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Pituitary
https://doi.org/10.1007/s11102-018-0921-3
Thyrotropin-secreting pituitary adenomas: asystematic review
andmeta-analysis ofpostoperative outcomes andmanagement
GiuliaCossu1 · RoyThomasDaniel1· KatarzynaPierzchala2· MoncefBerhouma3· NellyPitteloud4· FaizaLamine4·
AnnamariaColao5· MahmoudMesserer1
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Purpose TSH-secreting pituitary adenomas are rare pituitary tumors. An efficient treatment is essential to limit the mortality
and morbidity in untreated patients. The aim of this study is to summarize the evidence about the postoperative outcomes
and management of this rare pathology.
Methods A systematic search and meta-analysis of surgical series was performed.
Results Our analysis included 23 articles (536 patients). No sex difference was observed and mean age at diagnosis was
45years. Hyperthyroidism was reportedly clinical in 67% and biochemical in 90% of patients. Co-secretion of other pituitary
hormones was present in 42% of cases. Macroadenomas were found in 79% of patients, showing in 44% and 30% of cases
respectively extrasellar extension and cavernous sinus invasion. The pooled rate of postoperative biochemical remission was
69.7% and a gross total resection (GTR) was observed in 54% of patients. The extent of resection was significantly increased
in microadenomas (p < 0.001) and cavernous sinus invasion was predictive of lower GTR rate (p < 0.001). A biochemical
remission was achieved in 66% of patients after adjuvant radiation therapy and in 76% after adjuvant medical treatment.
The combination of both allowed remission in 67% of cases. At final follow-up the overall biochemical remission rate was
significantly improved (85.8%) when compared to the postoperative biochemical remission (p < 0.001).
Conclusion When compared to the early postoperative period, at last follow-up biochemical remission was significantly
greater (p < 0.001). GTR was achieved in half of patients; the size of tumor and cavernous sinus invasion determined the
extent of resection.
Keywords Endoscopy· Pituitary adenoma· SITSH· Thyrotropin secreting adenoma· Transsphenoidal· TSH-secreting
adenoma
Introduction
TSH-secreting pituitary adenomas (TSH-omas) are rare
entities and represent 0.5–3% of pituitary adenomas in
surgical series [1, 2]. Their pathogenesis is still unknown:
TSH-omas are monoclonal and the fact that TSH-produc-
ing cells account for < 5% of pituitary cells might explain
the rarity of these tumors [2, 3]. To date, no specific muta-
tions in oncogenes or anti-oncogenes have been charac-
terized [4, 5]. Functioning adenomas present a combina-
tion of transcription factors similar to those observed in
physiological conditions [6] and Pit-1 and GATA-2 might
play a key role in the development of TSH-omas. Some
papers advance a possible role of mutations of the thy-
roid hormone receptor, responsible for refractoriness to
the inhibitor effect of thyroid hormone. This might favor
* Giulia Cossu
giulia.cossu@chuv.ch
1 Department ofNeurosurgery, University Hospital
ofLausanne, Lausanne, Switzerland
2 Center forBiomedical Imaging, EPFL, Lausanne,
Switzerland
3 Skull Base Surgery Unit, Department ofNeurosurgery B,
Pierre Wertheimer Neurological andNeurosurgical Hospital,
Hospices Civils de Lyon, Lyon, France
4 Department ofEndocrinology, University Hospital
ofLausanne, Lausanne, Switzerland
5 Department ofEndocrinology, University Hospital ofNaples,
Naples, Italy
Pituitary
1 3
TSH-omas development [7–9]. The correct diagnosis and
an early treatment are imperative because of the higher
risk of mortality and morbidity in patients with untreated
hyperthyroidism [10]. The surgical treatment is consid-
ered the mainstay of treatment and the transsphenoidal
approach is considered the gold standard [11].
TSH-omas are generally diagnosed as macroadenoma
and usually present an extrasellar extension. Accord-
ing to literature data, a gross total resection (GTR) may
be achieved in a variable percentage of cases (14–84%)
[12–15] and the factors limiting the extent of resection
are the important intralesional fibrosis and the suprasellar
extension or cavernous sinus invasion of the tumor at diag-
nosis [16–18]. The biochemical remission is also highly
different among studies and may vary from 30 to 96% [19,
20].
The 2013 European Guidelines [21] on the subject clearly
state that the criteria of cure for patients with TSHomas
operated and/or irradiated have not been clearly established.
The clinical remission of hyperthyroidism, resolution of
neurological symptoms and of radiological abnormalities
and biological normalization of thyroid hormones and TSH
are the factors commonly considered. However none seems
to be useful in predicting cure and long-term remission.
Adjuvant treatments such as radiotherapy and medi-
cal therapy, most frequently somatostatin receptor ligands
(SRL) and dopamine agonists (DA), may be considered in
cases of persistent disease after surgery [11, 12, 15, 16].
Some authors recently suggest that SRL may play a role in
the treatment of these adenomas as primary therapy [15,
22–27].
In this context we aimed to review all the surgical series
treating TSH-secreting adenomas to summarize the litera-
ture evidence and obtain objective data on epidemiology,
postoperative outcomes in terms of GTR and biochemical
remission and establish the role of adjuvant treatments to
update the knowledge on this field.
Materials andmethods
Search strategy
A literature search was performed using PubMed platform
and including articles published from January 1990 till
March 2018. The search was performed using the MeSH
terms: “Thyrotropin” AND “Pituitary Neoplasms”.
The “related articles” function was used to find addi-
tional pertinent studies and a screening of the bibliography
of included studies was performed manually to identify any
relevant report. No unpublished data or congress presenta-
tions were included.
Study selection
Two authors (GC and MM) reviewed independently all
the titles and abstracts to assess eligibility. Included study
fulfilled the following requirements:
1. include patients with TSH-secreting pituitary adenomas;
2. patients should be treated through a surgical procedure
alone or combined with any other neoadjuvant or adju-
vant treatment
3. the postoperative outcome should be reported, in terms
of clinical and biochemical remission and radiological
extent of resection.
Reviews, case reports and small case series report-
ing ≤ than 5 patients were not included. Also larger series
with no surgical treatment or where the postoperative out-
comes were not specified were excluded.
Only studies in English, French, Italian, German and
Spanish were considered.
Data abstraction
Two authors (GC and MM) independently abstracted
epidemiological and clinical data as well as radiological
features. Adenomas were classified as microadenomas
when the size was < 10mm and macroadenoma when the
diameter was ≥ 10mm. The cavernous sinus invasion was
defined as present or absent and the Knosp classification
was reported when specified.
Authors also analyzed the treatments performed in
terms of surgical procedures, neoadjuvant and adjuvant
treatments as well as the clinical and biological outcomes
in the early postoperative period and at follow-up. The
criteria used to define remission were also reported for
each article included.
Statistical analysis
We used meta-analytic techniques to calculate a pooled
estimate of the postoperative outcomes in terms of bio-
chemical remission and extent of resection (weighted sum-
mary rates were obtained through meta-analysis models)
and we stratified the results according to the tumor size
(macro versus microadenoma) and to the cavernous sinus
invasion.
The pooled postoperative biochemical remission was
defined as the normalization or detection of low levels
of thyroid hormones and TSH and it was recorded in the
immediate postoperative period, after adjuvant treatments
Pituitary
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and at last follow-up. The extent of resection was defined
as GTR or subtotal resection on the basis of the postopera-
tive imaging.
Tests for heterogeneity were performed for each meta-
analysis and if the heterogeneity was significant, a binary
random effects model (DerSimonian-Laird method) was
used. The random effects model incorporates the variance
of treatment effect and gives the magnitude of heterogeneity
of treatment effect.
The OpenMetaAnalyst platform from AHRQ was used to
perform these analyses.
If a 100% or a 0% success rate were reported, the vari-
ance was estimated as the pooled variances obtained from
the other studies. Fisher exact test was performed to check
the independence of categorical variables recorded in the
population of study. Values of p < 0.05 were considered sta-
tistically significant.
Results
The literature search identified a total of 651 articles. After
exclusion of 628 articles, 23 full-text articles were included
for further analysis [2, 11–17, 19, 20, 28–40] for a total of
536 patients (Fig.1 flow chart).
Seventeen studies were monocentric [12–14, 17, 19, 20,
28–30, 32–35, 37–40] and 6 multicentric [2, 11, 14–16, 31,
36]. All the included studies were retrospective analysis
except one, which was prospective [40].
The remission criteria varied among studies and in one
study they were not directly defined in the text [19]. They
are reported in details in Table1.
Cohort description
A total of 536 patients were described in surgical series
of TSH-secreting adenomas. There were no differences in
sex ratio (260 males, 48%) and the mean age at diagnosis
was 45years. 67% of patients presented a clinical hyper-
thyroidism (241/358), while 90% presented a biochemical
hyperthyroidism (410/455).
Patients without clinical symptoms of hyperthyroidism
(23%) were diagnosed during headaches investigations or
secondarily to the presence of visual symptoms. In most of
cases a blood test confirmed the TSH-dependent hyperthy-
roidism and only in a minority of cases (10%) there was no
biochemical hypersecretion. In these cases the diagnosis of
TSH-secreting adenoma was possible thank to the immu-
nohistochemical analysis, which was positive for TSH.
A biological cosecretion was described in 42% of
patients (147/350), most frequently GH and PRL (in 53%
and 40% of cases respectively) (Fig.2).
Macrodenomas were reported in 79.6% of patients
(395/499). The percentage of microadenomas diagnosed
in surgical series significantly increased in papers pub-
lished after 2000 (22% versus 11% before 2000, Fisher
exact test p = 0.04).
The presence of an “extrasellar extension” was specified
in 15 studies [11, 14–17, 19, 28, 31–36, 38, 40] and it was
present in 44.5% of cases (146/328).
The invasion of the cavernous sinus is a well-recog-
nized factor predictive of biological aggressiveness [41].
It was specified only in 12 studies [12–17, 19, 28, 30–32,
37] and it was present in 30% of cases (95/315). Only one
study [12] used the Knosp classification [42].
Immunohistochemical analysis other than TSH was
specified in 14 articles [13, 14, 16, 17, 28–32, 35–39]
and the staining for other pituitary hormones was vari-
able between 20 and 100%. Most frequently tumor tissue
stained for GH and PRL.
Post‑operative outcomes
The postoperative follow-up was available in 92.5% of
patients (496/536).
Biochemical remission
The biochemical remission in the postoperative period
was specified in 21 studies [2, 11–17, 19, 20, 29–34,
36–40] and it was achieved in 69.7% of cases (95% CI
61.1–78.4%). A binary random-effects estimate analysis
was used because of evidence of heterogeneity (I2 = 83%;
p < 0.001), (Fig.3).
651 articles identiied with
the search:
"Thyrotropin AND
Pituitary
Neoplasms"[Mesh]
in March 2018
Excluded 443 articles:
-reviews / editorials : 91
-case reports / series: 167
-preclinical / pediatric studies: 144
-languages other than English: 41
208 articles screened
for title and abstract
Excluded 185 articles:
PICO not pertinent in 184
1 duplicated study
23 full-text articles
assessed for
eligibility and
included
Fig. 1 Flow chart illustrating the procedure of article selection
Pituitary
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Table 1 The characteristics of each study and the remission criteria used are specified for every study included in our analysis
Article No. of pts Type of study Remission criteria
Monocentric Multicentric Retrospective Prospective TH and TSH
normalization
TH and TSH normali-
zation at stimulation
tests
Normalization
of cosecretion
No residue
at postop
MRI
Long-
term FU
(> 12mo)*
Rotermund 2017 [20] 15 x x x x
Astaf’eva 2016 [28] 21 x x x x
Azzalin 2016 [13] 20 X x x x
Gatto 2015 [31] 13 x x x x x
Kirkman 2014 [32] 32 x x x x x
Malchiodi 2014 [11] 70 x x x x x x x
Van Varsseveld 2014 [15] 18 x x x x x
Yamada 2014 [12] 90 X x x x x x
Onnestam 2013 [2] 28 X x x x x
Zhao 2012 [40] 8 X x x x x
Elston 2010 [19] 6 x x x x x x
Macchia 2009 [34] 26 X X x x x
Marucci 2009 [14] 10 X x x x x
Clarke 2008 [30] 21 X x x x x
Ness-Abramof 2007 [36] 11 X x x x x
Socin 2003 [16] 43 x x x x x
Wu 2003 [38] 7 X X x X x
Sanno 2000 [37] 16 x x x x x x
Brucker-Davis 1999 [17] 25 X x x x x x
Losa 1999 [33] 24 X X x X
Mindermann and Wilson 1993 [35] 19 X X x x
Wynne 1992 [39] 6 X X x x x
Beckers 1990 [29] 7 x x x
Pituitary
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Extent ofresection
The extent of resection was specified in 19 studies [11–17,
19, 28, 30–34, 36–40] and GTR was obtained in 54.1% of
cases (95% CI 41.2–66.9%; test for heterogeneity I2 = 89.2%,
p < 0.001) (Fig.4).
When the adenomas were stratified according to the
size, GTR was obtained in 49% of cases of macroadeno-
mas (95% CI 32–66%; test for heterogeneity I2 = 90.6%,
p < 0.001) and in 87% of microadenomas (95% CI
76.6–96.7%; test for heterogeneity I2 = 47.6%, p = 0.05)
(Fig.5).
A statistically significant difference was found between
the two groups (p < 0.001).
GTR in cases of cavernous sinus invasion was speci-
fied only in 6 studies [12, 14, 17, 19, 28, 30] and it was
obtained only in 15.6% of cases (10/49) presenting a cav-
ernous sinus involvement at diagnosis (95% CI 2.2–29.3%;
test for heterogeneity I2 = 50.1%, p = 0.075). The invasion
of the cavernous sinus predicted an inferior rate of GTR
(p < 0.001) (Fig.5).
Only three studies [11, 17, 37] used a stimulation or
suppression test in the early postoperative period (within
3 months from surgery) to verify the biological remission
and only 39% of patients with a postoperative biological
remission (26/66) presented a normal response to TRH
stimulation or T3 suppression tests. It was not specified
in these studies if these patients had a longer remission
period than patients with abnormal provocative tests.
Fig. 2 Graphical representation of the distribution of the co-secretion
of TSH with other pituitary hormones. Most of patients presented as
associated secretion of TSH and GH or TSH and PRL
Fig. 3 The postoperative outcome in terms of biochemical remission with normalization or low levels of TSH and thyroid hormones is reported
for every study included. It was achieved in about 70% of patients
Pituitary
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Neo‑adjuvant treatments
The percentage of misdiagnosed patients treated with chemi-
cal and surgical thyroid ablation is variable among studies,
with a mean of 33.8%. Only 6 studies had no initial misdi-
agnosis [11, 13, 14, 31, 32, 36]. The rate of misdiagnosed
patients significantly decreased in studies published after
2000 (17% versus 56% till 2000; p < 0.001).
A neo-adjuvant treatment was used in 34.5% of patients
(167/484): SRL in 88% of cases and DA in 10% of cases,
while a combination of both treatments was used in 2% of
cases. Authors reported no differences in terms of post-
operative outcomes when a neo-adjuvant treatment was
administered [11, 13, 34] but a pooled data analysis was
not possible.
Adjuvant treatments
Patients not in remission after surgery were treated with
adjuvant treatments that included radiation therapy and
medical therapy.
Fig. 4 The gross total resection rate, evaluated trough the analysis of postoperative MRI or CT scan, is specified for every study. The mean esti-
mate was 54%
Fig. 5 Rates of gross total resection are stratified according to the
size of the adenoma (macro versus micro-adenomas) and according
to the invasion of the cavernous sinus. A statistically significant lower
rate of gross total resection was noted in patients with macroadeno-
mas (versus micro-adenomas, p < 0.001) and in patients with cavern-
ous sinus invasion (p < 0.001)
Pituitary
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Adjuvant radiotherapy was administered using different
protocols of treatment: 9 studies used stereotactic forms of
radiotherapy as gamma knife radiosurgery or cyberknife [11,
12, 16, 17, 19, 30, 33, 34, 40] and 6 studies used fraction-
ated pituitary irradiation [11, 12, 16, 17, 19, 30]. The dose
administered for the stereotactic irradiation was specified
in only one case [11] and it was between 15 and 25Gy.
The fractionated conventional radiotherapy was between 46
and 54Gy with fractions of 2Gy according to Malchiodi
[11], 42–45Gy in 28 treatments according to Socin [16] and
50Gy according to Sanno [37].
Fifteen studies specified the biological outcome after
adjuvant radiotherapy [2, 11–13, 16, 17, 19, 30–34, 37, 39,
40] and the use of radiation therapy allowed achieving a
biochemical remission in 65,9% of patients (34/50; 95% CI
48–83,8%; test for heterogeneity I2 = 72.95%, p < 0.001)
(Fig.6). Radiation therapy favors reaching euthyroidism
(OR 3.71, 95% CI 0.85–16.33).
The adjuvant medical treatment employed the use of SRL
or DA. The choice was taken according to the presence of
hormonal cosecretion and/or from the immunohistochemical
analysis of the tissue if performed. Two studies also reported
the use of antithyroid drugs as adjuvant treatment to achieve
euthyroidism [33, 34]. Fifteen studies [12, 14–17, 19, 20,
29, 31–34, 36–38] specified patients’ outcome after adju-
vant medical therapies. Three studies used DA [20, 33, 37],
while 3 others used SRL [17, 32, 36]. In 3 studies [12, 15,
38] a combination of both drugs was used. With the use
of a medical adjuvant treatment, 76% of patients (36/44)
reached a biochemical remission (95% CI 63.1–88.4%;
test for heterogeneity I2 = 41%, p = 0.048) (Fig.6). The use
of a medical adjuvant treatment significantly favored the
achievement of biochemical remission (OR 6.1, 95% CI
1.65–22.96).
No differences in terms of statistical significance were
observed in terms of biochemical remission between radia-
tion therapy and medical therapy (p = 0.16).
A combined adjuvant treatment, including radiation ther-
apy associated with a medical treatment was used in patients
not responsive to a single treatment to achieve a biochemi-
cal remission. The outcome was reported in 12 studies [2,
11–13, 15–17, 19, 32, 33, 36, 38] and a biochemical remis-
sion was reached in 28 out of 38 patients (67%, 95% CI
50.4–83.6%; test for heterogeneity I2 = 50.5%, p = 0.023);
(OR 4.19, 95% CI 0.99–17.66) (Fig.6).
A long-term follow-up was defined as a follow-up period
longer than 24 months and it was reported in 17 articles
(474 patients) [2, 11, 12, 14–17, 19, 30–32, 34–37, 39, 40].
When all the treatments were summarized, a biochemical
remission was obtained in 85.8% (95% CI 80.7–90.8%)
and a statistically significant difference was reported when
compared with the postoperative biochemical remission
(p < 0.001) (Fig.6).
Unfortunately it was not possible to stratify the biochemi-
cal remission according to the size of the adenoma, as this
was specified only in one study [34]. Intuitively we could
suppose that the biochemical rate is better with microadeno-
mas but no definitive conclusions on the subject are possible
through the analysis of our data.
Discussion
The number of patients diagnosed with TSHomas has tripled
in the last decade [2, 43] and our knowledge about this rare
pathology is improving thanks to an increase in the num-
ber of publications dealing with this subject. Through an
extensive systematic review of the literature published on
this subject since 1990, we want to summarize the existing
knowledge on the state of the art of the surgical and adjuvant
management of this rare variety of pituitary adenoma.
TSHomas present the same prevalence in both sexes.
According to our meta-analysis, less than 70% of patients
have clinical manifestations of hyperthyroidism and a bio-
logical profile of secondary hyperthyroidism was docu-
mented in 90% of cases. This means that about one-third
of patients have no signs or symptoms of hyperthyroidism
whilst 10% of patient may have no modification of the thy-
roid profile and are diagnosed essentially by immunohis-
tochemistry, as clinical and radiological features are not
specific.
Azzalin etal. [13] reported a series of 20 beta TSH-posi-
tive adenomas of which only 6 provoked a hyperthyroidism,
Fig. 6 The biochemical remission rate is stratified according to
the treatment performed. A statistically significant difference was
reported between the early postoperative remission and the remission
recorded at last follow-up, when all the adjuvant treatment are sum-
marized (p < 0.001)
Pituitary
1 3
while 14 presented with headaches, mass effect or other
hypersecretory syndromes. Silent TSHomas may thus be
defined as tumors with TSH immunopositivity and no evi-
dence of preoperative hypersecretion or mild hypersecretion
and no clinical features. They seems to have a similar out-
come than secreting adenomas [13, 32] but in our analysis
it was not possible to stratify the postoperative outcomes
according to the secretory status as patients were analyzed
together in all study but two [13, 32].
Plurihormonal pituitary adenomas with biological co-
secretion are considered rare but in the case of TSHomas
a biological co-secretion was documented in 42% of cases
and in some cases the primary clinical manifestation was
acromegaly or galactorrhea rather than manifestations of
hyperthyroidism. The prevalent co-secretion of GH and PRL
is secondary to the fact that GH-PRL-and TSH-producing
cells share the same cell lineage (Pit-1 lineage) [44].
According to our review, the immunohistochemistry
stained positive for pituitary hormones other than TSH in
a percentage of cases variable between 20 and 100%, thus
superior than general series where plurihormonal pituitary
adenomas represent 10–15% of all pituitary lesions [45].
When all the surgical series are considered together, in
80% of cases a macroadenoma is described. However a trend
towards a greater prevalence of microadenomas is evident
in more recent articles if the studies are stratified according
to the year of publication. An earlier diagnosis is probably
responsible for the higher rate of microadenomas described
in the series published after 2000 (p = 0.04).
Thanks to the greater attention of clinicians, the num-
ber of misdiagnosed patients decreased over the years with
an important drop after 2000 (p < 0.001). Improper thyroid
ablation and administration of anti-thyroid agents or radi-
oiodine neutralize the physiologic negative feedback loop of
thyroid hormones and it is associated with the development
of pituitary hyperplasia in patients with no previous pitui-
tary disease [46, 47]. This has also a deleterious impact in
patients with a known pituitary adenoma, as it is associated
with an increase in size and aggressiveness of the tumor
[1], like in Nelson’s syndrome for Cushing’s disease [48].
However, the real role of this absent negative feedback in
TSH-oma pathogenesis is still matter of debate.
Tumor size was predictive of GTR, as a complete resec-
tion was achieved in 49% of macroadenomas versus 87% of
microadenomas (p < 0.001). The invasion of the cavernous
sinus was reported in 30% of cases, thus higher than other
general series reporting an invasion in 6–10% of cases [49,
50]. In published series the rate of cure falls from 78 to 92
to 20–52% in cases of adenomas with parasellar extension
[51]. Our analysis also confirms that TSH-omas follow a
pattern similar to other secreting tumors, where cavernous
sinus invasion is a factor predicting the extent of resection,
as GTR declines from 54% for all the patients to 16% in
cases presenting with cavernous sinus invasion (p < 0.001).
According to our data, studies presenting a cavernous sinus
invasion in less than 20% of cases report a GTR rate of
60–90% [13, 14, 31, 32], against 14–50% of GTR when the
cavernous sinus invasion was reported in more than 50% of
patients [15, 28, 37] (p = 0.06).
Other probable factors predicting GTR described in lit-
erature, such as tumor consistency and co-secretion of GH
[12], were not analyzed. The Ki-67 was rarely specified and
it didn’t differ from other adenoma histotypes [32].
Since 2000 the endoscope was progressively introduced
to perform trans-sphenoidal approaches [52–54], initially as
an adjunct to microscopic techniques and then as primary
tool to perform the procedure. However, even with these
technological advances and higher prevalence of microad-
enomas, the GTR rate did not improve in series published
before and after 2000 (p = 0.13).
The different studies are heterogeneous in their defini-
tion of remission criteria and the standardization of the term
“cured” remains difficult with these rare tumors.
Surgical cure may be defined by the presence of a bio-
chemical and clinical euthyroidism, associated with normali-
zation of other pituitary hormones in cases of co-secretion
[12] and absence of residual tumor on postoperative imaging
[16, 17, 21, 30, 31, 55]. Nevertheless all these criteria are
insufficient to predict a long-term remission, as recurrences
were observed after GTR and complete biochemical remis-
sion in one-third of cases [15, 32].
Biochemical remission was observed in about 70% of
cases and results seems to be better than those recorded
using the 2010 remission criteria with GH-secreting adeno-
mas [56] but similar to the results obtained using the 2000
remission criteria for GH secreting adenomas [56] and to
those recently described in a cohort with Cushing’s disease
[57]. As in other secreting adenomas, a postoperative bio-
chemical remission is not predictive of the extent of resec-
tion [12, 13, 37]. The residual tumor may in fact secrete
hormones inefficiently and thus determine biochemical nor-
malization, as described for GH adenoma [58, 59].
Nevertheless, unlike GH-adenomas, the cut-off of TSH
value to define the surgical cure is not mentioned in litera-
ture. Losa etal. [18, 33] tried to define patients with long-
term remission while measuring the TSH in the first post-
operative week: no recurrence was observed during a mean
follow-up of 44 months if the early postoperative TSH was
undetectable. Also measurements of alpha subunit and TSH
molar ratio as well as the TRH stimulation and T3 suppres-
sion tests were used to predict which patient would obtain a
long-term remission. However, no conclusive results were
obtained to support the widespread use of these measure-
ments [16–18, 21, 33, 37].
The use of neoadjuvant treatments was not associated
with improved postoperative outcomes [11, 13, 34] and the
Pituitary
1 3
presence of a preoperative euthyroid status was not associ-
ated with a higher rate of remission [13].
On the other hand, the use of adjuvant treatment like
radiation therapy and SRL or DA therapy in cases of persis-
tent disease after surgery, was determinant in improving the
long-term remission rate (p < 0.001).
A long-term clinico-radiological and biochemical follow-
up is necessary to detect delayed recurrence.
Conclusion
TSH-omas form a rare subgroup of secreting pituitary ade-
nomas and can represent a challenge in their diagnosis and
treatment. The trans-sphenoidal surgery forms the mainstay
of treatment. Overall GTR was observed in 54% of patients
and the size of the tumor as well as cavernous sinus inva-
sion were the principal factors determining the extent of
resection. This meta-analysis showed that postoperative bio-
chemical remission was observed in 70% of patients. When
adjuvant treatments like radiotherapy, SRL/DA therapy or a
combination of both were used, a pooled overall biochemical
remission was observed in 86% of patients at last follow-up.
Neoadjuvant therapy, when used, had no effect on the surgi-
cal outcome in our analysis.
Larger surgical series and longer follow-up periods
should prove useful to determine the factors predicting a
long-term remission.
Compliance with ethical standards
Conflict of interest The authors report no conflict of interest concern-
ing the materials or methods used in this study or the findings specified
in this paper.
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