We were able to identify 429 patients who were treated via the transsphenoidal approach for tumors of the sellar and parasellar region from April 2006 to January 2019 in our clinical neurosurgical department. 62 patients with hormone-producing adenoma causing Acromegaly and M. Cushing were excluded due to their distinct preoperative cortisol levels (Figure 1). 59 patients were excluded due to histopathological diagnosis of tumors other than pituitary adenoma (meningioma, Rathke’s cleft cysts, hypophysitis) due to their distinct clinical outcome. 97 patients were lost to follow-up endocrinological data at 1 year.
In total, 211 patients were included for further analysis. Comparing the numbers over the years, we observed a trend towards increasing numbers of surgeries performed for transnasal pituitary adenoma resection (number of cases included between 2006-2012: n= 72, 2013-2019: 139 cases).
Median age was 56 years with a range of 20-86 years. 60% (n= 127) were male and 40% (n= 84) female patients. Median preoperative KPS was 90% (range 20-100%). 97.6% of the patients suffered from pituitary macroadenoma, only 5 patients presented with progressive hormone-inactive pituitary microadenoma (only selected cases such as patients presenting with tumor growth on follow-up imaging leading to the indication of surgical removal (2.4%)).
All patients were given intra and postoperative hydrocortisone substitution according to the following standard scheme: patients obtained 50mg of intravenous hydrocortisone injection on induction, followed by immediate initiation of a continuous infusion of hydrocortisone 100 mg/24h. On postoperative day 1, patients obtained 80mg (infusion for 24h). On day 2 after surgery, we continued with an oral administration of 60mg hydrocortisone (20mg in the morning, noon and evening) with continuous re-duction of 10mg per day until the maintenance dosage of 20mg per day (10 mg in the morning and at noon).
Table 1 describes the preoperative values, postoperative values and long-term cortisol results after one year of patients grouped by corticotropic deficiency. Mean pre-operative early morning cortisol level was 11.7 µg/dl (range 0.2 to 37.1 μg/dl) and mean postoperative (5 days after TSS) level was 12.6 µg/dl (range 0.2 to 45.1 μg/dl). At 6 weeks to 12 weeks, mean early morning cortisol level was 11.9 µg/dl (range 0.1 to 59.8 µg/dl) and long-term data (minimum 1-year follow-up) revealed a mean basal cortisol level of 11.2 µg/dl (range 0.1- 35.1 µg/dl).
If grouped by preoperative hormone corticotropic deficiencies (with clinical cortico-tropic deficiency symptoms and need for hydrocortisone substitution), mean basal serum cortisol values in patients with corticotropic hormone deficiency were 3.99 µg/dl and 15.1µg/dl. Mean hormone levels of basal cortisol at long-term follow-up (minimum 1 year) were 6.01 µg/dl for patients with long-term need of hydrocortisone substitution and 13.7 µg/dl for the healthy counterpart without replacement therapy (Figure 2 and 3, Table 1).
Clinical and surgical outcome
The overall clinical outcome showed satisfying postoperative results. Median postoperative KPS of our patients was 90% (range 40-100%). Mean duration of surgery was 84 minutes, ranging from 24 to 489 minutes. Of all performed surgeries, 68.1% of the TSS were performed with a microscope, and in 31.9% of the cases with an 0° or 30° endoscope. We did not identify any significant differences in terms of complications or clinical out-come between patients operated with the endoscope or microscopical approach.
Overall, perioperative complications occurred in 18% of the operated cases (occurrence of transient diabetes insipidus with the need for desmopressin substitution in 7.1%, occurrence of an intraoperative dural tear with the need for postoperative surgical revision in 4.7%, operative revision due to postoperative hemorrhage in only 3 cases 1.4%).
GTR was achieved in 79.1% (evaluated by analyzing the postoperative imaging and determined as no residual tumor detected on the postoperative MRI). Patients with residual (mostly suprasellar) tumor were advised to perform a follow-up MRI after 6-12 weeks. In cases with good access to the descended residual tumor, the patients underwent a second transnasal surgery.
Cut-off values, sensitivity and specificity
According to the Receiver Operator Characteristic (ROC) curves, cortisol levels analyzed 6 weeks to 3 months after surgery were more accurate in predicting long-term corticotropic deficiency (Area Under the Curve AUC 0.808) compared to the directly postoperative assessed levels (AUC 0.740). Naturally, the AUC of long-term basal cortisol levels predicted the hormone deficiency most appropriately (AUC 0.864) (Figure 4).
The cut-off value for direct postoperative basal cortisol level was 6.9 µg/dl (sensitivity 86.4%, specificity 56%, Youden-Index 0.424). For values measured after 6 to 12 weeks after surgery, the cut-off prognostic basal cortisol was 6.95 µg/dl with a sensibility of 94.1% and specificity of 68% (Youden-Index 0.621). Basal cortisol measured after at least one year after surgery had the highest prognostic power at a value of 8.35 µg/dl (sensitivity 90%, specificity 82%, Youden-Index 0.718) (Table 2).
Long-term hormone deficiency
Long-term hydrocortisone replacement after 1 year was observed in 30.9% of the patients and in 30.4% of the patients before surgical treatment. Overall, 9% recovered from a preoperative hormone deficiency of the HPA-axis, and 10.4% developed a new postoperative impaired HPA-axis leading to a corticotropic deficiency. In total, 80.6% of our patients had no changes regarding the pituitary function (persistent corticotropic deficiency without recovery or intact function postoperatively in patients without pre-operative corticotropic deficiency).
In 14.6%, the postoperative cortisol level was above the measured threshold of 6.9 µg/dl while patients still suffered from long-term hormone deficiency (false negative patients). False positive results occurred in 11.1% of the cases with our assessed direct postoperative cortisol cut-off value of 6.9 µg/dl (unnecessary hydrocortisone substitution in patients with intact HPA-axis). In total, regarding that all patients had a hydrocortisone replacement for safety reasons until the first endocrinological follow-up 6 weeks to 3 months after surgery, 66.3% of the patients underwent substitution while having a basal postoperative cortisol level above the determined threshold.
Gender, age, year of operation, GTR and preoperative KPS did not significantly influence the occurrence of a new postoperative corticotropic deficiency (p> 0.05). The occurrence of complications significantly increased the risk for a new postoperative corticotropic deficiency (r: 0.281, p <0.01) and the postoperative clinical outcome in terms of KPS (KPS, r: -0.165, p: 0.018).