Pseudocapsular resection in elderly patients with non-functioning pituitary adenoma

Purpose The safety of transsphenoidal surgery (TSS) for pituitary adenoma in elderly patients is becoming a new topic in our aging society. However, previous studies did not focus on the surgical procedures in elderly patients. We attempted to clarify the safety of TSS and the inuence of pseudocapsular resection in elderly patients with non-functioning pituitary adenoma (NFPA). Methods


Introduction
As the elderly population has increased in Japan, there has been an increase in the proportion of elderly patients with pituitary adenomas [1,2]. The role of transsphenoidal surgery (TSS) in the treatment of pituitary adenomas in elderly patients should be further highlighted. Some recent studies have reported that the risk of complications associated with TSS was higher in elderly patients, hence it was recommended that TSS should be carefully conducted for elderly patients [3][4][5]. However, whether the risk of TSS is increased by aging is controversial.
Unfortunately, previous studies about TSS in elderly patients did not consider the differences among hypothalamic-pituitary tumors, including non-functioning pituitary adenoma (NFPA), functioning pituitary adenoma (FPA), craniopharyngioma and Rathke's cleft cyst (RCC). The hormonal state at FPA would in uence the perioperative condition and could cause speci c complications. Craniopharyngioma or RCC were treated with different surgical procedures in TSS and might require additional treatments. Thus, when examining the effects of age on TSS, the types of tumor pathology should be strictly de ned.
Another important discussion point is the surgical strategy and procedure of TSS for elderly patients.
Some authors noted that neurosurgeons should exercise caution when performing TSS for elderly patients, but there have been no reports focusing on the speci c procedures needed in elderly patients. Pseudocapsular resection has become an essential technique in TSS for FPA [6]. The safety of pseudocapsular resection in TSS for NFPA has also been reported [7]. However, it has not been clari ed in elderly patients. Preserving the pseudocapsule of a pituitary adenoma might help to avoid surgical complications in elderly patients; however, this might also result in an increasing risk of postoperative hemorrhage and recurrence from residual tumor cells. In this study, we focused on NFPA to evaluate the pure surgical effects and aimed to clarify the safety of TSS and the in uence of pseudocapsular resection in elderly patients with NFPA. These patients were diagnosed with NFPA according to preoperative endocrinological examinations and postoperative histological ndings.

Materials And Methods
These 272 patients were categorized into two groups based on past reports [5,8,9], as follows: 1) Elderly group (n=66; age ≥70 years); and 2) Younger group (n=206; age <70 years). We further divided all of these patients into the following two categories: 1) Resected group (n=113; total resection of pseudocapsule was conducted); and 2) Non-Resected group (n=159; total resection of pseudocapsule was not conducted). In this study, pseudocapsular resection was de ned as the separation of the tumor pseudocapsule and normal pituitary gland. Patients with total resection of the pseudocapsule underwent the removal of >80% of the pseudocapsule [7].
The following data were collected: maximum diameter of the tumor and Knosp grade on the preoperative MRI, American Society of Anesthesiologists (ASA) class, the rate of total tumor removal, peri-operative complications (intraoperative and postoperative cerebrospinal uid (CSF) leakage, transient and permanent diabetes insipidus (DI), delayed hyponatremia, postoperative hemorrhage), period of hospitalization, incidence of preoperative and postoperative severe growth hormone de ciency (sGHD) based on provocation tests, and identi cation of preoperative and postoperative anterior pituitary hormone replacement therapy (hydrocortisone, and/or levothyroxine sodium hydrate).

Endocrinological studies
The basal growth hormone (GH) levels of the anterior pituitary hormones and responses to induced hypoglycemia were evaluated in patients under 65 years of age. The other patients, who were older than 65 years of age or who had a history of heart disease or epilepsy, underwent arginine-loading tests to evaluate the GH axis, rather than hypoglycemia tests. In this present study, sGHD was de ned as a GH peak of <1.8 µg/L in a provocation test. The 217 patients received both of preoperative and postoperative provocation tests (at three months postoperatively). The insulin-like growth factor-1 (IGF-1) level was evaluated as the standard deviation score (SD score) based on a reference range established for the Japanese population according to both age and sex [10].

Surgical procedures
Transsphenoidal surgery was performed through one nostril under microscopic and endoscopic observation in all patients. A completely endoscopic procedure was adopted from 2010. Extracapsular dissection was attempted before internal decompression, or pseudocapsular resection was attempted after the internal decompression of the adenoma. The details of our surgical procedures were described in a previous report [7]. In this study, the pseudocapsular resection was not related to the total removal of the tumor. The total removal of the tumor means the complete resection of the adenoma, and does not consider whether the pseudocapsule is resected or not.

Statistical analysis
All statistical analyses were performed using the JMP ® Pro 15.0 software program (SAS Institute Inc.). The values are expressed as the median. The median values were compared using the Mann-Whitney Utest, Kruskal-Wallis test, Fisher's exact test and chi-squared test with 95% con dence intervals. p values of <0.05 were considered to indicate statistical signi cance.

Characteristics of the patients
The background characteristics of the patients are shown in Table 1. Sixty-six patients (mean age; 74.4 years) were included in the Elderly group and 206 patients (mean age; 53.3 years) were included in the Younger group. The ASA score in the Elderly group was higher than that in the Younger group (p=0.0279). There were no other signi cant differences in the background characteristics of the two groups (Table 1). Table 2 shows the surgical outcomes and the incidence rates of perioperative complications. The rate of perioperative mortality was zero in this series. No data indicated that TSS was associated with greater risk in elderly patients. Furthermore, we examined the surgical outcomes and complications in superelderly patients (≥75 years of age). There was no signi cant difference between the younger (<75 years of age) and super-elderly (≥75 years of age) patients (data are not shown).

Surgical outcomes and complications
The rates of sGHD in the preoperative and postoperative periods are shown in Figure 1. In the Elderly group, ve patients obtained an improvement of sGHD after TSS; however, ve patients newly developed sGHD after TSS. In the Elderly group, the total rate of sGHD (n=25/56, 45%) did not change between the preoperative and postoperative periods. On the other hand, although seven patients newly suffered from sGHD after TSS in the Younger group, 28 patients recovered from preoperative sGHD after TSS. The total rate of sGHD decreased signi cantly from before surgery (n= 64/161, 40%) to after surgery (n= 43/161, 27%; p=0.0178). The incidence of newly developed sGHD after TSS in the Elderly and Younger groups did not differ to a statistically signi cant extent.

Effects of pseudocapsular resection
The effects of pseudocapsular resection were examined ( Table 3). The rate of total tumor removal was signi cantly higher in the Resected group. Furthermore, we emphasize that postoperative hemorrhage did not occur in the Resected group. On the other hand, the incidence of perioperative complications in the Resected and Non-Resected groups did not differ to a statistically signi cant extent. These results were similarly observed in the Elderly and Younger groups. Figure 2 shows the rates of preoperative and postoperative sGHD in the Resected and Non-Resected groups. In the Elderly group, the total rate of sGHD did not change after TSS, irrespective of whether pseudocapsular resection was performed. Furthermore, the rate of newly developed sGHD after TSS in the Resected and Non-Resected groups did not differ to a statistically signi cant extent. On the other hand, in the Younger group, the overall rate of sGHD decreased after surgery in both the Resect and Non-Resect groups. Only the Resected group showed a signi cant difference in the preoperative and postoperative rates of sGHD (p=0.0165): the rate of sGHD before surgery was 39%, while that after surgery was 21%.
Cutoff age of patients with the possibility of recovering from sGHD As stated above, preoperative sGHD was not likely to improve after TSS in the Elderly group (≥70 years of age). We focused on the cutoff age of patients who had a possibility of recovering from preoperative sGHD after undergoing TSS. Figure 3 shows the rates of recovering from preoperative sGHD at intervals of ve years of age. The preoperative sGHD was likely to improve in younger patients. The possibility of improvement was signi cantly higher in patients aged under 55 years old (p=0.0015). The rate of newly developed sGHD after TSS did not differ to a statistically signi cant extent in any of the groups: minimum 0% in the category of 55-59 years; maximum 8% in the categories of 50-54 years, 65-69 years, and ≥75 years.

Discussion
The present study showed that the perioperative risk of TSS did not increase in elderly patients. Recovery of sGHD after TSS was expected in patients younger than 55 years of age; however, pseudocapsular resection in elderly patients was not associated with the deterioration of GH secretion. To the best of our knowledge, the present study is the rst report to focus on pseudocapsular resection in elderly patients.
Past studies have described the safety and the successful application of TSS in elderly patients, reporting that the outcomes were similar to those in younger patients. However, studies of large series have shown that elderly patients have a higher incidence of morbidity and inpatient mortality after pituitary surgery [4]. As TSS is generally less invasive than transcranial surgery and is associated with a lower incidence of perioperative complications, it is di cult to detect the difference between younger and elderly patients in small series of patients undergoing TSS. Although we also showed the safety of TSS in elderly patients with NFPA in this study, additional large studies are required to determine the effects of aging on TSS.
Pseudocapsular resection has contributed to the improvement of endocrinological remission rates in patients with FPA [6]; hence, this surgical technique is absolutely essential in the treatment of FPA. On the other hand, whether this technique should be applied to NFPA is controversial. We clari ed the safety of pseudocapsular resection in patients with NFPA in a previous report [7], and this subsequent report con rmed the safety of pseudocapsular resection in elderly patients with NFPA.
The rate of recurrence in elderly patients was reported to be lower than that in younger patients [11], and the tumor volume doubling time of residual NFPA in elderly patients (≥61 years of age) was approximately 2-fold longer than that in younger patients (<61 years of age) [12]. From the viewpoint of prevention of tumor recurrence, pseudocapsular resection might not be so important in some elderly patients, while some tumors may recur at older age and require additional treatments, such as radiotherapy or re-operation when the patient is older. Moreover, we would like to emphasize the importance of pseudocapsular resection in hemorrhagic tumors causing postoperative hematoma, and hard or brous tumors. Pseudocapsular resection cannot be conducted in all cases; however, pseudocapsular resection can contribute to reducing the surgical risk and reducing the incidence of tumor recurrence in some cases without increasing the perioperative risk. In the present study, we showed that pseudocapsular resection was not associated with the deterioration of the pituitary functions in elderly patients with NFPA; moreover, pseudocapsular resection might reduce the risk of postoperative hemorrhage. Further studies are needed to con rm the advantage from the aspect of the recurrence rate.
We showed that it was di cult to improve sGHD in elderly patients. Jahangiri et al. reported that younger age predicted the recovery from preoperative pituitary dysfunction after TSS for NFPA [13]. Liu et al. also reported that elderly patients had signi cantly more di culty in recovering from preoperative hypopituitarism [14]. No studies in the relevant literature have reported that elderly patients show superior recovery from preoperative hypopituitarism. We also showed that the elderly patients (≥55 years of age) were not likely to recover from preoperative sGHD after surgery. On the other hand, the improvement of sGHD was obtained especially in younger patients, especially those with pseudocapsular resection. This result was probably associated with the background characteristics of patients with pseudocapsular resection, who tended to have small-size tumors [7]. From the beginning, younger patients who received pseudocapsular resection were likely to recover from sGHD, irrespective of whether the pseudocapsule was resected. We recognize that pseudocapsular resection does not contribute to recovery from preoperative hypopituitarism, but that appropriate pseudocapsular resection procedures have no negative in uence on the pituitary function, even in elderly patients. These results also suggest that the application of pseudocapsular resection can be considered in elderly patients with FPA. We assume that pseudocapsular resection is not necessary for all elderly patients with NFPA, but that surgeons should not be hesitant in applying this technique because of their elderly age.
The present study was associated with some limitations. First, the number of elderly patients was relatively small. The incidence rates of perioperative complications are intrinsically low in TSS; thus, studies in larger populations are needed to assess the safety of TSS in elderly patients. Second, the application of pseudocapsular resection is depends on the pituitary surgeon. The selection of patients with pseudocapsular resection is not free from some bias. Third, some patients did not receive preoperative and postoperative pituitary provocation tests. The incidence of sGHD would be affected by the selection bias in the patients who receive provocation tests.

Conclusions
Aging was not a negative factor in TSS for NFPA, moreover pseudocapsular resection did not increase the risk of surgical complications, even in elderly patients. However, postoperative recovery from sGHD was expected in younger patients, irrespective of whether pseudocapsular resection was performed.

Declarations
Funding: This study was partially supported by a Grant-in-Aid from the Japan Society for the Promotion of Science Grant-in-Aid for Young Scientists (A) No. 19K17987.
Con icts of interest/Competing interests: The authors declare no con ict of interest in association with the present study.
Availability of data and material: The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.   "Total removal of tumor" did not consider whether the pseudocapsule was resected or not. 2) "Anterior hormones" included hydrocortisone and levothyroxine sodium hydrate.
CSF cerebrospinal uid, DI diabetes insipidus