- Email: [email protected]
The Surgical Side Effects of Pseudocapsular Resection in Nonfunctioning Pituitary Adenomas
Accepted Manuscript The surgical side effects of pseudocapsular resection in non-functioning pituitary adenomas Yasuyuki Kinoshita, M.D., Ph.D., Atsushi Tominaga, M.D., Ph.D., Satoshi Usui, M.D., Kazunori Arita, M.D., Ph.D., Tetsuhiko Sakoguchi, M.D., Ph.D., Kazuhiko Sugiyama, M.D., Ph.D., Kaoru Kurisu, M.D., Ph.D. PII:
S1878-8750(16)30560-5
DOI:
10.1016/j.wneu.2016.07.036
Reference:
WNEU 4329
To appear in:
World Neurosurgery
Received Date: 12 May 2016 Revised Date:
8 July 2016
Accepted Date: 9 July 2016
Please cite this article as: Kinoshita Y, Tominaga A, Usui S, Arita K, Sakoguchi T, Sugiyama K, Kurisu K, The surgical side effects of pseudocapsular resection in non-functioning pituitary adenomas, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.07.036. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Kinoshita
ACCEPTED MANUSCRIPT
1
The surgical side effects of pseudocapsular resection in non-functioning pituitary
RI PT
adenomas
Yasuyuki Kinoshita, M.D., Ph.D.1), Atsushi Tominaga, M.D., Ph.D.2), Satoshi Usui, M.D. 1),
SC
Kazunori Arita, M.D., Ph.D.3), Tetsuhiko Sakoguchi, M.D., Ph.D.2), Kazuhiko Sugiyama, M.D.,
1)
M AN U
Ph.D.4) and Kaoru Kurisu, M.D., Ph.D.1)
Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima
University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan 2)
Department of Neurosurgery, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku,
3)
TE D
Hiroshima, 734-8530, Japan
Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima
4)
EP
University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan Department of Clinical Oncology and Neuro-oncology Program, Hiroshima University
AC C
Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
Key words: extracapsular dissection, non-functioning pituitary adenoma, pseudocapsular resection, transsphenoidal surgery
Running title: Surgical side effects of pseudocapsular resection in NFPAs
1
Kinoshita
ACCEPTED MANUSCRIPT
2
Funding: This study was partially supported by a Grant-in-Aid from the Japan Society for the
Correspondence to: Yasuyuki Kinoshita
RI PT
Promotion of Science [grant number 15K103345D].
University 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan Fax: +81-82-257-5229
AC C
EP
TE D
Email: [email protected]
M AN U
Phone: +81-82-257-5227
SC
Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima
2
Kinoshita
ACCEPTED MANUSCRIPT
3
ABSTRACT
RI PT
OBJECTIVE: Pseudocapsular resection has been accepted as a useful surgical technique for
removing functioning pituitary adenomas; however, the significance of this procedure in
non-functioning pituitary adenomas (NFPAs) had not been well discussed. We attempted to
M AN U
complications and evaluations of the pituitary functions.
SC
clarify the safety of pseudocapsular resection in NFPAs based on the incidence of surgical
METHODS: A total of 143 patients received initial surgery for NFPAs and underwent
preoperative and postoperative pituitary provocation tests. These 143 patients were categorized
TE D
into three groups: 1) the Total group (n=65), in which the pseudocapsule was totally removed;
2) the Partial group (n=11), in which the pseudocapsule was partially removed; and 3) the
EP
Non-removal group (n=67), in which the pseudocapsule was not removed or did not exist. The
AC C
main outcome measure was the incidence of surgical complications and the postoperative
pituitary functions.
RESULTS: Intraoperative cerebrospinal fluid (CSF) leakage and temporary diabetes insipidus
(DI) occurred more frequently in the Total group than in the Non-removal group; however, the
differences were not statistically significant. Furthermore, there was no difference in the
3
Kinoshita
ACCEPTED MANUSCRIPT
4
incidences of any other complications, including postoperative CSF leakage and permanent DI,
RI PT
between the Total and Non-removal groups. The postoperative anterior pituitary functions
improved to the same degree in both the Total and Non-removal groups. Univariate and
postoperative deterioration of the pituitary functions.
SC
multivariate analyses revealed that pseudocapsular resection was not a factor in the
M AN U
CONCLUSION: Pseudocapsular resection in NFPAs does not increase the risk of surgical
AC C
EP
TE D
complications or aggravate the postoperative pituitary functions.
4
Kinoshita
ACCEPTED MANUSCRIPT
5
INTRODUCTION
RI PT
Pseudocapsular resection has contributed to improved rates of endocrinological
remission in patients with functioning pituitary adenomas.1-3 This well-known surgical
technique is applied in the removal of pituitary adenomas.4-6 Although the safety of this
SC
procedure has been reported by several authors,1, 7-9 previous studies examined the procedure in
M AN U
the context of functioning pituitary adenomas or mixed adenomas with functioning and
non-functioning pituitary adenomas (NFPAs).1, 7-9 The role of surgery in the treatment of NFPAs
differs from that in functioning pituitary adenomas, thus pseudocapsular resection should be
TE D
discussed separately in these two different contexts. We aim to clarify the safety of
pseudocapsular resection in NFPAs based on the incidence of surgical complications and
AC C
EP
examinations of the pituitary functions.
METHODS
The institutional ethics committee approved all aspects of this study. The requirement
for patient-informed consent was waived for this retrospective study, as it included no unique
patient identifiers. Furthermore, the patients were informed about the information disclosure on
5
Kinoshita
ACCEPTED MANUSCRIPT
6
the institutional home page and were able to opt out of this study.
RI PT
The study population
Between January 2008 and July 2015, a total of 161 patients underwent initial
surgery for NFPAs at Hiroshima University Hospital. Among these patients, the 143 patients
SC
who received both preoperative and three-month postoperative pituitary provocation tests were
M AN U
included in this retrospective study. The median age of the 76 male (53.1%) and 67 female
(46.9%) patients at the time of surgery was 60.0 (range: 17-81) years. All of the patients
underwent preoperative 3-Tesla magnetic resonance imaging (MRI) examinations. These 143
TE D
patients were diagnosed with NFPAs based on the results of preoperative endocrinological
examinations and the postoperative histological findings. Immunohistochemically, the adenoma
EP
cells were positive for luteinizing hormone (LH) (n=7), follicle-stimulating hormone (FSH)
AC C
(n=27), or LH and FSH (n=14), or were negative for all anterior pituitary hormones (null cell
adenoma) (n=95). Patients with silent corticotroph, somatotroph, or lactotroph adenomas were
excluded from the present study.
These 143 patients were categorized into three groups as follows: 1) the Total group
(n=65), in which the pseudocapsule was totally removed; 2) the Partial group (n=11), in which
6
Kinoshita
ACCEPTED MANUSCRIPT
7
the pseudocapsule was partially removed; and 3) the Non-removal group (n=67), in which the
RI PT
pseudocapsule was not removed or was found to not exist (or could not be found) during
and/or the authors based on the surgical videos.
The definition of pseudocapsular resection
SC
surgery. The rates of pseudocapsular removal were retrospectively assessed by the surgeon
M AN U
Pseudocapsular resection was defined as the separation of the tumor pseudocapsule
from the normal pituitary gland. The rate of pseudocapsular removal indicated the degree of
pseudocapsule peeled from the normal pituitary gland, not the rate of tumor removal; thus,
TE D
tumor resection in the cavernous sinus was not associated with pseudocapsular resection.
The Non-removal group included some patients with an apparent remnant
EP
pseudocapsule; however, in most of the patients in the Non-removal group, the pseudocapsule
AC C
did not exist or could not be found during surgery.
Endocrinological studies
The basal levels of anterior pituitary hormones and responses to induced
hypoglycemia and the administration of thyrotropin-releasing hormone (TRH) and luteinizing
hormone-releasing hormone (LHRH) were evaluated in 75 of the 143 patients. The remaining
7
Kinoshita
ACCEPTED MANUSCRIPT
8
68 patients, who were older than 65 years of age or who had a history of heart disease or
RI PT
epilepsy, underwent corticotropin-releasing hormone (CRH)- and arginine-loading tests to
evaluate the adrenocorticotropic hormone (ACTH) and growth hormone (GH) axis, rather than
hypoglycemia tests. Pituitary provocation tests were conducted according to the guidelines
SC
established by the Japanese Society for Hypothalamic and Pituitary Tumors.10 Based on the
M AN U
results of the provocation tests, the medical costs of the patients with hypopituitarism (which is
designated as a rare and intractable diseases by the Japan Ministry of Health, Labour and
Welfare) were subsidized from 2009.
TE D
In this present study, a decline in anterior pituitary hormones was defined by the
following conditions: thyroid stimulating hormone (TSH) peak < 8.0 IU/L, prolactin (PRL)
EP
peak < 15.0 µg/L, GH peak < 3.0 µg/L, and cortisol peak < 15.0 µg/dL in response to
AC C
provocation tests. The LH and FSH responses to LHRH were not evaluated because 48 of the
patients in our series had NFPAs that were immunohistochemically-positive for LH and/or
FSH.
Surgical procedures
8
Kinoshita
ACCEPTED MANUSCRIPT
9
Transsphenoidal surgery was performed through one nostril under microscopic and
RI PT
endoscopic observation in all patients. During surgery, extracapsular dissection was attempted
before internal decompression, or pseudocapsular resection was attempted after the internal
decompression of the adenoma (Fig. 1). The pseudocapsule was resected under an oblique view
SC
with a 30° or 70° endoscope. The 70° endoscope was indispensable in the resection of the
M AN U
upper and lateral part of the tumor and pseudocapsule. In the patients in whom the adenoma
showed a great deal of extension at the top of the tumor, spinal drainage was performed prior to
surgery to push down the upper part of the tumor by injecting saline through the drainage tube
TE D
(to increase intracranial pressure). In contrast, after the removal of the tumor, the cavity could
be expanded to confirm that there was no residual tumor or pseudocapsule by draining the
EP
cerebrospinal fluid (CSF). Tumors in the cavernous sinus were removed to the maximum
AC C
possible extent; however, the removal of a tumor from the cavernous sinus was not associated
with the resection of the pseudocapsule from the normal pituitary gland in the present study.
Statistical analysis
All of the statistical analyses were performed using the software package SPSS 16.0
J for Windows software program (SPSS Inc.). The values are expressed as the median. The
9
Kinoshita
ACCEPTED MANUSCRIPT
10
median values were compared using the Mann–Whitney U-test, Kruskal-Wallis test, Fisher’s
RESULTS
M AN U
The background of the patients in the three groups
SC
considered to indicate a statistically significant difference.
RI PT
exact test and the chi-squared test with 95% confidence intervals. P values of < 0.05 were
The characteristics of the patients are listed in Table 1. The patients who underwent
pseudocapsular resection had some biases. Smaller tumors with lower Knosp grades11 were
TE D
more likely to be removed with the pseudocapsule.
The postoperative complications in the three groups
EP
Table 2 shows the number of patients with postoperative complications.
AC C
Intraoperative CSF leakage and temporary diabetes insipidus (DI) was more common in the
Total group; however, there were no significant differences between the groups. There were no
significant differences in the incidence rates of other complications caused by pseudocapsular
resection.
The
incidence
of
a
decline
in
the
anterior
pituitary
hormone
levels
and
10
Kinoshita
ACCEPTED MANUSCRIPT
11
hyperprolactinemia
RI PT
The Partial group was excluded from this analysis, because the number of patients
(n=11) was too small for a statistical analysis. Furthermore, this group included non-uniform
patients with various rates of pseudocapsular resection.
SC
Figure 2 shows the incidence of a decline in the anterior pituitary hormone levels and
M AN U
hyperprolactinemia at the preoperative and three-month postoperative provocation tests.
Preoperatively, a decline in the anterior pituitary hormone levels and hyperprolactinemia were
more likely to be observed in the patients of the Non-removal group because they had larger
TE D
tumors than the patients in the Total group. However, the postoperative change in the incidence
of reduced anterior pituitary hormone levels and hyperprolactinemia was the same in both the
EP
Total and Non-removal groups; after surgery, the incidence rates of reduced ACTH, TSH and
AC C
GH levels were slightly lower, while the incidence of hyperprolactinemia was significantly
reduced (P < 0.01).
The change in the anterior pituitary functions of each patient after surgery
Figure 3 shows that a similar pattern of change was observed in the anterior pituitary
functions after surgery in each of the patients of the Total and Non-removal groups. In a few
11
Kinoshita
ACCEPTED MANUSCRIPT
12
patients, the peak hormone levels declined after surgery (according to our criteria); however, the
RI PT
peak hormone levels improved in a greater number of patients. In the end, the incidence of a
decline in the anterior pituitary hormone levels was lower after surgery in both the Total and
Non-removal groups (Fig. 2). Two patients newly required hormonal replacement after surgery;
SC
one in the Total group and one in the Non-removal group. Both of the patients required
M AN U
1-deamino-8-d-arginine vasopressin (DDAVP) after surgery.
The factors affecting the postoperative anterior pituitary functions
There were 23 patients in whom more than one axis of the anterior pituitary
TE D
hormones was found to have deteriorated after surgery. The clinical features of the 23 patients
are shown in Table 3. No factors affecting the postoperative anterior pituitary functions were
EP
identified (including pseudocapsular total resection). A multiple regression analysis also
AC C
revealed that there was no significant correlation between the performance of pseudocapsular
total resection and the postoperative anterior pituitary functions (Supplemental Table). Although
there were biases with regard to the tumor size and the Knosp grade in each of the groups, these
factors did not have a significant effect on the postoperative anterior pituitary functions.
12
Kinoshita
ACCEPTED MANUSCRIPT
13
DISCUSSION
RI PT
A pseudocapsule is identified in approximately half of pituitary adenomas, and tumor
cell clusters are found in approximately 50% of pseudocapsules.8 Pseudocapsular resection has
been shown to contribute to the endocrinological remission of acromegaly and Cushing
SC
disease.1, 2 The importance of pseudocapsular resection in the removal of functioning pituitary
M AN U
adenomas is well recognized. Thus, it is anticipated that pseudocapsular resection will reduce
the possibility of a tumor remnant and the rate of tumor recurrence in patients with NFPA.8
Although side effects may occur due to the radical removal of tumors during
TE D
pseudocapsular resection in patients with pituitary adenoma, some investigators have reported
the safety of this procedure. The incidence of DI, postoperative CSF leakage and visual
EP
deterioration did not differ between patients undergoing extracapsular resection and those
AC C
undergoing intracapsular resection.7 Moreover, the anterior pituitary function was not
aggravated by pseudocapsular resection.1,
7-9
However, the previous investigations included
patients with GH-producing pituitary adenoma or mixed patients with functioning and clinical
NFPA.1, 7-9 The permissible risk of surgery should differ between patients with NFPA and those
with functioning pituitary adenoma. Furthermore, NFPAs are generally larger than functioning
13
Kinoshita
ACCEPTED MANUSCRIPT
14
adenomas. It is therefore very important to evaluate the safety of pseudocapsular resection in a
RI PT
study population that is restricted to patients with NFPA.
To the best of our knowledge, the present study is the first report to focus on
pseudocapsular resection in NFPAs. The incidence of visual deterioration, postoperative CSF
SC
leakage, permanent DI, postoperative hyponatremia and deterioration of the anterior pituitary
M AN U
function did not differ between the groups that were treated with and without pseudocapsular
resection. We clarified that pseudocapsular resection did not increase the incidence of surgical
complications and did not aggravate the postoperative pituitary functions in patients with NFPA.
TE D
However, intraoperative CSF leakage was likely to occur in the Total group. There is a
possibility that the incidence of intraoperative CSF leakage might have been found to be
EP
significantly high among patients undergoing total pseudocapsular resection if the study had
AC C
included a greater number of patients.
This study aims to clarify the safety of pseudocapsular resection in NFPAs rather
than the rate of tumor recurrence. However, different recurrence rates could be expected in each
of the groups in this study. Three groups were categorized by the resection rate of
pseudocapsule peeled from the normal pituitary gland, not the rate of tumor removal. Thus, all
14
Kinoshita
ACCEPTED MANUSCRIPT
15
of the groups included tumors that invaded the cavernous sinus. All of the groups had the
RI PT
potential for tumor recurrence, and we would expect the recurrence to be high in the Partial
group, because the patients had a pseudocapsule remnant, that could include tumor cells.
Furthermore, the recurrence rate in the Total and Non-removal groups is expected to be the
SC
same, because the Non-removal group mostly consisted of patients without an original
M AN U
pseudocapsule, while the Total group consisted of patients without a remnant pseudocapsule.
When the pseudocapsule can be totally removed in half of patients with pituitary adenoma,
tumor recurrence is expected to depend on the invasion of cavernous sinus, rather than
TE D
pseudocapsular resection. In the present study, it is difficult to evaluate the recurrence rate
because of short follow-up period. Follow-up studies will lead to the clarification of the
EP
relationship between pseudocapsular resection and the rate of recurrence in NFPAs.
AC C
The present study is associated with some limitations. First, this study has some
biases with regard to the patients undergoing pseudocapsular resection: they tended to have
smaller and less invasive tumors. These facts might have affected our results. Second, the rates
of pseudocapsule removal cannot be objectively assessed. The Total group might have included
patients in whom the pseudocapsule was partially removed. However, the surgical procedures in
15
Kinoshita
ACCEPTED MANUSCRIPT
16
the Total group were radically different from those in the Non-removal group. We are of the
RI PT
opinion that a small difference in the removal rates did not greatly affect our results. Third, the
safety of pseudocapsular resection depends on the technical skills of pituitary surgeons. Safe
pseudocapsular resection in large NFPAs requires more skilled techniques than those that are
SC
required for small pituitary adenomas because it is more difficult to resect the pseudocapsule
M AN U
from a stretched normal pituitary gland than from a maldistributed thick normal pituitary gland.
The pseudocapsules in larger adenomas might be discontinuous or disrupted.1,
8
Thus, an
inexperienced surgeon should pay careful attention when resecting the pseudocapsule in patients
EP
CONCLUSION
TE D
with NFPA.
AC C
Pseudocapsular resection did not increase the risk of surgical complications or
aggravate the postoperative pituitary functions in patients with NFPA. Pseudocapsular resection
is expected to contribute to the prevention of tumor recurrence in patients with NFPA.
REFERENCES
16
Kinoshita
ACCEPTED MANUSCRIPT
1.
17
Kawamata T, Kubo O, Hori T. Surgical removal of growth hormone-secreting pituitary
remission of acromegaly. Neurosurg Rev. 2005;28:201-208.
2.
RI PT
adenomas with intensive microsurgical pseudocapsule resection results in complete
Jagannathan J, Smith R, DeVroom HL, Vortmeyer AO, Stratakis CA, Nieman LK, et al.
3.
M AN U
disease. J Neurosurg. 2009;111:531-539.
SC
Outcome of using the histological pseudocapsule as a surgical capsule in Cushing
Ceylan S, Cabuk B, Koc K, Anik I, Vural C. Endoscopic distinction between capsule
and pseudocapsule of pituitary adenomas. Acta Neurochir (Wien). 2013;155:1611-1619.
Prevedello DM, Ebner FH, de Lara D, Ditzel Filho L, Otto BA, Carrau RL.
TE D
4.
Extracapsular dissection technique with the Cotton Swab for pituitary adenomas
EP
through an endoscopic endonasal approach - How I do it. Acta Neurochir (Wien).
5.
AC C
2013;155:1629-1632.
Qu X, Xu G, Qu Y, Song T. The pseudocapsule surrounding a pituitary adenoma and its
clinical significance. J Neurooncol. 2011;101:171-178.
6.
Oldfield EH, Vortmeyer AO. Development of a histological pseudocapsule and its use
as a surgical capsule in the excision of pituitary tumors. J Neurosurg. 2006;104:7-19.
17
Kinoshita
ACCEPTED MANUSCRIPT
7.
18
Qu X, Yang J, Sun J-D, Mou C-Z, Wang G-D, Han T, et al. Transsphenoidal
RI PT
pseudocapsule-based extracapsular resection for pituitary adenomas. Acta Neurochir
(Wien). 2011;153:799-806.
8.
Lee EJ, Ahn JY, Noh T, Kim SH, Kim TS, Kim SH. Tumor tissue identification in the
SC
pseudocapsule of pituitary adenoma: should the pseudocapsule be removed for total
9.
M AN U
resection of pituitary adenoma? Neurosurg. 2009;64:S62-S70.
Kim EH, Ku CR, Lee EJ, Kim SH. Extracapsular en bloc resection in pituitary adenoma
surgery. Pituitary. 2015;18:397-404.
The Japanese Society of Hypothalamic and Pituitary Tumors. The guidelines for
TE D
10.
diagnoses and treatments of diencephalo-hypophysial dysfunction (Japanese); Accessed
Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the
AC C
11.
EP
July 08, 2016.
cavernous sinus space: a magnetic resonance imaging classification compared with
surgical findings. Neurosurg. 1993;33:610-618.
FIGURE LEGENDS
18
Kinoshita
ACCEPTED MANUSCRIPT
19
Figure 1
RI PT
A 50-year-old male underwent preoperative MRI, which showed a heterogeneously
enhanced non-functioning pituitary adenoma on coronal T1-weighted imaging after gadolinium
injection (A). An intraoperative photograph taken under a 70° endoscope showed internal
SC
decompression by the double suction technique on the left lateral wall of tumor cavity (B). After
gland under a 30 °
M AN U
the internal decompression of tumor, the pseudocapsule was resected from the normal pituitary
endoscope. Open triangles indicate the borderline between the
pseudocapsule and the normal pituitary gland (C). Intraoperative CSF leakage occurred after the
TE D
total removal of the tumor and pseudocapsule (arrow head) (D). Postoperative MRI showed no
residual tumor (E), and postoperative pituitary provocation tests demonstrated the normal
AC C
Figure 2
EP
pituitary function of the patient.
A graph showing the incidences of a reduction in the anterior pituitary hormone
levels and hyperprolactinemia (Hyper PRL) at the preoperative and three-month postoperative
provocation tests. The postoperative change in the anterior pituitary function was the same in
both the Total and Non-removal groups.
19
Kinoshita
ACCEPTED MANUSCRIPT
20
Figure 3
RI PT
A graph showing the change in the anterior pituitary functions after surgery in each
patient. The peak hormone levels in the provocation tests declined after surgery in a few patietns,
but improved in a greater number of patients. The Total and Non-removal groups showed a
AC C
EP
TE D
M AN U
SC
similar ratio of patients with improved and deteriorated of anterior pituitary functions.
20
ACCEPTED MANUSCRIPT
Table 1. Patients characteristics Total
Partial
Non-removal
(n = 65)
(n = 11)
(n = 67)
55.0
61.0
61.0
0.37
33 / 32
8 / 3
33 / 34
0.34
21.0
28.0
27.0
< 0.01
1
2
2
< 0.01
Age (years, median) Sex (male/female) Tumor size (mm, median)
AC C
EP
TE D
M AN U
SC
Knosp grade10
RI PT
P Value
ACCEPTED MANUSCRIPT
Table 2. Postoperative complications Total
Partial
Non-removal
(n = 65)
(n = 11)
(n = 67)
26 (40.0)
4 (36.4)
0
0
14 (21.5)
2 (18.2)
9 (13.4)
0.47
1
0
1
> 0.99
Cerebrospinal fluid leakage Intraoperative (%) Postoperative
Permanent Postoperative hyponatremia (Na 135) (%) Visual deterioration Temporary Permanent
Temporary Permanent
AC C
EP
Postoperative hematoma
0.13
1
> 0.99
19 (29.2)
2 (18.2)
21 (31.3)
0.67
0
0
0
> 0.99
0
0
0
> 0.99
1
0
0
> 0.99
0
0
0
> 0.99
0
0
1
> 0.99
TE D
Oculomotor nerve palsy
M AN U
Temporary (%)
16 (23.9)
SC
Diabetes insipidus
RI PT
P Value
ACCEPTED MANUSCRIPT
Table 3. Clinical features of the patients deteriorated postoperative anterior pituitary functions Deterioration No deterioration cases
P Value
(n = 23)
Sex (male/female) Tumor size (mm, median) Knosp grade10
63.0
59.0
0.15
16 / 7
52 / 57
0.07
25.0
23.0
0.21
2
2
0.91
Pseudocapsular total 13 (56.5)
52 (47.7)
M AN U
resection (n, %)
SC
Age (years, median)
RI PT
cases (n = 109)
AC C
EP
TE D
Partial group (n = 11) was excluded in the present analysis.
0.50
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Highlights:
RI PT
Pseudocapsular resection in NF does not increase the risk of surgical complications.
Pseudocapsular resection in NF does not cause the pituitary dysfunctions.
AC C
EP
TE D
M AN U
SC
Safety of pseudocapsular resection in NF is clarified.
ACCEPTED MANUSCRIPT
Supplemental Table. Factors affecting the postoperative anterior pituitary functions OR
95% CI
Age (years)
0.19
1.02
0.99-1.07
Sex
0.12
0.45
Tumor size (mm)
0.08
1.08
Knosp grade
0.46
0.80
Pseudocapsular total resection
0.19
0.50
OR, odds ratio; CI, confidence interval.
SC
10
RI PT
P Value
0.17-1.24 0.99-1.17 0.44-1.44 0.17-1.42
AC C
EP
TE D
M AN U
Partial group (n = 11) was excluded in the present analysis.
ACCEPTED MANUSCRIPT
Abbreviations list: ACTH:
Adrenocorticotropic
hormone,
CRH:
Corticotropin-releasing
hormone,
CSF:
Cerebrospinal fluid, DDAVP: 1-deamino-8-d-arginine vasopressin, DI: Diabetes insipidus, FSH: Follicle-stimulating hormone, GH: Growth hormone, LH: Luteinizing hormone, LHRH:
RI PT
Luteinizing hormone-releasing hormone, MRI: Magnetic resonance imaging, NFPA: Non-functioning pituitary adenomas, PRL: Prolactin, TRH: Thyrotropin-releasing hormone
AC C
EP
TE D
M AN U
SC
TSH: Thyroid-stimulating hormone
ACCEPTED MANUSCRIPT
Disclosure:
AC C
EP
TE D
M AN U
SC
RI PT
We have no financial disclosure and conflicts of interest whatsoever.
S1878-8750(16)30560-5
DOI:
10.1016/j.wneu.2016.07.036
Reference:
WNEU 4329
To appear in:
World Neurosurgery
Received Date: 12 May 2016 Revised Date:
8 July 2016
Accepted Date: 9 July 2016
Please cite this article as: Kinoshita Y, Tominaga A, Usui S, Arita K, Sakoguchi T, Sugiyama K, Kurisu K, The surgical side effects of pseudocapsular resection in non-functioning pituitary adenomas, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.07.036. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Kinoshita
ACCEPTED MANUSCRIPT
1
The surgical side effects of pseudocapsular resection in non-functioning pituitary
RI PT
adenomas
Yasuyuki Kinoshita, M.D., Ph.D.1), Atsushi Tominaga, M.D., Ph.D.2), Satoshi Usui, M.D. 1),
SC
Kazunori Arita, M.D., Ph.D.3), Tetsuhiko Sakoguchi, M.D., Ph.D.2), Kazuhiko Sugiyama, M.D.,
1)
M AN U
Ph.D.4) and Kaoru Kurisu, M.D., Ph.D.1)
Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima
University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan 2)
Department of Neurosurgery, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku,
3)
TE D
Hiroshima, 734-8530, Japan
Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima
4)
EP
University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan Department of Clinical Oncology and Neuro-oncology Program, Hiroshima University
AC C
Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
Key words: extracapsular dissection, non-functioning pituitary adenoma, pseudocapsular resection, transsphenoidal surgery
Running title: Surgical side effects of pseudocapsular resection in NFPAs
1
Kinoshita
ACCEPTED MANUSCRIPT
2
Funding: This study was partially supported by a Grant-in-Aid from the Japan Society for the
Correspondence to: Yasuyuki Kinoshita
RI PT
Promotion of Science [grant number 15K103345D].
University 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan Fax: +81-82-257-5229
AC C
EP
TE D
Email: [email protected]
M AN U
Phone: +81-82-257-5227
SC
Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima
2
Kinoshita
ACCEPTED MANUSCRIPT
3
ABSTRACT
RI PT
OBJECTIVE: Pseudocapsular resection has been accepted as a useful surgical technique for
removing functioning pituitary adenomas; however, the significance of this procedure in
non-functioning pituitary adenomas (NFPAs) had not been well discussed. We attempted to
M AN U
complications and evaluations of the pituitary functions.
SC
clarify the safety of pseudocapsular resection in NFPAs based on the incidence of surgical
METHODS: A total of 143 patients received initial surgery for NFPAs and underwent
preoperative and postoperative pituitary provocation tests. These 143 patients were categorized
TE D
into three groups: 1) the Total group (n=65), in which the pseudocapsule was totally removed;
2) the Partial group (n=11), in which the pseudocapsule was partially removed; and 3) the
EP
Non-removal group (n=67), in which the pseudocapsule was not removed or did not exist. The
AC C
main outcome measure was the incidence of surgical complications and the postoperative
pituitary functions.
RESULTS: Intraoperative cerebrospinal fluid (CSF) leakage and temporary diabetes insipidus
(DI) occurred more frequently in the Total group than in the Non-removal group; however, the
differences were not statistically significant. Furthermore, there was no difference in the
3
Kinoshita
ACCEPTED MANUSCRIPT
4
incidences of any other complications, including postoperative CSF leakage and permanent DI,
RI PT
between the Total and Non-removal groups. The postoperative anterior pituitary functions
improved to the same degree in both the Total and Non-removal groups. Univariate and
postoperative deterioration of the pituitary functions.
SC
multivariate analyses revealed that pseudocapsular resection was not a factor in the
M AN U
CONCLUSION: Pseudocapsular resection in NFPAs does not increase the risk of surgical
AC C
EP
TE D
complications or aggravate the postoperative pituitary functions.
4
Kinoshita
ACCEPTED MANUSCRIPT
5
INTRODUCTION
RI PT
Pseudocapsular resection has contributed to improved rates of endocrinological
remission in patients with functioning pituitary adenomas.1-3 This well-known surgical
technique is applied in the removal of pituitary adenomas.4-6 Although the safety of this
SC
procedure has been reported by several authors,1, 7-9 previous studies examined the procedure in
M AN U
the context of functioning pituitary adenomas or mixed adenomas with functioning and
non-functioning pituitary adenomas (NFPAs).1, 7-9 The role of surgery in the treatment of NFPAs
differs from that in functioning pituitary adenomas, thus pseudocapsular resection should be
TE D
discussed separately in these two different contexts. We aim to clarify the safety of
pseudocapsular resection in NFPAs based on the incidence of surgical complications and
AC C
EP
examinations of the pituitary functions.
METHODS
The institutional ethics committee approved all aspects of this study. The requirement
for patient-informed consent was waived for this retrospective study, as it included no unique
patient identifiers. Furthermore, the patients were informed about the information disclosure on
5
Kinoshita
ACCEPTED MANUSCRIPT
6
the institutional home page and were able to opt out of this study.
RI PT
The study population
Between January 2008 and July 2015, a total of 161 patients underwent initial
surgery for NFPAs at Hiroshima University Hospital. Among these patients, the 143 patients
SC
who received both preoperative and three-month postoperative pituitary provocation tests were
M AN U
included in this retrospective study. The median age of the 76 male (53.1%) and 67 female
(46.9%) patients at the time of surgery was 60.0 (range: 17-81) years. All of the patients
underwent preoperative 3-Tesla magnetic resonance imaging (MRI) examinations. These 143
TE D
patients were diagnosed with NFPAs based on the results of preoperative endocrinological
examinations and the postoperative histological findings. Immunohistochemically, the adenoma
EP
cells were positive for luteinizing hormone (LH) (n=7), follicle-stimulating hormone (FSH)
AC C
(n=27), or LH and FSH (n=14), or were negative for all anterior pituitary hormones (null cell
adenoma) (n=95). Patients with silent corticotroph, somatotroph, or lactotroph adenomas were
excluded from the present study.
These 143 patients were categorized into three groups as follows: 1) the Total group
(n=65), in which the pseudocapsule was totally removed; 2) the Partial group (n=11), in which
6
Kinoshita
ACCEPTED MANUSCRIPT
7
the pseudocapsule was partially removed; and 3) the Non-removal group (n=67), in which the
RI PT
pseudocapsule was not removed or was found to not exist (or could not be found) during
and/or the authors based on the surgical videos.
The definition of pseudocapsular resection
SC
surgery. The rates of pseudocapsular removal were retrospectively assessed by the surgeon
M AN U
Pseudocapsular resection was defined as the separation of the tumor pseudocapsule
from the normal pituitary gland. The rate of pseudocapsular removal indicated the degree of
pseudocapsule peeled from the normal pituitary gland, not the rate of tumor removal; thus,
TE D
tumor resection in the cavernous sinus was not associated with pseudocapsular resection.
The Non-removal group included some patients with an apparent remnant
EP
pseudocapsule; however, in most of the patients in the Non-removal group, the pseudocapsule
AC C
did not exist or could not be found during surgery.
Endocrinological studies
The basal levels of anterior pituitary hormones and responses to induced
hypoglycemia and the administration of thyrotropin-releasing hormone (TRH) and luteinizing
hormone-releasing hormone (LHRH) were evaluated in 75 of the 143 patients. The remaining
7
Kinoshita
ACCEPTED MANUSCRIPT
8
68 patients, who were older than 65 years of age or who had a history of heart disease or
RI PT
epilepsy, underwent corticotropin-releasing hormone (CRH)- and arginine-loading tests to
evaluate the adrenocorticotropic hormone (ACTH) and growth hormone (GH) axis, rather than
hypoglycemia tests. Pituitary provocation tests were conducted according to the guidelines
SC
established by the Japanese Society for Hypothalamic and Pituitary Tumors.10 Based on the
M AN U
results of the provocation tests, the medical costs of the patients with hypopituitarism (which is
designated as a rare and intractable diseases by the Japan Ministry of Health, Labour and
Welfare) were subsidized from 2009.
TE D
In this present study, a decline in anterior pituitary hormones was defined by the
following conditions: thyroid stimulating hormone (TSH) peak < 8.0 IU/L, prolactin (PRL)
EP
peak < 15.0 µg/L, GH peak < 3.0 µg/L, and cortisol peak < 15.0 µg/dL in response to
AC C
provocation tests. The LH and FSH responses to LHRH were not evaluated because 48 of the
patients in our series had NFPAs that were immunohistochemically-positive for LH and/or
FSH.
Surgical procedures
8
Kinoshita
ACCEPTED MANUSCRIPT
9
Transsphenoidal surgery was performed through one nostril under microscopic and
RI PT
endoscopic observation in all patients. During surgery, extracapsular dissection was attempted
before internal decompression, or pseudocapsular resection was attempted after the internal
decompression of the adenoma (Fig. 1). The pseudocapsule was resected under an oblique view
SC
with a 30° or 70° endoscope. The 70° endoscope was indispensable in the resection of the
M AN U
upper and lateral part of the tumor and pseudocapsule. In the patients in whom the adenoma
showed a great deal of extension at the top of the tumor, spinal drainage was performed prior to
surgery to push down the upper part of the tumor by injecting saline through the drainage tube
TE D
(to increase intracranial pressure). In contrast, after the removal of the tumor, the cavity could
be expanded to confirm that there was no residual tumor or pseudocapsule by draining the
EP
cerebrospinal fluid (CSF). Tumors in the cavernous sinus were removed to the maximum
AC C
possible extent; however, the removal of a tumor from the cavernous sinus was not associated
with the resection of the pseudocapsule from the normal pituitary gland in the present study.
Statistical analysis
All of the statistical analyses were performed using the software package SPSS 16.0
J for Windows software program (SPSS Inc.). The values are expressed as the median. The
9
Kinoshita
ACCEPTED MANUSCRIPT
10
median values were compared using the Mann–Whitney U-test, Kruskal-Wallis test, Fisher’s
RESULTS
M AN U
The background of the patients in the three groups
SC
considered to indicate a statistically significant difference.
RI PT
exact test and the chi-squared test with 95% confidence intervals. P values of < 0.05 were
The characteristics of the patients are listed in Table 1. The patients who underwent
pseudocapsular resection had some biases. Smaller tumors with lower Knosp grades11 were
TE D
more likely to be removed with the pseudocapsule.
The postoperative complications in the three groups
EP
Table 2 shows the number of patients with postoperative complications.
AC C
Intraoperative CSF leakage and temporary diabetes insipidus (DI) was more common in the
Total group; however, there were no significant differences between the groups. There were no
significant differences in the incidence rates of other complications caused by pseudocapsular
resection.
The
incidence
of
a
decline
in
the
anterior
pituitary
hormone
levels
and
10
Kinoshita
ACCEPTED MANUSCRIPT
11
hyperprolactinemia
RI PT
The Partial group was excluded from this analysis, because the number of patients
(n=11) was too small for a statistical analysis. Furthermore, this group included non-uniform
patients with various rates of pseudocapsular resection.
SC
Figure 2 shows the incidence of a decline in the anterior pituitary hormone levels and
M AN U
hyperprolactinemia at the preoperative and three-month postoperative provocation tests.
Preoperatively, a decline in the anterior pituitary hormone levels and hyperprolactinemia were
more likely to be observed in the patients of the Non-removal group because they had larger
TE D
tumors than the patients in the Total group. However, the postoperative change in the incidence
of reduced anterior pituitary hormone levels and hyperprolactinemia was the same in both the
EP
Total and Non-removal groups; after surgery, the incidence rates of reduced ACTH, TSH and
AC C
GH levels were slightly lower, while the incidence of hyperprolactinemia was significantly
reduced (P < 0.01).
The change in the anterior pituitary functions of each patient after surgery
Figure 3 shows that a similar pattern of change was observed in the anterior pituitary
functions after surgery in each of the patients of the Total and Non-removal groups. In a few
11
Kinoshita
ACCEPTED MANUSCRIPT
12
patients, the peak hormone levels declined after surgery (according to our criteria); however, the
RI PT
peak hormone levels improved in a greater number of patients. In the end, the incidence of a
decline in the anterior pituitary hormone levels was lower after surgery in both the Total and
Non-removal groups (Fig. 2). Two patients newly required hormonal replacement after surgery;
SC
one in the Total group and one in the Non-removal group. Both of the patients required
M AN U
1-deamino-8-d-arginine vasopressin (DDAVP) after surgery.
The factors affecting the postoperative anterior pituitary functions
There were 23 patients in whom more than one axis of the anterior pituitary
TE D
hormones was found to have deteriorated after surgery. The clinical features of the 23 patients
are shown in Table 3. No factors affecting the postoperative anterior pituitary functions were
EP
identified (including pseudocapsular total resection). A multiple regression analysis also
AC C
revealed that there was no significant correlation between the performance of pseudocapsular
total resection and the postoperative anterior pituitary functions (Supplemental Table). Although
there were biases with regard to the tumor size and the Knosp grade in each of the groups, these
factors did not have a significant effect on the postoperative anterior pituitary functions.
12
Kinoshita
ACCEPTED MANUSCRIPT
13
DISCUSSION
RI PT
A pseudocapsule is identified in approximately half of pituitary adenomas, and tumor
cell clusters are found in approximately 50% of pseudocapsules.8 Pseudocapsular resection has
been shown to contribute to the endocrinological remission of acromegaly and Cushing
SC
disease.1, 2 The importance of pseudocapsular resection in the removal of functioning pituitary
M AN U
adenomas is well recognized. Thus, it is anticipated that pseudocapsular resection will reduce
the possibility of a tumor remnant and the rate of tumor recurrence in patients with NFPA.8
Although side effects may occur due to the radical removal of tumors during
TE D
pseudocapsular resection in patients with pituitary adenoma, some investigators have reported
the safety of this procedure. The incidence of DI, postoperative CSF leakage and visual
EP
deterioration did not differ between patients undergoing extracapsular resection and those
AC C
undergoing intracapsular resection.7 Moreover, the anterior pituitary function was not
aggravated by pseudocapsular resection.1,
7-9
However, the previous investigations included
patients with GH-producing pituitary adenoma or mixed patients with functioning and clinical
NFPA.1, 7-9 The permissible risk of surgery should differ between patients with NFPA and those
with functioning pituitary adenoma. Furthermore, NFPAs are generally larger than functioning
13
Kinoshita
ACCEPTED MANUSCRIPT
14
adenomas. It is therefore very important to evaluate the safety of pseudocapsular resection in a
RI PT
study population that is restricted to patients with NFPA.
To the best of our knowledge, the present study is the first report to focus on
pseudocapsular resection in NFPAs. The incidence of visual deterioration, postoperative CSF
SC
leakage, permanent DI, postoperative hyponatremia and deterioration of the anterior pituitary
M AN U
function did not differ between the groups that were treated with and without pseudocapsular
resection. We clarified that pseudocapsular resection did not increase the incidence of surgical
complications and did not aggravate the postoperative pituitary functions in patients with NFPA.
TE D
However, intraoperative CSF leakage was likely to occur in the Total group. There is a
possibility that the incidence of intraoperative CSF leakage might have been found to be
EP
significantly high among patients undergoing total pseudocapsular resection if the study had
AC C
included a greater number of patients.
This study aims to clarify the safety of pseudocapsular resection in NFPAs rather
than the rate of tumor recurrence. However, different recurrence rates could be expected in each
of the groups in this study. Three groups were categorized by the resection rate of
pseudocapsule peeled from the normal pituitary gland, not the rate of tumor removal. Thus, all
14
Kinoshita
ACCEPTED MANUSCRIPT
15
of the groups included tumors that invaded the cavernous sinus. All of the groups had the
RI PT
potential for tumor recurrence, and we would expect the recurrence to be high in the Partial
group, because the patients had a pseudocapsule remnant, that could include tumor cells.
Furthermore, the recurrence rate in the Total and Non-removal groups is expected to be the
SC
same, because the Non-removal group mostly consisted of patients without an original
M AN U
pseudocapsule, while the Total group consisted of patients without a remnant pseudocapsule.
When the pseudocapsule can be totally removed in half of patients with pituitary adenoma,
tumor recurrence is expected to depend on the invasion of cavernous sinus, rather than
TE D
pseudocapsular resection. In the present study, it is difficult to evaluate the recurrence rate
because of short follow-up period. Follow-up studies will lead to the clarification of the
EP
relationship between pseudocapsular resection and the rate of recurrence in NFPAs.
AC C
The present study is associated with some limitations. First, this study has some
biases with regard to the patients undergoing pseudocapsular resection: they tended to have
smaller and less invasive tumors. These facts might have affected our results. Second, the rates
of pseudocapsule removal cannot be objectively assessed. The Total group might have included
patients in whom the pseudocapsule was partially removed. However, the surgical procedures in
15
Kinoshita
ACCEPTED MANUSCRIPT
16
the Total group were radically different from those in the Non-removal group. We are of the
RI PT
opinion that a small difference in the removal rates did not greatly affect our results. Third, the
safety of pseudocapsular resection depends on the technical skills of pituitary surgeons. Safe
pseudocapsular resection in large NFPAs requires more skilled techniques than those that are
SC
required for small pituitary adenomas because it is more difficult to resect the pseudocapsule
M AN U
from a stretched normal pituitary gland than from a maldistributed thick normal pituitary gland.
The pseudocapsules in larger adenomas might be discontinuous or disrupted.1,
8
Thus, an
inexperienced surgeon should pay careful attention when resecting the pseudocapsule in patients
EP
CONCLUSION
TE D
with NFPA.
AC C
Pseudocapsular resection did not increase the risk of surgical complications or
aggravate the postoperative pituitary functions in patients with NFPA. Pseudocapsular resection
is expected to contribute to the prevention of tumor recurrence in patients with NFPA.
REFERENCES
16
Kinoshita
ACCEPTED MANUSCRIPT
1.
17
Kawamata T, Kubo O, Hori T. Surgical removal of growth hormone-secreting pituitary
remission of acromegaly. Neurosurg Rev. 2005;28:201-208.
2.
RI PT
adenomas with intensive microsurgical pseudocapsule resection results in complete
Jagannathan J, Smith R, DeVroom HL, Vortmeyer AO, Stratakis CA, Nieman LK, et al.
3.
M AN U
disease. J Neurosurg. 2009;111:531-539.
SC
Outcome of using the histological pseudocapsule as a surgical capsule in Cushing
Ceylan S, Cabuk B, Koc K, Anik I, Vural C. Endoscopic distinction between capsule
and pseudocapsule of pituitary adenomas. Acta Neurochir (Wien). 2013;155:1611-1619.
Prevedello DM, Ebner FH, de Lara D, Ditzel Filho L, Otto BA, Carrau RL.
TE D
4.
Extracapsular dissection technique with the Cotton Swab for pituitary adenomas
EP
through an endoscopic endonasal approach - How I do it. Acta Neurochir (Wien).
5.
AC C
2013;155:1629-1632.
Qu X, Xu G, Qu Y, Song T. The pseudocapsule surrounding a pituitary adenoma and its
clinical significance. J Neurooncol. 2011;101:171-178.
6.
Oldfield EH, Vortmeyer AO. Development of a histological pseudocapsule and its use
as a surgical capsule in the excision of pituitary tumors. J Neurosurg. 2006;104:7-19.
17
Kinoshita
ACCEPTED MANUSCRIPT
7.
18
Qu X, Yang J, Sun J-D, Mou C-Z, Wang G-D, Han T, et al. Transsphenoidal
RI PT
pseudocapsule-based extracapsular resection for pituitary adenomas. Acta Neurochir
(Wien). 2011;153:799-806.
8.
Lee EJ, Ahn JY, Noh T, Kim SH, Kim TS, Kim SH. Tumor tissue identification in the
SC
pseudocapsule of pituitary adenoma: should the pseudocapsule be removed for total
9.
M AN U
resection of pituitary adenoma? Neurosurg. 2009;64:S62-S70.
Kim EH, Ku CR, Lee EJ, Kim SH. Extracapsular en bloc resection in pituitary adenoma
surgery. Pituitary. 2015;18:397-404.
The Japanese Society of Hypothalamic and Pituitary Tumors. The guidelines for
TE D
10.
diagnoses and treatments of diencephalo-hypophysial dysfunction (Japanese); Accessed
Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the
AC C
11.
EP
July 08, 2016.
cavernous sinus space: a magnetic resonance imaging classification compared with
surgical findings. Neurosurg. 1993;33:610-618.
FIGURE LEGENDS
18
Kinoshita
ACCEPTED MANUSCRIPT
19
Figure 1
RI PT
A 50-year-old male underwent preoperative MRI, which showed a heterogeneously
enhanced non-functioning pituitary adenoma on coronal T1-weighted imaging after gadolinium
injection (A). An intraoperative photograph taken under a 70° endoscope showed internal
SC
decompression by the double suction technique on the left lateral wall of tumor cavity (B). After
gland under a 30 °
M AN U
the internal decompression of tumor, the pseudocapsule was resected from the normal pituitary
endoscope. Open triangles indicate the borderline between the
pseudocapsule and the normal pituitary gland (C). Intraoperative CSF leakage occurred after the
TE D
total removal of the tumor and pseudocapsule (arrow head) (D). Postoperative MRI showed no
residual tumor (E), and postoperative pituitary provocation tests demonstrated the normal
AC C
Figure 2
EP
pituitary function of the patient.
A graph showing the incidences of a reduction in the anterior pituitary hormone
levels and hyperprolactinemia (Hyper PRL) at the preoperative and three-month postoperative
provocation tests. The postoperative change in the anterior pituitary function was the same in
both the Total and Non-removal groups.
19
Kinoshita
ACCEPTED MANUSCRIPT
20
Figure 3
RI PT
A graph showing the change in the anterior pituitary functions after surgery in each
patient. The peak hormone levels in the provocation tests declined after surgery in a few patietns,
but improved in a greater number of patients. The Total and Non-removal groups showed a
AC C
EP
TE D
M AN U
SC
similar ratio of patients with improved and deteriorated of anterior pituitary functions.
20
ACCEPTED MANUSCRIPT
Table 1. Patients characteristics Total
Partial
Non-removal
(n = 65)
(n = 11)
(n = 67)
55.0
61.0
61.0
0.37
33 / 32
8 / 3
33 / 34
0.34
21.0
28.0
27.0
< 0.01
1
2
2
< 0.01
Age (years, median) Sex (male/female) Tumor size (mm, median)
AC C
EP
TE D
M AN U
SC
Knosp grade10
RI PT
P Value
ACCEPTED MANUSCRIPT
Table 2. Postoperative complications Total
Partial
Non-removal
(n = 65)
(n = 11)
(n = 67)
26 (40.0)
4 (36.4)
0
0
14 (21.5)
2 (18.2)
9 (13.4)
0.47
1
0
1
> 0.99
Cerebrospinal fluid leakage Intraoperative (%) Postoperative
Permanent Postoperative hyponatremia (Na 135) (%) Visual deterioration Temporary Permanent
Temporary Permanent
AC C
EP
Postoperative hematoma
0.13
1
> 0.99
19 (29.2)
2 (18.2)
21 (31.3)
0.67
0
0
0
> 0.99
0
0
0
> 0.99
1
0
0
> 0.99
0
0
0
> 0.99
0
0
1
> 0.99
TE D
Oculomotor nerve palsy
M AN U
Temporary (%)
16 (23.9)
SC
Diabetes insipidus
RI PT
P Value
ACCEPTED MANUSCRIPT
Table 3. Clinical features of the patients deteriorated postoperative anterior pituitary functions Deterioration No deterioration cases
P Value
(n = 23)
Sex (male/female) Tumor size (mm, median) Knosp grade10
63.0
59.0
0.15
16 / 7
52 / 57
0.07
25.0
23.0
0.21
2
2
0.91
Pseudocapsular total 13 (56.5)
52 (47.7)
M AN U
resection (n, %)
SC
Age (years, median)
RI PT
cases (n = 109)
AC C
EP
TE D
Partial group (n = 11) was excluded in the present analysis.
0.50
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Highlights:
RI PT
Pseudocapsular resection in NF does not increase the risk of surgical complications.
Pseudocapsular resection in NF does not cause the pituitary dysfunctions.
AC C
EP
TE D
M AN U
SC
Safety of pseudocapsular resection in NF is clarified.
ACCEPTED MANUSCRIPT
Supplemental Table. Factors affecting the postoperative anterior pituitary functions OR
95% CI
Age (years)
0.19
1.02
0.99-1.07
Sex
0.12
0.45
Tumor size (mm)
0.08
1.08
Knosp grade
0.46
0.80
Pseudocapsular total resection
0.19
0.50
OR, odds ratio; CI, confidence interval.
SC
10
RI PT
P Value
0.17-1.24 0.99-1.17 0.44-1.44 0.17-1.42
AC C
EP
TE D
M AN U
Partial group (n = 11) was excluded in the present analysis.
ACCEPTED MANUSCRIPT
Abbreviations list: ACTH:
Adrenocorticotropic
hormone,
CRH:
Corticotropin-releasing
hormone,
CSF:
Cerebrospinal fluid, DDAVP: 1-deamino-8-d-arginine vasopressin, DI: Diabetes insipidus, FSH: Follicle-stimulating hormone, GH: Growth hormone, LH: Luteinizing hormone, LHRH:
RI PT
Luteinizing hormone-releasing hormone, MRI: Magnetic resonance imaging, NFPA: Non-functioning pituitary adenomas, PRL: Prolactin, TRH: Thyrotropin-releasing hormone
AC C
EP
TE D
M AN U
SC
TSH: Thyroid-stimulating hormone
ACCEPTED MANUSCRIPT
Disclosure:
AC C
EP
TE D
M AN U
SC
RI PT
We have no financial disclosure and conflicts of interest whatsoever.