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ORIGINAL ARTICLE
Year : 2023 | Volume
: 71
| Issue : 5 | Page : 907-915
Role of Cavernous Sinus Extension and MRI T2 Hypointensity in the Extent of Resection following Trans-Sphenoidal Surgery for Giant Pituitary Adenomas
Raghav Singla, Ravi Sharma, Ashish Suri
Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
Correspondence Address:
Ashish Suri
Professor, Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/0028-3886.388120
Background: Giant pituitary adenomas (GPA) pose a significant neurosurgical challenge. In this study, we present an experience of 60 consecutive patients with GPA operated by trans-sphenoidal surgery (microscopic/endoscopic).
Objective: The aim of this study was to elucidate preoperative factors predicting extent of resection (EOR) following transsphenoidal surgery for GPA.
Materials and Methods: The study was a retrospective evaluation of 60 adult patients (>18 years) with GPA operated over a decade. The patients were analyzed for their clinical presentation, EOR, radiology, visual outcome, endocrinological outcome, and complications.
Results: The mean age of the cohort was 41.5 ± 13.3 years, mean tumor volume was 38.2 ± 19.1 cm3, and mean follow-up was 30.6 ± 21.7 months. Improvement in vision was seen in forty patients (66.7%), while another 16 (26.7%) had stable vision as prior to surgery. Duration of visual symptoms was found to be statistically significantly associated with postoperative improvement of vision (P = 0.001). Twenty-four patients (40.0%) underwent subtotal resection (STR), while the remaining 36 patients (60.0%) underwent either gross total or near-total resection. Factors associated with STR were retrosellar (P = 0.04), subfrontal (P = 0.02), Knosp 3,4 cavernous sinus extension (P = 0.03), and MRI T2 hypointensity (P = 0.02). During follow-up, eight patients (13.3%) had radiological evidence of growth of residual tumor.
Conclusions: Most cases of GPA can be adequately handled by trans-sphenoidal surgery. The presence of retrosellar, subfrontal, cavernous sinus extensions, and T2 hypointensity should alert the surgeon for likelihood of STR, postoperative residual tumor hemorrhage and need for second-stage endonasal or transcranial surgery. However, utilization of extended endoscopic route has allowed good debulking of tumors having subfrontal and parasellar extensions, which was not possible previously using traditional microscopic transsphenoidal surgery.
Keywords: Complication, endonasal, endoscopic, giant pituitary adenomas, pituitary tumors, resection, trans-sphenoidal
Key Message: The presence of retrosellar, subfrontal, cavernous sinus extensions, and T2 hypointensity significantly affect the extent of resection following transsphenoidal surgery for giant pituitary adenomas
After the original description by Jefferson, various authors have sought to define a radiological criterion for giant pituitary adenoma (GPA). Symon and Jakuwoski defined GPA as one with an extension of more than 40 mm above the planum sphenoidale in any direction, less than 6 mm distance from the highest point of the tumor to the foramen of Monroe or those with the multi-compartmental spread.[1] Cusimano et al. and Hofstetter et al. suggested a volume of >=10 cm3 as a definition for GPAs.[2],[3] Goel et al.[4] proposed a grading system for GPA in their landmark study of 118 patients – grade I – tumors which remained within the confines of sellar dura and under the diaphragma sellae and did not enter into the compartment of cavernous sinus, grade II showing transgression of the medial wall and invasion into the compartment of the cavernous sinus, grade III tumors with elevation of the dura of the superior wall of the cavernous sinus and extension of this elevation into various compartments of brain and grade IV tumors with supradiaphragmatic-subarachnoid extension.
Diverse surgical techniques including transcranial, microscopic transsphenoidal, endoscopic transsphenoidal, and combined suprasellar and infrasellar exploration have been developed for these gigantic tumors with gross and near-total excision rates varying between 23 and 91%.[4],[5],[6],[7],[8],[9],[10] In this study, we present a retrospective analysis of 60 consecutive patients with GPA operated by microscopic or endoscopic trans-sphenoidal surgery with long-term follow-up and elucidate preoperative factors predicting the extent of resection (EOR).
Materials and Methods
Medical records and imaging of sixty patients with GPA operated from 2009 to 2018 were retrospectively reviewed.
Inclusion criteria: The study included all adult patients (>=18 years) with biopsy-proven pituitary adenoma who had radiological diagnosis of GPA as per criteria by Symon et al. i.e., maximum tumor dimension >=4 cm above the planum sphenoidale, or tumor reaching within 6 mm of foramen of Monroe, or multi-compartmental spread. Patients undergoing primary transcranial surgery and recurrent tumors were not included in this study.
Radiological assessment
Preoperative magnetic resonance imaging (MRI) was reviewed for tumor dimensions, tumor volume, tumor hemorrhage, MRI T2 hypointensity, and extension to subfrontal, retrosellar, suprasellar compartments, and cavernous sinus. Cavernous sinus extension was analyzed using Knosp and Steiner classification.[11] The higher-grade among the two cavernous sinuses was used to define patients with cavernous sinus invasion Grade 3 and 4.[12],[13]
Postoperative MRI imaging at 3 months was reviewed for the presence of the residual tumor. The complete absence of the tumor on postoperative MRI was considered gross total resection (GTR). Excision of tumor volume >90% was defined as near-total resection (NTR) and anything less than 90% was termed subtotal resection (STR).[14] Follow-up imaging was done every 6 months for 2 years and then annually in patients with GTR and NTR. In patients with STR, follow-up imaging was done every 6 months to look for growth of the residual tumor. Any new neurological deterioration was evaluated with appropriate imaging modalities.
Endocrinological assessment
All patients were assessed preoperatively for the complete pituitary function. These investigations were repeated in the immediate postoperative period and at 3 months follow-up for assessing remission according standard guidelines.[15],[16],[17]
Surgical approach
The transsphenoidal approach was usually favored as the first approach. There was a gradual transition from the microscopic transsphenoidal approach to the endoscopic endonasal approach with increasing experience. Endoscopic endonasal transsphenoidal surgery was performed through the bi-nostril 3 hand technique, with an extended – trans-tuberculum and trans planum or trans cavernous transsphenoidal approaches used in cases with subfrontal or cavernous sinus extensions respectively.
In the case of subtotal resection with residual tumor hemorrhage, patients underwent emergency transcranial surgery. In neurologically stable patients with subtotal resection, transcranial or repeat transsphenoidal surgery was carried out as a staged procedure after 3 months. Patients harboring GPAs with supradiaphragmatic subarachnoid extension with encasement of arteries of the circle of Willis were taken up primarily for transcranial surgery and were not included in this study. The surgical steps of various approaches have been attached described in Videos 1–4.
Statistical analysis
Statistical analysis was done using statistical software SPSS 21 (SPSS Inc., Chicago, Illinois, USA). All data were expressed as mean and SD. Categorical data were analyzed using the Chi-square test. Continuous data were analyzed using the t test for independent samples.
EOR was compared with various variables using the Chi-square test. Variables that were significant predictors of the EOR on univariate analysis were subjected to multivariate regression analysis. A value of P <= 0.05 was considered to be significant.
ResultsBaseline characteristics
A total of sixty patients with GPA underwent trans-sphenoidal surgery. The mean age of the cohort was 41.5 years (SD 13.3; Range 18–70 years). Males contributed to 73.3% of the total study cohort. The mean follow-up period was 30.6 months (SD 21.7; Range 5–90). The median duration of symptoms presentation was 24 months (Interquartile range 10 months – 48 months) with fifty-seven patients (95.0%) presenting with visual complaints. Of the fourteen patients with functional GPA's, 10 presented with acromegaly.
Radiological characteristics
The mean tumor volume of the cohort was 38.2 cm3 (SD 19.1). Nineteen (31.7%) patients in this series had Knosp 3 or 4 extension. Patients undergoing STR were compared based on tumor volume and maximum tumor dimensions with patients undergoing GTR or NTR. The radiological parameters with a significant effect on EOR included retrosellar, subfrontal, and Knosp 3,4 cavernous sinus extension. Multi-lobulated shape and T2 hypointense tumor also contributed to poor EOR on univariate analysis. On multivariate analysis, multi-lobulated tumor shape lost significance as a marker for EOR [Table 1] and [Table 2].
Table 1: Radiological data of the patients enrolled in the study (n=60 Patients): Univariate analysisSurgery
All patients included in the series initially underwent trans-sphenoidal surgery; primary transcranial surgery was excluded from the study. Thirteen patients needed transcranial surgery later following primary trans-sphenoidal microscopic or endoscopic surgery. The flow chart summarizing the surgical management of the cases included in this study is illustrated in [Figure 1]. There was a gradual transition towards endonasal approaches and extended endonasal approaches with increasing experience.
Extent of resection
Twenty-four patients (40.0%) underwent subtotal resection while the remaining thirty-six patients (60.0%) underwent either a near-total (NTR) or gross total resection (GTR). Of those thirty-six patients, fifteen (25.0%) had NTR while 21 (35.0%) had GTR. Factors associated with the poor EOR were retrosellar, subfrontal, Knosp 3,4 cavernous sinus extension, and MRI T2 hypointense tumor. Details have been summarized in [Table 1] and [Table 2]. Preoperative and Postoperative MRIs of 2 patients with GPA who underwent STR and NTR are depicted in [Figure 2] and [Figure 3] respectively.
Figure 2: Patient operated with combined EES and Transcranial approach. (a) Pre operative CEMRI with GPA with retrosellar, cavernous sinus extension. (b) Post operative CEMRI images- sagittal and coronal sections showing subtotal resection with cavernous sinus residual tumor. The patient received hypofractionated radiotherapy for residual portion in cavernous sinus
Figure 3: (a and d) Pre operative CEMRI sagittal and coronal images with GPA (Acromegaly) with subfrontal, retrosellar and cavernous sinus extension. (b and c) Post op CEMRI sagittal and coronal images with near total excisionOn reviewing our data for the new Knosp sub-classification, we found that of the 17 patients with parasellar extension, four patients had Knosp 3a, two patients had Knosp 3b and eleven patients had Knosp 4 extensions. To evaluate the impact of this new subclassification on EOR we found that patients with Knosp 4 extension were found to have higher proportion of subtotal resection (8 of 11; 72.7%) as compared to Knosp 3a (2 of 4; 50%) or Knosp 3b (1 of 2; 50%) subgroups. Owing to the small number of patients in each subgroup of newer Knosp subclassification, we chose to represent all patients with Knosp 3a, 3b and 4 under an umbrella term of parasellar extension which was found to have significant impact on the EOR on multivariate analysis (P = 0.029).
Recurrence and follow-up
The mean follow-up of the study cohort was 30.6 months (SD 21.7 Range: 5-90 months). The patients who had a small residual disease and were clinically stable were followed up with regular imaging. Patients who could not come for regular follow-up were given the option of gamma knife radiosurgery (GKRS) for residual tumor. Six such patients received GKRS for their residual tumor. A total of 8 patients (13.3%) had radiological evidence of the growth of residual tumor during follow-up. Five of these patients with recurrent tumors belonged to the STR group. These recurrences were managed by repeat surgery (n = 3), GKRS (n = 1), and conventional radiotherapy (n = 1). In the NTR group, three patients had recurrences that were managed by GKRS (n = 1) and clinical observation (n = 1). The third patient developed shunt infection and succumbed to meningitis. Due to a variable duration of follow-up, the recurrences over time were evaluated using Kaplan Meier survival analysis and described in [Figure 4].
Visual outcome
Improvement in vision was seen in forty patients (66.7%) while another sixteen patients (26.7%) had a stable vision as before surgery. Four patients (6.7%) had postoperative visual deterioration. Of these 4 patients, 3 underwent craniotomy as the second procedure after the first trans-sphenoidal surgery for resection of the residual tumor. The remaining one was started on Inj. Methylprednisolone and taken up for the removal of fat graft. However, no improvement in vision was noticed despite these measures.
The duration of visual symptoms was found to be statistically significantly associated with postoperative improvement of vision (P value: <0.001). Twenty-six of 28 patients (92.9%) who had symptoms for <1 year showed improvement in vision. Twelve patients presenting with visual symptoms for >5 years duration having little or no perception of light in both eyes did not show any improvement in vision. There was no significant correlation between size of tumor, volume of tumor, EOR with visual outcome in our study.
Endocrinological outcome
Functional tumors
Among the ten patients with acromegaly, three achieved remission following the first surgery, and another achieved remission following a staged transcranial surgery. Two patients underwent staged transcranial surgery for their residual tumor. One of them achieved remission while another underwent GKRS for residual disease. Five patients continued medical management with parenteral Octreotide. None of these patients had a recurrence on follow-up.
Among the 3 patients with medically refractory prolactinomas, one had a gross total resection and achieved remission. The other two patients had near-total resection and were maintained on oral cabergoline to achieve remission. There was only one patient with Cushing's disease in this cohort who underwent subtotal resection by the endonasal approach followed by transcranial surgery for recurrence. He was in endocrinological remission till the last follow-up.
Non-functional tumors
Preoperatively, thirteen patients (28.2% of nonfunctional GPA) were on hormonal replacement. At three months follow-up, the number of patients requiring hormonal replacement was twenty-eight (60.8% of non-functional GPA).
Complications (compared in [Table 4])
Table 4: Review of clinical results and complications in major series on GPATwo patients had postoperative cranial nerve deficits. Residual tumor hemorrhage was noted in eleven patients (18.33%). However, symptomatic postoperative residual tumor hemorrhage was seen only in four of these eleven patients [Figure 5]. All of these patients had STR with suprasellar residual tumor during the first surgery. Two patients underwent transcranial removal of residual tumor and improved neurologically. They were doing well at 1-year follow-up. Vision improved in both these patients at follow-up. They required hormonal replacement (thyroxine and prednisolone) at follow-up. The other two patients also underwent transcranial excision but expired during postoperative stay secondary to meningitis and septicemia.
Figure 5: (a) Pre operative CEMRI coronal section showing a GPA with bilateral cavernous sinus extension. (d) Post op NCCT head showing residual tumor with hemorrhage. Emergency transcranial surgery was done and NTE of tumor done. Patient did well in post op period. (b and c) Post operative MRI sagittal and axial sections with near total excision of tumorA total of 16 patients (26.7%) had intraoperative CSF leak, necessitating packing with fat and fascia, and naso-septal flap[18] in extended endonasal approaches with fibrin glue reinforcement. None of these patients had postoperative CSF rhinorrhea. Only two patients (3.3%) developed chronic diabetes insipidus (DI) and required long term Desmopressin.
DiscussionThe best approach for the removal of these GPAs is still a matter of debate.[9],[10],[19],[20],[21] Transcranial approaches are quite useful for decompression of the tumor and optic apparatus but may require significant manipulation of the optic nerves and small perforators. On the other hand, the transsphenoidal route exploits the ventral midline corridor and gives direct access to the tumor. The use of endonasal endoscopic approaches for resection of pituitary adenomas has increased in recent years. They offer a panoramic view of the region and expansion into subfrontal and parasellar extensions of the tumor, thereby offering higher rates of gross total resection as compared to microscopic surgeries.[20],[22] A review of the literature of large series on GPA has been tabulated in [Table 3] and [Table 4].
Goals of surgery
Maximal safe tumor debulking is the most important goal of surgical resection. Particularly for functional adenomas, remission rates with adjuvant therapies are higher following adequate tumor debulking.[23],[24] Decompression of the optic chiasm, hormonal remission, and preservation of normal pituitary function are the secondary goals fulfilled by maximal safe resection. The presence of significant residual disease necessitates the use of either second stage surgery or adjuvant treatment.
Type of surgery
Some authors recommend transcranial surgery as the initial approach for GPAs.[25] Recent studies show higher rates of gross total resection, fewer recurrences, and improved visual outcomes in patients undergoing trans-sphenoidal surgery.[26] Multiple studies show better results with the endoscopic endonasal approach than microscopic trans-sphenoidal and transcranial surgeries.[20],[26],[27],[28] The expanded endonasal approaches allow ventral and medial cavernous sinus exposures, that allow surgeons to perform extracapsular tumor dissection.[29],[30] Our study included all patients with GPAs who underwent initial surgery from the transsphenoidal route. The EOR was comparable between microscopic (n = 12) and endoscopic approach (n = 47) in our study cohort. (P = 0.54)
Factors predicting Extent of Resection
In the present study, the GTR and NTR rates were 35% and 25% respectively, which are comparable to the recently reported series.[27],[31] In our study, we found that the presence of retrosellar, subfrontal, Knosp 3,4 cavernous sinus extension and MRI T2 hypointensity were associated with increased chances of subtotal resection. These patients should, therefore, be counseled regarding the increased risk of postoperative residual tumor hemorrhage, need for second-stage surgery, and need for adjuvant therapy.
However, the volume of the tumor and the maximum dimension of the tumor were not found to influence the EOR. Tumors limited to sellar and suprasellar compartments could be removed by the transsphenoidal approach regardless of the size. It is the spread of the tumor to various compartments mentioned above that poses a surgical challenge.
While cavernous sinus extension is associated with the poor EOR, it is not found to be a contraindication to trans-sphenoidal surgery. In the earlier part of the study, primarily microscopic transsphenoidal approach was used. Five of the 12 patients undergoing microscopic surgery had Knosp grade 3,4 cavernous sinus extension. In these cases, cavernous sinus tumor was not accessed. As a result four of these five patients had STR of their tumors and one had NTR. With the use of extended endonasal approaches, even Knosp grade 3 and 4 tumors were decompressed from the cavernous sinus. Some cavernous sinus residual tumor had to be left in situ after optimal debulking. In our endoscopic series, there were thirteen such cases with Knosp grade 3,4 cavernous sinus extension. Five of them (38.5%) underwent GTR or NTR and eight patients (61.5%) had STR (P = 0.61). Though the result is not statistically significant, it shows an increasing ability to tackle cavernous sinus extension in such cases. In our experience we realize that utilization of extended endoscopic route has allowed good debulking of tumors having subfrontal and parasellar extensions that were not possible previously using traditional microscopic transsphenoidal surgery. Hence, endoscopic endonasal transsphenoidal surgery is a great addition to the surgeon's armamentarium as it allows transnasal access to those corridors that were previously only approachable by transcranial transcavernous route.
Another factor influencing EOR was MRI T2 hypointensity of the tumor. In our series, many of these patients had fibrous tumors that were difficult to remove through the transsphenoidal route. Only three such patients were operated by the microscopic trans-sphenoidal route and two of them had STR (66.7%). With growing experience in endonasal endoscopic surgery and the use of three-handed technique, we progressively achieved more resection even in such tumors during the latter period of the study. Of twenty patients with T2 hypointense tumors undergoing endoscopic resection, 9 (45%) underwent GTR or NTR. While the result is not statistically significant, the authors now routinely attempt removal of such tumors by endoscopic transsphenoidal approach. In cases of fibrous tumors, the cavernous sinus component was decompressed meticulously with curved suctions and pituitary curettes aided with MRI guided neuro-navigation and Doppler probe to maintain proximity of dissection of cavernous ICA. However, intraoperative assessment of the consistency of the tumor is an important aspect that adds to the preoperative radiological assessment of T2 hypointensity.
Recurrence
After primary transsphenoidal surgery for GPA, many patients have small residual tumors. In our study population, recurrence (growth of residual tumor) was seen in 8 (13.3%) patients over a mean follow-up period of 30.6 months. This is comparable with world literature reporting recurrence rates ranging from 0 to 25%.[5],[21],[27],[31],[32],[33] Goel et al. suggest clinical and radiological follow-up for small, asymptomatic residual and re-exploration for large residual tumors.[4],[34] We follow a similar management protocol in managing residual tumors. Patients showing the growth of small residual tumors were advised adjuvant GKRS. In the case of recurrent tumors, close to optic chiasm or large size, re-exploration was preferred.
Visual outcome
Visual complaints were the predominant symptom in our study. While the majority of patients showed improvement in vision, four of our patients had deterioration of vision postoperatively. Of these, two patients had residual tumor hemorrhage; while we hypothesized that significant intra-operative manipulation of the optic nerve to be the culprit in the other two. Various studies showed that improvement in visual symptoms is more likely in patients who were operated through the transsphenoidal route than those who get operated via transcranial approaches.[26],[33] In most studies, higher EOR is associated with better visual outcomes and a longer duration of visual symptoms is associated with lesser chances of improvement in vision.[7]
Hormonal remission
In our study, complete endocrinological remission was achieved in four patients of acromegaly (40%). One of them had undergone transcranial surgery after subtotal resection following microscopic transsphenoidal surgery failed to achieve remission. The other three achieved remission by a single surgery. Another patient underwent transcranial surgery for subtotal resection. However, even after transcranial surgery remission, couldn't be achieved and the patient was treated with GKRS for residual disease. In the remaining five patients, remission could be achieved on octreotide therapy following tumor resection. We opine that patients with STR should be offered repeat surgery, if feasible.
Complications
None of our patients had persistent CSF leak after surgery. In other reports as well, postoperative CSF leaks have been minimal (<5%) with advanced skull base closure techniques.[32],[36][Table 4] reviews major complications reported in the literature in comparison with the current study.
Residual tumor hemorrhage is a feared complication in GPAs.[37],[38] Of the eleven patients who had residual tumor hemorrhage, four had deterioration in sensorium and were taken up for emergency surgery. The remaining patients were neurologically stable and were managed conservatively. They underwent staged surgery or adjuvant therapy (GKRS) later, depending upon the size of the residual tumor. It is our observation that patients with residual tumor hemorrhage in suprasellar region fared worse due to compression of the hypothalamus or obstructive hydrocephalus. Residual tumor hemorrhage in parasellar and subfrontal regions was better tolerated and rarely needed emergency re-operation.
ConclusionsTranssphenoidal surgery is a good modality for most cases of GPA. Factors influencing EOR following transsphenoidal surgery include retrosellar, subfrontal, Knosp 3,4 cavernous sinus extension, and T2 hypointense tumors. The presence of these factors should alert the surgeon for the likelihood of subtotal resection, postoperative residual tumor hemorrhage, and the need for second-stage surgery – endonasal or transcranial. In experienced hands, endoscopic trans-sphenoidal surgery offers favorable results and allows tackling T2 hypointense tumors and cavernous sinus extension of tumor.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (name of institute/committee) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Financial support and sponsorship
This manuscript is the result of Research Projects funded by extramural grants from
Department of Biotechnology-DBT, Ministry of Science and Technology, Govt. of India. BT/PR13455/CoE/34/24/2015. PI: Dr. Ashish Suri.Department of Health Research, Ministry of Health and Family Welfare, Govt. of India. DHR-ICMR/GIA/18/18/2020. PI: Dr. Ashish Suri.Conflicts of interest
There are no conflicts of interest.
References
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