The Endoscopic Transsphenoidal Technique for Acromegaly: Evaluating Remission

Patients

From January 2018 to December 2023, Mahatma Gandhi University of Medical Sciences and Technology in Jaipur conducted endoscopic transsphenoidal surgeries on 89 patients. These individuals, all diagnosed with GH-secreting adenomas, had their medical records carefully reviewed retrospectively, ensuring that informed consent was obtained from each one. Both neurological and endocrinological evaluations were performed before and after the surgeries. The information for this study was compiled from imaging studies and the patient’s medical records.

The study excluded patients under the following conditions:

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  Those who did not provide consent

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  Those deemed unfit for general anaesthesia

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  Those who were not available for follow-up

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  Those with a previous history of medical treatment or Gamma Knife radiosurgery

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  Those lacking essential biochemical data or MRI scans

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  Those who received a transcranial surgical approach instead

The diagnosis of acromegaly in these patients followed the clinical practice guideline, which involves IGF-1 levels that exceed the normal upper limit for the patient’s age and sex, coupled with the incapability to reduce GH levels to below 1.0 ng/mL after an OGTT (oral glucose tolerance test).^[5]

In addition to pre- and post-surgery assessments by neuro-ophthalmologists and endocrinologists, the study paid close attention to any declines in visual acuity or visual field defects, categorising these as visual deficits. Moreover, endocrine evaluations prior to surgery involved measuring all adenohypophyseal hormone levels.

Following their surgeries, all patients were monitored for a minimum of three months, with an average follow-up duration of 12 months.

Endocrine analysis

All patients were subjected to hormonal evaluations both before and after their surgery, focusing on GH and IGF-1 levels, alongside an examination of the anterior pituitary function. This process included an oral glucose tolerance test following the measurements of the initial IGF-1 as well as GH level. The pre-surgery GH levels had been organised into four groups: 0–20, 20–40, 40–60 and over 60 ng/mL. The GH as well as IGF-1 levels detection was carried out using a specialised immunoradiometric assay kit, which identified the minimum detectable levels as 0.02 ng/mL for GH and 4.55 ng/mL for IGF-1. The assessment of GH levels immediately after surgery was scheduled for the morning of the third postoperative day and again at the third and sixth months.

In all patients, the assessment for hypopituitarism was performed before and after the surgery. The levels of various hormones, including FSH (follicle-stimulating hormone), LH (luteinising hormone), ACTH (adrenocorticotropic hormone), free T4, E2 (estradiol) or total testosterone, prolactin, TSH (thyroid-stimulating hormone) as well as serum cortisol had been computed using RIA (radioimmunoassay), usually conducted from 8:00 a.m. to 10:00 a.m. A deficiency in ACTH has been identified by peak cortisol levels of ≤ 18 µg/dL after a short Synacthen test or by a low morning cortisol level (< 5 µg/dL) in conjunction with a low-normal ACTH level (10–65 pg/mL). A deficiency of TSH had been indicated by a reduced normal TSH level (reference range, 0.4−4.1 µIU/mL) in conjunction with a minimal free T4 level (< 0.70 ng/dL). For those diagnosed with hypopituitarism, the onset of normal menopause had been determined by an FSH level above 30 mIU/mL, along with estradiol levels under 50 pg/mL. Premenopausal women with adequate levels of FSH/LH were deemed free of menstrual issues. In males, diminished testosterone levels accompanied by low-normal FSH/LH levels indicate the necessity for an assessment of central hypogonadism. Patients exhibiting symptoms indicative of water diuresis as well as polydipsia were evaluated for diabetes insipidus, which had been classified as transient (less than one month) or else permanent (three months or more) according to the desmopressin need. Individuals exhibiting hypopituitarism in both clinical and laboratory settings were administered hormone replacement therapy as necessary.

Image analysis

Magnetic Resonance Imaging (MRI) scans were conducted on all patients before their operations as well as during follow-ups at three months and one year. Before surgery, every case of pituitary adenoma was identified using preoperative MRI. Dynamic MRI scans were conducted in both sagittal and coronal perspectives, with a focus on the sella turcica and the surrounding parasellar area, both before and following the administration of gadolinium contrast, in order to obtain additional evaluation of these adenomas [Figures 1 and 2]. The size of the tumours was determined by measuring the largest diameter found in the preoperative MRI scans. Adenomas were categorised into two groups based on size: tumours less than 10 mm in diameter are known as microadenomas, and macroadenomas in those that are larger than 10 mm. Additional evaluations included checking for growth beyond the pituitary area, pressure on the optic chiasm and invasion into the cavernous sinus, all categorised using the Knosp classification. Tumours that surrounded the internal carotid artery were given a grade 4 classification based on their appearance in coronal T1-weighted images post-contrast.^[37]

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Figure 1:

Sagittal T2 WI MRI image (preop) showing well-defined mass lesion in sella (heterogeneously hyperintense), (white arrow) (original).

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Figure 2:

Other endocrine deficiencies present preoperatively (original).

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Remission analysis

Remission evaluation adhered to the guidelines established in 2010, focusing on achieving normal IGF-1 levels adjusted for the individual’s sex and age, a post-surgery random GH level under 1 ng/mL or a GH level lower than 0.4 ng/mL following an oral glucose tolerance.^[25] Oral glucose tolerance tests and IGF-1 level measurements were employed to evaluate remission status three months after the procedure, and these measurements were repeated every three months for the first year.

This process of assessing remission involved a comparative analysis of data before and after surgery. The analysis covered a range of factors, including overall remission rates, rates of postoperative resection, the incidence of cavernous sinus invasion, success in achieving extra-pseudocapsular resection and the comparison of GH levels pre- and postoperation. The study further segmented remission rates by the size of the adenomas (macro versus micro) and by different classifications of tumour volume. An additional layer of assessment was provided for cases presenting with or without cavernous sinus invasion. The evaluation also extended to patients who had undergone extra-pseudocapsular resection.

Statistical analysis

For the statistical analysis, SPSS version 13 was employed. To determine ranges, means, frequencies as well as distributions, descriptive statistical methods were applied. An independent t-test was utilised to assess the variances among measurements taken before as well as after surgery. To analyse the variations in postoperative IGF values and the rates of remission, the chi-square test (χ²) was utilised. A p-value of less than 0.05 was designated as the significance threshold. The relationship between the adenoma’s size along with the volume, the resection rates, the incidence of cavernous sinus invasion as well as the groups undergoing extra-pseudocapsular resection was examined using the Pearson correlation test.

Surgical technique

The surgical techniques utilised in this study were in line with those outlined in the current literature.^[38,39] All surgeries were performed using a bi-nostril transseptal approach under endoscopic visualisation. Hemostatic material was applied to control nasal mucosa bleeding with minimal coagulation to maintain mucosal function as well as prevent postoperative synechiae. An anterior sphenoidotomy was conducted using a drill guided by anatomical landmarks such as the choana and sphenoid ostium. Septal differences were identified utilising a preoperative paranasal sinus CT (computed tomography) scan; the rostrum was crucial for midline identification. Employing a high-speed drill, the sellar floor was opened, revealing the bilateral cavernous sinus and superior intercavernous sinus. For GH adenoma surgery, meticulous removal of small remnants hidden by fibrin membranes was crucial, especially for tumours in challenging locations. Although extra-pseudocapsular excision was frequently challenging, it was typically successful in identifying the pseudocapsule.

In 82 cases, the pseudocapsule was identified, allowing for extra-pseudocapsular resection, while intracapsular resection had been accomplished in other cases. Resection of macroadenomas was done posteroinferiorly, laterally and anteroinferiorly; superior removal was done at the end to avoid premature cisternal collapse. Fibrotic adenomas were removed using an ultrasonic aspirator. The application of sharp, angled ring curettage in blind curettement was not established. After confirming the position of the interval carotid artery with intraoperative Doppler ultrasonography and neuronavigation, tumours in the cavernous sinus were removed using a two-suction approach. To eliminate adherent adenoma and reduce blood loss, particularly from the cavernous sinus, physiological serum irrigation was employed to conclude the surgery. If no CSF (cerebrospinal fluid) leakage had been detected, a fat graft was sufficient. In instances of intraoperative CSF leakage, a multilayer closure with fascia lata, nasoseptal flap, fat graft and fibrin sealant was performed.

Overall remission

The effectiveness of surgical treatments for acromegaly can be affected by various elements,^[52] notably the tumour’s size. It’s generally observed that the success of surgery varies with the size of the tumour, with smaller tumours (microadenomas) usually having a better chance of remission compared to larger ones (macroadenomas).^[47] Despite this, research conducted by Wang et al. indicated that the remission rates for large tumours, including macroadenomas and even giant adenomas, did not significantly differ from those for microadenomas.^[52]

In our research, we achieved remission in 70 out of 89 patients (78.7%); breaking it down, 61 out of 78 patients with macroadenomas (78.2%) and 9 out of 11 patients with microadenomas (81.8%) reached remission, indicating promising outcomes when compared to previous studies [Table 6].

Our statistical analysis identified a meaningful, though inverse, relationship between the size of the adenoma and the likelihood of remission. Additionally, there was a slight yet statistically significant inverse relationship between the volume of the tumour and remission rates.

Giant adenomas pose a distinct challenge, often complicating complete removal and achieving remission significantly. Shimon et al. pointed out that among 762 acromegaly patients, 34 had giant adenomas (4.5%),^[61] underlining the necessity for aggressive, multifaceted treatment strategies to reach biochemical remission and improve management outcomes. Such adenomas typically exhibit invasive growth beyond the sellar region, are tough to remove surgically and show limited response to pharmacological treatments.^[61] In our study, we included two patients with giant adenomas, but unfortunately, neither achieved remission.

Cavernous sinus invasion

Cavernous sinus invasion is a critical factor in GH-secreting adenomas that fail to achieve remission. According to recent research, there is an increase in the incidence of pituitary adenomas causing cavernous sinus invasion.^[22,62,60] For example, according to Nishioka et al., 69.1% of the 150 patients had remission after a cavernous sinus invasion in 55 out of the 150 patients (36.7%).^[44] Nonetheless, remission was unattainable in any of the four individuals exhibiting grade IV cavernous sinus invasion.

In our investigation, remission was attained in 7 (38.9%) of the 18 patients (20.2%) with Knosp grade III/IV cavernous sinus invasion. According to our statistical research, the most significant variable influencing remission rates is cavernous sinus invasion.

When performing endoscopic procedures on the cavernous sinus, the lateral and medial pathways are essential. A recent clinical series indicates that pituitary adenomas frequently infiltrate the cavernous sinus through the medial corridor.^[62,63] Pituitary adenomas establish access routes through these corridors, subsequently employed as surgical procedures. For lesions involving the cavernous sinus, we extended standard and contralateral surgical approaches.

Preoperative GH levels

Lower GH levels before surgery are connected along with an augmented probability of reaching biochemical remission. For example, research by Wilson indicated that patients with lower levels of GH prior to surgery have higher rates of remission.^[14] Sarkar, et al. found that individuals with non-invasive, smaller tumours and lower GH levels before surgery tend to have a better chance of remission.^[23] This study categorised patients based on their GH levels before surgery to assess whether these levels could serve as predictors for remission. It was found that 87.5% of individuals with GH levels below 20 ng/mL before surgery achieved remission; in contrast, only 33.3% of those had GH levels exceeding 60 ng/mL. The disparity in remission rates between these groups was statistically significant.

Postoperative GH levels

The measurement of levels of GH subsequent to an oral glucose tolerance test, performed 12 weeks or more post-surgery, is deemed a key predictor for determining whether acromegaly patients are heading towards remission.^[5] However, the accuracy of random GH level assessments immediately after surgery is more ambiguous. Research by Dutta et al. into random GH level checks within the initial five days following transsphenoidal pituitary surgery as an indicator of enduring remission revealed that early post-surgery GH evaluations might be beneficial in forecasting long-term remission.^[64] Specifically, a GH concentration lower than 1.5 ng/mL six hours postoperation was associated with remission in 2/3 of the cases. Hazer et al. also highlighted in their research that random GH concentrations < 2.33 ng/mL on the first-day post-surgery, coupled with a reduction exceeding 50% in the IGF-I levels after the first month, function as indicators of remission prediction.^[8]

The categorisation of preoperative IGF values into abnormal or normal was done based on the age range of the patients. A decline of > 50% in IGF-I levels in the month following surgery suggests a move towards remission. According to Kim et al., who tracked GH levels at set intervals across 194 post-surgical patients, the most accurate predictor of long-term remission was the GH value on the first day postoperation.^[50] A GH level lower than 1 ng/mL indicated an 88.6–92.1% likelihood of remission. In our investigation, 46 patients exhibited GH levels under 1 ng/mL within the initial 72 hours post-surgery.

It’s crucial to monitor IGF-I concentrations and GH levels, adjusted for age, to effectively track the response to treatment and the progression of the disease.^[27] Although GH levels can be assessed during the first week following surgery, the levels of IGF-I are recommended to be assessed no sooner than 12 weeks since they stabilise around three months and may vary up to a year.^[5] Sometimes, GH and IGF-I levels might show conflicting results, such as elevated IGF-I alongside normal GH levels or the reverse. In such scenarios, the clinical symptoms indicating excessive GH should be scrutinised. If clinical improvement is observed, it is advised to continue regular hormonal evaluations and follow-up visits every three to six months without rushing into further medical interventions.^[65]

Extra-pseudocapsular dissection

In previous studies, it was found that using a pseudocapsule-based extracapsular excision approach can lead to enhanced postoperative outcomes, for example, higher remission rates as well as lower recurrence rates.^[2,63,66,67] After confirming the presence of a pseudocapsule endoscopically, extra-pseudocapsular dissection was performed while maintaining the pseudocapsule’s integrity.^[68]

In this study, the pseudocapsular group mainly comprised 74 macroadenomas and 8 microadenomas. Detecting pseudocapsules in microadenomas using endoscopy is more challenging than in macroadenomas, possibly due to the limited detailed visualisation provided by the endoscopic technique in smaller areas compared to the microscopic technique. In the current investigations, extra-pseudocapsular dissection was carried out in 82 individuals, leading to remission in 68 patients (82.9%). Among the extra-pseudocapsular resection as well as remission, a statistically significant relationship had been identified, with remission not observed in most cases where extra-pseudocapsular resection could not be achieved.

Postoperative resection rates

In patients with GH-secreting adenomas, the surgical method is critical to obtaining total resection and postoperative remission. Extracapsular dissection can significantly increase the rates of total resection as well as remission.^[68] Therefore, an aggressive extracapsular method is preferred for these adenomas. Nevertheless, this method can occasionally result in complications, including CSF leakage along with suprasellar cistern rupture. In these instances, we often execute closure in several layers, and lumbar drainage may be utilised for four to five days to address elevated pressure CSF leak.

A previous study found no significant difference in pituitary insufficiency rates between patients who underwent an aggressive approach and those who did not.^[68] Despite this, the potential for pituitary insufficiency is considered an acceptable risk to achieve remission, with replacement therapy applied as needed.

Achieving remission in recurrent cases is more complex and often requires the use of neuronavigation to verify anatomical landmarks. In our experience, intraoperative observations of various macroscopic tumour characteristics, such as white soft adenomas, fibrotic membranes, hard shells and rarely calcified adenomas, necessitate different strategies. If postoperative clinical and biochemical evaluations indicate persistent disease, medical therapy is used to control the condition.^[5]

Medical treatment aims to normalise IGF-I levels and GH hypersecretion, control or reduce tumour size and address mortality and morbidity rates.^[1] Cabergoline may be employed as early adjuvant therapy for patients exhibiting mild symptoms and moderately raised serum IGF-1 levels. In more severe instances, initial therapy with a pegvisomant or an SRL (somatostatin receptor ligand) is suggested.^[1,5] Combination therapy utilising cabergoline, SRLs or pegvisomant is utilised for uncontrolled disease. Pituitary imaging in conjunction with GH and IGF-1 level tests is employed to evaluate the efficacy of treatment.

A current investigation highlighted the importance of understanding the genetic landscape and receptor profiles of different tumours.^[69] Understanding the molecular abnormalities that cause pituitary tumourigenesis is essential for patient care since it helps with early intervention, concomitant condition screening, genetic counselling and selecting the best course of treatment, including surgery and medicine.^[70]