Application Research on Endoscopic Pseudocapsule-Based Resection for Pituitary Adenomas

Pituitary adenomas are one of the most common primary central nervous system tumors and have an estimated prevalence of 17%. Management of pituitary adenomas involves a multidisciplinary approach that can incorporate surgical, medical, and/or radiation therapies. Over the last two decades, the endoscopic endonasal approach (EEA) has been extensively developed and refined for the resection of pituitary adenomas (PAs). In recent years, extracapsular resection (ER), which emphasized the importance of the pseudocapsule between the adenoma and surrounding normal gland tissue as a surgical plane, was adopted for more radical resection of the tumor. Therefore, dedicated high-resolution magnetic resonance imaging (MRI) protocols have been proposed to detect pituitary adenoma and accurately guide surgical removal. The evaluation of preoperative imaging for pseudocapsule is very important to the surgical method. Depending on different tumor sizes and pseudocapsule development, investigators adopted different resection strategies. To accomplish complete PA removal and minimize the impact on pituitary functions, intraoperative navigation was used to identify the tumor pseudocapsule, also the suspicious tissue was sent to the pathology department for histopathology intraoperatively. Long-term postoperative follow-up imaging and endocrine data were used to evaluate tumor prognosis. Standardized management and established biobank is critical for pituitary adenomas.

一、Project basis The pseudocapsule was first described by Costello in the early 1900s, which was formed by the compression between the tumor and normal gland. Adenoma growth leads to compression of the acinar structure of the adjacent normal gland, resulting in a reticulin-rich pseudocapsule that encases the entire adenoma in. Over the last two decades, the endoscopic endonasal approach (EEA) has been extensively developed and refined for the resection of pituitary adenomas (PAs). The endoscopic panoramic view is superior in terms of efficacy and safety for sellar surgery, and studies have reported that PAs can be effectively resected by EEA with minimal postoperative morbidity. Oldfield and colleagues used the phrase "surgical capsule of adenoma" to describe the histologically confirmed pseudocapsule in 2006 which was found in about 50% of patients and tends to be more frequent in larger tumors. The studies elaborated procedure along the outer face of the pseudocapsule between the adenoma and surrounding normal gland tissue achieved radical removal of the tumor while preserving normal pituitary function. Thus, in recent years, extracapsular resection (ER), which emphasized the importance of pseudocapsule as a surgical plane, was adopted for more radical resection of the tumor.

In smaller tumors, the pseudocapsule tended to exist more prominently and to cover the whole tumor, whereas in larger tumors the pseudocapsule tended to be discontinuous or disrupted. Similarly, in the present study, investigators found that ER was more performed in microadenomas, whereas intracapsular resection (IR) was more adopted in macroadenomas. Furthermore, in some macroadenomas, the pseudocapsule could not be seen until proper intracapsular debulking. By contrast, some PAs exhibited no or undefinable pseudocapsule; during the entire procedure, the adenoma was excised piecemeal progressively with a dissector, blunt ring curette, and aspirator.

Although PAs were frequently present within the pseudocapsule and complete tumor resection using the ER technique has been reported to maximize the effectiveness for PAs with pseudocapsules, many authors believe that resection without compromising pituitary function is imperative to improving the ultimate health outcome of patients. In some selective cases, an incomplete adenoma resection is advised because it is expected that this is best for the patients, through lower complication rates and preserving pituitary function. The actual effects of ER-based complete resection of PA are still under debate.

Intact pituitary gland function is deemed more important than adenoma total removal, Theoretically, it is hard for surgeons to extirpate only tumor cells completely during surgery without removing any normal pituitary gland tissue because in most cases the adenoma directly contacts with the normal pituitary gland. Some scholars found that the capsule itself contains tumor cells and may be a main cause of persistent hypersecretion of the hormone and possibly the source of recurrence. In addition, some studies found that the pseudocapsule is disrupted by tumor invasion so that the extracapsular removal and management of tumor invasion outside of the pseudocapsule are crucial to accomplishing complete PA removal. For these refractory pituitary adenomas, some research recommend aggressive resection, especially in IR resection cases. Partial gland resection or resection of the cavernous sinus medial wall is necessary in some cases since studies showed that it could help improve biochemical remission for the pituitary gland.

Pseudocapsule-Based Resection for Pituitary Adenomas has become a hot topic in recent years. However, it often focuses on the influence of pituitary function after surgical resection and the management and evaluation of surgical complications. How to strengthen the recognition of normal pituitary and pituitary pseudocapsule by imaging before operation? How to combine preoperative image enhanced recognition of pseudocapsule during operation? How to confirm the boundary between normal tissue and pituitary gland by Intraoperative pathology? What kind of treatment strategy should be adopted for pituitary adenomas of different sizes? There are few relevant reports on the above doubts. Standardized operation for pituitary adenoma is also lack, even if it can reduce trauma and complications; There are few studies on relationship among postoperative magnetic resonance imaging and related endocrine function examination and the evaluation of Extr-apseudocapsular resection for Pituitary Adenomas. It is urgent to establish a biological sample bank of pituitary tumor.

二、Research Contents:

1. To identify the pituitary tissue and the pseudocapsule by preoperative imaging data.
2. To evaluate the significance of preoperative imaging by relationship between tumor and pseudocapsule during operation.
3. To research the significance of intraoperative rapid pathology in excision of pituitary tumor
4. To establish Standardized surgical treatment strategies for pituitary tumors.
5. Postoperative imaging data and clinical endocrine function examination were used to evaluate the surgical efficacy.
6. To establish biological sample bank of pituitary tumor.

三、Research method, technical route and work plan

1. General Data and Clinical Manifestations In this retrospective study, investigators will review patients in our and cooperation institutions (Department of Neurosurgery, Affiliated Hospital of Nantong University, Jiangsu, China; Department of Neurosurgery, Subei People's Hospital of Jiangsu province, China; Department of Neurosurgery, The First People's Hospital of Changzhou, Jiangsu, China) who undergo EEA for PAs. The information will collect from patients' electronic medical records included presenting symptoms, operative notes, postoperative course,, laboratory data. Informed consent will obtain from all patients.
2. Endocrinological Evaluations All patients undergo a baseline preoperative pituitary hormone examination including serum cortisol, free thyroxine, thyroid stimulation hormone (TSH), adrenocorticotropic hormone (ACTH), growth hormone (GH) and insulin-like growth factor-1 (IGF-1), prolactin (PRL), luteinizing hormone (LH) and follicle stimulating hormone (FSH), testosterone (in males), and estradiol (in females). Postoperative biochemical remission will be defined as a nadir serum GH level of 3,000 ml/day. Hormonal status will be evaluated at 1 week and 3 months after surgery and twice per year thereafter to evaluate anterior pituitary functions.
3. Imaging Analysis All patients undergo high-resolution magnetic resonance imaging (MRI) examination before operation, within 3 days, 3 months, 6 months, and twice per year after surgery. The distribution and density of the pituitary gland could be seen on T1-weighted MR images. The position of the anterior communicating artery and internal carotid artery could be seen on T2-weighted images, also enabling us to reduce the surgical risks. Computed tomography is useful for demonstrating the degree of pneumatization and locations of septations in the sphenoid sinus. The degree of resection was calculated by measuring the residual tumor volume using MRI data. The magnetic resonance imaging (MRI) scanning was performed before surgery to provide excellent details about the tumor's size and texture, especially to distinguish the boundary between the location of normal adenohypophysis and pseudocapsule.
4. Pathological Examinations All resected tumor tissues were evaluated by routine pathological and immunohistochemical examination. The composition of complete and fragmentary pseudocapsules was pathologically examined. All tissues obtained in the study were paraformaldehyde fixed and paraffin embedded. The sections were stained using hematoxylin and eosin staining or Masson's trichrome staining.

   Intact pituitary gland function is deemed more important than adenoma total removal, Theoretically, it is hard for surgeons to extirpate only tumor cells completely during surgery without removing any normal pituitary gland tissue because in most cases the adenoma directly contacts with the normal pituitary gland.To minimize the impact on pituitary functions, the suspicious tissue was sent to the pathology department for histopathology intraoperatively.
5. Treatment strategies for different types of pituitary tumors Non-function pituitary adenoma, PRL, GH, ACTH
6. Depending on different tumor sizes and pseudocapsule development, investigators adopted different resection strategies.

In microadenoma, the exposed surface of the pituitary gland looks completely normal; a small cut was made in the gland at the location where the adenoma is expected according to preoperative imaging. The right dissector was used to separate the tumor and to preserve the integrity of the pseudocapsule, and achieved total extracapsular resection. Usually, the microadenoma texture is soft, limiting the option of extracapsular dissection. With small ring curettes, the tumor is removed and the tumor cavity was explored meticulously.

For macroadenomas, no attempt is made to remove the entire tumor or pull it forward during the initial phases of the dissection. After the intracapsular tumor is debulked and partially removed followed by a median-lateral or basal-superior order, the residual tumor was separated carefully along the pseudocapsular interface.

If the pseudocapsule was not visible in the first stage, investigators used conventional conservative intracapsular resection. Internal debulking was continued until visualization of the pseudocapsule or cavernous sinus wall was achieved. Extracapsular resection was continued along the plane, preserving as much integrity of the pseudocapsule as possible.

After internal debulking, if the pseudocapsule was still unidentifiable, the adenoma was excised piecemeal progressively. Noteworthily, investigators adopted intensive excision and meticulous sweeping to remove small remnants that are hidden behind the fibrin membranes for PA. The surface of the pituitary gland was peeled off as thin a slice as possible, and the tumor bed was circumferentially resected to remove any small tumor remnant in Cushing disease or acromegaly patients.

To minimize the impact on pituitary functions, the suspicious tissue was sent to the pathology department for histopathology intraoperatively.

Eligibility Criteria:
Inclusion criteria:

According to guidelines for treatment of pituitary tumors，Patients can be eligible for surgery.

Exclusion criteria:

1. Patients with other primary endocrine diseases.
2. Patients with obviously suprasellar and parasellar extensions or with cavernous sinus invasion (grade 4 of knosp classification ).
3. Patients with recent nasal trauma.
4. Patients with nasal infection or/and sphenoid sinus inflammation.
5. Patients with with abnormal coagulation.
6. Patients with other serious diseases.