TERT Expression in Pituitary Adenomas
Nuray CAN1, Mehmet ÇELİK2, Buket YILMAZ BÜLBÜL2, Necdet SÜT3, Filiz ÖZYILMAZ1, Semra AYTÜRK2, Sibel GÜLDİKEN2, Nurtaç SARIKAŞ1, Fulya ÖZ PUYAN1, Tülin Deniz YALTA1, Ali Kemal KUTLU1
1Department of Pathology, Trakya University, Faculty of Medicine, EDİRNE, TURKEY
2Department of Internal Medicine, Division of Endocrinology and Metabolism, Trakya University, Faculty of Medicine, EDİRNE, TURKEY
3Department of Biostatistics, Trakya University, Faculty of Medicine, EDİRNE, TURKEY
Keywords: Pituitary adenomas, Telomerase reverse transcriptase, Clinicopathological features
Although pituitary adenomas have benign histomorphological features, some of them may present in an aggressive manner. To
predict the behaviour of these tumours, telomerase reverse transcriptase (TERT) activity in pituitary adenomas has been the subject of a few
studies with contradictory results. This study aims to investigate whether immunohistochemical expression of TERT differs in neoplastic and
nonneoplastic pituitary tissues and aims to investigate whether TERT expression is related to clinicopathological features of pituitary adenomas.
Material and Method: The study included 48 patients who had been diagnosed with pituitary adenomas and had clinical follow-ups.
Nonneoplastic pituitary tissues were obtained from autopsy specimens (n=20). Immunohistochemistry for TERT antibody was performed. Both
the nuclear and cytoplasmic expression of TERT antibody was noted, and total combined TERT staining was evaluated according to nuclear and
Results: TERT expression did not differ between neoplastic and nonneoplastic pituitary tissues. Neither total (combined nuclear and cytoplasmic)
TERT nor nuclear TERT expression revealed any statistically significant relationship with any of the clinicopathological features. Higher
cytoplasmic TERT expression was observed in adenomas with recurrence than adenomas without recurrence (p=0.035).
Conclusion: This study introduces the notion that immunohistochemical expression of TERT does not differ in neoplastic and nonneoplastic
pituitary tissues. Pituitary adenomas with cytoplasmic immunohistochemical expression of TERT have significantly higher rates of recurrence.
Further studies, including combined methods of immunohistochemistry and molecular analyses in larger groups, may reveal applicable results
for the clinical significance of TERT in pituitary adenomas.
Pituitary adenomas are adenohypophyseal tumours with
increasing incidence due to the improving radiological
methods and hormone assays for detection1
prevalence of these tumours is 14.4% in autopsy series and
22.5% in radiological studies, with an overall estimated
prevalence of 16.7%2
. Several clinical outcomes
according to tumour size and hormonal activity may occur
in these tumours that evolve from a small endocrine gland1,3
. These clinical scenarios may include either local
mass effects or systemic effects resulting from endocrine
Pituitary adenomas can be classified according to size as
microadenomas (≤10 mm) or macroadenomas (>10 mm)
and according to radiological appearance as invasive,
noninvasive, or aggressive-invasive4. The World Health
Organization5 currently classifies pituitary adenomas
based on the immunohistochemical demonstration
of produced and expressed hormones with clinical
reflections. However, the most recent classification of pituitary adenomas is based on an immunohistochemical
panel consisting of immune profiling of adenohypophyseal
hormones by monoclonal antibodies, cell-specific
transcription factors, and low-molecular-weight keratin
(CAM5.2), Ki-67, and p536,7.
Although pituitary adenomas have benign histomorphological
features, some of these tumours may present in
an aggressive manner by invasion of surrounding tissues,
recurrences, and resistance to medical therapies4,8.
Thus, the WHO classification defined these tumours
as invasive pituitary adenomas with increased mitotic
activity, a Ki-67 proliferation index of >3%, and extensive
p53 immune staining, namely, ‘atypical adenomas'. To
predict the behaviour of these tumours, many studies have
been performed by investigating various markers related
to chromosomal alterations, microRNAs (miRNAs),
proliferation markers, oncogenes, tumour suppressor
genes, angiogenesis, cell adhesion, growth factors, and their
receptors1,4,9-12. Such studies show that none of these
markers may predict the behaviour of these tumours alone, but combinations of fibroblast growth factor receptor 4
(FGFR4), matrix metalloproteinases (MMPs), particularly
MMP2 and MMP9, Ki-67, p53, pituitary tumour
transforming gene (PTTG), and deletions in chromosome
11p seem to have benefits for predicting the aggressiveness
of pituitary adenomas1.
Moreover, investigations continue into several biomarkers
other than the suggested panel mentioned above13,14.
One of these markers is telomerase reverse transcriptase
(TERT). Telomerase is a ribonucleic protein complex
that includes a catalytic subunit TERT (telomerase
associated protein 2) and an RNA component (TERC),
and it maintains telomere homeostasis and chromosomal
integrity15. Telomeres are located at the end and inner
sides of chromosomes, and shortening of these nucleotide
sequences in cell divisions induces apoptosis or cell
senescence. On the other hand, lengthening of the telomeres
results in prevention of cell replication and thus is assumed
to be a part of tumorigenesis, particularly by expression
or activation of telomerase16. TERT expression is
suppressed in normal adult somatic tissues, but it can be
expressed in embryogenic tissues. Reactivation of TERT
has been detected in approximately 90% of human cancers3,17-20. Thus, TERT activity in pituitary adenomas has
been the subject of a few studies that showed contradictory
The present study aims to investigate mainly two
issues. Initially, the authors aim to investigate whether
immunohistochemical expression of TERT differs in
neoplastic and nonneoplastic pituitary tissues. Then, the
authors will investigate whether TERT expression is related
to clinicopathological features of pituitary adenomas such
as gender, age at the presentation, tumour size, hormonal
activity of the tumour, and recurrence.
The medical reports of patients who were referred to the
Department of Pathology were reviewed between August
2007 and August 2014. The study protocol was approved
by the local Ethics Committee of the University Hospital.
Patients selected for the study had been diagnosed with
pituitary adenomas and had clinical follow-ups. In all,
78 patients who fulfilled the criteria were included in the
study. Patient data regarding age at the time of diagnosis,
sex, and data from clinical follow-ups (recurrence of
disease, re-operation) were obtained from the records of
the Department of Clinical Endocrinology and Metabolism
Diseases. Also, nonneoplastic pituitary tissues were obtained
from autopsy specimens among those who died from causes
other than endocrine diseases (n=20). Haematoxylinand
eosin-stained slides (Figure 1A
), reticulin stained
slides (Figure 1B
), and immunohistochemical stainings of adenohypophyseal hormones (growth hormone [GH],
prolactin [PRL], adrenocorticotrophic hormone [ACTH],
follicle-stimulating hormone [FSH], luteinizing hormone
[LH], and thyroid stimulating hormone [TSH]) obtained
from paraffin-embedded blocks of specimens were reevaluated
by one pathologist (N.C.) who was blinded to the
original pathological diagnosis of the slide and to clinical
and prognostic data. The paraffin-embedded blocks
containing appropriate tissues representing the adenomas
of 48 patients were selected for immunohistochemical
studies for TERT. The patients whose specimens did not
represent tumour tissue were excluded from the study.
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|Figure 1: A) Pituitary adenoma surrounded by nonneoplastic pituitary tissue (H&E; x200). B) Destruction of reticulin meshwork in
pituitary adenoma, note the maintenance of reticulin meshwork in nonneoplastic pituitary tissue (Reticulin; x200).
Tumours were grouped according to the preoperative
radiological size and the secreted hormone(s) that caused
clinical signs. Tumours sized ≤10 mm were classified as
microadenomas, whereas tumours sized >10 mm were
classified as macroadenomas. Tumours were grouped
according to the clinical symptoms and dominant immune
reaction of secreted hormones as in the following (since
adenohypophyseal transcription factors could not be
performed, the classification was performed according to
the status of adenohypophyseal hormones):
- GH producing/expressing adenomas: Somatotroph
- PRL producing/expressing adenomas: Lactotroph
- FSH-LH producing/expressing adenomas: Gonadotroph
- ACTH producing/expressing adenomas: Corticotroph
- TSH producing/expressing adenomas: Thyrotroph
- GH and PRL producing/expressing adenomas: Mixed
somatotroph and lactotroph adenomas
- Nonproducing adenomas: Null cell adenomas
The clinical features considered in the statistical analysis
included age at the time of diagnosis, sex (male or female),
tumour size (≤10 mm, >10 mm) and recurrence (absent/
Immunostaining for the TERT antibody was performed
with a fully automated immunohistochemistry and in
situ hybridization (IHC/ISH) staining machine (Ventana
BenchMark XT, USA). The following primary antibody at the indicated dilutions was used for TERT immune staining
(TERT polyclonal antibody, unconjugated, 1:100; Bioss,
USA, Catalogue No. bs-1411R). A single pathologist (N.C.)
who was blinded to the clinical assessments of each case
evaluated the expression in tissues with a Nikon Eclipse 80i
microscope. Both nuclear and cytoplasmic expression of
TERT antibody was noted (22) and scored. Then, a total
(combined nuclear and cytoplasmic) score was obtained
from the sum of cytoplasmic and nuclear scores. The
scoring schema is presented below.
The scoring of cytoplasmic TERT expression:
- Cytoplasmic score 0: Cytoplasmic staining in <10% of
the tissue (Figure 2A),
- Cytoplasmic score 1: Mild cytoplasmic staining in ≥10%
of the tissue (Figure 2B),
- Cytoplasmic score 2: Moderate cytoplasmic staining in
≥10% of the tissue (Figure 2C),
- Cytoplasmic score 3: Significant cytoplasmic staining in
≥10% of the tissue (Figure 2D).
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|Figure 2: A) Cytoplasmic TERT staining in < 10% of the tissue, score 0 (TERT; x40). B) Mild cytoplasmic staining, score I (TERT; x40).
C) Moderate cytoplasmic staining, score II (TERT; x40), D) Significant cytoplasmic staining, score III (TERT; x40).
The scoring of nuclear TERT expression:
- N uclear score 0: Nuclear staining in <10% of the tissue,
- N uclear score 1: Dot-like nuclear staining in ≥10% of
the tissue (Figure 3A),
- N uclear score 2: Complete nuclear staining in ≥10% of
the tissue (Figure 3B).
Total (combined nuclear and cytoplasmic) TERT
- N egative for TERT expression: The sum of nuclear and
cytoplasmic scores <2,
- Positive for TERT expression: The sum of nuclear and
cytoplasmic scores ≥2 (Figures 3C-3D).
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|Figure 3: A) Dot-like nuclear staining of TERT; score 1 (TERT; x200). B) Complet nuclear staining of TERT; score 2 (TERT; x400).
C) Dot-like nuclear staining (Nuclear score 1) with mild cytoplasmic expression (cytoplasmic score I) (TERT; x200). D) Moderate
cytoplasmic expression (cytoplasmic score II) (TERT; x400).
Statistical analysis was carried out using SPSS v20.0
software (IBM SPSS, Inc., Chicago, IL, USA). Appropriate
chi-square tests (Pearson, Yates, or Fisher) were used to
compare the total TERT expression with clinicopathological
features such as tissue type, gender, tumour size, hormonal
tumour type, and recurrence. The Mann-Whitney U test
and Kruskal-Wallis test were used in the comparisons
of numerical data (nuclear/cytoplasmic TERT score
with tissue type, gender, tumour size, hormonal tumour
type, and recurrence). A p value of <0.05 was considered
|Clinicopathological Features of Patients in the Study
The clinicopathological features of the patients are
summarized in Table I
. The median age of the patients was
52.7 years (ranging from 18 to 79 years). Of the 48 patients,
18 (37.5%) were female and 30 (62.5%) were male. Tumour
type according to the hormonal status was somatotroph
adenoma in 13 (27.1%), lactotroph adenoma in 8 (16.7%),
gonadotroph adenoma in 3 (6.3%), corticotroph adenoma
in 5 (10.4%), thyrotroph adenoma in 1 (2.1%), mixed
somatotroph and lactotroph adenoma in 9 (18.7%), and
null cell adenoma in 9 (18.7%) of the patients.
When the patients were grouped according to tumour size,
8 (16.7%) had microadenomas, while the tumour size was
larger than 10 mm in 40 (83.3%) of the cases. Among all
of the cases, 4 (8.3%) of the tumours recurred after initial
surgery, whereas 44 (91.7%) did not. The mean follow-up
period for the patients was 57.5±31.07 months. All of the
patients were alive.
Comparisons of TERT Expression in Neoplastic and
Nonneoplastic Pituitary Tissues
TERT expression did not significantly differ between
neoplastic and nonneoplastic pituitary tissues. According
to these results, TERT expression was present in 4 (20%) of
20 nonneoplastic autopsy tissues, whereas it was expressed
in 16 (33.3%) of 48 neoplastic tissues. Despite the absence
of statistical significance, mean ranks of cytoplasmic and
nuclear TERT expression was higher in neoplastic tissues
than in nonneoplastic autopsy tissues (p>0.05) (Table II).
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|Table II: Comparisons of TERT expression in neoplastic and nonneoplastic pituitary tissues
Comparisons of Total (Combined Nuclear and
Cytoplasmic) TERT Expression with Clinicopathological
The results of the comparisons of clinicopathological
features with total (combined nuclear and cytoplasmic)
TERT expression are presented in Table III. TERT
expression did not reveal any statistically significant
relationship with any of the clinicopathological features.
TERT positivity was present in 30.8% (4/13) of somatotroph
adenomas, in 25.0% (2/8) of lactotroph adenomas, in
33.3% (1/3) of gonadotroph adenomas, in 40% (2/5) of
corticotroph adenomas, in none (0/1) of the thyrotroph
adenomas, in 33.3% (3/9) of mixed somatotroph and
lactotroph adenomas, and finally, in 44.4% (4/9) of null
cell adenomas. TERT staining was defined in 50.0% (4/8)
of microadenomas, while it was defined as 30.0% (12/40) of macroadenomas. Total TERT expression was observed
in 75.0% (3/4) of the patients with recurrence, whereas
staining was present in 29.5% (13/44) of the patients
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|Table III: Comparisons of total (combined nuclear and cytoplasmic) TERT expression with clinicopathological features
Comparisons of Nuclear TERT Expression with
The results of the comparisons of clinicopathological
features with nuclear TERT expression are presented
in Table IV. Nuclear TERT expression did not reveal
any statistically significant relationship with any of the
clinicopathological features. However, mean ranks of
nuclear TERT expression were higher in males than in
females, in mixed somatotroph and lactotroph adenomas,
in lactotroph adenomas, and in adenomas sized >10 mm
Click Here to Zoom
|Table IV: Comparisons of nuclear TERT expression and cytoplasmic TERT expression with clinicopathological features
Comparisons of Cytoplasmic TERT Expression with
The results of the comparisons of clinicopathological
features with cytoplasmic TERT expression are presented
in Table IV. Cytoplasmic TERT expression had a
significant relationship with recurrence (p=0.035); namely, higher cytoplasmic TERT expression was observed in some
adenomas with recurrence but not in adenomas without
recurrence. Cytoplasmic TERT expression was observed in
3 of 4 patients who had recurred. Nuclear TERT expression
was not observed in any of the patients with recurrence. Two
of these 3 patients were male and 1 was female. Tumours
were sized >10 mm in 2 of the patients and sized ≤10 mm
in 1 patient. Among these 3 patients, hormonal type was
corticotroph adenoma in 1 of the patients, gonadotroph
adenoma in 1, and null cell adenoma in 1. The follow-up
period ranged between 37 months and 256 months.
There was no significant relationship between cytoplasmic
TERT expression and clinicopathological features other
than recurrence. Although there was no significant
relationship, mean ranks of cytoplasmic TERT expression
were higher in males than in females, in corticotroph
and lactotroph adenomas than in other types, and in
microadenomas than in macroadenomas (p>0.05).
Pituitary adenomas have benign histomorphological
features, but some of these tumours may present in an aggressive manner by local invasion through surrounding
tissues, recurrences, and resistance to medical therapies4,8
. Many studies have aimed to discover a significant
predictor of an aggressive clinical course in pituitary
. Telomerase reverse transcriptase
(TERT), a catalytic subunit of telomerase that includes
an RNA component (TERC), therewithal maintains the
telomere homeostasis and chromosomal integrity15
Reactivation of TERT has been detected in approximately
90% of human cancers3,17-20
. This study attempted
to investigate whether immunohistochemical expression
of TERT differs in neoplastic and nonneoplastic pituitary
tissues and aimed to investigate whether TERT expression
is related to clinicopathological features of pituitary
adenomas. In this context, the results of the present study can
be summarised as follows: i) Total immunohistochemical
expression of TERT does not differ in neoplastic and
nonneoplastic pituitary tissues with significance, ii) Total
immunohistochemical expression of TERT does not have
any relationship to clinicopathological parameters, and
iii) Cytoplasmic immune staining with TERT antibody is
significantly more common in pituitary adenomas with
Telomerase activity in neoplastic and in nonneoplastic
pituitary tissues has been the subject of a few previous
studies using various methods of polymerase chain reaction
(PCR)14,21. The mentioned previous studies have
reported that there is no difference in telomerase activity
and telomere length between neoplastic and nonneoplastic pituitary tissues. It has been suggested that this may be
elucidated by the low mitotic activity of pituitary adenomas14. In agreement with previous studies, the present study
showed no significant difference in total TERT expression
in neoplastic and nonneoplastic pituitary tissues. Although
TERT expression was evaluated by immunohistochemistry
targeting only TERT and not TERC in the present
study and the comparisons showed a lack of statistical
significance (p>0.05), TERT expression rates were higher
in neoplastic tissues than in nonneoplastic tissues. The
most accurate state of telomerase activity and telomere
length in pituitary tumours/nonneoplastic pituitary tissues
should be investigated in larger study groups by combined
synchronous detection methods.
The effects of telomerase activity and telomere lengths on
clinicopathological features in pituitary adenomas have
been evaluated in several studies3,14,16,21,23-25. Some
of these papers have concluded that telomerase activity
and telomere length do not have any impact on the clinical
course of pituitary adenomas based on investigations of
telomerase activity and telomere length by various types
of polymerase chain reactions14,16,21,25. On the other
hand, some of the previous studies have suggested that
TERT expression is associated with an aggressive clinical
course, particularly recurrences and invasiveness3,23,24.
Harada et al.24 have reported telomerase activity by
using Southern blotting and reverse transcriptase-chain
reaction in a pituitary carcinoma evolving in a background
of an initially telomerase-negative PRL-producing benign adenoma. Yoshino et al.23 have reported telomerase
activity via PCR-based telomeric repeat amplification
protocol (TRAP) assay and PCR enzyme-linked
immunosorbent assay (ELISA) in 13% of adenomas with
invasive features. Ortiz-Plata et al.3 have examined
telomerase activity by TERT immunohistochemistry and
have reported that telomerase activity could be a marker for
cellular proliferation, angiogenesis and hormonal activity
in pituitary adenomas. However, the authors did not
inform either cellular localisation or the degree of TERT
expression in their study. In the present study, we could not
determine any significant relationship between total TERT
expression and clinicopathological features, including
presentation age, gender, tumour size, recurrence, and
hormonal type. But, we could observe that cytoplasmic
staining with TERT polyclonal antibody is significantly
related to tumour recurrence, as in the case reported by
Harada et al.24. Also, total TERT expression was present
in 75% of pituitary adenomas with recurrence without any
significance. Although the present study has limitations,
including the immunohistochemical evaluation of only
the TERT catalytic subunit of telomerase protein complex
but not TERC or any detections of mutational status, the
authors present the significant increase of recurrence in
pituitary adenomas with cytoplasmic TERT expression.
According to the current proposals, a panel of some
biomarkers, including PTTG1 and MMPs (MMP1), may
predict the aggressive behaviour of pituitary adenomas1. It is said that higher levels of electron transport system
(ETS) transcription factors induce MMP1 expression and
cause tumour invasion in pituitary adenomas1. One of
the most recent reports investigating the TERT expression
in malignant melanoma has concluded that mutations
in TERT promoter create additional binding sites for
ETS transcription factors, particularly ETS1, and finally
activates the mitogen-activated protein kinase (MAPK)
pathway and cell proliferation19. PTTG1 is a member
of the securin family and is highly expressed in hormonesecreting
invasive pituitary adenomas1. Another recent
study observing the relationship between PTTG1 and
TERT expressions in human mesenchymal stem cells has
reported that overexpression of TERT induces PTTG1
expression, and this interaction between TERT and PTTG1
is mediated by Ku70, which is a heterodimeric protein
involved in maintenance of telomeres, in an increase in the
cell cycle, autophagy, and self-renewal26.
Consideration of distinct results of the previous studies and
the present study about telomerase activity and telomere
length in pituitary adenomas and the recent observations revealing interactions of TERT with PTTG1 and ETS1 may
require further studies. Such studies should investigate
these interactions in pituitary adenomas and may
contribute detailed data in the issue of TERT expression as
a prognostic predictor in pituitary adenomas.
In conclusion, the present study posits that immunohistochemical
expression of TERT does not significantly differ in
neoplastic and nonneoplastic pituitary tissues. In addition,
pituitary adenomas with cytoplasmic immunohistochemical
expression of TERT have significantly higher rates of
recurrence. Further studies, including combined methods
of immunohistochemistry and molecular analyses in
larger groups, may reveal applicable results for the clinical
significance of telomerase activity and telomere length in
CONFLICT of INTEREST
The authors declare no conflict of interest.
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