transsph results in large series

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CLINICAL STUDIES

RESULTS OF TRANSSPHENOIDAL SURGERY IN A LARGESERIES OF PATIENTS WITH PITUITARY ADENOMA

Pietro Mortini, M.D.

Pituitary Unit,Department of Neurosurgery,

Istituto Scientifico San Raffaele,Universit Vita-Salute, Milan, Italy

Marco Losa, M.D.

Pituitary Unit,

Department of Neurosurgery,Istituto Scientifico San Raffaele,Universit Vita-Salute, Milan, Italy

Raffaella Barzaghi, M.D.Pituitary Unit,Department of Neurosurgery,Istituto Scientifico San Raffaele,

Universit Vita-Salute, Milan, Italy

Nicola Boari, M.D.

Pituitary Unit,Department of Neurosurgery,


Massimo Giovanelli, M.D.

Pituitary Unit,

Department of Neurosurgery,


Reprint requests:

Pietro Mortini, M.D.,Department of Neurosurgery,

Istituto Scientifico San Raffaele,Via Olgettina 60,20132 Milano, Italy.

Email: [email protected]

Received, February 10, 2004.

Accepted, February 7, 2005.

OBJECTIVE: To report the efficacy and safety of microsurgical transsphenoidal surgeryin 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 1990through December 2002 were included in our study. Postoperative results wereclassified uniformly during the period of the study. Patients were considered inremission 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. Meanage 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 surgicalsuccess 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 apoorer outcome (7.4%). In patients with NFPA, no residual adenoma was present in 234patients (64.8%). Normalization of visual defects occurred in 117 (40.5%) of the 289 patientswith 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 mostpatients with pituitary adenoma and could be considered the first-choice therapy in all

cases except for prolactinomas responsive to dopamine agonists. Other treatmentmethods, such as radiotherapy, stereotactic radiosurgery, and medical therapy, play animportant 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

Pituitary adenomas, which account for ap-proximately 10 to 15% of all intracranialtumors in surgical series, usually are clas-

sified according to their secretory activity asgrowth hormone (GH)-secreting adenomas,

prolactin (PRL)-secreting adenomas, adrenocor-ticotropin (ACTH)-secreting adenomas, thyro-tropin (TSH)-secreting adenomas, and clinicallynonfunctioning pituitary adenomas (NFPA).Clinical manifestations of pituitary adenomasare the result of excess hormone secretion (acro-megaly, hyperprolactinemia, hypercortisolism,hyperthyroidism) and/or to compression of thesurrounding structures (hypopituitarism, head-ache, visual disturbances, oculomotor palsy).

The aim of treatment of pituitary adenomas isreversal of endocrine dysfunction with preser-vation of normal pituitary function. Moreover,decompression of the nervous structures andcontrol of tumor growth become increasingly

important when large tumors are considered.Therapeutic options in patients with pituitaryadenomas include surgery, radiotherapy, andmedical treatment. The choice of the more ap-propriate treatment in the individual patientrests mainly on tumor type, age, and clinicalstatus of the patient (23).

Microsurgical removal is the preferred ther-apy for all pituitary adenomas, except for pro-lactinomas, which are usually well controlled

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by chronic medical therapy with dopamine agonists (21, 47).The transsphenoidal approach usually is preferred because ofa lower risk of complications, whereas only few adenomaswith prevalent suprasellar extension are approached througha transcranial route (23, 29, 73). Because of the continuingrefinement of the criteria of cure, it is essential to reexamine

the results of surgery in recently operated patients. The aim ofour study was to report the efficacy and safety of transsphe-noidal surgery in a large series of patients with pituitaryadenoma 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 reportin this study only the results pertaining to 1140 previouslynonoperated 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, symptomsat presentation, history and effectiveness of previous drugtherapy, hormonal data, and complications of surgery. Mag-netic resonance imaging (MRI) was performed on all but sevenpatients at the time of diagnosis. MRI was not performed because of claustrophobia in two patients, the presence ofmagnetic surgical material from previous surgery in threepatients, and placement of a pacemaker for heart disease intwo patients. In these seven patients, a high-resolution com-puted tomographic (CT) scan of the hypothalamic-pituitaryregion was performed. Maximum tumor diameter was mea-

sured on the preoperative MRI or CT scan. Tumors wereclassified as invasive into the cavernous sinus according toGrade III and IV of the classification proposed by Knosp et al.(34). Long-term information for patients not followed up atour center was obtained by directly contacting the patient, thepatients endocrinologist, or the referring physician by tele-phone. We collected information particularly on complica-tions related to surgery and last determination of hormonelevels, last neuroimaging examination, current or past use ofhormonal 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 normalgonadotropin levels were required in both cases. Secondaryhypothyroidism was diagnosed in patients with low free T4levels 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 toreplacement therapy with glucocorticoids. Postoperative dia-betes insipidus was diagnosed when hypotonic polyuria (40ml/kg body weight daily) ensued after surgery and lasted forat least 3 months. Hyponatremia was defined as the occur-rence of serum Na levels less than 132 nmol/L.

Hormone concentrations on referral as well as those duringfollow-up were measured at a large number of laboratoriesthat use different assay kits. During the period covered by thisstudy, histopathological diagnosis was based on hematoxylinand 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 onlateral 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 airinto the subarachnoid space.

The patient is placed in the supine position on the operativetable (OPT, Trento, Italy) with the back elevated to 30 degreesand the head tilted back to 20 degrees and toward the leftshoulder 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-mlsolution of mepivacaine and adrenaline (20 mg/ml; Mepifo-ran; Baxter, Glendale, CA) is injected bilaterally at the caudalend of the nasal septum and at the buccogingival junction toallow analgesia and to facilitate dissection of the nasalmucosa.

A microscope is used at the beginning of surgery. The upperlip is gently retracted superiorly. A transverse 2-cm incision ismade 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 untilthe nasal spina and the inferior border of the pyriform aper-ture are exposed. The nasal spina is left in place to avoidpostoperative downward displacement of the tip of the nose.The septal cartilage is detached from the nasal spina and asubperichondrial blunt dissection is carried out to develop aseptal 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 theperpendicular plate of the ethmoid, which forms the bony partof the septum. The cartilaginous portion of the septum isdislocated and deflected to the right. A longer nasal speculumis introduced, and the blunt dissection is continued.

The bony nasal septum then is dissected free from themucosa bilaterally. The rostrum sphenoidale is exposed. Alarge piece of the bony septum is removed and preserved inantibiotic solution for the sellar closure; however, its lowerpart is spared to have a midline landmark in case of reopera-tion for recurrence. In case of septal deviation, which is veryfrequent in acromegaly, this step of surgery treats the unilat-eral nasal obstruction often reported by patients.

The self-retracting Cushing-Landolt pituitary speculum isinserted and is opened gently. The anterior wall of the sphe-

SURGICAL THERAPY OF PITUITARY ADENOMAS

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noid is opened widely using a drill. The intrasphenoidal mu-cosa and the septa are removed. The sellar wall is identified. Incase of nonpneumatized sphenoid sinusthe so-called con-chal typethis is carried out starting from the upper half ofthe rostrum by gently drilling through the cancellous bone tofind 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 shapeand is reflected inferiorly. The removal of the tumor is carriedout using ring curettes, grasping forceps, and dissectors. Incase of macroadenomas with suprasellar extension, the air canbe injected through the lumbar needle into the subarachnoidspace to push the suprasellar tumor down into the sella. Afterthe removal of large macroadenomas and completion of he-mostasis, the inspection of the intrasellar space is carried outusing 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 thecases of microadenomas and intrasellar macroadenomas, asleeve of bovine pericardium (Tutopach; Tutogen MedicalGmbH, Neukirchen, Germany) is placed under the bony bor-der of the sellar opening. A fragment of bone from the nasalseptum is tailored and is placed superficially to the duralpatch and is kept in place by inserting it under the bonyborders of the sellar opening. The fibrin glue (Tissucol; BaxterCorp.) then is applied.

In cases of macroadenomas with suprasellar extension, thediaphragma sellae must be reconstructed using a sleeve of bovine pericardium attached to the suprasellar cisterns byfibrin glue and be reflected anteriorly to close the opening of

the sellar dura. A tailored bony fragment then is placed closeto the sellar wall as described above. The fibrin glue then isapplied. An antibiotic solution of rifamycin (250 mg; Rifocin;Lepetit S.p.A, Lainate, Milan, Italy) is left in the sphenoidsinus after washing with peroxide and saline solution. When asmall intraoperative cerebrospinal fluid (CSF) leak occurs, 20to 30 ml of CSF are drained through the lumbar needle duringthe diaphragma sellae reconstruction and the sellar closure. Ifa considerable CSF leak occurs, the same amount of CSFdescribed above is drained through the lumbar needle, but atthe end of surgery, a lumbar CSF external diversion is placedto drain 150 ml/24 h daily for 5 days. In this case, the antibioticprophylaxis 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 septalmucosa medially to cover the residual bony and cartilaginousseptum, which is placed on the midline in the primitive loca-tion, and having enlarged the sphenoidal mucosal ostia toavoid the formation of a postoperative mucocele. The nasalpacking is carried out under microscopic view using two softstandard nasal dressings (Merocel; Medtronic Xomed SurgicalProducts, Jacksonville, FL). Care is given to avoid displace-ment of the turbinates. Rifamycin solution is applied to soakthe nasal dressing after it has been introduced in the nasal

cavities. The sublabial wound then is sutured with absorbablethread (Safil Quick; Braun, Tuttlingen, Germany). The patientis awakened immediately and sent to the recovery room for 2hours. After the neurological function and vital parametershave 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 hourbefore, during, and 6 hours after surgery. On the first postop-erative day, patients receive 4 mg methylprednisolone bymouth thrice daily; on the second and third postoperativedays, they receive 4 mg methylprednisolone twice daily, andthen they receive 4 mg methylprednisolone in the morning.For patients with Cushings disease, glucocorticoid replace-ment therapy usually is stopped on the fourth postoperativeday 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-hourintake and output of fluids is monitored until discharge. Eachday, 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 medicalconditions, such as heart valvular disease and mitral valveprolapse, or the placement of a lumbar CSF external diversion.

Criteria of Cure

Postoperative results were classified uniformly during theperiod of the study. Patients were considered in remission ofdisease when the following criteria were met:

1) GH-secreting adenoma. Basal or oral glucose tolerancetest-suppressed GH less than 1 g/L (or 2 g/L until 1994when a radioimmunoassay not specific for the 22-K moiety ofGH was still in use) and normalization of elevated insulin-likegrowth factor 1 levels.

2) PRL-secreting adenoma. Normalization of basal PRL lev-els (20 g/L in women and 15 g/L in men) withoutdopaminergic therapy for at least 2 months.

3) ACTH-secreting adenoma. Presence of hypocortisolismrequiring glucocorticoid substitution therapy or, in the case ofnormal serum and urinary cortisol levels, suppression of se-rum cortisol level after an overnight low-dose dexamethasonetest.

4) TSH-secreting adenoma. Normalization of TSH, free tri-iodothyronine, and free thyroxine in hyperthyroid patients.Normal suppression of TSH levels after the administration of25 g triiodothyronine orally every 6 hours for 10 days inpatients who had previously received thyroablative therapies.

5) Nonfunctioning pituitary adenoma. Absence on the firstpostoperative MRI, usually performed 3 to 6 months aftersurgery, of residual adenomatous tissue.

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Moreover, in the case of a hormone-active pituitary ade-noma, hormone levels had to remain normal for a minimum of6 months, otherwise patients were considered to be surgicalfailures.

RESULTSPatient Characteristics

During the study period, 1140 patients were underwentsurgery at our department for a pituitary adenoma throughthe transsphenoidal approach. The most frequent tumor typewas NFPA (378 patients; 33.2%), followed by GH-secretingadenoma (320 patients; 28.1%), ACTH-secreting adenoma (262patients; 23.0%), PRL-secreting adenoma (151 patients; 13.2%),and TSH-secreting adenoma (29 patients; 2.5%). There were681 females (59.7%) and 459 males (40.3%). The mean age was43.0 0.4 years (range, 882 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 aclinical picture of pituitary apoplexy at presentation; most ofthem had an NFPA (38 patients) or a PRL-secreting adenoma(12 patients), whereas pituitary apoplexy was infrequent inthe 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 studypopulation, subdivided according to tumor type.

Deficit of visual acuity or visual fields was present in 289patients (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-secretingadenoma (2 patients). Moreover, 22 patients (1.9%) also hadimpairment of oculomotor function, causing diplopia and/orptosis in one eye. Fourteen of these patients had pituitaryapoplexy at presentation, whereas all the others had a tumorinvading the cavernous sinus. Again, the tumor type mostfrequently associated with oculomotor defect was NFPA (16patients), 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, mildhyperprolactinemia 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 Cushings diseasehad a very low frequency of hyperprolactinemia (5.4%), prob-ably reflecting the low number of macroadenomas in thisgroup. Data on gonadal function were available for 1087(95.4%) of the 1140 patients: hypogonadism was diagnosed in70.8% of NFPA patients, 41.8% of GH-secreting adenoma pa-tients, 88.0% of PRL-secreting adenoma patients, 41.1% ofACTH-secreting adenoma patients, and 20.7% of TSH-secreting adenoma patients. Excluding the 29 patients with aTSH-secreting adenoma, data on thyroid function were avail-able for 1054 of the 1140 patients (94.9%): hypothyroidism wasdiagnosed in 23.2% of NFPA patients, 4.5% of GH-secretingadenoma patients, 7.3% of PRL-secreting adenoma patients,and 2.0% of ACTH-secreting adenoma patients. Excluding the262 patients with Cushings disease, data on adrenal functionwere 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 atranssphenoidal approacha

Type of adenoma(no.)

Mean age SE (yr) Female (%) Macroadenoma (%)Invasiveness into thecavernous 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.




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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 criteriaoutlined under Patients and Methods. Table 2 summarizes theresults in patients with hormone-active pituitary adenoma,subdivided according to tumor size and invasiveness into thecavernous sinus. The overall rate of early surgical success wasachieved in 504 (66.1%) of the 762 patients with a hormone-active adenoma. As expected, surgical outcome was better inpatients 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%). Dataon a first postoperative MRI or CT scan (in patients withcontraindication to MRI) were available in 361 (95.5%) of the

378 patients with NFPA. No residual adenoma was present in234 patients (64.8%), whereas tumor rests were seen in 127patients (35.2%).

Normalization of visual defects occurred in 117 (40.5%) ofthe 289 patients with visual disturbances and improved inanother 148 patients (51.2%). In 21 patients (7.3%), visualdefects remained unchanged, whereas it worsened in the re-maining 3 patients (1.0%), of whom 1 patient experienced aretinal hemorrhage on the third postoperative day (Table 3).Defects of oculomotor nerves regressed after surgery in 18patients (85.7%) and remained unchanged in the remaining 3patients (14.3%).

Recurrence of pituitary adenoma was deemed to occur inhormone-active tumors when patients showed biochemicalsigns of hormone hypersecretion, independently of the MRIimage, whereas in patients with NFPA, tumor recurrence wasbased on MRI data, independently of the clinical picture.

TABLE 2. Early surgical outcome in 762 patients operated on for a hormone-active pituitary adenomaa

Type of adenomaOverall surgical

remissionSurgical remission in

microadenomasSurgical remission in

macroadenomaSurgical remission in

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

Series (ref. no.)Patients with deficits/

patients operatedNormalized Improved Unchanged Worsened

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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The mean follow-up in the 117 acromegalic patients in remis-sion of disease after surgery and a follow-up of longer than 1year 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 wasmanaged with medical therapy alone in four patients, radiationtherapy alone in four patients, and surgery plus radiation ther-apy in the remaining patient. The mean follow-up in the 73patients successfully operated for a PRL-secreting adenoma anda follow-up of longer than 1 year was 53.0 3.8 months. Duringthe 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 wasmanaged with dopamine agonists alone in 10 patients, surgeryplus dopamine agonists in 1 patient, and observation alone in theremaining 2 patients. The mean follow-up in the 114 patients inremission of Cushings disease after surgery and a follow-up oflonger than 1 year was 37.8 2.1 months. During the studyperiod, 12 patients (8.4%) had recurrence of hypercortisolism,which occurred 12, 21, 26, 32, 39, 44, 50, 55, 60, 63, 71, and 73months after surgery. Recurrence was managed with radiationtherapy alone in five patients, repeat transsphenoidal surgery in

TABLE 4. Surgical complications of transsphenoidal surgery in our series and in a review of the literaturea

Series (ref. no.)No. of

patientsPostoperative

CSF leakbPostoperative

meningitis

Intracranialarterial

lesions

Rebleedingb

after

surgery

Postoperativeoculomotor

nerve deficit

Postoperative

visualfunction

deterioration

Death

Guiot and Derome, 1976

(27)

613 1.3% 0.5% R 0.3% 1.4%

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

Wilson and Dempsey,1978 (77)

250 6.4% 2.0% No R 0.4% 1.2% 1.2% T 2.4% T

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

1% P

Fahlbusch and Stass, 1981(16)

601 1.2%

Hardy and Mohr, 1981(30)

355 0.8% 0.6% T 1.2% T

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

Hardy and Mohr, 1985c 1102 0.9%

Landolt, 1985c 496 0.8%

Tindall and Barrow, 1986(71)

709 0.3%

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

Buchfelder andFahlbusch, 1988 (8)

500 0.4% T 0.6% T

Buchfelder and

Fahlbusch, 1992 (9)

1024 0.4% R

1.0% No R

Onesti and Post, 1993(51)

700 0.4% R

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).




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two patients, medical therapywith ketoconazole alone intwo patients, transsphenoidalsurgery plus radiation therapyin one patient, radiation ther-apy plus bilateral adrenalec-

tomy in one patient, and bilat-eral adrenalectomy alone inthe remaining patient. Themean follow-up in the 16 pa-tients successfully operatedfor a TSH-secreting adenomaand a follow-up of longer than1 year was 50.6 9.2 months.During the study period, 3 pa-tients (18.7%) experienced re-currence of hyperthyroidismand/or regrowth of the pitu-itary tumor, which occurred 7,

41, and 50 months after sur-gery. Recurrence was man-aged with radiation therapyalone in two patients and withsurgery plus radiation therapyin the remaining patient. Themean follow-up in the 174NFPA patients without evi-dence of tumor rest on the firstpostoperative MRI scan and afollow-up of longer than 1year was 54.9 2.5 months.During the study period, 23

patients (13.2%) had MRI evi-dence of recurrent tumor. Themean time to recurrence was61.4 7.6 months (range, 12140 mo). Recurrence was man-aged with radiation therapyalone in 15 patients, surgeryplus radiation therapy in 4 pa-tients, and observation in theremaining 4 patients.

Complications of Surgery

Complications of surgery,together with a review ofother surgical series (6, 8, 9, 16,27, 30, 32, 36, 50, 51, 71, 77), aresummarized in Table 4. Threepatients (0.3%) died as a con-sequence of surgery. A 75-year-old man with a largeNFPA causing worsening vi-sual defects had intratumoralhemorrhage in the suprasellarpart of the tumor, which could

TABLE 5. Results of surgery for acromegaly in relation to different criteria ofpostoperative evaluationa


patientsPatients with GH


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not be removed completely through the transsphenoidal ap-proach. The patient had visual loss in one eye and altered sen-

sorium; however, because of old age and heart disease, transcra-nial evacuation of the suprasellar tumor was deemed not to befeasible and the patient was managed conservatively. The patientthen slowly improved but remained bedridden. Two monthsafter surgery, the patient died suddenly, probably because ofmyocardial infarction or pulmonary embolism. The second pa-tient, a 69-year-old woman with a giant NFPA causing blindnessin one eye and severe visual defect in the other eye, was operatedthrough the transsphenoidal route because of poor myocardialfunction with the aim of relieving compression of the optic path-way. However, the tumor was of firm consistency, thus prevent-ing removal of a large suprasellar part. Six hours after surgery,the patient had barely awakened and a CT scan showed a mas-sive hemorrhage within the residual adenoma. The patient diedon the fourth postoperative day. The third patient, a 72-year-oldwoman with Cushings disease, reported abdominal pain on thethird postoperative day. A surgical consultant advised laparos-copy. A ruptured colon diverticulum was found and repaired.However, there was wound dehiscence and infection. Despiteantibiotic treatment and further surgical procedures, the patientdied of heart failure 2 months after transsphenoidal surgery.Another patient with Cushings disease had an intraoperativecardiac arrest because of a pulmonary embolism, which resultedin the patient entering a permanent vegetative state.

Postoperative rhinoliquor-rhea requiring a new opera-tion occurred in three patients.In one patient, rhinoliquor-rhea was treated using an ex-ternal lumbar drain for 5 days.

Only one case of postoperativemeningitis occurred in a pa-tient who likely had contami-nation from the external lumbar drain placed to treat anintraoperative CSF leak. Post-operative intrasellar hema-toma, causing deterioration ofvisual function, developed infour patients and required ur-gent transsphenoidal evacua-tion of the hematoma. Visualfunction recovered in all four

patients. Deep vein thrombo-sis occurred in four patients,and pulmonary embolism oc-curred in another three pa-tients. Another three patientswith Cushings disease hadseizures 6 to 10 days after sur-gery, which was the result ofthrombosis of the cerebralveins. Rhinological complica-tions included one case of mu-

cocele that required surgery, two cases of epistaxis that requiredfurther nasal tamponade, one case of symptomatic septal perfo-

ration, and one case of sinusitis treated medically.Thirty-three patients experienced hyponatremia 5 to 7 days aftersurgery. Severe hypokalemia (3 nmol/L) was recorded in 10 pa-tients. Postoperative diabetes insipidus, lasting for at least 3 months,developed in 45 patients (4.1%). In 37 (82%) of 45 patients, however,it disappeared after a mean of 9 months (range, 449 mo).

New cases of hypogonadism occurred in 9 (2.0%) of the 456assessable patients at risk of experiencing it. The highest riskof developing hypogonadism was observed in patients withNFPA (3.7%) and Cushings disease (3.0%). New cases ofhypothyroidism occurred in 20 (2.2%) of the 916 assessablepatients at risk of experiencing it. The highest risk of devel-oping hypothyroidism was observed in patients with NFPA(6.1%). New cases of hypoadrenalism occurred in 25 (3.3%) ofthe 746 assessable patients at risk of experiencing it. Thehighest risk of developing hypoadrenalism was observed inpatients with NFPA (7.1%).

DISCUSSION

Transsphenoidal surgery in our series afforded good controlof tumor growth and led to remission of clinical and endocrino-logical dysfunction in a large percentage of cases. Our results arecomparable with those of other previously published major se-

TABLE 7. Surgical results in patients with Cushings disease: series with more than 50 cases reported


patientsPatients

curedPatients with

recurrenceMean

follow-up (mo)

Hardy et al., 1982 (28) 75 84% 0% 21

Fahlbusch et al., 1986 (17) 101 70% 7% 39

Nakane et al., 1987 (48) 100 86% 9% 38

Guilhaume et al., 1988 (26) 61 69% 14% 24

Mampalam et al., 1988 (41) 216 79% 5% 46

Burke et al., 1990 (11) 54 81% 5% 56

Tindall et al., 1990 (72) 53 87% 2% 57

Robert and Hardy, 1991 (57) 78 77% 8% 77

Bochicchio et al., 1995 (7) 668 76% 13% 57

Knappe and Ludecke, 1995 (33) 310 85% 11% 33Swearingen et al., 1999 (70) 161 85% 7% 104

Stevenaert et al., 2002 (69) 167 85% 15% 58

Rees et al., 2002 (56) 54 77% 5% 72

Shimon et al., 2002 (66) 77 78% 5% 50

Current series 262 78% 8% 38




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ries (Tables 3, 57) (1, 4, 5, 7, 11, 15, 1719, 22, 26, 28, 31, 33, 35,

3941, 43, 44, 46, 48, 49, 5258, 6062, 6467, 69, 70, 72, 75, 76).When considering the results of pituitary surgery, it is veryimportant to pay attention to the criteria of cure. Acromegalyexemplifies the continuing evolution of criteria of cure. Indeed,the old surgical series considered a basal GH level lower than 5g/L to indicate remission of disease, but it became clear laterthat a more thorough endocrine evaluation, including GH levelsduring oral glucose load and basal insulin-like growth factor Imeasurement, was necessary to avoid misclassification of surgi-cal results. Interestingly, the availability of very specific GHassays has led to gradual lowering of the GH level needed toestablish hormonal remission of the disease (25). There is stillsome disagreement on the criteria of cure for Cushings disease,with some authors (74) advocating postoperative hypocorti-solism as absolutely necessary to define surgical remission of thedisease, whereas we and others (7, 45) believe that normalizationof cortisol secretion, provided a normal suppressibility to low-dose dexamethasone testing exists, is sufficient to define remis-sion of disease. The acceptability of our criteria is demonstratedfurther by the relatively low incidence of recurrence of Cushingsdisease during follow-up. We have confirmed the data of otherauthors that, in experienced hands, surgery is an effective ther-apy for both endocrine active and nonfunctioning pituitary ad-enomas (2, 14, 24). Our results in hormone-active adenomas

confirm that microadenomashave the highest rate of surgi-cal remission, whereas inva-sion of the cavernous sinus isthe worst prognostic factor forcomplete tumor removal (Ta-

ble 2) (38).One of the major advan-

tages of surgical therapy is theimmediate effect on either hor-mone hypersecretion or com-pressive symptoms, such asvisual disturbances. On thecontrary, radiation therapymay take several years to beeffective, and during this pe-riod, patients remain exposedto the deleterious effects ofcontinued hormone hyperse-

cretion and/or tumor com-pression on surrounding ner-vous structures. Fractionatedradiation therapy, moreover,carries a higher risk than sur-gery of damaging residual pi-tuitary function duringfollow-up (37, 59, 68). Highlyfocused radiation therapy,such as gamma knife radiosur-gery, may diminish the risk ofhypopituitarism, especially

when the irradiated tumor is separated from the normal pituitary

gland and the pituitary stalk may be spared (20). At present,radiation therapy should be considered to be a very importantadjuvant treatment for those patients with residual disease aftermaximal surgical debulking. Only patients with clear contrain-dications to surgery or who express a strong preference fornoninvasive procedures should be considered for first-line radi-ation therapy.

The efficacy and safety of transsphenoidal surgery results infavorable cost savings. In fact, a course of radiotherapy or con-tinued medical treatment costs more than proper surgical treat-ment. Moreover, with the increasing experience of a dedicatedpituitary surgeon, the incidence of postoperative hypopituitar-ism, and hence the costs of replacement therapy, decrease (14).Our results in secreting adenomas were evaluated according tohormonal criteria of cure. Compared with other intracranial tu-mors, this is a completely different way to assess the results ofsurgical therapy. As previously reported, restrictive criteria ofcure are related to a lower percentage of early remission but to amore durable remission at follow-up (3, 10).

In NFPAs, the role of MRI follow-up is to assess the true recur-rence of a radically removed adenoma or the regrowth of residualtumor. This is of paramount importance to plan further treatments,such as radiosurgery or radiotherapy, before the mass becomessymptomatic and a second surgical procedure is needed.

TABLE 8. Morbidity of pituitary surgerya

No. of patients

500 Our series

Nasal septum perforation 7.6 4.6 3.3 0.1

Postoperative epistaxis 4.3 1.7 0.4 0.2

Sinusitis 9.6 6.0 3.6 0.1

Carotid artery injury 1.4 0.6 0.4 0

CNS injury 1.6 0.9 0.6 0

Hemorrhage into residual tumor bed 2.8 4 0.8 0.4

Permanent loss of vision 2.4 0.8 0.5 0

Ophthalmoplegia 1.9 0.8 0.4 0

CSF leak 4.2 2.8 1.5 0.3

Meningitis 1.9 0.8 0.5 0.1

Anterior pituitary insufficiency 20.6 14.9 7.2 2.7b

Diabetes insipidus 19 7.6 4.1

Death 1.2 0.6 0.2 0.3

a Overall comparison between our data and the data previously reported in the literature in a multicentric study (13) in

which patients were grouped according to the total number of cases operated on by the surgeon. CNS, central nervoussystem; CSF, cerebrospinal fluid.b At least one axis.

MORTINI ET AL.



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Our data suggest that the first transsphenoidal approach to thesella 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 theexperience of a well-trained pituitary surgeon is mandatory toavoid the loss of time and major complications related to the

approach, as previously reported by others (13) (Table 8). In ouropinion, the use of devices that help the surgeon to keep himoriented 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. Accordingto our data, the rhinological, neurological, and endocrine com-plications are lower than those reported in other series evenusing newly developed procedures (12).

The low percentage (0.4%) of postoperative CSF leak isexplained not only by a careful surgical technique, but also bythe use of the intraoperative lumbar needle that helps thecisternal repairing of small intraoperative CSF leaks. The CSFlumbar external diversion is not used as a routine procedure

but only in case of large leaks, which are expected to needseveral 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 probablythe 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 beperformed by an experienced pituitary surgeon supported byan equally experienced team of endocrinologists, neuroradi-ologists, neuroanesthetists, and neuropathologists specializedin pituitary pathology. The collaboration between these spe-cialists helps in achieving the best possible results and incollecting as much data as possible on the clinical aspects andbiological behavior of pituitary adenomas.

Taking into account our results and those reported in theliterature, 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.

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COMMENTS

This series of 1140 patients treated over a 13-year period by twoexperienced pituitary surgeons once again confirms, as has beenshown for at least 2 decades, that transsphenoidal surgery is a safeand effective first-line therapy for most patients with pituitary ade-nomas. The importance of accumulated surgical experience and adedicated 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, includingendonasal endoscopic and endonasal microscopic approaches, thisreportreminds us that thesublabial route remains in many ways thegold 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 nolonger taught to neurosurgical residents. Although it is true that themost important goal in treating patients with a pituitary adenoma isachieving as complete and safe a tumor removal as possible, otherissues, such as postoperative rhinological complaints and length ofhospital stay, are now gaining in importance as the overall safetyand efficacy of transsphenoidal surgery has become more uniform,particularly at dedicated pituitary surgery centers.

Consequently, these newer endonasal endoscopic and endonasalmicroscopic techniques, which require less mucosal dissection andno nasal packing, are gaining widely in popularity among bothneurosurgeons and their patients because they facilitate a morerapid rhinological recovery and a shorter hospital stay. Althoughthe authors claim that the sublabial approach had a lower rate of

rhinological complications than the endoscopic approach, it is im-portant to note that such complaints tend to be underreported aftertranssphenoidal surgery unless patients are specifically queried (1).It seems quite certain that these newer endonasal approaches arehere 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. KellyLos 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 98:350358, 2003.

This is an excellent article from a well-respected Italian academiccenter in Milan. It covers a large series of pituitary adenomasoperated 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 welcomefeature of this article, because it confirms theexcellentoutcomes thatare a testimony to the skills of their group. The data regardingrecurrence are of extreme importance and continue to remind usthat the longer patients with pituitary tumors are carefully followedup, the higher the true recurrence rates become. The outcomes arealso characterized by modern criteria for remission, and the articleincludes 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

This 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 usedan endonasal technique directed through the nostril without inci-sion or elevation of the mucosa on the nasal septum. The approachis directed between the septum and turbinates to the sphenoid face,which is opened. The technique is described elsewhere (1). Theadvantages of the endonasal, compared with the sublabial, ap-proach are the reduced operative time, reduced discomfort andcomplications related to the septal mucosal and septal dissection,reduced bleeding, and the infrequent need for nasal packing afterthe 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]:S335S374, 2002.



transsph results in large series

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