Surgical Technique and Efficacy Analysis of Extra-pseudocapsular Transnasal Transsphenoidal Surgery for Pituitary Microprolactinoma

To elucidate the role of transsphenoidal surgery in the treatment of pituitary microprolactinoma. The clinical data of 107 prolactinoma cases treated by extra-pseudocapsular transnasal transsphenoidal surgery (ETTS) for different indications in our department since 2011 was retrospectively analyzed. The most common indication was the ineffectiveness of oral medication (41.1%), followed by the personal willingness of the patient (35.5%), and 20.6% of the patients were young women with clear tumor boundaries. The pseudocapsule was not observed in 63 cases (58.9%), incomplete pseudocapsule was observed in 26 cases (24.3%), and complete pseudocapsule in 18 cases (16.8%). A total of 97 patients (90.7%) obtained 1-year post-operation remission. According to the relative location of the adenoma and pituitary gland on the MRI scan, 46 patients were classified into a central type, 59 a lateral type, and 2 a supra-pituitary type. Two patients developed hypogonadism, one patient developed hypocortisolism, and one patient developed post-operative hypothyroidism. Two patients were administrated with hormone replacement treatment, and the treatment was stopped within one week. There was no permanent hypopituitarism. Further investigation demonstrated that the adenoma types could affect the remission rates of hyperprolactinemia and gross total resection rate in microprolactinoma. ETTS was an effective treatment for pituitary microprolactinomas. This could be the first choice for patients who presented enclosed adenoma on the MRI and were potentially curable in a preoperative evaluation. Maximal safe removal of the adenoma by ETTS with the aim to increase the sensitivity of the drugs was also recommended for patients with invasive dopamine agonist resistant prolactinomas and patients with difficulty in childbirth.

Surgery has been used to treat pituitary prolactinomas for more than 100 years. However, since 1967, when the dopamine agonist (DA) bromocriptine (BC) was synthesized and introduced to treat pituitary prolactinomas, BC has gradually become the preferred modality [1][2][3] . The literature reported that oral DAs could normalize prolactin in about 90% of patients and shrink tumors in about two-thirds of the cases. Unfortunately, in addition to drug intolerance, drug resistance exists in 10%-20% of patients with prolactinoma [4] . With the introduction of the second-generation DA cabergoline (CAB), its therapeutic efficacy has further increased. Nevertheless, 4% of the patients were still intolerant to CAB therapy and nearly 10% were resistant to CAB [5] . Moreover, the heart valve damage caused by long-term use of DAs and the relapse of patients after discontinuation of the drug still deserve our attention [6,7] .
In recent years, with the continuous improvement of equipment and treatment concepts, transsphenoidal surgery has been explored for the treatment of prolactin microadenomas based on the treatment of pituitary macroadenomas. Several studies have shown that for experienced pituitary surgeons or in pituitary centers, the remission rate of pituitary prolactinomas could reach 71%-100% regardless of microscopic and endoscopic pituitary tumor resection [6,[8][9][10] . In addition, Jethwa et al showed that in a comparative analysis of 5-10 years of medical costs for patients with microadenoma in the United States, the cost of drug treatment increased each year as the number of years increased, while the increase in the cost of surgical treatment was not significant, consequently making drug treatment more costly and less effective than transsphenoidal surgery [11] . For these reasons, and given the adverse effects associated with patients taking longterm medication, the Pituitary Society's guidelines state that, "In a pituitary adenoma center where the experienced neurosurgeon could discuss with the possibility of surgical cure versus long-term dopamine agonist therapy of the patient, the patient's willingness to operate is also an indication to adopt transsphenoidal surgery." [12] Therefore, a growing number of scholars believe that some pituitary microprolactinomas could be treated surgically in pituitary tumor centers with experienced neurosurgeons [10,13] .
To elucidate the efficacy of transsphenoidal surgery in the treatment of pituitary microprolactinomas, this study retrospectively examined the clinical data of 107 micro-prolactinoma cases treated by extrapseudocapsular transnasal transsphenoidal surgery (ETTS) under microscopy in our department since 2011.

Patients
A total of 107 patients with pituitary microprolactinoma underwent ETTS at our center between 2011 and 2022. Patients who met the following criteria were excluded: 1. incomplete follow-up data; 2. The MRI did not meet the evaluation criteria; 3. age <18 years. A total of 107 patients were included. The study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (IRB number: TJ2019-S106).

Indications for Surgery
In addition to the current generally accepted indications of patient preference, drug intolerance tolerance, drug resistance, and pituitary apoplexy were indications for surgery. Surgery would also be recommended for patients who presented enclosed adenomas on the MRI and were potentially curable by operation. Moreover, for patients without a clear border or with invasion of the cavernous sinus, unsatisfactory outcome of drug therapy and wish for childbirth, the operation would also be suggested. In contrast, surgery would not be recommended for patients with a sella stenosis, as well as older women who had given birth and no longer wished to have children.

Imaging Evaluation
All imaging data were obtained on a 1.5-3.0 T MRI scanner. For patients with a history of DA treatment, the MRI before medication was also evaluated. The size of the prolactinoma was calculated from the initial MRI. The invasiveness of the tumor was assessed based on the Knosp classification, surrounding tissue invasion confirmed during intraoperative observation, and dural invasion demonstrated by a pathological post-operative examination. Briefly, invasiveness Classification 1 involves the categorization of pituitary adenomas (PAs) into four grades according to the radiological, surgical, and histological indicators as follows: grade 0, non-invasive PAs; grade Ⅰ, PAs meeting one of the three criteria for invasive PAs; grade Ⅱ, PAs that meet any two of the three criteria; grade Ⅲ, PAs meeting all three criteria [14] . The extent of the tumor resection was determined based on the comparison of the obtained preoperative radiological findings and postoperative MRI. Gross total resection (GTR) was defined as the absence of residual enhancing lesions on the postoperative MRI, and tumor volume reduction of 90%-99%, 70%-89%, and <70% were regarded as near-total resection (NTR), subtotal resection (STR), and partial resection, respectively. Based on the relative location of the patient's pituitary microprolactinoma to the pituitary gland, we classified  [15] respectively.

Surgical Technique
All cases were performed by the same experienced surgeon (Ting LEI), and all procedures were performed under a microscope. All cases were treated by ETTS. The method was as follows: Through the transnasal transsphenoidal approach to the sellar floor, a highspeed grinding drill was used to form a bone window, and the dura was fully exposed. The boundary between the normal pituitary and adenoma was taken as the center, the dura was cut as far as possible, and the adenoma was then fully exposed. An independent dural specimen was cut and sent to pathology department to determine the tumor invasion to the dura mater [3,9,13] . After the pseudocapsule was carefully identified under the microscope, the boundary between the pseudocapsule and the pituitary gland was initially separated from the side adjacent to the normal pituitary gland, and then the boundary between the pseudocapsule and other surrounding structures was gradually dissociated until the whole adenoma was completely removed. After the complete resection of the tumor, the fascia lata of the thigh and a small piece of fat were taken to repair the sellar floor. Additionally, it is worth mentioning that during the resection of the microprolactinoma with the para-pituitary type, bleeding from the cavernous sinus usually occurred when cutting the dura adjacent to the cavernous sinus. Therefore, the dura was carefully cut from the midline to the lateral and a few dura approaching the cavernous sinus were left for hemostasis. A small amount of sinus bleeding was treated by electrocoagulation. It should be noted that if the bleeding is difficult to stop, it could be compressed with a gelatin sponge and small cotton pieces, whereas this could affect the vision of operating. After the tumor resection, the bleeding would stop. Maximal safe removal should also be acceptable to avoid serious complications for the tough adenoma, such as patients with long-term medication and drug-resistantce, and patients with an unclear tumor boundary.

Histological Evaluation
Postoperative histological examination of the dura and tumor tissue of the sella was performed. Dural invasion could be used as one of the indicators to assess tumor invasiveness [16] . Hematoxylin and eosin (H&E) staining of the tumor tissues and immunohistochemistry were performed to examine the expression of the transcription factors and hormones to determine the subtype of the tumors, and Ki-67 was used to assess the proliferation index of the tumors.

Follow-up of the Patients
Anterior pituitary hormones were measured 1 day, 7 days, 1 month, 3 months, and 1 year postoperatively. Pituitary MRI-enhanced scans were collected at 3 months and 1 year postoperatively to assess hormonal remission, symptom improvement, occurrence of associated complications, and effectiveness of the surgical resection. The outcome of the patients 1 year after surgery was assessed in this study.

Statistical Analysis
All statistical analyses were performed using SPSS Statistics for Windows. The continuous variables were reported as mean ± standard deviation (SD) or median and interquartile range (IQR). The categorical variables were compared using chi-square tests or Fisher exact test. T-tests were used to assess the differences between normally distributed continuous variables, and multivariate Logistic regression analysis was used to explore the predictors for the remission after the operation. P<0.05 was considered statistically different.

Baseline Characteristics of the Patients
Of the 107 patients with microprolactinoma who underwent surgery at our center, 105 (98.1%) were women and two (1.9%) were men with a mean age of 28 years (range of 18-46 years). Among the symptoms presented by the patients, prolactin-related endocrine disorder symptoms were the most common, followed by dizziness and headache symptoms, which accounted for 91.6% and 27.1% of the patients' complaints, respectively (table 1). Visual field defects were uncommon due to the small size of the tumors. Notably, two patients with a supra-pituitary type presented symptoms of blurred vision. According to the relative location of the adenoma and pituitary gland on the MRI scan, 46 patients were classified into the central type, 59 the para-pituitary type, and 2 the suprapituitary type.
In this study, the indications for surgery in the patients are shown in table 1. The most common indicator was the ineffectiveness of oral medication (41.1%) and personal willingness of the patient (35.5%). Furthermore, 20.6% of the patients were young women with clear tumor boundaries. According to the morphological characteristics of the pseudocapsule observed during surgery, the adenomas could be classified into three groups: no pseudocapsule was observed in 63 cases (58.9%), incomplete pseudocapsule in 26 cases (24.3%), and complete pseudocapsule in 18 cases (16.8%). In addition, according to the method of grading pituitary adenoma invasiveness mentioned in the method part, there were 18 cases of grade 0, 53 cases of grade Ⅰ, 35 cases of grade Ⅱ and one case of grade Ⅲ . Ninety-seven patients (90.7%) obtained remission 1 year after surgery.

Remission of Hyperprolactinemia in Patients with Different Surgery Indications
The patients were classified into the remission or non-remission group, and the differences in the various indications for surgery were analyzed. The results are shown in table 2 with an overall remission rate of 90.7%. Thirty-six patients who underwent surgery according to their personal wishes had postoperative remission, and it was noteworthy that 9 female patients with strong fertility intentions who insisted on surgery had a positive outcome despite the adenoma borders were unclear. Thirty patients with drug resistance were alleviated postoperatively, and 22 young women with clear borders were also relieved. Therefore, surgery would be worth considering as a treatment method when the tumor borders were clear since the remission would more likely be achieved.

Adenoma Types Could Affect Long-term Remission in Microprolactinoma
The comparison of the clinical data between the two groups of patients is shown in table 3. There were statistically significant differences in two clinical factors: prolactin level and adenoma types (P<0.05). No other factors were significantly different in the two groups (P>0.05). Logistic regression was used to analyze the above two potential predictors for remission, and the results are shown in table 4. There were no independent predictors for the remission (P>0.05).

Adenoma Types Might Influence the GTR of Microprolactinoma
The clinical outcome and complication of patients with different adenoma types were compared, and the results are shown in table 5. In addition to the significant differences in the remission rate of the patients, the rates of the GTR of the adenomas were not all the same. All 46 patients with the central type achieved GTR compared with 51 and one patient with GTR in the 59 para-pituitary type patients and 2 suprapituitary type patients, respectively. The incidence of the cerebrospinal fluid leakage and diabetes insipidus was higher in the supra-pituitary type. For anterior pituitary hormones 1 year postoperatively, different adenoma types did not affect the rate of hypopituitarism. Notably, 3 patients who were recurrent belonged to the para-pituitary types, and 2 patients were classified into grade 2 invasion and one was classified into grade 3 invasion. The level of prolactin and adenoma size of the recurrent patients were under good control after being administrated with DA.

Illustrative Case
A 20-year-old female patient manifested menopause and lactation, and an MRI scan showed a pituitary microadenoma ( fig. 2). Her serum prolactin was 431.24 ng/mL, and she was treated with oral bromocriptine in a local hospital ( fig. 3). Two years later, the hormone was 303.93 ng/mL, so the patient visited our center and she was suggested to perform the ETTS. On the first day of the post-surgery, the PRL was 1.06 ng/mL, which returned to the normal range. One year later, no tumor residue was seen on the MRI, and the PRL was 3.90 ng/mL. There were no complications, such as cerebrospinal fluid leakage or hypopituitarism, during the follow-up.

DISCUSSION
The surgical treatment of pituitary prolactin microadenoma is still controversial [2,10,12,13] . The literature reports that patient preference, drug intolerance or drug resistance, and tumor apoplexy are the main surgical indications for pituitary microprolactinoma [8] . In this study, surgical treatment of pituitary microprolactinoma was adopted due to the ineffectiveness of the oral medication and a clear adenoma boundary, followed by the patient's willingness. It is noteworthy that a female patients showed an unclear adenoma boundary or even cavernous sinus invasion and DA resistance. As such, they were suggested to be operated, then after the surgery, the drug therapy sensitivity increased and the dose of DA was decreased. The patients who wished for pregnancy became pregnant after the operation. In addition, patients with enclosed pituitary microprolactinoma had a higher remission rate and fewer postoperative complications; therefore, aggressive operation was recommended for such patients in an experienced pituitary adenoma center. We classified microprolactinoma into the central, para-pituitary and supra-pituitary types with different remission of the surgical resection and possible postoperative complications arising from different sites. For the central pituitary microprolactinoma (most of these tumors had clear borders), the pseudocapsule adjacent to the normal pituitary gland was more intact, easily en bloc resected intraoperation, and had less impact on the normal pituitary function postoperatively. For the most common type of parapituitary type microprolactinoma, the tumor was usually closely adhered to or invaded the medial wall of the cavernous sinus on one side. When removing 0 (0.0%) 1 (100.0%) Hypogonadism 0 (0.0%) 2 (3.4%) 0 (0.0%) 0.44 Hypocortisolism 0 (0.0%) 1(1.7%) 0 (0.0%) 0.66 Hypothyroidism 0 (0.0%) 1 (1.7%) 0 (0.0%) 0.66 Recurrence 0 (0.0%) 3 (5.1%) 0 (0.0%) 0.28 GTR: gross total resection; CSF: cerebrospinal fluid the tumor near the cavernous sinus, bleeding from the cavernous sinus usually occurred, but compression with a gelatin sponge could stop it. For the supra-pituitary microprolactinoma, the tumor grew upward through the pituitary gland. The separation had a great impact on one side of the pituitary gland during the operation. A thin sellae diaphragm could be ruptured during the resection, cerebrospinal fluid outflow happened during the operation, and cerebrospinal fluid rhinorrhea possibly occurred after the operation. In this study, we found that all patients with the central type achieved GTR, while 54 patients with the para-pituitary type and one patient with the supra-pituitary type achieved GTR, respectively. The number of remission cases in patients with the central type, para-pituitary type and supra-pituitary type were 45, 51, and one respectively. Except for postoperative pituitary hormone deficiency, only one patient with the supra-pituitary type had cerebrospinal rhinorrhea, and no serious complications, such as death and disability, occurred.
In our cases, microprolactinomas were mainly found in young women, which could be due to the lack of typical symptoms in the early stage of the male patients. In addition, the age of the patients was an important indicator to consider surgery because young patients could need DA treatment for decades resulting in a high cumulative dose of DAs. Surgery could prevent unpredictable adverse sequelae caused by long-term DA treatment [10,17] . In our series of studies, the average operative age of patients was about 28 years old, which was consistent with previous reports. The average age of the cases reported by Honegger et al was 30 years old. The average age of the patients was 29.7 years old in the Milano series [18] . Tampourlou et al retrospectively analyzed the existing literature and found that the average age of women in microprolactinomas was 32 years old [17] . Therefore, the recommended indications for surgery were as follows: women of childbearing age who had childbirth requirements, clear boundaries, drug intolerance, or treatment resistance in patients with microadenomas. For the patients with narrow sella, the patients with long-term use of bromocriptine leading to local adhesion and separation difficulties, as well as elderly fertile women patients without any requirement for fertility were recommended to be treated conservatively.
ETTS is a safe microsurgery. According to the integrity of the pesudocapsule, the resection of the tumor could be preliminarily determined during the operation, so as to reduce the interference of the pituitary function. This greatly improved the cure rate of surgical treatment and avoided the occurrence of postoperative pituitary dysfunction and diabetes insipidus [15,19,20] . In this study, we found that the pituitary function had little influence after the operation. Among the 3 types, only 2 patients with the parapituitary type developed hypogonadism, one patient developed hypocortisolism, one patient developed hypothyroidism, only 2 patients were supplemented with hormone, and hormone supplementation was stopped within one week, and there were no permanent complications of hypopituitarism. Therefore, we believe that ETTS had a definite curative effect, less surgical complications, and little interference with the normal pituitary function, which was consistent with the previous reports [10,13,18] . There was no mortality and permanent complications in the cases reported by Honegger [10] . The incidence of complications in patients with prolactin microadenoma was 1.4%, while another retrospective analysis reported that the mortality of patients with prolactin microadenoma after transsphenoidal surgery was 0%, visual deterioration was 0%, and other neurosurgical complications were 0-1.8% [17] . Ikeda reported that in the study of 138 female patients treated with TSS, there was no mortality and no major complications, such as internal carotid artery injury and hypothalamic injury [21] . In the Erlangen series reports [13] , there was no mortality, and the complication rate of microprolactinoma was 1.8%.
There were 3 patients with recurrent postoperation, which could be related to tumor invasion, which was not related to the tumor size. Two cases were classified into grade 2 invasion, and one case grade 3 invasion. No statistical difference was found between the invasion and remission of microadenoma in this study, as it could be related to the small number of cases in this cohort. For patients with identified invasiveness, such as preoperative PRL >200 ng/mL, intraoperative tumor invasion of a cavernous sinus, postoperative pathology confirmed the dural invasion, and the level of serum PRL was still higher than normal range, thus, we recommend that DA treatment could be supplemented.
In conclusion, our results showed that ETTS was a safe and effective treatment for pituitary non-invasive microprolactinomas. It could be the first choice for patients who presented relative clear boundary on the MRI and were potentially curable by operation in the preoperative evaluation (central type). For the non-invasive para-pituitary and supra-pituitary types, surgical treatment could also be selected according to the wishes of the patients. Maximal safe removal of the adenoma by ETTS with the aim to increase the sensitivity of the drugs was also recommended for patients with invasive dopamine agonist resistant prolactinomas and patients with difficulty in childbirth. Hence, ETTS would be worthy of promotion because of the high remission rate and few complications after surgery.

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