Surgical Outcomes in Knosp grade 3 or 4 macroprolactinomas: What role does debulking surgery play?

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Christopher Dillon Ovenden, Victoria Tan, David J. Torpy, Ian Chapman, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8042272/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To determine the clinical outcomes of patients who had surgery to treat Knosp 3 and 4 prolactinomas with a particular focus on hormonal outcomes. Methods Retrospective cohort review of South Australian patients who had surgery to treat Knosp 3 and 4 prolactinomas from January 2000 to June 2025. Tumours were resected via an endoscopic, endonasal trans-sphenoidal approach. Demographic and clinical parameters were recorded. Hormonal outcomes were measured through assessment of prolactin levels and weekly cabergoline dose preoperatively and then at 3 months postoperatively. We also synthesised a set of criteria that can be used to assess outcomes in prolactinoma surgery. Results Of 54 total operated prolactinomas, 11 were Knosp 3 or 4 prolactinomas. Mean age at surgery was 43.3 years (± 16.2, range 26–77). Knosp grade was 3 in three cases and 4 in eight cases. The most common surgical indications were dopamine agonist resistance (5 cases) or intolerance (3 cases). Six patients had visual deficits preoperatively, with improvement following surgery in five cases (83%). PRL level prior to surgery was a mean of 82.2 times the upper limit of normal (± 168.5, range 0-576.1), with a decline to 28.4 (± 50.0, range 0.0-162.6) at 3 months postoperatively. In six patients on cabergoline preoperatively, three were on a reduced dose at 3 months postoperatively, with three on a stable dose. Conclusion Surgery was effective at addressing visual compromise in cavernous sinus invasive prolactinomas but had a limited effect on prolactin control and the ability to reduce dopamine agonist use. Figures Figure 1 Introduction Prolactinoma therapy has traditionally centred on dopamine agonist (DA) use, with the therapeutic goal of prolactin (PRL) reduction, restoration of eugonadism and reduction of tumour volume in order to provide relief of mass effect on surrounding structures. Though cabergoline treatment of PRL results in PRL normalisation in 81% of cases, relapse is common following withdrawal of therapy. Furthermore, significant DA side effects such as mood disturbance or impulse control disorders are increasingly recognised 1 , 2 . In Knosp 0 and 1 prolactinomas, trans-sphenoidal surgery (TSS) has reported remission rates of around 90% and low complication rates in selected centres, and may obviate the need for long term DA therapy, with a corresponding improvement in quality of life 3 , 4 . The Pituitary Society accordingly recommended in 2023 that surgical resection could be offered as a first line therapy for microprolactinomas and well-encased macroprolactinomas (Knosp 0 or 1) as an alternative to DA therapy, though it is not yet clear whether an initial trial of DA is warranted 5 , 6 . There is also a question of whether this recommendation should include Knosp 2 tumours which very rarely invade the cavernous sinus and often have a definable pseudocapsule that facilitates their resection 7 . Surgery has also traditionally been employed in the setting of cystic macroprolactinomas and macroprolactinomas with visual deficit, though evidence now suggests these tumours also respond well to DA 8,9 . A separate, unanswered question is the role that surgery plays in tumours in which preoperative imaging predicts a higher likelihood of cavernous sinus invasion and thereby incomplete resection. The rationale for surgery in these cases is that surgical debulking may potentiate DA dose reduction in resistant or intolerant patients, and is weakly recommended in the latest Pituitary Society guidelines 5 . However, there is a lack of data specific to cavernous sinus invasive prolactinomas to guide this recommendation. One study by Lundholm and colleagues investigated eight patients who had surgically managed giant prolactinomas with cavernous sinus invasion but did not report Knosp grading or how invasion was classified 10 . Studies reporting on surgery for DA resistant prolactinomas tend not to specifically report outcomes regarding DA dose reduction for invasive prolactinomas, instead grouping the results for these tumours with their non-invasive counterparts 11 – 13 . Complete remission is an unrealistic goal of surgery in this setting, with one study reporting rates of 0% in a series of 16 operated prolactinomas 11 ; however, it is plausible that tumour debulking might permit dose reduction or clinically meaningful structural control of the tumour. We therefore sought to perform an exploratory, descriptive analysis of surgery in a retrospective cohort of patients with radiologically invasive prolactinomas. A specific focus was placed on hormonal outcomes including influence of surgery on DA dose and PRL levels. Finally, we sought to develop a conceptual framework to help interpret the response of prolactinomas to surgery. Materials and Methods Study population Screening of the state-wide South Australia Pituitary Registry was performed to identify patients who had surgery for prolactinomas with potentially unresectable cavernous sinus invasion, defined as a modified Knosp grade of 3A (beyond lateral internal carotid artery (ICA) margin, superior to intracavernous ICA), 3B (beyond lateral ICA margin, inferior to intracavernous ICA) or 4 (encasement of ICA), between the period of January 2000 and June 2025. Inclusion criteria were: 1. a preoperative serum prolactin (PRL) level of ≥ 4 times the upper limit of normal or hyperprolactinaemia to any degree with tumour specimen hormone immunohistochemistry (IHC) solely positive for PRL, 2. modified Knosp grade 3 or 4 cavernous sinus invasion on the preoperative MRI closest to the time of surgery 14 , and 3. at least one postoperative PRL recorded at ≥ 3 months after the surgery. Knosp 0–2 prolactinoma surgical outcomes were assessed as a comparison group. Transcription factor IHC was not performed at our institution until recently, hence the selection criteria pertained only to hormone IHC. Ethical approval was obtained from the Central Adelaide Local Health Network Human Research Ethics Committee (reference number 2025/HRE00204). Due to the retrospective audit nature of the study, consent to publication was waived by the approving Ethics Committee in accordance with the National Health and Medical Research Council research guidelines. Study parameters Data was collated regarding demographic parameters (e.g., sex, age at time of first radiological diagnosis of pituitary adenoma and age at time of surgery), presenting symptoms (headaches, vision loss, galactorrhoea, amenorrhoea, low libido, fatigue, mood disturbance or double vision), hormone co-secretion and indication for surgery (DA intolerance, DA resistance, acute visual compromise or diagnostic resection). Maximum and latest preoperative PRL levels were recorded. Postoperative PRL levels were recorded within 1 week and at 3 and 12 months after surgery, and at latest follow-up. All serum PRL levels were recorded relative to the upper limit of normal of the corresponding reference range. Other preoperative and postoperative data were compared in regard to objective visual deficits, gonadal status, other pituitary hormone status, DA use (e.g., dose and tolerability) and MRI characteristics (e.g., maximal diameter, Knosp grade, the presence of haemorrhage and any cystic regions). Cumulative DA dose was calculated by summing the weekly dose of DA. The 3-month postoperative MRI was assessed for extent of resection, with results dichotomised to gross total resection (GTR) or subtotal resection (STR). Surgical approach was uniformly via an endoscopic, endonasal trans-sphenoidal approach. Duration of surgery was recorded, as were any postoperative complications. Available tumour characteristics were collated, including tumour specimen hormone and transcription factor immunohistochemistry (IHC), Ki-67 proliferative index and granulation status. Hormonal remission and surgical outcomes were assessed at 3 and 12 months postoperatively, in addition to latest follow-up. The need for further treatment in the form of additional surgery or radiation therapy was recorded. Prolactinoma response criteria Given the diverse clinical end-points after surgery for prolactinomas, we created a set of response criteria – the Prolactinoma Response Criteria (PRC; Supplementary Table 3) – to capture overall surgical outcome. The PRC aim to quantify and thereby compare the collective burden of tumour/treatment before and after surgery using a standardized framework. This framework covers potential negative outcomes from the tumour itself and its treatment. Each outcome is allocated points: 1 for negative outcomes with no anticipated clinical effect (e.g., infrasellar tumour invasion), 2 for negative outcomes with potential clinical risks (e.g., suprasellar tumour invasion, as this carries a significant risk of chiasmal compression), and 3 for negative outcomes of immediate clinical concern (e.g., tumour increase ≥ 30% within 12 months). The higher the PRC score, the greater the apparent burden of disease/treatment. The PRC are scored in the preoperative period and then at 12 months postoperatively; the difference reflects overall surgical response. Hormonal factors assessed in the PRC included the presence of high PRL, hypogonadism, other pituitary hormone deficit and a rapidly rising PRL (≥ 30% in one year). Anatomical factors were recorded regarding the extent of the prolactinoma (whether it extended to sellar, cavernous sinus, suprasellar or clival/sphenoid sinus region, whether there was visual deficit and whether it was rapidly growing). Cabergoline dose was categorised as low ( 2mg/week). DA side effects were recorded as tolerable or intolerable. Need for additional treatment such as radiation therapy, temozolomide or another tumour targeted therapy such as pasireotide was also recorded. Complications from surgery were recorded. Statistical analysis Given the small size of the study, statistical analysis was limited to descriptive statistics. Categorical variables were presented as counts and percentages, and continuous variables as means +/- standard deviation (SD) if normally distributed or medians (interquartile range, IQR) if distribution was skewed. Paired t-tests were used to assess differences in pre and postoperative PRL levels and dose. Statistical analysis was performed with EasyMedStat (version 3.40; www.easymedstat.com ). P values < 0.05 were considered statistically significant. Results Patient Characteristics and Visual Outcomes Over the study period, 54 patients had operated prolactinomas. Knosp grade was 0–2 in 43 comparison group cases, with 84% achieving remission with no DA requirement at 12 months postoperatively. The cohort of patients who had debulking surgery for prolactinomas with Knosp grade 3 or 4 prolactinomas consisted of 11 patients (6 males, 5 females). Mean age at time of initial imaging diagnosis was 39.3 years (± 15.1, range 18–64), with a mean age at surgery of 43.3 years (± 16.2, range 26–77). The major presenting complaints were visual symptoms (45%), symptoms of hypogonadism (amenorrhoea, low libido or low mood in 45%), headaches (36%) and seizures (9%); 18% of patients were asymptomatic. Six patients (55%) had objective visual field deficits on formal ophthalmological examination. Five of these patients had objective improvement of vision postoperatively, whilst one of the six patients experienced acute worsening of vision in the immediate postoperative period thought to be secondary to tension on the optic nerve. This returned to baseline at 3 months postoperatively. Histological Findings All tumours exhibited positive PRL staining on hormone immunohistochemistry. One tumour additionally stained for growth hormone (GH), but was not a co-secreter as is detailed in the biochemical section below. Eight samples had transcription factor IHC performed, with all eight positive for Pit-1 and negative for other transcription factors as expected. Granulation status was recorded in four patients, with two sparsely granulated and two densely granulated tumours. Surgical Goal Indication for surgery was DA resistance in five cases, DA intolerance in three cases, need for diagnostic resection in two cases (PRL not grossly elevated with visual apparatus compression) and apoplexy with acute visual compromise in one patient. In three patients the goal of surgery was complete resection, with the goal in the remaining eight patients being debulking. Biochemical Baseline and Outcomes No tumours exhibited co-secretion of another pituitary hormone. Ten patients were hypogonadal preoperatively, including two on sex hormone replacement. Postoperatively eight patients were hypogonadal, including four on sex hormone replacement. No patient was deficient in another hormonal axis preoperatively, whereas five patients developed at least one new pituitary hormone deficiency postoperatively that required replacement (5 required thyroid hormone replacement, 3 required cortisol replacement and 1 required growth hormone replacement). Maximum PRL level prior to any treatment was a mean of 148.4 times the upper limit of normal of the reference range (± 181.3, range 1.2-576.1), with this measurement taken a mean of 901 days (median 253, range 1-4441) preoperatively. Last PRL level prior to surgery was a mean of 82.2 times the upper limit of normal of the reference range (± 168.5, range 0-576.1), with this measurement taken at a mean of 46 days (± 52.3, range 1-180) preoperatively. Six patients had a PRL level taken in the first postoperative week, with a mean of 56.0 times the upper limit of normal of the reference range (± 116.0, range 2.0-292.3), with this measurement taken a mean of 3.2 days (± 2.6, range 1–7) postoperatively. Ten patients had a PRL level taken at 3 months postoperatively, with a mean of 28.4 (± 50.0, range 0.0-162.6) times the upper limit of normal of the reference range. Ten patients had a PRL level taken at 12 months postoperatively, with a mean of 17.1 (± 23.6, range 0.5–64.6) times the upper limit of normal of the reference range. Seven patients had an additional PRL level taken more than 12 months postoperatively, with a mean of 11.1 (± 20.5, range 0.2–55.1) times the upper limit of normal of the reference range, with this value being taken a mean of 2164 days (± 1710, range 158–4724) postoperatively. Supplementary table 1 provides a summary of pre and postoperative PRL levels for each patient. Changes in Cabergoline Therapy Eight patients had preoperative treatment with cabergoline. Mean duration of cabergoline therapy in these patients was 52.5 months (± 72.2, range 3-204), and the mean cumulative dose was 269mg (± 337, range 12–936). The reason for no preoperative cabergoline treatment in one patient was due to acute presentation with apoplexy and vision loss, with the reason in the other two patients being that their mild PRL rise was thought to reflect stalk effect hyperprolactinaemia due to a presumed non-functioning pituitary adenoma. Despite the mild PRL rise, these two patients had hormone IHC that was solely positive for PRL. Two further patients had significant DA intolerance requiring complete cessation by the time of surgery. For the remaining six patients, two were receiving 1mg weekly, one was receiving 3mg weekly, two were receiving 4mg weekly and one was receiving 6mg weekly. At three months postoperatively, amongst the six patients on a DA preoperatively, three had their dose reduced and three were on the same dose. At 12 months, three were on a lower dose compared to preoperatively, two were on the same dose and one patient was on a higher dose. The dose reduction for one of these patients notably occurred in the context of radiation therapy occurring 6 months postoperatively. Supplementary table 2 provides a summary of weekly cabergoline dose preoperatively and postoperatively. Figure 1 details individual patient’s changes in PRL levels and DA dose in relation to time from surgery. Structural Imaging Baseline and Response to Surgery Preoperative MRI showed a mean maximal diameter of 33.9mm (± 13.1, range 15–52). All cases were macroadenomas, with two Knosp 3A tumours, one Knosp 3B tumours and eight Knosp 4 tumours. One case demonstrated apoplexy and three had cystic components. Both Knosp 3A patients had GTR; all other patients had STR on 3 month postoperative MRI. In all cases of STR, residual disease was located in the cavernous sinus with the sellar, clival and suprasellar regions having clearance of tumour. Surgical Outcomes and Complications Duration of surgery was recorded in six patients, amounting to a mean of 231 minutes (± 30, range 170–250). Five patients had complications: three patients had transient arginine vasopressin deficiency (AVP-D), one patient had sepsis of unclear source that resolved with antibiotic therapy, and one patient sustained an avulsion injury of the superior hypophyseal artery (SHA) off the internal carotid artery that could not be controlled with a muscle patch. This injury required surgical clip application to the point of origin of the SHA, with postoperative digital subtraction angiography showing 40% stenosis of the ICA. The patient sustained no neurological deficits as a result of this injury and there was no evidence of pseudo aneurysm on neuro-imaging follow-up. Biochemical Remission Rates and Requirement for Further Treatment Of the 11 patients, three were in remission (two 3A grades and one grade 4 case) at three and 12 months postoperatively – both 3A patients were never treated with cabergoline pre or postoperatively, whilst the grade 4 patient that initially had hormonal remission had a PRL rise 57 months following surgery and was restarted on cabergoline therapy (0.25mg weekly dose). Four other patients had postoperative radiation therapy in the form of fractionated stereotactic radiotherapy with a dose of 54Gy/30# (one at 6 weeks, two at 6 months and one patient at 21 months postoperatively). No patient underwent additional surgery. Prolactinoma Response Criteria Supplementary table 3 provides the PRC scores for each patient pre- and 12-months postoperatively. Mean PRC score was 10.2 preoperatively compared to 8.9 to postoperatively. PRC fell in six postoperatively (indicating beneficial overall surgical outcome), was stable in one patient and, rose in four patients (indicating adverse overall surgical outcome). Discussion This is the first dedicated surgical cohort study of patients with Knosp grade 3 or 4 prolactinomas. The indications for surgery were heterogeneous with correspondingly heterogeneous outcomes. In summary, surgery provided a modest benefit in our patient cohort. Surgery resulted in complete remission with no need for DA therapy in three patients despite their high grade tumours. In patients with DA resistance, surgery allowed dose reduction in 50% of patients at 3 and 12 months, though the dose reduction in one of these patients followed radiation therapy which is a confounding factor. Surgery resulted in a trend towards decreased PRL levels, though this was not statistically significant, likely due to the small sample size. Preoperative visual compromise tended to be ameliorated by surgery, or at least stabilised. Finally, surgery was effective in eliminating tumour from the readily accessible sellar and suprasellar regions, thereby potentiating subsequent radiation therapy by reducing the volume needing to be treated and achieving separation from radiosensitive structures such as the optic chiasm. Surgery was generally well tolerated, with a low number of complications. These results suggest a quantifiable but modest reduction in the apparent burden of disease/treatment with debulking surgery, notwithstanding the limitations of the PRC framework discussed below. Our results align with the reports of previous studies assessing this patient population, though we provide more in depth analysis of the effect on DA dose. Primeau et al. reported on the hormonal outcomes of surgery in 16 patients with invasive prolactinomas within a larger cohort of 63 prolactinomas: none of the 16 patients had complete hormonal remission postoperatively 11 , mirroring the subset of patients in our study that had cavernous sinus invasion confirmed intraoperatively. However, no data were presented in their cohort on whether surgery allowed for DA dose reduction and complication rates in the subset of patients with invasive prolactinomas. Vroonen et al. reported on the outcomes of 15 patients who had ‘debulking surgery’ within a larger cohort of 92 patients 12 . They found that prolactin levels and weekly DA dose significantly decreased following debulking surgery. The Knosp grade and tumour size of these patients was not specified, and the time points that these measurements were made was also unclear. Our study provides a clearer picture of outcomes in patients with Knosp grade 3–4 tumours, a subset that may have a poorer hormonal response to operative intervention. Finally, Lundholm and colleagues reported on a cohort of eight operatively managed giant prolactinomas, with all reportedly having cavernous sinus invasion, though Knosp grade was not reported 10 . No patient experienced hormonal remission, and only one of the eight included patients was able to decrease their DA dose postoperatively. Though somewhat difficult to compare with our cohort as this study did not clearly define invasion, it highlights the difficulty that can be present in obtaining hormonal remission in invasive prolactinomas. Recent literature has described medial cavernous sinus wall resection and transcavernous approaches to resection of pituitary adenomas that can increase rates of gross total resection and enhance rates of hormonal remission postoperatively 15 , 16 . Utilisation of transcavernous techniques has been reported in a cohort of 59 operated prolactinomas with excellent rates of hormonal remission 17 . A major point of difference with our study is that no patients with Knosp grade 4 disease (cavernous sinus encasement) were included in this study. Therefore, our study provides insight into this subset of prolactinomas that are more rarely managed surgically, and in which complete resection is a less feasible goal. In our cohort, both Knosp 3A tumours did not have apparent cavernous sinus invasion intraoperatively and had gross total resection. In the remaining 9 tumours, gross invasion coupled with destruction of the medial wall of the cavernous sinus meant they would not have been appropriate candidates for medial cavernous sinus wall resection as this structure had essentially been destroyed by tumour infiltration. Prolactinomas tend to be more fibrotic at baseline than other subtypes of PAs which can complicate resection, and our local practice is to not aggressively pursue resection of the cavernous sinus component of pituitary adenomas when Knosp grade 4 disease is present 18 , 19 . This is particularly relevant in the setting of prolactinomas where the effects of hormone hypersecretion are less damaging (than Cushing’s disease and acromegaly) and non-surgical options such as radiation therapy have the capacity to control disease 20 . Our findings indirectly raise the possibility of earlier surgery in prolactinomas being beneficial, as complete resection would ameliorate the risk of progressive tumour developing significant cavernous sinus invasion. However, exploring this hypothesis will require large longitudinal studies and our practice remains a low surgical threshold approach as previously presented 21 . We acknowledge that our study has the attendant limitations of a retrospective cohort study with a small sample size. However, the aim of study was predominantly as an exploratory, descriptive study to describe outcomes in this rare situation in which there is currently scant information to guide management. We recognise that the PRC framework has been arbitrarily developed; however, there is no established framework to quantify prolactinoma-specific disease/treatment burden and the PRC values have been used herein as descriptive intraindividual comparisons before and after surgery rather than as predictors of future outcomes which would require validation in large independent datasets. DA dose adjustments were not systematised and reflected individual clinician practice, however, the clinicians were experienced in pituitary disease and the goal was to wean the DA wherever possible, guided principally by plasma prolactin. Unfortunately, prolactin values were taken infrequently in the first postoperative week which is a limitation, given that there is evidence that postoperative day one levels < 10ng/ml are predictive of longer term hormonal remission 22 . However, given the majority of patients in our cohort would not be expected to have complete hormonal remission, this parameter is less relevant in this setting. PRL levels at 3 and 12 months permit disease monitoring in the medium and longer term and are likely more useful time points in this subset of patients. In conclusion, we have detailed outcomes in a dedicated cohort of Knosp 3 and 4 prolactinomas in which the goal of surgery in a high proportion was debulking. We have developed the PRC framework that could help classify and integrate the various surgical outcomes in patients with prolactinomas in future studies, though this requires validation in larger patient cohorts. Our exploratory, descriptive study improves the evidence base for surgical outcomes in higher Knosp grade prolactinomas and sets the stage for further research into the currently unclear role for surgery in cavernous sinus invasive prolactinomas. Currently it seems that surgery is effective at addressing structural issues such as visual apparatus compression, but with a less consistent effect at facilitating DA dose reduction. Declarations Declaration of interest Contributions and Acknowledgements None of the authors have any conflicts of interest to declare. Funding This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. The PhD of author C.D.O. is supported by scholarships from the University of Adelaide, Royal Australian College of Surgeons and the Neurosurgical Research Foundation. Contributions C.D.O: Helped conceive study, designed paper, data collection, extracted data, analysed data, wrote manuscript. V.T: Helped with data collection and analysis and reviewed final manuscript. D.J.T: Helped with design of study, analysis and critical review of manuscript. I.C: Helped with design of study, analysis and critical review of manuscript. F.S: Helped with design of study, analysis and critical review of manuscript. A.J: Helped with design of study, analysis and critical review of manuscript. S.S: Helped with design of study, analysis and critical review of manuscript. N.V: Helped with design of study, analysis and critical review of manuscript. S.P: Helped conceive paper, helped design paper, contributed to critical review of manuscript. N.C: Helped conceive paper, helped design paper, contributed to critical review of manuscript. A.P: Designed and conceptualised study, data analysis and critical review and contribution to manuscript. S.D.S: Designed and conceptualised study, data analysis and critical review and contribution to manuscript. 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Dopamine agonist therapy for prolactinomas: do we need to rethink the place of surgery in prolactinoma management? Endocr Oncol. 2022;2(1):R31-r50. Amar AP, Couldwell WT, Chen JC, Weiss MH. Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg. 2002;97(2):307-314. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8042272","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":545610165,"identity":"10b4a642-62ce-4e33-a50a-fcc3d8a1361c","order_by":0,"name":"Christopher Dillon Ovenden","email":"data:image/png;base64,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","orcid":"","institution":"University of Adelaide","correspondingAuthor":true,"prefix":"","firstName":"Christopher","middleName":"Dillon","lastName":"Ovenden","suffix":""},{"id":545610168,"identity":"a5035104-9a87-4500-8bf4-babcc3f61f04","order_by":1,"name":"Victoria Tan","email":"","orcid":"","institution":"Flinders Medical Centre","correspondingAuthor":false,"prefix":"","firstName":"Victoria","middleName":"","lastName":"Tan","suffix":""},{"id":545610170,"identity":"4af5f55a-6fc8-42f8-98c4-4fb3c8431ecb","order_by":2,"name":"David J. Torpy","email":"","orcid":"","institution":"Royal Adelaide Hospital","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"J.","lastName":"Torpy","suffix":""},{"id":545610174,"identity":"d80866f3-5888-47dd-8672-aba32695960b","order_by":3,"name":"Ian Chapman","email":"","orcid":"","institution":"Royal Adelaide Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ian","middleName":"","lastName":"Chapman","suffix":""},{"id":545610175,"identity":"316f52da-e581-45ad-8284-d3e990d1b646","order_by":4,"name":"Frank Saran","email":"","orcid":"","institution":"Royal Adelaide Hospital","correspondingAuthor":false,"prefix":"","firstName":"Frank","middleName":"","lastName":"Saran","suffix":""},{"id":545610176,"identity":"7038e71f-50e6-40bf-95f6-b9fd9aa295ae","order_by":5,"name":"Alistair Jukes","email":"","orcid":"","institution":"University of Adelaide","correspondingAuthor":false,"prefix":"","firstName":"Alistair","middleName":"","lastName":"Jukes","suffix":""},{"id":545610177,"identity":"55b98514-c6d9-44ec-94d1-cddce64ede46","order_by":6,"name":"Stephen Santoreneos","email":"","orcid":"","institution":"Royal Adelaide Hospital","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Santoreneos","suffix":""},{"id":545610178,"identity":"14dbb968-2689-48e2-a841-2dde8e84546f","order_by":7,"name":"Nikitas Vrodos","email":"","orcid":"","institution":"Flinders Medical Centre","correspondingAuthor":false,"prefix":"","firstName":"Nikitas","middleName":"","lastName":"Vrodos","suffix":""},{"id":545610179,"identity":"61d1f4f0-3f95-4a02-907a-cc7c9f0c3555","order_by":8,"name":"Santosh Poonnoose","email":"","orcid":"","institution":"Flinders Medical Centre","correspondingAuthor":false,"prefix":"","firstName":"Santosh","middleName":"","lastName":"Poonnoose","suffix":""},{"id":545610180,"identity":"5214c6fb-e509-4d76-9e6c-71e7486549ed","order_by":9,"name":"Nicholas Candy","email":"","orcid":"","institution":"University of Adelaide","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"","lastName":"Candy","suffix":""},{"id":545610181,"identity":"a332df5e-0994-44ae-8dde-0a290c9e3333","order_by":10,"name":"Alkis Psaltis","email":"","orcid":"","institution":"University of Adelaide","correspondingAuthor":false,"prefix":"","firstName":"Alkis","middleName":"","lastName":"Psaltis","suffix":""},{"id":545610182,"identity":"c2839e44-615f-462e-ae49-d3b129e40336","order_by":11,"name":"Sunita M. C. Sousa","email":"","orcid":"","institution":"University of Adelaide","correspondingAuthor":false,"prefix":"","firstName":"Sunita","middleName":"M. C.","lastName":"Sousa","suffix":""}],"badges":[],"createdAt":"2025-11-06 00:38:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8042272/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8042272/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96075262,"identity":"c622b1a5-2c2f-4c3c-804e-af915fe3d456","added_by":"auto","created_at":"2025-11-17 10:37:28","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":208151,"visible":true,"origin":"","legend":"","description":"","filename":"61125Pituitarymanuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/905fb33786a8adb9601c9b5d.docx"},{"id":96075263,"identity":"f8567077-d074-4a10-a61e-f0a0aecc9dde","added_by":"auto","created_at":"2025-11-17 10:37:28","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12648,"visible":true,"origin":"","legend":"","description":"","filename":"3fb65f8ca28b405ebe49865b88c45dca.json","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/6267fa8570ff88da16803416.json"},{"id":96075264,"identity":"df98989b-e5df-41b9-9c6d-4beb01b778d6","added_by":"auto","created_at":"2025-11-17 10:37:28","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":125838,"visible":true,"origin":"","legend":"","description":"","filename":"3fb65f8ca28b405ebe49865b88c45dca1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/486a7e6f2cba97f59d62a2a8.xml"},{"id":96075259,"identity":"813bebd2-9647-4e37-85c1-a3175eca802e","added_by":"auto","created_at":"2025-11-17 10:37:28","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":104979,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/b20442b299a9e07840d4110b.png"},{"id":96075260,"identity":"7fcd34f3-b5f4-4316-93f7-d752c78c0450","added_by":"auto","created_at":"2025-11-17 10:37:28","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38394,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/4b59c59edbd2dce8aa72adcf.png"},{"id":96247355,"identity":"58a4813e-10ac-4469-9557-d57d7907408b","added_by":"auto","created_at":"2025-11-19 07:27:25","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":122460,"visible":true,"origin":"","legend":"","description":"","filename":"3fb65f8ca28b405ebe49865b88c45dca1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/04de7d452619c9bde53e04f2.xml"},{"id":96075266,"identity":"e876c0dc-36ac-4936-b934-a0d82145bd58","added_by":"auto","created_at":"2025-11-17 10:37:28","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":132734,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/cb26d3870f903da6426d2f48.html"},{"id":96075257,"identity":"93c89f5d-a285-41b4-9105-7b9c46671293","added_by":"auto","created_at":"2025-11-17 10:37:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":104979,"visible":true,"origin":"","legend":"\u003cp\u003eChange in prolactin level (recorded value:upper limit of normal of reference range) and weekly cabergoline dose (mg) following surgery for each patient. Time from surgery is reported as P (preoperative level), 3 (3 months postoperatively) and 12 (12 months postoperatively). Radiotherapy is indicated by a vertical purple line in relevant cases.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/acd85efa3aa4332cf8932c29.png"},{"id":96256035,"identity":"9293ac71-2b8c-4cf4-a032-0b61aa40637e","added_by":"auto","created_at":"2025-11-19 07:49:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":705068,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/a49e321c-a367-4019-9288-dd68a9c270a3.pdf"},{"id":96075258,"identity":"c95fca4b-a02a-4371-ba9a-221a2c9555c5","added_by":"auto","created_at":"2025-11-17 10:37:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":31189,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8042272/v1/897a05606c2b69fcf3da814f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Surgical Outcomes in Knosp grade 3 or 4 macroprolactinomas: What role does debulking surgery play?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProlactinoma therapy has traditionally centred on dopamine agonist (DA) use, with the therapeutic goal of prolactin (PRL) reduction, restoration of eugonadism and reduction of tumour volume in order to provide relief of mass effect on surrounding structures. Though cabergoline treatment of PRL results in PRL normalisation in 81% of cases, relapse is common following withdrawal of therapy. Furthermore, significant DA side effects such as mood disturbance or impulse control disorders are increasingly recognised\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn Knosp 0 and 1 prolactinomas, trans-sphenoidal surgery (TSS) has reported remission rates of around 90% and low complication rates in selected centres, and may obviate the need for long term DA therapy, with a corresponding improvement in quality of life\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The Pituitary Society accordingly recommended in 2023 that surgical resection could be offered as a first line therapy for microprolactinomas and well-encased macroprolactinomas (Knosp 0 or 1) as an alternative to DA therapy, though it is not yet clear whether an initial trial of DA is warranted\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. There is also a question of whether this recommendation should include Knosp 2 tumours which very rarely invade the cavernous sinus and often have a definable pseudocapsule that facilitates their resection\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Surgery has also traditionally been employed in the setting of cystic macroprolactinomas and macroprolactinomas with visual deficit, though evidence now suggests these tumours also respond well to DA\u003csup\u003e8,9\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eA separate, unanswered question is the role that surgery plays in tumours in which preoperative imaging predicts a higher likelihood of cavernous sinus invasion and thereby incomplete resection. The rationale for surgery in these cases is that surgical debulking may potentiate DA dose reduction in resistant or intolerant patients, and is weakly recommended in the latest Pituitary Society guidelines\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, there is a lack of data specific to cavernous sinus invasive prolactinomas to guide this recommendation. One study by Lundholm and colleagues investigated eight patients who had surgically managed giant prolactinomas with cavernous sinus invasion but did not report Knosp grading or how invasion was classified\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Studies reporting on surgery for DA resistant prolactinomas tend not to specifically report outcomes regarding DA dose reduction for invasive prolactinomas, instead grouping the results for these tumours with their non-invasive counterparts\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Complete remission is an unrealistic goal of surgery in this setting, with one study reporting rates of 0% in a series of 16 operated prolactinomas\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e; however, it is plausible that tumour debulking might permit dose reduction or clinically meaningful structural control of the tumour.\u003c/p\u003e\u003cp\u003eWe therefore sought to perform an exploratory, descriptive analysis of surgery in a retrospective cohort of patients with radiologically invasive prolactinomas. A specific focus was placed on hormonal outcomes including influence of surgery on DA dose and PRL levels. Finally, we sought to develop a conceptual framework to help interpret the response of prolactinomas to surgery.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003eScreening of the state-wide South Australia Pituitary Registry was performed to identify patients who had surgery for prolactinomas with potentially unresectable cavernous sinus invasion, defined as a modified Knosp grade of 3A (beyond lateral internal carotid artery (ICA) margin, superior to intracavernous ICA), 3B (beyond lateral ICA margin, inferior to intracavernous ICA) or 4 (encasement of ICA), between the period of January 2000 and June 2025. Inclusion criteria were: 1. a preoperative serum prolactin (PRL) level of \u0026ge;\u0026thinsp;4 times the upper limit of normal or hyperprolactinaemia to any degree with tumour specimen hormone immunohistochemistry (IHC) solely positive for PRL, 2. modified Knosp grade 3 or 4 cavernous sinus invasion on the preoperative MRI closest to the time of surgery\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, and 3. at least one postoperative PRL recorded at \u0026ge;\u0026thinsp;3 months after the surgery. Knosp 0\u0026ndash;2 prolactinoma surgical outcomes were assessed as a comparison group. Transcription factor IHC was not performed at our institution until recently, hence the selection criteria pertained only to hormone IHC. Ethical approval was obtained from the Central Adelaide Local Health Network Human Research Ethics Committee (reference number 2025/HRE00204). Due to the retrospective audit nature of the study, consent to publication was waived by the approving Ethics Committee in accordance with the National Health and Medical Research Council research guidelines.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy parameters\u003c/h3\u003e\n\u003cp\u003eData was collated regarding demographic parameters (e.g., sex, age at time of first radiological diagnosis of pituitary adenoma and age at time of surgery), presenting symptoms (headaches, vision loss, galactorrhoea, amenorrhoea, low libido, fatigue, mood disturbance or double vision), hormone co-secretion and indication for surgery (DA intolerance, DA resistance, acute visual compromise or diagnostic resection). Maximum and latest preoperative PRL levels were recorded. Postoperative PRL levels were recorded within 1 week and at 3 and 12 months after surgery, and at latest follow-up. All serum PRL levels were recorded relative to the upper limit of normal of the corresponding reference range.\u003c/p\u003e\u003cp\u003eOther preoperative and postoperative data were compared in regard to objective visual deficits, gonadal status, other pituitary hormone status, DA use (e.g., dose and tolerability) and MRI characteristics (e.g., maximal diameter, Knosp grade, the presence of haemorrhage and any cystic regions). Cumulative DA dose was calculated by summing the weekly dose of DA. The 3-month postoperative MRI was assessed for extent of resection, with results dichotomised to gross total resection (GTR) or subtotal resection (STR).\u003c/p\u003e\u003cp\u003eSurgical approach was uniformly via an endoscopic, endonasal trans-sphenoidal approach. Duration of surgery was recorded, as were any postoperative complications. Available tumour characteristics were collated, including tumour specimen hormone and transcription factor immunohistochemistry (IHC), Ki-67 proliferative index and granulation status. Hormonal remission and surgical outcomes were assessed at 3 and 12 months postoperatively, in addition to latest follow-up. The need for further treatment in the form of additional surgery or radiation therapy was recorded.\u003c/p\u003e\n\u003ch3\u003eProlactinoma response criteria\u003c/h3\u003e\n\u003cp\u003eGiven the diverse clinical end-points after surgery for prolactinomas, we created a set of response criteria \u0026ndash; the Prolactinoma Response Criteria (PRC; Supplementary Table\u0026nbsp;3) \u0026ndash; to capture overall surgical outcome. The PRC aim to quantify and thereby compare the collective burden of tumour/treatment before and after surgery using a standardized framework. This framework covers potential negative outcomes from the tumour itself and its treatment. Each outcome is allocated points: 1 for negative outcomes with no anticipated clinical effect (e.g., infrasellar tumour invasion), 2 for negative outcomes with potential clinical risks (e.g., suprasellar tumour invasion, as this carries a significant risk of chiasmal compression), and 3 for negative outcomes of immediate clinical concern (e.g., tumour increase\u0026thinsp;\u0026ge;\u0026thinsp;30% within 12 months). The higher the PRC score, the greater the apparent burden of disease/treatment. The PRC are scored in the preoperative period and then at 12 months postoperatively; the difference reflects overall surgical response.\u003c/p\u003e\u003cp\u003eHormonal factors assessed in the PRC included the presence of high PRL, hypogonadism, other pituitary hormone deficit and a rapidly rising PRL (\u0026ge;\u0026thinsp;30% in one year). Anatomical factors were recorded regarding the extent of the prolactinoma (whether it extended to sellar, cavernous sinus, suprasellar or clival/sphenoid sinus region, whether there was visual deficit and whether it was rapidly growing). Cabergoline dose was categorised as low (\u0026lt;\u0026thinsp;1mg/week), intermediate (1-2mg/week) or high dose (\u0026gt;\u0026thinsp;2mg/week). DA side effects were recorded as tolerable or intolerable. Need for additional treatment such as radiation therapy, temozolomide or another tumour targeted therapy such as pasireotide was also recorded. Complications from surgery were recorded.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eGiven the small size of the study, statistical analysis was limited to descriptive statistics. Categorical variables were presented as counts and percentages, and continuous variables as means +/- standard deviation (SD) if normally distributed or medians (interquartile range, IQR) if distribution was skewed. Paired t-tests were used to assess differences in pre and postoperative PRL levels and dose. Statistical analysis was performed with EasyMedStat (version 3.40; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.easymedstat.com\u003c/span\u003e\u003c/span\u003e). \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003ePatient Characteristics and Visual Outcomes\u003c/h2\u003e\n \u003cp\u003eOver the study period, 54 patients had operated prolactinomas. Knosp grade was 0\u0026ndash;2 in 43 comparison group cases, with 84% achieving remission with no DA requirement at 12 months postoperatively. The cohort of patients who had debulking surgery for prolactinomas with Knosp grade 3 or 4 prolactinomas consisted of 11 patients (6 males, 5 females). Mean age at time of initial imaging diagnosis was 39.3 years (\u0026plusmn;\u0026thinsp;15.1, range 18\u0026ndash;64), with a mean age at surgery of 43.3 years (\u0026plusmn;\u0026thinsp;16.2, range 26\u0026ndash;77). The major presenting complaints were visual symptoms (45%), symptoms of hypogonadism (amenorrhoea, low libido or low mood in 45%), headaches (36%) and seizures (9%); 18% of patients were asymptomatic. Six patients (55%) had objective visual field deficits on formal ophthalmological examination. Five of these patients had objective improvement of vision postoperatively, whilst one of the six patients experienced acute worsening of vision in the immediate postoperative period thought to be secondary to tension on the optic nerve. This returned to baseline at 3 months postoperatively.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eHistological Findings\u003c/h3\u003e\n\u003cp\u003eAll tumours exhibited positive PRL staining on hormone immunohistochemistry. One tumour additionally stained for growth hormone (GH), but was not a co-secreter as is detailed in the biochemical section below. Eight samples had transcription factor IHC performed, with all eight positive for Pit-1 and negative for other transcription factors as expected. Granulation status was recorded in four patients, with two sparsely granulated and two densely granulated tumours.\u003c/p\u003e\n\u003ch3\u003eSurgical Goal\u003c/h3\u003e\n\u003cp\u003eIndication for surgery was DA resistance in five cases, DA intolerance in three cases, need for diagnostic resection in two cases (PRL not grossly elevated with visual apparatus compression) and apoplexy with acute visual compromise in one patient. In three patients the goal of surgery was complete resection, with the goal in the remaining eight patients being debulking.\u003c/p\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003eBiochemical Baseline and Outcomes\u003c/h2\u003e\n \u003cp\u003eNo tumours exhibited co-secretion of another pituitary hormone. Ten patients were hypogonadal preoperatively, including two on sex hormone replacement. Postoperatively eight patients were hypogonadal, including four on sex hormone replacement. No patient was deficient in another hormonal axis preoperatively, whereas five patients developed at least one new pituitary hormone deficiency postoperatively that required replacement (5 required thyroid hormone replacement, 3 required cortisol replacement and 1 required growth hormone replacement).\u003c/p\u003e\n \u003cp\u003eMaximum PRL level prior to any treatment was a mean of 148.4 times the upper limit of normal of the reference range (\u0026plusmn;\u0026thinsp;181.3, range 1.2-576.1), with this measurement taken a mean of 901 days (median 253, range 1-4441) preoperatively. Last PRL level prior to surgery was a mean of 82.2 times the upper limit of normal of the reference range (\u0026plusmn;\u0026thinsp;168.5, range 0-576.1), with this measurement taken at a mean of 46 days (\u0026plusmn;\u0026thinsp;52.3, range 1-180) preoperatively. Six patients had a PRL level taken in the first postoperative week, with a mean of 56.0 times the upper limit of normal of the reference range (\u0026plusmn;\u0026thinsp;116.0, range 2.0-292.3), with this measurement taken a mean of 3.2 days (\u0026plusmn;\u0026thinsp;2.6, range 1\u0026ndash;7) postoperatively. Ten patients had a PRL level taken at 3 months postoperatively, with a mean of 28.4 (\u0026plusmn;\u0026thinsp;50.0, range 0.0-162.6) times the upper limit of normal of the reference range. Ten patients had a PRL level taken at 12 months postoperatively, with a mean of 17.1 (\u0026plusmn;\u0026thinsp;23.6, range 0.5\u0026ndash;64.6) times the upper limit of normal of the reference range. Seven patients had an additional PRL level taken more than 12 months postoperatively, with a mean of 11.1 (\u0026plusmn;\u0026thinsp;20.5, range 0.2\u0026ndash;55.1) times the upper limit of normal of the reference range, with this value being taken a mean of 2164 days (\u0026plusmn;\u0026thinsp;1710, range 158\u0026ndash;4724) postoperatively. Supplementary table 1 provides a summary of pre and postoperative PRL levels for each patient.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003eChanges in Cabergoline Therapy\u003c/h2\u003e\n \u003cp\u003eEight patients had preoperative treatment with cabergoline. Mean duration of cabergoline therapy in these patients was 52.5 months (\u0026plusmn;\u0026thinsp;72.2, range 3-204), and the mean cumulative dose was 269mg (\u0026plusmn;\u0026thinsp;337, range 12\u0026ndash;936). The reason for no preoperative cabergoline treatment in one patient was due to acute presentation with apoplexy and vision loss, with the reason in the other two patients being that their mild PRL rise was thought to reflect stalk effect hyperprolactinaemia due to a presumed non-functioning pituitary adenoma. Despite the mild PRL rise, these two patients had hormone IHC that was solely positive for PRL. Two further patients had significant DA intolerance requiring complete cessation by the time of surgery. For the remaining six patients, two were receiving 1mg weekly, one was receiving 3mg weekly, two were receiving 4mg weekly and one was receiving 6mg weekly. At three months postoperatively, amongst the six patients on a DA preoperatively, three had their dose reduced and three were on the same dose. At 12 months, three were on a lower dose compared to preoperatively, two were on the same dose and one patient was on a higher dose. The dose reduction for one of these patients notably occurred in the context of radiation therapy occurring 6 months postoperatively. Supplementary table 2 provides a summary of weekly cabergoline dose preoperatively and postoperatively. Figure 1 details individual patient\u0026rsquo;s changes in PRL levels and DA dose in relation to time from surgery.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003eStructural Imaging Baseline and Response to Surgery\u003c/h2\u003e\n \u003cp\u003ePreoperative MRI showed a mean maximal diameter of 33.9mm (\u0026plusmn;\u0026thinsp;13.1, range 15\u0026ndash;52). All cases were macroadenomas, with two Knosp 3A tumours, one Knosp 3B tumours and eight Knosp 4 tumours. One case demonstrated apoplexy and three had cystic components. Both Knosp 3A patients had GTR; all other patients had STR on 3 month postoperative MRI. In all cases of STR, residual disease was located in the cavernous sinus with the sellar, clival and suprasellar regions having clearance of tumour.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003eSurgical Outcomes and Complications\u003c/h2\u003e\n \u003cp\u003eDuration of surgery was recorded in six patients, amounting to a mean of 231 minutes (\u0026plusmn;\u0026thinsp;30, range 170\u0026ndash;250). Five patients had complications: three patients had transient arginine vasopressin deficiency (AVP-D), one patient had sepsis of unclear source that resolved with antibiotic therapy, and one patient sustained an avulsion injury of the superior hypophyseal artery (SHA) off the internal carotid artery that could not be controlled with a muscle patch. This injury required surgical clip application to the point of origin of the SHA, with postoperative digital subtraction angiography showing 40% stenosis of the ICA. The patient sustained no neurological deficits as a result of this injury and there was no evidence of pseudo aneurysm on neuro-imaging follow-up.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\"\u003e\n \u003ch2\u003eBiochemical Remission Rates and Requirement for Further Treatment\u003c/h2\u003e\n \u003cp\u003eOf the 11 patients, three were in remission (two 3A grades and one grade 4 case) at three and 12 months postoperatively \u0026ndash; both 3A patients were never treated with cabergoline pre or postoperatively, whilst the grade 4 patient that initially had hormonal remission had a PRL rise 57 months following surgery and was restarted on cabergoline therapy (0.25mg weekly dose). Four other patients had postoperative radiation therapy in the form of fractionated stereotactic radiotherapy with a dose of 54Gy/30# (one at 6 weeks, two at 6 months and one patient at 21 months postoperatively). No patient underwent additional surgery.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\"\u003e\n \u003ch2\u003eProlactinoma Response Criteria\u003c/h2\u003e\n \u003cp\u003eSupplementary table 3 provides the PRC scores for each patient pre- and 12-months postoperatively. Mean PRC score was 10.2 preoperatively compared to 8.9 to postoperatively. PRC fell in six postoperatively (indicating beneficial overall surgical outcome), was stable in one patient and, rose in four patients (indicating adverse overall surgical outcome).\u003c/p\u003e\n \n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first dedicated surgical cohort study of patients with Knosp grade 3 or 4 prolactinomas. The indications for surgery were heterogeneous with correspondingly heterogeneous outcomes. In summary, surgery provided a modest benefit in our patient cohort. Surgery resulted in complete remission with no need for DA therapy in three patients despite their high grade tumours. In patients with DA resistance, surgery allowed dose reduction in 50% of patients at 3 and 12 months, though the dose reduction in one of these patients followed radiation therapy which is a confounding factor. Surgery resulted in a trend towards decreased PRL levels, though this was not statistically significant, likely due to the small sample size. Preoperative visual compromise tended to be ameliorated by surgery, or at least stabilised. Finally, surgery was effective in eliminating tumour from the readily accessible sellar and suprasellar regions, thereby potentiating subsequent radiation therapy by reducing the volume needing to be treated and achieving separation from radiosensitive structures such as the optic chiasm. Surgery was generally well tolerated, with a low number of complications. These results suggest a quantifiable but modest reduction in the apparent burden of disease/treatment with debulking surgery, notwithstanding the limitations of the PRC framework discussed below.\u003c/p\u003e\u003cp\u003eOur results align with the reports of previous studies assessing this patient population, though we provide more in depth analysis of the effect on DA dose. Primeau et al. reported on the hormonal outcomes of surgery in 16 patients with invasive prolactinomas within a larger cohort of 63 prolactinomas: none of the 16 patients had complete hormonal remission postoperatively\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, mirroring the subset of patients in our study that had cavernous sinus invasion confirmed intraoperatively. However, no data were presented in their cohort on whether surgery allowed for DA dose reduction and complication rates in the subset of patients with invasive prolactinomas. Vroonen et al. reported on the outcomes of 15 patients who had \u0026lsquo;debulking surgery\u0026rsquo; within a larger cohort of 92 patients\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. They found that prolactin levels and weekly DA dose significantly decreased following debulking surgery. The Knosp grade and tumour size of these patients was not specified, and the time points that these measurements were made was also unclear. Our study provides a clearer picture of outcomes in patients with Knosp grade 3\u0026ndash;4 tumours, a subset that may have a poorer hormonal response to operative intervention. Finally, Lundholm and colleagues reported on a cohort of eight operatively managed giant prolactinomas, with all reportedly having cavernous sinus invasion, though Knosp grade was not reported\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. No patient experienced hormonal remission, and only one of the eight included patients was able to decrease their DA dose postoperatively. Though somewhat difficult to compare with our cohort as this study did not clearly define invasion, it highlights the difficulty that can be present in obtaining hormonal remission in invasive prolactinomas.\u003c/p\u003e\u003cp\u003eRecent literature has described medial cavernous sinus wall resection and transcavernous approaches to resection of pituitary adenomas that can increase rates of gross total resection and enhance rates of hormonal remission postoperatively\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Utilisation of transcavernous techniques has been reported in a cohort of 59 operated prolactinomas with excellent rates of hormonal remission\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. A major point of difference with our study is that no patients with Knosp grade 4 disease (cavernous sinus encasement) were included in this study. Therefore, our study provides insight into this subset of prolactinomas that are more rarely managed surgically, and in which complete resection is a less feasible goal. In our cohort, both Knosp 3A tumours did not have apparent cavernous sinus invasion intraoperatively and had gross total resection. In the remaining 9 tumours, gross invasion coupled with destruction of the medial wall of the cavernous sinus meant they would not have been appropriate candidates for medial cavernous sinus wall resection as this structure had essentially been destroyed by tumour infiltration. Prolactinomas tend to be more fibrotic at baseline than other subtypes of PAs which can complicate resection, and our local practice is to not aggressively pursue resection of the cavernous sinus component of pituitary adenomas when Knosp grade 4 disease is present\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. This is particularly relevant in the setting of prolactinomas where the effects of hormone hypersecretion are less damaging (than Cushing\u0026rsquo;s disease and acromegaly) and non-surgical options such as radiation therapy have the capacity to control disease\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Our findings indirectly raise the possibility of earlier surgery in prolactinomas being beneficial, as complete resection would ameliorate the risk of progressive tumour developing significant cavernous sinus invasion. However, exploring this hypothesis will require large longitudinal studies and our practice remains a low surgical threshold approach as previously presented\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eWe acknowledge that our study has the attendant limitations of a retrospective cohort study with a small sample size. However, the aim of study was predominantly as an exploratory, descriptive study to describe outcomes in this rare situation in which there is currently scant information to guide management. We recognise that the PRC framework has been arbitrarily developed; however, there is no established framework to quantify prolactinoma-specific disease/treatment burden and the PRC values have been used herein as descriptive intraindividual comparisons before and after surgery rather than as predictors of future outcomes which would require validation in large independent datasets. DA dose adjustments were not systematised and reflected individual clinician practice, however, the clinicians were experienced in pituitary disease and the goal was to wean the DA wherever possible, guided principally by plasma prolactin.\u003c/p\u003e\u003cp\u003eUnfortunately, prolactin values were taken infrequently in the first postoperative week which is a limitation, given that there is evidence that postoperative day one levels\u0026thinsp;\u0026lt;\u0026thinsp;10ng/ml are predictive of longer term hormonal remission\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. However, given the majority of patients in our cohort would not be expected to have complete hormonal remission, this parameter is less relevant in this setting. PRL levels at 3 and 12 months permit disease monitoring in the medium and longer term and are likely more useful time points in this subset of patients.\u003c/p\u003e\u003cp\u003eIn conclusion, we have detailed outcomes in a dedicated cohort of Knosp 3 and 4 prolactinomas in which the goal of surgery in a high proportion was debulking. We have developed the PRC framework that could help classify and integrate the various surgical outcomes in patients with prolactinomas in future studies, though this requires validation in larger patient cohorts. Our exploratory, descriptive study improves the evidence base for surgical outcomes in higher Knosp grade prolactinomas and sets the stage for further research into the currently unclear role for surgery in cavernous sinus invasive prolactinomas. Currently it seems that surgery is effective at addressing structural issues such as visual apparatus compression, but with a less consistent effect at facilitating DA dose reduction.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of interest Contributions and Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors have any conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\u003cbr\u003e\u0026nbsp;The PhD of author C.D.O. is supported by scholarships from the University of Adelaide, Royal Australian College of Surgeons and the Neurosurgical Research Foundation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC.D.O: Helped conceive study, designed paper, data collection, extracted data, analysed data, wrote manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eV.T: Helped with data collection and analysis and reviewed final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eD.J.T: Helped with design of study, analysis and critical review of manuscript.\u003c/p\u003e\n\u003cp\u003eI.C: Helped with design of study, analysis and critical review of manuscript.\u003c/p\u003e\n\u003cp\u003eF.S: Helped with design of study, analysis and critical review of manuscript.\u003c/p\u003e\n\u003cp\u003eA.J: Helped with design of study, analysis and critical review of manuscript.\u003c/p\u003e\n\u003cp\u003eS.S: Helped with design of study, analysis and critical review of manuscript.\u003c/p\u003e\n\u003cp\u003eN.V: Helped with design of study, analysis and critical review of manuscript.\u003c/p\u003e\n\u003cp\u003eS.P: Helped conceive paper, helped design paper, contributed to critical review of manuscript.\u003c/p\u003e\n\u003cp\u003eN.C: Helped conceive paper, helped design paper, contributed to critical review of manuscript.\u003c/p\u003e\n\u003cp\u003eA.P: Designed and conceptualised study, data analysis and critical review and contribution to manuscript.\u003c/p\u003e\n\u003cp\u003eS.D.S: Designed and conceptualised study, data analysis and critical review and contribution to manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZamanipoor Najafabadi AH, Zandbergen IM, de Vries F, et al. Surgery as a Viable Alternative First-Line Treatment for Prolactinoma Patients. A Systematic Review and Meta-Analysis. \u003cem\u003eJ Clin Endocrinol Metab. \u003c/em\u003e2020;105(3):e32-41.\u003c/li\u003e\n\u003cli\u003eDe Sousa SMC, Baranoff J, Rushworth RL, et al. Impulse Control Disorders in Dopamine Agonist-Treated Hyperprolactinemia: Prevalence and Risk Factors. \u003cem\u003eJ Clin Endocrinol Metab. \u003c/em\u003e2020;105(3).\u003c/li\u003e\n\u003cli\u003evan Trigt VR, Bakker LEH, Pelsma ICM, et al. The Changing Treatment Paradigm for Prolactinoma\u0026mdash;A Prospective Series of 100 Consecutive Neurosurgical Cases. \u003cem\u003eThe Journal of Clinical Endocrinology \u0026amp; Metabolism. \u003c/em\u003e2024;110(6):e1833-e1844.\u003c/li\u003e\n\u003cli\u003eGiese S, Nasi-Kordhishti I, Honegger J. Outcomes of Transsphenoidal Microsurgery for Prolactinomas - A Contemporary Series of 162 Cases. \u003cem\u003eExp Clin Endocrinol Diabetes. \u003c/em\u003e2021;129(3):163-171.\u003c/li\u003e\n\u003cli\u003ePetersenn S, Fleseriu M, Casanueva FF, et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. \u003cem\u003eNat Rev Endocrinol. \u003c/em\u003e2023;19(12):722-740.\u003c/li\u003e\n\u003cli\u003eDe Sousa SMC, Jukes AK, Candy NG, et al. Tumour fibrosis in dopamine agonist-exposed prolactinomas is a diminishing concern. \u003cem\u003eNat Rev Endocrinol. \u003c/em\u003e2024;20(5):314.\u003c/li\u003e\n\u003cli\u003eWu ZB. The shift of therapeutic strategy for prolactinomas: surgery as the first-line option. \u003cem\u003eNature Reviews Endocrinology. \u003c/em\u003e2024;20(5):310-310.\u003c/li\u003e\n\u003cli\u003eCasanueva FF, Molitch ME, Schlechte JA, et al. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. \u003cem\u003eClin Endocrinol (Oxf). \u003c/em\u003e2006;65(2):265-273.\u003c/li\u003e\n\u003cli\u003eFaje A, Chunharojrith P, Nency J, Biller BM, Swearingen B, Klibanski A. Dopamine Agonists Can Reduce Cystic Prolactinomas. \u003cem\u003eJ Clin Endocrinol Metab. \u003c/em\u003e2016;101(10):3709-3715.\u003c/li\u003e\n\u003cli\u003eLundholm MD, Yogi-Morren D, Pantalone KM, Recinos PF, Kshettry VR, Rao PPR. Surgical Management of Giant Prolactinomas: A Descriptive Study. \u003cem\u003eInt J Endocrinol. \u003c/em\u003e2023;2023:1990259.\u003c/li\u003e\n\u003cli\u003ePrimeau V, Raftopoulos C, Maiter D. Outcomes of transsphenoidal surgery in prolactinomas: improvement of hormonal control in dopamine agonist-resistant patients. \u003cem\u003eEur J Endocrinol. \u003c/em\u003e2012;166(5):779-786.\u003c/li\u003e\n\u003cli\u003eVroonen L, Jaffrain-Rea ML, Petrossians P, et al. Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients. \u003cem\u003eEur J Endocrinol. \u003c/em\u003e2012;167(5):651-662.\u003c/li\u003e\n\u003cli\u003evan Trigt VR, Bakker LEH, Pelsma ICM, et al. The Changing Treatment Paradigm for Prolactinoma-A Prospective Series of 100 Consecutive Neurosurgical Cases. \u003cem\u003eJ Clin Endocrinol Metab. \u003c/em\u003e2025;110(6):e1833-e1844.\u003c/li\u003e\n\u003cli\u003eMicko AS, W\u0026ouml;hrer A, Wolfsberger S, Knosp E. Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based classification. \u003cem\u003eJ Neurosurg. \u003c/em\u003e2015;122(4):803-811.\u003c/li\u003e\n\u003cli\u003eCohen-Cohen S, Gardner PA, Alves-Belo JT, et al. The medial wall of the cavernous sinus. Part 2: Selective medial wall resection in 50 pituitary adenoma patients. \u003cem\u003eJ Neurosurg. \u003c/em\u003e2019;131(1):131-140.\u003c/li\u003e\n\u003cli\u003ePontes JPM, Udoma-Udofa OC, de Oliveira JS, et al. Efficacy and safety of cavernous sinus medial wall resection in pituitary adenoma surgery: a systematic review and a single-arm meta-analysis. \u003cem\u003ePituitary. \u003c/em\u003e2023;26(4):340-351.\u003c/li\u003e\n\u003cli\u003eNakase T, Ljubimov VA, Chang JJ, et al. Endoscopic endonasal transcavernous surgery for a contemporary series of 59 prolactinomas. \u003cem\u003ePituitary. \u003c/em\u003e2025;28(4):81.\u003c/li\u003e\n\u003cli\u003eBaussart B, Villa C, Jouinot A, et al. Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study. \u003cem\u003eEur J Endocrinol. \u003c/em\u003e2021;185(6):783-791.\u003c/li\u003e\n\u003cli\u003eMenucci M, Qui\u0026ntilde;ones-Hinojosa A, Burger P, Salvatori R. Effect of dopaminergic drug treatment on surgical findings in prolactinomas. \u003cem\u003ePituitary. \u003c/em\u003e2011;14(1):68-74.\u003c/li\u003e\n\u003cli\u003eNiculescu DA, Gheorghiu ML, Poiana C. Radiotherapy in aggressive or dopamine agonists resistant prolactinomas; is it still worthwhile? \u003cem\u003eEuropean Journal of Endocrinology. \u003c/em\u003e2023;188(4):R88-R97.\u003c/li\u003e\n\u003cli\u003eDe Sousa SMC. Dopamine agonist therapy for prolactinomas: do we need to rethink the place of surgery in prolactinoma management? \u003cem\u003eEndocr Oncol. \u003c/em\u003e2022;2(1):R31-r50.\u003c/li\u003e\n\u003cli\u003eAmar AP, Couldwell WT, Chen JC, Weiss MH. Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. \u003cem\u003eJ Neurosurg. \u003c/em\u003e2002;97(2):307-314.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8042272/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8042272/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTo determine the clinical outcomes of patients who had surgery to treat Knosp 3 and 4 prolactinomas with a particular focus on hormonal outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eRetrospective cohort review of South Australian patients who had surgery to treat Knosp 3 and 4 prolactinomas from January 2000 to June 2025. Tumours were resected via an endoscopic, endonasal trans-sphenoidal approach. Demographic and clinical parameters were recorded. Hormonal outcomes were measured through assessment of prolactin levels and weekly cabergoline dose preoperatively and then at 3 months postoperatively. We also synthesised a set of criteria that can be used to assess outcomes in prolactinoma surgery.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOf 54 total operated prolactinomas, 11 were Knosp 3 or 4 prolactinomas. Mean age at surgery was 43.3 years (\u0026plusmn;\u0026thinsp;16.2, range 26\u0026ndash;77). Knosp grade was 3 in three cases and 4 in eight cases. The most common surgical indications were dopamine agonist resistance (5 cases) or intolerance (3 cases). Six patients had visual deficits preoperatively, with improvement following surgery in five cases (83%). PRL level prior to surgery was a mean of 82.2 times the upper limit of normal (\u0026plusmn;\u0026thinsp;168.5, range 0-576.1), with a decline to 28.4 (\u0026plusmn;\u0026thinsp;50.0, range 0.0-162.6) at 3 months postoperatively. In six patients on cabergoline preoperatively, three were on a reduced dose at 3 months postoperatively, with three on a stable dose.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eSurgery was effective at addressing visual compromise in cavernous sinus invasive prolactinomas but had a limited effect on prolactin control and the ability to reduce dopamine agonist use.\u003c/p\u003e","manuscriptTitle":"Surgical Outcomes in Knosp grade 3 or 4 macroprolactinomas: What role does debulking surgery play?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 10:37:23","doi":"10.21203/rs.3.rs-8042272/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6dd6ad87-e15b-4bbf-a5b8-569f8ac419ce","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-18T17:38:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-17 10:37:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8042272","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8042272","identity":"rs-8042272","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}