NEUROSURGICAL FOCUS Neurosurg Focus 48 (6):E10, 2020 Impact of tumor characteristics and pre- and postoperative hormone levels on hormonal remission following endoscopic transsphenoidal surgery in patients with acromegaly Tyler Cardinal, BS,1 Martin J. Rutkowski, MD,1 Alexander Micko, MD, PhD,1,2 Mark Shiroishi, MD,3 Chia-Shang Jason Liu, MD, PhD,3 Bozena Wrobel, MD,5 John Carmichael, MD,1,4 and Gabriel Zada, MD1 1Department of Neurosurgery, USC Pituitary Center, Keck School of Medicine of University of Southern California, Los Angeles, California; 2Department of Neurosurgery, Medical University of Vienna, Austria; 3Department of Radiology, Division of Neuroradiology, Keck School of Medicine of University of Southern California; 4Department of Medicine, Division of Endocrinology and Diabetes, Keck School of Medicine of University of Southern California; and 5Department of Otolaryngology, Keck School of Medicine of University of Southern California, Los Angeles, California OBJECTIVE Acromegaly is a disease of acral enlargement and elevated serum levels of insulin-like growth factor–1 (IGF-1) and growth hormone (GH), usually caused by a pituitary adenoma. A lack of consensus on factors that reliably predict outcomes in acromegalic patients following endoscopic endonasal transsphenoidal surgery (EETS) warrants additional investigation. METHODS The authors identified 52 patients with acromegaly who underwent an endoscopic endonasal approach (EEA) for resection of a GH-secreting pituitary adenoma. Preoperative and postoperative tumor and endocrinological characteristics such as tumor size, invasiveness, and GH/IGF-1 levels were evaluated as potential indicators of postop- erative hormonal remission. Endocrinological remission was defined as postoperative IGF-1 levels at or below the age- and sex-normalized values. RESULTS The 52 patients had a mean age of 50.7 ± 13.4 years and a mean follow-up duration of 24.4 ± 19.1 months. Ten patients (19%) had microadenomas and 42 (81%) had macroadenomas. Five patients (9.6%) had giant adenomas. Forty-four tumors (85%) had extrasellar extension, with 40 (77%) exhibiting infrasellar invasion, 18 (35%) extending above the sella, and 7 (13%) invading the cavernous sinuses. Thirty-six patients (69%) underwent gross-total resection (GTR; mean maximal tumor diameter 1.47 cm), and 16 (31%) underwent subtotal resection (STR; mean maximal tumor diameter 2.74 cm). Invasive tumors were significantly larger, and Knosp scores were negatively correlated with GTR. Thirty-eight patients (73%) achieved hormonal remission after EEA resection alone, which increased to 87% with adjunc- tive medical therapy. Ninety percent of patients with microadenomas and 86% of patients with macroadenomas achieved hormonal remission. Preoperative IGF-1 and postoperative day 1 (POD1) GH levels were inversely correlated with hor- monal remission. Postoperative CSF leakage occurred in 2 patients (4%), and none experienced vision loss, death, or injury to internal carotid arteries or cranial nerves. CONCLUSIONS Endoscopic transsphenoidal resection of GH-secreting pituitary adenomas is a safe and highly effec- tive treatment for achieving hormonal remission and tumor control in up to 87% of patients with acromegaly when com- bined with postoperative medical therapy. Patients with lower preoperative IGF-1 and POD1 GH levels, with less invasive pituitary adenomas, and who undergo GTR are more likely to achieve postoperative biochemical remission. https://thejns.org/doi/abs/10.3171/2020.3.FOCUS2080 KEYWORDS pituitary; adenoma; acromegaly; somatotroph; cavernous sinus; invasion; surgery; Knosp; endoscope ABBREVIATIONS DI = diabetes insipidus; EEA = endoscopic endonasal approach; EETS = endoscopic endonasal transsphenoidal surgery; EOR = extent of resection; GH = growth hormone; GTR = gross-total resection; IGF-1 = insulin-like growth factor–1; IHC = immunohistochemistry; LAC + USC = Los Angeles County + University of South- ern California; OGTT = oral glucose tolerance test; POD1 = postoperative day 1; SRL = somatostatin receptor ligand; STR = subtotal resection; TSH = thyroid-stimulating hormone. SUBMITTED January 30, 2020. ACCEPTED March 11, 2020. INCLUDE WHEN CITING DOI: 10.3171/2020.3.FOCUS2080. ©AANS 2020, except where prohibited by US copyright law Neurosurg Focus Volume 48 • June 2020 1 Unauthenticated | Downloaded 09/30/21 02:58 PM UTC Cardinal et al. CROMEGALY is a disease of excess growth hormone confirmed GH-secreting tumor but with significantly ele- (GH) secretion usually due to a GH-secreting pitu- vated preoperative IGF-1 levels and acromegalic signs and itary adenoma.14,19 It is characterized by bony and symptoms was included.22 The institutional review board Asoft-tissue enlargement, and a host of comorbidities, due to at the Keck School of Medicine approved the study. elevated levels of insulin-like growth factor–1 (IGF-1) and GH.13,14 Treatment is critical as normalization of GH levels Radiological Evaluation 13,14 significantly reduces comorbidity and mortality rates. All patients underwent preoperative MRI to assess Acromegaly is considered in remission when age- and sex- tumor size, presence of cavernous sinus invasion, infra- normalized IGF-1 levels fall within normal limits, when sellar invasion, suprasellar extension, sphenoid anatomy, random GH levels are less than 1 μg/L, or when a nadir carotid anatomy, presence of residual pituitary gland, and GH of less than 0.4 μg/L is obtained after oral glucose 7,15 the position of the optic chiasm and nerves. Patients un- tolerance test (OGTT). derwent MRI at 3 months postoperatively to assess extent Resection alone has been shown to control disease of resection (EOR), and then annually to monitor tumor in up to 88% of microadenoma cases and 50% of mac- 6 progression or recurrence. Tumor size was defined by its roadenoma cases. While resection remains the primary maximal diameter in either the anteroposterior, lateral, treatment for acromegaly, somatostatin receptor ligands or craniocaudal dimension. Parasellar extension into the (SRLs), GH receptor antagonists, dopamine agonists, and cavernous sinus(es) was assessed according to the Knosp radiotherapy offer further means of achieving biochemi- 13,14 classification, consisting of 4 grades based on proximity to cal remission and tumor control. the internal carotid artery. Knosp scoring was performed Numerous studies have investigated predictors of post- at weekly clinical conferences and confirmed by a second operative outcomes in patients with acromegaly who independent reader (M.S., A.M.) for all available images. undergo endoscopic endonasal transsphenoidal surgery 1–4, 6, 8–10, (EETS) for their GH-secreting pituitary adenomas. Endocrinological Evaluation 12, 16, 18, 21, 23–28 Tumor size has been shown to be predictive of disease remission, with patients harboring smaller tumors Levels of IGF-1 were measured preoperatively as part more likely to undergo postoperative remission.6,11,21 Ad- of a comprehensive endocrinological evaluation, includ- enomas that exhibit parasellar or infrasellar invasion have ing a full pituitary panel. Preoperative GH levels were been repeatedly shown to be independently associated not obtained in all patients due to low clinical utility as a with lower rates of postoperative cure.12,24,27 Other stud- result of its pulsatile nature. Postoperative GH and corti- ies have correlated preoperative GH levels,1,6 postopera- sol levels were measured on the morning of postoperative tive GH levels,12,24 and hormonal remission. Sex,25 history day 1 (POD1), and follow-up IGF-1 levels were obtained of prior surgery,27 and preoperative absence of pituitary at 6 weeks and 12 weeks postoperatively, in addition to a deficit1 have also all been found to be predictive of postop- full pituitary panel to assess for the presence of any new erative cure. The significance of pre- and immediate post- endocrinopathy or hypopituitarism. Biochemical remis- operative IGF-1 levels remains undetermined. sion was defined as IGF-1 levels at or below the age- and In the following study, we analyze information ob- sex-normalized values. OGTT was not performed in every tained from 52 acromegaly patients who underwent EETS patient but was reserved for equivocal cases with IGF-1 between September 2012 and June 2019. Here we study reduction not normalizing or rising during the postoper- the relationships among biochemical remission, tumor ative timeframe, and when performed was done after 12 control, and preoperative size, pattern of invasion, and lev- weeks postoperatively. els of GH and IGF-1. Surgical Technique Methods All patients underwent EETS. Briefly, patients were positioned supine with their heads in slight flexion and ro- Patient Cohort and Evaluation tated toward the surgeon to allow for a two-surgeon, four- We retrospectively reviewed our database of surger- handed binostril approach. The right lateral thigh was pre- ies performed by the senior author (G.Z.) at Los Ange- pared and draped universally to allow for fat and fascia les County + University of Southern California (LAC + lata harvest in cases of CSF leak. Following administra- USC) Medical Center and Keck Hospital of USC between tion of perioperative antibiotics, stereotactic neuronaviga- September 2012 and July 2019. Sixty-nine patients who tion was registered. The endoscope was introduced, the underwent EETS for resection of suspected GH-secreting inferior, middle, and superior turbinates were sequentially pituitary adenomas were identified, with