Endoscopic Transsphenoidal Surgery: Factors Associated with Tumor Progression in Pituitary Adenomas

doi:10.21203/rs.3.rs-1819301/v1

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Endoscopic Transsphenoidal Surgery: Factors Associated with Tumor Progression in Pituitary Adenomas

https://doi.org/10.21203/rs.3.rs-1819301/v1

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Objective: This study aimed to measure the incidence of tumor recurrence amongst patients that underwent endoscopic transsphenoidal surgery for pituitary adenomas, as well as the performance of the molecular and radiological factors that are commonly associated with recurrence.

Methods: Patients of both adult and pediatric populations with pituitary adenomas who were treated for the first time with endoscopic transsphenoidal surgery in a single tertiary care center, between June 2006 and December 2019 were included. Clinical features, laboratory

results, imaging findings and molecular test results were collected. Progression was measured in a follow-up MRI.

Results: 88 patients were included. 19.5% presented gonadotroph adenomas and nonfunctional adenomas, followed by corticotrophs (17.2%) and somatotrophs (13.8%). 20.7% had cellular atypia, 26.2% p53 mutation and up to 79.5% had Ki-67 under 3%. On postoperative MRI (available for 90.9% of patients) 43.8% had tumor residue. Tumor progression occurred in 32 patients (36.4%). The Median progression-free survival time was 5.37 years (95%CI= 3.29 - N/A). Cellular atypia, Ki-67 elevation, cavernous sinus invasion and tumor residue were suggested as significant prognostic factors. Nonetheless, the multivariate time-to-event analysis identified tumor residue as the only factor significantly associated with

progression: HR= 4.0, 95%CI= 1.56 - 10.31.

Conclusions: Residual tumor in postoperative imaging aids as a predictor for tumor progression and the invasion of the cavernous sinus, presence of cellular atypia and a proliferation index (Ki-67) above 3% influence the speed at which the recurrence appears, therefore not being a predictive factor but rather a modifier of the recurrence.

transsphenoidal surgery

endoscopic endonasal surgery

pituitary adenoma

sellar tumor

suprasellar tumor

minimally invasive surgery.

Tumoral pathology of the pituitary gland represents 15.3% of the primary neoplasms of the central nervous system (CNS). Several types of tumors affect the sellar region; among these are pituitary carcinoma, pituitary blastoma, tumors of the neurohypophysis, neuronal and paraneuronal tumors, craniopharyngiomas, mesenchymal tumors, adenomas and others. Adenomas are the most common and can induce great morbidity for patients due to their hormonal hypersecretion, mass-effect or invasion of adjacent structures. Nevertheless, they are considered malignant only when they metastasize and not when they recur (1)(2).

The prevalence of pituitary adenomas is estimated at 17% (3). In Europe, the incidence is reported around 3 to 4 of 100,000 new cases per year with a prevalence that oscillates between 78 to 94 of 100,000 people (4). Patients with these tumors generally have a good clinical response to surgical management, and suitable pharmacology therapy or radiotherapy. Nonetheless, a small proportion of these tumours can have unpredictable behaviour due to an aggressive pathology (5), and predicting the possibility of tumor progression after surgical resection is of great clinical value. Size, hormonal activity, and invasion of adjacent structures (6, 7, 8) can help establish a tumour’s aggressiveness and morbidity, and therefore aid in the decision-making process regarding the appropriate treatment for each patient. Morbidity usually involves clinical features or entities secondary to compression of adjacent neurovascular structures or excessive production of specific hormones (10, 11).

Higher aggressiveness in a pituitary adenoma increases the risk of recurrence, and thus several radiological and molecular markers have been studied to estimate the likelihood of total resection and predict the risk of recurrence at early stages. Regarding biomarkers, expression of p53, the Ki-67 index, oncogenes or microRNAs have been studied. A Ki-67 proliferation index above 3% has been associated with tumour aggressiveness because of increased tumoral growth, invasion of adjacent structures, recurrence and poorer treatment response.; and a higher Ki-67 of up to 15% is associated with pituitary carcinoma (1, 14, 15, 16). However, some studies have failed to find a prognostic value for this proliferation index, and P53 expression has not been directly associated with recurrence but cavernous sinus invasion may be related (12).

This study aimed to 1) measure the occurrence of tumor recurrence among patients with adenomas treated with transsphenoidal surgery and 2) assess the performance of described molecular and radiological factors associated with recurrence.

Design

This was an analytic cohort based on clinical records that included both adult and pediatric patients with pituitary adenomas that presented to a tertiary care university hospital in Cali, Colombia, and were treated for the first time with endoscopic transsphenoidal surgery, between June 2006 and December 2019. Patients that had previously undergone surgery in other institutions and/or those that prognostic data were not available, were excluded. This study was approved by the institutional ethics review board before its start.

Data collection and outcomes of interest

Both physical and electronic clinical records of all patients treated with transsphenoidal surgery within the period of interest were reviewed and screened for inclusion criteria. For included patients, clinical features, laboratory results (including TSH, free T4, growth hormone, prolactin, somatomedin C, ACTH, FSH, LH and cortisol), imaging findings and molecular test results were collected.

The outcomes of interest were incidence of progression including median progression-free survival time associated with resected pituitary adenomas. Also, imaging features and molecular markers were assessed as prognostic factors for tumor progression.

Statistical Analysis

Data were verified with sources when extreme or missing. A descriptive analysis was performed for all the collected variables. Nominal variables are described with absolute and relative frequencies and were compared using Chi2. The distribution of continuous variables was assessed with the Shapiro-Wilk test and either means (standard deviation [SD]) or medians (interquartile range [IQR]) were used as suited. The Student’s t-test or the Mann-Whitney test were used to assess differences in continuous variables according to distribution.

As different follow-up lengths were expected and progression-free survival was of interest, analysis of time to event was planned to describe the incidence of tumor progression. The Kaplan-Meier method and its derived curves were used to provide progression-free survival estimates and assess potential prognostic factors. The log-rank test was used to assess if the curves were different. A multivariate Cox-regression model was used to identify independent factors associated with progression and hazard ratios (HR) were estimated. A p value < 0.05 was considered to be statistically significant and estimates are accompanied by 95% intervals (95%CI). All analyses were conducted in RStudio version 1.3.10.

A total of 159 records were screened for eligibility; 88 patients fulfilled the selection criteria and were included for analysis. The median age was 50.9 years (IQR 35.3–62.5) and 51.1% were male. Around a third of the patients had a prior history of hypertension (37.5%) or hypothyroidism (30.7%). Most adenomas presented as macroadenomas (68.6%) followed by microadenomas (18.6%) and giant adenomas (12.8%). Cavernous sinus invasion was identified by revision of imaging features and official neuroradiology reports in 34.5% of patients. Table 1 displays these and other clinical characteristics at baseline.

Table 1

Demographic Characteristics
Clinical characteristics at baseline	Result (n = 88)
Age, median [IQR]	50.94 [35.32, 62.46]
Sex, masculine, n(%)	45 (51.1)
Hypertension, n(%)	33 (37.5)
Diabetes, n(%)	13 (14.8)
Hypothyroidism, n(%)	27 (30.7)
Smoking, n(%)	8 (9.1)
Adenoma characteristics
Lesion size
Microadenoma, n(%)	16 (18.6)
Macroadenoma, n(%)	59 (68.6)
Giant macroadenoma, n(%)	11 (12.8)
Cavernous sinus invasion, n(%)	30 (34.5)
Cellular atypia	18 (20.7)
Histology
Lactotroph	11 (12.6)
Gonadotroph	17 (19.5)
Corticotroph	15 (17.2)
Somatotroph	12 (13.8)
Plurihormonal	6 (6.9)
Non-functioning	17 (19.5)
Pituitary tissue	9 (10.3)
Ki-67
< 3%	66 (79.5)
≥ 3%	17 (20.5)
P53 mutation	22 (26.2)

The most frequently altered hormone pre-operatively was prolactin; abnormal in 58.2% of patients, followed by somatomedin C (50%) and cortisol (47.2%). Table 2 displays the frequency of normal, high or low pituitary hormones.

Table 2

Endocrine Profile
Pre-operative endocrine profile	Result (n = 88)
Pre-operative endocrine profile	Normal	High	Low
ACTH, n (%)	28 (80.0)	4 (11.4)	3 (8.6)
Cortisol, n(%)	38 (52.8)	16 (22.2)	18 (25.0)
FSH, n(%)	35 (76.1)	4 (8.7)	7 (15.2)
FT4, n(%)	49 (66.2)	2 (2.7)	23 (31.1)
GH, n(%)	33 (78.6)	8 (19.0)	1 (2.4)
LH, n(%)	28 (60.9)	3 (6.5)	15 (32.6)
PRL, n(%)	31 (41.9)	40 (54.1)	3 (4.1)
Somatomedin C, n(%)	18 (50.0)	8 (22.2)	10 (27.8)
TSH, n(%)	57 (73.1)	13 (16.7)	8 (10.3)

Upon histological analysis most lesions were gonadotrophs (19.5%) and non-functional adenomas (19.5%), followed by corticotrophs (17.2%), somatotrophs (13.8%), lactotrophs (12.6%) and plus hormonal adenomas (6.9%). The remaining 10.3% were identified histologically as normal pituitary tissue. Immunohistochemistry showed that 20.7% had cellular atypia, 26.2% p53 mutation and up to 79.5% had Ki-67 under 3%. Tumour sizes were observed to correlate with p53 mutation, as this feature was present in only 13.3% of microadenomas, but in 24.6% and 54% of macroadenomas and giant adenomas, respectively. On postoperative MRI (available for 90.9% of patients) 43.8% had tumour residue. Tumour residue was identified in 28.6% of microadenomas, 49.1% of macroadenomas and 44.4% of giant adenomas. It was associated with cavernous sinus invasion (CSI): 65.5% of patients with CSI had residue vs 34.5% without CSI, p value = 0.0046; but not with other molecular or clinical features.

Tumour progression occurred in 32 patients (36.4%). The Median progression-free survival time was 5.37 years (95%CI = 3.29 - N/A) and is displayed in Fig. 1.

Figure 2 displays the assessment of different potential prognostic factors for progression through Kaplan-Meier curves; the p-value corresponds to the log-rank test. Cellular atypia, Ki-67 elevation, CSI and tumour residue were suggested as significant prognostic factors. Nonetheless, multivariate time-to-event analysis identified tumour residue as the only factor significantly associated with progression: HR = 4.0, 95%CI = 1.56–10.31. Considering only preoperative factors, CSI was the only factor associated with progression: HR = 2.25, 95%CI = 1.04–4.93. Sex had no association with tumor progression.

This study found a median progression-free survival of 5.37 years in patients with pituitary adenomas treated with transsphenoidal surgery, and it identified tumor residue as the only prognostic factor for progression. In the first ~ 4 years after the procedure, 75% of patients with residue had progressed in contrast to those without residue where only 25% progressed. Other molecular, clinical and imaging features that were associated with tumor residue, such as CSI, can be useful in the prognosis for progression if postoperative imaging is not available. CSI is a frequent feature and it precludes complete resection in up to ⅔ of patients.

The histopathological analysis of patients included in this study revealed that up to a quarter of the operated patients presented gonadotroph adenomas, following what has been observed in studies from Brazil and Canada (18, 19). Another quarter represented non-functioning adenomas, as has also been reported previously (20). The frequency of different histological origins for pituitary adenomas that we report might differ from other reports where usually lactotroph adenomas are the most common. This is explained by our study population which only included patients that required surgical intervention. As lactotroph tumours usually have an adequate response to medical treatment, these are not represented in our study (1, 9, 21, 22, 23).

When reviewed in the available literature, the frequency of CSI in postoperative MRI is similar to the value we report and might affect the speed at which the tumour recurs, most likely associated with the extent of tumour residue (12, 13, 24, 25). However, it is interesting to highlight that recurrence has been reported to occur in about 50% of pituitary tumours in which gross macroscopic resection is reported; in this cohort, it occurred in 22.5% (13).

The presence of p53 mutation has been reported to be associated with CSI but not as an independent predictor of recurrence (12). A significant association between CSI and p53 mutation was not detected in this study, although the small sample size could explain this discrepancy. Ki-67 was not identified as an independent factor for recurrence, which also differs from the concept that has been previously stated that a proliferation index above 3% is a predictor of malignancy and invasion potential (1, 12, 14, 15, 16).

As seen in the results, when comparing the group that had tumour progression and the ones that did not, the only variable analysed that was statistically significant was the presence of residual tumour on the postoperative MRI as an isolated marker. This does not exclude the possibility of the other variables being risk factors for progression given that our sample was small and does not provide enough statistical power. However, as interesting as it might be, once the time factor was included in the analysis the invasion of the cavernous sinus, presence of cellular atypia and a proliferation index (Ki-67) above 3% show that they do influence the speed at which the recurrence appears, therefore not being a predictive factor but rather a modifier of the recurrence.

Our study further demonstrates that the presence of residual tumor in postoperative imaging aids as a predictor for tumor progression, and creates an opportunity for larger studies regarding the use of modifying factors for recurrence, such as invasion of the cavernous sinus, presence of cellular atypia and a proliferation index (Ki-67) above 3%, that do not affect whether or not the tumor recurs but that, when it does, how fast will it progress. Multicenter studies are warranted to further assess the usefulness of biological and imaging markers in the prognosis of recurrence after an initial transsphenoidal resection, which in the absence of post-operative MRI could be of value.

Data Availability Statement: Raw data were generated at Fundacion Valle del Lili. Derived data supporting the findings of this study are available from the corresponding author upon request.

Code Availability Statement: Code and data are available at the Centro de Investigación Cientifica (CIC) from Fundación Valle del Lili where they can be retrieved and access upon request and a formal application process specifying the need and future use of the data.

Ethical Compliance Statement: We confirm that we have read the position statement of the journal regarding the issues involved in ethical publication and affirm that this work adheres to those guidelines.

Ethical Approval: this study was approved by the committee for ethical research of the Fundación Valle del Lili.

Consent to Participate an Publish: Consent was not obtained since all patient information was coded and blinded for analysis. There is no individual personal data and no identifiers regarding patients included within the study.

Funding Source: No funding was secured for this study.

Financial disclosure statement: The authors declare there are no financial relationships relevant to this article.

Conflicts of interest: The authors declare no conflicts of interest.

Authors' contributions:

Laura Parrado-Sánchez: conceptualization, investigation, resources, data curation, writing - original draft, visualization, project administration.
Brian Bravo-Gamboa: investigation, resources, writing - original draft.
Andrés Gempeler: methodology, software, validation, analysis, writing – review draft.
Javier Lobato-Polo: conceptualization, supervision.

Declaration of non-duplication: I, Javier Lobato, certify that this manuscript is a unique submission and is not being considered for publication, in part or in full, with any other source in any medium. Previously submitted and rejected by the World Neurosurgery journal.

Overview of the 2017 WHO. Classification of Pituitary Tumors | SpringerLink [Internet]. [cited June 17 2020]. Available at: https://link.springer.com/article/10.1007/s12022-017-9498-z.
Asa SL, Ezzat S. Aggressive Pituitary Tumors or Localized Pituitary Carcinomas: Defining Pituitary Tumors. Expert Rev Endocrinol metabolism. 2016;11(2):149–62. https://doi.org/10.1586/17446651.2016.1153422.
Dolecek TA, Propp JM, Stroup NE, Kruchko C. (2012). CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-oncology, 14 Suppl 5(Suppl 5), v1–v49. https://doi.org/10.1093/neuonc/nos218.
Solari D, Zenga F, Angileri FF, Barbanera A, Berlucchi S, Bernucci C, Carapella C, Catapano D, Catapano G, Cavallo LM, D'Arrigo C, de Angelis M, Denaro L, Desogus N, Ferroli P, Fontanella MM, Galzio RJ, Gianfreda CD, Iacoangeli M, Lauretti L, … Cappabianca P. A Survey on Pituitary Surgery in Italy. World Neurosurg. 2019;123:e440–9. https://doi.org/10.1016/j.wneu.2018.11.186.
Asa SL, Mete O. What's new in pituitary pathology? Histopathology. 2018;72(1):133–41. https://doi.org/10.1111/his.13295.
Juraschka K, Khan OH, Godoy BL, Monsalves E, Kilian A, Krischek B, Ghare A, Vescan A, Gentili F, Zadeh G. Endoscopic endonasal transsphenoidal approach to large and giant pituitary adenomas: institutional experience and predictors of extent of resection. J Neurosurg. 2014;121(1):75–83. https://doi.org/10.3171/2014.3.JNS131679.
Mehta GU, Lonser RR. Management of hormone-secreting pituitary adenomas. Neurooncology. 2017;19(6):762–73. https://doi.org/10.1093/neuonc/now130.
Edal AL, Skjödt K, Nepper-Rasmussen HJ. (1997). SIPAP–a new MR classification for pituitary adenomas. Suprasellar, infrasellar, parasellar, anterior and posterior. Acta radiologica (Stockholm, Sweden: 1987), 38(1), 30–36. https://doi.org/10.1080/02841859709171238.
Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, McCutcheon IE. The prevalence of pituitary adenomas: a systematic review. Cancer. 2004;101(3):613–9. https://doi.org/10.1002/cncr.20412.
Clayton RN, Raskauskiene D, Reulen RC, Jones PW. Mortality and morbidity in Cushing's disease over 50 years in Stoke-on-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab. 2011;96(3):632–42. https://doi.org/10.1210/jc.2010-1942.
Dekkers OM, Biermasz NR, Pereira AM, Romijn JA, Vandenbroucke JP. Mortality in acromegaly: a metaanalysis. J Clin Endocrinol Metab. 2008;93(1):61–7. https://doi.org/10.1210/jc.2007-1191.
Hasanov R, Aydoğan B, Kiremitçi S, Erden E, Güllü S. The Prognostic Roles of the Ki-67 Proliferation Index, P53 Expression, Mitotic Index, and Radiological Tumor Invasion in Pituitary Adenomas. Endocr Pathol March. 2019;30(1):49–55.
Park P, Chandler WF, Barkan AL, Orrego JJ, Cowan JA, Griffith KA, et al. The Role of Radiation Therapy after Surgical Resection of Nonfunctional Pituitary Macroadenomas. Neurosurg July. 2004;55(1):100–7.
Zada G, Ramkissoon S. Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J Neurosurg. 2011;114:9.
Matsuyama J. Ki-67 Expression for Predicting Progression of Postoperative Residual Pituitary Adenomas: Correlations With Clinical Variables. Neurol Med Chir (Tokyo). 2012;52(8):563–9.
Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Peter JP, et al. Proliferative Activity and Invasiveness among Pituitary Adenomas and Carcinomas: An Analysis Using the MIB-1 Antibody. Neurosurg January. 1996;38(1):99–107.
Deng Y, Li Y, Li X, Wu L, Quan T, Peng C, et al. Long-term results of Gamma Knife Radiosurgery for Postsurgical residual or recurrent nonfunctioning Pituitary Adenomas. Int J Med Sci. 2020;17(11):1532–40.
Mete O, Cintosun A, Pressman I, Asa SL. Epidemiology and biomarker profile of pituitary adenohypophysial tumors. Mod pathology: official J United States Can Acad Pathol Inc. 2018;31(6):900–9. https://doi.org/10.1038/s41379-018-0016-8.
Gondim JA, Almeida JP, Albuquerque LA, Schops M, Gomes E, Ferraz T, Sobreira W, Kretzmann MT. Endoscopic endonasal approach for pituitary adenoma: surgical complications in 301 patients. Pituitary. 2011;14(2):174–83. https://doi.org/10.1007/s11102-010-0280-1.
Tjörnstrand A, Gunnarsson K, Evert M, Holmberg E, Ragnarsson O, Rosén T, Filipsson Nyström H. The incidence rate of pituitary adenomas in western Sweden for the period 2001–2011. Eur J Endocrinol. 2014;171(4):519–26. https://doi.org/10.1530/EJE-14-0144.
Mindermann T, Wilson CB. Age-related and gender-related occurrence of pituitary adenomas. Clin Endocrinol. 1994;41(3):359–64. https://doi.org/10.1111/j.1365-2265.1994.tb02557.x.
Han YL, Chen DM, Zhang C, Pan M, Yang XP, Wu YG. Retrospective analysis of 52 patients with prolactinomas following endoscopic endonasal transsphenoidal surgery. Medicine. 2018;97(45):e13198. https://doi.org/10.1097/MD.0000000000013198.
Gold EB. Epidemiology of pituitary adenomas. Epidemiol Rev. 1981;3:163–83. https://doi.org/10.1093/oxfordjournals.epirev.a036232.
Comtois R, Beauregard H, Somma M, Serri O, Aris-Jilwan N, Hardy J. The clinical and endocrine outcome to trans-sphenoidal microsurgery of nonsecreting pituitary adenomas. Cancer. 1991;68(4):860–6. https://doi.org/10.1002/1097-0142(19910815)68:4<860::aid-cncr2820680431>3.0.co;2-4.
Losa M, Franzin A, Mangili F, Terreni MR, Barzaghi R, Veglia F, Mortini P, Giovanelli M. Proliferation index of nonfunctioning pituitary adenomas: correlations with clinical characteristics and long-term follow-up results. Neurosurgery. 2000;47(6):1313–9.

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You are reading this latest preprint version

Endoscopic Transsphenoidal Surgery: Factors Associated with Tumor Progression in Pituitary Adenomas

Status:

Version 1

Abstract

Figures

Introduction

Methods

Design

Data collection and outcomes of interest

Statistical Analysis

Results

Discussion

Conclusion

Declarations

References

Status:

Version 1

Endoscopic Transsphenoidal Surgery: Factors Associated with Tumor Progression in Pituitary Adenomas

Status:

Version 1

Abstract

Figures

Introduction

Methods

Design

Data collection and outcomes of interest

Statistical Analysis

Results

​​

Discussion

Conclusion

Declarations

References

Status:

Version 1