CLINICAL STUDIES

RESULTS OF TRANSSPHENOIDAL SURGERY IN A LARGE

SERIES OF PATIENTS WITH PITUITARY ADENOMA
Pietro Mortini, M.D.
Pituitary Unit,
Department of Neurosurgery,
Istituto Scientifico San Raffaele,
Università Vita-Salute, Milan, Italy
Marco Losa, M.D.
Pituitary Unit,
Department of Neurosurgery,
Istituto Scientifico San Raffaele,
Università Vita-Salute, Milan, Italy
Raffaella Barzaghi, M.D.
Pituitary Unit,
Department of Neurosurgery,
Istituto Scientifico San Raffaele,
Università Vita-Salute, Milan, Italy
Nicola Boari, M.D.
Pituitary Unit,
Department of Neurosurgery,
Istituto Scientifico San Raffaele,
Università Vita-Salute, Milan, Italy
Massimo Giovanelli, M.D.
Pituitary Unit,
Department of Neurosurgery,
Istituto Scientifico San Raffaele,
Università Vita-Salute, Milan, Italy
Reprint requests:
Pietro Mortini, M.D.,
Department of Neurosurgery,
Istituto Scientifico San Raffaele,
Via Olgettina 60,
20132 Milano, Italy.
Email: mortinone@yahoo.com
OBJECTIVE: To report the efficacy and safety of microsurgical transsphenoidal surgery
in a series of previously untreated patients with pituitary adenoma.
METHODS: One thousand one hundred forty consecutive patients undergoing trans-
sphenoidal resection of a pituitary adenoma at our department from January 1990
through December 2002 were included in our study. Postoperative results were
classified uniformly during the period of the study. Patients were considered in
remission of disease when strict hormonal and radiological criteria of cure were met.
RESULTS: The most frequent tumor type was clinically nonfunctioning adenoma (NFPA)
(33.2%), followed by growth hormone-secreting adenoma (28.1%), adrenocorticotropin-
secreting adenoma (23.0%), prolactin-secreting adenoma (13.2%), and last, thyrotropin-
secreting adenoma (2.5%). The patient population was 59.7% female and 40.3% male. Mean
age was 43.0 ⫾ 0.4 years. There were 788 macroadenomas (69.1%), and in 233 patients
(20.4%), the tumor invaded one or both cavernous sinuses. The overall rate of early surgical
success was achieved in 504 (66.1%) of the 762 patients with a hormone-active adenoma.
Surgical outcome was better in patients with microadenomas than in patients with macroad-
enomas (78.9% and 55.5%, respectively), whereas tumors invading the cavernous sinus had a
poorer outcome (7.4%). In patients with NFPA, no residual adenoma was present in 234
patients (64.8%). Normalization of visual defects occurred in 117 (40.5%) of the 289 patients
with visual disturbances and improved in another 148 patients (51.2%). Three patients (0.3%)
died as a consequence of surgery.
CONCLUSION: Transsphenoidal surgery is an effective and safe treatment for most
patients with pituitary adenoma and could be considered the first-choice therapy in all
cases except for prolactinomas responsive to dopamine agonists. Other treatment
methods, such as radiotherapy, stereotactic radiosurgery, and medical therapy, play an
important role in patients not cured by surgery.
KEY WORDS: Pituitary adenoma, Transsphenoidal surgery
Neurosurgery 56:1222-1233, 2005 DOI: 10.1227/01.NEU.0000159647.64275.9D www.neurosurgery-online.com

P
ituitary adenomas, which account for ap-
Received, February 10, 2004. proximately 10 to 15% of all intracranial
Accepted, February 7, 2005. tumors in surgical series, usually are clas-
sified according to their secretory activity as
growth hormone (GH)-secreting adenomas,
prolactin (PRL)-secreting adenomas, adrenocor-
ticotropin (ACTH)-secreting adenomas, thyro-
tropin (TSH)-secreting adenomas, and clinically
nonfunctioning pituitary adenomas (NFPA).
Clinical manifestations of pituitary adenomas
are the result of excess hormone secretion (acro-
megaly, hyperprolactinemia, hypercortisolism,
hyperthyroidism) and/or to compression of the
surrounding structures (hypopituitarism, head-
ache, visual disturbances, oculomotor palsy).
The aim of treatment of pituitary adenomas is
reversal of endocrine dysfunction with preser-
vation of normal pituitary function. Moreover,
decompression of the nervous structures and
control of tumor growth become increasingly
important when large tumors are considered.
Therapeutic options in patients with pituitary
adenomas include surgery, radiotherapy, and
medical treatment. The choice of the more ap-
propriate treatment in the individual patient
rests mainly on tumor type, age, and clinical
status of the patient (23).
Microsurgical removal is the preferred ther-
apy for all pituitary adenomas, except for pro-
lactinomas, which are usually well controlled

1222 | VOLUME 56 | NUMBER 6 | JUNE 2005 www.neurosurgery-online.com


by chronic medical therapy with dopamine agonists (21, 47).
The transsphenoidal approach usually is preferred because of
a lower risk of complications, whereas only few adenomas
with prevalent suprasellar extension are approached through
a transcranial route (23, 29, 73). Because of the continuing
refinement of the criteria of cure, it is essential to reexamine
the results of surgery in recently operated patients. The aim of
our study was to report the efficacy and safety of transsphe-
noidal surgery in a large series of patients with pituitary
adenoma operated in the last decade.
PATIENTS AND METHODS
From January 1990 through December 2002, 1313 transsphe-
noidal microsurgical procedures were performed by two of us
(PM and MG) in patients with pituitary adenoma. We report
in this study only the results pertaining to 1140 previously
nonoperated patients, because indications for and results of
repeated surgery may differ considerably from those of pa-
tients who have not previously undergone surgery. Prospec-
tively recorded data included age at operation, sex, symptoms
at presentation, history and effectiveness of previous drug
therapy, hormonal data, and complications of surgery. Mag-
netic resonance imaging (MRI) was performed on all but seven
patients at the time of diagnosis. MRI was not performed
because of claustrophobia in two patients, the presence of
magnetic surgical material from previous surgery in three
patients, and placement of a pacemaker for heart disease in
two patients. In these seven patients, a high-resolution com-
puted tomographic (CT) scan of the hypothalamic-pituitary
region was performed. Maximum tumor diameter was mea-
sured on the preoperative MRI or CT scan. Tumors were
classified as invasive into the cavernous sinus according to
Grade III and IV of the classification proposed by Knosp et al.
(34). Long-term information for patients not followed up at
our center was obtained by directly contacting the patient, the
patient’s endocrinologist, or the referring physician by tele-
phone. We collected information particularly on complica-
tions related to surgery and last determination of hormone
levels, last neuroimaging examination, current or past use of
hormonal substitution therapy, and further treatment for pi-
tuitary adenoma, if needed. Hypogonadotropic hypogonad-
ism was diagnosed in premenopausal women with amenor-
rhea and in men with subnormal T levels. Low or normal
gonadotropin levels were required in both cases. Secondary
hypothyroidism was diagnosed in patients with low free T4
levels and normal or suppressed TSH concentrations. Second-
ary hypoadrenalism was diagnosed in patients with low 24-
hour free urinary cortisol levels, low morning cortisol levels,
and/or clinical symptoms of hypoadrenalism responding to
replacement therapy with glucocorticoids. Postoperative dia-
betes insipidus was diagnosed when hypotonic polyuria (⬎40
ml/kg body weight daily) ensued after surgery and lasted for
at least 3 months. Hyponatremia was defined as the occur-
rence of serum Na⫹ levels less than 132 nmol/L.
NEUROSURGERY
SURGICAL THERAPY OF PITUITARY ADENOMAS
Hormone concentrations on referral as well as those during
follow-up were measured at a large number of laboratories
that use different assay kits. During the period covered by this
study, histopathological diagnosis was based on hematoxylin
and eosin-stained sections and immunocytochemical charac-
terization of secretory activity, using commercially available
antisera as previously described (37).
Surgical Technique
Under general anesthesia, a lumbar needle is placed on
lateral decubitus before the operative positioning is reached.
This is carried out in every patient to allow both the intraop-
erative drainage of cerebrospinal fluid and the injection of air
into the subarachnoid space.
The patient is placed in the supine position on the operative
table (OPT, Trento, Italy) with the back elevated to 30 degrees
and the head tilted back to 20 degrees and toward the left
shoulder 25 degrees. The surgeon is placed on the right side of
the patient. The intraoperative radiofluoroscopy or neuronavi-
gation systems are not adopted.
The skin of the face, the nostrils, and the buccogingival
junction are disinfected with a iodinated solution. A 10-ml
solution of mepivacaine and adrenaline (20 mg/ml; Mepifo-
ran; Baxter, Glendale, CA) is injected bilaterally at the caudal
end of the nasal septum and at the buccogingival junction to
allow analgesia and to facilitate dissection of the nasal
mucosa.
A microscope is used at the beginning of surgery. The upper
lip is gently retracted superiorly. A transverse 2-cm incision is
made at the buccogingival junction crossing the midline sym-
metrically. Care is given to incise the mucosa quite far from
the gingival border to avoid postoperative gingival retraction.
The mucosa is elevated from the maxilla subperiosteally until
the nasal spina and the inferior border of the pyriform aper-
ture are exposed. The nasal spina is left in place to avoid
postoperative downward displacement of the tip of the nose.
The septal cartilage is detached from the nasal spina and a
subperichondrial blunt dissection is carried out to develop a
septal submucosal unilateral tunnel. The dissection is contin-
ued using a Killian nasal speculum and a blunt suction tube.
The entire left side of the nasal septum is exposed back to the
perpendicular plate of the ethmoid, which forms the bony part
of the septum. The cartilaginous portion of the septum is
dislocated and deflected to the right. A longer nasal speculum
is introduced, and the blunt dissection is continued.
The bony nasal septum then is dissected free from the
mucosa bilaterally. The rostrum sphenoidale is exposed. A
large piece of the bony septum is removed and preserved in
antibiotic solution for the sellar closure; however, its lower
part is spared to have a midline landmark in case of reopera-
tion for recurrence. In case of septal deviation, which is very
frequent in acromegaly, this step of surgery treats the unilat-
eral nasal obstruction often reported by patients.
The self-retracting Cushing-Landolt pituitary speculum is
inserted and is opened gently. The anterior wall of the sphe-
VOLUME 56 | NUMBER 6 | JUNE 2005 | 1223
MORTINI ET AL.
noid is opened widely using a drill. The intrasphenoidal mu-
cosa and the septa are removed. The sellar wall is identified. In
case of nonpneumatized sphenoid sinus—the so-called con-
chal type—this is carried out starting from the upper half of
the rostrum by gently drilling through the cancellous bone to
find the compact bone of the sellar wall, which has a charac-
teristic shape.
The sellar floor is opened widely by using both a drill and
a Kerrison punch. The dura is opened in a book page shape
and is reflected inferiorly. The removal of the tumor is carried
out using ring curettes, grasping forceps, and dissectors. In
case of macroadenomas with suprasellar extension, the air can
be injected through the lumbar needle into the subarachnoid
space to push the suprasellar tumor down into the sella. After
the removal of large macroadenomas and completion of he-
mostasis, the inspection of the intrasellar space is carried out
using a rigid endoscope 4-mm in diameter with 0- and 30-
degree lenses (Karl Storz, Tuttlingen, Germany).
The closure of the sella is performed in different ways
according to the dimension of the adenoma removed. In the
cases of microadenomas and intrasellar macroadenomas, a
sleeve of bovine pericardium (Tutopach; Tutogen Medical
GmbH, Neukirchen, Germany) is placed under the bony bor-
der of the sellar opening. A fragment of bone from the nasal
septum is tailored and is placed superficially to the dural
patch and is kept in place by inserting it under the bony
borders of the sellar opening. The fibrin glue (Tissucol; Baxter
Corp.) then is applied.
In cases of macroadenomas with suprasellar extension, the
diaphragma sellae must be reconstructed using a sleeve of
bovine pericardium attached to the suprasellar cisterns by
fibrin glue and be reflected anteriorly to close the opening of
the sellar dura. A tailored bony fragment then is placed close
to the sellar wall as described above. The fibrin glue then is
applied. An antibiotic solution of rifamycin (250 mg; Rifocin;
Lepetit S.p.A, Lainate, Milan, Italy) is left in the sphenoid
sinus after washing with peroxide and saline solution. When a
small intraoperative cerebrospinal fluid (CSF) leak occurs, 20
to 30 ml of CSF are drained through the lumbar needle during
the diaphragma sellae reconstruction and the sellar closure. If
a considerable CSF leak occurs, the same amount of CSF
described above is drained through the lumbar needle, but at
the end of surgery, a lumbar CSF external diversion is placed
to drain 150 ml/24 h daily for 5 days. In this case, the antibiotic
prophylaxis with 2 g/d ceftriaxone (Rocephin; Roche, Milan,
Italy) is administered after surgery for 6 days. Bilateral ante-
rior nasal packing is performed, having pushed the septal
mucosa medially to cover the residual bony and cartilaginous
septum, which is placed on the midline in the primitive loca-
tion, and having enlarged the sphenoidal mucosal ostia to
avoid the formation of a postoperative mucocele. The nasal
packing is carried out under microscopic view using two soft
standard nasal dressings (Merocel; Medtronic Xomed Surgical
Products, Jacksonville, FL). Care is given to avoid displace-
ment of the turbinates. Rifamycin solution is applied to soak
the nasal dressing after it has been introduced in the nasal
1224 | VOLUME 56 | NUMBER 6 | JUNE 2005
cavities. The sublabial wound then is sutured with absorbable
thread (Safil Quick; Braun, Tuttlingen, Germany). The patient
is awakened immediately and sent to the recovery room for 2
hours. After the neurological function and vital parameters
have been checked, the patient is sent back to the neurosur-
gical ward.
Perioperative Management
On the day of surgery, patients receive glucocorticoid cov-
erage with 100 mg hydrocortisone intramuscularly 1 hour
before, during, and 6 hours after surgery. On the first postop-
erative day, patients receive 4 mg methylprednisolone by
mouth thrice daily; on the second and third postoperative
days, they receive 4 mg methylprednisolone twice daily, and
then they receive 4 mg methylprednisolone in the morning.
For patients with Cushing’s disease, glucocorticoid replace-
ment therapy usually is stopped on the fourth postoperative
day to allow early testing of ACTH and cortisol secretion.
Postoperative pain usually is controlled by intravenous ad-
ministration of nonsteroidal anti-inflammatory analgesics.
Oral intake of fluids is allowed 6 to 8 hours after surgery,
whereas food is resumed the day after surgery. The 24-hour
intake and output of fluids is monitored until discharge. Each
day, serum Na⫹, K⫹, osmolality, and 24-hour urinary osmo-
lality are measured. No prophylactic antibiotics are given,
except when indicated by the presence of concomitant medical
conditions, such as heart valvular disease and mitral valve
prolapse, or the placement of a lumbar CSF external diversion.
Criteria of Cure
Postoperative results were classified uniformly during the
period of the study. Patients were considered in remission of
disease when the following criteria were met:
1) GH-secreting adenoma. Basal or oral glucose tolerance
test-suppressed GH less than 1 ␮g/L (or 2 ␮g/L until 1994
when a radioimmunoassay not specific for the 22-K moiety of
GH was still in use) and normalization of elevated insulin-like
growth factor 1 levels.
2) PRL-secreting adenoma. Normalization of basal PRL lev-
els (⬍20 ␮g/L in women and ⬍15 ␮g/L in men) without
dopaminergic therapy for at least 2 months.
3) ACTH-secreting adenoma. Presence of hypocortisolism
requiring glucocorticoid substitution therapy or, in the case of
normal serum and urinary cortisol levels, suppression of se-
rum cortisol level after an overnight low-dose dexamethasone
test.
4) TSH-secreting adenoma. Normalization of TSH, free tri-
iodothyronine, and free thyroxine in hyperthyroid patients.
Normal suppression of TSH levels after the administration of
25 ␮g triiodothyronine orally every 6 hours for 10 days in
patients who had previously received thyroablative therapies.
5) Nonfunctioning pituitary adenoma. Absence on the first
postoperative MRI, usually performed 3 to 6 months after
surgery, of residual adenomatous tissue.
www.neurosurgery-online.com
 SURGICAL THERAPY OF PITUITARY ADENOMAS

Moreover, in the case of a hormone-active pituitary ade-
noma, hormone levels had to remain normal for a minimum of
6 months, otherwise patients were considered to be surgical
failures.
RESULTS
Patient Characteristics
During the study period, 1140 patients were underwent
surgery at our department for a pituitary adenoma through
the transsphenoidal approach. The most frequent tumor type
was NFPA (378 patients; 33.2%), followed by GH-secreting
adenoma (320 patients; 28.1%), ACTH-secreting adenoma (262
patients; 23.0%), PRL-secreting adenoma (151 patients; 13.2%),
and TSH-secreting adenoma (29 patients; 2.5%). There were
681 females (59.7%) and 459 males (40.3%). The mean age was
43.0 ⫾ 0.4 years (range, 8–82 yr). There were 788 macroadeno-
mas (69.1%), and in 233 patients (20.4%), the tumor invaded
one or both cavernous sinuses. Forty-six patients (4.0%) had a
clinical picture of pituitary apoplexy at presentation; most of
them had an NFPA (38 patients) or a PRL-secreting adenoma
(12 patients), whereas pituitary apoplexy was infrequent in
the other tumor types (3 each in GH-secreting and ACTH-
secreting adenoma and none in TSH-secreting adenoma). Ta-
ble 1 summarizes the main clinical characteristics of the study
population, subdivided according to tumor type.
Deficit of visual acuity or visual fields was present in 289
patients (25.4%), all with a suprasellar extending macroad-
enoma. Most patients with visual impairment had an NFPA
(226 patients), followed by patients with a GH-secreting ade-
noma (38 patients), a PRL-secreting adenoma (19 patients), an
ACTH-secreting adenoma (4 patients), and a TSH-secreting
adenoma (2 patients). Moreover, 22 patients (1.9%) also had
impairment of oculomotor function, causing diplopia and/or
ptosis in one eye. Fourteen of these patients had pituitary
apoplexy at presentation, whereas all the others had a tumor
invading the cavernous sinus. Again, the tumor type most
frequently associated with oculomotor defect was NFPA (16
patients), followed by GH-secreting adenoma (3 patients),
PRL-secreting adenoma (2 patients), and ACTH-secreting ad-
enoma (1 patient).
Excluding patients with a PRL-secreting adenoma, mild
hyperprolactinemia was detected in 250 (26.8%) of the remain-
ing 934 patients for whom PRL measurement was available.
Hyperprolactinemia occurred more frequently in NFPA
(43.3%) than in GH-secreting adenoma (24.5%) and TSH-
secreting adenoma (20.1%). Patients with Cushing’s disease
had a very low frequency of hyperprolactinemia (5.4%), prob-
ably reflecting the low number of macroadenomas in this
group. Data on gonadal function were available for 1087
(95.4%) of the 1140 patients: hypogonadism was diagnosed in
70.8% of NFPA patients, 41.8% of GH-secreting adenoma pa-
tients, 88.0% of PRL-secreting adenoma patients, 41.1% of
ACTH-secreting adenoma patients, and 20.7% of TSH-
secreting adenoma patients. Excluding the 29 patients with a
TSH-secreting adenoma, data on thyroid function were avail-
able for 1054 of the 1140 patients (94.9%): hypothyroidism was
diagnosed in 23.2% of NFPA patients, 4.5% of GH-secreting
adenoma patients, 7.3% of PRL-secreting adenoma patients,
and 2.0% of ACTH-secreting adenoma patients. Excluding the
262 patients with Cushing’s disease, data on adrenal function
were available for 857 (97.6%) of the 878 patients: adrenal

TABLE 1. Clinical characteristics of 1140 patients operated on for a pituitary adenoma from 1990 through 2002 using a
transsphenoidal approacha
Type of adenoma Invasiveness into the
Mean age ⴞ SE (yr) Female (%) Macroadenoma (%)
(no.) cavernous sinus (%)

GH secreting 44.1 ⫾ 0.7 173 261 72

(320) (54.1%) (81.6%) (22.5%)

PRL secreting 30.4 ⫾ 0.8 114 82 20

(151) (75.5%) (54.3%) (13.2%)

ACTH secreting 38.4 ⫾ 0.8 214 48 19

(262) (81.7%) (18.3%) (7.3%)

TSH secreting 43.7 ⫾ 2.6 14 20 10

(29) (48.3%) (69.0%) (34.5%)

Nonfunctioning 51.9 ⫾ 0.7 166 377 112

(378) (43.9%) (99.7%) (29.7%)

a
SE, standard error; GH, growth hormone; PRL, prolactin; ACTH, adrenocorticotropin; TSH, thyrotropin.

NEUROSURGERY VOLUME 56 | NUMBER 6 | JUNE 2005 | 1225

MORTINI ET AL.

insufficiency was diagnosed in 20.6% of NFPA patients, 1.6%
of GH-secreting adenoma patients, 6.0% of PRL-secreting ad-
enoma patients, and 3.4% of TSH-secreting adenoma patients.
Surgical Outcome
Surgical outcome was classified according to the criteria
outlined under Patients and Methods. Table 2 summarizes the
results in patients with hormone-active pituitary adenoma,
subdivided according to tumor size and invasiveness into the
cavernous sinus. The overall rate of early surgical success was
achieved in 504 (66.1%) of the 762 patients with a hormone-
active adenoma. As expected, surgical outcome was better in
patients with microadenomas than in patients with macroad-
enomas (78.9% and 55.5%, respectively), whereas tumors in-
vading the cavernous sinus had a poorer outcome (7.4%). Data
on a first postoperative MRI or CT scan (in patients with
contraindication to MRI) were available in 361 (95.5%) of the
378 patients with NFPA. No residual adenoma was present in
234 patients (64.8%), whereas tumor rests were seen in 127
patients (35.2%).
Normalization of visual defects occurred in 117 (40.5%) of
the 289 patients with visual disturbances and improved in
another 148 patients (51.2%). In 21 patients (7.3%), visual
defects remained unchanged, whereas it worsened in the re-
maining 3 patients (1.0%), of whom 1 patient experienced a
retinal hemorrhage on the third postoperative day (Table 3).
Defects of oculomotor nerves regressed after surgery in 18
patients (85.7%) and remained unchanged in the remaining 3
patients (14.3%).
Recurrence of pituitary adenoma was deemed to occur in
hormone-active tumors when patients showed biochemical
signs of hormone hypersecretion, independently of the MRI
image, whereas in patients with NFPA, tumor recurrence was
based on MRI data, independently of the clinical picture.

TABLE 2. Early surgical outcome in 762 patients operated on for a hormone-active pituitary adenomaa
Overall surgical Surgical remission in Surgical remission in Surgical remission in
Type of adenoma
remission microadenomas macroadenoma invasive tumors

GH secreting 189/320 49/59 140/261 4/72

(59.1%) (83.1%) (53.6%) (5.6%)

PRL secreting 93/151 52/69 41/82 0/20

(61.6%) (75.4%) (50.0%) (0%)

ACTH secreting 203/262 168/213 35/48 2/19

(77.5%) (78.9%) (72.9%) (10.5%)

TSH secreting 19/29 7/9 12/20 3/10

(65.5%) (77.8%) (60.0%) (30%)

a
GH, growth hormone; PRL, prolactin; ACTH, adrenocorticotropin; TSH, thyrotropin.

TABLE 3. Outcome of visual disturbances after removal of pituitary adenomaa

Patients with deficits/
Series (ref. no.) Normalized Improved Unchanged Worsened
patients operated

Salmi et al., 1982 (60) 40/56 (71%) NR 28/40 (70%) 7/40 (17%) 5/40 (12%)

Ebersold et al., 1986 (15) 72/100 (72%) NR 53/72 (74%) 15/72 (21%) 3/72 (4%)

Bevan et al., 1987 (4) 33/58 (57%) 9/33 (27%) 20/33 (61%) 4/33 (12%) 0/33 (0%)

Shone et al., 1991 (67) 24/35 (69%) 8/24 (33%) 11/24 (46%) 4/24 (17%) 1/24 (4%)

Marazuela et al., 1994 (43) 21/35 (60%) 5/21 (23%) 7/21 (33%) 9/21 (43%) 0/21 (0%)

Current series 289/1140 (25.4%) 117/289 (40.5%) 140/289 (51.2%) 21/289 (7.3%) 3/289 (1%)b
a
Only series with more than 30 cases were included. NR, not reported.
b
Including one case of retinal hemorrhage 3 days after surgery.

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 SURGICAL THERAPY OF PITUITARY ADENOMAS

TABLE 4. Surgical complications of transsphenoidal surgery in our series and in a review of the literaturea
Postoperative
Intracranial Rebleedingb Postoperative
No. of Postoperative Postoperative visual
Series (ref. no.) arterial after oculomotor Death
patients CSF leakb meningitis function
lesions surgery nerve deficit
deterioration

Guiot and Derome, 1976 613 1.3% 0.5% R 0.3% 1.4%

(27)

Kautzy et al., 1978 (32) 130 1.5%

Wilson and Dempsey, 250 6.4% 2.0% No R 0.4% 1.2% 1.2% T 2.4% T
1978 (77)

Nicola et al., 1980 (50) 294 1.3% T

1% P

Fahlbusch and Stass, 1981 601 1.2%

(16)

Hardy and Mohr, 1981 355 0.8% 0.6% T 1.2% T

(30)

Laws, 1982 (36) 810 1.5% 0.6% No R 0.4% 0.5% 0.4% T 0.5% T 0.5%

0.2% P 0.2% P
c
Hardy and Mohr, 1985 1102 0.9%
c
Landolt, 1985 496 0.8%

Tindall and Barrow, 1986 709 0.3%

(71)

Black et al., 1987 (6) 255 0.8% 0.4% No R 0.4%

Buchfelder and 500 0.4% T 0.6% T

Fahlbusch, 1988 (8)

Buchfelder and 1024 0.4% R

Fahlbusch, 1992 (9)

1.0% No R

Onesti and Post, 1993 700 0.4% R

(51)

Current series 1140 0.3% 0.1% No R 0% 0.4% 0.3% T 1% T 0.3%

0% R 0% P 0.2% P
a
CSF, cerebrospinal fluid; R, rhinorrhea; No R, no rhinorrhea; T, transient; P, permanent.
b
Requiring operation.
c
Cited by Tindall and Barrow (71).

The mean follow-up in the 117 acromegalic patients in remis-
sion of disease after surgery and a follow-up of longer than 1
year was 43.1 ⫾ 3.0 months. During the study period, 9 patients
(7.7%) had recurrence of acromegaly, which occurred 16, 19, 21,
24, 28, 29, 36, 42, and 115 months after surgery. Recurrence was
managed with medical therapy alone in four patients, radiation
therapy alone in four patients, and surgery plus radiation ther-
apy in the remaining patient. The mean follow-up in the 73
patients successfully operated for a PRL-secreting adenoma and
a follow-up of longer than 1 year was 53.0 ⫾ 3.8 months. During
the study period, 13 patients (17.8%) had recurrence of hyperp-
rolactinemia, which occurred 8, 11, 12 (3 patients), 16, 29, 30, 32,
38 (2 patients), 41, and 65 months after surgery. Recurrence was
managed with dopamine agonists alone in 10 patients, surgery
plus dopamine agonists in 1 patient, and observation alone in the
remaining 2 patients. The mean follow-up in the 114 patients in
remission of Cushing’s disease after surgery and a follow-up of
longer than 1 year was 37.8 ⫾ 2.1 months. During the study
period, 12 patients (8.4%) had recurrence of hypercortisolism,
which occurred 12, 21, 26, 32, 39, 44, 50, 55, 60, 63, 71, and 73
months after surgery. Recurrence was managed with radiation
therapy alone in five patients, repeat transsphenoidal surgery in

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MORTINI ET AL.

two patients, medical therapy

TABLE 5. Results of surgery for acromegaly in relation to different criteria of with ketoconazole alone in
postoperative evaluationa two patients, transsphenoidal
Patients with GH Patients with surgery plus radiation therapy
No. of Patients with GH in one patient, radiation ther-
Series (ref. no.) suppression normal IGF-1
patients <5 ␮g (%)
during OGTT levels apy plus bilateral adrenalec-
tomy in one patient, and bilat-
Quabbe, 1982 (54) 152 55% 36% NR eral adrenalectomy alone in
Von Werder et al., 1984 (76) 181 57% NR NR the remaining patient. The
mean follow-up in the 16 pa-
Fahlbusch et al., 1992 (18) 224 71% 56% NR tients successfully operated
Abosch et al., 1998 (1) 254 76% NR NR for a TSH-secreting adenoma
and a follow-up of longer than
Freda et al., 1998 (22) 115 71% 61% 61% 1 year was 50.6 ⫾ 9.2 months.
Biermasz et al., 2000 (5) 59 NR 67% NR
During the study period, 3 pa-
tients (18.7%) experienced re-
Kaltsas et al., 2001 (31) 67 54%b NR 42% currence of hyperthyroidism
and/or regrowth of the pitu-
Kreutzer et al., 2001 (35) 57 79% NR 52%
itary tumor, which occurred 7,
Shimon et al., 2001 (65) 91 NR 74% 74% 41, and 50 months after sur-
gery. Recurrence was man-
Current series 320 NR 59% 59%
aged with radiation therapy
a
Only major series with more than 100 cases or published since 2000 are reported. GH, growth hormone; OGTT, oral alone in two patients and with
glucose tolerance test; IGF-1, insulin-like growth factor 1; NR, not reported. surgery plus radiation therapy
b
Patients with GH lower than 10 mU/L (1 mU/L ⫽ 0.4 ␮g/L).
in the remaining patient. The
mean follow-up in the 174
NFPA patients without evi-
dence of tumor rest on the first
TABLE 6. Early and late results of surgery in patients with prolactin-secreting adenomaa postoperative MRI scan and a
follow-up of longer than 1
No. of Patients Patients with Mean
Series (ref. no.) year was 54.9 ⫾ 2.5 months.
patients cured recurrence follow-up (mo)
During the study period, 23
Rawe et al., 1983 (55) 30 60% NR NR patients (13.2%) had MRI evi-
dence of recurrent tumor. The
Nelson et al., 1983 (49) 40 62% 36% NR
mean time to recurrence was
Serri et al., 1983 (64) 44 66% 55% 74 61.4 ⫾ 7.6 months (range, 12–
140 mo). Recurrence was man-
Rodman et al., 1984 (58) 65 71% 18% 50 aged with radiation therapy
Scanlon et al., 1985 (61) 35 74% 0% 32 alone in 15 patients, surgery
plus radiation therapy in 4 pa-
Schlechte et al., 1986 (62) 68 54% 31% 60 tients, and observation in the
Massoud et al., 1996 (44) 64 90% 43% 148 remaining 4 patients.

Otten et al., 1996 (52) 65 48% 6% 58 Complications of Surgery

Complications of surgery,
Feigenbaum et al., 1996 (19) 409 74% NR NR
together with a review of
Maira et al., 1999 (40) 119 62% 16% NR other surgical series (6, 8, 9, 16,
27, 30, 32, 36, 50, 51, 71, 77), are
Tyrrell et al., 1999 (75) 219 72% 15% 187 (Group 1)
summarized in Table 4. Three
38 (Group 2) patients (0.3%) died as a con-
sequence of surgery. A 75-
Ozgen et al., 1999 (53) 319 54% NR NR
year-old man with a large
Current series 151 62% 18% 53 NFPA causing worsening vi-
a
sual defects had intratumoral
NR, not reported.
hemorrhage in the suprasellar
part of the tumor, which could

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 SURGICAL THERAPY OF PITUITARY ADENOMAS

Postoperative rhinoliquor-
TABLE 7. Surgical results in patients with Cushing’s disease: series with more than 50 cases reported rhea requiring a new opera-
No. of Patients Patients with Mean tion occurred in three patients.
Series (ref. no.) In one patient, rhinoliquor-
patients cured recurrence follow-up (mo)
rhea was treated using an ex-
Hardy et al., 1982 (28) 75 84% 0% 21 ternal lumbar drain for 5 days.
Fahlbusch et al., 1986 (17) 101 70% 7% 39
Only one case of postoperative
meningitis occurred in a pa-
Nakane et al., 1987 (48) 100 86% 9% 38 tient who likely had contami-
nation from the external lum-
Guilhaume et al., 1988 (26) 61 69% 14% 24
bar drain placed to treat an
Mampalam et al., 1988 (41) 216 79% 5% 46 intraoperative CSF leak. Post-
operative intrasellar hema-
Burke et al., 1990 (11) 54 81% 5% 56
toma, causing deterioration of
Tindall et al., 1990 (72) 53 87% 2% 57 visual function, developed in
four patients and required ur-
Robert and Hardy, 1991 (57) 78 77% 8% 77 gent transsphenoidal evacua-
Bochicchio et al., 1995 (7) 668 76% 13% 57 tion of the hematoma. Visual
function recovered in all four
Knappe and Lüdecke, 1995 (33) 310 85% 11% 33 patients. Deep vein thrombo-
Swearingen et al., 1999 (70) 161 85% 7% 104 sis occurred in four patients,
and pulmonary embolism oc-
Stevenaert et al., 2002 (69) 167 85% 15% 58 curred in another three pa-
Rees et al., 2002 (56) 54 77% 5% 72
tients. Another three patients
with Cushing’s disease had
Shimon et al., 2002 (66) 77 78% 5% 50 seizures 6 to 10 days after sur-
gery, which was the result of
Current series 262 78% 8% 38
thrombosis of the cerebral
veins. Rhinological complica-
tions included one case of mu-
not be removed completely through the transsphenoidal ap- cocele that required surgery, two cases of epistaxis that required
proach. The patient had visual loss in one eye and altered sen- further nasal tamponade, one case of symptomatic septal perfo-
sorium; however, because of old age and heart disease, transcra- ration, and one case of sinusitis treated medically.
nial evacuation of the suprasellar tumor was deemed not to be Thirty-three patients experienced hyponatremia 5 to 7 days after
feasible and the patient was managed conservatively. The patient surgery. Severe hypokalemia (⬍3 nmol/L) was recorded in 10 pa-
then slowly improved but remained bedridden. Two months tients. Postoperative diabetes insipidus, lasting for at least 3 months,
after surgery, the patient died suddenly, probably because of developed in 45 patients (4.1%). In 37 (82%) of 45 patients, however,
myocardial infarction or pulmonary embolism. The second pa- it disappeared after a mean of 9 months (range, 4–49 mo).
tient, a 69-year-old woman with a giant NFPA causing blindness New cases of hypogonadism occurred in 9 (2.0%) of the 456
in one eye and severe visual defect in the other eye, was operated assessable patients at risk of experiencing it. The highest risk
through the transsphenoidal route because of poor myocardial of developing hypogonadism was observed in patients with
function with the aim of relieving compression of the optic path- NFPA (3.7%) and Cushing’s disease (3.0%). New cases of
way. However, the tumor was of firm consistency, thus prevent- hypothyroidism occurred in 20 (2.2%) of the 916 assessable
ing removal of a large suprasellar part. Six hours after surgery, patients at risk of experiencing it. The highest risk of devel-
the patient had barely awakened and a CT scan showed a mas- oping hypothyroidism was observed in patients with NFPA
sive hemorrhage within the residual adenoma. The patient died (6.1%). New cases of hypoadrenalism occurred in 25 (3.3%) of
on the fourth postoperative day. The third patient, a 72-year-old the 746 assessable patients at risk of experiencing it. The
woman with Cushing’s disease, reported abdominal pain on the highest risk of developing hypoadrenalism was observed in
third postoperative day. A surgical consultant advised laparos- patients with NFPA (7.1%).
copy. A ruptured colon diverticulum was found and repaired.
However, there was wound dehiscence and infection. Despite DISCUSSION
antibiotic treatment and further surgical procedures, the patient
died of heart failure 2 months after transsphenoidal surgery. Transsphenoidal surgery in our series afforded good control
Another patient with Cushing’s disease had an intraoperative of tumor growth and led to remission of clinical and endocrino-
cardiac arrest because of a pulmonary embolism, which resulted logical dysfunction in a large percentage of cases. Our results are
in the patient entering a permanent vegetative state. comparable with those of other previously published major se-

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MORTINI ET AL.

confirm that microadenomas

TABLE 8. Morbidity of pituitary surgerya have the highest rate of surgi-
No. of patients cal remission, whereas inva-
sion of the cavernous sinus is
<200 200 –500 >500 Our series the worst prognostic factor for
Nasal septum perforation 7.6 4.6 3.3 0.1 complete tumor removal (Ta-
ble 2) (38).
Postoperative epistaxis 4.3 1.7 0.4 0.2 One of the major advan-
tages of surgical therapy is the
Sinusitis 9.6 6.0 3.6 0.1
immediate effect on either hor-
Carotid artery injury 1.4 0.6 0.4 0 mone hypersecretion or com-
pressive symptoms, such as
CNS injury 1.6 0.9 0.6 0
visual disturbances. On the
Hemorrhage into residual tumor bed 2.8 4 0.8 0.4 contrary, radiation therapy
may take several years to be
Permanent loss of vision 2.4 0.8 0.5 0
effective, and during this pe-
Ophthalmoplegia 1.9 0.8 0.4 0 riod, patients remain exposed
to the deleterious effects of
CSF leak 4.2 2.8 1.5 0.3 continued hormone hyperse-
Meningitis 1.9 0.8 0.5 0.1 cretion and/or tumor com-
pression on surrounding ner-
Anterior pituitary insufficiency 20.6 14.9 7.2 2.7b vous structures. Fractionated
Diabetes insipidus 19 — 7.6 4.1 radiation therapy, moreover,
carries a higher risk than sur-
Death 1.2 0.6 0.2 0.3 gery of damaging residual pi-
a
Overall comparison between our data and the data previously reported in the literature in a multicentric study (13) in tuitary function during
which patients were grouped according to the total number of cases operated on by the surgeon. CNS, central nervous follow-up (37, 59, 68). Highly
system; CSF, cerebrospinal fluid. focused radiation therapy,
b
At least one axis. such as gamma knife radiosur-
gery, may diminish the risk of
hypopituitarism, especially
ries (Tables 3, 5–7) (1, 4, 5, 7, 11, 15, 17–19, 22, 26, 28, 31, 33, 35, when the irradiated tumor is separated from the normal pituitary
39–41, 43, 44, 46, 48, 49, 52–58, 60–62, 64–67, 69, 70, 72, 75, 76). gland and the pituitary stalk may be spared (20). At present,
When considering the results of pituitary surgery, it is very radiation therapy should be considered to be a very important
important to pay attention to the criteria of cure. Acromegaly adjuvant treatment for those patients with residual disease after
exemplifies the continuing evolution of criteria of cure. Indeed, maximal surgical debulking. Only patients with clear contrain-
the old surgical series considered a basal GH level lower than 5 dications to surgery or who express a strong preference for
␮g/L to indicate remission of disease, but it became clear later noninvasive procedures should be considered for first-line radi-
that a more thorough endocrine evaluation, including GH levels ation therapy.
during oral glucose load and basal insulin-like growth factor I The efficacy and safety of transsphenoidal surgery results in
measurement, was necessary to avoid misclassification of surgi- favorable cost savings. In fact, a course of radiotherapy or con-
cal results. Interestingly, the availability of very specific GH tinued medical treatment costs more than proper surgical treat-
assays has led to gradual lowering of the GH level needed to ment. Moreover, with the increasing experience of a dedicated
establish hormonal remission of the disease (25). There is still pituitary surgeon, the incidence of postoperative hypopituitar-
some disagreement on the criteria of cure for Cushing’s disease, ism, and hence the costs of replacement therapy, decrease (14).
with some authors (74) advocating postoperative hypocorti- Our results in secreting adenomas were evaluated according to
solism as absolutely necessary to define surgical remission of the hormonal criteria of cure. Compared with other intracranial tu-
disease, whereas we and others (7, 45) believe that normalization mors, this is a completely different way to assess the results of
of cortisol secretion, provided a normal suppressibility to low- surgical therapy. As previously reported, restrictive criteria of
dose dexamethasone testing exists, is sufficient to define remis- cure are related to a lower percentage of early remission but to a
sion of disease. The acceptability of our criteria is demonstrated more durable remission at follow-up (3, 10).
further by the relatively low incidence of recurrence of Cushing’s In NFPAs, the role of MRI follow-up is to assess the true recur-
disease during follow-up. We have confirmed the data of other rence of a radically removed adenoma or the regrowth of residual
authors that, in experienced hands, surgery is an effective ther- tumor. This is of paramount importance to plan further treatments,
apy for both endocrine active and nonfunctioning pituitary ad- such as radiosurgery or radiotherapy, before the mass becomes
enomas (2, 14, 24). Our results in hormone-active adenomas symptomatic and a second surgical procedure is needed.

1230 | VOLUME 56 | NUMBER 6 | JUNE 2005 www.neurosurgery-online.com


Our data suggest that the first transsphenoidal approach to the
sella can be carried out safely and quickly without any supple-
mentary device, such as the intraoperative fluoroscopy or neu-
ronavigation systems. However, it must be stressed that the
experience of a well-trained pituitary surgeon is mandatory to
avoid the loss of time and major complications related to the
approach, as previously reported by others (13) (Table 8). In our
opinion, the use of devices that help the surgeon to keep him
oriented during the procedure may be advisable for less experi-
enced or in-training surgeons. The sublabial-transseptal ap-
proach adopted by us has a low rate of complication. According
to our data, the rhinological, neurological, and endocrine com-
plications are lower than those reported in other series even
using newly developed procedures (12).
The low percentage (0.4%) of postoperative CSF leak is
explained not only by a careful surgical technique, but also by
the use of the intraoperative lumbar needle that helps the
cisternal repairing of small intraoperative CSF leaks. The CSF
lumbar external diversion is not used as a routine procedure
but only in case of large leaks, which are expected to need
several days to repair.
Infectious complications were very infrequent in our series,
despite the absence of preoperative prophylaxis with antibi-
otics. The only case of meningitis we recorded was probably
the result of skin bacteria infecting a lumbar drain. Our be-
havior is clearly in contrast with other authors who recom-
mend a prophylactic antibiotic and with the recent recommen-
dations reported in the literature on paranasal sinus surgery
(42, 63). However in our series, infections resulting from sap-
rophytic bacteria were very uncommon.
CONCLUSION
Surgical treatment of pituitary adenomas ideally should be
performed by an experienced pituitary surgeon supported by
an equally experienced team of endocrinologists, neuroradi-
ologists, neuroanesthetists, and neuropathologists specialized
in pituitary pathology. The collaboration between these spe-
cialists helps in achieving the best possible results and in
collecting as much data as possible on the clinical aspects and
biological behavior of pituitary adenomas.
Taking into account our results and those reported in the
literature, we believe that transsphenoidal surgery is an effec-
tive and safe treatment for most patients with pituitary ade-
noma. It could be considered the first-choice therapy in all
cases, except for prolactinomas responsive to dopamine ago-
nists. Other methods of treatment, such as radiotherapy, ste-
reotactic radiosurgery, and medical therapy, play an impor-
tant role in patients not cured by surgery.
REFERENCES
1. Abosch A, Tyrrell JB, Lamborn KR, Hannegan LT, Applebury CB, Wilson
CB: Transsphenoidal microsurgery for growth hormone-secreting pituitary
adenomas: Initial outcome and long-term results. J Clin Endocrinol Metab
83:3411–3418, 1998.
NEUROSURGERY
SURGICAL THERAPY OF PITUITARY ADENOMAS
2. Ahmed S, Elsheikh M, Stratton IM, Page RC, Adams CB, Wass JA: Outcome
of transsphenoidal surgery for acromegaly and its relationship to surgical
experience. Clin Endocrinol 50:561–567, 1999.
3. Arafah BM, Rosenzweig JL, Fenstermaker R, Salazar R, McBride CE, Selman
WR: Value of growth hormone dynamics and somatomedin C (insulin-like
growth factor I) levels in predicting the long-term benefit after transsphe-
noidal surgery for acromegaly. J Lab Clin Med 109:346–354, 1987.
4. Bevan JS, Adams CB, Burke CW, Morton KE, Molyneux AJ, Moore RA, Esiri
MM: Factors in the outcome of transsphenoidal surgery for prolactinoma
and non-functioning pituitary tumour, including pre-operative
bromocriptine therapy. Clin Endocrinol 26:5415–5456, 1987.
5. Biermasz NR, Van Dulken H, Roelfsema F: Ten-year follow-up results of
transsphenoidal microsurgery in acromegaly. J Clin Endocrinol Metab
85:2476–2482, 2000.
6. Black PMcL, Zervas NT, Candia GL: Incidence and management of compli-
cations of transsphenoidal operation for pituitary adenoma. Neurosurgery
20:920–924, 1987.
7. Bochicchio D, Losa M, Buchfelder M: Factors influencing the immediate and
late outcome of Cushing’s disease treated by transsphenoidal surgery: A
retrospective study by the European Cushing’s Disease Survey Group.
J Clin Endocrinol Metab 80:3114–3120, 1995.
8. Buchfelder M, Fahlbusch R: Komplikationen bei Operationen von
Hypophysenadenomen, in Bock WJ, Schirmer M (eds): Komplikationen bei
neurochirurgischen Eingriffen. München, Zuckschwerdt, 1988, pp 18–32.
9. Buchfelder M, Fahlbusch R: Risiken und Komplikationen bei Operationen
von Prozessen im Sellabereich. Nervenheilkunde 11:105–111, 1992.
10. Buchfelder M, Brockmeier S, Fahlbusch R, Honegger J, Pichl J, Manzl M:
Recurrence following transsphenoidal surgery for acromegaly. Horm Res
35:113–118, 1991.
11. Burke CW, Adams CBT, Esiri MM, Morris C, Bevan JS: Transsphenoidal
surgery for Cushing’s disease: Does what is removed determine the endo-
crine outcome? Clin Endocrinol (Oxf) 33:525–537,1990.
12. Cappabianca P, Cavallo LM, Colao A, de Divitiis E: Surgical complications
associated with the endoscopic endonasal transsphenoidal approach for
pituitary adenomas. J Neurosurg 97:293–298, 2002.
13. Ciric I, Ragin A, Baumgartner C, Pierce D: Complications of transsphenoidal
surgery: Results of a national survey, review of the literature, and personal
experience. Neurosurgery 40:225–236, 1997.
14. Clayton RN: How many surgeons to operate an acromegalic patient? Clin
Endocrinol 50:557–559, 1999.
15. Ebersold MJ, Quast LM, Laws ER Jr, Scheithauer B, Randall RV: Long-term
results in transsphenoidal removal of nonfunctioning pituitary adenomas.
J Neurosurg 64:713–719, 1986.
16. Fahlbusch R, Stass P: Pituitary adenomata: Status of diagnosis and therapy
[in German]. MMW Münch Med Wochenschr 123:549–555, 1981.
17. Fahlbusch R, Buchfelder M, Müller OA: Transsphenoidal surgery for
Cushing’s disease. J R Soc Med 79:262–269, 1986.
18. Fahlbusch R, Honegger J, Buchfelder M: Surgical management of acromeg-
aly. Endocrinol Metab Clin North Am 21:669–692, 1992.
19. Feigenbaum SL, Downey DE, Wilson CB, Jaffe RB: Transsphenoidal pitu-
itary resection for preoperative diagnosis of prolactin-secreting pituitary
adenoma in women: Long term follow-up. J Clin Endocrinol Metab 81:
1711–1719, 1996.
20. Feigl GC, Bonelli CM, Berghold A, Mokry M: Effects of gamma knife
radiosurgery of pituitary adenomas on pituitary function. J Neurosurg
97:415–421, 2002.
21. Freda PU, Wardlaw SL: Clinical review 110: Diagnosis and treatment of
pituitary tumors. J Clin Endocrinol Metab 84:3859–3866, 1999.
22. Freda PU, Wardlaw SL, Post KD: Long-term endocrinological follow-up
evaluation in 115 patients who underwent transsphenoidal surgery for
acromegaly. J Neurosurg 89:353–358, 1998.
23. Giovanelli M, Losa M, Baiguini M, Motti E, Ducati A: Transcranial versus
transsphenoidal approach in the surgical treatment of pituitary adenomas,
in Faglia G, Beck-Peccoz P, Ambrosi B, Travaglini P, Spada A (eds): Pituitary
Adenomas: New Trends in Basic and Clinical Research. Amsterdam, Excerpta
Medica, 1991, pp 313–320.
VOLUME 56 | NUMBER 6 | JUNE 2005 | 1231
MORTINI ET AL.
24. Gittoes NJ, Sheppard MC, Johnson AP, Stewart PM: Outcome of surgery for
acromegaly: The experience of a dedicated pituitary surgeon. Q J Med
92:741–745, 1999.
25. Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K,
Veldhuis J, Wass J, Von Werder K, Melmed S: Criteria for cure of acromeg-
aly: A consensus statement. J Clin Endocrinol Metab 85:526–529, 2000.
26. Guilhaume B, Bertagna X, Thomsen M, Bricaire C, Vila-Porcile E, Olivier L,
Racadot J, Derome P, Laudat MH, Girard F: Transsphenoidal pituitary
surgery for the treatment of Cushing’s disease: Results in 64 patients and
long term follow-up studies. J Clin Endocrinol Metab 66:1056–1064, 1988.
27. Guiot G, Derome P: Surgical problems of pituitary adenomas, in Krayenbühl
H (ed): Advances and Technical Standards in Neurosurgery. Wien, Springer
Velag, 1976, pp 3–33.
28. Hardy J: Cushing’s disease: 50 years later. Can J Neurol Sci 9:375–380, 1982.
29. Hardy J: Trans-sphenoidal approach to the pituitary gland, in Wilkins RH,
Rengachary SS (eds): Neurosurgery. New York, McGraw-Hill, 1996, pp 1375–
1384.
30. Hardy J, Mohr G: Prolactinoma: Surgical aspects [in French].
Neurochirurgie 27[Suppl 1]:41–60, 1981.
31. Kaltsas GA, Isidori AM, Florakis D, Trainer PJ, Camacho-Hubner C, Afshar
F, Sabin I, Jenkins P, Chew SL, Monson JP, Besser GM, Grossman AB:
Predictors of the outcome of surgical treatment in the acromegaly and the
value of the mean growth hormone day curve in assessing postoperative
disease activity. J Clin Endocrinol Metab 86:1645–1652, 2001.
32. Kautzy R, Lüdecke D, Nowakowski H: Transsphenoidal operation in acro-
megaly, in Fahlbusch R, Von Werder K (eds): Treatment of Pituitary Adeno-
mas. Stuttgart, Georg Thieme Verlag, 1978, pp 219–225.
33. Knappe UJ, Lüdecke D: Persistent and recurrent hypercortisolism after
transsphenoidal surgery for Cushing’s disease. Acta Neurochir Suppl
(Wien) 65:31–34, 1995.
34. Knosp E, Steiner E, Kitz K, Matula C: Pituitary adenomas with invasion of
the cavernous sinus space: Magnetic resonance imaging classification com-
pared with surgical findings. Neurosurgery 33:610–617, 1993.
35. Kreutzer J, Vance ML, Loper BS, Laws ER Jr: Surgical management of
GH-secreting pituitary adenomas: An outcome study using modern remis-
sion criteria. J Clin Endocrinol Metab 86:4072–4077, 2001.
36. Laws ER Jr: Complications of transsphenoidal microsurgery for pituitary
adenomas, in Brock M (ed): Modern Neurosurgery. Berlin, Springer Velag,
1982, vol 1, pp 181–186.
37. Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate G, Sutton ML:
Hypopituitarism following external radiotherapy for pituitary tumors in
adults. Q J Med 70:145–160, 1989.
38. Losa M, Barzaghi R, Mortini P, Franzin A, Mangili F, Terreni MR, Giovanelli
M: Determination of the proliferation and apoptotic index in
adrenocorticotropin-secreting pituitary tumors: Comparison between
micro- and macroadenomas. Am J Pathol 156:245–251, 2000.
39. Losa M, Giovanelli M, Persani L, Mortini P, Faglia G, Beck-Peccoz P: Criteria
of cure and follow-up of central hyperthyroidism due to thyrotropin-
secreting pituitary adenomas. J Clin Endocrinol Metab 81:3084–3090, 1996
40. Maira G, Anile C, De Marinis L, Barbarino A: Prolactin-secreting adenomas:
Surgical results and long-term follow-up. Neurosurgery 24:736–743, 1989.
41. Mampalam TJ, Tyrrell JB, Wilson CB: Transsphenoidal microsurgery for
Cushing’s disease: A report of 216 cases. Ann Intern Med 109:487–493, 1988.
42. Mangram AJ, Horam TC, Pearson ML, Silver LC, Jarvis WR: Guideline for
prevention of surgical site infection, 1999: Hospital Infection Control Prac-
tices Advisory Committee. Infect Control Hosp Epidemiol 20:250–280,
1999.
43. Marazuela M, Astigarraga B, Vicente A, Estrada J, Cuerda C, Garcia-Uria J,
Lucas T: Recovery of visual and endocrine function following transsphenoi-
dal surgery of large nonfunctioning pituitary adenomas. J Endocrinol In-
vest 17:703–707, 1994.
44. Massoud F, Serri O, Hardy J, Somma M, Beauregard H: Transsphenoidal
adenomectomy for microprolactinomas: 10 to 20 yr of follow-up. Surg
Neurol 45:341–346, 1996.
45. McCance DR, Besser M, Atkinson AB: Assessment of cure after transsphe-
noidal surgery for Cushing’s disease. Clin Endocrinol 44:1–6, 1996.
46. Mindermann T, Wilson CB: Thyrotropin-producing pituitary adenomas.
J Neurosurg 79:521–527, 1993
1232 | VOLUME 56 | NUMBER 6 | JUNE 2005
47. Molitch ME: Medical treatment of prolactinomas. Endocrinol Metab Clin
North Am 28:143–169, 1999.
48. Nakane T, Kuwayama A, Watanabe M, Takahashi T, Kato T, Ichihara K,
Kageyama N: Long term results of transsphenoidal adenomectomy in pa-
tients with Cushing’s disease. Neurosurgery 21:218–222, 1987.
49. Nelson PB, Goodman M, Maroon JC, Martinez AJ, Moossy J, Robinson AG:
Factors in predicting outcome from operation in patients with prolactin-
secreting pituitary adenomas. Neurosurgery 13:634–641, 1983.
50. Nicola GC, Tonnarelli GP, Griner AC: Complications of transsphenoidal
surgery in pituitary adenomas, in Derome PJ, Jedynak CP, Peillon F (eds):
Pituitary Adenomas. Paris, Asclepios Publishers, 1980, pp 237–240.
51. Onesti ST, Post KD: Complications of transsphenoidal microsurgery, in
Onesti ST, Post KD, Friedman ED, McCormick P (eds): Postoperative Com-
plications in Intracranial Neurosurgery. New York, Thieme, 1993, pp 61–73.
52. Otten P, Rilliet B, Reverdin A, Demierre B, Berney J: Pituitary adenoma
secreting prolactin: Results of their surgical treatment [in French].
Neurochirurgie 42:44–53, 1996.
53. Ozgen T, Oruckaptan HH, Ozcan OE, Acikgoz B: Prolactin secreting pitu-
itary adenomas: Analysis of 429 surgically treated patients, effect of adju-
vant treatment modalities and review of the literature. Acta Neurochir
(Wien) 141:1287–1294, 1999.
54. Quabbe HJ: Treatment of acromegaly by trans-sphenoidal operation, 90-
yttrium implantation and bromocriptine: Results in 230 patients. Clin
Endocrinol 16:107–119, 1982.
55. Rawe SE, Williamson HO, Levine JH, Phansey SA, Hungerford D, Adkins
WY: Prolactinomas: Surgical therapy, indications and results. Surg Neurol
80:161–167, 1980.
56. Rees DA, Hanna FW, Davies JS, Mills RG, Vafidis J, Scanlon MF: Long-term
follow-up results of transsphenoidal surgery for Cushing’s disease in a
single centre using strict criteria for remission. Clin Endocrinol 56:541–251,
2002.
57. Robert F, Hardy J: Cushing’s disease: A correlation of radiological, surgical
and pathological findings with therapeutic results. Pathol Res Pract 187:
617–621, 1991.
58. Rodman EF, Molitch ME, Post KD, Biller BJ, Reichlin S: Long-term follow-up
of transsphenoidal selective adenomectomy for prolactinoma. JAMA 252:
921–924, 1984.
59. Rush S, Cooper PR: Symptom resolution, tumor control, and side effects
following postoperative radiotherapy for pituitary macroadenomas. Int J
Radiat Oncol Biol Phys 37:1031–1034, 1997.
60. Salmi J, Grahne B, Valtonen S, Pelkonen R: Recurrence of chromophobe
pituitary adenomas after operation and postoperative radiotherapy. Acta
Neurol Scand 66:681–689, 1982.
61. Scanlon MF, Peters JR, Thomas JP, Richards SH, Morton WH, Howell S,
Williams ED, Hourihan M, Hall R: Management of selected patients with
hyperprolactinemia by partial hypophysectomy. Br Med J 291:1547–1550,
1985.
62. Schlechte JA, Sherman BM, Chapler FK, Van Gilder J: Long term follow-up
of women with surgically treated prolactin-secreting pituitary tumors.
J Clin Endocrinol Metab 62:1296–1301, 1986.
63. Schwartz M, Swearingen B, Black PMcL: Transsphenoidal surgery for pitu-
itary tumors, in Kaye AH, Black PMcL (eds): Operative Neurosurgery. Lon-
don, Churchill Livingstone, 2000, pp 672–683.
64. Serri O, Rasio E, Beauregard H, Hardy J, Somma M: Recurrence of
hyperprolactinemia after selective adenomectomy in women with
prolactinomas. N Engl J Med 309:280–283, 1983.
65. Shimon I, Cohen ZR, Ram Z, Hadani M: Transsphenoidal surgery for
acromegaly: Endocrinological follow-up of 98 patients. Neurosurgery 48:
1239–1245, 2001.
66. Shimon I, Ram Z, Cohen ZR, Hadani M: Transsphenoidal surgery for
Cushing’s disease: Endocrinological follow-up monitoring of 82 patients.
Neurosurgery 51:57–61, 2002.
67. Shone GR, Richards SH, Hourihan MD, Hall R, Thomas JP, Scanlon MF:
Non-secretory adenomas of the pituitary treated by trans-ethmoidal
sellotomy. J R Soc Med 84:140–143, 1991.
68. Snyder PJ, Fouble BF, Schwartz NJ, Savina PJ, Gennarelli TH: Hypopituitar-
ism following radiation therapy of pituitary adenomas. Am J Med 81:457–
462, 1986.
www.neurosurgery-online.com

69. Stevenaert A, Perrin G, Martin D, Beckers A: Cushing’s disease and
corticotrophic adenoma: Results of pituitary microsurgery [in French].
Neurochirurgie 48:234–265, 2002.
70. Swearingen B, Biller BM, Barker FG II, Katznelson L, Grinspoon S, Klibanski
A, Zervas NT: Long-term mortality after transsphenoidal surgery for
Cushing’s disease. Ann Intern Med 130:821–824, 1999.
71. Tindall GT, Barrow DL: Pituitary surgery, in Disorders of the Pituitary. St
Louis, C.V. Mosby, 1986, pp 349–400.
72. Tindall GT, Herring CJ, Clark RV, Adams DA, Watts NB: Cushing’s disease:
Results of transsphenoidal microsurgery with emphasis on surgical failures.
J Neurosurg 72:363–369, 1990.
73. Tindall GT, Woodard EJ, Barrow DL: Pituitary adenomas: General consid-
erations, in Apuzzo MLJ (ed): Brain Surgery. New York, Churchill
Livingstone, 1993, pp 269–276.
74. Trainer PJ, Lawrie HS, Verhelst J, Howlett TA, Lowe DG, Grossman AB,
Savage MO, Afshar F, Besser GM: Transsphenoidal resection in Cushing’s
disease: Undetectable serum cortisol as the definition of successful treat-
ment. Clin Endocrinol 38:73–78, 1993.
75. Tyrrell JB, Lanborn KR, Hannegan LT, Applebury CB, Wilson CB: Trans-
sphenoidal microsurgical therapy of prolactinomas: Initial outcomes and
long-term results. Neurosurgery 44:254–263, 1999.
76. Von Werder K, Eversmann T, Fahlbusch R: Endocrine-active pituitary ade-
nomas: Long-term results of medical and surgical treatment, in Camanni F,
Müller EE (eds): Pituitary Hyperfunction: Physiopathology and Clinical Aspects.
New York, Raven Press, 1984, pp 385–406.
77. Wilson CB, Dempsey LC: Transsphenoidal microsurgical removal of 250
pituitary adenomas. J Neurosurg 48:13–22, 1978.
COMMENTS
T his series of 1140 patients treated over a 13-year period by two
experienced pituitary surgeons once again confirms, as has been
shown for at least 2 decades, that transsphenoidal surgery is a safe
and effective first-line therapy for most patients with pituitary ade-
nomas. The importance of accumulated surgical experience and a
dedicated treatment team is demonstrated by the high tumor con-
trol rate and the very low surgical complication rate. Given all the
recent interest in less invasive approaches to the sella, including
endonasal endoscopic and endonasal microscopic approaches, this
report reminds us that the sublabial route remains in many ways the
“gold standard” transsphenoidal approach and that it is still effec-
tively used by many pituitary surgeons around the world. None-
theless, in many neurosurgical centers, these newer endonasal ap-
proaches are used almost exclusively, and the sublabial route is no
longer taught to neurosurgical residents. Although it is true that the
most important goal in treating patients with a pituitary adenoma is
achieving as complete and safe a tumor removal as possible, other
issues, such as postoperative rhinological complaints and length of
hospital stay, are now gaining in importance as the overall safety
and efficacy of transsphenoidal surgery has become more uniform,
particularly at dedicated pituitary surgery centers.
Consequently, these newer endonasal endoscopic and endonasal
microscopic techniques, which require less mucosal dissection and
no nasal packing, are gaining widely in popularity among both
neurosurgeons and their patients because they facilitate a more
rapid rhinological recovery and a shorter hospital stay. Although
the authors claim that the sublabial approach had a lower rate of
NEUROSURGERY
SURGICAL THERAPY OF PITUITARY ADENOMAS
rhinological complications than the endoscopic approach, it is im-
portant to note that such complaints tend to be underreported after
transsphenoidal surgery unless patients are specifically queried (1).
It seems quite certain that these newer endonasal approaches are
here to stay, and we may hope that with accumulated experience,
the overall efficacy and complication rates will be shown to be
comparable to those of the sublabial transsphenoidal approach.
Daniel F. Kelly
Los Angeles, California
1. Zada G, Kelly DF, Cohan P, Wang C, Swerdloff R: Endonasal transsphenoidal
approach to treat pituitary adenomas and other sellar lesions: an assessment
of efficacy, safety and patient impressions. J Neurosurg 98:350–358, 2003.
T his is an excellent article from a well-respected Italian academic
center in Milan. It covers a large series of pituitary adenomas
operated on transsphenoidally in the modern era. It includes excel-
lent follow-up of 1140 pituitary tumor patients not previously op-
erated on. The follow-up is exhaustive and is a very welcome
feature of this article, because it confirms the excellent outcomes that
are a testimony to the skills of their group. The data regarding
recurrence are of extreme importance and continue to remind us
that the longer patients with pituitary tumors are carefully followed
up, the higher the true recurrence rates become. The outcomes are
also characterized by modern criteria for remission, and the article
includes a very careful report of the complications. This is an excel-
lent benchmark article, providing a standard-of-care review for pi-
tuitary tumor surgery.
Edward R. Laws, Jr.
Charlottesville, Virginia
T his report provides information on a very large series of pitu-
itary tumors operated on by the sublabial transsphenoidal ap-
proach with a low complication rate. In recent years, we have used
an endonasal technique directed through the nostril without inci-
sion or elevation of the mucosa on the nasal septum. The approach
is directed between the septum and turbinates to the sphenoid face,
which is opened. The technique is described elsewhere (1). The
advantages of the endonasal, compared with the sublabial, ap-
proach are the reduced operative time, reduced discomfort and
complications related to the septal mucosal and septal dissection,
reduced bleeding, and the infrequent need for nasal packing after
the procedure, compared with what can be achieved with the sub-
labial approach. The authors have described the very good results
they have achieved with the sublabial approach.
Albert L. Rhoton, Jr.
Gainesville, Florida
1. Rhoton AL Jr: The sellar region. Neurosurgery 51[Suppl 1]:S335–S374, 2002.
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