Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based classification

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OBJECT

An important prognostic factor for the surgical outcome and recurrence of a pituitary adenoma is its invasiveness into parasellar tissue, particularly into the space of the cavernous sinus (CS). The aims of this study were to reevaluate the existing parasellar classifications using an endoscopic technique and to evaluate the clinical and radiological outcomes associated with each grade.

METHODS

The authors investigated 137 pituitary macroadenomas classified radiologically at least on one side as Grade 1 or higher (parasellar extension) and correlated the surgical findings using an endoscopic technique, with special reference to the invasiveness of the tumor into the CS. In each case, postoperative MRI was performed to evaluate the gross-total resection (GTR) rate and the rate of endocrinological remission (ER) in functioning adenomas.

RESULTS

The authors found a 16% rate of CS invasion during surgery for these macroadenomas. Adenomas radiologically classified as Grade 1 were found to be invasive in 1.5%, and the GTR/ER rate was 83%/88%. For Grade 2 adenomas, the rate of invasion was 9.9%, and the GTR/ER rate was 71%/60%. For Grade 3 adenomas, the rate of invasion was 37.9%, and the GTR/ER rate was 75%/33%. When the superior compartment of the CS (Grade 3A) was involved, the authors found a rate of invasion that was lower (p < 0.001) than that when the inferior compartment was involved (Grade 3B). The rate of invasion in Grade 3A adenomas was 26.5% with a GTR/ER rate of 85%/67%, whereas for Grade 3B adenomas, the rate of surgically observed invasion was 70.6% with a GTR/ER rate of 64%/0%. All of the Grade 4 adenomas were invasive, and the GTR/ER rate was 0%.

A comparison of microscopic and endoscopic techniques revealed no difference in adenomas with Grade 1 or 4 parasellar extension. In Grade 2 adenomas, however, the CS was found by the endoscopic technique to be invaded in 9.9% and by microscopic evaluation to be invaded in 88% (p < 0.001); in Grade 3 adenomas, the difference was 37.9% versus 86%, respectively (p = 0.002). Grade 4 adenomas had a statistically significant lower rate of GTR than those of all the other grades. In case of ER only, Grade 1 adenomas had a statistically significant higher rate of remission than did Grade 3B and Grade 4 adenomas.

CONCLUSIONS

The proposed classification proved that with increasing grades, the likelihood of surgically observed invasion rises and the chance of GTR and ER decreases. The direct endoscopic view confirmed the low rate of invasion of Grade 1 adenomas but showed significantly lower rates of invasion in Grade 2 and 3 adenomas than those previously found using the microscopic technique. In cases in which the intracavernous internal carotid artery was encased (Grade 4), all the adenomas were invasive and the GTR/ER rate was 0%/0%. The authors suggest the addition of Grades 3A and 3B to distinguish the strikingly different outcomes of adenomas invading the superior CS compartments and those invading the inferior CS compartments.

ABBREVIATIONSCS = cavernous sinus; ER = endocrinological remission; GTR = gross-total resection; ICA = internal carotid artery.

Abstract

OBJECT

An important prognostic factor for the surgical outcome and recurrence of a pituitary adenoma is its invasiveness into parasellar tissue, particularly into the space of the cavernous sinus (CS). The aims of this study were to reevaluate the existing parasellar classifications using an endoscopic technique and to evaluate the clinical and radiological outcomes associated with each grade.

METHODS

The authors investigated 137 pituitary macroadenomas classified radiologically at least on one side as Grade 1 or higher (parasellar extension) and correlated the surgical findings using an endoscopic technique, with special reference to the invasiveness of the tumor into the CS. In each case, postoperative MRI was performed to evaluate the gross-total resection (GTR) rate and the rate of endocrinological remission (ER) in functioning adenomas.

RESULTS

The authors found a 16% rate of CS invasion during surgery for these macroadenomas. Adenomas radiologically classified as Grade 1 were found to be invasive in 1.5%, and the GTR/ER rate was 83%/88%. For Grade 2 adenomas, the rate of invasion was 9.9%, and the GTR/ER rate was 71%/60%. For Grade 3 adenomas, the rate of invasion was 37.9%, and the GTR/ER rate was 75%/33%. When the superior compartment of the CS (Grade 3A) was involved, the authors found a rate of invasion that was lower (p < 0.001) than that when the inferior compartment was involved (Grade 3B). The rate of invasion in Grade 3A adenomas was 26.5% with a GTR/ER rate of 85%/67%, whereas for Grade 3B adenomas, the rate of surgically observed invasion was 70.6% with a GTR/ER rate of 64%/0%. All of the Grade 4 adenomas were invasive, and the GTR/ER rate was 0%.

A comparison of microscopic and endoscopic techniques revealed no difference in adenomas with Grade 1 or 4 parasellar extension. In Grade 2 adenomas, however, the CS was found by the endoscopic technique to be invaded in 9.9% and by microscopic evaluation to be invaded in 88% (p < 0.001); in Grade 3 adenomas, the difference was 37.9% versus 86%, respectively (p = 0.002). Grade 4 adenomas had a statistically significant lower rate of GTR than those of all the other grades. In case of ER only, Grade 1 adenomas had a statistically significant higher rate of remission than did Grade 3B and Grade 4 adenomas.

CONCLUSIONS

The proposed classification proved that with increasing grades, the likelihood of surgically observed invasion rises and the chance of GTR and ER decreases. The direct endoscopic view confirmed the low rate of invasion of Grade 1 adenomas but showed significantly lower rates of invasion in Grade 2 and 3 adenomas than those previously found using the microscopic technique. In cases in which the intracavernous internal carotid artery was encased (Grade 4), all the adenomas were invasive and the GTR/ER rate was 0%/0%. The authors suggest the addition of Grades 3A and 3B to distinguish the strikingly different outcomes of adenomas invading the superior CS compartments and those invading the inferior CS compartments.

The chances of complete resection and endocrinological remission (ER) of pituitary adenomas are reported to depend on their growth rate, size,8,51 histological subtype,3,46 and invasiveness into the surrounding structures. Special attention has been drawn to the endosteum of the sellar floor, the rate of histological invasion into which has been reported to be as high as 46%–85%.52,62 Overt parasellar invasion into cavernous sinus (CS) structures is found intraoperatively in 6%–10%1,20 of cases and is the most important reason for incomplete resection and the decrease in cure rates from 78%–92% (in cases without parasellar invasion) to 20%–52%.16,20,21,24,36,39,62,64

Because of the close relationship of the internal carotid arteries (ICAs), histological specimens of the medial wall are not routinely available,54,65,77 so surgical observations59 and/or radiological signs of invasion14 are still the most important methods of detection.

Previous studies on the prognosis of invasiveness defined by preoperative MRI based the true intraoperative status of invasiveness on observations through an operating microscope.44

Because of the ease of application and its practical relevance, a classification proposed previously44 has become a grading system for surgeons and radiologists.13,19,26,40,41,56,67,73 It is based on coronal sections of T1-weighted contrast-enhanced MRI scans, in which the circular cuts of the ICAs serve as easily detectable radiological landmarks for medial, center, and lateral tangents.14

At the time that these studies were published, the microscopic technique was standard for transsphenoidal surgery, although drawbacks included a limited lateral view toward the medial wall and problems removing tumor tissue compressing or invading the compartments of the space of the CS and the ICA itself. The application of endoscopes in transsphenoidal surgery in the 1990s changed this situation, because the lenses provided a wider field of view.11,15,36,39,60 This wider view enables the surgeon to inspect the medial wall of the CS directly and therefore to pass a more reliable judgment regarding parasellar invasiveness.

The aim of this study was to investigate direct endoscopic visualization of the medial wall of the CS to assess the invasiveness of pituitary adenomas into the CS space and reassess the established classification, which was originally based on observations from a microscopic view.44

Methods

This study was approved by the ethical review committee at the Medical University of Vienna and was performed in accordance with the principles of the Declaration of Helsinki.69

All data were culled from a prospectively acquired database of patients with sella turcica pathology who underwent surgery at the Medical University of Vienna Department of Neurosurgery.

We evaluated a consecutive series of 137 patients with pituitary macroadenomas with parasellar extension. All the surgeries were performed between 2003 and 2013 via a pure endoscopic transnasal transsphenoidal approach. Subsequent surgeries for pituitary adenomas and other pathologies inside the sella turcica were excluded from this study. For patient and tumor characteristics, see Table 1.

TABLE 1

Patient and tumor characteristics

CharacteristicValue
Sex, male/female1:0.85
Age (median ± SD [range]) (yrs)52.5 ± 15 (7–80)
Localization
 Subsellar19
  Suprasellar extension (suprasellar grading*) (no. [%])
  Grade 19 (7)
  Grade 23 (2)
  Grade A36 (26)
  Grade B57 (42)
  Grade C24 (17)
  Grade D8 (6)
 Parasellar grading (no. on rt side, no. on lt side)
  Grade 029, 29
  Grade 131, 37
  Grade 238, 33
  Grade 3A22, 27
  Grade 3B12, 5
  Grade 45, 6
Size (no.)
 Microadenoma0
 Macroadenoma137
 Diameter (median ± SD [range]) (mm)27 ± 10 (11–70)
  11–20 mm (no. [%])42 (31)
  21–30 mm (no. [%])59 (43)
  31–40 mm (no. [%])30 (22)
  >40 mm (“giant”) (no. [%])6 (4)
Hormonal subtype
 Inactive (no.)108
  Null-cell adenoma61
  Gonadotropinoma35
  Silent ACTH5
  Plurihormonal7
 Active (no.)29
  PRL cell adenoma14
  GH cell adenoma14
  ACTH cell adenoma1

ACTH = adrenocorticotropic hormone; GH = growth hormone; PRL = prolactin.

According to Hardy and Vezina30 and Hardy and Wigser.31

According to Knosp et al.44

Magnetic resonance images were acquired in each patient using standard 1.5- or 3.0-T scanners and included T1-weighted coronal slices with and without contrast enhancement preoperatively and postoperatively; T2-weighted images were added in most cases. Our MRI protocol also includes MR angiography as a part of preoperative navigation planning.

Parasellar Extension on MRI (Grading System)

To compare radiological characteristics of CS involvement with our surgical findings, we used a previously published grading system.44 This grading system classifies the parasellar extension of pituitary adenomas on coronal MRI. Three lines connecting the cross-section of the intracavernous and supracavernous ICAs distinguish 4 grades of parasellar adenoma extension: a medial tangent, a line through the cross-sectional centers, and a lateral tangent (Fig. 1). Using this grading system, the parasellar extension of all 137 pituitary adenomas on either side into 274 CSs was retrospectively assessed by A.M., who was blinded to the results of the intraoperative findings. In each case, the parasellar extension was at least Grade 1 on one side, which means that the tumor's growth extended beyond the medial tangent.

FIG. 1.
FIG. 1.

Graphic schemes (left), coronal MR images (center), and endoscopic views (right). A: Grade 0: the adenoma does not encroach on the CS space. Thus, the tangent of the medial aspects of the intracavernous and supracavernous ICAs is not passed.44 B: Grade 1: the medial tangent is passed, but the extension does not go beyond a line drawn between the crosssectional centers of the intracavernous and supracavernous ICAs (the intercarotid line).44 C: Grade 2: the tumor extends beyond the intercarotid line but not past the tangent on the lateral aspects of the intracavernous and supracavernous ICAs.44 D: Grade 3A: the tumor extends lateral to the lateral tangent of the intracavernous and supracavernous ICAs into the superior CS compartment.44 E: Grade 3B: the tumor extends lateral to the lateral tangent of the intracavernous and supracavernous ICAs into the inferior CS compartment. F: Grade 4: there is total encasement of the intracavernous carotid artery.44 AD = adenoma; LCSW = lateral CS wall (seen after removing the medial CS wall); MCSW = medial CS wall; PT = pituitary gland. The asterisk indicates an invaded medial CS wall, and arrows indicate trabeculae. Copyright Engelbert Knosp. Published with permission.

Surgical Technique—Observed Invasion Into the Space of the CS

We usually start with the wider nasal cavity, which facilitates the approach to the ostium.

Depending on the size and the parasellar extension of the adenoma, a mononostril or binostril approach was taken. In each case with encasement of the ICA (Grade 4), the turbinate ipsilateral to the lesion was dissected, and a partial or complete ethmoidectomy was performed to reach the anterior ICA siphon knee adequately.

The sella was approached through the nasal cavity ipsilateral to the side of parasellar tumor extension of higher grade. We used endoscopic equipment with a 4-mm diameter, an 18-cm length, and 0-, 30-, and 45-degree optics (Hopkins optics; Karl Storz GmbH) with a cleaning system. This tool became an important component of this technique.

After opening the bony sellar floor, from one side of the CS to the other side, a quadrangular piece of basal sellar dura was routinely excised and sent for histological assessment of adenoma invasion. If the adenoma invaded the dura diffusely, bone and/or mucosal specimens from the dura itself for histological analysis are sometimes missing. Adenoma resection was commenced after broadly opening the sella floor. Depending on the size and consistency of the tumor, the center of the endosellar part was removed to develop an extracapsular dissection. Whenever possible, the suprasellar component was left unremoved until the parasellar tumor was resected. After tumor debulking, extracapsular dissection was continued with special attention to the parasellar tumor extension.11 This is usually the time to apply 30- and/or 45-degree angled endoscopes and curved or angulated suction devices. Removal of the tumor from the CS space was performed with blunt curettes only. We avoided scissors and sharp instruments unless the ICA was clearly detected. Bleeding from the CS was controlled by hemostyptics and fibrin glue. In a close-up view, the integrity of the medial CS wall was assessed visually. Invasiveness of the adenoma tissue was judged by the performing neurosurgeons (E.K. and S.W.), who documented their impressions in the operating report.

If the medial wall was smooth and intact after tumor removal, we deemed invasion to be absent. If the medial wall was not detectable and trabeculae, intracavernous ligaments, or sympathetic nerve fibers were visible and surrounded by the tumor, we deemed invasion to be present. We also considered an invasion present if the adventitia of the intracavernous ICA was directly visible.

Only after inspection of the medial wall on both sides was the suprasellar tumor part dissected and removed.

Follow-Up

Each patient in this study received postoperative MRI (at 1.5 or 3.0 T) with and without contrast enhancement. MRI, performed 3 months postoperatively, determined gross-total resection (GTR), and yearly follow-up was performed. We used the most recent consensus statements5,6,25,53 to define ER.

Histologically Observed Invasiveness

We obtained basal sellar dura samples of the anterior sellar wall for histological examination. When explicit invasion was observed or suspected, we tried to obtain this part of the endosteum for histological examination. The reasons for not including the results of the remaining specimens were severe coagulation artifacts, fragments too small for a relevant decision to be made, and/or absent endosteum resulting from tumor invasion.

Pituitary adenoma tissue samples were taken not only for immunohistological staining but also for analysis of MIB-1, which is an antibody against Ki-67, a protein expressed in proliferating cells.66

Statistical Analysis

The radiologically determined grade of parasellar tumor extension according to preoperative MRI was evaluated with the reviewer blinded to the surgical results. The rate of tumor invasiveness was then calculated for each radiologically determined grade of parasellar extension. The data are presented as means and ranges for continuous variables and as frequencies for categorical variables.

For the comparison of our results from endoscopic assessments of invasiveness with our previous data from assessments with an operating microscope,44 we used the chi-square test. For comparison of the intraoperative status of invasiveness and the cell-proliferation (MIB-1) index, the independent-samples t-test was used.

A p value of < 0.05 was considered significant. For statistical analyses, SPSS version 20.0 software (SPSS, Inc.) was used.

Results

Parasellar Extension on MRI

On preoperative coronal MRI, the parasellar extension into 274 CSs was Grade 0 in 58 (21%), Grade 1 in 68 cases (25%), Grade 2 in 71 (26%), Grade 3 (into the superior ICA compartment [further named Grade 3A]) in 49 (18%), Grade 3 (into the inferior ICA compartment [further named Grade 3B]) in 17 (6%), and Grade 4 in 11 (4%) (Table 1).

Endoscopic Assessment of Invasiveness Into the CS Space

A comparison with our previously published data (Table 2) derived from a microscopic assessment of invasiveness44 revealed no differences in the invasiveness of Grade 0, 1, and 4 adenomas.

TABLE 2

Adenoma invasiveness into the CS space (left and right sides) according to grade and technique

GradeInvasiveness Observed EndoscopicallyInvasiveness Observed Microscopicallyp Value
No./Total No.%No./Total No.%
00/5800/110NS
11/681.50/80NS
27/719.97/888<0.001
325/6637.912/14860.002
411/111009/9100NS

NS = not significant.

None of the Grade 0 and all of the Grade 4 adenomas were invasive according to intraoperative observations.

In Grades 2 and 3, however, direct endoscopic visualization of the medial CS structures revealed a lower incidence of invasiveness by endoscopic than by microscopic visualization (9.9% vs 88% for Grade 2 and 37.9% vs 86% for Grade 3, respectively). These differences were significant (p < 0.001 and p = 0.002, respectively).

Grade 3 adenomas that extended beyond the lateral tangent of the ICAs into the inferior CS compartment were significantly more commonly invasive than those that extended into the superior compartment (70.6% vs 26.5%, respectively; p < 0.001).

Surgically Observed Invasiveness

In total, signs of invasion were observed in 44 (16.1%) of the 274 CSs. No adenomas with parasellar extension Grade 0 were found intraoperatively to be invasive. Adenomas with parasellar extension Grades 1, 2, and 3 were found to be invasive in 1.5%, 9.9%, and 37.9% of the cases, respectively. Grade 3B adenomas, which extended beyond the lateral tangent of the ICAs into the inferior CS compartment, were significantly more commonly invasive than those that extended into the superior compartment (termed Grade 3A adenomas) (70.6% vs 26.5%, respectively; p < 0.001).

In the analysis of the side of invasion, we found that the inferior compartment was affected more frequently than the superior compartment. Therefore, because of the significant difference, we decided to subdivide Grade 3 into Grade 3A (superior CS compartment) and Grade 3B (inferior CS compartment).

All adenomas with total encasement of the ICA (Grade 4) were confirmed intraoperatively to be invasive. In terms of the correlation between the dural and CS invasiveness of these macroadenomas, we did not find a statistically significant difference and therefore no correlation for the groups as a whole or for the different grades.

Follow-Up

The MRI and endocrinological follow-up period ranged from 3 months to 2 years. GTR, as shown on postoperative MRI, was achieved in 83%, 71%, 85%, and 64% of Grade 1, 2, 3A, and 3B adenomas, respectively. All cases of parasellar extension Grade 4 showed tumor remnants on follow-up MRI. Residuals were usually found as expected in the most difficult-to-access space lateral to the intracavernous ICA.

Endocrinological remission was achieved in 88%, 60%, 67%, 0%, and 0% of Grade 1, 2, 3A, 3B, and 4 adenomas, respectively. Grade 4 adenomas had a statistically significant lower rate of GTR than did all the other grades. In cases of ER, only Grade 1 adenomas had a statistically significant higher rate of remission than Grade 3B and Grade 4 adenomas (Table 3).

TABLE 3

Parasellar invasion compared with GTR /ER and MIB -1

GradeParasellar Invasiveness (%)GTR (%)ER (%)MIB-1 (%)
11.583882.5
29.971602.8
3A26.585672.5
3B70.66402.3
4100004.1

Histologically Observed Invasiveness

In 96 of 137 cases, we obtained samples of the basal sellar dura of the anterior sellar wall for histological examination. Histological signs of basal endosteum invasion were evaluated in 41 (42.7%) of the 96 cases studied.

The MIB-1 analysis of CS-invasive (MIB-1 mean 3.24) and -noninvasive (MIB-1 mean 2.17) adenomas revealed a strong tendency, but no statistically significant correlation, to higher MIB-1 in invasive cases (p = 0.075).

Discussion

Invasiveness

Larger tumor size and growth are the prime causes for incomplete tumor resection and failed ER of pituitary adenomas.16,20,21,36,39,62,64 In contrast to mere tumor extension with lateral displacement of CS structures, the term “invasiveness” is reserved for pituitary adenomas for which infiltrative growth into surrounding structures can be observed during surgery. This invasion by pituitary adenomas was described beautifully by Jefferson35 in 1955, when he identified 14 cases of local spread/infiltration into the CS and the sphenoid sinus, most of which had histological signs of anaplastic and undifferentiated cells. Jefferson reported surgical observations first and then later radiological observations, which resulted in the first radiological classification of pituitary adenomas (based on plain radiographs of the sella turcica).29,31 Hardy and Vezina30 distinguished noninvasive grades (enclosed) from invasive grades. Later, with CT scans, the suprasellar component was visible directly, which led to adoption of their classification (stages A–D). With coronal CT scans of the sella, the anatomy and pathology of the parasellar region came into focus.7 The breakthrough for imaging the CS was MRI technology, which inspired surgeons in this field.18,44,58,61 In coronary sections of the sella, the adenomas and ICAs were easily detectable within the CS space.

A radiological classification of the parasellar growth of adenomas had been proposed previously and applied widely.13,21,27,44,45,63,78 In the higher grades of the classification scale, invasion of the CS space is observed more often and the cure rate decreases inversely.

The judgment of adenoma invasion into the CS space during microscopic transsphenoidal surgery had considerable drawbacks because of the limited area of visualization of the medial wall.

Our study was performed using an endoscopic technique, which made direct visual inspection of the complete medial CS wall possible. Improved illumination, high magnification, and direct close-up views “around the corner” using angled endoscopes offer significant advantages over microscopic transsphenoidal surgery for detecting adenoma invasion of the CS space.9,10,12,22,27,34,36–38,49,57

For Grade 1 and 4 adenomas (with encasement of the ICA), there were no differences between microscopic and endoscopic judgments of invasiveness.

It is remarkable that we have succeeded in demonstrating a significantly lower rate of invasiveness in Grade 2 and 3 adenomas than in those in our original study. The analysis of Grade 3 adenomas revealed significant diversity within the grade. Therefore, the individual cases were further investigated. It became apparent that Grade 3 could be subclassified because of the tumors' extension into either the superior CS compartment or the inferior CS compartment. We therefore subdivided Grade 3 into Grades 3A and 3B. The growth of tumor tissue into the inferior compartment led significantly more often to an invasion of the medial wall of the CS. These results are in concordance with those in previous reports, especially in growth hormone–producing adenomas.4,28,78

With each increasing grade, we found not only a higher rate of invasion but also lower rates of GTR and ER in the follow-up (Table 3).

The histopathological assessment of adenoma invasion into the basal sellar dura adds an additional index for an overall picture of the biological behavior of these tumors. Histological invasiveness of dural structures has been reported to be as common as 46%–85% (42.7% in our present series).52,62

Despite the endoscopic technique, a direct biopsy of the connective tissue of the medial CS wall is not feasible in routine clinical practice because of the danger of injuring neurovascular structures. Resection of the medial wall should be performed by very experienced surgeons only.50

The only direct sign of adenoma invasiveness on preoperative MRI is interruption of the medial CS wall. Using the hypothesis that high-field MR scanners can visualize such discontinuation, we were able to directly demonstrate adenoma invasiveness with high-resolution T2-weighted coronal MRI with high sensitivity and specificity.70 In the clinical setting, however, high-field scanners have failed to routinely result in such high anatomical resolution, possibly because of the susceptibility to artifacts in the region of the skull base and a lack of dedicated imaging sequences. Therefore, to date, the preoperative assessment of CS invasion is still based on indirect radiological signs.

The medial wall of the CS was the focus of this study in cases without adenoma invasion. It is a shiny thin wall that, according to our experience with anatomical dissections, is a well-defined, dissectible membrane adjacent to the lateral part of the pituitary gland. This membrane is fragile but unfenestrated, contrary to reports from Yasuda et al.74–76 Only the inferior hypophyseal artery and the pituitary veins pass through the medial CS wall. Therefore, holes in and/or disruptions of the medial wall of the CS observed during surgery are, according to our experience, results of tumor invasion (when the tumor is found within the space of the CS).

Because it provides direct visualization of the medial wall, the endoscopic technique is the best available method for distinguishing between invasion and compression. Histopathological analysis of the medial wall itself remains the gold standard of diagnosis, but routine biopsies seem to be too dangerous.

MIB-1 Index

Following the revision of the 2004 WHO classification, diagnostic criteria for an atypical adenoma include excessive p53 immunoreactivity, an MIB-1 proliferative index of > 3%, and increased mitotic activity.17 We agree with the concept of atypical adenomas, higher proliferation rates, and invasive growth. We did not correlate our data with p53 expression, because it does not seem to be of pathogenetic significance in pituitary tumors.23,32,33,45,48,55,63 Tumor proliferation markers, such as the Ki-67–targeted MIB-1 labeling index, were observed by others47 and our group42,43,68,71,72 to correlate with more aggressive biological pituitary adenoma behavior, such as an increased growth rate and invasive growth. These recent data support our previous results, although MIB-1 did not achieve significance between the grades, most likely because all of the included tumors were macroadenomas.

Risk of Surgery Within the CS

Because of rupture of the ICAs and damage to cranial nerves III–VI, CS surgery had been avoided previously. Only after the pioneering works of Parkinson,58 Dolenc,18 and others has surgery of the CS (intradural or transcranial) become possible. Using the transsphenoidal route, the risk of ICA injury is currently reported to be 0.5%–1.6%.2

Although we tried to remove as much tumor from the CS space as possible, we caused no ICA injuries during pure endoscopic surgery. We never used sharp instruments such as forceps, scissors, or sharp spoons and inflicted no lacerations on the major vessels or the ICAs. With these precautions, no higher morbidity or mortality rates were encountered. Furthermore, there was no excessive venous bleeding to force the surgeon to stop the surgery or to apply a blood replacement therapy, and no newly diagnosed cranial nerve deficits were observed postoperatively.

Conclusions

Our study shows that at each higher grade, the likelihood of surgically observed adenoma invasion rises and the chance of GTR/ER decreases. Direct endoscopic visualization is the crucial difference that provides a decisive advantage over the microscopic technique. The direct endoscopic view confirmed a low rate of invasion in Grade 1 adenomas and showed significantly lower rates of invasion in Grades 2 and 3 than previously found using the microscopic technique. In cases in which the intracavernous ICA was total encased (Grade 4), all the adenomas were invasive, and the GTR/ER rate was 0%/0%. We suggest adding Grades 3A and 3B to the existing parasellar classification to distinguish the strikingly different outcomes of adenomas invading the superior CS compartments and those invading the inferior CS compartments.

Acknowledgment

We thank Brigitte Dobsak for drawing the illustrations.

Author Contributions

Conception and design: Micko. Acquisition of data: Micko. Analysis and interpretation of data: Micko, Wöhrer. Drafting the article: Micko. Critically revising the article: Knosp, Wolfsberger. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Knosp. Statistical analysis: Micko. Administrative/technical/material support: Wöhrer.

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    Gamea AFathi Mel-Guindy A: The use of the rigid endoscope in trans-sphenoidal pituitary surgery. J Laryngol Otol 108:19221994

  • 23

    Gejman RSwearingen BHedley-Whyte ET: Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol 39:7587662008

  • 24

    Giovanelli MLosa MMortini P: Surgical therapy of pituitary adenomas. Metabolism 45:8 Suppl 11151161996

  • 25

    Giustina AChanson PBronstein MDKlibanski ALamberts SCasanueva FF: A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 95:314131482010

  • 26

    Gondim JAAlmeida JPAlbuquerque LAGomes EFSchops M: Giant pituitary adenomas: surgical outcomes of 50 cases operated on by the endonasal endoscopic approach. World Neurosurg 82:e281e2902014

  • 27

    Guiot JRougerie JFourestier MFournier AComoy CVulmiere J: [Intracranial endoscopic explorations]. Presse Med 71:122512281963. (Fr)

  • 28

    Hagiwara AInoue YWakasa KHaba TTashiro TMiyamoto T: Comparison of growth hormone-producing and non-growth hormone-producing pituitary adenomas: imaging characteristics and pathologic correlation. Radiology 228:5335382003

  • 29

    Hardy JTranssphenoidal surgery of hypersecreting pituitary tumors. Kohler PORoss GT: Diagnosis and Treatment of Pituitary Tumors: Proceedings of a Conference AmsterdamExcerpta Medica1973. 179198

  • 30

    Hardy JVezina JL: Transsphenoidal neurosurgery of intracranial neoplasm. Adv Neurol 15:2612731976

  • 31

    Hardy JWigser SM: Trans-sphenoidal surgery of pituitary fossa tumors with televised radiofluoroscopic control. J Neurosurg 23:6126191965

  • 32

    Hentschel SJMcCutcheon EMoore WDurity FA: P53 and MIB-1 immunohistochemistry as predictors of the clinical behavior of nonfunctioning pituitary adenomas. Can J Neurol Sci 30:2152192003

  • 33

    Herman VDrazin NZGonsky RMelmed S: Molecular screening of pituitary adenomas for gene mutations and rear-rangements. J Clin Endocrinol Metab 77:50551993

  • 34

    Jankowski RAuque JSimon CMarchal JCHepner HWayoff M: Endoscopic pituitary tumor surgery. Laryngoscope 102:1982021992

  • 35

    Jefferson G: The Invasive Adenomas of the Anterior Pituitary LiverpoolUniversity Press1955

  • 36

    Jho HD: Endoscopic transsphenoidal surgery. J Neurooncol 54:1871952001

  • 37

    Jho HDCarrau RL: Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg 87:44511997

  • 38

    Jho HDCarrau RL: Endoscopy assisted transsphenoidal surgery for pituitary adenoma. Technical note. Acta Neurochir (Wien) 138:141614251996

  • 39

    Kabil MSEby JBShahinian HK: Fully endoscopic endonasal vs. transseptal transsphenoidal pituitary surgery. Minim Invasive Neurosurg 48:3483542005

  • 40

    Kim MSJang HDKim OL: Surgical results of growth hormone-secreting pituitary adenoma. J Korean Neurosurg Soc 45:2712742009

  • 41

    Kitano MTaneda MShimono TNakao Y: Extended transsphenoidal approach for surgical management of pituitary adenomas invading the cavernous sinus. J Neurosurg 108:26362008

  • 42

    Knosp EKitz KPerneczky A: Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery 25:9279301989

  • 43

    Knosp EKitz KSteiner EMatula C: Pituitary adenomas with parasellar invasion. Acta Neurochir Suppl (Wien) 53:65711991

  • 44

    Knosp ESteiner EKitz KMatula C: Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:6106181993

  • 45

    Kontogeorgos GKapranos NThodou ESambaziotis DTsagarakis S: Immunocytochemical accumulation of p53 in corticotroph adenomas: relationship with heat shock proteins and apoptosis. Pituitary 1:2072121999

  • 46

    Kovacs KHorvath EVidal S: Classification of pituitary adenomas. J Neurooncol 54:1211272001

  • 47

    Landolt AMShibata TKleihues P: Growth rate of human pituitary adenomas. J Neurosurg 67:8038061987

  • 48

    Levy AHall LYeudall WALightman SL: p53 gene mutations in pituitary adenomas: rare events. Clin Endocrinol (Oxf) 41:8098141994

  • 49

    Liu JKSchmidt MHMacDonald JDJensen RLCouldwell WT: Hypophysial transposition (hypophysopexy) for radiosurgical treatment of pituitary tumors involving the cavernous sinus. Technical note. Neurosurg Focus 14:5E112003

  • 50

    Lonser RRKsendzovsky AWind JJVortmeyer AOOldfield EH: Prospective evaluation of the characteristics and incidence of adenoma-associated dural invasion in Cushing disease. J Neurosurg 116:2722792012

  • 51

    Losa MMortini PBarzaghi RRibotto PTerreni MRMarzoli SB: Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence. J Neurosurg 108:5255322008

  • 52

    Meij BPLopes MBEllegala DBAlden TDLaws ER Jr: The long-term significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. J Neurosurg 96:1952082002

  • 53

    Melmed SCasanueva FFHoffman ARKleinberg DLMontori VMSchlechte JA: Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:2732882011

  • 54

    Messerer MDubourg JSaint-Pierre GJouanneau ESindou M: Percutaneous biopsy of lesions in the cavernous sinus region through the foramen ovale: diagnostic accuracy and limits in 50 patients. J Neurosurg 116:3903982012

  • 55

    Oliveira MCMarroni CPPizarro CBPereira-Lima JFBarbosa-Coutinho LMFerreira NP: Expression of p53 protein in pituitary adenomas. Braz J Med Biol Res 35:5615652002

  • 56

    Pan LXChen ZPLiu YSZhao JH: Magnetic resonance imaging and biological markers in pituitary adenomas with invasion of the cavernous sinus space. J Neurooncol 74:71762005

  • 57

    Papay FABenninger MSLevine HLLavertu P: Transnasal transseptal endoscopic repair of sphenoidal cerebral spinal fluid fistula. Otolaryngol Head Neck Surg 101:5955971989

  • 58

    Parkinson D: Surgical anatomy of the lateral sellar compartment (cavernous sinus). Clin Neurosurg 36:2192391990

  • 59

    Platta CSMackay CWelsh JS: Pituitary adenoma: a radiotherapeutic perspective. Am J Clin Oncol 33:4084192010

  • 60

    Rudnik AZawadzki TWojtacha MBazowski PGamrot JGaluszka-Ignasiak B: Endoscopic transnasal transsphenoidal treatment of pathology of the sellar region. Minim Invasive Neurosurg 48:1011072005

  • 61

    Sekhar LNMøller AR: Operative management of tumors involving the cavernous sinus. J Neurosurg 64:8798891986

  • 62

    Selman WRLaws ER JrScheithauer BWCarpenter SM: The occurrence of dural invasion in pituitary adenomas. J Neurosurg 64:4024071986

  • 63

    Shaw PH: The role of p53 in cell cycle regulation. Pathol Res Pract 192:6696751996

  • 64

    Shou XFLi SQWang YFZhao YJia PFZhou LF: Treatment of pituitary adenomas with a transsphenoidal approach. Neurosurgery 56:2492562005

  • 65

    Sindou MChavez JMSaint Pierre GJouvet A: Percutaneous biopsy of cavernous sinus tumors through the foramen ovale. Neurosurgery 40:1061111997

  • 66

    Thapar KKovacs KScheithauer BWStefaneanu LHorvath EPernicone PJ: Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38:991071996

  • 67

    Viera AJHinderliter AL: Evaluation and management of the patient with difficult-to-control or resistant hypertension. Am Fam Physician 79:8638692009

  • 68

    Widhalm GWolfsberger SPreusser MFischer IWoehrer AWunderer J: Residual nonfunctioning pituitary adenomas: prognostic value of MIB-1 labeling index for tumor progression. J Neurosurg 111:5635712009

  • 69

    Williams JR: The Declaration of Helsinki and public health. Bull World Health Organ 86:6506522008

  • 70

    Wolfsberger SBa-Ssalamah APinker KMlynárik VCzech TKnosp E: Application of three-tesla magnetic resonance imaging for diagnosis and surgery of sellar lesions. J Neurosurg 100:2782862004

  • 71

    Wolfsberger SKitz KWunderer JCzech TBoecher-Schwarz HGHainfellner JA: Multiregional sampling reveals a homogenous distribution of Ki-67 proliferation rate in pituitary adenomas. Acta Neurochir (Wien) 146:132313282004

  • 72

    Wolfsberger SWunderer JZachenhofer ICzech TBöcher-Schwarz HGHainfellner J: Expression of cell proliferation markers in pituitary adenomas—correlation and clinical relevance of MIB-1 and anti-topoisomerase-IIalpha. Acta Neurochir (Wien) 146:8318392004

  • 73

    Wu ZBYu CJSu ZPZhuge QCWu JSZheng WM: Bromocriptine treatment of invasive giant prolactinomas involving the cavernous sinus: results of a long-term follow up. J Neurosurg 104:54612006

  • 74

    Yasuda ACampero AMartins CRhoton AL Jrde Oliveira ERibas GC: Microsurgical anatomy and approaches to the cavernous sinus. Neurosurgery 56:1 Suppl4272005

  • 75

    Yasuda ACampero AMartins CRhoton AL Jrde Oliveira ERibas GC: Microsurgical anatomy and approaches to the cavernous sinus. Neurosurgery 62:6 Suppl 3124012632008

  • 76

    Yasuda ACampero AMartins CRhoton AL JrRibas GC: The medial wall of the cavernous sinus: microsurgical anatomy. Neurosurgery 55:1791902004

  • 77

    Yi WOhman KBrännström TBergenheim AT: Percutaneous biopsy of cavernous sinus tumour via the foramen ovale. Acta Neurochir (Wien) 151:4014072009

  • 78

    Zada GLin NLaws ER Jr: Patterns of extrasellar extension in growth hormone-secreting and nonfunctional pituitary macroadenomas. Neurosurg Focus 29:4E42010

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Article Information

Correspondence Engelbert Knosp, Department of Neurosurgery, Medical University of Vienna, Waehringer Guertel 18-20, 1097 Vienna, Austria. email: engelbert.knosp@meduniwien.ac.at.

INCLUDE WHEN CITING Published online February 6, 2015; DOI: 10.3171/2014.12.JNS141083.

DISCLOSURE The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graphic schemes (left), coronal MR images (center), and endoscopic views (right). A: Grade 0: the adenoma does not encroach on the CS space. Thus, the tangent of the medial aspects of the intracavernous and supracavernous ICAs is not passed.44 B: Grade 1: the medial tangent is passed, but the extension does not go beyond a line drawn between the crosssectional centers of the intracavernous and supracavernous ICAs (the intercarotid line).44 C: Grade 2: the tumor extends beyond the intercarotid line but not past the tangent on the lateral aspects of the intracavernous and supracavernous ICAs.44 D: Grade 3A: the tumor extends lateral to the lateral tangent of the intracavernous and supracavernous ICAs into the superior CS compartment.44 E: Grade 3B: the tumor extends lateral to the lateral tangent of the intracavernous and supracavernous ICAs into the inferior CS compartment. F: Grade 4: there is total encasement of the intracavernous carotid artery.44 AD = adenoma; LCSW = lateral CS wall (seen after removing the medial CS wall); MCSW = medial CS wall; PT = pituitary gland. The asterisk indicates an invaded medial CS wall, and arrows indicate trabeculae. Copyright Engelbert Knosp. Published with permission.

References

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Dehdashti ARGanna AKarabatsou KGentili F: Pure endoscopic endonasal approach for pituitary adenomas: early surgical results in 200 patients and comparison with previous microsurgical series. Neurosurgery 62:100610172008

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Enseñat JOrtega ATopcewski TVilalta JObiols GMesa J: [Predictive value of the Knosp classification in grading the surgical resection of invasive pituitary macroadenomas. A prospective study of 23 cases]. Neurocirugia (Astur) 17:5195262006. (Span)

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Fahlbusch RBuchfelder M: Transsphenoidal surgery of parasellar pituitary adenomas. Acta Neurochir (Wien) 92:93991988

21

Frank GPasquini E: Endoscopic endonasal cavernous sinus surgery, with special reference to pituitary adenomas. Front Horm Res 34:64822006

22

Gamea AFathi Mel-Guindy A: The use of the rigid endoscope in trans-sphenoidal pituitary surgery. J Laryngol Otol 108:19221994

23

Gejman RSwearingen BHedley-Whyte ET: Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol 39:7587662008

24

Giovanelli MLosa MMortini P: Surgical therapy of pituitary adenomas. Metabolism 45:8 Suppl 11151161996

25

Giustina AChanson PBronstein MDKlibanski ALamberts SCasanueva FF: A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 95:314131482010

26

Gondim JAAlmeida JPAlbuquerque LAGomes EFSchops M: Giant pituitary adenomas: surgical outcomes of 50 cases operated on by the endonasal endoscopic approach. World Neurosurg 82:e281e2902014

27

Guiot JRougerie JFourestier MFournier AComoy CVulmiere J: [Intracranial endoscopic explorations]. Presse Med 71:122512281963. (Fr)

28

Hagiwara AInoue YWakasa KHaba TTashiro TMiyamoto T: Comparison of growth hormone-producing and non-growth hormone-producing pituitary adenomas: imaging characteristics and pathologic correlation. Radiology 228:5335382003

29

Hardy JTranssphenoidal surgery of hypersecreting pituitary tumors. Kohler PORoss GT: Diagnosis and Treatment of Pituitary Tumors: Proceedings of a Conference AmsterdamExcerpta Medica1973. 179198

30

Hardy JVezina JL: Transsphenoidal neurosurgery of intracranial neoplasm. Adv Neurol 15:2612731976

31

Hardy JWigser SM: Trans-sphenoidal surgery of pituitary fossa tumors with televised radiofluoroscopic control. J Neurosurg 23:6126191965

32

Hentschel SJMcCutcheon EMoore WDurity FA: P53 and MIB-1 immunohistochemistry as predictors of the clinical behavior of nonfunctioning pituitary adenomas. Can J Neurol Sci 30:2152192003

33

Herman VDrazin NZGonsky RMelmed S: Molecular screening of pituitary adenomas for gene mutations and rear-rangements. J Clin Endocrinol Metab 77:50551993

34

Jankowski RAuque JSimon CMarchal JCHepner HWayoff M: Endoscopic pituitary tumor surgery. Laryngoscope 102:1982021992

35

Jefferson G: The Invasive Adenomas of the Anterior Pituitary LiverpoolUniversity Press1955

36

Jho HD: Endoscopic transsphenoidal surgery. J Neurooncol 54:1871952001

37

Jho HDCarrau RL: Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg 87:44511997

38

Jho HDCarrau RL: Endoscopy assisted transsphenoidal surgery for pituitary adenoma. Technical note. Acta Neurochir (Wien) 138:141614251996

39

Kabil MSEby JBShahinian HK: Fully endoscopic endonasal vs. transseptal transsphenoidal pituitary surgery. Minim Invasive Neurosurg 48:3483542005

40

Kim MSJang HDKim OL: Surgical results of growth hormone-secreting pituitary adenoma. J Korean Neurosurg Soc 45:2712742009

41

Kitano MTaneda MShimono TNakao Y: Extended transsphenoidal approach for surgical management of pituitary adenomas invading the cavernous sinus. J Neurosurg 108:26362008

42

Knosp EKitz KPerneczky A: Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery 25:9279301989

43

Knosp EKitz KSteiner EMatula C: Pituitary adenomas with parasellar invasion. Acta Neurochir Suppl (Wien) 53:65711991

44

Knosp ESteiner EKitz KMatula C: Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:6106181993

45

Kontogeorgos GKapranos NThodou ESambaziotis DTsagarakis S: Immunocytochemical accumulation of p53 in corticotroph adenomas: relationship with heat shock proteins and apoptosis. Pituitary 1:2072121999

46

Kovacs KHorvath EVidal S: Classification of pituitary adenomas. J Neurooncol 54:1211272001

47

Landolt AMShibata TKleihues P: Growth rate of human pituitary adenomas. J Neurosurg 67:8038061987

48

Levy AHall LYeudall WALightman SL: p53 gene mutations in pituitary adenomas: rare events. Clin Endocrinol (Oxf) 41:8098141994

49

Liu JKSchmidt MHMacDonald JDJensen RLCouldwell WT: Hypophysial transposition (hypophysopexy) for radiosurgical treatment of pituitary tumors involving the cavernous sinus. Technical note. Neurosurg Focus 14:5E112003

50

Lonser RRKsendzovsky AWind JJVortmeyer AOOldfield EH: Prospective evaluation of the characteristics and incidence of adenoma-associated dural invasion in Cushing disease. J Neurosurg 116:2722792012

51

Losa MMortini PBarzaghi RRibotto PTerreni MRMarzoli SB: Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence. J Neurosurg 108:5255322008

52

Meij BPLopes MBEllegala DBAlden TDLaws ER Jr: The long-term significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. J Neurosurg 96:1952082002

53

Melmed SCasanueva FFHoffman ARKleinberg DLMontori VMSchlechte JA: Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:2732882011

54

Messerer MDubourg JSaint-Pierre GJouanneau ESindou M: Percutaneous biopsy of lesions in the cavernous sinus region through the foramen ovale: diagnostic accuracy and limits in 50 patients. J Neurosurg 116:3903982012

55

Oliveira MCMarroni CPPizarro CBPereira-Lima JFBarbosa-Coutinho LMFerreira NP: Expression of p53 protein in pituitary adenomas. Braz J Med Biol Res 35:5615652002

56

Pan LXChen ZPLiu YSZhao JH: Magnetic resonance imaging and biological markers in pituitary adenomas with invasion of the cavernous sinus space. J Neurooncol 74:71762005

57

Papay FABenninger MSLevine HLLavertu P: Transnasal transseptal endoscopic repair of sphenoidal cerebral spinal fluid fistula. Otolaryngol Head Neck Surg 101:5955971989

58

Parkinson D: Surgical anatomy of the lateral sellar compartment (cavernous sinus). Clin Neurosurg 36:2192391990

59

Platta CSMackay CWelsh JS: Pituitary adenoma: a radiotherapeutic perspective. Am J Clin Oncol 33:4084192010

60

Rudnik AZawadzki TWojtacha MBazowski PGamrot JGaluszka-Ignasiak B: Endoscopic transnasal transsphenoidal treatment of pathology of the sellar region. Minim Invasive Neurosurg 48:1011072005

61

Sekhar LNMøller AR: Operative management of tumors involving the cavernous sinus. J Neurosurg 64:8798891986

62

Selman WRLaws ER JrScheithauer BWCarpenter SM: The occurrence of dural invasion in pituitary adenomas. J Neurosurg 64:4024071986

63

Shaw PH: The role of p53 in cell cycle regulation. Pathol Res Pract 192:6696751996

64

Shou XFLi SQWang YFZhao YJia PFZhou LF: Treatment of pituitary adenomas with a transsphenoidal approach. Neurosurgery 56:2492562005

65

Sindou MChavez JMSaint Pierre GJouvet A: Percutaneous biopsy of cavernous sinus tumors through the foramen ovale. Neurosurgery 40:1061111997

66

Thapar KKovacs KScheithauer BWStefaneanu LHorvath EPernicone PJ: Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38:991071996

67

Viera AJHinderliter AL: Evaluation and management of the patient with difficult-to-control or resistant hypertension. Am Fam Physician 79:8638692009

68

Widhalm GWolfsberger SPreusser MFischer IWoehrer AWunderer J: Residual nonfunctioning pituitary adenomas: prognostic value of MIB-1 labeling index for tumor progression. J Neurosurg 111:5635712009

69

Williams JR: The Declaration of Helsinki and public health. Bull World Health Organ 86:6506522008

70

Wolfsberger SBa-Ssalamah APinker KMlynárik VCzech TKnosp E: Application of three-tesla magnetic resonance imaging for diagnosis and surgery of sellar lesions. J Neurosurg 100:2782862004

71

Wolfsberger SKitz KWunderer JCzech TBoecher-Schwarz HGHainfellner JA: Multiregional sampling reveals a homogenous distribution of Ki-67 proliferation rate in pituitary adenomas. Acta Neurochir (Wien) 146:132313282004

72

Wolfsberger SWunderer JZachenhofer ICzech TBöcher-Schwarz HGHainfellner J: Expression of cell proliferation markers in pituitary adenomas—correlation and clinical relevance of MIB-1 and anti-topoisomerase-IIalpha. Acta Neurochir (Wien) 146:8318392004

73

Wu ZBYu CJSu ZPZhuge QCWu JSZheng WM: Bromocriptine treatment of invasive giant prolactinomas involving the cavernous sinus: results of a long-term follow up. J Neurosurg 104:54612006

74

Yasuda ACampero AMartins CRhoton AL Jrde Oliveira ERibas GC: Microsurgical anatomy and approaches to the cavernous sinus. Neurosurgery 56:1 Suppl4272005

75

Yasuda ACampero AMartins CRhoton AL Jrde Oliveira ERibas GC: Microsurgical anatomy and approaches to the cavernous sinus. Neurosurgery 62:6 Suppl 3124012632008

76

Yasuda ACampero AMartins CRhoton AL JrRibas GC: The medial wall of the cavernous sinus: microsurgical anatomy. Neurosurgery 55:1791902004

77

Yi WOhman KBrännström TBergenheim AT: Percutaneous biopsy of cavernous sinus tumour via the foramen ovale. Acta Neurochir (Wien) 151:4014072009

78

Zada GLin NLaws ER Jr: Patterns of extrasellar extension in growth hormone-secreting and nonfunctional pituitary macroadenomas. Neurosurg Focus 29:4E42010

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