Various Strategies of Transsphenoidal Pseudocapsule-Based Extracapsular Resection in Noninvasive Functional Pituitary Adenomas and their Effectiveness and Safety
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.273628
Source of Support: None, Conflict of Interest: None
Keywords: Clinical research, endonasal transsphenoidal approach, extracapsular resection, functional pituitary adenoma, microscope, neuroendoscope, noninvasive pituitary adenoma, pseudocapsule, surgical strategy
With the development of technologies and instruments for micro-neurosurgery, transsphenoidal surgery for pituitary adenomas has gradually become the preferred choice.,,, However, in the traditional endonasal transsphenoidal surgery, visual blind zones exist, which often lead to residual tumors. A considerable number of patients with functional pituitary adenomas cannot achieve the normal hormone level even after surgery. In recent years, endonasal transsphenoidal surgery has been divided into traditional pseudocapsule-based intracapsular resection (IR) and developed pseudocapsule-based extracapsular resection (ER). However, the operational style of the latter harasses the pituitary and the surrounding anatomic structures. Although some researchers have reported that ER can increase the tumors' total resection rate and postoperative endocrine remitted rate,,, the effectiveness and safety—especially the postoperative pituitary insufficiency, subarachnoid hemorrhage, and rhinorrhea—of this operative type have been argued for years.,, In addition, literature reports on any kind of functional pituitary adenomas are rare. This study attempts to present our experience with the different tehniques. ER surgeries were performed in our department on 116 patients suffering the noninvasive functional pituitary adenomas (NIFPAs) from October 2008 to November 2014. We adopted various surgical strategies to remove the tumors in order to identify and protect the surrounding normal tissues. Compared with the traditional IR surgeries, which were also performed for NIFPAs during the same period in our department, the surgical strategies of ER were found to increase the tumors' total resection rate and postoperative endocrine remitted rate, however, long-term complications did not occur more frequently. It confirms that they are effective and safe for NIFPAs.
There were 37 males and 79 females in the ER group, and the age ranged from 19 to 64 years, with the average age of 37.8 years. The disease history ranged from 1 month to 2.5 years, with the average being 8.5 months. There were 8 patients in the ER group who had once taken oral bromocriptine. There were 28 males and 62 females in the IR group, and the average age and disease history was 40.2 years and 9.1 months, respectively. All cases were excluded from other primary endocrine diseases, and were given initial surgical treatment. The patients with postoperative tumor recurrence were removed from the groups.
Clinical manifestations and endocrine examinations
The initial symptoms included headache, visual deficit, lactation, amenorrhea, menstruation disorder, sexual dysfunction, infertility, obesity, and acromegaly. Some patients also had coexisting hypertension, diabetes or impaired glucose tolerance. All patients underwent a comprehensive pituitary function and serum endocrine examination multiple times before surgery. In the ER group, there were 74 cases with prolactin levels >100 ng/ml, 31 cases with growth hormone levels >5 ng/ml, 7 cases with morning adrenocorticotropic hormone (ACTH) >46pg/ml, and 24 hour urinary free cortisol (24 h UFC) levels >100 μg, 1 case with thyroid-stimulating hormone (TSH) >2.5mIU/L, and 3 cases with increased poly-hormone levels. There were 56, 27, 5, 0, and 2 cases with increased abovementioned hormone levels, respectively, in the IR group.
Magnetic resonance imaging (MRI) scans were performed for all patients with and without the administration of gadolinium using a 1.5 T imaging system (GE, Signa, USA) preoperatively and 3 months later postoperatively. According to the Knosp–Steiner grading system, there were 104 cases with grade I and II and 12 cases with grade III in the ER group, whereas there were 79 cases with grade I and II and 11 cases with grade III in the IR group. There were 11 microadenomas (the maximal diameter of the adenoma was <10 mm), 83 macroadenomas (the maximal diameter of 10–30 mm), 22 giant adenomas (the maximal diameter of >30 mm) in the ER group, whereas there were 8 microadenomas, 69 macroadenomas, and 13 giant adenomas in the IR group. The longest diameter of the adenomas in both the groups was 40 mm, whereas 14 cases had adenoma stroke (infarction or hemorrhage).
In all cases, the single nasal transsphenoidal approach was used to remove the tumor. All surgical procedures with microscope were performed by Wei-Hong Wang or Qing-Xin Li, whereas procedures with endoscope were performed by Xian-Xiang Wang and Qing-Xin Li. The IR method was performed according to its traditional description, and the ER method was performed as follows: We ascertained the position of the aperture of sphenoidal sinus at the beginning of the surgery, and then cut apart the mucosa which remains intact during the operation (generally 1.5 ~ 2.0 cm long) at the junction of the nasal septum cartilage and ethmoid vertical plate. After removing the anterior floor of sphenoidal sinus, we defined the boundary of the sellar floor and drilled it to an approximately 1.5 cm × 1.5 cm area with the help of neuronavigation. After opening the dura of the sellar floor, a right dissector was used to separate the tumor from the underlying dura and to preserve the integrity of the pituitary capsule at first. With regard to the size and texture of the tumors, we adopted different resection strategies. (1) For microadenomas, internal decompression was not necessary to separate and resect the tumor and its pseudocapsule completely. (2) For macroadenomas, after partial removal of the intracapsular tumour, identification and dissection of the pseudocapsule along the outer surface of tumor was carried out. (3) If the tumor was large and its pseudocapsule was firm, we could dissect it piece-by-piece along the pseudocapsule with the assistance of an observing endoscope. After the tumor and its pseudocapsule were removed by these strategies, the management of the sellar floor was as follows: (A) Simple closing; it is suited for the patient whose tumor is totally resected and intrasellar pressure decreases satisfactorily with no rhinorrhea during the operation. The sellar cavity is packed with a gelfoam sponge, then a bioabsorbable membrane is placed on the inside surface of the sellar floor dura with the biological fibrin glue. (B) Repairing and reconstructing; it is suited for the patient who suffers intraoperative cerebrospinal fluid (CSF) rhinorrhea. The leaking aperture and sellar cavity are packed with gelfoam or autologous tissue, depending on the flow of CSF leakage, in order to form a bathtub plug's effect in the leakage site. Then the sellar floor is reconstructed with a bone board grafting from the nasal septum or anterior wall of sphenoid sinus, and gelfoam or autologous tissue with biological fibrin glue is reinforced outside it. (C) Simple opening; it is suited for the patient whose tumor texture is tough and diaphragm sella sags uncomfortably during the operation. Because of the partial removal of the tumor, the sellar cavity is only packed with a gelfoam sponge to stop the bleeding, whereas the sellar floor is not closed. At the end of the operation, the mucosa in the junction of the nasal septum cartilage and ethmoid vertical plate was replaced, and the operating nasal cavity was filled with swelled sponge.
The rate of CSF rhinorrhea during the operation was recorded, and a head computed tomography (CT) scan was performed to view whether an intracranial hematoma or subdural hemorrhage had formed 3 days after the operation. All cases underwent serum endocrine examination in the first 7 days, 3 months, and every 1–2 years after surgery; the complications were also recorded during the examination. Enhanced head MRI scans were performed in the outpatient department 3 months post-surgery. The extent of tumor removal was determined by intraoperative assessment and MRI 3 months post-surgery. The endocrine remission of the patient depended on the examination of 7 days, 3 months and every 1–2 years after the surgery. Biochemical remission of prolactin (PRL) adenomas was defined by the normalization of PRL levels (<20 ng/ml in females and <15 ng/ml in males)., Remission of growth hormone (GH) adenomas was defined as the following: glucose-suppressed plasma GH levels of less than 1.0 ng/ml, postoperative random GH levels of 2.5 ng/ml or less, and normalization of serum insulin-like growth factor 1 adjusted for age and sex., Remission in TSH adenomas was defined as normalization of TSH, free T3, and T4 levels. Remission in ACTH adenomas was defined as a normal 24-hour UFC level and normal serum morning cortisol and ACTH levels., Remission of polyhormone tumor was defined as all hormones levels remitted.
Statistical analysis was performed with the Statistical Package for the Social Sciences version 17.0 software (SPSS Inc., Chicago, IL). χ2 tests and Fisher's exact tests were used to determine the statistical significance of differences between the two groups. Two-tailed P values of less than 0.05 were considered statistically significant.
Surgical findings and resection strategies
In the ER group, the membrane-like structure, pseudocapsules, whose texture was tougher than the tumors could be found between the adenomas and normal pituitaries, whereas about 85% of the pseudocapsules were integrated with other partial defect [Figure 1] and [Figure 2]. Soft texture was found in 98 (84.5%) adenomas, and the tough texture was present in 18 (15.5%) adenomas. Depending on the volume and texture of the adenomas, strategy 1 was applied to 21 cases, strategy 2 to 62 cases, and strategy 3 to 33 cases in the ER group. It was confirmed that the inner walls of cavernous sinuses were smooth and integrated in all cases, and all the pituitary adenomas were noninvasive. In the ER group, after the tumors and its pseudocapsules were removed, the management of the sellar floors included method A in 82 cases, method B in 31 cases, and method C in 3 cases.
Imaging and endocrine outcomes
In the ER group, according to the intraoperative assessment of the surgeon and the enhanced MRI conducted 3 months post-surgery [Figure 3] and [Figure 4], the tumors were totally removed in 97 (83.7%) cases, subtotally removed in 15 (12.9%) cases, and partially removed in 4 (3.4%) cases [Table 1]. On the other hand, in the IR group, the tumors were totally removed in 62 (68.9%) cases, subtotally removed in 25 (27.8%) cases, and partially removed in 3 (3.3%) cases. The overall total removal rates for NIFPAs in the ER group were statistically higher than those in the IR group (P = 0.028).
Depending on the standard of the endocrine remission, in the ER group, the endocrine disorders were remitted in 89 (76.7%) cases and unremitted in 27 (23.3%) cases after the surgery [Table 2]. However, in the IR group, the endocrine disorders were remitted in 53 (58.9%) cases and unremitted in 37 (41.1%) cases after the surgery. The median follow-up duration was 21 months (range 12–40 months). Statistical analysis to compare the overall remission rates in both groups also showed significant differences (P = 0.006). For most of the unremitted cases in the ER group, the tumors always had tough texture or were tightly adherent to the arachnoid membrane around the diaphragm sella, which made them difficult to completely resect.
The clinical symptoms were cured or alleviated to some extent in all cases, especially for the cases with an initial complaint of headache or visual decline. Even 1-2 years after the surgery, the blood pressure or glucose levels in some patients, who had coexisting hypertension or impaired glucose tolerance, was totally or partially remitted, especially in the ACTH and GH cases.
Complications of the surgery
In the ER group, 31 (26.7%) cases suffered intraoperative CSF rhinorrhea, of which 2 (1.7%) cases persisted after the instant repair during the surgery [Table 3]. However, they all recovered through secondary surgical repair. In the IR series, 12 (13.3%) cases suffered intraoperative CSF rhinorrhea, of which 1 (1.1%) case persisted and received secondary surgery. In the ER group, 85 (73.3%) cases suffered transient diabetes insipidus after the operation, whereas there were 57 (63.3%) such cases in the IR group. However, there were no permanent cases in both groups, and all patients recovered after 3 months. There were no deceased patients and no cases with intracranial hematoma or pituitary crisis.
Definition and identification of pseudocapsule
Pituitary adenoma derives from the anterior lobe of the pituitary gland and has no intrinsic capsule. With continuous expansion of the tumor, the normal pituitary tissue around it is gradually compressed, and normal gland cells in pituitary tissue disappear and tend to undergo fibrosis gradually. Finally, pituitary gland loses the secretory function and forms the pseudocapsule of the adenoma. Oldfield and Vortmeyerg  summarized a three-stage formation of pituitary adenoma pseudocapsule through a long-term histological research and analysis of ACTH adenomas. They considered the pseudocapsule to be an integral and compact capsule merged by compressed reticular protein outside the layers of pituitary acinus. In the surgery, the boundary between the pituitary adenoma and normal tissue is considered to be the pseudocapsule, and dissecting and resecting the tumour outside it is defined as ER. Therefore, it is essential to identify the pseudocapsule during the surgery. On the basis of our experience and a review of the literature, several methods can be adopted to locate it. The first method is to judge it by its appearance. The normal pituitary usually shows as light-yellow or orange in the microscopic field, whereas the pseudocapsule mostly shows as gray-white. The second method is to judge by the texture of the tissue and the handle of the surgeon. The outer surface of the pseudocapsule is smooth and tough, and the texture of a tumor is relatively soft. According to this, some researchers have reported extracapsular dissection technique with cotton swab for pituitary adenomas through an endoscopic endonasal approach. The third method is to judge by the blood supply of the tissue and possible boundary. For microadenoma, the boundary between the tumor and normal gland can be mainly distinguished by preoperative MRI images. For macroadenoma, because of high blood supply, bleeding is very urgent through IR; the ER can decrease this bleeding due to the blocked vessels in the pseudocapsule. The fourth method involves the detection of fluorescence. It is reported that the pseudocapsule can be found in fluorescent microscope depending on the different distribution of fluorescence after administrating indocyanine green (ICG) in the surgery because the ICG distributes variously in the normal gland, tumor, and dura matter. The fifth method is relevant for the intraoperative suspicious tissues (ISCs), which are very similar to the normal structures and are difficult to differentiate. For them we can also adopt an intraoperative freezing resection to confirm the pseudocapsule in order to avoid excessive harassing of the normal pituitary gland and stalk. If the condition allows, an intraoperative MRI (iMRI) is effective in determining the boundary of the tumor pseudocapsule.
Different strategies of the pseudocapsule-based extracapsular resection
It is difficult to completely remove the tumor by traditional IR technique and realize a cure of the pituitary adenoma in imaging and endocrinology examination. Because the tumor boundary can be affirmed with the extracapsular excision, it can achieve content total resection rate and endocrine remission rate. In this group of patients, on the basis of tumor size and texture, we applied the following three resecting strategies.
Repair of cerebrospinal fluid rhinorrhea and sella floor
CSF leakage is one of the most common complications after endonasal transsphenoidal resection of pituitary adenoma. Compared with the traditional intracapsular resection, the range of dural incision in the sellar floor is large for ER, and the arachnoid membrane surrounding the sella diaphragm suffers more harassment during the surgery. Therefore, the probability of CSF leakage with ER is higher than the traditional style. The independent factors influencing it usually include the wide or forward opening of sella turcica, larger or stroked tumor, tough texture of the tumor, etc.,, On the basis of our experience and review of the literature, we can choose different repair methods for the surgery according to the site and size of leaking aperture.,,
For low leakage in the surgery, the leaking aperture and sellar cavity are usually packed with gelfoam or autologous tissue, and then a bioabsorbable membrane is placed on the inside surface of the sellar floor dura, with the biological fibrin glue and gelfoam reinforcing outside it. If the leakage is high, autologous fat or muscle tissue is usually applied to pack the sellar cavity, which should be accurately place in the leaking aperture, similar to the effect of a bathtub plug. If it is difficult to perform, we should also place autologous tissue around the leaking aperture and ensure that it does not shift. Then the sellar floor is restored with bone board grafting from nasal septum or anterior wall of sphenoid sinus, with bioabsorbable membrane and biological fibrin glue sealing it., Although the best repairing material for leaking aperture is the pedicle mucous flap,, it was only used for one case in this group. The others adopted free autologous tissue because of the following reasons. First, an ideal pedicle mucous flap needs to be of enough length and area and have unobstructed vessel in the pedicle, and hence will need a lot of time for preparation in the surgery. Second, the prepared pedicle mucosal flap often blocks the subsequent procedures during the surgery.
The postoperative disposition includes adopting a supine position or raising the head by approximately 20°, avoiding unnecessary movement, keeping urine and feces unobstructed, using external lumbar drainage,, etc. Some authors have postulated that intraoperative CSF drainage by lumbar subarachnoid catheter would diminish tension on the arachnoid, decrease the rate of intraoperative CSF leakage during surgery for larger tumors, and reduce the need for surgical repair of CSF leakage.
Experience and summary of the surgery
The psuedocapsule, as a native interface between the tumor and normal tissue, is good for finding the boundary of the tumor. If the intracapsular piecemeal resection is performed, the boundary may become vague during the surgery. The residual tumor cells in the pesuedocapsule could continue to secrete the hormone, which may explain the higher rate of recurrence associated with traditional IR techniques. Therefore, for the noninvasive functional pituitary adenomas, ER can achieve content imaging resection and high and sustained endocrine remission compared to the traditional IR. Consequently, the postoperative bleeding in the sella or subarachnoid cavity is lower, which is similar to the finding of this study.
On the other hand, the psuedocapsule, as a protective layer, also helps to identify and protect the normal tissues, such as diaphragm sella, arachnoid membrane, normal gland, and pituitary stalk. Although the incidence rate of intraoperative CSF leakage increases during the ER, the incidence rate of postoperative CSF leakage does not increase compared to IR if the appropriate repair strategies have been taken. Because the extracapsular resection increases the harassment of the pituitary stalk, the incidence of transient diabetes insipidus is higher than intracapsular resection, with no significant differences between groups (P = 0.126). However, we can identify and protect the stalk earlier during the surgery, and hence the incidence of long-term postoperative diabetes insipidus is lower. In addition, ER can decrease the intraoperative bleeding and prevent the normal pituitary from being harmed unintentionally, and therefore, the probability of postoperative deterioration of pituitary function is very low. In conclusion, ER approach is a safer alternative than the traditional intracapsular one, which is consistent with the results of some other studies.,
Judging by the integrity of psuedocapsule and invasion of tumor in the surgery, we can determine whether further treatment should be given after the operation. In some studies, it is reported that the existing probability of psuedocapsule in various functional pituitary adenomas is different, and some tumor cells usually invade the area outside the psuedocapsule. Therefore, the adjacent normal gland could be involved, and we need to remove the partial normal pituitary or the surrounding tissue in order to prevent postoperative recurrence. However, in this study (ER group), tougher pseudocapsules, compared with the tumors, could be found between the tumors and normal pituitaries, whereas about 85% of the pseudocapsules were integrated with other partial defects. However, the incidence rate of severe postoperative complications is high after partially removing the adjacent normal gland such as new hypopituitarism and long-term diabetes insipidus. Hence, the extracapsular resection is a relatively safe and effective surgical technique, especially combined with various strategies of resection and reconstruction during the operation. For the patients whose psuedocapsules have partial defect or for tumors invading the surrounding normal tissues, we should perform an imaging and endocrinological follow-up at regular intervals postoperatively. If necessary, subsequent treatment, such as drugs, conventional, or stereotactic radiotherapy should be taken into consideration.
Pseudocapsule is a protective tissue layer, which is good for finding the boundary of the tumor and protecting the normal pituitary. With different ER strategies, the total resection rate of the tumor is higher; the endocrine series decreases obviously and permanently after the operation, whereas the long-term complications are not higher than the traditional IR style.
Declaration of conflicting interests
All surgical procedures with the microscope were performed by Wei-Hong Wang or Qing-Xin Li, while procedures with endoscope were performed by Xian-Xiang Wang and Qing-Xin Li. Qing-Xin Li collected the figures, images, and clinical data, and wrote the papers at last. The authors declare no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]