 2). Most of them
are benign, slowly growing tumor presenting in middle-
aged and elderly patients. The well-known common clini-
cal characteristics of nonfunctioning adenomas are those of
this subtype.
Silent corticotroph adenomas
Traditionally, silent corticotroph adenomas had been dis-
tinguished from other nonfunctioning adenomas by their
ACTH immunoreactivity. However, regardless of the func-
tional status of the tumor, corticotroph adenomas, like
nontumorous corticotrophs, express Tpit [4, 5]. In our pre-
vious study, one quarter of hormone-negative adenomas
were Tpit-positive with increased pro-opiomelanocortin
(POMC) mRNA expression [6]. Thus, ACTH-immuno-
histochemistry alone is insufficient to detect this subtype,
whereas assessment of Tpit expression is required for
the accurate diagnosis in some case (Fig. 3). This sub-
type tends to show significant female preponderance and
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Brain Tumor Pathology (2018) 35:57–61 59

Fig. 2  Nonfunctioning pituitary
adenoma in a 60 years old man.
The chromophobe adenoma was
immunonegative for adenohy-
pophysial hormones and pit-1,
but was SF-1-positive. The
diagnosis was a gonadotroph
adenoma

Fig. 3  Large and invading non-

functioning pituitary adenoma
in a 35 years old woman. The
chromophobe adenoma was
immunonegative for adenohy-
pophysial hormones, SF-1, and
pit-1, but was immunopositive
for Tpit. In RT-PCR, POMC
mRNA level was elevated (data
not shown). The diagnosis was a
silent corticotroph adenoma

are more frequently large macroadenomas with marked Silent adenomas of pit‑1 derivation
cavernous sinus invasion [6–8]. Surgical total resection is
often difficult and some of them are considered to behave This subtype consists of less than 10% of nonfunctioning
aggressively. adenomas and is in the family of somatomammothyrotrophs.

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60
They are more complex than other subtypes and are morpho-
logical heterogeneous including plurihormonal pit-1-posi-
tive adenomas (previously called subtype 3 adenomas [9]),
silent thyrotroph adenomas, silent somatotroph adenomas,
et al. This subtype typically shows preponderance in younger
patients. Of clinical importance, most of them are invasive,
large macroadenomas with a high Ki-67 proliferation index,
and thus, tend to exhibit low resection rate and high recur-
rence rate after surgery [7, 9].
Null cell adenomas
The definition of null cell adenomas was revised extensively
in the new classification. This subtype is currently defined
as adenomas composed of adenohypophysial cells that do
not show any evidence of cell-type specific differentiation
using pituitary hormones, transcription factors, and ultras-
tructural features [10]. Hormone-immunonegative adenomas
account for 20–30% of nonfunctioning adenomas, whereas
null cell adenomas are quite rare, constituting less than 5%
of them (1.2% of nonfunctioning adenomas in our series
[6]). Although the clinical data on this subtype, as it is cur-
rently defined, are limited, they may represent an aggressive
adenoma [6, 11].
Malignancy, aggressiveness, and prognostic
parameters
Pituitary carcinoma (8272/3)
Definition of pituitary carcinoma has not been changed in
the new WHO book. It is strictly defined as a tumor of ade-
nohypophyseal cells that metastasizes craniospinally or is
associated with systemic metastasis. It must be emphasized
that the definition is independent of the histological appear-
ance. No histological features can distinguish carcinoma
from ordinary adenoma prior to metastasis.
Elimination of the term “atypical adenoma”
In the previous 3rd edition, pituitary adenoma was classi-
fied into typical adenoma (8272/0) and atypical adenoma
(8272/1). The latter was defined as adenomas with an ele-
vated mitotic index and a Ki-67 proliferation index greater
than 3%, as well as extensive nuclear immunostaining for
p53. These adenomas with atypical morphologic features
were considered to behave aggressively. However, the inci-
dence of this category was relatively variable and prognos-
tic significance could not be established despite more than
10 years of research on the utility of this classification [1,
2]. Therefore, the term “atypical adenoma” was no longer
recommended in the new classification.
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Brain Tumor Pathology (2018) 35:57–61
Prognostic clinical and pathological parameters
and the definition of “aggressiveness”
Despite elimination of the term “atypical adenoma”,
assessment of markers of tumor proliferation (i.e. mitotic
count and Ki-67 proliferation index) is recommended as an
important histological marker to predict recurrence, par-
ticularly following incomplete adenoma resection [1, 2].
However, no specific cutoff value is recommended. Clini-
cal parameters such as invasion assessed by MRI and/or
intraoperative examination should be considered an impor-
tant prognostic feature in identifying clinically aggressive
adenomas [1, 2, 12].
The definition of “aggressive” adenoma remains
ambiguous, but it is generally assumed to represent some
adenomas with rapid growth, significant invasion, large
and irregular configuration, and resistance to conventional
treatment, et al. In the 2017 WHO book, rapid growth,
radiological invasion, and a high Ki-67 proliferation
index are considered to represent clinical aggressiveness
and adenomas with these features are termed “high-risk”
pituitary adenomas [3].
On the other hand, it has been pointed out that ade-
noma subtypes are the most important determinant of
adenoma behavior [4, 5, 13]. Gonadotroph adenomas tend
to manifest particularly indolent behavior, especially in
older patients. In contrast, the 2017 WHO book indicates
that there are some special adenoma subtypes that com-
monly show aggressive behavior. These include sparsely
granulated somatotroph adenoma, lactotroph adenoma in
men, Crooke cell adenoma, silent corticotroph adenoma,
and plurihormonal pit-1-positive adenoma [1–3]. As has
been mentioned in the former chapter, an accurate diag-
nosis of the latter two subtypes requires assessment of
the appropriate transcription factors, i.e., Tpit and pit-1,
respectively.
A new proposal: from pituitary adenoma
to “pituitary neuroendocrine tumor (PitNET)”
Although most pituitary tumors behave benignly (i.e., do not
metastasize) and are, therefore, called adenomas, they fre-
quently invade into the adjacent structures, leading to recur-
rence. One of the misleading in the current classification is
a simplistic distinction between adenoma and carcinoma. In
2017, the International Pituitary Pathology Club proposed a
new terminology, pituitary neuroendocrine tumor (PitNET),
which is consistent with that used for other neuroendocrine
neoplasms and which recognizes the highly variable impact
of these tumors on patients [14]. PitNETs are not simply
endocrine diseases, but should be considered as tumors with
endocrine manifestations within the context of oncology.
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Brain Tumor Pathology (2018) 35:57–61 61
Conclusions
The new WHO classification is very practical and mostly
based on immunohistochemistry for pituitary hormones,
pituitary transcription factors, and other markers commonly
used in pathology practice [1]. In our previous study [6], the
new classification demonstrated a good correlation between
the subtypes of nonfunctioning adenomas and clinical fea-
tures. In the present article, the two major changes and a pro-
posal of a new terminology, PitNET, were introduced. The
new classification will hopefully benefit many pathologists,
clinician, and patients harboring pituitary tumors.
10. Nishioka H, Kontogeorgos G, Lloyd RV, Lopes BS, Mete O, Nose
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