J Neurosurg 118:621–631, 2013

©AANS, 2013

Endoscopic endonasal surgery for giant pituitary adenomas:

advantages and limitations
Clinical article
Maria Koutourousiou, M.D.,1 Paul A. Gardner, M.D.,1
Juan C. Fernandez-Miranda, M.D.,1 Alessandro Paluzzi, M.D.,1
Eric W. Wang, M.D., 2 and Carl H. Snyderman, M.D., M.B.A.1,2
Departments of 1Neurological Surgery and 2Otolaryngology, University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania

Object. Giant pituitary adenomas (> 4 cm in maximum diameter) represent a significant surgical challenge. En-
doscopic endonasal surgery (EES) has recently been introduced as a treatment option for these tumors. The authors
present the results of EES for giant adenomas and analyze the advantages and limitations of this technique.
Methods. The authors retrospectively reviewed the medical files and imaging studies of 54 patients with giant
pituitary adenomas who underwent EES and studied the factors affecting surgical outcome.
Results. Preoperative visual impairment was present in 45 patients (83%) and partial or complete pituitary defi-
ciency in 28 cases (52%), and 7 patients (13%) presented with apoplexy. Near-total resection (> 90%) was achieved
in 36 patients (66.7%). Vision was improved or normalized in 36 cases (80%) and worsened in 2 cases due to apo-
plexy of residual tumor. Significant factors that limited the degree of resection were a multilobular configuration of
the adenoma (p = 0.002) and extension to the middle fossa (p = 0.045). Cavernous sinus invasion, tumor size, and
intraventricular or posterior fossa extension did not influence the surgical outcome. Complications included apoplexy
of residual adenoma (3.7%), permanent diabetes insipidus (9.6%), new pituitary insufficiency (16.7%), and CSF leak
(16.7%, which was reduced to 7.4% in recent years). Fourteen patients underwent radiation therapy after EES for re-
sidual mass or, in a later stage, for recurrence, and 10 with functional pituitary adenomas received medical treatment.
During a mean follow-up of 37.9 months (range 1–114 months), 7 patients were reoperated on for tumor recurrence.
Three patients were lost to follow-up.
Conclusions. Endoscopic endonasal surgery provides effective initial management of giant pituitary adenomas
with favorable results compared with traditional microscopic transsphenoidal and transcranial approaches.
(http://thejns.org/doi/abs/10.3171/2012.11.JNS121190)

Key Words      •      cavernous sinus invasion      •      endoscopic endonasal surgery      •

endoscopic skull base surgery      •      giant pituitary adenoma      •
transsphenoidal surgery      •      oncology      •      pituitary surgery

G
iant pituitary adenomas, defined as tumors 4 cm
or greater in maximum diameter, account for
5%–14% of adenomas in surgical series.7,18,27 Be-
cause of their size, invasiveness, and irregular extension,
these tumors represent a significant treatment challenge.
Given these limitations, the degree of radical resection
of giant adenomas is restricted to less that 50% in every
published surgical study and is associated with a higher
complication rate compared with non–giant pituitary ad-
enomas.7,18,27 Additional therapies are usually necessary
to obtain long-term control of tumor growth.7,27 The most
common surgical approaches used for the treatment of
giant pituitary adenomas are the microscopic transsphe-
noidal or various frontal and frontotemporal transcranial
routes.7,18,26,27 Endoscopic endonasal surgery, supported
by recent technological advancements, has been used in-
creasingly over the last decade for the treatment of many
Abbreviations used in this paper: EES = endoscopic endonasal
surgery; GH = growth hormone; GTR = gross-total resection.
extended skull-base tumors.5,6,8,15,19,20,30 In this paper we
describe our experience in the management of 54 giant
pituitary adenomas treated with EES. We analyze the ad-
vantages of using this technique, as well as the variables
that limit the extent of tumor resection.
Methods
Patient Population
After approval by the Institutional Review Board, we
retrospectively reviewed the medical files and imaging
studies of patients with pituitary adenomas treated with
EES at the University of Pittsburgh Medical Center from
June 2002 to May 2011. Of 555 patients who underwent
EES for pituitary adenomas, 54 (9.7%) had tumors that
exceeded 40 mm in maximum diameter. The mean tu-
mor diameter was 50 mm (range 40–90 mm). Patient ages
This article contains some figures that are displayed in color
on­line but in black-and-white in the print edition.

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 M. Koutourousiou et al.

ranged from 18 to 80 years (mean 52.9 years) and there TABLE 1: Clinical presentation of 54 patients with giant pituitary
was a male predominance (85% male). Nonfunctioning adenomas*
pituitary adenoma was the most frequent type (75.9%),
followed by medication-resistant prolactinomas (22.2%) Clinical Presentation No. of Patients (%)
and 1 case of GH-secreting pituitary adenoma (1.9%).
Among the 13 patients with functional giant pituitary visual impairment 45 (83.3)
adenomas, 12 were receiving medical treatment but had pituitary insufficiency 28 (51.8)
shown resistance to pharmaceutical agents, and 3 pre- headache 16 (29.6)
sented with apoplexy and acute neurological symptoms. apoplexy 7 (13)
In total, 16 patients (13 with nonfunctioning pituitary ad- CN palsy 7 (13)
enoma and 3 with prolactinoma) had undergone previous hydrocephalus 6 (11.1)
surgery, either microscopic transsphenoidal surgery or
altered mental status 4 (7.4)
craniotomy; among them, 3 had multiple surgeries and
1 had received additional radiation therapy for a resistant seizures 2 (3.7)
prolactinoma. Only 29 patients (53.7%) had never been DI 2 (3.7)
treated medically or surgically. acromegaly 1 (1.8)

Clinical Presentation *  CN = cranial nerve; DI = diabetes insipidus.

The dominant clinical symptom at presentation was

all cases with erosion of the posterior clinoids. Further
visual impairment affecting visual acuity, the visual field,
or both, and occurred in 45 patients (83.3%; Table 1). intracranial tumor extension was assessed in the sagittal
Partial or complete pituitary insufficiency was evident plane (anterior fossa), coronal plane (middle fossa), axi-
in 28 patients (51.8%), including hypoadrenalism in 17 al plane (posterior fossa), and ventricular system. In 13
(31.5%), hypothyroidism in 20 (37%), hypogonadism in cases (24%) the tumor extended to the frontal lobe; in 14
17 males (35.4%), and GH deficits in 3 (GH levels were cases (25.9%), the tumor that invaded the cavernous sinus
not available preoperatively in every patient). Two pa- eroded the lateral wall of the sinus and extended to the
tients suffered from diabetes insipidus at presentation (1 temporal lobe (Fig. 1); 14 patients (25.9%) had retroclival
after previous transsphenoidal surgery), while 7 patients extension (Fig. 2); and in 23 cases (42.6%) the adenoma
(13%) presented with apoplexy. Seven patients (2 present-
ing with apoplexy and 5 without) suffered from cranial TABLE 2: Imaging characteristics of giant pituitary adenomas
nerve palsies. One patient with a GH-secreting pituitary
adenoma had clinical signs and symptoms of acromegaly. Tumor Characteristic No. of Patients (%)
size (mm)
Tumor Characteristics   40–49 37 (68.5)
Retrospective analysis of MRI studies showed vari-   50–59 10 (18.5)
able tumor shape, pattern of extension, and contrast en-   >60 7 (13)
hancement. Tumor volume was approximated by a modi- shape
fied ellipsoid volume ([A*B*C]/2), where A, B, and C
were the maximum diameters of the adenoma in each of  rounded 15 (27.8)
the 3 dimensions. The average tumor volume was 32.88  dumbbell 6 (11.1)
cm3 (range 11.23–116.68 cm3). Giant pituitary adenomas  multilobular 33 (61.1)
were rounded in shape in 15 cases (27.8%), dumbbell- extension
shaped in 6 (11.1%), and multilobular in 33 (61.1%; Table   ventricular system
2). Regarding tumor location, 53 tumors (98.1%) occupied   intraventricular 23 (42.6)
the sella, 50 (92.6%) extended to the suprasellar region,
and 50 (92.6%) extended to the sphenoid sinus. Cavern-   sagittal plane
ous sinus invasion was evaluated according to the Knosp   sphenoid sinus 50 (92.6)
criteria22 and was confirmed by intraoperative observa-   suprasellar region 50 (92.6)
tion in every case; cavernous sinus invasion was present   frontal lobe 13 (24.1)
in 51 cases (94.4%; unilaterally in 21 cases and bilater-   coronal plane
ally in 30). Among these 51 cases with cavernous sinus   cavernous sinus 51 (94.4)
invasion, 14 (27.5%) showed radiographic invasion of the
lateral wall of the cavernous sinus with tumor extension   temporal lobe 14 (25.9)
toward the ipsilateral middle fossa. Using the Knosp cri-   axial plane
teria, among the total of 108 cavernous sinuses, 12 were   clivus (upper) 54 (100)
classified as Grade 0 (11.1%), 6 were Grade 1 (5.6%), 24   retroclival 14 (25.9)
were Grade 2 (22.2%), 35 were Grade 3 (32.4%), and 31 contrast enhancement
were Grade 4 (28.7%). Grade 4 tumors represent the cases  homogeneous 28 (51.9)
with radiographic evidence of invasion of the lateral wall
of the cavernous sinus. The upper clivus was involved in  heterogeneous 26 (48.1)

622 J Neurosurg / Volume 118 / March 2013

Endoscopic endonasal surgery for giant pituitary adenomas

Surgical Management and Adjuvant Therapies

Fig. 1. Preoperative (A and B) and immediate postoperative (C and
D) T1-weighted MR images obtained in a patient who underwent GTR of
a rounded giant pituitary adenoma with cavernous sinus invasion.  A
and B: Coronal and sagittal images after contrast administration show
a giant (45 mm), rounded, heterogeneous adenoma that invaded the
right cavernous sinus (arrow), extended into the sphenoid sinus, eroded
the upper clivus, and elevated the floor of the third ventricle.  C and
D: Coronal and sagittal images obtained after contrast administration
demonstrate complete resection of the tumor. The invaded cavernous
sinus has been evacuated (C, arrow). The surgical defect was recon-
structed with a vascularized nasoseptal flap (D, arrowheads) that was
held in place with a Foley catheter balloon (D, arrow).
extended to the third (Fig. 2) or lateral ventricle. Intraven-
tricular tumor extension was confirmed intraoperatively
in every case. The tumor showed homogeneous enhance-
ment after contrast administration in 28 patients (51.9%)
and heterogeneous enhancement in 26 (48.1%; Table 2).
All of the patients underwent EES. The goal of sur-
gery was optic apparatus (nerves/chiasm/tract) decom-
pression and the maximum possible safe tumor resection.
Gross-total resection was not possible in the majority of
cases given the size, shape, and extension of the tumor. In
5 patients, we planned a staged approach. Based on the
location and extension of the giant adenoma, we planned
an endoscopic endonasal approach to facilitate the most
rad­ical tumor removal by simultaneously combining
trans­­sel­lar, transtuberculum, transplanum, transcavern-
ous, transpterygoid, and transclival approaches (Table 3).
As part of the initial management, 11 patients (20.4%)
received adjuvant radiation therapy for residual tumor,
including radiosurgery in 8 cases. Three more patients
underwent radiosurgery in a later stage for tumor recur-
rence. Ten patients with functional pituitary adenomas
(9 prolactinomas and 1 GH-secreting pituitary adenoma)
continued to receive medical treatment after surgery.
Evaluation of Surgical Results
Clinical outcome after EES was assessed using post-
operative visual tests (visual acuity and visual fields),
endocrinological studies, and clinical examinations. We
evaluated the degree of tumor resection on postopera-
tive MRI. In most cases, immediate postoperative MRI
was performed within a few days after surgery and used
as a baseline for further imaging follow-up. The degree
of resection was confirmed with 3-month postoperative
MRI in all but 3 patients, who were all lost to follow-
up. The volume of residual adenomas was calculated with
the same mathematical formula ([A*B*C]/2) that was
used for the initial tumor measurement. Cases involv-
ing postoperative linear contrast enhancement, in which
tumor volume could not in fact be measured, were not
considered GTR. Additionally, the absence of tumor on
postoperative MRI had to be accompanied by evidence
of biochemical remission in cases of functional adeno-
mas. Based on these criteria, we conducted a multivari-
able analysis of the degree of tumor resection. In residual

Fig. 2. Preoperative (A) and postoperative (B and C) coronal T1-weighted MR images with contrast enhancement obtained
in a patient who underwent near-total resection of a multilobular giant adenoma with extension to the temporal lobe.  A: Image
showing a giant adenoma (47 mm) with a lobular extension into the sylvian fissure, invasion of the right cavernous sinus, and ex-
pansion of the lateral wall of the cavernous sinus (arrowheads). The pituitary stalk (arrow) is compressed and the normal pituitary
gland is displaced to the left, toward the medial wall of the left cavernous sinus, which is intact.  B: Immediate postoperative
image demonstrates evacuation of the right cavernous sinus with residual tumor at the lateral wall of the sinus and in the sylvian
fissure (arrowheads). The pituitary stalk and normal gland are better visualized.  C: Image obtained 1 year after EES. The
residual tumor has collapsed and minimized (arrowheads) without any adjuvant treatment. The pituitary stalk and normal gland
(arrow) have descended into a more midline position.

J Neurosurg / Volume 118 / March 2013 623


TABLE 3: Variations of endoscopic endonasal approaches that
were performed to achieve maximum possible tumor resection
Endoscopic Endonasal Approach No. of Cases (%)
transsellar 53 (98.1)
transtuberculum 50 (92.6)
transplanum 38 (70.4)
transcavernous 51 (94.4)
transpterygoid 8 (14.8)
transclival 54 (100)
  upper clivus 14 (25.9)
  upper & middle clivus 33 (61.1)
  upper, middle, & lower clivus 7 (13)
tumors, we considered the degree of resection near total
when more than 90% of the tumor was resected and par-
tial for less than 90% resections.
Some patients with pituitary dysfunction do not re-
quire hormone replacement therapy. In an attempt to
maintain strict criteria regarding postoperative endocri-
nological deficit, we determined postoperative pituitary
dysfunction by biochemical examinations and not only by
the need for treatment.
Although optic apparatus decompression rather than
GTR is the goal of surgery in most giant pituitary ad-
enomas, we evaluated the GTR rates of these irregularly
extending, invasive giant tumors in an attempt to under-
stand the advantages and limitations of EES. The tumor
size (< 50 mm, 50–60 mm, > 60 mm), shape (rounded,
dumbbell, multilobular), extension (anterior, middle, pos-
terior fossa, ventricular system), evidence of apoplexy,
and previous treatment (medical or surgical) were studied
as independent factors to evaluate their influence on the
degree of tumor resection when EES is applied.
Statistical Analysis
Patient demographics, clinical presentation, tumor
characteristics, surgical approaches, and outcomes were
analyzed using descriptive statistics. Gross-total resec-
tion rates for every studied tumor characteristic were
compared using the chi-square and Fisher exact tests
within the studied variable. A p value < 0.05 was con-
sidered statistically significant. Data were collected using
Microsoft Excel 2010 (Microsoft Corporation).
Results
Clinical Outcome
Improvement or normalization of vision was achieved
in 36 patients (80%; Table 4). Two patients (3.7%) expe-
rienced visual deterioration due to apoplexy of residual
tumor; 1 of them showed partial recovery after reopera-
tion for evacuation of the hematoma, and the other had a
prolonged stay in the intensive care unit without available
visual follow-up. In 1 patient who presented with visual
impairment, postoperative visual examination was not
available. Twenty-two (78.6%) of 28 patients with pre-
existing pituitary dysfunction remained unchanged after
624
M. Koutourousiou et al.
EES. Only 1 patient recovered from pituitary impair-
ment; he presented with secondary adrenal insufficiency
requiring replacement with hydrocortisone and he was
fully recovered after EES. Five other patients (17.8%) ex-
perienced further deficiency in 1 or more hypothalamo-
pituitary axes (adrenal insufficiency in every case com-
bined with thyroid dysfunction in 3 patients). Preexisting
cranial nerve palsy persisted after surgery in 2 patients
(28.6%) and improved or normalized in every other case,
while headache and altered mental status resolved in the
majority of cases.
Degree of Tumor Resection
Eleven patients (20.4%) underwent GTR (Fig. 1) after
the initial treatment with EES. Although GTR was not
possible in the majority of the cases, near-total (> 90%)
resection was achieved in 36 patients (66.7%), resulting in
a high rate of post-EES visual improvement (80%), which
was the main goal of surgery. Primary giant pituitary ad-
enomas had a better surgical outcome compared with pre-
viously resected tumors (Table 5), but this did not reach
statistical significance (p = 0.144; discussed below). The
more complicated the tumor configuration, the lower the
radical resection rate. More than 90% of rounded giant
pituitary adenomas were resected in 93% of the cases,
with GTR attained in 46.7% (Fig. 1). On the other hand,
GTR for irregular tumor configuration occurred in only
6.1% (Fig. 2). Although the resection rates depend on
multivariate parameters, extreme intracranial tumor ex-
tension was also associated with lower rates of GTR.
To better understand the advantages and limitations
of EES in giant pituitary adenoma resection, we analyzed
the rate of GTR according to tumor size, shape, extension,
evidence of apoplexy, and previous treatment (Table 6).
Tumor size, extension to the ventricular system, extension
to the anterior or posterior fossa, apoplexy, and previ-
ous treatment (surgical or medical) were not limitations
of GTR with EES. Primary tumors had a better surgical
outcome compared with previously treated adenomas, but
there was not a significant difference. On the other hand,
tumor shape, and particularly a multilobular tumor con-
figuration, was the most important factor that limited the
degree of tumor resection. The extension of the adenoma
in the coronal plane (cavernous sinus or even more lateral
to the temporal lobe) was a clear limitation of EES. Com-
paring the degree of GTR between tumors that eroded
only the medial wall of the cavernous sinus (n = 37) and
those that eroded the lateral wall of the cavernous sinus
and extended to the temporal lobe (n = 14), we found that
cavernous sinus invasion in general is not a limitation for
GTR with EES; however, tumor extension lateral to the
intracavernous segment of the carotid artery with expan-
sion or erosion of the lateral wall of the cavernous sinus
represents the real limitation of the endoscopic endonasal
approach. In terms of relating these findings to the well-
described Knosp criteria, complete resection of the tumor
from the cavernous sinus was not possible in any of the
Knosp Grade 4 cases; however, complete evacuation of
the cavernous sinus was achieved in 27 (77.1%) of 35 cav-
ernous sinuses with Grade 3 invasion and in 40 (95.2%)
of 42 with Grade 0–2 invasion.
J Neurosurg / Volume 118 / March 2013
Endoscopic endonasal surgery for giant pituitary adenomas
TABLE 4: Clinical outcome in patients with giant pituitary adenomas following EES

Initial Deficit No. of Patients Resolved Improved Unchanged Worsened

visual impairment* 45 9 (20%) 27 (60%) 6 (13.3%) 2 (4.4%)
pituitary insufficiency 28 none 1 (3.6%) 22 (78.6%) 5 (17.8%)
CN palsy  7 2 (28.6%) 3 (42.8%) 2 (28.6%) none
altered mental status  4 3 (75%) none 1 (25%) none
headache 16 14 (87.5%) none 2 (12.5%) none

*  In 1 patient who presented with visual impairment, postoperative visual examination was not available.

Complications and Management

The most common surgical complication was post-
operative CSF leak, which occurred in 9 patients (16.7%; TABLE 6: Gross-total resection rates according to tumor size,
Table 7). It should be noted that this rate has been reduced shape, extension, evidence of apoplexy, and previous treatment
to 7.4% in recent years with routine use of a vascular-
ized nasoseptal flap for reconstruction. Specifically, after
Tumor Characteristic Total GTR (%) p Value
2006 we had 2 cases of CSF leak among 27 EESs for gi-
ant pituitary adenomas, while in the earlier years the rate size (mm)
of CSF leak was 25.9% (7 cases among 27 EESs). These   40–49 37 8 (21.6) 1.000
CSF leaks were managed with reoperation (EES) alone (n   50–59 10 2 (20)
= 3), lumbar drain placement alone (n = 2), or a combina-
  >60  7 1 (14.3)
tion of EES and lumbar drain placement (n = 4), based on
the surgeon’s judgment and perceived severity and source shape
of the leak. Among these patients, 2 developed meningitis  rounded 15 7 (46.7) 0.002
that was treated with antibiotics without any further clini-  dumbbell  6 2 (33.3)
cal consequence. A third case of postoperative meningitis  multilobular 33 2 (6.1)
occurred in a patient without postoperative CSF leak but extension
with a complicated postoperative course requiring mul-
  ventricular system
tiple surgeries.
Six transient cranial nerve palsies occurred: 2 cases   intraventricular 23 3 (13) 0.319
of left third cranial nerve palsy after postoperative apo-   extraventricular 31 8 (25.8)
plexy of residual tumor and 4 cases of left fourth cranial   anterior fossa
nerve palsy in cases with tumor extension in the cavern-   frontal lobe 13 1 (7.7) 0.261
ous sinus. All of the iatrogenic cranial nerve palsies re-    no anterior fossa 41 10 (24.4)
  middle fossa
TABLE 5: Degree of tumor resection according to previous
treatment, tumor shape, and tumor extension*    no middle fossa  3 1 (33.3) 0.045
  cavernous sinus* 37 10 (27) 1.0, 0.045†
Near-Total Partial   temporal lobe‡ 14 0
No. of GTR Resection Resection   posterior fossa
Tumor Characteristic Patients (100%) (>90%) (<90%)   retroclival 14 2 (14.3) 0.708
previous treatment    no posterior fossa 40 9 (22.5)
 primary 38 10 (26.3) 22 (57.9) 6 (15.8) presentation
  previous surgery 16 1 (6.2) 3 (18.8) 12 (75)  apoplexy  7 3 (42.9) 0.140
tumor shape   w/o apoplexy 47 8 (17)
 rounded 15 7 (46.7) 7 (46.7) 1 (6.7) previously treated
 dumbbell  6 2 (33.3) 3 (50) 1 (16.7)  primary 38 10 (26.3) 0.144
 multilobular 33 2 (6.1) 15 (45.4) 16 (48.5)   previous surgery 16 1 (6.25)
tumor extension   primary w/o medication 29 9 (31) 0.396
 intraventricular 23 3 (13) 12 (52.2) 8 (34.8)   primary w/ medication  9 1 (11.1)
  anterior fossa 13 1 (7.7) 6 (46.1) 6 (46.1) *  Cavernous sinus = invasion of the medial wall of the cavernous sinus
  middle fossa 51 10 (19.6) 23 (45.1) 18 (35.3) only (Knosp criteria and intraoperative observation).
  posterior fossa 14 2 (14.3) 4 (28.6) 8 (57.1) †  p = 1.0 (cavernous sinus vs no middle fossa); p = 0.045 (cavernous
whole cohort 54 11 (20.4) 25 (46.3) 18 (33.3) sinus vs temporal lobe).
‡  Temporal lobe = invasion of the lateral wall of the cavernous sinus
*  All values given as number of cases (%). (radiographic criteria).

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TABLE 7: Complications that occurred after EES*
Complication No. of Patients (%)
CSF leak 9 (16.7)
new pituitary deficit 9 (16.7)
transient CN palsy 6 (11.1)
permanent DI 5 (9.6)
meningitis 3 (5.6)
pulmonary embolism 3 (5.6)
apoplexy of residual adenoma 2 (3.7)
SIADH 2 (3.7)
respiratory failure 2 (3.7)
TIA hemiparesis 1 (1.8)
*  SIADH = syndrome of inappropriate antidiuretic hormone; TIA = tran-
sient ischemic attack.
solved within days or weeks. Interestingly, all of the cra-
nial nerve palsies were on the patients’ left sides.
Postoperative diabetes insipidus was observed in 13
cases, resulting in permanent diabetes insipidus in only 5
(9.6%). Two patients (3.7%) developed syndrome of inap-
propriate antidiuretic hormone that resolved with water
restriction.
At presentation, 26 patients were endocrinological-
ly intact; among them, 4 had evidence of new pituitary
deficit postoperatively (15.4%). Among 28 patients who
presented with some degree of pituitary dysfunction, 5
(17.9%) had additional pituitary deficit postoperatively. In
total, 9 patients had a new pituitary deficit following EES.
All 9 patients developed adrenal insufficiency (24.3%
among 37 patients without a preoperative adrenal defi-
cit). Seven patients experienced new thyroid dysfunction
(20.6% among 34 with preoperative intact thyroid func-
tion). Three male patients showed low testosterone levels
after EES (9.7% among 31 males with normal preopera-
tive testosterone levels) and 2 of them required treatment.
Two patients demonstrated a GH deficit not requiring
treatment (preoperative GH levels were not available in
every patient). Two patients with postoperative apoplexy
of residual adenoma underwent reoperation for hemato-
ma evacuation. Two patients suffered from postoperative
respiratory failure requiring tracheostomy on 1 occasion.
Pulmonary embolism occurred in 3 cases and was treated
with warfarin. One patient developed immediate postop-
erative transient hemiparesis (transient ischemic attack)
that eventually resolved.
During a mean follow-up period of 37.9 months, 6
patients in this cohort died. No deaths occurred in the im-
mediate postoperative period (within 1 month after EES).
Three patients (5.5%) died within 1 year after surgery as
a result of associated complications (hemorrhagic com-
plications of anticoagulation therapy for pulmonary em-
bolus [n = 1], multiple organ failure [n = 1], and respira-
tory failure and meningitis [n = 1]). One additional patient
died due to disease progression 10 months after surgery,
and in 2 cases, death was the result of other medical prob-
lems and happened 28 and 84 months after EES.
626
M. Koutourousiou et al.
Recurrences and Follow-Up
During the mean follow-up period of 37.9 months
(range 1–114 months), 8 patients (14.8%) showed tumor
regrowth and were managed with radiosurgery (n = 1),
repeat EES alone (n = 4), or a combination of EES and ra-
diosurgery (n = 3). In total, 54 patients underwent 66 sur-
gical procedures (EES) and 14 received radiation therapy
as part of the initial management or recurrence treatment.
All the patients who underwent GTR (20.4%) re-
mained free of tumors. Of those with residual tumor, in-
cluding those with recurrences who were further treated,
32 (59.3%) had a stable tumor, 7 (13%) showed decreased
residual volume, and 4 (7.4%) had a recent asymptomatic
increase of residual volume and are being closely moni-
tored during follow-up (Table 8). Although primary giant
adenomas had a higher rate of GTR, and thus remain free
of tumor, a high percentage of recurrent giant adenomas
had stable residual tumor.
Discussion
Giant pituitary adenomas can be extremely challeng-
ing to manage using surgery alone. The use of medical
therapy when indicated, and possibly radiation therapy,
is usually crucial for achieving long-term tumor control.7
Surgery, however, remains the first step in the treatment
of most of these tumors. Recently the use of endoscopes
has been adopted by many pituitary surgeons. Endoscopic
endonasal surgery allows more panoramic visualization
and wider access to the skull base compared with the tun-
nel vision and speculum limitations of the microscopic
transsphenoidal approach.3,8,19,20 Technological advances
such as angled endoscopes, specialized instrumentation,
image guidance, and neurophysiological monitoring of
the brain and cranial nerves are routinely used and have
extended the indications of EES. To our knowledge, this
report of 54 cases is the largest series of giant pituitary
adenomas treated endoscopically.
Goals of Surgery
The main goals of surgery for giant pituitary ad-
enomas are visual improvement, recovery from endo-
crinological and neurological symptoms, and maximal
tumor resection. Unfortunately, the inclusion criteria in
published series regarding tumor size and extension are
usually not specified in detail, and given their variety, the
surgical outcomes are very heterogeneous and not easily
available for comparison. Table 9 summarizes the out-
come of the most detailed surgical series.
Although postoperative visual improvement varies
among published series, it is more likely after transsphe-
noidal than transcranial surgery, with rates of approxi-
mately 80%.2,12,27 In a more recent series that includes
microscopic transsphenoidal approaches (occasionally en-
doscopic-assisted), the postoperative visual improvement
rate reached 81.5%.7 In our series, visual improvement oc-
curred in 36 (80%) of 45 patients with preoperative visual
defect; among these patients, 9 (20%) experienced com-
plete visual recovery postoperatively. Based on this expe-
J Neurosurg / Volume 118 / March 2013
Endoscopic endonasal surgery for giant pituitary adenomas
TABLE 8: Tumor control after management of giant pituitary
adenomas
Decreased Stable Increased
No. of Free of Residual Residual Residual
Adenoma Cases Tumor Volume Tumor Tumor
primary 38 10 (26.3%) 6 (15.8%) 18 (47.4%) 4 (10.5%)
recurrent 16 1 (6.2%) 1 (6.2%) 14 (87.5%) none
total 54 11 (20.4%) 7 (13%) 32 (59.3%) 4 (7.4%)
rience, the EES is at least as effective as transsphenoidal
surgery regarding visual improvement.
Postoperative improvement of hypopituitarism after
surgery for giant pituitary adenomas has not been stud-
ied in detail. The reported hormonal improvement rates
of 35%–50% after transsphenoidal surgery are in refer-
ence to macroadenomas and cannot be applied to giant
pituitary adenomas, in which hypopituitarism is usually
long-standing and more difficult to be corrected after sur-
gery.14,28,29 de Paiva Neto et al.7 reported that 22.5% of
giant pituitary adenomas treated with the microscopic-
or endoscopic-assisted transsphenoidal approach showed
resolution of at least 1 anterior pituitary hormone defi-
ciency. In our experience, only 1 patient with preexist-
ing hypoadrenalism (3.6%) recovered after EES, while
in 22 (78.6%) the pituitary function remained unchanged
after surgery. Given that some patients with giant adeno-
mas had undergone previous surgeries or even radiation
therapy and most of them presented for urgent treatment,
hormonal data are often incomplete for full evaluation.
Although there are no reported results in previous
studies regarding the improvement of ophthalmoplegia
after surgery for giant pituitary adenomas, our technique
was very successful, achieving 71.4% improvement of
preexisting cranial nerve palsies. Among 7 patients with
cranial nerve palsies, 2 (28.6%) showed complete recov-
ery after surgery. This may be a consequence of improved
access and visualization of the lateral cavernous sinus
and the use of intraoperative electromyographic monitor-
ing of extraocular nerves.
It is generally accepted that complete removal is un-
likely in giant pituitary adenomas.2,7,27,33 Once again, the
data reported in the literature regarding the rates of GTR
are variable. Mortini et al.,27 in a very detailed report of
their experience, found a GTR rate of 14.7% using mostly
microscopic transsphenoidal surgery. Other authors have
reported GTR rates of 29.65% or 41%, but it is unclear if
these patients were evaluated using the same criteria.7,18
We consider a surgery to be GTR only when there is the
absence of any hint of residual tumor on postoperative
MRI and resolution of hypersecretory symptoms in cases
of functional pituitary adenomas. Using these criteria,
the overall GTR with EES was 20.4%. However, this rate
was significantly different for different tumor configura-
tions (p = 0.002); for rounded adenomas the GTR rate
was 46.7%, for dumbbell-shaped the rate was 33.3%, and
the rate was only 6.1% for multilobular tumors (Fig. 3).
Gross-total resection of giant pituitary adenomas was de-
pendent on multiple factors, and the overall low resection
rates confirm the difficulty in their management.
Surgical Approaches and Limitations
Transcranial and Microscopic Transsphenoidal Sur-
gery. The transsphenoidal approach involves fewer com-
plications than transcranial procedures and represents
the first choice in the surgical treatment of giant adeno-
mas.7,11,27 Cavernous sinus invasion is one of the main lim-
itations that precludes complete tumor resection.7,10,13,18,27
Age, type of adenoma, maximum tumor diameter, degree
of suprasellar extension, retrosellar expansion, ethmoidal
and nasal involvement, history of previous pituitary sur-
gery, and type of surgery do not affect surgical outcome
with the transsphenoidal approach.27 However, dumbbell-
shaped tumors or irregular adenomas and tumor extension
into the subfrontal region, retrochiasmatic area, temporal
region, or posterior fossa are considered contraindications
for transsphenoidal surgery, and most authors suggest a
transcranial approach for these cases.2,27,32,33 Thus, the
transcranial route is usually adopted as a second choice if
the transsphenoidal approach is not indicated or has failed
to achieve the desired results, or when a residual suprasel-
lar adenoma does not descend and is considered fibrotic
following transsphenoidal surgery.
Endoscopic Endonasal Surgery. Although cavernous
sinus invasion is the main limitation of open and micro-

TABLE 9: Summary of the most recently published surgical series of giant (>4 cm) pituitary adenomas*

No. of Surgical Postop Visual Outcome Postop New Endocrinopathies Perioperative

Authors & Year Patients Approach GTR Improvement Worsening Hypopituitarism DI† Mortality
Mortini et al., 2007 95 TSS & transcranial 14 (14.7%) 59 (74.7%) 5 (4.5%) 15 (13.5%) 11 (9.9%) 3 (2.7%)
de Paiva Neto et al., 51 TSS & endoscopic as- 21 (41.1%) 31 (81.5%) 0 (0%) 7 (14.6%) 5 (10.4%) 0 (0%)
 2010  sisted
current series 54 EES 11 (20.4%) 36 (80%) 2 (3.7%)‡ 9 (16.7%) 5 (9.6%) 0 (0%)

*  Comparison is difficult because most of the authors did not use a single surgical technique, the location and/or extension of the tumor varied widely,
and outcome was not always evaluated using the same criteria. For example, Mortini et al. evaluated their surgical complications among the number of
surgeries performed (n = 111) and not among patients (n = 95), so their reported results underestimate the true number of complications. Abbreviation:
TSS = transsphenoidal surgery (microscopic).
†  Lasting over 3 months postoperatively.
‡  Transient due to apoplexy of residual tumor.

J Neurosurg / Volume 118 / March 2013 627


Fig. 3.  Bar graph showing resection rates after EES according to the shape of the giant pituitary adenoma. The degree of
GTR was gradually reduced as the tumor shape became more irregular. The GTR rate was 47% in rounded giant adenomas,
33% in dumbbell adenomas, and only 6% in multilobular tumors. Accordingly, partial resection increases in more demanding
tumor shapes.
scopic transsphenoidal approaches, resulting in a GTR
rate as low as 9.6%,7,18,27 this was not a significant limita-
tion with EES. In our experience, with wider exposures
and angled endoscopes, invasion of the medial wall of the
cavernous sinus does not restrict tumor resection. This
is exemplified by compete evacuation of the cavernous
sinus in 27 (77.1%) of 35 cavernous sinuses with Knosp
Grade 3 invasion and in 40 (95.2%) of 42 with Grade 0–2
invasion. The limitation of EES is invasion of the lateral
wall of the cavernous sinus and extension of the tumor to
the temporal lobe. In fact, it is not the extreme lateraliza-
tion of the tumor that prohibits resection, but the natural
boundary of the cranial nerves at the lateral wall of the
cavernous sinus. As a result of a dogmatic respect for this
boundary, no cases of Knosp Grade 4 invasion underwent
complete removal. In such a case, any midline approach is
inadequate to achieve GTR and this part of the tumor can
only be approached with an open craniotomy. It is rare
that this lateral component is significant or symptomatic
enough to warrant resection, even in the setting of post-
operative apoplexy. This is illustrated in this series where
no adjuvant transcranial approaches were used or found
to be necessary for long-term tumor control.
Multilobular giant adenomas, especially when they
extended far into the anterior fossa, were the most sig-
nificant limitation of EES (p = 0.002). In lobular tumors
there is no wide communication between the intra- and
suprasellar tumor components (Fig. 4), and the residual
adenoma of the frontal lobe is unlikely to descend into a
more accessible region. In this case, GTR can be achieved
with a combined endonasal/transcranial approach or pos-
sibly with a staged endoscopic endonasal approach after
several months.1
Retrochiasmatic extension of the tumor and expan-
sion into the ventricular system is considered a contra-
indication for microscopic transsphenoidal surgery.2,33
628
M. Koutourousiou et al.
However, intraventricular tumor extension does not pro-
hibit complete resection with EES. The panoramic visu-
alization and wide exposure provided by the endoscopic
endonasal approach enables safe tumor resection from
the retrochiasmatic area through the natural corridor cre-
ated by the tumor (Fig. 5). The endonasal route is the only
one that provides a direct access into the long axis of the
tumor.
Tumor extension to the posterior fossa could be an
indication for an open approach.1 With the transclival en-
doscopic endonasal approach, this part of the adenoma
can easily be accessed and removed (Fig. 6). Intraopera-
tive image guidance and neurophysiological monitoring
of the brainstem and abducens nerve facilitate accurate
tumor localization and prevent neurological damage.
Other variables, such as tumor apoplexy at presenta-
tion, can be consistently favorable in pituitary surgery. In
the present series, apoplexy was associated with a favor-
able surgical outcome without, however, being a signifi-
cant factor for GTR. This finding has been reported, and
it is considered that extensive necrotic and hemorrhagic
changes of the pituitary adenoma may facilitate complete
removal.24 In addition, the tumor may have been largely
or completely infarcted, leading to good long-term radio-
graphic outcomes. Finally, previous treatment may influ-
ence the degree of tumor resection in giant adenomas to a
small degree, as previously noted.27
Surgical Complications
In general, giant pituitary adenomas have a higher
surgical complication rate, highlighting the difficulty of
their treatment. The most common complication of EES
was postoperative CSF leak (16.7%) necessitating reop-
eration and/or lumbar drain placement. This complication
rate was even higher (25.9%) during the early years of
our experience. After routine adoption of the vascular-
J Neurosurg / Volume 118 / March 2013
Endoscopic endonasal surgery for giant pituitary adenomas

Fig. 4. Preoperative (left) and postoperative (right) sagittal T1-

weighted MR images after contrast administration obtained in a patient
who underwent near-total resection of a lobular adenoma with narrow
communication between the tumor components.  Left: Image show-
ing a giant adenoma with the upper lobular part almost separated from
the main mass of the adenoma.  Right: Image obtained 3 years after
EES illustrating a small residual tumor in front of the intact pituitary stalk
that represents a remnant of the upper tumor lobe that descended to
this location. The residual tumor remained stable in size over the years,
so no attempt was made to remove it.

ized nasoseptal flap for reconstruction, the CSF leak rate Fig. 5. Preoperative (A and B) and postoperative (C and D) coro-
was reduced to 7.4%.21,34 However, this rate is still high nal and sagittal T1-weighted MR images after contrast administration,
compared with CSF leaks after routine transsphenoidal obtained in a patient who underwent near-total resection of a giant ad-
surgery,7,27 likely due to wider exposures and more exten- enoma with intraventricular extension and a growth pattern that cre-
sive arachnoid dissection. ates the corridor to the ventricular system.  A and B: Images showing
Worsening of pituitary function occurred in 16.7% a lobular giant adenoma with extension into the third and right lateral
of patients after EES, which is comparable to new en- ventricle (with obstruction and disfiguration of the lateral ventricle) and
the prepontine cistern. The tumor’s growth pattern forms a prefixed op-
docrinopathy after microscopic transsphenoidal surgery tic chiasm (arrow) that allows tumor resection without manipulation of
and lower than new pituitary dysfunction after transcra- the optic apparatus.  C and D: Images obtained 24 months after EES
nial surgery.2,7,27 Postoperative loss of pituitary function demonstrate near-total resection of the tumor. Residual tumor is visual-
is generally more common in transcranial pituitary sur- ized at the anterior wall of the third ventricle, while the optic chiasm
gery.2 (arrows) is completely decompressed and the lateral ventricles have
Diabetes insipidus is also more common following returned to a more normal shape.
transcranial than transsphenoidal surgery for giant adeno-
mas.2,27 In transsphenoidal series, the reported incidence
of permanent postoperative diabetes insipidus is 8.2%27
and 10.4%.7 With the endoscopic endonasal approach,
permanent postoperative diabetes insipidus occurred in
9.6%, similar to the transsphenoidal experience.
Postoperative visual deterioration is also more com-
mon after transcranial than transsphenoidal surgery and
can be as high as 22%.11,27 In our series, we counted 2
cases (3.7%) of transient postoperative visual deteriora-
tion that occurred after apoplexy of residual adenoma.
Residual adenomas are more prone to hemorrhage with
resultant clinical deterioration. As a result, intrasellar
hemorrhage may occur during the early postoperative
period after the removal of an adenoma, which is more
common after partial resection of giant pituitary adeno-
mas.4,17,23
Postoperative cranial nerve dysfunction is a frequent Fig. 6. Preoperative (left) and postoperative (right) coronal T1-
complication after transcranial surgery for tumors in- weighted MR images after contrast administration, obtained in a pa-
volving the cavernous sinus, and it affects the oculomo- tient who underwent GTR of a rounded, giant pituitary adenoma that
tor nerve most often.9 Permanent ophthalmoplegia has eroded the entire clivus and extended to the posterior fossa.  Left:
Image demonstrating a giant (54 mm) adenoma (prolactinoma) that
not been reported in large transsphenoidal series of giant occupied the sphenoid sinus, eroded the clivus, and contacted the
pituitary adenomas and did not occur in our patient se- pons.  Right: Image obtained 7 months after EES showing GTR of
ries.7,27 However, we had 6 cases (11%) of transient post- the tumor. The pons is decompressed and the pituitary stalk is well
operative cranial nerve palsies that resolved after days or visualized, although the pituitary gland is difficult to distinguish from the
weeks; 2 developed after apoplexy of residual adenoma enhancing vascularized nasoseptal flap (arrowheads).

J Neurosurg / Volume 118 / March 2013 629


and 4 due to dissection of tumor from the cavernous si-
nus. Interestingly, all of the cranial nerve palsies were
on the left side. Further studies are necessary to assess
whether handedness of the surgeon is a potential limita-
tion or risk factor during EES.
Other complications such as syndrome of inappropri-
ate antidiuretic hormone, hydrocephalus, pulmonary em-
bolus, or cerebral ischemia may occur after transcranial
or transsphenoidal surgery (microscopic or endoscopic)
and are not correlated directly with the surgical approach.
Mortality rates after surgery are higher in giant pituitary
adenomas compared with non–giant adenomas and range
from 3.2% to 18.7%.16,25,27,31 One of the leading causes of
postoperative death is apoplexy of the residual adenoma.4
In our experience, there were no immediate postoperative
deaths, but 3 patients (5.5%) died within 1 year after sur-
gery due to multiple subsequent complications.
Conclusions
Multiple factors influence the surgical outcome of
giant pituitary adenomas. The treatment of these tumors
can be difficult to standardize and should be tailored to
individuals. Although long-term disease control may ne-
cessitate the use of adjuvant treatments, the initial man-
agement of giant adenomas is maximum resection. Endo-
scopic endonasal surgery has been used in recent years
and enables tumor resection from the cavernous sinuses,
intraventricular system, and retroclival region. The true
limitations of this approach are a multilobular configura-
tion of the adenoma and extension beyond the lateral wall
of the cavernous sinus. With the exception of increased
CSF leak rates that continue to decline with the use of
vascularized nasoseptal flap reconstruction, the compli-
cations of EES are equal to, if not less than, the reported
surgical complications of other approaches for these ex-
tremely challenging tumors.
Disclosure
The authors report no conflict of interest concerning the mate-
rials or methods used in this study or the findings specified in this
paper.
Author contributions to the study and manuscript preparation
include the following. Conception and design: Koutourousiou.
Acquisition of data: Koutourousiou. Analysis and interpretation of
data: Koutourousiou. Drafting the article: Koutourousiou. Critically
revising the article: all authors. Reviewed submitted version of
manuscript: all authors. Approved the final version of the manuscript
on behalf of all authors: Gardner. Study supervision: Gardner.
Acknowledgments
The authors thank Yue-Fang Chang, Ph.D., Research Assistant
Professor, Department of Neurosurgery, University of Pittsburgh
Medical Center, for the statistical analysis of the surgical results. The
authors also wish to thank Dr. Amin B. Kassam, Division of Neuro-
surgery, University of Ottawa, Ontario, Canada, and Dr. Daniel M.
Prevedello, Department of Neurological Surgery, and Dr. Ricardo L.
Carrau, Department of Otolaryngology-Head & Neck Surgery, The
Ohio State University Medical College, Columbus, Ohio, for their
involvement in the clinical and operative management of many of
these patients.
630
M. Koutourousiou et al.
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Manuscript submitted June 14, 2012.
Accepted November 28, 2012.
Portions of this work were presented in abstract form at The
North America Skull Base Society 22nd Annual Meeting, Las
Vegas, Nevada, February 2012; the 6th International Congress of
the World Federation of Skull Base Societies and the 10th European
Skull Base Society Congress, Brighton, United Kingdom, May
2012.
Please include this information when citing this paper: pub-
lished online January 4, 2013; DOI: 10.3171/2012.11.JNS121190.
Address correspondence to: Paul A. Gardner, M.D., Department
of Neurosurgery, UPMC Presbyterian, 200 Lothrop Street, Suite
B400, Pittsburgh, Pennsylvania 15213. email: gardpa@upmc.edu.
631